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IS 


HANDBOOK    OF     PHYSIOLOGY 


section   2:   Circulation,  volume   ii 


HANDBOOK  EDITORIAL  COMMITTEE 

Maurice  B.  Visscher,  Chairman 
A.  Baird  Hastings 
John  R.  Pappenheimer 
Hermann  Rahn 


HANDBOOK    OF    PHYSIOLOGY 

A  critical,  comprehensive  presentation 
of  physiological  knowledge  and  concepts 


SECTION   2: 


Circulation 


VOLUME    II 


Section  Editor :  W.  F.  HAMILTON 
Executive  Editor:    PHILIP    DOW 


American  Physiological  Society,  Washington,  d.  c,  1963 


©Ipopyright  !9^3>  American  Physiological  Society 

Library  oj  Congress  Catalog  Card  No.  60-4587 

Printed  in  the  United  States  of  America  by  Waverly  Press \  Inc.,  Baltimore,  .Maryland     21 202 

Distributed  by  The  Williams  &  Wilkins  Company,  Baltimore,  Maryland     21202 


Contents 


23.  Functional  anatomy  of  cardiac  pumping 

GERHARD  A.   BRECHER 

PIERRE   M.   GALLETTI 759 

24.  The  physiology  of  the  aorta  and 
major  arteries 

JOHN    \V.    REMINGTON 799 

25.  Pulsatile  blood  flow  in  the  vascular 
system 

MERRILL  P.   SPENCER 

ADAM   B.    DEMSON,  JR 839 

26.  The  anatomy  and  physiology  of  the 
vascular  wall 

HERMANN    BADER     865 

27.  Patterns  of  the  arteriovenous  pathways 

MARY  P.  WIEDEMAN        89 1 

28.  Resistance  (conductance)  and  capacitance 
phenomena  in  terminal  vascular  beds 

HAROLD  D.  GREEN 
CARLOS  E.  RAPELA 
MARGARET  C.  CONRAD 935 

29.  Exchange  of  substances  through  the 
capillary  walls 

E.  M.  LANDIS 

J.    R.    PAPPENHEIMER 96 1 

30.  The  physiologic  importance  of  lymph 

H.   S.    MAVERSON IO35 

3 1 .  The  peripheral  venous  system 

ROBERTS.   ALEXANDER I°75 

32.  Venous  return 

ARTHUR  C.  GUYTON I  O99 

33.  Effects  of  ions  on  vascular  smooth  muscle 

SYDNEY  M.    FRIEDMAN 

CONSTANCE   L.    FRIEDMAN I  I  35 

34.  Lipid  metabolism  in  relation  to  physiology 
and  pathology  of  atherosclerosis 

SAMI  A.   HASHIM 

WILLIAM  C.    FELCH 

THEODORE   B.   VAN   ITALLIE  I  1 67 

Note:  For  coverage  of  blood  flow  to  the  brain,  see  "The 
Cerebral  Circulation"  by  S.  S.  Kety,  chapter  LXXI,  pp.  1 751  — 
1760,  Neurophysiology  section  of  the  Handbook  series. 


35.  The  role  of  endocrines,  stress,  and 
heredity  on  atherosclerosis 

L.   N.   KATZ 

R.    PICK         I  I97 

36.  Peripheral  vascular  diseases — 
diseases  other  than  atherosclerosis 

GEORGE  E.  BURCH 

JOHN  PHILLIPS         1215 

37.  Situations  which  lead  to  changes  in 
vascular  patterns 

AVERILL   A.    LIEBOW 1 25 1 

38.  Methods  of  measuring  blood  flow 

KURT  KRAMER 

WILHELM  LOCHNER 

E.   WETTERER 1277 

39.  The  circulation  through  the  skin 

A.   D.    M.   GREENFIELD !325 

40.  Circulation  in  skeletal  muscle 

HENRY  BARCROFT 1 353 

41.  The  hepatic  circulation 

STANLEY  E.  BRADLEY '387 

42.  The  flow  of  blood  in  the  mesenteric  vessels 

EUGENE  GRIM 1439 

43.  The  renal  circulation 

EWALD  E.   SELKURT I457 

44.  Blood  supply  to  the  heart 

DONALD  E.   GREGG 

LLOYD  C.    FISHER I  51  7 

45.  Maternal  blood  flow  in  the  uterus  and 
placenta 

S.    R.    M.   REYNOLDS 1 585 

46.  The  fetal  and  neonatal  circulation 

MAUREEN  YOUNG         1619 

47.  The  flow  of  blood  through  bones  and  joints 

WALTER  S.    ROOT I  65  I 

48.  Dynamics  of  the  pulmonary  circulation 

ALFRED  P.    FISHMAN        1 667 

Index 1745 


82264 


CHAPTER     23 


Functional  anatomy  of  cardiac  pumping1 


GERHARD    A.    BRECHER 
PIERRE    M.    GALLETTI 


Department  of  Physiology,  Emory  University 
School  of  Medicine,  Atlanta,  Georgia 


CHAPTER    CONTENTS 

Macroscopic  Structures 

Composition  of  Cardiac  Tissues 

Architecture  of  the  Ventricular  Myocardium 

Architecture  of  the  Atrial  Myocardium 
Pressure  and  Flow  Effects  During  the  Cardiac  Cycle 
Correlation  of  Other  Cardiac  Events  With  the  Cardiac  Cycle 

Atrial  Pressures 

Electrocardiogram 

Vibrocardiogram  (Apex  Cardiogram  I 
Function  of  the  Heart  Valves 

Veno-Atrial  Junction 

Atrioventricular  Valves 

Arterial  Valves 
Ventricular  and  Atrial  Volumes  in  Various  Activities 

Ventricular  Volume 

Atrial  Volume 
Atrial  Filling 
Ventricular  Filling 

Differences  Between  Right  and  Left  Cardiac  Cavities 
The  Pericardium 
Closing  Remarks 


ALTHOUGH   THE   PURELY   MECHANICAL   NATURE   of 

cardiac  pumping  is  taken  for  granted  by  modern 
scientists,  this  view  has  not  always  been  accepted  in 
the  past.  Only  during  the  last  hundred  years  were  the 
forces  of  muscle  contraction  finally  stripped  of  the 
'vis  vitalis'  and  ascribed  exclusively  to  energy  trans- 
formation according  to  the  laws  of  physics  and 
chemistry.  In  this  historical  process,  the  heart  which 
had  been  formerly  thought  of  as  the  seat  of  emotions, 
was  deprived  of  all  metaphysical  connotations  and 
became  an  organ  of  purely  mechanical  function  just 

1  The  results  of  some  recent  experiments  of  the  authors  and 
their  colleagues  are  quoted  in  this  paper.  This  work  was  sup- 
ported in  part  by  USPHS  grant  H-3796,  and  grants  from  the 
Life  Insurance  Medical  Research  Fund  and  the  Georgia 
Heart  Association. 


as  the  skeletal  muscle.  It  is  of  interest  to  trace  briefly 
the  emergence  of  this  concept  (160,  161). 

During  the  age  of  the  pyramids  (3000-2500  B.C.) 
an  unknown  Egyptian  clearly  recognized  the  heart 
as  the  center  of  a  system  of  distributing  vessels  and 
associated  the  pulse  with  the  cardiac  beat.  The  Greek 
philosopher  Alcmaeon  of  Croton  (about  500  B.C.) 
distinguished  the  veins  from  the  arteries  and  asserted 
that  the  seat  of  sensation  was  not  in  the  heart  but  in 
the  brain.  The  function  of  the  heart  as  a  pump  was 
apparently  expressed  for  the  first  time  by  Plato  (427- 
347  B.C.)  when  he  stated:  it  "pumps  particles  as  from 
a  fountain  into  the  channels  of  the  veins,  and  makes 
the  stream  of  the  veins  flow  through  the  body  as 
through  a  conduit."  Hippocrates  (493-423  B.C.) 
had  described  the  cardiac  valves,  the  ventricles  and 
the  great  vessels,  but  he  did  not  refer  to  the  pumping 
action,  which  he  might  have  taken  for  granted.  For 
Aristotle  (384-322  B.C.)  the  heart  was  the  seat  of 
"innate  heat"  and  also  of  the  soul.  This  notion  was 
probably  based  on  the  observation  that  death  results 
from  dissection  of  the  beating  heart.  However,  from 
his  studies  on  the  embryonic  chick  heart  Aristotle 
may  have  had  knowledge  of  the  pumping  function. 
Erasistratus  (310-250  B.C.),  who  described  the 
aortic  valves,  pulmonary  valves,  and  chordae 
tendineae,  and  Galen  of  Pergamon  (131-201  A.D.) 
both  stated  that  the  heart  is  a  pressure-suction  pump. 
Their  view  was  founded  mainly  on  the  assumption 
that  during  diastole  blood  was  sucked  into  the 
ventricles  by  active  enlargement  of  the  cardiac  walls 
[discussed  by  Ebstein  (40),  Bohme  (14)].  They  also 
believed  that  blood  is  expelled  backward  into  the 
caval  veins  during  ventricular  systole.  The  first 
definite  statement  concerning  the  continued  forward 
flow  of  blood  from  the  right  ventricle  through  the 
lungs  into  the  left  heart  was  made  by  Ibn  an-Nafis 
(1210-1299  A.D.).  The  first  scientist  of  the  Renais- 


759 


760 


HANDBOOK    OF    PHYSIOLOGY 


CIROl'LATION    II 


sancc  who  recognized  the  heart  as  a  hollow  muscle 
and  probably  as  a  pump  was  the  artist-engineer, 
Leonardo  da  Vinci  (1452-1519  A.D.),  who  stated: 
"The  heart  is  a  principal  muscle,  in  respect  of  force, 
and  it  is  much  more  powerful  than  the  other  muscles" 
[Keele  (90)].  However,  it  remained  to  William 
Harvey  ( 1 578—1657)  to  prose  that  the  heart,  and  not 
the  liver,  is  the  center  of  the  vascular  system  and 
that  it  propels  the  blood  unidirectionally  by  its 
rhythmical  contractions  as  would  the  repeated 
strokes  of  a  man-made  pump.  The  microscopic  proof 
of  the  muscular  nature  of  the  heart  was  brought  by 
Niels  Stenson  (1 638-1 686),  who  demonstrated  that 
the  substance  of  the  heart  is  composed  of  fibers, 
membranes,  arteries,  veins,  and  nerves  just  as  is  the 
substance  of  other  muscles.  Once  this  important  point 
had  been  firmly  established,  it  became  customary  to 
consider  the  heart  as  a  pump,  to  develop  analogies 
with  mechanical  systems  of  fluid  transfer,  and  to 
apply  to  the  myocardium  the  increasing  knowledge 
about  skeletal  muscle  contraction.  The  present 
chapter  is  a  rather  general  and  classically  oriented 
treatment  of  the  mechanical  function  of  the  heart.  It 
attempts  to  provide  an  understanding  of  the  anatomi- 
cal structures,  while  avoiding  teleological  oxer- 
simplification  as  well  as  useless  controversies  about 
functions. 

The  role  of  the  heart  consists  of  providing  the  body 
tissues  with  a  continuous  stream  of  blood.  The  heart 
fulfills  this  function  by  converting  potential  energy 
(primarily  chemical  energy,  secondarily  energy  of 
position)  into  kinetic  energy,  as  movement  is  imparted 
to  the  blood  ejected  from  the  ventricular  cavities. 
From  the  standpoint  of  cellular  function  at  large,  it 
does  not  matter  whether  tissue  perfusion  is  brought 
about  by  alternate  contraction  and  relaxation  of 
myocardial  cells,  or  by  the  action  of  an  artificial 
pump.  This  concept  has  been  established  on  a  firm 
experimental  basis  by  the  advent  of  extracorporeal 
circulation  techniques,  whereby  a  mechanical  pump 
substituted  for  the  human  heart  can  fully  support  the 
circulation.  Thus  the  heart  can  be  looked  upon  as  a 
pump  inserted  in  the  circulatory  system  and  its 
function  can  be  described  by  analogy  with  purely 
mechanical  systems. 

Mechanical  pumps  are  divided  into  two  main 
classes:  kinetic  pumps  and  positive  displacement 
pumps.  In  the  former  class,  kinetic  energy  is  added  to 
the  fluid  by  the  forced  rotation  of  an  impeller  (fig. 
lA).  In  the  latter  class,  the  fluid  is  progressively 
displaced  from  a  suction  inlet  to  a  discharge  opening. 
Two  kinds  of  positive  displacement  pumps  need  to 


fig.  i .  Mechanical  analogues  for  some  pumping  principles 
embodied  in  the  heart.  A:  kinetic  pump  in  which  energy  is 
added  to  the  fluid  by  the  rotation  of  an  impeller.  B:  rotary 
pump  in  which  fluid  is  propelled  through  squeezing  a  resilient 
tube  by  means  of  rollers  mounted  on  a  rotating  arm.  C:  recipro- 
cating pump  in  which  fluid  is  displaced  by  the  back  and  forth 
movement  of  a  diaphragm  while  valves  give  direction  to  the 
stream. 

be  mentioned  here.  In  rotary  pumps  (fig.  \B), 
moving  members  trap  a  portion  of  the  fluid  in  a 
chamber  of  pliable  tubing  and  conduct  it  toward  the 
outlet.  The  segment  of  tubing  occluded  acts  as  a 
valve  to  prevent  backflow.  In  reciprocating  pumps 
(fig.  1 C)  a  cavity  limited  by  two  valves  is  subjected  to 
the  action  of  a  piston  or  diaphragm.  As  the  piston 
moves  back  and  forth,  fluid  is  drawn  in  through  the 
suction  valve  and  forced  out  through  the  discharge 
valve. 

The  action  of  the  heart  in  some  invertebrates  can 
be  compared  to  that  of  rotary  pumps,  since  forward 
movement  of  fluid  is  obtained  by  peristaltic  move- 
ments of  the  walls.  In  the  mammalian  heart  also 
some  degree  of  blood  propulsion  may  be  accomplished 
on  the  ''progressive  cavity  principle"  as  in  rotary 
pumps,  particularly  the  displacement  caused  by  the 
wringing  action  of  the  ventricles.  However,  cardiac 
action  in  vertebrates  most  closely  resembles  that  of 
reciprocating  pumps.  It  is  characterized  by  pulsatile 
action,  by  the  presence  of  valves,  and  by  the  capa- 
bility of  the  pump  to  be  adjusted  in  terms  of  either 
speed,  or  volume  displacement,  or  of  speed  and 
volume  displacement  simultaneously.  Although  the 
design  of  the  heart  has  nothing  in  common  with  that 
of  kinetic  (centrifugal)  pumps,  its  control  displays 
two  characteristics  for  which  kinetic  pumps  are 
appreciated  in  technology:  namely  that  the  volume 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


76. 


output  is  directly  related  to  the  input  pressure,  and 
is  inversely  related  to  the  pressure  head  against  which 
the  pump  works.  Like  centrifugal  pumps,  the  heart 
has  the  tendency  to  deliver  a  higher  flow  as  more 
blood  is  fed  into  it  at  the  atrial  level;  it  also  provides 
a  lower  flow  when  the  resistance  to  ejection  in  the 
vascular  system  increases. 

A  close  look  at  mechanical  pumps  for  cardiac 
substitution  throws  a  light  on  built-in  features  of  the 
natural  heart  that  one  easily  takes  for  granted. 
Adequate  perfusion  of  an  adult  human  organism 
under  all  possible  conditions  requires  that : 

/)  The  heart  be  able  to  move  blood  volumes 
ranging  from  3  to  30  liters  per  min  and  to  pump 
against  pressures  up  to  300  mm  Hg. 

2)  Even  at  maximal  cardiac  output,  the  flow 
velocity  must  not  exceed  the  limit  of  tolerance  for 
mechanical  trauma  to  blood  corpuscles  through 
turbulence,  friction,  or  cavitation  (1-2  m/sec). 

3)  The  relationship  between  stroke  volume  and 
stroke  rate  must  not  deviate  much  from  an  optimum 
which  is  set  by  the  elastic  properties  of  the  cardiac 
walls,  the  time  needed  for  efficient  transformation  of 
potential  into  kinetic  energy  and  by  the  lowest  flow- 
velocity  compatible  with  the  output  required. 

4)  The  valves  must  easily  open  during  their  flow- 
phase,  yet  be  competent  and  prevent  regurgitation 
of  blood  during  their  holding  period. 

5)  The  regulation  of  the  pumping  action  must  be 
automatically  controlled  through  sensing  elements 
with  feedback  mechanisms  which  adapt  the  output 
to  the  tissue  demands  [see  also  Wagner  (153)]-  These 
control  mechanisms  must  integrate  hemodynamic 
data  (e.g.,  perfusion  flow,  arterial  and  venous  pres- 
sures) and  metabolic  data  (e.g.,  arteriovenous  oxygen 
difference)  to  maintain  viable  conditions. 

Considering  these  points  in  more  detail,  one  must 
first  emphasize  the  pumping  capacity  of  the  heart. 
As  3  to  30  liters  per  min  of  blood  is  pumped  by  the 
left  ventricle  into  the  systemic  circulation,  practically 
the  same  amount  is  ejected  by  the  right  ventricle  into 
the  pulmonary  vascular  bed.  Furthermore,  the  atria 
have  some  pumping  function  of  their  own,  so  that 
the  combined  pumping  of  all  the  chambers  of  the 
human  heart  is  in  the  order  of  7  to  70  liters  per  min, 
depending  upon  the  state  of  muscular  activity.  A 
range  of  this  magnitude  (1:10)  is  not  easily  obtained 
in  artificial  pumps  and,  when  it  is  reached,  it  is  at  the 
price  of  considerable  sacrifices  in  mechanical  efficiency 
(ratio  of  work  produced  to  fuel  consumed).  On  the 
contrary,  the  mechanical  efficiency  of  the  heart  does 
not  seem  to  be  very  closely  related  to  cardiac  output. 


The  extended  scale  of  activity  over  which  the  heart 
can  perform  is  certainly  facilitated  by  the  elastoviscous 
properties  of  the  cardiac  walls.  The  cavities  are 
distensible  over  a  wide  range  of  volume  increments 
without  much  increase  in  intraventricular  or  intra- 
atrial  pressures  [see  fig.  2,  and  Little  (99)].  Therefore 
the  heart  can  easily  accommodate  and  deliver 
varying  stroke  volumes  even  if  the  stroke  frequency 
remains  unchanged.  Furthermore  the  time  needed 
for  the  transformation  of  chemical  into  mechanical 
energv  apparentlv  comprises  only  a  fraction  of  the 
systole.  At  a  constant  stroke  volume  the  heart  can 
increase  its  minute  output  simply  by  beating  faster 
and  shortening  the  pause  between  the  strokes  without 
affecting  the  energy  conversion  processes.  The  limiting 
factor  of  cardiac  output  at  high  heart  rates  is  not  an 
encroachment  on  the  time  needed  for  energy  con- 
version but  an  encroachment  on  the  time  needed  for 
filling  the  pump  chambers  (ventricular  filling  phase). 
Another  fundamental  difference  between  artificial 
pumps  and  the  heart  is  that  in  the  former  a  force  is 
applied  from  the  outside  to  activate  a  part  or  the 
entire  wall  of  the  pump  chamber,  whereas  in  the 
latter  the  force  is  developed  within  the  wall  of  the 
pump  chamber  itself  by  small  elements,  the  muscle 
fibrils,  which  alternately  shorten  and  lengthen. 
Furthermore,  since  the  heart  is  surrounded  by  other 
resilient  structures  in  the  thorax,  there  is  an  inter- 
action of  the  physical  forces  developed  in  the  myo- 
cardium and  those  developed  either  passively  or 
actively  in  these  structures  [Pfuhl  (129,  130),  Blair  & 
Wedd  (12)].  For  example,  during  ventricular  con- 
traction and  ejection  the  elastic  forces  of  the  lungs 
oppose  to  a  small  extent  the  diminution  of  the 
ventricular  size,  whereas  during  ventricular  relaxation 
the  same  forces  of  the  lunsjs  enhance  slightly  the 
expansion  of  the  ventricles.  These  forces  are  said  to 
be  negligible  as  compared  with  the  intravenous 
filling  pressures  (60,  64).  Mechanical  effects  are 
exerted  upon  the  rhythmical  form  changes  of  the 
heart  by  such  structures  as  the  pericardium,  the 
attachments  of  the  heart  to  the  large  vessels,  the 
sternum,  the  mediastinal  tissues,  and  the  diaphragm 
through  its  changes  in  position  during  respiration  or 
because  of  varying  degrees  of  abdominal  filling.  The 
complexity  of  these  forces,  in  terms  of  direction  and 
magnitude,  and  their  continuous  changes  during  the 
cardiac  and  the  respiratory  cycle  make  it  presently 
impossible  to  evaluate  quantitatively  the  contribution 
of  extracardiac  structures  to  cardiac  pumping. 
Nevertheless,  their  importance  is  demonstrated  by 
the  possibility  of  pumping  blood  solely  by  the  action 


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HWUBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


of  external  forces  on  the  heart  [Hosier  (81),  Stephen- 
son (150)].  In  closed-chest  cardiac  massage,  vigorous 
pressure  on  the  lower  part  of  the  sternum  causes 
ejection  of  the  ventricular  content  into  the  large 
arteries.  Conversely,  when  pressure  is  released,  the 
recoil  is  sufficient  to  permit  the  venous  pressure  to  fill 
the  ventricles  again  [Kouwenhoven  et  al.  (92)].  In 
this  manner,  a  sufficient,  though  subnormal,  cardiac 
output  can  be  maintained  in  the  absence  of  any 
myocardial  activity.  This  points  again  to  the  fact 
that,  in  principle,  it  does  not  matter  whether  the 
propulsion  of  blood  through  the  body  is  brought 
about  by  the  contraction  of  cardiac  fibers  or  by  any 
other  suitable  forces  applied  to  the  blood  contained 
in  the  ventricles. 


MACROSCOPIC    STRUCTURES 

A  great  deal  of  commonly  accepted  knowledge 
about  cardiac  pumping  is  derived  from  purely 
morphological  considerations.  Although  conclusions 
reached  in  this  manner  have  occasionally  proved  to 
be  correct,  morphological  reasoning  often  leads  to 
fallacious  lunctional  interpretations  of  structural 
findings.  In  the  case  of  the  heart,  physical  vector 
analvsis  of  all  the  mechanical  forces  involved  is 
especially  difficult  because  of  the  great  complexity  of 
the  anatomical  structures  and  of  the  perplexing 
geometry  of  cardiac  filling  and  emptying.  We  have 
only  a  limited  knowledge  of  the  sequence  of  events 
as  they  occur  during  muscular  contraction  and 
relaxation  within  various  parts  of  the  myocardium. 
In  this  particular  section  an  attempt  is  made  to 
describe  the  macroscopic  structures  of  the  heart  with 
reference  to  their  probable  function  as  deduced  from 
the  anatomical  observations.  A  topographic  anatomi- 
cal description  of  the  heart  is  available  in  standard 
texts  (51,  95,  98,  101). 

Composition  nj  Cardiac  Tissues 

The  myocardium  is  the  most  important  structure 
of  the  heart  because  its  contraction  causes  the  blood 
to  flow.  However,  it  should  be  realized  that  only 
part  of  the  cardiac  walls  consists  of  muscle  fibers,  and 
that  within  the  muscle  fibers,  the  contractile  substance 
is  limited  to  the  fibrils.  Indeed  about  half  of  the 
heart's  weight  is  made  of  noncontractile  material 
such  as  the  sarcolemma  in  the  muscle  fibers,  con- 
nective tissue  in  the  heart  skeleton,  tendons  and 
valves,  and  finally  blood  vessels,  lymphatics,  and 
nerve  fibers.  All  these  elements  are  interwoven  with 


the  muscle  fibers  or  closely  connected  to  them  (45, 
59).  During  cardiac  contraction  or  relaxation,  they 
are  deformed  and  resist  to  some  degree  the  shortening 
or  lengthening  of  the  myofibrils. 

Little  is  known  about  the  mechanical  effects  of  the 
coronary  vessels  upon  the  function  of  the  ventricles. 
Though  relatively  inconspicuous  in  a  "dead"  heart, 
they  appear  heavily  engorged  with  blood  in  the  live 
organ.  In  fact,  since  5  to  10  per  cent  of  the  cardiac 
output  passes  through  the  coronary  system,  a  signifi- 
cant mass  of  the  beating  heart  consists  of  circulating 
blood  contained  within  the  anatomical  bounds  of  the 
epicardium.  During  heavy  exercise  the  coronary- 
blood  supply  is  probably  so  great  that  one  might  look 
upon  the  myocardium  as  a  spongy  structure  of  muscle 
fibers  suspended  like  chains  of  islands  in  a  lake  of 
blood.  In  the  past  it  has  been  postulated  frequently 
that  the  degree  of  filling  of  the  coronary  vascular  bed 
affects    in    some    form    the    ventricular    contraction. 

AV  + 


fig.  2.  Left  ventricular  pressure-volumes  curves  of  a  dog 
heart  illustrating  the  changes  resulting  from  coronary  perfu- 
sion. The  freshly  excised  heart  of  a  13.5-kg  dog  was  submerged 
in  Locke's  solution  and  assumed  its  elastic  equilibrium  state 
(zero  transmural  pressure,  origin  of  the  coordinates)  upon 
cessation  of  spontaneous  contraction.  The  curves  were  obtained 
by  addition  or  reduction  of  the  intraventricular  volume 
[Brecher  &  Kissen  (22)].  The  origins  of  the  coordinates  for  the 
perfused  and  unperfused  heart  were  arbitrarily  superimposed. 
At  negative  (and  up  to  +5  mm  Hg)  intraventricular  pressures 
the  ventricle  accommodated  a  greater  volume  with  coronary 
perfusion  than  without.  At  pressures  above  +5  mm  He,  the 
ventricle  accommodated  less  fluid  with  coronary  perfusion 
than  without   (Horres  et  al.,  unpublished  data). 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


763 


Most  of  these  postulates  were  of  speculative  nature. 
For  example,  Donders  (39)  stated  that  "the  blood 
which  enters  at  the  end  of  systole  into  the  coronary 
arteries  seems  to  cause  a  slight  active  expansion  of  the 
heart,  especially  of  the  ventricles.-'  This  view  was 
originally  formulated  in  1855  by  Briicke  (26)  and 
also  advocated  by  Luciani  (102).  Based  on  X-ray 
kymograph  studies,  a  modern  modification  of  the 
same  hypothesis  was  presented  by  Cignolini  (34) 
without  conclusive  evidence.  However,  recent  work  by 
Salisbury  et  al.  (141)  indicates  that  the  filling  of  the 
coronary  bed  affects  the  ventricular  distensibility. 
There  are  indeed  significant  differences  in  the 
ventricular  pressure  volume  relationship  depending 
upon  whether  the  coronaries  are  perfused  or  not 
[Brecher  et  al.  (24)].  In  figure  2  the  S-shaped  pressure 
volume  curve  of  the  ventricle  with  an  empty  coronary 
bed  (solid  line)  is  different  from  that  obtained  during 
coronary  perfusion  (broken  line).  This  shift  of  the 
curve  when  the  coronary  bed  is  perfused  indicates 
that  the  perfused  heart  accommodates  more  fluid  at 
low  intraventricular  pressures  and  less  fluid  at  high 
intraventricular  pressures.  Around  the  elastic  equilib- 
rium state  (zero  transmural  pressure)  the  perfused 
heart  is  somewhat  stiffer  than  the  nonperfused  heart. 
The  effect  of  varying  degrees  of  engorgement  of  the 
coronary  bed  upon  the  distensibility  of  the  beating 
ventricle  during  the  different  phases  of  the  cardiac 
cvcle  is  still  unknown. 


The  heart  skeleton,  the  chordae  tendineae,  and 
the  cells  of  the  Purkinje  system  are  noncontractile, 
yet  are  functional  components  of  the  myocardium. 
The  heart  skeleton  (fig.  3)  is  represented  by  four 
interconnected  fibrous  rings  of  dense  connective 
tissue,  which  surround  the  orifices  of  the  great 
vessels.  The  musculature  of  the  ventricles  and  atria, 
the  roots  of  the  large  vessels,  and  the  heart  valves  are 
attached  to  this  skeleton,  which  also  anchors  the 
tendinous  endings  of  the  ventricular  muscle  (see 
below).  An  important  function  of  the  cardiac  skeleton 
is  to  provide  a  firm  basis  for  the  attachment  of  the 
cardiac  valves.  Another  function,  though  less  fre- 
quently mentioned,  is  to  aid  in  keeping  the  orifices 
open  during  the  phases  of  blood  inflow  and  outflow. 
During  ventricular  activity,  the  orifices  undergo 
changes  in  form  which  probably  involve  also  the 
cardiac  skeleton  as  indicated  in  the  different  outlines 
of  the  orifices  during  systole  and  diastole  in  figures  4, 
5,  and  6.  By  inserting  a  finger  through  the  atrial 
appendage  in  the  intact  beating  heart,  one  can 
easily  verify  that  the  atrioventricular  valve  rings 
become  smaller  during  ventricular  contraction  and 
larger  during  relaxation.  This  observation,  which 
has  not  been  substantiated  by  precise  measurements 
as  yet,  indicates  that  the  fibrous  tissues  of  the  heart 
skeleton  are  passively  deformed  by  myocardial  con- 
traction and  thereby  store  energy  which  is  released 


fig.  3.  Anatomic  components  of  the  heart 
depicting  the  relation  of  the  fibrous  skeleton 
to  the  heart  chambers  and  arterial  roots.  The 
trunks  of  the  aorta  and  pulmonary  artery  as 
well  as  the  atria  are  fastened  to  the  cranial 
aspect  of  the  four  annuli  fibrosi,  whereas  the 
ventricles  are  attached  to  the  caudal  aspect. 
[From  Rushmer  (139).] 


764  HANDBOOK    OF    PHYSIOLOGY  -^   CIRCULATION    II 


Yalvula  scmilui  ior  a,  pulmonale 


Valvula  semiltinai  is 


V"al\  ul..  -'  mihmaris 
: 


■     . 


Cuspis  anterior  \  alvulac 

l'i<  11-jnd.ih- 


(.  uspis  posh  rior 
i-alvulac  bit  u*pidalis 


■ 


■.,--■!.:-'.' 


Ivula  semilunaris  di -srr.i 
1-  pulu 

-  \  tlvnl.i  scmilun  1 
\  anti  n.ir  ,!   ■  ■ 

^       \  ■  1 ! '  ■  1 '  l     ■  : 


~  ~  ant"  i 


aritern  >r 

Cn>pw        f        .      , 

I 

tncuspidalu 

1 1 
1 

(.Anulu    ' 

,'  '  'I-  ■' 


Aniilus  fibroins  sinister 


\<-ntri<  nli 


fig.  4.  Base  of  the  human  ventricles  seen  from  their  cranial  aspect  after  the  atria  have  been  re- 
moved. The  shape  of  the  ostial  orifices  in  the  state  of  contraction  differs  significantly  from  the  shape 
in  the  state  of  relaxation,  as  indicated  by  the  dashed  lines.   [From  Spalteholz  (148).] 


by    elastic    rebound    at    the    beginning    of  muscular 
relaxation. 

Many  strands  of  myocardial  fibers  end  with 
tendinous  tissues.  Yet  one  cannot  compare  them  with 
skeletal  muscle,  since  there  is  no  bone  to  provide  a 
fixed  attachment.  In  reality,  all  myocardial  fibers  end 
on  other  myocardial  fibers  either  directly  or  by- 
insertion  of  connective  tissue.  For  instance  the  myo- 
cardial fibers  of  the  papillary  muscles  continue  as 
chordae  tendineae,  which  in  turn  lead  via  the  bicuspid 
and  tricuspid  valve  leaflets  and  the  fibrous  tissue 
of  the  heart  skeleton  to  other  myocardial  fibers.  This 
arrangement  forms  a  circle  of  myocardial  tissue, 
although  with  inclusion  of  a  tendinous  segment. 
Other  myocardial  fibers,  such  as  many  strands  in  the 
left  ventricular  deep  bulbospiral  bundles,  simply  form 
a  circle.  Since,  in  the  final  analysis,  all  myocardial 
fibers  pull  directly  or  indirectly  on  other  myocardial 
fibers,  the  concerted  effect  of  their  contraction 
diminishes  each  heart  cavity  more  or  less  concentri- 
cally  [see  also   Hawthorne   (67)].    It  also  stands  to 


reason  that  all  muscle  "■fiber-rings"  which  include  a 
noncontractile  segment  exert  during  their  contraction 
a  pull  on  the  noncontractile  segment,  storing  in  it 
potential  energy  for  release  during  myocardial 
relaxation. 

The  cells  of  the  conduction  system  have  a  special 
position  as  far  as  their  participation  in  the  contractile 
process  is  concerned.  They  are  derived  from  muscle 
cells,  but  their  primary  function  is  the  fast  conduction 
of  excitation.  Yet  they  do  contain  a  small  number  of 
myofibrils  and  therefore  must  be  expected  to  partici- 
pate in  the  over-all  myocardial  activity.  Since  nobody- 
has  measured  their  contractile  force,  it  remains  a 
matter  of  conjecture  whether  Purkinje  cells  contribute 
to  any  significant  extent  to  the  force  of  ventricular 
contraction.  It  may  be  that  their  contraction  serves 
only  the  purpose  of  diminishing  the  shear  forces  which 
would  develop  between  myocardial  and  Purkinje 
cells  if  the  latter  remain  purely  passive.  In  the 
longitudinal  direction  the  Purkinje  cells  are  joined  to 
intermediate  cells  which  connect  them  to  myocardial 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


765 


Auricula 

sinistra 


Basis  cordis 
Ati  nun  sinistrum 


\'.  pulmoaalis  dextra 

V.  cava  superior 

!    A    + 


Sinus  coronarius 


Septum  ventru  ul<  muo 


Ostium  vcn 
sinistrum  /- 


\  in    -    ill,: 

dextrum 


: 


(c. 


fig.  5.  Superficial  muscle  layers  of  the 
maximally  contracted  human  heart,  viewed 
from  the  caudal  aspect  after  separation  of  the 
atria  (above)  from  the  ventricles  (below). 
The  ostia  of  the  contracted  ventricles  can  be 
compared  with  their  state  in  the  relaxed 
ventricles  (dashed  lines).  The  changes  in 
ventricular  configuration  during  relaxation 
are  also  indicated  by  dashed  lines.  [From 
Spalteholz  (148).] 


Apex  cordis 


cells.  These  intermediate  cells  contain  an  increasingly 
larger  number  of  myofibrils  as  they  approach  the 
true  myocardial  cells.  Merely  judging  from  morpho- 
logical evidence,  they  must  contribute  to  some 
extent  to  the  over-all  contractile  process. 

Architecture  of  the  Ventricular  Myocardium 

Since  the  ventricles  perform  more  pumping  action 
than  the  atria,  the  architecture  of  the  ventricular 
myocardium  has  attracted  most  of  the  attention  of 
functionally  oriented  anatomists.  Despite  extensive 
description  by  MacCallum  (108),  Mall  (111), 
Monckeberg  (114),  Benninghoff  (10),  Robb  & 
Robb  (136),  Spalteholz   (148),  and  Lev  &   Simkins 


(97),  much  confusion  still  prevails.  Opinions  vary 
because  it  is  difficult  to  dissect  clearly  the  complexly 
arranged,  intertwined  and  crisscrossing  discrete 
muscle  bands.  Consequently,  it  is  even  harder  to 
derive  from  the  anatomic  findings  a  picture  of  the 
direction  of  maximal  pull  of  each  muscular  compo- 
nent, not  to  mention  the  concerted  action  of  several 
components. 

Many  of  the  muscle  bands  encircle  both  left  and 
right  ventricles.  According  to  the  most  commonly 
accepted  terminology,  one  distinguishes  four  different 
muscles,  the  course  of  which  can  be  best  understood 
from  semischematic  drawings:  the  superficial  bulbo- 
spiral  (fig.  7),  superior  sinospiral  (fig.  8),  deep  sino- 
spiral  (fig.  9),  and  deep  bulbospiral  muscle  (fig.  10.) 


766 


HANDBOOK    OF    PHYSIOLOGY    —    CIRCULATION    II 


V.  pulmoiLilb  dcxtra 


\trium  Binblrum 


V  i  iv      tpei 


Aiin<  nl  i  sinistra 


fig.  6.  Superficial  muscle  layers  of  the 
maximally  contracted  human  heart,  seen 
from  the  ventrocranial  aspect  after  separation 
of  the  atria  (above)  from  the  ventricles  (be- 
low). The  position  changes  of  the  great  vessels 
and  the  ventricle  outlines  during  relaxation 
are  indicated  by  dashed  lines.  [From  Spalte- 
holz  (148).] 


A.  pulmonalis 


i^iiuam.ilis 
anterior 


Ventriculus  dexter 


iDcfsura  [apicfe  ■  ordfc 


Apex  coidis 

Vol  ti  &  tunlii 


According  to  Benninghoff  (10),  who  uses  a  somewhat 
different  classification,  there  are  three  interconnected 
systems  which  intersect  rectangularly:  a)  the  outer 
longitudinal  fibers  which  connect  to  the  outer  contour 
fibers  at  the  ostia;  b)  the  ring  fibers  which  encircle  the 
entire  chamber  and  curve  around  to  form  fibers  of 
the  ventricular  septum;  c)  the  internal  longitudinal 
fibers  which  run  from  the  contour  fibers  toward  the 
apex  (figs.  11  and  12).  Benninghoff  (10)  analyzed 
the  function  of  these  various  bundles  on  the  basis  of 
careful  comparative  anatomical  studies  and  in  vivo 
observations.  He  emphasized  the  concept  that 
crossing  of  the  fiber  layers  at  right  angles  results  in  an 
over-all  reduction  of  the  cavity  size,  as  first  postulated 
by  Carl  Ludwig.  Each  of  the  three  systems  affects  the 
entire  heart  and  at  the  same  time  each  of  the  ventric- 


ular cavities.  They  act  in  such  a  manner  that  a 
reduction  of  the  heart  chambers  does  not  occur 
equally  in  all  directions  but  in  such  a  manner  and 
sequence  that  the  cavities  are  emptied  toward  their 
outflow  tracts.  The  evolution  proceeded  as  follows:  in 
lower  vertebrates  (fish,  amphibia)  there  are  no 
tendinous  elements  and  all  muscle  bundles  are  ring 
shaped.  In  the  mammalian  heart  secondary  valves 
(atrioventricular)  are  formed  from  which  the  con- 
nective tissues  of  the  fibrous  rings  of  the  atrioventricu- 
lar valves  and  of  the  chordae  tendineae  originate  and 
become  inserted  into  the  course  of  the  ring-shaped 
muscle.  The  fibrous  rings  become  connected  to  the 
roots  of  the  arteries  and  form  the  solid  trigona  fibrosa, 
which  furnish  new  insertions  for  many  myocardial 
fibers   (see  fig.   4).    In   the   evolutionary   process   the 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING     767 


FIG.  7.  The  superficial  bulbospiral  muscle  as  seen  from  the 
front  of  the  human  heart.  A  =  Aorta;  M  =  mitral  orifice; 
P  =  pulmonary  artery;  T  =  tricuspid  orifice;  AT  —  anterior 
leaflet  of  tricuspid  valve;  MT  =  medial  leaflet  of  tricuspid 
valve.  A  F-shaped  section  is  cut  from  those  fibers  encircling  the 
left  ventricle  subendocardially,  so  that  the  mitral  valve  may  be 
seen.  A  similar  band  on  the  right  is  not  sketched  in.  [From 
Robb  &   Robb   (136).] 

fig.  8.  The  superior  sinospiral  muscle  as  seen  from  the 
antreior  surface  of  the  heart.  Symbols  as  in  fig.  7.  Again  the  sub- 
endocardial layer  has  been  cut  through  in  order  to  show  deeper 
structures.  The  window  in  the  right  ventricular  wall  shows  the 
fibers  from  the  trabeculated  area  running  up  to  the  anterior 


and  medial  leaflets  of  the  tricuspid  valve.  In  both  of  these  super- 
ficial muscles,  blood  vessels  follow  the  muscle  strands  as  they 
encircle  the  apex.  [From  Robb  &  Robb  (136).] 

fig.  9.  The  deep  sinospiral  muscle  as  seen  from  the  front. 
Note  the  division  of  the  muscle  at  the  posterior  inter-ventricular 
sulcus,  with  fibers  passing  anteriorly  to  form  most  of  the  basal 
two-thirds  of  the  septum;  these  septal  fibers  lie  just  distal  to 
the  band  of  the  left  head  of  origin  at  the  base  of  the  aorta. 
Symbols  as  in  fig.  7.  [From  Robb  &  Robb  (136).] 

fig.  10.  The  deep  bulbospiral  muscle,  a  powerful  sphincter 
encircling  the  left  ventricular  base  and  enclosing  both  the 
aorta  and  the  mitral  orifice  within  its  sweep.  [From  Robb  & 
Robb  (136).] 


:m  ,irt<  n 


Willi  !■      , 

sinister  — 


fig.  11.  Human  ventric- 
ular myocardium  after  re- 
moval of  the  superficial 
muscle  layers  (seen  from 
the  caudal  aspect).  [From 
Spalteholz  (148).] 


spongiosa  (spongy  network  of  muscle  fibers)  is 
gradually  reduced  by  the  increasing  compacta  (solid 
tissue  of  muscle  fibers).  The  phylogenetic  remainders 
of  the  spongiosa  are  the  muscular  trabeculae,  which 
are  only  moderately  developed   in   the  mammalian 


heart  and  are  almost  completely  replaced  by  com- 
pacta in  the  bird  heart.  In  this  respect  the  birds 
represent  the  highest  functional  development.  Accord- 
ing to  Benninghoff  (10)  the  spiral  course  of  the 
muscle   bundles  toward  the  heart  skeleton  and   the 


768  HANDBOOK    OF    PHYSIOLOGY   ^  CIRCULATION    II 

Fihrac  mua  ulares  anuli  fibro 


i  :.     1    ob!  qua.    superl    iak-»  .id 

v  1  :,;;:■  Lllum  dl  Wnilii 


1  rigi  mum  Aorta 

fibrosum  : 

stnisti  niu 


Stratum  mu 
medium  [cin  ulare 


stratum 

mus  ularc  profundui 


t'ibrae  circularo 

?lral  i    tUI    Ei 


V'orti  x  1  "i.li- 


<  istium  a.-v.-smistmiii 
\    1 1  igi  inum  fibrosum 
---.  1 1'  strum 


\Fibrac  longitudi- 
J->  nali -  -11. .11 
\     profundi 


,'      Chord 
/  "   tendim  ai 

/  —   M.  papillaris 


.  Vortex 


fig.  12.  Course  of  the  left  ventricular  muscle  fibers.  Left:  preparation  of  human  heart  after  partial 
removal  of  the  superficial  and  medial  muscle  layers  (seen  from  the  dorsal  aspect  1.  Riaht:  schematic 
presentation  of  the  course  of  the  muscle  fibers  as  viewed  from  the  dorsal  aspect.  [From  Spalteholz 
(148).] 


vortex  formation  near  the  apex  are  more  pronounced 
in  the  mammalian  than  in  reptile  and  bird  hearts 
(see  fig.  1  2,  right). 

Rushmer  (139)  points  out  that  the  division  of  the 
heart  musculature  into  "sinospiral"  or  "bulbospiral" 
bundles  is  rather  arbitrary  and  complicates  the 
functional  analysis.  He  suggests  the  division  of  the 
ventricular  musculature  into  two  groups  of  myocardial 
bundles,  the  spiral  muscles  and  the  deep  constrictor 
muscles  (fig.  13).  He  states  in  his  unsurpassed  descrip- 
tion, the  "functional  anatomical  analysis  points  to 
the  direction  physiological  experimental  work  should 
pursue  to  verify  .  .  .  postulations  and  to  obtain 
quantitative  measurements." 

Architecture  of  the  Atrial  Myocardium 

The  atria  supply  blood  to  the  ventricles  through 
three  mechanisms:  /)  passively,  during  the  first  part 
of  their  diastole,  by  serving  as  blood  collecting 
chambers  as  long  as  the  atrioventricular  valves  are 
closed    by    the    high    ventricular    pressure;    2)    still 


passively,  during  the  second  part  of  their  diastole,  by 
serving  as  channels  to  permit  the  passage  of  blood 
from  the  systemic  or  pulmonary  veins  into  the  ven- 
tricles once  the  atrioventricular  valves  are  opened; 
3)  actively,  during  atrial  systole,  by  contracting  and 
thereby  pushing  some  blood  into  the  ventricles  shortly 
before  the  ventricular  myocardium  begins  to  con- 
tract. Since  usually  only  a  small  fraction  (10-30%) 
of  the  blood  for  ventricular  filling  is  actively  propelled 
by  the  atrial  musculature  and  the  resistance  to  inflow 
into  the  ventricular  cavity  is  negligible,  the  normal 
atrial  myocardium  does  not  need  to  be  thick  walled. 

The  arrangement  of  the  muscle  fibers  in  the  atria 
is  much  simpler  than  that  in  the  ventricles.  Two 
groups  of  fibers  can  be  distinguished :  /)  those  which 
belong  to  one  atrium  only,  and  2)  those  which  are 
common  to  both  atria  (151). 

Group  1:  The  fibers  which  lie  in  the  wall  of  each 
atrium  form  muscle  rings  around  the  entrance 
orifices,  i.e.,  the  pulmonary  veins  in  the  left  atrium 
and  the  coronary  and  caval  veins  in  the  right  atrium. 
These  annular  fibers  may  act  as  sphincters,  possibly 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


769 


0ORIENTATION  OF  MYOCARDIAL   FIBERS  IN   VENTRICULAR  WALLS 


RIGHT   VENTRICLE    — • 


LEFT  VENTRICLE 


(|)FUNCTIONAL  COMPONENTS  OF    VENTRICULAR   MUSCULATURE 


fig.  13.  Muscular  structures  of  the  ventricles  diagram" 
matically  arranged  so  as  to  reveal  their  functional  components. 
A:  blocks  of  tissue  removed  from  the  walls  of  the  ventricles  are 
composed  of  three  layers  of  muscle.  The  myocardial  fibers  in 
these  layers  are  oriented  roughly  in  the  three  general  directions 
indicated  by  the  arrows.  B:  from  a  functional  point  of  view, 
the  ventricles  are  formed  of  two  sets  of  myocardial  bundles: 
a,  the  internal  and  external  layers  of  spiral  muscle,  which  en- 
close b,  the  ventricular  constrictor  muscles.  The  internal  and 
external  investments  of  the  ventricular  chambers  are  composed 
of  the  same  muscle  bundles,  which  are  strongly  twisted  at  the 
vortex  and  spiral  in  opposite  directions  from  the  apex  toward 
the  base.  [From  Rushmer  (139).] 

impeding,  though  not  completely  blocking,  the 
backflow  of  blood  into  the  veins  during  atrial  systole. 
Looped  fibers  are  also  found  which  run  from  the 
anterior  to  the  posterior  segments  of  the  atrioventric- 
ular junction,  directly  beneath  the  endocardium.  At 
many  places  these  fibers  bulge  into  the  atrial  cavities 
forming  various  ridges  which  are  most  conspicuous 
at  the  inner  walls  of  the  atrial  appendages,  where  they 
are  named  musculi  pectinati  from  their  resemblance 
to  a  comb. 

Group  2:  The  fibers  common  to  both  atria  are  less 
numerous  and  lie  superficially  with  respect  to  the 
proper  fibers  of  each  individual  atrium.  They  consist 
of  two  thin  muscle  sheets  which  extend  in  a  transverse 
direction  from  one  atrium  to  the  other.  They  can  be 
subdivided  into  anterior  and  posterior  fascicles.  The 
muscle  fibers  of  the  atria  and  ventricles  are  separated 


by  connective  tissue  except  at  one  place,  known  as  the 
atrioventricular  bundle  or  bundle  of  His. 

The  atrial  cavity  is  surrounded  by  the  thin  myo- 
cardial fibers  of  both  groups  arranged  in  layers  which 
are  partly  parallel  and  partly  crisscrossed.  The  con- 
certed action  of  all  fibers  is  that,  upon  their  con- 
traction, they  diminish  the  size  of  the  atrial  cavity 
and  push  blood  into  the  region  of  least  resistance,  i.e., 
primarily  into  the  ventricles,  secondarily  into  the 
venous  orifices.  In  addition  to  the  main  atrial  cavity, 
there  is  an  adjoining  cavity  formed  by  the  lumen  of 
the  atrial  appendage,  also  called  "auricle"  because 
of  its  resemblance  to  a  little  ear.  The  function  of  the 
auricles  is  unknown.  Excision  of  the  auricles  in  various 
operative  procedures  does  not  influence  the  circulation 
noticeably.  Yet  one  cannot  state  bluntly  that  the 
atrial  appendages  have  no  function  at  all,  since  in  a 
complex  system,  such  as  the  heart,  the  function  of  a 
missing  part  may  often  be  taken  over  or  substituted 
by  increased  activity  of  other  components.  The 
mere  presence  of  the  atrial  appendages  results  in  an 
increase  in  the  cardiac  reserve.  According  to  Benning- 
hoff  (10)  and  Bohme  (14),  the  atrial  appendages  fill 
the  space  which  is  created  within  the  pericardial  sac 
during  ventricular  systole,  as  the  ventricles  eject 
blood  into  the  large  arteries  and  decrease  in  size. 
During  this  period  the  atrial  appendages  accommo- 
date a  considerable  amount  of  blood.  This  blood  is 
immediately  available  at  the  beginning  of  the  rapid 
ventricular  filling  phase  to  be  transferred  into  the 
ventricular  cavities. 


PRESSURE    AND    FLOW   EVENTS    DURINO 
THE    CARDIAC    CYCLE 

Historically  the  cardiac  cycle  was  first  divided  into 
"systole,"  or  period  of  contraction,  and  "diastole," 
or  period  of  relaxation  of  the  ventricles.  It  was  soon 
recognized  that  the  terms  systole  and  diastole  should 
refer  equally  to  the  atrial  contraction  and  relaxation, 
although  the  ventricular  events  were  most  con- 
spicuous in  the  gross  observation  of  cardiac  activity. 
Since  the  atrial  contraction  precedes  that  of  the 
ventricle,  terminological  difficulties  arose  as  to  which 
systole  was  meant  in  describing  the  time  sequence  of 
cardiac  events.  As  knowledge  about  the  heart's 
action  increased,  it  was  also  deemed  necessary  to 
subdivide  the  cardiac  cycle  in  greater  detail  [see  also 
Mackenzie  (no)].  With  the  advent  of  methods  for 
precise  pressure  recording  from  the  cardiac  chambers 
and  great  vessels,   the  ventricular  pressure  tracings 


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became  the  deciding  guidelines  for  characterizing  the 
phases  of  the  cycle.  The  generally  adopted  sub- 
divisions of  Wiggers  (156)  stem  from  this  era.  Since 
other  landmarks  of  cardiac  activity  such  as  flow, 
volume  changes,  or  biochemical  processes  were 
difficult  to  record  adequately,  they  were  only  corre- 
lated with  the  pressure  curves  at  a  later  date. 

It  is  still  impossible  to  subdivide  the  cardiac  cycle 
according  to  the  most  important  physiological 
events :  the  blood  flow  into  and  out  of  the  cavities. 
The  approximate  beginning  and  end  of  systolic 
ejection  can  be  determined  from  simultaneous  pres- 
sure tracings  in  a  ventricle  and  in  an  arterial  outflow 
tract.  However,  the  precise  timing  of  flow  is  only 
possible  through  direct  recording  of  flow  either  at  the 
root  of  the  aorta  or  at  the  pulmonary  artery  [see  also 
Moscovitz  &  Wilder  (117)].  The  recent  advent  of 
refined  flowmeters  will  probably  necessitate  some 
adjustments  in  the  original  Wiggers  scheme  of  the 
cardiac  cycle.  For  the  time  being  it  is  still  preferable 
to  retain  the  well-established  scheme  and  to  fit 
modifications  into  it,  rather  than  to  advocate  a  com- 
pletely new  one  [see  also  Horowitz  (80)]. 

Figure  14  [modified  from  Wiggers  (156,  159)] 
illustrates  in  schematic  form  the  sequence  of  pressure 
events  during  the  cardiac  cycle  in  the  left  ventricle, 
left  atrium  and  aorta,  and  the  volume  changes  in  the 
combined  ventricles  [from  Henderson  (69)].  For 
time  correlation,  tracings  of  the  heart  sounds  and 
of  the  electrocardiogram  are  added.  This  composite 
chart  is  mainly  based  on  curves  obtained  in  animal 
experiments. 

The  cycle  is  divided  into  two  periods,  systole  and 
diastole.  The  former  begins  with  the  rise  of  ventricular 
pressure  caused  by  ventricular  contraction  (fig.  1 4,  1 ) 
and  ends  at  the  onset  of  myocardial  relaxation,  4, 
at  the  point  when  ejection  actually  ceases.  This  point 
then  also  represents  the  beginning  of  the  diastole. 
The  systolic  period  is  subdivided  into  1-2,  isovolu- 
metric  ventricular  contraction  (50  msec);  2-3, 
maximum  ventricular  ejection  (90  msec);  and  3-4, 
reduced  ventricular  ejection  (130  msec).  The  diastolic 
period  is  subdivided  into  4-5,  isovolumetric  ventricular 
relaxation  (120  msec),  which  includes  a  phase 
occurring  just  prior  to  the  incisura  and  formerly 
called  protodiastole  (40  msec),  plus  the  phase  formerly 
known  as  isometric  relaxation  (80  msec);  5-6,  rapid 
ventricular  filling  (no  msec);  6-7,  slow  ventricular 
filling  or  diastasis  (190  msec);  and  7-1,  ventricular 
filling  by  atrial  contraction  (60  msec). 

Numerous  other  cyclical  events  occur  with  each 


fig.  14.  Scheme  of  the  cardiac  cycle.  Time,  totaling  1  sec, 
on  upper  margin.  Numbers  under  lower  margin  indicate  be- 
ginning and  end  of  phases.  Period  of- ventricular  systole  lasts 
from  1  to  4,  period  of  ventricular  diastole  lasts  from  4  to  1 . 
Detailed  description  in  text.  [Figure  (but  not  numbers  in  text) 
slightly  modified  from  Wiggers   (159).] 

heart   beat.   They  are  correlated   timewise  with   the 
phases  of  the  pressure-volume  cycle  as  follows. 

1-2:  Isovolumetric  ventricular  contraction.  During  this 
phase  the  myocardium  builds  up  tension  and  this 
gives  a  fast  rise  of  intraventricular  pressure  without 
change  in  the  volume  of  blood  contained  in  the 
ventricular  cavity.  The  intraventricular  pressure 
must  rise  to  the  level  of  the  diastolic  pressure  pre- 
vailing in  the  aorta  (or  pulmonary  artery)  before 
blood  can  be  ejected  from  the  ventricles  during  the 
next  two  phases.  The  term  "isovolumetric  contrac- 
tion" suggested  by  Rushmer  (139)  should  supersede 
the  older  term  "isometric  contraction,"  since  at  the 
beginning  of  this  phase  there  is  an  actual  shortening 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


771 


of  the  fibers  of  the  papillary  muscles  and  trabeculae 
carneae  which  results  in  a  tension  of  the  chordae 
tendineae,  and  an  approximation  of  the  atrioventri- 
cular valves  (139)-  Simultaneously,  there  is  a  passive 
stretching  of  the  other  still  relaxed  myocardial  layers, 
mainly  those  of  the  outer  walls  of  the  heart  [see  also 
Hawthorne  (67),  Anzola  (4),  and  Burton  (29)]. 
The  older  term  ''isometric  contraction''  had  the 
misleading  implication  that  all  myocardial  fibers 
contract  simultaneously  and  isometrically  from  the 
very  start.  Since  in  fact  some  muscle  fibers  shorten 
whereas  others  are  passively  lengthened  during  this 
phase,  while  the  intraventricular  volume  remains 
constant,  the  term  isovolumetric  contraction  provides 
a  more  accurate  description  than  isometric  con- 
traction. Apparently  instrumentation  has  not  yet  been 
refined  sufficiently  to  decide  whether  or  not  there  is 
in  this  phase  a  brief  "latent  relaxation"  of  cardiac 
muscle  fibers  as  there  exists  in  skeletal  muscle  fibers. 

The  shortening  of  the  ventricle  in  the  longitudinal 
axis  results  in  a  descent  of  the  atrioventricular 
junction  which  in  turn  expands  the  atrial  cavities. 
This  leads  to  a  precipitous  lowering  of  the  atrial 
pressure  (fig.  14)  which  is  often  observed  even  before 
'  the  ventricle  ejects  blood.  The  ventricular  muscle 
fibers  contract  in  a  successive  order,  probably  follow- 
ing the  same  time  sequence  as  their  depolarization 
(75,  142).  As  a  consequence  the  blood  contained  in 
the  ventricular  cavity  is  pushed  from  the  apex  region 
toward  the  center  of  the  ventricle  and  moves  thereby 
closer  to  the  outflow  tract.  The  subsequent  ejection 
from  the  ventricles  can  be  looked  upon  as  a  con- 
tinuation of  the  intraventricular  movement  of  blood 
which  already  starts  before  the  semilunar  valves  open. 
At  the  same  time  the  ventricular  cavity  changes  from  a 
cylindrical  to  a  more  spherical  shape,  which  from 
the  energy  standpoint  represents  a  more  economical 
way  of  discharging  the  ventricular  content,  once  the 
aortic  diastolic  pressure  is  overcome.  As  pointed  out 
by  Rushmer  (139),  the  asynchronous  contraction  of 
the  ventricular  myocardium  readily  explains  the 
brief  upward  deflection  at  the  beginning  of  iso- 
volumetric contraction  in  the  ventricular  volume 
curve  described  by  Wiggers  (156)  in  fig.  14. 
This  was  formerly  interpreted  as  an  artifact  in  the 
recording. 

Some  arbitrariness  is  invoked  in  determining 
accurately  the  start  of  isovolumetric  contraction.  In 
all  pressure  tracings  the  upward  movement  begins 
slowly  in  the  form  of  a  rounded  curve.  There  is  no 
abrupt  beginning,  inflection,  or  break.  This  becomes 
especially  evident  if  one  records  the  pressure  events 


by  drawing  out  the  time  axis  with  fast  moving  paper 
as  can  be  easily  done  today  with  electrical  recording 
apparatus.  The  rounded  beginning  of  the  upward 
limb  results  from  the  combined  effect  of  a)  the 
contraction  of  the  papillary  muscles,  and  b)  the 
simultaneous  passive  distention  of  some  of  the  muscle 
fibers  in  the  ventricular  wall.  Whenever  the  trans- 
figuration of  the  ventricle  causes  a  detectable  rise  of 
intraventricular  pressure,  then  by  convention  the 
ventricular  isometric  contraction  is  said  to  begin.  The 
fact  that  the  different  strands  of  myocardial  fibers 
contract  in  sequence  rather  than  simultaneously  may 
also  explain  the  great  variability  of  the  slopes  of  the 
pressure  tracings  in  the  early  part  of  isovolumetric 
contraction. 

The  steepness  of  the  slope  during  isovolumetric 
contraction  is  predominantly  determined  by  the 
forcefulness  of  the  fiber  contraction.  If  the  difference 
between  the  end-diastolic  ventricular  and  end- 
diastolic  aortic  pressure  remains  unchanged,  the 
duration  of  the  ventricular  isovolumetric  contraction 
is  shortened  by  sympathetic  or  sympathomimetic 
stimulation  and  lengthened  by  agents  or  conditions 
which  depress  the  sympathetic  control  of  the  heart 
[Cotton  &  Maling  (35),  Gleason  &  Braunwald 
(54);  see  also  Reeves  et  al.  (133)].  Thus  in  forcefully 
contracting  ventricles,  the  slope  will  be  steeper  than 
in  feebly  contracting  preparations. 

The  atrioventricular  valves  close  approximately  at 
the  beginning  of  isovolumetric  contraction;  the 
opening  of  the  semilunar  valves  marks  the  end  of  this 
phase.  The  precise  moment  of  the  valve  actuation  is 
difficult  to  establish  experimentally  (discussed  in  the 
section  on  heart  valves).  In  the  interval  between 
closure  of  the  atrioventricular  valves  and  opening  of 
the  aortic  and  pulmonary  valves,  the  blood  contained 
in  the  ventricular  cavities  is  temporarily  isolated  from 
the  fluid  columns  in  the  atria  and  arteries.  However, 
the  ventricular  content  does  not  remain  still  (10). 
In  fact  the  blood  which  rushed  into  the  ventricles  at 
high  velocity  during  diastole  may  aid  in  expanding 
the  ventricular  cavities.  Since  the  inflow  is  primarily 
directed  toward  the  apex,  it  is  this  part  of  ventricular 
wall  which  could  be  preferentially  expanded.  As  the 
papillary  muscles  and  trabeculae  carneae  begin  to 
contract,  the  movement  of  the  blood  is  deviated 
toward  the  outflow  tract.  This  change  in  direction  of 
flow  is  favored  anatomically  by  the  fact  that  the  axis 
of  the  inflow  tract  and  that  of  the  outflow  tract  form 
an  angle.  In  other  words,  the  inflowing  blood  prob- 
ably does  not  come  to  a  complete  standstill  in  order  to 
reverse   its   direction    of  flow   for   ejection   into    the 


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CIRCULATION    II 


arteries,  but  rather  it  keeps  flowing  in  a  curve  from 
the  main  direction  of  the  inflow  tract  toward  the 
outflow  tract.  This  translocation  of  blood  within  the 
ventricle  during  the  isovolumetric  phase  is  energy  pre- 
serving. In  fact,  there  seems  to  be  rather  little  turbu- 
lence and  not  always  complete  mixing  of  blood  during 
this  "intraventricular"  streaming  from  the  inflow  side 
to  the  outflow  region.  This  explains  why  the  streamlin- 
ing of  flow  in  the  venous  circulation  is  not  always  com- 
pletely interrupted  by  the  passage  of  blood  through  the 
ventricle.  For  example,  the  systemic  venous  blood  is 
transferred  into  the  pulmonary  arteries  in  such 
manner  that  superior  caval  blood  reaches  predomi- 
nantly the  right  lung  and  inferior  caval  blood  the  left 
lung  [see  also  Bucher  et  al.  (27)].  Obviously,  the 
possibility  of  incomplete  mixing  deserves  attention 
when  samples  of  so-called  mixed  venous  blood  are 
drawn. 

How  much  does  the  velocity  of  the  blood  flow 
decrease  during  the  transit  in  the  ventricle?  In  the 
resting  organism  with  a  slow  heart  rate,  the  velocity 
of  blood  streaming  into  the  ventricle  toward  the  end 
of  diastole  is  rather  small,  as  may  be  surmised  from 
the  fairly  flat  portion  of  the  ventricular  volume  curve. 
When  the  cardiac  output  is  elevated,  the  velocity  of 
the  intraventricular  flow  during  isovolumetric  con- 
traction will  probably  increase  for  two  reasons:  /) 
the  velocity  of  end  diastolic  ventricular  inflow  in- 
creases through  a  shortening  of  diastole  due  to  high 
heart  rates  and  through  a  more  forceful  atrial  con- 
traction; 2)  the  transit  time  through  the  ventricle  is 
shortened  by  the  more  powerful  and  often  shorter 
myocardial  contraction.  Such  higher  intraventricular 
flow  velocities  under  sympathetic  activity  could  then 
result  in  a  better  energy  conservation  by  not  letting 
the  speed  of  blood  flow  slow  down  too  much  before 
ventricular  ejection  begins  again. 

[It  is  the  feeling  of  the  editors  that  there  is  not 
sufficient  evidence  to  show  that  continued  transloca- 
tion of  blood  within  the  ventricular  cavity  during  iso- 
volumetric contraction  could  contribute  significantly 
to  the  subsequent  ejection.  Ed.] 

2-4:  Rapid  and  reduced  ventricular  ejection.  As  soon  as 
the  pressure  in  the  ventricular  cavities  exceeds  that 
in  the  aorta  or  the  pulmonary  artery,  the  blood  is 
suddenly  ejected.  Although  flow  is  created  by  a 
difference  between  the  intraventricular  and  arterial 
pressures,  an  inspection  of  pressure  curves  alone, 
simultaneously  recorded  from  the  ventricle  and  the 
root  of  the  artery,  furnishes  only  meager  information 
about  the  rate  of  volume  flow  and  its  time  course. 
However,    from    simultaneously    recorded    flow    and 


fig.  15.  Phase  relationships  between  pressure  and  flow  as 
revealed  by  simultaneously  recorded  curves  from  the  ascending 
aorta  of  a  conscious  dog.  Upper  tracings:  rate  of  volume  flow 
measured  with  a  permanently  implanted  electromagnetic 
flowmeter.  Lower  tracings:  aortic  pressures  obtained  through  a 
permanently  implanted  cannula  leading  to  a  strain  gauge 
manometer.  A:  curves  from  the  quiet  reclining  animal.  B: 
curves  from  the  animal  running  behind  a  car  during  moderate 
exercise.  [Original  curves  by  the  courtesy  of  Frederick  Olm- 
stead,  Cleveland  Clinic,  Cleveland,  Ohio  (personal  communi- 
cation,  1961 ).] 

pressure  curves  in  the  aorta  or  in  the  pulmonary 
artery,  the  process  of  ventricular  ejection  is  now 
fairly  well  understood  [VVetterer  (155)].  The  ejection 
starts  abruptly  (fig.  15).  The  blood  column  in  the 
root  of  the  aorta,  which  is  practically  stationary  at  the 
end  of  diastole  and  during  isovolumetric  contraction, 
is  rapidly  accelerated  and  pushed  toward  the  periph- 
ery. The  greatest  flow  acceleration  occurs  during 
the  steeply  ascending  limb  of  the  aortic  pressure 
curve,  so  that  the  highest  flow  rate  (peak  of  the 
flow  curve)  is  actually  reached  prior  to  the  summit 
of  the  pressure  curve.  When  the  flow  then  becomes 
less  rapid,  the  phase  of  reduced  ejection  is  said  to 
begin.  The  border  between  rapid  and  reduced 
ejection  is  quite  arbitrary.  When  only  pressure  and 
cardiometer  curves  were  available  [Wiggers  (156)], 
it  was  difficult  to  determine  from  the  gradual  leveling 
off  of  the  downward  limb  of  the  volume  curve  when 
the  rapid  ejection  started  to  slow  down.  The  summit 
of  the  ventricular  pressure  curve  was  thought  to 
indicate  the  end  of  rapid  ejection  (fig.  14).  It  is  now 
known  that  the  flow  slows  down  earlier,  since  the  peak 
of  the  flow  curve  definitely  precedes  the  peak  of  the 
ventricular  or  aortic  pressure  curve  (upper  tracings 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


77  1 


in  fig.  15).  The  fact  that  the  ventricular  and  aortic 
pressures  continue  to  rise  even  after  the  flow  rate 
starts  to  drop  is  not  surprising,  since  during  the  period 
of  reduced  ejection,  blood  continues  to  accumulate 
in  the  aortic  arch.  Because  aortic  pressure  at  any  one 
instant  is  determined  both  by  the  distention  of  the 
arterial  walls  with  blood  coming  from  the  ventricle 
and  by  the  runoff  into  the  periphery,  the  pressure 
continues  to  rise  as  long  as  more  blood  enters  the 
aortic  arch  than  runs  off  toward  the  periphery.  There 
is  no  fixed  and  easily  definable  time  relation  between 
the  summits  of  the  flow  and  pressure  curves,  because 
the  factors  determining  the  position  of  each  of  the 
summits  are  numerous  and  variable  (149). 

Some  aspects  of  the  time  relation  between  the  flow 
and  pressure  curves  A  and  B  are  illustrated  in  figure 
15.  During  exercise  the  rapid  ejection  occupies  a 
relatively  shorter  portion  of  the  total  ventricular 
ejection.  In  this  example  the  whole  ventricular 
ejection  lasts  374  msec  at  rest  and  only  234  msec 
during  exercise.  However,  the  delay  between  the 
summits  of  the  flow  and  pressure  curves  is  109  msec, 
in  both  cases,  or  29  per  cent  of  the  whole  ventricular 
ejection  at  rest,  and  46  per  cent  during  exercise.  In 
other  words,  during  exercise  the  aortic  pressure 
continues  to  rise  relatively  longer  after  the  aortic  flow 
rate  has  started  to  drop,  indicating  that  there  is 
relatively  more  blood  accommodated  in  the  central 
arteries  (arterial  compression  chamber)  during 
systole.  This  also  means  that,  when  ventricular 
ejection  ceases,  there  is  a  higher  aortic  pressure  and 
consequently  a  larger  amount  of  peripheral  runoff 
during  early  diastole.  Such  conditions  help  to  main- 
tain greater  tissue  perfusion  in  the  active  organism. 

The  configuration  of  the  aortic  flow  curve  is  not 
the  same  in  the  organism  at  rest  and  during  exercise 
or  sympathetic  stimulation.  At  rest,  the  descending 
limb  of  the  flow  curve  first  declines  gently,  then 
progressively  faster,  forming  thereby  a  shallow  hump 
(see  fig.  15.4).  During  exercise  the  ascending  limb  is 
steeper  and  the  descending  limb  declines  precipi- 
tously (fig.  15B).  This  pattern  indicates:  /)  an  increase 
in  the  myocardial  contractile  force,  which  continues 
to  exert  its  strong  effect  after  the  end  of  the  iso- 
volumetric  contraction  phase  and  achieves  a  more 
rapid  flow  acceleration;  2)  a  longer  duration  of  flow 
at  near  maximal  velocity  (Olmstead,  personal 
communication);  and  3)  a  faster  return  to  the  begin- 
ning of  myocardial  relaxation.  Despite  shortening  of 
the  ejection  phase,  the  stroke  volume,  which  can  be 
calculated  from  the  area  under  the  curve,  is  approxi- 
mately the  same  during  moderate  exercise  as  it  is  at 


rest.  However,  during  strenuous  exercise  (running  of 
dog  at  16  miles  per  hour  over  rough  terrain)  the 
stroke  volume  appears  to  be  increased  by  approxi- 
mately 25  to  40  per  cent  (Olmstead,  personal  com- 
munication). Whether  or  not  there  is  always  an 
increase  in  stroke  volume  during  exercise  is  still  a 
matter  of  debate  among  various  investigators  [see  also 
Rushmer  (139)]. 

Toward  the  end  of  the  reduced  ejection  phase  the 
intraventricular  and  aortic  pressures  drop  quickly. 
The  ejection  stops  and  forward  flow  in  the  ascending 
aorta  ceases  shortly  after  closure  of  the  semilunar 
valves  as  seen  by  the  crossing  of  the  flow  curve  through 
the  horizontal  zero  flow  line  in  figure  15.  Flow  in  the 
root  of  the  aorta  near  the  valves  momentarily  reverses 
its  direction,  because  of  a  translocation  of  blood  into 
the  sinuses  of  Valsalva  and  the  coronary  vessels, 
which  helps  to  close  the  aortic  valves.  Although  there 
is  a  brief  backflow  near  the  valves,  in  the  more 
distal  part  of  the  aorta  the  flow  continues  forward  for 
a  while,  since  the  energy  momentarily  stored  in  the 
distended  aortic  arch  propels  the  blood  to  the  area  of 
lower  pressure,  i.e.,  the  peripheral  vessels  (compres- 
sion chamber  effect).  The  precise  moment  of  valve 
closure  cannot  be  easily  correlated  with  the  pressure 
and  flow  curves.  It  can  be  stated  from  the  flow  curve 
that  the  valves  must  have  closed  at  least  by  the  time 
when  the  downward  deflection  is  suddenly  stopped 
(fig.  1 5)  and  after  which  blood  again  is  propelled 
forward  in  the  ascending  aorta.  How  much  blood  is 
regurgitated  into  the  ventricles  and  how  much  flows 
into  the  coronary  arteries  while  the  valves  are  in  the 
process  of  closing,  has  not  yet  been  determined. 

4-5:  Isovolumetric  relaxation.  It  is  also  difficult  to 
establish  the  exact  moment  when  the  myocardial 
fibers  start  to  relax  after  maximal  shortening.  Wiggers 
(156)  took  the  steepening  of  the  decline  in  the  ventric- 
ular pressure  curve  prior  to  the  deepest  point  of  the 
aortic  incisura  as  the  beginning  of  the  relaxation 
process  and  referred  to  the  brief  interval  from  the 
beginning  of  muscular  relaxation  to  semilunar  valve 
closure  as  the  protodiastolic  phase.  Since  little  is 
gained  by  singling  out  this  interval,  which  cannot 
be  accurately  measured,  the  phases  of  protodiastole 
and  isovolumetric  relaxation  will  be  treated  here  as  a 
single  process  as  Wiggers  ( 1 59)  also  suggested  in  his 
recent  discussion  on  this  subject. 

It  appears  reasonable  to  assume  that,  just  as  the 
contraction  began  asynchronously,  some  myocardial 
fibers  will  begin  to  relax  earlier  than  others.  However, 
no  direct  measurements  are  available  to  document 
this  hypothesis.  At  the  end  of  isovolumetric  relaxation, 


774 


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CIRCULATION     II 


fig.  1 6.  Phase  relationships  between  aortic 
pressures,  Ao;  left  ventricular  volume,  LV, 
(dots);  atrial  volume,  LA,  (open  circles); 
and  electrocardiogram,  ECG,  in  an  anesthe- 
tized normal  dog  with  a  spontaneous  heart 
rate  of  iio/min.  The  pressure  tracings  were 
simultaneously  recorded  and  correlated  with 
the  volume  measurement  from  the  kinemato- 
graphic  frames.  [Original  curves  and  labeling 
by  courtesy  of  Peo  Gribbe,  Wenner-Gren 
Research  Laboratory,  NorrtulPs  Hospital, 
Stockholm,  Sweden  (personal  communica- 
tion,  1 961).] 


PROTODIASTOLE 

EJECTION 

ISOMETRIC 
CONTRACTION 


ISOMETRIC    RELAXATION 
RAPID    INFLOW 

DIASTASIS 
/       ATRIAL    SYSTOLE 


ORMOTHERMIA      36C 
EART     RATE     110 


0.5  sec 


the  intraventricular  pressure  drops  to  the  level  of 
the  atrial  pressure.  The  pressure  decline,  like  the 
pressure  rise,  is  more  rapid  under  the  action  of 
epinephrine  (158,  124)  and  apparently  also  in 
exercise.  Therefore,  with  epinephrine  and  during 
exercise  the  duration  of  the  isovolumetric  relaxation 
phase  is  shorter  for  the  same  pressure  difference 
between  the  incisura  and  atrial  pressure.  Neither  the 
precise  moment  of  the  valve  opening  at  the  end  of 
isovolumetric  relaxation  nor  the  pressure  difference 
necessary  to  actuate  them  has  been  satisfactorily 
determined  as  yet.  One  usually  takes  the  decline  in 
atrial  pressure  after  the  V  point  as  an  indication  that 
the  atrioventricular  valves  have  just  opened  and  flow 
through  the  orifice  has  begun.  The  crossing  over  of  the 
atrial  and  ventricular  pressure  tracings  is  therefore 
taken  as  the  end  of  isovolumetric  relaxation.  How- 
ever, even  with  the  most  careful  recording,  it  is 
difficult  to  establish  such  a  crossing  over  without 
artifacts.  Since  at  this  part  of  the  cardiac  cycle  the 
heart  has  become  a  low-pressure  system,  instru- 
mentation errors  are  commonly  experienced  with 
positioning  of  pickup  devices,  movement  artifacts,  lack 
of  sensitivity,  Bernoulli  effect,  and  lack  of  a  common 
and  reliable  reference  zero  pressure  level. 

5-7 :  Rapid  and  slow  ventricular  filling.  There  is  no 
satisfactory  procedure  to  measure  directly  the  inflow 
of  blood  from  the  atrium  into  the  ventricle.  The  best 
information  stems  from  X-ray  kinematographic 
studies  such  as  those  of  Rushmer  (139),  Chapman 
et  al.  (31,  32),  Gribbe  et  al.  (56).  A  good  time  resolu- 
tion was  obtained  by  Gribbe,  who  took  40  to  50  frames 
per  sec  using  an  image  intensifier.  The  individual 
frames  of  film  were  projected  and   the  volume  was 


calculated  from  the  contrast  silhouette  of  the  left 
atrium  and  ventricle,  assuming  that  the  left  ventricu- 
lar cavity  resembles  an  ellipsoid  of  rotation.  Figure  16 
illustrates  the  steep  upward  slant  of  the  curve  during 
the  phase  of  rapid  ventricular  filling.  The  incline  of 
this  part  of  the  curve  is  even  steeper  than  the  decline 
of  the  curve  during  rapid  ventricular  ejection, 
indicating  that  blood  actually  rushes  into  the  ven- 
tricle faster  than  it  is  ejected  from  the  ventricle.  This 
observation  has  an  important  bearing  upon  the 
concepts  of  the  forces  which  bring  about  ventricular 
filling  (see  later  section).  After  the  rate  of  ventricular 
inflow  has  reached  its  maximum,  it  begins  gradually 
to  slow  down  until  finally  the  curve  tends  to  level 
off.  There  is  no  distinct  break  which  could  serve  as  a 
criterion  for  precise  determination  of  the  end  of  the 
rapid  filling  phase  and  the  beginning  of  the  slow 
phase.  Nevertheless,  the  distinction  between  these 
two  phases  remains  useful  at  slow  heart  rates,  as  for 
instance  under  strong  vagotonic  influence,  because 
the  slow  phase  of  ventricular  filling  then  lasts  much 
longer  than  depicted  in  figure  16. 

7-1  :  Filling  by  atrial  contraction.  With  the  contraction 
of  the  atrial  myocardium  an  additional  volume  of 
blood  is  pushed  into  the  ventricle,  as  shown  by  the 
sudden  final  incline  of  the  curve  in  figure  16.  The 
contribution  of  atrial  contraction  to  ventricular 
filling  has  been  much  debated  [see  Mitchell  et  al. 
(113)].  According  to  the  measurements  of  Gribbe 
et  al.  (56),  it  should  amount  to  about  20  to  25  per  cent 
of  the  volume  entering  the  ventricle.  Atrial  pressure 
drops  after  the  peak  of  atrial  systole  but  seemingly 
without  a  measurable  decrease  in  ventricular  volume 
by  backflow   through   the  atrioventricular  valves.    11 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPINC 


775 


ventricular  pressures  are  recorded  with  instruments  of 
sufficient  sensitivity,  the  transfer  of  the  atrial  pressure 
rise  can  be  observed  on  the  ventricular  pressure  trac- 
ing, since  atrium  and  ventricle  form  a  common  cavity 
during  atrial  systole.  Similarly,  after  the  peak  pressure 
of  atrial  systole  has  been  reached,  the  pressure  drops 
not  only  in  the  atrium  but  also  in  the  ventricular 
cavity.  When  the  atrioventricular  valves  actually 
close  is  still  a  matter  of  debate  (see  also  later  section). 
It  may  well  be  that  the  large  valve  leaflets  begin  to 
approximate  each  other  at  the  moment  when  the 
atrial  pressure  starts  dropping  and  that  they  continue 
to  move  toward  each  other  because  ventricular  blood 
flows  into  the  large  spaces  behind  the  closing  leaflets. 
Therefore,  the  valves  may  start  to  close  at  a  time 
when  the  ventricular  pressure  is  decreasing  slightly. 
Complete  closure  would  then  be  achieved  when  the 
dropping  atrial  and  intraventricular  pressures  level 
off  (Z  point  in  atrial  pressure  curve). 

As  the  heart  rate  becomes  faster  under  sympathetic 
stimulation  or  in  exercise,  the  period  of  slow  ventric- 
ular filling  is  progressively  shortened  by  an  earlier 
onset  of  the  atrial  systole  [see  Mitchell  ct  a/.  (113)]. 
At  heart  rates  above  1 20  per  min  the  phase  of  slow 
ventricular  filling  is  more  or  less  abrogated  (56). 
Figure  17  illustrates  how  at  a  heart  rate  of  160  per 
min  the  phase  of  rapid  ventricular  filling  is  directly 
followed  by  the  inflow  due  to  atrial  contraction.  In 
these  curves  one  cannot  discern  the  usual  hump  in  the 
upstroke  of  the  filling  curve  which  occurs  when  rapid 
ventricular  filling  changes  to  slow  ventricular  filling 
before  the  atrium  adds  its  contribution.  It  is  likely  that 
at  still  faster  heart  rates,  the  atrial  component  of  the 
curve  blends  completely  with  the  inclined  tracing 
characteristic  of  rapid  ventricular  filling.  At  extreme 
degrees  of  tachycardia  even  the  phase  of  rapid  ventric- 
ular filling  may  be  encroached  upon.  This  would 
explain  why  the  stroke  volume  decreases  at  very- 
rapid  heart  rates  since  there  is  not  sufficient  time 
for  adequate  filling  of  the  ventricle. 

The  force  of  atrial  contraction  usually  varies 
concomitantly  with  that  of  ventricular  contraction. 
Therefore,  the  percentile  contribution  of  atrial 
systole  to  ventricular  filling  is  lower  under  vagal 
influence  and  higher  under  sympathetic  excitation. 
In  extreme  tachycardia,  when  atrial  systole  begins 
during  the  phase  of  rapid  ventricular  filling,  the 
actual  contribution  of  the  atrium  to  the  filling  of  the 
ventricle  may  be  as  high  as  30  to  40  per  cent.  The 
atrial  contraction  would  then  serve  to  increase  the 
pressure  difference  between  the  atrium  and  ventricle 
in  the  later  part  of  the  rapid  filling  phase  and  thereby 


0.5  sec 

Fig.  17.  Phase  relationships  among  aortic  pressure,  [eft 
ventricular  volume  (dots),  atrial  volume  (open  circles),  and 
electrocardiogram  (ECG),  in  an  anesthetized  normal  dog  with 
a  spontaneous  heart  rate  of  160/min.  The  pressure  tracings 
were  simultaneously  recorded  and  correlated  with  the  volume 
measurement  from  the  kinematographic  frames.  [Original 
curves  and  labeling  by  courtesy  of  Pco  Gribbe,  Wenner-Grcn 
Research  Laboratory,  Norrtull's  Hospital,  Stockholm,  Sweden 
(personal  communication,  1 96 1 ).] 

produce  a  maximal  velocity  of  inflow  throughout  the 
entire,  though  brief,  phase  of  rapid  ventricular 
filling. 


CORRELATION  OF  OTHER  CARDIAC  EVENTS 
WITH  THE  CARDIAC  CYCLE 

The  time  sequence  of  cardiac  events  originally 
described  by  Wiggers  (156)  was  based  upon  those 
pressure  changes  in  the  circulatory  system  which  were 
measurable  at  the  time.  However,  during  the  last 
three  decades  our  trend  of  thinking  about  cardiac 
events  has  been  greatly  affected  by  the  progress  of 
electrocardiography.  At  the  very  beginning  of  the 
investigations  of  the  field  (about  1910-1920)  the 
electrocardiogram  could  only  be  correlated  second- 
arily with  the  time  course  of  the  more  easily  meas- 
urable pressure  events  (138).  Nowadays  one  can 
record  electrocardiograms  with  a  higher  degree  of 
time  resolution  than  intracardiac  pressures.  For  this 
reason  it  is  rather  common  to  use  the  electrocardio- 
gram as  the  basis  or  guideline  for  dividing  the  cardiac 
cycle  into  phases  and  then  to  fit  secondarily  the 
pressure  and  flow  events  into  the  patterns  of  the 
electrical  events  (17,  157).  However,  there  is  a  varying 
time  lag  between  electrical  and  mechanical  events 
under  different  experimental  conditions  [see  Luisada 
&  Liu  (104)],  so  that  such  a  correlation  system  is  not 
entirely  satisfactory. 


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CIRCULATION    II 


Atrial  Pressures 

The  recording  of  atrial  pressures  is  beset  with 
considerable  experimental  difficulty,  as  is  the  case 
with  all  fast  changing  phasic  events  in  low  pressure 
s\  stems.  The  finer  details  of  atrial  pressure  contours 
are  therefore  often  affected  by  artifacts  from  impacts 
or  vibrations  which  make  it  difficult  to  arrive  at 
accurate  deductions  concerning  atrial  flow  dynamics. 
Indeed  the  atrial  pressure  pulse  contour  depicted  in 
figure  14  is  highly  schematized. 

Atrial  pressure  begins  to  rise  at  the  onset  of  atrial 
systole  (A  wave).  Since  at  this  moment  the  atrium 
and  ventricle  form  a  common  cavity,  the  height  which 
the  atrial  pressure  attains  is  influenced  by  the  volume 
distensibility  characteristics  both  of  the  atrium  and 
of  the  ventricle,  in  addition  to  the  rate  of  translocation 
of  the  fluid  from  one  part  of  the  cavity  into  the  other. 
The  resistance  to  flow  through  the  normal  atrio- 
ventricular orifice  is  so  low  that  it  cannot  be  measured 
with  presently  available  techniques. 

Little  is  known  about  the  synchronicity  or  asyn- 
chronicity  of  the  contraction  of  atrial  muscle  fibers. 
The  excitation  wave  spreading  over  the  atrial  walls 
proceeds  from  the  sino-atrial  node.  Therefore  it  can 
be  assumed  that  the  contraction,  which  follows 
depolarization  after  a  brief  interval,  similarly  pro- 
ceeds in  a  wave.  The  concept  of  asynchronous  atrial 
muscle  contraction  is  based  on  the  premise  that  the 
delay  between  depolarization  and  contraction  is  the 
same  for  all  atrial  muscle  fibers.  It  is  not  certain  that 
diis  is  the  case.  A  contractile  wave  is  difficult  to 
demonstrate  conclusively  and  consistently  by  means 
of  slow  motion  pictures. 

The  drop  in  atrial  pressure,  after  the  pressure  has 
reached  a  peak  during  atrial  contraction,  is  probably 
caused  by  the  beginning  of  atrial  muscle  fiber  relaxa- 
tion. Again,  it  is  not  possible  to  state  whether  this 
occurs  synchronously  or  in  a  sequential  order  and  to 
state  what  effect  diis  process  has  on  the  flow  dynamics. 
From  the  configuration  of  the  atrial  pressure  curve 
one  cannot  necessarily  infer  the  exact  onset  of  atrial 
muscle  relaxation.  Just  as  the  ventricular  pressure 
curve  can  still  rise  although  the  rate  of  ejection  already 
declines  (see  fig.  15),  the  atrial  pressure  could  well 
start  to  decrease  before  or  after  the  relaxation  in  the 
atrial  musculature  actually  begins.  The  convention  of 
calling  the  leveling  off  of  the  declining  atrial  pressure 
curve  the  "end  of  atrial  systole"  is  also  arbitrary 
[Opdyke  el  al.  (126);  Opdyke  &  Brecher  (125)]. 

There  is  often  a  brief  period  (Z  point)  during  which 
the  atrial  pressure  curve  remains  level  after  its  decline 


from  the  systolic  rise.  This  is  the  last  moment  at  which 
the  atrial  and  ventricular  cavities  are  probably  still 
in  communication  before  complete  closure  of  the 
atrioventricular  valves.  The  atrial  Z  point  pressure 
is  almost  equal  to  the  ventricular  end-diastolic 
pressure  because  the  rate  of  ventricular  inflow  has 
become  minimal  at  this  moment.  Therefore  it  is 
fairly  safe  to  take  the  Z  point  as  a  representative  of 
end-diastolic  ventricular  pressure.  It  is  definitely  more 
accurate  to  use  the  Z  point  than  the  mean  atrial 
pressure,  which  depends  upon  numerous  factors 
unrelated  to  the  end-diastolic  ventricular  pressure, 
such  as  integration  of  artifacts  and  peaks  at  the  A,  C, 

V  points  ( 126). 

After  the  Z  point  the  atrial  pressure  often  rises 
briefly  and  precipitously  (C  wave).  This  pressure 
rise,  frequently  accompanied  by  vibrations,  is  ascribed 
to  the  bulging  of  the  atrioventricular  valves  into  the 
atrial  cavity  during  ventricular  isovolumetric  con- 
traction. Immediately  following  the  sharply  peaked  C 
wave,  atrial  pressure  usually  declines  to  a  level 
corresponding  to  atmospheric  zero  in  an  open-chest 
preparation  (see  fig.  14),  or  to  near-zero  transmural 
pressure  in  a  closed-chest  organism.  It  is  believed  that 
this  pressure  drop  is  caused  by  the  pull  of  the  papillary 
muscles  on  the  atrioventricular  valve  leaflets  and  by 
the  descent  of  the  atrioventricular  junction  which 
suddenly  enlarges  the  atrial  cavity.  The  bottom  of  the 
pressure  drop  is  called  the  X  point  (or  wave).  There- 
after atrial  pressure  rises  slowly  up  to  the  V  point  (or 
wave)  located  at  the  end  of  ventricular  isovolumetric 
relaxation.  The  pressure  rise  from  the  X  point  to  the 

V  point  is  probably  caused  by  an  inflow  of  blood 
which  distends  the  atrial  walls.  The  atrial  pressure 
drop  (V  point  or  wave)  after  the  opening  of  the 
atrioventricular  valves  results  from  the  rapid  transfer 
of  blood  into  the  ventricular  cavity  in  which  a  lower 
pressure  prevails.  While  it  is  assumed  that  the  actual 
opening  of  the  atrioventricular  valves  occurs  at  the 
summit  of  the  V  wave,  there  is  some  debate  whether 
or  not  it  occurs  slightly  afterward  [see  also  Xixon 
(120)]. 

A  minor  change  in  the  conventional  labeling  of 
atrial  pressure  tracings  has  been  used  by  Kaplan  (88). 
Without  mentioning  the  Z  point,  he  refers  to  the 
small  decline  in  pressure  which  frequently  follows 
atrial  systole,  before  the  C  wave,  as  the  X  wave.  Then 
he  designates  the  pressure  decline  after  the  C  wave 
as  the  X1  wave.  There  is  no  conspicuous  advantage 
to  this  svstem  of  notation. 


Electrocardiogram 

Since  the  electrocardiogram  is  easily  obtainable  and 
serves  as  an  important  diagnostic  tool,  considerable 
efforts  have  been  made  by  theoretical  and  clinical 
scientists  to  correlate  timewise  electrical  and  mechani- 
cal events  of  cardiac  contraction.  Nearly  half  the 
large  volume  of  the  Physiology  of  the  Heart,  by  Schiitz 
(144),  is  devoted  to  this  subject  and  should  be  referred 
to  for  detailed  information. 

From  the  standpoint  of  cardiac  pumping,  the 
electrocardiogram  is  principally  of  interest  insofar  as 
it  may  furnish  a  convenient  method  of  determining 
precisely  the  course  of  mechanical  events  without 
resorting  to  surgical  interventions,  cannulations,  etc. 
Present  attempts  along  these  lines  are  still  inadequate. 
They  are  also  theoretically  limited  for  the  following 
reasons:  a)  although  the  electrical  event  always 
precedes  the  mechanical  event,  it  is  not  known 
whether  the  time  intervals  between  depolarization 
and  beginning  of  contraction  are  identical  in  all 
heart  muscle  fibers,  b)  There  may  be  differences  in 
the  rates  of  impulse  propagation  along  various  fibers 
resulting  in  varying  rates  of  contraction  once  de- 
polarization has  started  at  one  point,  c)  As  repeatedly 
emphasized  by  Rushmer  (139)  and  Scher  (142), 
there  is  considerable  mechanical  asynchronicity  in 
the  contraction  of  cardiac  muscle  fibers,  which  cannot 
be  completely  unraveled  by  recording  the  over-all 
electrical  changes  from  a  large  mass  of  tissues  such  as 
the  heart,  d)  There  are  possibly  time  differences 
between  the  right  and  left  heart  depolarizations  and 
contractions,  but  these  differences  are  inconstant 
and  change  with  various  factors. 

An  example  of  the  difficulties  encountered  in 
attempting  to  establish  empirical  time  correlations  in 
the  cardiac  cycle  is  shown  in  figure  18.  Using  normal 
anesthetized  dogs,  Gribbe  et  al.  (57)  studied  the 
volume  changes  in  the  cardiac  chambers  with 
cineradiography  and  timed  the  events  with  the 
conventional  electrocardiogram.  Comparison  of  the 
time  relations  in  figure  19  with  those  shown  in 
figures  14  and  18  reveals  considerable  discrepancies. 

Vibrocardiogram  (Apex  Cardiogram) 

The  intracardiac  pressures  are  not  easier  to  corre- 
late with  the  electrocardiogram  than  with  a  number 
of  other  mechanical  events  [e.g.,  Harrison  et  al. 
(65)].  For  instance,  the  classical  mechanocardio- 
gram  or  apex  cardiogram,  now  often  referred  to  as 
precordial  vibrocardiogram,  offers  a  good  example  of 
the    present    limitations    in    the    description    of    the 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING      777 
I  2  3  4  5 


RIGHT 


-v 


LEFT 


.,...,..,.,.  ..  ...  1 ,,  j.. 


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10 

+4- 


fig.  18.  Schematic  presentation  of  the  relationship  between 
electrical  and  mechanical  events.  Heart  rate  120  beats/min. 
The  markings  in  lower  part  of  the  figure  indicate  the  picture 
frequency  at  an  exposure  rate  of  48  frames/sec.  1 ,  Onset  of 
right  atrial  contraction;  2,  onset  of  right  ventricular  contrac- 
tion; 3,  onset  of  right  ventricular  ejection;  4,  end  of  right 
ventricular  ejection;  5,  onset  of  right  ventricular  filling;  6, 
onset  of  left  atrial  contraction,  7,  onset  of  left  ventricular  con- 
traction; 8,  onset  of  left  ventricular  ejection;  g,  end  of  left 
ventricular  ejection;  10,  onset  of  left  ventricular  filling.  The 
striped  areas  represent  the  phase  of  ventricular  isovolumetric 
contraction.  The  stippled  areas  represent  the  phase  of  ventricu- 
lar ejection.  [From  Gribbe  el  al.  (57).] 

cardiac  cycle.  Figure  1 9  shows  a  composite  chart  made 
up  of  superimposed  schematized  tracings  as  they  are 
observed  in  normal  man.  The  chart  has  been  con- 
structed by  Agress  et  al.  (2)  from  the  most  appropriate 
tracings  which  they  could  find  in  the  recent  literature. 
The  authors  state:  "Although  this  is  a  composite 
graph,  an  accuracy  of  0.005  second  per  scale  division 
was  made  possible  by  using  a  simultaneouslv  in- 
scribed electrocardiogram  as  the  time  base."  It  is 
evident  that  claims  for  an  accuracy  of  5  msec  can  be 
only  referred  to  the  electrocardiogram,  since  the 
time  definition  of  intracardiac  pressure  recording 
through  long  catheters  is  usually  poorer  than  0.005 
sec.  This  fact  is  not  pointed  out  in  criticism  of  the 
well-deserving  attempts  to  correlate  the  various 
events  of  the  cardiac  cycle  in  man,  but  only  for  the 
purpose  of  cautioning  against  hasty  conclusions. 

Agress  et  al.  (2)  divide  the  cardiac  cycle  into 
phases,  which  differ  slightly  from  those  customarily 
accepted  in  the  past.  The  curves  (fig.  19)  are  inter- 
sected by  vertical  lines  based  on  the  time  relation  of 
left  atrial  and  left  ventricular  pressures,  as  indicated 
by  the  upper  margin  band,  /.,  of  the  graph  and  the 
small  heart  schemes  above  it.  The  phases  are  labeled 


778  IIWDBOOK    OF    PHYSIOLOGY  ^>  CIRCULATION    II 


a  £r  o 


FIG.  19.  Compos- 
ite graph  of  the 
events  of  the  cardiac 
cycle  in  the  human 
heart.  For  discus- 
sion see  text.  [From 
Agress  et  ai   (2). 


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FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPINC 


779 


in  the  next  lower  band,  where  P.S.  stands  for  proto- 
systole  and  P.D.  for  protodiastole.  The  lowest  band 
of  the  upper  margin,  R,  illustrates  the  time  difference 
between  the  activities  of  the  right  and  left  heart.  A 
number  of  points  warrant  brief  comments.   For  all 
intracardiac  and  arterial  pressures  a  common  zero  is 
used.  The  "low"  pressure  events  (left  atrium,  right 
ventricle,   and  pulmonary   artery)    are   plotted  on   a 
scale  from  o  to  45  mm  Hg  (left),  whereas  the  "high" 
pressure  events  (left  ventricle  and  aorta)  are  graphed 
on  a  scale  from  o  to  150  mm  Hg  (right).  The  use  of 
two   different   pressure   scales  for  correlating   simul- 
taneous   events   on    the   same    time    basis    results   in 
different  slopes.  The  casual  viewer  may  hastily  con- 
clude that  the  rate  of  pressure  rise  during  isovolu- 
metric   contraction  is  greater  in   the  right  ventricle 
than  in  the  left  ventricle,  which  is  actually  not  the 
case.     Correspondingly,     the    pressure    drop    during 
ventricular  isovolumetric  relaxation  appears  to  occur 
faster  on  the  right  than  on  the  left  side,  which  does  not 
happen  either.  The  ascending  limbs  of  the  aortic  and 
pulmonary  arterial  pressure  curves  have  been  obtained 
from  overdamped   recording  systems,   such  as  often 
happens    with    long   catheters.    This    might    explain 
why  the  tracings  of  the  arterial  pressures  have  gentle 
slopes  and  remain  considerably  below  the  summits  of 
the     ventricular     pressure     curves.     An     interesting 
innovation    is   the   protosystolic    phase    (P.S.)    which 
apparently  extends  from  the  leveling  off  of  the  left 
atrial  A  wave  until  the  beginning  of  the  left  ventricu- 
lar pressure  rise.  It  seems  to  correspond  to  the  con- 
ventional Z  point.  According  to  the  tracings  in  figure 
19,   the  protosystolic  phase  appears  to   be   timewise 
closely  related  to  the  electrocardiogram.  It  seems  to 
last  from  the  beginning  of  the  Q  wave  until  the  tip  of 
the    R    wave.    The    usefulness    of    introducing    this 
distinctly   different   phase   seems   to   lie   in    the   easy 
correlation   of  certain   characteristics  of  the   phono- 
cardiogram   and   vibrocardiogram   with   the   cardiac 
cycle  during  this  time  interval. 

A  number  of  other  cyclical  events  occurring  in  the 
circulatory  system  also  can  be  more  or  less  accurately 
correlated  with  the  cardiac  cycle.  Examples  would 
be:  various  peripheral  arterial  and  venous  pressure 
pulse  curves  as  well  as  flow  pulse  curves;  intra- 
myocardial  pressures  (96);  the  ballistocardiogram; 
electrokymogram  (42,  163,  135);  angiokymogram 
( 147);  angiocardiogram;  cardiorheogram  (3,  68);  and 
heart  sounds  [Luisada  et  al.  (105)].  In  all  cases  the 
previously  mentioned  difficulties  in  precise  timing 
must  be  given  serious  scrutiny.   A  discussion  of  all 


events  which  lend   themselves  to  correlation   would 
exceed  the  scope  of  this  chapter. 


FUNCTION  OF  THE  HEART  VALVES 

Valves  are  essential  for  efficient  action  of  all 
reciprocating  pumps  in  order  to  maintain  unidirec- 
tional flow.  Valves  must  offer  a  minimal  impedance 
to  flow,  yet  be  able  to  close  abruptly  with  minimal 
leakage  and  minimal  displacement.  The  heart  dif- 
fers from  a  mechanical  pump  in  that  a  perfect  seal 
must  be  obtained  in  orifices  which  are  continuously 
changing  in  shape,  size,  and  position  throughout 
the  cardiac  cycle.  Therefore,  the  valves  must  be 
somewhat  larger  than  the  area  to  be  covered  in  order 
to  remain  competent  under  all  normal  working 
situations.  The  heart  valves  are  also  located  in 
orifices  beyond  which  the  blood  enters  wider 
chambers.  This  provides  for  a  rapid  stream  along 
the  axis  of  the  orifice,  with  decrease  in  lateral  pressure 
at,  and  just  beyond,  the  restricted  valvular  plane 
(Bernoulli  effect)  and  possibly  the  production  of 
eddy  currents.  This  mechanism  keeps  the  valves 
floating  in  the  blood  stream  and  insures  rapid  ap- 
proximation of  the  valve  leaflets  as  soon  as  the  axial 
stream  of  blood  ceases. 

The  movements  of  the  atrioventricular  and  semi- 
lunar valves  are  passive  since  the  valve  leaflets  do 
not  contain  muscle  fibers  [see  also  Moritz  (116)]. 
The  consideration  of  this  aspect  is  important  because 
it  is  easier  to  replace  passive  structures  by  protheses 
than  it  is  to  create  protheses  for  active  structures 
such  as  muscles.  It  is  also  possible  to  investigate  the 
forces  involved  in  the  movement  of  passive  structures 
by  observing  the  function  of  a  prothesis  which  simu- 
lates a  natural  organ  in  suitable  physical  analogues. 
Davilla  (36)  summarizes  this  trend  of  thought  as 
follows:  "The  most  successful  protheses  have  been 
those  which  fulfill  a  passive  role  in  the  functional 
complex:  a  metal  plate  on  the  skull,  a  nail  in  a  long 
bone,  steel  or  plastic  mesh  in  a  weak  abdominal  wall, 
a  tube  of  cloth  to  replace  a  blood  vessel.  .  .  .  Fortu- 
nately, the  role  of  the  cardiac  valves  in  hemodynamics 
is  a  passive  one.  They  are  not  parts  that  move  but 
parts  which  are  moved.  Their  role  is  identical  to  that 
of  a  simple  check  valve.  It  is  their  environment  which 
complicates  the  matter.  They  are  immersed  in  flowing 
tissue  which  is  chemically  unstable  but  which  must 
not  be  subjected  to  extreme  unbalance;  which  pos- 
sesses a  clotting  mechanism  that  must  not  be  activated 
by  the  valve;  and  which  transports  vital  cells  that 


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CIRCULATION    II 


must  not  be  traumatized.  The  valves  must  open  and 
close  an  orifice  which  continuously  changes  in  size 
and  provides  scant  room  for  support  between  pul- 
satile and  irregular  chambers.  The  motion  of  the 
valves  depends  upon  cardiac  action  and  must  be 
coordinated  with  those  structures  which  impart  it. 
And,  finally,  the  valvular  apparatus  must  withstand 
the  stress  of  beating  more  than  forty  million  times  a 
year  during  the  life  span  of  the  subject." 

In  a  multichambered  pump  such  as  the  heart, 
valves  or  valve-like  mechanisms  are  expected  at  each 
boundary  between  functionally  separate  chambers. 
We  shall  therefore  discuss  the  function  of  the  struc- 
tures which  prevent  backflow:  a)  at  the  veno-a trial 
junction;  b)  at  the  atrioventricular  junction;  c)  at 
the  ventricle-arterial  junction. 

I  <  no- A/rial  Junction 

In  adult  mammals  the  sinus  venosus  is  completely 
incorporated  in  the  atrium  and  there  are  only 
remnants  of  "valves"  which  are  incapable  of  prevent- 
ing backflow  into  the  superior  caval  vein  (valvula 
Eustachii)  or  in  the  coronary  sinus  (valvula  Thebesii). 
In  the  left  atrium  there  is  not  even  the  most  rudi- 
mentary valve  to  prevent  backflow  in  the  pulmonary 
veins.  Nevertheless,  there  are  some  structures  which 
may  contribute  to  prevent  backflow  from  the  atria, 
such  as  circular  muscle  fibers  around  the  pulmonary 
veins  and  the  coronary  sinus,  and  a  complex  system 
of  more  or  less  discrete  muscular  bundles  around  the 
orifices  of  the  caval  veins.  It  has  been  speculated  that 
these  fibers  contract  very  early  in  atrial  systole  and 
that  by  a  narrowing  of  the  orifices  a  valve-like  or 
sphincter-like  action  occurs  [see  also  Kjellberg  & 
Olsson  (91),  Burch  &  Romney  (28),  Campeti  et  al. 
(30)].  This  would  prevent  or  at  least  diminish  back- 
flow  of  blood  from  the  atria  into  the  venous  trees  at 
the  beginning  of  atrial  systole.  Although  backflow 
from  the  atria  into  the  caval  veins  can  be  frequently 
observed  and  quantitatively  registered  with  flow- 
meters (18)  and  contrast  media  (14),  the  amount  of 
backflow  is  surprisingly  small  as  compared  to  the 
amount  of  blood  simultaneously  pushed  by  the  atria 
into  the  ventricles.  The  precise  mechanism  by  which 
backflow  is  kept  so  small  is  still  enigmatic  (144).  An 
interesting  light  has  been  cast  upon  this  problem 
recently  by  Little  (101).  He  determined  pressure- 
volume  curves  in  the  left  atrium  of  dogs  during  tem- 
porary ventricular  asystole.  His  findings  suggest  that 
upon  a  slight  rise  in  atrial  pressure  above  the  pul- 
monary  venous   pressure    there   is   a   closure   of  the 


pulmonary  veins  near  their  atrial  junction.  This 
closure,  apparently  brought  about  by  collapse  of  the 
vein  in  a  critical  region,  prevents  regurgitation  of 
blood  from  the  atrium  into  the  pulmonary  bed. 
However,  at  high  atrial  pressures  the  closed  segment 
opens  and  blood  flows  into  the  pulmonary  veins. 

Atrioventricular  Valves 

The  atrioventricular  valves  are  funnel-shaped 
structures  inserted  on  a  fibrous  ring.  They  are  de- 
veloped as  an  ellipsoidal  diaphragm  and  separated 
by  commissures  into  somewhat  independent  cusps, 
the  edges  of  which  delineate  the  valvular  orifice 
(37,  38).  The  commissures  do  not  extend  all  the 
way  to  the  valve  ring  (see  fig.  3).  Traditionally,  one 
distinguishes  two  cusps  on  the  mitral  valve  and  three 
on  the  tricuspid  valve,  although  both  valves  es- 
sentially consist  of  two  large  opposite  cusps  and  a 
variable  number  of  small  intermediate  cusps  at 
each  end  of  the  ellipse  [see  also  Rusted  et  al.  (140)]. 
The  strands  of  collagenous  fibers  known  as  chordae 
tendineae  extend  from  the  papillary  muscles  either 
to  the  free  edge  of  the  cusps  (first  order  chords)  or  to 
a  few  millimeters  beyond  the  edge  (second  order 
chords),  or  even  quite  far  back  into  the  substance  of 
the  valve  through  a  kind  of  ''goose  foot"  forked 
insertion  (third  order  chords).  The  anatomy  of 
papillary  muscles  is  quite  variable.  One  usually 
recognizes  in  the  right  ventricle  three  groups  of 
papillary  muscles  to  which  the  tricuspid  valve  is 
fastened,  whereas  there  are  usually  two  such  groups 
to  fulfill  the  corresponding  function  in  the  left  ven- 
tricle. The  chords  are  of  unequal  length,  so  that 
probably  the  same  tension  is  exerted  on  each  at  the 
time  the  valve  closes.  The  chords  from  adjacent 
regions  of  opposite  cusps  are  inserted  on  the  same 
or  adjacent  papillary  muscles,  in  order  to  insure 
leakproof  closure  [see  also  Brandt  (15),  Hubacher 
(82)]. 

The  exact  mechanism  of  closure  of  the  atrioven- 
tricular valves  has  been  the  subject  of  much  debate 
[Kantrowitz  et  al.  (87)].  The  old  theory  of  closure 
mainly  by  active  contraction  of  the  papillary  muscles 
has  been  abandoned,  and  the  role  of  active  contraction 
of  muscular  fibers  at  the  base  of  the  valves  just  after 
atrial  systole  is  taken  as  either  minor,  or  nonexistent 
[see  also  Little  (100)].  The  decisive  factor  is  prob- 
ably the  onset  of  ventricular  contraction,  which 
establishes  a  higher  pressure  in  the  ventricle  than 
in  the  atrium.  It  can  be  shown  that  whenever  the 
ventricles   begin    to   contract,    there   is   a   retrograde 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


78. 


flow  of  blood  toward  the  atria  which  catches  the 
valves  like  a  pair  of  sails  and  flings  them  into  apposi- 
tion. As  pointed  out  by  Rushmer  ( 1 39)  this  mechanism 
inevitably  involves  a  leak  before  the  orifice  is  closed. 
The  occurrence  of  such  regurgitation  is  widely 
acknowledged  when  the  atrioventricular  valves  are 
closed  by  a  ventricular  systole  which  is  not  preceded 
by  atrial  contraction,  i.e.,  "premature  ventricular 
contraction"  [see  also  Paul  et  al.  (128)].  Since  the 
normal  wave  of  excitation  propagated  by  the  Purkinje 
fibers  enters  the  ventricular  myocardium  over  the 
endocardial  surface,  at  the  roots  of  the  papillary 
muscles,  the  early  contraction  of  papillary  muscles 
draws  the  valve  edges  toward  the  apex  and  thereby 
produces  some  shortening  of  the  ventricular  chamber 
with  a  resulting  passive  lateral  displacement  of  the 
ventricular  walls.  During  ventricular  ejection,  the 
decrease  in  ventricular  volume  is  accompanied  by  a 
further  shortening  of  the  papillary  muscles,  taking 
up  any  slack  in  the  valves  which  might  develop. 

It  has  been  suggested  that  under  normal  condi- 
tions, the  valves  approximate,  i.e.,  begin  to  close 
before  the  onset  of  ventricular  contraction,  although 
it  is  difficult  to  substantiate  this  view  by  chrono- 
logically precise  measurements.  Many  explanations 
have  been  advanced  for  this:  passive,  upward  move- 
ment of  the  valves  at  the  end  of  diastole  caused  by 
retrograde  flow  of  blood  along  the  ventricular  wall, 
or  by  elastic  recoil  of  the  ventricular  wall  to  the 
strain  of  atrial  systole  (8);  eddy  formation  beyond 
the  valves  during  atrial  systole  (102);  or  develop- 
ment of  a  wave  of  negative  pressure  as  atrial  inflow 
abruptly  ceases  [Henderson  &  Johnson  (70)]. 
Through  these  mechanisms,  the  atrioventricular 
valves  are  approximated  or  almost  closed  just  before 
ventricular  systole.  Then,  when  the  ventricular 
myocardium  contracts,  the  valves  are  completely 
closed  to  prevent  backflow  into  the  atria. 

The  concept  of  a  presystolic  approximation  of  the 
atrioventricular  valves  received  considerable  impetus 
when  Dean  (37)  succeeded  in  obtaining  direct  re- 
cording of  the  valve  movement  in  an  isolated,  sur- 
viving heart.  Dean  demonstrated  that  when  the 
interval  between  atrial  and  ventricular  systole  is 
sufficiently  long,  there  is  indeed  a  rapid  movement 
of  the  valves  toward  the  atrium  at  the  end  of  atrial 
systole,  followed  by  a  second  period  of  separation  of 
the  cusps  just  before  the  onset  of  ventricular  systole. 
When  the  period  of  ventricular  filling  is  shorter  (at 
faster  heart  rates)  there  is  no  time  to  observe  sepa- 
rately the  effects  of  atrial  systole  and  of  ventricular 
systole.  Then  there  is  '"only  a  single  closure  move- 


ment beginning  before  ventricular  systole,  a  single 
movement  due  in  part  to  auricular  contraction  and 
in  part  to  ventricular  contraction"   (37). 

The  extent  to  which  the  valves  and  their  attach- 
ments move  in  the  intact  organism  has  been  recently 
questioned  by  Rushmer  (139).  Having  observed  that 
exposed  or  excised  hearts  tend  to  shrink,  he  and  his 
associates  surmised  that  the  valves  might  have  much 
less  slack  under  their  normal  operating  conditions 
than  reported  by  previous  investigators.  They  used 
cinefluorography  to  observe  the  movements  of  the 
mitral  valves  which  had  been  marked  with  tiny  metal 
clips  at  a  previous  operation.  These  studies  demon- 
strated that  the  excursion  of  the  valves,  at  least  where 
the  metal  clips  were  placed,  toward  the  atrium  is 
remarkably  small,  and  pointed  to  a  more  or  less  con- 
tinuous restraint  by  the  chordae  tendineae. 

Arterial  Valves 

The  aortic  and  pulmonary  valves  consist  of  three 
symmetrical  cusps  attached,  similarly  to  suspension 
bridges,  around  the  circumference  of  the  valve  orifice 
(see  fig.  3).  When  the  cusps  are  approximated  they 
form  a  starlike  figure;  when  open,  they  delineate  a 
nearly  rounded  but  still  somewhat  triangular  orifice 
of  an  area  slightly  smaller  than  that  of  the  artery.  At 
the  tip  of  each  triangular  valve  leaflet,  where  the 
three  valve  leaflets  come  in  contact,  there  is  a  dis- 
crete thickening  called  the  nodulus  Arantii.  There 
are  also  thin,  membrane-like  structures  (lunulae) 
on  the  free  edges  of  the  valves  on  either  side  of  the 
noduli.  Normally  the  free  edges  come  into  contact 
surface  against  surface  rather  than  border  to  border. 
Toward  the  valvular  orifice,  the  ventricular  muscula- 
ture assumes  the  shape  of  a  funnel  (conus  arteriosus), 
whereas  bevond  the  valves  at  the  origin  of  the  aorta 
and  pulmonary  artery  there  are  three  outpouchings 
which  provide  some  free  space  behind  the  valve 
cusps  even  when  they  are  maximally  opened. 

The  mechanism  of  action  of  the  arterial  valves  can 
be  described  as  follows.  During  ventricular  ejection, 
the  blood  stream  opens  the  valves  from  below  and  a 
rapid  flow  is  established  along  the  axis  of  the  valvular 
orifices.  However,  the  valves  are  not  pushed  flush 
against  the  arterial  wall.  On  the  contrary,  eddy  cur- 
rents, generated  by  the  axial  jet  of  blood,  swirl  in  the 
spaces  behind  the  cusps.  Indeed,  the  action  of  turbu- 
lent eddies  is  such  that  the  faster  the  ventricular 
ejection,  the  closer  to  the  center  of  the  axial  stream 
the  valve  edges  are  brought  [Hochrein  (76)].  Thereby 
the  valves  are  prepared  to  close  almost  instantane- 


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ously  as  soon  as  ventricular  ejection  ceases.  It  is 
likely  that  contractions  of  muscle  fibers  in  the  conus 
arteriosus  tend  to  make  the  valve  rings  more  narrow 
during  ejection,  as  discussed  in  an  earlier  section.  In 
this  manner  axial  velocity  of  flow  is  increased  and 
turbulence,  which  may  prepare  the  valves  for  closure, 
is  enhanced.  At  the  end  of  systole  when  ejection 
ceases,  the  forward  movement  of  blood  in  the  root 
of  the  artery  continues  for  a  very  brief  period.  Then, 
the  action  of  the  eddies  on  the  upper  surface  of  the 
valves  prevails  over  the  force  exerted  from  below 
(rapidly  falling  intraventricular  pressure).  Hence 
the  retrograde  surge  of  blood  toward  the  ventricle 
(see  fig.  15)  is  arrested  by  valve  closure,  and  marked 
pressure  differences  between  the  relaxing  ventricle 
and  the  elastically  distended  aorta  can  develop. 


VENTRICULAR   AND   ATRIAL   VOLUMES 
IN  VARIOUS  ACTIVITIES 

Certainly  one  of  the  most  important  features  of  a 
pump  is  the  volume  which  can  be  propelled  per 
stroke.  This  is  easy  to  measure  in  a  mechanical  pump, 
but  it  requires  complex  and  sophisticated  instru- 
mentation to  determine  the  stroke  volume  of  the 
intact  heart.  Successful  attempts  in  this  direction  have 
recently  been  reported,  e.g  ,  by  Rushmer  ( 1 39)  and 
his  school,  by  Hawthorne  (67),  and  by  Olmstead 
(personal  communication).  Nevertheless,  numerous 
questions  remain  still  unanswered,  namely,  a)  the 
quantitative  correlation  of  the  stroke  volume  with  the 
other  parameters  of  cardiac  activity,  and  b)  the 
relationships  of  the  ventricular  stroke  volume  to  the 
volumes  remaining  in  or  passing  through  the  atria, 
the  ventricles,  and  the  large  vessels.  At  the  present 
time  most  of  these  questions  can  only  be  approached 
under  highly  controlled  situations  which  limit  the 
significance  of  the  experiment.  Discrepancies  are 
therefore  encountered  depending  upon  the  method  of 
approach  used.  At  this  point,  it  must  also  be  re- 
marked that  heart  volumes  have  traditionally  been 
measured  by  X-ray  or  cardiometer  techniques  which 
include  the  volumes  of  the  walls.  Only  recently  have 
radiopaque  dyes  and  other  media  been  developed 
which  permit  measuring  the  content  of  the  cardiac 
cavities  and  not  their  over-all  volumes  (56).  Conse- 
quently a  large  part  of  the  data  incorporated  in  the 
literature  require  critical  attention.  In  this  chapter, 
the  word  "volume"  refers  exclusively  to  the  liquid  con- 
tent of  the  cardiac  cavities  and  excludes  the  volume  oc- 


cupied by  the  walls  and  by  the  blood-filled  vessels  or 
channels  in  the  walls. 


I  'entricular  Volume 

To  describe  the  changes  in  ventricular  volumes 
under  dynamic  conditions,  it  is  advisable  to  review 
the  modern  terminology  introduced  bv  Rushmer 
(139).  This  terminology  is  illustrated  and  somewhat 
expanded  in  figure  20  by  drawing  a  parallel  between 
the  familiar  lung  volumes  (left)  and  the  ventricular 
volumes  (right). 

The  stroke  volume  of  the  organism  at  rest  corre- 
sponds to  the  tidal  volume  of  respiration.  In  exercise 
the  ventricle  can  also  eject  some  of  the  blood  which 
at  rest  would  remain  in  the  ventricular  cavity  at  the 
end  of  systole.  Rushmer  suggests  the  term  "systolic 
reserve  volume"  for  that  additional  amount  of  blood 
which  is  not  ejected  under  resting  conditions,  but  can 
be  maximally  ejected  with  a  more  forceful  contrac- 
tion. This  corresponds  to  the  expiratory  reserve 
volume  of  the  lungs.  The  volume  of  blood  left  in  the 
ventricle  after  a  normal  systole  used  to  be  called 
"residual  volume."  Rushmer  restricts  the  term 
residual  volume  to  that  amount  of  blood  remaining 
in  the  ventricle  after  maximal  ejection.  Then  the 
term  corresponds  truly  to  the  lung  residual  volume. 
The  ventricle  can  also  increase  its  stroke  volume  by  an 
augmented  venous  return  during  diastole  and  sub- 
sequent ejection  of  this  extra  volume  in  addition  to 
the  resting  stroke  volume.  The  term  "diastolic 
reserve  volume"  defines  the  maximal  amount  of 
blood  which  the  ventricle  can  receive  and  then  eject 
in  addition  to  the  normal  diastolic  inflow.  This 
volume  corresponds  to  the  inspiratory  reserve  volume 
of  the  lungs.  The  resting  stroke  volume,  systolic 
reserve  volume,  and  diastolic  reserve  volume  together 
define  the  maximal  stroke  volume,  which  corre- 
sponds to  the  vital  capacity  of  the  lungs. 

The  parallelism  can  be  carried  even  further  (fig. 
21).  In  the  resting  organism,  the  amount  of  blood 
remaining  in  the  ventricle  at  the  end  of  ejection 
(called  by  some  authors  the  "end-systolic  volume") 
would  best  be  referred  to  as  functional  residual  capac- 
ity since  it  is  now  customary  to  use  the  term  capacity 
for  the  sum  of  two  or  more  "volumes."  ("Capacity" 
does  not  imply  something  that  is  absolute  or  fixed, 
despite  the  unfortunate  analogy  suggested  by  the 
age-old  and  uneradicated  expression  "vital  capacity.") 
The  functional  residual  capacity  of  the  ventricle 
comprises  the  systolic  reserve  volume  plus  residual 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING  783 


fig.  20.  Scheme  of  lung  volumes  {left)  and  ventricular  volumes  (right)  at  rest  and  during  exercise 
or  sympathetic  stimulation.  For  details  see  text. 


fig.  31.  Scheme  of  lung  volumes  (left)  and  ventricular  volumes  (rig/it)  at  rest  to  illustrate   the 
parallelism  between  respiratory  and  ventricular  volumes. 


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CIRCULATION    II 


volume,  much  as  the  functional  residual  capacity  of 
the  lungs  comprises  the  expiratory  reserve  volume 
and  the  residual  volume.  Correspondingly,  the 
amount  of  blood  accumulated  in  the  ventricle  at  the 
end  of  ventricular  diastole  (often  called  the  end- 
diastolic  volume)  could  be  referred  to  as  '"diastolic 
capacity,"  including  the  stroke  volume  plus  systolic 
reserve  volume  plus  residual  volume.  Since  the  stroke 
volume  varies  with  changes  in  activity,  the  diastolic 
capacity  is  not  a  fixed  amount  but  functionally 
variable.  It  becomes  larger  as  the  stroke  volume 
increases  and  smaller  as  the  stroke  volume  decreases. 
There  are  two  more  terms  which  can  be  described  in 
parallelism  with  the  nomenclature  used  in  respira- 
torv  physiology.  The  volume  level  reached  at  the  end 
of  systolic  ejection  is  termed  '"end-systolic  level"  and 
corresponds  to  the  expiratory  level  of  the  lungs.  The 
volume  level  reached  at  the  end  of  diastolic  filling  is 
called  ""end-diastolic  level"  in  analogy  to  the  in- 
spiratory level  of  the  lungs. 

The  importance  of  a  clear  terminology  for  the 
description  of  the  dynamic  shifts  of  ventricular 
volumes  under  varying  conditions  of  activity  has 
been  pointed  out  by  Rushmer  (139)  and  many 
others  have  followed  his  lead.  The  parallel  with  the 
lung  volumes  also  permits  useful  analogies.  For  in- 
stance, an  increase  in  residual  volume  of  the  lungs 
in  emphysema  diminishes  the  ventilatory  efficiency. 
In  a  somewhat  similar  manner  an  increase  in  the 
ventricular  residual  volume,  such  as  occurs  in  ex- 
cessive ventricular  dilatation,  diminishes  the  pump- 
ing efficiency  of  the  heart. 

To  compare  with  the  cardiac  ventricles,  a  piston 
pump  would  need  the  following  features.  The  course 
of  the  piston,  which  defines  the  stroke  volume,  would 
have  to  be  limited  in  order  to  leave  fluid  in  the  pump- 
ing chamber  at  the  end  of  ejection  (functional 
residual  capacity).  If  a  greater  output  were  needed, 
the  piston  would  have  to  push  farther  and  increase 
its  stroke  volume  by  encroaching  upon  the  systolic 
reserve  volume.  Yet  the  volume  filling  the  dead  space 
of  the  pump  (residual  volume)  could  never  be  ejected. 
The  diastolic  reserve  volume  would  be  represented 
by  a  farther  pulling  back  of  the  piston  to  allow  greater 
filling  of  the  pump  chamber.  In  this  mechanical 
system,  the  need  for  a  greater  output  could  be  met 
instantaneously  by  the  ejection  of  part  of  systolic 
reserve  volume.  However,  the  diastolic  reserve 
volume  could  not  be  utilized  instantaneously  because 
the  pump  chamber  has  first  to  be  filled  to  a  greater 
extent  before  more  can  be  ejected.  The  situation 
seems  to  be  the  same  in  the  heart.  The  left  ventricular 


stroke  volume  can  be  increased  from  one  heart  beat 
to  the  next  by  drawing  upon  the  systolic  reserve 
volume,  as  occurs  for  instance  when  the  organism 
passes  abruptly  from  rest  to  exercise  (33,  139,  146). 
On  the  contrary,  the  mechanism  of  greater  diastolic 
filling  (Starling'.,  law)  always  involves  a  brief  delav 
brought  about  by  the  need  for  greater  venous  return 
before  increased  ejection.  Apparently,  onlv  in 
strenuous  exercise  and  in  some  pathological  condi- 
tions is  the  diastolic  reserve  volume  called  upon. 

Indeed  the  ventricular  stroke  volume  varies  almost 
continuously  and  is  not  identical  from  beat-to-beat 
even  under  resting  conditions.  Some  of  the  variations 
are  probably  caused  by  the  fluctuating  play  of  poorly- 
known  neural  feedback  processes.  Others  are  caused 
by  mechanical  forces  such  as  those  which  accompanv 
respiration.  In  fact  the  respiratory  variations  of  the 
ventricular  stroke  volume  are  remarkable  even  under 
resting  conditions  (21).  Figure  22  shows  the  typical 
changes  in  right  ventricular  output  during  five 
heartbeats  modified  by  the  action  of  one  respiratory 
cycle.  After  the  onset  of  inspiration,  .-1,  there  is  first 
an  increase  in  venous  inflow  (second  heartbeat)  and 
then  in  ventricular  stroke  volume  (third  heartbeat). 
Similarly,  the  drop  in  venous  return  during  expira- 
tion (at  the  fourth  heartbeat)  is  reflected  by  a  de- 
crease in  stroke  volume  one  beat  later.  From  this 
record  it  appears  that  the  right  ventricle  temporarily 
accommodates  part  of  the  large  inspiratory  inflow  of 
venous  blood,  and  releases  it  into  the  pulmonary 
circulation  during  the  respiratory  pause.  This  in- 
dicates that  with  respiration  not  only  the  stroke 
volume  varies  but  also  the  functional  residual  capacity 
(or  end-systolic  level ) . 

The  functional  residual  capacity  cannot  be  meas- 
ured directly  in  the  intact  organism.  Most  of  the  esti- 
mates obtained  with  indirect  methods  display  con- 
siderable variation  according  to  the  technique 
emploved.  The  volume  curves  shown  in  figures  16  and 
1 7  were  obtained  with  multiple  plane  high-speed 
X-ray  cinematography.  They  show  not  only  the 
volume  changes  throughout  the  cardiac  cycle,  but 
also  the  end-systolic  level.  The  functional  residual 
capacity  of  the  left  ventricle  of  these  12-kg  dogs 
amounts  to  approximately  5  to  6  ml.  In  unanes- 
thetized,  quiescent  dogs,  the  values  measured  were 
of  the  same  order  of  magnitude.  Gribbe  et  al.  (56,  57) 
estimate  that  on  the  average  the  stroke  volume  of 
dogs  is  60  per  cent  of  the  diastolic  capacity.  Thus 
functional  residual  capacity  amounted  to  40  per 
cent  of  the  diastolic  capacity.  It  should  be  pointed  out 
that    Gribbe's    values    are    much    smaller    than    tht 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


785 


fig.  22.  Effect  of  spontaneous  respiration  on  right  ventricu- 
lar stroke  volume,  measured  by  the  directly  recorded  pulmonary 
blood  flow  in  an  anesthetized  normal  dog.  The  simultaneously 
recorded  pattern  of  right  atrial  filling  (represented  by  superior 
vena  cava  flow),  arterial,  venous,  and  intrathoracic  pressures 
permit  a  time  correlation.  Tracings  from  top  to  bottom:  time 
and  base  line,  aortic  pressure  in  mm  Hg,  pulmonary  artery, 
superior  vena  caval  and  intrathoracic  pressures  in  mm  water, 
pulmonary  arterial  and  superior  vena  caval  flows  in  ml/min. 
A  =  beginning  of  inspiration;  S  =  acceleration  of  superior 
vena  caval  flow  during  ventricular  systole;  D  =  acceleration 
of  superior  vena  caval  flow  during  ventricular  diastole.  Stroke 
volume  (in  ml)  entered  under  pulmonary  arterial  flow  curve. 
Flow  (in  ml)  through  superior  vena  cava  during  each  cardiac 
cycle  entered  at  bottom  of  record.  Electrical  frequency  re- 
sponse of  both  flowmeters  reduced  from  400  to  40  cycles/sec. 
Superior  vena  caval  pressure  curve  damped.  [From  Brecher  & 
Hubay  (21).] 

estimates  of  Holt  (77)  with  dye  dilution  techniques, 
which  range  from  30  to  76  ml  for  a  dog  of  1 5  to  1 6  kg 
in  weight.  This  enormous  discrepancy  cannot  be 
reconciled  at  present.  Simultaneous  determinations 
under  rigidly  controlled  conditions  with  both  methods, 
the  cineangioradiography  and  the  indicator  dilution 
technique,  may  elucidate  this  point. 

That  the  situation  is  equally  unsettled  for  measure- 
ments in  man  is  shown  by  the  work  of  Rushmer 
(139),  Chapman  et  al.  (32),  Nylin  (122),  Reindell 
et  al.  (134),  Folse  et  al.  (47),  Luthy  (personal  com- 
munication, and  106).  Generally,  determinations 
using  roentgenologic  technique  furnish  smaller  values 
for  the  functional  residual  capacity  than  measure- 
ments with  dye  dilution  techniques.  For  instance, 
Folse  et  al.  (47),  employing  radio-iodinated  Diodrast, 
found  in  20  resting  persons  that  the  left  ventricular 


stroke  volume  averaged  42.2  ±  8.8  ml  per  m2  of  body 
surface  area.  The  diastolic  capacity  averaged  90  ± 
26  ml  per  m2  (functional  residual  capacity  48  ml/m2). 
On  the  other  hand,  Luthy  (106)  found  with  thermo- 
dilution  techniques  that  in  normal  patients  the  left 
ventricular  stroke  volume  amounted  to  45  ml  per 
m2  of  body  surface  (range  39-57  ml/m2)  but  the 
diastolic  capacity  to  145  ml  per  m2  (range  128-173 
ml/m2).  According  to  these  data  the  stroke  volume 
would  be  only  one-third  of  the  diastolic  capacity 
[39 %,  Folse  et  al.  (47);  31  ';,  Luthy  (106)]  whereas, 
in  the  dog  it  is  apparently  about  two-thirds  (60%, 
Gribbe). 

The  problem  is  further  complicated  by  the  fact 
that  the  ratio  of  stroke  volume  to  functional  residual 
capacity  changes  markedly  under  various  normal  and 
pathological  conditions.  This  is  well  illustrated  by 
the  observation  that  a  great  increase  in  resistance  to 
ventricular  ejection  (e.g.,  in  extreme  hypertension) 
causes  the  heart  size  to  become  much  larger  while 
the  stroke  volume  decreases.  This  implies  a  large 
increase  in  the  functional  residual  capacity.  Direct 
evidence  for  an  increase  in  functional  residual 
capacity  under  this  condition  is  the  observation  that, 
when  the  aortic  resistance  is  suddenly  reduced  by 
opening  of  an  arteriovenous  shunt,  the  first  stroke 
volume  is  twice  the  normal  size  [Hamilton  (61)]. 
From  the  foregoing  it  is  obvious  that  much  more 
information  based  on  direct  measurements  of  heart 
volumes  under  various  conditions  is  needed. 

Atrial  Volume 

The  volume  of  blood  contained  in  the  atrium  at 
any  time  has  evoked  much  less  interest  than  the 
ventricular  volume.  No  quantitative  information 
has  been  available  until  recently.  Even  the  termi- 
nology of  atrial  blood  volumes  is  more  difficult  to 
define  than  that  of  ventricular  volumes.  During  two 
phases  of  the  cardiac  cycle  (isovolumetric  contraction 
and  isovolumetric  relaxation),  the  ventricle  contains 
a  definite  volume  because  the  atrioventricular  and 
semilunar  valves  lock  the  ventricular  content.  The 
atria,  however,  are  always  open  on  the  venous  inflow 
side.  On  the  outflow  side  they  are  closed  only  from 
the  beginning  of  isovolumetric  ventricular  contraction 
to  the  end  of  isovolumetric  ventricular  relaxation. 
Consequently,  the  volume  contained  at  any  one 
instant  represents  the  balance  of  almost  continuously 
changing  inflow  and  outflow. 

The  changes  in  atrial  volumes  can  be  understood 
by  following  the  atrial  volume  curves  (open  circles) 


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CIRCULATION    II 


in  figures  16  and  17.  The  left  atrial  volume  is  greatest 
during  isovolumetric  relaxation  of  the  left  ventricle. 
During  the  rapid  ventricular  inflow*  phase  the  atrial 
volume  decreases  rapidly,  but  not  so  fast  as  the 
ventricle  fills.  This  indicates  that  some  blood  enters 
the  atrium  from  the  veins  while  at  the  same  time  a 
greater  amount  leaves  it  toward  the  ventricle.  During 
the  phase  of  slow  ventricular  inflow  (diastasis)  the 
atrial  volume  remains  practically  unchanged,  point- 
ing out  that  inflow  from  the  veins  and  outflow  toward 
the  ventricle  are  approximately  in  balance.  Inci- 
dentally, this  gives  a  measure  of  the  rate  of  venous 
return  to  the  atrium  during  this  phase  by  simply 
calculating  the  increase  in  ventricular  volume. 
During  atrial  systole  (approximately  end  of  P  wave 
of  electrocardiogram,  fig.  1 7)  the  atrial  volume 
decreases  precipitously.  The  rate  at  which  the  atrial 
volume  decreases  and  the  ventricular  volume  simul- 
taneously increases  speaks  in  favor  of  a  negligible 
backflow  of  atrial  blood  into  the  veins  during  atrial 
systole.  At  the  peak  of  atrial  systole  the  volume  of 
blood  contained  in  the  atrium  is  minimal,  but  still 
amounts  to  approximately  4  ml  in  dogs.  During  the 
phase  of  isovolumetric  ventricular  contraction,  the 
atrial  volume  already  begins  to  increase  owing  to 
an  accelerated  venous  inflow.  It  continues  to  increase 
at  a  rather  fast  rate  during  rapid  ventricular  ejection 
and  at  a  slower  rate  during  the  phase  of  reduced 
ventricular  ejection.  Whereas  the  ventricular  stroke 
volume  of  the  1 2-kg  dog  amounts  to  about  8  ml, 
the  difference  between  the  largest  and  smallest 
atrial  volume  amounts  to  only  5  ml.  This  indicates 
that  during  the  ventricular  rapid  and  slow  filling 
phases  approximately  3  ml  passes  from  the  veins 
through  the  atrium  into  the  ventricle  without  being 
recorded  as  an  atrial  volume  increase.  It  further 
indicates  that  during  ventricular  isovolumetric  con- 
traction, rapid  and  reduced  ventricular  ejection, 
about  5  ml  pass  from  the  veins  into  the  atrium 
while  the    atrioventricular   valves  are    closed. 

Obviously,  one  expects  during  exercise  a  greater 
accommodation  of  blood  in  the  atrium  during  ven- 
tricular ejection  and  a  greater  outflow  of  blood  from 
the  atrium  into  the  ventricle  during  the  ventricular 
rapid  and  slow  filling  phase.  There  are  still  no  meas- 
urements available  concerning  such  physiological 
adaptations.  It  appears  reasonable  to  suggest  that 
in  exercise  the  atrium  ejects  during  its  own  systole  a 
greater  volume,  thereby  drawing  upon  the  amount 
of  blood  usually  remaining  at  rest  in  the  atrium  at 
the  end  of  atrial  systole.  This  might  be  termed  the 
"atrial    systolic    reserve    volume." 


ATRIAL     FILLING 

The  phasic  changes  of  venous  return  which  bring 
about  atrial  filling  are  still  a  subject  of  debate.  It  is 
often  stated  that  venous  blood  returns  to  the  heart 
solely  as  a  result  of  the  force  imparted  to  it  on  the 
arterial  side  of  the  circulation  (vis  a  tergo).  Yet  there 
are  reasons  to  believe  that  the  systolic  contraction 
of  the  ventricular  myocardium  also  contributes  to 
atrial  filling  by  causing  an  expansion  of  the  atria 
[see  also  Hamilton  (60)  and  Holzlohner  (79)]. 
This  view-  was  originally  advocated  by  Purkinje 
(132)  who  observed  that  during  ventricular  systole 
the  atrioventricular  junction  (the  plane  of  the  heart 
valves)  descends  toward  the  apex  and  pulls  on  the 
atrial  walls.  The  atrial  cavity  is  then  passively  ex- 
panded and  the  pressure  in  it  drops,  causing  an 
acceleration  of  blood  from  the  veins  into  the  atria. 
Among  functional  anatomists,  the  concept  of  the 
attraction  of  blood  into  the  atrium  by  the  descent  of 
the  valvular  plane  toward  the  apex  during  ventric- 
ular systole  has  gained  great  favor.  By  injecting 
drops  of  radiopaque  contrast  material  into  peripheral 
veins  and  taking  X-ray  cinematographic  pictures, 
Bohme  (14)  could  demonstrate  a  remarkable  acceler- 
ation of  central  venous  flow  during  ventricular  sys- 
tole. Records  obtained  from  direct  measurements 
of  blood  flow  in  the  superior  and  inferior  venae  cavae 
with  a  high  fidelity  flowmeter  by  Brecher  &  Praglin 
(25)  and  by  Brecher  (19)  confirmed  Bohme's  ob- 
servations. It  appears  now  that  ventricular  contrac- 
tion does  cause  a  sudden  expansion  of  the  atrium. 
This  mechanism  lowers  the  pressure  in  the  atrium 
and  produces  the  X  wave,  much  as  a  plunger  with- 
drawn in  the  barrel  of  a  syringe  lowers  the  pressure 
therein.  The  expansion  of  the  atrium  probably  begins 
with  the  asynchronous  contraction  of  the  papillary 
muscles  during  the  early  part  of  the  isovolumetric 
phase  and  continues  during  rapid  ventricular  ejec- 
tion. In  the  hands  of  Rushmer  (136,  139)  the  lipiodol 
injection  technique  indicated  only  a  moderate  accel- 
eration of  caval  blood  flow  during  early  ventricular 
systole  [see  also  Lynch  (107)].  However,  Rushmer's 
findings  can  be  reconciled  with  those  of  Bohme  and 
Brecher,  if  one  considers  the  differences  in  the  various 
experimental  conditions  (open  or  closed  chest, 
anesthetized  or  awake  animals,  slow  or  fast  heart 
rate,  inspiration,  expiration,  volemic  status,  etc.). 
The  measurements  of  Gribbe  (56,  57)  in  intact  closed- 
chest  animals  definitely  indicate  an  increased  atrial 
inflow  beginning  at  isovolumetric  ventricular  con- 
traction  and  continuing  during  the  rapid  phase  of 


FUNCTIONAL  ANATOMY  OF  CARDIAC  PUMPING 


787 


ventricular  ejection  (see  atrial  volume  curve  in 
fig.  16  and  superior  vena  cava  flow  curve  in  fig.  22). 
In  Chapter  1 7,  vol.  I,  of  this  Handbook,  evidence  is 
given  that  in  normal  man  the  venous  stream  toward 
the  heart  pulsates  reciprocally  to  the  aortic  stream 
leaving  the  chest.  The  exactitude  of  the  reciprocal 
relationship  is  said  to  be  measured  by  the  very  small 
volume  equivalent  of  the  cyclic  changes  (cardiac)  in 
intrathoracic  pressure  after  making  allowance  for 
the  elasticity  of  the  chest  walls  (60,  64). 

In  conclusion,  the  filling  of  the  atrium  during  ven- 
tricular systole  depends  not  only  upon  the  pressure 
of  blood  in  the  venous  reservoir  which  is  available 
for  passive  filling  from  behind;  it  depends  also  on 
the  vigor  with  which  ventricular  systole  moves  the 
atrioventricular  junction.  Thus  a  more  forceful  con- 
traction (commonly  associated  with  a  larger  stroke 
volume)  ensures  additional  inflow  into  the  atrium 
and  therefore  facilitates  the  next  ventricular  ejection 
without  the  need  for  further  decreasing  the  systolic 
reserve  volume  to  maintain  a  large  stroke  volume. 
The  increase  in  ventricular  outflow  and  in  atrial 
inflow  are  mediated  by  the  same  force,  ventricular 
contraction,  and  both  favor  a  more  thorough  filling 
of  the  ventricle  during  the  next  diastole. 

The  central  veins  are  most  suitable  for  this  reser- 
voir function  because  through  partial  collapse  of 
their  walls,  their  content  can  change  rapidly  without 
much  change  of  pressure.  They  form  a  collapse 
chamber  which  is  the  functional  counterpart  of 
the  aortic  compression  chamber  (18).  On  the  ar- 
terial side,  the  compression  chamber  based  on  the 
elastic  distensibility  of  the  walls  assures  the  trans- 
formation of  the  discontinuous  cardiac  ejections  into 
steady  flow  to  the  tissues.  On  the  venous  side,  the 
collapse  chamber  based  on  the  pliability  of  the  walls 
assures  at  the  atrial  entrance  the  transformation 
of  the  steady  flow  from  the  tissues  into  the  pulsatile 
flow  which  is  needed  for  the  discontinuous  cardiac 
filling  [see  also  Irisawa  et  al.  (83)]. 

The  filling  of  the  venous  collapse  chamber  is  in 
turn  aided  by  the  atrial  systole.  From  a  hemodynamic 
standpoint  the  function  of  atrial  contraction  is  two- 
fold: /)  It  ejects  some  blood  into  the  ventricular 
cavity,  a  well-established  fact,  and  2)  it  passively 
enlarges  the  central  venous  reservoir  by  briefly- 
slowing  down  or  stopping  atrial  inflow.  The  small 
amount  of  backflow  which  is  often  recorded  during 
atrial  systole  at  the  caval-atrial  junction  normally 
does  not  extend  far  into  the  periphery  (18).  It  is 
readily  taken  up  by  a  widening  of  the  collapse 
chamber   and,    together  with   the   continued    inflow 


from  the  periphery,  creates  the  pool  from  which  the 
next   ventricular   filling   derives   its   supply. 

Any  force  which  lowers  pressure  in  a  region  toward 
which  flow  occurs,  is  called  suction,  whether  or  not 
the  pressure  developed  in  that  region  drops  below 
atmospheric  zero.  Physically  "suction"  is  the  same 
as  pressure  (force  per  area).  It  is  a  reduction  of  pres- 
sure at  some  point  in  a  system  by  the  application  of  a 
force  which  results  from  an  energy  conversion  proc- 
ess, e.g.  muscular  contraction,  elastic  recoil,  pulling 
of  a  plunger.  Since  blood  is  attracted  into  the  atrium 
by  ventricular  contraction,  one  may  therefore  state 
that  atrial  filling  is  at  least  in  part  brought  about 
by  suction  upon  the  venous  blood  mediated  through  a 
stretching  and  enlargement  of  the  atrial  cavity  by 
the  contracting  ventricular  muscles  which  cause  a 
descent  of  the  atrioventricular  junction.  This  phe- 
nomenon can  be  termed  ''ventricular  systolic  suction" 
upon  the  atrial  content. 

[A  semantically  more  rigid  definition  of  the  concept  of 
"suction"  holds  that  suction  can  be  thought  of  only  in  locations 
where  the  transmural  pressure  is  negative  (142).  Accordingly 
suction  cannot  be  transmitted  through  viscera  (atria,  veins) 
which  have  collapsible  walls.  As  long  as  these  viscera  contain 
blood  at  a  greater  pressure  (including  equivalent  kinetic  energy) 
than  the  extra  visceral  pressure,  the  dominant  force  is  "pressure" 
from  upstream  rather  than  "suction"  from  downstream.  This 
pressure  maintains  the  walls  of  the  atria  and  intrathoracic  veins 
under  elastic  tension  during  the  entire  cardiac  cycle.  Ed.] 

When  the  atrioventricular  valves  open  during 
ventricular  diastole,  there  is  another  decrease  in 
atrial  pressure  (Y  wave),  which  results  once  more 
in  an  acceleration  of  venous  blood  inflow  into  the 
atrium.  This  second  acceleration  is  more  pronounced 
at  slow  heart  rates  and  is  usually  greater  in  closed- 
chest  than  in  open-chest  animals.  Apparently  the 
expansion  of  all  the  cardiac  cavities  through  the 
pulling  force  of  the  lungs  [Pfuhl  (129,  130)]  helps 
to  make  the  atrial  inflow  during  ventricular  diastole 
slightly  greater  than  during  ventricular  systole.  The 
increase  in  atrial  inflow  during  ventricular  diastole 
may  also  be  a  consequence  of  the  attraction  of  atrial 
blood  into  the  ventricle  through  the  forces  which 
expand  the  ventricle  during  diastole  (ventricular 
diastolic  suction,  see  following  section).  These  forces 
not  only  affect  the  blood  contained  in  the  atrium 
but  in  turn  even  affect  the  adjoining  veins  by  lowering 
the  atrial  pressure,  particularly  during  the  phase  of 
rapid  ventricular  filling.  Figure  22  illustrates  the 
phasic  increases  in  superior  vena  caval  flow  during 
ventricular  systole  (S)  and  during  ventricular  diastole 
(D)  in  an  anesthetized  closed-chest  dog. 


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CIRCULATION    II 


In  summary,  ventricular  myocardial  contraction 
could  have  a  threefold  effect  upon  atrial  filling: 
/)  It  imparts  so  much  energy  to  the  arterial  stream 
that  even  after  passing  through  the  capillaries,  the 
blood  continues  to  flow  in  the  veins  and  fills  the  cen- 
tral reservoirs;  2)  during  ventricular  systole  blood 
is  drawn  actively  into  the  atrium  through  an  expan- 
sion of  the  atrial  cavities  by  a  movement  of  the  atrio- 
ventricular junction  toward  the  apex  ("ventricular 
systolic  suction");  j)  during  ventricular  diastole 
the  elastic  forces,  created  by  the  preceding  systole 
in  the  ventricular  walls,  can  aid  in  drawing  blood 
from  the  atrium  into  the  ventricle  and  even  in  attract- 
ing blood  from  the  veins  into  the  atrium  ("ventric- 
ular  diastolic   suction"   upon   the   atrial   content). 


VENTRICULAR    FILLING 

While  the  forces  causing  ventricular  ejection  are 
unquestionably  those  originating  from  myocardial 
contraction,  there  is  considerable  debate  concerning 
the  forces  responsible  for  ventricular  filling  [for  de- 
tails see  Brecher  (19),  Krug  &  Schlicher  (95),  El- 
dridge  &  Hultgren  (41),  Bauereisen  et  al.  (7)]. 
The  ejection  of  fluid  from  a  pump  is  more  spec- 
tacular than  the  filling  phase.  This  may  be  the  reason 
why  the  forces  dealing  with  ventricular  contraction 
have  received  considerably  more  attention  than  the 
forces  dealing  with  ventricular  filling.  For  a  long 
time  it  has  been  believed  that  the  heart  is  filled  ex- 
clusively by  a  force  which  pushes  blood  into  the  ven- 
tricle from  behind  [vis  a  tergo,  Galli  (50)].  This 
force  results  from  the  preceding  ventricular  contrac- 
tions and  is  imparted  to  the  blood  for  circulating  it 
through  the  arteries,  capillaries,  and  veins.  Others 
have  maintained  that  some  part  of  ventricular  filling 
is  produced  by  a  force  from  the  front  (vis  a  fronte) 
which  attracts  or  sucks  blood  from  the  atrium  into 
the  ventricle.  This  force  would  manifest  itself  in 
the  ventricle  during  diastole  and  would  probably  be 
caused  by  an  elastic  recoil  of  the  ventricular  walls. 
It  would  lower  the  intraventricular  pressure  below 
the  level  which  would  prevail  if  such  a  vis  a  fronte 
did  not  exist.  The  history  of  the  issue  between  vis  a 
tergo  and  vis  a  fronte  is  treated  in  detail  by  Ebstein 
(40),  Hamilton  &  Lombard  (64),  Bohme  (14), 
Brecher  (19,  20),  Krug  &  Schlicher  (95).  One  can 
summarize  as  follows  the  evidence  in  favor  of  the 
existence  of  a  vis  a  fronte:  Ventricles  of  cold-blooded 
animals,  in  the  observations  of  Kraner  &  Ogden  (94), 
Kraner  (93),  Hennacy  &  Ogden  (73),  Hennacy  (72), 


Peiper  &  Weigand  (131),  and  of  mammals  according 
to  Bloom  (13),  Fowler  et  al.  (48,  49)  Brecher  (19),  and 
O'Brien  (123),  can  definitely  suck  in  blood  when  the 
filling  pressure  at  the  atrioventricular  orifice  is  atmos- 
pheric (zero)  or  subatmospheric  (negative).  Whether 
or  not  ventricular  suction  also  contributes  to  ventricu- 
lar filling  in  the  presence  of  a  positive  filling  pressure 
at  the  atrioventricular  orifices  has  not  yet  been  experi- 
mentally established. 

It  has  been  objected  that  the  ventricles  in  which 
suction  forces  were  demonstrated  had  an  abnormally 
small  functional  residual  capacity.  The  question  there- 
fore arises  whether  or  not  ventricles  with  physiological 
volumes  would  also  exert  a  suction  force.  Scheu  & 
Hamilton  (143),  using  the  intact  spontaneously 
breathing  anesthetized  dog,  made  simultaneous  re- 
cordings of  the  intraventricular  and  thoracic  pres- 
sure and  thus  established  the  transmural  ventricular 
pressure  gradient.  They  held  that  "suction,"  prob- 
ably by  the  elastic  recoil  of  the  ventricular  walls, 
could  be  demonstrated  only  if  and  when  the  trans- 
mural pressure  was  negative.  They  concluded  that 
suction  did  not  occur  during  normal  diastole  but 
could  be  brought  about  by  compressing  the  mitral 
orifice  or  by  hemorrhage.  These  two  maneuvers 
made  the  diastolic  ventricular  shadow  smaller  and 
were  thought  to  have  reduced  the  residual  blood  to  a 
subnormal  figure. 

Brecher  &  Kissen  (23)  demonstrated  that  dog 
ventricles  of  an  approximately  normal  functional 
residual  capacity  filled  by  suction  at  zero  ventricular 
inflow  pressure.  Nevertheless,  as  long  as  there  is  not 
unequivocal  experimental  proof  of  the  existence  of 
ventricular  diastolic  vis  a  ironte  in  the  unanesthe- 
tized  intact  mammalian  organism,  one  should  be  ex- 
ceedingly cautious  with  any  statement  concerning 
the  role  of  diastolic  suction  in  ventricular  filling 
[Brecher  (20)]. 

Horres  and  his  group  (unpublished  observations) 
determined  the  average  left  ventricular  volumes  of 
excised  submerged  hearts  at  equilibrium  state  and 
found  it  to  be  17  (±6)  ml  for  dogs  weighing  12  kg 
(fig.  23).  If  one  assumes  that  the  elastic  equilibrium 
state  of  the  relaxed  ventricle  in  vivo  is  the  same 
as  that  of  the  freshly  excised,  and  still  responding 
ventricle  in  vitro,  then  diastolic  ventricular  suction 
could  occur  at  any  ventricular  volume  below  the 
equilibrium  point  (i.e.,  less  than  17  ml).  Unfor- 
tunately the  values  of  the  functional  residual  capac- 
ity reported  for  the  dog  heart  vary  too  much  to  per- 
mit an  unbiased  conclusion  about  the  role  of  suction 
in  ventricular  filling.  According  to  the  data  of  Holt 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


789 


40- 

• 

30- 

e 

0 

> 

• 

•             ** 

^^^LEFT 

^/ventricle 

*^r     V  V  LEFT  = 
^r      -0.80*1.68   BW 

20- 

UJ 

CL 

■z 
> 

•£ 

0                            +S 

m    /   • 

B9^9                    •                      RIGHT 

VENTRICLE 

^,''''v.V.    RIGHT  = 
-.^-"             6.26  +0.67  BW 
0                               0 
0 

10- 

c 

0 

0 

o° 

BODY      WT       kg 

1 
6 

10                    14 

18 

1           1           '           I 

22           26 

fig.  23.  Relationship  of  ventricular  volume  (VV)  and  body 
weight  (BW)  in  dogs.  Ventricular  volume  measured  at  the 
equilibrium  state  (zero  transmural  pressure).  [See  also  fig.  2 
(Horres  et  al.,  unpublished  obser%'ations).] 

(77)  the  average  functional  residual  capacity  of  the 
left  ventricle  would  be  approximately  30  ml  for 
dogs  weighing  12  kg.  According  to  Gribbe  et  al. 
(57),  it  is  only  5  ml.  The  discrepancy  between  Holt's 
and  Gribbe's  measurements  in  terms  of  ventricular 
diastolic  suction  is  illustrated  in  figure  24.  If  Holt's 
data  are  correct,  ventricular  diastolic  suction  never 
occurs  under  normal  conditions.  On  the  contrary 
Gribbe's  figures  speak  for  the  occurrence  of  diastolic 
ventricular  suction  during  all  phases  of  diastole. 
Obviously  the  controversy  cannot  be  resolved  on 
the   basis   of  presently   available  data. 

There  has  been  some  speculation  about  the  pos- 
sible nature  of  the  frontal  force,  particularly  whether 
it  originates  from  an  active  or  a  passive  process. 
An  active  process  would  be  the  contraction  of  muscle 
fibers  which,  owing  to  their  anatomical  arrangement, 
could  widen  the  ventricular  cavity  during  diastole 
[Guasp  (58)].  There  is  no  experimental  evidence  to 
support  such  a  view.  Another  active  process  would 
be  the  development  of  a  force  acting  to  lengthen  the 
muscle  fibers  upon  completion  of  their  contraction 
("active  decontraction").  However,  it  has  never 
been  satisfactorily  demonstrated  that  processes  of 
energy  conversion  from  chemical  to  kinetic  energy 
occur  during  muscular  relaxation  [Villa  (152); 
for  review,  Brecher  (19,  20)].  The  most  acceptable 
evidence  is,  at  present,  that  the  diastolic  ventricular 
vis  a  fronte  is  caused  by  passive  processes,  such  as 
one  of  the  following,  a)  During  systole  an  interfas- 
cicular tension  develops  through  shear  forces  be- 
tween myocardial  strands  which  contract  to  different 
extents  and  asynchronously  [details  in  Rushmer 
(•39)]-  f>)  During  systole  noncontractile  elements  in 


the  heart  and  possibly  also  some  components  of  the 
muscle  fibers  are  elastically  deformed  beyond  their 
equilibrium  state,  thereby  storing  potential  energy 
which  is  released  through  elastic  recoil  during  diastole 
(see  fig.  2).  c)  In  the  closed-chest  mammal,  additional 
external  forces  residing  in  the  elastic  recoil  of  the 
lungs  exert  their  effect  upon  the  heart  by  tending  to 
expand  the  cardiac  cavities  beyond  the  size  these 
cavities  would  assume  in  the  absence  of  the  lung 
forces. 

In  conclusion,  some  of  the  classical  views  concern- 
ing the  filling  of  the  heart  may  need  revision.  The 
ventricle  acts  as  a  reciprocating  pump  in  which  the 
output  stroke  simultaneously  provides  energy  for 
the  filling  of  the  pump  for  the  next  stroke.  In  other 
words,  the  heart  does  not  act  merely  as  a  pressure 
pump  as  William  Harvey  (66)  believed,  but  it  actu- 
ally functions  as  a  pressure-suction  pump  [see  also 
Gauer,  (52,  53)].  The  amount  of  energy  necessary 
for  pump  filling  is,  however,  only  a  fraction  of  that 
needed  for  ejection,  since  the  filling  occurs  through  a 
fluid  transfer  into  a  low  resistance  system  in  which 
small  pressure  differences  will  cause  a  rapid  flow  of 
large  amounts  of  blood. 


DIFFERENCES    BETWEEN    RIGHT    AND 
LEFT    CARDIAC    CAVITIES 

Functional  differences  between  the  right  and  left 
cardiac  cavities  can  be  expected  from  their  anatom- 
ical characteristics.  Yet  it  had  long  been  tacitly 
assumed  that  the  two  atria  and  the  two  ventricles 
initiate  and  terminate  their  contraction  simultane- 
ously, and  that  a  description  of  cardiac  events  on 
both  sides  would  be  redundant. 

In  fact,  there  are  significant  differences  between 
the  left  side  and  the  right  side  chambers  [see  also 
Katz  (89),  Hamilton  et  al.  (62),  Luisada  &  Fleischner 
(103),  Segers  (145),  Braunwald  et  al.  (16),  McKusick 
(109)].  For  instance,  at  equal  pressures  the  right 
atrium  has  a  volume  twice  that  of  the  left  atrium, 
which  is  thicker  and  less  distensible  than  the  right 
(99).  Experimentally,  the  volume-pressure  curve 
relationship  in  the  left  atrium  has  been  found  to  be 
linear  only  as  long  as  the  pressure  remains  within 
the  normal  limits  (pressure  below  150  mm  H20). 
When  this  limit  is  exceeded,  a  slight  increase  in 
volume  causes  a  much  larger  increase  in  pressure. 
The  normal  level  and  patterns  of  pressure  also 
differ  somewhat  between  the  right  and  the  left 
atrium.  The  A  wave  of  the  right  atrium,  produced 


79° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  24.  Functional  residual  capacity 
of  the  clog's  ventricle  and  its  relation  to 
ventricular  diastolic  suction.  Lejt:  data 
derived  from  Holt  (77),  assuming  that  a 
functional  residual  capacity  of  50  ml  in 
a  20.9-kg  dog  corresponds  to  30  ml  in 
a  12-kg  dog  (regression  line  of  fig.  23). 
Right:  data  of  Gribbe  et  al.  (56)  for  a 
12-kg  dog.  Center:  elastic  equilibrium 
state  of  the  ventricle  in  a  12-kg  dog 
(Horresf/  al.,  unpublished  observations). 


FUNCTIONAL  RESIDUAL  CAPACITY 


HOLT 
(in  vivo) 


t 


NO 

SUCTION 

I 

I 
I 

NEUTRAL  POSITION 


I 

(ELASTIC  EQUILIBRIUM; 

I 

I 
SUCTION 


HORRES  et  al, 
(in  vitro) 


FUNCTIONAL  RESIDUAL  CAPACITY 


GRIBBE  et  al  . 
(in  vivo) 


ml 
30 


by  atrial  systole,  is  often  not  so  steep  and  tall  as  that 
of  the  left  atrium,  and  normally  precedes  it  slightly. 
The  peak  of  the  right  atrial  V  wave  is  usually  lower 
than  that  of  the  left  atrial  V,  and  the  mean  right 
atrial  pressure  is  usually  less  than  the  left  atrial 
pressure. 

At  the  level  of  the  ventricles  the  bundles  of  myo- 
cardial fibers  which  encircle  the  two  cavities,  much 
as  the  windings  of  a  turban,  belong  to  a  common 
anatomical  structure.  The  combined  effect  of  their 
contraction  is  to  wring  blood  out  of  the  ventricular 
chambers  into  the  respective  arteries.  Yet  the  mus- 
cular arrangement  is  such  that  contraction  of  the 
left  ventricle  produces  primarily  a  reduction  in  the 
lateral  diameter  with  only  a  moderate  shortening 
along  the  vertical  axis,  whereas  on  the  right  side 
there  is  much  ventricular  shortening  between  apex 
and  base  with  relatively  less  pulling  of  the  free  wall 
toward  the  septum.  The  mechanical  effects  of  left 
ventricular  contraction  occur  a  trifle  earlier  than 
those  of  right  ventricular  contraction,  since  the  rise 
in  right  ventricular  pressure  usually  lags  by  0.01 
to  0.02  sec  behind  the  rise  in  left  ventricular  pressure 
(see  also  fig.  19).  It  is,  therefore,  understandable 
that  mitral  valve  closure  usually  precedes  tricuspid 
valve  closure.  Nevertheless,  it  is  by  no  means  es- 
tablished whether  the  later  start  of  right  ventricular 
contraction  is  the  only  cause  of  asynchronicity. 
Other  factors  could  also  operate,  such  as  a  faster 
rate  of  contraction  of  the  left  ventricular  wall  or  a 
quicker  reaction  of  the  mitral  cusps  to  the  rising 
wave  of  pressure  in  comparison  with  the  tricuspid 
valve.   The  characteristics  of  the  vascular  bed  into 


which  ejection  proceeds  cause  differences  in  the  se- 
quence of  pumping  events  on  the  right  and  on  the 
left  side.  Since  the  pressure  in  the  pulmonary  artery 
is  low  (low  resistance  to  flow  in  the  pulmonary  vas- 
cular bed),  the  pulmonary  valve  opens  first.  Indeed, 
for  an  interval  of  about  0.02  sec,  the  ventricular 
contraction  produces  an  ejection  on  the  right  side 
while  there  is  still  an  isovolumetric  pressure  rise 
on  the  left  side.  Similarly,  right  ventricular  ejection 
continues  well  after  cessation  of  left  ventricular  ejec- 
tion. In  other  words,  the  end  of  left  ventricular 
systole  precedes  that  of  the  right  and  closure  of  the 
aortic  valve  precedes  closure  of  the  pulmonary  valve. 
On  the  other  hand,  because  of  a  much  longer  phase 
of  isovolumetric  relaxation  in  the  left  ventricle  as 
compared  to  the  right,  the  opening  of  the  mitral 
valve  is  thought  to  follow  that  of  the  tricuspid,  as 
seen  in  table  1,  which  is  borrowed  from  Luisada  & 
Liu  (104)  and  summarizes  the  sequence  of  events  of 
right  and  left  ventricular  contraction  (see  also  figs. 
18  and  19). 

Because  of  these  differences  in  the  pumping  action 
of  the  ventricles,  reference  is  often  made  to  right 
and  left  ventricles  as  being  a  ''volume  pump"  and 
"pressure  pump,"  respectively.  Implied  in  this  no- 
menclature are  the  facts  that  the  right  ventricle 
can  easily  handle  an  increase  in  volume  output  with- 
out apparent  strain,  whereas  it  is  not  so  well  equipped 
for  raising  its  pressure  to  a  high  level.  On  the  con- 
trary, the  left  ventricle,  with  a  much  larger  mass 
of  active  musculature  and  a  more  nearly  spherical 
geometry  is  better  able  to  face  an  increase  in  out- 
flow   resistance    than    the    right    ventricle.    What    is 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


79' 


Interval, 
in  Sec 

0.06-0 

.07 

O.OO-O 

.02 

0.01-0 

•03 

0.01-0 

.02 

0.02 

0.03-0 

,04 

0.04-0 

.08 

0 . 00-0 

.04 

0 . 04-0 

.08 

table  i .  The  Cardiac  Cycle.  Time  Intervals  Between 
Valvular  Motions  (Normal  Dogs) 

Event 

Q  wave  (ECG) 
Closure  of  mitral  valve 
Closure  of  tricuspid  valve 
Opening  of  pulmonic  valve 
Opening  of  aortic  valve 

Closure  of  aortic  valve 
Closure  of  pulmonic  valve 
Opening  of  tricuspid  valve 
Opening  of  mitral  valve 
Rapid  filling  of  right  ventricle 
Rapid  filling  of  left  ventricle 

Each  peak  of  rapid  ventricular  filling  follows  A-V  valve 
opening  by  0.08-0.10  sec,  and  the  closure  of  the  respective 
semilunar  (i.e.,  pulmonary  or  aortic)  value  by  0.12-0. 18 
sec.  This  table  shows  the  sequence  of  events  in  normal, 
large  dogs,  whose  figures  are  probably  very  close  to  those  of 
normal  man.  [From  Luisada  &  Liu  (104).] 

meant  by  the  terms  "volume  pump"  and  "pressure 
pump"  is  actually  "low-pressure  head  pump"  and 
"high-pressure  head  pump." 

There  is  no  fundamental  difference  in  the  pump- 
ing action  of  the  two  ventricles  before  birth.  They 
both  receive  blood  from  a  common  atrial  chamber, 
their  walls  are  of  the  same  thickness,  they  have  the 
same  capacity,  and  they  both  eject  their  contents 
into  a  common  aortic  chamber  via  either  the  ductus 
arteriosus  or  the  ascending  aorta.  The  pressure  against 
which  the  fetal  ventricles  eject  their  contents  is  lower 
than  that  in  the  adult  systemic  circuit,  but  after 
birth  the  resistance  in  the  lesser  circuit  drops  sud- 
denly with  the  first  breath,  whereas  that  in  the  sys- 
temic circuit  gradually  increases.  The  difference 
in  pumping  action  that  prevails  in  the  normal  adult 
exists  essentially  because  of  the  difference  in  resist- 
ance to  flow. 

In  the  adult  the  resistance  to  flow  in  the  pulmonary 
vascular  bed  is  estimated  to  be  only  about  one- 
eighth  of  that  in  the  systemic  circulation.  On  the 
other  hand,  it  is  estimated  that  a  sizable  amount  of 
the  mechanical  energy,  both  pressure  and  kinetic, 
imparted  to  the  blood  by  left  ventricular  ejection 
is  still  available  at  the  point  of  venous  inflow  into 
the  right  ventricle,  and  is  partly  responsible  for  right 
ventricular  filling  and  distention  during  diastole 
(vis  a  tergo).  Connecting  these  two  observations, 
one  may  wonder  whether  right  ventricular  contrac- 
tion is  necessary  at  all,  or  whether  the  left  ventricle 
alone  could  not  only  circulate  the  blood  through  the 
systemic  vascular  bed  but  also  through  the  pulmonary 


vascular  bed.  The  problem  has  been  approached  in 
different  ways.  It  was  first  observed  that  major  de- 
struction of  the  right  ventricular  wall  (by  cauteriza- 
tion, for  instance)  causes  but  slight  changes  in  sys- 
temic venous  and  arterial  pressure  [Bakos  (5), 
Kagan  (86)].  Yet  a  doubt  remains,  since  some  inner 
layers  of  the  right  ventricular  wall  are  left  intact 
in  such  experiments,  and  conceivably  contractions 
of  muscular  bundles,  which  belong  to  the  left  ven- 
tricular wall,  could  still  pull  on  passive  strands  of 
the  remaining  right  ventricular  wall  and  thus  in- 
directly eject  blood  through  the  pulmonary  ostium. 
In  such  a  case,  the  noncontracting  cauterized  re- 
mainder of  the  right  ventricular  wall  would  passively 
compress  the  half-moon-shaped  right  ventricular 
cavity.  Also,  the  still  intact,  powerful  ventricular 
septum  could  contribute  to  the  right  ventricular 
systolic  pressure  rise.  Acute  experiments  in  which  the 
entire  heart  is  arrested  and  only  the  left  ven- 
tricle, but  not  the  right,  is  replaced  by  a  mechanical 
pump,  indicate  that  apparently  stable  circulatory 
conditions  in  both  the  systemic  and  the  pulmonary 
vascular  beds  can  be  maintained  using  a  single  "left 
ventricle"  pump  [see  also  Rodbard  &  Wagner 
(137),  Jamison  et  al.  (85),  Warden  et  al.  (154), 
Patino  (•/  al.  (127),  Xuland  et  al.  (121),  Monod- 
Broca  (115),  Glenn  (55)].  Obviously,  the  pressure 
in  the  vena  cava  is  then  raised  to  maintain  sufficient 
pressure  for  the  pulmonary  circulation,  and  there 
may  be  an  impairment  to  cerebral,  coronary,  and 
hepatic  venous  outflow.  However,  the  conditions  are 
compatible  with  survival  of  the  animal.  The  question 
is  not  solely  of  academic  interest,  since  it  is  not  im- 
possible to  envision  that  some  day  surgical  tech- 
niques will  be  devised  to  drain  the  entire  systemic 
venous  return  directly  into  the  pulmonary  artery, 
thereby  placing  the  entire  load  of  circulation  on  the 
left  ventricle. 


the  pericardium 

The  function  of  the  pericardium  in  the  cardiac 
pumping  process  has  been  the  subject  of  much  de- 
bate. Some  authors  consider  that  the  pericardium 
does  not  affect  cardiac  performance,  because  con- 
genital absence  of  this  structure  in  man  is  compat- 
ible with  maintenance  of  a  seemingly  normal  cardiac 
function  [see  Ellis  et  al.  (43)  and  Hering  et  al.  (74)]. 
Others  have  speculated  that  the  primary  function  of 
the  pericardium  is  to  confine  in  space  the  pumping 
structures  which  are  characterized  by  their  expansi- 


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CIRCULATION    II 


bility,  pliability,  and  limited  anchorage  [see  Pfuhl, 
(129)  and  Nelemans  (118)].  A  number  of  additional 
functions  have  been  ascribed  to  the  pericardium, 
namely :  protection  of  the  entire  heart  from  over- 
dilatation;  protection  from  overdilatation  of  the  left 
ventricle  only;  protection  from  overdilatation  of  the 
right  ventricle  only;  increase  of  cardiac  performance 
because  of  higher  filling  pressure;  better  harmonic 
coordination  of  right  and  left  ventricular  contrac- 
tions; facilitation  of  atrial  filling;  and  facilitation  of 
the  gliding  of  the  epicardium  through  lymph  lubrica- 
tion. 

Most  experimental  studies  on  the  function  of  the 
pericardium  concern  abnormal  situations  such  as 
are  met  in  pericardial  effusion  and  tamponade 
from  various  other  causes  [Feinberg  (46),  Adcock 
et  al.  (1),  Evans  et  al.  (44),  Nerlich  (119),  Metcalfe 
et  al.  (112),  Isaacs  et  al.  (84),  Bencini  &  Parola 
(9)].  The  information  from  these  studies,  though  in 
some  respects  limited  to  abnormal  hemodynamic 
situations,  has  contributed  much  to  the  elucidation 
of  normal  functions  of  the  pericardium. 

Since  some  of  the  functions  are  implicit  from  the 
architecture  of  the  pericardium,  a  brief  anatomical- 
histological  review  will  be  helpful  (118).  The  parietal 
pericardium,  generally  just  called  pericardium, 
forms  a  thin,  but  firm  sac  of  connective  tissue  en- 
veloping the  ventricles  and  atria.  At  the  base  of  the 
heart,  near  the  entry  of  the  veins  into  the  atria, 
the  parietal  pericardium  joins  the  visceral  pericar- 
dium or  "epicardium."  Pericardium  and  epicardium 
are  separated  by  a  thin  fluid  film  of  pericardial 
liquor  which  is  similar  to  the  fluid  filling  the  intra- 
pleural space.  The  outer  aspect  of  the  pericardium 
is  covered  with  a  thin  layer  of  loose  connective  tissue 
which  constitutes  the  pericardial,  or  parietal,  pleura. 
The  pericardium  is  attached  to  the  diaphragm  with 
two  septa  (right  and  left)  to  the  sternum  and  to  the 
mediastinum.  This  anchorage  limits  the  mobility  of 
the  sac  and  in  turn  confines  the  heart  to  a  definite 
space   within   the   thorax,    especially   in    primates. 

Histologically  the  pericardium  consists  of  three 
layers  of  regularly  oriented  collagenous  and  elastic 
fibers,  each  oriented  in  a  different  direction.  The 
fibers  of  the  outer  and  middle  layer  form  a  thicker 
structure  than  those  of  the  inner  layer.  In  a  prepara- 
tion which  is  not  submitted  to  stretch,  the  collage- 
nous fibers  appear  wavy  and  the  elastic  fibers  appear 
straight.  Nelemans  (118)  showed  that  with  an  acute 
dilatation  of  the  normal  heart,  the  pericardium 
extends  itself  by  approximately  20  per  cent  until 
the   elastic    fibers   are   markedly    stretched    and    the 


120 


150         VOLUME   (ml)         300 


fig.  25.  Pericardial  pressure-volume  curve  in  a  dead  dog, 
determined  after  removal  of  heart.  The  volume  of  the  heart 
is  replaced  by  fluid  injected  into  the  pericardial  space.  [From 
Holt  (78).] 


rather  tense  collagenous  fibers  hinder  further  ex- 
pansion. This  elastic  stretching  is  quickly  reversible, 
since  the  sac  will  again  fit  snugly  when  cardiac  dila- 
tation is  abrogated.  If,  however,  the  heart  dilates 
beyond  the  limit  of  elastic  stretch,  which  obviously 
can  only  happen  if  venous  return  and  end-diastolic 
pressures  rise  substantially,  then  the  pericardium 
will  "give"  or  yield.  However,  this  additional  stretch- 
ing is  not  quickly  reversible  and  persists  for  a  long 
time  after  the  heart  has  returned  to  its  normal  shape, 
as  evidenced  by  the  slackness  of  the  pericardial  sac. 
The  additional  stretching  is  of  "plastic"  nature  and 
can  be  attributed  to  the  collagenous  fibers  which 
return  only  very  slowly  to  their  previous  length 
after  stretching.  This  dual  mechanism  of  "elastic" 
and  "plastic"  stretch  hinders  acute  overinflation 
(elastic  limitation)  but  permits  long  term  dilatation 
of  the  heart   (plastic   adaptation). 

Nelemans'  (118)  views  concerning  the  "plastic" 
behavior  of  the  pericardium  are  supported  by  ob- 
servations made  in  experimental  pericardial  effusion : 
following  the  infusion  of  50  ml  of  saline  into  the  peri- 
cardial sac  in  an  open-chest  dog,  the  mean  intra- 
pericardial  pressure  first  rises  markedly  but  then 
gradually  decreases  to  a  lower  level.  Withdrawal 
and  immediate  reinfusion  of  the  same  amount  of 
fluid  results  in  a  lower  pressure  than  the  one  initially 
obtained.  Withdrawing  the  saline,  but  then  waiting 
for   about   2   hours    before    reinjecting   it,    results   in 


FUNCTIONAL    ANATOMY    OF    CARDIAC    PUMPING 


793 


approximately  the  same  pressure  rise  as  initially 
recorded  upon  the  first  infusion. 

The  pressure-volume  relationships  of  the  peri- 
cardial sac  without  the  heart  were  recently  studied  by 
Holt  et  al.  (78)  in  experiments  which  emphasize  the 
relatively  nondistensible  nature  of  the  pericardium. 
The  curve  in  figure  25  illustrates  that,  as  the  fluid 
volume  in  a  dog's  pericardial  cavity  increases,  the 
pressure  remains  at  zero  until  the  volume  has  reached 
about  200  ml.  Further  volume  increments  cause  a 
rather  steep  rise  in  pericardial  pressure.  The  results 
of  these  and  other  experiments  [Isaacs  et  al.  (84), 
Berglund  et  al.  (11)]  point  to  an  important  function 
of  the  pericardium,  i.e.,  to  restrain  the  heart's  cav- 
ities from  overdistention. 

In  1 91 4,  Henderson  &  Prince  (71)  showed  that 
the  filling-force  relationships  which  later  became 
known  as  Starling's  law  were  such  in  the  right  and 
left  ventricles  as  to  prevent  the  engorgement  or  de- 
pletion of  the  lung  blood.  The  lungs  were  further 
safeguarded  against  congestion  by  the  fact  that  a 
sudden  dilation  of  the  left  ventricle  within  the  peri- 
cardium would  prevent  the  filling  of  the  right  heart, 
limit  the  amount  of  blood  that  could  be  pumped  into 
the  lungs  and  thus  prevent  their  engorgement. 

There  has  been  much  debate  as  to  whether  during 
diastole  the  heart  normally  fills  the  entire  pericardial 
sac  [see  also  Wilson  &  Meek  (162)].  Nelemans 
(118)  concluded  that  the  heart  fills  the  pericardium 
completely  during  diastole  and  that  the  sac  has  a 
restraining  influence  upon  the  expansion  of  the  heart. 
However,  this  question  has  not  been  studied  ex- 
tensively until  modern  recording  techniques  enabled 
Holt  et  al.  (78)  to  follow  the  phasic  changes  of  intra- 
cardiac and  intrapericardial  pressures  during  the 
cardiac  cycle  under  various  filling  conditions  ranging 
from  hypovolemia  to  plethora.  It  was  found  that  in 
an  open-chest  dog  any  increase  in  ventricular  end- 
diastolic  pressure  above  approximately  1  mm  Hg 
causes  a  nearly  equal  rise  in  pericardial  pressure. 
Since  end-diastolic  pressures  of  this  order  of  magni- 
tude are  found  under  normal  circulatory  conditions, 
it  appears  that  the  ventricle  does  occupy  the  peri- 
cardial sac  completely  and  even  stretches  it  slightly 
at  the  end  of  the  filling  phase.  Since  under  conditions 
of  plethora  a  positive  pressure  is  maintained  in  the 
pericardial  space  throughout  the  cardiac  cycle,  the 
transmural  ventricular  or  transmural  atrial  pressure 
must  then  be  taken  as  the  difference  between  intra- 
cardiac and  pericardial  pressures  rather  than  as  the 
difference  between  intracardiac  and  intrapleural 
pressures. 


In  comparing  the  phasic  changes  in  intra-atrial, 
intraventricular,  and  pericardial  pressures,  Holt  et  al. 
(78)  also  made  observations  which  cast  light  on  the 
contribution  of  the  pericardium  to  the  pumping 
action  of  the  heart  by  facilitating  atrial  filling.  The 
pericardial  pressure  drops  markedly  during  the  early 
part  of  ventricular  systole.  "Since  the  atria  are  lo- 
cated within  the  pericardial  sac  .  .  .  ,  the  pressure 
in  the  right  atrium  decreases  in  early  systole  and 
the  atrium  becomes  distended  by  blood  rushing 
into  it  from  the  great  veins.  A  measure  of  the  degree 
of  this  atrial  'filling  pressure'  is  the  difference  be- 
tween right  atrial  end  diastolic  pressure  and  the 
pericardial  pressure  in  early  systole."  When  the  atrial 
pressure  drops,  "the  pressure  gradient  from  the 
great  thoracic  veins  to  the  right  atrium  is  markedly 
increased.  This  appears  to  be  a  mechanism  by  which 
blood  is  drawn  into  the  atrium  during  ventricular 
systole,  and  in  this  way  blood  is  ready  to  fill  the  ven- 
tricles immediately  on  cessation  of  ventricular  systole. 
Thus,  with  the  pericardium  intact,  the  act  of  ven- 
tricular systole  draws  blood  to  the  ventricle  [sic]  and 
insures  ventricular  filling  in  early  diastole.  These 
results  are  in  agreement  with  those  of  Bohme  and 
Brecher  who  showed  that  there  was  a  large  sudden 
flow  of  blood  through  the  superior  vena  cava  toward 
the  heart  during  early  ventricular  systole.  This 
has  been  attributed  by  several  investigators,  and 
most  recently  by  Brecher,  to  the  sudden  piston-like 
downward  movement  of  the  atrioventricular  junction 
attracting  blood  from  the  central  veins  into  the  right 
atrium.  Our  data  indicate  that  the  increased  flow 
into  the  right  atrium  is  caused  by  the  sudden  de- 
crease in  pericardial  pressure  with  ventricular  sys- 
tolic ejection,  and  that  this  factor  becomes  greater 
with  higher  ventricular  diastolic  pressures.  Confirma- 
tion of  the  importance  of  the  pericardium  in  this 
connection  is  the  observation  of  Brecher  that  the 
acceleration  of  venous  flow  toward  the  right  atrium 
during  ventricular  systole  is  decreased  by  opening 
the  pericardium.  It  would  appear  that  the  increased 
flow  into  the  right  atrium  during  ventricular  systole 
was  caused  in  large  part  by  the  decrease  in  peri- 
cardial pressure  during  early  ventricular  systole. 
The  question  as  to  how  much  of  this  flow  is  caused 
by  a  downward  movement  of  the  atrioventricular 
junction  remains  unanswered.  Quantitative  data  on 
this  point  could  be  obtained  by  measuring  the  flow 
into  the  right  atrium  in  the  open-chest  dog,  with 
the  pericardium  intact  and  after  complete  removal  of 
the  pericardium"  (78). 

Obviously,  both  the  piston-like  downward  move- 


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CIRCULATION    II 


ment  of  the  atrioventricular  junction  and  the  drop 
of  pericardial  pressure  during  early  ventricular 
ejection  are  caused  by  the  same  force,  i.e.,  the  ven- 
tricular myocardial  contraction.  Which  of  the  two 
factors  is  predominant  in  facilitating  atrial  filling 
during  ventricular  systole  will  not  be  easily  decided. 
From  the  presently  available  evidence  one  can 
conclude  that  the  pericardium  aids  the  pumping 
function  of  the  heart.  In  contradiction  to  the  wide- 
spread opinion  that  the  absence  of  the  pericardium 
does  not  have  a  noticeable  effect  upon  the  circulation, 
there  is  some  experimental  evidence  that  a  large 
percentage  of  pericardiectomized  animals  develop 
heart  hypertrophy  and  perform  poorly  on  the  tread- 
mill [see  Nelemans  (118)].  It  is  quite  possible  that 
under  conditions  of  rest  or  mild  exercise  the  heart 
without  pericardium  can  satisfy  the  metabolic 
demands  of  the  tissues.  However,  under  conditions  of 
strenuous  exercise  the  reserve  power  of  the  heart 
without  pericardium  is  probably  diminished. 


CLOSING    REMARKS 

In  recent  years  the  opinion  has  been  often  voiced 
that  hemodynamics  is  a  dead  science,  in  which  no 
more  essential  work  needs  to  be  done.  This  view  refers 
primarily  to  the  mechanical  features  of  the  cardio- 
vascular system  which  are  supposedly  well  known. 
It  applies  less  to  the  regulatory  aspects  which  ad- 
mittedly require  further  clarification.  However,  the 
analysis  of  such  a  presumably  simple  function  as  the 
heart's  normal  pumping,  even  without  consideration 
of  any  neural  or  hormonal  regulatory  processes, 
reveals  wide  gaps  in  our  knowledge. 

There  are  numerous  reasons  for  these  shortcomings. 


Many  of  the  measurements  on  which  present  con- 
cepts are  based  were  obtained  under  highly  artificial 
conditions,  such  as  excised  heart  preparations  and 
open-chest  animals,  which  limit  the  applicability  of 
the  results  to  intact  normal  organisms.  Findings  in 
one  animal  species  often  cannot  be  transferred  or 
extrapolated  to  other  species.  For  instance,  the  me- 
chanics of  cardiac  pumping  in  man  differ  from  those 
in  other  animals  because  of  his  upright  position, 
minimal  splanchnic  pooling,  and  several  other  fac- 
tors. Finally,  measurements  are  often  performed  with 
inadequate  instrumentation.  For  example,  errors 
caused  by  insufficient  sensitivity  and  time  resolution 
make  it  difficult  to  correlate  simultaneous  events  in 
the  cardiac  cycle. 

Only  rather  guarded  conclusions  can  therefore  be 
drawn  from  the  available  experimental  evidence 
as  to  the  exact  nature  of  the  heart's  pumping  func- 
tion. Wide  discrepancies  of  information  obtained 
with  different  methods  need  to  be  reconciled.  For 
example,  measurements  of  the  ventricular  volumes 
by  various  methods  differ  so  greatly  in  their  order  of 
magnitude  that  it  is  today  still  impossible  to  state 
how  large  is  the  normal  functional  residual  capacity 
of  the  heart.  Obviously,  views  based  on  insufficient 
data  must  remain  in  the  realms  of  speculations  and 
postulates.  This  is  the  state  of  knowledge  about  many 
age-old  problems  such  as  cardiac  filling  and  the 
precise  moment  of  valve  closure.  How  much  more 
complex  these  problems  become  under  various  patho- 
logical conditions  does  not  need  to  be  elaborated 
upon.  In  view  of  the  recent  progress  in  the  bio- 
medical sciences,  it  is  shocking  to  observe  how  a 
seemingly  simple  mechanical  process  such  as  cardiac 
pumping  still  remains  so  enigmatic. 

The  help  of  Dr.  Robert  C.  Schlant  in  reviewing  the  manu- 
script is  gratefully  acknowledged. 


REFERENCES 


i.  Adcock,  J.  D.,  R.  H.  Lyons,  and  J.  B.  Barnwell. 
The  circulatory  effects  produced  in  a  patient  with  pneu- 
mopericardium by  artificially  varying  the  intrapericardial 
pressure.  Am.  Heart  J.  ig:  283-291,  1940. 

2.  Agress,  C.  M.,  L.  G.  Fields,  S.  Wegner,  M.  Wilburne, 
M.  D.  Shickman,  and  R.  M.  Muller.  The  normal  vibro- 
cardiogram. Physiologic  variations  and  relation  to  cardio- 
dynamic  events.  Am.  J.  Cardiol.  8:  22-31,  1961. 

3.  Akman,  L.  C,  A.J.  Miller,  E.  N.  Silber,  J.  A.  Schack, 
and  L.  N.  Katz.  The  ventricular  electrokymogram. 
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relation  between  mean  left  atrial  pressure  and  left  ventricu- 
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Physiologic  7:  85-113,  1926. 

Monod-Broca,  P.  Recherches  experimentales  sur  la 
circulation  pulmonaire  apres  exclusion  du  coeur  droit. 
Arch.  mal.  coeur.  51  :  841-846,  1958. 

Moritz,  F.  Physiologie  und  Pathologie  der  Herzklappen. 
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199.  '926- 

Moscovitz,  H.  L.,  and  R.  J.  Wilder.  Pressure  events  of 

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Circulation  Research  4:  574-578,  1956. 

Nelemans,  F.  A.  Die  Funktion  des  Perikards.  Arch,  neerl. 

physiol.  24:  337-390,  1940. 

Nerlich,  W.  E.  Determinants  of  impairment  of  cardiac 

filling  during  progressive  pericardial  effusion.   Circulation 

3:  377-383,  i95!- 

Nixon,  P.  G.  F.  Time  relationships  of  the  left  atrial  V 
wave  in  mitral  valvular  disease.  Brit.  Heart  J.  23:  637- 
642,  1 96 1. 

Nuland,  S.  B.,  W.  W.  L.  Glenn,  and  P.  H.  Guilfoil. 
Circulatory  bypass  of  the  right  heart.  III.  Some  observa- 
tions on  long-term  survivors.  Surgery  43:  184-201,  1958. 
Nylin,  G.  The  clinical  applicability  of  roentgenological 
heart  volume.  Determination  with  special  reference  to 
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hypothermic  dog  heart.  Circulation  Research  8:  956-960, 
i960. 

Opdyke,  D.  F.  Effect  of  changes  in  initial  tension,  initial 
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Am.  J.  Physiol.  169:  403-41 1,  1952. 

Opdyke,  D.  F.,  and  G.  A.  Brecher.  Effect  of  normal  and 
abnormal  changes  of  intrathoracic  pressure  on  effective 
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566,  1950. 

Opdyke,  D.  F.,  J.  Duomarco,  W.  H.  Dillon,  H. 
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Patino,  J.  F.,  W.  W.  L.  Glenn,  P.  H.  Guilfoil,  M. 
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134.  Reindell,  H.,  R.  Weyland,  H.  Klepzig,  E.  Schildge, 
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148.  Spalteholz,  W.  Hand  Atlas  and  Textbook  oj  Human  Anat- 
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155.  Wetterer,  E.  Die  Wirkung  der  Herztatikgeit  auf  die 
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156.  Wiggers,  C.  J.  Studies  on  the  consecutive  phases  of  the 
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157.  Wiggers,  C.  J.  The  independence  of  electrical  and  me- 
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158.  Wiggers,  C.  J.  Studies  on  cardiodynamic  actions  of  drugs; 
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159.  Wiggers,  C.  J.  Circulatory  Dynamics.  New  York:  Grune  & 
Stratton,  1952. 

160.  Willius,  F.  A.,  and  T.  J.  Dry.  A  History  of  the  Heart  and 
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The  electrokymograph:  studies  in  recording  fidelity. 
Circulation  2:  197-204,  1950. 


CHAPTER     24 


The  physiology  of  the  aorta  and  major  arteries1 


JOHN    W.  RE  MINGTON  Department  of  Physiology,  Medical  College  of  Georgia,  Augusta,  Georgia 


CHAPTER      CONTENTS 

Measurement  of  Aortic  Distensibility 

General  Characteristics  of  the  Tension -Length  Curve 

The  Hysteresis  Loop 

Selection  of  Representative  Curves 

Histological  Considerations 

Effects  of  Active  Muscular  Contraction  on  Distensibility 

Effects  of  Aging  on  Arterial  Distensibility 

Expression  of  Extensibility  in  Terms  of  Moduli 

Changes  in  Length  and  Wall  Thickness  of  Arteries 
Action  of  the  Aorta  as  a  Conduit 

Pulsatile  Flow  in  Rigid  and  Distensible  Tubes 

Quantitation  of  Fluid  Displacement  and  Wall  Distensibility 
Relationships 

Phase  Lag  and  the  Harmonics  of  the  Arterial  System 

Construction  of  a  Hypothetical  Ejection  Curve 
The  Aorta  as  a  Blood  Reservoir 

Changes  in  Central  Pulse  Contour  During  Propagation 

Resonance  and  Standing  Waves 

Other  Factors  Which  May  Alter  the  Central  Pulse  Contour 

Calculation  of  the  Stroke  Volume  From  the  Central  Pressure 
Pulse 


AT  outset,  may  I  say  that  this  article  on  the  function 
of  the  aorta  and  the  major  arteries  makes  no  pretense 
of  being  an  authoritative  review  of  the  literature, 
and  is  not  only  a  generalized  treatment  but  is  written 
with  a  bias.  I  came  to  cardiovascular  study  via  Biol- 
ogy, in  an  era  when  Physics  was  not  such  a  firmly 
trothed  bride  of  Physiology-  I  do  not  think  glibly  in 
terms  of  abstract  formulas,  of  electrical  analogues,  or 
the  other  erudite  devices  now  so  commonly  used  to 
clarify  the  complex  problems  which  underlie  pressure 
wave  formation  and  propagation.  I  believe  that  I 
understand  a  process  only  when  I  can  construct  some 

1  This  manuscript  was  completed  January  15,  1 961 ,  and  its 
references  include  only  papers  I  had  read  in  published  form  at 
that  time. 


sort  of  a  visual  image  of  just  how  it  operates.  In  many 
aspects  of  the  subject  such  a  visual  model  is  at  present 
impossible.  I  can  only  describe  what  I  have  been  able 
to  gather  about  the  function  of  the  major  arteries,  and 
speculate  about  what  trends  future  research  will 
follow. 

These  large  arteries  serve  two  clear  functions.  First, 
they  comprise  a  network  of  conduits  through  which 
blood  is  moved  from  the  centrally  located  cardiac 
pump  to  the  various  capillary  beds.  It  is  important 
that  this  transfer  be  made  with  a  minimal  loss  of 
energy.  The  problem  of  proper  conduit  design  became 
more  acute  when  the  body  form  became  elongated, 
instead  of  remaining  spherical.  Second,  the  distensible 
wall  of  the  vessels  allows  a  temporary  storage  of  blood 
during  the  ejection  phase  of  the  pump  cycle,  which 
allows  a  buffering  of  the  oscillatory  pressure  changes. 
This  aspect  will  be  spoken  of  as  the  reservoir  action  of 
the  vessels,  admittedly  an  inadequate  label.  While 
the  buffering  action  might  serve  to  protect  the  small 
vessels  from  large  pressure  changes,  it  also  involves 
considerable  change  in  the  conduit  properties. 

We  cannot  yet  form  a  definitive  analysis  of  the 
effectiveness  of  aortic  design  in  meeting  these  funda- 
mental requisites.  Progress  has  been  handicapped 
because  it  has  been  so  difficult  to  make  critical  studies 
on  intact  vessels.  Pressure  changes  at  various  points 
along  the  arterial  system  have  been  measured  often 
over  the  past  50  years  (1,  16,  18,  28-30,  40,  42,  99, 
116,  132,  134,  135).  This  has  given  us  knowledge, 
still  far  from  complete,  about  the  speed  of  pulse-wave 
propagation,  the  contour  of  the  pressure  pulse  as 
formed  in  the  upper  aorta,  and  the  changes  in  this 
form  as  the  pulse  moves  into  the  distal  aorta  and  large 
arteries.  Itisdoubtful  that  any  great  progress  toward  an 
understanding  of  arterial  dynamics  will  be  made  by 


799 


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CIRCULATION    II 


further  studies  on  pressure  values  alone,  without 
a  simultaneous  recording  of  vessel  diameter  or  flow. 

A  study  of  two  parameters  has  often  been  at- 
tempted, but  not  too  successfully.  It  has  not  proven 
practical  to  remove  the  aorta  from  the  body  and 
insert  it  into  an  artificial  system  where  the  volume 
change  and  the  flow  through  might  be  measured 
directly,  as  from  a  calibrated  stroke  of  a  pump.  The 
problems  of  coupling  this  distensible  tube  to  rigid 
fittings  without  having  an  orifice  that  will  severely 
distort  the  flow  pattern  are  considerable.  No  effective 
means  has  been  devised  to  occlude  completely  all 
exit  vessels,  including  the  vasa  vasorum,  and  thus 
prevent  loss  of  fluid  along  the  length  of  the  vessel. 
Sometimes  a  rubber  insert  has  been  used  (137)  but, 
since  most  rubber  tubes  are  less  extensible  than  the 
aorta,  this  stratagem  may  have  confused  matters 
more  than  it  helped.  And  we  still  have  no  pump  which 
has  an  ejection  pattern  like  that  of  the  ventricle. 
Curiously  enough,  an  artificial  pump  capable  of 
producing  a  pressure  rise  similar  to  that  seen  with  a 
natural  pulse  invariably  produces  turbulence  and 
vibrations  of  the  pressure  recorder  sufficient  to  obscure 
the  pulse  contour  being  formed. 

A  recording  of  aortic  flow  in  vivo  by  a  technique 
which  requires  vessel  cannulation  causes  enough  dis- 
tortion of  the  pressure  pulse  contours  that  one  must 
be  cautious  in  inferring  a  direct  pertinence  to  the 
intact  system.  Fortunately,  several  techniques  are  now 
in  use  for  the  recording  of  flow  (27,  31,  55,  82,  110, 
120,  131)  and  the  registration  of  diameter  change  (88, 
91,  113)  which  do  not  require  cutting  the  vessel. 
Most  flow  recorders  do  require  a  crimping  of  the 
vessel  in  the  region  where  flow  is  being  measured, 
which  may  not  be  without  effect  on  the  flow  profile. 
As  yet,  the  frequency  of  many  such  devices  usually 
does  not  approach  that  of  a  good  pressure  recording 
system,  so  that  they  may  not  be  able  to  give  a  faithful 
picture  of  rapid  change. 

An  engineer  faced  with  the  problem  of  designing  a 
conduit  system  for  the  most  efficient  movement  of 
blood  would  start  with  some  basic  equations.  First, 
there  would  be  the  Poiseuille  formula  which  states 
that  the  pressure  fall  (for  frictional  energy  dissipation) 
will  be  directly  related  to  the  flow  rate,  the  fluid 
viscosity,  and  the  length  of  pipe,  and  inversely  related 
to  the  fourth  power  of  the  radius.  The  last  is  because 
adsorptive  forces  between  the  fluid  and  the  wall  prevent 
or  retard  longitudinal  movement  of  the  outermost  fluid 
layer.  This  in  turn  forces  the  adjacent  shell  to  shear 
past  it,  retarding  it  with  a  frictional  dissipation  of 
energy,  which  in  turn  slows  the  next  shell  of  fluid,  and 


so  on  to  the  middle  of  the  pipe.  For  a  given  volume 
flow,  the  greater  the  pipe  diameter,  the  less  is  the 
total  fluid  frictional  loss.  He  would  also  include  in  his 
formulas  factors  relating  to  the  smoothness  of  the 
wall  and  the  material  of  which  his  conduit  will  be 
made,  since  these  condition  the  size  of  the  boundary 
layer.  He  must  make  corrections  if  the  fluid  does  not 
have  a  constant  viscosity  at  all  flow  rates,  as  blood 
apparently  does  not  (9,  86).  He  also  knows  that  an 
equation  which  applies  to  laminar  flow  will  not  be 
correct  if  fluid  molecules  whorl  laterally  across  the 
fluid  shells,  i.e.,  when  the  flow  becomes  turbulent. 
The  frictional  cost  increases  whenever  this  happens. 
Finally,  when  he  is  required  to  use  pipes  of  different 
sizes,  he  must  carefully  design  the  transition  areas  so 
that  turbulent  eddies  will  not  form.  Tapered  changes 
in  diameter  are  less  conducive  to  turbulence  than 
abrupt  shoulder  joints. 

All  these  formulas,  which  may  be  found  in  texts  on 
hydraulics,  are  based  on  the  assumption  that  flow  is 
being  maintained  steady,  and  that  the  conduits  have 
rigid  walls.  But  blood  flow  is  not  steady,  for  it  shows 
several  accelerations  and  decelerations  with  each 
pump  stroke.  A  calculation  of  the  energy  loss  accom- 
panying such  rapid  changes  in  flow  rate  must  be 
complicated.  A  whole  new  set  of  equations  will  be 
required  and,  to  check  them,  we  must  be  able  to 
measure  precisely  the  amount  of  acceleration  in  all 
parts  of  the  arterial  system.  Quantitative  evaluations 
of  the  degree  of  smoothness  or  of  the  absorptive  forces 
for  plasma  on  the  endothelial  lining  cannot  be  given. 
Microscopic  observation  of  moving  blood  in  tiny 
vessels  has  shown  that  the  red  cells  congregate  in  the 
center  of  the  stream,  which  is  presumptive  evidence 
for  a  greater  axial  velocity.  Whether  we  can  assume 
from  this  that  a  parabolic  flow  distribution  would  be 
found  in  the  large  arterial  vessels  is  open  to  question. 
While  streamline  flow  has  been  described  for  the 
aorta  (92),  there  remains  some  question  as  to  whether 
a  normal  flow  pattern  could  be  said  to  have  persisted 
during  the  measurements,  and  whether  the  streaming 
would  apply  over  the  whole  cardiac  cycle  (84). 

The  large  arteries  are  not  rigid,  so  that  any  equa- 
tion relating  energy  dissipation  to  tube  radius  will  be 
complex.  Further,  the  arterial  system  seldom  has  any 
tubes  which  continue  uninterrupted  for  an  apprecia- 
ble distance.  Each  vessel  has  frequent  branchings. 
With  the  exception  of  the  ascending  aorta  (44)  and 
the  main  pulmonary  artery  (88),  with  each  branching 
there  is  an  increase  in  the  aggregate  cross-sectional 
area.  These  junctions  appear  smooth  and  tapered,  so 
that  the  orifice  problem  is  probably  at  its  simplest. 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


80  I 


Further,  most  trunk  vessels  show  a  gradual  taper 
through  their  length.  Exceptions  to  this,  that  come  to 
mind,  are  a  region  of  the  descending  thoracic  aorta 
and  one  of  the  carotid  artery,  which  appear  to  be 
more  nearly  true  cylinders. 

Too  detailed  a  particularization  of  the  various 
factors  which  give  rise  to  frictional  resistance  may  be 
nonessential.  The  total  effect  of  them  all  should  be 
measurable  by  a  decrease  in  mean  pressure,  over  a 
whole  cardiac  cycle,  from  the  upper  aorta  to  the 
peripheral  arteries.  Several  studies  have  shown  that 
in  the  aorta  such  a  decrease  is  so  small  as  to  be  within 
the  error  of  measurement  (42,  68).  In  fact,  there  is  no 
clear  loss  in  mean  pressure  in  man  until  the  brachial 
or  femoral  arteries  are  reached. 

Despite  this  small  frictional  dissipation  of  energy 
attending  propagation,  there  is  a  very  clear  differ- 
ence between  the  pressure  energy  developed  in  systole 
and  in  diastole.  Except  under  rare  circumstances,  the 
mean  systolic  pressure  is  greater  than  the  mean 
diastolic  pressure.  This  excess  of  pressure  energy 
could  denote  an  inability  of  the  stretch  of  the  extensi- 
ble wall  to  keep  pace  with  the  force  applied  by  cardiac 
ejection,  so  that  energy  is  stored  in  potential  form  in 
the  visco-elastic  walls,  or  it  could  indicate  a  different 
pressure-flow  relationship  in  the  large  vessels  being 
filled  during  systole,  and  that  which  marks  "drainage" 
through  the  peripheral  arterioles. 

To  go  from  generalities  to  the  specifics,  an  analysis 
of  aortic  function  could  be  focused  upon  three  large 
questions:  /)  What  are  the  essential  features  of  the 
tension-length  curves  shown  by  the  walls  and  the 
derived  pressure-volume  curves,  and  to  what  extent 
are  these  curves  subject  to  physiological  and  patho- 
logical change?  2)  How  does  wall  distention  affect  the 
conduit  properties  of  the  vessels?  j)  What  factors 
influence  the  capacity  of  the  arteries  to  serve  as  a 
blood  reservoir? 


MEASUREMENT    OF    AORTIC    DISTENSIBILITY 

General  Characteristics  of  the  Tension-Length  Curve 

Until  quite  recently,  measurements  of  the  extensi- 
bility ot  blood  vessels  were  made  on  isolated  tissues, 
using  two  procedures  (11,  15,  22,  37,  51,  62,  65-67, 
76,  107,  118).  Usually  a  ring  (for  circular  stretching 
to  produce  an  increase  in  circumference)  or  a  cut 
strip  (for  measuring  longitudinal  change)  was  sub- 
jected to  weight  loads,  the  changes  in  length  being 
recorded.  In  a  few  cases,  volume  was  injected  into  a 


tied-off  vessel,  recording  pressure.  Any  change  in  the 
other  dimension,  e.g.,  a  longitudinal  change  during 
circular  stretching,  was  either  inadequately  measured 
or  ignored.  Although  the  specific  techniques  for  in- 
creasing load  have  varied,  the  stretches  were  made 
rather  slowly  so  that  the  vessel  could  approach,  if 
not  attain,  a  stable  length  value,  i.e.,  a  "static"  value. 
Whether  the  load  was  applied  in  a  continuously  in- 
creasing manner  or  stepwise,  the  data  were  generally 
presented  as  a  single  tension-length  curve  covering 
the  whole  physiological  range.  All  workers  agree  that 
such  a  curve  is  not  linear,  but  shows  a  relatively 
great  extensibility  at  low  tension  settings  and  a 
progressive  wall  stiffening  as  the  load  increases  (fig. 
1).  This  curve  is  therefore  different  from  that  shown 
by  metals,  even  those  that  obey  Hooke's  law  over  the 
greatest  part  of  their  extension,  or  by  rubber,  where 
the  length  change  becomes  relatively  greater  at  high 
tension  levels  (46).  A  rubber  tube  wrapped  with  a 
fibrous  jacket,  such  as  a  garden  hose,  shows  the  same 
type  of  curve  as  does  the  aorta  (14).  Rings  taken  from 
the  aorta  or  from  arteries  appear  to  differ  only  quan- 
titatively. Further,  the  longitudinal  stretch  curves  are 
qualitatively  similar  to  those  obtained  with  a  circular 
stretch. 

The  tension  given  in  figure  1 A  is  the  weight  load 
divided  by  the  product  of  the  length  of  the  ring  of  the 
thoracic  aorta  and  the  wall  thickness.  This  can  be 
converted  to  internal  pressure  by  dividing  by  the 
radius.  To  express  pressure  in  the  usual  physiological 
terms  of  mm  Hg,  the  obtained  value  is  divided  by  1 3.5. 
We  can  calculate  the  volume  per  unit  length  of  vessel 
as  tit2.  Both  pressure-diameter  and  pressure-volume 
curves  show  two  inflections,  to  give  the  curve  a  some- 
what sigmoid  appearance  (figs.  \B  and  C).  The 
pressure  level  at  which  these  inflections  are  seen  varies 
with  different  regions  of  the  aorta.  Hence  both  inflec- 
tions are  set  at  a  higher  pressure  in  the  upper  aorta 
than  in  the  lower,  and  the  lower  inflection  may  not 
be  seen  at  all  in  the  arteries  (46).  There  is  no  simple 
formula  which  will  fit  this  sigmoid  type  of  curve,  or 
even  that  portion  of  greatest  physiological  significance. 
At  outset,  it  is  clear  that  any  comparison  of  vessel  dis- 
tensibility  from  time  to  time,  or  between  animals,  will 
require  the  use  of  the  same  arterial  region  and  the 
same  pressure  span. 

There  are  several  inadequately  explained  properties 
of  the  isolated  specimens  which  seriously  affect  the 
recorded  extensibility  curves.  First,  as  the  vessel  is 
dissected  out  of  the  body,  there  is  an  immediate 
shortening  of  its  length  and  a  tensing  of  its  walls. 
This  is  true  whether  the  animal  has  just  been  killed, 


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Circumference,  mm  Ci  rcumference,  m  m 

fig.  I .  Stretch  curves  for  a  ring  of  thoracic  aorta  of  a  dog.  In  situ  length  =  10.5  mm.  Curves 
I  represent  the  first  stretch  curve,  made  by  continuous  tension  increase  over  1  min.  Curves  2 
are  the  results  of  a  second  stretch  identical  in  load  and  timing  to  the  first.  Curves  R  show  the 
curves  taken  during  the  gradual  release  of  tension,  over  1  min.  Curves  C  show  the  effect  of 
muscle  contraction  by  immersion  of  the  ring  in  epinephrine. 


I  2 

Volume,  cc 


or  has  been  dead  for  some  time,  and  whether  the 
voluntary  muscles  are  in  a  state  of  rigor  mortis  or  not. 
The  change  develops  no  matter  how*  carefully  the 
removal  is  done.  The  interpretation  placed  upon  this 
change  in  the  past  is  that  it  reflects  a  strong  contrac- 
tion of  the  smooth  muscle  contained  in  the  wall. 
Aside  from  the  speed  of  its  development,  which  con- 
trasts with  the  slower  time  courseof  muscle  contraction, 
and  the  lack  of  correlation  between  the  amount  of 
longitudinal  shortening  and  the  proportionate  amount 
of  muscle  in  the  wall  (ascending  aorta,  for  example, 
contracts  to  the  greatest  degree),  there  are  other 
features  which  do  not  fit  too  well  with  this  interpre- 
tation. 

When  such  a  tensed  ring  is  subjected  to  stretch, 
and  the  load  is  then  removed,  the  walls  are  no  longer 
so  tense,  and  the  circumference  is  about  30  per  cent 
greater  than  before  the  stretch.  What  was  not  real- 
ized in  the  earlier  studies  was  that  the  amount  of  this 
diameter  increase  bears  a  direct  relation  to  the  total 
stretch  imposed  (96).  Now,  if  a  second  stretch  of  the 
same  size  is  made,  the  stretch  curve  starts  from  the 
greater  initial  value  and  courses  almost  parallel  to 
the  first  through  the  region  of  greatest  extensibility 
(fig.  1  A).  Then,  as  the  wall  stiffens,  the  second  curse 
becomes  enough  steeper  that  it  merges  with  the  first 
some  time  before  the  peak  load  is  reached.  This 
merging  argues  against  a  conclusion  that  the  first 
stretch  had  caused  some  irreparable  tissue  damage, 
such  as  an  internal  tearing.  If,  after  the  first  stretch 
and  stretch  release  is  completed,  the  tissue  is  allowed 


to  remain  unloaded  for  a  long  period  (several  hours), 
the  original  small  diameter  may  be  almost,  if  not 
fully,  restored.  If  the  first  stretch  had  ""pulled  out"  an 
existing  muscle  spasm,  why  should  it  reform  and  take 
so  long  in  doing  so?  Experiments  designed  to  test  this 
"pulling  out"  idea  with  smooth  muscle  organs,  such  as 
the  gut,  have  given  little  indication  that  an  active 
contraction  itself  is  eliminated  by  an  extension  of  the 
whole  tissue  under  load  (6,  101). 

With  a  relatively  large  load,  a  third  stretch  made 
after  the  second  usually  gives  a  stretch  curve  identical 
to  that  of  the  second.  This  fact  has  been  recognized 
by  many  past  workers  who  were  aware  that  a  large 
initial  stretch,  which  was  not  quantitated,  made 
subsequent  stretch  curves  more  reproducible.  Such 
reproducibility  does  not  mean  that  they  are  necessarily 
more  descriptive  of  the  behavior  of  the  vessel  in  vivo. 
With  a  similar  load,  successive  stretches  may  start 
Irom  progressively  increasing  initial  diameters,  but  a 
reproducible  stretch  curve  is  reached  within  5  to  10 
stretches.  Unfortunately,  when  examining  past 
studies,  it  is  impossible  to  be  sure  whether  a  prelimi- 
nary stretch  was  used,  and,  if  so,  how  much  tension 
was  involved  and  how  long  a  time  interval  was  al- 
lowed before  the  recorded  stretch  was  made. 

The  Hysteresis  Loop 

Until  recently,  too,  little  attention  was  paid  to  the 
fact  that  as  the  loads  were  removed  the  length  curve 
did  not  follow,  during  this  stretch  release,  the  previous 


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stretch  curve  (fig.  1).  Hence  for  any  given  stretch  two 
different  tension-length  curves  must  be  considered, 
one  for  the  extension  and  the  other  for  the  elastic 
recoil.  The  difference  between  the  two  comprises  a 
hysteresis  loop.  The  amount  of  hysteresis  is  always 
greatest  with  the  first  stretch  done  after  a  prolonged 
rest  period.  If  this  first  stretch  is  followed  by  repetitive 
stretches  of  the  same  size,  the  hysteresis  is  progressively 
reduced  until  it  becomes  relatively  constant.  The 
number  of  successive  stretches  required  to  achieve 
this  stable  loop  varies  among  vessels,  for  two  or  three 
stretches  will  suffice  with  the  aorta,  but  more  may  be 
needed  with  a  muscular  artery.  In  the  gradual  re- 
duction of  hysteresis,  the  stretch-release  curve 
remains  almost  or  completely  constant,  its  values 
being  set  by  the  peak  load  used  (96).  It  is  the  exten- 
sion curve  which  shows  progressively  larger  length 
values  at  any  given  tension  value.  Hysteresis  is  present 
in  some  metals,  too,  although  its  amount  is  relatively 
small  as  compared  to  that  seen  with  vascular  tissues. 

The  presence  of  hysteresis  is  often  taken  to  indicate 
simplv  a  viscous  retardation  of  the  extension  of  elastic 
elements,  and  handled  in  formulas  as  though  it  were 
simple  viscosity  (48).  This  would  mean  that  the  size 
of  the  loop  is  an  index  to  the  frictional  energy  dis- 
sipation, which,  in  turn,  would  be  directly  related 
to  the  rate  of  the  imposed  stretch.  Hysteresis  of  the 
vessel  wall  is  not  so  easily  formulated.  We  can  sum- 
marize its  main  features  by  saying  that  at  least  three 
factors  seem  involved. 

/)  While  a  viscous  retardation  is  present,  it  can  be 
demonstrated  for  the  aorta  only  at  very  rapid  rates 
of  stretch  (96).  A  rate  dependency  has  not  been  seen 
for  the  stretch-release  curve.  The  muscular  arteries 
have  more  rate-dependent  hysteresis  than  does  the 
aorta. 

2)  When  a  stretched  length  is  held  constant  for  a 
period  of  time,  some  internal  elongation  of  elements 
still  continues,  so  that  the  tension  falls.  This  decline 
is  called  stress  relaxation.  Or  if  a  tension  value  is 
maintained,  the  length  will  continue  to  increase 
slowly,  which  process  is  known  as  "creep."  The 
amount  of  creep  is  a  function  of  time,  but  the  relation 
is  not  easily  formulated  in  quantitative  terms. 

Muscle  physiologists  have  frequently  referred  to 
this  slow  continued  elongation  under  stress  as  plasticity 
(13,  93).  This  use  of  the  term  "plastic"  is  not  very 
appropriate.  With  metals,  when  an  applied  increasing 
stress  reaches  a  certain  critical  value,  the  material 
becomes  deformed.  The  length  change  accompanying 
this  deformation  may  show  the  properties  of  viscosity, 
but  the  term  plastic  does  not  denote  the  presence  or 


absence  of  such  viscosity.  Once  deformed,  the  material 
does  not  return  to  the  original  length  upon  removal 
of  the  stress,  but  retains  the  increased  length.  The 
choice  of  the  word  plasticity  for  the  slow  elongation 
of  muscle  lay  with  the  belief  that  any  reversibility 
could  be  brought  about  only  by  an  active  muscle 
contraction.  However,  the  process  which  underlies 
stress  relaxation  is  spontaneously  and  completely 
reversible,  if  enough  time  is  allowed,  whether  the 
muscle  is  alive  or  dead  (101).  Muscle  contraction 
may,  of  course,  hasten  the  return  to  the  original 
length.  Stress  relaxation  involves  a  complicated  type 
of  internal  viscosity  which  is  so  arranged  that  the 
driving  force  for  length  return  lies  with  some  parallel 
elastic  unit  which  is  under  stretch. 

Just  as  with  rate-dependent  viscosity,  the  stress- 
relaxation  component  is  but  a  minor  part  of  hysteresis 
as  seen  in  the  aorta  (96).  Its  influence  is  more  evident 
the  longer  the  vessel  is  kept  at  a  peak  load,  or  the 
longer  the  vessel  remains  under  no  load,  so  that  creep 
recovery,  or  the  reversible  phase  of  stress  relaxation, 
can  continue. 

3)  When,  with  successive  stretches,  a  final  "stable 
hysteresis  loop"  is  obtained,  neither  the  values  from 
the  stretch  phase  nor  those  from  the  release  phase 
show  any  dependency  upon  the  rate  of  stretch,  and  a 
dependence  upon  time  cannot  be  easily  described. 
For  want  of  a  better  term  for  the  remaining  factor, 
which  seems  to  dictate  the  greatest  part  of  the  hyster- 
esis behavior,  I  have  called  it  simply  an  architectural 
rearrangement.  The  change  is  certainly  dependent 
upon  the  amount  of  stress  and  involves  a  reversible 
change  in  length.  While  there  must  be  some  time 
dimension  to  this  internal  rearrangement,  the  change 
presumably  is  very  rapid.  It  may  be  at  a  molecular 
level  or  at  a  tissue  fiber  level. 

What  should  be  firmly  emphasized  is  that  a  tissue 
probably  has  a  great  many  different  viscous  elements 
with  different  time  constants.  When  we  refer  to  such 
a  tissue  as  being  visco-elastic,  it  does  not  mean  that 
all  the  different  viscosities  can  be  lumped  to  give  a 
single  viscosity,  with  an  easily  definable  rate  de- 
pendency. 

In  view  of  the  complexities  that  influence  a  tension- 
length  curve,  it  is  possible  that  we  should  think  of  the 
firming  of  the  aortic  wall,  upon  removal  from  the 
body,  in  terms  quite  different  from  that  of  a  muscle 
contraction.  The  vessel  is  held  in  situ  under  con- 
siderable longitudinal  restraint  (104,  107).  When  a 
segment  is  cut,  elastic  elements  held  lengthwise  under 
stretch  should  recoil  and  make  the  wall  thicker.  When, 
with  a  circular  stretch,  no  attempt  is  made  to  restore 


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the  original  length,  there  could  be  a  reorientation  of 
these  elements  into  the  circular  plane,  leaving  a  ring 
with  a  larger  circumference.  This  indicates,  as  is 
probable,  that  both  longitudinal  and  circular  elastic 
elements  are  part  of  a  linked  network,  and  therefore 
not  independent.  In  our  studies  on  isolated  rings, 
when  we  converted  the  actual  tension-length  values 
to  pressures  and  volume,  we  used  in  situ  length 
rather  than  the  actual  one.  This  mathematical  step 
was  better  than  using  the  actual  lengths,  but  is  not 
necessarily  sufficient  as  a  correction  if  elements 
previously  oriented  longitudinally  were  participating 
in  the  circular  stretch. 

This  is  not  to  say  that  all  the  hysteresis  phenomenon 
could  be  due  to  a  progressive  recruitment  of  longi- 
tudinal fibers  into  a  circular  plane.  The  loop  still 
present,  despite  many  consecutive  stretchings,  prob- 
ably denotes  a  structural  rearrangement  of  elements 
under  load  that  were  already  in  the  plane  of  the 
stretch.  It  is  admittedly  strange  that  such  a  rear- 
rangement would  have  no  clear  time  dimension. 

An  occluded,  in  situ  aorta  being  pulsed  by  volume 
injections  shows  a  similar  pattern  of  hysteresis  and 
change  in  extensibility  curve  with  successive  stretches 
(5).  We  attempted  a  quantitative  assessment  of 
possible  differences  between  total  aortic  distensibility, 
as  measured  by  injections  of  saline  into  dead  but  in 
situ  aortas,  and  as  compiled  from  stretch  data  made 
on  rings  cut  serially  from  the  same  vessels  (103).  The 
volume  required  to  produce  a  given  rise  in  pressure 
was  greater  than  that  estimated  from  the  first  stretch 
curves  of  the  isolated  rings.  It  was  also  a  little  greater, 
although  perhaps  not  significantly  so,  than  that 
expected  from  the  second  stretch  curves. 

On  hindsight,  this  comparison  may  not  have  been 
so  definitive  as  we  supposed.  At  the  time  the  experi- 
ments were  done,  we  were  not  so  aware  of  the  large 
effect  of  the  time  interval  between  successive  stretches, 
of  the  initial  pressure  level,  and  of  the  peak  pressure 
reached,  on  the  contour  and  values  of  the  extension 
curve. 

Selection  of  Representative  Curves 

Historically,  an  interpretation  of  vessel  wall  archi- 
tecture has  been  based  on  the  contour  of  a  first,  or  a 
second,  large  and  continuous  extension  curve.  It 
should  now  be  obvious  that  this  contour  should  not 
be  regarded  as  characteristic  of  wall  extension  during 
unceasing,  repetitive  stretches,  such  as  would  be 
present  during  life.  How  large  the  differences  between 
the   two  curves   might   be  will   be   elaborated   more 


fully  later  in  this  paper.  Ultimately,  a  study  of  vessel 
wall  behavior  must  be  based  on  pressure  and  diameter 
or  volume  measurements  made  during  life.  Such 
studies  will  be  technically  difficult,  and  interpretation 
of  the  records  will  be  difficult,  since  in  life  the  heart 
rate  and  the  pulse  pressure  are  continually  changing 
from  beat  to  beat.  Work  on  this  problem  is  in  progress 
in  a  number  of  laboratories,  and  some  results  have 
been  published  (87,  91,  113).  Unfortunately,  these 
show  some  differences,  and  the  adequacy  of  the 
various  techniques  has  yet  to  be  firmly  established. 
But  taking  the  data  as  they  now  stand,  it  appears 
possible  that  while  the  amount  of  hysteresis  varies 
among  arteries,  it  is  probably  less  than  that  shown 
by  the  isolated  rings.  This  may  be  because  the  living 
aorta  is  being  cyclically  stretched  without  pause. 

The  suggestion,  which  needs  further  corroboration, 
that  the  diameter  change  of  a  living  vessel  for  a  given 
pulse  pressure  is  less  than  that  given  by  an  isolated 
ring  (61,  78,  87,  91)  could  indicate  that,  for  some 
quite  unknown  reason,  a  very  different  distensibility 
is  present  in  the  living  vessel.  In  one  study  (91)  the 
reported  diameter  change  is  so  much  smaller  that  our 
whole  concept  of  the  functional  character  of  the  vessel, 
as  will  be  developed  in  this  paper,  would  have  to  be 
changed.  We  are  not  satisfied  yet  that  the  instrument 
used  could  record  a  change  as  large  as  that  expected 
from  the  ring  stretch  data.  Reconciliation  between 
the  various  sets  of  data  should  not  be  long  delayed. 

Until  the  properties  of  the  in  vivo  aorta  are  known 
more  surely,  we  must  base  a  description  of  the  factors 
which  might  condition  the  extensibility  curve  on 
data  taken  from  isolated  rings.  If  these  data  should 
eventually  prove  quantitatively  wrong,  we  can  only 
hope  that  the  fundamental  properties  of  the  vessel 
would  nonetheless  be  qualitatively  the  same.  First, 
the  nonlinearity  of  the  continuous  stretch  curve  is 
evidence  for  an  internal  architecture  more  com- 
plicated than  that  seen  even  with  rubber  or  other 
polymers.  In  the  range  of  maximal  extensibility,  the 
aorta  shows  more  length  change  per  unit  tension 
increase  than  anv  other  material  of  comparable  wall 
thickness.  Nature  seems  to  have  created  a  far  better 
volume  reservoir  than  man  can  duplicate. 

Histological  Considerations 

We  know  from  histological  evidence  that  the  large 
vessels  have  four  general  types  of  tissue — endothelial 
cells  (with  associated  intracellular  materials),  smooth 
muscle  cells,  elastic  fibers,  and  collagenous  fibers. 
Because  histology  texts  tend  to  emphasize  a  collection 


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of  these  tissues  into  more  or  less  well-demarcated 
layers,  physiologists  have  taken  what  probably  is  an 
oversimplified  approach  to  an  analysis  of  wall  ex- 
tensibility, and  have  considered  each  of  these  tissue 
types  to  be  unconnected  and  arranged  in  parallel. 
But  while  elastic  tissue  does  appear  to  be  condensed 
into  layers,  it  also  is  interspersed  between  muscle  and 
collagenous  fibers.  And  there  seem  to  be  connections 
between  the  gross  layers  themselves,  which  means 
that  we  can  hardly  consider  the  influence  of  any  one 
tissue  type  alone.  Nor  are  we  at  all  certain  about  the 
elastic  characteristics  of  the  different  tissues,  even  if 
they  were  to  behave  independently.  The  extensibility 
of  the  endothelial  cells  is  relatively  unknown  in  any 
quantitative  sense.  Since  they  comprise  but  a  very 
small  part  of  the  wall,  and  since  they  certainly  are 
not  stiff  enough  that  they  are  torn  by  even  large 
stretches,  they  probably  are  relatively  extensible,  and 
their  influence  can  probably  be  neglected  for  the 
present.  An  estimate  of  the  extensibility  of  collagenous 
fibers  has  been  taken  from  that  shown  by  tendon, 
although  the  collagenous  fibers  of  the  latter  are  larger 
and  more  densely  packed.  As  opposed  to  a  tissue 
containing  elastic  fibers,  tendon  is  quite  inextensible 
and  shows  a  linear  stress-strain  relation  with  no 
discernible  visco-elastic  properties  (21,  52,  67,  97, 
103,  112).  The  aortic  wall  stiffening  seen  when  the 
pressure  rises  above  about  100  mm  Hg  has  thus  been 
attributed  to  the  resistance  to  stretch  offered  by  the 
enclosing  jacket  of  collagenous  fibers  (21,  103).  Aortic 
walls  from  which  elastic  tissue  and  muscle  have  been 
digested  show  a  similar  stiff  wall  (50,  1 1 1 ).  This 
jacket  must  fit  loosely  and  be  considered  in  parallel 
to  the  underlying  elastic  tissue.  Once  it  starts  to 
participate  in  the  stretch,  it  will  assume  the  bulk  of 
the  applied  load. 

On  the  basis  of  stretch  curves  shown  by  ligamentum 
nuchae,  which  is  predominantly  elastic  tissue,  elastic 
fibers  are  much  more  extensible  than  collagenous 
fibers.  Chemically  treated  aortas  which  retain  only 
their  elastin  show  an  increased  extensibility,  one  not 
greatly  different  from  that  of  the  whole  vessel  in  the 
lower  stretch  range  (51,  52,  74,  111).  Most  workers 
ascribe  a  linear  stress-strain  relation  to  these  fibers, 
too.  Hence  my  work  (97)  seems  to  stand  alone  in  the 
claim  that  ligamentum  nuchae  shows  a  nonlinear 
curve  not  unlike  that  of  the  arteries  (with  a  stiffening 
in  the  upper  tension  range  despite  the  absence  of  any 
clear  collagenous  fibrous  coat),  and  also  has  visco- 
elastic  properties  similar  to  those  of  the  aorta.  Since 
the  elastic  fibers  in  both  organs  seem  arranged  in  a 
reticulum,   and   since  the  visco-elastic   properties  of 


dog  ligamentum  nuchae  seem  clear,  the  following 
analysis  will  be  based  on  a  similarity  in  stretch  be- 
havior of  the  two  tissues. 

Assessment  of  the  extensibility  of  smooth  muscle 
cells  is  on  most  insecure  ground.  Studies  have  been 
made  of  the  stretch  properties  of  muscular  organs, 
such  as  the  bladder  or  gut,  for  this  purpose  (6,  97, 
101,  102),  although  the  muscle  fibers  here  are  en- 
meshed in  a  loose  weave  of  collagenous  and  even  some 
elastic  fibers  too.  If  this  muscular  tissue  is  subjected 
to  a  moderately  rapid  stretch,  its  extensibility  is  only 
about  a  third  as  great  as  that  shown  by  ligamentum 
nuchae  (97).  But  because  these  tissues  have  such  a 
pronounced  time-dependent  creep,  if  one  waits  for 
the  length  to  approach  a  final  value  under  a  given 
load,  the  total  extensibility  is  greater  than  that  of 
elastic  tissue.  This  has  been  the  procedure  used  when 
elastic  moduli  for  muscular  structures  have  been 
derived.  But  it  seems  unreasonable  that  the  muscle 
contained  in  the  aortic  wall  could  show  such  a  pro- 
longed creep.  If  the  muscle  cells  are  coupled  to  the 
elastic  fibers,  creep  would  be  effectively  prevented  by 
the  resistance  these  fibers  would  offer  to  an  elonga- 
tion. Of  course,  the  greater  the  amount  of  muscle 
involved  in  the  vessel  wall,  the  greater  would  be  the 
creep.  At  one  extreme,  the  umbilical  artery,  which  is 
almost  solely  muscle,  shows  a  very  pronounced  stress 
relaxation  under  load  (122,  141).  In  most  large 
arterial  vessels  the  relaxation  is  of  more  limited 
degree.  Hence  the  muscle  contained  would  probably 
be  stiffer  than  the  elastic  fibers,  which  would  remain 
the  most  extensible  part  of  the  wall. 

It  should  be  noted  that  the  pulmonary  artery  shows 
a  difference  in  distensibility  behavior  from  the  aorta. 
The  form  of  the  stretch  curve  is  more  akin  to  that  of 
a  large  vein  (105).  The  vessel  shows  more  creep  than 
does  the  aorta  (32).  The  form  and  the  total  length 
change  of  the  stretch  curve  are  different  in  pulmonary 
vessels  that  have  been  frozen  and  thawed  than  when 
simply  kept  in  Ringer-Tyrode  solution  (a  reflection  of 
the  effect  of  viable  muscle?)  (32). 

There  is  histological  evidence  that,  in  the  aortic 
wall  at  least,  muscle  cells,  elastic  fibers,  and  some 
collagenous  fibers  are  interlinked  into  a  three- 
dimensional  network  (11,  109).  The  elements  in  this 
network  could  be  partly  in  series  and  partly  in 
parallel.  The  extensibility  of  the  whole  tissue  could 
be  a  reflection  of  the  form  of  the  net  just  as  well  as 
it  could  be  conditioned  by  the  individual  tissues.  For 
example,  Bull  (20)  showed  that  while  a  single  nylon 
thread  obeyed  Hooke's  law,  and  had  no  visco-elastic 
behavior,    a    stocking    woven    from    such    a    thread 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


showed  a  bowed  extensibility  curve  not  unlike  that 
of  the  aorta  or  of  ligamentum  nuchae,  and  also 
showed  a  pronounced  hysteresis  loop.  When  f 
stretched  a  stocking  by  the  techniques  used  for  an 
isolated  ring  of  aorta,  the  dry  specimen  showed  an 
appreciable  rate-dependent  element  (viscosity)  in  the 
tension  response  to  a  given  strain.  When  the  stocking 
was  wet,  this  viscous  element  was  relatively  reduced, 
and  there  was  unmasked  both  a  prolonged  creep  and 
the  "architectural  dependency"  which  is  so  con- 
spicuous for  the  hysteresis  behavior  of  the  aorta. 

If  the  analogy  of  the  stocking  is  valid,  the  first 
part  of  the  stretch  curve  of  the  aorta  would  reflect 
only  a  geometrical  rearrangement  of  the  net.  The 
resistance  to  stretch  would  be  a  function  of  the  loose- 
ness of  the  "weave"  and  the  presence  of  a  lubricant 
(as  in  the  wet  stocking);  there  also  could  be  a  "set" 
of  the  net,  which  could  be  subject  to  change  with 
time,  with  muscular  activity,  and,  very  definitely,  be 
influenced  by  the  size  of  a  previous  stretch.  When, 
under  applied  load,  the  net  lost  its  form,  the  ex- 
tensibility would  progressively  decrease,  both  because 
the  mechanical  advantage  of  the  fibers  in  resisting 
the  stretch  would  be  increased  and  because  the  fibers 
themselves  would  now  be  involved  in  the  extension. 
If  our  ideas  of  the  relative  extensibilities  of  the 
different  components  is  correct,  and  if  they  were 
arranged  in  the  net  in  series,  the  elastic  fibers,  being 
most  extensible,  would  condition  the  extension  of  the 
whole  wall.  With  more  load,  these  elastic  fibers  would 
become  stiffer  (as  they  do  in  ligamentum  nuchae), 
and  other  components  of  the  net  could  be  increasingly 
involved.  Probably  the  idea  of  a  parallel  outer 
collagenous  jacket  should  still  be  retained  to  con- 
tribute to  the  final  wall  stiffness. 

In  an  earlier  analysis  (103)  we  treated  the  aorta 
as  though  it  contained  the  three  tissue  types  as 
arranged  in  parallel.  Since  muscle  had  to  be  able  to 
reduce  the  vessel  diameter  below  its  normal  unloaded 
size,  we  conceived  of  the  elastic  jacket  as  fitting 
loosely  over  the  muscle  coat.  This  would  mean  that 
muscle  alone  would  be  involved  in  the  very  first  part 
of  the  stretch  curve,  and  that  only  later  in  the  stretch 
would  the  elastic  fibers  start  to  participate.  Such  an 
arrangement  seemed  amply  supported  by  evidence 
obtained  with  stretchings  repeated  daily,  using  rings 
as  they  were  allowed  to  putrefy.  In  this  process  muscle 
cells  lost  their  integrity  first  and  the  unloaded  diameter 
increased  while  the  initial  slope  of  the  stretch  curve 
became  steeper.  Much  later,  the  elastic  fibers  softened 
and  their  continuity  became  disrupted.  Now  the 
unloaded  diameter  had  again  increased,  and  the  aorta 


showed  a  stiffness  not  unlike  that  seen  at  high  load 
levels  in  the  normal  state,  which  was  attributed  to  the 
collagenous  fibers  still  present.  The  net  model  would 
fit  these  putrefaction  studies  equally  well,  for  loss  of 
muscle  could  partly  disrupt  the  net  to  give  an  increase 
in  unloaded  diameter  and,  at  the  same  time,  leave  the 
wall  less  extensible. 

There  still  remain  several  features  of  the  visco- 
elastic  behavior  of  the  aortic  wall  which  would  not  be 
easily  explained  on  the  basis  of  the  net.  And  the 
details  of  net  construction  are  left  purposefully  vague. 
The  general  concept  has  much  in  common  with  the 
model  proposed  by  Burton  (21),  except  for  its  de- 
emphasis  of  the  specific  location  and  role  of  the 
muscle  fibers  themselves.  He  was  much  concerned 
that  the  muscle  be  afforded  a  great  mechanical 
advantage,  so  that  it  could  always  effect  a  diameter 
change.  Hence  he  placed  these  fibers  across  the  plane 
of  a  fibrous  net,  which  would  protect  them  from 
elongation.  In  muscular  tissues  it  remains  uncertain 
that  the  contractile  ability  of  muscle  fibers  is  neces- 
sarily impaired  when  they  are  elongated,  even  by  the 
amount  that  may  normally  be  developed  in  an  organ 
such  as  the  urinary  bladder.  Further,  it  may  be  that 
even  in  smooth  muscle  organs  the  muscle  cells  are 
arranged  into  a  somewhat  similar  net  (101,  102).  It 
may  be  that  the  muscles  in  the  aortic  wall  are  at- 
tached to  adjacent  loops  of  the  net  (which  would 
give  them  more  of  a  parallel  arrangement  than  a 
series  one  with  the  elastic  and  collagenous  fibers),  so 
that  they  could,  by  shortening,  act  to  "open  the 
weave,"  and  perhaps  increase  its  "set."  This  need  not 
mean  that  the  stiffer  muscle  would  now  condition  the 
extensibility  curve,  for  we  could  have,  with  extension, 
a  warping  of  the  net  toward  these  muscle  links.  Hence, 
the  internal  architecture  could  be  quite  different 
when  muscle  was  contracted  than  when  relaxed, 
even  though  the  diameter  values  under  a  given  load 
might  be  the  same. 

Effects  of  Active  Muscular  Contraction  on  Distensibility 

Whether  it  is  necessary  that  a  model  provide 
muscle  with  a  large  mechanical  advantage  cannot  be 
answered.  We  are  not  sure  just  how  effective  muscle 
contraction  really  is  in  a  vessel  under  a  load  equivalent 
to  that  of  the  usual  physiological  pressure  values. 
Much  work  is  currently  being  done  in  which  strips 
of  aorta  are  used  as  conveniently  long  tissues  to  test 
the  effect  of  drugs,  or  changed  electrolyte  environ- 
ment, on  muscle  contraction  (35,  79,  80,  121).  To  be 
useful   as  a  bio-assay   material,   such  strips  must  be 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


807 


under  minimal  load.  Isolated  aortic  rings  will,  when 
unloaded,  respond  to  immersion  in  epinephrine,  for 
example,  by  a  shortening  of  both  their  diameter  and 
length,  to  produce  a  pressure  rise  of  some  3  to  5  mm 
Hg.  But  if  these  contracted  rings  are  subjected  to 
stretch,  the  decreased  diameter  is  lost  rather  early 
(fig.  1A),  so  that  by  the  time  loads  equivalent  to  the 
usual  working  pressures  are  reached,  the  contracted 
and  relaxed  rings  show  identical  extensibility  curves. 
With  stretch  release,  the  diameter  does  not  return 
to  the  contracted  size.  Either  the  muscle  loses  its 
contraction  early  in  the  stretch,  or  the  other  parts  of 
the  net  have  contributed  more  than  usual  to  the  total 
extension.  Even  in  muscular  organs,  such  as  the 
bladder  (102),  the  effect  of  contraction  on  the  ex- 
tensibility curve  is  small,  and  the  contraction  itself 
seems  not  to  be  eliminated  by  the  imposed  stretch 
(97,  1 18).  The  extensibility  of  a  muscular  organ  is  not 
very  different  in  the  contracted  or  relaxed  state  (6, 

'3)- 

What  is  more  disquieting  is  that  if  an  aortic  ring 

is  first  subjected  to  a  load  equivalent  to  a  pressure  in 
the  usual  physiological  range,  immersion  in  epi- 
nephrine will  no  longer  produce  a  discernible  diameter 
or  pressure  change.  It  is  hard  to  accept  this  finding 
as  rational.  Yet  neither  viable  isolated  specimens  nor 
a  temporarily  occluded  aorta  in  situ  (5)  has  been 
shown  to  have  a  more  powerful  muscle  action.  This 
is  not  to  say  that  a  contraction  in  muscular  arteries, 
where  the  ratio  of  wall  muscle  to  internal  diameter  is 
greater,  could  not  influence  the  diameter  at  the 
higher  pressure  levels. 

Attempts  have  been  made  to  record  the  effects  of 
muscle  contraction  in  the  intact  aorta  while  it  is 
being  pulsed  by  the  heart.  Most  of  these  I  have 
learned  of  through  conversations,  since  there  is 
reluctance  toward  publication  of  negative  findings. 
In  the  literature  are  the  older  experiments  of  Wiggers 
&  Wegria  (138)  in  which  an  aortagraph  was  placed 
around  the  thoracic  aorta  of  a  dog.  After  an  intra- 
venous injection  of  epinephrine  or  elicitation  of  a 
strong  pressor  reflex,  there  was  a  recorded  decrease 
in  diameter  (the  actual  values  not  being  given)  at  a 
time  when  the  aortic  pressure  was  not  changing.  For 
many  years  these  results  stood  unchallenged  and  yet 
unsupported.  More  recently,  Patel  and  co-workers 
(88)  found  a  change  in  both  diameter  and  wall 
stiffness  in  the  main  pulmonary  artery  with  muscle 
contraction,  a  change  persisting  through  several 
normal  pulsations.  The  pulmonary  pressure  is,  of 
course,  much  lower  than  that  of  the  aorta  and  the 
wall  architecture  is  not  the  same.  Then  Peterson  and 


co-workers  (91)  showed  a  change  in  diameter  and  an 
increased  stiffness,  with  arterial  pressure  unaltered, 
when  the  femoral  artery  or  carotid  artery  was  painted 
with  norepinephrine.  Opposite  results  were  obtained 
with  acetylcholine.  The  authors  claim  a  similar 
directional  change,  but  furnish  no  supporting  figures, 
for  the  aorta.  These  results,  and  particularly  the 
claim  for  the  aorta,  must  be  amplified  and  confirmed. 

Diameter  and  extensibility  changes  in  the  aorta  of 
living  animals  following  the  use  of  constrictor  or 
dilator  drugs  have  been  recorded  (78)  which  do  not 
appear  to  fit  with  the  stretch  data  obtained  with 
isolated  rings.  Since  the  arterial  pressure  also  changed, 
and  since  the  physiological  distensibility  curve  for 
the  intact  aorta,  quite  aside  from  any  muscle  action, 
remains  to  be  formulated,  an  attempt  to  interpret 
these  changes  on  the  basis  of  muscle  contraction 
would  be  premature. 

We  are  not  yet  in  a  position,  then,  to  answer  the 
long-debated  question  as  to  whether  muscle  con- 
traction should  increase  or  decrease  the  wall  ex- 
tensibility. The  effects  of  such  contraction  on  the 
stretch  curves  shown  by  isolated  vessels  are  difficult 
to  phrase  in  terms  of  generalities.  With  an  unloaded 
vessel,  contraction  is  not  followed  by  relaxation. 
Instead,  over  a  period  of  time,  the  wall  gradually 
becomes  stiffer,  as  though  the  fibers  had  been  reset 
to  the  shorter  length.  Whether  the  contraction  had 
any  essential  role  in  this  resetting,  aside  from  the 
first  reduction  in  length,  remains  uncertain.  De- 
pending upon  the  amount  of  this  resetting,  a  small 
stretch,  starting  from  zero  tension,  will  reflect  this 
initial  stiffness  of  the  wall.  With  more  stretch,  the 
distensibility  suddenly  increases,  so  that  the  stretch 
curves  of  the  once  contracted  and  the  relaxed  ring 
are  now  parallel.  At  higher  loads  the  two  curves 
merge.  If  one  assays  distensibility,  it  must  always  be 
with  respect  to  the  amount  of  load  used.  Thus,  if  the 
stretch  is  sufficient  to  cause  the  shift  toward  the 
increased  distensibility,  one  would  conclude  that  the 
muscle  contraction  had  rendered  the  wall  more 
extensible.  If  the  assay  were  on  the  basis  of  the  very 
first  part  of  the  stretch  curve  only,  one  would  reach 
the  opposite  conclusion  of  a  lessened  extensibility. 
Whether  the  effects  shown  by  an  unloaded  tissue 
have  any  pertinence  to  what  might  happen  at  physio- 
logical pressure  levels  remains  to  be  shown.  If,  for 
some  reason,  the  muscle  in  the  living  aorta  were  more 
powerful,  or  if  the  imposed  stretch  were  made  quite 
small,  we  might  anticipate  a  decreased  wall  dis- 
tensibility. Even  so,  any  interpretation  of  the  effect 
of  muscle  contraction  would  have  to  be  phrased  in 


8o8  HANDBOOK    OF    PHYSIOLOGY    -i    CIRCULATION    II 


terms  of  the  shape  of  the  stretch  curve,  and  the  total 
stretch  employed. 

Effects  of  Aging  on  Arterial  Dislensihility 

The  effects  of  aging  on  arterial  distensibility  are 
supposed  to  be  well  established — at  least  the  textbooks 
so  report.  The  actual  evidence  leaves  much  to  be 
desired.  On  the  one  hand  is  the  story  of  pathologists 
that  aging  is  accompanied  by  a  reduction  in  muscle 
mass  and  in  elastic  tissue,  with  a  replacement  by 
collagenous  fibers.  The  reduction  of  muscle  mass  needs 
documentation  by  actual  cell  counts.  Chemical 
digestion  of  the  aortic  walls,  to  leave  only  elastin, 
left  Lansing  (74)  unwilling  to  accept  the  dictum  that 
the  elastic  fibers  had  been  reduced  in  number  with 
age.  He  would,  of  course,  accept  the  possibility  of  a 
chemical  change  which  might  influence  the  wall 
extensibility. 

Extensibility  studies  made  on  isolated  vessels  taken 
from  humans  of  different  ages  suffer  from  our  un- 
certainty about  how  to  compare  extensibility  among 
different  specimens.  The  repeatedly  quoted  studies 
of  Hallock  &  Benson  (37),  based  on  a  small  series, 
in  which  only  the  average  results  of  a  given  age  group 
were  presented,  showed  some  decrease  in  extensibility 
with  age,  with  the  only  truly  large  change  seen  in 
individuals  over  70  years.  The  comparative  data  were 
expressed  in  terms  of  an  elastic  modulus  (AP/(AV/V). 
Here,  as  in  all  other  reports  (10,  62,  66,  81,  107,  127), 
there  was  a  progressive  increase  in  unloaded  diameter 
with  age,  which  in  itself  could  increase  the  value  of 
this  modulus.  In  a  study  of  a  larger  series  of  human 
aortas  (107)  we  presented  results  taken  from  the 
second  of  two  consecutive  stretch  curves.  Variations 
within  the  age  groups  were  large.  While  the  group 
averages  showed  a  progressive  increase  in  initial 
diameter,  it  was  also  true  that  a  man  of  68  showed 
the  same  diameter  as  a  girl  of  18.  All  these  aortas 
were  screened  so  as  to  include  none  showing  athero- 
sclerosis, and  any  from  individuals  with  a  history  of 
hypertension  were  placed  in  a  separate  category. 
The  diameter  increase  was  especially  noticeable  in 
these  hypertensives.  The  slopes  (AP/AV)  given  by 
the  stretch  curves  also  showed  intraindividual  varia- 
tion, but  they  were  very  much  more  constant  than 
were  the  initial  diameters,  and  there  was  no  clear 
trend  for  this  slope  to  change  with  age.  A  changed 
modulus  value  with  aging  was,  then,  predominantly 
conditioned  by  a  change  in  the  initial  diameter. 


Expression  of  Extensibility'  in  Terms  of  Moduli 

This  raises  the  question  as  to  just  how  meaningful 
a  modulus  value  is  in  expressing  extensibility  data. 
Certainly  having  to  present  a  whole  stretch  curve  for 
each  specimen  studied  is  cumbersome,  and  such  data 
are  difficult  to  handle  statistically.  But  a  modulus  is 
supposed  to  afford  insight  into  the  architecture  of  the 
specimen.  Thus  when  a  physicist  wishes  to  describe 
the  extensibility  as  a  property  of  a  material,  he  uses 
Young's  modulus,  or  a  related  one,  which  is  simply 
the  ratio  of  the  applied  extending  force  or  stress,  as 
expressed  per  unit  area  of  material,  to  the  proportion- 
ate change  in  length  from  the  unloaded  value.  Most 
of  his  materials  are  so  stiff  that  the  strain  is  small. 
Further,  the  material  promptly  returns  to  the  initial 
length  upon  removal  of  the  stress,  and  in  measuring 
extensibility  he  obtains  a  clue  to  the  force  of  this 
return.  He  therefore  calls  his  modulus  one  of  elasticity, 
despite  the  fact  that  he  is  measuring  extensibility  and 
not  elasticity  at  all.  Any  time  delay  in  effecting  the 
strain  is  usually  so  brief  as  to  be  inconsequential.  When 
the  ratio  of  stress  to  proportional  strain  is  constant 
(he  carefully  avoids  a  load  sufficient  to  cause  per- 
manent yield  or  plastic  deformation),  this  ratio  can  be 
calculated  by  using  any  convenient  load.  Because 
most  materials  do  not  have  a  constant  ratio,  and  some, 
as  cast  iron,  depart  quite  significantly  from  a  linear 
relation,  he  tries  to  make  his  applied  stress  as  small 
as  feasible. 

When  we  turn  to  materials  such  as  the  polymers, 
the  stress-to-strain  ratio  is  definitely  not  linear. 
Further,  the  recorded  strain  is  a  function  of  the  time 
allowed  under  load;  and  the  material  may  not 
promptly  return  to  the  same  unloaded  length.  Be- 
cause of  the  last,  it  is  definitely  not  proper  to  call  the 
modulus  one  of  elasticity.  As  a  substitute,  one  could 
construct  a  modulus  of  extensibility,  which  would  be 
the  reciprocal  of  what  is  usually  called  the  modulus 
of  elasticity.  On  the  thesis  that  there  has  been  no 
internal  change  in  the  material  because  of  the  stress, 
and  that  the  original  internal  architecture  will  be 
precisely  restored  after  load  release,  the  physicist 
continues  to  use  a  modulus  as  a  proper  expression  of 
extensibility  even  with  polymers.  To  emphasize  the 
fact  that  the  modulus  calculations  are  based  only  on 
the  values  seen  during  extension,  rather  than  during 
the  elastic  recoil,  I  have  used  the  symbol  S  rather 
than  the  conventional  E  in  all  the  equations  pre- 
sented below.  It  should  be  obvious  that  one  must 
append  to  any  modulus  calculation  a  careful  descrip- 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


8o9 


tion  of  the  stress  used  and  the  time  over  which  it 
acted.  This  has  seldom  been  done.  A  derived  slope 
obtained  by  the  use  of  a  conveniently  large  stress, 
because  of  the  nonlinearity  of  the  stretch  curve,  often 
has  no  counterpart  in  this  curve — the  modulus 
represents  a  mathematical  figure  only. 

Evidence  presented  above  leaves  room  for  doubt 
that  the  internal  structure  of  a  vascular  tissue  is 
necessarily  the  same,  just  because  the  unloaded 
diameter  might  be  restored.  This  restoration  might 
involve  muscle  contraction,  or  it  might  be  due  to  a 
passive  creep  recovery.  Even  in  the  latter  case,  an 
architectural  rearrangement  conditioned  by  the 
stretch  might  still  be  present.  We  have  seen  that,  with 
enough  load,  the  contracted  ring  may  start  from  a 
smaller  diameter  but  reach  the  same  stretched  value 
as  an  unstimulated  one.  Shall  we,  from  the  calculated 
modulus  value,  deduce  that  the  tissue  has  been 
weakened  because  of  the  muscle  contraction?  We 
have  seen  that  with  aging  the  unloaded  diameter 
tends  to  increase — an  increase  which  may  or  may  not 
be  at  the  expense  of  the  elements  which  condition  the 
major  portion  of  wall  extensibility.  Here,  a  calculated 
modulus  value  might  seem  to  be  evidence  for  a  wall 
stiffening,  which  may  or  may  not  have  developed. 
In  those  cases  where  the  slope  of  the  pressure-volume 
curve  remains  unchanged,  we  may  seriously  doubt 
that  the  increased  modulus  value  is  an  overly  mean- 
ingful index  to  wall  stiffness. 

The  claim  is  often  made  that  the  increase  in 
diameter  is  a  way  of  compensating  for  a  wall  stiffening 
with  age.  This  statement  arose  from  the  modulus 
formula  itself.  If  the  ratio  of  AP/AV  remains  constant, 
the  volume  uptake  for  a  unit  length  of  vessel  remains 
constant,  and  the  change  in  initial  diameter  can 
hardly  be  said  to  be  a  compensation  at  all.  Actually, 
as  will  be  discussed  later,  the  diameter  change  will 
affect  the  propagation  velocity  of  the  pulse  wave, 
which  will  affect  the  length  of  vessel  that  is  receiving 
volume  at  any  given  time  interval.  Thus,  indirectly, 
some  compensation  for  a  wall  stiffening  might  be 
effected,  but  it  is  questionable  that  this  effect  can  be 
stated  in  quantitative  terms,  and  any  such  formulation 
certainly  would  not  use  the  same  equation  as  is  used 
for  a  modulus  calculation.  For  the  time  being,  it 
appears  essential  that  before  we  can  talk  in  meaning- 
ful fashion  about  changes  in  stiffness  of  the  wall,  a 
change  in  the  actual  slope  of  the  pressure-diameter  or 
pressure-volume  curve  alone  must  be  shown.  It  is  on 
this  last  point  that  the  evidence  on  the  effect  of  aging 
seems  to  be  weakest. 


Since,  when  one  is  working  with  a  vessel  during 
life,  the  stretch  does  not  start  from  an  unloaded  size, 
another  modulus  has  often  been  substituted,  in  which 
the  diameter  change  is  related  to  the  real  size  seen 
just  before  the  new  increment  in  stress  was  applied, 
i.e.,  the  diastolic  diameter.  This  modulus  is  just  as 
justifiable  as  that  given  above,  but  its  value  must  be 
quite  different.  One  can  be  converted  to  the  other 
arithmetically  only  if  the  tension-length  relation  is 
linear.  Unfortunately,  the  two  moduli  have  too  often 
been  treated  as  interchangeable.  Finally,  since 
changes  in  pressure  and  volume  are  usually  the 
primary  data  in  the  living  aorta,  a  modulus  based  on 
the  pressure-volume  relation  has  been  substituted. 
Conversion  of  this  modulus  to  that  using  tension  and 
length  is  quite  complicated.  Perhaps  the  interrelations 
could  be  best  expressed  in  terms  of  their  derivations: 

Young's  modulus  (length)  is  the  applied  force  per 
unit  area  divided  by  the  proportionate  length  change. 
For  a  circumference  increase,  the  area  over  which  a 
given  load  is  applied  will  be  the  length  of  the  ring 
(/)  times  the  wall  thickness  (a).  The  strain  will  then 
be  the  relative  increase  in  circumference,  i.e.,  2irAr/ 
2irr,  or  Ar/r.  Since  the  material  is  being  stretched 
from  an  unloaded  state,  the  applied  tension  will  be 
AT,  and  r  will  be  ra. 

Thus 


AT 
Ar 


*Tr0 
Ar 


:d 


If  the  change  in  radius  and  in  tension  are  small 
enough  that  they  lie  on  the  actual  stretch  curve,  the 
equation  can  be  written  as 


S.OIr*- 


dr 


(2) 


This  derivation  assumes  that  there  will  be  no  signifi- 
cant change  in  length  or  in  wall  thickness  accompany- 
ing the  radial  stretch,  which,  with  large  diameter 
changes  at  least,  is  certainly  not  true,  as  will  be 
discussed  later. 

Now  let  us  suppose  that  the  initial  radius  is  not  the 
unloaded  value,  but  is  taken  when  the  tissue  is 
already  under  stretch.  The  basic  equation  would  not 
be  altered: 


S   -^ 
**      Ar 


(3) 


8  m 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


but  the  value  for  Sa  would  not  be  the  same  as  that 
for  S0.  It  the  changes  are  very  small, 


and 


„  -  Ilia 

</       dr 


(4) 


Next,  let  us  express  the  stress  in  terms  of  pressure. 
This  is  usually  clone  by  taking  the  pressure  (P)  as 
equal  to  T/r  (21).  As  pointed  out  by  Frank  (29),  and 
stressed  recently  by  Peterson  et  al.  (91),  when  the  wall 
is  relatively  thick  in  relation  to  the  internal  radius, 
the  more  proper  expression  would  be  P  =  Ta/r, 
where  a  is  wall  thickness.  With  an  imposed  stretch: 
P  +  AP  =  a  (T  +  AT), '(r  +  Ar).  When  P  =  o 
and  T  =  o,  this  becomes  AP{r„  +  Ar)/a  =  AT. 
Substituting  for  AT  in  equation  1  : 


__  AP(r„+  Ar)r0 
o  a  Ar 


(5) 


If  Ar  and  AP  are  very  small,  their  product  will  be 
infinitesimal,  so  that 


5    -    dPro 

0      a  dr 


And  from  equations  3  and  4  we  obtain: 
AP(rd  +  Ar)rd 


a     Ar 


and 


dPr/ 

"        a  dr 


(6) 


(7) 


-    (8) 


Now    to    express   the   radius   change    in    terms    of 
volume: 

V=  Ivr2,   and  V  +  AV  *  lir(r  +  Ar)Z 

'  lir(r2  +  2rAr  +  Ar2),  or 

AV  =  lrr(2rAr  +  Ar2),     or 
AV 


Ar 


Iw(2r  +  Ar) 


Substituting  for  Ar  in  the  denominator  and  then  for 
lief-  in  the  numerator  of  equation  5: 

_   AP(r„  +  Ar)r0l*-(2r0  +  Ar) 
o 


AP(2lri 

a  AV 
/  +  3/jrr2Ar  v-  lvr0Ai 

*) 

a 

AP(2Var„ 
0  0 

AV 
+  3V0Ar 

.  "■*'', 

a 
APV0(2rg 

AV 
+  3Ar  + 

*£> 

a  AV 


(9) 


..    2dPVarn 
0  adV 


(10) 


Substituting  for  Ar  in  the  denominator  of  equation  7, 
and  following  through  as  in  equations  9  and  10: 


AP(rd  + 

Ar)rdl 

w(2rd  i 

■  Ar) 

a 
APV„(2rd 

AV 

+  3Ar 

+   Ar2 

*      rd 

-) 

and 


a  AV 


2dPVdrd 
0         a  dV 


(II) 


(12) 


A    commonly    used,    but    incomplete,    modulus    (see 
equation  7)  is: 


.     APr, 


5,  -- 


d       Ar 
And  another  (see  equation  11)  is: 

b<        AV 


(13) 


(14) 


The  relationship  between  these  moduli  could  be 
illustrated  by  taking  a  hypothetical  tube  with  an 
unloaded  radius  of  10  mm,  in  which  the  radius 
increased  1  mm  for  each  1  g  per  cm2  increase  in 
tension.  The  stress-strain  relation  will  then  be  as 
shown  in  figure  iA.  The  value  for  the  modulus 
(equation  1  )  would  be  10.  The  calculated  pressure- 
radius  and  pressure-volume  curves  would  not  be 
linear  (fig.  2P  and  C). 

A  modulus  calculated  on  the  basis  of  a  loaded 
initial  radius  (equation  3)  will  increase  as  rrf  increases 
(table  1).  A  modulus  based  on  pressure  change  would 
give  the  constant  value  of  10  if  equation  5  is  used,  but 
if  equation  6  is  employed,  the  S0  value  decreases  as 
the  strain  becomes  larger,  so  that  even  a  1  per  cent 
change  in  strain  produces  a  decreased  value.  Curi- 
ously enough,  the  value  of  Sd  calculated  from  equa- 
tion 7  shows  a  constant  value,  while  that  from  equa- 
tion 8  progressively  decreases. 

Converting  the  radius  changes  to  volume  increases 
makes  the  formulas  very  cumbersome.  Once  again, 
equation  10  gives  a  changing  modulus  for  Sot  as 
does  equation  1 2  for  Sj.  There  is  no  simple  way  of 
converting  the  moduli  values  obtained  from  the 
different  formulas  to  each  other. 

Based  on  studies  with  rubber,  King  (62,  63) 
introduced  another  measure  of  extensibility,  /3,  which 
is  the  ratio  of  the  unstretched  length  L0  to  the  maxi- 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


8ll 


® 


3- 

E 

2- 
1- 

UJ 

tr 

l/> 
LU 

a 

RADIUS 

m  m 

1             1 

1 

© 

3n 

o 
UJ 

tr 

2- 

3 
in 

UJ 

1  - 

Q. 

VOLUME    cc 
■   T            1             1 

fig.  2.  Extensibility  and  derived  distensibil- 
ity  relations  for  a  hypothetical  tube  showing  a 
linear  tension-length  relationship. 


10      II 


12       13 


TABLE 

I 

T 
g/crn* 

r 
mm 

P 
cm  X  1  o-a 

V 
cm3 

(3) 

So 

(5) 

So 

(6) 

Sd 
(7) 

Sd 
(8) 

So 

(9) 

Sd 
(12) 

Sd' 

(.3) 

Sd" 
(>4) 

0.  I 

IO. I 

9-9 

3'7 

10.0 

IO.O 

9-9 

10.0 

10.0 

21 .0 

20.6 

9-9 

IO.3 

0.2 

I0.2 

■9 

6 

326 

IO.  I 

10. 0 

9.8 

10.0 

9-8 

10.6 

6.9 

9.8 

3-3 

o-3 

IO.3 

29 

i 

333 

10.2 

10. 0 

9-7 

10.0 

9-9 

10. 1 

9.0 

9-7 

4.4 

0.4 

IO.4 

3B 

5 

34o 

10.3 

10.0 

9.6 

10.0 

9-8 

9-7 

9.2 

9-7 

4-5 

o-5 

IO.5 

47 

6 

346 

10.4 

10.0 

9-5 

10.0 

9.8 

10.0 

10.6 

9-5 

5-2 

1 .0 

I  I  .O 

90 

9 

382 

10.5 

10. 0 

9.1 

10.0 

9-5 

9-7 

8.8 

9-i 

4.2 

2.0 

I2.0 

166 

7 

452 

I  I  .0 

10.0 

8-3 

10.0 

9-2 

10.0 

9.0 

8-3 

4.1 

3-0 

13.O 

230 

8 

532 

12  .O 

10.0 

7-7 

10.0 

9-2 

10.0 

8.2 

7-7 

3-6 

mum  extension  possible.  Hence  /3  =  L0/(Lm!xx  —  L0). 
If  a  proper  Lmax  can  be  determined,  this  ratio  has 
several  advantages,  but  it  also  suffers  from  the  same 
uncertainty  as  to  what  a  proper  L„  value  should  be, 
particularly  if,  in  constructing  the  relationship,  the 
tissue  has  been  stretched  so  as  to  approach  Lmax. 

It  has  become  common  to  compare  a  "dynamic" 
modulus,  as  obtained  with  rapidly  repeated  small 
stretches,  to  a  "static"  modulus.  For  example,  Lawton 
(77)  and  Cope  (22)  reported  a  small  increase  in  the 
dynamic  value  over  the  static  for  the  aorta,  which 
presumably  reflects  the  influence  of  the  rate-de- 
pendent factors  involved  in  the  visco-elastic  behavior. 
But  there  is  confusion  as  to  how  a  static  value  should 
be  determined.  Sometimes  values  taken  from  a 
single  continuous  stretch  curve  covering  the  whole 
range  of  physiological  pressures  are  used  if  the  in- 
volved stretch  has  been  done  slowly.  In  other  cases, 
a  pressure-length  value  representing  the  center  of 
the  dynamic  loop  is  taken  as  indicating  the  static 
value.  Only  rarely  does  this  give  a  value  different 
from  one  based  on  the  peak  values  of  the  loop,  and  it 
would  appear  to  strain  the  definition  to  take  this  as  a 
static  value  at  all.  A  third  method  is  to  hold  a  peak 
load  constant  until,  through  creep,  the  length  has 
approached  a  final  value.  All  three  methods  give 
different  values,  which  simply  indicates  again  that 
more  than  viscosity  is  concerned  in  tissue  hysteresis. 
This  can  be  illustrated  by  an  experiment  shown  in 
figure  3.  An  isolated  ring  of  dog  thoracic  aorta  was 
first  subjected  to  a  continuously  increasing  stretch. 


over  2  min,  to  a  high  tension.  Tension  was  converted 
to  pressure,  and  half-circumference  to  volume.  The 
peak  tension  thus  represented  a  pressure  of  350  mm 
Hg.  The  load  was  then  slowly  released,  over  2  min, 
and,  as  before,  the  ring  did  not  return  to  the  same 
initial  volume  setting.  A  second  identical  stretch  (in 
terms  of  tension)  was  then  made.  The  relations 
obtained  during  this  second  stretch  and  stretch 
release  are  plotted  as  the  solid  line  in  the  figure.  This 
stretch  curve  is  not  different  from  those  we  have  used 
in  the  past  to  classify  the  distensibility  of  aortic  rings. 
Now  the  ring  was  allowed  to  remain  in  Locke- 
Ringer's  solution  for  2  hours,  during  which  time  the 
unloaded  volume  was  very  slowly  decreased.  It  was 
mounted  on  the  stretching  apparatus,  care  being 
taken  not  to  stretch  it  in  the  process.  A  small  length 
change  was  then  made  rather  rapidly  (0.1  sec),  and 
the  stretch  repeated  in  rapid  succession  ten  times. 
Stable  stretch  and  stretch-release  curves  were  es- 
tablished by  this  time.  The  pressure-volume  relations 
of  this  stable  loop  are  given  in  the  figure  as  loop  A. 
The  same  stretch  was  then  performed  an  11th  time, 
but  the  peak  value  was  held  constant  for  5  min, 
allowing  the  pressure  to  fall  to  its  static  value,  some 
2  mm  Hg  lower.  The  ring  was  then  returned  to  a 
volume  setting  part  way  up  the  original  loop,  and  a 
new  series  of  rapid  stretches  made,  the  last  loop 
being  shown  as  B  in  figure  3.  Again  a  static  pressure 
was  obtained.  The  whole  process  was  repeated  13 
times. 

The  initial  volume  for  the  loops  was  first  smaller 


8l2  HANDBOOK    OF    PHYSIOLOGY    -~    CIRCULATION    II 

20C- 


fig.  3.  Pressure-volume  relations  for  a  ring 
of  dog  thoracic  aorta,  in  situ  length  10  mm, 
with  stretch  done  by  continuous  stretch  (curve 
S)  and  by  successive,  repeated  dynamic 
stretches.  The  broken  line,  curve  R,  is  the 
stretch-release  curve  for  the  continuous 
stretch.  The  crosses  mark  the  mid  points  of  the 
successive  hysteresis  loops.  The  solid  points 
represent  the  postdecay  (static)  tension  values 
reached  5  min  after  completion  of  the  stretch. 


150 


100- 


50 


0- 


V0LUME     cc 


1.3 


1.5 


2.1 


2.3 


than  that  given  by  the  continuous  curve,  but  crossed 
it  and  became  greater  at  high  pressure  levels.  The 
continuous  curve  reflected  the  large  stretch  which 
had  preceded  it.  If  less  load  had  been  used  for  this 
stretch,  the  curve  would  have  differed  less  at  low 
pressure  settings,  but  even  more  at  high  pressures. 
It  might  seem  that  a  pressure-volume  curve  obtained 
by  joining  the  midpoints  of  the  respective  loops  might 
give  a  better  measure  of  aortic  distensibility.  But,  in 
life,  the  aorta  is  never  free  from  stretches,  and  any 
departure  from  normotensive  pressure  levels  is  but 
temporary.  We  would  expect,  then,  that  when  the 
pressure  did  fall  below  normal,  the  aortic  volume 
would  be  greater  than  indicated  by  this  curve  con- 
structed from  the  loops. 

More  important,  the  volume  change  (AF)  for  the 
different  pulse  pressures  was  almost  the  same  for  the 
different  loops  as  when  taken  from  the  continuous 
curve.  This  is  particularly  true  in  the  normotensive 
pressure  range.  Hence,  the  very  different  methods  of 
stretching  produced  some,  but  not  large,  changes  in 
the  AP/AF  value.  Now  let  us  express  these  distensi- 
bility curves  in  terms  of  moduli,  using  equation  1 4. 
As  shown  in  figure  4,  the  dynamic  S&  for  each  of  the 
loops,  using  the  peak  value  only,  was  greater  than 


the  static  by  an  average  of  10  per  cent.  The  con- 
tinuous stretch  curve  gave  modulus  values  varying 
from  —  1 5  to  +12  per  cent  of  the  static,  with  an 
average  difference  of  +2  per  cent.  Also  shown  in 
figure  4  are  the  modulus  values  calculated  for  only 
the  very  first  part  of  the  stretch  curve  for  each  of  the 
loops.  The  fit  with  the  other  moduli  is  erratic,  but  the 
values  are  considerably  greater  than  those  based  on 
peak  values.  These  results  are  given  in  detail  only  to 
illustrate  how  difficult  it  is  to  classify  the  behavior  of 
the  aorta  on  the  basis  of  any  single  technique  of 
performing  stretches. 

Changes  in  Length  and  Wall  Thickness  of  Arteries 

In  all  modulus  calculations,  it  is  unrealistically 
assumed  that  length  and  wall  thickness  remain 
constant.  Lawton  (76)  presented  evidence  that  the 
volume  of  the  aortic  wall  remained  unchanged  during 
a  stretch.  This  means  that  as  the  circumference 
increases,  there  should  be  either  a  shortening  in 
length  or  a  decrease  in  thickness.  Fenn  (26)  and 
Fawcett  calculated  that  if  the  wall  is  isotropic,  there 
should  be  no  length  change,  so  that  only  wall  thick- 
ness would   be  involved.   A   direct  recording;  of  the 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


8l3 


180- 
150- 

/ '/  ' 

//// 

//// 

/?/<. 

100- 

1  '/        s 

£ 

1/    * 

E 

/  \ 

V 

a 

(»/ 

ui 

fc                  "" 

a> 

T                   '' 

a. 

'             / 

*P 

/ 

t 

/ 

50- 

tL 

\ 

it  I 

\ 

/ 

9r\- 

U/ 

Dd" 

S 


10 


20 


30 


40 


50 


fig.  4.  Distensibility  modulus  (eq.  14)  calculated  from  the 
data  of  fig.  3.  Solid  line,  from  continuous  stretch  curve.  Dotted 
line  with  dots,  from  peak  values  for  hysteresis  loops.  Dotted 
line  with  triangles,  from  postdecay  (static)  values  for  loops. 
Broken  line,  from  initial  slopes  of  stretch  curves  of  hysteresis 
loops. 

change  in  thickness  during  a  stretch  has  not  been 
made.  There  are  some  sparse  references  to  the  relation 
of  the  unloaded  thickness  (a)  to  the  outside  diameter 
(£)).  Thus  King  (62)  found  an  a/D  ratio  of  .09  for 
human  aortas.  McDonald  (84),  in  a  survey  of  many 
arteries  from  the  dog,  found  a  constant  ratio  of 
.08.  In  studying  the  effect  of  age  on  the  human 
aorta,  King  (64)  found  a  progressive  decrease  in 
thickness,  so  that  the  product  of  thickness  and  radius 
was  nearly  constant.  On  the  other  hand,  young  aortas 
show  more  longitudinal  retraction  upon  excision 
than  do  those  from  older  people  (107),  which  might 
account  for  part,  at  least,  of  the  difference  in  wall 
thickness.  The  question  of  how  much  the  wall  thins 
during  a  stretch  needs  documentation,  since  this 
factor  will  affect  the  derived  modulus  value. 

In  isolated  vessels  subjected  to  a  volume  increase, 
Fenn  found  a  lengthening,  from  which  he  concluded 
that  the  wall  was  anisotropic  (26).  McDonald  (84) 
is  quite  correct  in  emphasizing  that  the  longitudinal 
extensibility  observed  in  isolated  vessels  may  not  be 
a  measure  of  changes  that  might  take  place  in  the 
in  situ  vessel  under  longitudinal  restraint.  Hence  if 
the  intact  vessel  is  in  the  steep  portion  of  the  longi- 


tudinal extensibility  curve,  its  length  changes  with 
each  pulse  would  not  be  large.  The  presence  of  the 
aortic  sheath  might  also  reduce  length  change  in  the 
in  situ  aorta.  It  is  of  interest  here  that  a  pulmonary 
artery  freed  from  surrounding  connective  tissue  showed 
a  longitudinal  thrust  with  a  volume  injection,  while 
one  still  bound  showed  but  minor  change  (32).  Yet 
the  vessel  wall  should  not  become  anistropic  simply 
because  it  was  released  from  its  longitudinal  restraint. 
Length  changes  in  living  animals  have  not  been 
completely  measured.  Lawton  (78),  working  with 
serial  photographs  of  a  dog  abdominal  aorta,  found  a 
small  shortening  in  early  systole  and  a  lengthening 
in  diastole.  This  made  the  length  and  circumference 
changes  almost  180  degrees  out  of  phase.  Similar 
length  changes  for  the  abdominal  aorta  were  found 
by  Patel  and  co-workers  (87).  In  contrast,  they  found 
length  and  diameter  changes  to  be  in  phase  in  the 
thoracic  aorta. 

The  small  length  changes  recorded  seem  in  sharp 
contrast  to  the  sometimes  rather  striking  longitudinal 
thrusts  seen  in  the  aortic  arch.  And  at  times  a  freed 
carotid  artery,  or  more  rarely  a  femoral  artery, 
visually  seems  to  be  showing  a  length  change.  These 
thrusts  might  reflect  factors  other  than  a  distention 
upon  invasion  by  the  pulse  wave,  however.  The  heart 
is  anchored  in  the  chest  by  the  large  vessels.  It  has 
long  been  known  that  the  base  of  the  heart  is  lowered 
in  contraction,  which  must  serve  to  lengthen  the 
aorta  and  pulmonary  artery  (47).  Rushmer  (1 13)  has 
described  this  movement  as  starting  in  the  period  of 
isometric  contraction.  The  motion  of  the  arch,  and  of 
the  brachiocephalic  arteries  which  serve  as  anchor 
points  for  the  arch,  would  reflect  not  only  the  geom- 
etry of  the  vessels  but  the  firmness  of  attachment  of 
the  descending  arch  to  the  body  wall.  Further, 
respiration  displaces  the  aorta,  which  acts  as  though 
it  is  bound  rather  firmly  to  the  diaphragm.  These 
longitudinal  thrusts  would  bear  no  necessary  time 
relation  to  the  arrival  of  the  pulse  wave,  and  a  de- 
ciphering of  the  origin  of  length  changes  in  a  vessel 
may  not  be  easy. 

Considerable  confusion  was  raised  by  a  report  (113) 
that  when  diameter  and  pressure  were  simultaneously 
recorded  in  the  thoracic  aorta,  an  unorthodox 
hysteresis  loop  was  obtained  in  which,  during  stretch, 
the  diameter  change  was  proportionately  greater 
than  the  pressure  change.  These  loops  were  taken 
from  an  oscilloscope.  Inspection  of  the  individual 
diameter  and  pressure  records  indicates  that  the 
whole  of  the  diameter  curve  simply  preceded  the 
pressure  curve  (126).  If  the  two  were  superimposed, 


814 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


ignoring  the  time  lag,  the  expected  hysteresis  loop, 
although  small  in  magnitude,  was  seen.  Maintenance 
of  strict  identity  between  the  site  of  measurement  of 
the  two  variables  is  difficult  at  best.  If  there  has  been 
a  longitudinal  displacement  of  the  aorta,  and  hence 
of  the  circumference  recorder,  through  influences 
other  than  the  arrival  of  a  volume  pulse,  a  seeming 
"phase  lag"  between  the  two  recorders  could  be 
produced. 

Curiously  enough,  with  isolated  strips  of  arteries, 
the  time  lag  is  reported  in  the  opposite  direction  for 
pressure  leads.  From  this  lag  is  calculated  the  viscous 
component  of  a  dynamic  modulus  (48,  84). 

Summarizing,  we  can  say  that  despite  many 
studies  on  the  extensibility  of  the  aorta  and  large 
vessels,  it  is  still  uncertain  whether  the  presented 
stretch  curves  may  be  reflecting  to  such  a  great 
degree  the  techniques  used  that  they  are  not  readily 
illustrative  of  the  characteristics  of  the  wall.  Work  of 
the  future  will  certainly  be  concentrated  on  measure- 
ments made  on  living  vessels,  that  will  include  not 
only  diameter  change  but  changes  in  length,  and 
perhaps  in  wall  thickness.  There  are  not  sufficient 
data  to  allow  a  well-based  speculation  as  to  how  the 
in  vivo  measurements  might  fit  with  those  obtained 
from  isolated  specimens.  The  question  of  how  muscle 
contraction  might  affect  tissue  extensibility,  for  the 
aorta  and  for  the  muscular  arteries,  is  yet  to  be  defini- 
tively answered.  Whether  an  expression  of  extensi- 
bility in  terms  of  a  modulus  is  the  most  satisfactory 
tool  remains  questionable. 


ACTION    OF    THE    AORTA    AS    A    CONDUIT 


Pulsatile  F/01 


Rigid  and  Distensible  Tubes 


Since  the  aortic  flow  is  never  steady,  we  can  turn 
immediately  to  a  consideration  of  pulsatile  accelera- 
tions and  decelerations  rather  than  deal  further  with 
the  classic  hydrodynamic  equations.  As  a  start,  let  us 
visualize  a  piston  pump  connected  to  a  rigid  pipe  of 
uniform  bore,  with  the  piston  being  driven  by  a  large 
force.  Let  us  leave  the  distal  end  of  the  pipe  open,  so 
that  a  flow  through  can  be  established.  Also,  let  us 
imagine  a  valve  system  so  constructed  that  the  barrel 
of  the  pump  can  be  filled,  during  piston  withdrawal, 
from  an  external  reservoir.  To  start  a  pump  cycle,  the 
first  tiny  forward  movement  of  the  piston  will  produce 
a  compression  of  the  adjacent  fluid.  This  initial 
compression  will  represent  a  high  pressure — one  that 
cannot  be  recorded,  since  anv  manometer  used  would 


of  necessity  have  a  membrane,  the  resistance  of  which 
toward  displacement  would  be  less  than  that  of  the 
fluid  or  the  rigid  pipe  walls.  Once  the  involved  force 
is  sufficient  to  overcome  the  factional  resistance  to 
fluid  displacement,  or  to  overcome  the  inertia  of  the 
fluid  column,  flow  can  start.  While  the  time  interval 
between  may  be  short,  we  can  say  that  there  will 
always  be  a  temporal  separation  between  the  creation 
of  the  pressure  force  and  flow  through  the  tube.  This 
is  commonly  spoken  of  as  a  phase  lag,  with  pressure 
leading.  The  definition  of  the  physical  forces  and  the 
quantitation  of  such  lags,  for  both  rigid  and  dis- 
tensible systems,  have  occupied  the  attention  of  many 
physically  minded  workers  of  late  (33,  48,  54,  60,  70, 
^5>  '39)-  I  do  not  consider  myself  qualified  to  judge 
the  relative  contributions  of  these  papers. 

Now  let  the  piston  complete  its  stroke,  and  reverse. 
The  pressure  in  the  pump  will  show  a  sharp  fall,  the 
amount  depending  upon  the  speed  of  inflow  from 
the  side  reservoir.  Since  a  pressure  gradient  has  been 
previously  constructed  in  the  pipe  to  produce  dis- 
placement toward  the  open  end,  or,  if  preferred, 
since  fluid  has  already  been  accelerated  toward  this 
end,  flow  will  continue  for  a  brief  interval  despite 
the  pressure  fall  in  the  pump.  Once  again,  then,  we 
have  a  phase  lag,  and  the  fluid  column  can  be  said 
to  have  an  inertial  force.  If  the  pump  strokes  are 
repeated  at  a  rapid  frequency,  the  flow  per  cycle  will 
be  related  to  how  well  matched  the  duration  of  each 
phase  of  the  pump  cycle  is  to  the  phase  lag,  as  set  by 
the  factional  and  inertial  characteristics  of  the  tube. 
This  principle  of  matching  can  be  illustrated  by 
another  model.  Suppose  a  U-tube  mercury  manom- 
eter is  made  to  oscillate  by  a  periodic  blowing  of 
air  into  a  side  arm  on  one  side  of  the  U-tube.  The 
first  buildup  in  air  pressure  will  displace  the  mercury, 
and  after  this  the  mercury  column  will  oscillate  back 
and  forth,  the  period  being  conditioned  by  the  size 
of  the  tube  and  the  other  components  of  fluid  re- 
sistance to  flow.  If  the  frequency  of  the  air  puffs 
matches  that  of  the  mercury  column,  the  excursions 
will  be  reinforced.  Conversely,  if  the  generating 
frequency  is  out  of  phase  with  the  mercury  oscilla- 
tions, movement  of  the  mercury,  or  "flow,"  will  be 
minimal. 

Equations  which  relate  flow  to  pressure  usually 
express  the  phase  lag  in  terms  of  a  component  of  the 
frequency  of  the  repeated  strokes.  This  is  simplest  if 
the  pressure  buildup  by  the  pump  has  a  sinusoidal 
form.  If  the  stroke  is  of  a  different  form,  the  pressure 
curve  is  broken  down  into  terms  of  a  fundamental 
sine  wave  and  a  number  of  superimposed  harmonics. 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


8l5 


Matching  with  the  resonant  characteristics  of  the 
fluid-filled  tube  could  be  either  with  the  fundamental 
wave  or  one  of  the  prominent  harmonics. 

Use  of  the  same  pump  coupled  to  a  distensible  tube 
of  uniform  bore  and  wall  extensibility  will  present  a 
somewhat  different  pattern.  Because  the  wall  can 
yield,  a  large  part  of  the  energy  imparted  by  the 
piston  can  cause  an  increased  tension  in  the  tube  wall. 
It  is  no  longer  necessary  to  construct  a  pressure 
sufficient  to  overcome  the  resistance  of  the  whole 
fluid  column,  for  as  soon  as  the  fluid  resistance  to 
displacement  in  the  first  small  segment  of  tube  is 
overcome,  piston  movement  can  displace  volume 
into  this  segment.  The  pressure  energy  of  this  fluid 
will  go  into  a  stretching  of  the  walls  of  the  segment. 
If  the  wall  extensibility  is  great  (as  with  condom 
rubber),  the  first  segment  could  accomodate  all  the 
fluid  displaced  from  the  pump,  and  there  would  be 
no  appreciable  pressure  rise  in  the  tube  and  no  flow- 
through  its  length.  It  might  be  pointed  out  that  the 
molecular  movements  in  this  wall  stretching  are 
directed  toward  the  side  of  the  tube,  so  that  the 
displacement  pattern  is  more  like  that  of  turbulent 
flow  in  a  rigid  pipe  than  that  of  streamline  flow. 

If  the  tube  is  less  distensible,  only  part  of  the  fluid 
compression  transmitted  to  the  first  segment  will 
go  to  produce  wall  extension,  for  the  fluid  must 
retain  enough  pressure  to  prevent  the  elastic  recoil  of 
the  stretched  walls.  This  erects  a  pressure  differential 
between  the  first  and  next  segment  of  tube,  a  differ- 
ential related  to  wall  elasticity  (which  need  not  be 
identical  with  wall  extensibility)  and  the  fluid  re- 
sistance of  the  second  segment.  When  the  differential 
becomes  larger  than  the  resistance,  fluid  displacement 
will  follow.  In  a  tube  of  uniform  distensibility,  then, 
except  for  the  frictional  energy  dissipation,  the  same 
volume  will  be  accepted,  per  unit  length  of  time,  by 
each  successive  tube  segment  as  the  first  part  or  front 
of  the  wave  moves  through  the  tube.  Hence,  if  the 
piston  displacement  is  linear  against  time,  the  pressure 
in  the  pump  and  the  upper  part  of  the  tube  will 
simply  remain  constant,  since  all  the  pump  outflow 
will  be  taken  to  establish  the  wave  front  as  it  moves 
from  segment  to  segment  through  the  tube.  This 
pattern  of  a  constant  pressure  can  be  demonstrated 
in  a  rubber-tube  model.  As  the  pressure  front  moves, 
flow  through  the  stretched  segments  behind  it  will 
be  streamlined.  While  the  frictional  cost  of  such 
movement  will  be  small,  the  further  the  wave  pro- 
gresses the  greater  will  be  the  cumulative  energy- 
dissipation.  This  analysis  also  means  that  once  fluid 
displacement  into  the  first  tube  segment  occurs,  the 


first  part  of  a  pressure  wave  has  been  created.  This 
wave  will  continue  to  move  through  the  tube  whether 
piston  movement  continues  or  not.  Further  piston 
movement  does  act  to  support  the  later  parts  of  the 
wave,  or  to  broaden  it  in  time. 

A  sinusoidal  piston  movement  leads  to  a  rising  and 
falling  pressure  in  the  upper  end  of  the  tube.  This 
produces  a  pressure  wave,  positive  or  negative,  which 
is  propagated  back  and  forth  through  the  tube.  No 
matter  in  which  direction  waves  may  be  traveling 
through  the  tube,  the  pressure  in  any  one  tube  segment 
at  a  given  time  simply  reflects  the  balance  between 
the  amount  of  fluid  entering  it  and  that  leaving  it. 
The  extensible  tube  should  show  a  phase  lag,  too, 
but  since  only  tiny  segments  of  tube,  acting  more  or 
less  independently,  presumably  are  involved,  the 
resistance  to  fluid  movement  out  of  the  pump  should 
be  very  small.  Hence  a  phase  lag  should  also  be 
small.  It  is  well  to  note  here  that  the  loss  in  pressure 
in  the  aorta,  due  to  frictional  dissipation,  is  within 
the  error  of  recording. 

Our  model  of  a  tube  with  uniform  distensibility  has 
no  counterpart  in  the  arterial  bed.  Figure  5  shows 
four  drawings  taken  from  an  earlier  analysis  of  this 
problem  (04),  based  primarily  on  the  extensibility 
values  given  by  isolated  rings.  That  on  the  upper 
left  depicts  a  part  of  the  arterial  bed  of  a  dog,  drawn 
to  scale  in  respect  to  anatomical  length  and  cross- 
sectional  area  at  a  pressure  of  100  mm  Hg.  But  in 
describing  fluid  displacements,  we  are  more  concerned 
with  the  propagation  time  of  the  pulse  wave  through 
a  region  than  we  are  with  actual  length.  The  natural 
pulse  wave  moves  slowly  in  the  upper  aorta,  more 
rapidly  in  the  lower  aorta,  and  faster  yet  in  the 
large  arteries  (10,  24).  Suppose  we  redraw  the  figure 
so  that  the  length  now  represents  the  distance  tra- 
versed by  the  wave  in  a  unit  length  of  time  (lower 
left).  Next,  since  the  pressure  rise  in  the  parts  of  the 
bed  will  be  set  by  the  segmental  distensibility  (ne- 
glecting wall  hysteresis),  let  us  redraw  the  figure 
(upper  right)  letting  the  assigned  width  represent  the 
distensibility,  expressed  as  AF/AP,  rather  than  the 
cross-sectional  area.  Lastly,  if  frictional  resistance  is  to 
be  discounted  as  of  small  amount,  we  can  neglect  the 
effect  of  tube  diameter  per  se,  and  group  together 
into  a  single  composite  tube  all  vessels  which  might 
lie  at  the  same  time  distance  from  the  heart  (lower 
right).  Such  a  theoretical  tube  has  a  funnel  shape, 
distensibility  being  great  in  the  top  (ascending  aorta) 
and  tapering  down  gradually  to  the  stiff  vessels  that 
are  farthest  from  the  heart,  those  of  the  hind  legs. 

A  linear  piston  displacement  into  such  a  tube  will 


8l6  HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


fig.  5.  A  reconstruction  of  the  arterial  reservoir  of  the  dog.  [From  Remington   (94).]  For 
description,  see  text. 


no  longer  produce  a  constant  pressure  in  the  upper 
end.  The  lower  part  of  the  tube  will  require  less  fluid 
to  construct  the  same  pressure  rise.  Hence  the  pressure 
in  the  pump  will  continue  to  rise  as  the  wave  front 
moves  through  the  tube,  the  pressure  rise  being  a 
function  of  the  distensibility  of  the  lower  part  of  the 
funnel.  This  increased  pressure  at  the  upper  end  will 
also  be  propagated,  so  that  we  are  now  creating  a 
whole  pressure  wave. 

Quantitation  of  Fluid  Displacement  and   ]Vall 
Distensibility  Relationships 

The  propagation  of  the  wave  front  is  really  the 
same  as  the  initial  displacement  of  fluid  from  segment 
to  segment  in  the  tube.  The  rate  of  this  displacement 
should  be  a  function  of  wall  distensibility,  and  it 
should  be  possible  to  formulate  the  relationship  in 
quantitative  terms.  This  is  another  case  where  the 
textbooks  have  such  a  formula  so  well  established 
that  it  has  assumed  the  nature  of  a  physiological  law. 
The  supporting  evidence  is  far  from  adequate. 
Discounting  all  friction  and  other  resistance  factors, 
Korteweg  presented  a  theoretical  formula,  and  Moens 
(see  46),  working  independently,  arrived  at  almost 
the  same  formula  on  the  basis  of  experiments  done 
with  various  distensible  tubes.  The  latter  used  arti- 
ficial waves  which  were  relatively  slow  in  their  rate  of 
pressure  rise,  and  he  used  not  the  first  part  of  the 
pressure  wave  for  his  measurements  of  wave  velocity, 
but  the  time  interval  between  successive  peaks  as  the 
whole  wave  was  propagated  back  and  forth  through 
his  closed  end  system.  His  formula  differs  from  that 
of  Korteweg  in  that  he  had  a  constant  of  0.9.  We 
have  shown  (46)  that  the  velocity  of  the  peak  of  such 


artificial  wave  is  less  than  that  of  the  start,  by  a 
factor  not  greatly  different  from  Moens'  constant. 
Using  the  Korteweg  formula,  then,  the  velocity  of  the 
wave  foot  (v)  is  related  to  an  "elastic  modulus"  (E) 
of  the  tube,  and  the  density  of  the  contained  fluid 
(p),  thus: 

.      g_Ea_ 
2r/> 

where  g  is  the  gravitational  constant  and  a  is  the  wall 
thickness.  Neglecting  hysteresis,  E  would  be  the  same 
as  Sd  of  equation  4  derived  above.  Hence  by  sub- 
stitution: 


,2  - 


gadTrd         gadT 
2t ■  />dr    '   2/>dr 


(15) 


If  p  is  regarded  as  a  constant,  and  given  the  value  of 
1 .055  for  blood,  and  a  is  taken  as  unity,  then 


2  .  9.3dT'  _  4.65 dT' 
'  2dr  dr 

where  T'  is  the  tension  per  unit  length  of  tube. 
Similarly,  from  equation  8: 

s  _  godPrf       4.65  d  Prd 

and    from    equation    1 2 : 


(16) 


dr 


(17) 


.2  = 


ga2dPVdrd   _  9.3dPVd 
2rd/>adV  dV 


(18) 


This  equation  18  is  the  same  as  that  derived  by 
Bramwell  &  Hill  (15)  and  has  since  borne  their 
name.  They  further  corrected  the  constant  by  multi- 
plying it  by  the  weight  of  mercury,  so  that  pressure 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


would  be  in  terms  of  mm  Hg.  Hence  their  formula 
reads : 

#      12.7  VdP 
dV 

Bramwell  and  Hill  did  not  use  the  first  slope  to 
determine  dP  and  dV,  but  appreciable  increments  in 
pressure  and  volume  instead.  Commonly  the  pressure 
increment  is  taken  to  be  the  pulse  pressure,  which 
strains  the  use  of  even  AP.  Because  our  methodology 
is  not  adequate  to  give  dP  and  dV  values,  we  have 
no  right  to  use  the  above  equations.  If,  instead,  the 
formula  is  derived  from  equation  1 1  : 

e      gaAPvj2rd  +  3Ar  +  %.) 
2rd/,aAV 


.   12.7 AP  Vd(rd+  1.5  Ar  +  0.57T  ) 


AV 


(19) 


Actually,    Arz/rd   is   so    small    it   can    be    practically- 
neglected,  so  that 


.i  - 


Ar 
12.7  APVd(l  +  l.5~) 

AV 


(20) 


Validation  of  these  formulas  has  centered  on  the 
Bramwell  and  Hill  equation.  The  earlier  results, 
which  have  been  reviewed  (46),  offer  no  clear  evi- 
dence that  the  velocity  of  artificially  generated  or 
natural  pressure  waves  shows  either  a  quantitative  or 
qualitative  agreement  with  values  predicted  by  the 
formula,  when  it  is  applied  to  stretch  data  taken  from 
isolated  vessels.  The  solid  line  of  figure  6  shows  an 
average  relation  of  pulse  wave  velocity  to  diastolic 
pressure  for  some  200  pulses  of  a  living  dog,  taken 
from  the  aortic  arch  to  the  diaphragm.  The  broken 
line  shows  the  velocity  calculated,  using  equation 
19,  from  the  continuous  second  stretch  curve  given 
in  figure  3.  Agreement  is  certainly  not  good.  If  the 
mean  slope  for  each  loop  given  in  figure  3  is  used 
instead,  then,  as  shown  by  the  dotted  lines,  agreement 
with  the  actual  becomes  qualitatively  better,  with 
equation  20  giving  a  better  fit  than  ig.  But  the  mean 
slope  can  have  little  significance  as  far  as  the  propaga- 
tion velocities  of  the  parts  of  a  wave  are  concerned. 
The  speed  of  the  wave  front  should  be  dictated  by 
the  slope  taken  at  the  beginning  of  the  stretch  phase 
of  the  loop.  Calculation  from  these  initial  slopes, 
using  equation    19   (which  is  here  valid),   gives  the 


125- 


100' 


50 


Pulse    wave    velocity,  M  /  Sec 
1 r 


5  6  7  8 

fig.  6.  Relation  of  pulse  wave  velocity  to  diastolic  pressure. 
Solid  line,  actual  values  from  a  living  dog.  Broken  line,  calcu- 
lated (eq.  19)  from  continuous  stretch  curves  of  fig.  3  Dotted 
line,  closed  circles,  calculated  (eq.  19)  from  mean  slopes  of 
loops  shown  in  fig.  3.  Dotted  line,  open  circles,  calculated  (eq. 
20)  from  mean  slopes  of  loops  of  fig.  3.  Crosses,  calculated  (eq. 
19)  from  initial  slopes  of  stretch  phase  of  loops  of  fig.  3. 


unconnected  crosses  of  figure  6.  These  velocities  are 
greater  than  the  actual  by  10  to  20  per  cent. 

In  our  earlier  study  (103),  in  which  we  compared 
a  curve  such  as  the  broken  line  of  figure  6  (based, 
however,  upon  a  careful  compilation  of  the  stretch 
curves  of  all  rings,  taken  in  sequence,  from  the  aorta 
being  studied)  with  the  actual,  we  believed  that  the 
underestimation  would  be  correctable  by  using  the 
slopes  resulting  from  a  hysteresis  steepening  of  the 
first  part  of  the  stretch  curve.  The  loops  obtained  in 
this  earlier  study  were  not  numerous,  and  we  did  not 
attempt  any  quantitative  verification  of  this  belief. 
Further,  and  unfortunately,  in  this  study  we  used 
both  a  rubber  tube  and  the  excised  aorta,  leaving  the 
implication  (although  it  very  definitely  was  never 
stated)  that  the  two  behaved  similarly.  With  rubber, 
the  initial  slope  of  the  stretch  phase  of  a  loop  proved 
clearly  dependent  on  the  rate  of  stretch.  In  keeping, 
the  propagation  velocity  of  artificial  pulses  through  a 
rubber  tube  was  found  to  be  directly  related  to  the 
rate  of  initial  pressure  rise.  But  with  the  aorta,  using 
either  artificial  or  natural  pulses,  there  was  no  similar 
relation  between  the  rate  of  pressure  rise  and  the 
wave  velocity.  My  more  recent  evidence  (96)  that  a 
dependency  of  the  aortic  stretch  curve  upon  the  rate 
of  stretch  is  minor  is  quite  compatible  with  this 
finding. 

A  calculated  velocity  for  the  wave  start,  in  excess 
of  the   actual   velocity,    may   be   explained   by   four 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


things.  /)  The  loops  given  by  an  isolated  ring  may  be 
much  wider  than  those  found  in  the  living  aorta. 
Evidence  was  cited  above  that  this  might  be  true. 
2)  The  velocity  may  be  dictated  not  by  the  wall 
extensibility,  but  rather  by  the  force  of  elastic  recoil. 
Calculation  from  a  stretch-release  curve  would  indeed 
give  smaller  values.  The  question  is  what  amount  of 
stretch  should  be  used  to  produce  pertinent  stretch- 
release  curves,  j)  The  distensibility  slope  of  the  aorta 
during  life  may  be  entirely  different  from  that  indi- 
cated by  the  isolated  rings.  The  data  of  Peterson 
(91),  for  example,  seem  to  have  it  greatly  different. 
4)  Factors  which  act  to  slow  the  pulse  wave  should 
be  introduced  into  the  formula.  To  the  extent  that 
the  aorta  acts  as  a  rigid  tube,  fluid  resistance  toward 
flow  can  act  in  this  manner,  as  will  a  phase  lag  be- 
tween the  pressure  pulse  and  the  corresponding  fluid 
displacement.  Many  workers  now  accept  the  presence 
of  an  appreciable  lag.  As  will  be  seen,  acceptance  of 
such  a  lag  cannot  be  readily  reconciled  with  the 
failure  to  find  a  correlation  between  wave  velocity  and 
the  rate  of  pressure  rise,  as  mentioned  above. 

Phase  Lag  and  the  Harmonics  of  the  Arterial  System 

Since  phase  lag  is  formulated  in  terms  of  the 
frequency  of  harmonic  components,  the  first  step  is 
to  perform  a  Fourier  analysis  of  the  pressure  wave. 
For  this,  a  sinusoidal  fundamental  wave  must  be 
selected.  Since  such  a  fundamental  is  not  readily 
apparent  in  the  contour  of  the  natural  pulse  wave,  it 
is  selected  on  the  basis  of  a  time  duration  (123,  124). 
Usually  the  length  of  the  pulse  cycle  is  used.  As 
emphasized  by  McDonald  in  the  introduction  to  his 
book  (84),  such  a  mathematical  analysis  can  start 
from  one  of  two  premises.  First,  we  can  assume  that 
each  pulse  is  an  isolated  or  transient  phenomenon, 
with  the  aortic  volume  being  almost  static  when  a 
new  cardiac  ejection  and  sudden  flow  acceleration 
are  begun.  Second,  we  can  say  that  the  heart  rate  is 
virtually  stable,  so  that  the  ventricle  is  repeatedly 
pulsing  the  arteries  at  a  set  frequency.  The  latter 
premise  makes  the  cycle  length  a  true  measure  of  the 
wave  fundamental,  makes  the  harmonics  relatively- 
reproducible  from  beat  to  beat,  and  makes  all  the 
mathematical  compilations  very  much  easier.  A 
change  in  heart  rate  will  vary  the  contained  har- 
monics and  alter  the  phase  lag  between  pressure  and 
fluid  displacement.  It  will,  then,  alter  the  wave 
velocity. 

But  the  fact  that  an  analysis  on  the  basis  of  a 
uniform  heart  rate  is  easier  to  make  does  not  mean 
that  the  premise  is  correct.  Much  evidence  can  be 


quoted  for  the  stand  that  each  pulse  is  indeed  an 
independent  event.  Strict  regularity  of  the  pulse  rate 
is  infrequent,  usually  being  found  only  in  rather 
prolonged  experiments  in  animals  under  deep  anes- 
thesia. In  the  unanesthetized  dog  or  human,  variation 
from  cycle  to  cycle  is  clear.  In  this  variation  the 
diastolic  period  is  affected  predominantly  or  ex- 
clusively. The  pulse  contour  during  systole,  and  its 
duration,  is  affected  but  little.  Further,  when  the 
heart  rate  changes  outside  the  limits  of  such  beat-to- 
beat  variations,  systolic  durations  and  contour  are 
altered  far  less  than  is  the  cycle  length  (100).  If  the 
fundamental  is  reset  each  time  this  cycle  length 
changes,  a  different  harmonic  picture  will  be  re- 
quired to  construct  the  same  systolic  pressure  contour. 
If  the  fundamental  is  taken  as  the  average  cycle 
length  for  a  number  of  pulses,  then  we  must  proceed 
cautiously  in  interpreting  the  influence  of  the 
harmonic  pattern  on  the  contour  of  any  single  pulse 
of  the  group. 

The  whole  approach  seems  more  hazardous,  too, 
when  it  is  recalled  that  the  length  of  systole  almost 
never  equals  half  the  cycle  length.  This  makes  the 
heart  quite  unlike  most  pumps.  Perhaps  it  would  be 
more  logical  to  use  twice  the  length  of  the  systolic 
period  as  the  fundamental  wave.  This  might  be  done 
for  a  central  pulse,  but  certainly  not  for  a  peripheral 
one,  where  the  incisura  has  been  lost  through  damp- 
ing. 

Believing  in  the  principle  of  a  stable  heart  rate, 
McDonald  (84)  would  have  the  velocity  of  the  wave 
foot  increasing  with  the  heart  rate.  He  offers  no 
experimental  support  for  the  claim.  We  have  looked 
often  for  evidence  of  such  a  dependency  on  heart 
rate  and,  with  the  single  exception  presented  below, 
have  not  found  it.  However,  McDonald  has  calculated 
that  in  a  vessel  the  size  of  the  aorta  neither  the  viscous 
resistance  factors  nor  the  pulse  frequency  would 
affect  the  velocity  to  significant  degree.  In  a  smaller 
vessel,  such  as  the  femoral  artery,  he  calculates  that 
the  viscosity  would  slow  the  velocity  by  about  10 
per  cent,  and  an  increased  heart  rate  might  restore 
it  to  the  value  expected  from  the  Bramwell  and  Hill 
formula.  Much  larger  changes  than  these  would  be 
needed  to  correct  the  formula  if  the  data  given  by 
the  crosses  in  figure  6  are  correct. 

We  did  offer  evidence  (46)  that  a  slower  foot 
velocity  was  seen  in  the  early  part  of  the  response 
of  an  animal  to  an  injection  of  acetylcholine,  when 
the  heart  rate  was  slow,  than  was  seen  later  when, 
at  the  same  diastolic  pressure  levels,  the  heart  rate 
increased.   A   similar  effect   at   higher   pressures  has 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


8l9 


not  been  observed.  We  then  attributed  the  velocity 
change  not  to  the  heart  rate  but  to  a  changing 
hysteresis  loop  behavior  of  the  wall.  A  long  diastolic 
interval  could  allow  more  time  for  recovery  after  a 
stretch,  and  the  diastolic  size,  and  hence  the  distensi- 
bility  modulus,  would  be  thereby  reduced.  It  is  less 
clear  now  (96)  that  the  difference  in  this  size  could 
be  sufficient  to  account  for  the  difference  in  wave 
velocity.  Yet  it  remains  possible  that  the  correlation 
with  heart  rate  was  still  only  coincidental,  and  that 
when  the  pressure  was  abruptly  lowered  the  slope  of 
the  stretch  curve  could  be  shallower  for  the  first  few 
beats  than  it  would  be  after  the  pressure  had  re- 
mained low  for  some  time. 

Most  especially,  if  we  regard  the  pulse  wave  as  an 
independent  phenomenon,  the  velocity  of  the  wave 
start  would  be  affected  least  by  a  change  in  harmonic 
frequency.  The  upper  parts  of  the  pressure  pulse 
could  have  their  propagation  speed  affected  to 
greater  degree  by  these  frequencies  or  by  the  speed 
of  the  pressure  upstroke.  A  different  velocity  for  the 
parts  of  the  wave  was  fully  accepted  by  Bramwell 
and  Hill  simply  on  the  basis  of  their  formula.  They 
went  further  (14)  and  held  that  the  difference  in 
velocity  could  be  such  that  the  anacrotic  rise  of  the 
pulse  would  progressively  steepen  in  transit  until 
finally  the  wave  force  would  become  unstable,  and  a 
"breaker"  (like  that  seen  when  an  ocean  wave  enters 
shallow  water)  would  form.  Evidence  of  such  breaker 
phenomena  was  seen  when  pulses  were  generated  in 
a  bicycle  tire.  As  will  be  described  later,  evidence  is 
not  clear  that  the  natural  pulse  does  so  progressively 
steepen  during  propagation,  and  there  is  no  evidence 
at  all  for  sudden  pressure  vibrations  that  would  mark 
a  breaker.  However,  the  calculated  differences  in 
velocity  between  the  start  and  the  peak  of  a  natural 
wave  are  not  large  enough  to  create  a  breaker  within 
the  length  of  the  aorta. 

If  there  is  a  velocity  differential  between  the  parts 
of  the  wave  (and  it  would  appear  to  be  quite  small 
if  present),2  it  could  reflect  the  progressive  increase 

2  There  is  an  obvious  discrepancy  between  the  statement  that 
there  is  no  clear  evidence  for  a  difference  in  propagation 
velocity  of  the  parts  of  a  natural  wave  and  our  published 
results  (103)  which  showed  clear  differences  in  transit  time  for 
the  parts  of  an  artificial  wave.  There  are  few  inflections  on  the 
natural  pulse  form  which  can  be  measured  with  the  necessary 
precision  to  establish  a  difference  in  propagation  velocity.  The 
start  of  the  wave  and  the  incisural  notch  can  be  so  timed,  and 
these  two  parts  of  the  pulse  contour  appear  to  move  with  the 
same  velocity.  Since  we  have  no  clear  idea  as  to  which  tension- 
length  slope  should  be  used  to  predict  the  velocity  of  the  in- 
cisura,  or  to  which  volume  on  the  stretch-release  curve  this 
slope  should  be  referred,  this  identity  of  velocity  with  that  of 


in  the  stiffness  modulus  as  the  reference  volume  in- 
creases, without  requiring  a  dependency  upon  the 
harmonic  frequencies.  Landowne  (72,  73)  did  show 
that  when  small  impact  waves  were  formed  at  a 
point  on  the  human  brachial  artery,  the  speed  of 
their  propagation  was  faster  if  they  fell  during  the 
systolic  portion  of  the  pressure  pulse  than  during  the 
diastolic  portion.  The  propagation  velocity  of  these 
small  waves  was  much  greater  than  that  of  the 
natural  wave.  Van  Citters  (125)  believes  that  the 
velocity  is  of  the  order  to  be  expected  if  they  were 
being  transmitted  by  longitudinal  strain  through  the 
wall  itself,  rather  than  by  fluid  accelerations  within 
the  artery. 

Landowne  (71)  has  also  shown  that,  with  a  rubber 
tube  or  umbilical  artery,  either  small  impact  waves  or 
rapidly  repeated  sinusoidal  waves  moved  at  a  velocity 
which  bore  a  direct  relation  to  the  frequency.  Our 
experiments  showing  a  dependency  of  wave  velocity 
upon  the  rate  of  stretch  of  rubber  fit  with  this  (46). 
The  umbilical  artery  has  a  uniquely  large  time- 
dependent  factor  in  its  visco-elastic  behavior  (141), 
so  that  it  would  not  be  at  all  unreasonable  that  the 
velocity  could  also  show  a  clear  rate  dependency. 
These  results  should  not  be  regarded  as  transferable 
to  the  aorta,  and  perhaps  not  even  to  arteries  such 
as  the  femoral  or  carotid.  We  are  left,  then,  with  the 
conclusion  that  the  actual  pulse  wave  velocity  remains 
to  be  explained  in  a  quantitative  way.  A  mathe- 
matical analysis  of  the  determinants  of  pulse  wave 
velocity  is  presented  in  the  chapter  by  Hardung  (49). 

We  still  have  the  fundamental  question  as  to 
whether  there  would  be  an  appreciable  time  lag 
between  the  pressure  pulse  and  the  fluid  displace- 
ment, or  the  movement  of  the  pulse  wave  from 
segment  to  segment  through  the  tube.  The  idea  of  a 
large  lag  was  presented  first  in  the  papers  of  Peterson 
(89,  90).  He  perfected  a  mechanism  which  could 
produce  a  very  rapid  input  of  fluid  into  the  ascending 
aorta,  and  thereby  generate  pressure  curves,  of  rather 
strange  form,  which  were  propagated.  The  shape  of 
these  curves  was  explained  on  the  basis  of  a  sum- 
mation of  three  forces.  First,  a  very  small  amount  of 
fluid  would  be  driven  into  the  aorta  more  rapidly 
than  the  walls  could  stretch,  so  that,  just  as  in  a 
rigid  pipe,  there  would  be  a  sudden  rise  in  pressure. 

the  wave  foot  may  be  coincidental,  and  not  be  evidence  for  or 
against  a  dependency  of  wave  velocity  upon  frequency.  It 
should  also  be  stressed  that  while  the  wave  parts  of  the  artificial 
wave  moving  through  an  excised  aorta  showed  different 
transit  times,  these  times  were  not  conditioned  by  the  rate  of 
pressure  rise  or  fall. 


820 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


This  initial  peak  he  labeled  the  acceleration  transient, 
and  its  force  was  equated  to  the  small  fluid  mass 
involved  times  the  acceleration.  Next,  he  added  a 
force  which  increased  with  the  velocity,  representing 
the  resistance  offered  to  fluid  displacement  through 
the  tube.  This  reached  significant  proportions  only  as 
the  volume  displacement  did,  which  placed  its  con- 
tribution later  in  time  than  the  acceleration  transient. 
Finally,  after  a  time  lag,  he  added  a  straight  line 
increase  in  pressure  to  represent  the  force  necessary 
to  prevent  an  elastic  recoil  of  the  walls  as  they  were 
stretched. 

Certainly  the  presence  of  these  three  forces  in 
constructing  an  aortic  pulse  cannot  be  denied.  The 
problem  is  to  ascertain  how  large  a  role  each  of  them 
plays,  and  how  much  of  a  time  delay  between  them 
exists.  Peterson's  acceleration  transient  lasts  for  many 
milliseconds.  While  wall  hysteresis  could,  to  use  a 
term  employed  long  ago  (46),  make  the  vessel  seg- 
ment show  a  "reluctance  to  stretch,"  no  studies  on 
isolated  rings  indicate  that  the  reluctance  could  last 
nearly  this  long.  Just  as  crucial  is  his  claim  that  the 
same  pressure  excess  which  marks  the  acceleration 
transient  would  persist  through  the  whole  systolic 
period,  so  that  all  the  pressure  pulse  would  have  a 
higher  value  than  would  be  predicted  from  a  pressure- 
volume  diagram  taken  from  stretch  data.  The  fact 
that  he  dealt  with  the  whole  arterial  bed  as  a  lumped 
system  has  made  it  difficult  to  follow  his  argument. 

Rather  than  a  discrete  time  lag  of  this  sort,  other 
workers  are  supporting  the  presence  of  a  sinusoidal 
phase  lag  (34,  36,  83,  120,  128,  129).  Using  an 
electrical  analogue,  the  aorta  is  said  to  have  an 
inductive,  capacitative,  and  a  resistive  impedance  to 
flow.  Of  these,  the  inductive  and  resistive  factors 
would  be  in  phase,  but  the  capacitative  would  lag  up 
to  90  degrees.  In  hydraulic  terms,  the  first  of  these  is 
called  inertance,  which  represents  the  mass  of  blood 
displaced  into  the  tube  segment  times  its  acceleration. 
Opposing  this  inertance  is  the  compliance  (capaci- 
tance) reflecting  the  volume  taken  to  accomodate  the 
wall  stretch,  and  the  resistance,  which  represents  all 
fluid  and  wall  factors  that  cause  dissipation  of  energy 
as  heat.  In  an  actual  vessel  subjected  to  pulsatile  flow, 
the  interrelation  of  the  three  would  be  dependent 
upon  the  rate  of  change  in  the  driving  pressure, 
usually  expressed  in  terms  of  the  frequencies  of  the 
harmonics.  The  better  matched  these  frequencies  are 
to  the  inherent  frequency  of  the  vessel  compliance, 
which  is  a  function  of  the  visco-elastic  properties  of 
the  wall,  the  greater  is  the  flow  into  and  through  a 


segment.  The  most  proper  match  would  be  at  the 
"resonant"  frequency  of  the  vessel. 

If  an  isolated  vessel  is  suddenly  stretched  and  then 
allowed  to  vibrate,  it  will  show  a  definite  period  of 
oscillation  (77).  This  frequency  will  be  different  at 
various  pressure  levels  and  with  different  parts  of 
the  arterial  system.  It  also  can  be  changed  by  any 
factor  which  influences  the  visco-elastic  properties. 
The  matching  frequency  between  a  segment  and  the 
driving  pressure  is  therefore  subject  to  considerable 
variation. 

But  it  remains  uncertain  why  such  factors  should 
play  a  significant  role  in  a  distensible  tube  composed 
of  tiny  segments.  Certainly  any  final  analysis  of  the 
pressure-flow  relation  must  reconcile  the  recent 
data,  based  on  the  dictum  that  a  phase  lag  must  be 
present,  with  the  older  descriptive  work,  which 
includes  evidence  of  a  general  absence  of  effect  of 
any  physiological  factor  other  than  the  diastolic 
pressure  level  on  pulse  wave  velocity,  the  details  of 
pulse  contour  change  which  takes  place  during 
propagation  (to  be  treated  later),  and  the  actual 
time  relation  between  flow  and  pressure  curves.  The 
last  of  these  has  been  least  well  covered.  Records  of 
the  flow  pattern  seen  at  different  parts  of  the  aorta 
have  been  presented,  and  such  records  have,  super- 
ficially at  least,  much  in  common.  But  discrepancies 
exist  between  them  in  regard  to  quantitation,  timing 
of  peaks,  and  amount  of  end-systolic  backflow. 
(27,  53,  56,  84,  120).  Unfortunately,  a  simultaneously 
recorded  pressure  pulse  is  so  rarely  given  that  one 
can  never  be  sure  whether  the  cardiodynamic  con- 
ditions were  enough  alike  in  the  different  experiments 
that  one  should  expect  similar  flow  curves. 

In  the  ascending  aorta,  the  flow  rises  sharply  to  a 
peak  reached  in  early  systole  and  then  falls  more 
gradually  to  reach  a  zero  value,  or  below,  at  the 
time  of  the  aortic  valve  closure  (fig.  7).  The  flow  then 
remains  negligible  throughout  the  diastolic  period 
(119),  or  may  show  a  small  sinusoidal  increase  in 
diastole  (131).  In  records  taken  from  other  parts  of 
the  aorta,  the  amount  of  retrograde  flow  seen  just 
after  the  end  of  systole  progressively  increases  as  one 
moves  out  the  vessel,  and  the  diastolic  wave  also 
increases  in  magnitude  (119). 

It  may  be  well  to  digress  into  a  semantic  problem 
that  continually  proves  worrisome  to  students.  The 
point  is  frequently  made  or  implied  that  there  is  a 
clear  distinction  between  the  fluid  displacement  that 
accompanies  the  movement  of  a  pulse  wave  and  the 
"stream  flow'"  through  the  vessel.  In  the  aorta  there 
really  is  no  stream  flow  as  such,  and  fluid  displace- 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


82  1 


120-t 


100- 


80J 


200 


100 


100- 


100 


50- 


o-1 


1   01  SEC  1 

fig.  7.  Carotid  pressure  pulse  (.4)  and  ascending  aorta  flow 
(C).  [From  E.  Wetterer  (131).]  B  =  change  in  volume  uptake 
curves  for  arterial  bed  regions.  Broken  line  of  C  =  the  summed 
uptake  values  taken  from  B.  D  =  change  in  volume  uptake  as 
calculated  from  a  hysteresis  loop,  as  taken  from  fig.  3.  The 
summed  uptake  values  are  given  in  C  as  the  dotted  line. 

ment  simply  accompanies  the  movement  of  the  pulse. 
This  displacement  is  toward  the  periphery  in  systole, 
but  some  may  be  toward  the  heart  for  a  period  in 
diastole.  It  should  not  be  difficult  to  understand  that 
the  molecules  involved  in  such  displacements  in  the 
lower  aorta,  for  example,  are  not  the  same  ones  as 
left  the  ventricle  during  the  corresponding  ejection. 
The  stroke  volume  is  of  the  order  of  a  fourth  of 
the  aortic  volume.  In  contrast,  a  stream  flow  is 
established  in  the  stiffer  resistance  vessels,  which 
approach  more  nearly  the  characteristics  of  a  rigid 
tube.  Another  way  of  saying  this  is  that  flow  through 
the  aorta  starts  and  stops,  rather  than  being  con- 
tinuous. 

At  present,  the  aortic  flow  curves  available  offer  no 
clear  indication  of  the  amount  oi  time  lag  between 
pressure  and  fluid  displacement.  Spencer  (119) 
makes  the  statement  that  in  the  upper  aorta  pressure 
and  flow  start  together,  but  he  offers  no  supporting 
figure.  If  this  is  true,  any  phase  lag  will  be  based 
simplv  on  a  relatively  slower  increase  of  flow  than 
of  pressure.  On  the  other  hand,  the  left  ventricle 
usually  develops  a  pressure  above  the  aortic  level 
before  ejection  apparently  begins,  which  excess  is 
then  gradually  lost  (98).  Thus  there  appears  to  be  a 
true  time  lag  of  about  5  msec,  similar  to  that  en- 


visioned by  Peterson.  But  a  study  of  pressure  pulses 
taken  from  adjacent  parts  of  the  aorta  offers  no  clear 
evidence  that  a  similar  excess  and  time  lag  exist 
there.  Thus,  after  the  initial  delay  between  ventricle 
and  ascending  aorta,  the  pressure  pulse  seems  to  be 
propagated  at  a  steady  rate  through  the  aorta  (98, 

99)- 

At  present,  a  major  obstacle  in  the  interpretation 
of  the  presented  flow  curves  is  a  lack  of  a  reference 
standard  against  which  they  can  be  compared. 
Quantitatively,  the  curve  from  the  ascending  aorta 
should  integrate  to  the  stroke  volume  less  the  coronary 
flow.  But  our  knowledge  of  the  time  contour  of 
cardiac  ejection  rests  only  on  cardiometer  curves, 
which  come  from  open-chest  animals  and  bear 
distortions  that  make  one  question  the  value  of  a  too 
detailed  study  of  their  time-flow  dimensions.  Flows 
taken  from  other  aortic  regions  can  be  related  to  the 
stroke  volume  only  if  one  assumes  a  distribution  of 
volume  between  the  parts  of  the  arterial  bed. 

Construction  of  a  Hypothetical  Ejection  Curve 

It  might  be  of  interest  to  construct  a  hypothetical 
ejection  curve,  derived  from  the  contour  of  the 
central  pressure  pulse  (104).  This  requires  that  all 
animals  be  assigned  the  same  wave  transmission  time 
and  the  same  arterial  distensibility,  the  latter  taken 
from  an  average  of  stretch  curves  of  isolated  rings. 
Certainly  no  claim  can  be  made  for  the  accuracy  of 
such  curves.  All  we  do  know  is  that  the  total  stroke 
volume  derived  in  this  way  usually  agrees  reasonably 
well  with  that  given  by  a  direct  measurement  (94). 
In  this  construction  the  arterial  funnel,  as  shown  in 
figure  5,  is  divided  into  segments,  the  lengths  of  which 
are  approximately  10  msec  of  transmission  time.  The 
total  volume  uptake  of  the  arterial  region  is  then 
divided  by  the  number  of  segments  included,  with  the 
various  segmental  uptake  curves  starting  in  sequence 
every  10  msec.  This  derivation  assumes  that:  a)  the 
aortic  pressure  pulse,  as  taken  from  the  ascending 
aorta,  has  no  distortion  because  of  a  contained 
acceleration  transient;  b)  the  wall  stretch  shows  no 
hysteresis  lag;  c)  the  control  pulse  is  propagated  as  an 
entity,  without  damping  and  without  augmentation; 
and  d)  there  is  no  time  lag  between  pressure  change 
and  the  corresponding  fluid  displacement. 

Suppose  we  take  first  the  pressure  pulse  presented 
by  Wetterer  (131)  corresponding  to  his  ascending 
aorta  flow  pulse  shown  in  figure  7.  This  pulse  is  ob- 
viously from  an  open-chest  animal,  the  length  of 
systole  probably  indicates  that  the  animal  was  cold, 


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CIRCULATION    II 


and  the  contour  is  not  one  we  would  regard  as  repre- 
sentative of  that  to  be  obtained  from  an  animal  in 
good  circulatory  condition.  The  ascending  aorta  and 
arch  are  taken  as  the  first  tube  segment.  From  our 
tabulated  pressure-volume  tables  (104)  a  volume  up- 
take curve  can  be  constructed  for  this  segment  in  10- 
msec  intervals,  starting  at  the  time  the  central  pressure 
pulse  begins  its  upstroke.  Because,  in  the  Wetterer 
experiment,  the  ascending  aorta  had  a  flowmeter 
attached,  we  have  arbitrarily  reduced  the  volume 
uptake  of  this  segment  by  one  half.  Rather  than 
plotting  the  total  uptake,  only  the  net  gain  or  loss  of 
volume  for  each  time  interval  is  given  as  the  solid 
line  curve  of  figure  yB.  While  the  pressure  in  this 
segment  is  still  rising,  the  volume  will  be  increasing. 
When  the  pressure  falls  in  late  systole,  there  will  be 
a  net  loss  of  volume. 

The  thoracic  aorta  and  head  and  foreleg  arteries 
are  grouped  together  in  the  next  part  of  the  funnel, 
and  it  takes  the  wave  some  30  msec  to  move  through 
the  whole.  Hence,  for  uptake  calculation  the  total 
region  is  divided  into  three  parts,  displaced  10  msec 
behind  each  other.  The  summed  net  volume  change 
for  all  three  is  given  by  the  broken  line,  labeled  H, 
in  figure  yB.  Next,  the  pressure  wave  invades  the 
abdominal  aorta  and  visceral  arteries,  which  takes 
another  30  msec.  The  summed  volume  change  of 
the  three  units  involved  is  given  as  the  dotted  line 
(V).  Finally,  the  summed  changes  of  the  three  leg 
vessel  units  are  given  in  curve  L.  Flow  through  the 
ascending  aorta  must  not  only  accomodate  the  volume 
acceptance  of  more  distal  arteries,  but  must  supply 
systolic  drainage  through  the  arterioles  as  well.  The 
calculation  of  this  latter  will  not  be  gone  into  here 
(see  ref.  44),  but  it  is  indicated  in  figure  ~]B  by  curve 
D.  Ascending  aorta  flow  now  should  equal  the  alge- 
braic sum  of  all  these  curves  at  any  given  time  in- 
stant. The  value  obtained  is  per  square  meter  of 
body  surface.  It  is  assumed  that  the  dog  Wetterer 
used  was  medium  size,  i.e.,  had  about  0.6  m2  surface 
area.  The  use  of  this  assumed  value  means  that  we 
should  not  expect  quantitative  agreement  between 
the  derived  curve  and  the  actual  one,  but  only 
qualitative  agreement.  The  total  flow  calculated  in 
the  above  manner  is  given  as  the  broken  line  in  figure 
yC.  The  actual  curve  presented  by  Wetterer  is  given 
by  the  solid  line.  The  calculated  values  therefore 
indicate  a  flow  increasing  more  steeply  in  early 
systole,  and  decreasing  sooner  and  more  sharply  after 
the  peak.  This  discrepancy  in  flow  might  have  four 
causes:  /)  the  flowmeter  might  be  slurring  the  actual 


curve;  2)  there  might  be  a  distortion  of  the  aortic- 
flow  curve  because  of  vessel  constriction  produced  by 
the  meter;  3)  there  might  be  a  true  time  lag,  of  ap- 
preciable proportions,  between  the  pressure  curve  and 
the  flow  curve;  and  j)  wall  hysteresis  might  change 
the  form  of  this  calculated  flow  curve.  The  influence 
of  the  last  of  these  can  be  directly  tested.  If  the  volume 
uptake  values  are  calculated  from  a  hysteresis  loop  of 
the  same  pattern  as  those  given  in  figure  3,  the 
rate  of  volume  gain  in  early  systole  would  be  de- 
creased, and  there  would  be  little  volume  change 
while  the  pressure  first  starts  its  fall  in  late  systole. 
The  summed  flow  curve,  as  given  in  figure  7C  by 
the  dotted  line,  differs  but  little  in  form  from  that 
given  by  the  broken  line.  Hence  it  would  be  difficult 
to  reconcile  the  calculated  curve  with  the  actual  with 
even  a  large  amount  of  vessel  hysteresis. 

A  similar  calculation  was  done  for  the  only  three 
pulses  presented  by  Spencer  and  co-workers  (119, 
120)  which  have  accompanying  pressure  pulses. 
The  flow  recorder  here  was  on  the  upper  thoracic 
aorta,  so  that  the  uptake  of  the  arch,  head,  and 
foreleg  vessels  were  omitted  when  the  volume  changes 
were  summed  to  give  the  flow  curve.  The  same  type 
of  discrepancy  between  the  calculated  and  the  re- 
corded flow  pattern  is  again  seen  (fig.  8).  It  might 
be  noted  that  these  pressure  pulses  are  unusual  in 
that  they  have  a  very  steep  initial  rise  in  pressure, 
with  a  relatively  flat  systolic  crest.  This  might  be 
evidence  of  an  effective  aortic  constriction  by  the 
meter.  If  so,  the  flow  profile  in  the  lower  aorta  would 
not  be  expected  to  match  the  form  of  this  pressure 
pulse. 

On  the  premise  that  flow  should  lag  behind  the 
instantaneous  pressure,  Fry  and  co-workers  (34) 
derived  an  equation  in  which  the  pressure  difference 
between  two  points  in  the  aorta  was  equated  to  the 
sum  of  an  inertial  term  and  a  factional  resistance. 
Solution  of  their  equation  was  achieved  by  use  of 
an  electronic  computer.  After  checking  their  equa- 
tion by  use  of  a  sinusoidal  pump  with  a  tube  (rigid?), 
they  proceeded  to  construct  a  flow  velocity  curve 
for  the  upper  aorta,  using  catheter  tips  6  cm  apart 
for  the  pressure  recordings.  Xot  knowing  the  exact 
positions  of  the  catheters,  one  is  uncertain  as  to 
just  what  vessel  segments  should  be  included  in  an 
attempt  to  construct  a  similar  flow  curve  on  the 
basis  of  vessel  distensibility.  We  used  the  whole 
aorta,  as  though  we  were  calculating  a  cardiac 
ejection  curve.  Xot  knowing  dog  size  or  diastolic 
aortic  dimensions,  the  calculated  peak  flow  value  was 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


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120- 


fig.  8.  Pressure  and  flow  values  given 
by  Spencer.  Pulse  a  from  Spencer  & 
Denison  ( 1  20) ;  pulses  b  and  c  from  Spen- 
cer el  al.  (119).  Dotted  line,  summed 
arterial  bed  uptake  values,  as  described 
in  text. 


arbitrarily  made  to  coincide  with  the  presented 
values.  The  agreement  in  contour  between  the  curve 
presented  by  Fry  (solid  line,  fig.  9)  and  that  calculated 
(broken  line)  bears  a  good  deal  of  resemblance  to 
those  seen  with  the  actual  flow  curves.  It  should  be 
mentioned  that  the  differential  pressure  recording 
presented  by  Fry  indicates  a  peculiarly  long  delay 
period  between  the  two  recording  catheters,  with  a 
slow  transmission  velocity  through  that  particular 
aorta  (about  3  M/sec). 

These  constructions  provide  presumptive  evidence, 
then,  that  there  is  a  delay  between  the  pressure  and 
fluid  displacement  curves.  There  will  certainly  con- 
tinue to  be  interest  in  the  factors  which  contribute  to 
this  lag.  Whether  harmonic  analysis  of  the  pressure 
pulse  curves  may  be  the  most  profitable  tool  for  this 
assessment  remains  to  be  decided.  It  is  important 
that  we  do  not  let  sophisticated  mathematics  allow 
us  to  lose  sight  of  the  basic  processes  by  which  a 
distensible  tube  seems  to  be  filled.  Volume  is  displaced 
from  segment  to  segment,  establishing  and  maintain- 
ing a  moving  pressure  wave.  Since  the  distal  parts  of 
the  aorta  are  stiffer  than  the  proximal,  we  would  not 
expect  that  the  pattern  of  fluid  displacement  out  of 
the  arch  would  be  qualitatively  similar  to  that  of  the 
pressure  curve,  for  the  amount  of  fluid  leaving  the 
upper  aorta  would  be  decreasing  when  the  pressure 
was  rising.  Toward  the  end  of  systole,  when  the  wave 
front  has  invaded  the  whole  network  of  distensible 


vessels,  flow  would  fall  sharply  to  a  low  level  which 
represents  mainly  the  drainage  loss  from  the  bed. 
At  this  time,  the  aorta  would  be  behaving  more  like 
a  rigid  tube. 

Judging  from  cardiometer  curves,  ventricular  ejec- 
tion starts  slowly,  then  rapidly  attains  a  maximal  and 
constant  rate  which  lasts  through  the  first  part  of 
systole.  The  outflow  then  slows,  reaching  a  small 
value  some  time  before  the  valves  actually  close. 
Because  the  first  outflow,  although  slow,  is  confined 
to  the  ascending  aorta,  the  pressure  rise  produced 
must  be  relatively  large.  As  the  wave  moves  through 
the  aorta,  an  even  faster  ejection  rate  will  produce  less 
rise  in  ascending  aorta  pressure.  This  tendency  is  in 
part  offset  by  the  stiffer  walls  of  the  more  distal 
vessels.  But  in  any  aortic  segment  a  pressure  rise 
simply  means  that  more  blood  is  entering  than  is 
leasing  for  the  more  distal  regions. 

A  pressure  difference  curve  based  upon  a  subtrac- 
tion of  pulses  taken  at  two  different  sites  can  be  mis- 
leading. Even  assuming  no  change  in  contour,  until 
the  wave  reaches  the  distal  recorder  the  difference 
will  be  but  a  replica  of  the  proximal  pulse.  When  the 
pressure  upstroke  in  the  peripheral  recording  begins, 
this  difference  curve  must  show  a  sharp  inflection 
and  a  fall,  depending  upon  the  duration  of  the  first 
steep  pressure  rise  and  the  separation  of  the  recorders. 
As  long  as  pressure  is  still  rising  in  the  proximal  seg- 
ment, the  difference  should  remain  slightly  positive. 


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HANDBOOK    OF    PHYSIOLOGY    -^    CIRCULATION    II 


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140" 


I20J 


< 


.1     SEC 


fig.  g.  Pressure  and  flow  values  given  by  Fry  et  at.  (34). 
Broken  line  of  B,  calculated  flow  values  as  described  in  text. 

When  it  starts  to  fall,  the  difference  should  swing  to  a 
negative  value.  This  does  not  mean  that  flow  down 
the  aorta  will  then  cease.  The  volume  displacement 
is  part  of  a  wave  movement,  and  the  pressure  differ- 
ential simply  reflects  the  time  lag  between  the  wave's 
arrival  at  two  points  in  the  tube.  Such  a  continuation 
of  fluid  displacement  toward  the  periphery,  despite  a 
negative  pressure  differential,  could  properly  be 
called  an  inertial  property  of  the  fluid.  What  all 
workers  are  seeking  is  a  complete  description  of 
what  we  mean  by  a  wave,  and  what  factors  con- 
tribute toward  its  progression  through  the  tube. 

Before  leaving  the  descriptive  model,  it  should  be 
pointed  out  that  no  length  dimensions  were  placed  on 
the  tube  segments  that  were  acting  independently. 
With  wall  fibers  distributed  longitudinally  as  well  as 
circularly,  there  cannot  be  such  an  independence  of 
action  of  tube  segments.  A  unit  of  a  distensible  tube 
must  have  a  finite  length,  which,  however,  has  not 
been  defined.  This  tying  of  segments  to  each  other 
must  give  a  distensible  tube  some  of  the  characteristics 
of  a  rigid  tube.  However,  it  remains  rather  incon- 
ceivable that  a  whole  aorta  could  act  as  a  single 
bound  entity,  and  could  be  given  a  single  lumped 
resistance  value. 

To  summarize  this  section  on  the  behavior  of  the 
aorta  as  a  conduit,  the  initiation  of  flow  through  a 


rigid  system  certainly  requires  the  acceleration  of  a 
whole  column  of  fluid,  an  overcoming  of  fluid  re- 
sistance for  the  whole  length  of  the  tube,  and  a  phase 
lag  between  pressure  built  up  at  the  generating  source 
(pump)  and  the  flow  out  the  end  of  the  tube.  In 
such  a  rigid  system,  resistance  factors  can  certainly 
be  treated  as  a  unit.  With  a  distensible  tube,  how- 
ever, depending  upon  the  stiffness  of  the  wall,  only 
a  small  segment  of  fluid  need  be  accelerated  in  any- 
given  unit  of  time,  and  the  fluid  resistance  and  the 
phase  lag  can  be  relatively  small.  A  model  has  been 
presented  in  which  a  pressure  wave  is  propagated 
from  a  minute  segment  of  such  a  tube  to  the  next 
adjacent  segment.  Of  course,  the  tube  is  linked  lon- 
gitudinally by  extensible  fibers,  and  the  length  of  what 
is  being  called  a  tube  segment  cannot  be  defined. 
But  it  is  not  clear  that  the  current  trend  of  treating 
pressure-flow  relations  in  the  aorta  as  though  re- 
sistance was  lumped  and  as  though  there  were  an 
appreciable  phase  lag  between  pressure  and  flow  is 
helping  our  understanding.  The  propagation  velocity 
of  the  wave  must  be  linked  in  some  way  to  tube 
dimensions  and  to  wall  distensibility,  but  no  com- 
pletely satisfactory  formula  for  quantitating  this 
relation  appears  yet  to  have  been  presented. 


THE   AORTA   AS  A   BLOOD    RESERVOIR 

Changes  in  Central  Pulse  Contour  During  Propagation 

In  the  description  of  how  fluid  displacement 
through  the  arterial  bed  might  be  calculated  from 
the  distensibility  values  of  the  various  vessels,  and 
the  course  of  pressure  change  in  the  ascending  aorta, 
the  assumption  was  made  that  the  central  pulse 
would  be  propagated  intact.  This  assumption  is 
clearly  false.  The  pulse  contour  is  modified  during 
transmission,  this  modification  resulting  perhaps 
from  damping,  or  from  a  poor  matching  between  the 
frequencies  of  the  volume  input  curve  and  those  set 
by  the  clistensibilities  and  flow  resistances  of  each 
arterial  segment,  or  from  an  augmentation  of 
"matched"  frequencies,  or  even  from  superposition 
of  a  wave  reflected  from  the  periphery  upon  the 
incident  wave.  It  should  not  be  implied  that,  because 
pulse  contours  change,  the  whole  method  of  calcula- 
tion of  the  form  of  the  cardiac  ejection  curve  is 
invalid.  If  the  contour  changes  do  not  appreciably 
alter  the  total  displacement  of  fluid  out  of  the  as- 
cending aorta,  the  total  quantitation  need  not  be 
greatly  in  error. 

Contour    differences    between    a    central    and    a 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


825 


fig.  10.  Reconstruction  of  aortic- 
pressure  pulses,  showing  comparison 
between  control  in  aortic  arch  (dotted 
lines)  and  records  taken  simultaneously 
with  their  controls  at  indicated  distances 
down  the  aorta  from  the  arch  (solid 
lines).  Below,  five  of  the  above  ten,  semi- 
diagrammatically  superimposed  on  a 
somewhat  larger  scale,  with  a  repre- 
sentative control.  [From  Hamilton  & 
Dow  (42).] 


peripheral  pulse  were  recognized  even  in  the  days 
when  pressure  recordings  were  made  using  low 
frequency  manometers.  When  Frank  (28)  developed 
his  high  fidelity  manometer,  he  established  this 
difference  in  precise  terms.  This  was  verified  and 
amplified  by  the  work  of  Wiggers  and  his  associates 
(1,  135,  136)  and  Hamilton  and  his  group  (40,  42, 
140)  in  this  country,  as  well  as  by  continued  work  in 
Europe  (17,  29,  57,  58,  75,  115,  117,  133).  In  con- 
trast to  the  broad  systolic  crest  of  the  central  pulse, 
the  femoral  artery  pulse,  for  example,  shows  a  high, 
narrow  systolic  profile.  Sudden  slope  changes,  such 
as  the  shoulder  of  the  central  pulse  and  the  incisural 
notch,  are  no  longer  present  in  the  distal  vessel, 
having  been  lost  through  damping  (fig.  10).  Such 
damping  is  most  obvious  when  the  aortic  pressure  is 
low,  and  least  obvious  when  the  pressure  is  at  hyper- 
tensive levels.  This  is  probably  related  to  the  fact 
that  the  visco-elastic  properties  of  the  wall  are  more 
prominent  at  low  pressure  levels. 

The  changes  in  contour  are  similar  to  those  that 
would  be  obtained  if  a  central  pressure  pulse  were 
recorded  by  a  slow-frequency  manometer  system, 
which  would  allow  an  overswing  of  pressure  in 
systole,  and  an  exaggerated  fall  to  a  low  level  in  early 


diastole.  The  German  workers,  after  Frank,  have 
therefore  thought  of  the  portion  of  the  arterial  bed 
which  stores  blood  in  systole,  i.e.,  the  arterial  reservoir 
or  Windkessel,  as  having  a  lumped  distensibility 
value,  like  a  manometer  (12,  17,  58,  132).  It  should 
be  remembered,  of  course,  that  the  distensibility  of 
the  arterial  bed  is  not  that  of  a  single  membrane, 
and  it  does  not  follow  that  the  arterial  reservoir  could 
vibrate  as  a  single  unit  as  a  manometer  system  does. 
Despite  much  descriptive  work  on  the  contour 
changes  which  attend  propagation  of  the  pulse,  our 
basic  knowledge  of  the  underlying  principles  remains 
incomplete.  In  their  classic  paper  on  this  subject, 
Hamilton  &  Dow  (42)  presented  for  the  first  time  a 
mapping  of  the  changes  in  pulse  form  in  the  dog  as 
recorded  serially  from  various  points  in  the  aorta 
(fig.  10).  This  mapping  reveals  that  as  the  wave 
moves  toward  the  periphery  the  steep  initial  anacrotic 
rise  remains  unchanged  in  slope,  but  persists  for  a 
longer  time.  Hence  the  deflection  marking  its  end, 
or  the  shoulder,  comes  at  progressively  higher  pressure 
levels.  The  systolic  peak  becomes  gradually  narrower, 
so  that  the  time  from  the  start  of  the  pulse  to  the 
peak  is  reduced.  Hence,  in  spite  of  the  transmission 
delay  of  the  start  of  the  wave,  the  peak  is  reached  at 


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just  about  the  same  time  in  all  pulses  taken  from  the 
lower  part  of  the  aorta.  It  is  most  difficult  to  time  the 
peak  of  a  pulse  exactly,  but  this  approximate  identity 
was  taken  as  evidence  that  this  peak  was  "standing." 
This  suggests  that  the  aorta  was  achieving  a  "reso- 
nance" with  the  first  transit  of  the  pulse  wave. 

Resonance  and  Standing  (1  m  <  s 

To  explain  the  resonance  concept,  let  us  visualize 
a  somewhat  elongated  rubber  balloon,  filled  with 
fluid,  and  connected  at  one  end  to  a  syringe.  A  sudden 
imput  of  fluid  would  start  the  bag  oscillating,  due 
to  a  sloshing  of  fluid  from  one  end  to  the  other  with 
a  reversal  of  movement,  or  a  reflection,  taking  place 
at  each  blind  end.  The  period  of  such  oscillations 
must  reflect  the  time  required  for  the  fluid  slosh  to 
traverse  the  balloon,  and  therefore  is  related  to  the 
conduction  velocity  of  the  fluid  wave  and  the  length 
of  the  bag.  The  first  of  these  is  a  function  of  the 
distensibility  of  the  part  ot  the  bag  through  which 
the  wave  is  moving,  as  described  earlier.  If  the  wave 
length  of  the  slosh  is  just  twice  that  of  the  transmission 
time  through  the  bag  (or  a  simple  multiple  of  it), 
we  could  say  that  the  bag  was  resonating,  for  a)  the 
pressure  changes  at  the  ends  would  be  just  180  degrees 
out  of  phase;  b)  the  peak  pressure,  produced  by  a 
summing  of  the  incident  wave  with  the  reflected 
wave,  would  be  reached  at  the  same  time  through 
half  the  length  of  the  tube.  This  means  that  there 
would  be  a  point  of  minimal  pressure  oscillation,  or 
a  "node,"  at  the  mid  point  of  the  tube,  and  all  peaks 
and  pressure  troughs  seen  on  either  side  of  this  node 
would  be  "standing"  through  half  the  tube;  c)  the 
time  interval  between  two  successive  pressure  peaks, 
as  recorded  from  any  point  in  the  tube,  should  be  a 
constant,  and  be  an  index  to  the  length  of  tube  and 
the  wave  velocity. 

The  records  of  Hamilton  and  Dow  suggest  that 
all  three  criteria  can  be  met  in  the  arterial  system. 
There  are  pressure  oscillations  at  the  two  ends  of 
the  dog  aorta  which  seem  180  degrees  out  of  phase, 
and  which  maintain  approximately  (but  not  exactly) 
the  same  period  until  they  are  damped  out.  The 
amount  of  pressure  change  with  such  oscillations  is 
much  smaller  in  the  arch  of  the  aorta  than  in  the 
abdominal  aorta,  just  as  the  distensibility  of  the  two 
regions  is  different.  There  are  times  when  all  three 
criteria  are  not  met  in  the  dog,  but  more  recent  map- 
pings indicate  that  what  seems  to  be  a  true  resonance 
very  often  is  achieved  (4,  101). 

The  carotid  artery  (or  whole  head  system?)  shows 


no  similar  oscillations,  or  even  any  great  change  in 
pulse  pressure  with  outward  propagation  of  the 
pulse  (39).  In  man,  the  arm  system  shows  augmenta- 
tion of  the  pulse  pressure  but  not  resonance  as  defined 
above  (108).  Records  made  in  this  laboratory  indicate 
that  the  foreleg  system  of  the  dog  produces  pulse  con- 
tour changes  similar  to  those  seen  in  the  human  arm. 
Further,  the  aorta-femoral  system  does  not  show  such 
resonance  or  even  clear  oscillations  in  very  small 
animals  (140).  There  is  question  whether  resonance 
occurs  in  an  animal  as  large  as  man  (108).  The 
German  workers  do  believe  the  human  aorta  to  show 
resonance,  but,  as  will  be  discussed  later,  their  con- 
clusion is  not  based  on  a  standing  peak  for  the  periph- 
eral pulses. 

Attempts  to  design  a  model  that  could  illustrate 
the  prompt  achievement  of  resonance,  as  occurs  in 
the  dog,  have  not  been  successful.  Certainly,  ex- 
periments in  which  independent  pulses  were  gen- 
erated in  a  closed  and  moderately  long  rubber  tube 
(46)  provided  little  insight  into  how  it  would  be 
possible  to  make  a  previously  quiet  bag  resonate 
with  the  first  propagation  of  a  pressure  pulse  through 
it.  Granted  that  if  the  time  of  volume  injection  was 
made  identical  to  the  transmission  time  of  the  wave 
peak  through  the  tube,  reciprocal  oscillations  at  the 
ends  would  be  seen  from  the  time  of  completion  of 
the  injection.  But  if  the  injection  period  was  ap- 
preciably longer  or  shorter  than  this,  there  was  no 
such  immediate  resonance.  Instead  the  formed  wave 
peak  could  be  followed  back  and  forth  through  the 
tube,  as  it  was  propagated  at  a  steady  rate,  and 
reflected  at  each  blind  end.  Because  the  wave  length 
changed  during  these  propagations,  the  foot  moving 
more  rapidly  than  the  peak,  which  in  turn  moved 
faster  than  the  "tail,"  after  several  trips  through  the 
tube  the  wave  could  finally  achieve  a  length  equal 
to  that  which  would  make  the  tube  resonate.  Whether 
a  given  wave  ever  attained  such  resonance  would 
depend  upon  the  number  of  trips  required  to  1  hange 
its  wave  length,  and  the  number  that  were  possible 
because  of  incomplete  reflection  and  continued 
damping.  The  change  in  wave  length  attending 
propagation  was  attributed  to  the  hysteresis  behavior 
of  the  wall. 

Similar  changes  in  the  length  of  an  artificial  pulse 
were  seen  in  a  tied  off  but  in  situ  dog  aorta  (46). 
This  change  is  directly  opposite  to  that  predicted  by 
the  Bramwell  and  Hill  formula,  which  would  have 
the  peak  moving  faster  than  the  foot.  Of  course, 
artificial    waves    never    attained    the    same    rate    ot 


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pressure  rise  seen  with  a  natural  pulse,  and  they 
were  truly  independent  phenomena. 

McDonald  (84)  believes  that  because  the  natural 
pulse  is  but  one  of  a  continuous  train  of  waves  with 
virtually  identical  wave  lengths,  each  ejection  could 
serve  to  reinforce  the  component  frequency  which 
happens  to  match  the  transmission  time  through  the 
resonating  part  of  the  reservoir.  This  premise  would 
permit  development  of  resonance  with  the  first  transit 
of  each  wave.  But,  by  extension,  this  premise  would 
also  require  that  the  pulse  pressure  augmentation 
be  a  function  of  the  heart  rate.  Again,  all  we  can  say 
is  that  neither  the  pressure  augmentation  nor  the 
period  of  the  diastolic  oscillations  has  been  shown  to 
have  any  relation  to  heart  rate  per  se  when  the 
diastolic  pressure  remains  the  same.  The  reciprocal 
oscillations  between  aortic  arch  and  abdominal  aorta 
pulses  in  the  dog  appear  to  be  the  rule  and  not  the 
exception.  They  appear  with  the  first  beat  after  a 
prolonged  cardiac  arrest,  as  with  vagal  stimulation; 
they  are  not  clearly  accentuated  at  any  given  heart 
rate;  it  is  most  difficult  to  so  alter  the  cardiovascular 
status  through  nerve  stimulations  or  injected  drugs  as 
to  make  them  disappear. 

The  prompt  achievement  of  resonance  by  the 
aorta  would  seem  to  require,  then,  that  the  whole 
vessel  could  act  as  a  unit,  and  "mold"  any  ejection 
wave  into  a  pattern  consistent  with  its  own  resonant 
properties.  Alexander  (7)  has  used  the  analogy  of 
an  orchestral  chime,  which,  when  struck,  vibrates 
at  a  frequency  set  by  its  own  geometry,  unaffected 
by  the  characteristics  of  the  impacting  force.  Use  of 
this  analogy  is  not  easily  reconciled  with  the  theorem 
that  wave  propagation  is  from  tiny  tube  segment  to 
adjacent  segment.  Instead  the  pressure  rise  in  the 
upper  end  of  the  aorta  would  have  to  be  aisle,  by 
some  mechanism,  to  throw  the  whole  aorta  into  vibra- 
tions. Yet  there  is  no  evidence  that  this  pressure  rise 
"signals  ahead"  of  the  propagated  pulse  wave.  There 
is  no  pressure  change  in  the  lower  aorta  at  the  time 
the  central  pulse  is  first  being  ejected. 

One  question  which  must  be  decided  is  whether  it 
is  the  propagated  pressure  wave  itself  which  sets  the 
aorta  into  resonance.  No  alternative  suggestion  has 
yet  been  advanced,  unless  one  can  read  into  a  paper 
describing  the  genesis  of  the  ballistocardiographic 
waves  the  notion  that  whole  body  thrusts  might  in- 
duce this  resonance  pattern  within  the  vessels  (43). 
The  propagated  wave  in  an  aorta  has  much  in  com- 
mon with  an  artificial  wave  being  propagated 
through  a  stoppered  rubber  tube,  although  the  latter 
does  not   readilv  create   immediate   resonance.   The 


aorta  should  be  even  less  conducive  to  the  attainment 
of  resonance  than  the  rubber  tube.  There  certainly 
is  no  single  reflection  point,  for  exit  vessels  are 
distributed  along  the  whole  length  of  the  system.  One 
would  expect,  then,  innumerable  returning  waves 
bearing  no  necessary  time  relation  to  each  other. 
Further,  the  exit  vessels  are  not  blind  end  tubes,  bur 
continue  on  to  become  the  resistance  vessels  of  the 
arterial  tree.  This  has  led  some  to  the  conclusion 
that  the  aortic  reservoir  should  be  considered  as  more 
comparable  to  an  open-end  tube,  the  resonant  wave 
of  which  would  then  be  twice  as  long  as  that  of  a 
closed-end  tube  (60,  134).  On  the  other  hand,  Hamil- 
ton (38)  has  maintained  that  the  sudden  increase  in 
the  resistance  to  flow  in  these  vessels  will  serve  to 
produce  the  positive  reflection.  While  such  reflections 
could  take  place  wherever  the  flow  pattern  is  changed, 
as  at  a  vessel  bifurcation,  or  even  in  the  curvature  of 
the  aortic  arch,  these  reflections  within  the  tube 
would  be  small  when  compared  to  those  arising  from 
the  small  resistance  vessels.  He  has  documented  this 
belief  by  experiments  done  on  a  rubber  tube  model 
fitted  with  many  small  rigid  tubes  of  high-flow  re- 
sistance, but  with  a  greater  aggregate  cross-sectional 
area,  placed  in  series  with  the  rubber  tube  (41). 

Alexander  (1,  4,  8)  recorded  pulses  from  the  arch, 
the  abdominal  aorta,  and  the  femoral  artery  of  dogs 
under  a  variety  of  physiological  conditions.  Usually 
the  two  peripheral  pulses  showed  simultaneous 
peaks,  although  at  times  they  did  not.  If  the  central 
pulse  was  subtracted  from  the  peripheral  one,  to 
give  the  contour  of  the  reflected  wave,  two  different 
waves  in  the  subtraction  curve  could  be  seen.  The 
first  of  these  was  taken  to  represent  the  propagated 
peak  of  the  incident  wave,  •"distorted"  by  damping 
and  the  other  factors  which  may  give  rise  to  contour 
change  during  propagation.  The  second,  a  swell  of 
more  sinusoidal  form,  was  the  first  of  the  resonant 
oscillations.  When  the  two  waves  coincided,  the 
femoral  pulse  pressure  was  at  its  greatest.  In  some 
central  pulses,  a  late  systolic  trough  could  be  seen 
that  appeared  simultaneously  with  the  distal  resonant 
swell.  When  the  length  of  the  ventricular  ejection 
period  was  slowed  through  induced  hypothermia 
(7),  this  trough  came  far  enough  ahead  of  the  incisura 
to  be  clearly  recognizable. 

The  resonant  swell  obtained  by  such  a  subtraction 
did  not  have  the  same  wave  length  as  the  central 
pressure  pulse.  In  fact,  there  is  no  real  evidence  that 
the  whole  of  the  incident  pulse  is  reflected.  When 
subtraction  curves  of  the  same  tvpe  were  obtained 
for  human  subclavian  pulses  (108),  a  reflected  wave 


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seemed  to  be  present,  but  it  was  small  in  magnitude 
and  short  in  duration.  It  was  as  though  only  the 
first  sudden  acceleration  of  flow  produced  a  reflected 
wave.  Whether  this  should  be  regarded  as  a  common 
finding,  true  for  the  whole  arterial  tree  and  also  for 
a  closed-end  rubber  tube,  is  not  clear. 

Hamilton  &  Dow  (42)  showed  that  when  the  aorta 
was  occluded,  the  frequency  of  the  pressure  oscilla- 
tions seen  on  a  pulse  was  more  rapid  than  that  usually 
found  in  a  normal  dog.  By  moving  the  point  of 
occlusion  distally,  they  concluded  that  the  "end"  of 
the  resonating  system  must  lie  outside  the  aorta. 
Taking  the  time  from  the  start  of  the  central  pulse 
to  the  peak  of  a  lower  abdominal  aortic  pulse  as 
equal  to  half  the  total  resonant  wave  length,  they 
calculated  that  the  end  should  be  near  the  knee,  and 
the  node  should  be  in  the  lower  thoracic  aorta. 
Wezler  &  Boger  (134)  placed  the  end,  which  they 
took  as  the  point  of  negative  reflection,  in  the  femoral 
artery  near  the  inguinal  ligament  in  the  human. 
Schmitt  (115)  located  the  node  in  the  abdominal 
aorta  in  man,  and  the  end  in  the  distal  part  of  the 
tibial  artery.  This  was  based  simplv  on  transmission 
times  of  the  wave,  for  the  time  delay  from  the  heart 
to  the  node  should  also  equal  the  time  from  the  node 
to  the  end,  and  equal  a  fourth  of  the  total  interval 
between  successive  pressure  peaks  of  a  peripheral 
pulse.  Similar  studies  by  Wetterer  and  co-workers 
(58,  132)  placed  the  end  of  the  system  beyond  the 
ankle  in  the  foot.  An  occlusion  by  cuff  inflation  of 
the  legs  shortened  the  interval  between  the  systolic 
and  the  postincisural  pressure  peaks,  which  they 
reasoned  could  be  true  only  if  the  cuffs  were  still 
proximal  to  the  end  of  the  system  (59).  There  are 
two  aspects  of  studies  such  as  these  that  give  room 
for  concern.  First,  the  pressure  peaks  of  pulses  taken 
from  the  leg  arteries  are  not  coincident  with  those 
of  the  femoral  artery  (fig.  1  1),  nor  are  they  timed  to 
reciprocal   oscillations   of  the  central   pulse.    Of  the 


Subclavian 


Popliteal 

Femoral 
Tibial 


fig.   11.  Pulse  contours  from  peripheral  arteries.   [Redrawn 
from  Kapal  et  al.  (59).] 


three  criteria  listed  above  for  resonance,  they  satisfy 
only  one,  i.e.,  the  time  interval  between  peaks  re- 
mains about  the  same  as  that  seen  more  proximally. 
It  remains  possible  that  the  truly  resonant  pulse  form 
could  be  propagated  with  but  little  distortion  of  time 
relations  through  the  leg  arteries.  This  seems  to  be 
what  happens  in  the  arm  vessels  (108).  Second,  oc- 
clusion of  the  aorta  seems  to  make  it  behave  as  a 
blind-end  rubber  tube  would,  and  the  waves  which 
are  propagated  back  and  forth  in  this  occluded  length 
of  vessel  do  not  have  the  same  characteristics  as  the 
natural  wave.  It  may  be  that  leg  occlusion  could 
introduce  a  reflection  of  the  wave,  and  change  the 
timing  between  peaks,  but  that  use  of  the  occlusion 
technique  to  identify  the  end  of  the  resonant  system 
is  not  theoretically  sound.  It  should  be  repeated  that 
our  studies  on  aortic  pulses  in  man  (108)  gave  no 
evidence  of  a  standing  peak. 

Alexander  (3)  believed  that  the  node  for  the  clog 
was  in  the  upper  abdominal  aorta  where  the  large 
visceral  arteries  exit.  This  is  a  point  of  sudden  increase 
in  total  cross-sectional  area,  where  the  flow  rate, 
relative  to  the  vessel  size,  accounts  for  a  large  fraction 
of  the  total  cardiac  output.  When  he  occluded  the 
visceral  arteries,  the  frequency  of  the  resonant  waves 
seen  in  femoral  pulses  was  increased,  and  the  pre- 
incisural  trough  of  the  pulse  of  the  ascending  aorta 
became  less  conspicuous.  Unfortunately,  the  pressure 
was  also  raised  by  this  maneuver,  so  that  the  changes 
evoked  are  not  indisputable  evidence  for  his  hy- 
pothesis. Converselv,  an  intra-arterial  injection  of 
histamine  into  the  visceral  arteries  decreased  the 
frequency  of  oscillations  (and  also  lowered  the 
systemic  pressure).  Ryan  and  co-workers  (114) 
repeated  the  occlusion  experiments,  and  concluded 
that  the  pressure  rise  might  have  been  sufficient  to 
explain  the  changed  frequency  of  the  resonant  waves 
in  the  femoral  pulse,  but  observed  that  the  occlusion 
did  eliminate  the  preincisural  trough  of  the  central 
pulse.  In  general,  however,  occlusion  of  exit  arteries 
has  very  little  influence  on  the  timing  of  the  pressure 
oscillations  (57 ). 

Alexander  (4)  postulated  that  the  aorta-femoral 
system  was  essentiallv  two  open-end  systems  in 
series,  the  region  of  visceral  artery  exit  marking 
an  open  end  common  to  both.  Arrival  of  the  incident 
wave  at  this  area  would  be  followed  by  a  reflection 
of  a  negative  wave  back  toward  the  arch  to  produce 
the  preincisural  trough.  The  incident  wave  would 
also  be  propagated  into  the  lower  aorta  as  a  positive 
wave.  Hence  the  two  systems  would  be  effectively 
resonating  with  each  other. 


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0.1  SEC 

fig.  12.  A  mapping  of  the  change  in  pulse  form  in  the  dog 
aorta.  Pulses  from  ascending  aorta  (/t),  descending  arch  (4), 
upper  thoracic  aorta  (7),  mid  thoracic  aorta  (10),  lower 
thoracic  aorta  (14),  abdominal  aorta  (18)  and  iliac  artery  (22). 
[From  Remington  (100).] 

The  German  workers  have  also  been  concerned 
about  the  effect  the  large  visceral  arteries  might  have 
on  the  resonant  wave.  They  (58),  like  Hamilton, 
would  locate  the  only  significant  reflection  point  in 
the  small  arteries.  The  influence  of  any  single  aortic 
branch  as  an  independent  reflection  unit  (particu- 
larly that  of  a  vessel  so  far  proximal  to  the  "end"  of 
the  system  as  a  visceral  artery)  causes  them  no  great 
concern.  Assuming  the  resonant  frequency  to  be 
already  established  (they  have  presented  no  analysis 
as  to  how  this  might  be  achieved),  they  conclude  that 
reflections  in  this  branch  would  serve  to  augment  the 
pressure  excursion  without  altering  the  fundamental 
wave  length  of  the  incident  wave.  An  example  of 
this  is  seen  when  two  manometers  of  different  fre- 
quency response  record  in  parallel  a  rapid  pressure 
change;  the  records  from  both  will  be  the  same  and 
reflect  the  response  characteristics  of  the  slower 
manometer.  This  would  not  explain  Alexander's 
preincisural  trough  seen  on  the  central  pulse. 


In  a  number  of  mappings  of  the  dog  aorta  (99) 
I  found  that  while  in  some  pulses  the  late  systolic 
trough  could  be  seen,  it  was  not  present  in  pulses 
taken  from  the  descending  arch  of  thoracic  aorta 
(fig.  12).  Hence  this  trough  apparently  is  not  prop- 
agated back  from  the  upper  abdominal  aorta,  but 
rather  appears  de  novo  in  the  ascending  aorta  pulse. 
Although  there  were  some  time  discrepancies  be- 
tween the  systolic  peaks  of  the  peripheral  aortic 
waves,  there  was  a  general  tendency  for  a  standing 
wave  to  occur.  But  this  standing  wave  seemed  to 
develop  as  a  sinusoidal  swell  taking  off  from  the 
broad  crest  of  the  propagated  wave,  and  appeared 
first  in  the  aortic  arch  or  at  least  high  in  the  thoracic 
aorta.  Its  size  progressively  increased  as  the  wave 
moved  toward  the  periphery.  If  this  swell  represented 
the  first  of  a  resonant  wave,  we  would  have  to  con- 
clude that  the  node  for  this  first  peak  was  within  the 
aortic  arch  itself.  This  swell  developed  at  about  the 
same  time  that  the  foot  of  the  incident  wave  reached 
the  femoral  artery.  Later  reciprocal  oscillations  be- 
tween ascending  aorta  and  lower  abdominal  aorta 
could  be  seen,  with  minimal  pressure  change  in  the 
upper  thoracic  aorta.  The  node  of  these  oscillations 
would  thus  appear  to  be  more  distal  than  that  for 
the  systolic  peak.  All  that  we  can  conclude  is  that 
the  genesis  of  aortic  resonance  remains  obscure. 

Other  Factors  Which  May  Alter  the  Central  Pulse  Contour 

Fascinating  as  this  whole  problem  of  resonance 
may  be,  it  certainly  is  not  the  sole  factor  which  may 
produce  contour  change  and  pulse  pressure  change 
when  the  pulse  of  the  ascending  aorta  is  propagated 
to  the  lower  aorta  or  to  the  brachial  artery.  Possible 
factors  which  may  bear  on  these  changes  are: 

a)  A  loss  of  sharp  inflections  and  an  attenuation  of 
the  pulse  pressure  might  result  from  damping.  In  a 
distensible  tube  such  damping  is  due  in  part  to  fluid 
friction,  but  probably  much  more  to  a  conversion  of 
energy  from  kinetic  to  potential  form  because  of  the 
extension  of  the  walls,  with  a  delayed  recoverability 
of  this  energy  because  of  the  visco-elastic  properties 
of  the  wall.  Clear  illustrations  of  such  a  reduction  in 
pulse  pressure  and  lengthening  of  the  systolic  wave 
contour  during  propagation  can  be  seen  in  dogs  with 
a  deteriorated  circulation,  or  at  least  a  weakened 
heart,  after  the  use  of  a  strong  vasodilator  agent  (94) 
and  when  the  rate  of  flow  from  the  upper  aorta  to 
the  lower  is  severely  reduced,  as  by  a  partial  occlu- 
sion (23). 

b)  A  peaking  of  the  pulse  contour  could  follow  a 


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speeding  of  the  upper  portions  of  the  pulse  as  the 
modulus  of  extensibility  is  increased.  This  would 
probably  cause  an  augmentation  of  the  pulse  pressure. 
This  effect  seemingly  would  be  operative  only  if  wall 
hysteresis  were  of  minimal  importance.  However,  I 
am  not  convinced  that  there  is  any  difference  in 
transit  time  of  the  wave  foot  and  of  the  incisura,  for 
example. 

c)  The  same  sort  of  peaking  could  indicate  an 
attenuation  of  mismatched  harmonic  frequencies. 
If  the  electrical  analogy  is  apt,  there  would  be  no 
augmentation  of  the  pulse  pressure  in  this  case,  how- 
ever, but  simply  less  attenuation  of  the  matched 
frequencies.  In  a  hydraulic  system,  of  course,  it 
might  be  that  attenuation  of  one  part  of  the  pulse 
might  yield  fluid  and  energy  for  another  frequency, 
which  conceivably  could  produce  pulse  pressure 
augmentation.  Such  a  redistribution  of  energy  has 
not  been  shown  to  be  true. 

d)  There  could  be  a  reflection  of  the  whole  or  a 
part  of  the  incident  wave,  whether  the  vascular 
bed  did  or  did  not  achieve  resonance  as  it  has  been 
described.  The  maximum  possible  increase  in  pulse 
pressure  by  reflection  would  be  to  twice  the  original 
value,  which  would  be  realized  only  if  the  whole 
pulse  pressure  showed  complete  reflection,  and  the 
pulse  recording  was  very  near  the  reflection  "end" 
of  the  system.  Usually  the  pulse  pressure  in  a  femoral 
artery  is  less  than  twice  that  of  the  central  pulse. 
However,  Alexander  has  shown  femoral  pulse  pres- 
sures in  the  dog  which  are  greater  than  twice  the 
value. 

e)  As  an  extension  of  d),  or  perhaps  as  a  result  of 
another  property  of  the  bed  entirely,  when  the  aorta 
does  show  resonance,  augmentation  of  the  pulse 
pressure  is  appreciably  greater  than  when  a  standing 
wave  is  not  seen. 

/)  In  some  cases  where  the  cycle  length  is  short, 
the  diastolic  pressure  swell  (presumably  the  reflected 
wave)  may  begin  late  in  the  diastolic  period.  If  a 
new  systolic  upstroke  coincides  with  the  upswing  of 
this  swell,  very  high  pulse  pressure  values  can  be 
obtained.  This  mechanism  of  augmentation  by  "su- 
perposition" was  illustrated  by  pulses  recorded  from 
the  system  of  man  ( 1 08 ) . 

Aside  from  changes  in  pulse  pressure  and  the  form 
of  the  systolic  peak,  there  are  other  aspects  of  pulse 
contour  transformation  which  have  no  clear  explana- 
tion. The  pulse  formed  in  the  ascending  aorta  shows, 
after  a  variable  but  short  period  in  which  the  pressure 
rise  from  the  diastolic  level  is  slow,  a  rather  abrupt 
assumption  of  a  steep  and  constant  slope  of  pressure 


rise.  This  anacrotic  rise  is  maintained  unchanged  for 
at  least  30  msec.  It  is  then  usually  lost  rather  abruptlv, 
often  with  a  temporary  interruption  of  pressure 
rise.  This  halt  is  called  the  shoulder  of  the  pulse. 
The  steeper  the  preceding  slope,  the  more  con- 
spicuous is  this  shoulder.  The  rate  of  anacrotic  pres- 
sure rise  is  clearly  related  to  the  amount  of  sympathetic 
stimulation  of  the  left  ventricle,  which  serves  to  speed 
the  whole  contractile  process.  Thus,  with  such  stimu- 
lation, maximal  outflow  is  reached  earlier  in  systole, 
the  shoulder  tends  to  be  at  a  relatively  high  pressure 
level,  and  the  systolic  peak  of  the  pulse  occurs  earlier. 
A  shortening  of  the  length  of  the  ejection  period 
can  be  used  as  the  basis  of  an  assay  method  for 
sympathomimetic  stimulation  (100).  With  extreme 
cardiac  stimulation,  particularly  when  the  stroke 
volume  is  reduced  because  of  inadequate  venous 
return,  the  shoulder  may  be  so  abrupt  as  to  throw 
the  whole  aorta  into  vibrations.  Under  such  circum- 
stances, the  height  of  the  shoulder  may  be  greater 
than  that  of  any  other  part  of  the  pulse,  which 
makes  the  shoulder  height  represent  the  systolic 
pressure.  In  such  cases,  the  pulse  pressure  may  have 
higher  values  than  would  be  anticipated  from  the 
stroke  volume  (94),  in  the  peripheral  vessels  as  well 
as  in  the  ascending  aorta. 

The  slope  of  pressure  rise  preceding  the  shoulder 
was  found  by  Hamilton  &  Dow  (42)  to  be  propagated 
unchanged  through  the  aorta.  Alexander  (4)  showed 
some  loss  of  steepness  in  the  abdominal  aorta,  while 
I  (99)  found  it  to  remain  constant  in  the  thoracic 
aorta  and  then  to  steepen  in  the  abdominal  aorta. 
The  slope  change  is  never  marked,  however,  so  that 
all  three  studies  are  compatible  with  the  general 
conclusion  that  this  first  part  of  the  pressure  wave 
seems  to  move  as  an  unchanged  unit.  All  three  also 
agree  that  the  steep  upstroke  continues  for  a  longer 
time  interval  the  further  from  the  heart  the  recording 
is  made.  This  might  lead  one  to  the  conclusion  that 
this  early  part  of  the  wave  cannot  be  thought  of  as 
being  propagated  by  repetitive  accelerations  of  tiny 
segment  volumes.  It  was  pointed  out  earlier  that  the 
length  of  what  is  called  a  "small  segment"  of  the 
aorta  is  undefined.  The  segment  may  have  an  ap- 
preciable length,  and  the  volume  contained,  which 
is  accelerated  as  a  unit,  have  an  appreciable  mass. 
Thus  it  may  be  that  the  propagation  of  the  first 
part  of  the  pulse  wave  would  involve  fluid  accelera- 
tions which  would  have  many  of  the  physical  prop- 
erties of  a  volume  surge  with  inertia.  If  so,  one 
would  expect  the  "surge"  to  produce  a  progressiveh 
greater  pressure  rise  in  the  lower  regions  of  the  aortic 


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83I 


funnel,  where  the  distensibility  is  reduced.  The 
speed  at  which  the  wave  front  would  move  would 
be  dependent  in  part  upon  the  force  of  the  drive. 
For  under  these  conditions,  the  ascending  aorta 
would  be  "driving"  the  fluid  through  the  various 
exit  branches,  one  of  which  would  be  the  thoracic 
aorta.  These  statements  are  similar  to  those  made 
previously  in  the  discussion  of  the  relation  between 
the  pressure  curve  and  the  fluid  displacement.  It 
remains  for  future  work  to  reconcile  evidence  which 
seems  to  favor  the  presence  of  a  fluid  surge  with  that 
which  supports  the  proposed  model,  having  wave 
propagation  based  on  fluid  displacement  from  one 
tiny  vessel  segment  to  the  next. 

A  study  of  a  great  number  of  pulse  forms  leaves 
the  impression  that  the  volume  uptake  of  the  aorta 
in  the  period  when  the  pressure  shows  this  initial 
fast  rise  is  not  so  large  as  would  be  expected  from 
volume-pressure  relations  taken  from  a  static  stretch 
curve.  This  impression  has  not  been  proven.  A  rapid 
pressure  rise  at  a  time  when  the  volume  input  is 
small  was  a  pillar  of  the  acceleration  transient  story 
of  Peterson  (90).  One  would  like  to  explain  an  excess 
pressure  height,  if  present,  on  the  basis  of  wall  hystere- 
sis. If,  in  studies  with  rapid  stretches  of  isolated 
vessels,  there  had  ever  been  a  considerable  overfling 
of  pressure  at  the  end  of  a  stretch,  I  would  feel  happier 
about  this  possible  answer.  If  the  impression  is  correct 
that  pressure  rise  exceeds  the  expected  volume  gain, 
then  it  could  also  be  true  that  in  the  interval  of  the 
shoulder  of  the  pulse,  the  volume  gain  would  con- 
tinue, and  thus  "catch  up"  with  the  pressure. 

When  the  pulse  enters  either  the  arm  system  or  the 
aorta-leg  system,  the  height  of  the  shoulder  is  in- 
creased. In  the  human  arm  system,  this  elevation  of 
the  shoulder  takes  place  largely  in  the  subclavian 
arteries.  The  brachial  pulse  then  shows  two  systolic 
waves,  one  representing  the  shoulder,  and  the  other 
the  later  systolic  part  of  the  entering  wave  (12,  69, 
108)  (fig.  13).  Very  often  the  first  is  higher  than  the 
second,  and  hence  sets  the  pulse  pressure.  This  is 
particularly  true  when  the  anacrotic  rise  formed  in 
the  ascending  aorta  is  steep  and  the  shoulder  is 
high.  Late  in  a  Valsalva  maneuver,  for  example,  the 
aortic  pulse  shows  a  steep  anacrotic  rise  and  high 
shoulder,  but  the  rest  of  the  pulse  tends  to  collapse 
toward  a  low  incisura.  This  contour  is  in  keeping  with 
the  much  reduced  stroke  volume.  But  in  the  brachial 
pulse  the  shoulder  may  remain  at  almost  the  normal 
height,  which  means  that  a  pulse  pressure  measured 
from  this  height  would  have  no  relation  to  the  stroke 
volume  (108). 


II                 1                  1 

1       1       1 

1               1 

- 

ISO 

2 0(->    •■'"»<s«9i 

)  — _    s,» 

1                 Jf^^Si 

I?<1 

5   IS  en 

I     &' 

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no 

SUR 

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00 

PRES 

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- 

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90 

~.ij' 

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TIME  —  SECONDS 

1             1 

- 

fig.  13.  Transformation  of  pulse  in  subclavian-arm  system 
(subject  1).  A:  arterial  pressure  pulses  recorded  at  5-cm  inter- 
vals during  withdrawal  of  catheter  through  subclavian-upper 
brachial  system  of  normal  subject.  Curve  1  is  the  aortic  pulse, 
recorded  from  the  thoracic  aorta  through  a  catheter  inserted  via 
right  femoral  artery.  It  has  been  set  back  by  0.03  sec.  Curve  2 
(starting  at  o  time)  is  the  pulse  in  most  proximal  point  in  sub- 
clavian artery  reached  by  catheter  inserted  via  left  radial 
artery.  B:  continued  withdrawal  of  catheter  into  lower  brachial 
and  radial  system.  Heavy  solid  line  represents  pulse  from  most 
proximal  position  in  subclavian  (o-cm  withdrawal  in  A).  The 
30-cm  withdrawal  curve  is  last  pulse  from  proximal  unit  (A), 
which  still  showed  the  simultaneous  initial  pressure  peak.  The 
70-cm  withdrawal  is  point  at  which  catheter  again  entered 
needle  in  left  radial  artery.  Pulse  from  right  radial  artery,  re- 
corded through  a  similar  needle  itself,  is  labeled  "radial." 
[From  Remington  &  Wood  (108). j 

Conversely,  when  the  pressure  is  well  supported 
in  the  upper  aorta  in  late  systole,  the  second  wave 
of  the  brachial  pulse  becomes  higher,  and  may  then 
determine  the  pulse  pressure.  The  maintenance  of 
high,  late  systolic  pressure  in  the  upper  aorta  may  be 
related  to  a  large  stroke  volume.  Hence  in  aortic 
regurgitation,  where  the  ventricle  is  large  and  the 
total  stroke  volume  much  increased,  the  second  wave 
of  the  brachial  pulse  becomes  quite  large.  In  the 
aortic  pulse,  the  ejection  interval  is  prolonged  and 


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the  systolic  peak  tends  to  come  late.  ( )n  the  other 
hand,  this  maintenance  of  a  high,  late  systolic  pressure 
may  also  reflect  a  change  in  the  acceptance  by  the 
aorta  of  ejected  blood.  For  example,  if  the  aortic 
pressure  is  acutely  raised,  the  first  result  is  a  reduced 
stroke  volume  and  a  tendency  toward  shortening  of 
the  ejection  period.  This  is  presumably  because  the 
energy  cost  of  ejection  has  been  raised.  As  the  heart 
size  increases,  the  stroke  volume  shows  some  tendency 
to  increase,  and  the  duration  of  ejection  becomes 
longer.  The  systolic  peak  comes  later  in  systole. 
This  pattern  is  clearest  in  animals  with  chronic  hy- 
pertension. Part  of  this  change  may  be  due  to  a 
change  in  cardiodynamics  (although  not  documented 
as  such).  A  more  likely  explanation  is  that  as  the 
pressure  rises,  the  front  of  the  wave  moves  more 
rapidly  through  the  whole  receiving  arterial  reservoir, 
so  that  by  midsystole  the  whole  reservoir  may  be  so 
nearly  filled  that  the  vessels  act  more  as  rigid  conduits 
than  as  extensible  tubes.  As  discussed  previously,  this 
tends  to  maintain  the  pressure  at  higher  levels  in 
the  ascending  aorta. 

Conversely,  when  the  aortic  pressure  is  acutely 
lowered,  the  first  few  beats  show  a  prolongation  ot 
systolic  duration,  with  the  systolic  peak  remaining 
in  midsystole.  After  the  first  few  beats,  as  the  heart 
size  becomes  smaller,  the  stroke  volume  is  reduced, 
and  the  peak  tends  to  occur  earlier  (45,  94).  At  low 
pressures,  the  wave  front  moves  so  slowly  through  the 
reservoir  that  volume  is  still  being  readily  accepted 
by  the  lower  aorta,  and  hence  by  the  ascending  aorta, 
toward  the  end  of  systole. 

The  location  of  the  systolic  peak  and  the  contour  of 
the  main  part  of  the  systolic  portion  of  the  pulse 
contour  depend  upon  the  varying  characteristics  of 
both  the  arterial  reservoir  and  the  cardiac  ejection 
curve.  This  can  also  be  taken  to  mean  that  the  form 
of  the  ejection  curve  is  molded  by  the  rate  of  aortic 
acceptance  of  blood.  Hence  when  the  pressure  is 
elevated,  and  the  wave  moves  more  rapidly  through 
the  vessels,  the  whole  reservoir  is  filled  in  less  time. 
Toward  the  end  of  systole,  then,  cardiac  ejection 
need  only  compensate  for  the  drainage  loss,  and  the 
pressure  can  be  held  relatively  high  until  ventricular 
relaxation  begins  (106).  Conversely,  when  the  aortic 
pressure  is  lowered  and  the  pulse  moves  more  slowly, 
the  ejection  of  the  same  amount  of  blood  will  produce 
a  greater  rise  in  pressure  in  the  upper  aorta.  If  the 
pressure  peak  is  still  being  propagated  into  the  more 
distal  vessels  toward  the  end  of  systole,  we  would 
expect  a  fall  in  pressure  in  the  ascending  aorta,  for 
the    small    amount    of   cardiac    ejection    could    not 


compensate  for  the  fluid  displacement  required  to 
construct  the  pulse  wave. 

The  incisural  vibration  is  formed  in  the  ascending 
aorta  and  is  propagated  at  an  orderly  rate  not  greatly 
different  from  that  of  the  wave  foot  (98,  99).  In 
many  cases,  and  particularly  when  the  systolic  peak 
is  reached  late  in  the  ejection  period,  it  develops  as 
soon  as  the  ventricular  pressure  falls  below  the  aortic 
level.  In  other  cases,  an  appreciable  pressure  differ- 
ence between  ventricle  and  ascending  aorta  is  de- 
veloped before  the  notch  appears.  This  is  particularly 
true  in  pulses  which  have  a  high  anacrotic  shoulder 
and  a  collapsing  pulse  late  in  systole  (98).  Valve 
closure  is  also  delayed  when  the  aortic  pressure  is 
low.  At  times  it  may  not  appear  until  the  isometric 
relaxation  phase  of  the  ventricle  is  almost  complete 
(106). 

It  may  be  more  than  coincidence  that  the  delay 
of  the  incisura  is  seen  in  those  cases  where  the  wave 
front  is  still  moving  through  the  reservoir.  Valve 
closure  must  require  a  certain  amount  of  flow  reversal 
in  the  ascending  aorta.  It  seems  reasonable  that  this 
reversal  could  be  accomplished  more  readily  when 
outflow  from  the  upper  aorta  is  minimal  (as  with 
high  pressure). 

In  most  normotensive  pulses  the  incisura  has  been 
damped  out  by  the  time  the  pulse  enters  the  ab- 
dominal aorta.  With  elevated  pressure,  it  may  be 
seen  as  far  as  the  femoral  artery.  With  a  lowered 
pressure  level,  it  may  be  lost  in  the  thoracic  aorta. 
This  difference  is  presumably  attributable  to  the 
various  visco-elastic  properties  of  the  wall  at  the 
different  pressure  levels.  Whether  the  incisura  is  still 
present  or  not,  the  pulse  of  the  lower  aorta  and  the 
leg  arteries  shows  a  deep  early  diastolic  trough.  This 
is  accentuated  in  fever,  hyperthyroidism,  and  aortic 
regurgitation.  Three  different  factors  contribute  to 
the  presence  and  size  of  this  trough.  First,  it  is  in- 
fluenced by  the  late  systolic  fall  in  pressure  of  the 
central  pulse.  Second,  the  trough  contains  the  remnant 
of  the  incisural  vibration.  Third,  the  trough  appears 
to  be  set  by  the  same  mechanism  that  gives  rise  to 
the  augmentation  of  the  systolic  peak,  especially 
when  this  augmentation  appears  attributable  to  the 
achievement  of  resonance  in  the  aortic  system  (2,  7, 

99)- 

The  fundamental  form  of  the  diastolic  part  of  the 

pulse  is  probably  the  same  for  all  pulses,  no  matter 

where  recorded,  except  for  the  size  of  the  periodic 

oscillations    which    are    superimposed.    Where    such 

oscillations  are  minor,  the  slope  appears  exponential 

(140),  but  the  relation  of  the  rate  of  pressure  fall  to 


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833 


existing  pressure  level  does  not  remain  constant  during 
a  prolonged  diastolic  period  (25).  It  is  difficult  to 
generalize  about  the  factors  which  contribute  to  the 
height  of  the  diastolic  oscillations.  When  the  pressure 
is  raised  to  hypertensive  levels,  the  postincisural 
hump  of  the  central  pulse  is  usually  much  less  con- 
spicuous. This  is  due  in  part  to  the  fact  that  it  is 
then  superimposed  upon  a  part  of  the  pressure  curve 
which  falls  much  more  steeply,  since  the  vessel 
distensibility  is  decreased  in  the  high  pressure  range. 
It  is  much  more  probable  that  the  relatively  small 
size  of  the  hump  is  a  result  of  the  fact  that  it  starts 
near  the  time  of  the  incisura  (or  even  before),  because 
the  propagation  velocity  of  the  returning  wave  is 
more  rapid.  Conversely,  at  low  aortic  pressures,  the 
postincisural  hump  of  the  central  pulse  may  be  quite 
conspicuous.  This  is  partly  because  the  basic  diastolic 
slope  is  so  shallow  that  any  pressure  increase  is 
clearly  evident,  and  partly  because  the  frequency  of 
the  "'resonant"  oscillations  is  decreased,  so  that  the 
swell  comes  later  in  diastole;  also,  it  may  be  due  partly 
to  an  actual  augmentation  of  the  swell  itself. 

Calculation  of  the  Stroke  Volume  From 
the  Central  Pressure  Pulse 

On  the  theory  that  the  aorta  achieved  immediate 
resonance,  which  means  that  the  time  interval  be- 
tween two  successive  pressure  oscillations  on  all 
peripheral  pulses  would  be  the  same  and  would  be 
an  index  to  the  length  and  distensibility  charac- 
teristics of  the  aortic  reservoir,  Frank  (30)  regrouped 
a  formula  similar  to  that  of  Bramwell  and  Hill  to 
have  it  express  the  total  distensibility  of  the  whole 
resonant  system.  Hence  where  v  is  the  pulse  wave 
velocity,  --1  the  cross-sectional  area  of  the  bed,  L 
its  length,  p  the  specific  gravity  of  blood,  and  AP/AV 
the  slope  characterizing  the  system  distensibility : 


ALAP 
0  AV 


(21) 


With  the  simplifying  assumption  that  AP  AV  remains 
constant  throughout  the  range  covered  by  a  given 
pulse,  we  can,  with  extreme  reservations,  take  AP  to 
be  the  recorded  pulse  pressure,  and  AV  the  cor- 
responding volume  change.  This  assumes  that  the  V 
for  a  given  vessel  would  have  a  fixed  relationship  to 
the  volume  gain  by  the  whole  arterial  bed.  Re- 
arrangement of  the  formula  gives: 


Since  the  time  interval  between  successive  pressure 
peaks  is  assumed  to  be  that  required  for  the  pulse 
wave  to  make  a  round  trip  through  the  system,  T  = 
1  L/v,  or  L  =  Tv/2.  Substituting  in  the  formula 
then  gives: 


AV  -" 


ATvAP 


2/>v' 


ATAP 
2pv 


(22) 


AV 


ALAP 


pv* 


German  workers  have  continued  to  use  the  Frank 
formula,  or  modifications  of  it.  These  formulas  have 
received  only  restricted  support  in  this  country  (124). 
While  they  may,  perhaps,  predict  in  reasonable 
degree  the  volume  input  into  a  rubber  tube  where 
the  distensibility  is  uniform  through  the  tube  length, 
their  use  with  the  complicated  arterial  bed  requires 
very  large  assumptions.  First,  there  is  the  inference 
given  above  that  the  AP/AV  relation  for  any  single 
vessel  is  indicative  of  the  relation  for  the  whole 
reservoir  system.  Second,  A  does  not  represent  the 
area  of  any  single  vessel,  but  rather  that  of  a  hy- 
pothetical tube  which  happens  to  have  the  same 
dimensions  as  the  mean  of  the  whole  reservoir  net- 
work. Attempts  have  been  made  to  take  values  for 
A  from  autopsy  data,  using  the  upper  aorta,  which 
certainly  would  not  have  the  same  dimensions  as 
this  mean.  Further,  autopsy  data  give  a  diameter  at 
near  zero  pressure  and  not  that  at  a  physiological 
pressure.  Third,  since  AV  is  the  volume  stored  in  the 
Windkessel  during  systole,  it  is  not  directly  measur- 
able. If  a  calculation  is  made  for  the  drainage  loss 
during  systole  (and  various  formulas  have  been  pro- 
posed for  calculating  this  loss),  then  the  stored  volume 
plus  the  calculated  drainage  loss  would  equal  the 
stroke  volume,  which  can  be  measured  directly  only 
under  restricted  conditions,  but  which  is  usually 
taken  from  a  cardiac  output  determination.  Fourth, 
L,  the  length  of  the  reservoir  network,  cannot  be 
directlv  measured.  As  described  earlier,  it  has  instead 
been  calculated  from  the  length  of  the  resonant 
wave,  as  indicated  by  the  time  interval  between 
successive  pressure  peaks  of  a  peripheral  pulse.  This, 
of  course,  assumes  that  the  reflecting  end  of  the 
system  is  also  the  end  of  the  Windkessel.  The  estima- 
tion of  wave  velocity  and  of  the  time  interval  between 
pressure  peaks,  by  the  techniques  employed,  leaves 
room  for  doubt  as  to  the  validity  of  any  strict  quan- 
titation. 

If  the  stroke  volume  could  be  directly  measured, 
it  might  be  that  the  various  unknowns  could  be 
combined  into  a  single  constant.  Its  value,  however, 
would  apply  only  at  the  diastolic  pressure  for  which 
it  was  derived,  only  if  neither  A  nor  L  was  subject 


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CIRCULATION    II 


to  physiological  change,  and  only  if  a  constant  so 
derived  for  one  individual  could  be  applied  to 
another.  All  these  assumptions  have  seemed  so 
precarious  that  the  German  formulas  have  not 
received  favor  in  this  country. 

Yet  the  hope  remains  that  some  means  can  be 
devised  by  which  the  stroke  volume  can  be  predicted 
from  the  values  of  the  pressure  pulse.  This  would 
allow  a  quantitation  of  beat-to-beat  changes,  and 
also  of  the  acute  change  in  ejection  volume  that  occur 
as  the  cardiovascular  status  is  rapidly  changed.  We 
have  no  direct  method  applicable  to  closed-chest 
animals  that  can  measure  these  stroke  volume  changes. 
Until  we  do,  an  indirect  approach  can  serve  a  limited 
but  useful  purpose. 

Another  attempt  at  making  this  sort  of  indirect 
calculation  was  made  by  Bazett  and  co-workers  (10). 
They  divided  the  arterial  reservoir  into  four  parts: 
/)  the  aortic  arch  and  its  large  branches;  2)  the 
whole  of  the  descending  aorta  through  the  iliacs; 
3)  the  subclavian-brachial  systems;  and  4)  the 
femoral-leg  system.  They  recognized  that  the  pulse 
pressure  would  be  different  in  these  regions,  and 
therefore  concentrated  instead  on  the  pressure  change 
taking  place  during  diastole,  when  the  previously 
stored  blood  was  being  discharged  through  the  re- 
sistance vessels.  They  assumed  that,  by  the  time  of 
the  incisura,  the  whole  arterial  reservoir  would  be 
draining  as  a  single  unit,  and  that  the  pressure 
change  could  therefore  be  that  from  the  level  of  the 
incisura  of  a  central  pulse  to  the  end-diastolic  value. 
Unfortunately,  their  central  pressure  pulses  were 
rather  inadequately  recorded.  Next,  using  calcula- 
tions based  on  the  size  of  the  larger  vessels  of  each 
arterial  region  as  taken  from  autopsy  data,  and 
using  assumptions  and  empirical  adjustment  of  the 
derived  diastolic  volume  values,  they  arrived  at 
figures  for  the  total  diastolic  volume  for  each  region. 
The  change  in  volume  from  this  level  was  then 
equated  as  a  function  of  the  pulse  wave  velocity 
through  the  region,  or 


,v.         v      V,       v4    , 


V 


V3 


where  AC  is  the  total  stored  volume,  the  I"s  are  the 
calculated  diastolic  volumes  of  the  four  parts  of  the 
reservoir,  and  the  v\  the  respective  wave  velocities 
(which  could  be  measured  only  rather  crudely). 
With  more  modern  technology,  the  basic  data  could 
be  much  more  accurately  recorded.  The  formula 
would  still  be  rather  cumbersome,  and  the  necessarv 


measurements  many.  Two  of  the  major  weaknesses 
still  present  are  that  V  cannot  be  directly  obtained, 
any  more  than  the  A  of  Frank's  equation  can  be, 
and  that  the  v  values  of  necessity  must  be  taken  from 
a  single  large  artery  in  each  of  the  regions.  This 
assumes  that  this  artery  can  fairly  represent  the  whole 
system,  and  also  that  this  velocity  gives  a  true  indica- 
tion of  vessel  distensibilitv. 

We  presented  another  approach  to  the  problem, 
worked  out  on  the  dog  rather  than  on  the  human. 
For  reasons  which  have  been  covered  previously, 
we  regarded  the  wave  velocity  as  a  most  dubious 
measure  of  vessel  distensibilitv.  Instead,  we  sub- 
stituted volume-pressure  relations  taken  from  data 
obtained  by  stretching  isolated  rings,  and  by  inject- 
ing saline  into  occluded  arteries  of  dead  animals. 
We  necessarily  assumed  that  the  values  obtained 
would  be  practically  the  same  for  different  animals. 
To  make  some  correction  for  differences  in  body  size, 
all  values  were  expressed  per  square  meter  of  body 
surface  area.  We  also  assumed  that  the  transmission 
time  through  the  various  arterial  beds  would  be  the 
same  for  all  animals,  at  the  same  diastolic  pressure 
level.  After  making  the  studies  described  above,  in 
which  we  calculated  the  presumed  cardiac  ejection 
curve  on  the  basis  of  a  summation  of  volume  uptake 
values  of  the  arterial  regions  taken  serially  as  they 
were  invaded  by  the  pulse  wave,  as  described  above, 
we  settled  on  the  premise  that  such  a  summed  total 
uptake,  with  a  calculated  systolic  drainage  added, 
should  equal  the  stroke  volume  at  the  time  of  valve 
closure.  Hence  we  could  work  with  a  single  central 
pressure  pulse,  laying  back  the  transmission  time  to 
each  of  the  four  major  divisions  of  the  arterial  bed, 
from  the  incisura.  The  pulse  pressure  to  be  quan- 
titated  for  each  bed  would  then  simply  be  the  pres- 
sure shown  at  this  interval  before  valve  closure.  In 
other  words,  the  point  at  which  this  time  interval 
intercepts  the  pressure  pulse  curve  indicates  the 
pressure  developed  in  the  bed  in  question  at  the  end 
of  systole.  This  assumes  that  there  was  no  change  in 
pulse  contour  during  propagation.  More  rightly,  it 
assumes  that  any  contour  change  present  during 
propagation  would  be  constructed  by  a  redistribution 
of  the  volume  of  blood  ejected  into  the  ascending 
aorta  to  create  the  given  central  pressure  pulse.  At- 
tempted modifications  based  on  actual  pulse  contours 
taken  at  various  points  in  the  aorta  did  not  alter  the 
value  of  the  calculated  stroke  volume  to  significant 
degree. 

Without  introducing  any  empirical  correction 
factor,    the    agreement    between    the    predicted    and 


PHYSIOLOGY    OF    AORTA    AND    MAJOR    ARTERIES 


83! 


the  stroke  volume  derived  from  the  dye  injection  or 
Fick's  procedure  was  within  12  per  cent  (44).  Further 
work  brought  to  light  two  areas  of  discrepancies. 
First,  the  predictions  tended  to  underestimate  the 
actual  stroke  volumes  at  high  pressure  ranges.  The 
volume-pressure  values  were  then  empirically  adjusted 
to  take  care  of  this  (94).  The  correction  used  is 
almost  identical  to  the  difference  between  the  single 
continuous  stretch  curve  of  figure  3  and  the  curve 
connecting  the  midpoints  of  the  consecutive  loops, 
which  fact  suggests  that  there  may  be  a  theoretical 
foundation  for  the  empirical  correction.  The  second 
and  more  serious  failure  of  the  method  is  that  it 
yields  a  definite  overestimation  of  the  actual  stroke 
volume  in  some  shock  states  in  which  the  pressure 
shows  a  brisk  anacrotic  rise  with  a  high  shoulder, 
but  is  then  poorly  sustained  later  in  systole.  This 
type  of  pulse  has  been  described  above.  The  possible 
causes  of  the  failure  in  prediction  for  these  rare 
pulses  were  discussed  rather  fully  in  a  symposium 
presented  in  1952  (86a)  and  little  more  light  has 
been  shed  on  the  problem  since. 


A  modification  of  our  method  to  make  it  applicable 
to  the  human  has  been  presented  (19,  130).  Omitted 
from  the  description  here  are  the  attempts  to  equate 
the  stroke  index  with  the  pulse  pressure.  Most  es- 
pecially when  the  pulse  pressure  is  taken  from  the 
brachial  artery,  such  a  prediction  can  be  relatively 
gross  (95). 

In  summary,  the  search  for  an  understanding  of 
the  nature  and  functions  of  the  distensible  vessels 
through  which  blood  passes  on  its  way  from  the  heart 
to  the  periphery  of  the  circulation  is  a  fascinating 
pursuit.  The  physical  basis  of  wave  propagation  and 
of  the  changes  in  pulse  form,  attending  such  propaga- 
tion, remain  indefinite.  Some  of  the  possible  factors 
which  may  contribute  to  such  contour  changes  have 
been  described.  It  remains  clear  that  we  are  in  no 
position  to  predict  a  stroke  volume  from  the  form  or 
pressure  values  of  a  peripheral  pulse.  The  form  of  the 
pulse  in  the  upper  aorta,  however,  can  reveal  much 
about  cardiodynamics.  It  can  also  be  used  for  the 
only  practical,  if  indirect,  technique  yet  developed 
for  reasonably  accurate  stroke-by-stroke  quantitation 
of  the  cardiac  output. 


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■947- 
King,  A. 


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837 


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80.  Mallov,  S.  Effects  of  sodium  ion  and  solution  tonicity  on 
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'945- 

93.  Reichel,  H.  Die  elastischen  Eigenschaften  des  glatten 
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95.  Remington,  J.  W.  Relation  between  the  stroke  volume 
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96.  Remington,  J.  W.  Hysteresis  loop  phenomenon  of  the 
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97.  Remington,  J.  W.  Extensibility  behavior  and  hysteresis 
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100.  Remington,  J.  W.,  and  R.  P.  Ahlquist.  Effect  of  sympa- 
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102.  Remington,  J.  W.,  and  R.  S.  Alexander.  Relation  of 
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103.  Remington,  J.  W.,  W.  F.  Hamilton,  and  P.  Dow.  Some 
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1945- 

104.  Remington,  J.  W.,  and  W.  F.  Hamilton.  Quantitative 
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109. 


"3- 
114. 

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116. 

117. 
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I23- 
124. 


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CHAPTER     25 


Pulsatile  blood  flow  in  the  vascular  system 


MERRILL    P.    SPENCER 
ADAM   B .    DENISON,  JR. 


Department  of  Physiology  and  Pharmacology,  Bowman  Gray 
School  of  Medicine,  Winston-Salem,  North  Carolina 


CHAPTER     CONTENTS 

Methods  of  Measurement 

Properties  and  Principles  of  Flowmeters 

Cognate  Phenomena 
Elements  of  Vascular  Hydraulics 

Resistance 

Inertance 

Compliance 

Axial  Flow 

Radial  Flow 

Hydraulic  Impedance 

Flow  Source  Versus  Pressure  Source 

The  Analogy  Approach 
Systemic  Arterial  Flow 

Blood  Flow  in  the  Ascending  Aorta 

Pressure-Flow  Relationship  in  the  Ascending  Aorta 

Ventricular  Ejection  Gradients 

Windkessel  Model  of  the  Arterial  System 

Aortic  Transformation  of  Flow  and  Pressure  Pulses 

Resonant — Network  Model  of  the  Arterial  System 

Transmission  Line  Model  (Distributed  System) 

Distribution  of  the  Blood  in  the  Aortic  Arch 

Abdominal  Aorta  and  Its  Terminal  Branches 

Function  of  the  Resonant  Wave 

Renal  Blood  Flow 

Carotid  Artery  Flow 

Coronary  Blood  Flow 
Flow  in  the  Systemic  Veins 

Effect  of  the  Heart's  Action  on  Vena  Caval  Flow 

Effect  of  Normal  Respiration  on  Vena  Caval  Flow 
Pulmonary  Flow 

Right  Ventricular  Ejection  Pulse 

Pulsatile  Flow  in  the  Pulmonary  Capillary  Bed 
Nonlaminar  Flow  and  Murmurs 

Normal  Murmurs 

Relationship  Between  the  Murmur  of  Coarctation  Stenosis 
and  Blood  Flow  Through  the  Stenotic  Area 

The  Murmur  Envelope  and  Contour  Rule 

General  Rules  Relating  Murmurs  to  Nonlaminar  Flow 
Normal  and  Pathological  Flow  Pulses  in  Humans 


Flow  in  the  Ascending  Aorta 
Descending  Thoracic  Aorta 
Tricuspid  Valve 


THE    HIGHLY   PULSATILE   NATURE    of  the    blood    flow    in 

both  the  systemic  and  pulmonary  circuits  primarily 
arises  from  the  intermittent  action  of  the  heart  as  a 
pump.  Each  ventricle  has  a  valve  at  its  exit  and 
entrance  such  that  the  blood  flow  and  velocity 
oscillate  from  near  zero,  when  the  valves  are  closed, 
to  relatively  great  values  during  the  time  when  the 
valves  are  open.  Great  changes  in  the  velocity  arise 
from  the  starting  and  stopping  of  the  blood  stream 
with  the  opening  and  closure  of  these  valves.  Second- 
ary causes  of  flow  pulsations,  particularly  in  the  veins, 
arise  from  the  respiratory  fluctuations  and  muscular 
contractions. 


I.    METHODS    OF    MEASUREMENT 

Methods  for  the  detection  of  blood  flow  and  pres- 
sure oscillations  within  this  system  require  a  frequency 
response  flat  to  at  least  ioo  cps  and  without  phase 
shift.  Present  day  pressure  systems  achieve  this  ideal 
quite  well  if  one  does  not  introduce  long  elastic 
catheters  between  the  pressure  tap  and  the  transducer. 
Present  day  blood  flowmeters,  however,  have  not 
achieved  this  degree  of  perfection,  but  recently  great 
progress  has  been  made.  In  addition  to  the  frequency 
and  phase  characteristics  mentioned,  a  blood  flow- 
meter should  be  capable  of  detecting  the  blood  flow  or 


839 


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CIRCULATION    II 


velocity  from  either  the  surface  of  a  surgically  exposed 
vessel  or  by  means  of  a  catheter  tip  introduced  into 
the  flow  stream,  but  without  causing  significant  dis- 
tortion of  the  flow  dynamics. 

All  the  blood  flow  recordings  gathered  by  the 
authors  for  this  chapter,  if  not  otherwise  indicated, 
have  been  made  with  a  240-cycle  square-wave  elec- 
tromagnetic flowmeter  (11)  introduced  in  1953  as  the 
first  practical  instrument  for  measuring  blood  flow  in 
any  of  the  body's  arteries  and  veins  which  have  been 
surgically  exposed.  As  used  here,  this  instrument  has  a 
flat  frequency  response  to  40  cps,  and  is  down  by  50 
per  cent  at  100  cps,  and,  although  the  principle  is 
capable  of  an  infinite  frequency  response,  these 
limitations  are  necessary  in  a  practical  instrument 
primarily  because  of  the  carrier  frequency  residual 
which  would  otherwise  appear  on  the  flow  record. 
The  magnetic  probes  applied  to  the  blood  vessels 
restrict  pulsations  and  encroach  on  the  lumen  to  the 
extent  of  reduction  in  cross-sectional  area  by  approxi- 
mately 5  to  10  per  cent.  Such  slight  constriction 
assures  firm  contact  of  the  electrodes  to  the  arterial 
wall.  Experimental  testing  showed  that  this  amount  of 
constriction  caused  no  perceptible  change  in  the  re- 
corded flow  pulse  (45). 

Properties  and  Principles  oj  Flowmeters 

For  recording  of  vascular  flow  velocity  pulses  an 
ideal  flowmeter  should  possess  several  properties:  a 
linear  response  to  forward  and  backward  flows,  a 
stable  zero  reference,  and  a  frequency  response  ade- 
quate to  follow  the  phasic  phenomena  being  re- 
corded. It  should  also  be  unaffected  by  nonrelated 
phenomena  such  as  blood  pressure,  internal  noise, 
and  muscle  action  potentials.  Furthermore,  its  opera- 
tion should  not  modify  the  phasic  flow  patterns,  mean 
flows,  or  blood  pressure.  To  meet  this  last  requirement 
completely  would  mean  that  not  only  must  the  blood 
vessel  under  consideration  be  unobstructed  and  non- 
cannulated,  but  also  that  the  recording  be  done 
without  anticoagulants  or  anesthesia  and  without 
psychic  trauma  to  the  experimental  subject  (59). 

Obviously,  a  practical  flow-recording  system  re- 
quires some  compromise  with  the  above  ideals;  also, 
such  an  elegant  device  would  not  be  necessary  for 
most  research  work.  If  one  knows  the  general  charac- 
ter of  the  quantities  to  be  recorded,  he  may  use  with 
confidence  an  equipment  the  characteristics  of  which 
are  considerably  more  restricted  than  the  ideal.  For 
instance,  a  frequency  response  of  zero  to  50  cps  is  felt 
to  be  adequate  for  cardiovascular  work  (6,  46);  also, 


when  recording  ascending  aorta  flow,  zero  drift  is  not 
serious  since  the  flow  can  be  taken  to  be  zero  at  the 
end  of  diastole,  thus  giving  a  continuously  repeated 
zero  check.  Therefore,  an  instrument  used  for  cardiac 
output  measurements  may  have  considerable  drift  of 
zero  and  still  be  satisfactory  for  the  purpose  if  it  meets 
the  other  requirements,  although  it  might  be  unsatis- 
factory for  other  situations  where  a  stable  zero  refer- 
ence is  essential  (14). 

Many  different  principles  have  been  used  for  flow 
recording;  all  have  inherent  potentialities  for  errors  in 
application  or  interpretation.  These  principles  and 
the  instruments  which  embody  them  are  discussed  in 
detail  in  Chapter  38.  Here  it  will  be  necessary  only  to 
list  the  different  types  of  instrument  and  certain 
references  to  the  literature  which  are  not  found  else- 
where either  in  this  chapter  or  in  Chapter  38. 

a)  Electromagnetic  flowmeters  (1,  3,  5,  8,  9,  16, 
24>  53>  57>  63).  b)  Ultrasonic  flowmeters  (25).  c) 
Nuclear  magnetic  resonance  (4,  23).  d)  Pendulum  or 
bristle  flowmeters,  e)  Catheter  tip  pickups  (36,  38). 
/)  Turbinometers  (40,  41).  g)  Differential  pressure 
flowmeters  (10,  17,  39). 

Cognate  Phenomena 

LATERAL  AND  DIFFERENTIAL  PRESSURES.  Ill  any  Critical 

study  of  the  relationship  of  the  dynamics  of  pulsatile 
flow  it  is  necessary  that  pressure  and  flow  be  measured 
simultaneously,  and  that  the  pressure  be  picked  up 
from  a  pressure  tap  the  orifice  perimeter  of  which  is 
in  a  plane  parallel  to  the  flow  stream.  One  highly 
practical  system  is  to  use  a  "clip  needle"  which  by 
means  of  a  flexible  clip  holds  the  end  of  the  needle 
against  the  inside  of  the  blood  vessel  wall  (49).  If  a 
Huber  point  is  used  on  the  clip  needle,  the  recorded 
pressure  can  be  a  true  lateral  pressure. 

The  use  of  differential  pressure  measurements  has 
greatly  enhanced  our  interpretation  of  the  phenomena 
occurring  simultaneously  within  the  vascular  system. 
Such  a  method  usually  takes  the  form  of  two  pressure 
taps  conducted  separately  to  either  a  differential 
pressure  transducer  or  to  two  individual  pressure 
transducers  the  amplified  signals  of  which  are  elec- 
trically subtracted  from  one  another  continuously. 
The  latter  system  has  the  advantage  of  being  able  to 
view  the  individual  pressures  which  make  up  the 
differential  pressure  recording.  These  individual  re- 
cordings are  useful  in  identifying  artifacts  which  may 
arise. 

computer  techniques.  For  a  proper  understanding  of 
the  hemodynamics  of  the  cardiovascular  system,  a  full 


PULSATILE    BLOOD    FLOW 


84I 


appreciation  should  be  had  for  the  relationship  be- 
tween flow  velocity,  volume,  and  displacement.  These 
relationships  may  be  expressed  best  by  means  of 
calculus  symbology,  as  follows: 

Displacement  (cm)   =     /     Velocity  (cm/sec)  dt 
Jo 

Velocity  (cm/sec)   =     /     Acceleration  (cm/sec2),  dt  and 
Jo 


Volume  (cm1) 


Flow  (cm3/sec) 


=    /     Flow  (cm3/sec)  dt 
Jo 


f 

Jo 


Volume  acceleration  (cm3/sec2)  dt 


For  example,  the  cardiometer  tracings  during  the 
systolic  ejection  period  may  be  said  to  be  the  negative 
integral  of  flow  through  the  aortic  and  pulmonary 
valves,  and  the  diastolic  cardiometer  tracing  is  the 
integral  of  the  flow  through  the  A-V  valves.  Also,  the 
radial  displacement  of  the  arteries  and  veins  may  be 
said  to  be  the  integral  of  the  radial  velocity  of  blood 
flow  within  the  lumen. 

Analogue  computer  techniques,  useful  in  the  study 
of  vascular  hemodynamics  (50),  allow  one  to  move 
from  volume  to  flow  to  acceleration  by  means  of 
integration,  or  the  reverse,  through  differentiation. 
Two  types  of  integration  are  currently  in  use:  /)  the 
true  time  integral  which  is  an  instantaneous  sum  of  a 
given  function,  beginning  from  any  given  time;  and 
2)  damping  or  "meaning,"  an  older  usage  of  the  word 
which  implies  a  mean  value  of  a  periodic  function. 
Damping  may  be  accompished  either  mechanically  or 
electrically.  The  most  practical  way  to  perform  this 
mechanically  in  a  pressure  recording  system  is  to 
introduce  compliance  or  resistance  into  the  trans- 
mitting system,  e.g.,  by  means  of  a  bubble  in  the 
gauge  or  a  partial  occlusion  clamp  on  the  catheter 
tubing.  Damping  in  an  electrical  system  amounts  to  a 
fully  charged  integrating  circuit  in  which  the  rate  of 
current  inflow  into  the  integrator  over  one  pulse 
cycle  equals  the  rate  of  current  outflow. 


Resistance  (R) 

This  arises  from  the  friction  between  shearing  mole- 
cules flowing  through  the  segment.  Expressed  in 
terms  of  the  pressure  difference  (15)  across  the  re- 
sistance, APR  ,  in  dynes  per  square  centimeter1;  the 
blood  velocity,  u,  in  centimeters  per  second;  the  cross- 
sectional  area,  A,  in  square  centimeters;  and  the  flow 
(FR  =  uA),  in  cubic  centimeters  per  second, 


APP      APR 


u-A 


F* 


(I) 


After  Poiseuille,  in  terms  of  vessel  dimensions,  length 
(/)  in  centimeters,  radius  (r)  in  centimeters,  and  blood 
viscosity  (77)  in  dynes  •  second  per  square  centimeter, 


8t,1 


(2) 


The  vessel  wall  also  has  a  small  resistance  opposing 
radial  distention  and  collapse.  The  inverse  of  resist- 
ance or  conductance  (1//?)  is  often  a  useful  term. 
The  symbol  for  hydraulic  and  viscous  resistance  is 
taken  from  electronics  (  A/WV~). 

Inertance  (L) 

This  resides  primarily  as  the  mass  of  blood  and 
secondarily  as  the  mass  of  the  arterial  wall.  It  is  ex- 
pressed in  terms  of  acceleration  (a),  and  attendant 
pressure  difference  across  the  inertance,  AP;,  ,  in 
dynes  per  square  centimeter. 


AP, 


AP, 


a- A       dF, 


(3) 


L/dt 


where  FL  is  the  flow  through  the  inertance,  and 
where  L  =  m/A2,  m  is  the  mass  of  the  blood  in  the  seg- 
ment of  artery  under  consideration  expressed  in  grams, 
and  A  is  the  cross-sectional  area  in  square  centimeters. 
In  terms  of  vessel  dimensions  (55),  /  and  r,  in  centi- 
meters and  blood  density  (pH)  in  grams  per  cubic 
centimeter, 


II.    ELEMENTS    OF    VASCULAR    HYDRAULICS 

The  arterial  system  is  a  many-branched  elastic 
conduit  for  distribution  of  blood  from  the  heart  to  all 
body  tissues.  The  caliber  ranges  from  35  mm  for  the 
human  aorta  to  7  n  for  the  capillaries.  Over  this  wide 
range  each  vascular  segment  may  be  described  by 
three  fundamental  physical  properties:  resistance, 
inertance,  and  compliance. 


Pf,  I 


(4) 


1  Pressure  in  dynes  per  square  centimeter  should  be  used 
instead  of  the  conventional  pressure  in  millimeters  of  mercury. 
The  following  expression  is  used  to  convert  from  millimeters  of 
mercury  (h)  to  pressure  in  dynes  per  square  centimeter  (P) : 

P  =  0.1  g  pneh  =   '323  X  mm  Hg 

where  g  is  the  acceleration  of  gravity  in  cm/sec2,  and  pnK  is  the 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


The  symbol  for  inertance  is  that  for  electrical  induc- 
tance (13£R5T~").  Because  inertance  is  defined  in  terms 
of  volumetric  acceleration,  the  larger  the  cross  section 
of  the  vessel  lumen,  the  smaller  is  the  inertance  in 
a  vessel  of  given  length. 


-'ffOTffWW^ 


) 


Compliance  (C) 

Compliance  is  a  property  of  the  arterial  wall 
arising  from  its  distensibility  and  chiefly  residing  in  the 
elastic  fibers.  The  contribution  of  smooth  muscle  and 
fibrous  tissue  has  not  been  determined.  It  is  expressed 
in  terms  of  blood  volume  (V)  in  the  segment  and  the 
attending  pressure  difference  across  the  vascular  wall 
APC. 


APC      APC    J 


(5) 


where  Fr  is  the  flow  into  the  compliance,  or  in  terms  of 
dimensions  (22)  length  (/),  radius  (r),  wall  thickness 
(0),  and  the  modulus  of  elasticity  (£) : 


C° 


2irr- 
Eo-l 


(6) 


The    symbol    for    compliance    is    that    of    electrical 
capacitance  ( — I  1 — ). 

Axial  Flow 

In  a  segment  of  rigid  pipe  axial  flow  is  analogous  to 
the  current  in  the  diagram  of  figure  1 .  Where  APaxiai 
=  pl  —  P2  ,  APa  at  any  instant  in  time  will  be  equal 
to  the  sum  of  the  pressure  differences  due  to  the  R  and 
L  components.  Thus : 


A  P. 


axial 


=  AP, 


*■  AP 
Rtsislono  r  "  r  Inertanca 


(7) 


(Any  pressure  gradient  resulting  from  gravity 
cancels  if  the  pressures  are  referred  to  the  same  level.) 
Substituting  from  equations  1  and  3,  and  considering 
FR  =  FL  =  F, 


AP=RF+L 


dF 
dt 


(8) 


integrating  with  respect  to  time  we  have 

F-j-f(AP0-RF)dt  (9) 

This   equation   may   be   solved   continuously    by   an 
analogue  computer  and  has  some  practical  applica- 

density  of  mercury  at  the  existing  experimental  conditions  in 
g/cm3. 


fig.   I.   Electrical  analogue  of  axial  flow  and  pressure  in  a 
rigid  tube. 


i 


Fr  I 


J' 


fic.  2.  Electrical  analogue  of  radial  How  in  an  elastic  tube. 

tion  in  the  ascending  aorta  (12,  13).  The  procedure 
is  to  subtract  P>  from  Pi  to  obtain  i\P,  and  then  to 
subtract  RF  from  AP  and  integrate  the  result.  If 
j/L  is  known  or  is  chosen  arbitrarily,  R  may  then  be 
adjusted  until  F  achieves  some  known  boundary 
condition  such  as  F  =  o  during  diastole.  Figure  3.Z? 
graphically  illustrates  the  procedure.  If  accurate 
values  for  vessel  dimensions,  blood  density,  and 
viscosity  are  available  to  calculate  L  and  R,  the 
result  can  be  obtained  in  terms  of  actual  flow  in 
cubic  centimeters  per  second,  otherwise  the  answer 
only  yields  the  velocity  in  centimeters  per  second. 

Radial  Flow 

In  a  visco-elastic  artery,  radial  flow  is  analogous  to 
the  current  in  the  diagram  of  figure  2. 


4Pm*m"A%*AIk 


(10) 


where  APradiai  represents  the  pressure  difference  across 
the  arterial  wall  (PT\  —  Pr2).  Substituting  from  equa- 
tions 1  and  5,  where  Fr  =  Fc  =  FR  , 


AP,'7-fFdt  +  RF 


(II) 


and  differentiating, 


PULSATILE    BLOOD    FLOW 


843 


F  =  C 


dAPr 
dt 


R 


dF 
dt 


(12) 


or  rearranging  equation  1 1 


w  [Apr-~rfFdt]      <"> 


Since  measurements  of  pressure  and  vessel  diameter 
are  very  similar,  friction  within  the  arterial  wall  and 
radial  inertance  are  apparently  quite  small,  although 
in  the  final  analysis,  as  clearly  indicated  by  Peterson 
(35),  one  must  consider  acceleration  along  with  dis- 
tensibility  and  friction. 

When  the  total  flow  (FT)  in  an  elastic  pipe  is  con- 
sidered, both  radial  and  axial  flow  equations  must  be 
combined  as  follows  for  instantaneous  flow:  FT  = 
!'„,,,, 1    +    FTmiial,    and,    from   equations    9    and    12, 

V  Jrf(APo-Ralra)dt+  (14) 

In  analogue  computer  language  this  equation  is 
solved  as  in  figure  3.  Patel  et  al.  (33)  have  found 
negligible  degrees  of  inertiance  and  resistance  in  the 
pulmonary  artery  wall. 

A  more  complete  hydraulic  diagram  of  an  arterial 
segment  may  be  well  shown  as  in  figure  4.  L,  ,  Ri  , 
and  C'i  represent  its  most  important  elements,  with 
R2  and  R3  representing  radial  and  axial  resistance, 
and  C-i  representing  axial  compliance.  The  complete 
arterial  system  may  be  viewed  as  a  continuous  linkage 
of  such  segments,  each  branch  and  segment  having 
quantitative  differences  in  magnitude  of  the  individual 
physical  elements.  At  the  same  time,  the  physical 
elements  of  any  segment  or  group  of  segments  may  be 
described  by  over-all  "lumping"  of  the  elements. 

The  arterial  system  is  not  a  passive  network  because 
the  elements  may  be  influenced  by  the  nervous 
system,  endocrine  system,  metabolic  processes  in  the 
wall,  and  changes  in  the  physical  properties  of  the 
blood.  In  addition,  the  values  of  the  elements  are 
nonlinear  functions  of  pressure,  vascular  dimensions, 
velocity  profile  and  many  other  influences.  In  spite  of 
these  complications,  much  can  be  learned  by  linear 
analysis  of  the  pressure  and  flow  pulses  at  various 


fig.  3.  Analogue  computer  diagram  for  solution  of  the  equa- 
tion of  liquid  flow  in  an  clastic  tube.  P,  and  ft  represent  the 
lateral  pressures  from  two  stream  points.  AP  is  the  independent 
variable  (AP  =  Pl  -  ft). 


U  R, 


L, 


-VWA 

R, 


fig.  4.  Elaborate  electrical  analogy  of  a   vascular  segment. 

points    within    the    arterial    network    studied    under 
reasonably  steady-state  conditions. 

Hydraulic  Impedance 

This  is  the  concept  of  total  opposition  to  pulsating 
and  constant  flow.  Drawing  on  the  electrical  symbol- 
ogy,  we  have  Z,  XL,  A'c,  and  XR,  where  Z  represents 
the  total  impedance,  and  A'L,  Xc,  and  XR  equal  the 
inertial,  compliant,  and  resistive  impedances.  XR  is  the 
opposition  to  flow,  XL  is  the  opposition  to  change  in 
flow,  and  A'c  is  the  opposition  to  change  in  volume.  Both 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


X,  and  Xc  depend  on  the  frequency  (v)  as  follows: 

/ 


Xj2iryL 


XC    2wvC 


The  impedance  to  blood  flow  through  L  and  C 
elements  will  therefore  be  expected  to  be  frequency 
dependent,  and  may  be  termed  hydraulic  reactance 
in  contradistinction  to  resistance  which  is  not  fre- 
quency dependent.  Hydraulic  impedance  mayr  be 
expressed  as  dP/dF,  i.e.,  the  rate  of  change  of  pressure 
with  respect  to  simultaneous  rate  of  change  of  flow. 
On  a  pressure-flow  diagram,  impedance  would  be 
represented  by  the  tangent  to  the  curve  at  any  given 
time. 

Flow  Source  Versus  Pressure  Source 

The  impedance  or  "stiffness"  of  the  flow  source 
and  pressure  source  may  be  expected  to  influence  the 
response  of  a  vascular  segment.  For  example,  a  small 
branch,  such  as  a  renal  artery  arising  directly  from 
the  aorta,  is  fed  by  a  stiff  pressure  source,  inasmuch  as 
great  changes  in  renal  vascular  impedance  encoun- 
tered within  extreme  physiological  ranges  have  no 
effect  on  the  abdominal  aorta  pressure. 

On  the  other  hand,  the  left  ventricle  without 
external  controls  behaves  as  a  flow  source  because 
relatively  great  changes  in  systemic  arterial  imped- 
ances (viz.,  aortic  stenosis,  hypertension,  vasodila- 
tion) cause  small  changes  in  the  cardiac  output.  On 
a  beat-to-beat  basis,  therefore,  the  left  ventricle  may 
be  considered  to  be  a  stiff  flow  source  or  volume  pump, 
and  the  response  of  the  arterial  system  is  greatly 
influenced  by  this  fact.  The  performance  of  the  left 
ventricle  as  a  volume  pump  is  illustrated  in  figure  5. 
The  carotid  sinus  feedback  loop  tends  to  make  the 
heart  rate  and  strength  of  contraction  vary  inversely 
with  the  arterial  pressure,  but  requires  several  beats 
for  its  correcting  action.  Hormonal  negative  feedback 
loops  also  act  on  the  heart  to  cause  it  to  perform  as  a 
stiff  pressure  source,  but  act  even  more  slowly  than 
the  reflexes. 

The  Analogy  Approach 

This  is:  a)  to  diagram  an  electrical  network  model 
of  specific  segments  of  the  arterial  system  based  on 
qualitative  facts  available  from  physiology  by  identi- 
fying blood  pressure  and  blood  flow  with  electrical 
voltage  and  current;  b)  to  test  the  model  against 
conditions  in  an  experimental  animal  by  pulsing  a 
direct  analogue  or  an  analogue  computer  with 
electrical    voltage    or    current    transduced    from    the 


100 
80 
60 

8 


0 

+  100 

+  50 

0 
-50 


BLOOD  PRESSURE 


5 


AORTIC    BLOOD 
FLOW 


AP 
(LV.P-A.A.P) 


0.5  sec 


fig.  5.  Response  of  the  dog's  left  ventricle  to  sudden  increase 
in  outflow  resistance  caused  by  partial  occlusion  of  the  as- 
cending   aorta.     — ■ —    Control;    moderate    obstruction; 

■  •  •  •     severe  obstruction. 

blood  pressure  or  flow.  The  computer  is  programmed 
to  solve  the  equation  of  the  electrical  network,  but  in 
this  case  in  terms  of  pressure  and  flow  instead  of 
voltage  and  current.  Several  general  considerations 
of  the  analogue  approach  are  available  (32,  34,  54, 
60). 

Considerations  of  this  section  approach  the  vascular 
system  from  the  standpoint  of  a  transient  response  as 
distinguished  from  the  usual  use  of  steady-state 
oscillation  in  which  the  harmonic  content  must  be 
known  to  reach  a  solution  (20,  26,  51,  61,  62).  The 
transient  response  method  has  the  advantage  of 
giving  an  instantaneous  solution  while  in  addition 
each  term  of  the  equation  has  physiological  meaning. 
To  regard  the  arterial  pulse  as  a  steady-state  oscilla- 
tion is  to  fail  to  recognize  the  input  pulse  and  the 
response  of  the  vessels  as  two  independent  phenomena 


PULSATILE    BLOOD    FLOW 


845 


and  overemphasize  the  regularity  of  the  heart  rate. 
Also,  the  terms  of  a  series  such  as  the  Fourier  have  no 
real  physiologic  meaning  and  in  fact  may  fail  to  show 
a  dominant  and  important  frequency  such  as  the 
arterial  resonant  wave. 


III.    SYSTEMIC    ARTERIAL    FLOW 

Shipley  et  al.  (44)  and  Pritchard  et  al.  (37)  made 
one  of  the  most  comprehensive  recordings  of  the 
arterial  flow  pulses  using  the  differential  pressure 
flowmeter.  They  offered  no  fundamental  theory  to 
explain  the  recorded  phasic  pressure-flow  relationship. 
Although  some  exception  may  be  taken  to  their  flow- 
meter, the  general  form  of  the  flow  pulses  agrees  well 
with  more  recent  electromagnetic  noncannulating 
recordings. 

Blood  Flow  in  the  Ascending  Aorta 

The  arterial  network  is  pulsed  by  a  flow  pulse  from 
the  left  ventricle  normally  of  the  configuration  in 
figure  6.  This  recording  is  taken  with  the  square-wave 
electromagnetic  flowmeter  on  the  ascending  aorta,  3 
to  5  cm  distal  to  the  aortic  valve.  What  were  ap- 
parently the  first  accurate  phasic  recordings  were 
made  by  Wetterer  (58).  The  linear  acceleration  of  the 
blood  by  the  left  ventricle  is  remarkable,  reaching 
greater  than  8000  cm  per  sec  per  sec  in  an  anesthe- 
tized open-chest  dog  (47).  At  the  end  of  acceleration, 
the  velocity  of  the  blood  in  the  ascending  aorta  may 
easily  exceed  100  cm  per  sec  in  the  resting  state. 
Deceleration  takes  place  at  a  rate  approximately  one- 
sixth  of  acceleration  until  closure  of  the  aortic  valve 
when  a  sharp  notch  of  deceleration  and  acceleration 
brings  the  flow  to  nearly  zero  for  the  duration  of 
diastole. 

For  many  practical  purposes  this  flat  "uneventful" 
tracing  during  diastole  in  the  ascending  aorta  may  be 
used  as  a  zero  flow  reference  to  compute  the  stroke 
volume.  The  fact  that  coronary  flow  is  not  included 
may  produce  a  small  unknown  error.  Apparently,  the 
diastolic  flow  curve  in  the  ascending  aorta  is  flat  at 
nearly  zero  because  the  reversing  effect  of  coronary- 
flow  is  balanced  by  the  forward  effect  of  decompres- 
sion of  the  first  portion  of  the  ascending  aorta.  The 
left  ventricular  ejection  velocity  at  the  root  of  the 
aorta  recorded  by  Pieper  (fig.  7)  is  similar  to  the  flow 
pulse  throughout  the  ascending  aorta.  Since  this 
instrument  records  the  axial  velocity,  it  appears  that 
the  velocity  profile  of  the  ascending  aorta  is  relatively 


0.5  sec 


10- 

c 

— 

5- 

^ 

0- 

2.5- 

fig.  6.  Flow  pulses  in  the  ascending  aorta  of  an  unanesthe- 
tized  dog.  C-core  electromagnetic  probe  was  implanted  6  weeks 
prior  to  this  record  on  the  ascending  aorta.  Electrical  connec- 
tions were  made  by  means  of  implanted  subcutaneous  wires, 
brought  to  the  surface  through  a  small  superficial  incision. 


Aortic     Pressure 
133  mm  Hg 


fig.  7.  Axial  flow  pulse  in  the  ascending  aorta  recorded  by 
means  of  velocity  probe  situated  in  midstream.  [From  Pieper 
(36).] 

flat.  More  backflow  occurs  here  during  early  diastole 
presumably  because  of  diastolic  coronary  flow. 

The  effect  of  exercise  on  the  ventricular  ejection 
pulse  is  illustrated  by  a  remarkable  experiment  by 
Olmsted  (personal  communication),  figure  8.  The 
animal  had  a  magnetic  probe  implanted  on  the  as- 
cending aorta  and  an  arrangement  for  remote  pres- 
sure recording.  After  one  month's  recovery  from  the 
surgical  procedure  he  was  exercised  by  running  in  a 
harness  behind  a  station  wagon  carrying  recording 
equipment.  Suitable  wiring  carried  the  electrical 
signals  between  the  automobile  and  the  dog.  The 
course  was  one-half  mile  over  rough  terrain  at  an 
average  speed  of  10  mph.  Upon  standing,  the  cardiac 
output  increased  primarily  because  of  increased 
heart  rate  without  change  in  stroke  volume  and  with 
little  change  in  form  of  the  ejection  pulse.  Running 
at  5  mph  increased  cardiac  output  by  increasing  both 


846 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


T~ig """TH 


table  i .  Ascending  Aorta  Flow  During  Exercise 


ID 


I — *  —  zz  —  ~~ 

r_^^i"_T~U  I 


o 
a 


O'S 


x. 
a 
5 


<n    II 

■S  £ 

_   a, 


o  X! 

g  I 


™     C 


o 


be 


r    •  - 

O      . 


Exercise 

Elapsed 
Time  Sec 

Cardiac 

Output 

Liter  min 

Blood 

Pressure 

A  re  h 

Stroke 

Volume 

ml 

Heart 
Rate/min 

Lying 

O 

2-9 

139/86 

25 

"3 

Standing 

O 

3-5 

122/73 

25 

140 

5  mPh 

18 

5-6 

86 

28 

200 

8  mph 

25 

6.2 

81 

3' 

200 

10  mph 

55 

6.0 

79 

28 

214 

Hill  (5%  grade) 

120 

7-5 

92 

35* 

214 

Half  mile 

180 

6.6 

98 

33 

200 

*  40%  above  control. 

heart  rate  and  stroke  volume.  Further  effort  increased 
output  primarily  by  increasing  the  stroke  volume 
with  little  change  in  heart  rate.  The  increase  in 
stroke  volume  was  evidenced  by  a  change  in  the 
contour  of  the  ejection  pulse  from  its  normal  tri- 
angular shape  toward  that  of  a  square  wave.  The 
failure  to  increase  greatly  the  peak  velocity  may  have 
been  due  to  turbulence  impedance  or  to  a  limit  in  the 
rate  of  ventricular  contraction.  As  a  result  of  the 
limiting  factor  on  peak  velocity,  the  animal  may  have 
been  near  his  maximum  cardiac  output.  Table  1  gives 
the  flow  and  pressure  values  for  figure  8. 

Pressure-Flow  Relationship  in  the  Ascending  Aorta 

Figure  9  illustrates  the  instantaneous  pressure 
difference  (AP)  along  3  cm  of  the  ascending  aorta  with 
the  axial  flow  through  the  same  segment.  AP  deflec- 
tions lead  the  flow  deflections  by  approximately  90 
degrees,  which  suggests  that  mass-acceleration  laws 
dominate.  A  very  close  approximation  of  actual  flow 
may  be  computed  from  &P  using  equations  5  and  9.  In 
this  situation  radial  flow  is  small  compared  to  axial 
flow,  thus  absence  of  the  radial  flow  term  seems  unim- 
portant especially  when  only  the  net  axial  flow  is 
desired. 

Fry  (13)  originally  pointed  out  this  relationship  and 
its  practical  use  in  a  catheter-tip  flowmeter.  Assuming 
that  the  flow  profile  in  the  ascending  aorta  is  flat, 
one  would  theoretically  need  only  the  cross-sectional 
area  of  the  ascending  aorta  to  compute  cardiac  output 
from  the  pressure  gradient.  The  application  of  this 
principle  using  a  double  lumen  catheter  is  at  the 
moment  fraught  with  many  practical  difficulties, 
primarily  concerning  Pitot  effects  at  the  catheter  tip 
and  accurate  measurement  of  the  lumen  cross  section. 

Ventricular  Ejection  Gradients 

Because  of  mass-acceleration  effects,  ventricular  ejec- 
tion during  the  deceleration  phases  takes  place  against 


PULSATILE    BLOOD    FLOW 


847 


the  pressure  gradient  (47).  Figure  10  demonstrates 
this  fact  at  the  aortic  valve  where,  during  late  systole 
blood  is  flowing  through  the  valve  against  a  pressure 
gradient.  A  similar  finding  has  been  shown  for  the 
right  ventricle  (H.  Okino,  unpublished  work).  These 
findings  prove  dynamically  that  the  forward  resistance 
of  the  aortic  and  pulmonary  valves  is  slight.  Further, 
the  energy  of  external  work  of  the  ventricles  is  spent  in 
raising  the  blood  pressure  to  sufficient  level  to  acceler- 
ate the  blood  into  the  aorta  and  pulmonary  artery. 

Windkessel  Model  of  the  Arterial  System 

This  has  been  a  concept  of  limited  usefulness  to 
explain  the  form  of  the  arterial  pulses.  It  may  be 
represented  by  the  analogue  of  figure  1 1 .  The  arterial 
chamber  is  represented  by  the  compliance  (C),  and 
the  peripheral  resistance  by  the  resistance  term  (R). 
The   basic  relationship   here,   between   pressure  and 


'ihMMiM  0.5  sec  mmmum 

IIIJiiiiMiillTiliiliiiiliWHki'liiliil^iiillliiHHill 


A  P 


EMF 


F(tfCdf   +   yiAP-RFL>dt 


fig.  9.  Computer  solution  to  blood  flow  in  the  ascending 
aorta  using  the  analogue  computer  of  fig.  3.  Femi  =  the  flow 
measured  by  the  electromagnetic  flowmeter.  Ft  =  computed 
How.  C(dP/dt)  =  the  radial  flow  pattern  derived  from  the  time 
differential  of  the  aortic  arch  pressure  P. 


flow,  is  F  =  C  (dP/dt)  +  (i/R)  P.  When  this  electrical 
model  is  experimentally  pulsed  by  a  current  trans- 
duced from  the  flow  in  the  ascending  aorta  (F),  the 
voltage  form  (V)  is  obtained.  By  comparison,  the 
actual  pressure  pulse  in  the  aortic  arch  (P)  deviates 
in  several  details  from  1":  1)  P  has  a  superimposed 
3  to  6  cps  oscillation  apparent  from  midsystole 
throughout  diastole,  and  2)  P  has  a  more  prominent 
"incisura"  marking  aortic  valve  closure  and  a  more 
abrupt  rise,  often  with  an  anacrotic  wave.  In  addition, 
the  windkessel  model  fails  to  explain  the  changes  in 
form  occurring  along  the  arterial  network.  Detail  2 
appears  if  the  analogy  is  elaborated  by  the  placement 
of  some  restraint  on  the  distensible  element,  i.e., 
taking  into  consideration  the  friction  in  lateral 
expansion  of  the  arterial  wall,  as  in  equations  1 2  and 
13.  Detail  /  requires  a  concept  of  reflections  or 
resonant  network  filter  as  explained  in  the  succeeding 
paragraphs.  Cope  (7)  has  attempted  new  use  of  the 
windkessel    concept    using    empirical    constants. 

Aortic  Transformation  of  Flow  and  Pressure  Pulses 

Figure  1 2  illustrates  the  changes  in  form  and 
magnitude  of  the  flow  pulses  between  the  ascending 
aorta  and  the  abdominal  aorta.  The  flow  in  the 
descending  thoracic  aorta  represents  an  intermediary 
form  and  well  illustrates  the  superimposition  of  a 
prominent  smooth  3  to  6  cps  wave  decreasing  in 
amplitude  throughout  diastole.  This  wave  referred  to 
as  the  "resonant"  wave  frequently  causes  backflow  in 
diastole  throughout  the  aorta  and  many  of  its 
branches.  Considered  as  a  whole,  the  arterial  system 
is  a  low-pass  filtered  hydraulic  supply,  i.e.,  it  is 
designed  to  offer  negligible  impedance  to  steady  flow 
and  frequencies  up  to  10  cps.  There  is  normally  one 
frequency  between  3  and  6  cps  to  which  it  offers 
lowest  impedance,  and  resonates  at  that  frequency 
with  each  beat  of  the  heart.  Early  physiological 
workers  recognized  this  resonant  system  as  analogous 
to  a  low-frequency  underdamped  manometer  system. 

Resonant-Network  Model  of  the  Arterial  System 

This  represents  an  improved  concept  to  explain 
the  transformation  of  arterial  pressures  and  flow 
pulses.  It  is  diagramed  in  figure  13.  C\  roughly 
represents  the  lumped  compliance  of  the  aortic  arch 
and  its  branches,  and  C2,  the  lumped  compliance  of 
the  abdominal  aorta  and  its  branches.  L  represents 
the  lumped  inertance  of  the  blood  in  the  descending 
aorta.  FH  represents  the  forcing  function  of  the  left 


848 


HANDBOOK     OF    PHYSIOLOGY    ^    CIRCULATION    II 


fig.  10.  Relationship  between 
the  differential  pressure  and  flow 
through  the  normal  aortic  valve. 
The  ordinates  refer  to  the  tops  of 
these  simultaneous  tracings.  AP 
=  left  ventricular  pressure  {LVP) 
minus  ascending  aorta  pressure 
(AAP).  The  pressure  gradient 
is  against  the  direction  of  flow 
in  the  latter  part  of  systole. 


Stroke  Vol.  =  18.2  cc 


**A»«» 


^-Vvj"^ -_\w\xv^t^  ^-L^V  "yJ 


Bockflow   Vol.  =  0.58  cc 


ventricular  ejection  pulse.  R\  and  R2  represent  periph- 
eral resistances  which  may  be  adjusted  relative  to 
Ci  and  C2  to  give  any  desired  ratio  of  pulse  pressure 
to  mean  pressure  at  Pi. 

Ci,  C2,  and  L  form  a  series  resonant  circuit  and  may- 
be adjusted  to  give  any  resonant  frequency,  and  Rz 
and  Rt  are  chosen  to  provide  the  proper  damping 
ratio  of  the  observed  resonant  wave  in  the  arterial 
system,  as  well  as  the  high  frequency  details.  When 
C2  is  smaller  than  Ci,  the  P>  pulse  pressure  is  greater 
than  Pi  pulse  pressure,  thus  explaining  a  time- 
honored  observation  that  the  arterial  pressure  in  the 
legs  rises  higher  than  in  the  arms  during  systole. 

Figure  14  demonstrates  the  degree  of  accuracy 
with  which  such  a  grossly  lumped  electronic  model 
may  reproduce  the  observed  set  of  pressure  and  flow- 
values  in  the  arterial  network.  The  resonant-network 
model  embodies  several  concepts  which  provide  a 
rational  explanation  of  the  major  hydraulic  features 
of  the  arterial  system. 

/)  The  over-all  frequency  response  characteristics 
of  the  arterial  system  may  be  taken  as  that  of  an 
analogous  filter  network  (56),  figure  15. 

2)  The  resonant  frequency  (vn)  varies  from  2  to  10 
cps  and  is  increased  by  hypertension  produced  by 
increased  cardiac  output  and  sympathetic  con- 
strictor agents.  It  is  also  increased  in  cardiac  failure 
due  to  mitral  stenosis.   Hypotension  from  decreased 


fig.  11.  Electrical  analogue  of  the  windkessel  model  of  the 
arterial  system  with  experimental  testing.  P  represents  the 
pressure  in  the  aortic  arch.  V  represents  the  voltage  across  the 
parallel  resistor  and  condenser.  F  represents  the  measured 
blood  flow  in  the  ascending  aorta  and  the  electrical  input  cur- 
rent forcing  the  analogy. 


PULSATILE    BLOOD    FLOW 


849 


0.5  sec 


H 


y  I  26  mm  Hg 

Abdominal   Aorta 


table  2.  Distribution  of  Arterial  Flow  Pulse 

Mean  Peak  Velocity 


fig.  12.  Transformation  of  the  aortic  blood  flow  between  the 
ascending  aorta  and  abdominal  aorta.  High  frequencies  are 
attenuated  and  a  resonant  frequency  is  superimposed. 

cardiac  output  decreases  the  resonant  frequency. 
Presumably  the  over-all  compliance  changes  more 
than  the  inertance  in  these  conditions. 

3)  The  amplitude  of  the  resonant  wave  is  increased 
when,  in  tachycardia,  the  systolic  flow  pulse  is  in 
phase  (48)  with  the  resonant  wave. 

4)  The  pressures  and  movements  in  the  arterial 
system  represent,  at  any  steady  state  of  the  hormonal 
and  nervous  controlling  conditions,  transient  re- 
sponses to  the  flow  input  from  the  left  ventricle. 

5)  The  augmentation  of  the  pressure  pulse,  as  it  is 
transmitted  to  the  abdominal  aorta,  results  from  the 
lower  gross  compliance  of  the  abdominal  arterial  bed 
as  compared  to  the  aortic  arch  vascular  bed. 


Artery 

Circumfer 
ence,  cm 

Mean  Peak 
Flow,  ml  min 

cm  min 

cm/sec 

Ascending  aorta 

6.28 

II ,870 

3.780 

63 

Descending 

5° 

3.243 

1,621.5 

27 

thoracic  aorta 

Abdominal 

3-4 

1,108 

1 ,256.2 

21 

aorta 

I  ,  260 

■  -429 

23 

Iliac 

1.8 

750 

3.275 

54-6 

Femoral 

0.7 

182 

2,045 

34-1 

Renal 

1.4 

176 

1 ,401 

23-4 

Carotid 

'•5 

'93 

1 ,162 

■9-4 

Brachial 

0.7 

94 

'.774 

29.6 

6)  The  30-100  cps  components  prominent  in  the 
central  aortic  pressure  pulse,  as  in  the  anacrotic 
wave  and  the  incisura,  result  from  the  stiffness  of  the 
arterial  walls  and  are  damped  out  as  they  proceed 
away  from  the  heart.  The  dicrotic  wave  so  prominent 
in  the  peripheral  pulse  does  not  arise  from  this 
source  but  is  an  expression  of  the  resonant  wave 
phenomenon. 

Transmission  Line  Model  {Distributed  System) 

This  is  a  useful  concept  in  the  arterial  system,  as  in 
any  hydraulic  continuum.  It  is  represented  by  van  der 
Tweel  (55)  in  figure  16.  No  matter  how  short  or  how 
long  a  given  segment  may  be,  there  is  always  present 
some  combination  of  inertance,  compliance,  and 
resistance  which  may  be  lumped  in  a  close  approxima- 
tion of  the  behavior  of  that  particular  segment. 

The  performance  of  the  transmission  line  is  greatly 
affected  by  the  relation  of  the  terminating  impedance 
to  the  characteristic  impedance  (52)  of  the  line.  If 
the  terminal  impedance  is  equal  to  the  characteristic 
impedance  all  the  energy  will  be  absorbed  and  no 
reflections  occur.  The  characteristic  impedance, 
however,  is  frequency  dependent,  increasing  with 
frequency.  If  the  terminal  Z  is  greater  than  the  line 
Z,  positive  reflections  will  occur.  Negative  reflec- 
tions will  occur  if  the  terminal  Z  is  less  than  the 
characteristic  Z. 

Distribution  of  the  Blood  in  the  Aortic  Arch 

This  is  shown  in  figure  17.  In  a  manner  analogous 
to  Kirchoff's  current  law,  the  flow  into  the  arch  at 
any  given  instant  from  the  ascending  aorta  is  equal 
to  the  sum  of  the  flows  into  the  brachiocephalic  and 
left  subclavaian  arteries,  and  the  flow  into  the  de- 
scending thoracic  aorta  plus  the  uptake  rate  of  the 


85o 


HANDBOOK    OF    PHYSIOLOGY     ^    CIRCULATION    II 


€> 


R 


I 

IOOK 


I5MFD.' 
/    ' 


/ 
/ 

/     9 


M    FH 

/      -i- 


/ 

Peripheral  / 

Resistance       r.'     ,„,„ 
u  o  m  p  1 1  a  n  c  e 


nppnr^ 


© 


200h  /  0.5K 
/ 


/ 
Inertiance 


BLOOD     MASS 


fig.  13.  The  resonant  network  model  of  the  arterial  system.  Component  values  indicated  are  those 
found  in  one  typical  experiment  on  an  anesthetized  open-chest  dog. 


Adjust  Restraint  (R4)  of  Compliance  (C2)    Adjust  Restraint  (R3)  of  Compliance  (C,) 

P, 

1                1           ' 

■  m 

■  ?=    t  i 

-J       J. 

\                            1   \ 

r^/. — v"      '  „^. — ,v- 

\ 

— *-V~~~-fS*                  '■    —wu.—    —,'■-' 

V, 

R3'  0     R4-O 

t.       ! 

1 

t 

R3*0       R4    1.5  K 

R3-0.6      R4*I.5K 

v2 

1            1 

fig.  14.  Experimental  testing  of  the  resonant  network  model  of  the  arterial  system.  Pi  =  pressure 
in  the  aortic  arch.  Pi  =  pressure  in  the  femoral  artery.  F  =  flow  in  the  ascending  aorta.  l\  =  the 
voltage  across  the  capacitor-  C,  to  ground.  V«  =  the  voltage  across  the  capacitor  Ci  to  ground.  In 
the  first  panel  the  values  of  G  and  Co  have  been  adjusted  to  give  the  correct  resonant  frequency  as 
represented  in  the  arterial  pulses.  Between  the  first  and  second  panels,  R4  was  adjusted  to  give  the 
proper  damping  ratio  of  the  series  resonant  elements  C\  ,  C«  ,  and  L.  The  third  panel  shows  the 
closest  equivalent  achieved  by  adjusting  R:i  to  reduplicate  in  Vi  the  high  components  of  Pl  .  Delay  in 
transmission  time  is  not  present  because  the  simplicity  of  the  analogue  limited  the  number  of  L-C-R 
transmission  line  segments. 


I      2      3     4     5     6 


fig.  15.  Transfer  function  of  the  arteries  computed  by  War- 
ner (56).  i/n  is  equal  to  a  resonant  frequency. 


40  KS      =4= 


1  H 

0  Olp 


0  005fJ 


0  Oil 


110*0  01 11) 


-nST^~ 


0005JJ 


=r=0SC 


fig.  16.  Transmission  line  model  of  the  arterial  system, 
showing  the  stacking  of  L-C  transmission  line  segments.  [From 
van  der  Tweel  (55).] 


compliance  of  the  arch  (CAA),  or 


dP 


Faa  =  FBroch  +  F5lJbcl  +  FDTA  +  CAA  —        (15) 


figure  1 7  demonstrates  this  fact  experimentally  by 
comparing  a  plot  of  the  instantaneous  sums  of  -FBrach.> 
FDTA.,  FSubci.,  and  CAA  (dP/dt)  to  FAA.  The  value  of 
CAA  was  adjusted  arbitrarily. 

Abdominal  Aorta  and  Its  Terminal  Branches 

By  the  time  the  pressure  and  flow  pulses  reach  the 
abdominal  aorta,  the  highest  frequency  components 
are  so  attenuated  that  the  flow  pulses  are  dominated 
by  a  strong  resonant  wave  superimposed  on  the  mean 
forward  flow  (fig.  18).  The  resonant  flow  wave  in  the 
abdominal  aorta  is  in  phase  with  that  in  the  de- 
scending thoracic  and  the  resonant  pressure  wave 
[standing  wave  of  Hamilton  &  Dow  (21)]  of  the 
abdominal   aorta  is    180  degrees  out  of  phase  with 


z 

=  5- 

in 
a. 

u 

1- 


PULSATILE    BLOOD    FLOW  85 1 

125. 

Aortic    Arch 
Pressure  (P) 
100^3" 

\\      ^Flow   Out   of    Aortic    Arch 
12   F2,F3,  F4,  F5) 

Flow    into    Aortic    Arch  (F,) 
(Left    Ventriculor    Outflow) 

H 


0  5  sec 


0— V 


5—1 


5  — 


Aortic  Arch    Radial    Flow   (F2) 

* — 


Flow    out    Arch    Branches 

<  S  F3,  F4,  F5  ) 
Descending  Thoracic  Aorta  Flow  (F3) 
Brachiocephalic    Artery    Flow   (F4  ) 
Subclavian   Artery  Flow    (F5) 


fig.  17.  Distribution  of  blood  flow  in  the  aortic  arch  in  a 
manner  analogous  to  KirchhofF's  current  law.  It  is  shown  that 
the  volumetric  flow  of  blood  into  the  arch  of  the  aorta  is  equal 
to  the  sum  of  the  instantaneous  flows  into  the  subclavian  artery, 
brachiocephalic  artery,  descending  thoracic  aorta,  and  the 
radial  flow  uptake  in  the  aortic  arch.  The  dotted  line  in  the 
lower  section  illustrates  the  branch  outflows  (not  including 
radial  flow). 

that  in  the  upper  aorta  (48).  These  phase  relation- 
ships are  similar  to  those  of  the  series  resonant  circuit 
of  figure  13.  When  the  resonant  flow  wave  reaches  a 
maximum  moving  down  the  aorta,  the  attending 
pressure  wave  in  the  arch  is  falling  most  rapidly. 
When  the  resonant  flow  wave  reverses,  and  flows  at 
maximal  rate  headward  in  the  aorta,  the  pressure 
falls  rapidly  in  the  lower  aorta  while  it  rises  rapidly 
in  the  arch.  There  is  a  nodal  area  in  the  descending 
thoracic  aorta  where  the  pressure  wave  is  minimal 
(2)  and  the  flow  wave  is  maximal.  These  findings 
support  the  resonant-network  model  of  the  arterial 
system. 

Figure    18    demonstrates    the    remarkable    simul- 


852 


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CIRCULATION    II 


I  25  mm  Hg 


fig.  1 8.  Blood  flow  in  the  aortic  branches.  All  flow  ordinates 
are  scaled  equally.  The  contours  of  the  various  flow  pulses  here 
may  be  considered  characteristic  of  the  flow  in  the  indicated 
branches.  Carotid  flow  and  renal  flow  characteristically  pulsate 
around  a  mean  value  representing  considerable  continuous 
forward  velocity.  Blood  flow  in  the  femoral  artery,  iliac  artery, 
abdominal  artery,  and  brachial  artery  may,  in  the  resting  condi- 
tion, oscillate  through  zero  in  early  diastole  but  are  also,  under 
the  conditions  of  muscular  exercise,  or  metabolic  demands,  or 
vasodilator  drugs,  raised  to  a  level  corresponding  to  considera- 
ble mean  forward  velocity. 


taneity  of  the  peaks  and  troughs  of  the  abdominal  and 
descending  thoracic  aorta,  iliac,  and  femoral  flow 
pulses.  The  time  of  the  initial  rise  is  delayed  according 
to  the  transmission  time  between  the  two  points  under 
comparison. 

Function  of  the  Resonant  Wave 

The  finding  of  a  large  backflow  component  to  the 
flow  wave  in  the  descending  aorta  and  vessels  of  the 
extremities  is  at  first  surprising  when  viewed  from 
the  point  of  efficiency  needs  of  the  circulation.  This 
finding,  however,  observed  in  the  resting  state  of 
dogs  (31),  sheep  (F.  C.  Greiss,  unpublished  observa- 
tions), and  in  humans  (48),  disappears  upon  exercise 
of  the  extremities  as  the  muscle  vascular  beds  dilate 
to  accommodate  a  greater  flow. 

The  normal  terminal  impedance  (peripheral 
resistance)  of  the  arterial  transmission  line  is  ap- 
parently greater  than  the  characteristic  impedance 
during  the  resting  state.  The  vasodilator  mechanisms 
of  exercise  bring  the  terminal  impedance  down  to  and 
below  that  of  the  line,  thereby  eliminating  positive 
reflections.  Negative  reflections  do  not  arise  because 
they  are  damped  out  by  the  resistance  of  the  larger 
channels  made  more  effective  by  increased  flow.  The 
circulation  is  thus  brought  up  to  more  efficient 
operating  conditions  when  the  demands  are  increased. 
All  the  pulse  energy  passing  to  the  periphery  is 
completely  absorbed  without  reflections  when  the 
peripheral  resistance  is  decreased  by  exercise,  injection 
of  vasodilator  drugs,  and  in  peripheral  A-V  fistulas. 
Figure  1 9  illustrates  the  action  of  lowered  terminal 
impedance  in  increasing  the  more  efficient  transfer 
of  energy.  Reflection  from  the  bed  beyond,  seen  in 
the  control  blood  flow  of  a  small  artery  in  the  dog's 
paw,  disappears  under  vasodilation  conditions  caused 
by  an  intra-arterial  injection  of  acetylcholine.  The 
resonant  flow  wave  disappears  and  the  flow  is  a 
simpler  function  of  the  arterial  pressure.  Okino 
[see  (42)]  has  also  recorded  these  changes. 

Renal  Blood  Flow 

The  renal  vascular  circuit  may  be,  as  a  first  approxi- 
mation, compared  to  a  simple  parallel  RC  circuit 
(30).  The  dominant  hydraulic  elements  of  the  renal 
artery  flow  are  resistance  and  compliance,  and  the 
equation  relating  abdominal  aorta  pressure  (Pi),  and 
renal  artery  flow   (F)  is: 


dt  R 


(16) 


PULSATILE    BLOOD     FLOW 


853 


^    ,0 


CONTROL 
FLOW 


ACETYLCHOLINE 


FLOW 


ISO 

glOO 
6 

SO 


AP 


VP 


VP 


-"•9-- 


fig.  19.  Blood  flow  in  a  small  peripheral  artery  and  the  effect 
of  vasodilation.  According  to  the  definitions  of  the  text,  the 
control  flow  may  be  considered  a  resonant  flow  form  which  is 
converted  to  resistant  flow  form  by  the  injection  of  acetylcholine 
into  the  arterial  channel.  AP  represents  the  arterial  pressure, 
immediately  proximal  to  the  flowmeter  probe  applied  to  a  small 
artery  in  the  dog's  paw.  VP  represents  the  venous  pressure  in  a 
small  vein  of  the  dog's  paw.  Conversion  of  the  flow  from  reso- 
nant flow  to  resistant  flow  by  the  action  of  acetylcholine  lowers 
the  arterial  pressure  and  raises  the  venous  pressure.  (Tracings, 
courtesy  of  M.  C.  Conrad  and  H.  D.  Green.) 

i/R  represents  the  conductance  at  the  existing  pres- 
sure, and  A'  represents  the  fact  that  the  pressure- 
resistive-flow  relationship  (excluding  the  dynamic 
compliant  flow  term,  C(dP/dt)),  is  not  constant  and  is 
a  nonlinear  function  of  pressure.  Presumably  this 
results  from  the  fact  that  i/R  is  directly  dependent  on 
the  pressure  in  a  manner  similar  to  that  shown  by 
the  vascular  beds  of  the  skin.  If  this  is  true,  then  the 
relationship  is: 


°dt     + 


I 


R(v)  +     R(P) 


(17) 


where  R{v)  equals  resistance  controlled  by  vaso- 
motor tone,  and  R(F)  equals  resistance  controlled  by 
intraluminal  pressure  P.  At  present,  the  coefficients 
C],  Riy,  and  R(P)  are  obtained  only  by  measuring 
the  flow  and  pressure  without  any  means  of  indirect 
evaluation.  Figure  20  illustrates  one  example  of  how 
C  and  R  of  equation  16  were  adjusted  until  the 
dynamic  flow  pulse  was  computed  from  P  (30).  In 
this  case  flow  was  alreadv  known  from  simultaneous 


measurement  with  the  square-wave  electromagnetic 
flowmeter. 

There  are  apparently  no  positive  reflections  from 
the  normal  renal  bed,  hence  the  flow  computed  for 
the  total  renal  circuit  according  to  equation  16  and 
without  an  inertance  term  represents  the  flow  in  the 
renal  artery.  To  compute,  however,  the  instantaneous 
flow  in  other  arteries  from  whose  bed  there  are 
reflections  one  must  use  the  difference  in  pressure 
along  the  artery  (i.e.,  two  pressure  sources  in  the 
artery  itself)  and  the  equations  9  and  12.  The  most 
important  term  is  then  the  inertial  one  of  equation 
9  although,  as  explained  earlier,  a  further  step  in 
precise  computation  brings  in  the  compliance  of 
equation  12. 

Carotid  Artery  Flow 

This  is  illustrated  in  figure  18.  Like  the  renal  flow 
there  is  a  large  constant  flow  component  upon  which 
there  is  superimposed  a  dynamic  component.  It  is 
related  to  the  carotid  pressure  by  equation  1 6  with 
the  conductance  term  i/R  being  the  largest  by  far. 

Because  the  carotid  and  renal  flow  patterns  are 
governed  largely  by  the  resistance,  they  are  called 
viscous  or  resistance  flow  patterns.  The  resting  flow 
patterns  of  the  entire  aorta,  iliac,  femorals,  and 
subclavian  arteries  are  called  reactance  flow  patterns 
because  inertance  and  compliance  are  dominant. 
They  have  a  small  constant  flow  when  compared  to 
their  dynamic  component  and  this  frequently  demon- 
strates a  period  of  negative  flow  in  early  diastole. 

Coronarx  Blood  Flow 

Coronary  blood  flow  in  the  unopened  artery  was 
first  measured  by  Marston  and  Spencer  with  the 
square-wave  electromagnetic  flowmeter  (24).  The 
resting  patterns  differ  little  from  those  of  Gregg  (18) 
who  used  a  cannulating  system  and  orifice  meter. 
The  equation  relating  coronary  flow  to  the  vascular 
pressures  is  a  modification  of  equation   16: 


'">§++"' 


(18) 


where  AP  equals  the  aortic  pressure  minus  the 
ventricular  pressure  minus  the  right  atrial  pressure. 
Figures  21  and  22  (27)  illustrate  the  measured  left 
anterior  descending  coronary  flow  and  the  circumflex 
coronary  artery  flow. 

These   coronary   inflow   curves   display   a   marked 
dependence    on    both    aortic    pressure    and    intra- 


854 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  20.  Computed  renal  blood  flow. 
P  =  the  abdominal  aorta  pressure  at 
the  level  of  the  renal  artery.  dP/dt  = 
the  first  derivative  of  the  abdominal 
arterial  pressure.  Fc  =  computed  blood 
flow  using  equation  16.  The  lower 
tracing  is  measured  blood  flow  using 
the  square-wave  electromagnetic  flow- 
meter on  the  renal  artery. 


dt 


Fc 


v\.  w  Vy 

500 

Femf 


0. 5  sec 


-^vv' 


ventricular  pressure  where  coronary  resistance 
is  a  complex  function  of  vasomotor  tone,  intra-arterial 
pressure,  and  intramuscular  pressure.  The  function  of 
intramuscular  pressure  which  reduces  inflow  during; 
systole  increases  venous  outflow  during  systole  and 
may  also  increase  capillars-  flow  at  the  same  time. 

IV.    FLOW    IN    THE    SYSTEMIC    VEINS 

Phasic  variations  in  venous  blood  flow  result  from 
three  principle  sources:  /)  the  beat  of  the  heart; 
2)  the  respiratory  fluctuations;  and  j)  the  contraction 
of  skeletal  muscle.  Severe  changes  in  position  and 
acceleration  of  the  body  also  may  have  profound 
effects  on  venous  flow.  Pulsatile  flow  originating  from 
the  heart  beat  may  occur  in  the  small  peripheral 
veins,  as  a  result  of  transmitted  oscillations  from  the 
arterial  system.  These  pulsations  are  generally  small 
in  the  normal  condition  because  of  the  damping 
action  of  the  resistance  of  the  small  arteries  and 
arterioles  and  the  elasticity  of  the  capillary  bed.  They 
may  be  accentuated,  however,  by  vasodilatation, 
either  by  reactive  hyperemia  or  by  means  of  drugs, 
such  as  acetylcholine.  Flow  in  the  renal  vein,  normally 
phasic  presumably  because  of  the  low  renal  vascular 
resistance,  causes  less  damping  than  in  most  vascular 
beds.  Great  variations  in  blood  flow  within  the 
thoracic  vena  cava  have  been  recorded  by  Brecher 
(5)  and  others. 

Effect  of  the  Heart's  Action  on  Vena  Caval  Flow 

It  has  been  shown  by  Gauer  and  Sieker  [quoted  in 
(5)]  that  there  is  an  almost  immeasurable  gradient 


in  the  mean  blood  pressure  along  the  venae  cava 
toward  the  heart.  Since  there  is  a  net  movement  of 
blood  in  that  direction,  some  small  gradient  must  be 
present  which  may  be  sufficient,  in  view  of  the  large 
size  of  the  channels,  to  move  considerable  blood.  It 
is  also  true,  according  to  the  principles  of  vascular 
hydraulics  discussed  in  sections  II  and  III,  this 
chapter,  that  considerable  blood  may  be  moved  by 
an  oscillatory  pressure  gradient  without  consideration 
of  a  mean  frictional  gradient  (fig.  23). 

Atrial  contraction  injects  a  late  diastolic  quota  of 
blood  through  the  tricuspid  valve  and  also  causes  a 
pressure  transient  to  pass  along  the  vena  cava  away 
from  the  heart.  This  pressure  transient  produces  a 
sharp  reduction  in  flow  which  may  or  may  not  cause 
a  reversal  depending  upon  its  amplitude  and  the  level 
of  mean  flow  (fig.  24).  This  impediment  or  reversal 
is,  however,  overcome  immediately  by  a  large  for- 
ward flow  caused  by  ventricular  contraction.  This 
"vis  a  fronte"  which  draws  blood  toward  the  heart 
during  ventricular  systole  arises  from  movement  of 
the  base  of  the  heart  (tricuspid  valve  closed)  toward 
its  apex,  producing  a  transient  pressure  gradient  in 
favor  of  flow  toward  the  heart.  Flow  may  be  expected 
to  follow  this  differential  pressure  transient,  approxi- 
mately 90  degrees  out  of  phase. 

As  the  base  of  the  heart  moves  away  from  the  apex 
during  diastole,  the  tricuspid  ring  dilates  and  filling 
of  the  heart  takes  place  as  much  by  the  ventricle 
sliding  over  the  atrial  blood  as  by  the  atrial  blood 
flowing  into  the  ventricle.  From  direct  observations 
of  the  heart  and  from  slow  motion  movies,  it  can  be 
seen  that  the  ventricle  fills  by  a)  dilation  of  the  tri- 


PULSATILE    BLOOD    FLOW  855 


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n — 

:i:.._.....± 4= 

LEFT    VENTRICULAR    PRESSURE 


200 

mm 
Hg 


0     - 


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fed— H         ffV         ^r- 

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fig.  21.  Coronary  blood  flow  in  the  left  anterior  descending 
branch.  The  upper  tracing  represents  the  electrocardiogram 
taken  simultaneously  with  the  left  ventricular  pressure,  aortic 
arch  pressure,  and  coronary  flow.  [From  Schenk  (43).] 

cuspid  ring,  b)  engulfing  of  the  atrial  blood  by  the 
right  ventricle,  and  c)  a  final  quota  of  blood  delivered 
by  atrial  contraction.  The  question  of  whether  or  not 
the  ventricle  produces  a  sucking  force  during  diastole 
is  unresolved.  The  answer  will  await  definitive 
differential  pressure  measurements  made  across  the 
ventricular  wall. 


Effect  of  Normal  Respiratio 


Carol  Flow 


This  is  illustrated  in  figure  25  (28).  Inspiration 
greatly  increases  the  venous  return  as  shown  in  the 
thoracic  vena  cava  and  abdominal  vena  cava  caudal 
to  the  renal  veins. 

V.    PULMONARY    FLOW 

Right  Ventricular  Ejection  Pulse 

The  form  of  the  right  ventricular  ejection  pulse 
(fig     26)    differs   from   that   of  the   left  ventricle   in 


!      1      i      i      1       1 

i.    ! 

■  i 

1 

r     '   a 

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-        -       ■      ■•    -4 1 

r  -  H±r 

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LEFT    VENTRICU 

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prYssur 

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200 


ASCENDING  'AORTA     PRESSURE 


200  — 
mm 

Hg      I 


est 


fcs: 


ci rcumfl ex  to ro nAry  "artery 


*l 


&si: 


FLOW 


f^ 


232 


I   SEC 


fig.  22.  Coronary  blood  flow  in  the  circumflex  branch. 
Tracings  taken  from  the  same  animal  as  in  fig.  2 1 .  [From 
Schenk  (43).] 

general  by  an  over-all  lack  of  the  higher  frequency 
components.  The  initial  acceleration  is  slower,  peak 
more  rounded,  at  a  somewhat  lower  velocity;  and  the 
reverse  flow  due  to  pulmonary  valve  closure  forms  a 
more  rounded  notch  followed  by  a  lower  frequency 
aftervibration.  There  are  also  fewer  random  frequency 
vibrations  throughout  diastole.  Presumably  these 
differences  arise  from  a  slower  rate  of  contraction  of 
the  right  ventricle  versus  that  of  the  left,  and  a 
greater  compliance  per  unit  of  arterial  wall  in  the 
pulmonary  artery  than  that  of  the  aorta,  the  latter 
arising  perhaps  from  the  lower  distending  pressure. 
When  flow  recordings  are  taken  off  the  pulmonary 
trunk  near  the  bifurcation,  one  frequently  notices  a 
low-frequency  vibration  during  the  diastolic  period 
which  may  be  due  to  some  reflections  from  the  pulmo- 
nary periphery. 

Measurements  of  differential  pressure  across  the 
pulmonary  valve  between  the  right  ventricle  and 
pulmonary  artery  display  less  of  a  tendency  for  the 


856 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


A  P  =  P,  -  P2 


fig.  23.  The  "raking  in"  or  "vis  a  fronte"  action  of  the  right 

ventricle  and  tricuspid  valve   ( diastole ; systole),  and 

the  principle  of  blood  movement  without  net  gradient. 


SURCAVA  PRES. 

fig.  24  Pulsatile  How  in  the  superior  vena  cava  [Brecher  (5)] 
as  measured  by  the  bristle  flowmeter,  showing  the  effect  of 
changes  in  heart  rate  on  inflow  into  right  atrium.  Venous 
return  is  phasically  recorded  with  the  bristle  flowmeter  in  the 
superior  vena  cava  (open  chest).  From  above  downward  the 
tracings  are  time,  aortic  pressure  in  mm  Hg,  superior  vena 
caval  flow  in  ml/min,  and  superior  vena  caval  pressure  in  mm 
HjO.  PAS  denotes  peak  of  atrial  systole. 

systolic  pressure  reversal  demonstrated  already  across 
the  aortic  valve.  This  difference  is  possibly  due  to  two 
causes:  first,  there  may  be  more  effective  resistance  in 
the  pulmonary  artery  due  to  the  sharp  turn  that  it 
makes  immediately  after  arising  from  the  ventricle, 
and,  second  and  more  importantly,  since  there  is  a 
smaller  acceleration  and  more  sustained  peak  flow, 
the  differential  term  of  the  equation  relating  flow  and 
differential  pressure  is  relatively  small.  This  equation 
rewritten  for  convenience  is  as  follows:  AP  =  L/ 
dF  dt  +  RF. 


Pulsatile  Flow  in  the  Pulmonary  Capillary  Bed 

Direct  observations  through  the  microscope  of 
pulmonary  capillaries  in  vivo  clearly  indicate  a 
markedly  pulsatile  character  of  the  blood  flow.  In 
addition,  nitrous  oxide  uptake  curves  in  the  body 
plethysmograph  which  represent  an  integral  relation- 
ship to  the  pulmonary  capillary  flow  demonstrate 
pulsatile  flow  through  the  vessels  perfusing  the  al- 
veoli. These  pulsations  are  relatively  small,  however, 
and  are  superimposed  upon  a  strong  mean  flow 
through  the  same  vessels.  Pulmonary  capillary 
pressures,  taken  through  the  wedged  cardiac  catheter, 
generally  demonstrate  a  marked  pulsatile  pressure 
in  the  pulmonary  capillaries,  and  thus  represent 
indirect  evidence  of  phasic  flow  in  these  vessels. 


VI.    NONLAMINAR    FLOW    AND    MURMURS 

Normal  Murmurs 

Careful  evaluation  of  the  normal  circulation  for 
murmurs  by  means  of  sensitive  microphones,  in- 
cluding the  application  of  a  barium  titanate  phono- 
catheter  directly  to  the  surface  of  the  heart  and 
blood  vessels,  has  been  made.  The  assumption  is 
made  that  the  presence  of  a  murmur  indicates  a 
nonlaminar  and  turbulent  flow  pattern.  Frequently, 
one  can  detect  a  brief  systolic  murmur  in  the  arch  of 
the  aorta  corresponding  in  time  to  the  peak  of  the 
ejection  pulse.  Groom  (19)  has  also  shown  con- 
siderable indirect  evidence  that  systolic  murmurs  can 
frequently  be  recorded  from  normal  humans  with 
sensitive  microphones  on  the  body  surface  under  the 
low-background  noise  conditions  of  a  soundproof 
room.  In  addition,  low-frequency  vibrations  can  be 
recorded  from  the  normal  cardiac  chambers  during 
diastole  by  means  of  intracardiac  phonocatheters. 


Relationship  Between  the  Murmur  of  Coarctation 
Stenosis  and  Blood  Flow  Through  the  Stenotic  Area 

A  study  of  the  pressure-flow-murmur  dynamics  in 
coarctation  of  the  aorta  illustrates  many  principles 
applicable  to  stenosis  of  the  larger  arteries  as  well  as 
flow  through  the  pathological  heart  valve  orifices  of 
stenosis  and  regurgitation. 

Coarctation  was  produced  by  progressively  con- 
stricting a  wire  loop  passed  around  the  descending 
aorta  of  an  experimental  animal  (49)  (fig.  27). 
Changes  in  the  flow  contour  were  noted  during 
constriction  from  a  normal  diameter  of  6.5  mm  down 


PULSATILE    BLOOD    FLOW 


857 


rO 


-100 


-200 


IT 


IA 


■         ■         I — 
1.0 


SECONDS 


20 


90 


■70 


L50 


30 


fig.  25.  The  effect  of  natural 
breathing  on  flow  in  the  thoracic 
and  abdominal  vena  cava  of  the 
dog  (closed  chest).  Tracings 
represent  from  above  downward. 
AO  =  the  aortic  pressure  in  mm 
Hg;  IT  =  intrathoracic  pressure 
in  mm  H20;  VC-\  =  thoracic 
inferior  vena  caval  blood  flow  in 
ml/sec;  VC-i  =  flow  in  IVC 
below  renal  veins  in  ml/sec; 
RA  =  right  atrial  pressure  in 
mm  H20;  FV  =  femoral  vein 
pressure  in  mm  H20;and  IA  = 
intra-abdominal  pressure  in  mm 
H,0.  [After  Mixter  (28).] 


PULMONARY      BLOOD     FLOW 


AORTIC    BLOOD     FLOW 

-i  ■■■>■  AfttfH 


fig.  26.  Left  and  right  ventricular 
ejection  pulses  in  congenital  atrial 
septal  defect  before  and  after  repair 
(7 -year-old  boy).  Repair  consisted  of 
an  open-heart  procedure  using  total 
cardiopulmonary  bypass  while  closing 
the  defect  by  means  of  a  suture  tech- 
nique. Figures  between  the  flow  pulse 
tracings  represent  the  mean  output  of 
the  ventricles  averaged  over  several 
heart  cycles.  The  contour  of  the  trac- 
ings is  typical  of  normal  tracings  found 
in  humans  and  dogs.  Stroke  volume 
differs  markedly,  however,  between  the 
two  ventricles  before  and  after  repair. 
The  repair  diminished  pulmonary  flow 
and  increased  the  aortic  flow.  Pre- 
sumably the  difference  between  the 
pulmonary  and  aortic  flow  after  repair 
results  from  either  /)  incomplete 
closure,  or  2)  actual  difference  in  the 
cardiac  output  between  the  measure- 
ments which  were  not  taken  simul- 
taneously. 


to  an  internal  diameter  of  3  mm.  Blood  flow  through- 
out these  degrees  of  experimental  coarctation  was 
maintained  at  the  normal  level  and  the  stroke  flow 
was  maintained  primarily  by  flattening  the  peak  flow 


and  broadening  of  the  systolic  area.  During  this  time 
a  systolic  murmur  began  softly  and  increased  in 
loudness  and  duration;  its  envelope  maintained  a 
contour  similar  to  the  contour  of  the  peak  of  the  flow 


858 


HANDBOOK    OF    PHYSIOl  I  »  , -i 


CIRCULATION    II 


AP     j'ISOmmHg 


.124 


752 

ml/min 


-446 


4,059 


CONTROL 
AP   .-l26mmHg 


AF 
AS 


iFA^/ID.  2mm  A;2,87l     i 
/     V  /    \ml/min 


«•»* 


m> 


fig.  27.  Experimental  graded  coarctation  of  the  descending 
thoracic  aorta.  ID  =  internal  diameter;  AP  =  aortic  pressure; 
AF  =  aortic  flow  in  the  descending  thoracic ;  and  AS  =  aortic 
sounds.  The  sounds  are  taken  by  means  of  a  barium  titanate 
phonocatheter  downstream  to  the  point  of  constriction.  During 
control,  systolic  pressure  was  1 30  mm  Hg,  diastolic  86  mm  Hg. 
The  peak  systolic  flow  was  4,752  ml/min,  while  the  mean  flow 
in  the  descending  thoracic  aorta  was  446  ml/min.  In  spite  of  the 
reduced  peak  flow,  there  was  little  reduction  of  mean  during  the 
early  stages  of  constriction  because  of  change  of  contour  of  the 
flow  pulse.  The  pressure  gradient,  flow  pulse  contour  and  mur- 
mur envelope  follow  the  "contour  rule." 

pulse.  Presumably,  this  remarkable  reduction  in 
cross-sectional  area  without  reduction  in  flow  is 
attributable  to  the  progressively  increasing  gradient 
across  the  stenotic  area. 

Beyond  this  degree  of  obstruction  any  further 
change  in  the  internal  diameter  becomes  extremely 
critical  as  far  as  blood  flow  is  concerned.  With  an 
internal  diameter  of  approximately  2  to  3  mm,  the 
murmur  consistently  filled  systole  throughout,  and 
further  reduction  caused  the  murmur  to  increase  in 
duration  beyond  the  second  sound  and  extend  into 
the  diastolic  period.  Internal  diameters  of  1  mm  or  less 
frequently  caused  a  continuous,  high-pitched,  blow- 


ing murmur  distal  to  the  site  of  coarctation  in  both 
experimental  animals  as  well  as  in  congenital  lesions. 

The  Murmur  Envelope  and  Contour  Rule 

The  "envelope"  of  a  murmur  is  defined  as  the 
amplitude  of  the  full  wave  rectified  murmur  averaged 
over  several  heart  cycles.  The  term  envelope  is 
similar  to  the  "shape"  of  a  murmur  which  itself 
means  amplitude  of  the  unrectified  murmur.  The 
envelope  of  a  blowing  murmur  follows  a  "contour 
rule,"  which  means  that  it  corresponds  closely  to  the 
contour  of  the  flow  pulse  originating  the  murmur. 
This  is  true  because  apparently  once  the  critical 
velocity  is  reached  where  turbulent  flow  begins 
(turbulence  is  used  in  a  general  sense  to  indicate 
nonlaminar  flow),  the  amplitude  of  the  resultant 
turbulence  or  lateral  velocities  of  the  nonlaminar 
flow  is  proportional  to  the  mean  axial  velocity. 
Further,  the  flow  under  these  conditions  is  principally 
viscous  in  nature  and  therefore  the  extant  resistant 
pressure  gradient  contour  parallels  the  flow  pulse 
contour.  The  correspondence  of  the  murmur  envelope 
and  the  pressure  gradient  to  the  flow  pulse  exists  only 
when  the  flow  is  highly  viscous  in  nature  (having  no 
significant  reactance  flow  term),  and  may  occur 
without  stenosis  in  a  normal  vessel  under  high- 
velocity  conditions  producing  nonlaminar  flow  or  in 
an  aneurysm  where  nonlaminar  flow  may  be  achieved. 
Some  examples  of  the  contour  rule  are  given  in 
section  VII. 

General  Rules  Relating  Murmurs  to  Nonlaminar  Flow 

From  this  and  other  studies  in  section  VII,  general 
rules  concerning  the  interpretation  of  frequency  band 
width  and  envelope  (amplitude  and  duration)  of 
"blowing"  murmurs  may  be  made  relative  to  the 
functional  anatomy  of  the  source  as  follows: 

/)  Blowing  murmurs  with  high  pitch  and  low 
intensity  are  associated  with  small  orifices  through 
which  blood  is  flowing  at  high  velocity,  driven  by 
large  pressure  gradients. 

2)  Loud,  blowing  murmurs  of  relatively  low- 
frequency  spectrum,  generally  sounding  coarse  to 
the  ear  are  associated  with  relatively  large  orifices 
through  which  large  volumes  of  blood  flow  under 
relatively  high-pressure  gradients. 

3)  Very  low-frequency  (rumbling)  murmurs  of  low 
intensity  are  associated  with  turbulent  flow  beyond 
large  orifices  through  which  blood  flows  under  low- 
pressure  gradients. 


PULSATILE    BLOOD    FLOW 


859 


4)  The  contour  of  the  time-intensity  pattern  or 
"envelope"  of  a  murmur  corresponds  to  the  contour 
of  the  flow  pulse  passing  through  the  region  at  the 
time  of  murmur  production. 

5)  Musical  murmurs,  that  is,  murmurs  with  periodic 
reproductions  in  the  frequency  pattern  as  opposed  to 
the  random  vibrations  of  blowing  murmurs,  arise 
from  tissue  structures,  or  other  coherent  material, 
set  into  oscillation  by  blood  flow  of  high  velocity. 

Examples  of  general  rule  /  are  found  in  the  con- 
tinuous aortic  murmur  of  severe  degrees  of  coarcta- 
tion and  the  diastolic  murmur  of  minimum  aortic  re- 
gurgitation. Examples  of  general  rule  2  are  moderate 
degrees  of  coarctation,  aortic  and  pulmonary  valve 
stenosis,  Korotkoff's  sounds,  patent  ductus  arteriosus, 
and  the  murmurs  of  most  arteriovenous  fistulae. 
Examples  of  general  rule  3  are  mitral  stenosis,  tri- 
cuspid stenosis,  and  occasional  right  atrial  murmur 
of  an  interatrial  septal  defect.  Examples  of  general 
rule  4  are  really  found  among  all  murmurs  wherever 
one  compares  the  murmur  envelope  with  the  flow 
pattern  as  illustrated  in  section  VII  on  flow  in  patho- 
logical conditions.  Examples  of  general  rule  5  are  the 
vibrations  of  a  vein  wall  giving  rise  to  a  "venous 
hum,"  the  "sea  gull"  murmur  arising  from  vibration 
of  aortic  valve  cusps  in  aortic  regurgitation,  and  the 
"moaning"  systolic  murmur  of  retroverted  mitral 
cusps,  or  arising  from  vegetation  on  the  mitral  cusps 
giving  rise  to  a  systolic  low-frequency  periodic 
murmur  in  mitral  regurgitation.  In  addition,  musical 
qualities  may  be  heard  in  arteriovenous  fistulas  which 
are  presumably  due  to  the  vibration  of  the  vascular 
wall,  and  are  usually  superimposed,  like  most  musical 
murmurs,  upon  blowing  or  random  noise  vibrations. 


VII.    NORMAL    AND    PATHOLOGICAL    FLOW 
PULSES    IN    HUMANS 

The  normal  human  flow  pulses  closely  resemble  in 
pattern  those  which  have  been  found  in  the  cor- 
responding vessels  of  the  dog  and  sheep.  Most  records 
of  human  flow  pulses  have  been  made  at  the  time  of 
a  surgical  procedure  indicated  because  of  some 
pathological  condition.  The  pulses  in  this  section 
presented  as  "normal"  tracings  are  so  called  because 
there  was  no  physiological  reason  to  doubt  their 
normalcy  and  second,  because  they  correspond  to 
those  found  in  the  experimental  animal. 


Flow  in  the  Ascending  Aorta 

Normal  blood-flow  patterns  are  shown  in  figure 
26.  As  in  the  dog,  they  show  a  rapid  acceleration 
phase,  a  slower  deceleration  phase  with  a  high- 
frequency  (40-60  cps)  backflow  coincident  with  aortic 
valve  closure.  The  volume  of  the  flow  pulse  has  little 
effect  on  these  contour  features  (fig.  26)  except  from 
hypodynamic  ventricles  and  severe  degrees  of  exercise. 
Diastole  is  relatively  uneventful  with  the  resonant 
wave  not  appearing.  The  ejection  pattern  of  the  left 
ventricle  in  the  presence  of  aortic  valve  stenosis  is 
shown  in  figure  28.  The  principal  deviations  from 
normal  contour  seen  here  are  a  more  flattened  and 
delayed  peak,  with  flow  vibrations  superimposed. 
In  addition,  there  is  less  prominence  of  the  valve 
closure  backflow  wave.  The  backflow  wave  incident 


20 

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fig.  28.  Aortic  valve  stenosis  of  rheumatic  origin  without 
regurgitation  in  a  1 4-year-old  boy.  Measurements  were  made 
during  thoracotomy  prior  to  repair.  Flow  pulse  shows  the 
rounded  irregular  top  of  turbulent  blood  flow,  corresponding  to 
a  diamond-shaped  murmur  and  a  pressure  gradient  between  the 
left  ventricle  and  ascending  aorta  which  follows  the  contour  rule 


86o 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  29.  Blood  flow  and  pressure  gradient  in  aortic  valve 
regurgitation  without  stenosis  in  a  19-year-old  girl.  In  ascending 
aorta  flow,  the  zero  reference  is  estimated.  The  regurgitant 
blood  flow,  the  envelope  of  the  diastolic  murmur,  and  the  pres- 
sure gradient  between  ascending  aorta  and  left  ventricle  follow 
the  contour  rule.  The  blood  flow  pattern  during  systole  is  not 
greatly  altered  from  that  of  the  normal,  in  spite  of  increased 
stroke  volume  (see  also  atrial  septal  defect,  fig.  26). 

to  valve  closure  is  not,  per  se,  dependent  upon 
absence  of  aortic  stenosis,  but  rather  upon  the  degree 
of  flexibility  of  the  valve.  If  the  valve  is  stiff  and 
immobile,  this  wave  will  disappear.  If  the  valve,  as 
in  congenital  stenosis,  is  flexible,  this  wave  will 
persist  and  also  one  may  differentiate  subaortic 
stenosis  or  outflow  stenosis  from  valvular  stenosis  by 
the  presence  of  a  stenosis  pattern  during  systole  which 
retains  the  normal  amplitude  of  the  valve  closure 
wave. 

The  severe  pressure  gradient  across  the  stenotic 
valve,  as  shown  by  the  difference  in  the  aortic  pressure 
and  ventricular  pressure  when  recorded  directly,  is 


quite  similar  in  contour  to  the  flow-pulse  contour 
(fig.  28).  The  murmur,  which  is  harsh,  loud  and 
blowing,  and  is  located  in  the  ascending  aorta  and 
arch,  has  an  envelope  with  a  contour  closely  paral- 
leling that  of  both  the  peak  of  the  flow  curve  and 
differential  pressure  curve.  Experimental  aortic 
stenosis  produced  by  means  of  a  wire  tightened  about 
the  ascending  aorta  at  the  sinus  of  Valsalva  is  shown 
in  figure  5.  The  effect  of  varying  degrees  of  stenosis 
is  demonstrated  on  the  flow  curve,  the  aortic  arch 
pressure,  and  the  differential  pressure  between 
ventricle  and  ascending  aorta.  Also  of  note  here  is 
the  heart's  ability  to  maintain  a  stroke  volume  in  the 
face  of  this  severe  increase  in  load  impedance.  Under 
the  conditions  of  this  experiment,  in  which  several 
heartbeats  were  allowed  for  cardiac  compensatory 
mechanisms  to  act,  the  left  ventricle  functions  as  a 
constant  flow  source.  Further  compensatory  mech- 
anisms brought  into  play  over  long  periods  of  time, 
particularly  allowing  hypertrophy  of  the  left  ventric- 
ular wall,  further  enhance  the  heart's  ability  to 
maintain  a  constant  stroke  with  a  severe  increase  in 
load  impedance. 

Aortic  regurgitation  causes  changes  both  in  the 
systolic  and  diastolic  contour  of  the  left  ventricular 
ejection  pulse  (fig.  29).  The  systolic  stroke  volume 
exceeds  the  normal  volume  by  the  amount  necessary 
to  compensate  for  regurgitation  during  diastole.  As  a 
result  the  flow  pulse  tends  to  be  somewhat  more 
rounded,  but  otherwise  maintains  the  general  shape 
of  the  normal  pulse.  However,  because  of  the  greater 
stroke  volume,  there  is  necessarily  a  greater  accelera- 
tion and  deceleration  at  the  onset  and  termination  of 
ejection.  The  valve  closure  notch  disappears,  and  in 
its  place  one  sees  a  sustained  backflow  deflection. 
The  backflow,  diminishing  throughout  diastole,  is  a 
function  of  the  diastolic  pressure  gradient  across  the 
valve,  and  the  size  of  the  regurgitant  orifice.  The 
murmur,  which  has  a  wide  frequency  band  extending 
above  100  cps,  sounds  high  pitched  and  blowing, 
begins  with  reversal  of  the  pressure  gradient  across 
the  valve,  usually  builds  up  early  in  diastole  to  a 
maximum,  and  then  follows  a  decrescendo  pro- 
portional to  the  backflow.  As  seen  from  figure  29, 
the  envelope  of  the  diastolic  murmur  is  similar  to  the 
pattern  of  the  diastolic   backflow. 


Descending  Thoracic  Aorta 

Figure  30  illustrates  flow  in  the  descending  thoracic 
aorta  immediately  distal  to  a  ductus  arteriosus,  before 
and  after  the  closure  of  the  ductus.  The  descending 


PULSATILE    BLOOD    FLOW 


86 1 


Ductus     Open 


Ductus     Occluded 


Flow   f 

"J? 

Back  + 


AGE  3  YR 
28  FEB  1958 


fig.  30.  Flow  in  the  descending 
thoracic  aorta  distal  to  a  ductus  arterio- 
sus while  patent  and  after  the  ductus 
was  occluded.  Simultaneous  recording 
of  the  descending  aorta  pressure  was 
made  by  means  of  a  needle  inserted 
near  the  square-wa%'e  electromagnetic 
probe. 


thoracic  flow  following  closure  of  this  ductus  may  be 
taken  as  the  shape  of  the  normal  flow  in  the  human 
descending  thoracic  aorta.  Variations  in  contour 
show  basic  similarities  to  those  of  the  dog's  descending 
thoracic  aorta  of  section  III.  It  is  of  interest  to  note 
that  the  mean  forward  flow  in  the  descending  thoracic 
aorta  distal  to  a  patent  ductus  arteriosus  is  not 
affected  by  closure  of  the  ductus.  This  finding  indi- 
cates what  is  confirmed  by  flow  in  the  descending 
thoracic  aorta  proximal  to  the  patent  ductus,  namely, 
that  the  left  ventricle  compensates  for  a  ductus 
arteriosus  by  increasing  its  output  just  a  sufficient 
amount  to  make  up  for  the  flow  passing  through  this 


-JWtESSUaE 
180-1    A«t<» 


fig.  31.  Blood  flow  through  a  patent  ductus  arteriosus.  Con- 
tour of  the  flow  pulse  follows  closely  that  of  the  contour  of  the 
aortic  pressure  thereby  indicating  strong  predominance  of 
resistant  blood  flow  in  this  situation.  The  murmur  was  con- 
tinuous and  had  an  envelope  the  contour  of  which  followed  the 
contour  rule.  Pulmonary  pressures  were  normal. 


fig.  32.  Blood  flow  through  a  patent  ductus  arteriosus  in  a 
patient  with  pulmonary  hypertension.  There  was  a  net  flow  of 
blood  into  the  aorta.  Flow  from  pulmonary  artery  into  the 
aorta  took  place  during  systole,  and  from  aorta  into  the  pulmo- 
nary artery  during  diastole.  The  greater  pulse  pressure  in  the 
pulmonary  artery  as  compared  to  that  in  the  aorta  undoubtedly 
resulted  from  the  lower  compliance  of  the  pulmonary  tree  as 
compared  to  that  of  the  systemic  arterial  tree.  The  three  records: 
aortic  pressure,  pulmonary  artery  pressure,  and  patent  ductus 
flow,  were  taken  at  different  times  in  rapid  succession. 

shunt  to  the  pulmonary  artery.  The  flow  through  the 
ductus  is  predominantly  viscous  in  type,  as  its  contour 
follows  closely  that  of  the  contour  of  the  differential 
pressure  between  the  aorta  and  pulmonary  artery 
(fig.  31).  The  envelope  of  the  murmur  follows  the 
contour  rule  of  the  differential  pressure  and  flow 
pulse  in  a  viscous  flow  situation.  The  murmur 
envelope  and  flow  contour  are  closely  represented 


862 


HANDBOOK    OF    PHYSIOLOGY    ^-    CIRCULATION    II 


BEFORE  RESECTION 


.186 


# 


mean  flow      660      ^„^ 
475  320 


AP     " 

(mmHg) 


AFTER  RESECTION 


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Medium  Frequency 


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High  Frequency 
Transcription 


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fig.  33.  Congenital  coarctation.  Tracings  from  above  downward  both  before  and  after  resection 
are :  descending  thoracic  aorta  pressure,  blood  How  through  the  coarctation  area,  low-frequency 
phonocardiogram,  and  high-frequency  phonocardiogram.  Blood  flow  records  both  before  and  after 
resection  were  made  at  the  same  sensitivity  setting  of  the  electromagnetic  flowmeter.  Zero  reference 
after  resection  was  not  obtainable  because  of  danger  of  rupture  of  the  suture  line.  On  the  basis  that 
zero  was  somewhat  lower  than  the  lowest  flow  point,  the  mean  flow  was  estimated  to  be  greater  than 
1800  ml/min  after  resection,  while  the  mean  flow  before  resection  was  475  ml/min.  Some  constric- 
tion remained  after  resection  and  suture. 


fig.  34.  Tricuspid  regurgitation  after  the  differential  pressure 
method  of  Miiller  &  Shillingford  (29).  Blood  flow  is  recorded 
between  the  superior  vena  cava  and  the  right  atrium  in  a 
normal  subject  in  record  A,  and  in  a  patient  with  tricuspid 
incompetence  and  high  venous  pressure  in  record  B. 

by  the  contour  of  the  aortic  pressure  pulse  alone, 
because  normally  it  greatly  exceeds  the  pulmonary 
artery  pressure  at  all  times  throughout  the  cardiac 
cycle.  Because  of  this  situation,  the  murmur  is  con- 
tinuous throughout  the  cardiac  cycle. 

Figure  32  illustrates  a  flow  pulse  through  a  ductus 
of  an  unusual  type.  In  this  situation,  chronic  pulmo- 
nary hypertension   had  developed  until   the  pulmo- 


nary pressure  exceeded  that  in  the  aorta  during 
systole,  and  was  less  than  that  in  the  aorta  during 
diastole.  (The  larger  pulse  pressure  in  the  pulmonary 
tree  than  in  the  systemic  arteries  probably  resulted 
from  the  smaller  compliance  of  the  pulmonary  tree.) 
As  a  result,  ductus  flow  was  from  pulmonary  artery 
to  aorta  during  systole,  and  from  aorta  to  pulmonary 
artery  during  diastole. 

Coarctation  of  the  aorta  also  produces  a  viscous 
type  flow  through  the  stenotic  region  (43,  49).  Most 
patients  with  coarctation  have  a  severe  degree  of  the 
type  illustrated  in  figure  33.  The  differential  pressure 
and  murmur  envelope  both  follow  the  contour  rule 
with  reference  to  the  flow  pulse.  Flow  pulses  in  the 
aortic  branches  are  considerably  altered  (43). 

Tricuspid  Valve 

Blood  flow  between  the  superior  vena  cava  and  the 
right  atrium  was  measured  by  a  pitometer  by 
Miiller  &  Shillingford  (29).  This  record  probably 
represents  a  close  approximation  of  the  flow  pulse  at 
the  tricuspid  valve  except  for  the  period  of  atrial 
contraction  which  is  inverted  to  show  forward  flow 
(fig.  34)- 


PULSATILE    BLOOD    FLOW 


863 


REFERENCES 


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24- 


25- 
26. 

27. 


29- 

3°- 

3i- 

32- 
33- 

34- 

35- 
36. 

37- 

38. 

39- 
40. 

41- 


Hamilton,  W.  F.,  and  P.  Dow.  An  experimental  study  of 
the  standing  waves  in  the  pulse  propagated  through  the 
aorta.  Am.  J.  Physiol.  125:  48,  1939. 

Hardung,  V.  Die  nichtstationare  Stromung  undehnbarer 
Rohrleitungen.  Proc.  II  Intern.  Congr.  on  Angiology,  edited  by 
Lazst,  Meier,  and  Miiller.  Fribourg,  Switzerland:  Univ. 
Fribourg  Press,  1956,  p.  384. 

Kudravcev,  V.,  and  R.  L.  Bowman.  Utilization  of  nuclear 
magnetic  resonance  for  flow  rate  measurement.  Proc.  13th 
Ann.  Conf.  on  Electromedical  Techniques  in  Med.  and  Biol., 
Washington,  D.C.,  i960,  p.  21. 

Marston,  E.  L.,  C.  A.  Barefoot,  and  M.  P.  Spencer. 
Non-cannulating  measurement  of  coronary  blood  flow. 
Surg.  Eorum  1  o :  636,  1 960. 

Maxson  Instruments.  Rev.  Set.  Instr.  27:  116,  1956. 
McDonald,    D.    A.    Blood    Flow    in    Arteries.    Baltimore: 
Williams  &  VVilkins,  i960. 

Menno,  A  D.,  and  VV.  G  Schenk,  Jr.  Dynamics  of  coro- 
nary arterial  flow:  flow  alterations  resulting  from  certain 
surgical  procedures  and  drugs  of  surgical  importance 
Surgery  50:  82 ;  196 1. 

Mixter,  G.,  Jr.  Respiratory  augmentation  of  inferior 
caval  flow  demonstrated  by  low-resistance  phasic  flow- 
meter. Am.  J.  Physiol.  172:  446,  1953. 

Muller,  O.,  and  J.  Shillingford.  The  blood  flow  in  the 
right  atrium  and  superior  vena  cava  in  tricuspid  incompe- 
tence. Brit.  Heart  J.  17:  163,  1955. 

Okino,  H.,  and  M.  P.  Spencer.  Analysis  of  the  dynamic 
pressure-flow  relationship  in  the  renal  artery.  Federation 
Proc.  20  (No.  1):  109,  1961. 

Okino,  H.,  K.  Fujisaku,  D.  Sakaguchi,  and  H.  Sasamoto. 
Pulsatile  blood  flow  in  the  arterial  system.  Respiration  & 
Circulation  8 :  4g,  1  g6o. 

Olson,  H.  F.  Dynamical  Analogies  (2nd  ed.).  New  York: 
Van  Nostrand,  1958. 

Patel,  D.  J.,  D.  P.  Schilder,  and  A.J.  Mallos.  Mechani- 
cal properties  and  dimensions  of  the  major  pulmonarv 
arteries.  J.  Appl.  Physiol.  15:  92,  i960. 

Paynter,  H.  M.  Hydraulics  by  analog:  An  electronic 
model  of  a  pumping  plant.  J.  Boston  Soc.   Civil  Eng.,  July 

'959- 

Peterson,   L.   H.   The  dynamics  of  pulsatile  blood  flow. 

Circulation  Research  2:  127,   1954. 

Pieper,   H.    P.    Registration   of  phasic   changes    of   blood 

flow  by  means  of  a  catheter-type  flowmeter.  Rev.  Sci.  Instr. 

29:965.  <958- 

Pritchard,  W.  H.,  D.  E.  Gregg,  R.  E.  Shipley,  and  A.  S. 

Weisberger.   A  study   of  flow   and   pattern   responses   in 

peripheral  arteries  to  the  injection  of  vasomotor  drugs.  Am. 

J.Physiol.  138:731,  1943. 

Richards,  A.   M.,  and  F.  W.   Kuether.  A  new  velocity 

probe  for  sensing  pulsatile  blood  flow.  IRE  Trans,  on  Med. 

Electronics  ME-6:  286,  igsg. 

Robiscek,    F.    Orifice-plate   flowmeter   for   extracorporeal 

circuit.  IRE  Trans,  on  Med.  Electronics  ME-6:  249,  ig5g. 

Sarnoff,  S.  J.,  and  E.  Berglund.  The  Potter  electroturbi- 

nometer;  an  instrument  for  recording  total  systemic  blood 

flow  in  the  dog.  Circulation  Research  1 :  331,  1953. 

Sarnoff,  S.  J.,  and  E.  Berglund.  The  Potter  electroturbi- 

nometer;  an  instrument  for  recording  total  systemic  blood 


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CIRCULATION    II 


flow  in  the  dog.  IRE  Trans,  on  Med.  Electronics  ME-6:  270, 

■959- 

42.  Sasamoto,  H.,  H.  Okino,  K.  Fujisaku,  and  D.  Sakaguchi. 
The  blood  flow  in  the  arterial  system;  asynchronism  of  the 
electrical  and  mechanical  phenomenon  of  the  heart. 
Thoracic  Surg.  13:  230,  i960. 

43.  Schenk,  W.  G.,  Jr.,  A.  D.  Menno,  and  J.  W.  Martin. 
Hemodynamics  of  experimental  coarctation  of  the  aorta. 
Ann.  'Surg.  153:  163,  i960. 

44.  Shipley,  R.  E.,  D.  E.  Gregg,  and  E.  F.  Schroeder.  An 
experimental  study  of  flow  patterns  in  various  peripheral 
arteries.  Am.  J.  Physiol.  138:  718,  1 943. 

45.  Spencer,  M.  P.,  and  A.  B.  Denison,  Jr.  The  square-wave 
electromagnetic  flowmeter;  theory  of  operation  and  design 
of  magnetic  probes  for  clinical  and  experimental  applica- 
tion. IRE  Trans,  on  Med.  Electronics  ME-6:  220,  1959. 

46.  Spencer,  M.  P.,  and  A.  B.  Denison,  Jr.  Square-wave 
electromagnetic  flowmeter  for  surgical  and  experimental 
application.  Methods  111  Medical  Research,  edited  byBruner. 
Chicago:  Yr.  Bk.  Pub.,  1960,  vol.  8,  p.  321. 

47.  Spencer,  M.  P.,  and  F.  C.  Greiss.  Dynamics  of  ventricular 
ejection.  Circulation  Research  10:  274,  1962. 

48.  Spencer,  M.  P.,  F.  R.  Johnston,  and  A.  B.  Denison,  Jr. 
Dynamics  of  the  normal  aorta:  "Inertiance"  and  "Compli- 
ance" of  the  arterial  system  which  transforms  the  cardiac 
ejection  pulse.  Circulation  Research  6:  491,  1958. 

49.  Spencer,  M.  P.,  F.  R.  Johnston,  and  J.  H.  Meredith. 
The  origin  and  interpretation  of  murmurs  in  coarctation 
of  the  aorta.  Am.  Heart  J.  56:  722,  1958. 

50.  Stacy,  R.  W.  Computers:  Analog.  In.  Medical  Physics, 
edited  by  Glasser.  Chicago:  Yr.  Bk.  Pub.    i960,  vol.  Ill,  p. 

"93- 

51.  Taylor,  M.  G.  An  experimental  determination  of  the 
propagation  of  fluid  oscillations  in  a  tube  with  a  visco- 
elastic  wall;  together  with  an  analysis  of  the  characteristics 
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52.  The  Radio  Amateur's  Handbook  (35th  ed.).  West  Hartford 
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Electronics  ME-6:  237,  1959. 

54.  Usher,  T.,  Jr.  Dynamics  of  lumped-parameter  mechanical 
systems,  I  In:  Vibration  Topics.  Hamden,  Conn.:  Unholtz 
Dickie,  i960,  vol.  1. 

55.  Van  der  Tweel,  L.  H.  Some  physical  aspects  of  blood 
pressure  pulse  wave,  and  blood  pressure  measurements 
Am.  Heart  J.  53:4,  1957. 

56.  Warner,  H.  R.  A  study  of  the  mechanism  of  pressure  wave 
distortion  by  arterial  walls  using  an  electrical  analog. 
Circulation  Research  5:  79,  1957. 

57.  Westersten,  A.,  G.  Herrold,  E.  Abbott,  and  N.  S. 
Assali.  Gated  sinewave  electromagnetic  flowmeter.  IRE 
Trans,  on  Med.  Electronics  ME-6 :  2 1 3,  1 959. 

58.  Wetterer,  E.  Flow  and  pressure  in  the  arterial  system, 
their  hemodynamic  relationship  and  the  principles  of  their 
measurement.  Minn.  Med.  37:  77,  1954. 

59.  Wilhelmj,  C.  M.,  E.  B.  Waldmann,  T.  F.  McGuire,  and 
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60.  Wolff,  J.  Electrical  analogues  of  mechanical  systems. 
Electronic  Equipment  Engineering  8:  75,  iq6o. 

61.  Womersley,  J.  R.  Method  for  the  calculation  of  velocity, 
rate  of  flow  and  viscous  drag  in  arteries  when  the  pressure 
gradient  is  known.  J.  Physiol.,  London  127:  553,  1955. 

62.  Womersley,  J.  R.  Oscillatory  motion  of  a  viscous  liquid  in 
a  thin-walled  elastic  tube — I :  The  linear  approximation  for 
long  waves.  Phil.  Mag.  46:  199,  1955. 

63.  Yanof,  H.  M.,  and  P.  Salz.  A  new  trapezoidal-wave  elec- 
tromagnetic blood  flowmeter.  Abstr.  of  jth  Ann.  Meeting 
Biophysical  Soc,  St.  Louis.  1 961,  No.  FE-5. 


CHAPTER     26 


The  anatomy  and  physiology  of  the  vascular  wall 


HERMANN    BADER  Physiologisches  Inslilut,  Universitiit  Wurzburg,  Wiirzburg,  Germany 


CHAPTER      CONTENTS 

Elements  of  the  Vascular  Wall 

Endothelium 

Collagen  Tissue 

Ground  Substance 

Elastic  Tissue 

Smooth  Muscle 
Different  Types  of  Vessels 

Arteries  of  the  Elastic  Type 

Vessels  of  the  Muscular  Type 

Capillaries  and  Arteriovenous  Anastomoses 

Veins 
Nutrition  of  the  Vascular  Wall 

Diffusion  from  the  Inside 

Vasa  Vasorum 


blood  vessels  serve  as  a  conducting  system  for  the 
blood.  They  carry  the  blood,  forced  by  the  heart, 
throughout  the  whole  body  and  back  again  to  the 
heart.  To  make  this  possible  there  must  be  a  pressure 
gradient  with  its  highest  values  in  the  aorta  and  its 
lowest  values  in  the  large  veins.  The  circulation  there- 
fore withstands  a  much  higher  pressure  on  the  arterial 
side  than  on  the  venous  side,  a  difference  which  is 
reflected  in  the  architecture  of  the  wall. 

The  stress  on  the  vessel  wall  is,  according  to  Frank 
(30),  proportional  to  the  blood  pressure  and  the  ratio 
of  radius  to  wall  thickness 


<r~  = 


t 


(I) 


[a  =  stress  (force  per  unit  area),  p  =  pressure,  r  = 
radius,  /  =  wall  thickness]. 

The  relationship  r/t  and  the  composition  of  the 
vessel  wall  (fig.  1 )  show  the  level  of  blood  pressure. 
For  example,  the  aorta  has  a  much  smaller  ratio  of 


r/t  than  the  vena  cava,  which  means  that  the  differ- 
ence between  the  wall  tensions  of  the  two  vessels  is  less 
than  might  be  expected,  considering  the  difference 
between  the  blood  pressures  to  which  they  are  sub- 
jected [Burton  (20)].  The  relationship  r/t  is  smaller  in 
vessels  where  the  principal  component  is  smooth 
muscle  than  in  vessels  where  the  major  component  is 
elastic  tissue.  For  that  reason,  the  smooth  muscles,  the 
contractile  elements  of  the  wall,  need  to  withstand 
smaller  stress  than  the  elastic  tissue,  one  of  the  passive 
elements  of  the  wall. 

The  vessels  must  be  tight,  so  that  no  blood  is  lost 
on  the  way  through  the  circulatory  system.  The  vessel 
wall  is  therefore  lined  with  the  endothelium,  which 
serves  as  a  semipermeable  membrane  for  the  exchange 
of  material  between  blood  and  tissue. 

The  arterial  side  of  the  circulatory  system  is  not 
only  a  simple  conducting  system,  but  is  also  an  elastic 
buffering  chamber.  The  vessels,  mainly  the  aorta,  are 
stretched  during  systole,  and  store  energy  which 
enables  them  to  force  the  blood  along  by  elastic  recoil 
during  diastole.  This  ability  is  given  the  vessels  by 
their  elastic  tissue.  However,  as  Frank  (3 1 )  has  shown, 
tubing  which  consists  only  of  distensible  material  like 
rubber  will  "blow  out"  at  a  critical  pressure.  This  does 
not  occur  in  normal  blood  vessels,  since  they  have  a 
relatively  inextensible  jacket  in  addition  to  the 
elastic  tissue.  This  jacket  is  composed  of  collagen 
tissue,  and  is  located  in  all  arteries  and  veins.  The 
collagen  tissue  bears  the  stress  when  the  pressure 
becomes  high,  protecting  the  vessel  from  rupture  or 
blow  out. 

Another  quality  of  blood  vessels  is  their  ability 
to  regulate  the  blood  supply  to  different  organs, 
depending  on  the  need.  When  an  organ  is  active, 
more  blood  must  be  carried  to  it  than  when  it  is  at 


865 


866 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Aorta 


M.dlum 

Small  Art. 

Sphinctar 

Art. 
0.4  cm. 

1  mm 

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Pri-Cap.  A.V 
33,ii 

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fig.  I .  Variety  of  admixture  of  the  four  tissues  in  the  wall 
of  different  blood  vessels.  The  figures  under  the  name  of  the 
vessel  are  the  diameter  of  the  lumen  and  below  it  the  thickness 
of  the  wall.  [Burton  (20).] 

rest.  This  is  best  done,  according  to  the  law  of  Poi- 
seuille,  by  changing  the  radius  of  the  small  supplying 
vessel  by  relaxation  of  the  smooth  muscles  in  the 
arterial  wall. 

Any  living  organ  must  be  nourished.  All  but  the 
smallest  blood  vessels  have  their  own  circulatory- 
system,  the  vasa  vasorum,  which  supplies  blood  to  the 
vessels  from  the  outside.  In  addition,  simple  diffusion 
from  the  inside  transports  nutrients  and  oxygen  to  the 
inner  avascular  layer  of  the  blood  vessel.  This  outward 
fluid  shift  may  be  aided  by  the  radial  pressure  gradient 
through  the  vessel  wall. 

The  purpose  of  this  chapter  is  to  discuss  and  to 
interpret  these  qualities  and  functions  of  the  vascular 
wall  and  to  explain  the  performance  of  the  various 
wall  elements  in  the  different  types  of  vessels. 


ELEMENTS  OF  THE  VASCULAR  WALL 

The  terms  used  in  this  article  are,  for  the  most 
part,  those  denned  by  Landowne  &  Stacy  (50).  Here 
we  will  consider  some  of  these  terms  in  detail.  Collagen 
tissue,  elastic  tissue,  and  smooth  muscle  have  three 
qualitites  in  common,  which  appear  differently.  These 
qualities  are  elasticity,  visco-elasticity,  and  plasticity. 

Elasticity    is    that    property   of  a    material   which 


determines  its  tendency,  when  stressed,  to  return  to 
its  unstressed  geometrical  configuration  without  loss 
of  energy.  If  a  material  is  completely  elastic,  all  energy 
applied  to  it  by  an  external  straining  force  can  be 
recovered  as  mechanical  energy.  Figure  2a  shows  an 
extension  release  cycle  of  such  a  perfectly  elastic 
material,  illustrated  by  a  spring.  Any  given  length 
has  its  particular  tension.  The  extension  curve  and 
release  curve  are  the  same.  It  can  be  linear,  as  in 
figure  2(7,  or  convex  or  concave  to  the  abscissa,  de- 
pending on  the  material  stretched.  Tension-length 
diagrams  of  organic  materials  usually  show  a  curve 
which  is  convex  to  the  abscissa.  A  perfectly  elastic 


c 
o 
l/l 

c 


length 

fig.  2.  Behavior  with  stretch  of  different  materials.  Tension 
and  length  are  taken  as  arbitrary,  a:  Elastic  material,  demon- 
strated by  a  spring.  Extension  and  release  curve  are  the  same. 
b:  Visco-elastic  material  demonstrated  by  a  spring,  which  has 
a  brake  disc  on  the  top  and  which  moves  in  a  liquid.  Extension 
and  release  curves  inscribe  a  hysteresis  loop,  the  size  of  which 
depends  on  the  velocity  of  the  extension  and  release.  Outer 
curve:  fast  stretch;  inner  curve:  slow  stretch.  An  infinitely  slow 
stretch  gives  the  same  curve  as  a.  c:  Viscous  or  plastic  material 
demonstrated  with  a  brake  disc,  which  moves  in  a  liquid.  The 
material  keeps  every  length  to  which  it  was  brought  by  an 
external  force.  The  force  depends  on  the  velocity  of  the  exten- 
sion. Upper  curve:  fast  stretch;  lower  curve:  slow  stretch.  In  each 
the  rate  of  viscous  deformation  is  constant. 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


867 


material  can  maintain  a  constant  tension  at  any  given 
length  for  an  indefinite  time. 

Thus,  the  term  visco-elasticity  applies  to  materials 
having  the  combined  properties  of  elasticity  and  vis- 
cosity, the  elastic  action  being  damped  by  a  viscous 
one.  Such  a  system  is  most  easily  illustrated  by  a  spring 
which  has  a  brake  disc  at  the  top  and  moves  in  a 
viscous  fluid.  The  tension  of  such  a  system  depends 
not  only  on  the  length  but  also  on  the  velocity  with 
which  it  is  extended.  The  tension  will  be  higher  the 
faster  it  is  stretched,  and  also  lower,  the  faster  the 
stretch  is  released.  When  the  extension-release  cycle 
of  such  a  system  is  plotted  with  tension  on  the  ordinate 
and  length  on  the  abscissa,  the  graph  forms  what  is 
called  a  ''hysteresis  loop.''  Two  such  cycles  are  shown 
in  figure  2b.  The  large  loop  results  from  a  quick 
stretch  cycle,  with  immediate  release,  the  small  loop 
from  a  slow  stretch  cycle.  The  area  between  the  exten- 
sion curve  and  the  abscissa  is  always  larger  than  the 
area  below  the  release  curve.  This  behavior  indicates 
loss  of  energy  increasing  with  the  velocity  of  the 
stretch.  More  energy  is  required  to  stretch  such  a 
visco-elastic  material  than  can  be  recovered  during 
release.  The  area  within  the  hysteresis  loop  can  be 
expressed  as  percentage  of  the  area  under  the  exten- 
sion curve.  It  depends  only  on  the  velocity  with  which 
the  system  is  stretched.  Rapid  cyclic  stretches  are 
called  "dynamic  stretches,"  and  the  shape  of  the 
extension-release  curves  depends  on  the  frequency  of 
the  cycles.  The  hysteresis  loop  of  a  pure  visco-elastic 
element  will  be  larger  in  area,  the  more  frequent  the 
cycles.  The  hysteresis  should  vanish  if  the  stretch  is 
made  slowly  enough,  and  this  is  called  "static  stretch." 
If  the  stretched  material  is  purely  visco-elastic,  it 
returns,  after  an  extension-release  cycle,  to  its  original 
length.  But  if  it  is  kept  at  a  constant  stretched  length, 
the  tension  will  decrease  with  time  in  a  hyperbolic 
manner  until  it  reaches  an  equilibrium.  This  process 
is  similar  to  that  shown  in  the  two  curves  in  figure  5. 

A  material  is  called  plastic  when  it  shows  the  tend- 
ency to  retain  its  new  shape  after  deformation.  Plas- 
ticity is  usually  understood  as  the  quality  of  a  material 
which  allows  it  to  withstand  stresses  of  less  than  a 
critical  or  yield  magnitude  without  suffering  a  per- 
manent set,  but  which  will  then  allow  a  viscous 
deformation  with  stress  above  this  yield  value.  The 
appearance  of  plastic  yield  is  not  time-dependent. 

Viscous  or  plastic  behavior  is  illustrated  in  figure 
ic  by  a  disk  which  is  moved  in  a  viscous  fluid.  The 
force  required  depends  upon  the  velocity  with  which 
the  disc  is  moved.  The  top  curve  in  figure  2c  is  derived 
by  a  quick  movement  of  the  disc,  the  bottom  curve  by 


a  slow  movement.  As  long  as  the  velocity  remains 
constant,  the  stress  will  be  constant  too.  If  the  applied 
force  is  removed,  the  stress  decreases  without  reducing 
the  length.  In  contrast  to  the  behavior  of  a  visco- 
elastic  element,  a  viscous  or  plastic  element  will  never 
go  back  to  its  original  shape  by  itself. 

The  systems  shown  in  figure  2a,  b,  and  c  are  very 
much  simplified  models  to  describe  the  physical  defini- 
tions of  elastic,  visco-elastic,  and  plastic  properties. 
These  properties  reflect,  in  organic  materials,  their 
complicated  molecular  structure.  In  organic  materials 
there  is  usually  a  combination  of  the  three  qualities 
described,  with  elastic,  visco-elastic,  and  plastic  prop- 
erties behaving  as  though  arranged  in  series,  and 
present  in  different  amount.  Such  a  combination  is 
described  by  the  term  "elastic  incompleteness." 

For  instance,  if  an  elastic  and  a  visco-elastic  element 
are  in  series,  then  the  element  which  offers  the  smaller 
resistance  to  extension  will  dominate  the  stretch 
behavior.  Since  the  resistance  of  the  visco-elastic 
element  is  greater  at  high  rates  of  stretch,  the  prop- 
erties of  this  series  combination  is  determined  more 
by  the  elastic  element.  The  more  frequent  are  the 
stretch  cycles,  the  less  is  the  hysteresis.  If  there  is  also 
a  purely  viscous  or  a  plastic  element  in  series,  after 
every  stretch  cycle  the  material  assumes  a  greater 
length.  There  is  also  the  possibility  that  many  visco- 
elastic  and  viscous  elements  may  be  in  series,  each 
having  a  different  rate-  and  time-dependency.  Such 
combinations  of  elastic,  visco-elastic,  and  plastic 
elements  can  show  a  very  slight  rate-dependency,  if, 
for  instance,  the  elastic  element  offers  the  smallest 
resistance  to  stretch  when  compared  with  the  other 
elements  present.  Because  of  the  visco-elastic  or  plastic 
units,  the  system  may  show  a  great  time-dependency, 
which  occurs  as  an  elastic  aftereffect  or  a  relaxation 
when  the  material  is  kept  on  a  constant  stress  or 
length. 

The  viscosity  of  organic  materials  may  not  only 
derive  from  a  viscous  flow  within  the  tissue,  but  also 
from  an  architectural  reanangement  involving  the 
uncoiling  or  slippage  of  twisted  elements.  Such  proc- 
esses may  be  involved  in  the  phenomenon  of  the 
"stable  loop"  seen  in  elastic  arteries  after  a  number  of 
stretches,  which  does  not  show  any  rate  or  time- 
dependency  but  does  depend  on  the  existing  tension 
level  [Remington  (73);  see  also  Chapter  24].  The  so- 
called  viscosity  or  plasticity  of  organic  materials  may 
be  complicated,  and  thus  not  follow  the  physical 
definitions.  Further,  there  is  usually  a  certain  polarity 
to  these  tissues  in  that  tension-length  relations  are 
different  in  various  directions.  Most  organic  materials 


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cannot  be  extended  ad  infinitum,  but  tear  at  a  certain 
length. 

Smooth  muscle  is  a  special  case.  It  can  be  elongated 
like  a  purely  plastic  material  and  can  behave  at  any 
given  length  like  an  elastic  or  visco-elastic  material. 
But  it  can  also  recover  its  original  length  by  contrac- 
tion. This  means  that  the  plastic  property  of  smooth 
muscle  can  be  neutralized  or  hindered,  leaving  only 
the  elastic  or  visco-elastic  elements  under  stress,  as  a 
result  of  the  action  of  the  contractile  element.  [For 
further  details  see  Reichel  (71)-] 

Endothelium 

The  circulatory  system  is  lined  almost  completely 
by  a  single  layer  of  very  thin  polygonal-shaped  cells, 
the  endothelium.  This  forms  a  tight,  smooth  surface 
on  the  inside  of  the  vascular  wall  and  serves  as  a 
semipermeable  membrane  for  the  interchange  of 
materials  between  blood  and  tissues.  It  has  a  high 
distensibility.  Its  ability  for  regeneration  is  very  good. 
For  instance,  3  weeks  after  implantation  aortic  grafts 
show  a  smooth  continuous  lining  of  endothelial  cells, 
which  presumably  are  built  from  fibrocytes  [Petry  & 
Heberer  (67)].  A  detailed  discussion  of  the  qualities 
of  the  endothelium  is  given  in  Chapter   29. 

Collagen  Tissue 

Collagen  tissue  is  produced  by  fibroblasts,  which  are 
located  in  all  connective  tissues.  The  probable  pre- 
cursors of  collagen  fibers  are  the  reticular  fibers.  These 
are  argyrophilic  fibers  which  are  found  especially  in 
places  where  collagen  fibers  are  forming,  as  around 
aortic  grafts.  They  both  show  a  banded  appearance 
under  the  electron  microscope  [see  Wassermann  (95)]. 
The  collagen  fibers  consist  of  a  network  of  long 
protein  chains  which  are  linked  by  H  bonds  and  ionic 
bonds.  This  network  is  filled  with  an  amorphous 
substance  (mucopolysaccharide).  Smaller  fibers  are 
glued  together  to  larger  fibers  by  a  cement  substance 
which  is  continuous  with  the  ground  substance. 

This  structure  gives  the  collagen  fibers  a  very  high 
elastic  modulus  and  also  makes  them  very  flexible  [see 
Harkness  (36)].  Collagen  fibers  are  nearly  25  times  as 
strong  as  elastic  tissue  but  15  times  less  extensible 
(table  1).  Collagen  fibers  are  found  in  all  vessels, 
spread  over  the  whole  wall.  They  appear  in  the  un- 
stretched  vessel  wall  as  wavy  bundles,  but  some  of 
them  become  straightened  if  the  pressure  within  the 
vessel  is  raised  above  the  mean  blood  pressure  [Reuter- 
wall  (74)].  This  anatomical  design,  together  with  the 


table  1.  Elastic,  Visco-E/astic  and  Plastic  Behavior 
of  Collagen  and  Elastic  Tissue  (102) 


Maximal  Ten- 
sile Strength, 
kg/cm! 

Maximal  Ex- 
tension, in  ',' 

Irrevers- 
ible 
Elonga- 
tion in  % 
of  Total 
Elonga- 
tion 

Hysteresis 

IN     '    J      Ml 

Area 
Under 
Stretch 
Curve 

Collagen  tissue 

660 

10 

67 

57 

(tendon) 

(250-750) 

(5-12) 

Elastic  tissue 

25 

150 

'9 

60 

(ligamentun 

(■2-45) 

(I2O-220) 

nuchae) 

high  elastic  modulus,  enables  them  to  form  a  "jacket" 
[Burton  (20)],  which  is  put  in  action  only  when  the 
fibers  are  straightened,  by  increased  intraluminal 
pressure.  Thus  the  collagen  fibers  are  not  strained  by 
the  normal  blood  pressure;  they  serve  as  a  safety  factor 
for  the  vessels  and  keep  them  from  ''blowing  out"  at 
high  pressure. 

Only  the  collagen  fibers  increase  in  number  with 
aging,  replacing  frayed  elastic  fibers  and  degenerated 
smooth  muscle  cells  [Meyer  (58),  Kobayashi  (46)]. 
Since  the  elastic  and  muscular  tissues  originally  sup- 
ported the  wall  tension  at  normal  blood  pressures,  the 
replacing  collagen  fibers  must  take  over  this  task 
[Bader  &  Kapal  (7)]  with  the  result  that  the  wall 
becomes  less  distensible.  This  is  compensated  until 
the  sixth  decade  of  life  by  enlargement  of  the  diame- 
ters of  the  vessels  involved  [Simon  &  Meyer  (86)]. 
However,  collagen  tissue,  when  overloaded,  does  show 
elastic  incompleteness,  which  means  that  it  is  to  some 
extent  a  plastic  material  (table  1).  The  fibers  do  not 
return  to  their  original  length  immediately  after  exten- 
sion and  the  residual  elongation  can  be  67  per  cent 
of  the  total  elongation.  This  plasticity  may  produce  a 
large  hysteresis.  It  may  be  that  such  plastic  property 
can  account  for  the  increase  in  vessel  volume  seen  in 
aging. 

Ground  Substance 

The  ground  substance  has  the  properties  of  a  col- 
loid— it  is  water-insoluble,  but  can  bind  water.  It 
consists  of  the  mucopolysaccharides:  hyaluronic  acid 
and  chondroitin  sulfate.  It  is  likely  that  chondroitin 
sulfate  forms  the  cement  substance  which  binds 
collagen  fibers  together,  and  hyaluronic  acid  serves 
as  a  lubricating  material  [see  Harkness  (36)].  Such 
a  lubricating  substance  is  necessary  in  the  vessel  wall, 
since  the  fibrous  elements  of  the  wall  (collagen  fibers, 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


869 


elastic  fibers,  and  smooth  muscles)  must  be  able  to 
slide  past  each  other  with  minimal  friction  during  the 
pulsatile  expansion  of  the  vessel.  The  ground  substance 
is  a  very  viscous  material  and  it  probably  contributes 
to  the  typical  visco-elastic  behavior  of  distensible 
vessels. 


Elastic  Tissue 

Elastic  tissue  is  a  rubberlike  material  with  high 
extensibility.  It  contains  the  protein  elastin  without 
any  detectable  amount  of  carbohydrate  [Lansing 
(52)].  In  contrast  to  collagen  tissue,  it  is  an  extremely 
insoluble  material,  and  is  not  influenced  by  boiling  or 
autoclaving.  X-ray  diffraction  and  electron  micros- 
copy do  not  ordinarily  show  any  internal  organization 
in  elastic  fibers.  It  is  therefore  assumed  that  the  protein 
fibrils  lie  without  orientation  within  the  fibers  [see 
Lansing  (52)].  This  disorder  gives  the  elastic  tissue  its 
high  extensibility.  It  can  be  extended  to  twice  its 
original  length,  but  its  tensile  strength  is  ^o  to  H$0 
that  of  collagen  tissue  (table  1).  This  explains  why  it 
must  be  protected  from  excessive  elongation  and 
tearing  in  the  vascular  wall  by  the  much  stronger 
collagen  fibers. 

Elastic  tissue  forms  fenestrated  membranes  which 
lie  one  over  the  other  in  elastic  vessels.  These  mem- 
bra nes  serve  as  footholds  for  the  tension  muscles 
(fig.  3).  There  is  less  elastic  tissue  in  the  more  periph- 
eral muscular  vessels.  It  is  only  a  very  minor  com- 
ponent in  the  arterioles  and  precapillary  sphincters 
(fig.  1).  Elastic  fibers  appear  in  the  veins,  increasing 
in  amount  as  they  near  the  heart.  They  are  partly- 
straight  and  partly  wavy  in  unstretched  vessels.  The 
wavy  ones  become  straight  before  the  collagen  fibers 
straighten  out  as  the  pressure  rises  [Reuterwall  (74)]. 
At  ordinary  pressures  the  elastic  tissue  supports  most 
of  the  tension  in  elastic  vessels,  whereas  this  task  is 
performed  by  smooth  muscles  in  the  muscular  vessels. 

Elastic  tissues  usually  fray  with  age.  This  is  a  normal 
change  which  appears  in  all  vessels  of  old  people. 
Calcification  of  the  fibers  is  also  progressive  with  age. 
In  addition,  the  fibers  undergo  fragmentation,  which 
finally  leaves  little  more  than  dispersed  granular 
material  [see  Lansing  (52)].  Calcification  is  especially 
great  in  arteriosclerosis.  However,  Lansing  (52)  has 
shown  that  the  percentage  of  elastin  in  the  vessel  wall 
does  not  decrease  with  age,  while  the  calcium  content 
rises  in  the  human  aorta  from  0.4  per  cent  in  the 
second  decade  to  7  per  cent  in  the  eighth  decade. 
Frayed  and  fragmented  elastic  fibers  remaining  can- 
not support  the  wall  tension  at  normal  pressures.  This 


® 


M 

1  -I 

1 


fig.  3.  Axillary  artery  (human).  Irradiation  of  tension 
muscles  in  the  elastica  externa — a:  in  situ;  b:  elastica  externa 
artificially  lifted  off.  Muscle  endings  fasten  on  the  elastic 
membrane.    [Benninghoff    (10).] 

task  is  taken  over  in  old  age  by  collagen  fibers,  which 
are  under  stress  with  ordinary  blood  pressure  [Bader 
&  Kapal  (7)].  Thus,  the  distensibility  of  the  vessels 
decreases,  but  the  volume  of  the  aorta  increases  and 
its  total  elastic  uptake  may  remain  within  normal 
limits  so  long  as  the  increase  in  volume  keeps  pace  with 
the  decrease  in  distensibility  [Kapal  &  Bader  (44), 
Simon  &  Meyer  (86)]. 

Smooth  Muscle 

The  smooth  muscle  cell  is  an  elongated  spindle  with 
a  single  elongated  nucleus  in  the  thickest  part  of  the 
cell.  The  cells  vary  very  much  in  size.  In  the  vascular 
wall  they  are  between  20  and  50  n  in  length,  with  their 
greatest  diameter  between  5  and  10  n.  There  are  two 
types  of  smooth  muscles  in  the  vascular  wall:  "Spann- 
muskeln''  (tension  muscles),  which  are  described  in 
detail  by  Benninghoff  (10,  11),  and  ring  muscles. 

The  tension  muscles  are  connected  to  elastic  fibers 
and  membranes,  using  them  as  tendons  (fig.  3).  They 
can  thus  raise  the  tension  on  the  elastic  tissue  in  the 
vessel  wall  by  contraction  (fig.  7)  and  so  affect  the 
blood    pressure    (see    Arteries   of  the   Elastic   Type, 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


below).  The  smooth  muscles  of  the  aorta  and  the 
pulmonalis  are  almost  exclusively  tension  muscles. 
But  the  proportion  of  tension  muscles  diminishes 
toward  the  periphery.  The  smallest  arteries  and 
arterioles  have  almost  no  tension  muscles.  They  may 
appear  again  on  the  venous  side  of  the  circulatory 
system,  but  not  in  as  large  numbers  as  in  the  elastic 
arteries  [Grau  (34)]. 

The  ring  muscles  are  connected  with  each  other. 
How  they  are  related  to  the  elastic  and  collagen  tissue 
is  not  certain,  but  it  is  very  likely  that  they  have  slack 
connections  with  both  tissues.  Since  smooth  muscles 
are  almost  completely  surrounded  by  reticular  fibers, 
it  is  possible  that  these  fibers  bind  them  together.  The 
ring  muscles  form  the  greatest  part  of  the  wall  in  the 
muscular  vessels,  where  they  form  a  helical  arrange- 
ment [Fischer  (23),  Schultze-Jena  (84)].  Arterioles 
and  precapillary  sphincters  consist  mostly  of  ring 
muscles. 

Smooth  muscles  have  the  general  quality  of  sponta- 
neous activity  and  self-conduction  [see  Biilbring  (17)]. 
Bozler  (16)  has  concluded  from  this  behavior  that 
they  form  a  syncytium,  which  would  mean  that  the 
individual  muscle  cells  are  interconnected  by  proto- 
plasmic bridges.  But  in  reality  they  form  a  network 
in  which  every  muscle  fibril  is  surrounded  by  its  own 
membrane,  so  that  there  are  double  membranes  at 
places  where  the  cells  are  in  contact  with  each  other 
[see  Prosser  (68)].  This  network  acts  like  a  functional 
"syncytium,"  since  an  excitation  can  be  conducted 
over  the  double  membranes.  This  double  membrane 
has  a  high  resistance,  and  therefore  the  conduction  in 
smooth  muscles  is  much  slower  than  that  in  nerve 
fibers.  The  conduction  can  be  propagated  over  the 
whole  organ,  as  in  the  uterus  or  the  ureter  (single-unit 
smooth  muscles),  or  it  can  be  limited  to  a  certain  area, 
as  in  the  intestine  [Bozler  (16),  Greven  (35),  Biilbring 
(17)].  The  limitation  results  from  the  presence  of  a 
higher  resistance  of  the  double  membranes  at  certain 
places.  The  resistance  can  be  changed  so  that  the  area 
which  responds  to  a  stimulus  can  be  increased  or 
decreased.  Another  characteristic  of  the  syncytium 
is  its  response  to  stretch  [Biilbring  (17)].  If  smooth 
muscles  of  the  intestine  are  stretched,  the  membrane 
depolarizes  and  spikes  are  produced  (fig.  4).  Contrac- 
tion occurs  and  tension  rises  in  direct  proportion  to  the 
increase  in  spike  frequency.  But  in  addition  to  having 
independent  conductivity  and  excitability,  smooth 
muscles  also  receive  innervation  from  both  the  sympa- 
thetic and  parasympathetic  nerve  system.  There  are 
ganglion  cells  around  the  adventitia  [Leontowitsch 
(55)]  and  nerve  fibers  in  the  media  [Boeke  (15)]  of  the 


56- 
mv 
54 

52- 

A 

/ 

vWv 

48- 
46- 

r 

Resting      Potential 

A    /•     * 

.      ,            <}     tx         a     "00             d-o 

'                                                         d 
,       a        1                               o-cr 
;           "3     ;     Spike     Frequency 

7-5- 

g 

\  6-6 

1           \     /    Tension 

7-0 

6-5  + 

1           1 

M  IN 

15 

o 

uu 

1/1 
IO  p 

— 
in 

c       111 


O  2  4  6  8 

fig.  4.  Graph  showing  correlation  between  membrane 
potentials,  spike  frequency,  and  tension  during  spontaneous 
pendular  rhythm  recorded  for  10  min.  [Biilbring  (17).] 

blood  vessels  [see  also  Staubesand  (87)].  The  auto- 
nomic nervous  system  can  change  the  spontaneous 
activity  of  the  smooth  muscles  by  changing  their 
membrane  potentials. 

In  addition  to  the  syncytium-like  smooth  muscles, 
there  are  also  multiple-unit  smooth  muscles  which  are 
neither  self-conducting  nor  spontaneously  active.  They 
receive  extensive  innervation  and  appear  to  be  or- 
ganized in  some  tvpe  of  motor-unit  plan  [see  Prosser 
(68)]. 

Little  work  has  been  done  on  the  problem  of  the 
excitation  and  conduction  of  vascular  smooth  muscle. 
Therefore  it  is  hard  to  say  whether  it  represents  a 
multiple-unit  system  or  a  syncytium.  Monnier  (62) 
has  shown  that  the  conduction  of  excitation  in  the 
mesenteric  artery  of  cattle  (an  artery  of  the  muscular 
type)  is  very  slow  (only  about  2  mm/sec).  This  is 
much  slower  than  the  conduction  of  any  known  nerve, 
and  in  a  range  similar  to  other  syncytium-like  smooth 
muscles  [see  Biilbring  (17)].  The  mesenteric  artery 
also  responds  to  stretch  with  a  contraction.  It  may  be 
assumed  therefore  that  the  muscles  in  the  peripheral 
arteries  behave  as  a  syncytium.  This  is  likely,  in  view 
of  the  relationship  of  blood  pressure  to  flow.  For  in- 
stance, Thurau  &  Kramer  (91)  have  shown  that  the 
flow  in  the  kidney  becomes  constant  if  the  pressure  is 
raised  above  90  mm  Hg.  This  special  flow-pressure 
relationship  is  due  to  an  increase  of  resistance,  effected 
by  contraction  of  the  smooth  muscles  in  the  pre- 
glomerular  arteries.  Similar  behavior  in  the  arteries  of 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


87  ■ 


the  extremities  is  reported  by  Folkow  (26).  This  idea 
has  a  long  history,  beginning  with  the  contribution  of 
Bayliss  (9)  in  1902. 

It  may  be  assumed  that  the  contraction  of  smooth 
muscle  is  caused  by  the  increase  of  tension  in  the 
vascular  wall  as  a  result  of  the  rising  blood  pressure. 
There  is  no  adaptation  to  the  tension  stimulus,  which 
agrees  with  the  results  of  Bulbring  (17)  on  the  in- 
testinal smooth  muscle.  Folkow  (28)  suggests  that  the 
tonus  of  the  resistance  vessels  is  maintained  by  myo- 
genic activity  of  their  smooth  muscles,  which  are 
excited  by  the  tension  of  the  wall  (similar  to  the  case 
for  intestinal  smooth  muscles  shown  in  fig.  4).  How- 
ever, this  autoactivity,  in  both  types  of  smooth 
muscle,  is  controlled  by  the  autonomic  nervous  system. 
Since  the  smooth  muscles  in  the  peripheral  arteries  are 
mostly  ring  muscles,  it  may  be  that  the  ring  muscles 
can  behave  like  a  syncytium.  The  tension  muscles  are 
always  interrupted  by  elastic  fibers,  and  Prosser  et  al. 
(69)  have  found  a  much  larger  intercellular  distance 
between  the  individual  muscle  cells  in  vessels  of  the 
elastic  type  than  in  other  organs  (1000  nm  in  the  pig 
carotid  artery  as  against  120  nm  in  the  cat  intestine). 
It  is  therefore  very  likely  that  they  form  a  multiunit 
system  in  which  the  muscle  cells  receive  extensive 
sympathetic  and  parasympathetic  innervation.  This 
impression  is  confirmed  by  Burnstock  &  Prosser  (18), 
who  got  no  response  to  stretch  from  the  carotid  artery, 
a  vessel  of  the  elastic  type,  or  from  the  renal  vein. 

Over  and  over  the  idea  appears  in  the  literature  that 
arteries  may  contract  and  relax  as  quickly  as  the 
heart  and  so  force  the  blood  to  the  periphery  just  as 
the  intestine  propels  a  bolus  to  the  colon.  One  of  its 
newer  proponents,  Dickinson  (22),  shows  a  contrac- 
tion curve  of  a  sheep's  hepatic  artery  which  develops 
its  peak  tension  in  about  3  sec  after  an  unphysiological 
stimulus  of  120  v.  The  slowness  of  contraction  and  the 
long  latency  speak  against  the  possiblity  of  the  propul- 
sion of  blood  by  arterial  contraction.  This  latter 
attitude  is  shared  by  Fleisch  (25)  and  Wetterer  & 
Kapal  (99). 

If  smooth  muscles  are  extended  slowly  they  behave 
like  a  plastic  material.  They  can  maintain  a  given 
length,  either  short  or  long,  for  protracted  periods 
with  very  low  metabolism.  However,  this  length 
maintenance  does  depend  upon  repeated  stimulations 
of  constant  magnitude.  If  the  stimulation  is  increased, 
these  muscles  respond  by  contracting,  regardless  of 
their  initial  length  (except,  of  course,  if  already  maxi- 
mally contracted).  From  this  it  follows  that  there  must 
be  some  mechanism  which  enables  smooth  muscle  to 
shift  its  behavior  from  plastic  when  "set"  in  length  to 


visco-elastic,  when  contracting.  Uxkiill  (93)  has  postu- 
lated for  this  a  "Sperrung"  (catch  mechanism), 
signifying  that  the  protein  filaments  within  the  muscle 
fibers  "catch"  at  a  certain  length  so  that  they  cannot 
slip  apart  when  tension  is  applied. 

Three  possible  explanations  have  been  offered  for 
this  behavior.  The  first,  suggested  by  Reichel,  is  that 
the  smooth  muscle  consists  of  two  elements  in  series, 
an  elastic  element  and  a  contractile  element,  where 
the  contractile  element  can  behave  with  either 
plasticity  or  contractility  (70).  If  this  is  true,  the 
"catch  mechanism"  could  be  described  as  a  trans- 
formation of  plasticity  to  contractility,  where  the 
element  is  "caught"  at  any  length  and  thus  is  able  to 
keep  a  given  tension  with  a  low  metabolism  or  to 
contract.  An  alternative  to  this  theory,  suggested  by 
Lowy  &  Hanson  (56a),  is  called  the  sliding  filament 
mechanism.  They  assume  that  thin  discontinuous 
actin-containing  filaments  move  relative  to  thick 
discontinuous  paramyosin-containing  filaments,  as  in 
striated  muscles.  Linkages  are  presumably  formed 
during  contraction  between  both  filaments  all  of  one 
type,  with  one  rate  of  formation.  The  rate  of  breaking 
can  vary  from  slow  (tonic  contraction,  visco-elastic) 
to  fast  (phasic  contraction,  plastic)  depending  on  the 
concentration  of  a  relaxant  present  (i.e.,  5-hydrox- 
ytryptamine).  Repeated  excitatory  stimulation  could 
maintain  these  linkages,  whereas  stimulation  of 
inhibitory  nerves  could  increase  the  rate  at  which  they 
break  [Lowy  &  Millman  (57)].  A  second  possibility 
is  that  the  plastic  and  the  contractile  elements  are  in 
parallel,  with  an  elastic  element  in  series.  In  such  an 
arrangement  the  catch  mechanism  could  be  in  the 
plastic  element,  whereas  the  contractile  element 
could  cancel  any  plastic  deformation  by  contraction. 
Such  a  parallel  arrangement  is  postulated  by  Johnson 
(41a).  He  assumes  that  the  contractile  system  is 
formed  by  the  actomyosin,  and  that  paramyosin  is 
situated  parallel  to  it  as  the  plastic  element.  Laszt 
(54)  assumes  a  similar  mechanism  in  the  vascular 
smoothVmuscle.  A  third  possibility  is  that  the  plastic 
and  contractile  elements  are  in  series.  In  such  an 
arrangement  the  contractile  element  could  work 
only  if  the  catch  mechanism  were  put  in  action. 
But  it  would  then  be  necessary  to  have  a  special 
mechanism  to  cancel  the  plastic  deformation,  such  as 
the  presence  of  both  fast  and  slow  contractile  elements 
within  the  smooth  muscle,  the  slow  elements  being 
virtually  "plastic." 

Whether  any  of  these  three  mechanisms  may  be 
the  real  one  is  not  clear.  It  is  possible,  too,  that  one 
smooth  muscle  may  work  by  one  mechanism   and 


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CIRCULATION    II 


FIG.  5.  Average  stress-relaxation 
curves  of  carotid  and  umbilical  arteries. 
Vertical  coordinate  is  given  in  per- 
centage of  total  pressure  rise,  following 
injection.  Upper  curve,  common  carotid 
artery  of  the  dog.  Lower  curve:  umbilical 
artery  of  the  human.  [Zatzman  el  al. 
(103).] 


OO  - 


80 


6O- 


40-x 


20- 


Secorid  t 


others  by  another,  since,  for  example,  the  uterus  and 
the  bladder  are  very  different  in  properties  and  action 
[Bader  (3)]. 

If  a  smooth  muscle  is  stretched  quickly  to  a  certain 
length,  it  will  show  a  tension  increase.  If  this  length 
is  held  for  a  longer  time,  the  tension  will  decrease,  at 
first  quickly,  later  more  slowly.  This  typical  stress 
relaxation  is  a  result  of  the  visco-elasticity  of  the 
smooth  muscle,  which  may  be  due  to  breaking  of 
the  linkages  within  the  myofilaments.  A  typical 
stress-relaxation  curve  of  smooth  muscles  is  like 
that  of  the  lower  curve  of  figure  5.  For  further 
details  of  the  mechanical  properties  of  muscles,  see 
Reichel    (71). 

If  these  mechanical  properties  of  smooth  muscles 
are  to  be  compared  with  those  of  the  vascular  wall, 
one  must  keep  in  mind  the  modifying  effects  of  col- 
lagen and  elastic  tissue  [Remington  (73)].  Another 
point  is  that  most  of  the  experiments  with  smooth 
muscles  are  made  on  organs  other  than  blood  vessels, 
in  vitro,  and  without  innervation.  Smooth  muscles 
in  vivo  are  under  a  continuous  stimulation,  and  they 
are  also  under  constant  contraction  and  tension  in  the 
vascular  wall.  It  is  therefore  very  likely  that  the 
smooth  muscles  of  the  vessel  wall  in  vivo  would  show 
different  visco-elastic  and  plastic  behavior  from  those 
found   during   in   vitro   experiments. 

Zatzman  et  al.  (103)  have  shown  that  there  is  a 
great  difference  in  the  stress-relaxation  behavior  of 
the  elastic  carotid  artery  and  the  muscular  umbilical 
artery.  After  10  sec  of  stress,  relaxation  of  the  carotid 
artery  amounts  to  about  20  per  cent  of  the  original 
tension,  whereas  in  the  umbilical  artery  it  is  about  95 
per  cent  (fig.  5).  This  indicates  that  in  the  umbilical 
artery  the  tension  is  applied  mostly  to  smooth  muscle 
with  its  large  visco-elasticity  and  plasticity.  It  is  not 
easy  to  say  to  what  degree  smooth  muscle  is  respon- 


sible for  the  relaxation  of  the  carotid  artery,  since 
elastic  and  collagen  tissues  may  each  have  both  a 
visco-elastic  component  (hysteresis  loop  during  stretch 
cycle)  and  a  plastic  component  [irreversible  elonga- 
tion (table  1)].  This  passive  behavior  is  responsible 
in  part  for  the  stress  relaxation  of  elastic  arteries 
[see  Kapal  (42)]. 

Smooth  muscle  tissue  degenerates  and  decreases  in 
amount  with  age,  and  is  replaced  by  collagen  fibers 
[Meyer  (58),  Kobayashi  (46)].  This  tends  to  render 
the  arterial  tree  more  rigid  and  to  explain  the  systolic 
hypertension  of  old  age.  The  high  systolic  pressure  in 
this  condition  puts  an  extra  burden  on  the  heart. 
[See  Bader  &  Kapal  (5)  and  the  paragraphs  on  elastic 
arteries  below.] 

Smooth  muscles  have  the  ability  to  regenerate. 
For  example,  Petry  &  Heberer  (67)  have  described 
cell  formations  which  are  found  on  the  inside  of  aortic 
grafts  some  weeks  after  implantation.  These  cells  seem 
to  be  muscle  cells,  and  are  assumed  to  originate  from 
fibroblasts. 


DIFFERENT  TYPES  OF  VESSELS 

Vessels  differ  in  their  architectural  structure  and 
their  behavior  according  to  their  varied  tasks.  There 
are,  in  general,  four  different  vessel  types:  on  the 
arterial  side  are  elastic  arteries  and  muscular  arteries, 
but  it  is  hard  to  say  where  the  one  ends  and  the  other 
begins,  since  the  structural  changes  are  gradual. 
Usually  the  aorta,  the  pulmonary  artery,  the  common 
carotid  artery,  the  subclavian  artery,  and  the  common 
iliac  artery  are  regarded  as  elastic  arteries.  Arteries 
more  peripheral  than  the  above,  down  to  the  ar- 
terioles, are  classed  as  muscular  arteries.  After  these 
are  the  capillaries,  which  consist  mostly  of  endothe- 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


873 


lium.  Then  there  are  veins,  which  are  built  to  some 
extent  like  the  arteries.  The  most  striking  difference 
between  them  is  their  mounting,  for  most  arteries 
have  a  slack  connection  with  the  surrounding  tissues, 
whereas  the  veins  are  more  intimately  bound  up  with 
the  surrounding  tissues  to  make  a  functional  svstem. 


Arteries  of  the  Elastic  Type 

The  wall  of  the  elastic  arteries  is  characterized  by 
a  high  percentage  of  elastic  tissue  (fig.  1),  which  may 
be  40  per  cent  of  the  wall  in  the  thoracic  aorta,  but 
decreases  toward  the  periphery.  The  elastic  tissue 
is  mostly  present  as  fenestrated  membranes — up  to 
50  membranes  located  one  upon  the  other.  There 
are  also  star-shaped  membranes  in  the  wall  of  the 
pulmonary  artery  [Meyer  (59)].  There  is  a  network  of 
elastic  fibers  between  all  these  membranes.  The 
membranes  are  connected  by  smooth  muscles,  the 
tension  muscles,  described  by  Benninghoff  (10,  11). 
These  tension  muscles  use  the  elastic  membranes  as 
footholds  (fig.  3).  There  are  no  ring  muscles  in  the 
thoracic  aorta,  but  they  appear  in  increasing  numbers 
in  the  more  peripheral  arteries.  Where  the  ring  mus- 
cles exceed  the  tension  muscles  in  amount  the  arteries 
are  called  muscular  arteries.  The  collagen  fibers  are 
distributed  over  the  entire  wall.  They  lie  there  in 
wavy  bundles,  which  become  straight  if  the  blood 
pressure  rises  over  the  normal  mean  value  [Reuter- 
wall  (74)]. 

The  large  amount  of  elastic  tissue  and  looseness  of 
the  collagen  fibers  give  elastic  arteries  high  disten- 
sibility.  For  instance,  the  aorta  can  be  distended  to  a 
threefold  increase  in  contained  volume  over  that  at 


300 


ZOO 


fig.  6.  Pressure-volume  diagram  of  the  thoracic  aorta  of 
the  pig.  a:  Extension  curve  made  shortly  after  sacrificing. 
The  aorta  was  stimulated  with  epinephrine,  b:  Extension 
curve  made  8  days  later.  Smooth  muscles  were  dead.  [Bader  & 
Kapal  (5).] 


zero  pressure.  This  high  distensibility  enables  an 
elastic  vessel  to  act  as  would  an  air  chamber  (Wind- 
kessel).  The  aorta  contributes  over  50  per  cent  to  the 
total  vascular  air  chamber  action  [Wetterer  (98)].  If 
an  elastic  artery  is  stretched,  it  shows  a  typical  S- 
shaped  pressure-volume  diagram,  like  that  in  figure 
6  where  "static"  stretch  curves  are  given  for  the 
thoracic  aorta  of  a  pig.  [See  Chapters  7  and  24  for 
the  explanation  of  the  typical  S-shaped  pressure- 
volume  diagram  of  elastic  arteries  and  its  relation 
to  the  tension-length  diagram.  [See  also  Frank  (30, 
31).]  A  similar  S-shaped  curve  may  be  obtained  from 
a  rubber  tube  within  a  nylon  tube,  where  the  nylon 
tube  serves  as  a  "jacket"  [Bader  &  Kapal  (6)].  In 
such  a  pressure-volume  diagram  the  rubber  tube  is 
responsible  for  the  curve  below  the  inflexion  point 
and  which  appears  concave  to  the  abscissa;  the  nylon 
jacket  for  the  convex  part  above  the  inflexion  point. 
This  fact,  together  with  the  finding  of  Reuterwall  (74) 
that  when  elastic  tissue  becomes  straight  collagen 
tissue  is  still  wavy  (i.e.,  still  relatively  unstretched) 
and  the  study  of  Roach  &  Burton  (75)  which  in- 
volved differential  digestion  of  collagen  and  elastic 
fibers  of  the  iliac  artery,  indicates  that  the  part  of  the 
pressure-volume  diagram  from  zero  pressure  to  the 
inflexion  point  reflects  the  extension  of  elastic  tissue, 
whereas  the  part  above  the  inflexion  point  is  due  to 
the  collagen  tissue  [see  Bader  &  Kapal  (7)]. 

The  upper  curve  of  figure  6  is  derived  from  a  stretch 
curve  made  shortly  after  death,  after  the  aorta  was 
stimulated  with  epinephrine;  the  lower  curve  was 
made  8  days  later  when  the  smooth  muscles  were  dead. 
Schonenberger  &  Miiller  (83)  got  similar  results  on 
cow  aortas  with  dynamic  stretches.  Millahn  &  Jaster 
(61)  stretched  pig  and  cow  aortas  after  relaxing  the 
smooth  muscles  with  acetylcholine,  finding  that  the 
stretch  curve  lay  below  the  curve  given  by  the  stimu- 
lated vessel.  The  pressure-volume  diagram  can  shift 
to  higher  or  lower  pressures  depending  on  the  con- 
tractile state  of  the  smooth  muscle,  but  the  shape  of 
the  curve  never  changes.  This  proves  that  smooth 
muscles  can  increase  the  wall  tension  without  chang- 
ing the  elastic  properties  of  the  vessel,  a  finding  which 
Benninghoff  (10,  11)  had  proposed  as  a  result  of  his 
microscopic  studies.  Bader  &  Kapal  (5)  concluded 
from  their  experiments  that  smooth  muscle  can  be 
arranged  neither  in  series  with  the  elastic  elements 
nor  in  parallel.  Both  arrangements  would  give,  with 
stimulation,  not  only  a  shift  of  the  stretch  curve  to 
higher  pressures,  but  also  a  change  of  the  shape  of 
the  curve. 

Since  the  tension  muscles  are  attached  to  the  elastic 


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CIRCULATION    II 


© 


fig.  7.  Model  for  the  arrangement  of  tension  muscles  and 
elastic  tissue.  Stretch  in  vertical  direction,  a:  Tension  muscles 
relaxed;  b:  tension  muscles  contracted.  [Kapal  &   Bader   (43).] 


fig.  7A.  Baroceptor  in  the  adventitia  of  the  human  aortic 
ar<  li  a:  End  fiber  of  the  aortic  depressor  nerve;  b:  network; 
c:  end  network;  d:  neurofibrils.  Method  after  Biclschowsky. 
X    1100.   [Abraham   (1).] 

membranes,  and  the  contraction  of  the  smooth  mus- 
cles seems  to  influence  only  the  part  of  the  curve 
which  is  ascribed  to  the  extension  of  elastic  tissue, 
Kapal  &  Bader  (43)  have  designed  a  model  which  is 
similar  to  an  arrangement  which  Burton  (20)  had 
published  in  1953  in  his  highly  stimulating  review 
article.  It  shows  the  action  of  the  tension  muscles  in 
elastic  arteries. 

In  figure  ~ja  the  smooth  muscles  are  relaxed;  in 
yb,  thev  are  contracted.  The  smooth  muscles  fasten 


on  the  elastic  fibers  or  membranes  at  right  angles  to 
the  direction  in  which  the  elastic  fibers  are  stretched. 
These  fibers  become  elongated  by  contraction  of  the 
smootli  muscles,  but  the  circumference  of  the  vessel 
is  not  changed  (fig.  jb).  The  consequence  is  a  rise 
in  the  tension  of  the  elastic  fibers.  Since  the  model  will 
be  involved  in  a  stretch  in  the  direction  of  the  elastic 
fibers,  the  tension  muscles  do  not  need  to  develop 
tension  as  great  as  the  total  wall  tension,  but  can 
increase  the  stress  on  the  elastic  tissue  with  relatively 
little  work. 

This  model  has  an  advantage  to  neurophysiologists 
as  well  as  to  muscle  physiologists.  Heymans  &  Delau- 
nois  (37)  have  shown  that  the  blood  pressure  decreases 
if  the  smooth  muscles  of  the  carotid  sinus  are  stimu- 
lated by  noradrenalin.  Heymans  et  al.  (38)  obtained 
the  same  results  by  elongating  the  carotid  sinus.  They 
concluded  from  these  experiments  that  the  pres- 
soreceptors located  in  the  carotid  sinus,  which  cause  a 
decrease  of  the  mean  blood  pressure  after  stimulation, 
do  not  respond  to  the  blood  pressure,  but  rather  to  the 
wall  tension  [see  Heymans  &  van  den  Heuvel-Hey- 
mans  (39)].  It  is  very  likely  that  the  pressoreceptors 
situated  in  the  aorta  work  in  the  same  way. 

The  pressoreceptors  appear  as  a  very  fine  network 
of  neurofibrils  (fig.  J  A).  They  are  mainly  located  in 
the  adventitia  of  the  carotid  sinus  [Sunder-Plassmann 
(89)]  and  in  the  adventitia  and  the  outer  part  of  the 
media  of  the  aortic  arch  [Seto  (85)].  Stohr  (88)  has 
the  impression  that  this  network  of  neurofibrils  shown 
in  figure  yA  may  be  only  a  part  of  the  whole 
neurofibril  mass  of  which  the  pressoreceptor  is 
constituted.  He  assumes  that  smaller  fibrils  exist  but 
are  not  visible  because  of  limitations  in  the  staining 
method  and  in  the  optical  properties  of  the  light 
microscope. 

There  are  very  few  clues  as  to  how  the  network  of 
the  pressoreceptor  is  related  to  the  surrounding  tissue. 
Sunder-Plassmann  (89)  has  shown  that  the  media  of 
the  carotid  sinus  is  thinner  than  that  of  the  nearby 
vessel,  but  the  membrana  elastica  externa  is  thickened. 
The  elastica  externa  in  the  carotid  sinus  shows  a 
sharp  boundary  separating  it  from  the  media,  but  a 
more  gradual  merging  with  the  adventitia.  In  this 
diffuse  zone,  which  shows  collagen  fibers  and  large 
elastic  membranes,  the  pressoreceptors  of  the  carotid 
sinus  are  located,  and  the  neurofibril  networks  show 
a  certain  degree  of  adaptation  to  the  shape  of  the 
connective  tissue.  Abraham  (1)  describes  the  neuro- 
fibril networks  of  the  aortic  arch  as  nestling  flat 
against  the  vessel  wall.  Their  position  follows  the  direc- 
tion of  the  fibrous  elements. 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


87: 


It  may  very  likely  be  that  in  both  the  carotid  sinus 
and  the  aortic  arch,  the  neurofibril  networks  of  the 
pressoreceptors  are  in  one  way  or  another  attached 
to  the  connective  tissue,  especially  the  elastic  mem- 
branes or  fibers.  Thus  the  pressoreceptors  are  assumed 
to  be  parallel  to  the  elastic  membranes  or  fibers,  an 
assumption  which  agrees  with  the  facts  now  available. 
They  will  be  stimulated  if  the  smooth  muscles  increase 
the  tension  of  the  elastic  tissue  by  contraction.  But 
now  the  stimulated  pressoreceptors  reflexly  lower  the 
blood  pressure  until  the  tension  of  the  elastic  fibers, 
and  with  them  that  of  the  pressoreceptors,  decreases 
again  to  the  normal  value  (equation  1).  The  tension 
muscles  are  thus  able  to  change  the  blood  pressure, 
as  shown  in  the  work  of  Bader  &  Kapal  (5).  The 
model  of  Kapal  &  Bader  (43),  and  the  results  of 
Heymans  et  al.  (37-39)  agree  very  well.  It  also  fits  very 
well  with  the  idea  that  the  tension  muscles  are  mul- 
tiple-unit muscles,  since  they  are  a  type  of  control 
organ  which  does  not  depend  on  the  wall  tension. 

The  model  may  also  explain  the  higher  resistance 
and  blood  pressure  of  older  people  in  contrast  to 
younger  people.  Smooth  muscles  degenerate  with  age 
and  are  replaced  by  collagen  fibers  [Meyer  (58), 
Kobayashi  (46)].  This  means  that  the  smooth  muscles 
are  no  longer  able  to  stretch  the  elastic  tissue  as  much 
as  in  younger  individuals.  But  if  the  tension  of  the 
elastic  tissue  is  lowered  by  lack  of  smooth  muscle 
function,  the  blood  pressure  will  rise  until  the  tension 
reaches  a  physiological  value  for  the  pressoreceptors. 
As  the  muscles  continue  to  degenerate,  the  pressure 
needed  to  stimulate  the  receptors  continues  to  rise, 
and  this  may  be  one  of  the  various  mechanisms  which 
cause  essential  hypertension.  Such  a  hypertension 
must  be  called  "essential,"  since  the  weakness  of  the 
tension  muscles  cannot  be  diagnosed  and  there  may 
be  no  clearly  diagnostic  anatomical  change  of  the 
arterial  wall.  The  only  evident  sign  of  such  muscle 
weakness  would  be  the  hypertension. 

However,  in  the  aging  process  degeneration  of 
smooth  muscles,  fraying  of  elastic  tissue,  and  increase 
of  the  collagen  tissue  are  accompanied  by  a  decrease 
in  the  distensibility  of  the  arteries.  A  20-year-old 
aorta  can  be  distended  to  300  per  cent  of  its  zero- 
pressure  volume,  but  a  go-year-old  aorta  can  be 
distended  only  about  25  per  cent  [Simon  &  Meyer 
(86)].  If  the  inflexion  point  of  the  volume  pressure  is 
high  and  the  curve  reaches  its  slope  of  maximum 
distensibility  at  about  100  mm  Hg  (the  normal  mean 
blood  pressure)  (cf  the  13-year-old  aorta  in  fig.  8a), 
the  work  required  of  the  heart  is  reduced  in  maintain- 
ing  a   physiological   pressure  level.    If  the  inflexion 


occurs  at  a  lower  pressure  level,  as  after  an  increase 
of  collagen  tissue  (older  aortas),  the  mean  blood  pres- 
sure falls  on  a  steeper  slope  of  the  pressure-volume 
curve.  Under  this  condition  the  heart  would  have  to 
work  more  were  this  disadvantage  not  compensated 
by  enlarging  the  volume  of  the  aorta.  Figure  8a  shows 
a  fivefold  increase  in  the  volume  at  100  mm  Hg 
between  the  13-year-old  and  the  85-year-old  aorta. 
The  volume  change  of  the  elastic  chamber  with  each 
heart  beat,  that  is,  the  volume  which  can  be  injected 
to  give  the  physiological  pulse  pressure  amplitude, 
remains  nearly  constant  until  about  the  sixth  decade 
of  life,  as  a  result  of  the  initial  volume  increase.  This 
means  that  the  heart  work  need  not  increase  with  the 
decrease  of  the  wall  distensibility  [Simon  &  Meyer 
(86)].  The  aortas  over  60  years  do  not  show  any 
inflexion  point;  they  are  convex  to  the  abscissa  from 
the  very  beginning.  This  signifies  that  collagen  tissue 
is  already  stressed  near  zero  pressure.  The  pulmonary 
artery  shows  similar  behavior,  but  the  inflexion  point 
occurs  at  a  lower  pressure,  just  as  the  pulmonary 
pressure  is  lower  [Meyer  &  Simon  (60),  Frasher  & 
Sobin  (32)]. 

The  ratio  of  radius  to  wall  thickness,  which  is  im- 
portant in  the  relationship  of  the  wall  stress  to  the 
blood  pressure  (equation  1 ),  is  the  same  at  zero 
pressure    in     aortas     of    different     ages  [Hieronymi 


fig.  8.  a:  Pressure-volume  diagrams  of  the  thoracic  aorta  of 
the  human  at  different  ages,  b:  The  relationship  of  radius  to 
wall  thickness  of  the  same  aortas  in  relation  to  the  pressure. 
[Bader  (4).] 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  9.  Schematic  presentation  of  the 
behavior  of  the  different  tissues  in  the 
wall  of  elastic-type  vessels  at  different 
degrees  of  extension.  Description  in  the 
text.  [Bader  &  Kapal  (7).]  The  stretch 
is  in  the  vertical  direction.  The  S- 
shaped  line  is  the  pressure-volume 
curve  of  a  young  human  aorta. 


(40)],  but  at  100  mm  Hg  this  ratio  is  age-dependent 
(fig.  86).  It  increases  from  the  first  decade  of  life  until 
the  end  of  the  third  decade  and  decreases  from  then 
until  the  end  of  life.  The  shift  of  this  ratio,  like  the 
shift  of  the  inflexion  point,  is  caused  by  the  increase 
of  the  collagen  tissue.  The  arteries  become  more 
and  more  rigid  with  age.  A  rise  of  the  blood  pres- 
sure in  older  people  does  not  change  the  tension 
on  the  elastica,  and  thus  prevents  stimulation  of  the 
pressoreceptors.  This  indicates  that  the  regulation  of 
the  blood  pressure  of  old  people  would  become  more 
and  more  unstable  [Bader  (4)].  Since  the  decrease 
of  the  ratio  of  radius  to  wall  thickness  in  the  aging 
aorta  simultaneously  decreases  the  wall  tension  (equa- 
tion 1),  the  tension  of  the  pressoreceptors  must  also 
become  lower  and  lower.  But  this  process  may  re- 
sult in  an  increase  of  the  mean  blood  pressure  to 
get  the  pressoreceptor  again  on  the  normal  tension 
level.  A  similar  change  has  already  been  mentioned 
with  the  degeneration  of  the  tension  muscles.  But 
since  the  changes  in  smooth  muscles,  and  in  the  ratio 
of  radius  to  wall  thickness,  with  aging,  are  greater  in 
proportion  than  the  usual  increase  of  the  mean  blood 
pressure,  one  may  assume  also  a  change  in  receptor 
sensitivity. 

The  interaction  of  the  three  wall  elements  in  the 
elastic  arteries,  elastic  tissue,  collagen  tissue,  and 
smooth  muscle,  may  be  illustrated  by  the  scheme  of 
figure  9.  Sections  1  through  4  represent  different 
stretch  phases.  The  stretch  takes  place  in  vertical 
direction.  Both  halves  of  each  phase  must  be  regarded 
together.  The  element  a  represents  two  elastic  fibers 
which  are  connected  by  smooth  muscles  as  in  figure  7. 
Both  elastic  fibers  are  already  straight  at  zero  pres- 


sure. The  element  b  is  an  elastic  fiber  which  is  still 
wavy  (unstressed).  Both  a  and  b,  in  the  upper  and  the 
lower  half,  are  under  minimal  stress.  Element  c  is  a 
collagen  fiber.  In  the  upper  half  it  is  less  wavy  than 
in  the  lower  half.  Phase  2  will  be  reached  after  the 
stress  has  begun.  Element  a  is  already  stressed,  whereas 
element  b  is  just  straightened.  By  this  means  the 
recruitment  of  the  elastic  fibers  is  represented.  The 
stretch  proceeds  in  phase  3,  so  that  collagen  fibers 
are  partly  straight  and  included  in  the  stress  (upper 
half).  The  collagen  fiber  in  the  lower  half  is  still  wavy. 
Elastic  fibers  only  are  stressed  in  phases  1  and  2, 
whereas  elastic  and  collagen  fibers  are  functional  in 
series  in  phase  3.  Now  the  length  available  for  further 
stretching  of  the  elastic  fibers  is  only  half  as  much  as 
in  phases  1  and  2,  since  a  further  stretch  of  the  elastic 
fibers  in  the  upper  half  is  prevented  by  the  collagen 
fibers.  This  means  that  the  increase  in  extension,  per 
unit  rise  in  pressure,  becomes  less  and  the  pressure 
volume  diagram,  which  until  now  was  concave  to  the 
abscissa,  becomes  convex.  At  last  a  point  is  reached 
where  all  collagen  fibers  are  straight:  phase  4.  Elastic 
and  collagen  fibers  are  straight  and  parallel.  Since 
collagen  tissue  is  much  less  distensible  than  elastic 
tissue,  the  wall  distensibility  at  this  point  depends  only 
on  collagen  tissue.  This  model  illustrates  the  wall 
architecture  of  a  proximal  elastic  artery.  The  more 
peripheral  the  vessel,  the  more  the  ring  muscles 
participate  and  the  more  the  model  of  figure  g  will  be 
combined  with  the  model  of  figure  13  (see  below). 
The  effect  of  changes  with  age  in  the  arterial  wall 
can  be  illustrated  by  having  the  stretch  start  in  phase 
2,  3,  or  4.  Thus  unextensible  elements  are  put  in 
action    at    lower    pressures    than    in    young    arteries 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


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fig.  10.  Extension-release  curves  of  the 
thoracic  aorta  of  the  human  at  different  ages 
and  with  different  numbers  of  stretches.  I: 
14  years  old — (a)  4th  stretch  cycle;  (b)  100th 
stretch  cycle.  II :  63  years  old — (a)  3rd  stretch 
cycle,  (4)  15th  stretch  cycle.  [Wagner  & 
Kapal     (94).] 


[Bader  &  Kapal  (7)].  The  unextensible  fibers  might 
be  collagen  fibers  or  calcified  elastic  fibers  which  are 
under  stress  with  small  extension  of  the  arterial  wall 
[Roach  &  Burton  (76)]  or  even  with  no  extension  at 
all. 

Elastic  vessels,  like  any  tissue,  show  typical  visco- 
elastic  and  plastic  behavior.  An  extension-release  cycle 
gives  a  hysteresis  loop  which  depends  in  part  on  the 
velocity  with  which  the  stretch  was  applied  [see 
Remington  (72)].  There  is  also  a  shift,  on  repeated 
stretching,  of  the  pressure-volume  diagram  toward 
greater  volume  at  the  initial  pressure  level,  indicating 
some  plasticity.  Wagner  &  Kapal  (94)  have  found 
with  experiments  on  the  human  aorta  that  hysteresis 
is  not  only  dependent  on  the  stretch  velocity,  but  also 
on  the  age  of  the  vessel  (fig.  10).  It  becomes  smaller, 
the  older  the  vessel  is.  The  same  effect  appears  if  an 
aorta  is  stretched  repeatedly.  The  more  frequently 
the  artery  is  stretched,  the  smaller  is  the  hysteresis. 
The  hysteresis  is  greater  above  the  inflexion  point  of 
the  pressure- volume  curve  than  below  [Wagner  & 
Kapal  (94)]. 

In  large  elastic  vessels,  contraction  of  smooth 
muscles  does  not  influence  the  hysteresis  [Remington 
(72)].  Kapal  (42)  has  shown  that  the  aorta  responds 
to  dynamic  stresses  as  would  collagen  and  elastic 
tissue,  but  not  like  smooth  muscle.  Therefore,  it  seems 
that  the  visco-elastic  and  plastic  behavior  of  elastic 
arteries  depends  mostly  on  elastic  tissue,  collagen 
tissue,  and  ground  substance,  but  only  to  a  small 
degree  on  smooth  muscles.  This  is  confirmed  by  the 


curves  of  figures  6  and  the  model  in  figure  7,  where 
smooth  muscles  do  not  affect  the  mechanical  prop- 
erties of  the  vessel  (see  also  fig.  5).  However,  in  the 
more  peripheral  vessels  the  increasingly  plentiful  ring 
muscles  have  a  correspondingly  greater  effect  on  visco- 
elastic  behavior  [see  Peterson  et  al.  (66),  Bergel  (12, 
13)].  The  greater  elastic  incompleteness  of  collagen 
fibers,  as  compared  to  elastic  fibers  (see  table  1), 
agrees  very  well  with  the  larger  hysteresis  in  the  upper, 
collagen-dependent  part  of  the  pressure-volume 
diagram.  But  with  both  collagen  and  elastic  tissue, 
the  elastic  incompleteness  seems  to  diminish  as  more 
stretch  cycles  are  made.  The  similarity  between 
decrease  of  the  hysteresis  with  age  and  with  repeated 
cycles  has  led  to  the  assumption  that,  as  a  result  of 
their  elastic  incompleteness,  the  vessels  are  distended 
more  and  more  by  the  pulse  pressure  during  their 
life,  until  they  reach  a  stable  state,  eliminating  the 
visco-elastic  and  plastic  elements  [Wagner  &  Kapal 
(94)]- 

Vessels  of  the  Muscular  Type 

The  more  peripherally  the  arteries  are  located,  the 
higher  is  the  percentage  of  smooth  muscles  in  the  wall 
(fig.  1).  In  elastic  arteries  one  cannot  distinguish  easily 
between  intima,  media,  and  adventitia,  whereas  in 
muscular  arteries  there  is  a  clear  separation  of  these 
layers.  The  media  consists  mostly  of  smooth  muscles, 
the  ring  muscles.  Between  them  are  collagen  and 
elastic  fibers.  The  elastic  membranes,  typical  for  the 


878 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


o 
o 


fig.  10A :  Longitudinal  muscles  in  the  intima  of  the  branches 
of  the  bronchia]  artery.  Schematic  presentation  of  their  differ- 
ent arrangements.  [Weibel  (97).] 


elastic  vessels,  are  concentrated  in  the  elastica  interna, 
which  separates  the  intima  from  the  media,  and  in 
the  elastica  externa,  which  separates  the  media  from 
the  adventitia.  Attached  to  these  membranes  are  the 
tension  muscles,  but  they  account  for  but  a  small  per- 
centage of  the  total  vascular  smooth  muscles  [Ben- 
ninghoff  (10,  11)].  The  ring  muscles  are  arranged  in 
the  wall  in  a  helical  structure  [Schultze-Jena  (84), 
Fischer  (23)]. 

Arteries  which  are  frequently  extended  in  the 
longitudinal  direction,  like  the  branches  of  the  bron- 
chial artery  of  the  lung,  possess  longitudinal  muscles 
in  addition  to  the  ring  muscles  [Weibel  (96)].  These 
longitudinal  muscles  are  situated  in  the  split  mem- 
brana  elastica  interna  and  can  be  arranged  either  in 
fairly  thick  one-sided  bundles,  or  as  concentric  shells 
which  surround  the  whole  lumen   (fig.   10A). 

The  mechanical  behavior  changes  in  the  same  way 
as  the  anatomical  picture,  smooth  muscle  forming 
the  major  support  of  muscular  arteries,  elastic  tissue 
of  elastic  arteries.  In  contrast  to  the  elastic  vessels, 
the  muscular  arteries  can  change  their  radius  over  a 
wide  range.  The  smallest  vessels,  like  the  arterioles 
and  the  precapillary  sphincters,  can  even  close  their 
lumens  completely.  Figure  1 1  shows  pressure-diame- 


fig.  1 1  :  Pressure-diameter  diagrams  of  a  small  branch  of  the 
mesenteric  artery  of  the  horse — a:  1st  stretch  cycle;  b:  2nd 
stretch  cvcle;  c:  6th  stretch  cycle.  [After  Wezler  &  Schliiter 
(100).] 


fig.  i  2  :  Pressure-volume  diagrams  of  the  vessels  of  the  hand : 
an  in  vivo  experiment,  a-  Temperature  in  the  plethysmograph : 
25.5  C  (vessels  contracted);  b:  temperature  31.5  C  (vessels 
normal);  c:  temperature  36.0  C  (vessels  relaxed).  [After  Thron 
et  al.   (90).] 

ter  diagrams  of  a  small  branch  of  the  mesenteric 
artery  of  the  horse  [Wezler  &  Schliiter  (100)].  Six 
extension-release  curves  are  made  successively,  the 
first,  second,  and  sixth  being  shown.  During  the  first 
stretch  cycle  the  smooth  muscles  are  assumed  to  be 
contracted,  during  the  following  cycles  they  are  more 
and  more  relaxed.  The  first  extension-release  curve 
shows  a  large  hysteresis,  where  the  extension  curve  is 
concave  to  the  abscissa  and  the  release  curve  is  con- 
vex. This  indicates  a  very  large  visco-elasticity  of  the 
vessel  wall,  and  very  different  behavior  from  that  of 
elastic-type  vessels  for  which  the  extension  and  the 
release  curves  have  a  similar  shape.  Later  extension- 
release  cycles  show  smaller  hysteresis,  and  the  exten- 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


879 


n 


fig.  13.  Schematic  presentation  of 
the  behavior  of  the  different  tissues  in 
the  wall  of  muscular  vessels  with  differ- 
ent degrees  of  extension.  Description 
in  the  text.  [After  Wezler  &  Schliiter 
(.00).] 


sion  curves  also  become  convex  to  the  abscissa. 
Schliiter  &  Wezler  (80)  have  described  other  curves 
where  the  first  extension  curve  had  an  S-shape  or  was 
convex  to  the  abscissa.  In  all  these  cases  the  shape  of 
the  diagram  seems  to  depend  very  much  on  the  state 
of  contraction  of  the  smooth  muscles.  The  extension 
diagram  will  be  concave  to  the  abscissa  if  the  smooth 
muscles  are  contracted,  and  the  slope  of  the  curve 
will  be  steeper  the  stronger  the  contraction.  If  the 
smooth  muscles  are  less  contracted,  the  extension 
curve  will  show  an  S-shape  or  be  concave  to  the 
abscissa.  The  whole  diagram  moves  with  frequent 
stretches  to  larger  diameters  or  volumes,  but  comes 
back  to  the  original  place  if  the  smooth  muscles  are 
stimulated.  Thron  et  al.  (90)  obtained  similar  results 
in  vivo.  Figure  12  shows  plethysmographically  ob- 
tained pressure-volume  diagrams  of  the  human  hand 
vessels  at  different  states  of  contraction  of  the  vascular 
muscles,  due  to  different  temperatures.  The  extension 
curve  of  the  constricted  vessels  (a)  is  nearly  straight 
and  is  followed  during  release  by  a  large  hysteresis. 
The  less  constricted  vessels  have  less  hysteresis  with 
both  distention  and  release  convex  to  the  abscissa. 
This  agrees  very  well  with  the  diagrams  of  Wezler  & 
Schliiter  (100),  which  were  made  in  vitro  (fig.  1 1). 

The  diagrams  shown  in  figures  1 1  and  1 2  are  in 
many  ways  different  from  the  diagrams  in  figures  6, 
8,  and  10,  which  were  made  from  the  elastic  aorta. 
The  most  striking  differences  are:  first,  the  shape  of 
the  aortic  diagram  remains  the  same  whether  the 
smooth  muscles  are  contracted  or  relaxed;  second, 
the  hysteresis  of  the  elastic  vessels  is  smaller  than  that 
of  the  muscular  vessels.  This  indicates  that  the  ar- 
rangement of  the  different  wall  elements  must  differ  in 
the  two  types  of  vessels.  The  smooth  muscles,  which 
play  only  a  minor  role  in  the  elastic  vessels,  take  a 
major  one  in  the  stretch  curve  of  muscular  vessels. 
Wezler  &  Schliiter  (100)  have  designed  a  model  which 
may  give  the  action  of  the  three  wall  elements  and  in 


different  contracted  states.  This  model  is  shown  (sim- 
plified) in  figure  13.  It  is  distinguished  from  the 
model  in  figure  9  by  the  parallel  arrangement  of  the 
smooth  muscles  to  the  other  elements.  Sections  1 
through  3  represent,  as  in  figure  9,  different  stretch 
phases.  The  stretch  takes  place  in  the  vertical  direc- 
tion. The  element  a  represents  an  elastic  fiber,  the 
two  elements  b  are  smooth  muscles,  w-here  the  in- 
dividual muscle  fibers  are  in  series,  and  element  c  is 
a  collagen  fiber.  Both  the  elastic  and  the  collagen 
fibers  are  wavy  (unstressed)  in  phase  1.  At  the  begin- 
ning of  the  stretch,  near  zero  pressure,  only  the  smooth 
muscles  bear  the  stress.  If  the  muscle  fibers  are  con- 
tracted the  slope  of  the  pressure-volume  diagram 
will  be  steep  in  the  beginning  and  concave  to  the 
volume  abscissa.  Since  the  contracted  smooth  muscles 
behave  in  general  like  a  visco-elastic  material,  the 
pressure-volume  diagram  will  show  prominent  hys- 
teresis as  described  in  figure  o.b.  If  the  muscle  fibers 
are  relaxed,  the  slope  of  the  pressure-volume  diagram 
will  be  flatter.  As  extension  proceeds,  phase  2  will  be 
reached,  in  which  the  elastic  fibers  are  straightened. 
This  will  be  at  a  higher  pressure  if  the  muscles  are 
contracted  than  if  they  are  relaxed.  Finally,  the 
collagen  fibers  are  involved  in  the  stretch  (phase  3). 
If  the  smooth  muscles  are  in  strong  contraction,  the 
whole  diagram  within  physiological  pressure  limits 
is  concave  to  the  volume  abscissa.  If  the  contraction 
is  less,  the  elastic  and  collagen  fibers  come  into  play 
at  lower  pressures  and  the  pressure-volume  diagram 
shows  an  inflexion  point  and  an  S-shape.  The  pres- 
sure at  which  the  inflexion  point  is  located  depends 
on  the  intensity  of  the  contraction.  If  the  smooth 
muscles  are  relaxed,  the  vessels  will  show  in  the 
beginning  only  a  plastic  elongation  without  a  rise  of 
pressure,  but  the  pressure  will  increase  when  the 
elastic  and  collagen  fibers  are  involved  in  the  exten- 
sion. The  pressure-volume  diagram  is,  from  the  very 
beginning,  convex  to  the  abscissa.  The  collagen  fibers 


88o 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


serve  as  a  "jacket"  just  as  they  do  in  the  elastic  vessels. 
They  provide  a  safety  factor  to  prevent  overstretching 
the  smooth  muscles. 

The  model  of  figure  i  3  gives  only  the  arrangement 
of  the  ring  muscles  in  relation  to  the  other  elements. 
The  more  centrally  the  arteries  of  the  muscular  type 
are  located,  the  greater  is  their  amount  of  tension 
muscles  [Benninghoff  (10,  11)].  We  must  then  assume 
a  mixture  of  models  shown  in  figures  9  and  13.  The 
change  over  from  the  pure  elastic-type  model  (fig. 
9)  to  the  pure  muscular-type  model  (fig.  13)  is  grad- 
ual. The  different  behavior  of  the  arteries  may  be 
the  reason  why  different  authors  have  different  opin- 
ions about  the  architecture  of  the  same  wall.  For 
instance  Burton  (20)  suggests  an  arrangement  similar 
to  figure  9,  whereas  Bergel  (12,  13)  speaks  of  an 
arrangement  similar  to  figure  13.  Both  may  be  right. 

The  smooth  muscles  in  the  muscular  arteries  are, 
during  life,  under  a  continuous  stress  since  they  are 
in  parallel.  Therefore  they  must  have  a  certain  basic 
tone  to  withstand  the  stress  of  the  blood  pressure. 
There  is  strong  evidence  that  this  basic  tone  may 
derive  from  myogenic  activity.  Bayliss  (9)  suggested, 
in  1902,  that  the  blood  pressure  might  act  as  a  me- 
chanical stimulus  to  the  vascular  wall.  Lately  it  has 
become  more  and  more  evident  that  the  smooth 
muscle  possesses  the  capability  of  spontaneous  activity 
(see  above).  For  instance,  denervated  intestinal 
smooth  muscles  respond  to  a  stretch  with  a  contraction 
(fig.  4).  The  tonus  of  the  vascular  smooth  muscles 
may  be  assumed  to  depend  on  the  tension  of  the  wall 
and  consequently  on  the  pressure  within  the  vessel. 
Folkow  (26),  Thurau  &  Kramer  (91),  and  earlier 
workers  have  found  that  the  blood  flow  becomes 
constant  above  a  certain  pressure  which  may  mean 
that  the  pressure  or,  rather,  the  wall  tension  serves 
as  a  stimulus  for  contraction  of  the  smooth  muscles, 
and  so  causes  an  increase  in  the  peripheral  resistance 
(see  above).  This  autoregulation  of  flow  results  in  a 
homeostasis  of  wall  tension  for,  in  contracting,  the 
smooth  muscles  increase  the  thickness  of  the  wall  and 
reduce  the  radius  of  the  lumen.  Both  of  these  changes 
reduce  tension  on  individual  muscle  fibers.  So  the 
vascular  smooth  muscles  may  keep  their  tension  near 
a  constant  level  by  contraction,  when  the  pressure 
rises. 

The  suggestion  has  been  made  that  basal  tone  may 
derive  from  locally  released  constrictor  agents  or 
regional  reflex  arcs  of  independent  nerve  plexuses  in 
the  vascular  wall.  However,  Folkow  &  Oberg  (29) 
have  recently  published  experiments  which  eliminate 
these  possible  mechanisms.  These  experiments  show 


that  the  basic  tone  of  precapillary  resistance  vessels 
and  autoregulation  of  flow  is  not  due  to  nerve  plexuses 
or  vasoconstrictor  agents,  but  to  myogenic  activity. 
The  task  of  the  autonomic  nervous  system,  which 
innervates  the  vascular  muscles,  would  then  be  to 
control  the  myogenic  activity  and  adjust  it  to  the 
appropriate  situation  of  the  circulatory  system  (see 
above).  In  the  same  way  tone  may  be  controlled  by 
chemical  agents.  This  matter  is  also  discussed  in 
Chapter    37. 

As  the  pressure  perfusing  a  vascular  bed  is  gradually 
reduced,  the  flow  becomes  less  in  proportion,  the 
exact  nature  of  this  relation  changing  under  different 
circumstances  and  with  various  vascular  beds,  as 
discussed  in  Chapter  28.  The  flow  stops  before  the 
arteriovenous  pressure  difference  reaches  zero.  The 
pressure  at  which  this  stoppage  occurs  has  been 
called  the  "critical  closing  pressure"  by  Burton  (19). 
The  physical  and  physiological  factors  which  deter- 
mine the  height  of  this  pressure  are  discussed  in 
Chapter  6. 

Capillaries  and  Arteriovenous  Anastomoses 

The  arterial  side  of  the  circulatory  system  is  con- 
nected with  the  venous  side  by  two  types  of  vessels: 
capillaries  and  arteriovenous  anastomoses  (see  also 
Chapter  27). 

Capillaries  are  the  tiny  vessels  through  the  walls  of 
which  materials  are  exchanged  between  blood  and 
the  tissues.  They  consist  of  a  thin  layer  of  endothelial 
cells,  which  sit  on  a  basal  membrane.  On  the  outside 
of  the  capillaries  are  found  the  pericytes,  which  are 
cells  with  many  irregular  branches.  Capillaries  have 
no  smooth  muscles  and,  in  spite  of  earlier  contentions 
to  the  contrary,  it  is  the  current  consensus  that  the 
pericytes  cannot  constrict  mammalian  capillaries 
(see  Chapter  27);  nor  can  the  swelling  of  endothelial 
cells  cause  stoppage  of  flow  [for  additional  references 
see  Illig  (41)]. 

The  arteriovenous  anastomoses  are  vessels  the 
walls  of  which  consist  almost  entirely  of  smooth 
muscle.  They  serve  as  a  direct  connection  between 
the  arteries  and  veins,  bypassing  the  capillaries.  The 
large  amount  of  smooth  muscle  enables  the  arterio- 
venous anastomoses  to  keep  their  lumens  closed  over 
long  periods  of  time.  It  is  not  impossible  that  these 
anastomoses  regulate  the  capillary  blood  flow-  through 
the  several  organs,  according  to  their  activity.  If  an 
organ  is  active  the  anastomoses  close  and  the  blood 
may  flow  through  the  capillaries,  whereas  in  a  resting 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


7    Z   3  t    S  S    7   8   9   10  It  IZ  13  IV  IS  16  17  IB  '9  20 21  22  23  29  ZS  26  27  26  29  30  31  32 
Obere  Exfreraitat   \  Thorax   \ Bavchttoh/e J   \  Unterz  Extremitat 

fig.  14.  Percentage  of  transverse  (circular)  muscles  (black  columns),  longitudinal  muscles  (white 
columns),  and  collagen  and  elastic  tissue  (hatched  columns)  of  the  human  veins  at  different  sites 
1  :  Skin  vein  of  the  forearm;  2 :  v.  mediana  cubiti;  3 :  v.  basilica;  4:  v.  comitans  of  the  a.  brachialis 
5:  v.  brachialis,  proximal  part;  6:  v.  comitans  of  the  a.  circumHexa  humeri  dorsalis;  7:  v.  axillaris 
8:  v.  brachiocephalica  dextra;  9:  v.  thoracica  interna;  10:  v.  thoracica  longitudinalis  dextra;  1 1  :  v 
cava  cranialis;  1  2 :  v.  cava  caudalis;  13:  v.  portae;  14:  v.  coronaria  ventriculi;  15:  v.  lienalis;  16:  v 
renalis  sinistra;  1  7  :  v.  renalis  dextra;  18:  v.  mesenterica  caudalis;  19:  v.  cava  caudalis,  most  distal 
part;  20:  v.  spermatica;  21  :  v.  iliaca communis  sinistra;  22:  v.  iliaca  communis  dextra;  23  :  v.  dorsalis 
penis  subcutanea;  24:  v.  saphena  magna  of  the  thigh;  25:  v.  femoralis;  26:  v.  poplitea;  27:  v.  saphena 
of  the  shank;  28:  v.  comitans  of  the  a.  tibialis  posterior;  29:  v.  comitans  of  the  a.  tibialis  anterior; 
30:  v.  comitans  of  the  a.  dorsalis  pedis;  31  :  skin  vein  of  the  back  of  the  foot;  32  :  v.  comitans  of  the 
a.  plantaris  fibularis.  [v.  Kiigelgen  (48).] 


organ,  the  anastomoses  may  open  and  let  the  blood 
bypass  the  capillaries. 

Anastomoses  in  the  lung  possess  longitudinal 
muscles.  Weibel  (96,  97)  has  demonstrated  that  these 
muscles  always  appear  in  those  vessels  which  have 
to  withstand  longitudinal  elongation.  He  assumes 
that   the   longitudinal   muscles    support   this    stretch. 

Veins 

The  veins,  in  contrast  to  the  arteries,  are  verv 
variable  in  their  wall  structure.  Usually  they  have  a 
larger  percentage  of  collagen  fibers  than  the  arteries, 
but  there  are  veins  in  which  the  muscular  mass  exceeds 
by  far  that  of  the  collagen  fibers.  Veins  have  little 
elastic  tissue  (fig.  1).  The  arrangement  of  the  wall 
elements  is  both  circular  and  longitudinal  in  varying 
proportions  in  different  veins.  Tension  muscles  seen 
attached  to  elastic  fibers  in  arteries  seldom  appear 
in  veins.  Grau  (34)  described  elastic-muscular  sys- 
tems in  the  large  veins  of  the  cow,  similar  to  the 
tension  muscles  described  by  Benninghoff  (10,  11). 
However,  v.  Kiigelgen  (47,  49)  could  never  find  such 
tension  muscles  in  human  veins.  He  described,  rather, 
muscles  like  the  arterial  ring  muscles,  the  individual 
muscle  cells  being  connected  together  as  a  network. 
This  network  of  smooth  muscles  is  tied  to  the  collagen 
fibers  and  the  intima. 


Figure  14  shows  the  percentages  of  smooth  muscles 
and  collagen  and  elastic  fibers  in  different  human 
veins.  The  smooth  muscles  are  separately  graphed  as 
transverse  (circular)  and  longitudinal  muscles.  The 
longitudinal  muscles  of  the  veins  are  not  arranged 
in  bundles  in  the  intima,  as  are  those  of  the  arteries. 
Rather,  they  form  a  network  in  the  wall  with  the 
circular  muscles,  the  smooth  muscles  being  either 
longitudinal  or  transverse,  or  at  any  other  angle. 

The  circular  muscles  are  mainly  in  the  veins  of 
the  leg,  whereas  the  longitudinal  muscles  predomi- 
nate in  the  abdominal  veins.  Figure  1 5  shows  that 
the  proportion  of  circular  muscles  parallels  the 
pressure  in  the  veins  in  the  erect  posture,  there  then 
being  considerable  hydrostatic  pressure  in  the  human 
leg  veins.  Since  the  wall  tension  in  a  tube,  in  the 
transverse  direction,  is  twice  that  in  the  longitudinal 
direction  [Frank  (30)],  the  percentages  of  circu- 
lar muscles  are  higher  in  veins  subject  to  higher 
pressures.  Hydrostatic  pressure  and  wall  tension  vary 
with  posture;  therefore  this  variable  pressure  load 
can  be  supported  better  by  muscles  capable  of 
myogenic  activity,  as  in  arteries,  than  by  collagen  or 
elastic  tissues  (see  above).  Along  with  the  higher 
amount  of  smooth  muscles  in  the  leg  veins  the 
relationship  of  radius  to  wall  thickness  is  less  than  that 
of  other  veins  [v.  Kiigelgen  (48)].  Veins  of  the  thorax, 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  15.  The  relationship  of  the 
abundance  of  transverse  (circular) 
muscles  in  human  veins  {smooth  line) 
to  the  venous  pressure  in  the  erect 
posture  {dotted  line).  The  numbers 
indicate  the  same  veins  as  in  fig.  14. 
[v.   Kiigelgen   (48).] 


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abdomen,  and  neck  are  not  under  this  hydrostatic 
stress  and  have  less  circular  muscle  tissue. 

The  mechanical  properties  of  the  veins  are  similar 
to  those  of  the  arteries.  Smaller  veins  show  different 
pressure-volume  diagrams,  depending  upon  the  state 
of  contraction  of  their  smooth  muscles,  as  do  those  of 
muscular  arteries  [Alexander  (2)].  The  only  differ- 
ence between  the  diagrams  of  the  muscular  arteries 
and  the  veins  is  that  the  diagram  of  the  veins  is 
located  at  much  lower  pressures.  This  indicates  that 
the  elasticity  of  small  veins  depends  to  a  high  degree 
on  smooth  muscle.  The  large  veins,  like  the  vena  cava, 
give  a  pressure-volume  diagram  more  like  that  of 
elastic  arteries  [Blomer  (14)].  It  shows  an  S-shape, 
like  the  aorta,  with  an  inflexion  point  at  the  low 
pressure  of  about  7  mm  Hg.  This  S-shape  does  not 
depend  on  the  activity  of  the  smooth  muscles.  The 
main  support  of  the  wall  tension  of  the  large  veins, 
at  least  above  7  mm  Hg,  is  the  collagen  tissue  rather 
than  the  elastic  tissue,  as  is  the  case  for  elastic  arteries, 
since  the  amount  of  collagen  exceeds  by  far  the 
amount  of  elastic  tissue  in  the  vein  wall.  The  relatively 
high  distensibility  of  the  vena  cava,  in  spite  of  the 
collagen  fibers,  may  depend  on  a  gradual  recruit- 
ment of  these  fibers,  as  shown  in  figure  9,  phases  3 
and  4,  or  it  may  be  due  to  a  reorientation  of  the  net- 
work formed  by  the  collagen  fibers  in  the  venous 
wall  [see  v.  Kiigelgen  (49)]. 

The  most  striking  difference  between  arteries  and 
veins  are  that  the  veins  possess  valves  and  are  securely 
embedded  in  the  surrounding  tissue  (33,  51,  53,  78), 


whereas  the  arteries  never  have  valves  and  they  are 
loosely  connected  with  the  surrounding  tissue. 

The  valves  of  the  veins  are  folds  of  the  intima.  They 
consist  of  collagen  and  elastic  fibers  but  not  of  smooth 
muscles.  Around  the  vein  at  the  base  of  the  valve  is  a 
thickened  band  of  collagen  fiber  (51).  Usually  two 
valves  face  each  other  [Bardeleben  (8)].  The  leg  veins 
are  best  guarded  by  valves.  Very  small  veins  are  said 
to  be  free  of  valves  [Klotz  (45)],  as  are  the  venae 
cavae.  The  valves  minimize  postural  hydrostatic 
pressure  changes  in  the  leg  veins,  protecting  the 
capillaries  and  the  veins  themselves  from  unphysio- 
logical   pressures. 

The  action  of  the  skeletal  muscles,  compressing, 
stretching,  and  releasing  the  veins,  and  even  arterial 
pulsation  (53,  78),  cause  periodic  changes  in  venous 
capacity.  Since  the  valves  open  toward  the  heart, 
these  movements  cause  the  veins  to  act  as  pumps, 
promoting  return  of  blood  to  the  heart  and  main- 
taining low  capillary  pressures  (for  further  details 
see  Chapter  32). 

The  numbers  of  valves  in  the  veins  depend  very 
much  on  the  age  of  the  individual.  Many  valves 
degenerate  with  aging.  Bardeleben  (8)  has  ascer- 
tained, for  example,  that  the  greater  saphenous  vein 
of  a  child  has,  on  the  average,  1 3.6  valves,  whereas 
that  of  an  adult  has  only  10.7  valves.  Klotz  (45)  has 
even  found  up  to  70  per  cent  of  atrophied  valves  at 
age  70.  The  first  sign  of  degeneration  is  a  functional 
insufficiency  of  the  valves  permitting  leaking  at  higher 
pressures  when  the  vein  is  distended,  although  they 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


883 


still  are  tight  at  low  pressures  [Schliiter  (79)].  Further 
degeneration  makes  them  leaky  at  low  pressures  and 
later  they  are  so  degenerated  that  only  a  small  margin 
remains  or  the  valve  leaflets  are  broken  through.  At 
last  they  vanish  completely.  The  effects  of  venous 
valvular  insufficiency  are  discussed  in  Chapter  36. 

The  firm  anchorage  of  the  proximal  part  of  the 
veins  may  facilitate  transmission  of  arterial  pulsation 
from  arteries  to  their  venae  comitantes  [Schade  (78), 
v.  Lanz  et  al.  (53)],  but  it  seems  also  very  convenient 
for  another  task.  Any  distensible  tube  which  stands 
upright  and  is  filled  with  fluid  tends  to  pull  down- 
ward. The  radius  in  the  proximal  part  is  then  small 
and  the  wall  is  stretched  mainly  in  a  longitudinal 
direction.  It  is  therefore  necessary  that  the  tube  be 
supported  in  the  proximal  part  in  the  longitudinal 
direction  and  be  fixed  to  its  surroundings.  Such  a 
support  may  be  formed  in  the  veins  by  the  bracing 
straps  (33,  53)  and  also  by  the  longitudinal  muscles. 
In  the  distal  part  of  such  an  upright  tube  the  radius 
is  enlarged  and  the  wall  is  stretched  mainly  in  a 
transverse  direction.  As  indicated  above,  this  is 
countered  by  the  increasing  amount  of  circular 
muscles. 


NUTRITION    OF    THE    VASCULAR   WALL 

The  vascular  wall  is  a  living  organ  and  its  smooth 
muscles  need  a  source  of  energy.  Their  nutrition  is 
accomplished  by  two  different  means:  diffusion  from 
the  circulating  blood  from  the  inside  of  the  vessel 
toward  the  outside,  and  from  the  vasa  vasorum 
vessels  which  dip  into  the  vascular  wall  from  the 
outside.  These  two  supply  routes  meet  in  the  vascular 
wall.  Miiller  (64)  has  demonstrated  a  model  in  which 
ten  coaxial  thin  rubber  tubes  with  increasing  diam- 
eters were  telescoped  and  fixed  so  that  the  fluid 
between  the  different  sheets  could  not  escape  during 
distention.  This  model  satisfies  very  well  the  situation 
in  the  vascular  wall,  which  is  also  built  from  different 
layers  consisting  of  different  materials.  The  pressure 
between  the  sheets  is  equal  to  the  negative  radial 
stress,  and  the  tension  of  the  different  sheets  of  the 
model  decreases  nearly  linearly  from  the  inside  to 
the  outside  at  any  given  internal  pressure.  The  inner- 
most sheet  has  almost  the  same  pressure  as  the  filling 
fluid,  whereas  the  outermost  sheet  is  at  the  ambient 
pressure.  This  means  that  the  vessels  which  supply 
the  vascular  wall  meet  progressively  higher  pressures 
the  further  they  penetrate  the  wall.   On   the  other 


hand,  the  pressure  gradient  from  the  inside  toward 
the  outside  facilitates  the  movement  of  materials 
directly  from  the  circulating  blood  through  the  wall. 
The  border  between  diffusion  and  vascular  supply  in 
the  vascular  wall  depends  on  the  thickness  of  the 
wall.  The  limit  for  diffusion  is  set  by  oxygen,  which 
is  transported  in  the  blood  by  the  hemoglobin  and 
which  can  supply  tissues  adequately  if  the  distance 
from  the  hemoglobin,  which  stays  in  the  blood,  to 
the  tissue  cells  is  not  too  great.  This  distance  is,  in 
the  vascular  wall,  about  500  ju  [Linzbach  (56)].  The 
limit  for  the  vasa  vasorum  is  set  by  the  pressure  in 
the  wall.  Since  the  vasa  vasorum  come  mostly  from 
the  adventitia,  the  pressure  fall  over  the  length  of 
the  vasa  vasorum  allows  them  only  to  penetrate  as 
far  as  the  pressure  in  the  wall  is  less  than  the  pressure 
of  the  intramural  capillaries. 

Diffusion  from  the  Inside 

The  whole  circulatory  system  is  lined  with  a  single 
layer  of  endothelium.  This  lining  prevents  extra- 
vasation of  blood  even  if  the  pressure  in  the  vessels 
exceeds  by  far  the  surrounding  pressure.  Any  nutrient 
material  entering  the  vascular  wall  from  the  inside 
must  pass  across  this  endothelial  lining.  Such  pene- 
tration is  rendered  possible  either  through  the  pres- 
sure and  concentration  gradient  between  the  blood 
and  the  wall  tissue  or  by  means  of  active  transport. 
Chambers  &  Zweifach  (21)  assume  that  the  individual 
endothelial  cells  are  held  together  by  a  cement 
substance  and  that  this  cement  substance  makes 
penetration  possible.  However,  Linzbach  (56)  could 
never  find  such  a  cement  substance.  He  describes 
cell  branches  which  are  near  the  basal  side  of  the 
endothelial  cells,  and  with  which  the  endothelial 
cells  are  very  tightly  connected.  The  boundary 
between  the  cells  may  form  fissures,  where  capillary 
attraction  may  be  effective  and  render  penetration 
possible.  Pappenheimer  (65)  suggests  channels 
between  the  endothelial  cells  with  a  diameter  of  30 
to  45  A,  through  which  the  materials  can  enter  the 
wall.  All  these  mechanisms  depend  on  a  pressure 
gradient  between  the  blood  and  the  wall  tissue  or  an 
osmotic  concentration  gradient  of  the  different 
materials. 

However,  there  may  also  be  active  transport. 
Moore  &  Ruska  (63)  described  small  vacuoles  on 
the  surface  of  the  endothelial  cells  which  contain 
blood  plasma.  These  vacuoles  separate  themselves 
from  the  surface  and  wander  through  the  cell   sub- 


884 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  1 6.  Vasa  vasorum  in  the 
wall  of  the  aorta  of  the  horse. 
China  ink,  thick  cuts.  Left: 
longitudinal  section;  right:  cross 
section.  [Straubesand  (87).] 


1.5mm 


6.0mm  < 


Interna 


>  Media 


\  fig.  17.  Schematic  longitudinal  section  through  the  aortic 
wall  at  the  origin  of  an  intercostal  artery.  /  =  intercostal 
artery;  V  =  vas  vasis  externum;  a  =  outer  branch;  ;  =  inner 
branch.  [Schonenberger  &  Muller  (82).] 

stance  to  the  basal  side  of  the  endothelial  cells,  where 
thev  release  their  contents  to  the  wall  tissue.  This 
transport  is  called  cytopempsis.  Another  possibility 
of  active  transport  through  the  endothelium  may  be 
by  a  similar  mechanism  which  was  described  by 
Ussing  (92)  for  the  frog  skin.  He  demonstrated  that 
sodium  is  actively  transported  across  the  skin  cells 
l>\  a  carrier  system  located  in  the  cell  membrane.  This 
would  mean  that  ions  or  other  materials  enter  the 
endothelial  cell  passively  through  the  surface  mem- 
brane, along  a  concentration  gradient,  and  are  then 
actively  transported  out  of  the  cell  and  into  the  wall 
tissue  against  a  concentration  gradient.  Sawyer  & 
Yalmont  (77)  have  published  evidence  for  such  a 
mechanism  in  the  canine  thoracic  aorta  and  vena 
cava,  where  the  net  flux  of  sodium  or  chloride  ions 


fig.  18.  Cross  section  through  the  thoracic  aorta  of  the  dog, 
showing  a  vas  vasis  internum.  There  is  no  branching  of  capil- 
laries in  the  intima  and  the  innermost  part  of  the  media.  The 
dark  masses  in  the  outer  third  of  the  media  are  accumulations 
of  injected  material  that  has  broken  out  of  the  capillaries. 
[Woerner   (101  I 

in  the  aorta  is  from  the  inside  to  the  outside.  In  the 
vena  cava  it  is  in  the  opposite  direction  (for  a  possible 
explanation  of  this  contrasting  behavior  see  below). 
The  variety  of  theories  about  the  transport  of  material 
across  the  endothelial  lining  shows  that  much  work 
remains  to  be  done.  Most  of  these  theories  are  deduced 
from  experimental  results  on  capillary  endothelial 
cells  but  it  may  be  that  transport  differs  in  the  capil- 
lary endothelium  and  the  endothelium  of  larger 
vessels.  There  is  also  the  possibility  that  different 
tissues  use  different  transport  mechanisms.  (See  also 
Chapter  29.) 

The  further  transport  through  the  intima  and  the 
media    may    be    passive    in    the    intercellular    space, 


ANATOMY    AND    PHYSIOLOGY    OF    THE    VASCULAR    WALL 


885 


fig.  19.  Schematic  drawing  of  the  vascularization  of  a 
middle-sized  artery  with  both  its  venae  comitantes.  a:  Artery; 
b:  venae  comitantes;  c:  arterial  vasa  vasorum;  d:  venous  vasa 
vasorum;  e:  lymphatic  vessel;  /.■  capillaries  of  the  arterial 
sheath;  g:  capillaries  in  the  stratum  longitudinale  fibroelasti- 
cum  of  the  artery  =  wall  capillaries;  h:  small  channel,  less 
than  3  fi  thick;  i:  vascular  network  in  the  venous  wall;  j: 
capillary  network  in  the  venous  wall;  k:  nerve;  /.•  stratum 
longitudinale  fibroelasticum  =  adventitia  of  the  artery; 
m:  media  of  the  artery;  n:  circular  sheath  of  the  vessel  group; 
0:  conjunctiva  of  the  sheath.  [Lang  (51).] 

effected  by  the  pressure  and  concentration  gradient 
across  the  vascular  wall. 

Vasa  Vasorum 

The  vasa  vasorum  penetrate  the  vessel  wall  to 
different  depths,  depending  on  the  thickness  of  the 
wall  and  the  type  of  vessel.  The  thicker  the  wall, 
the  greater  the  part  of  the  wall  tissue  they  supply. 
In  general,  veins  have  greater  vascularization  than 
arteries.  The  vasa  vasorum  penetrate  the  aortic  wall 
as  far  as  the  inner  third  of  the  media  (fig.  16).  The 
innermost  part  of  the  media  and  the  intima  are 
always  free  of  capillaries.  Only  arteriosclerotic  vessels 
with  a  thickened  intima  show  vascularization  of  the 
innermost  part  of  the  wall  [Woerner  (101)]. 

The  vasa  vasorum  of  the  aorta  can  be  classified  as 
vasa  vasorum  externa  and  vasa  vasorum  interna. 
The  vasa  vasorum  externa  originate  near  the  origin 


of  arterial  branches,  such  as  the  intercostal  arteries. 
They  soon  divide  into  an  outer  branch  and  an  inner 
branch  (fig.  17).  The  outer  branch  goes  into  the 
adventitia  and  from  there  sends  branches  into  the 
wall,  whereas  the  inner  branches  remain  within  the 
wall.  Their  branching  is  mostly  trichotomous.  The 
vasa  vasorum  interna  originate  directly  from  the 
lumen  (fig.  18)  far  away  from  branching  vessels, 
that  is,  in  the  aorta  on  the  ventral  side  [Schonen- 
berger  &  Miiller  (82)].  They  are  not  very  numerous; 
according  to  Woerner  (101),  there  are  never  more 
than  two  per  square  centimeter.  They  are  mostly- 
found  in  the  proximal  part  of  the  aorta  and  very 
seldom  in  the  distal  part.  The  vasa  vasorum  externa 
and  interna  anastomose  in  the  aortic  wall.  The  vasa 
vasorum  externa  are  about  65  to  70  mm  in  length, 
the  vasa  vasorum  interna  about  30  to  50  mm. 

The  more  peripherally  the  arteries  are  located, 
the  less  vascularized  is  their  wall.  Figure  19  shows 
a  schematic  drawing  of  an  artery  with  its  two  venae 
comitantes  from  a  human  shank.  The  vasa  vasorum 
of  the  peripheral  arteries  arise  at  smaller  branches 
of  the  artery,  similar  to  the  vasa  vasorum  externa  of 
the  aorta.  There  are  no  vasa  vasorum  interna  in  these 
arteries.  The  vasa  vasorum  never  dip  into  the  media. 
They  are  located  in  the  stratum  longitudinale  fibro- 
elasticum, the  innermost  part  of  the  adventitia.  They 
form  their  capillary  loops  mostly  in  the  longitudinal 
direction.  In  addition  to  these  capillary  loops  there 
are  still  smaller  vessels.  Lang  (51)  has  described  two 
types  of  such  small  vessels.  The  first  type  is  a  small, 
blind-ending  channel  about  3  mm  in  length  and 
1  to  3  ju  diameter  (fig.  19)  which  is  much  too  small 
for  blood  cells  to  pass.  These  small  channels  run  into 
the  tip  or  the  venous  part  of  the  capillary  loop.  The 
second  type  is  a  network  of  small  channels  of  about 
the  same  diameter  (fig.  20). 

The  same  vas  vasis  which  supplies  the  artery  also 
supplies  its  venae  comitantes  (fig.  19).  In  contrast 
to  the  case  for  arteries,  the  capillaries  in  the  venous 
wall  form  a  dense  network  which  extends  to  the  media. 
The  segment  around  the  valves  is  usually  not  vascular- 
ized. The  venous  vasa  vasorum  do  not  drain  directly 
into  the  large  vein  along  which  they  lie;  rather  they 
and  their  counterparts  in  the  arterial  wall  drain  into  a 
small  venous  branch  [Lang  (51)]. 

Schonenberger  &  Miiller  (82)  have  calculated  the 
drop  of  pressure  in  the  vasa  vasorum  externa  of  the 
aorta,  finding  that  the  capillary  pressure  within  the 
wall  can  be  sufficiently  high  only  if  the  origin  of  the 
main  vas  vasis  is  very  near  the  inner  surface  of  the 
aortic  wall  (fig.  17).  The  intramural  capillaries  must 
be  quite  near  to  the  origin  of  the  vasa  vasorum  externa 


886 


HANDBOOK.    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  20.  Net-shaped  small  channels  with  a  diameter  of 
1-2  n  in  the  adventitia  of  the  peroneal  artery.  Capillaries  of  the 
sheath  and  the  arterial  sheath  partly  removed.  The  small 
channels  were  connected  with  the  capillaries  of  the  sheath. 
a:  Wall  capillaries  in  the  stratum  longitudinale  hbroelasticum; 
b:  network  of  small  channels;  c:  arterial  sheath  and  capillaries 
of  the  sheath,  in  situ.  [Lang  (51).] 


to  maintain  a  pressure  which  is  necessary  to  exceed  the 
tissue  pressure.  If  the  capillaries  are  too  far  from  the 
origin,  the  pressure  will  be  too  low  to  supply  the  wall 
efficiently.  At  greater  distances  from  the  intercostal 
arteries,  the  vasa  vasorum  interna,  with  their  short 
delivery  system,  may  provide  sufficient  blood  supply. 
Schonenberger  &  M  tiller  (82)  have  also  deter- 
mined the  flow  and  resistance  in  the  vasa  vasorum  of 
the  cow's  aorta.  Flow  increases  and  resistance 
decreases,  with  rising  pressure,  with  a  maximum  at 


about  140  mm  Hg  (distended  vessels).  At  higher 
pressures,  a  decrease  of  flow  and  an  increase  of 
resistance  occurs  (collapsed  vessels).  The  maximal 
flow  seems  to  occur  at  the  systolic  blood  pressure 
level.  This  indicates  that  nutrition  of  the  vascular 
wall  may  be  problematic  in  hypertension,  if  the 
diastolic  pressure  exceeds  the  physiological  systolic 
pressure,  since  the  flow  in  the  vasa  vasorum  may  never 
reach  the  maximum.  The  inner  region  of  the  wall, 
which  is  not  nourished  by  the  vasa  vasorum,  also 
suffers  ischemic  changes,  including  a  compensating 
increase  in  vascularity. 

The  lymphatics  certainly  play  no  role  in  the  circu- 
lation of  the  tissue  fluid  within  the  vessel  wall  itself, 
as  they  do  in  other  organs.  The  very  small  channels 
which  arise  from  capillaries  (see  above)  and  which 
have  a  diameter  of  1  to  3  fi  may  function  like  the 
lymphatics  with  local  drainage  (51).  The  mechanical 
or  hydrostatic  pressure  gradients  are  irrelevant  to 
this  diffusion  transport  and  determine  only  the 
direction  of  flow  in  the  vasculature  of  the  vessel  wall — 
whether  the  supply  to  a  capillary  comes  from  an 
internal  or  an  external  arterial  branch. 

The  situation  in  the  veins  is  quite  different  from 
that  in  the  arteries.  There  are  no  channels  of  supply 
from  the  lumen  of  the  vein  as  is  the  case  in  the  artery 
and,  since  the  venous  blood  is  depleted  of  oxygen  and 
nutrients,  the  supply  by  diffusion  through  the  intima 
is  nonexistent  or  very  limited.  The  pressure  gradient 
is  from  the  external  arterial  plexus  to  the  capillary 
plexus,  extending  as  far  as  the  intima.  Venous 
drainage  is  into  small  venae  vasorum  rather  than  into 
the  lumen  of  the  large  vein.  The  interstitial  space  is 
probably  drained  by  "lymphatics",  although  the  fluid 
may  pass  directly  across  the  intima  and  into  the 
lumen.  The  pressure  gradient  is  favorable  for  this 
movement  of  fluid  and  it  might  nourish  the  non- 
vascular inner  wall.  This  concept  agrees  very  well 
with  the  experiments  of  Sawyer  &  Valmont  (77),  who 
have  found  a  net  transport  of  Na  and  CI  from  the 
outside  to  the  inside  in  the  canine  vena  cava. 


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Acta  18:  136-150,  i960. 

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Schultze-Jena,  B.  S.  Uber  die  schraubenformige  Struktur 

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94.  Wagner,  R.,  and  E.  Kapal.  Uber  die  Eigenschaften  des 
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413-492. 

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segments.  Am.  J.  Physiol.  177:  299-302,  1954. 


CHAPTER     27 


Patterns  of  the  arteriovenous  pathways 


MARY   P.    WIEDEMAN 


Department  of  Physiology, Temple  University 
School  of  Medicine,  Philadelphia,  Pennsylvania 


CHAPTER    CONTENTS 

Definitions 

Techniques  for  Microscopic  Observation  of  Small  Blood  Vessels 

Hamster  Cheek  Pouch 

Transparent  Chamber 

Fused  Quartz  Rod 

Bulbar  Conjunctiva 

Rat  Mesoappendix 

Bat  Wing 
Structure  of  Terminal  Vascular  Beds 

Microcirculation  in  the  Bat  Wing 

Microcirculation  in  the  Rabbit  Ear 

Microcirculation  in  the  Mesentery 

Microcirculation  in  the  Hamster  Cheek  Pouch 

Microcirculation  in  Skeletal  Muscle 

Microcirculation  in  Myocardium 

Microcirculation  in  Skin 

Microcirculation  in  Stomach  and  Intestine 

Microcirculation  in  the  Bulbar  Conjunctiva 

Microcirculation  in  the  Spleen 

Microcirculation  in  the  Lung 

Microcirculation  in  the  Cochlea 

Preferential  or  Thoroughfare  Channel 

Arteriovenous  Anastomoses 
Blood  Flow  Through  Terminal  Vascular  Beds 

Capillary  Contractility 

Vasomotion 
Summary 


although  capillary  vessels  in  living  animals  have 
been  observed  microscopically  for  three  hundred 
years,  there  is  a  great  diversity  of  opinion  regarding 
the  structure  and  function  of  minute  vessels  in  terminal 
vascular  beds.  Actually,  a  survey  of  the  descriptions 
of  patterns  formed  by  capillary  networks  and  the 
flow  of  blood  through  them  in  a  wide  variety  of  tissues 
and  organs  reveals  great  similarity  in  vascular 
patterns  and  also  in  the  manner  in  which  blood  flows 


from  arterioles  through  capillary  nets  on  to  collecting 
venules.  This  similarity  of  structure  and  function 
leaves  the  impression  that  acceptable  generalizations, 
applicable  to  these  terminal  beds,  must  be  developed 
in  order  that  future  studies  may  prove  profitable. 

It  is  well  known  that  unnecessary  disagreement 
arises  from  lack  of  uniformity  in  terminology.  It  is 
equally  obvious  that  unnecessary  confusion  arises 
from  assigning  complex  functions  to  isolated  com- 
ponents of  a  specific  vascular  bed  when,  in  truth, 
both  the  activity  and  the  structure  are  common 
features  of  small  blood  vessels  anywhere. 


DEFINITIONS 

Any  attempt  to  supply  a  list  of  universally  accept- 
able definitions  of  vascular  structures  would  be 
useless,  and  yet  it  is  necessary  to  present  some  general- 
izations regarding  current  usage  of  terms  before 
describing  the  types  and  variations  of  structural 
patterns  that  connect  distributing  arteries  and  col- 
lecting veins. 

The  term  "microcirculation"  is  used  to  designate 
blood  flow  through  small  vessels  at  the  capillary  level 
(48).  The  microcirculatory  bed  is  the  ultimate  portion 
of  the  cardiovascular  system  which  is  generally 
accepted  as  being  concerned  with  the  transfer  of 
gases  and  nutrients  and  the  removal  of  metabolic 
waste  products.  Minute  precapillary  arterioles  and 
postcapillary  venules  are  included  with  the  capillaries 
as  major  components  of  the  microcirculation  (53). 

Terminal  arterioles  are  the  final  arterial  ramifica- 
tions, the  branchings  of  which  continue  as  non- 
muscular    capillary    vessels    (88).    They    are   further 


891 


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defined  (152)  as  vessels  which  have  a  single  layer  of 
smooth  muscle  and  very  little  supporting  connective 
tissue.  The  "metarteriole,"  a  term  introduced  by 
Chambers  &  Zweifach  (20),  is  defined  by  Zweifach 
(148)  as  a  primary  structural  unit  which  serves  as  a 
framework  for  the  distribution  of  capillaries. 

The  term  "precapillary  sphincter"  was  first  used 
by  Chambers  &  Zweifach  (20)  to  designate  the 
muscular  investment  at  the  origin  of  the  outflowing 
branches  of  the  preferential  channel  (distal  con- 
tinuations of  arterial  vessels  that  go  directly  to  the 
venous  side).  These  outflowing  branches  lead  into 
true  capillaries.  In  more  general  usage,  a  precapillary 
sphincter  is  the  last  smooth  muscle  cell  along  any 
branch  of  a  terminal  arteriole  (130). 

A  capillary  may  most  simply  be  described  as  an 
endothelial  tube  devoid  of  smooth  muscle  and  having 
a  minimal  amount  of  supporting  elements  (48).  In 
descriptions  of  vascular  patterns  and  flow  it  is  not 
necessary  to  add  any  qualifications  as  to  size,  direc- 
tion of  flow,  or  function. 

Venules  originate  at  the  appearance  of  the  first 
smooth  muscle  cell  on  a  postcapillary  vessel.  Venules 
merge  into  veins  which  have  a  double  coat  of  circular 
and  longitudinal  muscle  cells. 

Vasoconstriction  is  the  contraction  of  the  smooth 
muscle  of  the  vessel  wall,  vasodilation  is  relaxation  of 
the  smooth  muscle.  Vasomotion  refers  to  any  active 
change  in  the  diameter  of  blood  vessels  (81,  89). 

There  are  numerous  other  designations  for  vascular 
structures,  unique  to  specific  organs  or  tissues,  which 
will  be  discussed  where  they  appear  in  the  descriptions 
of  arteriovenous  pathways  in  various  sites. 

TECHNIQUES    FOR    MICROSCOPIC    OBSERVATION 
OF   SMALL    BLOOD    VESSELS 

In  discussing  the  techniques  used  for  microscopic 
observation  of  small  blood  vessels,  the  most  com- 
monly used  sites  and  methods  have  been  included. 
There  are  numerous  adaptations  of  the  basic  tech- 
niques for  specific  approaches,  and  also  many  highly 
specialized  adaptations  for  specific  areas  that  will  be 
described  in  sections  of  this  chapter  where  they  are 
pertinent. 

In  general,  there  are  four  basic  methods:  /)  obser- 
vation of  tissues  and  organs  in  situ  illuminated  by  the 
fused  quartz  rod,  2)  exteriorization  of  internal  tissues 
or  organs  which  can  be  spread  out  as  a  thin  layer  for 
examination,  3)  preparation  of  tissues  using  trans- 
parent chambers,  4)  utilization  of  superficial  structures 
which  can  be  seen  with  direct  or  transmitted  light. 


The  brevity  of  the  descriptive  material  should  not 
mislead  the  reader  as  to  the  difficulty  of  mastering 
the  technical  problems  associated  with  each  method, 
nor  should  he  overlook  the  necessity  of  being  com- 
pletely familiar  with  the  characteristics  of  the  site 
selected  for  observation.  A  survey  of  the  methods 
should  make  it  clear  that  some  sites  or  structures  are 
more  suitable  than  others  for  any  specific  investiga- 
tion and  should  be  evaluated  on  that  basis. 

Hamster  Cheek  Pnuch 

A  method  for  observation  of  peripheral  circulation 
at  the  microscopic  level  in  the  membranous  cheek 
pouch  of  the  hamster  has  been  developed  by  Fulton, 
Jackson,  and  Lutz  (51,  52,  80).  The  cheek  pouch  of 
the  anesthetized  hamster  is  everted  and,  when 
properly  exposed  for  viewing,  forms  a  flat  double- 
layered  preparation  suitable  for  low  power  magni- 
fication. The  pouch  is  bathed  in  a  37  C  Ringer's 
solution.  If  higher  magnifications  (200  X  to  1200  X) 
are  used,  it  is  necessary  to  cut  through  the  upper 
layer  to  form  a  flap  of  a  single  layer.  The  originators 
of  the  method  believe  that  the  cheek  pouch  is  ideally- 
suited  for  investigations  on  small  blood  vessels  be- 
cause the  thin  membrane  presents  a  normal  physio- 
logical surface  with  blood  vessels  in  their  usual  tissue 
environment.  A  valuable  feature  of  the  pouch  is  also 
that  the  same  natural  vascular  bed  can  be  studied 
over  long  periods  and  thus  changes  in  circulation  or 
other  characteristics,  such  as  growth  of  vessels,  can  be 
followed.  The  pouch  is  more  vascular  than  the 
mesentery  of  rats  or  membranes  in  transparent 
chambers.  Its  vascularity  makes  tumor  transplanta- 
tion extremely  successful.  Other  investigations  made 
on  the  hamster  cheek  pouch  include  the  study  of 
blood  pressure,  inflammation,  hemostasis,  petechial 
formation,  thromboembolism,  bacterial  and  parasitic 
infections,  drugs,  and  the  vascularization  of  tumor 
transplants. 

The  disadvantages  of  the  preparation  are  that  the 
animal  is  anesthetized,  the  exposed  tissue  must  be 
irrigated  and  kept  at  body  temperature,  and  for 
high  magnifications  the  integrity  of  the  vascular  bed 
is  disrupted  by  surgery  needed  to  obtain  a  single- 
layered  membrane.  The  membranous  surface  con- 
tinuously exudes  mucus,  which  reduces  visibility  of 
the  underlying  structures.  In  the  hands  of  its  origi- 
nators, judging  by  their  excellent  films,  the  method  is 
very  satisfactory  for  the  investigations  in  which  it  has 
been  used. 


PATTERNS    OF    THE    A-V    PATHWAYS 


H<|  1 


Transparent  Chamber 

The  development  of  the  transparent  chamber 
technique  and  its  utilization  in  numerous  tissues  have 
been  extensively  reviewed  recently  (3,  24,  25).  For  a 
detailed  description  of  the  methods  for  installation 
and  observation,  the  reader  may  refer  to  these  papers. 

Basically,  the  method  consists  of  the  insertion  of  a 
glass  and  mica  chamber  fastened  to  the  cartilage  of 
the  rabbit  ear  or  other  applicable  site.  Since  the  first 
chamber  was  designed  by  Sandison  (104)  in  1924, 
several  types  have  evolved,  with  modifications  and 
improvements  introduced  for  specific  purposes.  The 
round-table  chamber,  essentially  the  same  as  the 
original  Sandison  model,  was  introduced  in  1930  by 
Clark  et  al.  (36).  The  chamber  is  constructed  to  allow 
new  tissue  to  grow  into  an  empty  space  from  the 
edges  of  cartilage  left  by  a  punctured  hole.  This 
chamber  has  been  used  to  study  the  growth  and 
development  of  blood  vessels,  lymphatics,  and  nerves. 
The  preformed  tissue  chamber  (36)  is  one  in  which 
the  original  tissues  can  be  observed  after  removal  of 
the  cartilage  and  skin  of  the  inner  side  of  the  ear. 
The  moat  chamber  was  developed  to  study  the 
response  of  the  vessels  to  various  chemical  substances 
(1,  2).  It  contains  a  small  space  or  moat  to  permit 
injection  and  withdrawal  of  fluids.  The  chamber  has 
been  used  to  investigate  absorption,  diffusion,  and  the 
reactions  of  vessels  to  chemical  solutions.  A  remov- 
able-top chamber  was  designed  by  Williams  (138) 
for  the  purpose  of  obtaining  easy  access  to  living 
tissue  of  the  chamber  for  transplantation  of  organs  or 
tissues.  The  most  recent  improvements  have  been 
developed  by  Williams  &  Roberts  (140),  who  de- 
signed a  versatile  and  highly  useful  chamber  which 
has  the  following  characteristics:  it  has  a  longer  life 
than  any  other  type  of  chamber,  produces  very  little 
irritation  to  the  ear,  is  quickly  and  easily  installed, 
can  be  used  for  transplants  of  tissue,  may  be  modified 
to  study  existing  or  preformed  vessels,  and  may  be 
adapted  for  the  introduction  or  removal  of  fluids. 
Epidermis,  which  invades  the  round-table  chamber, 
is  never  seen  to  grow  into  this  new  tantalum  and  mica 
chamber. 

Clark  (25)  points  out  the  many  advantages  of  the 
transparent  chambers,  among  them  the  fact  that  the 
manner  of  growth  and  extension  of  capillaries,  the 
growth  of  nerves  along  arterioles,  and  the  develop- 
ment of  inflammatory  reactions  can  be  observed  for 
long  periods  of  time  in  unanesthetized  animals.  The 
disadvantages  include  injury  to  the  nerves  during 
installation,  the  rigidity  of  the  chamber  which  may- 


result  in  an  abnormally  high  external  pressure, 
especially  with  inflammation,  and  the  occurrence  of 
infection.  The  advantage  of  having  an  unanesthetized 
animal  is  great,  and  equally  helpful  is  the  fact  that 
the  exposed  tissues  need  not  be  warmed  or  irrigated 
as  is  the  case  for  visceral  or  other  exteriorized  tissues. 
A  serious  disadvantage  of  the  technique  is  the  dis- 
ruption of  normal  circulatory  patterns  and  behavior 
by  installation  of  the  chamber  in  which  the  new 
tissue  must  form. 


Fused  Quartz  Rod 

A  lengthy  discussion  of  this  method  of  transillumi- 
nation of  living  internal  organs  in  situ  for  microscopic 
study  is  given  by  Knisely  (70).  The  limitations  and 
the  applications  of  the  method  are  fully  covered. 

The  method  is  based  on  conducting  intense  lia;ht 
to  the  structure  to  be  studied  by  a  fused  quartz  rod. 
These  rods  conduct  light  around  bends  and  turns  by 
internal  reflection.  Overheating  and  drying  of  the 
tissue  is  prevented  by  an  isotonic  wash  solution. 
Magnifications  from  20  times  to  1000  times  can  be 
used. 

Transillumination  with  the  fused  quartz  rod  has 
been  carried  out  in  a  wide  variety  of  tissues  including 
frog  skin,  tongue,  brain,  gastrointestinal  tract, 
stomach,  bladder,  striated  muscle,  lung,  kidney,  and 
liver.  In  mammals,  the  small  vessels  in  smooth 
muscle,  mesentery,  uterus,  spleen,  and  liver  have  been 
studied. 

Knisely  feels  that  the  limitations  of  the  method 
include  the  necessity  for  an  anesthetic,  surgery,  and 
the  exposure  of  internal  organs  to  the  air.  The  method 
is  best  used  to  examine  structures  at  their  natural 
anatomical  surfaces  or  free  edges  rather  than  at  cut 
surfaces.  In  examining  a  thick  organ,  such  as  liver  or 
spleen,  one  is  limited  in  the  degree  of  magnification 
of  the  deeper  structures  due  to  the  direct  relationship 
between  the  focal  length  and  magnifying  power  of 
lenses.  Fulton  (49)  points  out  that  this  procedure  does 
not  reveal  certain  details  of  vascular  structure  or 
permit  critical  discernment  of  individually  formed 
elements.  It  remains,  however,  the  only  method 
applicable  to  many  types  of  tissues,  but  requires 
rational  selection  of  the  problems  to  be  studied. 


Bulbar  Conjunctiva 

Although  observations  of  the  conjunctival  vessels  are 
not  new,   recent  improvements  in   microscopes  and 


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lights  have  made  this  site  a  popular  one,  especially  for 
observing  changes  in  vascular  patterns  and  flow  in 
diseases  in  humans.  Specific  instructions  for  its  use 
can  be  found  in  papers  by  Bloch  (15),  Grafflin  & 
Corddry  (56),  and  Lee  (76). 

The  type  of  microscopic  and  lighting  equipment, 
as  well  as  the  position  of  the  patient  (supine  or  up- 
right), varies  with  the  investigator,  but,  generally, 
compound  microscopes,  routine  ophthalmological 
supports,  and  lights  of  moderate  intensity  constitute 
the  basic  components. 

Bloch  (13)  notes  that  the  walls  of  the  blood  vessels 
are  not  clearly  seen  because  of  the  use  of  oblique 
illumination,  although  a  moving  column  of  blood 
can  be  clearly  seen  against  the  white  background  of 
the  sclera.  Other  limitations  are  that  optical  resolu- 
tion is  lost  by  the  patient's  inability  to  hold  the  eye 
still,  edema,  highlights  due  to  lacrimation,  and 
excessive  abnormal  pigmentation  in  some  cases. 
Very  high  magnification  is  difficult  because  of  move- 
ments of  the  eyeball  and  the  inability  of  the  patient  to 
tolerate  light  of  high  intensity.  Also,  high  power 
objectives  must  be  too  close  to  the  eyeball  if  they  are 
to  be  in  focus. 

The  advantages  of  the  technique  are  that  blood 
vessels  in  an  unanesthetized  human  can  be  readily 
observed  without  any  surgical  intervention  or  any 
preparation  to  render  the  vascular  beds  visible. 
Tears  supply  the  proper  irrigation  for  this  membra- 
nous tissue.  An  entire  vascular  field  can  be  studied 
again  and  again  in  the  same  subject,  and  blood  flow 
can  be  followed  from  arteriole  through  capillary  to 
venule. 

Rat  Mesoappendix 

The  technique  for  microscopic  observation  of 
mesenteric  structures,  as  described  in  detail  by  Zwei- 
fach  (145),  has  been  used  by  him  in  studies  on  dog 
omentum  and  mesenteric  structures  in  several  ani- 
mals, but  primarily  in  the  cecal  mesentery  (mesoce- 
cum)  of  the  rat. 

Preparation  of  this  tissue  consists  of  exteriorizing 
the  cecum  of  the  anesthetized  rat  and  then  spreading 
the  mesentery,  which  lies  between  the  cecum  and  the 
terminal  ileum,  for  observation.  The  mesentery  is 
continuously  irrigated  with  a  warm  Ringer's  gelatin 
solution. 

Zweifach  (147)  believes  that  the  advantages  of 
using  this  terminal  vascular  bed  are:  a)  the  accessibil- 
ity of  the  vessels  for  direct  stimulation  by  mechanical, 
chemical,  or  electrical  means;  b)  clarity  of  visualiza- 


tion; r)  minimum  interference  by  surgical  procedures 
to  normal  vascular  behavior;  d)  adequate  display  of 
the  entire  extent  of  the  terminal  vascular  bed. 

The  disadvantages  include  those  which  apply  to 
any  technique  using  anesthetized  animals  subjected 
to  surgical  procedures  to  expose  the  tissue  for  observa- 
tion. An  idea  of  the  lability  of  this  vascular  bed  may 
be  obtained  by  reading  the  precautions  to  be  taken  in 
using  the  rat  mesoappendix  for  bioassay  (1 53). 

Bat  Wing 

Microscopic  observations  of  vascular  structures  in 
the  bat  wing,  a  comparatively  old  technique  (68), 
was  revived  by  Nicoll  &  Webb  (88)  in  1946.  A  de- 
scription of  the  preparation  and  current  uses  may  be 
found  in  papers  by  Webb  &  Nicoll  (130)  and  Wiede- 
man  (136). 

An  unanesthetized  animal  is  slipped  into  a  holder 
that  allows  the  wings,  lightly  held  by  spring  clips,  to 
be  extended  over  a  glass  plate.  Magnifications  up  to 
2500  times  can  be  used  with  good  resolution. 

The  simplicity  of  the  preparation  is  one  of  its  great 
advantages,  coupled  with  the  elimination  of  anesthesia 
and  surgery  which  permits  observation  without  dis- 
turbing the  normal  circulation  or  subjecting  the 
animal  to  undue  stress.  The  blood  vessels  and  lym- 
phatics are  accessible  for  cannulation  which  permits 
perfusion  of  drugs  or  measurements  of  pressure,  and 
the  nerves  can  be  readily  stimulated  or  sectioned.  Also, 
in  this  mammal  the  two  wings  can  be  used  simulta- 
neously, which  allows  one  for  control  and  the  other 
for  experimental  procedures. 

One  undesirable  feature  is  the  difficulty  in  obtaining 
bats  during  the  entire  year,  and,  because  the  animals 
will  not  eat  in  captivity,  their  survival  time  in  the 
laboratory  is  limited  to  a  few  months.  Also,  histological 
sections  are  difficult  to  prepare  for  study  because  of 
the  extreme  thinness  of  the  wing. 

Utilization  of  these  various  techniques  has  resulted 
in  the  resolution  of  some  old  controversies,  e.g.,  the 
role  of  the  Rouget  cell,  and  has  clarified  to  some  ex- 
tent the  anatomical  structure  and  physiological  func- 
tion of  terminal  vascular  beds.  It  has  made  many 
investigators  aware  of  the  danger  of  ascribing  specific 
changes  in  blood  pressure  or  the  rate  or  volume  of 
blood  flow  to  the  activity  of  small  blood  vessels,  on  the 
basis  of  indirect  measurements.  While  the  change 
in  systemic  pressure  following  some  experimen- 
tal procedure  need  not  be  challenged,  the  means  by 
which  it  is  brought  about  may  be  better  explained 


PATTERNS    OF    THE    A-V    PATHWAYS  895 


if    direct    observations     of     the     vessels    controlling 
peripheral   resistance   are  employed. 


STRUCTURE  OF  TERMINAL  VASCULAR  BEDS 

From  the  foregoing  section  it  is  apparent  that  the 
microscopic  blood  vessels  which  connect  the  venous 
and  arterial  systems  have  been  studied  in  a  wide 
variety  of  tissues  with  equal  variety  in  the  choice  of 
experimental  animals.  Differences  in  vascular  pat- 
terns and  structural  components  are  to  be  expected, 
but  these  differences  are  minor  compared  to  the  more 
general  similarities  among  the  various  microcircula- 
tory  beds.  It  is  this  aspect  that  will  be  emphasized  in 
the  following  descriptions  of  the  microcirculation. 

Microcirculation  in  the  Bat  Wing 

Utilization  of  the  bat  wing  for  studies  of  the  struc- 
ture and  function  of  small  blood  vessels  has  a  long 
history.  An  interesting  and  detailed  report  appeared  in 
1852,  written  by  T.  Wharton  Jones  (68),  who  de- 
scribed the  impressive  rhythmical  vasomotion  of  the 
veins.  Scattered  publications  by  other  investigators 
appeared  (18,  63,  87)  early  in  the  twentieth  century 
when  new  interest  in  capillary  circulation  was  at  its 
peak.  The  interest  in  the  wing  of  the  bat  as  a  site  for 
microscopic  observation  of  vascular  beds  was  stimu- 
lated in  1946,  when  Nicoll  &  Webb  (88)  published 
the  results  of  several  years  of  observations.  A  descrip- 
tion of  the  vessels  and  their  patterns  in  the  terminal 
vascular  beds  of  the  wing  follows. 

The  major  site  of  peripheral  resistance  was  found 
to  be  in  the  small  arteries  which  anastomosed  to  make 
interconnected  channels  or  loops.  These  small  arteries, 
which  arose  from  the  main  arterial  plexus  and  formed 
arteriolar  nets,  had  the  capacity  for  changing  their 
lumen  size  by  vasoconstriction.  The  smaller  arterioles 
of  the  nets  usually  had  an  inside  diameter  that  was 
equal  to  or  smaller  than  that  of  a  red  blood  cell. 
Nonmuscular  capillaries  arose  as  branches  of  any  of 
these  vessels  of  the  arteriolar  plexus,  the  parent  vessel 
of  the  nonmuscular  capillary  being  designated  the 
terminal  arteriole.  The  muscular  coat  of  the  terminal 
arteriole  became  less  regular  as  the  vessels  advanced 
peripherally,  as  did  the  number  of  muscle  cells  on  the 
branches  arising  from  it. 

The  pathways  between  the  arteriolar  and  venous 
plexuses  were  seen  to  be  similar  to  those  of  the  rabbit 
ear,  as  described  by  Clark  &  Clark  (34)  and  Sandison 
(106),  with  no  preferential  channel  to  carry  blood 


To  venule 


fig.  I.  Paths  of  blood  flow  in  capillary  bed  in  small  area  of 
the  bat's  wing.  [From  Nicoll  &  Webb  (88).] 

from  the  arterial  to  the  venous  side.  Blood  was  seen 
to  take  alternate  routes  through  the  capillary  nets. 
At  times,  especially  in  the  terminal  arterioles,  there 
appeared  to  be  a  major  path  of  flow  through  the 
capillary  vessels  to  the  venules,  but  this  path  was  seen 
to  be  inconsistent  and  changed  to  alternate  routes 
with  modifications  in  arteriolar  or  venular  circulation 
in  adjacent  regions  (see  fig.  1 ). 

Supravital  staining  made  it  possible  to  study  the 
arrangement  of  the  vascular  smooth  muscle  of  the 
various  vessels.  Arteries  had  both  circular  and  longi- 
tudinal muscle  fibers,  the  latter  disappearing  in  the 
arteriolar  vessels.  The  terminal  arteriole  gradually 
lost  its  circular  muscle  investment  until  areas  of  bare 
endothelium  could  be  seen  and  finally  a  single  coiled 
muscle  cell  formed  the  precapillary  sphincter.  The 
spiral  arrangement  of  a  muscle  fiber  continued  for  a 
number  of  turns,  presumably  reaching  a  length  of  over 
100  fj.  if  uncoiled.  Postcapillary  vessels  acquired  a 
muscular  coat  in  the  region  of  the  first  valves,  and  thus 
veins  were  formed.  Veins  had  the  usual  double  layer 
of  circular  and  longitudinal  muscle  fibers. 

Because  of  the  small  caliber  of  arterioles  and  capil- 
laries, flow  was  frequently  seen  to  stop  due  to  obstruc- 
tion by  a  leukocyte.  In  some  instances,  an  internal 
pressure  increase  would  cause  the  leukocyte  to  move 
on.  At  other  times,  the  leukocyte  could  be  seen  to 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


migrate  slowly  along  the  vessel  wall  until  it  reached  a 
larger  vessel  where  it  was  swept  forward  in  the  blood 
stream.  Plugging  of  small  vessels  by  leukocytes  was 
found  in  normal  fields  with  vigorous  flow,  and  this 
obstruction  determined  to  some  extent  the  flow  of 
blood  through  the  capillary  nets. 

In  1954,  Webb  &  Nicoll  (130)  discussed  the  angle 
which  an  arterial  branch  forms  as  it  leaves  its  parent 
vessel.  The  downstream  angle  was  found  to  approach 
45  degrees.  Webb  and  Nicoll  postulate  that  this  helps 
to  insure  almost  equal  pressure  in  the  artery  and  the 
branch  which  arises  from  it.  A  similar  type  of 
branching  is  seen  in  the  arcuate  arrangement  formed 
by  arterioles.  Arterioles,  however,  usually  leave  ar- 
teries at  right  angles.  The  arteriolar  branches  have 
sphincters  at  their  point  of  origin  that  regulate  the 
size  of  the  lumen  of  the  branching  vessel  as  it  leaves 
the  artery. 

The  arcuate  system  formed  by  the  arterioles  affords 
collateral  pathways  and  contributes  to  a  uniform 
distribution  of  blood  at  uniform  pressure  within  the 
capillaries. 

The  capillaries  form  an  extensive  anastomosing  net 
which  is  supplied  by  terminal  arterioles  arranged  in 
such  a  manner  that  no  capillary  net  is  very  far  away 
from  its  arteriolar  supply. 

Active  vasomotion  of  arteriolar  vessels  is,  according 
to  Webb  and  Nicoll,  the  principal  factor  of  a  local 
nature  that  regulates  blood  flow  and  blood  pressure  in 
the  capillary  beds.  The  activity  of  the  muscular  wall 
of  the  arterioles,  which  constitutes  active  vasomotion, 
is  independent  of  central  nervous  control.  Degenera- 
tion of  nerves  supplying  an  area  does  not  affect  active 
vasomotion  in  the  smaller  arterioles,  nor  does  stimu- 
lation of  intact  nerves,  although  this  does  result  in  a 
contractile  response  from  the  arteries  or  the  larger 
arterioles. 

Blood  flow  and  blood  pressure  in  capillary  nets, 
then,  are  controlled  by  two  factors,  one  being  the 
anatomical  arrangement  of  the  arterioles  which  form 
arcades,  and  the  second  being  the  active  vasomotion 
of  the  arterioles  which  is  determined  by  local  condi- 
tions. 

Further  discussion  of  the  arcuate  patterns  formed 
by  arterioles  in  the  bat  wing  appeared  in  a  report  by 
Nicoll  &  Webb  (89)  in  1955.  Arteriolar  vessels  form 
arcuate  configurations.  These  anastomosing  vessels 
are  approximately  equal  in  diameter.  Several  distinct 
arteriolar  arcuate  systems  can  be  identified  arising 
from  either  an  artery  or  a  large  arteriole.  Two 
characteristic  features  were  found  in  the  manner  in 


* 


I 


I 


fig.  2.    Enlargement  of  an  arteriolar  branch  at  its  point  of 
origin.  Bat  wing.   X875. 


which  the  arcuate  systems  began.  One  was  the  angle 
of  origin  of  the  arteriolar  vessels  lrom  the  parent  vessel, 
and  this  was  found  to  be  90  degrees  or  less  in  reference 
to  the  forward  direction  of  flow  in  the  parent  vessel. 
The  second  characteristic  feature  is  a  dilatation  or 
enlargement  of  the  arteriolar  branch  at  its  point  of 
origin  compared  to  its  diameter  throughout  its  length. 
Also,  the  inside  diameter  of  the  opening  between  the 
parent  vessel  and  branch  is  much  smaller  than  the 
average  inside  diameter  of  the  branch  (fig.  2).  This 
formation,  described  by  Nicoll  and  Webb  in  the  bat 
wing  and  named  "Indian  Club,"  has  not  been  de- 
scribed in  microscopic  vessels  in  other  terminal  vascu- 
lar beds.  In  view  of  the  fact  that  the  notable  appear- 
ance of  the  enlargement  of  a  vessel  at  its  junction 
depends  to  some  degree  on  tonus,  it  may  not  be 
readily  apparent  in  anesthetized  animals  in  which 
vessel  tone  is  low.  If  the  tonus  of  the  branch  is  quite 
low,  there  may  be  little  or  no  apparent  difference  be- 


PATTERNS    OF    THE    A-V    PATHWAYS 


897 


fig.  3.  Arcuate  patterns  in  the  terminal  vascular  bed.  [From 
Nicoll  &  Webb  (89).] 

tween  the  outside  diameter  of  the  branch  at  its 
junction  and  along  its  length.  Terminal  arterioles 
originate  mainly  from  the  smallest  arcuate  vessels, 
but  may  also  arise  from  any  of  the  arcuate  arterioles 
or  a  small  artery  (see  fig.  3). 

The  capillaries  form  extensive  nets,  and  the  distri- 
bution of  blood  within  the  nets  from  any  particular 
terminal  arteriole  is  limited.  Local  conditions,  which 
must  be  considered  to  be  a  major  factor  of  control, 
constantly  change  the  paths  of  blood  flow  through 
the  capillary  bed. 

Venous  vessels  show  an  arcuate  pattern  that 
roughly  follows  that  of  the  arteriolar  vessels.  At  the 
point  where  a  capillary  vessel  joins  a  venule,  a  valve 
may  often  be  seen,  although  in  many  instances  no 
such  structure  is  evident.  Nicoll  and  Webb  suggest 
that  since  the  muscular  coat  of  the  venule  begins  in 
the  immediate  vicinity  of  the  valve,  this  site  may  be 
considered  as  the  true  junction  between  capillary 
and  venule. 

The  flow  of  blood  through  the  capillary  nets  is  con- 
trolled chiefly  by  activity  of  the  terminal  arterioles. 
When  they  are  dilated,  flow  is  rapid  and  continuous 
in  the  capillary  nets.  Constriction  of  a  terminal 
arteriole  necessarily  stops  the  flow  of  blood  through 
the  capillary  vessels  supplied  by  it.  When  the  numer- 
ous terminal  arterioles  which  supply  an  interconnec- 
tive  network  of  capillary  vessels  are  contracting  and 
relaxing  intermittently  and  aphasically,  the  flow  of 
blood  into  collecting  venules  may  be  continuous.  Ces- 
sation of  flow  from  venous  capillaries  into  venules  is 
often  produced  when  resistance  to  inflow  is  met  be- 
cause of  a  closed  valve  at  the  junction  of  the  two 


converging  vessels.  Forward  flow  is  seen  on  opening 
of  the  valve. 

Nicoll  and  Webb  offer  several  features  of  both  the 
anatomical  arrangement  and  the  behavior  of  vessels 
in  terminal  vascular  beds  as  the  regulators  of  blood 
flow  and  blood  pressure  at  this  level,  a)  The  arcuate 
pattern  of  arterioles  provides  a  means  for  intrinsic 
regulation  of  flow  and  pressure.  The  roughly  concen- 
tric organization  of  the  arcuate  systems,  made  up  of 
anastomosing  vessels  of  the  same  size,  serve  as  volume 
reservoirs  for  capillaries.  Such  an  arrangement  assures 
an  adequate  blood  supply  for  capillary  nets  which 
does  not  fluctuate  widely  with  changes  in  flow  and 
pressure  in  single  arterial  vessels.  The  authors  con- 
sider such  an  arrangement  to  be  necessary  in  a  system 
in  which  the  demand  for  blood  varies  and  in  which 
some  of  the  distributing  vessels  are  distensible,  thus 
allowing  increases  in  pressure  to  be  absorbed  in  the 
stretched  vessels  rather  than  to  contribute  to  increased 
flow,  b)  The  angle  of  origin  formed  by  an  arteriole  in 
reference  to  its  parent  vessel  affords  a  means  by 
which  pressure  may  be  abruptly  reduced.  Also,  this 
manner  of  branching  off  at  a  90-degree  angle  or  more 
assures  an  adequate  pressure  head  for  each  outlet  from 
a  given  vessel.  This  arrangement,  coupled  with  the 
fact  that  a  capillary  bed  receives  blood  from  several 
terminal  arterioles,  results  in  equal  pressure  in  all 
capillaries  regardless  of  their  distance  from  their 
arterial  supply.  Capillary  pressure,  sufficient  for 
proper  function,  can  be  maintained  with  minimal 
arterial  pressure,  c)  Nicoll  and  Webb  believe  that  the 
Indian  Club  formation  at  the  arteriolar  origins  is 
most  important  in  pressure  regulation.  The  actual 
size  of  the  orifice  of  each  arteriole  aids  in  reducing 
pressure  from  artery  to  arteriole.  The  variability  in 
the  size  of  the  orifice,  which  depends  on  contraction  or 
relaxation  of  the  muscle  cells  which  form  it,  adds 
another  means  of  control  of  pressure  in  small  arteries 
and  arterioles.  It  is  possible  that  the  contraction  and 
relaxation  of  the  muscular  elements  at  arteriolar 
origins  is  determined  by  intra-arterial  pressure.  This 
myogenic  response  would  afford  another  intrinsic 
mechanism  whereby  the  pressure  and  flow  through 
capillary  nets  could  be  kept  at  a  constant  level  inde- 
pendent of  wide  variations  among  these  values  in 
arterial  vessels,  d)  Neural  control  of  larger  arteries 
does  not  seem  to  be  important  in  the  regulation  of 
capillary  blood  flow,  e)  Active  vasomotion  in  the 
terminal  arterioles  causes  blood  flow  through  capillary 
nets  to  alternate  between  very  vigorous  flow  and  no 
flow  at  all.  Local  conditions  determine  the  degree  and 


898 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


extent  of  contractile  activity  of  the  smooth  muscle 
cells  which  encircle  the  terminal  arterioles,  and  there- 
fore local  conditions  can  be  responsible  for  controlling 
capillary  flow  to  meet  the  requirements  of  the  tissues 
in  the  immediate  environment. 

Microcirculation  in  the  Rabbit  Ear 

Collection  of  new  and  important  data  on  mam- 
malian small  blood  vessels  began  in  1924,  following 
the  introduction  of  the  transparent  chamber  technique 
by  Sandison  (104).  He  reported  (106)  observations  on 
circulation  in  the  rabbit  ear  primarily  concerned  with 
contractility  of  small  blood  vessels.  Local  control  of 
blood  flow  was  seen  to  reside  in  the  smooth  muscle 
cells  which  developed  on  newly  formed  capillaries  as 
they  were  transformed  into  arterioles.  In  observing 
circulation  of  blood  through  the  vessels  which  formed 
in  the  chamber,  Sandison  saw  an  axial  stream  of  cells 
surrounded  by  a  narrow,  clear  plasma  layer.  Leuko- 
cytes were  thrown  into  the  peripheral  layer  of  plasma 
and  slowly  rolled  along  the  vessel  wall.  An  uneven 
mixture  of  blood  cells  and  plasma  was  observed  during 
sluggish  or  irregular  flow  through  capillary  nets,  this 
type  of  flow  resulting  from  the  aphasic  and  independ- 
ent contraction  of  arterioles  which  causes  blood  to  be 
fed  to  the  veins  through  capillaries  and  venules  in  a 
broken  stream.  "Plasma  skimming"  was  seen  mainly 
in  partially  contracted  vessels  or  in  capillaries  con- 
necting two  vessels  and  in  which  there  was  no  circula- 
tion due  to  equal  pressure  at  each  end  of  the  con- 
necting capillary.  In  a  capillary  loop,  the  two  ends  of 
which  were  connected  to  a  larger  vessel,  plasma  flow 
(indicated  by  the  passage  of  blood  platelets)  would 
continue  in  the  absence  of  circulation  of  blood  cells. 
An  increase  in  the  blood  supply  to  the  larger,  parent 
vessel  often  caused  red  blood  cells  and  leukocytes  to 
be  forced  through  the  capillary  loop.  The  blood  cells 
were  often  seen  to  take  long  narrow  shapes  as  they 
were  forced  through  the  constricted  entrance  to  the 
capillary  loop. 

Although  capillary  circulation  was  almost  entirely 
regulated  by  contraction  of  the  arterial  vessels  sup- 
plying the  capillary  plexus,  flow  was  seen  to  be  slowed 
or  even  stopped  by  a  single  leukocyte  caught  in  a 
constricted  portion  of  a  vessel.  One  of  the  most 
favorable  places  for  plugging  by  a  leukocyte  was 
found  to  be  at  the  origin  of  the  small  arterioles  from 
their  arteries.  This  region  was  normally  partly  con- 
stricted because  of  the  bulging  of  endothelial  cells  into 
the  lumen  of  the  vessel.  This  site  bears  a  close  re- 
semblance to  the  Indian  Club  structure  described  by 


Cap. 


fig.  4.  Camera-lucida  drawing  of  a  precapillary  branch  of 
an  artery.  Muse.  =  muscle  cells;  End.  nucl.  =  endothelial 
nucleus;  Adv.  =  adventitial  cell;  Cap.  =  capillary.  [From 
Sandison  (106).] 

Nicoll  &  Webb  (89)  (see  fig.  4).  The  leukocytes  were 
dislodged  by  an  increase  in  force  of  the  blood  stream 
or  by  the  ameboid  activity  of  the  leukocytes.  A  similar 
occurrence  was  seen  by  Nicoll  &  Webb  (88)  in  blood 
flow  through  comparable  vessels  in  the  bat  wing. 

Clark  &  Clark  (29),  in  the  same  year,  reported  on 
the  behavior  of  microscopic  vessels  seen  in  the  rabbit 
ear  using  a  "preformed-tissue"  chamber,  one  in  which 
the  original  structures  were  present  as  opposed  to 
newly  formed  vessels  and  nerves  seen  in  the  first 
studies  using  the  transparent  chamber.  The  Clarks 
were  impressed  with  the  contraction  of  arteries  and 
arterioles;  spontaneous  rhythmical  contractions  as 
well  as  contractions  in  response  to  artificial  stimulation 
(mechanical,  tactile,  or  auditory).  Spontaneous  rhyth- 
mical contraction  was  seen  to  play  an  important  role 
in  regulation  of  blood  flow,  causing  changes  in  the 
distribution  of  blood  to  different  capillary  areas  and 
causing  continuous  alterations  in  the  direction  of  flow. 
Contractions  of  arterial  vessels  were  found  to  be 
varied.  Contraction  of  the  main  artery  reduced  the 
blood  flow  to  the  whole  area,  but  the  distribution  of 
blood  to  different  portions  was  dependent  on  contrac- 
tions of  different  arterial  branches,  each  at  a  different 
tempo  and  independent  of  the  contraction  of  the  main 
artery  and  of  each  other.  An  arteriole  might  contract 
to  complete  closure  and  thus  cut  off  blood  to  the 
capillaries  it  supplied  while  an  adjacent  vessel,  a 
branch  from  the  same  artery,  would  remain  open  to 
allow  rapid  passage  of  blood.  Arteriovenous  anasto- 
moses were  seen  to  contract  actively  and  so  influence 
the  distribution  of  blood.  Contractions  were  seen  to 
decrease  in  animals  that  were  asleep  or  anesthetized. 

Further  studies  on  the  activity  of  arterial  vessels, 


PATTERNS    OF    THE    A-V    PATHWAYS 


899 


including  arteriovenous  anastomoses,  appeared  in 
1934  (30).  Clark  and  Clark  again  described  the 
fluctuation  in  rate  and  amount  of  blood  flow  through 
any  given  vessel,  as  well  as  the  frequent  reversals  in 
the  direction  of  flow.  A  single  capillary  or  venule  was 
seen  to  have  an  abundant  flow  of  blood  in  one  direc- 
tion and  a  few  seconds  later  an  equally  great  flow  in 
the  opposite  direction.  The  variation  in  flow  included 
scanty  flow  of  a  few  blood  cells,  or  plasma  and  plate- 
lets only,  or  stasis,  or  complete  emptying.  Such 
changes  were  brought  about  by  periodic  active  con- 
tractions of  arterial  vessels  or  portions  of  arterial 
vessels.  The  numerous  thick-walled  arteriovenous 
anastomoses  were  most  conspicuous  for  their  active 
contractility.  Their  contractions  were  usually  more 
frequent,  quicker,  and  more  powerful  than  those  of 
the  arteries,  and  their  effect  on  venous  circulation  was 
more  sudden.  Definite  active  contraction  of  veins  was 
reported  to  occur  near  the  point  of  entrance  of  a 
cluster  of  arteriovenous  anastomoses. 

Clark  &  Clark  (32)  studied  the  growth  of  capillaries 
into  a  transparent  chamber  and  found  that  new 
capillaries  arose  as  endothelial  outgrowths  from  vascu- 
lar endothelium.  They  advanced  as  blindly  ending 
sprouts,  connecting  with  neighboring  sprouts  to  form 
loops,  and  continued  to  advance  as  a  plexus  with  a 
growing  edge  of  new  sprouts.  The  growing  vascular 
network  showed  differentiation  of  vessels  in  the  older 
portions  of  the  first-formed  capillary  plexus  and  many 
of  the  capillaries  were  seen  to  retract  and  disappear. 
An  entire  chamber  was  revascularized  in  2  or  3  weeks 
with  further  differentiation  continuing  through  en- 
largement of  new  arterioles  which  were  receiving  a 
large  blood  supply  and  widening  of  venules  draining 
large  amounts  of  blood.  There  was  a  further  reduction 
in  surplus  capillaries.  After  a  few  days,  the  vascular 
pattern  was  relatively  stable. 

The  Clarks  next  directed  their  attention  to  the 
development  of  extra-endothelial  cells  on  the  walls  of 
peripheral  blood  vessels  (33).  Three  months  after 
vessels  had  regenerated  it  was  found  that  venules  were 
wider  than  capillaries,  both  vessels  having  similar 
walls,  while  arterioles  were  as  narrow  as  capillaries 
and  narrower  than  venules.  The  walls  of  the  arterioles 
differed  in  number  and  arrangement,  and  in  the 
form  of  the  extra-endothelial  cells.  Blood  flow  was 
seen  to  be  steady  and  rapid  in  arteries  and  arterioles, 
steady  and  slower  in  veins,  and  slow  with  frequent 
hesitations  and  reversals  in  capillaries.  Circulation  in 
capillaries  was  variable,  with  intervals  of  steady  flow- 
being    interspersed    with    periods    of   stasis,    plasma 


skimming,  or  absence  of  flow  during  which  the  vessels 
remained  open  and  were  filled  with  plasma.  The 
subsequent  fate  of  the  extra-endothelial  cells  depended 
on  the  fate  of  the  vessel  on  which  they  appeared.  If 
the  vessel  remained  a  capillary,  they  were  occasionally 
seen  to  increase  in  number  by  mitotic  division  or  to 
retain  the  same  number.  The  cells  were  inert.  If  the 
capillaries  became  parts  of  venules,  the  adventitial 
cells  increased  in  number,  retained  their  longitudinal 
arrangement,  and  remained  inert.  The  change  of  a 
capillary  to  an  arteriole  involved  straightening  of  the 
vessel,  loss  of  side  branches,  narrowing  of  caliber,  and 
an  increase  in  thickness  of  the  endothelium.  There 
was  a  rapid  increase  in  the  number  of  extra-endothelial 
cells  which  assumed  a  transverse  position.  Definite 
active  contractility  was  seen  to  develop  in  these  cells 
which  became  smooth  muscle  cells,  providing  they 
were  reached  by  a  regenerating  vasomotor  nerve. 

The  caliber  changes  in  minute  vessels  were  dis- 
cussed by  Clark  &  Clark  (34)  in  1943.  In  earlier 
published  studies,  the  attention  of  the  authors  had 
been  on  the  main  arteries,  their  branches,  the  arterio- 
venous anastomoses,  and  the  larger  veins.  Observa- 
tions on  newly  formed  arteries  indicated  that  the 
number  of  arteries  which  developed  contractility,  the 
rate  at  which  contractility  appeared,  and  its  final 
extent  on  individual  vessels  and  their  branches  de- 
pended on  the  rate  and  extent  of  growth  of  new  vaso- 
motor nerves.  Terminal  arterioles  in  original  vascular 
beds  in  the  preformed  type  of  chamber  were  seen  to 
show^  spontaneous  contractions  which  in  most  cases 
obliterated  the  lumen.  These  vessels  could  sometimes 
be  made  to  contract  by  prodding  the  animal,  but 
their  behavior  was  erratic.  A  terminal  arteriole  was 
seen  to  divide  immediately  beyond  its  last  muscle  cell 
into  a  capillary  plexus.  In  some  instances  a  terminal 
arteriole  was  prolonged  for  a  distance  beyond  the 
point  of  the  final  muscle  cells  before  forming  a  capil- 
lary plexus.  Such  vessels  had  longitudinally  arranged 
adventitial  cells  rather  than  muscle  cells  on  their  walls. 
Except  for  this,  they  had  the  characteristics  of  ar- 
terioles, being  straight,  uniformly  narrow,  and  having 
a  relatively  thick  endothelium.  The  region  of  active 
contraction  was  confined  to  the  portion  of  the  vessel 
which  had  smooth  muscle  cells,  but  the  distal  portion 
at  times  showed  a  narrowing,  with  protrusions  of 
endothelial  nuclei  into  the  lumen,  after  blood  flow 
was  shut  off  by  active  contraction  of  the  proximal 
portion  of  the  vessel.  The  vessel  showed  an  increase  in 
caliber  following  increased  blood  flow  through  it. 
The  Clarks  refer  to  these  vessels  as  arterial  capillaries. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Microcirculation  in  the  Mesentery 

Early  descriptions  of  mesenteric  circulation  patterns 
by  Zweifach  (143)  and  Chambers  &  Zweifach  (20) 
dealt  primarily  with  establishing  a  structural  and 
functional  unit,  the  preferential  or  thoroughfare 
channel,  which  was  thought  by  the  authors  at  that 
time  to  be  a  representative  structure  of  terminal 
vascular  beds.  A  discussion  of  the  vascular  compo- 
nents of  the  mesenteric  circulation  and  blood  flow 
through  them  appeared  in  1954  (147)-  Zweifach 
stated  that  the  mesentery  represented  a  simplified 
vascular  structure  devoid  of  ancillary  features  peculiar 
to  specific  organs.  In  observing  normal  circulation  in 
the  rat  mesoappenctix  (cecal  mesentery),  Zweifach 
found  the  larger  arteries  along  one  side  of  the  mesen- 
tery to  be  about  one-third  as  large  in  diameter  as 
their  paired  veins.  The  depth  of  anesthesia  influenced 
the  caliber  of  these  vessels,  deep  anesthesia  causing 
them  to  dilate  until  both  vessels  had  the  same  diame- 
ter. Respiratory  difficulties  caused  venous  constriction. 
Terminal  arterioles  in  the  mesentery  proper  had  a  very 
rapid  flow  of  blood.  Collecting  veins  had  a  steady  flow 
of  blood  with  continuous  forward  flow  without  cessa- 
tion or  temporary  reversal.  Capillary  circulation, 
however,  showed  intermittent  flow  produced  by  the 
contraction  of  precapillary  sphincters,  the  activity  of 
which  was  irregular  and  unpredictable.  Preferential 
channels  were  found  to  be  unusually  prominent  in 
the  mesentery.  The  most  important  structural  compo- 
nent for  regulating  capillary  blood  flow  was  the  pre- 
capillary sphincter.  The  precapillary  sphincter  was 
found  at  the  junction  of  all  offshoots  of  the  muscu- 
lar components  of  the  vascular  bed.  The  true  capillary 
network  was  made  up  of  endothelial  tubes  with  no 
perivascular  muscle  cells.  In  some  areas  the  collecting 
venules  were  formed  by  the  joining  of  several  side 
branches  leading  from  precapillary  sphincters.  Both 
terminal  arterioles  and  venules  were  seen  to  be  inter- 
connected to  form  a  series  of  arcades,  so  extensive  in 
some  cases  that  they  completely  circumscribed  the 
capillary  bed.  The  metarterioles  originated  as  off- 
shoots of  the  arteriolar  arcades,  extended  toward  the 
center  of  the  tissue  distributing  typical  precapillary 
branches.  The  arteriolar  channels  terminated  as  one 
or  two  short  capillaries  which  fed  directly  into  a 
venous  vessel.  Zweifach  expresses  the  opinion  that  the 
primary  mechanisms  which  readjust  circulation 
through  the  capillary  bed  are  essentially  of  a  humoral 
nature.  Neurogenic  mechanisms,  local  metabolic  fac- 
tors, and  blood-borne  substances  from  organs  con- 
tribute to  the  local  regulation. 


Microcirculation  in  the  Hamster  Cheek  Pouch 

The  use  of  the  hamster  cheek  pouch  for  microscopic 
study  of  the  peripheral  circulation  was  introduced  by 
Fulton  et  al.  (50,  51). 

Although  there  is  no  detailed  description  by  these 
authors  of  the  basic  vascular  pattern  that  is  seen  in 
this  mucous  membrane,  the  literature  contains  refer- 
ences to  the  presence  or  absence  of  various  vascular 
structures  which  will  be  presented  here. 

The  cheek  pouch  is  exceedingly  vascular  compared 
to  rat  mesentery  or  membranes  in  transparent  cham- 
bers. The  pattern  differs  also  from  the  mesentery  in 
that  no  preferential  channels  have  been  found.  A  rich 
network  of  anastomoses  between  venous  vessels  and 
arteriolar  vessels  is  present.  Arterioles,  which  supply 
the  capillary  network,  bifurcate  progressively  into 
branches  of  equal  significance  for  the  distribution  of 
blood  (fig.  5).  The  arterioles  exhibit  spontaneous 
vasomotion  (80,  82).  Lutz  &  Fulton  (81)  state  that 
precapillary  sphincters  were  seen  to  contract  inde- 
pendently of  adjacent  smooth  muscle  in  cheek  pouch 
vessels.  Intermittent  flow  from  small  veins  was  also 
seen,  but  no  venous  sphincters  were  identified. 

Lutz  &  Fulton  (81)  point  out  that  there  is  always 
variation  in  the  demand  for  blood  by  the  organs,  and 
this  variable  demand  can  be  satisfied  by  vasomotor 
responses  without  involving  the  heart  or  other  large 
structures.  The  complex  anastomosing  system  of  ves- 
sels in  the  cheek  pouch,  for  instance,  coupled  with 
vasomotion,  permits  changes  in  flow.  Neither  the 
vessel  wall  nor  the  flow  are  ever  quiescent,  the  most 
striking  feature  of  the  small  vessels  being  their  con- 
stant activity. 

More  vein-to-vein  than  artery-to-artery  anasto- 
moses are  seen  in  the  hamster  cheek  pouch.  Venules 
make  up  the  greatest  amount  of  endothelial  surface 
and  contain  the  greatest  proportion  of  circulating 
blood  at  any  one  time.  Lutz  and  Fulton  believe  that 
60  to  70  per  cent  of  the  peripheral  circulating  blood 
is  in  the  venous  vessels. 

Poor  &  Lutz  (97)  studied  the  functional  anastomotic 
vessels  in  the  cheek  pouch  and  reported  that  artery- 
to-artery  anastomoses  were  generally  one-third  to 
one-half  the  size  of  the  parent  arteriole.  These  were 
outnumbered  by  the  vein-to-vein  anastomoses.  The 
venous  anastomoses  were  nearly  the  size  of  the  veins 
which  they  connected  (fig.  6). 

Microcirculation  in  Skeletal  Muscle 

The  description  of  the  distribution  of  minute  vessels 
in  skeletal  muscle  has  not  changed  to  anv  marked 


PATTERNS    OF    THE    A-V    PATHWAYS  90 1 


-Ut 


1             'iV-"'    •  ' ^AI 

V       \    1               \ 

v 

■vfV  \     1 

fig.  5.  Vascular  pattern  of  the  hamster  cheek  pouch. 
(Courtesy  of  Dr.  E.  P.  Fowler,  Jr.) 

degree  in  the  last  eight  decades.  The  early  information 
comes  from  studies  of  injected  and  fixed  material,  and 
in  recent  years  there  have  been  investigations  using 
microscopic  techniques  on  living  animals. 

Krogh  (73)  reviews  the  work  of  Spalteholz  (116), 
who  depicted  the  vascular  arrangement  as  follows: 
freely  branching  arteries  with  numerous  anastomoses 
between  the  branches  form  a  primary  network  which 
in  turn  gives  off  anastomosing  small  arteries  that  form 
a  second  network.  Arterioles  branch  from  this  net- 
work, usually  at  right  angles  to  muscle  fibers  at 
regular  intervals.  The  arterioles  then  split  up  into  a 
large  number  of  capillaries  which  run  along  parallel 
to  the  muscle  fibers  with  numerous  anastomoses.  The 
capillaries  unite  into  venules.  The  pattern  of  the 
venous  system  is  almost  exactly  that  of  the  arterial 
systems. 

Clark  (37)  and  Walls  (126)  state  that  skeletal 
muscle,  which  is  highly  vascular,  is  supplied  by 
branches  from  neighboring  arteries  which  invade  the 
epimysium  and  travel  into  the  perimysium,  dividing 


fig.  6.  Vascular  network  of  hamster  cheek  pouch  near 
buccal  end,  lead  chromate  injection.  [From  Poor  (97).] 

as  they  do  so.  Various  branches  of  the  vessels  entering 
the  perimysium  anastomose  with  one  another.  The 
finer  branches  lie  transversely  to  the  long  axes  of  the 
muscle  fibers  and  give  rise  to  the  capillaries  which  run 
parallel  to  the  muscle  fibers.  These  parallel  capil- 
laries lie  in  the  endomysium.  This,  then,  is  the  anatom- 
ical sequence:  arteries  and  veins  run  together  until 
terminal  arterioles  and  venules  are  reached.  The 
terminal  arterioles  and  venules  then  come  ofF  of  the 
parent  vessels  in  alternate  sequence.  The  capillaries, 
running  longitudinally  between  muscle  fibers,  are 
connected  frequently  by  transverse  vessels  which  run 
over  or  under  the  intervening  fibers  and  thus  form  a 
fine  capillary  network  of  tiny  oblong  meshes. 

Zweifach  &  Metz  (151,  152)  have  studied  the 
vascular  supply  of  the  spinotrapezius  muscle  in  the 
rat.  Their  observations  were  primarily  of  vessels  in  the 
epimysium  and  the  perimysium.  They  found  two 
distinct  components  in  the  capillary  circulation  of 
muscle  bundles,  /)  a  vascular  bed  that  was  distributed 
along  the  natural  cleavage  planes  in  the  connective 
tissue  sheath  that  binds  collections  of  muscle  bundles 
together,  and  2)  a  second  capillary  network  originated 
by  short  muscular  arterioles  which  penetrate  into  the 


902 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


depth  of  the  muscle  proper  and  terminate  by 
branching  into  numerous  capillaries. 

There  are  impressive  numbers  of  anastomoses  be- 
tween both  arterial  and  venous  vessels  which  form  a 
series  of  arcades.  Direct  anastomoses  between  ar- 
terioles and  venules  are  also  found. 

The  capillary  bed  of  the  perimysium  is  supplied  by 
metarterioles  which  come  off  at  right  angles  from  the 
arterial  or  arteriolar  arcades.  These  metarterioles 
terminate  as  one  or  two  capillaries  which  unite  with 
other  capillaries  to  form  venous  effluent  vessels.  The 
capillaries  lie  directly  on  the  surface  of  the  small 
muscle  bundles,  thus  each  muscle  bundle  is  sur- 
rounded by  a  network  of  arterial  and  venous  vessels 
which  interconnect  freely  with  one  another  within 
the  connective  tissue  separating  the  bundles.  The 
muscle  fibers  are  supplied  with  blood  by  branches 
from  the  arteriolar  arcades  which  penetrate  the  con- 
nective tissue  and  give  rise  to  capillaries  which  run 
along  the  length  of  the  muscle. 

Zweifach  and  Metz  report  the  presence  of  metar- 
terioles along  the  free  margins  of  the  skeletal  muscle 
which  can  be  traced  directly  to  the  venous  system. 
These  vessels,  they  believe,  represent  preferential 
pathways  which  convey  the  most  rapid  stream  of 
blood  from  the  arterial  to  the  venous  side. 

In  addition  to  structural  features,  spontaneous 
vasomotor  changes  were  seen  by  Zweifach  and  Metz  in 
arterial  and  venous  vessels.  The  vasoconstriction  was 
not  often  intense  enough  to  stop  blood  flow  through 
the  vessels  involved,  except  at  the  level  of  the  pre- 
capillary sphincters. 

In  investigations  of  red  and  white  skeletal  muscle 
in  rabbits  (75,  113)  injected  preparations  showed 
arterial  vessels  which  branched  profusely  to  end  in 
capillaries  running  parallel  to  muscle  fibers.  Also 
shown  were  numerous  anastomotic  connections  be- 
tween small  vessels. 

Algire  (4)  and  Algire  &  Merwin  (5)  studied  the 
panniculus  carnosus  through  a  transparent  chamber 
in  the  rat's  back  and  also  saw  many  arterial  anasto- 
moses as  well  as  arteriovenous  anastomoses.  Arterial 
branches  from  the  subcutaneous  layer  supplied  the 
thin  striated  muscle  layer  with  blood.  The  arterioles 
from  these  branches  subdivided  into  capillaries  which 
ran  parallel  to  the  muscle  fibers,  with  cross  connec- 
tions between  them,  joining  other  capillaries  to  form 
collecting  venules. 

The  capillary  blood  flow  was  noted  to  be  inter- 
mittent, the  result  of  active  vasomotion  of  the  ar- 
terioles. Algire  &  Merwin  (5)  estimated  the  length  of 
capillaries  that  were  seen  between  the  muscle  fibers 


fig.  7.   Capillary  vessels  in  skeletal  muscle. 

to  be  between  0.3  and  1.0  mm,  with  anastomoses  oc- 
curring at  intervals  of  about  o.  1  mm. 

Observations  of  the  capillary  network  of  the  skeletal 
muscle  bands  that  course  through  the  bat  wing  show  a 
vascular  pattern  similar  to  the  descriptions  given 
above  (see  fig.  7). 

There  are  notable  differences  between  the  distribu- 
tion of  capillaries  in  the  endomysium  and  that  in  the 
areas  adjacent  to  the  skeletal  muscle.  The  vessels 
which  run  parallel  to  the  muscle  fibers  are  generally 
longer  and  straighter  than  comparable  vessels  in  the 
surrounding  connective  tissue.  An  arteriolar  branch 
that  crosses  the  muscle  fibers  often  subdivides  into 
two  capillaries  that  originate  at  right  angles  to  the 
parent  vessel  and  go  off  in  opposite  directions.  Thev 
usually  do  not  lie  in  the  same  plane,  one  going  deep 
between  the  fibers,  occasionally  until  lost  from  view, 
while  the  other  vessel  continues  on  the  upper  surface. 
As  a  result  of  this  downward,  or  sometimes  upward, 
turn  it  is  possible  to  look  directly  down  into  the  lumen 
of  a  capillary  rather  than  at  the  customary  longitudi- 
nal view.  An  arteriole  with  its  accompanying  venule 
mav  cross  the  muscle  band  without  either  of  the  vessels 


PATTERNS    OF    THE    A-V    PATHWAYS 


9°3 


fig.  8.   Red  blood  cells  "on  edge"  in  a  capillary  of  skeletal 
muscle. 


giving  off  branches  to  contribute  or  to  receive  blood 
from  the  underlying  muscle.  When  capillary  vessels 
running  parallel  to  the  muscle  fibers  are  confined  to 
the  narrow  space  between  two  fibers,  the  capillaries 
are  flattened  and  the  cells  face  the  fibers  (fig.  8),  as 
reported  by  Reynolds  et  al.  (ioo)  in  similar  vessels  in 
the  myocardium.  In  a  wider  space,  the  cells  are  often 
seen  broadside. 

Anastomoses  between  the  capillary  vessels  running 
parallel  to  the  muscle  fibers  are  numerous,  the  con- 
nections occurring  sometimes  between  adjacent  ves- 
sels and  just  as  frequently  with  vessels  lying  some  dis- 
tance away.  Short  connections  between  arterial  and 
venous  pathways  are  also  seen. 

Intermittent  flow  occurs  in  the  capillaries  of  these 
skeletal  muscle  bands  as  a  result  of  spontaneous  closure 
of  short  duration  of  terminal  arterioles  that  give  rise 
to  the  capillaries  which  lie  in  the  endomysium. 

Studies  made  thus  far  in  these  beds  have  established 
no  characteristic  pattern  formed  by  vessels  supplying 
the  muscle  bands  that  deviates  from  what  is  normallv 


seen  elsewhere,  except  for  the  parallel  course  of  the 
vessels  lying  between  the  muscle  fibers. 


Microcirculation  in  Myocardium 

There  is  a  paucity  of  descriptive  literature  on  the 
capillary  beds  in  the  myocardium.  Although  a  few- 
investigations  on  fixed  material  appear,  no  studies 
have  been  made  on  circulation  through  the  minute 
vessels  in  the  living  animal,  presumably  because  of 
the  difficulty  of  microscopic  observations  of  an  organ 
in  motion. 

In  1928,  Wearn  (127)  studied  sections  of  myocar- 
dium obtained  from  man,  cats,  and  rabbits.  The  ves- 
sels were  filled  with  material  injected  through  coro- 
nary arteries.  Wearn  observed  that  almost  every 
cardiac  muscle  fiber  was  in  direct  contact  with  one 
capillary  and  some  fibers  were  touched  by  two  or 
more.  A  muscle  fiber  was  completely  surrounded  in 
some  instances  due  to  numerous  anastomoses  between 
capillaries.  These  interconnecting  branches  ran  across 
the  parallel  muscle  fibers.  Capillary  vessels  were 
found  to  lie  between  the  cardiac  muscle  fibers  and 
did  not  actually  penetrate  the  muscle  substance. 

Saunders  &  Knisely  (107)  reported  having  watched 
through  a  microscope  the  circulation  in  the  myocar- 
dium of  beating  frog  hearts.  Blood  flow  was  seen  to 
stop  during  systole  and  to  flow  profusely  during 
diastole.  The  cessation  of  flow  in  systole  was  brought 
about  by  compression  of  the  small  vessels  by  the 
contracted  myocardial  fibers. 

Reynolds  et  al.  (100)  studied  fixed  sections  of  heart 
muscle,  the  hearts  having  been  taken  from  dogs 
without  loss  of  blood  from  the  coronary  vessels.  They 
report  that  capillaries  had  a  diameter  of  approxi- 
mately 4  m-  The  capillaries  were  seen  to  run  along  the 
muscle  fibers  as  described  by  Wearn  (127),  about  one 
capillary  to  every  muscle  cell.  The  orientation  of  the 
red  blood  cells  within  the  capillary  vessels  was  be- 
lieved to  be  unusual,  in  that  the  cells  were  often 
seen  edgewise,  i.e.,  with  the  flat  surface  of  the  red 
cell  facing  the  parallel  myocardial  fibers.  The  authors 
conclude  that  the  capillary'  vessels  running  between 
the  muscle  fibers  are  elliptical  in  cross  section  rather 
than  round. 

In  normal  hearts,  more  capillaries  were  found  in 
the  epicardium  than  in  the  middle  portion  or  the 
endocardium.  Various  explanations,  none  conclusive, 
were  given  for  this. 

Terminal  arterioles  were  identified  by  the  presence 
of  an  endothelium  with  distinguishable  smooth  muscle 
cells  along  their  walls.  The  terminal  arteriole  gave  rise 


9°4 


HANDBOOK    OF    PHYSIOI.n<;V 


CIRCX'LATION    II 


to  a  number  of  capillaries  that  ran  parallel  to  each 
other  in  the  same  direction  as  their  parent  vessel. 

A  postcapillary  venule  was  formed  by  the  union  of 
capillaries  which  came  from  opposite  directions  along 
the  muscle  fibers.  The  postcapillary  venule  increased 
in  size  as  it  was  joined  by  similar  tributaries.  These 
tributaries  formed  venules,  which  were  identified  by 
their  muscular  walls. 

Provenza  &  Scherlis  (99)  studied  sections  made 
from  dog  hearts  and  placed  great  emphasis  on  the 
appearance  of  "muscle  sphincters"  in  various  small 
vessels.  Although  the  authors  have  used  the  terminol- 
ogy of  Chambers  &  Zweifach  (20),  it  has  not  in  every 
instance  been  properly  applied,  and  comparison 
with  other  terminal  vascular  beds  is  difficult.  A  highly 
imaginative  diagram  indicates  the  presence  of  arterio- 
venous anastomoses,  metarterioles,  thoroughfare 
channels,  and  precapillaries. 

Microcirculation  in  Skin 

Zweifach  (149)  has  presented  a  description  of  the 
cutaneous  circulation  in  a  flap  of  skin  of  the  rat  from 
which  the  connective  tissue  had  been  cleaned  off. 

A  network  of  arterial  vessels  in  the  connective  tissue 
between  the  skin  and  underlying  muscle  gives  rise  to 
small  arteries  which  enter  the  dermis.  These  small 
arteries,  as  well  as  the  ones  from  which  they  originate, 
form  a  regular  pattern  of  interconnecting  links  or 
arcades.  The  capillary  bed  of  the  dermis  is  composed 
of  a  secondary  network  lying  between  the  inter- 
arcading  arterioles.  This  secondary  network  is  formed 
by  precapillary  and  capillary  vessels  that  are  branches 
of  the  interarcading  arterioles. 

Blood  flows  away  from  the  capillary  bed  in  wide 
vessels,  which  join  to  form  collecting  venules.  The 
collecting  venules  form  an  interconnecting  plexus  that 
is  similar  to,  but  more  extensive  than,  the  arterial 
plexus.  Many  short  arteriolar  branches  are  seen  to  go 
directly  into  the  vessels  of  the  venous  plexus.  Also 
seen  are  direct  connections  between  arterial  and 
venous  arcades  that  allow  blood  to  go  from  arterial 
to  venous  side  without  going  through  a  capillary  net- 
work. The  venous  vessels  form  the  major  portion  of 
the  cutaneous  vascular  beds. 

Zweifach  believes  that  the  branches  which  leave 
the  arterial  arcades  are  structurally  similar  to  metar- 
terioles in  that  they  have  a  thin  layer  of  smooth 
muscle  and  a  comparatively  straight  course.  The 
vessel  finally  becomes  part  of  the  capillary  bed  after 
giving  off  branches  along  its  course.  These  offshoots, 
or    side    branches,    are    precapillary    vessels,    having 


spirally  arranged  muscle  cells  in  the  immediate  junc- 
tional region.  The  precapillary  vessels  show  character- 
istic spontaneous  vasomotion.  Yasomotion  is  also  seen 
in  the  deeper  lying  arterioles.  The  small  venules  of 
the  cutaneous  bed  show  a  continuous  almost  rhyth- 
mic pattern  of  spontaneous  activity  that  is  unrelated 
to  the  vasomotion  of  the  deeper  lying  vessels. 

The  arteriolar  arcades  were  found  to  be  very  re- 
sponsive to  constrictor  and  dilator  agents.  The  venous 
arcades  showed  a  20-fold  increase  in  responsiveness  to 
epinephrine  when  the  temperature  was  made  to  fall  1 
or  2  degrees,  indicating  that  they  are  greatly  influ- 
enced by  temperature  change.  Zweifach  considers  the 
venous  network  in  the  skin  to  be  unique  in  this  regard. 

From  his  studies,  Zweifach  concluded  that  the 
structural  pattern  of  the  cutaneous  circulation  was 
atypical,  since  it  was  composed  predominantly  of 
highly  reactive  venous  vessels.  The  circulation  in  the 
skin  appeared  to  be  regulated  locally  by  tissue 
mediators. 

The  description  of  the  cutaneous  vascular  pattern 
and  its  vasomotion  conforms  in  most  respects  to  that 
of  other  terminal  vascular  beds  that  have  been  studied, 
with  the  possible  exception  of  the  mesentery  and  the 
omentum.  The  interconnecting  arcades  of  both  arte- 
rial and  venous  vessels  with  a  secondary  network 
forming  the  capillary  bed  are  prominent  features  of 
the  pattern  of  small  blood  vessels  in  the  hamster 
cheek  pouch  and  the  bat  wing.  Such  an  arrangement 
seems  to  be  a  common  denominator  in  vascular 
patterns  of  the  microcirculation. 

Microcirculation  in  Stomach  and  Intestine 

Until  a  recent  paper  by  Baez  (6),  descriptions 
dealing  with  the  vascular  patterns  of  small  blood 
vessels  in  the  stomach  and  intestine  have  been  based 
on  injected  and  fixed  material,  ft  is  extremely  difficult 
to  establish  the  paths  of  blood  flow  in  a  tissue 
without  observing  the  flow  in  living  material.  This 
would  apply  especially  in  such  a  vast  network  of 
venules  and  arterioles  which  intercommunicate  so 
freely  by  a  system  of  arcades  as  is  present  in  the  muscu- 
lature of  the  gut.  Although  the  early  investigations 
briefly  discussed  here  are  not  concerned  with  the 
smallest  vessels,  they  will  serve  as  a  background  for  a 
more  detailed  description  of  the  terminal  vascular 
beds  of  the  alimentary  canal. 

Xoer  (90)  studied  the  vascular  patterns  in  the 
jejunum  and  ileum  of  specimens  prepared  by  liquid 
latex  injections.  The  descriptions  are  of  the  mesenteric 
circulation  and  the  superficial  vessels  of  the  gut  wall 


PATTERNS    OF    THE    A-V    PATHWAYS 


905 


fig.      9.  Types      of     antimesenteric 
anastomoses.  [From  Noer  (90).] 


(the  mural  trunks).  In  his  search  for  an  experimental 
animal  which  might  have  a  vascular  distribution 
similar  to  man,  he  observed  14  different  animals.  The 
basic  architecture  was  found  to  be  similar  in  all 
animals  in  that  the  intestinal  arteries  formed  mesen- 
teric arcades  or  arches  which  in  turn  gave  rise  to  vasa 
recta,  which  then  proceeded  to  the  intestinal  wall  to 
form  mural  trunks.  Striking  variations  in  the  numbers 
of  mesenteric  arcades  were  found  among  the  species 
as  well  as  differences  in  the  pattern  of  the  vasa  recta, 
including  their  length  and  whether  or  not  they  had 
anastomotic  connections  with  one  another.  The  mural 
trunks  in  the  human  stomach  were  found  to  ramify  in 
two  ways,  a  similar  arrangement  being  seen  in  other 
animals.  A  single  vessel  passing  to  the  antimesenteric 
area  might  give  off  lateral  branches  along  the  way, 
or  the  vessel  might  break  up  into  several  branches 
rather  quickly  and  subdivide  in  an  arboreal  fashion. 
Three  types  of  anastomoses  between  the  mural  trunks 
in  the  antimesenteric  area  were  found  to  be  /)  direct 
communication  between  the  mural  trunks  of  the  two 
sides,  2)  a  plexiform  arrangement,  3)  short  vessels 
joining  arcuate  mural  anastomoses  (fig.  9).  Veins 
were  found  to  follow  the  arteries  with  few  exceptions. 

Although  Noer  was  not  the  first  to  describe  the 
arcuate  patterns  found  in  the  arterial  and  venous 
vessels  of  the  intestine,  his  report  is  extensive  and  de- 
tailed, and  contains  a  comprehensive  review  of  the 
literature  up  to  that  time. 

Investigations  of  the  alimentary  tract  during  the 
next  few  years  centered  around  the  absence  or 
presence  of  arteriovenous  anastomoses,  especially  in 
the  human  stomach.  Barclay  &  Bentley(7),  stimulated 
by  the  findings  of  Trueta  et  al.  ( 1 20)  of  vascular  shunts 
in  the  kidney,  proposed  that  in  the  wall  of  the  stomach 
there  were  arteriovenous  anastomoses  in  the  region  of 
the  submucous  plexus,  and  that  when  these  arterio- 
venous anastomoses  were  open,  active  circulation 
through   the   vessels  of  the  mucous  membrane  was 


excluded.  Their  conclusions  were  based  on  the  absence 
of  radiopaque  material  in  the  mucous  membrane 
of  stomach  injected  immediately  after  surgical  re- 
moval. They  suggest  that  the  injected  material  flowed 
from  arteries  of  the  submucosal  plexus  to  the  gastric 
veins  directly  through  a  shunt  located  in  the  sub- 
mucous plexus.  In  1952,  Walder  (125),  accepting  the 
presence  of  arteriovenous  anastomoses  in  the  sub- 
mucous layer  of  the  human  stomach  after  what  seemed 
to  be  confirmation  of  them  by  Barlow  (8)  through 
microdissection,  carried  out  investigations  to  deter- 
mine their  function,  size,  and  responses  to  stimuli, 
both  physical  and  pharmacological.  Cannulation  of 
the  right  gastroepiploic  artery  and  its  accompanying 
vein  permitted  him  to  introduce  glass  beads,  40  to  200 
11  in  diameter,  into  the  artery  and  to  recover  them  in 
the  venous  outflow.  The  presence  of  spheres,  1 40  n  in 
diameter,  in  the  venous  outflow  was  believed  to  be 
indicative  of  patent  arteriovenous  anastomoses,  be- 
cause spheres  of  this  size  could  not  travel  through 
the  capillary  network.  The  results  of  the  injection  of 
drugs,  nerve  stimulation,  and  varying  perfusion  pres- 
sures to  determine  their  influence  on  the  size  of  the 
arteriovenous  anastomoses  were  inconclusive. 

In  an  extensive  study  of  the  vascular  patterns  in  the 
alimentary  canal,  Barlow  (8),  in  describing  the  arte- 
rial supply  to  various  portions  of  the  stomach,  notes 
frequent  anastomoses  of  the  arteries  in  the  submucous 
plexus  and  the  mucosa.  The  mucosal  arteries  give 
rise  to  capillaries  which  also  have  anastomotic  connec- 
tions. He  found  arteriovenous  anastomoses  in  the 
stomach  which  consisted  of  an  arterial  end,  variable  in 
length,  a  short  narrow  junction  area,  and  a  short 
wide  venous  channel.  This  structure  was  demon- 
strated by  Barlow's  double  injection  technique.  The 
arterial  end  may  be  a  direct  branch  of  a  mucosal 
artery  or  arise  from  a  main  channel  in  the  submucous 
plexus.  It  terminates  by  joining  either  a  distant  mu- 
cosal vein  or  may  double  back  on  itself  and  anasto- 


go6  HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


fig.  io.  Arteriovenous  anas- 
tomosis in  the  submucous  plexus. 
[From  Barlow  (8).] 


mose  with  a  tributary  of  its  accompanying  vein  (fig. 
io). 

In  1959,  Baez  (6),  using  the  small  intestine  of  the 
rat,  gave  a  detailed  account  of  the  vasculature  at 
various  levels  based  on  observations  in  the  living 
animal.  In  discussing  the  method  of  observations, 
Baez  points  out  the  advantage  of  having  an  intact 
animal  in  which  the  distribution  of  large  supplying 
arteries  and  accompanying  veins  of  the  wall  as  well 
as  their  relation  to  the  small  vasa  recta  can  be  deter- 
mined. The  type  of  a  vascular  connection  at  the  anti- 
mesenteric  border  as  well  as  the  vessels  of  the  submu- 
cosal plexus  and  the  final  ramifications  of  the  vessels 
to  the  muscular  coat  can  be  established. 

The  description  of  the  vessels  in  the  submucosal 
plexus  is  as  follows:  Main  arteries  (60-80  n),  which 
pierce  the  muscularis  in  the  mesenteric  region  at 
intervals,  divide  into  two  or  three  branches  in  the 
submucosa.  Each  branch  subdivides  into  four  or  six 
smaller  branches  (30-40  //)  which  then  proceed  to  the 
antimesenteric  border  where  they  connect  with  simi- 
lar arterial  branches  from  the  other  side.  Other  arte- 
rial anastomoses  are  formed  by  interconnections  of 
branches  between  neighboring  recta.  Baez  uses  a 
general  description  for  main  arterial  arcades  with 
three  characteristics:  /)  they  are  located  in  the  outer 
plane  of  the  submucosa  and  average  30  to  40  m  in 
diameter;  2)  all  give  rise  to  secondary  arcades,  muco- 
sal arteries,  and  vessels  to  nourish  the  muscular  coat; 
3)  the  direction  of  blood  flow  through  them  is 
changing  constantly. 

The   small   vasa   recta  which   arise   from   the   last 


mesenteric  arcade  terminate  quickly  by  anastomosing 
with  secondary  branches  of  other  arcades.  The  small 
vasa  recta  lie  between  the  large  vasa  recta.  They  sup- 
ply the  vessels  to  the  submucosa  and  muscular  coats 
of  the  gut  wall  near  the  mesenteric  border  (fig.  11). 
These  vessels  go  in  opposite  directions,  some  to  the 
outer  smooth  muscle  coat  and  others  to  the  inner 
absorptive  surface  of  the  gastrointestinal  tract.  They 
seem  to  have  a  unique  type  of  blood  flow.  Unidirec- 
tional flow  in  the  large  and  small  vasa  recta  is  altered 
in  the  meshwork  of  interconnected  arterial  vessels  in 
the  submucosal  plexus.  A  main  arterial  arcade  may 
show  complete  reversal  of  flow  or,  as  more  frequently 
happens,  blood  may  flow  from  both  sides  of  an  arterial 
arcade  into  a  mucosal  artery.  At  times,  when  blood 
is  rushing  into  an  arcade  from  opposite  directions, 
the  converging  currents  may  produce  a  space  of 
clear  plasma  at  the  point  where  they  meet.  When  this 
occurs  at  the  origin  of  a  mucosal  vessel,  plasma  is 
"skimmed"  into  it. 

The  muscular  coat  of  the  ileum  is  supplied  by 
vessels  that  originate  from  the  proximal  end  of  mu- 
cosal arteries  or  from  secondary  arcades  in  the  sub- 
mucosa. Baez  considers  these  vessels  to  be  metar- 
terioles,  18  to  24  n  in  diameter,  which  enter  the 
muscularis  and  run  in  the  plane  of  cleavage  between 
the  circular  and  longitudinal  muscle  bundles.  In 
the  intermuscular  septum  the  capillaries  for  the 
circular  muscle  bundles  stay  on  the  same  plane  as  the 
parent  vessel,  while  those  for  the  longitudinal  muscle 
bundles  turn  outward.  The  capillaries  communicate 
freelv  to  form  a  network,  both  in  the  same  plane  and 


PATTERNS    OF    THE    A-V    PATHWAYS 


907 


fig.  11.  Photomicrograph  from  the  anterior  wall  of  rat 
ileum.  (Courtesy  of  Dr.  Silvio  Baez.) 

between  adjacent  layers  of  muscle.  The  parent  vessel 
either  divides  in  two,  or  arches  and  becomes  a  venule 
which  isjoined  by  venules  from  neighboring  capillary 
nets  before  entering  a  submucosal  vein.  Such  an 
arrangement,  whereby  a  metarteriole  leaves  the  sub- 
mucosa  and  enters  the  smooth  muscle  coat  where  it 
gives  off  a  capillary  network  and  then  returns  to  the 
submucosa  as  a  venule,  constitutes,  according  to 
Baez,  a  distinctly  organized  terminal  vascular  unit. 

The  minute  vessels  of  this  unit  are  both  muscular 
and  nonmuscular,  the  muscular  component  being  the 
centrally  located  metarteriole  and  the  precapillary 
vessels  which  branch  from  it  and  in  turn  give  rise  to 
the  nonmuscular  capillary  network.  The  muscular 
vessels  and  their  parent  metarterioles  are  considered 
by  Baez  to  be  the  most  highly  reactive  of  the  mural 
vasculature,  a  fact  demonstrated  by  vasoactive  drugs 
and  varying  intraluminal  pressures.  The  capillary 
bed  of  the  muscular  coat  of  the  gut,  which  is  served 
by  these  metarterioles,  shows  periodic  changes  in 
blood  flow;  the  changes  being   independent  of  flow 


through  the  arterial  plexus  of  the  submucosa.  The 
muscular  coat  may  be  devoid  of  circulation  while 
blood  continues  to  flow  through  arteries  of  the  sub- 
mucosa and  mucosa. 

In  some  instances  the  parent  vessel  may  begin  as  a 
short  arteriole,  rather  than  a  metarteriole,  which  in 
turn  then  gives  rise  to  several  metarterioles  when  it 
reaches  the  muscular  coat.  The  pattern  of  distribution 
is  then  the  same  as  described  above;  the  metarteriole 
forms  a  central  channel,  and  turns  inward  to  become 
a  venule  or  breaks  up  into  two  or  three  capillaries. 

The  mucosal  artery  continues  toward  the  muscu- 
laris  mucosa  after  having  given  off  the  vessels  just 
described  which  go  to  the  outer  muscular  coat.  One 
or  two  short  vessels  are  now  seen  to  branch  from  the 
mucosal  artery.  The  short  vessels  subdivide  into 
several  capillaries  which  reunite  as  a  venule  and 
empty  into  a  submucous  vein.  Deeper  in  the  sub- 
mucosa all  mucosal  arteries  anastomose  with  a  sim- 
ilar mucosal  artery  and  give  rise  to  one  or  two 
branches  which  in  turn  subdivide  to  form  capillary 
nets.  The  mucosal  artery  terminates  by  penetrating 
the  base  of  a  villus. 

Baez  was  unable  to  find  any  arteriovenous  anasto- 
moses in  the  submucosa  of  the  jejunum  or  ileum.  It 
was  possible  to  follow  all  the  arteries  and  arterioles  of 
the  submucous  plexus  to  their  finest  ramifications 
without  observing  any  short  cuts  from  the  arterial 
to  the  venous  side.  This  was  also  true  in  vessels  in  the 
muscular  coat.  He  does  elaborate,  however,  on  the 
direct  connection  between  arterioles  and  venules  at 
the  bases  of  villi.  While  the  arterial  component  does 
deliver  arterial  blood  directly  to  the  venule  which 
drains  the  villus,  it  cannot  be  called  a  true  arterio- 
venous anastomosis  in  that  the  arteriole  gives  off 
branches  to  neighboring  structures.  The  location  of 
these  vessels  is  the  same  as  the  location  of  vessels 
described  by  an  earlier  investigator  (117)  as  arterio- 
venous anastomoses.  Baez  points  out  that  in  an  in- 
jected and  fixed  preparation  the  capillary  offshoots 
might  be  closed,  giving  the  appearance  of  a  true 
arteriovenous  anastomosis. 

Two  or  three  venules  from  adjacent  villi  were  seen 
to  converge  to  form  a  mucosal  venule.  The  mucosal 
venule  also  was  joined  by  an  arterial  capillary  which 
originated  as  a  branch  of  the  nearest  mucosal  artery. 
The  small  vein  thus  formed  then  emerged  into  the 
submucosa  where  it  was  joined  by  other  veins  of 
similar  origin  to  form  an  intricate  anastomosing 
arcade.  These  submucous  arcades  were  further  en- 
larged by  venules  from  the  outer  muscular  coat.  The 
flow  of  blood  through  the  venules  of  the  muscular 


9o8 


HANDBOOK    OF    PHYSIOLOGY     ^    CIRCULATION    II 


coat  and  the  mucosal  venules  was  rapid  and  unidirec- 
tional. Backflow  of  blood  was  observed  in  veins  of  the 
submucosal  plexus. 

.1//.  rot  initiation  in  the  Bulbar  Conjunctiva 

The  bulbar  conjunctiva  is  a  highly  vascularized 
transparent  mucous  membrane  on  the  anterior  surface 
of  the  eye.  It  extends  from  the  palpebral  conjunctiva, 
which  lines  the  eyelid,  to  the  cornea.  The  pattern  of 
its  blood  vessels  were  derived  primarily  from  studies 
by  Grafflin  &  Corddry  (56)  and  Lee  &  Holze  (77). 

A  description  of  the  arrangement  of  the  superficial 
blood  vessels  of  the  human  conjunctiva  is  given  by 
Lack  et  al.  (74)  in  a  study  designed  to  observe  vascular 
changes  in  hypertension.  Arterioles  were  seen  to 
divide  into  numerous  side  capillaries  and  terminate 
with  an  end  capillary.  The  term  "end  capillary"  is 
not  defined.  The  end  capillary  on  occasion  functioned 
as  a  "through-and-through"  channel.  The  capil- 
laries appeared  to  be  uniform  in  caliber.  Only  rare 
arteriovenous  anastomoses  of  the  short  type  were 
seen. 

A  more  detailed  description  appears  in  a  paper  by 
Lee  &  Holze  (77)  in  1950,  in  which  they  state  that 
the  arrangement  of  terminal  arterioles,  capillaries, 
and  venules  in  the  human  conjunctiva  was  in  accord 
with  the  pattern  of  vessels  as  seen  in  the  omentum 
and  mesentery  of  other  animals,  referring  to  the  de- 
scriptions of  Chambers  &  Zweifach  (20)  and  Lee  & 
Lee  (78).  Capillaries  arose  at  intervals  from  end  ar- 
terioles to  form  an  irregular  network  of  vessels  which 
then  rejoined  to  form  the  venular  system.  The  ar- 
terioles were  also  seen  to  terminate  in  main  channels 
which  communicated  directly  with  a  venule.  This 
pattern  was  most  often  seen  at  the  corneoscleral 
junction.  It  was  also  noticed  that  blood  continued  to 
flow  from  arterioles  to  venules,  through  the  patent 
arteriovenous  channels,  at  a  time  when  there  was 
widespread  arteriolar  and  precapillary  constriction. 
The  precapillaries  were  found  to  be  more  sensitive  to 
stimuli  than  their  parent  arterioles. 

Observations  of  blood  flow  revealed  active  contrac- 
tion of  vessels.  Constriction  of  precapillaries  was  seen 
to  occur  at  their  point  of  origin  from  the  parent  ar- 
teriole. Attention  was  directed  to  these  precapillary 
sites  because  of  the  difficulty  in  determining  minor 
changes  in  diameter  or  flow  in  the  arterioles.  Com- 
plete constriction  occurred  at  the  precapillary  region 
lasting  for  2  to  3  min.  After  a  gradual  relaxation, 
blood  flow  continued  for  1  to  5  min  before  the  next 
constriction.  The  periods  of  constriction  and  relaxa- 


tion were  found  to  be  very  irregular,  with  relaxation 
predominating. 

Arteriolar  flow  was  rapid,  capillary  flow  was  slower, 
and  also  intermittent  due  to  spontaneous  changes  in 
diameter  at  the  precapillary  sites,  while  venous  flow 
speeded  up  after  entering  the  system  of  collecting 
venules  and  was  consistently  regular. 

The  proposal  of  a  definite  structural  and  functional 
unit,  such  as  the  preferential  channel,  as  described  by 
Chambers  &  Zweifach  (20)  in  the  rat  mesentery  and 
seconded  by  Lee  &  Holze  (77)  in  the  human  conjunc- 
tiva, prompted  Grafflin  &  Bagley  (55)  to  reinvestigate 
the  human  conjunctiva.  These  investigators  were  im- 
pressed by  an  endless  variety  of  vascular  patterns 
with  no  apparent  plan  of  organization.  This  paper 
was  followed  by  one  by  Grafflin  &  Corddry  (56)  who 
reinvestigated,  with  improved  equipment,  the  archi- 
tecture of  vascular  beds  in  the  human  conjunctiva 
in  an  effort  to  resolve  the  differences  between  the 
earlier  observations  and  those  of  Lee  &  Holze  (77). 
Once  again  they  reported  a  great  variety  of  vascular 
patterns  with  the  lack  of  any  recognizable  structural 
and  functional  unit  similar  to  that  proposed  by 
Chambers  &  Zweifach  (20).  They  saw,  however, 
vessels  between  arterial  and  venous  channels  that 
were  larger  than  capillaries.  They  believed  that  these 
vessels  were  arteriovenous  communications  with  a 
functional  significance  different  from  that  of  capil- 
laries. They  do  not  say  what  the  difference  is.  The 
arteriovenous  communications  were  seen  so  fre- 
quently that  the  investigators  believed  that  they  were  a 
characteristic  feature  of  the  conjunctival  vascular 
beds.  In  freehand  drawings  at  magnifications  up  to 
80  times,  a  variety  of  vascular  patterns  are  shown. 
The  arteriovenous  communications,  veno-venous 
anastomoses  and  arterio-arterial  anastomoses  are 
common  features  (fig.  12).  Although  at  first  glance 
the  vascular  pattern  may  seem  very  complex,  it  is 
comparable  in  its  arrangement  to  other  terminal 
vascular  beds  which  have  been  presented  in  such 
detail  covering  a  large  area.  A  smaller  area  is  seen 
in  figure  13. 

A  representative  type  of  arteriovenous  anasto- 
mosis, as  seen  in  vascular  beds  below  the  surface  of 
the  conjunctiva  (presumably  on  the  episcleral  sur- 
face), is  shown  in  figure  14.  It  bears  a  striking  re- 
semblance to  both  photomicrographs  and  diagrams 
of  the  vascular  bed  in  the  rat  mcsoappendix.  The 
authors  do  not  describe  the  kind  of  blood  flow  through 
these  vessels  which  would  qualify  them  as  preferential 
channels  on  a  functional  basis. 

The  vascular  patterns  presented  by  these  authors 


PATTERNS    OF    THE    A-V    PATHWAYS 


909 


fig.  12.  Superficial  vascular  pattern,  temporal  quadrant, 
right  eye.  [From  Grafflin  &  Corddry  (56).] 

may  be  considered  to  contain  all  the  blood  vessels  in 
the  areas  under  observation.  While  the  walls  of  capil- 
laries were  never  seen  and  their  detection  is  dependent 
on  the  presence  of  blood  in  the  vessels,  it  is  unlikely 
that  the  same  vessels  would  be  devoid  of  blood  con- 
sistently over  a  period  of  months  during  which  re- 
peated observations  were  made. 

Vasomotion  was  a  prominent  feature  of  flow  in  the 
vessels  of  this  mucous  membrane.  It  was  indicated  by 
variations  in  the  speed  of  flow,  alterations  in  the 
caliber  of  individual  vessels,  and  intermittent  blood 
flow  through  capillary  vessels.  Arterial  vessels  usually 


fig.   13.   Superficial  vascular  pattern,  nasal  quadrant,  right 
eye.   [From  Grafflin   &   Corddry   (56).] 


had  a  rapid  and  continuous  flow.  At  times  the 
arterial  vessels  showed  irregular  alterations  in  the 
rate  of  flow,  a  reduction  in  the  speed  occurring  some- 
times gradually,  sometimes  abruptly,  and  sometimes 
stopping  completely  for  a  brief  interval  before  surging 
forward. 

Concerning  small  arteriovenous  communications, 
there  are  three  criteria  to  distinguish  them  from 
true  capillaries:  /)  a  larger  caliber  than  capillaries, 
2)  vasomotion,  3)  continuous  flow  at  variable  speeds. 
However,  one  or  all  of  these  criteria  might  be  un- 
satisfied on  occasion.  Grafflin  &  Corddry  (56)  were 
unable  to  detect  precapillary  sphincters  at  the  points 
of  emergence  of  true  capillaries  from  the  arteriovenous 
channels.  It  may  be  assumed  that  this  failure  was  due 
to  the  limitations  of  the  technique,  in  that  the  walls  of 
the  small  vessels  were  not  seen  distinctly. 

Venous  flow  is  described  as  being  continuous  at  a 
relatively  moderate  speed  with  irregular  alterations 
in  flow.  At  times  the  flow  stopped  completely.  This 
does  not  concur  with  the  description  given  by  Lee  & 
Holze  (77),  who  reported  venous  flow  as  consistently- 
regular. 

Bloch  (15),  in  a  lengthy  article  dealing  primarily 
with  red  cell  aggregates,  describes  arterioles  and 
venules  in  the  bulbar  conjunctiva  in  the  following 
way:  Arterioles  in  the  bulbar  conjunctiva  do  not 
differ  from  arterioles  in  other  tissues.  As  elsewhere, 


giO  HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


c    ]  mm 


fig.  14.  Prominent  arteriovenous  anastomosis  lying  below  the  superficial  layer  of  the  conjunctiva. 
[From  Grafflin  &  Corddry  (56).] 


arterioles  are  most  readily  identified  by  noting  the 
direction  of  blood  flow.  The  direction  of  flow  in  these 
vessels  is  toward  progressively  smaller  vessels,  and 
the  smallest  of  them  empty  into  the  capillary  bed. 
Bloch  states  that  when  there  is  a  low  blood  volume, 
only  one  capillary  may  be  seen  connecting  the 
arterial  and  venous  systems.  The  arterial  segment  of 
this  single  vessel  has  a  more  rapid  rate  of  flow  through 
it  (does  not  say  more  rapid  than  what),  differs  in 
regard  to  the  direction  of  taper  of  its  walls  (pre- 
sumably larger  at  the  venous  than  the  arterial  end), 
and  is  less  permeable  than  the  venous  segment  (no 
basis  given  for  this  statement). 

Bloch  feels  that  the  difficulty  in  determining  which 
vessel  is  an  arteriole  has  arisen  partly  because  of 
sudden  changes  in  the  direction  of  flow.  According 
to  Bloch,  changes  in  direction  occur  when  an  arterio- 
venous anastomosis  opens,  causing  flow  in  the  peri- 
pheral segment  of  the  arteriole  to  stop  while  flow  in 
the  central  portion  of  the  venule  speeds  up.  He  states 
that  there  is  no  difficulty  in  recognizing  the  cause  of 
this  directional  change  if  the  arteriovenous  anasto- 
mosis opens  while  the  observer  is  watching  and  when 
the  site  of  the  arteriovenous  anastomosis  can  be 
found.  He  further  states  that  usually  the  site  of  the 
arteriovenous  anastomosis  is  not  identified. 

Linear  velocity  of  arterioles  is  greater  than  venules 
of  corresponding  diameter.  The  course  of  the  arte- 
rioles is  straight  compared  to  the  relatively  sinuous 
course  of  the  accompanying  venules.  Arteriolar 
branches  arise  gradually  from  their  parent  vessels, 
while  venules  branch  more  nearlv  at  right  angles. 
Arterioles  are  deeper  in  the  tissue  than  corresponding 
venules,  their  flow  rates  being  so  rapid  that  individual 
cells  cannot  be  recognized. 

Capillaries  are  described  as  cylinders,  in  contra- 
distinction to  arterioles  and  venules  which  are  cones. 

Some  difficulty  arises  in  comparing  the  descrip- 
tions of  the  vascular  structure  as  given  by  Bloch  with 
that  of  other  investigators  due  to  the  absence  of 
detailed  diagrams.  True  arteriolar  branches  are  not 
represented    in    other    vascular    beds    as    branching 


gradually,  although  this  type  of  branching  occurs  in 
vascular  nets  forming  arcuate  systems. 

Microcirculation  in  the  Spleen 

Differences  of  opinion  regarding  the  manner  in 
which  blood  is  conveyed  from  terminal  arterioles  to 
collecting  venules  in  the  spleen  still  exist  in  spite  of 
the  continued  efforts  of  numerous  investigators  to 
resolve  the  controversy.  Current  histology  textbooks 
(9,  112)  present  three  views.  The  theory  of  closed 
circulation  is  that  blood  in  the  spleen  flows  through 
completely  endothelium-lined  pathways  from  its 
entrance  into  the  spleen  through  the  splenic  artery 
to  its  exit  from  the  spleen  through  the  splenic  vein. 
The  theory  of  open  circulation  proposes  that  arterial 
terminations  in  the  spleen  pour  blood  flowing  through 
them  into  the  interstices  of  the  reticulum  of  the  red 
pulp.  The  walls  of  the  venous  sinusoids  are  incom- 
plete, having  longitudinal  slits  between  the  reticular 
cells  which  make  up  the  lining  of  the  sinuses.  A  third 
view  is  a  compromise  between  the  open  and  closed 
systems  in  that  some  of  the  capillaries  are  thought  to 
open  into  the  intercellular  spaces  while  others  open 
directly  into  the  sinuses. 

It  was  hoped  that  the  introduction  of  a  technique 
which  permitted  observation  of  the  spleen  of  a  living 
animal  might  settle  the  controversy.  In  1936,  Knisely 
(69)  studied  living  transilluminated  spleens  of  mice, 
rats,  and  cats  and  reported  that  each  vessel  traced  in 
the  spleen  was  connected  to  the  arterial  system  and 
the  venous  system.  No  vessels  were  seen  to  open  out 
into  or  pour  blood  into  intercellular  pulp  spaces. 
The  lining  of  the  arterioles,  arterial  capillaries, 
capillaries,  venous  sinuses,  and  venules  was  readily 
apparent  through  the  microscope  as  a  narrow,  clear, 
sharply  refractile  line,  visible  also  during  periods 
when  no  blood  was  flowing  through  the  vessels. 
Knisely's  conclusion  was  that  the  vascular  system  of 
the  spleen  consisted  of  a  series  of  completely  inter- 
connected, preformed,  lined  channels.  He  describes 
spontaneous  vasoconstriction  in  the  arterial  branches 


PATTERNS    OF    THE    A-V    PATHWAYS 


9" 


as  well  as  in  the  venous  sinuses,  and  assigned  this 
normal  activity  of  vascular  smooth  muscle  to  ''physio- 
logical sphincters."  No  significant  differences  were 
noted  in  the  structure  or  activities  of  living  mouse, 
rat,  and  cat  spleens. 

In  1941,  MacKenzie  et  al.  (83)  reported  that  they 
had  been  unable  to  confirm  Knisely's  findings.  They 
point  out  that  the  modern  concensus  favored  a 
splenic  circulation  that  had  an  open  component 
which  allowed  flooding  of  the  pulp  interstices  with 
whole  blood,  and  additional  pathways  afforded  a 
closed  circulatory  component.  The  reception  of 
Knisely's  investigations  had  been  favorable  and 
"offered  a  reasonable  conclusion  to  an  otherwise 
apparently  interminable  discussion.''  However,  they 
were  not  able  to  see  what  Knisely  had  seen.  In 
transilluminated  spleens  of  mice,  the  walls  of  follicle 
arteries  were  seen  as  sharply  refractile  lines,  running 
parallel,  the  diameters  of  the  vessels  uniform  except 
when  constriction  occurred.  The  follicle  arteries 
branched  two  or  three  times  to  form  penicilli,  syno- 
nyms being  pulp  arteries,  sheathed  arteries,  or  pulp 
arterioles.  They  were  able  to  see  only  the  peripheral 
portion  of  the  follicle  capillary  network,  the  ultimate 
twigs  penetrating  the  marginal  zone  of  the  red 
pulp.  Terminal  capillary  branches,  as  many  as  eight 
in  number,  enter  the  adjacent  red  pulp  and  develop 
funnel-shaped  dilatations.  These  arteriocapillary 
ampullae  communicate  directly  with  the  pulp 
interstices  by  way  of  numerous  apertures.  As  the 
lumen  of  the  capillary  widens  in  the  formation  of  its 
ampulla,  the  refractive  quality  of  the  vessel  wall  is 
rapidly  lost.  The  parallel  linear  shadows  produced 
by  the  capillary  are  replaced  by  the  contours  of  pulp 
cells. 

Venous  sinuses  originate  in  the  red  pulp  by  an 
enclosure  of  pulp  spaces.  A  venous  sinus  gradually 
increases  in  diameter  to  a  maximum  and  then  joins  a 
vein.  The  wall  of  the  venous  sinus  is  composed  of 
loosely  connected  cells  lying  parallel  to  the  long 
axis.  The  openings  between  these  cells,  according  to 
MacKenzie  et  al.,  permit  the  free  passage  of  blood 
cells. 

The  interstices  of  the  pulp  provide  the  one  and  only 
type  of  connection  seen  by  them  to  link  the  arterial 
and  venous  systems  in  the  spleens  of  mice,  rats, 
rabbits,  guinea  pigs,  and  cats.  They  state,  however, 
that  in  all  spleens  there  were  instances  when  an 
arterial  capillary  appeared  to  be  connected  by  a 
vessel  to  an  adjacent  venous  sinus,  but  this  proved  to 
be  an  optical  illusion  caused  by  weaknesses  inherent 
in     the     transillumination     technique.     Spontaneous 


arterial  vasoconstrictions  were  seen  to  occur  inter- 
mittently and  were  a  factor  in  the  control  of  circula- 
tion of  blood  through  the  small  vessels  as  were  trabec- 
ular and  capsular  contractions.  MacKenzie  et  al. 
believed  that  the  results  of  their  work  supplied 
additional  confirmation  of  an  open  circulation  for  the 
mammalian  spleen. 

Bjorkman  (11)  studied  rabbit  spleens  following  the 
injection  of  starch  granules  and  concluded  from  the 
distribution  of  the  grains  that  circulation  through  the 
spleen  was  the  open  type. 

A  detailed  and  convincing  report  in  favor  of  the 
closed  system  of  circulation  appeared  in  1 951 , 
authored  by  Peck  &  Hoerr  (94).  They  selectively 
attacked  statements  made  in  the  paper  by  Mac- 
Kenzie et  al.  (83),  pointing  out  where  possible 
technical  variances  could  explain  the  differences  in 
their  observations.  Peck  and  Hoerr  found  the  inter- 
mediate circulation  of  the  spleen  of  the  mouse  to  be 
essentially  as  Knisely  (6g)  described  it.  They  say  that, 
on  arriving  at  the  red  pulp,  arteries  branch  two  to  six 
times  to  form  the  penicillar  arteries  which  then 
extend  into  the  red  pulp  10  to  15  u  before  branching 
several  times  to  form  capillaries.  Where  more  than  two 
capillaries  arise  from  a  red  pulp  artery,  the  termina- 
tion of  the  artery  may  be  ampulla-shaped  (see  fig.  15). 
There  is  no  discontinuity  of  the  refractile  lines  from 
artery  to  capillary,  and  these  lines  caused  by  the 
vessel  walls  must  be  endothelium  or  reticular  fibers. 
Capillaries  extend  in  all  directions  from  the  ampulla- 
like terminations  of  the  penicillar  arteries  to  terminate 
in  venous  sinuses  or  venules  (fig.  16). 

The  course  taken  by  a  capillary  may  be  straight, 
curved,  or  tortuous.  If  they  have  a  tortuous  course  it 
is  often  difficult  to  follow  them  because  they  run 
under  other  vessels  or  extend  beyond  the  range  of 
focus.  Capillaries  may  turn  away  from  view  at  their 
point  of  origin,  giving  the  ampulla-like  termination 
of  the  penicillar  artery  the  appearance  of  ending  in  a 
sac  or  pouring  its  blood  into  the  pulp.  The  capillaries 
can  be  seen  to  terminate  in  the  venous  sinuses,  the 
walls  of  which  (more  difficult  to  see  in  the  contracted 
spleen)  are  continuous  with  the  walls  of  the  capillary. 

Penicillar  arteries  have  a  powerful  sphincter  action, 
although  an  artery  may  contract  along  its  entire 
length.  Individual  arteries  may  exhibit  this  con- 
striction independently  of  neighboring  arteries,  which 
continue  to  have  a  rapid  flow.  Fairly  constant  blood 
flow  over  a  period  of  hours  is  seen  in  straight  capil- 
laries which  terminate  in  venules.  In  some  cases  red 
cells  may  seem  to  wander  in  the  extravascular  tissue, 


912 


HANDBOOK    OF    PHYSIOLOGY    -^    CIRCULATION    II 


fig.    15.   An  ampulla  of  a  red  pulp  artery. 
[From  Peck  &  Hoerr  (94).] 


fig.  16.  Diagram  summarizing  the  main  types  of  arterio " 
venous  connections  in  the  mouse  spleen.  [From  Peck  &  Hoerr 

(94)-] 

but  proper  focusing  shows  them  to  be  within  tortuous 
capillaries. 

Peck  and  Hoerr  conclude  from  their  observations 
that  blood  in  the  spleen  passes  through  lined,  intact 
blood  vessels  which  join  the  arterial  and  venous 
systems. 

The  next  major  reports  on  intermediate  circulation 
in  the  spleen  were  by  Parpart  et.  al.  (93)  and  Whipple 
et  al.  (133),  and  favored  open  circulation.  These 
investigators  saw  three  ways  in  which  trabecular 
arteries,    terminating    as    arterioles,    connected    with 


collecting  veins.  Most  of  the  arterioles  spewed  blood 
through  funnel-shaped  openings  into  large  pulp 
spaces  from  which  the  blood  flowed  into  collecting 
veins.  Some  of  the  arterioles  made  direct  connection 
with  collecting  veins,  and  such  connections  were 
called  arteriolar-venous  anastomoses.  A  few  of  the 
arterioles  were  seen  to  branch  into  a  loose,  irregular 
capillary  network  which  formed  venules  that  returned 
to  the  collecting  veins.  Considering  each  component 
of  the  system  from  arteriole  to  veins  separately, 
Parpart  et  al.  (93)  state  the  following:  Terminal 
arterioles  are  thick  and  muscular  and  show  con- 
tinuous diameter  changes  clue  to  constriction  and 
relaxation  of  the  vascular  muscle.  The  terminations 
of  these  arterioles  are  usually  three-dimensional  and 
funnel-shaped  with  the  flared  ends  becoming  too  thin 
to  be  seen  with  the  microscope.  This  indicates, 
according  to  Parpart  et  al.,  that  the  flare  thins  out  to 
a  condition  of  no  endothelial  covering  of  the  blood 
that  flows  out  of  the  ampulla  into  the  pulp.  The  pulp 
space  may  be  fed  by  only  one  arteriole  or  by  several. 
Pulp  (reticular)  cells  are  scattered  throughout  the 
space  seemingly  held  in  position  by  connective  tissue 
strands.  Red  and  white  blood  cells  can  be  seen  to 
enter  and  leave  the  main  stream  of  blood  flowing 
through  the  pulp  space,  remaining  outside  the  stream 
and  thus  stationarv  for  variable  periods.  The  pulp 
spaces  are  interconnected  as  shown  by  the  passage  of 
blood  cells  between  them.  Collecting  veins  are  seen 
in  the  pulp  spaces  at  positions  opposite  to  the  arteriole 
entrance,  receiving  blood  through  end  and  lateral 
openings  in  their  walls.  The  lateral  openings  are 
large  enough  in  some  instances  to  allow  the  passage 


PATTERNS    OF    THE    A-V    PATHWAYS 


9'3 


of  several  red  cells  abreast.  The  collecting  veins  are 
described  as  thin-walled  structures  randomly  per- 
forated with  holes  of  varying  sizes  that  are  part  of  a 
branched-treelike  arrangement.  Although  capillary 
networks  supplied  by  an  arteriole  and  feeding  into 
veins  are  occasionally  seen,  there  are  relatively  few 
of  them.  The  capillaries  are  said  to  have  holes  in  their 
walls  through  which  blood  enters  or  leaves  the  ad- 
jacent pulp  space. 

Parpart  et  al.  report  that  they  have  never  seen  a 
venous  sinus  of  the  type  described  by  Knisely  (69), 
nor  have  they  seen  any  activity  in  the  venous  pulp 
spaces  that  could  be  regulatory  to  the  blood  flowing 
through  them.  This  is  in  direct  opposition  to  state- 
ments by  Knisely  (71)  and  by  Peck  &  Hoerr  (94) 
regarding  the  regulation  of  blood  flow  through  the 
splenic  pulp.  Knisely  (71)  took  exception  to  the 
conclusions  of  Parpart  et  al.  (93),  particularly  pointing 
out  that  their  optical  arrangements  were  such  that 
not  all  structures  present  in  the  tissue  would  neces- 
sarily be  observed.  With  the  quartz  rod,  which 
Knisely  used,  it  is  possible  to  direct  the  light  first  one 
way  and  then  another  and  thereby  make  previously 
unobserved  structures  visible  (69). 

In  1958,  Snook  (115),  who  believed  one  reason  for 
disagreement  concerning  splenic  circulation  was  the 
structural  variability  of  the  spleen  among  mammals, 
reported  on  fixed  rabbit  spleens.  He  had  previously 
classified  the  mouse  with  mammals  that  had  non- 
sinusal  spleens  (114),  and  comparative  studies 
showed  that  the  rabbit  spleen  was  more  nearly  like 
human  spleen  than  the  other  animals  observed. 
Conclusions  from  his  histological  studies  of  the  rabbit 
were  that  rabbit  spleen  had  the  open  type  of  inter- 
mediate circulation,  that  white  pulp  capillaries 
occasionally  connected  directly  with  premarginal 
sinuses,  and  that  penicillar  branches  terminated  in 
pulp  cords  in  ampullary  dilatations. 

In  the  1958  edition  of  Bailey's  Textbook  of  Histology 
(112)  the  authors  take  the  stand  that  "there  is  a 
fairly  direct  connection  from  the  capillary  to  the 
venous  sinus  in  most  cases,  but  the  system  is  open  in 
the  sense  that  the  lining  membrane  changes  from 
endothelial  cells  to  flattened  reticular  cells,  and 
contains  perforations  through  which  erythrocytes 
may  readily  pass." 

Fleming  &  Parpart  (41)  investigated  the  spleens  of 
young  rats  and  found  them  to  be  very  different  from 
mice.  Capillary  networks  were  seen  which  had  a 
pattern  very  similar  to  that  of  mesenteric  circulation 
(144).  No  venous  sinus  or  pulp  spaces  were  found. 


Vascular  walls  were  easily  seen  and  very  few  red  blood 
cells  were  free  in  the  intercellular  space. 

Fleming  and  Parpart  suggest  that  such  a  capillary- 
pattern  in  the  rat  is  an  infantile  characteristic  and 
that  pulp  spaces  develop  when  the  animal  becomes 
more  mature.  They  believe  that  the  fact  that  endo- 
thelial walls  can  be  seen  with  such  clarity  in  this 
preparation  proves  that  they  could  also  be  seen,  if 
present,  in  the  spleens  of  mice.  Thus  the  position 
taken  by  Parpart  for  an  open  system  of  intermediate 
circulation  in  the  mouse  spleen  appears  strengthened. 

It  is  very  difficult  for  an  unbiased  reader  to  decide 
in  favor  of  one  or  the  other  types  of  circulation  in  the 
spleen  because  of  the  convincing  arguments  presented 
by  the  proponents  of  each.  It  has  been  suggested, 
however,  that  the  burden  of  proof  rests  upon  those 
who  favor  the  open  type  of  circulation,  since  endo- 
thelium is  universally  present  in  every  other  vascular 
system  (26). 

There  are  one  or  two  structural  arrangements 
described  by  Parpart  et  al.  which  would  be  unique  if 
they  do  exist,  i.e.,  capillary  vessels  with  holes  in  their 
walls  through  which  blood  enters  or  leaves  the  ad- 
jacent pulp  area,  and  veins  which  have  end  and 
lateral  openings  varying  in  size  from  5  to  20  jx,  the 
latter  openings  being  randomly  spaced  along  the 
endothelial  lining  of  the  veins. 

Williams  (139)  expressed  the  opinion  that  the 
entire  spleen  might  be  thought  of  as  a  modified  blood 
vessel  with  certain  special  structures  in  its  lumen  and, 
therefore,  that  the  endothelial  lining  of  the  internal 
blood  channels  might  have  a  different  significance 
than  elsewhere. 

Microcirculation  in  the  Lung 

Microscopic  observations  of  pulmonary  circulation 
date  back  to  Malpighi  (84)  in  1661.  Occasional 
reports  appeared  in  the  literature  from  time  to  time 
after  this,  possibly  the  greatest  concentration  being 
in  the  1930's. 

In  1930,  Olkon  &  Joannides  (gi,  92)  studied  the 
pulmonary  circulation  in  dogs,  frogs,  and  alligators ! 
The  optical  magnification  was  quite  low  by  present 
day  standards  (60  X)  and  the  fact  that  the  animals 
were  on  artificial  respiration  and  their  lungs  in  con- 
stant motion  must  have  added  considerable  difficulty 
to  their  investigation.  They  describe  what  appeared 
to  be  a  large  capillary  lying  between  the  walls  of  the 
alveoli  from  which  many  smaller  capillaries  were 
given  off.  They  believed  that  the  single  large  capillary 
surrounding  the  alveolus  was  most  likely  a  capillary 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  i  7.  Sketch  of  air  sac  and  its  vessels  in  the  lung  of  a  cat. 
[From  VVearn  et  al.  (128).] 

network  seen  on  edge.  The  smaller  capillaries  anasto- 
mosed frequently  with  each  other  and  appeared  to 
contract  and  relax. 

In  1933,  Daly  (38)  reviewed  pulmonary  circulation 
and  briefly  mentioned  microscopic  observations  of 
pulmonary  vessels,  but  these  studies  were  concerned 
primarily  with  the  response  of  small  vessels  to  epi- 
nephrine. There  were  no  papers  in  which  normal 
vascular   patterns  were  described. 

Wearn  et  al.  (128)  introduced  a  method  for  the 
observation  of  minute  vessels  in  the  lung  which 
utilized  a  quartz  rod,  for  transmitting  light,  placed 
inside  the  chest  cavity.  The  vessels  were  observed 
microscopically  in  the  lung  tip  through  a  window  in 
the  chest  wall.  Observations  were  made  on  both 
moving  and  immobilized  lungs.  Arteriolar  vessels 
showed  pulsatile  flow  and  steady  flow,  a  different 
type  of  flow  often  occurring  in  two  arteriolar  branches 
from  the  same  parent  arteriole.  Arterioles  were  seen 
to  contract  and  relax,  and  reversal  of  the  direction  of 
blood  flow  was  common.  The  walls  of  the  capillaries 
were  invisible,  so  that  the  caliber  of  the  vessel  and  its 
course  were  determined  by  the  column  of  blood  it 
contained.  Capillary  vessels  were  seen  to  branch  and 
anastomose  frequently  (see  fig.  17).  Wearn  et  al. 
report  spontaneous  opening  and  closing  of  capillaries, 
but  the  fact  that  the  differentiation  between  arteriole 
and  capillary  was  based  on  the  number  of  blood  cells 
which  the  vessel  would  accommodate  (three  or  less 
for  a  capillary)  throws  some  doubt  on  the  validity  of 
this  statement.  Also,  the  suggestion  is  made  later  in 
the  report  that  intermittent  flow  in  capillaries  was 


probably  due  to  changes  in  the  flow  of  arterioles 
from  which  the  capillaries  arose  and  that  no  proof  of 
contraction  of  capillary  walls  was  obtained.  The 
capillary  network,  depicted  by  Wearn  et  al.  as  covering 
an  alveolus,  is  very  similar  to  that  in  many  other  sites. 

The  next  detailed  report  of  vascular  architecture  of 
the  lungs  appeared  in  1954,  when  Irwin  and  his 
associates  (66)  published  the  results  of  microscopic 
observations  on  guinea  pigs  and  rabbits.  The  tech- 
nique used  was  that  of  transillumination  with  a 
quartz  rod  and  oxygen  insufflation  to  prevent  re- 
spiratory movements.  These  investigators  traced 
pulmonary  arterioles  to  terminal  pulmonary  arterioles 
which  branched  to  form  capillaries.  Blunt  termina- 
tions of  pulmonary  arterioles,  which  lie  in  the  septa 
between  alveoli,  gave  rise  to  capillaries  which  then 
spread  over  several  adjacent  alveoli.  Pulmonary 
capillaries  were  seen  to  be  completely  lined  cylindrical 
tubes  which  branched  and  anastomosed  to  form 
intricate  networks  over  the  surfaces  of  alveoli.  The 
capillary  network  was  often  supplied  by  several 
terminal  arterioles  and  each  network  was  drained  by 
more  than  one  venule.  Arteriovenous  shunts  were 
found  between  a  pulmonary  arteriole  and  venule  that 
ran  side  by  side  in  an  alveolar  septum. 

Additional  observations  by  Irwin  &  Burrage  (67) 
were  that  the  diameters  of  arterioles  and  venules 
changed  size  when  measurements  of  their  walls  were 
made  over  long  periods  of  time,  affecting  the  flow  of 
blood.  Alterations  in  the  diameters  of  the  arterioles 
were  more  marked  than  venular  changes.  Irwin  and 
Burrage  report  that  the  walls  of  the  capillaries  cover- 
ing an  alveolus  were  seen  to  come  together  to  ob- 
literate their  lumina.  They  suggest  that,  although  the 
intermittent  blood  flow  in  pulmonary  capillaries 
could  be  due  to  contraction  of  either  arterioles  or 
venules,  the  possibility  of  activity  in  the  capillary  walls 
must  be  considered.  That  capillary  walls  might 
contain  contractile  tissue,  or  that  the  endothelium 
lining  the  cells  might  swell  to  block  the  lumina  are  the 
possible  means  offered  by  the  authors  for  causing 
intermittent  flow  in  pulmonarv  capillaries. 

A  surprisingly  small  number  of  investigations  of  the 
normal  vascular  structures  and  flow  of  blood  in 
microscopic  pulmonarv  vessels  have  been  carried  out. 
However,  Wearn's,  diagrams  (128)  and  the  descrip- 
tions by  Irwin  et  al.  (66)  of  capillary  networks  covering 
alveoli  indicate  that  this  terminal  vascular  bed  is  made 
up  of  the  same  structural  components  with  the  same 
basic  form  as  that  of  beds  in  other  tissues  and  organs. 
Perhaps  further  investigations  will  explain  the  ap- 
parent closure  of  "capillary"  walls  seen  by  Irwin  & 


PATTERNS    OF    THE    A-V    PATHWAYS 


9'5 


Burrage  (67).  The  most  likely  explanation  for  inter- 
mittent flow  through  these  minute  capillary  vessels 
is  that  the  terminal  arterioles  and  precapillary 
vessels  which  supply  the  capillary  nets  exhibit  spon- 
taneous vasomotion  as  seen  in  other  areas. 

Microcirculation  in  the  Cochlea 

The  general  pattern  of  blood  vessels  of  the  cochlea 
has  been  known  for  some  time,  the  early  descriptions 
being  obtained  from  injected  and  fixed  material. 
In  general  terms  (40)  the  cochlea  is  supplied  by  the 
cochlear  artery.  This  vessel  enters  the  modiolus 
through  the  internal  auditory  meatus.  The  spiral 
ganglion  has  a  rich  supply  of  capillaries,  and  many 
arterioles  find  their  way  to  the  spiral  ligament  by  way 
of  the  roof  of  the  scala  vestibuli.  The  stria  vascularis 
is  a  rich  network  of  small  blood  vessels  with  many 
anastomotic  connections.  The  limbus  has  a  capillary 
supply,  and  the  tympanic  surface  of  the  basilar 
membrane  often  has  a  small  arteriole  running  along 
it.  Renewed  interest  in  the  blood  supply  of  the 
cochlea  in  the  past  few  years  has  resulted  from  apply- 
ing microcirculatory  techniques  to  this  rather  in- 
accessible site. 

The  capillary  networks  of  several  portions  of  the 
cochlea  have  been  studied  in  detail.  The  areas  so 
studied  include  the  spiral  ligament,  a  projection  of 
thickened  periosteum  lying  on  the  outer  wall  of  the 
osseous  canal  of  the  cochlea;  the  spiral  prominence, 
a  slight  ridge  which  projects  into  the  cochlear  duct; 
and  the  stria  vascularis,  the  part  of  the  spiral  ligament 
lying  on  the  outer  wall  of  the  cochlear  duct  between 
the  spiral  prominence  and  the  vestibular  membrane. 

Two  papers  by  Smith  (1 10,  1 1 1),  which  contain  a 


detailed  description  of  cochlea  blood  vessels  obtained 
from  fixed  material,  will  be  considered  before  dis- 
cussing in  vivo  preparations.  Investigations  of 
capillary  beds  following  intravascular  precipitation 
of  Prussian  blue  or  lead  chromate  in  the  cochlea  of 
guinea  pigs,  cats,  and  humans  were  carried  out  by 
Smith.  She  felt  that  while  large  features  of  the  circu- 
latory patterns  had  been  adequately  demonstrated, 
the  capillary  beds  had  been  indistinctly  shown  and 
no  attempts  had  been  made  to  locate  them  precisely 
in  relation  to  various  portions  of  the  inner  ear. 

In  these  studies,  the  radiating  arteriole  was  found 
to  ramify  into  terminal  branches  before  entering  the 
spiral  ligament.  In  the  cat  and  guinea  pig  four  groups 
of  small  vessels,  depending  on  their  location  and  the 
course  which  they  took,  were  designated  by  Smith. 
The  first  group  was  the  network  of  the  upper  spiral 
ligament,  group  two  was  in  the  stria  vascularis,  group 
three  was  found  in  the  spiral  prominence,  while 
group  four  was  formed  by  the  capillaries  of  the  lower 
portion  of  the  spiral  ligament.  In  human  labyrinths 
a  fifth  group,  straight  vessels  in  the  thicker  portion  of 
the  spiral  ligament,  was  included  in  the  classification 
(see  fig.  18).  The  network  in  the  upper  spiral  ligament 
is  described  as  follows:  Small  branches  from  the 
radiating  arteriole  or  one  of  its  terminal  ramifications 
have  a  winding  course  in  a  spiral  direction  usually 
above  the  attachment  of  Reissner's  membrane.  These 
small  branches  are  seen  to  anastomose  with  other 
tributaries.  They  leave  the  upper  spiral  ligament  bv 
turning  downward  to  the  thicker  part  of  the  spiral 
ligament  where  they  join  venules,  or  they  may  turn 
upward  and  go  through  the  bone  wall  to  end  in  a 
collecting  vein.  The  capillaries  in  the  second  group, 
the  stria  vascularis,   are  extensively  connected  with 


fig.  18.  Schematic  drawing  showing  typical 
distribution  of  small  blood  vessels  in  the  spiral 
ligament  of  the  human  cochlea.  [From  Smith  & 
Giovacchine  (113).] 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


one  another  and  give  the  appearance  of  a  network 
superimposed  upon  the  deeper  vessels  of  the  spiral 
ligament.  The  superior  and  inferior  borders  appear 
straight  and  parallel.  A  large  venule  drains  the 
network,  formed  by  the  junction  of  three  or  four 
strial  capillaries.  The  venule  turns  backward  and 
leaves  the  stria  vascularis  in  its  lower  half  where  it 
descends  peripherally,  sometimes  joined  by  other 
venules  before  entering  into  the  collecting  venous 
system  at  the  lower  edge  of  the  spiral  ligament.  The 
blood  supply  of  the  spiral  prominence,  the  third 
group,  is  different  in  the  guinea  pig  from  cat  and  man. 
In  the  guinea  pig  a  single  vessel  is  found  near  the 
epithelial  layer,  with  perhaps  a  single  layer  of  con- 
nective tissue  cells  interposed.  The  vessel  courses 
parallel  to  the  network  of  the  stria  vascularis  just 
below  its  inferior  border,  although  no  vessel  of  the 
spiral  prominence  is  ever  connected  to  the  network  of 
the  stria  vascularis.  At  times  the  vessel  is  double,  with 
the  duplicate  vessel  running  under  the  edge  of  the 
stria  vascularis.  The  venules  join  the  collecting 
venules  of  the  lower  spiral  ligament.  In  the  human, 
the  vessels  in  the  spiral  prominence  form  a  separate, 
narrow,  rolled  network  below  the  stria  vascularis, 
supplied  by  large  arteriolar  vessels  and  drained  by 
large  veins.  Small  vessels  leave  the  network  by  turning 
upward  and  laterally  into  the  spiral  ligament  before 
emptying  into  veins.  They  also  may  enter  venules  in 
the  lower  spiral  ligament. 

The  capillary  network  in  the  lower  spiral  ligament 
is  also  supplied  by  direct  large  arteriolar  branches. 
These  arteriolar  branches  descend  close  behind  the 
stria  vascularis  and  terminate  in  a  spiral  vessel  in  the 
crest  of  the  spiral  ligament.  Branches  are  given  off 
to  the  stria  vascularis  and  spiral  prominence  on  the 
way.  The  spiral  vessel  marks  the  upper  limit  of  a 
network  which  originates  from  it.  Where  the  spiral 
ligament  is  quite  thin,  the  network  can  be  seen  as  a 
loose  mesh  of  vessels  under  the  mesothelium  of  the 
scala  tympani. 

The  fifth  group  found  in  the  human  is  made  up  of 
straight  vessels  found  in  the  connective  tissue  between 
the  scalae  and  the  bone.  They  show  variations  in  size 
and  structure,  and  course  directly  from  arteriole  to 
venule.  Some  seem  to  be  capillaries,  being  devoid  of 
perivascular  cells,  while  others  are  larger  and  may 
represent  a  type  of  arteriovenous  shunt. 

The  radiating  arteriole  was  found  to  have  both 
longitudinal  and  tangential  smooth  muscle  cells  and 
a  thin  adventitia  of  two  or  three  layers  of  connective 
tissue  cells.  Capillaries  were  composed  of  endothelial 
cells  and  infrequent  smooth  muscle  cells.  The  capil- 


laries of  the  stria  vascularis  were  composed  only  of 
endothelial  cells,  although  occasionally  a  perivascular 
cell  was  seen.  It  could  not  be  determined  whether  it 
was  a  smooth  muscle  cell  or  not.  The  large  draining 
vein  was  seen  to  have  a  few  smooth  muscle  cells 
arranged  transversely  or  tangentially. 

Smith  concludes  that  the  human  cochlea  shows  a 
definite  arteriolar  supply  to  the  various  vascular 
groups  of  the  spiral  ligament.  There  are  several 
distinct  capillary  networks  rather  than  one  large 
continuous  field,  and  these  networks  are  separated  by 
their  vascular  supply  and  drainage.  She  suggests  that 
such  a  vascular  pattern  makes  it  possible  to  have 
regional  circulatory  variations  within  a  small  segment 
of  the  spiral  ligament. 

In  1954,  Weille  et  al.  (131,  132)  published  two 
papers  describing  the  circulation  in  the  spiral  liga- 
ment and  stria  vascularis  of  the  living  guinea  pig. 
The  cochlea  was  first  exposed  and  then  microscopic 
fenestration  of  either  the  apical  or  third  cochlear  turn 
was  carried  out.  The  vessels  observed  included 
arterioles,  arteriovenous  anastomoses,  capillaries, 
and  venules  of  the  spiral  ligament  and  the  capillary 
network  of  the  stria  vascularis.  Capillaries  of  the 
spiral  ligament  formed  an  intricate  network  of 
dividing  and  anastomosing  vessels  fed  by  arterioles. 
Arteriovenous  anastomoses  were  formed  as  a  branch 
of  an  arteriole  that  entered  a  venule  with  no  inter- 
vening capillary  network.  The  capillaries  of  the  stria 
vascularis  formed  a  network  of  branching  and 
anastomosing  vessels  that  emptied  into  the  venules  of 
the  spiral  ligament. 

All  arterioles,  arteriovenous  anastomoses,  and 
venules  contracted  and  dilated  independently.  The 
rate  of  blood  flow  varied  in  each  vessel  from  time  to 
time,  going  from  very  rapid  to  no  flow  at  all. 

A  more  detailed  description  followed  (65),  in  which 
it  was  reported  that  there  were  two  distinct  types  of 
tiny  vessels,  one  in  the  area  of  the  upper  spiral  liga- 
ment and  the  other  in  the  area  of  the  pigmented 
cells  (the  cochlear  duct).  Branching  and  anastomosing 
were  frequent  in  these  networks.  Both  received  blood 
from  the  arterioles  and  both  drained  into  the  venules 
in  the  area  of  the  cochlear  duct. 

Collecting  venules,  into  which  the  capillaries  drain, 
pass  transversely  through  the  area  of  the  cochlear 
duct,  and  drain  into  the  venules  which  are  perpen- 
dicular to  them  and  lie  outside  this  area. 

Vessels  which  ran  from  arterioles  to  venules  were 
seen  to  give  off  capillaries,  but  no  capillaries  were 
seen  to  re-enter  them.  For  this  reason  they  were 
called    arteriovenous   anastomoses  rather   than   met- 


PATTERNS    OF    THE    A-V    PATHWAYS 


9J7 


arterioles,  a  name  given  to  them  by  Seymour  (109). 
The  anastomoses  were  seen  to  contract  to  complete 
closure. 

Microscopic  observations  of  cochlear  blood  vessels 
in  living  guinea  pigs  were  reported  by  Perlman  & 
Kimura  (95,  96)  in  1955.  Special  attention  was  given 
to  the  small  vessels  of  the  spiral  ligament  and  the 
stria  vascularis.  The  quartz  rod  technique  was  used 
after  the  cochlea  was  fenestrated  in  the  fourth  turn. 
The  fenestra  was  o.  1  to  0.2  mm'2  and  exposed  the 
spiral  ligament  on  the  lateral  wall  of  the  cochlear 
duct  as  well  as  the  stria  vascularis.  Perlman  and 
Kimura  were  certain  that  all  vessels  in  the  field  were 
visible  to  them  and  that  all  the  basic  units  of  a  vascu- 
lar bed  were  present.  The  identification  of  the  various 
components  was  based  on  the  diameter,  the  wall 
thickness,  shape  of  the  vessels,  the  rate  and  direction 
of  flow,  and  the  presence  of  smooth  muscle  cells  and 
vasomotion.  Numerous  anastomoses  between  all 
types  of  vessels  were  seen,  but  the  distribution  and 
direction  of  flow  from  the  radiating  arteriole  to  the 
collecting  venule  suggested  a  segmental  blood  supply. 

The  arterioles  of  the  spiral  ligament  were  seen  to 
branch  into  a  number  of  different  vessels.  A  small 
branch  at  right  angles  to  the  radiating  arteriole  was 
seen  to  run  parallel  to  the  cochlear  duct  in  the  upper 
portion  of  the  spiral  ligament.  It  anastomosed  with  a 
similar  vessel  from  an  adjacent  arteriole. 

Another  branch  was  seen  that  crossed  the  under- 
lying stria  vascularis  and  emptied  into  the  collecting 
vein  below  the  cochlear  duct.  This  type  of  vessel, 
regularly  seen  in  the  area,  has  no  branches,  is  narrow 
and   straight,   and   has   a   rapid    blood   flow.    It   has 


ft.  COCHLEAE 
PROPRIA 


H   .V.  SPIRALIS 

'/■  POSTERIOR 


fig.  19.  Segment  of  cochlea  showing  relation  of  exposed 
vessels  to  the  cochlear  duct  and  the  main  trunks  in  the  modiolus. 
[From  Perlman  &  Kimura  (95).] 


smooth  muscle  cells  regularly  distributed  along  its 
walls.  The  authors  have  called  this  vessel  an  arterio- 
venous arcade.  (See  figs.  19  and  20.) 

Another  branch  of  the  radiating  arteriole  with  a 
uniform  diameter  extends  over  the  underlying  stria 
vascularis,  has  no  branches,  and  ends  at  the  level  of 
the  spiral  prominence  just  below  the  stria  vascularis. 
The  vessel  with  which  the  branch  connects  runs  paral- 
lel to  cochlear  duct  and  tributaries  from  it  join  collect- 
ing venules  of  the  spiral  ligament.  The  blood  vessels  in 
the  stria  vascularis  are  at  right  angles  to  the  radiating 
arteriole,  the  collecting  veins,  and  the  arteriovenous 
arcade. 

The  last  branch  from  the  radiating  arteriole  is  the 
one  which  enters  the  stria  vascularis.  Diameters  of 
the  strial  vessels  are  usually  larger  than  the  diameters 
of  the  radiating  arteriole  or  arteriovenous  arcades. 
Strial  vessels  do  not  have  a  regular  distribution  of 
smooth  muscle  cells  and  were  not  seen  to  contract. 

The  vessel  in  the  spiral  prominence  is  independent 
of  the  stria  vascularis,  being  directly  supplied  by  a 
branch  from  the  radiating  arteriole.  A  large  number 
of  tributaries  leave  this  vessel  to  join  the  collecting 
vein.  Anatomically,  it  seems  to  have  the  qualifications 
of  a  capillary,  being  small  in  size  and  devoid  of 
smooth  muscle  cells,  and  having  a  slow  rate  of  blood 
flow.  It  shows  no  vasomotion. 

In  commenting  on  the  vascular  pattern,  Perlman 
and  Kimura  state  that  the  segmental  type  of  blood 
flow  suggests  that  interference  with  function  may  be 
localized.  Interruption  of  flow  in  a  radiating  arteriole 
of  an  arteriovenous  arcade  may  occur  while  flow 
continues  in  the  underlying  stria  vascularis.  Flow  in 
the  stria  vascularis  may  cease  while  active  flow  con- 
tinues in  the  radiating  arteriole,  arteriovenous  arcade, 
spiral  prominence  vessels,  and  venules.  The  presence 
of  arteriovenous  arcades  in  the  spiral  ligament  sug- 
gests a  possible  regulatory  mechanism  for  controlling 
flow  in  the  stria  as  well  as  affording  anastomotic 
channels  to  insure  continuity  in  blood  flow  along  the 
spiral  ligament. 

Perlman  believes  that  the  strial  vessels,  the  arterio- 
venous arcade,  and  the  spiral  prominence  vessels 
have  functional  roles.  The  strial  vessels  may  be  called 
capillaries  with  regard  to  their  position,  the  fact  that 
they  have  the  lowest  blood  flow  rate,  and  the  fact 
that  they  have  no  smooth  muscle  cells  in  their  walls. 
The  decrease  in  the  rate  of  blood  flow  from  the  radiat- 
ing arteriole  to  these  capillaries  of  the  stria  vascularis 
is  large  and  abrupt.  The  final  exchange  of  diffusible 
substances  probably  occurs  in  these  vessels. 

The  role  of  the  cochlear  blood  vessels  in  the  absorp- 


9i8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


RADIATING     ARTERIOLE 
165 


fig.  20.  Schematic  drawing  showing  rela- 
tions of  basic  vascular  units  exposed  by  the 
fenestra  and  the  average  blood  velocity  in 
micra  per  sec.  [From  Perlman  &  Kimura 
(95)-] 


STRIA 
VASCULARIS 


SPIRAL 

PROMINENCE 


SCALA 
VESTIBULI 


COCHLEAR 
DUCT 


SCALA 
TYMPANI 


COLLECTING    VEIN 


tion  and  secretion  of  perilymph  and  cndolymph  is 
still  not  clear,  although  it  is  believed  that  endolvmph 
is  secreted  by  the  stria  vascularis  (40).  It  is  interesting 
that  this  fluid,  which  fills  the  scala  media,  differs  in 
ionic  content  from  perilymph  which  fills  the  scala 
vestibuli  and  the  scala  tympani.  Unlike  all  other 
extracellular  fluids  in  the  body,  endolvmph  is  high  in 
potassium  and  low  in  sodium,  thus  more  nearly 
resembling  an  intracellular  fluid.  The  very  slow  rate 
of  blood  flow  in  the  stria  vascularis  may  be  necessary 
to  allow  the  formation  of  this  intracellular-like  fluid. 
It  has  been  suggested,  also,  that  the  slow  flow  rate 
and  the  absence  of  vasomotion  in  the  strial  vessels 
contribute  to  the  fact  that  blood  flowing  through  the 
cochlea  is  not  heard. 


Preferential  or  Thoroughfare  Channel 

The  attempt  to  give  a  representative  description  of 
vascular  patterns  in  terminal  vascular  beds  has  not 
escaped  the  usual  criticisms  aimed  at  generalization 
from  one  animal  to  another  or  among  different  tissues 
within  the  same  animal.  One  of  the  major  issues 
among  investigators  of  the  microcirculation  has  been 
the  acceptance  of  a  preferential  channel  as  a  com- 
ponent of  all  capillary  networks.  A  chronological 
presentation  of  the  development  of  the  concept,  the 
modifications,  and  current  status  might  assist  in 
clarifying  the  issue. 

The  first  description  of  the  arteriovenous  (a-v) 
bridge,  later  to  be  called  the  thoroughfare  or  prefer- 
ential channel,  appeared  in  1937  (143).  Zweifach, 
in  studies  of  the  mesentery,   nictitating  membrane, 


and  undersurface  of  the  tongue  of  the  frog,  described 
two  types  of  vessels  present  in  these  structures.  One 
was  a  continuous  central  trunk  that  connected  an 
arteriole  and  a  venule.  This  vessel,  a  direct  continua- 
tion of  an  arteriole,  was  invested  with  widely  sepa- 
rated atypical  smooth  muscle  cells  which  were  less 
responsive  to  mechanical  stimulation  than  smooth 
muscle  cells  of  the  arterioles.  The  a-v  bridges  did  not 
always  take  a  direct  linear  course  from  the  arterial 
to  the  venous  side,  but  appeared  in  three  basic  pat- 
terns: /)  a  direct  course  without  other  terminal 
branches,  2)  a  fountain-shaped  pattern,  3)  a  horse- 
shoe-shaped pattern,  which  was  to  become  regarded 
as  the  basic  design  for  the  preferential  channel.  The 
a-v  bridge  was  functionally  different  in  that  it 
always  had  a  patent  lumen  with  uninterrupted  blood 
flow.  The  second  type  of  vessel  was  the  true  capillary, 
a  nonmuscular  vessel  which  was  an  off-shoot  or 
branch  from  the  a-v  bridge,  not  in  the  direct  path  of 
blood  flow  from  arteriole  to  venule.  In  a  camera- 
lucida  drawing  of  the  vascular  pattern  in  the  frog 
mesentery  it  can  be  seen  that  the  a-v  bridge  either 
formed  a  loop  to  return  to  the  venule  accompanying 
the  arteriole  from  which  it  arose,  or  continued  across 
the  capillary  bed  to  join  another  venule  (fig.  21). 

In  a  second  paper  the  same  year,  the  arteriovenous 
bridge  was  reported  in  the  mesentery  and  ear  of  the 
mouse  (150).  In  1939,  Zweifach  (144)  extended  his 
studies  on  living  vessels  in  the  mesentery,  tongue,  skin, 
and  intestinal  wall  of  the  frog,  and  in  the  mesentery 
and  ear  of  the  mouse.  Little  new  information  was 
added,  but  the  functional  significance  of  the  a-v 
bridge  was  stressed.  The  main  central  pathways  were 


PATTERNS    OF    THE    A-V    PATHWAYS 


9>9 


fig.  21.  Camera-lucida  outline  of 
vessels  in  the  capillary  bed  of  the  frog 
mesentery.  [From  Zweifach  (143)-] 


said  to  have  a  vigorous  circulation  even  when  tissues 
were  in  a  resting  or  anemic  state.  The  bridge  was 
regarded  as  a  muscular  capillary  and  was  the  central 
pathway  from  which  the  remainder  of  the  capillary 
vessels  were  distributed  as  side  channels. 

In  1944,  Chambers  &  Zweifach  (20)  collaborated 
on  a  paper  in  which  the  studies  were  confined  to  the 
mesenteric  circulation  in  the  dog  and  the  rat.  They 
state  that  the  fundamental  architecture  is  the  same 
for  both  tissues.  The  mesoappendix  of  the  rat  differs 
from  other  parts  of  the  mesentery  in  its  lack  of  any 
major  vessels  coursing  from  the  aorta  or  to  the  vena 
cava,  all  vessels  in  the  mesoappendix  being  less  than 
80  to  ioo/x  in  diameter.  The  description  of  the  capil- 
lary bed  is  based  primarily  on  observations  in  the 
mesoappendix  of  the  rat,  in  which  the  a-v  bridge  is  a 
prominent  structure.  The  term  "metarteriole"  (Gr. 
meta — beyond)  is  introduced  to  designate  the  proxi- 
mal contractile  portion  of  the  central  channel. 
Beyond  the  metarteriole,  muscle  cells  disappear  and 
the  channel  continues  as  the  a-v  capillary  until  it 
joins  a  venule.  Other  contractile  muscle  cells,  desig- 
nated precapillary  sphincters  (the  precursors  of  the 
true  capillary),  were  found  at  the  proximal  end  of  the 
channel  but  were  absent  at  the  venular  end.  Each 
central  channel  and  its  side  branches  with  their  inter- 
posed true  capillaries  were  said  to  constitute  a  struc- 
tural unit.  In  a  summary  in  1946,  Chambers  & 
Zweifach  (21)  state  that  the  basic  topography  of  a 
predominantly  nutritive  type  of  capillary  bed  is 
presented  as  a  central  channel  of  which  the  true  capil- 
laries are  side  branches.  The  different  portions  of  the 
central  channel,  in  sequence,  were  the  metarteriole 
which  exhibits  vasomotion  and  has  typical  but  dis- 
continuous muscle  cells;  the  proximal  portion  with 
atypical  muscle  cells;  the  distal  portion  with  no 
muscle  cells;  and  the  nonmuscular  venule.  The  pre- 
capillaries were  described  as  the  proximal  muscular 
portions  of  the  abrupt  offshoots  of  the  muscular  por- 
tion of  the  central  channel,  acting  as  sphincters  and 


controlling  blood  flow  through  capillaries.  The  true 
capillaries  continue  from  the  piecapillaries  and  are 
also  direct  branches  of  the  distal  portion  of  the  central 
channel  and  of  the  nonmuscular  venule. 

In  1947,  the  functional  aspect  of  the  structural  unit 
was  again  emphasized  (22).  It  was  pointed  out  that 
in  some  tissues  which  maintain  a  constant  level  of 
flow  volume  there  is  no  discernible  organization  of 
capillaries,  while  in  tissues  such  as  the  muscular  sys- 
tem and  the  gastrointestinal  tract  with  varying 
activity  the  structural  unit  exists.  This  vascular 
pattern  allows  for  great  expansion  in  the  number  of 
vessels  with  an  active  circulation  at  one  time  and 
restriction  of  flow  to  the  preferential  channel  during  a 
period  of  inactivity.  In  the  decade  following  the 
introduction  of  the  preferential  channel,  new  ideas 
and  new  terminology  were  added.  For  clarification 
of  the  structure  and  function  of  the  terminal  vascular 
bed  in  the  rat  mesentery,  excerpts  from  a  paper  by 
Chambers  &  Zweifach  (22)  follow.  "The  preferential 
vessels  have  been  termed  thoroughfare  or  a-v 
channels.  The  proximal  portion  of  these  channels, 
termed  metarterioles,  together  with  their  precapillary 
sphincteric  offshoots,  are  muscular  and  spontaneously 
undergo  periodic  changes  in  caliber.  This  type  of 
movement  has  been  termed  vasomotion,  a  slow  inter- 
mittency  of  partial  relaxation  and  constriction  at 
intervals  of  about  30  seconds  to  3  minutes.  .  .  .  The 
precapillary  sphincteric  offshoots  lead  into  an  inter- 
anastomosing  system  of  true  capillaries  (devoid  of 
muscle  elements)  which  constitutes  the  bulk  of  the 
bed.  The  capillaries  rejoin  the  distal  continuation  of 
the  thoroughfare  channels  through  inflowing  tribu- 
taries." The  thoroughfare  channels,  always  open,  are 
said  to  maintain  a  constant  pressure  relationship 
between  their  arteriolar  and  venous  ends,  the  flow  of 
blood  through  them  being  more  rapid  than  thiough 
other  vessels  in  the  bed.  The  channel  is  said  to  be  the 
site  of  outward  filtration,  while  inward  filtration 
occurs  in  the  true  capillaries. 


920 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


One  significant  anatomical  difference  noticed  in 
comparing  microphotographs  of  circulatory  patterns 
in  the  rat  mesoappendix  with  that  of  other  tissues  is 
the  absence  of  paired  arteriole  and  venule  in  the 
mesoappendix  of  the  rat.  An  arteriole  emerges  singly 
from  its  parent  vessel,  descends  into  the  mesentery, 
then  forms  a  loop  which  in  its  return  is  joined  by  other 
capillary  vessels  before  emptying  into  the  vein  which 
accompanies  the  artery  of  origin.  In  most  vascular 
beds,  other  than  the  mesentery,  arterioles  and  venules 
are  found  to  be  adjacent  and  to  branch  together  until 
the  final  ramification  which  forms  the  capillary  net. 
The  small  arterioles,  from  which  the  true  capillaries 
arise,  form  arcades  or  arcuate  patterns  with  other 
arterioles  rather  than  continuing  as  a  direct  pathway 
to  the  venous  side.  It  is  not  uncommon  to  see,  in  the 
bat  wing  at  least,  a  short  terminal  arteriole  that 
quickly  joins  a  collecting  venule  after  giving  off  one 
or  two  branches  (see  fig.  22).  Contrary  to  the  descrip- 
tion given  to  preferential  channels  these  terminal 
arterioles  will  close  down  completely  or  may  be  devoid 
of  blood  when  their  parent  vessel  is  occluded  by  con- 
traction of  the  circular  smooth  muscle  which  invests 
them. 

According  to  subsequent  papers  by  Zweifach  ( 1 46, 
147)  and  Zweifach  &  Metz  (151,  152),  in  which 
vascular  patterns  are  compared,  it  seems  that  the 
preferential  channel  occurs  mainly  in  rat  mesentery, 
outer  edge  of  rat  skeletal  muscle,  and  the  serosa  of 
the  small  intestine  of  the  same  animal.  He  states  that 
the  preferential  channel  is  unusually  prominent  in 
the  mesentery  but  is  not  a  major  structural  feature  of 
the  urinary  bladder  and  the  skin.  Further  reservations 
as  to  the  ubiquitousness  of  the  preferential  channel 
have  appeared  as  a  result  of  observations  in  the  under 
surface  of  the  skin,  the  skeletal  muscle,  urinary  blad- 
der, several  mesenteric  structures,  and  the  serosal 
surface  of  the  small  intestine.  Zweifach  states  that  "a 
major  variable  lies  in  the  structural  organization  of 


fig.  22.   Arteriovenous  pathways  in  the  subcutaneous  area 
of  the  bat  wing. 


the  different  vascular  beds,  especially  the  mode  of 
distribution  of  the  capillary  system  from  the  arterial 
vessels.  In  such  tissues  as  skin  and  intestinal  wall,  the 
majority  of  capillaries  originate  as  direct  offshoots  of 
larger  arteries  and  arterioles.  The  distal  ramifications 
of  the  arterioles  have  relatively  few  capillary  offshoots 
and  usually  terminate  by  interconnecting  freely  with 
one  another  in  a  series  of  arcades.  This  is  in  direct 
contrast  to  the  mesentery  where  the  arterial  subdi- 
visions, the  metarterioles,  serve  as  the  parent  stem 
from  which  the  precapillaries  and  capillaries  branch 
out." 

Other  investigators  who  have  found  thoroughfare 
channels  in  various  tissues  include  Lutz  el  al.  (82),  who 
confirmed  their  presence  in  frog  mesentery  but  failed 
to  identify  them  in  the  hamster  cheek  pouch  or  retro- 
lingual  membrane  of  the  frog.  Baez  (6)  reports  a  short 
arteriole  which  turns  inward  to  become  a  draining 
venule,  thus  forming  a  thoroughfare  channel  in  the 
muscular  coat  of  the  small  intestine.  Staple  &  Copley 
(118)  describe  a  thoroughfare  channel  in  the  labial 
marginal  gingiva  of  the  mandibular  incisor  of  the 
hamster.  Lee  &  Holze  (77)  observed  the  thorough- 
fare channel  in  the  human  conjunctivae,  and  Lee  & 
Lee  (78)  describe  the  structure  in  the  mesentery  of  the 
guinea  pig. 

The  preferential  or  thoroughfare  channel,  either  as 
a  structural  or  functional  unit,  has  not  been  seen  in 
some  areas  which  have  been  subjected  to  extensive 
studv  by  various  microcirculatory  investigators.  Nicoll 
&  Webb  (88)  report  that  there  are  no  preferential 
pathways  in  the  subcutaneous  tissues  of  the  bat's 
wing.  Clark  &  Clark  (29)  do  not  report  them  in  the 
rabbit  ear.  Grafflin  &  Bagley  (55)  found  no  such  struc- 
ture in  the  frog  web  and  urinary  bladder,  nor  in  the 
human  conjunctivae.  Later,  Grafflin  &  Corddry  (56), 
reporting  a  more  detailed  study  on  the  bulbar  con- 
junctiva of  man,  described  vessels  between  arterial 
and  venous  channels,  arteriovenous  communications 
that  seem  similar  to  the  preferential  channel. 

It  would  seem  then  that  the  preferential  channel 
should  not  be  considered  as  a  component  of  a  typical 
capillary  network.  Although  it  is  possible  to  demon- 
strate a  similar  anatomical  arrangement  in  terminal 
vascular  beds  other  than  in  the  mesentery,  there  is  no 
confirmation  of  the  existence  of  a  preferential  channel 
on  a  functional  basis.  It  is  possible  that  such  a  flow 
pattern  is  necessary  for  the  relatively  avascular  mesen- 
tery, and  therefore  constitutes  a  special  rather  than  a 
typical  entity  of  microcirculation. 


PATTERNS    OF    THE    A-V    PATHWAYS  92 1 


Arteriovenous  Anastomoses 

A  detailed  and  comprehensive  review  by  Clark  (23) 
in  1938,  dealing  with  arteriovenous  anastomoses, 
obviates  the  necessity  of  reporting  individual  investi- 
gations up  to  that  time.  The  discussion  here  is  mostly 
confined  to  the  results  of  in  vivo  studies. 

A  direct  connection  between  arteries  and  veins  by 
passages  through  which  blood  is  carried  without  inter- 
change with  extravascular  fluids  had  been  described 
repeatedly  since  the  early  1800's.  Such  passages  were 
then  considered  to  be  rare,  occurring  as  a  result  of 
injury  or  as  a  developmental  anomaly.  Their  presence 
in  the  ear  of  the  living  rabbit,  as  demonstrated  by 
Clark  &  Clark  (29,  30)  and  Grant  (57),  established 
their  existence  in  the  normal  vascular  bed. 

Grant  (57)  concluded  from  his  observations  of  reac- 
tions of  these  vessels  that  arteriovenous  anastomoses 
were  important  in  regulating  body  temperature. 
Responses  to  heating  the  animal  indicated  that  when 
the  body  temperature  was  elevated,  dilation  of 
arteriovenous  anastomoses  permitted  a  large  amount 
of  blood  to  flow  through  the  ear,  thereby  increasing 
heat  loss.  Constriction  of  arteriovenous  anastomoses 
occurred  when  the  animal  was  cooled  and  thus  heat 
was  conserved.  This  concept  was  extended  in  studies 
of  the  toes  of  birds  and  the  fingers  and  toes  of  man  (58). 

Clark  &  Clark  (30)  studied  the  arteriovenous 
anastomoses  in  transparent  chambers  in  the  rabbit 
ear  with  observations  over  long  periods  at  high  magni- 
fications. High  magnifications  made  possible  the 
descriptions  of  structural  components.  Many  arterio- 
venous anastomoses  are  present  in  the  ear  of  the  rab- 
bit, with  considerable  variations  in  their  arrangement. 
Some  arise  directly  from  the  central  arterv  of  the 
ear,  others  from  secondary  or  smaller  branches,  and 
some  form  the  termination  of  an  artery  or  arteriole. 
Most  of  these,  however,  arise  from  small  arterial 
branches.  They  all  empty  primarily  into  larger  veins 
(see  fig.  23). 

As  to  the  structure,  arteriovenous  anastomoses  are 
found  to  be  straight  or  coiled,  with  a  thick  muscular 
wall  on  the  arterial  side  and  a  thinner,  funnel-shaped 
widening  on  the  nonmuscular  venous  end.  Variations 
from  this  general  pattern  include  the  absence  of  the 
funnel-shaped  venous  end  and  a  continuous  muscular 
wall  throughout  the  entire  vessel.  The  narrow  inter- 
mediate portion  has  a  wall  of  extra  thickness  which 
seems  to  be  the  most  contractile  portion.  The  venous 
portion  is  noncontractile,  but  the  large  veins  with 
which  the  communicating  vessel  connects  often  have 
substantial  muscle  walls  and  show  definite  contrac- 


ART 


fig.  23.  Camera-lucida  drawing  of  a  plexus  of  regenerated 
vessels  in  the  rabbit  ear.  [From  Clark  &  Clark  (34).] 

tility.  Most  of  the  cross  connections  show  inside  di- 
ameters of  20  to  40  n  during  dilatation.  Typical 
anastomoses  may  be  as  small  as  5  y.  in  diameter  or  as 
large  as  40  n- 

Arteriovenous  anastomoses  are  more  active  than 
arteries  and  arterioles  and  show  a  greater  tendency  for 
independent  action.  They  contract  and  dilate  spon- 
taneously and  periodically,  but  with  a  rhythm  inde- 
pendent of  either  neighboring  anastomoses  or  even  of 
the  artery  from  which  they  arose.  They  generally  con- 
tract more  rapidly  than  arteries,  both  rhythmically 
and  in  response  to  stimuli. 

Clark  (23),  did  not  attempt  to  explain  the  function 
of  the  arteriovenous  anastomoses,  but  felt  that  it  was 
significant  that  they  occur  normally  in  greatest  num- 
bers at  sites  most  frequently  subjected  to  mechanical 
and  thermal  irritations,  the  kinds  of  stimuli  which 
produce  prolonged  dilation  of  arteries  and  arterioles. 

From  his  observations  of  the  frog  mesentery, 
Zweifach  (143)  describes  short  arteriolar-venular 
anastomoses  between  vessels  only  slightly  larger  than 
capillaries.  These  short  channels  effectively  divert 
arterial  blood  directly  into  veins.  Their  caliber  changes 
seem  related  to  the  activity  of  the  capillary  circulation. 
When  most  capillary  vessels  are  open  and  have  active 
blood  flow,  the  arteriolar-venular  anastomoses  remain 
closed,  and  then  open  when  capillary  circulation  de- 
creases. The  anastomoses  differ  in  this  respect  from 
arteriovenous  bridges  which  maintain  a  relatively 
fixed  diameter.  Arteriolar-venous  anastomoses  in  the 
mesentery  of  the  mouse  were  described  as  short,  tor- 


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CIRCULATION    II 


tuous  vessels  that  never  branched  and  were  not  part 
of  the  capillary  bed. 

Later,  similar  vessels  in  the  rat  mesoappendix  were 
described  (20).  The  connecting  passages  in  that  tissue 
join  a  metarteriole  with  a  neighboring  venule,  or  an 
arteriole  with  a  venule.  They  are  muscular  for  about 
two-thirds  of  their  length  from  the  arterial  end.  When 
such  shunts  dilate,  blood  flow  ceases  in  the  arterial 
components  distal  to  the  shunts. 

Direct  microscopic  observations  in  other  tissues  of 
living  animals  have  revealed  arteriovenous  anastomo- 
ses. Wakim  &  Mann  (124)  carried  out  microscopic 
studies  on  the  liver  of  frogs  and  various  mammals  at 
magnifications  up  to  600  times,  utilizing  the  quartz 
rod  transillumination  technique.  They  found  arterio- 
venous anastomoses  in  all  animals  studied.  They  saw 
anastomotic  connections  between  the  interlobular 
branches  of  the  hepatic  artery  and  the  portal  vein  in 
both  amphibian  and  mammalian  livers.  Seneviratne 
(108)  observed  blood  vessels  of  the  livers  of  frogs, 
mice,  and  rats,  and  described  similar  anastomoses. 
For  frog  liver  he  described  several  phenomena.  Many 
short  branches  from  a  hepatic  artery  enter  the  ac- 
companying portal  vein.  Arterioles  cross  a  lobule  and 
enter  a  portal  vein  on  the  other  side.  Occasionally  the 
arteriole  enters  a  hepatic  vein.  Small  arterial  branches 
pass  through  the  liver  and  anastomose  with  subcapsu- 
lar arteries.  In  the  mouse  and  rat  many  types  of 
anastomoses  occur  between  arterial  and  venous 
vessels,  the  commonest  being  a  direct  communication 
by  short  branches  between  the  hepatic  artery  and  the 
accompanying  portal  vein. 

Irwin  &  MacDonald  (64)  studied  guinea  pig  livers 
using  the  quartz  rod  technicjue  and  found  the  vascular 
bed  to  be  similar  to  that  described  for  the  liver  by 
Knisely  et  al.  (72).  The  Knisely  group  found  connec- 
tions between  hepatic  arterioles  and  portal  venules 
which  they  called  arterioportal  anastomoses.  Bloch 
(14)  described  arterioportal  anastomoses  (APA)  as 
being  completely  lined  smooth-walled  tubes  that 
connect  hepatic  arterioles  with  portal  venules  at 
irregular  intervals.  The  hepatic  arteriole  winds  itself 
around  the  portal  venule  and  then  sends  short 
branches  out  to  form  APA. 

Parpart  et  al.  (93)  describe  arteriovenous  anasto- 
moses in  the  spleen  of  the  mouse  as  seen  by  micro- 
scopic observation.  There,  about  one  artery  in  ten 
makes  direct  connection  with  a  collecting  vein.  An 
arteriole  may  anastomose  with  a  collecting  vein  at 
any  point  on  the  vein,  lateral  connections  occurring 
more  frequently  than  end-to-end  anastomoses.  When 
the  connection  is  lateral,  the  arteriole  is  perpendicular 


to  the  venous  wall.  In  the  end-to-end  anastomosis,  the 
arteriole  gradually  widens  to  become  a  collecting  vein. 

Poor  &  Lutz  (97)  found  no  arteriovenous  anasto- 
moses in  the  hamster  cheek  pouch.  Irwin  et  al.  (66) 
found  arteriovenous  shunts  in  the  lungs  of  guinea 
pigs  and  rabbits,  although  they  appeared  infrequently. 
Blood  flow  through  the  shunts  was  unidirectional, 
going  from  arteriole  to  venule.  Blood  flow  through 
arteriovenous  anastomoses  in  the  bulbar  conjunctiva 
has  been  described  by  Bloch  (15).  Weille  et  al.  (132) 
saw  them  in  the  stria  vascularis. 

Zweifach  (148)  has  said  that  there  is  little  doubt 
that  occasional  shunts  between  arteries  and  veins 
exist  in  almost  every  tissue  in  the  body,  but  are  not  a 
prominent  feature  of  most  tissues.  He  further  suggests 
that  pathways,  not  distinct  anatomical  shunts,  go  from 
arterial  to  venous  systems  allowing  blood  to  bypass 
the  capillary  network.  Communications  between  ar- 
terial and  venous  vessels  occur  more  frequently  in 
terminal  vascular  beds  than  in  more  proximal  por- 
tions. 

It  does  not  seem  necessary  to  assign  any  highly  spe- 
cialized function  to  arteriovenous  anastomoses,  such 
as  heat  regulation,  although  this  is  still  done  (39,  98). 
Folkow  (44)  is  of  the  firm  opinion  that  arteriovenous 
anastomoses  in  the  skin  are  specialized  structures  pre- 
dominantly engaged  in  regulation  of  heat  loss  and 
are  regulated  by  their  own  constrictor  fibers.  His 
evidence,  while  convincing,  is  indirect.  Van  Dobben- 
Broekema  &  Dirken  (121,  1 22),  in  a  study  of  the  reac- 
tion of  rabbit  ear  vessels  to  heating,  offer  evidence 
that  there  is  no  obvious  relationship  between  the 
temperature  of  the  ear  and  the  diameter  of  the 
arteriovenous  anastomoses.  Zweifach  (148)  mentions 
the  possibility  that  selective  vasoconstriction  may 
reduce  capillary  circulation  and  cause  blood  to  be 
shunted  through  passages  which  would  offer  the  least 
resistance  to  flow  from  the  arterial  to  the  venous  side. 

The  information  derived  from  the  above  investiga- 
tions indicates  that  terminal  vascular  beds  of  most 
tissues  are  supplied  with  short  communicating  vessels 
between  arterial  and  venous  systems.  These  arterio- 
venous connections  allow  arterial  blood  to  be  shunted 
into  the  venous  system  without  first  passing  through  a 
capillary  network.  As  Zweifach  (148)  has  suggested, 
the  shunts  may  be  preferentially  in  use  when  vasocon- 
striction of  small  arterial  vessels  beyond  the  shunts 
increases  resistance  to  flow.  Arterial  blood  would  then 
be  diverted  through  shunts  which  afford  the  path  of 
least  resistance.  The  selective  vasoconstriction  to  which 
Zweifach  refers  might  result  from  the  response  of 
terminal     arterioles    or    precapillary    sphincters    to 


PATTERNS    OF    THE    A-V    PATHWAYS 


923 


changes  in  the  local  environment,  and  thus  whether  or 
not  blood  flowed  through  capillary  networks  would  be 
determined  by  the  immediate  needs  of  the  tissue. 
Thus,  no  complex  central  nervous  control  is  neces- 
sary, if  the  postulate  that  terminal  vasculature  is 
primarily  under  the  control  of  local  conditions  is 
acceptable. 


BLOOD   FLOW  THROUGH  TERMINAL  VASCULAR  BEDS 

Capillary  Contractility 

Ideas  regarding  contractility  of  capillary  vessels 
have  come  full  circle,  beginning  and  ending  with  the 
concept  that  capillaries  are  noncontractile  and  the 
blood  flow  through  them  depends  on  contraction  or 
dilatation  of  the  arterioles  which  supply  them.  Dur- 
ing the  intervening  periods,  investigators  have  pro- 
moted the  concept  of  independent  contractility  of 
capillary  vessels,  first  believed  to  be  brought  about  by 
the  contraction  of  perivascular  or  Rouget  cells  and 
later  thought  to  be  due  to  the  contraction  of  endothe- 
lial cells.  At  present  it  is  generally  accepted  that  true 
capillaries  do  not  contract.  By  definition  they  are 
devoid  of  muscular  elements,  so  that  muscular  contrac- 
tility is  out  of  the  question,  and  the  endothelial  cells  of 
which  they  are  composed  are  also  noncontractile. 
The  internal  diameter  of  capillaries  may  vary,  how- 
ever, by  passive  response  to  changes  in  pressure  or  in 
the  size  of  the  endothelial  cells  which  form  the  basic 
structure  of  their  walls. 

Independent  contractility  of  capillaries  was  a  con- 
troversial subject  in  the  eighteenth  century.  The 
opinion  expressed  by  Haller  (60)  in  1  756  that  capil- 
laries did  not  contract  was  generally  accepted  by  most 
physiologists  until  early  in  the  twentieth  century  [(54), 
see  also  (87)].  At  this  time  publications  by  August 
Krogh  (73)  appeared.  Krogh's  belief  that  capillaries 
really  contracted  is  found  in  a  description  of  an  ex- 
periment in  his  book  "which  demonstrates  in  a  crucial 
manner  that  the  whole  length  of  a  capillary  from  an 
arteriole  to  a  venule  can  be  contractile,  that  it  cannot, 
when  contracted,  be  forced  open  by  the  available 
arterial  pressure.  .  .  ."  Krogh  was  convinced  of  the 
independent  contractility  of  capillaries  but  he  also 
believed  that  no  evidence  obtained  thus  far  was  con- 
clusive enough  to  explain  the  mechanism  by  which 
this  was  carried  out. 

Two  possible  means  of  decreasing  the  diameter  of 
capillary  vessels  had  been  suggested.  One  was  that 
either  osmosis,  or  imbibition  by  endothelial  cells,  was 


responsible,  and  the  other  was  that  active  contraction 
of  extraendothelial  cells  occurred,  as  described  by 
Rouget  (103)  in  1873.  Krogh  believed  that  the  imbibi- 
tion theory  was  ruled  out  by  data  published  by  Stein- 
ach  &  Kahn  (119),  showing  that  the  outside  diameter 
of  contracting  vessels  decreased,  rather  than  remain- 
ing constant  or  increasing  as  it  would  if  the  endothe- 
lial cells  enlarged.  He  believed  that  anatomical  proof 
was  lacking  to  establish  the  functional  role  of  Rouget's 
cell.  Because  of  this  need  for  more  histological  infor- 
mation, he  encouraged  Yimtrup  to  conduct  a  detailed 
study  of  the  structure  of  the  capillary  wall.  Vimtrup 
(123)  examined  stained  sections  of  frog  tongue  and 
found  cells  such  as  those  described  by  Rouget.  He 
subsequently  named  them  Rouget  cells.  He  was  also 
successful  in  identifying  these  cells  on  living  minute 
vessels  in  the  tail  of  newt  larvae,  and  in  seeing  them 
contract.  The  frequent  spontaneous  contractions  and 
dilatations  of  vessels  seemed  to  occur  at  the  location 
of  the  nucleus  of  a  Rouget  cell.  This  was  final  proof 
for  Krogh  that  capillaries  possessed  independent  con- 
tractility, the  contractile  element  being  the  Rouget 
cell.  He  explained  away  the  conclusions  of  the  Clarks 
(27,  28)  that  the  Rouget  cells  were  noncontractile  by 
saying  that  there  was  no  proof  that  the  cells  they 
described  on  vessels  in  tadpole  tails  were  the  same  as 
Rouget  cells  or  that  the  contractions  they  saw  were 
similar  to  normal  contractility.  Krogh,  convinced 
that  the  controversy  regarding  capillary  contractility 
was  settled,  extended  his  belief  in  the  Rouget  cell  to 
include  its  occurrence  on  all  capillaries  in  both 
Amphibia  and  mammals. 

In  a  very  short  time,  however,  the  concept  of  the 
Rouget  cell  as  a  contractile  cell  controlling  the  diame- 
ter of  capillary  vessels  was  challenged  by  detailed 
studies  on  small  vessels  in  the  rabbit  ear,  a  technique 
introduced  by  Sandison  (104)  in  1924,  and  used  by 
him  and  the  Clarks,  in  whose  laboratory  he  began  his 
work.  A  chamber  for  the  rabbit  ear  was  perfected  in 
which  original  vessels  as  well  as  newly  formed  ones 
could  be  watched  for  many  months.  In  1931,  Sandi- 
son (105)  reported  that  the  appearance  of  Rouget  or 
adventitial  cells  on  newly  formed  vessels  occurred  in  a 
few  hours.  Using  a  magnification  of  400  times  he  could 
find  a  clear  space  between  these  cells  and  the  vessel 
wall  or  an  endothelial  nucleus.  The  cells  did  not  re- 
main fixed,  but  wandered  along  the  vessel  wall. 
Sandison  stated  that  the  function  of  the  Rouget  cell 
was  obscure,  except  that  it  helped  form  a  supporting 
framework  for  the  vessels.  He  was  able  to  demonstrate 
in  the  rabbit  ear  vessels  that  a  widening  of  the  space 
between  the  adventitial  cell  and  the  arteriolar  wall 


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CIRCULATION    II 


occurred  when  the  arteriole  narrowed.  Clark  &  Clark 
(27)  had  previously  made  a  similar  observation  in 
Amphibia,  and  also  had  observed  that  the  contraction 
of  small  vessels  on  which  no  adventitial  cells  de- 
veloped was  the  same  as  those  in  which  adventitial 
cells  were  present.  These  observations  seemed  to  rule 
out  any  possibility  that  the  adventitial  or  Rouget  cell 
was  responsible  for  contraction.  Sandison  also  noticed 
that,  as  newly  formed  vessels  changed  from  capillary 
to  arterial  forms,  the  adventitial  cells  disappeared  and 
circular  smooth  muscle  cells  took  their  place.  It  was 
shown  later  by  Clark  &  Clark  (33)  that  adventitial 
cells  actually  differentiated  into  smooth  muscle  cells 
as  new  capillaries  developed  into  arterioles. 

A  year  later  Sandison  (106)  stated  that  it  was  clear 
from  continuous  microscopic  observation  of  minute 
vessels  that  contraction  and  relaxation  of  smooth 
muscle  cells  of  arteries  and  arterioles  were  responsible 
for  alterations  in  blood  flow  through  capillaries,  and 
that  neither  Rouget  cells  nor  endothelial  cells  played 
any  part  in  contraction  of  vessels. 

In  the  same  year,  Clark  &  Clark  (29),  after  observing 
capillaries  of  normal  ear  tissue  through  a  trans- 
parent chamber,  stated  that  if  any  capillary  contrac- 
tility did  occur  it  was  too  negligible  to  have  any  influ- 
ence on  the  circulation.  In  subsequent  papers  Clark  & 
Clark  (33,  34)  summarized  the  accepted  ideas  regard- 
ing capillary  and  endothelial  contractility  as  follows: 
a)  Studies  on  mammalian  vessels  in  transparent  cham- 
bers, where  details  of  the  cellular  structures  could  be 
clearly  seen  in  unanesthetized  animals,  gave  no  evi- 
dence for  any  contractile  power  of  either  endothelial 
or  adventitial  cells.  This  view  was  supported  by  other 
investigators  (61,  101,  102).  b)  The  real  factors  re- 
sponsible for  the  control  of  circulation  in  the  minute 
vessels  of  the  mammal  are  smooth  muscle  cells  on 
arteries,  arteriovenous  anastomoses,  and  large  veins 
(105).  c)  No  contractile  activity  is  seen  in  mammalian 
capillary  endothelium  (29,  31,  33,  86),  although 
definite  active  spontaneous  contractions  occur  in  the 
capillary  endothelium  of  Amphibia  (28,  142,  143). 
They  point  out  that  the  experimental  evidence  for 
contractility  of  mammalian  capillaries  was  based,  in 
some  instances,  on  studies  of  nontransparent  regions  in 
which  the  structure  of  the  wall  of  the  minute  vessels 
and  their  true  diameters  could  not  be  seen.  Therefore, 
conclusions  as  to  whether  they  were  contracted  or 
dilated  could  only  be  inferred  from  the  number  of  red 
cells  present  in  them.  Also,  belief  in  contraction  of 
mammalian  capillaries  was  often  based  on  observa- 
tions of  amphibian  vessels  in  which  contractions  had 


been  seen  to  occur  with  and  without  extra-enclothelial 
cells. 

In  spite  of  overwhelming  contrary  evidence,  some 
investigators  still  held  for  a  time  to  their  belief  in 
capillary  contractility.  It  seems  unnecessary  to  review 
the  disagreements  in  the  face  of  the  general  accept- 
ance at  the  present  time  of  the  opinions  originally  ex- 
pressed by  Sandison  (106)  and  extended  by  Clark  & 
Clark  (29).  If  one  accepts  the  definition  of  a  capillary 
as  a  nonmuscular  endothelial  tube  between  the  ar- 
terial and  venular  systems,  one  may  state  unequiv- 
ocally that  mammalian  capillaries  are  noncontractile. 

Nicoll  &  Webb  (88)  stated  that  observations  on 
capillaries  in  the  bat  wing  showed  that  no  perivascu- 
lar cells,  such  as  Rouget  cells,  existed  in  the  region  of 
these  vessels.  The  smooth  muscle  cells,  at  the  tran- 
sitional points  from  the  terminal  arteriole  to  the 
capillary,  end  rather  abruptly.  Beyond  the  termina- 
tion of  smooth  muscle  cells  within  the  walls  no  change 
in  the  diameter  of  the  capillaries,  due  to  activity  of 
perivascular  cells,  has  been  observed. 

The  question  of  the  role  played  by  the  endothelial 
cell  in  caliber  changes  in  capillaries  is  more  unsettled. 
To  cite  some  of  the  recent  descriptions  of  endothelial 
cell  activity,  Nicoll  &  Webb  (88)  reported  modifica- 
tions in  capillary  diameter  that  may  result  from  elas- 
tic recoil  of  the  endothelial  wall  due  to  pressure  varia- 
tions either  inside  or  outside  the  vessel.  The  caliber 
change  is  due  neither  to  active  contraction  of  the 
endothelium  nor  to  intracellular  swelling.  Later, 
Webb  &  Nicoll  (130)  pointed  out  that  loss  or  gain  of 
fluid  through  the  walls  of  endothelial  cells  may  result 
in  apparent  changes  in  their  size.  Also,  since  capil- 
laries are  distensible,  they  may  show  deformation 
under  variable  conditions  (89).  These  responses  are 
usually  slow  in  their  development  and  give  no  indica- 
tion of  active  participation  by  the  endothelial  cells. 
Chambers  &  Zweifach  (2 1 )  believe  that  slow  spon- 
taneous endothelial  responses  for  the  most  part  repre- 
sent accommodation  to  changes  in  pressure;  that 
endothelial  cells  possess  a  cellular  tone  which  gives  a 
degree  of  elasticity  to  the  capillary  wall.  Lutz  el  al. 
(82)  found  that  endothelium  did  not  respond  to  me- 
chanical stimulation. 

Folkow  (44)  summarizes  current  opinion  in  stating 
that  "slow  swellings  of  the  capillary  endothelium  are 
sometimes  observed,  but  are  more  probably  to  be 
looked  upon  as  passive  osmotic  effects  or  deformations 
due  to  passive  luminal  changes,  caused  by  variations 
in  intravascular  pressure." 


PATTERNS    OF    THE    A-V    PATHWAYS 


925 


Vasomotion 

The  word  "vasomotion"  has  had  extensive  use 
since  its  first  appearance  in  1944  (20).  The  term  was 
used  at  this  time  by  Chambers  and  Zweifach  to 
describe  the  spontaneous  contractions  and  dilations  of 
small  arterioles  (metarterioles)  and  the  muscle  cells 
of  their  branches  (precapillary  sphincters)  in  the  rat 
mesentery,  also  called  mesoappendix.  It  has  subse- 
quently come  to  be  used  to  indicate  observed  diame- 
ter changes  of  any  blood  vessel. 

Reports  of  variations  in  the  caliber  of  small  blood 
vessels  have  been  in  existence  for  almost  as  long  as 
microscopic  studies  of  them  have  been  carried  out. 
Special  interest  in  this  phenomenon  was  shown  during 
the  period  of  controversy  over  capillary  contractility. 
In  the  years  following  the  introduction  of  the  rabbit 
ear  chamber  for  microscopic  observation  of  small 
blood  vessels,  numerous  papers  appeared  in  which 
spontaneous  alterations  in  small  blood  vessels  were 
described.  Clark  &  Clark  (29)  spoke  of  the  normal 
occurrence  of  spontaneous  rhythmic  contractions  of 
arteries  down  to  their  smallest  branches.  Different 
arteries  and  parts  of  arteries  were  seen  to  contract  at 
different  rates  (30).  Sandison  (106)  reported  rhyth- 
mical contractions  of  arterial  vessels  but  saw  no  active 
contractions  of  veins  or  venules.  Clark  el  al.  (35)  be- 
lieved that  an  intact  nerve  supply  was  necessary  for 
spontaneous  contraction  of  the  arterial  vessels.  Nu- 
merous other  investigators  reported  periodic  altera- 
tions of  small  vessel  diameters  (17,  57,  62,  141  ). 

Chambers  &  Zweifach  (20)  described  vasomotion 
in  terminal  arterioles  and  larger  arterioles  as  irregu- 
larly periodic  dilatations  that  are  slower  and  more 
regular  than  the  diameter  changes  seen  in  metarteri- 
oles and  precapillary  sphincters.  When  metarterioles 
were  exhibiting  vasomotion,  they  usually  showed  a  de- 
crease in  diameter  of  about  one-third,  but  were  even 
seen  to  reduce  the  diameter  by  one-half  or  more. 
Other  observations  were  that  when  a  tissue  was 
hyperemic,  the  dilator  phase  was  most  prominent,  the 
constrictor  phase  dominating  in  ischemic  tissue.  No 
synchrony  in  vasomotion  of  neighboring  arterioles 
was  seen.  Vasomotion  was  seen  to  continue  in  a  metar- 
teriole  in  the  absence  of  blood  flow  through  it.  Also, 
diminished  blood  flow  was  followed  by  an  increased 
dilator  phase,  while  increased  blood  flow  apparently 
brought  on  an  intensified  constrictor  phase.  Vaso- 
motion was  affected  by  local  environmental  condi- 
tions (irritation  of  the  tissue  caused  vasomotion  to 
disappear).  Vasomotion  also  stopped  when  the  ani- 
mal was  deeply  anesthetized. 


The  recurrent  vasomotion  in  metarterioles  was 
considered  by  Chambers  and  Zweifach  to  be  the 
factor  which  controls  the  rate  of  flow  through  the 
central  vessels  of  a  capillary  bed  while  the  vasomotion 
of  precapillary  sphincters  controlled  the  flow  through 
the  true  capillaries. 

An  extensive  discussion  of  vasomotion  bv  Nicoll  & 
Webb  (88)  in  1946  described  various  types  of  caliber 
changes  seen  in  both  arterial  and  venous  vessels.  They 
suggested  that  the  word  vasomotion  should  be  pre- 
ceded by  a  suitable  adjective  to  indicate  a  specific  kind 
of  change  in  vessel  diameter,  e.g.,  if  the  caliber  change 
is  brought  about  by  contraction  or  relaxation  of  the 
vascular  musculature,  reference  should  be  made  to 
active  vasomotion.  If,  on  the  other  hand,  caliber 
changes  are  produced  by  internal  or  external  altera- 
tions of  pressure  not  due  to  the  activity  of  vascular 
musculature,  reference  should  be  made  to  passive 
vasomotion.  Active  vasomotion  was  further  classified 
into  three  groups.  "Tonic  active  vasomotion"  was 
the  term  used  to  describe  the  maintained  contraction 
of  arteries,  considered  to  be  a  tonus  response.  Super- 
imposed on  tone  was  the  rapid  contraction  and  relaxa- 
tion of  vessels  that  occur  in  response  to  nerve  impulses. 
This  was  called  irregular  active  vasomotion.  The  third 
type  of  movement  was  called  rhythmical  active  vaso- 
motion and  referred  to  a  regular  alternation  of  con- 
traction and  relaxation  of  the  vascular  smooth  muscle. 

An  analysis  of  the  various  types  of  active  vasomo- 
tion, as  given  by  Nicoll  &  Webb  (88),  follows.  That 
arteries  and  arterioles  possess  tone,  or  are  in  a  con- 
tinuous state  of  active  contraction,  can  best  be  demon- 
strated by  noting  the  marked  increase  in  their  diame- 
ter that  follows  denervation.  The  diameters  of  ar- 
terial vessels  in  a  denervated  area  have  been  shown  to 
increase  27  to  29  per  cent  following  nerve  section 
(134).  Nicoll  and  Webb  state  that  the  outstanding 
characteristics  of  tonic  active  vasomotion  are  its  con- 
stancy and  sluggishness,  and  suggest  it  may  function 
to  correlate  blood  vessel  volume  and  blood  fluid 
volume. 

Irregular  active  vasomotion  is  characterized  by 
rapid  changes  in  the  caliber  of  arteries  and  arterioles. 
The  changes  vary  as  to  their  magnitude  and  the 
length  of  time  they  endure.  Such  caliber  changes  are 
the  direct  result  of  impulses  from  the  vasomotor 
nerves,  controlled  by  the  vasomotor  center.  Nerve 
section  obliterates  this  type  of  activity.  Nicoll  and 
Webb  are  of  the  opinion  that  the  function  of  irregular 
active  vasomotion  is  to  modify  peripheral  resistance 
and  also  to  regulate  the  pressure  gradient  in  the 
capillaries. 


926 


HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


Rhythmical  active  vasomotion  is  the  third  type  of 
activity  seen  in  vascular  beds.  It  has  been  observed  in 
arteries,  arterioles,  precapillary  sphincters,  and  veins. 
This  regular  alternation  of  contraction  and  relaxation 
of  vascular  smooth  muscle  cells  has  been  shown  to 
continue  after  denervation  (129).  It  becomes  more 
marked  in  the  most  peripheral  vessel,  the  best  example 
of  it  on  the  arterial  side  being  at  the  level  of  the  pre- 
capillary sphincters.  It  is  the  predominant  type  of 
activity  shown  by  veins.  In  general,  the  more  normal 
conditions  are,  the  more  outstanding  is  the  rhythmical 
active  vasomotion. 

Nicoll  &  Webb  (88)  offer  several  reasons  to  give 
support  to  the  hypothesis  that  this  rhythmical  ac- 
tivity is  the  result  of  an  inherent  property  of  smooth 
muscle  cells  rather  than  the  response  of  vascular 
muscle  to  a  rhythmical  discharge  from  the  vasomotor 
center  or  from  humoral  influences  or  physical  condi- 
tions. The  reasons  are  these:  a)  Terminal  arterioles, 
precapillary  sphincters,  and  veins  exhibit  rhythmical 
active  vasomotion  after  denervation,  b)  This  type  of 
vasomotion  is  most  highly  developed  in  the  venous 
muscular  coat  and  precapillary  sphincters,  neither  of 
which  appears  to  be  under  direct  control  of  vasomotor 
nerves,  c)  Adjacent  vessels  vary  independently  in  the 
rate  and  magnitude  of  their  rhythmical  activitv. 

Rhythmical  active  vasomotion  in  veins  is  fre- 
quently powerful,  reducing  the  vascular  lumen  to 
one-third  or  one-fourth  of  its  resting  diameter  at  the 
peak  of  contraction.  The  rate  at  which  the  contrac- 
tions and  relaxations  occur  is  usually  much  faster 
than  that  observed  in  arterial  vessels. 

In  later  reports,  Chambers  &  Zweifach  (19,  22)  dis- 
cussed vasomotion  and  its  relation  to  fluid  exchange 
across  the  capillary  wall.  The  term  "vasomotion"  was 
still  used  only  in  reference  to  spontaneous  contraction 
and  relaxation  of  the  metarteriole  and  its  branches. 
Vasomotion  in  the  precapillary  offshoots  was  said  to 
produce  alternate  periods  of  varying  hydrostatic  pres- 
sure, thus  greatly  influencing  fluid  exchange  in  the 
capillary  bed.  When  vasomotion  was  reduced  or  ab- 
sent, blood  pressure  in  the  arterioles  was  spread 
through  the  numerous  capillaries  of  the  bed  resulting 
in  a  slower  flow  through  the  capillaries  and  a  subse- 
quent accumulation  of  fluid  in  the  collecting  venules. 
Such  a  situation  would  create  a  sufficient  back  pres- 
sure to  favor  outward  filtration.  When  vasomotion 
was  active,  blood  flow  went  primarily  through  the 
arteriovenous  pathways,  bypassing  the  capillary  ves- 
sels and  producing  a  rapid  flow  in  collecting  venules. 
This  bypassing  of  capillaries  would  favor  drainage 
from  the  capillary  network,  a  condition  which  would 


increase  inward  filtration.  In  summarizing  the  sig- 
nificance of  vasomotion  in  fluid  exchange  in  the 
capillary  bed,  they  state  that  the  delicate  vasomotor 
adjustments,  which  vary  the  surface  area  over  which 
hydrostatic  pressure  may  cause  outward  filtration, 
play  a  greater  role  than  the  differences  between 
hydrostatic  and  colloidal  pressure.  Osmotic  uptake, 
which  is  responsible  for  inward  filtration,  is  depend- 
ent upon  and  reinforced  by  adequate  venous  outflow, 
a  factor  influenced  by  vasomotion. 

Webb  &  Nicoll  (130)  refer  to  rhythmical  active 
vasomotion  as  being  the  outstanding  activity  in  the 
entire  minute  vascular  bed  and  regard  it  as  the  prin- 
cipal factor  of  a  local  nature  that  regulates  blood  flow, 
and  probably  pressure,  in  the  capillaries.  All  types  of 
anesthesia  reduce  or  abolish  active  vasomotion  of  the 
smaller  vessels,  and  the  authors  suggest  that  this  may 
be  the  reason  why  such  activity  is  overlooked  in  many 
vascular  studies.  Active  vasomotion  is  greatly  reduced 
in  conditions  in  which  vascular  flow  is  sluggish  or 
irregular,  or  when  the  arterial  pressure  is  low.  Active 
vasomotion  in  arterioles  can  be  augmented  by  sudden 
increases  in  intra-arteriolar  pressure. 

Active  vasomotion  was  further  discussed  by  Xicoll 
&  Webb  (89)  in  a  paper  in  which  investigations  to 
determine  the  effect  of  environmental  changes  on 
active  vasomotion  were  described.  Arteries  and  the 
largest  arterioles  were  said  to  show  two  types  of  active 
vasomotion,  one  being  a  slowly  developing  diameter 
change  dependent  on  tonus  and  the  other,  a  rapid 
diameter  change  dependent  on  the  response  of  vascu- 
lar muscle  to  nerve  excitation.  The  smaller  arcuate 
and  terminal  arterioles  showed  active  vasomotion 
independent  of  nerve  connection,  and  no  classifica- 
tion of  this  activity  into  tonus  changes  or  contractile 
responses  was  possible.  However,  two  different  types 
of  muscular  activity  were  seen  in  these  small  vessels, 
one  being  peristaltic  waves  sweeping  along  the  ter- 
minal arterioles  and  the  other  being  localized  contrac- 
tion of  the  precapillary  sphincters. 

The  effect  that  active  vasomotion  has  on  blood  flow 
through  capillary  beds  depends  on  both  its  intensity 
and  its  duration.  When  constriction  is  not  great 
enough  to  close  the  lumen  completely,  plasma  and 
platelets  continue  to  flow  through  the  capillary  vessels 
while  the  cellular  elements  are  held  back.  This  is  re- 
ferred to  as  "plasma  skimming.'"  When  contraction  of 
the  vascular  muscle  is  great  enough  to  occlude  the 
lumen,  blood  flow  into  the  capillary  nets  is  necessarily 
curtailed.  The  occlusion  is  normally  temporary,  result- 
ing in  intermittent  flow  through  the  capillary  nets. 

Veins  and  venules  in  the  bat  wing  with  smooth 


PATTERNS    OF    THE    A-V    PATHWAYS 


92  7 


muscle  as  a  component  of  their  walls  exhibit  marked 
active  vasomotion.  Nicoll  and  Webb  describe  the  con- 
traction as  sharp,  and  one  that  sweeps  along  the  vein 
as  a  peristaltic  wave  in  a  central  direction.  Each  wave 
of  contraction  seems  to  originate  at  a  distal  valve 
and  die  out  at  the  next  valve  central  to  it.  Since  the 
majority  of  valves  are  located  at  the  confluence  of 
tributaries,  valve  action  and  blood  flow  may  seem 
unrelated  due  to  asynchronous  waves  in  two  segments 
which  are  separated  by  their  valves. 

Two  major  tributaries  which  form  a  vessel  may  con- 
tract alternately.  One  tributary  may  empty  into  a 
segment  ahead  while  the  other  tributary  is  relaxed. 
Irregular  flow  results  when  the  frequency  of  contrac- 
tion of  the  two  tributaries  is  not  coordinated.  Single 
tributaries  empty  into  a  segment  of  the  central  vessel 
during  its  period  of  relaxation. 

Nicoll  and  Webb  adopt  the  concept  that  vascular 
smooth  muscle  cells  possess  an  inherent  ability  to 
change  their  tonus  or  exhibit  sudden  contraction  in 
response  to  changes  in  their  immediate  environment. 
In  order  to  determine  what  environmental  changes 
affect  vascular  smooth  muscle,  they  observed  changes 
in  vasomotion  in  response  to  nerve  stimulation,  various 
gas  mixtures,  and  temperature  changes.  They  found 
that  arteries  and  large  arterioles  responded  to  nerve 
stimulation  with  intense  constriction.  The  smaller 
vessels,  arcuate  and  terminal  arterioles,  precapillary 
sphincters,  veins,  and  venules  never  showed  initiation 
or  modification  of  active  vasomotion  as  a  direct  re- 
sponse to  central  impulses  (129).  Changing  the  local 
environment  by  flow  of  constant  current  between  a 
single  fluid  electrode  on  the  wing  surface  and  an 
indifferent  electrode  produced  alternate  areas  of 
marked  constriction  and  dilatation  on  arteries  and 
arterioles.  Reversal  of  the  current  caused  previously 
constricted  areas  to  dilate  and  previously  dilated 
areas  to  constrict.  Nicoll  &  Webb  (89)  believe  that  this 
observation  should  be  taken  into  account  when  inter- 
preting responses  to  direct  excitation  of  nerves  with 
microelectrodes.  Inhalation  of  carbon  dioxide  in  a 
specific  concentration  proved  to  be  a  powerful  stimu- 
lus of  the  contractile  phase  of  active  vasomotion. 
Variations  in  temperature  showed  the  frequency  of 
active  vasomotion  to  vary  directly  with  the  tem- 
perature. 

Changes  in  internal  pressure  of  vessels  have  marked 
effects  on  vasomotion.  Slow  changes  in  pressure  caused 
a  vessel  to  adjust  its  tone  gradually.  Sudden  increases 
in  pressure,  however,  first  caused  a  vessel  to  be  dis- 
tended mechanically  and  then  to  contract  with  great 
intensity.    The   contraction    then    spread    along    the 


vessel  as  a  peristaltic  wave.  Nicoll  and  Webb  suggest 
that  rhythmical  variations  in  small  arterial  vessels 
may  originate  from  sudden  internal  pressure  changes 
at  their  origins  from  parent  vessels. 

Spontaneous  changes  in  vascular  tone,  resulting 
from  a  rise  or  fall  in  internal  pressure,  were  demon- 
strated. After  blood  flow  to  an  area  had  been  stopped 
by  occlusion  of  a  small  supplying  artery  and  was  then 
allowed  to  resume,  the  vessels  were  first  distended  as 
they  filled  and  then  were  seen  to  contract  as  a  response, 
presumably,  to  the  distention.  Thus,  blood  was  forced 
along  to  the  next  branches.  Another  example  of  ad- 
justment of  tone  to  a  change  in  internal  pressure  is  seen 
following  denervation.  The  resulting  dilatation  of  the 
main  arteries  probably  raises  internal  pressure  in  the 
arterioles  and  increases  their  tone,  sometimes  reducing 
the  flow  through  the  arterioles  to  the  capillary  beds 
due  to  the  reduction  in  lumen  of  the  arterioles. 

Nicoll  and  Webb  express  the  opinion  that  the  ul- 
timate result  of  active  vasomotion  in  terminal  arteri- 
oles is  to  establish  flow  through  capillary  beds,  the 
muscle  cells  of  the  terminal  arterioles  being  the  prin- 
cipal targets  of  changes  in  the  local  environment. 

Active  vasomotion  in  venules  and  veins  may  repre- 
sent the  adaptation  of  an  inherent  property  of  vascu- 
lar smooth  muscle  to  aid  venous  return.  Nicoll  and 
Webb  suggest  that  this  activity  may  be  more  wide- 
spread in  vascular  systems  than  is  currently  recog- 
nized. It  may  be  more  prominent  in  the  veins  of  the 
bat  wing  than  in  small  veins  in  other  mammals  due  to 
the  structure  of  the  wing.  Pressure  within  the  veins 
seems  to  be  the  principal  stimulus  for  the  action. 

Experimental  evidence  in  confirmation  of  this  pro- 
posal appears  in  the  investigations  by  Wiedeman 
(135),  in  which  veins  in  the  bat  wing  were  observed 
during  elevations  in  venous  pressure.  Both  diverting 
excess  blood  into  a  vein  by  ligating  other  venous  path- 
ways and  infusing  dextran  to  increase  total  volume 
caused  a  significant  increase  in  cycles  of  venous  vaso- 
motion. Similar  results  were  obtained  when  venous 
pressure  was  elevated  by  direct  infusion  with  saline 
(136). 

Although  venous  vasomotion  is  most  prominent  in 
the  bat  wing  and  shows  a  definite  rhythmicity  (fig.  24), 
spontaneous  changes  in  pressure  which  are  unrelated 
to  arterial  pressure  or  respiration  have  been  demon- 
strated in  small  veins  in  hind  legs  of  dogs  (59,   1 37) 

^A/VvAAAAAAAAAAA/WN 

fig.  24.  Rhythmical  variations  in  the  pressure  in  a  vein 
resulting  from  alternate  contraction   and  relaxation. 


928 


HANDBOOK.    OF    PHYSIOLOGY 


CIRCULATION    II 


(see  fig.  25).  Such  changes  have  also  been  recorded  in 
rabbit  ear  veins  (unpublished  data).  (See  fig.  26.) 
Recently,  spontaneous  changes  in  venous  tone  were 
recorded  from  the  arm  veins  of  man  (16).  Folkow  has 
long  supported  the  concept  that  rhythmic  changes  in 
tone  of  vascular  smooth  muscle  is  due  to  myogenic 
automaticity  (42,  43,  45,  46).  He  points  out  (45)  that 
because  the  rhythmical  reactions  seem  to  be  com- 
pletely unsynchronized,  even  in  closely  adjacent 
smooth  muscle  cells,  it  is  improbable  that  they  should 
be  due  to  activity  in  a  local  syncytial  nerve  cell  plexus 
in  the  vascular  wall,  as  suggested  by  others  (85).  He  is 
of  the  opinion  (43)  that  intravascular  pressure  in  a 
purely  mechanical  way  to  some  degree  will  add  "ex- 
citatory drive"  to  myogenic  activity  as  proposed  by 
Bayliss  (10)  and  confirmed  in  Folkow's  laboratory 
(42).  Further  confirmation  appears  in  recent  studies  of 
forearm  blood  flow  by  Blair  el  al.  (12). 

At  the  present  time  then,  in  concurrence  with  Lutz 
&  Fulton  (81),  the  term  "vasomotion"  should  refer 
to   anv   active  change   in   the  diameter   of  a    blood 


vessel.  It  may  be  seen  in  one  form  or  another  where 
vascular  smooth  muscle  exists,  such  as  in  arteries, 
arterioles,  terminal  arterioles,  precapillary  sphincters, 
venules,  and  veins.  Any  definite  conclusions  now  as  to 
the  actual  mechanism  or  mechanisms  which  initiate 
or  control  this  vascular  activity  would  be  premature 
insofar  as  both  direct  and  indirect  evidence  indicate 
that  vasomotion  in  its  various  forms  may  be  ac- 
tivated or  modified  through  the  central  nervous  sys- 
tem, reflexly  or  automatically,  through  myogenic 
automaticity,  or  through  local  metabolic  factors. 

This  activity  in  venous  vessels,  especially  if  pri- 
marily dependent  on  myogenic  automaticity  excited 
by  increased  intravascular  pressure,  could  serve  as  an 
effective  aid  to  venous  return  from  postcapillary 
vessels.  On  the  arterial  side  it  could  serve  as  the  regu- 
lator of  blood  flow  through  capillary  nets  as  well  as  a 
protective  mechanism  whereby  capillary  vessels  could 
not  be  subjected  to  sudden  or  prolonged  increases  in 
pressure  which  might  rupture  their  thin  walls. 


fig.  25.  Spontaneous  pressure  waxes  in  a 
small  \ein  in  the  hindleg  of  the  dog.  [From 
Wiedeman  (137)] 


rYVVY 


I  Art.  Press. 


10  Sec. 


TflJJjTrlT^^ 


fig.    26.   Spontaneous    pressure    variations 
in  a  small  vein  of  the  rabbit  ear. 


Smoll    Vein 


W^mfflTO^TOBfflffi 


10  Sec 


PATTERNS    OF    THE    A-V    PATHWAYS 


9'29 


SUMMARY 

It  is  apparent,  from  the  foregoing  descriptions  of 
structural  organization  of  microcirculatory  beds  and 
regulation  of  the  flow  of  blood  through  them,  that  the 
investigations  have  revealed  more  similarities  than 
dissimilarities.  Minor  differences  among  patterns 
seem  to  be  associated  with  the  structural  organization 
of  the  tissue  in  which  the  vessels  lie,  but  the  basic  pat- 
terns remain  the  same. 

Although  presentation  of  an  anatomical  pattern 
that  would  be  "typical"  for  terminal  vascular  beds 
would  be  likely  to  meet  some  resistance,  it  does  seem 
necessary  to  agree  on  such  features  as  arcuate  or  ar- 
cade connections,  gradual  divestment  of  spiral  smooth 


muscle  cells  along  terminal  arterioles  to  form  capil- 
laries, absence  of  direct  association  and  control  of 
capillaries  through  nerves,  and  similarity  of  the 
courses  taken  by  small  arteries  and  small  veins.  Also, 
certain  functional  activities  which  regulate  blood  flow 
and  blood  pressure  through  these  beds  must  be  con- 
sidered as  universal,  these  being  spontaneous  vaso- 
constriction and  relaxation  of  arterioles,  reversal  of 
flow  paths,  alternation  of  routes  of  blood  flow  from 
arterial  to  venous  vessels,  and  variations  in  the  filling 
of  capillary  networks  depending  on  local  conditions. 
Future  investigations  may  permit  generalizations  con- 
cerning the  angles  of  branching  in  the  arterial  system 
and  spontaneous  vasomotion  in  the  venous  system. 


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583.  '95°- 

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PATTERNS    OF    THE    A-V    PATHWAYS 


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35:  176-239,  1956. 


CHAPTER     28 


Resistance  (conductance)  and  capacitance 
phenomena  in  terminal  vascular  beds1 


HAROLD    D.    GREEN 

CARLOS    E.    RAPELA 

MARGARET   C.    CONRAD2 


Department  of  Physiology  and  Pharmacology,  Bowman  Gray 

School  of  Medicine,  Wake  Forest  College,  Winston-Salem,  North  Carolina 


CHAPTER     CONTENTS 

Resistance  Vessels 

Pressure-Flow  Relations  in  Vascular  Beds 
Methods 

Passive  curvilinear  relationship  of  pressure-flow  plots 
Mathematical  relationships 
Effects  of  Viscosity  on  Pressure-Flow  Relationships 
Effects  of  Extravascular  Pressure  on  Pressure-Flow  Relation- 
ships 
Effects  of  Alterations  of  Venous  Pressure 
Autoregulatory  Control  of  Resistance  Vessels 

Modification    of    passive    pressure-flow    relationship    by 

autoregulation 
Artifacts  induced  in  autoregulation  studies  by  pump   per- 
fusion schemas 
Autoregulation  in  different  vascular  beds 
Reactive  hyperemia 

Mechanisms  responsible  for  autoregulation 
Interpretation  of  change  of  vasomotor  tone  induced   by 
constrictor  and  dilator  agents  in  vascular  beds  which 
demonstrate  autoregulation 
Chemical  Effects  on  Resistance  Vessels 
Extrinsic  Control  of  Resistance  Vessels 

Effects    of   vasomotive    agents    on    total    resistance    in    a 
vascular  bed 
Segmental  Resistances  in  Vascular  Beds 
Methods 

Effects  of  Changes  of  Perfusion  Pressure  and  Venous  Pressure 
on   Large   Artery  and  Vein,   and   Distal   Small   Vessel 
Pressures 
Effects  of  Extrinsic  Agents  on  Segmental  Resistance 


1  Preparation  of  this  chapter  and  most  of  the  original  work 
reported  herein  were  aided  by  Grant  H-487,  National  Heart 
Institute,  United  States  Public  Health  Service. 

2  Formerly  trainee,  Cardiovascular  Graduate  Training 
Program  (HTS-539.2)  National  Heart  Institute,  United  States 
Public  Health  Service;  currently  Fellow  of  the  American 
Heart  Association. 


Blood  Volume  in  Vascular  Beds  (Vascular  Capacity) 
Methods 

Effects  of  Various  Factors  on  Vascular  Volume 
Estimation  of  Change  of  Vascular  Volume  Due  to  Extrinsic 

Influences 
Pulsatile  Changes  in  Vascular  Volume 

Interpretation  of  Vascular   Behavior   from    Measurements   of 
Flow,  Pressure,  and  Vascular  Volume 


since  most  vascular  beds  do  not  permit  direct 
microscopic  study,  indirect  methods  have  to  be  used 
to  evaluate  them.  In  this  chapter,  the  behavior  of 
vascular  beds  is  deduced  from  recordings  of  the  rate 
of  blood  flow,  the  accompanying  small  vessel  pressures, 
and  the  changes  in  vascular  volume  that  occur  as  the 
result  of  varying  the  artery  to  vein  pressure  difference 
across  the  bed  and  as  a  result  of  other  intrinsic  and 
extrinsic  influences. 

Using  the  above  measurements,  the  role  of  the 
terminal  vascular  beds  is  analyzed  in  terms  of  the 
behavior  of  those  segments  which  determine  the 
resistance  to  flow  through  the  bed,  i.e.,  the  resistance 
vessels,  and  those  segments  which  are  related  to  the 
volume  of  blood  contained  in  a  terminal  bed  at  any 
moment,  i.e.,  the  capacitance  vessels.  These  functions 
of  the  terminal  vascular  beds  are  shown  to  be  in- 
fluenced by  such  physical  factors  as  arterial  perfusion 
pressure,  presence  of  communication  with  collateral 
vascular  beds,  viscosity  of  the  blood,  extravascular 
pressure,  venous  pressure,  by  local  autoregulation, 
and  by  extrinsic  factors  such  as  vasoactive  agents  and 
the  autonomic  nerves. 


935 


936  HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


RESISTANCE    VESSELS 

Pressure-Flow  Relations  in  I  'ascular  Beds 

methods.  Pressure-flow  relations  in  vascular  beds 
have  been  studied  by  two  principal  methods.  In  one, 
the  bed  was  perfused  by  a  constant  flow  pump  at 
various  flow  rates  while  the  artery  to  vein  pressure 
differences  were  recorded.  More  usually  inflow  or 
outflow  from  the  vascular  bed  was  recorded  while  the 
perfusion  pressure  was  varied  by  using  a  constant 
pressure  pump  or  by  varying  the  degree  of  com- 
pression of  the  artery  supplying  the  vascular  bed.  In 
most  cases,  the  arterial  and  venous  pressures  were 
recorded  together  with  the  flow.  Varying  perfusion 
pressure  by  altering  the  degree  of  compression  of  the 
supplying  artery  has  the  advantage  of  providing  a 
more  nearly  physiological  situation  with  a  minimum 
of  complicating  equipment,  but  does  not  allow 
exploration  of  the  pressure-flow  relationships  above 
the  animal's  existing  mean  arterial  pressure.  Flow 
has    been    measured    by    orifice   meters,    rotameters, 


Perfusion 

Aorta 

cannulo  — ^ 
Inflow 

V      1 

B 

Arterial  pressure 

-      meter 

/\,  Arterial  pressure 
^\         gouge 

K 

Metered  ortery- 
(cognote) 

— mb 

Arteria 

Colloleral  artery 

It" 
M*h     one 

stamotic 

channel 

25 

—  >- 

1     . 
1    / 

/'      /   X 

tt: 

UJ 

my   1  /  / 

15 

/     '  1/ 

"5 

]/r 

_Q 

UJ 

S /  1 

cc 

/    1 

Uj 

/     ' 

5 

—  1- 

/      1 

Uj 

5    ^^^ 

^^         n/ 

/       1 

1 

0 

g 

1 

Pressure    in 

-  5 

-  ;fc 

O 

/          C 

ollateral   Artery 

J 

1 

-IB 

_  U.                      

1    -I 

1           1 

1 
1          1           1          1 

0       40       80 
PERFUSION  PRESSURE 


120       160 
N  METERED  ARTERY 


fig.  2.  Relationship  between  perfusion  pressure  and  arterial 
inflow.  I — curve  representing  the  direct  relationship  between 
arterial  pressure  and  flow  through  the  cognate  bed  when  clamps 
were  applied  to  the  arterial  anastomotic  channels  as  at  point  C 
in  fig.  1.  II — artifactual  curve  obtained  if  clamp  C  remains 
open  when  the  arterial  pressure  supply  to  the  cognate  bed  is 
varied.  Note  that  at  perfusion  pressures  higher  than  that  existing 
in  the  collateral  artery,  the  metered  flow  is  greater  than  the 
flow  through  the  cognate  bed,  and  at  pressures  a  little  below 
that  in  the  collateral  artery,  the  inflow  is  less  than  that  through 
the  cognate  bed  while  at  some  lower  perfusion  pressure  back- 
flow  is  recorded.  Ill — artifactual  curve  obtained  if  clamps  are 
applied  to  the  arterial  supply  to  the  collateral  bed  as  at  point 
B  in  fig.  1 .  Note  that  while  no  backflow  is  obtained,  the  metered 
inflow  is  greater  than  the  flow  through  the  cognate  bed  at  all 
levels  of  pressure,  and  the  magnitude  of  the  error  increases  with 
the  perfusion  pressure.  [Modified  from  Green  el  at.  (41)-] 


Cognate  bed- 


Venous  pressure 
gauge  - 


anastomotic  channel 


Outflow 
meter 


-Collateral  bed 


-Collateral  vein 


s  Venous  pressure 
gauge 


fig.  1 .  Diagram  of  collateral  communications  between  a 
metered  (cognate)  capillary  bed  and  collateral  bed.  Inflow 
meter — meter  used  to  measure  flow  through  the  metered  or 
cognate  bed;  outflow  meter — meter  used  to  measure  the  outflow 
from  the  metered  or  cognate  bed;  anastomotic  channels — com- 
munications between  cognate  bed  and  collateral  bed  on  the 
arterial  and  venous  sides,  respectively,  of  the  metered  or  cognate 
bed.  A — clamp  used  to  occlude  the  inflow  to  the  metered  bed 
when  perfusing  it  with  fluid  at  various  pressures;  B — position 
where  clamp  might  be  placed  to  occlude  the  arterial  supply  to  a 
collateral  bed ;  C  and  D — positions  where  clamps  must  be  placed 
in  order  to  occlude  the  communications  between  cognate  and 
collateral  beds;  E — point  of  occlusion  to  prevent  outflow  from 
a  collateral  bed.  [Modified  from  Green  el  al.  (41).] 


electromagnetic     flowmeters,     drop     recorders,     and 
Gaddum-type  ordinate  recorders  (20,  27-29,  46). 

In  studying  pressure-flow  relationships  in  intact 
vascular  beds,  it  is  necessary  that  all  anastomotic 
communications  with  collateral  vascular  beds  be 
occluded.  If  they  are  not,  then,  during  measurement 
of  inflow  at  perfusion  pressures  above  the  animal's 
mean  arterial  pressure,  part  of  the  perfusion  fluid  will 
leak  across  the  anastomotic  channels  from  the  cog- 
nate into  collateral  vascular  beds  (fig.  i-a),  giving 
an  inflow  which  is  higher  than  the  true  flow  through 
the  cognate  bed  (fig.  2— II).  Similarly,  at  perfusion 
pressures  below  the  animal's  mean  arterial  pressure, 
blood  will  leak  across  the  communicating  channels 
from  the  animal's  collateral  arteries  to  the  metered 
(cognate)  vascular  bed  (fig.  i-b);  as  a  result  the 
metered  inflow  will  be  less  than  the  actual  flow 
through  the  cognate  bed.  At  some  lower  pressure 
inflow  in  the  metered  artery  will  cease  and,  at  still 
lower  pressures,  backflow  from  the  artery  will  be 
recorded,  thus  giving  an  entirely  false  picture  of  the 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


937 


behavior  of  the  cognate  vascular  bed  (41).  Analysis 
of  the  rate  of  backflow  may  be  useful,  however,  as  a 
measure  of  the  effectiveness  of  existing  communica- 
tions between  cognate  and  collateral  arteries. 

Errors  analagous  to  those  on  the  arterial  side  may 
occur  when  recording  venous  outflow,  due  to  the 
presence  of  postcapillary  communications  with 
veins  draining  collateral  vascular  beds  (fig.  i-c,  d). 

PASSIVE  CURVILINEAR  RELATIONSHIP  OF  PRESSURE-FLOW 

plots.  The  simplest  relationships  between  pressure 
and  flow  occur  in  vascular  beds  which  do  not  show 
autoregulation  such  as  skin  or  "nonreactive"  hind 
limbs  (46,  88,  115)  or  the  pulmonary  vascular  bed 
(78).  All  such  curves  are  curvilinear  with  the  con- 
vexity toward  the  pressure  axis  (fig.  3).  In  such 
studies  changes  of  vasomotor  tone  have  occurred 
spontaneously  (46)  or  have  been  induced  by  infusion 
of  epinephrine  (88).  With  increase  in  vasomotor  tone 
the  curves  rotate  toward  the  pressure  axis  so  that  for 
any  given  level  of  pressure,  flow  is  less  (fig.  3).  In  all 
such  experiments,  using  blood  as  the  perfusate,  the 
curves  approach  the  zero  flow  axis  asymptotically.  A 
'critical  closing  pressure,"  such  as  was  described  by 


Burton  (6)  and  others  (10,  37)  was  not  noted  in  the 
above  studies  (see  also  32,  35,  64).  Curves  of  this 
type  may  be  said  to  exhibit  a  "passive"  relationship 
between  pressure  and  flow. 

mathematical  relationships.  When  the  data  from 
the  above  experiments  are  plotted  on  log-log  paper, 
approximately  straight  lines  with  varying  foci  and 
slopes  are  obtained  (fig.  3).  It  appears,  therefore,  that 
the  mathematical  relationship  between  flow  and 
pressure  is  a  power  function 

F  =  c  X  Pn 

where  F  =  flow  in  ml  per  min,  c  is  a  constant,  P  = 
arteriovenous  pressure  difference  in  mm  Hg,  and  n 
is  an  exponent  having  a  value  between  1  and  3  (46). 
The  lowest  value  of  n  and  the  highest  value  of  c  were 
found  at  "low  vasomotor  tone"  (fig.  4,  point  A)  and 
vice  versa  (fig.  4,  point  C).  Levy  &  Share  (74)  have 
confirmed  these  findings  and  demonstrated  that  with 
maximal  dilation  induced  by  a  10-min  period  of 
ischemia  and  subsequent  perfusion  with  hypoxic 
blood,  the  value  of  n  is  1 .0.  The  relationship  of  c  to  n 


48 


»— 

—  A 

A 

F 

495 

X 

10 

-3 

p  1.768 

•  —  . 

• 

B 

F 

4  67 

X 

10 

-5 

p  2.315 

■  — 

— ■ 

C 

F 

2.23  X 

10 

-6 

p2  735 

50.0 


/        / 

1      /' ■  J 


80  120  160 

PRESSURE 


10        20  50        100 

PRESSURE 


300 


fig.  3.  Plots  of  the  arteriovenous  difference  pressure  vs.  the  blood  flow  in  a  cutaneous  (saphenous) 
bed  at  three  levels  of  spontaneous  "vasomotor  tone."  Left  half,  plotted  linearly;  right  half,  plotted  on 
log-log  paper.  Triangles  represent  the  lowest  level  of  vasomotor  tone;  circles  represent  an  intermediate 
level  and  squares,  the  highest  level  of  vasomotor  tone.  The  figures  in  the  upper  left-hand  corner  of  the 
graph  represent  the  parameters  for  the  straight  lines  reproduced  in  the  log-log  plot  and  for  the  curvi- 
linear lines  reproduced  in  the  linear  plot.  Flow — ml/min;  pressure — mm  Hg.  [Modified  after  Green 
et  al.  (46).] 


938 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


200 


O  ■  PRUf  VS  C 

•  ■  PRUp  vs  c 

A  .  PRUF  vs  n 

A.  .  PRUp  vs  n 

x  -  c  vs  n 


i  i  i  i  i  i 
6   8  I 


i    i  i  i  ii  i 
4     6    8  1 


4      6    8   1 


i    I  i 
4     6 


XIO" 


X  10" 


X  10" 


X  10" 


fig.  4.  Log-log  plots  of  the  interrelations  of  the  parameters  from  fig.  3.  Open  circles — plot  of  the 
relationship  of  the  resistance  at  a  How  of  5  ml/min  to  the  constant  c;  solid  circles — plots  of  the  rela- 
tionship of  the  resistance  at  a  perfusion  of  100  mm  Hg  to  the  constant  c;  open  triangles — plots  of  the 
resistance  at  a  flow  of  5  ml/min  to  the  exponent  n;  solid  triangles — plots  of  the  relationship  of  the  re- 
sistance at  a  pressure  of  100  mm  Hg  to  the  exponent  n;  X — plot  of  the  relationship  of  the  constant  c 
to  the  exponent  «;  points  labeled  A,  B,  and  C  refer  to  curves  A,  B,  and  C,  respectively,  in  tig.  3.  Ordi- 
nate scale  applies  to  resistance  at  a  flow  of  5  ml/min  (PRUf),  to  resistance  at  a  perfusion  pressure  of 
100  mm  Hg  (PRUp),  and  to  n.  Abscissal  scales  apply  to  n  (left  graph)  and  to  the  constant  c  (right 
graph).  See  Table  1  for  further  identification  of  symbols. 


in  the  above  experiments  (46)  was  also  approximately 
linear  in  a  log-log  plot  (fig.  4). 

There  are  at  least  two  possible  explanations  for  a 
value  of  n  greater  than  1 .  a)  The  apparent  viscosity 
of  whole  blood  decreases  as  the  pressure  difference 
across  a  length  of  rigid  capillary  tubing  0.3  mm  or 
less  in  diameter  is  increased,  i.e.,  as  flow  increases 
(40) ;  this  is  due  probably  to  the  red  cells  being 
clumped  progressively  closer  together  as  a  solid  core 
in  the  middle  of  the  tube  as  the  rate  of  flow  increases, 
leaving  a  sleeve  of  plasma  adjacent  to  the  intima  of 
the  blood  vessel  and  thus  reducing  viscous  drag,  b) 
Other  factors  being  constant,  flow  through  a  conduit 
is  proportional  to  the  fourth  power  of  the  diameter. 
If,  with  increasing  internal  pressure,  a  slight  but 
progressive  increase  in  the  diameter  of  the  resistance 
vessels  occurs,  then  flow  through  vascular  beds  con- 
taining such  distensible  structure  will  increase  in 
proportion  to  some  power  of  P  greater  than  1  [Green 
el  al.  (46);  Folkow  (27-29,  32)].  From  the  data  in 
figure  4  it  appears  that  these  effects  become  aug- 
mented with  increase  in  "tone"  of  the  resistance 
vessels.  Computations,  based  on  data  compiled  by 
Burton    (7),    indicate    that    an    increase    of  internal 


pressure  from  o  to  102  mm  Hg  in  an  arteriole  might 
increase  the  cross-sectional  area  sufficiently  that  the 
relative  conductance  would  be  146  per  cent  of  that 
at  zero  pressure,  i.e.,  at  the  unstretched  diameter 
(fig.  5).  However,  Baez  &  Lamport  (2)  report  that 
arterioles  of  34  to  42  /u  diameter  showed  essentially  no 
change  in  diameter  under  considerable  pressure 
variation.  They  did  note  selective  closing  of  pre- 
capillary sphincters  at  positive  pressures. 

The  relationship  of  resistance  to  flow,  PRU 
(peripheral  resistance  unit  =  P/F  =  mm  Hg  (ml/ 
min)),  to  either  flow  or  A-V  pressure  difference  was 
also  a  power  function  in  the  above  studies;  for  each 
level  of  tone  the  resistance  to  flow  varied  inversely 
with  either  flow  or  perfusion  pressure  (table  1). 
Since  both  the  constant  and  the  exponent  varied  as 
vasomotor  tone  changed,  the  relationship  of  resist- 
ance at  one  level  of  tone  to  that  at  another  (B  A; 
C/A  in  table  1 )  was  also  a  power  function  of  either 
flow  or  pressure;  this  ratio,  which  was  inversely  re- 
lated to  pressure  and  flow,  can  be  expressed  as  a 
number  if  the  same  pressure  (i.e.,  100  mm  Hg  = 
PRUPl00)  or  flow  (i.e.,  5  ml/min  =  PRUF.)  is  used 
for  each  curve  (table  1). 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


939 


CC     00 

£  II 

5  6 


4    - 


Relotive 
Pressure 

(|-"r7  '       0  0  01  0.09 

0  4 


P(mm.Hg)=  7.5xlO"4  »Y«    f/r  (1 

Y    =  Young's  modulus  (-^f5  for 
r                                                  cm' 

•t' 

100% 

extension 

) 

^J 

■ 

for  Elostic   Fibers  =  3xl0   , 

Burfon 

(1954) 

.«■»• 

:  r/r° 

=  woll   thickness/unstretched  rodlus 
■  stretched/unstretched  radius 

s 

+  r 

t 

l           1 

1 

1 

t 

Pressure 
(mm  Hg) 

Per  Cent 
Extension 


0  II 
0  30 

0  I 


33 

102 

256 

10 


0.5 
181 
565 
1470 

100 


1.0 
362 


Vessel 


-Aorto 
1130 -Med.  Art. 
3940— Arteriole 


»/r. 

(mm) 

2'l2  5 
'/2 
°2/0,5 


Relative 

Conduct.     I     104    1.46 

(Flow/Press.) 


16 


fig.  5.  Relationship  of  internal  pressure  to  radius  in  elastic  tubes.  Radius  is  expressed  as  ratio  of 
the  radius  at  any  pressure  to  the  unstretched  radius  (r/r0).  Pressure  is  plotted  over  the  range  from 
zero  to  1 ,  1  representing  that  pressure  at  which  the  vessel  extends  indefinitely,  and  zero  the  pressure 
at  which  the  vessel  is  unstretched.  Corresponding  values  of  actual  pressure,  opposite  the  bracket,  are 
given  in  mm  Hg;  below  this  is  given  the  per  cent  extension  of  the  vessel  at  each  of  the  levels  of  rela- 
tive pressure,  and  below  that  is  given  the  conductance  which  the  vessel  would  have  relative  to  that  in 
its  unstretched  state.  Conductance  is  expressed  as  the  ratio  of  Mow  to  pressure  drop  along  unit  length 
of  the  vessel.  These  plots  arc  calculated  from  data  in  Burton  (7). 


It  is  of  interest  that  c'  vs.  n'  and  c"  vs.  n"  (table  1) 
both  plotted  as  straight  lines  on  log-log  paper,  as  did 
c  vs.  n  in  figure  4.  It  is  of  interest  also  that  the  lines  on 
the  log-log  plot  in  figure  3  approach  each  other  at 
high  pressures  and  flows.  As  a  result,  if  the  data 
could  be  extrapolated  to  such  values,  a  point  would 
be  found  at  which  the  resistance  in  state  B  would 
equal  that  in  A  (i.e.,  P  =  5,000,  F  =  16,000)  and 
another  point  at  which  the  resistance  in  state  C 
would  equal  that  in  A  (i.e.,  P  =  2,950,  F  =  5,400). 
In  a  log-log  plot  these  two  points  are  so  close  together 
that  a  common  point  of  intersection  could  be  assumed 
for  all  three  lines — A,  B,  and  C.  This  suggests  that  a 
rise  of  perfusion  pressure  acts  to  overcome  the  con- 
strictor tone,  and  that  this  effect  is  proportionally 
greater  the  higher  the  vasomotor  tone. 

From  the  above  data  it  appears  that  the  most  satis- 
factory method  for  defining  "vasomotor  tone"  in 
passive  vascular  beds  is  by  means  of  a  pressure-flow 
plot,  or  by  means  of  the  equation  for  such  plot.  The 
best  quantitative  expression  for  the  comparison  of 
vasomotor  tone  at  one  moment  with  that  at  another 
is  to  determine  the  plot  of  the  pressure-flow  relation- 
ship during  a  control  phase  of  vasomotor  tone  and  to 


compare  this  with  a  similar  plot  obtained  in  the 
experimental  period  (see  fig.  3  and  table  1,  columns 
B/A,  C/A,  lines  II  and  III).  Often  this  mode  of  ex- 
pression is  impractical  because  of  the  difficulty  in 
maintaining  vasomotor  tone  constant,  particularly 
in  the  experimental  period.  A  more  practical  com- 
promise for  expressing  change  of  vasomotor  tone  may 
be  to  determine  the  pressure-flow  relationship  over  a 
suitable  range  of  pressures  and/or  flows  during  the 
control  period  and  to  compare  isolated  experimental 
observations  of  pressure  and  flow  with  this  control 
curve  (see  figs.  21  and  22  and  table  1,  columns 
B/A,  C/A,  lines  IV,  V). 

From  an  inspection  of  figures  3  and  4  and  table  1 , 
it  appears  that  comparison  of  the  experimental  per- 
fusion pressure  with  that  required  in  the  control 
period  to  induce  the  same  rate  of  flow  (table  1 , 
lines  III  and  V)  may  provide  a  ratio  which  approxi- 
mates the  apparent  separation  of  the  lines  more 
nearly  than  does  the  ratio  of  pressures  at  constant  flow 
(table  1,  lines  II  and  IV).  This  would  provide  merit 
in  perfusing  passive  (nonautoregulating)  vascular 
beds  at  a  constant  rate  of  flow  while  recording  the 


94-0  HANDBOOK    OF    PHYSIOLOGY     -"    CIRCULATION    II 

table  i.   Mathematical  Relationships  Between  Resistance  and  Pressure  and  Between  Resistance  and  Flow 


A 

B 

c 

B/A 

C/A 

I 

F  =  c  X  P- 

495Xio-3-P1768 

4.67Xiir5P2  31S 

2.23XlO-6-P2735 

po.547 
1.05X  102 

po    967 

2.22X  103 

11 

c' 

PR  Up  =  

P"' 

2.02X  IO2 

1 ■ 

2.14X104 

pi. 315 

4.40X1O5 
pi. 735 

1.05XI02 

pO  .547 

2.22X103 
pO.967 

III 

PRUf  =  — 

F°" 

20.3 

p  0.434 

74 

p0.668 

Il6 

3-65 

|7  0.134 

5-72 

p 0.635 

p  0.2  01 

IV 

PRUPlM 

5-93 

5°-3 

152 

8-49 

25.6 

V 

PRUf„ 

10. 1 

29.7 

4I.8 

2-9 

4.I4 

The  columns  correspond  to  the  curves:  A  =  solid  triangles;  B  =  solid  circles,  and  C  =  solid  squares  in  fig.  3.  PRUp  = 
resistance  in  mm  Hg/(cc/min)  expressed  as  a  function  of  the  arteriovenous  difference  in  pressure  in  mm  Hg;  PRUf  =  resistance 
expressed  as  a  function  of  the  rate  of  flow;  PRUp1M  =  resistance  computed  at  an  arteriovenous  pressure  difference  of  100  mm 
Hg;  PRUfb  =  resistance  calculated  at  a  flow  of  5  cc/min;  B/A  and  C/A  =  ratios  of  values  in  columns  B  and  C,  respectively, 
to  those  in  column  A.  Note — columns  B/A  and  C/A:  for  lines  II  and  IV  these  values  are  also  reciprocal  ratios  of  flow  at  con- 
stant arteriovenous  pressure  difference  and  for  lines  III  and  V  they  are  also  direct  ratios  of  arteriovenous  difference  of  pressure 
at  constant  rate  of  flow. 

F  =  c  X  P" 

P 
PRUp 


PRUf  =  -  = 


p 

C"1 

c' 

c-P»  ~ 

pn-1    ~ 

p7' 

pi/n 

C-l/n 

c" 

Cl/n.p 

pi-l/n 

p„ 

F 

The  data  in  this  table  were  computed  from  results  reported  by  Green  et  al.  (46). 


arteriovenous  difference  of  pressure  during  experi- 
mentally induced  changes  of  vasomotor  tone. 

On  the  other  hand  the  convergence  of  the  pressure- 
flow  plots  at  high  pressures,  discussed  above,  suggests 
a  secondary  influence  of  change  of  perfusion  pressure 
on  vascular  distensibility  and  measured  resistance. 
On  this  basis  there  is  merit  in  using  a  constant  per- 
fusion pressure  and  allowing  the  flow  to  vary  with 
experimentally  induced  changes  of  vasomotor  tone 
rather  than  keeping  the  flow  constant  and  allowing 
the  perfusion  pressure  to  be  the  dependent  variable. 
At  present  we  cannot  find  sufficient  grounds  for  a 
decision  between  the  two  methods  of  perfusion  when 
studying  "passive"  vascular  beds. 

In  those  vascular  beds  which  show  autoregulation 
(p.  948)  anything  which  induces  a  change  of  flow, 
i.e.,  alteration  of  perfusion  pressure,  tends  to  be  count- 
ered by  an  active  change  of  vasomotor  tone  which 
will  tend  to  maintain  flow  constant.  In  this  type  of 
bed  it  is  particularly  desirable  to  have  data  on  the 
control  steady-state  pressure  and  flow  relationships 
in  order  to  make  adequate  quantitative  comparisons 
with  experimental  data. 


Effects  of  Viscosity  on  Pressure-Flow  Relationships 

The  viscosity   of  blood   relative  to  that   of  water 
increases    nonlinearly    with    red    cell    concentration, 


0  20        40         60        80        100 

CORPUSCULAR    CONCENTRATION  (P  C) 

fig.  6.  Mean  and  probable  error  of  the  apparent  viscosity 
of  blood  relative  to  saline  in  a  glass  viscometer  and  in  the 
hind  limb  of  a  dog  at  different  corpuscular  concentration. 
[Redrawn  after  Whittaker  &  Winton  (115).] 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


94' 


varying  from  around  2  with  pure  plasma  to  around  5 
at  high  hematocrit  readings  when  measured  in  a  low 
velocity  viscosimeter  (fig.  6).  Lower  relative  viscosities 
are  obtained  with  high  velocity  viscosimeters  and 
still  lower  relative  viscosities  are  noted  in  perfused 
organs.  The  relative  viscosity  in  the  latter  two  systems 
decreases  as  the  pressure  difference  and  flow  rate  are 
raised.  Most  of  the  viscosity  of  normal  blood  is  due 
to  the  suspended  red  cells,  but  the  effect  of  the  cells 
is  slight  until  the  hematocrit  begins  to  exceed  30 
per  cent  (40,  74,  115);  however,  the  plasma  proteins, 
particularly  the  globulins,  contribute  significantly 
(112).  In  terms  of  effective  oxygen  delivery  to  the 
tissues,  a  hematocrit  of  around  45  appears  to  represent 
the  best  compromise  between  viscosity  and  O2 
carrying  capacity  (50). 

Effects  of  Extravascular  Pressure  on 
Pressure-Flow  Relationships 

In  most  vascular  beds  extravascular  pressure 
exerts  little  effect.  However,  in  muscle  vascular  beds, 
a  marked  increase  in  resistance  to  flow  occurs  with 
contraction.  This  is  exemplified  best  in  the  myo- 
cardium in  which  during  svstole  a  rise  in  resistance 


FLOW 


PERIPHERAL    PRESSURE 


fig.  7.  Records  of  systemic  arterial  pressure  (BP),  and 
lateral  pressure  (CP)  and  moment-to-moment  flow  (F)  in 
the  descending  ramus  of  the  left  coronary  artery  during  the 
period  labeled  "flow."  During  the  period  labeled  "peripheral 
pressure"  flow  was  interrupted  by  occlusion  of  the  coronary 
artery  inflow  proximal  to  the  site  of  pressure  measurement  so 
that  the  gauge  recorded  "peripheral  coronary  artery  pressure." 
Note  that  the  latter  pressure  begins  to  rise  during  the  phase  of 
isometric  contraction  that  precedes  the  rise  of  systemic  arterial 
pressure,  and  that  the  peripheral  coronary  pressure  begins  to 
fall  with  the  onset  of  protodiastole,  just  before  the  incisura  in 
the  systemic  arterial  pressure.  [Reproduced  in  modified  form 
from  Denison  &  Green  (19).] 


occurs  which  closely  parallels  intraventricular  pres- 
sure in  magnitude  and  duration,  as  shown  in  figure  7 

(19.  43  >• 

Coles  &  Gough  (10)  applied  external  pressure  to  a 
cup  applied  to  a  digit  while  observing  the  capillaries 
with  a  microscope.  They  noted  that  arrest  of  capillary 
flow  occurred  consistently  at  cup  pressures  of  32  to 
60  mm  Hg  in  subjects  with  mean  brachial  artery 
pressures  of  80  to  1 20  mm  Hg  obtained  with  the 
sphygmomanometer.  They  spoke  of  the  pressure  at 
which  flow  ceased  as  the  critical  closing  pressure  and 
reported  that  it  rose  with  the  arterial  pressure  in 
hypertensives  and  fell  with  digital  vasodilation 
induced  by  body  warming.  The  use  of  the  term 
"critical  closing  pressure"  in  this  sense  seems  to  us  to 
be  ambiguous.  Quite  possibly,  in  their  experiments 
the  pressure  decreased  progressively  from  the  brachial 
artery  to  the  small  digital  arteries.  If  this  were  the 
case  the  vessels  in  the  digits  may  have  collapsed  when 
the  extravascular  pressure  just  exceeded  the  intra- 
vascular pressure.  However,  since  the  true  intra- 
luminal pressure  of  the  vessels  which  close  was 
unknown,  the  role  of  the  elastic  forces  producing 
critical  closure  (see  Burton,  Chapter  6,  vol.  1,  sect.  2, 
of  this  Handbook)  as  against  the  role  of  simple  mechani- 
cal collapse  can  hardly  be  differentiated.  This  makes 
it  quite  difficult  to  assign  a  figure  for  the  critical 
closing  pressure  if  indeed  one  may  use  that  concept 
here. 

Cerebrospinal  fluid  pressure  may  have  a  tendency 
to  vary  directly  with  cerebral  blood  flow;  however, 
artificially  induced  changes  of  cerebrospinal  fluid 
pressure  have  little  effect  on  flow  unless  the  pressure 
is  elevated  above  arterial  pressure  (76  and  un- 
published data). 

Effects  of  Alteration  of  Venous  Pressure 

When  extremities  were  perfused  with  varying 
pressures,  while  venous  pressure  was  altered  simul- 
taneously so  as  to  maintain  artery  to  vein  pressure 
difference  constant,  flow  still  varied  with  the  level  of 
the  arterial  pressure  (89).  The  authors  conclude  that 
some  vascular  structures  were  dilated  as  the  arterial 
(and  total)  pressure  throughout  the  vascular  bed 
rose.  In  the  supine  anesthetized  dog,  inspiration  was 
accompanied  by  a  rise  of  intra-abdominal  pressure 
and  of  small  vein  pressure  in  the  hind  leg.  Widely 
opening  the  abdomen  abolished  both  (113).  The 
small  vein  pressure  effects  apparently  were  trans- 
mitted peripherally  from  the  inferior  vena  cava. 


942 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


0 


Verfebrol  Artery  Pressure 
85 


43 


79 
47   jr 


ir°* 


b2      5  --e^ 

Cerebral  Venous  Outflow 
16 


12.5 


Autoperfused 
Perfused   with  pump 


J L 


J_ 


J L 


J I L 


0  20         40         60  80         100 

Meon  between  Carotid  and  Vertebral  Pressures  - 
Cerebral  Outflow  Pressure  mmHg 

fig.  8.  Autoregulation  in  the  cerebral  vascular  bed  of  the 
dog.  Above:  records  representing  vertebral  arterial  pressure  in 
mm  Hg  and  cerebral  venous  outflow  in  ml/min.  Below:  heavy 
solid  line,  relationship  between  the  cerebral  venous  outflow  and 
the  mean  of  the  carotid  and  vertebral  artery  pressures  minus 
the  cerebral  outflow  pressure  during  autoperfusion  of  the 
brain  from  the  carotid  arteries.  The  perfusion  pressure  was 
regulated  by  means  of  clamps  on  the  carotid  arteries.  Light 
solid  line,  similar  relationship  but  during  the  perfusion  of  the 
carotid  arteries  with  an  artificial  perfusion  system. 

Alitor  egulatory  Control  of  Resistance  Vessels 

For  the  purpose  of  this  chapter,  we  propose  that 
the  term  autoregulation  be  defined  to  include  all 
processes  which  operate  locally  in  a  vascular  bed  to 
maintain  some  factor  constant  in  the  face  of  various 
externally  or  internally  induced  stresses.  The  factor 
which  is  kept  constant,  i.e.,  the  controlled  variable 
(see  below)  may  be  blood  flow,  or  the  tissue  concen- 
tration or  tension  of  some  nutrient  (O2,  etc.)  or  some 
metabolite  (such  as  CC^)-  As  proposed  here,  the  term 
autoregulation  would  exclude  extrinsic  mechanisms 
such  as  reflexes  involving  the  central  nervous  system, 
variation  in  arterial  pressure,  or  changes  in  hormone 
activity. 

The  activity  of  autoregulatory  mechanisms  has  been 
studied  by  subjecting  isolated  or  semi-isolated  organs 
to  stresses  such  as  changes  in  arterial  perfusion  pressure 
or  blood  gas  content,  or  by  altering  tissue  metabolism 
while  recording  the  resulting  change,  or  lack  of  change 


in  blood  flow,  venous  gas  content,  or  the  content  of 
other  metabolites. 

MODIFICATION  OF  PASSIVE  PRESSURE-FLOW  RELATION- 
SHIP by  autoregulation.  In  many  vascular  beds,  the 
above-mentioned  power  relationship  between  per- 
fusion pressure  and  flow  in  passive  vascular  beds  is 
modified  by  occurrence  of  autoregulation.  The  insert 
in  the  upper  portion  of  figure  8  shows  recordings  of 
blood  flow  in  the  brain  obtained  during  autoperfu- 
sion (76  and  unpublished  data).  In  these  studies, 
carotid  artery  inflow  pressure  was  lowered  abruptly 
from  84  to  44  mm  Hg;  after  flow  stabilized,  perfusion 
pressure  was  returned  to  the  control  level.  Immedi- 
ately upon  lowering  perfusion  pressure,  flow  dropped 
from  12.5  to  8.5  ml  per  min,  then  rose  to  a  stabilized 
level  of  approximately  10  ml  per  min.  Upon  restora- 
tion of  control  pressure,  flow  rose  abruptly  to  16  ml  per 
min  and  then  stabilized  at  approximately  its  original 
level  of  1 2.5  ml  per  min.  The  rise  in  flow  following  the 
initial  decline  probably  was  due  to  vasodilation,  and 
the  secondary  decline  in  flow  following;  restoration  of 
the  original  perfusion  pressure  probably  was  due  to 
vasoconstriction.  When  data  from  such  experiments 
are  plotted  they  yield  a  series  of  curves  such  as  are 
reproduced  in  figure  9. 

The  heavy  line  in  the  graph  in  figure  8  corresponds 
to  the  heavy  line  in  figure  9  and  is  a  plot  of  the 
stabilized  flows  at  each  level  of  perfusion  pressure  from 
85  to  15  mm  Hg.  This  line  is  almost  horizontal, 
indicating  an  almost  constant  level  of  stabilized  flow 
over  the  pressure  range  of  80  to  35  mm  Hg.  In  view 
of  the  observations  in  figures  3  and  4,  this  finding 
can  be  explained  only  by  assuming  some  reactive 
change  in  the  diameter  of  the  resistance  vessels  so  as 
to  compensate  for  alteration  of  perfusion  pressure 
(76  and  unpublished  data).  The  mechanism  respon- 
sible for  compensation  for  pressure  change  has  been 
termed  local  reaction  of  the  arterial  wall,  reactive 
vasodilation,  intrinsic  regulation,  autoregulation  and 
''genuine  autoregulation"  (3,  27-29,  36,  46,  63,  66, 

7'2,  9°.  92.  99»  I05»  I09>  "O- 

Observations,  similar  to  those  in  the  brain,  were 

recorded  in  artificially  perfused  skeletal  muscle 
vascular  beds  (fig.  10).  At  pressures  above  normal  the 
pressure-flow  relationship  was  curvilinear  and  similar 
to  that  described  for  skin  (fig.  3)  and  the  resistance  to 
flow,  after  stable  flow  was  established,  increased 
progressively  as  perfusion  pressure  was  lowered. 
However,  as  perfusion  pressure  dropped  below  100 
mm  Hg  the  curve  began  bending  more  sharply  to  the 
left  so  as  to  become  approximately  horizontal  to  the 
pressure  axis,   and  the  stabilized  resistance  to  flow 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


943 


PRESSURE 


fig.  9.  Sequential  flow  readings  following  a  series  of  square 
wave  changes  of  perfusion  pressure  in  a  vascular  bed  showing 
autoregulation.  The  pressure-flow  points  are  numbered  suc- 
cessively As,,  Ai,  At,  A3,  and  A,  for  the  first  square  wave  change 
of  pressure  (on  both  insert  and  graph).  The  points  for  the 
second  pressure  change  are  numbered  similarly  Bn-Bt  and  for 
the  third,  C0-Ca.  Light  solid  line  represents  the  pressure-flow 
relationship  which  would  be  found  if  vasomotor  tone  remained 
constant  at  the  level  which  existed  during  perfusion  at  a 
pressure  corresponding  to  Aq  for  a  period  of  time  sufficient  to 
establish  a  steady-state  flow  at  this  pressure.  Dash-dot  line 
represents  the  corresponding  pressure-flow  plot  which  would 
be  found  if  the  vasomotor  tone  were  to  remain  constant  at  a 
level  corresponding  to  that  found  when  steady-state  flow  was 
established  at  a  perfusion  pressure  corresponding  to  point  B2- 
Dash-dash  line  represents  the  pressure-flow  plot  which  would 
correspond  with  the  steady-state  flow  established  for  perfusion 
pressure  A?  assuming  no  change  in  vasomotor  tone  were  to 
occur  with  subsequent  change  of  perfusion  pressure.  These 
three  plots  then  represent  three  levels  of  vasomotor  tone.  Heavy 
solid  line  represents  the  actual  "steady  state"  pressure-flow  rela- 
tionship after  reactive  changes  have  occurred  in  the  vasomotor 
tone  following  each  change  of  perfusion  pressure;  it  is  the  plot 
characteristic  of  autoregulation. 


decreased  with  further  lowering  of  perfusion  pressure 
down  to  about  50  mm  Hg.  This  progressively  de- 
creasing resistance  tended  to  maintain  flow  relatively 
constant  over  the  range  of  arterial  pressure  from  90 
down  to  approximately  50  mm  Hg.  Below  50  mm 
Hg  arterial  pressure,  flow  dropped  rapidly  and 
approached  zero  at  a  pressure  of  10  to  20  mm  Hg. 

When  the  pressures  and  flows  in  figure  1  oA  are 
plotted  on  log-log  graphs  (fig.  10B),  the  portion 
corresponding  to  the  pressures  above  90  mm  Hg  plots 
as  a  straight  line  with  a  slope  greater  than  1 ;  this  por- 
tion of  the  curve  corresponds  to  a  "passive"  relation- 
ship between  pressure  and  flow  (see  above).  On  the 
other  hand,  in  the  range  between  50  and  90  mm  Hg 
the  slope  is  less  than  1.  In  the  equation  F  =  cPn, 
the  corresponding  values  of  n  are  greater  than  and 
less  than  1,  respectively.  Values  for  n  of  less  than  1  are 
characteristic  of  autoregulation  (28,  29). 

ARTIFACTS    INDUCED    IN    AUTOREGULATION    STUDIES    BY 

pump  perfusion  schemas.  Failure  to  detect  auto- 
regulation in  vascular  beds  has  been  attributed  to 
occurrence  of  some  alteration  in  the  vascular  bed  as  a 
result  of  changes  in  the  blood  due  to  contact  with 
artificial  structures  or  to  traumatization  of  the  blood 
by  perfusion  pumps  (28,  29,  66).  This  effect  is  notice- 
able particularly  in  the  cerebral  vascular  bed,  as 
shown  in  figure  8  (76  and  unpublished  data). 

The  heavy  line  in  figure  8  represents  the  stable 
pressure-flow  relationship  in  a  cerebral  vascular  bed 
during  an  initial  study  when  the  pressure  was  regu- 
lated by  compressing  the  arteries  supplying  the  brain. 
The  light  line  gives  the  stable  pressure-flow  relation- 
ship during  a  subsequent  period  when  a  perfusion 
pump  was  inserted  in  the  arterial  inflow  circuit.  With 
the  perfusion  pump  in  operation,  flow  at  all  levels  of 
pressure  was  significantly  above  that  with  the  brain 
perfused  directly  from  the  heart.  Furthermore,  the 
flow  did  not  remain  constant  but  increased  regularly 


200 

<D 

/ 

150 

- 

/ 

100 

: 

J 

70 

50 

/• 

30 

20 

1  5 

10 

7 

11   111 

fig.  10.  Plots  of  the  relationship  between 
blood  flow  in  a  skeletal  muscle  vascular  bed  in 
the  dog  and  the  arterial  perfusion  pressure 
(arterial  pressure  minus  venous  pressure).  A: 
linear  plot;  B:  log-log  plot.  Pressures  were 
varied  from  the  control,  at  approximately 
160  mm  Hg,  to  successively  lower  or  higher 
pressures  and  returned  to  the  control  following 
each  determination  at  the  experimental 
pressure.  Each  point  represents  the  data  after 
the  flow  had  stabilized  at  the  new  pressure. 


100  140  180  30        50    70     100 

ARTERIAL    PERFUSION    PRESSURE    mm  Hg 


200 


944 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


as  the  perfusion  pressure  was  varied  from  40  to  100 
mm  Hg.  These  findings  suggest  that  a  vasodilator 
effect  induced  by  the  pump  prevented  the  increase 
in  vasomotor  tone  that  occurs  normally  as  perfusion 
pressure  is  increased  from  35  to  85  mm  Ha;  ( 76  and 
unpublished  data).  Autoregulation  may  be  absent 
from  kidney  and  skeletal  muscle  beds  in  the  presence 
of  strong  extrinsic  stimuli  (69,  73,  111),  and  from 
intestine  during  the  initial  period  of  the  perfusion 
(66). 

AUTOREGULATION       IN       DIFFERENT       VASCULAR       BEDS. 

Autoregulation  in  brain  lias  been  both  denied  (22, 
95)  and  supported  (8,  26,  39,  71,  76).  Autoregulation 
has  been  observed  in  the  kidney  by  many  investigators 
(58,  59,  65,  72,  97,  99,  105,  1 10,  1 16).  Failure  to  note 
autoregulation  when  the  kidney(s)  is  perfused  via  the 
aorta  could  be  due  to  failure  to  ligate  the  two  lumbar 
arteries  that  arise  from  the  aorta  between  the  right 
and  left  renal  artery  origins  (58). 

Fairly  potent  autoregulation  was  observed  in 
skeletal  muscle  (27-29,  46,  109)  and  modest  auto- 
regulation in  the  intestine  (66,  68,  101,  102)  and  in 
the  liver  (36,  92);  but  significant  autoregulation  was 
not  elicited  in  skin  (Rapela  and  Green,  unpublished 
data).  It  would  be  anticipated  that  myocardium 
would  demonstrate  prominent  autoregulation;  how- 
ever, to  date  this  has  not  been  demonstrated  with 
certainty  (17,  21,  24,  43,  84,  85,  98). 


Muscle  Flow 
cm3/min       l0 


Skin  Flow 
cm3/min 


37.5 


41.0 


1 


Arterial 

Pressure 

Constant 


Occlusion 
I  min. 


fig.  11.  Records  of  flow  in  a  dog  skeletal  muscle  vascular 
bed  and  in  a  cutaneous  vascular  bed  (saphenous  bed)  before 
and  following  a  i-min  period  of  occlusion  of  the  arterial  inflow. 
Arterial  pressure  upstream  from  the  point  of  occlusion  re- 
mained constant  during  these  studies. 


300- 
200- 

1 

v. 

%  OF  CONTROL 

FL( 

S 
1 

18 

150- 

1 

S          *      ' 

•S  .* 

v 

* 

£3; 

Wt 

80- 

fig.  12.  Bar  graphs  of  the  magnitude  of  the  reactive  hyper- 
emia computed  from  data  such  as  that  in  fig.  1 1.  The  ordinate 
values  are  the  maximum  flow  during  the  postocclusion  period 
expressed  as  per  cent  of  the  control  flow.  The  width  of  each 
bar  represents  approximately  the  proportion  of  the  cardiac 
output  which  normally  flows  through  the  indicated  vascular 
bed;  total  is  the  integrated  effect  for  the  body  as  a  whole. 
[Reproduced  from  Green  &  Kepchar  (45).] 

reactive  hyperemia.  Occlusion  of  the  arterial  supply 
to  a  skeletal  muscle  bed  for  30  sec  to  1  min  is  followed, 
upon  restoration  of  the  original  pressure,  by  a  marked 
overshoot  of  flow  (fig.  1 1,  upper  curve).  This  response 
has  been  thought  to  represent  a  local  reaction  of  the 
arterial  wall  to  changes  in  internal  pressure  (3). 
However,  it  is  more  likely  that  the  overshoot  repre- 
sents a  special  manifestation  of  autoregulation.  When 
muscle  contracted  during  a  period  of  occlusion  the 
excess  0>  delivery  during  the  period  of  reactive 
hyperemia  underpaid  the  O2  debt  accumulated 
during  the  period  of  occlusion,  if  the  muscle  was  at 
rest  during  the  occlusion  the  reactive  hyperemia 
overpaid  the  debt  (9,  108). 

Momentary  overshoot  of  flow  after  a  period  of 
occlusion  was  noted  on  occasion  in  the  dog's  paw. 
However,  comparison  of  weight  changes  (see  below) 
with  the  integral  of  the  flow  during  the  period  of 
overshoot  suggested  that  the  overshoot  represented 
refilling  of  small  vessels,  which  had  emptied  by- 
elastic  recoil  into  the  vein  during  the  period  of  arterial 
occlusion  (114  and  Rapela  and  Green,  unpublished 
data). 

Reactive  hyperemia  following  temporary  occlusion 
of  the  arterial  supply  is  maximal  in  myocardium  and 
brain  (49,  84;  and  Rapela  et  «/.,  unpublished  data), 
active  in  skeletal  muscle,  present  in  the  mesenteric 
artery  bed  and  in  kidney,  but  is  almost  absent  in 
spleen,  skin  (fig.  1 1,  lower  curve),  hepatic  artery,  and 
portal  vein  vascular  beds  (45),  as  shown  in  figure  12. 

MECHANISMS  RESPONSIBLE  FOR  AUTOREGULATION.  Feed- 
back loop.  /)  General  concept.  The  engineer's  feedback 
loop  provides  a  convenient  way  to  visualize  control 
mechanisms  (fig.  13).  The  controlled  variable  is  that 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


945 


measurement  which  the  controlling  mechanism  is 
attempting  to  keep  constant  (such  as  arterial  pres- 
sure, or  tissue  Os  tension).  The  level  of  the  controlled 
variable  may  be  disturbed  by  various  loads,  i.e., 
bleeding  in  the  case  of  arterial  pressure,  or  variations 
of  tissue  metabolism  in  the  case  of  tissue  Oo  tension. 
The  detector  senses  continuously  the  magnitude  of  the 
variable  and  feeds  the  information  to  a  summator  or 
discriminator  where  it  is  compared  with  the  desired 
value  (set  point)  and  modified  by  signals  from  other 
loops.  The  resulting  signal  is  then  fed  to  an  effector 
which  controls  the  activity  of  whatever  process 
is  necessary  to  maintain  the  controlled  variable 
constant. 


Input  from 
other  loops 


Set 
point 


Ui 


I 


control 


signal  (s) 


Feedback  signal 


Load 


Detector 


fig.  13.   Schematized  diagram  for  a  feedback  loop  (see  text 
or  discussion). 


2)  Present  evidence  suggests  that,  in  skeletal 
muscle,  a  possible  controlled  variable  in  the  feedback 
loop  for  autoregulation  is  the  tissue  oxygen  tension 
(69).  The  detector  is  unknown;  but  the  feedback  loop 
may  involve  adenine  formed  from  adenosine  triphos- 
phate (ATP)  in  the  presence  of  insufficient  oxygen. 
The  summation  point  may  be  the  receptor  site  on  the 
arteriolar  smooth  muscle,  and  the  effector  may  be 
the  arteriole  which  controls  the  rate  of  blood  flow  by 
means  of  which  the  controlled  variable  is  regulated 

(5)- 

3)  There  are  other  possible  controlled  variables  in 
the  feedback  loop  for  autoregulation.  The  increased 
flow  that  occurs  in  skeletal  muscle  during  and  follow- 
ing a  tetanic  contraction  may  represent  another 
manifestation  of  this  pattern  of  autoregulation 
although  axon  reflexes  in  the  sympathetic  nerve 
supply  have  been  postulated  as  playing  a  role  (62). 
The  vasodilation  that  occurs  in  skeletal  muscle  during 
activation  of  the  patellar  reflex  is  thought  to  be  due 
to  the  same  mechanism  as  that  of  the  postcontraction 
hyperemia  ( 107). 

The  controlled  variable  responsible  for  auto- 
regulation (and  reactive  hyperemia)  may  vary  with 
different  vascular  beds.  Tissue  oxygen  tension 
appears  to  be  the  controlled  variable  in  the  myo- 


® 


e/vjw/wt: 


95" 
Arterial 
Pressure 
mm  Hg 


Coronary 

Flow 

em'/min 


-0 


Control 


90  sec      5%   O2 


Mean   Flow 
cm3/min     30 


67 


Control 

Wean   Flow 
cm3/min     21 


I  mg     NaCN 

into    Coronory  Artery 


fig.  1 4.  Left  anterior  coronary  artery  inflows  in  the  dog.  A :  in  response  to  a  90-sec  period  of 
breathing  5%  Oo.  B:  effects  of  an  intra-arterial  injection  of  1  mg  of  sodium  cyanide.  Note  the  calibra- 
tion for  flow  is  nonlinear  (the  deflection  is  approximately  proportional  to  the  square  of  the  flow). 
[Modified  after  Green  &  Wegria  (49).] 


946 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


cardium  and  skeletal  muscle,  since  reducing  the 
oxygen  content  of  the  arterial  blood  produces  a 
rather  large  increase  in  coronary  (fig.  14A)  and  in 
skeletal  muscle  flow,  whereas  there  is  almost  no  change 
in  flow  in  either  bed  when  arterial  blood  C02  content 
is  increased  (12,  49).  The  fact  that  coronary  flow  is 
influenced  more  by  coronary  artery  Oo  content  than 
tension  (51)  is  not  incompatible  with  the  concept 
that  tissue  O2  tension  is  the  controlled  variable.  The 
feedback  loop  in  the  heart  must  involve  something 
other  than  O2  tension,  since  intra-arterial  injection  of 
cyanide  causes  as  great  an  increase  of  coronary  flow- 
as  does  hypoxia  (fig.  14Z?)  (49). 

The  increase  in  blood  flow  in  the  brain  in  response 
to  decreased  arterial  blood  oxygen  content  is  relatively 
minor  compared  to  that  which  follows  an  increase  in 
CO2  content  (fig.  15)  (44),  suggesting  that  brain  CO2 
tension  may  be  the  controlled  variable  for  this  tissue. 

Elevation  of  arterial  blood  hydrogen  ion  concen- 
tration decreases  resistance  to  flow  through  cutaneous 
(18,  25),  renal  (23),  and  skeletal  muscle  (18)  vascular 
beds.  Depression  of  the  hydrogen  ion  concentration 
below  normal  is  accompanied  by  increase  of  resistance 
to  flow  in  skin  (18,  25)  and  kidney  (23);  however,  in 
skeletal  muscle  depressed  hydrogen  ion  causes  about 
the  same  degree  of  decrease  of  resistance  to  flow  as 


104  . 


Arterial   Pressure 
mm    Hg 

0 


123 


94 


Cerebral   Flow 

cm*/ mm 
0 


II  6 


4'  30"         8%   02 


100 


Arterial   Pressure 

mm    Hg 
0- 


Cerebral   Blood   Flow 
cm3 /mm 


5'  10%  C02     90%    02 

fig.  15.  Records  of  cerebral  venous  outflow  and  systemic 
arterial  pressure  during  a  4.5-min  period  of  breathing  8%  O2 
(upper  pair  of  curves)  and  in  response  to  a  5-min  period  of  breath- 
ing 10%  CO;  in  90%  O2  (lower  pair  of  curves)  in  the  dog.  Brain 
was  perfused  directly  from  the  aorta. 


does  an  elevation  of  hydrogen  ion  concentration  (18). 
Effects  of  hydrogen  ion  concentration  on  myocardial 
blood  flow  are  reported  to  be  the  reverse  of  those 
in  skin  and  kidney  (38).  These  findings  suggest  that 
hydrogen  ion  might  be  one  of  the  controlled  variables 
in  autoregulation. 

Role  of  nervous  system  in  autoregulation.  Autoregulation 
is  prominent  in  denervated  vascular  beds.  High 
activity  in  the  extrinsic  nerves  may  even  minimize  or 
prevent  manifestation  of  autoregulation;  for  instance, 
central  reflex  effects  of  hypoxia  may  overpower  the 
local  dilatory  effect  in  the  anesthetized  dog's  inner- 
vated skeletal  muscle  vascular  bed  (75)  (see  also 
p.  943).  Autoregulation  in  kidney  is  not  abolished 
by  procaine  anesthetization,  adrenergic  blocking 
agents,  or  gamma-aminobutyric  acid  (m),  suggest- 
ing that  the  feedback  loop  contains  no  essential  link 
that  responds  pharmacologically  as  does  nervous 
tissue. 

The  behavior  of  cerebral  blood  flow  in  response  to 
changes  of  perfusion  pressure  (see  above)  cannot  be 
stated  conclusively  to  represent  strict  autoregulation, 
since  in  these  studies  a  reflex  neural  mechanism  was 
not  excluded.  However,  no  influence  of  extrinsic 
autonomic  constrictor  nerves  upon  cerebral  blood 
flow  has  been  demonstrated  conclusively  (45),  and 
therefore,  it  is  unlikely  that  an  autonomic  reflex  is 
involved  in  the  cerebral  studies. 

Myogenic  theory  of  autoregulation.  Bayliss  (3)  proposed 
from  studies  of  dog's  hind  legs  and  isolated  arteries, 
that  the  arterial  wall  responds  directly  to  a  rise  of 
intraluminal  pressure  by  an  increase  in  its  state  of 
contraction  (or  tone)  sufficient  to  bring  about  a 
reduction  in  the  lumen  of  the  vessel  (and  presumably 
therefore,  a  decrease  in  the  flow  through  the  vessel). 
This  concept  received  support  from  Johnson  (66) 
who  failed  to  find  an  appropriate  correlation  between 
change  in  the  O2  concentration  of  the  venous  blood 
draining  an  isolated  segment  of  gut  and  the  occurrence 
of  a  decreased  resistance  to  flow  as  perfusion  pressure 
was  lowered.  Since  he  found,  also,  no  correlation  with 
nerve  activity,  gut  contraction,  or  presence  of  meta- 
bolites, Johnson  concluded  that  the  autoregulatory 
change  of  flow  represented  a  myogenic  response. 
Waugh  &  Shanks  ( 1 1 1 )  observed  that  hypothermia 
(3-10  C),  intrarenal  infusion  of  chloral  hydrate,  or 
high  concentrations  of  procaine  abolished  auto- 
regulation but  that  anoxic  perfusion  did  not  depress 
the  autoregulatory  reaction;  since  nerve  block  also 
did  not  interfere  (see  above)  they  concluded  that 
renal  autoregulation  is  due  to  "•myogenic  vaso- 
motion."    Folkow    (27)    also   postulated   a   myogenic 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


947 


basis  for  autoregulation  in  skeletal  muscle  since  it 
was  not  abolished  by  breathing  oxygen  at  either  high 
or  low  partial  pressure.  It  should  be  noted  that  the 
above  conclusions  regarding  the  myogenic  theory  are 
based  solely  on  negative  evidence.  It  seems  quite 
unlikely  to  us  that  a  vascular  wall  could  respond 
appropriately  to  changes  of  intraluminal  pressure 
per  se. 

Physical  factors  related  to  autoregulation.  Renal  blood 
flow  at  a  given  level  of  arterial  pressure  was  the  same 
whether  the  perfusion  pressure  was  steady  or  pulsatile. 
Autoregulatory  changes  in  resistance  were  observed 
with  both  types  of  perfusion  (93). 

A  rise  in  renal  interstitial  and  intrarenal  venous 
pressure  was  found  to  parallel  an  elevation  of  arterial 
pressure  over  the  ''autoregulatory  range."  This 
finding  is  proposed  as  the  explanation  for  the  auto- 
regulatory rise  in  renal  vascular  resistance  that 
accompanies  an  elevation  of  renal  arterial  pressure 
(65,  96).  On  the  other  hand,  two  other  groups  of 
investigators  (81,  111)  could  not  account  for  the 
observed  autoregulation  in  their  dogs'  kidneys  on  the 
basis  of  such  changes  in  intrarenal  tissue  or  venous 
pressures. 

An  increase  in  postglomerular  viscosity  which 
parallels  glomerular  filtration  rate  (116)  has  been 
proposed  to  explain  the  ''autoregulatory"  increase  in 
renal  vascular  resistance  that  accompanies  a  rise  of 
arterial  perfusion  pressure  above  80  mm  Hg.  How- 
ever, Selkurt  et  al.  (100)  found  that  arterial  perfusion 
pressure  could  be  varied  between  100  and  160  mm 
Hg  without  significant  change  in  blood  flow  (para- 
minohippurate  clearance),  glomerular  filtration  rate 
(creatinine  clearance),  or  filtration  fraction.  In  their 
experiment,  therefore,  the  postglomerular  viscosity 
remained  unchanged,  and  the  autoregulatory  varia- 
tion in  renal  vascular  resistance  must  have  occurred 
solely  in  the  preglomerular  vessels.  An  increase  in 
effective  viscosity  of  the  blood  flowing  in  the  cortical 
layers  due  to  plasma  skimming  in  the  intralobular 
arteries  (cell  separation  theory)  has  been  proposed  by 
Pappenheimer  &  Kinter  (72,  87)  to  explain  renal 
autoregulation.  However,  Waugh  &  Shanks  (111) 
were  able  to  demonstrate  autoregulation  in  the  kidney 
using  a  cell-free  perfusate,  so  long  as  the  fluid  con- 
tained plasma.  Evidently  simple  physical  phenomena 
will  not  serve  to  explain  renal  autoregulation. 

Enlargement  of  collateral  communications  following 
occlusion  of  the  cognate  arterial  supply  as  a  manifestation  of 
autoregulation.  It  is  well  known  that,  following  occlu- 
sion of  an  artery,  collateral  communications  between 
the  cognate  bed  and  collateral  arteries  enlarge  rapidly 


until  within  a  few  hours  to  weeks  they  can  supply 
almost  a  normal  rate  of  flow  to  the  cognate  bed.  Such 
enlarged  channels  are  demonstrated  beautifully 
during  arteriography.  The  dilation  of  the  communica- 
ting channels  may  be  considered  a  special  case  of 
autoregulation,  although  almost  nothing  is  known 
regarding  its  mechanism  of  action.  It  does  not  appear 
to  be  brought  about  by  any  special  change  in  arterial 
pressure  proximal  to  the  occlusion.  The  enlargement 
of  the  communicating  channels  is  more  likely  related 
to  an  increased  rate  of  flow  or  enhanced  pressure  drop 
through  the  communicating  channels  (60). 

Summary  of  present  status  of  feedback  control  of  auto- 
regulation. Though  the  mechanism  of  the  autoregula- 
tion of  blood  flow  has  not  been  established  as  yet,  the 
following  trends  may  be  stated,  a)  Most  likely  there 
is  more  than  a  single  factor  involved  and  the  pre- 
dominant one  may  vary  in  different  organs.  In  the 
kidney,  for  example,  maintenance  of  a  constant 
glomerular  filtration  rate  may  be  more  significant 
than  satisfaction  of  the  metabolic  requirements  of  the 
organ;  consequently  the  sensing  mechanism  to  regu- 
late blood  flow  should  be  related  directly  or  indirectly 
to  glomerular  filtration.  The  juxtaglomerular  appa- 
ratus may  serve  this  function  (97,  111).  In  organs 
such  as  a  skeletal  muscle  and  the  heart,  metabolism 
fluctuates  rapidly;  in  these  a  mechanism  must  be 
available  to  allow  adaptation  of  flow  to  the  varying 
metabolic  demands.  Such  mechanism  should  be 
capable  of  sustaining  the  metabolic  activity  in  the 
face  of  fluctuations  in  arterial  pressure.  In  either  case 
the  sensing  mechanism  may  detect  the  adequacy  of 
supply  (i.e.,  tissue  Oa  tension)  or  the  adequacy  of 
removal  of  metabolic  products  (i.e.,  tissue  CO2 
tension).  It  appears  probable  that  the  former  is  sensed 
in  heart  and  muscle  and  the  latter  in  the  brain,  b) 
Autoregulation  may  be  absent  in  vascular  beds  such 
as  the  paw  or  skin  which  have  very  low  metabolic 
requirements,  c)  Whatever  the  mechanism  of  auto- 
regulation, at  times  it  appears  to  be  dependent  on  the 
presence  of  certain  "normal  factors"  in  plasma 
required  for  maintenance  of  "normal  vascular  tone," 
and  at  other  times  to  be  masked  by  certain  "abnormal 
factors"  which  may  induce  either  "abnormally  high" 
or  "abnormally  low  vascular  tone." 

INTERPRETATION  OF  CHANGE  OF  VASOMOTOR  TONE  IN- 
DUCED BY  CONSTRICTOR  AND  DILATOR  AGENTS  IN  VAS- 
CULAR   BEDS    WHICH    DEMONSTRATE    AUTOREGULATION. 

In  artificially  perfused  beds.  When  studying  responses  to 
vasoconstrictor  and  vasodilator  stimulation  in  a  vas- 
cular bed  which  demonstrates  autoregulation  it  may 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


be  advantageous  to  use  a  constant-flow  technique. 
This  is  particularly  the  case  if  the  autoregulation  is 
operating  to  maintain  flow  in  proportion  to  metabolic 
need.  Under  these  circumstances  the  change  in 
arteriovenous  difference  of  pressure  probably  will  re- 
flect the  action  of  the  infused  agent  with  a  minimum 
of  complication.  On  the  other  hand,  if  constant  pres- 
sure perfusion  is  used  the  autoregulatory  mechanism 
may  mask  the  effect  of  the  vasoactive  agent  by  provid- 
ing a  counterdilation  or  constriction  in  an  attempt 
to  maintain  flow  constant  (see  p.  940). 

Interpretation  of  change  of  vasomotor  tone  in  autoperfused 
vascular  beds.  Intravenous  infusion  of  a  constrictor  agent 
which  raises  systemic  arterial  pressure  may  fail  to 
alter  blood  flow  in  a  vascular  bed  showing  autoregu- 
lation. This  lack  of  response  may  be  interpreted 
incorrectly  as  indicating  that  the  agent  has  exerted  a 
vasoconstrictor  effect.  Such  misinterpretation  has  been 
made  in  the  case  of  the  cerebral  vascular  bed.  In  such 
instances  the  vasoactive  agent  should  be  injected 
directly  into  the  arterial  supply  to  the  vascular  bed. 
If  there  should  be  no  response  to  the  intra-arterial 
injection  then  the  lack  of  response  during  the  rise  of 
systemic  arterial  pressure  with  intravenous  injection 
of  the  agent  would  be  due  to  local  autoregulation.  In 
this  case  the  vascular  bed  would  be  attempting  to 
maintain  flow  constant  despite  the  rise  of  arterial 
pressure  (90b). 

Chemical  Effects  on  Resistance  Vessels 

Hypertonic  solutions  (above  5  '!c  NaCl)  decrease 
the  resistance  to  flow  in  systemic  vascular  beds  (56) 

Control 


by  an  unknown  mechanism,  but  increase  that  in  the 
lung.  The  latter  seems  to  be  due  to  intravascular  red 
cell  agglutination  (91). 

Potassium  and  magnesium  ions  cause  active  limb 
arteriolar  dilation,  calcium  induces  constriction  (54) 
while  sodium  has  little  effect  (86).  Acetate,  among 
the  anions,  produces  arteriolar  dilation  (82). 

Extrinsic  Control  of  Resistance  Vessels 

EFFECTS  OF  VASOACTIVE  AGENTS  ON  TOTAL  RESISTANCE 

in  a  vascular  bed.  Extrinsic  control  of  resistance 
vessels,  i.e.,  of  the  peripheral  resistance  in  the  various 
vascular  beds  is  illustrated  most  typically  by  the 
responses  in  a  skeletal  muscle  vascular  bed,  since 
reactions,  characteristic  of  all  beds,  are  present  in  this 
bed.  In  a  skeletal  muscle  bed,  intra-arterial  injections 
of  epinephrine  and  of  levarterenol  cause  a  marked 
decrease  in  flow  followed,  often,  by  a  secondary  rise 
above  control  level  (fig.  16).  Such  response  occurs 
characteristically  after  all  injections  of  levarterenol 
and  after  injections  of  1  fig  or  more  of  epinephrine. 
Smaller  amounts  of  epinephrine  often  induce  either 
no  response  or  an  increase  in  flow  indicative  of 
vasodilation.  Lumbar  sympathetic  chain  stimulation 
usually  decreases  flow  (fig.  16),  although  occasionally 
an  initial  increase  followed  by  decrease  or  solely  an 
increase  in  flow  occurs  (30,  45,  1  17). 

After  induction  of  adrenergic  blockade  (fig.  16), 
levarterenol  may  have  no  effect  or  may  cause  a  slight 
increase  in  flow  while  both  epinephrine  and  lumbar 
sympathetic  chain  stimulation  increase  flow.  Atropine 
injected  intra-arterially  abolishes  the  increase  in  flow 

After   Phenoxybenzamine   0  3rng/Kg 
58 


26 

30 

14 

26 

fig.  16.  Curves  of  arterial  inHow  in  a  skeletal  muscle  vascular  bed  in  the  dog  in  response  to  intra- 
arterial injections  of  10  /jg  of  epinephrine,  10  /ng  of  levarterenol  (norepinephrine),  and  a  1  -min  period 
of  stimulation  of  the  lumbar  sympathetic  chain,  during  a  control  period  {left  half)  and  after  an  intra- 
arterial injection  of  0.3  mg/kg  of  phenoxybenzamine  (right  half).  Flow  measured  in  ml/min;  arterial 
pressure  remained  constant  through  the  study.  [Modified  after  Youmans  et  at.  (1 17).] 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


949 


CORTEX 


Metabolic  Products  (?) 
No  Known  blockade  — 
5  Receptor  (dilator) 


Receptor    (Constrictor) 
No  known  blockade 


Circulating  Vasoconstrictor 
(Angiotensin) 


Epinephrine 

<X  Receptor 

(Constrictor) 

Adrenergic  Constrictor 
Blockade  (PhenoxyDenzamine) 

Levarterenol 
(L  Norepinephrine) 

Sympatholytic 
(Guanethidine.  bretyliumi 


"J  Receptor  (dilator) 

Cholinergic  Blockode 
(atropine) 

Acetylcholine 


Sympathetic 


15 

< 


Dilator 


Epinephrine 
(isoproterenol) 


Adrenergic  Dilator  Blockade 
(di-chloro- isoproterenol) 


Ganglionic  Blockade 
(tetroethylammonium) 


/9  Receptor  (dilator) 


Sympathetic   Constrictor 


Acetylcholine 


o-J 

-Acetylcholine 

fig.  17.   Diagram  of  hypothetical  receptor  sites  on  arterioles  in  skeletal  muscle.  (See  text  for  dis- 
cussion.) [Modified  from  Green  &  Kepchar  (45).] 


induced  by  lumbar  sympathetic  chain  stimulation, 
but  has  essentially  no  effect  upon  the  dilator  response 
to  epinephrine  (45,  90a,  1 17). 

On  the  basis  of  detailed  studies  similar  to  the  above, 
Ahlquist  (1)  proposed  that  two  adrenergic  receptors 
are  present  in  blood  vessels  controlling  the  resistance 
to  flow  in  vascular  beds  (fig.  17).  The  first  of  these 
has  a  constrictor  (excitatory)  action  on  vascular 
smooth  muscle;  but  because  it  has  an  inhibitory  action 
elsewhere  (notably  in  the  gut)  it  was  not  referred  to 
as  an  excitatory  receptor  but,  noncommittally,  as  the 
alpha  receptor.  It  is  blocked  by  phenoxybenzamine 
and  similar  adrenergic  blocking  agents.  The  second 
type  of  receptor  causes  relaxation  of  vascular  smooth 
muscle  but  because  it  has  an  excitatory  effect  on  the 
heart  it  was  denoted  as  the  beta  receptor.  It  is  blocked 
by  dichloroisoproterenol.  The  alpha  receptor  is 
most  sensitive  to  epinephrine,  and  least  sensitive  to 
isoproterenol,  whereas  the  beta  receptor  is  most 
sensitive  to  isoproterenol  and  least  sensitive  to 
arterenol. 

We  would  prefer  to  limit  the  term  alpha  receptor 
to  those  receptors  which  are  located  on  blood  vessels. 
As  such  the  alpha  receptor  would  always  be  constrictor 
and    innervated    by    sympathetic    nerve    fibers.    We 


would  prefer  also  to  limit  the  beta  receptor  to  vascular 
sites.  As  such  it  would  always  be  inhibitory  (vaso- 
dilator) and  to  the  best  of  our  knowledge  never 
innervated. 

In  addition  to  these  two  adrenergic  receptors  of 
Ahlquist,  other  vascular  receptors  have  been  proposed 
(45).  A  third  group,  the  gamma  dilator  receptors,  are 
excited  by  acetylcholine  and  by  stimulation  of 
sympathetic  dilator  fibers  and  blocked  by  cholinergic 
blocking  agents  such  as  atropine  (45).  A  fourth 
possible  group,  the  delta  dilator  receptors,  may  be 
excited  by  metabolic  products  or  low  tissue  02 
tension;  they  are  probably  the  receptors  which 
participate  in  autoregulation  and  reactive  hyperemia. 
At  present  no  agents  are  known  which  block  the 
delta  receptors.  Several  more  receptors  are  probably 
present;  those  receptors,  which  respond  to  constrictor 
agents  such  as  angiotensin,  vasopressin,  and  similar 
polypeptides,  are  grouped  together  under  the  term 
"epsilon  constrictor  receptors";  no  agents  are  known 
which  can  block  these  receptors. 

The  potency  of  various  agents  in  inducing  con- 
striction or  dilation  varies  from  one  vascular  bed  to 
another.  Cerebral  and  cardiac  vascular  beds  show 
essentially    no    constrictor    response    to    adrenergic 


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HANDBOOK    ciF     1'IIYSIOLOGY 


CIRCULATION    II 


agents,  whereas  all  other  beds  show  a  significant 
response  (fig.  18).  Secondary  dilation  and  the  dilation 
following  adrenergic  blockade  which  occur  with 
epinephrine  are  due  probably  to  excitation  of  beta 
receptors;  this  effect  is  of  significant  magnitude  in 
skeletal  muscle  bed  and  of  lesser  magnitude  in  cardiac, 
mesenteric  arterial,  and  splenic  vascular  beds  (fig.  19). 
Sympathetic  constrictor  fibers  exert  maximal  effects 
in  kidney,  skin,  and  mesenteric  beds.  Significant 
constriction  is  noted  in  muscle,  spleen,  and  hepatic 


fig.  18.  Bar  graph  of  responses  in  various  vascular  beds  to 
an  intra-arterial  injection  of  1-10  fig  of  epinephrine.  Light- 
colored  bars — initial  responses;  dark-colored  bars — secondary 
(dilator)  responses.  See  legend  to  fig.  12  for  additional  infor- 
mation. [Reproduced  from  (45).] 


arterial  and  portal  venous  beds;  but  no  significant 
reduction  of  flow  occurs  in  cerebral  or  cardiac  beds 
(fig.  20). 

In  the  dog,  unequivocal  cholinergic  dilator 
responses  in  response  to  sympathetic  nerve  stimulation 
are  seen  only  in  skeletal  muscle  (fig.  20)  (45).  How- 
ever, Beck  &  Brody  (4)  believe  that  another  active 
dilator  pathway  can  be  demonstrated  in  the  dog's 
hind  quarters  perfused  at  a  constant  rate  of  flow. 
Dilation,  primarily  induced  by  this  pathway,  is  most 
readily  obtained  by  release  of  tracheal  occlusion  and 
is  not  blocked  readily  by  atropine.  It  is  claimed  that 
in  man  there  is  a  cutaneous  vasodilator  innervation 
(61,  94).  It  is  claimed  also  that  when  sweat  fibers  are 
activated  there  is  a  release  of  bradykinin  which 
causes  secondary  dilation  in  blood  vessels  adjacent  to 
the  sweat  glands  (34).  However,  Senay  el  al.  (103) 
often  found  marked  dissociation  between  sweating 
and  vasodilation  in  the  forearm. 


SEGMENTAL    RESISTANCES    IN    VASCULAR    BEDS 

Methods 

The  behavior  of  the  small  vessels,  i.e.,  the  arterioles 
and  venules,  may  be  inferred  from  comparison  of  the 
pressures  recorded  from  fine  catheters  fed  distally  into 
small  arteries  and  veins  via  the  large  vessels,  with  the 
lateral  pressures  recorded  from  the  larger  vessels 
(53,  57).  Additional  information  is  yielded  when 
flows  are  measured  simultaneously  (14,  15).  Micro- 
puncture  studies  have  been  used  to  obtain  the 
pressures  in  the  portal  venous  tree,  portal  venules,  and 
central  veins  of  the  liver  (83). 


0?N 


400 
300 


200- 
150 


100 
80 


"® 


.!_ 

\      1 

o  PER  CENT   OF  TOTAL  FLOW 

Heart  4  7,   Brain  3  8,  Muscle  29.6,  Mes.  Art.  19  7,   Spleen  14 
Skin  9  4,    Kidney  26  3,   Hep   Art.  5.2,  (Portal  V.  21.1) 

fig.  19.  Bar  graphs  of  responses  to  intra-arterial  injections  of  isoproterenol  (B)  compared  with 
those  to  epinephrine  during  adrenergic  blockade  with  phenoxybenzamine  (Dibenzyline)  (.4).  The 
ordinate  values  are  the  maximum  flows  in  response  to  the  agent,  expressed  as  per  cent  of  the  control 
flow.  The  last  bar  (unshaded)  represents  the  computed  integrated  effect  on  the  total  body  flow 
I  cardiac  output).  The  sequence  of  the  bars  appears  in  the  figure;  the  figures  on  the  abscissa  represent 
the  per  cent  of  cardiac  output  which  flowed  through  the  bed  in  the  control  period.  See  legend  to  fig. 
12  for  further  explanation.  [Reproduced  from  (45).] 


PER  CENT  OF  TOTAL  FLOW 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


95 1 


Effects  of  Changes  of  Perfusion  Pressure  and  of  Venous 
Pressure  on  Large  Artery  and  Vein,  and 
Distal  Small  Vessel  Pressures 

In  general,  when  perfusion  pressure  is  varied  while 
other  factors  remain  constant,  pressure  in  the  small 
vessels  parallels  that  in  the  large  vessels  (fig.  21). 


200- 

150- 


100' 
80 

60- 
40 


20 


10 

150  H 


100 
80 


® 


ADRENERGIC 


I 


5; 

<0  <o 


tr 


I 


/ 


CHOLINERGIC 

"CD  1 

1                         1 

- 

fig.  20.  Bar  graph  of  responses  to  stimulation  of  sympathetic 
constrictor  nerve  supply  (A)  and  of  sympathetic  dilator  nerves 
(B).  The  ordinate  values  give  the  flow  at  the  moment  of  maxi- 
mal response  to  the  stimulation,  expressed  as  per  cent  of  the 
control  flow.  See  legend  to  figs.  1 2  and  1 9  for  further  explana- 
tion. [Reproduced  from  (45).] 

PRESSURE  -  mmHg 
80  120  160 


Elevation  of  an  intestinal  large  vein  outflow  pres- 
sure leads  to  a  progressive  increase  in  the  venous 
volume  (yielding  a  measurable  venous  compliance), 
to  a  decrease  in  the  venous  resistance,  to  a  progressive 
elevation  of  capillary  pressure,  and  to  a  slower  change 
in  gut  volume  due  to  capillary  nitration  (67). 


Effects  of  Extrinsic  Agents  on  Segmental  Resistance 

Decrease  in  C02  tension  and  hydrogen  ion  concen- 
tration, produced  by  hyperventilation,  induced  dila- 
tion of  the  arteries  with  concomitant  constriction  of 
small  vessels  in  intact  forelegs.  Opposite  changes  in 
both  vessel  segments  were  induced  by  increased  CO2 
tension  and  hydrogen  ion  concentration.  Serotonin 
decreased  small  artery  pressure  markedly  associated 
with  an  increase  in  small  vein  pressure  and  no  change 
in  large  artery  and  vein  pressure  or  total  resistance 
[Haddy  (52)].  These  findings  suggest  that  serotonin 
exerts  its  effects  predominantly  on  vessels  larger  than 
the  arterioles  and  venules. 

Intra-arterial  infusion  of  epinephrine  into  the 
dog's  paw  caused  the  large  artery  to  small  vein 
pressure  difference  to  increase  as  flow  decreased  (fig. 
21C).  Simultaneously,  the  small  vein  to  large  vein 
pressure  difference  decreased  with  flow  in  about  the 
same  degree  as  that  which  had  been  noted  during  con- 
trol studies  in  which  perfusion  pressure  had  been 
lowered  progressively  (fig.  21  A).  Subsequently,  large 
artery  to  small  vein  pressure  difference  decreased,  and 
flow  rose,  but  small  vein  to  large  vein  pressure  differ- 


30 


20 


10 


ART   PRESS. 


40  80  120  160 

- PERIPH   VENOUS    PRESS   mmHg 


Control 

Infusion  of  Epinephrine  -Art.  Press 

Constant  at  200  mmHg  (1/jg/mm  ) 


o-  Control 

Cs  -  During  Infusion 

o-  Post  Infusion 


fig.  21.  Plots  of  relationship 
of  blood  flow  in  the  dog's  paw 
to  pressure.  A — flow  vs.  the 
difference  between  distal  small 
vein  and  large  vein  pressure; 
B — flow  vs.  the  large  artery  to 
large  vein  pressure  difference; 
C — flow  vs.  large  artery  to  distal 
small  vein  pressure.  Heavy  lines 
— successive  responses  to  an  in- 
tra-arterial infusion  of  1  Mg/min 
of  epinephrine  while  the  perfu- 
sion pressure  was  held  constant 
at  200  mm  Hg.  Abscissal  values 
for  C  =  abscissal  values  for  B 
minus  abscissal  values  for  A.  Dis- 
tal small  vein  pressures  were  re- 
corded from  an  0.5-mm  poly- 
ethylene catheter  inserted  into  a 
superficial  vein  and  passed  as  far 
distally  as  it  would  go. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Fic.  22.  Plots  similar  to  those  in  fig. 
21  showing  the  responses  to  an  intra- 
arterial infusion  of  acetylcholine  at  the 
rate  of  25  jug/min,  /;  and  to  an  intra- 
arterial influsion  of  acetylcholine  at 
the  rate  of  100  Mg/min,  2.  Arterial 
pressure  was  held  constant  at  75  mm 
Hg  for  /,  at  105  mm  Hg  for  2. 


PRESSURE  -    mm  Hg 
40  80  120  160  200 


1 1        1        1        r 


Periph   Venous 
Press  vs    Flow 


0  40  80  120  160 

ART    PRESS  -  PERIPH.  VENOUS    PRESS        mm  Hg 


■  Control 

■Infusion  of  Acetylcholine 


o  -  Control 

A—  During  Infusion 

a— Post  Infusion 


ence  increased.  These  findings  suggest  a  dual  effect  of 
epinephrine,  i.e.,  an  initial  small  artery  or  arteriolar 
constriction,  or  both,  and  a  subsequent  small  to 
intermediate  vein  constriction  as  the  arterioles  dilate 
[(55)  and  Rapela  and  Green,  unpublished  data]. 
Similar  changes  were  recorded  in  dog's  leg  during 
sympathetic  stimulation  (13). 

Acetylcholine,  infused  into  a  dog's  paw,  caused 
effects  opposite  from  those  of  epinephrine.  Small  doses 
had  no  effect  on  the  arterioles  (fig.  22C,  1)  but  in- 
creased the  small  vein  resistance  (fig.  22.<4,  1);  larger 
doses  decreased  the  arteriolar  resistance  (fig.  22C,  2), 
but  only  slightly  increased  small  vein  resistance  (fig. 
22.4,  2)  [(52)  and  Rapela  and  Green,  unpublished 
data]. 

Intermediate  artery  and  vein  behavior  has  been 
studied  by  inserting  fine  (0.5  mm)  catheters  centrally 
into  a  small  artery  and  a  small  vein  at  the  dog's 
ankle  and  recording  the  pressures  during  a  control 
state  and  during  strong  stimulation  of  the  peripheral 
homolateral  lumbar  sympathetic  chain  (15,  70). 
During  stimulation  pressure  in  the  small  artery  fell 
dramatically  while  that  in  the  small  vein  rose.  These 
findings  suggest  a  marked  increase  in  the  resistances 
to  flow  in  the  artery  and  vein  between  the  points  of 
cannulation  and  the  more  proximal  points  of  pressure 
measurement  in  the  larger  arteries  and  veins.  The 
stimulations  were  repeated  as  the  catheters  were  fed 
into  the  artery  or  vein  toward  the  knee  (15).  In  the 
control  state  the  arterial  pressure  was  the  same  at  all 
levels   of  the   catheter   tip    but,   during   sympathetic 


stimulation,  a  marked  drop  in  pressure  was  noted  in 
the  artery  at  all  points  distal  to  15  cm  proximal  to  the 
ankle.  These  findings  indicate  that  strong  vaso- 
constriction occurred  in  the  arterial  tree  midway 
between  knee  and  ankle  sufficient  to  stop  flow  and 
pulsations.  Similar  closures  were  recorded  in  the 
veins  midway  between  knee  and  ankle.  The  morpho- 
logical background  for  this  was  described  by  Shadle 
et  al.  (104);  they  noted  that  the  dorsal  foot  veins  were 
thick  walled  and  difficult  to  distinguish  from  small 
arteries  while  veins  from  thigh  muscles  were  thin 
walled. 

In  a  subsequent  paper,  Davis  &  Hamilton  (16) 
studied  the  responses  further  by  a  "cross-perfusion" 
method  which  allowed  the  blood  to  flow  out  of  the 
proximal  cut  end  of  a  small  artery  of  the  foot  through 
a  flowmeter  and  into  the  distal  cut  end  of  the  corre- 
sponding artery  of  the  opposite  foot.  Similar  cross 
perfusion  was  arranged  in  the  veins.  Thus  stimulation 
of  the  sympathetics  on  one  side  could  affect  flow  only 
by  causing  constriction  of  the  intermediate  size  vessels 
proximal  to  the  ankle,  whereas,  stimulation  of  the 
sympathetic  fibers  on  the  opposite  side  of  the  body 
could  affect  flow  only  by  causing  constriction  of  small 
distal  arteries,  arterioles,  venules,  and  small  distal 
veins.  They  found  that  sciatic  nerve  stimulation 
produced  intense  constriction  in  both  proximal 
intermediate  and  distal  small  arteries  and  veins  which, 
in  either  case,  was  sufficient  to  stop  flow.  Lumbar 
sympathetic  stimulation  produced  similar  effects  but 
they  were  slightly  less  intense  in  the  paw  than  with 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


953 


sciatic  nerve  stimulation.  Incidentally,  they  noted  that 
retrograde  flow  could  be  induced  in  the  distal  small 
vessels  from  vein  to  artery  when  these  were  not  being 
stimulated,  and  the  arterial  pressure  was  low. 

It  should  be  noted  that  Davis  and  Hamilton  speak 
of  recording  "'small  vessel"  pressures,  but  it  is  our 
interpretation  that  the  data  indicate  the  role  of 
intermediate  vessels  as  well  as  arterioles  and  venules. 
It  remains  to  be  demonstrated  whether  the  above 
observations  represent  a  response  that  might  occur 
under  reasonable  degrees  of  physiologic  stress  or  a 
change  that  would  occur  only  under  unusual  condi- 
tions such  as  intense  electrical  stimulation  of  the 
sympathetic  chain.  Effects  such  as  these  were  signifi- 
cantly less  marked  in  the  intermediate  vessels  supply- 
ing the  rabbit  ear  during  stimulation  of  the  third 
cervical  nerve  or  the  ipsilateral  cervical  sympathetic 
trunk  (14). 

INDICATOR    CONCENTRATION   (lo»er)        INTEGRATOR   (upper) 


J  Ml  1  II      1  1  1      1      1  1  II      1  1  1  Ml 
®   | 

L-21.2  sec 

,XJ  1  1  1  I'l  1  1  1  1  1  1  1  1  1  1  11  1  w  1 

§}                                                DX  58 
1              1 

!   .£1.6  sec 

!          r 

1 I      — 

-IxP" 

1 
1          1 

1 
A     ' 

\  A — Areo  =  283  m9  sec 
y  '                               cc 

\      /Fl°*  =  265sfjf 

i\    / 

02 

i 
1            1     .           ...  mg  sec 
^■^Areo  =  .224  — ^ 

|   f\    ^FIow  =  33.6^ 

III       !      "-— 

1 ! 

— t 1 

CONTROL    166  mm  Hg 


ACETYLCHOLINE 


fig.  23.  Records  obtained  from  the  dog's  paw  showing  the 
time  course  of  the  concentration  of  an  indicator  (indocyanine 
green)  recorded  in  the  venous  outflow  following  an  intra- 
arterial injection  of  the  indicator,  C.  A .  curve  recorded  from 
the  output  of  an  integrator  whose  input  was  the  output  from 
the  indicator  concentration  recorder.  Time  lines  at  the  top — 5 
sec.  B  and  D:  similar  records  obtained  during  an  intra-arterial 
infusion  of  acetylcholine,  which  were  recorded  after  a  stable 
rate  of  flow  had  been  attained.  Perfusion  pressure  1 16  mm  Hg 
for  all  four  curves.  In  each  case,  0.125  mg  01  indicator  was 
injected  as  a  square -wave  pulse  during  a  i-sec  period.  The 
upper  asymptote  was  drawn  parallel  to  '"integrator  base 
line."  The  slight  inclination  of  the  latter  was  due  to  a  failure 
to  balance  the  integrator  to  the  densitometer  output  when 
control  blood  was  flowing  through  the  cuvette.  A  2-  to  3-sec 
delay  is  noted  between  the  beginning  movement  of  the  densi- 
tometer and  the  beginning  movement  of  the  integrator  pens. 
This  is  due  in  part  to  the  lag  of  the  recorder  and  possibly  to 
slight  delay  in  the  integrator.  It  is  corrected  in  the  calculations 
since  the  true  mean  transit  time  is  obtained  by  subtracting 
the  delay  time  from  the  apparent  mean  transit  time.  The 
delay  time  is  obtained  by  making  a  second  injection  at  the 
sampling  site  in  the  venous  outflow. 


BLOOD    VOLUME    IN    VASCULAR    BEDS 
(VASCULAR    CAPACITY) 

Methods 

The  volume  of  the  various  components  of  the 
vascular  bed  has  been  studied  by  injection  techniques 
(77).  The  volume  in  a  given  vascular  bed  can  be 
computed  also  by  ligating  abruptly  the  artery  and 
vein,  washing  out  the  contained  blood,  measuring  the 
hemoglobin  content  of  the  washout  and  comparing 
this  with  the  hemoglobin  content  of  the  blood  per- 
fusing the  bed. 

Estimates  of  vascular  capacity  in  an  intact  bed  can 
be  made  by  intra-arterial  injection  of  an  indicator 
with  determination  of  the  time  course  of  the  indicator 
concentration  in  the  venous  effluent  (42).  A  typical 
record  (fig.  23)  shows  an  abrupt  rise  in  the  indicator 
concentration,  beginning  about  5  sec  after  the 
injection;  the  concentration  reaches  a  peak  in  10  sec 
and  then  returns  to  control  level  at  approximately  90 
sec.  The  rate  of  flow  can  be  computed  by  dividing 
the  milligram  of  indicator  injected  by  the  area  under 
the  indicator  concentration  curve,  expressed  in 
mg   •  sec/ml  (fig.  23,  C  and  D). 

Curves  A  and  B  in  figure  23  show  the  integration 
of  the  indicator  concentration  curve.  By  integrating 
the  area  above  and  to  the  left  of  the  upper  curve  and 
dividing  this  area  by  the  height  of  the  curve,  the  mean 
transit  time  of  the  indicator  through  the  vascular  bed 
can  be  obtained.  Multiplication  of  the  mean  transit 
time  by  the  rate  of  flow  gives  the  volume  in  the 
vascular  bed.  In  this  experiment  on  the  paw,  flow  was 
26.5  ml  per  min  (0.44  ml/sec),  mean  transit  time 
21.2  sec,  and  vascular  volume  9.35  ml.  Comparison 
of  the  flow  measured  with  the  indicator  concen- 
tration curve  with  that  measured  simultaneously  with 
the  electromagnetic  flowmeter  shows  the  former  to 
average  103  percent  (sd  4.6)  of  the  latter.  Correlation 
of  the  last  determination  of  vascular  volume  with  the 
vascular  volume  determined  by  the  hemoglobin 
washout  method  shows  that  the  former  averaged  94 
per  cent  (sd  38.5)  of  the  latter  (48). 

Effects  of  Various  Factors  on  I'ascular  Volume 

In  a  set  of  experiments  on  the  dog's  paw,  changes 
in  perfusion  pressure  produced  approximately  propor- 
tional changes  in  flow  (fig.  24),  whereas  mean  transit 
time  varied  inversely.  As  a  consequence  neither  vas- 
cular volume  nor  conductance  (1 /resistance)  was 
altered    to    any    significant    extent.     Acetylcholine, 


954 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Flo.  24.  Effects  of  perfusion  pressure  per  se  (circles)  and  of  an  infusion  of  acetylcholine  at  each 
level  of  perfusion  pressure  (triangles)  on  flow,  mean  transit  time,  volume,  and  conductance  in  the 
dog's  paw.  Same  experiment  as  that  in  fig.  23.  .-1 :  plot  of  perfusion  pressure  (arteriovenous  difference 
of  pressure)  vs.  flow.  [In  a  larger  series  of  experiments  the  pressure-flow  relationship  in  the  vascular 
bed  of  the  paw  was  best  represented  by  a  curve  with  convexity  towards  the  pressure  axis,  when  plotted 
in  linear  coordinates,  similar  to  that  observed  in  the  skin  (fig.  3)].  B:  plot  of  perfusion  pressure  vs. 
mean  transit  time.  C:  plot  of  perfusion  pressure  vs.  vascular  volume  (computed  from  product  of  flow 
X  mean  transit  time).  D :  plot  of  conductance  vs.  vascular  volume.  Figures  in  D  represent  the  per- 
fusion pressures  used  for  each  pair  of  determinations. 


infused  intra-arterially  in  this  experiment  had  similar 
effects  at  all  levels  of  perfusion  pressure.  This  agent 
increased  flow  and,  thereby,  lowered  the  amplitude  of 
the  indicator  concentration  curve  (fig.  23).  However, 
mean  transit  time  did  not  change  appreciably  and 
therefore  vascular  volume  and  conductance  were  both 
increased,  the  latter  proportionately  more  than  the 
former  (fig.  24).  The  straight-line  relationship  between 
flow  and  pressure  may  indicate  a  considerable 
though  not  maximal  dilation    of   the    arterioles    (p. 

937)- 

When  using  indicators  it  is  necessary  that  a  stable 

state  exist  since,  if  the  volume  is  changing  during  the 

determination,  a  false  reading  will  be  obtained.  When 

this    occurs,    the    flow    computed    by    the    indicator 

method  may  differ  significantly  from  that  recorded 

simultaneously  by  a  flowmeter. 


ESTIMATION    OF    CHANGE    OF    VASCULAR    VOLUME 
DUE    TO    EXTRINSIC    INFLUENCES 

Changes  in  vascular  volume  in  an  organ  may  be 
measured  by  recording  continuously  the  organ's 
weight  or  its  volume  with  a  plethysmograph.  These 
methods  give  the  relative  change  of  vascular  volume 
but  not  the  actual  volume  of  blood  in  the  bed  at  any 
moment.  Changes  in  vascular  volume  measured  by 
these  methods  may  be  used  to  confirm  changes  in 
volume  obtained  with  the  indicator  method.  Com- 
parison of  change  of  vascular  volume  with  simul- 
taneously recorded  blood  flow  gives  an  indication  of 
the  interplay  of  resistance  and  capacitance  vessels 
(31,80). 

Different  vascular  beds  vary  significantly  in  their 
response    to    factors   causing    a   change   of  vascular 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


955 


volume.  In  response  to  intra-arterial  epinephrine  the 
vascular  volume  in  the  dog's  paw  tends  to  decrease  as 
the  resistance  to  flow  increases,  i.e.,  as  flow  decreases. 

During  constant-flow  perfusion  of  the  isolated  dog's 
hind  quarters  intra-arterial  perfusion  of  levarterenol 
caused  a)  a  marked  rise  in  the  perfusion  artery 
pressure  (increased  resistance  to  inflow  through  the 
arterioles);  b)  a  decreased  venous  outflow;  and  c)  a 
rise  in  limb  weight  (due  to  distention  of  the  arteries 
proximal  to  the  site  of  constriction).  When  the  rising 
arterial  pressure  overcame  the  arteriolar  resistance 
outflow  increased  above  inflow  and  limb  weight  fell 
despite  persistence  of  the  elevated  arterial  pressure. 
The  authors  concluded  that  the  latter  effect  was  due 
to  translocation  of  blood  by  constriction  of  the  veins. 
Because  of  the  small  changes  of  T-1824  and  P32  tag 
concentrations,  they  concluded  also  that  only  a  very 
small  percentage  of  the  leg  weight  change  was  due 
to  transcapillary  movement  of  either  plasma  or 
interstitial  water  (104). 

Reductions  in  flow  and  volume  were  noted  in  cat's 
hind  legs  in  response  to  levarterenol;  this  finding  was 
interpreted  as  being  due  to  constriction  of  both  the 
"resistance"  and  the  "capacitance  section"  of  the 
vascular  bed  (31,  80).  In  this  preparation  intra- 
arterial epinephrine  caused  an  initial  increase  in  out- 
flow simultaneously  with  a  decrease  in  volume, 
whereas  isoproterenol  and  acetylcholine  increased 
both  flow  and  volume.  Since  levarterenol  seemed  to 
be  more  potent  than  angiotensin  in  reducing  the 
volume  of  blood  contained  in  the  capacitance  section 
of  the  hind  leg  (muscle  and  skin)  of  cats,  Folkow 
et  al.  (33)  claimed  that  a  greater  constrictor  effect  on 


the  capacitance  vessel  (larger  veins)  is  exerted  by 
levarterenol  than  by  angiotensin.  As  we  visualize  it, 
the  data  should  be  interpreted  oppositely,  i.e.,  that 
angiotensin  has  a  more  potent  effect  than  does 
levarterenol  on  the  postcapillary,  or  a  less  potent 
effect  on  the  precapillary  vessels  (see  below). 

The  vascular  volume  of  the  spleen  decreased  more 
rapidly  and  abruptly  than  the  inflow  in  response  to 
intra-arterial  epinephrine,  levarterenol,  or  sympa- 
thetic nerve  stimulation.  After  a  period  of  time  the 
inflow  began  to  increase  rapidly  exceeding  outflow 
and  resulting  in  a  progressive  augmentation  of 
spleen  weight  (47)  (fig.  25). 

The  usual  accompaniment  of  an  increase  in  vascular 
resistance  of  an  organ  is  a  decrease  in  its  volume  as 
measured  plethysmographically  or  by  weight  changes. 
This  change  is  the  result  of  a  diminution  of  the  volume 
of  the  resistance  vessels  (arteriolar  constriction)  and 
perhaps  more  importantly  the  lessening  of  the 
distention  of  the  postarteriolar  vessels  and  even  the 
closure  of  some  of  the  capillaries  and  venules  (fig.  26). 
Only  rarely  is  an  increase  in  resistance  accompanied 
by  an  increase  in  organ  volume.  When  this  occurs,  it 
is  due  probably  to  a  preponderance  in  the  resistance 
increase  of  postcapillary  or  even  venular  vessels  over 
that  occurring  in  the  precapillary  vessels,  thus  causing 
an  increase  in  upstream  (capillary)  pressure  which 
may  lead  to  an  augmentation  of  organ  volume  by 
distending  the  capillaries  (fig.  26)  and  by  increasing 
the  filtration  of  fluid  into  extravascular  spaces.  The 
kidney  is  the  only  organ  in  which  a  well-documented 
increase  in  volume  accompanies  an  increase  in 
resistance.  That  this  is  due  in  part  to  an  increase  in 


Arfenol 

SPLEEN 

Inflow 

Cm3/min 

15 

II 

12 

0 — 

Venous 

^03/ 

r43 

Outflow 

cmVmin 

12 

q  1           

II 

22  6 


196 


fig.  25.  Records  of  arterial  inflow,  venous 
outflow,  and  relative  weight  changes  of  the 
dog's  spleen  in  response  to  stimulation  of 
sympathetic  nerve  supply  and  of  the  dog's 
paw  in  response  to  slow  intra-arterial  infusion 
of  1  Mg/min  of  epinephrine.  [Modified  after 
Green  el  al.  (47).] 


956 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


intravascular  volume  rather  than  an  increase  in 
extravascular  volume  (106)  has  been  shown  by 
Mehrizi  and  Hamilton  (79)  using  calculations  from 
mean  transit  time.  It  has  been  attributed  classically  to 
constriction  of  efferent  glomerular  arterioles  and  a 
passive  distention  of  upstream  vessels. 

In  short,  changes  in  vascular  volume  as  a  result  of 
increased  resistance  to  flow  can  be  attributed  to  any 
combination  of  three  causes,  all  operating  at  the  same 
time:  /)  decreased  volume  of  constricting  vessels,  2) 
decreased  distention  of  downstream  vessels,  and  5) 
increased  distention  of  vessels  upstream  to  the  site  of 
preponderant  increase  in  resistance.  The  net  change 
in  vascular  volume  will,  then,  depend  on  the  location 


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Increased    precapillary   resistance  — 

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Increased   postcapillary  resistance 

—  decreased 

flow*  increased  vascular  volume 

fig.  26.  Hypothetical  plots  of  the  pressure  drops  in  various 
portions  of  the  terminal  vascular  bed  during  a  control  state, 
solid  line;  during  a  state  of  increased  precapillary  resistance, 
dash-dot  line;  and  increased  postcapillary  resistance,  dashed  line. 


of  the  resistance  increase  in  the  morphological  pattern 
of  the  vascular  network.  A  lessening  of  resistance  in 
any  part  of  the  network  will  presumably  induce  oppo- 
site changes  in  vascular  volume.  These  structures  are 
affected  differentially  by  various  vasoactive  agents. 
Data  are  insufficient  at  present  to  draw  significant 
generalizations  regarding  the  various  vascular  beds. 


PULSATILE    CHANGES    IN    VASCULAR    VOLUME 

Pulsatile  flow  through  a  dog's  ulnar  artery  was 
measured  with  a  square  wave  electromagnetic  flow- 
meter together  with  pressure  recorded  in  a  small 
branch  just  proximal  to  the  flowmeter  and  with  paw 
volume  pulse  recorded  plethysmographically  (fig.  27). 
The  flow  record  showed  a  dicrotic  notch  but  never 
fell  to  or  below  zero  during  diastole.  A  volume  pulse 
calculated  by  integrating  the  flow  pulse  and  sub- 
tracting an  assumed  constant  venous  output  was 
essentially  similar  (fig.  27).  Both  showed  two  humps 
of  approximately  similar  magnitude. 

In  man,  the  normal  digital  volume  pulse  rises 
relatively  more  rapidly  than  that  of  the  dog's  paw, 
has  a  sharp  peak  at  the  end  of  the  first  quarter  of  the 
pulse  interval,  and  a  slight  notch  about  halfway  down 
the  descending  limb  (fig.  28).  If  the  supplying  artery 
is  occluded  but  adequate  collateral  circulation  is 
available,  the  digital  pulse  shows  a  peak  which  is 
rounded  and  delayed,  and  the  notch  on  the  descending 
limb  is  absent.  In  the  presence  of  vasospastic  disease, 
the  peak  may  be  delayed  slightly,  the  notch  raised  or 
may  occur  sooner  on  the  descending  limb,  and  the 
area  of  pulse  per  unit  amplitude  increased  in  com- 
parison with  the  normal.  With  elevation  of  venous 
pressure  or  interference  with  venous  outflow,  the  peak 
of  the  pulse  is  sharper  than  normal  and  a  second  hump 


Pulsatile  arterial  inflow        Pulsatile  orteriol  pressure       Pulsatile  plethysmogroph  vol    Calculated  pulsatile  vol 

fig.  27.  Records  of  A — pulsatile  arterial  inflow;  B — pulsatile  arterial  pressure;  and  C — pulsatile 
plethysmographic  volume,  in  the  dog's  paw.  Arterial  inflow  recorded  with  an  electromagnetic  meter 
on  the  ulnar  artery.  D — pulsatile  volume  calculated  from  the  pulsatile  arterial  inflow,  assuming  a 
constant  venous  outflow. 


RESISTANCE    AND    CAPACITANCE    PHENOMENA    IN    VASCULAR    BEDS 


957 


Normal 


Arterial  occlusion 


Vosospasm 


Venous  obstruction 


fig.  28.  Averaged  plethysmographic  pulses  from  the  digits  of  patients.  A — normals;  B — patients 
with  arterial  occlusion,  but  with  good  collateral  circulation;  C — patients  with  vasospasm;  D — pa- 
tients with  deep  thrombophlebitis.  All  pulses  are  redrawn  to  the  same  amplitude  and  same  time  dura- 
tion. Note :  the  flow  to  pulse  ratios  in  the  patients  with  arterial  occlusion  were  2  to  5  times  those  of 
the  normals. 


follows  the  notch,  indicating  a  larger  than  normal 
reflected  wave  component  in  the  volume  pulse  (11). 

INTERPRETATION    OF    VASCULAR    BEHAVIOR 
FROM    MEASUREMENTS    OF    FLOW, 
PRESSURE,   AND    VASCULAR    VOLUME 

Flow  through  a  vascular  bed  is  dependent  upon 
arterial  pressure,  arteriolar  inflow  and  venous  outflow 
resistances,  viscosity  of  the  blood,  and  extravascular 
pressure.  Physiologic  control  of  flow  is  exerted  in  many 
vascular  beds  by  local  autoregulation  as  modified  by 
the  influence  of  autonomic  nerves  and  by  circulating 
constrictor  substances. 

Analysis  of  the  influences  of  autonomic  nerves  and 
circulating  vasoactive  substances  under  conditions  of 
various  physiological  stresses  is  complicated,  particu- 
larly if  there  is  an  accompanying  change  of  arterial 
pressure.  For  instance,  if  there  is  a  decrease  in  arterial 
pressure  to  50  per  cent  of  the  control,  the  measured 


peripheral  resistance  might  increase  in  a  nonreactive 
bed  such  as  the  skin,  whereas  the  resistance  might 
decrease  in  a  reactive  bed  such  as  that  of  kidney, 
brain,  or  skeletal  muscle.  These  changes  would  occur 
in  the  absence  of  extrinsic  influence.  Therefore,  in 
order  to  analyze  the  potency  of  extrinsic  influences 
upon  the  resistance  vessels,  it  is  necessary  to  obtain 
previous  data  on  the  behavior  of  the  resistance  vessels 
during  changes  of  pressure  per  se  in  the  absence  of 
extrinsic  influences,  and  then  compare  the  measured 
changes  in  resistance  with  these  pre-established 
findings  before  drawing  any  conclusions  as  to  the 
influence  of  extrinsic  factors  on  the  vascular  bed. 

Similar  observations  apply  to  measurements  of 
vascular  volume.  The  latter  measurements  become 
important,  particularly  in  conditions  such  as  shock 
in  which  it  is  presumed  that  there  is  a  stagnation  and 
pooling  of  blood  in  various  vascular  beds;  however, 
extensive  data  are  not  as  yet  available  on  such 
changes  in  vascular  volume. 


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76.  Machowicz,  P.  P.,  G.  Sabo,  G.  Lin,  C.  E.  Rapela,  and 
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78.  Marshall,  R.  J.,  Y.  Wang,  H.  J.  Semler,  and  J.  T. 
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79.  Mehrizi,  A.,  and  W.  F.  Hamilton.  Effect  of  levarterenol 
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80.  Mellander,  S.  Comparative  studies  on  the  adrenergic 
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81.  Miles,  B.  E.,  M.  G.  Ventom,  and  H.  E.  deWardenkr. 
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82.  Molnar,  J.  I.,  R.  A.  Renn,  and  F.  J.  Haddy.  Local 
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83.  Nakata,  K.,  G.  F.  Leong,  and  R.  W.  Brauer.  Direct 
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84.  Olsson,  R.  A.,  and  D.  E.  Gregg.  Reactive  hyperemia 
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85.  Osher,  W.  J.  Pressure-flow  relationship  of  the  coronary 
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88.  Pappenheimer,  J.  R.,  and  J.  P.  Maes.  A  quantitative 
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g6o 


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CIRCULATION    II 


sistance  to  flow  in  the  dog's  hind  leg.  Circulation  Research:  3 
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no.  Rapela,  C.  E.,  E.  J.  Fox,  S.  Welborne,  Jr.,  and  H. 
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91.  Read,  R.  C,  J.  A.  Johnson,  J.  A.  Vick,  and  M. 
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Ritter,  E.  R.  Pressure/flow  relations  in  the  kidney: 
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Roddie,  I.  C,  J.  T.  Shepherd,  and  R.  F.  Whelan.  The 
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Schmid,  H.  E.,  and  M.  P.  Spencer.  Characteristics  of 
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Selkurt,  E.  E.  The  relation  of  renal  blood  flow  to  effec- 
tive arterial  pressure  in  the  intact  kidney  of  the  dog.  Am. 
J.  Physiol.  147:537-549.  '946- 

Selkurt,  E.  E.,  P.  W.  Hall,  and  M.  P.  Spencer.  In- 
fluence of  graded  arterial  pressure  decrement  on  renal 
clearance  of  creatinine,  />-aminohippurate  and  sodium. 
Am.  J.  Physiol.  159:  369-378,  1949. 

101.  Selkurt,  E.  E.,  and  P.  C.  Johnson.  Effect  of  acute  eleva- 
tion of  portal  venous  pressure  on  mesenteric  blood  volume, 
interstitial  fluid  volume  and  hemodynamics.  Circulation 
Research  6:  592-599,  1958. 

Selkurt,  E.  E.,  M.  P.  Scibetta,  and  T.  E.  Cull.  Hemo- 
dynamics of  intestinal  circulation.  Circulation  Research  6: 
92-99,  1958. 


92 


93 


94 


95- 


96. 


97- 


99- 


100. 


103. 

104. 
105. 

106. 

107. 

108. 
109. 


"3- 
114. 

•  15- 

116. 
117. 


102. 


Senav,  L.  C.,Jr.,  M.  Christensen,  and  A.  B.  Hertzman. 
Cutaneous  vascular  responses  in  finger  and  forearm  during 
rising  ambient  temperatures.  J.  Appl.  Physiol.  15:61 1-618, 
i960. 

Shadle,  O.  W.,  M.  Zukof,  and  J.  Diana.  Translocation 
of  blood  from  the  isolated  dog's  hindlimb  during  levartere- 
nol  infusion  and  sciatic  nerve  stimulation.  Circulation 
Research  6:  326-333,  1958. 

Shipley,  R.  E.,  and  R.  S.  Study.  Changes  in  renal  blood 
flow,  extraction  of  inulin,  glomerular  filtration  rate,  tissue 
pressure  and  urine  flow  with  acute  alterations  of  renal 
artery  blood  pressure.  Am.  J.  Physiol.  167:  676-688,  1951. 
Smith,  H.  W.  The  Kidney,  Structure  and  Function  in  Health  and 
Disease.  New  York:  Oxford  Univ.  Press,  1951 ,  p.  424. 
Sonnenschein,  R.  R.  Vasodilation  in  skeletal  muscle 
during  activation  of  patellar  reflex.  Am.  J.  Physiol.  200: 
685-688,  1961. 

Stainsby,  VV.  N.  Effect  of  muscle  contractions  on  auto- 
regulation of  blood  flow  through  skeletal  muscle.  Federa- 
tion Proc.  20:  103,  1 96 1. 

Stainsby,  W.  N.,  and  E.  M.  Renkin.  Autoregulation  of 
blood  flow  in  resting  skeletal  muscle.  Am.  J.  Physiol.  201  : 
1 17-122,  1961. 

VVaugh,  W.  H.  Myogenic  nature  of  autoregulation  of 
renal  flow  in  the  absence  of  blood  corpuscles.  Circulation 
Research  6:  363-372,  1958. 

Waugh,  W.  H.,  and  R.  G.  Shanks.  Cause  of  genuine 
autoregulation  of  the  renal  circulation.  Circulation  Research 
8:871-888,  i960. 

Wells,  R.  E.,  R.  D.  Perera,  and  E.  W.  Merrill.  In- 
fluence of  plasma  proteins  upon  blood  viscosity.  Federation 
Proc.  21  :  94,   1962. 

Wiedeman,  M.  P.  Pressure  variations  in  small  veins  in  the 
hind  leg  of  the  dog.  Circulation  Research  8 :  440-445,  1 960. 
Wiederhielm,  C.  A.,  and  R.  F.  Rushmer.  Time  course  of 
reactive  hyperemia  in  isolated  dog  hind  limbs.  Federation 
Proc.  20:   103,   1 96 1. 

Whittaker,  S.  R.  F.,  and  F.  R.  Winton.  The  apparent 
viscosity  of  blood  flowing  in  the  isolated  hindlimb  of  the 
dog,  and  its  variation  with  corpuscular  concentration.  J. 
Physiol.,  London  78:  339-369,  1933. 

Winton,  F.  R.  Hydrostatic  pressures  affecting  the  flow  of 
urine  and  blood  in  the  kidney.  Harvey  Lectures  1951-52. 
New  York  :  Academic  Press,  series  47,  pp.  21-52,  1953. 
Youmans,  P.  L.,  H.  D.  Green,  and  A.  B.  Denison,  Jr. 
Nature  of  the  vasodilator  and  vasoconstrictor  receptors  in 
skeletal  muscle  of  the  dog.  Circulation  Research  3:  1 71-180, 
'955- 


CHAPTER     29 


Exchange  of  substances  through  the  capillary  walls 


E.    M.   LAND  IS 
J.    R.    PAPPENHEIMER1 


Harvard  Medical  School,  Boston,  Massachusetts 


CHAPTER    CONTENTS 

Filtration  and  Absorption;  General  Formulation 
Capillary  Blood  Pressure,  Pc 
Methods  of  Measurement 
Capillary    Pressures    in    Various    Tissues;    Relation    to    the 

Osmotic  Pressure  of  the  Plasma  Proteins 
Variability    of   Capillary    Blood    Pressures    Under    Control 

Conditions 
Functional  Changes  of  Capillary  Blood  Pressure 
Effects  of  Venous  Pressures  and  of  Venular  Constriction  on 
Capillary  Pressure 
Osmotic  Pressure  of  the  Plasma  Proteins,  Upi 
Methods  of  Measurement 
Protein  Osmotic  Pressure  of  Human  Plasma 
Species  Differences,  Fetal  Plasma 
Physiological    Significance    of   the    Deviations    from    van't 

Hoff's  Law 
Physicochemical   Aspects   of  Protein   Osmotic   Pressure 
Interstitial   Fluid   Pressure   ('Tissue   Pressure'),  P,f 
Proteins  in  Extracapillary  Fluids;  n,y 

Capillary  Filtrate   from  Limb   Capillaries;  Protein   Content 
Interstitial  Fluid,  Protein  Content  and  n,y 
Circulation    of    Interstitial    Fluid;    Circulation    of    Protein 
Filtration   Coefficients   of  Capillaries,   kc;    and   of   Tissues,    k, 
Normal  Capillaries 

Effects  of  Temperature  on  Filtration  Coefficients 
Adsorbed  Plasma  Protein  and  Filtration  Coefficients 
Effects  of  Injury  on   Filtration,  Absorption,   and  Filtration 
Coefficients 
Capillary  stasis 

Filtration   coefficients,   kc,  of  injured   capillaries 
Capillary  pressure  in  injury 
Tissue  asphyxia;  relation  of  filtration  coefficients  to  O2, 

CO»,  and  pH 
Adrenal    cortical    hormones     and     filtration    coefficients 
Porosity  of  the  injured  capillary  wall 
Diffusion,  General  Principles 
Free  Diffusion 
Diffusion  Through  Porous  Membranes,  Restricted  Diffusion 


Career    Investigator,    American   Heart  Association. 


Diffusion   and   Hydrodynamic  Flow,    Relation   to   Pore   Di- 
mensions 
Diffusion 

Hydrodynamic  flow 
Simultaneous    Flow    and    Restricted    Diffusion;    Theory   of 

Molecular  Sieving 
Distribution  of  Pore  Sizes 

Osmotic  Pressure  and  Osmotic  Flow  Through  Leaky  Mem- 
branes, Osmotic  Reflection  Coefficients 
Transcapillary      Movement      of     Lipid-Insoluble      Molecules 
Structure  of  Muscle  Capillaries  as  Deduced  from  Permeability 
Measurements  and  from  Electron  Microscopy.  Quantita- 
tive Aspects  of  Transcapillary  Diffusion 
Molecular  Sieving  of  Large  Molecules;  Regional  Differences 

in  Porosity 
Capillary   Permeability   to   Lipid-Soluble  Molecules;  Respira- 
tory Gases 
Capillary  Permeability  and  Blood  Flow  in  Relation  to  Exchange 
of  Materials  Between  Blood  and  Tissues 
Blood-Tissue  Transport  of  Oxygen 
Blood-Tissue  Exchange  of  Small,  Nonmetabolized  Molecules 

or  Ions 
Nonuniform    Distribution    of   Blood    Flow    in    Relation    to 
Blood-Tissue  Exchange 


I  .  FILTRATION  AND  ABSORPTION;  GENERAL  FORMULATION 

"transudation  of  water  and  solids"  through  the 
walls  of  blood  vessels  was  proposed  by  Bartholin 
(10)  in  1653  to  explain  the  flow  of  lymph.  This  sug- 
gestion was  largely  neglected  though  a  somewhat 
similar  process  was  expressed  vaguely  by  Hales 
(140)  in  1753  as  an  "insinuation  of  liquid"  into  the 
wall  of  the  intestine  in  connection  with  some  of  his 
more  prolonged  perfusion  experiments.  Ludwig 
(223)  proposed  a  definite  filtration  theory  in  1861 
based  largely  upon  observations  made  by  Noll  (263) 


961 


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CIRCULATION    II 


in    his   laboratory   in    1850.    According    to    Ludwig: 

".  .  .  the  blood  which  is  contained  in  the  vessel 
tends  to  equalize,  through  the  porous  vessel  walls,  its 
pressure  and  its  chemical  composition  with  those  of 
the  fluids  which  lie  outside  the  vessels.  If,  for  example, 
the  contents  of  the  vessels  increases,  the  pressure  in 
the  vessels  also  increases,  and  immediately  a  portion 
of  blood  passes  out  into  the  tissues,  driven  by  a  fil- 
tration pressure." 

But  this  "filtration  pressure"  proved  unable,  by 
itself,  to  explain  either  the  control  of  the  volume  of 
lymph  flow  or  the  regulation  of  the  constancy  of 
blood  volume.  Many  of  Ludwig's  earlier  experiments 
supported  his  belief  that  this  was  accomplished  by  a 
direct  relationship  between  blood  pressure,  filtration, 
and  lymph  formation,  followed  by  return  of  this 
lymph  to  the  blood  stream.  Elevating  venous  pressure 
in  portions  of  the  circulation  of  a  whole  animal  in- 
creased lymph  flow,  as  did  also  elevating  arterial 
pressure  in  perfused  tissues.  However,  others  showed 
very  soon  that  elevations  of  blood  pressure  produced 
by  vasomotor  changes  did  not  always  produce  the 
predicted  increase  of  filtration.  Moreover,  little 
lymph  could  be  obtained  from  the  resting  limb; 
whereas  Ludwig's  filtration  hypothesis  required  that 
even  resting  blood  pressure  should  have  produced 
both  filtration  and  lymph  flow. 

The  problem  became  temporarily  still  more  obscure 
after  1880  when  Heidenhain  began  studying  the 
abundant  flow  of  lymph  from  the  thoracic  duct  which 
continued  even  during  rest.  The  actions  of  his  two 
classes  of  lymphagogues,  coupled  with  slight  but 
definite  inequalities  of  solute  concentrations  in  plasma 
and  lymph  (explained  now,  in  large  part,  by  the 
Gibbs-Donnan  equilibrium)  led  him  to  postulate 
active  secretion  by  the  cells  of  the  capillary  walls  and 
possibly  by  the  lymphatics  (145a).  Heidenhain  found 
Ludwig's  simple  filtration  theory  adequate  for  some 
conditions  and  quite  unable  to  explain  others.  On 
the  other  hand,  Heidenhain's  secretion  theory  was 
supported  by  no  direct  proof.  At  this  point  Starling 
measured  the  osmotic  pressure  of  the  plasma  proteins 
and  added  absorption  to  Ludwig's  filtration.  In  1896, 
under  the  title  "On  the  absorption  of  fluids  from  the 
connective  tissue  spaces,"  Starling  wrote: 

".  .  .  although  the  osmotic  pressure  of  the  proteids 
of  the  plasma  is  so  insignificant,  it  is  of  an  order  of 
magnitude  comparable  to  that  of  the  capillary  pres- 
sures; and  whereas  capillary  pressure  determines 
transudation,  the  osmotic  pressure  of  the  proteids 
of  the  serum  determines  absorption."  (345) 
This  hypothesis,  despite  its  attractiveness,  did  not 


find  general  acceptance  for  several  decades  until 
improved  methods  were  developed  for  measuring  the 
osmotic  pressure  of  the  plasma  proteins  and  also 
capillary  blood  pressure.  Apparent  exceptions  to  the 
hypothesis  became  explicable  as  investigators  learned 
more  about  the  nature  of  the  capillary  wall  itself, 
the  hydrostatic  pressure  of  the  interstitial  fluid,  and 
the  osmotic  pressure  of  the  proteins  in  that  fluid. 
For  purposes  of  summary,  and  of  consecutive,  more 
detailed  discussions  of  each  factor,  a  general  relation- 
ship can  be  formulated.  It  must  be  emphasized,  how- 
ever, that  this  formulation  is  a  composite  which  is 
based  on  many  overlapping  experiments,  each  of 
which  dealt  simultaneously  with  several  of  the  varia- 
bles, but  not  with  all. 

em.        --  k(p  -  n.  -p.  +n.)     (1.1) 

+  -  filtration 
-  -  absorption 

F.M.  represents  fluid  movement  through  the 
capillary  wall,  with  a  plus  sign  to  indicate  filtration, 
and  a  minus  sign  to  indicate  absorption.  Pr  is  capil- 
lary blood  pressure  (hydrostatic);  LTP;,  the  osmotic 
pressure  of  the  plasma  proteins;  P,<,  the  pressure  in 
the  interstitial  fluid  compartment  (hydrostatic); 
and  Hi/,  the  osmotic  pressure  of  the  proteins  in  the 
interstitial  fluid  immediately  outside  the  capillary 
walls.  The  proportionality  factor,  k,  has  been  called  a 
filtration  constant  or,  more  appropriately,  a  filtration 
coefficient  and  is  a  measure  of  the  permeability  of 
the  capillary  wall  to  isotonic  fluid.  Each  of  these 
factors  will  be  considered  in  succession. 


2.    CAPILLARY    BLOOD    PRESSURE,    Pc 

A.  Methods  of  Measuremt  ni 

The  pressure  under  which  blood  flows  through  the 
capillary  vessels  was  very  much  in  the  minds  of  the 
earliest  investigators  even  when  pressure  measure- 
ments were  limited  to  large  blood  vessels  and  to  lower 
animals.  Thus  Hales,  in  1773,  having  determined 
the  first  arterial  and  venous  pressures,  went  on  at 
once  to  make  certain  assumptions  and  then  calculated 
the  "force  of  the  blood  in  the  capillary  vessels"  to  be 
1.838  gr.  with  the  qualification  that  to  this  "must 
be  added  the  velocity  which  the  blood  has  acquired 
at  its  first  entrance  in  the  capillary  vessel,  which  can 
be  but  small  as  appeared  by  the  great  resistance  it 
meets  within  the  capillary  vessels.  .  ."  (140).  In 
1828  Poiseuille  (286)  devised  the  U-tube  mercury 
manometer  and  measured   the  gradient  of  pressure 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


963 


in  the  arterial  system.  With  smaller  and  smaller 
cannulae  he  measured  pressures  in  the  aorta,  carotid 
artery,  and  even  in  a  2-mm  branch  of  the  crural 
artery,  and  reported :  "that  a  molecule  of  blood  moved 
with  the  same  force  throughout  the  course  of  the 
arterial  system,  which  a  priori,  with  all  physiologists, 
we  were  far  from  thinking."  It  followed,  therefore, 
that  the  major  fall  of  blood  pressure  must  occur  some- 
where in  the  smaller  vessels  beyond  the  ones  he  can- 
nulated.  Poiseuille  then  turned  his  attention  to 
capillary  tubes  and  studied  the  relation  which  volume 
flow  of  liquids  per  unit  time  bears  to  pressure,  viscosity, 
tube  radius,  tube  length,  and  wall  surface  (287-289). 
Hence  Poiseuille's  equation,  which  underlies  the 
science  of  hydrodynamics,  emerged  from  questions 
concerning  arterial  and  capillary  blood  pressure  in 
animals. 

In  1875  von  Kries  (182)  tried  to  measure  capillary 
blood  pressure  in  man  by  an  indirect  method.  He 
placed  a  glass  plate,  2  to  5  mm2  in  area,  on  the  skin 
and  hung  from  this  plate  a  small  scale  pan  on  which 
weights  were  placed  until  the  skin  blanched.  Five 
years  later  Roy  &  Brown  (309)  used  a  capsule  fitted 
with  a  distensible,  transparent  membrane  to  de- 
termine, under  the  microscope,  the  pressures  required 
to  modify  or  obstruct  flows  through  single  arterioles, 
capillaries,  and  venules  in  the  more  or  less  trans- 
parent tissues  of  experimental  animals,  e.g.,  the  web 
of  the  frog.  From  1886  to  the  present,  various  modifica- 
tions of  these  two  basic  methods  were  used  for  many 
measurements  but  yielded  discordant  results,  ranging 
even  in  one  species,  man,  and  in  one  tissue,  skin,  from 
1  to  71  mm  Hg  (207).  Most  of  these  studies  were  made 
after  1900  because  figures  for  capillary  blood  pressure 
were  necessary  to  prove  or  disprove  Starling's  filtra- 
tion-absorption hypothesis.  Even  as  late  as  1925  no 
conclusions  could  be  reached  because  the  lower  values 
were  less  than  venous  pressure  and  obviously  ques- 
tionable. 

The  higher  values  were  criticized  because  they  were 
based  on  blanching  of  the  skin  or  on  arrest  of  blood 
flow  by  microscopic  examination,  and  so  indicated 
arteriolar  rather  than  capillary  pressure.  Moreover, 
no  indirect  method  could  yield  information  concern- 
ing the  presence  or  absence  of  a  gradient  of  pressure 
in  the  capillary  network  itself.  When  reviewed  in 
1934  (207)  indirect  methods  were  found  inadequate 
a)  because  of  variable  transmission  of  pressure  through 
overlying  tissues  to  the  capillaries  beneath,  and  b) 
because  of  the  arbitrary  and  unproved  criteria 
adopted  by  various  investigators  to  indicate  when 
externally    applied    pressure    equaled    the    pressure 


within  the  capillaries.  Direct  measurements  of  the 
sort  attempted  by  Poiseuille  a  century  earlier  were 
still  necessary. 

The  requirements  for  direct  measurements  of 
pressure  in  single  capillaries  are  basically  simple, 
though  technically  somewhat  difficult  (198,  203). 
Figure  2.1  shows  (upper  left)  a  micropipette,  5  n 
in  diameter  at  its  tip,  under  the  microscope  and 
ready  for  use.  A  somewhat  smaller  pipette  (lower 
left)  is  shown  inserted  into  a  capillary  of  the  frog's 
mesentery.  The  micropipettes  are  first  carefully 
filled  with  a  saline  solution  containing  heparin, 
mounted  in  a  micromanipulator  and  connected  to  a 
manometer  and  syringe  (right)  so  that  the  pressure 
exerted  on  the  saline  at  the  tip  of  the  micropipette 
can  be  changed  rapidly  and  accurately  to  balance 
the  changing  pressure  in  the  capillary.  The  micro- 
manipulator is  required  not  only  to  insert  the  pipette 
into  the  capillary,  but  also  to  keep  the  lumen  of  the 
pipette  in  free  communication  with  the  lumen  of  the 
capillary.  Minute  rods  (fig.  2.1,  upper  left),  each 
controlled  by  its  own  micromanipulator,  are  fre- 
quently necessary  in  addition  to  hold  steady  thin 
tissues  such  as  mesentery.  Pressure  readings  from  the 
manometer  can  be  made  only  at  true  pressure  equi- 
librium without  net  flow  of  liquid  through  the  tip 
of  the  pipette  because  orifices  of  5  to  10  n  interpose 
considerable  resistance  to  flow  and  consequent 
inaccuracies.  Failure  to  observe  this  precaution  has 
yielded  fallaciously  low  values  for  capillary  pressure 

(36>  2°3)- 

With  these  requirements  in  mind,  suitable  criteria 
were  developed  for  measuring  mean,  systolic,  and 
diastolic  pressures  in  single  capillaries,  arterioles,  or 
venules  in  mesentery  (198),  skin  (205),  and  muscle 
of  lower  animals  as  well  as  in  the  skin  of  man  (203) 
with  an  accuracy  of  a  few  millimeters  of  water.  Tests 
showed  that  changes  of  capillary  pressure  induced 
by  graded  venous  congestion  could  be  detected 
promptly  and  accurately  by  the  direct  method  (203) 
but  not  by  an  indirect  method  (88). 

B.   Capillary  Pressures  in  Various  Tissues;  Relation 
to  the  Osmotic  Pressure  of  the  Plasma  Proteins 

Direct  measurements  of  pressures  in  single  capil- 
laries, arterioles,  and  venules  provided  answers  to 
Poiseuille's  questions  concerning  the  nature  and  the 
location  of  the  pressure  gradient  in  the  circulatory 
system.  Figure  2.2  shows  that  in  the  mesenteric  blood 
vessels  of  the  frog,  the  major  decrease  of  pressure 
(70  to  80%)  occurred  in  the  arterioles,  but  there 


964 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


FIG.  2.1.  Diagram  of  apparatus  for  measuring  capillary  blood  pressure  directly.  Micro- 
pipette  shown  before  introduction  {upper  left)  and  in  capillary  [after  introduction  {lower  left). 
[From  Landis  (198).] 


fig.  2.2.  Curve  showing  aver- 
age gradient  of  pressure  through 
the  mesenteric  blood  vessels  of 
the  frog.  [From  Landis  (198).] 


44 

^Systolic    Pressure 

X) 

' ^"""— -Ol 

36 

n. 

w 

\ 

s         28 

\ 

a. 

n         20 
v> 

UJ 

K 
D. 

0 

^Diastolic    Pressure         ^.          9 

0 

1 

3 
2 

12 

^N>^_ 

4 

- 

*      400 

Artery                Artery  -  first 

Vein 

- 

l:5  2oo 

bifurcation                                    Venous 

I5  0 

H  Arteriole   Capillary  Capillary 

1                1                1                1                1                1                1 

■                ' 

' 

8  10 

LENGTH 


12 
MM 


30 
25 
20 
15 
10 


-    5 


18  20 


was  also  a  significant  drop  in  the  capillaries,  amount- 
ing on  the  average,  with  ordinary  blood  flows,  to  20 
or  30  per  cent  of  the  total  (198).  A  somewhat  smaller 
gradient  was  also  calculated  from  Poiseuille's  equa- 


tion and   motion   picture   analyses  of  flow   through 
capillary  networks  (206). 

The  same  determinations  provided  direct  support 
for     the     Starling     filtration-absorption     hypothesis. 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


96; 


table  2.1.  Resting  Average  Capillary  Blood  Pressure  (Pc)* 
and  Osmotic  Pressure  of  Plasma  Proteins  (Jlpi) 


npi 

Animal 

mm  Eg 

Frog 

5-10 

Rat 

16-21 

Guinea  pig 

17-21 

Cat 

19-26 

Man 

21-29 

Man,  avg 

25 

values 

Average  Pc 


Arteriolar 
end 


mm  Eg 
10.6 
I  I  .O 

10.7 

22.  I 
28.3 

3'-3 


Venous  end 


mm  Eg 

7-4 
7.0 

7-4 
'2-5 

26.8 


32.O  2of  12.1 

34-3  I  !2-2 

3O.6  29.5!  21.9 

-  22  f 


32 


24t 


•5 


Tissue  (and  Reference 
for  Pc) 


Mesentery  (198) 
Muscle  (205) 
Skin  (205) 

Mesentery  (202) 

Mesentery  (202) 

Intestine  (178) 

Skin  (203) 
Skin  (92) 
Skin  (89) 
Skin  (225) 


*  Direct  measurements  only.  f  Summit  of  the  capillary 

loop. 

In  the  arteriolar  end  of  the  frog's  mesenteric  capillary 
network  pressure  averaged  14.5  cm  H20  or  10.6 
mm  Hg;  in  the  venous  end  about  10  cm  H20  or 
7  mm  Hg.  Since  the  osmotic  pressure  of  the  plasma 
proteins  ranged  in  normal  frogs  from  5  to  10  mm  Hg 
(41 ),  the  approximate  balance  predicated  by  Starling 
was  present  except  when  starvation,  as  in  winter 
frogs,  reduced  the  concentration  of  plasma  proteins 
(23,  41).  As  shown  in  table  2.1,  capillary  blood 
pressures  in  frog's  muscle  and  skin  were  similar  to 
those  in  the  mesentery  (205).  In  the  mesenteries  of 
rats  and  guinea  pigs  a  balance  was  also  found  but  at 
a  higher  level  of  pressure  (202).  Pressures  were  highest 
in  the  intestinal  capillaries  of  the  cat  (178)  and  in 
the  cutaneous  capillaries  of  man  (89,  92,  203,  225), 
but  again  in  balance  with  the  higher  osmotic  pressure 
of  the  plasma  proteins  as  shown  in  figure  2.3.  Thus 
in  four  tissues  and  in  five  species  the  pressures  found 
were  generally  compatible  with  Starling's  view  that, 
on  the  average  and  at  resting  blood  flows,  these 
pressures  favor  filtration  in  the  arteriolar  portion 
of  the  capillary  network  and  a  balancing  absorption 
in  the  venous  end  of  the  capillary  network.  But 
generalizations  cannot  be  extended  to  tissues  with 
specialized  functions.  Capillary  blood  pressures  may 
be  higher  in  kidney  and  lower  in  lung. 

Hayman    (145)    found    that   glomerular   capillary 


pressure  in  the  frog  averaged  54  per  cent  of  the 
simultaneously  measured  aortic  blood  pressure.  White 
(377)  observed  pressures  of  similar  magnitude  in 
Necturus.  For  mammalian  glomeruli  direct  measure- 
ments are  lacking,  but  indirect  estimates  have  ranged 
from  two-thirds  of  arterial  pressure  by  Winton  (384) 
to  about  50  per  cent  of  arterial  pressure  by  Gottschalk 
&  Mylle  (124).  The  high  rate  of  glomerular  filtration 
can  be  explained  by  these  high  capillary  pressures 
and  the  greater  effective  pore  area  of  the  glomerular 
membranes  (278).  The  mechanism  by  which  98 
per  cent  or  more  of  this  filtrate  passes  back  into  the 
blood  of  the  peritubular  capillaries  cannot  be  ex- 
plained so  simply. 

Postglomerular  or  peritubular  capillary  pressures 
have  been  measured  directly  by  Wirz  (385)  who 
reported  17.4  ±  2.6  mm  Hg  for  a  small  series  of 
rats  and  by  Gottschalk  &  Mylle  (124)  who  found 
averages  of  20.4  and  14.2  mm  Hg  for  large  and 
small  peritubular  capillaries,  respectively,  under 
normal  conditions.  These  pressures  increased,  how- 
ever,   to   very   high   levels   not   only   during   venous 


100 


MAN -Finger  tip,  heart  level 


100 


ARTERIES    ]    CAPILLARIES 
ARTERIOLES 


fig.  2.3.  Curves  comparing  gradient  of  pressure  drop 
(open  circles)  in  four  species  with  the  corresponding  osmotic 
pressures  (filled  circles)  of  their  plasma  proteins.  [Modified  from 
Landis  (207).] 


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CIRCULATION    II 


congestion,  but  also  after  dextrose  infusions,  e.g., 
to  37  mm  Hg,  and  during  ureteral  occlusion,  e.g., 
to  40  mm  Hg,  with  relatively  close  parallelism  be- 
tween intratubular,  interstitial,  and  peritubular 
capillary  pressures.  Evidently,  the  hydrostatic  pressure 
difference  across  the  walls  of  renal  peritubular 
capillaries  is  far  less  than  across  the  walls  of  peripheral 
capillaries  generally.  This  implies  that  the  full 
osmotic  force  of  the  plasma  proteins,  unopposed  by 
hydrostatic  pressure  differences,  may  be  available 
for  withdrawal  of  tubular  reabsorbate  from  renal 
interstitial  fluid  to  blood. 

Pulmonary  capillary  pressure  presents  an  exception 
in  the  opposite  direction.  Though  direct  measurements 
arc  not  available  as  yet,  an  indirect  "wedging" 
method  (146,  147)  has  made  it  clear  that  in  the  lung 
capillary  pressure  is  normally  between  5  and  1 5 
mm  Hg  in  dog  and  man  and  is,  therefore,  well  below 
the  osmotic  pressure  of  the  plasma  proteins.  Ab- 
sorption is  favored  (55)  and  ensures  a  minimum  of 
interstitial  fluid  in  the  alveolar  walls,  which  is  an 
important  consideration  in  a  tissue  the  prime  function 
of  which  is  to  permit  rapid  exchange  of  gases.  In 
normal  subjects  these  "wedge  pressures"  are  quite 
constant;  exercise  produces  elevations  of  not  more 
than  3  or  4  mm  Hg.  Greater  elevations  than  this 
during  exercise  have  been  found  to  be  helpful  in 
detecting  early  left  ventricular  failure  or  slight  mitral 
stenosis  not  yet  severe  enough  to  produce  clinical 
symptoms  or  signs  (291). 

Retinal  capillary  pressure  has  not  been  measured 
directly,  but  must  be  considerably  higher  than  that 
in  muscle  or  skin  in  order  to  maintain  blood  flow 
despite  an  intraocular  pressure  of  about  20  mm  Hg. 
Nor  are  any  reliable  figures  available  for  capillary 
pressures  in  other  special  regions,  e.g.,  brain,  pleural 
and  peritoneal  surfaces,  joints,  etc.  In  view  of  the 
differences  between  capillary  pressures  in  skin, 
kidney,  and  lung,  generalizations  are  obviously 
unjustified  and  direct  measurements  are  needed  tor 
each  tissue. 


C.    Variability  of  Capillary  Blood  Pressures 
I  'nder  Control  Conditions 

The  average  figures  so  far  given  would,  by  them- 
selves, present  an  erroneous  idea  of  the  potential 
role  of  capillary  pressure  in  the  filtration  and  ab- 
sorption of  fluid.  In  any  one  tissue  capillary  pressure, 
like  the  more  easily  observed  capillary  blood  flow, 
varies  from  moment  to  moment  and  from  capillary 
to   capillar)    even    when    they   arise   from   the   same 


arteriole.  This  is  to  be  expected  from  the  responsive- 
ness of  the  terminal  arterioles  and  arteriocapillary 
sphincters  to  nerve  impulses,  both  constrictor  and 
dilator,  to  local  metabolic  products  and  also  to 
mild  injury  such  as  that  produced  by  manipula- 
tion, exposure  to  air,  and  cannulation  itself  (198, 
203,  205).  In  the  skin  of  frog  (205)  and  man  (203) 
the  mere  introduction  of  a  minute  pipette  sometimes 
produces  a  brief  rise  of  capillary  pressure  accom- 
panying the  transient  vasodilatation  of  a  "'triple 
response"  to  injury. 

It  must  also  be  emphasized  that  capillary  pressure 
has  been  measured  directly  in  relatively  few  tissues. 
In  man,  determinations  have  been  limited  to  the 
capillary  loops  in  the  nailfold  where  arteriovenous 
anastomoses  are  also  present  and  may  influence 
pressure  measurements.  As  shown  in  table  2.1, 
in  one  series  pressure  in  the  arteriolar  loops  averaged 
32  mm  Hg.  However,  the  single  readings  ranged  from 
21  to  48  mm  Hg;  in  the  venous  loops  the  correspond- 
ing figures  were  12  and  from  6  to  18  (203).  In  an- 
other series  of  control  measurements  Eichna  & 
Bordley  (89)  found  even  larger  variations,  much 
more  overlapping  of  values,  and  a  smaller  average 
gradient,  viz.  31  to  22  mm  Hg  rather  than  32  to  12 
(table  2.1).  These  differences  may  possibly  be  re- 
lated to  room  temperature  because  the  larger  gradient 
and  lower  pressures  in  the  venous  limbs  of  the  capil- 
laries were  found  at  room  temperatures  of  18  to  qo  C 
(203).  The  smaller  gradient  and  higher  venous  capil- 
lary pressures  were  observed  in  a  warm  room  where 
temperatures  were  23  to  28  C  (89).  It  seems  likely 
that  capillary  pressures  in  human  digital  skin,  par- 
ticularly in  the  venous  limbs  next  to  the  subpapillary 
venous  plexus,  can  be  influenced  by  the  state  of  the 
arteriovenous  anastomoses.  At  higher  room  tempera- 
tures opening  of  these  large  channels,  and  increased 
blood  flow  direct  from  larger  arterioles  to  larger 
venules,  may  well  increase  pressure  locally  in  the 
subpapillary  plexus  into  which  the  true  capillaries 
also  discharge  their  blood. 

Chambers  &  Zweifach  (37)  have  suggested,  in 
addition,  a  division  of  function  in  the  minute  vessels, 
viz.  that  higher  pressures,  and  hence  filtration,  may 
occur  chiefly  in  the  direct,  arteriovenous  channels, 
with  lower  pressures  and  absorption  located  in  the 
true  capillaries.  For  such  specialization,  however, 
no  supporting  evidence  in  the  form  of  pressure 
measurements  in  direct  channels  is  available.  More- 
over, very  high  pressures  and  filtration  rates  were 
frequently  found  in  true  capillaries  (200).  Zweifach 
(387)  also  suggested  that  "the  arrangement  whereby 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


967 


the  true  capillaries  come  off  at  right  angles  to  the 
A-V  vessels  favors  the  development  of  "suction  forces,' 
especially  where  a  rapid,  continuous  flow  courses 
only  through  the  A-V  channels."  No  suction  forces 
were  encountered  in  any  of  the  many  direct  measure- 
ments of  capillary  pressure.  The  reason  for  this 
becomes  clear  in  considering  actual  rather  than 
apparent  velocities  of  flow  in  the  minute  vessels. 
Under  the  microscope,  which  magnifies  linear  velocity 
as  well  as  size,  flows  that  seem  very  rapid  indeed  are 
really  between  1  and  2  mm  per  sec.  Calculation  of  the 
magnitude  of  the  corresponding  velocity  effect  by 
the  Bernoulli  equation  shows  the  insignificance  of 
any  possible  suction  force,  viz.  for  a  linear  velocity  of 
2  mm  per  sec  a  pressure  difference  of  only  .000015 
mm  Hg. 

Far  more  important  is  the  conspicuous  variability 
of  pressures  found  throughout  the  entire  minute 
vessel  system  as  shown  in  figure  2.4  for  the  exposed 
frog's  mesentery  where  measurements  could  include 
larger  vessels  as  well  as  capillaries.  In  general,  high 
capillary  pressures  were  associated  with  very  rapid 
flows  (if  venous  outflow  was  normally  free)  and  with 
increased  pulse  pressure  in  the  capillary  network. 
Lower  pressures,  approaching  venous  pressure, 
were  associated  with  slower  flow  or  absence  of  flow 
(ig8).  Hence,  as  arteriolar  diameter  or  tone  of 
precapillary  sphincters  changes  from  moment  to 
moment,  even  under  resting  or  control  conditions, 
the  average  balance  between  highly  variable  capillary 
pressures  and  the  much  less  variable  osmotic  pressure 
of  the  plasma  proteins  often  includes  temporary 
imbalances  in  single  capillaries  and  corresponding 
shifts  toward  periods  of  filtration  or  absorption. 
McMaster  (235)  has  suggested   that  such  shifts  ex- 


plain, in  part,  the  intermittent  entry  of  Locke's 
solution  at  atmospheric  pressure  into  the  skin  through 
a  fine  needle  introduced  carefully  to  avoid  both 
blood  vessels  and  lymphatics. 

Position  of  a  capillary  bed,  relative  to  the  heart, 
affects  capillary  blood  pressure  in  general  accordance 
with  changes  of  hydrostatic  pressure  (203).  In  the 
finger  tip  of  man  at  heart  level  average  pressure  in 
the  arteriolar  portion  of  the  capillary  loop  was  32 
mm  Hg  and  in  the  venous  portion  1 2  mm  Hg,  with 
large  individual  variations  in  single  capillaries  around 
these  averages.  When  the  hand  was  30  era  above 
heart  level  these  average  pressures  became  23  and 
10  mm  Hg,  respecti\ely,  further  drop  being  ar- 
rested presumably  because  of  collapse  of  the  thin- 
walled  veins  in  the  arm.  Conversely,  lowering  the 
forearm  to  40  cm  below  heart  level  increased  average 
arteriolar  and  venous  capillary  pressure  to  45  and 
33  mm  Hg,  respectively. 

The  relation  between  capillary  blood  pressure  and 
the  osmotic  pressure  of  the  plasma  proteins  is  there- 
fore extremely  labile,  both  as  to  time  and  the  area 
of  capillary  wall  involved.  Absorption  may  be  favored 
in  a  large  segment  of  the  capillary  bed  for  consider- 
able periods,  e.g.,  during  vasoconstriction  or  eleva- 
tion of  an  extremity  and  filtration  favored  for  other 
periods,  e.g.,  during  vasodilatation  or  dependency. 
Nevertheless,  a  net  equilibrium  is  maintained  and 
favors  constancy  of  plasma  volume  and  interstitial 
fluid  volume.  Under  exceptional  conditions,  e.g., 
muscular  activity,  prolonged  dependency  of  an 
extremity,  high  temperature,  injury,  and  inflamma- 
tion, excessive  capillary  filtrate  must  be  returned  to 
the  blood  stream  by  the  lymphatic  vessels.  These 
ancillary  vessels,  as  described  in  the  following  section, 


n _□ 


40 


u      24 


-Arterioles 


,  1  rr 


-Capillaries 
arteriolar 
venous 


Artery  Artery -first 

bifurcation 


L  E  NGTH   -    MM 
J I I I L. 


35 


30 


25 


20 


15 


10 


fig.  2.4.  Chart  showing  vari- 
ability of  capillary  blood  pressure 
and  of  pressure  gradient  in  the 
blood  vessels  of  the  frog's  mes- 
entery. The  higher  capillary 
pressures  and  increased  capillary 
pulse  pressure  are  characteristic 
of  vasodilatation.  The  lower 
capillary  pressures  and  absence 
of  measurable  pulse  pressure 
are  characteristic  of  vasocon- 
striction.   [From    Landis    (198).] 


10 


14 


16 


18 


20 


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CIRCULATION    II 


provide  an  important  safeguard  against  abnormal 
accumulations  of  capillary  nitrate  in  the  interstitial 
fluid  compartment. 

D.  Functional  Changes  of  Capillary  Blood  Pressure 

Hemorrhage  and  local  application  of  epinephrine 
produced  vasoconstriction  in  the  frog's  mesentery 
and  reduced  capillary  blood  pressure  as  shown  in 
the  lowermost  curves  of  figure  2.4  (198).  In  man  the 
marked  vasoconstriction  and  cessation  of  blood  flow 
found  in  Raynaud's  disease  reduced  capillary  blood 
pressure  in  the  affected  digits  to  between  5  and  8 
mm  Hg,  i.e.,  to  levels  approaching  local  venous 
pressure  (204).  During  the  hyperemia  of  recovery, 
pressures  in  these  same  capillary  loops  rose  rapidly 
to  between  32  and  45  mm  Hg.  In  normal  subjects, 
however,  local  cooling  and  vasoconstriction  reduced 
capillary  blood  pressure  only  moderately  and  the 
rise  of  pressure  during  the  secondary  hyperemia  of 
cold  was  likewise  moderate  (203).  Also  in  man  Eichna 
&  Wilkins  (90)  found  that  neurogenically  induced 
vasoconstriction  reduced  cutaneous  capillary  pressure 
by  1  to  8  mm  Hg  in  52  of  89  observations  with  no 
change  or  slight  elevations  of  1  or  2  mm  Hg  in  the 
remainder.  Intravenous  injection  of  1  or  2  jug  of 
epinephrine  reduced  capillary  pressure  by  1.5  to  22 
mm  Hg  in  seven  of  ten  experiments  but  in  three 
subjects  elevations  of  1  or  2  mm  Hg  were  observed. 
Svmpathectomy  obliterated  neurogenic  effects,  but 
not  those  of  epinephrine.  In  the  vasoconstriction  of 
human  hypertension  capillary  pressure  was  not 
significantly  elevated  and  minor  increases  found  in 
some  subjects  were  independent  of  arterial  pressure 
(89);  this  was  also  true  of  the  temporary  rise  of 
arterial  pressure  produced  by  Paredrinol  intra- 
venously (87)  with  or  without  prior  sympathectomy. 

Conversely,  vasodilatation  increased  capillary 
blood  pressure,  frequently  to  very  high  levels  ap- 
proaching arteriolar  pressure  (see  fig.  2.4).  Capillary 
pressure  also  rose  during  local  vasodilatation  induced 
in  the  frog  by  dilute  urethan  (198),  by  injuries  which 
produced  hyperemia  and  capillary  stasis  (199), 
by  a  simple  triple  response  and  after  muscular  con- 
traction (205).  In  human  skin  the  hyperemias  of 
local  heating,  intradermal  histamine,  inflammation, 
and  reactive  hyperemia  after  cold  (203)  were  ac- 
companied by  elevations  of  capillary  pressure  to 
maxima  between  49  and  60  mm  Hg.  In  these  ob- 
servations room  temperatures  were  low,  18  to  20  C. 
At  higher  temperatures,  23  to  28  C,  Eichna  & 
Bordley     (89)     found     that     intradermal     histamine 


elevated  capillary  pressures  much  less  conspicuously 
and  more  in  the  venous  than  in  the  arteriolar  limbs 
in  both  normal  and  hypertensive  subjects.  It  was 
emphasized  that  arteriovenous  anastomoses  may 
have  been  involved  in  these  effects  (203). 

From  the  higher  capillary  pressures  found  in 
localized  vasodilatation  and  hyperemia  it  might  be 
thought  that  excessive  filtration  and  increased  lymph 
flow  must  occur  with  any  vasodilatation.  This  is  not 
always  the  case,  however.  The  most  notable  excep- 
tion is  the  repeated  finding  that  denervation  of  an 
extremity  produces  hyperemia  and  evidence  of 
increased  blood  flow  without  change  of  lymph  flow, 
or  at  most  a  very  slight  increase,  as  reviewed  by 
Drinker  &  Field  (76).  This  failure  of  widespread 
vasodilatation  to  increase  the  flow  of  lymph  was,  in 
fact,  for  many  years  cited  as  evidence  against  the 
Starling  hypothesis.  Eichna  &  Bordley  (89)  found  that 
reactive  hyperemia  and  also  indirect  or  reflex  vaso- 
dilatation in  man,  produced  by  body  warming,  did 
not  increase  cutaneous  capillary  pressure  significantly. 
The  reason  for  this  may  lie  in  the  lowering  of  pres- 
sures in  the  digital  arteries  by  1  o  to  40  mm  Hg  during 
the  generalized  vasodilatation  produced  by  body- 
warming  (73,  114,  115,  244),  by  exercising  the 
forearm  muscles  (73),  or  by  reactive  hyperemia 
(365).  The  named  arteries  to  an  extremity  are  ap- 
parently large  enough  to  conduct  blood  at  resting 
flow  rates  with  little  pressure  drop.  The  lesser  in- 
crements of  flow  required  by  localized  vasodilatation 
are  associated  with  little  drop  in  arterial  pressure 
and  capillary  pressure  rises  conspicuously.  However, 
when  vasodilatation  involves  the  resistance  vessels 
of  a  whole  extremity,  and  blood  flow  through  the 
large  arteries  is  increased  severalfold,  the  pressure 
drop  from  brachial  artery  to  digital  artery  becomes 
significant.  Then,  arterial  pressure  head  being  much 
reduced  locally,  the  rise  of  capillary  pressure  is 
limited  even  with  maximal  arteriolar  dilatation. 
In  addition,  the  capillaries  lie  between  two  resistances 
and  it  is  quite  possible  that  arteriolar  dilatation 
will  not  raise  capillary  pressure  if  the  venules  and 
veins  are  simultaneously  dilated  in  similar  or  greater 
proportion. 

E.  Effects  of  J'erwus  Pressures  and  of  Venular 
Constriction  on  Capillary  Pressure 

Elevations  of  venous  pressure  produce,  as  might 
be  expected,  a  rapid  increase  of  capillary  pressure 
to  levels  above  the  pressure  in  the  veins.  Direct 
measurements  have  shown  this  to  be  true  of  localized 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


969 


obstruction  of  a  venule  in  the  frog's  mesentery  (198) 
and  also  when  the  human  extremity  was  congested 
by  inflating  a  cuff  previously  placed  on  the  upper 
arm  (88,  203).  When  blood  flow  was  normal,  capil- 
lary pressure  equalled  cuff  (and  venous)  pressure 
within  15  to  45  sec  and  eventually  exceeded  cuff 
(and  venous)  pressure  by  8  to  1 4  mm  Hg  in  the 
2nd  to  4th  minute  of  congestion  (203).  When  blood 
flow  was  very  slow,  however,  as  in  the  arteriolar 
constriction  of  acrocyanosis  (220),  capillary  pressure 
rose  much  more  slowly,  requiring  up  to  8  min  to 
equal  venous  pressure  and  finally  exceeding  that 
pressure  by  only  1  or  2  mm  Hg.  Other  direct  measure- 
ments have  shown  that  capillary  pressure  is  elevated 
in  congestive  heart  failure  (92)  and  also  in  glomerulo- 
nephritis (225)  whenever  venous  pressure  is  high, 
returning  to  normal  as  venous  pressure  declines. 
In  all  these  measurements  the  variability  of  normal, 
resting  capillary  pressures  prevents  making  any 
meaningful  comparison  of  the  increment  of  capillary 
pressure  which  corresponds  to  any  given  increment 
of  venous  pressure. 

The  effect  of  venous  pressure  on  capillary  pressure 
was  emphasized  in  1894  on  the  basis  of  indirect 
evidence  by  Bayliss  &  Starling  (12)  when  they  ob- 
served that  elevating  venous  pressure  increased 
lymph  flow  more  than  similar  changes  of  arterial 
pressure.  In  the  absence  of  a  direct  method  of  measur- 
ing capillary  pressure  they  suggested  using  changes 
of  venous  pressure  to  deduce  changes  of  capillary 
blood  pressure.  Also,  from  studies  of  lymph  formation, 
Drinker  &  Field  (76)  in  1933  suggested  that,  other 
things  remaining  constant,  the  state  of  the  veins  might 
modify  capillary  pressure  and  thereby  influence 
filtration  of  fluid  through  the  capillary  wall.  In  1948 
Pappenheimer  &  Soto-Rivera  (282)  found  in  the 
denervated,  perfused  extremities  of  cats  and  dogs 
that  a  given  change  of  venous  pressure  influenced 
filtration  and  absorption  five  to  ten  times  more  than 
did  a  similar  change  of  arterial  pressure.  They 
formulated  the  dependence  of  mean  capillary  pressure 
on  arterial  and  venous  pressures  and  resistances  as 
follows: 


pc 


r         P    +  P 

ra    'a      hv 


'*  t 


(2.1) 


in  which  r,.  and  ra  are,  respectively,  the  precapillary 
and  postcapillary  resistances,  while  pA  and  pv  are, 
respectively,  arterial  and  venous  pressures.  From  this 
equation   it  follows  that  at  given  values  of  arterial 


and  venous  pressures  the  mean  capillary  pressure 
depends  on  the  ratio  of  the  postcapillary  to  pre- 
capillary resistance  to  blood  flow.  Contractility  of 
the  large  veins  has  been  well  established  for  a  long 
time,  but  even  in  1950  a  general  review  (210)  re- 
vealed little  information  concerning  reactions  of  small 
veins  or  venules  and  only  a  few  instances  of  inde- 
pendence of  such  reactions  from  those  of  the  arterioles. 

Beginning  in  1954  Haddy  et  al.  (137)  approached 
the  question  of  differential  changes  in  precapillary 
and  postcapillary  resistances  by  threading  catheters, 
outside  diameter  0.2  to  0.5  mm,  as  far  as  possible  into 
"small  veins"  and  "small  arteries''  for  measurement 
of  pressures.  Under  control  conditions  small  artery 
pressures  averaged  65  ±  25  mm  Hg,  while  small 
vein  pressures,  under  local  anesthesia,  averaged  13 
mm  Hg  with  a  range  of  8  to  25  mm.  Small  vein 
pressure  varied  independently  of  the  relatively  con- 
stant large  vein  pressure,  indicating  that  the  small 
vein  system  must  be  responding  independently  to 
nervous  or  humoral  stimuli.  Kelly  &  Visscher  (171) 
found  that  independent  pressure  changes  in  small 
arteries  and  small  veins  were  produced  by  stimulating 
the  lumbar  sympathetic  chain  in  dogs.  Variability 
of  these  changes  in  timing,  magnitude,  and  even 
direction  was  considerable  and  three  main  types  or 
combinations  of  pressure  changes  had  to  be  described. 
In  further  studies  small  vein  pressure  increased  to 
as  much  as  36  mm  Hg  and  led  to  the  suggestion  by 
Lee  &  Visscher  (2 1 4)  that  edema  of  the  skin  could 
have  a  neural  origin.  However,  were  this  an  impor- 
tant possibility  one  would  expect  that  cutaneous 
edema  would  be  observed  at  some  stage  in  the  pro- 
gressive, neural  vasoconstriction  found  in  hemorrhage 
and  shock.  This  is,  however,  not  the  case.  It  must 
be  remembered,  too,  that  if  arterial  pressure  remains 
constant,  or  especially  if  it  falls,  any  constriction, 
whether  arteriolar  or  venous,  tends  to  reduce  blood 
flow  and  this  then  tends  to  limit  edema  formation 
to  the  extent  that  renewed  volumes  of  blood  plasma 
are  not  available  for  filtration;  at  zero  blood  flow- 
even  the  wheal  of  histamine  does  not  appear  (216, 
217,  219). 

Extending  this  method  to  humoral  agents,  Haddy 
and  others  found  that  independent,  and  sometimes 
opposite,  reactions  of  arteries,  small  arteries,  small 
veins,  and  large  veins  were  produced  by  change  of 
tissue  temperature  (135,  364),  change  of  pH  (105), 
epinephrine  (134),  norepinephrine  (134,  364), 
serotonin  (134,  136)  and  histamine  (133).  As  sum- 
marized by  Haddy  et  al.  (134),  "almost  every  possible 
combination   of  active   and   passive  change   in   seg- 


97o 


II  Wlll',1  H  IK     HI      I'HYMM  OCY 


CIRCULATION    II 


120 


100 


bO 


40 


20 


Histamine  IA 
-2-1—6-1 14—1 43- 


Brachial  Artery 


Small  Artery 


r 


V 


V. 


\ 


\ 


■*\- 


SmallVein  <** 


/- 


Subcutaneous   Tmsue 

25  50  75         100         125 

Time  in  Minutes 


ISO         17  5         20  0 


fig.  2.5.  Effect  of  histamine  infused  intra-arterially  upon 
vascular  and  interstitial  pressures  in  the  dog's  foreleg.  Num- 
bers at  top  refer  to  /ig/min  histamine  base  administered  into 
the  brachial  artery.  [From  Haddy  (133).] 

mental  resistances  and  pressures  has  been  observed 
during  one  or  another  arrangement."  The  true  signifi- 
cance of  these  findings  is  correspondingly  difficult  to 
evaluate.  In  the  case  of  histamine  (fig.  2.5),  which 
has  been  more  thoroughly  studied  at  controlled  flow- 
rates,  this  elevation  was  ascribed  for  small  doses 
simply  to  arteriolar  dilatation,  and  for  large  doses 
to  an  added  selective  constriction  of  small  veins.  This 
constriction  in  turn  was  ascribed  in  part  to  the  direct 
action  of  histamine  and  in  part  to  indirect  effects 
stemming  from  release  of  norepinephrine  from  the 
adrenal  medulla.  It  was  suggested  also  that  the  result- 
ing changes  of  capillary  pressure  might  be  sufficient 
to  explain  the  protein-rich  edema,  produced  by 
histamine,  on  hydrostatic  grounds  by  passive  con- 
gestion, increased  capillary  pressure  and  stretching 
of  the  capillary  wall,  without  invoking  injury  of  the 
wall  by  histamine.  The  production  of  a  protein-poor 
filtrate  is  certainly  possible,  but  the  production  of  a 
protein-rich  filtrate  seems  unlikely.  The  small  vein 
pressures  reported  were  all  below  40  mm  Hg,  whereas 
it  has  been  shown,  with  venous  pressures  of  40  to  60 
mm  Hg,  that  capillary  filtrate  contained  at  most 
0.7  g  per  cent  of  protein  and  averaged  only  0.3  g 
per  cent  (211),  not  the  4  or  5  g  per  cent  found  in 
the  histamine  wheal  (217). 

The  validity  of  conclusions  based  on  such  catheteri- 
zation of  small  veins  is  doubtful  for  several  reasons. 
In  addition  to  inescapable,  even  though  slight,  ob- 
struction to  venous  outflow  and  false  elevations  of 
"small  vein  pressure"  there  is  the  possibility  of  effects 
from  trauma  to  the  intima  of  the  venules  under 
study.    Davis    &    Hamilton    (65-67)    stimulated    the 


sympathetic  nerves  to  the  rabbit's  ear  and  the  dog's 
paw  and  found  that  the  pressures  developed  in  the 
small  veins  depended  upon  the  nerve  stimulated, 
upon  the  frequency  of  stimulation,  upon  the  rate  of 
blood  flow,  and  upon  the  presence  or  absence  of 
mechanical  obstruction  to  venous  outflow.  They 
found  also  that  the  highest  small  vein  pressures  oc- 
curred while  flow  in  the  region  had  stopped.  Pressures 
in  the  small  veins  sometimes  exceeded  those  in  the 
small  arteries  (fig.  2.6,  right).  They  concluded  that 
when  this  occurred  the  walls  of  the  small  veins  were 
constricting  against  a  static  column  of  blood  isolated 
probably  from  the  capillaries,  and  certainly  from  the 
arterioles.  Burch  (29)  observed  similar  elevations  of 
pressure  in  isolated  segments  of  large  veins  in  man. 

More  recently  still,  an  isovolumetric  technique  has 
been  used  by  Mellander  (243)  to  measure  the  effects 
of  sympathetic  stimulation  on  the  resistance  and 
capacitance  vessels  in  cats  with  hind  legs  placed  in  a 
plethysmograph.  As  shown  in  figure  2.7,  frequency  of 
stimulation  was  kept  within  physiological  limits, 
i.e.,  from  0.25  to  16  stimuli  per  sec.  Both  the  capaci- 
tance vessels  and  resistance  vessels  constricted.  The 
former  responded  more  actively  at  first  and  reached 
maximum  constriction  at  8  stimuli  per  sec.  The  re- 
sistance vessels  were  influenced  less  at  low  stimulation 
rates  and  more  at  higher  rates.  Precapillary  resistance 
increased  more  than  postcapillary  resistance  and 
increasing  absorption  was  found,  with  calculated 
reductions  of  capillary  blood  pressure  ranging  from 
2  to  15  mm  Hg.  Mellander  suggested  that  Kelly 
and  Yisscher,  by  manipulating  and  cannulating  the 
small  veins,  may  have  produced  local  constriction  of 
their  walls.  In  addition  to  the  obstruction  already 
mentioned,  it  is  also  possible  that  intimal  irritation, 
secondary  to  catheterization  or  cannulation,  may 
make  the  small  veins  abnormally  susceptible  to 
vasoconstrictor  impulses.  In  any  event  it  seems  clear 
that,  under  some  conditions,  stimulation  of  sym- 
pathetic vasoconstrictor  nerves  increases  arteriolar 
resistance  more  than  venous  resistance,  reduces 
capillary  blood  pressure,  and  leads  to  rapid  and 
significant  absorption  of  fluid  and  not  to  elevated 
capillary  pressure  and  filtration. 

By  the  same  technique  Mellander  showed  that 
epinephrine  in  small  doses,  and  in  muscle,  relaxed 
the  arterioles  and  probably  constricted  the  venules 
slightly,  producing  filtration  and  hence  indirect 
evidence  of  a  rise  of  capillary  blood  pressure.  In 
skin,  all  doses,  and  in  muscle  large  doses  of  epinephrine 
produced  effects  like  those  of  sympathetic  stimula- 
tion,  but  only  20  to  25  per  cent  as  great.   Norepi- 


120. 
'70 

A. 

'm 

%0 

68 
&            '4!> 

0. 

.L.»n>« ■ 

4 

4.5 

5 

V. 

5 

2.5 

10/IOsec 

5 

E 

EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 

A. 


971 


16 


'140 


fig.  2.6.  Left:  small  vessel  pressure  and  flow  response  to  a  low-frequency  stimulation  of  the 
ipsilateral  lumbar  sympathetic  trunk  (15  v,  1  stimulation/to  sec  for  1  min)  Aortic  pressure  (A), 
small  artery  pressure  (a),  small  vein  pressure  (»),  and  small  vein  flow  (/•')  against  atmospheric 
pressure.  Numerals  on  pressure  tracings  indicate  pressure  in  mm  Hg.  Numerals  on  flow  tracing 
represent  flow  in  ml/min.  Timer  set  at  10  sec.  Rig/it:  same  but  with  high  frequency  stimulation 
(15  v,  10  stimulations/sec  for  1  min).  Symbols  same  except  that  F  is  small  artery  flow  proximal  to 
distal  segment.  [From  Davis  &  Hamilton  (66).] 


fig.  2.7.  Effects  on  resistance  and  capacitance  vessels  and  net  transcapillary  fluid  shift  produced 
by  maximal  lumbar  vasoconstrictor  fiber  stimulation  at  different  frequencies.  Changes  in  blood 
flow  reflect  effects  on  resistance  vessels  (inflow  and  outflow  pressures  kept  constant).  The  initial 
and  rapid  decreases  in  volume  reflect  effects  on  capacitance  vessels  and  the  subsequent  slower  and 
continuous  decreases  in  volume  (slopes  indicated  by  dashed  lines),  transcapillary  influx  of  extra- 
vascular  fluid.  Reductions  in  mean  hydrostatic  capillary  pressure  calculated  in  approximate  figures. 
[From  Mellander  (243).]  3 


nephrine  was  also  constrictor  and  produced  absorption 
of  fluid.  Acetylcholine  increased  blood  flow  markedly 
but  produced  less  filtration  than  small  doses  of  epi- 
nephrine. Presumably  capillary  pressure  increased 
very  little  because  pre-  and  postcapillary  resistances 
were  reduced  equally.  Johnson  and  Hanson  ( 1 68a) 
have  recently  applied   the  isogravimetric   technique 


to  a  study  of  pre-  and  postcapillary  resistance  in  the 
intestine  of  the  dog.  In  this  preparation,  the  isogravi- 
metric capillary  pressure  is  only  about  65  per  cent  of 
the  plasma  protein  osmotic  pressure,  probably  reflect- 
ing the  higher  permeability  to  protein  of  intestinal 
capillaries.  The  postcapillary  resistance  to  blood  flow 
through  the  intestine  was  increased  markedly  when 


972 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


arterial  perfusion  pressure  was  decreased  and  evidence 
was  presented  that  this  reaction  depends  upon  sympa- 
thetic innervation  of  the  postcapillary  blood  vessels 
(142a). 

One  more  series  of  studies  must  be  mentioned 
briefly  because  the  possible  role  of  the  arteriovenous 
anastomoses  on  small  vein  pressures  has  not  been 
mentioned  so  far.  These  relatively  large  vessels  run 
parallel  to  the  capillaries  and  are  numerous  in  the 
skin,  particularly  of  the  digits.  Schroeder  (324), 
using  a  pressure  plethysmograph  similar  to  that  used 
in  man  by  McLennan  et  al.  (234),  studied  the  effects 
of  acetylcholine,  epinephrine,  histamine  (325), 
hypoxia  (327),  calcium,  and  rutin  (326)  on  vascular 
volumes  and  pressures  in  the  dog's  foreleg.  External 
pressure  was  set  arbitrarily  at  35  mm  Hg  to  measure 
"changes  of  capillary  pressure"  and  at  15  mm  Hg 
to  measure  "changes  of  venous  pressure."  No  abso- 
lute pressure  readings  could  be  obtained  by  this 
method.  The  curves  were  variable  and  often  difficult 
to  interpret.  However,  Schroeder  placed  considerable 
emphasis  upon  independent  reactions  of  the  arterio- 
venous anastomoses  and  their  secondary  effects  upon 
venous  and  capillary  pressures.  It  is  conceivable  that 
some  of  the  variability  in  the  observed  small  vein 
pressures  in  the  skin  of  the  extremities  may  be  reduced, 
or  at  least  explained  in  part,  if  body  temperature  and 
environmental  temperatures  are  adjusted  to  maintain 
the  arteriovenous  anastomoses  in  as  constant  a  state 
as  possible.  In  any  case  it  is  clear  that  pressures  and 
resistances  in  large  veins  and  in  small  veins,  together 
with  any  factors  which  modify  them,  must  be  taken 
into  account  when  describing  the  mechanisms  which 
determine  changes  of  capillary  blood  pressure. 


3.    OSMOTIC  PRESSURE  OF  THE  PLASMA  PROTEINS,  Upl 

A .   Methods  of  .Measurement 

Starling's  conception  of  a  balance  between  capillary- 
hydrostatic  pressure  and  protein  osmotic  pressure 
was  supported  by  actual  measurement  of  the  pressure 
required  to  maintain  fluid  balance  across  a  semi- 
permeable membrane  separating  blood  serum  from 
serum  ultrafiltrate.  Starling's  osmometer  consisted 
of  a  small  glass  bell,  provided  at  the  top  with  two  side 
arms.  A  piece  of  peritoneal  membrane,  soaked  in 
10  per  cent  gelatin,  was  tied  over  the  mouth  of  the 
bell  and  prevented  from  bulging  by  a  perforated 
silver  plate.  One  sidearm  was  connected  to  a  vertical 
tube  and  the  other  side  arm  was  used  to  introduce 
serum  into  the  bell.  The  lower  end  of  the  bell,  in- 


cluding the  membrane,  was  then  dipped  into  serum 
ultrafiltrate  or  other  protein-free  salt  solution.  Within 
a  few  hours  osmotic  flow  of  fluid  from  the  salt  solu- 
tion through  the  membrane  was  made  evident  by  a 
rise  of  fluid  in  the  vertical  tube.  Equilibrium  was 
established  in  2  to  6  days;  at  this  time  the  pressure  on 
the  membrane,  exerted  by  the  fluid  column  in  the 
vertical  tube,  was  considered  equal  and  opposite  to 
the  osmotic  pressure  of  the  serum  proteins.  In  a  typical 
measurement  Starling  (345)  found  that  serum  con- 
taining 7.56  per  cent  "proteids"  caused  fluid  to  rise 
in  the  vertical  tube  to  a  height  of  53  cm  (~4i  mm 
Hg).  This  value  is  considerably  higher  than  modern 
estimates  shown  in  figure  3.1,  probably  as  a  result  of 
bacterial  degradation  of  protein  during  the  long 
period  required  to  reach  equilibrium.  In  later  work 
(1899)  Starling  (347)  obtained  values  which  were 
generally  lower  than  his  first  estimate  and  well 
within  the  range  expected  for  capillary  hydrostatic 
pressures. 

Starling's  measurements  were  of  great  interest  to 
colloid  chemists  as  well  as  to  physiologists.  Accord- 
ing to  van't  Hoff's  analogy,  in  1887,  between  ideal 
solutions  and  gases  (157),  the  osmotic  pressure,  II, 
should  be  given  by 

IT 'CRT  (30 

where  c  is  expressed  in  moles  per  liter. 


fig.  3.1.  Osmotic  pressure-concentration  curves  for  whole 
plasma  and  selected  plasma  proteins.  Based  on  data  from 
references  (268,  270,  312,  313,  343),  original  measurements 
corrected  to  37  G.  Experimental  points  for  7-globulin  are 
included  to  indicate  magnitude  of  experimental  error. 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


973 


20,000 


-  25,000 


l--   30,000 


-  60,000 


fig.  3.2.  First  derivative  of  protein  osmotic  pressure-con- 
centration curve  to  show  deviation  from  van't  Hoff's  law.  At 
infinite  dilution  the  mean  number  average  molecular  weight  of 
plasma  proteins  is  almost  100,000  but  in  normal  plasma  their 
osmotic  behavior  corresponds  to  an  ideal  solute  of  mol  wt 
37,000. 

If  c  is  expressed  in  g  per  100  ml,  RT  in  liter-atmos- 
pheres, and  IT  in  atmospheres,  then 

Mol  Wght.   =   10c    RT/II  (3.2) 

The  potential  application  of  equation  3.2  to  the 
determination  of  molecular  weights  led  protein 
chemists  to  investigate  in  detail  the  theory  and 
technique  of  osmotic  measurements.  As  early  as 
1905,  Reid  (293)  used  Starling's  technique  to  esti- 
mate the  molecular  weight  of  hemoglobin.  Subse- 
quent studies  by  S0rensen  (342),  Adair  (1,  2),  and 
others  showed  that  protein  osmotic  pressure  is  de- 
pendent upon  ionic  strength,  net  charge,  and  other 
factors  not  included  in  van't  Hoff's  limiting  law  for 
ideal  solutions.  Deviations  from  the  limiting  law 
increase  rapidly  as  a  function  of  protein  concentration 
(figs.  3.1  and  3.2)  and  estimates  of  molecular  weight 
can  only  be  made  on  the  basis  of  extrapolation  to 
zero  concentration.  The  chief  technical  difficulty  con- 
fronting early  workers  was  the  long  period  required 
to  reach  equilibrium  across  artificial  membranes. 
In  order  to  avoid  bacterial  degradation  of  protein 
it  was  necessary  to  carry  out  measurements  at  low 
temperature;  days  or  even  weeks  were  required  for 
each  determination.  Nevertheless,  the  first  satis- 
factory estimates  of  the  molecular  weights  of  serum 
albumin  (3),  ovalbumin  (342),  and  hemoglobin  (2) 
were  obtained  by  this  method. 


Advances  in  the  technique  of  osmometry  have 
reduced  considerably  the  time  required  for  the 
equilibration  process. 

Equilibration  across  a  semipermeable  membrane,  following 
a  step  change  in  either  hydrostatic  or  osmotic  pressure,  pro- 
ceeds exponentially  with  a  time  constant  equal  to  the  product 
of  membrane  resistance  and  volume  distensibility 

%  Equilibrium  =  IOo[l-exp-f-j^ — — -. J        (3.3) 

ffi    p       fn' 

where  rm  is  membrane  resistance  to  solvent  flow  and  vpy  vm 
are  the  volume  distensibilities  of  the  pressure  measuring  device 
and  membrane,  respectively.  The  resistance  (rm)  of  membranes 
capable  of  restraining  the  passage  of  serum  albumin  is  seldom 
less  than  io1  mm  Hg  per  ml  per  hour  per  cm2  membrane. 
The  essential  factor  limiting  the  rate  of  approach  to  equilibrium 
is  therefore  the  volume  of  fluid  which  must  pass  through  the 
membrane  in  order  to  actuate  the  pressure  detector  and 
satisfy  the  volume-pressure  characteristics  of  the  membrane. 
For  example,  a  typical  osmometer  with  a  membrane  surface 
area  of  10  cm2  must  have  a  total  volume  distensibility  of  less 
than  3  X  io~4  ml  per  mm  Hg  in  order  to  achieve  95  per  cent 
equilibrium  in  1  hour  (equation  3.3). 

In  1936  Hepp  (151)  described  an  osmometer  in  which 
distensibility  of  the  membrane  (»,„)  was  made  extremely  small, 
the  chief  volume  displacement  being  confined  to  slight  changes 
in  fluid  level  of  the  capillary  tube  manometer  used  to  detect 
pressure  balance.  Equilibration  time  was  reduced  to  about  2 
hours.  Osmometers  of  the  Hepp  type  have  been  widely  used 
by  subsequent  investigators  and  the  osmotic  pressure-concen- 
tration curves  shown  in  figure  3.1  are  based  on  data  obtained 
with  this  instrument.  A  recent  description  of  the  construction 
and  use  of  Hepp  osmometers  has  been  published  by  Meschia 
(248).  Further  reduction  in  volume  displacement  can  be  ob- 
tained through  the  use  of  sensitive,  recording  pressure  trans- 
ducers having  volume  distensibilities  less  than  io~6  ml  per  mm 
Hg.  With  the  aid  of  such  transducers  it  is  theoretically  possible 
to  achieve  95  per  cent  equilibration  across  available  protein- 
impermeable  membranes  in  less  than  1  min.  Recording  os- 
mometers of  this  type,  having  time  constants  of  less  than  5 
min,  have  been  in  use  in  the  authors'  laboratory  for  several 
years  (277,  280I.  Similar  instruments,  suitable  for  the  rapid 
estimation  of  protein  osmotic  pressure  in  o.  1  ml  plasma,  have 
recently  been  described  by  Hansen  (142). 


B.  Protein  Osmotic  Pressure  of  Human  Plasma 

Osmotic  pressure-concentration  curves  for  normal 
human  plasma,  serum  albumin,  and  two  globulin 
components  of  plasma  are  shown  in  figure  3.1. 
The  curves  were  obtained  at  physiological  pH  and 
ionic  strength,  but  the  original  measurements  have 
been  corrected  to  37  C.  Experimental  points,  taken 
from  Oncley  et  al.  (268),  are  shown  for  7-globulin 
in  order  to  indicate  the  magnitude  of  experimental 
error  when  a  pure  component  is  measured.  The 
smooth  curves  for  albumin,  whole  plasma,  and 
ft-globulin  are  based  on  data  in  references  (268, 
270,  312,   313,  343)-  Normal  human  plasma  has  a 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


protein  osmotic  pressure  of  24  to  26  mm  Hg,  cor- 
responding to  a  total  protein  concentration  of  about 
7  per  cent.  It  is  impossible  to  give  a  significant  mean 
value  because  the  protein  concentration  depends 
upon  procedures  used  for  drawing  blood  samples 
and  in  any  given  sample  the  value  obtained  depends 
upon  the  method  of  measurement.  Electrophoretic 
measurements  yield  slightly  lower  values  for  total 
protein  than  estimates  based  upon  salt  precipitation 
or  protein  nitrogen.  In  the  following  discussion  a 
nominal  value  of  7.0  g  per  100  ml  will  be  considered 
normal. 

The  osmotic  pressure-concentration  curves  for 
albumin  and  for  normal  plasma  are  described  by  the 
following  empirical  equations  which  fit  the  experi- 
mental data  closely  over  the  range  o  to  25  per  cent 
protein. 

II  albumin  =  2.8  c  +  0.18c*  +  0.012c3      (3.4) 

n plasma  *  2.1c  +  0.16  cz  +  0.009c3      (3.5) 

In  each  equation  the  first  term  represents  the  ideal 
limiting  law  of  van't  Hoff.  Thus  the  molecular  weight 
of  albumin,  calculated  from  the  first  term  of  equation 
3.4,  is  10  RT/2.8  =  69,000.  The  second  and  third 
terms  in  each  equation  represent  deviations  from 
van't  HofPs  law  caused  by  Donnan  effects  and 
protein-protein  interaction. 

The  chief  osmotically  active  protein  in  normal 
mammalian  plasma  is  albumin,  which  can  be  sepa- 
rated and  identified  as  a  homogeneous  component 
representing  about  50  per  cent  of  the  total  protein  in 
plasma  and  contributing  about  65  per  cent  of  the 
protein  pressure.  The  globulins,  on  the  other  hand, 
comprise  a  spectrum  of  components  with  molecular 
weights  ranging  from  45,000  to  1,000,000  as  shown  in 
table  3.1.  The  widely  different  osmotic  activities 
of  jSj-globulin  and  7-globulin  shown  in  figure  3.1 
serve  to  emphasize  that  no  simple  physicochemical 
meaning  can  be  attached  to  the  osmotic  pressures 
developed  by  crude,  heterogeneous  globulin  frac- 
tions. Precipitation  methods  fail  to  separate  albumin 
from  low  molecular  weight  globulins  which  contribute 
substantially  to  total  protein  osmotic  pressure;  for 
this  reason  many  early  studies  attempting  to  relate 
total  protein  pressure  to  albumin: globulin  ratios 
(380)  need  to  be  reevaluated.  Current  estimates  of 
A :  G  ratio  in  normal  plasma  are  close  to  1 . 1 ,  in 
comparison  with  values  in  the  range  1.8  to  2.6  ob- 
tained by  classical  fractionation  procedures. 

The  osmotic  pressure  contributed  by  globulins 
can  be  calculated  from  the  difference  between 
albumin  and  whole  plasma  (equations  3.4,  and  3.5), 


it  being  assumed  that  the  A:G  ratio  is  1.1  and  that 
osmotic  interactions  between  globulins  and  albumin 
are  not  significantly  different  from  interaction  be- 
tween albumin  and  albumin  (270,  314).  The  "aver- 
age" globulin  curve  so  calculated  is  given  by 

//globulins  '  1.6c  +  O.I5cz+  0.006c3      (3.  6) 

In  normal  plasma  about  15  per  cent  of  the  total 
protein  pressure  is  contributed  by  known  globulin 
components  and  about  20  per  cent  by  unidentified 
components  (table  3.1).  Bennhold  et  al.  (14)  have 
studied  two  extremely  interesting  cases  of  complete 
analbuminemia;  the  osmotic  pressure-concentration 
curve  of  the  albumin-free  plasma  from  these  unique 
patients  (brother  and  sister)  conforms  closely  to 
equation  3.6  (271).  These  patients  have  been  in  good 
health  for  many  years  despite  the  fact  that  the  protein 
osmotic  pressure  of  their  plasma  is  less  than  50  per 
cent  of  normal.  Presumably  they  have  compensated 
by  permanent  reduction  of  mean  capillary  pressure 
to  balance  the  low  protein  pressure. 

C.  Species  Differences,  Fetal  Plasma 

Comparative  studies  of  colloid  osmotic  pressure 
have  been  reviewed  by  Meyer  (251)  and  by  Keys  & 
Hill  (175).  A  summary  of  data  pertaining  to  plasma 
of     Elasmobranchs,      Pisces,     Amphibia,      Reptilia, 


table  3.1.  Some  Protei 

n  Components 

of  Human  Plasma* 

Component 

Cone. 

g/100 
ml 

%  of 
Total 
Protein 

mol  wt 

Approx.  k 

in  Plasma 

mm  Hg 

Whole  plasma 

7-0 

100 

25 

Albumin 

3-6 

51 

69,000 

16.4 

-y-Globulins 

•7 

1 1 

156,000 

0.9 

Fibrinogen 

•3 

4 

340,000 

0.2 

a-Lipoprotein 

.28 

4 

160-400,000 

0.2 

(1.0  <  p  <   1. 14) 

^-Lipoprotein 

•  25 

3-8 

2    X    IO6 

(p  =    1 .03  ±  .02) 

/3i-Metal  combining 

.2 

3 

90,000 

0.7 

/32-Globulins 

.2 

3 

(150,000) 

O.4? 

ft-Lipid   poor  euglobu- 

•'3 

2 

(150,000) 

0.2? 

lin 

ai-Acid  glycopro- 

•03 

0.4 

45,000 

0.2? 

tein 

Remaining  known 

•4 

5 

<I.O 

components 

Total 

6.0 

87 

ca.  20 

Unidentified 

1 

13 

5 

Prepared  with  J.  L.  Oncley;  cf  also  ref.  267. 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


975 


Aves,  and  Mammalia  will  be  found  in  reference  (4). 
It  is  a  striking  fact  that  all  mammals  have  approxi- 
mately the  same  protein  osmotic  pressure.  Mean 
values  for  the  various  species  of  mammals  listed  by 
Meyer  (251)  range  from  19  mm  Hg  (guinea  pig) 
to  26  mm  Hg  (human),  but  data  from  most  species 
lie  in  the  range  21  to  25  mm  Hg.  These  relatively 
small  variations  among  species  may  well  be  spurious. 
Excitement,  posture,  anesthesia,  and  many  other 
factors  can  cause  substantial  hemodilution  or  hemo- 
concentration  prior  to  withdrawal  of  blood  samples. 
It  would  be  unjustified  to  compare  blood  obtained 
from  a  confident,  unanesthetized  human  with  blood 
obtained  from  animals  in  various  states  of  excitement 
and  anesthesia. 

Protein  concentrations  and  osmotic  pressures  in 
plasma  of  poikilotherms  are  in  general  far  lower  than 
in  mammals.  Values  in  the  range  of  5  to  10  mm  Hg 
have  been  reported  for  frogs  and  turtles  (35,  189, 
200),  the  lower  values  being  associated  with  the 
spring  season.  The  low  protein  osmotic  pressure  of 
poikilotherms  is  to  be  expected  in  view  of  their 
relatively  low  blood  pressure.  It  is  surprising,  however, 
to  find  similarly  low  values  in  birds  in  which  blood 
pressure  is  relatively  high. 

The  protein  osmotic  pressure  of  fetal  plasma  is  of 
special  interest  in  relation  to  fluid  exchanges  be- 
tween maternal  and  fetal  blood.  Meschia  (249) 
has  carried  out  a  careful  series  of  osmotic  measure- 
ments in  fetuses  from  sheep  and  goats.  At  midterm 
the  protein  osmotic  pressure  in  fetal  blood  is  7  to  10 
mm  Hg;  the  pressure  gradually  increases  during 
gestation  but  never  exceeds  that  in  maternal  blood. 
The  average  molecular  weight  of  proteins  in  fetal 
plasma  is  only  65,000  as  compared  with  96,000  in 
the  adult.  This  difference  is  largely  due  to  the  presence 
of  fetuin  (283a),  a  low  molecular  weight  globulin 
which  accounts  for  about  90  per  cent  of  the  globulin 
fraction.  The  mean  molecular  weight  increases 
dramatically  within  24  hours  after  birth,  owing  partly 
to  absorption  and  retention  in  the  blood  of  7-globulins 
from  colostrum. 


D.  Physiological  Significance  of  the 
Deviations  from  van't  Hoff's  Law 

The  disproportionate  increase  in  protein  osmotic 
pressure  as  a  function  of  concentration  tends  to 
amplify  osmotic  forces  contributing  to  homeostasis 
of  blood  volume.  The  magnitude  of  this  effect  is 
seldom  appreciated  and  will  therefore  be  discussed 
in  some  detail.  Figure  3.2  shows  the  rate  of  change  of 


osmotic  pressure  per  unit  change  in  concentration,  as 
a  function  of  concentration.  At  small  protein  con- 
centrations, such  as  those  existing  in  tissue  fluids, 
the  osmotic  coefficient,  dU'dc,  is  relatively  small  and 
the  proteins  behave  as  the  osmotic  equivalent  of  an 
ideal  solute  of  molecular  weight  80,000  to  90,000. 
Thus  the  osmotic  forces  in  interstitial  fluid  tending  to 
withdraw  fluid  from  blood  are  relatively  small  and 
insensitive  to  quite  large  percentual  alterations  in 
protein  concentration.  At  concentrations  which 
exist  in  plasma,  however,  the  osmotic  coefficient  is 
almost  threefold  greater  so  that  the  plasma  proteins 
behave  as  the  osmotic  equivalent  of  an  ideal  solute 
of  molecular  weight  37,000.  If  the  proteins  behaved 
as  ideal  solutes  they  would  have  to  be  present  in 
plasma  at  a  concentration  of  1 2  per  cent  in  order 
to  exert  the  same  osmotic  pressure.  The  viscosity  of 
such  a  concentrated  solution  would  more  than  double 
peripheral  resistance  to  blood  flow.  On  the  other 
hand,  an  ideal  solute  of  molecular  weight  37,000 
(i.e.,  osmotically  equivalent  to  the  proteins  in  plasma) 
would  pass  rapidly  through  the  capillary  walls  and 
therefore  be  ineffective  in  balancing  capillary  hydro- 
static pressure. 

The  functional  significance  of  the  nonlinear  osmotic 
properties  of  the  plasma  proteins  is  further  illustrated 
in  figure  3.3.  Fluid  loss  from  plasma,  amounting  to 


CHANGE  IN  OSMOTIC 

PRESSURE   OF    PLASMA 

PROTEINS 

mm  Hg 
+  40T 


~*--Actuol 


deviotion  from 
Van't  Hoff's  Law 


X-20 


fig.  3.3.  Physiological  significance  of  deviations  from 
van't  Hoff's  law.  Fluid  loss  from  plasma  causes  a  dispro- 
portionately large  increment  in  the  osmotic  restoring  force; 
conversely,  hemodilution  causes  a  relatively  small  diminution 
of  protein  osmotic  pressure. 


976 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


80i-  mm   Hg 


Approximate 
hydrostatic 
pressure  in 
glomerular 
capillaries 


FILTRATION   FRACTION 
04  0.5  0.6 


0.7 


fig.  3.4.  Illustrating  the  significance  of  protein  osmotic 
pressure  for  glomerular  filtration.  The  rapid  increase  of  protein 
osmotic  pressure  as  a  function  of  concentration  places  an  upper 
limit  to  the  filtration  fraction  of  the  kidney. 


30  ml  per  100  ml,  results  in  an  increase  of  18  mm  Hg 
in  the  osmotic  restoring  force,  resisting  further  fluid 
loss.  If  the  plasma  proteins  behaved  as  ideal  solutes, 
however,  the  restoring  force  would  be  only  6  mm  Hg. 
Conversely,  dilution  of  the  plasma  results  in  a  greater 
reduction  of  osmotic  pressure  than  would  obtain  if 
the  proteins  behaved  as  ideal  solutes.  These  considera- 
tions are  of  special  importance  normally  in  connection 
with  glomerular  filtration  where  a  relatively  large 
fraction  of  plasma  fluid  may  be  filtered.  Figure  3.4 
shows  protein  osmotic  pressures  in  efferent  glomerular 
blood  as  a  function  of  filtration  fraction.  It  is  clear 
that  the  steep  rise  of  protein  osmotic  pressure  is  an 
important  factor  limiting  filtration  rate.  For  example, 
a  filtration  fraction  of  0.45  is  the  highest  possible 
value  consistent  with  a  normal  plasma  protein  con- 
centration (ca.  7%)  and  a  normal  hydrostatic  pres- 
sure (ca.  70  mm  Hg)  in  the  glomerular  capillaries.  It 
is  probable  also  that  the  high  protein  osmotic  pressure 
in  efferent  glomerular  blood  plays  a  major  role  in 
providing  the  force  for  transcapillary  absorption  ol 
fluid  in  the  peritubular  circulation. 

E.  Physicochemical  Aspects  of  Protein  Osmotic  Pressure- 
In  the  preceding  paragraphs  we  have  emphasized 
the  functional  significance  of  the  large  deviations  from 
van't  Hoff's  law  which  characterize  osmotic  behavior 
of  plasma  proteins.  It  therefore  seems  appropriate  to 
discuss  briefly  the  physical  forces  which  contribute 
to  nonlinear  osmotic  behavior  of  this  type. 

The  disproportionate  increase  in  osmotic  pressure 
as  a  function  of  protein  concentration  (figs.  3.1  and 


3.2)  can  be  explained  in  part  by  net  charges  on  the 
protein  molecules  which  cause  unequal  distribution  of 
electrolytes  across  the  semipermeable  membrane 
(Donnan  effect).  Combination  of  van't  Hoff's  limiting 
law  (equation  3.1  )  with  the  ionic  distribution  required 
by  Donnan  equilibrium  for  univalent  ions  yields  the 
following:  relation. 


17  --  RT(c  +  yS^cT+Tmf  -2mJ  (3.  7) 

where  c  =  protein  concentration,  moles  per  liter; 
Z  =  net  charge2  on  the  protein,  and  ms  =  the  con- 
centration of  salt  solution  with  which  the  protein  is 
equilibrated.  A  simple  derivation  of  equation  3.7 
may  be  found  in  reference  (156).  A  more  convenient 
form  of  equation  3.7  may  be  obtained  from  expansion 
of  the  second  term  by  means  of  the  binomial  theorem. 
Thus, 


■y/z*CZ '  +  4m f  -  i. 


Z*C* 


/V 


s     4mc       64m? 


(3.8) 


The  third  term  of  the  series  is  negligible  except  at 
very  low  salt  concentrations.  Substituting  the  first 
two  terms  of  the  series  in  equation  3.7  we  obtain  the 
form  derived  by  Scatchard  et  al.  (3 1 3) 

n*  rt(c  + 


4m/ 


(3.9) 


Equation  3.7  or  3.9  describes  qualitatively  some  of  the 
observed  changes  in  osmotic  pressure  as  a  function  of 
protein  concentration,  charge,  and  salt  concentration. 
Thus  osmotic  pressure  is  increased  when  the  salt  con- 
centration (ms)  is  reduced  or  if  the  charge  (c)  is  in- 
creased in  either  direction  from  the  true  isoelectric 
point.  For  a  limited  range  of  conditions,  equation 
3.7  or  3.9  predicts  quantitatively  the  observed  osmotic 
pressure-concentration  curves. 

For  example,  when  albumin  is  equilibrated  against 
.15  m  NaCl  (m,  =  .15)  at  pH  7.4  the  charge,  z,  is 
—  1 7,  whence 


n  -"  RT  (c  + 


17' 


cV 


(3.10) 
4x.l5        ' 

Taking  69,000  as  the  molecular  weight  of  albumin  and 
expressing  c  in  g  per  100  ml  this  becomes 

77--  2.8c  +  0  I9cz  (3.11) 

Equation  3.1 1   is  almost  identical  with  the  first  two 

2  Net  charge,  z,  is  defined  as  the  algebraic  sum  of  all  charges 
on  the  ionizable  constituents  of  the  protein  molecule  plus 
those  charges  which  result  from  binding  of  ions  by  the  protein. 
In  the  case  of  serum  albumin  at  pH  7.4  in  .15  m  NaCl  at  25  C 
the  net  charge  estimated  from  the  titration  curve  is  —17,  made 
up  of  approximately  100  negative  and  83  positive  charges  on 
the  protein.  In  addition  9  or  10  chloride  ions  are  bound  to  each 
molecule  (86). 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


977 


terms  of  the  empirical  equation  3.4  describing  the 
observed  osmotic  pressure-concentration  curve  for 
albumin  under  the  stated  conditions  (fig.  3.1).  This 
close  correspondence  between  observed  osmotic  pres- 
sure and  the  pressure  calculated  on  the  basis  of 
Donnan  theory  might  lead  one  to  believe  that  the 
problem  has  been  solved.  Unfortunately,  this  is  not 
the  case.  The  correspondence  between  theory  and 
fact  only  occurs  at  two  particular  values  of  charge, 
one  of  which  occurs  (fortuitously)  at  physiological  pH 
and  salt  concentration.  Figure  3.5  shows  clearly  the 
discrepancy  between  observed  osmotic  pressure  and 
the  theoretical  pressure  predicted  on  the  basis  of 
Donnan  theory  and  van't  Hofl's  law.  This  dis- 
crepancy may  be  explained  in  part  by  the  binding  of 
chloride  ions  to  the  albumin  molecule  (86,  315). 
Binding  of  chloride  (or  other  anions)  to  the  protein 
decreases  the  fraction  of  salt  free  to  take  part  in  the 
Donnan  distribution  and  at  the  same  time  causes  an 
error  in  the  calculation  of  net  charge  from  titration 
data.  For  this  reason,  also,  the  isoelectric  point  differs 
from  the  isoionic  point  (86).  When  corrections  are 
made  for  chloride  binding  it  appears  that  the  true 
isoelectric  point  for  albumin  is  closer  to  pH  4.2  than 
to  pH  5.4  as  might  be  inferred  from  its  titration  curve. 
As  shown  in  figure  3.5,  the  osmotic  pressure  does  ap- 
proach the  van't  Hoff  pressure  at  pH  4.2  as  would  be 


40  -  TT,  mm   Hg 


35 


30 


25 


20 


15- 


+  30  +20  +10 


Van't  Hoff's  Law 


-10  -20   Charge,  Z 


4  2  4.5  4.7  5.4  6.8  8.0    pH 

OSMOTIC  PRESSURE  OF   6  %   ALBUMIN 
In  .15  M  NaCI  (ms  =  .l5)  at  37    C 

fig.  3.5.  Illustrating  the  discrepancy  between  osmotic 
pressure  calculated  on  the  basis  of  Donnan  theory  and  protein 
osmotic  pressure  measured  experimentally.  Agreement  with 
theory  occurs  fortuitously  at  pH  4.7  and  pH  7.6.  [Calculated 
from  data  in  reference  (313).] 


predicted  from  the  Donnan  relation   (equation  3.6) 
for  the  case  z  =  o. 

Even  after  corrections  have  been  made  for  chloride 
binding,  however,  the  Donnan  theory  fails  to  account 
quantitatively  for  observed  osmotic  pressure  under 
most  circumstances.  Other  factors  involved  include 
electrostatic  interactions  between  protein  molecules 
and  between  protein  and  salt.  These  interactions  are 
presumably  represented  in  the  third  term  of  the  em- 
pirical equations  (e.g.,  equation  3.4)  describing 
osmotic  pressure-concentration  curves,  but  no  precise 
theoretical  explanation  of  these  forces  can  be  offered 
at  the  present  time. 


4.    INTERSTITIAL    FLUID    PRESSURE 

("tissue  pressure"),  P,, 

Capillary  blood  pressure  is  only  one  point  on  the 
transmural  gradient  of  hydrostatic  pressure  which  is 
concerned  with  the  filtration  of  fluid  through  the 
capillary  wall.  The  other  point  is  the  pressure  on  the 
interstitial  fluid  outside  the  capillary  wall.  Landerer 
(197)  in  1884  attempted  the  first  direct  measurements 
of  interstitial  fluid  pressure  by  introducing  a  fine 
cannula  or  needle  into  the  subcutaneous  or  cutaneous 
tissues  and  recording  the  pressures  required  to  cause 
fluid  to  flow  into  the  tissues.  Landerer's  figures,  like 
those  of  Hajen  (139)  and  others  (158,  252)  proved  to 
be  fallacious  because  too  much  fluid  was  injected  be- 
fore pressure  was  measured  (238).  Nevertheless  these 
experiments  were  significant  because  they  showed  that 
considerable  resistance  must  be  overcome  if  the 
volume  of  interstitial  fluid  is  increased  suddenly. 

Even  when  the  volume  of  interstitial  fluid  was  in- 
creased more  gradually  and  physiologically,  evidence 
of  mounting  interstitial  fluid  pressure  appeared  almost 
at  once,  at  least  in  some  tissues.  Drury  &  Jones  (80) 
used  an  ordinary  plethysmograph  to  measure  rates 
of  filtration  in  the  leg  during  venous  congestion,  and 
found  this  rate  declined  as  filtration  progressed, 
though  their  figures  were  irregular  because  their 
method  measured  changes  of  vascular  volume  and  of 
interstitial  fluid  volume  together.  A  ''pressure  plethys- 
mograph" (188,  209)  made  it  possible  to  exclude 
changes  of  vascular  volume  and  thereby  to  measure 
changes  of  interstitial  fluid  volume  more  accurately. 
Landis  &  Gibbon  (209)  found  in  the  human  forearm 
that  the  filtration  produced  by  given  venous  pressures 
declined  rapidly,  beginning  even  during  the  first  10 
min  of  filtration.  With  a  venous  pressure  of  20  cm  of 
water,  filtration  ceased  in  35  to  55  min  after  the 
accumulation  of  less  than  1  ml  of  filtrate  per  100  ml 


978 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


.120 


RATE   OF 
FILTRATION 
ML  /MIN  /  100  ML 
FOREARM 
TISSUE  -080 


.040- 


0^ 


JS  PRESSURE  =  /T\ 

CM    WATER    FROM        ^-^ 


VENOU 
60 

TIME    ZERO 


30 


-20 


INCREASE 

OF 

INTERSTITIAL 

FLUIO 

PRESSURE 

ABOVE 

RESTING 

LEVEL 

CM    H20 

(CALC.) 


10 


20  40 

TIME    -  MIN 


2  4  6 

VOLUME    OF    NEWLY   FILTERED 

INTERSTITIAL  FLUIO 

ML/IOOML    OF    FOREARM   TISSUE 


fig.  4.1.  Chart  showing  decreasing  filtration  rate  ( in  A)  measured  in  human  forearm  by 

pressure  plethysmograph  when  venous  pressure  was  elevated  to  60  cm  H>0  for  80  min.  Interstitial 

fluid  pressure  (O O)  was  calculated  by  dividing  the  cumulative  decrease  of  observed  filtration 

rates  by  the  previously  determined  average  normal  filtration  coefficient  (.0033  ml/ 100  ml  forearm 
tissue/min/cm  H2O  increase  of  venous  pressure),  and  then  correcting  each  value  for  the  local  in- 
crease of  plasma  protein  concentration  and  of  n,,(  produced  by  net  filtration.  As  shown  in  A  calcu- 
lated interstitial  fluid  pressure  increases  steadily  with  time,  reaching  a  maximum  of  almost  30  cm 
H20  by  75  min.  In  B  the  same  calculated  interstitial  fluid  pressures  are  charted  against  the  cumula- 
tive volume  of  added  interstitial  fluid.  As  the  interstitial  compartment  is  distended  by  an  increasing 
volume  of  filtered  fluid,  interstitial  pressure  in  the  forearm  tissues  probably  rises  slowly  at  first  and 
then  more  rapidly.  [Recalculated  from  data  of  Landis  &  Gibbon  (209).] 


of  forearm  tissue.  As  shown  in  figure  4.1  {left)  when 
venous  pressure  was  raised  to  60  cm  water,  the  initial 
filtration  rate  was  .156  ml  per  min  per  100  ml  of 
forearm  tissue  but  declined  rapidly  to  less  than  .040 
after  75  min  of  congestion.  At  this  time  the  volume  of 
newly  filtered  fluid  was  approximately  6  ml  per  100 
ml  of  tissue,  i.e.,  about  60  per  cent  of  the  amount 
which  produces  manifest  edema,  detectable  by 
"pitting  on  pressure."  Knowing  the  decrease  of  filtra- 
tion rate,  the  normal  filtration  coefficient  (209),  and, 
approximately,  the  increase  in  the  osmotic  pressure 
of  the  plasma  proteins  of  the  blood  in  the  congested 
forearm  (188,  211),  it  is  possible  to  calculate  inter- 
stitial fluid  pressure,  with  results  shown  in  figure  4. 1 . 
Accumulations  of  interstitial  fluid  from  prior  filtra- 
tion also  increased  the  rate  at  which  extravascular 
fluid  was  removed  from  the  forearm  (188,  209),  as 
would  be  expected  with  higher  interstitial  fluid  pres- 
sures. It  is  still  impossible  to  decide  to  what  extent  this 
fluid  was  removed  via  the  blood  capillaries  by  absorp- 
tion or  via  lymphatics  by  flow,  though  indirect  evi- 
dence (188)  indicated  that  small  accumulations  were 
probably  removed  by  the  former,  larger  accumula- 
tions by  the  latter  in  addition.  The  importance  of 


interstitial  fluid  pressure  seemed  clear,  although  de- 
pendable direct  measurements  were  not  available  as 
yet. 

In  a  review  of  this  topic  in  1934  (207)  it  was  neces- 
sary to  consider  the  conflicting  views  then  current 
concerning  bound  and  free  water  in  the  interstitial 
fluid  compartment.  It  is  now  generally  agreed  on  the 
basis  of  many  studies  by  several  dilution  methods 
that  the  volume  of  truly  "bound  water"  is  negligible. 
Yet  in  normal  tissues  interstitial  fluid  cannot  be 
identified  microscopically  as  a  distinct  and  continuous 
compartment  or  layer  around  capillaries  or  between 
cells  except  in  a  few  locations.  This  is  not  surprising 
because  a  simple  calculation  shows  that  if  the  normal 
volume  of  interstitial  fluid,  approximately  1 5  per 
cent  of  gross  tissue  volume,  is  distributed  uniformly 
between  surfaces  of  cells,  connective  tissue  fibrils, 
blood  capillaries,  etc.,  the  average  thickness  of  this 
layer  cannot  be  greater  than  1  n  and  is  probably  less 
than  0.5  fi.  This  coincides  with  the  findings  of  Mc- 
Master  &  Parsons  (240,  241)  who  injected  dye  solu- 
tions into  small  lymphatic  vessels  and  observed  under 
high  magnification  that  the  dye  penetrated  into  the 
tissues  in  the  form  of  hair-like  projections  or  "bristles," 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


979 


apparently  between  or  along  connective  tissue  fibrils 
(fig.  4.2).  Hemorrhage  and  dehydration,  which  they 
used  to  diminish  the  volume  of  interstitial  fluid, 
delayed  the  appearance  of  these  bristles  of  dye,  but 
eventually  they  became  clearer  than  usual,  as  well  as 
more  resistant  to  displacement  by  massage.  On  the 
other  hand,  hydremic  plethora,  and  particularly  the 
edema  of  inflammation,  tended  to  obliterate  the 
bristles  and  permitted  instead  a  diffuse  and  more 
rapid  distribution  of  dye  which  could  easily  be  dis- 
placed by  pressure  from  one  area  into  another,  pre- 
sumably because  it  dissolved  in  a  larger  and  more 
freely  movable  volume  of  edema  fluid. 

The  paucity  of  normal  interstitial  fluid,  its  layered 
distribution,  and  the  disruptive  effects  of  injecting 
even  small  volumes  of  fluid  (238)  makes  it  necessary, 
as  with  capillary  blood  pressure,  to  determine  inter- 
stitial fluid  pressure  by  a  "null  point"  method  which 
provides  a  balance  of  pressures  with  minimal  move- 
ment of  fluid  into,  or  out  of,  the  interstitial  fluid  com- 
partment. Wells  et  al.  (375)  used  a  capillary  tube 
placed  between  the  manometer  and  the  saline-filled 
needle  that  was  inserted  into  the  tissue.  By  observing 
the  meniscus  under  a  microscope,  they  saw  that  a 


change  of  2  or  3  mm  water  pressure  sufficed  to  re- 
verse the  flow  at  the  point  of  balance  and  hence,  after 
correcting  for  capillarity  in  the  tube,  they  measured 
interstitial  fluid  pressure  with  a  small  volume  artifact. 
Burch  &  Sodeman  (30)  and  McMaster  (238)  re- 
duced the  volume  change  further,  but  still  more  re- 
fined methods  are  needed  to  reduce  the  likelihood  of 
local  hemorrhage  and  mechanical  artifacts. 

Table  4. 1  summarizes  several  representative  series 
of  values  given  in  mm  Hg  for  easier  comparison  with 
capillary  blood  pressure  and  the  osmotic  pressure  of 
the  plasma  proteins.  In  skin,  McMaster  (238)  found 
it  necessary  to  determine  "interstitial  resistance"  to 
very  slow  rates  of  inflow  of  fluid  because  paucity  of 
freely  movable  fluid  prevented  determining  a  true 
interstitial  pressure.  Although  some  of  the  values  in 
table  4. 1  may  be  artificially  high,  their  order  of 
magnitude  is  consistent.  P,t  in  skin  and  subcutaneous 
tissues,  under  resting  conditions,  ranges  from  1  to  5  or 
6  mm  Hg  and  averages  about  2.5  mm  Hg.  In  muscle, 
P,f  tends  to  be  slightly  higher,  1  to  9  mm  Hg  and 
averages  4.5  mm  Hg.  In  some  comparisons  Plf  was 
higher  in  the  tightly  sheathed  muscles,  e.g.,  soleus 
and  anterior  tibial,  than  in  the  more  loosely  enclosed 


/     '  yi-BM 


•u^v/-r/',^    Mi  _ 


I 


fig.  4.2.  Diagrammatic  sketch  of  the  extravascular  interstitial  movement  of  a  2%  solution  of 
pontamine  sky  blue  after  its  escape  from  the  lymphatics,  a:  Dye  first  appears  as  colored  bristles  at 
2-7  min.  b:  Color  becomes  more  intense  and  bristles  longer  at  3-10  min.  c:  Colored  lines  become 
broader  at  5-12  min.  d:  Second  phase.  Diffuse  blue  staining  between  bristles  which  cannot  be  dis- 
lodged by  pressure.  Bristles  disappearing.  During  a  to  d  color  was  apparently  fixed  on  tissue  ele- 
ments and  not  dislodged  by  pressure,  e;  Diffuse  blue  cloud  easily  displaced  with  pressure,  free  fluid. 
/.■  Dye  escaping  from  ruptured  lymphatics,  no  bristles.  [From  McMaster  &  Parsons  (240).] 


98o 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


table  4  i .  Interstitial  Fluid  Pressure,  Ptf,  Ranges  at  Rest 


Pressure  (Range) 

Tissue,  Species 

mm  Hg 

Reference 

Subcutaneous, 

man 

Forearm  and  leg 

'-5-5-1 

(375) 

Foot 

1. 1-3. 2 

(30) 

Pretibial 

1.3-4.0 

(3o) 

Forearm 

0.8-2.9 

(30) 

Hand 

0 . 6-2 . 2 

(30) 

Foot 

1.2-3.0 

(23O 

Leg 

4.1-6.5 

(23O 

Eyelid 

1.2-3.0 

(28) 

Cutaneous 

Mouse* 

0-4-3-7 

(238) 

Man* 

1 .8-4.9 

(238) 

Muscle,  man 

Gastrocnem 

us 

0-7-3-7 

(375) 

Soleus 

3-7-7-3 

(375) 

Gastrocnemius 

2.6-8.9 

(23O 

Biceps 

3.2-6.6 

(231  ) 

Biceps 

2.9-6.6 

(127-129) 

*  "Interstitial    resistance' 

to    very    slow 

flow,    probab 

0.5  mm  above 

Pi,  (238). 

gastrocnemius  and  biceps  (375)-  Very  high  pressures, 
up  to  85  mm  Hg,  were  found  briefly  in  some  muscles 
during  powerful  contractions  (375),  and  values  lower 
than  average  were  common  during  anesthesia,  hemor- 
rhage, surgical  operations,  and  shock  (127-129). 

The  effects  of  venous  congestion,  and  consequent 
filtration,  on  directly  measured  P ,;  have  been  highly 
variable,  depending,  as  might  be  expected,  upon  the 


distensibility  of  the  tissue  studied.  McMaster  (239) 
found  pressures  up  to  32  cm  water  or  23  mm  Hg  in  the 
skin  of  the  mouse  (fig.  4.3),  and  up  to  23  cm  water  or 
1  7  mm  Hg  in  human  skin,  in  good  agreement  with 
the  calculated  interstitial  fluid  pressures  found  by 
Landis  &  Gibbon  (209)  in  the  congested  forearm 
(fig.  4.1).  Mayerson  &  Burch  (231)  found  much 
lower  maximum  pressures  in  subcutaneous  tissue  of 
man  during  venous  congestion  or  during  quiet  stand- 
ing, e.g.,  5.6  to  8.8  cm  water,  while  intramuscular 
pressure  rose  to  maxima  of  22  cm  water  in  nonfainting 
subjects  and  only  1  1  cm  water  in  fainting  subjects. 

In  isolated,  perfused  extremities  Hyman  (162) 
and  Pappenheimer  &  Soto-Rivera  (282)  found  little 
interference  with  prolonged  filtration,  and  hence  no 
evidence  of  increased  interstitial  fluid  pressure,  until 
manifest  edema  appeared.  Hinshaw  &  Day  (155), 
however,  made  direct  measurements  of  P,f  in  per- 
fused extremities  and  found  increases  from  control 
values  of  0.5  and  1.2  mm  Hg  to  8  and  15  mm  Hg 
when  1+  edema  was  present  and  to  10.5  and  24  mm 
Hg  when  2+  edema  had  appeared.  This  pressure 
was  enough  to  produce  measurable  collapse  of  blood 
vessels.  If  this  collapse  involves  the  small  veins  it  may 
well  distort  fluid  movement  through  changes  in  resist- 
ance to  flow,  as  well  as  through  direct  opposition  to 
capillary  blood  pressure  itself. 

Interstitial  fluid  pressures  up  to  25  mm  Hg  help 
explain  the  slowness  with  which  edema  forms  in 
normal  human  beings,  despite  the  high  capillary  pres- 


fig.  4.3.  Changes  of  interstitial  fluid 
pressure  in  the  skin  and  lower  leg  of 
mouse  during  and  after  venous  con- 
gestion of  40  mm  Hg.  Black  dots 
indicate  pressure  readings  which  yielded 
neither  inflow  into  the  skin  nor  back- 
flow  into  the  apparatus; i.e.,  the  pressure 
of  the  extravascular  fluid  was  accurately 
balanced.  Plus  signs  indicate  pressure 
readings  at  which  fluid  moved  into  the 
tissues;  i.e.,  pressure  in  the  apparatus 
was  above  interstitial  pressure.  Minus 
signs  show  that  backflow  occurred  into 
the  apparatus  and  that  the  plotted 
pressure  was  lower  than  that  of  the 
extravascular  fluid.  The  interstitial 
resistance  during  the  control  period  is 
shown  by  asterisks.  [From  McMaster 
(239)-] 


320 

30.0 

b 

d  260 

o 

c  22  0 

O  2 

-  18.5 

4) 

§  16.0 

<n  150 

g  130 

^  11.0 


80 
70 


42 


O 
C 

a"  ° 

1    *; 

- 

— 

•  •• 

- 

9 

++• 

— 

V 

- 

n 

- 

c 

•*+ 

- 

n 

e 
6 

0 

0 
40 

• 

•++ 

•  ••+ 

— 

-0 

0) 

••*- 

— 

0 

••++ 

_ 

z 

— 

-  • •  •++ 

— 

1 

* 

*  - 

1 

1 

Time  in 

1            _J 

minutes 

1                1 

1                1 

10 


20 


30 


40 


50 


60 


70 


80 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


98l 


sures  and  rapid  initial  filtration  found  in  the  lower 
extremities  during  sitting  or  quiet  standing.  How- 
ever, the  occurrence  of  edema  indicates,  of  itself, 
that  the  tissue  elements  are  slowly  separable,  and 
so  cannot  resist  higher  than  normal  interstitial  fluid 
pressures  indefinitely.  P,,  in  manifest  edema  of  man 
has  proved  to  be  highly  variable  though  frequently 
above  normal  limits.  During  accumulation  of  edema 
fluid  it  ranged  from  4  to  18  cm  water  in  one  series 
(336)  and  from  4  to  26  cm  water  in  others  (30,  340), 
returning  in  all  instances  toward  normal  or  below  as 
the  edema  fluid  disappeared.  Holland  &  Meyer  (158) 
reported  pressures  below  normal  in  edema,  but  their 
method  was  open  to  question  (238).  In  the  skin  of  the 
mouse  McMaster  (238)  found  that  P,,  was  little 
elevated  in  some  forms  of  experimental  edema  and 
greatly  elevated  in  others  with  the  further  anomaly 
that  in  some  instances  beefy  indurations  occurred  in 
which  paucity  of  freely  movable  fluid  permitted  only 
measurement  of  interstitial  resistance  to  slow  intro- 
duction of  fluid.  In  general,  both  clinically  and  experi- 
mentally, the  highest  interstitial  fluid  pressures  were 
found  in  skin  which  had  become  recently  and  rapidly 
edematous.  Slowly  developing  edema  often  occurred 
without  significant  elevations  of  P,/.  The  distensibility 
of  tissues  is  also  an  important  variable.  The  eyelids 
accommodated  rapidly  injected  fluid  most  easily, 
the  face  and  pretibial  areas  least  easily  (28).  In 
edema  P,j  was  found  to  be  lower,  1  to  8  cm  water  in 
the  former  and  higher,  2  to  1 4  cm  water,  in  the  latter. 

The  limited  and  transitory  resistance  of  tissues  to 
slowly  introduced  fluid  has  been  described  quantita- 
tively by  McMaster  (237).  At  pressures  ranging  from 
4.5  to  14  cm  water  the  entry  of  Locke-Ringer's 
solution  through  a  needle  into  a  tissue  was  slow  and 
also  intermittent.  Above  these  pressures,  which  he 
termed  the  "breaking  point,"  fluid  flowed  into  the 
tissue  continuously  and  at  much  higher  rates,  which 
increased  linearly  with  further  pressure  increments. 
Once  the  tissues  had  been  separated  by  this  "breaking 
pressure,"  high  rates  of  flow  were  observed  even  at 
low  pressures  (237).  The  resistance  which  the  normal 
interstitium  offers  to  flow  of  filtered  fluid  from 
capillaries  to  lymphatics  has  been  demonstrated  in 
different  fashion  recently  during  venous  congestion  in 
the  dog's  leg  by  Irisawa  &  Rushmer  (166).  When 
venous  pressure  was  elevated  to  between  65  and 
55  cm  water  for  270  min  the  pressure  in  the  draining 
lymphatic  vessels  rose  very  slow-ly  reaching,  after  90 
min,  plateaus  of  18  cm  water  or  less. 

The  positive  interstitial  fluid  pressures  so  far  de- 
scribed were  obtained  in  acute  experiments  of  rela- 


tively brief  duration.  There  is  some  evidence,  how- 
ever, that  interstitial  fluid  pressure  may  be  slightly 
but  definitely  negative  under  some  conditions  and  in 
more  prolonged  observations.  McMaster  (235,  236) 
observed  at  atmospheric  pressures  that  fluid  flowed 
intermittently  from  a  needle  into  cutaneous  tissue  at 
rates  up  to  .08  mm3  per  min.  This  suggests  a  negative 
interstitial  pressure,  but  the  subatmospheric  pressure 
required  to  arrest  inflow  was  not  determined.  Inflow 
of  fluid  was  increased  in  transitory  fashion  by  painful 
stimuli  and  by  the  intravenous  injection  of  hypertonic 
sucrose  solution.  These  changes  are  explicable  on  the 
basis  of  increased  absorption  by  capillaries  during 
vasoconstriction  and  decreased  capillary  blood  pres- 
sure in  the  first  instance,  and  by  temporary  hyper- 
tonicity  of  capillary  blood  in  the  second  instance. 
Outflow  of  fluid,  that  could  be  arrested  by  positive 
pressure  on  the  fluid  in  the  needle,  was  found  during 
venous  congestion  and  when  an  irritant  solution  pro- 
duced localized  edema.  These  outflows  may  be 
explained  respectively  by  heightened  capillary  pres- 
sure and  by  injury.  On  the  other  hand,  the  hyper- 
emia induced  by  heat,  either  directly  or  reflexly, 
increased  inflow  of  fluid  into  the  tissue,  despite  ob- 
served vasodilatation  and  presumable  elevation  of 
capillary  pressure.  It  is  possible  that  locally  increased 
arterial  pulsation  may,  by  pumping  action,  have 
evacuated  the  regional  lymphatics  and  so  increased 
inflow  mechanically  (283,  373). 

Very  recently  Guyton  el  al.  ( 130)  have  extended  the 
time  of  observation  to  hours  or  days.  Immediately 
after  insertion  of  needles,  and  in  agreement  with 
previous  studies,  slightly  positive  readings,  e.g.,  +  1 
to  +2  cm  water,  were  obtained.  During  the  next  4  or 
5  hours,  however,  the  balancing,  null-point  pressures 
decreased  gradually  to  —2  or  —3  cm  water  with  in- 
dications that  this  decline  was  still  continuing.  To  ex- 
tend readings  to  days  or  weeks,  perforated  plastic  cap- 
sules were  implanted  in  the  subcutaneous  tissue  and 
after  1  or  2  weeks  pressures  were  —3  to  —  14  cm  water 
in  the  abdominal  wall,  axillary  space,  scrotum,  muscle, 
and  quiet  limb.  They  decreased  slowly,  over  a  period 
of  minutes,  when  the  respective  parts  of  the  body  were 
moved.  Venous  congestion  changed  the  pressure  to 
positive  values,  but  not  until  edema  was  apparent. 
Protein  in  the  capsule  also  produced  positive  values. 

Chronic  experiments  of  this  type  tend  to  avoid  some 
of  the  artifacts,  e.g.,  acute  reactions  to  the  insertion  of 
a  needle  or  pipette,  that  may  influence  immediate 
measurements  of  interstitial  fluid  pressures.  On  the 
other  hand,  their  long  duration  introduces  the  possi- 
bility of  slower  reactions  to  foreign  bodies,  including 


982 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


local  changes  of  pressure  from  contraction  of  fibrin 
strands  or  of  newly  formed  connective  tissue.  It  may 
be,  too,  as  Guyton  suggests,  that  the  negative  pres- 
sures result  in  part  from  intermittent  evacuation  of 
lvmphatics  by  the  mechanical  pumping  which  ac- 
companies movement. 

Again,  the  kidney  has  proved  to  be  a  special  case. 
Gottschalk  (123)  found  interstitial  fluid  pressures 
averaging  +10  mm  Hg  in  rats,  guinea  pigs,  rabbits, 
and  cats,  and  +16  mm  Hg  in  dogs.  These  pressures 
rose  promptly  whenever  renal  venous  pressure  or 
ureteral  pressure  was  increased.  Inside  the  renal 
capsule  the  pressures  in  tubules,  peritubular  capil- 
laries, and  the  interstitium  changed  together,  and  by 
approximately  equal  increments,  without  evidence  of 
the  breaking  pressure  found  by  McMaster  (237)  in 
skin  and  subcutaneous  tissue.  It  seems  clear  that  inter- 
stitial fluid  pressure,  like  capillary  blood  pressure, 
must  be  considered  tissue  by  tissue. 


5.    PROTEINS  IN  EXTRACAPILLARY    FLUIDS;  U,f 

A.   Capillary  Filtrate  From  Limb 
Capillaries;  Protein  Content 

The  concentration  of  protein  in  the  fluid  which  is 
filtered  through  the  capillary  wall  is  an  important 
figure  for  several  reasons.  In  the  first  place,  it  is  the 
most  direct  measure  of  capillary  permeability  to 
protein,  and  hence  of  the  effectiveness  of  the  capillary 
wall  as  a  protein-retaining  membrane.  Second,  this 
original  capillary  filtrate  is  the  raw  material  from 
which  interstitial  fluid,  and  eventually  lymph,  are 
produced.  Third,  just  as  filtration  is  produced  by 
Pc  —  P,f,  so  absorption  is  produced  by  UPi  —  11,/, 
i.e.,  by  the  effective  osmotic  pressure  of  the  plasma 
proteins.  Fourth,  studies  on  the  volumes  and  protein 
concentrations  of  capillary  filtrates  in  various  tissues, 
and  under  various  conditions,  have  established  the 
existence  and  approximate  magnitude  of  a  physio- 
logically important  circulation  of  protein  from  capil- 
lary blood,  through  the  interstitial  fluid  compart- 
ment around  the  tissue  cells,  thence  to  the  lymphatics, 
lymph  nodes  and  via  the  lymphatic  trunks  back  to 
the  circulatory  system. 

By  1 898  large  regional  differences  in  the  concentra- 
tion of  protein  in  lymph  were  well  known,  and  corre- 
sponding differences  in  the  permeability  of  capillary 
walls  to  protein  were  postulated.  Thus  Starling  wrote: 
"The  lymph  in  the  limbs,  the  filtrate  through  the  im- 
permeable limb  capillaries,  contains  only  from  2  to  3 
per  cent  proteids;  that  from  the  intestines  contains 


from  4  to  6  per  cent  proteids;  while  that  from  the 
permeable  capillaries  of  the  liver  contains  from  6  to  8 
per  cent  proteids — in  fact  almost  as  much  as  the 
blood  plasma  itself"  (346).  Over  half  a  century  of 
work  on  lymph  has  confirmed  these  figures,  providing 
some  allowance  is  made  for  improved  analytic  meth- 
ods. In  the  most  recent  compilations  (79,  386)  the 
total  protein  in  lymph  from  legs  at  rest  ranged  from 
1.3  to  3.3  g  per  100  ml;  from  intestine,  2.8  to  4.0,  and 
from  liver,  4.4  to  6.1.  However,  the  interpretation  of 
these  figures,  particularly  with  respect  to  the  lymph 
from  the  limbs,  has  changed.  Starling  (346)  and  also 
Drinker  &  Yoffey  (79)  believed  that  the  protein  con- 
tent of  lymph  and  of  interstitial  fluid  must  be  identi- 
cal, a  view  that  now  is  not  tenable.  Hence  it  is  helpful 
to  consider  in  sequence  a)  the  protein  content  of  the 
original  capillary  filtrate,  b)  the  fate  of  this  protein  as 
the  capillaries  absorb  fluid,  c)  the  resulting  protein 
content  of  interstitial  fluid,  and,  finally,  d)  the  protein 
content  of  lymph.  For  reasons  already  described  in  the 
previous  section  it  has  so  far  proved  impossible  to 
collect  normal  capillary  filtrate  directly.  However, 
for  limb  capillaries  relatively  consistent  estimates  of 
the  protein  content  of  capillary  filtrate  have  been  ob- 
tained indirectly  a)  from  analyses  of  certain  edema 
fluids,  b)  from  studies  of  plasma  proteins  during 
venous  congestion,  and  c)  from  studies  of  lymph 
during  venous  congestion  and  during  chronic  plasma- 
pheresis. 

In  severe  hypoproteinemic  edemas,  e.g.,  nephrosis, 
malnutrition,  and  amyloid  disease,  absorption  is  pre- 
sumably abolished  because  of  the  lowered  osmotic 
pressure  of  the  plasma  proteins.  Hence,  as  previously 
reviewed  (207),  the  presence  in  these  edema  fluids  of 
0.09  to  0.40  per  cent  of  protein,  with  most  values 
between  0.1  and  0.27  per  cent,  provided  the  first 
estimates  of  the  protein  content  of  capillary  filtrate 
with  the  reservation,  however,  that  disease  may  have 
modified  the  permeability  of  the  capillary  walls.  In 
cardiac  failure,  edema  fluids  contained  from  o.  1  to 
1 .0  per  cent  protein  with  an  average  of  0.4  per  cent. 

In  normal  subjects,  elevating  venous  pressure  to 
25  mm  Hg  or  more,  i.e.,  to  exceed  the  osmotic  pres- 
sure of  the  plasma  proteins,  also  abolishes  absorption 
of  fluid.  Landis  et  al.  (211)  congested  the  forearms  of 
human  subjects  and  computed  from  the  hematocrit 
ratios  of  venous  blood  the  volume  of  filtrate  from 
each  100  ml  blood  plasma,  and  divided  this  into  the 
amount  of  protein  simultaneously  lost  from  the 
plasma  during  the  same  congestion.  The  errors 
involved  in  small  filtered  volumes,  and  even  in  tripli- 
cate protein  analyses,  prevented  any  conclusions  with 
congestions  of  40  mm  Hg;  but  at  60  mm  Hg  the  calcu- 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


983 


lated  average  protein  content  of  the  nitrate  was  about 
0.3  g  per  100  ml  of  filtrate,  though  with  very  wide 
variations.  At  a  venous  pressure  of  80  mm  Hg  the 
average  protein  content  of  capillary  filtrate  was  1.5  g 
per  100  ml,  but  this  was  attributed  to  leakage  because 
of  marked  vascular  distention  and  slowed  blood  flow 
with  possible  increased  permeability  from  local 
hypoxia.  Fractionation  studies  of  plasma  proteins 
before  and  after  congestion  indicated  qualitatively 
that  capillary  filtrate  contained  both  albumin  and 
globulin.  All  that  this  approach  could  provide,  how- 
ever, was  a  rough  order  of  magnitude  for  the  normal 
protein  content  of  capillary  filtrate.  It  indicated 
merely  that  it  was,  on  the  average,  considerably  less 
than  the  protein  content  of  lymph.  In  passing,  it 
should  be  emphasized  that  this  venous  congestion 
method  is  of  doubtful  utility  in  measuring  capillary 
permeability  to  protein  in  individual  patients  with 
various  diseases  (e.g.,  6,  32,  33)  because  normal 
values  vary  greatly  from  subject  to  subject  even 
under  carefully  controlled  conditions  (17,  211).  The 
reasons  for  this  variability  are  still  not  clear.  Probable 
factors  are  streamline  flow  in  veins  with  sampling 
errors  and,  in  addition,  analytic  errors  even  with 
triplicate  hematocrits  and  protein  analyses. 

Shortly  after  the  studies  of  Landis  et  al.  (211),  White 
et  al.  (379)  approached  the  problem  more  directly 
and  found  that  venous  congestion  of  the  dog's  leg 
reduced  the  concentration  of  protein  in  lymph  from 
0.77  per  cent  to  0.21  per  cent  while  the  rate  of  lymph 
production  increased  sixfold,  as  would  be  expected 
with  exclusion  of  absorption.  In  another  experiment 
lymph  protein  fell  during  venous  congestion  from 
1 .24  per  cent  to  0.78,  but  lymph  flow  failed  to  increase 
as  much  as  in  the  previous  experiment,  and  the  lymph 
contained  a  considerable  number  of  erythrocytes.  By 
still  another  method  Pappenheimer  &  Soto-Rivera 
(282)  found  in  the  perfused  hind  limbs  of  cats  that 
capillary  filtrate  contained  an  average  of  0.3  per  cent 
protein  with  values  of  0.2  and  0.4  per  cent  falling 
within  the  range  of  error. 

Thus,  in  mechanical,  i.e.,  noninflammatory, 
edemas  and  in  congestion  of  the  human  forearm,  the 
capillary  walls  were  found  to  be  approximately  95 
per  cent  effective  as  protein-retaining  membranes 
(207).  During  rapid  filtration  the  protein  concentra- 
tion of  capillary  filtrates  is  extremely  small  even  in  the 
more  permeable  capillaries  of  the  intestine  (168a).  It 
is  probable  that  under  these  conditions  the  protein 
concentration  is  reduced  by  molecular  sieving  as  dis- 
cussed in  sections  7D  and  10. 

Concerning  the  fate  of  the  protein  that  has  passed 
from  the  blood  stream  with  capillary  filtrate  into  the 


interstitial  fluid  compartment,  information  is  far  from 
complete  though  generally  in  favor  of  minimal  re- 
entry into  capillary  blood  despite  absorption  of  fluid. 
Lewis  (215)  injected  horse  serum  subcutaneously  in 
dogs  and  detected  it  in  thoracic  duct  lymph  within 
40  min.,  but  in  blood  only  after  3.5  hours.  Field  & 
Drinker  (97)  also  injected  horse  serum  subcutane- 
ously into  dogs  and  found,  by  a  precipitin  reaction, 
that  when  all  possible  lymphatics  were  blocked  no 
foreign  serum  could  be  detected  in  the  blood  stream 
in  periods  up  to  7  hours  after  injection.  They  con- 
cluded that  the  blood  capillaries  of  the  subcutaneous 
tissues  are  not  ordinarily  concerned  in  the  absorption 
of  protein.  Courtice  et  al.  (56,  58,  59)  injected  plasma 
protein  labeled  with  T-1824,  into  the  peritoneal 
cavity  and  recovered  nearly  all  of  it  in  lymph.  Jepson 
et  al.  (167)  followed  the  removal  from  skin  of  protein 
labeled  with  I131  and  in  normal  dogs  found  that  lymph 
exhibited  far  more  radioactivity  than  blood  plasma. 
From  similar  studies  in  man,  Hollander  et  al.  (159) 
concluded  that  protein  is  returned  to  the  circulation 
chiefly  or  exclusively  by  lymphatic  flow.  In  the  lung 
of  dogs,  however,  Drinker  et  al.  (78)  found  that  pro- 
tein injected  into  the  alveoli  appeared  first  in  blood 
though  very  slowly  and  in  small  amount. 

It  seems  likely  that  most  of  the  protein  in  capillary 
filtrate  normally  fails  to  enter  capillary  blood,  even 
during  absorption  of  fluid,  because  such  direct  return 
to  plasma  involves  the  movement  of  protein  molecules 
against  a  considerable  concentration  gradient.  More 
information  is  needed  because  the  mechanism  and 
completeness  of  this  exclusion  of  protein  during  ab- 
sorption of  fluid  is  still  far  from  clear,  particularly  in 
abnormal  states.  Thus,  Field  &  Drinker  (98)  found 
in  dogs  with  ligated  lymphatics  that  acute  plasma- 
pheresis increased  the  absorption  of  foreign  protein 
from  the  tissue  spaces.  Jepson  et  al.  (167)  found  this 
true  of  labeled  protein  in  lymphedema  also. 

B.   Interstitial  Fluid;  Protein  Content  and  II, 7 

The  protein  content  of  interstitial  fluid  under 
normal,  resting  conditions,  and  the  protein  osmotic 
pressure  of  that  fluid,  U,/,  have  also  been  determined 
so  far  only  by  indirect  methods.  The  protein  concen- 
tration in  capillary  filtrate  being  0.2  to  0.4  g  per  100 
ml,  and  that  in  lymph  from  a  resting  extremity  being 
1.3  to  3.3  g  per  100  ml  it  follows  that  the  protein 
content  of  interstitial  fluid  under  resting  conditions 
lies  between  these  figures  and  is  not  uniform.  Depend- 
ing upon  localized  filtration  or  absorption,  it  can 
range  from  protein-poor  capillary  filtrate,  just  pro- 
duced,  to  an  interstitial  fluid  which  is  protein  rich 


984 


HANDBOOK    OF    I'll YSIOl  (  ><  ,Y 


CIRCULATION    II 


at  the  end  of  absorption  and  about  to  enter  the 
lymphatic  system.  Pappenheimer  &  Soto-Rivera 
(282)  have  pointed  out  that  the  diffusion  coefficients 
of  the  plasma  proteins  are  such  that  in  the  absence  of 
flow  or  mechanical  movement  relatively  large  con- 
centration gradients  are  possible  in  the  interstitial 
fluid  compartment.  "'Even  if  all  filtration  and  absorp- 
tion processes  were  stopped,  some  20  minutes  would  be 
required  to  reach  90  per  cent  equalization  of  protein 
concentration  over  a  distance  of  50  microns"  (282). 
In  perfused  limbs  of  cats  the  average  protein  osmotic 
pressure  of  interstitial  fluid  was  1.4  ±  0.4  mm  Hg, 
corresponding  to  an  average  protein  concentration  of 
0.7  ±  0.2  g  per  100  ml. 

The  average  concentration  of  proteins  in  inter- 
stitial fluid  can  also  be  estimated  by  a  totally  different 
method.  The  dilution  of  labeled  plasma  albumins  and 
globulins  after  intravenous  injection  has  shown  that 
the  total  mass  of  exchangeable  plasma  protein  is 
about  twice  the  mass  of  plasma  proteins  in  the  blood 
stream  itself  (103,  117).  Sterling  (352)  found  in  man 
that  the  average  intravascular  albumin  averaged 
117  g,  the  extracellular  albumin,  147  g.  Assuming 
extravascular  fluid  volume  to  be  the  usual  15  per 
cent  of  body  weight,  the  average  albumin  concentra- 
tion in  extravascular  fluid  was  calculated  to  be  1 .4  g 
per  100  ml.  By  using  Myant's  figures  (259)  to  estimate 
globulin  content  in  addition,  the  total  average  protein 
concentration  for  extravascular  fluid  becomes  ap- 
proximately 2.1  g  per  100  ml,  which  corresponds  to 
an  average  protein  osmotic  pressure,  or  LI,/,  of  5 
mm  Hg.  Similar  calculations  applied  to  the  data  of 
Wasserman  et  al.  (368,  372)  yield  slightly  lower  figures, 
because  in  the  dog  the  fraction  of  albumin  and 
globulin  found  normally  in  the  interstitial  fluid  and 
lymph  appears  to  be  rather  less  than  that  found  by- 
Sterling  for  albumin  in  man.  Both  estimates  are 
larger  than  those  given  by  Pappenheimer  and  Soto- 
Rivera  (282)  for  the  perfused  leg  of  dogs  as  expected, 
because  the  determinations  made  by  the  perfusion 
method  were  restricted  to  the  fluid  in  the  immediate 
vicinity  of  the  capillaries  and  were  limited  to  the 
limb,  both  factors  tending  to  give  lower  values.  On 
the  other  hand,  calculations  based  upon  exchangeable 
protein  mass  include  protein  in  the  whole  of  the  inter- 
stitial fluid  plus  that  in  the  lymphatics.  In  addition, 
they  include  the  extravascular  fluids  of  the  liver  and 
intestines  where  lymph  is  known  to  contain  large 
amounts  of  protein.  Both  factors  tend  to  make  the 
figure  for  average  LT,y  greater  for  the  whole  body  than 
for  the  limb  alone,  but  still  not  as  high  as  that  prob- 
ably present  in  the  liver  and  intestines. 


With  this  qualification  it  can  be  concluded  that 
LT,,  lies  between  0.1  and  5.0  mm  Hg,  with  the  lower 
value  applying  to  capillary  filtrate  in  the  limbs  and 
the  higher  including  the  total  interstitial  fluid  of  liver 
and  intestines,  as  well  as  lymph.  This  can  be  com- 
pared to  P,,  which  ranges  from  1  to  g  mm  Hg,  with 
the  lower  values  in  subcutaneous  tissues  and  skin,  the 
higher  values  in  muscle.  The  formulation  given  in 
equation  1 . 1  can  now,  with  certain  license  for  pur- 
poses of  summary,  be  provided  with  very  approxi- 
mate values  in  mm  Hg  for  man  at  heart  level  and 
under    resting    conditions,    viz. : 


FM.      - 
+  -  filtration 


k(P 
c 

32 


pi 


p„  *v 


25      I  to  9      0.1  to  5 


-  -  absorption        15 

With  equal  or  greater  license  an  average  limb 
capillary  and  lymphatic  can  be  drawn,  as  in  figure  5. 1 , 
to  summarize  the  filtration-absorption  process  as  it 
may  operate  to  produce  a  small  volume  of  lymph 
with  relatively  high  protein  content.  Table  5. 1 
provides  a  schematic  summary  of  the  changes  that 
occur  in  the  fluids  of  the  limb  during  several  of  the 
more  thoroughly  studied  functional  states.  Ranges  of 
determined  values  are  given  whenever  possible. 
Figures  in  parentheses  are  values  that  can  reasonably 
be  inferred  on  the  basis  of  available  evidence.  They 
are  given  merely  to  show  the  probable  direction  of 
presumed  change  and  its  order  of  magnitude.  In 
some  instances  even  inferences  are  impossible,  as 
indicated  by  a  question  mark.  The  columns  are 
given  letters  to  correspond  with  the  schematic 
capillary  in  figure  5.1. 

Beginning  at  the  top  of  the  table  with  control  con- 
ditions and  resting  blood  flow,  the  composition  of 
capillary  filtrate  has  not  been  determined,  but  its 
protein  content  may  be  inferred  to  be  0.2  to  0.4  g  per 
100  ml  from  the  composition  of  capillary  filtrate  pro- 
duced during  mild  venous  congestion  in  man  and 
dog.  The  average  protein  content  of  interstitial  fluid 
ranges  from  0.7  g  per  100  ml  in  perfusion  studies 
(281)  to  2.1  g  per  100  ml  by  calculation  from  extra- 
vascular protein  mass.  Lymph  protein  content  range 
from  1.3  to  3.3  g  per  100  ml  (386)  and  the  volume 
flow  is  small,  requiring  massage  or  passive  movement 
for  collection  of  samples  (76)  as  would  be  expected 
with  the  absorption  that  occurs  under  resting  condi- 
tions. 

Conversely,  in  venous  congestion  the  protein  con- 
centration in  capillary  filtrate  is  known  but  the 
average    and    highest    concentrations    in    interstitial 


ARTERIOLE 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 

VENULE 


985 


30h 

TTpl 

PRESSURE 
MM  20 

HG 

10 


(a) 


P,         Capillary  filtrate 


(b) 

Average 
concentration 


(c) 

Highest 

concentration 


_"pl__ 


13  to  3.3 


(d) 


LYMPH 


Protein  concentrations  given  in  g  /I00  ml    fluid 

fig.   5.1.   Schematic  diagram  of  "an  average  limb  capillary"  to  indicate  approximate  protein 
concentrations  in  capillary  nitrate,  interstitial  fluid,  and  lymph. 


table  5.1.  Protein  Concentrations  in  Extravascular 
Fluids  of  the  Limb 


Interstit 

al  Fluid 

Capillary 
Filtrate 

Condition 

Avg 

Highest 

Lymph 
d 

cone, 
b 

cone, 
c 

g/lOO  ml 

g/100  ml 

g/100  ml 

g/100  ml 

Normal, 

(0.2-O.4) 

0.7-2.1 

(1-3-3-3) 

1-3-3-3 

resting 

Venous  con- 

O.2-O.4 

(0.2-0.4) 

(0.2-0.8) 

0.2-0.8 

gestion 

Hypopro- 

(0.OI-O.4) 

0 .  04-0 . 5 

(0.01-0.6) 

0.01-0.6 

teinemia 

Burns 

(3-5-5-o) 

(3-5-5-°) 

(3-5-5-o) 

3-5-5-° 

Muscular 

? 

■> 

(0-5-I-5) 

o-5-!-5 

activity 

Lymphedema 

? 

1-9-3-5 

? 

2-3-3-4 

fluid  have  to  be  inferred  from  studies  on  lymph.  This 
inference  is  valid  after  newly  formed  capillary  filtrate 
has  washed  out  of  the  interstitial  compartment  the 
fluid  which  was  present  before  congestion  and  while 
the  interstitial  fluid  compartment  is  being  constantly 
irrigated  by  newly  formed  capillary  filtrate  with  no 
absorption  possible. 

Hypoproteinemia  in  man,  as  mentioned  above, 
produces  edema  fluids  with  protein  concentrations 
ranging  from  0.09  to  0.40  per  cent.  Weech  et  al.  (374) 
used  chronic  plasmapheresis  to  produce  severe  edema 
of  this  type  in  dogs.  Edema  fluid  contained  between 
0.04  and  0.4  g  protein  per  100  ml  with  all  but  a  few 
values  below  0.25.  Lymph  protein  in  the  same  ani- 


mals ranged  from  0.01  to  0.6,  with  almost  all  values 
below  0.3.  In  some  instances  the  protein  content  of 
edema  fluid  was  slightly  higher  than  that  of  lymph 
collected  simultaneously,  indicating  again  the  possi- 
bility of  imperfect  mixing  of  the  interstitial  fluid  com- 
partment and,  consequently,  some  sequestration  of 
edema  fluid.  Capillary  filtrate,  however,  has  not 
been  studied  and  so  its  protein  content  can  only  be 
inferred.  Lessened  permeability  to  protein  has  been 
suggested  (374)  but  not  proved  so  far.  Sieving  of 
protein  molecules  may  be  involved  (see  section  10). 

Massive  injury  in  burns,  produced  by  immersing 
the  extremities  of  anesthetized  dogs  in  hot  water 
(48,  99,  100,  119,  120)  increases  lymph  flow  con- 
spicuously and  increases  the  protein  in  lymph  to 
between  3.5  and  5  g  per  100  ml.  In  view  of  the  known 
effects  of  injury  on  capillary  permeability  to  protein 
(200)  it  is  safe  to  infer  that  protein  concentrations  in 
capillary  filtrate  and  interstitial  fluid  are  equally 
high;  particularly  because  lymph  flow  is  rapid  and 
the  interstitial  compartment  is  well  irrigated  by 
capillary  filtrate. 

For  contracting  muscle,  information  is  still  meager. 
White  et  al.  (379)  found  in  dogs  that  while  the  flow  of 
lymph  was  much  increased  by  exercise,  its  protein 
content  declined  to  between  0.5  and  1.5  per  cent, 
average  1 .0,  and  then  remained  constant  as  long  as 
exercise  continued.  The  elevations  of  capillary  blood 
pressure  and  of  interstitial  fluid  pressure  during  exer- 
cise have  already  been  described  in  sections  2D  and  4. 
Inferences  concerning  capillary  filtrate  and  inter- 
stitial fluid   are   unjustified   because  the  lymph  col- 


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HANDBOOK    OF    1'HYSIOLOGY 


CIRCULATION    II 


lected  during  exercise  (379)  contains  more  erythro- 
cytes than  control  lymph  does.  This  finding  suggests 
mechanical  rupture  of  some  capillaries,  probably 
when  compressed  between  adjacent  contracting 
fibers.  If  this  occurs,  undetermined  amounts  of  whole 
plasma  may  accompany  the  erythrocytes  and  con- 
tribute to  the  protein  found  in  lymph.  The  possibility 
of  osmotic  shifts  of  fluid  produced  by  small  molecules, 
e.g.,  lactic  acid,  from  contracting  muscle  has  also 
been    proposed    (207). 

Finally,  in  lymphedema,  the  effect  of  obliterating 
lymph  flow  by  obstructive  fibrosis  of  the  larger 
lymphatic  vessels  (77)  is  an  accumulation  of  extra- 
vascular  fluid  with  abnormally  high  concentrations 
of  protein  in  both  the  edema  fluid  as  well  as  in  the 
stagnant  lymph.  The  protein  content  of  capillary 
filtrate  is  unknown  and  may  be  quite  variable  be- 
cause of  the  tendency  in  lymph  stasis  toward  inter- 
mittent infection  and  consequent  injury  to  capillaries 
in  severely  lymphedematous  extremities  (77).  It  is 
clear  that  more  information  is  needed  in  all  these 
conditions. 

C.   Circulation  of  Interstitial  Fluid; 
Circulation  of  Protein 

It  has  been  customary  in  the  past  to  say  that  capil- 
laries '"leak"  protein  as  if  this  were  a  useless  defect  of 
the  capillary  wall.  However,  many  lines  of  evidence 
indicate  that  passage  of  plasma  proteins  through  the 
capillary  wall  is  quite  as  important  for  cellular 
metabolism  and  for  defense  against  infection  as  the 
retention  of  plasma  protein  is  for  normal  fluid  balance. 
Whipple  &  Madden  (376)  showed  that  the  circulating 
plasma  proteins  within  the  blood  vessels  form  a 
"medium  of  exchange"  which  is  an  important  part 
of  a  larger  nutritional  pool.  For  example,  dogs  were 
maintained  in  full  nitrogen  equilibrium  by  intra- 
venous administration  of  dog  plasma  only.  Drinker 
(75)  called  attention  to  the  benefits  derived,  during 
infection,  from  the  passage  of  globulins,  including 
antibodies,  through  the  capillary  wall  into  the  inter- 
stitial fluid  around  the  cells  and  thence  to  the  lym- 
phatics. Still  more  recently  several  reviews  have  de- 
scribed the  binding  of  hormones  (63,  304),  fatty 
acids  (iog),  and  drugs  (121)  to  plasma  proteins.  It  is 
significant,  too,  that  the  greatest  passage  of  protein 
through  the  capillary  walls  occurs  in  the  liver,  where 
metabolic  requirements  are  greatest  and  most  varied, 
and  where  albumin  is  synthesized. 

Two  paracapillary  circulations  (i.e.,  beside  and 
beyond  the  capillaries)  can  be  identified.  The  first  is  a 


filtration-absorption  circulation  which  includes  the 
total  capillary  filtrate,  the  total  interstitial  fluid,  and 
finally  that  part  of  the  interstitial  fluid  which  passes 
back  into  the  capillary  blood  by  the  process  of  absorp- 
tion. The  second  paracapillary  circulation  begins  also 
with  capillary  filtrate  but  then  reduces  to  the  unab- 
sorbed  fraction  of  interstitial  fluid  and  its  contained 
protein,  both  of  which,  after  bathing  the  tissue  cells, 
enter  the  finest  lymphatic  capillaries  and  are  con- 
ducted, via  the  major  lymphatic  trunks,  back  to 
venous  blood  (see  Chapter  30).  Enough  information 
is  available  now  to  justify  approximate  calculations  of 
the  magnitudes  of  these  two  circulations.  Because  both 
depend  upon  the  total  volume  of  capillary  filtrate 
this  figure  can  be  considered  first. 

Continued  blood  flow  through  the  resistance  of  the 
capillaries  requires,  even  at  resting  flow  rates,  a  sig- 
nificant pressure  gradient  in  the  capillary  bed  itself. 
As  indicated  in  table  2.1  and  figure  2.3  this  average 
gradient  lies  above  the  osmotic  pressure  of  the  plasma 
proteins  in  the  first  half  of  the  capillary  network.  It 
follows  that,  secondary  to  the  basal  pressure  head 
which  is  necessary  for  this  resting  blood  flow,  there  is 
necessarily  a  "basal  filtration"  of  fluid  under  resting 
conditions.  Most  of  this  filtrate  is  absorbed  and  the 
low  rates  of  lymph  production  in  resting  extremities 
can  give  no  indication  of  the  rate  at  which  the  original 
capillary  filtrate  is  formed.  A  simple  calculation  sug- 
gests, however,  that  in  the  resting  animal  capillary 
filtrate  is  continuously  produced  at  an  average  rate 
which  is  at  least  five  to  ten  times  greater  than  average 
resting    lymph   flow. 

Landis  &  Gibbon  (209)  found  in  the  human  fore- 
arm at  34  to  35  C  that  elevating  venous  pressure  by 
1  cm  H20  increased  filtrate  by  .0033  ml  per  100  ml 
forearm  tissue  per  min.  Assuming  that  80  per  cent  of 
a  rise  in  venous  pressure  is  transmitted  to  the  capil- 
laries, this  becomes  .0040  ml  per  100  ml  forearm 
tissue  per  min  for  a  1  cm  water  increase  of  capillary 
pressure.  From  capillary  pressure  measurements  in 
human  skin,  mean  resting  filtering  pressure  is  (32  - 
25  mm  Hg)/2  or  3.5  mm  Hg,  or  4.8  cm  H2O.  Assum- 
ing, for  the  purpose  of  obtaining  a  minimum  figure, 
that  the  unit  increment  of  filtration  given  above 
applies  to  the  whole  body,  the  total  resting  capillary 
filtrate  for  a  75-kg  human  being  is  approximately  20 
liters  per  24  hours.  To  the  extent  that  filtration 
coefficients  in  liver  and  intestine  may  be  greater  than 
in  the  forearm  the  volume  of  filtrate  formed  per  24 
hours  will  be  somewhat  larger  still. 

For  total  lymph  flow  in  man  the  most  helpful  data 
are   those  of  Crandall  et  al.    (60)   obtained  from  a 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


987 


patient  with  a  freely  draining  fistula  of  the  thoracic 
duct.  Average  basal  lymph  flow  during  fasting  was 
0.93  ml  per  min.  After  a  heavy  meal,  flow  from  the 
thoracic  duct  reached  a  peak  volume  of  3.9  ml  per 
min  and  remained  above  1 .0  ml  per  min  for  several 
hours.  If  allowance  is  made  for  the  additional  and 
uncollected  lymph  from  the  right  lymphatic  duct  by 
adding  an  increment  of  one-fourth  to  one-third  of 
fasting  thoracic  duct  flow,  then  total  lymph  flow  in 
fasting  man  at  rest  is  approximately  2  liters  per  24 
hours.  With  allowance  made  for  the  effects  of  meals 
and  activity,  it  probably  approaches  3  or  4  liters  per 
24  hours. 

Figure  5.2  shows  schematically  the  volumes  of 
these  several  '"circulations"  in  terms  of  exchanges  in 
24  hours.  With  a  cardiac  output  of  6.0  liters  per  min 
the  first  circulation,  that  of  blood  itself,  amounts  to 
about  8000  liters  per  24  hours.  From  this  volume, 
filtration  in  the  capillary  bed  removes  a  minimum  of 
20  liters  per  24  hours,  a  "filtration  fraction"  of  0.25 
per  cent.  This  capillary  filtrate  begins  the  second 
circulation,  that  of  interstitial  fluid  (fig.  5.2,  F  to  IF 
to  A)  with  capillary  absorption,  during  rest,  of  80  to 
90  per  cent  or  16  to  18  liters,  of  the  original  capillary 


CARDIAC   OUTPUT 
8400  L   per  24  HOURS 


DIFFUSION   EXCHANGE 
80,000  L 
20,000g  glucose  (400 utilized) 


LYMPH 
2  to  4  L 


FILTRATION  -   ABSORPTION 


LYMPH   FLOW 


FLUID  20  L+      -        16  to  18  L       =C=        2  to  4  L 

PROTEIN    80  to  200g       -         5  (?)  O       75  to  195  g 

Glucose  20  g  (see  diffusion  exchange) 

fig.  5.2.  Diagram  of  the  ''several  circulations"  with  ap- 
proximate magnitudes  of  each.  For  explanation  of  diffusion 
exchanges  see  section  9.  For  explanation  of  figures  relating  to 
filtration,  absorption,  and  lymph  flow  see  text  of  this  section. 


filtrate.  The  remaining  2  to  4  liters,  including  the 
unabsorbed  protein  of  the  original  capillary  filtrate, 
then  produces  the  third  circulation,  that  of  proteins  in 
lymph. 

The  potential  magnitude  of  this  protein  circulation 
can  be  estimated  from  the  observations  of  Wasser- 
man  &  Mayerson  (370-372)  on  the  rates  at  which 
intravenously  injected  labeled  albumin  and  globulin 
disappeared  from  plasma  and  appeared  in  thoracic 
duct  lymph.  The  faster  component  of  these  two- 
phase  disappearance  curves  indicated  a  steady  disap- 
pearance of  plasma  albumin  from  plasma,  and 
corresponding  appearance  in  lymph,  at  the  rate  of 
approximately  0.1  per  cent  of  the  total  circulating 
plasma  protein  per  minute.  Allowing  for  the  slightly 
slower  disappearance  rate  of  globulin  (372),  this 
amounts  to  the  passage  through  the  capillary  wall  in 
24  hours  of  a  mass  of  plasma  protein  approximately 
equal  to  that  in  the  circulating  blood  itself.  This 
includes  passage  from  the  more  permeable  hepatic 
and  intestinal  capillaries  as  well  as  from  the  less 
permeable  limb  capillaries.  Courtice  (49;  386,  p.  87) 
collected  lymph  simultaneously  from  the  thoracic, 
right  lymphatic,  cervical,  foreleg,  and  hind  leg  ducts. 
Expressed  as  percentage  of  total  intravascular  protein, 
the  lymph  collected  from  these  several  sources  con- 
tained a  24-hour  protein  mass  equaling,  respectively, 
47.5,  3.6,  2.4,  2.2,  and  1.8  or,  in  total,  57.5  per  cent 
of  the  intravascular  protein  mass.  Again  this  rate  of 
passage  is  a  basal  rate  found  in  resting  animals.  Intra- 
venous infusions  increased  the  rate  of  protein  passage 
severalfold  (371)  and  increased  lymph  flow  from  the 
thoracic  duct  correspondingly  (180),  indicating  that 
the  interstitial  circulation  of  both  protein  and  fluid 
can  be  very  rapid  indeed.  Studies  during  muscular 
exercise  would  be  most  interesting,  but  have  not  been 
done  so  far. 

For  man  the  magnitude  of  this  protein  circulation 
can  be  estimated  in  two  ways.  First,  the  obligatory 
capillary  filtrate  of  20  liters  per  24  hours,  containing 
0.2  to  0.4  g  per  cent  protein,  would  carry  with  it  a 
minimum  of  40  to  80  g  of  protein  per  24  hours.  This 
figure  is  unquestionably  too  low  because  it  does  not 
include  the  higher  protein  content  of  capillary  fil- 
trates from  liver  and  intestine.  Second,  collections  of 
thoracic  duct  lymph  with  analyses  of  protein  content 
have  been  carried  out  in  two  patients  with  accidental 
fistulae  (57,  60)  and  in  patients  with  terminal  neo- 
plasm (15).  As  mentioned  above,  the  data  of  Crandall 
ct  al.  (60)  justify  an  estimate  of  2  to  4  liters  of  lymph 
per  24  hours.  Since  the  protein  content  of  this  lymph 
ranged  from  3.19  to  4.88  g  per  100  ml  the  circulation 


HANDBOOK    OF    PHYSIOloc.l 


CIRCULATION    II 


of  protein  can  range  from  60  to  200  g  per  24  hours, 
depending  upon  conditions.  Hence  the  third,  or 
protein,  circulation  passing  from  capillaries  to  inter- 
stitial fluid  to  lymph  (fig.  5.2,  F-IF-L)  involves  daily 
a  volume  of  fluid  which  approaches  the  volume  of 
circulating  plasma  and  a  mass  of  protein  equivalent 
to  a  quarter  or  more  of  the  mass  of  the  circulating 
plasma  proteins.  Cope  &  Litwin  (45a)  have  recently 
emphasized  the  compensatory  importance,  during  re- 
covery from  hemorrhage,  of  this  continuing  flow  of 
lymph  and  its  contained  protein  from  the  interstitial 
spaces  into  the  blood  stream. 


6.     FILTRATION    COEFFICIENTS    OF 

CAPILLARIES    {kc)  J    AND    OF    TISSUES    (kt) 


A.  Nc 


■jl  Capillaries 


Measurements  of  fluid  movement  through  the 
capillary  wall  as  a  function  of  hydrostatic  and  osmotic 
pressures  have  been  made  in  single  capillaries  of 
amphibian  mesenteries  (23,  200,  201,  383);  in  the 
human  forearm  (24,  188,  209),  in  the  perfused  ex- 
tremities of  frogs  (61,  74);  of  rats  (162,  302);  of 
cats  and  dogs  (281,  282);  and  in  lung  (132). 

The  primary  measurements  necessary  to  test  the 
validity  of  the  Starling  hypothesis  were  first  obtained 
by  micromanipulation  techniques  in  single  capillaries 
of  the  frog's  mesentery  (200,  201)  with  results  shown 


TTp|  in  vivo=  e.6  to  II  7cm  H2O 
higher  in  summer 
frogs       lower   in 
winter  frogs 
(hypoproteinemia) 


E 

ST  .04 


5-°2 

E 

o    04 


.06 
0 


ABSORPTION 


CAPILLARY    PRESSURE    CM  WATER 


,.."* Slope  -kc  = 

filtration  coefficient 
.0056  juVsec/ju2/  cm  H20 
A(Pc-TTpl) 


20       25       30 


fig.  6. 1 .  Relation  between  fluid  movement  through  walls 
of  single  capillaries  of  frog's  mesentery  and  capillary  blood 
pressure  as  determined  by  micromanipulation  methods.  Slope 
of  line  indicates  filtration  coefficient  \kr)  in  n3  of  fluid  filtered 
(or  absorbed) /sec /m2  of  capillary  wall/cm  H2O  capillary 
pressure.  Intercept  of  line  with  zero  axis  measures  effective 
osmotic  pressure  (in  vivo)  of  the  plasma  protein.  [From  Landis 
(200).] 


in  figure  t>.  1  .  When  capillary  pressure  exceeded  12  cm 
water,  fluid  passed  from  the  plasma  inside  the  capil- 
lary to  outside  the  capillary  (filtration).  When  capil- 
lary pressure  was  less  than  10  cm  water,  fluid  was 
withdrawn  from  the  e.xtravascular  space  into  the 
capillary  (absorption).  At  capillary  pressures  be- 
tween 9  and  1 3  cm  water  there  were  many  instances 
in  which  little  or  no  movement  of  fluid  occurred.  In 
this  range  hydrostatic  pressure  was  apparently 
balanced  by  the  osmotic  pressure  of  the  plasma  pro- 
teins. This  was  taken  to  be  indirect  evidence  that  the 
walls  of  the  mesenteric  capillaries  of  the  frog  were 
relatively  impermeable  to  protein  and  that,  at  least 
in  these  vessels,  9  to  13  cm  water  (average  1 1.5  cm) 
represented  the  effective  osmotic  pressure  of  the 
plasma   proteins  in  vivo. 

In  addition  to  supporting  the  filtration-absorption 
hypothesis  of  Starling  these  results  also  provided  the 
first  measure  of  the  permeability  of  the  capillary  wall 
to  isotonic  fluid.  When  plotted  against  capillary  pres- 
sure the  rates  of  fluid  movement  were  directly  pro- 
portional to  the  difference  between  the  capillary 
pressure  and  the  effective  osmotic  pressure  of  the 
plasma  proteins  measured  against  the  capillary  wall 
as  a  filter.  The  proportionality  constant  was  com- 
puted from  the  slope  of  the  straight  line  drawn  through 
the  observed  points  by  the  method  oi  least  squares. 
This  was  originally  called  a  "filtration  constant," 
but  for  reasons  given  below  the  term  "filtration 
coefficient"  is  preferable  (276).  For  normal  mesenteric 
capillaries  of  the  frog  the  filtration  coefficient,  kc, 
derived  from  70  observations,  averaged  .0056  /j:l  of 
fluid  per  sec  per  fi2  of  capillary  wall  per  cm  water 
difference  between  capillary  pressure  and  the  osmotic 
pressure  of  the  plasma  proteins.  Wind  (383)  found 
great  variation  from  capillary  to  capillary  in  the 
toad's  mesentery.  Collectively,  these  figures  provide  a 
slightly  lower  average  figure,  about  .0032,  during 
the  first  1 5  min  after  the  mesentery  was  exposed  and 
a  somewhat  higher  average  figure,  .0084,  thereafter. 
Deviations  from  these  normal  filtration  coefficients 
have  proved  helpful,  as  will  be  described  below,  in 
measuring  the  effects  of  temperature  (23),  oxygen 
lack  (201),  and  injury  (200)  on  the  filtration-absorp- 
tion mechanism  in  the  frog's  mesenteric  capillaries. 

To  test  the  validity  of  the  Starling  hypothesis  in 
another  tissue,  and  particularly  in  man,  Krogh  et  al. 
(188)  studied  the  movement  of  fluid  through  the 
capillary  walls  of  forearm  tissue  in  a  pressure  plethys- 
mograph,  by  means  of  which  the  blood  vessels  could 
be  collapsed  in  order  to  measure  small  increments  of 
tissue  volume  produced  by  filtered  fluid.  As  shown  in 


I   VII  \\(,1      ill     SUBSTANCES     I  Hid  1 1   '.II     CAPILLAR"*      WALLS 


989 


figure  6.2  net  filtration  of  fluid  increased  linearly 
with  venous  pressures  above  10  cm  water.  A  unit 
rise  of  venous  pressure  (1  cm  water)  increased  the 
filtration  rate  by  .0023  ml  per  min  per  100  ml  of 
forearm  tissue  when  congestion  periods  of  30  min 
were  used  (188)  and  by  0033  ml  per  min  per  100  ml 
forearm  tissue  when  congestion  periods  of  10  min  were 
used  (209).  As  described  in  section  4,  this  difference 
was  regarded  as  the  result  of  increasing  interstitial 
fluid  pressure  as  the  volume  of  filtrate  in  the  tissues 
increased. 

Brown  et  al.  (22)  have  more  recently  studied,  by  a 
totally  different  method,  the  filtration  coefficient  for 
the  whole  body  of  man  (except  the  thorax )  during  a 
systemic  rise  of  venous  pressure  produced  by  repeated 
Valsalva  maneuvers.  Though  results  varied  slightly, 
depending  on  the  method  of  calculation,  representa- 
tive filtration  coefficients  for  the  whole  body  were 
in  the  first  9.5  min,  .0036  ml  per  min  per  100  g  body 
wt  per  cm  rise  of  venous  pressure  and,  for  a  total 
of  29.5  min,  .0014.  These  values  can  be  compared  to 
.0033  and  .0023  for  the  forearm  alone.  The  two  sets 


.200 


.160 


080 


.040 


-020* 


fig.  6.2.  Rates  of  filtration  measured  by  pressure  plethys- 
mograph  in  human  forearm  during  graded  elevation  of  venous 
pressure  for  10-min  periods.  Plethysmograph  temperature, 
34-35  C.  The  slope  of  the  line  corresponds  to  a  nitration  co- 
efficient (ki)  of  .0033  ml/min/100  ml  forearm  tissue  per  cm 
H2O  increase  of  venous  pressure.  [From  Landis  &  Gibbon 
(209).] 


of  figures  are  similar,  presumably  because  the  collec- 
tive capillary  beds  of  muscle  and  subcutaneous  tissue 
are  large  compared  to  the  smaller,  though  more 
permeable,  capillary  beds  of  liver  and  intestine.  A 
similar  relationship  has  been  found  with  respect  to 
diffusion  (see  section  8).  The  '"whole  body"  filtration 
rate  appears  to  decline  more  rapidly  than  that  of  the 
forearm,  owing  probably  to  more  rapid  return  of 
capillary  filtrate  by  way  of  the  lymphatics,  particu- 
larly during  the  vigorous  respiratory  movements 
required  for  repeated,   brief  Valsalva  maneuvers. 

Landis  &  Hortenstine  (210)  calculated  from  the 
forearm  filtration  figures  (188,  209)  that  a  rise  of 
venous  pressure,  throughout  the  body,  to  10  cm 
water  above  normal  might,  in  a  man  weighing  75  kg, 
filter  as  much  as  250  ml  of  fluid  from  the  plasma  in  the 
first  10  min.  This  has  proved  a  fairly  good  estimate. 
Brown  et  al.  (22)  observed  the  filtration  of  333  ml 
to  501  ml  when  systemic  venous  pressure  was  ele- 
vated by  20  cm  for  9.5  min.  Over  29.5  min  an 
increase  of  venous  pressure  by  20  cm  water  filtered 
460,  41  7,  and  687  ml  of  fluid,  calculated  to  contain 
between  1  and  2  g  of  protein  per  100  ml  owing,  pre- 
sumably, in  part  to  the  very  high  protein  content 
of  capillary  filtrate  from  hepatic  and  intestinal 
capillaries. 

The  pressure  plethysmograph  was  used  by  Krogh 
et  al.  (188)  also  to  test  the  effect  on  filtration  rate 
of  changing  the  osmotic  pressure  of  the  plasma 
proteins.  Filtration  rates  at  given  venous  pressures 
were  measured  with  the  subject  recumbent  and  then 
at  the  same  venous  pressures  while  the  subject  stood 
quietly  on  a  tilt  table  for  30  min  or  more.  Quiet 
standing  increased  the  concentration  of  the  circulating 
plasma  proteins  by  0.6  to  1.1  g  per  100  ml  and  the 
protein  osmotic  pressure  of  plasma  by  33  to  8.7  cm 
water.  At  these  higher  protein  osmotic  pressures  the 
rate  of  filtration  produced  by  a  given  venous  pressure 
was  always  lower.  A  unit  rise  of  protein  osmotic 
pressure  (1  cm  water)  was  accompanied  by  a  reduc- 
tion of  filtration  rate  ranging  from  .0027  to  .0045  ml 
per  min  per  100  ml  forearm  tissue.  These  values  were 
quantitatively  similar  to  the  effect  produced  by 
elevating  venous  pressure  by  1  cm  water,  but  opposite 
in  sign.  Within  the  limitations  of  the  method  these 
results  justified  extending  the  Starling  hypothesis  to 
the  forearm  capillaries  of  man,  and  were  compatible 
with  the  view  that  the  capillaries  of  the  human  fore- 
arm were  relatively  impermeable  to  the  plasma 
proteins. 

In  the  first  studies  with  the  pressure  plethysmo- 
graph (188,  209)  it  was  perplexing  to  find  that  venous 


99° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


CC  /MIN 

+  50 


J  •  Normal   Plasma 

lAlburnin 

28% 

Globu 

n  24% 

TTp  = 

16.0 

mm 

»i 

f  x  After 

add 

ng   bov 

ne   Albumin 

1  Albumin 

6.7% 

Globu 

in  20% 

TTp  = 

501 

mm 

»t 

fig.  6.3.  Relation  of  net  fluid  move- 
ment in  perfused  hind  leg  of  cat  to 
difference  between  the  mean  hydro- 
static pressure  in  the  capillaries  {pC) 
and  the  sum  of  all  pressures  opposing 
filtration  (isogravimetric  capillary 
pressure,  pCi).  The  slope  of  the  line 
corresponds  to  a  filtration  coefficient 
(kt)  of  0.014  ml/min/100  g  tissue/ 
mm  Hg  pressure  difference.  [From 
Pappenheimer    &    Soto-Rivera    (282).] 


ABSORPTION 


FILTRATION 


pressure  had  to  be  elevated  by  10  to  17  cm  water 
before  net  nitration  could  be  detected  (fig.  6.2). 
Brown  et  al.  (24)  showed  later,  however,  that  the 
regression  lines  relating  filtration  and  venous  pressure 
passed  through  zero,  provided  a)  that  interstitial 
fluid  was  carefully  evacuated  from  the  forearm  prior 
to  congestion,  and  b)  that  a  correction  was  made  for 
the  volume  of  interstitial  fluid  pressed  out  of  the  fore- 
arm segment  during  each  volume  measurement. 

From  regression  lines  such  as  the  one  shown  in 
figure  6.2  it  is  possible  to  calculate  an  approximate 
filtration  coefficient  (kt)  for  forearm  tissue  if  allow- 
ance is  made  for  the  fact  that  a  given  elevation  of 
venous  pressure  produces  a  somewhat  smaller  eleva- 
tion of  mean  capillary  pressure.  On  the  assumption 
that  the  latter  is  80  per  cent  of  the  former,  kt  for 
human  forearm  capillaries  becomes  approximately 
.0057  ml  per  min  per  100  g  tissue  per  mm  Hg  as 
given  in  table  6.2.  The  filtration  coefficient  for  the 
whole  body  becomes  .0061. 

Among  the  several  perfusion  methods  that  have 
been  used  to  measure  filtration  coefficients,  the  most 
precise  and  revealing  is  the  isogravimetric  technique 
developed  by  Pappenheimer  &  Soto-Rivera  (282) 
in  which  filtration  and  absorption  were  identified  by 
changes  in  weight  of  an  isolated  limb.  Arterial  pres- 
sure, venous  pressure,  osmotic  pressure  of  the  perfus- 
ing fluid,  blood  flow,  and  temperature  could  be 
varied  at  will  and  their  influence  on  the  filtration- 


absorption  equilibrium  could  be  measured  separately. 
A  detectable  effect  on  fluid  movement  resulted  from 
a  change  of  venous  pressure  by  0.5  mm  Hg  and  some- 
times less,  or  from  a  change  of  arterial  pressure  by 
2  to  4  mm  Hg.  Capillary  pressure  was  5  to  10  times 
more  sensitive  to  a  change  of  venous  pressure  than 
to  a  change  of  arterial  pressure. 

Figure  6.3  shows  net  fluid  movement,  i.e.,  filtration 
or  absorption,  plotted  against  the  difference  in  pres- 
sure across  the  capillary  membranes  themselves. 
Filtration  and  absorption  were  proportional  to  the 
difference  between  the  calculated  mean  capillary 
blood  pressure  and  the  isogravimetric  capillary  pres- 
sure which  is,  by  definition  in  this  method,  the  sum  of 
all  pressures  opposing  filtration.  In  figure  6.3  the 
slope  of  the  regression  line  indicates  a  filtration 
coefficient  of  0105  ml  per  100  g  tissue  per  min  per 
mm  Hg  change  of  capillary  blood  pressure.  The  filtra- 
tion coefficient  was  independent  of  the  absolute  value 
of  the  isogravimetric  capillary  pressure  when  this  was 
varied  by  diluting  or  concentrating  the  proteins  in  the 
perfusing  fluid.  Similar  methods  have  been  applied 
recently  by  Renkin  &  Zaun  (302)  to  the  hind  legs  of 
the  rat. 

The  constancy  of  filtration  coefficients  at  high  and 
low  capillary  blood  pressures  (figs.  6.1,  6.2,  6.3) 
suggest  that  under  these  conditions  capillary  surface 
area  and  capillary  porosity  are  not  significantly 
modified  by  pressure.  This  may  be  related  to  the  con- 


EXCHANGE    OF   SUBSTANCES    THROUGH    CAPILLARY    WALLS 


99 1 


elusions  reached  by  Burton  (31)  that  vessels  of  small 
diameter  are  relatively  indistensible.  Under  more 
severe  conditions  and  in  other  tissues,  however,  the 
permeability  of  the  capillary  walls  may  be  increased 
when  capillary  blood  pressures  are  very  high  (211) 
or  when  blood  volume  is  much  increased  (131,  331, 
361,  369). 

In  all  the  regions  so  far  considered,  resting  average 
capillary  blood  pressure  is  approximately  equal  to 
the  osmotic  pressure  of  the  plasma  proteins.  In  the 
lung,  however,  as  described  in  section  2,  average 
capillary  pressure  is  only  5  to  10  mm  Hg  and  there- 
fore less  than  half  the  osmotic  pressure  of  the  plasma 
proteins.  Figure  6.4  shows  the  rate  of  edema  forma- 
tion in  the  lungs  of  dogs  plotted  against  left  atrial 
pressure  (132).  In  contrast  to  other  tissues,  net  filtra- 
tion and  increase  of  interstitial  fluid  volume  were  not 
observed  until,  at  atrial  pressures  of  25  to  30  mm  Hg, 
pulmonary  capillary  pressure  began  to  exceed  the 
protein  osmotic  pressure  of  25  mm  Hg.  Thereafter 
filtration  increased  linearly  with  left  atrial  pressure 
at  a  rate  of  0.21  g  of  fluid  per  hour  per  mm  Hg  per  g 
dry  wt  of  lung  tissue  or  0.065  g  per  min  per  mm  Hg 
per  100  g  wet  lung  tissue.  The  relative  ''dryness"  of 
lung  tissue  which  is  produced  by  a  low  capillary 
pressure  is  indicated  by  the  absence  of  filtration 
between  atrial  pressures  o  and  23  mm  Hg.  This 
margin  of  dryness  was  reduced  to  half  normal  when 
the  plasma  protein  concentration  was  decreased  by 
plasmapheresis  to  an  average  of  47  per  cent  of  the 
control  protein  concentration.   Taken   together,   the 


10 


20 

ATRIAL 


30 

PRESSURE 


40 

m  m  Hg) 


50 


fig.  6.4.  Rate  of  edema  formation  (nitration)  in  lungs  of 
dogs  subjected  to  prolonged  elevations  of  left  atrial  pressure. 
Significant  nitration  did  not  appear  until  left  atrial  pressure 
exceeded  25  mm  Hg,  i.e.,  the  osmotic  pressure  of  the  plasma 
proteins.   [From  Guyton  &  Lindsey   (132).] 


results  shown  in  figures  6.1  to  6.4  permit  concluding 
that  in  these  four  regions  the  net  rates  of  filtration  or 
absorption  through  the  capillary  walls  depend  upon 
the  difference  between  hydrostatic  and  osmotic 
forces  acting  across  the  membrane.  In  view  of  this 
evidence  the  Starling  hypothesis  of  1896  (345)  can 
fittingly  be  called  now  the  Starling  filtration-absorp- 
tion principle. 

Progress  has  gone  beyond  this  qualitative  stage, 
however,  because  the  meaning  of  k,  the  filtration 
coefficient,  has  been  expanded  not  only  by  numerical 
values  for  a  number  of  capillary  beds  and  membranes 
(tables  6. 1  and  6.2)  but  also  by  more  precise  definition. 
Pappenheimer  (276)  called  attention  to  the  fact  that 
the  several  different  "filtration  constants,"  "unit 
filtration  rates,"  or  "filtration  coefficients"  used  by 
various  authors  can  be  related  to  the  equation  used 
by  Darcy  (62)  to  describe  the  viscous  flow  of  fluids 
through  inert  porous  or  fibrous  materials,  viz. : 


0. 


(6.1) 


where 


Qj  =  quantity  filtered  per  unit  time 

k      =   specific  filtration  constant  of  the  porous  material  or 

membrane 
Am  —  area  of  membrane 
AP  =   pressure  difference  across  membrane  (in  capillaries 

ap  =  pc-  Pif  -  np,  +  n;/) 

Ax   =   path    length    through    membrane    (for    capillaries 

usually  assumed  to  be  0.3  ju) 
7j      =   viscosity  of  filtrate 

If  the  area  of  capillary  wall  can  be  measured 
directly  (23,  200,  201,  383)  or  computed  (281,  282)  as 
in  table  6.1,  the  proportionality  factor  or  filtration 
coefficient  consists  of  k/riAx  including  the  Darcy 
"specific  filtration  constant,"  the  thickness  of  the  wall, 
and  viscosity  of  the  fluid.  On  the  other  hand,  for 
tissues  in  which  the  capillary  surface  per  weight  or 
volume  of  tissue  is  not  yet  known  precisely,  e.g.,  in 
the  human  forearm,  the  hind  quarters  of  the  rat,  and 
the  lung,  the  proportionality  factor  for  unit  tissue 
weight  or  volume  will  consist  of  kAc/qAx  including, 
in  addition,  the  area  of  the  capillary  walls,  Ac-  The 
term  "filtration  constant"  is  certainly  inappropriate 
and  should  be  abandoned  for  a  membrane  system  as 
heterogeneous  as  that  in  the  capillary  wall.  Filtration 
coefficient  is  a  preferable  term  and  it  is  suggested  that 
the  symbol  kc  be  used  for  cases  where  the  area  of 
capillary  wall  is  measured  or  computed  and  kt  be 
used  for  coefficients  based  on  mass  or  volume  of 
tissue.   Newer  developments  in  pore  theory  have  led 


992  HANDBOOK    OF    PHYSIOLOGY    -"    CIRCULATION    II 

table  6.1.  Filtration  Coefficients  {Hydr adynamic  Conductivity)  Through  Various  Membranes* 


Filtration  Coefficient, 

Type  of  Membrane 

Temperature.  C 

ml                     X  io» 

References 

sec  X  cm2  X  cm  II 2O 

Cell  membranes 

Arbacia  egg  (unfertilized) 

20 

0.016 

(221,  222) 

Fibroblasts  imouse,  rat,  chick) 

20-22 

O.06-0. 16 

(25) 

Leucocytes  (rabbit,  man) 

20-23 

O . 05-0 . 2 

(329) 

Erythrocytes  (man) 

20 

O.92 

'  334  1 

Capillary  membranes 

Muscle  (dog,  cat) 

37 

2-5 

(281,  282) 

Mesenteric  (frog) 

22-26 

48-74 

(23,  200,  201) 

Glomerular  (frog) 

25 

220 

(281) 

Glomerular  (mammal) 

37 

3OO-60O 

(281,  276,  339) 

Artificial  membranes^ 

Dialysis  tubing  (Visking)  r  =   16-23  A 

25 

IOO-180 

(82,  298) 

Cellophane  (DuPont  450-PT-62)  r  =  30-40  A 

25 

35O-9OO 

(82,  298) 

Viscose  wet  gel  (Sylvania)  r  =   75-85  A 

25 

32OO-420O 

(82,  298) 

*  Modified  from  Renkin  &  Pappenheimer  (301).  t  Thickness,  0.5  M,  r  =   pore  radius. 


Pappenheimer  (276)  to  suggest  also  that  the  term 
"capillary  permeability"  be  reserved  for  describing 
the  properties  of  the  capillary  wall  with  reference  to 
the  diffusion  of  small  molecules.  Filtration  coeffi- 
cients, because  they  deal  with  flow  of  fluid  through  a 
membrane,  would  then  be  a  measure  of  hydraulic  or 
hydrodynamic  conductivity  of  the  capillary  wall. 

Table  6.1  is  taken  from  the  review  by  Renkin  & 
Pappenheimer  (301)  with  inclusion  of  some  more 
recent  values.  It  compares  filtration  coefficients  of 
cell  membranes  (upper  section),  of  capillary  walls 
(middle  section),  and  of  certain  artificial  membranes 
(lower  section).  Cell  membranes  have  smaller  filtra- 
tion coefficients  than  capillaries,  although  the  differ- 
ence between  the  values  for  the  erythrocyte  and  the 
mammalian  muscle  capillary  is  small.  The  range  of 
filtration  coefficients  for  capillary  walls  is  very  large, 
amounting  to  a  200-fold  difference  in  the  mammal 
between  muscle  capillaries  and  glomerular  capil- 
laries. The  coefficients  for  artificial  membranes, 
calculated  for  comparable  thickness,  are  in  turn 
much  higher  still  and,  with  other  evidence,  led 
Pappenheimer  et  al.  (281)  to  the  conclusion  that  the 
collective  area  of  the  pores  involved  in  the  filtration 
process  is  only  a  small  fraction  of  the  total  capillary 
surface.  Support  for  this  conclusion  came  from 
measurements  of  capillary  permeability  to  small 
lipid-insoluble  molecules,  and  will  be  given  in  sec- 
tions 8  to  10. 

Table  6.2  compares  average  filtration  coefficients 
(kt)  for  extremities  of  four  species.  In  the  forearm  of 


table  6.2.  Average  Filtration  Coefficients  for  Tissues,  kt 


Species  and  Tissue 

Filtration  Coefficient 
at  37  C,  ml 

min  X 

100  g  tissue 

X  mm  Hg  Reference 

Man 

,  forearm,  intact 

0.0057* 

(188,    209) 

Man 

,  whole  body,  intact 

0.0061  * 

(22) 

Dog, 

perfused  hind  leg 

0.014 

(282) 

Cat, 

perfused  hind  leg 

0.0105 

(281,    282) 

Rat, 

perfused  hind  legs 

O.O33 

(302) 

*  In  the  text  these  coefficients  are  described  for  a  rise  oi 
venous  pressure  by  1  cm  water.  To  facilitate  comparison, 
values  given  here  have  been  corrected  to  1  mm  Hg  rise  of 
capillary  pressure.   It  is  assumed  that  \PC  =   0.8  APV. 

man,  on  the  assumption  that  capillary  pressure  is 
increased  by  80  per  cent  of  given  increases  in  venous 
pressure,  the  average  filtration  coefficient  becomes 
.0057  ml  per  min  per  mm  Hg  per  100  g  tissue.  From 
the  data  of  Brown  et  al.  (22)  k,  for  the  whole  body  is 
.0061.  In  smaller  animals  progressively  larger  filtra- 
tion coefficients  are  found.  As  Renkin  &  Pappen- 
heimer suggest  (301),  this  relationship  is  ideologically 
fitting  because  the  smaller  the  mammal,  the  more 
active  are  its  metabolic  processes  and  therefore  the 
greater  will  be  the  requirement  for  a  more  extensive 
capillary  bed  (320)  and  for  more  rapid  exchanges 
between  blood  and  tissue.  To  obtain  comparable 
filtration  coefficients  for  other  tissues,  e.g.,  liver, 
intestine,  lung,  and  brain,  is  far  more  difficult.  Values 
for  lung  have  been  published  recently  by  Guyton  & 
Lindsey  (132)  and  for  brain,  or  perhaps  chiefly  the 
arachnoidea,  by  Coulter  (47). 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


993 


B.  Effects  of  Temperature  on  Filtration  Coefficients 

As  noted  above,  the  Uarcy  equation  indicates  that 
flow  through  porous  materials  changes  with  tem- 
perature in  inverse  proportion  to  viscosity,  and  accu- 
rate measurements  of  flow  through  artificial,  porous 
membranes  have  confirmed  this  expectation  (16,  81). 
The  filtration  coefficients  for  capillaries,  kc,  and  for 
tissues,  kt,  include  the  viscosity  of  the  filtered  fluid 
and  should  change  with  temperature.  This  was  found 
to  be  clearly  the  case  by  Pappenheimer  (277)  in  the 
perfused  limb  in  which  the  capillary  membranes 
retain  their  normal  impermeability  to  plasma  pro- 
teins over  a  temperature  range  of  8  to  44  C.  The 
ratio  of  the  filtration  coefficient  measured  at  36  ±  2  C 
to  that  measured  at  10  ±  2  C  averaged  1.68  (se  = 
±0.08).  This  value  was  within  10  per  cent  of  the 
ratio  of  viscosities  of  water  at  the  two  temperatures 
(77  10  77  36  =  185)  and  the  difference  between  the 
two  ratios  was  not  significant  (P  >   .05). 

In  the  frog  mesentery  Brown  &  Landis  (23)  had 
observed  earlier  a  decrease  of  filtration  coefficient 
(kc)  from  .0070  to  .00 1  g  when  temperature  was  re- 
duced from  24  ±  2  C  to  o  ±  2  C.  However,  as  men- 
tioned by  Pappenheimer  (276),  the  decrease  in  filtra- 
tion coefficient  was  larger  than  that  to  be  expected 
theoretically  and  the  scatter  of  values  for  individual 
capillaries  was  too  great  for  quantitative  conclusions. 

In  the  human  forearm,   Landis   &   Gibbon   (209) 


found  the  filtration  coefficient  (kt)  almost  halved  as 
the  temperature  of  the  plethysmograph  (and  of  the 
superficial  tissues  of  the  forearm)  was  changed  from 
44  or  45  C  to  14  or  15  C.  Brown  el  al.  (24)  extended 
these  observations  to  4  to  5  C.  Figure  6.5  (heavy  line) 
shows  the  filtration  coefficients  observed  in  the  fore- 
arm at  plethysmograph  temperatures  over  the  total 
range  of  44  to  4  C.  Using  the  data  of  Barcroft  &  Ed- 
holm  (9),  the  figures  just  above  the  bottom  line  of  the 
chart  show  the  probable  temperatures  in  muscle  and 
subcutaneous  tissues  corresponding  to  each  surface 
temperature.  Starting  from  the  filtration  coefficient 
at  a  tissue  temperature  of  35  to  36  C  (surface  tempera- 
ture 34  to  35  C)  the  fainter,  dash  lines  indicate  coeffi- 
cients of  filtration  calculated  on  the  basis  of  deep 
tissue  temperature  and  the  corresponding  change  in 
viscosity  of  capillary  filtrate.  Observed  and  calculated 
filtration  coefficients  agree  fairly  well  at  tissue  tem- 
peratures ranging  from  35  to  17  C.  Above  35  C  the 
observed  coefficient  is  much  higher  than  the  calcu- 
lated one,  indicating  that  changes  other  than  viscosity- 
are  involved.  To  be  considered  are  such  factors  as 
increased  capillary  pressure  and  filtering  area  (8) 
secondary  to  vasodilatation  or,  possibly,  opening  of 
arteriovenous  anastomoses  with  elevation  of  small 
vein  pressure.  Below  a  tissue  temperature  of  1  7  C,  the 
observed  filtration  coefficient  does  not  decrease  as 
it  should   if  viscosity   alone  were   involved,    but   in- 


0040 

COEFFICIENTS 
CALCULATED 

FILTRATION 
COEFFICIENT 

.0035 

POSSIBLE    EFFECTS 

OF  CHANCING   VISCOSITY 

OF   FILTRATE 

ml    per    mm 
per  cm    H,0  change 
of  venous   pressure 
in  100  ml   of  tissue 

<K      \ 
\     \ 

<B ©   SUBCUTANEOUS 

TISSUES 

«                      O O  MUSCLE 

.0030 

. 

t    ^^. 

.0025 

\ 

COMPARISON  ' 

CALCULATED   FROM 
RATE  OBSERVED 

A^ 

.0020 

AT  34    to  35  C 

7     V^ 

OBSERVED                            •" ^n. 

>@ 

PROBABLE    TISSUE    TEMP      C 

"""© 

38                           3 

i                           28                            21 

17 

talc    from                           MUSCLE                     > 

,,  ,.„           SUBCUTANEOUS  -> 
Barcroft   1946 

40                           3 

5                           25                            17 

1                               1 

II 

fig.  6.5.  Effects  of  tempera- 
ture on  filtration  coefficients,  kt, 
observed  in  the  human  forearm 
(solid  line),  compared  with  fil- 
tration coefficients  to  be  expected 
by  calculation  from  change  of 
viscosity  of  water  by  reason  of 
temperature  changes  in  muscle 
( —  — )  and  subcutaneous  tis- 
sue ( —  -  —  -  — )  [Calculated 
from  results  of  Landis  &  Gibbon 
(209),  Brown  et  al.  (24)  and, 
for  deep  temperatures,  Barcroft  & 
Edholm  (9).] 


34  to  35  24  to  25  14  to  15 

TEMPERATURE   OF   WATER  AROUN0  FOREARM     C 
PRESSURE    PLETHYSMOGRAPH  -  COMBINED    RESULTS 


994 


HANDBOOK.    OF    PHYSIOLOGY 


CIRCULATION    II 


creases  considerably.  Moreover,  Brown  et  al.  (24) 
found  that  even  at  normal  venous  pressures  cooling 
the  surface  of  the  forearm  to  4  C  produced  a  slow  but 
steady  increase  of  the  reduced  forearm  volume  pre- 
sumably because  of  filtration  and  augmented  inter- 
stitial fluid  volume.  These  results  suggested  "cold 
injury"  of  surface  capillaries  and  diminished  effective 
osmotic  pressure  of  the  plasma  proteins.  Passage  of 
protein  through  the  capillary  wall  in  severe  cold  has 
been  described  by  Lewis  (218),  who  found  up  to  3  g 
per  cent  of  protein  in  the  edema  fluid.  In  summary,  it 
appears  that  for  intact  tissues  the  effects  of  moderate 
changes  of  temperature  on  filtration  coefficients  can 
be  explained  fairly  well  by  the  changing  viscosity  of 
capillary  filtrate.  At  very  high  and  very  low  tem- 
peratures other  factors,  as  yet  unanalyzed,  become 
more  important. 

C.  Adsorbed  Plasma  Protein  and  Filtration  Coefficients 

The  functional  dimensions  of  capillary  pores,  and 
hence  the  filtration  coefficients  of  capillaries,  are 
probably  determined  in  part,  by  a  layer  of  adsorbed 
plasma  protein.  Krogh  &  Harrop  (186)  were  the 
first  to  note  that  perfusion  of  extremities  with  non- 
protein colloids  fails  to  prevent  edema.  Their  observa- 
tions were  confirmed  and  extended  by  Drinker  (74), 
Danielli  (61),  and  Shleser  &  Freed  (332).  Kinter  & 
Pappenheimer  (cf  table  6.3)  found  that  dextrans 
failed  to  exert  their  full  osmotic  pressure  in  vivo 
unless  more  than  0.2  per  cent  protein  was  present 
in  the  perfusion  fluid.  Net  filtration  usually  occurred 
in  dextran-Ringer  perfused  muscle  at  all  venous 
pressures;  10  to  20  min  after  addition  of  1  per  cent 
plasma  protein  the  direction  of  net  fluid  movement 
was  reversed  as  the  osmotic  pressure  of  the  dextran 
became  effective  across  the  capillary  walls.  The 
phenomenon  was  fully  reversible  and  could  be  re- 
peated several  times  on  the  same  preparation  during 
the  course  of  a  few  hours.  The  capillary  filtration 
coefficient  was  usually  more  than  doubled  when 
Ringer's  solution  (295)  or  Ringer-dextran  solutions 
were  substituted  for  plasma.  In  nine  experiments  the 
filtration  coefficient  averaged  0.016  ±  .003  ml  per 
min  per  100  g  tissue  during  perfusion  with  blood, 
0.037  ±  .002  during  perfusion  with  protein-free  red 
cell  suspensions,  and  0.019  ^  °°3  when  protein  was 
restored  to  the  perfusion  fluid.  The  effect  appears  to 
be  nonspecific,  since  normal  filtration  coefficients 
were  found  in  cat  or  rat  hind  limbs  perfused  with 
human  or  bovine  serum  albumin  (295),  cat  hemo- 
globin, or  bovine  hemoglobin  (299). 


table  6.3.  Effective  Osmotic  Pressures  of  Clinical 
Dextran  in  Capillaries  of  Perfused  Cat  Hind  Limbs 


Effective 
Pressure 

Osmotic 
mm  Hg 

Perfusion  Fluid 

In  vitro 
(Hepp 
osmom- 
eter) 

In  vivo 

(perfused 

limb) 

Experiment  I 

a)  3rc  Dextran 

1°7t  Plasma  protein  in  Ringer 

24.6 

21  .O 

b)  3%  Dextran  in  Ringer 

22 

6.6 

Experiment  2 

a)  3%  Dextran 

2.4^,  Plasma  protein  in  Ringer 

30.8 

28.5 

b)  ■>,%  Dextran 

0.2%  Plasma  protein  in  Ringer 

23.2 

'3-7 

Experiment  3 

a)  3%  Dextran  in  Ringer 

25.O 

12.2 

b)  3%  Dextran 

3%  Plasma  protein  in  Ringer 

31-4 

26.4 

From  unpublished  experiments  of  Kinter  and  Pappen- 
heimer. 

The  minor  axis  of  serum  albumin  is  about  30  A 
and  complete  removal  of  albumin  from  the  inside  of 
a  pore  might  increase  effective  pore  radius  by  this 
amount.  Given  a  mean  pore  radius  of  45  A  (see 
sections  9  and  10),  the  filtration  coefficient  would  be 
expected  to  increase  by  the  factor  (30  +  45)4  -f-  (45)4 
or  more  than  sevenfold.  A  reversible  increase  of  this 
magnitude  was  observed  in  only  one  preparation, 
but  it  is  possible  that  even  prolonged  washout  with 
protein-free  solutions  fails  to  remove  all  adsorbed 
protein.  The  effects  of  adsorbed  protein  should  be  con- 
sidered, however,  in  comparing  pore  dimensions 
calculated  from  permeability  measurements  with  pore 
dimensions  observed  in  electron  micrographs. 

D.   Effects  of  Injury  on  Filtration,  Absorption, 
and  Filtration  Coefficients 

capillary  stasis.  Cohnheim  in  1867  postulated  a 
"molecular  alteration  in  the  vessel  walls"  and  aug- 
mented "porousness"  to  explain  the  transudation  of 
fluid,  protein,  and  cells  in  inflammation  (42,  43). 
Since  then  abundant  qualitative  evidence  has  indi- 
cated that  injury  of  many  types  increases  the  perme- 
ability of  the  capillary  wall  to  fluid  and  protein  (207). 
Inflammation  is,  however,  an  exceedingly  complex 
series  of  reactions  (246,  247,  344),  of  which  increased 
capillary  permeability  is  only  one  part.  Physiologists 
have,    therefore,    tended   to   study   simpler   forms   of 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


995 


injury.  A  few  quantitative  measurements  in  terms  of 
filtration  coefficients  are  available  and  provide  esti- 
mates of  the  increased  porousness  even  though  in- 
formation on  the  "molecular  alterations"  of  the 
vessel  walls  is  still  completely  lacking. 

In  considering  the  mechanism  of  simple,  chemical 
injury,  Krogh  &  Harrop  (187)  in  1921  described 
'capillary  stasis"  as  direct  microscopic  evidence  of 
increased  permeability  of  the  capillary  wall.  The  steps 
by  which  chemical  injury  leads  to  capillary  stasis 
merit  full  description,  because  capillary  pressure, 
flow,  filtration,  absorption,  and  diffusion  are  all 
affected.  The  changes  observed  in  a  single,  damaged 
capillary  form  a  unit  lesion  which  helps  to  explain 
the  effects  of  more  generalized  injury. 

Blood  corpuscles,  when  first  entering  a  capillary, 
are  clearly  separated  by  plasma.  As  long  as  the  capil- 
lary wall  is  normal  this  remains  the  case  and  flow  con- 
tinues. Even  when  capillary  blood  pressure  is  high, 
filtration  reduces  the  volume  of  plasma  in  flowing 
capillary  blood  very  slightly,  because  the  fraction  of 
plasma  filtered  is  normally  less  than  4  per  cent  of  the 
plasma  volume  at  most,  and  usually  1  to  2  per  cent. 
However,  as  soon  as  injury  is  produced,  e.g.,  by  ap- 
plying 25  per  cent  urethan  or  10  per  cent  alcohol  in 
Ringer's  solution,  the  corpuscles  clearly  begin  to 
move  closer  together  as  they  flow  along  the  capillary, 
because  plasma  is  lost  progressively  through  the  now 
injured  capillary  wall.  Eventually,  at  the  venous  end 
of  the  capillary,  nearly  all  the  plasma  having  been 
filtered  off,  the  corpuscles  become  so  closely  packed, 
and  collectively  so  viscous,  that  they  come  to  a  stand- 
still in  the  capillary  and  form  a  localized  plug  of  cells 
just  short  of  the  venule.  Meanwhile  plasma,  with  few 
or  many  erythrocytes,  continues  to  enter  the  arteriolar 
end  of  the  capillary,  though  much  more  slowly  than 
before  and  in  a  distinctly  pulsatile  fashion,  because 
entry  is  now  limited  by  the  volume  of  plasma  being 
filtered  through  the  damaged  capillary  wall. 

The  plasma  of  this  blood  is  also  lost  by  rapid  filtra- 
tion. The  additional  corpuscles  are  progressively  con- 
centrated in  their  turn  and  finally  deposited  cumu- 
latively on  the  already  existing  column  of  erythrocytes 
in  the  venous  end  of  the  capillary.  Eventually  a 
column  of  packed  cells  fills  the  whole  capillary  and 
takes  on  a  characteristic,  transparent,  bright  red 
color,  apparently  because  the  erythrocytes  are  so 
closely  packed  that  light  rays  are  no  longer  refracted 
as  they  are  when  the  surfaces  of  single  corpuscles  are 
lormally  separated  by  intervening  plasma.  Flow 
ceases  entirely  in  capillaries  thus  filled  and  plugged. 

If  injury  is  severe,  capillary  stasis  is  irreversible.  If 


injury  is  mild,  resumption  of  flow  is  frequently  ob- 
served. The  first  indication  of  beginning  recovery  is 
the  loosening  of  corpuscles  in  the  packed  column, 
followed  by  slow,  then  more  rapid,  squeezing  of  the 
column  into  the  stream  of  the  nearest  venous  capillary 
or  venule.  Here  the  cells  can  be  seen  separating 
easily  in  the  plasma  of  the  venules  as  they  are  carried 
away.  In  this  respect  simple  stasis  differs  from  the 
"sludged"  corpuscles  described  by  Knisely  et  al. 
(176)  for  more  drastic  states  in  which  the  corpuscles 
adhere  to  each  other  and  form  minute  emboli. 

Even  after  flow  has  returned  some  erythrocytes 
and  leukocytes  usually  remain  adherent  to  the  inner 
surface  of  the  damaged  wall,  but  eventually  these, 
too,  float  free  (199).  Platelets  may  be  seen  adhering 
to  the  wall  for  still  longer  periods  and  probably  help 
restore  relative  impermeability  to  protein  as  sug- 
gested by  Danielli's  perfusion  studies  (61)  in  which 
platelets  reduced  the  rate  of  edema  formation  to 
one-tenth  that  found  with  platelet-free  perfusion 
media.  Platelet  protein,  in  association  with  calcium, 
has  also  been  found  to  restore  normal  permeability 

(380- 

Chemical  injury  of  the  grade  just  described  in- 
creases capillary  permeability  enough  to  permit 
passage  of  plasma  proteins  (200),  colloidal  dyes  (107, 
152,  184,  199),  and  colloidal  starch  (184)  but,  as 
observed  by  light  microscope,  the  walls  of  true  capil- 
laries still  retain  most  of  the  carbon  particles  of  in- 
jected India  ink  (152,  184,  199).  This  is  true  also  of 
localized  mechanical  injury  produced  by  compressing 
capillaries  with  a  glass  rod  (199),  or  by  prodding 
with  a  minute  needle  (37).  In  these  simpler  forms  of 
injury  gross  ruptures  of  the  capillary  wall  are  not 
present  because  carbon  particles,  as  well  as  erythro- 
cytes, are  retained  as  plasma  is  filtered  off. 


FILTRATION  COEFFICIENTS,  kc,  OF  INJURED  CAPILLARIES. 

The  permeability  of  injured  capillaries  has  been 
measured  in  the  frog's  mesentery  by  determining  their 
filtration  coefficient  during  stasis  using  the  method 
already  described  for  normal  capillaries  (200). 
Figure  6.6  shows  filtration  rates  plotted  against 
capillary  blood  pressure,  injury  having  been  pro- 
duced by  irrigating  the  mesentery  with  10  per  cent 
alcohol  or  1'.  10,000  mercuric  chloride  in  Ringer's 
fluid.  As  with  the  normal  capillary  wall,  filtration 
increased  linearly  with  capillary  blood  pressure. 
Comparison  of  the  regression  lines  for  injured  capil- 
laries (above)  and  normal  capillaries  (below)  indi- 
cates,   however,    that    the    filtration  coefficient    was 


996 


HANDBOOK    OF    PHYSIOLOGY 


CIRCl  I .ATION    II 


50 

FILTRATION 

• 

+ 

40 

- 

Injured                     j 
copillaries           / 

• 

RATE 

•  / 

OF              30 

- 

+    / 

FLUID 
MOVEMENT 

•  •  /  • 
/     • 

20 

•     / 

cubic  micro 

/      • 

per  second 

_ 

per  sq  micron 

+ 

10 

" 

• 

" 

•        / 

Normol 

0 

copillories 

" 

-in 

ABSORPTION 

i 1 1 

i i 

5  10  15  20 

CAPILLARY   PRESSURE  -  cm   woter 


fig.  6.6.  Effects  of  severe  chemical  injury  on  fluid  move- 
ment through  walls  of  frog's  mesenteric  capillaries.  Slope  of 
lower  regression  line  shows  filtration  coefficient,  kc,  for  normal 
capillaries.  Slope  of  upper  regression  line  indicates  the  7-fold 
increase  of  filtration  coefficient  found  after  injury.  Filled  circles 
refer  to  injury  by  io^i  alcohol  in  Ringer's  fluid;  plus  signs, 
to  1:10,000  mercuric  chloride  in  Ringer's  fluid.  [From  Landis 
(200).] 

increased  from  the  normal  value  of  0.0056  to  ap- 
proximately 0.0390  y?  per  sec  per  p*  of  capillary  wall 
per  cm  water  of  capillary  pressure,  indicating  a 
sevenfold  increase  of  hydrodynamic  conductivity. 
Increased  permeability  of  the  injured  wall  to  plasma 
proteins  is  indicated  by  the  absence  of  absorption  even 
at  low  capillary  pressures  and  by  the  reduction  of  the 
in  vivo  osmotic  pressure  of  the  plasma  proteins  from 
the  normal  value  of  1 1  cm  water  to  between  3  and  4 
cm  water.  Thus  the  effects  of  severe  injury  are  a)  in- 
creased filtration,  b)  absence  of  absorption,  c)  reduced 
effective  osmotic  pressure  of  the  plasma  proteins, 
and  d)  eventual  cessation  of  flow  in  any  capillary 
injured  to  the  point  of  stasis.  Diffusion  rates  have  not 
been  measured  in  such  capillaries.  Presumably,  since 
capillary  permeability  to  fluid  and  protein  is  greater, 
net  diffusion  of  small  molecules  should  be  increased 
as  long  as  blood  flow  continues.  However,  since  net 
diffusion  is  flow  limited,  its  effectiveness  in  exchanges 
of  substances  will  decline  as  flow  decreases  and  will 


soon  cease  in  those  capillaries  that  are  filled  with 
stationary,  closely  packed  erythrocytes. 

capillary  pressure  in  injury.  The  appearance  of 
edema  in  injured  regions  is  due  primarily  to  increased 
capillary  permeability,  but  is  enhanced  by  increased 
capillary  blood  pressure.  Local  injury  elevates  capil- 
lary blood  pressure  by  at  least  two  mechanisms:  /) 
the  vasodilatation  and  increased  blood  flow  which 
are  parts  of  the  triple  response  to  injury  described  by 
Lewis  (217),  and  2)  the  temporary  blockage  of 
capillary  blood  flow  and  passive  congestion  produced 
by  stasis  (199). 

Application  of  a  minute  silver  nitrate  crystal  to  the 
skin  of  the  frog's  web  increases  capillary  pressure  in 
the  neighborhood  of  the  lesion  to  peak  values  which 
are  as  much  as  double  the  earlier  control  values  (205). 
Within  10  to  20  min  capillary  pressure  is  again 
within  the  normal  range.  In  human  skin  the  flare  of 
the  triple  response  produced  by  histamine  is  accom- 
panied by  peak  capillary  pressures  of  10  to  25  mm 
Hg  above  preceding  control  values  (203),  but  again 
with  relatively  prompt  return  to  control  values.  The 
onset  and  duration  of  these  elevations  suggest  that 
they  are  a  part  of  the  flare  due  to  the  "axon  reflex." 

Elevations  of  capillary  blood  pressure  are  also 
found  in  capillaries  injured  to  the  point  of  stasis. 
These  elevations  are  more  important  in  the  formation 
of  edema  fluid  during  injury  because  they  occur  in 
vessels,  the  walls  of  which  are  permeable  to  protein 
and  hence  already  the  site  of  rapid  filtration  without 
any  balancing  absorption.  Figure  6.7  shows  the  cycle 
of  pressure  changes  which  occurred  in  one  experi- 
ment involving  stasis  and  recovery.  Control  capillary 
blood  pressure,  with  normal  blood  flow,  ranged  from 
12  to  15  cm  water.  At  the  time  marked  A  25  per  cent 
urethan  was  applied  to  the  mesentery  and  the  onset 
of  stasis,  as  indicated  by  visible  loss  of  plasma,  was 
clearly  present  at  B.  The  sharp  rise  of  capillary  pres- 
sure between  B  and  C  occurred  as  the  venous  end  of 
the  capillary  was  filled  and  blocked  by  packed 
erythrocytes.  As  flow  ceased  capillary  pressure  rose 
rapidly  to  approach  the  pressure  in  the  feeding 
arteriole.  At  C  a  pressure  of  22.5  cm  water  merely 
stopped  the  advance  of  erythrocytes  toward  the 
pipette.  Even  30  cm  water  did  not  move  the  cor- 
puscles away  so  that  capillary  blood  pressure  was 
well  in  excess  of  the  22.5  cm  charted.  The  very  rapid 
filtration  observed  during  this  period  is  due,  there- 
fore, to  increased  permeability  and  also  to  high 
capillary  pressure.  Between  C  and  D  this  enhanced 
filtration     of    whole     plasma     packed     erythrocytes 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


997 


CAPILLARY 

BLOOD 
PRESSURE 

CM 
H,0 


10  15 

TIME   -  MINUTES 

fig.  6.7.  Chart  indicating  the  changes  of  capillary  blood 
pressure  in  frog's  mesentery  during  capillary  stasis  produced 
by  applying  25^0  urethan  solution  (A  to  C)  and  during  re- 
covery with  resumption  of  capillary  blood  flow  (C  to  D). 
[From  Landis  (199)-] 

tightly  throughout  the  capillary.  After  D,  arteriolar 
pressure  having  been  blocked  by  the  packing  of 
erythrocytes  up  to  the  arteriocapillary  junction, 
capillary  blood  pressure  fell  to  the  level  in  the  venule. 
This  secondary  fall  of  pressure  seems  to  assist  recovery 
from  stasis  because,  as  it  occurs,  one  can  observe  that 
the  erythrocytes  become  less  tightly  packed  and  slow 
movement  toward  the  nearest  venule  begins.  At  D 
sluggish  flow  was  being  resumed.  Hence  in  injury, 
capillary  stasis  and  the  rapid  accumulation  of  rela- 
tively large  volumes  of  protein-containing  edema  fluid 
or  blister  fluid  depend  primarily  upon  increased  per- 
meability, but  also  upon  increased  capillary  blood 
pressure.  Recovery  from  stasis,  while  assisted  by  tem- 
porary lowering  of  capillary  blood  pressure,  cannot 
occur  until  the  permeability  of  the  wall  to  protein 
returns  toward  normal. 

TISSUE  ASPHYXIA;  RELATION  OF  FILTRATION  COEFFI- 
CIENTS to  0>,  C02,  and  pH.  The  effects  of  arrested 
blood  flow  and,  more  specifically,  of  hypoxia  on  capil- 
lary permeability  and  the  filtration-absorption  mecha- 
nism are  still  uncertain.  In  general,  it  appears  that 
arrest  of  blood  flow  must  be  total  and  prolonged,  and 
that  hypoxia  must  be  severe,  before  changes  in 
permeability  become  demonstrable.  Lazarus-Barlow 
(213)  in  1894  studied  the  edema  of  passive  congestion, 
and  also  the  edema  which  appeared  when  blood  flow 
was  restored  after  a  prior  period  of  complete  arterial 
and  venous  occlusion.  He  ascribed  the  latter  edema 


to  functional  modification  of  the  vessel  walls  secondary 
to  "starvation  of  the  tissues"  and  accumulated 
waste  products.  More  recently  Pochin  (285)  found 
in  the  rabbit's  ear  that  occluding  the  circulation  for  2 
hours  led  to  demonstrable  edema  which  appeared 
shortly  after  circulation  was  re-established.  Occlusions 
of  16  to  18  hours  produced  enough  edema  fluid  to 
permit  collecting  samples  in  which  the  protein  con- 
tent approached  5  g  per  cent.  Edema  alone  might 
conceivably  have  been  the  result  of  vasodilatation 
and  high  capillary  blood  pressure  that  probably 
followed  this  arrest  of  the  circulation,  but  the  high 
concentration  of  protein  in  the  edema  fluid  indicated 
that  increased  permeability  was  also  present. 

Among  the  factors  that  might  change  capillary- 
permeability  under  these  conditions,  the  first  to  be 
considered  are  those  associated  with  continued 
metabolism  of  tissues  in  the  absence  of  blood  flow, 
viz.  a)  reduced  oxygen  tension,  b)  increased  carbon 
dioxide  tension,  and  c)  local  decrease  of  pH  due  to 
accumulation  of  metabolites  such  as  lactic  acid. 
Table  6.4  summarizes  the  effects  of  these  variables 
on  the  filtration  coefficients  (kc)  and  on  the  in  vivo 
effective  osmotic  pressures  of  the  plasma  proteins 
measured  in  single  mesenteric  capillaries  of  the  frog 
(201).  They  indicate  that  Ringer's  solution,  saturated 
with  C02  or  acidified  by  HC1  to  pH's  between  7.0 
and  5.0,  had  no  significant  effect  on  the  permeability 
of  the  capillary  wall.  Only  when  pH  was  made  4.0 
or  less,  and  hence  unphysiologically  low,  was  there 
evidence  of  increased  permeability  to  fluid  and 
protein. 

Severe  and,  so  far  as  possible,  total  oxygen  lack 
made  the  capillary  wall  permeable  to  protein  and 
fluid  as  indicated  by  decreased  effective  osmotic 
pressure  of  the  plasma  proteins  and  by  increased 
filtration  coefficient,  respectively.  It  must  be  em- 
phasized that  the  lowering  of  02  tension  in  these 
experiments  was  maximal  because  not  only  was 
blood  flow  stopped  by  tightening  a  loop  around  the 
mesenteric  artery,  but  the  mesentery  was  also  ir- 
rigated freely  with  Ringer's  solution  previously  boiled 
and  kept  saturated  with  nitrogen.  The  possibility 
that  metabolites  from  anaerobic  metabolism  were 
responsible  could  not  be  excluded.  The  effects  on 
permeability  were,  however,  still  reversible  because, 
if  the  period  of  severe  hypoxia  was  brief  enough,  e.g., 
3  min,  resumption  of  blood  flow  and  irrigation  with 
oxygenated  Ringer's  solution  restored  both  the 
filtration  coefficient  and  the  in  vivo  osmotic  pressure 
of  the  plasma  proteins  toward  normal,  as  shown  in 
table  6.4.  For  comparison,  at  the  bottom  of  table  6.4 


998 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


table  6.4.  Effects  of  C02,  02,  f>H,  and  Severe 
Chemical  Injury  on  Frog's  Mesenteric  Capillaries 


Filtration  Coefficient, 


Effective  npi 

(in  vivo) 
cm  H2O 


sec  X  if-  X  cm  H2O 
.004B-.0074*         8. 6-1  I. 7 

.0088  11.8 


.005b 

"■5 

.0065 

11. 7 

.0074 

n. 4 

.0152 

11. 6 

.0207 

7.8 

rapid  stasis 

.0231 

6-5 

.0080 

"•5 

.0390 

<4.o 

Capillaries  Irrigated  by 
Ringer's  Fluid  with 

Usual  aeration 

Saturated  CO» 

pH  8.0 
HC1  to  pH  6.0 
5-o 
4.0 
3-5 
3-o 


()■.  lack  and  arrested  blood 

How  for  3  min 
After  15  min  recovery 

10%  alcohol  or  mercuric  chlo- 
ride, 1 :  10,000 

*  Accumulated  control  measurements  (23,  200,  201). 

is  shown  the  still  greater  effect  of  chemical  injury 
severe  enough  to  produce  irreversible  capillary  stasis. 

In  contrast  to  the  effects  of  extreme  local  hypoxia 
just  described,  studies  of  graded  hypoxemia  have 
demonstrated  that  the  capillary  wall  tolerates  less 
severe  grades  of  oxygen  lack  very  well.  In  the  human 
forearm,  Henry  el  al.  ( 1 50)  found  that  oxygen  tension 
of  venous  blood  must  be  reduced  to  between  1 5  and 
25  mm  Hg  before  protein  passage  was  increased 
above  normal.  This  corresponds  to  an  oxygen  satura- 
tion of  15  to  25  per  cent  or  an  oxygen  content  of  4  to 
6  vol  per  cent,  assuming  the  blood  has  a  normal 
hemoglobin  content.  The  method  used  to  measure 
protein  passage  was,  however,  indirect  and  the 
protein   content   of  capillary   filtrate   varied   widely. 

DiPasquale  &  Schiller  (70)  and  Hendley  &  Schiller 
(148)  studied  the  effects  of  hypoxemia  on  the  rate  of 
edema  formation  in  limbs  of  rats  perfused  with  Krebs- 
Ringer  solution  containing  20  per  cent  washed  red 
cells  of  dog  and  0.33  per  cent  gelatin.  When  the 
oxygen  content  of  the  perfusing  fluid  was  kept  above 
5  vol  per  cent,  the  rate  of  edema  formation  remained 
at  the  control  level.  Reducing  oxygen  content  to 
between  0.88  and  2.60  vol  per  cent  increased  the 
rate  of  edema  formation  above  control  levels  by  42 
per  cent  in  the  first  20  min,  by  87  per  cent  in  the 
next  20  min,  and  by  151  per  cent  in  the  third  20- 
min  period.  Blood  flow  having  been  kept  constant 
to  exclude  effects  of  the  vasodilatation  which  ac- 
companied this  hypoxemia,  they  concluded  that  the 
critical     level     below    which     hypoxemia     influences 


the  permeability  of  a  capillary  wall  was  probably 
about  2.6  vol  per  cent.  No  observations  on  protein 
passage  were  made.  In  further  studies  Hendley  & 
Schiller  (149)  found,  however,  that  either  histaminic 
(Xeo-Antergan)  or  adrenergic  (Dibenzyline)  blockade 
eliminated  these  results  on  the  basis  either  of  specific 
blocking  action  or  of  hemodynamic  effects,  and  the 
meaning  of  these  studies  therefore  remains  a  chal- 
lenging problem. 

Systemic  hypoxemia,  within  the  range  compatible 
with  the  life  of  the  organism,  has  no  certain  effect  on 
capillary  permeability.  Maurer  (228,  229)  and 
Warren  &  Drinker  (367)  found,  in  dogs,  that  breath- 
ing 8.0  to  1  1 .5  per  cent  oxygen  in  nitrogen  augmented 
the  flow  of  lymph  from  the  lungs  and  cervical  region, 
increased  the  total  amount  of  lymph  protein  col- 
lected in  unit  time,  but  decreased  the  concentration 
of  protein  in  that  lymph.  Although  an  increase  of 
capillary  permeability  was  postulated,  the  decreased 
protein  concentration  in  lymph,  taken  together  with 
the  studies  of  Courtice  &  Korner  (53,  1 79)  make 
it  unlikely  that  permeability  to  protein  was  changed. 
In  the  human  forearm  McMichael  &  Morris  (242) 
found  that  breathing  9.5  per  cent  oxygen  did  not 
increase  filtration  hum  capillaries  during  venous 
congestion.  Moreover,  in  patients  with  generalized 
hypoxemia  sufficient  to  impair  cerebral  function, 
Stead  &  Warren  (351)  observed  no  significant  in- 
crease in  the  protein  content  of  edema  fluids  collected 
from  the  extremities. 

Only  in  agonal  or  antemortem  stages  of  asphyxia 
(34)  or  anoxemia  ( 1 60 )  is  there  some  slight  evidence 
of  increased  capillary  permeability.  In  shock  the 
possibility  that  generalized  hypoxemia  might  increase 
capillary  permeability  has  been  considered  on  many 
occasions.  Careful  studies  with  labeled  plasma  proteins 
(45,  101,  102)  have  shown  the  expected  rapid  passage 
of  protein  through  capillary  walls  locally  in  burned 
or  crushed  tissues.  However,  no  abnormal  passage 
through  capillary  walls  elsewhere  in  the  body  has 
been  found  until  just  before  death,  again  as  an 
agonal  or  antemortem  occurrence. 

In  view  of  the  many  uncertainties  already  men- 
tioned it  is  important  to  note  that  Bayliss  &  Lunds- 
gaard  fii)  perfused  isolated  kidneys  with  cyanide- 
containing  blood  and  found  that  some  tubular 
functions  were  reduced  conspicuously,  but  that  the 
glomerular  capillaries  and  membranes  remained 
nevertheless  normally  impermeable  to  protein  in  the 
two  instances  tested.  In  an  earlier  study  Starling  & 
Verney  (348)  found  that  the  urine  contained  only  a 
trace  of  protein  after   1 5  min  of  cyanide  perfusion, 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


999 


though  stepwise  increases  of  proteinuria  occurred 
after  that.  Pappenheimer  found  (unpublished  studies) 
in  the  perfused  cat's  leg  by  the  isogravimetric  method 
that  cyanide  did  not,  under  certain  conditions, 
increase  either  the  filtration  coefficient  or  the  per- 
meability of  the  capillary  wall  to  protein.  This  raises 
the  interesting  possibility  that  any  effects  which  severe 
hypoxia  may  have  on  capillary  permeability  do  not 
involve  the  better  known  cyanide-sensitive  oxidations, 
but  involve  rather  the  2  to  50  per  cent  (71,  224)  of 
tissue  oxygen  consumption  which  cyanide  does  not 
inhibit  even  in  high  concentration.  It  is  possible,  too, 
that  the  edema  of  prolonged  ischemia  arises  from  the 
effects  of  anaerobically  produced  metabolic  products 
or  from  other  substances  liberated  by  hypoxic  tissue 
cells.  In  summary,  the  effects  on  capillary  permeability 
of  arrested  blood  flow,  and  more  specifically  of 
hypoxia,  are  still  uncertain  and  require  more  carelul 
studies  both  as  to  quantitative  aspects  and  as  to 
mechanism. 

ADRENAL       CORTICAL       HORMONES       AND        FILTRATION 

coefficients.  Adrenal  hormones  have  frequently 
been  considered  to  be  a  factor  in  maintaining  filtra- 
tion coefficients  and  capillary  permeability  within 
normal  limits  even  after  injury.  Menkin  (245)  and 
others  (110,  332)  observed  that  adrenal  extracts  and 
some  adrenal  steroids  inhibited  or  delayed  the  ap- 
pearance of  intravenously  administered  trypan  blue 
in  the  skin  of  rabbits  where  leukotaxine  (110,  245) 
or  peptone  (332)  had  been  injected  locally.  Some 
blanching  of  the  skin  was  observed  in  the  area  treated 
with  adrenal  cortical  hormones  (1 10,  332),  suggesting 
possible  vasoconstriction.  Hyman  &  Chambers 
(163)  found  in  the  perfused  hind  legs  of  frogs  that 
the  rate  of  edema  formation  was  reduced  by  addition 
of  certain  adrenal  cortical  extracts  to  the  perfusing 
fluid,  but  their  method,  like  the  preceding  ones,  did 
not  exclude  possible  changes  in  capillary  blood  pres- 
sure. 

Renkin  &  Zaun  (302)  applied  to  this  problem  the 
isogravimetric  perfusion  method  of  Pappenheimer  & 
Soto-Rivera  (282)  which  permitted  measurement  of 
a)  filtration  coefficients  to  indicate  permeability  to 
fluid  and  protein,  b)  osmotic  transients  to  indicate 
permeability  to  small  molecules,  and  c)  blood  flow 
to  identify  vasoconstriction.  Addition  of  adrenal 
cortical  extracts  to  both  normal  and  adrenalectomized 
preparations  produced  vasoconstriction  which  was 
shown  to  be  clue  to  the  presence  of  small  amounts  of 
an  easily  oxidizable  substance,  presumably  epi- 
nephrine.    Limbs    from    adrenalectomized    animals 


showed  no  increase  of  capillary  permeability  to 
protein  and  filtration  coefficients  for  fluid  did  not 
differ  significantly  from  normal.  Addition  of  adrenal 
cortical  extracts  to  the  perfusing  fluid  produced 
slight  decreases  of  the  filtration  coefficient,  but  evi- 
dence of  vasoconstriction  was  also  present.  The  ad- 
dition of  epinephrine  to  the  perfusing  fluid  in  amounts 
similar  to  that  contaminating  the  extract  produced 
corresponding  changes,  both  of  resistance  to  flow  and 
of  filtration  coefficient.  Permeability  of  the  capillary 
wall  to  sucrose  was  also  normal  in  adrenalectomized 
rats  and  was  not  affected  by  aqueous  adrenal  cortical 
extract. 

The  lack  of  agreement  concerning  the  effects  of 
adrenal  extracts  and  steroids  emphasizes  again  (208) 
the  necessity  for  devising  methods  which  separate 
a  direct  action  of  substances  on  capillary  permeability 
per  se  from  the  indirect  effects  of  complicating 
vasodilatation  or  vasoconstriction.  Vasodilatation 
can  increase  capillary  blood  pressure;  thus  favoring 
greater  filtration  through  an  unchanged  capillary 
wall.  Conversely,  vasoconstriction  can  reduce  capil- 
lary blood  flow  and  pressure,  and  also  the  area  of 
capillary  wall  available  for  diffusion  and  filtration. 
Such  hemodynamic  changes  will,  of  themselves, 
modify  exchanges  of  substances,  and  thus  simulate  a 
change  of  permeability.  The  quantitative  measure- 
ment of  increases  or  decreases  of  capillary  per- 
meability is  still  one  of  the  most  difficult  problems  in 
physiology. 

POROSITY     OF     THE     INJURED     CAPILLARY     WALL.     The 

effect  of  injury  on  the  size  of  possible  pores  in  the 
capillary  wall  was  considered  by  Krogh  (184)  in 
1922.  From  the  passage  of  soluble  starch  and  the 
retention  of  carbon  particles  he  concluded  that 
pore  diameter  was  not  less  than  50  A  nor  more  than 
2000  A.  For  normal  limb  capillaries  of  cats  the 
present  corrected  estimate  for  mean  effective  pore 
diameter  lies  between  80  and  90  A  (see  sections  8  to 
10).  If  it  be  assumed  a)  that  injury  merely  enlarges 
existing  pores,  and  b)  that  Poiseuille's  equation  holds 
for  filtration  through  these  pores,  then  a  sevenfold 
increase  of  filtration  coefficient  can  be  explained  by  a 
65  per  cent  increase  of  pore  diameter,  i.e.,  from  the 
normal  80  to  90  A  up  to  between  130  and  150  A. 
Judging  from  the  effects  of  reduced  pH  shown  in 
table  6.4  a  doubling  of  filtration  coefficient  does  not 
increase  protein  passage  measurably,  whereas  a 
threefold  to  fourfold  increase  does.  It  may  be,  how- 
ever, that  injury  increases  the  size  or  number  of  the 
larger  openings  postulated  by  Grotte  (126)  and  by 


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CIRCULATION    II 


Mayerson  et  al.  (232)  or  that  ultramicroscopic  dis- 
ruption of  vessel  architecture  produces  new  and  still 
larger  apertures.  Electron  microscopy  has  shown 
recently,  for  instance,  that  histamine  can  produce 
separation  of  endothelial  cells  in  venules  so  that 
carbon  particles  pass  between  endothelial  cells  to 
rest  against  the  basement  membrane  (226,  226a).  Ad- 
ditional evidence  in  favor  of  enlarged  leaks  or  of 
new  openings  in  injury  has  been  provided  recently 
by  Courtice  &  Morris  (50-52,  54).  Concentrations 
of  total  cholesterol  and  of  phospholipids  were  studied 
in  order  to  determine  the  plasma  to  lymph  gradients 
of  lipoproteins  in  the  limbs  of  cats  and  rabbits  before 
and  after  injury.  These  gradients  were  compared 
with  those  for  albumin  and  globulins.  In  lymph 
from  normal  legs  the  concentrations  of  albumin, 
globulins,  cholesterol,  and  phospholipids  were, 
respectively,  48,  35,  24,  and  33  per  cent  of  the  plasma 
levels.  After  thermal  injury  the  corresponding  figures 
for  lymph  were  81,  74,  60,  and  74  per  cent  of  the 
plasma  levels.  Increased  permeability  to  protein  was 
accompanied  by  increased  permeability  to  lipopro- 
teins, the  diameters  of  which  have  been  placed 
tentatively  at  150  to  350  A  (144).  Larger  fat  particles, 
measuring  perhaps  1500  A  or  more,  e.g.,  the  particles 
in  chyle  or  in  an  artificial  fat  emulsion,  were  not 
transferred  through  the  capillary  wall  to  lymph  to 
any  measurable  extent,  even  after  injury.  However,  as 
Courtice  mentions  (52),  although  the  passage  of 
lipoproteins  and  lipids  becomes  less  as  the  size  of  the 
molecule  or  complex  increases,  the  exact  mechanism 
of  their  passage,  whether  between  or  through  endo- 
thelial cells,  is  still  obscure.  In  addition,  the  molecular 
mechanism  and  ultramicroscopic  location  of  capillary 
damage  may  well  differ,  depending  upon  the  type  of 
injurious  agent  involved  (208).  Hence  the  basic  nature 
of  Cohnheim's  "molecular  alteration  in  the  vessel 
walls"  in  various  types  of  injury  remains  still  a  prime 
unknown  requiring  study  by  pathologists,  physi- 
ologists, and  electron  microscopists  alike. 


7.    DIFFUSION,    GENERAL    PRINCIPLES 

The  extravascular  circulation  caused  by  capillary 
filtration  and  absorption  is  exceedingly  important  for 
homeostasis  of  blood  volume  and  for  removal  of  large 
protein  molecules  via  the  lymphatics.  However,  the 
magnitude  of  the  extravascular  circulation  is  too  small 
to  be  of  significance  for  the  metabolic  exchange  of 
small  molecules  between  blood  and  tissues  (see  fig. 
5.2).  Metabolic  exchange  takes  place  largely  by 
diffusion  processes  which  are  almost  independent  of 
the  magnitude  and  direction  of  net  fluid  movement. 


Evidence  to  be  discussed  below  indicates  that  diffusion 
of  lipid-insoluble  molecules  takes  place  through 
aqueous  channels  between  capillary  endothelial  cells. 
Lipid-soluble  molecules,  on  the  other  hand,  diffuse 
rapidly  through  the  lipid  plasma  membranes  of  the 
endothelial  cells  themselves  and  are  thus  free  to 
utilize  the  entire  capillary  surface  area  for  the  ex- 
change process.  Before  undertaking  a  detailed  analysis 
of  diffusion  processes  in  the  capillary  circulation,  it 
will  be  helpful  to  review  some  physical  laws  governing 
molecular  diffusion  in  free  solution  and  in  simple 
membranes. 

A.  Free  Diffusion 

The  fundamental  laws  of  free  diffusion  were  first 
described  by  Fick  (96)  in  1855. 

Adolf  Fick  (1829-igoi)  was  Professor  of  Physiology  in 
Wiirzburg.  His  most  numerous  publications  were  in  the  field 
of  muscle  physiology,  but  his  several  classical  contributions  to 
science  were  in  the  form  of  short,  single  publications  in  unre- 
lated fields.  Among  circulatory  physiologists  he  is  known  chiefly 
as  the  originator  of  the  "Fick  principle"  for  determination  of 
cardiac  output.  Among  ophthalmologists  he  is  noted  for  the 
development  of  tonometry  and  as  author  of  "Fick's  law"' 
relating  deformation  of  the  cornea  to  intraocular  pressure. 
It  is  probable,  however,  that  his  greatest  contribution  to  science 
was  his  clear  formulation  of  the  laws  of  diffusion  based  on 
analogy  with  Fourier's  description  of  the  flow  of  heat.  "Die 
Verbreitung  eines  gelosten  Korpers  in  Losungsmittel  geht, 
wofern  sie  ungestort  unter  dem  ausschliesslichen  Einfluss 
der  Molecularkrafte  stattfindet,  nach  demselben  Gesetze 
vorsich,  welches  Fourier  fur  die  Verbreitung  der  Warme  in 
einem  Leiter  aufgestellt  hat.  .  .  Man  darf  nur  in  dem 
Fourier'schen  Gesetz  das  Wort  Warmquantitat  mit  dem  Worte 
Quantitat  des  gelosten  Korpers,  und  das  Wort  Temperature 
mit  Losungsdichtigkeit  vertauschen." 

According  to  Fick's  formulation,  the  rate  of  linear 
diffusion  (quantity,  n,  per  unit  time,  /)  in  direction  .v 
and  through  cross-sectional  area,  A,  is  proportional 
to  the  concentration  gradient,  dc  dx. 

dn/dt  --  D  A  dc/dx  (7. 1) 

The  constant  of  proportionality,  D,  is  known  as  the 
diffusion  coefficient  and  its  dimensions  are  Pr1.  The 
simplest  possible  application  of  equation  7.1  is  to 
steady-state  diffusion  where  dc/dt  is  constant  as  a 
function  of  both  distance  and  time.  In  this  case,  the 
equation  7.1  can  be  written 

n   -"  DA  Ac/ Ax  (7.  2) 

where  the  concentration  gradient  Ae  A.v  is  constant 
all  along  the  diffusion  path.  Equation  7.2  is  specially 
applicable  to  diffusion  through  thin  membranes 
where   the   concentrations   on   the   two   sides   of  the 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


membrane  can  be  maintained  constant.  This  con- 
dition is  frequently  encountered  in  the  capillary 
circulation  where  blood  on  the  luminal  side  of  the 
capillary  membrane  is  maintained  at  constant 
composition  by  virtue  of  an  adequate  blood  flow  and 
fluid  on  the  tissue  side  of  the  capillary  membrane  is 
maintained  at  a  different  constant  composition  as  a 
result  of  tissue  metabolism.  A  specific  example  will 
serve  to  illustrate  the  use  of  ecjuation  7.2  and  at  the 
same  time  indicate  the  magnitude  of  diffusion  in 
systems  of  capillary  dimensions.  Consider  the  diffusion 
of  glucose  across  an  aqueous  boundary  .5  /i  (0.5  X 
io-4  cm)  thick  and  with  a  surface  area  of  10  cm-.  The 
diffusion  coeflicient  of  glucose  is  0-9  X  io~~5  cm2  per 
sec  (see  table  9.1).  Let  the  concentration  of  glucose 
on  one  side  of  the  boundary  be  maintained  constant 
at  100  mg  per  cent  and  the  concentration  on  the 
other  side  of  the  boundary  at  99  mg  per  cent,  thus 
producing  a  constant  concentration  difference  of  0.01 
mg  per  cm3.  Substituting  these  values  in  equation 
7.2,  we  have 


cm2  .01  mg/cm3 

n  =  .9  X   1  o-5 X  10  cm2  X 


0.5X1  cr4  cm 
=  0.018  mg/sec  or  1.08  mg/min 

This  rate  of  transfer  is  greater  than  the  normal 
metabolic  consumption  of  glucose  in  100  g  of  skeletal 
muscle  containing  more  than  5,000  cm-  of  total 
capillary  surface  and  it  is  thus  obvious  that  even  a 
small  concentration  difference  operating  over  a 
relatively  small  aqueous  area  will  provide  a  physio- 
logically sufficient  diffusion  flow  of  glucose  through 
distances  comparable  in  thickness  with  the  capillary 
wall. 

Fick  realized  that  the  driving  force  for  diffusion 
results  from  random  kinetic  motions  of  the  diffusing 
molecules,  but  he  did  not  perceive  the  physical  sig- 
nificance of  the  diffusion  coefficient.  It  remained  for 
Nernst  (1888)  to  relate  diffusion  coefficient  to  osmotic 
and  frictional  forces  in  solution  (260).  Nernst  showed 
that 


D  '  RT/fN 


(7.3) 


where  /  is  the  frictional  force  opposing  unit  linear 
velocity  of  each  molecule  and  N  is  the  number  of 
molecules  per  mole  (Avogadro's  number).  For  the 
case  of  large  spherical  molecules  the  frictional  force 
opposing  diffusion  is  given  by  Stokes'  law  describing 
the  motion  of  a  sphere  falling  at  unit  velocity  in  a 
viscous  medium 


f  =  6irVa  (7.  4) 

where  r\  is  the  viscosity  of  the  medium  and  a  is  the 
molecular  radius.  In  1905  Sutherland  (355)  and 
Einstein  (91)  independently  noted  the  possibility 
of  combining  equations  7.3  and  7.4  to  obtain  the 
relationship  between  free  diffusion  coefficient  and 
molecular  radius 


D  =  RT/6vya  N 


(7.5) 


Equation  7.5  indicates  that  diffusion  coefficient  is 
inversely  related  to  molecular  radius  and  to  the 
viscosity  of  the  diffusion  medium;  conversely  the 
equation  allows  calculation  of  molecular  radius  from 
measurements  of  free  diffusion  coefficient.  It  should 
perhaps  be  emphasized  that  molecules  are  rarely 
spherical  and  the  molecular  radius  calculated  from 
the  Einstein-Stokes  relation  (equation  7.5)  is  a 
virtual  quantity  represented  by  a  sphere  of  equivalent 
diffusion  coefficient.  Moreover,  the  equation  is 
derived  on  the  assumption  that  the  diffusing  molecules 
are  large  compared  to  the  solvent  molecules;  for 
molecules  smaller  than  glucose  it  is  necessary  to 
apply  corrections  such  as  those  given  by  Gierer  & 
W'irz  (116).  Additional  methods  for  estimating 
molecular  dimensions  include  calculations  from 
density,  intrinsic  viscosity,  and  X-ray  diffraction  data. 
Table  9.1,  based  on  more  detailed  tables  published  in 
references  82,  281,  and  2g8,  shows  free  diffusion 
coefficients  and  approximate  molecular  radii  of  a 
variety  of  molecular  species  which  have  been  used 
in  studies  of  capillary  permeability. 

B.      Diffusion   Through  Porous  Membranes, 
Restricted  Diffusion 

The  diffusion  of  small  molecules  through  thin, 
large-pored  membranes  takes  place  according  to 
Fick's  law;  the  only  effect  of  the  membrane  is  to 
reduce  the  total  area  available  for  free  diffusion. 
Indeed,  the  most  accurate  method  of  estimating  the 
pore  area,  Ap,  in  a  membrane  with  large  water-filled 
pores  is  to  measure  the  diffusion  rate,  ii,  through  the 
membrane  of  small,  uncharged  molecules  of  known 
free  diffusion  coeflicient.  From  rearrangement  of 
Fick's  law 


n   x 


Ax 
DAc 


In  most  practical  applications  the  path  length,  A\, 
through  the  membrane  is  also  unknown  and  it  is  more 
useful  to  solve  for  the  pore  area  per  unit  path  length, 

Ap/Ax 


1002 


HANDBOOK    OF    I'HYSIOI.OUY 


CIRCULATION    II 


P 

Ax 


n 
D~Ac 


(7.6) 


Once  the  pore  area  per  unit  path  length,  Ap  Ax,  has 
been  established  from  equation  7.6  for  a  given  large- 
pored  membrane,  the  membrane  may  be  used  to 
determine  free  diffusion  coefficients  of  test  molecules 
(233,  264,  316).  Membranes  employed  for  this 
purpose  generally  have  pores  which  are  at  least 
100-fold  larger  than  the  diffusing  molecules. 

In  the  case  of  diffusion  through  membranes  having 
pores  of  molecular  dimensions  the  kinetic  motions  of 
the  diffusing  molecules  are  restricted  by  the  pore 
structure;  in  such  membranes  the  effective  pore  area 
per  unit  path  length  decreases  as  a  function  of  mo- 
lecular size,  becoming  zero  when  the  test  molecules  are 
the  same  size  as  the  pores.  Capillary  permeability  to 
lipid-insoluble  molecules  of  graded  sizes  can  be 
explained,  in  large  part,  by  restricted  diffusion 
through  aqueous  channels  of  molecular  dimension. 
For  this  reason  it  will  be  necessary  to  discuss  physical 
aspects  of  restricted  diffusion  in  some  detail. 

Figure  7.1  shows  apparent  pore  areas  per  unit 
path  length  for  molecules  of  graded  sizes  diffusing 
through  a  cellulose  membrane  of  the  type  commonly 
used  for  ultrafiltration  or  dialysis  (Visking  sausage 
casing).  It  is  evident  that  the  apparent  pore  area  for 
free  diffusion  decreases  rapidly  as  a  function  of 
molecular  size.  The  true  pore  area  in  the  membrane 
is,  of  course,  constant  and  it  is  useful  to  think  of  the 
apparent  decrease  in  terms  of  a  restricted  diffusion 
coefficient,  D',  such  that 


D   *  D  A  ,/A. 


(7.7) 


where  As  is  the  apparent  pore  area  for  the  solute  and 
Av  is  the  true  pore  area.  Substitution  of  D'  for  D  in 
equation  7.6  would  yield  the  true  membrane  pore 
area  per  unit  path  length  for  all  molecular  species. 
The  essential  theoretical  problem  is  now  to  relate 
the  observed  restriction  to  diffusion,  D'  D,  to  di- 
mensions of  the  membrane  pores. 

The  theory  of  restricted  diffusion  proposed  by 
Pappenheimer  el  al.  (281)  takes  into  account  two 
factors  impeding  the  passage  of  molecules  through 
pores  of  molecular  dimensions.  The  first  factor  is 
concerned  with  steric  hindrance  at  the  entrance  of 
the  pore.  It  is  assumed  that  for  entrance  into  a  pore 
a  molecule  must  pass  through  the  opening  without 
striking  the  edge  as  originally  suggested  by  Ferry 
(95).  For  the  case  of  cylindrical  pores  the  effective 
target  area,  As,  for  the  solute  is  then 


Ap  (l-a/r)* 


As     dn/dt 
Ax"~  DAC 


VISKING   CELLULOSE 

Mean  pore  radius 

r  =  16  S 


-V—if 


MOLECULAR   RADIUS, A 
*  5  6 


H3HO 


—If-, 

GLUCOSE 


SUCROSE 
ANTIPYRINE 


RAFFINOSE 


fig.  7.1.  Apparent  pore  areas  per  unit  path  length  as  a 
function  of  molecular  size.  The  smooth  curve  is  constructed 
from  the  theory  of  restricted  diffusion,  equation  7.9,  assuming  a 
mean  pore  radius  of  16  A.  Mean  pore  radius  determined  on 
the  same  membrane  from  combination  of  diffusion  and  filtra- 
tion was  19  A  (equation  7.13).  Similar  data  for  diffusion  of 
lipid  insoluble  molecules  through  the  walls  of  muscle  capillaries 
are  shown   in  figure  9.2.   [Adapted  from   Renkin   (298).] 

where  A v  is  the  true  geometrical  area  of  the  opening 
and  a  r  is  the  ratio  of  molecular  radius  to  pore 
radius. 

The  second  factor  takes  account  of  friction  between 
a  molecule  moving  within  a  pore  and  the  stationary 
walls  of  the  pore.  This  factor,  first  studied  by  Laden- 
burg  (193),  was  employed  by  Friedman  &  Kraemer 
(112)  to  describe  the  diffusion  of  sugars  through 
gelatin  gels.  The  Ladenburg  treatment  of  the  problem 
is  strictly  applicable  only  to  cases  where  a  r  <  .1 
and  it  is  preferable  to  use  the  more  general  formula- 
tion of  Faxen  (94) 


1-2.10  (£)  *  2 09(f)  -0.95(f) 


(78) 


where  / ,'/o  is  the  frictional  resistance  to  diffusion  in 
the  pore  relative  to  that  in  free  solution.  Taking  into 
account  both  steric  hindrance  (equation  7.7a)  and 
wall  effects  (equation  7.8),  the  theoretical  restriction 
to  diffusion  through  cylindrical  pores  becomes 


£  -  |-  (I-  °7f[-zJ0(f).  2.09(?) 

4fl 


-0.95 


(7  9) 


(7.7a) 


The  last  term  of  the  series  is  negligible  when  a/r  < 
0.5.    During    net    flow    through    the    membrane    the 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


IOO3 


velocity  of  flow  at  the  center  of  the  pore  is  twice  the 
average  velocity  and  the  effective  target  area  pre- 
sented by  the  pore  to  the  incoming  molecules  is 
slightly  increased  (95).  Under  these  conditions  the 
restricted  diffusion  equation  becomes 


(\):[2('-arf-(l-aT)]h'0(f) 
^2.09(ff -0.95(ff] 


P  f/Ou    ' 


(7. 10) 


Figure  7.2  shows  that  equation  7.9  describes 
observed  diffusion  through  artificial  porous 
membranes  with  considerable  accuracy.  The  data 
were  obtained  using  seven  molecular  species  and 
three  membranes  having  porosities  in  the  range  of 
interest  for  capillary  physiology.  Analogous  develop- 
ment of  theory  for  restriction  to  diffusion  through 
rectangular  slits,  rather  than  cylindrical  pores,  leads 
to  a  theoretical  curve  closely  approximating  that 
shown  in  figure  7.2  (281).  However,  electron  micro- 
graphs indicate  that  true  pore  geometry  of  artificial 
membranes  is  closer  to  the  cylindrical  than  to  the 
rectangular  model  (27). 

Study  of  figure  7.2  reveals  that  pores  of  sufficient 
size  to  allow  the  slow  penetration  of  plasma  proteins 
(i.e.,  30-40  A)  will  nevertheless  impose  differential 
restriction  to  diffusion  of  much  smaller  molecules. 
Thus  diffusion  of  glucose  (a  =  3.7  A)  through  pores 
of  radius  40  A  will  be  slowed  by  34  per  cent,  whereas 
diffusion  of  water  through  the  same  pores  will  be 
slowed  by  only  14  per  cent.  This  differential  restric- 
tion  to  diffusion  of  small  solutes  and  water  is  the 


% 


,tf/D-o-f)8['-«-«>(f)+"»e-f-ft*(?f] 


a 

Sylvonia 

Viscose  Wet  Gel,  r  = 

77A 

O 

Dupont 

Cellophane,  r  =  31  A 

X 

Visking 

Cellulose,  r  =  16  A 

fic.  7.2.  Restricted  diffusion  through  artificial  porous 
membranes  of  various  pore  sizes.  The  smooth  curve  is  drawn 
from  the  theory  of  restricted  diffusion,  equation  7.9.  [Adapted 
from  Renkin  (298).] 


essential  factor  underlying  transcapillary  fluid  shifts 
caused  by  transient  changes  in  the  concentration  of 
small  molecules  in  either  plasma  or  tissue  fluids. 

The  theory  of  restricted  diffusion  provides  a 
method  for  estimation  of  effective  pore  radius,  both 
in  artificial  membranes  and  in  living  capillaries.  Thus 
equation  7.9  contains  only  two  unknowns,  D'  and  r, 
and  it  is  therefore  possible  to  solve  for  r  from  observed 
diffusion  rates  of  two  molecular  species  of  known  free 
diffusion  coefficients  and  molecular  radii.  Greater 
accuracy  can  be  obtained  from  the  best  fit  of  equation 
7.9  to  results  obtained  from  several  molecular  species 
as  shown  in  figure  7.1.  Pore  dimensions  calculated 
from  the  theory  of  restricted  diffusion  agree  well  with 
values  obtained  by  independent  methods  (298). 

C.  Diffusion  and  Hydrodynamic  Flow, 
Relation  to  Pore  Dimensions 

Hydrostatic  or  osmotic  forces,  acting  across  a 
porous  membrane,  cause  net  fluid  movement  in 
proportion  to  the  difference  between  hydrostatic 
and  effective  osmotic  pressure  (equation  1.1).  Two 
different  mechanisms  are  involved,  diffusion  and 
hydrodynamic  flow. 

diffusion.  The  effective  concentration  (thermo- 
dynamic activity)  of  water  depends  upon  pressure, 
temperature,  and  solute  concentration.  An  increase 
of  pressure  or  temperature  increases  the  kinetic 
energy  of  the  water  molecules  and  therefore  increases 
the  statistical  probability  of  net  movement  toward  a 
region  of  lower  pressure  or  temperature.  Conversely, 
the  addition  of  solute  molecules  to  water  decreases 
the  probability  of  net  diffusion  of  water  to  a  region  of 
lower  solute  concentration.  For  an  ideal  semiperme- 
able membrane  Fick's  law  may  be  restated  as  follows 
to  take  account  of  these  variables 


dn 


dt 


V  ho  Ax 

h2o         * 


/AP-A/7) 
1    RT      ' 


(7.  II) 


where  q  is  rate  of  net  water  flow  (ml/sec)  and  FH2o 
is  the  partial  molal  volume  of  water  (18  cm3/mole). 
The  term  (A  j>  —  Ml)/R T  replaces  the  concentration 
term  in  Fick's  law  and  represents  the  difference  in 
activity  of  water  molecules  on  the  two  sides  of  the 
membrane.  Formal  derivations  of  equation  7.1 1  may 
be  found  in  references  (38)  or  (170). 

hydrodynamic  flow.  The  minimum  dissipation  of 
energy    for    net    water    flow    through    a    membrane 


1004 


HANDBOOK    OF    PHYSIOLOGY- 


CIRCULATION    II 


containing  A'  cylindrical  pores  of  radius  r  will  occur 
if  the  velocity  profile  assumes  the  parabolic  distribu- 
tion of  Poiseuille's  law. 


^(ar-ah) 


i.o 


8yA> 


" A-x-8-JAp-AJI) 


(7 12) 


Equation  7.12  implies  that  hydrodynamic  stream- 
ing occurs  even  when  the  hydrostatic  pressure  differ- 
ence across  the  membrane  is  zero,  i.e.,  during  flow 
caused  by  purely  osmotic  forces.  The  question  is  often 
raised  as  to  how  Poiseuille  flow  could  occur  in  the 
apparent  absence  of  a  difference  in  hydrostatic 
pressure.  An  explanation  of  this  apparent  paradox 
was  first  offered  in  an  important  paper  by  Schlogl 
(317)  who  pointed  out  that  a  hydrostatic  pressure 
drop  accounting  for  hydrodynamic  flow  does  indeed 
exist  along  most  of  the  length  of  the  membrane 
pores,  even  though  the  hydrostatic  pressures  on  the 
two  sides  of  the  membrane  are  equal.  The  intra- 
membrane  hydrostatic  pressure  gradient  reverses 
sharply  near  the  edge  of  the  pore  where  it  becomes 
equal  and  opposite  to  the  steep  gradient  of  diffusion 
potential.  A  more  detailed  treatment  of  this  hypoth- 
esis will  be  found  in  the  recent  paper  by  Ray  (292). 

Comparison  of  equation  7.1  1  with  equation  7.12 
reveals  that  for  a  given  total  pore  area,  Ap,  net  flow 
by  diffusion  is  independent  of  pore  radius,  whereas 
hydrodynamic  flow  varies  with  the  second  power  of 
the  pore  radius.  It  follows  that  for  a  given  difference 
in  hydrostatic  pressure  the  hydrodynamic  component 
of  flow  will  increase  rapidly  as  a  function  of  pore 
size.  Figure  7.3  shows  the  relative  importance  of 
diffusion  and  hydrodynamic  flow  as  a  function  of 
pore  radius.  For  porosities  in  the  range  of  interest  for 
capillary  permeability  (e.g.,  20-50  A)  the  hydro- 
dynamic  component  of  net  flow  is  overwhelmingly 
greater  than  the  diffusion  component.  The  capillary 
filtration  coefficient  discussed  in  section  6  is  therefore 
a  measure  of  hydrodynamic  conductivity  rather  than 
diffusion  permeability.  Detailed  discussions  of  the 
relations  between  diffusion  permeability  and  hydro- 
dynamic  conductivity  will  be  found  in  papers  by 
Koefoed- Johnson  &  Ussing  (177),  Pappenheimer 
(276,  277),  Garby  (1 13),  Durbin  et  al.  (83)  Kedem  & 
Katchalsky  (170)  Katchalsky  (169),  Mauro  (230), 
and  Ray  (292).  A  recent  experimental  evaluation  of 
diffusion  and  hydrodynamic  flow  through  artificial 
membranes  has  been  published  by  Robbins  & 
Mauro  (303). 

Combination  of  diffusion  data  with  hydrodynamic 


o 


<     .6 


01  ? 


1 

HYDRODYNAMIC   FLOW 

\  1 

-V 

-   h 

_/'     \ 

NET  DIFFUSION 

/        \ 

/ 

-jC___                    PORE   RADIUS 

20 

-N- 


30 


40 


50,  A 

> 


REGION  of  uncertainty  re- 

STRICTIOM  TOHrORODrNANIC 
flOW  AND  DIFFUSION  UNKNOWN 
1MIS  RANGE  OF  INTEREST  FOR 
CELLULAR   PERMEABILITY 


RECiil   IN   WHICH  EVIDENCE 
SUPPORTS    VALIDITY  OF 
POISEUILLE    FLOW     THIS 
NANCE   OF  INTEREST   FOR 
CAPILLARY    PERMEABILITY 


fig.  7.3.  Net  diffusion  and  hydrodynamic  flow  of  water  as 
a  function  of  pore  size  during  flow  induced  by  hydrostatic  or 
osmotic  forces.  For  membranes  with  effective  pore  radii  greater 
than  about  20  A  the  net  flow  of  water  by  diffusion  is  negligible 
compared  to  hydrodynamic  flow.  [From  Pappenheimer  (276).] 

data  leads  to  a  solution  for  pore  dimensions.  Equation 
7.11  describing  hydrodynamic  or  osmotic  flow  through 
cylindrical  pores  can  be  rearranged  to  give 


A  /Ax 


But  Q/(Ap  —  All)  is  the  filtration  coefficient  defined 
by  equation  1.1  and  {Au,/Ax)  can  be  determined  from 
diffusion  of  labeled  water  as  shown  in  figure  7.1. 
Therefore,  the  effective  pore  radius  is  defined  by 
measurable  quantities 


8yKf 

A.   /Ax 


(7  13) 


Similar  equations,  based  on  diffusion  and  hydro- 
dynamic  flow,  can  be  derived  to  estimate  the  dimen- 
sions of  slit  pores  (18,  281)  or  any  other  pore  geom- 
etry for  which  the  laws  of  hydrodynamic  flow  are 
known. 

Equation  7.13  has  been  used  to  estimate  pore  size 
in  artificial  membranes  (82,  298)  and  in  living 
capillaries  (281).  In  general  there  is  good  agreement 
between  pore  size  estimated  from  flow  and  diffusion 
and  pore  size  estimated  from  restricted  diffusion 
(fig.  7.1). 

D.     Simultaneous  Flow  and  Restricted  Diffusion: 
Theory  of  Molecular  Sieving 

In  the  capillary  circulation  both  filtration  and 
restricted  diffusion  usually  occur  simultaneously  and 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


IOO5 


these  two  processes,  operating  together,  are  largely 
responsible  for  observed  concentrations  of  large 
molecules  in  lymph  (126)  and  renal  glomerular 
nitrate  (194,  278,  366).  From  the  theory  of 
molecular  sieving  described  below  it  is  possible  to 
make  deductions  concerning  capillary  permeability 
for  comparison  with  results  obtained  by  independent 
methods.  The  degree  of  molecular  sieving  of  a  given 
solute  may  be  defined  as  the  ratio  of  its  concentration 
in  the  filtrate  (r2)  to  its  concentration  in  the  filtrand 
(ci).  It  is  often  supposed  that  during  ultrafiltra- 
tion of  a  monodisperse  solute  through  an  isoporous 
membrane,  the  value  of  ( 2/<  1  will  be  zero  when  the 
pores  are  smaller  than  the  solute  molecules  and  unity 
when  the  pores  are  larger  than  the  solute  molecules. 
If  intermediate  values  are  actually  observed  they  are 
said  to  be  evidence  for  heteroporosity.  If,  for  example, 
the  concentration  of  a  given  solute  in  a  capillary 
ultrafiltrate  is  50  per  cent  of  that  in  plasma  it  is 
supposed  that  half  the  capillary  pores  were  smaller 
than  the  solute  molecules  and  half  were  larger  (21, 
208,  232,  254).  This  reasoning  fails  to  explain  the 
dependence  of  molecular  sieving  on  filtration  rate. 
The  following  considerations  show  that  molecular 
sieving  of  a  monodisperse  solute  through  an  isoporous 
membrane  is  determined  by  the  ratio  of  restricted 
diffusion  to  rate  of  filtration. 

If  the  passage  of  solute  through  a  porous  membrane 
is  restricted  relative  to  passage  of  solvent,  then  the 


filtration,  c2  approaches  c-y  (dialysis)  and  at  high  rates 
of  filtration  c,  c,  approaches  the  ratio  of  restricted 
pore  areas  Aa/Aw.  Equation  7.14  is  derived  on  the  as- 
sumption that  the  concentration  gradient  through  the 
membrane  is  linear.  Grotte  (126),  Garby  (113),  and 
Kuhn  (192)  have  pointed  out  that  the  concentration 
gradient  in  the  membrane  will  in  general  be  an  ex- 
ponential function  of  flow  velocity,  but  this  correction 
was  shown  by  Grotte  to  be  a  small  one  and  will  be 
neglected  here. 

The  restricted  pore  areas,  Aw  and  As,  have  been 
expressed  by  equation  7.10  as  a  function  of  molecular 
radius  and  pore  radius.  Substitution  of  this  function 
in  equation  7.14  yields  a  cumbersome  but  explicit 
expression  for  molecular  sieving  as  a  function  of 
filtration  rate  when  molecular  and  membrane  pore 
dimensions  are  known;  conversely,  it  provides  an 
independent  method  for  calculation  of  pore  size  from 
experimental  measurements  of  molecular  sieving  and 
filtration  rate. 

Figure  7.4  shows  experimentally  determined  values 
of  molecular  sieving  as  a  function  of  filtration  rate 
through  Visking  dialysis  membrane.  The  theoretical 
curves  were  drawn  according  to  equation  7.15,  using 
the  value  of  Aw/Ax  determined  from  diffusion  of 
tritiated  water  and  choosing  pore  radii  to  provide  the 
best  fits  to  the  experimental  data  for  each  molecular 
species.  Satisfactory  fits  were  obtained  with  pore  radii 
15  to  17  A.  Pore  radius  for  the  same  membrane 
estimated    irom    the    theory    of   restricted    diffusion 


C2 


I   + 


Ax 


/*{<-&'-{'-?/ %  ][<-2'0(^)  +  2.09(±-f-0.95(^)5]    +°< 


(7. 15) 


filtrate  will  be  diluted  during  filtration,  thus  giving 
rise  to  a  concentration  difference  for  diffusion  at  a 
rate  determined  by  the  restricted  diffusion  coefficient, 
D' ,  through  the  membrane.  The  ultimate  steady- 
state  composition  of  the  filtrate  relative  to  filtrand 
(ci/ci)  is  therefore  determined  by  a  race  between 
hydrodynamic  flow  (Qj)  tending  to  dilute  the  filtrate 
and  restricted  diffusion  tending  to  restore  the  concen- 
tration difference.  A  quantitative  expression  for 
molecular  sieving  through  isoporous  membranes 
was  derived  by  Pappenheimer  (276) 


C? 


I  + 


J-=         Of       Ax 


*.+$. 


(7. 14) 


Ax 


Inspection  of  equation  7.14  shows  that  at  low  rates  of 


Ax 


(fig.  7.1)  was  16  A,  and  pore  radius  estimated  from 
combination  with  Poiseuille's  law  was  ig  A  (equation 
7.13).  The  internal  consistency  of  these  various 
estimates  of  pore  radius  in  artificial  membranes 
constitutes  the  chief  evidence  justifying  the  application 
of  similar  techniques  to  biological  membranes. 

E.  Distribution  of  Pore  Sizes 

Observed  values  for  diffusion  and  molecular  sieving 
through  artificial  porous  membranes  are  in  reasonable 
accord  with  theoretical  predictions  for  isoporous 
membranes.  Equal  or  slightly  better  agreement 
between  experiment  and  theory  can  be  obtained  by 
assuming  certain  limited  distributions  of  pore  sizes 
(298).  An  upper  limit  to  pore  size  may  be  determined 


ioo6 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


(a)VISKING    SAUSAGE   CASING 

.a. 


I5A  UREA 


I5A  GLUCOSE 


SUCROSE 


r-RAFFINOSE 


FILTRATION    RATE     Cm  ^ec  x  10* 


0.2 


0.4 


0.6 


0.8 


fig.  7.4.  Molecular  sieving  through  an  artificial,  porous 
membrane.  The  smooth  curves  are  constructed  from  the  theory 
of  molecular  sieving,  equation  7.15.  The  data  fit  pore  radii  in 
the  range  15-17  A.  Mean  pore  radius  for  the  same  membrane 
estimated  from  the  theory  of  restricted  diffusion  was  16  A 
and  pore  radius  estimated  from  combination  with  Poiseuille's 
law  was  19  A.  The  internal  consistency  of  these  various  esti- 
mates of  pore  radius  in  artificial  membranes  constitutes  the 
chief  evidence  justifying  the  application  of  similar  techniques 
to  biological  membranes  of  comparable  pore  size.  [Adapted 
from  Renkin  (298).] 

from  the  size  of  the  largest  molecule  which  just  fails 
to  pass  through  the  membrane.  A  less  obvious  limit 
to  any  assumed  distribution  arises  from  the  fact  that 
filtration  rate  varies  with  the  fourth  power  of  the 
radius  so  that  the  total  fraction  of  large  pores  must 
be  limited  in  order  to  satisfy  the  requirements  im- 
posed by  the  observed  filtration  coefficient.  If  a 
membrane  contains  cylindrical  pores  of  different 
radii  then  the  mean  equivalent  pore  radius,  r,  for 
hydrodynamic  flow  is  given  by 


7'Vfc+tf 


F„r; 


(7. 16) 


where  Fn  is  the  fraction  of  total  pore  population 
having  a  radius  rn.  For  example,  the  membrane 
illustrated  in  figures  7.1  and  7.4  did  not  allow  the 
passage  of  hemoglobin  (a  32  A)  and  therefore  an 
upper  limit  to  its  pore  size  distribution  is  32  A.  How- 
ever, less  than  20  per  cent  of  the  pores  could  be  as 
large  as  30  A  otherwise 

7>yh.2x  (30)4  >20A 

which  would  not  fit  the  requirement  that  r  =  19  A 
set  by  the  observed  filtration  coefficient  and  diffusion 


area  for  water  (equation  7.13).  The  detailed  com- 
putation of  possible  pore  distributions  which  would 
fit  the  data  for  filtration,  restricted  diffusion  and 
molecular  sieving  is  possible  but  laborious.  For  the 
membrane  illustrated  in  figures  7.1  and  7.4  the 
broadest  Gaussian  distribution  of  pore  radii  com- 
patible with  the  data  is  defined  by  a  mean  pore  radius 
of  14  A  with  a  standard  deviation  of  7  A  (298). 

F.  Osmotic  Pressure*  and  Osmotic  Flow  Through 

Leaky  Membranes;   Osmotic  Reflection   Coefficients 

Van't  Hoff's  law  relating  osmotic  pressure  to 
concentration  was  derived  for  a  perfectly  semi- 
permeable membrane.  Relatively  little  is  known  of 
osmotic  forces  associated  with  diffusion  and  osmotic 
flow  through  membranes  which  restrict,  but  do  not 
prevent  entirely,  the  diffusion  of  solute  molecules. 
The  quantitative  significance  of  this  problem  may  be 
illustrated  by  a  specific  example.  Consider  a  two- 
compartment  system  separated  by  a  membrane 
containing  pores  of  radius  30  A.  Addition  to  one 
compartment  of  an  ideal  solute  of  molecular  radius 
30  A  will  cause  osmotic  flow  through  the  membrane 
at  a  rate  equal  to  that  caused  by  a  hydrostatic  pressure 
difference  of  cRT  mm  Hg  (equation  7.12).  However, 
if  the  same  molar  concentration  of  a  small  molecule 
such  as  urea  (molecular  radius  2.7  A)  is  added  to  one 
compartment,  it  will  be  found  that  the  osmotic  flow- 
is  less  than  5  per  cent  of  that  obtained  by  the  hydro- 
static equivalent  (82). 

In  1 951  Staverman  (349,  350)  introduced  the 
expression  "osmotic  reflection  coefficient,"  a,  as  an 
empirical  descriptive  term  modifying  van't  Hoff's 
law  for  the  case  of  leaky  membranes. 

n  -"  CRT*  (7. 17) 

The  value  of  a  ranges  from  unity  in  perfectly  semi- 
permeable membranes  to  less  than  zero  when  the 
mobility   of  the   solute   exceeds   that   of  the   solvent 

(333)- 

Very   small   values   of  a   have   been   reported   for 

osmotic    flow    caused    by    small    molecules   diffusing 

3  "Osmotic  pressure"  is  ordinarily  defined  for  the  case  of 
thermodynamic  equilibrium  across  ideal  semipermeable 
membranes  and  the  term  has  no  equivalent  meaning  for  the 
irreversible  process  to  be  considered  here.  Possibly  a  different 
term  should  be  coined  to  describe  the  transmembrane  pressures 
arising  during  restricted  diffusion  through  porous  membranes. 
"Restricted  diffusion  pressure"  would  be  accurate  but  could 
only  be  applied  to  the  case  of  zero  net  flow  of  solvent  through 
the  membrane. 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


IOO7 


through  large  pored  artificial  membranes.  Thus 
Meschia  &  Setnikar  (250)  found  that  less  than  2  per 
cent  of  the  ideal  osmotic  potential  was  developed  by 
sucrose  during  osmotic  flow  through  a  collodion 
membrane  having  pores  of  radius  no  A  (i.e.,  when 
the  radius  of  the  pore  was  approximately  25-fold 
greater  than  the  radius  of  the  diffusing  molecule). 
Similarly  low  values  for  osmotic  reflection  coefficient 
have  been  reported  by  Grim  (125)  and  by  Shuler 
et  al.  (333)  on  the  basis  of  osmotic  flow  through 
uncalibrated  membranes. 

Durbin  (82)  has  recently  completed  a  study  of 
osmotic  flow  caused  by  molecules  of  graded  sizes 
diffusing  through  calibrated  porous  membranes.  His 
results  shows  that 


-('■%.) 


where  As  is  the  restricted  pore  area  available  to  the 
solute  and  Au.  is  the  restricted  pore  area  available  to 
the  solvent  as  defined  by  equation  7.9  and  figure  7.1. 
Durbin's  results  indicate  that  during  osmotic  flow- 
through  artificial  membranes  the  value  of  a  is  less 
than  o.  1  when  the  radius  of  the  diffusing  molecule  is 
10  per  cent  of  the  radius  of  the  pore. 

From  existing  data  one  must  therefore  conclude 
that  only  a  small  fraction  of  the  theoretical  van't 
Hoff  pressure  is  operative  across  artificial  membranes 
during  restricted  diffusion  of  small  molecules  through 
the  membranes.  On  the  other  hand,  relatively  large 
osmotic  forces  have  been  observed  during  the  re- 
stricted diffusion  of  small  molecules  through  biological 
membranes  under  conditions  involving  little  or  no 
net  fluid  movement  (122,  281).  Under  these  con- 
ditions the  osmotic  reflection  coefficient  appears  to 
depend  upon  the  restricted  diffusion  coefficient  of 
solute  relative  to  that  of  the  solvent. 

uw  »  w 

Combination  of  equation  7.18  with  equation  7.9 
allows  numerical  evaluation  of  a  for  the  case  of  zero 
net  fluid  movement  when  molecular  radius  and  pore 
radius  are  known.  Thus, 


rapidly  in  the  virtual  absence  of  net  fluid  movement 
(281). 

In  experiments  involving  artificial  membranes  it  is 
exceedingly  difficult  to  measure  osmotic  forces  in  the 
absence  of  osmotic  flow,  as  pointed  out  in  section  3. 
For  this  reason  all  investigations  of  osmotic  reflection 
coefficient  in  artificial  systems  have  thus  far  invoked 
net  flow  of  fluid.  Under  these  conditions  the  frictional 
forces  determining  osmotic  reflection  coefficient  will 
contain  hydrodynamic  as  well  as  diffusional  terms  as 
emphasized  in  recent  derivations  by  Ray  (292)  and 
Katchalsky  (169).  Discussion  of  these  derivations  is 
beyond  the  scope  of  this  chapter  but  it  seems  fair  to 
say  that  no  well-substantiated  theory  is  yet  available 
to  predict  osmotic  reflection  coefficients  as  a  function 
of  membrane  permeability  and  flow  rate.  Since  most 
biological  membranes  allow  the  restricted  passage  of 
environmental  solutes,  the  problem  remains  as  one  of 
the  most  important  unsolved  questions  in  contem- 
porary studies  of  permeability. 


8.    TRANSCAPILLARV    MOVEMENT    OF 

LIPID-INSOLUBLE    MOLECULES 

The  concentration  gradients  which  provide  the 
driving  force  for  diffusion  exchange  between  blood 
and  tissues  are  normally  maintained  by  tissue  me- 
tabolism. However,  the  transcapillary  exchange 
process  is  so  efficient  that  normal  transcapillary 
concentration  differences  of  small  molecules  would  be 
too  small  to  be  detectable  by  existing  methods,  even 
supposing  it  were  feasible  to  collect,  for  analysis, 
tissue  fluid  from  the  immediate  vicinity  of  the  capillary 
wall.  From  an  experimental  point  of  view  it  is  there- 
fore necessary  to  establish  abnormally  large  trans- 
capillary concentration  ratios  in  order  to  study 
diffusion  characteristics  of  the  capillary  walls. 

Figure  8.1  summarizes  data  showing  rates  of 
disappearance  from  the  circulatory  system  of  various 
lipid-insoluble  substances  which  distribute  primarily 
in  extracellular  fluid.  It  is  evident  that  these  sub- 
stances leave  the  vascular  system  at  rates  which  vary 


IT.*  I- 


D'/0-  &f*0&+  2.09&-0.95&]  I 


(7. 19) 


Equation    7.19    is   specially   applicable    to   capillary 
membranes  where  osmotic  forces  can  be  measured 


inversely  with   molecular  size.    Disappearance   from 
plasma  is  accompanied  by  simultaneous  appearance 


ioo8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


SERUM  ALBUMIN 
MW   69,000 


fig.  8.1.  Disappearance  of  substances  from  arterial  plasma 
of  rabbits.  Data  for  albumin  are  from  Gitlin  et  al.  (118),  data 
for  inulin  and  sucrose  are  from  Kruhoffer  (190,  191),  and  data 
for  NaCl  are  from  Morel  (257).  C  is  concentration  in  arterial 
plasma  at  time  /,  C,„  is  concentration  in  plasma  at  equilibrium; 
C0  is  initial  concentration  in  arterial  plasma  obtained  by 
extrapolation  to  zero  time. 


of  the  test  molecules  in  tissue  spaces,  again  at  rates 
which  vary  inversely  with  molecular  size.  Most 
tissues  of  the  body  participate  in  the  distribution 
process,  though  at  widely  different  rates. 

The  rapid  penetration  of  capillary  walls  by  mole- 
cules as  large  as  sucrose  or  inulin  implies  a  high  order 
of  permeability  to  lipid-insoluble  molecules.  Cell 
membranes  generally  (i.e.,  the  plasma  membranes 
which  envelop  the  protoplasm  of  all  living  cells)  are 
virtually  impermeable  to  metabolically  inert,  lipid- 
insoluble  molecules  as  large  as  sucrose;  indeed  they 
generally  have  a  low  order  of  permeability  to  most 
ions.  The  behavior  illustrated  in  figure  8.1  is  more 
characteristic  of  artificial  porous  membranes  and  this 
resemblance  has  given  rise  to  the  hypothesis  that 
capillarv  blood  communicates  directly  with  extra- 
vascular  fluid  via  a  system  of  aqueous  pores  or 
channels.  Recent  studies  of  capillary  ultrastructure 
(93)  support  earlier  views  (37,  276)  that  the  structural 
basis  for  this  type  of  permeability  is  associated  with 
junctional  regions  between  capillary  endothelial  cells. 
The  number,  dimensions,  and  properties  of  trans- 
capillary  pores  which  would  be  necessary  to  account 


for  observed  capillary  permeability  to  lipid-insoluble 
molecules  will  be  considered  more  fully  in  section  g. 
Initial  experiments  with  isotopic  tracers  led  to  the 
suggestion  that  arterial  disappearance  curves  might 
provide  a  quantitative  measure  of  capillary  perme- 
ability (106,  138).  For  this  purpose  it  was  assumed 
that  diffusion  from  blood  to  extravascular  space 
could  be  represented  by  a  simple  two-compartment 
diffusion  system  separated  by  the  capillary  membranes 
and  that  concentrations  in  each  compartment  would 
be  uniform  at  each  moment  during  the  diffusion 
process.  The  theoretical  equation  describing  diffusion 
in  this  simplified  model  is  easily  derived  from  Fick's 
law  and  leads  to  the  expression 


X- 


DAS   (Vi  +  Vg) 


Ax 


V  V 

V  2 


(8.1) 


where  X  is  the  (negative)  slope  of  the  observed  ex- 
ponential disappearance  curve,  V\  is  plasma  volume 
and  Fo  is  extravascular  distribution  volume  (106,  233). 
Reference  to  equation  7.2  shows  that  the  term  DA  Sx 
is  the  flux  per  unit  concentration  difference,  n  A< , 
and  is  therefore  a  direct  measure  of  capillary  perme- 
ability to  the  test  molecules.  More  complex  equations 
describing  arterial  disappearance  curves  have  been 
derived  to  take  account  of  loss  by  the  kidneys,  loss 
by  metabolism  and  distribution  between  more  than 
two  compartments  in  series  or  in  parallel  (318,  319, 

33°.  34'-  363)- 

Equation  8.1   is  specially  applicable  to  the  case  of 

large,  lipid-insoluble  molecules  such  as  proteins  or 
synthetic  polymers.  Diffusion  of  such  substances 
from  the  vascular  system  is  so  slow  that  their  concen- 
trations in  arterial  plasma  may  be  taken  as  a  close 
approximation  of  mean  concentration  in  capillary 
plasma,  i.e.,  the  concentration  gradient  along  the 
length  of  each  capillary  is  negligible  at  all  times  during 
the  diffusion  process.  In  the  example  of  figure  8.1  the 
slope,  \,  for  albumin  is  about  — 0.1  per  cent  of  the 
initial  concentration  per  min,  or  100  per  cent  of  the 
plasma  albumin  every  16.6  hours.  Similar  values  for 
transcapillary  exchange  rates  of  serum  albumin  have 
been  observed  in  dog  (370)  and  man  (352).  The  free 
diffusion  coefficient  of  albumin  is  0.085  X  io-5  cm2 
per  sec.  Given  a  normal  plasma  volume,  V\t  of  4  per 
cent  of  body  weight  and  a  normal  extracellular  fluid 
volume,  r2,  of  20  per  cent  then  from  equation  8.1 
the  effective  capillary  pore  area  per  unit  path  length 
available  for  restricted  diffusion  of  serum  albumin  is 
65  cm  per  100  g  tissue.  This  value  may  be  compared 
with  the  value  of  70  cm  per  100  g  muscle  calculated 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


IOOg 


from  the  theory  of  restricted  diffusion  through  pores 
of  radius  43  A  (table  9.1). 

Arterial  disappearance  curves  therefore  provide  a 
method  for  quantitative  studies  of  overall  capillary 
permeability  to  large  molecules.  It  is  not  possible, 
how  ever,  to  extend  this  type  of  analysis  to  molecules 
which  diffuse  rapidly  through  capillary  walls.  In 
this  case  the  mean  concentration  in  capillary  plasma 
may  be  only  a  small  fraction  of  that  in  arterial  plasma, 
particularly  in  early  phases  of  the  distribution  process. 
Application  of  equation  8. 1  to  such  data  leads  to 
estimates  of  capillary  permeability  which  are  too  low, 
often  by  1  or  2  orders  of  magnitude  [see  (281)  and 
(382)  for  critical  review].  Factors  which  determine 
mean  concentration  differences  of  small  molecules 
across  capillary  walls  during  diffusion  include  rate  of 
blood  flow,  diffusion  rate,  and  the  geometry  and 
volume  of  extravascular  diffusion  space.  Several 
interesting  attempts  have  been  made  to  take  account 
of  these  factors  by  mathematical  techniques  but  the 
solutions  are  complex  and  involve  assumptions  which 
are  difficult  to  evaluate  experimentally  (19,  319). 

Specialized  experimental  methods  for  estimating 
capillary  permeability  to  small  molecules  were 
developed  by  Pappenheimer  et  al.  (281)  for  the  study 
of  molecular  exchanges  in  the  capillary  circulation  of 
hind  limbs  of  cats  or  dogs.  Results  obtained  by  these 
methods  lead  to  conclusions  of  general  interest 
relating  capillary  permeability  to  the  number  and 
dimensions  of  capillary  pores  which  would  be  re- 
quired to  explain  observed  transcapillary  diffusion 
rates  of  lipid-insoluble  molecules  ranging  in  size  from 
D20  to  hemoglobin. 


9.    STRUCTURE  OF  MUSCLE  CAPILLARIES  AS  DEDUCED  FROM 
PERMEABILITY  MEASUREMENTS  AND    FROM  ELECTRON 
MICROSCOPY'.    QUANTITATIVE    ASPECTS    OF 
TRANSCAPILLARY    DIFFUSION 

In  isolated  perfused  tissues  the  rate  of  net  trans- 
capillary  movement  of  test  substances  can  be  de- 
termined from  the  product  of  blood  flow  and  arterio- 
venous concentration  difference.  Thus, 

(9.1) 

where  Q  is  blood  for  plasma)  flow  and  ca,  cv  are  the 
simultaneously  measured  concentrations  of  the  test 
substance  in  arterial  and  venous  bloods  (or  plasma). 
The  driving  force  for  diffusion  (i.e.,  the  mean 
concentration  difference  across  the  capillary  walls) 
may  be  estimated  from  the  partial  osmotic  pressure 


n=  Qb(ca-cJ 


0.6  x  10   cm 


0.4 


As      RTo-       h 


38  « 10* cm 


0.2 


mq  /sec 
per  IOOg  muscle 
0.15 


0.10 


NET  FLUX, 
n  =  Q(C0-CV) 


0.05 


PARTIAL  OSMOTIC   PRESSURE 

DEVELOPED  ACROSS 

CAPILLARY  MEMBRANES 


10 


15 


20 


JlL 


30 

1 


MINUTES  AFTER  ADDITION  OF  RAFFINOSE 

no.  9.  i .  Diffusion  of  raffinose  from  the  capillaries  of  a 
perfused  cat  hind  limb.  At  zero  time  20  mM/liter  raffinose  was 
added  to  the  perfusion  reservoir.  The  final  distribution  volume 
of  raffinose  in  perfused  tissue  was  19%  of  limb  volume.  The 
capillary  diffusion  area  per  unit  path  length  calculated  for 
raffinose  was  0.38  X  io5  cm2;  this  value  was  independent  of 
time,  extravascular  fluid  volume,  or  of  mechanically  induced 
changes  of  blood  flow.  [Adapted  from  Pappenheimer  et  al. 
(281).] 

exerted  by  the  test  molecules  during  the  diffusion 
process.  Figure  9. 1  illustrates  a  typical  experiment 
showing  the  simultaneous  measurement  of  net  flux 
rate  and  partial  osmotic  pressure  during  the  diffusion 
of  raffinose  from  the  capillaries  of  a  perfused  cat 
hind  limb.  The  ratio  of  flux  rate  to  partial  osmotic 
pressure  is  proportional  to  permeability  and  may  be 
related  to  the  restricted  pore  area  per  unit  path 
length  in  the  capillary  wall  by  combining  equations 
7.6  and  7.1  7. 


Ax 


RTcr        ft 
Dt      * AIT 


(9.2) 


ioio 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


\  Ax 

xlO~5cm 

RESTRICTED   PORE    AREA 

-    \ 

PER  UNIT   PATH   LENGTH 
IN   lOOg    MUSCLE 

-\ 

iX  GLUCOSE 

\  NaCI 
\UREA 

As      RTo-      li 
flx  ~  "D7*flTT 

\    X  SUCROSE 

\    X  RAFFINOSE 

Theoretical  curves  for 

membrane  with  cylindrical 

- 

pores  of  rodios   40 -45 A 
and  some   filtration  coef- 

ficient as  capillaries 

^X  INULIN 

^5^— _                                        SERUM 

MYOGLOBIN    X                  -^=^~-— _          ALBUMIN 
_J 1 1 1 1                     1-                   IX 

0  5  10  15  20  25  30  35 

MOLECULAR   RADIUS,   A 

FIG.  Q.2.  Restricted  diffusion  of  lipid-insoluble  molecules 
from  the  capillaries  of  perfused  cat  hind  limbs.  Each  point 
represents  the  mean  value  of  data  from  several  experiments. 
The  curves  are  constructed  from  the  theory  of  restricted  diffu- 
sion and  filtration  (equation  9.3)  on  the  assumption  that  the 
osmotic  reflection  coefficient  is  determined  by  equation  7.19. 
The  data  fit  theoretical  restricted  diffusion  through  pores  of 
radius  40-45  A  in  a  membrane  having  the  same  filtration 
fcoefficient  as  the  capillaries  in  the  hind  limb.  [Recalculated 
rom  the  data  of  Pappenheimer  et  al.  (281).] 

The  upper  panel  of  figure  9. 1  shows  that  for 
rafnnose    the    restricted    pore    area    per    unit    path 


cm2  or  less  than  0.1  per  cent  of  the  total  capillary 
surface  area  in  100  g  muscle.  This  conclusion  is 
consistent  with  the  view  that  transcapillary  ex- 
changes of  lipid-insoluble  molecules  take  place  at 
junctional  regions  between  endothelial  cells  and  we 
have  already  seen  that  pore  areas  of  this  magnitude 
can  provide  a  physiologically  sufficient  flow  of  small 
molecules  under  the  influence  of  small  concentration 
gradients  (section  7  A). 

In  the  original  analysis  of  Pappenheimer  et  al.  (281) 
the  mean  pore  radius  was  estimated  from  combina- 
tion of  the  capillary  filtration  coefficient  with  the 
pore  area  per  unit  path  length  for  a  molecule  the 
size  of  water  (equation  7.13).  However,  the  latter 
quantity  was  uncorrected  for  the  osmotic  reflection 
coefficient  and  therefore  cannot  be  employed  for  the 
present  analysis  in  which  the  osmotic  reflection 
coefficient  is  included  as  an  unknown.  In  order  to 
solve  for  this  additional  unknown  it  is  necessary  to 
introduce  an  additional  equation  relating  osmotic 
reflection  coefficient  to  pore  dimensions  as  suggested 
by  equation  7.19.  This  equation  is  cumbersome  and 
its  use  may  not  be  entirely  justified  on  the  basis  of 
our  present  inadequate  knowledge  of  factors  de- 
termining osmotic  reflection  coefficients.  Neverthe- 
less, it  leads  to  a  solution  for  capillary  pore  dimensions 
which  is  more  consistent  with  available  data  than  the 
dimensions  originally  proposed  by  Pappenheimer 
et  al.  (281).  Substitution  of  equations  7.19  and  9.2  in 
equation  7.13  yields 


(,-^f[i-2,0(^)+2.09(^)3-0.95(±)5] 


(,-  f*ffziO&)  +  2.09(^-)-0.95(^ 


8VK,     An 
D„[      RTD.    *  n 


(9.3) 


length,  calculated  from  equation  9.2,  was  0.38  ±  .04 
X  io6  cm.  Results  of  similar  measurements,  made 
with  a  variety  of  molecular  species,  are  shown  in 
figure  9.2.  It  is  seen  that  in  capillaries,  as  in  artificial 
porous  membranes  (fig.  7.1),  the  restricted  pore  area 
decreased  as  a  function  of  molecular  radius  as  pre- 
dicted from  the  theory  of  restricted  diffusion  (equa- 
tion 7.9).  Extrapolation  to  zero  molecular  radius 
suggests  that  the  true  pore  area  per  unit  path  length 
in  the  capillaries  of  100  g  muscle  is  approximately 
0.6  X  io5  cm.  Since  the  average  thickness  of  the 
capillary  walls  is  less  than  io~4  cm  (fig.  9.3),  this 
suggests  that  the  total  pore  area  available  for  diffusion 
exchange  of  lipid-insoluble  molecules  is  less  than  6 


where 

j       =  mean  capillary  pore  radius,  A 
aw     =  radius  of  water  molecule  =   1.5  A 
a,      =  radius  of  test  molecule,  A 

=  free    diffusion    coefficient   of  water    =    3.4    X     io-5 

cm2  per  sec-1 
=  free  diffusion  coefficient  of  test  molecule 
=  viscosity   of  water    =    0.007   dyne-sec-cm-2   at   37   C 
Kf    =  filtration  coefficient  of  capillaries,  average  value  1.8  X 

io-7  cm5-dyne~'-sec~l  per  100  g 
All    =  observed    partial    osmotic    pressure,    dynes-cm-2    at 

time,  / 
n       =  observed  flux  rate,  mole-cm3  at  time,  i 
RT  =  25  X   io9  dyne-cm-mol-1  at  37  C 

Study  of  equation  9.3  in  relation  to  the  experimental 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


101 


600  A   QftWW«i!*5*»&iw 


fig.  9.3.  Diagram  illustrating  current  concepts  of  fine  structure  in  muscle  capillaries.  [From 
Fawcett  (93).]  The  nucleus  of  a  single  endothelial  cell  is  shown  at  left.  The  capillary  cross  section 
may  be  formed  by  a  single  cell  rolled  into  a  tube  or  may  be  made  up  of  several  cells.  The  inter- 
endothelial  region  appears  as  a  thin  slit  pore  with  direct  connection  from  inside  to  outside  of  capil- 
lary. The  slit  may  be  straight  or  slightly  tortuous  (inset  and  fig.  9.4)  and  is  usually  about  90  A  wide 
and  0.5-1  n  in  length.  It  occupies  only  a  fraction  of  1  %  of  the  total  endothelial  surface.  The  cyto- 
plasm contains  the  usual  organelles,  but  in  addition  contains  numerous  small  vesicles  and  inpocket- 
ings  of  the  surface  which  are  characteristic  of  microphagocytosis  or  pinocytosis.  Palade  (273)  has 
suggested  that  this  mechanism  may  be  involved  in  the  transcapillary  passage  of  particles  which 
are  too  large  to  traverse  interendothelial  openings.  The  outer  surface  of  the  endothelium  is  en- 
veloped by  an  amorphous  basement  membrane  about  600  A  in  thickness  and  with  histochemical 
properties  indicative  of  a  mucopolysaccharide.  The  permeability  properties  of  this  membrane  are 
unknown.  Dilute  solutions  of  mucopolysaccharides,  in  contrast  to  gelatin-gels  (112),  may  offer 
appreciable  resistance  to  free  diffusion  (266).  Finally,  it  should  be  emphasized  that  the  diagram 
refers  only  to  muscle  capillaries.  Morphological  differences  between  capillaries  in  different  vascular 
beds  have  been  reviewed  by  Bennett  it  al.  (13). 


data  of  figure  9.2  reveals  that  the  pore  radius,  r,  is 
the  only  unknown  quantity.  The  numerical  evalua- 
tion of  r  from  equation  9.3  may  be  carried  out  by 
successive  approximation  or  by  graphical  analysis. 
For  the  specific  example  illustrated  in  figure  9. 1  the 
value  of  r  is  41  A.  Similar  analysis  of  data  for  NaCl, 
urea,  glucose,  and  sucrose  leads  to  mean  pore  radii  of 
44,  43,  45,  and  41  A,  respectively.  These  results  are 
in  accord  with  values  in  the  range  35  to  45  A  esti- 
mated by  Grotte  (126)  from  molecular  sieving  of 
dextrans  in  hind  limb  capillaries  (section  10  and 
fig.  10. 1).  They  are  in  contrast  to  the  value  of  30  A 
estimated  by  Pappenheimer  et  al.  (281)  from  combi- 
nation of  filtration  coefficient  with  uncorrected 
diffusion  data  and  to  the  value  of  25  A  estimated  by 
Renkin  &  Pappenheimer  (301)  from  uncorrected 
restriction  to  diffusion.  The  dimensions  and  fractional 


surface  area  of  aqueous  transcapillary  pores  cor- 
respond closely  with  dimensions  of  interendothelial 
junctions  as  determined  by  electron  microscopy. 
Figure  9.3  summarizes  pertinent  aspects  of  pore 
structure  in  muscle  capillaries;  details  of  a  typical 
interendothelial  junction  are  illustrated  in  figure  9.4. 
On  the  basis  of  present  information  we  can  compare 
the  permeability  of  capillaries  in  100  g  of  muscle  to 
that  of  an  artificial  membrane,  7000  cm2  in  total 
area,  0.5  it  thick  and  containing  5  X  io12  uniform, 
water-filled,  cylindrical  pores  of  radius  40  to  45  A. 
Such  an  artificial  membrane  would  have  the  same 
filtration  coefficient  as  the  capillaries  in  100  g  muscle 
and  would  restrict  the  diffusion  of  uncharged,  lipid- 
insoluble  molecules  to  about  the  same  degree  (fig. 
9.2).  There  are  no  reasons  for  supposing,  however, 
that  the  channels  through  capillary  walls  are  either 


1012 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  9.4.  A  portion  of  the  wall  of  a  capillary  (heart  musclel 
to  show  details  of  the  interendothelial  junction.  The  junction 
provides  a  continuous  channel  connecting  the  inside  of  the 
capillary  with  the  outside  basement  membrane.  The  width  of 
the  channel  is  about  100  A.  The  interior  of  the  capillary  is 
almost  filled  with  an  erythrocyte.  [From  Fawcett  (93).] 


cylindrical  or  perfectly  uniform.  Alternative  models 
utilizing  different  pore  geometries  or  a  limited  distri- 
bution of  pore  sizes  could  be  devised  to  simulate  ob- 
served capillary  permeability.  The  significant  fact  is 
that  both  the  hydrodynamic  and  diffusional  char- 
acteristics of  the  capillaries  can  be  explained  in  terms 
of  a  simple  physical  model  which  closely  approxi- 
mates the  morphology  of  the  capillary  wall.  The  mean 
pore  radius  calculated  as  above  may  be  regarded  as 
analogous  to  the  Einstein-Stokes  molecular  radius 
(equation  7.5)  which  by  itself  tells  nothing  of  the 
actual  shape  of  the  molecule  but  is  nevertheless 
valuable  for  predicting  kinetic  behavior. 

The  restricted  pore  areas  shown  in  figure  9.2  repre- 
sent only  a  minute  fraction  of  the  total  capillary 
surface,  but  they  nevertheless  provide  for  extremely 
rapid  transcapillary  diffusion  of  small  lipid-insoluble 
molecules.  The  pore  area  per  unit  path  length  avail- 


able for  diffusion  of  water  through  the  capillary  walls 
of  100  g  muscle  is  about  0.6  X  io5  cm  (fig.  9.2).  The 
concentration  of  water  available  for  diffusion  in  either 
direction  is  about  55  molar  (0.99  g/ml)  and  the  diffu- 
sion coefficient  of  water  is  3.4  X  io5  cm2  per  sec. 
Substitution  of  these  values  in  Fick's  diffusion  equa- 
tion leads  to  a  calculated  diffusion  rate  of  2  g  per  sec. 
Since  the  total  volume  of  plasma  in  the  capillaries  of 
100  g  of  muscle  is  only  about  1  ml,  this  suggests  that 
plasma  water  exchanges  2  times  per  sec  or  1 20  times 
per  min  with  the  interstitial  water  immediately  sur- 
rounding the  capillaries.  Similar  calculations  for 
NaCl,  urea,  and  glucose  yield  exchange  rate  of  60,  55, 
and  30  times  the  plasma  content  of  these  substances 
per  minute.  An  alternative  method  of  expressing  the 
results  is  in  terms  of  the  ratio  of  exchange  rate  to 
plasma  flow.  The  latter  is  generally  in  the  range  2  to  4 
ml  per  min  per  1 00  g  tissue.  Taking  3  ml  per  min  as 
an  average,  we  would  estimate  that  the  diffusion  of 
water,  NaCl,  urea,  and  glucose  back  and  forth  through 
the  capillary  wall  occurs  at  rates  which  are,  respec- 
tively,  40,  20,  18,  and  10  times  the  rate  at  which 
these  substances  are  brought  to  the  tissues  by  the  in- 
coming blood.  In  contrast,  the  extravascular  circula- 
tion of  fluid  caused  by  net  filtration  and  absorption  is 
only  about  2  per  cent  of  the  plasma  flow  as  indicated 
in  figure  5.2.  For  this  reason  the  rates  of  exchange  of 
small  molecules  between  blood  and  tissues  are  but 
little  affected  by  simultaneous  net  fluid  movement. 
For  example,  //-aminohippurate  and  related  sub- 
stances diffuse  rapidly  out  of  the  peritubular  capil- 
laries in  the  direction  opposite  to  net  fluid  flow  (peri- 
tubular capillary  reabsorption).  The  rates  of  clearance 
of  NaM  of  I131  from  skin  are  not  appreciably  affected 
by  concurrent  edema  formation  (164). 

The  permeability  of  biological  membranes  is  usually 
expressed  in  terms  of  flux  rate  per  unit  concentration 
difference  divided  by  the  area,  Am  ,  of  the  entire  mem- 
brane surface  (specific  permeability  coefficient ) 
n      .     „    .  DtAs 


P,  -- 


-*-A„ 


(9.4) 


Ac         ~m     A  Ax 

m 

Values  of  Ps  for  muscle  capillaries  are  listed  in  table 
9.1.  Information  of  the  type  summarized  in  table  9.1 
is  not  yet  available  from  capillaries  in  regions  other 
than  muscle,  with  the  possible  exception  of  renal 
glomerular  capillaries  (section  10).  Nevertheless,  there 
are  many  indications  that  permeability  properties  of 
capillaries  may  differ  greatly  in  different  organs. 
Studies  of  the  rates  at  which  labeled  proteins  or 
dextran  fractions  appear  in  lymph  from  different 
regions  suggest  that  porosity  of  capillaries  in  visceral 
organs  may  be  considerably  greater  than  in  capillaries 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


table  9.1.  Permeability  of  Mammalian  Muscle 

Capillaries  to  Lipid  Insoluble  Molecules 


Substance 

Mol  Hi 

D  i7  C 

cm-  >ci    ' 

X  10s 

Approx. 
Mol 

Radius, 
a  cm 
X  108 

As/Ax 
Restricted 

fi.ll       \lr.l 

*  Path 

Length,*  cm 

X  io5 

in  100 

g  \hi>t  le 

S|n-<  in 
Permea- 
bilityt 

4-  Am 

cm  sec'1 

X  io- 

H„0 

18 

3-4 

'•5 

■55 

28 

NaCl 

58 

2.0 

2-3 

■5' 

'5 

Urea 

60 

'■95 

2.6 

■49 

'4 

Glucose 

180 

0.90 

3-7 

•44 

6 

Sucrose 

34* 

0.70 

4.8 

■39 

4 

Raffinose 

5°4 

0.64 

5-7 

■34 

3 

Inulin 

5.500 

0.21-.26 

12-15 

. 1 0- . 1 4 

o-3 

Myoglobin 

1 7 , 000 

0.17 

'9 

•°3 

0. 1 

Serum 

67,000 

0.085 

36 

.0007 

0.001 

albumin 

. 00065 1 

*  From  smooth  curves  of   figure  9.2.  f  Mols/sec/cm2 

membrane  per  mol/ml  concentration  difference.  The  total 
membrane  surface  in  100  g  muscle,  Am,  is  assumed  to  be 
7000  cm2  (281 ).  t  Calculated  from  over  all  bodily  arterial 

disappearance  curves  (equation  8.1). 

of  muscle  (126,  232).  Anatomical  studies  of  visceral 
capillaries  also  suggest  a  relatively  high  degree  of 
porosity  (13).  Exchange  rates  of  lipid-insoluble  mole- 
cules between  central  nervous  system  tissue  and  blood 
are  far  lower  than  in  peripheral  tissues  (68,  185,  357) 
although  the  anatomical  site  of  the  "blood-brain 
barrier"  has  not  been  localized  with  certainty  to  the 
capillary  walls.  Exchanges  between  blood  and  cere- 
brospinal fluid  are  complicated  by  absorption  in  bulk 
through  large  channels  in  the  arachnoid  villi  and  by- 
specific  active  secretory  mechanisms  involving  the 
choroid  plexuses  and  ependymal  linings  of  the  ven- 
tricular system  (279). 

In  spite  of  these  regional  differences  in  capillary 
permeability,  it  may  be  said  that  over-all  bodily 
capillary  permeability,  determined  from  arterial  disap- 
pearance rates  of  large  molecules,  does  not  differ 
greatly  from  that  of  isolated  muscle.  For  example,  the 
average  plasma  clearance  (n/Ac)  of  a  dextran  fraction 
of  known  free  diffusion  coefficient  (D  =  0.10  X  io~5 
cm2  sec-1,  a  =  32  A)  was  found  by  Grotte  (126)  to  be 
about  .6  ml  per  min  per  kg  dog  or  io-3  ml  per  sec 
per  100  g  tissue.  From  equation  7.  6, 

AS  f>  -3-5  5 

Xx"  2HT  "*"  D  *  ,0    +'x  /0     --O/x  10  cm 

Application  of  the  theory  of  restricted  diffusion  (equa- 
tion 7.9)  for  average  porosities  of  40,  45,  and  50  A 
leads  to  true  pore  areas  per  unit  path  length  of  1 .4,  0.5, 
and  0.3    X    io-5  cm  per   100  g  tissue,  respectively. 


These  values,  pertaining  to  over-all  bodily  permeabil- 
ity, may  be  compared  with  the  value  of  0.6  X  io5  cm 
per  1 00  g  tissue  determined  by  the  method  of  osmotic 
transient  in  isolated  muscle  (Fig.  9.2).  The  close 
correspondence  between  permeability  to  serum  albu- 
min computed  from  over-all  arterial  disappearance 
curves  on  the  one  hand  and  restricted  diffusion 
through  the  capillaries  of  muscle  on  the  other  has 
already  been  noted  (table  9.1).  Similarly,  the  over- 
all bodily  filtration  coefficient  is  not  greatly  different 
from  that  determined  in  intact  extremities  or  isolated 
perfused  muscle  (section  6).  This  correspondence  be- 
tween over-all  capillary  permeability  and  capillary 
permeability  determined  in  isolated  muscle  is  not  too 
surprising  since  muscle  accounts  for  some  65  per  cent 
of  total  body  weight  exclusive  of  skeleton  and  fat 
which  do  not  participate  to  a  large  extent  in  the  capil- 
lary exchange. 


IO.    MOLECULAR    SIEVING    OF    LARGE    MOLECULES: 
REGIONAL    DIFFERENCES    IN    POROSITY 

In  artificial  systems  it  is  possible  to  apply  high  pres- 
sure differentials  for  rapid  ultrafiltration,  and  under 
these  conditions  even  small  molecules  can  be  "sieved" 
through  porous  membranes  as  illustrated  in  figure 
7.4.  In  the  capillary  circulation,  however,  the  trans- 
membrane pressure  differentials  are  necessarily  small 
and  no  appreciable  steady-state  concentration  differ- 
ences of  small  molecules  can  be  maintained,  even  at 
abnormally  high  rates  of  filtration.  Substitution  of 
approximate  value  of  Aw/Ax  and  r  in  equation  7.  15 
suggests  that  appreciable  molecular  sieving  should  be 
detectable  with  molecules  of  radius  10  to  15  A  at  high 
rates  of  filtration  caused  by  venous  occlusion.  This 
prediction  has  been  verified  in  perfused  hind  limbs 
for  the  case  of  inulin  (a  =  12-15  A)  during  net  filtra- 
tion at  the  rate  of  0.2  ml  per  min  per  100  g  tissue. 
Under  these  conditions  the  steady-state  concentration 
of  inulin  in  capillary  filtrate  was  found  to  be  70  per 
cent  of  that  in  plasma  (281);  the  theoretical  value 
calculated  from  equation  7.15  is  77  per  cent.  In  the 
case  of  still  larger  molecules,  including  the  plasma 
proteins,  the  restriction  to  diffusion  becomes  suffi- 
ciently great  to  allow  a  high  degree  of  molecular 
sieving,  even  at  normal  filtration  rates. 

Grotte  (126)  has  carried  out  a  detailed  study  of 
molecular  sieving  in  relation  to  steady-state  concen- 
trations of  large  molecules  in  leg  lymph,  liver  lymph, 
and  cervical  lymph.  Grotte  worked  with  dextran 
polymers  of  known  free  diffusion  coefficient  and  mo- 


ioi4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


1.0 


8 


Cf_  [lymph] 

C,  "   [PLASMA] 


.6  - 


.2  - 


Theoretical  curves 

for  42  A  pores 

nT\° 

\    X* 

\»  \ 

A 

b           .NORMAL   LYMPH 
\/^            FLOW 

\° 

DOUBLE                      ' 

LYMPH  FLOW 

(VENOUS  CONGESTION) 

\     V^^^\ 

- 

\     S           ^^^ 

MOLECULAR    RADIUS,  o=  — — 
6TTIJ 

•\\                  ^^j_ 

^ — 

D                           ^N                        -"""• 

l                      ' 

1                                 1^                          1 

1 

20 


30 


40 


50 


60  A 


fig.  i  o.  i .  Molecular  sieving  of  dextrans  in  leg  lymph 
obtained  from  dogs.  The  results  are  in  accord  with  the  theory 
of  molecular  sieving  ^equation  7.15)  through  pores  of  radius 
42  A  and  for  molecules  up  to  32  A  in  radius.  Increased  lymph 
flow  induced  by  venous  congestion  produced  the  expected 
increase  in  sieving.  The  unexpected  passage  of  dextran  mole- 
cules exceeding  40  A  in  radius  suggests  an  additional  "large 
pore"  system  estimated  by  Grotte  to  comprise  1/30,000  of  the 
total  population  of  pores.   [Adapted  from  Grotte   (126).] 

lecular  radius.  Figure  10. 1,  adapted  from  Grotte' 
shows  lymph :  plasma  concentration  ratios  as  a  func- 
tion of  molecular  radius  at  two  different  lymph  flows. 
The  theoretical  curves  for  a  capillary  ultrafiltrate  are 
drawn  from  equation  7.15,  assuming  a  pore  radius  of 
42  A,  that  Aw/Ax  was  constant  and  that  capillary 
filtration  rate  was  proportional  to  observed  lymph 
flow.  The  agreement  between  theoretical  and  ob- 
served concentration  ratios  is  surprisingly  good  for 
molecules  up  to  about  32  A  in  radius.  However,  the 
observed  lymph  concentrations  of  dextran  molecules 
ranging  in  size  from  50  to  90  A  cannot  be  explained 
on  the  basis  of  molecular  sieving  through  pores  of 
radius  42  A.  In  order  to  explain  capillary  permeabil- 


FIG.  10.2.  Distribution  of  "leaks,"  "large  pores"  or  gaps  in 
the  walls  of  the  minute  vessels  of  frog's  mesentery  as  indicated 
by  cinephotomicrographs  of  rapid,  spotty  passage  of  T-1824 
(Evans  blue  dye).  With  camera  running  at  the  rate  of  25  frames 
per  sec,  the  dye  solution  was  perfused  through  the  capillary 
network  from  a  micropipette  introduced  into  the  terminal, 
feeding  arteriole.  From  the  film  thus  obtained  single  frames 
have  been  removed  to  show  sites  and  extent  of  dye  passage  at 
intervals  of  seconds  (e.g.,  1",  2",  3",  etc.)  timed  from  that 
frame  in  which  the  dye  had  first  filled  the  capillaries  (labeled 
0).  The  frames  labeled  C  show  the  network  before  dye  entry; 
those  labeled  2'  and  C-»  after  the  perfusion  was  ended  to  indicate 
absence    of   stasis    and    hence    absence    of   detectable    injury. 


ity  to  these  large  molecules  Grotte  postulated  the 
existence  of  large  capillary  leaks,  corresponding  to 
pores  of  radius  200  to  350  A  but  comprising  only  1 
part  in  30,000  of  the  total  population  of  pores  as  com- 
puted by  equation  7.16.  In  cervical  lymph  and  liver 
lymph  the  molecular  sieving  curve  was  shifted  to  the 
right  and  the  relative  number  of  calculated  capillary 
leaks  was  increased  to  1  in  20,000  and  1  in  340,  re- 
spectively. 

Concerning  the  locations  of  these  leaks  or  large 
pores  along  the  length  of  the  minute  vessels  very  little 
is  known.  There  is  some  evidence,  however,  that  they 
may  be  more  frequent  in  the  walls  of  venous  capillaries 
and  venules  than  in  the  walls  of  true  capillaries.  In 
recent  studies  (Landis,  unpublished)  solutions  of 
T-1824  in  Ringer's  solution,  with  and  without  protein, 
have  been  perfused  by  microinjection  through  single 
vessels  or  through  portions  of  peripheral  networks  in 
the  frog's  mesentery.  Motion  pictures  (25-40  frames 
per  sec)  reveal  sites  at  which  the  dye  solutions  pass 
rapidly  through  the  vessel  wall  during  the  first  few 
seconds  of  perfusion  (fig.  10.2).  In  true  capillaries  the 
loci  of  such  early,  spotty  passage  of  dye  are  few  in 
number;  the  extravascular  spots  of  dye  are  small  in 
size  and  distinct  in  outline.  In  venous  capillaries  and 
venules  the  loci  of  passage  are  more  numerous;  the 
extravascular  spots  of  dye  tend  to  be  larger  and,  par- 
ticularly around  venules,  often  coalescent.  It  seems 
likely,  therefore,  that  while  the  small  pore  system  is 
uniformly  distributed  throughout  the  capillary  net- 
work, the  leak  or  large  pore  system  is  more  promi- 
nent in  the  venous  capillaries  and  venules.  A  differen- 
tial distribution  of  this  type  helps  explain  earlier  work 
(reviewed  in  detail  in  ref.  207)  on  the  spotty  passage 
of  certain  dyes  through  the  walls  of  true  capillaries 
(200,  262)  and  on  the  gradient  of  permeability  to 
poorly  diffusible  dyes  described  by  Rous  and  co- 
workers (e.g.,  161,  307,  308,  337,  338). 

Results  similar  to  those  obtained  by  Grotte  (126) 


Left:  perfusion  of  .01  M  T-1824  freshly  prepared  in  frog  Ringer's 
solution.  Top  section  (magnification  X  17)  shows  progression 
of  spotty  passage  involving  true  capillaries,  a  venous  capillars' 
and  a  minute  venule.  Middle  and  lower  sections  show  greater 
detail  (magnification  X  60)  at  2  sec  and  12  sec,  respectively. 
Right:  perfusion  of  .01  M  T-1824,  ar'd  3  g/100  mg  albumin,  in 
frog  Ringer's  solution.  Top  section  (magnification  X  35)  shows 
spotty  passage  in  true  capillaries  and  a  venous  capillary.  Middle 
and  lower  sections  show  greater  detail  (magnification  X  120) 
at  2  sec  and  12  sec,  respectively.  Rapid,  spotty  passage  of  per- 
fused dye  persisted  despite  protein  binding.  In  general,  how- 
ever,  protein   binding   made   spots  of  passage   more   discrete. 


fig.    10.2.  See  legend  on  facing  page. 


EXCHANGE  OF  SUBSTANCES  THROUGH  CAPILLARY  WALLS 


IOI7 


have  been  reported  by  Mayerson  et  al.  (232)  who 
found  that  dextran  fractions  of  mean  molecular 
weights  greater  than  about  100,000  (a  >  60  A)  appear 
in  hepatic,  intestinal,  and  cervical  lymph  in  concen- 
trations which  are  almost  independent  of  molecular 
size.  Mayerson  et  al.  follow  Grotte  in  ascribing  these 
results  to  the  presence  of  large  capillary  leaks  but 
they  also  mention  an  interesting  alternative  possibility 
that  very  large  molecules  may  be  transported  by  active 
endothelial  vesiculation  (pinocytosis)  as  described  by 
Palade  (273)  and  Moore  &  Ruska  (255).  In  calcu- 
lating pore-size  distributions  Mayerson  et  al.  do  not 
take  into  account  sieving  effects  nor  the  fact  that 
filtration  varies  with  the  fourth  power  of  pore  radius. 
They  assume  that  filtration  rate  through  pores  of 
given  collective  area  will  be  the  same,  regardless  of 
pore  radius.  If  5  per  cent  or  more  of  the  capillary 
pores  had  a  radius  >  200  A,  as  suggested  by  Mayerson 
et  al.,  then  from  equation  7.16 

r>  ]/05(200  x  id8)  "  >  95  A 

A  mean  pore  radius  of  95  A  for  hydrodynamic  flow 
would  lead  to  an  improbably  high  value  for  the 
filtration  coefficient.  For  this  reason  we  favor  Grotte's 
interpretation  in  terms  of  molecular  sieving  through 
pores  of  radius  40  to  45  A  combined  with  relatively 
few  large  capillary  leaks.  Both  interpretations  are 
subject  to  the  criticism  that  lymph  is  not  a  capillary 
ultrafiltrate  and  may  well  be  modified  by  capillary 
reabsorption  (208),  particularly  at  low  rates  of  lymph 
flow. 


A  more  clear-cut  application  of  the  theory  of 
molecular  sieving  is  possible  in  the  case  of  renal  glo- 
merular membranes.  Figure  10.3  shows  the  glomeru- 
lar clearances  of  several  proteins  and  dextrans  relative 
to  creatinine  in  the  dog.  The  apparent  differences 
between  glomerular  sieving  of  dextran  molecules  and 
proteins  of  equivalent  molecular  radius  may  be 
spurious  because  the  dextran  fractions  were  not 
perfectly  monodisperse  and  it  is  possible  that  the 
lesser  degree  of  sieving  for  each  nominal  molecular 
radius  represents  the  contribution  of  smaller  dextran 
molecules.  The  data  agree  well  with  theoretical  curves 
for  molecular  sieving  through  an  isoporous  membrane 
having  pores  35  to  42  A  in  radius  and  a  total  pore 
area  per  unit  path  length  for  water  of  1.6  X  io5  cm 
per  g  kidney  (278).  Substitution  of  these  values  in 
equation  7.13  leads  to  filtration  coefficients  in  the 
range  3.5  to  5.0  X  io-5  cm5  dyne-1  sec-1  per  g  or  2.7 
to  3.9  ml  per  min  per  mm  Hg  per  100  g  kidney. 
These  values  are  in  excellent  agreement  with  esti- 
mates based  on  hemodynamic  data  (339,  384).  Al- 
most identical  values  for  renal  glomerular  perme- 
ability have  also  been  derived  by  Lambert  and  his 
associates  (194-196)  from  molecular  sieving  of  hemo- 
globin as  a  function  of  glomerular  filtration  rate. 

The  greater  permeability  of  renal  glomerular  mem- 
branes relative  to  peripheral  capillaries  is  evidently 
due  to  a  relatively  large  fractional  pore  area  rather 
than  to  large  pores.  Given  a  path  length  for  filtra- 
tion and  diffusion  of  0.5  X  io~4  cm,  the  glomerular 
pore  area  for  passage  of  water  would  be  8  cm2  per  g 


C2/C1 

GLOMERULAR  CLEARANCE 

RELATIVE   TO   CREATININE 

1.0 


DEXTRAN 
FRACTIONS 


fig.  10.3.  Theoretical  vs.  ac- 
tual molecular  sieving  through 
renal  glomerular  membranes 
of  dogs.  Molecular  sieving  of 
myoglobin,  egg  albumin,  and 
hemoglobin  calculated  as  in 
references  278  and  194.  Data 
for  dextran  fractions  are  taken 
from  Wallenius  (366). 


40A 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


kidney  or  5  to  10  per  cent  of  the  available  glomerular 
surface  estimated  histologically  by  Vimtrup  (360). 

Recent  studies  of  glomerular  ultrastructure  suggest 
that  the  anatomical  basis  for  glomerular  sieving  is  not 
in  the  fenestrated  capillary  endothelium,  but  rather 
in  the  epithelial  cells  (podocytes)  covering  glomerular 
capillaries.  According  to  Hall  (141)  these  cells  form 
foot  processes  which  approximate  the  endothelial 
basement  membranes  in  such  fashion  as  to  form  inter- 
cligitating  "slit-pores"  which  appear  to  be  80  to  100  A 
wide  and  occupy  2  to  3  per  cent  of  the  total  surface. 


ii.  capillary  permeability  to  lipid-soluble 
molecules;  respiratory  gases 

Capillary  permeability  to  lipid-soluble  molecules 
has  been  studied  by  Renkin  (296,  297)  using  the  per- 
fused hind-limb  preparation.  Urethan  (mol  wt  89), 
paraldehyde  (mol  wt  132)  and  triacetin  (mol  wt  218) 
traversed  the  capillary  walls  so  rapidly  that  no  os- 
motic transients  were  detectable  (figure  11.1).  Glyc- 
erol and  acetic  esters  of  glycerol  were  shown  to  pass 
through  capillary  walls  at  high  rates  which  varied  in 
order  of  their  oil :  water  partition  coefficients  but  in 
order  opposite  to  that  expected  on  the  basis  of  their 
aqueous  diffusion  coefficients.  The  temperature  co- 
efficients of  capillary  permeability  to  antipyrine  and 
antipyrine  derivatives  were  found  to  be  related  to  the 
temperature  coefficients  of  their  lipid  solubilities 
rather  than  to  their  aqueous  diffusion  coefficients. 

These  results  suggest  that  lipid-soluble  molecules 
can  diffuse  through  regions  in  the  capillary  wall 
which  are  relatively  impermeable  to  lipid-insoluble 
materials.    The    permeability   characteristics    of   this 


additional  pathway  are  similar  to  those  of  cell  mem- 
branes in  general.  It  seems  logical,  therefore,  to  iden- 
tify the  diffusion  pathway  for  lipid-soluble  molecules 
with  the  plasma  membranes  of  the  capillary  endothe- 
lial cells  themselves,  as  opposed  to  the  system  of 
water-filled  pores  penetrating  through  or  between 
these  cells,  which  is  capable  of  accounting  for  passage 
of  water  and  lipid-insoluble  molecules. 

The  respiratory  gases  have  relatively  large  oil: 
water  partition  coefficients  (212)  and  may  therefore 
be  expected  to  utilize  the  entire  endothelial  surface 
for  the  transcapillary  diffusion  process.  Recent  meas- 
urements of  pulmonary  diffusing  capacity  (306)  indi- 
cate that  permeability  of  human  alveolar  mem- 
branes (alveolar  capillaries  plus  alveolar  epithelium) 
is  approximately  60  ml  02  per  min  per  mm  Hg  O2 
pressure  difference.  In  terms  of  oxygen  concentration 
difference,  this  value  becomes  0.4  X  io5  cm3  sec-1 
(i.e.,  ml/sec,  ml/ml  concentration  difference).  The 
capillary  surface  area  in  the  lungs  is  approximately 
4  X  10s  cm'2  (258),  whence  the  specific  permeability 
coefficient  for  oxygen  is  10,000  X  io~B  cm  sec-1.  This 
value  may  be  compared  with  23  X  io~5  cm  sec-1, 
representing  the  specific  permeability  of  muscle  capil- 
laries to  water  (table  9.1).  Presumably  the  greater 
permeability  to  oxygen  is  a  result  of  lipid  solubility, 
since  the  pulmonary  capillaries  resemble  peripheral 
capillaries  in  being  relatively  impermeable  to  small 
lipid-insoluble  molecules  (378).  In  100  g  of  quiescent 
muscle  containing  a  capillary  surface  area  of  5,000- 
10,000  cm2  the  steady-state  flow  of  oxygen  across  the 
capillary  walls  is  about  0.4  ml  per  min  (fig.  12.2). 
During  maximal  muscular  activity  the  oxygen  re- 
quirements increase  20-fold  to  30-fold  and  the  avail- 
able capillary  surface  may  increase  2-fold  to  4-fold. 


fig.  1 1.1.  Osmotic  transients  produced  by 
urethan  and  urea  in  an  isolated  perfused  cat 
hind  limb.  pCi  =  isogravimetric  capillary 
pressure.  Pv  =  protein  osmotic  pressure  in 
perfusion  fluid.  36  msi/liter  of  urea  produced 
a  large  osmotic  transient  owing  to  restricted 
diffusion  of  urea  through  the  capillary  walls. 
Urethan,  despite  its  larger  molecular  size, 
failed  to  produce  a  detectable  osmotic  effect. 
The  results  are  attributed  to  the  greater  lipid 
solubility  of  urethan  which  enables  it  to  diffuse 
through  the  entire  capillary  endothelial 
surface.  [From  Renkin  (296 1.] 


pCi 
or 

PP 

mm 

H* 


25 


20 


15 


1 


T 

pp 


URETHAN 
36mM/l 


°«t>-c>J 


-I-"- 

UREA 

+ 
URETHAN 
36  mM/1  of  each 


UREA 
36mM/l 


80  100  120  140  160  180  200  220 

TIME,   MINUTES   AFTER    START   OF    PERFUSION 


240 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


IOig 


If  the  specific  permeability  of  muscle  capillaries  for 
oxygen  were  comparable  with  that  of  alveolar  mem- 
branes, then  transcapillary  oxygen  pressure  differ- 
ences of  0.3  to  0.6  mm  Hg  and  3  to  8  mm  Hg  would 
suffice  to  account  for  observed  rates  of  tissue  oxygen 
consumption  at  rest  and  during  maximal  work,  re- 
spectively. For  CO i  the  corresponding  values  are  20- 
fold  smaller  owing  to  its  greater  solubility.  It  therefore 
seems  unlikely  that  capillary  permeability  is  an  im- 
portant factor  limiting  the  exchange  rates  of  respira- 
tory gases,  except  possibly  during  maximal  muscular 
activity. 


12.    CAPILLARY   PERMEABILITY   AND   BLOOD    FLOW   IN 
RELATION  TO  EXCHANGE  OF  MATERIALS 
BETWEEN  BLOOD  AND  TISSUES 

In  previous  sections  evidence  was  reviewed  showing 
that  lipid-soluble  molecules  and  small  lipid-insoluble 
molecules  or  ions  diffuse  back  and  forth  across  capil- 
lary walls  at  rates  which  greatly  exceed  rates  at  which 
these  substances  are  brought  to  or  from  the  tissues  by 
the  blood.  For  such  substances  capillary  permeability 
is  clearly  not  an  essential  factor  determining  net  rates 
of  blood-tissue  exchange.  Other  more  essential  factors 
include  the  distribution  and  rate  of  flow  of  capillary 
blood,  the  volume  and  permeability  of  extravascular 
distribution  compartments,  and  rates  of  chemical 
reaction  in  the  tissues.  For  molecules  of  intermediate 
size,  including  products  of  intermediary  metabolism, 
capillary  permeability  may  become  more  important 
but  is  still  only  one  of  the  several  factors  determining 
over-all  kinetics  of  the  exchange  process.  Only  in  the 
case  of  relatively  large  molecules  (e.g.,  inulin  in- 
larger)  can  capillary  permeability  be  considered  as  a 
primary  factor  limiting  exchange  with  well-perfused 
tissues. 

Mathematical  descriptions  of  diffusion  kinetics  in 
the  capillary  circulation  are  included  in  papers  by 
Krogh  (183),  Hill  (153,  154),  Kety  (173,  174),  Opitz 
&  Schneider  (269),  Morales  &  Smith  (256),  Schmidt 
(318,  319),  Sangren  &  Sheppard  (310),  Renkin  (300), 
and  Blum  (19).  Each  of  these  mathematical  descrip- 
tions is  based  upon  a  particular  model  of  capillary- 
tissue  geometry  and  each  involves  simplifying  assump- 
tions concerning  permeability  which  do  not  apply  to 
all  molecular  species.  Such  models  are  nevertheless 
useful,  if  only  to  provide  a  definite  hypothesis  with 
which  experimental  results  may  be  compared.  Exam- 
ples illustrating  the  use  of  such  models  are  given 
below. 


A.  Blood- Tissue  Transport  of  Oxygen 

The  essential  role  of  the  capillaries  in  the  blood- 
tissue  exchange  of  respiratory  gases  was  considered  by 
Krogh  (183)  in  terms  of  spatial  distribution  of  blood 
vessels  relative  to  tissue  metabolism.  Krogh  proposed  a 
simple  model  in  which  each  capillary  of  radius,  r,  sup- 
plied a  cylinder  of  tissue  of  radius  R.  The  intercapil- 
lary  distance  was  therefore  iR  and  the  number  of 
capillaries  per  cm2  was  (1/2R)-.  It  was  assumed  that 
rate  of  tissue  metabolism  would  be  uniform  through- 
out the  cylinder  and  that  the  diffusion  coefficients 
of  gases  through  the  cylinder  would  be  uniform  and 
identical  with  values  measured  in  dead  tissues.  The 
mathematical  solution  for  steady-state  radial  diffu- 
sion under  these  conditions  was  derived  for  Krogh  by 
Erlang  (183)  and  has  formed  the  starting  point  for 
many  subsequent  discussions  of  the  blood-tissue  ex- 
change of  gases  [cf  (174)  for  contemporary  review]. 

Figure  12.1  is  a  graph  of  the  Krogh-Erlang  equa- 
tion for  capillaries  of  radius  4  ft;  the  equation  is  rela- 
tively insensitive  to  values  of  r  and  for  all  practical 
purposes  the  same  graph  applies  to  capillaries  of  radii 
3  to  5  /j.  This  model  suggests  that  as  few  as  25  open 
capillaries  per  mm2  would  suffice  to  supply  the  oxygen 
requirements  of  resting  muscle  without  exceeding  the 
limiting  diffusion  pressure  head  set  by  oxygen  in 
venous  blood  (i.e.,  a  finite  oxygen  pressure  would 
exist  even  in  the  outermost  region  of  the  diffusion 
cylinder  surrounding  each  capillary).  The  corre- 
sponding figure  for  maximal  muscular  activity  is  500 
capillaries  per  mm2.  Brain  and  liver  would  require  200 
anc  100  capillaries  per  mm2,  respectively.  Estimates  of 
capillary  density  usually  exceed  these  values  by  a  wide 
margin  and  suggest  that  the  oxygen  pressure  head  re- 
quired to  supply  the  diffusion  cylinder  around  each 
capillary  is  far  less  than  that  available  in  capillary 
blood,  even  at  maximal  rates  of  tissue  metabolism. 

Capillary  counts  on  injected  muscles  from  anesthetized 
animals  lead  to  estimates  in  the  range  200  to  600  per  mm2 
for  resting  muscle  and  600  to  5000  per  mm2  for  contracting 
muscle  (84,  143,  183,  22-j,  272,  284,  320,  335,  353).  There  is 
considerable  variation  among  skeletal  muscle,  heart  (305), 
and  abdominal  wall  muscle  (184)  representing  examples  of 
high  and  low  density,  respectively.  In  general,  muscles  from 
small  animals  have  a  higher  capillary  density  than  from  large 
animals  (320).  In  maximal  vasodilatation  there  is  often  a  1 : 1 
relation  between  number  of  capillaries  and  number  of  muscle 
fibers,  but  maximum  capillary  density  can  be  increased  by 
exposure  to  high  altitudes  or  by  daily  physical  exercise  (358). 
Capillary  counts  made  on  fixed  preparations  tend  to  be  high 
because  of  shrinkage  artifact;  in  frozen  sections  the  muscle 
fibers  are  larger  and  estimated  capillary  densities  smaller. 
In   the   author's   experience,    150-200  capillaries   per   mm2  is 


[020 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Q0  ,ml  /min    per  lOOg    Tissue 


20       10 


fig.  1 2. 1.  Steady-state  radial  diffu- 
sion of  oxygen  (Qo:)  as  a  function  of 
capillary  density  (abscissa)  and  radial 
oxygen  pressure  gradient  from  capil- 
laries to  tissue  (ordinate).  [Graph  con- 
structed from  the  Krogh-Erlang  equa- 
tion (183).] 


90 
80 
70 
60 
50 

40 
30 

20 


-   MM   Hg 

02  PRESSURE 

/ARTERIAL*g0_ 

/       BLOOD       80- 

/                              70- 

GRADIENT 

/                                60- 

-        PC  -  PR            / 

/                                  50- 
02Sot.  =  72% 

VENOUS 
BLOOD 

02Sat   =  55% 

/   *»    / 
/   *  / 

AY 

20- 

/  kr 

///      / 

-  /*/  */ 

/  0  /    / 

~Av  / 

A 

/"V 

7 

/                     10— 

/       KROGH-ERLANG   EQUATION 
/                                                                           5" 

II   / 

PC-PR  = 

4aD 

^H**-r*}- 

20 


30      40  60      80    100      140       200        300  Intercopillary  distarce,  2R,  u. 


1600 

800 

400 

200 

100 

50 

25 

10 

Capillaries  per  mm2 

8.0 

40 

2.0 

1.0 

0.5 

0.25 

0.12 

0.05 

Capillary  volume, %  of  tissue 

400 

200 

100 

50 

25 

12 

6 

2.5 

Surfoce,  cm2  per  g  tissue 

usual  in  frozen  sections  of  muscles  from  hind  limbs  of  an- 
esthetized cats.  Many  of  the  higher  estimates  imply  capillary 
blood  volumes  in  the  range  5  to  15  per  cent  of  tissue  volume. 
In  most  skeletal  muscles  the  entire  blood  volume  is  less  than 
4  per  cent  of  tissue  volume  (328,  335)  and  at  least  half  of  this 
may  be  accounted  for  by  large  blood  vessels  (243).  Even  taking 
low  estimates  for  capillary  density,  however,  (200/mm2  at 
rest,  600/mm2  in  activity)  the  oxygen  pressure  gradient  pre- 
dicted by  the  Krogh-Erlang  model  would  be  less  than  5  mm  Hg 
at  rest  and  less  than  20  mm  Hg  in  maximum  work,  leading  to 
tissue  oxygen  pressures  of  10  to  30  mm  Hg  in  the  outermost 
regions  of  each  diffusion  cylinder. 

The  Krogh-Erlang  model  provides  a  theoretical 
basis  for  analysis  of  the  blood-tissue  gas  exchange,  but 
several  lines  of  evidence  suggest  that  factors  other  than 
simple  radial  diffusion  in  a  homogeneous  medium 
may  be  involved.  In  the  case  of  skeletal  muscle,  Milli- 


Pc    ,  c  opi 1 1 ory   02  pressure,   mm   Hg 

PR  .tissue  02  pressure  at  R 

Qn  ,  Op  consumption    ml  /sec   per  ml  tissue 

u2 

a  ,0t  solubility  =2. 8  «  10"'  ml  /ml  «mm  Hg"1 

D  ,  tissue  02  diffusion  coeff.  =  1.5  x  10"' cmJ/sec    (   ) 

R  ,  radius  of  diffusion  cylinder 

r  .capillary   radius  =  4  u. 


kan  (253)  showed  that  intracellular  myoglobin  rapidly 
becomes  desaturated  during  contraction  of  the  soleus 
muscle  in  the  cat.  Since  the  half  saturation  pressure 
of  myoglobin  at  physiological  pH  is  only  3  mm  Hg 
this  implies  that  intracellular  oxygen  tension  falls  to 
extremely  low  values  during  contraction.  Lactic  acid 
increases  rapidly  in  venous  blood  from  contracting 
muscle  (7,  181),  also  indicating  that  oxygen  supply 
cannot  keep  up  with  demand  at  high  rates  of  metabo- 
lism, despite  normal  oxygen  pressures  in  venous  blood. 
Mechanical  reduction  of  blood  flow  to  resting  muscle 
may  cause  substantial  reduction  of  steady-state  oxygen 
consumption  even  when  the  blood  vessels  are  dilated 
and  when  venous  oxygen  pressure  is  sufficiently  high 
to  meet  the  diffusion  requirements  estimated  from  the 
Krogh-Erlang  model    (275,    359)    (fig.    12.2).    Inter- 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


1021 


capillary  oxygen  pressures  may  be  extremely  low  in 
brain  (64)  despite  normal  oxygen  pressures  in  cerebral 
venous  blood.  The  critical  venous  oxygen  pressure  at 
which  brain  suffers  a  decrease  in  oxygen  consumption 
is  20  to  25  mm  Hg  (269);  presumably,  under  these 
conditions,  oxygen  pressure  is  zero  in  regions  most 
remote  from  the  capillaries. 

These  observations  suggest  that  the  gradient  of 
oxygen  pressure  from  capillary  blood  to  tissues  is 
greater  than  predicted  from  the  simplified  model 
proposed  by  Krogh.  One  factor  neglected  by  Krogh's 
treatment  of  the  problem  is  the  rate  at  which  oxygen 
can  be  released  from  red  cells  during  their  brief  expo- 
sure to  the  tissues  in  capillary  blood.  Roughton  & 
Forster  (306)  and  Forster  (108)  have  recently  dis- 
cussed evidence  that  chemical  reaction  velocity  and 
diffusion  in  the  red  cell  account  for  almost  one-half 
the  total  resistance  to  transfer  of  oxygen  between 
alveolar  gas  and  blood.  The  rate  of  dissociation  of 
oxygen  from  hemoglobin  is  slower  than  its  rate  of 
combination  and  recent  measurements  by  Niesel  et  al. 
(261)  and  Thews  (356)  indicate  that  the  intracapil- 
lary  component  of  oxygen  diffusion  may  be  a  major 
factor  limiting  the  rate  at  which  oxygen  can  be  sup- 
plied to  adjoining  tissues.  This  factor  could  be  evalu- 
ated experimentally  and  deserves  attention  in  future 
studies  of  the  blood-tissue  exchange  of  gases.  Scho- 
lander's  recent  demonstration  of  facilitated  diffusion 
of  oxygen  through  thin  films  of  hemoglobin  or  myo- 
globin (32 1 )  may  also  be  of  significance  for  diffusion 
of  oxygen  in  muscle,  especially  cardiac  muscle. 

B.   Blood-  Tissue  Exchange  of  Small, 
Xonmctabolized  Molecules  or  Ions 

A  simple  model  of  blood-tissue  exchange  has  been 
employed  by  Renkin  (299,  300)  to  describe  diffusion 
kinetics  of  urea,  antipyrine,  sucrose,  and  K42  in  perfused 
muscle.  This  model  is  particularly  useful  for  illus- 
trating the  relative  effects  of  permeability  and  blood 
flow  on  diffusion  kinetics  in  uniformly  perfused  tissue. 
In  its  simplest  form  the  model  assumes  two  compart- 
ments representing  total  blood  volume,  V\  ,  and  extra- 
vascular  distribution  volume,  V2  ■  The  compartments 
are  separated  by  a  barrier  of  virtual  area  Am  and  per- 
meability coefficient,  P.  V\  is  allowed  to  flow  past  the 
barrier  at  rate,  Q.  V%  is  assumed  to  be  homogeneous 
with  respect  to  concentration  of  diffusing  materials. 
The  mathematical  solution  for  this  model  (300)  is 
given  bv 

d/i-e    « J  (12.1) 


v.v, 


(v,  +  v2) 


where  C  =  clearance  from  the  blood  compartment, 
V 1  ,  ml  per  min,  and  X  =  slope  of  the  exponential 
disappearance  curve  from  the  blood  compartment, 
min-1.  In  perfused  preparations  the  rate  of  blood  flow- 
may  be  varied  over  a  wide  range  by  simple  adjustment 
of  perfusion  pressure.  Clearance,  C,  from  the  perfu- 
sion reservoir  can  be  measured  accurately.  It  is  there- 
fore possible  to  determine  over-all  permeability,  P  X 
Am,  of  barriers  separating  blood  from  the  final  distri- 
bution volume,  provided  the  original  assumption  of 
uniform  distribution  in  extravascular  space  is  correct. 
For  many  substances  this  assumption  will  not  be  valid 
and  in  such  cases  PAm  must  be  considered  as  a  virtual 
permeability  which  includes  the  effects  of  nonuniform 
distribution  in  extravascular  space. 

Figure  12.3  shows  capillary  clearances  of  anti- 
pyrine, K42  and  urea  as  a  function  of  blood  flow  in 
widely  dilated  blood  vessels  of  mammalian  muscle. 
The  changes  in  blood  flow  were  produced  by  change 
of  arterial  perfusion  pressure  and  presumably  reflect 
changes  in  flow  velocity  through  a  constant  capillary 
surface  as  required  by  the  model.  Comparison  of  the 
results  with  theoretical  curves  drawn  from  equation 
1 2. 1,  suggest  blood-tissue  permeabilities  (PAm)  of 
about  3  and  10  ml  per  min  per  100  g  muscle  for  urea 
and  K42,  respectively.  For  antipyrine  the  observed 
capillary  clearances  were  equal  to  blood  flow,  indi- 
cating that  for  this  (lipid-soluble)  substance  perme- 
ability (PAm)  was  large  with  respect  to  blood  flow. 

Blood-tissue  permeabilities  estimated  by  equation 
1 2. 1  from  measurements  of  blood  flow  and  clearances 
are  compared  in  table  12.1,  with  capillary  permeabil- 
ity estimated  from  osmotic  transients  and  the  theory 
of  restricted  diffusion.  In  the  case  of  sucrose  the  blood- 
tissue  permeability  is  30  to  60  per  cent  of  capillary 
permeability.  Sucrose  distributes  primarily  in  inter- 
stitial fluid  and  the  only  barriers  to  diffusion  are 
capillary  walls  and  interstitial  fluid  volume.  From 
the  available  data  (table  12.1)  it  appears  that  in 
muscle  about  one-half  the  total  resistance  to  distribu- 
tion is  located  in  the  capillary  wall.  Cotlove  (46) 
has  shown  that  distribution  rates  of  NaCl,  sucrose,  and 
inulin  into  connective  tissue  spaces  of  extremities  are 
limited  by  the  long  path  length  for  diffusion  along 
fascial  planes  and  by  retardation  of  diffusion  in  the 
interstitial  matrix.  Recent  measurements  by  Ogston  & 
Sherman  (266)  indicate  that  diffusion  of  molecules  as 
small  as  glucose  may  be  appreciably  restricted  in 
dilute  gels  formed  by  hyaluronic  acid  and  the  action 
of  hvaluronidase  in  reducing  resistance  to  flow- 
through  connective  tissue  has  been  described  by  Day 
(69)- 


1022 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


40 

„  02    CONSUMPTION 

ml  /min  /I00g  Muscle               ' 

35 

/ 

• 

& 

• 

40    C          

30 

A-/ 

O, 

• —■"" 

O'                    / 

\ 

• 

.25 

o'           / 

K/         / 
,-V'      / 

S  =  39  % 

Pv    =  40mm  Hg 

.20 

la!  A 

kfi    /*X        ______ 

£:  /  ^- —         x 

*    X      31    C 

.15 

' //              s  =  42% 

'  //                  Pvrt   =  28 

.10 

/  //                                                 V0  2 
'  if 
' // 

.  //                       h        no         n —  | p. 

C 

05 

■  ;/y\ 

///            XS=55% 

n 

V                   Pv0!=l6 
/             i                i                i                i 

02  SUPPLY     ml 
i                 i                 i 

02/min  /I00  g   Muscle 
i                i                i                i 

.2 


1.0 


BLOOD    FLOW    ml/min/IOOg 


fig.  12.2.  Steady-state  oxygen  consumption  as  a  function  of  blood  flow  and  tissue  temperature 
in  the  hind  limb  muscles  of  an  anesthetized  cat.  Oxygen  consumption  was  lowered  when  oxygen 
supply  (blood  flow)  was  reduced  below  a  critical  value  at  each  temperature.  Critical  oxygen  pressures 
in  venous  blood  were  40,  28,  and  16  mm  Hg  at  oxygen  consumptions  of  0.3,  0.15,  and  0.06  ml/min 
respectively.  A  capillary -tissue  pressure  gradient  of  less  than  5  mm  Hg  would  suffice  to  supply  these 
rates  of  oxygen  utilization  by  simple  radial  diffusion  in  tissue  containing  100  perfused  capillaries 
per  mm:  (fig.  12. 1).  The  results  indicate  that  the  gradient  of  oxygen  pressure  from  capillary  blood 
to  tissue  is  greater  than  that  predicted  from  the  simplified  model  proposed  by  Krogh  (183).  Oxygen 
saturation,  S,  measured  by  oximeter  and  gas  analysis.  Oxygen  pressure  in  venous  blood,  Pv0i, 
estimated  from  measured  oxygen  dissociation  curves  at  each  temperature.  Tissue  temperature  ad- 
justed by  passing  femoral  arterial  blood  through  a  heat  exchanger.  Blood  flow  adjusted  by  variable 
arterial  resistance.  (From  unpublished  experiments  by  Rapela  et  al.) 


Urea  and  K42  distribute  in  intracellular  water  and 
for  these  substances  the  chief  barrier  to  diffusion  is 
probably  located  at  cell  membranes  in  the  tissues. 
Table  12. 1  shows  that  blood-tissue  permeabilities  to 
these  substances  are  far  less  than  respective  capillary- 
permeabilities. 

When  blood-tissue  permeability  is  large  with  respect 
to  blood  flow,  equation  12.1  approaches  the  limit  C 
=  Q,  and  blood-tissue  distribution  is  said  to  be  flow 
limited.  This  is  the  case  for  lipid-soluble  molecules  in 
general  (e.g.,  antipyrine,  fig.  12.3)  and  provides  the 
theoretical  basis  for  estimating  regional  blood  flow 
from  blood  or  tissue  clearances  of  these  substances 
(173).  Johnson  et  al.  (168)  have  shown  that  distribu- 
tion of  labeled  water  is  blood  flow  limited  in  cardiac 
and  skeletal  muscle  and  Sapirstein  (311)  has  used  the 


blood  clearances  of  Rbs6  or  K42  as  a  measure  of  rela- 
tive regional  blood  flow.  The  clearances  of  labeled 
Xa  or  I  from  blood  or  interstitial  space  have  also  been 
used  for  this  purpose  (72,  165,  172,  290,  362)  but  in 
view  of  the  interstitial  component  of  blood-tissue 
permeability  this  may  not  be  justified.  Several  investi- 
gators have  measured  fractional  extractions  (C/Q)  of 
test  materials  during  single  passage  through  vascular 
beds  of  extremities  (40,  in),  head  (40),  liver  (40), 
heart  (44)  and  lungs  (39).  Equation  12.1  suggests 
that  the  values  so  obtained  reflect  the  exponential 
ratios  of  blood-tissue  permeability  to  blood  flow  under 
the  conditions  of  vascular  tone  prevailing  at  the  time 
of  measurement. 

For  large  lipid  molecules  the  chief  barrier  to  tissue 
distribution  is  the  capillary  wall  and  in  this  case  PAm 


EXCHANGE    OF    SUBSTANCES    THROUGH    CAPILLARY    WALLS 


1023 


14    CAPILLARY 
CLEARANCE 

ml  /min   per  lOOg 

PA 


fig.  12.3.  Diffusion  kinetics  of  anti- 
pyrine,  K",  and  urea  in  vasodilated 
muscle.  Permeability  to  antipyrine 
(lipid-soluble)  is  so  large  that  its 
clearance  is  limited  by  rate  of  blood 
flow.  The  clearances  of  K.41  and  urea 
are  limited,  in  part,  by  permeability 
of  cell  membranes  in  extravascular 
distribution  volume.  Less  than  10% 
of  the  diffusion  barrier  to  urea  is  con- 
tributed by  the  capillary  wall  (table 
1 2.1).  [Adapted  from  Renkin  (299, 
3°°)-] 


BLOOD  FLOW,    Q,      ml  /min   per  lOOg 

table   1 2. 1.  Comparison  of  Blood-Tissue  Permeability 
with  Capillary  Permeability 


Permeability. 

ml/min/ioo  g  Muscle 

Substance 

Blood-tissue 
PAm* 

Capillary  walls 
D„A,/Axt 

Sucrose 
Urea 

K42 

5-i  1 
4  ±   2 

7    ±   3 

18 
54 
90 

*  From  equation  12.1  f  From  table  9.1. 

=  Ds  A,/ Ax.  For  these  substances  PAm  is  small  com- 
pared to  normal  rates  of  blood  flow  and  equation  12.1 
reduces  to  equation  8. 1  describing  arterial  disappear- 
ance curves  of  large  molecules. 

C.   Nonuniform  Distribution  of  Blood  Flow  in 
Relation  to  Blood-Tissue  Exchange 

The  model  discussed  in  the  previous  paragraphs  was 
designed  to  simulate  effects  of  changes  in  flow  velocity 
through  a  constant  number  of  open  capillaries  and  the 
results  illustrated  in  figure  12.1  refer  to  widely  dilated 
blood  vessels.  At  any  given  over-all  blood  flow,  the 
clearance  of  test  molecules  may  be  very  much  smaller 
during  vasoconstriction  (299,  300).  In  supine,  anes- 
thetized dogs  the  fractional  extraction  of  antipyrine 
or  D20  from  the  circulation  to  extremities  may  be 
only  0.6  to  0.8  (40)  in  contrast  to  values  close  to  unity 


in  perfused,  vasodilated  muscle  (168)  or  the  intact 
human  forearm  (111).  The  fraction  of  total  blood 
flow  passing  through  true  (nutrient)  capillaries  is 
subject  to  wide  variation  according  to  metabolic  de- 
mands of  the  tissue  or  to  hemodynamic  demands  of 
the  organism  as  a  whole.  In  some  tissues,  such  as  skin, 
liver,  or  intestine,  the  nonnutrient  fraction  of  total 
blood  flow  may  pass  through  arteriovenous  anasto- 
moses of  potentially  large  caliber;  in  other  tissues, 
such  as  mesentery  or  muscle,  effective  physiological 
shunts  are  formed  by  arteriovenous  capillaries  (388). 
Nonuniform  distribution  of  blood  flow  within  single 
organs  may  also  occur  between  regions  of  different 
function  and  metabolic  rate,  examples  being  medulla 
and  cortex  of  the  kidney  or  gray  and  white  matter  of 
the  central  nervous  system. 

It  is  obvious  that  nonuniform  alterations  of  blood 
flow  in  the  microcirculation  will  change  the  relations 
between  total  blood  flow  and  blood-tissue  exchange 
rates;  conversely,  it  may  be  anticipated  that  quantita- 
tive studies  of  effective  tissue  perfusion  will  depend 
heavily  upon  information  obtained  from  exchange 
rates.  At  the  present  time,  available  information  is 
mostly  qualitative  and  derives  in  large  part  from 
observations  on  muscle. 

A  striking  example  of  nonuniform  distribution  of 
blood  flow  in  skeletal  muscle  can  be  observed  following 
electrical  or  reflex  stimulation  of  sympathetic  vaso- 
constrictor nerves.  Closure  of  precapillary  sphincters, 


iO'->4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


innervated  by  the  sympathetic  vasoconstrictor  system, 
can  stop  nutrient  blood  flow  through  large  areas  of 
capillary  bed,  leaving  blood  to  flow  through  arterio- 
venous thoroughfare  channels  or  other  regions  of 
low  metabolic  rate.  Under  these  conditions,  total 
blood  flow  is  reduced  but  oxygen  saturation  of  venous 
blood  approaches  that  of  arterial  blood  (26,  274,  294) 
and  respiratory  gas  exchange  may  be  reduced  to  one- 
half  or  less  of  its  normal  value.  In  diving  mammals, 
drastic  vasoconstriction  of  this  type  greatly  reduces 
tissue  gas  exchange  for  periods  of  one-half  hour  or 
more  (322,  323).  This  is  in  contrast  to  uniform  reduc- 
tion of  total  blood  flow  caused  by  decrease  in  arterial 
pressure  or  infusion  of  vasoconstrictor  drugs  (274); 
under  these  conditions,  oxygen  extraction  is  increased 
and  oxygen  utilization  remains  relatively  constant 
over  a  wide  range  of  blood  flow  (fig.  12.2). 

Recent  investigations  of  the  rates  at  which  labeled 
ions  are  removed  from  interstitial  space  in  muscle  also 
suggest  that  vasomotor  nerves  control  the  distribution 
of  blood  between  nutrient  and  nonnutrient  circula- 
tions (165).  There  is  general  correspondence  between 
clearance  of  Na24  or  I131  and  over-all  blood  flow  when 
flow  is  altered   by  pressure,   reactive  hyperemia,   or 


exercise  (72,  165,  172,  290,  362).  However,  activation 
of  the  vasomotor  system  to  muscle  or  skin  generally 
results  in  large  changes  of  flow  without  corresponding 
changes  of  clearance.  Hyman  el  al.  (165)  have  shown 
that  I131  clearance  may  actually  decrease  during  large 
increases  of  flow  caused  by  activation  of  the  sympa- 
thetic vasodilator  system.  They  suggest  that  vasodi- 
lator nerves  act  primarily  to  increase  flow  through 
arteriovenous  thoroughfare  channels. 

Studies  of  this  type  are  only  beginning  and  they 
point  to  new  directions  for  research  on  the  peripheral 
circulation.  The  principal  function  of  the  circulation 
is  to  provide  for  exchange  of  materials  between  blood 
and  tissues  and  it  seems  logical  to  study  this  function 
directly  in  terms  of  exchange  rates.  Such  studies  will 
only  be  meaningful,  however,  if  the  limitations  im- 
posed by  over-all  permeability  are  considered  in  rela- 
tion to  tissue  perfusion.  In  the  present  article  we  have 
provided  a  quantitative  background  for  assessing  the 
role  played  by  capillary  permeability  in  the  distribu- 
tion process,  indicating  only  briefly  the  contributions 
of  interstitial  diffusion,  cellular  permeability,  or 
chemical  reaction  velocity. 


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of  glomerular  permeability.  Ada  Soc.  Med.  Upsallen  59: 
Suppl.  4,  1-91,  1954. 

367.  Warren,  M.  F.,  and  C.  K.  Drinker.  The  flow  of  lymph 
from  the  lungs  of  the  dog.  Am.  ./.  Physiol.  136:  207-221, 

1942- 

368.  Wasserman,  K.,  J.  D.  Joseph,  and  H.  S.  Mayerson. 
Kinetics  of  vascular  and  extravascular  protein  exchange 
in  unbled  and  bled  dogs.  Am.  .1 .  Physiol.   184:  175-182, 

'956- 

369.  Wasserman,  K..,  L.  Loeb,  and  H.  S.  Mayerson.  Capil 
lary     permeability    to     macromolecules.     Circulation    Re- 
search 3:  594-603,  1955. 

370.  Wasserman,  K..,  and  H.  S.  Mayerson.  Exchange  of 
albumin  between  plasma  and  lymph.  .4m.  J.  Physiol. 
165:  15-26,  1951. 

371.  Wasserman,  K.,  and  H.  S.  Mayerson.  Mechanism  of 
plasma  protein  changes  following  saline  infusions.  Am. 
J.  Physiol.  170:  1-10,  1952- 

372.  Wasserman,  K.,  and  H.  S.  Mayerson.  Dynamics  of 
lymph  and  plasma  protein  exchange.  Cardiologia  21: 
296-307,  1952. 

373.  Webb,  R.  C,  Jr.,  and  T.  E.  Starzl.  The  effect  of  blood 
vessel  pulsations  on  lymph  pressure  in  large  lymphatics. 
Bull.  Johns  Hopkins  Hasp.  93:  401-407,   1953. 

374.  Weech,  A.  A.,  E.  Goettsch,  and  E.  B.  Reeves.  The 
flow  and  composition  of  lymph  in  relation  to  the  forma- 
tion of  edema.  J.  Exptl.  Med.  60:  63-84,   1934. 

375.  Wells,  H.  S.,  J.  B.  Youmans,  and  D.  G.  Miller,  Jr. 
Tissue  pressure  (intracutaneous,  subcutaneous,  and 
intramuscular)  as  related  to  venous  pressure,  capillary 
filtration,  and  other  factors.  J.  Clin.  Invest.  1 7 :  489-499, 

I938- 

376.  Whipple,  G.  H.,  and  S.  C.  Madden.  Hemoglobin, 
plasma  protein  and  cell  protein — their  interchange  and 
construction  in  emergencies.  Medicine  23:  215-224, 
1944. 


377.  White,  H.  L.  Observations  on  the  nature  of  glomerular 
activity.  Am.  J.  Physiol.  90:  689-704,   1929. 

378.  White,  11.  L.  Measurement  of  cardiac  output  by  a 
continuously  recording  conductivity  method.  Am.  J. 
Physiol.  151:45-5/.  >947- 

379.  White,  J.  C,  M.  E.  Field,  and  C.  K.  Drinker.  On  the 
protein  content  and  normal  flow  of  lymph  from  the  foot 
of  the  dog.  Am.  J.  Physiol.   103:  34-44,   1933. 

380.  Wies,  C.  H.,  and  J.  P.  Peters.  The  osmotic  pressure  of 
proteins    in    whole    serum.    J.    Clin.    Invest.     16:    93-102, 

■937- 

381.  Wilbrandt,  W.,  E.  Luscher,  and  H.  Asper.  Der  Einfluss 
von  Thrombocytenprotein  auf  die  Permeabilitat  der 
Blutkapillaren.  Helvet.  Physiol,  et  Pharmacol.  Acta  14:  C81- 
84,  1956. 

382.  Wilde,  W.  S.  Transport  through  biological  membranes. 
Ann.  Rev.  Physiol.  17:  17-36,  1955. 

383.  Wind,  F.  Versuche  zur  unmittelbaren  Bestimmung  des 
Flussigkeitsaustritts  aus  den  Blutkapillaren  des  Mesen- 
terium  und  des  Nierenglomerulus  beim  Kaltbliiter.  I. 
Mitteilung.  Arch,  exptl.  Pathol.  Pharmakol.  Naunyn- 
Schmiedeberg's  186:  161-184,    1937. 

384.  Winton,  F.  R.  Physical  factors  involved  in  the  activities 
of  the   mammalian   kidney.    Physiol.    Revs.    1 7 :   408-435, 

1937- 

385.  Wirz,  H.  Druckmessung  in  Kapillaren  und  Tubuli  der 
Niere  durch  Mikropunktion.  Helvet.  Physiol,  et  Pharmacol. 
Acta  13:42-49,  1955. 

386.  Yoffey,  J.  M.,  and  F.  C.  Courtice.  Lymphatics,  Lymph 
and  Lymphoid  Tissues  (2nd  ed.).  Cambridge,  Mass.: 
Harvard  Univ.  Press  1956,  pp.  87,  238. 

387.  Zweifach,  B.  W.  The  structural  basis  of  permeability 
and  other  functions  of  blood  capillaries.  Symposia  Qiiant. 
Biol.  8:  216-223,  1940. 

388.  Zweifach,  B.  W.,  and  D.  B.  Metz.  Selective  distribu- 
tion of  blood  through  the  terminal  vascular  bed  of 
mesenteric  structures  and  skeletal  muscle.  Angiology 
6:  282-290,  1955. 


CHAPTER     30 


The  physiologic  importance  of  lymph1 


H.    S.    MAYERS  OX 


Department  of  Physiology,  Tulane  University 
School  of  Medicine,  New  Orleans,  Louisiana 


CHAPTER     CONTENTS 

Methods  of  Study 

Development  and  Structure  of  Lymphatic  Vessels 

Lymph  vs.  Tissue  Fluid 

Distribution  of  Lymphatic  Vessels 

General  Anatomic  Arrangement  of  Main  Trunks 
Contractility  of  Lymphatics 
Exchange  of  Substances  Between  Plasma  and  Lymph 

Extravascular  Pool  and  Circulation  of  Protein 
Lymphatic  Return  and  Blood  Volume  Regulation 
Transport  Function 

Lipids 

Enzymes 

Coagulation  Principles 

Iron 

Miscellaneous 
Significance  of  Some  Regional  Lymphatics 

Thoracic  Duct 

Hepatic  Lymph 

Pulmonary  Lymphatics  and  Edema 

Cardiac 

Renal 
Lymph  and  Lymphatics  in  Shock 

Anaphylactic  Shock 

Traumatic  Shock 

Burns 

Permeability  Factors 
Permeability  of  Lymphatic  Vessels 


from  a  physiologic  point  of  view,  the  lymphatic 
system  is  primarily  a  drainage  system.  Its  need  arose 
phylogenetically  with  the  development  of  a  high 
pressure  circulation.  The  latter  development,  de- 
signed  to  insure  an  adequate   supply  of  oxygen   to 

1  The  work  described  as  emanating  from  this  laboratory  was 
supported  by  grants  from  the  Research  and  Development 
Command,  U.  S.  Army,  the  American  Heart  Association,  and 
the  U.  S.  Public  Health  Service. 


tissues,  created  a  situation  favoring  transudation  of 
fluid  and  other  substances  from  the  capillaries.  An 
increase  in  plasma  protein  served  to  counteract 
partially  this  leakage,  since  the  plasma  proteins 
exerted  an  osmotic  pressure.  There  still  remained, 
however,  the  problem  of  clearing  the  tissue  spaces  of 
substances  which  had  leaked  out  of  blood  capillaries 
or  which  were  not  absorbed  into  the  blood  stream. 
In  this  sense,  the  lymphatic  system  must  be  regarded 
as  a  homeostatic  mechanism,  important  in  the 
maintenance  of  the  constancy  of  the  milieu  interieur. 
It  is  this  point  of  view  that  will  be  emphasized  in  the 
present  discussion.  The  role  of  the  lymphatic  system 
in  the  transport  of  materials  from  the  liver  and  in- 
testines to  the  blood  stream  will  also  be  considered. 
No  attempt  will  be  made  to  cover  all  that  has  been 
done  regarding  lymph  and  lymphatics  nor  will  the 
extensive  literature  on  lymph  nodes  and  lymphoid 
tissues  be  discussed.  Various  aspects  of  the  general 
subject  have  been  treated  in  depth  during  the  last 
several  decades  in  reviews  and  monographs  (45,  58- 
60,  62,  66,  88,  135-137,  185,  189,  215,  223,  227,  234) 
and  the  reader  is  referred  to  these  sources  for  basic 
material  not  included  in  the  present  review.  Two 
recent  monographs  will  be  found  most  helpful  (189, 
234).  The  latter  source  will  interest  those  concerned 
with  clinical  implications  of  disturbed  lymphatic 
function.  It  also  includes  results  of  work  in  Hungarian 
and  Russian  laboratories  not  readily  available  in  the 
English  literature. 


METHODS    OF    STUDY 

Although   lymphatics   presumably   had   been  seen 
by  members  of  the  Alexandrian  school  (Herophilos, 


■035 


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CIRCULATION    II 


300  B.C.;  Erasistratus,  310-250  B.C.)  the  documented 
study  of  lymphatics  dates  from  1622,  when  Asellius 
(3)  demonstrated  "lacteals"'  in  the  mesentery  of  a 
well-fed  dog  and  at  a  later  date  had  the  opportunity 
of  observing  these  channels  in  a  criminal  who  had 
been  executed  following  a  large  meal.  Jean  Pecquet 
(169)  in  1651  described  the  cisterna  chyli  and  the 
thoracic  duct.  The  term  "lymphatics"  was  first  used 
by  Thomas  Bartholin  (12,  13)  and  he  and  Rudbeck 
(186)  are  usually  considered  to  be  the  co-discoverers 
of  the  lymphatic  system.'2  In  1692  Nuck  (160)  intro- 
duced the  use  of  mercury  for  injection  of  lymphatic 
vessels,  a  method  which  was  used  extensively  by 
many  investigators  during  the  eighteenth  century  to 
describe  the  location  and  distribution  of  the  main 
lymphatic  vessels.  Of  particular  importance  was  the 
work  of  Hewson  (99),  a  pupil  of  William  Hunter, 
who  made  extensive  dissections  of  the  lymphatic 
system  and  noted  that  lymph  glands  were  absent  in 
fishes  (also  in  the  turtle),  few  in  number  in  birds, 
and  well  developed  only  in  mammals.  He  also  noted 
the  presence  of  lymphocytes  in  lymph  and  thought 
they  came  from  lymph  glands  to  enter  blood  via  the 
lymph  channels.  Hunter  himself  speculated  that  "the 
lymphatic  vessels  are  the  absorbing  vessels,  all  over 
the  body"  (101). 

Anatomical  studies  during  the  nineteenth  century 
further  delineated  the  distribution  and  characteristics 
of  the  lymphatic  supply  of  various  organs  (194),  but 
it  remained  for  Ludwig  (129)  and  Heidenhain  (96) 
to  provide  the  stimulus  for  studies  of  function.  Ludwig 
developed  techniques  for  the  collection  of  lymph  by 
cannulating  lymph  vessels  in  different  parts  of  the 
body.  He  contended  that  lymph  was  a  filtrate  derived 
from  blood,  a  point  of  view  contested  by  Heidenhain 
who  maintained  that  it  was  actively  secreted  by  the 
lymphatic  epithelium.  This  classic  controversy  was 
finally  settled  by  the  extensive  work  of  Starling  during 
the  first  part  of  this  century  (203),  who  demonstrated 
the  relationships  between  hydrostatic  and  osmotic 
pressures  in  the  exchange  of  substances  between 
plasma  and  lymph,  concepts  still  fundamental  and 
generally  applicable.  These  relationships  have  been 
discussed  in  Chapter  29. 

The  study  of  lymph  and  lymphatics  has  lagged 
behind  that  of  other  parts  of  the  circulation  because 
of  inherent  difficulties  in  identification  and  dissec- 
tion of  the  lymphatics  and  their  cannulation.  Since 

2  There  is  an  interesting  biographical  note  by  G.  Liljestrand 
and  a  translation  of  Rudbeck's  "Nova  exercitatio  anatomica" 
by  A.  E.  Nielsen  in  the  Bulletin  of  the  History  of  Medicine  1 1 : 
304-339.  I942- 


lymph  is  virtually  colorless,  it  does  not  help  in  the 
visualization  of  these  small  vessels.  Even  the  identi- 
fication and  dissection  of  the  largest  trunk,  the  thoracic 
duct,  is  a  formidable  challenge  to  the  uninitiated 
investigator  unless  its  visualization  is  aided  by  previous 
injection  of  dyes  or  feeding  of  fats.  Once  identified 
and  dissected,  cannulation  of  a  lymphatic  still 
presents  a  problem  because  of  the  ease  with  which 
the  thin  vessel  can  be  torn.  This  may  explain  the 
temptation  for  investigators  to  forsake  the  actual 
collection  of  lymph  for  the  much  less  frustrating 
study  of  the  effects  of  ligation  of  the  vessels.  Rudbeck 
expressed  these  difficulties  very  well  in  1653  when  he 
said: 

"Of  the  many  structures  difficult  to  find  in  ana- 
tomical dissections,  these  vessels,  I  must  confess,  are 
by  no  means  the  least.  For  usually  they  will  not 
tolerate  the  finest  blunt  probe,  a  sharp  knife,  a  suction 
tube,  or  any  other  instrument  whatever.  And  even 
though  abundantly  present,  they  are  often  obscured 
by  fat,  or  are  overlooked  if  not  at  the  moment  filled 
with  fluid.  When  seen  they  may  disappear  if  not 
ligated.  Thus  in  elusiveness  they  rival  the  lacteals 
and  must  be  handled  with  utmost  care." 

Several  recent  developments  have,  however,  made 
the  lives  of  the  lymphatic  investigators  less  trying 
and  their  labors  more  rewarding.  Availability  of 
nontoxic  and  radiopaque  dyes  has  facilitated  tracing 
of  lymphatic  pathways  and  stimulated  a  new  interest 
in  this  aspect,  particularly  in  surgery  (20,  52,  112). 
To  the  physiologist,  the  greatest  boons  have  been 
the  availability  of  polyethylene  tubing  and  isotopes. 
The  range  of  sizes  and  flexibility  of  polyethylene 
tubing  and  relative  freedom  from  clotting  in  this 
tubing  have  made  cannulation  easier  and  have 
made  chronic  experiments  possible  not  only  in  un- 
anesthetized  experimental  animals  but  in  man  (16, 
31,  54,  125,  177,  201,  208).  Small  vessels  entered 
with  glass  cannulae  only  with  the  greatest  difficulty 
can  now  be  studied  (198,  199).  The  use  of  isotopes 
has  facilitated  the  study  of  lymphatic  uptake  from 
subcutaneous  tissues  (100,  209).  It  has  also  made 
possible  more  quantitative  studies  on  the  exchange 
of  substances  between  plasma  and  lymph.  These 
gains  will  be  apparent  in  the  discussions  to  follow. 


DEVELOPMENT    AND    STRUCTURE    OF 
LYMPHATIC  VESSELS 

It  is  now  generally  agreed  that  lymphatic  vessels 
are  derived  from  veins.  To  quote  Sabin  (190)  "Lym- 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


IO37 


phatics  are  modified  veins.  They  are  vessels  lined  by 
an  endothelium  which  is  derived  from  the  veins. 
They  invade  the  body  as  do  blood  vessels  and  grow 
into  certain  constant  areas;  their  invasion  of  the 
body  is,  however,  not  complete  for  there  are  certain 
structures  which  never  receive  them.  The  lymphatic 
capillaries  have  the  same  relation  to  tissue  spaces  as 
have  blood  capillaries.  None  of  the  cavities  of  the 
mesoderm,  such  as  the  peritoneal  cavity,  the  various 
bursae  and  serous  capillaries,  forms  any  part  of  the 
lymphatic  system.  The  lymphatic  endothelium  once 
formed  is  specific.  Like  blood  vessels  the  lymphatics 
are  for  the  most  part  closed  vessels." 

The  lymphatic  capillaries  may  be  considered  as 
endothelial  tubes  resembling  blood  capillaries  but 
thinner.  The  medium-size  vessels  (100-200  n)  have 
muscle  fibers,  whereas  the  larger  lymphatics  are  com- 
posed of  an  endothelial  layer  covered  by  a  diffuse 
connective  tissue  sheath  in  which  elastic  and  muscular 
elements  are  irregularly  scattered.  Amyelinated  nerves 
can  be  traced  to  the  muscle  fibers.  Valves  develop 
during  intra-uterine  life  in  the  large  vessels  and  are 
usually  unicuspid  or  bicuspid.  These  structures  deter- 
mine the  direction  of  flow  toward  sites  of  emptying 
into  the  blood  stream. 


LYMPH    VS.    TISSUE     FLUID 

It  is  now  generally  accepted,  primarily  from  the 
work  of  Sabin  (191)  and  MacCallum  (132),  that  the 
lymphatics  form  a  closed  system.  "Lymph,"  therefore, 
is  not  synonymous  with  "tissue  fluid,"  but  is  the 
fluid  found  in  lymphatics.  This  is  more  than  a 
semantic  distinction  because,  as  will  be  apparent 
later,  the  composition  of  lymph  is  more  particularly 
determined  by  the  permeability  of  blood  capillaries 
in  a  definite  area  and  the  consequent  pcricapillary 
filtrate  than  it  is  by  the  metabolism  of  tissue  cells.  In 
this  sense,  lymph  is  pericapillary  filtrate  which  has 
mixed  with  tissue  fluid  and  has  entered  the  closed 
lymphatic  system. 

Clark  &  Clark  (43)  showed  that  lymphatic  capil- 
laries are  sometimes  closely  associated  with  small 
blood  vessels,  with  virtually  nothing  between  the  two 
membranes,  while  in  other  cases  they  bear  no  rela- 
tionship to  such  vessels.  In  any  region,  the  fluid  that 
enters  the  lymphatic  system  to  become  lymph  may  be 
that  which  is  adjacent  to  the  arterial  end  or  to  the 
venular  end  of  a  blood  capillary,  or  it  may  be  fluid 
that  is  relatively  distant  from  a  blood  capillary. 
Mc Master  (137)  studied  the  relative  pressures  within 


the  cutaneous  lymphatic  capillaries  and  the  surround- 
ing tissues  in  the  mouse's  ear.  He  reported  that  the 
mean  lymphatic  pressure  was  1.2  cm  water  and  the 
interstitial  pressure  1.9  cm  water.  There  was  always 
a  gradient  of  pressure  from  the  interstitial  tissue  to 
the  lumen  of  the  lymphatic  even  in  conditions  of 
increased  lymphatic  pressure.  Presumably,  whenever 
increased  amounts  of  fluid  are  present  in  the  inter- 
stitial tissues,  the  lymphatic  vessels  are  kept  open  by 
swelling  of  connective  tissues  and  increase  in  the 
tension  of  the  fibers  attached  to  the  lymphatic  capil- 
laries (42,  43,  137,  175).  Many  more  data  are  needed 
in  other  tissues  and  species  to  establish  firmly  the  fact 
that  a  gradient  of  pressure  is  always  present  between 
interstitial  tissues  and  the  lymphatics,  and  is  an  im- 
portant factor  in  the  formation  of  lymph.  Particularly 
disturbing  in  this  connection  is  the  recent  report  of 
Guyton  et  al.  (93)  suggesting  the  existence  of  negative 
pressures  in  interstitial  spaces. 

The  close  anatomical  relationship  between  the 
lymphatic  and  venous  systems  has  raised  the  question 
as  to  the  relationship  of  lymphatic  and  venous  pres- 
sures. Little  definitive  information  is  available,  how- 
ever, in  this  area,  due  primarily  to  the  difficulties  in 
measurement  of  lymphatic  pressure.  Many  of  the 
pressures  that  have  been  recorded  are  end  pressures 
(234)  and  not  particularly  representative  of  the  actual 
pressures  under  normal  conditions  of  flow.  Thus,  Lee 
(124)  found  the  average  end  thoracic  duct  pressure 
in  dogs  to  be  15  cm  HjO,  whereas  Rouviere  & 
Valette  (185)  found  side  pressure  at  the  entrance  to 
the  subclavian  vein  to  be  6.4  cm  H>0.  They  also 
found  the  pressure  in  the  internal  jugular  vein  of  the 
same  animal  to  be  2.4  cm  H20,  thus  demonstrating 
the  existence  of  a  gradient  capable  of  promoting 
emptying  of  lymph  from  the  thoracic  duct  to  the 
jugular  vein.  Webb  &  Starzl  (222)  found  side  pres- 
sures of  3.5  to  5.5  cm  HjO  in  the  thoracic  duct  just 
above  the  diaphragm  in  anesthetized  dogs.  At  this 
point,  arterial  pulsations  affected  the  lymph  pressure, 
the  difference  between  the  pressures  during  systole 
and  diastole  being  2  to  3  cm  H20.  Although  these 
values  are  lower  than  those  of  Rouviere  and  Valette, 
they  still  permit  of  a  gradient  toward  the  vein. 
Irisawa  &  Rushmer  (103)  recently  reported  on  the 
relationship  between  lymphatic  and  venous  pressure 
in  the  legs  of  dogs.  Although  previous  investigators 
had  regarded  lymphatic  pressure  of  a  resting  dog  leg 
as  being  too  low  to  measure,  these  authors,  working 
with  unanesthetized  dogs,  found  the  leg  lymphatic 
pressures  to  range  from  2.5  to  12.0  cm  H«0,  while 
the  range  of  pressures  in  ankle  veins  was  from  5.5  to 


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15  cm  FLO.  Pressure  levels  in  veins  and  lymphatics 
were  generally  very  similar  at  rest,  the  venous  pres- 
sures being  only  slightly  higher.  It  would  thus  seem 
that  pressure  in  the  lymphatic  capillaries  may  be 
comparable  to  the  pressure  in  the  venous  end  of 
capillaries  at  rest.  These  authors  found  the  leg 
lymphatic  pressure  to  fluctuate  with  respiration.  With 
increased  venous  pressures,  lymphatic  pressure  rose 
slowly  but  never  reached  the  level  of  venous  pressure, 
a  reflection,  perhaps,  of  the  distensibility  of  lymphatics 
(156)  and  collection  of  fluid  in  the  tissues.  Similar 
experiments  in  our  laboratory  (Miller,  unpublished) 
on  the  anesthetized  dog  also  showed  a  lack  of  direct 
correspondence  between  leg  lymphatic  and  venous 
pressures  under  a  variety  of  experimental  procedures. 


DISTRIBUTION    OF    LYMPHATIC    VESSELS 

Although  lymphatic  capillaries  spread  into  a  tissue 
after  the  blood  vessels,  the  density  of  the  lymphatic 
plexus  does  not  always  run  parallel  with  the  richness 
of  the  blood  supply.  Furthermore,  capillary  plexuses 
vary  tremendously  in  richness  in  different  organs 
and  tissues.  For  example,  they  are  abundant  in  the 
dermis,  the  conjunctiva,  the  periostium  of  bone,  and 
in  the  mucosa  and  submucosa  of  the  alimentary, 
respiratory,  and  genitourinary  tracts,  but  are  pre- 
sumably absent  in  cartilage,  bone  marrow,  the  central 
nervous  system,  epithelium,  and  fetal  part  of  the 
placenta  (62).  Voluntary  muscle  contains  lymphatics 
only  in  fascial  planes.  It  is  generally  believed  that 
lymphatic  capillaries  do  not  actually  reach  the  pul- 
monary alveoli,  but  that  their  distribution  ceases  at 
the  beginning  of  the  respiratory  portion  of  the  ulti- 
mate lung  structure,  the  atrium  leading  into  the 
alveolus.  Likewise  in  the  liver,  the  ultimate  functional 
unit,  the  lobule,  is  not  supplied  with  lymphatic 
capillaries.  The  fluid  leaving  the  liver  sinusoids  passes 
through  capillary  endothelium  and,  in  the  lobule,  lies 
between  this  endothelium  and  the  liver  cells.  Lym- 
phatic capillaries  are  found  at  the  periphery  of  the 
lobule,  and  these  carry  the  highly  proteinized  liver 
lvmph  to  collecting  trunks  which  join  the  thoracic 
and  right  lymph  ducts.  In  the  spleen,  too,  lymphatics 
are  observed  only  in  the  capsule  and  the  thickest 
trabeculae.  Fluid  which  filters  through  the  walls  of 
the  capillaries  and  sinuses  must  permeate  the  stroma 
before  reaching  the  lymphatic  vessels. 

Lymphatic  vessels  in  the  kidney  appear  to  begin 
blindly  in  two  areas  (181).  The  first  of  these  is  near 
Bowman's  capsule,   and   the   second   is   beneath   the 


mucosa  of  the  papilla.  Two  networks  of  lymphatics 
then  arise,  accompanying  venous  and  arterial  blood 
vessels  of  the  kidney.  Those  which  originate  in  the 
medulla  drain  upward  and  outward  toward  the 
arcuate  vessels,  where  they  join  with  those  beginning 
near  Bowman's  capsule  draining  in  the  opposite 
direction.  When  the  junction  occurs,  larger  trunks 
then  drain  with  the  arcuate  vessels  toward  the  hilum 
of  the  kidney.  They  may  be  seen  around  the  renal 
artery.  There  do  not  seem  to  be  any  demonstrable 
lymphatic  channels  in  the  glomeruli  or  about  the 
afferent   and   efferent   arterioles. 

The  lymphatic  drainage  of  the  eye  has  only  re- 
cently been  clarified  (165).  The  explanation  of  the 
almost  zero  concentration  of  proteins  in  the  anterior 
chamber  has  long  been  a  major  problem  since  no 
lymphatic  drainage  had  previously  been  described. 
Papamiltiades,  in  an  anatomical  study  of  lymphatics 
at  the  iridocorneal  angle  of  the  eye,  described  lym- 
phatic pathways  in  the  neighborhood  of  the  canal  of 
Schlemm  (possibly  connecting  with  the  canal)  ade- 
quate to  allow  continual  removal  of  proteins  from  the 
anterior  chamber. 


General  Anatomic  Arrangement 
of  the  Main  Trunks 

The  large  lymphatic  trunks  join  the  subclavian  or 
jugular  veins  near  their  junctions.  On  the  left  side, 
the  deep  cervical  duct,  draining  the  head  and  neck, 
the  subclavian  duct,  draining  the  arm,  and  the 
thoracic  duct,  draining  the  abdominal  viscera  and 
lower  extremities,  enter  the  venous  system  in  close 
association  with  one  another.  The  left  broncho- 
mediastinal trunk,  draining  the  left  sides  of  the  thorax, 
lung,  and  heart  may  join  the  thoracic  duct  in  the  neck 
or  open  independently  into  the  junction  of  the  left 
subclavian  and  internal  jugular  veins.  Sometimes  all 
of  the  trunks  empty  into  a  sinus  or  dilatation  from 
which  the  lvmph  then  empties  into  the  vein;  at  other 
times,  thev  may  form  a  network  before  entering  the 
vein  or  they  may  all  enter  the  vein  close  together 
but  independently  of  one  another.  On  the  right  side, 
the  right  jugular  trunk,  draining  the  head  and  neck, 
the  right  subclavian  trunk,  draining  the  right  upper 
extremity,  and  the  right  bronchomediastinal  trunk, 
draining  the  right  side  of  the  thorax,  lung,  and  heart 
and  part  of  the  convex  surface  of  the  liver,  empty  into 
the  right  lymphatic  duct  which,  in  turn,  ends  in  the 
right  subclavian  vein  at  its  angle  of  junction  with  the 
right  internal  jugular  vein.  As  on  the  left  side,  the 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I°39 


three  collecting  ducts  not  infrequently  enter  the  vein 
separately  at  the  junction  of  the  two  veins. 

The  thoracic  duct  is  somewhat  more  complex 
than  other  lymphatic  vessels.  It  usually  begins  in 
front  of  the  body  of  the  second  lumbar  vertebra,  to 
the  right  of  and  behind  the  aorta,  by  a  dilatation  of 
the  cysterna  chyli.  It  enters  the  thorax  through  the 
aortic  hiatus  and  ascends  through  the  posterior 
mediastinum  between  the  aorta  and  azygos  vein. 
Somewhere  between  the  fourth  and  sixth  vertebral 
level  it  inclines  to  the  left,  enters  the  superior  medi- 
astinum, passes  behind  the  arch  of  the  aorta  and 
thoracic  portion  of  the  left  subclavian  artery  into  the 
neck  where,  after  passing  in  front  of  the  left  common 
carotid  artery,  vagus  nerve,  and  jugular  vein,  it 
ends,  as  previously  noted,  by  emptying  into  the 
angle  of  junction  of  the  left  subclavian  vein  and  left 
internal  jugular  vein.  The  thoracic  duct  is  the  largest 
lymph  vessel  and  is  composed  of  an  endothelial  layer, 
a  distinct  subendothelial  layer  of  elastic  fibers,  a 
media  of  irregularly  arranged  but  mainly  circular 
smooth  muscle  cells  interspersed  with  elastic  and 
connective  tissue  fibers,  which  is  succeeded  by  the 
adventitia  containing  longitudinal  and  transverse 
bundles  of  smooth  muscle  cells  as  well  as  blood  vessels 
and  nerves.  It  contains  valves  which  are  quite  efficient. 
Kampmeier  (106)  found  many  more  valves  in  the 
thoracic  duct  of  early  embryos  than  in  later  stages.  In 
one  human  fetus,  of  4.3  months,  he  found  42  valves 
between  the  jugular  confluence  and  renal  arteries.  In 
older  fetuses  he  found  as  few  as  three  complete  valves 
with  numerous  vestiges  present.  Obviously,  many  of 
the  early  valves  never  progress  to  the  functional  stage 
and  some  vanish  entirely.  Kampmeier  suggested  that 
the  valves  which  did  remain  in  postnatal  life  were 
determined  by  areas  of  direct  pressure  on  the  duct 
as,  for  example,  in  the  area  between  aorta  and 
esophagus  as  they  cross,  an  area  in  which  a  bolus  of 
food  exerts  pressure  upon  the  duct. 

The  above  general  descriptions  are  actually  subject 
to  more  exceptions  than  have  been  indicated.  Studies 
of  large  numbers  of  animals  or  species  soon  demon- 
strate this  variability7.  McClure  &  Silvester  (134) 
drew  attention  to  this  variability,  as  far  back  as  1909, 
in  their  report  of  a  study  of  25  species  involving  50 
mammals  (primates,  carnivora,  rodentia,  ungulata, 
and  marsupialia).  In  the  adult  cat,  communication 
between  the  lymphatic  system  and  the  systemic  veins 
may  normally  occur  on  each  side  of  the  body,  within 
either  one  of  two  or  within  two  typical  districts. 
These  two  districts  include,  approximately,  the  angle 
of  confluence  formed   by  the  union  of  the  external 


and  internal  jugular  veins  (common  jugular  angle) 
and  the  angle  of  confluence  formed  by  the  union  of 
the  external  jugular  and  subclavian  veins  (jugulo- 
subclavian  angle).  In  the  adult  cat,  neither  one  of 
these  two  districts  predominates  as  the  place  of  com- 
munication between  the  lymphatics  and  the  veins; 
either  one  of  the  two,  or  both,  may  serve  equally  in 
this  capacity.  Their  studies  in  other  mammals  showed 
that  these  two  districts  were  the  predominant  sites 
of  communication  between  lymphatics  and  veins,  but 
there  was  a  marked  variability  in  lymphatic  arrange- 
ment, more  so  than  in  veins,  not  only  in  different 
species  but  among  members  of  the  same  species.  These 
variations  are  presumably  due  to  differences  in  the 
establishment   of  these   connections   in   the   embrvo. 

One  factor  which  has  been  relatively  neglected  in 
recent  years  has  been  the  possible  existence  of  direct 
lymphatic  communications  between  veins  at  points 
other  than  the  entrance  of  the  main  ducts.  Silvester 
(200)  injected  89  adult  monkeys  and  studied  their 
lymphatic  arrangements.  He  made  the  significant 
observation  that  "Whenever  the  mesenteric  or 
inguinal  lymphatic  nodes  of  a  New  World  species 
were  injected,  the  injection  mass  never  passed  from 
the  lumbar  or  intestinal  lymphatic  trunks  into  the 
thoracic  duct  or  into  the  anterior  regions  of  the  body, 
but  passed  directly  into  the  postcava  into  the  region 
of  the  renal  veins.  A  more  detailed  examination  of 
the  vessels  in  this  region  of  the  body  revealed  the  fact 
that  the  lymphatics  of  the  digestive  organs  and  of  the 
posterior  extremities  invariably  enter  the  venous 
system  at  the  level  of  the  renal  veins."  Silvester  found 
the  posterior  communications  between  the  lymphatic 
and  the  venous  system  to  vary  from  two  to  nine  in 
number  and  to  open  at  almost  any  point  on  the  renal 
segment  of  the  postcava  and  its  immediate  tributaries. 
He  examined  16  different  species  of  Old  World 
monkeys  and  found  no  evidence  of  these  communica- 
tions. 

It  would  be  of  great  interest  to  know  if  similar 
communications  exist  in  the  dog,  rat,  and  man, 
animals  most  frequently  used  in  studies  of  the  lym- 
phatic system.  Their  existence  might  modify  inter- 
pretations based  on  the  supposition  that  all  lymph 
from  the  viscera  and  posterior  extremities  finds  its 
way  back  to  the  blood  stream  only  via  the  main 
lymphatic  channels. 

CONTRACTILITY    OF    LYMPHATICS 

In  lower  animals,  as  in  the  frog,  lymph  hearts 
serve  to  actively  propel  lymph  and  distribute  it  to 


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CIRCULATION    II 


various  parts  of  the  organism.  In  the  mammal,  there 
are  no  lymph  hearts  and  lymph  is  moved  along  the 
vessel  wherever  and  whenever  the  vessel  is  compressed, 
a  situation  analogous  to  that  obtaining  with  veins  and 
venous  flow.  The  presence  of  smooth  muscle  fibers 
in  the  walls  of  at  least  the  larger  vessels,  and  nerve 
fibers  running  to  them,  raises  the  question  as  to 
whether  lymphatic  vessels  have  contractility  or  show 
vasomotion.  Of  particular  interest  are  their  responses 
to  sympathetic  and  parasympathetic  stimulation  and 
to  the  chemical  mediators,  epinephrine  and  acetyl- 
choline. 

Spontaneous  contraction  of  lymph  vessels  was 
described  as  far  back  as  1774  by  Hewson  (99),  who 
reported  briefly  of  having  seen  actively  contracting 
lacteals  in  horses  and  dogs  killed  immediately  after 
the  ingestion  of  food.  Since  then,  many  observers 
have  also  reported  spontaneous  contraction  of  these 
and  other  lymph  vessels,  but  there  seem  to  be  species 
differences  (159,  160,  175,  202,  224).  Definite  spon- 
taneous contractions  have  been  observed  in  the 
peripheral  lymphatic  vessels  of  the  bat,  rat,  and 
guinea  pig.  No  spontaneous  contractions  have  been 
demonstrated  in  the  cat,  dog,  rabbit,  and  squirrel. 
The  results  on  mice  have  been  equivocal.  The  few 
casual  observations  in  man  have  shown  none.  The  rate 
of  contraction  appears  to  be  directly  proportional  to 
the  rate  of  formation  of  lymph  and  the  contractions 
are  apparently  initiated  by  an  increase  in  intra- 
luminal pressure.  They  are  not  dependent  on  neural 
control  (225).  The  vasomotion  in  these  vessels  seems 
to  be  similar  to  that  seen  in  blood  vessels  and  possibly 
related  to  it.  Baez  and  his  co-workers  (9)  observed 
mesenteric  lymphatics  during  experimental  hemor- 
rhagic shock  in  rats  and  reported  that  the  lymphatics 
undergo  pronounced  compensatory  and  decom- 
pensatory  adjustments  recalling  those  seen  in  met- 
arterioles  and  precapillaries  of  the  same  region. 
During  the  period  when  the  animal  is  recoverable  by 
transfusion,  the  lymphatic  vessels  exhibit  progressive 
enhancement  of  spontaneous  motion  and  of  sensitivity 
to  topically  applied  epinephrine.  Reversal  of  these 
features  occurs  upon  the  prolongation  of  drastic 
hvpotension.  Lymph  vessel  adjustments  after  sublethal 
drum  trauma  are  of  a  compensatory  type,  compatible 
with  survival,  whereas  following  lethal  trauma,  the 
lymphatics  invariably  appear  atonically  distended  and 
resemble  those  seen  in  irreversible  shock. 

Experiments  with  drugs  and  faradic  and  other 
types  of  stimulation  have  also  given  equivocal  results, 
due  probably  to  differences  in  experimental  proce- 
dures, in  species,  and  in  a  failure  to  distinguish  be- 


tween effects  on  rhythmicity  and  on  caliber  of  the 
vessels.  There  is  a  suggestion  that  the  response  of 
different  lymph  vessels  may  not  be  uniform.  Thus  the 
usual  response  to  sympathetic  stimulation  or  epi- 
nephrine administration,  in  general,  appears  to  be  a 
constriction  (175,  187-189,  202),  whereas  the  thoracic 
duct  is  dilated  by  the  same  procedures  (1).  Much 
more  careful  work  needs  to  be  done  in  this  area. 


EXCHANGE    OF    SUBSTANCES    BETWEEN 
PLASMA    AND    LYMPH 

Much  evidence  has  accumulated  during  the  last 
decade  regarding  the  exchange  of  substances  between 
plasma  and  lymph.  As  discussed  previously,  the  avail- 
ability of  isotopes  has  made  possible  quantitative 
studies  of  the  disappearance  of  labeled  substances 
from  plasma  and  their  subsequent  appearance  in 
lymph.  The  availability  of  polyethylene  tubing  has 
facilitated  the  collection  of  lymph  and,  with  a  few 
exceptions,  it  has  been  collected  from  all  areas  of  the 
body  and  its  contents  more  or  less  completely  char- 
acterized. Beginnings  have  been  made  in  the  study 
of  human  lymph  (97,  98,  125,  192)  under  a  variety 
of  experimental  conditions.  The  latter  studies  have 
been  concerned  with  thoracic  duct  lymph  because 
of  the  greater  ease  of  its  collection,  but  will  unques- 
tionably be  extended  in  the  near  future  to  the  investi- 
gation of  lymph  from  other  areas. 

Concepts  of  capillary  permeability  and  factors 
which  influence  it  are  discussed  in  detail  in  Chapter 
29.  Two  concepts  have  influenced  contemporary 
thinking  in  the  problem  of  interchange  of  substances 
between  plasma  and  lymph,  /)  the  familiar  "Starling 
hypothesis,"  and  2)  the  "pore"  concept  of  capillary 
permeability. 

Starling  maintained  that  the  direction  and  rate  of 
fluid  transfer  was  proportional  to  the  algebraic  sum 
of  the  effective  hydrostatic  pressure  in  the  blood 
capillaries  and  the  osmotic  pressure  of  the  plasma 
proteins.  While  the  capillary  membrane  was  freely 
permeable  to  crystalloids,  it  did  not  allow  larger 
protein  molecules  to  diffuse  readily.  The  evidence  in 
general  confirmation  of  Starling's  hypothesis  has 
recently  been  reviewed  by  Yoffey  &  Courtice  (234). 

Although  Starling  conceived  the  capillary  mem- 
brane as  being  only  relatively  impermeable  to  protein, 
there  developed  a  point  of  view  implied  or  stated  in 
textbooks  that  capillaries  were  impermeable  to  pro- 
tein if  they  were  healthy  and  that  proteins  leaked 
only  when  the  permeability  was  abnormal.  As  will 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I  04  I 


be  discussed  in  detail  below,  there  is  now  no  question 
but  that  "normal,"  "healthy"  capillaries  leak  protein 
(and  other  macromolecules)  and  that  the  protein 
content  of  lymph  collected  from  different  areas  of 
the  body  is  primarily  an  expression  of  the  leakage  of 
these  macromolecules  from  the  blood  stream.  Thus, 
during  the  course  of  a  day,  50  per  cent  or  more  of 
the  total  circulating  protein  escapes  from  the  blood 
stream  and  is  returned  to  it  via  the  lymphatic  system. 
An  additional  factor  in  the  reluctance  to  the  ac- 
ceptance of  the  idea  that  lymph  was  primarily 
derived  from  capillary  filtrate  was  literal  adherence 
to  the  pore  concept  of  capillary  permeability.  It  was 
difficult  to  reconcile  the  appearance  of  proteins  and 
other  macromolecules  in  lymph  with  the  size  of  the 
"pores"  postulated  for  capillary  membranes  (118). 
It  is  now  obvious  that  the  pore  concept  as  originally 
reviewed  by  Pappenheimer  (166)  must  be  modified 
and  reconciled  with  the  more  recent  work  on  lymph 
to  permit  of  the  possible  operation  of  active  processes 

(141). 

Drinker  and  his  colleagues  elaborated  on  Starling's 
concept  of  capillary  permeability.  As  a  result  of 
analysis  of  lymph  from  different  areas  of  the  body 
they  concluded  "that  the  capillaries  practically  uni- 
versally leak  protein,  that  this  protein  does  not 
reenter  the  blood  vessels  unless  delivered  by  the  lym- 
phatic system;  that  the  filtrate  from  the  blood  capil- 
laries to  the  tissue  spaces  contains  water,  salts,  and 
sugars  in  concentrations  found  in  blood,  together 
with  serum  globulin,  serum  albumin,  and  fibrinogen 
in  low  concentrations,  lower  probably  than  that  of 
tissue  fluid  or  lymph;  that  water  and  salts  are  re- 
absorbed by  blood  vessels  and  protein  enters  the 
lymphatics  together  with  water  and  salts  in  the  con- 
centrations existing  in  the  tissue  fluid  at  the  moment 
of  lymphatic  entrance"  (61).  During  the  last  decade, 
as  will  be  discussed  below,  experiments  particularly 
with  isotope-labeled  proteins  and  other  macromole- 
cules have  confirmed  the  point  of  view  of  the  Drinker 
group  and  have  shown  unequivocally  that  "healthy" 
capillaries  leak  plasma  protein  and  other  macro- 
molecules and  that  these  are  returned  to  the  blood 
stream  via  the  lymphatics.  To  date,  all  plasma  pro- 
teins have  been  shown  to  be  present  in  lymph  from 
all  areas  studied  (234). 

Exlr avascular  Pool  and 
Circulation  of  Protein 

When  a  labeled  protein  is  injected  intravenously, 
the  specific  activity  (ratio  of  concentrations  of  labeled 


and  natural  protein)  of  lymph  gradually  rises  (44, 
116,  149)  until  it  reaches  that  of  plasma  in  7  to  13 
hours  in  the  case  of  the  thoracic  duct  (220).  Samples 
of  lymph  and  plasma  analyzed  after  this  time  show 
that  the  specific  activities  in  the  two  compartments 
remain  equal  and  decline  at  the  same  slow  rate.  This 
early  growth  type  of  curve  suggests  that  protein 
leaves  the  blood  stream  and  mixes  with  the  extra- 
vascular  protein  pool  before  being  taken  up  by  the 
lymph  ducts.  If  lymph  were  a  direct  product  of 
plasma,  the  experiments  should  yield  a  "decay"  type 
of  curve.  This  point  of  view  is  strengthened  by  experi- 
ments in  which  large  infusions  were  given  to  dogs 
(116,  221).  Infusions  roughly  equivalent  to  or  greater 
than  plasma  volume  resulted  in  increased  flow  of 
thoracic  duct  lymph  and  albumin  leakage  increased 
significantly  (fig.  1).  It  was  obvious  that  the  eventual 
level  of  total  circulating  plasma  protein  was  deter- 
mined by  a  number  of  factors.  Infusion  results  in  the 
filtration  of  a  more  dilute  protein  solution  than  that 
filtered  before  the  infusion,  but  one  which  has  a 
relatively  greater  albumin  content  as  well  as  a  larger 
volume.  This  then  mixes  with  the  relatively  more 
concentrated  preinfusion  interstitial  fluid  so  that  the 
concentration  of  albumin  in  lymph  after  the  infusion 
is  intermediate  between  that  of  the  interstitial  fluid 
formed  before  the  infusion  and  the  newly  formed 
interstitial  fluid.  The  eventual  effect  of  an  infusion 
on  the  total  plasma  protein  level  will  thus  depend 
upon  a)  the  degree  of  distention  of  the  interstitial 
space  as  a  result  of  the  infusion,  since  a  greatly  dis- 
tended interstitial  space  may  hold  much  of  the  protein 
which  ordinarily  might  have  gone  back  to  the  circu- 
lation via  the  lymphatics;  b)  the  rate  (and  amount) 
of  albumin  leaving  the  capillaries;  c)  the  amount  of 
albumin  present  in  interstitial  fluid  available  for 
mixing  with  the  plasma  filtrate;  and  d)  the  rate  of 
lymph  flow.  If  the  lymph  does  not  return  to  the 
venous  system  or  if  the  amount  disappearing  from 
the  plasma  is  greater  than  the  amount  returning  via 
lymph,  plasma  albumin  will  be  decreased  and  remain 
low  until  the  usual  conditions  of  flow  are  re-estab- 
lished. These  results  with  isotopically  labeled  albumin 
emphasize  that  we  are  not  concerned  with  mobiliza- 
tion of  cell  protein,  as  has  been  suggested  in  the  litera- 
ture (4,  59),  but  primarily  with  the  movement  of 
interstitial  fluid  protein.  Addition  of  new  protein 
from  any  source  drained  by  lymph  coming  to  the 
thoracic  duct  would  have  been  apparent  by  a  lowering 
of  specific  activity.  This  was  never  seen. 

Evidence    for    the    existence    of   an    extravascular 
albumin  mass  as  a  separate  entity  and  in  equilibrium 


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fig.  I.  A:  Ratio  of  lymph  volume  flow 
(ml/min)  after  the  start  of  the  infusion  to 
the  preinfusion  (control)  lymph  volume  flow 
plotted  against  the  time  after  the  beginning 
of  the  infusion.  The  250-ml  infusions  lasted 
approximately  8  min,  the  500-ml  infusions 
lasted  15  min,  the  1000-ml  infusions  lasted 
30  min,  and  the  2000-ml  infusions  lasted 
approximately  1  hour.  Average  control 
lymph  flow  for  these  experiments  is  0.5  ml/min. 
B:  Ratio  of  albumin  flow  (ml/min)  after  the 
start  of  the  infusion  to  the  preinfusion  (con- 
trol) lymph  albumin  flow  plotted  against 
time  after  the  beginning  of  the  same  experi- 
ments as  in  A.  Numerals  to  the  right  of  the 
infusion  volumes  are  the  numbers  of  experi- 
ments which  were  averaged  in  each  group. 
Average  control  albumin  flow  for  these 
experiments  is  8.5  mg/min. 


16.0 


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MINUTES 


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500ml  (4) 

250ml  (6) 


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60  90 


1.20 


with  the  intravascular  mass  was  obtained  from  experi- 
ments on  unanesthetized,  healthy  greyhounds,  infused 
with  25  per  cent  albumin  or  bled,  into  which  we  in- 
jected I131-labeled  albumin  and  then  determined  the 
albumin  specific  activities  (218).  We  showed  that 
albumin  specific  activity  curves  can  be  altered  by 
changing  the  ratio  of  intravascular  to  extravascular 
albumin  masses  in  a  manner  predicted  by  a  two- 
compartment  system.  Increase  of  intravascular  mass 
(by  infusion)  relative  to  extravascular  mass  results  in 
a  smaller  initial  disappearance  of  albumin  specific 
activity  from  the  blood  stream  and  a  faster  approach 
to  equilibrium.  Decrease  of  intravascular  albumin 
mass  relative  to  extravascular  mass  by  bleeding  shows 
that  50  per  cent  of  albumin  replacement  after  hemor- 
rhage appears  to  be  accomplished  within  24  hours. 
Almost  all  this  protein  comes  from  the  extravascular 
compartment.  Rapid  anabolism  accounts  for  the 
replenishment  of  protein  for  the  next  2  to  5  days, 
during  and  after  which  there  is  a  reduced  catabolism 
of  the  existing  plasma  albumin.  Thus  there  are  net 
movements  from  the  extravascular  mass  into  plasma 
when  the  equilibrium  between  intravascular  and 
extravascular  masses  is  disturbed. 

Benson  et  al.  (14)  concluded  that  under  stand- 
ardized resting  conditions  a  given  tissue  eliminates  a 
nearly  constant  amount  of  protein  in  its  lymph  per 
unit  of  time  and  that  the  protein  concentration  in  the 
lymph  from  the  intestine  or  liver  of  the  rat  varies 
inversely  with  the  volume  of  lymph  flow.  The  concen- 
trations of  protein  fractions  in  rabbit  lymphs,  and  the 
rates  of  exchange   of  radioiodinated    human   serum 


albumin  between  plasma  and  lymph  which  they  ob- 
served, suggested  that  the  equilibration  of  plasma 
proteins  with  lymph  is  rapid  in  the  liver,  intermediate 
in  the  intestine,  and  slow  in  skeletal  muscles.  These 
findings  are  consistent  with  our  recent  demonstration 
(see  figs.  2  and  3)  of  differences  in  blood  capillary 
permeability  in  different  areas  to  macromolecules 
(141)  and  the  suggestion  that  there  are  several  sets 
of  capillary  pores  of  different  sizes,  large  pores  pre- 
dominating in  the  liver,  small  pores  in  muscles,  and 
both  size  pores  in  the  intestinal  capillaries.  Alter- 
nately, the  suggestion  was  made  that  cytopempsis  or  a 
similar  process  may  be  involved. 


LYMPHATIC    RETURN    AND 
BLOOD    VOLUME    REGULATION 

Lymph  not  only  returns  protein  and  other  macro- 
molecules  from  the  extravascular  to  the  vascular 
system  but  also  drains  fluid  representing  the  excess 
of  filtration  over  reabsorption  through  the  capillary- 
wall.  As  discussed  later,  the  amount  of  lymph  re- 
turned to  the  blood  stream  via  the  thoracic  duct 
alone  per  24  hours  is  roughly  equivalent  to  the  plasma 
volume.  It  is  thus  obvious  that  the  return  of  lymph 
plays  an  essential  role  in  the  maintenance  of  the  blood 
volume  level.  However,  little  definitive  data  is  avail- 
able on  this  point.  Courtice  et  al.  (50)  state  that  in 
unpublished  experiments  on  dogs  anesthetized  with 
Nembutal  "the  rate  of  escape  of  fluid  and  protein 
in  lymph  was  equivalent  to  a  daily  loss  of  60  per  cent 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


1043 


1000 


800 


600 


400 


200 


CERVICAL    LYMPH 
• •- 


IN     HOURS    AND    MINUTES 


030 


100 


fig.  2.  Typical  experiment  in  anesthetized 
dog  showing  disappearance  of  dextran  of 
average  molecular  weight  of  35,000  from 
plasma  and  its  appearance  in  lymph  of 
various  areas. 


130 


200 


230        300 


3  30 


4:00 


2500 


2000 


1500 


1000 


500 


fig.  3.  Same  experiment  as  in  fig.  2  showing 
disappearance  of  radioactive  albumin  from 
plasma  and  its  appearance  in  lymph  of  various 
areas. 


0  30 


I  00 


130 


200 


230 


300 


3  30 


400 


of  the  plasma  and  45  per  cent  of  the  circulating 
plasma  proteins."  We  have  confirmed  these  observa- 
tions (Magruder,  Kern,  and  Mayerson,  unpublished). 
In  20  dogs,  drainage  of  thoracic  duct  lymph  for  8 
hours  resulted  in  an  average  drop  of  16  per  cent  in 
plasma  volume.  CoTui  and  his  colleagues  (46,  196) 
found  that  when  they  bled  dogs  whose  thoracic  ducts 
were  ligated  there  was  a  greater  drop  in  the  hema- 
tocrit level  than  in  dogs  bled  but  with  intact  lymphatic 
circulation.  This  hemodilution  lasted  at  least  8  days 
after   hemorrhage    in    the   duct-ligated    animals   but 


disappeared   in   about   48   hours   in   nonduct-ligated 
animals. 

Another  aspect  of  the  problem  is  the  well-known 
lymphagogue  effect  of  infusions.  As  infusions  are 
made  larger,  lymph  flow  increases  proportionately 
so  that  with  large  infusions  in  dogs  (2000  ml)  the 
thoracic  duct  lymph  flow  may  reach  a  peak  value  of 
about  14  times  that  of  the  preinfusion  value  (221). 
The  displacement  of  fluid  from  the  circulation  supple- 
ments the  diuresis  through  the  kidneys  and  may  be 
considered  as  a  fine  adjustment  of  the  blood  volume 


ro44 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


so  that  not  all  of  the  fluid  is  irrevocably  lost  from  the 
body.  Large  infusions  also  increase  protein  leakage 
but  here  again  the  protein  is  slowly  returned  to  the 
blood  stream  and  minimizes  changes  in  total  circu- 
lating protein  and  loss  of  its  oncotic  effect. 

It  should,  perhaps,  be  emphasized  that  blood  is 
the  chief  source  of  the  water  of  lymph.  Benson  et  al. 
(15)  measured  the  content  of  either  D20  or  Na'-4  in 
intestinal  lymph,  portal  venous  blood,  and  femoral 
arterial  blood  of  anesthetized  hydrated  rats  after 
administration  of  the  isotope  into  the  stomach, 
duodenum,  or  peripheral  or  portal  vein.  Little,  if  any, 
water  or  sodium  found  its  way  into  lymph  after 
absorption  from  the  small  intestine.  At  least  99  per 
cent  appeared  to  be  carried  in  portal  venous  blood. 
The  amount  of  isotope  found  in  intestinal  lymph  was 
proportional  to  lymph  volume  whatever  the  route 
of  administration.  Thus,  even  during  absorption  of 
water  or  sodium  ion  from  the  small  intestine,  blood 
is  the  principal  source  of  the  water  and  sodium  in 
lymph. 


TRANSPORT    FUNCTION 

Lipids 

There  has  been  considerable  interest,  particularly 
during  the  last  decade,  in  the  transport  of  lipids — the 
physical  state  in  which  they  are  carried  in  the  blood 
and  their  exchange  between  blood  plasma  and  tissue 
cells.  The  availability  of  isotopes  has  facilitated  the 
design  of  experiments  concerned  with  lipid  transport 
by  lymph.  It  is  now  apparent  that  the  lymphatic 
system  plays  an  important  role  in  lipid  transport  as 
it  does  in  protein  transport.  This  may  be  because  the 
passage  of  plasma  lipids  through  the  capillary  mem- 
brane depends  on  lipid-protein  complexes  rather  than 
on  the  physical  properties  of  the  lipids  themselves. 

All  the  different  lipid-protein  associations  present 
in  the  plasma  have  been  identified  in  thoracic  duct 
lymph  (162),  as  well  as  in  cervical  and  leg  lymph 
(49).  In  the  dog  and  cat,  alpha-lipoprotein  pre- 
dominates. When  rabbits  are  fed  cholesterol,  however, 
the  plasma  beta-lipoprotein  may  increase  consider- 
ably with  a  much  smaller  rise  in  alpha-lipoprotein. 
Lender  these  circumstances  lymph  contains  beta- 
lipoprotein.  The  evidence  suggests  that  beta-lipopro- 
tein leaves  the  blood  circulation  at  a  slower  rate  than 
does  alpha-lipoprotein.  Not  only  do  alpha-  and  beta- 
lipoproteins  appear  in  the  lymph  in  the  postabsorptive 
state,  but  lymph  from  the  cervical,  hepatic,  and  leg 


ducts — all  draining  tissues  remote  from  the  alimentary 
tract — also  contains  chylomicrons  (49).  As  Yoffev  & 
Courtice  (234)  state:  "We  can  readily  understand 
how  the  intestinal  lymph  always  contains  chylomi- 
crons even  in  what  we  call  the  postabsorptive  state. 
The  presence  of  chylomicrons  in  lymph  from  other 
tissues,  however,  suggests  that  they  come  either  from 
the  blood  stream  by  passing  through  the  capillary 
membrane  or  from  the  fat  depots.  The  evidence 
indicates  that  the  chylomicron  count  in  the  lymph 
may  vary  with  that  in  the  blood,  which  suggests  that 
these  particles  may  pass  through  the  capillary  mem- 
brane and  so  appear  in  the  lymph.  For  example,  the 
hepatic  and  cervical  lymph  ducts  were  cannulated 
in  a  fat-fed  cat  and  chylomicron  counts  made  on 
lymph  and  plasma.  The  thoracic  duct  which  was 
pouring  very  fatty  chyle  into  the  blood  stream  was 
then  cannulated  and  the  lymph  collected.  The 
chylomicron  count  in  the  plasma  fell  in  the  next 
few  hours  and  with  this  fall  the  counts  in  the  hepatic 
and  cervical  lymph  also  fell.  The  fatty  chyle  which 
had  meantime  been  collected  from  the  thoracic  duct 
was  then  injected  intravenously  making  the  plasma 
quite  milky.  The  chylomicron  counts  in  the  hepatic 
and  cervical  lymph  subsequently  rose."  Geyer  et  al. 
(83)  attempted  to  assess  the  permeability  of  capillaries 
to  serum  cholesterol  in  humans  by  measuring  the  dis- 
appearance of  cholesterol  from  the  blood  in  the 
forearm  during  various  degrees  of  venous  congestion. 
L'nder  these  circumstances,  measurable  amounts  of 
cholesterol  were  filtered  and  were  related  to  the  rate 
of  fluid  filtration  and  the  initial  level  of  the  serum 
cholesterol.  The  results  were  similar  to  those  of 
Landis  et  al.  (1 19)  for  serum  proteins.  It  may  also  be 
of  interest  to  mention  that  the  rise  of  plasma  choles- 
terol occurring  in  the  hypothyroid  state  does  not 
appear  to  be  due  to  any  decrease  in  its  ability  to 
diffuse  out  of  the  plasma  (79).  Electron  microscope 
studies  suggest  that  chylomicrons  can  be  transferred 
directly  across  cell  membranes  (5,  164)  by  the  active 
process  of  pinocytosis.  The  probability  that  some 
active  process  is  concerned  in  the  transfer  of  macro- 
molecules  from  the  capillaries  to  lymph  is  discussed 
elsewhere  (141). 

When  fatty  chyle  or  artificial  fat  emulsions  are 
injected  into  the  blood  stream,  they  leave  the  circula- 
tion very  rapidly,  but  the  amounts  found  in  lymph 
are  relatively  small  (140,  142,  148,  151,  233).  The 
latter  investigators  injected  fatty  chyle  collected  from 
fat-fed  cats  into  postabsorptive  cats  and  determined 
the  lipid  disappearance  from  plasma  and  its  ap- 
pearance in  hepatic,  intestinal,  and  cervical  lymph. 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


1045 


These  calculations  showed  that  protein  left  the  circu- 
lation at  the  rate  of  77,  142,  and  11  mg  per  hour  in 
the  liver,  intestine,  and  cervical  tissues,  respectively, 
or  a  total  leakage  of  230  mg.  In  another  cat,  2540  mg 
of  injected  fat  left  the  circulation  within  2  hours 
during  which  time  the  leakage  of  protein  was  448  mg. 
It  is  obvious  that  fat  in  chylomicron  form  can  dis- 
appear from  the  blood  stream  much  faster  than  pro- 
tein. The  chylomicron  fraction  of  lymph  appears  to 
carry  neutral  fat  (233). 

Reinhardt  el  al.  (182)  injected  biosynthesized 
P32-Iabeled  phospholipid  into  a  peripheral  vein  of 
rats  with  thoracic  duct  fistula  and  reported  that  9  to 
20  per  cent  of  the  injected  phospholipid  could  be 
recovered  in  the  thoracic  duct  lymph  in  the  succeed- 
ing 3  to  6  hours.  McCandless  &  Zilversmit  (131) 
obtained  labeled  lymph  by  feeding  dogs  with  re- 
labeled triolein.  The  labeled  lymph  was  administered 
to  recipient  dogs,  and  the  rate  of  disappearance  of 
the  lymph  lipids  from  plasma  was  followed.  Lymph 
t  131  triglycerides  were  found  to  disappear  from  the 
circulation  rapidlv,  with  an  initial  half-time  of  several 
minutes.  Disappearance  of  I131  phospholipids  was 
slower  as  determined  in  the  same  animals,  10  to  40 
per  cent  of  the  injected  dose  remaining  in  the  blood 
1  to  2  hours  after  injection.  These  results  were  similar 
to  those  previously  obtained  by  the  same  authors 
using  artificially  prepared  fat  emulsions  (130). 

The  presence  or  absence  of  bile  appears  to  influence 
the  pattern  of  absorption  and  lymph  transport  of 
dietary  soaps  and  triglycerides  in  the  dog.  Rampone 
&  Sigurdson  (179)  recently  reported  that  the  ab- 
sorption of  triolein  and  sodium  oleate  was  signifi- 
cantly diminished  in  the  absence  of  bile.  In  the  normal 
dog,  90  per  cent  of  fed  triolein  and  94  per  cent  of 
fed  sodium  oleate  were  recovered  from  the  thoracic 
duct  as  lymph  lipid.  In  dogs  with  bile  fistula  only  8 
per  cent  of  fed  triolein  was  recovered  in  lymph  com- 
pared to  40  per  cent  of  sodium  oleate. 

The  route  of  absorption  of  steroids  from  the  gas- 
trointestinal tract  seems  to  be  determined  largely  by 
the  chemical  nature  of  the  compounds.  Methyl 
testosterone,  1 7a-methylestradiol  and  cortisone-4-C14 
acetate  are  absorbed  in  the  rat  by  way  of  the  portal 
circulation  (23,  24,  102).  Studies  in  human  subjects 
have  shown  that  testosterone,  cortisone,  and  cortisone 
acetate  are  also  absorbed  in  this  manner  and  are 
virtually  absent  from  lymph  (97).  In  contrast,  ab- 
sorption of  cholesterol  into  lymph  of  the  rat  (17,  41) 
and  dog  (152)  accounts  for  essentially  all  the  sterol 
that  enters  these  species  from  the  diet.  This  is  also 
true  for  man   (98).  Data  from  the  different  species 


studied  is  consistent  in  showing  that  much  of  the 
cholesterol  is  esterified  by  the  intestinal  mucosa  (25, 
41,  98,  213).  A  number  of  factors  appear  to  influence 
the  lipid  composition  of  lymph  during  cholesterol 
absorption  (212).  In  rats  given  intragastrically 
emulsions  containing  cholesterol,  oleic  acid,  and 
sodium  taurocholate,  addition  of  albumin  resulted 
in  a  rapid  increase  in  total  lymph  lipid  which  was 
much  more  marked  than  in  those  animals  not  re- 
ceiving albumin.  The  amount  of  lymph  cholesterol, 
however,  was  less  for  a  24-hour  period.  The  presence 
of  taurocholate  and  oleic  acid  in  administered  emul- 
sions resulted  in  elevation  of  ester  cholesterol,  indi- 
cating increased  absorption  of  endogenous  cholesterol 
(211).  Addition  of  cholesterol  to  the  emulsions  also 
resulted  in  further  significant  increase  in  the  ester 
cholesterol  fraction  in  thoracic  duct  lymph.  In 
further  studies  (207),  it  was  shown  that  small  doses 
of  fed  cholesterol-4-C14  lead  to  labeling  of  cholesterol 
fractions  of  mucosa  and  lymph  without  an  increase 
in  the  level  or  turnover  in  lymph.  Feeding  tracer 
dose  with  oleic  acid  and  sodium  tauracholate  in- 
creases the  turnover  rate  of  the  pool  which  leads  to  an 
increased  amount  of  labeled  and  unlabeled  cholesterol 
in  lymph.  In  fasting  rats,  the  major  fatty  acids  in 
lymph  are  palmitic,  linoleic,  and  oleic  acids  with 
polyunsaturated  fatty  acids  comprising  36  per  cent 
of  the  total  cholesterol  fatty  acids  (206).  After  feeding 
oleic  acid  only  42.3  per  cent  of  the  total  was  present 
as  oleic  acid.  The  total  cholesterol  fatty  acid  composi- 
tion of  lymph  is  evidently  determined  not  only  bv 
dietary  fatty  acid,  but  by  the  composition  of  the  fatty 
acid  pool  in  the  mucosa  from  which  fatty  acids  are 
drawn  for  esterification  of  cholesterol,  a  suggestion 
which  had   been  made  earlier  bv  previous  workers 

(30). 

Bloom  el  al.  (22)  fed  unanesthetized  rats  C14- 
labeled  stearic  and  myristic  acids  and  found  that 
nearly  all  the  absorbed  C14  was  recovered  in  intestinal 
lymph.  This  finding,  taken  in  conjunction  with  earlier 
work  with  labeled  palmitic  and  pentadecanoic  acids, 
showed  that  lymph  is  the  major  if  not  the  exclusive 
agent  for  the  transport  of  absorbed  long-chain  fatty 
acids.  On  the  other  hand,  when  similar  experiments 
were  carried  out  with  labeled  lauric  acid  and  decanoic 
acid,  recoveries  of  the  absorbed  C14  amounted  to  15 
to  55  and  5  to  19  per  cent,  respectively.  Since  it  was 
shown  that  the  findings  were  not  the  result  of  bacterial 
action,  it  would  appear  that  the  major  portion  of  a 
short-chain  fatty  acid  is  transported  via  the  blood 
stream  from  its  site  of  absorption.  Blomstrand  et  al. 
(21)  have  extended  this  type  of  study  to  man.  They 


1046 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


found  that  linoleic  acid-1-C14  incorporated  in  dietary 
triglycerides,  or  fed  as  free  acid,  becomes  esterified 
with  the  same  classes  of  lipids  in  human  thoracic 
duct  lymph  as  oleic  and  palmitic  acid.  Evidently, 
digestion  and  absorption  of  these  fatty  acids  are  com- 
parable, as  well  as  their  transfer  into  intestinal 
mucosa  and  resynthesis  in  lymph  lipids.  This  is  in 
confirmation  of  work  on  animals  by  the  same  group. 
They  also  confirmed  earlier  findings  on  animals  that 
stearic  acid-1-C14  was  found  in  a  higher  percentage 
incorporated  in  lymph  phospholipids  than  was 
found  for  linoleic  acid  and  for  palmitic  and  oleic 
acids.  After  isolation  of  lymph  lecithins,  there  was  a 
difference  in  the  position  of  the  label  in  lecithins  of 
lymph  according  to  the  fatty  acid  used.  After  feeding 
linoleic  acid-i-C14,  approximately  75  per  cent  of  the 
label  in  lymph  lecithins  was  localized  in  the  alpha- 
position.  With  stearic  acid-i-C14,  however,  about  80 
per  cent  of  the  label  was  found  in  the  beta-positions. 
Their  evidence  indicates  that  there  is  a  distinct 
manner  in  which  stearic  acid-i-C14  and  linoleic 
acid- 1 -C14  are  incorporated  into  thoracic  duct  lymph 
lecithins,  reflecting  probable  differences  in  their 
metabolism. 

Rampone  (178)  recently  reported  experiments  in 
which  he  measured  phospholipids  of  lymph  in  rela- 
tion to  the  total  lipid  in  16  dogs  with  chronic  thoracic 
duct  fistula  during  the  postabsorptive  state  and  fol- 
lowing the  administration  of  various  lipid  types 
(triolein,  soya  lecithin,  oleic  acid,  etc.)  in  the  diet. 
He  found  that  phospholipid  transport  related  linearly 
to  total  lipid  transport  under  all  conditions  studied, 
including  the  postabsorptive  state.  The  percentage 
of  lymph  lipid  transported  as  phospholipid  ranged 
from  3  to  18  per  cent  and  was  independent  of  the 
type  of  lipid  led.  Depriving  the  animals  of  phospho- 
lipid precursors  in  the  diet  for  as  long  as  90  days 
previously  failed  to  alter  this  relationship  or  the  total 
quantity  of  lipid  transported.  Since  the  phospholipids 
increased  linearly  with  the  total  lipid  under  all  condi- 
tions studied,  Rampone  believes  it  likely  that  the 
phospholipids  associate  with  the  absorbed  lipid  in 
some  manner  which  relates  to  lipid  transport,  possibly 
serving  in  the  capacity  of  chylomicron  emulsion 
stabilizers  during  the  transport  phase.  He  points 
out  that  while  the  plasma  may  be  the  source  of  the 
phospholipids,  the  rate  of  filtration  from  plasma  to 
lymph  would  be  somehow  dependent  on  the  lipid 
concentration  in  lymph,  since  the  phospholipids  of 
lymph  increased  in  proportion  to  the  total  lymph. 
Previous  work  by  Bollman  et  al.  (26)  suggests  that 
the  mucosa  of  the  small  intestine  mav  normally  be 


the   source   of  phospholipids  for  plasma   during  fat 
absorption. 

An  interesting  application  of  the  study  of  lymph 
and  its  possible  role  in  the  pathogenesis  of  athero- 
sclerosis was  reported  by  Kellnor  (1 1 1).  He  collected 
leg  lymph  from  rabbits  rendered  hyperlipemic  by 
cholesterol  feeding,  by  the  injection  of  the  surface- 
active  agent  Triton  A-20,  and  by  the  injection  of 
alloxan.  He  found  (as  have  others)  that  leg  lymph 
contained  protein  in  a  concentration  equal  to  one- 
third  to  one-half  that  of  the  blood  serum.  Electro- 
phoretic  analyses  showed  a  pattern  similar  to  that 
of  serum.  The  total  lipid  concentration  was  also  about 
one-third  to  one-half  that  of  blood  serum  and  the 
major  lipid  fractions,  cholesterol  and  phospholipid, 
were  present  in  lymph  in  about  the  same  relation- 
ship. In  the  cholesterol-fed  rabbits,  the  leg  lymph 
showed  a  striking  increase  in  lipids  as  did  the  serum. 
On  the  basis  of  his  results  he  concluded  that:  "It 
seems  likely  that  under  normal  conditions  there  is  a 
constant  flow  of  fluid  containing  various  serum  lipids 
and  proteins  across  the  endothelium  into  the  walls 
of  blood  vessels;  this  material  normally  passes  through 
the  wall  and  is  completely  removed  by  way  of  vasa 
vasorum  and  lymphatics.  In  certain  conditions,  how- 
ever, where  there  are  increased  amounts  of  lipid  in 
the  blood,  or  where  there  are  excessive  quantities  of 
certain  types  of  lipids  (beta-lipoproteins  of  the  Sf  12- 
20  molecules  of  Gofman),  the  removal  of  these 
particles  from  the  wall  of  the  vessel  is  incomplete  and 
some  remain  behind  to  initiate  the  process  of  athero- 
sclerosis. In  hypertension,  the  increased  hydrostatic 
pressure  appears  to  cause  an  increase  in  the  quantity 
of  serum  lipoprotein  that  diffuses  across  the  vessel 
wall,  thereby  increasing  the  possibility  for  incomplete 
removal  and  hence  for  deposition  of  lipids.  In  those 
areas  of  the  vascular  tree  where  the  removal  mech- 
anism has  been  altered,  as  for  example  in  syphilitic 
aortitis  or  in  experimentally  produced  trauma  to  the 
vessel  wall,  the  free  transport  of  lipid  and  other 
particles  across  the  vessel  wall  is  impeded,  and  in 
these  areas  the  lipid  is  therefore  more  apt  to  pre- 
cipitate and  to  give  rise  to  atherosclerosis.  In  this 
theoretical  formulation  of  the  pathogenesis  of  athero- 
sclerosis, the  artery  wall  is  regarded  as  an  organ  which 
is  constantly  bathed  by  a  serum  transudate  containing, 
among  other  things,  various  serum  lipoproteins,  most 
of  which  pass  on  through,  some  of  which  doubtless 
are  metabolized  locally,  and  a  few  of  which  remain 
behind  to  cause  mischief.  Atherosclerosis,  broadly 
considered,  may  thus  result  either  from  qualitative 
or   quantitative   changes   in    the   serum   lipoproteins 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


IO47 


that  filter  constantly  across  the  walls  of  blood  vessels, 
or  from  local  structural  changes  inherent  in  the  vessel 
wall,  or  the  result  of  age  or  disease,  that  serve  to 
hamper  the  normal  passage  of  these  fatty  substances." 

Enzymes 

Many  enzymes  are  found  in  lymph  in  small  con- 
centrations (234).  Their  concentrations  are  usually 
higher  in  intestinal  and  liver  lymph  than  in  cervical 
or  leg  lymph,  but  are  usually  lower  than  in  plasma 
and  run  parallel  with  the  concentration  of  proteins 
(18,  28).  It  is  probable  that,  in  most  instances,  these 
substances  have  leaked  from  the  blood  stream  and 
take  part  in  the  extravascular  circulation  via  the 
lymphatics. 

On  the  other  hand,  certain  enzymes  seem  to  be 
transported  to  the  blood  stream  from  their  cells  of 
origin  via  the  lymph.  Flock  &  Bollman  (74)  made 
an  interesting  comparison  between  the  activity  of 
rat  intestinal  lymph  with  respect  to  amylase  and 
tributyrinase.  The  activities  of  the  two  enzymes  in 
intestinal  lymph  are  generally  less  than  in  plasma. 
The  24-hour  secretion  of  amylase  in  lymph  is  greater 
in  fed  than  in  fasting  rats,  but  much  of  the  increase 
is  due  to  the  increase  in  lymph  volume.  External 
drainage  of  lymph  for  2  days  does  not  significantly 
alter  the  plasma  amylase  level.  On  the  other  hand, 
although  the  24-hour  secretion  in  lymph  of  tributy- 
rinase is  also  much  greater  in  fed  than  in  fasting  rats, 
it  appears  to  represent  a  specific  effect  of  ingested 
fat  on  the  chemical  composition  of  intestinal  lymph. 
External  drainage  of  the  lymph  markedly  decreases 
the  tributyrinase  content  of  plasma.  These  results  are 
similar  to  those  previously  obtained  by  the  same 
authors  with  respect  to  alkaline  phosphatase  (72). 
The  increase  of  alkaline  phosphatase  of  intestinal 
lymph  following  the  feeding  of  fat  is  abolished  or 
greatly  diminished  when  the  bile  duct  is  ligated  or 
the  bile  drained  away  in  a  biliary  fistula  (73).  The 
presence  of  bile  thus  seems  to  be  essential  for  the 
release  of  alkaline  phosphatase  from  the  intestinal 
mucosa. 

The  histaminase  activity  of  lymph  has  received 
considerable  attention  from  Carlsten  and  his  col- 
leagues. They  were  led  to  these  studies  by  their  failure 
to  demonstrate  the  presence  of  histamine  in  venous 
blood  during  reactive  hyperemia  and  muscular 
tetanus,  where  histamine  was  alleged  by  some  in- 
vestigators to  be  liberated.  They  then  turned  to 
lymph  on  the  grounds  that  lymph  is  closer  to  the  tissue 
cells  which  are  thought   to  liberate  histamine,   and 


therefore  histamine  should  accumulate  in  greater 
concentration  in  lymph  than  in  plasma.  They  used 
dogs,  anesthetized  with  Nembutal,  and  collected 
lymph  from  the  thoracic  duct  (37).  Lymph  had  no 
histamine  in  detectable  amounts.  In  contrast  to 
guinea  pigs,  rats,  and  rabbits,  dogs  show  low  plasma 
histamine  activity.  The  plasma  histamine  concentra- 
tion could  be  raised  to  very  high  levels  by  histamine 
infusion  or  by  intravenous  injection  of  histamine 
liberators  (curare  and  trypsin)  without  the  appear- 
ance of  detectable  amounts  of  histamine.  Study  of 
the  histaminolytic  activity  of  the  lymph  showed  it 
to  be  more  than  30  times  as  powerful  as  in  plasma 
when  tested  in  vitro.  In  vivo,  intralymphatically 
administered  histamine  was  inactivated  at  a  very 
high  rate.  This  same  group  has  also  used  cats  and 
have  described  a  simple  micromethod  for  estimation 
of  the  small  amounts  found  in  lymph  and  plasma 
(38,  231),  and  showed  that  the  histaminolytic  activity 
of  lymph  is  not  changed  by  routine  procedures  such 
as  anesthesia,  laparotomy,  gentle  handling  of  the 
viscera,  or  by  reactive  hyperemia  or  pregnancy  (35, 
232).  Adrenalectomy  is  followed  by  a  marked  increase 
in  histaminase  content  of  thoracic  duct  lymph  (but 
not  in  plasma)  which  reaches  a  maximum  within  2 
hours  and  persists  approximately  24  hours  (36).  In- 
fusion of  an  adrenocortical  extract  will  reverse  this 
increased  activity  (39).  The  histaminolytic  activity 
of  cervical  and  leg  lymph  is  less  than  that  of  the 
thoracic  duct  and  seems  to  originate  from  the  kidneys 
and  gut  (34). 

It  has  been  suggested  that  the  lymphatic  transport 
of  lipase  may  be  concerned  with  the  changes  seen 
in  disseminated  pancreatic  fat  necrosis  (171).  So- 
called  pancreatic  and  peripancreatic  fat  necrosis  is 
supposedly  due  to  the  splitting  of  neutral  fat  into 
glycerol  and  free  fatty  acid  by  pancreatic  lipase 
which  has  escaped  from  the  injured  pancreas.  The 
free  fatty  acids  are  thought  to  combine  subsequently 
with  calcium  in  the  tissue  and  tissue  fluids  to  form 
insoluble  calcium  soaps  which  give  rise  to  the  opaque 
white  areas  seen  in  the  fat  depots  of  the  abdominal 
cavity  and  elsewhere.  Perry  made  intraperitoneal 
injections  of  a  mixture  of  pancreatin  and  graphite 
suspension  in  rats  and  at  necropsy  found  multiple 
areas  of  fat  necrosis  in  the  abdominal  and  thoracic 
cavities,  closely  associated  with  graphite-delineated 
lymph  channels.  The  evidence  of  the  participation 
of  the  lymphatics  in  this  disease  is  quite  suggestive 
and  indicates  the  desirability  of  further  investigation 
of  the  role  of  lymphatics  in  this  and  other  diseases. 

Reizenstein  el  al.    (183)   recentlv  reported   experi- 


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merits  on  two  beagles  to  which  they  gave  C058-Bi_.  by 
stomach  tube  and  measured  its  absorption  and  dis- 
tribution between  thoracic  duct  lymph  and  plasma. 
They  found  only  a  very  small  amount  of  the  total 
dose  in  lymph  which  they  believe  to  have  leaked  from 
the  plasma.  They  interpret  their  results  as  suggestive 
that  vitamin  B12  is  absorbed  directly  into  the  blood 
stream  as  a  compound  with  a  molecular  weight  only 
slightly  higher  than  that  of  pure  crystalline  B]>.  If  it 
were  absorbed  as  the  entire  intrinsic-factor-molecule 
(mol  wt  ±  70,000)  more  should  have  been  found  in 
the  lymph,  since  this  large  molecule  probably  cannot 
easily  get  into  the  plasma. 

Coagulation  Principles 

Lymph  from  all  parts  of  the  body  clots,  but  does 
so  less  readily  than  plasma.  The  concentrations  of 
fibrinogen  and  of  prothrombin  in  lymph  are  always 
less  than  in  plasma  and  vary  considerably  in  different 
regions  just  as  concentrations  of  other  proteins  vary. 
Mann  et  al.  ( 1 39)  drained  intestinal  lymph  from  rats 
and  found  that  marked  hypoprothrombinemia  de- 
veloped rapidly,  usually  within  24  hours.  If  adequate 
amounts  of  vitamin  K  were  administered  parenterally, 
a  normal  level  of  prothrombin  was  maintained, 
despite  loss  of  lymph.  Transfusion  of  twice  the  animal's 
normal  volume  of  plasma  did  not  maintain  a  normal 
value  for  prothrombin  while  lymph  was  lost.  Under 
the  conditions  of  their  experiments,  it  appeared  that 
vitamin  K  was  absorbed  practically  exclusively 
through  the  lymph  and  very  little  of  it  was  stored, 
whereas  the  turnover  of  prothrombin  was  extremely 
rapid. 

The  concentration  of  fibrinogen  of  canine  thoracic 
duct  lymph  is  about  50  per  cent  that  of  plasma  (29, 
70).  Brinkhous  &  Walker  (29)  found  that  the  mean 
prothrombin  level,  expressed  as  a  percentage  of  that 
in  the  plasma,  was  93.2,  51.2,  and  7.6  for  hepatic, 
thoracic  duct,  and  leg  lymph,  respectively.  These 
findings  are  consistent  with  the  known  differences  in 
permeability  of  capillaries  to  macromolecules  in  the 
leg  and  liver.  Infusion  of  heparin  into  anesthetized 
dogs  (214)  prolonged  thrombin  and  prothrombin 
times  of  plasma  immediately,  but  the  effect  was 
delayed  in  thoracic  duct  lymph  and  required  larger 
doses  for  its  production.  The  differences  between 
plasma  and  lvmph  were  more  marked  with  cervical 
lvmph,  which  again  may  reflect  the  differences  in 
permeability  between  the  capillaries  in  the  areas 
drained  bv  the  cervical  and  thoracic  ducts. 


Langdell  et  al.  (120)  have  extended  and,  in  general, 
confirmed  these  observations.  They  also  found  that 
lymph  samples  are  not  fully  active  at  the  time  of 
collection.  On  exposure  to  glass  surfaces  in  the  pres- 
ence of  anticoagulant,  the  clotting  time  becomes 
shorter  during  the  first  20  to  40  min.  Coagulating 
lymph  has  a  high  residual  prothrombin  even  after 
18  to  24  hours  in  glass  containers.  Thoracic  duct 
lymph  contains  sufficient  thromboplastic  materials 
so  that  adequate  amounts  of  thrombin  can  form  to 
produce  a  fibrin  clot,  but  it  does  not  contain  the 
thromboplastic  materials  required  for  complete 
prothrombin  utilization.  These  authors  conclude 
"thoracic  duct  lymph  in  this  respect  might  be  com- 
pared with  platelet-poor  native  plasma;  however, 
the  initial  phase  of  relatively  rapid  prothrombin 
utilization  in  clotting  lymph  is  unlike  the  slower 
initial  utilization  reported  to  occur  in  platelet- 
deficient  plasma  systems.  The  nature  of  the  thrombo- 
plastic material  in  lymph  is  not  known,  but  it  would 
appear  that  the  lipid  materials  being  transported 
could  furnish  clot-accelerating  activity.  Additional 
studies  are  needed  to  evaluate  the  role  of  the  lipid 
materials  in  the  coagulation  of  lymph.  Such  studies 
promise  to  furnish  considerable  information  on  the 
role  of  alimentarv  lipemia  on  blood  coagulation  since 
lymph  drains  directly  into  the  venous  circulation." 

Iron 

The  demonstration  of  iron  within  leukocytes  of 
the  intestinal  villi,  subsequent  to  the  oral  administra- 
tion of  iron,  led  Macallum,  in  1894,  to  suggest  that 
leukocytes  are  partially  responsible  for  the  transfer 
of  iron  from  the  intestine  (133).  Since  then,  other 
investigators  (81,  84)  demonstrated  an  increase  of 
iron  within  mesenteric  lymphatics  after  oral  iron 
administration  and  suggested  that  lymphatics  are 
involved  in  iron  absorption  and  transport.  Histo- 
chemical  studies  indicated  that  phagocytes  might  be 
concerned  in  mediating  the  transfer  of  iron  from  the 
intestine  into  the  lymphatics  (84),  but  more  recent 
evidence  does  not  support  these  concepts.  Thus, 
Moore  et  al.  (147)  showed  that  iron  absorbed  from 
the  intestine  of  dogs  passes  directly  into  the  blood 
stream  and  only  a  minimal  amount  appears  within 
the  intestinal  lymphatics.  Endicott  et  al.  (68)  showed 
that  the  iron  demonstrable  in  intestinal  lymph  of 
dogs  and  guinea  pigs  was  derived  from  sources  other 
than  a  single  test  meal.  They  showed  that  in  the  dog 
iron  was  transported  chiefly  via  the  portal  vein  with 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I°49 


only  an  insignificant  amount  appearing  in  thoracic 
duct  lymph.  Similar  conclusions  were  reached  by 
Reizenstein  et  al.  (183).  Koler  &  Mann  (115)  found 
that  the  iron  content  of  intestinal  lymph  of  cats 
maintained  on  a  normal  diet  was  relatively  constant 
over  periods  as  long  as  7  days.  At  lymph  outputs  of 
1  ml  per  hour,  there  was  an  hourly  output  of  0.5  ^ig 
of  iron.  Peterson  &  Mann  (174),  using  radioiron, 
found  that  only  an  insignificant  portion  of  an  orally 
administered  amount  of  radioiron  appeared  in  the 
lymph  of  rats  with  total  intestinal-lymph  fistulas — 
less  than  o.  1  per  cent  of  the  total  amount  of  radioiron 
administered  and  only  2.0  to  5.0  per  cent  of  the  total 
amount  of  iron  absorbed  from  the  gastrointestinal 
tract  after  8  hours.  Everett  et  al.  (69)  confirmed 
these  results  in  the  rat.  The  absorption  of  subcutane- 
ous FeCl3  occurred  primarily  via  the  blood  vessels, 
but  subcutaneous  plasma-bound  iron  passed  almost 
exclusively  into  the  lymphatics.  Intravenously  ad- 
ministered iron  appeared  rapidly  in  the  lymph. 
These  observations  and  those  of  previous  workers  are 
unquestionably  related  to  the  fact  that  iron  is  nor- 
mally bound  to  protein  in  plasma.  Since  proteins 
leak  slowly  from  blood  capillaries,  we  would  expect 
to  find  small  quantities  of  iron-protein  compounds 
in  lvmph  from  all  areas.  Since  the  capillaries  of  the 
intestine  are  more  permeable  to  protein  than  those 
of  other  areas,  and  since  protein  leakage  is  greatest 
in  the  liver,  larger  amounts  would  be  present  in 
intestinal,  hepatic,  and  thoracic  duct  lymph.  It  is 
also  of  interest  that  Everett  and  co-workers  found  no 
evidence  that  leukocytes  played  more  than  a  negligible 
role  in  iron  absorption  regardless  of  the  method  of 
iron  administration. 

Miscellaneous 

Scattered  reports  deal  with  a  variety  of  substances 
transported  in  lymph.  Thus  Salter  (193)  reported 
that  the  protein-bound  iodine  per  gram  of  protein  in 
cervical  lymph  was  concentrated  relative  to  the 
homologous  serum  value.  Klitgaard  et  al.  (113,  114) 
found  that  about  3  per  cent  of  a  subcutaneously 
administered  dose  of  thyroxin-C14  appeared  in 
thoracic-duct  lymph  in  rats  during  an  8-hour  experi- 
mental period.  The  level  of  radioactivity  in  lymph 
was  lower  than  in  plasma  on  a  volume  basis  but 
significantly  higher  when  calculated  on  the  basis  of 
protein  content.  Chromatographic  analysis  of  lymph 
samples  showed  the  radioactivity  present  to  be  from 
unaltered  thyroxin.  It  would  be  interesting  to  know 


the  extent  to  which  other  protein-bound  hormones  are 
transported  in  lymph.  We  can  assume  that  small 
quantities  escape  from  the  capillaries  as  do  other 
macromolecules  and  are  returned  via  the  lymphatic 
system. 

Dietrich  &  Siegel  (53)  recently  reported  an  in- 
teresting study  designed  to  determine  whether 
nucleotides  or  nucleotide  precursors  synthesized  in 
an  organ  or  tissue,  e.g.  liver,  were  available  to  nourish 
other  tissues  and  organs.  The  stimulus  for  their 
studies  arose  from  observations  that  certain  cell 
types  cannot  utilize  free  bases  and  must  secure  the 
nucleoside  containing  the  base  from  an  external 
source,  apparently  other  cell  types.  They  argued  that 
if  bases  and  other  nucleotide  precursors  are  secreted 
by  a  distant  organ  or  cell  type,  these  compounds 
may  be  present  in  both  the  blood  and  lymph  which 
bathes  the  cell  or  organ.  Blood,  however,  contains 
such  a  mass  of  living  cells  that  it  is  difficult  to  deter- 
mine whether  intermediates  found  in  the  plasma 
are  derived  from  the  cells  within  the  blood  or  from 
other  somatic  cells  nourished  by  and  yielding  their 
products  to  the  blood.  Since  the  cell  population  in 
lymph  is  insignificant  when  compared  with  that  of 
blood,  it  might  be  assumed  that  metabolites  found 
in  the  lymph  would  reflect  more  closely  the  metabo- 
lism of  the  tissue  through  which  it  has  passed  than 
that  of  the  lymphocytes.  Working  on  rats  anesthetized 
with  Nembutal,  they  injected  glycine-2-C14  and  nico- 
tinamide-7-C14  and  found  adenine,  guanine,  cytosine, 
uracil,  and  uric  acid  in  measurable  amounts  in 
thoracic  duct  lymph.  Xo  detectable  quantities  of 
nucleosides  were  observed.  The  quantity  of  acid- 
soluble  nucleotides  found  was  equivalent  to  that 
which  would  be  expected  from  the  lymphocytes 
present  in  the  lymph  samples  analyzed.  Lymph 
collected  for  a  45-hour  period  following  the  injection 
of  carbon-labeled  glycine  contained  no  significant 
amount  of  labeled  purine  derivatives.  At  the  end  of 
this  period,  however,  liver  tissue  still  contained 
appreciable  quantities  of  labeled  acid-soluble  nu- 
cleotides. Lymph  collected  for  a  similar  period  of 
time  after  the  injection  of  carbon-labeled  nicotinamide 
contained  very  small  amounts  of  radioactivity.  While 
the  results  raised  many  unexplainable  questions  and 
suggested  the  need  of  further  work,  they  did  confirm 
previous  investigations  of  plasma  in  indicating  that 
if  these  compounds  are  essential  for  the  proper  nutri- 
tion of  certain  cell  types,  these  purine  derivatives  are 
not  transported  from  sites  of  synthesis,  such  as  the 
liver,  via  the  lymphatic  ducts. 


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SIGNIFICANCE    OF    SOME    REGIONAL    LYMPHATICS 

Thoracic  Duct 

The  size,  high  rate  of  flow  and  accessibility  for 
cannulation  have  made  the  thoracic  duct  the  duct 
of  choice  in  studies  on  lymph.  A  considerable  amount 
of  data  has  therefore  accumulated  during  the  last 
125  years  relative  to  its  characteristics  under  a  variety 
of  conditions  in  many  species,  including  man  (50, 
51).  During  the  last  decade,  as  previously  indicated, 
the  advent  of  polyethylene  tubing  made  possible 
chronic  experiments  in  which  the  cannulas  could  be 
left  in  place  and  the  data  collected  in  the  unanes- 
thetized  animal  and  man  and  in  a  reasonably  ''nor- 
mal" physiological  situation. 

The  thoracic  duct  receives  lymph  from  the  ab- 
dominal viscera,  the  lower  part  of  the  trunk,  and  the 
lower  extremities,  and  empties  it  into  the  jugular 
vein.  The  rate  of  flow  in  the  thoracic  duct  is  greater 
than  the  sum  total  of  flow  from  all  other  ducts. 
Yoffey  &  Courtice  (234)  have  assembled  available 
data  on  the  rates  of  flow  in  the  dog,  cat,  rabbit,  rat, 
horse,  bull,  cow,  goat,  and  man.  To  this  list  may  be 
added  the  data  of  Shrewsbury  on  the  mouse  (198). 
It  is  interesting  that  in  spite  of  the  many  variables 
involved  in  the  experimentation  (anesthesia,  time  of 
feeding,  duration  of  collection,  etc.)  the  thoracic 
duct  lymph  flow  in  all  species  studied  averages  about 
2  ml  per  kg  per  hour  in  nonruminants  and  somewhat 
more  in  ruminants.  If  we  accept  the  average  figure 
for  plasma  volume  for  most  animals  of  45  ml  per  kg, 
it  is  obvious  that  the  amount  of  lymph  returned  to  the 
blood  stream  via  the  thoracic  duct  per  24  hours  is 
roughly  equivalent  to  the  plasma  volume.  The  above 
calculations  are  in  terms  of  the  quiet,  resting  animal. 
Under  conditions  of  activity,  the  return  is  consider- 
ably greater. 

Hepatic  Lymph 

The  contribution  of  the  liver  to  thoracic  duct 
flow  appears  to  be  variable.  It  may  contribute  from 
one-fourth  to  one-half  of  the  flow  in  the  dog  (33) 
and  cat  (149,  150),  and  only  about  10  per  cent  in 
rats  (138).  Actually,  the  anatomy  of  the  hepatic 
lymphatic  drainage  is  such  that  direct  measurement 
of  total  hepatic  lymph  flow  is  difficult  and  the  data 
available  have  been  derived  from  indirect  estimates 
or  from  experiments  where  usually  only  one  large 
hepatic  duct  was  cannulated.  The  values  obtained 
by  such  direct  cannulation  (0.4-1.2  ml  kg  hour) 
suggest  that  liver  lymph  flow  is  higher  than  that  of 
any  other  part  of  the  body  of  the  clog. 


Two  hilar  lymphatic  pathways  have  been  described 
for  the  canine  liver  (184):  /)  a  main  hilar  system, 
draining  predominantly  the  right  lobes;  and  2)  an 
accessory  hilar  system,  draining  mainly  the  left  lobe. 
Usually  all  of  the  hilar  lymph  seems  to  pass  into  one 
common  efferent  trunk  which  then  discharges  it  into 
the  cisterna  chyli.  About  80  per  cent  of  lymph  leaving 
the  canine  liver  probably  travels  by  the  hilar  route 
and  the  remaining  20  per  cent  by  the  hepatic  venous 
lymph  route. 

Not  only  is  liver  lymph  flow  higher  than  from  any- 
where else  in  the  body,  but  it  also  has  the  highest  pro- 
tein concentration,  equaling  from  80  to  95  per  cent  of 
plasma  concentration  in  dogs,  rats,  and  cats  ( 141 ,  149, 
1 57,  158,  234).  Electrophoretic  analyses  show  that 
protein  distribution  in  hepatic  lymph  is  similar  to  that 
in  plasma.  These  data  are  derived  from  acute  experi- 
ments on  anesthetized  animals,  from  animals  with 
chronic  lymph  fistulae,  experiments  in  which  T-1824 
or  other  dyes  have  been  used  to  label  proteins,  and 
from  isolated  liver  preparations. 

The  extraordinarily  high  permeability  of  the  hepatic 
endothelia  involved  in  hepatic  lymph  formation  has 
been  demonstrated  by  the  use  of  dextran  fractions  of 
graded  molecular  weights  (92,  141  ).  While  the  results 
of  these  investigations  differ  in  details,  they  are  con- 
sistent in  showing  that  high  molecular  weight  dextrans 
appear  in  hepatic  lymph  in  greater  concentration  than 
in  lymph  from  other  areas  (fig.  4)  and  suggest  that 
hepatic  lymph  represents  a  plasma  filtrate  formed  in 
a  region  of  highly  permeable  capillary  walls.  In  a 
recent  review  of  hepatic  circulation  (27)  Brauer  sug- 
gests: "As  a  working  hypothesis  compatible  with  the 
major  part  of  the  available  data,  one  may  accept  the 
following:  Liver  lymph  formation  involves  two  sites. 
The  first  of  these  would  appear  to  be  the  sinusoidal 
portion  of  the  hepatic  vascular  tree  where  a  very  large 
area  of  endothelium  with  demonstrably  large  pores 
surrounds  the  blood  stream,  and  where  one  would  ex- 
pect the  formation  of  a  large  volume  of  lymph,  differ- 
ing from  the  blood  principally  in  the  absence  (in  the 
normal  liver,  at  least)  of  erythrocytes  and  of  the  greater 
part  of  the  leukocytic  elements.  This  primary  lvmph 
for  the  most  part  moves  countercurrent  to  the  blood 
stream  to  enter  the  lymphatic  vessels  within  the  Glis- 
son  sheath.  Here  it  passes  through  the  peribiliary 
plexus,  the  second  site  important  in  liver  lymph  forma- 
tion. The  principal  role  of  this  plexus  in  the  normal 
liver  should  be  sought  in  the  opportunity  it  provides 
for  secondary  modification  of  liver  lymph  composi- 
tion by  exchange  of  soluble  components  between  bile, 
lymph,  and  blood."' 

The  high  rate  of  flow  of  hepatic  lymph  coupled 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


IO=,I 


50 


400 


fig.  4.  Curves  illustrating  relative  permeability  coefficients 
for  dextrans  of  different  molecular  weights.  Relative  perme- 
ability coefficient  is  ratio  of  dextran  between  lymph  and  plasma 
divided  by  ratio  of  albumin  between  lymph  and  plasma.  See 
(141). 

with  its  high  protein  concentration  emphasized  the 
importance  of  the  hepatic  lymph  system  in  the  turn- 
over of  plasma  volume  and  plasma  proteins.  Little  or 
no  new  protein,  as  such,  is  added  to  lymph  in  the 
liver  (234),  and  the  large  amount  of  protein  is  that 
which  has  leaked  from  blood  capillaries  and  sinusoids. 
Nix<7  al.  (157,  158)  estimated  that,  in  the  anesthetized 
dog,  the  volume  of  lymph  collected  from  the  liver,  in- 
testine, and  thoracic  duct  was  equivalent  in  24  hours 
to  47,  39,  and  95  per  cent,  respectively,  of  the  es- 
timated plasma  volume.  They  found,  as  have  others, 
that  more  than  half  of  the  total  circulating  plasma 
proteins  passes  through  the  thoracic  duct  daily.  When 
they  produced  hepatovenous  congestion  or  cirrhosis, 
the  flow  of  hepatic  lymph  was  two  to  five  times  that 
found  in  normal  dogs.  The  equivalent  of  70  to  207 
per  cent  of  the  total  circulating  plasma  protein  passed 
through  the  liver  lymphatics  in  24  hours.  Likewise, 
Friedman  et  al.  (78)  collected  hepatic  lymph  from  the 
rat  in  chronic  experiments  and  reported  an  average 
flow  of  1.5  ml  in  12  hours  (12  rats).  This  rate  of  flow 
was  increased  to  an  average  of  5. 1  ml  in  1 2  hours  (6 
rats)  following  biliary  obstruction. 


The  role  of  liver  lymphatics  in  the  problem  of  ascites 
is  discussed  by  Yoffey  &  Courtice  (234).  They  point 
out  that  in  the  shifts  of  fluid  which  take  place  when 
ascites  develops,  three  major  sets  of  lymphatics  are  in- 
volved: lymphatics  of  the  alimentary  tract,  liver 
lymphatics,  and  lymphatics  of  the  diaphragm.  All 
three  are  capable  of  carrying  very  large  volumes  of 
lymph,  much  greater  than  lymphatics  from  any  other 
region  of  the  body.  Only  in  extreme  circumstances 
and  in  the  presence  of  severe  disease  does  gross  ascites 
become  evident.  Baggenstoss  &  Cain  (10,  11)  studied 
the  relationship  of  hepatic  hilar  lymphatics  to  ascites 
in  man.  In  various  conditions  associated  with  ascites, 
they  found  these  structures  increased  in  size  and  num- 
ber when  ascites  was  caused  by  cirrhosis  of  the  liver  or 
congestive  heart  failure  but  not  when  it  was  caused  by 
neoplastic  involvement  of  the  peritoneum  or  by  renal 
disease.  Other  clinical  and  pathologic  conditions  asso- 
ciated with  ascites  which  revealed  an  increase  in 
lymphatic  vessels  at  the  hilus  were  lupus  erythemato- 
sis,  fatal  virus  hepatitis,  and  massive  liver  involvement 
by  neoplasms. 

Pulmonary  Lymphatics  and  Edema 

There  is  a  very  large  literature  on  the  anatomy  and 
pathology  of  the  pulmonary  lymphatic  system  but 
there  is  comparatively  little  information  on  the  func- 
tion of  the  widespread  lymph  vessels  in  the  lungs. 
Warren  &  Drinker  (216)  were  the  first  to  collect  lung 
lymph  in  1942  when  they  succeeded  in  cannulating  a 
large  lymphatic  in  the  anterior  mediastinum  of  dogs. 
In  18  animals,  they  reported  an  average  lymph  flow  of 
1.1  ml  per  hour  and  an  average  protein  concentration 
of  3.7  g  per  100  ml.  As  they  realized,  their  experiments 
were  subject  to  the  criticism  that  the  thorax  was  open 
and  the  usual  intrathoracic  pressure  absent.  To  ob- 
viate this  difficulty,  they  and  subsequent  investigators 
turned  to  collection  of  lymph  from  the  right  duct. 
This  procedure,  although  eliminating  the  above  ob- 
jection, introduces  other  variables.  The  right  duct,  as 
usually  cannulated  in  the  dog  for  lymphatic  studies, 
not  only  drains  the  lungs  but  also  carries  lymph  from 
the  heart,  right  side  of  the  thorax,  and  part  of  the 
convex  surface  of  the  liver.  It  is  thus  difficult  to  quan- 
tify the  contribution  of  the  lungs  to  total  right  duct 
lymph  flow.  However,  since  the  contribution  from 
thorax  and  liver  are  small,  it  is  probably  valid  to 
assume  with  Drinker  (60)  that  "in  the  quiescent, 
anesthetized  dog  the  amount  of  lymph  collected  from 
the  right  duct  expresses  the  lymph  delivery  from  the 
contracting  heart  and  moving  lungs.  If  cardiac  ac- 
tivity is  kept  reasonably  constant,  the  quota  of  right 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


duct  lymph  arising  from  the  heart  is  constant,  and 
variation  in  output  reflects  conditions  in  the  lungs." 

A  second  variable  is  introduced  by  the  occasional 
occurrence  of  anastomotic  connections  with  the 
thoracic  duct  and  thus  free  flow  between  the  two  ducts. 
Freeman  (76)  found  anastomotic  connections  in  1 2 
out  of  25  carefully  injected  and  examined  animals. 
In  the  living  animal,  the  presence  of  anastomotic 
connections  is  obvious  if  right  duct  lymph  is  milky 
rather  than  clear  or  becomes  milky  and  increases  in 
rate  of  flow  after  pressure  upon  the  abdomen,  a 
maneuver  which  is  very  effective  in  increasing  flow 
from  the  thoracic  duct  but  not  from  the  right  duct. 
Drinker  (60)  also  suggested  that  shifting  from  natural 
breathing  to  artificial  respiration  through  a  tracheal 
cannula  was  a  useful  test,  since  artificial  respiration 
increases  right  duct  flow  but  reduces  thoracic  duct  flow. 
Further  tests  can  be  made  by  introducing  T-1824  dye 
into  one  of  the  lungs  via  a  long  catheter  or  by  injecting 
the  dye  into  the  paw  or  a  leg  lymphatic.  The  former 
procedure  results  in  coloring  only  right  duct  lvmph 
if  no  anastomotic  connections  are  present;  the  second 
procedure  results  in  coloring  only  thoracic  duct 
lymph.  Using  these  tests,  our  experience  has  been  that 
fewer  than  20  per  cent  of  dogs  show  functional  anas- 
tomotic connections. 

It  is  interesting  that,  in  spite  of  the  difficulties 
described  as  inherent  in  the  study  of  right  duct  lymph, 
estimations  of  its  flow  and  protein  concentration  are 
not  too  different  from  those  originally  reported  by 
Warren  and  Drinker  for  lymph  collected  from  the 
mediastinal  lymph  duct,  and  the  protein  concentra- 
tions are  similar  to  those  found  in  leg  and  cervical 
lymph.  Thus  Courtice  (47)  found  that  the  average 
flow  from  the  right  lymph  ducts  of  dogs  was  2.3  ml 
per  hour  and  the  average  protein  concentration  was 
3.7  per  cent,  levels  similar  to  those  found  in  our  labo- 
ratory (197).  As  Yoffey  &  Courtice  (234)  point  out 
this  would  amount  to  about  2  g  of  protein  daily  or  3.6 
per  cent  of  the  total  circulating  plasma  proteins.  The 
lymph  flow  is  small  in  terms  of  the  rich  blood  supply 
of  the  lungs.  It  should  be  borne  in  mind,  however, 
that  these  experiments  were  done  on  anesthetized  dogs 
in  the  supine  position  and  levels  of  flow  and  concentra- 
tion may  only  at  best  reflect  minimum  values. 

The  pulmonary  circulation  is  a  low  pressure  system 
and  pulmonary  capillary  pressure  is  ordinarily  less 
than  plasma  colloid  osmotic  pressure,  a  situation  con- 
ducive to  "dry"  lungs.  According  to  the  Starling 
principle,  edema  would  be  expected  to  occur  either 
when  capillary  filtration  pressure  was  high  or  protein 
concentration  reduced.  Paine  et  al.   (163),  using  the 


heart-lung  preparation,  showed  this  to  be  true  in  ex- 
periments in  which  a)  they  lowered  the  plasma  pro- 
teins by  plasmapheresis  or  by  replacement  with 
Locke's  solution,  and  b)  they  elevated  hydrostatic 
pressures  by  imposing  a  left  ventricular  overload.  The 
onset  and  progression  of  pulmonary  edema  were  al- 
ways attended  by  an  increase  in  the  flow  of  lymph 
from  the  right  thoracic  duct.  They  conclude  that 
measurement  of  an  increased  pulmonary  lymph  flow 
is  a  reliable  indicator  of  the  presence  of  pulmonary 
edema.  Uhley  et  al.  (210)  and  Rabin  &  Meyer  (176) 
also  studied  the  relationship  between  pulmonary 
hypertension,  lymph  flow,  and  edema.  The  former 
investigators  devised  a  technique  to  collect  pulmonary 
lymph  flow  more  completely.  Instead  of  cannulating 
the  right  lymphatic  duct,  they  create  a  chamber 
within  the  right  external  jugular  vein  which  traps 
lymph  between  the  outside  of  a  tube  secured  in  the 
vein  and  the  vein  wall.  Lymph  is  removed  from  the 
chamber  by  a  polyethylene  catheter.  In  13  anesthe- 
tized, open-chest  dogs  under  artificial  respiration  they 
found  average  lymph  flow  to  be  0.3  ml  per  hour. 
This  value  is  considerably  less  than  that  found  by 
others,  as  indicated  above.  Elevation  of  pulmonary- 
venous  pressure  to  30  mm  Hg  by  introduction  of  a 
balloon  into  the  left  atrium  resulted  in  an  increase  in 
lymph  flow  to  an  average  of  1 .  14  ml  per  hour,  the  rise 
occurring  about  15  min  after  inflation  of  the  balloon. 
After  maintenance  of  elevated  pulmonary  venous 
pressure  and  progressive  increase  of  lymphatic  flow 
for  approximately  30  min,  critical  pulmonary  edema 
ensued.  The  protein  content  of  lymph  paralleled 
lymph  flow.  Both  increased  lymph  flow  and  pulmo- 
nary edema  were  generally  promptly  decreased  with 
relief  of  the  high  pulmonary  venous  pressures.  The 
authors  conclude  that  the  small  absolute  increase  in 
right  duct  lymph  suggests  that  lymphatics  were 
unable  to  function  significantly  to  relieve  the  acute 
pulmonary  edema.  Rabin  and  Meyer  raised  left 
atrial  pressures  by  means  of  previously  appropriately 
placed  snares  and  found  that,  with  this  method,  an 
acute  elevation  of  left  atrial  pressure  could  be  precisely 
controlled  at  any  desired  level  up  to  a  mean  of  60  mm 
Hg  in  dogs  with  an  intact  thorax.  Right  lymphatic 
duct  flow  did  not  increase  at  acutely  elevated  left 
atrial  mean  pressures  below  25  mm  Hg,  whereas  flow 
increased  3-  to  4-fold  at  mean  pressures  above  25  mm 
Hg.  The  total  amount  of  lymph  at  maximum  flow, 
however,  was  only  0.3  ml  per  min.  Lymph  flow  re- 
mained elevated  for  as  long  as  1  hour  after  left  atrial 
pressure  was  restored  to  normal.  Pulmonary  edema 
did  not  occur  readily  when  left  atrial  mean  pressure 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I°53 


was  elevated  only  slightly  above  plasma  oncotic 
pressure.  It  was  observed  onlv  after  a  considerable 
elevation  of  left  atrial  pressure,  above  plasma  oncotic 
pressure,  was  maintained  for  a  period  of  one-half  hour 
or  more.  Chronic  elevation  of  left  atrial  pressure  was 
achieved  in  15  dogs.  Left  atrial  mean  pressure  varied 
from  10  to  23  mm  Hg.  The  dogs  were  followed  for  10 
months.  Right  lymphatic  flow  did  not  increase  at 
chronically  elevated  mean  pressure  below  25  mm  Hg. 
They  did  not  study  flow  at  higher  pressures  because 
they  were  unable  to  sustain  left  atrial  mean  pressure 
above  25  mm  Hg  in  any  dog  in  the  chronic  group. 
The  animals  that  were  brought  to  left  atrial  mean 
pressure  between  30  to  40  mm  Hg,  and  in  which  these 
high  levels  were  presumably  maintained,  were  found 
dead  in  their  cages  with  pulmonary  edema  1  to  2  days 
after  the  snare  was  tightened. 

Drinker,  while  admitting  that  hemodynamic 
changes  might  be  responsible  for  pulmonary  edema, 
stressed  the  importance  of  changes  in  capillary  per- 
meability due  to  anoxia  (60).  He  believed  that  "in- 
creased pressure  in  the  pulmonary  capillaries  does  not 
readily  cause  recognizable  pulmonary  edema  unless 
coupled  with  heightened  permeability,  most  fre- 
quently due  to  anoxia."  His  conclusions  were  based 
on  a  variety  of  experiments  by  him  and  his  group  (65, 
216,  217).  Thus,  forced  breathing  of  dogs  against  re- 
sistance without  hypoxia  did  not  cause  pulmonary- 
edema,  although  right  duct  lymph  flow  was  aug- 
mented. On  the  other  hand,  when  anoxia  was  present 
under  the  same  circumstances,  increased  lymph  flow 
and  pulmonary  edema  were  evident.  Increased  capil- 
lary filtration,  according  to  Drinker,  results  in  ac- 
cumulation of  fluid  in  the  alveoli,  interfering  with 
oxygen  uptake.  A  vicious  cycle  is  set  up  as  the  hypoxia 
further  increases  capillary  permeability  and  filtration. 
Courtice  &  Korner  (48),  on  the  other  hand,  failed  to 
observe  pulmonary  edema  when  they  made  animals 
breathe  a  mixture  containing  1 1  per  cent  oxygen. 
They  believe  that  the  results  of  the  Drinker  group  can 
be  equally  well  explained  by  postulating  an  increase 
in  filtration  pressure  rather  than  changes  in  capillary 
permeability.  There  is  considerable  evidence  to  indi- 
cate that  the  permeability  of  systemic  capillaries  does 
not  change  at  the  levels  of  anoxia  produced  in  the 
Drinker  and  in  the  Courtice  and  Korner  experiments, 
and  the  latter  correctly  conclude  that  there  is  no 
evidence  to  indicate  that  the  permeability  character- 
istics of  the  pulmonary  capillaries  are  different  with 
respect  to  anoxia.  Courtice  and  Korner  gave  large 
infusions  of  Ringer-Locke's  solution  to  rabbits  breath- 
ing low  oxygen.  The  presence  of  anoxia  led  to  edema 


at  a  lower  level  of  infusion  than  when  anoxia  was  not 
present.  The  authors  believe  that  this  effect  can  be 
explained  by  the  hemodynamic  changes  observed 
(decrease  in  cardiac  output,  systemic  vasoconstriction, 
etc.)  without  postulating  an  increase  in  permeability. 
It  may  be  pertinent  in  this  connection,  however,  that 
Fishman  et  al.  (71)  recently  reported  that  acute  anoxia 
in  human  subjects  produces  a  rise  in  cardiac  output 
and  that  significant  changes  in  pulmonary  arterial 
pressure  (average  7  mm  Hg)  are  not  found  except 
when  the  arterial  blood  oxygen  saturation  is  below 
85  per  cent.  It  also  appears  that  acute  hypoxia  does 
not  affect  the  thoracic  blood  volume  (80). 

The  conclusions  of  Courtice  and  Yoffey  should  also 
perhaps  be  modified  in  light  of  more  recent  findings 
in  our  laboratory  (197).  We  injected  radioactive 
iodinated  serum  albumin  and  dextran  fractions  of 
average  molecular  weights  of  51,000  to  255,000  into 
dogs  anesthetized  with  Nembutal  and  followed  con- 
centration changes  in  plasma  and  thoracic  and  right 
duct  lymphs  for  4  to  6  hours.  At  this  time,  when  a 
"steady  state"  had  been  established  between  plasma 
and  lymph,  we  infused  40  ml  per  kg  of  5  per  cent 
serum  albumin  in  0.9  per  cent  saline.  This  resulted 
in  a  significant  and  striking  increase  in  the  concentra- 
tion of  the  injected  radioactive  iodinated  albumin  and 
dextrans  in  right  duct  and  thoracic  duct  lymph  in 
spite  of  increased  lymph  flows.  We  interpreted  these 
results  (and  earlier  ones)  to  be  the  result  of  "stretch- 
ing" of  capillary  pores  as  a  result  of  raised  hydrostatic 
pressure  resulting  from  the  expanded  blood  volume. 
It  is  conceivable  that  the  hypoxia  in  Courtice  and 
Korner's  experiments  may  have  served  to  exaggerate 
this  phenomenon  of  the  capillary  wall.  It  is  interesting, 
in  this  connection,  that  the  possibility  of  pore  stretch- 
ing was  suggested  by  Casten  &  Kistler  (40)  as  an  ex- 
planation of  the  acute  pulmonary  edema  which  they 
observed  in  mice  and  rats  following  blast  injury  and 
irradiation.  They  hypothesized:  "The  intercellular 
cement  substance  of  capillary  walls  is  postulated  to 
consist  of  processes  having  elastic  properties  that  tie 
the  cell  walls  together.  These  processes  are  assumed 
to  be  normally  under  tension.  If  the  intracapillarv 
pressure  increases,  but  remains  below  a  critical  value, 
the  tension  of  the  intercellular  processes  may  be  still 
sufficient  to  hold  the  cell  mosaic  tightly  together  and 
prevent  gross  fluid  leakage.  If  the  internal  pressure 
exceeds  this  critical  value,  then  the  elastic  processes 
may  be  stretched  to  a  degree  which  causes  the  cell 
mosaic  to  be  separated,  and  thereby  permit  gross  fluid 
effusion  to  occur.  With  still  greater  internal  pressure, 
the  processes  may  be  stretched  beyond  their  elastic 


1054 


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CIRCULATION    II 


limit,  hereby  producing  an  irreversible  damage  to  the 
capillary  wall.  It  is  assumed  that  in  the  extravasation 
stage  following  acute  radiation  damage,  the  elasticity 
and  the  stretchability  of  these  processes  are  greatly 
reduced." 

It  should  be  obvious  from  the  brief  review  given 
that,  in  discussing  the  pathogenesis  of  pulmonary 
edema,  we  are  concerned  with  a  syndrome,  like  cir- 
culatory shock,  in  which  many  factors  may  be  opera- 
tive. In  an  individual  case,  a  single  factor  may  produce 
indeterminable  effects  unless  it  is  very  powerful.  On 
the  other  hand,  several  factors  may  combine  to  pro- 
duce the  syndrome  at  a  threshold  lower  than  that 
necessary  for  each  to  act  singly.  In  the  final  analysis 
we  must  assume  that  in  the  healthy  animal,  fluid  and 
proteins  which  leak  from  the  capillaries  are  drained 
off  as  an  equal  amount  of  lymph.  Pulmonary  edema 
arises  when  capillary  filtration  exceeds  the  point 
where  the  lymphatic  drainage  is  adequate  to  main- 
tain the  relatively  "dry"  state  of  pulmonary  tissue. 
This  concept,  that  pulmonary  edema  results  from  a 
relative  deficiency  in  lymph  drainage  is  further 
supported  by  the  experiments  of  Foldi  and  his  col- 
laborators (75).  They  studied  dogs  in  which  they  had 
experimentally  produced  mitral  insufficiency,  mitral 
stenosis,  or  bilateral  vagal  section  and  ligated  the  right 
and  thoracic  lymph  ducts  and  lymph  nodes  of  the 
anterior  mediastinum.  Only  tying  off  the  lymphatic 
supply  failed  to  produce  edema  as  did  each  experi- 
mental procedure  under  control  conditions.  When  the 
procedure  was  combined  with  lymphatic  ligation, 
however,  edema  ensued  in  most  animals.  Failure  to 
occur  under  the  combined  procedure  was  correlated 
with  lack  of  lymph  congestion  presumably  to  incom- 
plete cutting  off  of  lymph  drainage. 

Cardiac 

The  lymphatic  supply  of  the  myocardium  was  first 
described  by  Rudbeck  in  1653  and  has  been  debated 
ever  since,  particularly  as  to  whether  myocardial 
lymphatic  capillaries  exist.  Patek  (167)  described 
three  plexuses,  subendocardial,  myocardial,  and  sub- 
epicardial. The  subendocardial  vessels  comprise  capil- 
laries in  a  single  plane  which  drain  into  the  myocardial 
plexus,  a  profuse  system  of  interconnected  capillaries. 
According  to  Patek,  there  were  no  efferent  lymphatics 
but  only  anastomoses  with  the  subepicardial  system. 
Rusznyak  et  al.  (188),  however,  review  more  recent 
work  of  Zhemcherzhnikova  and  Zhdanov  showing 
that  "the  musculature  of  the  ventricles  in  man  con- 
tains reticularly  arranged  true  lymphatic  capillaries. 


The  loops  of  these  capillaries  are  situated  along  the 
fasciculated  muscles."  According  to  these  workers,  the 
lymphatic  system  of  the  epicardium  consists  of  a  dou- 
ble, intercommunicating  deep  and  superficial  plexus. 
The  efferent  lymphatics  are  chiefly  situated  subepi- 
cardially,  i.e.,  on  the  surface,  and  follow  the  branches 
of  the  coronary  artery.  The  lymphatic  trunks  of  the 
anterior  surfaces  of  the  two  ventricles  unite  to  form  two 
lymphatics  which  run  in  the  anterior  longitudinal 
sulcus  from  the  apex  to  the  base  of  the  heart.  The 
lymphatic  which  unites  the  lymph  vessels  of  the 
posterior  surface  of  the  left  ventricle  runs  in  the 
posterior  longitudinal  sulcus  and  reaches  the  anterior 
surface  of  the  heart  in  the  coronary  sulcus.  Uniting 
below  the  left  auricle,  these  lymphatics  form  the 
heart's  main  collecting  lymph  vessel  which  drains  into 
a  bifurcation  or  laterotracheal  lymph  node.  The 
lymphatics  of  the  posterior  and  part  of  the  anterior 
aspect  of  the  right  ventricle  unite  in  the  right  efferent 
main  lymphatic  trunk  which  starts  in  the  posterior 
longitudinal  sulcus,  passes  over  to  the  anterior  surface 
of  the  aorta  and  runs  along  the  surface  of  the  right 
auricle  to  the  cranial  mediastinal  lymph  node  which 
usually  lies  on  the  aortic  arch  at  the  origin  of  the  left 
common  carotid  artery. 

Miller  et  al.  (146)  have  recently  raised  the  question 
as  to  whether  lymphatic  vessels  exist  in  the  heart  valves 
of  the  dog.  They  examined  mitral  valves  in  three 
groups  of  dogs:  /)  stock  dogs  killed  during  the  course 
of  other  laboratory  experiments,  2)  "sham"-operated 
dogs,  and  3)  dogs  in  which  surgical  obstruction  of 
cardiac  lymphatic  drainage  was  produced  and  which 
were  then  killed  at  varying  periods  of  time  after 
surgery.  Only  an  occasional  thin-walled  channel 
was  found  on  histological  study  in  the  first  two  groups. 
However,  numerous  channels,  presumed  to  be  lym- 
phatics, appeared  in  animals  with  obstructed  lymph 
flow.  The  authors  believe  that  interference  with  lymph 
flow  may  play  a  direct  role  in  heart  valve  scarring  and 
may  provide  an  additional  clue  to  the  mechanism  of 
progressive  valvular  fibrosis  in  the  years  following  an 
inflammatory  insult  (such  as  rheumatic  valvulitis). 
These  authors  also  reported  ventricular  endomyo- 
cardial pathology  produced  by  chronic  cardiac  lym- 
phatic obstruction  in  the  dog  (145).  Their  results  are 
similar  to  those  previously  described  by  Rusznyak 
(187)  who  reported  many  variations  in  the  anatomy  of 
the  cardiac  lymphatic  system.  They  did  not,  however, 
find  cardiac  lymphatics  entering  the  thoracic  duct  as 
Rusznyak  reported.  They  found  interstitial  edema 
most  often  with  dilatation  of  lymph  capillaries.  Dis- 
seminated focal  necrosis  in  the  myocardium  was  pres- 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


10 


3D 


ent  in  3  dogs  and  left  ventricular  subendocardial 
hemorrhages  in  7  of  1 7  dogs.  They  describe  other 
changes  and  point  out  the  merit  of  further  investiga- 
tion of  cardiac  lymphatics  and  the  relationships  of  dis- 
turbances of  their  function  to  pathologic  states. 
Rusznyak  and  co-workers  have  also  described  the 
results  of  similar  experiments  done  by  their  group. 
They  report  in  detail  the  electrocardiographic  changes 
seen  after  cardiac  lymphatic  obstruction  and  after 
ligation  of  the  coronary  sinus  and  cardiac  lymph 
nodes.  They  also  emphasize  the  possibility  that  lym- 
phatic congestion  may  play  an  important  role  in  the 
pathogenesis  of  mitral  stenosis  and  other  cardiac 
diseases. 

Drinker  and  his  colleagues  (64)  are  the  only  group 
to  date  who  have  collected  and  studied  cardiac 
lymph.  They  reported  measurements  of  flow  in  10 
dogs  as  varying  between  0.31  to  1.65  ml  per  hour 
(average  0.8  ml /hour)  with  no  correlation  between 
dog  weight,  heart  weight,  blood  pressure,  and  lymph 
flow.  Since  only  one  lymphatic  was  cannulated  and 
since  there  are  usually  two  main  efferent  trunks,  the 
total  flow  was  probably  approximately  twice  the 
values  obtained.  This  would  mean  that  about  60  to 
70  per  cent  of  the  total  right  lymph  duct  flow  comes 
from  the  heart.  The  lymph  always  contained  a  rela- 
tively high  concentration  of  protein.  The  average  for 
18  dogs  was  3.69  per  cent  with  a  range  between  2.50 
to  4.73  per  cent.  Since  right  duct  lymph  contains 
approximately  the  same  concentration,  this  suggests 
that  cardiac  and  lung  lymph  have  about  the  same 
concentration  of  protein.  This  is  also  supported  by  the 
values  obtained  by  Warren  &  Drinker  (216)  in  collec- 
tion from  a  large  lymphatic  in  the  anterior  mediasti- 
num. Thus  there  is  in  the  heart,  as  in  all  other  tissues 
studied,  a  continuous  leakage  of  protein  from  the 
capillaries  and  the  rhythmic  contractions  of  the  car- 
diac muscle  insure  its  rapid  removal  by  the  extensive 
lymphatic  plexuses.  These  investigators  also  found 
that  cardiac  lymph  flow  increased  after  the  injection 
of  epinephrine  and  ephedrine,  the  rise  appearing  to  be 
correlated  to  the  increased  cardiac  work.  Experiments 
with  a  Starling  heart-lung  preparation  designed  to 
simulate  exercise  (increased  input  and  peripheral 
resistance  and  addition  of  epinephrine)  showed  a 
marked  increase  in  lymph  flow  to  24  ml  per  hour.  As 
Yoffey  &  Courtice  (234)  point  out,  even  if  we  accept 
a  figure  of  18  ml  per  hour,  a  hound  engaged  in  a  12 
hours'  chase  would  be  putting  out  216  ml  of  cardiac 
lymph.  With  a  heart  weight  of  91  g,  this  would  mean 
2.4  ml  of  lymph  per  g  of  heart  during  the  1  2  hours. 


Renal 

Although  a  relatively  extensive  literature  has  ac- 
cumulated concerning  the  distribution  of  kidney 
lymphatics  and  their  possible  role  in  clinical  disorders 
(88),  the  physiological  role  of  renal  lymph  is  less  well 
documented.  This  is  due  to  the  difficulty  in  cannulat- 
ing  the  vessels  because  of  their  location  and  extremely 
small  size.  The  main  hilar  trunks  are  particularly  in- 
accessible to  cannulation,  whereas  capsular  lym- 
phatics, although  more  accessible,  are  quite  small  and 
difficult  to  cannulate.  This  has  led  some  investigators 
to  the  highly  unphysiologic  compromise  of  eviscerat- 
ing animals  and  collecting  thoracic-duct  lymph  on 
the  assumption  that  this  lymph  was  now  derived 
solely  from  the  kidney. 

The  first  physiological  experiments  on  renal  lym- 
phatics were  made  by  Ludwig  &  Sawarykin  (129), 
who  showed  that  ligation  of  a  ureter  was  followed  by 
dilatation  of  efferent  renal  lymphatics.  They  did  not 
study  lymph  flow  or  composition  under  these  condi- 
tions, but  their  experiments  form  the  basis  of  a  more 
recent  elaborate  study  by  Babies  and  his  collaborators 
(7,  8),  whose  work  will  be  discussed  later.  Sugerman 
et  al.  (204)  were  probably  the  first  to  collect  renal 
lymph  directly  and  begin  its  characterization  in  dogs. 
They  cannulated  both  capsular  and  hilar  lymphatic 
trunks  and  reported  a  wide  fluctuation  in  flow  and 
protein  concentration.  The  slower  the  lymph  flow, 
the  greater  was  the  concentration  of  protein.  Their 
average  figure  for  flow  from  1 1  dogs  was  0.0232  g  per 
min  (1.392  g/'hour)  and  for  protein  concentration 
1 .84  g  per  cent.  Of  interest  was  the  finding  of  a  higher 
average  urea  concentration  in  renal  lymph  (69.7 
mg%)  than  in  plasma  (53.1  mgTt).  In  some  animals, 
the  lymph  urea  concentration  was  considerably  higher 
than  that  in  plasma  of  the  renal  artery  or  vein.  These 
findings  posed  two  questions:  /)  Do  the  renal  lym- 
phatics drain  only  the  larger  collecting  ducts  of  the 
kidney,  thus  accounting  for  the  high  urea  content  of  its 
lymph?  2)  Is  renal  lymph  derived  from  tubular  reab- 
sorbed fluid,  the  blood  plasma,  or  from  both  types  of 
fluid?  Attempts  to  answer  these  questions  were  made 
by  Kaplan  et  al.  (107)  who  determined  and  compared 
the  glucose  content  of  renal  and  cervical  lymph  sam- 
ples as  well  as  their  inulin  content  during  an  intra- 
venous infusion  of  inulin.  The  average  concentration 
of  glucose  in  8  renal  lymph  samples  was  92.7  mg  per 
cent  and  10 1.9  mg  per  cent  in  8  cervical  lymph  sam- 
ples. They  concluded  that  this  high  glucose  concen- 
tration in  renal  lymph  suggests  that  renal  lymph  could 
not  be  derived  exclusively  from  the  relatively  sugar- 


1056 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


free  fluid  contained  in  the  larger  collecting  ducts  of 
the  kidney.  The  average  concentration  of  inulin  in 
renal  lymph  from  8  dogs  was  found  to  be  82.5  mg 
per  cent  or  94  per  cent  of  the  plasma  concentration. 
The  authors  considered  these  results  as  evidence  that 
the  composition  of  renal  lymph  is  determined  by  the 
character  of  both  tubular  reabsorbed  fluid  and  renal 
blood  plasma.  If  it  were  derived  exclusively  from  the 
renal  tubular  reabsorbed  fluid,  its  inulin  content 
would  be  practically  nil  and  if  it  were  derived  exclu- 
sively from  renal  blood  plasma,  its  inulin  content 
would  be  equal  to  that  present  in  plasma. 

Swann  and  his  colleagues  (205)  reported  measure- 
ments on  renal  capsular  lymph  from  5  dogs.  Lymph 
flow  was  between  o.  1  to  0.3  ml  per  hour.  They  also 
found  urea  concentration  of  renal  lymph  to  be  higher 
than  plasma  and  glucose  concentration  to  be  lower. 
They  found  total  protein  content  to  be  quite  constant 
at  about  3.2  g  per  cent,  about  half  that  present  in 
plasma,  and  failed  to  observe  the  inverse  relation  of 
protein  content  to  lymph  flow  reported  by  Sugerman 
et  al.  Electrophoretic  separation  of  the  proteins  showed 
that  their  distribution  in  lymph  was  similar  to  that  in 
plasma. 

About  5  years  ago,  my  colleague,  Dr.  S.  J.  LeBrie, 
and  I  began  a  comprehensive  study  of  renal  lymph  as 
part  of  a  general  study  of  lymph  and  lymphatics.  We 
have  collected  renal  capsular  lymph  in  a  variety  of 
experimental  situations  which  will  be  detailed  below. 
We  have  found  the  lymph  flow  to  be  quite  variable 
and  unrelated  to  sex,  age,  or  size  of  the  animal.  The 
average  control  flow  for  63  dogs  studied  up  to  the 
present  time  is  0.0128  ml  per  min  or  0.768  ml  per 
hour.  Total  protein  concentration  for  40  dogs  averages 
2.76  g  per  100  ml  or  about  half  of  plasma  concen- 
tration. 

We  find  protein  distribution  to  be  similar  to  that 
of  plasma,  confirming  the  findings  of  Swann  et  al. 
All  plasma  proteins,  including  fibrinogen,  are  present 
in  renal  lymph.  Potassium  concentrations  appear  to 
be  identical  in  lymph  and  plasma.  We  previously 
reported  (121)  that  the  average  lymph  sodium  con- 
centration for  30  dogs  was  1 1.3  per  cent  higher  than 
in  plasma.  Addition  of  more  data  and  refinement  of 
experimental  procedures  suggests  that  this  value  may 
be  too  high  and  the  difference  may  or  may  not  be  sig- 
nificant. Limited  data  on  osmotic  pressure  also  have 
been  equivocal.  Data  on  30  dogs  show  lymph  chloride 
concentration  to  average  13  per  cent  higher  than 
plasma,  a  difference  which  is  statistically  significant. 
We  have  some  indication  that  bicarbonate  concen- 
tration is  lower  in  lymph  than  in  plasma.  Obviously 


we  need  more  data  to  clarify  the  situation  with  respect 
to  these  constituents.  These  data  are  being  accumu- 
lated. 

It  is  of  interest  to  compare  renal  lymph  flow  with 
urine  flow  in  the  same  kidney.  It  is  reasonable  to 
assume  that  there  are  at  least  ten  lymphatics  draining 
each  kidney.  Using  the  average  flow  which  we  ob- 
tained from  one  lymphatic,  the  average  total  lymph 
flow  from  both  kidneys  would  amount  to  o.  1 28  ml 
per  min,  which  is  approximately  half  of  the  average 
amount  of  urine  flow.  In  some  animals  with  high 
lymph  flows,  the  amount  of  capsular  lymph  drained 
equals  the  amount  of  urine  formed.  Similar  admittedly 
rough  calculations  for  protein  yield  a  value  of  10.2  g  of 
protein  returned  to  plasma  per  day  via  capsular 
lymphatics  of  both  kidneys.  It  should  be  emphasized 
that  these  are  average  values  for  the  anesthetized  dog 
and  probably  reflect  minimum  levels. 

Renal  lymph  flow  is  markedly  increased  by  raising 
venous  pressures.  This  was  first  shown  by  Schmidt  & 
Hayman  (195)  and  later  confirmed  by  Katz  &  Cockett 
(109)  and  by  us  (123).  Schmidt  and  Hayman  analyzed 
the  changes  in  thoracic  duct  lymph  flow  in  eviscerated, 
hepatectomized,  and  uninephrectomized  dogs  follow- 
ing ligation  of  the  remaining  functional  renal  vein. 
They  concluded  that  the  increase  in  renal  lymph  flow 
was  responsible  for  the  observed  rise  in  thoracic  duct 
lymph  flow  when  venous  pressure  was  raised.  Katz 
and  Cockett  likewise  concluded  that  changes  in  renal 
lymph  were  responsible  for  changes  in  thoracic  duct 
lvmph  which  they  observed.  They  observed  an  in- 
crease in  thoracic  duct  lymph  flow  and  sodium  concen- 
tration as  well  as  a  decrease  in  urinary  flow  and 
sodium  concentration  when  venous  pressure  was 
raised.  The  changes  occurred  only  when  the  kidneys 
were  intact.  Haddy  and  his  colleagues  (94),  in  ex- 
periments designed  to  study  pressure  and  flow  rela- 
tionships in  the  kidney,  also  reported  that  renal 
lvmph  flow  increased  as  a  function  of  venous  pressure. 
In  our  experiments,  we  collected  capsular  lymph  and 
raised  the  venous  pressure  by  partially  occluding  the 
inferior  vena  cava  with  a  balloon  catheter.  We  also 
measured  protein  and  electrolyte  changes.  Renal 
lvmph  flow  increased  about  five  times  during  the 
periods  of  increased  venous  pressure  and  the  flow 
from  one  lymphatic  equaled  and  often  exceeded 
urine  flow  from  the  same  kidney.  Electrolytes  and 
protein  levels  changed  proportionately  except  at  high 
venous  pressure  levels  (30-35  cm  HaO)  when  dispro- 
portionately high  levels  of  protein  were  found  in  renal 
lymph. 

In  discussing  the  significance  of  the  changes  in  lym- 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


1057 


phatic  flow  and  composition  produced  by  increased 
venous  pressure,  we  suggested  that  they  might  have 
some  bearing  on  the  problem  of  plasma  volume  in- 
crease and  sodium  retention  in  congestive  heart  fail- 
ure, a  syndrome  in  which  venous  pressures  not  infre- 
quently approximate  the  high  levels  used  in  our 
study.  We  pointed  out  that  under  conditions  of  signifi- 
cantly increased  venous  pressure  the  total  lymph  flow 
from  both  kidneys  may  amount  to  as  much  as  2400  ml 
per  24  hours.  This  would  represent  a  total  of  ±379 
meq  of  sodium  not  excreted  by  the  kidneys  but  re- 
tained by  the  lymphatic  system.  A  study  of  kidney 
lymph  flow  in  postural  proteinuria  might  also  be  of 
interest.  Bull  (32)  believes  that  "A  rise  in  pressure  in 
the  inferior  vena  cava  is  produced  by  compression  of 
the  vessel  against  the  spine  by  the  posterior  surface  of 
the  liver.  This  pressure  is  conducted  back  to  the  kid- 
ney, inducing  passive  congestion  and  proteinuria. 
The  compression  occurs  when  the  subject  is  in  a  lor- 
dotic posture  and  when  the  anterior  surface  of  the 
liver  rotates  inferiorly.  This  rotation  of  the  liver 
normally  occurs  when  the  subject  is  lordotic  and  is 
maximal  in  the  erect  lordotic  posture."  Goodwin  & 
Kaufman  (89)  suggest  the  possibility  of  thoracic  duct 
or  cisterna  chyli  lymphatic  obstruction  and  retrograde 
lymph  flow  as  a  possible  explanation  of  the  proteinuria 
and  cite  the  report  of  Lowgren  (128)  as  suggesting  this 
explanation. 

If  we  agree  that  one  of  the  primary  functions  of  the 
lymphatic  system  is  to  return  to  the  vascular  system 
those  proteins  and  other  large  molecules  which  have 
leaked  out  of  the  blood  capillaries,  our  accumulated 
data  emphasize  that  kidney  lymphatics  are  no  excep- 
tion. This  is  a  function  of  considerable  importance  for 
the  kidney.  Maintenance  of  a  relatively  low  concen- 
tration of  interstitial  protein  is  necessary  for  the  main- 
tenance of  the  countercurrent  action  in  the  kidney. 
This  concept  visualizes  the  vasa  recta  as  a  counter- 
current  exchanger  carrying  off  salt  and  water.  Gott- 
schalk  &  Mylle  (go)  believe  the  efficiency  of  the  coun- 
tercurrent exchange  in  the  vasa  recta  to  be  critical, 
"for  they  probably  remove  not  only  the  blood  enter- 
ing the  medulla,  but  also  the  water  that  diffuses  from 
the  thin  descending  limbs  of  the  loops  of  Henle  and 
the  collecting  ducts.  This  water,  with  solute  isosmotic 
for  the  particular  level  of  the  medulla,  presumably 
moves  into  the  vasa  recta  because  of  the  gradient  of 
its  chemical  potential  established  by  the  colloid  os- 
motic pressure  of  the  plasma  proteins,  since  the  hydro- 
static pressure  in  the  capillaries  and  interstitium  are 
the  same."  The  gradient  of  colloid  osmotic  pressure 
between  the  interstitium  and  the  plasma  can  be  main- 


tained only  if  the  colloid  osmotic  pressure  of  the  in- 
terstitium is  kept  well  below  that  of  the  plasma.  We 
believe  that  this  is  an  important  function  of  renal  lym- 
phatics, the  maintenance  of  a  relatively  low  oncotic 
pressure  in  the  interstitium  and  thus  the  establish- 
ment of  a  gradient  with  the  higher  oncotic  pressure 
within  the  vasa  recta.  Thus,  as  the  lymphatics  carry 
off  plasma  protein  that  has  pooled  in  the  medullary 
interstitium,  the  colloid  osmotic  pressure  of  these  pro- 
teins draws  water  with  a  higher  or  lower  solute  con- 
centration, depending  upon  the  level  of  the  counter- 
current  gradient  at  which  the  lymph  is  formed.  The 
medullary  and  cortical  lymph  passes  into  lymph  col- 
lecting trunks,  mixing  the  two  and  thus  reducing  the 
electrolyte  concentration  and  osmolarity.  Some  col- 
lecting trunks  lease  the  kidney  through  the  cortex 
while  others  follow  the  path  of  the  artery  and  vein  to 
the  hilus.  When  renal  venous  pressure  is  increased, 
more  protein  is  lost  in  both  cortex  and  medulla  due  to 
increased  hydrostatic  pressure.  Thus,  although  filtra- 
tion of  protein  increases  as  does  water,  the  concen- 
tration of  filtered  electrolytes  does  not  increase  over 
control  values.  We  assume  that  filtered  electrolvtes 
from  cortical  capillaries  are  isosmotic  with  both 
plasma  and  cortical  interstitial  tissue,  while  filtered 
electrolytes  from  the  vasa  recta  are  hyperosmotic  to 
plasma  but  isosmotic  to  the  countercurrent  gradient 
in  which  they  lie.  Thus,  if  these  fluids  are  mixed,  one 
might  expect  the  concentration  of  sodium  in  milli- 
equivalents  per  liter  to  remain  unchanged.  This  is  es- 
sentially what  we  find. 

In  terms  of  the  above  discussion,  we  would  expect 
ligation  or  obstruction  of  lymphatic  outflow  to  produce 
edema  and  significantly  alter  kidney  function.  Kaiser- 
ling  &  Soostmeyer  (105)  succeeded  in  tracing  the 
lymphatic  vessels  to  the  main  hilar  branch  in  rabbits 
and  in  tying  it  off.  The  kidney  began  to  swell  immedi- 
ately and  had  reached  double  its  original  size  within 
10  to  15  min  as  a  result  of  massive  interstitial  edema. 
There  was  a  marked  increase  in  urinary  output  on 
the  side  with  lymphatic  ligation  and,  significantly, 
the  urine  from  the  experimental  side  had  a  specific 
gravity  of  1  013,  whereas  the  control  side  had  a  specific 
activity  of  1  035.  Later,  the  urine  flow  diminished, 
proteinuria  was  present,  and  the  kidney  and  its 
parenchymal  cells  degenerated  8  to  10  days  after  the 
lymphatics  were  ligated. 

These  and  other  similar  studies  and  their  implica- 
tions are  discussed  at  length  by  Babies  (7,  8)  and 
Rusznyak  et  al.  (189). 

Earlier  mention  was  made  of  the  fact  that  the  first 
experiments  on  renal  lymph  were  those  of  Ludwig  & 


o=s8 


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CIRCULATION    II 


Sawarykin  ( 1 29)  who  noticed  that  ligation  of  a  ureter 
was  followed  by  dilatation  of  the  efferent  renal  lym- 
phatics. Similar  observations  have  since  been  made  by 
many  investigators  (88,  153,  154,  and  LeBrie  and 
Mayerson,  unpublished)  who  have  also  shown  that 
renal  lymph  flow  is  significantly  increased.  Katz  (108) 
measured  renal  lymphatic  pressure  in  two  dogs  with 
pyelonephritis  and  found  the  pressures  to  rise  when 
either  the  renal  vein  or  the  ureters  were  compressed. 
It  is  apparent  that  the  renal  parenchyma  shows  no 
significant  changes  for  a  number  of  weeks  after  the 
experimental  ligation  of  the  ureter;  the  only  histo- 
pathological  symptoms  that  can  be  observed  for  a 
considerable  time  are  a  high  degree  of  interstitial 
edema  and  marked  dilatation  of  lymphatics.  Babies  & 
Rrnyi-Yamos  (7)  ascribe  the  survival  and  continued 
performance  of  the  hydronephrotic  kidney  to  the  fact 
that  urine  passes  from  the  renal  pelvis  into  the  inter- 
stitial space  of  the  kidney  where  it  is  continuously 
absorbed  into  lymphatics.  Histamine  is  presumed  to 
be  liberated,  increasing  capillary  permeability  and 
transudation  of  protein.  This  protein,  too,  is  carried 
away  by  the  lymphatics.  If,  on  the  other  hand,  the 
lymphatics  are  also  tied  off,  necrosis  is  seen  within  a 
few  days  [see  Babies  &  Renyi-Vamos  (7)  andRusznyak 
el  al.  (189)  for  detailed  discussion]. 

The  general  effect  of  diuretics  is  to  increase  renal 
lymph  flow.  Reference  has  been  made  to  the  work  of 
Schmidt  and  Hayman  who  showed  this  to  be  true  for 
phosphate,  sodium  chloride,  and  caffeine.  We  have 
collected  renal  capsular  lymph  in  dogs  during  diuresis 
produced  by  sodium  chloride,  urea,  mannitol,  and 
mercury  (LeBrie  and  Mayerson,  unpublished).  Under 
the  conditions  of  our  experiments,  we  obtained  the 
most  marked  diuresis  with  urea  and  mannitol  and  the 
least  with  mercury.  Mannitol  produced  the  greatest 
increase  in  lymph  flow  (average  10  dogs  =  587%), 
while  mercury  and  urea  produced  the  least  (Hg,  15 
dogs,  42  %;  urea,  7  dogs,  41  '",  ).  These  experiments  are 
being  continued  and  attempts  are  being  made  to  eluci- 
date the  mechanism  of  the  changes  in  flow,  electro- 
lyte and  protein  concentration,  and  to  explain  the 
differences  seen  with  the  different  diuretics. 

We  have  also  studied  the  influence  of  uranium- 
nitrate  injury  on  the  flow  and  composition  of  renal 
lymph  (122).  Lymph  flow  was  increased  approxi- 
mately 15  times  in  the  experimental  animals.  Like- 
wise, the  increase  in  lymph  flow  with  mannitol 
infusion  was  about  twice  as  great  in  the  experimental 
animals  (iooofT  increase)  as  in  control  animals 
(542%  increase).  The  experimental  animals  showed 
a  significant  proteinuria  and  decreased  urine  flows, 


and  the  data  appear  to  be  consistent  with  the  histo- 
logic findings  of  primary  damage  to  the  distal  seg- 
ment of  the  proximal  tubule. 

The  finding  of  an  increased  lymph  flow  when 
ureters  are  obstructed  and  diuretics  are  administered 
has  given  rise  to  the  concept  emphasized  in  clinical 
literature,  that  the  renal  lymphatics  act  as  a  "safety- 
valve"  mechanism,  capable  of  taking  the  extra  load 
from  the  kidney  under  conditions  of  overload. 
Backflow  from  the  kidney  pelvis  to  the  renal  lym- 
phatics has  also  been  suggested  by  experiments  of 
Murphy  &  Myint  (153)  and  Goodwin  &  Kaufman 
(89).  The  former  introduced  glucose  and  the  dye 
T-1824  into  the  renal  pelvis  and  found  these  sub- 
stances earlier  and  in  greater  concentration  in  lymph 
of  the  cisterna  chyli  than  in  renal  or  femoral  blood. 
The  latter  injected  radioactive  Diodrast  into  the 
renal  pelvis  during  ureteral  occlusion  and  found 
the  same  radioactivity  at  the  same  time  in  thoracic 
duct  lymph  and  in  the  control  vascular  area.  More 
work  along  these  lines  is  needed,  particularly  defining 
the  mechanisms  involved  and  the  effects  of  pyelo- 
lymphatic  backflow  in  kidney  disease.  However,  it 
may  be  pertinent  to  emphasize,  as  has  been  previously 
suggested,  that  the  general  function  of  the  lymphatic 
system  is  to  act  as  a  "safety  valve"  and  as  an  acces- 
sory circulation,  clearing  the  interstitium  of  excess 
substances  which  leak  out  of  or  are  not  absorbed 
directly  into  the  blood  stream  and  returning  them  to 
the  blood  circulation.  This  is  not  a  peculiar  or  special 
function  of  renal  lymphatics.  Thus,  an  overload  of 
the  circulatory  capacity  as  produced  by  a  large 
intravenous  infusion  results  in  an  increased  lymph 
flow,  etc.  The  particular  importance  of  lymph  with 
respect  to  normal  renal  function  lies  in  the  fact  that 
the  oncotic  pressure  of  the  interstitium  must  be  kept 
low  in  order  for  the  vasa  recta  to  act  as  a  counter- 
current  exchanger.  In  the  absence  of  adequate 
lymph  drainage  the  kidney  becomes  unable  to 
concentrate  urine  (105). 


LYMPH  AND  LYMPHATICS  IN  SHOCK 

Anaphylactic  Shock 

Petersen  &  Levinson  (173)  found  that  injection  of 
antigen  into  dogs  resulted  in  an  increased  perme- 
ability of  splanchnic  endothelium  and  subsequent 
reaction  of  the  hepatic  parenchymal  cells  with  the 
antigen.  In  further  work,  Petersen  &  Hughes  (172) 
showed  the  injection  of  egg  white  into  dogs  sensitized 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I°59 


to  egg  albumin  to  result  in  an  immediate  and  marked 
increase  in  thoracic  duct  lymph  flow  with  increased 
concentrations  of  calcium,  amino  nitrogen,  and 
magnesium,  and  decreased  concentrations  of  sodium 
and  potassium.  They  did  not  measure  proteins. 
Dragstedt  and  his  colleagues  (55-57,  82)  reported 
that,  in  the  dog  at  least,  the  vasomotor  symptom 
and  death  occurring  in  anaphylactic  shock  are 
brought  about  by  the  sudden  discharge  into  the 
circulating  blood  of  a  vasodepressor,  smooth  muscle- 
stimulating  substance  which  is  apparently  histamine. 
They  were  able  to  detect  this  substance  in  blood  and 
thoracic  duct  lymph  for  brief  periods  of  time  after 
the  assaulting  or  shocking  dose  of  serum,  and  to  corre- 
late its  appearance  with  varying  grades  of  severity  of 
the  shock  in  such  a  way  as  to  indicate  that  it  had  a 
causal  relationship  to  the  shock  symptoms.  More 
specific  results  were  recently  reported  by  Logan  (127) 
who  showed  that  bovine  globulin  is  a  satisfactory 
antigen  for  sensitizing  rats  when  given  intraperi- 
toneally  simultaneously  with  Bordetella  pertussi 
vaccine.  Intestinal  lymph  of  animals  so  sensitized 
contained  increased  amounts  of  histamine  when 
collected  6  min  after  intravenous  injection  of  the 
shocking  dose.  The  amount  of  lymph  histamine  was 
roughly  proportional  to  the  degree  of  shock.  The  rate 
of  lymph  flow  increased  8  to  25  times  during  the  12 
min  immediately  after  administration  of  the  shocking 
dose  and  the  lymph  contained  o  to  0.02  /ig  histamine 
per  ml,  an  amount  similar  to  that  in  plasma. 

The  lymphagogue  action  of  histamine  is  well 
known  and  can  readily  be  demonstrated  by  the 
intravenous  injection  of  small  amounts  of  the  sub- 
stance (95).  This  effect  has  usually  been  ascribed  to 
dilation  and  increased  permeability  of  capillaries, 
although  the  exact  mechanisms  involved  have  never 
been  clearly  defined.  Rusznyak  et  al.  (189)  review 
much  of  the  evidence  and  report  experiments  done 
in  their  own  laboratories  by  Szabo  and  Magyar.  The 
latter  injected  a  dextran  fraction  of  approximately 
the  same  molecular  weight  as  albumin  simultaneously 
with  histamine  and  with  Evans  blue.  In  dogs,  flow 
of  intestinal  and  hepatic  lymph  increased  two  to 
three  times  and  remained  high;  appearance  of  dextran 
and  dye-labeled  albumin  in  lymph  was  much  sooner 
as  was  equilibration  between  plasma  and  lymph.  The 
authors  believe  they  have  ruled  out  the  factor  of 
increased  filtration  pressure  in  favor  of  increased 
capillary  permeability.  Repetition  of  the  same  experi- 
ments in  cats  gave  entirely  negative  results,  i.e.,  no 
increased  lymph  flow  or  accelerated  equilibration. 
The  authors  explain  these  differences  as  being  due 


to  the  fact  that  in  the  dog  not  only  the  capillaries 
and  small  veins  but  also  the  arterioles  are  dilated  by 
histamine  (and  only  the  larger  visible  arteries  con- 
stricted), while  in  the  cat  this  constrictor  effect  begins 
more  peripherally  in  the  arterioles.  The  authors 
take  issue  with  the  assumption  by  Krogh  (117)  that 
dilation  of  capillaries  leads  to  increased  permeability, 
since  capillaries  dilate  in  the  cat  quite  as  much  as 
in  the  dog  without  showing  increased  permeability. 

Changes  in  blood  coagulability  are  among  the 
important  findings  in  the  anaphylactic  reaction 
(67,  104)  and  result  from  the  release  of  heparin  from 
the  liver.  The  possibility  that  this  substance  may  be 
transported  from  the  liver  to  the  blood  stream  by- 
way of  the  thoracic  duct  was  first  suggested  by  Gley 
(87)  who  found  that  ligation  of  the  liver  lymphatics 
prevented  the  incoagulability  of  blood  following 
peptone  shock.  White  &  Woodward  (228-230) 
showed  that  the  incoagulability  of  thoracic  duct  lymph 
following  an  anaphylacytic  or  peptone-induced 
shock  is  due  to  heparin  and  that  the  main  portal  of 
entry  for  this  substance  into  the  blood  stream  is  via 
the  thoracic  duct  from  the  liver.  The  concentration  of 
heparin  in  lvmph  in  these  situations  was  greater  than 
in  arterial  or  hepatic  venous  blood  and  it  was  fre- 
quently present  only  in  thoracic  duct  lymph.  When 
heparin  was  given  intravenouslv  the  concentration  of 
heparin  was  the  same  in  thoracic  duct  lymph  and  in 
plasma.  Furthermore,  heparin  did  not  appear  in 
cervical  or  right  duct  lymph  unless  it  first  appeared  in 
blood.  Removal  of  the  liver  prevented  the  appearance 
of  heparin  in  peptone-shocked  dogs.  These  findings 
confirm  the  liver  as  being  the  origin  of  heparin  under 
these  circumstances.  Heparin  was  not  released  into 
thoracic  duct  lvmph  or  blood  during  a  hemorrhage- 
induced  shock,  thus  ruling  out  hypotension  as  a  factor 
in  the  heparin  release.  It  is  suggested  that  the  release 
of  the  heparin  may  depend  upon  limited  cellular 
reactions  and  not  upon  general  cellular  activity. 

Traumatic  Shock 

There  has  been  considerable  interest  in  studying  the 
participation  of  the  lymphatic  system  in  traumatic 
shock.  These  studies  have  taken  different  forms. 
The  Hungarian  workers  (188)  have  done  a  consid- 
erable amount  of  work  in  which  they  have  measured 
lymph  flows  from  various  areas  and  used  the  compo- 
sition of  lymph  as  a  measure  of  capillary  permeability. 
There  has  been  a  recurrent  interest  in  the  presence 
or  absence  in  lymph  of  a  "toxic"  substance  which  may 
or  may  not  have  come  from  the  plasma. 


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CIRCULATION    II 


The  question  as  to  whether  capillary  permeability 
is  altered  in  shock  has  been  a  hardy  perennial.  A 
detailed  discussion  of  this  topic  would  be  out  of 
place  at  this  point.  It  is,  however,  appropriate  to 
call  attention  to  the  studies  of  the  Hungarian  group 
referred  to  above  in  which  they  have  made  extensive 
observations  on  the  role  of  lymph  and  lymphatics  in 
dogs  during  and  after  traumatic  shock.  They  have 
used  the  same  general  approach  as  we  have  used 
(141,  219)  of  introducing  dextrans  of  molecular 
weights  similar  to  those  of  albumin  and  globulin  into 
the  blood  stream,  following  their  disappearance  from 
the  blood  stream  and  their  appearance  in  lymph  from 
various  regions.  Since  radioisotopes  were  not  available 
to  them,  they  used  the  dye,  T-1824,  which  is  known 
to  bind  onto  albumin  and  thus  constitute  a  label. 
Their  results  on  control  animals  resemble  in  general 
those  which  we  obtained;  albumin  or  de.xtran  of 
molecular  weight  of  about  50,000  appeared  in  thoracic 
duct  lymph  within  10  min  and,  in  their  experiments, 
the  average  de.xtran  concentration  was  29  per  cent 
of  that  in  plasma  at  1 5  min  and  about  75  per  cent  at 
60  to  go  min.  In  tourniquet  shock  produced  by 
arresting  the  circulation  of  the  hind  legs  for  5  hours, 
they  found  a  more  rapid  disappearance  of  the  dextran 
from  the  blood  stream  but  a  much  slower  appearance 
and  accumulation  in  thoracic  duct  lymph.  At  90 
min  there  was  only  an  average  of  43  per  cent  of 
dextran  in  the  lymph.  Lymph  flow  was  considerably 
reduced.  These  workers  also  studied  cervical  lymph 
and,  while  their  results  were  not  definitive,  it  seems 
reasonably  certain  that  the  capillary  permeability  in 
peripheral  regions  was  not  increased.  Attempts  to 
find  the  reasons  for  the  decreased  thoracic  duct 
lymph  flow  and  the  delayed  appearance  of  protein 
and  dextran  were  not  successful.  It  was  apparently 
not  due  to  diminished  hepatic-lymph  formation  or  to 
lymphangiospasm.  They  interpret  the  faster  disap- 
pearance of  the  dextran  from  blood  as  reflecting  the 
increase  in  capillary  permeability  in  the  ischemic 
area  rather  than  a  generalized  increase  in  perme- 
ability. One  of  the  group  (226)  has  extended  some 
of  the  work  to  hemorrhagic  and  burn  shock  and 
again  finds  a  decreased  thoracic  duct  lymph  flow 
which  parallels  the  severity  of  the  shock.  He  also 
interprets  his  data  as  denying  any  generalized 
increase  in  capillary  permeability. 

Since  edema  is  prominent  in  the  ischemic  areas, 
these  investigators  went  on  to  study  the  flow  of  leg 
lymph  and  the  behavior  of  albumin  and  dextran  in 
the  hope  of  ascertaining  whether  the  edema  was  due 
to  an  inability  of  the  lymphatic  system  to  cope  with 


an  increased  tissue  fluid  formation  or  whether  there 
was  injury  to  the  lymphatics  caused  by  the  ligatures. 
Although  the  small  lymph  flow  in  leg  lymphatics 
precluded  quantitative  data,  there  was  no  question  of 
the  direction  of  change  and  that  protein  leakage  was 
increased  in  the  ischemic  area.  The  increased  lymph 
flow  argued  against  lymphatic  injury  or  occlusion  as 
factors  in  the  edema  production. 

The  occurrence  of  a  vasoconstrictor  substance  in 
blood  during  shock  induced  by  trauma,  hemorrhage, 
and  burns  was  reported  in  dogs  by  Page  (161)  and 
denied  for  ischemic  compression  shock  (91).  Rapport 
et  al.  (180)  also  reported  the  occurrence  of  a  "toxic 
factor"  in  tourniquet  shock  in  rabbits. 

In  1943,  Blalock  (ig)  reported  the  results  of 
experiments  in  which  he  produced  crush  injury  in 
anesthetized  dogs  by  applying  a  press  to  a  hind  leg. 
Thoracic  duct  lymph  collected  from  these  dogs  after 
removal  of  the  pressure  and  injected  into  other  dogs 
brought  on  a  decrease  in  blood  pressure  and  death 
of  some  of  the  animals.  Less  marked  results  were 
obtained  when  trauma  was  produced  by  striking  the 
legs  with  a  blunt  instrument.  Blalock  explained  his 
results  as  due  to  the  presence  of  a  toxic  substance  in 
lymph  of  the  traumatized  animals.  Katzenstein 
et  al.  (1 10)  reported  similar  results  in  shock  produced 
by  tourniquets  around  the  hind  legs.  These  authors 
appreciated  the  possible  vasodepressor  effects  of 
large  doses  of  Nembutal  which  they  used  but  showed 
that  when  narcosis  was  controlled  to  avoid  vaso- 
depression,  injection  of  thoracic  lymph  from  normal 
dogs  had  no  effect.  In  contrast,  a  fall  in  blood  pressure 
followed  in  50  per  cent  of  the  animals  injected  with 
lymph  of  shocked  animals.  The  problem  was  further 
studied  by  Nathanson  and  his  collaborators  (155),  who 
devised  a  method  of  producing  tourniquet  shock  in 
dogs  which  permitted  the  collection  of  muscle 
exudate.  They  collected  the  exudate,  which  accumu- 
lated after  muscle  anoxia,  and  injected  it  into  the 
same  or  recipient  dogs  (6).  Shock  was  produced  in 
only  25  per  cent  of  the  animals  tested.  The  incon- 
stancy of  the  presence  of  the  toxic  factor  suggested 
that  the  factor  was  an  extraneous  agent,  not  present 
in  the  usual  cellular  constituents  and  metabolic 
products  found  in  all  muscle  exudates,  and  possibly 
bacterial  in  origin.  They  further  showed  (235)  that 
the  toxic  properties  of  a  collection  of  pooled  muscle 
exudates  were  contained  in  a  nondialyzable  fraction, 
could  be  salted  out  between  0.25  and  0.7  saturation 
with  ammonium  sulfate  and  were,  therefore,  prob- 
ably protein  in  nature.  The  toxic  substances  were 
tentatively  classified  as  an  aminoexopeptidase  and  a 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I06l 


trypsinase  which  were  present  in  the  exudates.  Free- 
man &  Schecter  (77)  tested  leg  lymph  obtained 
from  dogs  whose  hind  legs  were  traumatized  or  heated 
and  found  that  it  produced  an  increase  in  permeability 
as  judged  by  leakage  of  dye  when  injected  into  re- 
cipient animals.  Arterial  and  venous  serum  and 
plasma  also  contained  a  similar  factor  which  increased 
capillary  permeability,  and  the  authors  concluded 
that  it  was  likely  that  the  presence  in  lymph  of  a 
substance  capable  of  producing  an  increase  in  capil- 
lary permeability  is  dependent  upon  the  appearance, 
after  trauma,  of  blood  plasma  in  the  lymph  draining 
from  the  extremity.  On  the  other  hand,  Lindner 
et  al.  (126)  failed  to  find  any  evidence  of  a  perme- 
ability factor  either  in  lymph  or  plasma  in  shock 
produced  by  manipulation  of  the  intestine.  Their 
experience  was  similar  to  the  earlier  one  reported 
by  Dragstedt  &  Mead  (57),  who  produced  shock  by 
sustained  trauma  with  a  padded  hammer  to  one  or 
both  hind  legs,  by  trauma  to  the  intestine,  or  by  a 
combination  of  the  two  methods. 

Burns 

Some  work  has  been  done  on  the  study  of  lymph 
in  burns.  Aldrich  (2)  collected  leg  lymph  from  burned, 
anesthetized  dogs  and  perfused  it  through  rabbit 
ears.  Blood  flow  as  measured  by  drop  rate  definitely 
decreased  when  lymph  from  burned  animals  was 
used  as  compared  to  lymph  from  healthy  clogs.  No 
attempt  was  made  to  identify  the  vasconstrictor 
substance. 

Glenn  and  his  colleagues,  in  Drinker's  laboratory, 
studied  the  changes  in  lymph  composition  after  leg 
burns  produced  with  hot  water  in  calves  (85,  86, 
170).  Cervical  and  leg  lymph  was  followed.  Lymph 
flow  in  the  burned  legs  was  significantly  increased  as 
was  the  protein  concentration  of  the  leg  lymph. 
Cervical  lymph,  however,  did  not  show  the  increase 
in  protein.  Electrophoretic  studies  showed  the  occur- 
rence of  a  new  protein  in  the  lymph  from  the  burned 
leg,  a  component  migrating  with  half  the  speed  of 
7-globulin.  Cope  &  Moore  (44)  also  reported  a  signifi- 
cant increase  in  capillary  permeability  following  hot 
water  burns  of  legs  of  dogs.  They  injected  radioactive 
colloidal  dyes  into  the  blood  stream  and  measured 
their  appearance  in  leg,  cervical,  and  thoracic  duct 
lymph  before  and  after  the  burn.  They  also  injected 
radioactive  bromine,  which  they  found  to  appear  in 
lymph  from  the  three  areas  within  5  min  and  to 
reach  equilibrium  with  serum  in  20  min.  In  contrast, 
the    colloidal    dyes    were    slower    in    appearance    in 


lymph  and  no  equilibrium  was  established  with  serum 
under  control  conditions.  Following  the  burn,  the 
concentration  of  radioactive  colloids  in  lymph  of  the 
burned  leg  rose  abruptly  and  approached  that 
encountered  after  injection  of  radioactive  bromine. 
The  specific  activity  of  protein  was  actually  higher 
in  lymph  than  in  serum  after  the  burn.  In  confirma- 
tion of  Glenn  et  al.,  they  also  found  that  the  increased 
capillary  permeability  was  usually  restricted  to  the 
burned  leg.  A  rise  in  colloid  concentration  in  cervical 
lymph  was  observed  in  only  one  dog. 

Permeability  Factors 

During  the  last  decade,  considerable  interest  has 
been  aroused  in  the  presence  in  plasma  of  endogenous 
substances  which,  when  activated,  induce  pathologi- 
cal increases  in  capillary  permeability  (144).  Two 
classes  of  natural  mediators  have  been  suggested: 
7)  the  pharmacologically  active  amines,  histamine, 
and  hydroxytryptamine;  and  2)  proteases  and  prod- 
ucts of  proteolysis.  This  latter  group  includes  the 
proteases  of  plasma  (plasmin,  the  serum  globulin 
permeability  factors,  and  polypeptides  like  leuko- 
taxine  and  bradykinin).  The  groups  overlap  in  that 
polypeptides  may  act  as  histamine  liberators.  There 
is  direct  and  indirect  evidence  that  these  substances 
participate  in  the  mediation  of  the  response  to 
injury,  but  much  more  evidence  is  needed  to  define 
their  role  in  the  healthy  animal  and  in  animals 
suffering  from  hemorrhage,  burn,  or  other  trauma. 
It  would  be  interesting  to  extend  the  observations 
of  Miles  &  Wilhelm  (144)  to  other  substances, 
species,  and  experimental  conditions.  These  investi- 
gators showed  the  presence  in  the  guinea  pig  of  the 
precursor  (pro-PF)  and  the  inhibitor  (IPF)  of  one  of 
the  globulin  permeability  factors,  both  in  intercellular 
perfusates  of  skin  and  in  normal  lymph  from  the 
cervical  lymph  ducts  (143).  It  appears  that  the 
proteins  constituting  the  pro-PF/IPF  system  of  the 
blood,  like  other  plasma  proteins,  pass  continuously 
via  the  extravascular  tissues  to  the  lymph,  and  that 
the  extravascular  tissues,  including  the  outer  surface 
of  the  capillary  wall,  are  bathed  in  tissue  fluid  con- 
taining pro-PF. 


PERMEABILITY    OF    LYMPHATIC    VESSELS 

Although  a  considerable  amount  of  work  has  been 
done  relative  to  the  permeability  of  blood  vessels,  we 
have    very    little    definitive    information    regarding 


1062 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


permeability  characteristics  of  lymph  vessels.  Light 
microscope  studies  suggested  that  lymph  and  blood 
capillaries  are  morphologically  similar,  a  suggestion 
which  has  been  confirmed  by  recent  studies,  particu- 
larly those  of  Casley-Smith  &  Florey  (39a).  These 
authors  showed  that  there  were  no  species  differences 
in  lymphatics  of  mice,  guinea  pigs,  and  rats,  and 
that  the  lymphatics  of  the  ear  and  the  deep  lymphatics 
of  the  diaphragm  and  colon  were  similar.  In  general, 
the  structure  of  the  lymphatic  capillaries  and  lacunes 
appeared  to  be  similar  to  that  of  blood  capillaries. 
All  the  lymphatic  endothelial  cells  contained  many 
vesicles  and  caveolae  intracellulares.  No  fenestrations 
in  the  endothelium  were  seen,  but  some  intercellular 
junctions  were  patent,  especially  in  diaphragmatic 
lacunes.  The  basement  membrane  was  less  regular 
than  that  of  blood  capillaries  or  of  mesothelium 
and  in  many  places,  especially  in  diaphragmatic 
lacunes,  it  appeared  to  be  absent.  These  results  are 
similar  to  those  of  Palay  &  Karlin  (164)  and  French 
et  al.  (77a).  The  absence  of  a  definable  basement 
membrane  would  not,  as  Casley-Smith  and  Florey 
point  out,  fully  differentiate  lymphatic  from  vascular 
endothelium,  since  the  endothelium  lining  large 
blood  vessels  may  have  at  best  a  very  tenuous  base- 
ment membrane.  The  significance  of  the  absence  of 
fenestrations  in  the  lymphatic  endothelium  also 
remains  questionable  in  the  absence  of  definite 
information  as  to  the  importance  of  their  presence  in 
determining  permeability  characteristics.  The  signifi- 
cance of  their  other  findings  will  be  discussed  further 
below. 

The  permeability  pattern  in  lymphatics  presents  an 
interesting  and  challenging  problem.  It  is  obvious 
from  the  preceding  discussion  that  proteins,  chylo- 
microns, and  lymphocytes  are  normal  constituents  of 
lymph  as  routinely  collected  from  healthy  animals. 
Experimentally,  bacteria,  viruses,  red  blood  cells, 
graphite  particles,  etc.  have  been  shown  to  penetrate 
the  lymphatic  system  with  no  apparent  difficulty. 
Lane  Allen  (ia)  showed  that  every  type  of  cell  which 
occurs  normally  in  tissue  fluid  and  blood  will  pene- 
trate lymphatic  endothelium.  He  felt  he  had  identified 
every  cell  of  the  hematopoietic  series,  except  giant 
cells,  in  diaphragmatic  lymph  after  intraperitoneal 
injection  of  bone-marrow  suspensions.  Likewise,  he 
found  that  the  entire  series  of  lymphoid  cells  will 
enter  through  lymphatic  endothelium.  The  large 
amount  of  literature  published  before  1956  describing 
these  experiments  has  been  thoroughly  reviewed  by 
Yoffey  &  Courtice  (234).  The  more  recent  publica- 
tions will  be  discussed  later. 


In  spite  of  the  apparent  ease  with  which  substances 
can  penetrate  into  the  lymphatic  vessels,  the  avail- 
able evidence  suggests  that  once  these  substances  are 
in  the  lymphatic  system,  they  are  retained  and 
eventually  find  their  way  into  the  blood  stream  via 
the  larger  ducts.  Thus  MacCallum  (132a)  retroin- 
jected  the  lymphatics  of  the  diaphragm  and  failed  to 
force  suspended  particles  back  into  the  peritoneal 
cavity,  except  when  he  used  pressures  sufficient  to 
rupture  the  lymphatics.  Hudack  &  McMaster 
(100a)  injected  dyes  into  the  ears  of  mice  and  studied 
the  escape  of  these  substances  from  the  lymphatics. 
They  reported  that  poorly  diffusible  dyes  (pontamine 
sky  blue,  Chicago  blue  6B)  which  pass  with  difficulty 
out  of  blood  capillaries  into  the  tissues,  tend  to  be 
retained  by  the  lymphatic  wall  as  well,  whereas  more 
highly  diffusible  dyes  (trypan  red,  bromphenol  blue, 
and  Neptune  blue)  pass  out  with  ease.  Rusznyak 
et  al.  (189)  have  more  recently  reported  similar  results 
using  fluorescent  dyes  (thiazine  red,  acridine  yellow) 
in  intestinal  lymphatics  of  cats.  Hudack  and  Mc- 
Master concluded  that  "all  the  evidence  we  have 
obtained  supports  the  view  that  permeability  of  the 
lymphatic  wall  resembles  the  permeability  of  the 
capillary  wall  in  its  essential  features  and  perhaps  in 
its  degree."  Drinker  &  Field  (61  a)  retroinjected 
lymphatics  of  the  frog  web  with  graphite  acacia  and 
found  no  passage  of  the  graphite  particles  until  rupture 
resulted  from  excessive  pressure.  Pullinger  &  Florey 
(175)  found  that  when  they  injected  graphite  particles 
into  ear  lymphatics  of  the  mouse,  the  fluid  leaked  out 
but  the  graphite  particles  remained.  Similarly,  Lee 
(124a)  found  that  large  particles  of  centrifuged, 
dialyzed  India  ink  were  retained  in  lymph  vessels, 
whereas  small  particles  passed  through.  Courtice  & 
Steinbeck  (50a)  attempted  to  evaluate  lymphatic 
permeability  by  injecting  T-1824-labeled  plasma 
proteins  intraperitoneally  into  rabbits  and  collecting 
lymph  containing  the  protein  from  the  exteriorized 
thoracic  duct.  They  found  that  the  injected  proteins 
were  almost  entirely  absorbed  by  the  diaphragmatic 
lymphatics.  In  further  work  (50b)  they  demonstrated 
that  ligation  of  the  parasternal  lymph  channels  in 
rabbits,  rats,  and  guinea  pigs  prevented  the  dye- 
labeled  protein  from  reaching  the  circulation  via  the 
thoracic  duct,  but  instead,  after  entering  diaphrag- 
matic and  mediastinal  lymph  channels,  it  proceeded 
to  leak  into  the  mediastinum  and  pleural  cavities. 
They  concluded  from  these  experiments  that  lympha- 
tics leaked  protein,  a  conclusion  open  to  question  in 
view  of  the  obviously  unnatural  conditions  of  their 
experiments.  Ligation  of  the  parasternal  lymph  chan- 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


I  ul,  ; 


nels  and  the  resultant  increased  intralymphatic 
pressure  and  distention  of  the  lymph  vessels  might 
conceivably  permit  leakage  of  substances  which 
ordinarily  would  be  retained  within  the  lymphatic 
vessels  as  has  been  previously  shown  to  be  true  in 
earlier  work  cited  above.  This  has  been  shown  to  be  true 
of  blood  capillaries  (197).  Furthermore,  the  fact  that 
Courtice  and  Steinbeck  found  no  protein  leakage  when 
the  ducts  were  not  ligated  suggests  that  the  lymphatics 
of  the  anterior  mediastinum,  under  normal  circum- 
stances, will  not  permit  leakage  of  significant  amounts 
of  the  protein  which  is  contained  by  them. 

In  a  recent  study  (168)  we  attempted  to  obtain 
answers  to  the  questions:  a)  Does  the  capillary  filtrate, 
once  it  is  in  the  lymph  ducts,  empty  without  loss  into 
the  venous  circulation  or  is  protein  free  to  pass  out 
of  the   lymphatic   vessels   throughout   their   lengths? 

b)  Does  any  protein  pass  into  the  blood  capillaries? 

c)  Is  any  considerable  amount  of  protein  phagocytized 
by  the  reticuloendothelial  cells  of  lymph  nodes? 
Furthermore,  to  what  degree,  if  any,  is  lymph 
shunted  to  the  blood  stream  through  lymph-blood 
anastomoses  without  returning  via  the  thoracic 
duct?  Anomalous  shunts,  consisting  of  multiple 
outlets  of  right  and  left  ducts,  have  been  described 
as  well  as  shunts  between  the  right  and  left  thoracic 
ducts  in  about  15  per  cent  of  dogs  (234,  197).  One 
phase  of  our  study  involves  the  cannulation  of  a  leg 
lymphatic  in  an  anesthetized  dog,  the  infusion  into  it 
of  substances  of  different  molecular  weights,  and 
obtaining  and  analyzing  samples  of  thoracic  duct 
lymph  and  plasma.  The  infused  material  thus  travels 
through  a  number  of  lymph  nodes,  through  lymphatic 
vessels    of   different    sizes,    and    through    capillaries. 

The  second  approach  to  the  problem  is  to  utilize  a 
preparation  developed  some  years  ago  by  Drinker 
and  his  group  (63).  One  afferent  and  one  efferent 
duct  going  to  and  from  the  popliteal  node  are  isolated 
and  catheterized  with  polyethylene  tubing.  All  other 
lymphatics  are  tied  off.  Test  substances  are  infused 
through  the  node  from  the  afferent  side  and  collec- 
tions are  made  on  the  efferent  side.  Nodal  and  systemic 
plasma  are  also  obtained  and  analyzed. 

When  radioactive  iodinated  albumin  is  infused  into 
a  leg  lymphatic,  there  is  a  typical,  consistent  pattern 
of  appearance  of  the  albumin  in  thoracic  duct  lvmph 
as  shown  in  figure  5.  There  is  a  lag  time  of  approxi- 
mately 10  min  between  the  start  of  the  infusion  into 
the  leg  lymphatic  and  the  appearance  of  measurable 
amounts  of  radioactive  albumin  in  thoracic  duct 
lymph.  This  is  followed  by  an  abrupt  rise  to  a  plateau 
which  is  maintained  at  an  approximately  constant 


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fig.  5.  Concentration  of  dextran  and  I131  albumin  in  lymph 
and  plasma.  Dextran  and  I131  albumin  solutions  infused  cen- 
trally into  leg  lymphatic  of  anesthetized  dog  at  zero  time  at 
rate  of  0.5  ml/min.  Infusions  of  dextran  and  albumin  stopped 
after  50  min  and  0.9%  saline  infusion  started  at  same  rate  for 
next  1 00  min.  All  values  are  corrected  for  free  iodine. 


level  for  the  50-min  duration  of  the  albumin  infusion 
and  for  10  min  of  a  subsequent  saline  infusion.  At 
this  time,  radioactivity  in  thoracic  duct  lymph  falls 
sharply  and  continues  to  fall  until  the  level  approxi- 
mates zero  in  about  140  to  150  min.  Plasma  radio- 
activity rises  to  a  maximum  concentration  after  60  to 
90  min  and  remains  at  this  level  for  the  remainder 
of  the  experiment.  The  maximum  plasma  concentra- 
tion is  less  than  0.00 1  of  the  thoracic  duct  lymph 
concentration  during  its  50-min  plateau  period. 
Figure  5  also  shows  the  similar  behavior  of  dextran  of 
approximately  the  same  average  molecular  weight 
as  albumin.  It  is  apparent  that  these  infused  sub- 
stances do  not  leave  the  lymphatic  system  and  that 
they  return  to  the  circulation  primarily  by  the 
thoracic  duct.  Actually  less  than  3  per  cent  of  the 
infused  material  reaches  the  circulation  by  routes 
other  than  the  thoracic  duct,  except  in  unusual  cases 
of  right  and  left  duct  anastomoses.  The  experiments 


1064 


HANDBOOK    ()!•'     I'HVSIHLOGV 


CIRCULATION    II 


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fig.  6.   Concentrations  of  urea  in  lymph.   Same  procedure 
as  in  experiment  shown  in  fig.  5. 

with  the  isolated  lymph  node  preparation  suggest 
that  most  of  the  3  per  cent  or  less  not  recovered  from 
the  thoracic  duct  goes  into  the  blood  stream  via  the 
popliteal  node,  and  that  there  is  little  further  loss  in 
the  other  nodes  through  which  the  lymph  passes  on 
its  way  to  the  thoracic  duct.  We  suspect  that  this  is 
due  to  the  fact  that  we  are  infusing  under  some 
pressure  which  is  dissipated  after  the  first  node  is 
passed.  Nisimaru  &  Irisawa  (156),  in  studying  lym- 
phatics of  the  frog's  web,  found  that  the  permeability 
of  injected  lymphatic  capillaries  to  particles  of 
increasing  sizes  was  directlv  related  to  increases  in 
intraluminal  pressure  when  applied  via  the  lymph 
sac.  Thus,  patent  blue  dye  escaped  with  5  mm  H»0 
pressure,  Congo  red  with  20  to  50  mm  H20  pressure. 
We  have  tested  a  variety  of  substances  of  different 
molecular  weights  including  dextran  fractions, 
radioactive  sodium  (Na22),  urea,  sodium  thiocyanate, 
glucose,  cellobiose,  raffinose,  and  insulin.  Briefly,  we 
have  found  that  all  the  macromolecules  with  molecu- 
lar weight  as  large  as  or  larger  than  6000,  the  molecu- 
lar weight  of  insulin,  are  retained  almost  quantita- 
tively in  the  lymph  ducts  and  are  returned  to  the 
venous  system  by  the  thoracic  duct.  On  the  other 
hand,    smaller    molecules    like    sodium,    urea,    etc. 


shuttle  back  and  forth  from  lymph  ducts  and  equili- 
brate with  plasma  very  rapidly.  Recently,  we  were 
fortunate  in  obtaining  a  dextran  fraction  of  molecular 
weight  of  2300.  This  substance  appears  to  leave  the 
lymphatic  system  as  do  the  smaller  substances.  The 
limit  of  permeability  thus  seems  to  be  somewhere 
between  molecular  weights  of  2300  and  6000. 

In  these  experiments,  we  always  include  radioactive 
albumin  with  the  test  substance  and  thus  are  able  to 
assess  any  changes  in  permeability  which  may  occur. 
In  early  experiments  with  urea,  we  infused  high 
concentrations  of  urea  (over  10%)  in  order  to  get  a 
sufficiently  high  concentration  for  accurate  analysis 
of  our  samples.  Under  these  circumstances,  there  was 
a  striking  escape  of  albumin  from  the  lymphatic 
system.  Further  experiments  have  shown  that  this 
phenomenon  occurs  only  with  concentrations  of 
urea  greater  than  3  per  cent  (Fig.  6).  Similar  results 
showing  increased  leakage  of  albumin  were  obtained 
with  the  infusion  of  25  ml  of  a  solution  containing  60 
mg  per  cent  sodium  thiocyanate  and  20  per  cent 
radioactive  albumin  in  saline.  The  mechanism  of 
this  apparently  "toxic"  effect  of  urea  is  being  in- 
vestigated as  are  the  effects  of  high  urea  concentra- 
tions on  blood  capillary  permeability. 

Experiments  with  the  isolated  node  preparation 
have  given  results  which  parallel  those  given  above. 
As  indicated,  the  small  amount  of  albumin  that  finds 
its  way  to  the  plasma  without  going  through  the 
thoracic  duct  pathway  evidently  gets  into  plasma 
through  capillaries  of  the  node.  The  nature  of  this 
uptake  has  not  been  clarified.  This  preparation,  al- 
though requiring  patience  and  care  in  its  use,  should 
continue  to  be  particularly  useful  in  studies  of 
uptake  of  other  materials  by  nodes,  and  the  functions 
of  these  nodes  as  part  of  the  lymphatic  circulation. 

Much  of  the  evidence  relating  to  the  absorption  of 
substances  by  lymphatics  has  been  concerned  with 
absorption  from  the  peritoneum.  Here  absorption 
occurs  predominantly  through  those  parts  of  the 
peritoneal  surface  of  the  diaphragm  which  overlie 
the  lymphatic  lacunes.  To  enter  the  lumen  of  a 
lymphatic  lacune,  materials  must  pass  through  a 
composite  structure  or  "roof"  consisting  of  a)  a  sheet 
of  mesothelial  cells,  facing  the  peritoneal  cavity  and 
in  continuity  with  the  mesothelium  of  the  rest  of  the 
peritoneum;  b)  a  layer  of  connective  tissue  which 
forms  a  lattice  of  fibers;  and  c)  an  inner  layer  of 
endothelium  in  continuity  with  the  endothelium  in 
the  walls  and  floor  of  the  lacunae  and  ultimately 
with  the  endothelium  of  the  efferent  lvmphatics. 

The  earliest  and  perhaps  most  tempting  concept  of 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


1065 


the  mechanism  by  which  macromolecules  and  parti- 
cles entered  lymphatics  from  the  peritoneum  was  the 
postulation  of  openings  in  the  endothelial  walls.  This 
concept  was  supported  by  the  early  work  of  von 
Recklinghausen  (181a,  181  b)  and  the  presence  or 
absence  of  "stigmata"  and  "stomata"  have  been 
debated  for  the  last  century.  Cunningham  (51a),  in 
reviewing  the  subject  in  1926,  concluded,  "In  general, 
then,  we  may  summarize  the  work  which  has  been 
done  on  the  mechanism  involved  in  the  absorption  of 
particulate  matter  from  the  peritoneal  cavity  in  the 
following  way:  The  earlier  work  all  tended  to  estab- 
lish the  concept  of  the  presence  of  actual  preformed 
physical  openings  between  the  peritoneal  cavity  and 
the  diaphragmatic  lymphatics.  This  idea  was  gradu- 
ally eliminated  and  in  its  place  the  concept  of  poten- 
tial physical  openings  between  the  walls  was  offered. 
In  turn  this  hypothesis  is  being  replaced  by  one  which 
assumes  that  most,  if  not  all,  of  the  particulate 
material  that  is  being  absorbed  from  the  peritoneal 
cavity  passes  directly  through  the  cytoplasm  of  the 
mesothelial  cells." 

Lane  Allen  and  his  group  have  more  recently 
revived  the  concept  of  potential  physical  openings. 
In  experiments  designed  to  test  the  upper  limits  of 
absorption,  Allen  (ib)  injected  intraperitoneally  a 
variety  of  particles,  yeast,  mold,  paraflin,  and 
paraffin-asphalt  spheres,  and  monitored  diaphrag- 
matic lymph  for  their  recovery.  He  recovered  spheres 
of  mold  of  10  /x,  glass  beads  of  12.5  n,  and  paraffin- 
asphalt  spheres  of  up  to  22.5  /x  in  diameter.  He  also 
recovered  red  blood  cells  in  lymph  at  a  level  of  up 
to  16  million  per  mm3.  In  later  experiments,  Allen  & 
Weatherford  (ic)  injected  polystyrene  spheres  with  a 
range  from  chylomicron  size  up  to  30  n  into  the 
peritoneal  cavities  of  mice,  rats,  and  cats  and  re- 
covered the  particles  from  regional  lymph  nodes.  The 
largest  recovered  spheres  in  the  mouse  were  16.8  ^ 
in  diameter,  in  the  rat  and  cat,  24  /j.  Allen  (ib) 
presents  his  concept  of  diaphragmatic  lymphatic 
absorption  as  follows:  "As  the  diaphragm  moves 
upward  in  expiration  the  lymphatic  plexus  expands 
and  a  relative  negative  pressure  is  established  in  the 
lymphatic  lumen.  At  the  same  time  the  triple- 
layered  membrane  which  separates  the  peritoneal 
cavity  from  lymphatic  lumen  is  stretched.  On  either 
side  of  the  fenestrations  of  the  basement  membrane 
the  peritoneal  mesothelium  and  lymphatic  endo- 
thelium open,  sometimes  to  form  openings  as  great  as 
22.5  /x  in  diameter.  Through  these  openings  suspen- 
sions are  'sucked'  into  the  lymphatic  lumen.  As  the 
diaphragm   contracts   the   tension   on    the    lymphatic 


wall  is  released,  the  openings  close,  and  are  no  longer 
demonstrable  by  usual  techniques,  and  compression 
of  the  plexus  results  in  lymphatic  flow." 

The  possible  mechanisms  of  absorption  of  particles 
by  the  lymphatics  of  the  diaphragm  have  been  further 
clarified  in  a  recent  definitive  study  by  French  et  al. 
(77a)  using  the  light  and  electron  microscopes. 
They  point  out  that  the  mesothelial  cells  of  the  roofs 
differ  from  other  cells  at  the  peritoneal  surface  of  the 
diaphragm  in  that  they  are  more  closely  set,  stain 
more  darkly,  and  separate  from  each  other  more 
readily,  particularly  at  the  base  of  the  intercellular 
junctions.  The  cells  are  supported  by  a  lattice  of 
coarse  and  fine  fibers.  In  the  meshes  of  this  lattice, 
mesothelial  and  lymphatic  endothelial  cells  are 
separated  only  by  the  basement  membrane  of  the 
mesothelium  which  may  be  incomplete.  The  authors, 
using  rabbits,  injected  India  ink,  thorium  dioxide,  and 
saccharated  iron  oxide  intraperitoneally  and  found 
that  the  particles  entered  the  intercellular  spaces  of 
the  mesothelium  and  spread  freely  within  the  fibers 
of  the  fiber  lattice.  The  particles  appeared  to  pass 
through  the  mesothelium  by  a  predominantly  extra- 
cellular pathway  and  probably  entered  the  lymphatic 
lumen  through  temporary  channels  formed  by 
separation  of  endothelial  cells  at  the  intercellular 
junctions.  These  gaps  formed  by  separation  of  meso- 
thelial and  endothelial  cells  also  permit  the  passage 
of  erythrocytes.  The  authors  found  that  absorbed 
colloidal  particles  accumulated  in  the  cytoplasm  of 
mesothelial  and  lymphatic  endothelial  cells  in  the 
roofs,  and  their  observations  suggested  that  some  of 
the  absorbed  material  may  be  transported  intracellu- 
lar^- through  these  two  layers  in  cytoplasmic  vesicles. 
In  addition  to  uptake  of  particles  by  the  endothelial 
cells  in  the  roofs,  cells  in  other  sites  in  the  diaphragm 
can  also  take  up  colloidal  particles  from  the  lumen 
of  the  lymphatic.  In  this  respect,  their  results  are 
similar  to  those  of  Odor  (160a),  who  showed  that 
particles  of  mercuric  sulphide  or  Thorotrast  were 
rapidly  taken  up  from  the  peritoneal  cavities  of  rats 
by  mesothelial  cells  over  the  mesentery  and  dia- 
phragm. On  the  other  hand,  Felix  &  Dalton  (70a) 
found  that  melanin  particles  introduced  intraperi- 
toneally were  actively  ingested  by  free  macrophages 
but  not  by  mesothelial  cells.  These  differences  may  be 
related  to  the  difference  in  particle  size  or  in  the 
electron  microscope  preparations. 

The  evidence  accumulated  from  recent  studies  thus 
suggests  at  least  two  possible  pathways  for  the  absorp- 
tion of  large  particles  (and  erythrocytes)  from  the 
peritoneal     cavity:     /)     an     extracellular     pathway 


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IIWDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


consisting  of  gaps  between  mcsothelial  cells  caused  by 
pressure  or,  as  suggested  by  Allen,  by  aspiration; 
2)  an  intracellular  pathway  developed  by  infolding 
of  the  plasma  membrane  around  particles  and  the 
subsequent  pinching  off  of  small  pinocytic  vesicles 
(13a).  This  vesicular  mechanism  may  be  concerned 
not  only  in  transport  from  the  exterior  to  the  interior 
of  the  cell  but  also  in  transport  through  cells  by  a 
process  termed  cytopempsis  (147a).  The  upper  limit 
to  the  size  of  particles  which  can  be  absorbed  through 
the  extracellular  route  is  probably  determined  by 
the  size  of  the  meshes  in  the  connective  tissue  layer 
rather  than  by  the  potential  openings  between  the 
mesothelial  or  endothelial  cells.  Smaller  particles  may 
travel  through  intercellular  spaces  in  the  roofs  of 
the  lacunes  where  the  mesothelial  cells  separate 
from  each  other  more  readily  than  they  do  elsewhere. 
Evidence  that  small  particles  take  an  extracellular 
route  through  the  lymphatic  endothelium  is  perhaps 
not  so  convincing,  but  that  particles  can  enter  the 
interspace  between  lymphatic  endothelial  cells  has 
been  conclusively  shown  by  Palay  &  Karlin  (163a) 
in  the  central  lacteal  of  an  intestinal  villus  and  by 
Casley-Smith  &  Florey  (39a)  in  their  study  on  lym- 
phatics in  ears  of  mice  and  guinea  pigs,  colons  of 
rats,  and  diaphragms  of  mice.  These  authors  suggest 
the  possibility  that  lymphatic  endothelial  cells  in 
general  are  less  compactly  joined  than  those  in  blood 
capillaries  and  may  separate  from  each  other  more 
easily.  The  apparent  absence  of  a  continuous  base- 
ment membrane  to  lymphatic  endothelium,  as  dis- 
cussed above,  may  possibly  facilitate  this  separation 
of  cells  and  be  important  in  determining  the  perme- 
ability of  lymphatic  endothelium  to  macromolecules 
and  particles  traveling  from  without  inward. 

If  we  accept  the  fact  that  two  possible  pathways, 
intercellular  and  intracellular,  are  available  for 
movement  of  substances  through  lymphatic  mem- 
branes, their  relative  importance  remains  to  be 
determined.  How,  too,  are  we  to  explain  the  striking 
difference  between  the  ability  of  substances  to  enter 
and  to  leave  lymphatic  vessels?  Cunningham  reviewed 
the  evidence  available  before  1926  and  concluded 
that  the  main  pathway  of  absorption  is  intracellular. 
Florey  and  his  group,  on  the  other  hand,  interpret 
their  more  recent  results  with  the  electron  microscope 
as  evidence  of  the  possible  greater  importance  of  the 
intercellular  pathway.  They  (77a)  point  out  that 
there  is  no  evidence  that  the  greater  permeability  to 
colloidal  particles  shown  by  lymphatic  endothelium 
when  compared  with  blood  capillary  endothelium  is 
explained    by    a    greater    frequency    of   cytoplasmic 


vesicles.  It  is  not  too  dfficult,  perhaps,  to  accept  the 
point  of  view  that  the  morphological  basis  of  this 
relatively  high  permeability  of  lymphatic  endo- 
thelium from  without  inward  is  related  to  cleavage 
at  intercellular  junctions  and  absence  of  a  well- 
defined  basement  membrane.  The  available  evidence 
from  varied  sources,  although  not  always  direct  or 
definitive,  is  sufficient  to  suggest  that  mechanical 
factors,  pressure  and  concentration  gradients,  elastic- 
ity of  connective  tissue,  etc.  (74a,  52a)  may  operate 
to  move  these  substances  from  the  interstitial  space. 
Difficulty  arises,  however,  in  visualizing  the  same 
process  as  operating  from  within  outward.  Peters 
(171a)  in  1935  appreciated  this  difficulty  when  he 
attempted  to  formulate  a  comprehensive  theory  of 
lymphatic  absorption  and  raised  the  question  as  to 
how  one  could  expect  to  hold  water  in  a  sieve  by 
putting  a  valve  at  its  mouth.  Admittedly  we  still  do 
not  have  sufficient  information  to  provide  an  over-all 
sophisticated  concept  of  permeability  of  lymphatic 
vessels.  For  the  time  being,  it  may  therefore  be 
wise  to  consider  the  following  simple  concept.  We 
believe  it  to  be  consistent  with  the  available  evidence 
and  to  offer  an  explanation  of  the  apparent  one-way 
flow  of  materials  into  but  not  out  of  the  lymphatics. 
Lacking  evidence  to  the  contrary,  we  may  assume 
that  the  smallest  terminal  lymphatic  capillaries  are 
freely  permeable  to  small  and  large  molecules  and 
particles  moving  in  either  direction  through  inter- 
cellular gaps.  Compression  of  these  vessels  in  any 
manner  will  force  their  contents  in  all  directions. 
Some  of  the  contents  can,  however,  be  forced  centrally 
into  larger  vessels  and  ducts.  The  valves  in  these 
vessels  will  prevent  backflow.  Once  the  lymph 
reaches  the  larger  vessels,  it  no  longer  loses  its  macro- 
molecules  and  particles,  since  the  walls  of  the  larger 
vessels,  as  previously  discussed,  restrict  molecules 
larger  than  molecular  weight  of  approximately  2000 
(at  least  in  the  dog). 

This  simple  concept  implies  a  relatively  inept  and 
inefficient  system,  a  "leaky  pump"  system  about 
which  Peters  complained.  As  Allen  commented, 
however,  a  leaky  pump  will  still  pump,  and  as 
Drinker  emphasized,  the  lymphatic  system  is,  in  the 
final  analysis,  a  rather  casual  system.  It  does  a 
reasonably  good  job  under  "normal"  conditions.  Its 
ineffectiveness  becomes  manifest  chiefly  under  patho- 
logical situations.  This  aspect  of  the  functions  of  the 
lymphatic  system,  its  inadequacy  in  various  patho- 
logical situations,  will  continue  to  merit  careful 
study. 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


1067 


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55.  Dragstedt,  C.  A.,  and  E.  Gebauer-Fuelnegg.  Studies 
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56.  Dragstedt,  C.  A.,  and  F.  B.  Mead.  Further  observations 
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69.  Everett,  N.  B.,  W.   E.   Garrett,  and  B.  S.  Simmons. 


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IO69 


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79.  Friedman,   M.,   and   R.   H.   Roseman.    Effects  of  hyper- 

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Gebauer-Fuelnegg,  E  ,  and  C.  A.  Dragstedt.  Studies 

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81 


82 


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102.  Hyde,  P.  M.,  E.  A.  Doisy,  Jr.,  W.  H.  Elliott,  and  E.  A. 
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104.  Jaques,  L.  B.,  and  E.  B.  Waters.  The  identity  and  origin 
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105.  Kaiserling,  H.,  and  T.  Soostmeyer.  The  importance  of 
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106.  Kampmeier,  O.  F.  Further  observations  on  the  numerical 
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108.  Katz,  Y.  J.  Some  factors  affecting  renal  lymphatic 
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109.  Katz,  Y.  J.,  and  A.  T.  K.  Cockett.  Elevation  of  inferior 
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1 10.  Katzenstein,  R.,  E.  Mvlon,  and  M.  C.  Winternitz. 
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111.  Kellnor,  A.  The  lipid  and  protein  content  of  tissue 
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116.  Korner,  P.  I.,  B.  Morris,  and  F.  C.  Courtice.  An 
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117.  Krogh,  A.  Anatomy  and  Physiology  of  Capillaries.  New 
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118.  Landis,  E.  M.  Capillary  permeability  and  the  factors 
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119.  Landis,  E.  M.,  L.  Jonas,  M.  Angevine,  and  W.  Erb. 
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120.  Langdell,  D.  R.,  L.  \V.  Bowersox,  R.  A.  Weaver,  and 
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122.  LeBrie,  S.  J.,  and  H.  S.  Mayerson.  Influence  of  uranium 
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123.  LeBrie,  S.  J.,  and  H.  S.  Mayerson.  Influence  of  elevated 
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126.  Lindner,  E.,  W.  Marx,  and  H.  E.  Kruger.  Absence  in 
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128.  Lowgren,  E.  Lymphuria  as  an  explanation  of  the  postural 
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131.  McCandless,  E.  L.,  and  D.  B.  Zilversmit.  Disappearance 
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i77-'9°.  195°- 

139.  Mann,  J.  D.,  F.  D.  Mann,  and  J.  L.  Bollman.  Hypo- 
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140.  Marble,  A.,  M.  E.  Field,  D.  K.  Drinker,  and  R.  M. 
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141.  Mayerson,  H.  S.,  C.  G.  Wolfram,  H.  H.  Shirley,  Jr., 
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142.  Meng,  H.  C.  Removal  of  intravenously  injected  fat  from 


PHYSIOLOGIC    IMPORTANCE    OF    LYMPH 


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PHYSIOLOGIC    IMPORTANCE     OF    LYMPH 


10/3 


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850-855.  !945- 


CHAPTER     31 


The  peripheral  venous  system 


ROBERT    S.    ALEXANDER 


Department  of  Physiology,  Albany  Medical  College, 
Union  University,  Albany,  New  York 


CHAPTER     CONTENTS 

Anatomical  Considerations 

Structure 

Vasa  Venarum 

Innervation 

Venous  Valves 

Venous  Capacity 
Physiological  Characteristics  of  Veins 

Principles  of  Venous  Hemodynamics 

Venous  Distensibility 

Nature  of  Venous  Constriction 
Assessment  of  Venomotor  Activity 

In  Vitro  Studies 

Direct  Observation 

Inferences  from  Venous  Pressure 

Measurements  of  Pressure  Gradients 

Pressure  Measurements  in  an  Occluded  Venous  Segment 

Pulse  Methods 

Venous  Distensibility  Patterns 

Distensibility  by  Venous  Increment 
Summary  of  Venomotor  Responses 


insight  which  anyone  may  gain  into  the  function  of 
the  arterial  system  by  the  simple  registration  of  arte- 
rial blood  pressure.  As  a  consequence,  very  few 
physiologists  or  students  of  physiology  have  had  any 
personal  opportunity  to  make  observations,  other 
than  the  experiments  of  Harvey,  which  could  be 
interpreted  with  confidence  as  manifestations  of 
venous  function.  A  major  effort  of  this  presentation, 
therefore,  will  be  to  stress  the  technical  problems  of 
obtaining  reliable  information  concerning  venous 
function  and  to  review  the  degree  to  which  presently- 
imperfect  methods  have  yielded  interpretations  that 
are  in  substantial  agreement.  This  will  lead  us  to 
some  positive  convictions  about  the  functional  role 
of  the  venous  system  in  spite  of  many  unresolved  prob- 
lems of  methodology. 


ANATOMICAL  CONSIDERATIONS 


if  one  were  to  consult  textbooks  for  information 
on  venous  physiology,  the  impression  would  be  gained 
that  knowledge  of  this  subject  has  not  progressed 
since  the  classical  observations  of  William  Harvey. 
The  error  of  this  misconception  should  have  been 
laid  to  rest  by  the  excellent  review  of  Gollwitzer-Meier 
(36),  in  1932  and  the  comprehensive  monograph  of 
Franklin  (32)  published  in  1937.  The  bibliography  of 
this  monograph,  containing  well  over  1 000  references, 
is  scarcely  compatible  with  the  ignorance  of  the  subject 
which  is  often  reported.  It  is  our  impression  that  a 
major  deterrent  to  appreciation  of  our  knowledge  of 
venous  function  stems  from  a  failure  to  develop  valid 
techniques  that  can  be  applied  to  the  venous  system 
with  ease  and  technical  accuracy,  comparable  to  the 


Structure 

In  general  structural  pattern,  veins  are  composed  of 
the  same  elements  as  are  the  arteries,  but  with  some 
important  quantitative  differences.  Surrounding  the 
endothelial  lining  of  the  lumen  is  a  network  of  elastic 
and  collagenous  fibers  which  form  a  clearly  defined 
intima  only  in  the  larger  veins;  in  the  smaller  veins 
there  is  very  poor  differentiation  of  the  intimal  layer. 
Encircling  these  intimal  fibers  is  the  muscular  media, 
which  remains  essentially  a  layer  of  spirally  arranged 
smooth  muscle  fibers  without  any  major  contribution 
of  elastic  fibers.  This  lack  of  a  heavy  elastic  investment 
of  the  media  constitutes  the  major  structural  differ- 
ence between  veins  and  arteries.  Externally,  the  vessel 
is  surrounded  bv  the  meshwork  of  elastic  and  col- 


!°75 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


lagenous  fibers  constituting  the  adventitia.  The 
adventitial  layer  becomes  the  major  component  of 
the  wall  of  larger  veins. 

Another  important  difference  between  arteries  and 
veins  is  in  the  structural  relationships  adjacent  to  the 
capillary  bed.  Whereas  the  arterial  channels  possess 
significant  muscle  terminating  in  conspicuous  pre- 
capillary muscular  elements  at  the  arteriole-capillary 
junction,  minute  venules  are  devoid  of  muscle.  Con- 
verging capillaries  become  surrounded  with  a  col- 
lagenous network  to  form  small  venules  which  mav 
not  acquire  a  continuous  muscular  media  until 
diameters  of  the  order  of  0.5  mm  are  reached.  It  must 
be  clearly  recognized  on  a  purely  structural  basis, 
therefore,  that  there  is  no  mechanism  at  the  venous 
end  of  the  capillaries  capable  of  throttling  blood  flow- 
in  the  way  that  blood  flow  may  be  controlled  at  the 
arteriolar   end    (85). 

In  describing  these  general  structural  features  of 
veins,  reference  is  specifically  being  omitted  to  some 
of  the  important  variations  which  are  found  in  the 
adaptations  of  specific  venous  beds  to  local  problems. 
Bv  way  of  illustration,  suffice  it  to  say  that  in  the  long 
veins  of  the  extremities  there  is  the  development  of  a 
significant  component  of  longitudinally  oriented 
muscle  capable  of  counteracting  the  gravitational 
stresses  to  which  these  vessels  are  subjected,  while 
within  the  cranium  venules  develop  to  considerable 
size  without  the  appearance  of  any  muscular  ele- 
ments (61). 

Vasa  Yenarum 

Crucial  to  an  understanding  of  some  aspects  of 
venous  function  is  a  recognition  of  the  role  of  the  vasa 
venarum,  which  constitute  the  normal  route  through 
which  both  nutrients  and  vasoactive  substances  reach 
the  vein  wall.  Older  literature  on  this  topic  has  been 
reviewed  by  Ramsey  (76).  There  is  a  dense  network 
of  minute  vessels  in  the  adventitia  of  the  larger  blood 
vessels  which  is  particularly  conspicuous  in  veins. 
Although  some  techniques  have  failed  to  reveal  a 
penetration  of  the  capillary  plexus  into  the  media, 
adequate  methods  have  succeeded  in  demonstrating  a 
profuse  capillary  bed  extending  almost  to  the  intima 
(67).  In  addition  to  the  capillary  plexus,  there  is  clear 
evidence  of  an  accessory  duct  system,  presumably 
lymphatic  in  nature,  which  is  distributed  through  the 
adventitia  and  media. 

It  mast  be  emphasized,  however,  that  the  vasa 
venarum  do  not  penetrate  the  intimal  layer  and  drain 
through  the  local  endothelium.  Venous  drainage  from 


the  capillary  plexus  returns  to  venules  running  along 
the  superficial  layer  of  the  adventitia,  and  eventually 
drains  into  either  an  entirely  different  vein  or  a 
remote  site  of  the  same  vein.  O'Neill  has  pointed  out 
that  this  relationship  assures  that  local  obstruction  in 
a  venous  segment  will  not  block  the  flow  in  the  vasa 
venarum,  nor  can  local  pockets  of  high  intraluminal 
pressure  induce  backflow  in  the  vasa  venarum  of  the 
venous  wall.  A  similar  relationship  exists  in  the 
arteries. 

Functional  confirmation  of  the  anatomical  rela- 
tionships described  above  has  been  provided  by 
O'Neill  (67).  Extensive  damage  to  the  intima  fol- 
lowed stripping  the  tissues  surrounding  the  vein  so  as 
to  interrupt  the  vasa  venarum,  even  though  blood 
flow  was  maintained  through  the  lumen  of  the  vein. 
This  indicates  that  oxygen  and  nutrients  do  not  pass 
in  significant  amounts  from  the  lumen  into  the  sur- 
rounding tissue  of  the  vein  wall,  and  that  the  venous 
wall  is  clearly  dependent  upon  the  vasa  venarum. 
Comparable  evidence  may  be  observed  with  drugs. 
Minimal  response  to  vasoactive  agents  can  be  demon- 
strated when  the  drug  flows  through  the  lumen  of  the 
veins,  while  very  effective  vascular  responses  result 
when  the  drug  is  applied  systemically  or  topically  so 
that  it  may  reach  the  media  from  the  adventitial  side. 

This  anatomical  arrangement  seriously  handicaps 
the  study  of  functional  changes  in  the  vasa  venarum. 
In  the  case  of  arteries,  the  vascular  wall  is  supplied 
not  only  by  vessels  penetrating  from  the  adventitial 
side,  but  also  by  some  vasa  vasorum  interna  which 
penetrate  the  wall  directly  from  the  lumen.  Smith 
(83,  84)  has  taken  advantage  of  this  relationship  to  use 
the  amount  of  leakage,  in  response  to  internal  pres- 
sure changes,  from  the  surface  of  an  excised  arterial 
segment  as  a  measure  of  vasa  vasorum  flow.  A  similar 
technique  would  not  be  applicable  to  veins.  In  the 
study  of  diseased  veins,  a  further  complication  arises 
in  that  the  anatomical  pattern  changes  qualitatively 
as  well  as  quantitatively.  The  early  inflammatory 
phase  of  vascular  disease  stimulates  a  dense  invasion 
of  vascular  elements  into  the  wall  of  the  vessel  with  the 
creation  of  venous  channels  that  penetrate  the  intima 
directly  into  the  lumen  of  the  vessel,  creating  vasa 
venarum  which  have  no  counterpart  in  normal  veins. 

Innervation 

Veins  are  copiously  supplied  with  nerves  which 
Thompson  (86)  demonstrated,  in  1893,  to  be  capable 
of  producing  constriction  of  the  vein.  Bayliss  &  Star- 
ling (8)  confirmed  the  existence  of  neurogenic  veno- 


PERIPHERAL  VENOUS  SYSTEM 


IO77 


constrictor  mechanisms  and,  on  the  basis  of  changes 
in  arterial  and  venous  pressure  following  spinal 
transection,  inferred  that  the  nervous  system  must  be 
of  importance  in  maintaining  venous  tone.  Donegan 
(19)  studied  this  innervation  in  greater  detail  and 
established  that  it  was  sympathetic  in  nature.  As  with 
other  sympathetic  pathways,  localization  is  rather 
gross,  with  a  given  vein  segment  responding  to  stim- 
ulation from  several  adjacent  spinal  segments.  There 
is  now  clear  evidence  of  a  tonic  constrictor  activity 
of  this  sympathetic  innervation,  since  venous  dilation 
occurs  with  sympathectomy  (9,  54)  or  with  sym- 
patholytic drugs.  This  adrenergic  sympathetic  influ- 
ence appears  to  be  purely  constrictor  without  any 
dilator  component  (62).  Conversely,  there  appears 
to  be  no  evidence  of  parasympathetic  innervation  of 
veins.  Although  pharmacological  doses  of  cholinergic 
drugs  may  influence  venous  musculature,  neither 
parasympathetic  stimulation  nor  atropinization  have 
any  effect  on  venous  tone  (31).  Even  in  such  a  highly- 
specialized  vascular  function  as  penile  erection,  para- 
sympathetic control  appears  to  be  restricted  to  the 
arterial  side  of  the  circulation,  with  the  veins  playing 
a  purely  passive  role  (47). 

Venous  Valves 

A  unique  feature  of  the  venous  system  is  the  pres- 
ence of  venous  valves.  The  dramatic  simplicity  with 
which  the  nature  of  this  valve  action  can  be  demon- 
strated in  the  veins  on  the  dorsum  of  the  hand  remains 
one  of  the  classical  observations  of  physiology.  Clini- 
cally, the  role  of  the  venous  valves  in  the  lower  ex- 
tremities have  received  particular  attention.  The 
superficial  veins  of  the  leg,  lacking  protection  from 
surrounding  muscle,  are  often  subjected  to  prolonged 
hydrostatic  loads.  This  excessive  distension  of  the 
vessels  may  eventuate  in  valvular  incompetence.  The 
consequences  of  this  valvular  incompetence  and  its 
relation  to  venous  varicosities  and  varicose  ulcers  has 
been  analyzed  extensively  in  the  literature  on  periph- 
eral vascular  surgery.  (See  Burch,  Chapter  36.) 

This  focusing  of  attention  on  the  venous  valves  of 
the  extremities  has  distorted  an  appreciation  of  the 
significance  of  valves  in  the  venous  system  as  a  whole. 
For  example,  a  widely  prevalent  notion  is  typified  by 
the  following  statement  from  a  leading  textbook  of 
histology  (46):  "Valves  are  especially  abundant  in 
the  veins  ot  the  extremities  and  they  are  generally 
absent  from  the  veins  of  the  thorax  and  abdomen." 
In  actual  fact,  valves  or  valve-like  structures  have 
been  reported  in  most  segments  of  the  venous  system, 


although  generalizations  are  difficult  because  of  the 
marked  species  variation  which  has  been  reported 
(29).  The  distinguishing  feature  of  the  valves  in  the 
extremities  is  not  their  presence  but  the  degree  of 
competence  which  thev  exhibit;  venous  valves  in 
areas  not  confronted  with  severe  hydrostatic  strains 
are  usually  more  rudimentary  and  therefore  less 
easily  demonstrated. 

An  example  of  the  latter  type  of  valvular  structure 
in  abdominal  veins  is  illustrated  in  figure  1  from  a 
preparation  made  by  Dr.  Darrell  Davis.  This  is  a 
photograph  of  a  plastic  cast  of  venous  vessels  obtained 
by  retrograde  injection  of  a  segment  of  dog  intestine. 
Numerous  valve  impressions  are  clearly  indentifiable 
on  this  preparation.  Just  before  each  point  of  junction, 
most  of  the  tributaries  contain  a  valve.  In  every  in- 
stance the  injection  mass  terminates  with  a  bilobed 
indentation  which  clearly  represents  a  valve.  Blood 
traversing  this  venous  bed  must  pass  through  a  series 
of  valves  before  gaining  access  to  the  portal  vein. 

It  should  be  appreciated  that  figure  1  also  demon- 
strates a  relative  incompetency  of  these  valves,  in  that 
the  injection  mass  has  readily  passed  beyond  a  num- 
ber of  the  valves.  Accordingly,  in  spite  of  the  profusion 
of  valves  in  this  bed,  it  is  reasonably  easy  to  reverse 
the  flow  of  blood  in  the  intestine.  If  artery  and  vein  of 
a  loop  of  dog  intestine  are  sectioned  and  a  circuit 
re-established  whereby  the  intestinal  vein  is  connected 
to  an  arterial  supply  and  the  artery  led  out  to  a  route 
of  venous  drainage,  a  substantial  retrograde  flow  is 
observed  for  several  minutes,  eventually  becoming 
reduced  as  massive  edema  develops  from  the  abnormal 
capillary  pressure  relationships.  Measurement  of 
pressure  gradients  and  flow  demonstrates  that  retro- 
grade flow  encounters  a  resistance  of  three  to  ten 
times  the  vascular  resistance  to  forward  flow  during 


fig.  1 .  Plastic  cast  of  mesenteric  veins  of  a  dog  demonstrating 
multiple  valves.  (Preparation  made  by  Dr.  Darrell  Davis.) 


1078 


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CIRCULATION    II 


the  early  phase  of  the  reversal.  While  a  good  part  of 
this  resistance  is  undoubtedly  attributable  to  the 
valves,  the  situation  contrasts  with  that  observed 
in  healthy  veins  in  the  extremities  where  valves 
present  infinite  resistance  to  retrograde  flow  until 
very  high  pressures  are  reached. 

The  functional  contribution  of  venous  valves 
should  be  clearly  defined.  In  the  idealized  circulatory 
scheme  with  continuous  venous  flow,  the  valves  must 
necessarily  remain  open  and  hence  make  no  func- 
tional contribution.  With  intermittency  of  flow,  due, 
for  example,  to  intermittency  of  flow  in  the  peripheral 
bed,  the  valves  would  tend  to  close  during  the  inter- 
vals of  flow  cessation.  Nevertheless,  we  must  reject 
the  view  that  this  "breaking  up"  of  the  venous 
column  into  segments  relieves  the  dependent  parts 
from  the  hydrostatic  load  of  a  continuous  fluid 
column.  The  hydrostatic  gradient  is  inherent  in  the 
hydraulics  of  the  system;  energetically  the  valves 
cannot  contribute  to  the  need  for  adequate  pressure 
energy  to  overcome  the  hydrostatic  barrier  between 
dependent  parts  and  the  heart.  In  the  system  as  a 
whole,  intermittent  flow  must  preserve  the  same  mean 
pressure  gradient  as  is  required  of  continuous  flow. 

Valves  make  their  functional  contribution  by 
translating  extramurally  applied  forces  into  flow 
energy.  When  an  external  force  compresses  a  fluid- 
filled  vessel,  local  intramural  pressure  will  rise  and 
tend  to  drive  the  blood  in  both  directions  from  the 
point  of  compression.  The  actual  flow  which  will 
occur  in  the  two  possible  directions  will  be  a  function 
of  the  pressure  gradients  and  resistances  in  the  alter- 
nate directions.  The  resistance  to  retrograde  flow 
toward  the  capillary  bed  is  far  higher  than  the  re- 
sistance to  forward  flow  toward  the  heart,  and  the 
pressure  gradient,  which  normally  favors  central 
return,  would  very  strongly  favor  central  flow  the 
moment  the  retrograde  flow  combined  with  con- 
tinuing capillary  drainage  to  build  up  peripheral 
venous  pressure.  Thus  it  should  be  appreciated  that  a 
'"milking"  action  of  intermittent  venous  compression 
will  effectively  propel  blood  toward  the  heart  even 
in  the  complete  absence  of  valves.  Valves,  however, 
can  greatly  increase  the  efficiency  of  this  process  by 
producing  an  almost  immediate  rise  of  retrograde 
resistance   to   infinitv. 

The  importance  of  this  process  is  most  clearly 
demonstrated  by  the  dramatic  relief  from  orthostatic 
hypotension  which  is  produced  by  movements  of  the 
legs  and  their  associated  compressing  forces  on  the 
leg  veins.  Walking  movements  are  so  effective  in  pro- 
pelling flow  up  the  venous  channels  that  they  can 


restore  adequate  venous  return  to  the  heart  even 
when  vasomotor  tone  has  been  completely  abolished 
by  sympatholytic  drugs  (71).  Direct  measurements 
have  demonstrated  that  the  sequential  compression 
of  venous  segments  during  walking  milks  blood  up  the 
legs  efficiently  enough  to  reduce  the  pressure  in  the 
uncompressed  veins  of  the  ankle  to  less  than  one 
quarter  of  the  hydrostatic  gradient  from  the  ankle  to 
the  heart  (74).  There  is  no  question  that  such  extra- 
vascular  forces  constitute  a  significant  "booster  pump" 
(49)  for  maintaining  the  circulation.  The  idea  cham- 
pioned by  Henderson  (48),  that  muscular  activity 
acting  in  conjunction  with  the  venous  valves  was  the 
primary  "venopressor"  mechanism,  should  therefore 
not  be  dismissed  lightly,  even  though  this  mechanism 
does  not  appear  to  play  quite  such  a  comprehensive 
role  in  maintaining  venous  return  as  Henderson 
claimed  (90). 

Venous  Capacity 

Because  of  the  relatively  large  caliber  of  veins,  and 
also  the  conspicuous  venous  sinusoids  which  occur  in 
some  organs,  it  is  commonly  supposed  that  the  capaci- 
tative  function  of  the  vascular  bed  resides  dominantly 
in  the  venous  system.  The  full  functional  significance 
of  this  concept  will  be  developed  in  the  next  chapter. 
Our  concern  at  the  moment  is  confined  to  examining 
the  evidence  underlying  this  basic  assumption. 

Widely  quoted  data  in  support  of  this  venous  reser- 
voir concept  are  those  published  by  Green  (37)  calcu- 
lated from  an  analysis  of  the  intestinal  vascular  bed 
of  the  dog  reported  by  Mall.  These  data  picture  some 
70  per  cent  of  the  vascular  capacity  to  reside  in  the 
venous  system  with  62  per  cent  in  veins  greater  than 
1  mm  in  diameter.  Landis  &  Hortenstine  (58)  carried 
out  a  very  similar  calculation  based  upon  the  in- 
testinal data  of  Schleiser,  which  yielded  a  value  of 
75  per  cent  of  the  vascular  volume  within  the  venous 
system,  50  per  cent  of  the  total  being  found  in  veins 
greater  than  1  mm  in  diameter.  The  Landis  calcula- 
tion did  not  include  the  venae  cavae,  inclusion  of 
which  would  have  increased  the  percentage  of 
volume  in  the  large  veins. 

It  is  distressing,  however,  when  one  realizes  how 
little  direct  evidence  there  is  to  support  these  esti- 
mates. By  measuring  the  mean  transit  time  for  dye 
passage  between  the  femoral  vein  and  the  right 
atrium,  Milnor  &  Bertrand  (65)  were  able  to  calcu- 
late a  volume  between  these  two  sites  which  averaged 
18  per  cent  of  the  total  blood  volume.  Since  the  in- 
ferior vena  caval  system  is  a  notoriously  poor  mixing 


PERIPHERAL  VENOUS  SYSTEM 


1079 


chamber,  one  would  expect  the  true  volume  to  exceed 
that  calculated  by  this  method.  This  study  therefore 
represents  some  substantial  support  for  the  idea  that 
large  veins  represent  a  significant  contribution  to  the 
total  vascular  capacity.  On  the  other  hand,  Knisely 
and  associates  (57)  have  challenged  the  conventional 
point  of  view  with  some  data  obtained  from  plastic 
injections  of  whole  rats.  Using  a  plastic  free  of 
particulate  matter  which  flowed  freely  through  the 
circulation  when  initially  injected,  they  obtained 
casts  of  the  entire  vascular  bed.  When  these  casts  were 
fragmented,  and  the  fragments  sorted  according  to 
caliber,  over  80  per  cent  of  the  plastic  was  found  to 
be  contained  in  vessels  with  a  diameter  of  less  than 
200  n  and  only  12  per  cent  in  vessels  larger  than  700  n. 
This  study  suffers  from  the  fact  that  veins  are  col- 
lapsible, and  it  is  not  at  all  clear  that  their  method 
would  have  preserved  a  normal  degree  of  filling  of 
the  venous  system.  Nevertheless,  such  an  extreme  dis- 
crepancy between  the  relative  contribution  of  large 
vessels  and  small  vessels  to  total  vascular  capacity 
clearly  challenges  the  point  of  view  that  is  usually 
held.  The  burden  of  proof  has  been  returned  to  the 
proponents  of  the  venous  reservoir  concept  to  offer 
some  more  substantial  documentation  of  their 
hypothesis. 

Apart  from  the  question  of  total  capacity,  however, 
there  is  much  better  support  for  the  thesis  that  the 
venous  division,  together  with  the  lesser  circulation,  is 
the  most  variable  capacity  of  the  vascular  bed.  One 
very  simple  observation  leading  to  such  an  inference 
is  the  minimal  change  in  pressure  produced  by  an 
injection  into  the  venous  system  as  compared  to  the 
pressure  change  produced  by  an  injection  of  an  equal 
volume  at  the  same  rate  into  the  arterial  system.  More 
direct  evidence  on  this  point  was  presented  by  Green- 
field &  Paterson  (39),  who  compared  volume  changes 
in  the  forearm  produced  by  venous  obstruction  to 
the  volume  changes  produced  by  a  negative  pressure 
applied  to  the  whole  arm.  In  the  former  instance,  the 
increase  in  transmural  vascular  pressure  would  be 
essentially  confined  to  the  venous  side;  in  the  suction 
experiment,  the  transmural  pressure  of  all  vessels 
should  be  increased  equally.  Yet  venous  occlusion 
provided  85  per  cent  of  the  volume  increase  observed 
when  suction  was  applied  to  the  whole  arm.  A  similar 
experiment  was  reported  by  Capps  (16).  Such  data, 
together  with  venous  distensibility  characteristics  to 
be  discussed  later,  justify  reasonable  confidence  in  the 
hypothesis  that  the  venous  system  plays  an  important 
role  in  contributing  a  reservoir  of  variable  capacity 
to  the  vascular  system. 


PHYSIOLOGICAL    CHARACTERISTICS    OF    VEINS 

Principles  of  Venous  Hemodynamics 

The  most  frequent  measurement  made  of  the 
venous  system  is  the  venous  pressure.  For  the  pur- 
poses of  our  interests  however,  venous  pressure  is  of 
relatively  little  meaning.  As  competently  reviewed  by 
Landis  &  Hortenstine  (58),  venous  pressure  can  have 
profound  influence  on  capillary  dynamics  and  the 
transudation  of  fluid  across  the  capillary  endothelium. 
Central  venous  pressure  plays  a  key  role  in  cardiac 
filling  and  the  control  of  cardiac  output.  For  reasons 
that  will  be  developed  shortly,  however,  venous  pres- 
sures tell  very  little  about  the  venous  system  itself. 
Indeed,  it  can  be  fairly  stated  that  venous  pressure 
measurements  in  themselves  are  just  as  unimportant 
to  the  physiologist  interested  in  the  venous  system  as 
they  are  important  to  the  physiologist  interested  in  the 
arterial  system. 

Before  specifically  considering  the  principles  of 
hemodynamics  underlying  this  statement,  a  word  of 
emphasis  should  be  given  in  reference  to  the  implica- 
tion of  the  studies  of  Pappenheimer  (69,  70)  on  the 
capillary  bed.  He  has  lucidly  argued  that,  under 
steady-state  conditions,  the  mean  capillary  pressure 
must  be  in  equilibrium  with  the  effective  osmotic 
pressure  of  the  plasma  proteins,  excluding  lymph 
flow  which  at  best  is  a  small  fraction  of  total  blood 
flow.  Since  central  venous  pressure  shows  relatively 
small  variations  under  most  conditions,  this  indicates 
a  relatively  constant  pressure  gradient  from  capillaries 
to  the  central  veins.  Furthermore,  large  changes 
in  blood  flow  may  occur  without  significant  altera- 
tions in  either  plasma  protein  concentration  or  central 
venous  pressure,  yielding  the  apparent  paradox  of 
blood  flow  that  varies  widely  in  spite  of  a  fixed  pres- 
sure gradient.  A  corollary  to  this  is  that  the  venous 
smooth  musculature  cannot  effectively  control  blood 
flow  by  imposing  a  variable  resistance  in  the  venous 
portion  of  the  circulation.  The  role  of  the  venous 
musculature  must  therefore  be  confined  to  producing 
capacity  changes  in  the  system.  These  capacity 
changes  can  indirectly  influence  blood  flow  only 
insofar  as  more  effective  venous  return  increases 
cardiac  output,  or  higher  mean  circulatory  pressures 
increase  capillary  transudation. 

If  some  of  the  preceding  statements  appear  to  be 
in  conflict  with  irrefutable  principles  of  fluid  dy- 
namics, the  reader  must  be  reminded  that  the  venous 
system  is  a  collapsible  system  and  is  therefore  not 
governed  by  the  usual  principles  of  fluid  dynamics  in 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


cylindrical  tubes.  The  phenomenon  of  venous  col- 
lapse was  inherent  in  the  classical  observations  of 
Harvey.  It  has  remained  a  commonplace  observation 
in  the  use  of  the  height  above  the  heart  at  which  super- 
ficial veins  collapse  as  a  clinical  estimate  of  central 
venous  pressure.  Yet  the  hemodynamic  significance  of 
venous  collapse  has  been  all  too  rarely  appreciated. 

First,  it  is  important  to  note  that  '"collapse"  of 
veins  is  not  an  all-or-none  characteristic.  Complete 
collapse  of  the  vein  with  obliteration  of  its  lumen 
represents  an  obstruction  to  blood  flow  which  can 
onlv  exist  on  a  transient  basis.  The  collapse  phenome- 
non relates  to  the  fact  that  the  vein  wall  is  not  struc- 
turally self-supporting.  Energy  is  required  to  push 
the  vein  walls  out  into  a  cylindrical  configuration. 
Any  time  that  the  intraluminal  pressure  becomes 
equal  to  or  less  than  the  extravascular  pressure,  the 
venous  walls  will  tend  to  approximate  each  other  in 
an  ellipsoidal  cross  section  (73). 

This  is  best  visualized  by  examining  veins  above 
heart  level.  Hydrostatic  forces  will  act  to  drain  blood 
from  these  veins  and  create  a  negative  intraluminal 
pressure.  In  addition,  finite  tissue  pressures  always 
produce  some  degree  of  positive  extravascular  com- 
pression. In  the  absence  of  blood  flow,  such  a  vessel 
would  remain  completely  collapsed.  To  preserve 
flow  in  such  a  segment,  intraluminal  pressure  must 
be  raised  until  it  slightly  exceeds  the  extravascular 
pressure  so  as  to  open  the  collapsed  vein.  Intraluminal 
pressure  must  further  be  elevated  enough  above 
extravascular  pressure  to  provide  the  necessary  pres- 
sure head  to  produce  forward  flow  against  the  re- 
sistance it  confronts.  However,  since  a  slightly  positive 
transmural  pressure  will  widen  the  collapsed  lumen 
and  produce  a  marked  fall  in  resistance,  very  little 
pressure  gradient  is  required  to  produce  flow.  There- 
fore, the  pressure  measured  in  veins  that  are  above 
heart  level  will  be  essentially  the  same  as  the  extra- 
vascular tissue  pressure,  as  originally  emphasized  by 
Holt  (51,  52,  80).  It  follows  that  such  pressures  have 
no  hemodynamic  significance  in  the  usual  sense  of 
gradients  along  the  vascular  circuit,  and  they  are  in 
no  way  specifically  related  to  constriction  or  dila- 
tion of  the  veins. 

A  more  rigorous  statement  of  this  relationship  has 
been  clearly  set  forth  in  the  exposition  by  Brecher 
(11).  The  classical  formulation  of  the  Poiseuille  law 
for  cylindrical  tubes: 

resistance    oc    radius  * 
must  be  modified  for  collapsible  tubes  to  the  more 


complex  expression: 


Rex 


2a3b3 


in  which  R  is  resistance  and  a  and  b  are  the  major 
and  minor  axes  of  the  ellipse.  It  should  be  noted  that 
in  a  cylinder  where  a  =  b,  the  second  expression 
reduces  to  the  first.  As  an  operational  tool,  this 
formulation  of  resistance  relationships  is  rarely  of 
practical  value  to  the  physiologist  because  the  desired 
dimensions  are  not  accessible.  Nevertheless,  from  a 
theoretical  standpoint  it  defines  the  fact  that  re- 
sistance to  flow  will  increase  markedly  as  the  vessel 
progressively  collapses  to   a   flattened  ellipse. 

The  full  import  of  this  collapsibility  resides  in  the 
consequences  it  has  upon  the  significant  variables 
determining  blood  flow.  In  a  system  of  cylindrical 
tubes,  as  represented  by  the  arterial  system,  pressure 
is  normally  maintained  at  homeostatic  levels  in  the 
arterial  reservoir  and,  for  any  given  vascular  bed, 
blood  flow  is  controlled  by  resistance  changes  through 
the  activity  of  the  vascular  smooth  muscle  in  the 
arterial  supply  to  that  bed.  To  emphasize  this  point, 
one  might  consider  the  pressure  as  essentially  con- 
stant (Pa)  under  a  given  situation  and  the  significant 
variables  of  flow  (Q)  and  resistance  (Ra)  expressed  as: 

6  =  4r  x  P„ 
R„ 

In  contrast,  in  any  local  venous  bed,  the  flow  is 
obligate  since  in  a  steady  state  the  veins  must  trans- 
port the  volume  of  blood  delivered  by  arterial  inflow. 
Flow  may  therefore  be  considered  constant  and  in 
any  venous  segment  resistance  is  controlled  by  the 
local  pressure  (P,,)  which,  as  outlined  above,  must 
represent  a  small  increment  over  the  extravascular 
pressure : 

Stated  descriptively,  in  the  venous  system  operating 
under  a  state  of  partial  collapse,  local  venous  pressure 
determines  the  cross  section  of  the  ellipse  and  thereby 
adjusts  resistance  to  accommodate  the  volume  of 
flow  presented  to  the  system. 

Extending  this  analysis  further,  in  the  arterial 
system  an  increase  in  the  reference  pressure  (P„)  will 
immediately  lead  to  an  equivalent  increase  in  the 
flow  (neglecting  factors  of  vessel  elasticity  and  auto- 
regulation).  In  the  venous  system,  an  increase  in  the 
reference  flow  (Q.)  will  tend  to  increase  pressures 
slightly  along  the  venous  route.  This  will  widen  the 


PERIPHERAL  VENOUS  SYSTEM 


I08l 


0 

z 

1                                                   *// 

\                           « 1      ///« 

\             K|^ 

in 
in 

LxJ 
LEV 

(0 

a 

to 
« 

UJ 

a. 

+           \                       / 

-0                       \                                /' 

^/                                          \l                Resistance 

/                                                  1            . 

-    0    + 

* 
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Flow            -— — »^^ 

-O+i 
1          1 

ad 
ca 

CENTRAL     VENOUS       PRESSURE 

fig.   2.    Hemodynamic    relationships    in    the   venous     bed, 
apted    from   Holt    (51)    and   Brecher   (10).  Solid  lines  indi- 
te   relationships   without    compensation;    dashed    lines    indi- 

cate  relationships  with  compensation  in  arterial  inflow  resis- 
tance. "O"  pressure  refers  to  the  hydrostatic  level  of  the 
peripheral  vein. 

ellipse  and  lower  resistance  so  as  to  support  an  in- 
creased flow  without  change  in  the  total  pressure 
gradient  from  capillaries  to  heart. 

The  key  relationships  in  this  pattern  of  venous 
hemodynamics  are  illustrated  in  figure  2.  For  veins 
above  heart  level,  the  hydrostatic  column  of  blood 
descending  toward  the  heart  creates  a  potentially 
subatmospheric  intraluminal  pressure  tending  to  suck 
the  walls  of  the  vein  in  to  cause  collapse.  Typically, 
this  phenomenon  will  be  most  manifest  at  the  point 
just  before  the  venous  channel  enters  the  thoracic 
cavity,  since  in  this  region  the  negative  intrathoracic 
pressure  combines  with  the  hydrostatic  forces  to 
aspirate  blood  from  the  veins.  At  the  left  of  figure  2, 
therefore,  central  venous  pressure  is  indicated  as 
below  atmospheric  pressure;  yet  peripheral  venous 
pressure  is  maintained  at  a  definite  positive  value. 
Since  under  these  conditions  there  is  a  significant 
pressure  gradient,  an  appreciable  resistance  exists 
between  the  peripheral  and  the  central  veins.  This 
resistance  is  created  by  the  state  of  partial  collapse 
near  the  central  end  of  the  channel.  As  the  central 


venous  pressure  rises  toward  atmospheric  pressure, 
the  aspiration  effect  causing  collapse  becomes  pro- 
gressively less,  so  that  the  resistance  to  flow  progres- 
sively lowers.  Peripheral  pressure,  however,  remains 
unchanged.  As  the  central  venous  pressure  rises 
above  atmospheric  pressure,  there  continues  to  be  an 
interval  when  the  intravascular  pressure  remains 
below  the  extravascular  pressure  because  of  the 
existence  of  a  positive  tissue  pressure  in  the  area  sur- 
rounding  the   veins. 

As  the  central  venous  pressure  reaches  the  value  of 
the  extravascular  tissue  pressure,  a  dramatic  altera- 
tion occurs.  The  intraluminal  pressure  will  now  be 
sufficient  to  prevent  collapse  of  the  vein.  As  a  conse- 
quence, the  venous  channel  is  distended  and  the  more 
typical  Poiseuille  relationship  pertains.  Neglecting 
the  minor  influence  of  elastic  distension  of  the  veins, 
resistance  between  the  peripheral  and  central  veins 
remains  constant  at  a  relatively  low  value,  and  corre- 
spondingly a  relatively  constant  small  pressure  differ- 
ence exists  between  the  peripheral  and  the  central 
veins.  Peripheral  venous  pressure  will  therefore  rise 
almost    parallel    with   central    venous    pressure. 

It  is  to  be  emphasized  that  at  all  central  pressures 
below  the  level  of  tissue  pressure,  the  peripheral 
venous  pressure  remains  at  essentially  the  same  level 
as  the  tissue  pressure.  Assuming  there  are  no  changes 
in  arterial  pressure  or  resistance  factors,  a  constant 
peripheral  venous  pressure  dictates  a  constant 
capillary  blood  flow.  It  is  to  be  noted,  therefore,  that 
flow  remains  constant  in  spite  of  the  significant 
changes  in  pressure  gradient  and  resistance  along  the 
venous  route.  Once  the  central  venous  pressure  rises 
above  the  tissue  pressure,  venous  congestion  occurs 
with  a  rise  in  peripheral  venous  pressure  and  a  corre- 
sponding reduction  in  the  arteriovenous  pressure 
gradient.  This  will  have  some  influence  in  reducing 
flow  through  the  system  unless  compensated  by  other 
changes.  In  actual  fact,  a  large  rise  in  peripheral 
venous  pressure  reduces  peripheral  blood  flow  so 
that  vasodilator  metabolites  accumulate  in  the 
tissues.  The  resulting  compensatory  dilation  of  the 
arterial  inflow  channels  will  counteract  the  elevation 
of  peripheral  venous  pressure  and  maintain  constant 
flow,  as  illustrated  in  the  dashed  lines  of  figure  2. 

Any  factors  leading  to  a  change  in  the  extra- 
vascular tissue  pressure  will  produce  an  equivalent 
change  in  the  peripheral  venous  pressure,  a  corre- 
sponding alteration  in  resistance,  and  a  shift  of  the 
point  of  inflection  of  the  curves.  Flow,  however,  will 
remain  unchanged. 

Students  of  the  venous  svstem  must  wrestle  with 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


this  concept  until  they  come  to  recognize  its  profound 
implications.  While  the  application  of  Poiseuille's 
law  to  collapsible  tubes  requires  only  minor  modifica- 
tions in  arithmetic,  the  degree  of  determinacy  of  the 
respective  variables  is  radically  different.  For  example, 
there  is  a  vast  body  of  older  literature  which  demon- 
strates that  venous  pressure  is  not  altered  by  a  host 
of  physiological  factors  known  to  alter  the  regulation 
of  the  cardiovascular  system.  The  conclusion  of  these 
authors,  that  the  venous  system  therefore  played  no 
part  in  cardiovascular  regulation,  may  be  a  signifi- 
cant reason  why  most  textbooks  are  devoid  of  positive 
statements  in  regard  to  venomotor  mechanisms. 
What  these  experiments  actually  proved  was  that 
the  various  experimental  maneuvers  had  no  effect  on 
the  extravascular  tissue  pressure  which  is  the  major 
determinant  of  venous  pressure;  such  measurements 
are  completely  meaningless  in  reference  to  venous 
tone. 

It  would  be  a  serious  error,  moreover,  to  regard  the 
collapsibility  of  veins  as  a  structural  defect  in  the 
system  which  serves  no  better  purpose  than  to  com- 
plicate the  understanding  of  venous  hemodynamics. 
Since  the  venous  system  operates  in  the  same  pressure 
ranges  as  the  gravitational  forces  and  tissue  pressures 
to  which  it  is  exposed,  drastic  disturbances  would 
result  if  veins  were  rigid  tubes.  Consider,  for  example, 
an  individual  turning  a  handspring.  If  veins  were 
rigid,  there  would  be  drastic  surges  in  venous  blood 
flow  and  chaotic  alterations  in  venous  return  to  the 
heart.  More  conventional  running  and  jumping  move- 
ments would  seriously  tax  the  homeostatic  adjustment 
of  a  low  pressure  system  of  cylindrical  tubes.  The 
collapse  mechanism  serves  to  check  such  hydrostatic 
shifts  of  venous  blood.  As  soon  as  pressure  in  the 
veins  becomes  reduced  to  tissue  pressure  levels,  col- 
lapse occurs  to  throttle  flow  and  maintain  the  periph- 
eral bed  at  more  nearly  normal  functional  levels. 

Duomarco  and  associates  (22-24)  have  extended 
this  concept  of  venous  hemodynamics  to  claim  that 
the  design  of  a  collapsible  venous  system  guarantees 
that  extravascular  factors  capable  of  altering  pressure 
relationships  can  have  no  influence  on  venous  flow. 
Duomarco's  enthusiasm  for  the  teleological  magnifi- 
cence of  such  a  scheme  apparently  exceeds  the  actual 
facts.  It  must  be  appreciated  that,  with  normal 
blood  volume,  a  significant  fraction  of  the  venous  bed 
is  distended  so  that  it  does  behave  as  a  system  of 
cylindrical  tubes.  This  will  hold  for  most  of  the 
extrathoracic  veins  which  are  below  heart  level  and 
which  are  not  in  regions  subjected  to  significant 
extravascular   compression.    Furthermore,    the   work 


of  Brecher  (10)  has  established  that  phasic  pressure 
changes  are  capable  of  producing  phasic  changes  in 
flow  during  the  intervals  when  geometric  adjustments 
in  the  degree  of  collapse  are  taking  place.  Such 
phasic  pressure  changes  are  conspicuous  in  intra- 
thoracic and  intra-abdominal  veins  in  association 
with  respiration,  and  also  seem  to  be  a  characteristic 
manifestation  of  venous  vasomotion  in  the  small 
peripheral  veins  (44). 

An  additional  word  of  caution  should  be  appended 
to  emphasize  that  there  are  some  important  excep- 
tions to  generalizations  as  to  the  collapsibility  of 
veins.  This  is  particularly  true  of  venous  structures 
that  are  bound  by  connective  tissue  to  rigid  skeletal 
elements  which  prevent  their  collapse,  such  as  the 
sinuses  of  the  dura  mater  and  the  vertebral  venous 
sinuses.  In  these  vessels,  gravitational  or  respiratory 
forces  may  lower  the  intraluminal  pressure  to  values 
significantly  below  the  pressure  existing  on  the  out- 
side of  the  vessel.  A  clinical  consequence  is  the  danger 
of  air  aspiration  into  the  vascular  system  if  these 
vessels  are  opened  to  the  atmosphere  during  surgical 
procedures  or  by  accidental  trauma.  A  similar  prob- 
lem exists  to  a  lesser  degree  at  the  point  where  veins 
enter  the  chest.  The  thyroid  surgeon  is  well  aware 
that  veins  near  the  base  of  the  neck  have  sufficient 
connective  tissue  attachments  so  that  traction  may 
pull  open  an  incised  vein  that  has  not  been  securely 
ligated,  and  aeroembolism  result  when  inspiratory 
pressure  changes  lower  the  central  venous  pressure 
below    atmospheric    pressure. 

To  qualify  generalizations  about  venous  collapse, 
however,  should  not  obscure  the  importance  of  this 
phenomenon  in  venous  function  as  a  whole.  Any 
approach  to  the  venous  circulation  which  neglects 
the  collapsibility  of  veins  will  lead  to  serious  distor- 
tions of  the  hemodynamic  factors  which  control  the 
flow  of  venous  blood. 


Venous  Distensibihty 

In  view  of  the  collapsible  nature  of  veins,  a  vein 
segment  will  empty  freely  from  cut  ends,  the  vessel 
will  flatten  and  all  blood  will  leave  the  lumen  except 
for  a  minute  amount  retained  within  the  folds  on 
opposite  sides  of  the  vessel.  If  fluid  is  now  added  to 
this  collapsed  vessel,  two  theoretically  distinct  proc- 
esses will  occur.  The  first  phase  will  be  '"filling," 
during  which  the  geometry  of  the  vessel  wall  is 
restored  to  the  cylindrical  shape  without  increasing 
in  circumference.  The  succeeding  phase  will  repre- 


PERIPHERAL  VENOUS  SYSTEM 


IO83 


sent  elastic  distension  of  the  vein  segment  through 
increase  in  its  circumference  and  length. 

The  inference  sometimes  encountered,  however, 
that  the  vein  remains  at  "zero"  pressure  until  it  is 
"filled"  is  quite  unrealistic.  Some  finite  pressure  is 
required  to  restore  the  wall  to  its  cylindrical  shape. 
For  veins  in  situ,  filling  the  vein  must  also  overcome 
tissue  pressure,  and  local  tissue  pressure  will  itself 
be  augmented  by  the  swelling  of  the  vein.  Finally,  as 
fluid  starts  to  fill  the  vein,  hydrostatic  pressures  will 
be  created  unless  the  vein  is  perfectly  horizontal. 
Consequently,  if  one  records  intraluminal  pressure 
accurately  while  fluid  is  progressively  added  to  an 
empty  vein  in  vivo,  pressure  starts  to  rise  almost 
immediatelv  and  does  not  show  any  recognizable 
inflection  when  the  vein  is  "filled"  (fig.  3). 

The  pressure-volume  curves  obtained  from  venous 
segments,  or  the  tension-length  curves  obtained  from 
strips  or  rings,  are  most  commonly  described  as 
curvilinear  with  considerable  convexity  toward  the 
length  or  volume  axis.  Clark  (17)  was  the  first  to 
recognize  that  these  two  types  of  measurement  must 
be  related  by  the  Laplacian  relationship  whereby 
in  a  cylindrical  tube,  wall  tension  ( T)  increases  as  a 


function  of  pressure  (P)  and  radius  (R ) : 
T  =  P  X  R 

It  follows  that  at  small  radii,  relatively  less  wall 
tension  is  created  by  a  given  pressure  increment  than 
at  large  radii.  The  pressure-volume  curve  shows 
correspondingly  less  curvature  than  the  tension- 
length  curve. 

Figure  3  illustrates  the  volume  change  due  to  radial 
distension  as  contrasted  with  the  volume  increase  due 
to  elongation.  It  is  apparent  that  most  of  the  volume 
increment  results  from  radial  distension  within  the 
physiological  range  of  venous  pressures.  It  is  only 
above  pressures  of  30  to  40  cm  H20  that  radial  dis- 
tension becomes  restricted  to  the  relatively  low  degree 
of  distensibilitv  which  is  characteristic  of  longitudinal 
distension.  A  further  important  characteristic  of  the 
longitudinal  distension  of  veins,  that  is  not  shown  by 
such  data,  is  the  spiral  twist  which  veins  exhibit  when 
they  are  subject  to  sufficient  pressure  to  produce 
significant  longitudinal  stretch.  Presumably  because 
of  the  spiral  structures  within  the  vein  wall,  there  is  a 
definite  rotation  of  one  end  of  the  vein  in  respect  to 
the  other  end  as  the  vein  lengthens.  Teleologically, 


70 


60 


so-: 


40  — 


30- 


20- 


10 


c 

—  0 
01 

e 

u 

— ul 

en 

in     1 
t/i    I 

_UJ       J 

a.    f 
a.   1 

/  Elongation 

Radiol 
D  istension 

-  J 

'To » a  1 

"                                         VOLUME 

1               1 

—  cc 

1 

1 

fig.  3.  Volume  distensibility  of  a  segment  of  a  dog's  jugular  vein  in  vivo  88.8  mm  in  initial  length, 
prepared  by  double  ligation,  cannulation,  and  ligation  of  side  branches  through  small  skin  incisions 
with  as  little  disturbance  of  the  surrounding  tissue  as  possible.  Length  measurements  were  obtained 
directly  with  calipers;  radial  distension  was  calculated  from  the  known  length  and  volume.  Fluid 
added  at  the  rate  of  0.4  cc/min. 


1084 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


it  appears  reasonable  to  suggest  that  this  spiral  twist 
of  a  distended  vein  may  be  of  importance  in  relieving 
kinking  of  the  veins  when  the  tissue  is  mechanically 
distorted. 

Quite  a  different  curve  of  vascular  distensibility 
was  presented  by  MacWilliam  (60)  as  shown  in 
figure  4.  He  took  the  precaution  to  collect  fresh 
tissues  and  observe  their  behavior  carefully  during 
the  postmortem  period.  Shortly  after  a  segment  of 
living  vessel  was  excised,  it  developed  marked  spasm. 
This  spasm  persisted  for  many  hours  if  the  tissue  was 
kept  cool.  In  this  contracted  condition  a  stretch  curve, 
such  as  that  shown  in  the  lower  half  of  the  figure,  was 
observed.  When  the  state  of  contraction  was  elimi- 
nated by  warming  the  vessel,  a  more  conventional 
stretch  curve  was  obtained  as  shown  in  the  upper 
portion  of  the  figure.  The  marked  sigmoid  curve  ob- 
served originally  has  now  been  replaced  by  a  simple 
bow  convex  to  the  length  axis.  MacWilliam  inter- 
preted the  lower  curve  as  a  manifestation  of  the 
resistance  to  stretch  of  the  smooth  muscle,  which 
gradually  gave  way  as  tension  increased  until  even- 
tually stretch  was  restricted  by  the  elastic  and  fibrous 
tissue  of  the  vessel  wall.  The  upper  curve  lacked  this 
muscle  component,  and  therefore  revealed  the  simpler 
manifestation  of  elastic  tissue  distension.  This  change 
in  the  distensibility  pattern  was  quite  characteristic 
of  arteries;  it  was  not  so  evident  in  the  veins  studied 
bv  MacWilliam. 


BRARY     * 


Length 

fig.  4.  Stepwise  loading  of  a  ring  of  artery  which  in  the 
lower  section  was  in  a  contracted  state  from  preservation  in  the 
cold.  In  the  upper  tracing  the  identical  loading  sequence  was 
repeated  after  the  vessel  had  been  dilated  by  warming.  [From 
MacWiUiam  (60).] 


Constricted 


Total      Venous     Volume     *• 

Fic.  5.  Distensibility  patterns  recorded  from  veins  in  vivo  (4). 

A  majority  of  investigators  have  considered  this 
spasm  of  the  excised  vessel  as  a  postmortem  artifact, 
and  many  describe  techniques  employed  to  remove 
this  state  of  spasm  in  the  tissue  before  carrying  out 
studies  of  its  elastic  behavior.  The  potential  signifi- 
cance of  this  observation  of  MacWilliam  therefore 
lay  dormant  for  many  years,  until  Capps  (16)  ob- 
served the  same  type  of  curves  in  plethysmographic 
recordings  obtained  from  the  human  arm.  The  sig- 
moid type  of  distensibility  curve  was  associated  with 
constricted  veins,  and  the  smooth  bow  was  associated 
with  dilated  veins. 

More  recently  the  significance  of  this  distensibility 
pattern  of  constricted  vessels  and  of  dilated  vessels 
has  been  analyzed  by  the  author  (2-4,  78).  There  is 
now  ample  evidence  that  these  distensibility  patterns 
are  exhibited  by  living  veins  in  vivo  (fig.  5)  and,  as 
will  be  discussed  later,  their  analysis  can  serve  as  a 
useful  index  to  the  state  of  contraction  of  the  veins. 

Another  feature  of  vascular  distensibility,  which  has 
been  recognized  since  the  time  of  Roy  (79),  is  the 
marked  time  dependency  in  elastic  behavior  (1). 
This  has  been  variously  identified  as  "elastic  after- 
action," "elastic  hysteresis,"  "delayed  compliance," 
or  probably  more  properly  by  the  physical  phe- 
nomena of  "stress  relaxation,"  in  which  pressure  dissi- 
pates following  sudden  distension  to  a  constant 
volume,  and  "creep,"  in  which  volume  slowly  in- 
creases after  sudden  distension  by  a  constant  pressure. 
With  a  continuous  cycle  of  injection  and  withdrawal 
of  fluid,  this  characteristic  manifests  itself  as  a  wide 
loop  of  disparity  between  the  pressure-volume  rela- 
tionships observed  on  injection  and  the  pressure- 
volume  relationships  found  on  withdrawal  (figs.  6 
and  7).  To  a  degree,  the  width  of  this  loop  demon- 
strates time  dependency,  in  that  it  tends  to  become 


PERIPHERAL  VENOUS  SYSTEM 


I085 


60 

c 

J 

V) 

/ 1 

E 

/  / 

40 

„  u 

Id 

tr 

^3 

yV 

,/ 

to 

**'/                   *' 

IO 

20 

or 

-f^\/     y' 

a. 

~?* 

,*' 

^^<y^^ 

VOLUME    INJECTED-  cc 

—        1 

~* 

1          .  .1        — i_            i 

0  2  4  6 

fig.  6.  Continuous  injection  (upper  dashed  line)  and  with- 
drawal Kloiver  dashed  line)  of  blood  into  mesenteric  veins  of  a 
dog  at  the  rate  of  37.5  cm3/min,  compared  with  an  injection 
performed  at  the  same  rate  but  interrupted  at  three  points  for 
intervals  of  10  sec.  Note  that  the  stress  relaxation,  demonstrated 
by  the  loop  in  the  continuous  curve,  is  significantly  greater  as 
the  higher  pressures  are  reached  in  the  interrupted  curve  (38). 

narrower  at  very  fast  and  very  slow  rates  of  injection, 
being  widest  when  the  rate  of  injection  and  with- 
drawal permits  the  greatest  degree  of  stress  relaxation 
to  occur  between  the  injection  phase  and  the  with- 
drawal phase.  In  addition  to  this  simple  visco-elastic 
type  of  behavior,  moreover,  veins  also  exhibit  plastic 
properties,  in  that  the  stress  relaxation  is  minimal  at 
very  low  pressures,  and  becomes  disproportionately 
exaggerated  at  higher  pressures,  as  indicated  in 
figure  6.  It  appears  that  certain  "yield  pressures" 
are  required  to  produce  the  transformation  which 
gives  rise  to  the  stress  relaxation. 

The  complex  problem  of  the  exact  basis  for  these 
properties  of  blood  vessels  (78)  is  beyond  our  scope 
here,  but  it  should  be  appreciated  that  these  charac- 
teristics have  two  implications  of  importance  in 
evaluating  distensibility  determinations.  First,  pres- 
sure-volume data  obtained  from  veins  are  strongly 
influenced  by  the  exact  conditions  of  venous  disten- 
sion, and  data  are  never  rigorously  comparable  unless 
identical  rates  and  magnitudes  of  distension  are  used. 
Unfortunately  this  requirement  has  often  been  over- 
looked, and  a  large  bulk  of  published  data  must  be 
questioned  because  of  failure  to  impose  exactly 
defined  and  standardized  procedures  for  obtaining 
distensibility  determinations. 

A  second  important  facet  to  this  problem  is  the 
effect  of  a  repeated  stretch.  As  is  to  be  expected  of  a 
tissue  showing  a  significant  stress  relaxation,  a  second 
stretch  curve  differs  greatly  from  an  initial  stretch. 
This  characteristic  is  most  prominent  in  the  con- 
stricted vein,  in  which  the  sigmoid  pattern  of  dis- 
tensibility characteristic  of  an  initial  stretch  is  ob- 
literated   in   succeeding   stretches    (5).    Studies   have 


shown  that  20  to  30  min  are  required  for  a  complete 
restoration  of  the  initial  distensibility  pattern  follow- 
ing an  initial  stretch  of  the  tissue.  Related  to  this  is 
the  fact  that  the  distensibility  pattern  observed  on 
release  of  stretch  of  a  constricted  vessel  is  identical 
to  the  pattern  observed  with  the  release  of  stretch 
of  a  dilated  vessel  (fig.  7).  Stretch  of  the  tissue  appears 
to  "pull  out"  the  muscle  so  that  it  no  longer  con- 
tributes to  the  distensibility  characteristics  of  the  tissue 
until  considerable  time  has  elapsed  for  this  muscular 
influence  to  become  restored.  This  dictates  that  not 
only  must  precise  distensibility  data  be  gathered  with 
rigorously  defined  rates  of  stretch,  but  also  the  in- 
tervals between  stretches  must  be  rigidly  controlled. 
A  further  problem  should  be  mentioned  to  which 
there  is  at  present  no  satisfactory  answer.  Many  have 
argued  that  distensibility  data  have  no  absolute  mean- 
ing until  they  are  converted  into  terms  of  a  quanti- 
tative modulus  of  elasticity  which  relates  the  tension- 
length  or  pressure-volume  increments  to  the  initial 
length  or  volume  parameters  of  the  tissue.  There  are 
certain  practical  difficulties  which  interfere  with  ac- 
complishing this  objective.  With  in  vivo  measure- 
ments, accurate  estimates  of  initial  dimensions  are 
extremely  difficult  to  obtain  even  when  pressure  and 
volume  increments  are  readily  measured.  Further- 
more, inherent  to  the  calculation  of  an  elasticity 
modulus  is  the  assumption  of  homogeneity  of  the 
tissue,  and  some  investigators  have  questioned  whether 
a  meaningful  modulus  can  be  calculated  from  tissue 


40 

35 

OJ 

c 

NEC)/^                    /             \ 

50 

1—  en 

E 

25 

1 

LU 

3 

a.a/                  / 

20 

t/l 

—  1/1 

UJ 

or 
a. 

/         ^ 

15 

10 

^*< 

5 

VOLUME     INJECTED-   cc 
1                          1                          1                          1                          1 

fig.  7.  Injection  and  withdrawal  of  blood  at  the  rate  of  50 
cm3/min  into  mesenteric  veins  of  a  dog  constricted  by  neo- 
synephrine  (NEOj  and  subsequently  dilated  by  adenylic  acid 
(A.A.).  The  injection  curves  demonstrate  the  characteristic 
convexity  and  concavity  patterns  portrayed  in  fig.  5,  but  the 
withdrawal  curves  were  perfectly  superimposed. 


io86 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


dimensions  which  include  many  components  in  ad- 
dition to  those  controlling  the  elasticity  of  the  struc- 
ture. As  a  consequence,  most  of  the  data  in  the  liter- 
ature are  presented  as  pressure-volume  increments 
of  a  system,  the  total  volume  of  which  remains  un- 
defined. 

A  significant  point  in  this  connection  relates  to  the 
interpretation  of  the  sigmoid  distensibility  pattern 
of  the  constricted  vein  (fig.  5).  If  we  accept  the  in- 
terpretation given  that  stretch  acts  to  "pull  out"  the 
muscle  so  that  distensibility  is  eventually  restricted 
by  the  elastic  and  fibrous  tissue,  it  follows  that  at 
extreme  degrees  of  stretch  both  constricted  and  dilated 
tissues  should  possess  the  same  length  at  the  same 
tension.  The  record  in  figure  4  accords  with  this  as  a 
first  approximation,  although  actual  measurements 
reveal  a  minor  discrepancy  in  the  recorded  lengths. 
In  vivo  measurements,  by  direct  injection  (2)  and 
by  indirect  plethysmography  studies  (39),  also  sug- 
gest that  with  maximum  distension  the  volumes  of 
constricted  and  dilated  veins  converge.  Burton  (15), 
however,  has  challenged  this  interpretation,  and 
offered  evidence  that  constricted  vessels  retain  a 
smaller  caliber  than  dilated  vessels  regardless  of  how 
much  they  are  stretched.  Recent  studies  on  isolated 
tissues,  the  dimensions  of  which  can  be  accurately 
recorded,  have  thrown  additional  light  on  this  prob- 
lem (77).  There  appears  to  be  no  fixed  correlation 
between  the  unstretched  length  of  a  tissue  and  the 
pattern  of  its  distensibility  curve.  Although  repeated 
stretch  of  a  constricted  tissue  can  eliminate  the  sig- 
moid distensibility  pattern  and  yield  a  convex  curve 
indistinguishable  from  that  of  a  dilated  tissue,  this 
stretch  does  not  erase  the  shorter  unstretched  length 
of  the  constricted  tissue.  In  other  words,  the  "pulling 
out"  of  the  muscle  by  stretching  a  constricted  tissue 
does  not  transform  it  into  a  dilated  tissue.  An  ulti- 
mate resolution  of  the  nature  of  these  changes  must 
await  a  fundamental  understanding  of  tissue  elasticity, 
very  probably  extending  to  the  molecular  level  (78). 
Until  that  understanding  is  at  hand,  we  must  be 
cautious  not  to  oversimplify  the  distensibility  charac- 
teristics of  veins. 

Nature  of  Venous  Constriction 

Most  references  to  venous  constriction  visualize  a 
uniform  increase  in  tonic  activity  of  the  muscle  so  as 
to  reduce  the  caliber  of  the  vessel,  without  further 
definition  of  the  process  or  processes  involved.  There 
is  evidence,  however,  that  in  addition  to  increases  in 
venous  tone  there  are  more  extreme  and  more  sus- 


tained forms  of  venous  constriction  which  justify  the 
designation  of  "venospasms."  The  latter  may  be 
localized  or  may  involve  more  extensive  segments  of 
the  venous  bed. 

The  local  spasm  which  frequently  is  induced  by 
the  trauma  of  venipuncture  is  a  commonplace  ob- 
servation to  both  the  experimentalist  and  the  cli- 
nician. Since  this  response  cannot  be  abolished  by 
denervation,  it  must  include  a  significant  local  mecha- 
nism in  its  genesis.  Inversely  related  to  this  traumatic 
venous  spasm  may  be  the  localized  dilation  which 
can  be  evoked  by  tapping  a  vein  (33).  There  are  also 
occasional  reports  of  localized  rings  of  constriction 
in  a  venous  bed  under  conditions  where  there  appears 
to  have  been  uniform  stimulation  of  the  bed.  Such 
irregular  segments  of  constriction  are  shown  in  figure 
8,  which  illustrates  intestinal  veins  following  the 
intra-arterial  administration  of  levarterenol.  In  ex- 
treme cases,  this  pattern  of  reactivitv  may  distort  the 
vein  so  that  it  resembles  a  string  of  sausages,  with 
rings  of  constriction  separating  distended  segments. 

There  are  two  plausible  lines  of  explanation  for 
this  type  of  segmental  venospasm.  One  could  relate 
to  anatomical  or  functional  differentiation  of  different 
regions  of  the  vein  wall  in  which  certain  segments 
are  more  sensitive  to  stimulation  or  more  powerful 
in  the  magnitude  of  response  that  they  can  develop. 
Another  possible  explanation  relates  to  the  Laplacian 
phenonemon  discussed  earlier  (17).  The  moment  one 
area  of  vein  reduces  its  caliber  slightly  more  than  an 
adjacent  area,  its  mechanical  ability  to  compress  the 
lumen  increases,  even  though  the  tangential  tension 


fig.  8.  Segment  of  dog  mesentery  following  the  intra-arterial 
injection  of  levarterenol,  demonstrating  the  irregular  distri- 
bution of  constriction  sometimes  exhibited  by  veins. 


PERIPHERAL  VENOUS  SYSTEM 


1087 


in  the  wall  remains  the  same.  Much  as  in  the  classical 
soap  bubble  or  balloon  experiments,  the  smaller  ele- 
ment will  force  its  contents  into  the  larger  element. 
Although  more  information  is  needed  to  clarify  this 
phenomenon,  it  appears  worthy  of  mention  because 
of  its  possible  relationship  to  certain  aspects  of  venous 
varicosities. 

The  phenomenon  of  more  generalized  venospasm 
still  remains  largely  unsolved.  An  important  charac- 
teristic is  that  this  type  of  venospasm  involves  a  sig- 
nificant neurogenic  spread  which  influences  both 
arterial  and  venous  elements  so  as  to  throttle  blood 
flow  through  the  entire  bed.  In  experimental  venous 
thrombosis,  for  example,  the  reduction  in  blood  flow 
to  an  extremity  far  exceeds  anything  attributable  to 
the  local  mechanical  block,  apparently  due  to  reflex 
constriction  involving  all  vascular  elements  of  the 
limb  (66).  A  suggestion  as  to  the  factors  responsible 
for  the  maintenance  of  venospasm  under  these  con- 
ditions is  found  in  the  observations  of  Donegan  (19). 
In  the  presence  of  good  blood  flow  and  well-filled 
veins,  nerve  stimulation  evoked  a  brief  phasic  con- 
striction of  veins  which  resembled  the  typical  response 
of  smooth  muscle  to  nerve  stimulation.  When  a  vein 
was  poorly  filled,  on  the  other  hand,  little  detectable 
response  was  observed  unless  intense  stimulation  was 
given,  whereupon  the  vein  constricted  strongly  and 
remained  constricted  for  a  period  of  6  to  12  min.  It 
is  therefore  evident  that  venous  distension  has  an  in- 
fluence on  the  ability  of  the  venous  musculature  to 
contract  maximally,  which  is  quite  compatible  with 
the  influence  of  venoconstriction  on  venous  distensi- 
bility,  as  previously  discussed.  It  leads  us  to  the  con- 
clusion that  venospasm  is  a  phenomenon  produced 
when  dynamic  conditions  are  such  as  to  displace  the 
vein  over  to  the  bottom  of  the  sigmoid  distensibility 
curve  (fig.  5).  It  is  still  far  from  clear,  nevertheless, 
as  to  just  what  types  of  conditions  of  stimulation  can 
evoke  such  a  venospasm. 

ASSESSMENT    OF    VENOMOTOR    ACTIVITY 

In  ]'itro  Studies 

The  most  direct  method  for  studying  venous  smooth 
musculature  is  to  measure  the  reactivity  of  rings  of 
venous  tissue  in  vitro.  Rings,  circumferential  strips, 
or  spirally  cut  strips  (59)  are  most  suitable  for  such 
studies;  longitudinal  preparations  exhibit  minimal 
change.  It  was  with  such  venous  rings  that  Gunn 
&  Chavasse  (40)  first  demonstrated  clearly  that  veins 
contract  strongly  in  the  presence  of  adrenergic  drugs. 
This    adrenergic    response   has   remained    somewhat 


of  a  reference  standard  for  comparing  other  agents, 
and  for  evaluating  the  effectiveness  of  other  tech- 
niques for  measuring  venous  tone.  The  action  of  many- 
other  agents  has  been  examined  in  isolated  prepara- 
tions, so  that  there  has  developed  an  appreciable 
literature  on  the  pharmacology  of  veins  (28,  30,  61). 
Although  the  basic  importance  of  these  in  vitro  studies 
must  be  recognized,  such  techniques  give  us  limited 
insight  into  the  physiological  responses  of  veins  in 
vivo. 

Direct  Observation 

The  simplest  method  for  detecting  activity  of  the 
muscular  elements  of  a  vein  in  vivo  is  to  observe 
changes  in  the  caliber  of  the  vein.  Many  such  obser- 
vations have  been  reported  and  much  valid  infor- 
mation has  been  deduced  from  such  observations. 
As  a  general  approach  to  the  problem,  however,  this 
technique  cannot  be  accepted  as  reliable.  The  ob- 
server can  only  detect  changes  in  the  volume  of  blood 
within  the  vessel.  This  change  in  blood  volume  may 
be  caused  by  a)  changes  in  flow  through  the  periph- 
eral vascular  bed,  b)  alterations  in  the  pressure  and/or 
resistance  to  flow  in  more  central  portions  of  the 
venous  channels,  c)  changes  in  the  extravascular  tissue 
pressure,  or  finally  d)  changes  in  the  venomotor  tone 
in  the  vessel  under  observation.  Unless  the  first  three 
factors  can  be  confidently  excluded,  it  is  hazardous 
to  infer  that  the  last  factor  is  the  crucial  variable. 

It  is  rare  that  simple  observation  of  veins  will  jus- 
tify sound  conclusions  as  to  the  cause  of  changes  in 
venous  caliber.  An  exception  to  this  exists  in  some 
of  the  better  controlled  microscopic  studies  in  which 
attention  is  directed  toward  unique  vessels  in  the 
microscopic  field.  In  this  case  the  observer  has  the 
advantage  of  being  able  to  assess  directly  the  rate  of 
capillary  flow  as  well  as  the  caliber  and  flow  of  vessels 
in  parallel  and  series  with  the  vessel  under  study.  The 
contributions  of  such  studies  of  the  "microcirculation" 
are  reviewed  in  Chapter  27.  At  this  point  we  would 
only  stress  the  principle  that  any  observer  of  blood 
vessels  must  be  thinking  in  rigorous  hemodynamic 
terms  if  he  is  to  make  valid  inferences  from  his  ob- 
servations, and  refrain  from  any  conclusions  in  regard 
to  venous  tone  without  reasonably  secure  evidence 
that  other  hemodynamic  factors  are  not  the  signifi- 
cant ones. 

Inferences  from  Venous  Pressure 

It  has  already  been  emphasized  that  inferences 
about  venous  tone  based  solely  on  venous  pressure 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


are  virtually  worthless.  Large  portions  of  the  venous 
bed  are  in  a  state  of  partial  collapse,  in  which  case 
pressures  are  not  conditioned  by  vascular  tone  but 
b\  the  interplay  of  extravascular  pressures  with  intra- 
vascular dynamics.  The  small  magnitude  of  venous 
pressure  further  complicates  the  problem,  since  an 
adequate  definition  of  zero  reference  levels,  appro- 
priate to  the  specific  conditions  of  the  experiment, 
is  often  extremely  difficult.  Finally,  in  situations  where 
venomotor  activity  exhibits  any  significant  change, 
there  are  usually  associated  changes  in  cardiac  ac- 
tivitv  and  blood  flow  which  produce  passive  changes 
in  venous  pressure.  These  further  confound  any  valid 
assessment  of  venous  tone. 

Measurement  of  Pressure  Gradients 

Errors  in  attempting  to  draw  inferences  from  iso- 
lated venous  pressure  might  be  reduced  by  measuring 
successive  venous  pressures  along  the  venous  gradient 
in  conjunction  with  determinations  of  blood  flow. 
Unfortunately,  this  approach  is  still  confronted  by 
the  obstacle  of  collapse  phenomena,  aggravated  in 
the  case  of  intrathoracic  and  intra-abdominal  veins 
by  respiratory  variations  in  extravascular  pressure. 
The  author  is  not  alone  among  investigators  who 
have  spent  frustrating  hours  attempting  to  interpret 
pressure  gradients  in  such  veins. 

An  older  method  for  surmounting  this  obstacle  in 
the  larger  veins  was  introduced  by  Donegan  (19). 
He  selected  appropriate  vein  segments  which  could 
be  isolated  and  perfused  artifically,  at  sufficient  rates 
to  keep  them  well  distended,  and  could  yield  mean- 
ingful pressure  gradients.  By  judicious  selection  of 
the  segment  to  be  perfused,  it  is  possible  to  preserve 
innervation  to  the  vein  and  thus  study  the  normal 
venomotor  responses  of  such  a  vein  segment  in  vivo. 
This  technique  has  yielded  a  great  deal  of  significant 
information  in  the  hands  of  Fleisch  (25),  Gollwitzer- 
Meier  (35,  36),  and  others.  Unfortunately  such  prepa- 
rations are  rather  difficult  to  prepare  and  maintain 
in  good  reactive  condition,  perhaps  due  to  the  trauma 
of  isolation  and  double  cannulation,  possible  inter- 
ferences with  vasa  venarum  circulation,  temperature 
changes,  and  other  artifacts  introduced  by  the  arti- 
ficial perfusion.  Fleisch  particularly  stresses  the  pre- 
cautions which  must  be  observed  if  a  reactive 
preparation  is  to  be  obtained.  This  technique  can 
therefore  only  be  trusted  when  significant  positive 
results  are  obtained;  it  is  difficult  to  dissociate  valid 
negative  responses  from  deterioration  of  the  prepa- 
ration. 


Another  method  of  avoiding  the  collapse  problem 
would  be  to  proceed  out  far  enough  into  the  periph- 
eral venous  system  to  areas  of  steeper  pressure  gradi- 
ents and  higher  absolute  pressure  levels,  preferably 
in  superficial  areas  where  one  can  be  confident  that 
extravascular  pressures  will  never  approach  the  order 
of  magnitude  of  intravascular  pressures.  A  very  sig- 
nificant advance  is  therefore  represented  by  the  work 
of  Haddy  (27,  41-45)  who  has  employed  fine  plastic 
catheters  and  passed  them  in  a  retrograde  direction 
into  minute  peripheral  blood  vessels,  such  as  those  of 
the  paw.  This  retrograde  catheterization  must  avoid 
areas  with  valves.  By  simultaneously  recording  pres- 
sures from  minute  vessels  approached  from  both  the 
arterial  and  the  venous  sides,  and  also  from  the  corre- 
sponding large  arteries  and  veins,  he  has  been  able 
to  plot  the  pressure  gradient  through  the  total  vascular 
bed.  When  combined  with  flow  measurements,  the 
flow  resistance  of  each  segment  of  the  bed  may  be 
calculated.  As  has  been  previously  discussed,  moderate 
changes  in  the  pattern  of  flow  resistance  and  pressure 
gradient  in  local  segments  of  the  peripheral  venous 
bed  may  not  produce  any  alterations  in  the  total 
capillary-to-heart  pressure  flow  gradient;  yet  these 
changes  will  signify  alterations  in  venous  tone  and 
the  shifts  in  venous  capacity  which  presumably  result. 
With  more  intense  venoconstrictor  responses,  venous 
resistance  may  become  elevated  to  the  point  that 
capillary  pressure  rises,  in  which  case  this  technique 
also  becomes  a  very  useful  adjunct  to  the  study  of 
factors  leading  to  tissue  edema  (41). 

This  technique  has  proven  quite  fruitful  in  the 
analysis  of  the  effect  of  a  variety  of  agents  on  the  pe- 
ripheral venous  system.  One  example  is  shown  in 
figure  9.  The  upper  part  of  this  figure  indicates  the 
pressures  recorded  from  the  vessels  in  the  foreleg  of  a 
dog  that  was  being  perfused  artificially  at  a  constant 
rate;  below  are  plotted  the  resistances  calculated  from 
the  flow  and  pressure  gradient  data.  On  the  left  of 
the  figure,  the  innervation  was  intact  and  vascular 
tone  was  high,  as  reflected  in  a  high  arterial  pressure. 
Administration  of  5-hydroxytryptamine  (serotonin) 
produced  a  significant  drop  in  pressure  and  resistance 
on  the  arterial  side,  particularly  in  the  smaller  vessels, 
attributed  to  antagonism  of  the  adrenergic  constrictor 
mechanism.  In  contrast,  there  was  a  dramatic  rise 
in  small  vein  pressure,  interpreted  as  due  to  a  direct 
constrictor  action  of  this  drug  on  the  veins.  Following 
denervation,  the  right  of  the  figure  indicates  a  low 
initial  pressure  on  the  arterial  side  because  of  a  loss 
of  sympathetic  tone.  Under  these  conditions,  5-hy- 
droxvtn  ptamine  is  observed  to  produce  a  significant 


PERIPHERAL  VENOUS  SYSTEM 


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fig.  9.  Pressure  gradients  and  resistance  changes  recorded 
from  the  foreleg  and  paw  of  a  dog  that  was  artificially  perfused 
at  a  constant  rate  of  flow,  demonstrating  the  application  of  the 
Haddy  technique  (45). 

constriction  of  the  large  arteries  and  veins,  and  only 
a  minor  change  in  the  smaller  vessel  segment. 

The  fact  that  pressures  in  minute  vessels  show  con- 
siderable pulsatile  variation  (41,  55),  presumably 
associated  with  a  type  of  venovasomotion  (44),  renders 
such  measurements  of  greater  qualitative  than  quan- 
titative value,  since  it  is  difficult  to  have  faith  that 
the  discrete  vessel  from  which  the  peripheral  pressure 
was  recorded  is  accurately  representative  of  the  mean 
pressure  in  the  peripheral  venous  bed  as  a  whole. 
This  reservation  is  reinforced  by  the  possibility  that 
the  catheter  might  be  wedged  so  that  the  recorded 
pressure  represents  that  of  a  collateral  somewhat 
remote  from  the  catheter,  and  also  the  possibility 
that  the  presence  of  the  catheter  itself  might  alter 
pressure-flow  dynamics.  Nevertheless,  if  one  keeps 
these  reservations  in  mind,  and  takes  precautions  to 
be  extremely  critical  of  instrumental  techniques  and 
record  analysis  so  as  to  exclude  the  many  possible 
artifacts  which  may  creep  into  a  method  of  this  type, 
this  appears  to  be  one  of  the  most  valuable  techniques 
currently   available   for   studying   peripheral   venous 


function.  It  should  be  appreciated  that  this  method 
also  has  the  merits  of  being  applicable  to  human 
studies  (88). 

Pressure  Measurements  in  an 
Occluded  Venous  Segment 

Doupe  and  associates  (20)  appear  to  have  been 
the  first  to  have  employed  the  method  of  isolating  a 
segment  of  a  superficial  vein  between  a  pair  of  com- 
pressing wedges.  If  the  wedges  are  placed  so  that  the 
intervening  segment  is  free  of  branches,  this  creates 
a  blind  cul-de-sac  with  an  entrapped  volume.  If  a 
needle  is  then  carefully  introduced  into  this  segment, 
it  is  possible  to  record  pressures  in  a  system  of  fixed 
volume,  hence  any  change  in  pressure  must  reflect  a 
change  in  the  muscle  tone.  In  actual  practice,  it  ap- 
pears to  be  necessary  to  distend  the  vein  with  a  con- 
siderable volume  increment  so  as  to  yield  basal  pres- 
sures of  the  order  of  40  to  60  cm  H20  in  order  to 
achieve  significant  pressure  changes.  This  also  serves 
the  purpose  of  elevating  the  recorded  pressure  out  of 
the  range  of  confusion  with  extravascular  pressure 
effects. 

A  recording  from  such  a  preparation  is  illustrated 
in  figure  10.  This  illustrates  one  feature  that  is  con- 
spicuously demonstrated  by  this  technique:  the 
marked  influence  of  psychic  stimulation  on  venomotor 
response  as  the  experimental  subject  witnesses  the 
preparation  of  some  experimental  maneuver  which 
he  is  to  undergo.  Since  responses  of  the  type  illu- 
strated in  figure  10  disappear  after  sympatholytic 
drugs,  there  can  be  little  doubt  as  to  their  venomotor 
origin.  This  technique  has  been  exploited  with  con- 
siderable success  (14,  68)  and  is  the  most  direct  quali- 
tative method  for  studying  the  venous  reactions  of 
the  human  subject.  Because  it  concerns  itself  with  a 
unique  venous  segment,  however,  it  does  not  appear 
feasible  to  standardize  the  quantitation  of  pressure 
responses  observed  in  such  studies. 

A  variation  of  this  technique  is  to  introduce  a  small 
cylindrical  balloon  into  a  vein  segment  and  measure 
pressure  changes  in  this  balloon.  This  obviates  the 
necessity  of  selecting  a  segment  free  of  branches,  and 
gives  greater  confidence  that  the  observations  are 
being  obtained  from  a  closed  system.  As  with  the 
method  previously  described,  it  also  seems  essential 
to  distend  the  balloon  to  pressure  of  30  cm  H20  or 
higher  in  order  to  observe  significant  changes.  Salz- 
man  (81)  has  successfully  applied  this  technique  to 
the  study  of  the  venomotor  response  to  pressoreceptor 
reflexes.  Connolly  &  Wood  (18),  on  the  other  hand. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


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fig.   io.  Pressure  changes  recorded  from  a  segment  of  a  superficial  vein  of  the  forearm  that  had 
been  isolated  between  wedges  and  kept  at  constant  volume.  [From  Duggan  et  al.  (21).] 


were  unable  to  record  temperature  reactions  in 
superficial  veins  in  man  by  this  technique,  even 
though  veins  adjacent  to  that  containing  the  balloon 
exhibited  obvious  caliber  changes.  The  author  has 
similarly  been  unsuccessful  in  attempting  to  get  suffi- 
cient response  for  accurate  analysis  in  a  variety  of 
applications  of  this  technique  to  various  dog  prepa- 
rations. Further  studies  are  in  order  to  determine  the 
full  potentialities  and  limitations  of  this  method. 

Another  type  of  method  which  is  based  on  the 
same  principle  was  introduced  by  Hooker  (54)  and 
has  been  adapted  to  human  studies  by  Wallace  (87, 
88).  By  use  of  a  pressure  cuff  on  the  arm,  pressure 
is  first  developed  to  occlude  venous  drainage  and 
produce  venous  congestion,  and  then  further  elevated 
to  stop  all  blood  flow  to  the  arm.  Venous  pressures 
measured  between  2  and  8  min  after  obstruction  to 
blood  flow  show  a  slow  decline,  presumably  due  to 
capillary  transudation.  Yenomotor  stimulation  pro- 
duces pressure  changes  superimposed  on  this  slow 
decline.  Although  this  method  has  yielded  clear  quali- 
tative evidence  of  venomotor  reactions  (64),  and 
possibly  has  some  merits  of  simplicity,  it  introduces 
a  number  of  complicating  features,  such  as  prolonged 
ischemia,  which  would  vitiate  precise  quantitation 
and  therefore  place  it  in  an  unfavorable  position  as 
compared  with  other  methods  that  are  available. 

Pulse  Methods 

Pulsatile  changes  in  the  volume  contained  within 
a  vascular  segment  will  produce  pulsatile  pressure 
changes,  the  magnitude  and  rate  of  transmission  of 


which  are  determined  by  the  elastic  properties  of  the 
vessel  wall.  Since  muscle  tone  is  one  of  the  factors 
influencing  elasticity  of  the  venous  wall,  this  suggests 
another  possible  approach  to  an  assessment  of  ven- 
omotor tone.  Unfortunately,  the  pulsations  which 
occur  normally  in  the  venous  system  are  too  small 
in  magnitude  and  too  complex  in  etiology  to  be  sus- 
ceptible to  this  type  of  analysis. 

Peterson  (72,  73)  has  overcome  this  limitation  by 
generating  pulses  artificially  with  a  high  speed  in- 
jection system.  There  results  a  momentary  peak  of 
pressure  which  increases  in  magnitude  as  venous  tone 
increases.  As  yet,  limited  applications  of  this  type  of 
method  have  been  reported.  The  author  has  had 
extensive  experience  with  a  related  phenomenon  that 
he  has  referred  to  as  the  ""acceleration  transient" 
which  appears  at  the  moment  of  initiating  a  constant 
speed  injection  into  a  vein.  It  is  clear  that  many  de- 
tails at  the  tip  of  the  injection  cannula  can  influence 
the  pressure  peak  produced.  The  exact  dimensions 
and  orientation  of  the  injection  orifice  in  relation  to 
the  vessel  lumen  are  of  critical  importance  in  deter- 
mining the  exact  pattern  of  pressure  development, 
and  this  problem  can  be  gravely  augmented  by  the 
tendency  for  some  veins  to  develop  a  segment  of  local 
constriction  in  the  area  of  cannulation.  Extending 
the  orifice  to  a  site  somewhat  remote  from  the  point 
of  cannulation  introduces  problems  of  proper  orien- 
tation of  the  injection  tip,  and  also  requires  pressure 
recording  through  a  separate  channel  in  order  to 
prevent  the  flow  resistance  of  an  elongated  injection 
cannula  from  dominating  the  pressure  recording. 
Although  the  potentialities  of  such  a  pulse  method 


PERIPHERAL  VENOUS  SYSTEM 


iogi 


should  not  be  overlooked,  at  present  it  has  not  been 
developed  to  the  point  that  it  can  be  applied  to  the 
accurate  measurement  of  venous  tone. 

Venous  Distensibility  Patterns 

As  has  been  pointed  out  in  reference  to  figure  5, 
constriction  of  a  vein  alters  its  distensibility  diagram. 
The  maximally  dilated  vein  exhibits  a  smooth  curve 
convex  toward  the  volume  axis.  As  progressively 
more  constriction  occurs,  the  distensibility  curve  is 
transformed  into  a  sigmoid  form  showing  initially  a 
relatively  rapid  rise  in  pressure  with  initial  volume 
increments,  a  very  much  slower  pressure  rise  as  inter- 
mediate volumes  are  added,  and  then  a  final  steep 
rise  in  pressure  as  still  further  volume  is  introduced. 
If  the  rate  of  venous  distension  is  carefully  controlled 
so  as  to  prevent  stress  relaxation  effects  from  dis- 
torting the  slopes  of  these  curves,  evidence  of  venocon- 
striction  should  be  obtainable  from  studies  of  the 
shape  of  the  distensibility  curve. 

The  first  application  of  this  principle  was  presented 
by  Capps  (16)  using  a  plethysmographic  method  on 
the  human  forearm.  The  use  of  the  plethysmographic 
technique  for  venous  distensibility  measurements 
was  a  logical  outgrowth  of  measurements  of  blood 
flow  by  the  Hewlett  &  Van  Zwaluwenburg  method 
(50).  In  the  latter  method,  while  the  distal  portion 
of  the  arm  is  enclosed  in  a  plethysmograph  to  record 
arm  volume,  a  pressure  cuff  around  a  proximal  por- 
tion is  suddenly  inflated  to  a  pressure  slightly  less 
than  the  arterial  diastolic  pressure.  This  suddenly 
blocks  venous  outflow  from  the  arm  without  any 
immediate  interference  with  arterial  inflow,  and 
hence  the  arm  will  increase  in  volume  at  a  rate  equal 
to  the  rate  of  blood  flow  into  the  arm.  After  a  short 
interval,  this  blood  flow  will  be  reduced  by  the  pro- 
gressive congestion  of  the  distal  vascular  bed.  The 
point  is  reached  eventually  where  arm  volume  be- 
comes relatively  stable,  and  this  must  mean  that 
venous  pressure  has  increased  to  equal  cuff  pressure 
so  that  venous  blood  will  be  forced  past  the  occluding 
cuff  at  a  rate  equal  to  the  reduced  inflow  rate.  As 
has  been  pointed  out  earlier,  the  most  significant 
factor  in  the  change  in  the  volume  of  the  arm  under 
these  conditions  is  the  congestion  of  the  venous  bed 
(17,  39).  Therefore,  using  stepwise  increments  in 
pressure  in  the  occluding  cuff  yields  a  series  of  incre- 
ments in  arm  volume  which,  as  a  reasonably  good 
first  approximation,  represents  the  increase  in  venous 
volume  at  the  corresponding  occluding  pressures. 
With  this  method,  Capps  obtained  clear  evidence  of 


a  sigmoid  distensibility  curve  in  veins  constricted  by 
cold  and  other  venoconstrictor  stimuli,  while  dilated 
veins  exhibited  a  typical  convex  distensibility  pattern. 

Many  subsequent  authors  have  reported  on  veno- 
motor  reactions  using  the  plethysmographic  method. 
A  number  of  modifications  in  technique  have  been 
introduced  to  minimize  the  artifact  associated  with 
inflation  of  the  pressure  cuff,  and  to  permit  accurate 
pressure  reference  levels.  Errors  in  the  pressure-volume 
determinations  due  to  unequal  distribution  of  pres- 
sure in  the  transitional  zone  at  the  margin  of  the 
plethysmograph  may  be  corrected  by  use  of  a  double 
plethysmograph.  Both  compartments  are  exposed  to 
equal  pressures,  but  only  the  distal  segment  is  used 
for  volume  recording  (93).  Burch  (12)  has  used 
another  method  to  correct  for  the  occlusion  artifact 
in  developing  the  plethysmographic  technique  for 
use  on  the  digit.  By  measuring  the  volume  change 
produced  by  the  venous  occlusion  cuff  during  an 
interval  when  all  blood  flow  had  been  arrested  by 
arterial  compression,  he  obtains  an  uncomplicated 
record  of  the  artifact  alone,  which  can  be  subtracted 
from  the  blood  flow  curves.  When  these  corrected 
curves  are  compared  with  unoccluded  digital  pulse 
curves,  he  feels  that  he  can  analyze  arterial  inflow 
and  venous  outflow  dynamics  with  sufficient  accuracy 
to  quantitate  the  phasic  changes  that  occur  during 
each  pulse  wave. 

Other  plethysmographic  devices,  such  as  the  mer- 
cury-in-rubber  resistance  strain  gauge  (89)  or  the 
impedance  plethysmograph  (75),  may  be  adapted 
for  venous  studies,  although  the  simplicity  of  their 
application  should  not  encourage  neglect  of  estab- 
lishing their  quantitative  reliability. 

There  is  one  inherent  difficulty  in  the  plethysmo- 
graphic method  for  distensibility  determinations, 
however,  which  in  the  opinion  of  the  author  has  not 
been  adequately  resolved.  The  sudden  increment  in 
venous  outflow  pressure  will  have  its  most  direct 
effect  in  elevating  venous  pressure;  to  a  lesser  extent 
it  will  elevate  capillary  pressure,  and  to  a  slight  ex- 
tent it  will  elevate  the  distal  portions  of  the  arterial 
pressure  gradient.  This  justifies  the  assumption  that 
most  of  the  immediate  volume  change  will  occur  on 
the  venous  side,  an  assumption  which  has  been  rea- 
sonably well  substantiated.  On  the  other  hand,  the 
elevated  capillary  pressure  promotes  capillary  transu- 
dation, so  that  the  recorded  volume  never  reaches  a 
true  plateau,  but  shows  a  slow  increase  persisting 
after  the  initial  major  increase.  Owing  to  the  time- 
dependent  characteristics  of  vascular  elasticity,  more- 
over,  venous  distension  occurs  rapidly   at  first  and 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


then  distends  more  slowly  toward  its  equilibrium 
condition.  As  a  consequence,  volume  increase  due 
to  the  delayed  distension  of  the  veins  merges  indis- 
tinguishably  with  the  volume  increase  due  to  capillary 
leakage.  One  might  attempt  to  control  this  problem 
by  using  rigorously  standardized  intervals  of  pressure 
exposure  before  reading  the  volume.  Since  the  magni- 
tude of  the  effect  increases  as  higher  pressures  are 
reached,  however  (cf  fig.  6),  virtually  all  reports  of 
the  use  of  the  plethysmography  technique  have  de- 
scribed vague  and  highly  subjective  criteria  for  select- 
ing the  end  point  at  which  to  read  the  volume.  There 
results  a  random  scatter  of  the  determined  points 
which  often  obscures  the  actual  form  of  the  distensi- 
bility  curve.  Therefore  most  recent  authors  have 
abandoned  any  attempt  to  interpret  the  form  of  the 
curve,  and  base  their  interpretations  solely  on  the 
total  volume  increment  between  two  arbitrary  pres- 
sure levels.  We  will  return  to  consider  the  significance 
of  this  type  of  interpretation  after  first  considering 
other  techniques  which  have  focused  on  the  form  of 
the  distensibility  curve. 

The  author  has  developed  a  method  based  upon 
the  change  in  distensibility  pattern  of  intestinal  veins 
in  the  dog.  After  surgical  isolation  of  the  blood  flow 
through  an  intestinal  loop,  the  circulation  is  momen- 
tarily interrupted  while  blood  is  injected  in  a  retro- 
grade direction  into  the  venous  bed.  By  dividing 
the  volume  change  required  to  raise  the  venous  pres- 
sure from  10  to  20  cm  saline  into  the  volume  change 
required  to  raise  the  pressure  from  20  to  30  cm  saline, 
it  is  possible  to  calculate  a  "venomotor  index"  which 
expresses  numerically  the  degree  of  sigmoid  curvature. 
This  method  has  been  standardized  by  use  of  a  motor- 
driven  syringe  and  accurate  timing  of  the  injections 
so  that  highly  reproducible  readings  can  be  obtained, 
permitting  following  changes  in  venomotor  tone  in 
an  animal  over  a  period  of  several  hours  (5).  Also, 
if  injection  rates  are  adjusted  so  as  to  yield  equivalent 
rates  of  pressure  rise  in  preparations  of  different  sizes, 
reasonably  quantitative  comparisons  can  be  made 
between  different  animals. 

Unfortunately,  this  method  is  not  without  its  limi- 
tations. There  remain  some  unanswered  questions 
as  to  the  exact  nature  of  such  a  retrograde  injection. 
The  method  was  originally  designed  on  the  assump- 
tion that  there  were  no  valves  in  this  bed.  Since  India 
ink  injections  invaded  the  minute  vessels  of  the  viscus, 
and  yet  there  was  no  suggestion  of  any  rise  in  pressure 
on  the  arterial  side  of  the  loop,  there  was  an  empiri- 
cal basis  for  accepting  with  some  confidence  that 
the  distensibility  measurements  were  representative 


of  the  venous  bed.  Recognition  that  these  veins  are 
in  fact  well  supplied  with  valves  of  rather  poor  com- 
petence (fig.  1)  raises  the  question  as  to  whether  the 
valves  might  be  making  some  contribution  to  the 
pattern  of  the  distensibility  curves.  To  admit  this 
possibility,  however,  would  not  alter  the  actual  inter- 
pretation of  the  data.  The  retrograde  pressure  re- 
quired to  force  blood  past  a  valve  must  be  a  function 
of  the  muscular  tone  in  the  wall  of  the  vessel.  A  dilated 
vein  should  develop  valvular  incompetence  quite 
readily,  while  a  constricted  vein  should  be  able  to 
withstand  somewhat  higher  back  pressures  before 
developing  incompetence.  Such  valve  action  might 
act  to  exaggerate  the  degree  of  sigmoid  curvature 
in  the  distensibility  of  a  constricted  venous  bed,  but 
this  would  reinforce  rather  than  detract  from  the 
acceptance  of  the  degree  of  sigmoid  pattern  as  an 
index  to  the  degree  of  venoconstriction. 

A  more  serious  difficulty  relates  to  the  moderately 
extensive  surgical  preparation  required  in  the  tech- 
nique for  setting  up  the  loop,  which  taxes  the  com- 
pensatory ability  of  the  animal.  Any  further  major 
manipulation,  such  as  an  open-chest  procedure,  often 
leads  to  deterioration  of  its  circulatory  status.  This 
method  is  also  restricted  to  the  analysis  of  pressure- 
volume  increments;  a  satisfactory  quantitation  of  the 
total  venous  volume  has  not  yet  proved  feasible.  This 
negates  some  of  the  potential  value  of  obtaining  a 
quantitative  index,  since  it  cannot  be  related  in  mean- 
ingful terms  to  total  circulatory  function.  Although 
this  is  a  defect  which  this  technique  shares  in  common 
with  most  other  methods  for  assessing  the  functional 
activity  of  the  peripheral  venous  bed,  it  is  important 
not  to  lose  sight  of  the  ultimate  goal  of  being  able  to 
evaluate  quantitatively  the  contribution  of  the  pe- 
ripheral venous  bed  to  over-all  circulatory  dynamics. 

A  further  extension  of  this  general  method  has 
recently  been  introduced  by  Bartelstone  (7),  wfho 
has  studied  the  pattern  of  pressure  development  be- 
hind a  sudden  obstruction  of  the  vena  cava.  His  re- 
sults also  afford  evidence  of  the  sigmoid  distensibility 
pattern  which  develops  with  venous  constriction, 
although  in  this  method  the  quantitative  interpreta- 
tion is  complicated  by  simultaneous  changes  in  flow. 

Distensibility  by  Volume  Increment 

As  implied  above,  the  plethysmographically  re- 
corded distensibility  of  the  venous  bed  has  been  sub- 
jected to  two  types  of  interpretation.  Capps  stressed 
the  pattern  of  the  data,  with  the  constricted  veins 
showing  relatively  less  distensibility  at  low  pressures 


PERIPHERAL  VENOUS  SYSTEM 


I093 


and  greater  distensibility  at  intermediate  pressures. 
A  majority  of  authors,  however,  have  stressed  the 
increment  in  volume  between  two  arbitrary  pressures, 
and  interpreted  a  decrease  in  the  volume  change  be- 
tween these  two  pressures  as  an  indication  of  venous 
constriction. 

To  argue  that  a  decreased  volume  increment  is  an 
indication  of  venoconstriction  might  appear  to  repre- 
sent a  conflict  with  our  previous  discussion  of  dis- 
tensibility patterns.  The  great  distensibility  of  the 
constricted  vein  over  the  intermediate  range  of  the 
sigmoid  curve  would  seem  to  demand  a  great  total 
distensibility  in  the  constricted  vein.  As  can  be  ap- 
preciated by  reference  back  to  figure  5,  however,  a 
comparison  of  the  volume  increments  in  constricted 
and  dilated  veins  between  any  two  arbitrary  pressures 
will  yield  different  relationships  at  different  pressure 
levels.  In  the  experiment  shown  in  figure  7,  for  ex- 
ample, the  injection  happens  to  have  been  stopped 
at  the  point  that  the  pressure-volume  relationships 
in  the  constricted  and  dilated  veins  were  virtually 
identical;  a  comparison  of  the  total  pressure-volume 
increment  would  offer  no  suggestion  of  the  significant 
differences  in  distensibility  above  and  below  this 
particular  point. 

The  author  is  not  aware  of  any  data,  obtained  with 
sufficient  precision  to  identify  the  pattern  of  the  dis- 
tensibility curve,  in  which  apparent  discrepancies 
in  the  interpretation  of  decreased  venous  distensi- 
bilities  cannot  be  resolved  by  reference  to  the  pressure 
level.  To  illustrate  this  point,  the  data  in  figure  1 1 
were  taken  from  a  report  of  a  reasonably  well-stand- 
ardized application  of  the  plethysmographic  method 
and  described  by  the  authors  as  a  "'typical"  response. 


fig.  1 1 .  Volume  increments  in  the  human  forearm  recorded 
by  congesting  the  veins  to  successively  higher  pressure.  Open 
circles  indicate  control  values;  solid  circles  are  the  volumes 
determined  while  infusing  noradrenaline  at  the  rate  of  0.4 
jug/min.  [Redrawn  from  Glover  el  al.  (34).] 


The  authors  interpreted  these  data  as  demonstrating 
that  noradrenaline  acts  to  decrease  venous  disten- 
sibility. One  cannot  argue  with  such  an  interpretation 
as  a  correct  description  of  the  data  as  far  as  they  go. 
Nonetheless,  this  interpretation  ignores  the  different 
form  of  the  curves.  Although  the  control  data  ex- 
hibit a  relationship  convex  to  the  volume  axis,  the 
data  recorded  during  noradrenaline  infusion  are 
clearly  concave  to  the  volume  axis.  These  data  are 
therefore  completely  compatible  with  the  pattern 
interpretation  used  by  Capps  and  generalized  in 
figure  5.  An  extrapolation  of  the  curves  in  figure  1 1 
to  higher  pressures  would  clearly  lead  to  a  relative 
increase  in  the  total  distensibility  of  the  constricted 
vessels  and  a  relative  decrease  in  the  total  disten- 
sibility of  the  dilated  vessels.  Unfortunately,  since 
the  plethysmographic  method  cannot  be  used  effec- 
tively when  venous  congesting  pressures  approach 
arterial  pressures,  this  technique  does  not  appear 
suitable  for  bringing  out  the  full  sigmoid  distensibility 
pattern  in  these  veins.  It  should  be  recognized  that 
veins  in  the  extremities  are  subjected  to  much  greater 
hydrostatic  loads  than  are  visceral  veins,  and  there- 
fore it  would  not  be  at  all  surprising  to  discover  that 
much  higher  pressures  were  required  to  achieve  the 
full  sigmoid  pattern  in  arm  veins. 

It  is  of  interest  to  note  that  a  similar  argument  has 
arisen  in  reference  to  isolated  vein  preparations. 
Leonard  &  Sarnoff  (59)  state  unequivocally  that  a 
constrictor  drug  always  reduces  venous  distensibility. 
Inspection  of  the  Leonard  and  Sarnoff  report, 
however,  reveals  a  definite  alteration  of  the  pattern 
of  their  distensibility  data  which  is  quite  compatible 
with  the  suggestion  that  sufficient  stretch  will  even- 
tually reveal  a  very  significant  distensibility  of  the 
constricted    vein. 

Nevertheless,  there  is  another  factor  in  these  disten- 
sibility characteristics  which  must  be  considered. 
The  original  interpretation  of  the  sigmoid  curve 
visualized  that  at  high  pressures  the  constricted 
vessel  was  pulled  out  to  the  same  dimension  as  the 
dilated  vessel,  and  thus  demands  that  the  total 
distensibility  must  be  greater  in  the  constricted 
vessel.  As  has  been  discussed  earlier,  the  validity  of 
this  interpretation  is  open  to  some  question.  It  is 
conceivable  that  a  sigmoid  distensibility  pattern  may 
be  compatible  with  some  reduction  in  total  disten- 
sibility. If,  in  addition,  dilated  veins  were  in  a  state 
of  partial  collapse  at  the  point  that  the  initial  volume 
was  measured,  this  would  augment  the  possibility  of 
observing  a  greater  total  distensibility-  in  the  dilated 
vein. 


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CIRCULATION    II 


One  is  therefore  justified  to  interpret  distensibility 
data  in  whatever  fashion  appears  compatible  with  the 
responses  observed  with  his  particular  method.  Since 
there  is  overwhelming  evidence  that  adrenergic 
drugs  are  potent  venoconstrictors,  a  reproducible 
response  to  such  drugs  may  be  used  as  a  reference 
standard  to  which  responses  evoked  by  other  stimuli 
may  be  related.  It  would  nonetheless  be  desirable 
to  adopt  accurately  standardized  methods  for  dis- 
tending veins  so  that  data  will  have  greater  validity. 
In  view  of  the  significant  stress  relaxation  and  creep 
phenomena  demonstrated  by  veins,  one  can  scarcely 
hope  to  obtain  any  precise  information  by  making 
measurements  "as  soon  as  the  volume  seems  rea- 
sonably   stable." 


SUMMARY'  OF  VENOMOTOR  RESPONSES 

From  the  great  variety  of  techniques  that  have  been 
employed  for  the  assessment  of  venomotor  activity,  a 
wealth  of  information  has  been  obtained  which 
demonstrates  at  least  qualitativelv  the  types  of 
stimuli  which  evoke  venomotor  responses.  In  table  i 
are  listed  responses  which  stand  without  controversy 
as  representative  of  the  active  responses  of  the 
venous  system.  It  should  be  understood  that  this 
listing  does  not  pretend  to  be  comprehensive  or 
cover  any  significant  fraction  of  the  full  literature  on 
the  subject;  in  general  it  has  proven  convenient  to 
confine  the  citations  in  this  table  to  reports  which 
have  been  referred  to  for  other  purposes  in  our  pre- 
vious discussion.  This  evidence  of  a  broad  spectrum 
of  reactivity  suggests  that  the  venous  system  must 
play  an  important  function  in  active  regulation  of 
the  circulation  as  a  whole.  For  a  discussion  of  this 
important  aspect  of  venomotor  action,  the  reader 
is  referred  to  Chapter  32.  The  remainder  of  our 
comments  will  be  confined  to  response  characteristics 
which  appear  to  be  of  some  unique  importance  to 
the  venous  system. 

Most  investigators  of  the  venous  system  have  been 
impressed  with  the  fact,  first  emphasized  by  Goll- 
witzer-Meier  (36),  that  the  venous  system  appears 
to  act  synergistically  with  the  arterial  system.  This 
is  emphasized  in  the  evidence  presented  in  table  1 ; 
with  the  exception  of  histamine,  all  responses  listed 
are  direct  counterparts  of  similar  reactions  known  to 
occur  on  the  arterial  side  of  the  circulation.  Beyond 
this  qualitative  similarity,  the  interesting  question 
arises   as  to   the   relative  sensitivity  of  arteriomotor 


1  'enoconstrictor  Responses 

References 

Adrenergic  drugs 

'2,  4,  '4.  >9.  25.  34.  4°.  43. 

59.  61,  63,82,  88,  91,  93 

5 -Hydroxy  try  ptamine 

34.  43.  45 

Histamine 

25,  61 

Carotid  sinus  hypotension 

4,  5,  68,  81 

Hypercapnia  (central) 

4.  *'.  35.  54 

Hypoxia 

4 

Cold 

16,  20,  39,  42,  56,  68,  88,  93 

Deep  inspiration 

14,  21 ,  64 

Intense  sensory  stimulation 

4.  8>  54 

Psychic  stimulation 

14,  21 ,  68 

Exercise 

41 ,  64,  68 

Venodilator  Responses 

Nitrites 

61 ,  91,  92 

Acetyl  choline 

*5 

Adenylic  acid 

3 

Carotid  sinus  hypertension 

4,  68,  81 

Neurogenic  syncope 

'4 

Sleep 

'4 

and  venomotor  systems.  The  literature  contains 
definite  suggestions  that  the  venous  system  may  have 
a  greater  sensitivity  (55,  92)  and  also  make  a  greater 
contribution  to  the  total  circulatory  response  (53), 
although  more  information  is  needed  to  permit 
sound    generalizations. 

There  are  a  few  instances,  however,  in  which  the 
responses  of  the  venous  system  appear  to  be  unique. 
One  is  the  influence  of  5-hydroxytryptamine  pre- 
viously discussed  in  reference  to  figure  g.  Haddy's 
data  would  indicate  that  this  compound  is  more 
effective  in  producing  venoconstriction  than  it  is  in 
blocking  pre-existing  venous  constriction  resulting 
from  high  sympathetic  tone,  while  for  the  small 
vessels  on  the  arterial  side  of  the  circulation,  the 
svmpathetic  blockade  can  dominate  the  direct  con- 
strictor action  of  the  compound.  Therefore,  5- 
hydroxytryptamine  shares  with  histamine  the  capacity 
to  produce  both  venoconstriction  and  arteriolar 
dilation;  as  a  consequence  both  of  these  compounds 
have  the  capacity  to  induce  edema  formation.  There 
is  an  indication  that  local  tissue  acidity  may  also 
have  such  an  action  (27,  32).  An  inverse  type  of 
dissociation  between  arterial  and  venous  effects  has 
been  reported  to  occur  in  circulatory  shock,  where 
venoconstrictor  mechanisms  fail  at  a  point  at  which 
arterial  constrictor  tone  is  still  well  maintained  (5). 

A  particularly  interesting  dissociation  also  appears 
to  exist  in  reference  to  temperature  effects.  While  cold 
produces  significant  constriction  of  cutaneous 
arterioles,  it  is  even  more  effective  as  a  venoconstric- 


PERIPHERAL  VENOUS  SYSTEM 


io95 


tor.  This  cold  venoconstriction  has  a  significant 
reflex  basis  as  well  as  a  local  component  (18).  As  a 
consequence,  capillary  pressure  should  rise,  account- 
ing for  the  increased  transudation  of  fluid  and  the 
tendency  for  the  hematocrit  to  rise  in  cold.  Second- 
arily, the  fall  in  temperature  so  interferes  with  dissocia- 
tion of  oxyhemoglobin  as  to  produce  some  tissue 
anoxia.  The  anoxic  metabolites  tend  to  act  as  vaso- 
dilators competing  with  the  cold  constriction  of  the 
arterioles,  but  seem  to  have  no  capacity  to  cause 
venodilation.  As  a  consequence,  the  skin  becomes 
plethoric  because  of  some  arterial  inflow  in  the  face 
of  a  continued  resistance  to  venous  outflow.  Rewarm- 
ing  of  the  tissue  will  now  cause  arteriolar  dilation. 
There  is  considerable  evidence,  however,  that  the 
veins  do  not  dilate  in  response  to  heat  (39,  42,  56, 
93).  Indeed,  the  extreme  venoconstriction  produced 
by  the  previous  cold  stimulus  seems  to  dissipate 
slowly  after  the  tissue  is  rewarmed,  so  that  during 
the  initial  phase  there  is  significant  arteriolar  dilation 
in  spite  of  persisting  venous  constriction  (42).  This 
accounts  for  the  extreme  degree  of  plethora  and 
tendency  toward  edema  formation  which  is  observed 
in  the  rewarming  phase. 

Finally,  attention  should  be  called  to  fragmentary 
information  relating  to  the  possibility  of  venovenous 
reflexes.  Apart  from  the  general  homeostatic  regula- 
tors of  the  circulation,  such  as  the  arterial  presso- 
receptor mechanism  and  the  chemoreceptor  responses, 
are  there  mechanisms  for  adjusting  venous  capacity 
as  a  function  of  the  venous  pressure?  In  view  of  the 
importance  of  the  central  venous  pressure  in  deter- 
mining cardiac  output,  circulatory  homeostasis 
would  be  enhanced  if  there  were  such  a  mechanism 
for  adjusting  venous  capacity  to  central  venous 
pressure,  so  that  the  venous  reservoir  tended  to 
expand  in  response  to  an  increase  in  venous  pressure 
and  contract  in  response  to  a  decrease  in  venous 
pressure. 

There  are  several  suggestions  that  such  a  mecha- 
nism exists.  With  acute  hypotension  produced  by 
vagal  bradycardia,  Fleisch  (26)  observed  an  initial 
venous  constriction,  attributable  to  the  carotid 
sinus  reflex,  followed  by  a  secondary  venous  dilation 
which  he  felt  was  associated  with  the  venous  conges- 
tion produced  by  the  bradycardia.  A  very  similar 
observation  was  reported  by  Schretzenmayr  (82)  in 
the  response  to  adrenergic  drugs.  Although  these 
drugs  usually  produced  a  conspicuous  venocon- 
striction, in  instances  where  the  circulatory  load 
became  so  great  as  to  momentarily  embarrass  the 
heart  and  produce  cardiac  distension,  there  appeared 


to  be  some  mechanism  that  was  counteracting  the 
venous  constriction.  More  direct  evidence  of  this 
mechanism  has  been  provided  by  the  author  (6), 
who  demonstrated  venodilation  to  be  produced 
reflexly  when  venous  congestion  was  produced  by 
inflating  a  balloon  in  the  thoracic  vena  cava.  It  is 
important  to  note,  however,  that  to  demonstrate 
this  effect  it  proved  quite  essential  to  prevent  changes 
in  pressure  on  the  arterial  side  of  the  circulation. 
Unless  such  precautions  are  taken,  the  arterial 
pressoreceptor  system  dominates  the  circulatory 
responses,  and  the  venovenous  reflex  mechanism 
described  above  is  completely  overwhelmed. 

This  dominance  of  the  arterial  pressoreceptor 
reflexes  accounts  for  a  number  of  observations  which 
otherwise  would  argue  against  the  venovenous 
reflex.  Wood  (93)  has  demonstrated  reflex  venous 
constriction  in  man  associated  with  venous  con- 
gestion produced  by  occluding  cuffs  on  the  extremi- 
ties. Inasmuch  as  they  observed  a  reflex  tachycardia 
as  well  as  arterial  constriction  associated  with  what 
was  estimated  to  be  a  15  per  cent  reduction  in  cir- 
culating blood  volume,  this  response  would  relate 
primarily  to  arterial  pressoreceptor  mechanisms. 
In  confirmation  of  this,  when  the  subjects  were  in  a 
supine  position  so  as  to  minimize  pooling  of  blood 
with  venous  tourniquets,  neither  the  venous  reflex 
nor  other  signs  of  compensation  to  arterial  hypoten- 
sion were  observed.  Similarly,  Page  and  co-workers 
(68)  found  venoconstriction  to  be  produced  by  the 
Valsalva  maneuver,  which  would  also  be  explainable 
in  terms  of  baroreceptors  on  the  arterial  side  dominat- 
ing the  simultaneous  effects  of  congestion  on  the 
venous   side. 

There  remains  the  problem  of  interpreting  the 
evidence  presented  by  Burch  (13)  that  patients  in 
congestive  heart  failure  are  characterized  by  an 
augmented  venomotor  tone.  If  one  assumes  that  the 
only  significant  feature  in  this  condition  is  venous 
distention,  this  finding  would  not  be  compatible 
with  the  postulation  of  a  reflex  venodilation  in 
response  to  venous  distension.  It  may  be  of  signifi- 
cance that  Burch  found  definite  evidence  of  veno- 
constriction only  in  those  patients  who  were  rather 
severely  decompensated  and  in  whom  numerous 
other  sources  of  reflex  stimulation  might  therefore 
have  been  operable.  Our  inability  to  define  more 
clearly  the  exact  nature  of  the  venomotor  reactions 
occurring  in  such  an  important  clinical  problem 
should  afford  adequate  stimulus  to  seek  still  further 
clarification  of  the  nature  of  venomotor  control. 


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REFERENCES 


i.  Alexander,  R.  S.,  W.  S.  Edwards,  and  J.  L,  Ankeney. 

The    distensibility    characteristics   of   the    portal    vascular 

bed.  Circulation  Research   I:  271,    1953. 
a.   Alexander,  R.  S.  The  influence  of  constrictor  drugs  on  the 

distensibility  of  the  splanchnic  venous  system,  analyzed  on 

the   basis  of  an   aortic   model-    Circulation   Research   2:    140, 

IQ54- 

3.  Alexander,  R.  S.  The  source  of  delayed  compliance  in 
the  vascular  bed.  Circulation  Research  2:  183,  1954. 

4.  Alexander,  R.  S.  The  participation  of  the  venomotor 
system  in  pressor  reflexes.  Circulation  Research  2:  405,   1954. 

5.  Alexander,  R.  S.  Venomotor  tone  in  hemorrhage  and 
shock.  Circulation  Research  3.  181 ,  1955. 

fi.  Alexander,  R.  S.  Reflex  alterations  in  venomotor  tone 
produced  by  venous  congestion.  Circulation  Research  6:  49, 

[956- 

7.  Bartelstone,  H.  J.  Role  of  the  veins  in  venous  return. 
Circulation  Research  8:  1059,  i960. 

8.  Bayliss,  W.  M.,  and  E.  H.  Starling.  Observations  on 
venous  pressures  and  their  relationship  to  capillary  pres- 
sures. J.  Physiol.   16:  159,  1894. 

9.  Beaconsfield,  P.  Veins  after  sympathectomy.  Surgery  36: 

-71.  1954- 

10.  Brecher,  G.  A.  Mechanism  of  venous  flow  under  different 
degrees  of  aspiration.  Am.  J.  Physiol.  169:  423,  1952. 

11.  Brecher,  G.  A.  Venous  Return.  New  York:  Grune  & 
Stratton,  1956. 

12.  Burch,  G.  E.  A  method  for  recording  and  a  study  of  the 
venous  occlusive  technique  for  measuring  the  time  course 
of  the  rate  of  inflow  and  the  time  course  of  the  rate  of 
outflow  in  the  finger  tip  of  man  during  a  single  pulse  cycle. 
In  :  Peripheral  Circulation  in  Man.  Boston  :  Little,  Brown,  1954. 

13.  Burch,  G.  E.  A  method  for  measuring  venous  tone  in 
digital  veins  of  intact  man.  Evidence  for  increased  digital 
venous  tone  in  congestive  heart  failure.  A.M. A.  Arch. 
Internal  Med.  94:  724,  1954. 

14.  Burch,  G.  E.,  and  M.  Murtadha.  A  study  of  the  veno- 
motor tone  in  a  short  intact  venous  segment  of  the  forearm 
of  man.  Am.  Heart  J.  51  :  807,   1956. 

15.  Burton,  A.  C.  Relation  of  structure  to  function  of  the 
tissues  of  the  wall  of  blood  vessels.  Physiol.  Revs.  34:  619, 

■954- 

16.  Capps,  R.  B.  A  method  for  measuring  tone  and  reflex 
constriction  of  the  capillaries,  venules  and  veins  of  the 
human  hand  with  the  results  in  normal  and  diseased  states. 
J.  Clin.  Invest.  15:  229,  1936. 

17.  Clark,   J.  H.  The  elasticity  of  s'eins.  Am.  J.  Physiol.  105: 

4'8>  '933- 

18.  Connolly,  D.  G,  and  E.  H.  Wood.  Distensibility  of 
peripheral  veins  in  man  determined  by  a  miniature  balloon 
technique.  J.  Appl.  Physiol.  7:  239,  1954. 

ig.  Donegan,  J.  F.  The  physiology  of  the  veins.  ./.  Physiol.  55: 
226,  1 92 1 . 

20.  Doupe,  J.,  R.  A.  Krynauw,  and  S.  R.  Snodgrass.  Some 
factors  influencing  venous  pressure  in  man.  J.  Physiol.  92: 

383>  !938- 

21.  Duggan,  J.  J,  V.  L.  Love,  and  R.  H.  Lyons.  A  study  of 
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PERIPHERAL  VENOUS  SYSTEM 


'097 


51 


52 


epinephrine,  norepinephrine,  and  serotonin  upon  systemic 
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thoracic pressure  on  peripheral  venous  pressure  in  man. 
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53.  Holt,  J.  P.,  W.  J.  Rashkind,  R.  Bernstein,  and  J.  C. 
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54.  Hooker,  D.  R.  The  veno-pressor  mechanism.  Am.  J. 
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55.  Kelly,  W.  D.,  and  M.  B.  Visscher.  Effect  of  sympathetic 
nerve  stimulation  on  cutaneous  small  vein  and  small 
artery  pressures,  blood  flow,  and  hindpaw  volume  in  the 
dog.  Am.  J.  Physiol.  185:  453,  1956. 

56.  Kidd,  B.  S.  L.,  and  S.  M.  Lyons.  The  distensibility  of  the 
blood  vessels  of  the  human  calf  determined  by  graded 
venous  congestion.  ./.  Physiol.  140:  122,  1958. 

57.  Knisely,  W.  H.,  M.  S.  Mahaley,  and  H.  J.  Harriman. 
Approximation  of  "total  vascular  space"  and  its  distri- 
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Circulation  Research  6  :  20,  1 958. 

58.  Landis,  E.  M.,  and  J.  C.  Hortenstine.  Functional  sig- 
nificance  of  venous   blood    pressure.    Physiol.   Revs.    30 :    1 , 

>95°- 

59.  Leonard,  E.,  and  S.J.  Sarnoff.  Effect  of  aramine-induced 
smooth  muscle  contraction  on  length-tension  diagrams  of 
venous  strips.  Circulation  Research  5:  i6g,  1 957- 

60.  MacWilliam,  J.  A.  On  the  properties  of  the  arterial  and 
venous  walls.  Proc.  Roy.  Soc,  London  B  70:  109,  1902. 

6t.  Maloff,  G.  Pharmakologische  versuche  an  isolierten  Ve- 
nen  des  Menschen.  Pfliigers  Arch,  ges.  Physiol.  229:  38,  1932. 

62.  Maynard,  E.  A.,  R.  L.  Schultz,  and  D.  C.  Pease. 
Electron  microscopy  of  the  vascular  bed  of  rat  cerebral 
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63.  Mellander,  S.  Comparative  studies  on  the  adrenergic 
neuro-hormonal  control  of  resistance  and  capacitance 
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i960. 

64.  Merritt,  F.  L.,  and  A.  M.  Weissler.  Reflex  venomotor 
alterations  during  exercise  and  hyperventilation.  Am. 
Heart  J.  58:  382,    1959. 


65.  Milnor,  W.  R.,  and  C.  A.  Bertrand.  Estimation  of 
venous  blood  volume  in  the  dog  by  the  indicator-dilution 
method.  Circulation  Research  6:  55,  1958. 

66.  Ochsner,  A.,  and  M.  DeBakey.  Thrombophlebitis:  the 
role  of  vasospasm  in  the  production  of  the  clinical  mani- 
festations. J.  Am.  Med.  Assoc.  114:  117,  1940. 

67.  O'Neill,  J.  F.  The  effects  on  venous  endothelium  of 
alterations  in  blood  flow  through  the  vessels  in  vein  walls, 
and  the  possible  relation  to  thrombosis.  Ann.  Surgery  126: 
270,  1947. 

68.  Page,  E.  B.,  J.  B.  Hickam,  H.  O.  Sieker,  H.  D.  McIntosh, 
and  M.  D.  Pryor.  Reflex  venomotor  activity  in  normal 
persons  and  in  patients  with  postural  hypotension.  Cirt  il- 
lation 1  1  :  262,  1955. 

69.  Pappenheimer,  J.  R.,  and  J.  P.  Maes.  A  quantitative 
measure  of  the  vasomotor  tone  in  the  hindlimb  muscles  of 
the  dog.  Am.  J.  Physiol.  137:  187,  1942. 

70.  Pappenheimer,  J.  R.,  and  A.  Soto-Rivera.  Effective 
osmotic  pressure  of  the  plasma  proteins  and  other  quantities 
associated  with  the  capillary  circulation  in  the  hindlimbs 
of  cats  and  dogs.  Am.  J.  Physiol.  152:  471,  1948. 

7 1 .  Paton,  YV.  D.  M.  The  paralysis  of  autonomic  ganglia  with 
special  reference  to  the  therapeutic  effects  of  ganglion 
blocking  agents.  Brit.  Med.  .1 .   1  :  773,  1951. 

72.  Peterson,  L.  H.  Participation  of  the  veins  in  active  regu- 
lation of  the  circulation.  Federation  Proc.  10:  104,  1951. 

73.  Peterson,  L.  H.  Certain  aspects  of  reflex  and  mechanical 
influences  upon  venous  circulation.  Federation  Proc.   1  1  :  122, 

'952- 

74.  Pollack,  A.  A.,  and  E.  H.  Wood.  Venous  pressure  in  the 
saphenous  vein  at  the  ankle  in  man  during  exercise  and 
changes  in  posture.  J.  Appl.  Physiol.  1  :  649,  1 949. 

75.  Powers,  S.  R.,  C.  Schaffer,  A.  Boba,  and  Y.  Nakamura. 
Physical  and  biological  factors  in  impedance  plethysmog- 
raphy. Surgery  44:  53,  1958. 

76.  Ramsey,  E.  Nutrition  of  the  blood  vessel  wall:  review  of 
the  literature.  Yale  J.  Biol,  and  Med.  9:14,  1936. 

77.  Remington,  J.  W.,  and  R.  S.  Alexander.  Relation  of 
tissue  extensibility  to  smooth  muscle  tone.  Am.  J.  Physiol. 
185:  302,  1956. 

78.  Remington,  J.  YV.  (editor).  Tissue  Elasticity.  YVashington : 
Am.  Physiol.  Soc,  1957. 

79.  Roy,  C.  S.  The  elastic  properties  of  the  arterial  wall.  J. 
Physiol.  3  :  1  25,  1881 . 

80.  Ryder,  H.  YV.,  W.  E.  Molle,  and  E.  B.  Ferris.  The 
influence  of  the  collapsibility  of  veins  on  venous  pressure, 
including  a  new  procedure  for  measuring  tissue  pressure. 
J.  Clin.  Invest.  23:  333,  1944. 

81.  Salzman,  E.  YV.  Reflex  peripheral  venoconstriction  induced 
by  carotid  occlusion.  Circulation  Research  5:  149,  1957. 

82.  Schretzenmayr,  A.  Die  Motorik  des  intakten  Venen- 
systems.  II.  Nachweis  und  Bedeutung  der  Hohlvene- 
motorik.  Arch.  Expll.  Pathol.  Pharmakol.  180:  295,  1936. 

83.  Smith,  D.  J.  Constriction  of  isolated  arteries  and  their 
vasa  vasorum  produced  by  low  temperatures.  Am.  J. 
Physiol.  171:528,  1952. 

84.  Smith,  D.  J.  Immediate  sensitization  of  isolated  swine 
arteries  and  their  vasa  vasorum  to  epinephrine,  acetyl- 
choline, and  histamine  by  thyroxine.  Am.  J.  Physiol,  \-j~j: 
7,  '954- 


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85.  Spalteholz,  YV.  Die  Vcrtheilung  der  Blutgefasse  in  der 
Haut.  Arch.  Anal.  u.  Physiol.  Anat.   1  :  1893. 

86.  Thompson,  W.  H.  Uber  die  Abhangigkeit  der  Gliedervenen 
von   motorischen   Nerven.   Arch.   Anal.   u.   Physiol.   8:    102, 

87.  Wallace,  J.  M.  Pressure  relationships  among  arteries  and 
large  and  small  veins.  Circulation  14:  1013,  1956. 

88.  Wallace,  J.  M.,  and  E.  A.  Stead.  Spontaneous  pressure 
elevations  in  small  veins  and  effects  of  norepinephrine  and 
cold.  Circulation  Research  5:  650,   1 957- 

89.  Whitney,  R.  J.  The  measurement  of  volume  changes  in 
human  limbs.  J.  Physiol.   121:  I,   1953. 


90.  Wiggers,  C.  J.  Peripheral  circulation.  Ann.  Rev.  Physiol.  9: 

255.  '947- 

91.  Wilkins,  R.  YV.,  F.  W.  Haynes,  and  S.  YVeiss.  The  role  of 
the  venous  system  in  circulatory  collapse  induced  by 
sodium  nitrite.  J.  Clin.  Invest.   16:  85,  1937. 

92.  Wilkins,  R.  YV.,  S.  YY'eiss,  and  F.  W.  Haynes.  The  effect 
of  circulatory  collapse  induced  by  sodium  nitrite.  J.  Clin. 
Invest.  17:41,  1938. 

93.  Wood,  J.  E.,  and  J.  YV.  Eckstein.  A  tandem  forearm 
plethysmograph  for  study  of  acute  responses  of  the  pe- 
ripheral veins  of  man:  the  effect  of  environmental  and  local 
temperature  change,  and  the  effect  of  pooling  blood  in  the 
extremities.  J.  Clin.  Invest.  37:  41,  1958. 


CHAPTER     32 


Venous   return 


ARTHUR  C.  GUYTON 


Department  of  Physiology  and  Biophysics,  University  of  Mississippi 
School  of  Medicine,  Jackson,  Mississippi 


CHAPTER      CONTENTS 

Introduction 

Principles   of  Circuit  Analysis   as  They   Apply   to  Venous 

Return 
The  problem 
Solution  to  the  problem 
The   Classical   Analysis   of  Venous   Return — Vis   a   Tergo 

and  Vis  a  Fronte 
History  of  More  Complete  Circulatory  Analyses 
Simplified   Graphical   Analysis   of  Venous    Return,    Cardiac 

Output,  and  Right  Atrial  Pressure 
Cardiac  Output  Curves 

Effectiveness  of  the  heart  as  a  pump 

Alteration    of  the   load    against   which    the    heart    must 

pump 
Alterations  in  pressure  on  the  outside  of  the  heart 
Summary    of    factors    that    affect    the    cardiac    output 

curves 
Venous  Return  Curves 

Venous  return  curves  as  complements  to  cardiac  output 

curves 
Method  for  recording  venous  return  curves 
Effect   of  right    atrial    pressure   on    venous    return — the 

normal  venous  return  curve 
Effect  of  peripheral  resistance  on  venous  return 
Effect  of  mean  systemic  pressure  on  venous  return 
Summary    of    factors    that    affect    the    venous    return 

curves 
Equating  the  Venous  Return  and  Cardiac  Output  Curves 
Effect    of   sympathetic    stimulation    on    venous    return, 

cardiac  output,  and  right  atrial  pressure 
Effect   of  muscular  exercise  on   venous   return,   cardiac 

output,  and  right  atrial  pressure 
Effect   of  rapid    transfusion    on   venous   return,   cardiac 

output,  and  right  atrial  pressure 
Effect  of  shock  on   venous  return,  cardiac  output,   and 

right  atrial  pressure 
Effect  of  opening  the  chest  on   venous  return,   cardiac 

output,  and  right  atrial  pressure 
Effect  of  myocardial  damage  on  venous  return,  cardiac 

output,  and  right  atrial  pressure 
Analysis  of  decompensation   and  compensation   in  con- 
gestive heart  failure 


Analysis   of  effects   resulting   from   changes   in    vascular 

resistance 
A   More   Complex    Graphical    Analysis   of    Venous    Return, 

Ventricular  Outputs,  and  Atrial  Pressures 
Balance  of  the   two  ventricular  outputs  with  each  other 
Effect    of   acute    left   heart    failure    on    cardiac   output, 

venous   return,    left   and   right   atrial   pressures,   mean 

systemic  pressure,  and  mean  pulmonary  pressure 
Effect  of  acute  right  heart  failure 
Effect  of  blood  volume  change 
Summary  of  the  complex  analysis 
Specific  Factors  that  Affect  Venous  Return 

Effect  of  the  venous  pump  on  venous  return 

Effect  of  venous  collapse  on  venous  return 

Effect  of  central  pulsation  on  venous  return 

Effect    of  local  tissue   activity  on   venous   return — effect 

of  oxygen  usage  by  the  tissues 
Venous  Pressures 

Effect  of  resistance  to  flow  in  the  veins 

Effect  of  venous  flow  on  peripheral  venous  pressures 

Effect    of    hydrostatic    pressure    on    peripheral    venous 

pressures 
Summary 


INTRODUCTION 

the  term  "venous  return"  means  very  simply  the 
flow  of  blood  from  the  veins  into  the  heart,  and  this, 
obviously,  can  be  divided  into  ''systemic  venous  re- 
turn" and  "pulmonary  venous  return."  The  function 
of  the  veins  and  the  importance  of  venous  return  have 
been  covered  from  different  points  of  view  in  several 
important  monographs  (31,  70)  and  reviews  (72, 
82-85,  1 33>  137)-  Also,  the  basic  characteristics  of  the 
veins  as  blood  vessels  are  reviewed  by  Alexander  in 
Chapter  31 .  Therefore,  the  purpose  of  this  chapter  will 
be  to  discuss  especially  the  regulation  of  venous  return 
and  secondarily  the  associated  factor  venous  pressure. 


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Though  the  venous  return  is  normally  exactly 
equal  to  ventricular  output,  this  may  not  be  true  for 
short  periods  of  time.  However,  when  the  venous 
return  is  greater  than  the  ventricular  output,  blood 
will  accumulate  in  the  heart.  During  the  ensuing  few 
heartbeats  a  new  state  of  equilibrium  will  develop, 
and  venous  return  will  again  become  equal  to  the 
output.  Yet,  since  there  are  times  when  venous  return 
and  cardiac  output  are  not  equal,  it  is  justified  to  use 
the  term  ""venous  return"  separately  from  the  term 
"cardiac  output." 

Normally,  in  speaking  of  cardiac  output,  one  thinks 
principally  of  cardiac  activity,  whereas  in  speaking  of 
venous  return,  he  thinks  of  all  the  functions  of  the 
peripheral  circulation  that  have  to  do  with  blood 
flow  into  the  heart.  For  this  reason  many  circulatory 
physiologists  consider  cardiac  output  to  be  regulated 
principally  by  the  heart  and  venous  return  to  be  regu- 
lated principally  by  peripheral  factors.  By  all  means, 
the  reader  must  be  cautioned  at  the  outset  against 
this  viewpoint,  because  except  for  instantaneous 
periods  of  time,  any  factor  that  affects  cardiac  output 
also  affects  venous  return,  and  any  factor  that  affects 
venous  return  also  affects  cardiac  output.  This  princi- 
ple can  be  expressed  in  another  way:  The  circulatory 
system  is  a  circuit,  and  the  total  flow  of  blood  through 
any  one  cross  section  of  the  circuit  is  exactly  the  same 
as  the  total  flow  through  any  other  cross  section. 

Principles  of  Circuit  Analysis  <v\  They 
Apply  To  I  'enous  Return 

( )ften,  physiologists  have  attempted  to  analyze  the 
regulation  of  venous  return  entirely  on  the  basis  of 
local  factors  in  the  veins  and  right  heart.  However, 
this  is  a  completely  fallacious  approach,  for  any 
factor  that  affects  blood  flow  in  any  single  unit  of  the 
entire  circulation  will  likely  at  the  same  time  affect 
venous  return.  For  this  reason,  a  complete  circuit 
analysis  of  the  entire  circulation  is  required  for  any 
degree  of  accuracy  in  determining  the  factors  that 
regulate  venous  return  (46,  47,  78,  81,  126-128,  192). 
This  means  that  the  same  factors  that  regulate  cardiac 
output  are  those  which  also  regulate  venous  return. 
In  general,  these  can  be  divided  into  two  major 
groups:  those  concerned  with  the  ability  of  each  side 
of  the  heart  to  pump  blood,  and,  second,  those  con- 
cerned with  the  ability  of  blood  to  flow  through  the 
two  divisions  of  the  peripheral  circulation,  the  sys- 
temic circulation,  and  the  pulmonary  circulation.  In 
this  chapter  we  will  be  concerned  with  both  of  these 
groups  of  factors  and  with  the  manner  in  which  thev 


operate  together  to  regulate  blood  flow  in  the  circula- 
tion. However,  the  contribution  of  the  heart  to  the 
regulation  of  blood  flow  in  the  circulation  is  discussed 
in  great  detail  in  several  other  chapters,  including 
especially  those  by  Hamilton,  Sarnoff  &  Mitchell, 
Brecher,  and  Rushmer  (Chapters  17,  15,  23,  and  16, 
respectively).  Therefore,  in  this  chapter  we  will  discuss 
the  cardiac  factors  only  briefly  while  discussing  the 
peripheral  factors  in  far  greater  detail. 

the  problem.  Figure  1  depicts  a  highly  simplified 
diagram  of  many  of  the  important  factors  that  must 
be  considered  in  analyzing  blood  flow  around  the 
circulatory  circuit.  First  of  all,  we  note  in  the  diagram 
the  term  blood  flow  (F)  appearing  at  four  different 
points:  /)  at  the  output  of  the  right  heart,  2)  at  the 
output  of  the  pulmonary  circulation,  j)  at  the  output 
of  the  left  heart,  and  ./)  at  the  output  of  the  systemic 
circulation.  Under  steady-state  conditions,  the  blood 
flow  at  all  of  these  four  points  will  be  exactly  equal. 
Yet,  in  a  circulatory  analysis  we  must  consider  them 
separately,  because  they  are  not  always  equal,  and 
during  the  periods  of  time  when  they  are  unequal, 
blood  will  be  actively  translocated  from  one  part  of 
the  circulation  to  another,  thus  causing  new  equilib- 
rium conditions  to   develop.    Now    to    describe    the 


fig.  1.  Circulatory  schema,  showing  the  effects  of  indi- 
vidual factors  in  different  parts  of  the  circulation  on  other 
functions  of  the  circulation.  Each  arrow  represents  a  separate 
effect,  and  a  composite  analysis  of  the  circulation  requires 
that  all  these  effects  be  considered  simultaneously  as  explained 
in  the  text. 


VENOUS  RETURN 


events  depicted  in  figure  i ,  we  can  start  by  pointing 
out  that  each  arrow  represents  an  effect  of  one  factor 
on  another  factor.  The  different  effects  denoted  in 
this  figure  can  be  listed  as  follows : 


(i 

(a 

(3 
(4 
(5 
(6 

(7 
(8 

(9 

(10 

(n 

(.2 

('3 
('4 
('5 
(16 

(17 
08 
('9 

(20 

(a  i 

(aa 

(23 
(24 


Right  heart  blood  flow  (Frh)  directly  affects  pulmonary 
arterial  pressure   (Pap). 

Right  heart  blood  flow  (Frh)  inversely  affects  systemic 
venous  pressure  (Pv,). 

Pulmonary    arterial    pressure     (Pap)     inversely    affects 
right  heart  blood  flow  (Frh). 

Pulmonary     arterial     pressure     (Pa„)     directly     affects 
pulmonary  blood  volume  (Vp). 

Pulmonary     arterial     pressure     (Pap)     directly     affects 
pulmonary  blood  flow  (Fp). 

Pulmonary    blood    volume    (Vp)    inversely    affects    pul- 
monary resistance  (Rp). 

Pulmonary   resistance    (Rp)    directly   affects   pulmonary 
arterial  pressure  (Pap). 

Pulmonary  resistance   (Rp)   inversely  affects  pulmonary 
blood  flow  (Fp). 

Pulmonary  blood  flow   (Fp)   directly  affects  pulmonary 
venous  pressure  (Pvp). 

Pulmonary  venous   pressure    (Pvp)   directly   affects  pul- 
monary blood  volume  (Vp). 

Pulmonary     venous     pressure     (Pvp)     inversely     affects 
pulmonary  blood  flow  (Fp). 

Pulmonary   venous   pressure    (Pvp)    directly   affects   left 
heart  flow  (Flh). 

Left  heart  blood  flow  (Flh)  inversely  affects  pulmonary 
venous  pressure  (Pvp). 

Left    heart    blood    flow    (Flh)    directly    affects   systemic 
arterial  pressure  (Pas). 

Systemic    arterial    pressure    (PaB)    inversely    affects    left 
heart  blood  flow  (Flh). 

Systemic  arterial  pressure  (Pa J  directly  affects  systemic 
blood  volume  (Vs). 

Systemic  arterial  pressure  (Pa^)  directly  affects  systemic 
blood  flow   (F.I. 

Systemic   blood   volume    (Vs)   inversely   affects  systemic 
resistance  (Rs). 

Systemic  resistance  (Rs)  directly  affects  systemic  arterial 
pressure  (Pa,). 

Systemic  resistance  (Rs)  inversely  affects  systemic  blood 
flow  (Fs). 

Systemic     blood     flow     (Fs)     directly     affects    systemic 
venous  pressure  (Pv,). 

Systemic    venous    pressure    (Pv,)    inversely    affects   sys- 
temic blood  flow  (Fs). 

Systemic    venous    pressure     (Pv„)    directly    affects    sys- 
temic blood  volume  (Vs). 
Systemic    venous    pressure    (Pv,)    directly    affects    right 


^        heart  flow  (Frh). 

Now  we  have  completed  the  circuit,  giving  most  of 
the  major  factors  within  the  circulation  that  affect 
each  other;  obviously,  a  change  in  any  one  of  these 
will  change  all  the  others.  However,  this  has  been  a 
highly  simplified  schema,  for,  onto  these  basic  me- 
chanical factors,  we  must  superimpose  the  effects  of 


circulatory  reflexes,  hormones,  special  conditions  such 
as  exercise,  hemorrhage,  myocardial  infarction,  or 
any  other  condition  that  can  affect  the  function  of 
any  single  segment  of  the  circulation. 

To  complicate  the  picture  further,  we  must  also 
note  how  greatly  simplified  some  of  the  individual 
effects  illustrated  in  figure  i  have  been  made.  For 
instance,  one  of  the  effects  noted  in  this  figure  is  the 
direct  effect  of  systemic  venous  pressure  on  right  heart 
blood  flow.  Actually,  the  systemic  venous  pressure 
does  not  directly  affect  the  right  heart  blood  flow  but 
instead  affects  the  filling  of  the  right  heart.  This  in 
turn  affects  the  degree  of  stretch  of  the  cardiac 
musculature,  which  then  affects  the  force  of  contrac- 
tion. Finally,  it  is  this  force  of  contraction  that  di- 
rectly affects  the  right  heart  blood  flow.  Thus,  it  can 
be  seen  that  four  steps  have  actually  been  compressed 
into  one  in  the  simplified  diagram  of  figure  i . 

We  can  summarize  the  problem,  therefore,  by 
pointing  out  that  the  regulatory  factors  of  the  circula- 
tory system  can  be  divided  into  literally  hundreds  or 
even  thousands  of  individual  factors  distributed 
throughout  the  circulation.  Indeed,  even  closure  of  a 
single  capillary  exerts  its  infinitesimal  effect  on  the 
functions  of  all  other  parts  of  the  circulation.  This, 
then,  is  the  problem  with  which  we  are  faced  in  this 
chapter,  to  unravel  the  myriad  of  different  factors 
that  affect  blood  flow  in  the  circulation  and  to  deter- 
mine those  that  are  especially  important  in  relation 
to  venous  return. 

solution  to  the  problem.  Several  reasonably  satis- 
factory solutions  to  the  above  problem  have  now  been 
offered,  and  all  of  them  have  taken  the  same  general 
form  [Guyton  (8i),  Grodins  (78),  Warner  (192)]. 
First,  in  each  of  the  solutions,  many  or  most  of  the 
parallel  segments  of  the  circulation  are  grouped  to- 
gether. For  instance,  in  a  general  solution  of  the 
problem  one  would  not  attempt  to  analyze  the  effect 
of  occluding  each  single  arteriole  on  the  circulatory 
dynamics,  but,  instead,  all  of  the  arterioles  are 
grouped  together.  Similarly,  the  capillaries  are 
grouped  together,  the  venules,  the  large  arteries,  the 
large  veins,  and  so  forth.  This  is  done  separately  for 
the  systemic  circulation  and  pulmonary  circulation. 
The  next  step  in  the  solution  is  to  group  the  individual 
segments  of  the  circulation  into  several  convenient 
larger  segments  and  then  to  analyze  the  function  of 
each  of  these  larger  segments  separately,  this  followed 
by  a  synthesis  of  the  separate  analyses  into  a  composite 
analysis.  Thus,  as  we  shall  show  later  in  the  chapter, 
the  function  of  the  right  heart  can  be  analyzed  sepa- 


1 1 02 


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CIRCULATION    II 


rately;  then  the  function  of  the  pulmonary  circulation 
can  be  analyzed;  then  that  of  the  left  heart,  and  that 
of  the  systemic  circulation.  Once  these  four  analyses 
have  been  made  they  can  be  put  together  either 
algebraically  or  graphically  to  derive  a  composite 
analysis  of  the  entire  circulation.  In  a  still  further 
simplified  analysis  one  can  even  analyze  the  function 
of  the  entire  heart  and  pulmonary  circulation  as  a 
single  segment  of  the  circulation,  such  as  is  usually 
done  in  studying  the  heart-lung  preparation.  Then 
the  svstemic  circulation  can  be  analyzed  as  a  separate 
segment  and  the  two  analyses  put  together  to  provide 
a  composite  analysis  for  the  entire  circulation. 

Obviously,  the  more  extensively  the  different  parts 
of  the  circulation  are  grouped  into  large  circulatory 
segments  the  less  accurate  becomes  the  over-all 
analysis.  Furthermore,  the  type  of  analysis  and  the 
tvpe  of  grouping  of  circulatory  segments  that  will  be 
used  will  depend  to  some  extent  on  the  factors  of  the 
circulation  and  the  type  of  circulatory  stress  one  wishes 
to  study.  Fortunately,  it  is  usuallv  possible  to  find 
some  specific  grouping  of  circulatory  segments  that 
is  both  simple  and  yet  accurate  enough  for  the  desired 
purpose. 

The  Classical  Analysis  of  Venous  Return — 
Vis  a  Tergo  and  Vis  a  Fronte 

The  classical  method  for  analyzing  the  factors  that 
affect  venous  return  has  been  to  consider  that  two 
forces  affect  blood  flow  from  the  systemic  veins  into 
the  right  atrium  (31,  70,  132,  133):  /)  the  force  from 
behind,  called  "vis  a  tergo,"  which  pushes  blood  along 
the  veins  toward  the  right  atrium,  and  2)  the  force 
from  in  front,  that  is,  from  the  right  heart  itself,  called 
"vis  a  fronte,"  which  either  impedes  blood  flow  into 
the  heart  or  perhaps  at  times  aids  the  flow.  Actually, 
the  vis  a  tergo  is  the  force  that  remains  after  dissipation 
of  the  arterial  pressure  during  the  course  of  blood  flow 
through  the  systemic  vessels.  Conversely,  the  vis  a 
fronte  is  a  back  pressure  from  the  heart  that  depends 
principally  on  the  over-all  pumping  activity  of  the 
heart.  If  the  heart  is  very  active  as  a  pump,  the  back 
pressure  will  be  low  and  consequently  the  vis  a  tergo 
can  force  blood  into  the  heart  with  ease.  Conversely, 
if  the  pumping  activity  of  the  heart  is  weakened,  then 
the  back  pressure  from  the  heart  will  be  greatly  en- 
hanced, this  in  turn  impeding  the  flow  of  blood  into 
the  heart. 

A  specific  factor  that  must  be  considered  in  relation 
to  the  vis  a  fronte  is  the  possibility  of  suction  of  blood 
into  the  heart  caused  by  relaxation    of  the   cardiac 


chambers  or  caused  by  respiratory  movements,  and  a 
vast  segment  of  the  literature  on  venous  return  has 
concerned  itself  with  these  considerations.  They  will 
be  discussed  in  detail  in  the  latter  part  of  the  chapter. 

History  of  More  Complete  Circulatory  Analyses 

Unfortunately,  the  classical  analysis  of  venous  re- 
turn has  never  been  quantitative  because  such  a 
simple  presentation  does  not  provide  an  adequate 
basis  for  delineating  either  the  many  different  periph- 
eral or  cardiac  factors  that  affect  vis  a  tergo  or  those 
that  affect  vis  a  fronte.  For  this  reason,  progressive 
attempts  have  been  made — very  slowly,  to  be  sure, 
but  beginning  about  one  hundred  years  ago — to 
provide  more  complete  analyses  of  the  circulation, 
with  consequently  higher  degrees  of  quantitation  of 
the  interrelationships  between  the  individual  circula- 
tory factors.  The  first  real  attempt  in  this  direction 
seems  to  have  been  made  by  Weber  (194)  in  1850,  at 
which  time  he  expressed  in  general  the  complexity 
of  the  relationships  illustrated  in  figure  1,  though  not 
expressing  these  in  precisely  the  same  manner  as 
shown  here.  From  the  literature  it  is  equally  as 
evident  that  these  general  principles  have  been  well 
understood  by  Starling  (179),  Bolton  (23),  Starr  (180, 
182),  Katz  et  al.  (126-128),  Daly  et  al.  (46,  47),  Rose 
et  al.  (168),  and  Rashkind  et  al.  (158).  Yet,  it  has 
been  only  in  the  last  half  decade  that  serious  attempts 
have  been  made  to  provide  composite  analyses  of  the 
circulation.  From  our  laboratory  has  come  a  graphical 
approach  to  this  problem  (81 ),  both  in  a  simplified 
version  and  in  a  more  complex  version,  portions  of 
each  of  which  will  be  presented  in  this  chapter.  In 
addition  to  this,  two  different  and  closely  similar 
algebraic  analyses  have  been  presented  by  Grodins 
(78)  and  by  Warner  (192).  All  these  analyses  are 
based  on  the  general  principles  illustrated  in  figure  1. 
However,  each  of  the  analyses  groups  the  components 
of  the  circulation  somewhat  differently,  they  go  to 
greater  or  lesser  degree  into  the  details  of  either 
cardiac  or  peripheral  circulatory  factors,  and  they 
make  slightly  different  basic  assumptions.  Yet,  the 
results  of  these  three  entirely  independent  and  differ- 
ent analyses  are  almost  exactly  identical.  For  this 
reason  they  all  deserve  the  highest  degree  of  considera- 
tion. Since  each  of  these  analyses  is  relatively  complex 
and  long,  it  would  be  impossible  to  present  them  all  in 
this  chapter.  Therefore,  this  chapter  will  be  limited 
to  a  presentation  of  the  graphical  analysis,  and  the 
serious  student  of  this  subject  will  be  referred  to  the 
very  complete  and  interesting  algebraic  analysis  by 


VENOUS  RETURN 


I  103 


Grodins  (78)  and  also  to  Chapter  50  by  Warner  in 
this  Handbook,  as  well  as  to  the  paper  presenting  his 
algebraic  analysis  (192).  The  algebraic  method  of 
circuit  analysis  depends  upon  expressing  the  functions 
of  the  individual  segments  of  the  circulation  in  terms 
of  mathematical  equations.  Then,  for  a  composite 
analysis  of  the  entire  circulation,  the  equations  are 
solved  by  standard  methods  for  simultaneous  equa- 
tions. 


SIMPLIFIED  GRAPHICAL  ANALYSIS  OF  VENOUS  RETURN, 
CARDIAC    OUTPUT,    AND    RIGHT   ATRIAL    PRESSURE 

A  simplified  method  for  graphical  analysis  of  venous 
return,  cardiac  output,  and  right  atrial  pressure  de- 
pends upon  dividing  the  circulatory  system  into  two 
major  segments.  The  first  segment  is  a  composite  of 
the  right  heart,  the  lungs,  and  the  left  heart.  The 
second  segment  is  the  systemic  circulation.  By  studying 
flows  and  pressures  at  different  points  while  stressing 
the  circulation  in  any  one  of  many  different  ways,  one 
can  analyze  the  circulatory  functions  of  the  heart- 
lung  segment  in  a)  the  heart-lung  preparation,  or  b) 
the  intact  animal.  On  the  other  hand,  the  functional 
characteristics  of  the  systemic  circulation  can  be 
studied  a)  in  an  isolated  systemic  system  in  which  the 
entire  heart  or  part  of  the  heart  is  replaced  by  a  pump 
(98),  or  b)  in  the  intact  circulation  by  measuring 
pressures  and  flows  at  different  points  while  stressing 
the  circulation.  These  studies  yield  graphical  function 
curves  that  are  complements  to  each  other.  These 
complementary  curves  can  then  be  plotted  on  the 
same  coordinates  and  thus  solved  by  their  points  of 
intersection.  The  function  curves  depicting  function 
of  the  heart-lung  segment  are  called  "cardiac  output 
curves,"  and  they  are  one  form  of  Starling's  curves  of 
the  heart.  The  curves  depicting  function  in  the 
systemic  circulation  are  called  "venous  return  curves." 
Before  we  can  procede  further  with  this  analysis  we 
must  now  characterize  the  various  types  of  cardiac 
output  and  venous  return  curves  that  occur  in  differ- 
ent circulatory  conditions. 

Cardiac  Output  Curves 

In  figure  2,  the  middle  curve  represents  the  normal 
cardiac  output  curve  of  the  heart  of  a  10-kg  dog.  The 
shape  of  this  curve  has  been  confirmed  by  numerous 
investigators,  beginning  with  Patterson  &  Starling 
(154)  in  1 91 4  and  extending  through  studies  by  Katz 
(123),  Krayer  (131),  and  especially  Sarnoff  and  his 


4000 


3600 


3200-  _ 


2800- 


1600- 


800 


fig.  2.  Cardiac  output  curves  for  the  normal  heart,  for 
hyper-  and  hypoeffective  hearts,  and  for  hearts  subjected  to 
increased  or  decreased  resistive  loads. 

colleagues  (18-20,  38,  120,  171,  172).  The  quantita- 
tive values  used  in  this  graph  were  derived  princi- 
pally from  the  original  quantitation  made  by  Patter- 
son and  Starling,  data  presented  by  Sarnoff  and  his 
colleagues,  and  many  measurements  made  in  our  own 
laboratories. 

A  particular  problem  in  determining  the  quantita- 
tive values  for  the  cardiac  output  curves  has  been  the 
fact  that  almost  all  such  curves  have  been  recorded  in 
open-chest  animals.  Yet,  in  circuit  analysis  we  need  to 
know  the  quantitative  values  for  the  cardiac  output 
curves  in  the  normal  closed-chest  animal  rather  than 
in  the  open-chest  animal.  We  shall  see  below  that  the 
quantitative  values  for  the  curves  change  markedly 
upon  opening  the  chest.  The  figures  expressed  in  this 
chapter  will  be  for  the  closed-chest  animal  unless 
otherwise  specified,  and  the  quantitative  values  that 
are  presented  are  based  upon  curves  obtained  in 
open-chest  animals  but  extrapolated  to  the  closed- 
chest  animal  on  the  basis  of  unpublished  determina- 
tions that  we  have  made  in  this  laboratory  while 
stressing  the  circulation  with  rapidly  increasing  or 
decreasing  blood  volume. 

Basically,  three  different  groups  of  factors  determine 


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CIRCULATION    II 


the  shape  and  quantitative  values  of  the  cardiac  out- 
put curve.  These  are  /)  the  effectiveness  of  the  heart 
as  a  pump,  2)  the  pressure  against  which  the  heart 
must  pump,  and  3)  factors  that  affect  the  pressure  on 
the  outside  of  the  heart. 

EFFECTIVENESS   OF   THE    HEART    AS   A    PUMP.    When    the 

effectiveness  of  the  heart  as  a  pump  increases,  the 
cardiac  output  curve  correspondingly  increases,  as 
illustrated  by  the  upper  curve  of  figure  2.  That  is, 
for  any  given  right  atrial  pressure  the  cardiac  output 
is  considerably  greater  from  the  "hypereffective" 
heart  than  from  the  normal  heart.  There  are  only 
three  major  causes  of  a  hypereffective  heart;  these 
are:  /)  stimulation  of  the  heart  by  the  sympathetic 
nervous  system,  2)  inhibition  of  the  parasympathetic 
nerves  to  the  heart,  and  3)  hypertrophy  of  the  heart. 
In  each  one  of  these  instances  the  heart  contracts  with 
increased  force  or  increased  rate  and  consequently 
pumps  more  blood  for  any  given  input  pressure  than 
does  the  normal  heart. 

Figure  2  also  illustrates  the  effect  of  a  hypoeffective 
heart  on  the  cardiac  output  curve.  That  is,  for  any 
given  input  right  atrial  pressure,  the  hypoeffective 
heart  pumps  far  less  blood  than  does  the  normal  heart. 
Among  the  different  factors  that  can  cause  a  hypo- 
effective heart  are  a)  myocardial  infarction,  b)  coro- 
nary sclerosis,  c)  myocarditis,  d)  valvular  heart 
disease,  e)  congenital  heart  disease,  /)  cardiac  ar- 
rhythmias, g )  hypothermia,  h)  abnormal  electrolytes 
in  the  extracellular  fluids,  i)  parasympathetic  stimula- 
tion, j)  sympathetic  inhibition,  or  any  other  factor 
that  reduces  the  ability  of  the  heart  to  pump  blood. 

Obviously,  there  can  be  all  degrees  of  hypereffec- 
tiveness  or  hypoeffectiveness  of  the  heart.  Therefore, 
an  infinite  number  of  curves  would  be  required  to 
depict  the  various  degrees  of  pumping  effectiveness  of 
the  heart  under  all  different  conditions.  Yet,  at  any- 
given  instant  in  the  life  of  the  heart,  there  is  only  one 
of  these  curves  which  depicts  its  instantaneous 
pumping  effectiveness. 

ALTERATION  OF  THE  LOAD  AGAINST  WHICH  THE  HEART 

must  pump.  It  is  quite  obvious  that  the  greater  the 
resistance  against  which  the  heart  must  pump  blood, 
the  less  effectively  can  it  pump  (171).  Consequently, 
increased  resistive  load  in  either  the  pulmonary  or 
systemic  circulation  decreases  the  cardiac  output 
curve,  while  decreased  resistive  load  increases  the 
cardiac  output  curve.  These  effects  are  also  illustrated 
in  figure  2. 

Obviously,  cardiac  load  can  vary  through  all  differ- 


ent degrees  at  different  times.  Therefore,  once  again  a 
vast  "family"  of  cardiac  output  curves  is  required  to 
depict  the  effects  of  varying  loads  on  the  function  of 
the  heart-lung  segment.  This  family  of  curves  is 
almost  identical  with  that  which  depicts  the  func- 
tional characteristics  of  the  hypereffective  versus  the 
hypoeffective  heart. 

ALTERATIONS    IN     PRESSURE    ON    THE    OUTSIDE     OF    THE 

heart.  The  degree  of  filling  of  the  heart  is  determined 
by  the  effective  filling  pressures  of  the  cardiac  cham- 
bers, that  is,  by  the  differences  between  the  pressures 
inside  the  cardiac  chambers  and  the  pressure  on  the 
outside  of  the  heart.  Ordinarily,  the  heart  is  sur- 
rounded by  the  negative  pressure  of  the  intrathoracic 
cavity  and  this  negativity  contributes  greatly  to  the 
effective  filling  pressure.  However,  at  times  the  nega- 
tive pressure  becomes  altered  or  completely  lost.  For 
instance,  opening  the  chest  immediately  shifts  the 
heart  from  negative  pressure  surroundings  to  zero 
pressure  surroundings  (atmospheric  pressure).  And, 
even  more  important,  pericardial  fluid  (145,  157), 
pericardial  constriction  (25),  intrapleural  fluid,  pneu- 
mothorax ( 1 86),  or  mediastinal  compression  can  all 
cause  intensive  positive  pressure  on  the  outside  of  the 
heart,  thereby  markedly  reducing  the  effective  filling 
pressures  of  the  cardiac  chambers. 

In  circuit  analysis,  an  increase  in  the  external  pres- 
sure on  the  heart  is  an  extremely  important  considera- 
tion for  the  following  very  simple  reason:  The 
resultant  changes  in  filling  pressures  are  not  compen- 
sated by  simultaneous  changes  in  pressure  in  the 
systemic  circulation.  As  a  consequence,  venous  return 
ordinarily  becomes  greatly  reduced. 

Figure  3  illustrates  the  effects  of  opening  the  chest 
and  of  cardiac  tamponade  on  the  cardiac  output 
curves.  Simply  opening  the  chest  shifts  the  entire 
curve  approximately  5  mm  Hg  to  the  right  because  of 
loss  of  the  normal  5  mm  Hg  negative  pressure  in  the 
intrathoracic  cavity.  This  means  that  for  the  heart  to 
pump  an  equivalent  amount  of  blood  after  opening 
the  chest  as  before,  the  right  atrial  pressure  must  be 
increased  5  mm  Hg,  thus  explaining  the  detrimental 
effect  of  opening  the  chest  on  blood  flow  in  the  circu- 
lation. 

The  lowest  curve  of  figure  3  illustrates  even  more 
drastic  depression  of  the  cardiac  output  curve,  this 
time  caused  by  severe  cardiac  tamponade.  Because 
in  this  condition  the  intrapericardial  pressure  rises  as 
the  heart  fills  to  greater  volumes,  the  curve  is  not 
simply  shifted  to  the  right  as  one  might  have  expected, 
but  its  slope  and  its  maximum  value  are  also  reduced, 


VENOUS  RETURN 


I  I  05 


2400-, 


2000-   " 


1600 


1200 


-4  0  +  4  +8  +  12 

RIGHT       ATRIAL       PRESSURE  (mmHg) 


+  16 


fig.  3.  Cardiac  output  curves,  showing  the  effect  of  open- 
ing the  chest  and  of  cardiac  tamponade. 

the  degree,  of  course,  depending  upon  the  degree  of 
cardiac  tamponade. 

SUMMARY     OF     FACTORS     THAT     AFFECT     THE     CARDIAC 

output  curves.  From  the  above  discussion  of  the 
different  factors  that  affect  cardiac  output  curves,  we 
see  that  the  curves  fall  into  two  simple  patterns.  First, 
any  factor  that  increases  the  effectiveness  of  the  heart 
as  a  pump  or  decreases  the  load  against  which  it  must 
pump  will  elevate  the  curves.  Conversely,  any  factor 
that  decreases  the  effectiveness  of  the  heart  as  a  pump 
or  increases  its  load  will  depress  the  curves.  The 
second  pattern  of  cardiac  output  curves  occurs  when 
pressure  on  the  outside  of  the  heart  alters  the  effective 
cardiac  filling  pressures.  The  greater  the  pressure 
outside  the  heart,  the  further  to  the  right  is  the  cardiac 
output  curve  shifted. 

Bv  keeping  these  basic  principles  in  mind  one  can 
determine  with  relative  accuracy  what  the  cardiac 
output  curve  of  any  given  heart  under  any  given 
condition  will  be,  but  it  must  always  be  remembered 
that  at  any  instant  the  pumping  effectiveness  of  the 
heart  is  depicted  by  only  a  single  cardiac  output 
curve,  not  by  a  family  of  curves.  With  this  discussion 
of  cardiac  output  curves  as  a  background,  we  can  now 
proceed  to  the  somewhat  more  complicated  venous 
return  curves  which  are  the  "complements"  to  the 
cardiac  output  curves. 

Venous  Return  Curves 

VENOUS  RETURN  CURVES  AS  COMPLEMENTS  TO  CARDIAC 

output  curves.  Referring  back  to  figures  2  and  3,  one 


sees  that  each  cardiac  output  curve  represents  an 
infinite  series  of  cardiac  outputs  over  a  range  of  right 
atrial  pressures.  However,  it  is  obvious  that  the  cardiac 
output  at  any  given  time  can  be  only  one  value,  not 
an  infinite  number  of  values.  The  next  question  that 
arises  is,  how  does  one  determine  where  on  the  cardiac 
output  curve  the  circulatory  system  will  be  operating 
at  a  given  time?  Obviously,  if  one  can  determine  the 
right  atrial  pressure,  he  can  then  determine  the 
cardiac  output.  However,  the  right  atrial  pressure, 
like  the  cardiac  output,  is  a  variable.  For  this  reason, 
we  must  find  some  method  to  determine  the  right 
atrial  pressure  at  the  same  time  that  we  determine  the 
cardiac  output.  A  method  for  doing  this  is  to  analyze 
the  systemic  circulation  in  terms  of  right  atrial  pres- 
sure and  flow,  just  as  the  heart-lung  segment  has  been 
analyzed  for  right  atrial  pressure  and  flow.  This  time 
we  use  the  term  "venous  return"  for  the  flow,  but  we 
still  use  right  atrial  pressure  as  the  opposite  coordinate. 
If  we  remember  that  venous  return  equals  cardiac 
output  except  for  transient  instantaneous  differences, 
we  see  that  we  are  using  exactly  the  same  coordinates 
for  analyzing  the  characteristics  of  the  systemic  circu- 
lation as  we  have  used  for  the  heart-lung  segment  of 
the  circulation.  Once  this  is  done,  the  curves  de- 
picting the  respective  functions  of  the  two  segments  of 
the  circulation  can  be  plotted  on  the  same  coordinates, 
and  the  point  at  which  the  two  curves  cross  provides  a 
solution  that  gives  the  venous  return,  the  cardiac 
output,  and  the  right  atrial  pressure,  all  simul- 
taneously (81). 

METHOD  FOR  RECORDING  VENOUS  RETURN  CURVES.  To 

determine  the  effect  of  right  atrial  pressure  on  the 
return  of  blood  from  the  systemic  circulation  to  the 
heart,  we  must  use  one  of  three  different  procedures: 
/ )  isolate  the  systemic  circulation  and  use  a  con- 
trolled pump  in  place  of  the  heart,  2)  control  the 
action  of  the  heart  itself  by  placing  a  controlled  pump 
in  place  of  one  portion  of  the  heart,  or  3)  make 
measurements  of  flows  and  pressures  in  different  parts 
of  the  systemic  circulation  while  artificially  altering 
the  pumping  ability  of  the  heart.  In  our  laboratory, 
we  have  studied  the  effect  of  right  atrial  pressure  on 
venous  return  using  all  these  three  different  methods, 
in  open-chest  animals  when  using  the  first  two 
methods  (87,  96,  98,  99,  102,  103,  105)  and  in  closed- 
chest  animals  when  utilizing  the  third  method  (97). 
The  results  have  been  identical  within  the  limits  of 
experimental  error.  Furthermore,  contrary  to  the 
effects  on  the  cardiac  output  curve,  opening  the  chest 


I  1 06 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION     II 


does  not  significantly  alter  the  effect  of  right  atrial 
pressure  on  venous  return. 

Figure  4  illustrates  one  of  the  typical  methods  used 
to  study  venous  return.  This  procedure  substitutes  an 
external  perfusion  circuit  for  the  right  heart.  The 
right  atrium  is  cannulated,  and  blood  is  pumped  from 
this  cannula  through  a  system  that  includes  a)  a 
collapsible  tube  that  can  be  raised  or  lowered  to  adjust 
the  right  atrial  pressure,  b)  a  heater  used  to  maintain 
a  normal  blood  temperature,  c)  a  pump  that  always 
provides  sufficient  propulsive  force  to  keep  flowing 
through  the  circuit  all  the  blood  that  is  allowed  to 
pass  the  collapsible  tube,  and  d)  a  recording  flow- 
meter, usually  of  the  rotameter  type.  After  passing 
through  this  external  circuit,  the  blood  is  reinfused 
into  the  distal  stump  of  the  pulmonary  artery.  Thus, 
all  the  blood  entering  the  right  atrium  must  pass 
through  this  external  circuit.  This  system  allows  con- 
tinuous recording  of  the  blood  flow  through  the  heart, 
which  can  be  termed  either  "venous  return"  or 
"cardiac  output."  Indeed,  even  all  the  coronary  blood 
flow,  which  empties  into  the  right  atrium,  courses 
through  this  circuit.  Furthermore,  the  pressure  inside 
the  collapsible  tube  automatically  adjusts  exactly  to 
the  atmospheric  pressure;  therefore,  the  right  atrial 
pressure  can  be  elevated  or  lowered  and  maintained 
at  a  very  exact  value,  regardless  of  how  much  blood 
flows  into  the  right  atrium,  by  simply  raising  or 
lowering  the  collapsible  segment. 

Still  another  important  feature  of  this  system  is  that 
the  right  atrial  pressure,  except  during  periods  of 
measurements,  can  be  maintained  at  a  negative  value, 
thus  allowing  blood  to  flow  from  the  extrathoracic 
veins  into  the  right  atrium  with  equally  as  much  ease 


Flowmeter 


t  '  Right    atrium 

Collapsible    tube 

fig.  4.  External  perfusion  system  in  which  a  pump  controls 
the  activity  of  the  heart.  Using  this  external  system  it  is 
possible  to  raise  and  lower  the  right  atrial  pressure  at  will 
while  studying  the  effect  of  right  atrial  pressure  on  venous 
return. 


as  in  the  closed-chest  animal.  Therefore,  in  using  this 
preparation,  the  circulatory  system  does  not  deterio- 
rate, as  is  usually  the  case  when  the  veins  are  cannu- 
lated (178),  but,  instead,  will  continue  in  an  active 
state  for  many  hours. 

EFFECT  OF  RIGHT  ATRIAL  PRESSURE  ON  VENOUS  RE- 
TURN  THE  NORMAL  VENOUS  RETURN  CURVE.   Figure  5 

illustrates  the  normal  effect  on  venous  return  of  in- 
creasing the  right  atrial  pressure  (96).  Note  that  this 
curve,  like  the  cardiac  output  curves  discussed  above, 
does  not  tell  one  exactly  what  the  venous  return  will 
be,  but  tells  instead  what  the  venous  return  would  be 
if  the  right  atrial  pressure  were  known.  Furthermore, 
this  venous  return  curve  depicts  the  circulatory 
conditions  at  a  given  instant,  but  it  can  become 
considerably  altered,  as  will  be  discussed  below,  from 
one  instant  to  another.  For  this  reason,  all  the  different 
points  along  the  curve  must  be  measured  under 
identical  circulatory  conditions.  This  has  been  diffi- 
cult to  do,  because  any  time  the  venous  return  falls 
to  subnormal  values,  circulatory  reflexes  immediately 
ensue,  attempting  to  return  the  venous  return  back 
toward  a  normal  value.  In  so  doing,  the  venous 
return  curve  becomes  greatly  altered,  which  also 
will  be  discussed  below.  To  prevent  this,  two  different 
methods  have  been  used  to  measure  the  venous 
return  curve  without  altering  systemic  conditions  by 
circulatory  reflexes  or  by  other  circulatory  changes 
during  the  course  of  measurement.  First,  venous 
return  curves  have  been  measured  in  animals  sub- 
jected to  total  spinal  anesthesia,  which  abrogates  all 
circulatory  reflexes.  However,  to  determine  the 
normal  venous  return  curve,  a  drip  of  epinephrine  or 
norepinephrine  is  administered  to  the  animal  to 
return  the  vasomotor  tone  back  to  normal  prior  to 
making  the  measurements  necessary  to  establish  the 
curve. 


Plateau 


c     1 200- 


z 
a. 

3 


O 

z 

UJ 

> 


800 


400- 


Mean   systemic 

pressure  = 

7  mm  Hg 


0  44 

RIGHT      ATRIAL      PRESSURE    (mm  Hg) 

fig.  5.  The  normal  venous  return  curve. 


-4 
ATRIAL 


+  8 


VENOUS  RETURN 


I  IO7 


The  second  method  for  establishing  the  normal 
venous  return  curve  has  been  to  determine  different 
points  along  the  curve  intermittently  by  suddenly 
elevating  the  right  atrial  pressure  and  making  venous 
return  measurements  within  the  next  5  to  7  sec 
before  circulatory  reflexes  can  take  place.  Then  the 
circulation  is  returned  to  normal,  and  after  a  reason- 
able control  period  another  intermittent  measure- 
ment is  made. 

The  venous  return  curves  recorded  by  these  two 
different  procedures  have  been  identical.  Further- 
more, venous  return  curves  have  been  recorded  in 
closed-chest  animals  in  which  a  special  occluding 
system  has  been  surgically  placed  around  the  pul- 
monary artery  so  that  the  pulmonary  artery  could  be 
occluded  to  any  desired  degree  (97).  Then,  using 
especially  the  intermittent  procedure,  points  along 
the  venous  return  curve  were  established.  The  results 
agree  with  the  measurements  established  when  using 
the  above  two  procedures. 

The  venous  return  curve  of  figure  5  is  the  average 
curve,  recorded  in  approximately  100  separate  dogs 
anesthetized  with  sodium  pentobarbital,  and  then 
extrapolated  on  a  weight  basis  to  the  12-kg  dog. 
Several  features  of  this  curve  deserve  special  comment. 

First,  when  the  right  atrial  pressure  becomes  more 
negative  than  o  to  —  4  mm  Hg,  a  further  increase  in 
the  negativity  of  the  right  atrial  pressure  does  not 
cause  a  further  increase  in  venous  return.  In  other 
words,  the  venous  return  curve  reaches  a  '"plateau." 
The  cause  of  this  effect  is  the  well-known  collapse 
factor  in  veins  (88,  112).  One  can  actually  see  the 
veins  entering  the  thoracic  cavity  begin  to  collapse 
when  the  right  atrial  pressure  becomes  negative  with 
respect  to  atmospheric  pressure.  Furthermore, 
measurements  in  the  veins  immediatelv  bevond  the 
collapsed  points  show  that  these  veins  all  have  ap- 
proximately o  mm  Hg  pressure  in  them  regardless  of 
how  low  the  right  atrial  pressure  falls.  Thus,  the 
collapse  factor  effectively  sets  the  venous  pressure  of 
the  blood  leaving  the  systemic  circulation  almost 
exactly  at  o. 

The  second  important  point  in  relation  to  the 
venous  return  curve  is  that  elevation  of  the  right 
atrial  pressure  above  o  causes  a  very  rapid  decrease 
in  return  of  blood  from  the  systemic  circulation 
(98).  On  the  average,  for  each  mm  Hg  rise  in  pressure 
above  o,  the  venous  return  decreases  14  per  cent,  and 
it  reaches  zero  when  the  right  atrial  pressure  has 
risen  to  approximately  +7  mm  Hg  in  "areflex"  dogs. 

The  third  important  point  is  that  when  venous 
return  reaches  zero,  the  right  atrial  pressure  at  this 


level  is  equal  to  the  mean  systemic  pressure  (98).  The 
mean  systemic  pressure  is  the  pressure  in  the  systemic 
circulation  that  is  measured  if  the  root  of  the  aorta 
and  the  large  systemic  veins  entering  the  heart  are 
suddenly  occluded  and  all  pressures  in  the  systemic 
circulation  are  brought  instantaneously  to  equilib- 
rium. That  is,  when  blood  flow  ceases  absolutelv 
in  the  systemic  circulation,  the  pressures  in  all  its 
segments  become  equal.  Therefore,  the  right  atrial 
pressure  becomes  equal  to  the  pressure  everywhere 
in  the  systemic  vessels.  This  equilibrium  pressure  is 
the  mean  systemic  pressure. 

The  fourth  point  of  major  significance  in  relation 
to  the  venous  return  curve  is  the  almost  complete 
linearity  of  the  venous  return  curve  in  the  range 
between  o  right  atrial  pressure  and  the  mean  systemic 
pressure  level.  That  is,  the  venous  return  is  approxi- 
mately proportional  to  the  difference  between  mean 
systemic  pressure  and  right  atrial  pressure  (Pms  - 
Pra).  This  difference  is  called  the  "pressure  gradient 
for  venous  return"  (81),  and  it  is  an  important 
concept  in  establishing  the  forces  that  lead  to  the  flow 
of  blood  toward  the  heart.  This  will  be  seen  below, 
especially  in  relation  to  alterations  in  systemic 
resistances,  for  when  there  is  no  pressure  gradient  for 
venous  return,  there  will  be  no  venous  return  to  the 
heart  regardless  of  the  changes  in  systemic  resistances. 

EFFECT  OF  PERIPHERAL  RESISTANCE  ON  VENOUS  RETURN. 

Figure  6  illustrates  the  effect  on  the  venous  return 


2400 


2000- 


1600 


CE 

\- 
UJ 
CC 

w 

z> 
o 

z 

UJ 

> 


1200 


800 


400- 


+4  +8 

RIGHT    ATRIAL     PRESSURE    (mm  Hg) 

fig.  6.  Effect  on  the  venous  return  curve  of  changing  the 
peripheral  resistance.  Note  that  the  mean  systemic  pressure 
remains  constant  at  approximately  7  mm  Hg. 


no8 


HANDBOOK    OF    PHYSIOLOOV 


CIRCULATION    II 


fig.  7.  Effect  on  the  venous  return  curse  of  suddenly  open- 
ing large  bilateral  femoral  A-V  fistulae. 

curve  of  changing  the  systemic  resistance  from  normal 
(87).  Note  that  the  venous  return  is  exactly  zero  in 
the  case  of  each  of  these  three  curves  when  the  right 
atrial  pressure  is  equal  to  the  mean  systemic  pressure. 
That  is,  when  there  is  no  pressure  gradient  for  venous 
return,  there  is  likewise  no  flow  toward  the  heart. 
Yet,  when  the  right  atrial  pressure  falls  to  some  value 
below  the  mean  systemic  pressure,  then  a  pressure 
gradient  does  exist  for  forcing  blood  toward  the 
heart,  and  the  return  of  blood  is  inversely  propor- 
tional to  the  resistance.  The  greater  the  resistance, 
the  less  is  the  return  of  blood  to  the  heart,  and  the 
less  the  resistance,  the  greater  is  the  venous  return. 
Thus,  figure  6  shows  the  normal  venous  return  curve, 
a  venous  return  curve  in  which  the  resistances 
throughout  the  systemic  circulation  are  approximately 
one-half  normal,  and  a  venous  return  curve  in  which 
the  resistances  are  approximately  two  times  normal. 
Figure  7  illustrates  a  typical  experiment  in  which 
peripheral  resistance  was  suddenly  changed  while 
all  other  conditions  of  the  circulation  were  kept  as 
nearly  constant  as  possible  (103).  In  this  instance  two 
large  femoral  A-V  fistulae  were  suddenly  opened  so 
that  the  total  peripheral  resistance  was  decreased  to 
approximately  60  per  cent  of  the  control  value. 
Circulatory  pressures  remained  exactly  constant. 
Note  that  the  study  depicts  precisely  the  same  effects 
as  those  illustrated  in  the  previous  figure  but  this 
time  showing  a  typical  and  actual  experimental 
study 


It  should  not  be  supposed,  however,  that  increasing 
the  resistance  to  blood  flow  in  the  arteries  affects 
venous  return  equally  as  much  as  increasing  the 
resistance  in  the  veins.  Indeed,  for  a  given  increase 
in  venous  resistance,  the  venous  return  decreases 
approximately  eight  times  as  much  as  when  the 
arterial  resistance  is  increased  the  same  amount. 
This  was  illustrated  by  a  comparative  study  in  which 
arterial  resistance  was  increased  by  injecting  micro- 
spheres into  the  arterial  system  and  venous  resistance 
was  increased  by  progressive  occlusion  of  all  the  large 
veins  emptying  into  the  right  atrium  (87).  Figure  8 
illustrates  the  difference  between  these  two  effects, 
the  upper  curve  showing  that  the  total  peripheral 
resistance  could  be  increased  by  arterial  embolization 
to  as  much  as  400  to  500  per  cent  of  control  values 
before  the  venous  return  decreased  a  great  amount. 
On  the  other  hand,  increasing  the  total  peripheral 
resistance  only  30  per  cent  by  the  method  of  venous 
compression  decreased  the  venous  return  to  one-half 
normal. 

The  cause  of  this  difference  between  venous  re- 
sistance and  arterial  resistance  is  that  the  arterial 
system  proximal  to  the  arterioles  has  very  little 
capacitance  (DV/DP)  in  relation  to  the  total  capa- 
citance of  the  s\stemic  circulation  proximal  to  the 
venous  constriction  at  the  outflow  of  the  veins  into 
the  heart  (89).  Because  of  the  small  storage  ability  of 
the  arteries  for  blood,  increasing  the  resistance  at 
the  arterioles  elevates  the  arterial  pressure  almost  as 


100 


°  80- 


60- 


C40- 


S20i 
o 


^9   °"er,ol    resistance 


100  200  300  400  500 

TOTAL     PERIPHERAL     RESISTANCE  (%  of  control   value) 

fig.  8.  Effect  on  venous  return  of  increasing  the  total 
peripheral  resistance  when  the  resistance  is  increased  in  three 
different  ways :  1 )  by  injecting  microspheres  into  the  arteries 
to  increase  arterial  resistance,  2)  by  constricting  the  inflow- 
veins  to  the  heart,  and  3)  by  a  combination  of  these  two 
procedures.  [From  Guyton  et  til.  (87).] 


VENOUS  RETURN 


I  IOg 


much  as  the  resistance  rises,  and  the  arterial  pressure 
then  simply  forces  the  blood  on  past  the  resistance. 
On  the  other  hand,  constricting  the  veins  where  they 
empty  into  the  heart  causes  the  pressure  in  the  veins 
to  rise  only  a  few  mm  Hg  because  of  the  great  storage 
capacity  of  the  veins.  This  small  rise  in  venous 
pressure  is  far  too  little  to  overcome  the  increasing 
resistance,  and,  as  a  consequence,  the  venous  return 
becomes  tremendously  depressed.  Therefore,  venous 
resistance  affects  venous  return  to  the  heart  many 
times  as  much  as  arteriolar  or  arterial  resistance  of 
the  same  magnitude. 

EFFECT      OF      MEAN      SYSTEMIC      PRESSURE      ON      VENOUS 

return.  Basically  the  mean  systemic  pressure  is  the 
resultant  of  the  ratio  of  a)  the  blood  volume  to  b)  the 
ability  of  the  circulatory  system  to  hold  blood.  As 
the  blood  volume  increases,  the  mean  systemic 
pressure  remains  essentially  zero  until  the  blood 
barely  begins  to  distend  the  blood  vessels.  But,  once 
this  point  has  passed,  any  further  increase  in  blood 
volume  increases  the  mean  systemic  pressure  directly 
in  proportion  to  the  additional  amount  of  blood 
injected  into  the  circulation,  the  mean  systemic 
pressure  rising  approximately  1  mm  Hg  for  each  2 
per  cent  increase  in  blood  volume  (86).  Thus,  it  can 
be  seen  that  very  small  changes  in  blood  volume  can 
cause  relatively  large  changes  in  mean  systemic 
pressure  and,  as  a  consequence,  can  have  a  marked 
effect  on  venous  return  unless  other  circulatory 
compensations  prevent  this. 

Only  a  few  measurements  of  mean  systemic  pressure 
have  ever  been  made,  for  this  requires  instantaneous 
stoppage  of  the  circulation  and  then  rapid  equilibra- 
tion of  the  pressures  in  all  segments  of  the  systemic 
circulation  before  any  blood  can  leave  or  before 
circulatory  reflexes  or  other  factors  can  change  the 
vascular  distensibility.  In  our  laboratory,  we  have 
measured  this  pressure  a  few  times  by  suddenly 
constricting  the  aorta  and  pulmonary  arteries  (138), 
utilizing  devices  implanted  several  weeks  previously 
in  the  thoracic  cavity  to  cause  the  constrictions.  These 
pressure  measurements  showed  a  normal  mean 
systemic  pressure  of  almost  exactly  7  mm  Hg. 

Far  more  measurements  have  been  made  of  the 
mean  circulatory  pressure  (101,  105,  180,  182)  than 
of  the  mean  systemic  pressure;  approximately  1000 
such  measurements  have  been  made  in  our  laboratory. 
Since  the  mean  systemic  pressure  is  of  such  extreme 
importance  in  determining  venous  return  to  the 
heart,  the  few  measurements  of  mean  systemic 
pressure  have  been  compared  with  measurements  of 


mean  circulatory  pressure.  In  all  instances,  the  mean 
systemic  pressure  has  been  almost  identical  with  the 
mean  circulatory  pressure  except  in  the  case  of 
extreme  engorgement  of  the  pulmonary  circulation, 
and  even  here  the  difference  has  been  only  1  mm  Hg 
or  so.  Therefore,  insofar  as  venous  return  from  the 
systemic  circulation  is  concerned,  one  can  consider 
the  mean  systemic  pressure  and  mean  circulatory- 
pressure  to  be  almost  identical. 

Measurements  of  mean  circulatory  pressure  can  be 
made  very  easily  by  electrically  fibrillating  the  heart 
with  60-cycle  current  applied  to  needle  electrodes  in 
the  anterior  chest  wall  at  approximately  50  v.  Studies 
have  demonstrated  that  all  pressures  of  significance  in 
the  measurement  of  mean  circulatory  pressure  come 
to  equilibrium  within  only  a  few  seconds  after  cardiac 
fibrillation  begins,  except  for  the  pressures  of  the  sys- 
temic arterial  chamber  and  the  systemic  venous 
chamber.  Therefore,  immediately  after  fibrillation  of 
the  heart  begins,  arterial  blood  is  pumped  from  a 
catheter  lying  in  the  descending  aorta  and  thence 
through  another  catheter  into  the  inferior  vena  cava. 
After  only  3  to  5  sec,  the  pressures  in  these  two  cham- 
bers are  brought  to  equilibrium  and  the  mean  circu- 
latory pressure  measured.  During  the  next  few  seconds 
the  heart  is  defibrillated  by  passing  4  to  10  amperes 
of  60-cycle  alternating  current  at  440  v  for  i/[0  sec 
directly  through  the  chest  anteroposteriorly  (104). 
After  2  to  3  min  of  recovery,  the  animal  returns  to 
essentially  normal  circulatory  conditions. 

Figure  9  illustrates  the  typical  effect  on  the  venous 


2400- 

2000- 

\ 

1600- 

" 

Nor 

mal 

1200- 

800- 

"2 

X 

normal     ft^              \ 

400- 

^""sf                \ 

0 

\    Pms ;  \ 
\    ,35mm^ 

Pms  = 
\l,  7  mm 

\   Pms  ■ 
\yl4mn 

1 

— 1 

1                    1 

1 

1                    1 

-12  -8  -4  0  +4  +8  +12  +16 

RIGHT     ATRIAL     PRESSURE     (mm  Hg) 

fig.  9.  Effect  on  the  venous  return  curve  caused  by  changes 
mean  systemic  pressure. 


I  I  10 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


return  curve  caused  by  altering  the  mean  systemic 
pressure.  Note  that  when  the  mean  systemic  pressure 
is  increased  from  the  normal  value  of  7  mm  Hg  up 
to  1 4  mm  Hg  the  curve  is  shifted  to  the  right  and  its 
plateau  becomes  approximately  twice  as  high  as 
normal.  Conversely,  when  the  mean  systemic  pressure 
is  decreased  to  3.5  mm  Hg,  which  is  one-half  normal, 
the  curve  is  shifted  to  the  left,  and  the  plateau  becomes 
reduced  to  one-half  normal.  Since  the  flow  of  blood 
to  the  heart  is  proportional  to  the  pressure  gradient 
for  venous  return,  which  in  turn  is  equal  to  the  mean 
systemic  pressure  minus  the  right  atrial  pressure,  one 
can  see  that  any  increase  in  mean  systemic  pressure 
causes  a  corresponding  increase  in  venous  return  at 
any  given  right  atrial  pressure.  Likewise,  any  decrease 
in  the  mean  systemic  pressure  will  cause  a  cor- 
responding decrease  in  venous  return  at  all  right 
atrial  pressures. 

Figure  10  depicts  venous  return  curves  in  a  series 
of  normal  dogs  and  then  again  in  the  same  dogs  after 
an  average  infusion  of  200  ml  of  blood  and  also 
after  hemorrhage  of  122  ml  (99).  Note  that  the 
normal  mean  systemic  pressure  was  approximately 
7.7  mm  Hg,  that  this  rose  to  1 1 .3  mm  Hg  in  the 
infused  dog,  and  that  it  fell  to  4.7  mm  Hg  in  the 
hemorrhaged  dog.  This  experiment  illustrates  typical 
shift  of  the  venous  return  curves  to  the  right  as  the 
blood  volume  increases,  thereby  increasing  the  mean 
systemic  pressure. 

Changes  in  the  distensibility  of  the  vascular  system 
or  changes  in  the  pressure  on  the  outside  of  the 
vessels  can  alter  the  mean  circulatory  pressure  in 
exactly  the  same  manner  as  can  alterations  in  blood 
volume.   These  changes   include   a)    increased   vaso- 


motor tone,  caused  either  by  sympathetic  stimulation 
or  by  infusion  of  sympathomimetic  drugs;  b)  pressure 
on  the  abdomen,  which  compresses  large  intra- 
abdominal blood  reservoirs;  c)  increased  intrathoracic 
pressure,  which  compresses  the  blood  reservoirs  of 
the  chest;  and  d)  increased  interstitial  fluid  volume, 
which  causes  pressure  on  the  outside  of  blood  vessels 
throughout  the  body.  In  normal  circulatory  ad- 
justments the  most  important  of  these  is  the  effect  of 
vasomotor  tone  on  the  mean  systemic  pressure. 

Figure  1  1  illustrates  the  average  results  from  1  1 
typical  experiments  in  dogs  in  which  the  degree  of 
vasomotor  tone  was  altered  from  the  minimal  level 
up  to  almost  the  maximal  level  (95).  This  shows  the 
typical  effects  one  would  expect  when  the  mean 
systemic  pressure  is  elevated,  that  is,  progressive 
shift  of  the  venous  return  curves  to  the  right  as  the 
vasomotor  tone  is  increased. 

One  might  have  expected  the  administration  of  a 
sympathomimetic  drug  to  cause  increased  resistance 
to  blood  flow  toward  the  heart  as  well  as  to  increase 
the  mean  circulatory  pressure.  This  was  not  evident 
from  these  studies,  for  the  venous  return  curves  did 
not  decrease  in  slope  as  the  rate  of  epinephrine  in- 
jection was  increased.  On  second  thought,  one  can 
understand  why  this  was  true.  When  vasomotor  tone 
is  increased  throughout  the  circulation  while  the  blood 
volume  remains  constant,  pressures  everywhere  in 
the  circulation  will  tend  to  rise  because  of  tightening 
of  the  vessels  around  the  blood.  But,  if  any  single 
segment  of  the  circulation  constricts,  some  other 
segment  of  the  circulation  must  dilate.  On  the 
average,  then,  for  every  constriction  that  occurs  in 
the   systemic   circulation    following   the   injection    of 


fig.  10.  Effect  of  increasing  or  decreasing  the 
blood  volume  on  the  venous  return  curves.  Total 
spinal  anesthesia  was  instituted  to  prevent  cardio- 
vascular reflexes  during  the  course  of  the  experi- 
ment. [From  Guyton  et  a/,  (qq).1 


Z> 
h- 
LU 

<r 

CO 

o 


2400 

2000 

1600 

1200 

800 

400 


TOTAL  SPINAL  ANESTHESIA 
0.0005  mg  EPINEPHRINE  /kg  /mm 
TEN  DOGS 
AVERAGE  WEIGHT  =12.94  kg 


AVG  ART  PRESS   --  131  1  mm  Hg 


INFUSION    200 
AVG  ART   PRESS    = 


NORMAL 


-16       -12       -8        -4  0        +4        +8        +12 

RIGHT    ATRIAL    PRESSURE   (mm  Hg) 


+  16 


VENOUS  RETURN 


U1 

Z> 

o 

z 

UJ 

> 


2400 

2000 

1600 

1200 

800 

400  H 

0 


MEAN  ART  PRESS  =184 


TOTAL  SPINAL  ANESTHESIA 
EPINEPHRINE 
ELEVEN    DOGS 
MEAN  WEIGHT  =  14  kg 


0.0035  mg  /kg  /minute 
MEAN  ART  PRESS.  =  120 


0.0015  mg  /kg  /minute 
MEAN  ART  PRESS.  =  62 


0.0005  mg  /kg  /minute 
MEAN   ART  PRESS  =  4 


NO  EPINEPHRINE 


fig.  II.  Effect  of  different  rates  of  epinephrine 
injection  on  the  venous  return  curves.  Note  that 
the  principal  effect  is  to  increase  the  mean  systemic 
pressure.  [From  Guyton  el  al.  (95  I 


■16       -12       -8       -4  0       +  4        +8       +12 

RIGHT    ATRIAL    PRESSURE    (mm  Hg) 

epinephrine,  as  depicted  in  the  experiments  of  figure 
1 1 ,  there  had  to  be  equal  dilatation  somewhere  else. 
Indeed,  measurements  have  shown  that,  as  the 
arterioles  constrict  under  these  conditions,  there  is  a 
tendency  for  the  veins  to  dilate  even  though  the  walls 
of  the  veins  do  tighten  to  a  very  great  extent  (55). 
This  elevates  the  mean  systemic  pressure  but  does  not 
increase  the  resistance  to  blood  flow  from  the  systemic 
vessels  toward  the  heart.  In  essence,  then,  we  can  say 
that  an  increase  in  vasomotor  tone  affects  venous 
return  principally  by  increasing  the  mean  systemic 
pressure,  and,  usually,  an  increase  in  vasomotor 
tone  does  not  increase  the  average  resistance  that 
opposes  the  return  of  blood  to  the  heart. 

SUMMARY     OF      FACTORS     THAT     AFFECT     THE     VENOUS 

return  curves.  Basically,  there  are  only  two  different 
patterns  of  changes  in  venous  return  curves,  those 
that  result  from  a)  changes  in  resistance  in  the  systemic 
circulation,  and  h)  changes  in  the  mean  systemic 
pressure.  Figure  6  depicts  the  pattern  of  venous 
return  curves  that  results  from  alteration  of  vascular 
resistance,  while  figure  9  illustrates  the  curves  that 
result  from  alteration  of  mean  systemic  pressure. 

Any  factor  that  alters  resistance,  whether  this  be  a 
localized  or  generalized  alteration,  will  correspond- 
ingly alter  the  venous  return  curve.  However,  altera- 
tion of  the  venous  resistance  affects  venous  return  far 
more  drastically  than  alteration  of  the  arterial  re- 
sistance. 

The  factors  that  affect  the  mean  systemic  pressure 
can  be  divided  into  two  main  groups:  /)  those  that 
affect  the  blood  volume,  and  2)  those  that  affect  the 
ability  of  the  circulatory  system  to  hold  blood.  The 
two  most  important  factors  of  all  that  affect  mean 


systemic  pressure  are  blood  volume  itself  and  changes 
in  vasomotor  tone. 

The  interrelationships  of  all  these  different  factors 
on  the  return  of  blood  to  the  heart  can  be  expressed 
mathematically  by  the  following  formula   (98) : 


VR- 


P 


Pro 


RvCv+(Rv+Ro)Ca 

cv  +  ca 

In  this  formula  VR  is  venous  return,  Pms  is  mean 
systemic  pressure,  Pra  is  right  atrial  pressure,  C,.  is 
capacitance  of  the  veins,  C„  is  capacitance  of  the 
arterial  tree,  Rv  is  the  average  resistance  to  blood  flow 
from  the  veins  to  the  heart,  and  R„  is  the  resistance 
from  the  arterial  tree  to  the  venous  tree.  This  formula 
shows  that  venous  return  is  approximately  pro- 
portional to  the  mean  systemic  pressure  minus  right 
atrial  pressure,  which  has  been  called  the  ''pressure 
gradient  for  venous  return,"  while,  on  the  other  hand, 
venous  return  is  inversely  proportional  to  the  re- 
sistances in  the  systemic  circulation.  The  capacitances 
in  the  formula  are  constants  for  any  given  animal, 
and  they  determine  the  relative  importance  of  arterial 
resistance  versus  venous  resistance.  In  the  normal 
animal  a  given  change  in  venous  outflow  resistance 
affects  venous  return  approximately  eight  times  as 
much  as  the  same  change  in  arterial  resistance  (87). 

Equating  the  Venous  Return  and  Cardiac  Output  Curves 

If  one  understands  the  different  factors  that  affect 
venous  return  and  cardiac  output  curves,  he  can 
readily  determine  the  approximate  effects  of  any 
given  circulatory  change  on  each  of  these  two  types 


I  I  12 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


2400, 


f    2O0O- 


-4  0  +4  +8  +12 

RIGHT     ATRIAL    PRESSURE     (mmHql 

fig.  i  2.  Equating  of  a  normal  cardiac  output  curve  and  a 
normal  venous  return  curve  for  a   12-kg  dog. 

of  curves.  Then  by  plotting  the  two  curves  on  the  same 
coordinates,  as  shown  in  figure  12,  the  equations 
represented  by  the  separate  curves  can  be  solved 
(8i).  Figure  12  illustrates  the  equating  of  a  normal 
venous  return  curve  with  a  normal  cardiac  output 
curve,  as  depicted  for  the  10-kg  dog.  Note  that  there 
is  only  one  single  point  at  which  the  flows  and  the 
pressures  for  the  two  curves  are  equal,  and  this  point 
is  called  the  "equilibrium  point."  It  represents  the 
solution  to  our  graphical  analysis,  depicting  in  figure 
12  that  this  particular  dog  at  this  particular  time  has 
a  cardiac  output  of  1200  ml  per  min,  a  venous  return 
also  of  1200  ml  per  min,  and  a  right  atrial  pressure 
of  —  2  mm  Hg  (referred  to  the  level  of  the  tricuspid 
valve). 

Looking  once  again  at  figure  1  2,  let  us  assume  that 
an  extra  quantity  of  25  ml  of  blood  is  suddenly 
injected  into  the  right  atrium.  This  would  raise  the 
right  atrial  pressure  to  approximately  +4  mm  Hg, 
and,  as  depicted  by  the  venous  return  curve,  the 
elevated  right  atrial  pressure  would  decrease  the 
venous  return  to  approximately  500  ml  per  min.  On 
the  other  hand,  the  high  right  atrial  pressure  would 
cause  the  cardiac  output,  as  depicted  by  the  cardiac 
output  curve,  to  rise  to  approximately  2000  ml  per 
min.  Thus,  a  disparity  of  1500  ml  per  min  develops 
between  venous  return  and  cardiac  output  so  that 
far  more  blood  is  pumped  out  of  the  heart  than 
returns  to  it.  Therefore,  within  the  next  three  to  six 
heartbeats,  the  right  atrial  pressure  falls  back  to  the 
level  of  —2,  thus  causing  the  venous  return  to  rise  up 
to  1200  ml  and  the  cardiac  output  to  fall  to  1200  ml. 
In  other  words,  within  a  few  seconds,  equilibrium 
will  be  re-established  whenever  venous  return  and 
cardiac  output  deviate  from  each  other  (35). 


EFFECT  OF  SYMPATHETIC  STIMULATION  ON  VENOUS 
RETURN,  CARDIAC  OUTPUT,  AND  RIGHT  ATRIAL  PRES- 
SURE. Using  the  same  principles  for  equating  venous 
return  and  cardiac  output  curves  as  depicted  in 
figure  12,  we  can  now  show  in  figure  13  the  effect  of 
strong  sympathetic  stimulation  on  venous  return, 
cardiac  output,  and  right  atrial  pressure.  The  dashed 
curves  of  the  figure  illustrate  the  normal  curves.  Then, 
suddenly,  sympathetic  stimulation  changes  both  the 
venous  return  and  cardiac  output  curves  to  the 
respective  solid  curves  (95).  Note  that  the  venous 
return  curve  shifts  far  to  the  right  and  upward  be- 
cause of  an  increase  in  "mean  systemic  pressure," 
and  the  cardiac  output  curve  shifts  upward,  as  is 
characteristic  of  a  hypereffective  heart.  These  two 
curves  equate  at  an  entirely  new  point,  the  new 
equilibrium  point  occurring  at  a  right  atrial  pressure 
of  —3  mm  Hg  and  a  cardiac  output  and  venous 
return  of  1800  ml  per  min. 

This  analysis  of  the  effects  of  sympathetic  stimula- 
tion agrees  with  the  typical  experimental  result 
found  when  the  sympathetics  are  stimulated  through- 
out the  body,  that  is,  a  mild  to  moderate  increase  in 
venous  return  and  cardiac  output  and  usually  a 
slight  decrease  in  right  atrial  pressure  (169).  Almost 


E  2800 


-8  -4  0  +4  +8  412 

RIGHT    ATRIAL     PRESSURE     (mm  Hg) 

fig.  13.  Effect  of  sympathetic  stimulation  on  the  venous 
return  and  cardiac  output  curves,  showing  an  increase  in 
cardiac  output  and  venous  return  and  a  decrease  in  right 
atrial  pressure. 


VENOUS  RETURN 


III3 


exactly  the  opposite  effects  occur  when  vasomotor 
tone  is  greatly  reduced  throughout  the  body  by  the 
administration  of  nitrites  (195)  or  ganglion-blocking 
agents  ( 1 89).  Likewise,  pooling  of  blood  in  the  lower 
part  of  the  body  when  one  stands  (5,  76,  14Q-144, 
175,  184,  196)  or  sequestration  of  blood  in  the  limbs 
by  the  application  of  tourniquets  (59,  193)  reduces 
the  venous  return  and  cardiac  output  in  a  closely 
similar  manner. 

EFFECT  OF  MUSCULAR  EXERCISE  ON  VENOUS  RETURN, 
CARDIAC  OUTPUT,  AND  RIGHT  ATRIAL  PRESSURE.   Figure 

14  illustrates  an  analysis  of  the  circulation  during 
exercise,  showing  changes  in  both  the  cardiac  output 
and  venous  return  curves.  The  cardiac  output  curve 
is  elevated  as  a  result  of  a)  sympathetic  stimulation  of 
the  heart,  and  b)  inhibition  of  the  vagi  to  the  heart, 
thus  giving  a  cardiac  output  curve  of  a  hypereffective 
heart. 

Three  different  factors  cause  the  observed  altera- 
tions in  the  venous  return  curve.  First,  tightening  of 
the  musculature   throughout   the   body,   particularly 


4000 


-8  "4  0  +4  +8  +  12  +16  +20 

RIGHT     ATRIAL     PRESSURE    (mm  Hg) 

pig.  14.  Effect  of  exercise  on  the  venous  return  and  cardiac 
output  curves,  showing  that  the  new  curves  equate  at  greatly 
elevated  venous  returns  and  cardiac  outputs.  Also,  the  right 
atrial  pressures  are  still  close  to  zero  mm  Hg. 


tightening  of  the  abdominal  musculature,  causes  an 
instantaneous  increase  in  mean  systemic  pressure  of 
several  millimeters  of  mercury  (100).  Second,  sympa- 
thetic stimulation  causes  considerable  increase  in 
mean  systemic  pressure  (101).  Third,  the  blood  vessels 
of  the  musculature  are  likely  to  become  markedly 
dilated,  thus  decreasing  the  resistance  to  blood  flow 
through  the  systemic  circulation  (12);  this,  in  turn, 
increases  the  slope  of  the  venous  return  curve  (87). 
Thus,  we  find  that  in  moderate  exercise  the  cardiac 
output  and  venous  return  may  be  increased  to  two  or 
more  times  normal,  and  the  right  atrial  pressure  will 
still  be  only  slightly  elevated  (14,  169,  174).  On  the 
other  hand,  in  severe  exercise,  the  heart  is  then  often 
taxed  to  its  limit  so  that  the  right  atrial  pressure  rises 
considerably  as  depicted  by  the  highest  equilibrium 
point  in  the  figure.  In  an  animal  or  human  being  that 
has  been  thoroughly  trained  for  athletics,  the  cardiac 
output  curve  of  the  heart  can  rise  to  one  and  one-half 
to  two  times  that  depicted  in  figure  13,  thus  giving  as 
much  as  a  five-  to  sevenfold  increase  in  cardiac  output 
without  an  elevation  of  right  atrial  pressure  above 
zero. 

Here,  again,  it  is  quite  evident  that  simultaneous 
analysis  of  the  function  of  the  heart  and  of  peripheral 
circulatory  factors  is  needed  to  ascertain  the  inte- 
grated effects  of  exercise  on  venous  return,  cardiac 
output,  and  right  atrial  pressure  (10,  39,  50,  169, 
177,  188). 

EFFECT  OF  RAPID  TRANSFUSION  ON  VENOUS  RETURN, 
CARDIAC  OUTPUT,  AND  RIGHT  ATRIAL  PRESSURE.  Figure 

1 5  depicts  the  effects  of  rapidly  infusing  an  animal 
with  whole  blood.  The  immediate  effect  stems  mainly 
from  an  increase  in  mean  systemic  pressure  (99) — in 
this  instance  from  7  mm  Hg  to  1  1.5  mm  Hg.  How- 
ever, the  increased  blood  volume  also  distends  the 
vessels  of  the  systemic  circulation,  thus  decreasing 
the  peripheral  resistance  and  therefore  increasing 
the  "slope"  of  the  venous  return  curve.  In  the  case 
of  the  heart,  circulatory  reflexes,  especially  the 
pressoreceptor  reflex,  actually  weaken  the  heart 
because  the  excess  blood  volume  tends  to  elevate 
arterial  pressure,  thereby  initiating  inverse  reflexes. 
As  a  consequence,  the  cardiac  output  curve  decreases 
very  slightly.  The  net  result,  as  depicted  by  the 
equilibrium  point,  is  a  moderate  increase  in  venous 
return  and  cardiac  output  and  a  very  marked  rise  in 
right  atrial  pressure,  which  are  effects  that  have  been 
observed  many  times  by  many  different  investigators 
(66-69,  M5>  1 83)-  This  figure  and  the  previous  one 
illustrates  that  the  relationship  between  right  atrial 


ii4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


O 

< 

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2800- 

2400- 

^ 
^ 

2000- 

s 
/ 

/ 

s                                                      

1600- 

/ 

1           / 

Normol       /         / 

v    / 

if*- Rapid     transfusion 

1200- 

'   / s 

800- 

7  \ 

/  / 

\                    \ 

/  / 

\                    \ 

400- 

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\                   \ 

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*  / 

\                  \ 
\                  \ 

/  / 

\                 \ 

0- 

«4 1 

-, ^ \ ■ 

"8  "4  0  +4  +8  +12  +16 

RIGHT    ATRIAL     PRESSURE     (mm  Hg) 

fig.  15.  Effect  of  rapid  transfusion  of  blood  on  venous 
return  and  cardiac  output  curves,  showing  the  result  to  be  an 
elevated  venous  return  and  cardiac  output  and  also  a  con- 
siderably elevated  right  atrial  pressure. 

pressure  and  cardiac  output  is  not  always  even 
directionally  the  same  (169),  for  in  some  circulatory 
conditions  the  cardiac  output  rises  while  the  right 
atrial  pressure  falls;  at  other  times,  as  in  figure  15, 
the  right  atrial  pressure  can  rise  very  greatly  while 
the  venous  return  and  cardiac  output  change  rela- 
tively little. 


EFFECT  OF  SHOCK  ON  VENOUS  RETURN,  CARDIAC  OUT- 
PUT, and  right  atrial  pressure.  Figure  1 6  depicts 
by  the  dashed  curves  the  normal  equating  of  venous 
return  and  cardiac  output  curves  and  then  by  the 
solid  curves  the  effects  immediately  after  hemorrhage 
in  the  so-called  compensated  stage  of  shock.  In  this 
instance,  the  hemorrhage  has  reduced  the  mean 
systemic  pressure  considerably,  shifting  the  venous 
return  curve  to  the  left  (99).  Immediately,  however, 
circulatory  reflexes  have  become  active,  causing  the 
heart  to  become  hypereffective  and  greatly  elevating 
the  cardiac  output  curve.  The  decreased  blood  volume 
also  causes  the  slope  of  the  venous  return  curve  to 
decrease.  Therefore,  for  two  reasons,  /)  decreased 
mean  systemic  pressure,  and  2)  increased  resistance 
to  venous  return,  the  venous  return  curve  is  shifted 
to  the  left,  and  its  plateau  is  reduced.  Therefore,  the 
venous  return  and  the  cardiac  output  curves  equate 


-8  -4  0  +4  +8         +12 

RIGHT    ATRIAL     PRESSURE    (mm  Hg) 

fig.  1 6.  Effect  of  shock  on  the  venous  return  and  cardiac 
output  curves,  showing  in  the  early  compensated  stage  of 
shock  a  low  venous  return  and  cardiac  output  but  also  a 
greatly  depressed  right  atrial  pressure  (point  A).  In  irrever- 
sible shock  the  cardiac  output  becomes  greatly  depressed  as 
illustrated  by  the  dash-dot  curve;  venous  return  and  cardiac 
output  become  greatly  reduced  while  the  right  atrial  pressure 
rises  (point  B). 


at  point  A,  the  cardiac  output  and  venous  return 
falling  to  about  one-half  normal  and  the  right  atrial 
pressure  falling  to  —5  mm  Hg.  These  are  typical 
effects  observed  following  acute  hemorrhage  (90, 
160,  161,  167).  Very  similar  effects  occur  in  persons 
with  vasomotor  collapse  except  that  the  partial  reflex 
compensation  which  occurs  following  hemorrhage  is 
absent  (147). 

In  the  irreversible  stage  of  shock  an  entirely  differ- 
ent situation  ensues,  because  the  heart  then  begins 
to  deteriorate.  This  has  been  shown  especially  by  the 
work  of  Crowell  (92),  but  also  by  measurements  made 
in  Wiggers'  laboratory  (61,  150,  197,  198)  and  by 
Remington  (161).  The  cardiac  output  curve  falls  to 
the  lower  curve  of  the  figure,  and  the  new  equilibrium 
point  is  now  point  B.  Thus,  the  venous  return  and 
cardiac  output  fall  to  a  still  lower  value  while  the 
right  atrial  pressure  begins  to  rise;  these  are  typical 
events  in  the  irreversible  and  terminal  stage  of  shock. 
As  a  result  of  this  additional  decrease  in  cardiac  out- 
put, the  heart  deteriorates  still  more,  and  a  vicious 
cycle  of  cardiac  deterioration  develops,  causing  a 
progressive  rise  in  right  atrial  pressure  and  a  pro- 
gressive fall  in  venous  return  and  cardiac  output. 


VENOUS  RETURN 


III5 


EFFECT  OF  OPENING  THE  CHEST  ON  VENOUS  RETURN, 
CARDIAC  OUTPUT,  AND  RIGHT  ATRIAL  PRESSURE.   Figure 

i  7  illustrates  the  changes  that  occur  in  the  circulation 
when  the  chest  is  opened.  The  dashed  curves  repre- 
sent the  normal  circulatory  conditions  and  then  the 
long  dashed  curve  represents  the  immediate  effects 
on  the  cardiac  output  curve  caused  by  opening  the 
chest.  The  new  equilibrium  point,  point  A,  shows 
that  the  cardiac  output  falls  to  approximately  two- 
thirds  normal  and  the  right  atrial  pressure  rises  im- 
mediately from  —2  mm  Hg  to  +  2  mm  Hg.  How- 
ever, within  approximately  30  sec  to  1  min,  circulatory 
reflexes,  especially  pressoreceptor  reflexes,  cause  a)  the 
cardiac  output  curve  to  rise  to  that  depicted  by  the 
solid  curve,  and  b)  the  venous  return  curve  to  shift 
to  the  solid  venous  return  curve.  These  two  curves 
equate  at  point  B  which  depicts  the  final  effects  of 
opening  the  chest  on  cardiac  output,  that  is,  only  a 
little  decrease  in  cardiac  output  (22)  but  a  con- 
siderable rise  in  right  atrial  pressure.  One  might 
immediately  ask,  therefore:  Does  opening  the  chest 
have  any  significant  detrimental  effect  on  the  circu- 
lation? The  answer  to  this  is  very  definitely  "yes", 
for  the  following  reasons:  In  order  for  the  venous  re- 
turn and  cardiac  output  to  recompensate  essentially 
to  normal,  strong  circulator)-  reflexes  will  have  been 
set  into  play.  Thus,  an  animal  with  his  chest  open 
has  already  utilized  a  major  share  of  his  circulatory 
reflex  power  simply  to  compensate  for  opening  the 
chest.  Now,  the  reserve  reflex  power  left  to  compen- 


sate for  other  circulatory  stresses,  such  as  hemorrhage, 
has  been  greatly  reduced.  Therefore,  it  can  be  said 
that  the  '"circulatory  reserve''  has  been  considerably 
reduced  as  a  result  of  the  opened  chest.  This  analysis, 
therefore,  explains  why  the  cardiac  outputs  of  open- 
chest  animals  are  normally  only  slightly  below  those 
of  normal  animals,  but  it  also  explains  why  animals 
and  human  beings  under  these  conditions  can  with- 
stand far  less  circulatory  stress  than  can  the  normal 
(42). 

EFFECT  OF  MYOCARDIAL  DAMAGE  ON  VENOUS  RETURN, 
CARDIAC  OUTPUT,  AND  RIGHT  ATRIAL  PRESSURE.   Figure 

1 8  illustrates  the  progressive  changes  that  occur  in 
the  circulation  following  sudden  acute  myocardial 
damage  to  both  sides  of  the  heart  approximately 
equally.  The  short  dashed  curves  illustrate  normal 
equilibrium  conditions.  Then,  suddenly,  the  heart 
becomes  severely  damaged  as  a  result  of  acute  myo- 
cardial infarction,  reducing  the  cardiac  output  curve 
to  that  depicted  by  the  long  dashes.  As  a  result,  the 
new  equilibrium  point  is  now  approximately  one- 
third  normal,  and  the  right  atrial  pressure  has  risen 
to  +4  mm  Hg.  However,  these  conditions  do  not 
obtain  for  a  prolonged  period  of  time  because  auto- 
nomic reflexes,  mainly  sympathetic,  cause  immediate 
compensations  within  the  next  30  sec  to  2  min  (2-4,40, 
80,  152).  At  the  end  of  this  period,  the  sympathetic 
stimulation  will   have  increased   the  cardiac  output 


■g  2400 


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RIGHT    ATRIAL     PRESSURE     (mm  Hg) 

fig.  17.  Effect  of  opening  the  chest  on  the  venous  return 
and  cardiac  output  curves,  showing  by  point  A  the  immediate 
effect  and  point  B  the  effect  after  circulatory  reflexes  ensue. 


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fig.  18.  Effect  of  acute  myocardial  infarction  and  subse- 
quent stages  of  recovery  on  the  cardiac  output  and  venous 
return  curves.  The  sequence  of  events  is  explained  in  the  text. 


1 1 16 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


and  venous  return  curves  up  to  those  depicted  by  the 
dashes  and  dots.  Therefore,  within  2  min,  the  venous 
return  and  cardiac  output  will  have  returned  to  ap- 
proximately two-thirds  normal,  and  the  right  atrial 
pressure  will  have  risen  another  2  mm  Hg  up  to  +6 
mm  Hg.  But,  even  this  is  an  abnormally  low  cardiac 
output  which  is  still  insufficient  to  supply  all  the  tissues 
of  the  body  with  adequate  amounts  of  blood.  Further- 
more, there  is  intense  sympathetic  vasoconstriction 
throughout  the  circulatory  system  during  this  period 
of  time  as  well  as  sometimes  a  decreased  arterial  pres- 
sure; the  intense  sympathetic  vasoconstriction  (134) 
and  the  decreased  arterial  pressure  (135)  both  de- 
crease renal  output.  Furthermore,  the  semishock 
state  that  exists  at  this  stage  causes  the  adrenal  glands 
to  secrete  large  quantities  of  aldosterone.  This,  in 
turn,  promotes  rapid  reabsorption  of  sodium  from 
the  renal  tubules,  associated  also  with  rapid  reabsorp- 
tion of  water  (48).  The  net  effect  on  the  kidneys, 
therefore,  is  to  reduce  renal  output  greatly  or,  at 
times,  even  to  stop  renal  output  completely.  Over  a 
period  of  the  next  few  days,  fluid  is  progressively  re- 
tained in  the  circulatory  system,  thus  shifting  the 
venous  return  curve  in  figure  1 8  further  and  further 
to  the  right  (99,  105).  The  solid  venous  return  curve 
depicts  approximately  that  which  will  obtain  after  a 
week  or  so  of  fluid  retention. 

Simultaneously  with  the  changes  that  take  place 
in  the  venous  return  curve,  the  heart  will  also  be 
changing.  If  the  infarction  is  an  uncomplicated  one 
and  recovery  from  the  infarction  begins  immediately, 
then  the  cardiac  output  curve  of  figure  18  will  pro- 
gressively rise.  The  solid  cardiac  output  curve  depicts 
approximately  that  which  one  would  expect  after  a 
week  of  recovery.  As  illustrated  by  the  point  at  which 
the  solid  cardiac  output  curve  equates  with  the  solid 
venous  return  curve,  we  find  that  the  cardiac  output 
and  venous  return  will  have  now  returned  almost 
completely  to  normal  but  that  the  right  atrial  pressure 
again  will  have  risen  another  2  mm  Hg.  This  is  charac- 
teristic of  the  chronic  stage  of  congestive  heart  failure, 
that  is,  the  cardiac  output  may  be  normal  or  slightly 
below  normal,  but  the  venous  pressures  are  essentially 
always  greatly  elevated. 

Another  effect  that  occurs  as  the  cardiac  output 
approaches  normal  is  that  the  degree  of  sympathetic 
activity  throughout  the  body  also  gradually  becomes 
reduced  toward  normal.  Furthermore,  the  body  is 
no  longer  in  a  shocklike  state  so  that  the  output  of 
aldosterone  also  becomes  reduced.  As  a  consequence, 
renal  output  once  again  returns  toward  normal,  thus 
preventing  further  retention  of  fluid.  Therefore,  the 
circulatorv   svstem   has   now   reached    a   new   steady 


state,  with  the  cardiac  output  and  venous  return 
essentially  normal,  renal  output  once  again  essen- 
tially normal,  but  the  right  atrial  pressure  consider- 
ably  elevated. 

It  should  be  noted  again  that  the  analysis  illus- 
trated in  figure  1 8  is  that  for  myocardial  damage 
affecting  both  ventricles  approximately  equally.  The 
course  of  events  depicted  by  the  dotted  line  is  typical 
of  that  normally  observed  following  acute  generalized 
myocardial  infarction  (13,  71,  73,  75,  106-108,  121, 
162,  163,  166).  We  shall  see  that  the  more  complicated 
graphical  analysis  presented  later  in  the  chapter  is 
much  more  satisfactory  than  the  simple  graphical 
analysis  when  one  side  of  the  heart  fails  to  a  greater 
extent  than  the  other  side. 

ANALYSIS    OF    DECOMPENSATION    AND    COMPENSATION    IN 

congestive  heart  failure.  Figure  ig  illustrates  an 
analysis  of  decompensation  in  severe  cardiac  failure. 
This  shows  by  the  two  dashed  curves  the  analysis  for 
the  normal  circulatory  system  in  a  normal  10-kg  dog. 
Then,  at  the  bottom  of  the  graph,  it  shows  the  typical 
cardiac  output  curve  for  a  severely  damaged  heart 
after  all  sympathetic  reflexes  and  all  recovery  that 
are  possible  have  taken  place  (38).  If  we  assume  that 
the  cardiac  output  curve  suddenly  falls  from  the 
normal  down  to  this  depressed  curve,  then  we  find 
that  the  cardiac  output  immediately  falls  to  point  Ay 
about  two-fifths  normal,  with  a  right  atrial  pressure 
of  approximately  +4  mm  Hg.  This  cardiac  output 
is  far  too  little  to  cause  normal  renal  function,  and, 
for  the  same  reasons  discussed  above,  renal  output 
becomes  severely  depressed.  As  a  result,  fluids  are 
retained  in  the  body,  and  the  mean  systemic  pressure 
progressively  rises,  shifting  the  venous  return  curves 
to  the  right  and  progressively  elevating  their  plateaus. 
Thus,  during  the  ensuing  days,  with  the  progressive 
retention  of  fluid,  the  equilibrium  points  in  figure  19 
proceed  to  B,  C,  D,  E,  F,  and  G.  It  is  especially  in- 
teresting that  cardiac  output  curves  of  severely  dam- 
aged hearts  do  not  rise  to  a  plateau  but,  instead,  rise 
to  a  peak  and  then  begin  to  descend  (117).  Therefore, 
after  the  process  of  decompensation  has  proceeded 
past  the  peak  at  point  E,  further  retention  of  fluid 
causes  a  reduction  in  cardiac  output  rather  than  an 
increase. 

The  significant  factor  in  decompensation  is  that 
even  at  its  greatest  peak,  the  cardiac  output  curve 
never  reaches  the  necessary  cardiac  output  level  re- 
quired to  re-establish  normal  renal  function.  Con- 
sequently, fluids  continue  to  be  retained  indefinitely 
until  death  of  the  animal. 


VENOUS  RETURN 


I  I  I  7 


fic.  19.  Analysis  of  decompensated  heart 
disease,  showing  a  greatly  depressed  cardiac 
output   curve   and   a   progressive   shift   of  the 

venous  return  curves  to  the  right  until  death 

occurs,  as  explained  in  the  text. 


-4  0  +  4 

RIGHT      ATRIAL 


+  8  +12  »I6 

PRESSURE     (mm  Hq) 


Figure  20  depicts  recompensation  of  the  animal 
that  had  been  almost  dead  from  decompensated 
heart  disease.  The  lower  curve  illustrates  a  cardiac 
output  curve  of  a  decompensated  heart,  showing  that 
after  a  period  of  time  the  venous  return  curve  had 
already  reached  the  far  right  curve  with  equilibrium 
occurring  at  point  A.  Then,  upon  instituting  appropri- 
ate treatment,  such  as  the  administration  of  digitalis 
(117),  the  heart  becomes  considerably  stronger,  and 
the  cardiac  output  curve  rises  to  the  upper  curve.  If 
this  rise  is  relatively  rapid,  the  venous  return  curve 
will  not  be  immediately  affected.  Therefore,  the  new 
equilibrium  point  becomes  point  B,  which  represents 
a  cardiac  output  greater  than  that  required  for  normal 
renal  function.  As  a  consequence,  the  output  of  urine 
now  becomes  actually  far  greater  than  normal,  which 
is  a  well-known  effect  of  digitalis  when  a  decompen- 
sated state  is  converted  into  a  compensated  state.  The 
output  of  urine  causes  a  decrease  in  mean  circulatory 
pressure  and  a  progressive  shift  in  the  venous  return 
curves  toward  the  left.  Thus,  during  the  ensuing  days, 
the  equilibrium  points  in  figure  20  shift  from  point 
B  to  C,  to  D,  and  finally  E.  At  point  E  the  venous 
return  curve  becomes  stable  because  now  the  cardiac 
output  has  fallen  back  to  a  value  that  is  just  sufficient 
to  maintain  a  renal  output  equal  to  the  daily  intake 
of  fluid  and  salts.  One  can  see  that  we  now  have  three 
different  curves  equating  with  each  other,  the  cardiac 
output  curve,  the  venous  return  curve,  and  a  straight 
line  which  is  a  curve  representing  the  level  required 
for  normal  renal   function.    It   is  where  these  three 


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fig.  20.  Analysis  of  recompensation  after  a  bout  of  cardiac 
decompensation.  The  lower  cardiac  output  curve  represents 
the  decompensated  heart  and  the  upper  curve  the  recom- 
pensated  heart.  The  sequence  of  events  is  explained  in  the 
text. 

curves  equate  that  the  circulatory  system  finally  es- 
tablishes its  steady-state  equilibrium. 

A  heart  can  also  be  recompensated  without  in- 
creasing the  cardiac  output  curve  at  all  but  simply 
by  lowering  the  level  required  for  normal  function. 
For  instance,  in  figure  20,  if  this  were  lowered  down 
to  a  value  of  700  ml  per  min,  then  point  A  would  be 
approximately  1 00  ml  per  min  greater  than  the  level 
required  for  normal  renal  function.  As  a  result  fluid 


1 1 1 8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


would  be  lost  and  the  venous  return  curves  would 
proceed  toward  the  left.  This  would  continue  until 
the  cardiac  output  should  fall  to  700  ml  per  min, 
which  would  be  the  equilibrium  point  for  the  three 
different  curves.  The  method  by  which  this  third 
curve,  the  level  required  for  normal  renal  function, 
can  be  lowered  is  by  administration  of  a  diuretic  or 
by  drastic  reduction  of  fluid  and  salt  intake.  Under 
either  of  these  conditions  the  kidneys  can  then  put 
out  an  amount  of  fluid  equal  to  the  daily  intake  de- 
spite the  fact  that  the  cardiac  output  is  greatly  re- 
duced. Thus,  the  animal  is  kept  from  dying  as  a  result 
of  decompensation,  and  over  a  period  of  time  its 
heart  can  perhaps  recover  or  at  least  its  life  can  be 
saved  by  continual  adherence  to  a  strict  diuretic  and 
fluid  regimen. 

ANALYSIS     OF    EFFECTS     RESULTING     FROM     CHANGES     IN 

vascular  resistance.  The  simplified  graphical  ap- 
proach can  also  be  used  to  analyze  the  effect  of  vascu- 
lar resistance  changes  resulting  from  several  different 
causes.  For  instance,  the  effects  of  anemia  and  poly- 
cythemia have  been  studied  (102),  and  the  results  of 
the  analyses  are  in  accord  with  the  experimental 
findings  in  these  conditions  (60,  109,  164,  176).  Sec- 
ond, an  analysis  for  A-V  fistulae  (104)  also  accords 
with  the  often  repeated  findings  in  these  conditions 
(43,  116,  140,  148,  173).  Third,  a  graphical  analysis 
showing  a  very  detrimental  effect  on  venous  return 
of  increasing  venous  resistance  (87)  is  in  accord  with 
many  studies  which  have  demonstrated  that  relatively 
slight  venous  constriction  can  cause  either  shock  in 
the  acute  situation  (63)  or  peripheral  congestion  in 
the  chronic  preparation  (26). 


a  more  complex  graphical  analysis  of 
venous  return,  ventricular  outputs, 
and  atrial  pressures 

The  simplified  graphical  analysis  which  has  just 
been  presented  is  ordinarily  quite  satisfactory  for 
analyzing  the  effects  of  most  circulatory  stresses  on 
the  circulation  except  when  the  stresses  involve  an 
imbalance  between  the  left  and  right  hearts.  Such 
imbalances  can  result  from  unilateral  cardiac  failure 
or  unilateral  excess  load  on  the  heart.  To  determine 
the  effects  of  these  unilateral  disturbances  on  the  cir- 
culation, we  now  need  to  analyze  the  functions  of  all 
the  four  different  segments  illustrated  in  figure  1, 
all  at  the  same  time,  that  is,  of  the  systemic  circulation, 
the  right  heart,  the  pulmonary  circulation,  and  the 


left  heart.  Then  all  of  these  must  be  equated  against 
each  other.  To  do  this  we  can  proceed  by  pointing 
out,  first,  that  the  analyses  of  right  heart  venous  re- 
turn and  right  ventricular  output  are  approximately 
the  same  as  the  analyses  for  the  entire  heart-lung 
segment.  Therefore,  right  heart  function,  for  practical 
purposes,  can  be  depicted  by  the  usual  simplified 
analysis  which  has  already  been  presented. 

Also,  the  analyses  for  the  pulmonary  circulation 
and  the  left  heart  obey  identically  the  same  principles 
as  those  already  discussed  for  the  systemic  circulation 
and  right  heart,  though  the  quantitative  values  are 
entirely  different.  Figure  21  illustrates  a  typical  analy- 
sis of  venous  return  in  the  pulmonary  circulation 
and  also  of  the  ventricular  output  of  the  left  heart. 
Note  that  the  left  atrial  pressure  scale  has  been  greatly 
shortened  in  relation  to  the  right  atrial  pressure  scale 
used  in  previous  figures.  The  reason  for  this  is  that 
in  later  figures  we  will  wish  to  use  this  analysis  for 
the  left  heart  in  association  with  analyses  for  the 
right  heart.  When  blood  is  shifted  from  the  systemic 
circulation  to  the  pulmonary  circulation,  the  mean 
pulmonary  pressure  rises  approximately  7  mm  Hg 
for  each  1  mm  Hg  fall  in  mean  systemic  pressure 
(138,  139,  146).  Therefore,  in  the  following  equating 
procedures  the  scale  for  right  atrial  pressure  will  in 
all  instances  be  seven  times  as  great  as  the  scale  for 
left  atrial  pressure. 


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fig.  21.  Analysis  of  pulmonary  venous  return  to  the  left 
heart  and  output  from  the  left  ventricle,  illustrating  the 
equating  of  these  with  each  other  in  the  steady -state  condition. 


VENOUS  RETURN 


1119 


In  order  to  equate  the  events  that  take  place  in 
the  left  heart  with  those  that  take  place  in  the  right 
heart,  we  now  need  to  transpose  the  direction  of  the 
scale  for  left  atrial  pressure.  Figure  22  illustrates  this 
transposition,  showing  now  the  left  atrial  pressure 
rising  from  right  to  left  rather  than  from  left  to  right. 


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LEFT    ATRIAL    PRESSURE    (mm  Hg) 

pig.  22.  Transposition  of  the  curves  illustrated  in  fig.  21. 
This  transposition  allows  the  left  heart  analysis  to  be  correlated 
with  the  right  heart  analysis  in  the  following  figures. 


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RIGHT    ATRIAL      PRESSURE     (mm  Hg) 


+  50    +40     .30     +20     +10        0         -10 
LEFT     ATRIAL    PRESSURE  (mm  1+)) 


fig.  23.  Simultaneous  analysis  of  left  and  right  heart 
function,  showing  that  in  the  steady  state  the  venous  returns 
and  outputs  of  the  two  sides  of  the  heart  are  all  in  equilibrium 
with  each  other. 


Finally,  we  superimpose  the  analysis  for  the  left 
heart  onto  a  simultaneous  analysis  for  the  right  heart, 
as  shown  in  figure  23.  In  this  superimposition,  we 
place  the  left  atrial  and  right  atrial  pressure  scales 
so  that  the  7  mm  Hg  level  of  one  coincides  with  the 
7  mm  Hg  level  of  the  other.  The  reason  for  this  is 
that  our  preliminary  measurements  of  mean  pulmo- 
nary pressure  show  it  to  be  almost  identical  in  the 
normal  state  with  the  mean  systemic  pressure,  that 
is,  almost  exactly  7  mm  Hg.  Now,  we  can  explain 
the  composite  analysis  of  the  two  sides  of  the  heart. 

Note  in  figure  23  that  the  right  ventricular  output 
curve  and  the  right  ventricular  venous  return  curve 
equate  at  the  1200  ml  per  min  level.  Likewise,  the  left 
ventricular  output  curve  and  the  left  ventricular 
venous  return  curve  also  equate  at  this  same  level. 
Therefore,  under  normal  circumstances  the  two 
venous  returns  and  the  two  ventricular  outputs  are 
all  equal  to  each  other,  and  the  circulation  is  in  a 
steady  state,  without  any  momentary  transference 
of  blood  from  one  of  the  circulatory  segments  to 
another. 

BALANCE    OF    THE    TWO    VENTRICULAR    OUTPUTS    WITH 

each  other.  Proceeding  to  figure  24,  we  see  the 
normal  situation  again  depicted  by  the  solid  curves. 
However,  the  dotted  venous  return  curves  represent 
a  situation  in  which  excess  blood  has  momentarily 
been  transferred  from  the  pulmonary  circulation  to 
the  systemic  circulation.  Note  especially  that  the  two 
venous  return  curves  intersect  the  zero  venous  return 


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RIGHT     ATRIAL     PRESSURE    (mm  Hg) 


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LEFT    ATRIAL    PRESSURE    (mmHg) 


pig.  24.  An  analysis  showing  the  manner  in  which  the  two 
sides  of  the  heart  automatically  balance  their  outputs.  The 
sequence  of  events  is  explained  in   the   text. 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


level  at  the  same  point,  and  this  point  represents  the 
mean  systemic  pressure  on  the  right  atrial  pressure 
scale  and  the  mean  pulmonary  pressure  on  the  left 
atrial  pressure  scale.  Thus,  the  mean  systemic  pres- 
sure has  risen  from  7  mm  Hg  to  7.5  mm  Hg,  and 
this  has  caused  the  right  ventricular  output  to  rise  to 
point  B,  a  value  about  10  per  cent  above  normal. 
On  the  other  hand,  the  shift  of  blood  out  of  the  lungs 
has  decreased  the  mean  pulmonary  pressure  from 
7  mm  Hg  to  3.5  mm  Hg,  thus  shifting  the  left  ven- 
tricular venous  return  curve  to  the  right  and  decreas- 
ing the  left  ventricular  output  to  point  B' ,  an  output 
40  per  cent  below  normal.  This  represents  a  disparity 
of  outputs  between  the  two  ventricles  of  2  to  1  with 
far  greater  amounts  of  blood  being  pumped  by  the 
right  heart  than  by  the  left  heart.  As  a  consequence, 
a  major  shift  of  blood  occurs  from  the  systemic  circu- 
lation back  to  the  pulmonarv  circulation,  increasing 
the  mean  pulmonary  pressure  and  decreasing  the 
mean  systemic  pressure.  As  a  result,  the  outputs  of 
the  two  sides  of  the  heart  once  again  become  equi- 
librated. 

Conversely,  a  sudden  shift  of  blood  from  the  sys- 
temic circulation  into  the  pulmonary  circulation  is 
illustrated  by  the  dashed-dot  curves,  showing  a  de- 
crease in  mean  systemic  pressure  to  6  mm  Hg  and  a 
rise  in  mean  pulmonary  pressure  to  14  mm  Hg.  The 
net  result  is  diminution  of  right  ventricular  output 
by  approximately  10  per  cent  and  enhancement  of 
left  ventricular  output  by  approximately  40  per  cent. 
Here  again  there  is  almost  2  to  1   disparity  between 


the  outputs  of  the  two  ventricles,  thus  resulting  in  a 
rapid  shift  of  blood  out  of  the  lungs  into  the  systemic 
circulation;  this  shift  continues  until  the  right  ven- 
tricular output  rises  to  equal  the  falling  left  ventricular 
output.  In  this  manner,  the  outputs  of  the  two  ven- 
tricles once  again  hecorre  re-equilibrated,  thus  ex- 
plaining the  experimental  findings  of  many  different 
investigators  that  the  two  sides  of  the  heart  always 
automatically  re-equilibrate  with  each  other  within 
a  few  heartbeats  (11,   18,   129,   159). 

EFFECT  OF  ACUTE  LEFT  HEART  FAILURE  ON  CARDIAC 
OUTPUT,  VENOUS  RETURN,  LEFT  AND  RIGHT  ATRIAL 
PRESSURES,  MEAN  SYSTEMIC  PRESSURE,  AND  MEAN  PUL- 
MONARY pressure.  Figure  25  illustrates  the  sequence 
of  events  that  occurs  when  the  left  ventricle  suddenly 
fails.  Point  A  is  the  normal  equilibrium  point  for  the 
right  ventricle  and  point  A'  the  normal  equilibrium 
point  for  the  left  ventricle.  These  two  are  in  equi- 
librium with  each  other.  Then,  suddenly,  the  left 
ventricular  output  curve  falls  to  less  than  one-half 
normal  as  depicted  by  the  lower  solid  curve.  Instan- 
taneously, this  depressed  left  ventricular  output  curve 
equilibrates  with  the  normal  left  ventricular  venous 
return  curve  at  point  B  which  represents  onlv  30  per 
cent  of  normal  output.  Now  a  70  per  cent  disparity- 
exists  between  the  momentary  right  ventricular  out- 
put and  the  momentary  left  ventricular  output,  this 
causing  blood  to  shift  into  the  lungs  from  the  systemic 
circulation  (138,  139).  In  a  matter  of  a  few  heart- 
beats the  new  venous  return  curves  become  the  dashed 


fig.  25.  Effect  of  sudden  reduction  in  pumping 
effectiveness  of  the  left  ventricle.  This  shows  a  shift 
of  both  venous  return  curves  (as  illustrated  by  the 
dashed  curves)  to  the  left  until  right  ventricular 
output  falls  (point  C)  to  equal  the  rising  left  ventric- 
ular output    (point   C) 


O 

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RIGHT    ATRIAL    PRESSURE   (mm  Hg) 


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LEFT     ATRIAL    PRESSURE    (mm  Hj) 


VENOUS  RETURN 


I  121 


curves  of  the  figure,  with  the  systemic  venous  return 
curve  being  governed  by  a  new  mean  systemic  pres- 
sure of  only  4  mm  Hg  and  the  pulmonary  venous 
return  curve  being  governed  by  a  very  high  pulmo- 
nary pressure  of  +28  mm  Hg.  Blood  continues  to 
shift  from  the  systemic  circulation  into  the  pulmonary 
circulation  until  the  output  of  the  left  ventricle  rises 
to  equal  the  falling  output  of  the  right  ventricle.  These 
conditions  are  reached  at  equilibrium  point  C  for 
the  right  ventricle  and  equilibrium  point  C"  for  the 
left  ventricle.  Since  the  mean  pulmonary  pressure 
has  risen  to  28  mm  Hg,  the  pulmonarv  circulation 
has  become  engorged  with  blood,  and  the  pulmonary 
capillary  pressure  will  probably  be  above  the  critical 
value  of  about  25  mm  Hg,  above  which  pulmonary 
edema  begins  to  appear  (94). 

This  is  only  a  partial  analysis  because  within  the 
next  30  sec  or  so  sympathetic  reflexes  will  elevate  at 
least  three  of  the  curves,  the  right  ventricular  output 
curve,  the  systemic  venous  return  curve,  and  the  left 
ventricular  output  curve,  thereby  resulting  in  a  fur- 
ther elevated  equilibrium  level  of  cardiac  output 
but  also  further  increase  in  atrial  pressures. 

EFFECT    OF    ACUTE    RIGHT    HEART    FAILURE.    Figure    26 

illustrates  the  sequence  of  events  when  the  right  heart 
fails  acutely.  Points  A  and  A'  represent  normal  con- 
ditions, and  point  B  represents  the  instantaneous 
effect  of  the  acute  failure  on  right  heart  output,  show- 
ing that  the  right  heart  output  is  only  about  one-half 
the  output  of  the  left  ventricle  at  that  point.  Immedi- 


ately, blood  begins  to  shift  from  the  pulmonary  circu- 
lation into  the  systemic  circulation  (138,  139),  and 
this  shift  continues  until  the  left  ventricular  output 
falls  to  equal  the  rising  right  ventricular  output.  The 
new  equilibrium  points  are  C  for  the  right  heart  and 
C"  for  the  left  heart,  both  of  which  now  have  the  same 
ventricular  outputs  and  venous  returns  of  700  ml  per 
min.  During  the  re-equilibration  of  blood  between 
the  systemic  and  pulmonary  circulation,  the  mean 
systemic  pressure  has  risen  from  7  to  7.4  mm  Hg, 
while  the  mean  pulmonarv  pressure  has  fallen  from 
7.0  to  4  mm  Hg.  This  minute  increase  in  mean  sys- 
temic pressure  explains  the  failure  of  systemic  vascu- 
lar pressures  to  rise  greatly  in  acute  right  heart  failure 
(122,  181).  After  another  moment  or  so,  sympathetic 
reflexes  tend  to  elevate  the  different  curves  as  ex- 
plained above,  and  the  cardiac  output  can  return 
part  way  toward  normal. 

effect  of  blood  volume  change.  Figure  27  analyzes 
the  effect  of  hemorrhage  on  the  outputs  of  both  ven- 
tricles. Note  that  the  primary  effect  of  reduced  blood 
volume  is  to  shift  the  scales  for  left  and  right  atrial 
pressures,  moving  the  zero  pressure  points  toward 
each  other.  An  increase  in  blood  volume  causes  ex- 
actly the  opposite  effect.  Here  again,  since  the 
capacitance  of  the  pulmonary  circulation  is  only  one- 
seventh  that  of  the  systemic  circulation,  the  left  atrial 
pressure  scale  is  still  one-seventh  that  of  the  right 
atrial  pressure  scale.  Thus,  in  figure  27,  the  mean 
systemic  pressure  has  fallen  to   1.7  mm  Hg  and  the 


■|  2800- 


fig.  26.  Analysis  of  the  effect  of  sudden  right 
ventricular  weakness  on  cardiovascular  dynamics 
showing  a  decrease  in  right  ventricular  output  to 
point  C  and  left  ventricular  output  to  point  C". 


-4  -2  0  +2  +  4  +6 

RIGHT     ATRIAL      PRESSURE   (mm  Hg) 


+  50    +40     +30     +20    +10         0       -10 
LEFT     ATRIAL     PRESSURE  (mm  Hg) 


I  12  2 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


-4  -2  ~0~  +2  +4 

RIGHT     ATRIAL      PRESSURE    ImmHg) 

jj!  +50      +40     +30      +20     +10         0         -10 

LEFT     ATRIAL      PRESSURE  (mm  Hg) 

fig.  27.  Effect  of  reduced  blood  volume  on  cardiovascular 
dynamics.  This  figure  shows  that  the  mean  systemic  pressure 
and  mean  pulmonary  pressure  are  both  greatly  reduced,  thus 
causing  corresponding  decreases  in  the  two  venous  return 
curves. 

mean  pulmonary  pressure  to  2.5  mm  Hg.  Thus,  the 
net  effect  of  a  decrease  in  blood  volume  is  simply  to 
reduce  both  the  mean  systemic  and  mean  pulmonary 
pressures.  This  does  not  affect,  at  least  temporarily, 
the  output  curves  of  either  the  left  or  the  right  ven- 
tricles until  sympathetic  reflexes  occur.  Also,  it  does 
not  affect,  at  least  temporarily,  the  slopes  of  the  two 
venous  return  curves.  Therefore,  the  only  significant 
effect  is  a  reduction  in  both  the  systemic  and  pul- 
monary venous  return  curves  because  of  the  reduced 
mean  systemic  and  mean  pulmonary  pressures.  As  a 
consequence,  both  the  right  ventricular  and  left 
ventricular  outputs  are  reduced,  in  this  instance  to 
approximately  55  per  cent  of  normal. 

summary  of  the  complex  analysis.  This  more  com- 
plex analysis  of  the  circulation  has  been  presented 
to  illustrate  a  method  for  analyzing  the  effects  of 
unilateral  excess  load  or  unilateral  alteration  in  pump- 
inn  effectiveness  of  the  heart.  It  has  particular  im- 
portance in  analyzing  abnormalities  of  the  pulmonary 
circulation.  On  the  other  hand,  as  one  can  readily 
see  from  the  last  few  figures,  even  when  relativelv 
large  quantities  of  blood  shift  into  or  out  of  the  pul- 
monary circulation,  rather  small  changes  occur  in 
the  dynamics  of  the  svstemic  circulation.  Therefore, 


from  a  practical  point  of  view,  when  one  is  concerned 
principally  with  systemic  effects  of  the  circulation, 
the  simplified  analysis  is  usually  quite  adequate. 

Obviously,  only  a  few  examples  of  the  vast  number 
of  uses  of  these  two  types  of  analysis  have  been  given. 
Because  of  the  multitude  of  different  quantitative 
values  that  can  be  assumed  by  different  venous  re- 
turn and  different  output  curves,  the  analyses  can 
likewise  assume  literally  thousands  of  different  forms. 
However,  the  various  alterations  in  the  individual 
curves  that  can  occur  under  manv  different  circu- 
latory conditions  obey  rather  simple  principles. 
Therefore,  in  almost  any  circulatory  condition,  one 
can  either  establish  the  different  curves  experimentally 
or  can  predict  them  very  accurately,  and  from  these 
he  can  proceed  with  an  analysis  of  the  different  effects 
which  will  occur  in  the  circulation,  particularly  as 
they  relate  to  venous  return,  cardiac  output,  left  and 
right  atrial  pressures,  pulmonary  blood  volume,  and 
svstemic  blood  volume. 


SPECIFIC    FACTORS    THAT    AFFECT    VENOUS    RETURN 

Thus  far,  we  have  considered  only  a  general  analy- 
sis of  venous  return.  Now  we  need  to  consider  several 
factors  that  at  times  play  highly  significant  and  spe- 
cific roles  in  the  local  process  of  blood  flow  along 
the  veins.  These  include  especially  the  effects  of  a) 
the  venous  pump,  b)  the  collapse  factor,  c)  central 
pressure  pulsations,  and  d)  local  factors  in  the  tissues 
that  help  to  govern  venous  return  such  as  local  tissue 
activity  and  tissue  utilization  of  oxygen. 

EFFECT  OF  THE  VENOUS  PUMP  ON  VENOUS  RETURN.  Al- 
most every  student  of  physiologv  is  already  familiar 
with  the  function  of  the  so-called  "venous  pump." 
That  is,  all  peripheral  veins  beyond  the  visceral  cavi- 
ties are  supplied  with  valves  oriented  toward  the 
heart,  and  any  factor  that  causes  successive  compres- 
sions of  the  veins  exerts  a  pumping  action  that  propels 
blood  toward  the  heart.  The  different  types  of  com- 
pression that  have  been  implicated  in  the  venous 
pump  include  a)  compression  incident  to  muscular 
movement  either  as  a  result  of  direct  muscular  pres- 
sure on  the  veins  or  indirectly  as  a  result  of  movements 
of  the  joints  and  tissues,  and  b)  pulsatile  compression 
of  the  veins  caused  by  arteries  lying  in  the  same 
sheaths  as  the  veins.  The  second  of  these  has  not 
proved  to  be  of  any  particular  significance.  Therefore, 
the  venous  pump  is  also  frequently  called  simply  the 
"muscle  pump"  (16,  17,  27,  49,  155,  156,  191). 


VENOUS  RETURN 


I  I  23 


In  quiet  standing,  blood  from  the  legs  returns  to 
the  heart  only  with  great  difficulty,  and  the  pressures 
in  the  veins  of  the  lower  limb  rise  to  values  equal  to 
the  weight  of  blood  between  the  lower  limbs  and  the 
heart,  that  is,  to  as  much  as  90  mm  Hg.  However, 
during  walking,  the  venous  return  from  the  lower 
limbs  will  be  so  satisfactory  that  venous  pressures  in 
the  feet  may  be  as  low  as  20  to  25  mm  Hg  (156).  In 
the  absence  of  an  active  venous  pump,  a  person  can 
develop  such  high  pressures  in  the  lower  part  of  the 
body  when  he  stands  that  he  actually  loses  as  much 
as  15  to  20  per  cent  of  his  blood  volume  in  less  than 
one-half  hour,  thereby  in  many  instances  provoking 
fainting. 

EFFECT  OF  VENOUS  COLLAPSE  ON  VENOUS  RETURN.  The 

phenomenon  of  "venous  collapse"  is  based  on  the 
simple  fact  that  it  is  impossible  to  suck  fluid  through 
a  collapsible  tube.  Since  the  heart  is  located  in  the 
thoracic  cavity  where  the  pressure  is  normally  ap- 
proximately —  5  mm  Hg  and  since  the  right  atrial 
pressure  often  is  also  in  the  range  of  —2  to  —3  mm 
Hg,  suction  frequently  is  applied  to  the  central  veins. 
This  is  particularly  true  of  the  veins  entering  from 
above  downward  when  a  person  is  in  an  upright  po- 
sition, because,  under  these  conditions,  the  negative 
hydrostatic  pressure  of  the  blood  flowing  downward 
toward  the  heart  adds  to  the  negative  pressures  al- 


ready in  the  chest,  thus  causing  essentially  complete 
collapse  of  the  veins  in  the  neck.  However,  this,  too, 
is  a  very  old  story  known  by  almost  every  student  of 
physiology  (34,  54-58,  112,  114,  170),  and  it  can  be 
summarized  by  simply  saying  that  any  factor  which 
makes  the  right  atrial  pressure  more  negative  than 
normal  does  not  cause  a  significant  increase  in  venous 
return.  That  is,  the  venous  return  will  be  as  great 
when  the  right  atrial  pressure  is  approximately  —2 
mm  Hg  as  it  will  be  should  the  right  atrial  pressure 
fall  to  as  low  as  —  1 5  mm  Hg.  For  instance,  when  a 
person  breathes  air  from  a  chamber  that  is  under 
negative  pressure,  this  negative  pressure  is  trans- 
mitted through  his  lungs  to  the  chambers  of  his  heart. 
Yet,  breathing  against  the  negative  pressure  does  not 
increase  the  venous  return  to  values  above  normal — 
all  because  the  veins  collapse  any  time  there  is  an 
attempt  to  suck  blood  from  the  periphery. 

Venous  collapse  also  occurs  whenever  pressure  is 
applied  to  the  outside  of  the  veins.  This  very  fre- 
quently occurs  in  the  case  of  elevated  abdominal 
pressure  (24,  88).  Figure  28  illustrates  the  effect  of 
intra-abdominal  pressure  on  the  pressure  along  the 
inside  of  the  inferior  vena  cava.  In  these  studies,  a 
catheter  was  introduced  upward  from  the  femoral 
vein  until  it  entered  the  right  atrium,  showing  that 
the  venous  pressure  all  along  the  extent  of  the  intra- 
abdominal   veins   was    always    slightly  greater   than 


36- 

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28 


AP=35CMH20  AP=ABDOMINAL 

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NORMAL  AP  =  -0  7  CM    H20 


fig.  28.  Effect  of  increased  abdomi- 
nal pressure  (AP)  on  pressures  meas- 
ured from  the  tip  of  a  catheter  inserted 
up  the  femoral  vein  and  along  the  vena 
cava  until  it  entered  the  right  atrium. 
[From  Guyton  &  Adkins  (88).] 


2         6         10        14        18       22       26        30       34       38       42      46       50 
LENGTH   OF  CATHETER    INTRODUCED    IN  CM 


124 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


the  intra-abdominal  pressure.  In  other  words,  for 
blood  to  flow  through  a  vein  as  it  returns  toward  the 
heart,  the  pressure  inside  the  vein  must  be  greater 
than  the  pressure  applied  to  the  outside  of  the  vein. 
If  the  abdominal  pressure  is  25  mm  Hg,  then  the 
pressure  in  all  the  lower  veins  of  the  body  that  feed 
blood  through  the  abdominal  cavity,  including  the 
leg  veins,  must  be  greater  than  the  25  mm  Hg  intra- 
abdominal pressure.  Likewise,  if  a  bone  or  some  other 
structure  presses  against  a  vein  with  a  pressure  of 
10  mm  Hg,  the  pressure  in  the  vein  beyond  that  point 
must  rise  above  10  mm  Hg  to  force  blood  past  the 
compression  point.  These  are  simple  hydrodynamic 
principles. 

EFFECT  OF  CENTRAL  PULSATION  ON  VENOUS  RETURN. 

Probably  the  most  extensively  studied  factor  that  has 
been  considered  to  affect  local  venous  flow  is  central 
pulsation.  There  are  two  different  types  of  central 
pulsation  which  can  affect  blood  flow  to  the  heart. 
These  are  /)  increases  and  decreases  in  venous  pres- 
sure resulting  from  the  contractions  of  the  heart  it- 
self (6,  21,  30,  124,  185),  and  2)  increases  and  de- 
creases in  central  venous  pressure  resulting  from 
respiration  (1,  28,  32,  33,  62,  130,  149,  187).  All  studies 
that  have  ever  been  reported  on  phasic  blood  flow 
from  the  peripheral  veins  to  the  heart  have  demon- 
strated that  the  flow  of  blood  toward  the  heart  in- 
creases greatly  during  the  negative  phases  of  the 
central  pressure  pulses.  Then,  during  the  positive 
phases,  blood  flow  becomes  markedly  reduced  and 
can  even  flow  backward  from  the  right  atrium  into 
the  veins.  A  very  significant  inflow  of  blood  into  the 
right  atrium  occurs  during  inspiration  for  two  differ- 
ent reasons:  First,  movement  of  the  diaphragm  down- 
ward decreases  the  intrathoracic  and  right  atrial 
pressures  slightly,  which  helps  to  move  blood  toward 
the  heart.  Second,  and  much  more  important,  down- 
ward depression  of  the  diaphragm  compresses  the 
veins  of  the  abdomen,  thus  forcing  large  quantities 
of  blood  toward  the  heart.  Brecher  and  his  colleagues 
(31)  have  recently  been  foremost  among  a  long  line 
of  investigators,  extending  back  a  hundred  years,  in 
pointing  out  the  phasic  flow  of  blood  to  the  heart 
caused  by  central  pressure  pulsations. 

Still  more  important  to  our  present  discussion, 
however,  is  not  whether  or  not  blood  flows  into  the 
heart  in  greater  amount  during  the  negative  phase 
than  the  positive  phase  but,  instead,  whether  or  not 
central  pulsation  on  the  average  aids  venous  return. 
Different  investigators  in  the  past  have  gone  so  far 
as  to  state  that  central  pulsations  are  among  the  most 


important  of  all  the  factors  tending  to  return  blood 
to  the  heart,  while  others  have  gone  so  far  as  to  state 
that,  if  anything,  central  pulsations  are  harmful  to 
the  venous  return  rather  than  beneficial.  Brecher's 
monograph  on  venous  return  presents  very  admirably 
the  first  point  of  view  (31 ).  On  the  other  hand,  studies 
from  our  own  laboratories  during  the  past  year  have 
indicated  that  central  pulsations  on  the  average 
(though  not  during  the  negative  phases  of  the  pulsa- 
tions) cause  considerable  diminution  of  venous  return 
rather  than  enhancement  (91  ).  For  this  reason,  it 
would  be  impossible  for  the  author  to  present  any 
arguments  in  favor  of  the  importance  of  central  pul- 
sations in  returning  blood  to  the  heart.  Therefore, 
the  reader  is  referred  to  Brecher's  thorough  mono- 
graph for  this  point  of  view. 

The  basis  for  our  belief  that  central  pulsations  are 
harmful  rather  than  helpful,  on  the  average,  to  venous 
return  is  depicted  in  figure  29.  This  shows  the  typical 
venous  return  curve,  and  it  shews  by  means  of  the 
horizontal  sine  waves  the  central  pulsation  excursions, 
varying  in  this  instance  between  the  values  —6  and 
+  2  mm  Hg.  The  figure  then  shows  by  the  vertical 
pulsations  the  effects  of  these  pressure  changes  on 
venous  return  as  would  be  predicted  from  the  venous 
return  curve.  Note  that  venous  return  is  considerably 
depressed  during  the  positive  phase  of  the  pulsatile 
cycle.  On  the  other  hand,  venous  return  is  only  slightly 
increased  during  the  negative  phase.  Therefore,  the 
average  venous  return  is  decreased  approximately 
10  per  cent  as  a  result  of  the  central  venous  pulsation. 

To  test  this  premise  experimentally  a  cannula  was 
inserted  in  the  wall  of  the  right  atrium,  and  varying 
quantities  of  blood  were  injected  and  removed  from 
the  right  atrium  at  frequencies  varying  between  60 


—  I6OO-1 

c 

Mean 

right    atrial    pressure 

E 
^- 
u 

-Average   venous    return 
^t 1 ■*« — ^^—  y^-  -7^  *y 

a  1200- 

Nr^^tTTTr7vE 

RETURN 

1 

r\iWt 

CO 

S   40O- 

z 
111 

> 

1 

fed  \ 

u- 

8 

1 
-4 

6             +4           +8           +12 

RIG 

-IT 

ATRIAL     PRESSURE    (mm  Hg) 

fig.  29.  Effect  of  central  pulsations  on  venous  return, 
illustrating  a  rectification  phenomenon  that  causes  depressed 
venous  return  when  central  pulsations  occur. 


VENOUS  RETURN 


1125 


and  160  cycles  per  min  and  in  volume  between  o  and 
64  ml  per  cycle.  In  over  200  successive  records  not  a 
single  instance  of  increased  venous  return  occurred. 
On  the  contrary,  even  the  minutest  increase  in  right 
atrial  pulsation  always  reduced  venous  return,  and 
very  intensive  pulsations  actually  reduced  venous 
return  (at  any  given  mean  right  atrial  pressure)  to  as 
low  as  50  per  cent  of  normal.  Thus,  there  is  a  "rectifi- 
cation phenomenon"  occurring  in  the  venous  return 
to  the  heart.  That  is,  on  the  negative  pressure  cycle 
collapse  of  the  veins  prevents  very  much  enhance- 
ment of  venous  return,  while  on  the  positive  pressure 
cycle,  no  such  event  prevents  the  positive  pressure 
from  reducing  venous  return  (29,  36,  37,  44,  113,  118, 
141,  151).  The  net  effect,  based  on  both  theoretical 
grounds  and  experimental  grounds,  and  supported 
by  studies  from  other  laboratories  as  well  as  from  our 
own  (54),  is  that  central  pulsations  are  not  of  any 
value  in  promoting  venous  return. 

EFFECT  OF  LOCAL  TISSUE  ACTIVITY  ON  VENOUS  RETURN  — 
EFFECT    OF    OXYGEN    USAGE    BY    THE    TISSUES.    The    best 

known  condition  in  which  local  tissue  activity  affects 
venous  return  is  muscular  exercise,  in  which  case  the 
venous  return  may  be  increased  several  fold.  Earlier 
it  was  pointed  out  that  this  is  caused  both  by  an  in- 
crease in  mean  circulatory  pressure  and  by  vascular 
dilatation  in  the  muscles.  The  problem  still  remains, 
however,  to  explain  the  cause  of  the  vascular  dilata- 
tion in  the  muscles  which  in  turn  leads  to  the  greatly- 
enhanced  venous  return.  In  recent  years,  much  evi- 
dence has  accumulated  that  oxygen  usage  by  the 
tissues  might  well  be  the  initiating  factor  that  con- 
trols vascular  dilatation  (9,  41,  45,  51,  64,  65,  77,  79, 
119,  125,  136,  190,  199).  Some  research  workers  have 
felt  that  relative  oxygen  lack  in  the  tissues  causes  them 
to  form  a  humoral  substance  which  then  causes  vaso- 
dilatation (7,  8,  15,  153).  Humoral  substances  that 
have  been  suspected  are  carbon  dioxide,  hydrogen 
ions,  adenosine  phosphate  compounds,  histamine, 
and  lactic  acid.  Thus  far,  however,  none  of  these 
substances  has  been  isolated  in  sufficiently  large  quan- 
tities from  the  blood  to  prove  that  it  is  truly  acting 
as  a  vasodilator  substance. 

Another  concept  is  that  the  tissue  cells  compete 
for  the  available  oxygen  in  the  arterial  blood  with 
the  vascular  smooth  muscle,  perhaps  with  the  smooth 
muscle  of  the  metarterioles  and  precapillary  sphinc- 
ters (45).  If  the  tissues  utilize  excess  oxygen,  then 
the  blood  vessels  will  be  without  adequate  oxygen. 
As  a  result,  these  vessels  might  dilate  simply  because 
their  smooth  muscle  walls  cannot  remain  contracted 


in  the  face  of  oxygen  lack.  This  concept  is  supported 
by  the  following  experiment :  venous  blood  was  re- 
moved from  the  right  ventricle,  and  arterial  blood 
was  removed  from  the  aorta  of  the  same  dog  at  the 
same  time.  These  two  bloods  were  then  alternately 
passed  through  an  isolated  hind  limb  of  a  dog  in  which 
the  input  and  outflow  pressures  were  controlled  and 
in  which  the  blood  temperature  was  very  exactly 
controlled.  The  arterial  blood  always  caused  vaso- 
constriction, while  the  venous  blood  always  caused 
vasodilatation  (to  250%  of  the  arterial  value).  Fur- 
thermore, the  degree  of  vasodilatation  depended  al- 
most proportionately  on  the  degree  of  unsaturation 
of  the  blood  entering  the  limb  as  shown  in  figure  30. 
The  onlv  difference  between  the  two  bloods  was  that 
one  had  passed  through  the  lungs  and  the  other  had 
not.  Therefore,  if  any  vasodilator  substance  were  in 
the  venous  blood,  then  it  would  have  to  have  been 
removed  by  the  lungs.  Since  the  lungs  are  not  known 
to  have  this  ability  to  remove  vasodilator  substances 
of  any  type,  and  since  controlled  breathing  of  carbon 
dioxide  illustrated  that  carbon  dioxide  had  no  sig- 
nificant local  effect  on  peripheral  vascular  flow,  we 
must  presume  that  it  is  lack  of  oxygen  that  initiates 
the  vasodilatation  in  the  limb  and  not  some  inter- 
mediary vasodilator  substance. 

The  reason  for  discussing  this  oxygen  lack  theory 
of  peripheral  vasodilatation  so  completely  is  that,  in 
the  final  analvsis,  it  may  be  oxygen  usage  by  the  tis- 


100 


BLOOD     FLOW    (Per  cent  of  control  volue) 


100 


120 


WO 


160 


180 


200 


220 


240 


fig.  30.  Effect  of  reducing  arterial  oxygen  saturation  on 
the  blood  flow  through  an  isolated  hind  limb  of  the  dog. 
[From  Crawford  el  al.   (45).] 


1 126 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


sues  that  is  the  primary  factor  which  normally  regu- 
lates venous  return  and,  therefore,  also  cardiac  output. 
That  is,  the  degree  of  local  dilatation  of  peripheral 
vessels  would  increase  with  each  increase  in  local 
tissue  activity;  consequently,  the  return  of  blood  to 
the  heart  would  be  governed  by  tissue  utilization  of 
oxygen.  On  summating  all  the  individual  flows 
through  all  the  individual  tissues  of  the  body  we  ob- 
tain a  summated  value  which  equals  venous  return, 
and,  since  this  automatically  equates  with  cardiac 
output,  the  summated  flows  of  the  individual  tissues 
are  also  equal  to  the  cardiac  output.  Therefore,  if  it 
is  true  that  oxygen  lack  in  all  individual  tissues  does 
cause  vasodilatation,  then  we  find  that  in  the  final 
analysis  the  rate  of  local  oxygen  utilization  could  be 
the  single  most  important  controller  of  venous  return 
and  cardiac  output.  Indeed,  this  is  supported  by 
many  isolated  studies  of  the  relationship  between 
oxygen  utilization  or  oxygen  lack  and  circulatory 
blood  flow,  beginning  with  the  study  of  Douglas 
&  Haldane  (51)  in  1922  in  which  it  was  shown  that 
oxygen  lack  increases  the  cardiac  output  to  a  con- 
siderable extent,  and  extending  through  studies  by 
Gorlin  and  co-workers  showing  a  greatly  increased 
cardiac  output  in  severe  oxygen  lack  (77),  and  a 
more  recent  study  by  Huckabee  (119)  showing  an 
increase  in  cardiac  output  of  as  much  as  twofold 
in    animals    poisoned    with   cyanide. 

Besides  the  acute  peripheral  dilatation  that  re- 
sults from  oxygen  lack,  a  very  marked  additional 
increase  in  tissue  blood  flow  occurs  over  a  period  of 
several  weeks  if  excessive  oxygen  usage  or  oxygen 
deficiency  persists  for  this  long  period  of  time  (130a). 
This,  however,  results  from  increased  ''vascularity" 
of  the  tissues,  that  is,  increased  numbers  of  blood 
vessels.  Nevertheless,  this  too,  despite  its  slowness  to 
develop,  represents  a  very  important  and  very  power- 
ful regulatory  mechanism  for  control  of  venous  re- 
turn  in  response   to  oxygen   need   by   the   tissues. 

Aside  from  the  experimental  observations  on  the 
control  of  venous  return  and  cardiac  output  by  oxy- 
gen lack,  there  is  one  compelling  theoretical  reason 
for  believing  that  oxygen  lack  should  be  the  main 
controller  of  venous  return  and  cardiac  output,  and 
that  is  the  following:  Of  all  the  essential  substances 
supplied  to  the  tissues  by  the  blood,  oxygen  is  by  far 
the  one  most  critically  dependent  upon  an  adequate 
blood  flow.  For  instance,  blood  flow  can  be  de- 
creased to  as  little  as  '20  normal,  and  adequate 
quantities  of  glucose,  fats,  and  proteins  can  still  be 
carried  to  the  tissues.  Also,  if  the  depth  of  breathing 


is  increased,  carbon  dioxide  can  be  carried  away 
from  the  tissues  in  adequate  quantities  even  when 
the  cardiac  output  is  decreased  to  as  little  as  }/\§ 
normal.  On  the  contrary,  the  tissues  become  severely 
damaged  from  anoxia  whenever  cardiac  output 
remains  only  slightly  below  normal  for  a  prolonged 
period  of  time.  Therefore,  it  is  readilv  obvious  that 
oxygen  transport  to  the  tissues  is  normally  markedly 
"flow  limited,"  while  the  transport  of  no  single 
other  essential  substance  to  or  from  the  tissues  is 
limited  to  a  significant  extent  under  normal  or  any- 
where near  normal  conditions.  For  this  reason,  it  is 
especially  reasonable  that  oxygen  should  be  the  major 
regulator  of  venous  return  and  cardiac  output;  this 
would  provide  a  closed  loop  regulatory  system  that 
would  help  to  maintain  an  adequate  supply  of  oxygen 
to  all  the  tissues  at  all  times. 


VENOUS    PRESSURES 

The  regulation  of  venous  pressure  is  inextricably 
related  to  the  regulation  of  venous  return  and  car- 
diac output,  as  has  already  been  pointed  out  in 
both  the  simplified  and  more  complex  circuit  analy- 
ses presented  earlier  in  this  chapter.  All  the  different 
significant  factors  which  affect  right  atrial  pressure 
have  already  been  discussed.  On  the  other  hand, 
the  right  atrial  pressure  is  not  the  same  as  the  more 
peripheral  venous  pressures.  Therefore,  we  need 
now  to  conclude  our  discussion  of  the  return  of  blood 
to  the  heart  by  summarizing  the  different  factors 
that  determine  the  peripheral  venous  pressures. 
These  include,  first  and  paramount,  the  right  atrial 
pressure  itself.  In  addition,  they  include  a)  resistance 
to  blood  flow  along  the  veins,  b)  rate  of  blood  flow 
in  the  veins,  and  c)  hydrostatic  pressure  effects. 

EFFECT  OF  RESISTANCE  TO  FLOW  IN  THE  VEINS.   Dilated 

central  veins  are  so  large  that  they  have  almost  no 
resistance  to  blood  flow,  but  semicollapsed  veins, 
on  the  other  hand,  have  very  high  resistance.  This 
effect  is  particularly  important  at  the  different  com- 
pression points  where  the  veins  pass  over  the  ribs 
or  lie  against  some  relatively  solid  organ  (52,  53). 
In  the  ordinary  circulation,  therefore,  the  resistance 
to  venous  flow  is  not  negligible,  principally  because 
of  the  compression  points  against  the  veins.  On  the 
other  hand,  when  the  right  atrial  pressure  rises  to  a 
very  high  value,  blood  can  dam  up  in  the  veins, 
elevating  the  pressures  in  the  veins  to  values  equal 


VENOUS  RETURN 


I  127 


to  or  perhaps  considerably  greater  than  those  on 
the  outside  of  the  veins.  In  these  instances  the  vein 
become  distended  and  the  venous  resistance  becomes 
automatically  reduced.  This  turns  out  to  be  an  im- 
portant safety  factor  in  venous  return,  for  often  an 
elevated  right  atrial  pressure  results  from  a  damaged 
heart,  in  which  case  return  of  blood  to  the  heart 
would  become  inadequate  if  the  venous  resistance 
should  remain  as  high  under  these  conditions  as  it 
is  in  the  normal  circulation.  Fortunately,  however, 
the  reduced  resistance  of  the  veins  allows  the  existing 
pressure  gradient  from  the  periphery  to  the  heart  to 
force  blood  toward  the  heart  almost  equally  as  well 
as  it  occurs  normally.  For  this  reason,  the  peripheral 
pressures  ordinarily  do  not  rise  significantly  until 
the  right  atrial  pressure  has  risen  above  approxi- 
mately +  4  to  +6  mm  Hg  (74).  Above  this  point, 
the  veins  by  then  will  have  become  distended,  and 
any  additional  rise  in  right  atrial  pressure  is  there- 
after reflected  by  a  similar  increase  in  peripheral 
venous  pressure  (83). 


parts  of  the  body  and  creates  negative  pressure  in 
areas  above  the  heart.  The  collapse  factor  and  the 
venous  pump  that  modify  these  pressures  were 
described  earlier  in  the  chapter.  Particularly  impor- 
tant is  the  fact  that  the  veins  of  the  neck  collapse  and 
their  resistances  automatically  become  greatly  ele- 
vated. Therefore,  venous  pressure  in  the  neck  almost 
never  falls  below  atmospheric  pressure  unless  un- 
usual circumstances  prevent  the  veins  from  collaps- 
ing. 

Because  of  the  importance  of  the  hydrostatic  fac- 
tor in  all  venous  pressure  measurements,  two  very- 
similar  methods  have  been  suggested  for  determin- 
ing a  "physiological  zero"  pressure  in  the  venous 
system  (93,  1 1 1 ).  The  second  of  these,  which  was 
presented  from  our  laboratory,  depends  on  rotating 
a  dog  about  two  different  axes.  It  was  found  that 
venous  pressures  referred  to  a  point  barely  inside 
the  right  ventricle  at  the  tricuspid  valve  did  not 
vary  a  measurable  amount  regardless  of  the  position 
of  the  animal. 


EFFECT     OF     VENOUS     FLOW      ON     PERIPHERAL     VENOUS 

pressures.  An  increase  in  the  volume  of  venous 
blood  flowing  toward  the  heart  theoretically  would 
cause  essentially  the  same  effects  on  peripheral 
venous  pressures  as  would  an  increase  in  venous 
resistance.  However,  from  a  practical  point  of  view 
this  is  not  true,  because  an  increase  in  volume  of  flow 
normally  simply  distends  the  collapsed  veins  to  a 
greater  degree,  thus  reducing  the  resistance  to  flow. 
The  flow  and  decreased  resistance  ordinarily  com- 
pensate for  each  other  so  that  increasing  the  flow- 
has  relatively  minor  effect  in  increasing  the  peripheral 
venous  pressures  rather  than  a  major  effect  as  might 
be  expected  (88).  This  has  been  demonstrated  es- 
pecially in  the  case  of  blood  flowing  from  the  periph- 
eral limbs  through  the  abdominal  cavity  when  the 
intra-abdominal  pressure  is  elevated.  For  instance, 
if  the  intra-abdominal  pressure  is  +10  mm  Hg, 
whether  the  flow  from  the  leg  to  the  right  heart 
is  0.5  ml  per  min  or  200  ml  per  min,  the  pressure 
in  the  femoral  vein  leading  into  the  abdominal  cavity 
still  remains  only  1  mm  Hg  or  so  greater  than  the 
10  mm  Hg  intra-abdominal  pressure. 

EFFECT     OF     HYDROSTATIC     PRESSURE     ON     PERIPHERAL 

venous  pressures.  Finally,  we  have  the  well-known 
effect  of  hydrostatic  forces  on  peripheral  venous 
pressures.  That  is,  the  simple  weight  of  the  blood 
increases    the    venous    pressures    in    the    dependent 


SUMMARY 

To  summarize  this  entire  chapter,  its  important 
point  has  been  that  one  cannot  analyze  venous  re- 
turn separately  from  a  simultaneous  analysis  of 
many  other  factors  in  the  circulation.  However, 
relatively  simplified  analyses,  based  principally  on 
four  major  segments  of  the  circulation,  the  right 
heart,  the  pulmonary  circulation,  the  left  heart, 
and  the  systemic  circulation,  can  provide  an  almost 
complete  understanding  of  the  interrelationships 
between  a)  venous  return,  /;)  cardiac  output,  c) 
right  atrial  pressure,  d)  left  atrial  pressure,  e)  mean 
systemic  pressure,  /)  mean  pulmonary  pressure,  g) 
mean  pulmonary  volume,  and  /()  mean  systemic  blood 
volume. 

If  we  should  choose  any  single  factor  that  might 
be  the  primary  regulator  of  venous  return,  and 
hence  also  the  primary  regulator  of  cardiac  output, 
it  might  be  the  tissue  utilization  of  oxygen.  Cer- 
tainly, in  over  half  of  the  tissues  of  the  body  if  not 
in  the  entire  body,  local  blood  flow  seems  to  be 
controlled  by  the  local  utilization  of  oxygen,  and 
the  summated  value  of  all  the  local  flows  is  the  venous 
return.  Therefore,  oxygen  utilization  by  the  tissues 
might  well  be,  in  the  final  analysis,  the  primary 
regulator  of  venous  return. 


I  I2t 


H  \M)H(  ic  IK     (H      I'm  SIIH.l  ICY 


CIRCULATION    II 


R  I .  F  E  R  E  N  C  E  S 


>3' 


14. 


15 


17 


Alexander,  R.  S.  Influence  of  the  diaphragm  upon 
portal  blood  flow  and  venous  return.  Am.  J.  Physiol.  167: 

738,  I95i-  2'- 

Alexander,   R.   S.   The   participation  of  the   venomotor 

system    in    pressure    reflexes.    Circulation    Research    2 :    405,  22. 

'954- 

Alexander,   R.   S.  Venomotor  tone  in  hemorrhage  and 

shock.  Circulation  Research  3:   181,   1955.  23. 

Alexander,  R.   S.  Reflex  alterations  in  venomotor  tone 

produced    by    venous    congestion.    Circulation    Research    4: 

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Allen,  S.  C,  C.  L.  Taylor,  and  V.  E.  Hall.  A  study 

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Barcroft,  H.  Cardiac  output  and  blood  distribution. 
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'952- 

Bowers,  E.,  E.  J.  M.  Campbell,  and  C.  H.  P.  Johnston. 
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Brecher,  G.  A.  Mechanism  of  venous  flow  under  differ- 
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423.  '954- 

Brecher,  G.  A.  Venous  Return.  New  York:  Grune  &  Strat- 
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Brecher,  G.  A.,  and  G.  Mixter,  Jr.  Augmentation  of 
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Buckley,  N.  M,  E.  Ogden,  and  D.  S.  Linton,  Jr.  The 
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Candel,  S.,  and  D.  E.  Ehrlich.  Venous  blood  flow  dur- 
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Case,  R  B.,  E.  Berglund,  and  S.  J.  Sarnoff.  Ventric- 
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Charlier,   R.    Le   role   des   regions   sinusales   et  cardio- 


VENOUS  RETURN 


I  I  29 


aortique  dans  la  regulation   reflexe  du   debit  cardiaque. 
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41.  Chiodi,  H.,  D.  B.  Dill,  F.  Consolazio,  and  S.  M. 
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■94!  • 

42.  Clowes,  G.  H.  A.,  and  L.  R.  Del  Guercio.  Circulatory 
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43.  Cohen,  S.  M.,  O.  G.  Edholm,  S.  Howarth,  J. 
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44.  Cournand,  A.,  H.  L.  Motley,  L.  Werko,  and  D.  W. 
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45.  Crawford,  D.  G.,  H.  M.  Fairchild,  and  A.  C.  Guyton. 
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46.  Daly,  I.  de  B.  A  closed  circuit  heart-lung  prepara- 
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47.  Daly,  I.  de  B.,  P.  Egcleton,  C.  Hebb,  J.  L.  Linzell, 
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48.  Davis,  J.  O.,  B.  Kliman,  N.  A.  Yankopoulos,  and  R.  E. 
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49.  Desliens,  L.  Muscular  contractions  and  blood  circula- 
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50.  Donald,  K.  W.,  J.  M.  Bishop,  G.  Gumming,  and  O.  L. 
Wade.  The  effect  of  exercise  on  the  cardiac  output  and 
circulatory   dynamics   of  normal   subjects.    Clin.   Set.    1 4 : 

37,  1955- 

51.  Douglas,  C.  G.,  and  J.  S.  Haldane.  The  regulation  of 
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52.  Duomarco,  J.,  and  R.  Rimini.  La  pression  veineuse  des 
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53.  Duomarco,  J.,  and  R.  Rimini.  La  presion  venosa  en  los 
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54.  Duomarco,  J.,  and  R.  Rimini.  Energy  and  hydraulic 
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55.  Duomarco,  J.,  R.  Rimini,  and  F.  N.  Predari.  Sobre 
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56.  Duomarco,  J.,  R.  Rimini,  and  P.  Recarte.  La  presion  de 
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57.  Duomarco,  J.,  R.  Rimini,  and  J.  P.  Sapriza.  Intento  de 
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59.  Ebert,  R.  V.,  and  E.  A.  Stead,  Jr.  The  effect  of  the 
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60.  Eckstein,  R.  W.,  D.  Book,  and  D.  E.  Gregg.  Blood 
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61.  Eckstein,  R.  VY\,  G.  R.  Graham,  I.  M.  Liebou,  and 
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62.  Eckstein,  R.  W..  C.  J.  Wiggers,  and  G.  R.  Graham. 
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63.  Farber,  S.  J.,  J.  D.  Alex\nder,  and  D.  P.  Earle. 
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64.  Feinburg,  H.,  A.  Gerola,  and  L.  N.  Katz.  Effect  of 
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65.  Feldman,  M.,  Jr.,  S.  Rodbard,  and  L.  N.  Katz.  Rela- 
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66.  Fergusen,  T.  B.,  D.  E.  Gregg,  and  O.  W.  Shadle. 
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67.  Fergusen,  T.  B.,  O.  W.  Shadle,  and  D.  E.  Gregg. 
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1  :    62,    1953. 

68.  Fleisch,  A.,  and  W.  Temaszewski.  L'influence  de  la 
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69.  Fletcher,  A.  G.,  Jr.,  J.  D.  Hardy,  C.  Riegel,  and 
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2i-  405.  '945- 

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"955- 

72.  Gauer,  O.  H.  Die  wechselbenziehungen  zwischen  herz- 
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■95°- 

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9-847.  1954- 


II    |0 


HANDBOOK    OF    PHYSIOI.OCY 


CIRCULATION    II 


76.  Goldbloom,  A.  C,  M.  L.  Kramer,  and  A.  Lieberson. 
Clinical  studies  in  circulatory  adjustments;  physiologic 
relation  between  posture  and  cardiac  output.  Arch. 
Internal  Med.  65:  175,  1940. 

77.  Gorlin,  R.,  and  B.  M.  Lewis.  Circulatory  adjustments 
to  hypoxia  in  dogs.  J.  Appl.  Physiol.  7:  180,   1954. 

78.  Grodins,  F.  S.  Integrative  cardiovascular  physiology:  a 
mathematical  synthesis  of  cardiac  and  blood  vessel  hemo- 
dynamics. Quart.  Rev.  Biol.  34:  93,  1959. 

79.  Grollman,  A.  Effect  of  high  altitude  on  cardiac  output 
of  man  and  its  related  functions;  account  of  experiments 
conducted  on  summit  of  Pike's  Peak,  Colorado.  Am.  ./. 
Physiol.  93:   19,   1930. 

80.  Guntheroth,  W.  G.  Function  of  liver  and  spleen  as 
venous  reservoirs.  Federation  Proc.   1  7  :  63,   1  958. 

81.  Guyton,  A.  C.  Determination  of  cardiac  output  by 
equating  venous  return  curves  with  cardiac  response 
curves.  Physiol.  Revs.  35:  123,  1955. 

82.  Guyton,  A.  C.  Factors  which  determine  the  rate  of 
venous  return  to  the  heart.  In:  World  //ends  in  Cardiology. 
New  York:  Hoeber,  1956,  p.  32. 

83.  Guyton,  A.  C.  The  venous  system  and  its  role  in  the 
circulation.     Modern     Concepts    Cardiovascular     Disease     27 : 

483,  '958- 

84.  Guy'TON,  A.  C.  La  circulation  veineuse.  Symposia  from  the 
Illrd  World  Congress  of  Cardiology.  Brussels,  1958,  p.  109. 

85.  Guyton,  A.  C.  Cardiac  output  and  venous  return  in 
heart  failure.  In:  Cardiology.  New  York:  McGraw-Hill, 
vol.  4,   1959,  p.   18. 

86.  Guyton,  A.  C.  Textbook  of  Medical  Physiology  (2nd  ed.). 
Philadelphia:  Saunders,  1961,  pp.  350  and  446. 

87.  Guyton,  A.  C,  B.  Abernathy,  J.  B.  Langston,  B.  N. 
Kaufmann,  and  H.  M.  Fairchild.  Relative  importance 
of  venous  and  arterial  resistances  in  controlling  venous 
return   and   cardiac   output.    Am.    ./.    Physiol.    197:    1008, 

'959- 

88.  Guy'ton,  A.  C,  and  L.  H.  Adkins.  Quantitative  aspects 
of  collapse  factor  in  relation  to  venous  return  (relation 
between  intra-abdominal  pressure  and  venous  pressure). 
Am.  J.  Physiol.  177:  523,  1954. 

89.  Guyton,  A.  C,  G.  C.  Armstrong,  and  P.  L.  Chipley. 
Pressure-volume  curves  of  the  entire  arterial  and  venous 
systems  in  the  living  animal.  Am.  ./.  Physiol.  184:  253,  1956. 

90.  Guyton,  A.  C,  Batson,  H.  M.,  Jr.,  and  G.  M.  Smith, 
Jr.  Adjustments  of  the  circulatory  system  following  very 
rapid   transfusion   or    hemorrhage.    Am.    ./.    Physiol.    164: 

35'.  '95'- 
in.  Guyton,   A.   C,   and  O.   Carrier.   Decrease  in  venous 

return   caused   by   venous   pulsation.    Federation   Proc.    20: 

1 20,  1 96 1 . 
92    Guyton,  A.  C,  and  J.  W.  Crowill.  Dynamics  of  the 

heart  in  shock.  Federation  Proc.  20:  51,  Suppl.  9,  1961. 

93.  Guyton,  A.  C,  and  F.  P.  Greganti.  A  physiologic 
reference  point  for  measuring  circulatory  pressures  in  the 
dog — particularly   venous   pressure.   Am.   J.   Physiol.    185: 

'37.  '956- 

94.  Guyton,  A.  C,  and  A.  VV.  Lindsey.  Effect  of  elevated 
left  atrial  pressure  and  decreased  plasma  protein  concen- 
tration on  the  development  of  pulmonary  edema.  Circula- 
tion Research  7:  649,   1959. 

95.  Guyton,  A.  C,  A.  W.  Lindsey',  B.  Abernathy,  and 
J.    B.    Langston.    Mechanism    of   the    increased    venous 


return   and  cardiac  output  caused   by  epinephrine    Am. 
J.  Physiol.  192:  126,  1958. 

96.  Guyton,  A.  C,  A.  W.  Lindsey,  B.  Abernathy,  and  T.  Q. 
Richardson.  Venous  return  at  various  right  atrial  pres- 
sures and  the  normal  venous  return  curve.  Am.  J.  Physiol. 
189:  609,  1957. 

97.  Guyton,  A.  C,  A.  VV.  Lindsey,  and  J.  J.  Gilluly.  The 
limits  of  right  ventricular  compensation  following  acute 
increase  in  pulmonary  circulatory  resistance.  Circulation 
Research   2:   326,    1954. 

98.  Guyton,  A.  C,  A.  VV.  Lindsey,  and  B.  N.  Kaufmann. 
Effect  of  mean  circulatory  filling  pressure  and  other 
peripheral  circulatory  factors  on  cardiac  output.  Am.  J. 
Physiol.   1 80 :  463,   1 955. 

99.  Guyton,  A.  C,  A.  W.  Lindsey,  B.  N.  Kaufmann,  and 
J.  B.  Abernathy.  Effect  of  blood  transfusion  and  hemor- 
rhage on  cardiac  output  and  on  the  venous  return  curve. 
Am.  J.  Physiol.  194:  263,  1958. 

100.  Guyton,  A.  C,  B.  H.  Douglas,  J.  B.  Langston,  and 
T.  Q.  Richardson.  Instantaneous  increase  in  mean 
circulatory  pressure  and  cardiac  output  at  onset  of 
muscular  activity.  Circulation  Research.  In  press. 

101.  Guyton,  A.  C,  D.  Polizo,  and  G.  G.  Armstrong.  Mean 
circulatory  filling  pressure  measured  immediately  after 
cessation  of  heart  pumping.  Am.  J.  Physiol.  179:  261,  1954. 

102.  Guyton,  A.  C,  and  T.  Q.  Richardson.  Effect  of  hema- 
tocrit on  venous  return.  Circulation  Research  9:  157,  1961. 

103.  Guyton,  A.  C,  and  K.  Sagawa.  Compensations  of 
cardiac  output  and  other  circulatory  functions  in  areflex 
dogs  with  large  A-V  fistulae.  Am.  J.  Physiol.  200:  1157, 
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104.  Guyton,  A.  C,  and  J.  Satterfield.  Factors  concerned 
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I  I;}  I 


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CIRCULATION    II 


151.  Otis,  A.  B.,  H.  Rahn,  and  W.  O.  Fenn.  Venous  pressure  168. 
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198.  Wiggers,  C.  J.,  and  J.  M.  Werle.  Cardiac  and  pe- 
ripheral resistance  factors  as  determinants  of  circulatory 
failure  in  hemorrhagic  shock.  Am.  J.  Physiol.  136:  421, 
■942- 

199.  Yonge,  L.  R.,  and  W  F.  Hamilton.  Oxygen  consump- 
tion in  skeletal  muscle  during  reactive  hyperemia.  Am. 
J.  Physiol.  197:  190,  1959. 


CHAPTER      33 


Effects  of  ions  on  vascular  smooth  muscle1 


SYDNEY    M .    FRIEDMAN 
CONSTANCE    L.    FRIEDMAN 


Department  of  Anatomy,   The  University  of 
British  Columbia,  Vancouver,  Canada 


CHAPTER     CONTENTS 

Introduction 

General  Physical  Chemistry  of  Ions 
Osmotic  equilibrium 
Ion  size 
Ion  activity 
Ion  mobility 

Ion  penetrability  or  membrane  permeability 
Special  Properties  of  Ions  in  Biological  Systems 
Donnan  equilibrium 

Electrochemical  gradients  and  membrane  potentials 
Special  Properties  of  the  Physiologically  Important  Ions 
Classification  and  Critical  Appraisal  of  Methods 

Studies  of  Vascular  Smooth  Muscle  Tension  Associated 
with  Manipulation  of  the  Milieu 
Measurement  of  diastolic  blood  pressure 
Measurement  of  peripheral  resistance  in  regional  vascular 

beds 
Measurement  of  tension  in  the  vascular  strip  or  ring  or  in 
an  analogous  smooth  muscle  strip 
Studies  of  the  Milieu  During  Manipulation  of  Vascular  or 
Analogous  Smooth  Muscle  Tension 
Measurement   of  extracellular   and/or   intracellular   ions 

and  water 
Measurement  of  osmotic  pressure  and  pH 
Electrical  measurements 

Continuous  monitoring  of  Na  or  K.  ion  activity 
Role   of  Sodium   and  Potassium  in  Vascular  Smooth  Muscle 
Tension 
Evidence  from  Studies  of  Diastolic  Blood  Pressure  or 
Reactivity 
General  relation  of  Na  and  K  to  clinical  and  experimental 

hypertension 
Effects  of  varying  Na  and  K.  intake  or  loss  on  blood 
pressure 
Evidence  from  Studies  of  Tension  or  Reactivity  of  Vascular 
or  Analogous  Tissue 
Effects  of  manipulation  of  Na  in  the  medium 
Effects  of  manipulation  of  K  in  the  medium 

1  Submitted  for  publication  December  ->o,  i960. 


Evidence  From  Studies  of  Resistance  in  Regional  Vascular 
Beds 
Effects  of  Na  infusions 
Effects  of  K  infusions 
Evidence  from  Measurement  of  Na  and  K  in  Relation  to 
Blood  Pressure 
Measurement  of  Na  and  K  in  chronic  hypertension  or 

hypotension 
Measurement  of  Na  and  K.  in  acute  hypertension  or 
hypotension 
Evidence  from  Studies  of  the  Relation  of  Electrical  Activity 
to  Tension  in  Vascular  or  Analogous  Tissues 
Role  of  Calcium  and  Magnesium  in  Vascular  Smooth  Muscle 
Tension 
Calcium 
Magnesium 
Role  of  H+  and  OH"  in  Vascular  Smooth  Muscle  Tension 
Role  of  Anions  in  Vascular  Smooth  Muscle  Tension 
Theoretical  Interpretations 
Summary 


INTRODUCTION 

General  Physical  Chemistry  of  Ions 

We  are  here  concerned  only  with  pointing  out  in 
simplified  form  the  basic  physical-chemical  features 
of  ions  and  the  manner  in  which  these  affect  their 
role  in  biological  processes.  For  detailed  treatment  of 
this  subject  the  reader  is  referred  to  standard  chemistry 
texts  as  well  as  to  the  basic  articles  of  Conway  (31, 
32),  Hodgkin  (112)  and  Shanes  (182,   183). 

osmotic  equilibrium.  We  may  begin  by  considering 
osmotic  pressure  to  be  the  equivalent  of  the  mechanical 
pressure  which  must  be  applied  to  a  solution  to 
prevent  osmosis  of  the  surrounding  solvent  into  the 
solution  through  the  membrane.  It  is,  therefore,  not 


"35 


■  36 


HANDBOOK    OF    PHYSIOLOGY 


(  !IR(   I'LATION    II 


primarily  a  characteristic  of  the  membrane  but  is  a 
measure  of  some  real  difference  between  pure  solvent 
and  solution.  The  membrane  merely  allows  this 
difference  to  show  itself. 

The  osmotic  pressure,  IT,  of  any  solution  is  propor- 
tional to  temperature  and  concentration: 

II*kCT 

Accordingly,  in  dealing  with  a  cell,  we  must  con- 
sider the  osmotic  pressure  not  only  of  the  solution 
inside  the  cell  but  also  that  of  the  environment  which 
bathes  it.  The  cell  contains  an  amount  of  nondif- 
fusible  material  in  solution  which  is  essential  to  its 
metabolism.  Clearly,  the  amount  of  this  material 
which  can  be  retained  without  causing  the  cell  to 
swell  will  be  sharply  limited  unless  there  is  also  a 
counterbalancing  nondiffusible  material  outside  its 
membrane.    This    is    perhaps    the   major   niche    into 


o  7 


o  3 


I 


(No)  +-  5-7 


(X  100) 


02 


06 


10 


I  -A 


IB 


pig.  I.  The  dependence  of  sartorius  weight  on  [Na+]  of 
the  medium  (24-hour  immersion  at  3  C).  Closed  circles :  stepwise 
NaCl  reduction  replaced  by  KC1.  Crosses:  stepwise  NaCl  reduc- 
tion not  replaced  by  K.C1.  Open  circles:  stepwise  NaCl  reduction 
in  the  presence  of  cyanide  (2  X  io-3  m).  Volume  control  at 
equilibrium  depends  on  [Na+]  even  in  the  presence  of  cyanide 
and  is  independent  of  [K+]  above  maintenance  level  (20 
meq/liter).  [From  Conway  (31). 


which  evolution  has  fitted  the  sodium  ion.  Cell 
membranes  are  almost  impermeable  to  this  ion  and, 
since  the  cellular  nondiffusible  material  is  almost 
constant,  the  amount  of  cellular  water  is  controlled 
In  variations  in  extracellular  sodium,  Na0.  Conway 
(31)  has  demonstrated  this  point  by  showing,  for 
example,  that  K.  concentration  in  the  medium,  K„, 
can  be  varied  over  wide  limits  without  influencing 
the  basic  dependence  of  cell  volume  on  Na<,  after 
equilibration  (fig.  1  ).  This  essential  point  is  often 
overlooked  in  experiments  dealing  with  alterations 
of  the  medium. 

The  development  of  osmotic  pressure  is  one  of  the 
colligative  properties  of  solutions.  Ideally  it  is  de- 
termined by  the  number  of  particles  in  solution : 

/7i/--/?/?r 

Its  expression,  however,  depends  on  whether  or  not 
the  membrane  is  permeable  to  the  particle  in  question. 
At  equilibrium,  no  osmotic  pressure  is  exerted  by 
a  particle  to  which  a  membrane  is  freely  permeable. 

ion  size.  Ions  may  be  defined  as  particles  which  have 
gained  or  lost  an  electron  on  passing  into  solution. 
The  elements  of  Group  1  of  the  periodic  table,  the 
alkali  metals  Li,  Na,  K,  Rb,  and  Cs,  are  all  charac- 
terized by  possessing  a  single  electron  in  their  outer 
orbital  shell.  In  solution  this  is  lost  so  that  the  element 
loses  its  electroneutralitv  and  remains  positively 
charged  as  Li+,  Na+,  etc.  Other  elements,  like  those 
in  Group  7,  take  up  one  or  more  electrons  into  their 
outer  shell  and  so  become,  in  solution,  negatively 
weighted,  e.g.,  Cl— ,  Br-,  I  ,  etc.  The  formation  of 
ions  is  not  restricted  to  elements  but  also  occurs  with 
more  complex  radicals  which  can  collectively  gain 
or  lose  one  or  more  electrons,  e.g.,  OH-,  XH4+, 
etc. 

Ions  share  the  ordinary  colligative  properties  of 
substances  in  solution  as,  for  example,  freezing  point 
depression,  osmotic  pressure,  etc.  Additionally,  they 
possess  a  number  of  special  properties  based  on  the 
fact  that  they  are  electrically  charged. 

We  must  distinguish  here  the  size  of  the  ion  con- 
sidered as  a  solid  ball,  so  to  speak,  and  defined  by  its 
crystal  radius,  from  its  size  when  associated  with 
water  molecules  and  defined  by  its  hydrated  radius. 
The  increase  in  size  of  the  monoatomic  crystals  of 
Group  1  falls  naturally  into  the  same  order  as  their 
periodic  arrangement  Li  <  Na  <  K  <  Rb  <  Cs. 

For  many  years  it  has  been  the  accepted  practice 
to  emphasize  the  hydrated  ion  in  biological  systems. 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


I  137 


Crystal  Radius, 

A 

Hydrated  Radii,  A 
From  Mobility 

O.60 

2.31 

°-95 

1.78 

1  -33 

I  .22 

1  .48 

I  ,|8 

1.69 

1. 16 

..48 

I  .21 

table  I .  Ionic  Radii  of  Alkali  Metal  Ions 


Li 

Na 

K 

Rb 

Cs 

NH,+ 

From  Ussing  et  a/.  (202;. 

The  smaller  the  ionic  crystal  the  more  densely  is 
its  electrical  field  packed  and  the  greater  its  attraction 
for  water  dipoles.  Consequently,  the  size  of  the  pack- 
age, crystal  plus  water,  moving  in  a  solution,  is 
larger  the  smaller  the  crystal.  Thus,  the  rank  order 
for  the  hydrated  ion  size  is  Cs  <  Rb  <  K  <  Na  <  Li 
(table  1).  This  model  should  not  be  accepted  un- 
critically (160)  although  it  does  provide  us  with  a 
useful  working  framework. 

ion  activity.  Ions  in  solution  are  subject  to  interionic 
forces  which  limit  their  availability.  In  consequence, 
the  measured  concentration  of  an  ion  may  be  greater 
or  less  than  its  reactive  concentration  by  some 
measurable  degree  defined  as  the  activity  coefficient. 
The  concentration  of  the  substance,  corrected  by  the 
activity  coefficient,  defines  the  activity  of  the  ion  in 
the  given  solution.  Since  reactions  in  solutions  and 
their  resultant  equilibria  are  determined  by  activities 
rather  than  by  concentrations  this  point  has  special 
importance.  As  figure  2  shows,  each  salt  has  its  own 
characteristic  curve  relating  activity  to  concentra- 
tion. Standard  tables  are  available.  For  similar 
reasons,  the  ionization  constant  of  salts  is  also  of 
import,  since  not  all  salts  dissociate  with  equal  com- 
pleteness into  ions.  Activity  will  be  symbolically 
written  (Na+)  and  concentration  [Na+].  Where  such 
precision  is  not  necessary  in  a  given  context  we  shall 
simplv  write  Na  for  sodium  or  Na+  for  sodium  ion. 

ion  mobility.  In  general,  the  mobility  of  an  ion  in 
free  solution  varies  inversely  with  its  hydrated  size. 
In  fact,  the  concept  of  ion  hydration  was  in  part 
developed  to  explain  the  relative  mobilities  of  ions. 
Ion  mobility  is  ordinarily  measured  as  velocity  in  a 
standard  electrical  field.  Table  2  shows  the  relation 
of  increasing  size  to  slower  velocity. 

ion  penetrability  or  membrane  permeability.  Cell 
membranes  in  general  appear  to  have  channels  so 
limited  in  size  as  to  allow  K  to  enter  freely  and  just 


fig.  2.   Mean  activity  coefficients  of  various  electrolytes  at 
25  C.  [From  Prutton  &  Maron  (161  a).] 


to  exclude  Na.  Conway  (32)  has  presented  interesting 
and  basic  data  pertinent  to  this  point  (table  3). 
Frog  sartorius  immersed  in  Ringer  fluid,  to  which  100 
iriM  of  a  particular  salt  is  added,  at  first  loses  weight 
(osmotic  withdrawal  of  water).  Then,  if  the  membrane 
is  freely  permeable  to  the  salt,  the  weight  increases 
back  to  its  original  base.  Thus,  at  equilibrium,  the 
added  salt  has  not  upset  the  osmotic  balance.  The 
time  required  to  recover  50  per  cent  of  the  weight  loss 
is  taken  as  a  measure  of  the  permeability  of  the  mem- 
brane for  the  particular  ion  and  table  3  is  so  con- 
structed. It  is  evident  that  taking  KC1  as  standard, 
RbCl  and  CsCl  enter  readily,  while  the  chlorides  of 
Na,  Li,  Ca,  and  Mg  do  not  enter  appreciably.  Simi- 
larly, in  the  anion  series,  bromide  and  nitrate  enter 
easily  while  phosphate,  acetate,  bicarbonate,  and 
sulfate  are  excluded. 

On  the  right  side  of  the  table  Conway  compares 
the  diffusion  coefficients  of  the  ions  rather  than  rela- 
tive ion  diameter  with  K  and  points  out  that  the 
correspondence  is  far  from  exact  (cf  Rb  and  Cs  pene- 
tration rates  with  diffusion  rates). 

The  permeability  of  the  cell  membrane  to  ions  is 
not  a  fixed  characteristic  but  must  be  expected  to 
vary  physiologically  and  pathologically. 


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CIRCULATION    II 


table  2.  Relation  0}  Ion  Size  to  Mobility  in  an  Electric  Field 

Velocities  of  Ions  Under  Gradient  of  i  17cm  or  0.5  17cm  for  Divalent  Ions 


Relative  Ion  Diameters  (Diameter  of  Potassium  Ion  =  1.00J 


Cations 

Anions 

Cations 

Anions 

H 

3>5-2 

OH 

'73-8 

H 

O.20 

OH 

°-37 

Rb 

67-5 

Br 

6/.3 

Rb 

O.96 

Br 

0.96 

Cs 

64.2 

I 

66.2 

Cs 

I  .00 

1 

o-97 

NH, 

643 

CI 

65.2 

NH, 

I  .00 

CI 

0.98 

K 

64.2 

NO3 

61  .6 

K 

I  .OO 

N03 

1  .04 

Na 

43-2 

CH3COO 

35-° 

Na 

I.49 

CH3COO 

1  .84 

Li 

33  0 

SO, 

34° 

Li 

'•95 

so. 

..89 

Ca 

25-5 

HPO, 

28.0 

Ca 

2-5' 

HPO, 

2.29 

Mg 

22.5 

Mg 

2.84 

From  Conway  (32). 

table  3.  Relative  Entrance  Rates  of  Ions  into 
Muscle    (Left   Column)    Compared   with    Their 
Diffusion   Constants,  D,   Though  Water  Relative  to  A 
Taken  as  100  (Right  Column). 


Cation  series 

D  for  sinp 

le  ions,  with  K  value  = 

=   100 

KC1 

100 

K 

100 

RbCl 

38 

Rb 

103 

CsCl 

8 

Cs 

104 

NaCl 

0 

Na 

67 

LiCl 

0 

Li 

52 

CaCL 

0 

Ca 

40 

MgCl2 

0 

Mg 

35 

Anion  series 

KC1 

100 

CI 

100 

KBr 

63 

Br 

105 

KN03 

'7 

N03 

96 

K  phosphate 

4 

H2PO, 

5° 

KOOCCH3 

3 

HPO, 

39 

KHCOs 

1 

CH3COO 

54 

K,SO, 

0 

HCO., 

67 

so. 

53 

From  Conway  (31). 

Special  Properties  of  Ions  in  Biological  Systems 

donnan  equilibrium.  By  thermodynamic  principles 
it  can  be  demonstrated  that  the  product  of  diffusible 
cations  and  anions  on  the  two  sides  of  a  membrane 
must  attain  equality  at  equilibrium.  Thus: 

(cations),  (anions),  =  (cations)<,(anions)e, 

When  the  cell  is  nonpermeable  to  some  charged 
material  on  one  side  of  its  membrane,  a  sufficient 
number  of  diffusible  ions  of  opposite  charge  is  re- 
quired to  balance  this.  In  the  cell  this  fixed  material 
is  mainly  negative  in  charge  so  that  it  can  be  shown 
that  at  equilibrium  the  sum  of  the  diffusible  cellular 
cations  must  be  rather  larger  than  the  sum  of  dif- 
fusible  anions.   In   brief,  this   shows  up   in   the   low 


intracellular  and  high  extracellular  CI-.  It  is  im- 
portant to  realize  that  in  determining  an  expected 
Donnan  equilibrium  in  a  tissue  only  the  diffusible 
ions  count.  Thus,  Na+  figures  only  to  the  small  extent 
that  it  penetrates  the  cell  membrane. 

electrochemical  gradients  and  membrane  po- 
tentials. It  is  beyond  the  scope  of  this  article  to  at- 
tempt to  deal  with  this  fascinating  subject  in  any  sort 
of  detail.  Since  our  discussion  of  ions  and  smooth 
muscle  must  make  frequent  reference  to  bioelectric 
potentials,  however,  a  brief  outline  will  be  presented. 
Two  different  dilutions  of  a  substance  A'  and  A" 
have  necessarily  different  activities  and  different 
chemical  potentials  stored  in  them.  This  may  be 
expressed  as  the  change  in  free  energy  required  to 
move  one  mole  of  A'  from  the  lower  to  the  higher 
activity  or,  conversely,  the  amount  of  free  energy 
liberated  when  A"  slides  from  higher  to  lower  activity. 
This  relation  follows  the  very  general  form 

(A)' 
(A) 

AG  can  be  expressed  in  electrical  terms  as  volt-cou- 
lombs and  factored  into  a  potential  difference  E  and 
nF  faradays  so  that : 

F_RT  .(A)' 
E  — P  ln  777" 
nF       (A) 

At  25  C  this  simplifies  to 

E<mvi58,0'wr 

Clearly,  the  osmotic  balancing  of  the  nondiffusible 
material  in  the  cell  and  the  associated  Donnan  rear- 
rangement together  produce  a  situation  in  which  the 
diffusible  ions  are  distributed  unequally  on  the  two 
sides  of  the  membrane  and  so  contain  stored  energy. 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


i '39 


By  far  the  major  diffusible  ion  concerned  is  K.+  and 
so  we  may  write  as  a  first  approximation : 


m     F        (K% 


where  E„,  is  the  potential  at  equilibrium  across  the 
membrane  and  i,  inside,  o,  outside.  Concentrations 
are  usually  written  but  activities,  as  shown,  are  more 
precise. 

The  movements  of  Na+  and  Cl~  are  essentially 
quite  limited;  yet,  to  the  extent  that  they  are  perme- 
able, their  distribution  must  also  contribute  to  the 
over-all  transmembrane  potential.  Goldman  (92)  has 
therefore  proposed  a  constant  field  equation : 


.  RT  s    <«*>!  *  l>(Na*Jj  *  P<Cr)0 
m '  F     "  (K%+  p(No%  *  ptcDj 


Bv  convention  E„,  is  regarded  as  positive.  The  symbol, 
p,  expresses  the  permeability  of  the  ion  relative  to 
A'+  taken  as  unity,  influx  and  efflux  being  considered 
separately.  This  equation  may  or  may  not  be  entirely 
correct  but  it  is  applicable  to  our  purpose,  since  it 
takes  into  account  the  contributions  of  ions  other 
than  K+  and  their  relative  mobilities. 


Special  Properties  of  the  Physiologically  Important  Ions 

The  particular  role  of  Na+  and  K+  has  already  been 
described.  They  are  the  major  bulk  ions  of  the  body 
and,  in  fact,  the  maintenance  of  their  distribution 
may  consume  a  major  share  of  the  body's  energy. 
Their  role  has  been  the  subject  of  comprehensive 
monographs  (61,  202). 

Calcium  and  magnesium,  belonging  to  Group  2  of 
the  periodic  table,  have  in  their  outer  orbital  shell 
two  electrons  which  are  given  up  readily  in  solution. 
They  may,  and  probably  do,  participate  in  the  phe- 
nomena described  above,  but  they  are  also  particu- 
larly important  in  enzymatic  processes.  They  are  far 
more  readily  complexed  than  either  sodium  or  potas- 
sium. 

Hydrogen  and  hydroxyl  ions  are  distinguished  by 
their  mobility  and  easy  penetrability  into  and  out  of 
cells.  Their  primary  involvement  in  acid-base  equilib- 
ria needs  no  comment  at  this  point. 

The  physiologically  important  anions  have  also 
been  the  subject  of  an  extensive  monograph  (54). 


CLASSIFICATION    AND    CRITICAL 
APPRAISAL   OF    METHODS 

It  is  not  our  purpose  here  to  describe  all  the  methods 
used  to  study  the  effects  of  ions  on  vascular  smooth 
muscle  directly  or  indirectly.  The  aim  is  rather  to 
seek  the  general  principles  underlying  each  approach 
and  to  indicate  to  what  extent  the  methods  used  can 
further  our  understanding.  On  this  basis  we  can 
classify  the  methods  broadly  into  two  groups:  those 
in  which  the  experimental  variable  is  the  cell  environ- 
ment and  those  in  which  the  vascular  tension  is  the 
manipulated  variable. 

Studies  of  Vascular  Smooth  Muscle  Tension  Associated 
with  Manipulation  of  the  Milieu 

In  these  studies  the  ionic  milieu  or  environment  of 
the  cells  has  been  manipulated  in  vivo  by  varying  the 
dietary  salt  intake  or  by  loading  with  various  salts 
given  by  stomach  tube,  by  infusion,  or  by  injection. 
In  this  group  we  have,  too,  studies  of  the  effects  of 
hormones  known  to  affect  salt  metabolism  and  in 
vitro  studies  in  which  the  medium  has  been  directly 
manipulated.  Obviously,  the  more  prolonged  the 
treatment  and  the  more  general  its  effects,  the  more 
difficult  it  is  to  pin  down  any  direct  relation  between 
treatment  and  vascular  smooth  muscle  tension.  Even 
so,  all  approaches  must  be  examined  if  we  are  not  to 
lose  sight  of  important  clues 

The  effects  of  these  manipulations,  of  varying  de- 
grees of  remoteness  from  the  target,  have  been  as- 
sessed by  three  principal  methods. 

MEASUREMENT  OF  DIASTOLIC   BLOOD   PRESSURE.    Since   a 

major  determinant  of  the  diastolic  blood  pressure  is 
the  peripheral  vascular  resistance  this  approach  has 
some  limited  value.  The  results  can  always  be  attacked 
on  the  grounds  that  a  change  may  indicate  an  effect 
on  cardiac  output,  on  blood  viscosity,  or  on  blood 
volume,  etc.,  rather  than  on  peripheral  resistance. 
Such  studies  have  value,  however,  if  they  correlate 
well  with  other  more  direct  approaches.  Experiments 
of  this  type  in  the  rat  suffer  still  more  seriously  from 
the  fact  that  most  of  the  indirect  methods  do  not 
measure  diastolic  blood  pressure  at  all  but  some 
mixed  level  which  approximates  the  mean  pressure. 

MEASUREMENT  OF  PERIPHERAL  RESISTANCE  IN  RE- 
GIONAL vascular  beds.  This  approach  is  necessarily 
confined  to  studies  of  the  effects  of  fairly  rapid  changes 
in  the  milieu.  Within  this  limitation,  it  can  be  highly 


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CIRCULATION    II 


accurate.  The  variable  of  cardiac  output  can  be 
eliminated  by  controlling  the  rate  of  inflow  into  the 
vascular  bed  with  a  constant  output  pump  (101).  It 
can  remain  as  a  variable  when  blood  flow  rate  and 
pressure  are  monitored  simultaneously  in  the  vascular 
bed  under  study  (148).  Additionally,  this  type  of 
approach  can  give  direct  information  concerning 
vascular  tonus  in  different  segments  of  a  given  bed. 
At  the  present  time,  in  vivo  studies  carried  out  in  this 
manner  are  the  best  available. 

The  alterations  of  the  environment  attainable  with 
this  approach  are  exceedingly  limited  if  the  circula- 
tion of  the  bed  is  continuous  with  that  of  the  general 
systemic  pool.  The  imposed  change  must  not  be  great 
enough  to  elicit  a  systemic  reaction  and  the  change  of 
milieu  induced  must  be  analytically  confirmed.  To 
avoid  these  difficulties  many  studies  have  been  carried 
out  using  totally  isolated  vascular  beds,  e.g.,  rabbit 
ear,  dog  hind  limb,  rat  hind  limb,  perfused  with 
artificial  solutions.  The  gain  in  control  of  the  medium 
does  not,  however,  compensate  for  the  loss  of  a  physio- 
logical preparation;  hence  such  studies  have  not  been 
extensively  used  for  our  particular  problem. 

Microscopic  observations  of  various  circulatory 
beds  have  yielded  useful  information  concerning  the 
physiology  and  pharmacology  of  these  beds  (114). 
Because  the  mesoappendix  or  meso-omentum,  the 
beds  usually  studied  (217),  have  rather  special 
properties,  they  have  not  been  extensively  or  profit- 
ably used  to  study  the  effects  of  ions. 

MEASUREMENT  OF  TENSION  IN  THE  VASCULAR  STRIP 
OR   RING    OR   IN    AN    ANALOGOUS  SMOOTH    MUSCLE   STRIP. 

The  in  vitro  approach  has  the  value  of  enabling  the 
experimenter  to  control  the  environment  although, 
of  course,  the  results  must  later  be  fitted  to  the  in  vivo 
framework.  This  type  of  study  has  suffered  greatly 
from  the  fact  that,  so  far,  no  one  has  been  able  to 
mount  a  representative  of  the  vessels  that  actually 
control  peripheral  resistance.  As  substitutes,  rings  of 
large  arteries  or  strips  of  aorta  (87)  have  been  used, 
although  Bohr  &  Goulet  (14)  have  recently  reported 
briefly  that  a  spiral  strip  of  rabbit  mesoappendix 
arteriole  may  be  practicable. 

The  aorta  seems  to  us  a  particularly  poor  choice 
because  of  its  specialized  elastic  tissue  content.  It  be- 
haves quite  differently  from  peripheral  vasculature  in 
vivo  and,  in  particular,  shows  a  slow  and  prolonged 
response  time  (11,  48,  88).  An  additional  criticism  is 
that  the  smooth  muscle  cells  are  abnormally  oriented 
in  the  spiral  strip.  One  would  hope  that  a  suitable 
preparation   using   a    length   of  artery   under   intra- 


luminal pressure  distributed  radially  from  its  fluid 
content  will  soon  be  devised  to  replace  the  present 
strip  techniques.  Pa  ton  (157)  and  Davey  (44)  have 
both  had  some  success  with  this  approach  and  our 
own  preliminary  studies  seem  promising.  For  the 
present,  we  must  discuss  the  results  derived  from  cur- 
rent techniques  with  necessary  reservation. 

Although  it  is  clear  that  different  types  of  smooth 
muscle  differ  in  their  drug  responses,  they  do  have 
certain  histological  features  in  common.  We  shall, 
therefore,  round  out  this  part  of  the  discussion  by 
surveying  the  findings  with  uterus  and  gut  strips  in 
order  to  recognize  generalizations  where  possible. 

Studies  oj  the  Milieu  During  Manipulation  of  Vascular 
or  Analogous  Smooth  Muscle  Tension 

In  these  studies,  vascular  smooth  muscle  tension 
has  been  increased  or  decreased,  acutely  or  chroni- 
callv,  by  a  diversity  of  procedures  ranging  from  hor- 
mones through  drugs  to  direct  ionic  manipulation. 
Some  well-defined  parameter  outside  and/or  inside 
the  cell  has  been  measured.  The  principal  analyses  are 
as  follows: 

MEASUREMENT  OF  EXTRACELLULAR  AND  OR  INTRA- 
CELLULAR ions  and  water.  The  external  environ- 
ment of  the  smooth  muscle  cell  has  for  a  long  time 
been  estimated  from  measurements  chiefly  of  plasma 
Na,  K,  CI,  and  Ca.  The  analytical  procedures  have 
gradually  been  improved  but  Na  determination  by 
flame  photometry  with  greater  than  1  per  cent  error, 
exclusive  of  the  sampling  error,  has  made  the  world 
of  small  changes  in  plasma  or  serum  Xa  unapproach- 
able. 

More  recently  it  has  become  apparent  that  a  knowl- 
edge of  the  extracellular  fluid  volume  is  required  if 
extracellular  ionic  quantities  are  to  have  any  mean- 
ing. The  volume  distribution  of  exogenously  ad- 
ministered inulin  so  far  gives  the  most  reliable  estimate 
of  this  (89,  206,  207).  Earlier  studies  used  chloride 
which,  under  basal  conditions,  was  thought  to  be 
almost  entirely  extracellular.  It  is  now  generally 
realized,  however,  that  not  only  is  the  chloride  space 
larger  than  the  extracellular  space  but  also  that  pro- 
cedures which  alter  cation  distribution  of  necessity 
produce  variable  chloride  shifts  for  the  preservation 
of  electroneutrality  within  the  cell.  Accordingly,  we 
must  interpret  the  ion  partitions  based  on  chloride 
measurements  with  caution.  Other  substances  such  as 
bromide  or  thiosulfate  used  as  measures  of  extra- 
cellular space  suffer  from  similar  criticisms. 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


i  i  4  i 


table  4.  Some  Representative  Vascular  Tissue  Analyses 

Author 

Tissue 

Total  V. 
meq/kg 
Drj  Wt 

Total  K. 
meq  kg 
Dry-  Wt. 

Total 

CI, 

meq/kg 

Dry 

Wt. 

Total 

IhO. 

ml  kg 

Wet  Wt. 

Cell  Na, 
meq/i- 

Cell  K. 
meq/1. 

Cell 

HjO, 

ml  kg 

Wet  Wt. 

Inulin 
Space. 
ml  'kg 
Wet  Wt. 

«  1  Spai  e.  ml  kg 
Wet  Wt. 

Na 
Spai  e, 

Wet  Wt. 

Daniel  &  Dawkins  (40) 

Rat 

stomach 

271  ±14 

35°±8 

77o±4 

Barr  (9) 

Cat  small 

int. 
Rat 

322 

405 

350 

8l0±2 

65  ±5 

io8±6 

101  ±17 

544 

432 

Laszt  1 133) 

3io±o.8 

352±°-7 

784±3 

bladder 

Daniel  &  Daniel  (39) 

Immature 
rabbit 
uterus 

45'  ±24 

266±30 

792±I2 

101 
29 

100 
236 

522 
219 

270^=30 

573±36 

613 

Immature 

632  ±43 

274±3 

8.9±i5 

143 

120 

414 

405  ±20 

75' 

cat 

119 

213 

261 

558±i5 

uterus 

Tobian  &  Binion  (195) 

Human 
renal  art 

395±7' 

1 87  ±36 

76o±23 

Tobian  &  Binion  (196) 

Rat  aorta 

358±5 

95±' 

254±9 

Daniel  el  al.  (41) 

Rat  aorta 

336±2o 

141  ±7 

.89 

646±i  1 

Daniel  &  Dawkins  (40) 

Rat  aorta 

296  ±29 

'3'±7 

664±9 

Tobian  &  Redleaf  (200) 

Rat  aorta 

292  ±4 

1  ig±2 

222  ±2 

Laszt  (133) 

Rat  aorta 

265  ±0.8 

■  49±°-5 

638  ±6 

Dodd  &  Daniel  (49) 

Rabbit 
aorta 

327±44 

59±.6 

663±i4 

'58 

192 

483 
"corrected" 

650  ±48 

Sreter  (unpub.) 

Rat  aorta 

227  ±4 

iogdzi.4 

°59±5 

92  ±5 

"3±4 

322±I0 

337±'i 

Sample  analyses  of  nonvascular  smooth  muscle  are  presented  for  illustration.  Estimate  of  variance  is  omitted  wherever 
original  data  were  recalculated  to  fit  the  tabular  description.  Derived  data  depend  on  either  inulin  or  chloride  spaee  value 
shown  on  same  horizontal  line.  (Table  prepared  by  Dr.  F.  A.  Sreter.) 


Tissue  analyses  have  also  been  carried  out  in  an 
attempt  to  measure  Na,  K,  and  water  and  their 
extracellular/intracellular  partition  under  a  variety 
of  conditions.  Few  of  these  have  encompassed  a 
representative  vascular  tissue,  and  even  these  few 
have  been  quite  incomplete.  Table  4  presents  basic 
data  taken  from  the  work  of  several  laboratories. 

Total  aorta  Na  and  K.  vary  from  about  200  to  350 
and  95  to  150  meq  per  kg  dry  tissue,  respectively,  the 
variation  probably  reflecting  the  animal's  age,  pre- 
vious diet,  and  the  sampling  method.  An  aorta  sodium 
so  much  higher  than  potassium  is  consistent  with  a 
large  extracellular  space. 

It  is  apparent  that  the  chloride  space  sometimes 
exceeds  the  readily  measured  total  water  content  of 
the  tissues  and  hence  is  a  poor  measure  of  extracellular 
space.  Tobian  &  Binion  (196),  for  example,  reported 
an  extracellular  fluid  volume  based  on  chloride  which 
recalculates  to  some  750  ml  per  kg  wet  tissue  and  this 
exceeds  most  investigators'  estimates  of  total  water. 
Dodd  &  Daniel  (49)  reported  a  chloride  space  of  633 
and  a  sodium  space  of  650  ml  per  kg  rabbit  aorta,  and 
again  the  total  tissue  water  was  only  640  to  660  ml 


per  kg.  They  argued  that  there  was  probably  a  frac- 
tion of  bound  chloride  wrongly  included  in  the  calcu- 
lation. Even  after  a  correction  for  this,  however,  they 
still  obtained  an  extracellular  fluid  volume  of  483 
ml  per  kg. 

Using  inulin  in  a  revised  procedure  we  estimate 
extracellular  space  as  about  50  per  cent  of  the  total 
tissue  water.  This  compares  favorably  with  the  esti- 
mate of  Prosser  et  al.  (161)  of  39  per  cent  of  the  total 
tissue  volume. 

The  ratio  of  extracellular  to  total  water  runs  lower 
in  other  types  of  smooth  muscle  than  in  aorta.  Inulin 
space  measures  1 2  per  cent  of  the  total  water  in  cat 
small  intestine  (9)  and  34  per  cent  in  the  rabbit 
uterus  (39).  These  again  are  in  line  with  the  electron 
microscopic  observations.  [The  high  inulin  space  re- 
ported for  the  immature  cat  uterus  (39)  is  out  of  line.] 

Intracellular  Na  runs  higher  in  the  aorta  and  in 
other  types  of  smooth  muscle  than  in  skeletal  muscle. 

MEASUREMENT     OF     OSMOTIC     PRESSURE     AND     PH.     The 

development  of  techniques  suitable  for  measurement 
of  osmotic  pressure  and  pH  in  small  samples  has  made 


I  142 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION     II 


it  quite  feasible  to  study  these  parameters  directly. 
Unfortunately,  these  have  not  been  much  applied  to 
the  problem  of  ions  and  vascular  tissue.  This  is  an 
important  deficiency. 

electrical  measurements.  It  is  now  generally  be- 
lieved that  electrical  potentials  developed  across  cell 
membranes  depend  on  ionic  distribution,  mobility, 
and  the  permeability  characteristics  of  the  membrane 
itself.  Unfortunately,  because  of  technical  difficulties, 
vascular  tissue  has  not  been  approached  until  very 
recentlv  and  only  minimal  information  is  available. 
We  shall  thus  have  to  lean  heavily  on  electrical  meas- 
urements obtained  from  other  types  of  smooth  muscle, 
especially  guinea  pig  taenia  coli. 

CONTINUOUS    MONITORING    OF    Na    OR    K.    ION    ACTIVITY. 

The  development  of  ion-specific  glasses  responding 
especially  to  Na+  or  K+  (55)  has  made  it  possible  to 
prepare  electrodes  suitable  for  monitoring  Na+  or  K+ 
in  flowing  blood  (79).  These  electrodes  can  discrimi- 
nate ion  activity  with  far  greater  resolution  than  any 
methods  hitherto  available  and  can  also  be  applied 
to  the  analysis  of  single  samples  or  to  the  continuous 
monitoring  of  activity  in  a  tissue  bath.  Their  applica- 
tion to  the  problem  in  hand  has  only  just  begun,  but 
already  they  have  furnished  several  important  pieces 
of  information. 


ROLE    OF    SODIUM    AND    POTASSIUM    IN 
VASCULAR    SMOOTH    MUSCLE    TENSION 

Evidence  from  Studies  of  Diastolic  Blood 
Pressure  or  Reactivity 

GENERAL    RELATION    OF    Na    AND    K    TO    CLINICAL    AND 

experimental  hypertension.  More  than  50  years 
ago  Ambard  &  Beaujard  (4)  suggested  that  the  de- 
velopment of  clinical  hypertension  was  abetted  by 
salt,  although  they  incorrectly  stressed  Cl~  rather  than 
Na+.  Allen  &  Sherrill  (2)  revived  the  idea  some  25 
years  later,  correctly  identified  Na+  as  the  important 
ion,  and  urged  the  use  of  low  salt  diets  in  treatment. 
After  a  period  of  neglect  the  idea  recurred  when 
Kempner  (126)  advocated  the  unpalatable  rice  diet 
for  hypertensive  patients  and  indeed,  in  so  doing, 
came  close  to  starting  a  food  cult  (27).  Shortly  there- 
after the  main  therapeutic  benefit  of  the  rice  diet  was 
distinguished  from  its  psychological  benefit  and  shown 
to  reside  in  its  low  sodium  content  (34,  98,  159).  By 
the  beginning  of  the  last  decade  the  low  sodium  diet 


was  firmly  established  as  a  measure  of  limited  but 
certain  usefulness  in  the  management  of  the  hyper- 
tensive patient.  Because  of  difficulties  inherent  in  its 
use  it  could  not  be  widely  applied  but,  even  so,  pa- 
tients were  routinely  encouraged  to  reduce  their 
voluntary  salt  intake  for  fear  of  accelerating  the  prog- 
ress of  their  disease. 

The  effort  to  reduce  the  amount  of  sodium  available 
to  the  body  in  hypertension  led  naturally  to  attempts 
to  increase  its  loss  through  the  kidneys.  This  approach 
was  dramatically  successful  as  specific  natriuretic 
agents,  such  as  chlorothiazide  and  hydrochlorothia- 
zide, were  developed  and  shown  to  be  highly  effective 
in  the  treatment  of  hypertension  (1,  8,  97).  These 
agents  show  clearly  that  as  long  as  the  kidneys  are 
competent,  the  simple  desalting  of  the  body  will  re- 
duce an  elevated  diastolic  blood  pressure  and,  even 
though  normotensive  levels  may  not  be  attained,  will 
tend  to  keep  it  down. 

Studies  of  experimental  forms  of  hypertension  have 
also  underlined  the  general  relation  between  available 
salt  and  blood  pressure.  This  was  first  shown  by  the 
fact  that  hypertension  induced  by  the  prolonged 
administration  of  desoxycorticosterone  acetate  (DCA) 
is  accelerated  by  concomitantly  increasing  the  salt 
intake  (179)-  This  effect  was  shown  to  be  specifically 
due  to  the  sodium  ion  (180).  A  slower  blood  pressure 
rise  can  be  induced  without  adding  extra  salt  to  the 
intake  above  that  supplied  by  the  food,  but  no  rise 
occurs  if  the  diet  is  sodium-free  (18,  84,  181).  A  similar 
dependence  on  Na  intake  has  been  found  to  obtain 
for  the  hypertension  which  occurs  during  adrenal 
regeneration  (184,  185)  and  in  the  subtotally  nephrec- 
tomized  animal  (128).  Thus  far,  most  forms  of  experi- 
mental hypertension  respond  to  Na  deprivation  or 
depletion  with  a  reduction  in  blood  pressure  (194). 

The  implication  of  Na  metabolism  in  the  hyper- 
tensive process  has  also  been  sharply  underlined  by 
studies  of  the  response  of  man  and  animals  to  acutely 
imposed  salt  loads.  The  results  have  been  strikingly 
uniform  and  the  accelerated  excretion  of  such  loads, 
first  systematically  demonstrated  in  various  forms  of 
hypertension  in  the  rat  (77,  93),  is  also  a  consistent 
feature  in  hypertensive  man  (35,  94). 

There  is  reliable  but  not  so  extensive  evidence  im- 
plicating K  in  a  general  way  with  the  hypertensive 
process.  Most  of  these  studies  have  come  from  M. 
Friedman  and  his  associates.  These  investigators  first 
pointed  out  that  the  rise  in  blood  pressure  produced 
by  renal  compression  in  the  rat  can  be  reduced  by 
prolonged  K  deprivation  (6  weeks)  and  argued  that 
this  effect  is  related  to  the  decrease  in  smooth  muscle 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


"43 


tonus  known  to  occur  in  gut  and  urinary  bladder 
during  potassium  deficiency  (72,  170,  210).  An  ade- 
quate K  intake  was  also  shown  to  be  essential  for  the 
development  of  DC. A  hypertension  although,  unlike 
the  effect  of  Na,  an  excessively  high  K  intake  does 
not  accelerate  the  process  (68,  169).  In  later  studies, 
these  authors  concluded  that  the  effect  of  varying  the 
K  intake  depends  on  its  simultaneous  relation  to  the 
Na  intake  and  that  the  development  of  hypertension 
depends  on  a  high  K  Na  ratio  (167,  169).  This 
important  theme  will  recur  in  our  later  discussion. 
Perera  (158)  confirmed  the  basic  observation  by  show- 
ing that  essential  hypertension  in  man  could  be  re- 
duced by  a  low  K  diet,  although  this  was  not  a  practi- 
cable therapy. 

EFFECTS    OF   VARYING    Na    AND    K    INTAKE    OR    LOSS   ON 

blood  pressure.  Sapirstein  and  associates  first  re- 
ported in  1950  (172)  that  rats  given  various  hyper- 
tonic NaCl  solutions  to  drink  develop  an  arterial 
h\  pertension  after  a  latency  of  1  to  4  weeks.  This  was 
confirmed  by  Toussaint  et  al.  (201)  and  extended  by 
Meneely  and  his  collaborators  (151,  152)  who  showed 
that  the  rise  in  blood  pressure  in  such  salt  fed  animals 
is  proportional  to  their  salt  inake.  A  latter  report  from 
this  same  laboratory  (150)  pointed  out  that  the  effect 
of  adding  NaCl  to  the  diet  can  be  partly  offset  by  a 
simultaneous  increase  in  K  as  well.  From  this,  they 
suggested  that  the  blood  pressure  rise  is  dependent  on 
an  increase  in  the  Na  K  ratio.  This  is  diametrically 
opposite  to  the  work  of  M.  Friedman  and  co-workers, 
cited  above,  which  implicated  a  high  K/Na  ratio. 

Fregly  (71)  has  sharply  underlined  the  importance 
of  salt  as  a  determinant  of  vascular  resistance.  He  has 
recently  produced  hypertension  in  the  adrenalecto- 
mized  salt-fed  rat  and  has  shown  the  relation  of  the 
blood  pressure  rise  to  the  amount  of  salt  ingested. 
Vick  et  al.  (203)  found  that  vascular  sensitivity,  meas- 
ured as  the  response  of  the  aorta  strip  to  epinephrine, 
increased  in  rats  after  10  to  15  weeks  of  high  salt 
feeding. 

The  idea  that  an  excessive  intake  of  salt  may  itself 
be  a  sufficient  etiological  factor  in  essential  hyper- 
tension has  been  staunchly  supported.  In  an  extensive 
series  of  studies  Dahl  and  his  colleagues  (36-38)  have 
attempted  to  relate  the  incidence  of  hypertension  in 
man  to  his  salt-eating  habits.  Others  have  studied 
areas  of  reputedly  high  or  low  salt  intake  in  order  to 
relate  the  incidence  of  hypertension  to  the  dietary 
habits  of  the  inhabitants  (176,  194).  So  far,  however, 
the  evidence  that  Na  intake  plays  a  primary  etio- 
logical role  is  still  shaky. 


A  serious  deficiency  in  Na  may  occur  naturally 
during  exposure  to  excessive  heat;  the  advance  of  the 
deficiency  is  associated  with  vascular  collapse  (100). 
Excessive  salt  depletion  for  therapeutic  purposes  may 
produce  a  similar  picture  (175).  In  the  rat,  acute  Na 
depletion  may  be  readily  induced  by  equilibrating  an 
intraperitoneal  isosmotic  mannitol  or  sucrose  solution 
with  the  extracellular  compartment.  Such  a  depletion 
is  always  accompanied  by  hypotension  (unpublished 
observation). 

Although  the  prolonged  intake  of  large  amounts 
of  K  does  not  affect  the  blood  pressure  of  the  normo- 
tensive  rat,  K  restriction  is  an  effective  hypotensive 
procedure  (66).  The  depressor  effect  depends  on  the 
associated  Na  intake,  for  it  does  not  occur  in  the 
presence  of  a  low,  but  only  with  a  normal  to  high 
intake  (67).  Such  K-deficient  hypotensive  rats  show  a 
marked  decrease  in  pressor  response  to  epinephrine, 
norepinephrine,  angiotensin,  and  renin  (168).  Both 
basal  blood  pressure  and  reactivity  are  rapidly  re- 
stored by  KC1  given  subcutaneously  (72). 

These  highlights  selected  from  an  extensive  litera- 
ture show  the  limitations  of  this  type  of  approach. 
They  also  show,  however,  that  sodium  and  potassium 
can  be  implicated  in  the  regulation  of  blood  pressure 
and  that  sodium  in  particular  plays  some  kind  of 
critical  role  in  hypertension.  Unfortunately,  too  many 
steps  intervene  in  the  processes  to  permit  any  kind  of 
valid  interpretation.  Even  as  far  as  this  type  of  infor- 
mation is  concerned  we  are  faced  with  a  major  omis- 
sion, for  there  is  no  assessment  of  the  possible  role  of 
water  in  relation  to  salt  intake.  Sapirstein  (171),  in  an 
attempt  to  reconcile  the  conflicting  evidence,  has 
drawn  attention  to  the  importance  of  water  in  the 
renal  handling  of  electrolytes.  It  is  evident  that  ani- 
mals given  various  salt  solutions  to  drink  are  con- 
fronted in  each  case  with  a  fixed  ratio  of  salt  to  water, 
and  an  ensuing  rise  in  blood  pressure  may  reflect 
either  the  increased  salt  ingestion  or  the  inability  of 
the  animal  to  make  an  adjustment  in  its  water  intake. 
Similarly,  in  states  involving  salt  loss,  any  speculation 
must  also  take  into  account  the  simultaneous  changes 
in  water  distribution.  McC.ance  &  Morrison  (143) 
have  pointed  out  this  unsatisfactory  aspect  of  experi- 
ments which  do  not  distinguish  between  salt  and 
water  as  separate  variables. 

Evidence  from  Studies  of  Tension  or  Reactivity 
of  Vascular  or  Analogous  Tissue 

EFFECTS    OF    MANIPULATION     OF    Na     IN    THE     MEDIUM. 

There    is   consistent   evidence   that    the   exposure   of 


"44 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


smooth  muscle  to  a  sudden  reduction  of  Na  concen- 
tration in  the  medium,  Na„,  osmotic  pressure  being 
held  constant,  produces  an  immediate  increase  in 
tension  (i  16).  This  increase  in  tension  is  not  sustained 
as  equilibration  proceeds.  Streeten  &  Vaughan 
Williams  (189)  noted  an  increase  in  motility  of  in- 
testinal loops  (dog)  during  the  first  stage  of  Na  deple- 
tion by  intraperitoneal  lavage.  Whitehead  (208) 
noted  an  increase  in  tone  of  isolated  ileal  or  jejunal 
segments  (rabbit).  We  (78)  studied  the  response  in 
greater  detail  using  a  colon  strip  (rat)  suspended  in  a 
sensitive  strain-gauge  tensometer  and  found  that  the 
increase  in  tension  and  the  duration  of  response  are 
proportional  to  the  degree  of  reduction  of  Na0. 
Dodd  &  Daniel  (49)  observed  a  similar  immediate 
increase  in  the  tension  of  an  aorta  strip  following  a 
reduction  in  Na0. 

The  sudden  reduction  of  Na+  in  the  medium  must 
at  once  unbalance  ionic  equilibrium  across  the  smooth 
muscle  cell  membrane.  The  restoration  of  equilibrium, 
while  still  retaining  electroneutrality  in  each  com- 
partment, may  require  a  migration  of  positive  ions 
from  within  the  cell  to  the  exterior.  Since  K.  ions 
are  the  only  ones  freely  available  for  this  they  must 
shift  outward  (31,  32).  The  increase  in  tension  re- 
corded may  be  primarily  related  to  the  applied  re- 
duction of  the  Na  gradient,  Na„/Na,  ,  or  perhaps  to 
an  induced  K+  efflux  from  the  cell. 

We  may  suppose  that,  with  time,  the  Na  gradient 
is  gradually  built  back  up  toward  its  basal  state  as  Na 
is  actively  but  relatively  slowly  extruded.  Thus,  when 
fully  equilibrated,  tissues  in  a  low  Na  medium  contain 
a  reduced  intracellular  Na  concentration,  Na,-. 
Working  with  guinea  pig  taenia  coli,  Holman  (118) 
has  shown  that  at  this  stage  the  tissue  still  responds 
normally  to  stimuli,  but  Bohr  et  al.  (13)  claim  hyper- 
responsiveness  for  the  vascular  strip.  Daniel's  group 
does  not  agree  with  this  (49).  When  such  tissues  are 
equilibrated  in  very  low  levels  of  Na„  ,  however,  all 
agree  that  they  become  first  hyposensitive  and  finally 
unresponsive  (49,  116,  118,  147,  188,  189).  This  sug- 
gests that  the  response  falls  off  either  because  Na, 
reaches  some  critical  level  or  that  Na„/Na,  has  itself 
fallen  below  some  critical  value. 

The  observation  that  tone  or  responsiveness  or  both 
decline  after  equilibration  in  very  low  Na„  seems 
quite  uniform.  The  experiments  of  Dodd  &  Daniel 
(49)  and  Yamabayashi  &  Hamilton  (214)  show  that 
the  phenomenon  applies  equally  well  to  vascular 
smooth  muscle.  It  appears,  however,  that  a  fairly 
extreme  reduction  in  Na„  is  necessary  to  elicit  this 
change  and,  since  techniques  vary,  there  is  no  uniform 


answer  concerning  the  absolute  level  at  which  the 
hyporeactivity  occurs.  Indeed  this  level  may  also  vary 
in  different  types  of  smooth  muscle  (43).  We  shall 
later  see  whether  the  decline  in  responsiveness  after 
equilibration  in  low  Na  media  can  be  related  to  a 
reduction  in  the  Na„  Na,  gradient. 

The  time  used  by  various  workers  for  equilibration 
of  their  tissues  varies  over  a  wide  range.  This  may 
well  condition  the  responses  obtained,  since  all  tissues 
incubated  in  vitro  for  any  length  of  time  (in  hours) 
take  up  Na  and  water  and  may  extrude  some  K  (165). 
Put  another  way,  these  tissues  fail  to  maintain  a  nor- 
mal sodium  gradient.  This  process  is  accelerated  by 
cooling  and  is  more  marked  in  artificial  than  in 
natural  media,  for  example,  plasma. 

Despite  the  detailed  differences  between  the  experi- 
mental results  with  various  smooth  muscle  types,  we 
may  conclude  that,  in  general,  an  induced  reduction 
in  the  sodium  gradient  produces  an  immediate  in- 
crease in  tension,  while  the  continued  presence  of 
such  a  low  gradient  leaves  the  tissue  less  primed  for 
the  next  stimulus,  that  is,  hyporesponsive.  Several 
additional  observations  now  fall  into  line  and  a  few 
of  these  may  be  dealt  with  at  this  point.  Hughes  et  al. 
(120)  found  that  rat  uterus  immersed  in  normal 
Krebs  solution  for  3  hours  gained  Na,  ,  as  do  all 
tissues,  and  became  less  responsive  to  test  doses  of 
histamine.  We  have  incubated  dog  femoral  artery  in 
Krebs  solution  at  o  C  overnight,  a  situation  in  which 
the  cells  must  gain  Na  (165),  and  in  the  morning  find 
the  tissue  contracted  and  totally  incapable  of  respond- 
ing to  drug  stimulation.  Revvarming  to  37  C,  the 
standard  procedure  for  re-extruding  Na,  relaxes  the 
tissue  and  restores  its  responsiveness.  McDowall  & 
Zayat  (145)  have  concluded  that  smooth  muscle 
(uterus)  takes  up  sodium  during  drug-induced  con- 
traction and  in  this  state  is  less  responsive  to  stimula- 
tion. 

McDowall  &  Soliman  (144)  suggest  that  the  post- 
stimulatory  refractoriness  is  due  to  difficulty  in  reprint- 
ing the  cell  by  extruding  Na.  In  brief,  they  relate 
unresponsiveness  to  the  simple  increase  in  Xa,  and 
support  this  idea  by  the  fact  that  responsiveness  can 
be  quickly  restored  to  a  refractory  uterus  strip  by 
reducing  Na  in  the  medium.  Three  facts  militate 
against  this  oversimplified  explanation.  In  the  first 
place,  the  acute  reduction  of  Na  in  the  medium  can 
be  expected  to  facilitate  Na  extrusion  but  only  during 
the  prolonged  equilibration  period.  In  fact,  however, 
the  reduction  of  Na„  restores  responsiveness  at  once. 
In  the  second  place,  as  we  have  pointed  out  earlier, 
the  sudden  reduction  of  Na„  immediately  unbalances 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


I  145 


the  cell's  ionic  relation  with  its  environment  and  may 
demand  an  efflux  of  K  ions;  this  may  be  the  basic 
process.  This  is  supported  by  the  fact  that  under 
similar  circumstances,  responsiveness  can  be  as  well 
restored  by  increasing  K  in  the  medium.  In  the  third 
place,  as  described  above,  hyporesponsiveness  occurs 
also  in  extremely  low  Na  media  when  Na,  must 
necessarily  be  very  low  rather  than  high  as  after 
stimulation.  Clearly,  however,  a  reduction  in  the  Na 
gradient  is  common  to  both  hyporesponsive  situations. 

If  an  increase  of  tension  in  smooth  muscle  is 
ordinarily  associated  with  a  shift  of  Na  from  outside 
to  within  the  cell  as  McDowall  &  Zayat  (145)  have 
suggested  for  uterine  muscle  and  as  we  shall  later 
suggest  is  a  general  process,  we  can  distinguish  in  this 
the  importance  of  the  Na  gradient.  Thus,  we  (78) 
have  shown  that  contraction  of  a  colon  strip,  induced 
by  a  variety  of  agents,  can  be  aborted  by  adding  Na 
to  the  medium.  This  procedure  affects  only  Na„  and 
not  Na,  and  thus  directly  implicates  the  Na  gradient 
in  the  induction  of  the  tension  increase  and  not  the 
simple  intracellular  gain  in  Na  considered  alone.  We 
shall  later  associate  these  changes  with  K  distribution 
as  well. 

There  is  reasonably  consistent  evidence  concerning 
the  events  following  exposure  of  a  smooth  muscle 
strip  to  a  medium  containing  supranormal  Na  con- 
centration. If  the  concentration  of  Na  is  high  enough, 
the  first  response  appears  to  be  an  increase  of  tension 
which  is  sustained  for  some  minutes  (10  or  so)  and 
then  declines  to  subnormal  levels  as  equilibration 
proceeds.  This  has  been  shown  to  apply  to  guinea 
pig  taenia  coli  (1  16)  and  to  the  dog  aorta  strip  (214). 
The  increase  in  tension  can  be  partially  but  not  en- 
tirely attributed  to  an  increase  in  osmotic  pressure  of 
the  bathing  solution.  Other  authors  who  did  not  raise 
Na„  quite  so  extremely  noted  no  change  in  tension, 
but  agree  that  tissues  so  exposed  become  hyporespon- 
sive to  drug  stimulation.  We  (78)  recorded  such  a 
decline  in  reactivity  of  the  colon  strip  following  ex- 
posure to  even  moderate  elevations  of  Na„  .  William- 
son &  Moore  (aog)  observed  that  a  rise  in  Na0  and  a 
fall  in  K„  ,  either  individually  or  in  combination, 
caused  a  lessened  response  of  the  isolated  rabbit  aorta 
strip  to  norepinephrine.  Similar  findings  were  re- 
ported earlier  by  Bohr  et  a/.  (13).  We  cannot  account 
for  the  observation  of  an  increase  in  responsiveness  to 
epinephrine  under  similar  circumstances  (214). 

Although  the  complexity  of  the  procedures  and 
responses  used  to  study  this  problem  almost  defy 
rational  interpretation,  several  fundamental  facts  do 
emerge. 


/ )  Vascular  smooth  muscle,  like  other  types  of 
smooth  muscle,  responds  to  sudden  reduction  of  Na„ 
with  a  temporary  increase  of  tension  proportionate  to 
the  degree  of  change  in  the  medium.  Tension  declines 
as  equilibration  proceeds. 

2)  After  equilibration  in  moderately  low  Na0 
media,  the  responsiveness  of  vascular  smooth  muscle 
is  unchanged  or  increased.  At  critically  low  levels  of 
Na„  the  tissue  becomes  hyporesponsive. 

3)  Vascular  smooth  muscle  exposed  to  high  Na,, 
may  show  a  temporary  increase  in  tension,  but  very 
high  levels  of  Na  are  required  for  this. 

^)  After  equilibration  in  high  Na„  media  the  re- 
sponsiveness of  vascular  smooth  muscle  is  substantially 
reduced. 

5 )  Studies  of  the  effects  of  ions  must  distinguish 
between  immediate  effects  which  reflect  a  temporary 
instability  and  later  effects  which  depend  on  the  new 
equilibrium. 

EFFECTS  OF  MANIPULATION  OF  K  IN  THE  MEDIUM.  Al- 
though the  procedures  and  responses  vary  a  good  deal, 
it  has  been  found  that  most  types  of  smooth  muscle 
increase  their  tension  upon  exposure  to  a  potassium- 
enriched  environment.  The  older  literature  has  been 
reviewed  by  Evans  (60)  and  the  more  recent  by 
Goffart  &  Bacq  (91).  The  latter  authors  indeed  go  so 
far  as  to  point  out  that  the  potassium-induced  con- 
traction can  be  used  as  a  basic  procedure  for  the 
study  of  agents  which  enhance  (sensibilize)  or  inhibit 
the  response.  The  following  reports  are  typical  of  the 
studies  carried  out  and  of  the  results  obtained. 

Holman  (118)  studying  guinea  pig  taenia  coli 
reported  that  at  first  a  reduction  of  K  in  the  medium 
produced  little  effect.  After  a  few  minutes,  however, 
tension  began  to  fall  and  on  prolonged  exposure  low 
levels  were  reached  and  maintained. 

Exposure  of  the  uterus  of  the  rat,  guinea  pig,  rabbit, 
or  cat  to  an  elevation  of  K  in  the  medium  produces  an 
immediate  contraction  (190).  So,  too,  the  intestine 
strip  shows  an  immediate  increase  in  tension  (3,  1 18, 
147,  204).  Cantoni  &  Eastman  (28)  observed  that  the 
temporarv  depression  which  follows  maximal  con- 
traction of  the  guinea  pig  intestine  exposed  to  hista- 
mine, acetylcholine,  pilocarpine,  barium  chloride,  or 
Mecholyl  can  be  overcome  by  a  small  increase  of  K. 
in  the  medium.  Similarly,  Hazard  &  Cornec  (107) 
found  that  small  amounts  of  K  increased  the  response 
of  the  rat  duodenum  to  acetylcholine. 

In  general,  vascular  tissue  follows  similar  patterns. 
As  early  as  1926  Gellhorn  (90)  attempted  to  place  a 
series  of  cations  in  a  rank  order  based  on  their  effects 


I  I46  HANDBOOK    OF    PHYSIOLOGY  -~  CIRCULATION    II 

300 


fig.  3.  Tension  changes  in  carotid  artery  strips  on  exposure  to  different  concentrations  of  .-1, 
K+  and  B,  Cs+.  Concentration  of  the  cation  in  millimolars  appears  at  the  right  of  each  line.  [From 
Laszt  (135).] 


on  an  isolated  aorta  strip.  He  pointed  out  that  the 
addition  of  Li+  relaxed  the  strip  and  that  Na+  pro- 
duced no  obvious  change,  while  NH4+,  Cs+,  Rb+,  and 
K+  in  that  ascending  order  caused  increasing  degrees 
of  contraction.  He  did,  however,  use  fairly  extreme 
quantities,  adding  in  each  case  3  ml  of  an  isotonic 
concentration  of  the  chloride  to  10  ml  of  Tyrode's 
solution.  In  effect  he  raised  the  K  concentration  of  the 
medium  to  about  50  meq  per  liter. 

Furchgott  &  Bhadrakom  (88),  in  the  course  of 
pioneer  studies  which  established  the  rabbit  aorta 
strip  as  a  standard  test  object,  observed  the  effects  of 
more  moderate  increases  in  K„  .  They  noted  that 
contraction  followed  if  the  K  level  was  raised  to  three- 
or  fourfold  normal.  The  addition  of  smaller  amounts 
of  K,  sufficient  only  to  double  that  of  the  normal 
medium  (Krebs),  did  not  cause  visible  contraction 
but  did  potentiate  the  response  to  low  doses  of  epi- 
nephrine. 

Bohr  et  a/.  (13)  confirmed  and  extended  these 
findings.  Using  the  Furchgott  procedure,  they  noted 
a  marked  increase  in  the  response  of  the  aorta  strip  to 
norepinephrine  when  the  medium  K.  was  doubled. 
Additionally,  they  observed  a  marked  and  progressive 
reduction  of  responsiveness  in  a  K-free  medium.  More 
recently,  Barr  et  al.  (10)  studied  the  responsiveness  of 
clog  carotid  artery  strips  stored  in  the  cold  and  then 
rewarmed.  Stored  in  the  cold,  4  C,  these  strips,  like 
most  tissues  (165),  gained  Na,  and  lost  K,  ,  and  with 
this  their  responsiveness  declined.  The  recovery  of 
maximal  responsiveness  was  roughly  parallel  to  the 
steady-state  K  reaccumulation  during  the  progression 
of  rewarming.  Williamson  &  Moore  (209)  observed 
that  the  sensitivity  of  the  rabbit  aorta  strip  varied 


with  changes  of  K  in  the  medium  in  a  manner  inverse 
to  Na.  Thus,  lowering  Na  or  raising  K,  singly  or  in 
combination,  increased  the  sensitivity  to  norepineph- 
rine. Conversely,  raising  Na  or  lowering  K,  singly 
or  in  combination,  decreased  the  norepinephrine- 
induced  contraction.  Dodd  &  Daniel  (49)  also  pointed 
out  that  contractile  responses  increase  in  a  high  K 
medium.  They  observed  a  transient  increase  of  sensi- 
tivity in  a  K-free  medium  as  well,  but  this  rapidly 
yielded  to  the  usual  reduction  in  responsiveness 
observed  by  most  workers. 

Laszt  (133-135)  has  recently  produced  unequivocal 
evidence  relating  tension  and  the  concentration  of  K. 
in  the  medium  (fig.  3).  Using  a  carotid  artery  strip 
(specified  only  as  from  "cattle")  this  worker  has  shown 
that  the  stepwise  elevation  of  K„  produces  a  stepwise 
increase  in  tension.  The  threshold  concentration  of 
cesium  (5  ran)  or  rubidium  (10  mill,  which  can  simi- 
larly induce  a  contraction  when  added  to  the  medium, 
is  less  than  that  required  for  potassium  (30  mil),  and 
this  Laszt  considers  to  be  direct  evidence  relating 
the  effect  to  ion  size.  Similarly,  the  tension  induced  In- 
equal  concentrations  of  cesium,  rubidium,  and  potas- 
sium chloride  shows  the  same  dependence  on  rank 
order.  The  interpretation  which  this  investigator 
places  upon  these  findings  argues  that  the  tension 
increase  is  a  function  of  the  rate  at  which  Cs+,  Rb+, 
or  K+  can  move  into  cells.  This  neglects  the  fact  that 
the  ability  of  ions  to  cross  cell  membranes  is  not 
an  exclusive  function  of  their  hydrated  radius  (see 
table  3). 

One  group  of  observations  stands  alone  and  con- 
trasts sharply  with  the  examples  cited  above.  In  these 
a  reduction  of  K„  is  reported  to  be  associated  with 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


I  147 


hyperexcitability  (140),  while  an  increase  in  K0  re- 
versibly  abolishes  the  ability  to  contract  (47).  These 
two  rather  baffling  reports,  although  stemming  from 
different  authors,  are  united  in  one  major  respect:  the 
artery  preparation  was  driven  electrically  rather  than 
by  means  of  a  known  physiologically  active  mediator. 

Although  once  again  we  find  that  it  is  difficult  to 
equate  the  complex  procedures  used  and  the  complex 
results  obtained,  several  fundamental  facts  emerge. 

/ )  Vascular  smooth  muscle,  like  other  types  of 
smooth  muscle,  responds  to  the  sudden  reduction  of 
K,,  with  little  immediate  change. 

2)  As  equilibration  in  low  K„  media  proceeds,  the 
responsiveness  of  vascular  smooth  muscle  and  its 
basal  tension  progressively  decline  to  reach  a  new  low 
level  which  is  steadily  maintained  for  long  periods. 
The  experiment  of  continuing  to  lower  K„  by  succes- 
sive washout  has  apparently  not  been  attempted. 

2)  Vascular  smooth  muscle  exposed  to  high  K„  (at 
least  fourfold  normal)  shows  an  increase  in  tension 
proportionate  to  the  increase  in  K„  ,  and  this  is 
usually  sustained.  Responsiveness  too  is  increased  in 
high  K„  media. 

^)  Time  is  an  important  variable  in  the  responses 
studied — too  often  an  insufficiently  considered  vari- 
able. 

j)  In  general,  there  is  a  suggestive  inverse  relation 
between  K„  and  Na„. 

Evidence  from  Studies  of  Resistance  in 
Regional  I  'ascular  Beds 

effects  of  Na  infusions.  It  is  exceedingly  difficult 
to  attempt  to  alter  only  one  constituent  of  a  perfusing 
solution  in  an  in  vivo  preparation  and  still  remain 
within  the  bounds  of  physiological  decency.  Even 
so,  considerable  progress  has  been  made  in  demon- 
strating that  at  least  some  of  the  in  vitro  observations 
have  important  implications  for  vascular  homeo- 
stasis. We  shall  now  examine  the  major  lines  of  these 
investigations,  noting  especially  where  they  are 
consistent  with  the  evidence  already  cited. 

All  workers  who  have  infused  Na  salts  into  the 
arterial  circulation  have  observed  peripheral  vaso- 
dilatation. Eliakim  et  at.  (56)  observed  a  fall  in 
systemic  blood  pressure  in  the  dog  on  injecting  1  ml 
per  kg  of  qo  per  cent  NaCl  fairly  rapidly.  We  (78) 
observed  that  Na  salts  depress  diastolic  and  systolic 
blood  pressure  in  the  rat  even  in  the  presence  of  a 
simultaneously  administered  pressor  agent.  Katz  & 
Lindner  (125)  perfused  the  coronary  arterial  circula- 
tion in  the  dog  with  defibrinated  blood  in  a  classic 


4.01 
111 

e  30J 


Potassium 


150 

e 

;  100 

> 

j  50 

> 
I 

0  J 

:  1.5 1 


Brachial  Artery 


Small  Artery 


Small  Vein 
Cephalic  Vein 
Total 


10  -    Small  VeBfit-l 


s 
i 


pi 


Arteries 


Veins 


MHmMWHH«M»l»B»tt«Mmwitr-»VWHJM» 


1478 


155.5  1685 

mEij   Na/L 

fig.  4.  Relation  of  serum  [Na+]  in  venous  outflow  to  %  as- 
cular pressures  and  resistances  in  the  dog  forelimb.  Average 
of  1 1  animals.  Ten  per  cent  NaCl  infused  into  brachial  artery 
at  0.0,   1.0,  2.3,  and  0.0  ml/min  in  that  order.  [From  Haddy 

(101).] 

series  of  experiments  and  observed  that  even  fairly 
small  additions  of  Na  produced  vasodilatation. 

Marshall  &  Shepherd  (148),  in  a  beautiful  series, 
used  the  newly  developed  ultrasonic  flowmeter  to 
monitor  flow  in  the  femoral  artery  of  the  dog  and 
studied  changes  in  limb  resistance  in  response  to  Na 
salts.  They  found  that  the  rapid  injection  of  2  ml  of 
10  to  20  per  cent  NaCl  produced  vasodilatation.  The 
same  effect  was  obtained  with  a  continuous  infusion 
of  the  same  solutions  at  2.3  ml  per  min.  A  series  of 
other  salts  (citrate,  lactate,  bicarbonate,  acid  and 
alkaline  phosphate)  all  produced  the  same  effect. 
Binet  &  Burstein  (12)  obtained  similar  results  in  the 
dog  limb  isolated  from  the  circulation  of  the  rest  of 
the  body,  except  as  perfused  under  control  from  the 
systemic  circulation  through  a  constant  pressure 
pump. 

Haddy  and  his  associates  have  used  perhaps  the 
most  detailed  and  elegant  technique  to  study  this 
same  problem.  Basically,  these  workers  perfuse  the 
forelimb  of  the  dog  with  arterial  blood  rerouted  from 
the  femoral  artery.  The  connecting  polvethylene 
tubing  uniting  the  femoral  to  the  brachial  artery 
passes  through  a  constant  output  pump  which  operates 
by  intermittent  compression  of  the  tubing.   Pressure 


1 148 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


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5  25  45  65 

fig.  5.  A:  changes  in  renal  vein  flow,  FRy,  and  venal  artery  pressure,  PRA,  with  perfusate  composi- 
tion changes.  TRV  =  temperature  of  renal  vein  outflow.  [From  Harvey  (104).]  B:  effect  of  hypertonic 
saline  solution  on  blood  flow  through  femoral  artery  measured  with  ultrasonic  flowmeter.  Note  the 
zero  calibration  check  at  the  beginning  of  the  record  and  again  during  the  period  of  increase  in  How. 
The  fall  in  flow  rate  at  time  of  injection  is  an  artifact.  [From  Marshall  &  Shepherd  (148).] 


is  monitored  by  means  of  fine  cannulae  passed  into 
the  vascular  tree  at  several  points  distal  to  the  pump 
so  that  a  detailed  description  of  the  resistance  of  the 
various  segments  of  the  circulation  can  be  compiled. 
Haddv  (101),  too,  found  that  amounts  of  NaCl, 
insufficient  to  alter  systemic  pressure,  produced 
arteriolar  dilatation  in  the  dog  forelimb. 

Unfortunately,  it  is  not  possible  to  elevate  plasma 
Na  concentration  in  the  perfusing  blood  without  at 
the  same  time  raising  its  tonicity.  Marshall  & 
Shepherd  (148)  first  noted  this  as  an  experimental 
defect  and  found  that  they  could  obtain  a  similar 
degree  of  vasodilatation  by  infusing  dextrose  and 
urea  matched  for  tonicity  to  their  sodium  salts  and 
concluded  that  the  mechanism  of  vascular  relaxation 
was  uncertain.  Muirhead  et  al.  (154)  had  earlier 
noted  this  effect  of  hypertonic  infusions.  This  point 
led  Overbeck  &  Haddy  (156)  to  restudy  the  problem. 
Thev  found  that  hypertonic  solutions  of  NaCl, 
Na->S04  and  Na>HP04,  which  produced  the  same 
final  serum  Na  concentration,  evoked  decreases  in 
limb  vascular  resistance  in  parallel  with  their  actual 
tonicity.  Equally  hypertonic  infusions  of  Na>S04, 
and  NaCl,  irrespective  of  the  amount  of  Na  supplied, 
evoked  equal  decreases  in  small  vessel  resistance. 
They  concluded  that  the  addition  of  Na  apparently 
had  little  or  no  independent  effect  apart  from  that  of 
its  tonicity.  On  the  other  hand,  these  same  workers 
(102)  have  obtained  some  evidence  that  a  reduction 


of  Na  in  the  perfusing  medium  is  slightly  vasocon- 
strictive and  decreases  the  caliber  of  the  small  vessels. 
Harvey  (104)  and  Read  et  al.  (164)  have  studied  the 
effects  of  hypertonic  solutions  on  the  renal  vascular 
bed  and  have  arrived  at  the  same  conclusion  regarding 
the  relation  of  hypertonicity  of  the  infusion  and  its 
vasodilators-  effect. 

These  findings  are  in  substantial  agreement  with 
those  obtained  with  vascular  and  other  smooth 
muscle  strips  studied  in  vitro.  It  will  be  recalled  that 
following  exposure  to  high  Na„  such  tissues  may  show 
a  temporary  increase  in  tension,  but  very  high  levels 
are  required  for  this.  On  the  other  hand,  after  equili- 
bration in  such  high  Na  media,  tension  is  usually  lower 
than  normal  and  responsiveness  of  these  tissues  is 
reduced,  and  this  obtains  in  vivo  as  well.  Thus, 
following  perfusion  of  the  rat  with  Na  salts  we  (86) 
found  the  blood  pressure  responses  to  norepinephrine 
and  to  Pitressin  sharply  reduced.  Haddy  (ioi),  in 
more  precise  studies,  has  shown  this  to  be  due  to  a 
reduction  in  the  responsiveness  of  peripheral  vessels 
to  both  pressor  and  depressor  agents.  Since  this  effect 
persists,  it  max  not  be  directly  related  to  the  osmotic 
effect  of  the  hypertonic  solution. 

It  should  be  emphasized  that  an  osmotic  effect 
produced  by  infusing  a  hypertonic  solution  cannot, 
in  fact,  be  dissociated  from  an  ionic  effect.  The 
withdrawal  of  water  from  cells  causes  a  proportionate 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


"49 


increase  in  both  Na,  and  K.,.  We  shall  deal  with  the 
quantitative  aspects  of  this  type  of  shifi  later. 

effects  of  K.  infusions.  Attempts  to  link  the  effects 
observed  in  vitro  to  in  vivo  responses  of  vascular 
tissue  have  necessarily  been  limited  in  scope.  This 
again  reflects  the  technical  problems  limiting  such 
exploration. 

Mathison  (149)  long  ago  produced  what  is  still  one 
of  the  best  pieces  of  work  on  this  subject.  He  injected 
a  few  milliliters  of  M/7  (isotonic)  KC1  into  the  arterial 
circulation  of  the  cat.  A  rise  in  blood  pressure  followed 
at  once;  this  was  also  obtained  in  the  decerebrate, 
spinal,  or  spinal-pithed  animal.  The  effect  was  not 
of  cardiac  origin  and  was  only  partly  due  to  excitation 
of  vasomotor  centers,  since  a  considerable  rise  of 
pressure  was  still  obtained  after  ergotoxine.  This 
author  paid  careful  attention  to  tonicity,  anion 
control,  and  pH.  He  pointed  out  also  that  peripheral 
vascular  relaxation  rather  than  constriction  followed 
the  injection  of  less  concentrated  solutions  beginning 
at  mil  Hoff  et  al.  (115)  obtained  much  the  same 
result. 

Hazard  &  Quinquaud  (108)  carried  out  an  ex- 
ceedingly nice  pharmacological  study  of  the  pressor 
effect  of  intra-arterially  injected  K.C1.  They  showed 
that  a  large  part  of  the  effect  was  due  to  adrenal 
medullary  discharge.  Then,  using  a  series  of  blocking 
agents,  they  came  to  the  conclusion  that  a  significant 
part  of  the  vasoconstrictive  action  of  K  was  directly 
exerted  on  vascular  smooth  muscle. 

McKeever  and  associates  (146)  perfused  the  left 
coronary  in  the  dog  with  blood  from  a  donor  animal, 
interposing  a  constant  output  pump  in  the  line 
(cf  101).  K.C1  was  then  added  at  constant  rate  to 
raise  plasma  K  from  2  to  20  meq  per  liter.  Except  at 
the  very  lowest  concentrations  the  infusions  produced 
a  transient  dilatation  of  large  and  small  arterial 
segments  lasting  for  about  1  min,  followed  by  a  more 
sustained  constriction.  Still  higher  concentrations  were 
entirely  constrictive,  but  the  degree  to  which  an 
adrenal  discharge  may  have  contributed  was  not 
assessed. 

Emanuel  et  al.  (58)  have  carried  out  a  careful 
analysis  of  the  changing  pattern  of  resistance  in  the 
different  segments  of  the  dog  forelimb  during  infusion 
of  K.  salts  and  have  correlated  their  findings  with 
systemic  and  local  measurements  of  serum  Na  and  K. 
Small  vessel  resistance  decreased  at  all  infusion  rates. 
By  contrast,  arterial  resistance  did  not  change  at 
lower  rates  and  then,  as  the  rate  increased,  gradually 
began  to  show  an  increase.  The  net  effect  of  these 


changes  was  an  over-all  fall  in  resistance  at  low  rates 
and  a  rise  at  higher  ones.  The  primary  phenomenon 
held  for  increases  in  serum  K  up  to  about  8  meq 
per  liter,  at  which  point  the  secondary  net  constrictive 
effect  appeared.  The  arterial  constrictive  phase  may 
be  in  large  part  related  to  adrenal  discharge.  These 
results  were  similar  for  the  chloride,  nitrate,  lactate, 
and  acetate.  They  applied  equally  well  to  the  renal 
vascular  bed  (178).  Even  these  moderate  elevations 
of  K„  reduced  the  sensitivity  of  the  peripheral  vas- 
culature to  challenging  doses  of  pressor  and  depressor 
agents. 

The  work  of  this  group  satisfactorily  explains  the 
phase  of  falling  peripheral  vascular  resistance  noted 
by  all  authors  who  have  infused  small  amounts  of 
KC1.  It  also  shows  that  K  does  not  produce  smooth 
muscle  vasoconstriction  in  the  physiological  range 
and  agrees  in  this  with  in  vitro  studies.  It  leaves 
unexplored,  and  correctly  so,  the  effect  of  high, 
unphysiological  amounts  of  K  which  are  vasocon- 
strictive in  vitro.  This  latter  point  has  great  theoreti- 
cal importance  if  a  change  in  membrane  potential 
is  involved  in  peripheral  vasoconstriction.  Un- 
fortunately, the  experimenter  cannot  explore  the 
problem  in  vivo,  for  although  high  K  infusions  do  not, 
like  Na,  raise  problems  of  osmotic  pressure  they  do 
produce  adrenal,  cardiac,  and  nervous  effects  which 
presently  defy  rational  interpretation. 

Speaking  critically,  the  perfusion  of  regional 
vascular  beds  is  not  a  totally  satisfactory  approach  to 
the  problem.  Technically,  many  of  the  procedures 
give  detailed  information  concerning  the  responses  of 
each  segment  of  the  vascular  bed  and  for  this  are 
most  satisfactory.  The  problem  resides  not  in  this 
facet  of  the  approach  but  in  the  attempt  to  alter  a 
single  variable  in  the  medium  while  still  perfusing 
with  whole  blood.  Such  a  situation  cannot  be  fully 
controlled.  Using  the  Na  and  K  electrodes  we  have 
found  many  times  that  the  solution  we  thought  was 
presented  to  the  cells  was  not  the  same  as  the  solution 
the  cells  actually  met.  To  interpret  such  perfusion 
data  fully  requires  information  about  the  Na,  K,  and 
Ca  levels  actually  attained,  together  with  an  estimate 
of  pH. 

Evidence  from  Meamrement  of  Xa  and  A  in 
Relation  to  Blood  Pressure 

measurement  of  Na  and  K  in  chronic  hypertension 
or  hypotension.  Deoxycorticosterone  (DC  A)  hyper- 
tension. Ledingham  (137,  138)  studied  the  relation  of 
Na  and  K.  partition  to  blood  pressure  in  a  series  of 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


DCA-treated  rats  using  inulin  to  estimate  water 
distribution.  Unfortunately,  he  analyzed  only  skeletal 
and  cardiac  muscle  and  hence  his  report  of  an  absence 
of  correlation  must  be  treated  cautiously.  Despite  his 
own  rather  negative  conclusion,  if  we  assume  that  his 
methods  can  only  distinguish  extremes  and  not 
transitional  stages,  his  tables  show  several  striking 
features.  Blood  pressure  in  the  control-adrenal- 
ectomized  group  averaged  86  mm  Hg,  while  the 
adrenalectomized  saline-treated  group  reached  114 
mm  Hg.  The  two  groups  attaining  the  highest 
pressure  were  likewise  adrenalectomized  and  received 
either  DCA-saline  or  DCA-saline-cortisone  and  had 
average  blood  pressures  of  1 9 1  and  221  mm  Hg, 
respectively.  Both  Na»  and  Na,  values  were  highest 
in  these  groups  and  the  Na0/Na,  gradients  lowest. 
Again,  K„  was  lowest  in  both  these  groups,  while  K, 
did  not  fit  any  pattern.  The  value  for  K„  is  perhaps 
particularly  important,  since  it  has  also  been  reported 
as  a  finding  in  the  accelerated  phase  of  essential 
hypertension  in  man  (111,  151).  Low  levels  of  serum 
Na  have  also  been  noted  at  this  stage  of  the  disease 
(46). 

Woodbury  &  Koch  (211)  also  noted  in  the  rat  that 
DCA  and  aldosterone  produce  an  increase  in  skeletal 
muscle  Na  which,  judging  by  measurements  of 
chloride  space,  is  largely  intracellular  and  represents 
an  increase  in  Na,.  Potassium  was  little  altered. 
Unfortunately,  blood  pressure  was  not  measured. 
Ferrebee  et  al.  (62),  using  more  laborious  techniques, 
had  long  ago  shown  that  DCA  in  the  dog  caused  a 
gain  in  Na,  at  the  expense  of  K,.  Cier  and  co-workers 
(29)  and  Gross  &  Schmidt  (99)  also  claimed  that 
DCA  increases  Na,   in  skeletal  muscle. 

Insofar  as  blood  pressure  regulation  is  concerned 
it  is  more  important  to  attempt  to  estimate  the  effect 
of  DCA  on  Na  and  K.  in  a  representative  of  vascular 
tissue.  The  aorta  has  so  far  been  the  only  tissue 
amenable  to  study  and  here,  by  and  large,  the 
evidence  points  the  same  way.  The  classic  and  most 
quoted  paper  in  this  field  is  that  of  Tobian  &  Binion 
(196),  who  reported  an  increase  in  both  Na  and  K 
in  the  aorta  of  rats  made  hypertensive  with  DCA. 
From  estimates  of  the  extracellular  space  (based  on 
chloride  measurements)  they  believed  that  most  of 
the  increase  represented  a  true  intracellular  gain. 
Tobian  &  Redleaf  (199,  200)  reaffirmed  these 
findings  in  later  studies. 

Daniel  &  Dawkins  (40)  claimed  that  aorta  electro- 
lyte changes  demonstrable  in  early  DCA  hypertension 
disappeared  later  in  the  disease.  In  early  hypertension 
they  noted  a  tendency  for  a  gain  in  Na,  but,  more 


significantly,  for  K  depletion  in  hypertensive  rats 
under  treatment  compared  with  normotensive  also 
under  treatment.  Most  recently,  Laszt  (133)  also 
reported  a  gain  in  aorta  Na  following  DCA  treat- 
ment. 

By  and  large  it  would  seem  that  DCA  causes  a  gain 
in  Na  in  both  skeletal  muscle  and  in  aorta  in  the  rat; 
a  goodly  part  of  this  gain  probably  represents  a  true 
intracellular  increase,  but  with  the  methods  so  far 
used  it  is  difficult  to  assess  just  how  much  is  actually 
intracellular.  The  gain  in  Na  is  apparently  not 
accompanied  by  a  parallel  gain  in  water,  so  we  are 
fairly  safe  in  inferring  from  all  authors  that  intra- 
cellular Na  concentration,  Na„  is  elevated.  All  reports 
uniformly  fail  to  provide  us,  however,  with  simul- 
taneous estimates  of  Na,  of  the  aorta  and  Na„  of  the 
medium,  which  is  a  crucial  piece  of  information.  This 
same  lack  of  information  tends  to  nullify  Laszt's 
claim  (133)  that  blood  pressure  cannot  be  related  to 
the  total  Na  content  of  the  aorta.  In  our  opinion,  it 
would  be  exceptional  if  blood  pressure  could  indeed 
be  related  to  one  such  simple  parameter  as  that. 

Other  hypertensive  states.  We  have  considered  DCA 
separately  because  of  its  obvious  effects  on  electrolvte 
metabolism  which  might  perhaps  be  considered  to 
make  it  a  special  case.  We  turn  now  to  a  more  general 
review  of  the  findings  for  Na  and  K  analysis  in  a 
divergent  series  of  conditions  united  only  by  the  fact 
that  a  sustained  hypertension  is  a  common  feature. 

Ledingham  (139)  has  recently  reviewed  this  and 
decided  that  the  onlv  common  feature  in  these  varied 
states  is  the  elevated  blood  pressure  itself.  His  negative 
view  is  based  on  his  findings  in  hvpertension  induced 
by  DCA,  cortisone,  renal  arterv  constriction,  and 
bilateral  nephrectomy  (136-138).  As  described  above, 
he  may  have  overemphasized  the  negative  aspects  of 
his  data.  It  is  unfortunate  too  that  this  conclusion 
should  have  been  arrived  at  without  any  attempt  to 
measure  electrolytes  and  water  in  vascular  tissue. 

In  their  original  report  Tobian  &  Binion  (196) 
considered  renal  as  well  as  DCA  hypertension  in  the 
rat.  Aorta  Na  and  K  were  both  elevated  following 
renal  constriction  in  rats  developing  hypertension 
compared  to  animals  remaining  normotensive  after 
the  same  operation.  Tobian  (192)  extended  this  work 
by  using  a  low  sodium  diet  to  control  the  blood 
pressure  rise  of  animals  with  renal  constriction  and 
found  the  changes  directly  related  to  the  presence  or 
absence  of  hypertension. 

More  recently  Tobian  &  Redleaf  (200)  found  that 
rats  with  post-DCA  sustained  hypertension,  with 
adrenal    regeneration    hvpertension,    and    with    the 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


hypertension  that  may  persist  after  excision  of  an 
ischemic  kidney  all  show  an  increase  in  aorta  Na  and 
K..  This  increase  seemed  to  them  to  represent  a  true 
gain  in  Na,  and  K,.  There  is  a  suggestion  that  these 
studies  may  be  pertinent  to  the  problem  of  hyper- 
tension in  man,  for  Tobian  &  Binion  ( 1 95 )  found  an 
increase  of  both  Na  and  water  in  the  renal  arteries  of 
human  hypertensives.  Na  was  increased  more  than 
water,  but  the  technique  used  cannot  distinguish 
intracellular  from  extracellular  locations.  Not  too 
much  weight  should  be  given  this  type  of  stud\ , 
however,  for  as  all  workers  in  the  field  know,  electro- 
lytes may  exchange  rapidly  across  vessel  walls  both 
immediately  preceding  and  certainly  after  death. 

In  general,  experiments  in  many  laboratories 
support  the  thesis  that  Na  and  K  in  tissues  are  altered 
in  hypertension,  but  the  emphasis  shifts  now  to  the 
one,  now  to  the  other.  Thus,  Eichelberger  (53)  long 
ago  measured  an  increase  in  Na  and  fall  in  K  in  the 
skeletal  muscle  of  dogs  made  hypertensive  by  renal 
constriction.  Assuming  an  extracellular  position  for 
chloride  there  appeared  to  be  a  true  rise  in  Na,  and 
fall  in  K,.  Laramore  &  Grollman  (132)  found  a 
general  rise  in  tissue  Na  and  water  and  a  fall  in  K 
in  the  later  stages  of  renal  hypertension  in  the  rat. 
Later,  however,  Grollman  (96)  found  the  same 
quantities  unchanged  in  hypertension  produced  as  a 
late  sequela  of  choline  deficiency.  More  recently 
Kolctsky  et  al.  (i2g)  analyzed  the  mesenteric  arteries 
of  rats  with  acute  renal  hypertension  and  also  found 
a  gain  in  Na,  K,  chloride,  and  water.  These  authors, 
however,  cautiously  refrained  from  attempting  to 
partition  the  electrolytes  on  the  basis  of  chloride 
space. 

In  agreement  with  Tobian  and  associates,  Freed 
et  al.  (70)  found  an  elevation  in  aorta  K  in  renal 
hypertensive  rats  but  a  less  well-defined  increase  in 
Na.  The  reduction  of  the  hypertension  by  dietary  K 
deprivation  was  followed  by  a  proportionate  decrease 
in  aorta  K,  and  the  return  to  hypertensive  levels  on 
refeeding  K  was  accompanied  by  a  return  rise  in 
aorta  K.  On  examining  the  data,  however,  it  is 
evident  that  the  increase  in  aorta  K  occurs  in  rats 
with  renal  constriction  whether  or  not  the  pressure 
goes  up.  This  same  inconsistency  was  noted  by 
Tobian  &  Binion  (196). 

Laszt  (133)  does  not  find  an  increase  in  aorta  Na 
at  all  consistent  with  the  presence  of  hypertension  in 
rats,  but  claims  the  rise  of  K  to  be  so. 

Houck  (119)  pointed  out  that  dogs  maintained  in 
good  balance  for  5  to  1 1 1  days  following  bilateral 
nephrectomy  show  a  gain  in  tissue  Na  and  fall  in  K 


despite  relatively  normal  extracellular  values.  This 
apparently  indicates  an  association  of  their  sustained 
hypertension  with  an  elevation  of  Na,  and  fall  in  K.,. 
Greene  &  Sapirstein  (95)  found  an  increase  in  total 
body  Na  in  rats  made  hypertensive  by  subtotal 
nephrectomy.  Haight  &  Weller  (103)  studied  rats 
made  hypertensive  by  chronic  high  salt  feeding; 
they  found  hypernatremia  and  an  increase  in  skeletal 
and  heart  muscle  Na  and  K.  especially  pronounced  in 
the  hypertensive  rats  but  no  conspicuous  differences 
in  aorta  electrolytes. 

Other  sustained  abnormal  blood  pressures.  The  regularly 
observed  fall  in  blood  pressure  in  Addison's  disease  or 
following  adrenalectomy  requires  no  comment. 
Among  other  phenomena,  it  is  associated  with  a 
reduction  of  tissue  Na  from  both  intracellular  and 
extracellular  compartments  (30,  52). 

Freed  et  al.  (69)  examined  the  relation  of  plasma 
to  aorta  Na  and  K  in  rats  made  hypotensive  by  K 
deprivation.  Both  Na  and  K  declined  in  plasma  as 
well  as  in  the  aorta,  although  the  authors  stress  only 
the  change  in  K.  Tobian  (191)  found  that  rats  on  a 
low  Na  diet  lose  a  sizeable  amount  of  aorta  Na,  while 
serum  Na  may  actually  rise  a  little.  Although  blood 
pressure  was  not  measured  it  was  assumed  to  tend 
toward  lower  values. 

Trauma  may  lead  to  a  "posttraumatic  sodium- 
potassium  shift"  during  which  plasma  Na  falls  and 
K  rises.  This  is  associated  with  hypotension  (186). 

MEASUREMENT    OF    Na   AND    K    IN    ACUTE    HYPERTENSION 

or  hypotension.  Although  investigation  of  the 
association  between  acute  changes  in  blood  pressure 
and  electrolyte  exchanges  is  comparatively  recent, 
the  findings  are  more  clear-cut  than  any  we  have  so 
far  considered.  The  independent  findings  from 
different  laboratories  all  fit  together  nicely  even 
though  interpretations  vary.  Since  this  approach 
bears  directly  on  the  relation  of  ions  to  vascular 
smooth  muscle  tension,  the  facts  obtained  must  form 
the  basis  of  all  theoretical  discussion.  Accordingly, 
we  shall  present  these  facts  in  some  detail. 

Perhaps  the  earliest  report  of  a  relation  between 
ionic  concentration  in  the  serum  and  a  pressor  agent 
was  that  of  D'Silva  (50)  in  1934.  He  reported  that, 
in  the  cat,  following  the  intravenous  injection  of  50 
/ig  of  epinephrine  or  10  units  of  Pitressin  intra- 
venously serum  K.  rose  sharply  as  much  as  3  meq  per 
liter  within  1  min.  Since  these  massive  doses  of  the 
order  of  10  fig  per  kg  epinephrine  and  2  units  of 
Pitressin  per  kg  also  caused  a  rise  in  blood  sugar,  this 
author  related  the  K  rise  to  the  glycogenolytic  effect 


1152 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


IWJECTIOM 


(.005  mg/>g  EPIWEPHRIIIE) 
CYCLOPROPANE 
NEMBUTAL 
UNANESTHETIZED 
D— O        ETHER 


40       SO 


imecTioi    (b) 
i    iv    I    ^ 


VT 


JOIVEIS. 


CYCLOPROPANE  30  MINUTES 
EPINEPHRINE 
•— •     ARANTHOL 
a — □     NEOSYNEPHRIN 
O— O     EPHEORIBE 


SECONDS 


40        80 


120 


110 


240 


300 


fig.  6.  A:  influence  of  anesthesia  on  plasma  [K+j  rise  induced 
by  epinephrine  in  the  dog.  Arrhythmias  and  time  of  their 
occurrence  shown  by  horizontal  lines  at  top  of  figure.  VT 
=  ventricular  tachycardia.  B:  effect  of  a  series  of  sympatho- 
mimetic amines  on  plasma  [K+]  in  the  dog.  VT  =  ventricular 
tachycardia,  NVEXS  —  numerous  ventricular  extrasystoles. 
[From  O'Brien  et  al.  (155).] 


of  the  injections  rather  than  to  the  blood  pressure 
effect.  This  explanation  for  the  rise  of  K  remained 
unchallenged  and  uncritically  accepted  for  almost  two 
decades. 

O'Brien  et  al.  (155)  in  1953  obtained  beautiful 
curves  showing  the  rise  of  plasma  K  after  rather  lower 
doses  of  norepinephrine,  5  ng  per  kg,  in  dogs.  Although 
norepinephrine  does  not  have  any  marked  effect  on 
the  mobilization  of  glucose  and  although  these  authors 
pointed  out  that  it  is  blocked  by  Dibenamine,  which 
would  not  block  a  glycogenolytic  effect,  the  original 
explanation  still  persisted.  O'Brien  and  his  associates 
also  pointed  out  that  the  choice  of  anesthetic  modified 
the  effects,  ether  being  the  worst  for  blurring  the 
effect,  cyclopropane  affecting  it  least,  Nembutal 
almost  as  good  as  cyclopropane.  These  important 
observations  were  unfortunately  ignored  by  most 
later    workers    including    ourselves.     (In    our    more 


recent  studies  we  have  found  the  effects  considerably 
sharpened  if  a  barbiturate  mixture  is  used  instead  of 
ether. ) 

Muirhead  et  al.  (153)  in  the  next  year  restudied  the 
problem.  They  gave  norepinephrine  by  infusion  in 
total  doses  of  1  to  7  mg  per  kg  in  50  to  180  ml  of 
saline  over  periods  ranging  from  20  to  50  min.  Con- 
cerning their  results  they  wrote:  "In  many  of  the 
experiments  the  sodium  curve  represents  an  approxi- 
mate mirror  image  of  the  blood  pressure  curve.  In 
most  of  the  experiments  the  changes  of  potassium 
were  not  as  pronounced  as  those  of  sodium.  In 
addition  there  seemed  to  be  little  if  any  correlation 
between  blood  pressure  and  plasma  potassium.  The 
latter  is  in  contrast  to  the  variations  in  sodium  levels 
which  reflected  even  sudden  changes  in  blood  pres- 
sure." No  real  change  in  radiosulfate  space  or  in 
chloride  concentration  was  observed.  These  observa- 
tions did  not  have  the  impact  they  ought  to  have  had 
for  the  doses  used  were  very  large. 

Tobian  &  Fox  (197)  then  approached  the  problem 
directly  and  analyzed  segments  of  dog  femoral 
artery  before  and  after  infusing  norepinephrine 
sufficient  to  maintain  a  blood  pressure  elevation  for 
30  min.  A  consistent  fall  in  artery  K  and  a  less  con- 
sistent gain  in  Na  was  observed.  These  changes  were 
believed  to  represent  a  fall  in  K,  and  rise  in  Na„  but 
the  authors  tended  to  underestimate  the  importance 
of  the  Na  change  since  it  was  less  consistent.  In  our 
view,  the  difficulties  inherent  in  such  tissue  anah  sis 
and  their  basic  range  of  error  make  it  highly  sig- 
nificant that  even  this  trend  for  a  sodium  increase  was 
observed;  in  fact,  a  sizeable  Na  gain  was  found  in  9 
of  12  dogs.  In  the  light  of  later  evidence,  we  must 
conclude  that  a  fall  in  K,  and  a  real  gain  in  Na„ 
probably  with  water,  actually  did  occur. 

Shortly  thereafter,  following  up  the  possibility 
that  Pitressin  might  have  an  extrarenal  action,  we 
observed  that  this  agent  caused  a  shift  of  water  out 
of  the  extracellular  space  in  the  bilaterally  nephrecto- 
mized  rat.  In  a  more  detailed  study,  we  found  that 
Na  also  left  the  extracellular  space  in  association 
with,  but  in  excess  of,  water  so  that  there  was  a 
measurable  fall  in  plasma  Na  concentration  (82).  The 
relation  of  dose  to  response  was  presented  at  this  time 
and  the  correlation  of  the  shifts  with  blood  pressure 
noted.  In  interpreting  these  exchanges  of  salt  and 
water,  we  took  into  account  the  changes  which 
other  workers  had  previously  observed  to  follow 
norepinephrine  administration  and  hypothesized  thai 
both  sets  of  observations  could  be  related  by  a  general 
rule  that  blood  pressure  regulation  depends  on  the 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


I  153 


sodium  transfer  systems,  broadly  defined.  The  rise  in 
plasma  K  following  Pitressin  administration  was 
considered  an  integral  part  of  the  phenomenon,  but 
left  aside  from  this  first  theoretical  approximation  for 
later  consideration. 

In  these  first  studio  uc  overestimated  the  absolute 
magnitude  of  the  water  shift  that  follows  Pitressin 
administration.  This  was  corrected  in  subsequent 
studies.  The  effects  of  norepinephrine  on  Xa,  K,  and 
inulin  space  in  the  nephrectomized  rat  were  then  com- 
pared with  those  produced  by  Pitressin  and  again  a 
net  loss  of  extracellular  Na  was  observed  in  association 
with  the  blood  pressure  rise  (75).  Pitressin  in  the  large 
doses  used  caused  a  measurable  fall  in  plasma  Na 
indicating  that  Na  moved  in  excess  of  water.  With  the 
techniques  at  hand  (flame  photometry,  arterial  blood 
sampling)  no  clear  fall  in  plasma  Na  concentration 
taken  alone  was  observed  with  norepinephrine,  but  a 
shift  of  Na  and  water  was  claimed  on  the  basis  of 
replicate  experiments  in  which  extracellular  sodium 
was  calculated.  Angiotensin  was  then  compared  with 
Pitressin  in  the  nephrectomized  rat  (76).  Both  agents 
given  intravenously  produced  a  measurable  fall  in 
plasma  Na  concentration  and  a  fall  in  extracellular 
fluid  volume  (inulin)  associated  with  the  rapid  rise 
of  blood  pressure.  While  Pitressin  produced  a  meas- 
urable increase  in  extracellular  K,  angiotensin  did 
not. 

It  was  clear  at  this  time,  at  least  for  norepinephrine, 
that  the  fall  in  Na  and  water  and  the  rise  in  K  which 
we  were  measuring  in  the  extracellular  compartment 
of  the  rat  corresponded  qualitatively  to  the  gain  in 
Na  and  loss  in  K  which  Tobian  &  Fox  (197)  had 
measured  in  the  femoral  arterv  of  the  dog.  Daniel  et 
al.  (41 )  then  injected  a  pressor  dose  of  norepinephrine 
within  the  physiological  range,  1  /xg  per  kg,  in  the  rat. 
They  found  that  the  aorta  was  rapidly  depleted  of  K 
while  Na  tended  to  increase.  This  is  surprisingly  good 
confirmation  in  view  of  the  fact  that  the  Na  shift  is 
probably  partly  obscured  by  a  movement  of  water 
which  these  workers  could  not  measure. 

Subsequently,  this  group  (42)  studied  the  effects  of 
Pitressin  and  isoproterenol  (isopropyl  norepinephrine, 
a  peripheral  vasodilator)  on  aorta  electrolytes  in  the 
rat.  They  concluded  from  the  variations  in  aorta 
sodium  that  during  blood  pressure  changes,  Na 
moves  into  (rising  blood  pressure)  and  out  of  (falling 
blood  pressure)  vascular  muscle  cells.  Since  they  were 
dealing  with  the  aorta,  an  outward  movement  of  K 
occurred  only  with  those  drugs  known  to  cause  an 
aorta  strip  to  contract.  They  pointed  out,  however, 
that  the  total  amount  of  Na  which  we  had  reported  to 


leave  the  extracellular  space  could  not  possibly  be 
accommodated  within  the  cells  of  the  vascular  tree. 
This  difficulty  has  now  been  satisfactorily  resolved  by 
our  observation  that  skeletal  muscle  also  takes  up 
sodium  under  the  influence  of  Pitressin  (85). 

In  the  rat,  studies  of  changes  in  plasma  Na,  K,  and 
inulin  space  during  changes  in  blood  pressure  are 
technically  difficult,  since  each  step  in  drug,  dose,  or 
time  interval  requires  the  use  of  separate  groups  of 
animals.  To  circumvent  this,  as  well  as  to  extend  the 
observations  to  the  dog,  we  studied  the  problem  in  the 
bilaterally  nephrectomized  dog  using  norepinephrine, 
isoproterenol,  angiotensin,  and  Pitressin  (73).  We 
found  that  the  calculated  extracellular  Na  (product  of 
inulin  space  and  plasma  Na)  declined  as  pressure  rose 
and  increased  as  it  fell;  the  two  measurements  con- 
sistently formed  mirror  images.  Calculated  extracellu- 
lar K  in  general  moved  inversely  to  Na  and  hence  in 
parallel  with  the  pressure  except  in  the  case  of  angio- 
tensin where,  as  in  the  rat,  no  K  shift  was  found. 

In  the  case  of  norepinephrine,  the  simple  measure- 
ment of  plasma  Na  was  an  inconsistent  index  of  Na 
movement,  since  the  real  decrease  in  this  ion  is 
partially  masked  by  a  movement  of  water  in  the  same 
direction.  For  the  same  reason,  K  concentration  is  a 
consistent  but  inaccurate  estimate  of  K  movement, 
since  the  change  is  magnified  by  inverse  movement  of 
water.  In  the  case  of  Pitressin,  although  both  Na  and 
water  move  out  of  the  extracellular  compartment,  the 
Na  shift  is  well  in  excess  of  the  water  so  that,  if  the 
dose  is  adequate,  a  fall  in  plasma  Na  is  readily  ob- 
served. These  findings  are  remarkably  similar  to  those 
obtained  in  the  rat. 

Warren  (205)  has  recently  studied  the  effect  of 
Pitressin  on  Na,  K,  and  inulin  space  in  the  trained, 
conscious,  intact  dog.  He  observed  similar  exchanges 
to  those  previously  reported  in  the  nephrectomized 
dog  even  though  he  used  considerably  smaller  doses 
of  Pitressin  (30  mU  kg  as  a  single  i.v.  injection  versus 
200  mU/kg/min  for  10  min  by  infusion). 

Recently  the  Na  and  K.  electrodes  have  been  ap- 
plied to  this  problem.  In  the  first  experiments  we  used 
only  a  sodium  electrode  interposed  into  the  femoral 
artery  of  the  dog  (80).  The  aim  was  to  determine 
whether  pressor  and  depressor  agents  actually  shift  Na 
levels  as  blood  sampling  procedures  indicated.  The 
result  was  unequivocal;  the  pressor  response  to  nor- 
epinephrine, epinephrine,  and  angiotensin  was  regu- 
larly accompanied  by  a  fall  in  electrode  potential 
indicating  a  fall  in  sodium  concentration,  or  more 
precisely,  sodium  activity.  In  terms  of  degree  of 
change,  time  course,  and  duration  of  effect,  each  agent 


1 1 54 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


DOG    9. 


ISOPROPYL 
NOREPINEPHRINE 
J  Iy   /Kq/min. 
« 2 » 


40  50 

TIME  —  MINUTES 


80 


90 


fig.  7.  Changes  in  extracellular  Na  and  K  associated  with  blood  pressure  changes  in  the  dog. 
[From  Friedman  et  al.  (73).] 


produced  its  own  characteristic  pattern.  The  depres- 
sor response  to  acetylcholine,  histamine,  and  isopro- 
terenol was  accompanied  by  oscillations  in  the  tracing 
which  tended  to  be  inverse  to  those  observed  with 
pressor  agents.  Later,  in  a  similar  arrangement  using 
two  electrodes,  norepinephrine  was  shown  to  produce 
a  rise  in  (K+)  inverse  to  the  fall  in  (Na+)  (81 ). 

The  technique  for  electrode  monitoring  of  (Na+) 
and  (K+)  in  flowing  blood  was  then  modified  after 
Haddy  so  as  to  control  flow  rate  through  the  electrode 
as  well  as  through  the  vasculature  of  the  limb  (122). 
The  femoral  artery  of  the  dog  was  interrupted  by  a 
length  of  polyethylene  fed  through  a  Sigmamotor 
pump.  The  femoral  vein  was  similarly  lengthened  and 
passed  through  a  smaller  division  of  the  pump.  The 
venous  outflow  passed  through  Na  and  K  cannula 
electrodes  in  a  shielded  enclosure.  This  arrangement 
ensured  not  only  a  constant  limb  inflow  but  also  the 
passing  of  a  proportion  of  the  venous  outflow  at 
a  constant  rate  past  the  electrodes.  Quantitative 
measurements  could  also  be  made,  since  calibrating 
solutions  could  be  injected  into  the  venous  tubing 
proximal  to  the  pump.  One  pressure  transducer  was 
inserted  on  the  arterial  side  between  pump  and  limb 
and  another  into  a  brachial  artery.  Small  amounts  of 


vasoactive  agents  sufficient  only  to  activate  the  limb 
vasculature  without  producing  any  noticeable  sys- 
temic effects  were  used. 

In  general,  limb  vasoconstriction  induced  by  nor- 
epinephrine or  epinephrine  was  associated  with  a  fall 
in  blood  (Na+)  and  often  with  a  rise  of  (K+).  Larger 
doses  tended  to  produce  a  biphasic  response  in  (Na+), 
that  is,  an  initial  transient  rise  preceding  the  fall. 
Vasoconstriction  produced  by  serotonin  or  angioten- 
sin was  associated  with  similar  (Na+)  change  unac- 
companied by  any  consistent  (K+)  deflection.  Vaso- 
constriction produced  by  Pitressin  was  associated  with 
a  fall  in  (Na+)  and  consistent  rise  in  (K+),  both  notice- 
ably greater  in  degree  and  duration  than  with  other 
agents  producing  an  equal  degree  of  vasoconstriction. 
Limb  vasodilatation  induced  by  isoproterenol,  acetyl- 
choline, or  histamine  was  accompanied  by  a  rise  in 
blood  (Na+)  without  any  consistent  change  in  (K+). 

A  full  analysis  of  rates  and  relations  of  ion  and  water 
movement  is  clearly  required.  For  the  moment,  we 
mav  conclude  that  the  movements  of  Na  and  K. 
associated  with  changes  in  blood  pressure  reflect 
changes  in  tension  in  the  peripheral  blood  vessels. 

Onlv  one  report  disturbs  the  general  consistency 
of  this  phase  of  the  investigation.  Headings  et  al.  (109) 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE  I  1 55 


"""  man 


8.M9  NOREPI 
14  kg  cf 


fig.  8.  Changes  in  blood  (Na+)  and  (K+J  monitored  with  the  Na  electrode  (Na/K  =  250/1) 
and  K  electrode  (K/Na  =  5/1)  in  the  dog  during  A,  systemic  blood  pressure  rise  induced  with 
norepinephrine  and  B,  limb  pressure  rise  induced  with  norepinephrine.  [.4,  from  Friedman  et  at. 
(81).] 


found  that  dog  carotid  artery  rings  stimulated  electri- 
cally gained  Na  and  lost  K.  Epinephrine,  however,  in 
an  amount  sufficient  to  produce  the  same  contractile 
response  did  not  produce  these  changes. 

We  may  conclude  that,  in  general,  an  acute  in- 
crease in  tension  of  vascular  smooth  muscle  is  asso- 
ciated with  a  gain  in  Na,  and  a  gain  in  water.  There 
is  a  strong  suggestion  that  in  some  instances,  at 
least,  the  gain  in  water  may  overshadow  the  gain  in 
Na  and  may  also  anticipate  it.  A  loss  in  K  from  cells 
to  environment  is  almost  always  observed.  Similar 
ionic  exchanges  have  been  observed  both  in  taenia 
coli  and  uterus  during  activity  (16,  124). 

These  experiments  give  no  information  regarding 
the  time  relations  connecting  these  phenomena  nor  do 
they  suggest  which  event  is  cause  and  which  is  effect. 

Evidence  from  Studies  of  the  Relation  of  Electrical 
Activity  to  Tension  in  Vascular  or  Analogous  Tissues 

Bacq  &  Monnier  (7)  studied  the  relation  of  electri- 
cal activity  to  tension  in  a  variety  of  smooth  muscles 
obtained  from  the  cat.  They  claimed  that  the  laws 
common  to  all  excitable  tissues  apply  to  smooth 
muscle  as  well.  In  their  view  the  response  to  every 
excitation,  in  this  case  contraction  or  increase  in  tone, 
no  matter  how  produced,  is  accompanied  by  a  de- 
crease in  polarization.  They  considered  the  change  in 
polarization  to  be  the  cause  of  the  change  in  tonus. 
In  accordance  with  theories  current  at  that  time  de- 


polarization was  attributed  to  the  exit  of  K+  from 
cells. 

Although  Bozler  (17)  carried  out  the  first  basic 
studies  of  electrical  activity  in  smooth  muscle  using 
modern  techniques  it  remained  for  Bulbring  and  her 
associates  to  carry  out  the  difficult  task  of  denning  the 
ionic  basis  of  that  activity.  In  1954  data  were  pre- 
sented for  guinea  pig  taenia  coli  suggesting  that 
tension  is  inversely,  and  spike  frequency  directly,  re- 
lated to  the  membrane  potential  (19). 

We  can  summarize  these  first  experiments  in  a 
simplified  form.  A  resting  membrane  potential  of  60 
±  9  mv  fell  to  43  ±  10  and  spike  frequency  increased 
when  the  tissue  was  stretched  (increased  tension). 
Histamine  induced  a  fall  in  potential  from  58  to  40  mv 
while  tension  and  spike  frequency  increased.  Epi- 
nephrine induced  an  increase  in  potential  and  a  de- 
crease in  tension  and  spike  frequency.  Acetylcholine 
caused  a  fall  in  potential  and  increase  in  spike  fre- 
quency and  tension.  Shortly  thereafter  Bulbring  (20) 
reported  that  the  increase  in  rate  of  spike  discharge 
was  proportional  to  the  increase  in  tension.  Then, 
in  1 955  (2 1 ),  fluctuations  in  membrane  potential  were 
observed  to  be  related  to  the  spontaneous  rhythm  of 
the  taenia  coli  strip  and  periods  of  depolarization  as- 
sociated with  increased  tension  and  increased  rate  of 
spike  discharge  alternated  with  periods  of  repolariza- 
tion, reduced  spike  frequency,  and  lower  tension. 

From  this  basis  Born  &  Bulbring  (16)  then  pro- 
ceeded to  the  still  more  difficult  technical  problem  of 


1 1 56 


HANDBOOK    OF    PHYSIOLOGY 


(  IRCI1.ATION    II 


120" 


o  100- 


o 


12        3        4         5  12        3        4        5        6 

fig.  g.  Fluctuations  of  tension  {broken  line)  and  of  radioactivity  (K.12)  appearing  in  washing  solu- 
tion (continuous  line)  of  taenia  coli  during  spontaneous  activity  .4,  before.  B,  in  the  presence  of  atro- 
pine 2   X   io-6.  [From  Born  &  Biilbring  (16).] 


--110 


--90     m 


3 


o 


adding  measurements  of  ionic  exchange  to  the  simul- 
taneous monitoring  of  tension  and  electrical  activity. 
By  restricting  their  attempt  to  the  simpler  problem 
of  measuring  only  K  they  succeeded  quite  elegantly 
and  in  so  doing  proved  beyond  doubt  that  basic  ionic 
theory  is  generally  valid,  at  least  for  the  gut  strip. 
They  used  K42  as  tracer  and  analyzed  the  medium 
flowing  past  the  tissue.  Spontaneous  activity  was 
characterized  by  the  parallel  rise  and  fall  of  K  efflux 
and  tension  so  that  as  tension  rose,  K  efflux  increased 
and  as  tension  fell,  K  efflux  decreased.  Similarly, 
histamine  and  acetylcholine  produced  contraction 
associated  with  a  parallel  increase  in  K  efflux.  Epi- 
nephrine, which  causes  relaxation  of  this  particular 
preparation,  seemed  to  do  so  by  increasing  K  influx. 
The  fall  in  membrane  potential  previously  observed 
to  parallel  the  increase  in  tension  was  evidently  asso- 
ciated with  an  ionic  shift  here  measured  as  K  efflux. 
Presumably,  if  it  had  been  technically  feasible  to 
measure,  a  primary  sodium  influx  would  have  been 
recorded. 

Born  (15)  then  turned  to  a  study  of  some  of  the 
metabolic  problems  concerned  with  contraction  in 
smooth  muscle  and  for  the  first  time  we  find  a  firm 
separation  of  the  relatively  rapid  changes  in  tension 
from  the  maintained  changes  which  we  recognize  as 
tonus.  The  position  is  best  stated  by  the  author:  "The 
development  of  tension  by  smooth  muscle  involves 
two  mechanisms.  One  mechanism  is  responsible  for 


the  immediate  rise  in  tension  which  occurs  when  the 
muscle  is  stimulated  and  this  mechanism  continues 
to  function  in  anoxia  and  in  the  presence  of  2:4 
dinitrophenol.  The  other  mechanism  is  responsible  for 
the  sustained  tension  which  the  muscle  shows,  both 
spontaneously  and  following  stimulation.  This  mecha- 
nism is  abolished  when  metabolism  is  interfered  with, 
e.g.,  by  depriving  the  muscle  of  glucose  or  of  oxygen, 
or  by  exposing  it  to  2:4  dinitrophenol." 

Later  studies  of  electrical  activity  have  rather 
tended  to  cloud  the  picture.  Biilbring  &  Ltillman  (22) 
demonstrated  that  spike  frequency  and  tension  could 
be  dissociated.  Using  dinitrophenol  they  showed  that 
spike  frequency  could  be  made  to  increase  or  decrease 
without  particular  reference  to  tension  changes.  The 
inverse  relation  of  tension  to  membrane  potential  still 
held  under  these  circumstances,  however,  so  that  at 
this  point  we  might  tend  to  disregard  spike  activity. 
This  idea  is  reinforced  by  Holman's  observation  (117) 
that  the  addition  of  KC1  to  the  medium  bathing  a 
taenia  coli  strip  increases  tension  and  decreases  the 
membrane  potential.  Further,  at  concentrations  above 
20  meq  per  liter,  the  relation  of  K„  to  membrane 
potential  is  linear  with  a  33  mv  slope  per  log  unit 
change,  an  important  fit  with  ionic  theory  although 
the  low  slope  remains  to  be  accounted  for. 

Burnstock  &  Straub  (26)  using  an  improved  pro- 
cedure, the  sucrose-gap  technique,  verified  the  fact 
that  K  salts  produced  a  membrane  depolarization, 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


I]57 


showed  the  importance  of  penetrability  of  the  ac- 
companying anion,  and  improved  the  relation  of  E„, 
to  log  K„  to  yield  a  slope  of  45  mv.  This  is  still  lower, 
however,  than  the  ideal  58  mv  which  one  would 
expect. 

Holman  (116)  found  more  evidence  to  relate  E„, 
and  tension.  She  reported  that  raising  Na„  to  two  or 
three  times  the  normal  level  first  increased  tension  and 
spike  rate  while  reducing  Em.  Later,  as  exposure  was 
prolonged,  the  spikes  disappeared  although  tension 
remained  high  and  E„,  low.  These  observations  again 
argue  for  dissociation  of  spikes  and  tension,  but  later, 
Holman  (118)  took  the  position  that  spike  frequency 
was  an  important  factor  in  the  development  of  ten- 
sion and  Axelsson  (5)  sustained  this  view. 

The  question  of  whether  or  not  tension  changes 
and  electrical  spikes  are  interdependent  is  of  particu- 
lar importance  to  our  problem,  since  vascular  tissue, 
so  far  as  it  has  been  studied,  shows  no  spike  activity 
whatever.  Accordingly,  tissues  such  as  taenia  coli  are 
relevant  only  insofar  as  their  tension  may  correlate 
with  electrical  activity  other  than  that  of  a  train  of 
action  potentials  constituting  the  spike  activity.  Burn- 
stock's  recent  study  and  argument  is  thus  particularly 
important  (24).  He  noted  that  smooth  muscle  of 
guinea  pig  taenia  coli  is  relaxed  by  epinephrine  and 
that  this  is  associated  with  a  rise  in  Em  and  decrease 
of  spike  activity.  The  smooth  muscle  of  the  muscularis 
mucosa  of  the  dog,  by  contrast,  is  contracted  by 
epinephrine  and  in  this  case  the  epinephrine  effect  is 
associated  with  a  fall  in  E„,  and  an  increase  in  spike 
activity.  It  would  therefore  appear  that  at  least  for 
these  types  of  visceral  muscle  both  the  membrane 
potential  and  the  spike  activity  are  correlated  with 
tension.  Under  certain  circumstances  it  is  possible  to 
dissociate  the  spike  activity  from  the  tension  and  the 
membrane  potential  alone  then  remains  inversely 
correlated. 

A  similar  situation  arises  in  connection  with  studies 
of  the  uterus.  The  observation  of  Woodbury  &  Mc- 
Intyre  (212)  that  oxytocin,  which  contracts  the 
pregnant  uterus,  reverses  the  membrane  potentials  of 
the  single  muscle  cell  is  quite  relevant  for  it  again 
relates  membrane  potential  to  activity.  On  the  other 
hand,  the  claim  (43)  that  tension  of  the  uterus  strip  is 
only  correlated  with  spike  activity  suggests  that  this 
tissue  is  not  analogous  to  vascular  smooth  muscle. 

Electrical  studies  of  vascular  smooth  muscle  were 
almost  nonexistent  until  very  recently.  Bozler  (17) 
considered  this  type  of  muscle  to  be  distinctive  in 
being  "multi-unit"  unlike  many  other  types  which 
behave  like  single  units.  Recent  detailed  and  elegant 


studies  by  Burnstock  &  Prosser  (25)  and  Prosser  et  al. 
(161)  have  placed  this  on  a  firmer  footing.  Vascular 
smooth  muscle  is  here  shown  to  consist  of  widely  sepa- 
rated cells  and  its  extracellular  space  calculated  from 
electron  microscopy  is  about  40  per  cent  of  the  total 
(see  table  4).  This  contrasts  strikingly  with  the  other 
types  of  smooth  muscle  in  which  the  extracellular 
space  is  estimated  at  less  than  20  per  cent.  Vascular 
smooth  muscle  shows  no  conducted  electrical  activity 
and  no  spikes.  Our  theoretical  discussion  must  reckon 
with  these  distinctive  features.2 


ROLE    OF    CALCIUM    AND    MAGNESIUM    IN 
VASCULAR   SMOOTH    MUSCLE   TENSION 

Calcium 

There  is  too  little  information  concerning  the  de- 
tailed effects  of  calcium  and  magnesium  on  vascular 
tissue  to  permit  any  elaborate  discussion.  What  little 
evidence  we  do  have  is  fortunately  consistent.  The 
older  literature  has  been  reviewed  by  Evans  (60).  A 
much  larger  literature  deals  with  the  general  direct 
involvement  of  calcium  in  the  actomyosin  system  (51) 
and  in  the  metabolic  cycle  of  cells  (141).  We  shall 
not  develop  this  broad  field  of  physiological  chemistry, 
which  would  lead  us  far  from  our  immediate  subject, 
but  we  must  note  that  calcium  ions  are  evidently 
necessary  for  the  contractile  machinery  to  work. 

The  physiological  implications  of  this  have  been 
demonstrated  by  Heilbrunn  &  Wiercinski  (1 10).  They 
showed  that  Ca  in  high  dilution  injected  directly  into 
the  single  skeletal  muscle  fiber  caused  an  immediate 
and  pronounced  shortening.  This  effect  is  not  shared 
by  any  other  ion  normally  present  in  any  quantity 
in  muscle,  but  it  is  also  produced  by  Ba.  These  au- 
thors, like  others  since  (142),  support  the  view  that 
Ca  links  the  ionic  processes  at  the  membrane  to  the 
contractile  mechanism.  This  point  obviously  has  as 
much  importance  for  contraction  and  tonus  in  vascu- 
lar as  in  any  other  muscle  tissue. 

In  studies  of  intestinal  segments  there  seems  to  be 
general  agreement  that  the  addition  of  Ca  to  the 
medium  increases  tone  (189,  208).  More  important 
to  our  thesis  is  the  demonstration  that  withdrawal  of 

2  Recent  successful  impalement  of  single  smooth  muscle  cells 
in  turtle  aorta  and  inferior  vena  cava  segments  has  shown 
specialized  types  of  action  potential  in  association  with  tension 
changes.  (Roddie,  I.  C.  and  S.  Kirk.  Transmembrane  action 
potentials  from  smooth  muscle  in  turtle  arteries  and  veins. 
Science  134:  736,  1961.) 


n58 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


' — 


MAGNESIUM 


SMALL  VESSEL 


SMALL 

VESSEL 


r 


-VFNOUS 


O      O     Jj?      O  O      ro      to      O      O 

§600  666-0 

INFUSION    RATE     ml/mm 

fig.  10.  Average  effect  of  10%  CaCU  or  iofc  MgS04 
infused  into  the  brachial  artery  on  dog  forelimb  vascular 
resistances.  [Graph  prepared  from  tabular  data  in  Haddy 
(101).] 

Ca  from  the  medium  causes  a  dissociation  of  the  con- 
tractile mechanism  from  action  potentials  in  the 
guinea  pig  taenia  coli.  From  this,  Axelsson  &  Biil- 
bring  (6)  have  concluded  that  Ca  is  essential  for  the 
activation  of  the  contractile  mechanism  by  action 
potentials.  Hurwitz  et  al.  (121)  have  shown  this  in 
another  equally  direct  way.  They  observed  that  pro- 
longed exposure  of  the  guinea  pig  ileum  to  a  calcium- 
free  environment  divests  the  tissue  of  its  ability  to 
contract  in  the  presence  of  an  appropriate  chemical 
stimulus.  Further,  the  substitution  of  Mg  for  Ca  in 
the  medium  accelerates  the  loss  of  contractility.  Even 
so  the  membrane  processes  governing  ionic  exchanges 
still  function  so  that  a  stimulus  which  no  longer  causes 
contraction  will  still  cause  K  efflux 

Zsoter  &  Szabo  (216)  have  reported  that  the 
feeding  of  a  high  calcium  diet  to  rats  for  10  to  15  weeks 
causes  an  increased  sensitivity  of  the  mesoappendix  to 
the  topical  application  of  epinephrine.  As  we  have 
discussed  earlier,  however,  this  type  of  result  is 
difficult  to  interpret,  since  the  variable  (calcium 
feeding)  is  so  remote  from  the  target.  Much  more  re- 
vealing is  the  observation  of  Haddy  who  showed  that 
the  infusion  of  hypertonic  calcium  salts  caused  con- 
striction of  all  segments  of  the  peripheral  vascular  bed 
of  the  dog  forelimb  under  conditions  of  controlled 
flow  (101 ).  It  will  be  recalled  that  hypertonic  solutions 
in  general  produce  vasodilatation  so  that  the  result 
with  calcium  is  particularly  striking.  In  a  later  study 
Overbeds  &  Haddy  (156)  reported  that  while  the 
infusion  of  isotonic  KC1  produced  peripheral  vasodila- 
tation, isotonic  CaCl2  caused  vasoconstriction. 


Woolley  (213)  has  suggested  that  serotonin  acts 
directly  on  the  cell  membrane  to  transfer  calcium 
from  the  exterior  to  the  interior  of  the  cell.  His  evi- 
dence is  quite  incomplete,  however,  and  a  similar 
argument  could  be  developed  with  equal  reason  to 
suggest  that  most  if  not  all  smooth  muscle-contracting 
agents  act  through  some  similar  mechanism  involving 
calcium. 


Magnesium 

Haury  (105)  has  clearly  demonstrated  that  Mg 
relaxes  bronchial  smooth  muscle  and  opposes  the 
action  of  stimulating  drugs.  In  well-controlled  experi- 
ments in  the  dog  and  frog  he  found  that  small 
amounts  of  Mg  given  intravenously  produced  a  blood 
pressure  fall  which  was  in  large  part  due  to  peripheral 
vasodilatation  (106).  Schmid  et  al.  (174)  carried  out  a 
careful  hemodynamic  study  in  conscious  dogs  and  also 
concluded  that  Mg  salts  produce  peripheral  vasodila- 
tation as  Hoff  et  al.  (115)  had  earlier  claimed.  Stan- 
bury  (187)  emphasized  that  the  action  of  Mg  is  com- 
plex, since  it  produces  changes  in  the  autonomic 
nervous  system  and  the  heart  as  well  as  the  peripheral 
vasculature.  Zadina  &  Kriz  (215)  claimed  that  Mg 
had  a  direct  relaxing  effect  on  the  isolated  guinea  pig 
intestine  and  depressed  the  response  to  stimulating 
agents. 

Engbaek  (59)  reviewed  the  subject  in  1952  and 
concluded  that  although  it  seemed  reasonably  certain 
that  Mg  ions  acted  to  relax  peripheral  blood  vessels 
this  had  not  yet  been  shown  to  be  a  direct  effect. 

Pending  any  evidence  to  the  contrary  it  seems 
reasonable  to  conclude,  in  summary,  that  Ca  causes 
peripheral  vasoconstriction  and  Mg  relaxation.  In 
general,  these  actions  do  not  appear  to  be  in  any 
way  specific  to  vascular  smooth  muscle.  The  special 
role  of  these  bivalent  metal  ions  in  the  chemistry  of 
contractile  protein  may  be  involved  and  both  ions,  or 
at  least  Ca,  may  link  membrane  phenomena  to  the 
contractile  mechanism. 


ROLE    OF    H+   AND    OH-  IN    VASCULAR 
SMOOTH   MUSCLE   TENSION 

This  subject  is  in  a  highly  unsatisfactory  state  and 
permits  no  real  conclusions  other  than  that  the  pH  of 
the  medium  is  a  most  important  variable,  as  we  might 
have  guessed.  At  this  stage  in  the  investigation  of  ions 
most  workers  are  more  concerned  with  maintaining 


EFFECTS    OF    IONS    ON    VASCULAR    SMOOTH    MUSCLE 


• '  59 


pH  as  an  invariant  than  with  noting  and  interpreting 
the  effects  of  changes. 

Schuler  (177)  measured  the  tension  of  mesenteric 
and  phrenic  artery  rings  while  shifting  pH  to  either 
side  of  normal.  He  found  that  tonus  increased  in  both 
cases.  Tobian  et  al.  (198),  using  the  spiral  aorta  strip 
of  the  rat,  found  that  the  contractile  response  to 
norepinephrine  was  maximal  at  relatively  higher  pH 
and  minimal  at  lower.  It  seems  to  us  that  nowhere  is 
the  duration  of  immersion  or  exposure  to  the  altered 
environment  more  important  than  in  studies  of  the 
effect  of  H  ions.  Reference  to  table  2  will  remind  us 
of  the  extremely  high  mobility  of  H+  and  the  ease  with 
which  it  penetrates  the  membrane. 

Rogers  &  Fenn  (166)  have  shown  that  H+  added 
to  the  medium  exchanges  rapidly  with  K+  and  Na+ 
of  cells.  More  recently,  Saunders  et  al.  (173)  have  also 
shown  a  partial  replacement  of  K,+  with  H,+  during 
dietary  potassium  depletion.  At  equilibrium,  then, 
an  original  alteration  in  medium  pH  is  replaced  by  an 
altered  Na+  and  K+  distribution.  Duration  of  exposure 
must  then  be  a  critical  variable.  With  this  in  mind, 
we  can  now  examine  the  findings  of  workers  using  in 
vivo  preparations.  Technically,  all  the  procedures  to 
be  quoted  are  beyond  reproach  as  far  as  they  go. 

Burget  &  Visscher  (23)  showed  a  nice  decrease  in 
epinephrine  response  of  the  pithed  cat  proportionate 
to  a  stepwise  fall  in  pH.  This  accords  with  Tobian  et 
al.  (198).  Fleisch  et  al.  (63)  used  good  techniques  to 
measure  flow  and  pressure  and  found  that  a  fall  in 
pH  of  as  little  as  0.05  caused  generalized  vasodilata- 
tion. 

More  recent  studies  using  the  technique  of  con- 
trolled perfusion  of  a  vascular  bed  are  conflicting.  Deal 
&  Green  (45),  like  Kester  et  al.  (127)  earlier,  reported 
that  solutions  on  the  acid  or  alkaline  side  of  physio- 
logical neutrality  increased  blood  flow  to  limb  mus- 
cles, indicating  peripheral  vascular  relaxation.  Skin 
vessels,  however,  showed  a  decrease  in  resistance  as 
pH  fell  and  an  increase  as  pH  rose.  Fleishman  et  al. 
(64)  showed  that  the  picture  is  complicated  by  the 
fact  that  small  vessel  segments  constitute  independent 
resistances  the  magnitudes  of  which  may  actively 
vary  in  opposite  directions.  The  net  effects  were 
dilatation  of  small  vessels  with  an  acute  fall  in  pH  and 
constriction  with  a  rise  in  pH.  Emanuel  et  al.  (57) 
also  reported  that  an  acute  rise  in  pH  caused  an  in- 
creased peripheral  vascular  resistance  through  the 
renal  vascular  bed. 

Clearly,  we  are  in  no  position  yet  to  draw  any  sort 
of  general  conclusions  except  that  H  ion  effects  are 
interwoven  with  those  of  Na+  and  K+. 


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TIME   IN  MINUTES 
fig.   1 1 .  Average  effects  of  pH  change  upon  total  and  seg- 
mental vascular  resistances  in  the  nerve  intact,  nerve  blocked 
and  nerve  blocked  phentolamine  dog   forelimb.  [From   Fleish- 
man et  al.  (64).] 


ROLE   OF   ANIONS   IN   VASCULAR 
SMOOTH  MUSCLE  TENSION 

There  is  a  great  need  for  systematic  study  in  this 
field.  So  far,  although  anions  have  been  considered 
from  time  to  time,  they  have  been  studied  only  to 
underline  the  effect  of  their  associated  cations.  No 
approach  to  this  problem  will  really  make  much  sense, 
however,  until  an  acceptable  basic  model  for  the  role 
of  cations  in  the  regulation  of  vascular  tension  is  pre- 
sented. This  model  need  not  be  the  final  one  as  long 
as  it  provides  a  good  rational  framework.  We  hope  to 
present  such  an  integrated  view  in  the  theoretical 
discussion  to  follow. 


THEORETICAL  INTERPRETATIONS 

A  rational  theoretical  interpretation  of  the  available 
evidence  is  now  quite  possible  and  has  been  attempted 


i  i6o 


HANDBOOK    OF    PHYSIOLOGY 


cikcn.ATION    II 


by  several  workers  Raab  (  i  •  > _•  i  has  suggested  that  the 
amount  of  sodium  in  the  smooth  muscle  cell  deter- 
mines its  responsiveness  to  catecholamines  which  he 
considers  important  in  the  pathogenesis  of  hyperten- 
sive states  Tobian  &  Redleaf  (200)  suggest  that  the 
amount  of  both  sodium  and  potassium  increases  in 
the  vascular  smooth  muscle  cell  in  chronic  hyperten- 
sion and,  by  osmotic  attraction,  causes  cell  swelling 
and  water  logging.  Tobian  has  recently  reviewed  this 
position  (193,  194)-  VVe  have  presented  the  theory 
that  the  sodium  transfer  systems,  broadly  defined, 
and  expressed  in  the  sodium  gradient,  determine 
vascular  tone  (78).  Raab  (163)  has  recently  revised  his 
position  to  incorporate  the  sodium  gradient  into  his 
basic  thesis  ol  catecholamine  sensitivity. 

Insofar  as  the  cell  is  concerned,  neither  the  amount 
nor  the  concentration  of  Na  or  K  enclosed  by  its 
membrane  has  any  meaning  apart  from  their  relation 
to  the  external  environment  as  the  gradients  Na„/Na, 
and  K,  K.„.  An  increase  in  Na,-,  for  example,  attracts 
water  into  the  cell  until  osmotic  equilibrium  is  estab- 
lished only  if  Na,  has  increased  relative  to  Na„.  Again, 
an  increase  in  K„  will  redistribute  itself  so  as  to  pro- 
duce no  osmotic  effect  at  equilibrium  if  Na„  Na,  is 
kept  constant.  Or  again,  insofar  as  membrane  poten- 
tials are  concerned,  an  increase  in  K,  hyperpolarizes 
the  cell  only  if  K,   K.„  is  made  steeper  thereby. 

We  need  not  belabor  the  point  implicit  in  the  basic 
principles  of  the  introduction  to  this  chapter  but  only 
urge  that  a  satisfactory  theory  must  be  based  on  con- 
centration (or  activity)  gradients  and  not  stress  either 
cell  or  environment  alone  in  isolation.  It  is  equally 
apparent  from  the  evidence  presented  that  a  satisfac- 
tory theory  must  embrace  both  sodium  and  potassium. 
We  believe  that  the  following  theoretical  interpreta- 
tion will  lit  many  of  the  presently  known  facts  and 
will  perhaps  serve  to  stimulate  further  thought.  It  will 
be  presented  in  the  form  of  generalizations  with  some 
supporting  evidence.  The  remainder  of  the  evidence 
is  contained  in  the  body  of  this  chapter. 

/  )  Vascular  smooth  muscle  tension  is  inversely  pro- 
portional to  the  membrane  potential,  that  is,  to  the 
sum  of  the  equilibrium  potentials  of  Na+  and  K+ 
where,  in  the  basal  state,  the  permeability  of  the  cell 
lo  K4  considerably  exceeds  its  permeability  to  Na+. 
Laborit  &  Huguenard  (130)  and  Furchgott  (87)  have 
already  expressed  this  view. 

The  simple  shift  of  water  from  cells  to  environment 
which  can  be  induced  b\  increasing  the  external 
tonicity  will  increase  both  Na,  and  K,,  hyperpolarize 
the  membrane  and  relax  the  cell.  This  explains  the 


vasodilatation  which  consistently  follows  the  infusion 
of  hyperosmotic  solutions.  Sustained  exposure  to  hy- 
perosmotic solutions  containing  particles  other  than 
Na+  will  not  only  lower  Na0  but  induce  a  flow  of  K+ 
from  cells  to  medium  so  that  at  equilibrium  the  mem- 
brane potential  will  be  reduced  and  tension  increased. 
This  may  explain  postnephrectomy  hypertension  (83). 

2)  Acute  change  in  vascular  smooth  muscle  tension 
is  ordinarily  accomplished  by  agents  which  alter  the 
permeability  of  the  membrane  to  Na+.  An  agent 
which  increases  the  permeability  to  Na+  will  produce 
an  immediate  depolarization  and  increase  in  tension 
followed  by  a  flow  of  sodium  from  environment  to  cells. 
Such  a  flow  of  sodium  has  been  consistently  induced 
in  vivo  by  all  vasoconstrictors. 

If  cell  volume  is  to  be  maintained  unchanged  during 
this  process,  potassium  must  leave  the  cell  as  sodium 
enters.  The  expected  increase  in  K„  does  not  occur 
with  all  vasoconstrictors.  In  this  case  we  must  assume 
that  some  cell  swelling  occurs.  Fending  further  data 
we  recognize  that  real  changes  in  cell  volume  may 
also  be  involved  in  changes  of  tension  in  vascular 
smooth  muscle  (65,  195). 

■-;)  Sustained  change  in  vascular  smooth  muscle 
tension  may  be  accomplished  by  agents  which  ad- 
just and  sustain  the  membrane  permeability  to  Na. 
The  equilibrium  state  fora  given  permeability  is  mani- 
fest in  the  Na  gradient.  Since  the  entrance  and  exit 
mechanisms  for  sodium  are  not  necessarily  the  same 
(see  Goldman  equation)  the  same  result  can  be 
achieved  by  varying  either  influx  or  efflux  rate.  The 
sodium  gradient  falls,  for  example,  if  influx  rate  is 
increased  or  efflux  hindered.  If  Na,  tends  to  accumu- 
late in  a  sustained  manner  due  to  either  of  these 
changes  the  cell  can,  within  reason,  compensate  by 
increasing  its  work  of  extrusion.  Presumably  the  first 
effort  of  the  cell  to  compensate  will  be  reflected  by  an 
increase  in  the  cell  machinery  involved  in  the  work  of 
such  Na  extrusion.  This  capacity  must,  however,  be 
limited  so  that  equilibrium  will  next  be  attained  at  a 
lower  gradient,  that  is,  Na,  increases  until  equilibrium 
is  re-established.  The  resultant  accumulation  of  .Na, 
must  lead  to  the  extrusion  of  K,,  a  new  and  lower 
membrane  potential  and  an  increase  of  tension. 

We  have  described  the  evidence  that  Na,  is  actually 
increased  in  sustained  hypertensive  states.  It  is 
equally  clear  that  chronic  sodium-depleting  proce- 
dures tend  to  re-establish  the  basic  normal  situation. 
There  is  also  good  evidence  that  mineralocorticoids 
regulate  the  permeability  of  cell  membranes  to 
sodium  (33,  74,  123).  A  control  system  which  allows  ,i 
small   trickle  of  sodium  to  enter  the  cell  and   then 


EFFECTS    OF    IONS    UN    VASCULAR    SMOOTH    MUSCLE 


I  l6l 


regulates  the  case  with  which  it  is  extruded  permit> 
very  fine  control  of  the  sodium  gradient. 

4)  The  role  of  cell  volume  remains  to  be  assessed 
both  in  acute  and  chronic  changes  of  vascular  smooth 
muscle  tension.  This  is  self-evident.  We  are  repeating 
this  point  at  this  time  to  emphasize  the  fact  that  this 
problem  cannot  be  dealt  with  properly  until  such  time 
as  water  movements  can  be  accurately  measured  (65, 
195)- 

SUMMARY 

The  detailed  supporting  evidence  leading  to  our 
final  theoretical  interpretation  is  contained  in  the  body 


of  this  chapter.  In  order  to  underline  our  intention 
we  have  referred  briefly  to  some  essential  evidence 
which  cannot  be  easily  explained  in  any  alternate 
way.  It  is  our  opinion  that  most  of  the  apparentlv 
complex  material  presented  can  be  temporarily  but 
usefully  rationalized  by  reference  to  the  theory  pre- 
sented. It  is  allied  with  general  ionic  theory  as  it 
applies  to  other  contractile  elements  (113)  modified 
to  serve  the  special  needs  of  this  particular  tissue. 

We  conclude  that  vascular  smooth  muscle  tension 
depends  on  ionic  distributions  and  mobilities  across 
the  cell  membrane.  The  transmembrane  equilibra- 
tion of  both  sodium  and  potassium  has  been  stressed 
as  has  the  possibility  of  a  direct  link  with  calcium. 


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193.  Tobian,  L.  Physiology  of  the  juxtaglomerular  cells. 
Ann.  Internal  Med.  52:  395,   i960. 

194.  Tobian,  L.  Interrelationship  of  electrolytes,  juxtaglo- 
merular cells  and  hypertension.  Physiol.  Revs.  40:  280, 
i960. 

195.  Tobian,  L.,  and  J.  T.  Binion.  Tissue  cations  and  water 
in  arterial  hypertension.  Circulation  5:  754,  1952. 

196.  Tobian,  L.,  and  J.  T.  Binion.  Artery  wall  electrolytes 
in  renal  and  DCA  hypertension.  ./.  Clin.  Invest.  33:  1407, 

'954- 

197.  Tobian,  L.,  and  A.  Fox.  The  effect  of  nor -epinephrine 
on  the  electrolyte  composition  of  arterial  smooth  muscle. 
./.  Clin.  Incest.  35:  297,   1956. 

198.  Tobian,  L.,  S.  Martin,  and  W.  Eilers.  Effect  of  pH  on 
norepinephrine-induced  contractions  of  isolated  arterial 
smooth  muscle.  Am.  ./.  Physiol.   1 96 :  998,   1  959. 

199.  Tobian,  L.,  and  P.  D.  Redi.eaf.  Effect  of  hypertension 
on  arterial  wall  electrolytes  during  desoxycorticosterone 
administration.  Am.  J.  Physiol.  189:  451,   1 957. 

200.  Tobian,  L. ,  and  P.  D.  Redi.eaf.  Ionic  composition  of 
the  aorta  in  renal  and  adrenal  hypertension.  Am.  J. 
Physiol.    192:  325,    1958. 

201.  Toussaint,  C,  R.  Wolter,  and  P.  Sibille.  Hyperten- 
sion et  lesions  arterielles  provoquees  chez  le  rat  par 
l'ingestion  de  quantites  excessives  de  chlorure  de  sodium. 
Rev.  beige  pal  hoi.  et  rned.  exptl.  23 :  83,  1 953. 

202.  USSING,     H.      H.,      P.      K.RUH0FFER,     J.     H.     THAYSEN,     AND 

N.  A.  Thorn.  The  alkali  metal  ions  in  biology.  Handbuch 
der  Experimeniellen  Pharmakologie.  Berlin:  Springer,  i960, 
vol.   13. 


203.  Vick,  J.,  H.  E.  Ederstrom,  and  T.  Vergeer.  Epin- 
ephrine sensitivity  of  blood  vessel  strips  from  salt-fed 
and  castrated    rats.  Proc.  Soc.  Exptl.   Biol.  Med.  93:  536, 

>956- 

204.  Vogt,  M  The  site  of  action  of  some  drugs  causing  stim- 
ulation of  the  circular  coat  of  the  rabbit's  intestine  J. 
Physiol.    102  :  1  70,   1943. 

205.  Warren,  J.  D.  Cation  and  Water  Shifts  in  Response  to  Pressor 
Agents  in  the  Conscious  Dog.  (Thesis).  Univ.  British  Colum- 
bia, 1 96 1. 

206.  White,  H.  L.,  and  D.  Rolf.  Whole  body  and  tissue 
inulin  and  sucrose  spaces  in  the  rat.  Am.  ./.  Physiol.   188: 

'5'.    '957- 

207.  White,  II.  L.,  and  D.  Rolf.  Comparison  of  various 
procedures  for  determining  sucrose  and  inulin  space  in 
the  dog.  J.  Clin.  Invest.  37:  8,  1958. 

208.  Whitehead,  R.  W.  Responses  of  excised  intestines  to 
alterations  of  electrolyte  concentrations  (Na,  Ca,  K). 
Am.  J.  Physiol.  89:  253,  1929 

209.  Williamson,  A.  W.  R.,  and  F.  D.  Moore.  Norepinephrine 
sensitivity  of  isolated  rabbit  aorta  strips  in  solutions 
of  varying  pH  and  electrolyte  content.  Am.  ./.  Physiol. 
198:  1 157,  i960. 

210.  Winter,  H.  A.,  H.  E.  Hoff.  and  L.  Dso.  Effects  of 
potassium  deficiency  upon  gastrointestinal  motility. 
Federation  Proc.  8:  169,   1949 

211.  Woodbury,  D.  M.,  and  A.  Koch.  Effects  of  aldosterone 
and  desoxycorticosterone  on  tissue  electrolytes.  Proc.  Soc. 
Exptl.  Biol.  Med.  94:  720,   1957. 

212.  Woodbury,  J.  W.,  and  D.  M.  McIntyre.  Electrical 
activity  of  single  muscle  cells  of  pregnant  uteri  studied 
with    intracellular   ultramicroelectrodes.    Am.    J.    Physiol. 

■77:  355.   '954- 

213.  Woolley,  D.  W.  A  probable  mechanism  of  action  of 
serotonin.  Proc.  Null.  Acad.  Sci.  44:  197,  1958. 

214.  Yamabayasiii,  II.,  and  W.  F.  Hamilton.  Effect  of 
sodium  ion  on  contractility  of  the  dog's  aortic  strip  in 
response    to   catecholamines.    Am.    J.    Physiol.    197:   993, 

■959- 

215.  Zadina,  R.,  and  V.  Kriz.  L'action  du  magnesium  sur 
la  contraction  de  l'intestin  isole.  Compt.  rend.  soc.  biol.  142: 
1037,    1948. 

216.  Zsoter,  T.,  and  M.  Szabo.  Effect  of  sodium  and  calcium 
on  vascular  reactivity    Circulation  Research  6:  476,   1958. 

217.  Zweifach,  B.  W.  Microscopic  observations  of  circulation 
in  rat  meso-appendix  and  dog  omentum:  use  in  study  of 
vasotropic  substances.  In:  Methods  in  Medical  Physics 
Chicago:  Yr.  Bk.  Publ.,  1948,  vol.  1,  p.  131. 


CHAPTER     34 


Lipid  metabolism  in  relation  to  physiology 
and  pathology  of  atherosclerosis 


SAMI    A.    HA  SHIM 

WILLIAM    C .    FELCH 

THEODORE    B.    VAN    ITALLIE 


Department  of  Medicine,  St.  Luke's  Hospital,  and  Institute  of 
Nutrition  Sciences,  Columbia  University,  New  York  City 


CHAPTER      CONTENTS 

Pathology 

Pathogenesis 

Metabolic  Consequences  of  Ingestion  of  Food 

Diet 

Fat  Absorption  and  Digestion 

Adipose  Tissue 

Hormonal  Influences  on  Adipose  Tissue 
The  Serum  Lipids 

Chylomicrons 

The  Lipoproteins 

Free  Fatty  Acids 

Role  of  the  Liver 

Cholesterol  Disposal 
Factors  That  Influence  Serum  Lipids 

Stress 

Sex 

Dietary  Fatty  Acids 

Essential  Fatty  Acid  (EFA)  "Deficiency" 

Chain  Length,  Unsaturation,  and  Melting  Point 

Dietary  Cholesterol 

Practicable  Diets 

Mechanism  of  Cholesterol  Lowering 

Additional  Influences  on  Serum  Lipids 
Blood  Lipids  and  Atherosclerosis 
Role  of  Blood  Clotting  and  Thrombosis 


the  term  "lipid"  enables  us  to  assemble  under  one 
heading  a  number  of  organic  substances  which, 
although  variable  in  chemical  structure,  are  closely 
related  in  biological  behavior.  The  physical  and 
chemical  processes  by  which  a  living  organism  oper- 
ates   are   summarized    bv    the    term    "metabolism." 


Thus,  lipid  metabolism  refers  to  the  behavior  in 
living  organisms  of  fatty  acids,  their  esters,  certain 
hydrocarbons,  phospholipids,  and  sterols.  Recent 
technical  advances  permitting  better  separation, 
identification,  and  quantification  of  the  various  lipids 
have  resulted  in  a  vast  store  of  new  information  about 
lipid  metabolism.  Much  of  this  material  still  needs 
to  be  organized  and  evaluated  in  terms  of  its  relevance 
to  problems  of  human  health. 

''Atherosclerosis"  (Gr.  athero,  mush)  refers  to  a 
lesion  of  the  arterial  wall  characterized,  inter  alia, 
by  accumulation  of  lipid  in  the  intima.  The  term  was 
first  suggested  in  1904  by  Marchand  (144).  Today 
atherosclerosis,  by  virtue  of  its  deleterious  effects  on 
the  various  arteries  of  the  heart,  brain,  and  other 
important  areas  of  the  body,  appears  to  be  the  major 
public  health  problem  of  Western  man.  Thus,  by 
extension,  lipid  metabolism  as  it  relates  to  the  physi- 
ology and  pathology  of  blood  vessel  walls  has  become 
a  subject  of  vital  importance. 

The  search  for  the  etiology  of  atherosclerosis  has 
included  consideration  of  all  elements  in  the  classic 
epidemiologic  triad — agent,  host,  and  environment. 
Environmental  factors  have  received  special  attention 
since  evidence — epidemiologic,  experimental,  and 
clinical — has  accumulated  suggesting  that  dietary 
constituents  and  particularly  dietary  fats  influence  the 
development  of  atherosclerosis.  Such  evidence  as 
applied  to  man  necessarily  has  been  indirect  because 
of  the  inaccessibility  of  atherosclerotic  lesions  during 
life.  It  is  now  recognized  that  dietary  constituents 
can  profoundly  influence  lipid  metabolism.  The  role 


1 167 


I  1 68  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


of  diet-induced  changes  in  serum  lipids  in  the  de- 
velopment of  atherosclerosis  has  not  been  established. 
In  man,  atherogenesis  appears  to  be  a  chronic  process, 
requiring  considerable  time,  perhaps  years,  to  evolve. 
The  disease  can  culminate  in  an  acute  obstructive 
event,  frequently  with  disastrous  consequences.  At 
such  a  time  a  disturbance  in  the  coagulability  of  the 
blood  may  occur  resulting  in  the  formation  of  an 
arterial  thrombus.  Thus,  attempts  have  been  made 
to  correlate  changes  in  serum  lipids  as  influenced  by 
diet  with  the  development  not  only  of  atherosclerosis 
but  also  of  a  more  acute  change  in  coagulability  of 
the  blood. 

The  clinical  sequelae  of  atherosclerosis,  ischemia, 
and  infarction  of  the  heart,  brain,  and  other  tissues, 
have  been  carefully  documented  for  years.  Also,  the 
gross  pathologic  processes,  such  as  lumen  encroach- 
ment, fibrosis,  ulceration,  calcification,  and  throm- 
bosis, which  underlie  these  clinical  events  base  been 
understood  by  pathologists  since  the  time  of  Virchow. 
Moreover,  a  reasonable  explanation  for  the  patho- 
genesis of  the  disease  was  advanced  more  than  half  a 
century  ago  and  has  not  been  disproved.  Yet  from 
the  standpoint  of  etiology  and  intimate  pathogenesis 
the  basic  nature  of  the  disease  remains  obscure  and 
debatable. 


PATHOLOGY 

The  pathologic  entity  atherosclerosis  must  be  dis- 
tinguished from  other  blood  vessel  lesions,  some  ot 
which  have  been  previously  lumped  together  with 
atherosclerosis  under  the  generic  designation,  arterio- 
sclerosis. Monckeberg's  medial  sclerosis  differs  patho- 
logically, pathogenetically,  and  clinically  from  ath- 
erosclerosis. Various  inflammatory  lesions  of  blood 
vessel  walls  also  can  be  sharply  separated,  although 
the  generally  held  concept  that  thromboangiitis 
obliterans  is  an  entity  different  from  peripheral  ath- 
erosclerosis   recently    has    been    questioned  (209). 

Another  important  consideration  is  that  common 
textbook  descriptions  of  atherosclerosis  may  in  fact 
describe  mostly  complications  or  sequelae  of  an  initial, 
clinically  silent  process  that  may  start  in  infancy. 
Thus,  lumen  encroachment,  fibrosis,  calcification, 
ulceration,  hemorrhage,  and  thrombosis  are  all  late 
conditions. 

What  then  is  the  initial  lesion?  What  is  the  patho- 
logic essence  of  the  disease?  The  answer  to  these 
questions  necessarily  involves  consideration  of  patho- 
genesis (to  be  discussed  later)  as  well  as  descriptive 


pathology.  Fortunately,  precise  studies  of  early  gross 
and  microscopic  lesions  from  human  and  experi- 
mental material  are  available  (21,  55,  108,  109,  130, 
162).  The  first  gross  lesion,  often  visible  in  infants, 
is  the  fatty  streak,  a  linear  yellow  elevation  usually 
found  in  the  aorta.  Microscopic  examination  of  such 
a  streak  reveals  underneath  the  heaped-up  intima 
an  accumulation  of  lipophages,  cells  which  show  a 
foamy,  reticular  cytoplasm  with  ordinary  stains  con- 
taining lipid  solvents,  but  which  are  found,  with 
appropriate  fat  stains,  to  be  packed  with  lipid.  Lipid 
is  also  found  lying  free  between  the  lipophages. 
Whether  the  lipid  which  makes  up  the  fatty  streak  is 
first  intracellular  or  extracellular  is  as  yet  unknown. 
With  larger  lesions,  lipid  is  also  found  below  the 
internal  elastic  lamella  in  the  media,  but  the  smallest, 
earliest,  grossly  invisible  lesions  consist  of  a  few  foam 
cells  lying  directly  under  the  endothelial  surface  of 
the  intima.  Thus,  the  lipid-containing  foam  cell  is 
usuallv  considered  to  be  the  earliest  recognizable  unit 
of  the  atherosclerotic  process. 

However,  careful  microscopic  studies  show  other 
subtle  anatomic  changes  (39,  126,  195)  occurring 
pari  passu  with  the  appearance  of  lipid  in  the  blood 
vessel  wall.  Elastic  tissue  stains  reveal  stretching  and 
fragmentation  of  elastic  fibers  in  the  intima  as  an 
early  feature.  Other  special  stains  show  metachro- 
matic changes  in  the  ground  substance  of  the  arterial 
wall,  and  chemical  studies  have  demonstrated  muco- 
polysaccharide accumulations  that  occur  along  with, 
or  possibly  before,  the  appearance  of  visible  lipid.  An 
abundance  of  evidence,  clinical  and  experimental, 
has  shown  that  preceding  damage  to  the  arterial  wall, 
toxic,  infectious,  chemical  or  physical,  will  accelerate 
and  will  influence  the  site  of  the  atherosclerotic 
proce^.  These  findings  have  given  rise  to  the  theory 
that  subtle,  perhaps  submicroscopic,  alterations  in 
the  physicochemical  state  of  the  arterial  wall  may 
actually  precede  the  more  gross  lipid  accumulations. 


PATHOGENESIS 

Since  the  earliest  pathologic  lesions  are  only  adum- 
brative, even  with  modern  histochemical  techniques, 
it  follows  that  the  intimate  pathogenesis  of  the 
atherosclerotic  lesion  also  remains  obscure.  It  is 
understandable  that  nineteenth  century  pathologists 
considered  the  disease  a  degenerative  one,  an  inevi- 
table concomitant  of  the  aging  process  and  a  simple 
result  of  wear  and  tear  on  the  arterial  wall.  Even 
when  atherosclerosis  was  separated  from  other  arte- 


LIPID    METABOLISM 


I  l6g 


rial  lesions,  it  must  still  have  appeared  to  pathologists 
of  that  era  to  be  another  phenomenon  of  aging,  found 
along  with  cataracts,  osteoarthritis  and  wrinkled  skin, 
and  occurring  with  increasing  frequency  with  advanc- 
ing years. 

The  pendulum  did  not  swing  until  Ignatowski  (1 10) 
in  1908  succeeded,  by  administering  lipid-rich  foods 
to  rabbits,  in  producing  arterial  lesions  similar  to 
those  occurring  spontaneously  in  human  subjects.  A 
few  years  later  Anitschkow  (10)  demonstrated  con- 
vincingly that  cholesterol  in  the  diet  was  the  athero- 
genic factor  in  experimental  rabbit  atherosclerosis. 
Since  that  time,  a  large  body  of  evidence  has  led 
away  from  the  degenerative  theory.  Some  of  these 
evidences  are:  the  finding  at  autopsy  of  an  occasional 
octogenarian  virtually  free  of  arterial  disease;  the 
contrary  finding  of  fatal  atherosclerosis  in  soldiers  in 
their  twenties;  the  relative  freedom  from  the  disease 
of  premenopausal  women;  the  increased  incidence  at 
autopsy  of  atheromatous  lesions  in  patients  with 
diseases  involving  lipid  abnormalities  such  as  diabetes, 
hypothyroidism,  and  other  processes  associated  with 
hypercholesteremia  and  hyperlipidemia.  Further 
information  resulted  from  the  epidemiologic  finding 
of  certain  population  groups  relatively  free  of  the 
disease  at  postmortem  examination.  Pathologists 
made  further  contributions  to  this  change  in  concept 
by  their  studies  in  experimental  animals;  it  is  now 
recognized  that,  although  man,  certain  other  pri- 
mates, birds,  and  swine  are  the  only  animals  which 
seem  regularly  to  acquire  atherosclerosis  sponta- 
neously, there  is  a  wide  variety  of  species  which  can 
be  caused  to  develop  arterial  lesions  similar  to  those 
found  in  human  material,  providing  only  that  appro- 
priate experimental  manipulations  involving  lipid 
metabolism  are  made. 

All  this  pathologic  evidence,  along  with  a  huge 
volume  of  clinical,  epidemiologic,  and  biochemical 
studies,  has  led  to  the  modern  concept  that  athero- 
sclerosis is  potentially  a  preventable  disease,  a  result 
of  metabolic  disorder  rather  than  a  degenerative 
process.  This  lipid  concept  of  the  pathogenesis  of 
atherosclerosis  can  be  stated  in  simple  terms:  man 
ingests  an  excess  of  lipid  which  overwhelms  the  mech- 
anisms for  its  disposal;  lipid  then  accumulates  in  the 
circulating  blood  and  is  deposited  in  the  arterial  wall. 

How  does  this  rather  simple  concept  fit  with  the 
facts  of  the  earliest  recognizable  pathologic  lesion 
described  above?  At  first  glance,  the  fit  seems  perfect. 
An  excess  of  lipoprotein  material  in  the  circulating 
blood  filters  through  the  endothelium  of  the  arterial 
wall  and  is  taken  up  there  by  tissue  histiocytes  to 


form  foam  cells;  the  simple  accumulation  of  these 
lipophages  results  in  the  gross  arterial  atheroma  and 
sets  off  the  chain  of  events  leading  to  fibrosis,  throm- 
bosis, and  the  rest.  Yet  there  are  a  number  of  ques- 
tions which  cast  doubt  on  this  simple  hypothesis. 

First,  if  the  mechanism  is  merely  one  of  filtration 
through  the  endothelium  to  the  arterial  intima,  why- 
are  the  anatomically  similar  veins  not  more  susceptible 
to  the  atheromatous  process?  That  intraluminal  pres- 
sure plays  some  role  is  shown  by  the  increased  inci- 
dence of  atherosclerosis  in  hypertensive  patients,  the 
occurrence  of  pulmonary  artery  atherosclerosis  in 
individuals  with  pulmonary  hypertension,  and  the 
finding  of  phlebosclerosis  adjacent  to  arteriovenous 
fistulas. 

Another  disturbing  question  concerns  the  fact 
that  the  lipid  deposit  is  not  a  universal  arterial  finding, 
coating  the  intima  of  the  entire  arterial  tree,  but 
rather  a  spotty,  localized  one,  involving  certain  seg- 
ments of  certain  arteries.  A  number  of  possible  ex- 
planations for  this  finding  have  been  offered.  One 
argument  is  that  localized  changes  in  filtration  pres- 
sure, occasioned  by  intraluminal  physical  forces  such 
as  whirlpool  and  eddy  formation,  determine  the  site 
at  which  lipid  is  deposited;  the  frequent  occurrence 
of  atheromatous  lesions  at  bifurcations,  branches  and 
coarctations  favors  this  theory  (175).  Another  pro- 
posal relates  the  clinical  predilection  for  thrombosis 
in  atherosclerosis  to  its  pathogenesis;  the  earliest 
lesion,  by  this  concept,  is  a  chance  fibrin  deposit  on 
the  endothelial  surface,  the  spotty  lipid  lesion  occur- 
ring secondarily  to  fibrin  deposition  (56).  Another 
explanation  depends  on  the  clinical  and  experimental 
evidence  that  preceding  arterial  wall  damage,  physi- 
cal, chemical,  mechanical,  or  bacterial,  will  foster 
premature  and  extensive  lipid  deposits;  by  this  theory, 
occult  damage  to  the  elastic  tissue  or  ground  sub- 
stance (or  both)  of  the  arterial  wall,  from  degenera- 
tive or  extraneous  cause,  serves  as  the  spotty  focus  for 
lipid  deposit.  Still  another  theory  explains  the  spotti- 
ness on  the  basis  of  localized  differences  in  various 
areas  of  the  arterial  wall,  in  the  mechanisms  for 
removal  of  lipid,  either  metabolic  (enzyme  overload), 
scavenging  (number  of  histiocytes  present)  or  ana- 
tomic (number  of  lymph  channels  present).  Yet 
another  hypothesis  explains  localization  by  denying 
filtration  from  the  lumen;  according  to  this  concept, 
atheromatous  lesions  are  preceded  by  a  localized 
overproduction  in  the  arterial  wall  of  the  lipids  which 
make  up  the  lesion  (105).  Sensitive  radioactive  tracer 
studies  have  indeed  shown  that  arterial  tissue  can 
synthesize  lipids,  but  recent  reports  (214)  have  indi- 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


cated  that  if  any  atheroma  lipid  comes  from  local 
synthesis,  it  is  probably  only  the  phospholipid  com- 
ponent. 

One  other  major  question  relating  to  the  intimate 
pathogenesis  of  the  atherosclerotic  lesion  remains 
unanswered:  What  are  the  mechanisms  for  incorpora- 
tion of  lipid  into  cells  to  form  lipophages?  In  each  of 
the  hypotheses  mentioned  above  for  the  pathologic 
background  of  the  early  lesion,  the  common  hall- 
mark, whether  primary  or  secondary  in  time  and  in 
importance,  is  the  lipophage  or  foam  cell  (156),  the 
very  name  of  which  suggests  incorporation  of  lipid 
(fig.  1).  The  knowledge  of  the  exact  derivation  of  the 
foam  cell  is  fundamental  to  a  better  understanding 
of  atherogenesis. 

Is  anabolic  activity  neccsary  for  the  accumulation 
of  lipid  in  the  cellular  cytoplasm  (as  opposed  to  an 
engulfing  mechanism)?  One  clue  may  be  that  the 
lipophage  differs  from  the  lipocyte,  or  adipose-tissue 
cell,  by  the  former's  higher  content  of  protein  and 
lipids  other  than  neutral  fat.  Current  attempts  to 
studv  this  problem  bv  in  vitro  tissue  culture  tech- 
niques   (180)    may    help    to    answer   this   and    other 


important  questions  about  the  role  of  the  lipophage 
in  atherogenesis. 

Do  lipophages  form  simply  because  there  is  lipid 
material  available  to  be  engulfed  or  phagocytized? 
In  favor  of  this  concept  is  the  observation  that  lipo- 
phages are  not  peculiar  to  the  atherosclerotic  lesion; 
they  are  found  as  part  of  the  detritus  in  hemorrhage 
into  the  various  tissues;  they  are  found  as  apparent 
scavengers  in  lipoid  pneumonia;  they  occur  in 
degenerating  tumors;  they  are  found  experimentally 
after  the  subcutaneous  injection  of  cholesterol  sus- 
pensions; and  they  are  found  in  the  lipoidoses 
(Niemann-Pick,  etc.)  in  massive  accumulations  in- 
volving the  reticuloendothelial  system.  In  most,  if 
not  all,  of  these  situations,  it  is  reasonable  to  assume 
that  a  scavenging  attempt  to  rid  the  tissue  of  a  local 
excess  of  lipid  is  involved. 

Yet,  in  the  atheromatous  lesion,  there  appears  to 
be  an  additional  element — one  of  accumulation.  A 
single  minute  atheroma,  invisible  to  the  naked  eye, 
is  made  up  of  a  tremendous  number  of  lipophages, 
packed  together  in  the  subintima  in  such  volume  as  to 
displace  adjacent  normal  tissue  and  to  project  into 


>* 


fig.  I.  Photomicrograph  of  a 
foam  cell  protruding  from  the 
subendothelial  space  of  a  rat 
aorta.  X  8,400.  (Courtesy  of 
Robert  M.  O'Neal,  Baylor 
University.) 


LIPID    METABOLISM 


I  171 


the  lumen.  What  the  stimulus  is  to  cause  this  pro- 
liferative (or  accumulative)  element  is  unknown;  the 
answer  to  this  question  is  vital  to  a  proper  under- 
standing of  the  intimate  pathogenesis  of  athero- 
sclerosis. 

In  summary,  the  major  facts  concerning  the  pa- 
thology of  atherosclerosis,  particularly  its  grosser 
aspects  and  its  sequelae,  are  well  documented.  Debate 
still  exists,  however,  concerning  the  more  subtle, 
microscopic  manifestations  of  the  early  atheroma, 
particularly  in  regard  to  the  primacy  of  lipid  deposi- 
tion. 

After  more  than  fifty  years,  the  lipid  theory,  despite 
some  unanswered  questions,  seems  to  be  standing  the 
test  of  time.  It  will  not  become  a  universally  accepted 
theory  until  certain  difficulties  are  overcome.  The 
spotty  localization  of  arterial  lesions,  the  mechanism 
of  incorporation  of  lipid  into  tissue  cells,  and  the 
stimulus  to  cellular  accumulation  in  atheromatous 
lesions  all  are  unsolved  problems. 


METABOLIC   CONSEQUENCES  OF  INGESTION   OF   FOOD 


rebuilt  by  the  body  into  new  protein.  Some  of  the 
amino  acids  can  be  converted  to  carbohydrate  and 
thence  to  fat.  Their  carbon  skeletons  also  are  available 
for  oxidation. 

Following  digestion,  fatty  acids  passing  through  the 
intestinal  mucosa  are  incorporated  into  very  low- 
density  lipoproteins  (chylomicrons);  these  "mole- 
cules" are  distributed  in  the  systemic  circulation  to 
be  disposed  of  by  hydrolysis,  oxidation,  interconver- 
sion  (but  not  into  carbohydrate),  or  storage  in  various 
tissues. 

Thus,  carbohydrate  and  protein  can  be  converted 
to  and  stored  in  the  body  as  fat. 

Soon  after  a  conventional  meal  has  been  consumed, 
changes  in  concentration  of  glucose,  amino  acids, 
and  fat  (chylomicrons)  occur  in  the  blood.  These 
"primary"  changes  induce  "secondary"  changes  in 
the  metabolic  state.  Ingestion  of  fat  is  followed  by  a 
postprandial  lipemia,  which  may  last  for  many 
hours.  Thus,  to  evaluate  the  serum  lipids  properly, 
it  is  important  to  obtain  blood  samples  from  subjects 
who  are  in  the  postabsorptive  state. 


Assimilation  of  foodstuffs  is  a  condition  of  animal 
life.  Yet  food  is  never  deposited  unchanged.  For 
absorption  to  take  place,  foodstuffs  must  be  split, 
and  far-reaching  chemical  transformations  follow  the 
absorption  of  digested  food.  The  transformed  food 
may  be  oxidized  for  the  immediate  production  of 
energy  or  stored  for  short  or  long  periods,  depending 
on  the  needs  of  the  body.  With  the  exception  of  cer- 
tain essential  nutrients,  the  body  is  able  to  synthesize, 
interconvert,  store,  and  mobilize  its  constituents. 

When  an  individual  ingests  an  assimilable  carbo- 
hydrate, practically  all  of  it  is  absorbed  from  the 
digestive  tract  and  eventually  reaches  the  liver  as 
hexose.  Part  of  the  hexose  is  converted  to  liver  glyco- 
gen; part  is  released  into  the  circulation  to  be  dis- 
tributed to  extrahepatic  tissues;  part  enters  muscle, 
where  it  is  either  burned  or  stored  as  glycogen.  Once 
glucose  enters  muscle,  becoming  phosphorylated,  it 
can  no  longer  leave  as  such.  One  of  its  breakdown 
products,  lactic  acid,  can  diffuse  out  of  muscle  cells 
and  re-enter  the  circulation.  The  adipose  cells  trans- 
form glucose  into  fatty  acids,  which  are  esterified  with 
a-glycerophosphate  to  form  triglyceride  and  are 
stored  in  this  form.  Glucose  products,  by  a  process  of 
transamination,  can  be  converted  into  amino  acids. 

Protein  must  be  hydrolyzed  into  amino  acids  prior 
to  absorption.  Subsequently  the  amino  acids  can  be 


DIET 

The  average  American  diet,  according  to  a  sum- 
mary of  the  1 955  Household  Food  Consumption 
Survey  conducted  by  the  United  States  Department 
of  Agriculture  (65),  derives  44  per  cent  of  its  caloric 
content  from  fat,  1 3  per  cent  from  protein,  and  43 
per  cent  from  carbohydrate.  The  survey  made  no 
deductions  for  food  discarded.  The  breakdown  of 
calories  derived  from  fat  was:  18.3  per  cent  from  satu- 
rated fatty  acids,  18.6  per  cent  from  oleic  acid,  and 
4.5  per  cent  from  linoleic  acid.  As  expected  from  such 
an  extensive  survey,  there  were  some  regional  differ- 
ences in  types  and  quantities  of  food  consumed. 

Knowledge  of  the  chemical  composition  of  natural 
fats  remains  incomplete,  although  great  strides  for- 
ward are  being  made.  It  is  generally  agreed  that 
most  natural  fats,  whether  animal  or  vegetable,  con- 
tain about  98  to  99  per  cent  triglycerides.  The  re- 
maining 1  or  2  per  cent  includes  diglycerides,  mono- 
glycerides,  free  fatty  acids,  phospholipids,  and 
unsaponifiable  sterols.  Fatty  acids  comprise  over  go 
per  cent  of  the  triglycerides,  with  the  remainder 
being  glycerol.  The  naturally  occurring  triglycerides 
are  mixtures  varying  widely  in  their  patterns  of  fatty- 
acids.  The  complexity  of  such  glycerides  is  underlined 


1 172 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


by  the  observation  that  at  least  64  different  fatty 
acids  have  been  identified  in  butter  fat  (101). 

In  general,  the  degree  of  unsaturation  of  the  fat 
depends  upon  the  source  of  the  fat.  Fats  of  aquatic 
origin  contain  a  wide  range  of  unsaturated  C16,  Cis, 
C2o,  and  C22  acids.  Fats  from  land  animals  contain 
25  to  30  per  cent  C^,  the  remainder  being  mostly  of 
the  Cis  series  (102).  The  so-called  essential  fatty  acids 
(mainly  linoleic)  apparently  cannot  be  synthesized 
by  animals,  and  must  be  obtained  from  the  diet. 
The  depot  fat  of  certain  animals,  such  as  the  pig,  can 
be  varied  markedly  in  its  content  of  linoleic  acid, 
depending  on  the  feed  (60).  Similarly,  the  adipose 
tissue  fatty  acids  of  man  eventually  reflect  the  dietary 
fatty  acid  pattern.  This  is  true  with  respect  to  linoleic 
acid  (103);  but  the  medium  chain  fatty  acids  (C12 
and  below)  have  not  been  identified  in  the  fat  depots. 
Fats  of  vegetable  origin  vary  tremendously  in  their 
pattern  of  fatty  acids,  as  well  as  in  their  degree  of 
unsaturation.  For  instance,  coconut  oil  contains  only 
a  small  quantity  of  linoleic  acid,  while  safflower  oil 
may  contain  70  per  cent  or  more.  Dietary  fats  should 
not  be  described  merely  as  "animal  or  vegetable," 
"saturated  or  unsaturated,"  but  the  actual  composi- 
tion in  terms  of  fatty  acids  should  be  identified.  Thus, 
when  the  effects  of  dietary  fats  on  lipid  metabolism 
are  being  evaluated,  the  specific  fatty  acids  involved, 
their  chain  length,  isomeric  configuration,  degree  of 
unsaturation,  and  relative  proportion  in  the  diet 
must  be  considered. 

Dietary  phospholipids  are  found  as  complex  mix- 
tures in  organ  fats  and  certain  raw  vegetable  fats, 
rather  than  in  depot  fats.  Egg  yolk  is  a  rich  source  of 
phospholipid.  As  indicated  by  their  name  the  phos- 
pholipids area  group  of  phosphorus-containing  lipids; 
in  addition,  they  contain  a  nitrogenous  base.  The 
lecithins,  in  which  the  base  is  choline,  and  the  cepha- 
lins,  in  which  the  base  is  ethanolamine  or  serine,  are 
classified  as  mono-amino-phosphatides.  The  com- 
ponent fatty  acids  are  usually  both  saturated  and 
unsaturated.  The  inositol  phospholipid  contains 
ethanolamine  and  tartaric  acid.  It  is  found  in  soy- 
bean phospholipids  and  in  brain  tissue.  Other  phos- 
pholipids include  sphingomyelin,  which  is  a  diamino- 
phosphatide  containing  choline  and  sphingosine. 
Plasmalogens  contain  higher  fatty  aldehydes  and 
ethanolamine  (69).  The  complexity  of  dietary  phos- 
pholipids is  illustrated  by  their  occurrence  in  egg 
yolk:  72.8  mols  per  cent  phosphatidyl  choline;  14.8 
per  cent  phosphatidyl  ethanolamine;  2.1  per  cent 
lysophosphatidyl  ethanolamine;  5.8  per  cent  sphingo- 
myelin; 0.9  per  cent  plasmalogen;  0.6  per  cent  inositol 


phospholipid;  and  0.2  per  cent  phosphatidyl  amine 
acids  (169).  One  egg  contains  about  2  g  of  phos- 
pholipid. 

The  unsaponifiable  fraction  of  food  fats  consists  of 
sterols,  including;  cholesterol  (absent  from  vegetable 
fats),  long-chain  aliphatic  alcohols,  glycerol  ethers, 
pigments,  etc.  Finally  the  fat-soluble  vitamins,  A,  D, 
E,  and  K,  may  be  found  in  this  fraction. 


FAT    DIGESTION    AND    ABSORPTION 

Generally  speaking,  lipids  are  not  readily  miscible 
in  water.  To  be  able  to  absorb,  transport,  and  utilize 
fatty  acids  and  other  lipids,  man  has  had  to  evolve 
rather  elaborate  mechanisms  for  making  these  water- 
immiscible  or  hydrophobic  materials  compatible  with 
a  system  whose  basic  medium  is  water.  The  mech- 
anisms used  to  deal  with  the  water-insoluble  lipids 
as  they  enter  the  body  include  hydrolysis,  emulsifi- 
cation,  chemical  combinations  with  substances  con- 
taining hydrophilic  groups,  and  complex  formation 
with  substances  conferring  greater  water  miscibility 
and  dispersibility,  such  as  bile  acids  and  proteins. 

The  mechanisms  of  digestion  and  absorption  of 
dietary  fat  have  been  subjects  of  controversy  for  many 
decades.  An  early  theory  was  proposed  by  Pfluger 
(161)  who  described  dietary  fats  as  being  emulsified 
by  bile  salts  in  the  small  intestine.  The  triglycerides 
were  then  completely  hydrolyzed  by  pancreatic  lipase 
to  fatty  acids  and  soaps.  Being  water-soluble,  these 
products  were  readily  absorbed.  However,  it  soon 
became  apparent  that  intestinal  pH  is  too  low  for 
fatty  acids  to  exist  as  soaps.  It  also  became  apparent 
that  the  absorbed  fat  in  lymph  is  mainly  in  triglyceride 
form.  Thus,  glyceride  resynthesis  by  the  intestinal 
mucosa  was  postulated.  The  modern  concepts  of  fat 
absorption  arise  from  Frazer's  work  (67,  68).  It  is 
now  believed  that  hydrolysis  of  dietary  glycerides 
need  not  be  complete  in  order  for  absorption  to  occur. 

Frazer's  original  "partition  theory"  (66)  postulated 
that  fatty  acids  passed  directly  into  the  portal  circula- 
tion while  the  partial  and  unchanged  triglycerides 
were  somehow  transported  across  the  mucosa  into 
lymph  as  chylomicrons.  This  theory  has  failed  to 
survive  in  its  original  form  as  a  result  of  more  recent 
work  (16,  145)  including  Frazer's  own  (70).  Portal 
venous  transport  of  fat  is  now  known  to  occur  only 
with  fatty  acids  of  less  than  ten  carbons,  which  com- 
prise less  than  5  per  cent  of  dietary  fats. 

The  digestion  and  absorption  of  long-chain  fats 
remain   a   subject    of   controversy.    Frazer   (70)    has 


LIPID    METABOLISM 


11  73 


presented  evidence  that  finely  emulsified  fat  particles 
of  0.5  fx  or  less  in  diameter  can  penetrate  intact  the 
small  spaces  between  mucosal  "microvilli.''  More 
recently,  evidence  has  been  presented  that  hydrolysis 
of  triglycerides  in  the  intestinal  lumen  is  extensive  but 
incomplete,  and  that  approximately  65  per  cent  of 
the  fatty  acids  is  absorbed  in  the  free  form  while  35 
per  cent  passes  into  the  mucosa  as  glycerides  ( 1  7,  29). 
The  mucosal  cells  resynthesize  the  free  fatty  acids, 
the  monoglycerides,  and  diglycerides  into  triglycer- 
ides. Studies  (48,  49,  127)  have  indicated  that  in- 
testinal mucosal  synthesis  of  triglycerides  proceeds 
along  pathways  similar  to  those  defined  by  Kennedy 
and  his  associates  (206)  for  hepatic  triglyceride  syn- 
thesis. In  contrast  to  what  may  happen  in  the  liver, 
free  glycerol  does  not  appear  to  be  a  starting  material, 
although  quite  recently  evidence  for  free  glycerol 
incorporation  into  triglyceride  in  the  intestine  in  man 
has  been  reported  (107).  Free  fatty  acids  become 
activated  by  linkage  with  coenzyme  A.  Two  such 
activated  fatty  acids  combine  with  L-a-glycerophos- 
phate  to  form  diglyceride  phosphate  (phosphatidic 
acid)  which  can  then  form  diglyceride  following 
dephosphorylation  by  a  suitable  phosphatase.  The 
diglyceride  reacts  with  a  third  activated  fatty  acid 
to  yield  a  triglyceride,  or,  like  phosphatidic  acid, 
may  also  be  converted  to  phospholipid.  The  major 
pathway  is  that  of  triglyceride  synthesis.  A  small 
amount  of  phospholipid  and  cholesterol  gets  in- 
corporated with  the  triglycerides  into  the  "chylo- 
microns" which  range  in  diameter  from  350  A  to 
0.5  /u.  The  chylomicrons  are  subsequently  discharged 
into  the  intestinal  lacteals  from  which  they  drain  into 
the  thoracic  duct  and  ultimately  the  systemic  circula- 


tion. Studies  on  the  composition  of  chylomicrons  in 
man,  rat,  and  dog  (98,  160,  182)  have  shown  that 
they  consist  of  85  to  93  per  cent  triglyceride,  8  to  1 1 
per  cent  phospholipid,  1.5  to  4.5  per  cent  cholesterol 
(free  and  ester)  and  1.9  to  2.5  per  cent  protein  (|3- 
globulin).  Some  events  that  occur  during  fat  digestion 
and  absorption  are  summarized  in  figure  2. 


ADIPOSE    TISSUE 

The  concept  that  adipose  tissue  is  a  dynamic 
"organ"  capable  of  participating  in  a  number  of 
metabolic  processes  is  now  generally  accepted.  The 
effect  of  caloric  abundance  or  inadequacy  on  the 
quantity  of  stored  fat  is  well  recognized.  A  variety  of 
stimuli  are  known  to  induce  an  increase  or  a  decrease 
in  body  fat.  However,  the  mechanisms  involved  in 
fat  deposition  (lipogenesis)  and  fat  release  (lipolysis) 
are  not  completely  understood.  Most  body  fat  acts  as 
a  highly  efficient  caloric  reservoir.  However,  it  must 
be  remembered  that  this  reservoir  is  composed  of 
myriads  of  living  cells  the  function  of  which  includes 
svnthesis  and  mobilization  of  fat  as  well  as  storage. 

The  number  of  calories  stored  as  fat  is  necessarily 
a  function  of  two  variables,  energy  intake  and  energy 
expenditure.  A  normal  young  adult  man  in  caloric 
balance  may  contain  an  average  of  14  per  cent  pure 
fat  (116).  Thus  a  young  man  weighing  70  kg  may 
carry  approximately  10  kg  of  fat.  This  is  almost  two 
and  a  half  times  the  weight  of  his  bone  minerals. 
The  relative  amount  of  fat  in  the  body  has  been 
shown  to  increase  with  age  reaching,  at  age  55, 
approximately  25  per  cent  of  body  weight  in  clini- 


LUMEN 
TRIGLYCERIDE 


MUCOSA 


FATTY  ACID 


CHOLESTEROL 


CHOLESTEROL 
Esters  and  Ereel 


LYMPHATICS 


-CHYLOMICRONS* 

Triglyceride  89% 

Phospholipid  7% 

Cholesterol  2% 

Protein  2% 


fig.  2.  Schema  of  lipid  absorp- 
tion (long -chain  fats).  *  Propor- 
tions of  chylomicron  constituents 
vary  with  diet. 


1 1 74 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


cally  normal  men  (38).  In  obese  individuals  the 
amount  of  body  fat  may  reach  33  to  40  per  cent  of 
body  weight. 

During  the  past  twenty  years  there  has  been  an 
increasing  awareness  that  adipose  tissue  is  a  dynamic 
organ  capable  of  responding  to  a  variety  of  stimuli. 
The  experiments  of  Schoenheimer  ( 1 84)  and  others 
have  shown  that  depot  fat  has  a  definite  turnover.  Its 
half-life  in  the  rat  has  been  estimated  to  be  6  to  8 
days.  In  man,  turnover  of  depot  fat  is  much  slower, 
with  a  half-life  of  many  months,  in  the  presence  of 
adequate  caloric  intake.  When  the  availability  of 
carbohydrate  is  reduced,  depot  fat  cells  can  quickly 
mobilize  free  fatty  acids  which  are  then  bound  to 
albumin  and  carried  in  the  blood  to  muscle,  liver, 
and  other  tissues  (52,  84). 

The  relationship  between  the  availability  of  carbo- 
hydrate and  the  rate  at  which  fatty  acids  are  mobilized 
from  depot  fat  is  important.  Breakdown  of  glucose 
through  the  Embden-Myerhof  pathway  and  the 
hexosephosphate  shunt  may  provide  certain  cofactors 
necessary  for  fatty  acid  synthesis  (lipogenesis).  Insulin 
promotes  entry  of  glucose  into  the  cell  and  thereby 
provides  a  stimulus  for  further  metabolism  of  this 
hexose.  Fatty  acid  synthesis  appears  to  be  somehow 
dependent  on  the  rate  of  glycolysis.  In  diabetes  melli- 
tus  glycolysis  is  depressed  because  of  insulin  lack;  in 
addition,  the  rate  of  fatty  acid  synthesis  is  greatly 
suppressed.  At  the  same  time,  the  rate  of  hydrolysis 
of  depot  fat  increases,  and  the  resultant  fatty  acids 
are  carried  into  the  circulation  as  free  fatty  acids. 
For  example,  in  uncontrolled  diabetes,  enormous 
amounts  of  fat  can  be  mobilized,  leading  to  fatty 
liver,  hypertriglyceridemia,  and  hyperketonemia. 
Administration  of  insulin  corrects  the  situation  in  a 
manner  that  has  not  been  elucidated  (203),  but  prob- 
ably relates  to  the  ability  of  insulin  to  reduce  the  rate 
of  fatty  acid  mobilization  from  adipose  tissue. 

Hormonal  Influences  on  Adipose  Tissue 

In  addition  to  insulin,  several  other  hormones  have 
been  found  to  influence  lipid  mobilization.  It  is  em- 
phasized that  hormones  do  not  initiate  events  within 
cells,  but  merely  regulate  the  rate  at  which  some  of 
these  events  occur.  Early  studies  (148)  indicated 
that  when  large  doses  of  posterior  pituitary  extract 
were  injected  into  rats  or  rabbits  there  resulted  an 
accumulation  of  fat  in  the  liver.  Similarly,  an  increase 
in  liver  fat  and  a  decrease  of  carcass  fat  of  the  rat 
were  found  following  the  injection  of  anterior  pitui- 
tary extract   (19).   There  have   been   recent   reports 


that  a  posterior  pituitary  component,  a  relatively 
small  polypeptide,  has  a  potent  mobilizing  effect  on 
omental  and  mesenteric  fat  in  animals  and  man  (185, 
213).  As  yet  there  have  been  no  reports  on  the  influ- 
ence of  this  posterior  pituitary  material  on  mobiliza- 
tion of  free  fatty  acids  (95).  In  contrast,  it  was  found 
(177)  that  the  injection  into  rabbits  of  crude  extracts 
of  whole  or  anterior  pituitary  gland  of  hogs,  sheep, 
cattle,  or  man  induced  visible  lipemia  which  was  con- 
siderably greater  than  that  induced  by  recognized 
anterior  pituitary  hormones.  Thus  it  was  suggested 
that  the  lipemia-producing  principle  might  be  an 
independent  hormone,  or  that  the  lipemia  was  the 
result  of  synergistic  action  of  known  hormones,  al- 
though the  lipemia-producing  anterior  pituitary 
component  apparently  contains  negligible  or  un- 
detectable amounts  of  eight  known  pituitary  hormones 
(178).  Also,  following  injection  of  this  material  into 
rabbits,  there  was  a  rapid  and  enormous  (tenfold) 
increase  in  free  fatty  acid  levels.  This  was  followed 
within  12  hours  by  a  twofold  to  fivefold  increase  in 
serum  total  lipid  concentration,  including  significant 
increases  in  the  serum  levels  of  triglycerides,  choles- 
terol, and  phospholipid.  It  is  difficult  to  ascertain 
from  these  studies  whether  or  not  the  lipemia  that 
was  produced  was  mediated  through  another  gland, 
since  the  recipient  animals  were  neither  hypophy- 
sectomized  nor  adrenalectomized.  The  authors  have 
explained  their  results  by  postulating  that  the  active 
principle  mobilizes  free  fatty  acids  from  depot  fat. 
The  increase  in  triglyceride,  cholesterol,  and  phos- 
pholipid in  serum  is  believed  due  to  increased  rate  of 
formation  of  these  substances  in  the  liver,  in  response 
to  increased  hepatic  uptake  of  free  fatty  acids. 

The  possibility  that  there  may  be  two  new  factors 
capable  of  mobilizing  depot  fat,  one  from  the  anterior 
and  one  from  the  posterior  pituitary,  deserves  further 
exploration  and  confirmation  by  other  investigators. 

Of  the  known  pituitary  hormones,  growth  hormone 
has  been  shown  to  possess  free  fatty  acid-mobilizing 
properties  in  the  intact  organism  (168).  Growth  hor- 
mone action  on  depot  fat  (and  other  sites)  appears 
to  depend  upon  the  phylogenetic  relationship  of  the 
recipient  animal  to  the  donor  source.  For  example, 
beef  growth  hormone  mobilizes  fat  in  cattle  and  in 
the  rat  but  not  in  monkeys  or  human  subjects.  Knobil 
(125)  has  shown  that  the  administration  of  growth 
hormone  stimulates,  while  hypophysectomy  inhibits, 
free  fatty  acid  release  from  the  epidydimal  fat  body  of 
rats.  The  manner  in  which  growth  hormone  promotes 
free  fatty  acid  release  has  not  been  fully  elucidated. 

Adrenocorticotropic   hormone   (ACTH)    has   been 


found  to  be  very  active  in  inducing  free  fatty  acid 
release  from  adipose  tissue  in  vitro  (43,  61).  However, 
such  an  effect  is  not  readily  demonstrated  in  vivo. 
The  reason  for  this  discrepancy  is  not  clear,  although 
a  difference  in  species  response  to  ACTH  with  respect 
to  free  fatty  acid  release  has  been  offered  as  a  possible 
explanation  (61 ). 

The  role  of  thyroid  in  the  metabolism  of  depot  fat 
also  is  under  study.  The  lipolytic  response  of  adipose 
tissue  from  thyroidectomized  animals  (which  had 
been  suppressed)  was  made  normal  by  restoration  of 
the  euthyroid  state,  while  hyperthyroidism  accen- 
tuated such  a  response  (170).  Moreover,  it  has  been 
shown  that  the  treatment  of  hypothyroid  patients 
with  thyroid  restored  to  normal  their  free  fatty  acid 
response  to  growth  hormone  (167).  Thus  the  thyroid 
appears  to  play  a  permissive  role  in  fat  mobilization, 
potentiating   the   action   of  certain   lipolytic   agents. 

The  autonomic  nervous  system  was  long  suspected 
of  playing  an  important  part  in  the  metabolism  of 
depot  fat  (24,  207).  Early  observations  on  the  auto- 
nomic innervation  of  adipose  tissue  have  received 
support  from  more  recent  studies  on  the  action  of  epi- 
nephrine and  norepinephrine  on  depot  fat.  Subcu- 
taneous administration  or  intravenous  infusion  of 
epinephrine  and  norepinephrine  induced  significant 
elevations  of  free  fatty  acids  in  the  plasma  of  intact 
animals  and  human  subjects  (52,  80,  84).  Moreover, 
adipose  tissue  in  vitro  has  been  found  to  be  exquisitely 
sensitive  to  epinephrine  and  norepinephrine  in  terms 
of  free  fatty  acid  release  (27,  61,  137,  210).  It  has 
been  shown  that  adipose  tissue  liberates  glycerol  in 
response  to  epinephrine  and  norepinephrine  (61,  137) 
suggesting  that  the  mode  of  action  of  these  hormones 
on  adipose  tissue  involves  hydrolysis  of  triglyceride. 
An  epinephrine-sensitive  lipolytic  system  has  been 
reported  in  adipose  tissue  (172).  The  influence  on 
depot  fat  of  chronic  administration  of  epinephrine 
and  norepinephrine,  as  well  as  other  sympathomi- 
metic agents,  remains  unknown. 

The  various  factors  influencing  lipogenesis  and 
mobilization  of  fat  from  adipose  tissue  are  summarized 
in  figure  3. 

In  view  of  the  importance  of  the  subject  of  lipid 
mobilization  and  lipogenesis  in  the  scheme  of  knowl- 
edge about  metabolism,  it  is  surprising  that  investiga- 
tion in  this  area  has  lagged  until  recently.  Conceiv- 
ably, as  knowledge  of  the  subject  increases,  the 
physician  will  be  the  beneficiary  of  valuable  adjuncts 
in  the  treatment  of  lipid  disorders.  Thus,  adipose 
tissue,  once  thought  to  be  a  relatively  inert  storehouse 
of  dense  calories,  has  been  found  capable  of  partaking 


Glucose 


Insulin 


LIPID    METABOLISM 

Fatty  Acid  -  Albumin 


'I  75 


CO, 


-ACETYL  CoA 


GLUCOSE  0  -  P 
x-  Glycer 


FATTY  ACID -CoA 

Glycerol 


Fat 
Droplet 


Chylomicron 


fig.  3.  A  scheme  of  lipogenesis  and  lipolysis  in  the  adipose 
cell.  Free  fatty  acid  release  is  promoted  by:  glucose  lack, 
starvation,  insulin  lack,  epinephrine,  glucagon  (in  vitro), 
norepinephrine,  growth  hormone,  ACTH  (in  vitro),  thyroid 
hormone  (?  permissive),  and  certain  extracts  from  anterior 
and  posterior  pituitary  glands. 

actively  and  rapidly  in  a  number  of  metabolic  proc- 
esses and  of  responding  to  a  variety  of  humoral  and 
autonomic  stimuli. 


THE    SERUM    LIPIDS 

The  serum  lipids  can  be  broadly  classified  under 
two  major  headings:  the  lipoproteins  and  the  free 
(or  nonesterified)  fatty  acids  (FFA  or  NEFA).  The 
lipoproteins  represent  a  whole  spectrum  of  lipid  mole- 
cules containing  varying  proportions  of  phospholipid, 
cholesterol  (free  and  esterified),  protein  (polypeptide), 
glyceride,  and  water.  The  lipoproteins  have  been 
classified  according  to  their  behavior  in  the  ultra- 
centrifuge,  by  their  migratory  behavior  during  elec- 
trophoresis, by  their  principal  X-terminal  amino 
acid  residue,  by  their  solubility  characteristics,  and 
other  ways  (155,  194).  The  density  of  the  lipoprotein 
molecule  is  largely  a  function  of  the  proportion  of 
lipid  contained  within  it;  hence,  the  more  "obese" 
the  molecule,  the  lower  its  density. 

The  lipoprotein  species  with  the  lowest  density  are 
the  chylomicrons;  the  remaining  species  can  be  further 
divided  according  to  their  electrophoretic  migration 
with  alpha  globulins  and  beta  globulins  into  two 
groups,  the  lower  density  (beta)  lipoproteins  and  the 
higher  density  (alpha)  lipoproteins. 

The  free  fatty  acids  are  present  in  a  relatively  low 
concentration  in  plasma  under  basal  conditions 
(approximately  0.2  to  12.0  meq  liter).  However, 
they  appear  to  have  a  rapid  turnover  rate.  They 
travel  in  the  circulation  bound  to  albumin  and  per- 


176 


HANDBOOK    OF    PHYSIOLOOY 


CIRCULATION    II 


haps  to  other  substances,  and  consist  principally  of 
fatty  acids  common  in  the  diet,  such  as  palmitate, 
stearate,    oleate,    and    linoleate. 


Chylomicrons 

The  elaboration  of  chylomicrons  by  the  intestinal 
mucosa  has  been  discussed.  These  small  particles 
enter  the  systemic  circulation  via  the  intestinal  lac- 
teals  and  thoracic  duct.  The  chylomicrons  in  the 
blood  are  responsible  for  the  visible  lipemia  that 
occurs  after  a  meal  containing  an  appreciable  quan- 
tity of  fat.  Similar  (but  not  identical)  particles  manu- 
factured by  the  liver  seem  to  be  responsible  for  the 
lactescence  that  occurs  in  uncontrolled  diabetes, 
nephrosis,  and  carbohydrate-induced  hyperlipemia. 
From  an  analytical  standpoint,  chylomicrons  have 
been  characterized  as  the  material  floating  at  the  top 
of  a  tube  when  chyle  or  serum  is  layered  under  sa- 
line of  density  1  006  and  centrifuged  for  a  few  min- 
utes at  high  speed.  Varying  speeds  and  time  of  cen- 
trifugation  have  been  suggested,  but  it  is  assumed 
that  the  lower  the  speed  and  the  shorter  the  time 
of  centrifugation,  the  purer  will  be  the  chylomicron 
fraction  (71).  One  procedure  (135)  uses  9500  g  for 
10  min.  The  actual  density  of  chylomicrons  is  0.94  g 
per  ml. 

When  chylomicrons  are  released  into  the  systemic 
circulation  from  the  thoracic  duct,  they  are  removed 
with  considerable  rapidity  by  the  liver  and  extra- 
hepatic  tissues.  The  mechanisms  of  removal  are  in- 
completely understood;  however,  these  small  fat 
particles  apparently  are  not  hydrolyzed  to  any  appre- 
ciable degree  in  the  circulating  blood,  although  evi- 
dence for  intravascular  hydrolysis  has  been  pre- 
sented (62).  To  some  extent,  fatty  acids  may  be  split 
away  from  chylomicron  triglyceride  through  the 
intervention  of  the  enzyme,  lipoprotein  lipase,  but 
this  action  probably  occurs  primarily  at  endothelial 
surfaces  and  other  cell  membranes  and  not  in  the 
main  stream  of  the  circulation  (71). 

More  important  mechanisms  for  chylomicron 
removal  may  include  direct  diffusion  into  cells  through 
"pores,"  and  phagocytosis  by  appropriate  cells. 
When  the  subject  is  in  the  postabsorptive  state  and 
carbohydrate  no  longer  is  readily  available,  a  larger 
proportion  of  the  chylomicrons  from  a  test  meal  of 
fat  will  be  removed  by  liver  and  muscle;  when  excess 
carbohydrate  is  available  (that  is,  during  hyper- 
glycemia), the  chylomicrons  are  shunted  to  a  greater 
extent  to  the  fat  depots.  The  clearing  of  visible 
lipemia  after  ingestion  of  fat  may  be  inhibited  if  a 


previous  fat  load  has  been  given  and  has  recently 
been  cleared.  Although  a  large  amount  of  chylo- 
micron fatty  acid  is  directly  oxidized,  some  of  it  may 
recirculate  in  the  form  of  free  fatty  acid.  Thus,  a 
variable  rise  in  free  fatty  acids  occurs  in  blood  during 
the  course  of  an  alimentary  lipemia  (71,  72). 

The  Lipoproteins 

In  normal  human  plasma,  the  lipoproteins  consti- 
tute approximately  12  to  15  per  cent  of  the  total 
protein  (155).  A  fundamental  difference  between  the 
lipoproteins  and  the  remainder  of  the  plasma  pro- 
teins is  that  the  former  are  lipid-laden  molecules  with 
relatively  low  density.  The  plasma  lipoproteins  ex- 
hibit densities  from  0.9  to  1.2,  in  contrast  to  densities 
of  1.26  to  1.38  for  most  other  proteins.  Thus,  the 
ultracentrifuge  has  become  a  useful  tool  in  the  sepa- 
ration of  the  plasma  proteins  and  lipoproteins,  utiliz- 
ing measurement  of  the  differing  sedimentation  rates 
of  molecules  in  solvent  systems  of  known  density. 
Gofman  and  his  associates  (78,  79,  135)  have  used 
a  sodium  chloride  solution  with  a  density  of  1 .063  to 
differentiate  lipoproteins.  These  workers  have  also 
introduced  the  "Sf"  nomenclature  which  is  used  to 
describe  the  rates  of  flotation  (varying  Sf  values)  of 
the  various  lipoproteins  in  sodium  chloride  of  density 
of  1.063.  Such  rates  of  flotation  are  measured  in 
Svedberg  units  (Sf  unit,  io~13  cm  g  sec-1  dyne-1). 
Apparently  the  Sf  value  is  dependent  on  the  density, 
shape  and  size  of  the  lipoprotein  molecules  (155). 

A  plethora  of  terminology  relating  to  the  lipopro- 
teins has  evolved  depending  on  methods  of  isolation 
and  identification  (71,  78,  134).  The  subdivisions 
sometimes  have  been  rather  arbitrary,  yet  certain 
correlations  have  been  made  as,  for  example,  be- 
tween the  ultracentrifugal  and  electrophoretic 
behavior  of  the  lipoproteins.  It  has  been  demon- 
strated that  there  are  two  major  groups  of  lipopro- 
teins (three  if  chylomicrons  are  included)  in  human 
plasma:  /)  high-density  lipoproteins  (density  >  1.063), 
or  a-lipoprotein  by  virtue  of  their  electrophoretic 
mobility;  2)  low-density  (<  1.063)  or /3-lipoproteins. 
The  latter  (<  1.063)  include  the  classes  Sf  0-400  of 
Gofman  (78).  The  chylomicrons  (density  0.94;  see 
above)  have  virtually  no  electrophoretic  mobility, 
but  exhibit  no  definite  line  of  demarcation  from  the 
Sf  400  low-density  lipoproteins,  and  their  Sf  value 
may  reach  40,000.  Studies  of  the  protein  moiety  of 
the  lipoproteins  have  yielded  information  which 
may  further  help  characterize  the  ultracentrifugally 
separated    fractions.    Information    is    available    (71) 


LIPID    METABOLISM 


■77 


with  respect  to  molecular  weight,  end  group  analyses 
for  specific  peptide  chains,  amount  and  type  of  N — 
and  C —  terminal  amino  acids,  etc.  Such  information 
remains  preliminary  in  nature.  A  schematic  concep- 
tion of  the  various  human  plasma  lipoproteins  is 
shown  in  figure  4. 

The  lipid  moieties  of  the  various  lipoproteins  (other 
than  chylomicrons)  may  comprise  from  40  to  (per- 
haps) 90  per  cent  of  the  molecule.  These  include  a 
small  amount  of  free  fatty  acids,  and  virtually  all  the 
esterified  fatty  acids  as  esters  of  glycerol  or  more 
complex  alcohols,  and  cholesterol.  Free  cholesterol 
also  is  present.  Normal  human  postabsorptive  plasma 
contains  approximately  400  mg  per  100  ml  esterified 
fatty  acids.  Approximately  70  per  cent  of  such  fatty 
acids  exist  as  triglycerides  and  phospholipids,  and 
the  remainder  as  cholesterol  esters  (141).  Small 
amounts  of  esterified  fatty  acids  may  be  found  as 
diglycerides  and  monoglycerides,  cerebrosides  and 
acetals  (71). 

Despite  the  high  proportion  of  lipid  in  the  lipo- 
proteins, they  have  the  chemical  and  physical  char- 
acteristics of  protein  molecules.  Such  behavior  sug- 
gests that  the  protein  moiety  is  on  the  surface  of  the 
molecule.  For  instance,  it  has  been  estimated  (35) 
that  a  chylomicron  of  0.5  ju  may  be  covered  com- 
pletely by  protein,  assuming  the  protein  to  be  all  at 
the  surface  and  constituting   1.5  per  cent  of  chylo- 


micron. However,  it  has  been  pointed  out  that  in  the 
larger  ^-lipoprotein  there  is  only  enough  protein  to 
cover  about  half  the  surface,  assuming  a  thickness  of 
one  peptide  chain.  On  the  basis  of  titration  data, 
Oncley  el  at.  (154)  have  postulated  a  kind  of  mosaic 
surface  comprising  both  peptide  and  phospholipids, 
the  latter  being  oriented  with  their  charged  groups 
at  the  surface. 

Under  ordinary  circumstances,  the  alpha  lipopro- 
teins, or  high-density  lipoproteins,  probably  do  not 
transport  triglyceride  for  oxidative  purposes.  Recent 
studies  (176)  with  labeled  amino  acids  have  suggested 
that  the  plasma  does  not  contribute  a  major  portion  of 
the  protein  found  in  either  the  chylomicrons  or  the 
high-density  lipoproteins  in  thoracic  lymph.  Since  the 
cells  of  the  intestinal  mucosa  incorporate  amino  acids 
into  proteins  having  the  same  electrophoretic  mobility 
as  chylomicron  protein,  it  was  theorized  that  the  in- 
testine may  be  the  source  of  the  protein  of  both  the 
high-density  (alpha)  lipoproteins  and  the  chylo- 
microns. 

The  alpha  lipoproteins  contain  approximately  40 
per  cent  lipid;  are  not  remarkably  influenced  by  diet 
or  fasting  and  do  not  increase  with  age.  In  terms  of 
blood  level,  they  are  relatively  stable. 

In  contrast,  the  low-density  (beta)  lipoproteins, 
which  contain  75  per  cent  or  more  lipid,  are  labile; 
they  are  affected  by  diet,  fasting,  age   and   gonadal 


DENSITY 


40,000 


LIPOPROTEIN    SPECIES 


PRINCIPAL 

N-TERMINAL  AMINO 

ACID    RESIDUE 


fig.  4.  Schematic  conception  of 
human  lipoproteins.  Cross-hatching  or 
stippling  represents  polypeptide  portions 
of  the  molecules.  [From  Frederickson 
&  Gordon  (71).] 


1 1 78 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


hormones,  and  by  a  variety  of  other  influences.  In 
fasting  states  and  when  carbohydrate  utilization  is  de- 
creased, serum  levels  of  these  low-density  lipoproteins 
tend  to  increase;  however,  appreciable  rises  in  concen- 
tration of  such  molecules  occur  only  after  the  fast  has 
been  sustained.  Ordinarily,  such  a  rise  in  circulating 
beta  lipoproteins  is  preceded  by  an  increase  in  plasma 
levels  of  free  fatty  acids. 

There  is  some  evidence  that  lipoprotein  interconver- 
sions  occur  and  that,  as  fatty  acids  are  split  off  a  low- 
density  lipoprotein  molecule,  its  density  progressively 
increases.  When  heparin  is  administered,  thereby  stim- 
ulating lipoprotein  lipase  activity,  the  interconversion 
process  is  greatly  accelerated  (62). 

Free  Fatty  Acids 

The  free  fatty  acids  comprise  less  than  10  per  cent 
of  the  total  fatty  acids  found  in  plasma.  Strictly  speak- 
ing, these  acids  are  not  "free"  since  they  circulate 
bound  to  albumin.  Each  molecule  of  albumin  can 
bind  two  or  more  molecules  of  long-chain  fatty 
acid  (83). 

The  free  fatty  acids  represent  one  important  form  in 
which  fatty  acids  are  transported  from  sites  of  storage 
(fat  depots)  to  working  cells  (see  above).  They  do  not 
appear  to  derive  directly  from  dietary  fat.  However, 
dietary  fatty  acids  with  chain  lengths  of  C10  or  less,  a 
very  small  fraction  of  fat  in  the  diet,  may  enter  the 
circulation  from  the  gut  via  the  portal  vein  in  the 
"free"  form  (28),  although  their  esterification  with 
glycerol  by  the  intestinal  mucosa  may  also  occur  (160). 
Actually,  the  level  of  circulating  free  fatty  acids  falls 
after  a  normal  meal.  On  the  other  hand,  during  the 
course  of  clearing  of  alimentary  lipemia,  a  variable 
fraction  of  the  circulating  free  fatty  acids  may  originate 
from  chylomicron  triglyceride  (71). 

Studies  of  the  distribution  of  C14-labeled  palmitate 
(bound  to  albumin)  in  rats  15  min  after  intravenous 
injection  have  disclosed  a  general  uptake  of  the  label 
by  various  organs  and  by  muscle.  Liver  lipids  were 
particularly  active,  whereas  adipose  tissue  had  no 
detectable  activity  (53).  If  such  experiments  can  be 
considered  representative  of  the  behavior  of  free  fatty 
acids  under  normal  circumstances,  it  would  seem  that 
the  plasma  free  fatty  acids  are  removed  rapidly  in 
various  parts  of  the  body,  with  subsequent  oxidation 
or  esterification,  depending  upon  metabolic  circum- 
stances. 

There  is  growing  evidence  that  the  free  fatty  acids 
constitute  an  important  source  of  the  body's  energy 
in  the  fasting  state;  they  are  released  in  increasing 


amounts  by  the  adipose  tissue  and  used  very  rapidly 
at  times  when  carbohydrate  utilization  is  diminished 
(52).  Experimentally  induced  elevation  of  the  blood 
sugar  or  of  blood  amino  acids  (94)  results  in  a  recipro- 
cal drop  in  plasma  levels  of  free  fatty  acids. 

Calculations  suggest  that  the  circulating  free  fatty 
acids  probably  do  not  supply  more  than  50  per  cent 
of  the  energy  in  the  fasting  state;  hence,  it  may  be 
suspected  that  another  important  source  of  energy 
during  fasting  is  esterified  fatty  acid  (71).  Isotope 
studies  have  shown  that  the  fatty  acid  turnover  is  much 
more  rapid  in  triglyceride  than  in  cholesteryl  ester 
and  phospholipid  (13).  Thus,  the  serum  glycerides 
may  well  function  as  a  major  vehicle  for  transport  of 
esterified  fatty  acid  to  sites  of  utilization. 

Ordinarily,  in  the  postabsorptive  state,  triglyceride 
moieties  travel  in  the  blood  as  parts  of  low-density 
lipoprotein  molecules  that  are  neither  large  nor  nu- 
merous enough  to  affect  the  gross  clarity  of  the  serum. 
However,  under  conditions  of  metabolic  stress,  and  in 
certain  disorders,  lipoproteins  of  very  low  density 
appear  in  the  circulation  in  quantities  sufficient  to 
render  the  plasma  lactescent.  It  is  unlikely  that  such 
particles  can  be  released  directly  from  the  fat  depots 
and  evidence  is  accumulating  that  they  originate  from 
the  liver. 

Role  of  the  Liver 

The  liver  plays  a  major  role  in  the  synthesis  and 
disposal  of  lipids  and  lipoproteins.  With  the  exception 
of  the  chylomicrons,  it  appears  that  lipoprotein 
manufacture  takes  place  principally,  if  not  exclu- 
sively, in  the  liver.  The  various  factors  that  influence 
hepatic  synthesis  of  lipoproteins  are  not  well  under- 
stood. The  process  whereby  the  intestinal  mucosa 
handles  dietary  fats  and  transforms  them  into  chylo- 
microns, some  of  which  are  removed  by  the  liver,  has 
been  discussed  already.  Adipose  tissue  releases  fat  in 
the  form  of  free  fatty  acids  "bound"  to  albumin.  These 
acids  also  are  extracted  in  appreciable  quantities  by 
the  liver.  Carbohydrate  and  protein  can  be  converted 
into  fat  by  the  liver.  In  short,  the  liver  is  presented 
with  lipid  from  several  sources,  and  can  itself  synthe- 
size lipid,  including  cholesterol  and  phospholipid. 
Thus,  the  lipoproteins  that  the  liver  manufactures 
and  sends  out  to  the  circulation  are  made  from  a 
variety  of  building  blocks  and  are  subject  to  a  variety 
of  metabolic  influences  including  diet  and  hormones. 
These  concepts  concerning  the  origin  of  serum  lipids 
are  shown  in  schematic  form  in  figure  5.  In  the  case 
of  certain  lipids,  such  as  cholesterol,  the  liver  is  the 


LIPID    METABOLISM 


'79 


V,   A    T/    0 


FFA 
CHYLOMICRONS 
CARBOHYORATE 


fig.  5.   Origins      of     serum      lipids. 
[From  Van   Itallie   &   Felch   (201).] 


major  organ  of  catabolism  and  excretion.  Elaborate 
mechanisms  exist  in  the  liver  for  disposal  of  the 
steroid  nucleus  of  cholesterol,  since  the  body  lacks 
the  mechanisms  capable  of  opening  the  rings  of 
phenanthrene-like  structure. 

Cholesterol  Disposal 

As  mentioned  above,  cholesterol  represents  a  spe- 
cial disposal  problem.  Fatty  acids  and  glycerol  are 
readily  metabolized,  and  phospholipids  are  freely 
miscible  with  water  and  can  be  degraded  rapidly.  On 
the  other  hand,  although  the  isopropyl  side  chain  of 
the  cholesterol  molecule  can  be  oxidized,  with  forma- 
tion of  bile  acids  and  certain  hormones,  the  steroid 
nucleus  itself  is  not  degraded. 

It  is  now  established  that  bile  acids  constitute  the 
major  catabolic  end  products  of  cholesterol  metabo- 
lism in  man  and  in  a  variety  of  animal  species  (17,  18, 
97).  In  man,  conversion  of  cholesterol  to  bile  acids  oc- 
curs in  the  liver.  The  biochemical  details  of  this  con- 
version have  not  been  completely  worked  out.  It  is 
generally  agreed  that  in  man  two  '"primary"  bile 
acids  (hydroxycholanic  acids)  result  from  catabolism 
of  cholesterol  in  the  liver:  cholic  acid  and  chenodeoxy- 
cholic  acid  (fig.  6).  Five  important  biochemical 
changes  must  occur  in  the  cholesterol  molecule,  and 
not  necessarily  in  the  order  listed :  a)  isomerization  of 
the  3  /J-OH  into  3  a-OH;  b)    saturation  of  the  5:6 


double  bond;  c)  hydroxylation  at  the  7  position 
(chenodeoxycholic)  d)  hydroxylation  at  both  7  and 
1 2  positions  (cholic) ;  and  e)  oxidation  of  the  terminal 
isopropyl  group  resulting  in  a  C-24  acid  (cholanic). 
The  resultant  bile  acids  are  secreted  into  the  extra- 
hepatic  biliary  system  as  micellar  conjugated  com- 
pounds with  either  glycine  or  taurine.  In  man  the  con- 
jugation process  favors  glycine  by  a  factor  of  three 
(18).  In  the  intestine  the  bile  acids  may  undergo  fur- 
ther chemical  transformations  attributed  to  intestinal 
microorganisms,  giving  rise  to  "secondary"  bile  acids. 
For  example,  cholic  acid  will  lose  its  7  a-OH  group  to 
yield  deoxycholic  (3a,  i2a-hydroxycholanic)  acid,  and 
in  a  similar  manner  chenodeoxycholic  acid  will  yield 
lithocholic  (3  a-hydrOxycholanic)  acid.  Thus  the 
7  a-dehydroxylation  is  a  bacterial  function.  A  number 
of  additional  bacterial  metabolites  of  hepatic  bile  acids 
have  been  found  in  human  feces,  although  their  impor- 
tance quantitatively  has  not  been  determined  (in). 
In  addition,  the  bacteria  split  the  conjugated  com- 
pounds into  glycine,  taurine  and  their  corresponding 
bile  acids.  Most  of  the  bile  acids  are  reabsorbed  from 
the  intestine  into  the  liver  via  the  portal  vein.  A  small 
portion  is  excreted  in  the  stool  in  unconjugated  form. 
In  the  normal  gastrointestinal  tract  virtually  no 
cholic  acid  can  be  identified  in  the  feces. 

It  has  been  estimated  that  the  normal  adult  indi- 
vidual synthesizes  about  1.2  g  of  cholesterol  per  day. 
Approximately  70  per  cent  of  this  amount  (0.8  g)  is 


Il8o  HANDBOOK    OF    PHYSIOLOGY  —  CIRCULATION    II 


HO     \"^  ^"-""^     OH 

CHENODEOXYCHOLIC   ACID 

I 
INTESTINAL 
BACTERIA 


OH 

CHOLIC    ACID 

I 
INTESTINAL 
BACTERIA 

* 

OH 


COOH 


LITHOCHOLIC    ACID 
I 


DEOXYCHOLIC    ACID 


C-NH-CH2-C00H   (GLYCINE  CONJUGATES) 
■NHCH,-CH,-SO,OH  (TAURINE       '  ) 


I      CONJUGATION    IN    LIVER 

fig.  6.  Formation  of  "primary"  and  "secondary"  bile  acids 
in  man.  (From  Van  Itallie  &  Hashim,  M.  Clin.  North  America. 
In  press.) 

excreted  as  bile  acids,  and  a  portion  of  the  remainder 
is  excreted  in  the  feces  as  cholesterol,  coprostanol, 
cholestanol,  and  other  nonacidic  sterols.  The  newly 
formed  bile  acids  are  excreted  into  the  small  intestine 
and  participate  in  an  enterohepatic  cycle  through 
which  20  to  30  g  of  bile  acids  circulate  per  day 
(fig.  7).  The  net  loss  of  bile  acids  in  the  feces  nor- 
mally corresponds  to  the  amount  converted  from 
cholesterol  in  the  liver. 

That  bile  acids  are  the  major  catabolic  products  of 
cholesterol  has  been  suspected  for  about  a  century. 
However,  this  fact  was  clearly  established  in  1943  by 
Bloch  et  al.  (26)  who  demonstrated  that,  when  choles- 
terol labeled  with  deuterium  was  administered  to 
dogs,  a  minimum  of  two-thirds  of  the  label  appeared 
in  the  excreted  bile  acids.  These  observations  have 
now  been  amply  confirmed  by  studies  involving  use 
of  C'Mabeled  cholesterol,  notably  by  Siperstein  et  al. 
(191,  192),  Bergstrom  et  al.  (17,  18),  and  others. 

The  behavior  of  the  enterohepatic  cycle  of  bile 
acids  profoundly  affects  the  rate  of  cholesterol  con- 
version to  bile  acids.  This  rate  in  turn  appears  to 
influence  plasma  cholesterol  concentration.  Rats  with 


approx  0.8gm/day 
in  feces 

fig.  7.   Enterohepatic   cycle   of  bile   acids.    [Adapted    from 
Bergstrom  (18).] 

indwelling  cannulae  in  the  common  bile  duct  exhibit 
a  10-fold  to  15-fold  increase  in  bile  acid  output 
through  the  externalized  cannulae  compared  with 
the  fecal  bile  acid  output  of  intact  rats  (18).  This  also 
has  been  observed  clinically  in  patients  with  common 
duct  intubation.  Conversely,  in  animals  with  experi- 
mental ligation  of  the  common  duct  (41),  and  in 
patients  with  cholestasis  (202),  the  rate  of  conversion 
of  cholesterol  to  bile  acids  decreases.  Moreover,  in 
such  situations  cholesterol  synthesis  actually  may 
increase,  sometimes  with  marked  elevation  of  serum 
cholesterol. 


FACTORS  THAT   INFLUENCE   SERUM    LIPIDS 

Serum  lipid  levels  result  from  a  complex  interaction 
between  host  and  environment  (157).  Genetic  dis- 
orders such  as  familial  hypercholesteremia  and  essen- 
tial hyperlipemia  are  associated  with  gross  abnormali- 
ties of  serum  lipids.  Among  the  environmental  factors, 
diet  and  "stress"  have  attracted  particular  attention. 
Certain  diseases  also  have  conditioning  effects  on 
serum  lipids.  Included  in  this  category  are  nephrosis, 
hypothyroidism,  biliary  cirrhosis,  diabetes  mellitus, 
pancreatitis,  and  others.  In  addition,  such  factors 
as  age,  sex,  race,  culture,  occupation,  exercise,  body 
composition,     and     cigarette     smoking     have     been 


LIPID    METABOLISM 


1 1 81 


regarded   by  investigators  as  capable  of  exerting  a 
significant  influence  on  serum  lipids. 

It  is  much  simpler  to  speak  of  ■"abnormalities"  in 
serum  lipids  than  to  define  what  is  ''normal."  The 
difficulty  has  arisen  because  of  a  discrepancy  between 
what  is  statistically  normal  and  what  is  probably 
physiologically  desirable.  Many  authorities  now 
believe  that  statistical  means  for  serum  total  choles- 
terol in  a  population  (like  that  of  the  United  States) 
that  is  beset  with  cases  of  atherosclerosis,  clinical  and 
subclinical,  may  be  misleading  if  they  are  used  as 
criteria  of  biologic  normality.  For  example,  in  popula- 
tion groups  in  which  clinically  manifest  athero- 
sclerosis is  very  rare,  the  mean  serum  total  cholesterol 
is  frequently  at  least  30  per  cent  lower  than  it  is  in 
the  United  States  (118). 

Stress 

Despite  many  attempts  to  characterize  "stress," 
this  phenomenon  remains  to  be  defined  in  generally 
acceptable  terms  and  its  physiologic  effects  codified. 
The  "epidemiology"  of  stress  is  exceedingly  complex. 
The  response  of  the  individual  to  his  environment 
seems  to  be  much  more  critical  than  the  events 
overtly  taking  place  in  the  environment.  Hence,  it  is 
difficult  to  assess  the  degree  of  stress  inherent  in  a 
given  occupation  unless  one  also  knows  how  the 
individual  is  reacting  to  the  "life  situation"  with 
which  he  is  confronted.  For  these  and  other  reasons 
the  effect  of  stress  on  serum  lipids  remains  contro- 
versial (11,  179).  It  has  been  reported  that  students 
displav  a  transient  elevation  of  the  serum  cholesterol 
level  immediately  prior  to  important  examinations 
(197)  and  that  accountants  exhibit  similar  elevations 
when  deluged  with  income  tax  returns  (73).  Even  if 
it  is  granted  that  such  changes  occur,  it  is  not  yet 
known  whether  the  lipid  elevations  result  principally 
from  direct  neurohumoral  stimulation  or  because  of 
some  associated  change  in  the  habits  of  the  person 
concerned.  For  example,  it  is  well  known  that  under 
stress,  activity  rates  may  change  and  certain  persons 
may  eat  more  or  otherwise  change  their  pattern  of 
living. 

There  is  some  evidence  that  a  certain  type  of  "per- 
sonality profile"  is  associated  with  predisposition  to 
coronary  heart  disease  and  that  patients  with  such  a 
profile  secrete  significantly  more  epinephrine  and 
norepinephrine  than  control  subjects  (74,  75,  147). 
The  coronary-prone  individual  is  characterized  as 
exhibiting  excessive,  frankly  competitive  drive  and  an 
enhanced  sense  of  time  urgency   (42).   In  addition, 


this  type  of  individual  may  display  a  rapid,  frequent, 
forced,  audible  inspiration,  tense  facial  and  body 
musculature,  frequent  fist  clenching  and  a  propensity 
for  hastening  the  pace  of  conversation.  Such  individ- 
uals have  been  found  to  have  higher  serum  cholesterol 
and  increased  urinary  excretion  of  vanillyl  mandelic 
acid  than  those  exhibiting  the  converse  of  this  be- 
havior pattern.  Vanillyl  mandelic  acid  (VMA)  con- 
stitutes about  75  per  cent  of  the  metabolic  end 
products  of  norepinephrine  and  epinephrine.  It  has 
already  been  mentioned  that  these  catecholamines 
stimulate  mobilization  of  free  fatty  acids  from  adipose 
tissue.  Chronic  administration  of  epinephrine  (187) 
has  been  found  capable  of  inducing  a  rise  in  serum 
cholesterol  and  phospholipids.  Presumably  this  effect 
is  secondary  to  fatty  acid  mobilization  from  adipose 
tissue.  It  is  too  early  to  draw  any  conclusions  from 
attempts  to  relate  coronary  proneness  to  behavior 
pattern  and  catecholamine  excretion  rate. 

Sex 

Surveys  have  shown  that  American  females  be- 
tween 20  and  50  years  of  age  have  significantly  lower 
levels  of  serum  total  cholesterol  and  low-density  lipo- 
proteins than  age-matched  American  males  (i2g). 
It  is  obvious  that  the  mode  of  life  of  females  usually 
differs  from  that  of  males  in  a  given  culture,  and  the 
effect  of  such  a  differing  pattern  of  activity  upon  serum 
lipids  and  susceptibility  to  coronary  heart  disease  is 
difficult  to  assess.  Nevertheless,  a  number  of  studies 
have  suggested  that  the  endocrine  differences  between 
male  and  female  can  adequately  account  for  the  fact 
that  during  their  reproductive  period,  women  have 
lower  levels  of  certain  serum  lipids.  In  general,  ad- 
ministration of  androgenic  hormones  to  patients  is 
associated  with  a  rise  in  concentration  of  /3-lipopro- 
teins,  while  estrogenic  hormones  induce  a  fall  in  this 
same   lipoprotein    fraction    (58,    59). 

Whether  such  differences  in  lipid  levels  can  account 
for  the  established  disparity  in  susceptibility  to  coro- 
nary-artery disease  between  men  and  women  remains 
to  be  proved.  However,  supporting  evidence  is  to  be 
found  in  the  fact  that  women  who  have  undergone 
oophorectomy  have  "male"  serum  lipids  and  an 
increased  incidence  of  coronary-artery  disease  (212), 
and  that  men  treated  with  estrogen  for  prostatic 
carcinoma  have  "female"  lipids  and  less  than  the 
expected  degree  of  atherosclerosis  (173).  A  recent 
report  from  Edinburgh  (151)  has  revealed  that,  over 
a  five-year  period,  one  hundred  men  who  had  recov- 
ered from  a  myocardial   infarction,   and  who  were 


1 1 82 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


treated  with  estrogen  daily,  showed  appreciable  lower- 
ing of  their  serum  cholesterol  levels  without  a  sig- 
nificant effect  on  their  death  rate,  compared  with  a 
comparable  untreated  control  group.  The  apparent 
lack  of  protection  may  have  been  related  to  the  choice 
of  subjects  who  already  had  experienced  myocardial 
infarction. 


Dietary  Fatty  Acids 

It  is  now  established  that  diet  can  have  a  profound 
influence  on  serum  lipids;  indeed,  the  relation  of  diet 
to  serum  lipids  has  been  under  intensive  study  in 
recent  years.  More  information  is  available  concern- 
ing the  influence  of  dietary  fat  on  serum  lipids  than 
about  the  effect  on  serum  lipids  of  other  dietary  con- 
stituents. Not  long  ago,  it  was  believed  that  the  total 
quantity  of  fat  in  the  diet  was  the  major  factor  affect- 
ing serum  lipids  (117).  In  particular,  the  American 
diet  providing  40  to  45  per  cent  of  its  calories  as  fat 
was  implicated  as  being  responsible  for  the  relatively 
high  serum  cholesterol  values  observed  in  adults  in 
the  United  States.  It  is  now  clear  that  the  "quality" 
of  the  fat  in  the  diet  is  of  primary  importance  in 
determining  the  response  of  the  serum  cholesterol 
fraction,  although  the  relative  proportions  of  carbo- 
hydrate and  fat  in  the  diet  appear  to  influence  the 
serum  triglyceride  concentration.  It  is  of  interest  to 
review  briefly  some  of  the  events  that  have  led  to 
these  conclusions. 

In  1933  Schoenheimer  (183)  reported  that  feeding 
a  wholly  vegetarian  diet  to  a  patient  with  hyper- 
cholesteremia resulted  in  marked  lowering  of  serum 
cholesterol.  During  the  ensuing  two  decades,  rela- 
tively little  further  information  of  this  kind  was  gath- 
ered. Extensive  studies  regarding  the  metabolism  of 
cholesterol  and  other  lipids  were  undertaken  during 
this  time  and  significant  discoveries  were  made.  It  was 
found  that  cholesterol  is  readily  synthesized  in  the 
body  from  small  carbon  fragments  (171),  and  that 
the  major  catabolic  pathway  for  cholesterol  involves 
conversion  to  bile  acids  (26). 

In  1952,  Groen  and  associates  (87)  demonstrated 
by  means  of  well-controlled  and  prolonged  experi- 
ments that  substitution  of  vegetable  for  animal  fats 
in  the  diet  can  lower  serum  cholesterol  in  man,  even 
if  the  total  fat  content  remains  unchanged.  During 
the  same  year  Kinsell  and  associates  (122)  reported 
that  ingestion  of  diets  containing  relatively  large 
amounts  of  vegetable  fat  consistently  resulted  in  a 
significant  fall  in  the  level  of  serum  cholesterol  and 


phospholipids  in  human  subjects.  These  observations 
have  been  amply  confirmed  (2,  3,  22,  36,  123,  140). 

It  soon  became  apparent  that  the  fatty  acid  com- 
position of  dietary  fat  was  of  primary  importance  in 
determining  serum  cholesterol  response.  The  experi- 
ments in  which  vegetable  oils  were  used  stimulated 
interest  in  the  possible  role  of  the  essential  fatty  acids. 
Subsequently,  Kinsell  and  associates  (124)  concluded 
that  the  major  cholesterol-lowering  ingredient  in 
various  vegetable  fats  was,  in  fact,  linoleic  acid.  Then, 
in  a  series  of  well-controlled  comparative  experiments 
in  man,  utilizing  formula  diets  deriving  40  per  cent  of 
their  calories  from  fat,  Ahrens  et  at.  (4)  observed  that 
the  effects  on  serum  cholesterol  of  various  edible  fats 
could  be  related  to  their  iodine  value.  Thus,  fats  with 
high  iodine  values  such  as  safflower,  corn,  and  cotton- 
seed oils  proved  to  be  relatively  hypocholesteremic, 
while  fats  with  low  iodine  values  such  as  palm  oil, 
beef,  butter,  cocoa  butter,  and  coconut  oil  tended  to 
raise  the  serum  cholesterol  level.  Intermediate  or 
neutral  effects  on  serum  cholesterol  were  obtained 
with  fats  with  intermediate  iodine  values  such  as 
peanut  and  olive  oils.  In  a  later  study  (5)  the  Rocke- 
feller group  found  that  menhaden  oil,  a  fat  virtually 
free  of  linoleic  acid  and  yet  with  an  extremely  high 
iodine  value  (I,  number  180)  was  at  least  as  effective 
as  corn  oil  in  lowering  serum  cholesterol.  Keys  and 
associates  (120)  have  proposed  a  formula  designed  to 
predict  the  effect  of  a  given  pattern  of  dietary  fatty 
acids  on  serum  cholesterol  in  man.  The  formula  at- 
tempts to  take  into  account  the  different  roles  of  the 
saturated,  monounsaturated,  and  polyunsaturated 
fatty  acids  in  the  diet;  however,  it  remains  to  be 
demonstrated  that  such  an  analysis  can  be  applied 
successfully  in  a  variety  of  dietary  situations  (4). 

In  any  event,  it  is  clear  that  serum  levels  of  choles- 
terol and  low-density  lipoproteins  can  be  changed 
significantly  when  the  pattern  of  fatty  acids  in  the 
diet  is  rearranged.  When  the  glycerides  of  a  dietary 
fat  contain  predominantly  saturated  long-chain  fatty 
acids,  concentrations  of  serum  total  cholesterol  and 
certain  low-density  lipoproteins  tend  to  rise.  When 
such  dietary  glycerides  contain  an  appreciable  pro- 
portion of  polyunsaturated  fatty  acids  (whether  essen- 
tial or  not),  serum  cholesterol,  and  low-density  lipo- 
proteins tend  to  decrease.  The  degree  of  change  in 
serum  lipids  seems  to  depend  upon  the  magnitude 
of  change  in  the  pattern  of  the  fatty  acids  in  the  diet. 
Thus,  it  may  be  necessary  to  double  or  triple  the 
polyunsaturated  fatty  acid  content  of  the  diet  (with- 
out change  in  the  total  fat  intake)  to  induce  an  appre- 
ciable lowering  of  serum  cholesterol.  However,  even 


LIPID    METABOLISM 


I  l83 


when   such   drastic   changes  are   made   in   the   diet, 
variations  in  individual  responses  are  great  (113). 

Essential  Fatty  Acid  (EFA)  "Deficiency" 

The  fact  that  serum  lipids  can  be  lowered,  when 
dietary  fats  rich  in  polyunsaturated  fatty  acids  are 
fed,  has  stimulated  considerable  interest  in  the  bio- 
chemistry of  the  essential  fatty  acids  (linoleate, 
arachidonate,  etc.),  their  role  in  nutrition,  and,  in 
particular,  their  possible  role  in  the  metabolism  of 
cholesterol.  Excellent  reviews  and  discussions  of  these 
subjects  are  available  (1,  51,  106,  146,  189).  Holman 
(106)  has  suggested  that  the  term  essential  fatty  acid 
(EFA)  include  "only  those  substances  which  are 
active  both  for  growth  and  for  maintenance  of  dermal 
integrity,  limiting  the  term  to  linoleic  and  arachidonic 
acids  and  to  such  other  acids  as  may  be  derived 
metabolically  from  them."  As  has  been  pointed  out 
by  Aaes-Jorgensen  (1),  this  definition  leaves  out  lino- 
lenic  acid  and  C22  polyenoic  acids  from  brain  phos- 
phatides which  have  been  shown  by  Thomasson  (50, 
198)  to  be  active  only  as  growth  factors. 

Despite  numerous  studies  since  1929,  when  Burr 
&  Burr  (40)  first  recognized  EFA  deficiencv  in 
young  rats,  the  EFA  requirement  for  human  adults 
has  not  been  determined.  In  fact,  EFA  deficiency  in 
adult  man  has  not  been  demonstrated.  In  1958,  the 
Food  and  Nutrition  Board  of  the  National  Research 
Council  (65)  suggested  that  one  per  cent  of  calories 
should  be  the  minimum  daily  EFA  allowance  for 
humans.  In  any  reasonable  variation  of  the  American 
diet,  this  quantity  is  certainlv  present.  In  the  human 
infant,  however,  Hansen  and  associates  (90)  have 
shown  that  linoleic  acid  is  definitely  required  in 
amounts  as  little  as  1.3  per  cent  of  daily  dietary 
calories  to  prevent  or  cure  certain  dermatoses.  In- 
fants fed  low  fat  diets  (EFA-deficient)  exhibited  low 
serum  values  for  dienoic  and  tetraenoic  fatty  acids, 
and  high  serum  values  for  trienoic  acids.  The  reverse 
serum  picture  was  obtained  following  addition  of 
linoleic  acid  to  the  diet. 

On  the  basis  of  evidence  now  available  it  seems 
unlikely  that  Sinclair's  (190)  hypothesis  attributing 
"nutritional"  hypercholesteremia  and  atherosclerosis 
to  essential  fatty  acid  deficiency  is  correct.  Patients 
with  clinically  manifest  atherosclerosis  and  elevated 
levels  of  serum  total  cholesterol  do  not  necessarily 
exhibit  a  lack  of  linoleic  acid  in  their  serum  or  depots 
(103,  112).  Moreover,  Ahrens  and  associates  (5)  have 
shown  that  formula  diets,  containing  as  their  source 
of  fatty   acids   the    nonessential    polyethenoid    fatty 


acids  predominating  in  certain  fish  oils,  lower  serum 
cholesterol  as  effectively  as  formula  diets  containing 
oils   exceedinglv   rich   in   linoleic   acid. 


Chain  Length,   Unsatnration,  and  Melting  Point 

Serum  lipid  responses  to  dietary  fats  have  been 
correlated  with  certain  characteristics  other  than 
essential  fatty  acid  content  or  iodine  value.  Two 
major  variables  affecting  the  physical  and  biochemical 
properties  of  fatty  acids  are  degree  of  unsaturation 
and  chain  length  (table  1).  For  example,  linoleic  acid 
(2  double  bonds)  and  stearic  acid  (no  double  bonds) 
have  the  same  chain  length,  and  yet  the  melting 
point  of  linoleic  acid  is  —  1 1  C,  whereas  that  of  stearic 
acid  is  69.4  C.  Stearic  acid  (Cw)  and  capric  acid 
(C10)  are  both  fully  saturated  acids;  however,  the 
melting  point  of  the  shorter  chained  capric  acid 
is  31.5  C. 

Since  the  melting  point  of  a  fat  (as  well  as  other 
characteristics)  depends  upon  the  component  fatty- 
acids,  it  is  possible  to  lower  the  melting  point  of  a  tri- 
glyceride either  by  increasing  the  unsaturation  or  by 
reducing  the  chain  length  of  its  fatty  acids.  Accord- 
ingly, many  of  the  physical  characteristics  of  a  fully- 
saturated  fat  containing  shorter  chain  saturated  fatty 
acids  may  resemble  those  of  a  highly  unsaturated  fat 
containing  predominantly  long-chain  monounsatu- 
rated  or  polyunsaturated  fatty  acids. 

As  previously  mentioned,  when  subjects  are  fed 
diets  containing  as  their  fat  source  solid  fats  such  as 
butter  and  mutton  tallow,  their  cholesterol  levels  tend 

table    1 .   Classification  of  Fatty  Acids  According  to  Chain 
Length  and  Degree  of  Unsaturation 


Category  & 

Number  of 

Number  of 

Typical 

Typical    Acid 

Carbon  Atoms* 
(Always  even  numbered) 

Double  Bonds 

Food  Sources 

1.     Medium  Chain 

6-12 

None 

Milk  fat 

Saturated 

(12) 

Coconut  oil 

Uauric) 

2.      Long  Chain 

14  -  24 

None 

Practically  oil 

Saturated 

(16) 

onimal  & 

(Palmitic) 

vegetable  fats 

3.      Long  Chain 

14  -  22 

One 

Most  fats 

Monoun  saturated 

(18) 

ond  oils 

(Oleic) 

4,      Polyunsaturated, 

18  -  20 

Two- Four 

Seed  fats 

Essential 

(18) 

(Two) 

(Organ  fats) 

(Linoleic) 

5.     Polyunsaturated, 

18-  26 

Three- Six 

Fish  oils 

Non-essential 

(22) 

(Five) 

(Clupanodonic) 

1 184 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


to  remain  elevated  or  to  rise.  When  highly  unsatu- 
rated liquid  fats  such  as  corn  oil  and  menhaden  oil 
are  substituted  isocalorically  for  the  "hard"  fats  in 
the  diet,  serum  cholesterol  levels  usually  fall  appre- 
ciably. A  reasonable  correlation  can  be  made  between 
the  physical  state  of  a  fat  and  its  effect  on  serum 
cholesterol.  It  has  been  suggested  that  the  cholesterol- 
lowering  effect  of  the  liquid  oils  may  be  a  function  of 
the  constituent  polyunsaturated  fatty  acids  and  that 
these  fatty  acids  have  an  effect  by  virtue  of  their 
polyethenoid  configuration. 

Recently,  it  was  reported  that  a  synthetic  medium- 
chain  triglyceride,  a  liquid  with  a  melting  point  below 
o  C,  made  up  entirely  of  saturated  fatty  acids  of  chain 
lengths  ranging  from  C6  to  C12,  can  lower  serum  cho- 
lesterol significantly  when  substituted  for  butter  in  a 
formula  diet  (96).  Such  results  are  of  interest  since 
medium-chain  triglyceride  (MCT)  is  devoid  of  poly- 
ethenoid fatty  acids  and  has  an  iodine  value  of  less 
than  1.0  (that  of  butter  is  approximately  40).  Al- 
though the  preparation  is  highly  saturated,  its  shorter 
chain  fatty  acids  confer  upon  it  many  of  the  physical 
characteristics  of  the  natural  vegetable  oils  rich  in 
long-chain    polyunsaturated    fatty    acids. 

Since  medium-chain  fatty  acids  may  be  metab- 
olized differently  from  longer  chain  fatty  acids,  the 
results  with  medium-chain  triglyceride  may  not  help 
one  interpret  the  cholesterol-lowering  effects  of  the 
highly  unsaturated  oils.  On  the  other  hand,  such 
studies  have  again  called  attention  to  the  possible 
importance  of  the  physical  properties  of  fatty  acids 
apart  from  the  number  and  location  of  their  double 
bonds. 

There  remains  a  great  need  for  further  character- 
ization of  dietary  glycerides  in  order  that  their  physi- 
cochemical  characteristics  may  be  better  related  to 
their  effects  on  serum  lipids.  The  mechanisms  whereby- 
dietary  fats  influence  cholesterol  metabolism  still  are 
not  well  understood.  The  picture  is  further  compli- 
cated by  the  complex  nature  of  the  dietary  glycerides. 
As  pointed  out  earlier,  64  different  fatty  acids  have 
been  identified  in  butter.  For  a  time  it  was  believed 
by  some  investigators  that  the  hypercholesteremic 
effect  of  butter  was  due  to  its  relatively  high  content 
of  shorter  chain  saturated  fatty  acids.  Studies  em- 
ploying synthetic  glycerides  of  simplified  fatty  acid 
composition  were  helpful  in  clarifying  this  problem 
inasmuch  as  it  was  possible  to  study  the  effect  on 
serum  lipids  (96)  of  a  synthetic  medium-chain  tri- 
glyceride (MCT)  containing  predominantly  the  very 
fatty  acids  thought  to  be  hypercholesteremic.  As  a 
result  of  such  experiments  it  was  shown  that  in  rela- 


tion  to   butter   the   MCT   preparation  was  actually 
hypocholesteremic. 

Dietary  Cholesterol 

Since  the  early  work  of  Ignatowski  (110)  and 
Anitschkow  (10)  on  experimental  atherosclerosis  in 
rabbits,  dietary  cholesterol  has  been  an  essential 
ingredient  of  diets  used  to  induce  hypercholesteremia 
and  atherosclerosis  in  a  variety  of  animal  species.  Not 
long  ago,  it  was  fashionable  to  prescribe  diets  low  in 
cholesterol  for  patients  with  an  elevated  serum  choles- 
terol. As  cholesterol  metabolism  in  man  was  studied 
more  intensively,  it  became  evident  that  the  liver 
normally  synthesizes  about  three  times  as  much  choles- 
terol per  day  as  is  consumed  in  the  average  diet.  It 
was  further  learned  that  an  increased  intake  of 
cholesterol  is  likely  to  result  in  a  proportionate  inhibi- 
tion of  cholesterol  manufacture.  Subsequently,  care- 
fully controlled  studies  by  Keys  et  al.  (119)  and  others 
have  suggested  that,  within  wide  limits,  variations  in 
the  cholesterol  content  of  an  ordinary  diet  do  not 
affect  serum  cholesterol  levels  to  any  significant  de- 
gree, provided  other  elements  in  the  diet  are  constant. 
Such  results  have  encouraged  many  physicians  to 
abandon  use  of  diets  specifically  low  in  cholesterol 
in  treating  patients  with  hypercholesteremia. 

Despite  such  negative  reports,  the  influence  of 
dietary  cholesterol  on  serum  cholesterol  in  man  con- 
tinues to  be  a  subject  of  investigation  and  contro- 
versy. Beveridge  et  al.  (23)  have  recently  reported 
that  the  addition  of  relatively  small  amounts  of  choles- 
terol to  formula  diets  can  raise  serum  cholesterol 
levels,  depending  on  the  nature  of  the  accompanying 
fat.  Indeed,  these  investigators  attribute  the  hyper- 
cholesteremic effect  of  butter  in  part  to  its  content  of 
cholesterol.  Keys  (121)  has  reviewed  the  results  of 
Beveridge  and  associates  and  has  questioned  their 
significance.  Connor  et  al.  (45)  have  studied  the  effect 
of  adding  or  subtracting  moderate  amounts  of  choles- 
terol as  egg  yolk  in  diets  equivalent  in  amounts  and 
composition  of  fat.  In  their  studies,  the  addition  of 
475  to  1425  mg  cholesterol  (the  amount  present  in 
one  to  three  large  eggs)  raised  serum  total  cholesterol 
by  an  average  of  68  mg  per  100  ml.  On  the  other 
hand,  crystalline  cholesterol  added  to  the  diet  in 
amounts  ranging  from  1 200  to  3600  mg  per  day 
increased  the  mean  cholesterol  level  by  only  18  mg 
per   100  ml. 

It  would  seem  that  the  effect  of  crystalline  choles- 
terol added  to  the  diet  cannot  be  equated  with  the 
effect  of  the  cholesterol  that  occurs  naturally  in  food. 


LIPID    METABOLISM 


ii  8= 


It  is  possible  that  the  differences  in  response  to  these 
two  forms  of  cholesterol  relate  to  considerations  of 
solubility  of  this  sterol  in  dietary  fat.  Recently,  it  has 
been  pointed  out  (37)  that  cholesterol  is  more  soluble 
in  the  saturated  than  in  the  polyunsaturated  fats. 

Practicable  Diets 

It  is  of  considerable  practical  interest  that  palatable 
diets  can  now  be  devised  that  are  rich  in  polyunsatu- 
rated fatty  acid  content  and  provide  the  same  pro- 
portion of  fat  to  which  Americans  are  accustomed.  At 
present,  need  exists  for  controlled  studies  in  man  to 
determine  the  effects  on  serum  lipids  of  "normal" 
diets  exhibiting  a  variety  of  fatty  acid  patterns.  At- 
tempts in  this  direction  have  begun  (46,  93,  111). 
Earlier  experiments  with  semipurified  formula-type 
regimens  suggested  that  when  the  ratio  of  poly- 
unsaturated to  saturated  fatty  acids  (P:S  ratio)  in 
the  diet  was  increased,  serum  cholesterol  usually 
could  be  lowered. 

Approximately  5  years  ago,  experiments  were 
begun  to  determine  whether  everyday  diets  could  be 
altered  so  as  to  reduce  serum  cholesterol  Levels  and 
yet  remain  palatable  and  acceptable  to  most  indi- 
viduals. From  progress  reports  of  these  studies,  it  is 
now  clear  that  manipulation  of  the  fatty  acid  pattern 
of  the  diet  is  effective  in  lowering  serum  cholesterol 
in  most  subjects  with  cholesterol  levels  higher  than 
230  mg  per  100  ml.  The  change  in  pattern  is  effected 
principally  by  substituting  one  form  of  dietary  fat  for 
another  in  order  to  increase  the  P:S  ratio.  In  prac- 
tice, this  change  involves  a  drastically  decreased 
consumption  of  butter  fat  and  of  certain  margarines, 
and  a  reduced  intake  of  meats  from  ruminants,  such 
as  bovine  animals  and  sheep.  At  the  same  time,  con- 
sumption of  poultry,  fish,  nuts,  and  plant  seed  oils 
is  materially  increased.  A  typical  diet  designed  to 
lower  cholesterol  prescribes  an  increase  in  intake  of 
polyunsaturated  fatty  acids  from  approximately  1 5 
to  42  per  cent  of  total  fat  and  a  decrease  in  intake  of 
saturated  fatty  acids  from  approximately  42  to  1 5  per 
cent.  The  intake  of  the  monounsaturated  fatty  acid, 
oleic  acid,  remains  unchanged.  Total  dietary  fat  is 
reduced  from  44  to  36  per  cent  of  calories,  although 
this  is  not  an  essential  feature  of  the  diet. 

Such  diets  are  acceptable  and  palatable.  The  effect 
of  a  diet  of  similar  fatty  acid  composition  on  serum 
cholesterol  in  97  men  of  normal  weight,  50  to  59 
years  old,  was  determined  by  Jolliffe  et  a/.  (113).  This 
study  demonstrated  the  fall  in  cholesterol  by  tertiles 
over  a  period  of  6  months.  The  upper   third,  with 


cholesterol  levels  of  270  mg  per  100  ml  and  over, 
dropped  an  average  of  45  mg  per  1 00  ml.  The  lower 
third,  with  cholesterol  values  under  230  mg  displayed 
a  decrease  averaging  16  mg  per  100  ml.  Similar 
studies  performed  on  smaller  groups  of  subjects  have 
yielded    generally    similar    results    (200). 

The  fact  that  it  is  indeed  feasible  to  lower  serum 
cholesterol  levels  by  dietary  means  has  had  and  is  con- 
tinuing to  have  a  tremendous  impact  on  the  public, 
the  medical  and  dietetic  professions,  and  the  food 
industry.  The  public  is  being  made  increasingly  aware 
of  the  possibly  ominous  significance  of  an  elevated 
serum  cholesterol  level  in  terms  of  danger  from 
obstructive  coronary  artery  disease.  At  the  same  time, 
there  appears  to  be  decreasing  use,  per  capita,  of 
butter  and  hydrogenated  products,  and  increasing 
use  of  liquid  vegetable  oils,  such  as  corn,  safflower, 
and  cottonseed  oils. 

A  number  of  cookbooks  on  the  subject  of  fatty  acid 
"control"  are  now  appearing,  and  the  demand  for 
them  is  great.  Recently,  several  food  companies  have 
come  out  with  new  margarines  with  an  increased 
content  of  cis-cis  linoleic  acid.  There  is  increasing 
interest  in  the  development  of  cheeses  and  spreads 
and  commercial  products  resembling  ice  cream,  all 
containing  appreciable  quantities  of  linoleate.  "Rea- 
sonable substitution  of  polvunsaturated  for  saturated 
fats,  under  medical  supervision"  has  been  recom- 
mended by  an  ad  hoc  committee  of  the  American 
Heart  Association  (8).  Whether  or  not  diets  of  this 
kind  will  have  a  clinically  useful  effect  is  one  of  the 
most  urgent  questions  facing  medicine  today. 

Mechanism  of  Cholesterol  Lowering 

The  exact  mechanism  whereby  a  diet  rich  in  poly- 
unsaturated fatty  acids  lowers  serum  total  cholesterol 
(and  low-density  lipoproteins)  remains  unknown.  A 
few  studies  have  indicated  that  when  such  a  diet  is 
fed  more  cholesterol  and  its  end  products  (including 
bile  acids)  are  excreted  in  the  feces.  When  a  diet  rich 
in  saturated  fatty  acids  is  fed,  less  sterols  and  bile 
acids  are  excreted  in  the  feces  and  the  serum  choles- 
terol level  rises  (85,  99,  1  1  1 ). 

There  appears  to  be  no  evidence  for  direct  inter- 
ference by  the  polyunsaturated  fatty  acids  with 
cholesterol  synthesis  in  the  liver.  However,  the  ability 
of  the  liver  to  excrete  cholesterol  and  to  convert 
cholesterol  to  bile  acids  may  depend  in  part  on  certain 
physicochemical  characteristics  of  cholesterol  esters 
or  of  the  lipoprotein  molecules  of  which  cholesterol 
and    its   esters  can   constitute   a  significant   portion. 


1 1 86 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION'    II 


Cholesterol  esterifies  readily  with  polyunsaturated 
fatty  acids  such  as  linoleic  acid  (115).  When  the  die- 
tary fatty  acids  are  predominantly  saturated,  esters 
such  as  cholesteryl  oleate  and  palmitate  are  likely  to 
occur  in  increasing  amounts  and,  conceivably,  may 
be  less  available  for  excretion  and  conversion  to  bile 
acids  bv  the  liver. 


Additional  Influences  on  Serum  Lipids 

Other  dietary  manipulations  also  can  influence 
serum  lipids  (63,  153,  166).  A  drastic  decrease  in 
dietary  intake  of  protein  is  associated  with  lowering 
of  serum  total  cholesterol  (and  fi-lipoproteins)  in 
man  (76,  152).  High  protein  intakes  above  10  per 
cent  of  total  daily  calories  have  been  found  to  be 
effective  in  lowering  serum  cholesterol  and  /3-lipo- 
proteins  in  animals  but  not  in  man  (153).  A  sub- 
stantial decrease  in  the  proportion  of  fat  in  the  diet 
may  be  associated  with  a  lowering  of  serum  choles- 
terol, but  in  certain  individuals  a  considerable  rise  in 
serum  triglycerides  may  occur  (4,  6).  Such  diets 
usually  contain  a  large  quantity  of  carbohydrate, 
much  of  which  gets  converted  by  the  body  into  fat. 

There  is  evidence  from  studies  in  laboratory  animals 
and  human  subjects  that  the  type  of  carbohydrate  in 
the  diet  can  affect  serum  lipids.  Compared  to  sucrose, 
starch  promotes  bile  acid  excretion  and  tends  to 
lower  serum  cholesterol  in  the  rat  (165).  It  has  also 
been  reported  that  when  the  carbohydrates  of 
legumes  are  substituted  isocalorically  for  sucrose  in 
the  diets  of  human  subjects,  cholesterol  levels  are 
reduced  to  a  slight  degree  (9). 

The  effect  of  a  given  diet  on  caloric  balance  must 
also  be  taken  into  account.  Patients  in  negative 
caloric  balance  can  often  have  a  transient  decrease  in 
serum  lipids  on  this  basis;  on  the  other  hand,  during 
active  weight  gain,  serum  lipids  tend  to  rise  (142, 
204).  Weight  reduction  may  induce  a  decline  in 
serum  lipids  in  persons  with  hyperlipidemia.  It  is 
not  certain  whether  such  a  decrease  occurs  only  while 
weight  actuallv  is  being  lost  or  whether,  in  some  in- 
stances, the  improvement  in  serum  lipids  will  be  sus- 
tained for  as  long  as  weight  is  maintained  at  a  reduced 
level.  However,  as  was  mentioned  earlier,  during  a 
sustained  fast  the  serum  levels  of  the  low-density 
lipoproteins  tend  to  increase;  this  contrasts  with  the 
decline  in  serum  lipids  shown  bv  nonfasting  patients 
in  negative  caloric  balance. 

Pharmacologic  approaches  to  lowering  serum 
cholesterol  have  included  use  of  agents  with  the  fol- 
lowing mechanisms  of  action : 

/)    Inhibition    of  cholesterol    biosynthesis.    Under 


this  category  are  included  triparanol  (138,  193), 
benzmalecene  (15),  and  possibly  nicotinic  acid  (7,  82, 
158).  Agents  which  inhibit  cholesterol  biosynthesis 
also  may  interfere  with  other  important  synthetic 
processes  such  as  steroid  biogenesis;  hence,  they  are 
potentially  toxic  for  man. 

_')  Inhibition  of  cholesterol  absorption  from  the 
gastrointestinal  tract.  Plant  sterols  such  as  sitosterol 
have  been  used  for  this  purpose  in  man  (20,  188).  The 
mechanism  for  inhibition  of  cholesterol  absorption 
remains  to  be  demonstrated.  Moreover,  the  effective- 
ness of  sitosterol  in  lowering  serum  cholesterol  in  man 
has  been  questioned.  Studies  by  Levere  and  his  asso- 
ciates (131)  suggested  that  no  decrease  in  serum 
cholesterol  could  be  attributed  confidently  to  sitos- 
terol administration,  and  that  any  apparent  decrease 
might  be  caused  by  great  fluctuations  in  serum  choles- 
terol observed  in  such  studies  in  man. 

3)  Promotion  of  cholesterol  degradation.  Reference 
already  has  been  made  to  the  polyunsaturated  fatty 
acids  and  the  possibility  that  they  might  act  by  pro- 
moting the  rate  of  cholesterol  breakdown  to  bile 
acids.  Simple  addition  to  the  diet  of  relatively  small 
quantities  of  polyunsaturated  fatty  acids  cannot  be 
relied  upon  to  induce  significant  lowering  of  the 
serum  cholesterol  level  (159).  Pharmaceutical  prepa- 
rations containing  linoleic  acid  and  sometimes  sup- 
plemented with  small  quantities  of  pyridoxine  and 
tocopherol  offer  no  advantage  over  the  various 
linoleate-rich  oils  such  as  corn  and  cottonseed  that 
can  be  purchased  inexpensively  at  the  grocery. 
Moreover,  as  mentioned  earlier,  the  polyunsaturated 
fatty  acids,  in  order  to  be  effective  in  lowering  serum 
cholesterol,  must  be  consumed  in  relatively  large 
amounts  and  their  intake  integrated  with  an  over-all 
reduction  in  the  consumption  of  saturated  fatty  acids 
as  part  of  a  carefully  adhered-to  regimen. 

An  interesting  group  of  substances  has  been  found 
capable  of  lowering  serum  cholesterol  by  binding  bile 
acids  in  the  gut  and  thereby  promoting  their  fecal 
excretion.  These  are  the  anion  exchange  resins  (14, 
196,  202)  that  form  nonabsorbable  complexes  with 
bile  acids.  Appropriately,  they  have  been  termed 
"bile  acid  sequestrants"  and  of  these  cholestyramine 
has  been  studied  extensively  in  man.  Cholestyramine 
is  apparently  innocuous  since  it  does  not  seem  to  enter 
the  body.  Long-term  effects  of  bile  acid  sequestration 
in  man  are  at  present  unknown.  The  net  effect  of  the 
bile  acid  sequestrants  appears  to  be  similar  to  that  of 
the  polyunsaturated  fatty  acids;  namely,  promotion 
of  cholesterol  degradation. 

Thyroid  hormones  and  their  analogues  ([]^,  77,  151) 
may  lower  cholesterol  bv  virtue  of  an  effect  on  bile 


LIPID    METABOLISM 


U87 


acid  metabolism  (100);  however,  the  exact  mecha- 
nism remains  to  be  clarified.  Studies  of  (/-thyroxine 
in  man  revealed  no  reliable  dose-response  of  serum 
cholesterol  over  a  6-month  period,  nor  was  there  a 
dose  which  would  be  effective  in  lowering  serum 
cholesterol  without  provoking  angina  (151 ). 

Neomycin  has  been  reported  to  lower  serum 
cholesterol  and  simultaneously  to  increase  fecal  ex- 
cretion of  bile  acids  (81,  82,  181).  The  influence  of 
neomycin  on  bile  acid  metabolism  may  be  related 
to  its  profound  effect  on  intestinal  flora  and  the 
possible  damage  it  inflicts  on  the  villi  of  the  intestinal 
mucosa. 

4)  Increased  tissue  removal  of  cholesterol.  It  is 
suspected  that  the  estrogenic  hormones  and  their 
congeners  (12,  34)  may  lower  serum  cholesterol 
by  increasing  the  activity  of  the  reticuloendothe- 
lial system  and  thereby  accelerating  the  removal 
of  cholesterol-rich  lipoproteins  from  the  plasma. 
Whether  cholesterol  catabolism  is  further  enhanced 
within  the  reticuloendothelial  system  remains  un- 
known. The  effect  of  estrogens  on  cholesterol  bio- 
synthesis also  is  not  clear;  however,  there  is  evidence 
that  estrogen  administration  is  not  associated  with 
an  increased  rate  of  bile  acid  excretion.  A  variety  of 


teals 


fig.  8.  Mechanisms  for  lowering  plasma  cholesterol. 
/  :  Inhibition  of  cholesterol  biosynthesis  (triparanol).  2: 
Inhibition  of  cholesterol  absorption  (sitosterols).  3:  Promotion 
of  cholesterol  degradation — a,  polyunsaturated  fatty  acids; 
b,  bile  acid  sequestrants.  4:  Increased  tissue  removal  of 
cholesterol  (estrogens).  (From  Bergen  &  Van  Itallie,  Ann. 
Internal  Med.  In  press.) 


other  substances  (63,  166)  too  numerous  to  discuss 
in  detail  also  are  capable  of  inducing  a  reduction  in 
serum  cholesterol.  The  four  mechanisms  for  lowering 
cholesterol  that  have  been  described  are  summarized 
in  figure  8. 


BLOOD  LIPIDS  AND  ATHEROSCLEROSIS 

Virtually  no  information  based  on  direct  observa- 
tion is  available  concerning  the  relationship  in  man 
between  circulating  lipids  and  atherosclerosis.  The 
difficulty  has  been  that  the  tools  for  diagnosing  occult 
atherosclerosis  are  inadequate.  There  is  indirect  evi- 
dence— epidemiologic,  experimental,  clinical,  and 
pathologic — that  sustained  elevation  of  the  plasma 
low-density  lipoproteins  is  associated  with  an  in- 
creased rate  of  atheroma  formation.  It  is  suspected 
that  plasma  lipoprotein  may  be  '"filtered"  through 
intimal  cells  under  arterial  pressure  and  that  accumu- 
lation of  lipid  in  the  subintimal  area  is  accelerated  by 
continued  traffic  of  plasma  rich  in  "unstable"  lipo- 
protein through  the  arterial  wall  (153,  201). 

Animal  experiments  have  shown  that  when  an 
increased  plasma  concentration  of  ^-lipoproteins  is 
achieved  by  dietary  or  other  means,  atherosclerosis 
usually  results  (64,  143,  211).  The  early  vascular 
changes  observed  in  experimental  atherosclerosis  are 
believed  by  many  observers  to  have  a  close  resem- 
blance to  early  human  lesions. 

Evidence  is  also  available  from  studies  in  man  that 
prolonged  elevation  of  the  serum  cholesterol  is  asso- 
ciated with  an  increased  susceptibility  to  athero- 
sclerosis and  its  clinical  manifestations.  In  diseases 
such  as  diabetes  and  hypothyroidism  in  which  serum 
lipids  tend  to  be  elevated,  the  incidence  of  athero- 
sclerosis also  is  increased.  Moreover,  patients  with 
angina  pectoris  or  a  history  of  myocardial  infarction 
tend  to  have  serum  lipid  levels  higher  than  those  of 
apparently  healthy  control  subjects.  This  difference 
in  lipid  levels  is  most  striking  when  groups  below  the 
age  of  45  are  compared  (201). 

Epidemiologic  studies  of  populations  in  various 
parts  of  the  world  (18)  involving  correlation  of  serum 
cholesterol  levels  with  prevalence  of  clinically  mani- 
fest atherosclerosis  and  presence  of  the  disease  at 
autopsy  have  given  additional  support  to  the  pro- 
posed relationship  between  hypercholesteremia  and 
atherosclerosis.  Most  epidemiologic  studies  attempt- 
ing to  relate  coronary  heart  disease  to  levels  of  serum 
cholesterol  are  retrospective  in  that  the  subjects 
studied  have  already  exhibited  clinical  manifesta- 
tions of  atherosclerotic  heart  disease.  The  Framing- 


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CIRCULATION    II 


ham  Heart  Program  (47,  114)  is  of  interest  because  it 
has  used  the  prospective  approach.  In  this  study, 
approximately  5,000  individuals  originally  free  of 
manifestations  of  overt  coronary  heart  disease  in  the 
town  of  Framingham,  Massachusetts,  have  been  fol- 
lowed for  8  years,  and  the  study  continues.  From  the 
Framingham  data,  it  has  been  shown  that  an  associa- 
tion exists  between  a  number  of  factors,  other  than 
age  and  sex,  and  an  increased  risk  of  developing 
coronary  heart  disease:  these  are  obesity,  hyperten- 
sion, electrocardiographic  evidence  of  left  ventricular 
hypertrophy,  heavy  smoking,  and  hypercholesteremia. 
Increasing  levels  of  serum  cholesterol  were  found  to 
be  associated  with  increasing  risk  of  developing  cor- 
onary heart  disease.  Among  the  various  lipid  meas- 
urements (excluding  cholesterol  esters  and  trigly- 
cerides about  which  data  were  lacking)  serum  total 
cholesterol  was  found  to  be  the  best  measurement  for 
predicting  the  occurrence  of  overt  coronary  heart 
disease.  While  the  results  of  the  Framingham  study 
have  been  interesting  and  provocative,  the  relatively 
small  number  of  subjects  studied  make  it  difficult  to 
arrive  at  firm  conclusions  about  the  relationship 
between  such  variables  as  the  serum  cholesterol  and 
incidence  of  obstructive  coronary  disease.  Until 
larger  samples  can  be  obtained  there  is  always  a  risk 
of  drawing  too  many  unqualified  conclusions  from 
insufficient  data  (132). 

In  addition  to  the  increased  risk  of  heart  disease 
associated  with  hypercholesteremia,  the  increased 
incidence  of  coronary  atherosclerosis  in  patients  with 
essential  hyperlipemia  (hypertriglyceridemia)  (139) 
should  be  mentioned,  as  well  as  the  reports  that 
patients  with  coronary  heart  disease  tend  to  display 
elevated  levels  of  serum  triglycerides  (6)  and  impair- 
ment of  rate  of  clearing  of  alimentary  lipemia  (186). 
Such  preliminary  observations  suggest  that  the  lower- 
density  lipoproteins  carrying  an  increased  burden  of 
triglyceride  may  play  a  more  important  etiologic 
role  in  coronary  atherosclerosis  than  has  been  hitherto 
appreciated. 

Although  it  is  common  practice  to  use  the  term 
"atherosclerosis"  as  though  it  described  one  disease, 
evidence  has  been  accumulating  that  in  certain 
countries  where  clinically  manifest  coronary-artery 
disease  is  rare,  atherosclerosis  of  the  aorta  may  be 
quite  common  (86).  Similarly,  American  women 
possess  a  relative  immunity  to  coronary  heart  disease 
during  their  reproductive  years;  yet  they  are  not 
equally  immune  from  atherosclerosis  at  other  ana- 
tomic sites  (174).  It  is  worthy  of  comment  that  al- 
though coronary  heart  disease   is  very  common  in 


patients  with  familial  hypercholesteremic  xantho- 
matosis (primary  hypercholesteremia),  this  disease 
does  not  seem  to  predispose  to  the  development  of 
peripheral  or  cerebrovascular  disease  (89).  Con- 
versely, coronary  heart  disease  is  rare  among  the 
South  African  Bantu,  a  group  in  whom  serum  choles- 
terol levels  tend  to  be  very  low;  yet,  cerebral  catas- 
trophes occur  as  frequently  among  Bantu  as  among 
populations  with  substantially  higher  levels  of  choles- 
terol (128,  205).  Thus,  coronary  heart  disease  may 
prove  to  be  a  special  manifestation  of  atherosclerosis, 
with  its  own  epidemiology  and,  perhaps,  its  own  bio- 
chemical pathology. 

Chemical  studies  of  the  atheroma  have  supported 
the  belief  that  a  number  of  the  fatty  constituents  of 
the  atheroma  are  derived  from  the  plasma.  Studies 
have  demonstrated  that  the  distribution  of  lipids  in 
early  atheroma  is  roughly  similar  to  that  in  plasma 
(104).  As  the  atheromas  of  human  aortas  progress  in 
severity,  they  exhibit  a  parallel  increase  in  content 
of  carotenoid  and  cholesterol  (25).  Since  carotenoid 
is  derived  entirely  from  the  diet,  such  observations 
also  suggest  that  atheromatous  lipid  derives  from  the 
circulation  and  does  not  originate  de  novo  within 
the  arterial  wall.  A  similar  interpretation  can  be 
made  of  the  demonstration  that  linoleic  acid,  a  sub- 
stance which  the  body  apparently  cannot  synthesize, 
is  a  significant  constituent  of  atheromas   (187). 

With  the  advent  of  gas-liquid  chromatography  and 
other  improved  techniques  for  lipid  separation  and 
identification,  it  has  become  possible  to  obtain  more 
precise  information  about  the  lipid  constituents  of 
atheromas  at  various  sites  and  at  various  stages  of 
evolution  (30,  31,  54,  133,  136,  199,  208).  It  has  been 
reported  that  the  saturated  and  monounsaturated 
fatty  acid  moieties  of  cholesterol  esters  tend  to  accumu- 
late preferentially  in  early  atheromatous  lesions. 
However,  linoleic  acid  also  can  be  found  in  atheromas 
in  appreciable  quantities.  A  report  from  Leiden  (32) 
has  described  the  results  of  detailed  analyses  of  the 
lipids  in  aortas  and  coronary  and  cerebral  arteries  in 
various  stages  of  atherosclerosis.  It  was  found  that 
as  the  aortic  lesions  became  more  advanced  their 
relative  content  of  cholesterol  and  cholesterol  esters 
increased  strikingly.  A  comparison  of  the  fatty  acid 
composition  of  "early"  and  "late"  atheromas  with 
uninvolved  aorta  showed  an  increase  in  the  propor- 
tion of  the  polyunsaturated  fatty  acids  of  cholesterol 
esters  in  the  older  lesions.  The  phospholipids  exhibited 
a  slight  increase  in  their  proportion  of  long-chain 
saturated  fatty  acids.  Generally  similar  results  were 
obtained  for  the  circle  of  Willis,  in  which  the  content 


LIPID    METABOLISM 


l89 


•of  cholesterol  esters  increased  in  more  advanced 
lesions  while  phospholipid  content  decreased.  In  the 
coronary  vessels,  the  content  of  triglycerides  in  rela- 
tively healthy  specimens  was  quite  high;  cholesterol 
and  its  esters  increased  with  advancing  atherosclerosis 
while  glyceride  content  fell.  With  respect  to  fatty  acid 
patterns,  the  trends  with  increasing  atherosclerosis 
in  coronary  and  cerebral  samples  were  similar  to 
that  shown  by  the  aorta. 

The  studies  reported  to  date  on  the  lipid  composi- 
tion of  atheromas  appear  to  support  the  impression 
that  the  cholesterol  esters  in  the  intima  and  media 
start  by  being  extremely  saturated  in  comparison  with 
those  circulating  in  the  plasma;  with  increasing  ather- 
osclerosis of  the  wall  the  apparently  healthy  parts 
contain  more  polyunsaturated  cholesterol  esters  than 
the  adjacent  lesions.  The  mechanism  whereby  even 
apparently  normal  vascular  tissue  becomes  infil- 
trated by  plasma  lipids  remains  unknown.  In  any 
event,  it  seems  clear  that  the  fatty  acids  of  the  arterial 
wall,  like  those  of  the  plasma,  are  responsive  to  dietary 
influences.  Hence,  this  variable  (among  others)  must 
be  taken  into  account  when  data  reported  by  various 
investigators  are  being  compared  and  evaluated. 

It  should  not  be  forgotten  that  a  number  of  en- 
vironmental and  host  factors  may  play  a  role  in  the 
pathogenesis  of  atherosclerosis.  Groen  (88)  has  listed 
eight  exogenous  and  six  endogenous  elements  that 
have  been  given  major  attention  by  various  investi- 
gators. Included  in  this  list  are  such  items  as  constitu- 
tion, age,  obesity,  physical  exercise,  social  class,  emo- 
tional influence  and  such  concomitant  diseases  as 
hypertension  and  diabetes.  This  very  multiplicitv  of 
considerations  makes  human  atherosclerosis  an 
exceedingly  complex  problem.  However,  a  common 
pathway  still  must  be  defined  through  which  a  given 
influence  can  operate.  In  the  present  discussion  the 
early  atheroma  has  been  viewed  as  a  phenomenon 
secondary  to  an  abnormality  of  the  serum  lipids; 
thus,  the  lesion  can  be  said  to  be  biochemical  first 
and  histologic  second. 


ROLE    OF    BLOOD    CLOTTING    AND    THROMBOSIS 

Commonly,  the  dramatic  clinical  manifestations  of 
atherosclerosis  such  as  myocardial  infarction  and 
"stroke"  result  from  acute  thrombotic  obstruction  of 
an  artery.  It  is  generallv  believed  that  the  athero- 
sclerotic lesion  acts  as  a  nidus  for  thrombus  formation 
which,  in  turn,  occludes  the  vessel.  This  assumption 
is   not   invariably   correct.    Arterial    thrombosis   can 


occur  at  sites  where  atherosclerosis  is  minimal  or 
absent,  and  arterial  occlusion  by  an  atherosclerotic 
lesion  can  occur  without  thrombosis.  The  events  that 
lead  to  thrombosis  in  vivo  still  are  not  clearly  under- 
stood. 

Certain  inconsistencies  appear  if  arterial  thrombosis 
is  regarded  as  a  simple  epiphenomenon  of  athero- 
sclerosis. Epidemiologic  studies  have  suggested  an 
increase  in  mortality  rates  from  coronary  artery  dis- 
ease in  the  Western  World  during  the  past  25  years 
without  a  corresponding  increase  in  atherosclerosis 
(149).  The  discrepancy  in  certain  countries  between 
clinical  coronary  artery  disease  (rare)  and  athero- 
sclerosis of  the  aorta  (common)  already  has  been 
mentioned.  In  certain  experimental  animals,  in  which 
atherosclerosis  has  been  produced  readily  by  dietary 
means,  production  of  myocardial  infarction  has  been 
difficult  [although  achieved  in  rats  fed  high  fat  diets 
supplemented  with  cholesterol,  cholic  acid,  and  thio- 
uracil  (91)].  Thus,  any  attempt  to  relate  development 
of  occlusive  arterial  disease  to  dietary  fat  consumption 
must  take  into  account  the  role  of  thrombosis  (150). 
In  this  regard,  Duguid  (56)  has  reviewed  and  modified 
a  concept  introduced  by  Rokitansky  a  century  ago 
relating  atherogenesis  to  fibrin  deposition  on  arterial 
intimal  surfaces.  Duguid  has  shown  that  arterial 
narrowing  can  be  produced  by  organization  of  mural 
thrombi  with  subsequent  endothelialization  and  lipid 
deposition.  The  end  result  is  difficult  if  not  impossible 
to  distinguish  from  "atherosclerosis.''  Subintimal 
hemorrhage  and  other  "mechanical"  factors  have 
been  considered  as  initiating  the  process  (57).  From 
such  a  standpoint,  lipid  deposition  in  atherosclerosis 
is  thought  to  be  secondary  to  thrombus  formation. 
However,  most  of  the  available  evidence  still  favors 
the  view  that  lipid  deposition  in  the  arterial  wall  is 
the  primary  event  in  atherogenesis. 

The  possible  influence  of  dietary  fat  on  blood  coagu- 
lation has  been  the  subject  of  several  reviews  (92, 
163).  It  is  clear  that  the  factors  involved  in  main- 
tenance of  blood  fluidity  are  complex  and  deserving 
of  further  investigation.  Methods  for  detecting  in- 
cipient thrombosis  in  the  intact  organism  are  inade- 
quate. A  distinction  must  be  made  between  results 
obtained  by  feeding  fat  on  the  various  coagulation 
tests  in  vitro  and  the  influence  of  lipemia  on  coagula- 
tion in  vivo.  There  appears  to  be  agreement  concern- 
ing the  accelerating  effect  of  certain  dietary  and 
synthetic  phospholipids,  platelet  lipid  extracts,  and 
postprandial  plasma  on  the  Stypven  time,  a  short- 
ening of  the  clotting  time  of  plasma  in  the  presence 
of  Russell's   viper  venom.    The    relevance   of  these 


ngo 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


findings  to  in  vivo  coagulation  remains  unknown. 
Recently  Poole  (164)  has  emphasized  the  difference 
between  clotting  and  thrombosis  and  has  pointed 
out  that  factors  important  in  clotting  may  be  un- 
important in  thrombosis.  Under  the  electron  micro- 
scope, clots  and  thrombi  are  different  in  structure. 
The  thrombus  contains  areas  of  closely  packed  plate- 
lets while  the  clot  contains  predominantly  red  cells 
and  a  few  platelets  distributed  at  random  in  a  fibrin 
network.  It  has  been  shown  (44)  that  the  coagulum 


formed  when  blood  is  made  to  flow  through  a  closed 
circular  loop  of  plastic  tubing  mounted  on  a  rotator 
resembles  a  natural  thrombus.  In  this  system  the 
unesterified  long-chain  saturated  fatty  acids  accel- 
erate thrombus  formation,  while  the  polyunsaturated 
and  shorter  chain  fatty  acids  are  inactive.  More 
information  is  needed  about  the  relationship  between 
clotting  and  thrombosis  before  a  decision  can  be 
made  concerning  the  part  played  by  dietary  fat  and 
lipemia  in  the  mechanism  of  thrombosis. 


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128.  Laurie,  W.,  and  J.  D.  Woods.  Atherosclerosis  and  its 
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129.  Lawry,  E.  Y.,  G.  V.  Mann,  A.  Peterson,  A.  P.  Wysocki, 
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7'7,  '953- 

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i  1 1,4 


HANDBOOK    OF    PHVSIOI  .Ol  ;"i 


CIRCULATION    II 


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23:  370-375.  ]961- 


CHAPTER     35 


The  role  of  endocrines,  stress,  and 
heredity  on  atherosclerosis1 


L.    N.    KATZ 
R.    PICK2 


Cardiovascular  Institute,  Michael  Reese  Hospital  and  Medical  Center,  Chicago,  Illir, 


CHAPTER    CONTENTS 

Hormones 
Thyroid 

Pancreatic  Hormones 
Chronic  pancreatitis 
Diabetes  mellitus 
Adrenal  and  Pituitary  Hormones 

Adrenal  cortical  hormones  and  ACTH 
Adrenal  medullary  hormones 
Anterior  pituitary  hormones 
Conclusion 
Sex  Hormones 
Heredity 
Stress 

Physical  Activity 
Emotional  Stress 
Summary 


atherosclerosis,  manifested  in  the  lipid-containing 
intimal  lesions  of  small  and  large  arteries,  is  the  most 
common  pathological  form  of  vascular  disease  and 
the  most  detrimental  in  its  effect  on  the  blood  and 
oxygen  supply  to  any  given  organ.  It  is  one  form  of 
arteriosclerosis,  the  most  important  one,  leading  to 
widespread  morbidity  and  mortality  in  man  in  our 
Western  civilization. 

Several  investigative  approaches  have  led   to  the 

1  Work  of  the  institute  mentioned  in  this  communication 
has  been  supported  by  grants  from  the  National  Institutes  of 
Health,  National  Heart  Institute  USPHS  (H-2276,  ^3031),  the 
Chicago  Heart  Association,  the  Albert  and  Mary  Lasker 
Foundation,  and  the  Michael  Reese  Research  Foundation. 

2  Established  Investigator  of  the  American  Heart  Association. 


conclusion,  held  by  most  but  not  by  all  workers  in  the 
field,  that  it  is  a  disease  primarily  due  to  disturbance 
of  the  metabolism  of  lipid,  lipoprotein,  or  cholesterol, 
or  all  three  (72).  Whether  atherosclerosis  develops 
into  a  major  health  problem  within  a  population 
depends  to  a  large  extent  on  the  life-span  pattern  of 
its  diet.  As  early  as  1934,  Rosenthal  (133)  established 
that  in  no  population  with  a  high  intake  of  fat  and 
protein  from  animal  sources  is  atherosclerosis  absent, 
while  populations  subsisting  on  a  diet  low  in  animal 
fat  and  protein  are  uniformly  free  from  the  disease 
anatomically  and,  therefore,  from  the  sequelae  which 
produce  morbidity  and  mortality.  These  findings 
have  been  amply  confirmed  in  recent  years  by  world- 
wide epidemiological  studies  (42,  74,  79,  107,  157). 
A  tangible  concomitant  of  the  ingestion  of  a  diet 
rich  in  saturated  fats  and  cholesterol  is  a  hypercholes- 
terolemic  tendency  in  a  population.  Thus,  while 
the  mean  serum  cholesterol  level  of  the  atherosclero- 
sis-free populations  is  150  to  180  mg  per  cent,  the 
level  for  clinically  healthy  men  of  comparable  age  in 
the  United  States  is  220  mg  per  cent  (74).  It  is  also  a 
well-accepted  fact  today  that  serum  cholesterol  level 
is  the  most  closely  related  single  factor  determining 
an  individual's  risk  of  developing  clinical  athero- 
sclerotic coronary  disease,  i.e.,  the  higher  the  serum 
cholesterol,  the  greater  is  the  risk  (30). 

According  to  our  present  knowledge,  the  mode  of 
action  by  which  a  diet  rich  in  fats,  particularly  satu- 
rated fats  and  cholesterol,  acts  to  influence  lipid 
metabolism  and  to  produce  atherosclerosis  can  be 
summarized  as  follows:  cholesterol  synthesis  in   the 


1 197 


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CIRCULATION    II 


liver  is  finely  attuned  to  the  amount  of  ingested 
cholesterol  (61).  This  homeostatic  mechanism  is 
disturbed  or  may  even  be  exhausted  by  a  high-fat, 
high-cholesterol  diet  over  the  life  span.  This  could 
explain  the  slowly  increasing  serum  cholesterol 
levels  with  aging  in  our  population.  Recent  findings 
also  suggest  that  cholesterol  synthesis  by  extrahepatic 
tissues,  not  regulated  by  dietary  intake,  may  con- 
tribute significantly  to  the  development  of  hyper- 
cholesterolemia and,  therefore,  atherosclerosis  (i). 
Animal  experiments  lead  us  to  suspect  that  the  daily 
pattern  of  eating,  the  number  of  meals,  for  example, 
may  help  to  determine  the  metabolic  fate  of  the 
constituents  of  a  potentially  atherogenic  diet  (28). 

In  the  case  of  a  particular  individual,  the  tendency 
to  develop  this  increase  in  blood  cholesterol  and  to 
acquire  vascular  disease  will  be  subject  to  many 
factors  other  than  the  nature  of  the  diet  (73,  114). 
These  other  factors  per  se  do  not  actually  produce  or 
prevent  atherosclerosis,  but  they  are  capable  of 
influencing  it  in  the  presence  of  a  potentially  athero- 
genic diet.  Those  which  will  be  considered  in  this 
chapter  are:  a)  the  endocrines,  b)  heredity,  and  c) 
stress.  They  are  the  most  significant  ancillary  factors 
so  far  known. 

Because  of  discrepancies  between  the  amount  of 
anatomical  vascular  disease  and  the  occurence  and 
magnitude  of  organ  involvement,  doubt  has  recently 
been  expressed  as  to  the  relationship  of  atherosclerosis 
and,  for  instance,  coronary  heart  disease  (129,  163). 
However,  no  evidence  is  available  that  ischemic  heart 
disease  and  ischemic  disease  of  the  brain,  the  extrem- 
ities, or  other  organs  occur  without  vascular  disease 
(except  on  rare  occasion).  The  major  exception  is  one 
in  which,  with  only  minimal  atheroma  formation,  it 
is  possible  to  produce  experimental  coronary  and 
renal  thrombosis,  and  myocardial  and  renal  infarction 
in  rats  (63),  but  even  here  vascular  abnormalities 
were  produced  only  in  the  presence  of  a  high 
saturated-fat  diet. 

It  is  safe  to  state  that  without  the  basic  arterial 
process  of  atheroma  no  morbid  consequences  would 
exist  except  as  a  rare  phenomenon.  Equally  well 
documented  is  the  fact  that  even  with  moderate  and 
se\  ere  atherosclerosis  no  such  morbid  or  mortal 
consequences  need  occur.  These  findings  clearly  point 
out  that  in  atherosclerosis  research  we  have  to  deal 
with  two  major  questions:  /)  What  produces  the 
basic  vascular  lesions?  2)  What  factor  or  factors  may 
lead  to  the  complications — ulceration,  thrombosis, 
hemorrhage  into  a  plaque—  that  will  ultimately 
determine   the  clinical   fate   of  an   individual?    It   is 


possible  that  the  same  factors  may  determine  both 
aspects.  For  example,  prolonged  hyperlipemia  and 
hypercholesterolemia  produce  lipid  deposition  and 
atheroma  in  the  arteries,  and  these  blood  changes  also 
facilitate  blood  clotting,  so  that  after  an  atheroma  has 
developed  in  this  fashion  the  stimulus  is  there  to  give 
rise  to  subsequent  thrombus  formation.  Similarly, 
different  neurogenic  or  hormonal  factors,  or  both, 
may  conceivably  influence  both  processes.  However, 
their  effect  may  be  preferential  upon  one  or  the  other 
of  these  two  stages.  It  must  also  be  remembered  that 
the  vascular  wall  as  an  organ  is  capable  of  synthesizing 
cholesterol  in  small  amounts  and  phospholipids  in 
larger  quantities  (170,  183).  Furthermore,  it  has 
been  shown  that  species  differences  exist  in  the  02 
uptake  between  normal  and  atherosclerotic  aortas, 
the  ()•>  uptake  being  higher  in  susceptible  species 
and  in  atherosclerotic  specimens  (173).  Permeability 
of  the  vascular  endothelium  is  another  factor  that 
may  be  influenced  by  metabolic  alterations  due  to 
hormonal,  genetic,  or  stressful  circumstances  mediated 
by  hormone  release.  Electron  microscopy  has  con- 
firmed the  concept  that  lipids  are  being  deposited 
in  the  intima  by  permeation  from  the  blood  stream 

('59)- 

Furthermore,  differences  in  the  responses  of  the 
vessels  in  different  vascular  beds  to  hormonal  and 
other  influences  must  not  be  overlooked.  Whether 
these  differences  are  due  to  the  particular  metabolism 
within  the  organ,  to  the  nervous  influences  acting 
upon  it,  or  to  anatomical  differences — possibly  due  to 
genetic  factors — is  not  known  at  present.  Some  evi- 
dence for  each  of  these  causes  is  available  (83,  94, 
138). 

Whether  a  given  duration  and  intensity  of  hyper- 
lipemia and  hypercholesterolemia  will  or  will  not 
lead  to  the  emergence  of  atherosclerotic  disease, 
either  in  the  form  of  the  anatomical  substrate  alone  or 
accompanied  by  the  associated  sequelae,  is  deter- 
mined by  the  genetic  make-up  of  the  individual  and 
very  likely  also  In  the  nature  of  the  environmental 
conditions  under  which  he  lives  out  his  existence. 
Emotional  factors,  dependent  in  part  upon  genetic 
make-up  and  in  part  upon  external  environment, 
have  recently  been  implicated  in  aberrations  of  lipid 
metabolism,  in  the  genesis  of  atherosclerosis,  and  in 
the  transformation  of  a  silent  vascular  disease  into  a 
clinically  overt  one.  Whether  emotional  states 
operate  through  hormones,  or  by  way  of  the  auto- 
nomic nervous  system,  or  both,  is  not  known  at 
present.  It  is  possible  that  hormonal  and  nervous 
factors  themselves  produce  the  emotional  upsets  as  a 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


I!99 


side  effect  independent  of  their  direct  actions  upon 
atherosclerosis  and  ischemic  disease.  It  is  more  likely, 
however,  that  emotional  upsets  induce  hormonal  and 
nervous  factors  which  lead  to  ischemic  disease. 

It  is  thus  apparent  that  any  attempt  to  understand 
the  pathogenesis  of  the  multifaceted  process  of 
atherosclerosis  requires  that  many  factors  be  con- 
sidered. In  considering  them,  the  effects  of  each  on 
lipid  metabolism,  on  the  vascular  wall,  on  blood 
coagulation,  and  on  fibrinolysis  have  to  be  studied 
separately,  and  after  that  all  the  facts  must  be  inte- 
grated to  reconstruct  the  whole  complex  process.  At 
present  there  are  many  gaps  in  our  knowledge  which 
are  difficult  to  bridge.  While  the  influences  of  hor- 
mones and  heredity  on  lipid  metabolism  and  on  the 
vascular  wall  have  been  studied  to  some  extent,  their 
influences  on  blood  clotting  and  fibrinolysis  are  poorly 
understood  at  present,  since  such  studies  are  still  in 
their  infancy.  Equally  scanty  is  our  knowledge  of  the 
effect  of  emotional  factors  on  atherosclerosis  and  its 
sequelae. 


HORMONES 

That  hormones  influence  lipid  metabolism  and 
atherosclerosis  has  long  been  suspected  from  clinical 
findings.  Several  diseases  of  endocrine  organs  show 
alterations  in  serum  lipid  levels  and  are  associated 
with  significant  deviations  in  the  incidence  and 
severity  of  atherosclerosis.  Several  hormones  are  also 
known  to  affect  the  morphologic  characteristics  of  the 
ground  substance  of  the  vascular  wall  and  its  cell 
membrane  permeability.  This  would  indicate  that 
hormones  may  influence  atherosclerosis  either  by  a 
direct  action  on  the  vascular  wall  or  through  their 
influence  on  lipid  metabolism  (synthesis,  absorption, 
transport,  storage,  excretion,  and  destruction),  or 
both.  The  recognition  of  these  factors  stimulated 
extensive  research  into  the  mechanism  of  these 
actions.  Only  the  action  of  the  following  hormones 
will  be  considered  here:  a)  thyroid,  b)  pancreas,  c) 
adrenal  and  pituitary,  and  d)  sex.  The  part  played 
by  others  is  too  poorly  understood  and  too  unimpor- 
tant to  warrant  discussion. 

Thyroid 

The  effect  of  thyroid  hormone  on  lipid  metabolism, 
particularly  cholesterol  metabolism,  has  been  studied 
extensively  in  man  and  in  various  species  of  experi- 
mental animals.  Endogenous  thyroid  hypersecretion, 


as  occurs  in  thyrotoxicosis,  and  the  exogenous 
administration  of  the  hormone  have  identical  effects 
and  will  be  discussed  together.  Different  forms  of 
hypothyroidism,  whether  primary  or  secondarily 
induced  in  man  and  animals  by  surgical  thyroid- 
ectomy or  by  I131  administration,  also  show  similar 
effects.  The  suppression  of  thyroid  hormone  secretion 
by  thiourea  drugs  shows — in  rats  at  least — a  greater 
effect  on  cholestrol  metabolism  than  that  produced 
by  the  other  methods  of  inducing  hypothyroidism 
(22,  62). 

Hyperthyroidism  decreases  serum  cholesterol  levels 
in  man  and  animals.  Recent  tracer  studies  indicate 
that  thyroid  hormone  increases  synthesis  of  cholesterol 
in  the  liver,  particularly  of  the  free  cholesterol 
fraction,  and  also  increases  catabolism  and  fecal 
excretion  of  this  sterol  (cf  22).  Boyd  (22)  found  in 
rats  that  neither  exogenous  thyroid  hormone  nor 
active  thyroid  hormone  analogues  lower  normal  serum 
cholesterol  levels  appreciably;  however,  if  animals  are 
made  slightly  hypercholesterolemic  by  dietary  means, 
then  these  hormone  preparations  depress  the  dietary 
hypercholesterolemia.  It  has  been  demonstrated  that 
this  action  of  thyroxin  or  thyroid  hormone  is  not  due 
to  the  increase  in  basal  metabolic  rate  per  se,  as 
several  thyroxin  analogues  show  the  cholesterol 
depressant  action  without  increase  in  basal  metab- 
olism (21).  Furthermore,  in  chicks  it  was  shown  that 
dinitrophenol,  a  drug  that  increases  basal  metab- 
olism, has  no  effect  on  serum  cholesterol  levels 
(148).  Thyroid  hormones  also  reduce  /^-lipoprotein 
concentration  and  that  of  certain  classes  of  high 
density  a-lipoproteins  (70). 

Hypothyroidism  in  man  and  animals  produces  a 
decreased  synthesis  of  cholesterol  while  the  biological 
half-life  of  serum  cholesterol  is  increased  and  fecal 
excretion  is  reduced  (22).  The  effect  of  hypothy- 
roidism on  lipoproteins  is  the  direct  opposite  of  the 
effect  of  exogenous  thyroid  hormone  administration, 
i.e.,  it  causes  an  increase  in  /3-lipoproteins. 

Pituitary  thyroid  stimulating  hormone  is  without 
direct  effect  on  cholesterol  metabolism  and  athero- 
sclerosis. 

Thyroid  hormone  also  affects  the  vascular  wall. 
This  has  long  been  established  in  the  older  literature. 
Large  doses  of  thyroxin  or  dessicated  thyroid  cause 
damage  to  the  vascular  media.  They  produce  necrosis 
and  calcification,  similar  to  the  changes  produced  by 
catecholamines  (10).  These  are  arteriosclerotic 
changes,  not  atherosclerosis.  Smaller  doses  of  thyroid 
hormone  preparations  have  been  shown  to  reduce 
cholesterol-oil-induced       hypercholesterolemia       and 


1200  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


atherosclerosis  in  rabbits  (164).  In  chicks,  larger 
doses  of  these  hormones  always  depress  diet-induced 
hypercholesterolemia;  however,  the  effect  on  the 
vascular  lesions  is  inconstant  and  inconsistent  (152, 
154).  This  may  be  due  to  the  second  action  of  the 
thyroid  in  producing  vascular  damage,  providing  a 
favorable  site  for  lipid  deposition  and  atherosclerosis. 
In  contrast  to  the  inconsistent  effects  of  excess 
thyroid  hormones,  the  deficiency  of  the  hormone 
(hypothyroidism)  always  produces  increased  athero- 
genesis  in  animals  on  a  potentially  atherogenic  diet. 
This  has  been  shown  in  chicks  (154),  rats  (178), 
rabbits  (165),  and  monkeys  (146).  Dogs  develop 
atherosclerotic  lesions  only  when  a  high-fat,  high- 
cholesterol    diet    is    combined    with    hypothvroidism 

(158). 

No  information  is  available  at  present  indicating 
an  effect  of  thyroid  hormones  on  blood  coagulation  or 
fibrinolysis. 

It  can  be  concluded  from  all  available  data  that 
thyroid  hormone  has  a  significant  and  important 
effect  on  cholesterol  metabolism.  The  direct  effect  on 
atherosclerosis  is  undetermined  and  questionable. 
The  continuing  effort  to  separate  calorigenic  from 
hypocholesterolemic  effects  in  thyroid  analogues 
ultimately  may  alter  the  utility  of  thyroid  preparations 
as  antiatherogenic  substances. 

Pancreatic  Hormones 

Studies  in  man  and  in  experimental  animals 
indicate  that  two  hormonal  systems  in  the  pancreas 
are  actively  involved  in  lipid  metabolism  and, 
therefore,  in  the  control  of  the  circulating  serum 
lipids.  These  can  operate  independently  or,  more 
often,  in  an  interrelated  manner. 

Knowledge  of  the  two  hormonal  systems  of  the 
pancreas  in  man  has  been  derived  from  the  study  of 
pancreatitis  and  diabetes  mellitus.  In  addition, 
pancreatic  enzyme  systems  are  known  to  influence 
absorption  from  the  upper  digestive  tract.  Elastase, 
presumably  a  pancreatic  enzyme,  by  influencing  the 
elastic  tissue  in  the  media  of  the  blood  vessels,  can 
change  wall  permeability  and  thus  modify  calcium 
and  lipid  deposition  in  the  intima  (82). 

chronic  pancreatitis.  Chronic  pancreatitis  in  man 
with  hyperlipemia  and  xanthomatosis,  without 
diabetes,  was  first  described  by  Wiesel  (175)  in  1905. 
Binet  &  Brocq  (15)  in  1929  reported  a  transient 
hyperlipemia  and  hypercholesterolemia  in  dogs  with 
experimental    pancreatitis.    An    antifatty    liver    sub- 


stance high  in  bound  choline  was  prepared  from  the 
pancreas  of  dogs  by  Drae;stedt  (34,  35).  Adlersberg 
and  co-workers  carried  out  the  most  recent  studies  on 
experimental  pancreatitis  in  dogs  and  rabbits,  and 
also  studied  chronic  pancreatitis  in  man  (7,  167). 
He  described  the  serum  changes  as  consisting  of  a 
two-  to  three-fold  increase  in  cholesterol  and  phos- 
pholipids with  a  four-  to  ten-fold  increase  of  total 
lipids,  the  triglycerides,  rendering  the  serum 
lactescent.  The  mechanism  producing  these  serum 
lipid  changes  has  not  been  clarified.  An  action  by  way 
of  the  enzyme  system  affecting  lipid  absorption  has 
to  be  considered.  Also  destruction  of  the  a-cells  of 
the  islets  of  Langerhans  and  their  glucagon  content 
may  be  involved  (26).  The  elevation  of  triglycerides 
is  considered  the  primary  change  leading  secondarily 
to  hypercholesterolemia  and  hyperlipemia  by  others 
(47).  The  significance  of  these  findings  in  the  patho- 
genesis of  atherosclerosis  needs  further  study. 

diabetes  mellitus.  The  grossly  and  significantly 
increased  incidence  of  atherosclerosis  in  individuals 
with  diabetes  mellitus  has  led  to  numerous  clinical 
and  experimental  studies  on  the  influence  of  the 
hormones  of  the  islets  of  Langerhans,  particularly 
insulin,  on  carbohydrate  and  lipid  metabolism  and  on 
atherosclerosis. 

The  morphology  of  the  arterial  lesions  in  the 
diabetic  does  not  differ  from  that  in  the  nondiabetic. 
The  difference  between  the  two,  then,  is  quantitative. 
However,  in  diabetes  mellitus  a  characteristic  capil- 
lary lesion  in  the  retina  and  the  kidney  is  found, 
consisting  of  capillary  microaneurysms.  Changes  in 
serum  lipids  and  complex  carbohydrates  are  usually 
found  when  capillary  lesions  are  present. 

Severely  atherosclerotic  diabetic  patients  frequentlv 
show  distinct  disturbances  of  lipid  and  lipoprotein 
metabolism,  including  hyperlipemia,  hypercho- 
lesterolemia, hyper-/j-lipoproteinemia,  and  a  marked 
elevation  of  esterified  fatty  acids  (5,  16).  They  also 
have  increased  levels  of  serum  polysaccharides.  In 
diabetic  acidosis  and  ketosis  marked  hyperlipemia  and 
hvpercholesterolemia  are  present,  in  addition  to 
hyperglycemia.  Insulin  treatment  results  in  bringing 
all  three  abnormalities  toward  normal.  However, 
insulin  given  to  normal  individuals  has  no  cho- 
lesterol-lowering effect  (20). 

Experimental  studies  on  the  effect  of  diabetes 
mellitus  and  of  insulin  on  lipid  metabolism  and 
atherosclerosis  have  been  carried  out  on  numerous 
animal  species,  including  dogs,  rabbits,  rats,  and 
chicks.   In  all  animals  tested,  diabetes  produced   b\ 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


I  20  I 


alloxan  injections  or  by  pancreatectomy  failed  to 
cause  atherosclerosis.  When  experimental  diabetes 
was  combined  with  cholesterol-fat  feeding,  athero- 
sclerosis incidence  was  not  higher  than  in  normal 
animals  on  the  same  diet.  Of  particular  interest  are 
the  findings  by  Duff  et  al.  (38),  who  showed  a  de- 
creased atherogenesis  in  diabetic  rabbits  on  a  cho- 
lesterol-oil diet.  This  trend  was  reversed  when  the 
animals  were  treated  with  insulin.  These  workers 
attributed  this  effect  to  the  particular  serum  lipid 
picture  developing  under  these  circumstances. 
Alloxan  diabetes  produced  a  marked  hyperphos- 
pholipemia  with  hypercholesterolemia  and  an  in- 
crease in  serum  neutral  fat.  These  animals,  therefore, 
had  a  low  ratio  of  total  cholesterol  to  phospholipids 
(C/P  ratio)  in  the  hypercholesterolemic  state.  This 
particular  lipid  picture  is  usually  accompanied  by  a 
low  incidence  and  severity  of  vascular  lesions.  Insulin 
given  to  these  rabbits  caused  the  lipid  picture  to 
change  so  as  to  resemble  the  usual  pattern  obtained 
by  cholesterol-fat  feeding  alone,  namely  a  marked 
hypercholesterolemia  with  a  mild  hyperphospho- 
lipemia.  This,  in  turn,  resulted  in  an  elevated  C/P 
ratio  and  the  attendant  increased  incidence  and 
severity  of  atherosclerosis. 

Interesting  results  were  also  obtained  in  studies  of 
the  pancreas  and  atherogenesis  in  chicks  (154,  156) 
Pancreatectomized  birds  show  no  overt  signs  of 
disturbances  of  lipid  or  glucose  metabolism.  However, 
latent  disturbances  can  be  detected  when  these  birds 
are  given  a  high-cholesterol,  high-fat  diet  or  when 
adrenal  steroids  are  administered.  On  this  diet  they 
show  enhanced  hypercholesterolemia  and  athero- 
sclerosis, as  well  as  retarded  healing  of  lesions.  With 
glucocorticoids  they  show  a  definite  hyperglycemic 
response  which  is  much  greater  than  occurs  in  normal 
animals  given  these  steroids.  Cholesterol-fed,  steroid- 
diabetic  chicks  do  not  show  increased  atherogenesis. 
Insulin,  in  hypoglycemic  doses,  when  given  to  normal 
chicks  does  not  increase  the  atherogenic  potential  of 
a  high-cholesterol,  high-fat  diet.  However,  in  these 
same  doses  insulin  prevents  regression  of  coronary 
artery  lesions  when  it  is  given  to  chicks  which  are 
first  made  atherosclerotic  and  then  placed  on  a 
plain,  nonatherogenic  diet — a  diet  which  by  itself 
normally  leads  to  rapid  regression  of  these  early 
coronary  lesions.  The  mechanism  by  which  insulin 
prevents  regression,  while  at  the  same  time  appearing 
to  be  without  effect  during  the  induction  phase,  is 
not  clear.  Large  doses  of  insulin  were  used  in  these 
experiments,  and  this  did  cause  marked  hypoglycemia 
which  in  some  way  acted  in  a  detrimental  manner. 


Also,  the  insulin  probably  increased  the  secretion  of 
catecholamines  and  corticoids,  as  evidenced  by  the 
occurrence  of  periods  of  reactive  hyperglycemia. 
Furthermore,  some  recent  observations  indicate  that 
chronic  insulin  administration  may  produce  pro- 
longed hyperglycemia  after  the  drug  administration 
is  discontinued,  indicating  some  profound  hormonal 
derangement.  Local  effects  within  an  atheroma  also 
cannot  be  excluded. 

How  much  of  the  effect  of  diabetes  mellitus  or 
insulin  on  atherosclerosis  is  due  to  the  changes  in 
lipid  metabolism  and  how  much  to  factors  influencing 
the  vascular  wall  is  not  clearly  established.  Further- 
more, several  authors  (32,  84)  have  suggested  that  in 
diabetics,  and  even  in  nondiabetic  members  of  their 
families,  the  ground  substance  of  the  vascular  wall  is 
subtly  changed,  making  it  particularly  prone  to 
atherosclerosis.  In  addition,  blood  coagulation  is 
changed  in  uncontrolled  diabetes  as  in  other  hyper- 
lipemia states. 

From  all  this  it  is  apparent  that  the  increased 
tendency  of  the  diabetic  to  develop  atherosclerosis 
must  depend  on  a  number  of  factors. 

Adrenal  and  Pituitary  Hormones 

Adrenal  cortical  and  medullary  hormones  have 
been  shown  to  influence  lipid  metabolism  and  the 
vascular  wall.  However,  the  lipid  metabolic  responses 
to  these  hormones  differ  among  the  several  animal 
species  studied,  including  man.  Also,  their  acute  and 
chronic  effects  on  circulating  serum  lipids  differ. 
The  mechanism  of  their  action  has  not  been  satis- 
factorily elucidated. 

adrenal  cortical  hormones  and  acth.  Hyper- 
activity of  the  adrenal  cortex  in  Cushing's  disease  is 
frequently  associated  with  hypercholesterolemia  and 
hyperlipemia  and  a  tendency  to  severe  premature 
atherosclerosis  (64,  68,  177).  In  contrast,  bilateral 
destruction  of  the  adrenals  in  Addison's  disease  is 
accompanied  by  low  serum  cholesterol  levels  (142). 
Furthermore,  the  adrenal  cortex  has  a  high  chol- 
esterol content  and  it  can  synthesize  and  discharge 
cholesterol  and  steroid  hormones  readily  (147,  1  74)- 

Adrenalectomized  dogs  maintained  on  desoxycorti- 
costerone  acetate  (DCA)  show  a  marked  decrease  of 
serum  cholesterol  and  phospholipid  levels  (31,  182). 
When  cortisone  is  substituted  for  DCA,  a  marked 
rise  in  these  lipids  occurs.  Combined  DCA  and  corti- 
sone administration  showed  no  further  increase  over 
cortisone  alone.  It  was  concluded  from  these  studies 


I  202  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


that  the  primary  effect  on  circulating  lipids  is  due  to 
cortisone  (31,  182).  It  has  to  be  borne  in  mind, 
however,  that  data  derived  on  adrenalectomized 
animals  are  complicated  by  the  fact  that  simul- 
taneously with  the  depletion  of  cortical  hormones 
there  is  also  a  lack  of  medullary  catecholamines,  and 
these,  too,  have  an  effect  on  lipid  metabolism. 

Aldosterone,  the  adrenal  hormone  affecting  elec- 
trolyte metabolism,  apparentlv  has  no  effect  on  the 
circulating  lipids,  but  may  affect  the  vascular  wall 
according  to  some  recent  data  (80). 

The  pituitarv  adrenocorticotropic  hormone 
(ACTH)  has  an  effect  similar  to,  but  less  marked  than, 
cortisone.  In  man,  the  administration  of  either  corti- 
sone or  ACTH  produces  an  initial  depression  of 
serum  cholesterol  levels  with  a  subsequent  rise  on 
continued  administration  (144).  In  the  dog,  the 
response  of  the  serum  lipids  to  corticosteroids, 
particularly'  cortisone,  is  relatively  mild.  In  the  rabbit 
and  the  rat,  the  effects  of  ACTH  and  corticosteroids 
are  qualitatively  similar  but  much  more  pronounced. 
The  serum  cholesterol  elevation  resulting  from  corti- 
sone treatment  is  especially  marked  in  the  free 
cholesterol  fraction.  Phospholipids  are  elevated 
concomitantly,  resulting  in  a  normal  C/P  ratio, 
despite  elevated  cholesterol  levels.  Triglycerides  are 
also  increased,  rendering  the  serum  lactescent  (7). 
In  the  chick,  the  active  steroid  is  1 7-hydroxycorti- 
costerone  (compound  F).  It  has  lipid  effects  similar 
to  those  described  in  the  rabbit  for  cortisone. 

Atherosclerosis  has  not  been  induced  in  dogs, 
rabbits,  or  chicks  by  the  administration  of  adrenal 
cortical  hormones  despite  the  lipid  changes  they 
produce.  If  these  steroids  are  given  in  the  presence  of 
an  atherogenic  diet,  the  effect  on  the  circulating 
lipids  is  variable  depending  upon  the  species,  but 
the  effect  on  atherogenesis  is  similar — corticoids 
depress  cholesterol-induced  atherogenesis. 

It  has  been  postulated  that  the  atherosclerosis- 
depressing  action  of  these  steroids  is  due  to  their 
decreasing  the  permeability  of  the  vascular  endo- 
thelium. Adlersberg's  group  has  shown  that  when 
hyaluronidase — a  substance  which  increases  cell 
permeability — is  given  simultaneously  with  cortisone 
the  atherosclerosis-inhibiting  action  of  the  corticos- 
teroids is  overcome  and  atherosclerosis  proceeds  as 
in  the  controls  (166). 

Some  authors  produced  increased  arteriosclerosis 
and  secondarily  atherosclerosis  by  the  administration 
of  ACTH  in  rats  (171,  172)  and  dogs  (100).  It  is 
possible  that  these  effects  are  due  to  the  action  of  the 


hormone  on  the  vascular  ground  substance  (muco- 
polysaccharides) and  fibroblasts  (102). 

No  specific  data  are  available  implicating  the 
adrenal  cortical  hormones  in  blood  coagulation  or 
clot  lysis. 

adrenal  medullary  hormones.  /-Epinephrine  is 
the  adrenal  medullary  hormone  most  extensively 
studied.  It  influences  lipid  metabolism  and  produces 
damage  of  the  vascular  wall  in  the  form  of  medial 
necrosis  and  calcification.  The  other  catecholamines 
probably  act  in  a  similar  manner.  Both  of  these 
actions  of  /-epinephrine  may  produce  arterio-  and 
atherosclerosis.  In  addition,  /-epinephrine,  being  a 
pressor  agent,  may  further  increase  atherogenesis  due 
to  the  arterial  hvpertension  which  ensues  on  chronic 
endogenous  overproduction  or  by  protracted  exog- 
enous administration  of  the  hormone  (126). 

In  the  older  literature  disparate  data  on  the 
circulating  lipids  after  catecholamine  administration 
have  been  described.  Some  observers  noted  a  transient 
hyperlipemia,  probably  due  to  an  action  on  mobiliza- 
tion and  transport  (33,  45,  60,  71).  Others  observed  a 
decrease  in  serum  cholesterol,  phospholipid,  and  total 
lipids  (39,  71).  Recently,  Shafrir  el  a!.  (143)  clarified 
some  of  these  discrepancies.  They  showed  that  a  single 
subcutaneous  injection  of  /-epinephrine  in  dogs 
produces  a  prompt,  transient  elevation  of  serum-free 
fatty  acids  and  a  delayed  elevation  of  /i-lipoproteins. 
Prolonged  daily  /-epinephrine  administration,  how- 
ever, produced  a  marked  increase  in  cholesterol 
levels,  with  a  smaller  concomitant  rise  in  phos- 
pholipids. This  epinephrine  reaction  was  abolished  by 
adrenalectomy  and  restored  by  cortisone  treatment. 

anterior  pituitary  hormones.  Pituitary  growth 
hormone  (somatotropin)  influences  lipid  mobilization 
and  transport  as  well  as  the  distribution  of  lipid 
between  the  liver  and  fat  depots  (85).  Information 
on  the  influence  of  this  hormone  on  circulating 
serum  lipids  is  scant  and  the  effects  are  variable  in 
different  species.  However,  this  may  be  due,  in  part 
at  least,  to  the  fact  that  there  are  differences,  both 
physiological  and  chemical,  in  the  nature  of  growth 
hormone  preparations  obtained  from  different  animal 
species  (19).  Some  stimulation  of  fibroblast  growth 
with  this  hormone  has  been  described  (102).  No  data 
are  available  indicating  any  possible  effect  of  this 
hormone  on  atherogenesis. 

Recently,  Rudman  et  al.  (134)  demonstrated  the 
existence  of  a  separate  and  distinct  hyperlipemia- 
producing  hormone  of  the  anterior  pituitary. 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


1203 


conclusion.  All  these  studies  would  suggest  that  the 
adrenal  and  pituitary  glands  have  a  significant 
influence  on  lipid  metabolism,  but  the  exact  mecha- 
nism of  these  effects  is  still  poorly  understood.  They 
also  affect  the  metabolism  of  the  vascular  wall  and 
may,  therefore,  be  intimately  related  to  athero- 
sclerosis. Whether  they  have  a  direct  effect  on  blood 
coagulation  and  clot  lysis  has  not  yet  been  explored. 
Some  effects  attributable  to  nervous  and  emotional 
factors  may  actually  be  related  to  the  release  of 
adrenal  hormones  under  these  circumstances.  Further 
studies  of  these  hormones  should  be  conducted. 

Sex  Hormones 

Numerous  clinical  and  experimental  studies 
indicate  a  profound  influence  of  male  and  female 
gonadal  hormones  on  lipid  and  lipoprotein  metab- 
olism and  atherosclerosis.  Also,  it  has  been  reported 
that  these  hormones  exert  a  marked  influence  on 
ground  substance  and  connective  tissue  elements  as 
well  as  a  slight,  less  well  understood,  effect  on  the 
clotting  mechanism.  The  influences  of  female  sex 
hormones  are  more  pronounced  than  those  of  the 
male  hormone,  and  the  effects  of  the  male  and  female 
hormones  are  in  general  opposite  and  antagonistic. 

The  levels  of  circulating  lipids  and  lipoproteins  in 
normal  males  and  females  of  all  ages  have  been 
extensively  studied  (6,  96,  135).  Up  to  the  age  of  20 
years,  total  cholesterol  and  phospholipid  levels  are 
similar  in  the  two  sexes.  Both  these  lipid  fractions  rise 
significantly  in  men  up  to  the  age  of  33,  and  then 
remain  stable  up  to  age  60.  In  women,  on  the  con- 
trary, they  stay  constant  up  to  the  age  of  32,  and 
from  then  on  a  steady  rise  occurs  until  58  years  of 
age.  The  1  :3  ratio  of  free  to  esterified  cholesterol  is 
fairly  constant  in  both  sexes  at  all  ages. 

Serum  lipoprotein  patterns  show  a  distinctly  sex- 
linked  difference,  as  does  the  cholesterol  content  in 
the  different  lipoprotein  fractions.  Young  women 
have  more  a-lipoproteins  and  a-lipoprotein  cho- 
lesterol than  men  of  all  ages,  postmenopausal  women, 
or  castrated  women.  Oliver  &  Boyd  (no,  111) 
studied  lipids  and  lipoproteins  during  the  menstrual 
cycle  and  during  pregnancy  and  found  a  depression  of 
^-lipoproteins  and  of  the  cholesterol  phospholipid 
(C/P)  ratio  coincident  with  the  peak  of  estrogen 
secretion  at  ovulation.  During  the  third  trimester  of 
pregnancy  /3-lipoproteins  and  the  C  P  ratio  increase 
despite  large  estrogen  secretion.  These  contradictory 
findings  need  clarification. 

Sex  differences  in  serum  cholesterol  levels  are  also 


observed  in  animals.  Female  rats  have  higher  serum 
cholesterol  levels  than  males  (22).  Egg-laying  hens  and 
pigeons  have  elevated  serum  cholesterol  levels  with 
very  high  phospholipid  levels  and,  therefore,  signifi- 
cantly depressed  C  P  ratios. 

The  normal  lipoprotein  pattern  of  the  chick  differs 
from  that  of  man  and  most  mammals  in  that  the  main 
component  is  a-lipoprotein  (151).  Furthermore, 
giving  estrogens  to  the  cockerel  elevates  ^-lipoprotein, 
instead  of  a-lipoprotein  as  in  man  (151).  Incidentally, 
the  effect  of  diet  on  lipoprotein  levels  in  chicks  is  also 
opposite  to  that  seen  in  man. 

In  man,  androgens  increase  /^-lipoproteins  and 
serum  cholesterol.  Eunuchs  have  lower  cholesterol 
and  /^-lipoprotein  le\-els  than  normal  men  (52). 

Estrogen  administration  to  men  or  postmenopausal 
women  changes  the  serum  lipoprotein  pattern  to  the 
young  female  type  and  this  pattern  remains  as  long 
as  therapy  is  continued,  even  over  several  years  (151, 
155).  The  effect  on  serum  cholesterol  is  not  so  uni- 
form. Several  authors  described  a  fall  (7,  110),  while 
others  found  no  change  (151,  155).  However,  there  is 
uniform  agreement  that  the  phospholipid  level 
rises  and  therefore  that  the  C/P  ratio  falls. 

Androgens  even  in  small  doses,  given  to  men 
concomitantly  with  estrogens,  counteract  the  estro- 
genic serum  lipid  effect  without  counteracting  the 
feminizing  effect  on  the  secondary  sex  characteristics. 
The  latter  action  represents  one  instance  where  the 
action  of  the  two  hormones  is  not  antagonistic,  at 
least  in  man. 

The  mechanism  by  which  the  gonadal  hormones 
influence  lipid  metabolism  is  not  yet  entirely  clarified. 
Boyd  (22)  carried  out  tracer  studies  with  C14-labeled 
acetate  in  rats  and  found  that  estrogens  slightly 
depress  plasma  cholesterol  synthesis  and  significantly 
reduce  the  biological  half-life  of  cholesterol.  Ovariec- 
tomy in  female  rats  had  the  opposite  effect  (22,  44). 

Furman  et  al.  (53)  have  shown  an  interrelationship 
of  methyltestosterone  and  dietary  protein  intake  on 
serum  lipoproteins  in  men.  On  a  low-protein  or 
protein-free  formula  diet  both  a-  and  ^-lipoproteins 
were  significantly  depressed,  beyond  the  depression  of 
the  protein-free  diet  alone.  These  findings  have  been 
confirmed  by  Olson  &  Vester  (1 15). 

A  very  definite  action  of  the  sex  hormones,  particu- 
larly the  estrogens,  on  atherosclerosis  has  also  been 
established.  Data  from  clinical  medicine  are  sugges- 
tive, experimental  data  on  animals  are  indicative. 

Premenopausal  women  have  less  gross  coronary 
atherosclerosis  than  men  or  castrated  women  (127, 
181)  and  a  markedly  lower  incidence  of  myocardial 


[204 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


infarction  (113,  130).  After  the  menopause  the 
incidence  of  myocardial  infarction  in  women  slowly 
rises  to  become  almost  equal  to  that  in  men  by  the 
eighth  decade  (110,  113).  Furthermore,  Marmorston 
et  al.  (99)  have  shown  that  postmenopausal  women 
with  coronary  artery  disease  have  lower  urinary 
estrogen  levels  than  healthy  women  of  the  same  age, 
and  also  have  lower  levels  of  protein-bound  iodine 
indicating  a  decreased  thyroid  function.  Bersohn  & 
Oelofse  (14)  made  similar  observations  in  man.  Aortic 
atherosclerosis  shows  no  significant  sex  difference  (43, 
128,  176).  The  protection  of  the  female  from  coronary 
atherosclerosis  is  lost  in  the  presence  of  familial 
hypercholesterolemia  and  in  diabetes  mellitus. 

Cockerels  on  a  high-fat,  high-cholesterol  (athero- 
genic) diet  are  protected  against  coronary  athero- 
sclerosis when  given  estrogens  (1 19).  Also,  previously 
induced  atherosclerosis  can  be  completely  reversed  by 
the  hormone  (120).  Aortic  atherosclerosis  is  not 
influenced.  Sexually  mature,  estrogen-secreting  hens 
fed  the  atherogenic  diet  develop  aortic  atherosclerosis 
but  no  coronary  atherosclerosis  (150).  Castration  of 
these  hens  makes  them  susceptible  to  coronary  lesions 
(121).  Estrogens  given  to  chicks  on  a  normal  non- 
estrogenic  diet  induce  aortic  atherosclerosis,  but  not 
coronary  atherosclerosis  (27,  67,  86).  These  different 
effects  of  estrogens  on  coronary  and  aortic  athero- 
sclerosis are  a  good  example  of  the  previously  stated 
observation  that  local  anatomic  or  metabolic  factors 
are  of  importance  in  atherogenesis.  This  makes  it 
imperative  for  the  investigator  to  study  the  several 
vascular  beds  separately,  and  not  to  draw  the  con- 
clusion that  observations  made  in  one  vascular  bed 
necessarily  apply  to  other  parts  of  the  arterial  tree. 

Freedom  from  coronary  lesions  in  chickens  is 
accompanied  by  the  previously  described  char- 
acteristic serum  lipid  changes  resulting  in  a  normal 
C  V  ratio  in  the  presence  of  hypercholesterolemia. 
The  same  effect  on  lesions  and  lipids  was  obtained 
in  rats  (108).  In  male  rabbits  neither  serum  lipid 
changes  nor  coronary  protection  can  be  achieved  by 
estrogen  administration  (151).  Ludden  et  al.  (91) 
observed  that  both  androgens  and  estrogens  protect 
intact  female  rabbits  from  cholesterol-induced  aortic 
atheroscerosis.  Neither  hormone  was  effective  in 
males  or  in  castrated  females. 

Another  exception  to  this  sex  phenomenon  is 
atherosclerosis  in  a  susceptible  strain  of  pigeons 
(vide  infra).  Old,  egg-laying  pigeons  show  coronary 
atherosclerosis  despite  the  usual  low  C/P  ratio 
characteristic  for  female  birds  (66,  88-90). 

Androgens    in    large    doses    depress    diet-induced 


hypercholesterolemia     without     influencing     athero- 
sclerosis (123). 

Studies  in  chicks  revealed  that  estrogen  protection 
is  preserved  even  if  estrogen  administration  is  com- 
bined with  androgen  administration  or  with  ad- 
ministration of  DCA  or  compound  F,  or  is  used  after 
pancreatectomy  (149,  154)-  The  only  clear-cut 
reversal  of  the  estrogen  effect  was  obtained  when 
chicks  were  made  hypothyroid  by  the  administration 
of  thiouracil  (122).  A  slight  decrease  of  estrogen 
reversal  of  previously  induced  lesions  was  observed 
when  insulin  was  administered  concomitantly  with 
estrogens  during  the  period  when  the  lesions  were 
regressing  (154).  Recently,3  we  have  noted  that 
blocking  the  reticulo-endothelial  system  also  pre- 
vented the  estrogen  effect. 

Estrogens  have  also  been  shown  to  stimulate 
growth  of  ground  substance,  particularly  collagen  and 
fibroblasts.  They  also  stimulate  the  reticuloendothelial 
system  (18,  25).  Furthermore,  there  is  some  indication 
that  estrogens  influence  fibrin  content  and  fibrinolytic 
activity  of  the  blood  (11,  56,  57).  It  has  also  been 
reported  that  intravenous  injection  of  estrogens, 
particularly  conjugated  equine  estrogens,  has  a 
hemostatic  effect  (58). 

An  indication  that  the  local  influence  of  estrogens 
on  the  vascular  wall  may  be  related  to  athero- 
sclerosis was  recently  obtained  in  chicks.  It  was  shown 
that  atherosclerotic  abdominal  aorta  and  coronary 
lesions,  produced  by  a  high-fat,  high-cholesterol,  low- 
protein  diet,  can  ulcerate  if  large  doses  of  estrogens  are 
given  (76).  In  the  chick  this  was  shown  to  occur  as  a 
stage  in  the  healing  process  of  these  lesions.  This  is 
the  first  suggestion  that  estrogens  may  also  influence 
the  vascular  wall  of  the  aorta. 

The  action  of  estrogens  on  lipid  metabolism  and 
atherogenesis  stimulated  several  long-term  research 
projects  in  man  using  different  female  sex-hormone 
preparations  in  the  therapy  of  patients  with  proven 
ischemic  heart  disease  (101,  112,  131,  151,  155).  The 
results  show  a  possible  life-prolonging  action  only 
when  a  natural  estrogen  preparation  (conjugated 
equine  estrogens)  is  being  used.  It  is  not  known  wh\ 
this  difference  exists  between  natural  and  synthetic 
compounds.  The  therapeutic  value  of  this  regimen  is, 
however,  limited  by  the  accompanying  feminizing 
action  of  the  hormone.  Several  nonfeminizing  estrogen 

3 Pick,  R.,  L.  N.  Katz,  P.  J.  Johnson,  and  D.  E.  Century.  The 
role  of  the  reticulo-endothelial  system  and  estrogens  on  coro- 
nary atherogenesis  in  cholesterol-fed  cockerels.  Circulation.  In 
press.  I  October  1962.) 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


I  21)- 


derivatives  are  being  explored,  so  far  without  worth- 
while results. 

From  all  these  data  it  is  evident  that  gonadal 
hormones  have  a  significant  influence  upon  lipid 
metabolism  and  atherogenesis. 


HEREDITY 

That  genetic  or  hereditary  factors  may  influence 
the  development  of  atherosclerosis  is  suggested  by 
animal  experimental  and  human  studies.  It  has  to  be 
emphasized,  however,  that  these  tendencies  become 
evident  only  in  the  presence  of  a  potentially  athero- 
genic diet.  If  the  environment  is  favorable,  genetic 
tendencies  may  not  become  evident.  As  in  many 
other  diseases,  the  interplay  between  host  and  en- 
vironment is  of  the  utmost  importance. 

Animal  experiments  have  indicated  species  differ- 
ences in  the  susceptibility  of  atherosclerosis.  Man  and 
several  species  of  birds  develop  atherosclerosis  spon- 
taneously (51).  Also  old  dogs,  kept  as  pets,  have  been 
found  to  exhibit  aortic  and  coronary  atherosclerosis 
(87).  Most  animals,  however,  living  in  their  natural 
environment  do  not  exhibit  vascular  lesions,  with  the 
possible  exception  of  the  baboon  (55,  93)  which 
shows  fatty  streaks  in  the  aorta. 

Species  differences  are  also  found  in  the  response  to 
high-level  cholesterol-fat  feeding.  Chicks  and  rabbits 
respond  to  this  regimen  with  severe  hypercholestero- 
lemia and  atherosclerosis  in  a  short  period  of  time 
(10,  72).  It  is  more  difficult  to  produce  similar  effects 
in  ducks,  guinea  pigs,  and  hamsters  (8,  9,  59).  In  the 
dog,  cholesterol  feeding  has  to  be  combined  with 
supression  of  the  thyroid  activity  in  order  to  produce 
both  lipid  and  vascular  changes.  In  the  monkey, 
cholesterol  feeding  has  to  be  combined  with  a  de- 
ficiency in  sulfur-containing  amino  acids  in  the  diet  to 
produce  lesions  (98).  Recently,  however,  athero- 
sclerosis was  induced  in  rhesus  monkeys  by  a  high- 
saturated  fat,  high-cholesterol,  nondeficient  diet  alone 
(29).  In  the  rat,  the  species  most  resistant  to  the 
induction  of  atherosclerosis,  this  disease  has  been 
produced  by  a  combination  of  multiple  dietary  and 
hormonal  manipulations,  i.e.,  cholesterol,  cholic  acid, 
and  saturated  fat  in  the  diet,  plus  hypothyroidism  and 
unilateral  nephrectomy  (63). 

The  cause  of  these  species  differences  has  not  been 
entirely  clarified.  Recent  tracer  studies,  however, 
indicate  species  differences  in  cholesterol  synthesis, 
turnover,  and  degradation  rates,  and  in  the  handling 
of  dietary  cholesterol  (61,  62).  Other  studies  indicate 


differences  in  the  number  of  vasa  vasorum  in  the 
aorta — richest  in  resistant  species  and  poorest  in  the 
very  susceptible  (139).  Whether  or  not  these  species 
differences  are  the  actual  cause  of  the  varied  suscepti- 
bility  to  hypercholesterolemia  and  atherosclerosis  is 
not  known.  Nor  is  it  known  how  they  are  inherited. 

More  significant  perhaps  than  species  differences, 
are  strain  differences  which  occur  within  a  single 
species.  These  have  been  demonstrated  in  rabbits 
(145).  In  chicks  they  have  been  described  by  Opdyke 
&  Ott  (116)  and  others  (46).  They  have  been  indi- 
cated in  dogs  (100).  The  most  recent  and  thorough 
investigations  into  strain  differences  was  carried  out 
by  Lofland  &  Clarkson  (88,  89,  90)  who  have  studied 
several  breeds  of  pigeons,  in  particular:  the  White 
Carneau,  the  White  Racer,  and  the  Autosexing  King. 
The  first  shows  severe  aortic  and  some  coronary 
atherosclerosis  in  old  birds  of  both  sexes  kept  on  a 
low-cholesterol,  low-fat  commercial  diet.  The  second 
strain  does  not  show  any  lesions  on  the  same  diet. 
The  third,  genetically  a  cross-breeding  between  the 
first  two,  has  intermediate  incidence  and  severity  of 
lesions.  The  onset  of  atherosclerosis  in  response  to 
high  cholesterol  feeding  of  the  three  breeds  parallels 
the  severity  of  the  spontaneous  lesions.  All  three 
breeds  spontaneously  have  high  serum  cholesterol 
levels,  around  400  mg  per  cent,  with  marked  seasonal 
variations  (66),  and  resemble  one  another  in  many  of 
the  biochemical  aspects  studied  by  these  authors. 
Wherein  lies  the  definitely  genetic  difference  in  the 
production  of  lesions  is  unexplained. 

In  man,  it  has  often  been  suggested  that  genetic 
and  hereditary  factors  may  play  a  role  in  lipid 
metabolism  and  coronary  atherosclerosis.  The  first 
indication  of  such  a  relationship  was  described  in 
1930  (65).  A  vast  literature  on  statistical  and  genetic 
investigations  has  since  appeared  proving  the  familial 
occurrence  of  a  xanthomatous  tendency,  i.e.,  a 
tendencv  for  hypercholesterolemia  and  atherosclerosis 
to  appear  in  families.  This  was  reviewed  recently  by 
McKusick  (94).  The  most  extensive  clinical  studies 
were  carried  out  by  Adlersberg  et  al.  (2-4)  and  by 
Thomas  &  Cohen  (161).  Some  limited  studies  are 
available  on  the  incidence  of  these  disorders  in 
identical  and  fraternal  twins,  living  together  or 
separately,  which  may  aid  in  determining  the  respec- 
tive roles  of  heredity  and  the  environment  (118). 

Adlersberg  and  others  (3,  17,  40,  137,  161)  con- 
sider hypercholesterolemia  an  inborn  error  of  metab- 
olism, probably  inherited  as  an  "incomplete" 
dominant  trait.  Familial  hypercholesterolemic  xantho- 
matosis, a  disorder  of  lipid  metabolism  characterized 


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by  the  triad:  hypercholesterolemia,  cutaneous  or 
tendon  xanthomata,  and  severe  premature  athero- 
sclerosis (sometimes  occurring  even  in  childhood), 
is  the  most  severe  stage  of  this  inherited  disorder.  It 
is  probably  homozygotic.  A  hypercholesterolemic 
tendency  without  xanthomata  also  occurs;  this 
milder  form  is  heterozygotic  (3).  Recently,  Epstein 
rt  a/.  (41  ),  restudying  the  families  originally  published 
l>\  Adlersberg,  re-emphasized  the  interplay  between 
genetic  tendency  and  the  environment.  C.  B.  Thomas, 
in  her  study  of  the  families  of  healthy  medical  stu- 
dents, showed  a  definite  trend  for  the  offspring  of 
parents  with  hypertension  and  or  coronary  artery 
disease  to  have  more  hypertension  and  coronary 
disease  than  children  of  parents  not  so  afflicted.  If  one 
parent  had  either  of  these  diseases  the  occurrence 
among  the  offspring  was  intermediate.  Also,  she 
reported  a  fourfold  greater  frequency  of  occurrence 
of  coronary  artery  disease  among  the  siblings  of  the 
afflicted  parents  than  among  siblings  of  parents  not 
so  afflicted.  She  concluded  that  the  gradation  of  the 
disorder  rates  were  consistent  with  the  Mendelian 
law  of  inheritance.  However,  she  could  not  exclude  a 
multiplicity  of  genetic  factors  and  associated  modify- 
ing environmental  agents. 

Whether  genetic  and  hereditary  factors  influence 
atherosclerosis  also  by  determining  the  anatomical 
pattern  of  the  circulatory  tree,  particularly  that  of 
the  coronary  circulation,  is  difficult  to  evaluate — but 
the  possibility  does  exist  (94). 

In  addition,  the  studies  of  Gertler  &  White  (54) 
on  young  coronary  patients  have  yielded  information 
regarding  body  build.  Even  though  no  particular 
'"coronar\-  habitus"  could  be  established,  young 
patients  with  coronary  disease  as  a  group  belonged 
predominantly  to  the  mesomorph  body  build.  Re- 
cently, attention  has  also  been  focused  on  personality 
and  character  traits,  as  well  as  the  responsiveness  of 
the  autonomic  nervous  system,  partially  genetically 
determined,  and  their  possible  relationship  to 
coronary  disease  proneness.  But  these  interrelation- 
ships need  further  clarification  (136). 

No  data  are  as  yet  available  on  the  familial  tend- 
ency  to  accelerated  blood  clotting  and  thrombus 
formation,  other  than  the  tendency  of  hyperlipemic 
serum  to  shorten  coagulation  time.  However,  it  is  not 
inconceivable  that  such  genetic  traits  may  be  un- 
c  1 1\  cred. 

From  the  evidence  presented  it  can  be  concluded 
that  genetic  and  hereditary  traits  may  be  an  important 
predisposing  factor  in  an  individual's  response  to 
dietary  and  environmental  factors  leading  to  athero- 


sclerosis, anatomically  and  clinically.  But  this  is  still, 
for  practical  purposes,  an  uncultivated  field  of 
systematic  study  of  great  importance. 


STRESS 

In  recent  years,  interest  has  grown  concerning  the 
possible  influence  of  physical  activity  and  psycho- 
logical or  emotional  stress  on  the  development  of 
atherosclerosis.  It  has  also  been  suggested  that  both 
of  these  types  of  "stress"  may  be  involved  in  precipitat- 
ing thrombosis  or  sudden  occlusion  of  a  blood  vessel 
in  which  pre-existing  but  clinically  occult  disease  is 
present.  Further,  such  stress  may  act  as  the  trigger 
mechanism  in  aggravating  the  ischemia  of  an  organ, 
particularly  of  the  heart  and  the  brain,  which  already 
has  a  deficient  blood  supply  because  of  an  athero- 
sclerotic process.  The  presence  of  atherosclerotic 
disease  per  se  limits  the  ability  of  the  circulation  of  an 
organ  to  adjust  to  augmented  demands  placed  upon  it. 

As  has  been  pointed  out  for  other  facets  of  the 
problem  in  previous  sections  of  this  chapter,  "stress," 
too,  exerts  its  role  only  in  the  presence  of  a  life-span 
pattern  of  diet  high  in  cholesterol  and  fat,  particularly 
saturated  fat.  When  this  potentially  atherogenic  diet 
is  absent,  differences  attributable  to  stress  and  other 
factors  fail  to  appear.  Therefore,  differences  in  the 
incidence  of  clinical  coronary  disease  according  to 
occupation  for  instance,  are  found  only  in  those 
populations  in  which  the  over-all  incidence  of  this 
disease  is  high,  presumably  because  of  the  dietary 
factor. 

Physical  Activity 

Results  from  the  animal  laboratory  with  regard  to 
the  influence  of  enforced  physical  activity  in  the 
presence  of  an  atherogenic  diet  are  contradictors. 
Brown  et  a/.  (24)  found  no  differences  in  rabbits. 
Kobernick  &  Niwayama  (81  ),  working  with  chol- 
esterol-fed rabbits  which  were  forced  to  exercise 
adequately  by  combining  a  mechanical  treadmill  with 
conditioning  to  electric  shocks,  found  significantly  less 
atherosclerosis  in  the  exercised  rabbits  as  compared  to 
the  sedentary  controls — although  the  degree  of 
hypercholesterolemia  was  similar  in  both  groups. 
Brainard  (23),  working  with  rabbits  exercised  on  a 
treadmill,  found  no  differences  in  the  amount  of 
aortic  cholesterol  between  the  active  and  the  seden- 
tary group.  Myasnikov  (109)  obtained  positive 
results  in  the  rabbit  in  favor  of  a  protection  of  the 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


exercised  group.  However,  he  also  found  an  increased 
incidence  of  myocardial  infarction  in  the  exercised 
group  despite  the  decrease  in  gross  aortic  and  coronary 
atherosclerosis.  Serum  cholesterol  levels  were  found 
to  be  significantly  lower  in  rats  forced  to  swim  than 
in  sedentary  controls  and  in  pair-gained  sedentary 
controls  (69).  Orma  (1  17),  Warnock  et  al.  (168),  and 
Wong  et  al.  (180)  reported  that  exercise  decreased 
hypercholesterolemia  and  atherogenesis  in  cholesterol- 
fed  cockerels.  McAllister  et  al.  (92),  on  the  contrary, 
found  more  severe  atherosclerosis  in  exercised, 
cholesterol-fed,  hypothyroid  dogs  as  compared  to 
sedentary  ones.  Their  findings  are  complicated  by 
the  fact  that  the  exercised  dogs  were  ingesting  their 
rations  as  meals  while  the  sedentary  hypothyroid 
animals,  with  the  usual  depression  of  appetite,  ate 
their  food  slowly  over  the  entire  24-hour  period. 
Such  differences  in  feeding  pattern  in  chicks  have 
been  shown  to  influence  the  atherogenicity  of  the 
diet  per  se  (28). 

Data  in  man  relating  physical  activity  to  anatomical 
atherosclerosis  or  clinical  coronary  disease  are  even 
more  difficult  to  evaluate.  Several  investigators  (78, 
97,  160)  observed  that  increasing  the  caloric  intake 
did  not  produce  the  expected  increase  in  serum 
lipoprotein  and  cholesterol  levels  when  the  subjects 
were  exercised  intensely  enough  to  prevent  weight 
gain.  They  concluded  that  only  a  positive  caloric 
balance  over  a  long-time  period  could  elevate  serum 
lipid  levels. 

Pomeroy  &  White  (125)  reviewed  the  life  history 
of  former  football  players  and  found  fewer  deaths 
from  cardiovascular  disease  among  those  who  con- 
tinued a  program  of  regular  exercise  into  the  middle 
years  than  among  those  who  stopped  physical  activity 
after  their  school  years. 

The  most  indicative  data  relating  the  amount  of 
physical  activity  at  work  with  a  decreased  incidence 
of  death  from  atherosclerotic  vascular  disease, 
particularly  ischemic  heart  disease,  come  from  the 
studies  of  Morris  in  Great  Britain  (104,  106).  His 
data  were  obtained  from  a  relatively  homogenous 
population  of  a  similar  socio-economic  group :  by  a 
comparison  of  sedentary  bus  drivers  with  physically 
active  conductors,  by  a  comparison  of  sedentary 
telephone  operators  with  active  postmen,  and  by 
other  comparisons  of  a  similar  nature.  His  findings 
indicate  that  the  incidence  of  ischemic  heart  disease 
in  middle  age  tends  to  be  lower  in  the  groups  habit- 
ually engaged  in  a  greater  amount  of  physical 
activity.  These  investigations,  although  indicative, 
are  not  to  be  taken  as  final  proof,  because,  in  the  bus 


workers  at  least,  there  was  a  difference  in  obesity — 
the  drivers  were  more  obese  from  the  start  than  the 
conductors,  as  judged  by  the  size  of  the  uniforms 
(103).  This  leaves  open  the  question  of  whether  the 
difference  between  jobs  was  fortuitous,  dependent 
upon  self-selection,  which  in  turn  was  dependent  on 
temperament  and  body  build  of  the  individual 
worker.  Studies  from  other  countries,  i.e.,  Sweden, 
Finland,  and  Italy  (74),  with  a  generally  high 
morbidity  and  mortality  rate  from  atherosclerotic 
heart  disease,  are  not  so  clear  cut  as  the  British 
studies.  Studies  from  the  United  States  show  no 
difference  between  active  and  sedentary  groups  in  an 
urban  population  (153,  157);  however,  farmers  have 
less  atherosclerotic  heart  disease  than  city  dwellers. 
Some  authors  suggest  that  continued  physical  activity 
through  middle  age  may  be  of  possible  benefit  in  the 
prevention  of  atherosclerotic  disease  ( 1  79). 

One  fact  clearly  emerges  from  these  studies:  that 
no  difference  between  physically  active  and  inactive 
groups  can  be  observed  in  populations  with  a  low 
incidence  of  atherosclerotic  heart  disease  and  low 
mean  serum  lipid  levels.  In  populations  with  a  high 
incidence,  however,  there  is  a  difference  in  some 
but  not  in  all  countries.  Furthermore,  even  where  a 
difference  has  been  well  documented,  as  in  Great 
Britain,  this  is  only  relative;  the  absolute  incidence  of 
this  disease  in  the  physically  active  is  still  high  com- 
pared to  all  groups  in  a  country  with  a  low  incidence. 
Therefore,  physical  activity  must  play  a  minor  role 
compared  to  other  factors  such  as  diet. 

The  mechanism  by  which  physical  activity  might 
influence  atherosclerosis  is  not  clear.  The  data 
regarding  serum  cholesterol  and  lipoprotein  levels 
suggest  an  influence  via  metabolism.  Other  data  also 
indicate  that  the  factors  preventing  blood  coagulation 
and  aiding  fibrinolysis  are  favorably  influenced  by 
heavy  physical  work  (11,  12,  77).  This  was  pointed 
out  in  human  studies,  and  Warnock  et  al.  (168)  report 
the  same  effect  in  chicks.  These  latter  effects  may  be 
important,  particularly  since  Morris'  work  points  to 
a  decrease  of  coronary  thrombosis  and  major  occlusion 
in  active  middle-aged  men,  without  any  noticeable 
decrease  in  vascular  atheroma  and  diffuse,  nonfatal 
myocardial  fibrosis  (104). 

Furthermore,  physical  work  may  have  another 
effect.  There  are  several  studies  indicating  a  stimula- 
tion of  the  production  of  intercoronary  anastomoses  by 
physical  work  (13,  105,  184).  Nor  must  it  be  over- 
looked that  physical  activity  is  a  form  of  training 
which  permits  the  body  to  adjust  more  readily  to 
periods  of  stress. 


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CIRCULATION    II 


It  is  apparent  that  there  is  room  for  further  studies 
of  this  important  aspect  of  atherosclerosis. 

Emotional  Stress 

A  number  of  investigators  have  shown  that  emo- 
tionally  stressful  life  situations  transiently  elevate 
serum  cholesterol  levels  and  shorten  the  blood- 
clotting  time.  This  has  been  noted  in  medical  students 
at  the  time  of  examination  (36,  162),  and  Friedman 
et  al.  (48)  observed  it  in  accountants  when  they  were 
under  professional  peak  loads.  Several  other  workers 
have  published  data  linking  the  acute  episode  of 
coronary  occlusion  to  immediately  preceding  stressful 
life  situations  (37,  136,  169).  The  proponents  of  the 
hypothesis  that  emotional  stress  influences  athero- 
genesis  and  may  precipitate  clinical  episodes  of 
occlusion  implicate  the  stresses  of  our  modern 
mechanized  civilization  in  particular.  Emotional 
stress  also  produces  elevation  of  blood  pressure,  and 
this  in  turn  may  have  a  deleterious  effect  on  the 
vascular  wall.  In  this  and  other  ways  hypertension 
favors  atheroma  formation. 

The  study  of  emotional  factors  in  relation  to 
cardiovascular  disease  is  in  its  infancy.  The  main 
reason  for  the  difficulties  in  the  evaluation  of  this 
factor  is  the  lack  of  an  effective  measure  of  emotional 
stress  and  of  the  various  personality  profiles  (75).  The 
mechanism  by  which  psychological  stress  influences 
body  homeostasis  is  also  difficult  to  assess.  It  may 
operate:  a)  by  disturbing  endocrine  balance,  e.g.,  via 
pituitary-adrenal  stimulation  and  catecholamine 
release  (50,  95,  132,  140,  162),  thereby  influencing 
blood  pressure,  cholesterol  metabolism,  coagulation, 
and  fibrinolytic  activity;  or  b)  by  other,  as  yet  un- 
known, mechanisms  including  an  action  via  the 
nervous  system.  Numerous  acute  psychological 
episodes  of  this  type  over  the  life  span  may  lead  to  the 
establishment  of  chronic  changes,  such  as  those  which 
may  operate  in  hypertension. 

Experience  from  the  animal  laboratory  is  equally 
fragmentary.  Cold  stress  was  shown  to  produce 
coronary  artery  changes  in  rats  (141).  Friedman  & 
Uhley  (49)  have  shown  that  rats  kept  tense  in  antic- 
ipation of  electric  shocks  showed  significantly 
shortened  blood-clotting  time.  They  found  no 
difference  in  coronary  atherosclerosis  between  aggres- 
sive and  passive  chicks  on  an  atherogenic  diet.  Other 
results  confirm  this  observation.  Recent  studies  in 
our  laboratorv  indicate  that  isolation  of  chicks  in  a 
quiet,  undisturbed  room  increases  the  atherogenic 
response   to   a   high-fat,    high-cholesterol   diet    (124). 


Also,  isolation  during  the  healing  phase  of  athero- 
sclerosis prevents  regression  of  lesions.  Such  isolated 
cockerels,  in  addition,  showed  retarded  sexual  growth 
as  evidenced  by  decreased  testis  weight  and  comb 
size,  as  well  as  a  decreased  food  efficiency  expressed  by 
smaller  weight  gain  on  a  food  intake  similar  to  that  of 
the  controls. 

It  cannot  yet  be  determined  from  these  results 
whether  the  observed  effects  of  isolation  of  the  birds 
constituted  a  response  to  a  severe  stress,  specifically 
the  unnatural  isolation,  or  were,  on  the  contrary,  the 
result  of  the  lack  of  normal  stresses.  However,  all 
these  data  indicate  that  certain  environmental 
influences,  mediated  via  the  central  nervous  system 
and  involving  the  nervous  and  hormonal  regulation 
of  body  functions,  including  that  of  the  vessels  them- 
selves, can  influence  the  vascular  response  to  a 
potentially  atherogenic  diet.  These  findings  may  have 
far  reaching  implications,  particularly  should  "lack 
of  normal  stress"  be  the  underlying  cause. 

The  evidence  relating  emotional  or  psychological 
stress  to  atherosclerosis,  clinical  or  experimental,  is 
at  best  fragmentary.  It  is  much  too  early  to  extrap- 
olate the  findings  and  to  make  any  major  generaliza- 
tion. Many  further  well-controlled  and  systematic 
studies  are  required  to  help  our  understanding  of  the 
complicated  mechanisms  which  operate  in  this  elusive 
area. 


SUMMARY 

From  the  data  presented  in  this  chapter  the 
following  conclusions  can  be  drawn: 

Whether  or  not  atherosclerosis  emerges  as  a  major 
health  problem  in  a  population  is  largely  and  mainly 
determined  by  the  life-span  pattern  of  the  diet.  In 
the  case  of  any  individual  member  of  a  population 
group  which  is  habitually  ingesting  a  potentially 
atherogenic  diet,  several  other  factors  will  determine 
the  degree  and  extent  of  atherosclerosis  and  clinical 
atherosclerotic  disease — this  is  not  always  mirrored 
by  the  blood  cholesterol  or  other  lipid  levels.  There  is 
a  complex  interplay  between  diet  and  these  other 
factors  which  operate  to  accelerate  or  retard  athero- 
genesis.  The  most  important  of  these  accessory  factors 
determining  the  individual's  fate  with  regard  to 
atherosclerosis  are  hormones,  heredity,  and  stress. 

It  is  hopefully  felt  that  by  taking  all  these  factors 
into  account  it  will  become  possible  to  single  out 
persons  particularly  prone  to  develop  atherosclerotic 
disease  at  a  relatively  early  age  and  to  suggest  dietary 


ENDOCRINES,    STRESS,    AND    HEREDITY    ON    ATHEROSCLEROSIS 


[20g 


or  other  measures  for  them,  with  the  expectation  that 
the  development  of  atherosclerosis  can  be  retarded, 
its  sequelae  avoided  or  delayed,  and  a  clinical 
catastrophe  prevented  or  put  off  for  a  variable  time. 
Much  work  is  still  needed  to  reach  this  goal  and  many 
aspects  of  the  problem  are  poorly  understood  at  the 
present  time.  But  progress  is  being  made  year  by 
year  in  the  multidisciplinary  attack  aiming  to  under- 
stand the  pathogenesis  of  atherosclerosis,  and  seeking 


to  further  its  prevention  and  to  improve  its  manage- 
ment once  it  develops. 

The  work  of  this  department,  which  is  included  in  this  review, 
was  accomplished  over  the  years  in  collaboration  with  the  fol- 
lowing former  associates:  Drs.  D.  V.  Dauber  (deceased),  L. 
Horlick,  S.  Rodbard,  and,  especially,  J.  Stamler. 

Several  dedicated  research  assistants  made  these  complicated 
investigations  possible.  They  were:  Mrs.  C.  Bolene-VVilliams, 
Mrs.  D.  Century,  and  Mr.  P.  Johnson.  Also,  the  cooperation 
of  many  research  technicians  is  gratefully  acknowledged. 


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ill.   Oliver,  M.  F.,  and  G.  S.  Boyd.  Plasma  lipid  and  serum 


HANDBOOK    OI      PHYSIOLOGY 


CIRCULATION    II 


I'3 


114. 


"5 


116. 


117. 


"9- 


123. 

124. 

'25- 

126. 
127. 

128. 


129. 
130. 


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1213 


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Circulation  4:  797,  1 951. 


CHAPTER     36 


Peripheral  vascular  diseases- 


diseases  other  than  atherosclerosis1 


GEORGE  E.  BURCH 
JOHN  PHILLIPS 


Department  of  Medicine,  Tulane  University  School  of  Medicine, 
and  Charity  Hospital  of  Louisiana,  New  Orleans,  Louisiana 


CHAPTER    CONTENTS 

Vascular  Malfunction  in  General 

Approach   of  the   Clinician   and   Clinical    Physiologist   to   the 
Study  of  Patients  with  Diseases  of  the  Peripheral  Circula- 
tion 
The  History 

Symptoms  of  arterial  disease 
Symptoms  of  venous  disease 

Manifestations  of  capillary  and  lymphatic  disease 
The   Physical   Examination    and    Simple    Clinical    Tests  of 
Vascular  Function 
Determination  of  the  adequacy  of  the  cutaneous  circula- 
tion 
Evaluation  of  the  status  of  the  main  arteries 
Evaluation  of  the  status  of  the  venous  system 
Evaluation  of  the  status  of  capillary  and  lymphatic  vessels 
Special  Laboratory  Procedures  for  Examining  the  Peripheral 
Circulation 
Effects  of  Circulatory  Arrest 
Classification   of  Peripheral   Vascular   Disease 
Mechanisms  in  Peripheral  Vascular  Disease 
Vasoconstrictor  Disease  Syndromes 
Raynaud's  syndrome  or  phenomenon 
Acrocyanosis 
Livedo  reticularis 
Causalgia  and  related  syndromes 
Miscellaneous  states 
Vasodilative  Syndromes 

Erythromelalgia  (erythermalgia) 
Mechanisms  in  Other  Vascular  Diseases 
Appendix 


one  of  the  great  interests  in  the  vascular  system 
is  its  reaction  and  response  to  disease.  Although  most 

1  Work  supported  by  grants  from  the  L'.  S.   Public  Health 
Service. 


physiologic  studies  have  been  concerned  with  the 
normal  state,  the  pathophysiology  of  vascular  disease 
is  of  considerable  importance  to  the  physiologist  and 
the  clinician.  Attempts  will  be  made  in  this  chapter 
to  correlate  the  interactions  of  vascular  malfunction 
with  the  pathologic  lesions  and  their  clinical  mani- 
festations. The  presentation  will  be  limited  primarily 
to  diseases  of  and  observations  on  man. 

In  the  discussions  to  follow  the  term  "peripheral 
vascular  disease"  will  refer  to  disease  affecting  largely 
the  circulation  to  the  limbs.  This  obviously  excludes 
a  discussion  of  disease  in  other  circulatory  beds; 
notable  among  these  sites  are  the  pulmonary,  portal, 
renal,  and  cerebral  vessels.  Further,  the  discussions 
will  be  limited  in  large  part  to  "primary"  vascular 
disease,  or  disease  states  in  which  alterations  in  blood 
vessels  and  their  function  are  the  basic  cause  for  the 
disease  manifestations.  Vascular  changes  associated 
with  or  secondary  to  primary  disease  in  other  organs 
are  important  but  they  are  beyond  the  scope  of  this 
presentation.  Examples  of  these  secondary  vascular 
disturbances  are  the  spider  angiomata  and  palmar 
erythema  occurring  in  liver  disease,  aging,  rheumatoid 
arthritis,  and  pregnancy;  the  pale  avascular  skin  of 
castrate  and  eunuchoid  men;  the  reddish  flushes  of 
the  menopausal  states;  the  cyanotic  flushes  of  seroto- 
nin-producing carcinoids;  the  pallor  of  the  nephrotic 
syndrome,  hypothyroidism,  and  pituitary  insuffi- 
ciency; the  vasoconstriction  of  pheochromocvtomas; 
the  vasodilatation  of  thyrotoxicosis;  the  vascular 
changes  of  acute  exanthema,  scarlet  fever,  and  other 
infectious  diseases;  and  the  digital  clubbing  and 
cyanosis  of  cardiac  and  pulmonary  disease. 


1215 


12  I  6 


HANDBOOK    OF    PHYSIOLOGY    "   CIRCULATION     II 


\  VSCULAR    MALFUNCTION    IN    GENERAL 

Vascular  malfunction  might  be  denned  as  that 
temporar\  or  permanent  condition  which  exists 
when  the  circulation  fails  to  meet  its  intended  func- 
tions of  a)  temperature  regulation,  b)  tissue  nutrition, 
and  c  I  repair. 

Malfunction  might  arise  through  active  vasomotor 
or  passive  structural  (anatomic)  mechanisms.  Vaso- 
motor (not  limited  only  to  neuromuscular)  mecha- 
nisms include  a)  increase  in  vessel  tone  ("vasotighten- 
ing"),  decrease  in  luminal  cross-sectional  area,  or  a 
combination  of  these  (vasoconstriction),  or  b)  decrease 
in  vessel  tone  ("vasoloosening"),  increase  in  luminal 
cross-sectional  area,  or  a  combination  ol  these 
(vasodilatation).  Vasomotor  changes  might  be 
induced  through  neural  mechanisms,  humoral 
mechanisms,  primary  muscular  action,  physical 
factors  affecting  any  of  the  vessel  wall  coats,  other 
unknown  factors,  or  any  combination  of  these.  These 
reactions  imply  a  degree  of  reversibility. 

Structural  or  anatomic  mechanisms  by  which 
vascular  malfunction  might  occur  are  a)  structural 
obstruction  (occlusive),  b)  structural  dilatation 
(aneurysm  or  varix),  or  c)  abnormal  vascular  com- 
munications. These  changes  imply  a  degree  of 
irreversibility. 

Somewhat  difficult  to  define  as  either  active  vaso- 
motor or  passive  structural  changes  are  vascular 
distention  and  vascular  collapse  (the  latter  not  refer- 
ring to  the  "shock  syndrome").  Vascular  distention 
or  congestion  implies  a  relative  increase  in  vessel 
tone  (as  opposed  to  vasodilatation)  but  with  an 
increase  in  luminal  cross-sectional  area.  Vascular 
collapse  implies  a  relative  decrease  in  vessel  tone  (as 
opposed  to  vasoconstriction)  but  with  a  decrease  in 
luminal  cross-sectional  area.  These  are,  of  course, 
potentially  reversible  states. 

Structural  diseases  have  been  termed  "organic," 
whereas  the  vasomotor  diseases  have  been  called 
"functional."'  Division  of  peripheral  vascular  diseases 
into  organic  and  functional  categories,  although 
convenient,  is  purely  arbitrary.  Certainly,  altered 
phvsiology  has  its  structural  counterpart.  Means  to 
resolve  this  artificial  dichotomy  then  are  dependent 
simply  on  the  sensitiveness  of  methods  for  morpho- 
logic observations.  In  the  past,  the  division  of  diseases 
from  the  anatomic  standpoint  has  been  dependent 
largely  on  light  microscopy.  Under  existing  classi- 
fications, for  example,  early  and  mild  Raynaud's 
disease  is  a  functional  disorder.  However,  with  the 
use    of    more    sensitive    methods     such    as    electron 


microscopy  the  same  stage  of  the  disease  might  be 
shown  to  be  associated  with  structural  defects  whether 
it  be  in  the  vasculature  itself  or  in  the  nervous  system 
or  in  both.  Thus,  by  present  "policy"  the  disease  is 
now  considered  both  organic  and  functional. 

Regardless  of  the  above  criticisms,  it  is  still  con- 
venient for  clinical  purposes  to  classify  vascular 
disease  within  organic  or  functional  categories.  This 
focuses  attention  on  the  more  observable  underlying 
mechanisms  in  the  characteristic  manifestations  of 
the  disease.  With  this  in  mind,  more  emphasis  shall 
be  placed  here  on  the  disorders  in  which  altered  phy- 
siology is  the  most  readily  detectable  underlying 
mechanism;  these  diseases  include  predominately, 
but  certainly  not  exclusively,  the  functional  disorders. 
It  should  be  remembered  that  none  are  purely 
organic  or  purely  functional  and  that  all  vascular 
diseases  have  elements  of  each. 

Changes  which  influence  the  circulation  and  its 
functions,  although  not  directly  arising  from  the 
vessel  wall  itself,  pertain  to  such  factors  as  blood 
volume,  cardiac  output,  pulse  rate,  blood  viscosity, 
sludging,  blood  gases,  neurogenic  and  psychogenic 
disorders,  endocrine  and  humoral  factors,  and  many- 
others.  Many  of  these  factors  operate  simultaneously 
to  various  degrees  and  with  temporal  variations.  These 
topics  are  covered  in  ether  chapters  of  this  volume. 


APPROACH   OF   THE   CLINICIAN    AND   CLINICAL 
PHYSIOLOGIST  TO  THE  STUDY  OF  PATIENTS  WITH 
DISEASES  OF  THE   PERIPHERAL  CIRCULATION 

The  clinical  peripheral  vascular  physiologist  has 
a  difficult  and  complex  task.  He  must  observe  the 
symptoms  and  clinical  and  laboratory  signs  in  his 
subject  which  suggest  the  possibility  cf  pathological 
alteration  in  the  peripheral  circulation.  He  must 
attempt  to  discover  the  underlying  pathologic  anat- 
omy of  the  clinical  manifestation.  Most  difficult  of 
all,  he  must  attempt  to  explain  the  observed  changes 
in  terms  of  pathophysiologic  mechanisms,  establish 
a  diagnosis  and  then  introduce  corrective  therapeutic 
measures  based  upon  established  pharmacodynamic 
and  physiologic  principles.  This  is  done  with  an  aim 
to  modify  the  altered  pathophysiology  in  order  to 
establish  as  near  normal  vascular  function  as  possible 
for  as  long  a  period  of  time  as  possible.  This  objective 
requires  a  satisfactory  understanding  of  the  normal 
and  abnormal  functions  of  the  interrelated  organ 
systems  which  may  influence  the  diseased  state.  The 
clinician    must    attempt    to    estimate    properly    the 


PERIPHERAL   VASCULAR    DISEASES 


12  I  7 


relative  quantitative,  qualitative,  and  temporal  roles 
of  the  many  contributing  factors  such  as  the  numerous 
effects  of  disease  of  other  organ  systems.  All  of  these 
factors  must  be  carefully  integrated  in  order  to  decide 
upon  the  type,  amount,  and  time  of  administering 
various  therapeutic  measures. 

Progress  in  the  basic  understanding  of  peripheral 
vascular  disease  has  been  slow.  Because  of  the  enor- 
mous number  of  variables  and  the  complex  nature 
of  these  diseases,  the  clinical  physiologist  has  had 
great  difficulty  in  elucidating  underlying  patho- 
physiologic mechanisms.  No  small  hindrance  to  this 
progress  has  been  the  nature  of  the  experimental 
animal  himself,  namely,  man.  Nowhere  else  in 
physiology  does  nondestructive  observation  place  its 
strictest  limitations.  Available  counterparts  of  spon- 
taneously acquired  human  peripheral  vascular  disease 
are  rare  indeed  in  lower  animals. 


The  History 

The  detection,  clarification,  and  interpretation  of 
a  patient's  own  experience  with  his  altered  circula- 
tion (symptoms)  may  be  just  as  important  to  the 
clinician  and  clinical  physiologist  as  graphic  record- 
ings of  circulatory  parameters  may  be  to  the  basic 
physiologist.  For  this  reason,  it  seems  worthwhile 
to  discuss  briefly  the  important  aspects  of  this  means 
of  investigation.  Where  known,  the  physiologic 
mechanisms  underlying  these  symptoms  will  be  noted. 

Several  general  aspects  of  the  history  are  note- 
worthy. Age,  sex,  and  race  are  important;  e.g.,  arterio- 
sclerosis is  more  common  in  the  aged;  Raynaud's 
disease  is  much  more  frequent  in  females;  and 
Buerger's  disease  is  extremely  rare  in  Negroes  and 
women  (74).  Because  of  their  predisposing  influences 
on  subsequent  vascular  disease,  a  past  history  of  poly- 
cythemia, frostbite,  thrombophlebitis,  diabetes  mel- 
litus,  and  many  other  disease  states  is  important. 
Occupational  factors  should  be  explored,  e.g.,  the 
predisposition  to  Raynaud's  phenomenon  seen  in 
truck  drivers  and  pneumatic  hammer  operators. 
Evaluation  of  environmental  influences  such  as 
temperature,  humidity,  and  body  position  is  also 
important.  The  effects  of  drugs  may  be  important, 
e.g.,  ergot,  nicotine,  and  sympathicomimetic  agents. 
Evaluation  of  emotional  and  other  psychic  factors 
are  also  of  considerable  importance. 

More  specific  aspects  of  the  history  are  as  follows: 

symptoms  of  arterial  disease.  Among  the  common 
symptoms  associated  with  reduced  arterial  flow  are 


pain,  tenderness,  fatigue,  paresthesia,  altered  sensa- 
tions ranging  from  hyperesthesia  to  anesthesia,  muscle 
cramps,  and  sensitivity  to  thermal  change.  Pain  may- 
be divided  into  three  main  groups:  intermittent 
claudication,  rest  pain  due  to  ischemic  neuritis,  and 
rest  pain  associated  with  trophic  changes. 

Intermittent  claudication  characteristically  is  pain 
produced  by  exercise  and  relieved  with  rest.  It  may 
appear  in  any  muscle  group  and  is  usually  due  to 
organic  arterial  obstruction.  It  is  related  to  the  degree 
and  or  rate  of  work  (in  the  physiologic  sense)  over 
a  certain  time  interval  performed  by  a  particular 
muscle  group  with  its  compromised  circulation. 
Increasing  the  amount  or  rate  of  work  produces  a 
more  rapid  onset,  a  more  severe  degree  of  pain,  or 
both.  With  reference  to  the  lower  extremities,  clini- 
cians attempt  to  quantitate  claudication  in  terms  of 
onset  of  pain  after  walking  a  certain  distance  (claudi- 
cation distance)  or  after  walking  a  certain  period  of 
time  (claudication  time)  at  a  prescribed  pace.  This 
symptom  usually  starts  as  a  sense  of  "fatigue"  then 
progresses  to  a  "cramping"  pain.  A  major  charac- 
teristic of  claudication  is  relief  with  rest.  When  post- 
exercise  relief  does  not  ensue  within  5  to  10  min, 
another  cause  for  the  pain  is  suspected. 

"Vasospastic  claudication"  is  a  term  used  to 
describe  a  syndrome  in  which  peripheral  arterial 
pulsations  are  normally  present  at  rest  but  disappear 
during  exercise.  The  affected  limb  may  then  become 
pale  and  typical  claudicatory  distress  occur  (43). 
From  clinical  studies  it  is  considered  that  the  majority 
of  this  comparatively  small  group  of  patients  have 
partial  segmental  occlusion  of  large  arteries  proximal 
to  the  site  of  claudication  (36)  and  that  superimposed 
arterial  spasm  is  responsible  for  the  ischemic  mani- 
festations on  exercise. 

The  exact  mechanism  of  intermittent  claudication 
is  not  clear.  That  claudication  is  not  clue  to  muscle 
cramps  has  been  repeatedly  stressed,  since  the  muscles 
are  flaccid  during  the  attack,  and  it  is  not  due  to 
vascular  spasm  of  small  vessels  because  the  vessels  to 
the  muscles  are  dilated  rather  than  constricted  with 
exercise.  Claudication  indicates  insufficient  blood 
supply  to  the  painful  muscles  to  meet  the  increased 
metabolic  needs  of  the  muscle  during  exercise. 

It  appears  that  there  are  at  least  two  basic  require- 
ments for  the  production  of  intermittent  claudication  : 
/)  oxygen  lack  and  2)  muscular  contraction  in  the 
presence  of  this  anoxia  (36).  In  this  regard  it  should 
be  noted  that  claudicatory  pain  has  been  produced 
in  severely  anemic  patients  with  patent  arteries  (78) 
and  that  it  has  been  produced  by  exercising  normal 


I2l8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION     II 


people  while  breathing  air  with  low  oxygen  concen- 
trations (40).  It  is  noteworthy  that  intermittent 
claudication  may  be  produced  in  a  normal  limb  by 
exercise  after  artificial  arrest  of  the  blood  supply. 
In  the  normal  limb  following  circulatory  arrest,  the 
pain  disappears  quickly  (usually  within  3  sec)  after 
restoration  of  the  circulation,  but  if  arrest  is  main- 
tained the  pain  persists,  presumably  because  the 
agents  responsible  for  the  pain  are  not  inactivated  in 
the  presence  of  an  inadequate  circulation. 

Lewis  has  shown  that  it  is  not  oxygen  lack  itself 
that  causes  the  claudicatory  pain  but  rather  the 
stimulation  of  sensory  nerves  by  metabolic  products 
of  muscular  activity  which  are  ordinarily  inactivated 
in  the  presence  of  an  adequate  blood  supply  with 
sufficient  oxygenation.  The  mediating  agent  or 
agents  from  ischemic  muscles  to  the  pain-sensitive 
nerve  endings  has  been  called  "factor  P"  or  "pain 
factor."  Apparently,  it  is  a  metabolic  product  of 
muscle  and  is  rather  stable,  acid,  and  nonvolatile. 
Whether  or  not  it  is  produced  in  increased  quantities 
or  is  inadequately  neutralized,  inhibited,  or  dis- 
persed in  the  face  of  ischemia  is  not  known.  Few 
definitive  studies  in  this  area  are  available.  Among 
the  more  important  are  those  of  Lewis  et  al.  (47, 
51 )  and  Katz  et  al.  (37). 

One  observation  that  requires  further  exploration 
is  the  relief  of  deep  pain  by  the  application  of  ethyl 
chloride  spray  to  the  skin  surface.  Travell  and 
associates  (98)  have  reported  pronounced  ameliora- 
tion of  claudicatory  distress  by  this  means. 

Ischemic  neuritis  is  considered  to  be  one  of  the 
mechanisms  of  rest  pain  in  arterial  disease.  This 
type  of  pain,  severe  lancinating  sensations  and 
paresthesias,  is  characteristic  of  stimulation  of  neural 
elements.  It  is  usually  more  troublesome  at  night 
when  the  patient  is  in  bed.  The  pain  of  ischemic 
neuritis  is  found  most  frequently  in  vascular  dis- 
turbances associated  with  diabetes  mellitus  and 
Buerger's  disease. 

The  pathogenesis  of  the  symptoms  due  to  ischemic 
neuritis  appears  to  be  related  to  neural  degeneration 
secondary  to  impairment  of  blood  flow  through 
the  nutrient  vessels  of  the  nerves.  In  support  ol 
nerve  degeneration  is  the  associated  reduction  in 
vibratory  sense  perception  and  pinprick  sensation. 

Trophic  changes  may  be  responsible  for  pain  occur- 
ring in  the  resting  state.  These  painful  sites  are  areas 
of  ulceration  and  pre-ulceration  which  probably 
cause  sensory  nerve  irritation  through  inflammation 
and  ischemia.  This  type  of  pain  is  usually  continuous 
in  nature.   It  is  more  common  in  Buerger's   disease 


and  in  diabetic  neuropathy  probably  because  of 
the  involvement  of  nerves  in  the  inflammatory 
processes. 

The  pain  associated  with  occlusive  arterial  disease 
is  frequently  accentuated  by  elevation  and  diminished 
by  dependency  of  the  involved  part.  Excessive  local 
heat  may  be  harmful  and  often  increases  the  pain 
because  of  increased  metabolism  with  restricted 
blood  supply.  Excessive  cold  may  induce  vascular 
spasm  and  also  accentuate  pain  and  tissue  damage. 

symptoms  of  venous  disease.  Symptoms  due  to 
disease  of  the  veins  may  include  pain,  muscle  fatigue, 
muscle  cramps,  and  paresthesias.  Many  of  the 
symptoms  of  venous  insufficiency  (deep-vein  throm- 
bosis and  obstruction,  valvular  incompetence,  and 
varicose  veins)  are  due  to  congestion  and  edema  of 
the  involved  parts  and  therefore  are  affected  by 
gravity.  These  symptoms  are  accentuated  by  depend- 
ency and  diminished  by  elevation.  Additional  man- 
ifestations of  venous  disease  and  their  pathogenesis 
will  be  found  in  subsequent  sections. 

manifestations  of  capillary-  and  lymphatic 
disease.  These  diseases  are  discussed  in  other  parts 
of  this  volume. 


Physical  Examination  and  Simple  Clinical 
Tests  of  Vascular  Function 

In  the  sense  that  the  basic  physiologist  must  define 
the  conditioning  influences  under  which  his  labora- 
tory experiments  are  conducted,  so  must  the  clinician 
define  the  conditions  under  which  he  makes  his 
observations  of  disease  processes.  In  this  respect, 
in  the  examination  of  his  patient  for  peripheral 
vascular  disease,  the  clinician  must  make  every 
attempt  to  control  influencing  variables  in  the 
environment.  LTnder  ideal  conditions  then,  the 
changes  observed  during  a  "steady  state"  estab- 
lished by  proper  conditions  for  examination  may  be 
assumed  to  be  due  to  the  disease  itself.  To  this  end, 
standardization  of  the  condition  and  technique  of 
the  examination  is  necessary. 

The  subject  should  rest  supine  in  bed  in  a  com- 
fortable position  with  no  constricting  garments. 
The  environmental  temperature  and  humidit) 
should  be  in  a  comfortable  range.  The  parts  should 
be  dry  and  free  from  exposure  to  drafts.  Blankets 
may  be  applied,  if  necessary,  but  when  employed 
should  cover  all  parts  symmetrically.  Local  heat  or 
cold   should    be   avoided.    Other   influencing   factors 


PERIPHERAL    VASCULAR    DISEASES 


12  19 


such  as  recent  use  of  tobacco,  alcohol,  or  certain 
drugs  should  be  controlled. 

Because  of  the  great  number  of  variables  in  disease 
and  because  of  the  wide  range  of  normal  variation, 
the  clinician  must  take  advantage  of  "built-in" 
controls.  To  this  end,  he  should  carefully  and  con- 
tinually examine  and  compare  symmetrical  parts 
of  the  body. 

DETERMINATION  OF  THE  ADEQUACY  OF  THE  CUTANEOUS 

circulation.  The  presence  and  location  of  cutane- 
ous ulcerations  should  be  noted.  In  arterial  disease 
these  tend  to  be  at  the  tips  of  the  digits  and  over 
pressure  areas,  whereas  in  venous  disease  they  tend 
to  be  located  over  the  medial  lower  one-third  of  the 
leg.  The  skin  should  be  examined  for  texture  and 
consistency.  The  skin  tends  to  be  thin  and  shiny  in 
arterial  disease  and  thick  and  brawny  in  long- 
standing venous  and  lymphatic  disease.  Tissue 
swelling  and  edema  tend  to  be  absent  in  arterial 
disease,  unless  there  has  been  considerable  capillary- 
injury,  but  they  are  frequent  findings  in  venous  and 
lymphatic  insufficiency.  Changes  in  the  growth  rate 
and  appearance  of  the  nails  may  be  clues  to  impaired 
cutaneous  circulation.  The  nails  tend  to  be  thickened, 
ridged,  deformed,  brittle,  and  pigmented.  In  vaso- 
spastic states  there  may  be  thinning  of  the  proximal 
nail  fold  with  merging  into  the  cuticle  (pterygium). 
Hair  growth  may  be  impaired.  The  degree  of  sweating 
is    important.    Absence    of    sweating    may    indicate 


complete  ischemic  destruction  of  sympathetic  nerve 
fibers  or  ischemic  impairment  of  sweat  gland  func- 
tion. Excessive  sweating,  in  the  absence  of  a  demand 
of  this  function  for  thermal  regulation,  usually 
indicates  increased  sympathetic  activity  with  intact 
nerves,  frequently  due  to  psychogenic  disturbances. 
Other  vascular  manifestations  of  increased  sympathe- 
tic activity  with  respect  to  temperature  and  color  of 
the  skin  are  usually  present. 

Temperature  and  color  changes  are  of  such 
importance  in  the  evaluation  of  the  cutaneous 
circulation  that  they  demand  special  comment.  The 
observations  of  Lewis  (49)  are  still  authoritative. 
Under  standardized  conditions,  the  amount  of  heat 
brought  to  the  skin  may  be  considered  a  gross  reflec- 
tion of  the  rate  of  local  blood  flow.  It  should  be  noted 
that  the  temperature  of  a  part  cannot  decline  more 
than  1  C  to  2  C  below  room  temperature  and  then 
only  if  the  part  is  moist  and  the  circulation  com- 
pletely arrested.  The  temperature  rarely  decreases 
below  20  C  in  a  cool  room  and  rarely  exceeds  34  C 
in  a  warm  room.  Temperature  differences  of  sym- 
metric areas,  similarly  exposed,  should  arouse  sus- 
picion of  circulatory  disorder.  When  exposed  to 
cold,  the  part  with  the  better  circulation  will  remain 
warm  longer  and  on  rewarming  its  temperature  will 
increase  faster. 

Except  for  modification  by  skin  pigments,  the 
color  of  the  skin  is  due  mostly  to  blood  in  the  venules 
of  the   subpapillary   venous   plexus   and   to   a   lesser 


34 


24. 


_^.^_     REFLEX    VASODILATATION 
(BODY    HEATED) 


POSTERIOR    TIBIAL 
NERVE    BLOCK 


MINUTES 


"I      I      I      I      I      I      I      I      I      T" 

5  10 


"~ 1     1    I    I    I    I    I    I    I    I    I     I    I     I    I     1    1    I    I     1    1    1    1    1    1    1    r~ 
15  20  25  30  35  40 


45 


fig.  I.  Thermocouple  recording  of  thermal  change  in  the  right  big  toe  demonstrating  the  effects 
of  reflex  vasodilatation  and  posterior  tibial  nerve  block. 


i  220 


HANDBOOK    OF    PHYSIOLOG1 


CIRCULATION-    II 


O 


Control     Stott 


Subj  JM.J5WM 
Tr*nchfool 


2RT  J 

_    IOTIOO     en 

S   olo      t 


E 

I 

=       4RT 

°     10  _  100 


«W   ^am) 


FIG.  2.  Rheoplethysmographic  recordings  showing  the  simultaneous  curves  of  volumes  and  rates 
of  digital  inflow,  outflow,  and  the  difference  between  inflow  and  outflow  for  the  tip  of  the  right 
second  toe  (2RT)  during  a  single  pulse  cycle.  A  represents  the  curves  for  the  subject  resting  supine 
in  a  comfortable  environmental  atmosphere,  B  following  heating  of  the  trunk,  and  C  following  pro- 
caine block  of  the  posterior  tibial  nerve.  Iy  and  IK  represent  the  time  courses  of  the  volume  and  rate, 
respectively,  of  inflow;  Oy  and  Or,  volume  and  rate,  respectively,  of  outflow ;  Dy  and  DR  difference 
between  the  volume  and  rate,  respectively,  of  inflow  and  outflow.  The  reader  should  refer  to  the 
iterature  (10,  11)  for  a  discussion  of  rheoplethysmography.  See  following  pages  for  2/?  and  iC. 


degree  to  blood  in  die  cutaneous  capillaries.  When 
the  velocity  of  blood  is  slow,  more  oxygen  is  removed 
by  the  tissues,  the  concentration  of  reduced  hemo- 
globin increases,  and  the  color  of  the  skin  darkens 
and  becomes  bluer. 

The  integration  of  skin  color  and  temperature 
has  been  aptly  stated  by  Lewis  (49).  These  charac- 
teristics, of  considerable  physiologic  and  clinical 
significance,   are: 

"Warm  pale  skin:  This  is  a  skin  through  which 
blood  flows  rapidly  for  many  minutes.  It  is  warm 
because  flow  is  fast,  pink  because  of  the  abundant 
supply  of  fully  oxygenated  blood,  and  pale  because 
the  skin  is  well  nourished  and  minute  vessel  tone  is 
therefore  high. 

"Warm  deeply  coloured  red  skin:  Such  skin  has  been 
irritated,   by  heat  or  otherwise,    it   is   in   a   state   of 


inflammation,  or  it  is  skin  in  which  arterial  vasodila- 
tation has  recently  been  brought  about  through 
nervous  channels  or  by  means  of  drugs  such  as 
amyl  nitrite. 

"Cold  pale  cyanosed  skin:  This  is  skin  to  which  the 
blood-flow  is  very  slow  or  absent.  If  the  tint  of  the 
cold  skin  is  violaceous  or  if  the  skin  is  blanched,  the 
circulation  to  it  is  absent  and  has  been  arrested  in  it 
for  many  minutes.  Minor  grades  of  cyanosis  are,  as 
previously  stated,  of  much  less  significance. 

"Cold  deeply  coloured  cyanosed  skin:  This  is  skin  in 
which  the  circulation  is  very  slow,  and  in  which 
blood-flow  has  been  failing  for  a  long  time  or  in 
which  there  is  a  process  of  low-grade  inflammation. 

"Cold  deeply  coloured  red  skin:  If  skin  is  sufficiently 
cold,  10°  C  (50°  F)  or  less,  the  blood  will  not  part 
with  its  oxygen,  but  the  minute  vessels  are  damaged 


PERIPHERAL    VASCULAR    DISEASES 


I  221 


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FIG.  2S 


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Ov 

and  dilate,  and  thus  the  skin  becomes  bright  red  in 
colour  although  the  blood-flow  through  it  may  be 
small." 

Some  generalizations  might  be  made  from  these 
correlations.  If  the  temperature  of  a  part  is  warm, 
there  is  a  large  volume  flow;  if  it  is  cool,  the  volume 
flow  is  small.  If  the  depth  of  skin  color  is  pale,  the 
cross-sectional  area  of  the  minute  vessels  is  decreased; 
whereas  if  a  deep  color  is  present,  the  cross-sectional 
area  is  increased  (vessels  open).  If  the  color  is  pink, 
the  velocity  of  blood  flow  is  fast  and  oxygen  satura- 
tion high;  if  red,  the  velocity  of  flow  is  intermediate 
and  the  oxygen  saturation  is  intermediate;  if  blue,  the 
blood  flow  velocity  is  slow  and  the  oxygen  saturation 
low. 

A  crude  estimation  of  the  cutaneous  circulatory 
status  may  be  obtained  from  the  subpapillary  venous 
plexus  filling  time.  Digital  pressure  on  the  skin  for 
several  seconds  results  in  displacement  of  blood  into 
adjacent  and  deeper  lying  areas.  On  sudden  release 
of  this  pressure,  the  normal  skin  shows  a  change 
from  the  pallor  to  a  normal  color  within  i  or  i  sec. 


Gravitational  effects  on  the  cutaneous  circulation 
may  be  employed  in  diagnosis  and  estimation  of  the 
state  of  the  circulation  by  means  of  elevation  and 
dependency  tests.  Here,  the  patient  lies  on  his  back 
with  the  legs  flexed  to  go  degrees  at  the  hip.  He  holds 
this  position  for  a  certain  length  of  time,  usually  i 
min.  If  he  will  tolerate  it,  the  patient  may  be  requested 
to  flex  and  extend  the  ankle  during  this  period.  With 
impairment  of  the  circulation,  the  skin  assumes  a 
white,  waxy  color  during  this  maneuver.  The  patient 
is  then  instructed  to  sit  on  the  edge  of  the  examining 
table  with  his  legs  hanging  dependent.  Normally, 
gravity  and  reactive  hyperemia  cause  a  return  of 
flushed  color  to  the  skin  within  a  short  interval  of 
time,  usually  1 5  sec.  A  delay  in  return  of  color  is 
roughly  proportional  to  the  degree  of  circulatory 
insufficiency. 

The  test  of  venous  filling  may  be  performed  simul- 
taneously with  the  above  gravitational  test.  The  dura- 
tion of  time  from  the  moment  the  patient  sits  until 
the  superficial  veins  of  the  legs  are  filled  is  a  gross 
indication    of    the    circulatory    status    in    the    legs. 


1222 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Procolnt     Block    ©t    PotHnor      Tlt-lol     N*rvt 


Sub>JM,35  WM 


FIG.   iC 


Normally,  venous  filling  starts  within  30  sec.  For  this 
maneuver  to  be  valid  as  a  test  for  arterial  sufficiency, 
the  veins  must  be  relatively  normal  with  competent 
valves.  Venous  valvular  insufficiency  is  evidenced  by 
abrupt  venous  filling. 

Tests  of  vascular  dilatability  may  be  useful  in  the 
evaluation  of  the  cutaneous  circulation.  Reactive 
hyperemia  may  be  employed  as  such  a  test.  The 
techniques  and  mechanisms  for  this  reaction  are 
discussed  in  detail  elsewhere  in  this  volume,  but  brief 
comments  may  be  in  order.  As  originally  recom- 
mended (49,  77),  the  part  to  be  tested  is  placed  in 
water  at  35  C  to  40  C  for  10  min  then  removed  and 
raised  above  body  level  until  pale.  The  purposes  of 
this  procedure  are  to  ensure  that  vessels  in  spasm  are 
relaxed  and  to  empty  the  minute  vessels  of  blood.  A 
sphygmomanometer  cuff  is  then  placed  about  the 
part  to  be  investigated  and  inflated  to  a  pressure 
above  systolic  blood  pressure.  The  limb  is  then 
returned  to  the  water  bath  and  maintained  there  for 
5,  10,  or  even  15  min  with  the  circulation  arrested,  if 
tolerated  by  the  patient.  The  limb  is  then  lifted  out 
of  the  bath,  dried,  and  its  circulation  released.  In 
normal  limbs,  the  reactive  hyperemic  flush  reaches 


the  tips  of  the  digits  within  2  to  5  sec,  becomes 
maximal  in  1  5  sec,  then  quickly  fades.  When  organic 
arterial  occlusion  is  present,  the  flush  spreads  slowly, 
is  patchv  in  distribution,  and  may  be  delayed  up  to 
a  minute  or  so  in  reaching  the  tips  of  the  fingers  or 
toes.  When  disease  is  present  and  the  onset  is  delayed, 
the  flush  lasts  for  much  longer  periods  of  time.  More 
quantitative  methods  such  as  plethysmography  or 
thermometry  may  be  used  to  measure  the  reaction. 

Vascular  dilatability  may  be  tested  by  methods 
which  decrease  lympathetic  tone.  For  example,  local 
nerve  block  (figs.  1,  2A,  B,  and  C)  or  paraverte- 
bral and  stellate  sympathetic  ganglionic  nerve  block 
mav  be  employed  with  the  responses  of  the  circula- 
tion being  measured  graphically  by  temperature 
recordings,  plethysmographic  recordings,  or  other 
means.  Vasospastic  states  due  to  sympathetic  nervous 
activitv  become  evident  from  the  recordings.  In 
normal  subjects  or  in  patients  with  functional  vaso- 
spasm, interruption  of  sympathetic  activity  results  in 
a  rise  in  digital  cutaneous  temperature  to  approxi- 
mately 32  to  35  C  when  the  subject  is  at  rest  in  a 
comfortable  environment.  For  obvious  reasons,  the 
total   rise   above   control    levels   is   much   greater   in 


PERIPHERAL    VASCULAR    DISEASES 


1223 


patients  with  vasospasm  than  in  normal  subjects.  In 
patients  with  obliterative  arterial  disease  (organic), 
interruption  of  sympathetic  innervation  results  in 
little  change  or  only  a  moderate  increase  in  digital 
cutaneous  temperature,  depending  upon  the  degree 
of  obstructive  disease  (usually  only  to  about  28  C). 
A  decline  in  cutaneous  temperature  from  control 
levels  following  sympathetic  inhibition  indicates 
severe  impairment  of  arterial  circulation.  This 
response  may  be  due  to  a  pre-existing  lack  or  dys- 
function of  sympathetic  innervation  in  the  diseased 
area  caused  by  ischemic  degeneration  of  sympathetic 
nerves.  Rigidity  of  the  diseased  blood  vessel  walls 
may  be  another  factor.  After  induced  sympathetic 
inhibition,  blood  is  apparently  shunted  away  to 
more  healthy  areas  where  the  resulting  decrease  in 
vascular  resistance  would  be  proportionately  greater. 
It  should  be  remembered  that  tests  dependent  on 
inhibition  of  sympathetic  innervation  are  of  value 
clinically  only  in  evaluation  of  the  cutaneous  circula- 
tion and  are  of  little  or  no  value  in  the  investigation 
of  the  circulation  to  muscle. 

The  above  tests,  however,  are  of  a  special  or  some- 
what complex  nature.  More  simply,  sympathetic 
inhibition  may  be  induced  by  means  of  reflex  vasodila- 
tation. Reflex  vasodilatation  is  produced  by  heating 
a  part  of  the  body  other  than  that  which  is  being 
tested.  Application  of  a  radiant  heat  tent  over  the 
trunk  may  be  used  with  the  temperatures  main- 
tained at  approximately  50  to  60  C.  Responses  can 
be  determined  graphically  by  temperature  or  plethys- 
mographic  recordings  (figs.  1,  2  A,  B,  and  C)  or  other 
suitable  means.  Normally,  the  unheated  tested  limb 
may  reach  approximately  32  C  when  other  parts  of 
the  body  are  warmed.  Reflex  vasodilatation  is 
caused  in  large  part  by  indirect  sympathetic  vaso- 
constrictor inhibition  resulting  from  the  action  of 
warmed  blood  on  central  sympathetic  temperature- 
regulating  centers  (30),  but  in  part  also  by  increased 
activity  of  the  vasodilator  fibers  (100). 

Another  simple  clinical  procedure  is  the  histamine 
wheal  test  (48,  93).  The  wheal  formation  of  the 
triple  response  produced  by  intradermal  injection  of 
histamine  is  dependent  upon  the  rate  of  local  blood 
flow  and  capillary  pressure.  The  rate  at  which  the 
wheal  forms  is  a  rough  indication  of  the  status  of 
cutaneous  circulation.  Briefly,  the  test  is  performed 
by  slightly  puncturing  the  skin  several  times  with  a 
sharp  needle  through  a  drop  of  1:1000  solution  of 
histamine  acid  phosphate.  The  subsequent  reaction 
is  then  observed.  It  has  been  stated  that  if  a  wheal 
fails  to  appear  within  3  to  5  min,  ischemia  of  tissue 


is  severe;  if  a  wheal  does  not  develop  at  all,  gangrene 
is  imminent.  Normally,  the  wheal  develops  in  3  min. 
The  mechanisms  of  the  triple  response  have  been 
discussed  in  detail  by  Lewis  (48,  49). 

EVALUATION    OF    THE    STATUS    OF    THE    MAIN    ARTERIES. 

In  the  evaluation  of  the  arterial  circulation,  one  of 
the  most  important  and  informative  procedures  is 
a  careful  and  methodical  palpation  of  the  main 
arteries,  including  all  the  major  branches  from  the 
aorta  to  the  digital  ones.  The  abdominal  portion  of 
the  aorta  is  readily  palpated.  The  thoracic  aorta  may 
be  palpated  in  advanced  aneurysm  formation.  The 
digital  arteries  of  normal  people  are  usually  palpable. 
When  arterial  spasm  is  present  and  the  pulses  are 
weak,  sublingual  administration  of  0.4  mg  of  nitro- 
glycerin (24)  or  the  inhalation  of  amyl  nitrite  may 
release  the  vascular  tone  sufficiently  to  cause  marked 
accentuation  of  arterial  pulses.  Obviously,  arteries 
which  have  been  totally  and  organically  occluded 
will  remain  impalpable  after  this  procedure. 

For  further  information  concerning  functional 
states  of  the  main  arterial  circulation,  one  often 
must  employ  more  specialized  procedures.  With 
the  foregoing  diagnostic  procedures,  however,  this 
is  usually  not  necessary. 

EVALUATION    OF    THE    STATUS    OF    THE    VENOUS    SYSTEM. 

The  common  signs  of  venous  disease  should  be 
observed  and  evaluated.  One  of  the  most  frequent  is 
edema,  which  tends  to  be  compressible  or  ""pitting" 
in  acute  or  subacute  stages  of  formation  but  firm  and 
less  compressible  when  of  long  duration.  Abnormally 
dilated  and  distended  veins  and  venous  varicosities 
are  frequently  present.  Ulcers  are  common  in  long- 
standing venous  insufficiency  and  tend  to  be  located 
over  the  medial  lower  one-third  of  the  leg.  Also 
located  in  this  area  and  frequently  found  in  chronic 
disease  is  the  so-called  ""stasis  dermatitis,"  an  atrophic, 
pigmented,  chronic,  low-grade  inflammatory  area 
of  skin. 

Several  simple  clinical  tests  are  available  for 
determining  the  competency  of  the  venous  valves 
and  the  patency  of  the  deep  veins.  They  are  usually 
employed  in  the  evaluation  of  varicose  veins.  Infor- 
mation pertaining  to  the  clinical  tests  may  be  found 
in  several  publications  (9,  54,  65,  67,  72,  7g,  80,  99). 
The  tests  are  well  known  and  will  not  be  repeated 
in  detail  here,  but  briefly  some  are  as  follows: 

Brodie- Trendelenburg  test  (gg)-  This  test  is  designed 
to  test  the  valvular  competence  of  the  saphenous 
and  communicating  venous  system.   It  involves  two 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


parts.  In  the  first  part  the  leg  is  elevated  above  the 
body,  the  veins  are  emptied,  and  a  tourniquet  is 
applied  over  the  upper  thigh  tightly  enough  to  occlude 
the  superficial  but  not  the  deep  veins.  The  patient 
then  stands.  If  the  superficial  veins  fill  quickly  (in 
less  than  30  sec)  then  the  valves  of  the  deep  to  super- 
ficial  communicating  veins  are  incompetent.  The 
second  part  of  the  test  is  similar  except  that  the 
tourniquet  is  removed  at  the  moment  the  patient 
stands.  If  the  superficial  veins  fill  immediately  in  a 
retrograde  fashion,  then  the  saphenous  valve  system 
is  incompetent. 

Perthes  test  (72).  This  test  is  designed  to  evaluate  the 
competency  of  the  saphenous  and  communicating 
valves  and  to  test  for  deep  vein  patency.  A  tourniquet 
is  applied  to  the  thigh  and  the  patient  is  asked  to 
walk  for  5  min.  If  the  superficial  veins  collapse  during 
this  walk,  there  is  an  indication  that  the  communicat- 
ing valves  are  competent  and  the  deep  veins  are 
patent.  If  no  change  is  observed,  the  indication  is 
that  the  communicating  valves  are  incompetent.  If 
the  superficial  veins  become  more  prominent  and 
pain  is  produced,  there  is  an  indication  that  the 
deep  veins  are  obstructed  and  the  communicating 
valves  may  be  incompetent.  This  test  utilizes  the 
pumping  effect  of  exercise  on  venous  flow. 

The  Perthes  test  has  been  modified  by  Mahorner 
&  Ochsner  (54)  to  determine  the  location  of  the 
incompetent  communicating  veins.  The  modifica- 
tion involves  the  application  of  tourniquets  to  the 
upper  thigh,  above  the  knee  and  below  the  knee 
before  walking.  Observations  are  made  on  the  veins 
below  the  tourniquet  before  and  after  each  walking 
period,  and  if  they  collapse  then  the  communicating 
valves  below  the  tourniquet  are  competent. 

The  mechanisms  involved  in  the  above  and  similar 
tests  should  be  obvious  and  will  not  be  pursued 
further. 

Determinations  of  venous  pressure  at  rest  and 
during  exercise  are  of  help  not  only  in  clinical  evalua- 
tion but  also  in  understanding  the  pathophysiology 
of  many  manifestations  of  venous  insufficiency  (valvu- 
lar incompetence  or  venous  obstruction)  (g,  79). 
With  significant  venous  obstruction  or  valvular  incom- 
petency, venous  pressure  in  the  leg  fails  to  drop 
during  walking  as  it  does  in  the  normal.  Venous 
blood  flow  also  fails  to  increase  during  walking.  Thus, 
high  venous  pressure  and  sluggish  venous  flow  persist 
during  the  normal  daily  activity  of  these  patients. 
When  venous  obstruction  is  marked,  venous  pressure 
is  even  higher  and  the  venous  flow  more  sluggish 
than    normal    even    in    a    recumbent    position.    The 


increase  in  venous  pressure  is  transmitted  back  to 
the  venules  and  capillaries.  Thus,  the  many  factors 
of  venous  hypertension,  stagnant  flow,  lowered  blood 
oxygen  tension,  compression  of  tissue  by  dilated 
veins,  delayed  removal  of  waste  products  of  metab- 
olism, previous  and  present  inflammatory  reactions, 
edema,  infection,  and  everyday  trauma  combine 
to  produce  the  secondary  manifestations  of  venous 
disease  such  as  stasis  dermatitis  and  dermal  ulcers. 
In  advanced  stages,  thickening  of  the  walls,  endo- 
thelial proliferation  and  degenerative  changes  may 
be  found  in  arterioles  as  well  as  venules  (3). 

Edema  formation  secondary  to  venous  obstruction 
or  valvular  incompetence  is  a  topic  of  its  own  and  will 
not  be  discussed  here.  Some  aspects,  however,  are 
discussed  in  a  subsequent  section  of  this  presentation. 

EVALUATION  OF  THE  STATUS  OF  CAPILLARY  AND  LYM- 
PHATIC vessels.  This  evaluation  is  available  in  other 
portions  of  this  volume. 

Special  Laboratory  Procedures  for  Examining 
the  Peripheral  Circulation 

Many  of  the  specialized  laboratory  procedures 
for  investigating  the  peripheral  circulation  are  dis- 
cussed elsewhere  in  this  volume  and  are  beyond  the 
scope  of  the  present  discussion.  Such  methods  include 
plethysmography,  thermometry,  calorimetry,  intra- 
vascular and  tissue  pressure  recordings,  circulation 
times,  blood-gas  analyses,  rate  of  radioisotopic 
clearance,  arteriography,  venography,  lymphangio- 
graphy, sweat  studies,  nailbed  and  scleral  capil- 
larioscopy,  infrared  photography,  and  oscillometry. 


EFFECTS  OF  CIRCULATORY  ARREST 

Complete  circulatory  arrest  lies  at  the  farthest  end 
of  the  spectrum  from  the  normal  state.  Before  pro- 
gressing to  disease,  the  effects  of  which  may  lie  any- 
where between  these  two  extremes,  it  might  be 
beneficial  to  review  briefly  the  effects  of  complete 
arrest  of  the  circulation.  Much  of  these  data  are 
found  in  the  publications  of  Lewis  (48,  49). 

With  complete  circulatory  arrest  the  temperature 
of  the  part  decreases  to  room  temperature.  The  rate 
of  decline  is  dependent  upon  environmental  tem- 
perature, relative  humidity,  and  air  currents.  The 
greater  the  mass  of  the  part,  the  slower  the  decline. 
Pallor  is  the  first  change  in  color  as  the  blood  drains 
out  of  the  minute  vessels  in  the  first  30  to  60  sec. 


PERIPHERAL    VASCULAR    DIS1 


[22  = 


During  the  next  few  minutes  the  part  becomes  bluer 
and  then  definitely  cyanotic. 

Lewis  (48)  made  interesting  observations  on  the 
blood  vessel  reactions  in  the  skin  of  the  arm  after 
obstruction  of  the  brachial  artery  by  a  pneumatic 
cuff.  After  a  few  minutes  of  obstruction,  reel  and 
white  spots  (Bier's  spots)  form  in  the  cyanotic  back- 
ground of  the  surrounding  skin.  The  red  spots  are 
due  to  leakage  of  blood  into  the  area  from  collateral 
circulation  through  bone.  The  white  spots  are  due  to 
intense  contraction  of  the  vessels  responsible  for 
skin  color,  in  particular,  the  subpapillary  plexus  of 
veins.  Lewis  excluded  cold  temperature  and  central 
and  local  nervous  factors  as  primary  causes  of  the 
white  spots.  They  are  formed  in  previously  dener- 
vated  areas.  Through  a  careful  series  of  experiments, 
Lewis  showed  that  in  cutaneous  areas  in  which  the 
circulation  has  been  sufficiently  reduced,  vaso- 
constrictor as  well  as  vasodilator  substances  are 
formed.  The  vasoconstrictor  substances  are  released 
locally  in  the  tissue  spaces  and  are  not  derived  from 
the  blood.  These  substances  act  against  potent 
vasodilator  factors  known  to  be  released  when  the 
circulation  is  arrested.  As  noted  by  Lewis  (48),  these 
white  spots  enlarge  and  coalesce  progressively  as  the 
skin  is  deprived  of  its  circulation.  He  noted  that  at 
death  the  skin  is  initially  congested  but  shortly  after- 
ward the  white  spots  appear,  spread,  and  coalesce 
until  all  but  dependent  parts  of  the  skin  are  white  or 
universally  blanched.  Responses  comparable  to  Bier's 
spots  have  been  described  for  organs  other  than  the 
skin    (86). 

After  its  induction,  if  circulatory  arrest  to  a  limb 
continues,  nervous  changes  develop,  distally  at  first 
and  then  progress  proximally  up  the  extremity. 
Numbness  occurs  within  15  min  and  is  followed  by 
hypesthesia,  first  for  pain  and  cold  and  last  for 
warmth.  With  respect  to  the  arm,  motor  changes  occur 
in  approximately  20  min,  appearing  first  in  the 
thenar  eminence.  Within  25  min  motor  paralysis  is 
usually  present  in  the  thenar  muscles  and  within 
30  min  in  the  interossi  and  extensor  muscles  of  the 
wrist. 

If  the  circulation  is  re-established  within  30  to  60 
min  after  its  arrest,  complete  recovery  usually  occurs. 
When  arrest  is  prolonged,  severe  changes  occur. 
Within  6  to  1 2  hours  there  is  muscle  death  and 
whealing  and  blistering  of  the  skin.  After  circulatory- 
arrest  for  12  to  20  hours  there  is  nerve  destruction 
and  after  24  to  48  hours,  necrosis  of  the  skin. 

Recent  studies  (33,  88)  of  pathologic  changes  from 
acute  ischemia  in  man  have  shown  that  after  a  few 


hours  of  circulatory  arrest  a  muscle  contracture  similar 
to  rigor  mortis  develops.  This  does  not  progress 
inevitably  to  fibrotic  (Yolkmann's)  contracture. 
Although  the  latter  is  a  frequent  occurrence,  the 
initial  contracture  can  be  reversible.  It  was  noted 
that  the  early  changes  can  be  accompanied  by  little 
or  no  obvious  histologic  alteration  but  somewhat 
paradoxically,  restoration  of  the  circulation  at  this 
stage  often  leads  to  sudden  increase  in  the  apparent 
severity  of  muscle  damage.  It  is  thought  that  the 
previous  "normal"  histology  might  be  merely  that 
of  dead  or  dying  muscle  preserved  in  a  cool  environ- 
ment and  that  subsequent  circulation  of  warm  blood 
results  in  the  demonstrable  vascular  engorgement, 
swelling,  exudation,  and  focal  hemorrhage  with 
release  of  myoglobin  and  consequent  muscle  pallor. 
Depending  on  severity  and  duration,  the  involved 
muscle  can  recover  completely  or  suffer  any  degree 
of  damage  (with  subsequent  fibrotic  contracture)  up 
to  complete  necrosis.  It  was  observed  that  skin  is 
more  resistant  to  ischemic  damage  than  is  muscle, 
and  muscle  can  be  irreversibly  damaged  even  though 
the  skin  remains  viable.  From  these  studies  it  was 
difficult  to  place  a  definite  length  of  time  for  circula- 
tory arrest  to  produce  irreversible  change,  but  a  gross 
estimate  was  1 2  hours  or  less. 

With  respect  to  the  clinical  implications  of  the 
above  studies  in  the  management  of  acute  arterial 
occlusion  by  thrombo-embolectomy,  it  is  worthwhile 
noting  that  blood  in  an  artery  distal  to  an  occlusion 
usually  remains  fluid  for  8  to  12  hours  (4).  After- 
ward the  tendency  to  thrombosis  and  progressive 
distal  arterial  occlusion  increases  rapidly. 


CLASSIFICATION   OF  PERIPHERAL  VASCULAR  DISEASE 

The  classification  of  peripheral  vascular  disease 
included  in  the  Appendix  to  this  chapter  although 
not  all-inclusive  is  fairly  complete.  It  represents  a 
modification  of  the  classification  suggested  by  the 
Criteria  Committee  of  the  New  York  Heart  Associa- 
tion (15).  It  serves  to  emphasize  the  enormous  prob- 
lem and  types  of  peripheral  vascular  disease.  Each 
entity  in  the  classification  represents  a  separate 
complex  experiment  in  nature.  An  adequate  dis- 
cussion of  each  would  be  impossible.  For  more  elabo- 
rate descriptions  of  these  diseases  and  for  references, 
the  reader  may  consult  monographs  on  the  subject 
(1,3,  87,  104)  and  two  recent  symposia  on  peripheral 
vascular  diseases  (95,  96).  The  diseases  selected  for 
discussion  here  are  the  more  common  ones  as  well 


I  _•_>(> 


HANDBOOK    OK     PHYSIOLOGY 


CIRCULATION     II 


as  tliose  primarily  oriented  best  from  the  standpoint 
of  discussion  of  mechanisms  in  peripheral  vascular 
disease.  Particular  emphasis  is  placed  on  vasocon- 
strictor and  vasodilator  disease  states. 


MECHANISMS   IN    PERIPHERAL   VASCULAR  DISEASE 

I  asoconstrictoi  Disease  Syndromes 

Raynaud's  syndrome  or  phenomenon.  This  syndrome 
or  phenomenon  had  been  known  for  years  before  the 
time  of  Raynaud.  Ragnetta,  Huguier,  Virchow, 
Zambaco  and  others  commented  on  the  syndrome, 
but  Raynaud's  thesis  published  in  1862  (84)  first 
brought  wide  attention  to  the  syndrome  as  a  distinct 
entity.  Since  that  time  Lewis'  work  has  been  out- 
standing (46,  48,  49). 

For  purposes  of  classification  and  diagnosis  one 
may  refer  to  a)  primary  (idiopathic)  Raynaud's 
syndrome  or  phenomenon,  and  b)  secondary  Ray- 
naud's syndrome  or  phenomenon.  When  Raynaud's 
svndrome  occurs  as  a  primary  manifestation  and 
without  any  obvious  underlying  or  predisposing 
cause,  it  is  termed  "primary."  When  the  syndrome 
occurs  as  a  result  of,  or  in  association  with,  some 
other  disease  which  is  known  to  be  of  significance  in 
predisposition  to  or  production  of  the  syndrome,  it  is 
termed  "secondary."  Obviously,  the  classification 
of  the  secondary  type  is  somewhat  crude,  since  it  is 
based  upon  empiric  observation  of  an  association  of 
the  syndrome  with  some  other  disease  process  with 
.1  frequency  not  expected  in  otherwise  normal  people. 
Certainly  the  primary  syndrome  must  be  secondary 
to  its  cause.  Nevertheless,  for  diagnostic,  prognostic, 
and  therapeutic  reasons,  this  classification  is  helpful. 
Raynaud's  disease  is  the  term  applied  when  the 
typical  phenomena  have  been  present  for  2  years 
without  detection  of  any  obvious  cause.  Although 
this  terminology  is  arbitrary,  it  is  clinically  valid 
since  most  diseases  in  which  Raynaud's  syndrome  is 
a  secondary  manifestation  are  usually  diagnosed 
within  a  2-year  period  (22). 

Raynaud's  syndrome  characteristically  consists 
of  transient  episodes  of  digital  pallor,  cyanosis,  and 
erythema.  The  typical  progression  would  be  from 
pallor,  to  cyanosis,  to  erythema,  but  this  is  not  always 
true.  Erythema  is  not  invariably  noted  and  its 
presence  is  not  a  requirement  for  diagnosis.  Although 
a  pale  blue-gray  reaction  usually  precedes  the  stage 
of  pallor  (or  cyanosis  when  pallor  is  absent),  it 
frequently    escapes    notice.     In    order    to    diagnose 


Raynaud's  syndrome  confidently  there  should  be  at 
least  intermittent  attacks  or  crises  of  either  digital 
pallor  (syncope)  or  digital  cyanosis.  Both  may  be 
present  and  either  or  both  may  be  associated  with 
subsequent  erythema. 

Primary  Raynaud's  phenomenon  and  Raynaud's  disease. 
Raynaud's  disease  usually,  but  not  invariably,  appears 
before  the  age  of  forty  and  is  much  more  frequent  in 
lemales.  Typically  the  vasomotor  episodes  are  precipi- 
tated by  exposure  to  cold  and  occasionally  by  emo- 
tional stress.  In  diagnosis,  blanching  can  often  be 
produced  by  submerging  the  hands  or  feet  in  water 
at  an  optimum  temperature  (49)  of  approximately 
15  C  (range,  12  to  18  C)  for  10  to  15  min,  but  failure 
to  produce  the  characteristic  manifestations  of  the 
attack  does  not  exclude  the  diagnosis  (1,  49,  60). 
However,  failure  to  produce  blanching  by  this 
means  plus  additional  preliminary  or  simultaneous 
general  body  cooling  (e.g.,  a  cold  shower)  is  reliable 
evidence  that  Raynaud's  syndrome  does  not  exist. 
Water  of  icy  coldness  tends  to  produce  a  red  reaction 
even  in  patients  with  Raynaud's  syndrome.  It  is 
important  to  differentiate  Raynaud's  phenomenon 
from  cold  allergy  which  produces  an  erythematous 
pruritic  edema  but  not  true  blanching  (60). 

The  vascular  reactions  and  color  changes  of  Ray- 
naud's syndrome  tend  to  occur  segmentally  and 
bilaterally  in  the  digits,  generally  terminating  at  the 
interphalangeal  or  metacarpophalangeal  articula- 
tions. Although  there  is  a  distinct  tendency  for  the 
syndrome  to  occur  bilaterally  and  symmetrically 
some  asymmetry  in  degree  of  involvement  of  either 
hand  is  not  uncommon.  Involvement  of  an  extremity 
characteristically  does  not  extend  proximal  to  the 
metacarpo(tarso)phalangeal  joint.  The  feet  may  be 
involved,  but  the  hands  are  involved  much  more 
frequently.  Involvement  of  other  parts  of  the  body 
is  occasionally  seen,  especially  such  acral  parts  as 
the  ear  lobes,  cheeks,  tongue,  and  the  tip  of  the  nose. 

The  localization  of  the  vascular  lesions  to  the 
hands  and  feet  is  of  interest.  When  only  a  single 
phalanx  is  involved,  it  is  the  distal  one;  when  two 
phalanges  are  involved,  they  are  the  distal  two.  All 
three  phalanges  of  a  digit  or  several  digits  of  either 
hand  may  be  involved.  In  a  single  digit  the  direction 
of  progression  of  changes  during  an  attack  is  from 
distal  to  proximal.  The  second  or  fifth  or  both  digits 
are  involved  most  often.  When  only  the  very  tip  of 
the  distal  phalanx  is  involved,  this  suggests  changes 
in  vessels  smaller  than  the  digital  arteries.  Localiza- 
tion of  Raynaud's  reaction,  which  rarely  occurs  in 
parts  of  the  body  other  than  the  digits,  is  apparently 


PERIPHERAL    VASCt   LAR    DISEASES 


[227 


due  to  vascular  changes  in  the  reticular-perpendicular 
arterioles  in  the  skin  of  these  sites. 

Manifestations  other  than  the  typical  color  changes 
may  be  present.  During  the  pallid  or  cyanotic  crises, 
digital  paresthesias  may  be  present.  During  the 
erythematous  phase  there  may  be  increased  warmth 
and  a  painful  throbbing  sensation  in  the  affected 
digits.  After  long-standing  or  severe  disease,  ulcera- 
tion, necrosis,  edema,  or  subungual  and  paronychial 
infection  may  develop  (fig.  3).  Ulcers  usually  occur 
on  the  digital  tips  and  these  may  be  quite  painful. 
When  they  heal,  they  typically  leave  small  pitted 
"stellate"  scars.  Another  change  that  occasionally 
develops  in  long-standing  or  severe  disease  is  sclero- 
dactylia. The  digits  show  a  tight,  tough,  inelastic, 
fibrotic,  and  contracted  skin  with  areas  of  hyper- 
pigmentation  and  hypopigmentation.  This  change 
must  be  differentiated  from  a)  acrosclerosis,  in  which 
similar  changes  involve  not  onlv  the  digits  but  also 
the  face  and  neck;  and  b)  scleroderma,  in  which 
fibrotic  changes  are  generalized,  even  involving 
multiple  visceral  organ  systems. 

Practically  nothing  is  known  of  the  earliest  patho- 
logic changes  in  Raynaud's  disease.  This  is  due  in 
large  part  to  the  lack  of  biopsy  specimens  obtained 
during  the  early  stages  of  the  disease.  Physicians 
and  investigators  have  been  reluctant  to  obtain 
biopsies  in  these  patients.  Simple  digital  biopsy 
methods  and  other  means  are  now  available  whereby 
early  changes  may  be  observed,  both  by  light  and 
electron  microscopy  not  only  in  Raynaud's  syndrome 
but  also  in  other  peripheral  vascular  disorders  (32, 
73,  75).  Based  on  light  microscopy,  it  has  been 
assumed  that  pathologic  changes  are  absent  in  early 
Raynaud's  disease.  More  sensitive  methods,  such  as 
electron   microscopy,   may  alter   this   impression.    In 


FIG.    3.   Primary    Raynaud's    disease    with    trophic    changes 
and  early  sclerodactylia. 


the  later  stages  of  the  disease,  intimal  thickening  of 
the  digital  arteries  is  almost  always  present.  In  still 
more  advanced  stages  the  internal  elastic  membranes 
split  and  there  is  endarteritis  obliterans  with  thrombi 
in  various  stages  of  recanalization.  The  latter  changes 
are  particularly  frequent  in  association  with 
ulceration. 

Briefly,  and  in  general,  the  mechanisms  for  Ray- 
naud's phenomenon  are  as  follows:  Pallor  is  due  to 
digital  arterial  constrictive  crises  to  the  point  of,  or 
almost  to  the  point  of,  complete  occlusion  with 
resultant  absence  or  near  absence  of  digital  arterial 
blood  flow.  Capillary  pressure  drops  to  about  5  to  10 
mm  Hg  (60).  Cyanosis  occurs  when  digital  arterial 
constrictive  crises  are  slightly  less  severe,  allowing 
some  blood  to  flow.  In  this  situation  the  slow  rate 
of  flow  fosters  an  increased  dissociation  of  ox\  gen 
from  hemoglobin  with  resulting  local  cyanosis. 
During  the  recovery  phase  from  the  vasoconstriction, 
erythema  frequently  ensues  due  to  reactive  hyperemia. 
These  physiologic  changes  are  fairly  well  accepted 
as  the  vascular  reactions  responsible  for  the  typical 
digital  color  changes.  Controversy  still  exists,  how- 
ever, regarding  the  location  and  nature  of  the  under- 
lying factors  responsible  for  initiating  vascular  reac- 
tions. Raynaud  felt  that  the  primary  factor  was  a 
derangement  of  the  nervous  system  (84).  Adson  & 
Brown  (2)  also  considered  the  basic  fault  in  early 
Raynaud's  disease  to  exist  entirely  in  the  vasomotor 
nerves,  since  complete  relief  of  Raynaud's  reaction 
occurred  in  many  patients  following  sympathetic 
ganglionectomy. 

Lewis  (48,  49),  however,  maintained  that  the 
basic  fault  is  in  the  digital  arteries  themselves  and 
that  the  defect  consists  of  an  abnormal  sensitivity 
of  the  arteries  to  direct  stimuli,  particularly  to  cold. 
In  Lewis'  own  words  (49),  "The  central  fact  is  tran- 
sient loss  of  circulation  to  the  digits  occurring  on 
exposure  to  cold.  I  have  shown  that  this  spasmodic 
loss  of  circulation  is  due  to  closure  of  the  digital 
arteries,  and  that,  irrespective  of  its  nature,  the  fault 
lies  in  these  vessels;  the  closure  does  not  involve 
arteries  of  much  larger  size,  neither  does  it  include 
arterioles  or  veins.  But  since  the  attack  is  induced  by 
exposure  to  cold,  to  which  all  vessels  normally 
respond,  a  general  reduction  of  their  size  happens. 
In  most  of  the  vessels  the  degree  of  closure  can  be 
regarded  as  no  more  than  normal.  In  the  small 
arteries  only  is  the  response  to  cold  manifestly  abnor- 
mal; these  are  in  a  state  rendering  them  particularly 
liable  to  shut  on  direct  exposure  to  cold.  In  sensitive 
cases,  the  blood-flow  to  a  single  finger  can  be  arrested 


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HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


at  will  by  cooling  this  finger  alone,  or  even  by  cooling 
a  short  stretch  of  it;  for  the  digital  arteries  in  their 
whole  length  possess  this  liability  to  closure.  The  state 
of  closure  once  established  can  be  released  by  warm- 
ins;  the  hands;  and  this  can  also  be  affected  in  the 
arteries  of  separate  fingers,  or  even  in  the  arteries 
at  the  base  of  a  finger,  by  warming  the  finger  or  its 
base  separately. 

"It  has  been  indicated  already  that,  when  a  normal 
subject  is  exposed  to  cold,  arteries  like  the  digital 
narrow  under  two  influences;  they  constrict  as  a 
direct  reaction  to  cold,  and  because  vasomotor 
nervous  tone  increases.  These  same  two  factors 
operate  in  the  fingers  of  the  cases  we  are  discussing, 
under  conditions  of  general  cooling.  But,  because 
in  these  cases  there  is  an  abnormality,  the  vessels 
do  what  they  will  not  do  in  normal  subjects,  they 
close  to  obliteration.  The  evidence  proves  that  the 
abnormal  element  is  local,  and  not,  as  formerly 
thought,  in  the  response  of  the  nervous  system.  Thus, 
if  vasomotor  tone  is  deliberately  reduced  by  warming 
the  subject's  body,  immersion  of  the  hand  of  a  sus- 
ceptible subject  in  cold  water  will  still  induce  the 
attack;  but  if  the  hand  is  kept  warm,  an  increase  of 
vasomotor  tone,  induced  by  cooling  the  body,  will 
not  provoke  the  attack.  Again,  if  the  circulation  to 
the  fingers  of  such  a  patient  has  become  arrested  by 
general  exposure  to  cold,  local  destruction  of  vaso- 
motor tone  by  nerve  anaesthetisation  does  not  bring 
instant  release  of  blood-flow,  which  would  happen 
inevitably  if  vasomotor  tone  were  alone  responsible: 
it  brings  delayed  release,  or  the  release  fails.  Likewise, 
as  experience  has  shown,  destruction  of  the  sympa- 
thetic nerve  supply  to  the  limb  by  surgical  inter- 
vention  does  not  cure  the  malady:  for  it  frequently 
happens  that  patients  so  treated  continue  subse- 
quently to  display  attacks  on  exposure  to  cold;  and 
after  sympathectomy  the  local  susceptibility  can 
always  be  demonstrated  by  special  tests  in  sensitive 
cases  and  this  is  so  even  when  the  sympathectomy  is 
preganglionic.  The  local  abnormality  is  the  reason 
for  this,  for  it  remains  unchanged. 

"Although  the  facts  show  that  the  fault  is  not  in 
the  nervous  system,  that  is  not  to  say  that  the  nervous 
system  plays  no  part  in  the  attacks.  If  under  the 
direct  influence  of  cold  the  arterial  channels  of  a 
hand  become  unusually  narrowed,  but  not  quite 
obliterated,  then  subsequent  cooling  of  the  trunk, 
or  an  emotional  disturbance,  or  a  painful  stimulus, 
by  normally  increasing  vasomotor  tone,  will  cause 
the  vessels  to  close  completely  and  thus  determine 
an   attack.    It   is   this   kind   of  event   that   has    been 


misinterpreted  in  the  past,  and  has  given  support  to 
the  wrong  idea  that  the  vasomotor  nervous  system  is 
primarily  at  fault.  Further  it  will  be  apparent  that 
anything  reducing  or  abolishing  vasomotor  tone  will 
on  occasion  bring  an  attack  to  an  end,  and  continuing 
as  an  influence  will  tend  to  prevent  the  recurrence  of 
attacks.  This  is  the  basis  upon  which  the  modern 
treatment  by  sympathectomy  rests;  its  successful 
results  are  due,  not  to  interference  with  the  passage 
of  abnormal  nervous  impulses,  but  to  the  destruction 
of  normal  vasomotor  tone." 

Lewis  emphasized  that  if  one  finger  of  a  subject 
with  the  disease  is  immersed  in  cold  water,  the  attack 
is  frequently  confined  to  this  finger.  He  felt  that  such 
a  sharply  localized  response  could  not  be  explained 
on  the  basis  of  a  nervous  reflex. 

More  recent  publications  (8,  52,  62)  presented  evi- 
dence in  support  of  Lewis'  theory  of  a  "local  fault"  in 
the  blood  vessels.  By  plethysmography  and  thermom- 
etry it  was  demonstrated  that  patients  with  Ray- 
naud's phenomenon  have  an  increased  sensitivity 
to  cold  as  compared  to  normal  subjects  and  that  this 
state  persists  even  after  successful  sympathetic  dener- 
vation. These  studies  were  not  meant  to  imply  that 
sympathectomy  is  of  no  benefit  to  the  patients.  When 
the  patient's  peripheral  vessels  are  maximally  dilated 
by  the  procedure  and  heated  by  the  warm  blood 
flowing  through  them,  a  decrease  of  the  vessel  tem- 
perature to  the  critical  level  is  not  as  easily  produced. 
Further,  cooling  of  the  vessels  by  vasoconstriction 
can  no  longer  be  induced  reflexly  from  emotional 
disturbances,  pain,  or  body  chilling. 

Whether  or  not  ether  vessels  besides  the  digital 
arteries  participate  actively  in  the  Raynaud's  reac- 
tion has  been  debated.  Naide  &  Sayen  (66)  con- 
sidered that  arterial  spasm  alone  cannot  explain  the 
entire  clinical  picture.  They  presented  evidence, 
though  not  conclusive,  that  spasm  of  the  digital  veins, 
as  well  as  the  digital  arteries,  exists.  It  was  based 
largely  on  observations  that  in  some  patients  with 
Raynaud's  disease  the  digits  began  to  appear  puffed 
and  cyanotic  before  blanching  occurred.  The  authors 
considered  this  to  indicate  venoconstriction  prior 
to  arterial  constriction. 

Capillarioscopy  has  been  of  value  in  detecting 
vascular  change  in  the  various  reactions  of  Raynaud's 
disease  (3,  18).  During  the  stage  of  pallor,  no  blood 
enters  the  capillaries  of  the  involved  digits.  During 
the  stage  of  cyanosis,  more  than  the  usual  number  of 
of  capillaries  are  engorged  with  blood,  and  many 
are  greatly  dilated.  They  are  filled  with  stagnant 
blood.  Venules  may  also  be  dilated  during  this  stage, 


PERIPHERAL    VASCULAR    DISEASES 


1229 


and  there  may  be  reflux  of  blood  from  the  venules 
into  the  capillaries.  The  transient  cyanotic  reaction 
in  Raynaud's  disease  is  similar  to  the  more  nearly 
permanent  cyanosis  of  acrocyanosis  in  which  second- 
ary dilatation  of  capillaries  and  venules  results  from 
arteriolar  spasm  (3).  During  the  erythematous  phase, 
capillary  pulsations  may  be  detected.  It  should  be 
recalled  that  in  Raynaud's  disease  the  vessels  supply- 
ing the  hand  (radial  and  ulnar)  are  normal  and 
continue  to  pulsate  normally  during  the  crises. 

The  main  controversy  remains  concerning  the 
initial  basic  defect  in  Raynaud's  disease,  that  is, 
whether  or  not  it  is  in  the  nervous  system  or  in  the 
vessel  wall  itself.  Certainly  in  advanced  stages  the 
easily  demonstrable  intimal  thickening  and  throm- 
bosis of  the  vessels  contribute  significantly  in  reducing 
blood  flow.  It  is  probable  that  a  vicious  cycle  is 
induced  whereby  repeated  vasospastic  attacks  cause 
increasing  injury  and  structural  changes  in  the 
digital  vessels  which  then  become  more  vulnerable 
to  vasospastic  influences  (60).  Nevertheless,  the 
important  pathogenic  factors  in  the  early  stages  are 
still  not  known  and  very  little  recent  definitive 
research  in  this  area  has  been  reported. 

Some  recent  studies,  however,  are  of  interest. 
Using  chromatography  and  biologic  assay,  Peacock 
(70)  determined  the  concentrations  of  epinephrine 
and  norepinephrine  in  the  peripheral  venous  blood 
collected  at  the  wrist  in  a  group  of  normal  subjects 
and  in  a  group  of  patients  with  primary  Raynaud's 
disease.  He  found  that  under  warm  resting  environ- 
mental conditions,  the  Raynaud's  patients  showed  a 
significantly  higher  blood  level  of  these  amines  than 
did  the  normal  subjects.  Following  sympathetic 
nervous  stimulation  by  cold,  the  patients  with 
Raynaud's  disease  had  an  increase  primarily  of  the 
norepinephrine  fraction.  This  increase  varied  directly 
with  the  clinical  severity  of  the  disease.  Peacock  con- 
sidered the  high  concentrations  of  these  amines  to 
be  due  to  an  abnormality  in  metabolism  of  these 
substances.  It  was  noted  that  in  Raynaud's  disease 
the  average  digital  cutaneous  temperature  in  a  room 
temperature  of  20  C  ±  5  was  22.3  C  compared  with 
30.2  C  for  the  normal  subjects.  Similar  differences 
had  been  reported  for  environmental  temperatures 
as  high  as  25  C.  It  was  reasoned  that  over  this  range 
of  temperature,  due  to  precooling  of  blood  by  counter- 
current  flow  mechanisms,  the  intraluminal  temper- 
ature of  the  blood  in  the  digital  arteries  of  patients 
with  Raynaud's  disease  was  probably  considerably 
lower  than  that  seen  in  normal  control  subjects.  Thus, 
it  was  concluded  that  the  lower  temperature  inhibited 


enzyme  systems  which  inactivate  epinephrine  and 
norepinephrine  and  that  this  was  responsible  for  the 
higher  concentrations  of  the  vasoconstrictor  sub- 
stances and  the  intense  peripheral  vasoconstriction. 
In  this  respect  monoamine  oxidase  activity  of  digital 
arteries  of  two  patients  with  Raynaud's  disease  was 
absent,  whereas  that  of  two  normal  subjects  was  found 
to  be  552  ii\  02  per  g  per  hour. 

These  studies  are  interesting  but  many  questions 
remain  unanswered.  For  example,  the  effect  of 
reduced  blood  flow  per  se  on  the  concentrations  of 
amines  in  the  venous  blood  draining  these  areas  is 
not  known.  Concentrations  may  be  greater  but  the 
total  amount  may  be  the  same  or  less.  Further,  with 
respect  to  these  amines,  the  relative  contributions  of 
a)  increased  amount  in  stores,  b)  increased  release 
from  stores,  c)  decreased  destruction,  d)  impeded 
physical  removal,  and  e )  increased  vascular  sensitivity- 
are  also  unknown.  Furthermore,  the  role  played  by 
reduced  formation  of  vasodilator  metabolites  from 
cooled  tissues  [as  proposed  by  Freeman  (27,  28)  and 
later  by  Perkins  et  al.  (71)]  in  the  pathophysiology  of 
Raynaud's  disease  needs  investigation. 

Recently,  Mendlowitz  &  Naftchi  (61)  have  reported 
observations  on  digital  blood  pressure  (Gaertner 
capsule)  and  digital  blood  flow  (calorimetry)  in  20 
patients  with  primary  or  idiopathic  Raynaud's 
disease.  The  patients  were  studied  at  rest,  under 
standardized  conditions,  before  and  after  vasodilata- 
tion (reflex  vasodilatation)  and  after  vasoconstriction 
produced  by  infused  /-norepinephrine.  After  appro- 
priate calculations,  they  noted  that  their  patients 
fell  into  two  groups:  /)  those  with  digital  vascular 
obstruction  and  normal  vasomotor  tone,  and  2) 
those  without  obstruction  but  with  heightened  vaso- 
motor tone.  Neither  group  showed  increased  sensitiv- 
ity to  norepinephrine.  Thus,  the  authors  suggested 
that  the  digital  vasospastic  crises  in  Raynaud's 
disease  could  be  produced  either  by  vascular  obstruc- 
tion acted  upon  by  normal  vasomotor  tone,  or  by 
heightened  vasomotor  tone  produced  by  increased 
sympathetic  neural  discharge  acting  on  otherwise 
normal  vessels. 

The  relationship  of  these  latter  findings  to  those 
of  Lewis  (49)  and  the  more  recent  ones  of  Peacock 
(70)  is  not  clear.  With  reference  to  the  grouping 
offered  by  Mendlowitz  and  Naftchi,  it  is  possible, 
but  not  proved,  that  Lewis  was  studying  patients  in 
the  group  with  vascular  obstruction  and  normal 
vasomotor  tone,  whereas  Peacock  was  studying 
patients  in  the  group  without  obstruction  but  with 


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CIRCULATION     II 


heightened  tone.  Thus,  there  are  many  problems  in 
Raynaud's  disease  which  await  clarification. 

Secondary  Raynaud's  syndrome  or  phenomenon.  A  glance 
at  the  classification  of  peripheral  vascular  disease 
(see  Appendix  to  this  chapter)  reveals  that  Ray- 
naud's phenomenon  occurs  as  a  secondary  mani- 
festation in  a  number  of  disease  states.  The  proposed 
mechanisms  invoked  in  these  entities  are  complex 
and  a  description  of  these  is  beyond  the  scope  of  the 
present  discussion.  Further,  little  definitive  work  has 
been  done  to  determine  the  true  physiologic  mecha- 
nisms responsible  for  the  relationship  between  these 
diseases  and  secondary  Raynaud's  syndrome.  In 
general,  what  has  been  said  regarding  primary 
Raynaud's  phenomenon  may  be  applied  to  the 
secondary  phenomenon.  There  are  a  lew  known 
differences.  In  the  secondary  state  the  associated 
manifestations  of  the  primary  predisposing  disease 
are  evident.  With  obliterative  arteriosclerotic  endarte- 
ritis, Buerger's  disease,  or  other  obliterative  arterial 
states,  the  degree  of  gangrene  associated  with  second- 
ary Raynaud's  phenomenon  may  be  considerably 
more  than  in  primarv  Raynaud's  because  of  the 
underlying  obliterative  disease.  In  the  secondary 
state,  exposure  to  cold  or  emotional  stress  may  or 
may  not  precipitate  Raynaud's  phenomenon.  Lastly, 
secondary  Raynaud's  phenomenon  is  frequently 
neither  bilateral  nor  symmetrical. 

It  is  often  suggested  that  the  observation  of  Ray- 
naud's phenomenon  occurring  in  diseases  of  the 
nervous  system  refutes  Lewis'  idea  of  a  local  arterial 
defect  and  that  primary  Raynaud's  disease  is  a 
disease  of  neural  origin.  Even  though  this  problem 
is  unsettled,  it  must  be  remembered  that  differences 
between  primary  and  secondary  Raynaud's  pheno- 
menon do  exist.  Further,  Raynaud's  phenomenon 
from  neural  disease  still  might  be  due  to  excessive 
sympathetic  nervous  activity  in  the  presence  of 
"normal"  digital  vessels,  whereas  primary  Raynaud's 
disease  might  be  due  to  a  local  vessel  defect  in  the 
presence  of  normal  sympathetic  nerve  activity. 

acrocyanosis.  Acrocyanosis  is  a  disorder  character- 
ized bv  a  persistent  cyanotic  rubor  to  the  skin  of  the 
hands  and  feet  and  other  acral  portions  of  the  bodv 
associated  with  a  reduced  skin  temperature.  The  term 
"acrocyanosis"  was  first  applied  by  Crocq  (16)  in 
iHi)ti,  and  Cassirer's  description  (12)  in  191 2  helped 
clarify  this  disorder  as  a  distinct  clinical  entity.  Lewis 
&  Landis  (50)  initiated  basic  investigations  into  the 
pathophysiology  of  this  disease,  but  only  a  few  con- 


tributions to  its  mechanisms  have  been  available 
since. 

The  etiology  of  acrocyanosis  is  unknown.  In  his 
large  series  of  several  hundred  patients,  Stern  (94) 
was  unable  to  detect  any  constant  precursor  or  accom- 
paniment of  the  disorder  other  than  cold,  with  fre- 
quent moderate  cooling  of  affected  parts,  and  possibly 
inactivity,  the  latter  because  of  the  occurrence  in 
lethargic  types  of  mental  disorders.  It  is  much  more 
frequent  in  females  and  usually  present  in  young  or 
middle-aged  individuals.  There  is  frequently  a  family 
history  of  the  disorder.  It  has  been  described  as  being 
rare  in  the  general  population  but  rather  common 
among  the  inmates  of  mental  institutions. 

The  patient  usually  visits  the  doctor  for  cosmetic 
reasons,  complaining  of  almost  constant  coldness  and 
bluish  discoloration  ol  the  fingers,  hands,  nose, 
cheeks,  chin,  and  pinna  of  several  years'  duration 
(fig.  4).  The  toes  and  feet  may  be  involved,  but  usually 
to  a  lesser  degree  than  the  hands.  The  changes, 
though  present  during  the  summer,  are  usually  more 
marked  in  the  winter.  The  affected  parts  are  usually 
deeply  cyanotic  when  cold,  and  bright  red  when  they 
are  very  cold  or  when  they  are  warm.  Frequently 
they  present  a  mixture  of  the  two  colors,  red  and 
bluish-purple.  The  deep  reddish  color  (as  opposed  to 
cyanosis)  produced  by  a  very  cold  temperature  (less 
than  10  C)  is  due  to  arteriolar  injury  and  dilatation 


n 


* 


fig.    4.  Acrocyanosis.    [Reprinted    with    the    permission    of 
H.  K.  Lewis  &  Company,  Ltd.,  London  (94).] 


PERIPHERAL    VASCULAR    DISEASES 


1231 


and    inhibition    of   oxygen    dissociation    from    hemo- 
globin. 

The  palms  are  often  sweaty.  The  hands  are  usually 
much  colder  than  normal  during  exposure  to  a  com- 
fortable temperature  but  warm  readily  in  a  hot  room. 
The  disease  varies  considerably  in  degree  from  very 
mild  to  severe. 

In  the  past,  acrocyanosis  has  been  confused  with 
Raynaud's  disease  but  many  differentiating  features 
are  apparent.  In  acrocyanosis  the  color  changes  are 
persistent  rather  than  episodic.  The  changes  are  not 
limited  to  the  digits  but  include  the  entire  hand  and 
foot,  though  they  rarely  extend  proximally  to  the 
wrist  or  ankle  areas.  There  may  be  associated  livedo 
reticularis  or  pernio  involving  more  proximal  areas 
of  the  extremities.  There  are  usually  no  episodes  of 
blanching,  sclerodactylia  does  not  develop,  and  areas 
of  ulceration  and  gangrene  are  generally  absent. 
Swelling  however  may  occur,  particularly  in  cold 
weather,  and  occasionally  localized  areas  may  become 
tender  or  painful.  Although  spontaneous  ulceration  is 
extremely  rare,  traumatic  lesions  in  affected  areas 
may  become  infected  and  heal  slowly.  Palmar  clammi- 
ness is  a  well-known  feature  of  acrocyanosis  and 
differs  from  the  dry  skin  of  Raynaud's  disease  which 
appears  when  the  local  circulation  ceases  (94).  In 
true  acrocyanosis,  examination  of  peripheral  arteries 
reveals  no  evidence  of  occlusive  organic  arterial  dis- 
ease. The  dependent  cyanosis  frequently  present  in 
the  feet  of  patients  with  occlusive  arterial  disease 
should  not  be  classified  as  acrocyanosis. 

As  in  early  Raynaud's  disease,  very  little  is  known 
of  the  pathology  of  acrocyanosis.  Stern  (94)  studied 
sections  from  the  dorsal  skin  of  the  hands  and  feet  of 
of  12  patients  with  acrocyanosis.  It  was  found  that 
the  medial  coats  of  nearlv  all  arterioles  were  thick- 
ened. Local  edema  and  dermal  fibrosis  frequently 
were  present  in  association  with  considerable  dilata- 
tion of  the  superficial  capillaries  with  formation  of 
new  capillaries.  Others  have  described  distention  of 
the  venules  and  venous  limb  of  the  capillaries  and 
have  noted  large  capillary  loops  occurring  in  increased 
numbers  in  the  nail  bed  (3,  6,  41).  In  fact,  this  tend- 
ency to  dilatation  of  the  venous  side  of  the  circulation 
with  a  marked  decrease  in  venomotor  tone  is  a  char- 
acteristic feature  of  acrocyanosis. 

Little  work  is  available  on  the  vascular  mechanisms 
responsible  for  acrocyanosis.  Most  evidence  points  to 
excessive  arteriolar  constriction  which  occurs  at 
ordinary  environmental  temperatures  and  which  is 
increased  by  cooling.  The  arteriovenous  anastomoses 
are  also  probably  constricted  (60).  This  constriction 


is  followed  by  secondary  dilatation  of  capillaries  and 
venules  with  stasis  in  the  minute  vessels  of  this  skin. 
There  is  loss  of  capillary  and  venular  tone  (6,  60), 
thought  to  be  due  in  large  part  to  anoxia.  Stasis  allows 
increased  formation  of  reduced  hemoglobin  and  the 
associated  deep  cyanosis,  the  blue  color  being  due  to 
increased  amounts  of  reduced  hemoglobin  and  the 
deep  character  of  the  color  being  due  to  the  engorge- 
ment of  the  vessels.  That  venous  obstruction  is  not  a 
significant  factor  has  been  pointed  out  by  Lewis  & 
Landis  (50)  from  the  simple  observation  that  cyanosis 
is  abolished  by  venous  drainage  produced  by  eleva- 
tion of  the  involved  part.  The  color  of  the  cyanosed 
'.kin  is  not  uniform,  since  it  frequently  contains 
bright  red  areas  (cinnabar  red  spots)  (94)  and  occa- 
sionally changing  reticular  areas  of  pink  color  due 
probably  to  temporary  relatively  normal  rate  of  blood 
through  the  perpendicular-arteriole  reticuiar-capil- 
lary  network  (22).  It  has  been  noted  that  acrocyanosis 
is  less  pronounced  in  the  presence  of  hypertension, 
since  the  latter  tends  to  produce  more  normal  circu- 
lation in  spite  of  the  dermal  arteriolar  spasm  (60). 

In  acrocyanosis,  the  white  spot  produced  by  ex- 
ternal pressure  on  the  cyanosed  part  disappears  spon- 
taneously in  a  very  characteristic  fashion  (94).  The 
color  returns  from  the  periphery  and  not  from  below 
as  in  normal  skin. 

Comments  by  Lewis  concerning  the  mechanism  of 
acrocyanosis  are  worth  quoting  (49) : 

"The  minute  vessels  of  the  skin  are  verv  dilated,  as 
is  evident  equally  Irom  macroscopic  and  microscopic 
examination.  But  the  temperature  of  the  hands  and 
other  tests  show  the  blood-flow  to  the  skin  to  be 
reduced  greatly.  The  veins  though  contracted  l>\  cold 
are  not  occluded.  The  pulses  in  the  main  arteries  are 
normal.  The  constriction  is  in  the  small  arteries  or 
arterioles  of  the  skin.  If  the  hand  at  the  time  is 
cyanosed  and  a  small  part  of  it  is  warmed,  the  latter 
soon  becomes  sharply  defined  as  a  bright  red  area; 
similarly  if  a  little  histamine  (1  in  3000)  is  pricked 
into  the  skin,  the  skin  reddens  locally  and  its  tempera- 
ture rises.  This  is  in  contrast  to  the  cyanosed  skin  in  the 
attack  of  Raynaud's  disease,  where  the  obstruction 
lies  in  the  main  digital  arteries,  and  in  which  redden- 
ing of  the  skin  does  not  occur  in  similar  tests,  but  only 
after  these  arteries  open.  In  acrocyanosis  all  the 
arteries  and  arterioles  are  capable  of  opening  widely; 
gross  structural  impediment  is  not  present  in  any  of 
their  channels." 

Again,  as  in  Raynaud's  disease,  whether  the  basic 
underlying  disorder  lies  in  the  sympathetic  nervous 
system  or  in  the  vessels  themselves  is  unknown.  As 


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CIRCULATION    II 


FIG.  5.  Livedo  reticularis   (lower  portions  of  both 
legs  of  patient  lying  supine). 


Lewis  (49)  noted,  however,  the  arterioles  in  affected 
areas  are  in  an  unusually  high  state  of  tone.  He  was  of 
the  opinion  that  this  is  due  to  a  fault  in  the  vessels 
themselves,  since  anesthetizing  the  appropriate 
nerves  does  not  result  in  prompt  relief  of  the  arteriolar 
spasm,  as  it  would  if  the  mechanism  were  neural  in 
origin.  In  contrast,  observations  by  Day  &  Klingman 
(17)  were  interpreted  as  showing  predominant  sym- 
pathetic nervous  influences  as  the  basic  mechanism. 
They  noted  that  during  sleep  the  cyanosis  and  cold 
skin  are  relieved  and  replaced  by  warm,  red  skin. 

No  definitive  studies  are  available  in  acrocyanosis 
concerning  the  significance  of  tissue  catecholamines 
and  other  vasoactive  substances.  Nevertheless,  com- 
ments made  above  on  Raynaud's  disease  in  this 
regard  might  be  equally  applicable  here. 

Since  the  course  of  acrocyanosis  is  relatively  benign 
and  complications  are  few,  sympathectomy  has  rarely 
been  indicated  in  its  treatment.  Because  of  this,  con- 
trolled studies  on  the  effects  of  sympathectomy  are 
unavailable.  In  severe  cases,  however,  sympathectomy 
may  be  of  value,  especially  when  there  is  an  associated 
hyperhidrosis.  The  usual  protection  from  cold  or 
sudden  and  marked  decline  in  temperature  is  indi- 
cated. The  patient  should  keep  warm  and  dry  with 
serious  attention  being  given  to  his  general  state  of 
health. 

livedo  reticularis.  Livedo  reticularis  is  character- 
ized by  a  prominent  mottled,  reticular,  or  blotchy 
reddish-blue  discoloration  of  the  skin  of  the  extremi- 
ties (fig.  5).  Between  the  reticular  discolorations,  the 
skin  presents  a  more  normal  but  pale  appearance. 

Kaposi  was  probably  the  first  to  use  the  term 
"livedo  reticularis"  (3).  The  etiology  of  this  disease 


is  unknown.  That  it  may  represent  a  congenital 
anomaly  of  blood  vessels  has  been  suggested  by 
some  (85,  103).  Some  are  of  the  opinion  that  there 
is  some  inherent  vascular  instability  in  the  back- 
ground of  most  patients  (3).  In  one  series,  30  per 
cent  of  the  patients  had  associated  hypertension  and 
50  per  cent  demonstrated  marked  nervous  instability 
(3,  5).  Livedo  reticularis  is  more  frequent  in  females 
and  usually  appears  before  the  age  of  40. 

The  disorder  usually  involves  the  skin  of  the  legs 
and  feet  in  greatest  severity,  but  it  frequently  also 
involves  the  arms  and  hands.  Occasionally,  the  thighs 
and  the  lower  part  of  the  trunk  may  be  affected. 
There  is  a  distinct  tendency  for  the  disease  to  occur 
bilaterally  and  symmetrically. 

The  characteristic  color  changes  are  usually  in- 
tensified on  exposure  to  cold  and  tend  to  be  alleviated 
on  exposure  to  a  warm  environment.  Patients  may 
complain  of  numbness,  tingling,  coldness,  or  aching 
over  the  involved  legs  and  feet.  Ulcerations  in  livedo 
reticularis  are  not  frequent  but  they  do  occur.  Ulcers 
usually  begin  as  an  intensification  of  change  in 
areas  of  marked  cyanosis,  usually  over  the  medial 
lower  one-third  of  the  leg.  These  lesions  may  be  very 
painful  and  slow  to  heal.  Ulcers  in  some  patients 
seem  to  be  precipitated  by  cold  weather,  whereas  in 
others  warm  weather  seems  to  be  important  in  their 
formation  (23). 

The  pathophysiology  and  clinical  findings  in 
livedo  reticularis  have  been  the  subject  of  several 
reports  (20,  48,  85,  103);  the  most  recent  one  of  sig- 
nificance is  by  Feldaker  el  al.  (23).  The  latter  authors, 
following  the  suggestion  of  Williams  &  Goodman 
(103),  preferred  to  classify  livedo  reticularis  into 
three    groups:    /)    cutis    marmorata,    2)    idiopathic 


PERIPHERAL    VASCULAR    DISEASES 


I233 


livedo  reticularis  (primary  livedo  reticularis),  and 
3)  symptomatic  livedo  reticularis  (secondary  livedo 
reticularis). 

Cutis  marmorata  refers  to  a  state  characterized 
by  transient  reticular  discoloration  producing  a 
marble  (hence  the  term  "marmorata")  pattern  to 
the  skin  which  appears  on  exposure  to  cold  but,  un- 
like the  other  types  of  livedo,  it  is  not  permanent  and 
disappears  with  warmth.  It  is  considered  that  in  this 
state  there  is  no  organic  pathologic  alteration  in  the 
peripheral  circulation  but  rather  that  the  disturb- 
ance is  a  vasomotor  phenomenon.  It  has  been  noted 
to  be  frequent  in  infants  and  young  girls  and  may 
disappear   as    they   grow    older. 

In  idiopathic  livedo  reticularis  (primary  livedo 
reticularis)  the  reticular  discoloration  is  relatively 
permanent  and  persists  to  some  degree  regardless 
of  temperature  changes.  As  noted  before,  however, 
the  degree  of  discoloration  is  accentuated  by  exposure 
to  cold.  There  may  be  minimal  to  no  organic  changes 
in  the  vessels  except  increased  number  and  dilatation 
of  capillaries  in  the  livid  areas.  Feldaker  et  al.  (23) 
also  noted  in  these  areas  varying  degrees  of  endar- 
teritis and  endophlebitis  of  the  smaller  vessels.  At 
times  there  is  occlusion,  periarteritis  and  periphlebitis 
and  occasionally,  thickening  of  the  walls  of  arterioles 
in  the  dermis  and  subcutaneous  tissue. 

Symptomatic  livedo  reticularis  (secondary  livedo 
reticularis)  is  the  form  of  the  disorder  associated 
with  or  secondary  to  other  dermal,  vascular,  or 
systemic  diseases.  These  have  been  outlined  in  the 
accompanying  classification  of  peripheral  vascular 
diseases  (see  Appendix  to  this  chapter). 

The  large  arteries  such  as  the  dorsalis  pedis,  pos- 
terior tibial,  and  popliteal  are  not  involved  by  occlu- 
sive disease  and  likewise  venous  insufficiency  is  not  a 
factor  in  livedo  reticularis.  Digital  blood  flow  after 
interruption  of  sympathetic  nerve  supply  is  usually 
normal  (60).  Feldaker  el  al.  (23)  have  recently 
summarized  the  probable  pathophysiology  of  this 
disease.  The  perpendicular  arterioles,  supplying  the 
skin  from  below,  and  the  central  zone  capillary 
arborizations  have  a  slightly  greater  tone  and  faster 
linear  rate  of  blood  flow  than  the  peripheral  capil- 
laries. Either  because  of  organic  change  (as  described 
earlier)  or  vasospasm  of  arteries  and  arterioles  of  the 
skin  or  both,  capillary  atony  and  slowing  of  blood  in 
peripheral  capillaries  are  further  increased,  resulting 
in  a  livedo  reticularis  pattern  in  annular  rings  about 
central  paler  areas.  Cold  causes  an  increased  vaso- 
constriction of  the  arteries  and  arterioles,  resulting 
in  an  intensification  of  the  livedo.  When  the  periph- 


eral capillaries  are  only  temporarily  atonic  and  di- 
lated, and  the  arteriolar  supply  is  only  temporarily 
reduced,  the  transient  cutis  marmorata  results; 
but  if  the  changes  are  more  or  less  permanent,  then 
true  livedo  reticularis  is  produced.  On  elevation  of 
the  affected  parts,  the  livedo  decreases  if  the  venules 
draining  the  areas  are  patent  and  can  drain  the 
stagnant  blood  from  the  capillaries.  Warmth  and 
sympathectomy  reduce  the  spasm  of  the  arteries 
and  arterioles  and  thus  reduce  the  degree  of  dis- 
coloration. 

These  observations  and  interpretations  are  at- 
tractive. As  in  Raynaud's  disease  and  acrocyanosis, 
however,  the  basic  factors  underlying  the  vascular 
disturbances  and  manifestations  are  unknown. 
Whether  or  not  the  defect  is  primarily  one  of  local 
vessel  fault  or  one  of  sympathetic  nerve  disturbance, 
and  whether  or  not  localization  of  the  disorder  to 
these  sites  is  determined  by  congenital  or  acquired 
mechanisms,  are  not  known.  Relief  of  livedo  reticu- 
laris and  return  to  normal  color  has  been  reported 
following  sympathectomy  and  also  following  the 
administration  of  acetyl-beta-methylcholine  (22). 
The  problems  surrounding  supposition  of  a  sympa- 
thetic nerve  disease  as  the  basic  disturbance  are 
essentially  as  discussed  for  Raynaud's  disease  and 
acrocyanosis. 

CAUSALGIA    AND    RELATED    SYNDROMES.    This    is    one    of 

the  most  confused  areas  of  all  in  peripheral  vascular 
disease  today.  Definitions  are  poor;  criteria  for  classi- 
fication and  diagnosis,  variable;  and  terminology, 
diffuse.  The  unifying  characteristic  of  this  group  is 
the  development  of  a  bizarre  symptom  complex 
following  some  type  of  injury  to  an  extremity.  This 
posttraumatic  syndrome  consists  in  general  of  pain, 
paresthesia,  trophic  changes,  edema,  and  evidence 
of  autonomic  nervous  system  dysfunction.  In  this 
group  of  diseases  are  included  major  causalgia, 
minor  causalgia,  traumatic  vasospasm,  acute  atrophy 
of  bone,  Sudeck's  atrophy,  reflex  nervous  dystrophy, 
traumatic  angiospasm,  posttraumatic  painful  osteo- 
porosis, neurovasospastic  phenomenon,  chronic  post- 
traumatic edema,  posttraumatic  reflex  dystrophy, 
sympathetic  dystrophy,  neurovascular  reflex  dys- 
trophy, atypical  causalgia,  posttraumatic  spreading 
neuralgia,  reflex  nervous  atrophy,  irritative  nerve 
lesions,  sympathalgia,  posttraumatic  pain  syndrome, 
peripheral  acute  trophoneurosis,  postamputation 
syndrome,  and  traumatic  neuralgia.  All  these  terms 
have  been  employed  in  reports  in  the  literature,  and 
undoubtedly  others  have  been  used.  Each  term  has 


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served  to  focus  not  only  on  the  outstanding  manifes- 
tations in  each  particular  patient  studied  but  also  on 
the  particular  interests,  specializations,  and  orien- 
tations of  the  various  investigators.  This  type  of 
terminology  usually  implies  gross  confusion,  and 
such  is  the  case.  Although  these  syndromes  have 
elements  of  both  vasodilator  and  vasoconstrictor 
mechanisms,  they  are  classified  under  the  latter, 
since  these  manifestations  are  the  most  classic  ol  the 
disorders. 

To  discuss  the  manifestations  of  each  of  the  dis- 
orders listed  above  would  be  beyond  the  scope  of  this 
presentation.  Adequate  descriptions  and  reference 
sources  may  be  found  in  other  publications  (i,  3, 
19.  34.  44,  49,  53,  58,  82,  87,  89,  90,  104). 

There  is  great  overlap  of  the  manifestations  in  the 
syndromes  listed.  In  general  they  may  follow  any 
type  of  injury  to  an  extremity  whether  minor  or 
severe.  Some  investigators  feel  that  there  is  a  con- 
stitutional predisposition  to  the  development  of 
these  syndromes  in  certain  individuals.  Whether  or 
not  psychogenic  factors  and  a  previous  history  of 
vasomotor  instability  are  important  has  been  de- 
bated. 

The  provoking  injury  usually,  but  not  invariably, 
involves  nerves  (especially  the  median  or  sciatic) 
or  tissues  around  joints  (particularly  the  wrist  or 
ankle).  Pain  and  vasomotor  disturbances  may  occur 
almost  immediately  after  the  injury,  or  be  delayed 
and  develop  gradually  over  the  next  several  weeks. 
Pain  from  the  original  injury  with  its  associated 
accentuation  on  movement,  with  resulting  disuse, 
may   be  important  factors  in  the   pathogenesis. 

The  outstanding  characteristic  of  the  causalgia 
syndrome  is  burning  superficial  pain.  Pain  is  usually- 
referred  distal  to  the  site  of  original  injury  and 
frequently  involves  the  digits  and  the  volar  surfaces 
of  the  hands  and  feet.  Hyperesthesia  is  a  common 
associated  complaint  which  may  be  localized  to  a 
sensory  nerve,  but  is  frequently  incomplete  and 
neither  segmental  nor  somatic  in  distribution.  Be- 
cause of  this,  these  patients  are  frequently  considered 
to  be  malingerers  or  "neurotic."  Patients  at  times 
go  to  extremes  to  protect  their  hyperesthetic  extrem- 
ities, avoiding  many  direct  as  well  as  indirect  stimuli, 
even  loud  noises.  Frequently  they  obtain  relief 
from  the  application  of  moist  cloths.  Obviously, 
since  the  disease  is  posttraumatic  the  symptoms  are 
usually  unilateral.  In  later  stages,  however,  vaso- 
motor disturbances  may  spread  to  the  opposite 
extremity. 

The  vasomotor  changes  are  of  particular  interest. 


Initially,  the  affected  extremity  is  usually  somewhat 
edematous,  erythematous,  dry,  and  warmer  than  its 
unaffected  counterpart.  The  blood  vessels  are  dilated, 
the  rate  of  blood  flow  is  increased,  and  local  tempera- 
ture and  oscillometrically  recorded  pulsations  are 
increased.  Later,  the  vasodilatation  subsides  and 
vasospastic  phenomena  usually  become  prominent 
and  remain  so  during  the  chronic  stage  of  the  disease. 
In  this  chronic  stage,  the  skin  is  usually  cold,  hyper- 
hidrotic,  cyanotic,  and  atrophic.  The  limb  may  then 
be  especially  sensitive  to  cold  and  secondary  Ray- 
naud's phenomenon  may  be  observed. 

Early  X-ray  study  reveals  a  spotted,  often  cyst- 
like,  decalcification  of  the  bones  in  the  involved 
part.  This  is  especially  true  for  the  ankle  and  wrist 
and  the  bones  of  the  hands  and  feet  (Sudeck's  at- 
rophy). It  is  considered  that  these  changes  in  bone 
occur  much  too  early  to  be  explained  simply  as 
atrophy  from  disuse.  Later  in  the  disease,  however, 
osteoporosis  may  become  diffuse  and  difficult  to 
differentiate  from  osteoporosis  of  disuse.  There  is 
emphasis  by  the  patient  on  immobilization  and 
disuse  of  the  part  because  of  pain  and,  therefore, 
disuse  may  be  a  contributing  factor. 

The  tendency  among  most  investigators  has  been 
to  divide  the  syndrome  into  at  least  two  subgroups: 
namely,  major  causalgia  and  minor  causalgia.  In  major 
causalgia  there  is  usually  a  history  of  a  penetrating 
wound  in  the  region  of  a  major  nerve  trunk  of  the 
limb  and  the  subsequent  characteristic  symptom  is 
that  of  severe  burning  superficial  pain.  In  minor 
causalgia  the  provoking  trauma  is  frequently  minor 
in  type  and  major  peripheral  nerve  trunks  are  not 
involved.  Although  there  are  evidences  of  vasomotor 
dysfunction  and  trophic  changes  in  both  the  major 
and  minor  varieties,  spotty  osteoporosis  and  edema 
have  been  much  more  frequently  seen  and  severe 
burning  superficial  pain  less  frequently  seen  in  the 
latter. 

Successful  treatment  with  marked  or  complete 
relief  of  symptoms  has  been  reported  to  follow  intra- 
arterial or  orally  administered  sympatholytic  drugs, 
paravertebral  sympathetic  nerve  blocks,  and  sym- 
pathectomy (82).  In  fact,  success  with  these  measures 
may  be  strong  ancillary  factors  in  substantiating 
the  diagnosis. 

The  pathogenesis  of  the  causalgia  syndromes  is 
unknown  and  it  would  be  profitless  to  discuss  the 
many  proposed  theories.  These  are  available  in  other 
publications  (1,3,19, 34.49. 53.  58,  82>  87,  89, 90,  104). 
They  are  interesting  and  thought-provoking  but 
largely  unfounded.  The  whole  field  is  complex  and 


PERIPHERAL    VASCULAR    DISEASES 


235 


confusing,  but  it  might  he  helpful  to  indicate  inter- 
esting factors  which  have  pathogenic  relationships 
to  the  disease. 

Though  sometimes  very  minor,  tissue  trauma  is  a 
regularly  associated  factor.  Fractured  bones  with 
injury  to  adjacent  nerves,  surgery,  tight  bandages 
and  dressings,  automobile  accidents,  falls  and  the 
like  seem  to  produce  the  syndrome. 

Afferent  neural  conducted  impulses  (possibly  ab- 
normally integrated,  distributed  or  modulated)  must 
certainly  be  factors.  Pain  is  perceived  by  the  patient 
and  is  frequently  the  outstanding  symptom.  That 
this  is  mediated  through  regular  sensory-type  nerves 
is  probable,  but  debatable. 

Efferent  neural  conducted  impulses  apparently 
play  a  part.  Most  probably  a  large  proportion  is 
mediated  through  the  sympathetic  nervous  system. 
As  in  the  afferently  conducted  impulses,  these  may 
be  integrated,  distributed,  or  modulated  abnormally. 
Vasomotor  disturbances  are  paramount  and  relief 
with  sympathetic  block  or  sympathectomy  is  frequent. 

Afferent  neural  conduction  and  efferent  neural 
conduction  imply,  but  do  not  prove,  since  they  may 
be  dissociated  phenomena,  that  some  reflex  arc  is 
involved  in  the  disturbance.  The  level  in  the  nervous 
system  at  which  this  occurs  and  how  it  functions  is 
not  clear.  It  could  be  an  axon  reflex,  a  short-circuiting 
in  a  peripheral  nerve  trunk,  or  an  arc  in  the  spinal 
cord  at  segmental  or  higher  levels  or  even  in  the 
vasomotor  centers  or  higher.  Furthermore,  the  in- 
tegration, distribution,  and  control,  as  well  as  the 
modulation  of  the  frequency,  intensity,  and  time 
course  of  the  action  potential  of  the  impulses  may  be 
abnormal  in  causalgia.  This  phase  of  the  patho- 
physiology has  been  neglected  and  needs  investigation. 

Blood  vessel  reactions  are  apparent  from  the  pre- 
ceding discussions  but  exactly  how  they  are  induced 
is  unknown. 

The  keynote  of  the  causalgia  syndromes  is  that  the 
magnitude  of  the  resulting  physiologic  and  anatomic 
manifestations  are  out  of  proportion  to  the  magni- 
tude of  the  provoking  injury.  This  implies  altered 
responsiveness  on  the  part  of  the  body  to  trauma. 

To  integrate  all  the  observed  or  apparent  mani- 
festations of  the  causalgia  syndromes  into  one  unified 
theory  is  difficult  at  the  present  time.  Lewis  (49)  had 
interesting  ideas  concerning  the  mechanisms  of  pain 
and  vasodilatation  in  the  syndrome.  He  referred  to 
evidence  from  Tinel  showing  that  section  of  the  nerve 
distal  to  the  responsible  lesion  may  relieve  the 
causalgic  pain  when  section  proximal  to  the  lesion 
had  alreadv  failed  to  do  so.   He  further  noted  that 


when  a  normal  cutaneous  nerve  or  the  posterior 
nerve  root  is  cut  and  its  distal  end  excited  electrically, 
that  the  corresponding  area  of  skin  reddens  and 
becomes  hotter  than  previously  ("antidromic  effect") 
and  a  burning  itching  pain  is  produced.  Lewis  be- 
lieved that  this  resulting  vasodilatation  in  the  skin 
is  produced  by  a  local  release  of  a  histamine-like 
substance.  He  thought  that  the  substance  released 
affects  overlapping  nerve  endings  in  the  area.  Thus, 
analogous  pain  impulses  in  causalgia  might  be  con- 
veyed back  along  these  intact  paths  as  well  as  along 
the  injured  nerve.  Lewis  thus  concluded  that  the 
erythema  and  heat  stage  of  causalgia  was  an  anti- 
dromic effect  produced  by  distal  stimulation  of  the 
injured  nerve  and  that  this  was  in  accordance  with 
the  observations  of  Tinel.  Lewis'  theory  does  not 
explain  all  the  findings,  however,  such  as  the  vaso- 
constrictor phenomena  and  the  relief  with  inter- 
ruption of  the  sympathetic  nerve  supply. 

One  theory  which  has  recently  been  attractive  to 
many  investigators  serves  in  part  to  explain  the  pain 
and  its  relief  with  sympathectomy  (19).  In  general, 
it  might  be  conceived  as  follows:  In  a  zone  of  nerve 
injury,  the  insulating  factors  that  normally  keep 
one  nerve  fiber  from  interfering  with  its  neighbor  are 
defective.  Thus,  efferent  impulses  might  cross- 
stimulate  afferent  fibers  resulting  in  sensory  dis- 
turbances and  pain.  Regarding  the  efferent  im- 
pulses, the  autonomic  fibers  logically  would  be  the 
most  offensive  in  the  damaged  nerve  since  these  have 
continuous  vasotonic  activity.  Therefore,  during 
periods  of  increased  vasomotor  activity  there  would 
be  more  cross  stimulation  in  the  injured  nerve  and 
thus  more  pain.  Increased  pain  might  thereby  result 
in  increased  sympathetic  nervous  activity  and  thus 
propagate  a  vicious  cycle. 

The  preceding  theory  may  adequately  explain 
changes  occurring  unilaterally  in  the  injured  limb, 
but  would  be  inadequate  to  explain  the  extension  of 
vasomotor  dysfunction  into  the  contralateral  mem- 
ber. Thus,  some  higher  source  of  nervous  dysfunction 
might  well  be  involved.  Further,  it  is  accepted  by 
some  that  chronic  neural  irritation,  especially  if 
excessive,  is  capable  in  some  way  of  changing  the 
normal  behavior  of  the  neurons  within  the  central 
nervous  system  and  of  eventually  modifying  the 
pattern  of  excitation  registered  in  the  conscious 
levels  (87).  This  may  be  an  expression  of  disturbance 
in  integration,  distribution,  and  modulation  of  the 
action  potentials  of  the  nerve  impulses  within  the 
central  nervous  system.  There  are  occasional  patients 
with  causalgia   unrelieved   by   peripheral  nerve  sec- 


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CIRCULATION    II 


tion,  section  of  the  posterior  roots  or  sympathectomy. 
It  has  been  assumed  that  these  patients  represent 
examples  of  "thalamic  dysfunction." 

Other  theories  involving  higher  centers  are  of 
interest,  but  will  not  be  expanded.  For  example,  it 
has  been  suggested  that  an  irritative  focus  in  the 
extremity  produces  afferent  impulses  over  sensory- 
nerves  to  the  spinal  cord  which  results  in  continual 
impulse  discharges  and  nervous  disturbance  in  this 
zone.  This  results  in  stimulation  of  the  elements  of 
the  lateral  and  anterior  horns,  which  then  produce 
the  characteristic  peripheral  signs  (53).  A  theory- 
proposed  by  Leriche  (44)  involved  reflex  overactivity 
of  the  central  vasomotor  center. 

Some  theories  of  note  have  suggested  involvement 
of  afferent  sympathetic  nerve  fibers.  Of  interest  in 
this  regard  are  studies  by  Kuntz  (42)  demonstrating 
afferent  spinal  nerve  fibers  which  traverse  the  sym- 
pathetic trunk  and  communicating  rami.  Stimulation 
of  appropriate  nerves  results  in  conduction  of  pain 
impulses  by  these  afferent  fibers  which  appear  to  be 
distributed  chiefly  in  relation  to  blood  vessels  rather 
than  to  the  skin  and  muscles  of  the  extremity.  Whether 
or  not  these  phenomena  function  in  the  causalgia 
svndromes  is  unknown,  but  relief  of  pain  by  sym- 
pathectomy   might    be    explained    by    such    mecha- 


miscellaneous  states.  Spasm  of  major  arteries.  Spasm 
of  a  large  artery  is  initiated  by  some  type  of  trauma 
in  or  near  the  artery.  The  initiating  trauma  is  usually 
a  severe  penetrating  injury  such  as  a  gunshot  wound, 
but  it  may  be  provoked  by  contusing  or  crushing 
injuries  even  though  the  artery  itself  is  not  directly- 
involved  in  the  injury.  The  spasm  may  be  sufficient 
to  occlude  the  lumen  completely.  The  spasm  may  be 
limited  to  a  small  isolated  discrete  segment  of  the 
artery  or  it  may  involve  a  long  segmental  length 
including  the  orifices  of  many  collateral  arteries  (3). 
The  exact  mechanism  of  this  type  of  spasm  is  not 
clear  but  the  ''myogenic"  factor  or  the  inherent 
property  of  smooth  muscle  to  contract  when  directly 
traumatized  appears  to  be  paramount.  It  has  been 
shown  experimentally  that  local  segmental  spasm 
in  large  arteries  can  be  produced  by  mechanical 
trauma  irrespective  of  the  presence  of  the  adventitia 
or  nerve  supply  (38).  These  facts  are  in  accordance 
with  observations  that  this  type  of  spasm  usually 
cannot  be  released  with  periarterial  injections  of 
local  anesthetics,  sympathetic  nerve  interruption, 
periarterial  nerve  stripping,  or  even  by  amputation 
of  the  involved  extremity  above  the  site  of  the  arterial 


spasm  (3,  13,  26).  It  has  been  shown,  however,  both 
experimentally  and  clinically,  that  direct  applica- 
tion of  a  2.5  per  cent  solution  of  papaverine  to  an 
artery  will  relieve  traumatic  spasm  in  the  majority 
of  instances  (39).  The  mechanism  of  this  response  is 
unknown. 

Vasoconstrictor  mechanisms  in  acute  arterial  occlusion. 
The  changes  which  occur  after  acute  circulatory 
arrest  have  been  presented  in  a  preceding  section.  It 
is  not  the  purpose  of  this  discussion  to  present  the 
clinical  signs  and  symptoms  nor  the  pathogenesis  of 
events  leading  to  acute  circulatory  arrest,  which 
include  occlusive  arterial  disease,  thrombosis,  and 
embolism.  Arteriosclerosis,  intravascular  clotting, 
and  embolism  are  discussed  in  other  chapters  of  this 
Handbook.  The  purpose  of  the  present  discussion  is  to 
indicate,  briefly,  concepts  concerning  possible  vaso- 
constrictor mechanisms  which  operate  in  acute 
arterial  occlusion. 

The  obvious  factor  in  acute  arterial  occlusion  is 
acute  impairment  of  blood  flow  through  the  arterial 
lumen.  Studies  suggest,  however,  that  this  is  not 
necessarily  the  major  cause  of  the  resulting  profound 
ischemia  associated  with  acute  arterial  occlusion, 
since  only  mild  to  moderate  degrees  of  ischemia  may- 
be produced  when  a  comparable  peripheral  artery  is 
ligated.  The  implication  then  is  that  a  superimposed 
functional  disturbance  must  be  operative  in  patho- 
logic occlusion. 

It  has  been  considered  that  reflex  vasospasm  of  the 
distal  portion  of  the  artery  and  the  collateral  arteries 
is  mediated  in  the  efferent  arc  through  the  sym- 
pathetic nervous  system  (3,  87).  This  has  been  the 
basis  for  recommendation  of  prompt  sympathetic 
interruption  in  patients  with  acute  arterial  occlusion 
(87).  Experimental  work  has  shown,  however,  that 
the  superimposed  diminution  in  blood  supply  af- 
fected by  spasm  and  inadequate  dilatation  of  col- 
lateral arteries  is  temporary  and  spontaneously 
disappears  in  a  few  hours  (31,  64).  Several  investi- 
gators (3)  have  postulated  that  the  spasm  in  col- 
lateral arteries,  if  prolonged,  produces  degenerative 
changes  in  the  intima  of  distal  arteries  and  veins 
which  in  turn  provokes  widespread  vascular  thrombo- 
sis with  the  resultant  organic  obstruction  to  flow  even 
after  the  spasm  disappears.  This  would  account  for 
progression  to  complete  irreversible  circulatory  arrest 
in  some  patients.  However,  when  spasm  has  not 
been  severe  or  prolonged,  a  satisfactory  collateral 
circulation  may  be  established  permitting  the  limb 
to  survive  (3). 

Some    experimental    studies    on    the    mesenteric 


PERIPHERAL    VASCULAR    DISEASES 


I237 


vascular  responses  in  young  dogs  are  of  interest  (56). 
After  acute  arterial  occlusion  the  artery  developed 
severe  spasm  whereas  the  vein  exhibited  a  mild 
degree  of  spasm.  On  release  of  the  occlusion  there 
was  a  period  of  residual  spasm  in  artery  and  vein. 
Sympathectomy  abolished  both  the  arterial  and 
venous  spasm  during  occlusion  as  well  as  after  re- 
lease. Papaverine  administered  during  the  arterial 
occlusion  had  no  effect  on  the  arterial  spasm,  but 
after  release  of  the  occlusion  the  residual  spasm  was 
abolished. 

Recent  studies,  however,  have  cast  considerable 
doubt  on  the  significance  of  diffusely  distributed 
vasospastic  phenomena  in  response  to  acute  arterial 
occlusion  in  man.  Compensatory  mechanisms  in 
response  to  sudden  arterial  occlusion  have  been  the 
subject  of  a  recent  report  on  clinical,  pathologic, 
and  experimental  observations  by  Wessler  et  al.  (102). 
They  noted  that  three  major  important  compensa- 
tory phenomena  follow  sudden  arterial  occlusion, 
namely,  clot  fragmentation,  clot  lysis,  and  function 
of  preformed  inter-arterial  collateral  anastomoses. 
The  authors  considered  that  clot  fragmentation  and 
clot  lysis,  although  not  disproving  the  role  of  "spasm," 
provide  an  alternative  to  the  concept  of  release  of 
spasm  as  an  explanation  for  the  occasionally  witnessed 
sudden  relief  of  arterial  insufficiency  in  some  pa- 
tients. The  gradual  enlargement  of  anastomotic 
channels,  bypassing  complete  obstructions,  accounts 
for  the  delayed  and  gradual  improvement  (even 
with  return  of  distal  pulsatile  flow)  observed  in  some 
patients  weeks  to  months  after  the  initial  occlusion. 
The  authors  further  stated  that  unlike  embolectomy, 
blockage  of  autonomic  nervous  supply  for  the  relief 
of  ischemia,  secondary  to  arterial  occlusion,  has 
neither  a  sound  physiologic  rationale  nor  satisfactory 
clinical  documentation  of  its  efficacy  (102).  Based 
on  their  own  (102)  and  other  studies  (76)  they  found 
little  evidence  that  vessels  in  the  ischemic  zone  are 
in  spasm  in  organic  arterial  insufficiency. 

More  recent  observations  by  Hardy  &  Tibbs  (33) 
have  further  minimized  the  role  of  diffuse  ''spasm"  in 
acute  arterial  thrombosis.  These  authors  emphasized 
that  a  healthy  artery  is  normally  in  a  state  of  con- 
siderable elastic  distention  and  that  when  occluded 
the  vessels  distal  to  the  occlusion  become  narrow  from 
"elastic  recoil."  Apparently  this  recoil  has  been  the 
basis  for  the  erroneous  diagnosis  of  diffuse  arterial 
"spasm."  Patients  are  described  (33)  in  whom  the 
distal  arteries  remained  contracted  and  pulseless  after 
embolectomy,  and  in  whom  a  residual  "consecutive" 
clot  was  found.  When  this  residual  clot  was  removed 


completely    by    retrograde    irrigation,    the    "spasm" 
disappeared  and  pulsation  returned. 

Regardless  of  the  above  and  other  arguments,  it 
is  impossible  to  state  dogmatically  whether  or  not 
arterial  "spasm"  is  significant  in  the  pathophysiology 
of  the  circulation  in  acute  arterial  occlusion.  The 
suggestion  that  a  powerful  vasoconstrictor  substance 
(possibly  serotonin)  is  released  from  a  fresh  thrombus 
and  that  it  causes  spasm  of  the  affected  vessel  and 
adjacent  collaterals  (25,  83,  101)  needs  further 
study. 

Vasoconstrictor  mechanisms  in  chronic  arterial  occlusion. 
This  topic  has  caused  considerable  discussion,  espe- 
cially among  surgeons  who  advocate  sympathectomy 
in  the  treatment  of  chronic  arterial  occlusive  disease. 
One  major  basis  for  this  suggestion  has  been  the 
thesis  that  even  if  superimposed  arterial  spasm  is  not 
of  pathogenic  importance,  sympathectomy  is  of 
benefit  because  it  reduces  normal  arterial  "tone" 
causing  arterial  dilatation  and  fostering  collateral 
circulation.  Particularly  with  respect  to  muscle 
circulation,  neither  experimental  nor  clinical  evidence 
in  man  justifies  pursuing  this  topic  further. 

Vasoconstrictor  mechanisms  in  collagen  diseases  and 
diseases  of  the  fine  blood  vessels.  These  diseases  and  dis- 
eases of  "immune"  mechanisms  arc  on  the  forefront 
of  medicine  today.  Much  progress  has  been  made  in 
understanding  these  conditions.  In  general,  the 
"collagen  diseases"  include  lupus  erythematosus, 
scleroderma,  dermatomyositis,  periarteritis  nodosa, 
rheumatic  fever,  and  rheumatoid  arthritis.  Also  in- 
cluded among  these  diseases  are  thrombotic  thrombo- 
cytopenic purpura,  multiple  forms  of  "vasculitis" 
(see  Appendix)  and  several  other  disease  states.  The 
present  day  concept  of  the  collagen  diseases  is  that 
they  represent  diseases  which  primarily  involve  con- 
nective tissue  structures.  Since  connective  tissue  is 
ubiquitous  the  manifestations  of  these  diseases  are 
protean.  Regardless  of  terminology,  there  is  no 
reason  to  assume  that  the  collagen  fiber  is  the  only 
structure  involved  in  these  processes,  but  rather  that 
the  disease  is  generalized  including  all  connective 
tissue  constituents  such  as  reticulum  fibers,  elastic 
fibers,  ground  substance,  and  all  related  cells  such 
as  fibroblasts,  histiocytes,  lymphoid  elements,  plasma 
cells,  and  mast  cells. 

Even  to  attempt  to  discuss  briefly  the  generalities 
of  this  group  of  diseases  would  be  beyond  the  scope 
of  this  presentation.  Numerous  sources  are  available 
in  the  literature.  A  brief  review  with  particular 
emphasis  on  cardiovascular  manifestations  has  been 
published   (97).  The  blood  vessels  certainly  are  the 


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CIRCULATION    II 


major  shock  organs  of  these 
diseases.  It  is  likely  that  the 
vasculitis  is  responsible  for  a 
great  portion  o  f  the  mani- 
festations  of  the  various  dis- 
ease entities.  Any  type  of 
vessel  may  be  involved,  but 
the  fine  blood  vessels  are 
usually  major  participants. 
Pathological  changes  in- 
clude subendothelial  fibrin- 
oid degeneration,  fibro- 
blastic proliferation,  intimal 
thickening,  varied  inflam- 
matory responses,  and 
thromboses. 

From  the  pathophysio- 
logic standpoint  the  vascular 
manifestations  probably  re- 
sult in  greatest  part  from 
organic  structural  change 
and  occlusion.  That  a  func- 
tional vasospastic  compo- 
nent may  be  superimposed, 

however,  has  been  proposed.  It  has  been  stated  that 
angiitis  of  the  fine  acral  vessels  is  particularly  apt 
to  give  rise  to  vasoconstriction  both  reflexly  and 
by  direct  stimulation  of  the  vessel  network  (21). 
The  organic  changes  plus  the  "spastic"  factors  lead 
to  agglutination  of  the  cellular  elements  of  blood  in 
the  fine  vessels  in  the  distal  reaches  of  the  circulation, 
which  is  an  effective  precursor  of  tissue  necrosis.  It 
is  impossible  to  quantitate  the  degree  to  which  func- 
tional vasospasm  contributes  to  the  pathogenesis  of 
these  diseases.  Vasospasm  probably  exists  to  some 
degree  as  suggested  (but  not  proved)  from  the  fre- 
quent association  of  secondary  Raynaud's  phenom- 
enon (as  high  as  25%  in  some  series). 

Scleroderma  {progressive  systemic  sclerosis).  The  terms 
sclerodactylia,  acrosclerosis,  and  scleroderma  (pro- 
gressive systemic  sclerosis)  have  been  introduced  in 
the  section  on  Raynaud's  phenomenon;  the  collagen 
diseases  in  general  have  been  discussed  above.  Be- 
cause of  its  importance,  scleroderma  or  progressive 
systemic  sclerosis  is  discussed  further. 

Scleroderma  is  a  systemic  disorder  which  involves 
connective  tissue  of  skin,  muscles,  tendons,  fascia,  and 
all  internal  organs.  Its  outstanding  manifestation  is 
a  generalized  increase  in  collagen  fibers  (97). 

As  with  other  collagen  diseases,  the  etiology  of 
scleroderma  is  unknown.  It  affects  both  the  white 
and  Negro  races  (74),  is  more  common  in  females, 


fig.  6.   Severe  scleroderma. 

and  usually  occurs  during  early  adult  life  and  middle 
age. 

Many  organs  of  the  bodv  may  be  involved.  Thicken- 
ing of  the  skin  with  tightening,  increased  rigidity, 
and  reduced  distensibility,  involving  the  face,  ex- 
tremities, and  trunk  produce  a  characteristic  ap- 
pearance (fig.  6).  In  the  early  stages  of  the  disease 
the  skin  may  be  edematous,  but  later  it  characteris- 
tically becomes  firm  and  nondistensible,  with  areas 
of  hyperpigmentation  and  hypopigmentation,  and 
the  joints  become  stiff  and  contracted.  Calcification 
of  tissues,  absorption  of  the  terminal  phalanges, 
atrophy  of  the  fingertips,  deformed  nails,  and  cutane- 
ous ulcers  may  occur.  The  face  may  offer  a  striking 
appearance  being  tight,  expressionless,  and  masklike 
without  wrinkles.  The  features  are  pinched,  the  nose 
is  pointed,  and  there  is  difficulty  in  smiling  and  open- 
ing the  mouth.  Acral  vasomotor  disturbances  such 
as  color  changes,  coldness,  hyperhidrosis,  and  Ray- 
naud's phenomenon  are  not  infrequent. 

Histologic  sections  through  affected  skin  show  that 
the  Malpighian  layer  is  atrophic.  The  deep  layers  of 
the  skin  show  increased  fibrosis  which  extends  into 
the  subcutaneous  tissues.  It  may  extend  into  muscles 
of  the  limbs  and  may  bind  the  skin  of  the  fingers  to 
bone.  Blood  vessels  are  entrapped  in  the  dense  fibrotic 
change.  The  feet  may  be  involved  but  the  hands 
show  by  far  the  most  extensive  change. 


PERIPHERAL    VASCULAR    DISEASES 


12  39 


Involvement  of  the  gastrointestinal  tract  is  common, 
especially  the  esophagus,  frequently  the  small  bowel 
and  occasionally  the  colon.  This  may  produce 
obvious  functional  changes  in  these  organs.  Joint 
involvement  may  mimic  rheumatoid  arthritis  and 
skeletal  muscle  involvement  with  atrophy  and  fibrosis 
may  resemble  dermatomyositis.  Pulmonary  involve- 
ment is  very  common  with  peribronchial  and  inter- 
stitial fibrosis  and  destruction  of  alveolar  walls. 

The  vascular  manifestations  of  the  disease  may  be 
widespread.  There  is  thickening  of  vessel  walls,  peri- 
vascular fibrosis,  intimal  proliferation,  obliterative 
vasculitis,  thrombosis,  fibrinoid  necrosis,  and  cellular 
infiltrations  with  polymorphonuclear  and  round 
cells. 

Usually  smaller  vessels  are  predominantly  affected, 
but  lesions  may  be  encountered  in  any  vessel  of  the 
body.  The  coronary,  pulmonary,  dermal,  and  renal 
vascular  beds  are  notable  participants  in  this  vascular 
disease.  Primary  changes  in  the  myocardium,  apart 
from  the  involvement  of  mvocardial  vessels,  are 
frequent.  There  is  interstitial  fibrosis,  myocardial 
degeneration,  endocardial,  epicardial  and  peri- 
cardial fibrosis,  and  ventricular  dilatation  and  hyper- 
trophy. 

Obviously,  clinical  manifestations  may  be  multiple 
and  varied.  Renal  involvement  may  cause  albumi- 
nuria, hematuria,  and  hypertension.  Myocardial 
disease  may  present  any  of  the  findings  seen  in 
congestive  heart  failure.  Pulmonary  involvement 
may  be  expressed  as  respiratory  alveolar-capillary 
block  syndrome,  fibrosis  and  emphysema,  obstructive 
and  restrictive  ventilatory  dysfunction,  hypoxia, 
carbon  dioxide  retention,  pulmonary  hypertension, 
polycythemia,  cor  pulmonale,  and  the  like.  Thoracic 
involvement  with  the  tight  constricting  skin  may 
produce  hypoventilation  and  circulatory  dysfunc- 
tion. 

All  the  above  and  other  changes  in  scleroderma 
are  obviously  of  importance  to  a  discussion  of  the 
peripheral  circulation  because,  potentially,  they  may 
all  contribute  to  disordered  peripheral  vascular 
physiology.  To  quantitate  their  effects,  however, 
would  be  a  difficult  or  impossible  task.  In  addition 
to  these  general  effects,  more  direct  factors  in  sclero- 
derma may  influence  vascular  function.  Comments 
made  in  the  preceding  section  on  vasculitis  and 
collagen  disease,  in  general,  are  applicable  here.  As 
noted,  obliterative  vascular  change  is  probably  the 
major  factor  in  vascular  dysfunction,  but  a  super- 
imposed functional  vasospastic  element  has  been 
suggested. 


The  frequent  occurrence  of  Raynaud's  phenome- 
non in  scleroderma  is  of  interest.  It  may  precede, 
accompany,  or  follow  the  clinical  disease  onset.  The 
true  relationship  between  the  two  is  unknown.  It 
was  long  held  by  many  that  the  vasomotor  ab- 
normality was  of  etiologic  importance  in  the  patho- 
genesis of  scleroderma.  The  majority  of  current 
opinion,  however,  is  that  associated  Raynaud's 
phenomenon  is  a  secondary  manifestation  of  sclero- 
derma due  to  the  primary  disturbance  in  blood 
vessels  and  connective  tissue.  In  this  regard  it  is 
analogous  to  secondary  Raynaud's  phenomenon 
occurring  in  other  collagen  diseases. 

Of  the  collagen  diseases,  however,  scleroderma 
presents  an  additional  unique  factor  in  that  the 
vessels  are  entrapped  in  a  fibrotic  ever-contracting, 
poorly  distensible  environment.  Thus,  in  addition  to 
intravascular  occlusion  there  may  be,  in  effect, 
extravascular  constriction  or  strangulation  (59,  81, 
92).  Greatly  increased  pressures  have  been  found 
in  the  subcutaneous  tissue  in  patients  with  sclero- 
derma. Studies  have  shown  tissue  pressure  values 
up  to  320  mm  of  water  in  patients  with  scleroderma, 
whereas  normal  persons  do  not  exceed  54  mm  (92). 
These  added  factors  may  be  of  significance  in  ex- 
plaining the  altered  peripheral  vascular  function  in 
scleroderma.  In  this  disease,  reduced  skin  tempera- 
ture and  decreased  digital  pulsations  are  common. 
That  these  changes  are  largely  structural  or  organic 
in  origin  is  suggested  by  failure  of  these  parameters 
to  return  to  normal  after  use  of  sympatholytic  drugs 
or  inhibition  of  sympathetic  tone  through  nerve 
block  or  sympathectomy. 

Vasoconstrictor  mechanisms  in  acute  thrombophlebitis. 
The  clinical  manifestations  of  thrombophlebitis  have 
been  adequately  described  in  a  number  of  publica- 
tions (1,  3,  87,  104)  and  will  not  be  repeated  here. 
Mechanisms  of  intravascular  clotting  are  discussed 
elsewhere  in  this  volume. 

Perhaps  a  few  words  regarding  terminology  are  in 
order.  It  has  been  common  practice  in  the  past  for 
clinicians  to  use  the  terms  "thrombophlebitis"  and 
"phlebothrombosis"  to  represent  two  different  and 
distinct  clinical  syndromes  (69).  Thrombophlebitis 
was  considered  to  represent  a  rather  intense  inflam- 
matory reaction  in  the  involved  vein  with  a  more 
firmly  attached  thrombus.  Although  it  produces  a 
more  dramatic  local  reaction,  it  was  considered  to  be 
less  dangerous,  since  there  was  less  likelihood  for 
emboli  to  break  from  the  thrombus.  In  contrast, 
phlebothrombosis,  although  bland  with  respect  to 
local  reactions  and  manifestations,  was  considered  to 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


be  the  more  lethal,  since  the  associated  loosely  at- 
tached thrombus  was  more  predisposed  to  break 
into  emboli.  Recent  experimental  and  clinical  evi- 
dence suggests,  however,  that  phlebothrombosis  is 
merely  the  silent  forerunner  of  thrombophlebitis  and 
that  the  two  diseases  are  stages  of  the  same  process 

(H.  29,  55)- 

Other  terminology  is  dependent  upon  whether  or 
not  superficial  or  deep  veins  are  involved  for  which 
the  terms  superficial  and  deep  thrombophlebitis  are 
applied.  The  process  of  course  is  named  according 
to  the  particular  vein  or  veins  involved.  When  in- 
fection is  a  predominant  accompaniment,  the  term 
"septic"  or  "suppurative"  thrombophlebitis  is  ap- 
plied. 

An  interesting  rare  variant  of  thrombophlebitis, 
the  Trousseau  syndrome,  or  "migratory  thrombo- 
phlebitis," should  perhaps  be  mentioned.  This  dis- 
ease may  involve  either  superficial  or  deep  veins,  in 
one  or  more  sites,  either  concurrently  or  separated  by 
considerable  lengths  of  time.  The  importance  of  this 
svndrome  is  related  to  the  frequency  with  which 
underlying  serious  disease  is  present,  especially, 
thromboangiitis  obliterans,  polycythemia  vera,  occult 
carcinoma  (usually  of  the  stomach,  pancreas,  or 
lung),  or  collagen  disease  (14). 

The  outstanding  finding  in  typical  acute  superficial 
thrombophlebitis  is  pain  and  tenderness  over  the 
involved  area,  but  embolic  phenomena  may  occur. 
Deep  thrombophlebitis  especially  predisposes  to 
embolism.  In  deep  thrombophlebitis  the  main 
physiologic  disturbance  is  obstruction  to  venous 
blood  flow.  Pain  of  various  types  may  be  a  feature 
and  is  helpful  in  diagnosis,  but  edema  is  the  most 
objectively  demonstrable  physiologic  alteration.  The 
degree  of  this  disturbance  is  obviously  dependent  on 
the  size  and  location  of  the  involved  vein,  the  extent 
of  the  thrombus,  and  the  adequacy  of  collateral 
circulation.  When  a  large  trunk  such  as  the  iliofemoral 
or  axillary  vein  is  involved  with  a  long  thrombus  also 
compromising  collateral  flow,  considerable  obstruc- 
tion to  venous  flow  may  occur  and  the  increase  in 
venous  pressure  may  be  marked.  This  is  in  contrast 
to  simple  ligation  of  a  venous  trunk  in  which  col- 
lateral circulation  is  not  adversely  affected. 

Edema  formation,  secondary  to  venous  occlusion 
in  thrombophlebitis,  is  much  more  than  a  simple 
process  of  increased  venous  pressure  with  resultant 
increase  in  mechanical  transudation  of  fluid  into 
the  tissue  space,  but  this  factor  seems  to  be  important. 
The  importance  of  associated  lymphatic  obstruction 


in  thrombophlebitis  in  the  production  of  the  edema 
is  debated  and  not  yet  clarified.  Certainly,  fibrotic 
reactions  in  long-standing  edema  with  a  high  protein 
content  of  the  extracellular  fluid  impairs  lvmph  flow. 

Appropriate  to  the  present  discussion  are  studies 
concerning  possible  vasomotor  or  sympathetic  factors 
in  the  pathogenesis  of  the  manifestations  in  thrombo- 
phlebitis. That  arterial  spasm  may  occur  in  some 
patients  with  deep  vein  thrombophlebitis  is  not 
denied,  but  whether  or  not  it  is  a  significant  factor 
in  most  instances  is  debatable.  In  some  patients 
during  the  acute  stages  of  the  disease  spasm  may  he 
so  severe  that  pulsations  in  the  large  arteries  disappear 
for  several  hours.  Several  patients  with  actual  ischemic 
gangrene  have  been  reported.  The  terms  "phlegmasis 
alba  dolens"  and  "phlegmasia  cerulea  dolens"  have 
been  used  in  some  of  these  patients  to  describe  the 
associated  color  changes  thought  to  be  due  to  ac- 
companying arterial  spasm. 

Some  studies  (68)  suggest  that  vasoconstrictor 
impulses  are  initiated  by  the  thrombosed  segment 
of  vein  which  produces  spasm  of  both  arterioles  and 
venules  in  the  distant  portions  of  the  limb.  Experi- 
mental and  clinical  evidence  has  been  presented  in 
favor  of  the  idea  that  the  thrombosed  venous  segment 
initiates  a  detrimental  spinal  reflex  arc  with  the 
sympathetic  nerves  as  its  efferent  arm.  The  induced 
arterial,  arteriolar,  venous,  and  venular  spasm  was 
said  to  propagate  edema  formation  by  increased 
venous  pressure  with  augmentation  of  filtration  pres- 
sure, by  relative  anoxia  of  capillary  endothelium 
with  increased  fluid  transudation  and  by  retarded 
lymph  flow  secondary  to  reduced  "pumping  action" 
from  the  arterial  and  arteriolar  vessels  in  spasm. 
Rather  dramatic  clinical  improvement  in  patients 
following  paravertebral  sympathetic  blocks,  both  in 
subsidence  of  pain  as  well  as  edema,  has  been  re- 
ported. 

Subsequent  experimental  studies  on  mesenteric 
vessels  of  young  dogs  support  some  of  these  concepts 
(56).  It  was  found  that  after  acute  occlusion  of  the 
main  stem  vein  the  artery  reflexly  underwent  spasm, 
whereas  the  vein  became  moderately  dilated.  On 
release  of  the  occlusion  there  was  a  period  of  residual 
arterial  constriction,  whereas  the  vein  returned  to  its 
preocclusion  caliber.  After  sympathectomy,  however, 
it  was  noted  that  all  reflex  arterial  constriction,  as 
well  as  the  residual  arterial  constriction  that  followed 
release  of  the  occlusion,  were  abolished.  It  was  noted 
that  during  occlusion  the  vein  became  dilated  to  a 
diameter   exceeding    that   of   the   control.    Although 


PERIPHERAL    VASCULAR    DISEASES 


I  24I 


these  experiments  tend  to  lend  support  in  part  to 
the  concept  of  reflex  arterial  constriction,  the  latter 
observation  regarding  venous  dilatation  is  not  in 
accordance  with  the  concept  of  venous  or  venular 
constriction.  This  factor  in  thrombophlebitis  had 
been  difficult  to  accept  in  the  light  of  the  intense 
congestion  and  obvious  distention  of  the  small  veins 

(3)- 

The  theory  that  associated  vasospasm  in  throm- 
bophlebitis is  a  frequent  and  important  pathophysio- 
logic factor  is  intriguing  but  more  definitive  ex- 
perimental work  is  required  for  confirmation  and 
general  acceptance  in  clinical  medicine. 

Vasodilative  Syndromes 

Vasodilatation  as  an  important  vascular  response 
is  seen  in  a  number  of  physiologic  states  such  as 
thermoregulation,  tissue  inflammatory  response,  reac- 
tive hyperemia,  early  stages  of  causalgia,  and  the  like, 
but  the  cardinal  condition  which  concerns  us  here 
is  erythromelalgia. 

erythromelalgia  (erythermalgia).  Early  con- 
tributors to  the  literature  of  this  disease  state  were 
Graves  in  1834  (63),  Mitchell  in  1872  (63),  Cassirer 
in  1 91 2  (12),  and  May  &  Hillemand  in  1924  (57). 
Significant  contributions  after  that  time  include  the 
work  of  Brown  in  1932  (7),  Lewis  in  1933  (45),  and 
Smith  &  Allen  in  1938  (91 ).  Since  then,  little  definitive 
work  has  been  done  and  published  on  erythro- 
melalgia. 

Erythromelalgia  is  a  vasodilative  syndrome  char- 
acterized by  episodes  of  erythema,  increased  heat 
and  pain  involving  the  hands  and  especially  the  feet. 
It  has  been  placed  into  primary  and  secondary 
categories.  "Primary  erythromelalgia"  occurs  in 
otherwise  healthy  individuals  who  manifest  no  de- 
tectable evidence  of  organic  disease  of  the  nervous 
or  vascular  systems.  Analogous  to  Raynaud's  phe- 
nomenon, "secondary  erythromelalgia"  occurs  in 
association  with  or  as  a  secondary  symptom  complex 
of  some  other  primary  disease,  such  as  hypertension, 
occlusive  organic  vascular  disease  or  polycythemia. 
Gout,  organic  neurologic  disease,  frostbite,  immersion 
foot,  trenchfoot,  infectious  diseases,  and  heavy  metal 
poisoning  are  also  incriminated. 

The  mechanism  of  erythromelalgia  is  unknown  and 
the  pathology  has  not  been  clarified.  Symptoms 
usually  start  in  middle  age  or  later  and  may  affect 
either  sex.   It  is  apparently  rare  in  the  Negro  (74). 


The  clinical  picture  may  be  quite  dramatic.  The  main 
complaint  is  usually  burning  pain  in  the  extremities, 
especially  in  the  feet  and  frequently  in  the  hands. 
Occasionally  the  disturbance  may  extend  as  high  as 
the  knees  or  thighs.  The  patient  usually  complains 
that  the  distress  affects  primarily  the  balls  of  the  feet 
and  tips  of  the  toes  or  corresponding  parts  of  the  hand. 
It  may  last  from  a  few  minutes  to  several  hours. 
Usually  the  patient  relates  aggravation  by  dependency 
of  the  part,  by  warmth,  accentuation  during  summer 
months,  relief  by  cold  and  elevation  of  the  part,  and 
lessened  symptoms  during  winter.  Attacks  may  be 
precipitated  by  exercise  which  increases  the  warmth 
of  the  skin.  For  unknown  reasons,  dry  heat  seems  to 
be  more  provocative  than  wet  heat  at  the  same  tem- 
perature. The  discomfort  may  start  as  a  "pricking" 
paresthetic  feeling  then  progress  to  a  more  typical 
severe  burning  pain.  During  the  subsidence  of  the 
episode  the  pricking  stage  may  again  be  noticed.  In 
the  primary  disease,  neurological  examination  is 
negative  and  examination  of  the  peripheral  vascula- 
ture shows  no  evidence  of  occlusive  arterial  disease. 
Trophic  changes,  ulceration,  and  gangrene  are  quite 
rare,  though  some  swelling  may  be  evident  in  the 
involved  extremities. 

What  is  known  of  the  pathophysiology  of  this 
syndrome  is  interesting.  The  most  important  part  of 
this  syndrome  is  its  intimate  relationship  with  the 
temperature  of  the  skin.  Lewis  (45)  has  designated  a 
"critical  point"  in  skin  temperature  at  which  this 
syndrome  may  be  produced  in  susceptible  individuals. 
It  usually  is  around  32  C  (range,  31  to  36  C).  With 
temperatures  higher  than  this  critical  point,  the 
distress  continues  and  with  temperatures  lower  than 
this  point  the  distress  disappears  (3,  91).  The  tem- 
perature at  which  the  syndrome  may  be  produced 
varies  with  different  patients  and  also  to  some  degree 
in  different  parts  of  the  extremity  in  the  same  person, 
but  in  the  same  person  the  range  is  usually  within 
±1  C. 

Vasodilation  per  se  seems  to  be  an  important 
vascular  factor  in  the  production  of  the  erythro- 
melalgic  crises.  Increased  blood  flow  is  only  an  indirect 
accompaniment.  Thus,  the  syndrome  may  be  pro- 
duced by  warming  the  extremity  to  the  critical  level, 
and  the  symptoms  continued  even  though  blood 
flow  is  arrested  by  an  inflated  constricting  blood 
pressure  cuff.  This  is  so,  provided  the  skin  tempera- 
ture is  maintained  at  levels  equal  to  or  greater  than 
the  critical  point. 

As    Lewis    has    pointed    out,    however,    although 


1242 


HANDBOOK    OF    PHYSIOLOGY    ^   CIRCULATION    II 


vasodilation  may  be  the  essential  vascular  reaction, 
it  alone  is  not  enough  to  explain  the  clinical  state, 
since  an  equivalent  degree  of  vasodilatation  may 
occur  in  asymptomatic  normal  subjects  in  response 
to  warmth  or  exercise.  Thus,  he  concluded  that  the 
essential  abnormality  was  a  hypersensitive  state  of 
the  cutaneous  pain  fibers  to  heat  or  tension  (by 
dilated  and  engorged  vessels),  i.e.,  a  "susceptible 
state"  of  the  skin.  Thus,  he  suggested  that  a  chemical 
substance  liberated  into  the  skin  served  as  the  im- 
mediate stimulus  to  the  nerve  endings  and  supported 
this  by  the  observation  that  the  pain  of  the  erythro- 
melalgic  skin  was  prolonged  or  intensified  by  arresting 
the  circulation  to  the  part. 

The  essential  vessels  involved  in  the  vasodilatation 
are  not  definite,  but  it  seems  that  all  small  vessels 
participate.  During  a  typical  attack,  the  accompany- 
ing features  of  vasodilation  may  be  observed.  In 
addition  to  increased  temperature  of  the  skin,  there 
may  be  increased  amplitude  of  arterial  pulsation, 
throbbing  sensations,  increased  elimination  of  heat, 
and  increased  content  of  oxygen  in  the  returning 
venous  blood.  The  affected  part  assumes  a  deep, 
dusky  red  color.  The  dusky  color  of  the  skin  which 
indicates  a  low  oxygen  content  of  small  vessel  blood 
is  of  interest  in  light  of  the  high  oxygen  content  of 
returning  venous  blood.  An  explanation  offered  for 
this  is  arteriolar-venous  shunting  of  some  of  the 
peripheral  flow  through  open  arteriovenous  anas- 
tomoses (91 ). 

Other  observations  are  of  interest  (3,  gi  ).  If  the 
skin  temperature  is  slightly  lower  than  the  critical 
point,  distress  may  be  induced  by  artificially  in- 
creasing the  venous  pressure  by  a  proximal  constrict- 
ing blood  pressure  cuff  inflated  to  a  pressure  less  than 
arterial  pressure  or  by  holding  the  part  below  heart 
level  to  produce  venous  congestion.  Similarly, 
symptoms  may  be  lessened  if  an  extremity  is  elevated 
even  though  the  skin  temperature  remains  unchanged. 
In  addition,  direct  pressure  on  the  skin  of  the  in- 
volved area  may  cause  relief. 

A  vasoconstrictor  factor  has  been  suspected  in 
some  patients  during  intervals  when  they  are  free 
of  the  burning  distress.  This  is  manifested  as  local 
coldness  and  cyanosis  or  pallor  of  the  skin  during 
these  pain-free  periods.  Some  patients  have  been 
reported  to  suffer  from  Raynaud's  phenomenon  when 
cold  and  erythromelalgia  when  warm. 

In  diagnosis  of  erythromelalgia,  one  must  exclude 
the  burning  sensations  in  the  extremities  of  patients 
who  are  suffering  with  peripheral  neuritis,  occlusive 
arterial   disease,   and   other  states,    but  who   do  not 


have  erythromelalgia  either  primary  or  secondary. 
In  these  patients  the  skin  temperature  is  frequently 
low  (especially  in  organic  vascular  disease)  or  normal, 
and  the  intimate  relationship  of  distress  to  a  critical 
thermal  level  is  not  apparent.  Further,  it  should  be 
noted  that  in  organic  vascular  disease  elevation  fre- 
quently accentuates  symptoms  and  causes  the  in- 
volved part  to  assume  a  pale  and  waxy  color,  whereas 
in  erythromelalgia  color  largely  persists  on  elevation 
and  the  symptoms  may  lie  somewhat  alleviated.  In 
establishing  a  diagnosis  of  erythromelalgia  it  is  es- 
sential to  demonstrate  that  skin  temperature  and  the 
distress  are  related.  For  this  purpose,  the  patient's 
reaction  and  skin  temperature  are  observed  while 
the  temperature  is  raised  either  by  reflex  vasodilata- 
tion or  by  direct  application  of  heat. 

One  other  interesting  fact  bears  comment.  Acetyl- 
salicylic  acid,  in  an  oral  dose  of  as  little  as  0.65  g, 
may  produce  marked  and  persistent  relief  in  erythro- 
melalgia for  as  long  as  several  days.  The  mechanism 
of  this  response  is  unexplained,  but  it  may  be  related 
to  effects  on  the  local  release  of  bradykinin. 

In  the  pathophysiology  of  erythromelalgia,  al- 
though the  vascular  responses  to  temperature  are  in 
part  well  established,  the  mechanisms  that  induce 
these  responses  are  unknown.  Whether  the  basic 
defect  is  in  the  nervous  system  or  in  the  blood  vessels 
themselves  is  not  clear.  Regardless  of  the  site,  the 
mediators  involved  need  study.  Furthermore,  it  is  not 
known  whether  or  not  the  disturbance  is  congenital 
or  acquired.  The  possible  contributions  of  vasoactive 
humoral  agents  and  the  vasodilator  nerves  and  the 
mechanisms  of  their  actions  are  also  unknown.  It  may 
be  worthwhile,  however,  to  direct  attention  to  the 
renewed  interest  in  vasodepressor  polypeptides,  in 
particular  bradykinin.  Depressor  polypeptides  have 
been  the  subject  of  a  recent  review  (35)  and  their 
possible  physiologic  functions  are  covered  elsewhere 
in  this  volume.  Further  study  might  well  incriminate 
bradykinin  as  an  important  factor  in  the  patho- 
physiology of  peripheral  vascular  disease,  not  only  in 
erythromelalgia,  but  in  numerous  other  vasodilator 
reactions. 


Mechanisms  in  Othc 


n  ular  Diseases 


In  the  preceding  discussions  it  was  not  possible 
to  survey  the  pathophysiologic  mechanisms  of  many 
other  diseases  of  the  peripheral  vascular  system.  The 
reader  may  obtain  insight  into  the  scope  of  the  prob- 
lem by  referring  to  the  appendix  of  this  chapter. 


PERIPHERAL    VASCULAR    DISEASES 


I243 


A  P  P  E  N  D  1  X 


CLASSIFICATION    OF    PERIPHERAL    VASCULAR    DISEASE 


Diseases  Affecting  Primarily  the  Arteries  and  Arterioles 

I.    FUNCTIONAL    CONDITIONS 

A.    Vasoconstrictor 

1 .  Raynaud's  syndrome   (primary   Raynaud's    disease) 

2.  Raynaud's  syndrome  (secondary) 

a.  Traumatic  vasospastic  syndrome 

b.  Neurovascular  mechanisms 
(1)   Shoulder  girdle  syndromes 

(a)  Scalenous  amicus 

(b)  Cervical  rib 

1 c  1    Costoclavicular 

(d)  Hyperabduction 

(e)  Thoracic  outlet 

(f)  Malposition 

(g)  Pectoralis  minor 
1  2  I    Spondylitis 

;  1   Neuritis 

c.  Secondary  to  organic  vascular  disease 
(1)  Arteriosclerosis 

1  j  1   Syphilitic  arteritis 

(3)  Thromboangiitis  obliterans 

(4)  Thrombotic  or  embolic  occlusion 

(5)  Other  occlusive  arterial  disease 

d.  Secondary  to  intoxications 
( 1 )  Arsenic 

j 1    Ergot 

(3)  Lead 

(4)  Nicotine 

(5)  Tobacco 

e.  Scleroderma  and  acrosclerosis 

f.  Miscellaneous  mechanisms  (e.g.,  rheumatoid 
arthritis,  lupus  erythematosus,  cold  injury,  and 
other  factors  listed  in  Category  5  below) 

3.  Acrocyanosis 

4.  Livedo  reticularis 

a.  Idiopathica 

b.  Svmptomatic  livedo  reticularis 

(1)  Questionable  factors 

Rickets,  mongolism,  various  endocrin- 
opathies,  malnutrition,  varicose  veins, 
other  peripheral  vascular  diseases,  infec- 
tious diseases,  intoxications,  congenital 
vascular  defects,  ectodermal  abnormalities, 
cirrhosis  of  the  liver  and  other  unusual 
diseases,    and   neural    disorders 

(2)  Probable  factors 

1  a )   Hypertension 

(b)  Nervousness  and  emotional  instability 

(c)  Arsenic  or  lead  poisoning  (?) 

(3)  Purported  causes 

(a)  Tuberculosis 

(b)  Syphilis 

(c)  Periarteritis     nodosa     and     allergic    cu- 
taneous vasculitis 

c.  Cutis  marmorata 


5.   Vasospasm,  secondary  to 

a.  Lesions  of  peripheral  nerves 

b.  Lesions  of  brain  and  spinal  cord  including  polio- 
myelitis, prolapsed  nucleus  pulposus,  hemiplegia, 
tumors,  multiple  sclerosis,  epileptic  equivalent, 
spinal  bifida,  spinal  arthritis,  lesions  of  midbrain 
and  internal  capsule,  etc. 

c.  Thrombophlebitis 

d.  Embolism 

e.  Thrombosis 

f.  Trauma 

(1)  Posttraumatic   reflex   sympathetic    dystrophy 

(2)  Major  causalgia 

(3)  Minor  causalgia 

(4)  Sudeck's  atrophy 

(5)  Posttraumatic  osteoporosis 

(6)  "Vibrating-machine  disease" 

(7)  Shoulder-hand  syndrome 

(8)  Crutch  arteritis 

(9)  Metabolic,  adynamic  and  hormonal,  includ- 
ing rheumatoid  arthritis,  malnutrition  and 
asthenia,  terminal  rheumatic  heart  disease, 
hypothyroidism,  castration,  menopause,  hy- 
poglycemia, Addison's  disease,  polycythemia, 
cold  hemagglutination  and  cryoglobulins, 
leprosy,  etc. 

B.    Vasodilator 

1 .  Erythromelalgia,  primary 

2.  Erythromelalgia,  secondary  to 

a.  Polycythemia  vera 

b.  Arteriosclerosis 

c.  Thromboangiitis  obliterans 

d.  Hypertension 

e.  Miscellaneous  factors:  trauma,  gout,  frostbite, 
immersion  foot,  trenchfoot,  infectious  diseases, 
heavy  metal   poisoning,  etc. 

II.    ORGANIC    CONDITIONS    (STRUCTURAL) 

A.   Occlusive  [organic) 

1.  Arteriosclerosis 

a.  Atherosis 

b.  Atherosclerosis 

c.  Atherosclerosis  obliterans 

d.  Medial  ( Monckeberg's)  arteriosclerosis 

e.  Arteriolosclerosis   and   hypertensive   ischemia 

f.  Combined 

2.  Thromboangiitis  obliterans 

3.  Arteritis   (inflammatory  diseases)  and  arteriolitis 

a.  Disseminated  arteritis 

b.  Erythema  induratum 

c.  Erythema  nodosum 

d.  Nodular  panniculitis 

e.  Nodular  vasculitis 

f.  Temporal  arteritis 

g.  Syndromes  of  necrotizing  and/or  allergic  vas- 
culitis 

(1)   General  syndromes 

(a)  Purpura  rheumatica 

(b)  Schonlein-Henoch  syndrome 

(c)  Allergic  angiitis 

(d)  Anaphylactoid  purpura 

(e)  Necrotizing  vasculitis 

(f)  Periarteritis  nodosa  of  hypersensitivity 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


(g)   Wegener's    granulomatosis    and    lethal 
midline  granuloma  of  the  face 
(2)   Cutaneous  syndromes 
1  a  )   Acute  parapsoriasis 

(b)  Nodular  allergid  of  Gougerot 

(c)  Allergic  granulomatosis 
d      \llcrgic  microbid 

(e)  Erythema  elevatum  diutinum 

(f)  Malignant   atropic   papulosus   of  Degos 

4.  Ergotism 

5.  Collagen  diseases 

a.  Dermatomyositis 

b.  Disseminated  lupus  erythematosus 

c.  Periarteritis  nodosa 

d.  Scleroderma 

6.  Hypertensive  vascular  disease 

7.  Arterial  thrombosis 

a.  Associated  with  infectious  diseases 

b.  Associated  with  blood  dyscrasias 

c.  Secondary    to    trauma    or    compression    (Volk- 
mann's  contracture,  shoulder  girdle  syndrome) 

d.  Secondary  to  surgery 

e.  Associated  with  parturition 

f.  Associated  with  cardiac  insufficiency 

g.  Associated  with  slowed  blood  stream 
h.  Associated  with  exposure  to  radiation 
i.    Idiopathic 

8.  Abscess  of  wall  of  artery 
q.   Cold  injuries 

a.  Chilblains  (pernio) 

b.  Cold  urticaria 

c.  Frostbite 

d.  Immersion  foot 

e.  Trenchfoot 

10.  Livedo  reticularis 

1 1 .  Arterial  embolism 

a.  Thrombus 

b.  Fat 

c.  Air 

d.  Bacterial 

e.  Neoplastic 

f.  Fungus 

g.  Inorganic  substances 

12.  Ainhum 

13.  Blood  agglutination 

a.  Dyscrasias  (polycythemia,  leukemia,  thrombotic 
thrombocytopenic  purpura) 

b.  Cold  reactions   (possible  cold  agglutinins,  cryo- 
globulinemia) 

c.  Idiopathic  (necrotizing  acrocyanosis) 

d.  Massive  venous  thrombosis 
B.  Nonocclusive  (organic) 

1 .  Aneurysm 

a.  Congenital 

b.  Syphilitic 

c.  Arteriosclerotic 

d.  Mycotic 

e.  Traumatic 

f.  Embolic 

g.  Idiopathic 

2.  Arteriovenous  anastomosis  (fistula) 
a.   Congenital 


b.  Traumatic 

c.  Secondary  to  malignancy 

d.  Secondary  to  bacterial  infections 

e.  Secondary  to  fungus  infections 

3.  Congenital  anomalies  of  artery 

4.  Trauma  of  artery 

5.  Shoulder  girdle  syndromes 

6.  Rupture  of  artery 

7     I.ffects  of  exposure  to  radiation 
8.   Nonocclusive  arteritis 


Diseases  Primarily  Affecting  the  Veins 

I.    FUNCTIONAL    CONDITIONS 

A.   Spasms 

II.     ORGANIC    CONDITIONS     (STRUCTURAL) 

A .  Occlusive 

1.  Thrombophlebitis  and  venous  thrombosis  (phlebo- 
thrombosis) 

a.  Primary 

(1)  Thromboangiitis  obliterans 

(2)  Migratory  thrombophlebitis 

(3)  Essential  or  idiopathic,  local 

b.  Secondary  to 

(  1  )    Mechanical  injury 

(2)  Muscular  effort  or  strain 

(3)  Chemical  injury 

(4)  Inflammatory  or  suppurative  lesions  (etio- 
logic  agent  to  be  indicated) 

(5)  Infectious  diseases 

(6)  Severe  ischemia 

( 7 )  Varices 

(8)  Blood  dyscrasias 
(a)    Polycythemia 

lb)   Myelogenous  leukemia 
(c)    Lymphatic  leukemia 
id)   Pernicious  anemia 

(e)   Disturbances   of  blood   clotting   mech- 
anism 
ill    Other  blood  dyscrasias 

(9)  Cardiac  insufficiency 
(10)   Carcinoma 

2.  Neoplastic  invasion  of  vein 

3.  Venous  compression  by 

a.  Gravid  uterus 

b.  Neoplasm 

c.  Aneurysm 

d.  Scar  tissue 

e.  Scalenus  amicus  syndrome 

f.  Hyperabduction  syndrome 

g.  Fractures 

h.  Dislocations 

i.    Increased    intra-abdominal    pressure    (ascites) 

4.  Postphlebitic  syndrome 

B.  Nonocclusive 

1 .   Varicose  veins 

a.  Primary 

b.  Secondary  to 

( 1 )  Posture 

(2)  Occupation 

(3)  Clothing 


PERIPHERAL   VASCULAR   DISEASES 


I245 


(4)  Proximal    obstructive    lesions    or    pressure 
(see  II,  A,  3) 

(5)  Thrombophlebitis 

(6)  Arteriovenous  anastomosis 

( 7 )  Hemangioma 

(8)  Congenital  anomalies  of  veins 
Arteriovenous  anastomosis  (fistula) 

a.  Congenital 

b.  Traumatic 

c.  Secondary  to  malignant  lesions 

d.  Secondary  to  bacterial  infections 

e.  Secondary  to  fungus  infections 
Aberrant  position  of  vein 
Hypoplasia  of  vein 
Phlebectasia 

Periphlebitis 
Phlebosclerosis 
Rupture  of  vein 


Neoplasms  of  Blood  Vessels 


BENIG!> 

r 

A. 

Hemangioma 
1 .   Cavernous 

2. 
3- 

Capillary 
Plexiform 

4- 

5- 

6. 

Sclerosing 

Sturge-Parkes  VVeber-Dimitr 

Von  Hippel-Lindau  disease 

syndrome 

B. 

7.  Maffucci's  syndrome 

8.  Multiple  hemangiomas  and 
syndrome) 

Glomus 

chrondromata 

(Kast's 

C. 

Telangiectasia 
1 .    Hereditary  hemorrhagic 

2. 

Senile 

3- 

4- 
5- 

Simple 
Spider 
Papillary  varices 

II. 


MALIGNANT 

A.  Ewing's  sarcoma 

B.  Hemangioendothelioma 

C.  Hemangiosarcoma 

D.  Kaposi's  sarcoma 


(3)  Fungus 

(4)  Erysipelis 

b.  Mechanical,  chemical  and  physical 

( 1 )  Abrasions 

(2)  Burns 

(3)  Chemical  irritation 

(4)  Lacerations 

(5)  Trauma 

(6)  X-ray 

c.  Granulomata 

(1)  Lymphogranuloma 

(2)  Syphilis 

(3)  Tuberculosis 

d.  Postphlebitic 

e.  Surgery 

(1)  Removal  of  lymph  nodes 

(2)  Removal  of  lymph  vessels 

f.  Neoplastic  invasion  of  lymph  nodes 

(1)  Endothelioma 

(2)  Hodgkin's  disease 

(3)  Leukemia 

(4)  Lymphangioma 

(5)  Lymphocytoma 

(6)  Lymphoma 

(7)  Lymphosarcoma 

(8)  Obstruction  of  thoracic  duct 

(9)  Sarcoma  of  lymph  nodes 
(10)  Reticular  cell  sarcoma 

g.  Dependency  edema 

II.  LYMPHANGITIS 

A.  Primary  (idiopathic) 

B.  Secondary 

1 .  Infection 

2.  Infestation 

3.  Trauma 

III.  NEOPLASMS    OF    LYMPH    VESSELS 

A.   Benign 

1.  Lymphangiectasia 

2.  Lymphangioma 

a.  Simple 

b.  Cavernous 

c.  Cystic 
B.   Malignant 

I .   Lymphangiosarcoma 


Diseases  Primarily  Affecting  the  Lymphatics 

I.    LYMPHEDEMA 

A.  Primary  (idiopathic) 

1.  Congenital  and  hereditary  (Milroy's  disease) 

2.  Congenital  but  not  hereditary 

a.  Without  constricting  bands 

b.  With  constricting  bands 

3.  Praecox 

B.  Secondary 

1.   Lymphangitis  and  lymphadenitis 
a.   Infection  and  infestations 

( 1 )  Filariasis 

(2)  Pyogenic 


Diseases  Affecting  Primarily  the  Minute   Vessels 

I.    INCREASED     FRAGILITY     (PURPURA)     OF    VESSELS 

A.    Thrombocytopenic  purpura 

1.  Primary:  idiopathic  (Werlhoff's)  disease 

2.  Secondary 

a.  Vascular  defects 

(1)  Thrombotic      thrombocytopenic 

(2)  Blood  dyscrasias 

(a)  Acquired  hemolytic  anemia 

(b)  Hodgkin's  disease 

(c)  Leukemia 

(d)  Malignant  lymphoma 

(e)  Myeloma 

(f)  Pernicious  anemia 


purpura 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


(3)  Infections 

(a)  Bacterial 

(b)  Rickettsial 

(c)  Viral 

(4)  Splenomegaly 

(a)  Band  s  syndrome 

(b)  Felty's  syndrome 

(c)  Gaucher's  disease 

(d)  Hodgkin's  disease 

(e)  Leukemia 

(5)  Malignancy 

(6)  Drugs  and  chemical  agents 

(a)  Allyl-isopropyl-acetyl-carbamide 
(Sedormid) 

(b)  Arsenic 

(c)  Benzene 

(d)  Bismuth 

(e)  Certain  foods,  such  as  orris  root 

(f)  Chloramphenicol 

(g)  Dichloro-diphenyl-trichloro-ethane 
(DDT) 

(h)  Digitoxin 

(j)    Dinitrophenol 

(j)    Ergot 

(k)   Gold 

(1)    Hair  dyes 

(m)  Iodine 

(n)   Methylphenylethyl  hydantoin 

( Mesantoin) 
(o)   Nitrogen  mustard 
(p)   Pertussis  vaccine 
(qj   Phenol 
(r)    Phenolphthalein 
(s)    Phosphorus 
(t)    Quinidine 
(u)  Quinine 
(v)  Snake  venom 
(w)  Streptomycin 
(x)   Sulfa  drugs 
(y)   Triethylenemelamine 
(z)   Trimethadione 

(7)  Physical  factors 

(a)  Heat  stroke 

(b)  Radiation 

(c)  Burns 

B.   Nonthrombocytopenic  purpura 
1 .   Primary 
a.  Senile 


b.  Purpura  simplex 

c.  Hereditary  hemorrhagic  diathesis 
2.   Secondary 

a.  Stasis — increased  venous  pressure 

b.  Traumatic  or  mechanical 

c.  Allergic  or  anaphylactoid 

( 1 )  Schoenlein-Henoch  purpura 

(2)  Purpura  fulminans 

(3)  Other 

d.  Skin  diseases 

e.  Chemical  agents 

(1)  Acetophenetidin  (Phenacetin) 
1 2 )   Atropine 

(3)  Belladonna 

(4)  Bismuth 

(5)  Chloral  hydrate 

(6)  Iodine 
(71    Mercury 

(8)  Penicillin 

(9)  Quinine 

( 10)   Salicylic  acid 

lii)   Various  anticoagulants 

f.  Systemic  diseases  and  infections 

( 1 )   Nephritis 

1  2  )    Purpura  fulminans 

(3)  Septicemia 

(4)  Enanthema 

(5)  Scarlet  fever 

(6)  Other  bacterial  diseases 

(7)  Rickettsial  diseases 

(8)  Viral  diseases 

g.  Avitaminosis 

( 1 )  Scurvy 

(2)  Vitamin  P  deficiency 

(3)  Vitamin  K  deficiency 
14)   Other  vitamin  deficiency 

h.  Cryoglobulinemia 

II.    INCREASED    PERMEABILITY    OF    VESSELS 

A.  Allergic  urticaria 

B.  Angioneurotic  edema 

C.  Inflammation 

D.  Physical  irritants 

1.  Trauma 

2.  Cold 

3.  Heat 

E.  Scrum  sickness 


REFERENCES 


1 .  Abramson,  D.  Diagnosis  and  Treatment  of  Peripheral  Vascular 
Disorders.  New  York:  Hoeber-Harper,  1956. 

2.  Adson,  A.,  and  G  Brown.  The  treatment  of  Raynaud's 
disease  by  resection  of  the  upper  thoracic  and  lumbar 
sympathetic    ganglia    and    trunks.    Surg.    Gynecol.    Obstet. 

48:577.  '929- 

3.  Allen,  E.,  N.  Barker,  and  E.  Hines.  Peripheral  Vascular 
Diseases   (2nd  ed.).    Philadelphia:   Saunders,   1956. 


4.  Allen,  J.,  P.  Moulder,  D.  Emerson,  C.  Basinger,  J. 
Landv,  and  D.  Glotzer.  Physiology  of  intravascular 
coagulation  in  health  and  disease.  Surg.  Clin.  North 
Am.  37:  1473,  1957- 

5.  Barker,  N,  E.  Hines,  and  W.  Craig.  Livedo  reticularis. 
A  peripheral  arteriolar  disease.  Am.  Heart  J.  21  :  592,  1 941 . 

6.  Boas,  E.  Capillaries  of  extremities  in  acrocyanosis.  J.  Am. 
Med.    Assoc.    79:    1404,    1922. 


PERIPHERAL    VASCULAR   DISEASES 


H7 


'3' 

14. 


>5' 


16. 

'7- 


'9- 


23- 

24- 

25- 

26. 
27- 

28. 


29- 


Brown,  G.  Erythromelalgia  and  other  disturbances  of 
extremities  accompanied  by  vasodilatation  and  burning. 
Am.  J.  Med.  Sci.  183:  468,  1932. 

Buchanan,  J.,  J.  Cranlev,  and  R.  Linton.  Observations 
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Surgery  31  :  62,  1952. 

Burch,  G.  A  Primer  of  Venous  Pressure.  Philadelphia :  Lea  & 
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Burch,  G.  Digital  Plethysmography.  New  York :  Grune  & 
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Burch,  G.  George  E.  Brown  Memorial  Lecture:  Digital 
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Cohen,  S.  Traumatic  arterial  spasm.  Lancet  1:1,  1944. 
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Doupe,  J.,  C.  Cullen,  and  C.  Chance.  Post-traumatic 
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Ebert,  M.  Livedo  reticularis.  Arch.  Dermatol,  and  Syphilol. 
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Edwards,  E.  Varieties  of  digital  ischemia  and  their  man- 
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!956- 

Feldaker,  M.,  E.  Hines,  and  R.  Kierland.  Livedo 
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Freeman,  N.  Effect  of  temperature  on  rate  of  blood  flow 

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30.  Goetz,  R.,  and  F.  Ames.  Reflex  vasodilatation  by  body 
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31.  Gosset,  A.,  I.  Bertrand,  and  J.  Patel.  Sur  la  physio- 
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33.  Hardy,  E.,  and  D.  Tibbs.  Acute  ischaemia  in  limb  in- 
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34.  Homans,  J.  Minor  causalgia,  a  hyperesthetic  neurovascu- 
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35.  Huggins,  C,  and  E.  Walaszek.  Depressor  polypeptides. 
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36.  Juergens,  J.  Intermittent  claudication.  Med.  Clin.  North 
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37.  Katz,  L.,  E.  Linder,  and  H.  Landt.  On  nature  of  sub- 
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38.  Kinmonth,  J.,  F.  Simeone,  and  V.  Perlow.  Factors 
affecting  diameter  of  large  arteries  with  particular  refer- 
ence to  traumatic  spasm.  Surgery  26:  452,   1949. 

39.  Kinmonth,  J.,  G.  Hadfield,  J.  Connolly,  R.  Lee,  and 
E.  Amoroso.  Traumatic  arterial  spasm:  its  relief  in  man 
and  in  monkeys.  Brit.  J.  Surg.  44:  164,   1956. 

40.  Kissin,  M.  Production  of  pain  in  exercising  skeletal  muscle 
during  induced  anoxia.  J.  Clin.  Invest.  13:  37,  1934. 

41.  Kistiakovsky,  E.  Erythrocyanosis  cutis  symmetrica, 
angioneurosis  endocrinopathica  polyglandularis.  Arch. 
Dermatol,  and  Syphilol.  20 :  780,  1 929. 

42.  Kuntz,  A.  Afferent  innervation  of  peripheral  blood 
vessels  through  sympathetic  trunks;  its  clinical  implica- 
tions. Southern  Med.  J.  44:  673,  1951. 

43.  Leary',  W.,  and  E.  Allen.  Intermittent  claudication  as  a 
result  of  arterial  spasm  induced  by  walking.  .4m.  Heart  J. 
22:  719,  1941. 

44.  Leriche,  R.  De  l'elongation  et  de  la  section  des  nerfs 
perivasculaires  dans  certain  syndromes  douloureux  d'ori- 
gine  arterielle  et  dans  quelques  troubles  trophiques. 
Lyon   chir.    1  :   378,    1 91 3. 

45.  Lewis,  T.  Clinical  observations  and  experiments  relating 
to  burning  pain  in  extremities,  and  to  so-called  "eryth- 
romelalgia" in  particular.  Clin.  Sci.  1  :  175,  1933. 

46.  Lewis,  T.  Experiments  relating  to  peripheral  mechanisms 
involved  in  spasmodic  arrest  of  circulation  in  fingers,  a 
variety  of  Raynaud's  disease.  Heart  15:  7,   1929. 

47.  Lewis,  T.  Pain  in  muscular  ischemia.  A. MA  Arch.  Inter- 
nal Med.  49:713,  1932. 

48.  Lewis,  T.  The  Blood  Vessels  of  the  Hitman  Skin  and  Their 
Responses.  London:  Shaw,  1927. 

49.  Lewis,  T.  Vascular  Disorders  of  the  Limbs  (2nd  ed.)  London  : 
Macmillan,  1949. 

50.  Lewis,  T.,  and  E.  Landis.  Observations  on  vascular 
mechanisms  in  acrocyanosis.  Heart   15:  229,   1930. 

51.  Lewis,  T.,  G.  Pickering,  and  P.  Rothchild.  Observa- 
tions upon  muscular  pain  in  intermittent  claudication. 
Heait  15:  359,   1 93 1. 

52.  Linton,  R.  Peripheral  vascular  diseases.  New  Engl.  J. 
Med.  260:  322,  1959. 


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53.  Livingston,  W.  K.  Pain  Mechanisms.  A  Physiological  Inter- 
pretation of  Causalgia  and  Its  Related  States.  New  York : 
Macmillan,  1943. 

54.  Mahorner,  H.,  and  A.  Ochsner.  A  new  test  for  evaluat- 
ing circulation  in  venous  system  of  lower  extremity 
affected  by  varicosities.  Aich.  Surg.  33:  479,   1936. 

55.  Marin,  H.,  and  M.  Stefanini.  Experimental  production 
of  phlebothrombosis.  Surg.  Gynecol.  Obstet.  110:  263, 
i960. 

56.  Martin,  W.,  H.  Laufman,  and  S.  Tuell.  Rationale  of 
therapy  in  acute  vascular  occlusions  based  upon  micro- 
metric  observations.  Ann.  Surg.    129:  476,   1949. 

57.  May,  E.,  and  P.  Hillemand.  Erythromelalgie;  etude  de 
la  pathologie   du  sympathique.   Ann.  med.,  Paris  16:  51, 

I924- 

58.  Mayfield,  F.  Causalgia.  Springfield,  111.:  Thomas,   1951. 

59.  Mayo,  W.,  and  A.  Adson.  Raynaud's  disease,  thrombo- 
angiitis obliterans  and  scleroderma :  Selection  of  cases  for 
and  results  of  sympathetic  ganglionectomy  and  trunk 
resection.  Ann.  Surg.  96:  771,   1932. 

60.  Mendlowitz,  M.  The  Digital  Circulation.  New  York: 
Grune  &  Stratton,  1954. 

61.  Mendlowitz,  M.,  and  N.  Naftchi.  The  digital  circula- 
tion in  Raynaud's  disease.  Am.  J.  Cardiol.  4:  580,  1959. 

62.  Menendez,  C,  and  R.  Linton.  Peripheral  vascular  dis- 
eases. New  Engl.  J.  Med.  251  :  382,  432,  1954. 

63.  Mitchell,  S.  Clinical  lecture  on  certain  painful  affections 
of  the  feet.  Philadelphia  Med.   Times  3:  81,   1872. 

64.  Mulvihill,  D.,  and  S.  Harvey.  Studies  on  collateral 
circulation.  I.  Thermic  changes  after  arterial  ligation  and 
ganglionectomy.   J.  Clin.  Invest.    10:  423,    1931. 

65.  Myers,  T.,  and  J.  Cooley.  Varicose  vein  surgery  in 
management   of  postphlebitic   limb.    Surg.    Gynec.    Obstet. 

99:733.  1954- 

66.  Naide,  M.,  and  A.  Sayen.  Venospasm:  Its  part  in  pro- 
ducing the  clinical  picture  of  Raynaud's  disease.  A.M. A. 
Arch.  Internal  Med.  77:  16,  1946. 

67.  Ochsner,  A.,  and  H.  Mahorner.  Varicose  Veins.  St.  Louis: 
Mosby,  1 939. 

68.  Ochsner,  A.,  and  M.  DeBakey.  Therapy  of  phlebo- 
thrombosis and  thrombophlebitis.  Arch.  Surg.  40 :  208, 
1940. 

69.  Ochsner,  A.,  and  M.  DeBakey.  Thrombophlebitis  and 
phlebothrombosis.    Southern   Surgeon   8:    269,    1939. 

70.  Peacock,  J.  Peripheral  venous  blood  concentrations  of 
epinephrine  and  norepinephrine  in  primary  Raynaud's 
disease.  Circulation  Research  7:  821,   1959. 

71.  Perkins,  J.,  M.  Li,  F.  Hoffman,  and  E.  Hoffman, 
Sudden  vasoconstriction  in  denervatcd  or  sympathec- 
tomized  paws  exposed  to  cold.  Am.  ./.  Physiol.  155:  165, 
1948. 

72.  Perthes,  G.  Ueber  die  operation  der  unterschenkel- 
varizen    nach    Trendelenberg.     Devi.    med.     Wochschr.     1 : 

253.  i895- 
73    Phillips,  J.,  and  G.  Burch.  Digital  biopsy  in  man:  An 

adjunct   to   the   study   of  peripheral   circulation.    Am.    J 

Med.   Sci.    235:   6,    1958. 

74.  Phillips,  J.,  and  G.  Burch.  Review  of  cardiovascular 
diseases  in  white  and  Negro  races.  Medicine  39:  241,  i960. 

75.  Phillips,  J.,  G.  Burch,  and  R.  Hibbs.  Applications  of 
digital    biopsy    to    peripheral    vascular    investigations    in 


man,   with  special   considerations   to   dermal   chromaffin 
cells.  Am.  J.  Med.  27:  320,   1959. 

76.  Pickering,  G.  Vascular  spasm.  Lancet  2:  845,   1951. 

77.  Pickering,  G.  On  clinical  recognition  of  structural  disease 
of  peripheral  vessels.  Brit.  Med.  J.  2:  1106,  1933. 

78.  Pickering,  G.,  and  E.  Wayne.  Observations  on  angina 
pectoris  and  intermittent  claudication  in  anaemia.  Clin. 
Sci.  1  :  305,  1934. 

79.  Pollack,  A.,  B  Taylor,  T.  Myers,  and  E.  Wood. 
Effect  of  exercise  and  body  position  on  venous  pressure 
at  ankle  in  patien's  having  venous  valvular  defects.  J.  Clin. 
Invest.  28:559,  1949. 

80.  Pratt,  G.  Cardiovascular  Surgery.  Philadelphia:  Lea  and 
Febiger,  1954. 

81.  Prinzmetal,  M.  Studies  on  mechanism  of  circulatory 
insufficiency  in  Raynaud's  disease  in  association  with 
sclerodactylia.  Arch.  Internal  Med.  58:  309,  1936. 

82.  Owens,  J.  Causalgia.  Am.  Surgeon  23:  636,  1957. 

83.  Rapport,  M.,  A.  Green,  and  I.  Page.  Serum  vasocon- 
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84.  Raynaud,  M.  De  lasphyxie  locale  el  de  la  gangrene  symitrique 
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85.  Rothman,  S.  Physiology  and  Biochemistry  of  the  Skin.  Chicago : 
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86.  Rous,  P.,  and  H.  Gilding.  Meaning  of  Bier's  spots. 
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88.  Scully,  R.,  and  C.  Hughes.  Pathology  of  ischemia  of 
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89.  Shumacker,  H.,  and  D.  Abramson.  Post-traumatic 
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90.  Shumacker,  H.,  I.  Spiecel,  and  F.  Upjohn.  Causalgia. 
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91.  Smith,  L.,  and  E.  Allen.  Erythermalgia  (erythro- 
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92.  Sodeman,  \V.,  and  G.  Burch.  Tissue  pressure:  An  objec- 
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93.  Starr,  I.,  Jr.  Change  in  reaction  of  skin  to  histamine. 
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94.  Stern,  E.  The  aetiology  and  pathology  of  acrocyanosis. 
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95.  Symposium  on  peripheral  vascular  diseases.  Am.  J. 
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12:903-  "955- 

98.  Travell,  J.,  S.  Baker,  B.  Hirsch,  and  S.  Rinzler. 
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PERIPHERAL   VASCULAR  DISEASES 


[249 


ioo.  Uvnas,  B.  Vasodilator  nerves.  Am.  Heart  J.  62:  277, 
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101.  Werner,  M.,  and  S.  Udenpriend.  Relationship  of 
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102.  Wessler,   S.,   S.    Sheps,   M.    Gilbert,   and   M.    Sheps. 


Studies   in    peripheral    arterial    occlusive    disease;    acute 
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104.  Winsor,  T.   Peripheral   Vascula)    Diseases.   Springfield,    111.: 
Thomas,  1959. 


CHAPTER     37 


Situations  which  lead  to  changes 
in  vascular  patterns 


AVE  RILL  A.   LIEBOW 


Department  of  Pathology,  Yale  University  School  of  Medicine, 
New  Haven,  Connecticut 


CHAPTER      CONTENTS 

Normally  Occurring  Arteriovenous  Communications 

Structure 

Distribution  and  Size 

Development  and  Fate 

Function 

Role  in  Bodily  Economy 
Abnormal  Arterial  Communications 

Traumatic   or   Surgically  Induced  Arteriovenous  Connections 
Collateral  Circulation 

Some  Aspects  of  Angiogenesis  in  General 

Types  of  Collaterals 

Forces  Affecting  the  Development  of  Collateral  Circulation 
Mechanical  factors 
Neural  factors 
Chemical  factors 

Rate  of  Development 

Regression  of  Collaterals 

Arterial  Versus  Venous  Collaterals 

Some  Effects  of  Collateral  Circulation 

Structure  of  Collateral  Vessels 
Measurement  of  Collateral  Circulation 
Some  Outstanding  Problems 


AFTER  WILLIAM  HARVEY  HAD  DISCOVERED  the  circu- 
lation of  the  blood,  there  remained  the  mystery  of  its 
transfer  from  arteries  to  veins.  A  solution  was  provided 
by  Marcello  Malpighi  in  1 66 1  when  he  first  saw  the 
capillaries  in  the  transparent  lung  of  the  frog  (146). 
It  took  another  half  century  before  direct  connections 
between  an  artery  and  vein  (the  spermatic),  in  this 
instance  probably  anomalous,  were  reported  by  Lealis 
Leali  (43).  Precapillary  arteriovenous  anastomoses 
are  now  known  to  exist  normally  in  many  organs  and 


tissues.  Masson  (117)  credits  Berres  (14)  with  their 
discovery  in  1832  in  erectile  tissue  where  they  were 
later  described  in  considerable  detail  by  Johannes 
Miiller  (123).  The  transparent  wing  of  the  bat  pro- 
vided an  opportunity  for  observing  the  vessels  in  the 
living  subject  and  here  Paget  (130)  saw  large  arterio- 
venous anastomoses.  Hyrtl  (88)  noted  that  when  these 
structures  were  open  there  was  pulsation  of  veins  and 
arterialization  of  the  blood  within  them.  Sucquet  (172) 
soon  found  precapillary  arteriovenous  connections  to 
be  widely  distributed  in  man,  but  his  results  were  dis- 
credited by  such  observers  as  Hover  (80)  and  Berliner- 
blau  (13)  for  the  reason  that  they  were  based  on 
injection  of  fluids  of  low  viscosity.  Arnold  (4,  7)  recog- 
nized the  "coccygeal  gland,"  which  had  been  dis- 
covered by  Luschka  in  1859,  to  be  analogous  to  the 
glomeruli  caudales  of  animals  and  to  represent  in 
reality  vascular  complexes  replete  with  arteriovenous 
anastomoses.  He  remarked  on  the  muscular  nature  of 
some  of  the  vessels.  The  first  detailed  histological 
description  of  the  specialized  transitional  segment  was 
by  Hover  (80)  and  this  was  elaborated  by  Grosser  (65) 
in  1902.  Max  Clara  (29,  30),  author  of  the  most 
extensive  monographs  on  these  structures,  considered 
Schumacher  (159)  to  be  the  discoverer  of  the  epi- 
thelioid cells.  The  relationship  of  arteriovenous  an- 
astomoses to  nerves  was  definitely  demonstrated  by 
Masson  (1 16-1 18),  and  was  subsequently  investigated 
by  Brown  (25),  and,  with  special  reference  to  tumors, 
by  Popoff  (134). 

Both  normal  and  abnormal  arteriovenous  shunts 
can  exert  physiological  effects,  but  these  have  been 
explored  only  in  part.  The  observations  of  Grant  (61) 


1 251 


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CIRCULATION    II 


on  the  intact  rabbit's  ear  have  been  supplemented  by 
a  whole  series  of  investigations  by  the  Clarks  (34,  36) 
who  used  a  chamber  technique.  Recently,  some  at- 
tention has  been  paid  to  a  possible  secretory  function 
of  these  structures. 

Arteriovenous  communications  can  be  classified  as: 

A.  "Normal"  arteriovenous  connections 

1.  Simple 

2.  Complex 

B.  -'Abnormal" 

1.  Congenital 

a.  Familial 

b.  Isolated 

2.  Progressive  acquired 

a.  Hemangiomatous 

b.  Within  neoplasms 

c.  Associated    with    disease,    e.g.,    cutaneous 
spiders 

C.  Traumatic 

D.  Surgically  induced 


NORMALLY  OCCURRING  ARTERIOVENOUS  CONNECTIONS 

Structure 

Connections  between  arteries  and  veins  can  range 
from  simple  bridges  only  slightly  larger  than  capil- 
laries (fig.  1)  to  complex  channels  with  specialized 
cells  in  their  walls  (figs.  2  and  3).  The  former  have 
been  well  described  as  components  of  the  microcircu- 
lation by  Zweifach  (200).  Both  extremes  can  be  en- 
countered, for  example  in  the  rabbit's  ear  (148). 
Spanner,  in  particular,  has  emphasized  the  existence 
of  transitional  forms  (165). 

The  more  complex  of  these  structures  can  be  de- 
rived from  a  larger  artery  at  a  bifurcation,  one  division 
of  which  may  be  distributed  to  capillaries  in  the  usual 
fashion.  The  other,  or  both,  can  become  remarkably 
contorted  and  characteristically  differentiated  before 
joining  a  vein.  In  the  intermediate  or  intercalated 
segment,  called  variously  the  Sucquet-Hoyer  or 
Hover-Grosser  canal,  the  wall  becomes  thickened  by 
the  presence  of  a  broad  layer  of  ''epithelioid"  cells 
which  abut  upon  or  partly  replace  the  endothelium 
and  appear  to  be  differentiated  from  smooth  muscle 
cells.  At  the  beginning  of  the  intercalated  segment  the 
epithelioid  and  muscle  cells  may  be  intermingled. 
When  fully  formed,  however,  the  former  approach  a 
spherical  shape  and  contain  few  or  no  myofibrils. 
Their  cytoplasm  is  hyaline,  or  somewhat  vacuolated, 
and  gives  no  reaction  for  glycogen,  fat,  or  mucin.  A 


fig.  i.  A  relatively  direct  arteriovenous  anastomosis  from  the 
human  ear.  Specimen  injected  with  Berlin  blue,  stained  with 
hematoxylin  and  cleared.  The  arrow  points  to  the  terminal 
portion  of  the  intercalated  segment.  There  is  a  slight  fusiform 
thickening  nearer  the  arterial  end  of  the  latter,  suggesting 
accumulation  of  muscle  or  epithelioid  cells.  [From  Prichard  & 
Daniel  (135).] 

circular  layer  of  muscle  fibers  may  or  may  not  be 
preserved  externally  to  the  epithelioid  cells.  The  elastic 
laminae  usually  disappear  in  the  intermediate  seg- 
ment. The  adventitia  is  a  delicate  collagenous  re- 
ticulum supporting  a  very  rich  plexus  of  both  medul- 
lated  and  nonmedullated  nerves.  The  latter  were  well 
described  by  Masson  (117,  118),  and  also  in  some  of 
their  finest  details  in  the  tongue  of  the  dog  by  Brown 
(25).  The  latter  noted  thin  unmyelinated  fibers  to 
terminate  in  the  media  and  thick  myelinated  fibers 
(afferents?)  with  termination  in  the  adventitia  (fig.  3). 
Groups  of  such  complicated  arteriovenous  anastomoses 
may  be  closely  associated  to  form  a  "glomus"  which 
may  be  enclosed  within  a  dense  connective  tissue 
capsule. 

Less  complex  arteriovenous  anastomoses  exist  in 
which  the  intercalated  segment  is  not  tortuous.  In 
some  there  is  simply  a  well-developed  inner  layer  of 
longitudinal  muscle  fibers  without  special  epithelioid 
characteristics. 


Distribution  and  Size 

The  distribution  of  arteriovenous  shunts  is  now 
known  to  be  almost  universal.  Aside  from  the  glomus 
coccygeum,  some  of  the  largest  and  most  complex 
glomera  in  man  have  been  described  in  the  skin  and 
subcutaneous  tissue  on  the  flexor  surfaces  of  the  fingers 
and  toes  and  in  the  nail  beds.  Their  numbers  have 


CHANGES    IN    VASCULAR    PATTERNS 


1253 


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■-~*lK  Vent 


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Venen 


Arterie 


fig.  2.  Graphic  reconstructions  of  arteriovenous  anastomoses;  relatively  simple  (left)  and  complex 
(rightj  communications.  The  accumulations  of  epithelioid  cells  are  indicated.  [From  Staubesand  & 
Genschovv  (168).] 


been  variously  stated.  For  example,  Grant  &  Bland 
(62)  found  593  per  cm2  in  the  nail  bed  of  the  toe,  and 
293  per  cm2  on  the  plantar  side,  but  Popoff  (134) 
counted  only  24  per  cm2  in  the  nail  bed,  and  18  on 
the  ventral  aspect  of  the  same  extremity.  The  latter 
considered  only  the  more  complicated  glomera.  Their 
size  also  varies:  Grosser  (65)  found  the  external  di- 
ameter to  be  between  55  and  85  y.  in  the  nail  bed, 
between  90  and  150  y,  in  the  finger  pad,  and  the 
internal  diameter  to  be  18  to  22  and  10  to  30  y,  re- 
spectively. In  the  wings  of  bats  the  intermediate  seg- 
ment had  an  external  diameter  of  from  go  to  280  y, 
and  an  internal  diameter  of  from  60  to  150  y.  The 
length  of  the  junctional  segment  as  measured  in  the 
tongue  of  the  dog  by  Prichard  &  Daniel  (136)  was 
between  100  and  500  y,  usually  between  200  and  300  y. 
Other  locations  where  arteriovenous  anastomoses 
have  received  detailed  study  include:  erectile  tissue, 
the  ears  in  man  (135);  the  nose,  including  skin, 
septum,  and  turbinates;  and  the  gastrointestinal  tract 
(8).  Their  existence  in  the  kidney  has  been  denied  by 


Trueta  (178),  and  by  Staubesand  &  Hammarsen 
(169),  although  Spanner  (165)  described  them  in  the 
region  of  the  sinus  renalis,  and  Simkin  et  al.  (162) 
found  that  spheres  as  large  as  90  to  440  y  would  pass 
from  renal  arteries  to  veins.  In  the  lung,  Weibel  (186) 
could  find  no  precapillary  connections  between  pul- 
monary arteries  and  veins,  but  Prinzmetal  et  al.  (137) 
found  that  glass  spherules  as  large  as  150  y  would 
pass  from  the  former  to  the  latter,  and  Parker  et  al. 
(131)  observed  that  spheres  of  75  to  80  y  would 
traverse  the  capillaries  but  those  of  300  y  would  not. 
Tobin  &  Zariquiey  (176)  and  Rahn  et  al.  (140)  have 
also  concluded  that  pulmonary  arteriovenous  com- 
munications must  exist  normally.  In  perfused  lobes 
Niden  &  Aviado  (126)  observed  glass  beads  as  large 
as  420  y  on  the  venous  side  in  a  perfusate  introduced 
intra-arterially.  Bostroem  &  Piiper  (23),  however, 
found  that  spheres  of  28  to  36  y.  would  pass  only 
exceptionally,  and  criticized  the  high  pressures  used 
by  Tobin  and  his  associates.  Gordon  et  al.  (60)  also 
concluded  from  their  own  work,  based  on  an  appli- 


'254 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  3.  An  arteriovenous  anastomosis 
from  the  tongue  of  the  dog.  The  richest 
nerve  supply  is  to  the  intercalated  seg- 
ment. The  filaments  end  in  all  levels  of 
the  wall,  in  which  large  rounded  epi- 
thelioid cells  predominate.  Portions  of  a 
thick  sensory  fiber  and  sensory  termi- 
nations are  seen  in  the  adventitia. 
[From  Brown  (25).] 


1 


cation  of  the  principles  of  surface  tension,  that  no 
connections  larger  than  25  /*  were  present  in  the  lungs, 
intestines,  or  kidneys  of  rats  and  rabbits,  in  contrast 
with  the  extremities  of  these  animals.  Fritts  and  co- 
workers (55)  stated  on  the  basis  of  recently  developed 
methods  utilizing  simultaneous  T-1824  and  radio- 
active krypton  injections  that  if  such  shunts  are 
functional  they  could  account  for  not  more  than  1  per 
cent  of  total  left  cardiac  output  in  normal  human 
subjects.  These  problems  have  been  judiciously  re- 
viewed by  de  Burgh  Daly  (41,  42)  with  special 
reference  to  possible  influences  of  the  nervous  system. 
Connections  between  bronchial  and  pulmonary 
arteries  are  mentioned  in  the  discussion  of  collateral 
circulation  in  this  chapter. 

Development  and  Fate 

Arteriovenous  shunts,  at  least  those  with  a  differ- 
entiated intercalated  segment  and  complex  "orga- 
noid" structure,  do  not  exist  in  embryos.  Popoff  (134) 
could  not  find  them  in  the  extremities  from  4.5 
months  of  intrauterine  life  to  term,  although  Clara 
(30)  stated  that  they  may  be  present  in  the  newborn. 
After  the  age  of  60  the  complex  cutaneous  arterio- 
venous shunts  tend  to  undergo  atrophy  and  sclerosis. 

Clark  &  Clark  (36)  observed  the  new  formation  of 
arteriovenous  anastomoses  in  transparent  chambers  of 
the  rabbit's  ear  where  the  tissue  was  induced  to  grow 
into  an  originally  vacant  space.  Here  the  anastomoses 
were  relatively  straight,  but  were  characterized  by  the 


addition  of  an  extraendothelial  layer  of  differentiated 
cells.  Stimuli  leading  to  increase  in  blood  flow  seemed 
to  increase  the  formation  of  these  structures.  Most  of 
these  shunts  were  temporary,  and  disappeared  early 
or  late,  but  some  were  permanent  and  had  the 
property  of  contractility.  This  seemed  to  be  associated 
with  the  development  of  nerves.  Newly  formed  arterio- 
venous shunts  were  also  found  within  2  weeks  after 
resecting  a  marginal  segment  of  the  rabbit's  ear  (148). 

Function 

With  the  disclosure  of  arteriovenous  anastomoses  in 
erectile  tissue  it  became  obvious  that  their  functional 
state  must  vary  from  time  to  time.  The  ability  of  these 
structures  to  close  was  established  in  the  living  trans- 
illuminated  rabbit's  ear  as  early  as  1930  by  Grant 
(61  ).  The  use  of  the  rabbit  ear  chambers  with  "pre- 
formed tissue"  provided  a  clearer  view  in  the  hands 
of  the  Chirks  (34),  and  they  were  able  to  make 
quantitative  observations  on  the  number,  size,  and 
rate  of  contraction  of  the  anastomoses  over  intervals 
of  many  months.  The  specialized  intercalated  seg- 
ments with  their  greater  thickness  and  complex  mural 
arrangements  and  rich  nerve  supplv  showed  a  faster 
and  more  complete  contraction  than  the  arteries,  and 
the  rhythm  was  independent  of  that  of  the  latter.  No 
explanation  was  apparent  for  the  extremely  variable 
responses  of  various  arteriovenous  anastomoses  (fig. 
4).  The  mechanism  of  closure  has  come  under  dis- 
cussion and  has  been  considered  to  be  contraction  ol 


CHANGES    IN    VASCILAR    PATTERNS 


1255 


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FIG.  4.  A  series  of  four  arteriovenous  communications  from 
the  rabbit's  ear.  The  curves  represent  the  rapid  and  uncoordin- 
ated rate  of  contraction  or  dilatation  of  each  of  these  structures. 
[From  Clark  &  Clark  (34)  as  modified  by  Clara  (29).] 

an  external  layer  of  circular  muscle  in  some  instances, 
the  accumulated  epithelioid  cells  simply  acting  as  a 
cushion  that  partly  restricts  the  lumen  even  when  the 
intercalated  segment  is  open.  In  the  absence  of  the 
circular  muscle  however  it  has  been  thought  that 
closure  is  the  result  of  swelling  of  the  epithelioid  cells, 
in  consequence  of  a  still  unknown  process.  Bcnning- 
hoff  (12)  was  the  first  to  suggest  this  idea,  and  Havlicek 
(71)  called  these  cells  "Quellzellen."  Since  these  are 
approximately  spherical,  shortening,  as  with  ordinary 
muscle  fibers,  is  not  possible.  This  mechanism  has 
been  extensively  considered  by  Mark  (112,  1 13). 

Even  direct  observations  have  their  limitations, 
since  the  functions  of  these  structures  may  be  multiple, 
and  are  not  necessarily  the  same  at  all  times,  nor  in 
all  vascular  beds  in  the  same  animal,  nor  in  different 
species.  There  is  now  good  evidence  that  they  can  re- 
spond both  to  neural  and  chemical  stimuli,  but  there 
are  numerous  contradictions  in  details  (119).  It  is  of 
interest  that  so  large  a  glomeroid  structure  as  the 
coccygeal  body  can  be  removed,  as  in  resection  of  the 
coccyx,  without  known  physiological  effects  (160). 

Local  mechanical  stimulation,  such  as  rubbing,  re- 
sults in  opening  of  the  intercalated  segments  (34,  61). 
The  effects  of  temperature  appear  to  be  determined 
in  degree  as  well  as  direction  by  quantitative  factors. 
Upon  warming  the  whole  animal  both  Grant  and  the 
Clarks  found  in  rabbits  a  widening  of  the  anastomoses. 
Moderate  cooling  was  accompanied  by  their  closure, 
and  this  was  observed  also  in  the  paw  of  the  dog  by 
Bostroem    &    Schoedel    (24).    Sonomoto    (163)    also 


found  that  the  arteries  and  a  majority  of  the  arterio- 
venous anastomoses  were  constricted  in  the  rabbit's 
ear  during  the  winter.  In  the  fingers  of  man,  however, 
the  anastomoses  were  closed  by  warming  to  an  ex- 
ternal temperature  of  33  to  37  C,  while  cooling  pro- 
duced the  opposite  result.  In  the  rabbit's  ear  Grant 
(61)  found  that  cooling  below  15  C  produced  an 
opening  of  the  anastomoses,  and  that  with  greater  or 
more  prolonged  reduction  in  temperature  the  arteries 
also  became  dilated,  whereupon  there  was  a  rapid 
flow  of  blood  through  the  anastomoses.  He  explained 
that  this  phenomenon  kept  the  extremities  from 
getting  too  cold.  In  human  skin  and  in  the  feet  of 
birds  Grant  &  Bland  (62)  further  established  this 
function  of  the  arteriovenous  shunts  by  temperature 
measurements. 

The  consequences  of  anoxia  were  examined  by 
Schroeder  et  al.  (158)  with  plethysmography  methods, 
under  the  assumptions  that  the  volume  of  an  ex- 
tremity kept  at  an  initial  pressure  of  35  mm  Hg  will 
reflect  changes  in  capillary  pressure,  and  that  of  an 
extremity  compressed  at  15  mm  Hg  will  reflect 
changes  in  venous  pressure.  They  found  that  when  the 
dog  was  breathing  an  atmosphere  containing  8  to  9 
per  cent  02,  the  capillaries  were  wide  without  alter- 
ation in  the  functional  state  of  the  arteriovenous 
anastomoses,  but  when  the  oxygen  concentration  was 
between  6  per  cent  and  8  per  cent  the  anastomoses  be- 
came narrow  without  change  in  capillaries.  In  an 
atmosphere  of  between  5  per  cent  and  6  per  cent  02, 
perfusion  was  slowed  in  consequence  of  constriction  of 
the  nutrient  bed  as  well  as  of  the  shunts. 

Stimulation  of  the  cervical  sympathetic  was  noted 
by  Grant  (61)  to  constrict  the  anastomoses  as  well  as 
the  small  arteries  in  the  rabbit's  ear.  The  denervation 
of  an  extremity  in  the  dog  resulted  in  dilatation  of  the 
shunts  (24).  Folkow  (54)  stated  that  the  cutaneous 
arteriovenous  anastomoses  become  maximally  dilated 
as  soon  as  their  constrictor  fibers  are  cut,  provided 
that  there  is  no  significant  increase  in  hormone  output 
of  the  adrenal  medulla.  Claude  Bernard's  classical 
observation  that,  when  the  peripheral  end  of  the 
chorda  tympani  is  stimulated,  the  rate  of  blood  flow 
from  the  submaxillary  vein  becomes  greater  and  the 
blood  becomes  bright  red,  has  been  interpreted  to 
indicate  the  shunting  of  blood  through  the  arterio- 
venous anastomoses  (71).  After  vagotomy  Curri  et  al. 
(40)  reported  that  the  arteriovenous  anastomoses  be- 
came widely  open  but  lost  reactivity  to  various 
stimuli. 

The  injection  studies  of  Vastarini-Cresi  (179)  had 
suggested  that,  in  general,  vasoconstrictor  substances 


1256 


HANDBOOK    OF    PHYSIOLOGY  -"  CIRCULATION    II 


decreased  and  vasodilators  increased  the  size  of  the 
arteriovenous  connections.  The  vasoconstrictor  effect 
of  adrenaline  was  evident  in  direct  observations  of 
living  vessels  in  rabbits'  ears  and  it  was  found  in  the 
same  preparations  that  histamine  and  acetylcholine 
dilated  these  shunts  (61).  This  has  been  confirmed. 
According  to  Curri  et  al.  (40)  serotonin  introduced 
intravenously  in  a  dose  of  8  mg  resulted  in  a  cessation 
of  rhythmic  activity  of  the  intercalated  segments. 

Role  in  Bodily  Economy 

Surely  one  function  of  the  arteriovenous  shunts  as  a 
component  of  the  microcirculation  is  concerned  with 
regulation  of  regional  blood  flow,  as  exemplified  in 
erectile  tissue.  In  general,  when  the  shunts  are  open 
the  capillary  bed  may  be  largely  or  entirely  bypassed, 
and  total  blood  flow  traversing  the  part  may  be 
maximally  increased.  This  phenomenon,  according  to 
Grant  (61,  62),  helps  to  maintain  the  temperature  of 
the  extremity  when  exposed  to  extreme  cold.  Also  it 
has  been  known  since  1840,  from  the  observation  of 
Julius  Robert  Mayer,  surgeon  to  the  threemaster 
"Java,"  that  venous  blood  tends  to  become  "arteri- 
alized"  in  the  tropics,  indicating  a  dilated  state  of  the 
arteriovenous  connections  (71).  Thus,  a  thermoregu- 
latory function  has  been  suggested  for  these  structures. 
Many  of  the  arteriovenous  anastomoses  are  however 
deeply  situated,  for  example,  in  the  periosteum  or 
even  within  parenchymatous  organs,  and  must  have 
other  than  thermoregulatory  functions.  A  third 
physiological  role  which  has  been  considered,  but 
which  has  not  been  truly  demonstrated  or  tested 
experimentally,  is  in  the  regulation  of  blood  pressure. 
It  seems  logical  that  if  sufficient  numbers  of  the  direct 
arteriovenous  anastomoses  are  widely  open,  systemic 
arterial  blood  pressure  might  fall. 

It  was  suggested  by  Schumacher  (160),  largely  on 
theoretical  grounds,  that  the  specialized  epithelioid 
cells  might  have  a  secretory  function — more  specifi- 
cally that  they  could  secrete  acetylcholine.  Luckner  & 
Staubesand  (no)  found  in  extracts  of  the  coccygeal 
body  a  substance  with  the  biological  properties  of 
acetylcholine  in  concentrations  of  9000  jug  per  g. 
Indeed  Schumacher  (160)  conceived  that  the  pulsa- 
tion of  the  arteriovenous  anastomoses  was  a  mecha- 
nism to  maintain  a  level  of  the  short-lived  acetyl- 
choline in  the  blood.  This  concept  is  of  interest  in  that 
the  epithelioid  cells  are  rather  widely  distributed  in 
small  groups  within  the  walls  of  arteries,  for  example 
at  the  vascular  pole  of  the  glomerulus,  where  they 


had  been  described  first  by  Ruyter  (149)  and  later  by 
Goormaghtigh  (59). 

Also  rather  theoretical  is  the  idea  that  the  connect- 
ing segments  may  be  pressoreceptors,  i.e.,  that  the 
metabolism  of  the  cells  could  be  altered  by  variations 
in  pressure,  and  that  this  effect  could  somehow  be 
transmitted  to  the  associated  extensive  neural  plexuses. 

Schumacher  (160)  thought  that  cells  of  the  non- 
chromaffin paraganglia  were  analogous  to  the  epi- 
thelioid cells  of  the  intercalated  segments,  but  there 
is  no  evidence  that  the  carotid  body  is  related  to 
arteriovenous  anastomoses,  although  some  of  these 
structures  exist  in  its  connective  tissue  capsule  (1). 

Clearly,  there  is  much  to  be  learned  in  the  domain 
of  function  of  the  arteriovenous  anastomoses.  Further 
study  doubtless  will  be  highly  rewarding. 


ABNORMAL    ARTERIOVENOUS    COMMUNICATIONS 

Arteriovenous  connections  of  unusual  size  or  loca- 
tion can  occur  as  single  or  multiple  lesions  and, 
especially  when  multiple,  can  be  familial  (Osler- 
Weber-Rendu  disease).  The  lesions  vary  from  insig- 
nificant blue  or  purple  spots  on  the  skin  or  mucous 
membranes  to  complex  cirsoid  masses  with  the 
arrangement  of  hemangiomas.  These  are  important 
chiefly  because  they  can  bleed,  as  for  example  into 
the  gastrointestinal  tract. 

In  the  lung,  the  pulmonary  arteries  and  veins  can 
come  into  free  anastomosis  with  a  right  to  left  shunt. 
When  of  sufficient  size,  there  are  the  expected  conse- 
quences of  desaturation  of  systemic  arterial  blood, 
cyanosis,  polycythemia,  clubbing,  and  at  times 
thrombotic  complications.  Cardiac  failure  does  not 
occur  unless  immense  numbers  of  the  arteriovenous 
fistulas  are  present  (66).  These  can  be  of  such  small 
size  as  to  be  undetectable  by  angiography. 

It  was  known  to  Virchow  that  acquired  hemangio- 
mas with  a  cavernous  component  also  are  the  seat  of 
arteriovenous  communications,  as  indicated  by  the 
bright  color  of  the  effluent  blood.  Fistulation  also  can 
occur  within  certain  neoplasms,  especially  when  they 
become  necrotic  or  hemorrhagic  as  in  the  case  of 
chorionepithelioma.  A  bruit  may  then  become  audi- 
ble  over   the   lesion. 

The  "cutaneous  arterial  spider"  has  been  recog- 
nized to  consist  in  part  of  arteriovenous  connections. 
The  arterial  component  has  in  its  walls  specialized 
"glomus  cells"  (epithelioid  cells),  like  other  arterio- 
venous shunts.  Such  structures  develop  commonly  in 


CHANGES    IN    VASCULAR    PATTERNS 


-01 


association  with  severe  chronic  liver  disease,  in  preg- 
nancy, in  persons  with  deficiency  of  the  vitamin  B 
complex,  in  the  carcinoid  syndrome,  and  also  in 
certain  apparently  healthy  individuals.  The  subject 
has  been  well  reviewed  by  Bean  (10). 


TRAUMATIC    OR    SURGICALLY    INDUCED 
ARTERIOVENOUS  CONNECTIONS 

The  establishment  of  a  connection  of  sufficient 
magnitude  between  an  artery  and  vein  may  have 
major  or  even  catastrophic  consequences.  These 
have  been  carefully  worked  out  by  experiment  (76, 

77>   79,    i53)- 

The  immediate  effects  upon  opening  the  fistula  are 
a  fall  in  blood  pressure,  an  increase  in  the  heart  rate 
and  venous  filling,  and  consequently  a  greater  cardiac 
output.  The  regional  veins  become  engorged.  A 
thrill  becomes  palpable  and  a  murmur  audible  over 
the  fistula,  and  these  can  be  abolished  by  exerting 
pressure  over  the  vein  proximal  to  the  fistula.  With  a 
sufficiently  large  shunt,  the  total  blood  volume  in- 
creases in  course  of  time,  and  the  blood  becomes  more 
dilute.  Although  initially  the  size  of  the  heart  and  of 
the  artery  on  both  sides  of  the  fistula  becomes  re- 
duced, there  is  gradually  a  dilatation  of  the  arteries 
and  veins  proximal  to  the  fistula.  The  heart  also 
becomes  enlarged,  chiefly  because  of  dilatation.  In 
late  stages,  the  proximal  artery  may  even  become 
aneurysmally  dilated  (144). 

Blood  flow  is  toward  the  fistula,  even  from  the 
distal  artery.  A  large  flow  depends  on  a  fistula  which 
exceeds  in  size  that  of  the  proximal  artery.  Lewis  (98) 
stated  that  the  blood  supply  to  the  distal  parts  of  the 
limb  is  at  first  diminished,  but  that  with  passage  of 
time  blood  flow  tends  to  become  restored  and  may 
even  exceed  that  to  the  normal  limb.  This  results 
from  the  development  of  an  extensive  collateral  circu- 
lation as  will  be  discussed  (fig.  5).  Evidence  for  in- 
crease in  the  flow  through  the  fistula  is  that  cardiac 
dilatation  and  decompensation  can  occur  late  after 
the  arteriovenous  fistula  is  established.  For  the  flow  to 
increase  progressively  the  distal  artery  must  be  dis- 
tensible. Excessive  scarring  can  interfere  with  this 
distensibility  (79).  Schenk  el  al.  (153)  made  quantita- 
tive observations  on  the  regional  blood  flow  in  all 
limbs  of  experimental  arteriovenous  fistulas  using  a 
square  wave  electromagnetic  flowmeter.  They  found 
that  in  the  femoral  fistulas  in  dogs,  flow  tended  to 
increase  and  at  the  end  of  approximately  1  year  had 


* 


fig.  5.  Traumatic  arteriovenous  fistula.  The  trauma  oc- 
curred accidentally  during  attempted  biopsy  of  lymph  nodes 
from  the  anterior  scalene  region  in  a  72-year-old  man.  Several 
weeks  later  the  patient  noted  pain  and  a  pulsatile  swelling  in 
the  region  of  the  wound  over  which  a  systolic  bruit  was  audible 
The  specimen  is  a  vinylite  cast  of  the  arteriovenous  fistula 
showing  numerous  tortuous  arterial  channels  related  to  the 
fistula. 


not  yet  reached  stability.  In  contrast  with  the  femoral 
fistulas,  flow  through  the  proximal  artery  of  carotid- 
jugular  fistulas  tended  to  diminish  with  passage  of 
time,  but  in  both  types  of  fistulas  there  was  a  marked 
increase  in  flow  through  both  the  arterial  and  venous 
distal   limbs. 


COLLATERAL    CIRCULATION 

Collateral  circulation  may  be  defined  as  blood  flow 
that  pursues  a  channel  or  system  of  vessels  which  is 
alternative  to  or  develops  in  substitution  for  a  major 
vascular  pathway.  To  understand  collateral  circula- 
tion would  require  not  only  a  complete  knowledge  of 
the  mechanisms  of  angiogenesis,  and  therefore  of  all 
growth,  but  also  of  the  anatomical  and  functional 
responses  of  blood  vessels  in  general.  At  the  present 
writing  only  limited  answers  can  be  supplied  to  such 
questions  as:  What  starts  the  growth  of  collateral 
vessels  and  what  controls  the  rate  of  their  increase; 
what  stops  them  from  expanding  indefinitely;  when 
newly  formed,  what  guides  them  to  their  proper 
place;  what  determines  the  structure  of  their  walls. 

Some  two  hundred  years  ago  the  great  John  Hunter 
was  amazed  to  find  that  not  only  did  the  growth  of 
the    stag's    antler    proceed    uninterrupted    when    its 


1  2  -,8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


major  nutrient  artery  was  ligated,  but  that  in  time 
there  was  a  prodigious  growth  of  new  vessels  (146). 
He  was  not  the  first  to  observe  this  providential 
activity  of  nature,  since  Antyllus,  a  pioneer  in  the 
surgical  treatment  of  aneurysms  fifteen  centuries 
before  him,  had  noted  that  interruption  of  the  artery 
to  a  limb  does  not  necessarily  result  in  its  loss  (97). 
Morgagni  also  had  anticipated  Hunter  in  observing 
collateral  vessels.  After  numerous  experiments  Hunter 
could  conclude  only  that  "vessels  go  where  they  are 
needed''  ( 124). 

In  attempting  in  this  chapter  a  precis  of  some 
major  advances  in  the  understanding  of  this  complex 
subject  a  sense  of  wonder  and  frustration  still  remains. 
Scholarly  reviews  have  been  published  by  Mulvihill 
&  Harvey  (124),  Quiring  (139),  Longland  (108), 
Learmonth  (96)  and  Rati  <!v  Schoop  (141)  among 
others.  Here  it  will  be  necessary  to  consider  chieflv 
what  is  known  of  general  principles,  and  little  con- 
sideration can  be  given  to  specific  collateral  beds.  To 
the  coronary  circulation  detailed  consideration  has 
been  given  by  Spalteholz  (164),  Gross  (64),  Gregg 
(63),  Schlesinger  (155),  and  very  recently  by  Blum- 
gart  (21 ),  Pepler  &  Meyer  (133)  and  Laurie  &  Woods 
(95).  The  pulmonary  collaterals  have  been  investi- 
gated by  Miller  (121)  Berry  &  Daly  (15),  Verloop 
(180,  181),  State  et  al.  (166,  167),  Parker  &  Smith 
(132),  Tobin  (175),  Tondurv  &  Weibel  (177)  and 
by  Liebow  et  al.  (101,  103)  among  others.  A  recent 
study  of  hepatic  collateral  circulation  has  been  pub- 
lished by  Hales  et  al.  (68). 

Some  Aspects  of  Angiogenesis  in  General 

A  brief  review  of  the  painstaking  observations  upon 
angiogenesis  by  such  devoted  students  as  Golubew 
(58),  Thoma  (174),  Evans  (48,  49),  Sabin  (150), 
Hughes  (81,  82),  and  the  Clarks  (31-37)  might  well 
serve  as  a  guide  to  approaching  the  problems  of  the 
developing    collateral    circulation. 

In  embryos  there  is  an  initial  phase  of  primary 
differentiation  of  vessels  from  connective  tissue  cells, 
and  a  later  stage  of  extension  and  elaboration.  The 
latter  occurs  from  endothelium  of  vessels  already 
formed  by  a  process  of  "sprouting,"  and  comes  largely 
if  not  entirely  to  replace  the  former.  Certainly  most  of 
the  vascularization  of  the  developing  organs  of  the 
embryo,  such  as  the  limb  buds  of  birds,  occurs  by 
ingrowth  of  sprouts  and  not  by  formation  de  novo  of 
vessels  within  the  tissue  (48,  49,  150).  As  early  as 
1869  Golubew  (58)  observed  in  the  transparent  tail 


of  the  living  tadpole  that  the  capillary  sprouts  were 
at  first  solid  but  then  developed  a  lumen  by  a  process 
of  "hollowing  out"  beginning  proximally  as  vacuola- 
tion.  The  development  of  new  capillaries  by  sprouting 
was  further  studied  soon  thereafter  by  Arnold  (5,  6). 
E.  R.  Clark  (31)  in  the  same  subject  noted  atrophy  of 
certain  newly  formed  capillaries.  Aeby's  (2)  concept 
that  the  anlage  of  the  entire  vascular  system  was 
represented  by  capillaries  in  retiform  arrangement 
received  strong  support  from  the  study  of  injected 
and  serially  sectioned  embryos  by  Evans  (48). 

It  has  been  established  that  vessels  destined  to 
become  major  conduits  for  blood  in  the  adult  can 
differentiate  to  a  limited  but  recognizable  degree 
even  in  the  absence  of  circulating  blood.  This  was 
known  to  such  early  embryologists  as  Baer  and  His, 
and  was  studied  in  greater  detail  by  Sabin  (150). 
Experimental  support  was  provided  by  Loeb  (107), 
who  stopped  the  heartbeat  in  fundulus  larvae  chemi- 
cally, and  later  by  Chapman  (28)  when  he  removed 
the  heart  in  chick  embryos.  The  aorta  and  certain 
other  main  arteries  and  veins  nevertheless  become 
recognizable.  Presumably,  this  limited  self-differentia- 
tion of  the  vascular  system  is  determined  by  hereditary 
factors. 

Thoma  (174),  long  a  student  of  responses  of  the 
vascular  system,  understood  these  influences,  but  to 
him  is  due  the  credit  of  recognizing  the  molding  force 
of  the  circulating  blood.  He  observed,  during  the 
first  3  days  of  development  of  the  area  vasculosa  of 
the  chick,  that  certain  pathways  of  most  rapid  blood 
flow  increased  in  caliber  and  length  and  thereby  ac- 
quired the  characteristics  of  magistral  vessels,  while 
others  underwent  diminution  and  atrophy.  He  codi- 
fied the  principles  of  what  he  termed  histodynamics: 
a)  The  growth  of  the  lumen  of  a  vessel,  that  is  the 
increase  in  surface  of  the  wall,  depends  upon  the 
rate  of  blood  flow,  b)  The  growth  in  thickness  is 
dependent  upon  the  tension  in  the  wall,  which  in  turn 
is  related  to  the  diameter  of  the  vessel  and  to  the  blood 
pressure,  c)  It  is  an  increase  in  blood  pressure  above  a 
certain  level,  which  limit  is  defined  by  the  metabolism 
of  the  particular  tissue,  that  determines  the  new 
formation  of  capillaries.  The  formulation  of  the 
principles,  although  they  have  not  been  universally 
accepted  in  toto,  has  stimulated  much  thought.  The 
factor  causing  enlargement  of  an  artery  was,  for 
example,  thought  by  Clark  (31)  to  be  the  amount  of 
blood  flow  rather  than  the  rate  as  suggested  by 
Thoma  (174).  Clark  proposed  the  hypothesis  that 
when  the  chemical  interchange  through  the  wall  of 


CHANGES    IN    VASCULAR    PATTERNS 


1259 


a  capillars  exceeds  a  certain  level,  a  sprout  is  sent  out. 
If  on  the  contrary  there  is  a  diminution  below  a 
critical  point,  there  results  a  decrease  in  the  caliber. 

Hughes  (82)  in  1937  for  the  first  time  supplied 
measurements  of  the  actual  rate  of  blood  flow  and 
was  able  to  substantiate  Thoma's  first  principle,  when 
he  found  a  relationship  between  the  diameter  of  an 
artery  and  the  rate  of  blood  flow  in  the  area  vasculosa 
of  the  chick.  He  had  found  that  the  first  differentia- 
tion of  the  vitelline  artery  was  mainly  effected  by  the 
disappearance  of  connections  with  smaller  vessels  to 
either  side  (81).  As  the  vessel  increased  in  diameter 
the  endothelial  cells,  and  their  nuclei,  became 
elongated  at  right  angles  to  the  axis  of  the  vessel. 
Mitosis  then  occurred.  By  counting  and  measurement 
Hughes  (82)  was  later  able  to  establish  that  increase 
in  cells  is  proportionate  to  increase  in  area.  He  ad- 
mitted however  that  some  of  these  cells  might  repre- 
sent incorporated  mesenchymal  elements,  rather 
than  the  products  of  division  of  earlier  endothelial 
cells,  especially  in  veins. 

The  development  of  the  transparent  chamber 
method  made  it  possible  to  explore  under  direct 
vision  to  what  extent  angiogencsis  in  the  adult  would 
recapitulate  ontogeny.  Ziegler  (196)  first  introduced 
glass  chambers  for  studying  the  genesis  of  tubercles, 
but  these  were  buried  in  muscle  or  subcutaneous 
tissue.  Sandison  (152),  at  the  suggestion  of  E.  R. 
Clark,  made  transillumination  possible  by  bringing 
the  chamber  to  the  surface.  This  enabled  an  intimate 
and  continuous  observation  of  vessels  in  process  of 
formation  in  adult  animals.  Sprout  formation, 
fusion  of  adjacent  sprouts,  the  development  of  lumina 
in  newly  formed  capillaries,  atrophy  of  some  capil- 
laries, and  the  differentiation  of  others  into  arterial 
and  venous  vessels,  were  all  observed  in  transparent 
chambers  in  the  ears  of  rabbits  by  Sandison  (152) 
and  the  Clarks  (33,  35),  and  in  similar  chambers  in 
dogs  (122).  For  a  further  discussion  of  the  transparent 
chamber  technique  see  Chapter  27. 

Williams  (190),  in  autografts  of  subcutaneous  tissue 
to  previously  vascularized  rabbit  ear  chambers, 
found  that  new  vessels  can  be  formed  by  lateral  saccu- 
lation or  "herniation"  of  the  endothelial  wall  as  well 
as  by  canalization  of  sprouts.  Such  adjacent  branches 
can  fuse  to  give  rise  to  new  connecting  channels.  He 
recorded  also  the  development  of  arteriovenous 
anastomoses.  In  previous  work  with  omental  auto- 
grafts he  observed  the  formation  of  connections 
between  host  and  graft  vessels,  in  some  instances 
within  48  hours  (191).  It  was  astonishing  to  note  the 


reconstitution  of  some  of  the  original  vessels  within 
separate  fragments  of  the  grafts,  and  that  this  could 
take  place  before  blood  flow  began.  He  considered 
that  the  principal  stimulus  to  endothelial  prolifera- 
tion was  probably  hypoxia  of  a  certain  degree  and 
duration  (190).  Under  conditions  where  hypoxia 
was  unquestionably  present  and  maintained  for  more 
than  3  days,  vascular  proliferation  was  extreme.  When 
free  blood  flow  was  established  rapidly,  however, 
plexus  formation  was  inhibited.  In  similar  chambers 
within  dorsal  skin  flaps  of  mice  Merwin  &  Algire  (1 20) 
found  that  the  original  vascular  channels  in  grafts  of 
thyroid  tissue  survived  and  were  the  active  structures 
in  establishing  connections  with  host  vessels.  Grafts 
of  tumor  tissue,  however,  were  quickly  provided 
with  a  rich  vascular  network  derived  from  the  host. 
Solid  sprouts  of  the  host  vessels  can  grow  against  the 
"grain"  of  connective  tissue,  while  ordinary  vessels  of 
the  graft  are  oriented  parallel  to  the  cells  and  fibers 
of  the  connective   tissue. 

The  Clarks  (32)  found  in  rabbit  ear  chambers  that 
arteries  can  be  developed  without  acquiring  a  nerve 
supply,  and  that  these  do  not  contract  spontaneously 
but  react  passively.  They  can,  however,  respond  to 
chemical  stimuli. 

Types  of  Collaterals 

Collateral  vessels  may  be  preformed,  or  newly 
formed,  but  it  may  be  difficult  to  distinguish  the  two. 
Weyrauch  &  De  Garis  (189),  after  ligature  of  suffi- 
cient original  arteries  and  veins  in  the  mesentery, 
considered  some  vessels  newly  formed  on  the  basis  of 
vastly  increased  numbers  and  unusual  position.  It 
may  be  questioned,  however,  whether  such  vessels 
were  not  developed  from  smaller  arterial  or  venous 
channels.  Under  some  circumstances,  as  for  example 
in  vascular  channels  traversing  a  former  serous  cavity, 
there  can  be  no  doubt  of  their  new  formation. 

In  discussing  pre-existing  collaterals  a  convenient 
terminology  has  been  devised  by  Longland  (108) 
according  to  their  ultimate  function.  The  plexus  of 
connected  arteries  that  may  span  an  obstructed  por- 
tion of  a  major  artery  he  has  called  the  "midzone," 
the  main  artery  proximal  to  the  midzone,  the  "stem," 
and  the  distal,  he  has  termed  the  "re-entrant"  (fig. 
6).  His  measurements  showed  that  in  the  extremities  of 
the  rabbit,  at  least  during  the  first  16  weeks,  the  ves- 
sels in  the  midzones  grow  relatively  more  than  the 
stem  or  re-entrant  vessels  (fig.  7). 

Learmonth   (96)   has  described   two   types  of   col- 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


VEIN 
CAPILLARIES 

ARTERIAL   BRANCHES 


■  MAIN    ARTERY 


VEIN 
CAPILLARIES 

COLLATERAL  ARTERY 


—  MAIN   ARTERY 

fig.  6.  Longland's  (108)  concept  of  the  stem  and  re-entrant 
vessels  and  midzone  in  a  collateral  circulation  after  occlusion 
of  an  artery. 

lateral  circulations:  In  the  first  type,  after  a  short 
course  in  alternative  channels,  the  arterial  blood  is 
returned  into  the  main  artery  or  arteries  of  the  part. 
In  the  second  type  blood  reaches  the  part  beyond  an 
obstruction  via  terminal  branches  only;  here  the 
pressure  is  low  and  quantity  probably  reduced.  In 
duodenal  transplants,  North  et  al.  ( 1 28)  found  that  in 
some  instances  only  numerous  fine  extramesenteric 
vascular  connections  had  formed,  while  in  others  the 
connecting  channels  were  quite  large. 

Forces  Affecting  the  Development  of  Collateral  Circulation 

In  the  general  consideration  of  angiogenesis  there 
emerged  at  least  three  significant  types  of  influences: 
hereditary,  mechanical,  and  chemical;  moreover,  the 
responses  of  vessels  once  formed  are  governed  also  by 
the  action  of  nerves.  These  same  forces  affect  col- 
lateral vessels.  Their  immediate  responses  must  be 
considered  separately  from  late  responses. 

mechanical  factors.  The  fall  in  pressure  peripheral 
to  the  interruption  of  a  major  artery  may  have 
mechanical  or  chemical  effects  that  could  stimulate 
the  development  of  collateral  circulation.  The  idea 
of  a  chemical  mechanism,  especially  anoxic,  was 
strongly  championed  by  Sir  Thomas  Lewis  (98). 
The    one    does    not    necessarily    exclude    the    other. 


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4  8  12 

WEEKS  AFTER  ARTERIAL  BLOCK 
fig.  7.  Mean  growth  rates  of  stems  and  midzones  {%  increase 
per  month  of  initial  diameter  [=  100%]).  The  relatively  greater 
growth  of  the  midzone  as  compared  with  the  stem  vessels  in  a 
collateral  system  as  established  from  measurement  of  angio- 
grams. Data  from  7  rabbits.  [From  Longland  (108).] 

Manv  attempts  have  been  made  to  assess  the  relative 
impact  of  the  two. 

Winblad  and  associates  (192)  measured  both  pres- 
sure and  pOa  in  an  extremity  of  the  dog  in  which  the 
superficial  femoral  artery  was  acutely  occluded. 
There  was  a  quick  drop  in  pressure  to  between  35 
and  60  mm  Hg.  After  4  min  the  pressure  level  re- 
mained constant,  with  the  systolic  pressure  exceeding 
the  diastolic  before  occlusion  (fig.  8).  Widening  of  the 
collateral  vessels  was  demonstrated  angiographically. 
The  pOo  of  the  tissue  fell  only  very  slightly,  and  rose 
again  to  control  values  within  5  to  8  min.  The  rate 
of  recovers'  was  not  affected,  whether  the  artery 
distal  to  occlusion  was  perfused  with  highly  oxy- 
genated or  venous  blood  by  means  of  an  artificial 
pumping  system.  Similar  experiments  were  per- 
formed by  John  &  Warren  (90)  with  like  conclusions. 
The  rapid  appearance  of  the  collateral  vessels  was 
also  demonstrated  angiographically,  as  was  their 
quick  regression  when  continuity  of  the  main  artery 
was  restored.  These  observations  suggest  the  relative 
importance  of  mechanical  factors.  Volpel  (184) 
found  that  with  repeated  interruption  of  the  femoral 
artery  the  blood  pressure  in  the  distal  segment  would 
rise  more  rapidly.  By  creating  a  shunt  between  the 
left  femoral  artery  and  right  femoral  vein,  and  inter- 
rupting the  left  femoral  artery  below  the  arteriovenous 
connections,  collaterals  did  not  des'elop;  but  if  the 
shunt  were  interrupted  they  quickly  reappeared. 
However,  in  the  distribution  of  the  right  femoral 
artery  the  collaterals  became  visible  upon  its  occlu- 
sion as  in  the  absence  of  a  shunt.  Further,  if  the  distal 


CHANGES    IN    VASCULAR    PATTERNS 


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fig.  8.  Pressure  and  oxygen  tension  in  the  lower  extremity  of 
a  dog  immediately  after  occlusion  of  the  superficial  femoral 
artery.  The  pressure  in  the  anterior  tibial  artery  falls,  but 
within  3-4  min  rises  to  a  plateau  below  the  initial  level  which  is 
thereafter  maintained.  The  tissue  pOo  drops  only  slightly  and 
temporarily.  [From  Winblad  el  al.  (192).] 

portion  of  a  right  femoral  artery  were  connected  by 
catheter  to  the  left  femoral  artery,  so  placed  that  the 
catheter  lay  in  the  region  of  re-entry  of  collaterals  and 
obstructed  these,  the  collateral  vessels  nevertheless 
expanded.  Schoop  &  Jahn  (157)  stress  that,  for  the 
later  development  of  collaterals,  flow  is  rather  more 
important    than    differential    pressure. 

The  appearance  of  alternative  arterial  channels  to 
peripheral  capillary  beds  is  well  exemplified  in 
coarctation  of  the  aorta,  where  collateral  circulation 
was  studied  centuries  ago. 

Valuable  insights  into  the  mechanisms  governing 
the  development  of  collateral  circulation  have  come 
from  the  thorough  and  long-continued  observations 
of  peripheral  arteriovenous  fistulas,  both  clinical  and 
experimental,  by  many  observers.  As  early  as  1 756 
and  again  in  1761  William  Hunter  published  on  this 
subject  and  noted  the  appearance  of  a  collateral  circu- 
lation in  relation  to  the  fistulas  (84,  85).  Mont  Reid 
(144)  and  Emile  Holman  (77,  79),  in  particular,  con- 
tributed important  information.  Holman's  major 
point  is  that  as  soon  as  these  fistulas  open,  there  is  a 
fall  of  pressure  in  the  arterial  segment  distal  to  the 
fistula,  as  indicated  by  the  cephalad  flow  of  blood 
within  it.  The  peripheral  resistance  to  onflow  of  blood 
in  smaller  arteries  circumventing  the  fistula  is  there- 
fore reduced,  whereupon  these  vessels  begin  to  carry 
more  blood.  If  the  artery  distal  to  the  fistula  is  ligated 
or  even  if  its  lumen  is  reduced  to  one-half  by  means  of 
a  constricting  aluminum  band,  the  collateral  circula- 
tion is  relatively  meager.  The  most  telling  experiment 


against  the  idea  of  "'tissue  need,"  as  a  determinant  of 
the  expansion  of  the  collateral  arteries,  is  that  ampu- 
tation of  the  extremity  does  not  reduce  the  extent  of 
the  collateral  circulation  associated  with  an  arterio- 
venous fistula.  It  appears  that  the  effect  of  the  fistula 
in  stimulating  a  collateral  circulation  is  greater  than 
simple  ligature  of  the  artery  to  a  limb. 

Deterling  el  al.  (44),  however,  cautioned  that  the 
abundant  collateral  circulation  related  to  an  arterio- 
venous fistula  may  be  to  a  great  extent  spurious,  being 
rather  an  enormously  dilated  plexus  of  veins  that 
does  not  function  as  collateral  circulation  after 
obliteration  of  the  fistula.  If  the  arteriovenous  fistula 
is  excised,  the  collateral,  according  to  these  observers, 
is  usually  no  greater  than  that  of  controls  after  simple 
ligature  of  the  artery.  They  also  observed  that  sym- 
pathectomy tends  to  insure  a  greater  collateral. 

A  closer  definition  of  conditions  at  an  arteriovenous 
fistula  has  been  given  by  Holman  &  Taylor  (79).  The 
development  of  a  large  collateral  circulation  was 
stated  to  depend  on  the  existence  of  a  fistula  larger 
than  the  proximal  artery  and  also  on  the  presence  of  a 
widely  patent  artery  distal  to  the  fistula.  Flow  through 
the  fistula  can  increase  progressively,  provided  that 
the  proximal  artery  and  vein  remain  distensible.  Sir 
Thomas  Lewis  (98)  presented  evidence,  based  on 
calorimetry,  that  the  blood  flow  to  a  leg  that  had  been 
the  seat  of  an  arteriovenous  fistula  for  18  years  was 
actually  greater  than  that  of  the  normal  side. 

Because  of  its  double  blood  supply,  the  lung  offers 
a  useful  stage  upon  which  various  factors  controlling 
collateral  circulation  can  be  analyzed.  Expansion  of 
this  circulation  can  occur  under  various  circum- 
stances of  disease.  Moreover,  it  can  easily  be  induced 
experimentally  and  measured  with  considerable 
accuracy,  at  various  stages,  by  application  of  broncho- 
spirometry  and  blood  gas  analysis,  or  by  use  of  dye 
distribution  techniques.  Finally,  it  is  possible  to  dis- 
tinguish with  confidence  certain  collaterals  as  newly 
formed  rather  than   preformed. 

The  relative  pressures  and  flows  in  the  pulmonary 
and  bronchial  arteries  have  been  measured  and  an 
increase  in  aortic  pressure  has  been  found  to  augment 
inflow  from  the  latter  (15,  26,  151). 

When  the  main  pulmonary  artery  to  one  lung  is 
ligated  in  the  dog,  expansion  of  the  collateral  circula- 
tion continues  for  at  least  18  months  (20).  The  mecha- 
nism is  only  partly  understood,  but  its  major  features 
appear  to  be  as  follows: 

Under  ordinary  circumstances  in  the  normal  lung 
the    bronchial   and    pulmonary    arterial   circulations 


I  262 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


meet  predominantly,  if  not  exclusively,  .is  capillaries 
in  the  region  of  the  alveolar  ducts  (121).  The  distal 
ramifications  of  the  pulmonary  artery  supply  the 
alveoli;  the  bronchial  arterial  distribution  is  to  the 
substance  of  the  bronchi,  vessels,  and  interstitial  tis- 
sue. There  are  at  least  two  forces  that  tend  to  prevent 
the  onflow  of  blood  within  the  terminal  bronchial 
arterial  radicals  to  the  alveoli.  The  first  of  these  is  the 
frictional  resistance  offered  by  the  narrow  vessels; 
the  second  is  the  counterpressure  transmitted  from  the 
terminal  branches  of  the  pulmonary  artery.  With 
interruption  of  the  major  pulmonary  artery  the 
second  of  these  forces  is  abrogated,  whereupon  further 
onflow  of  blood  takes  place  in  the  bronchial  vessels. 
As  the  flow  increases  in  these  vessels  they  become 
larger,  by  mechanisms  still  largely  mysterious. 
Thus  there  is  increasing  access  to  the  low  resistance 
capillary  bed  of  the  lung.  The  course  of  the  blood  flow 
is  from  the  aorta  through  the  bronchial  arteries  to  the 
pulmonary  capillaries,  pulmonary  veins,  and  left 
atrium.  This  represents  a  left-to-left  recirculation  of 
blood.  The  flow  increases  from  an  initial  value  of  less 
than  25  ml  per  m-  per  min  to  volumes  in  excess  of 
1  liter  per  m2  per  min  in  a  period  of  approximately 
18  months.  In  many  respects  this  shunt  is  analogous 
to  an  arteriovenous  fistula  between  the  aorta  and  left 
atrium  (109).  As  in  the  case  of  peripheral  arterio- 
venous fistula,  increase  in  flow  is  continuous  for  very 
long  periods.  Furthermore,  the  flow  is  many  times 
in  excess  of  the  "need"  of  the  tissue,  evidence  that  it  is 
induced  primarily  by  the  mechanical  effect  of  the 
low  peripheral  resistance  introduced  into  the  systemic 
arterial  circuit.  Collateral  flows  of  considerable 
magnitude  have  also  been  found  in  the  lungs  of 
patients  in  whom  pulmonary  arteries  had  been 
ligated  because  of  operative  misadventure  (52,  56). 

Great  anatomical  enlargement  of  the  bronchial 
arteries  occurs  in  such  congenital  lesions  of  the  heart 
and  great  vessels  as  result  in  a  low  pulmonary  arterial 
pressure,  i.e.,  tricuspid  or  pulmonic  atresia,  or  stenosis 
and  tetralogy  of  Fallot.  The  collateral  circulation 
tends  to  be  greatest  where  there  is  a  right  to  left 
shunt  with  polycythemia  and  a  consequently  greater 
tendency  to  further  obstruction  of  pulmonary  ar- 
teries by  thrombosis.  Ring  and  his  co-workers  (19) 
were  pioneers  in  attempting  measurements  of  the 
collateral  blood  flow  in  these  conditions,  although 
their  methods  were  subject  to  certain  errors.  In  a 
series  of  38  patients  with  tetralogy  they  found  col- 
lateral flows  to  exceed  500  ml  per  m'-  per  min  in 
26  patients,  1  liter  per  m-  per  min  in  16,  and  1.5  liter 
per  m-  per  min  in  8. 


The  problem  of  the  genesis  of  the  collateral  circu- 
lation is  perhaps  simpler  on  the  venous  side.  The 
major  pulmonary  veins  and  the  true  bronchial  veins 
that  drain  into  the  azygos  venous  system  and  right 
side  of  the  heart  are  always  connected  by  short  pre- 
capillary stems  (199).  With  occlusion  of  a  major  pul- 
monary vein  near  the  hilum  the  pressure  within  it 
increases,  and  with  this  the  vis  a  tergo  forcing  blood 
into  the  connected  bronchial  venous  stems  becomes 
greater.  Consequently,  blood  flow  in  the  stems  in- 
creases and  again  they  become  remarkably  enlarged 
(86,  87).  Here  flow  becomes  greater  not  because 
peripheral  resistance  is  reduced  but  because  pressure 
at  the  source  is  increased.  The  moment  of  force  again 
is  mechanical,  however.  Numerous  analogues  exist  in 
the  systemic  venous  circulation. 

neural  factors.  There  is  evidence  that  the  nervous 
system  can  exert  a  control  both  on  the  immediate  and 
even  late  development  of  collateral  circulation.  At 
least  in  part  this  is  related  to  its  influence  on  the 
musculature    of  vessels. 

As  early  as  1876  Latschenberger  &  Deahna  (94) 
observed  that  sectioning  of  the  major  nerves  of  the 
thigh  in  experimental  animals  prevented  collapse  of 
the  segment  of  femoral  artery  distal  to  the  point  of 
clamping  beneath  Poupart's  ligament;  thus  the  blood 
pressure  did  not  drop  when  the  artery  was  opened,  as 
it  usually  did  in  the  presence  of  intact  nerves.  Stefani 
( 1  70)  found  that  denervation  of  an  extremity  in  the 
salamander  was  associated  with  gangrene  upon  liga- 
ture of  the  axillary  artery,  while  neither  the  ligature 
itself  nor  denervation  alone  produced  this  untoward 
result.  Nothnagel  (129),  however,  observed  that  a 
much  greater  collateral  circulation  developed  in  a 
period  of  8  weeks  in  an  extremity  of  the  rabbit  after 
ligation  of  the  femoral  artery  when  the  sciatic  and 
crural  nerves  had  also  been  transected  than  when  the 
nerves  were  intact.  He  also  noted  that  the  more 
expanded  vessels  were  structurally  altered  in  that 
they  contained  more  muscle  (fig.  9). 

That  it  was  the  influence  of  the  sympathetic 
nervous  system  specifically  that  accounted  for  this 
observation  was  suggested  by  Ferris  &  Harvey  (50), 
who  recorded  a  sudden  rise  in  the  temperature  of  the 
dog's  extremity  some  4  hours  after  ligature  of  the 
femoral  artery.  That  this  was  the  result  of  a  reflex 
vasodilatation  was  previously  inferred  from  Halsted's 
(69)  observation  of  a  remarkable  increase  in  the  tem- 
perature of  the  upper  extremity  of  a  man  following  a 
resection  of  a  large  subclavian  aneurysm  and  ligature 
of  the  left  subclavian  and  axillarv  arteries.   Halsted 


CHANGES    IN    VASCULAR    PATTERNS 


1263 


V  .!+**lS         *J»    ftW  * 


■«  --.^CPi^ 


fig.  9.  Effect  of  denervation 
upon  collateral  circulation.  In 
the  upper  half  of  the  drawing  is 
shown  the  collateral  circulation 
22  days  after  interruption  of  the 
left  femoral  artery  in  a  rabbit. 
In  the  lower  half  the  more  exten- 
sive collateral  circulation  in  a 
comparable  preparation  but  with 
the  crural  and  sciatic  nerves  cut 
at  the  time  of  the  arterial  ligature. 
At  the  right  above  is  shown  a 
section  of  the  profunda  femoris 
on  the  control  side,  and,  below, 
a  comparable  section  after  func- 
tion for  8  weeks  as  a  collateral 
vessel  following  ligature  of  the 
femoral  artery.  There  is  hyper- 
plasia as  well  as  hypertrophy  of 
the  muscle.  [From  Nothnagel 
(i29>] 


had  become  intrigued  by  Leriche's  studies  of  the 
periarterial  sympathetic  nerves.  Mulvihill  &  Harvey 
(125)  found  that  with  sympathectomy  the  temperature 
of  an  extremity  did  not  fall  after  ligature  of  the 
external  iliac  artery  (fig.  10).  Theis  (173)  and  later 
Longland  (108)  confirmed  this  observation  by  various 
methods.  Both  indicated  the  persistence  of  the  effect 
over  several  months.  Injection  with  alcohol  of  the 
main  artery  beyond  a  ligature  in  the  anterior  ex- 
tremity of  the  dog,  a  procedure  that  was  presumed 
to  produce  a  destruction  of  the  sympathetic  nerves 
within  it,  seemed  to  result  in  a  better  development 
of  collateral  circulation  than  in  the  leg  of  the  control 
side  (91,  92). 

Turning  to  the  "microcirculation,"  Fulton  et  al. 
(57)  provide  a  description  of  several  orders  of  nerve 
plexuses  related  to  the  small  vessels  in  the  cheek 
pouch  of  the  hamster.  The  networks  are  sufficiently 
rich  to  innervate  all  the  smooth  muscle  cells  of  the 
vessels.  The  development  of  a  complement  of  non- 
medullated  nerve  fibers  in  newly  formed  arterioles 
in  chamber  preparation  of  the  rabbit's  ear  has  been 
demonstrated  by  the  Clarks  (37).  They  have  estab- 
lished that  only  vessels  supplied  with  such  fibers  are 
capable  of  spontaneous  contraction.  The  bearing  of 
these  observations  on  the  development  of  collateral 
circulation  remains  for  further  exploration. 

In  1958,  North  &  Sanders  (127)  reported  that  the 
innervation  of  the  mouse  ear  seemed  to  have  no 
effect  on  the  growth  of  collateral  vessels. 


The  existence  of  a  "basal  vascular  tone"'  of  local 
muscular  rather  than  neural  origin  has  been  con- 
sidered by  Folkow  (53,  54).  Evidence  for  an  appar- 
ently nonneural  dilator  response,  probably  trans- 
mitted by  the  musculature  of  the  vessel  itself,  has  been 
adduced  by  Hilton  (75).  He  found  that  cocainization 
of  a  femoral  artery  feeding  actively  contracting 
muscle  abolished  its  dilatation,  while  cutting  the 
nerve  to  the  extremity  and  curarizing  the  animal 
did  not.  This  dilator  response  traveled  up  the  artery 
at  a  slow  rate,  of  the  order  of  10  cm  per  sec.  Such 
phenomena  may  have  a  bearing  on  the  total  problem 
of  the  reaction  of  collaterals. 

When  the  influence  of  the  nervous  system,  and 
possibly  also  of  intrinsic  myogenic  influences,  is  con- 
sidered, it  is  clear  that  the  important  effect  relative 
to  collateral  circulation  is  the  lysis  of  vascular  tone. 
This  is  expressed  essentially  in  the  alteration  of 
mechanical  forces.  Possible  influences  on  the  growth 
of  vessels  are  as  yet  unknown. 

chemical  factors.  There  are  at  least  four  ways  in 
which  chemical  substance  could  affect  collateral 
circulation:  /)  By  regulating  vasodilatation.  2)  By 
controlling  the  proliferation  of  new  vessels.  5)  By- 
stimulating  and  inhibiting  the  growth  of  vessels. 
(Growth  itself  is  obviously  a  chemical  process, 
although  it  could  be  initiated  by  mechanical  or 
chemical  factors.)  ./)  By  guiding  vessels  to  specific 
destinations. 


1264 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  10.  Effect  of  left  sympa- 
thectomy upon  temperature  of  an 
extremity  after  bilateral  ligation 
of  iliac  artery.  On  the  side  of 
sympathectomy  the  temperature 
is  maintained.  On  the  opposite 
side  it  falls  gradually  to  room 
temperature  but  rises  with  great 
rapidity  at  about  the  8th  hour 
following  the  ligation.  [From 
Mulvihill  &  Harvey  (125).] 


The  idea  that  metabolites  formed  locally  in  anoxic 
tissue  can  produce  vasodilatation  received  early  ex- 
perimental support.  Marey  (115)  had  observed  that 
hyperemia  occurred  in  the  arm  after  a  sufficient 
degree  of  compression  either  by  mercury  (150-200 
mm  Hg)  or  in  a  pneumatic  chamber.  That  this  did 
not  require  participation  of  the  central  nervous 
system  and  that  it  was  not  the  result  of  squeezing  the 
nerve  itself  was  demonstrated  by  Bier  (17,  18),  who 
noted  reactive  hyperemia  after  clamping  and  then 
releasing  the  artery  in  the  limb  of  a  pig  severed  from 
all  connections  with  the  body  except  for  the  major 
vessels;  compression  of  the  nerve  in  another  prepara- 
tion produced  no  such  effect.  John  &  Warren  (90) 
showed  that  an  increased  flow  was  associated  with 
reactive  hyperemia.  Possible  sources  of  error  in 
interpretation  are  that  nerves  intimately  associated 
with  the  arteries,  or  axone  reflexes,  might  be  in- 
volved, or  that  a  local  myogenic  conducting  mecha- 
nism might  exist.  Bier  explained  enlargement  of  the 
major  arteries  on  the  basis  of  decrease  in  peripheral 
resistance  of  the  capillary  bed. 

Controversy  regarding  chemical  mechanisms  in 
collateral  circulation  was  further  stimulated  by 
Thomas  Lewis's  (98)  dictum  " — and  we  are  brought 
to  ask  if  arterial  growth  is  not  directly  controlled  by 
a  stimulant,  a  chemical  stimulant  arising  locally  as  a 
product  of  tissue  need  and  acting  locally."  If  this 
had  no  other  good  effect,  it  at  least  inspired  a  vigorous 
investigation  of  the  mechanisms  of  collateral  circula- 
tion, especially  those  related  to  arteriovenous  fistula. 
The    primacy    of   mechanical    over    chemical    phe- 


nomena, under  some  circumstances  when  both  might 
be  operative,  was  suggested  in  the  case  of  the  ex- 
tremity after  ligature  of  a  major  artery  by  Winblad 
et  a!.  (192),  and  by  John  &  Warren  (90),  among 
others,  and  in  the  case  of  arteriovenous  fistula  by 
Holman  (77)  in  his  amputation  experiment. 

Certain  factors,  such  as  anemia,  exercise,  and  de- 
creased arterial  pO-2,  can  increase  interarterial 
anastomoses  at  least  in  the  coronary  system  (45,  46, 
197,  198).  Just  how  this  is  brought  about  is  not 
known. 

The  Clarks  (33)  had  observed  that  the  same 
growth  conditions  which  favored  the  formation  of 
new  blood  vessels  also  stimulated  the  growth  of  other 
tissues  in  the  same  region.  They  were  led  to  suggest: 
"As  for  the  chemical  substance  or  substances  which 
may  stimulate  the  formation  of  new  capillaries,  they 
should  be  sought  in  embryonic  tissue  and  in  inflam- 
matory exudates,  since  it  is  in  such  environments  that 
active  vascular  formation  takes  place."  In  autografts 
of  connective  tissue  in  transparent  chambers  Williams 
(190)  concluded  that  hypoxia  of  a  certain  degree  is  a 
stimulus  for  growth  of  vascular  endothelium.  No 
specific  data  are  given,  however,  to  support  this 
statement. 

For  the  growth  of  vessels,  Nothnagel  (129)  offered 
a  deceptively  simple  explanation:  "'Anemia  of 
peripheral  parts  results  in  an  increased  flow  through 
collaterals,  whereupon  there  is  an  augmented 
nourishment  of  the  walls  of  these  vessels,  by  the  mate- 
rials with  which  they  become  increasingly  perfused." 
To  substantiate  this  idea  it  is  necessary  to  demonstrate 


CHANGES    IN    VASCULAR    PATTERNS 


1265 


that  substances  transported  through  the  lumen  of  a 
vessel  serve  to  nourish  it,  or  that  after  the  flow  be- 
comes greater  both  nourishment  and  growth  increase. 

Compelling  evidence  does  exist  that  chemical 
factors  affect  the  growth  of  vessels  in  general,  and  the 
development  of  collateral  circulation  in  particular. 
This  becomes  especially  clear  in  organs  with  a 
double  blood  supply  such  as  the  lung.  For  example, 
there  is  general  agreement  that  the  actively  metaboliz- 
ing cells  of  primary  malignant  pulmonary  neoplasms 
receive  their  blood  supply  from  systemic  vessels  (39, 
99,  194,  195).  This  would  indicate  the  effect  of 
chemical  rather  than  mechanical  factors,  since  the 
vast  majority  of  the  pulmonary  capillaries  represent 
a  bed  supplied  by  the  pulmonary  artery.  In  fact, 
with  the  growth  of  tumors  the  pulmonary  arteries  and 
veins  tend  to  be  obstructed  or  peripherally  displaced. 
This  may  have  some  practical  importance,  since  at- 
tempts have  been  made  to  subject  pulmonary  neo- 
plasms to  high  concentrations  of  cytotoxic  agents  by 
injecting  them  into  the  pulmonary  arteries  leading  to 
the  involved  segments.  There  is  disagreement  on  the 
blood  supply  of  metastatic  tumors,  since  some  (99) 
have  found  them  likewise  to  be  vascularized  from 
the  aorta,  while  others  (39)  concluded  that  the 
bronchial  arteries  did  not  nourish  the  metastatic 
tumors.  Possibly  the  disagreement  indicates  variation 
in  the  blood  supply.  In  the  case  of  the  liver,  according 
to  Hales  (personal  communication),  both  primary 
and  metastatic  tumors  are  supplied  by  the  hepatic 
arteries. 

Other  newly  formed  tissues  in  the  lung  also  are 
nourished  by  systemic  arteries.  Again  this  implies 
that  chemical  factors  must  be  at  work.  Thus,  in  or- 
ganizing pulmonary  disease,  as  in  bronchiectasis,  the 
granulation  tissue  is  derived  at  least  in  large  part 
from  the  bronchial  arteries  (104,  194).  Ultimately 
precapillary  anastomoses  are  formed  with  branches 
of  the  pulmonary  arteries.  That  this  is  not  necessarily 
the  outcome  of  enlargement  of  existing  precapillary 
anastomoses,  is  indicated  by  the  observation  that 
vessels  penetrating  into  the  lung  from  intercostal 
arteries  via  adhesions  anastomose  with  pulmonary- 
arteries  in  similar  fashion  (102). 

The  peculiar  "tropism"  exhibited  by  newly  formed 
collaterals  in  the  lung  must  also  have  a  chemical 
explanation.  It  is  well  established  that  ligature  of  the 
pulmonary  artery  induces  expansion  only  of  arterial 
collaterals  (102).  After  interruption  of  the  pulmonary 
veins,  only  the  venous  collaterals  expand  (86).  Pro- 
liferating branches  of  intercostal  vessels  that  enter  the 


lung  through  the  pleura  are  of  the  same  type,  arterial 
or  venous,  depending  on  the  stimulus,  and  the  ar- 
teries form  precapillary  connections  only  with  ar- 
teries, and  the  veins  only  with  veins.  When  both 
major  limbs  of  the  pulmonary  circulation  are  inter- 
rupted, the  expansion  of  both  collateral  systems  is 
induced,  and  both  types  of  collaterals  penetrate  in- 
ward through  pleural  adhesions  (183).  These  col- 
laterals must  be  newly  formed,  from  capillaries  in 
granulation  tissue  which  did  not  exist  previously  but 
which  comes  to  obliterate  the  pleural  space  after  the 
operative  manipulation.  Remarkably,  again  the 
transpleural  branches  of  the  intercostal  arteries 
establish  precapillary  connections  only  with  the  pul- 
monary arteries,  and  the  intercostal  veins  connect 
likewise  only  with  pulmonary  veins.  If  these  were 
mechanically  induced  there  should  be  "short  cir- 
cuits'' between  the  intercostal  arteries  and  veins, 
since  they  share  a  common  capillary  bed  in  the  granu- 
lation tissue  as  it  is  first  formed,  and  the  greatest 
pressure  gradient  under  the  circumstances  is  obvi- 
ously from  intercostal  arteries  to  intercostal  veins. 
Yet  such  short  circuits  have  rarely  if  ever  been  ob- 
served. Rather,  the  blood  pursues  the  longest  course, 
from  the  intercostal  arteries  through  precapillary 
anastomoses  into  the  pulmonary  arteries,  to  the  pul- 
monary capillaries,  to  pulmonary  veins,  and  finally 
through  precapillary  connections  into  the  collateral 
veins.  The  chemical  factors  that  must  be  responsible 
for  this  are  still  unknown. 

There  is  some  suggestive,  but  as  yet  imperfect, 
evidence  that  hormones  can  exert  an  influence  on  the 
development  of  collateral  circulation.  The  collateral 
circulation  that  develops  within  a  few  months  after 
ligature  of  a  pulmonary  artery  in  puppies  less  than 
48  hours  old  seems  immensely  greater  by  gross  in- 
spection than  that  appearing  after  a  comparable 
interval  of  time  in  adult  animals  after  the  same  pro- 
cedure (105).  The  results  of  a  study  of  the  effect  of 
hormones  on  collateral  circulation  after  interruption 
of  the  iliac  artery  in  rats  were,  however,  equivocal 
(147).  Cortisone  seemed  to  inhibit  the  collateral  circu- 
lation, just  as  it  did  the  connective  tissue  proliferation 
in  the  region  of  the  lower  abdominal  incision  where, 
as  a  result,  hernias  appeared.  The  weight  increase  of 
these  animals,  however,  stopped  when  cortisone  was 
administered.  It  might  be  expected  at  the  end  of  the 
experiment  that  the  smaller  animals  would  have 
smaller  vessels.  This  problem,  however,  should  be 
reinvestigated. 

Studies  of  the  earliest  phases  of  development  of  the 


1266 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


M 

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Y30=96-/.74-(X-54) 

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Y,rr  82-1.42  (x-45) 

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Y0=76-0.28(X  =  63) 

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fig.  1 1.  Trend  lines  of  curves  showing  relation  of  diameters  of 
bronchia]  arteries  (ordinate)  to  bronchi  and  bronchioles  which 
they  accompany  (abscissa),  as  calculated  from  observations  in 
individual  rats.  Between  the  5th  and  10th  days  there  is  a  sudden 
increase  in  slope.  This  corresponds  in  time  to  the  onset  of  proli- 
ferative activity  in  the  walls  of  the  collateral  vessels.  [From 
Weibel  (188).] 


collateral  circulation  after  interruption  of  the  left 
pulmonary  artery  in  the  rat  also  provide  information 
on  mechanisms  (188).  The  process  appears  to  be 
biphasic,  with  initial  mechanical  expansion,  followed 
by  active  proliferation  of  vessels.  This  is  reflected  in 
quantitative  observations  on  the  size  of  bronchial 
arteries  as  related  to  the  bronchioles  which  they 
accompany.  In  the  first  phase  the  arteries  increase  in 
diameter,  but  the  ratios  to  the  diameters  of  the 
bronchioles  have  approximately  the  same  slope,  sug- 
gesting simple  mechanical  expansion  (fig.  11).  Be- 
tween the  fifth  and  tenth  days,  the  slope  suddenly 
becomes  much  more  steep.  Histologically,  at  about  the 
fifth  day  mitoses  begin  to  appear  in  large  numbers 
both  in  endothelial  and  muscle  cells,  indicating  that 
active  proliferation  is  in  progress.  The  new  cells  appear 
as  solid  sprouts  that  seem  to  extend  to  their  desti- 
nations in  the  capillary  beds  of  the  alveoli  before  they 
acquire  a  lumen.  At  the  proximal  end  of  the  ligated 
pulmonary  artery  the  collateral  vessels  actually  pene- 
trate the  thick  musculo-elastic  wall  to  establish 
anastomoses   which   do    not    normallv    exist    in    rats 


(180).  All  of  these  observations  suggest  the  effect  of 
chemical  influences. 


Rate  of  Developmi  tit 

The  immediate  expansion  of  pre-existing  arterial 
collaterals  has  been  demonstrated  angiographically 
by  a  number  of  observers,  for  example,  Winblad  et  al. 
(192),  John  &  Warren  (go),  Longland  (108).  That 
persistent  sympathetic  activity  can  produce  some 
delay  has  been  shown  by  Ferris  &  Harvey  (50)  and 
by  Mulvihill  &  Harvey  (125),  among  others.  The 
existence  of  a  later  and  slower  phase  of  growth  has 
been  realized  for  a  long  time.  For  example,  in  Noth- 
nagel's  (129)  experiments  it  took  at  least  6  days  after 
interruption  of  the  femoral  artery  below  the  pro- 
funda and  circumflex  in  rabbits,  before  Teichmann's 
injection  mass  could  be  made  to  penetrate  beyond 
the  ligature.  Mention  has  previously  been  made  of 
the  sudden  increase  in  relative  size  of  the  collateral 
vessels,  as  compared  with  the  bronchi  as  a  reference, 
after  the  fifth  day  following  ligature  of  the  pulmonary 
artery  in  the  rat  (188). 

Quantitative  flow  data  are  relatively  sparse.  The 
problem  was  approached  in  various  collateral  beds 
by  Eckstein  et  al.  (47)  using  as  a  measure  not  only 
the  pressure  beyond  a  point  of  occlusion,  but  also  the 
retrograde  flow  at  intervals  varying  from  less  than 
1  hour  to  many  months.  In  general,  in  the  femoral 
and  carotid  distributions,  the  collaterals  opened 
rapidly,  for  example,  to  near  maximal  levels  within 
1  hour,  while  the  process  took  several  hours  to  a  week 
to  attain  a  comparable  relative  increase  in  the 
coronary  circulation.  When  both  the  femoral  arteries 
and  veins  were  ligated  there  was  an  increase  in  retro- 
grade pressure  and  flow  as  previously  observed  by 
Holman  &  Edwards  (78),  and  Eckstein  et  al.  (47) 
found  the  same  to  be  true  in  the  coronary  arteries 
upon  ligature  of  the  coronary  sinus.  The  conservative 
effect  on  tissue  of  ligating  the  corresponding  vein 
when  a  major  artery  is  interrupted  has  been  stressed 
by  Makins  (ill)  and  confirmed  by  Reichert  (143). 

In  the  lung  there  is  at  least  a  30-fold  increase  in 
arterial  collateral  circulation,  whether  or  not  the 
veins  are  also  ligated,  16  months  after  interruption  of 
the  pulmonary  artery  (fig.  12),  and  there  is  evidence 
still  of  a  continuing  rise  at  this  late  time,  although 
this  is  much  less  steep  than  in  the  first  2  months.  In- 
deed a  highly  pertinent  question  is  what  brings  the 
growth  of  these  collateral  vessels,  or  of  any  vessels,  to 
an  end. 


CHANGES    IN    VASCULAR    PATTERNS 


1267 


60- 
50- 

^   ^** — 

0 

40- 

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i 

30- 

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^ 

20- 

1 

1  0- 

• •   Pulmonary    artery    olone    Ligated 

MONTHS 

0  — 

1 

1                1                ■                >                1                ■ 

1 

fig.  12.  The  calculated  regression  lines  for  rates  of  increase 
of  collateral  blood  flow  are  plotted  when  both  pulmonary 
arteries  and  veins  are  ligated  (solid  line)  and  when  the  pulmon- 
ary artery  alone  is  interrupted  (broken  line).  These  are  re- 
markably congruent;  this  indicates  that  the  collateral  veins  can 
expand  at  least  as  rapidly  as  the  arteries.  The  data  for  "artery 
alone"  have  been  recalculated  in  ml/kg/min  from  a  paper  by 
Bloomer  el  al.  (20).  An  adjustment  for  nitrogen  shift  in  the 
bronchospirometry  has  also  been  made  and  this  has  made  pos- 
sible the  construction  of  the  graph,  using  also  data  previously 
published  by  Vidone  &  Liebow  (183). 

In  certain  other  situations  progressive  increase  in 
expansion  of  collateral  beds  can  take  place  for  at  least 
1  year  and  possibly  longer.  As  discussed  previously, 
this  has  been  observed  in  the  arterial  collateral  circu- 
lation related  to  an  arteriovenous  fistula. 


Regression  of  Collaterals 

That  preformed  collaterals  can  open  rapidly  and 
disappear  as  quickly  when  the  stimulus  to  their 
formation  is  abrogated  has  been  shown  angiographi- 
cally  by  Winblad  et  al.  (192)  and  John  &  Warren  (90). 

As  a  collateral  bed  develops,  certain  of  its  com- 
ponents tend  to  enlarge  and  to  persist  as  major 
channels,  while  others  regress.  This  was  noted  in 
successive  angiograms  after  ligating  the  femoral 
artery  in  the  rabbit  (108).  North  &  Sanders  (127) 
found  in  the  ear  of  the  mouse  that  when  continuity 
of  an  interrupted  vascular  channel  was  regained  cer- 
tain minor  collaterals  regressed. 

Even  collaterals  of  long  standing  remain  only  so 
long  as  the  stimuli  that  led  to  their  expansion  are 
maintained.  Bosher  et  al.  (22)  observed  regression  of 
collateral  circulation  associated  with  a  peripheral 
arteriovenous  fistula  by  comparing   angiograms  im- 


mediately and  again  6  weeks  after  fistulectomy;  some 
regression  was  apparent  as  early  as  the  fourth  or  fifth 
day.  Anatomically  the  collaterals  in  regression  were 
described  as  showing  marked  subendothelial  pro- 
liferation. The  results  after  fistulectomy  were  similar 
to  those  after  ligature  of  the  major  participating  ves- 
sels in  the  fistula,  and  this  was  considered  further 
evidence  against  the  "tissue  need"  theory.  Winblad 
et  al.  (192)  Schoop  (156)  and  Hasse  &  Schoop  (70) 
noted  the  regression  of  collaterals  after  adequate 
thrombo-intimectomy  or  bypass  grafting  in  major 
systemic  arteries.  Similar  phenomena  were  described 
by  Jacobson  &  McAllister  (89). 

Arterial  Versus  Venous  Collaterals 

"Nature  has  been  more  prodigal  in  the  provision  of 
alternative  venous  and  lymphatic  routes  than  she 
has  been  in  arranging  for  arterial  collaterals"  [Lear- 
month  (96)]. 

In  the  lung  the  stimuli  to  the  development  of 
arterial  and  of  venous  collaterals  are  independent. 
This  is  true  not  only  where  mechanical  forces  seem 
dominant  as  in  the  expansion  of  pre-existing  col- 
laterals, but  also  where  chemical  influences  appear  to 
be  pre-eminent  as  in  the  case  of  newly  formed  trans- 
pleural vessels. 

When  both  arteries  and  veins  are  compromised 
under  appropriate  conditions,  both  arterial  and 
venous  limbs  of  the  collateral  circulation  will  expand. 
This  has  already  been  discussed  for  the  lung.  In  seg- 
ments of  small  intestine  transplanted  to  the  sub- 
cutaneous tissue  by  the  Florey- Harding  method 
(128)  both  arterial  and  venous  collaterals  appeared 
when  the  original  mesenteric  vascular  pedicle  was 
severed. 

It  is  of  interest  that  in  these  experiments  the  venous 
collaterals  seemed  to  develop  to  a  larger  size  more 
quickly  than  the  arterial.  Similar  observations  had 
been  reported  by  North  &  Sanders  (127)  in  the  ear 
of  the  mouse.  The  veins  seemed  to  expand  within  24 
hours,  while  it  took  4  to  5  days  for  visible  expansion 
of  arteries  to  take  place.  Quantitative  data  are  avail- 
able for  the  lung.  When  both  the  pulmonary  arteries 
and  veins  are  interrupted,  the  collateral  blood  flow  is 
approximately  the  same  as  when  arteries  alone  are 
ligated  (fig.  12).  This  means  that  expansion  of  the 
venous  collateral  can  at  least  keep  pace  with  that 
of  the  arterial. 

In  these  experiments  arteries  became  joined  to 
arteries,   and  veins  to  veins,   but  there  are  circum- 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


stances  where  arteriovenous  connections  develop  in 
newly  formed  circulations,  as  in  the  rabbit  ear 
chamber  (36).  It  is  of  interest  that  such  arteriovenous 
shunts  are  normally  present  in  the  rabbit's  ear  (34). 

Some  Effects  of  Collateral  Circulation 

Blood  supply  arriving  of  necessity  by  way  of  col- 
lateral routes  is  usually  not  so  efficient  as  the  original 
in  maintaining  full  function.  Rarely  it  may  exceed 
the  needs  of  the  tissue,  as  in  association  with  large 
peripheral  arteriovenous  fistulas,  and  in  the  lungs,  as 
has  been  described.  In  the  latter,  however,  it  never- 
theless falls  short  of  normal  pulmonary  perfusion 
that  is  carried  on  in  the  service  of  the  body  as  a 
whole. 

Certain  special  effects  of  collateral  circulation 
occur  under  pathological  circumstances,  but  these 
can  only  be  mentioned  in  passing.  Thus,  in  the  lung, 
the  seat  of  severe  fibrosing  disease  such  as  bronchi- 
ectasis, where  large  precapillary  anastomoses  are 
formed  between  bronchial  and  pulmonary  arteries, 
the  higher  pressure  in  the  former  tends  to  shunt  the 
pulmonary  arterial  blood  into  normal  tissue  where 
oxygenation  can  occur.  Consequently,  there  may  be 
no  peripheral  arterial  desaturation.  When  suffi- 
ciently numerous,  these  connections  may  contribute 
to  an  increased  resistance  to  the  output  of  the  right 
ventricle.  Reverse  flow  in  pulmonary  arteries  from 
the  periphery  via  these  anastomoses  has  also  been 
demonstrated,  by  analysis  of  gases  in  blood  drawn 
from  catheters  placed  within  such  arteries,  and  by 
angiography  (103),  and  most  convincingly  by 
aortography  (3).  In  the  last  mentioned  a  radiopaque 
substance  introduced  above  the  origins  of  the  bron- 
chial vessels  has  been  shown  to  fill  the  pulmonary 
arteries  retrogradely. 

The  hepatic  circulation  bears  certain  analogies  to 
the  pulmonary.  Enlargement  of  the  hepatic  arteries 
has  been  demonstrated  in  cirrhosis,  and  the  suggestion 
has  been  made  that  they  may  contribute  to  portal 
hypertension  as  a  consequence  of  more  direct  connec- 
tions with  the  portal  veins  (68). 

Bronchial  veins  so  enlarged  that  their  valves  become 
incompetent  have  been  demonstrated  in  pulmonary 
emphysema,  and  the  possibility  of  reverse  flow  of 
blood,  i.e.,  from  the  azygos  system  into  the  pul- 
monary veins  has  been  inferred  (100,  114).  Such 
shunting  has  also  been  considered  as  an  explanation 
of  the  cyanosis  sometimes  encountered  in  fibrosis  of 
the  liver  (27).  Enlargement  of  bronchial  veins, 
probably  as  a  result  of  high  pressure  in  the  azygos 


system  which  may  carry  a  large  volume  of  blood 
bypassing  the  liver,  has  been  demonstrated  by  injec- 
tion. 

Structure  of  Collateral  Vessels 

It  is  now  well  established  that  vessels  reflect  in  their 
structure  the  mechanical  conditions  to  which  they 
are  subjected.  As  early  as  1883  von  Recklinghausen 
(142)  stated  in  his  textbook  that  as  collaterals  carry 
more  blood,  they  become  thicker  and  more  tortuous. 
That  there  is  both  hypertrophy  and  hyperplasia  of 
smooth  muscle  in  the  larger  collaterals  was  described 
and  illustrated  by  Nothnagel  (fig.  9).  Fischer  & 
Schmieden  (51)  provided  an  experimental  demon- 
stration of  adaptive  changes  in  larger  vessels  sub- 
jected to  altered  circumstances  of  pressure  and  flow. 
When  a  segment  of  external  jugular  vein  was  in- 
serted into  the  course  of  the  carotid  artery  of  a  dog, 
it  became  reduced  in  caliber,  firmer,  and  as  much  as 
two  or  three  times  thicker.  Histologically,  the  media 
was  shown  to  contain  much  more  muscle  and  con- 
nective tissue  (fig.  13).  The  medial  elastic  fibers  were 
thought  to  be  reduced,  but  this  was  not  convincingly 
demonstrated.  The  adventitia  also  was  seen  to  con- 
tain denser  connective  tissue.  The  intima  generally 
remained  unchanged.  The  trunk  of  the  pulmonary 
artery,  when  subjected  to  a  sufficiently  increased 
pressure,  becomes  markedly  thickened  with  an 
increase  both  in  elastic  tissue  and  smooth  muscle 
(105,  145). 

With  the  enlargement  of  small  arteries  as  they 
become  able  to  carry  more  blood  there  often  appear 
remarkable  aggregates  of  longitudinal  smooth  muscle 
fibers  that  dissect  or  even  replace  the  internal  elastic 
lamina,  and  that  may  lead  to  the  subtotal  or  even 
complete  obliteration  of  the  lumen.  Such  vessels 
have  been  most  extensively  studied  in  the  lung  and 
in  manv  tvpes  of  chronic  pulmonary  disease  where 
bronchial  collateral  circulation  is  characteristically 
increased  (109,  187).  Some  have  called  these  "Sperr- 
arterien"  (72-74,  93)  and  have  thought  them  to 
possess  a  regulatory  function  in  relation  to  their 
anastomoses  with  pulmonary  arteries.  In  more 
general  terms  it  may  be  said  that  longitudinal  muscle 
tends  to  increase  in  other  small  muscular  arteries  with 
an  augmentation  in  the  blood  that  they  carry,  as  in 
the  bases  of  the  cardiac  valves  in  rheumatic  fever,  in 
the  vasa  vasorum  of  the  aorta  in  syphilis,  and  in 
the  intercostal  vessels  as  they  traverse  adhesions  to 
enter  the  lung.  Probably  the  hypertrophy  and  hyper- 
plasia  of  muscle  is  in  fact  a  response  to  increased 


CHANGES    IN    VASCULAR    PATTERNS 


1269 


a 


I  k  % 


m 


fic.  13.  Adaptive  changes  in  a  seg- 
ment of  jugular  vein  which  had  been 
inserted  into  the  course  of  the  carotid 
artery  for  86  days.  At  left  is  shown  the 
appearance  of  the  vessel  before  its 
exposure  to  the  higher  pressure.  Key: 
i — intima;  m — media.  [From  Fischer  and 
Schmieden  (51).] 


tension  which,  in  general,  appears  to  increase  the 
tone  of  muscle  (9,  16,  171).  This  has  been  suggested 
for  the  increased  muscle  characteristic  of  bullae  in 
pulmonary  emphysema,  the  walls  of  which  are  under 
stretch  consequent  to  air  trapping  (106).  A  brilliant 
experimental  demonstration  of  this  mechanism  in 
small  vessels  has  been  provided  by  Weibel  (187). 
In  his  experiment,  increased  tension  in  mesenteric 
vessels  was  produced  by  stretching  the  mesentery 
slightly  and  attaching  it  to  the  diaphragm.  The  inner 
longitudinal  muscle  then  did  increase  to  a  remarkable 
degree. 

Gaps  in  the  internal  elastic  lamina  of  the  large 
arteries  serving  as  collaterals  have  been  noted  by 
several  observers  (102,  108).  Some  newly  formed 
collaterals  mav  possess  relatively  little  or  no  elastica 
(16.). 

Newly  formed  collateral  vessels  that  develop  from 
capillaries,  as  for  example  in  the  adhesions  between 
visceral  and  parietal  pleura,  ultimately  acquire  a 
structure  appropriate  to  their  function  as  arteries 
or  veins  at  the  size  which  they  ultimately  attain 
(86). 

The  growth  of  muscle  in  the  walls  of  vessels  func- 
tioning as  collaterals  in  the  mesentery  of  the  rat  has 
been  well  described  by  Weyrauch  &  De  Garis  (189). 
They  considered  the  stimulus  to  be  increased  blood 
volume.  The  tortuosity  of  the  vessels  was  said  to  be 
the  result  of  the  fact  that  the  muscle  fibers  do  not 
grow  in  a  single  plane  and  this  may  be  one  factor  to 


account  for  the  tortuosity  of  collaterals  in  general. 
They  also  described  the  appearance  of  muscle  in 
vessels  which  they  thought  were  newly  formed. 

Less  well  understood  than  the  structural  changes 
are  the  forces  that  bring  them  about.  They  are  prob- 
ably similar  to  those  that  govern  the  differentiation 
of  arteries  and  veins  from  the  retiform  capillary 
anlagen  of  the  early  embryo,  as  previously  discussed. 

Measurement  of  Collateral  Circulation 

Attempts  have  been  made  to  estimate  the  extent  of 
collateral  circulation  by  both  anatomical  and  physio- 
logical methods.  The  former  offers  only  a  general 
and  not  necessarily  reliable  guide  to  the  latter,  in  the 
sense  that  the  size  of  a  bridge  cannot  always  provide 
a  clue  to  the  magnitude,  nor  even  to  the  direction  of 
traffic. 

The  early  observers,  such  as  Morgagni  and  Porta, 
made  many  excellent  observations  with  the  naked 
eye.  Direct  visual  observation  continues  to  be  of 
value  and  details  of  the  formation  of  smaller  col- 
lateral vessels  can  be  observed  microscopically  at 
intervals  in  the  process  of  their  formation,  for  example, 
in  the  ear  of  the  living  mouse  (127).  John  Hunter 
(83)  early  used  injection  methods  in  his  famous 
studies  of  the  new  blood  supply  to  the  stag's  antler. 
Some  of  his  casts  of  the  vessels  are  preserved  to  this 
day  in  the  Museum  of  the  Royal  College  of  Surgeons 
in  London.  Attempts  have  been  made  to  quantitate 


12  70 


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CIRCULATION    II 


the  results  of  the  injections.  This  has  been  accom- 
plished by  some  who  have  standardized  an  injection 
mass  that  does  not  penetrate  through  vessels  of  less 
than  a  known  diameter.  Important  information  has 
been  \  ielded  by  such  radiopaque  materials  as  Schle- 
singer's  (154,  155).  Colored  masses  in  gelatin  or  simi- 
lar materials  have  also  been  used  to  inject  tissues 
that  have  subsequently  been  cleared,  for  example  by 
the  method  of  Spalteholz  (164).  Materials  that 
harden  to  provide  casts  of  the  vessels  and  which 
resist  subsequent  corrosion  of  the  tissues  have  been 
useful  in  many  applications.  In  the  study  of  such 
casts,  or  other  injections,  certain  critical  points  can 
be  established,  and  the  magnitude  of  the  collateral 
can  be  estimated  by  whether  or  not  the  material  has 
penetrated  into  particular  segments  of  the  system 
(147).  Casts  can  be  measured  or  weighed.  Glass  or 
plastic  beads  of  graded  sizes  have  been  used  to  es- 
tablish the  size  of  vascular  communications  (2,  3, 
126,  131,  137,  138,  162).  With  these  materials  over- 
pressure must  be  avoided  and  the  possibility  of  con- 
tamination must  also  be  considered.  Angiography, 
microangiography  (11),  and  more  recently  cineange- 
ography  have  become  increasingly  important  with 
improvements  of  technique,  especially  since  they 
offer  a  way  of  investigating  the  collateral  circulation 
in  intact  animals.  Quantitation  can  be  achieved  by 
such  procedures  as  that  of  Longland  (108),  who 
counted  the  number  of  vessels  in  his  angiograms  that 
exceeded  a  stated  size  at  a  selected  level.  In  the  lung, 
a  degree  of  refinement  can  be  obtained  by  relating 
the  vessels  to  the  diameters  of  the  bronchi  which  they 
accompany  (188).  The  same  can  be  done  in  any 
organ  with  an  appropriate  reference  structure. 

To  measure  collateral  blood  flow,  direct  and  more 
or  less  indirect  methods  have  been  applied.  The 
simplest  perhaps  is  the  collection  of  blood  from  the 
veins  draining  the  part.  This  procedure  is  useful  only 
if  the  tissue  is  supplied  exclusively  from  a  collateral 
source  during  the  period  of  measurement,  and  if  the 
veins  carry  away  all  or  a  known  proportion  of  blood. 
These  conditions  cannot  often  be  met.  In  man, 
plethvsmography  has  been  employed  in  the  study  of 
collateral  circulation  (193). 

The  collection  of  "backflow"  from  a  vessel  beyond 
a  point  of  occlusion  has  been  used  on  the  presumption 
that  it  will  increase  if  the  vessels  circumventing  an 
occlusion  come  to  carry  an  increased  volume  of 
blood.  This  principle  has  been  extensively  applied  in 
the  study  of  the  coronary  circulation  (63).  Upon 
opening  the  vessel  beyond  the  obstruction  the  periph- 


eral resistance  confronting  the  blood  in  the  collateral 
vessels  is,  of  course,  reduced,  and  the  backflow  can  in 
no  sense  be  considered  an  absolute  measure  of  col- 
lateral blood  supply.  As  a  relative  measure  the  prin- 
ciple is  valid  if  no  uncontrollable  change,  such  as 
spasm,  has  occurred  in  the  diameter  of  the  vessel 
beyond  the  point  of  occlusion.  Backflow  then  would 
reflect  the  pressure  in  the  vascular  bed  in  the  distal 
arterial  segment,  which  also  is  related  to  the  extent 
of  the  collateral  connections.  Pressures  as  well  as 
flows  have  been  measured  for  this  purpose. 

Other  "'direct"  measurements  have  been  made  by 
introducing  such  devices  as  the  bubble  flowmeter 
into  the  major  feeders  of  the  collateral  bed  (26). 
In  such  structures  as  the  lung,  attempts  have  been 
made  to  perfuse  separately  the  greater  and  lesser 
circulations  (151).  Both  procedures  require  extensive 
surgery,  with  denervation  and  possibly  other  dis- 
turbing factors. 

In  the  lungs  bronchospirometry  and  blood  gas 
analyses,  with  temporary  balloon  blockade  of  a  pul- 
monary artery  and  application  of  "mixing  formulas" 
where  indicated,  can  provide  data  on  "'effective" 
collateral  arterial  flow,  i.e.,  blood  arriving  by  syste- 
mic arteries  that  becomes  oxygenated  in  the  lungs 
(20,  52). 

The  fact  that  the  temperature  of  a  tissue  bears  a 
relationship  to  the  quantity  of  arterial  blood  perfusing 
it  in  a  unit  of  time  has  been  used  to  measure  col- 
lateral circulation  (50).  One  source  of  error  lies  in  the 
fact  that  blood  flow  is  not  necessarily  distributed  in  a 
uniform  manner  through  all  tissues  of  a  part,  nor 
through  all  portions  of  a  tissue. 

The  distribution  of  such  dyes  as  Evans  blue  or  Fox 
green  or  of  radioactive  materials,  or  "labeled" 
ervthrocytes  (138)  in  various  vascular  compartments 
has  been  used  for  qualitative  detection  of  shunts,  but 
under  specific  conditions.  Isotonic  solutions  differing 
in  temperature  or  conductivity  from  blood  can  be 
employed  instead  of  dyes,  and  records  similar  to  dye 
concentration  curves  can  be  obtained  with  appro- 
priate sensing,  amplifying,  and  recording  devices. 

Under  special  circumstances  such  methods  can 
also  be  applied  in  a  quantitative  fashion.  In  the  lung 
where  an  extensive  bronchial  collateral  circulation 
represents  a  left-to-left  shunt,  originating  as  it  does  in 
the  left  ventricle  and  aorta,  and  returning  from  the 
lungs  via  the  pulmonary  veins  to  the  left  heart,  intro- 
duction of  an  indicator  material  such  as  T-1824, 
Fox  green,  or  radioactive  iodinated  serum  albumin 
into   the   circulation    produces   characteristic   altera- 


CHANGES    IN    VASCULAR    PATTERNS 


tions  from  the  usual  in  the  arterial  dye  curve:  A  more 
rapid  reversal  of  the  downward  limb  of  the  first  wave 
and  a  double-humped  camel  rather  than  dromedary 
recirculation  curve.  A  known  quantity  of  the  indi- 
cator can  be  injected  rapidly  into  a  systemic  vein, 
and  concentration  curves  can  be  obtained  simul- 
taneously from  the  pulmonary  artery  and  aorta  by 
appropriate  methods  such  as  cuvette  densitometry. 
The  "left  cardiac  output"  measured  from  the  latter 
should  exceed  the  "right  cardiac  output"  calculated 
from  the  former  by  the  volume  of  the  collateral  blood 
supply  to  the  lung.  This  principle  has  been  applied 
by  a  number  of  workers  (38,  55,  56),  but  very  rapid 
left-to-left  recirculation  introduces  problems  that 
may  make  this  procedure  inapplicable  for  quantitative 
use. 

To  measure  collateral  blood  flow  from  extra- 
coronary  sources  to  the  heart  by  means  of  vessels  in 
anastomosis  with  the  coronary  arteries,  the  dye  has 
been  introduced  into  the  aorta  above  the  orifices  of 
the  presumed  collaterals  and  well  below  the  origins 
of  the  coronary  arteries  in  the  sinuses  of  Valsalva. 
If  collaterals  exist,  dyed  blood  will  reach  the  coronary 
sinus  by  the  collateral  route  before  recirculation  can 
take  place.  Quantitation  has  been  attempted  by  com- 
paring the  peak  concentrations  in  the  aortic  blood 
with  that  of  the  coronary  sinus  peak,  or  better,  the 
areas  beneath  appropriate  segments  of  the  two 
curves  (182). 


Some  Outstanding  Problems 

The  problems  of  collateral  circulation  are  in- 
separable from  those  of  angiogenesis,  "histodynamic->" 
in  Thoma's  sense  and  hemodynamics  in  general. 
Methods  for  study  have  advanced  notably,  but  new 
developments  can  be  expected  to  accelerate  progress. 
Catheters,  as  used  currently  for  measuring  pressures 
and  in  obtaining  dye  concentration  curves,  carry 
inherent  artifacts.  Accurate  sensing  units  sufficiently 
small  so  as  not  to  interfere  significantly  with  blood 
flow  are  needed  for  both  purposes 

It  is  clear  that  many  of  the  basic  mechanisms  must 
be  essentially  physicochemical.  These  must  underlie 
the  molding  influence  of  mechanical  forces  on  the 
structures  of  vessels.  They  must  also  be  responsible  for 
what  is  now  vaguely  recognized  as  "tropism."  None 
of  the  essential  chemical  information  is  yet  available 
to  explain  how,  in  a  newly  formed  collateral  bed, 
arteries  are  joined  directly  to  arteries  and  veins  to 
veins,  with  no  arteriovenous  connections,  while  the 
latter  are  constantly  present  normally  in  certain 
other  parts. 

John  Hunter's  (185)  remark  of  1785  still  well 
defines  the  present  state  of  knowledge:  "All  the  uses 
arising  from  the  anastomosing  of  the  vessels  are,  per- 
haps, not  yet  perfectly  understood;  general  reasons 
can,  I  think,  be  assigned  for  them,  but  these  will  not 
apply  to  all  cases;  it  is  something,  therefore,  more 
than  we  are  yet  acquainted  with." 


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166.  State,  D.,  P.  F.  Salisbury,  and  P.  Weil.  A  study  of  the 
bronchial  artery  How  in  the  dog.  Surg.  Forum  7:  214,  1957. 

167.  State,  D.,  P.  F.  Salisbury,  and  P.  Weil.  Physiologic 
and  pharmacologic  studies  of  collateral  pulmonary  flow. 
J.  Thoracic  Surg.  34:599,  1957. 

168.  Staubesand,  J.,  and  C.  Genschow.  Die  arterio-venosen 
Anastomosen  im  Loffel  des  Kaninchens  nach  graphischen 
Rekonstruktionen.  Z.  Anal.  Entwicklungsgeschichte  116: 
446,  I952- 

169.  Staubesand,  J.,  and  F.  Hammersen.  Zur  Problematik 
des  Nachweises  arterio-venoser  Anastomosen  im  Injek- 
tionspraparat.  Z.  Anat.  Entwicklungsgeschichte  iig:  365, 
1 955" '  95"- 

1 70.  Stefani,  A.  Delia  influenza  del  sistema  nervoso  sulla 
circolazione  collaterale.  Spenmentale  58:  225,   1886. 

171.  Straub,  W.  Zur  Muskelphysiologie  des  Regenwurms. 
Pfliigers  Arch.  ges.  Physiol.  79:  379,  1 900. 

172.  Sucquet,  J.  P.  De  La  Circulation  du  Sang  dans  les  Membres 
el  dans  la  Tete  chez  V Homme.  Paris :  Bailliere,  1 860. 

173.  Theis,  F.  V.  Effect  of  sympathetic  neurectomy  on  the 
collateral  arteriole  circulation  of  the  extremities.  Experi- 
mental study.  Surg.  Gynecol.  Obstet.  57:  737,  1933. 

174.  Thoma,  R.  I 'ntersuchungen  uber  die  Histogenese  und  Histo- 
mechamk  des  Gej'dsssy stems.  Stuttgart:  Enke,   1893. 

1 75.  Tobin,  C.  E.  The  bronchial  arteries  and  their  connec- 
tions with  other  vessels  in  the  human  lung.  Surg.  Gynecol. 
Obstet.  95:  741,  1952. 

176.  Tobin,  C.  E.,  and  M.  O.  Zariquiey.  Arteriovenous 
shunts  in  the  human  lung.  Proc.  Soc.  Exptl.  Biol.  Med. 
75 :  827.  !95°- 

177.  Tondury,  G.,  and  E.  Weibel.  Anatomie  der  Lungenge- 
fasse.  Ergeb.  ges.  Tuberk-Forsch.  14:61,  1958. 

178.  Trueta,  J.  Studies  of  the  Renal  Circulation.  Oxford:  Black- 
well,   1947. 

179.  Vastarini-Cresi,  G.  Comunicazioni  dirette  tra  le  arterie 
e  le  vene  (anastomosi  artero-venose ) .  Mordt.  zool.  ital. 
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180.  Verloop,  M.  C.  On  the  arteriae  bronchiales  and  their 
anastomosing  with  the  arteria  pulmonalis  in  some 
rodents:  A  micro-anatomical  study.  Acta  anat.  7:1,  1949. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


181.  Verloop,  M.  C.  The  arteriae  bronchiales  and  their 
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lung:  A  micro-anatomical  study.  Acta  anat.  5:  171,   1948. 

1 82.  Vidone,  R.  A.,  J.  L.  Kline,  M.  Pitel,  and  A.  A.  Liebow. 
The  application  of  an  induced  bronchial  collateral 
circulation  to  the  coronary  arteries  by  cardiopneumono- 
pexy.  II.  Hemodynamics  and  the  measurement  of  col- 
lateral flow  to  the  myocardium.  Am.  J.  Pathol.  32 :  897, 
1956. 

183.  Vidone,  R.  A.,  and  A.  A.  Liebow.  Anatomical  and 
functional  studies  of  the  lung  deprived  of  pulmonary 
arteries  and  veins,  with  an  application  in  the  therapy  of 
transposition  of  the  great  vessels.  Am.  J.  Pathol.  33 :  539, 

'957- 

184.  Volpel,  W.  Uber  die  Entstehungsbedingungen  des 
arteriellen   Kollateralskreislaufes.   Acta  Biol,   el  Med.   Ger. 

3-  557.  1959- 

185.  Wakeley,  C.  John  Hunter  and  experimental  surgery. 
Hunterian  oration,  1955.  Ann.  Roy.  Coll.  Surg.  Engl. 
16:  69,  1955. 

186.  VVeibel,  E.  Die  Blutgefassanastomosen  in  der  mensch- 
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187.  Weibel,  E.  Early  stages  in  the  development  of  collateral 
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353.  >96°- 

188.  VVeibel,  E.  Die  Entstehung  der  Langsmuskulatur  in  den 
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189.  Weyrauch,  H.  B.,  and  C.  F.  De  Garis.  Normal  and 
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190.  Williams,  R.  G.  Experiments  on  the  growth  of  blood 
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133:  465.  '959- 


191.  Williams,  R.  G.  The  fate  of  minute  blood  vessels  in 
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193.  Winsor,  T.,  J.  H.  Payne,  N.  Rudy,  and  J.  O.  Beatty. 
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194.  Wood,  D.  A.,  and  M.  Miller.  The  role  of  the  dual 
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the  lung.  J.  Pathol.  Bactenol.  47:  489,  1938. 

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197.  Zoll,  P.  M.,  and  L.  R.  Norman.  Effect  of  vasomotor 
drugs  and  of  anemia  upon  interarterial  coronary  anasto- 
moses. Circulation  6:  832,  1952. 

198.  Zoll,  P.  M.,  S.  Wessler,  and  M.  J.  Schlesinger. 
Interarterial  coronary  anastomoses  in  the  human  heart, 
with  particular  reference  to  anemia  and  relative  cardiac 
anoxia.  Circulation  4:  797,   1 951. 

199.  Zuckerkandl,  E.  Uber  die  Anastomosen  der  Venae 
pulmonales  mit  den  Bronchialvenen  und  mit  dem 
mediastinalcn  Venennetze.  Sitzber.  Akad.  Win.  Wien, 
Malh.-naturw.  Kl.  84,  Abt.  3:  1  10,  1882. 

200.  Zweifach,  B.  W.  Basic  mechanisms  in  peripheral  vas- 
cular homeostasis.  In :  Factors  Regulating  Blood  Pressure. 
Transactions  of  the  Third  Conference,  May  5-6,  1949, 
New  York:  Macy,  1950,  pp.   13-52. 


CHAPTER     3! 


Methods  of  measuring  blood  flow 


KURT    KRAMER 

WILHELM    LOCHNER 

E.    WETTERER 


Physiologisches  Inslitut  der  Universitdt,  Gbttingen,  Germany 
Physiologisches  Institut  der  Medizinischen  Akademie,  Diisseldorf,  Germany 
Physiologisches  Inslitut  der  Universitdt  Miinchen,  Miinchen,  Germany 


CHAPTER   CONTENTS 

Varied  Methods  and  Instruments  for  Flow  Measurement 
Admixing  Methods  for  Measurement  of  Regional  Blood  Flow 
Flowmeters:  Their  Theory,  Construction,  and  Operation 


Perhaps  no  other  field  of  physiological  methodology  encom- 
passes such  a  variety  of  physical  and  chemical  principles  as 
that  of  flow  measurement.  Principles  of  measurement  may  be 
and  have  been  developed  from  almost  every  topic  in  physics 
textbooks:  mechanics  {solid,  liquid,  and  gas),  sound,  elec- 
tricity, magnetism,  optics,  thermodynamics,  and  atomic 
physics.  For  this  reason  we  have  divided  the  duties  of  this 
section  and  each  author  has  taken  the  field  of  his  choice;  or, 
more  correctly,  two  authors  have  chosen  and  one  (K.  K.), 
like  Cinderella,  has  made  do  with  the  remainder. 

We  have  set  ourselves  the  task  first  to  review  these  various 
principles,  or  at  least  to  sketch  their  historical  development, 


and  second  to  acquaint  the  reader  with  the  manner  in  which 
each  method  fits  the  special  purposes  of  the  investigator. 

We  have  attempted  to  give  a  more  detailed  description  of 
modern  techniques  or  older  ones  which  are  still  in  use  today; 
in  this  we  have  tried  to  present  not  so  much  an  account  of 
technical  details  of  a  piece  of  apparatus  as  special  suggestions 
which  will  facilitate  its  use,  permit  judgment  of  its  reliability, 
and  guard  against  sources  of  error.  What  we  take  for  reality 
sometimes  changes  so  that  it  is  often  difficult  to  distinguish 
that  which  is  true  only  for  the  moment  from  that  which  will 
endure. 

If  older  methods  no  longer  in  use  today  are  mentioned,  it 
is  to  point  out  particular  disadvantages  which  caused  them 
to  be  abandoned.  In  this  way  we  hope  to  guide  the  young 
traveler  who  might  otherwise  take  these  fruitless  paths  again. 

K. KRAMER 
W.  LOCHNER 
E.  WETTERER 


I.  Varied  methods  and  instruments  for  flow  measurement 


KURT    KRAMER 


CONTENTS 

Outflow  Measurements 

Venous  Outflow  Collection 
Drop  Recording 

Methods  Based  on  Ludwig's  Principle 


Bubble  Flowmeter 
Venous-Occlusion  Methods 

Pulse  Plethysmography 

Photoelectric  Plethysmography 
Thermal  Methods 

Thermostromuhr 

Skin    Blood   Flow    Measurement   Based   on    Thermal    Con- 
ductance Measurement 

Flowmeters  Based  on   the   Measurement  of  Thermal   Con- 
ductivity 


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OUTFLOW  MEASUREMENTS 

Venous  Outflow  Collection 

the  simplest  and  most  reliable  way  to  measure  mean 
blood  flow  of  an  organ  consists  in  the  collection  of 
blood  from  an  opened  vein  into  a  graduated  cylinder 
over  a  measured  period  of  time.  Several  venous  out- 
flow recorders  with  intermittent  indication  of  flow 
rate  have  been  designed  (44).  In  Gaddum's  model 
(34)  blood  from  the  opened  vein  runs  into  a  cylinder, 
the  bottom  of  which  is  automatically  opened  after 
known  periods  of  time.  The  collected  volume  in  the 
cylinder  may  be  recorded  making  use  of  Brodie 
bellows,  strain  gauges,  or  other  devices  for  measuring 
volume  or  pressure.  The  Gaddum  principle  is  in  fact 
a  continuous  recording  of  graduated  cylinder  and 
stop  watch  readings.  The  dimensions  of  the  apparatus 
do  not  allow  measurements  lower  than  10  ml  per 
min.  Readings  every  2  sec  furnish  reliable  results. 
The  diameter  of  the  cylinder  must  be  adapted  to  the 
amount  of  blood  expected  to  leave  the  vein  per  unit 
time.  The  reliability  depends  mainly  on  the  rapidity 
of  emptying  the  cylinder  between  collection  periods. 

Drop  Recording 

Measurements  of  flow  rates  lower  than  2  ml  per 
min  can  be  obtained  by  recording  every  drop  of  blood 
leaving  the  blood  vessel.  In  most  devices  the  drop 
closes  an  electric  circuit  thereby  giving  an  electro- 
magnetic signal.  Enumeration  of  drop  signals,  how- 
ever, is  inaccurate  and  troublesome.  Therefore  con- 
struction of  an  instrument  that  records  time  elapsing 
between  two  drops  was  a  great  improvement  in  the 
method.  In  1935  Fleisch  (29)  described  an  apparatus 
in  which  a  motor-driven  lever  is  moved  up  on  a 
smoked  drum  until  the  drop  falls.  Closure  of  the 
electric  circuit  by  the  drop  initiates  the  interruption 
of  a  coupling  link  between  motor  and  lever  so  that  the 
lever  returns  to  its  original  level.  The  next  period  of 
measurement  always  begins  after  0.12  sec  regardless 
of  the  height  of  the  lever.  It  is  obvious  that  such  a 
recorder  is  more  complex  than  the  simple  marking 
apparatus  and  its  construction  involves  a  high  degree 
of  precision  work. 

With  the  development  of  electronics  a  principle 
was  applied  in  which  the  time  measurement  was 
performed  by  measuring  the  increase  of  voltage  on  a 
condenser  during  the  time  between  drops.  The  drop 
initiates  a  sudden  breakdown  of  the  condenser  charge. 


PERSPEX 
OR  POLY- 
ETHYLENE 

BLOOD 
SILICONE 

WATER 


fig.  i.  Schematic  drawing  of  the  drop  chamber  according 
to  Lindgren.  A  concentric  water  jacket  maintains  constant 
temperature  of  the  blood.  [From  Lindgren  (62).] 

The  voltmeter  records  deflections  which  are  pro- 
portional to  the  time  between  two  drops  (63a). 

Drop  recording  has  been  used  mainly  to  measure 
venous  outflow.  The  drawback  of  all  outflow  measure- 
ments is  loss  of  blood  and  the  necessity  for  prompt 
reinfusion.  A  definite  improvement  therefore  was  the 
introduction  of  a  drop  chamber  that  can  be  used  in  a 
closed  circulatory  system  (58).  The  blood  from  a  vein 
entering  the  drop  chamber  falls  in  drops  between 
electrodes  to  the  bottom  and  returns  to  the  distal  part 
of  the  dissected  vessel.  The  air  cushion  does  not  seem 
to  introduce  any  disadvantage  in  the  return  of  blood 
to  the  vein. 

Since  electrolysis  at  the  electrode  contacts  and  their 
coating  with  coagulated  blood  often  makes  readings 
unreliable,  a  photoelectric  drop  recording  device  has 
been  constructed.  A  combination  of  both  improve- 
ments— the  enclosed  drop  chamber  and  the  photo- 
electric recording  of  drops — seems  to  be  the  best  of  the 
fairly  simple  methods  (fig.  1).  Lingren"s  device  (62) 
uses  a  drop  chamber  filled  with  silicone  instead  of 
air,  thereby  avoiding  elastic  effects  especially  impor- 
tant in  arterial  blood  flow  measurements.  In  recording 
of  pulsatile  arterial  flow,  one  should  consider  also 
that  the  device  may  impair  the  transmission  of  pulse 
waves  to  the  peripheral  arterial  bed,  thereby  diminish- 
ing original   mean  flow   rate. 


METHODS    OF   MEASURING   BLOOD    FLOW 


12  79 


O 


Water 


^m^v, 


'IHMMMl 


Rotating 
plate 


A-\sB 


fig.  2.  Schematic  drawings  of 
direct  recording  flowmeters  de- 
rived from  Volkmann's  and 
Ludwig's  principles.  [From 
Dawes  et  al.  (22).]  a:  Volkmann 
(1850).  Open  7"i,  close  7\,  and 
time  movement  of  blood  through 
U-tube.  b:  Ludwig  (Dogiel, 
1867).  Time  movement  of  blood 
through  one  chamber  and  then 
reverse  chambers  by  hand,  c: 
Pavlov  (1887).  Time  movement 
of  blood  through  one  chamber 
and  reverse  direction  of  flow 
automatically  by  opening  elec- 
tromagnetic tap  Ti  and  closing 
T-..  d:  Dawes  et  al.  (22)  Close  T 
and  time  movement  of  blood  be- 
tween electrodes  A  and  B,  restore 
blood  levels  by  opening  T. 


METHODS     BASED     ON     LUDWIG  S     PRINCIPLE 

Volkmann,  (81  )  in  1850,  was  the  first  to  measure 
blood  flow  per  unit  time  in  arteries  (fig.  2a).  His  device 
consisted  of  a  U-tube  inserted  in  an  artery.  The  U- 
tube  could  be  bypassed  by  two  3-way  stopcocks.  When 
measurements  were  taken,  the  U-tube  was  filled  with 
saline.  After  turning  both  stopcocks  simultaneously 
the  blood  flowed  through  the  U-tube,  the  time  was 
measured  between  the  moments  when  the  blood 
entered  and  left  the  U-tube. 

This  method  obviously  did  not  allow  continuous 
measurement  of  blood  flow.  Another  drawback  was 
the  repeated  infusions  of  saline  with  each  measure- 
ment of  flow.  Therefore  Ludwig  and  colleagues 
(see  24)  modified  Volkmann's  device  (fig.  2b).  In  their 
version,  the  upstream  limb  of  the  U-tube  was  filled 
with  oil  and  the  downstream  one  with  blood.  The 
tube  itself  could  be  turned  by  hand  through  1800, 
to  connect  the  two  limbs  alternately  to  the  distal  and 
proximal  ends  of  the  artery.  The  blood  was  allowed  to 
enter  the  upstream  limb  and  the  tube  had  to  be  turned 
when  the  oil  content  reached  the  entrance  to  the 
distal  arterial  connection.  Each  turn  was  marked  on 
a  smoked  drum,  thereby  recording  blood  flow  con- 
tinuously. Apparatus  based  on  Ludwig's  principle 
have  been  constructed  with  many  modifications  and 
are  still  in  use  (6,  12,  69).  The  directness  of  the  meas- 
urement of  flow  can  be  regarded  as  the  main  reason 
for   its   popularity.    In    Ludwig's   laboratory    Pavlov 


(70)  developed  in  1887,  a  self-recording  flowmeter 
based  on  the  same  principle.  To  avoid  manipulations 
for  reversing  the  direction  of  flow,  he  designed  his 
meter  so  that  blood  could  be  made  to  enter  alternately 
either  limb  of  the  U-tube  by  opening  and  closing 
electromagnetic  taps,  (see  fig.  2c).  The  taps  were 
automatically  operated  by  means  of  floats  in  both 
limbs  moving  with  the  direction  of  flow  and  closing 
contacts  in  the  electromagnetic  circuit  when  the  rising 
float  reached  the  top  of  its  limb. 

The  Pavlov  type  flowmeter  has  been  used  in  numer- 
ous modifications.  The  U-tube  can  be  made  very 
small  for  low  flow  rates.  To  avoid  electrical  contacts 
within  the  blood  stream  the  electromagnetic  taps 
can  be  controlled  by  photoelectric  relays  (63). 

An  ingenious  device  based  on  Ludwig's  principle 
has  recently  been  described  by  Dawes  et  al.  (22)  (fig. 
2d).  The  upper  part  of  the  U-tube  is  filled  with  silicone 
oil,  the  lower  part  of  both  limbs  with  blood.  The  by- 
pass can  be  closed  by  an  electromagnetic  tap.  In  the 
inflow  limb  of  the  U-tube,  two  electrodes  which  oper- 
ate a  relay  for  opening  and  closing  the  electromag- 
netic tap  of  the  bypass  are  inserted  with  a  distance 
between  them,  such  that  about  1.5  ml  of  fluid  is 
enough  to  cover  both  contacts.  When  blood  enters 
the  proximal  limb  it  touches  one  electrode.  After 
1.5  ml  more  have  entered,  the  other  electrode  is  con- 
nected with  the  first,  thereby  closing  an  electric  cir- 
cuit and  setting  a  relay  causing  the  tap  to  open.  This 
allows  the  blood  which  entered   the  proximal  limb 


12  80 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Return 

chamber}; 


chamber 


I P 1 

5cm 

fig.  3.  Sectional  view  of  the  Dawes'  flowmeter.  The  cham- 
bers are  made  of  Perspex,  the  washers  of  Portex  sheet,  the  con- 
necting tubes  of  rubber,  and  the  electrodes  of  silver  wire.  The 
bag  is  molded  of  rubber  solution  on  a  form  (see  text).  [From 
Dawes  et  al.  (22).] 

to  return  to  the  arterial  stream  driven  by  a  pressure 
difference  between  the  two  limbs.  This  pressure  dif- 
ference is  supplied  by  the  density  difference  between 
blood  and  silicone  oil.  Therefore  the  authors  have 
called  their  apparatus  "density  flowmeter."  The  tech- 
nical details  are  more  involved  than  the  description 
of  the  principle  indicates.  As  can  be  seen  from  figure  3, 
in  the  actual  device  blood  is  not  allowed  to  enter  the 
electrode  chamber.  A  rubber  bag  filled  with  saline 
placed  in  the  lower  part  of  the  proximal  limb  is  com- 
pressed by  the  inflowing  blood,  emptying  its  contents 
into  the  part  of  the  limb  containing  the  electrode. 

The  apparatus  of  the  dimensions  given  in  figure  3 
can  measure  blood  flow  at  rates  as  high  as  45  ml  per 
min  with  an  absolute  accuracy  of  ±4  per  cent.  The 
pressure  drop  does  not  exceed  3  to  4  mm  Hg  at  maxi- 
mum rates.  The  dead  space  to  be  filled  with  blood 
amounts  to  about  4  to  5  ml.  The  range  of  flow  may  be 
extended  by  using  larger  measuring  chambers. 

For  measurement  of  time  intervals  any  kind  of 
ordinate  writer  (29)  can  be  used.  Gaddum's  drop- 
timer  (1938)  was  used  by  the  authors  (44). 


A  --till  simpler  sell-recording  flowmeter  making  use 
of  a  single  electromagnetic  tap  in  the  bypass  was  first 
described  by  Dawes  et  al.  and  has  been  constructed 
recently  by  Wretlind  (88).  When  the  bypass  is  closed 
the  blood  enters  the  U-tube,  consequently  bulging 
a  membrane  in  proportion  to  the  volume  flow.  The 
displacement  of  the  membrane  is  recorded  by  a  lever 
on  a  smoked  drum.  The  tap  is  automatically  opened 
every  2  sec  so  that  blood  in  the  U-tube  returns  to  the 
artery,  allowing  the  membrane  to  return  to  its  original 
position.  Then  the  cycle  begins  again  with  the  closing 
of  the  tap.  Since  the  lever  indicates  blood  flow  per  2 
sec,  the  record  gives  direct  readings  of  flow  rate. 


BUBBLE    FLOWMETER 

The  bubble  flowmeter  developed  by  Soskin  et  al. 
(75)  consists  of  a  glass  tube  of  known  caliber  and 


Amwiii 


fig.  4.  Schematic  drawing  of  a  bubble  flowmeter  :B,  bubble 
reservoir;  E,  entrance  of  the  bubble  into  the  flowmeter;  Mi  Aft, 
measuring  points  (platinum  electrodes)  for  timing  the  passage 
of  the  bubble;  S,  rubber  tubing;  V,  magnetic  tap  used  as  auto- 
matic bubble  injector.  [From  Rockemann  (72).] 


METHODS  OF  MEASURING   BLOOD   FLOW 


I28l 


length  which  is  inserted  into  the  blood  stream  from 
an  artery.  Near  the  proximal  end  of  the  tube  an  air 
bubble  of  such  a  size  as  to  completely  fill  a  short  sec- 
tion of  the  tube  is  injected  and  time  required  for  the 
bubble  to  pass  the  length  of  the  tube  is  recorded.  Near 
the  distal  end  of  the  tube  the  bubble  is  caught  in  a 
trap.  The  rate  of  flow  is  calculated  from  the  ratio  of 
volume  and  time,  as  is  done  for  all  the  foregoing  re- 
corders. 

To  utilize  this  principle  for  continuous  recording 
of  blood  flow,  an  automatic  injector  for  air  bubbles, 
automatic  removal  of  the  bubbles  after  they  pass  the 
tube,  and  a  recorder  of  time  required  for  passage  of 
each  bubble  are  necessary.  Several  solutions  of  the 
problem  have  been  proposed  (13,  15,  33,  57,  64,  65, 

87). 

A  recorder  for  the  passage  time  of  the  bubble  which 
uses  photoelectric  signals  caused  by  the  bubble  when 
passing  a  light  source  and  phototube  was  introduced 
by  Selkurt  (73).  Baumgartner  et  al.  (11)  added  an 
automatic  bubble  injector,  the  operation  of  which  is 
timed  by  the  passage  of  the  bubble  past  the  photocell 
detector.  A  schematic  drawing  of  a  recent  model  (72) 
is  seen  in  figure  4.  They  also  studied  the  over-all  prop- 
erties of  the  principle.  They  could  not  confirm  the 
assumption  that  blood  and  bubble  velocity  are  equal. 
Rather,  they  found  that  at  low  flows  the  bubble  ve- 
locity is  less  and  at  more  rapid  flows  it  is  greater  than 
the  blood  velocity.  The  reasons  for  these  deviations 
are  complex.  At  high  flows  the  bubble  seems  to  lose 
contact  with  the  wall  and  to  move  in  the  faster  axial 
stream  of  the  blood.  Viscosity  influences  the  bubble 
velocity  somewhat  but  not  seriously.  Maximal  devia- 
tions are  not  greater  than  ±5  per  cent.  However,  if 
an  accuracy  within  1  to  2  per  cent  is  desired,  they 
suggest  calibration  of  the  apparatus  with  blood  of  the 
animal.  Pulsation  is  without  influence  on  the  calibra- 
tion curve.  They  used  a  tube  3.5  mm  in  diameter 
and  35  cm  in  length.  The  resistance  to  flow  in  such 
a  tube  is  low  in  comparison  to  that  of  the  peripheral 
vascular  beds.  The  maximal  flow  they  studied 
amounted  to  300  ml  per  min.  At  this  rate  the  pressure 
gradient  was  not  more  than  4  cm  of  H.O.  This  value 
is  comparable  with  other  methods  used  on  opened 
vessels.  The  diameter  of  3.5  mm  cannot  be  much  in- 
creased because  at  diameters  of  more  than  4.5  mm 
the  air  bubble  will  not  fill  the  flowmeter  tube.  Length- 
ening the  tube  increases  the  sensitivity  of  the  meas- 
urement, but  also  increases  resistance  to  flow.  This 
fact  is  to  be  considered  mainly  in  measurements  of 
venous  flow. 


VENOUS-OCCLUSION    METHODS 

The  principle  of  the  venous-occlusion  method  con- 
sists in  temporarily  blocking  the  venous  outflow  from 
an  organ  which  is  enclosed  in  a  plethysmograph.  The 
blood  that  enters  the  organ  via  the  artery  is  thereby 
retained  and  indicated  as  a  volume  increase  by  the 
plethysmograph. 

In  this  way  the  method  is  an  almost  direct  volume 
measurement  per  unit  time  and  thus  comparable  in 
principle  to  those  described  in  the  foregoing  para- 
graphs. Brodie  &  Russell  (14),  who  first  described  the 
venous-occlusion  principle,  were  aware  of  the  main 
conditions  to  be  fulfilled:  ".  .  .  It  is  obviously  essential 
that  the  blockage  of  the  vein  must  not  be  maintained 
so  long  as  to  impede  the  flow  through  the  capillaries. 
Under  all  ordinary  conditions  the  veins  are  never 
completely  filled,  so  that  it  is  possible  to  store  up  in 
them  a  small  extra  quantity  of  blood  without  checking 
the  inflow  into  them  from  the  capillaries."  As  long 
as  the  volume  recorder  indicates  a  uniform  increase, 
the  inflow  is  not  impeded.  Brodie's  method  was 
adapted  by  Hewlett  &  von  Zwaluwenburg  (56)  to 
measure  blood  flow  in  extremities  in  man.  A  plethys- 
mograph similar  in  construction  to  that  of  Mosso 
was  used :  a  glass  cylinder  wide  enough  to  enclose 
the  hand  and  forearm,  from  which  a  rubber  tube  of 
small  dimensions  leads  to  the  recorder.  The  whole 
system  is  filled  with  water  to  avoid  volume  errors  due 
to  temperature  changes.  The  veins  are  blocked  by 
applying  pressure  of  50  mm  Hg  into  a  pneumatic  cuff" 
placed  on  the  upper  arm. 

Several  modifications  (79)  of  the  original  device 
have  been  described  (8-io,  46).  H.  Barcroft's  as- 
sembly is  now  most  commonlv  in  use  (fig.  5).  Mosso's 
glass  cylinder  is  replaced  by  a  conic  metal  tube.  The 
hand  is  covered  with  a  large  surgical  rubber  glove 
which  is  fixed  outside  the  plethysmograph  to  avoid 
leakage  of  water.  Since  any  movement  of  the  forearm 
will  change  the  volume  of  water  inside  the  plethys- 
mograph, the  circumference  of  the  glove  is  stiffened 
by  a  diaphragm  J/4-inch  thick.  The  diaphragm  is 
bolted  to  a  2-inch-wide  flange  on  the  end  of  the  ple- 
thysmograph by  means  of  metal  plates  and  wing 
nuts.  (For  further  details  see  the  original  paper.)  The 
pneumatic  cuff  is  connected  through  a  three-way  tap 
with  a  reservoir  of  compressed  air  at  60  to  70  mm  Hg. 
The  three-way  tap  allows  inflation  of  the  cuff  from 
the  reservoir  and  deflation  when  it  is  opened  to  room 
air.  Two  or  even  four  measurements  can  be  taken  in 
1  min,  if  blood  flow  is  high.  At  this  rate  of  measure- 
ment the  cuff  is  inflated  for  only  5  sec.  It  is  found  that 


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CIRCULATION    II 


TO    FLOAT   RECORDER 


THERMOMETER 


COLLECTING 
CUFF 


HIGGINSON  S      SYRINGE 


fig.  5.  Plethysmograph  for  the  hand  according  to  H. 
Barcroft.  The  hand  is  enclosed  in  a  loose-fitting  surgical  rubber 
glove.  [From  Barcroft  &  Swan  (10).] 

during  this  time  the  volume  of  the  hand  increases 
uniformly,  indicating  that  the  venous  reservoir  is  not 
filled  to  an  extent  which  would  impair  capillary  flow. 

The  recording  system  used  in  Barcroft's  experiments 
consists  of  a  small  spirometer  writing  on  a  smoked 
drum.  The  rubber  tubing  connection  between  the 
plethvsmograph  and  spirometer  is  filled  with  air.  The 
use  of  a  spirometer  makes  it  necessary  to  have  air  in 
the  rubber  tubing  connections  between  spirometer 
and  plethysmograph.  A  small  cylinder  on  top  of  the 
plethysmograph  allows  control  of  the  water  level  of 
the  apparatus.  An  electrically  recorded  tracing  of 
spirometer  movements  is  used  in  our  laboratory  mak- 
ing use  of  the  electromagnetic  principles  applied  in 
the  rotameter  recording  technique  (see  below). 

The  use  of  small  rubber  cuffs  as  plethysmography 
lias  been  recommended  recently  by  Dohm.  Models 
suitable  for  measurements  on  forearm  and  calf,  with 
which  it  is  possible  to  secure  good  venous-occlusion 
records  and  to  measure  blood  flow  during  muscular 
exercise,  are  especially  useful  on  moving  subjects  (41). 
The  plethysmographic  cuffs  are  made  of  thin-walled 
rubber  5  cm  wide.  The  filling  pressure  can  best  be 
about  +40  mm  H.,0  and  increase  with  1  per  cent 
volume  changes  of  the  extremity  segment  up  to  about 
50  mm  HaO.  The  pressure  was  measured  by  a  con- 
denser manometer. 

Avoiding  any  plethysmographic  devices,  Whitney 
(86)  proposes  the  use  of  a  strain  gauge  mounted  di- 
rectly on  the  limb.  It  records  the  changes  of  tension 


due  to  changes  in  blood  volume.  This  occlusion  tech- 
nique furnishes  results  not  remarkably  different  from 
those  obtained  by  using  water  or  air  plethysmography. 
Assuming  that  the  limb  is  distended  only  in  the  dia- 
metrical direction,  changes  of  circumference  can  be 
converted  directly  into  volume  changes.  However, 
corrections  for  compression  of  the  limb  by  increases 
in  blood  volume  are  deemed  to  be  necessary. 

A  serious  objection  to  the  venous-occlusion  method 
is  discussed  by  Gaskell  &  Burton  (35),  who  observed 
a  decrease  of  blood  flow  in  the  dependent  leg.  These 
authors  believe  in  a  venovasomotor  reflex  elicited 
by  distension  of  veins.  Since  the  venous-occlusion 
method  relies  on  the  fact  that  blood  entering  the 
region  of  measurement  is  collected  in  the  veins, 
thereby  distending  them,  it  is  important  to  the  valid- 
ity of  the  method  to  study  the  influence  of  venous 
distension  upon  vascular  reflexes. 

Greenfield  &  Patterson  (45)  showed  in  experiments 
on  the  forearm  at  different  states  of  venous  distention 
that  the  blood  flow,  as  measured  with  their  venous- 


Phase  1 


Phase  2 


Phase  3 


fig.  6.  Events  during  venous  occlusion  plethysmography. 
Actual  inflow  =  actual  outflow  +  apparent  inflow.  Each  divi- 
sion on  vertical  scale  for  inflow  and  outflow  represents  1  ml/ 100 
ml  of  forearm  per  min.  Total  duration  of  collection:  130  sec. 
[From  Greenfield  &  Patterson  (45).] 


METHODS    OF   MEASURING    BLOOD    FLOW 


!283 


occlusion  technique,  did  not  change.  Even  in  states  of 
venous  congestion  leading  to  2  per  cent  increase  of 
the  limb  volume,  the  blood  flow  was  almost  unaltered. 
Less  than  1  per  cent  increase  of  limb  volume  is  usually 
necessary  in  the  application  of  the  venous-occlusion 
method.  Considering  all  this,  they  offer  several  ex- 
planations of  Gaskell  and  Burton's  findings. 

Greenfield  and  Patterson  give  an  instructive  dia- 
gram of  events  during  venous  occlusion  (fig.  6).  In 
the  first  phase  of  occlusion  the  plethysmographic 
record  shows  a  straight  line  increase  indicating  a 
constant  inflow  of  blood  into  the  extremity.  In  the 
second  phase,  the  volume  increase  of  the  extremity 
declines  asymptotically,  indicating  that  the  inflow 
of  blood  progressively  decreases.  This  can  be  explained 
by  the  decreasing  arteriovenous  pressure  difference. 
In  a  third  phase  the  venous  pressure  reaches  the  oc- 
clusion pressure.  A  new  equilibrium  obtains  in  which 
there  probably  is  a  much  lower  blood  flow  through 
the  extremity.  The  volume  increase  in  the  occluded 
region  levels  off. 

The  "afterdrop"  (a  decrease  in  venous  pressure 
and  limb  volume  which  occurs  on  release  of  cuff  pres- 
sure if  the  veins  are  distended)  can  be  considered  as  a 
vasomotor  phenomenon.  It  can  also  be  explained  on 
mechanical  grounds.  The  release  of  the  pneumatic 
cuff  opens  up  an  area  of  compressed  veins  thereby 
acting  like  a  muscle  pump  on  the  underlying  veins 
(2).  [See  also  (1)  and  (82).] 


Pulse  Plethysmog  raphy 

According  to  Fick's  suggestion  it  is  generally  ac- 
cepted that  the  first  differential  quotient  of  volume 
change  in  an  extremity  occurring  during  the  course 
of  the  arterial  pulse  equals  the  change  in  the  rate  of 
arterial  inflow,  if  the  outflow  is  constant.  Von  Kries 
(60)  and  later  Frank  (31)  used  tachographs  and  ple- 
thysmographs  on  the  forearm  and  measured  changes 
of  volume  and  of  the  rate  of  arterial  inflow  during  the 
arterial  pulse.  A  combination  of  pulse  plethysmog- 
raphy and  venous-occlusion  technique  was  used  by 
Burton  (19,  27),  Burch  (16,  18),  and  others  in  order 
to  obtain  absolute  values  for  flow  rates  during  the 
time  course  of  the  arterial  pulse  in  fingers  and  hands. 
The  plethysmographic  devices  (cylinders,  cuffs,  re- 
cording systems)  are  adapted  to  the  size  of  the  ex- 
tremities in  question.  The  recording  systems  consist 
of  capsules  covered  with  thin  membranes,  the  bulging 
of  which  corresponds  to  volume  displacements  and 
are  recorded  optically.  [For  details  see  (17,  66).] 


Photoelectric  Plethysmography 

Measurements  of  transparence  and  reflectance  of 
infrared  light  in  skin  areas  furnish  almost  the  same 
values  for  blood  volume  changes  as  do  the  direct 
mechanical  methods  (52-55).  The  calibration  of  such 
instruments  involving  calorimetric  or  venous-occlu- 
sion techniques  cannot  claim  great  accuracy.  How- 
ever, the  simplicity  of  the  experimental  procedure 
allows  the  use  of  instruments  adapted  to  special  pur- 
poses not  only  in  various  skin  areas  but  also  on  the 
surfaces  of  organs  such  as  the  brain  or  kidney.  The 
latter,  especially  with  its  high  blood  content  (about 
23%),  has  been  the  object  of  blood  flow  studies  uti- 
lizing the  light  absorption  properties  of  Hb  in  the  red 
and  infrared  regions.  Procedures  have  been  elabo- 
rated (59)  that  allow  measurement  of  blood  content 
in  cortical  and  medullary  areas  of  the  kidneys,  as  well 
as  total  blood  flow  using  dye  dilution  and  oxymetric 
principles. 


THERMAL    METHODS 

Thermostromuhr 

Thermal  methods  of  measuring  blood  flow  are 
based  on  the  principles  of  measurement  of  heat  con- 
duction. It  is  assumed  that  any  condition  leading  to 
loss  or  gain  of  heat  in  the  blood  stream  would  depend 
among  other  variables  on  its  volume  flow.  Gesell  & 
Bronk  (37)  cannulated  the  blood  vessel  and  let  the 
blood  pass  through  a  tube  surrounded  by  a  concentric 
water  jacket  which  was  flushed  by  a  constant  flow 
of  water  at  room  temperature.  The  loss  of  heat  from 
the  blood  measured  by  the  temperature  increase  in 
the  outflowing  water  was  found  to  be  inversely  pro- 
portional to  the  volume  flow  of  blood.  Corrections 
were  of  course  made  for  different  blood  temperatures. 
The  response  to  changes  in  flow  is  slow — of  the  order 
of  1  min. 

A  few  years  later  H.  Rein  (71)  constructed  his 
thermostromuhr,  which  was  made  for  use  on  un- 
opened blood  vessels.  This  method  was  regarded  as  a 
great  improvement  both  as  to  lag  time  and  conven- 
ience. 

The  original  conception  of  the  thermostromuhr 
was  based  on  the  assumption  that  an  alternating  cur- 
rent of  high  frequency  applied  to  a  blood  vessel  would 
heat  the  blood  radially.  The  temperature  rise  (A 7") 
of  this  disc  of  blood  would  then  be  proportional  to 
the  product  of  square  of  the  current  (T2)  and  electrical 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


resistance  (/?)  and  inversely  proportional  to  the  blood 
flow  (V)  and  specific  heat  (c).  Measurements  of  blood 
flow  using  a  device  with  two  thermojunctions  placed 
on  each  side  of  a  pair  of  heating  electrodes  seemed 
to  justify  the  above  assumptions,  and  permit  using 
the  following  equation : 


1/-C-" 


AT 


0.239 


(I) 


According  to  this  equation,  the  calibration  curve  is 
hyperbolic.  This  type  of  curve  has  actually  been 
found  in  all  thermostromuhr  devices.  However,  quan- 
titative measurements  of  AT  (3)  show  values  about 
ten  times  higher  than  expected.  This  finding  indicates 
that  the  assumption  of  a  uniformly  heated  cross  sec- 
tion of  the  blood  vessel  is  not  valid.  The  error  in  de- 
termining AT  is  found  to  result  from  heating  the 
vessel  wall  much  more  than  the  blood.  Due  to  the 
complicated  arrangement  of  electrical  resistances  to 
high-frequency  current  in  the  wall,  the  liberation  of 
heat  in  the  blood  column  amounts  to  only  10  per  cent 
in  arteries  and  20  to  40  per  cent  in  veins  (83).  The 
original  assumption,  therefore,  must  be  revised:  the 
radial  heat  gradient  is  directed  from  outside  to  inside 
the  vessel  and  not,  as  suggested  by  Rein,  from  inside 
to  outside.  The  basic  principle  by  which  the  stromuhr 
measures  flow  is  the  change  in  T  in  the  vessel  wall 
with  blood  flow,  because  of  cooling  it  by  the  blood 
stream.  Findings  based  on  this  assumption  are  in  good 
agreement  with  the  earlier  results  obtained  with  the 
direct  current  method,  showing  that  there  is  no  basic 
difference  between  the  methods  (4,  5,  74,  77). 

Further  studies  (3)  on  heat  dissipation  in  the  wall 
of  the  vessel  and  in  the  blood  stream  have  revealed 
a  temperature  profile  of  complex  nature. 

The  temperature  gradients  are  directed  from  out- 
side to  inside  the  vessel  radially  and  also  along  the 
length  of  the  wall  both  upstream  and  downstream 
with  highest  temperature  underneath  the  heating 
electrodes. 

This  temperature  profile,  however,  is  not  sym- 
metrical for  two  reasons:  first,  since  heating  electrodes 
are  attached  to  a  segment  of  the  wall,  the  tempera- 
tures measured  in  the  plane  of  the  heating  electrodes 
are  higher  than  in  a  plane  at  an  angle  to  it;  second, 
since  the  blood  stream  cools  the  upstream  wall  sec- 
tion more  than  the  downstream  section,  the  tempera- 
ture profile  is  lengthened  in  the  downstream  direction. 

The  temperature  profile  changes  with  blood  flow. 
The  asymmetry  of  temperature  distribution  along 
the  wall  of  the  vessel  increases  with  decreasing  blood 
flow.  The  temperature  of  the  upstream  section  changes 


less  than  that  of  the  downstream  section.   It  is  this 
fact  which  makes  the  device  a  flowmeter. 

From  Gregg's  investigations  (43,  74)  on  direct  cur- 
rent stromuhrs  it  was  expected  that  pulsations  of  the 
blood  stream  should  distort  the  temperature  profile 
in  an  unpredictable  manner.  Wever  &  Aschoff  (84), 
working  with  a  stream  having  large  pulsations,  found 
that  thermojunctions  arranged  at  an  angle  of  90° 
to  the  heating  electrodes  yield  false  readings  which 
are  opposite  to  those  obtained  at  an  angle  of  0°.  The 
practical  application  of  these  studies  has  led  to  the 
construction  of  a  device  using  ring  electrodes,  by 
which  temperatures  of  the  complex  profile  are  aver- 
aged, and  errors  due  to  pulsation  are  avoided.  These 
electrodes  also  compensate  for  errors  resulting  from 
nonlinearity  of  the  calibration  curve  (fig.  7).  Since 
the  highest  temperature  exists  on  the  outside  of  the 
vessel  wall,  any  uncontrolled  heat  dissipation  to  the 
outside  of  the  unit  would  lead  to  an  undetectable 
error  of  measurement.  In  the  new  models  (3),  a 
double  wall  including  air  for  thermoisolation  is  in- 
troduced. 

Where  backflow  occurs,  the  deviation  in  the  meas- 
urements is  always  in  the  direction  of  increasing  flow. 
The  effect  of  backflow  can  be  diminished  by  means 
of  asymmetrical  placement  of  the  thermojunctions 
(77).  When  the  downstream  thermojunction  is  placed 
close  to  the  heating  electrodes  and  the  upstream  junc- 
tion is  farther  off,  the  backflowing  blood  heated  during 
its  passage  through  the  hot  vessel  wall  will  reach  the 
upper  junction  later  and  will  have  less  influence  on 
the  measurement. 

Although  methods  based  on  the  thermostromuhr 
principle  have  been  abandoned  during  the  last  dec- 
ades because  of  inherent  inaccuracies  (7,  25,  26,  43), 
the  new  analysis  given  by  Aschoff  and  Wever  has 
revived  interest  in  the  matter. 

Skin  Blood  Flow  Measurement  Based  on  Thermal 
Conductance  Measurement  (20,  32,  48-51,  85) 

Since  the  heat  produced  in  animals  and  humans  is 
transported  mainly  by  blood  flow,  the  heat  flow  of  a 
defined  area  of  the  skin  is  related  to  blood  flow  through 
it.  However,  it  is  obvious  that  any  change  of  tempera- 
ture gradient,  such  as  that  induced  by  changes  of  the 
surrounding  temperature,  will  influence  the  heat  flow 
and  therefore  invalidate  the  measurement  of  blood 
flow.  The  best  values  are  obtained  with  devices  which 
measure  heat  flow  and  temperature  gradient  simul- 
taneously. 

The  following  equation  gives  a  measure  of  blood 


METHODS   OF  MEASURING   BLOOD    FLOW 


1285 


flow  from  the  relationship  of  these  two  variables  in 
the  form  of  a  thermal  conductance  coefficient : 

a  (2) 


Tc 


Tsk 


where  Q  equals  heat  flow  in  (cal  cm2  sec),  Tc  =  core 
temperature  and  T,k  =  skin  temperature  in  °C.  The 
dimension  of  A  is  calories  per  square  centimeter  second 
°C.  The  Tc  as  measured  does  not  always  represent  the 
temperature  of  the  arterial  blood  in  the  region  under 
study.  Heat  may  be  lost  during  the  passage  of  blood 
irom  the  core  to  the  site  of  measurement.  Hensel  (50) 
points  out  that,  among  other  things,  the  special 
geometry  of  the  skin  area,  insulation,  local  metabo- 
lism, and  countercurrent  heat  exchange  between 
arteries  and  veins  may  modify  k  without  changes  of 
blood  flow. 

If  it  is  possible  to  keep  these  variables  constant, 
relative  changes  in  blood  flow  in  skin  areas  can  be 
estimated  by  measuring  k.  Several  methods  are  pro- 
posed. The  measuring  device  should  avoid  the  "re- 
action-error'' which  would  occur  if  calorimeter  de- 
vices are  used  with  large  heat  capacities  and 
temperatures  different  from  those  of  the  skin  (48). 
However,  it  is  necessary  that  the  heat  resistance  of 
the  device  be  made  much  lower  than  that  of  the  skin, 
the  resistance  of  which  is  determined  by  the  blood 
flow. 

A  device  (85)  that  fulfills  the  above  conditions  con- 
sists of  a  cork  plate  1  mm  thick  covered  with  two  silver 
plates  with  two  thermojunctions.  The  unit  is  fixed 
tightly  on  the  skin.  The  temperature  gradient  meas- 
ured between  these  plates  is  proportional  to  Q,  the 
heat  flow  from  the  skin.  The  temperature  difference 
Tc  —  T,k  is  measured  by  connecting  the  skin  thermo- 
junction  with  a  third  junction  placed  in  the  mouth 
or  rectum.  The  quotient  Q/(TC  —  Tsk)  is  measured 
by  a  bridge  circuit  or  by  a  ratiometer.  Q  can  only  be 
measured  if  the  thermal  conductivity  of  the  cork 
plate  is  known.  This  value  must  be  determined  ex- 
perimentally. Synchronous  measurement  of  k  and 
blood  flow  of  the  finger  with  the  venous  occlusion 
technique  furnish  a  fairly  good  proportionality.  This 
was  found  at  different  room  temperatures  (15-30  C) 
as  well  as  at  different  skin  and  rectal  temperatures. 
Also,  insulation  of  the  arm  did  not  influence  the  meas- 
urements. It  seems  therefore  that,  according  to  Aschoff 
and  Wever's  results,  blood  flow  is  the  main  factor 
determining  k. 


Vein 

Artery 


7 


50 


100       150       200 


fig.  7.  Measurements  with  original  Rein  elements  and 
Aschoff  and  Wever  ring-element.  Figure  shows  effect  on  flow 
readings  when  heating  electrodes  are  placed  at  900  and  o°  to 
the  thermojunctions.  The  compensating  effect  of  a  ring  unit  in 
which  the  thermojunctions  are  fixed  on  silver  rings  surrounding 
the  vessel  is  shown  to  be  effective  for  pulsations  up  to  1 20%  of 
mean  flow.  Abscissa  =  oscillations  in  percentage  of  mean  flow. 
Ordinate  =  thermostromuhr  readings.  [From  Wever  &  Aschoff 
(84)-] 

Flowmeters  Based  on  the  Measurement 
of  Thermal  Conductivity 

In  1 92 1  the  mathematician  Carlslaw  showed  that 
when  a  special  source  of  heat  is  surrounded  by  an 
infinitely  extended  mass  of  material  a  steady  state  is 
approached  in  which  the  relation  between  heat  pro- 
duction, such  as  that  generated  electrically,  and  heat 
loss  is  described  by  the  equation: 


IZR 


4vrATX 


(3) 


where  /  =  electric  current  heating  a  filament  with 
the  resistance  R,  r  =  radius  of  the  sphere,  T  =  tem- 
perature of  the  sphere,  and  X  =  the  thermal  con- 
ductivity constant. 

In  application  to  our  problem  we  have  to  consider 
that  X,  because  of  the  complexity  of  the  tissue,  is  not 
a  simple  constant  but  depends  on  several  parameters 
of  the  tissue  under  study  (80),  and  most  importantly 
on  blood  flow.  This  dependence  on  flow  provides  the 
basic  principle  for  measurement  with  this  type  of 
flowmeter.  Experimental  data  (42)  provided  by  meas- 
urements of  AT  on  living  organs  have  shown  that  a 


1286 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


linear  relationship  exists  between  blood  flow  and  the 
apparent  increment  of  X.  Direct  readings  of  X  may 
be  recorded  (42)  by  keeping  T  constant  through 
variation  of  7.  It  should,  however,  be  borne  in  mind 
that  only  relative  values  for  blood  flow  can  be  ob- 
tained. The  principle  can  be  applied  either  to  surfaces 
or  to  inner  regions  of  organs.  For  these  various  ap- 
plications several  types  of  instruments  have  been 
developed.  As  an  example,  for  measurements  of  blood 
flow  through  deep  layers,  heat  source  and  temperature 
measuring  units  are  contained  in  a  needle  (38,  39, 
42,  47,  68). 

Hensel's  modification  shown  in  figure  8  contains 
both  thermojunctions  within  the  needle,  one  at  the 
tip  together  with  the  heating  wire,  and  the  other  at 
the  middle  of  the  needle.  According  to  Graf  &  Rosell 
(40),  reliable  measurements  are  obtained  only  when 
the  tip  of  the  needle  is  placed  in  close  proximity  to  a 
vessel,  either  an  artery  or  vein.  This  condition  is 
checked  by  comparison  of  X-values  obtained  in  the 
ischemic  and  normal  state  which  should  be  in  the 
order  of  1    X    io~4  cal  per  sec  cm  C.  Lower  values 

Connections 

to  healing  sou/re 

nj^—to  galvanometer 


Cross 
section 


-Cannula 
-Heating   wire 

rhermojunction 
(hot) 


fig.  8.  Schematic  drawing  of  longitudinal  and  cross  sections 
of  Hensel's  needle  for  measuring  thermal  conductivity  in  tissue. 
[From  Hensel  el  at.  (47)-] 


T her  moj  unction 
( cold  J 


□  V2A  steel 
f~1  Copper 
^  Iron 
■I  Constantan 
r~"l  Solder  metal 
I     I  Glass 


■ 

350J 

A 

■     ■ 

- 

■ 

4 
O 

250- 

»* 

■ 
■ 

■ 
■ 

• 
■ 

• 
• 
•  • 

150- 

a 

'•a 

<a 

a°° 

50- 

A  m 

—i r 

A 

BLOOD     FLOW    IN  % 

1                      T                      I                      1 

50 


150 


250 


350 


fig.  9.  Relation  between  thermal  conductivity  increments 
(AX)  and  blood  How  in  muscles  of  the  cat's  hind  limb.  Changes 
in  blood  flow  were  induced  by  intra-aortic  infusions  of  adrena- 
line and  acetylcholine  and  by  hypothalamic  stimulation.  Four 
experiments  marked  with  different  signs.  [From  Graf  &  Rosell 
(40).] 

indicate  that  the  tip  is  placed  too  far  from  the  vessel. 
This  remote  position  would  also  result  in  a  slow  re- 
sponse to  blood  flow  changes.  A  plotting  of  direct 
recorded  values  of  blood  flow  through  a  hind  limb 
of  a  cat  and  values  obtained  with  Hensel's  needle 
show  that  the  percentage  changes  of  X  accord  well 
with  the  percentage  changes  of  direct  measurements. 
However,  the  above-mentioned  condition  of  a  con- 
ductivity increment  of  at  least  1.0  X  io"4  cal  per 
sec  cm  C  was  fulfilled  (fig.  9).  The  advantage  of  the 
device  lies  in  the  fact  that  it  can  be  used  in  humans 
without  interfering  with  the  normal  state  of  blood 
flow. 

To  record  blood  flow  on  organ  surfaces,  as  on  vkin, 
brain,  or  eye,  several  modifications  of  a  "surface 
thermostromuhr"  have  been  constructed.  A.  C.  Bur- 
ton has  utilized  the  principle  of  electrical  resistance 
changes  with  temperature.  "Two  flat  resistance  coils, 
the  smaller  a  central  disc  and  the  larger  a  ring  about 
it,  with  an  insulating  gap  between,  form  the  two  arms 
of  a  Wheatstone  bridge.  These  coils  are  of  wire  which 
has  a  high  temperature  coefficient  of  resistance,  while 
the  other  two  coils  of  the  bridge  are  of  constant  re- 
sistance. The  battery  supplying  the  bridge  is  arranged 
to  drive  current  through  the  two  'skin'  coils  in  parallel. 
Since  the  central  coil  is  of  lower  resistance,  greater 
heat  is  generated  since  the  current  is  greater  in  it, 
and  as  a  result  it  will  reach,  in  the  thermal  steadv 


METHODS   OF  MEASURING  BLOOD    FLOW 


1287 


001 3r 


0012  -: 


•0011 


0010  - 


0009 


0008  - 


0007 


fig.  10.  The  relationship  between  effective  thermal  conductivity  of  the  skin  and  blood  flow  in  the 
lingers.  The  three  curves  are  for  different  subjects.  The  points  for  zero  How  (circled)  were  obtained 
by  occlusion  of  the  flow  by  a  cuff  on  the  proximal  phalanx,  while  the  other  data  for  low  flows  were 
obtained  by  vasoconstriction  in  response  to  cold.  [From  Burton  ( 2 1 ).] 


state,  a  higher  temperature  above  the  skin  than  the 
other,  'ring'  coil.  The  difference  of  temperature  be- 
tween the  two  coils  is  registered  directly  by  the  de- 
flection of  the  galvanometer  of  the  bridge."  [Burton 

(2.).] 

Hensel's  device  consists  of  a  round  plexiglass  plate 
on  which  the  hot  and  cold  thermojunctions  are  placed 
at  a  distance  of  a  few  centimeters.  The  units  can  be 
applied  to  finger  tips  and  the  conductivity  increment 
obtained  with  changes  of  blood  flow  can  be  checked 
by  the  venous  occlusion  technique.  Burton's  results 
on  three  subjects  show  linear  relationships  (fig.  10). 
However,  in  the  ischemic  state  X  varies  significantly 
from  subject  to  subject  so  that  a  general  calibration 
cannot  be  used. 

A  similar  device  to  apply  on  the  brain  surface  in 
animal  experiments  has  been  designed  by  Kanzow 
(58a).  In  his  unit  heat  is  directly  applied  by  diathermy 
to  the  brain  tissue,  and  the  temperature  difference 
between  the  heated  area  and  the  unheated  control 
area    is    measured    by    thermocouples.    This    device 


shows  that  a  linear  relationship  between  X  and  blood 
flow  exists,  providing  the  electrical  resistance  of  the 
tissue  does  not  change.  Kanzow  claims  that  X-changes 
occurring  with  changes  in  blood  content  within  the 
tissue  can  be  detected  from  readings  of  tissue  resist- 
ance, thereby  helping  to  avoid  errors  in  blood  flow 
estimations. 

Thermocouples  can  be  replaced  by  thermistors 
which  are  placed  in  Cournand  catheter  tips  or  in 
glass  cannulas  used  for  blood  flow  measurements  in 
larger  vessels  (23,  28,  30,  36,  61,  67,  76,  78,  84,  8g). 
The  chief  advantage  of  such  units  is  their  small  size. 
However,  this  type  of  device  does  not  distinguish 
backward  from  forward  flow,  and  quantitative  meas- 
urement of  blood  flow  is  not  possible  with  it  since 
the  diameter  of  the  vessel  is  not  controlled.  Even 
with  measurements  on  arteries  cannulated  with  glass 
tubes  with  imbedded  thermistors  the  results  are 
doubtful,  since  the  velocity  profile  of  the  blood  is  not 
uniform.  Also,  recordings  of  flow  pulses  are  distorted 
because  of  the  low  frequency  response  of  such  units. 


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HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


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53.  Hertzmann,  A.  B.,  W.  C.  Randall,  and  K.  E.  Jochim. 

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55.  Hertzmann,  A.   B.   Photoelectric  plethysmography  of  the  74. 
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56.  Hewlett,  A.  W.,  and  J.   van  Zwaluwenburg.   Method 

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Blasengeber  fur  das  Bubble-flowmeter.  Pfliigers  Arch.  ges. 
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58.  Hilton,  S.  M.  A  perspex  drop  chamber.  ./.  Physiol., 
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59.  Kramer,  K.,  K.  Thurau,  and  P.  Deetjan.  Hamodynamik 
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Anal.  Abt.    (Physiol.  Abt.)  P,  254,  1887. 

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62.  Lindgren,  P.  An  improved  method  for  drop  recording  of         81. 
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Lullies,   H.    Ein    Zeitordinatenschreiber   auf  elektrischer 

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DurchflufigrolSe  und  elektrischer  Registrierung   auf  einem 

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i960. 

Lutz,  J.   Blasen-Stromuhr   (Bubble-flowmeter)  mit  Rohr- 

elektroden    und    einem    Mel5wertumformer    zur    linearen 

Registrierung    auf    Direktschreibern.    Arch,    exptl.    Pathol. 

Pharmacol.  240:341,  1961. 

Mead,  J.,   and   R.    C.    Schoenfeld.    Character  of  blood 

flow   in   the   vasodilated   finger.   J.   Appl.   Physiol.    2 :  680, 

1950. 

Mellander,  S.,  and  R.  F.  Rushmer.  Venous  blood  flow 

recorded  with  an  isothermal  flowmeter.  Acta  Physiol.  Scand. 

48:  13,  i960. 

Mowbray,  J.  F.  Measurement  of  tissue  blood  flow  using 

small  heated  thermocouple  needles.  J.   Appl.   Physiol.    14: 

647.  '959- 

Olerud,  S.  Experimental  studies  on  portal  circulation  at 
increased  intra-abdominal  pressure.  Acta  Physiol.  Scand. 
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Pavlov,  I.  P.  Uber  den  Einfluss  des  Vagus  auf  die  Arbeit 
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Rein,  H.  Uber  Durchblutungsmessungen  an  Organen  in 
situ,  insbesondere  mit  der  Thermostromuhr.  Ergeb. 
Physiol,  exptl.  Pharmacol.  45:  514,  1944. 

Rockemann,  W.  Ein  Bubble-Flowmeter  mit  elektrischer 
Blasenregistrierung  und  vereinfachtem  Blasengeber.  Pflii- 
gers Arch.  ges.  Physiol.  272:  393,   1961. 

Selkurt,  E.  E.  An  optically  recording  bubble  flowmeter 
adapted  for  measurement  of  renal  blood  flow.  J.  Lab.  Clin. 
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Shipley,  R.  E.,  D.  E.  Gregg,  and  S.  T.  Wearn.  Opera- 
tive mechanism  of  some  errors  in  the  application  of  the 
thermostromuhrs  method  to  the  measurement  of  blood 
flow.  Am.  J.  Physiol.  136:  263,  1942. 

Soskin,  S.,  W.  S.  Priost,  and  W.  J.  Schultz.  Influence 
of  epinephrine  upon  exchange  of  sugar  between  blood  and 
muscle.  Am.  J.  Physiol.  108:  107,  1934. 
Suckling,  E.  E.,  and  A.  Vogel.  Thermistor  bridge  for 
blood  flow  measurement.  J.  Appl.  Physiol.  15:  966,  i960. 
Schmidt,  C.  F. ,  and  A.  M.  Walker.  A  thermostromuhr 
operating  on  storage -battery  current.  Proc.  Soc.  Exptl. 
Biol.  Med.  33:346,  1935- 

Schmidt,  L.,  and  R.  Engelhorn.  Die  Abhangigkeit  der 
Coronardurchblutung  vom  arteriellen  Blutdruck.  Arch, 
exptl.  Pathol.  Pharmacol.  218:  115,  1953. 
Stead,  E.  A.,  Jr.,  and  P.  Kunkel.  A  plethysmographic 
method  for  the  quantitative  measurement  of  the  blood 
flow  in  the  foot.  J.  Clin.  Invest.  17:711,  1 938. 
Vendrik,  A.  J.  H.,  and  J.  J.  Vos.  A  method  for  the 
measurement  of  the  thermal  conductivity  of  human  skin. 
J.  Appl.  Physiol.  11:211-215,  1957. 

Volkmann,  A.  W.  Die  Haemodynamik.  Leipzig:  Breitkopf 
und  Hartel,  1850. 

Wallace,  W.  F.  M.  Does  the  hydrostatic  pressure  of  the 
water   in   a   venous   occlusion   plethysmograph   affect   the 
apparent  rate  of  blood  flow  to  the  forearm?   J.   Physiol., 
London  143:  380,  1958. 
Wever,    R.    Die   Verteilung   des    Diathermie-stromes    im 


1290 


HANDBOOK    OK    PHYSIOLOGY 


CIRCULATION    II 


Blutgefass     bei     der     Thermostromuhr-Messung.     Pflugers 
Arch.    ges.  Physiol.  262:  1,  1955. 

84.  Wever,  R.,  and  J.  Aschoff.  Durchfluflmessung  mit  der 
Diathermie-Thermostromuhr  bei  pulsierender  Stromung. 
Pflugers  Arch.  ges.  Physiol.  262:  152,  1956. 

85.  Wever,  R.,  and  J.  Aschoff.  Die  Warmcdurchgangszahl 
als  DurchblutungsmalS  am  Menschen.  Pflugers  Arch.  ges. 
Physiol.  264:  272,  1957. 

86.  Whitney,  R.  J.  The  measurement  of  volume  changes  in 
human  limbs.  ./.  Physiol.,  London  121  :  I,  1953. 


87.  Winder,  C.  V.,  J.  Wax,  and  R.  W.  Thomas.  Stable 
precision  in  a  readily  assembled,  continuously  recording 
bubble-flowmeter.  J.  Lab.  Clin.  Med.  42:  766,  1953. 

88.  Wretlind,  A.  Recorder  for  blood  flow  determination. 
Acta  Physiol.  Scand.  40:  196,  1957. 

89.  Zijlstra,  W.  G.,  J.  R.  Brunsting,  and  L.  B.  Slikke, 
Intravascular  and  intracardiac  blood  velocity  patterns 
recorded  by  means  of  NTC  resistors.  Xature  184:  Suppl 
13.  99>.  '959- 


II.  Admixing  methods  for  measurement  of  regional  blood  flow 


WILHELM    LOCHNER 


CONTENTS 


Blood  Tissue  Exchange  Methods 
Nitrous  Oxide  Method 

Measurement  of  cerebral  blood  flow 

Measurement  of  coronary  blood  flow 
Other  Test  Substances 
Test  Substance  Dilution  Methods 

Measurement  of  Coronary  Blood  Flow 

Measurement  of  Cerebral  Blood  Flow 

Measurement  of  Flow  in  Other  Organs 

Measurement  of  Flow  in  a  Blood  Vessel  Without  Interposing 

an  Organ 


BLOOD    TISSUE    EXCHANGE    METHODS 

X 1I1  mis  Oxide  Method 

MEASUREMENT  OF  CEREBRAL  BLOOD  FLOW.  The  nitrOUS 

oxide  method  for  determination  of  cerebral  blood 
flow  was  developed  by  Kety  &  Schmidt  (20,  22)  in 
1945.  Since  then  it  has  become  a  standard  method 
for  determinations  in  man  of  both  cerebral  and  cor- 
onary blood  flow,  especially  because  extensive  opera- 
tive procedures  can  be  avoided.  The  nitrous  oxide 
method  makes  use  of  Fick's  principle  of  blood  flow 
estimation.  The  test  substance,  nitrous  oxide,  is  an 
easily  diffusible,  inert  gas  which  diffuses  into  the  tis- 
sues fast  enough  to  allow  equilibrium  between  gas 
tensions  in  tissue  and  venous  capillaries.  With  a  known 
partition  coefficient  of  the  gas,  and  under  the  assump- 
tion  that   equilibrium   between    tissue   and    blood   is 


reached,  the  amount  of  test  substance  taken  up  by 
100  g  of  tissue  can  be  calculated  (21).  Simultaneous 
measurement  of  arteriovenous  nitrous  oxide  difference 
then  permits  calculation  of  the  blood  flow  per  minute 
per  100  g  of  tissue.  Applying  Fick's  principle,  the 
formula  (22)  is: 


CBF- 


IOOVu-S 


wherein 


.1  =  arterial  N-iO — concentration 
I"  =  venous  N;0 — concentration 
S         =  partition    coefficient   for   NoO    between    blood   and 

tissue 
['„       =   venous  N20  concentration  after  equilibrium  reached 

in  tissue  during  time  u 
CBF  =  cerebral  blood  flow  per  100  g  brain  tissue  per  min 

The  procedure  of  measurement  is  as  follows:  The 
patient  breathes  a  gas  mixture  of  oxygen,  nitrogen 
and  1  5  per  cent  nitrous  oxide  over  a  period  of  10  min 
(time  u).  During  this  time,  five  consecutive  blood 
samples  are  taken  simultaneously  from  the  internal 
jugular  vein  and  from  a  peripheral  artery.  The  sam- 
ples must  be  collected  under  anaerobic  conditions. 
They  are  analyzed  for  NoO  according  to  the  method 
of  Orcut  &  Waters  (33).  [See  also  Kety  (23).]  Figure  1 
shows  arterial  and  venous  time-concentration  curves 
of  nitrous  oxide  in  a  typical  determination.  As  can 
be  seen  from  the  figure,  ten  blood  samples  have  to  be 
analyzed,  an  undesirable  feature  of  the  method.  A 
modification  of  this  method  has  been  proposed  by 
Scheinberg  &  Stead  (38)  and  by  Bernsmeier  & 
Siemons  (3).  Intermittent  sampling  is  replaced  by 
continuous  sampling  of  only  two  probes,  one  arterial 


METHODS    OF   MEASURING    BLOOD    FLOW 


1291 


4  - 


3  - 


0  2 

fig.  i.  Typical  arterial  (A)  and  internal  jugular  (V)  curves 
of  N20  concentration  during  a  10-min  period  of  inhalation  of 
[5%  Nl.O.  [From  Kety  &  Schmidt  (22).] 

and  one  venous,  during  the  measuring  period  of  10 
min.  The  advantages  of  this  modification  are  seen 
in  the  fact  that  a)  only  one  person  is  needed  for  taking 
the  samples,  b)  less  blood  is  taken  from  the  patient, 
and  c)  the  number  of  gas  analyses  is  reduced  from 
ten  to  three  (25).  The  modified  method  yields  results 
identical  with  those  obtained  with  the  original 
method.  However,  Kety  (24)  prefers  his  primary  pro- 
cedure of  intermittent  sampling  since  he  believes  that 
the  course  of  arterial  and  venous  time  concentration 
curves  allows  an  estimation  of  the  volume  of  blood 
from  extracranial  vessels  which  has  been  intermixed 
with  cerebral  blood  flow.  This  point  is  of  general  im- 
portance and  will  be  briefly  discussed  here.  The  main 
premise  is  that  representative  mixed  venous  blood 
of  the  brain  is  obtained  for  measurement  of  gas  con- 
centrations. It  is  not  necessary  for  the  total  blood 
flow  of  the  organ  to  pass  through  one  vein.  However, 
it  is  required  that  the  concentration  of  test  substance 
be  equal  in  all  veins.  Samplings  from  the  bulbus 
cranialis  of  the  internal  jugular  vein  have  proved  to 
be  fairly  free  of  extracranial  blood.  Shenkin  et  al.  (40) 
estimate  a  maximal  admixture  of  2  to  3  per  cent.  For 
proper  use  of  the  partition  coefficient  of  nitrous  oxide 
in  blood  and  tissue — its  value  for  cerebral  tissue  is 
about  one — it  is  important  that  concentration  equilib- 
rium between  tissue  and  blood  has  been  reached. 
Even  small  differences  between  arterial  and  venous 
concentration  lead  to  errors,  as  Sapirstein  &  Ogden 
(37)  have  shown.  This  fact  would  seem  to  make  the 
original  intermittent  sampling  technique  the  method 


of  choice.  Simultaneous  measurements  of  cerebral 
blood  flow  in  monkeys  by  the  nitrous  oxide  method 
and  by  bubble  flowmeter  show  good  agreement  (22). 

MEASUREMENT   OF   CORONARY   BLOOD    FLOW.    Soon   after 

the  introduction  of  the  nitrous  oxide  method  for  the 
determination  of  cerebral  blood  flow,  the  method  was 
used  to  measure  coronary  blood  flow  (6,  7,  12).  The 
blood  of  the  coronary  sinus  is  representative  of  the 
left  ventricular  coronary  flow,  and  since  the  improve- 
ment of  catheterization  technique  has  made  it  pos- 
sible to  sample  blood  from  the  coronary  sinus,  the 
nitrous  oxide  method  can  be  applied  successfully  in 
man  (4).  In  coronary  blood  flow  experiments  on  dogs, 
Gregg  and  co-workers  (14)  found  good  agreement 
between  values  obtained  by  use  of  the  rotameter  and 
the  nitrous  oxide  method.  A  series  of  investigations 
has  been  undertaken  using  the  desaturation  course 
of  nitrous  oxide.  The  results  were  similar  to  those 
obtained  by  the  method  of  saturation  [Goodale  & 
Hakel  (1 1 )  and  Bargeron  et  al.  (2)]. 

Other  Test  Substances 

Radioactive  krypton  85  has  been  proposed  by 
Lassen  &  Munck  (26,  29)  for  use  in  the  determination 
of  cerebral  blood  flow.  The  procedure  is  very  similar 
to  that  of  the  nitrous  oxide  method.  The  application 
of  krypton  85,  although  it  allows  greater  accuracy, 
has  the  disadvantage  of  requiring  special  instrumenta- 
tion and  the  risk  to  the  patient  of  radiation  exposure. 
Munck  &  Lassen  have  recommended  that  internal 
jugular  blood  should  be  sampled  bilaterally  because 
concentration  of  the  test  substance  may  differ  in  the 
two  veins.  Blood  flow  is  then  calculated  twice  and 
the  mean  is  taken.  Since  gaseous  test  substances  re- 
quire special  care  in  sampling  and  storing  of  blood, 
and  since  the  analyses  are  time  consuming  and  diffi- 
cult under  conditions  of  gaseous  anesthesia,  Huckabee 
(17)  proposed  the  use  of  4-aminoantipyrine.  This  is 
a  nonvolatile,  biologically  inert  substance,  which 
diffuses  rapidly  from  blood  into  tissue  fluid,  and  is 
relatively  easy  to  measure.  [See  also  (14),  (19),  (18).] 


TEST-SUBSTANCE    DILUTION    METHODS 

These  also  employ  the  Fick  principle.  Blood  flow 
through  an  organ  is  determined  from  the  ratio  of  the 
amount  of  injected  test  substance  to  its  concentration 
in  the  effluent  blood.  In  case  there  is,  for  any  reason, 
some  of  the  indicator  substance  in  the  blood  at  the 


1292 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


time  of  injection,  the  arteriovenous  difference  in  con- 
centration of  the  substance  may  be  substituted.  A 
rapid  injection  of  the  substance  into  the  blood  stream 
is  used.  This  procedure  was  originally  developed  to 
determine  cardiac  output  (15).  Description  of  the 
method  and  its  theoretical  implications  have  been 
given  by  Hamilton  (14a)  and  Zierler  (41).  For  ap- 
plication of  the  method  to  blood  flow  of  any  organ, 
the  general  formula  holds: 


F- 


f0°°c(t)dt 


wherein 


F  =  blood  flow 

C  =  concentration  of  test  substance  in  the  effluent  blood 

I    =  time  elapsing  during  passage  of  test  substance 

m  =  amount  of  test  substance  injected. 


Measurement  oj  Coronary  Blood  Flow 

Hirche  &  Lochner  (16)  have  adapted  the  method 
to  determine  coronary  blood  flow  in  anesthetized 
dogs.  A  main  branch  of  the  left  coronary  artery  (de- 
scending branch  or  circumflex  branch)  and  the  cor- 
onary sinus  are  catheterized.  Cardiogreen  (5)  is  used 
as  the  test  substance.  For  continuous  measurement  of 
dye  concentration,  the  mixed  venous  blood  of  the 
heart  muscle  is  drawn  by  a  pump  from  the  sinus  cath- 
eter through  a  cuvette  photometer  (27).  When  the 
dye  is  injected  either  into  the  descending  or  circum- 
flex branch,  time-concentration  curves  of  equal  area 
are  obtained.  The  sinus  catheter  should  be  placed 
close  to  the  outflow.  Hirche  and  Lochner  have  con- 
cluded that  the  method  gives  values  of  the  sinus  out- 
flow only.  Since  about  10  per  cent  of  left  coronary 
artery  blood  may  not  be  returned  by  the  coronary 
sinus,  and  therefore  a  proportionate  amount  of  dye 
does  not  appear  with  this  venous  outflow,  10  per  cent 
of  the  calculated  blood  flow  must  be  subtracted  for 
quantitative  measurement.  Values  obtained  with  this 
method  are  in  agreement  with  those  measured  by 
other  methods  reported  in  the  literature.  The  meas- 
urements can  be  repeated  in  intervals  of  1  to  2  min 
and  in  practically  unlimited  number. 


Measurement  oj  Cerebral  Blood 
Flow  (10,  22,  30-32,  39) 

The  human  brain  receives  nearly  all  of  its  blood 
through  two  vertebral  and  two  internal  carotid  ar- 


teries. The  blood  leaves  the  brain  through  two  main 
veins,  the  two  internal  jugulars.  It  would  be  theoreti- 
cally justified  to  apply  the  test-substance  injection 
method  if,  following  injection  into  one  arterial  branch, 
one  could  obtain  identical  time-concentration  curves 
in  all  veins.  This  would  indicate  that  the  mixing  of 
the  test  substance  in  all  brain  vessels  was  complete. 
However,  the  results  described  below  show  that  such 
mixing  is  not  obtained.  Injection  of  test  substance  into 
one  internal  carotid  vields  three  distinct  types  of  time- 
concentration  curves  in  the  separate  internal  jugular 
veins. 

/)  The  test  substance  may  appear  only  on  one 
side.  This  finding  would  allow  the  conclusion  that 
blood  flow  of  only  one  hemisphere  is  measured.  2)  The 
concentration  curves  may  be  identical  in  both  in- 
ternal jugular  veins.  This  would  correspond  to  the 
ideal  case  where  blood  flow  through  the  brain  as  a 
whole  is  measured.  3)  Most  frequently,  however,  it 
happens  that  although  the  dye  appears  in  both  in- 
ternal jugular  veins,  the  concentrations  differ  to  a 
high  degree. 

It  is  proposed  to  average  the  blood  flow  values 
obtained  from  both  time-concentration  curves.  How- 
ever, it  seems  questionable  whether  this  procedure 
yields  accurate  quantitative  values  for  brain  blood 
flow.  Using  the  test-substance  injection  method, 
Shenkin  et  al.  (40)  have  studied  the  "dynamic  anat- 
omy of  the  brain,"  mainly  to  test  the  validity  of  the 
nitrous  oxide  method.  The  advantage  of  the  latter 
lies  in  the  fact  that  all  cerebral  arteries  show  the  same 
concentrations  of  nitrous  oxide  at  any  period  of  time. 
In  spite  of  this,  the  measurements  made  from  the  in- 
ternal jugular  veins  sometimes  do  not  give  identical 
values  (29).  When  the  method  of  sudden  and  short 
injection  of  the  test  substance  is  applied,  the  inter- 
pretation is  much  more  complicated.  Even  in  the 
simple  case  of  two  identical  time-concentration  curves 
cerebral  blood  flow  cannot  be  correctly  estimated, 
since  not  all  the  test  substance  appears  at  the  internal 
jugular  measuring  points.  About  22  per  cent  of  the 
blood  flow  through  the  external  jugular  vein  is  derived 
from  internal  carotid  blood,  as  Shenkin  has  shown. 
One  cannot  assume  that  the  test  substance  leaving 
the  brain  via  the  external  jugular  vein  has  mixed 
thoroughly  with  all  the  blood  passing  the  brain.  The 
difference  between  two  time-concentration  curves 
from  the  internal  jugular  veins  speaks  against  it.  This 
means  that  accurate  measurement  of  cerebral  blood 
flow  cannot  be  obtained  with  the  test-substance  in- 
jection method,  even  when  concentration  curves  of 
both  internal  jugular  veins  are  recorded. 


METHODS   OF  MEASURING  BLOOD   FLOW 


l293 


Measurement  of  Flow  in  Other  Organs 

The  blood  flow  of  the  extremities  has  been  measured 
in  man  using  the  test-substance  dilution  method 
[Andres  et  al.  (i)]  and  in  the  isolated  kidney  by  Loch- 
ner  &  Ochwadt  (28).  Piiper  (35,  36)  determined  the 
site  of  main  resistance  to  flow  in  the  vascular  bed  of 
the  lungs  by  injection  technique,  and  also  the  site  of 
capillaries  in  the  vascular  volume  of  the  isolated  lungs. 


Measurement  of  Flow  in  a  Blood  Vessel 
Without  Interposing  an  Organ 

In  the  procedures  described  above  the  perfusion  of 
an  organ  was  measured.  The  organ  served  as  a  mixing 
chamber,  and  a  reliable  time-concentration  curve  of 
the  test  substance  was  obtained  as  it  left  the  organ. 


Peterson  et  al.  (34),  on  the  other  hand,  have  developed 
a  method  to  measure  the  outflow  of  the  left  ventricle 
which  does  not  involve  mixing  of  the  blood  and  in- 
dicator substance  within  the  heart.  The  indicator  is 
injected  into  the  root  of  the  aorta  and  its  concentra- 
tion is  measured  in  an  artery.  In  the  same  way,  Grace 
et  al.  (13)  have  measured  flow  in  the  thoracic  aorta. 
Whereas  the  above-mentioned  two  groups  used  dyes, 
Frank  et  al.  (8)  used  cold  solutions.  Fronek  &  Ganz 
(9),  using  cold  injections,  were  able  to  measure  blood 
flow  in  individual  small  vessels  by  placing  the  in- 
jection and  recording  sites  in  close  proximity.  Since 
laminary  flow  is  dominant  in  the  blood  vessels,  special 
care  must  be  taken  to  achieve  complete  mixing  of  the 
test  substance  with  the  blood.  This  can  be  done  by 
choosing  a  proper  diameter  and  arrangement  of  holes 
at  the  tip  of  the  injection  catheter  or  needle. 


REFERENCES 


1.  Andres,  R.,  K.  L.  Zierler,  H.  M.  Anderson,  W.  N. 
Stainsbv,  G.  Cader,  A.  S.  Ghrayyib,  and  J.  L.  Lilien- 
thal,  Jr.  Measurement  of  blood  flow  and  volume  in  the 
forearm  of  men;  with  notes  on  the  theory  of  indicator- 
dilution  and  on  production  of  turbulence,  hemolysis  and 
vasodilation  by  intra-vascular-injection.  J.  Clin.  Invest.  33: 
482,  1954. 

2.  Bargeron,  L.  M.,  D.  Ehmke,  F.  Gonlubol,  A.  Castel- 
lanos,  A.  Siegel,  and  R.  J.  Bing.  Effect  of  cigarette 
smoking  on  coronary  blood  flow  and  myocardial  metabo- 
lism. Circulation  15:  251,  1957. 

3.  Bernsmeier,  A.,  and  K.  Siemons.  Die  Messung  der  Hirn- 
durchblutung  mit  der  Stickoxydulmethode  Pfliigers 
Arch.  ges.  Physiol.  258:  149,  1953. 

4.  Bing,  R.  J.,  M.  M.  Hammond,  J.  C.  Handelsman,  S.  R. 
Powers,  F.  C.  Spencer,  J.  E.  Eckenhoff,  W.  T.  Goodale, 
J.  H.  Hafkenschiel,  and  S.  S.  Kety.  The  measurement 
of  coronary  blood  flow,  oxygen  consumption  and  efficiency 
of  the  left  ventricle  in  man.  Am.  Heart  J.  38:  1,  1949. 

5.  Cherrik,  G.  R.,  S.  W.  Stein,  C.  M.  Leevy  and  Ch.  S. 
Davidson.  Indocyanine  green  :  Observations  on  its  physical 
properties,  plasma  decay  and  hepatic  extraction.  J.  Clin. 
Invest.  39:592,  i960. 

6.  Eckenhoff,  J.  E.,  J.  H.  Hafkenschiel,  C.  M.  Landmesser, 
and  M.  H.  Harmel.  Cardiac  oxygen  metabolism  and 
control  of  the  coronary  circulation.   Am.   J.   Physiol.    149: 

634.  '947- 

7.  Eckenhoff,  J.  E.,  J.  H.  Hafkenschiel,  M.  H.  Harmel, 
W.  T.  Goodale,  M.  Lubin,  R.  J.  Bing,  and  S.  S.  Kety. 
Measurement  of  coronary  blood  flow  by  the  nitrous  oxide 
method.  Am.  J.  Physiol.  152:  356,  1948. 

8.  Frank,  A.,  H.  J.  Bretschneider,  E.  Kanzow,  and  V. 
Bernard.  Uber  die  Wirkungen  von  Lacarnol,  Oxyaethyl- 
theophyllin,  Dioxypropyltheophyllin  und  von  Kombina- 
tionen  dieser  Stoffe  auf  Coronardurchblutung  und  Herz- 
stoffwechsel.  Z.  ges.  exptl.  Med.  128:  520,  1957. 


9.  Fronek,  A.,  and  V.  Ganz.  Measurement  of  flow  in  single 
blood  vessels  including  cardiac  output  by  local  thermo- 
dilution.  Circulation  Research  8:  175,  i960. 

10.  Gibbs,  F.  A.,  H.  Maxwell,  and  E.  L.  Gibbs.  Volume  flow 
of  blood  through  the  human  brain.  A.M. A.  Arch.  Neurol. 
Psychiat.  57:  137,   1947. 

11.  Goodale,  W.  T.,  and  D.  B.  Hackel.  Measurement  of 
coronary  blood  flow  in  dogs  and  man  from  rate  of  myo- 
cardial  nitrous  oxide   desaturation.   Circulation   Research   1  : 

502,  1953- 

12.  Goodale,  W.  T.,  M.  Lubin,  J.  E.  Eckenhoff,  J.  H. 
Hafkenschiel,  and  W.  G.  Banfield.  Coronary  sinus 
catheterization  for  studying  coronary  blood  flow  and 
myocardial  metabolism.  Am.  J.  Physiol.  152:  340,  1948. 

13.  Grace,  J.  B.,  I.  J.  Fox,  W.  P.  Crowley,  and  E.  H.  Wood. 
Thoracic-aorta  flow  in  man.  J.  Appl.  Physiol.  1 1  :  405,  1957. 

14.  Gregg,  D.  E.,  F.  H.  Longino,  P.  A.  Green,  and  L.  J. 
Czerwonka.  A  comparison  of  coronary  flow  determination 
by  the  nitrous  oxide  method  and  by  a  direct  method 
using  a  rotameter.  Circulation  3 :  89,  1 95 1 . 

1 4a. Hamilton,  W.  F.  Measurement  of  the  cardiac  output. 
In :  Handbook  of  Physiology.  Washington,  D.  C. :  Am. 
Physiol.  Soc,  1962,  Sect.  2,  vol.  II,  p.  551. 

15.  Hamilton,  W.  F.,  J.  W.  Moore,  J.  M.  Kinsman,  and 
R.  G.  Spurling.  Simultaneous  determination  of  the  pul- 
monary and  systemic  circulation  times  in  man  and  of  a 
figure  related  to  cardiac  output.  Am.  J.  Physiol.  84:  338, 
1928. 

16.  Hirche,  H.,  andW.  Lochner.  Messung  der  Durchblutung 
und  der  Blutfullung  des  coronaren  Gefalibettes  mit  der 
Teststoffmjektionsmethode  am  narkotisierten  Hund  bei 
geschlossenem  Thorax.  Pfliigers  Arch.  ges.  Physiol.  274: 
624,  1962. 

17.  Huckabee,  W.  E.  Use  of  4-aminoantipyrine  for  determining 
volume  of  body  water  available  for  solute  dilution.  J.  Appl. 
Physiol.  9:  157,  1956. 


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CIRCULATION    II 


10 


23' 


24- 


25- 


26. 


27 


29 


Huckabee,  \V.    E.,   and   G.   Walcott.   Determination  of  30. 

organ  blood  flow  using  4-aminoantipyrine.  J.  Appl. 
Physiol.  15:  1 139,  i960. 

Huckabee,  W.    E.,   and  D.   H.   Barron.   Factors  affecting  31. 

the  determination  of  uterine  blood  How  in  vivo.  Circulation 
Research  9:312,  1 961. 

Kety,  S.   S.,   and   C.   F.   Schmidt.  The  determination  of         32. 
cerebral  blood  How  in  man  by  the  use  of  nitrous  oxide  in 
low  concentration.  Am.  J.  Physiol.   143:  54,   1945. 
Kety,  S.  S.,  M.  H.  Harmel,  H   T.  Broomell,  and  C.  B. 
Rhode.  The  solubility  of  nitrous  oxide  in  brain  and  blood.  33. 

J.  Biol.  Chan.  173:  487,  1948. 

Kety.  S.  S. ,  and  C.  F.  Schmidt.  The  nitrous  oxide  method 
for  the  quantitative  determination  of  cerebral  blood  How 
in    man :    theory,    procedure   and   normal   values.  J.   Clin.  34. 

In.  est.  27:  476,  1948. 

Kety,  S.  S.  Quantitative  determination  of  cerebral  blood 
flow  in  man.  In:  Methods  in  Medical  Research.  Chicago:  Vr.  35. 

Bk    Pub.    1948,  vol.   I,  p.  204. 

Kety,    S.    S.     Comment     on    continuous,     constant-rate,  36. 

sampling  modification  of  nitrous  oxide  method  for  cerebral 
blood  flow  in  man.  In :  Methods  in  Medical  Research.  Chicago : 
Yr.  Bk.  Pub.  1961,  vol.  8,  p.  268.  37. 

Lambertsen,  C.  J.,  and  S.  G.  Owen.  Continuous,  con- 
stant-rate sampling  modification  of  nitrous  oxide  method 
for  cerebral  blood  flow  in  man.  In:  Methods  in  Medical  Re-  38. 

search.  Chicago:  Yr.  Bk.  Pub.  i960,  vol.  8,  p.  262. 
Lassen,  N.  A.,  and  O.  Munck.  Cerebral  blood  flow  in  man 
determined  by  the  use  of  radioactive  krypton.  Acta  Physiol. 
Scand.  33:30,  1955. 

Lochner,  \V.,  and  H.  Hirche.  Ein  Photometer  zur 
fortlaufenden  Messung  von  Farbstoffkonzentrationskurven  39. 

im  stromenden  Blut  bei  805  m^.  Klin.  Wochschr.  39:  1142, 
1 96 1. 

Lochner,    VV.,    and    B.    Ochwadt.    Uber   die    Beziehung  40. 

zwischen  arteriellem  Druck,  Durchblutung,  Durchflulizeit 
und  Blutfiillung  an  der  isolierten  Hundeniere.  Pfliigers 
Arch.  ges.  Physiol.  258:  275,  1954.  41. 

Munck,  O.,  and  N.  A.  Lassen.  Bilateral  cerebral  blood 
flow  and  oxygen  consumption  in  man  by  use  of  krypton -85. 
Circulation  Research  5:  163,  1957. 


Nylin,  G,  and  H.  Blomer.  Studien  uber  die  cerebrale 
Zirkulation   mit   radioaktiven   Isotopen.    Z.    Kreislaufforsch. 

44    ':»■  '955- 

Nyi  in,  G.,  and  H.  Blomer.  Studies  on  distribution  of  cer- 
ebral blood  How  with  thorium-B-labeled  erythrocytes.  Cir- 
culation Research  3:  79,  1955. 

Nylin,  G.,  H.  Blomer,  H.  Jones,  S.  Hedlu.nd,  and  C.  G. 
Ryi  \nder.  Further  studies  on  the  cerebral  blood  flow 
estimated  with  thorium-B-labeled  erythrocytes.  Brit. 
Hart  J.    18:  385,    1956. 

Orcutt,  F.  S.,  and  R.  M.  Waters.  Method  for  deter- 
mination of  cyclopropane,  ethylene  and  nitrous  oxide  in 
blood  with  Van  Slyke-Neill  manometric  apparatus.  J. 
Biol.  Chetn.  117:509,  1937. 

Peterson,  I.  H.,  M.  Helrich,  L.  Greene,  C.  Taylor, 
and  G.  Coquette.  Measurement  of  left  ventricular  output. 
./.  Appl.  Physiol.  7:  258,  1954. 

Piiper,  J.  Eine  Methode  zur  Lokalisierung  des  Stromungs- 
widerstandes.  Pfliigers  Arch.  ges.  Physiol.  266 :  1 99,  1 958. 
Piiper,  J.  Uber  die  Lage  der  Capillaren  im  Gefalibett  der 
isolierten   Hundelunge.   Pfliigers  Arch.  ges.    Physiol.    267 :   1 , 

'958. 

Sapirstein,  L.  A.,  and  E.  Ogden.  Theoretical  limitations 
of  the  nitrous  oxide  method  for  the  determination  of 
regional  blood  flow.  Circulation  Research  4:  245,  1956. 
Scheinberg,  P.,  and  E.  A.  Stead.  Cerebral  blood  flow  in 
male  subjects  as  measured  by  the  nitrous  oxide  technique: 
normal  values  for  blood  flow,  oxygen  utilization,  glucose 
utilization,  and  peripheral  resistance,  with  observations  on 
the  effect  of  tilting  and  anxiety.  J.  Clin.  Invest.  28:  1163, 

■949 

Schimmler,    W.    Zur    Messung    der    Gehirndurchblutung 

mit  T-1824  (Evans-blue)  am  Menschen.  Z.  Kreislaufforsch. 

45:47>  i956- 

Shenkin,  H.  A..  M.  H.  Harmal,  and  S.  S.  Kety.  Dynamic 
anatomy  of  the  cerebral  circulation.  A.M. A.  Arch.  Neurol. 
Psychiat.  60:  240,  1948. 

Zierler,  K.  L.  Circulation  times  and  the  theory  of  indi- 
cator-dilution methods  for  determining  blood  flow  and 
volume.  In:  Handbook  of  Physiology.  Washington.  D.  C. : 
Am.  Physiol.  Soc,  1962,  Sect.  2,  vol.  II,  p   585. 


III.  Flowmeters:  their  theory,  construction,  and  operation 


E     WETTERER 


Ultrasonic  Flowmeters 
Traveling  Markers 
Miscellaneous  Methods 


contents 


Flowmeters  Based  on  the  Registration  of  Pressure  Differences 

The  Rotameter 

The  Electroturbinometer 

Bristle  and  Pendulum  Flowmeters 

Methods  Based  on  the  Electromagnetic-Induction  Principle 


the  purpose  of  most  registrations  of  blood  flow  is  the 
recording  of  the  fluid  volume  passing  the  cross  section 
per  unit  of  time.  The  flowmeter  used  will  therefore 
be  calibrated  in  terms  of  rate  of  volume  flow.  In  ad- 


METHODS   OF  MEASURING   BLOOD    FLOW 


I295 


diameter   must    also    be   considered : 


fig  I.  Parabolic  velocity  profile  according  to  Poiseuille's 
law  in  steady  laminar  flow.  For  explanation  see  text. 

dition,  the  fluid  velocity  at  particular  points  within 
the  cross  section  may  be  of  interest,  especially  in  hy- 
drodynamic  studies.  In  these  cases,  the  flowmeter 
is  calibrated  in  terms  of  fluid  velocity. 

Since  different  flow  types  occur  in  the  circulation, 
and  even  in  the  same  blood  vessel,  any  calibration  in 
terms  of  flow  rate  presupposes  an  examination  of  the 
dependence  of  flowmeter  response  on  the  velocity 
distribution  over  the  cross  section. 

In  case  of  steady  laminar  flow,  the  velocity  distri- 
bution is  in  the  form  of  a  paraboloid,  the  profile  of 
which  is  represented  in  figure  i .  If  v  is  the  velocity 
at  the  distance  r  from  the  axis  and  R  is  the  radius  of 
the  tube,  then  we  have,  according  to  Poiseuille's  law: 


v  =  K(Rz-rz) 


(I) 


where  A'  =  (AP/Ax)-(i  4m);  AP  Ay  =  pressure 
gradient  in  axial  direction;  /x  =  viscosity  of  the  fluid. 
The  maximum  velocitv  is  at  the  axis  where  r  =  o: 


v     *KR' 
ax 


(2) 


while  the  lamina  adhering  to  the  wall  (r  =  R)  is  at 
rest.  When  equation  I  is  integrated  over  the  cross- 
sectional  area,  the  flow  rate  Q,  is  obtained : 


Q  =  2irfvrdr=  -jKirR 


(3) 


The  average  velocity  taken  over  the  cross-sectional 
area  is  vA: 


v.  '  —*—  *  —KR 


(4) 


It  follows  from  equations  i  and  4  that  the  fluid  lamina 
moving  at  the  velocity  f.,  is  at  a  distance  of  R/y/2 
from  the  axis. 

With    respect   to   the   performance   of  some   flow- 
meters, the  velocity  vK  averaged  over  the  radius  or 


;VD; 


o 

From  equations  2,  4  and  5  we  obtain  the  ratios: 


(5) 


ax 


=  2:1 


vK  =  4:3 

A 


(6) 


(7) 


If  the  critical  Reynolds  number  is  exceeded,  the 
flow  becomes  turbulent;  the  profile  of  the  net  forward 
velocities  is  then  flattened  and  approaches,  with 
increasing  turbulence,  complete  flatness.  Other  condi- 
tions, which  will  be  mentioned  below,  may  also  give 
rise  to  a  flattening  of  this  profile.  In  the  extreme  case 
of  complete  flatness,  all  fluid  particles  are  moving 
uniformly  at  the  net  forward  velocity  vA. 

Now  we  may  consider  how  different  flowmeter 
types  will  behave  when  the  velocity  profile  changes 
from  the  parabolic  shape  to  complete  flatness.  A 
flowmeter  which  responds  to  the  axial  flow  only  has 
a  relatively  high  sensitivity  when  the  flow  profile  is 
parabolic,  since,  according  to  equation  6,  Vox'-Va  = 
2:1.  When  the  profile  is  completely  flat,  the  axial 
velocity  will  be  as  high  as  the  velocity  at  any  other 
point  so  that  the  sensitivity  in  terms  of  flow  rate  is  now 
reduced  by  50  per  cent  from  the  case  of  a  parabolic 
profile.  In  theory,  this  loss  in  sensitivity  could  be 
avoided  by  placing  the  flow-sensing  element  at  a  dis- 
tance of  R/y/o.  from  the  axis  where,  in  the  parabolic 
profile,  the  local  velocity  equals  vA  as  discussed  above. 

If  the  response  of  a  flowmeter  is  determined  by  the 
sum  of  the  velocities  at  all  points  covering  the  diameter 
or  the  radius,  this  response  is  proportional  to  vR.  The 
sensitivity  in  terms  of  flow  rate  will  then  decrease  by 
25  per  cent  when  the  profile  changes  from  the  para- 
bolic shape  to  complete  flatness  since  vr'.va  =  4:3. 
It  is  obvious  that  the  sensitivity  of  those  flowmeters 
which  respond  primarily  to  the  velocity  vA  averaged 
over  the  cross-sectional  area  is  independent  of  the 
velocity  profile.  The  conditions  are  more  complicated 
if  the  flowmeter's  response  to  the  fluid  velocity  is  not 
linear,  as  is  the  case  with  most  devices  based  on  hydro- 
dynamic  principles. 

Particular  conditions  are  given  in  the  inlet  section 
of  a  tube  into  which  fluid  is  driven  from  a  larger 
reservoir  as  is  the  case  in  the  trunks  of  the  aorta  and 
pulmonary  artery.  At  the  entrance  of  such  a  tube  the 
velocity  profile  is  flat  except  in  a  small  marginal  zone 
where  a  thin  boundary  layer  showing  a  steep  radial 
velocity  gradient  exists.  When  the  site  of  observation 


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CIRCULATION    II 


is  shifted  along  the  tube,  the  boundary  layer  is  iound 
to  increase  in  thickness  and  will  finally  occupy  the 
whole  cross  section  forming  the  parabolic  profile  of 
laminar  flow,  provided  that  the  Reynolds  number 
is  below  the  critical  value.  The  so-called  inlet  length, 
i.e.,  the  distance  between  the  beginning  of  the  tube 
and  the  site  where  a  parabolic  profile  is  just  estab- 
lished, can  be  calculated  [see  McDonald  (93)].  If  the 
Reynolds  number  is  above  the  critical  value,  the  inlet 
length  is  the  distance  between  the  beginning  of  the 
tube  and  the  site  where  turbulence  is  fully  developed; 
this  inlet  length,  too,  is  calculable  and  will  be  much 
shorter  than  for  laminar  flow.  Under  both  conditions, 
however,  the  velocity  profiles  in  the  trunks  of  the 
aorta  and  pulmonary  artery  are  almost  flat  so  that 
the  use  of  flowmeters  involves  no  essential  difficulties 
regarding  the  velocity  profile,  unless  the  flow  type  is 
altered  by  abnormalities  such  as  valvular  stenosis. 
Some  flattening  of  the  velocity  profile  also  occurs 
when  the  fluid  is  streaming  from  a  wider  into  a  nar- 
rower tube  segment  through  a  conical  intermediate 
section.  This  effect  may  be  utilized  to  improve  the 
performance  of  some  flowmeters  regarding  the  de- 
pendence on   the  velocity  profile. 

The  pulsatile  flow  in  peripheral  arteries  is  charac- 
terized by  phase  differences  between  the  layers  oscil- 
lating at  various  distances  from  the  axis.  Generally, 
the  oscillation  of  the  layers  near  the  axis  shows  a 
phase  lag  in  relation  to  the  more  marginal  zones. 
While  at  low  frequencies  of  the  flow  oscillations  the 
phase  lag  increases  continuously  from  the  margin 
toward  the  axis,  the  inner  zones  will  swing  closer  in 
phase  to  each  other  when  the  frequency  is  raised.  At 
high  frequencies,  a  wide  central  column  of  fluid  will 
oscillate  uniformly,  and  the  profile  of  oscillation  will 
approach  flatness  (93).  It  is  obvious  that  flowmeters 
which  respond  to  v^  or  to  vR  are  showing,  in  case  of 
pulsatile  flow  in  peripheral  arteries,  errors  not  only  in 
amplitude  but  also  in  phase,  as  will  be  discussed  below 
with  special  reference  to  the  pendulum  and  bristle 
flowmeters.  Only  flowmeters  responding  to  vA  will 
deliver  records  free  from  such   distortions. 

Another  point  of  view  is  the  consideration  of  the 
frequency  characteristics  which  a  flowmeter  must 
possess  to  obtain  adequate  recordings  of  pulsatile 
flow.  The  highest  frequencies  occurring  in  the  central 
flow  pulse  of  the  dog  under  physiological  conditions 
amount  to  50  to  100  cycles  per  sec  (cps).  For  record- 
ing the  main  features  of  the  central  pulse  a  frequency 
response  up  to  about  50  cps  is  sufficient  (34,  35). 
In  larger  animals  and  in  man  the  upper  frequency 
limit  may  be  somewhat  lower,  but  it  is  remarkablv 


higher  in  small  animals.  In  case  of  mechanical  pickup 
systems  capable  of  vibrating,  the  natural  frequency 
should  be  at  least  double  the  highest  frequency  to  be 
recorded  when  the  system  is  critically  damped.  In  an 
electrical  system  based  on  a  carrier-frequency  proce- 
dure, the  carrier  frequency  must  be  high  enough  to 
reach  an  adequate  band  width.  Further  details  will 
be  discussed  in  the  description  of  the  various  flow- 
meters. 

The  application  of  flowmeters  to  the  circulation 
usually  involves  a  local  alteration  of  the  flow  condi- 
tions resulting  from  insertion  of  a  cannula,  from 
placing  an  obstacle  to  flow  within  the  streaming 
fluid,  from  constriction  of  the  blood  vessel  from  out- 
side, or  at  least  from  surrounding  the  vessel  with  a 
rigid  sleeve.  A  slight  constriction  extended  over  a 
short  length  generally  will  not  give  rise  to  objection- 
able changes  of  the  flow  conditions.  The  factional 
drop  of  the  mean  pressure  is  often  used  as  a  measure 
of  the  impediment  to  flow  caused  by  the  flowmeter. 
It  is  obvious  that  the  pressure  drop  should  be  small 
as  compared  to  the  absolute  pressure  level.  This 
criterion  alone,  however,  is  not  sufficient,  since  an 
arterial  segment  which  contains  an  obstacle  or  is 
made  rigid  by  an  inserted  cannula  or  a  surrounding 
sleeve  can  change  the  hemodynamic  conditions  by 
causing  pulse-wave  reflections  even  if  there  is  no 
remarkable  drop  of  the  mean  pressure.  For  this 
reason,  the  length  of  a  rigid  segment  should  not  exceed 
1  cm  (93). 


FLOWMETERS   BASED   ON    THE    REGISTRATION 
OF  PRESSURE  DIFFERENCES 

When  a  liquid  flows  through  a  tube,  a  pressure 
differerfce  between  two  points  along  the  tube  may  be 
generated  by  friction  and  by  mass  inertia.  Whereas 
the  influence  of  friction  results  in  a  pressure  difference 
proportional  to  the  flow  velocity,  the  effect  of  inertia 
is  causally  connected  with  flow  acceleration.  Two 
kinds  of  acceleration,  convective  and  local,  have  to  be 
considered.  Convective  acceleration  (dv/dx  =  change 
in  velocity  along  the  axial  direction)  occurs  in  steady 
as  well  as  in  pulsatile  flow  as  a  result  of  variation  in 
cross-sectional  area  of  the  tube  or  bv  an  arrangement 
which  causes  a  locally  circumscribed  stagnation  of  the 
fluid  or  a  change  of  the  flow  direction.  According  to 
Bernoulli's  theorem,  pressure  differences  due  to  con- 
vective acceleration  are  proportional  to  the  square  of 
flow  velocity.  Local  acceleration  (do  dt  =  velocity 
change   in   time,   observable  at   a  single   point,   i.e., 


"locally")  takes  place  only  when  the  flow  rate  is 
changing  in  time.  Pressure  differences  between  two 
points  which  are  caused  by  local  acceleration  are 
proportional  to  the  differential  quotient  of  the  flow 
velocity,  to  the  fluid's  density,  and  to  the  distance 
between  both  points.  Thus,  we  have,  according  to 
Frank   (39),  the  following  equation: 

(8) 


•p**F,v 


*  ?*v. 


n 


dv 


*   ?"» 


m 


where  Pi  and  P2  =  instantaneous  pressures  at  two 
different  points;  v  =  instantaneous  flow  velocity; 
t  =  time;  Cu  C2,  and  C3  =  coefficients;  I  =  frictional 
term;  II  =  inertia  term  due  to  convective  accelera- 
tion (Bernoulli);  III  =  inertia  term  due  to  local 
acceleration.  The  pressure  difference  (Pi  —  Pj)  is 
recorded  by  a  suitable  differential  manometer  (see 
below).  In  most  experimental  cases,  the  coefficients 
are  determined  by  practical  calibration  although  they 
are,  under  certain  conditions,  calculable  from  the 
tube  dimensions  and  from  density  and  viscosity, 
respectively,  of  the  fluid.  If,  instead  of  the  linear 
velocity  v,  the  rate  of  volume  flow  is  used  in  equation 
8,  then  d  is  equivalent  to  the  so-called  effective  mass 
M'  (Frank): 


M  -k 


<°L 


(9) 


where  p  =  density  of  fluid,  L  and  A  =  length  and 
cross-sectional  area,  respectively,  of  the  fluid  column 
contained  in  the  tube  between  both  points  and  k  = 
correction  factor  for  velocity  distribution  within  this 
column;  k  =  1.0  if  the  velocity  profile  is  flat  [see 
(46,  48)].  As  Ranke  (107)  pointed  out,  equation  8 
must  be  regarded  as  an  approximation,  since  the 
coefficients  change  with  the  Reynolds  number  for  the 
flow  and  further  terms  may  have  to  be  taken  into 
account. 

The  properties  of  most  differential-pressure  flow- 
meters which  respond  to  pulsatile  flow  are  dependent 
upon  the  three  terms  of  equation  8,  although,  for 
certain  models,  one  or  two  terms  may  play  a  dominat- 
ing role.  If  only  mean  flow  is  recorded,  term  III  can 
be  ignored;  nevertheless,  a  great  effective  mass 
(coefficient  C3)  should  be  avoided  because  it  alters 
hemodynamic  conditions  in  the  case  of  pulsatile 
flow  [cf  McDonald  (93)].  If  the  tube  diameter  is 
large,  as  in  great  central  vessels,  term  I  usually  has 
little  significance  as  compared  to  term  II. 

If  the  pressure  difference  is  generated  mainly  by 
friction  as  in  figure  2,  the  device  must  be  constructed 
in  such  a  way  that  the  resulting  pressure  drop  will 


METHODS  OF  MEASURING  BLOOD  FLOW      1 297 
UPO  DPO 


fig.  2.  Friction  device.  UPO,  DPO  =  lateral  openings 
upstream  and  downstream  from  the  constriction  for  connection 
with  differential  manometer.  [From  Green  (50).] 

not  be  so  great  as  to  disturb  the  physiological  condi- 
tions. A  friction  device  consisting  of  a  long,  narrow 
plastic  tube  inserted  into  a  blood  vessel  was  applied 
by  Ueno  &  Takenata  (129)  for  recording  the  mean 
flow;  the  pressure  drop  was  measured  by  a  rolling 
manometer.  It  seems  likely  that  it  interferes  with 
normal  blood  flow. 

An  older  method  may  be  mentioned  here.  In  1935, 
Green  et  al.  (53)  tried  to  estimate  the  systolic  and 
diastolic  coronary-artery  flow  from  the  pressure 
difference  between  the  aorta  and  a  peripheral  coro- 
nary branch.  There  is,  however,  no  simple  relation- 
ship between  these  magnitudes,  because  waves  travel- 
ing in  elastic  tubes  are  concerned.  Therefore,  the 
method  was  abandoned  [cf  Gregg's  criticism  (54)  and 
Chapter  7,  vol.  I,  this  Handbook]. 

The  principle  of  the  Venturi  meters  is  based  on  the 
generation  of  convective  acceleration  by  a  variation 
in  the  cross-sectional  area  of  a  tube  (Venturi  1797; 
Herschel  1887).  As  shown  in  figure  3,  the  fluid  has  to 
move  from  a  wider  into  a  narrower  tube  segment. 
According  to  the  continuity  law,  equal  quantities  of 
an  incompressible  fluid  must  pass  each  cross  section 
of  a  rigid  tube  during  the  same  time  interval.  The 
fluid's  linear  velocity  is  therefore  augmented  in  the 
narrow  segment  so  that  here  the  kinetic  energy  is 
increased  and  the  lateral  pressure  is  decreased.  This 
results  in  a  pressure  difference  between  UPO  and 
DPO  in  figure  3,  which  is  proportional  to  the  square 
of  the  average  flow  velocity  (term  II  in  equation  8). 
If  the  tube  widens  again  downstream  from  DPO  to 
the  same  cross-sectional  area  as  before,  the  former 
pressure  is  restored.  The  additional  influence  of  fric- 
tion will  augment  the  pressure  difference  between 
both  points  (term  I);  this  part  of  the  pressure  drop, 
of  course,  is  not  reversible  by  rewidening  of  the  tube. 
When  the  rate  of  volume  flow  is  changing  in  time,  a 
third  kind  of  pressure  difference  corresponding  to 
term  III  appears  which  should  be  kept  minimal 
because  it  distorts  the  records.  Devisers  of  such  flow- 
meters often  failed  to  take  this  source  of  error  into 
consideration.  Lauber's  Venturi  cannula  (87),  for 
instance,   was  criticized   by  Frank    (42)    because  its 


[2g8  HANDBOOK    OF    PHYSIOLOGY  <-"  CIRCULATION    II 


UPO 


fig.  3.   Venturimeter  of  original  type.  [From  Green  (50).] 

manometer  connections  were  very  distant  from  each 
other.  The  aortic  flow  records  obtained  with  this 
cannula  therefore  represented  acceleration  curves 
rather  than  velocity  curves.  A  detailed  polemic  was 
carried  out  on  this  point  by  Frank  (41,  42)  on  the 
one  side  and  by  Broemser  (16)  and  Ranke  (107)  on 
the  other.  To  minimize  the  distortions,  the  distance 
between  both  manometer  connections  (length  L  in 
equation  9)  must  be  as  small  as  possible.  In  contrast 
to  a  widely  held  opinion,  the  distorting  effect  of  term 
III  cannot  be  detected  by  comparing  the  directly 
measured  mean  flow  with  mean  pulsatile  flow  deter- 
mined by  planimetering  the  recorded  curves.  This  is 
true  because  when  areas  are  determined  by  the 
planimeter,  the  distortions  generated  during  flow- 
acceleration  may  be  compensated  for  by  opposite 
distortions  generated  during  flow  deceleration.  An 
analytical  correction  of  the  records  would  be  feasible, 
but  very  difficult.  The  best  way,  therefore,  is  to  keep 
Cz  minimal  by  appropriate  construction  of  the  flow- 
meter. Similar  considerations  apply  also  to  Pitot 
tubes  (see  below). 

Venturi  tubes  like  those  of  figure  3  are  used  rela- 
tivelv  seldom.  The  cannulae  of  de  Burgh  Daly  (20) 
and  of  Lauber  (87)  may  be  mentioned  here.  Lawson 
&   Holt  (88)  modified  Daly's  method. 

The  Venturi  principle  is  applicable  also  to  other 
designs.  Figure  4  shows  the  effect  of  an  inflection  of 
the  tube  wall  on  the  streamlines.  In  case  of  such  an 
inflection  of  small  length,  the  point  at  which  the 
streamlines  run  closest  to  each  other  is  not  situated 
at  the  tip  of  the  inflection,  but  somewhat  downstream 
from  it.  This  means  that  the  fluid's  linear  velocity 
is  higher  and  the  lateral  pressure  is  lower  on  the 
downstream  side  than  on  the  upstream  side  of  an 
inflection  or  constriction.  Thus  a  pressure  difference 
corresponding  to  term  II  is  generated  between  two 
points  situated  upstream  and  downstream  from  a 
nearby  constriction  even  if  the  tube's  cross  sections 
are  equal  at  both  points. 

Broemser  (15)  and  Reissinger  (109)  in  1928,  making 
use  of  this  effect,  constructed  an  instrument  which 
proved  appropriate  for  recording  pulsatile  flow  in  the 
ascending  aorta  (fig.  5).  The  advantages  of  this  can- 
nula consist  in  the  very  short  distance  between  the 


fig.  4.   Deviation  of  streamlines  caused  by  an  inflection  of 
the  wall.   [From  Reissinger  (109).] 


fig.  5.   Cannula    of   Broemser 
and  Reissinger.  [From  Reissinger 

(109).] 


lateral  openings  and  in  their  symmetrical  arrangement 
which  provides  equal  sensitivity  to  forward  and  back- 
ward flow.  The  optimal  inflection  angle  between  tube 
axis  and  wall  was  found  to  be  7  to  8°;  by  using  this 
angle,  sufficient  sensitivity  is  achieved  and  no  eddies 
occur  even  at  the  highest  physiological  flow  velocities. 
Since  the  planes  of  the  lateral  openings  are  not  par- 
allel with  the  vessel  axis,  an  additional  Pitot  effect 
(see  below)  may  be  involved. 

Nilsson  &  Kramer  (97)  in  1954  developed  a  Venturi 
meter  according  to  the  aforementioned  principles  for 
the  registration  of  the  pulsatile  flow  in  the  intra- 
thoracic vena  cava.  Steady  and  oscillatory  flow 
calibrations  showed  that,  for  this  device,  the  terms 
I   and   III   are  of  subordinate  significance. 

The  orifice  flowmeter  of  Gregg  &  Green  (55) 
[cf  Green  (50)  and  Gregg  (54)]  is  also  based  on  the 
Venturi  principle.  The  pressure  difference  is  generated 
by  an  opening  ( =  orifice)  in  a  thin  disk  placed  across 
the  stream  (see  fig.  6).  Lateral  manometer  connec- 
tions are  arranged  upstream  and  downstream  from 
the  disk  at  distances  equal  to  the  tube  radius.  As  seen 
from  figure  6,  the  streamlines  converge  downstream 
from  the  orifice  so  that  there  is  a  point  at  which  the 
pressure  reaches  a  minimum  as  described  above.  Due 
to  its  symmetrical  arrangement,  this  device  has  equal 
sensitivities  to  forward  and  backward  flow.  The  size 
of  the  orifice  can  be  adjusted  during  the  experiments 
either  by  substituting  disks  of  different  orifice  diam- 
eters through  a  slot  in  the  cannula  wall  or,  according 
to  a  modification  devised  by  Shipley  et  al.  (120),  it 
can  be  altered  from  the  outside  by  means  of  a  stud 
screw,  the  rounded  end  of  which  protrudes  into  the 


METHODS    OF   MEASURING    BLOOD    FLOW 


^99 


-P0« 


OP 

fig.  6.  Principle  of  orifice  flowmeter  of  Gregg  and  Green. 
PO,  connections  to  differential  manometer;  OP,  orifice  plate. 
[From  Green  (50).] 

cannula  lumen.  Details  of  construction,  as  well  as 
the  connection  of  the  orifice-meter  cannula  to  the 
differential  manometer,  are  shown  in  figure  7.  The 
rubber  membrane  of  the  manometer,  to  which  the 
mirror  is  attached,  bulges  under  the  action  of  pressure 
differences  between  its  two  sides,  while  it  is  insensitive 
to  the  absolute  pressure.  The  steady-flow  calibration 
curve  is  virtually  quadratic  if  saline  solution  is  used. 
When  blood  is  used,  the  effect  of  term  I  is  noticeable. 
The  natural  frequency  of  the  differential  manometer 
amounts  to  50  to  70  cps  or  more  (54).  It  is  difficult  to 
judge  the  effect  of  term  III  on  the  records  of  pulsatile 
flow;  the  coefficients  of  equation  8,  including  C3, 
vary  with  the  cannula  and  orifice  diameter.  Arterial 
flow  curves  recorded  with  the  orifice  meter,  particu- 
larly those  of  the  femoral,  axillary,  and  carotid 
arteries  (120),  might  suggest  that  the  contour  of  the 
svstolic  flow  peak  and  the  registered  backflow  phase 
could  be  markedly  affected  by  term  III,  although 
arterial  flow  patterns  are  widely  variable  for  physio- 
logical reasons,  as  McDonald  (93)  discusses  in  detail. 
The  applicability  of  the  orifice  meter  to  veins  is 
limited   because  of  its  frictional  pressure  drop. 

Schroeder's  differential  -  pressure  flowmeter 
("Druckdifferentialstromuhr")  (119)  may  be  re- 
garded as  a  further  developmental  stage,  obtained  by 
new  technical  means,  of  Broemser's  differential  sphyg- 
mograph  (see  below).  Schroeder  designed  his  instru- 
ment, which  is  shown  in  figure  8,  for  application  on 
unopened  carotid  and  femoral  loops  of  conscious  dogs. 
In  a  special  compartment  (C),  the  artery  (.4)  is  com- 
pressed by  a  screw  device  (S)  so  that  its  wall  is  relaxed. 
Two  rubber  diaphragms  (Di  ,  Z)2  ),  arranged  at  the 
bottom  of  the  compartment,  are  in  direct  contact  with 
the  skin  surrounding  the  vessel,  one  diaphragm  is 
placed  at  an  upstream  vessel  segment,  the  other  at  a 
downstream  segment.  Each  diaphragm  covers  a 
water-filled  chamber  [Chi  ,  Ch  ),  and  can  transmit 
the  pressures  from  both  vessel  segments  into  these 
chambers.  Due  to  the  compression  of  the  vessel,  its 
skin  and  wall  tissues  are  deformed  so  that  the  vessel 


lumen  is  narrowed  toward  the  middle  of  the  compart- 
ment; the  slight  constriction  gives  rise  to  a  flow-related 
pressure  difference  between  the  two  vessel  segments, 
which  is  detected  by  a  thin  metal  membrane  (.\/i  ) 
interposed  between  the  chambers  and  is  transferred 
by  a  lever  (L)  to  an  air-pressure  nozzle  amplifier 
(A.h  )  for  optical  manometer  registration.  By  two 
other  membranes  (Mo  ,  A/3  )  connected  to  similar  air- 
pressure  amplifiers  (NA2  ,  NAz  ),  the  pressure  of  each 
chamber  is  picked  up,  and  the  sum  of  both  pressures 
is  optically  recorded  by  an  adding  manometer.  In 
this  way,  the  difference  between  the  pressures  (related 
to  the  blood  flow)  and  their  sum  (related  to  the  blood 
pressure)  are  recorded  simultaneously.  The  steady- 
flow  calibration  curve  is  almost  quadratic;  it  is  cor- 
rected automatically  by  an  optical  linearizing  device. 
Distortions  due  to  term  III  of  equation  8  are  reduced 
by  attaching  an  air  chamber  to  the  differential- 
pressure  air-transmission  system.  Although  some  me- 
chanical functions  of  this  design  may  require  further 
theoretical  clarification,  its  records  of  pulsatile  ar- 
terial flow  and  pressure  resemble  to  a  surprisingly 
high  degree  those  obtained  by  other  well-recognized 
instruments. 

Two  other  devices  mav  be  mentioned  here  for  re- 


OP    O     PD 


fig.  7.  Construction  of  orifice  flowmeter  and  differential 
manometer.  OP,  orifice  plate;  0,  orifice;  PU  and  PD,  upstream 
and  downstream  connections  to  manometer.  .?,  shell;  B,  base; 
C,  cap  of  manometer.  L,  lens,  carried  by  a  ball.  M,  mirror 
attached  to  rubber  diaphragm   of  manometer    [From   Green 


(50).] 


1300 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


flow 


5  i> 

mmnri  wmisrffiM/WiIE/lWflM  WMMh 


WimUfiMM&lJBjIPWIIlL 

jgiMMBlinniMtBiaik 


wnnnk 


fig.  8.  Differential-pressure  flowmeter  of  Schroeder  (119) 
for  application  on  skin-coated  arterial  loops.  For  description 
see  text. 


cording  mean  flow.  A  Yenturi  cannula  in  connection 
with  a  differential  water  manometer,  for  application 
to  abdominal  arteries,  was  used  by  Wagoner  & 
Livingston  (131).  YVretlind  (138),  modifying  a  plan 
by  Stephenson  (1948),  carefully  designed  a  meter  for 
mean  flow  in  the  ascending  aorta  of  the  cat.  As  figure 
9  shows,  the  blood  streaming  from  A  to  B  passes  a 
constriction  (£>)  of  small  length  which  causes  a  pres- 
sure drop  of  a  few  mm  Hg.  Pulsations  in  the  differen- 
tial manometer  (G)  records  are  eliminated  by  expand- 
ing chambers  (C,E)  at  the  upstream  and  downstream 
side  of  the  constriction;  within  these  chambers, 
pulsating  blood  columns  rise  to  different  mean  levels 
corresponding  to  the  pressure  difference  which  is 
necessary  to  drive  the  mean  blood  flow  through  the 
constriction.  The  tops  of  the  two  chambers  are  con- 
nected to  each  other  by  an  air-filled  tube  (F)  which 
acts  as  an  elastic  bypass  transmitting  a  part  of  flow 
pulsations  from  the  central  to  the  peripheral  end  of 
the  meter. 

The  principle  of  Pitot  flowmeters  (1 728-1732) 
consists  in  the  measurement  of  the  hydrodynamic 
increment  in  pressure  which  is  generated  by  the 
locally  circumscribed  stagnation  of  a  small  part  of 
the  streaming  fluid.  For  this  purpose,  a  thin  tube,  the 
opening  of  which  faces  upstream,  is  placed  in  the 
fluid.  The  difference  between  the  pressure  exerted  on 
that  opening  ("end"  or  "total"  pressure)  and  the 
"lateral"  (or  •'static")  pressure  is  indicated  by  a 
differential  manometer.  The  opening  which  picks  up 
the  lateral  pressure  may  be  placed  in  the  wall  (fig. 
10)  or  near  the  opening  facing  upstream  (fig.  1 1).  In 
other  devices,  two  thin  tubes  are  inserted,  with  one 


fig.  9.  Flowmeter  of  YVretlind 
for  ascending  aorta  of  cat.  For 
description  see  text.  [From 
YVretlind  (138).] 


opening  upstream  and  the  other  downstream  (fig.  12); 
the  pressure  difference  is  greater  with  this  design 
because  suction  is  effected  at  the  downstream  opening 
by  eddy  formation.  This  arrangement  also  offers  the 
advantage  that  almost  equal  physical  conditions  can 
be  provided  to  measure  forward  and  reverse  flow.  If 
equation  8  is  applied  to  Pitot  meters,  v  of  term  II  is 
not  the  average  velocity  of  the  fluid,  but  the  velocity 
of  that  small  bundle  of  streamlines  which  hits  the 
opening  facing  upstream.  This  is  an  advantage  be- 
cause it  offers  the  possibility  of  using  Pitot  meters  like 
those  illustrated  in  figures  10  to  12  as  probes  which 
can  be  shifted  along  the  tube  radius  in  order  to 
measure,  point  by  point,  the  hydrodynamic  pressure 
distribution  between  the  axis  and  the  wall.  Thus,  the 
velocity  profile  is  determinable  for  hydraulic  investi- 
gations of  theoretical  and  practical  interest  [Miiller 
(95)].  If,  on  the  other  hand,  the  average  flow  velocity 
is  to  be  detected  by  Pitot  meters,  errors  resulting  from 
changes  of  the  velocity  profile  have  to  be  taken  into 
account.  If  the  flow  is  pulsatile,  term  III  of  equation  8 
requires  special  consideration. 

Prandtl's  tube  (fig.  1 1 )  is  a  modification  of  the  Pitot 
meter;  the  openings  lie  at  the  surface  of  a  probe  which 
is  placed  in  the  streaming  fluid.  This  device  minimizes 
eddy  formation. 

The  construction  of  most  Pitot  meters  applied  in 
cardiovascular  physiology  can  be  deduced  from  one  of 
the  types  shown  in  figure  10  to  12.  Aortic  flow  was  re- 
corded in  1899  with  Frank's  (36)  double-lumen  cathe- 
ter which  was  introduced  through  the  carotid  artery. 
Other  Pitot  devices  were  used  by  Baxter  &  Pearce  (4) 
and  by  Jameson  (67)  for  recording  the  pulmonary 
artery  flow,  by  Johnson  &  Wiggers  (70)  for  recording 
the  coronary  sinus  outflow,  and  by  Eckstein  et  al.  (26) 
for  recording  the  vena  cava  flow. 

"Torpedo"-shaped  Pitot  meters  offering  low  re- 
sistance to  flow  were  built  in  1953  by  Brecher  (8)  and 


METHODS   OF  MEASURING    BLOOD    FLOW  130I 


j  Fl  G    lg  I 


I  FIG.   II  I 


ML 


jm—_ 


>    .     1 


-  K 


fig.  10.  Pitot  meter  with  asymmetrical  pressure  taps,  one  facing  upstream,  the  other  arranged  to 
measure  lateral  pressure.  [From  Miiller  (95).] 

fig.  11.  Prandtl's  tube,  based  on  the  Pitot  principle.  1,  upstream  facing  pressure  tap.  2,  lateral 
pressure  tap.  L,  distance  between  1  and  2.  [From  Hardung  (57).] 

fig.  12.  Pitot  meter  with  symmetrical  pressure  taps  facing  upstream  and  downstream.  [From 
Miiller  (95).] 

within  a  wide  range  by  changes  of  viscosity  (water- 
blood), by  changes  of  the  flow  type  (laminar-turbulent), 
and  even  by  changes  of  the  velocity  profile  caused  by 
flow  pulsations,  provided  the  flow  remains  unidirec- 
tional. Using  his  modification  of  the  Pitot  meter,  he 
constructed  a  catheter-tip  cannula  for  recording  the 
coronary-sinus  outflow  as  well  as  another  cannula  for 
measuring  the  pump  output  in  extracorporeal-circu- 
lation  devices.  It  seems  possible  to  combine  these 
advantages  with  the  arrangement  described  by  Har- 
dung (see  below)  which  avoids  distortions  caused  by 
local  acceleration. 

Besides  the  aforementioned  Pitot  types,  there  is  an 
older  modification  used  by  Cybulski  (19).  As  shown  in 
figure  1 4,  the  sharp  angle  in  the  tube  causes  a  sudden 
change  in  direction  of  flow  creating  a  hydrodynamic 


by  Mixter  (94).  Brecher's  device  (fig.  13),  designed  for 
introduction  into  the  superior  vena  cava  from  the 
jugular  vein,  consists  of  a  rigid  three-tube  catheter  at 
the  tip  of  which  a  streamlined  lead  "torpedo"  is 
attached.  It  contains  the  upstream  and  downstream 
facing  ends  of  the  differential-manometer  tubes  U  and 
D  while  the  longer  tube  A,  serving  to  detect  the 
pressure  in  the  right  atrium,  is  connected  to  a  separate 
manometer.  Tube  A  can  be  moved  along  U  and  D  by 
working  an  outside  handle;  in  this  way,  springs  are 
expanded  to  form  a  basket  (dashed  lines  in  fig.  13) 
around  the  torpedo  in  order  to  keep  it  centered  in  a 
vessel  of  constant  diameter.  Mixter's  torpedo  is  placed 
in  a  metal  tube  for  direct  insertion  into  a  large  vein. 

A  promising  attempt  to  improve  the  performance 
of  the  Pitot  meter  was  recently  made  by  Bretschneider 
(13),  who  realized  the  difficulties  involved  in  the 
estimation  of  the  average  velocity  from  the  velocity  of 
a  small  bundle  of  streamlines.  He  placed  the  opening 
facing  upstream  at  a  point  where  the  local  fluid  veloc- 
ity equals  the  average  velocity  for  both  laminar  and 
turbulent  flow.  Theoretically,  this  point  is  situated  at  a 
distance  of  about  0.7  R  from  the  tube  axis,  or  0.3  R 
from  the  wall,  i.e.,  R/y/2.  This  arrangement,  how- 
ever, is  impracticable  if  the  lumen  diameter  is  6  mm 
or  less.  In  such  cases  a  greater  relative  distance  lrom 
the  wall  (0.4-0.6  R)  has  to  be  chosen.  Errors  due  to 
such  malposition  are  substantially  reduced  by  using  a 
flow  cannula  with  a  conical  inlet  section  which  flattens 
the  velocity  profile.  Thus  Bretschneider  obtained  an 
average   flow  calibration   curve  which  is   unaffected 


DIFFERENTIAL 

PRESSURE 

MANOMETER 


CATHETER 
FLOWMETER     HEAD 


*;e 


S3r 


'— .D' 


RIGHT 
ATRIUM 


->  SUP.  CAVAL   FLOW > 


ATRIAL 

PRESSURE 

MANOMETER 


fig.  13.   Pitot  "torpedo"  of  Brecher  for  recording  superior 
vena  cava  flow.  For  description  see  text.  [From  Brecher  (8).] 


1302 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fiu.  14.  Cybulski's  modification  of  the  Pitot  meter.  [From 
Muller  (95).] 

pressure  elevation  which  acts  upon  the  adjacent  limb  of 
the  differential  water  manometer. 

Broemser's  differential  sphygmograph  (14)  was 
built  for  application  on  unopened  arteries.  The  instru- 
ment (fig.  15)  consists  of  a  double  sphygmograph 
capsule,  the  two  lower  openings  of  which  are  covered 
with  thin  rubber  diaphragms.  The  planes  of  the  dia- 
phragms form  an  obtuse  angle  to  each  other.  The  air- 
filled  capsules  are  connected  to  an  optical  differential 
manometer  as  well  as  to  a  simple  optical  manometer. 
When  the  lower  end  of  the  instrument  is  pressed 
against  an  artery  so  that  one  diaphragm  is  directed 
upstream,  the  other  downstream,  a  wedge-shaped 
inflection  of  the  vessel  wall  is  produced,  and  the  blood 
pressure  bulges  the  diaphragms  into  the  capsules.  Due 
to  the  pressure  difference  effected  by  the  blood  flow, 
the  upstream  diaphragm  will  bulge  more  than  the 
downstream  one;  thus  a  flow-related  deflection  of  the 
differential  manometer  takes  place,  while  the  deflec- 
tion of  the  simple  manometer  is  proportional  to  the 
blood  pressure.  The  function  of  this  device  may  be 
derived  partly  from  the  Venturi  and  partly  from  the 
Pitot  principle  in  that  the  wall  inflection  is  typical  of 
the  Venturi  meters  while  the  inclination  of  the  dia- 
phragms to  the  vessel  axis  results  in  a  Pitot  effect.  The 
calibration  curve  determined  by  perfusion  of  excised 
arteries  or  of  elastic  tubes  is  almost  quadratic.  Al- 
though the  records  obtained  with  this  device  from  the 
ascending  and  abdominal  aorta  of  rabbit,  cat,  and 


dog  show  the  typical  contours  known  from  other 
flowmeter  registrations,  the  instrument  did  not  find 
frequent  application.  This  may  be  due  to  the  fact  that 
its  exact  positioning  and  its  calibration  in  situ  are 
difficult. 

Besides  historical  notes,  Muller  (95)  published  a 
theoretically  and  experimentally  based  criticism  of 
Pitot  meters.  He  stated  that  the  arguments  raised  by 
previous  investigators  against  these  meters  are,  on  the 
whole,  not  justified.  Pieper  &  Yogel  (101)  calculated, 
for  the  device  shown  in  figure  1 1 ,  the  distortions  due 
to  term  III  of  equation  8  at  various  distances  L.  Al- 
though, on  the  one  hand,  L  should  be  kept  as  small  as 
possible  so  as  to  minimize  C'3  ,  the  flow  sensitivity  of 
the  device  (term  II)  is,  on  the  other  hand,  also  dimin- 
ished when  opening  2  is  placed  too  near  to  1 .  The 
optimal  L  must  therefore  be  found  by  compromise. 
Hardung  (57)  came  to  the  conclusion  that,  for  instru- 
ments such  as  shown  in  figure  10,  term  III  can  theo- 
retically be  eliminated  by  placing  the  upstream-facing 
opening  at  a  certain  optimal  distance  from  the  long 
axis  of  the  lateral  tube. 

A  new  and  interesting  catheter-tip  method  for  re- 
cording the  blood  velocity  in  great  central  arteries  was 
developed  by  Fry  et  al.  (46-48).  The  tip  of  the  double- 
lumen  catheter  used  has  two  openings,  both  facing  in 
lateral  direction  and  placed  several  centimeters  apart. 
Here  the  difference  of  the  pressures  acting  on  the 
openings  ("axial  pressure  gradient")  is  due  neither  to 
a  Venturi  nor  to  a  Pitot  effect  so  that  only  the  terms 
I  and  III  of  equation  8  are  involved.  While,  in  the 
aforementioned  instruments,  term  III  is  a  very  un- 
desired  source  of  distortions,  this  very  term  plays  the 
main  role  in  Fry's  method.  For  this  reason,  the  co- 
efficient Ci  is  purposely  made  very  large  by  choosing  a 
great  distance  between  the  openings.  It  is  obvious 
that  the  time  course  of  the  pressure  difference  itself, 
which  is  picked  up  by  an  electrical  differential  manom- 


fic.  15.  Differential  sphygmograph 
of  Broemser  for  application  to  unopened 
arteries.  Thin  lines  at  the  lower  ends  = 
rubber  diaphragms.  Upper  ends  con- 
nected to  differential  and  adding 
manometers.  [From  Broemser  (14)] 


METHODS  OF  MEASURING  BLOOD  FLOW 


!303 


eter,  in  no  way  represents  the  time  course  of  the 
flow  velocity  v.  The  magnitude  v,  however,  is  con- 
tained in  the  linear  differential  equation  which  re- 
mains when  term  II  is  removed  from  equation  8.  In 
order  to  solve  this  equation  for  v  continuously,  the 
electrical  signal  delivered  by  the  differential  manom- 
eter is  fed  into  an  analogue  computer  which  has 
been  adjusted  according  to  the  magnitudes  C\  and  C3  . 
The  output  signal  of  the  computer  will  then  follow  the 
actual  flow  course,  provided  the  coefficients  C\  ("veloc- 
ity resistance")  and  C3  ("velocity  inductance")  are 
known  with  sufficient  accuracy  and  the  pressure 
difference  is  not  affected  by  other  physical  influences. 
Difficulties  arising  from  these  conditions  are  discussed 
by  Fry  (46)  and  by  McDonald  (93).  Flow  records 
from  the  ascending  aorta  of  dog  and  man  demonstrate 
this  method  to  be  promising,  while  records  of  the 
pulmonary  artery  flow  seem  to  require  further 
clarification.  For  simplified  catheter-tip  approaches, 
consult  the  papers  of  Evans  (29),  Jones  et  al.  (71),  and 
their  discussion  by  McDonald  (93). 

Many  types  of  differential  manometers  have  been 
used  to  record  the  pressure  differences  delivered  by 
the  instruments  described  above.  It  is  obvious  that 
low  frequency  manometers,  particularly  water  manom- 
eters, are  far  from  able  to  follow  the  rapid  fluctua- 
tions in  differential  pressure  which  occur  when  arterial 
or  central  venous  flow  is  recorded.  Therefore  mem- 
brane manometers  with  adequate  frequency  response 
are  required  for  recording  pulsatile  flow.  Their 
sensitivity  must  be  considerably  higher  than  that  of 
common  blood  pressure  recorders  because  the  flow- 
related  pressure  differences  are  relatively  small. 

The  difficulty  of  combining  high  sensitivity  and 
high  natural  frequency  in  the  same  instrument  is 
manifest  in  the  discussions  of  physical  principles  by 
Frank  and  the  models  designed  by  Frank  (37,  39), 
Gregg  (54)  and  Green  (50,  51 ). 

The  difficult  task  of  recording  the  very  small 
flow-conditioned  pressure  differences  is  made  possible 
by  the  amplification  of  electrical  signals  from  rela- 
tively stiff  manometers  of  high  natural  frequency. 
Most  important  of  these  are  capacitance  or  inductance 
manometers  as  well  as  resistance  manometers  of  the 
strain  gauge  type  (6,  50,  51). 

It  has  been  emphasized  that,  due  to  term  II  of 
equation  8,  the  calibration  curve  of  most  differential- 
pressure  flowmeters  is  not  linear.  As  in  the  case  of 
bristle  flowmeters,  an  attempt  has  been  made  to  avoid 
the  cumbersome  graphical  correction  of  records  by 
using  linearizing  or,  especially,  square-root  extracting 
devices,  some  of  which  a)  are  employed  after  registra- 


tion, for  evaluation  of  the  records,  while  others  b)  are 
designed  to  deliver  already  linearized  registrations. 
For  a,  Frank  (39)  proposed  a  photographic  projec- 
tion method,  Broemser  (15)  and  Ranke  (108)  com- 
bined the  linearizing  element  with  a  planimeter.  For 
b,  Schroeder  (119),  as  described  above,  uses  optical 
linearization  which  works  during  the  registration; 
Baxter  &  Pearce  (4)  connected  a  linearizing  circuit  to 
the  electrical  differential  manometer.  See  also  Green 

(50). 

Finally,  the  so-called  constant-pressure  flowmeters 
or  air-expansion  systems  may  be  mentioned  although 
they  are  not  differential-pressure  meters  in  the  proper 
sense  [see  Gregg  (54),  Green  (50)].  If  a  blood  reservoir 
is  connected  to  a  large  air  chamber,  any  inflow  or 
outflow  of  blood  will  change  the  air  pressure.  The 
rate  of  volume  flow  of  the  blood  entering  or  leaving 
the  reservoir  can  therefore  be  determined  from  the 
slope  of  the  change  in  air  pressure  which  is  recorded  by 
a  sensitive  manometer.  If  the  pressure  variations  are 
very  small  as  compared  to  the  absolute  pressure  level, 
the  system  delivers  a  virtually  constant  pressure  for 
perfusing  a  vascular  bed  and  acts,  at  the  same  time,  as 
a  flowmeter.  Such  systems  have  been  preferentially 
employed  for  studies  on  the  coronary  circulation 
[Wiggers  &  Cotton  (137);  Green  &  Gregg  (52);  Eck- 
stein et  al.  (25)]. 


THE  ROTAMETER 

The  rotameter  used  in  physiological  experiments  is 
a  device  for  measuring  mean  blood  flow  in  cannulated 
vessels.  The  prototype  instrument  was  designed  for 
measuring  gas  flow.  In  a  vertical  conic  tube  a  float 
moves  up  and  down  in  proportion  to  the  rate  of  flow, 
stabilizing  its  position  by  fast  rotation  which  results 
from  spiral  grooves  around  the  float  body.  This  rota- 
tion has  given  the  instrument  its  name.  If  fluid  instead 
of  gas  is  used,  the  float  does  not  rotate:  stabilization  is 
achieved  by  other  means.  Devices  in  use  are  based  on 
designs  by  Gregg  et  al.  (56).  The  instrument  of 
Shipley  &  Wilson  (121,  122)  is  shown  in  figure  16. 
The  conic  tube  is  made  of  Lucite  or  plexiglass  with 
various  flow  capacities  from  0.1  to  3.0  liters  per  min. 
The  movement  of  the  brass  float  is  detected  electro- 
magnetically.  An  iron  rod  pierces  the  middle  of  the 
float  vertically  and  is  fixed  in  such  a  position  that  it 
protrudes  equally  above  and  below  the  body  of  the 
float.  The  lower  part  of  the  rod  is  guided  by  a  ring, 
whereas  the  upper  part  enters  into  the  lumen  of  an 
electromagnetic  coil  fed  by  alternating  current.  As  the 


1304 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


I  — 


fig    16.   Rotameter  of  Shipley  and  Wilson.  .4,  contact  holder; 

B,  one  of  the  contacts  to  induction  and  compensating  coils, 

C,  detecting  assembly;  D,  rubber  cap  for  removing  air  bubbles; 
E,  coils;  F,  protecting  sleeve;  G,  outflow  spout;  H,  soft -iron 
float  wire;  /,  brass  float;  J,  metering  chamber;  A',  conical 
metering  portion;  L,  support;  M,  float  rest  at  zero  flow;  N, 
float  guide;  0,  inflow  spout.  [From  Shipley  &  Wilson  (121).] 


rod  moves  into  it,  the  inductance  of  the  coil  increases, 
and  this  is  recorded  continuously  by  means  of  a 
bridge  circuit,  rectifier,  and  galvanometer.  Since  the 
lift  of  the  float  is  proportional  to  the  flow  of  blood, 
the  record  can  be  calibrated  in  terms  of  flow  rate. 

The  theoretical  basis  of  the  rotameter  may  chiefly  be 
derived  from  mass  inertia  of  the  streaming  fluid  ac- 
cording to  the  Bernoulli  effect.  The  fluid  streaming 
upward  is  accelerated  in  the  ring  slot  around  the 
float.  The  fluid  reaches  its  maximal  velocity  not  in 
the  plane  of  the  slot,  but  at  a  somewhat  higher  level. 
This  velocity  difference  causes  a  pressure  difference  to 
develop  between  the  levels  below  and  above  the  float. 
Other  effects,  such  as  eddy  formation,  may  play  an 
additional  role.  The  pressure  difference  is  augmented 
by  friction  due  to  viscosity  of  the  fluid.  By  the  action 
of  the  total  pressure  difference  on  the  cross-sectional 
area  of  the  float,  a  force  is  brought  about  which  lifts 
the  float,  a  force  is  brought  about  which  lifts  the  float. 
In  steady  states  the  lifting  force  must  be  in  balance 
with  the  float's  weight  diminished  by  its  buoyancy. 


Since  the  weight  minus  buoyancy  remains  constant, 
the  force  must  be  constant  also.  This  is  achieved  by 
the  fact  that  the  ring  slot  area  increases  with  flow  rate 
by  elevation  of  the  float  to  a  higher  level  where  the 
tube  diameter  is  larger. 

Since  the  rotameter  should  be  independent  of 
viscosity  (due  to  changes  in  temperature  or  hemato- 
crit), the  frictional  force  must  be  kept  minimal  as 
compared  to  the  inertia  force.  This  can  be  achieved 
either  by  increasing  the  inertia  force  by  special 
shaping  of  the  float  (121)  or  by  diminishing  the  fric- 
tional force  by  using  large  ring  slot  areas  and  floats  of 
light  weight  (60). 

The  relationship  of  volume  flow  to  galvanometer 
deflection  can  be  made  linear  if  the  electrical  settings 
are  adjusted.  Since  the  response  to  changes  of  flow  is 
slow,  only  mean  flows  are  recorded.  However,  large 
pulsations,  such  as  occur  in  arteries,  are  not  averaged 
correctly,  particularly  by  units  which  use  heavy  brass 
floats.  This  results  in  the  recording  of  lower  mean 
values  than  are  actually  present  (60),  and  it  may  be 
useful  in  such  cases  to  diminish  the  amplitudes  of  the 
flow  pulsations  by  an  air  chamber  arranged  upstream 
from  the  rotameter  (122). 


THE    ELECTROTURBINOMETER 

The  Potter  electroturbinometer,  originally  built  for 
technical  purposes,  has  been  applied  by  Sarnoff  et  al. 
116,  117)  for  the  registration  of  aortic  blood  flow  in 
dogs.  It  consists  of  a  stainless-steel  turbine  which  is 
driven  by  the  blood  stream.  The  turbine  is  suspended 
within  a  Lucite  tube  by  spring  clips.  The  necessity  of 
using  thrust  bearings  is  avoided  by  shaping  the  rotor 
in  such  a  way  that  the  stream  generates,  in  addition  to 
rotation,  a  hydrodynamic  force  which  acts  in  an  up- 
stream direction.  The  rotor  contains  a  permanent 
magnet  which  induces,  by  its  rotation,  an  alternating 
voltage  in  a  pickup  coil  outside  the  tube.  The  fre- 
quency of  that  voltage  is  proportional  to  the  rotational 
speed;  by  means  of  a  counting  and  integrating 
electronic  system,  an  output  signal  is  obtained, 
the  strength  of  which  is  a  measure  of  the  number  of 
turbine  revolutions  per  time  unit.  Two  models  of 
different  sizes  are  described,  the  smaller  of  which 
responds  to  flow  from  about  0.5  to  more  than  4.5 
liters  per  min.  The  calibration  curve  shows  a  slight 
bend  and  is,  in  the  case  of  blood,  independent  of 
temperature  from  22  C  to  40  C  and  of  the  hematocrit 
down  to  22  per  cent.  Although  the  instrument  is  un- 
able to  follow  the  instantaneous  changes  of  the  aortic 


METHODS  OF  MEASURING   BLOOD    FLOW 


I305 


0 


flow- 


© 


0 


© 


diaphragm 
0\y 


© 


^■diaphragm 


© 


fig.  1 7.  Schematic  diagram  of  different 
arrangements  of  bristle  and  pendulum  flow- 
meters, a:  Bristle  in  the  proper  sense,  b:  Stiff 
needle  with  flexible  origin  (short  flat  spring  or 
similar),  c:  Stiff  needle  the  fulcrum  of  which  is 
formed  by  a  diaphragm,  d:  Similar  to  a  or  bt 
with  a  body  at  the  tip.  e:  Similar  to  c,  with  a 
body  at  the  tip.  /.•  Coaxial  compact  cylinder, 
held  by  one  or  two  springs.  The  types  a,  b,  c 
are  now  commonly  called  "bristles,"  the 
types  d,  e,  f:  "pendulums."  [Redrawn  and 
modified  from  Taylor   (127).] 


flow  pulses,  it  is  said  to  indicate  mean  flow  faithfully, 
irrespective  of  whether  the  flow  is  steady  or  pulsatile, 
provided  no  phases  of  essential  backflow  occur.  Its 
resistance  to  blood  flow  is  relatively  high.  The  small 
model  causes  pressure  drops  of  about  5,  1 3,  30,  and  50 
mm  Hg  at  flow  rates  of  1,  2,  3,  and  4  liters  per  min, 
respectively.  The  pressure  drops  caused  by  the  large 
model  are  lower.  Heparinization  of  the  dogs  is,  of 
course,  necessary.  Some  alteration  of  the  pulse  wave 
and  hemolysis  might  be  caused  by  the  instrument. 


BRISTLE    AND    PENDULUM    FLOWMETERS 

When  a  body  is  immersed  in  a  streaming  fluid,  it 
represents  an  obstacle  to  the  flow.  The  force  exerted 
on  the  body  by  the  streaming  fluid  is  due  partly  to 
friction  and  partly  to  mass  inertia  of  the  fluid.  Ac- 
cording to  Frank  (40),  this  force  F  is  given  approxi- 
mately by  the  formula: 

F'V  +  Cf*  ('0) 

where  v  =  velocity  of  the  fluid  acting  on  the  body;  C\ 
and  C2  =  coefficients  which  depend  on  the  viscosity 
and  density,  respectively,  of  the  fluid,  on  the  size  and 
shape  of  the  body,  and  on  the  local  distribution  of 
velocities;  C\  v  =  frictional  term;  C«  v2  =  inertia  term. 
Sometimes,  another  approximation  is  used: 


F  -"  Cv* 


(II) 


where,  in  case  of  blood,  the  exponent  k  is  found  to  be 
between  1.2  and  2.0.  As  will  be  discussed  below,  theo- 
retical estimation  of  the  coefficients  and  of  the  expo- 
nent is  impossible  except  under  very  simple  conditions, 


so  that  an  empirical  determination  is  usually  neces- 
sary. 

If  the  body  is  held  in  its  position  by  an  elastic  device, 
it  will  undergo  some  displacement  due  to  the  force  F, 
and  thus  the  degree  of  displacement  can  be  taken  as  a 
measure  of  that  force.  Since  the  force  is  related  to  the 
fluid  velocity,  according  to  equation  10  or  11,  the 
registration  of  the  displacements  by  mechanical, 
optical,  electrical,  or  other  means  represents  a  con- 
tinuous recording  of  the  flow.  For  the  construction 
of  such  devices,  the  following  requirements  should  be 
taken  into  account:  a)  The  resistance  to  flow  produced 
by  the  obstacle  must  be  so  small  that  the  flow  is  not 
significantly  influenced,  b)  Where  pulsatile  flow  is  to 
be  recorded,  the  natural  frequency  of  the  elastically 
suspended  body  must  be  much  greater  than  the 
highest  significant  frequency.  If  this  condition  is  ful- 
filled, the  displacements  of  the  body  will  be  very  small. 
c)  As  far  as  possible  a  fixed  relationship  should  be  ob- 
tained between  force  and  displacement  on  the  one 
hand  and  average  flow  velocity  on  the  other,  inde- 
pendently of  the  velocity  profile.  This  will  be  discussed 
below. 

The  body  itself  can  be  in  the  form  of  a  rod  or 
needle  set  perpendicularly  to  the  direction  of  flow. 
This  needle  is  usually  attached  at  its  origin  to  the  end 
of  a  side  tube  while  its  tip  remains  free  and  reaches  the 
axis  of  the  main  tube  as  shown  in  figure  1  7<j  to  c .  In 
some  devices,  the  needle  is  longer.  If  the  origin  is 
totally  fixed  whereas  the  needle  itself  is  flexible,  it 
will  be  called  a  bristle  in  the  proper  sense  (fig.  ija). 
In  most  cases  the  needle  is  rigid,  but  is  allowed  to 
move  about  a  fulcrum  (fig.  176  and  c).  While  this 
type  physically  represents  a  pendulum,  it  is  now  usu- 
ally called  a  bristle,  too.  The  common  characteristic 


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CIRCULATION    II 


of  these  types  is  that  they  are  placed  radially  so  that 
all  fluid  particles  moving  across  a  radius  between  the 
axis  and  the  wall  will  participate  in  causing  the 
needle's  deflection. 

In  the  ■'pendulum'"  type  of  figure  i  fd  to/,  however, 
the  device  is  represented  either  by  an  elastically  sus- 
pended coaxial  cylinder  (fig.  i  7/)  or  by  a  needle  which 
carries  at  its  tip  a  body  with  a  resistance  to  the  flow- 
that  is  very  great  as  compared  to  that  of  the  needle 
(fig.  \-jd  and  e).  In  these  cases,  the  deflections  are 
caused  mainly  by  the  axial  flow.  This  renders  greater 
sensitivity  than  a  simple  needle,  but  interferes  with 
the  flow  to  a  higher  degree  and  increases  the  errors 
which  result  from  changes  of  the  velocity  profile. 

The  first  model  of  a  hydrometric  pendulum  was 
employed  by  Castelli  [1 577-1 644,  quoted  from  (96)]. 
It  consisted  of  a  sphere  which  was  suspended  on  a 
thread  and  submerged  in  the  streaming  water.  The 
angular  deflection  of  the  thread  from  the  vertical  was 
used  as  a  measure  of  the  flow  velocity.  In  this  author's 
honor,  M  tiller  (96)  proposed  that  the  principle  of  all 
similar  flowmeters  be  called  the  "Castelli  principle." 
On  an  analogous  theoretical  basis,  Michelotti  (1710- 
1777)  built  a  hydraulic  balance  (96). 

Yierordt  [1858,  quoted  from  (38)]  was  the  first  to 
apply  the  hydrometric  pendulum  to  the  measurement 
of  blood  velocity,  but  his  instrument  was  far  from 
perfect. 

The  hemodromograph  of  Chauveau  and  Lortet 
[i860  and  1867,  quoted  from  (38)]  was  the  first  model 
of  a  hvdrometric  pendulum  which  allowed  continuous 
recording  of  the  blood  velocity.  The  design  was 
similar  to  that  of  figure  lje.  A  rubber  diaphragm 
represented  the  fulcrum  beyond  which  the  lever  of 
the  pendulum  was  prolonged  so  as  to  act  on  an  air- 
transmission  system.  Noteworthy  progress  was 
achieved  by  this  device  although  the  natural  fre- 
quency was  not  high  enough  and  blood  pressure  varia- 
tions changed  the  position  of  the  rubber  diaphragm 
which  held  the  pendulum. 

Frank  (40)  presented  some  basic  theoretical  prin- 
ciples of  the  hydrometric  pendulum  and  of  the 
mechanical  conditions  necessary  for  adequate  fre- 
quency response.  He  also  stated  that  submerging  the 
pendulum  into  fluid  markedly  increased  the  damping 
of  free  vibrations  while  only  slightly  lowering  the 
natural  frequency-  From  this  he  concluded  that  the 
mass  of  fluid  adhering  to  the  pendulum  must  be  rela- 
tively small.  He  built  an  elastically  suspended  pendu- 
lum for  optical  registration  (40). 

The  first  attempt  at  transmitting  the  pendulum 
deflections  electrically  was  made  by  de  Burgh  Daly 


fig.  18.  Bristle  flowmeter  of 
Holzlohner  and  Bergmann.  GL, 
glass  cannula;  BO,  bristle;  E, 
and  £2,  platinum  electrodes;  S, 
vertical  tube.  [From  Bergmann 
(5)-] 


(21),  who  installed,  in  the  vertical  limb  of  a  T-can- 
nula,  a  condenser  composed  of  two  copper  foils,  one 
being  attached  to  the  pendulum  rod  and  the  other 
being  placed  on  the  outside  surface  of  the  side  tube. 
The  variations  of  capacity  of  this  condenser  were 
caused  by  the  pendulum  deflections  and  detected  by 
high  frequency  and  rectifier  circuits. 

Another  type  of  electric  transmission  was  applied 
by  Holzlohner  (61),  who  used  the  streaming  blood 
itself  as  an  electrical  conductor.  In  his  device,  three 
electrodes  are  placed  in  the  flow  cannula  (fig.  18)  so 
that  they  form  two  limbs  of  a  Wheatstone  bridge.  The 
bristle,  belonging  to  the  type  of  figure  1  ja,  represents 
the  middle  electrode  and  consists  of  a  thin  platinum 
wire  covered  by  a  fine  glass  coating.  At  the  bristle  tip, 
the  wire  is  bare  and  in  direct  contact  with  the  blood. 
Two  other  platinum  electrodes  are  placed  in  the  tube 
wall  upstream  and  downstream  at  equal  distances 
from  the  bristle  tip.  When  the  bristle  is  bent  by  the 
blood  stream,  the  ratio  of  the  resistances  on  both 
sides  of  the  bristle  tip  is  changed.  The  electric  equip- 
ment contains  the  resistors  completing  the  bridge 
circuit,  a  20-kc  per  sec  oscillator,  an  a-c  amplifier,  and 
a  rectifier.  Holzlohner  called  his  instrument  "•Strom- 
(borste."  By  translating  this  name  into  English  (Borste 
=  bristle),  Brecher  (12)  introduced  the  expression 
"bristle  flowmeter"  into  the  literature,  where  it  is  now 
'  commonly  used  in  connection  with  all  types  shown  in 
figure  17a  to  c.  Holzlohner's  model  was  modified  by 
Bergmann  (5)  and  employed  for  recording  flow  in  the 


METHODS    OF   MEASURING    BLOOD    FLOW 


I3(,7 


carotid  artery  and  in  the  jugular  vein  (62).  Its  sensi- 
tivity and  frequency  response  were  satisfactory.  How- 
ever, the  base  line  was  often  shifted  by  spontaneous 
changes  of  the  resistances  between  the  electrodes.  This 
was  probably  due  to  minute  fibrin  deposits  at  the 
bristle  tip  (102). 

Further  improvement  of  the  electrical  transmission 
was  achieved  with  electromagnetic  devices.  The  bristle 
or  pendulum  is  made  of  or  mounted  with  ferromag- 
netic material  which  changes,  by  variation  of  its  posi- 
tion, the  magnetic  field  of  two  coils  installed  on  both 
sides  of  the  pendulum.  The  coils  are  fed  with  alterna- 
ting current.  In  1952,  Brecher  and  Crun  [quoted  from 
(9)]  arranged  two  induction  coils  around  a  Lucite  can- 
nula in  such  a  way  that  deflections  of  ferromagnetic 
pendulum  changed  the  coil  inductances  in  opposite 
directions.  Although  the  signal-to-noise  ratio  was 
high,  temperature  changes  produced  an  unfortunate 
instability  of  the  base  line. 

Pieper  &  Wetterer  (102-104)  developed  several 
models  with  electrical  transmission  based  on  the  prin- 
ciple of  the  differential  transformer.  While  in  the 
inductance  bridge  the  amplitude  of  the  resulting 
signal  voltage  is  the  outcome  not  only  of  changes  in 
inductance,  but  also  of  changes  in  ohmic  resistance, 
e.g.,  resulting  from  temperature  changes  of  the  coil 
wires,  the  differential  transformer  separates  the  ohmic 
component  from  the  inductive  component  so  that 
only  the  latter  is  measured.  The  transformer  consists 
of  two  symmetrical  parts,  each  of  which  contains  a 
primary  and  a  secondary  coil.  The  primary  coils, 
which  are  fed  with  alternating  current  of  5  to  10  kc  per 
sec,  are  connected  in  series  so  that  the  directions  of 
their  magnetic  a-c  fields  are  congruent.  The  secondary 
coils  are  also  arranged  in  series;  their  winding  direc- 
tions, however,  are  opposite  to  each  other,  and  the 
induced  secondary  a-c  voltage  will  be  proportional 
to  the  difference  of  the  mutual  inductances  present  in 
each  of  the  two  parts  of  the  transformer.  When  the 
conditions  are  equal  on  both  sides,  the  secondary 
voltage  will  be  null.  By  shifting  the  ferromagnetic  core, 
the  mutual  inductance  of  one  part  is  augmented,  and 
that  of  the  other  part  diminished.  If  the  primary 
alternating  current  is  kept  constant,  changes  in  ohmic 
resistance  of  both  the  primary  and  secondary  circuits 
will  have  no  influence  on  the  secondary  voltage.  This 
principle  had  already  proved  satisfactory  in  micro- 
manometers  (49,  135).  The  first  pendulum  flowmeter 
of  Pieper  and  Wetterer  consisted  of  a  compact  ferro- 
magnetic cylinder  (fig.  1  7/)  the  deflections  of  which 
were  detected  by  differential-transformer  coils  wound 
around  the  tube  upstream  and  downstream  from  the 


fig.  19.  Electromagnetic  bristle  flowmeter  of  Pieper  and 
Wetterer.  a:  Section  in  the  plane  of  the  two  axes  of  the  T-can- 
nula.  b:  Section  at  900  to  a.  FS,  flat  spring;  TC,  transformer 
case;  C,  coils  of  differential  transformer;  F,  ferromagnetic 
frame  of  transformer;  FC,  movable  ferromagnetic  core;  A", 
needle.  Proportions  not  to  scale.  Maximal  length  of  side  branch 
about  20  mm.  For  use,  the  T-cannula  is  completely  filled  with 
anticoagulant  fluid.  [From  Pieper  &  Wetterer  (104).] 

middle  of  the  cylinder.  This  model  was  abandoned  in 
spite  of  its  simplicity  because  of  two  disadvantages: 
The  cylinder  length  is  not  negligible  so  that  the  inertia 
of  the  fluid  column  around  the  cylinder  gives  rise  to  a 
third  term  in  equation  10  which  is  proportional  to  the 
flow  acceleration  and  may  distort  the  records  (see 
term  III  in  equation  8).  In  addition,  the  force  exerted 
on  the  cylinder  by  the  streaming  fluid  is  due  only  to 
the  flow  near  the  axis. 

The  authors,  therefore,  built  two  other  models,  the 
second  of  which  corresponds  to  figure  1  yb  and  is 
shown  in  figure  19.  A  flat  spring  is  fixed  at  the  end  of 
the  vertical  limb  of  the  T-cannula  and  carries  a  ferro- 
magnetic core  and  a  needle  protruding  into  the 
horizontal  tube.  The  differential  transformer  is  in- 
stalled on  both  sides  of  the  vertical  limb  so  that  deflec- 
tions of  the  needle  will  shift  the  core  toward  one  or  the 
other  transformer  part.  The  device  has  a  high  sensi- 
tivity and  satisfactory  temperature  stability.  Its  na- 
tural frequency  is  about  200  cps.  The  additional 
equipment  consists  of  an  a-c  source  of  5  to  10  kc  per 
sec  for  feeding  the  primary  coils  of  an  amplifier  and  a 
rectifier.  Attempts  to  linearize  the  calibration  curve 
have  also  been  made.  A  micromanometer  was  at- 
tached to  the  T-cannula  (fig.  19)  for  simultaneous 
blood-pressure  recording.  The  instrument  was  used 
for  the  registration  of  pressure  and  flow  in  the  carotid 
and  femoral  arteries  of  dogs. 

Independently,  Scher  et  al.  (118)  described  a  paddle 


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CIRCULATION    II 


flowmeter,  the  deflections  of  which  are  detected  either 
by  two  coils  acting  as  two  arms  of  an  inductance 
bridge  or  by  four  coils  forming  a  differential  trans- 
former. The  coils  are  wound  around  the  flow  cannula 
upstream  and  downstream  from  the  pendulum.  This 
pendulum  consists  of  a  flexible  ferromagnetic  paddle 
or  of  a  spring-suspended  ferromagnetic  disk  fixed  on 
the  inner  side  of  the  tube  wall.  The  authors  empha- 
sized improvement  in  stability  achieved  by  using  the 
differential  transformer.  They  implanted  such  devices 
into  the  abdominal  aorta  of  dogs  under  anesthesia 
and  obtained  flow  records  some  days  later,  the  animals 
being  conscious. 

The  most  recent  model  of  a  pendulum  flowmeter 
with  electromagnetic  transmission  was  built  by  Pieper 
(ioo).  The  flow-sensing  element  containing  a  differ- 
ential transformer  is  arranged  at  the  tip  of  a  catheter 
and  can  be  introduced  from  a  peripheral  vessel  into 
an  unopened  central  vessel,  e.g.,  from  the  carotid 
into  the  ascending  aorta.  The  transformer  coils  are 
wound  around  a  longitudinal  iron  core.  A  ferromagne- 
tic cylinder,  surrounding  the  coils  at  a  small  distance 
and  covering  about  three  fourths  of  their  length,  is 
suspended  by  elastic  springs  so  that  it  can  be  shifted 
to  and  fro  in  its  longitudinal  direction.  On  its  circum- 
ference, the  cylinder  carries  a  small  ring-shaped  disk 
which  faces  the  blood  stream.  The  force  exerted  on 
the  disk  by  the  flow  will  shift  the  cylinder  and  thus 
change  the  mutual  inductances  of  the  two  transformer 
parts  in  opposite  directions.  The  natural  frequency  of 
the  elastically  suspended  cylinder  is  120  cps  per  sec. 
The  frequencv  response  was  found  to  be  flat  up  to  20 
cps.  The  probe  is  held  centered  in  the  vessel  axis  by  an 
umbrella-like  arrangement.  Rods  surrounding  the 
probe  are  folded  when  the  catheter  is  introduced,  and 
are  spread  by  means  of  a  mechanism  actuated  from 
outside  when  the  tip  has  reached  its  final  position. 

The  RCA  5734  transducer  tube  represents  a  new 
and  very  useful  means  of  electrical  transmission  in 
pendulum  and  bristle  flowmeters.  This  tube,  which 
was  originally  built  for  physical  purposes,  was  em- 
ployed in  physiology  for  the  measurement  of  small 
forces,  such  as  in  the  manometers  and  sphygmographs. 
The  essential  characteristic  of  the  5734  triode  is  the 
movable  element  consisting  of  the  internal  tube  plate 
(anode)  and  the  external  plate  shaft  (fig.  20).  This 
movable  element  extends  through  a  thin  and  flexible 
metal  diaphragm,  the  center  of  which  acts  as  a  pivot 
permitting  small  angular  deflections  of  the  plate 
shaft  so  that  the  distance  between  the  plate  and  the 
fixed  grid  will  be  changed.  This  results  in  changes  of 
the  plate  current.  Under  the  triode-operating  condi- 


fig.  20.  Mechano-electric  transducer  tube  no.  5734  of  the 
Radio  Corporation  of  America.  Schematic  sectional  view. 
[Redrawn  from  Muller  (96).]  K,  cathode;  Hi,  H-_,  heater 
(filament)  connections;  6',  grid;  .4,  internal  plate  (anode);  S, 
external  plate  shaft;  M,  flexible  metal  diaphragm.  .4,  M,  and  S 
are  electrically  connected  to  the  tube's  metal  shell.  Terminal 
leads  in  clockwise  order.  Bottom  view:  heater,  grid,  heater, 
cathode.  Tube  dimensions  as  indicated  by  RCA :  maximal  total 
length  (excluding  leads),  1.3".  Maximal  diameter,  0.328". 
Tube  weight,  1.75  g.  Rotational  compliance  of  the  diaphragm, 
0.075  degree /g  crn-  Resonance  frequency  of  plate  shaft,  12,000 
cps.  The  connection  of  the  plate  to  the  electric  circuit  is  pro- 
vided by  the  supporting  clamp  attached  to  the  metal  shell  of 
the  tube.  If  there  exists  contact  between  tube  shell  and  blood  or 
tissues,  the  electric  circuit  has  to  be  designed  in  such  a  way 
that  the  tube  plate  is  grounded.  The  plane  of  deflection  of  the 
plate  shaft  must  coincide  with  the  plane  through  terminal 
lead  of  grid  and  tube  axis. 

tions  indicated  by  RCA  (plate-supply  voltage,  300 
volts;  grid  voltage,  o  volts;  load  resistance,  75,000 
ohms),  the  deflection  sensitivity,  i.e.,  the  ratio  of 
change  in  output  voltage  to  angular  deflection  of  the 
plate  shaft,  amounts  to  40  volts  per  degree.  Deflections 
of  more  than  ±  0.5  degree  from  the  normal  position 
of  the  shaft  may  damage  the  diaphragm  and  the  tube 
electrodes.  By  virtue  of  its  small  weight  and  dimensions, 
its  high  sensitivity  and  the  low  inertia  of  its  moving 
part,  the  5734  is  very  appropriate  to  use  in  con- 
structing a  pendulum  or  bristle  flowmeter.  A  further 
advantage  is  its  commercial  availability. 

In  1953,  the  5734  was  first  used  for  blood  flow 
measurement  independently  by  Brecher  and  his  co- 
workers, and  by  Scher  el  a!.,  and  in  1954  by  Muller. 
Fundamentally,  all  these  designs  were  based  on  the 
principles  shown  in  figure  1  yc  and  e.  The  transducer 
tube  is  placed  in  the  side  branch  of  a  T-cannula,  and 
a  needle  or  pendulum  which  protrudes  into  the 
streaming  blood  is  attached  to  the  plate  shaft. 

In  the  model  of  Scher  et  al.  (1 18),  the  T-cannula  is 
made  of  stainless  steel.  Two  types  of  obstacle  to  flow- 
are  used,  the  first  being  a  flat  paddle  placed  across 
the  stream,  the  second  a  streamlined  rod  or  tube  of 
plastic.  As  can  be  expected,  the  sensitivity  of  the 
paddle  type  is  very  high,  and  the  deflection  is  ap- 
proximately proportional  to  the  square  of  flow- 
velocity  so   that  in   such   cases  the  second   term   of 


METHODS  OF  MEASURING   BLOOD   FLOW 


'3°9 


FLOW 


Y-< 


w  < 


fig.  21.  Diagram  of  the  standard  transducer-tube  bristle 
flowmeter  of  Brecher.  a:  Flowmeter  cannula  similar  to  that  of 
Brecher  &  Praglin  (12),  with  improved  socket,  b:  The  same 
model  with  "zeroing"  cylinder.  Total  length,  50  mm.  For 
further  description  see  text.  [From  Brecher  (9,  10).] 

equation  10  is  preponderant.  The  streamlined  ob- 
stacle, however,  offers  much  lower  resistance  to  the 
flow;  its  sensitivity  is  therefore  smaller,  and  its  calibra- 
tion curve  approaches  linearity  in  that  the  deflection 
is  proportional  to  vl-\  thus  indicating  that  it  is  chiefly 
due  to  viscous  drag.  It  may  be  noteworthy  that  the 
authors  found  the  output  voltage  of  the  transducer 
tube  to  respond  to  cooling  by  the  streaming  blood  so 
that  the  base  line  of  the  records  was  not  sufficiently 
stable. 

The  most  extended  use  of  the  5734  tube-bristle 
flowmeter  in  arteries  and  veins  was  made  by  Brecher 
et  al.  Their  "standard  model"  was  published  by 
Brecher  &  Praglin  (12)  and  is  shown  in  figure  21  with 
two  additional  improvements  described  by  Brecher 
(10).  The  system  consists  of  four  parts  A',  Y,  W,  '/., 
which  are  screwed  together.  The  transducer  tube  is 
held  by  the  parts  X  and  W  which  form  a  metal  screw 
socket  pressing  the  two  lead  washers  R\  and  R< 
against  the  lower  rim  and  shoulder  of  the  tube's 
metal  shell.  In  this  way,  the  tube  is  fixed,  and  perm- 
anent electrical  contact  is  established  between  tube 
plate  and  grounded  cannula.  Also  seepage  of  fluid 
from  part  Z  to  the  lead  wires  M  is  prevented.  Part 
Z,  as  "head"  of  the  assembly,  is  ligated  into  the  blood 
vessel  and  connected  with  A'  by  part  Y.  Heads  of 
various  dimensions  are  available  for  use  in  blood 
vessels  of  different  diameters.  The  small  bristle  B  is 


20  to  35  mm  long;  it  can  be  made  of  glass,  nylon,  or 
metal.  The  natural  frequency  of  the  transducer 
system  with  the  bristle  amounts  to  about  200  cps. 
The  side  tube  A'  is  used  for  the  removal  of  air  bubbles 
and  for  attaching  a  manometer  for  pressure  record- 
ing. Temperature  changes  of  the  transducer  tube 
caused  by  the  streaming  blood  are  prevented  by  the 
long  stationary  fluid  column  in  the  parts  Y  and  Z. 
When  the  meter  is  inserted  into  the  blood  vessel,  zero 
flow  can  be  determined  at  any  time  by  means  of  the 
"zeroing"  cylinder  G  (fig.  216)  without  stopping  the 
blood  flow.  The  cylinder  position  is  controlled  by  the 
handle  (?;  it  can  be  moved  forward  beyond  the 
bristle  tip  in  order  to  protect  the  bristle  from  de- 
flection by  the  flow. 

For  blood-flow  recordings  in  large  arteries, 
especially  in  the  trunk  of  the  pulmonary  artery, 
Brecher  &  Hubay  (11)  developed  a  modification 
of  the  standard  bristle  flowmeter  which  can  be  in- 
serted without  clamping  the  vessel  (fig.  22).  The 
device  consists  of  three  main  parts  A,  B,  C.  The 
transducer  tube  is  fixed  in  C  by  cement.  The  most 
characteristic  part  of  the  device  is  the  lip  D  which  is 
introduced  into  the  vessel  through  a  "buttonhole" 
opening  with  little  loss  of  blood.  The  vessel  wall  is 
then  firmly  held  between  D  and  plate  E,  the  latter 
being  pressed  by  screw  nut  F.  In  order  to  protect 
the  bristle  against  damage  during  the  insertion  of  lip 
D  into  the  vessel,  the  tip  of  the  bristle  U  is  withdrawn 
behind   lip   D   by   screwing   part   C  backward.   The 


fig.  22.  Brecher's  bristle  flowmeter  modified  by  Brecher  & 
Hubay  (11)  for  use  in  large  arteries,  especially  in  pulmonary 
artery  trunk.  Total  length,  75  mm.  a:  Diagram  of  longitudinal 
section,  b:  Application  to  pulmonary  artery.  For  description 
see  text.  [From  Brecher  (10).] 


I3IO 


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CIRCULATION    II 


fig.  23.  Schematic  diagram  of 
the  transducer-tube  flowmeter  of 
Miiller.  T,  5734;  E,  micrometer 
screw.  A',  resistance  body.  [From 
Mailer  (96).] 


artery's  diameter  is  kept  constant  by  the  metal  band 
N  placed  around  the  vessel  wall.  As  in  the  standard 
model,  the  "zeroing"  cylinder  G  is  used  for  the 
determination  of  the  base  line  of  flow  during  the 
records,  and  the  side  tube  A'  for  the  removal  of  air 
bubbles  and  for  manometer  connection. 

As  to  the  additional  electrical  equipment,  Brecher 
uses  a  load  resistor  of  500,000  ohms  for  the  transducer 
tube  which  gives  higher  sensitivity  and  better  d-c 
stability  than  the  75,000-ohm  resistor  recommended 
by  RCA.  The  load  resistor  is  connected  to  the  cathode 
while  the  plate  is  grounded  in  all  cases.  The  changes 
in  plate  current  due  to  the  deflections  of  the  plate 
shaft  cause  proportional  variations  of  the  cathode 
potential  which  are  amplified  either  by  battery- 
operated  or  main-fed  d-c  amplifiers.  Both  types  were 
designed  by  Praglin  and  are  described  by  Brecher 
(g).  It  should  be  noted  that  the  greatest  plate-shaft 
deflection  ever  observed  in  Brecher's  blood-flow 
experiments  is  3  min  of  arc.  This  deflection  results  in 
a  potential  change  of  4  volts  at  the  tube's  cathode, 
corresponding  to  a  sensitivity  of  80  volts  per  degree. 
Thus  the  deflections  caused  by  the  blood  flow  remain 
within  the  mechanically  safe  range,  which  extends  to 
30  min  of  arc  on  either  side. 

The  transducer-tube  flowmeter  developed  by 
Miiller  (96)  is  shown  in  figure  23.  It  was  built  for 
flow  measurement  in  blood  vessels  as  well  as  for 
investigations  of  more  general  hydrodynamic  interest, 
particularly  for  the  study  of  the  forces  exerted  by 
streaming  fluids  of  various  Reynolds  numbers  on 
resistance  bodies  of  different  shapes.  An  accurate 
calibration  in  terms  of  force  is  therefore  needed  and 
can  be  performed  by  the  micrometer  screw  E  which 
causes  a  small  spring  to  press  on  the  tube's  plate  shaft. 
The  transducer  tube  is  arranged  in  a  bridge  circuit, 
the  adjacent  limb  of  which  contains  a  second  triode 
of  similar  properties  which  compensates  for  fluctua- 
tions of  operating  voltage,  etc.  The  bridge  output  is 
connected  to  a  push-pull  d-c  amplifier.  A  special 
model  for  coronary-artery  flow  recording  was  de- 
signed by  Laszt  &  Miiller  (86)  (fig.  24).  The  hori- 


IJ_ 


l-P 


M 


fig.  ->4-  Transducer-tube  flowmeter  of  Laszt  and  Miiller. 
^r'  5734;  A,  plate  shaft;  M,  manometer;  A\  vertical  limb  of 
T-cannula;  S,  extension  rod  of  bristle.  Si,  movable  cylinder 
around  R,  Wk,  cylindrical  resistance  body  at  the  bristle  tip;  A', 
horizontal  limb  of  T-cannula.  [From  Laszt  &  Miiller  (86).] 

zontal  cannula  A'  is  inserted  into  the  vessel  without 
interruption  of  the  flow  and  without  using  ligatures 
around  the  vessel.  The  vessel  wall  is  pierced  by  the 
sharp  edge,  and  the  cannula  is  tilted  and  moved 
slightly  until  A  slips  into  the  vessel.  The  cylinder  St 
is  then  pressed  downward  to  immobilize  the  vessel 
wall  around  the  incision. 

Critical  remarks  on  the  bristle  flowmeter  technique 
are  based  on  experimental  data  and  on  theoretical 
considerations.  The  main  practical  advantages 
enumerated  by  Brecher  (9)  are  as  follows:  negligible 
resistance  to  and  interference  with  the  flow;  equal  and 
opposite  response  to  forward  and  backward  flow; 
high  sensitivity  and  frequency  response.  The  main 
practical  disadvantages  are:  necessity  for  opening  the 
vessel  and  using  anticoagulants;  gravitational  effects 
on  the  bristle  when  the  position  of  the  cannula  is 
altered;  and  the  nonlinearity  of  the  calibration 
curve.  This  latter  drawback  can  be  overcome  by 
electrical  linearization  (9,  103).  Since,  for  this  purpose, 
the  amplification  of  low  flow  signals  is  made  much 
greater  than  that  of  high  ones,  the  device  becomes 
very  sensitive  to  minute  shifts  of  the  base  line  so  that 
an    exceedingly    stable    base    line    is    required.    The 


METHODS  OF  MEASURING  BLOOD  FLOW 


1311 


linearizing  circuit  has  to  be  adjustable  to  correct  the 
calibration  curves  in  the  range  from  about  v1'2  to  v2-0. 
In  case  of  large  flow  pulsations,  the  recording  of  the 
mean  flow  by  integrating  circuits  must  be  preceded 
by  linearization.  Obviously,  some  of  these  properties 
concern  other  flowmeters  as  well  (particularly  differ- 
ential-pressure flowmeters).  As  to  flowmeters  which 
are  equipped  with  the  transducer  tube,  the  temper- 
ature of  material  surrounding  the  tube  should  be  kept 
constant,  and  the  heater  current  should  be  stabilized. 
Furthermore,  some  5734  tubes  show  "pressure 
artifacts,"  i.e.,  changes  in  plate  current  when  the 
pressure  exerted  on  the  tube's  diaphragm  is  altered. 
According  to  Brecher,  very  few  new  factory-delivered 
tubes  respond  to  pressure;  however,  careless  handling 
of  a  tube,  especially  anything  causing  deflections  of 
the  plate  shaft  beyond  30  min  of  arc,  can  effect 
permanent  distortion  of  the  diaphragm  which  will 
give  rise  to  such  artifacts. 

Muller  (96)  showed  theoretically  that  at  present, 
exact  mathematical  calculation  of  the  forces  exerted 
on  a  body  immersed  in  the  streaming  fluid  is  im- 
possible even  in  the  case  of  steady  flow.  Only  in  the 
range  of  very  small  Reynolds  numbers  will  forces 
be  fully  calculable  as  the  sum  of  a  term  proportional 
to  v  and  another  term  proportional  to  ;»'2  (cf  equation 
10).  Also,  in  the  range  of  high  Reynolds  numbers, 
friction  cannot  be  ignored.  For  the  force  exerted  on 
the  body  is  due  to  a  thin  boundary  layer  of  fluid 
around  its  surface  (Prandtl's  theory).  Within  this 
layer,  the  velocity  gradient  perpendicular  to  the  body 
surface  is  very  high.  The  lower  the  fluid's  velocity, 
the  thinner  will  be  the  boundary  layer  and  the  greater 
the  velocity  gradient.  Muller's  experimental  data 
show  that  the  boundary  layer  around  a  streamlined 
bristle  is  stable  up  to  Reynolds  numbers  of  about  900; 
above  this,  disturbances  of  the  layer  and  hence 
irregularities  of  the  force  exerted  on  the  bristle  are 
observed,  even  if  the  flow  is  laminar.  As  to  pulsatile 
flow  in  blood  vessels,  the  conditions  are  still  more 
complicated  as  the  blood  is  nonhomogeneous  and 
a  very  large  range  of  Reynolds  numbers  (from  0  up  to 
several  thousand)  may  occur  within  one  pulse  cycle. 
According  to  Muller's  experimental  findings  as  well 
as  to  Womersley's  theory,  the  fluid  laminae  moving 
at  various  distances  from  the  vessel  axis  are  oscillating 
out  of  phase  with  each  other.  Thus,  one  must  consent 
to  Muller's  conclusion  that,  from  a  theoretical  point 
of  view,  this  type  of  flowmeter  type  is  far  from  having 
a  clear  theoretical  and  mathematical  basis. 

Taylor  (127)  simplified  some  of  the  physical 
presumptions   and   presented   a  valuable   theoretical 


study  of  the  recording  properties  of  bristle  and 
pendulum  flowmeters.  Considering  the  velocity 
profile  at  various  frequencies  (fundamental  and  higher 
Fourier  harmonics)  of  oscillatory  flow  according  to 
Womersley's  theory,  he  found  that  simple  bristles 
(see  fig.  1 7a,  b  and  c)  give  relatively  true  records  of 
the  oscillatory  flow.  Compared  with  their  response  to 
steady  laminar  flow,  these  instruments  progressively 
underestimate  the  average  velocity  as  the  flow 
oscillations  increase  in  frequency.  The  error  in 
amplitude  approaches  25  per  cent  at  higher  fre- 
quencies, and  the  maximum  phase  lag  is  about  70. 
Taylor  also  compared  an  actual  femoral-artery  flow 
curve  [recorded  by  McDonald  (g2)  with  gas-bubble 
high-speed  cinematography]  to  the  record  which  a 
bristle  would  give  according  to  his  calculation.  He 
showed  that  the  errors  which  are  mainly  due  to  the 
higher  harmonic  components  have  no  great  distorting 
effect  because  of  their  small  amplitude.  In  Taylor's 
words,  "the  final  "recording'  is  a  quite  acceptable 
reproduction  of  the  flow."  Attaching  a  paddle  to  the 
bristle  (fig.  1  yd  and  e)  gives  rise  to  greater  errors  in 
amplitude  and  phase  while  the  recording  by  a 
coaxial  cylinder  (fig.  1 7/)  shows  small  errors  in 
amplitude,  but  an  enormous  phase  lead  at  higher 
frequencies.  In  case  of  an  almost  flat  velocity  profile, 
as  in  the  great  arteries  near  the  heart,  bristles  and 
even  paddle-mounted  pendulums  will  give  still  more 
satisfactory  results. 


METHODS   BASED   ON   THE 
ELECTROMAGNETIC-INDUCTION   PRINCIPLE 

This  type  of  flow  measurement  is  notable  in  several 
respects.  It  furnishes  direct  transformation  of  the 
mechanical  magnitude  into  an  electrical  signal.  Its 
interference  with  the  blood  flow  is  so  small  that  it 
can  be  completely  neglected.  It  delivers  strictly  linear 
calibration  curves  and  equal  sensitivities  with  opposite 
signal  directions  to  forward  and  backward  flow  so 
that  the  assessment  of  mean  flow  by  integrating 
circuits  can  be  easily  achieved.  Its  calibration  in 
terms  of  average  velocity  or  flow  rate  is  independent 
of  the  velocity  profile  and  of  the  density,  viscosity, 
and  temperature  of  the  fluid.  Its  range  of  frequency 
response  is  theoretically  unlimited  and  depends  in 
practice  on  the  electrical  equipment  used.  It  is 
applicable  to  all  fluids  having  electrical  conductivity 
equal  to  or  higher  than  that  of  tap  water,  e.g.,  saline 
solutions,  blood,  mercury. 

In  addition  to  these  physically  inherent  character- 


I  3 1  2 


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CIRCULATION    II 


istics  which  render  the  method  almost  ideal,  there  are 
other  favorable  properties  of  great  practical  value. 
Most  important,  the  method  is  applicable  to  unopened 
blood  vessels  and  therefore  requires  neither  damaging 
the  vessel  wall  nor  using  anticoagulants.  For  this 
reason,  the  method  can  be  applied  to  the  anesthetized 
animal  and  man  under  surgery  and  by  implanting 
electromagnetic  probes,  measurements  can  be  made 
on  conscious  and  freely  moving  animals. 

The  electrical  flow  signal  is  produced  by  the  motion 
of  the  fluid  across  the  lines  of  a  magnetic  field.  For 
explanation,  a  simple  physical  experiment  is  shown 
in  figure  25.  A  metal  strip  is  moving  at  a  velocity  ;' 
in  the  direction  indicated  by  the  arrows.  This  direc- 
tion is  at  right  angles  to  the  lines  of  magnetic  force 
present  between  the  magnet  poles  N  and  S  so  that  a 
voltage  (potential  difference)  is  generated  in  the  metal 
strip  according  to  Faraday's  induction  law.  The 
induced  voltage,  which  is  directed  perpendicularly  to 
the  lines  of  magnetic  force  and  to  v,  is  picked  up  by 
sliding  contacts  ("electrodes")  et  and  c2,  and  measured 
by  the  voltmeter  I'.  Assuming  that  the  magnetic  field 
permeating  the  metal  strip  between  the  electrodes  is 
homogeneous  and  that  the  lines  of  force,  the  velocity 
v,  and  the  line  extended  between  the  electrodes  are 
directed  mutually  at  right  angles  to  each  other,  the 
induced  voltage  Eind  is: 


~ind 


BDvIO     volts 


(12) 


where  B  =  density  of  magnetic  flux  (gauss);  D  = 
width  of  the  metal  strip,  which  is  also  the  distance 
between  the  electrodes  (cm);  v  =  instantaneous 
velocity  of  the  metal  strip  (cm/ sec).  Reversal  either 
of  the  direction  of  the  magnetic  field  or  of  the  motion 
will  reverse  the  polarity  of  the  induced  voltage.  Small 
deviations  from  the  assumed  right-angle  arrangement 
between  the  directions  of  B  and  v,  say  by  ±10  per 
cent,  have  little  effect  on  £,„,,. 

Now  suppose  that  the  moving  metal  strip  in  figure 
25  is  replaced  by  a  conductive  fluid  streaming  through 
a  tube  (fig.  26).  The  tube  wall  may  consist  of  insu- 
lating material,  and  the  electrodes  et  and  e2  which  are 
inserted  into  the  wall  may  be  in  contact  with  the 
fluid.  In  this  case,  also,  equation  12  is  generally  valid 
if  D  is  the  diameter  of  the  fluid  column  and  ;■  the 
instantaneous  fluid  velocity.  The  velocity,  however, 
will  usually  not  be  uniform  within  the  space  between 
the  electrodes  (as  is  the  case  for  the  solid  strip  of  fig. 
25).  The  induced  voltage  must  therefore  be  calcu- 
lated   from    the    total    sum    of   all    differentials    v.dr 


fig.  25.  So-called  unipolar  induction  in  a  metal  strip 
moving  across  the  lines  of  magnetic  force.  For  explanation  see 
text. 

fig.  26.  Basic  arrangement  for  electromagnetic  flow  meas- 
urement. Metal  strip  of  fig.  25  is  replaced  by  conductive  fluid 
streaming  through  a  tube.  For  explanation  see  text. 

existing  along  D,  i.e.,  from 


fvdr  -  D7 


(12a) 


where  vR  =  velocity  averaged  over  the  diameter  D 
or  radius  R.  Thus,  this  velocity  has  to  be  used  in 
equation  1  2  instead  of  v,  and  the  induced  voltage  is 
obviously  dependent  on  the  velocity  profile.  This 
would  be  an  essential  drawback  of  the  method,  if 
there  were  not  an  additional  compensating  effect 
which  is  of  the  greatest  importance.  Let  us  assume 
that,  as  in  case  of  steady  laminar  flow,  the  fluid  near 
the  axis  runs  much  faster  than  that  near  the  wall.  The 
outer  fluid  layers,  in  which  smaller  voltages  per  unit 
length  are  induced  than  in  the  inner  layers,  act  as  a 
sort  of  load  resistor  to  the  latter,  and  circular  electric 
currents  take  place  within  the  fluid  thus  bringing 
about  a  change  in  the  originally  induced  voltage 
distribution.  Making  a  valuable  theoretical  and 
experimental  contribution  to  the  achievements  of 
earlier   workers    (see   historical    notes),   Thurlemann 


METHODS  OF  MEASURING  BLOOD   FLOW 


I3!3 


(128)  found  that,  due  to  this  effect,  the  resulting 
voltage  picked  up  by  the  electrodes  is,  in  case  of  a 
parabolic  velocity  profile,  just  as  high  as  £,„,,  would 
be  if  all  the  fluid  layers  were  to  move  uniformly  at  the 
velocity  vA  averaged  over  the  cross-sectional  area. 
This  means  that  the  method  delivers  a  flow-signal 
voltage  which  is  linearly  proportional  to  the  in- 
stantaneous velocity  vA  or  to  the  instantaneous  flow 
rate.  The  only  conditions  required  are  that  the 
magnetic  field  be  homogeneous,  that  the  fluid  be 
homogeneous  with  respect  to  its  electrical  con- 
ductivity, and  that  the  velocity  distribution  be  sym- 
metrical in  relation  to  the  tube  axis  (79).  It  follows 
that  the  flow-signal  voltage  Ef  which  is  picked  up  by 
the  electrodes  differs  from  the  originally  induced 
voltage  Eind  (except  the  extreme  case  of  a  completely 
flat  velocity  profile  where  both  are  equal)  so  that 
for  fluid  flow,  equation   12,  has  to  be  modified   to: 


E.  =  BDv.-IO'8  volts, 
f 


(13) 


As  Kolin  (78-80)  stated,  equation  13  is  valid  also 
in  case  of  any  other  velocity  profile  and  even  in  the 
idealized  case  of  a  central  and  coaxial  fluid  jet  which 
is  moving  through  a  tube  while  the  annular  fluid 
cylinder  around  this  jet  is  quiescent.  From  this  Kolin 
concluded  that  the  electrically  conducting  vessel 
wall  may  be  regarded  as  representing  such  a  quiescent 
fluid  cylinder  surrounding  the  streaming  blood  and 
that,  therefore,  no  error  is  caused  if  the  voltage  Es 
is  picked  up  by  electrodes  placed  at  the  outer  surface 
of  the  vessel  wall.  Thus  the  application  of  the  method 
on  unopened  blood  vessels,  which  had  been  carried 
out  earlier  as  an  experimentallv  proved  procedure  by 
Kolin  and  other  workers,  was  also  justified  on  a 
theoretical  basis.  Any  inaccuracy  due  to  the  differ- 
ence in  specific  conductivities  of  blood  and  wall 
tissue  is  of  minor  significance  (80,  82). 

If,  instead  of  v,,,  the  instantaneous  flow  rate  Q, 
(cm3/sec)  is  used  in  equation  1 3,  we  get  with  D  = 
2RandvA  =  Q,/(/x2tt): 


Ef 


2BQ 


-8 

■  10    volts 


(14) 


It  is  obvious  that,  according  to  the  aforementioned 
considerations,  R  is  the  vessel  radius  including  the 
wall  thickness.  Equation  14  shows  that  the  sensitivity 
£//Q,  is  inversely  proportional  to  R  or  to  the  distance 
between  the  electrode  tips  and  is  independent  of  the 
wall  thickness  (80,  82),  provided  that  B  is  fixed  and 
that  the  vessel  is  surrounded  by  insulating  material. 


The  history  of  electromagnetic  flow  measurement 
[see  notes  in  (78,  84,  123)]  shows  that  several  authors 
found  the  principle  independently  of  each  other. 
Faraday  demonstrated  electromagnetic  induction  in 
solid  as  well  as  in  liquid  conductors.  But  he  did  not 
conceive  the  idea  of  measuring  fluid  flow  which  in- 
volves recognition  of  velocity  distribution.  His  ex- 
periment at  the  Waterloo  Bridge,  in  which  he  tried  to 
detect  an  induced  electromotive  force  (emf)  in  the 
River  Thames  due  to  the  water's  motion  through  the 
earth's  magnetic  field,  simply  represented  his  search 
for  an  induction  phenomenon  on  a  terrestrial  scale. 
This  experiment  was  unsuccessful,  probably  due  to 
electrode-polarization  difficulties.  Young  et  al.,  in 
1920,  were  able  to  record  such  an  emf.  Williams,  in 
1 930,  performed  the  first  electromagnetic  measure- 
ments of  the  velocity  distribution  in  copper  sulfate 
solutions,  but  made  no  measurement  of  flow  rate.  In 
1932,  Fabre  (30)  suggested,  in  a  short  note,  electro- 
magnetic recording  of  variations  in  blood  flow  in  can- 
nulated  vessels  [see  also  (84)].  Kolin  [1936  (5)]  is  to  be 
regarded  as  the  real  founder  of  electromagnetic  blood- 
flow  measurement.  He  was  the  first  to  recognize  the 
applicability  of  the  method  to  unopened  vessels  and  to 
obtain  successful  records  from  dogs.  In  the  following 
years  and  decades,  he  also  made  the  major  contribu- 
tions to  further  development  of  the  procedure,  espe- 
cially by  introducing  and  refining  the  a-c  modification 
instead  of  the  d-c  type  which  was  employed  earlier. 
The  d-c  method  was  also  described  by  Wetterer  [1937 
(133)]  and  was  particularly  used  for  recording  flow  in 
the  unopened  ascending  aorta.  Valuable  contributions 
were  further  made  by  Einhorn  (28)  concerning  the  a-c 
method  and  by  Thurlemann  (128)  whose  findings 
have  already  been  mentioned.  In  1953,  the  square- 
wave  modification  was  initiated  by  Denison  (see  125) 
and,  since  then,  has  been  undergoing  considerable 
development  by  the  work  of  Denison  and  Spencer. 
It  combines,  at  least  theoretically,  the  advantages  of 
the  d-c  type  with  those  of  the  a-c  sine-wave  type. 

The  d-c  procedure  (68,  69,  72,  75,  84,  133)  is  the 
simplest  approach  to  the  electromagnetic  flowmeter 
technique  (see  fig.  26).  A  constant  magnetic  field  is 
used  from  either  an  electromagnet  or  a  permanent 
magnet.  The  pole  pieces  of  the  magnet  should  be  con- 
structed in  such  a  way  that  the  gap  can  be  adapted  to 
the  vessel  size  and  the  pole  faces  are  large  enough  to 
insure  a  uniform  magnetic  field  across  the  entire 
vessel  segment.  The  field  strength  should  be  as  high  as 
possible,  e.g.,  1000  to  more  than  10,000  gauss.  In  case 
of  10,000  gauss  and  a  vessel  diameter  of  0.5  cm,  a  flow 


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CIRCULATION    II 


rate  of  i  ml  per  sec  will  generate  a  flow-signal  voltage 
of  about  0.25-  io~3  volts  (equation  14).  In  the  ascend- 
ing aorta  or  pulmonary  artery  trunk,  signals  of  several 
millivolts  can  be  recorded  at  flow  peaks.  Non- 
polarizable  electrodes  are  indispensable.  Zn-ZnS04 
electrodes  are  useful;  calomel  half  cells  give  still  more 
satisfactory  results  [Katz  &  Jochim  (72);  Jochim 
(68)].  The  electrodes  are  connected  to  the  vessel  wall 
by  wicks  soaked  in  saline-agar  solution  or  by  saline- 
agar  filled  glass  tubes.  Also  Ag-AgCl  electrodes  are 
recommended  (33).  Furthermore,  the  vessel's  di- 
ameter and  cross-sectional  area  must  be  kept  constant 
throughout  the  measurements.  The  best  way  is  to  use 
a  rigid  sleeve  of  insulating  material  (76).  The  size  of 
the  sleeve  should  be  carefully  chosen  so  that  the 
vessel  is  narrowed  down  to  that  diameter  which  would 
be  reached  if  the  blood  pressure  fell  to  the  lowest 
level  expected  during  the  experiment.  This  moderate 
constriction  will  not  essentially  interfere  with  the 
hemodvnamic  conditions,  nor  will  the  rigid  sleeve 
give  rise  to  pulse-wave  reflections  if  it  is  not  longer 
than  about  1  cm.  The  tips  of  the  saline  connections  to 
the  electrodes  are  contained  in  two  small  holes  placed 
in  the  sleeve  wall  at  right  angles  to  the  vessel  axis  and 
to  the  lines  of  magnetic  force.  The  sleeve  also  assures 
a  fixed  position  of  the  vessel  relative  to  the  magnet  and 
protects  the  exposed  vessel  from  drying  as  well  as  from 
undesired  contact  with  neighboring  tissues.  To  permit 
introducing  the  vessel,  either  the  sleeve  has  a  small 
longitudinal  slot,  or  is  composed  of  two  halves  which 
are  joined  together  around  the  vessel.  If  the  flow- 
signal  voltage  picked  up  by  the  electrodes  is  high 
enough,  it  can  be  directly  recorded  by  a  string  gal- 
vanometer (75,  133).  However,  d-c  amplifiers  are 
generally  employed  (33,  64,  68,  110,  128,  134),  or 
the  input  voltage  is  converted  into  alternating  current 
by  a  mechanical  chopper  (72,  76),  and  a  capacitance- 
coupled  amplifier  may  then  be  used.  The  over-all  fre- 
quencv  response  of  the  amplifier  system  and  recording 
galvanometer  should  be  uniform  up  to  at  least  50  cps. 
The  base  line  is  assessed  during  the  experiment 
either  bv  clamping  the  vessel  distal  to  the  site  of 
measurement  or  by  de-energizing  the  magnet.  See 
also  (32).  Calibration  is  performed  by  perfusing  the 
excised  vessel  or  the  vessel  in  situ  with  blood  or  saline 
solution  at  known  flow  rates.  Because  of  the  strictly 
linear  calibration  curve,  it  is  sufficient  to  determine, 
in  addition  to  the  zero  point,  only  one  point  corre- 
sponding to  a  flow  rate  near  the  upper  limit  of  the 
range  under  investigation.  The  calibration  can  also 
be  done  using  a  nonsteady  flow:  a  known  quantity  of 


fluid  is  injected  into  the  vessel  by  means  of  a  syringe, 
and  the  course  of  the  corresponding  flow  signal  is  re- 
corded. Thus  the  mean  flow  rate  and  the  mean  flow 
signal  can  be  calculated  from  the  known  injected  vol- 
ume and  the  time  and  deflection  as  recorded  on  the 
tracing  (73). 

In  spite  of  its  theoretical  simplicity,  the  d-c  pro- 
cedure has  been  widely  abandoned  because  of  several 
practical  drawbacks.  The  magnet  and  most  types  of 
nonpolarizable  electrodes  are  rather  bulky.  In  the 
case  of  flow  measurements  on  small  vessels,  the  flow- 
signal  voltage  is  very  low  so  that  high-gain  d-c  ampli- 
fication with  its  inherent  difficulties  is  required  and 
changes  of  the  electrode  potential  will  cause  drift  of 
the  base  line.  The  results  of  Richards  &  Williams  (1 10) 
and  of  Inouye  el  al.  (65)  show  that,  in  spite  of  utmost 
care,  such  difficulties  are  present  even  in  the  applica- 
tion of  the  d-c  procedure  to  the  dog's  carotid  and 
femoral  arteries.  By  improving  the  electrodes  and 
using  modern  stabilized  d-c  amplifiers,  however,  satis- 
factory short-time  recordings  of  the  flow  in  the  de- 
scending aorta  of  the  dog  have  been  made  possible 
[Feder  &  Bay  (33)].  As  to  vessels  close  to  the  heart, 
cardiac  action  potentials  may  be  picked  up  by  the 
electrodes  in  addition  to  the  flow  signal. 

The  a-c  modification  [Kolin  (76,  77)]  is  character- 
ized by  the  use  of  an  alternating  magnetic  field  which 
is  generated  by  energizing  the  coils  of  the  electro- 
magnet with  sinusoidal  alternating  current: 


B  =  BQsin<ut 


(15) 


where  Bn  =  amplitude  of  magnetic  flux  density;  co  = 
2  ir  /;/  =  frequency;  t  =  time.  The  flow  signal  picked 
up  by  the  electrodes  is,  therefore,  an  a-c  voltage  which 
is  strictly  in  phase  with  the  a-c  magnetic-field  strength 
The  amplitude  of  the  flow-signal  voltage  is  further 
proportional  to  the  average  instantaneous  flow  veloc- 
itv  or  flow  rate: 


E'BDv.-IO 
f  A 


-8 


--  BDv  •  10  ■  sin  ut  volts.       (16) 
o    * 


This  means  that  an  amplitude-modulated  flow  signal 
is  delivered  so  that  the  well-known  advantages  of  a 
carrier-frequency  operation  result,  especially  with  the 
use  of  a-c  amplifiers  which  permit  higher  gain  and 
greater  stability  than  d-c  amplifiers.  A  further  ad- 
vantage of  the  a-c  modification  is  that  the  flow-signal 
voltage  can  be  picked  up  by  simple  metal  electrodes, 
such  as  platinum,  gold,  silver,  or  stainless  steel.  As 
much  higher  gain  is  obtainable  than  by  d-c  amplifica- 


METHODS  OF  MEASURING  BLOOD   FLOW 


'3'5 


tion,  lower  flow  signals  are  permissible.  The  magnetic 
field  strength  and  the  magnet  size  may  be  greatly- 
reduced,  and  the  method  can  therefore  be  applied  to 
very  small  vessels.  Since  miniaturization  of  the 
magnet-sleeve-electrode  assembly  is  possible,  the  de- 
vices may  even  be  adapted  for  chronic  implantation. 
Finally,  any  spurious  potentials  which  change  in 
time  at  a  much  lower  frequency  than  that  of  the 
carrier  used  can  be  excluded  from  registration  by 
appropriate  circuitry  of  the  amplifier  and  demodula- 
tor (123).  Usually  a  carrier  frequency  of  a  few  hundred 
cycles  per  second  will  be  high  enough  to  cancel  cardiac 
action  potentials. 

A  sufficiently  high  carrier  frequency  should  be 
chosen  for  a  more  important  reason  (123).  If  A/  is  the 
highest  frequency  of  the  flow  oscillations  to  be  re- 
corded and  /  is  the  carrier  frequency,  a  pass  band 
reaching  from  (/  —  Af)  to  (/  +  Af)  has  to  be  amplified 
while  by  the  demodulation  and  output  filtering  the 
carrier  is  suppressed  and  a  filtered  output  signal  of  a 
frequency  range  from  o  to  Af  is  obtained  for  registra- 
tion. According  to  generally  known  principles,/  must 
be  higher  than  lAf.  In  case  of  flow  recording,  Af  is 
usually  about  50  cps  (35);  in  special  cases,  Af  may  be 
higher,  say  up  to  about  100  cps.  Therefore,  /  should  be 
above  200  cps,  i.e.,  300  to  500  cps.  On  the  other  hand, 
/  should  not  be  higher  than  necessary  because  par- 
ticular difficulties  (see  below)  will  increase  with  rising 
frequency.  A  carrier  frequency  of  about  400  cps  will 
permit  reaching  an  adequate  frequency  response  of 
the  flow  signal  without  undesired  nonmodulated  sig- 
nals such  as  those  of  the  ECG.  Standard  line  current 
(J  =  60  or  50  cps),  which  was  used  in  the  earlier  de- 
velopmental stages  of  the  a-c  method,  may  be  suc- 
cessfully used  to  energize  the  magnet  when  a  smaller 
frequency  range  is  sufficient  (89,  1 1 1,  132). 

A  particular  difficulty  hampering  the  a-c  sine-wave 
procedure  has  been  hardest  of  all  to  overcome.  The 
electrode  leads,  the  electrodes,  and  the  vessel  segment 
lying  between  them  form  a  transformer  loop  in  which 
an  a-c  voltage  is  induced  by  the  alternating  magnetic 
field.  This  spurious  voltage,  which  is  commonly  called 
"transformer  component"  or  "transformer  emf,"  is 
proportional  in  strength  to  the  rate  of  change  of  the 
magnetic  field  strength  (dB/dt)  and  also  depends  on 
the  configuration  of  the  effective  transformer  loop.  It 
follows  from  equation  15  that  dB/dt  =  .Boar  cos  cat, 
and  the  transformer  component  will  be  Et  = 
A'Sow  cos  o)<,  where  A"  =  coefficient  related  to  the  loop 
configuration.  Thus  we  get  the  actual  a-c  voltage  £,■ 


fed  into  the  amplifier  input  (66,  80)  as  the  sum: 


ErEf+Et' 

B-IO'B(DV  smut  +  Kwcosut)  volts. 

O  A 


(17) 


Obviously,  E,  leads  in  phase  by  900  and  will  rise  in 
amplitude  with  increasing  frequency  of  the  magnet 
current.  Additional  spurious  a-c  voltage  may  also  be 
created  by  the  stray  capacitance  of  the  magnet  coils 
on  the  one  hand  and  the  vessel,  electrodes,  and  leads 
on  the  other;  it  can  be  minimized  by  electrostatic 
shielding  of  sleeve  and  leads  and  by  using  a  balanced 
push-pull  or  differential  amplifier  with  high  common- 
mode  rejection. 

Various  designs  have  been  worked  out  [for  a  survey 
see  (123)]  for  eliminating  or  at  least  minimizing  the 
transformer  emf.  The  most  important  of  these  are  as 
follows:  a)  A  special  variable-phase  transformer  is  fed 
by  the  magnet  current;  the  output  of  this  transformer 
is  arranged  in  series  with  one  of  the  electrode  leads  so 
that  cancellation  of  the  "transformer  component"  is 
wrought  by  an  opposite-phase  emf  delivered  by  the 
phase  transformer  (Kolin).  Complete  cancellation  is 
impossible  because  of  wave  form  distortion  due  to  non- 
linearity  of  magnetic-core  material,  b)  Cancellation 
voltage  is  derived  from  a  special  pickup  coil  wound 
around  the  magnet  core  (18,  112,  113).  Complete 
cancellation  is  possible  with  this  refinement  by  careful 
adjustment  of  a  potentiometer,  c)  A  split-lead  method 
(28)  can  be  used.  It  is  a  modification  of  b  in  which  one 
electrode  lead  is  split;  the  halves  are  placed  on  either 
side  of  the  magnet  core  and  are  joined  by  a  potenti- 
ometer. This  arrangement  also  makes  cancellation 
possible,  d)  An  auxiliary  pickup  coil  can  be  arranged 
at  the  sleeve  (80)  in  external-magnet  devices,  e)  Care- 
ful orientation  of  both  electrode  leads  can  form  a  non- 
inductive  loop  (66,  80,  82).  This  technique  is  mainly- 
applied  in  magnet-sleeve  units.  It  permits  approxi- 
mate cancellation.  Complete  cancellation  can  be 
achieved  by  additional  phase-sensitive  demodulation 
(82).  /)  Demodulation  with  phase  discrimination 
should,  theoretically,  permit  separating  Et  from  E/  to 
obtain  the  latter  only,  since  they  differ  in  phase  by  90°. 
Simple  demodulators  consisting  of  half-wave  or  full- 
wave  rectifiers  cannot  provide  any-  separation  of  sig- 
nals by  their  phase.  Kolin  (77)  first  applied  optical 
phase  discrimination  on  the  screen  of  an  oscilloscope. 
James  (66)  suggested  electronic  phase  discrimination 
in  a-c  flowmeters.  Continuous  phase-sensitive  de- 
modulation or  discontinuous  discrimination  by  gating 


1316 


HANDBOOK    OF    PHYSIOI.O(;Y 


circulation  ii 


fig.  27.  A-C  flowmeter  for  application  on  exposed  arteries 
(Kolin).  Left:  cross  section  of  sleeve  £.  E\,  E2,  electrodes,  Pi, 
Pi,  location  of  magnet  pole  pieces;  U\,  Ws,  braided  electrode- 
lead  wires;  Si,  slot  for  insertion  of  vessel.  Right:  total  view  with 
artery  A.  C,  magnet  coils;  5,  sleeve;  R,  rubber  sheet  for 
insulation  of  tissues  from  magnet  core.  [From  Kolin  182  1. | 


and  sampling  the  amplified  flow  signal  at  the  peaks 
of  B(B  =  B„;  dB  dt  =  o)  have  been  employed  (3,  83, 
132)  and  recommended  in  combination  with  mode  e. 
Another  way,  that  of  phase  detection  at  the  points 
(B  =  o;  dB/dt  =  maximum)  was  described  by 
Olmstead  &  Aldrich  (99)  and  found  to  yield  a  stable 
base  line,  g)  Abandoning  the  sine-wave  type  and 
using  rectangular  wave  shape  led  to  the  square-wave 
flowmeter  which  will  be  described  below. 

Cancellation  of  the  transformer  emf  E,  is  closely  re- 
lated to  the  assessment  and  stability  of  the  base  line. 
Only  if  Et  is  eliminated  or  compensated  for,  does 
switching  off  the  magnet  current  render  a  true  zero- 
flow  reading  as  is  obtained  by  occluding  the  vessel 
while  the  magnet  is  energized  (82). 

Although  there  is  the  possibility  that  zero  changes 
occur  as  a  result  of  changes  in  the  position  or  con- 
ductivitv  of  the  vessel  wall  at  the  site  of  measurement 
(23),  such  difficulties  are  not  a  necessary  accompani- 
ment of  the  application  of  the  a-c  procedure  to  intact 
vessels  as  shown  by  recent  reports  (82). 

Numerous  models  of  a-c  flowmeters  have  been  built, 
some  of  which  may,  as  examples,  be  mentioned  here. 
Figure  27  shows  an  early  a-c  device  (Kolin)  applicable 
to  exposed  and  unopened  arteries.  The  simplicity  of 
sleeve  and  electrodes  as  compared  with  d-c  devices  is 
obvious.  Special  sleeves  with  imbedded  electrodes 
have  been  used  for  chronic  implantation  (80,  81). 
After   recovery   from    the   operation,    the    animal   is 


placed  in  the  field  of  an  external  a-c  magnet.  Auxiliary 
coils  attached  to  the  sleeve  deliver  induced  a-c  sig- 
nals which  are  used  for  calibration,  orientation,  and 
compensation.  The  further  development  (see  81,  82) 
produced  miniaturized  devices  consisting  of  magnet- 
sleeve  assemblies  constructed  in  compact  units  and 
cast  in  acrylic  plastic.  These  provide  a  fixed  orienta- 
tion between  vessel  and  magnet  in  chronic-implanta- 
tion experiments.  Units  weighing  5  to  10  g  have  been 
successfully  built  which  reach  flux-density  peaks  (Bo) 
of  200  to  500  gauss  at  a  carrier  frequency  of  400  cps. 
For  chronic  implantation  around  small  arteries  of 
diameters  down  to  1.5  mm  or  less,  subminiature  units 
of  still  lower  weight  are  described.  As  to  the  skillful 
manufacturing  of  these  designs  see  (82)  and  figure  28. 

The  miniaturization  of  the  a-c  flowmeter  is  made 
possible  by  specially  tuned  amplifiers  (400  cps)  char- 
acterized by  extremely  high  gain  and  low  noise  (82, 
83).  Input  signals  of  1  nv  are  measurable  at  a  noise 
level  of  less  than  0.2  fiv.  The  high  amplifier  gain  allows 
the  use  of  coreless  coil-sleeve  units  for  implantation 
around  large  vessels  of  diameters  greater  than  1  cm, 
e.g.,  aorta  of  dog  (81 ,  82).  A  very  low  magnetic  field 
strength  (B0  =  10  gauss)  is  sufficient  in  these  cases. 
Core  magnets  are  also  used  in  a-c  devices  implantable 
about  the  aorta  of  dogs  (98). 

As  already  mentioned,  one  of  the  ways  ot 
eliminating  the  transformer  component  consists  in 
avoiding  the  sinusoidal  wave  shape  in  a-c  flowmeters. 
Thus,  a  group  of  "signal-separating"  a-c  flowmeters 
(126)  has  been  created,  the  most  important  model 
being  the  square-wave  type  developed  by  Denison 
et  al.  (22,  23,  126).  The  magnet  is  energized  by  an 
alternating  current  following  a  rectangular  time  course 


fig.  28.  Subminiature  flowmeter  (Kolin).  Dimensions  in 
mm.  7,  iron  cores;  C\,  d,  magnet  coils,  wy-Wi,  coil-terminal 
wires;  S,  sleeve;  C,  sleeve  channel  for  vessel;  Si,  slot,  E\,  E?, 
electrodes.  Leads  and  coating  of  the  unit  with  acrylic  plastic 
are  not  shown.  [From  Kolin  (82).] 


METHODS  OF  MEASURING   BLOOD    FLOW  1317 


so  that,  on  the  plateaus,  the  field  strength  (B  =  B,„„r) 
is  constant  and,  because  (dB  dt  =  o),  no  transformer 
emf  is  induced.  During  these  periods,  the  system  be- 
haves like  a  d-c  flowmeter  while  the  advantages  of  a 
carrier-frequency  a-c  procedure  are  achieved  by  the 
fact  that  B  =  Bmax  in  each  first  half  cycle  and  B  = 
—  B,„„j  in  each  second  half  cycle.  Therefore  two  flow- 
signals  of  opposite  polarity  are  delivered  in  each  cycle 
which  are  picked  up  by  simple  metal  electrodes, 
amplified  by  an  a-c  amplifier,  and  then  converted  to 
congruent  polarity  by  the  discriminating  demodula- 
tor. It  is  obvious  that  spurious  input  signals  which  do 
not  change  their  polarity  synchronously  with  B, 
such  as  ECG,  can  be  cancelled  out  if  the  carrier  fre- 
quencv  is  high  enough.  During  the  short  time  in- 
tervals of  magnet-field  reversal,  dB  dt  is  very  large  so 
that  high  spikes  of  transformer  emf  may  be  picked  up 
by  the  electrode  circuit.  This  emf  can  be  reduced  by 
the  aforementioned  split-lead  method.  However,  the 
preferred  way  to  eliminate  the  transformer  emf  con- 
sists in  blocking  the  amplifier  during  the  field  re- 
versals. Satisfactory  separation  of  the  flow  signal  from 
unwanted  a-c  voltages  is  therefore,  at  least  in  theory, 
quite  possible.  The  electric  circuitry  is  more  complex 
than  for  sine-wave  flowmeters.  Figure  29,  shows  the 
principle  of  operation.  .-1  is  the  idealized  rectangular 
time  course  of  the  magnetic  field  strength.  B  shows 
the  assumed  course  of  blood  flow  as  well  as  the  input 
signal  which  consists  of  the  amplitude-modulated 
flow  signal  and  the  transformer  spikes.  The  blanking 
periods  C  indicate  the  time  intervals  during  which  the 
amplifier  is  blocked.  Periodic  gaps  in  signal  voltage 
due  to  the  blanking  operation  are  filled  out  by  pro- 
longing the  duration  of  the  voltage  level  reached  im- 
mediately before  the  beginning  of  each  blanking 
period  ("filler  voltage").  The  demodulated  voltage 
shown  in  D  has  a  steplike  appearance  which  is,  for 
clarity,  exaggerated  in  figure  2g  and  will  be  smoothed 
by  filtering.  For  the  block  diagram  of  the  circuitry 
see  figure  30.  The  low-pass  inverse  feedback  between 
output  of  spike-blanking  circuit  and  input  of  pre- 
amplifier raises  the  lower  frequency  limit  for  sup- 
pressing the  ECG. 

The  method  is  used  for  flow  recording  on  intact 
vessels  in  human  surgery  as  well  as  in  acute  and 
chronic-implantation  experiments  on  animals  (see 
fig.  31).  Flow  measurements  in  extracorporeal  de- 
vices have  been  described  (126). 

The  heat  produced  by  the  magnet-coil  current  is 
relatively  great,  since  the  electric  power  used  to  ob- 
tain the  rectangular  wave  current  is  greater  than  that 


Magnetic  Field 
240  n^per  sec 


Flow  Generoted   Voltoge 


Zero  Flow  Voltage 


Transformer  Effect 


Blanking   Periods  H  H  H  1-1  H  n  M  H    H  H  M    H 


Rectified  Minus  Voltage 


Filler  Voltage 


fig  29.  Principle  of  operation  of  the  240  cps  square-wave 
flowmeter  of  Denison  and  Spencer.  For  description  see  text. 
[From  Spencer  &  Denison  (126).] 


needed  for  an  equally  effective  sine-wave  current.  In 
addition,  a  higher  ampere-turn  value  is  needed  to 
saturate  the  core  material  and  make  the  magnetic- 
field  plateaus  flat.  Even  so,  it  is  difficult  to  make  these 
plateaus  perfectly  flat  so  that  a  small  transformer  emf 
may  be  still  effective  during  the  sampling  periods.  A 
minor  difficulty  is  the  influence  of  the  blood 
hematocrit  on  the  flowmeter's  sensitivity,  the  nature  of 
which  is  not  understood. 

A  square-wave  flowmeter  similar  to  the  240-cps 
model  of  Denison  and  Spencer  was  also  described  by 
Ferguson  &  Wells  (34)  while  Abel  (1)  developed  a 
400-cps  chopper-operated  square-wave  meter.  Shirer 
et  al.  (123)  built  a  480-cps  square-wave  device  pos- 
sessing a  frequency  response  up  to  1 50  cps.  The  reader 
mav  refer  to  their  thorough  considerations  of  problems 
of  carrier  frequency,  filtering,  gating,  and  noise. 
Besides  rectangular  or  trapezoidal  wave  shape,  Spen- 
cer and  Denison  suggests  a  sawtooth-like  time  course 
of  the  magnetic  field  (126). 

At  the  present  state  of  flow  recording  technique,  the 
electromagnetic  method  is  a  superior  procedure.  Any 
decision  whether  the  preference  should  be  given  to  the 
sine-wave,  the  square-wave  or  another  wave-shape 
type  must  await  further  development. 


i3i8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Inverse 

Low  Pass 
-      Filter 

m 

Magnetic 
Probe 

-^ 

Pre- 
amplifier 

Spike 
Blanking 

Amplifier 

(adjustable 
gain) 

\ 

Discriminator 

x- 

Recording 
System 

n  i* 

nr 

} 

\ 

D.C. 

AA* 

t 

A 

HN 

t 

1    L_l 

240  cps 

240  cps 

Wove  form 
Correction 

Magnet 
Supply 

480  ffcr 
Oscillator 

a- 

t 

t 

Mixer 

A 

240-Ffc* 
Oscillator 

240  ft* 
Moster 

■v 

^, 

1 

-r-L 

1 

n  i  ■> 

40  cps 

pulse 

\\\z 

fig.  30.  Block  diagram  of  the  square-wave  flowmeter  circuits  required  to  energize  the  magnet, 
eliminate  spurious  emfs,  amplify  the  flow  signal,  and  convert  it  to  direct  current.  [From  Spencer  & 
Denison  (126).] 


TYPE    U 


TYPE    C 


C    3    2      I    A    B 


8  cm 


H 


r- 


5  cm 


H 


fig.  31.  Three  types  of  magnet-sleeve  units  used  in  the  square -wave  flowmeter  technique:  Type  U 
(horseshoe)  mainly  employed  in  surgical  measurements,  type  C  for  implantation  about  large  vessels, 
type  I  for  small  vessels.  .4,  B,  C,  magnet-coil  terminals;  I,  2,  3,  electrode  leads;  2,  3,  split  lead.  The 
units  are  imbedded  in  plastic  cast.  [From  Spencer  &  Denison  (126).] 


TYPE   I 


375cm 


ULTRASONIC    FLOWMETERS 

The  measurement  of  blood  velocity  by  recording 
sound-transit  times  upstream  and  downstream  within 
a  vessel  segment  of  small  length  offers,  in  principle, 
several  important  advantages.  The  device  placed 
around  the  vessel  is  very  lightweight  and  simple  in 
construction.  The  vessel  remains  intact,  and  there  is 
no  interference  with  the  blood  flow  or  pulse  wave 
except  that  effected  by  a  short  rigid  sleeve  causing  a 
moderate  constriction.  The  calibration  curve  can  be 
made  to  be  a  straight  line  passing  through  the  zero 
point  with  equal  slopes  for  forward  and  backward 
flow.  The  signals  obtained  can  follow  the  most  rapid 
changes  of  the  instaneous  blood  velocity  occurring  in 
the  circulation.  However,  in  contrast  to  the  simple 
device  applied  to  the  vessel  itself,  very  involved 
electronic  equipment  is  required  to  detect  and  evalu- 
ate the  extremely  small  effects  exerted  by  the  flow  on 


the  sound  transit  times.  Since  sound  velocity  in  blood 
is  about  1.5- 1  o5  cm  per  sec,  the  time  required  for 
traveling  over  a  distance  of  1  cm  is  about  7  n  sec.  If 
the  blood  is  moving  at  the  velocity  v  along  the  direc- 
tion of  sound  propagation,  the  apparent  sound  veloc- 
ity measured  between  two  quiescent  points  is  (c  —  v) 
or  (c  +  v)  for  upstream  or  downstream  sound  direc- 
tion, respectively.  A  flow  velocity  of  1  cm  per  sec  will 
therefore  change  the  sound  transit  time  (7  fisec/cm) 
by  about  ±5'io~n  sec.  Thus  utmost  precision  is 
necessary  if  differences  of  such  a  minute  order  of 
magnitude  are  to  be  measured  with  sufficient  accu- 
racy, and  the  admirable  advances  made  in  this  field 
to  date  are  based  on  very  difficult  and  detailed  work. 
The  development  of  ultrasonic  blood  flowmeters  has 
been  carried  out  mainly  by  two  groups  using  different 
approaches. 

Haugen  et  al.  (58)  and  Herrick  &  Anderson  (59), 
modifying  the  design  of  Kalmus,  developed  a  phase- 


METHODS  OF  MEASURING  BLOOD  FLOW 


>3>9 


difference  procedure.  Cylindric  ceramic  "trans- 
ducers" are  placed  about  i  inch  apart  around  the 
vessel  wall.  They  are  arranged  to  transmit  and  receive 
ultrasound  (/  =  400  kc  sec)  alternately  upstream  and 
downstream  at  a  rate  of  75  per  sec.  The  phase  differ- 
ences between  the  signals  received  upstream  and 
downstream  are  detected  by  phase  meters  and  used  as 
a  measure  of  the  differences  (A/)  between  the  upstream 
and  downstream  sound  transit  times: 


*"*■& 


c+v 


l_)  ~  2Lv 


(18) 


where  L  =   distance  between  the  transducers.  Since 
the  phase  angle  A<i>  =  2irf-At,  we  get: 


A<t> 


4irfLv 


radians. 


(19) 


In  the  present  design  (31,  59)  where/  =  .l-io5  cps 
and  L  =  2.5  cm,  a  blood  velocity  of  1  cm  per  sec  will 
cause  a  phase  angle  of  about  5-  io~4  radians  or  0.03°. 
The  output  signal  of  the  apparatus  is  proportional 
to  A4>.  Due  to  undesired  phase  differences,  assessment 
of  the  base  line  remains  a  difficult  problem.  An  im- 
provement was  achieved  by  introducing  an  automatic 
phase-shift  control.  The  authors  succeeded  in  con- 
structing a  reliable  recorder  of  extracorporeal  blood 
flow.  Preliminary  findings  indicate  that  satisfactory 
results  may  ultimately  be  attained  on  vessels  in  vivo. 
For  this  purpose,  the  switching  rate  of  the  transducers 
has  to  be  increased,  and  the  time  constants  of  some 
of  the  circuits  have  to  be  reduced  (59). 

Franklin  et  al.  (43-45)  made  use  of  the  pulse  tech- 
nique in  detecting  and  evaluating  the  differences  in 
upstream  and  downstream  sound-transit  times.  As 
seen  in  figure  32,  their  flow-sensing  element  consists 
of  a  short  (1-3  cm)  Lucite  cylinder  which  is  split 
longitudinally  and  mounted  snugly  about  the  vessel. 
The  sound  is  transmitted  and  received  by  two  barium 
titanate  crystals  placed  on  the  vessel  wall  diagonally 
from  each  other  across  the  vessel  lumen.  The  crystals 
are  set  to  function  alternately  800  times  per  sec  as 
transmitter  and  receiver.  The  respective  transmitter 
crystal  is  pulse-excited  at  a  repetition  rate  of  12,000 
per  sec  so  that  it  will,  during  each  switching  period  of 
1/800  sec,  give  off  a  train  of  ultrasound  bursts  at 
its  resonant  frequency  of  3  mc  per  sec.  These  waves 
travel  through  the  adjacent  vessel  wall,  the  blood,  and 
the  opposite  vessel  wall  to  reach  the  receiver  crystal. 
In  the  next  switching  period,  the  functions  of  both 
crystals  are  exchanged  so  that  in  every  1  400th  sec  a 
train  of  upstream  and  a  train  of  downstream  transits 
are  available  for  determination  of  At.  Equation  18  is 


applicable  to  this  device  if  L  is  replaced  by  d-cos  9 
where  d  =  length  of  diagonal  between  the  crystals 
and  9  =  angle  between  diagonal  and  vessel  axis. 
The  transit-time  voltage  converter  generates  a  ramp 
voltage  showing  a  strictly  constant  slope  of  40  volts 
per  ^sec.  This  ramp  voltage  is  started  at  the  beginning 
of  every  sound  transmission,  and  its  ascent  is  abruptly 
stopped  when  the  respective  receiver  crystal  begins  to 
be  excited  by  the  sound,  so  that  the  amplitude  of  the 
ramp  voltage  is  proportional  to  the  sound-transit 
time.  It  is  obvious  that,  due  to  the  blood  flow,  the  up- 
stream ramp-voltage  amplitude  is  greater  than  the 
downstream  one.  This  difference  amounts  to  4  mv  per 
io-10  sec  and  is  detected  by  the  voltage  comparator 
which  delivers  a  400  cps  square-wave  voltage  with  an 
amplitude  proportional  to  the  difference  between  the 
upstream  and  downstream  ramp-voltage  amplitudes. 
Finally,  a  synchronized  detector  converts  the  square 
wave  into  a  d-c  voltage,  which  indicates  the  instanta- 
neous magnitude  and  direction  of  the  blood  velocity. 
The  device  possesses  satisfactory  sensitivity  to  flow 
and  high  stability  of  the  base  line.  The  stability  is 
achieved  mainly  by  using  whenever  possible,  only  one 
functional  unit  or  channel  for  detecting  differences  in 
time  or  voltage  of  consecutive  events.  Due  to  the 
carrier  frequency  of  400  cps,  the  apparatus  is  capable 
of  an  excellent  frequency  response  to  pulsatile  blood 
flow.  As  far  as  seen  from  the  tracings  published  in 
reduced  scale,  the  flow  patterns  recorded  on  blood 
vessels  of  different  sizes  in  vivo  are  very  similar  to 
those  obtained  by  the  electromagnetic  method.  In 
addition,  the  simultaneous  application  of  several  or 
many  ultrasonic  meters  is  possible  without  any 
mutual  interaction  (44).  One  is  inclined  to  predict 
that  this  kind  of  versatile  flowmeter  is  on  its  way 
toward  becoming  a  favorite  instrument  in  cardio- 
vascular research.  The  same  may  happen  regarding 
the  application  of  ultrasound  to  the  recording  of 
instantaneous  dimensional  changes  of  organs  [Keidel 
(74);  Edler  &  Hertz  (27);  Rushmer  et  al.  (1 15)]. 

However,  it  seems  that  the  possible  dependence  of 
the  calibration  of  the  ultrasonic  flowmeters  on  the 
velocity  profile  has  not  yet  been  duly  considered.  The 
sound  passes  from  the  transmitter  to  the  receiver 
crystal  on  a  diagonal  path  which  crosses  the  stream- 
lines of  moving  fluid  at  the  angle  9  (see  fig.  32).  It 
may  be  assumed  that  only  the  streamlines  crossing 
this  diagonal  will  cause  flow-related  changes  of  the 
sound-transit  times.  Furthermore,  the  relative  velocity 
distribution  taken  over  the  diagonal  may  be  con- 
sidered to  equal  that  taken  over  the  vessel's  diameter 
or  radius.  This  means  that  the  device  will  indicate  the 


[320 


HANDBOOK    OF    PHYSIOLOGY  -^  CIRCULATION    II 


fig.  32.  Simplified  diagram  of  the 
pulsed  ultrasonic  flowmeter.  For  de- 
scription see  text.  [From  Franklin  el  al. 
(44)-] 


UPSTREAM-  DOWNSTREAM 
VOLTAGE    COMPARATOR 

1- 


SYNCHRONOUS 
DETECTOR 


RECORDER 


AORTIC  FLOW 


JUUjUX 


H-lsec* 


velocity  vR  averaged  over  the  vessel's  diameter  or 
radius,  and  that  therefore  the  calibration  in  terms  of 
the  flow  rate  varies  with  the  velocity  profile.  On  the 
other  hand,  corrections  might  be  brought  about  by 
additional  effects,  such  as  some  flattening  of  the 
velocity  profile  by  the  slight  constriction  of  the  vessel 
caused  by  the  sleeve,  and  the  fact  the  ultrasound 
beam  reaching  the  receiver  is  not  in  the  form  of  a  line, 
but  of  a  band.  Rushmer  describes  the  calibration  of 
his  ultrasonic  flowmeter  as  being  independent  of  the 
velocity  profile  within  ±5  per  cent  (44).  With  respect 
to  the  growing  importance  of  this  flowmeter  type,  the 
problem  should  be  reconsidered  both  theoretically 
and  practically. 


TRAVELING    MARKERS 

Estimations  of  blood  velocity  can  be  made  by 
observing,  continuously  photographing,  or  filming 
the  movement  of  any  substance  which  acts  as  a  dis- 
tinguishable marker  traveling  with  the  blood  stream. 
In  most  cases,  such  a  procedure  will  allow  only  single 
short-time  recordings  which  can  be  repeated  at 
intervals.  The  marker  may  be  represented  by  dye,  by 
a  drop  of  fluid  nonmiscible  with  the  blood  [see  (54, 
p.  60)  (50,  p.  116)],  by  radiopaque  material  for 
cineradiography  (2,  7,  24,  90,  106),  or  by  a  gas  bubble. 


Even  the  blood's  own  corpuscles  can  be  used  as 
markers  (63),  and  the  progress  of  blood  columns 
differing  in  oxygen  saturation  may  be  assessed  photo- 
electrically  (85)  (cf  Chapter  18,  vol.  I,  of  this  Hand- 
book). Foreign  substances  are  usually  injected  into  a 
side  branch  and  then  observed  through  the  wall  of 
the  vessel  under  investigation.  In  contradistinction 
to  flowmeters  in  the  proper  sense,  the  use  of  traveling 
markers  does  not  give  the  volume  flow  at  a  fixed  site; 
it  rather  gives  a  function  of  time  and  space  since  the 
mark  changes  position  during  the  measurement.  In 
case  of  relatively  small  displacements,  the  change  in 
the  site  of  measurement  may  be  neglected.  Dyes  are 
particularly  useful  for  the  study  of  the  flow  course  in 
small  vessels.  Valuable  results  were  obtained  with 
China  ink  and  high-speed  cinematography  on  pulmo- 
nary capillaries  (130)  and  on  very  small  arteries  of 
the  rabbit  ear  (136). 

In  a  carefully  elaborated  procedure,  McDonald  (91- 
93)  studied  the  flow  pulse  in  the  rabbit  aorta  and  in 
peripheral  arteries  of  the  dog  by  filming  the  move- 
ment of  injected  gas  bubbles  through  the  translucent 
vessel  wall.  Gas  embolism  was  avoided  by  using  pure 
oxygen  instead  of  air.  An  injected  gas  bubble  travels 
at  a  velocity  quite  near  to  the  average  blood  velocity 
vA  if  the  bubble  is  spherical  and  just  fills  the  lumen 
completely.  Smaller  spherical  or  larger  cylindrical 
bubbles  will  run  faster.    High-speed  cinematography 


METHODS  OF  MEASURING  BLOOD    FLOW 


1321 


at  about  1000  frames  per  sec  is  used,  the  exposure  of 
each  frame  being  200  /usee.  For  evaluation,  the 
distance-time  relation  is  plotted  from  the  projected 
film,  and  the  time  course  of  the  velocity  is  obtained 
by  graphic  differentiation.  McDonald's  work  is  of 
particular  significance  regarding  hemodynamics  be- 
cause his  simultaneous  recordings  of  the  pressure 
gradient  make  possible  hydrodynamic  flow  calcula- 
tions and  comparison  of  the  calculated  flow  pattern 
with  that  determined  by  cinematography. 


MISCELLANEOUS    METHODS 

Rockemann  (114)  tried  to  measure  the  blood 
velocity  by  means  of  electrolytic  polarization  taking 
place  at  electrode  surfaces  which  are  in  contact  with 
the  streaming  blood.  A  stable  calibration,  however,  is 
not  obtainable  for  this  method. 

The  application  of  nuclear  magnetic  resonance  to 
blood  flow  measurements  was  described  almost  simul- 
taneously by  Buchman  and  by  Singer  in  1959.  Buch- 
man's  device  (17)  passes  protons,  the  spin  axes  of 
which  have  been  aligned,  through  a  varying  magnetic 
field.  Energy  is  required  to  bring  them  into  resonance. 
Thus  the  absorbed  energy  is  a  measure  of  the  number 
of  protons  passing  per  time  unit,  and  hence,  is  propor- 
tional to  the  flow  rate.  Singer  (124)  uses  several 
methods  based  on  nuclear  magnetic  resonance.  In 
one  of  the  procedures,  the  nuclear  relaxation  time  of 
the  protons  in  the  water  of  streaming  blood  is  meas- 
ured and  compared  with  the  relaxation  time  of 
those  in  stopped  blood;  only  single  determinations  of 
relative  values  are  obtained.  By  another  procedure 
described  by  Singer,  absolute  flow  velocities  can  be 
recorded  at  short  time  intervals.  The  nuclei  are  per- 
turbed by  the  60  mc  per  sec  field  of  a  transmitter  coil, 
and  the  time  required  by  the  nuclei  to  reach  a  second 


detecting  coil  is  measured.  Singer  also  considers 
nuclear  or  electron  magnetic  resonance  as  a  tracer 
detection  system.  It  seems  worthwhile  to  carry  on  the 
development  of  these  methods  since  they  are  appli- 
cable to  unopened  vessels,  even  from  outside  through 
the  intact  skin. 


ADDENDUM 

Since  completion  of  the  manuscript,  several  papers  have 
been  published  which  should  be  referred  to: 

Elliott,  S.  E.,  J.  I.  E.  Hoffman,  and  A.  Guz.  An  electro- 
magnetic flowmeter  for  simultaneous  measurement  of  ventric- 
ular ejection  in  the  conscious  animal.  Digest  of  4th  Intern.  Conf. 
Med.  Electronics,  New  York,  1961,  p.  150.  Coreless  electro- 
magnetic flowmeter  units  were  implanted  around  the  ascending 
aorta  and  pulmonary  artery  of  the  dog.  A-c  sine-wave  type, 
400  cps.  Some  magnetic  interference  between  both  units  was 
observed. 

Yanof,  H.  M.  A  New  Trapezoidal-wave  Electromagnetic 
Blood  Flowmeter  and  Its  Application  to  the  Study  of  Blood 
Flow  in  the  Dog  (Ph.D.  thesis).  Berkeley:  Univ.  of  California, 
iq6o.  Description  of  circuitry.  1000  cps.  Adjustment  of  mini- 
mum transformer  emf  by  an  additional  ferrite  slug. 

Wyatt,  D.  G.  Problems  in  the  measurement  of  blood  flow 
by  magnetic  induction.  Phys.  in  Med.  Biol.  5:  289,  1961.  Thor- 
ough examination  of  performance,  and  possible  error  sources 
in  the  application,  of  electromagnetic  flowmeters. 

Zarnstorff,  W.  C,  and  C.  A.  Castillo.  An  ultrasonic  flow- 
meter. Digest  0/  4th  Intern.  Conf.  on  Med.  Electronics,  New  York, 
1 96 1,  p.  86.  Stable  phase-difference  device  appropriate  for 
recording  of  blood  How  in  unopened  arteries. 

Franklin,  D.  L.,  D.  W.  Baker,  and  R.  F.  Rushmer.  Pulsed 
ultrasonic  transit  time  flowmeter.  IRE  Trans,  on  Bio-Med. 
Electronics  BME-g,  44,  1962.  Diagrams  of  electronic  circuitry. 

Higasi,  K.  (ed.).  Platinum  blood  flowmeter.  Research  Inst. 
Appl.  Elec,  Hokkaido  Univ.,  Monograph  Ser.  No.  10,  1962.  Con- 
tains several  papers  by  M.  Mochizuki  and  co-workers  on  the 
relation  between  polarographic  current  for  oxygen  and  the  flow 
velocity.  Application  to  flow  measurement  in  arteries.  Catheter- 
tip  method.  Calibration  curve  concave  to  flow  abscissa  at  low 
velocities  and  linear  at  higher  velocities. 


REFERENCES 

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2.  Anschutz,  F.,  and  F.  Heuck.  Uber  die  durch  Aorten- 
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3.  Barnes,  C.  W.  A  new  method  for  obtaining  How  signals 
from  the  electromagnetic  flowmeter.  Naturwissenschaften 
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4.  Baxter,  I.  G,  and  J.  W.  Pearce.  Simultaneous  measure- 
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5.  Bergmann,  G.  Die  "Stromborste",  ein  elektrischer  Ge- 
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6.  Betticher,  A.,  J.  Maillard,  and  A.  Muller.  Un  mano- 
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■4- 
'5- 


it). 


'7- 


iq. 


23- 

24- 

26 

27- 
28. 

=9' 
3° 


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direct  recording  of  cardiac  output.  Proc.  Soc.  Expll.  Biol. 

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Bretschneider,  H.J.  Verhandl.  deut.  Ges.  Chirurgie,  1961. 

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Frank.  Z.  Biol.  91  :  267,  1931. 

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J.  Pharmacol.  Exptl.  Therap.  32:171,  1 928. 
Westersten,  A.,  G.  Herrold,  and  N.  S.  Assali.  A  gated 
sine  wave  blood  flowmeter.  J.  Appl.  Physiol.  15:  533,  i960. 
Wetterer,  E.  Eine  neue  Methode  zur  Registrierung  der 
Blutstromungsgeschwindigkeit  am  uneroffneten  GefalS. 
Z.  Biol.  98:  26,  1937. 

Wetterer,  E.  Der  Induktionstachograph.  Z.  Biol.  99: 
158,  1938. 

Wetterer,  E.  Eine  neue  manometrische  Sonde  mit  elek- 
trischer  Transmission.  Z.  Biol.  101  :  332,  1943. 
VVidmer,  L.  K.  Zur  Stromungsgeschwindigkeit  in  klein- 
sten  peripheren  Arterien.  Arch.  Kreislaufforsch.  27  :  54,  1 957- 
Wiggers,  C.  J.,  and  F.  W.  Cotton.  Studies  on  the  coro- 
nary circulation.  II.  The  systolic  and  diastolic  flow 
through  the  coronary  vessels.   Am.   J.  Physiol.    106:  597, 

■933- 

Wretlind,  A.  Apparatus  for  the  determination  of  the 
mean  blood  flow  in  the  ascending  aorta  of  the  cat.  Ada 
Physiol.  Scand.  46:  291,  1959. 


CHAPTER   39 


The  circulation  through  the  skin 


A.    D.    M.  GREENFIELD 


Department  of  Physiology,  The  Queen's  University  of  Be/fast, 
Belfast,  Northern  Ireland 


CHAPTER      CONTENTS 

Introduction 

Arrangement  of  the  Blood  Vessels  of  the  Skin 
Measurement  of  the  Flow  of  Blood  Through  the  Skin 

Total  cutaneous  blood  flow 
Color  of  the  Skin 
Temperature  of  the  Skin 
Responses  of  Skin  Blood  Vessels  to  Physical  Disturbances 

Response  of  the  Circulation  Following  Periods  of  Arrest  or 
Insufficiency 
Reactive  hyperemia 

Hyperemia  after  prolonged  insufficiency  of  the  circulation 
Responses  of  Skin  Vessels  to  Changes  in  Transmural  Pressure 
Effect  of  Local  Temperature  on  the  Skin  Circulation 
Local  temperatures  in  the  range  15  C  to  45  C 
Local  temperature  in  the  range  o  C  to  15  C:  Cold  vaso- 
dilatation 
Prolonged  exposure  to  cold:  Trench  foot  and  immersion 

foot 
Exposure  to  severe  cold :  Frostbite 
Reactions  to  Injury 
Mechanical  injury 
Ultraviolet  light 
Arterial  gas  embolism 
Nervous  Control  of  Skin  Blood  Vessels 
Vasomotor  Nerves 

Vasoconstrictor  sympathetic  nerves 
Vasodilator  sympathetic  nerves 

Vasodilatation     caused     by     antidromic     stimulation     of 
dorsal  root  sensory  nerves.  The  axon  reflex  pathway 
Innervation  of  the  Blood  Vessels  of  the  Skin   in   Different 
Areas 
The  human  hand  and  fingers 
The  human  forearm 
Other  areas  of  the  human  body 
The  skin  of  animals 
Late  effects  of  sympathetic  denervation 
Late  effects  of  total  denervation 
Reflex  Control  of  Blood  Vessels  of  the  Skin 
Body  temperature  regulation 
Emotion 
Fainting 


General  sensory  stimuli 

Response  to  a  deep  inspiration 

Response  to  distention  of  the  bladder 

Hypoglycemia 

Posture 

Responses  to  baroreceptor  stimulation 
Action  of  Humoral  Agents  on  the  Blood  Vessels  of  the  Skin 
Adrenaline  and  Noradrenaline 
Histamine 
Acetylcholine 

5-Hydroxytryptamine  (Serotonin) 
Adenosine  Triphosphate 
Bradykinin 
Carbon  Dioxide 
Vasopressin 
Oxytocin 


INTRODUCTION 

this  section  deals  principally  with  the  circulation 
through  human  skin,  since  this  has  been  so  frequently 
and  carefully  studied,  mostly  in  unanesthetized  sub- 
jects. In  selecting  references  no  attention  has  been 
in  general  paid  to  priority  of  discovery.  Papers  have 
been  chosen  for  the  completeness  of  the  information 
they  contain,  for  the  value  of  their  bibliography, 
and  very  often  because  the  work  is  personally  known 
to  the  present  author.  A  wider  bibliography  will  be 
found  in  several  excellent  monographs  and  reviews 
(1,  19,  22,  44,  115,  119,  139,  148,  152,  155,  165, 
176,  187,  193). 

The  great  bulk  of  observations  relates  to  the  cir- 
culation through  the  skin  of  the  extremities,  and  par- 
ticularly of  the  digits.  Here  the  striking  features  are, 
firstly,  the  very  great  variability  of  the  blood  flow 
under  different   circumstances,   greatest   in   the   tips 


'3*5 


[326 


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CIRCULATION    II 


fig.  I.  Projection  drawing  (X  95)  of 
a  group  of  anastomoses  in  the  nail  bed 
of  the  toe.  The  artery  crosses  the  center 
of  the  drawing  and  gives  rise  to  1 2 
thick-walled  anastomotic  branches.  The 
thin-walled  venous  terminations  ol 
several  are  shown.  [From  Grant  & 
Bland    (99).] 


of  the  fingers  where  the  maximum  flow  is  probably 
between  100  and  200  times  the  minimum  (42), 
and  secondly,  the  fact  that  in  normal  persons  the 
blood  flow  to  the  skin  is  greatly  in  excess  of  its  meta- 
bolic requirements,  being  chiefly  determined  by  the 
need  to  maintain  thermal  balance  (82).  This  lavish 
circulation  is,  no  doubt,  valuable  in  the  repair  of 
trauma  and  wounds  to  which  the  skin  is  especially 
exposed.  Perhaps  because  of  methodological  diffi- 
culties, there  is  very  little  information  about  the 
circulation  through  other  areas  of  skin,  but  it  is 
almost  certainly  much  less  reactive  than  that  through 
the  extremities. 

Arrangement  of  the  Blood  I  'esseli  of  the  Skin 

The  skin  is  supplied  with  a  profuse  system  of  capil- 
lary loops  which  rise  in  the  papillae  of  the  corium 
and  return  to  enter  a  subpapillarv  venous  plexus. 
The  vessels  of  the  latter  are  large  and  have  thin  walls, 
and  it  is  probable  that  when  distended  they  contain  a 


very  large  proportion  of  all  the  blood  in  the  skin. 
There  are  rich  capillary  networks  around  the  sweat 
glands,  at  the  base  of  hair  follicles,  around  the  seba- 
ceous glands,  and  in  the  nail  bed  and  nail  fold. 

In  the  skin  of  the  extremities  a  special  and  promi- 
nent feature  is  the  large  number  of  arteriovenous 
anastomoses  (50,  147).  These  are  coiled  channels 
(fig.  1 )  with  thick  muscular  walls  and  a  lumen  which 
in  the  dilated  state  is  between  20  and  70  n  in  diam- 
eter, the  average  being  35  /x-  They  are  abundantly 
supplied  with  nerve  endings,  and  a  high  concentra- 
tion of  cholinesterase  has  been  reported  around  them 
(28,  124,  151).  They  directly  connect  arterioles  and 
venules  in  the  dermis  at  the  level  of,  or  a  little  super- 
ficial to,  the  sweat  glands.  They  are  most  numerous 
in  the  nail  bed,  numerous  at  the  tips  of  the  digits, 
less  numerous  on  the  palmar  surface  of  the  phalanges, 
and  almost  absent  from  the  dorsum  of  the  phalanges. 
They  are  fairly  numerous  in  the  palm  of  the  hand 
and  sole  of  the  foot,  but  are  absent  from  the  areas 
of  the  forearm  and  calf  which  have  been  examined. 


CIRCULATION    THROUGH    THE    SKIN 


I327 


table  I.  Xumber  of  Anastomoses  per 
Square  Centimeter  of  Surface  Area 

Hand 

Index  finger 

Nail  bed  501 

Tip  236 

Palm,  3rd  phalanx  150 

2nd  phalanx  20 

1st  phalanx  93 

Palm 

Metacarpo-phalangeal  joint  3rd  finger  31 

Thenar  eminence  113 

Hypothenar  eminence  96 
Foot 

2nd  toe 

Nail  bed  593 

Pad  293 

Sole,  near  heel  197 

These  are  nil  for  dorsal  surfaces  of  fingers,  toes,  hand,  and 
foot;  flexor  surfaces  of  lower  forearm  and  lower  calf  of  leg; 
lower  half  of  ear.  [From  Grant  &  Bland  (99).] 

table  2.  Percentage  Composition  by  Volume 
of  Parts  of  Human  Limbs 


Hand 


Foot 


Forearm 


Skin 

30.2 

'7 

8.6 

'3-4 

Subcutaneous 
tissue 

24 

8.0 

Fat 

54-3 

2 

28.0 

Bone 

43 

'3-7 

Tendon 

6.1 

Muscle 

'5-5 

14 

63.6 

58.6 

REFERENCES 

Hand  Average  of  3  hands  (2). 

Foot  Average  of  2  feet  (12). 

Forearm  A  Average  of  5  forearms  (56). 
Forearm  B  Average  of  3  forearms     (2). 

Table  1,  from  Grant  &  Bland  (99),  summarizes  the 
distribution  in  the  human.  They  have  since  been 
found  in  the  human  ear  (164).  Some  observers  (151, 
163)  have  reported  rather  smaller  numbers  (20-25/ 
cm2)  than  did  Grant  and  Bland  in  the  finger  pad. 
They  are  numerous  in  the  external  ear  of  the  rabbit, 
where  their  reactions  have  been  carefully  studied 
(98),  in  the  ear  of  the  cat  and  dog  and  in  the  feet  of 
webfooted  birds.  Grant's  (98)  summary  of  the  func- 
tions of  the  anastomoses  is  still  valid,  and  applies  to 
the  human  extremities  as  well  as  to  the  rabbit's 
ear:  "The  anastomoses  serve  two  functions  (a)  local, 


and  (b)  general,  (a)  It  is  mainly  through  their  agency 
that  the  temperature  of  the  ears  is  maintained  when 
they  are  exposed  to  cold,  (b)  They  are  important 
factors  in  regulating  of  body  temperature,  aiding  the 
dispersal  of  heat  by  allowing  an  enormous  blood 
flow  through  the  ears."   (See  also  Chapters  27   and 

37-) 

Measurement  of  the  Flow  of  Blood  Through  the  Skin 

The  fingers  and  toes  are  composed  largely  of  skin. 
Of  the  total  flow  through  them,  the  greater  part 
normally  passes  through  skin,  and  total  digital  blood 
flow  is  often  used  as  an  index  of  digital  skin  blood 
flow  (table  2).  Digital  flow  may  be  directly  measured 
by  venous  occlusion  plethysmography  (40,  95),  a 
method  which  permits  variation  in  the  rate  to  be 
followed  from  one  heart  beat  to  the  next,  and  even 
during  a  single  beat.  Flow  may  be  estimated  by 
calorimetry  (148),  a  method  which,  because  of  the 
thermal  capacity  of  the  tissues,  is  incapable  of  follow- 
ing rapid  changes  in  flow,  but  which  conveniently 
integrates  flow  over  a  period  of  time.  Calorimetry 
finds  its  most  successful  application  in  the  digits, 
and  the  method  has  been  rendered  more  versatile  by 
the  use  of  copper-tellurium  heat  flow  discs  (47). 

In  the  more  proximal  parts  of  the  limbs,  the  total 
blood  flow  depends  a  great  deal  on  the  circulation 
through  tissues,  especially  muscle,  deep  to  the  skin. 
The  flow  through  the  skin  can  be  deduced  by  com- 
paring the  total  flow  in  a  pair  of  segments  in  one  of 
which  the  circulation  through  the  skin  has  been 
suppressed  by  iontophoresis  of  adrenaline  (71). 
More  often,  indirect  indices  of  skin  blood  flow  have 
been  employed.  If  venous  blood  can  be  obtained  from 
vessels  exclusively  draining  skin,  and  if  the  oxygen 
usage  of  the  skin  is  assumed  to  remain  constant, 
changes  in  flow  can  be  inferred  from  changes  in  the 
oxygen  content  of  the  blood  (170).  Measurements 
of  the  temperature  of  the  skin  have  provided  useful 
qualitative  information  in  the  proximal  as  well  as 
in  the  distal  parts  of  the  limbs  (100),  but  this  tempera- 
ture, as  explained  later,  depends  on  so  many  other 
factors  that  it  is  a  very  imperfect  index  of  skin  cir- 
culation. It  is  incapable  of  following  accurately 
rapid  fluctuations  in  flow;  if  the  circulation  is  com- 
pletely arrested  the  temperature  of  the  skin  falls 
very  slowly.  A  more  sensitive  index  of  blood  flow  is 
the  change  in  thermal  conductivity  of  the  skin,  which 
can  be  conveniently  measured  by  a  surface  applicator 
containing  two  small  plates,  one  of  which  is  elec- 
trically  warmed    while    the    temperature    difference 


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CIRCULATION    II 


between  the  plates  is  recorded  (1  14).  The  instrument 
does  not,  of  course,  distinguish  between  the  effect 
of  blood  circulating  through  the  local  blood  vessels 
of  the  skin,  and  blood  flowing  through  nearby  veins 
draining  distal  regions.  The  results  cannot  be  quan- 
titatively translated  into  measurements  of  blood 
flow,  but  the  method  retains  its  sensitivity  over  the 
wide  ranges  of  flow  for  which  measurement  of  skin 
temperature  is  of  little  help. 

The  rate  of  clearance  of  radiosodium  from  an  in- 
jection site  (130)  probably  depends  on  the  rate  of 
blood  flow  through  those  vesse's  which  nourish  the 
tissues,  and  is  probably  little  affected  by  the  rate  of 
blood  flow  through,  for  example,  arteriovenous 
anastomoses. 

The  capillary  loops  of  the  nail  fold  are  among  the 
most  easily  visualized  in  the  living  body,  and  they 
have  been  much  observed  ( 1 75). 

total  cutaneous  blood  flow.  This  quantity  has 
not  been  measured  with  precision,  but  in  a  warm 
subject  it  is  a  considerable  fraction  of  the  cardiac 
output.  Hardy  &  Soderstrom  (112)  by  a  study  of  deep 
and  superficial  temperature  and  heat  exchange  ar- 
rived at  a  blood  flow  through  the  skin  of  278  ml  per 
m2  of  body  surface  per  min  in  a  nude  subject  at  rest 
at  an  environmental  temperature  of  35  C.  Behnke  & 
Willmon  (29)  measuring  helium  absorption  through 
the  skin  under  similar  conditions  arrived  at  a  figure 
of  230  ml  per  m2  per  min.  During  generalized  maxi- 
mum cutaneous  vasodilatation  the  total  blood  flow- 
is  presumably  very  much  greater.  Assuming,  for 
example,  a  mean  thickness  of  1.2  mm,  and  a  maxi- 
mum flow  of  180  ml  per  100  ml  skin  per  min,  which 
has  been  reported  in  digits  and  inferred  in  the  fore- 
arm, the  flow  would  be  1200  ml  per  m'2  per  min. 
Another  estimate,  based  on  skin  conductance,  is 
2000  ml  per  m2  per  min  (1 15). 

Color  of  the  Skin 

The  color  of  the  skin  due  to  tissue  pigment  is  re- 
vealed by  expelling  the  blood  by  local  pressure.  The 
additional  color,  due  to  circulating  pigment,  de- 
pends on  the  quantity,  quality,  and  distribution  of 
this  pigment  in  the  skin  and  subcutaneous  vessels. 
It  is  not  dependent  on  the  rate  of  blood  flow  (139). 
Although  it  often  happens  that  the  skin  contains  more 
blood  when  the  flow  is  fast  than  when  it  is  slow,  the 
amount  of  blood  contained  in  the  tissue  and  the  rate 
at  which  blood  flows  through  the  tissue  by  no  means 
run  parallel  to  each  other  (54).  Thus,  the  intensity 


of  the  color  indicates  the  amount  of  pigment  present, 
and  how  near  the  surface  are  the  vessels  containing 
it.  The  hue  is  determined  by  the  proportions  of  the 
various  hemoglobin  derivatives  (oxy-,  reduced,  met-, 
carboxy-  etc.)  present. 

Temperature  of  the  Skin 

The  temperature  of  the  skin  in  air  depends  partly 
on  the  rate  of  blood  flow  through  it.  It  depends  on 
the  temperature  at  which  the  arterial  blood  arrives; 
that  of  the  blood  in  the  radial  artery  may  be  as  low 
as  21.5  C  in  a  subject  who  is  not  feeling  unduly 
cold  (25).  It  depends  also  on  the  rate  of  blood  flow 
through  both  distal  and  subjacent  tissues,  on  the 
activity  of  nearby  muscle  (101),  on  the  rate  of  evap- 
oration of  sweat,  on  the  temperature,  humidity, 
motion,  and  pressure  of  the  surrounding  air,  and  on 
the  exchange  of  radiant  heat  with  the  environment. 
It  is  clear,  therefore,  that  there  can  be  no  simple  rela- 
tionship between  the  temperature  of  the  skin  and  the 
rate  of  blood  flow  through  it.  The  simplest  relation- 
ship between  the  two  quantities  is  probably  found  in 
the  digits,  examined  in  still  air  at  a  comfortable 
temperature.  If  the  circulation  is  arrested,  the  fingers 
cool  until  their  temperature  settles  near  that  of  the 
air.  With  the  circulation  fully  opened  up,  the  tem- 
perature of  the  skin  of  the  fingers  comes  to  within 
about  1  C  and  that  of  the  toes  to  within  about  3  C  of 
the  temperature  of  the  mouth.  Between  these  ex- 
tremes the  relationship  between  flow  and  temperature 
is  by  no  means  linear.  For  example,  in  a  room  at 
22  C,  the  temperature  of  the  fingers  may  rise  to  34  C 
when  the  blood  flow  is  one  quarter  of  the  maximum, 
and  to  36  C  when  the  maximum  is  attained  (55).  In 
a  room  at  20.5  C,  a  skin  temperature  of  24  C  corre- 
sponded with  a  blood  flow  through  the  toes  of  3  ml  of 
blood  per  100  ml  of  toe  per  min;  29  C,  with  10  ml, 
and  32  C,  with  more  than  30  ml.  Even  flows  of  70  ml 
do  not  cause  the  temperature  to  reach  34  C  (75). 
This  does  not  mean  that  the  higher  ranges  of  blood 
flow  are  always  wastefully  employed  by  the  body, 
for  in  colder  air,  or  in  moving  air,  the  difference  in 
temperature  to  which  the  skin  is  raised  by,  and  the 
difference  in  heat  dissipation  at,  one  quarter  of  the 
maximum  flow  and  the  maximum  flow  may  be  very 
considerable. 

By  far  the  greatest  variations  in  skin  temperature 
are  found  in  the  extremities,  particularly  the  hands 
and  feet  in  man,  and  the  ears  in  the  rabbit. 

The  temperature  at  the  surface  of  the  skin  in 
thoroughly   stirred    water   is   essentially    that    of   the 


CIRCULATION    THROUGH    THE    SKIN 


1329 


water.  This  follows  because  stirred  water  can  convey 
heat  to  or  from  the  surface  at  a  rate  which  is  very 
great  indeed  compared  with  the  rate  at  which  it  can 
be  conveyed  to  or  from  the  surface  by  even  the  most 
profuse  flow  of  blood  through  the  tissues.  If  an  in- 
sulating layer  is  formed,  by  allowing  the  water  to 
stagnate,  or  by  covering  the  skin  with  fabric,  the 
skin  becomes  a  point  on  the  temperature  gradient 
from  the  body  core  to  the  water.  It  assumes  a  tempera- 
ture which  depends  on  the  ratio  of  the  thermal 
insulation  between  the  body  core  and  the  skin,  and 
between  the  skin  and  the  water.  The  thermal  insula- 
tion between  the  body  core  and  the  skin  is  highly- 
dependent  on  the  state  of  the  circulation.  The  circu- 
lation of  the  blood  is  the  main  means  of  transfer  of 
heat  between  the  body  core  and  the  periphery.  The 
thermal  conductivity  of  the  skin  is  also  highly  de- 
pendent on  the  rate  of  blood  flow  through  it  (44). 


RESPONSES    OF    SKIN    BLOOD    VESSELS    TO 
PHYSICAL    DISTURBANCES 

Response  of  the  Circulation  Following 
Periods  of  Arrest  or  Insufficiency 

reactive  hyperemia.  The  circulation  through  the 
skin  is  very  frequently  arrested  by  local  pressure;  it  is, 
for  example,  arrested  in  the  sole  of  the  foot  while 
standing  and  in  the  parts  of  the  hand  supporting  a 
heavy  object.  The  skin  is  better  able  than  most  other 
tissues  to  survive  fairly  prolonged  arrest  of  the  circu- 
lation without  permanent  damage.  It  shows,  con- 
spicuously, the  phenomenon  of  reactive  hyperemia, 
by  which  is  meant  the  bright  red  flushing  (51)  and 
increase  in  blood  flow  above  the  resting  level  (139) 
when  the  circulation  is  released  following  obstruction. 
This  is  a  local  change,  and  clearly  depends  upon  a 
local  dilatation  of  the  blood  vessels  responsible  for 
resistance  to  flow.  The  size  and  duration  of  the  reac- 
tive hyperemia  are  related  to  the  duration  of  previous 
arrest.  Although  some  observations  have  indicated 
that  the  extra  blood  flowing  during  the  period  of 
hyperemia  is  closely  similar  to  the  amount  that  would 
normally  have  flowed  during  the  period  of  arrest 
[debt  and  repayment  hypothesis  (142)]  the  corre- 
spondence is  by  no  means  always  exact  (83),  the  debt 
being  frequently  underpaid  (157).  Indeed,  it  is 
possible  in  the  forearm,  by  gradually  releasing  the 
main  vessel,  to  restore  the  circulation  without  any 
repayment  of  debt  (35),  the  blood  flow  never  exceed- 
ing the  resting  level. 


Reactive  hyperemia  is  most  readily  demonstrated 
when  a  limb  is  warm;  it  was  found  by  Lewis  &  Grant 
(142)  to  be  much  reduced  in  a  cooled  part.  Thus 
following  arrest  of  the  circulation  for  5  min,  Catch- 
pole  &  Jepson  (47)  found  average  peak  flows  of 
3.05  ml  per  100  ml  per  min  while  the  hand  was 
immersed  in  water  at  15  C,  6.8  ml  at  20  C,  g.8  ml  at 
25  C,  and  19.8  ml  at  30  C. 

Bier  (33,  34)  demonstrated  in  1897  that  reactive 
hyperemia  is  independent  of  nervous  connections 
with  the  central  nervous  system.  While  amputating 
limbs  he  first  divided  the  nerves  and  flesh,  leaving 
the  main  artery  and  vein  intact.  Occlusion  of  the 
artery  was  followed,  on  release,  by  the  usual  hypere- 
mia. Lewis  &  Grant  (141)  observed  that  skin  which 
had  long  been  anesthetized,  as  a  result  of  old  standing 
lesions  of  the  main  nerves,  flushes  uniformly  with  the 
adjacent  skin  still  possessing  normal  innervation.  In  a 
chronically  denervated  and  wasted  forearm,  the  peak 
blood  flow  during  reactive  hyperemia  was  found  by 
Eichna  &  Wilkins  (73)  to  be  26  per  cent  greater,  in 
relation  to  the  volume  of  the  part,  than  in  the  nor- 
mally innervated  arm.  Similar  observations  on  four 
other  cases  have  been  made  by  Duff  &  Shepherd 
(70).  The  height  and  the  duration  of  the  reactive 
hyperemia  were  found  by  Freeman  (83)  to  be  similar 
in  the  normal  and  the  chronically  sympathectomized 
hand.  The  reaction  seems,  therefore,  to  be  inde- 
pendent of  all  nervous  elements  which  degenerate 
following  section  of  peripheral,  somatic,  and  auto- 
nomic nerves. 

The  commonly  observed  rough  correspondence  of 
debt  and  repayment  has  suggested  that  a  chemical 
substance  may  accumulate  during  circulatory  arrest, 
and  act  as  a  vasodilator.  Histamine  has  been  found 
in  the  venous  blood  following  arrest  of  the  circulation 
(14),  but  in  the  forearm  antihistamine  substances  do 
not  influence  the  hyperemia  following  brief  arrest, 
though  they  somewhat  reduce  that  following  more 
prolonged  arrest  of  the  circulation  (6g). 

There  is  some  evidence  that  the  lowered  pressure 
in  the  resistance  vessels  during  circulatory  arrest 
may  lead  to  a  relaxation  of  their  muscular  tissue, 
perhaps  by  a  local  mechanism.  Thus  Wood  et  al. 
(194)  and  Patterson  (158)  have  found  that  reactive 
hyperemia  in  the  forearm  is  reduced  if  the  blood 
vessels  are  packed  with  blood,  thus  maintaining  a 
high  transmural  pressure  during  the  period  of  arrest 
of  the  circulation. 

Present  evidence  suggests  that  reactive  hyperemia 
depends    on    local    chemical   and    physical    changes, 


133°  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


which  may  contribute  in  varying  proportion  accord- 
ing to  the  circumstances. 

HYPEREMIA    AFTER    PROLONGED    INSUFFICIENCY   OF   THE 

circulation.  A  hyperemia,  with  the  blood  flow 
several  times  the  normal  level  and  lasting  for  some 
weeks,  is  seen  in  the  feet  of  some  patients  after  the 
relief  of  chronic  arterial  obstruction  by  an  arterial 
graft  (86).  The  mechanism  of  this  hyperemia  and  its 
relationship,  if  any,  to  reactive  hyperemia  is  not 
yet  known. 

Responses  oj  Skin  I  'essels  to  Changes 
in  Transmural  Pressure 

Measurements  of  the  circulation  through  the  finger 
have  led  Burton  (43)  and  co-workers  to  conclude  that 
in  the  resistance  vessels  there  is  an  unstable  equi- 
librium between  the  tension  in  the  wall  and  the 
transmural  pressure.  If  the  transmural  pressure  falls 
below  the  ''critical  closing  pressure,"'  the  value  of 
which  depends  on  the  state  of  activity  of  sympathetic 
vasomotor  nerves,  the  vessels  close  completely  and 
arrest  the  flow  of  blood.  This  behavior  of  the  vessels 
has  been  independently  confirmed  in  the  finger  tip 
by  Roddie  &  Shepherd  (167). 

Calorimetric  measurements  on  the  hand  (53)  and 
toes  (52)  indicate  that  when  the  transmural  pressure 
is  progressively  increased  beyond  the  normal  value 
(as  by  local  exposure  to  subatmospheric  pressure)  the 
resistance  vessels  at  first  are  passively  dilated.  At 
somewhat  higher  pressures  they  react  by  active  con- 
traction of  their  walls  and  may  become  narrower 
than  normal;  this  is  a  form  of  autoregulation  of  the 
skin  circulation,  the  purpose  of  which  may  be  to 
assist  the  antigravity  defenses  of  the  body  rather  than 
to  maintain  constancy  of  the  skin  blood  flow. 

Effect  of  Local  Temperature  on  the  Skin  Circulation 

The  effects  of  local  temperature  on  the  skin  circula- 
tion are  of  great  importance,  because  the  skin  is 
normally  exposed  to  a  greater  range  of  temperatures 
than  any  other  part  of  the  body  except  perhaps  the 
upper  end  of  the  alimentary  canal.  In  the  latter, 
exposure  to  extremes  of  temperature  is  brief,  but  in 
the  skin  it  may  be  prolonged. 

A  great  many  observations  have  shown  that  the 
circulation  through  the  skin  is  greatly  influenced  by 
local  temperature.  The  exposure  of  any  part  of  the 
body  to  a  change  of  temperature  probably  causes 
some  alteration  to  the  circulation  in  all  other  parts, 


40 


30 


20 


IO 


A  WARM 

•    COMFORTABLE 

O    COLD 


15  25  35 

LOCAL     TEMPERATURE       C 


45 


fig.  2.  The  blood  How  through  the  hand  measured  by  venous 
occlusion  plethysmography,  in  warm,  comfortable,  and  cold 
subjects,  and  with  the  hand  immersed  in  water  at  various  local 
temperatures.  [Data  from:  /)  Abramson  el  at.  (4),  2)  Catchpole 
&  Jepson  (47),  3)  Killian  &  Oclassen  (132),  4)  Kunkel  &  Stead 
(136),  5)  Kunkel  el  at.  (137),  6")  Peacock  (159),  7)  Roddie  & 
Shepherd  (166),  8)  Speaman  (180).] 

partly  by  nervous  reflexes  and  partly  by  alteration  in 
temperature  of  the  blood  returning  from  the  part  to 
the  heat-regulating  center.  However,  the  effects  now 
to  be  described  are  predominantly  local  ones.  When, 
for  example,  the  temperature  of  the  water  around 
one  finger  or  hand  is  altered,  the  changes  in  the 
circulation  through  it  are  very  much  greater  than 
those  simultaneously  observed  in  the  opposite  member 
immersed  in  water  at  a  constant  temperature  (55, 
166). 

LOCAL    TEMPERATURES    IN    THE    RANGE     1 3    C    TO    45    C. 

Figure  2  summarizes  some  representative  observa- 
tions on  the  effect  of  immersion  in  water  at  tempera- 
tures in  the  range  15  C  to  45  C  on  the  rate  of  blood 
flow  through  the  hand.  Between  the  observations 
there  are  differences  of  age,  sex,  and  number  of 
subjects,  of  present  and  previous  environmental 
temperature,  in  the  length  of  exposure  to  the  local 
temperature,  and  in  the  details  of  the  venous  oc- 
clusion plethysmography  technique.  In  general, 
however,  it  may  be  said  that  the  blood  flow  through 
the  hand  is  at  its  lowest  value  at  about  15  C,  when  it 
may  be  as  little  as  0.3  ml  per  100  ml  of  hand  per  min 
in  a  cold  subject,  and  0.9  ml  in  a  warm  one.  From 


CIRCULATION    THROUGH    THE    SKIN  1 33 1 


15  C  to  29  C  there  is  a  modest  rise,  and  from  29  C 
to  35  C  a  faster  rise  in  flow  with  temperature  (180); 
35  C  to  37  C  is  the  highest  temperature  to  which  the 
hand  is  normally  warmed  by  the  body's  own  heat. 
At  local  temperatures  in  the  range  25  C  to  35  C,  the 
level  of  blood  flow  is  greatly  influenced  by  the  heat- 
regulating  mechanism  of  the  body,  and  the  observed 
values  are  distributed  over  a  wide  range.  With  further 
rise  in  local  temperature  from  35  C  to  45  C,  there  is 
a  steep  increase  in  flow,  to  a  maximum  of  about 
35  ml  per  100  ml  per  min  (4);  Peacock  (159)  found 
in  12  women  an  average  of  36.0,  and  a  range  of  30.8 
to  41.0;  Kunkel  &  Stead  (136)  in  18  subjects  at  43  C 
found  an  average  of  32  and  a  range  of  18.7  to  54.4. 
Even  at  high  local  temperatures  the  heat-regulating 
mechanism  still  exerts  an  influence,  for  if  the  subject 
is  generally  warmed  the  blood  flow  through  the  hand 
at  44  C  increases  to  about  56  ml  per  100  ml  per  min, 
individual  observations  of  over  70  ml  per  100  ml  per 
min  having  been  recorded  (166).  Most  people  find 
immersion  in  stirred  water  hotter  than  45  C  to  be 
painful  or  intolerable. 

In  the  foot,  the  effect  of  immersion  in  water  at 
various  temperatures  is  very  similar  to  that  in  the 
hand,  but  the  blood  flow  per  unit  volume  of  tissue  is 
generally  about  50  per  cent,  and  per  unit  of  surface 
area  about  75  per  cent  (136),  of  that  in  the  hand. 
Allwood  &  Burry  (12)  report  average  blood  flows  in 
four  subjects  ranging  from  0.2  ml  per  100  ml  per 
min  at  15  C  to  16.5  ml  at  44  C,  and  these  seem  typi- 
cal. Thus  in  the  range  43  C  to  45  C  flows  have  been 
reported  of  14.8  in  one  subject  (132);  16.3  with  a 
range  11.1  to  20.9  in  33  male  feet;  and  18.7  with  a 
range  13.4  to  25.9  in  15  female  feet  at  43  C,  go  per 
cent  of  the  observations  falling  between  13  and  20 
(136);  15.2  in  one  subject  (4)  and  20.5  in  33  subjects 
(191).  The  high  blood  flow  with  local  heating  prob- 
ably has  a  useful  protective  effect.  By  conducting 
heat  away  from  the  tissues  it  reduces  the  temperature 
below  the  surface,  and  the  likelihood  of  thermal 
damage.  A  hand  immersed  in  stirred  water  at  45  C 
becomes  painful  if  the  circulation  is  arrested. 

It  takes  time  for  the  blood  flow  through  an  ex- 
tremity to  settle  after  a  change  of  the  temperature 
of  the  water  in  which  it  is  immersed.  Figure  3  shows 
blood  flows  after  immersing  the  feet  in  water  at 
various  temperatures.  The  delay  may  be  partly 
explained  by  the  time  needed  for  the  internal  tissues 
to  reach  a  new  equilibrium  temperature.  Once  estab- 
lished the  blood  flow  through  the  hand  and  fingers 
is  well  maintained  after  immersion  for  as  long  as  2 
hours  at  41  C  (8). 


40  60 

Time  (min) 

fig.  3.  Foot  blood  flow  plotted  against  time  of  immersion 
during  experiments  at  seven  different  temperatures.  Each 
point  represents  the  average  blood  flow  over  5  min.  [From 
Allwood   &    Burry    (12).] 

The  local  effect  of  temperature  is  usually  very- 
similar  to  normal  in  chronically  sympathectomized 
hands  (83),  but  an  anomalous  response  has  been 
reported  in  one  case  with  a  reduction  in  the  blood 
flow  through  a  sympathectomized  hand  on  raising 
the  temperature  to  41  C  (7).  The  response  after 
chronic  total  denervation  also  appears  to  be  similar 
to  normal  at  local  temperatures  above  18  C  (62). 
The  vessels  supposedly  respond  directly,  but  some 
recent  evidence  suggests  that  a  local  nervous  pathway 
may  assist.  Irradiating  the  proximal  half  of  the  fore- 
arm with  infrared  rays  causes  a  vasodilatation  which 
spreads  to  the  nonirradiated  distal  half;  the  spread 
is  prevented  by  a  cutaneous  nerve  block  at  the 
junction  of  the  two  halves  of  the  forearm,  and  it  is 
unaffected  by  sympathectomy,  or  by  nerve  block  at 
the  elbow  (59). 

LOCAL    TEMPERATURE     IN     THE    RANGE     O    C    TO     15    C: 

cold  vasodilatation.  Lewis  (140)  observed  that 
following  exposure  to  low  temperature  the  tempera- 
ture of  the  skin  rose  above  its  former  resting  level. 
For  example,  following  cooling  for  15  min  at  7  C, 
the  temperature  of  the  skin  of  the  index  finger  rose  to 
above  28  C,  while  that  of  the  nonimmersed  third 
finger  remained  at  19  C,  the  subject  being  in  a  room 
at  17.8  C  to  19. 1  C.  The  temperature  of  the  index 
finger  was  at  its  maximum  1 1  min  after  cooling 
ended,  and  was  raised  for  about  50  min. 

Further  observations  showed  that  the  vasodilata- 
tion started  while  the  finger  was  exposed  to  cold. 
Figure  4  shows  Lewis's  experiment  in  which  the  Ri 


'332 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


J         4 

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fig.  4.  Skin  temperature  measurements  with  a  thermoelectric  junction  covered  by  adhesive  plaster. 
Fingers  i?3  and  Z.3  in  air  throughout.  Finger  In  in  crushed  ice  from  11  to  71  min,  finger  R2  from 
16  to  71  min.  The  curves  of  temperature  rise  during  immersion  are  in  this  case  at  first  discordant, 
but  become  concordant.  [From  Lewis  (140).] 


and  L-2  fingers  were  immersed  in  a  mixture  of  crushed 
ice  and  water,  the  immersion  of  R-2  being  delayed  for 
5  min.  The  7?3  and  L3  fingers  remained  in  air  and 
served  as  controls.  The  temperature  of  all  digits 
was  measured  by  thermoelectric  junctions,  covered 
by  adhesive  plaster;  the  thermal  insulation  of  the 
plaster  enabled  the  junction  to  assume  a  temperature 
different  from  that  of  the  ice  water  with  which  it 
would  otherwise  have  been  in  direct  contact.  On 
immersing  the  fingers,  the  temperature  fell  at  first 
abruptly  and  then  more  slowly  to  about  3  C.  About 
10  min  from  the  start  the  temperature  of  both  im- 
mersed fingers  began  to  rise.  The  rise  was,  in  other 
experiments,  prevented  by  arrest  of  the  circulation 


and  it  clearly  indicated  vasodilatation.  The  tem- 
perature thereafter  fluctuated  slowly  (the  so  called 
"hunting  reaction")  and  in  the  case  shown  the 
fluctuations  in  the  two  fingers  became  synchronous, 
although  in  other  experiments  initially  synchronous 
fluctuations  sometimes  became  discordant.  Following 
removal  from  the  ice  water  the  immersed  fingers 
became  warmer  than  the  control  fingers. 

A  similar  cold  vasodilatation  is  strongly  manifested 
in  the  toes,  the  lobe  of  the  ear,  and  the  tip  of  the  nose; 
it  is  difficult  to  detect  in  the  skin  of  the  forearm,  calf 
of  the  leg,  and  on  the  dorsum  of  the  hand  and  foot 
(99,  140).  Strong  reactions  are  seen  in  the  rabbit's 
ear  (98)   and  in  the  foot  of  the  domestic  fowl  and 


CIRCULATION    THROUGH    THE    SKIN 


'333 


fic.  5.  Reaction  of  arteriovenous 
anastomoses  in  the  rabbit's  ear  to  local 
cooling,  0,  before  and  b,  during  cooling. 
.4,  artery,  !',  vein;  AV,  arteriovenous 
anastomosis,  closed  in  a  and  open  in  b. 
[From  Grant   (98).] 


Mkk  Ski  Oil 


LIBRA 


Mi  M  Hi 


60     o 


MINUTES 


60      O 


60 


fig.  6.  The  heat  loss  in  cal/100  ml/min  from  the  R  and  L  index  fingers  to  water  in  the  range 
0-6  C  with  intervals  of  o  min  (left),  5  min  (middle),  and  10  min  (right)  between  their  insertion 
into  the  calorimeters.  The  full  width  of  the  lower  frames  is  60  min.  The  clear  areas  represent  heat 
derived  from  the  tissues  of  the  finger  in  cooling  to  calorimeter  temperature  during  the  first  6  min 
of  insertion.  Pain  is  represented  on  a  roughly  quantitative  scale  by  marks  at  the  top  of  the  frames. 
The  full  height  of  the  frame  corresponds  to  a  blood  flow  of  not  less  (1 10)  than  80  ml/100  ml  of 
finger/min.  [From  Greenfield  el  al.  (109).] 


cluck.  The  arteriovenous  anastomoses  in  the  rabbit's 
ear  (fig.  5)  were  directly  seen  by  Grant  (98)  to  dilate 
to  cold.  In  the  hands  and  feet,  and  particularly  in 
the  digits,  the  intensity  of  the  cold  vasodilatation  was 
found  by  Grant  &  Bland  (99)  to  parallel  closely  the 
density  of  the  arteriovenous  anastomoses,  and  it  seems 
likely  that  the  dilatation  of  the  latter  is  mainly  re- 
sponsible for  the  increased  blood  flow. 

Subsequent  calorimetric  observations  (16,  105) 
have  shown  that  for  the  first  5  to  10  min  of  immersion 
in  ice  cold  water  there  is  a  constriction  of  the  vessels 
with  almost  complete  arrest  of  blood  flow  (fig.  6). 
At  this  time  there  is  a  considerable  degree  of  pain. 
The  vessels  then  rapidly  dilate,  the  pain  goes  and  the 
finger  feels  warm  and  comfortable.  In  a  warm  sub- 
ject, the  blood  flow  may  rise  to  a  value  which  is 
probably  as  high  as  is  attained  by  any  other  type  of 
vasodilatation  (105). 

With  continued  immersion,  the  dilatation  is  ir- 
regularly interrupted  by  periods  of  constriction 
lasting  a  few  minutes.  These  may  be  abrupt  in  onset 


and  termination,  and  may  cause  almost  complete 
arrest  of  blood  flow  (108).  The  pattern  and  timing  of 
these  periods  of  constriction  differ  in  different  digits 
simultaneously  observed,  and  appears  to  be  locally 
determined  (109).  During  continued  immersion  the 
general  level  of  the  peaks  of  vasodilatation  often 
tends  to  decline,  but  if  the  subject  is  kept  warm, 
alternation  of  dilatation  and  constriction  may  con- 
tinue for  several  hours  (37).  On  removal  of  a  finger 
from  the  cold  water  the  dilatation  persists,  and  for 
about  half  an  hour  the  finger  may  be  warmer  than 
its  nonimmerscd  neighbors  (192).  The  vasodilator 
response  is  conspicuous  on  immersion  at  temperatures 
near  o  C,  but  it  is  detectable  at  temperatures  as  high 
as  12  C  or  15  C. 

The  vasodilator  response  is  present  after  inter- 
ruption of  the  sympathetic  outflow  from  the  central 
nervous  system  by  local  anesthetic  block  or  by  chronic 
section.  It  is,  however,  influenced  by  sympathetic 
activity.  Among  chilled  individuals  there  are  con- 
siderable differences  in  the  response,   but  the  vaso- 


!334 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


15   C 

2000  • 

L 

IOOO  - 

O 

29    C 


2000 
IOOO 


mi 


42    C 


Hi  in 


60     O 


INUTES  6°      ° 


60 


fig.  ~.  Heat  loss  in  cal/ioo  ml  of  finger/min  to  water  in  the  range  o-6  C  from  the  L  (anesthetic) 
and  R  (normal)  5th  fingers,  the  observations  being  made  between  the  30th  and  40th  days  after  di- 
vision of  the  L  ulnar  nerve.  In  the  denervated  finger,  cold  vasodilatation  is  extremely  small  or  absent 
after  preliminary  immersion  in  water  at  1 5  C,  small  but  definite  after  2Q  C,  and  considerable  after 
42  C.  [From  Greenfield  et  al.  (109).] 


dilatation  is  delayed,  sometimes  for  as  much  as  90 
min  from  the  time  of  immersion,  and  it  is  reduced 
in  size  sometimes  to  less  than  one-tenth  (127).  The 
response  continues  in  the  early  days  after  interruption 
of  the  somatic  nerves,  but  becomes  difficult  to  elicit 
later  when  the  separated  distal  parts  of  the  nerves 
have  degenerated.  This  led  Lewis  (140)  to  conclude 
that  the  response  depends  on  a  local  axon  reflex  from 
cutaneous  receptors  to  the  blood  vessels.  If,  however, 
the  chronically  denervated  limb  is  warmed  for  some 
time  before  the  digits  are  immersed  in  cold  water 
(109),  a  reduced  (to  20-90  Tr)  but  definite  vasodilator 
response  is  seen  (fig.  7).  It  is  always  difficult  to  be 
certain  that  denervation  is  complete,  but  the  observa- 
tions probably  indicate  that  the  axon  reflex  pathway- 
is  not  essential  for  the  response.  This  view  is  strength- 
ened by  the  finding  of  a  vasodilator  response  in  a 
finger  tip  locally  injected  with  anesthetic  solution 
(110).  Other  vascular  responses  which  appear  to  be 
depressed  in  the  chronically  denervated  limb  are 
improved  if  the  limb  is  first  warmed  for  an  hour  or 
two. 

A  chemical  stimulus  to  cold  vasodilatation  has  not 
been  identified.  Acetylcholine  and  histamine  in- 
jected intra-arterially  or  introduced  by  electrophoresis 
during  the  first  few  minutes  of  immersion  of  a  finger 
in  ice  water  do  not  provoke  an  earlier  vasodilatation, 
but  it  is  possible  that  at  this  time  of  intense  vasocon- 
striction they  do  not  reach  the  blood  vessels.  Cold 
vasodilatation,  however,  is  not  reduced  by  atropine 
nor  by  antihistamine  (188).  The  mechanism  of  the 
response  remains  obscure. 

The  effect  of  the  dilatation  is  to  raise  the  tempera- 
ture of  the  exposed  extremities  at  the  expense  of  a 
considerable  loss  of  heat  from  the  bodv.  Even  while 


immersed  in  stirred  water  near  the  freezing  point, 
the  average  internal  temperature  of  a  finger  may  be 
raised  to  as  much  as  30  C,  and  in  the  central  parts 
must  presumably  be  only  slightly  below  the  tempera- 
ture of  the  body  core  (107).  In  a  warm  person  the 
heat  loss  per  minute  from  a  whole  hand  and  from  the 
distal  half  of  a  foot  may  be  800  and  407  cal  per  min, 
respectively  (104).  These  figures  are  similar  to  total 
resting  heat  production,  and  the  loss  of  heat  from  one 
hand  can  cause  a  fall  in  esophageal  temperature 
of  0.6  C  in  9  min  (106).  When  plenty  of  heat  is 
available,  the  reaction  keeps  fingers  exposed  to 
reasonable  cold  sufficiently  warm  to  preserve  move- 
ment and  sensation.  Dwellers  in  cold  climates  nor- 
mally wear  clothing  which  provides  their  body  with 
a  warm  microclimate,  and  are  able  to  afford  some 
heat  loss.  When  there  is  a  need  to  conserve  heat, 
the  reaction  is  greatly  diminished  and  the  fingers  are 
only  slightly  warmed  by  it.  For  example,  Australian 
aborigines  are  able,  by  restricting  the  peripheral 
circulation,  to  retain  sufficient  heat  to  sleep  naked 
through  the  night  in  a  temperature  which  may  fall 
to  o  C  (177). 

Several  observations  suggest  that  the  extremities 
can  become  acclimatized  to  cold  (44).  Local  pain, 
and  the  reflex  increases  in  arterial  pressure  and  pulse 
rate  are  reduced  after  repeated  immersion  in  water 
at  4  C  (92).  Exposure  of  the  fingers  to  severe  cold 
causes  less  numbness  in  persons  habitually  exposed 
than  in  others.  Such  observations  suggest  that  there 
may  be  a  local  adaptation  of  the  circulation  in  the 
exposed  parts  but  the  evidence  for  this  is  not  strong. 
Repeated  exposure  of  the  hands  to  cold,  as  in  Nor- 
wegian and  Lapp  fishermen,  leads  to  a  more  rapid 
onset  of  cold  vasodilatation  (135)  but  to  no  increase 


CIRCULATION    THROUGH    THE    SKIN' 


J335 


in  the  level  of  blood  flow  at  the  height  of  the  vaso- 
dilatation (113,  135)-  In  such  subjects,  kept  warm  to 
release  sympathetic  vasoconstrictor  tone,  the  reactive 
hyperemic  blood  flow  with  the  hands  at  40  C,  and 
the  resting  blood  flow  with  the  hands  at  40  C,  20  C, 
and  10  C  is  no  different  from  that  in  normal  controls 
(135).  The  improved  circulation  in  the  hands  of  cold- 
habituated  persons  reported  by  other  observers  may 
depend  more  on  general  adaptation  of  the  circula- 
tion than  on  a  local  adaptation  in  the  periphery. 

PROLONGED  EXPOSURE  TO  COLD:  TRENCH  FOOT  AND 

immersion  foot.  Prolonged  local  cooling  to  tempera- 
tures above  the  freezing  point  is  capable  of  causing 
serious  injury.  Although  in  many  recorded  cases  the 
parts  have  been  wet  as  well  as  cold,  the  main  factor 
is  the  cooling  of  the  extremities  in  a  chilled  subject 
(183).  The  feet  are  particularly  liable  to  injury,  and 
most  cases  have  been  seen  after  exposure  for  many 
hours  or  days  in  war  time. 

The  four  stages  of  the  condition  have  been  well 
described  by  Ungley  (183). 

/)  During  exposure,  the  limb  is  numb,  power  is 
reduced,  and  movement  is  clumsy.  Pain  is  unusual. 
Swelling  is  common,  the  limb  often  looks  bright  red, 
and  there  may  be  periods  of  warmth,  presumably  due 
to  cold  vasodilatation,  but  the  chilling  of  the  subject 
reduces  this  to  small  proportions. 

2)  Immediately  after  rescue  and  return  to  warmth 
and  shelter  there  is  a  prehyperemic  stage,  which  may 
last  for  2  to  5  hours.  The  limb  is  cold  and  either 
pale  with  cyanotic  patches  or  cyanosed.  The  arterial 
pulsations  cannot  be  felt.  There  is  a  partial  or  com- 
plete '"stocking"  sensory  loss. 

3)  A  hyperemic  stage  follows,  the  part  becoming 
red,  swollen,  painful,  and  sometimes  blistered.  When 
the  arterial  pulses  return,  they  are  very  strong,  and 
the  temperature  of  the  skin  is  as  high  as  that  of  the 
axilla  or  groin.  The  hyperemia  is  judged  clinically 
to  be  at  least  as  great  as  that  following  sympathec- 
tomy, and  it  is  often  much  more  persistent,  lasting  as 
long  as  14  weeks.  There  is  partial  anesthesia,  and 
vasomotor  and  sudomotor  paralysis,  indicating  nerve 
damage.  In  addition  there  is  direct  vascular  damage. 

4)  In  mild  cases  there  is  a  return  from  the  hy- 
peremic state  to  normal,  but  in  severe  cases  a  post- 
hyperemic  state  follows.  The  circulation  decreases 
greatly,  and  although  vasomotor  reflexes  to  heating 
and  cooling  the  rest  of  the  body  return,  the  response  is 
slow  and  incomplete.  There  is  often  an  increased 
sensitivity  to  cold,  reduction  of  the  blood  flow  for 
many  hours  sometimes  following  immersion  in  water 


at  a  temperature  as  high  as  24  C.  Once  constricted 
or  dilated,  the  vessels  tend  to  remain  so  for  a  long 
time.  The  cause  of  this  altered  vascular  reactivity  is 
not  known. 

Although  the  vascular  damage  may  not  be  an  es- 
sential feature  (183)  it  may  sometimes  be  severe  (84) 
with  dilatation  and  engorgement  of  vessels,  rupture, 
and  thrombus  formation.  Exposure  for  many  days 
to  water  at  as  high  a  temperature  as  21  C  has  been 
sufficient  to  cause  the  feet  to  become  swollen,  hy- 
peremic, and  painful  (186).  Of  nine  volunteers 
living  for  5  days  in  a  covered  raft  in  arctic  waters, 
seven  developed  hyperemic  swollen  feet,  a  condition 
which  in  two  cases  persisted  for  several  weeks;  the 
lowest  toe  temperature  recorded  during  exposure 
was  1 1  C,  and  the  temperatures  were  usually  13  C  to 
15  C.  (44).  The  vascular  changes  during  exposure 
have  not  been  followed  in  man.  It  is  presumed  that 
cold  vasodilatation  subsides  after  a  time,  perhaps 
because  the  subject  becomes  generally  chilled,  and 
that  there  is  an  extremely  low  blood  flow  for  a  long 
time. 

exposure  to  severe  cold,  frostbite.  Exposure  to  a 
temperature  sufficiently  low  to  cause  freezing  of  the 
tissues  may  cause  frostbite,  which  is  commonly 
followed  by  gangrene  and  loss  of  tissues.  During 
exposure  there  is  arterial  spasm  and  capillary  stasis. 
On  rewarming,  there  is  an  intense  hyperemia,  and 
the  capillary  permeability  is  greatly  increased,  lead- 
ing to  edema  and  to  blockage  of  the  vessels  with  blood 
cells.  There  is  frequently  thrombosis  in  some  vessels 
and  this  may  lead  to  a  permanent  reduction  in  blood 
flow  (149). 

The  freezing  point  of  living  fingers  is  about  —0.6  C, 
but  supercooling  is  usual  so  that  fingers  immersed  in 
brine  at  —1.9  C,  the  freezing  point  of  sea  water,  do 
not  always  freeze  (128).  Supercooling  to  —1.9  C 
does  not  cause  the  tenderness,  redness,  and  warmth 
which  persist  for  several  days  after  freezing  at  that 
temperature.  The  damage  on  freezing  the  tissues  is 
probably  caused  partly  by  the  formation  of  ice 
crystals,  and  partly  by  the  concentration  of  the  dis- 
solved substances  in  the  liquid  water  that  remains 

(i5°)- 

In  dogs,   after  immersion  of  the  hind   leg  in  an 

alcohol  and  dry  ice  mixture  at  —25  C  for  30  min, 

or  —  4  C  to   —  8  C  for  2 1  o  min,  the  blood  flow,  on 

rewarming  the  limb,  is  increased  for  several  hours 

to  several  times  the  level  in  the  contralateral  control 

limb  (125)  and  this  vasodilatation  appears  to  depend 

on  the  integrity  of  sympathetic  outflow  (126). 


'336 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Reactions  to  Injury 

mechanical  injury.  The  reactions  to  mechanical 
injury  were  very  completely  studied  by  Lewis  ( 1 39). 

The  while  reaction.  When  warm  skin  is  lightly  stroked 
with  a  blunt  point  there  is  a  temporary  blanching  as 
blood  is  expressed  from  and  then  returns  to  the  super- 
ficial vessels.  About  1 5  sec  later,  the  line  of  the  stroke 
becomes  pale  again,  the  pallor  reaching  its  maximum 
about  30  sec  after  the  stroke,  and  fading  in  about  3 
to  5  min.  The  white  line  is  sharply  localized  to  the 
area  stroked.  Its  development  is  unaffected  by  the 
temporary  arrest  of  the  circulation,  and  it  was  there- 
fore taken  by  Lewis  to  indicate  active  contraction  of 
the  vessels  responsible  for  the  color  of  the  skin,  and 
not  merely  deprivation  of  these  vessels  by  contrac- 
tion of  the  arterioles  that  supply  them.  The  vessels 
responsible  for  color  are  able  to  sustain  their  con- 
traction against  a  distending  pressure  of  80  to  100 
mm  Hg  produced  by  venous  congestion. 

The  triple  response.  When  the  stroke  is  much  or  very 
much  firmer,  the  white  reaction  is  replaced  by  a 
different  response  which,  when  fully  developed,  has 
three  components,  the  red  line,  flare,  and  wheal,  a) 
The  most  constant  component  is  a  sharply  de- 
marcated red  line  which  develops  along  the  line  of 
the  stroke  with  a  latency  of  3  to  15  sec,  and  the  in- 
tensity and  duration  of  which  increase  with  the 
strength  of  the  stimulus.  Like  the  white  reaction,  the 
red  line  develops  even  when  the  circulation  is  tem- 
porarily arrested.  It  was  considered  by  Lewis  (139) 
to  indicate  active  dilatation  of  the  vessels  responsible 
for  the  color  of  the  skin,  b)  In  susceptible  skins,  and 
with  strong  or  repeated  stimuli,  an  irregular  red 
flare  develops  about  15  to  30  sec  after  the  red  line, 
and  gradually  extends  for  2  to  3  cm  on  each  side  of 
the  line  of  the  stroke.  The  flare  remains  a  bright 
scarlet  color,  unlike  the  red  line  which  becomes 
progressively  dusky.  As  the  flare  fades,  it  becomes 
mottled.  A  white  reaction  can  be  developed  across 
the  flare  by  light  stroking,  but  not  across  the  red 
line.  The  flare  was  considered  by  Lewis  (139)  to 
indicate  arteriolar  dilatation,  c)  In  sensitive  skins, 
or  in  others  following  a  strong  stimulus  such  as  the 
lash  of  a  whip,  a  raised  wheal  usually  begins  to  appear 
along  the  line  of  stroke  in  1  to  3  min,  reaching  full 
development  in  3  to  5  min.  It  overlies  the  red  line 
and  the  line  becomes  pale,  presumably  because  of 
the  pressure  exerted  by  the  transuding  fluid  upon 
the  minute  vessels. 

The  triple  response  is  unaffected  when  the  sensory 
nerves   are   freshly    interrupted    by    section   or   local 


anesthesia.  The  red  line  and  the  wheal  continue  in 
chronically  denervated  skin,  but  the  flare  is  lost  after 
about  the  sixth  or  seventh  day  when  the  sensory 
nerves  degenerate.  This  led  Lewis  (139)  to  conclude 
that  the  red  line  and  wheal  are  independent  of  nerves, 
but  that  the  flare  depends  on  a  local  axon  reflex  (49). 
The  nerve  impulse  arises  in  a  receptor  in  the  skin 
and,  after  ascending  a  sensory  nerve  for  some  distance, 
returns  antidromically  along  a  branch  to  arrive  at  an 
arteriole  and  cause  it  to  dilate. 

The  triple  response  is  the  standard  reaction  of  the 
skin  to  a  great  variety  of  injurious  stimuli.  The  re- 
sponse to  mechanical  trauma  can  be  exactly  repro- 
duced by  pricking  histamine  into  the  skin.  Further, 
if  trauma  or  a  histamine  prick  is  applied  while  the 
circulation  is  arrested  the  development  of  the  flare 
is  delayed  until  the  circulation  is  released.  This  and 
other  evidence  led  Lewis  (139)  to  postulate  that  the 
flare  depends  on  the  activation  of  the  skin  receptors 
by  an  H-substance,  which  may  be  histamine,  rather 
than  directly  by  the  mechanical  trauma. 

ultraviolet  light.  Irradiation  with  ultraviolet 
light,  which  penetrates  to  a  very  small  depth  in  the 


fig.  8.  Two  experiments.  Hand  blood  How  in  ml/ 100  ml/ 
min.  Solid  circles:  injected  arm;  open  circles:  control  arm.  The 
heights  of  the  vertical  columns  indicate  the  percentage  satura- 
tion of  venous  blood  with  oxygen.  Intra-arterial  injection  of  5 
ml  of  nitrous  oxide  is  indicated  by  the  black  rectangle  starting 
at  o  min.  [From  Duff  el  at.  (67).] 


CIRCULATION    THROUGH    THE    SKIN 


'337 


skin,  causes  a  delayed  erythema  sharply  confined  to 
the  exposed  area.  It  is  probable  that  a  chemical 
agent  is  concerned,   but  that  this  is  not   histamine 

(•56). 

arterial  gas  embolism.  After  injection  into  the 
brachial  artery  of  1  to  10  ml  of  gas  there  is  usually 
an  immediate  reduction  in  blood  flow  through  the 
hand  lasting  for  a  few  minutes,  followed  by  a  pro- 
longed increase,  to  several  times  the  normal  resting 
rate,  which  does  not  entirely  subside  for  many  hours 
(66).  The  increase  in  the  oxygen  saturation  of  the 
venous  blood  parallels  the  increase  in  flow  (fig.  8). 
All  of  the  several  gases  tested  are  effective,  provided 
they  are  given  as  bubbles  and  not  in  solution.  The 
response  is  present  in  both  sympathectomized  and 
chronically  denervated  limbs,  and  is  unaltered  in  the 
presence  of  amounts  of  antihistamine  substances 
which  prevent  the  action  of  histamine  (67).  The 
vessels  of  muscle  as  well  as  of  skin  are  affected.  The 
mechanism  is  not  understood,  but  the  reaction  ap- 
pears to  result  from  some  trauma  to  the  tissues  caused 
by  the  bubbles,  and  a  peripheral  arterial  conducting 
mechanism  may  be  involved  (120). 


nervous  control  of  skin  blood  vessels 

Vasomotor  Nerves 

vasoconstrictor  sympathetic  nerves.  Claude  Ber- 
nard (30,  31)  showed  that  division  of  the  cervical 
sympathetic  chain  in  the  rabbit  caused  the  ear  on 
the  same  side  to  become  flushed  and  warm.  Stimula- 
tion of  the  trunk  had  the  reverse  effect  (32).  Similar 
observations  were  made  by  Brown-Sequard  (39). 
These  observations  indicate  that  the  sympathetic 
nerves  contain  vasoconstrictor  fibers,  and  that  under 
ordinary  conditions  the  activity  in  these  fibers  keeps 
the  vessels  in  a  partially  constricted  state.  The  warm- 
ing of,  and  increased  circulation  through,  the  human 
feet  and  hands  following  lumbar  and  thoracic  sym- 
pathectomy was  first  described  by  Adson  &  Brown 
(5,  6)  and  this  established  that  these  areas  were 
similarly  under  sympathetic  vasoconstrictor  control. 
Walker  et  al.  (184)  made  quantitative  measurements 
of  the  effects  of  sympathectomy  in  patients  with  ap- 
parently normal  blood  vessels  in  whom  the  operation 
had  been  carried  out  as  a  treatment  for  excessive 
sweating.  The  blood  flow  in  milliliters  per  100  ml  of 
hand  per  min  was  increased  from  an  average  value 


of  5.2  before  the  operation  to  peak  values  in  the  range 
22.7  to  59.2  after  the  operation,  and  in  the  feet  was 
increased  from  an  average  value  of  2.1  before  the 
operation  to  peak  values  in  the  range  20.8  to  28.0 
after  the  operation.  The  averaged  results  on  five 
hands  and  six  feet  are  shown  in  figure  g. 

In  vasoconstrictor  sympathetic  nerves  low  rates  of 
discharge  have  a  powerful  effect;  in  the  cat's  paw, 
stimulation  at  the  rate  of  1  per  sec  increases  the  re- 
sistance to  flow  about  10  times,  and  stimulation  at 
10  per  sec  increases  it  about  100  times  (48). 

vasodilator  sympathetic  nerves.  The  evidence  for 
vasodilator  nerves  to  the  skin  rests  at  present  on 
experiments  of  the  type  employed  by  Grant  & 
Holling  (100),  that  is  to  say,  on  the  simultaneous 
observation  under  suitable  conditions  of  reflex 
stimulation  of  a  greater  blood  flow  in  normally 
innervated  skin  than  in  a  corresponding  area  of  skin 
acutely  deprived  of  its  vasomotor  innervation.  Since 
both  areas  are  perfused  with  blood  of  identical  com- 
position and  at  the  same  pressure,  the  resistance 
vessels  may  be  presumed  to  be  more  widely  dilated 
in  the  innervated  skin,  and  this  dilatation  to  result 
from  nervous  activity.  It  must  be  noted  that  chroni- 
cally denervated  skin  is  not  a  satisfactory  tissue  for 
this  comparison,  because  of  the  decline  in  blood  flow 
due  to  contraction  of  the  blood  vessels. 

Grant  &  Holling  (100)  found  that  blocking  the 
cutaneous  nerves,  which  convey  sympathetic  fibers, 
to  parts  of  the  skin  of  the  forearm  not  only  failed  to 
cause  a  flushing  and  rise  of  temperature  but  pre- 
vented the  vasodilatation  and  also  the  sweating 
normally  seen  in  the  forearm  during  body  warming. 
Evidently,  in  the  forearm  vasomotor  nerves  actively 
bring  about  vasodilatation.  Whether  they  do  so  by  a 
direct  action  on  the  vessels  or  as  a  consequence  of 
increased  sweat  gland  activity,  or  by  both  means 
was,  and  is,  uncertain.  If  the  fibers  are  called  "vaso- 
dilator," it  must  be  remembered  that  vasodilatation 
may  be  only  a  consequential  and  not  a  direct  effect. 

It  is,  of  course,  important  for  heat  to  be  brought 
to  the  skin  if  sweat  is  to  be  evaporated.  At  least  60  ml 
of  blood  are  required  to  transport  from  the  body 
core  the  heat  required  to  evaporate  1  g  of  sweat  when 
the  skin  is  10°  below  the  temperature  of  the  core.  At 
least  600  ml  of  blood  are  required  when  the  skin  is 
1  C  below  the  temperature  of  the  core.  Sweating  can 
therefore  be  effective  only  when  accompanied  by 
vasodilatation. 


I338  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


fig.  9.  Abscissae:  time  in  days,  the  vertical  broken  line  indicating  the  day  on  which  sympathectomy 
was  performed.  Ordinatcs:  blood  flow  in  ml/100  ml  tissue/min.  The  averaged  results  of  experiments 
on  five  hands  and  six  feet  show  the  effect  of  sympathectomy  on  the  blood  flow  in  the  hand  and 
foot,  and  on  the  skin  temperatures  of  the  fingers  and  toes.  The  denervations  were  performed  to 
prevent  excessive  sweating;  hence  the  responses  are  those  of  normal  human  blood  vessels.  Note  the 
transient  increase  in  blood  flow  after  operation  and  the  subsequent  decline  as  intrinsic  tone  returns 
to  the  vessels.  [From  Barcroft  (18).] 


VASODILATATION  CAUSED  BY  ANTIDROMIC  STIMULATION 
OF  DORSAL   ROOT  SENSORY  NERVES:   THE    AXON    REFLEX 

pathway.  Stimulation  of  the  peripheral  end  of  a 
cut  sensory  nerve  often  causes  vasodilatation  in  the 
area  of  skin  supplied  by  the  nerve,  and  Bayliss  (24) 
showed  that  this  was  due  to  impulses  traveling  toward 
the  periphery  along  neurons  of  the  dorsal  root  system. 
The  vasodilator  effect  of  such  antidromic  nervous 
impulses  is  considerable,  but  evidence  has  not  been 
forthcoming  for  the  use  of  this  route  from  the  central 
nervous  system  to  the  periphery  for  any  reflex  ad- 
justments of  the  circulation.  It  seems  probable  that 
the  artificially  provoked  antidromic  impulses  travel 
to  the  vascular  nerve  endings  of  the  peripheral  axon 
reflex  pathway.  The  usual  source  of  impulses  ar- 
riving here  is  from  nearby  sensory-  nerve  endings, 
probably  subserving  pain  sensation.  The  transmitter 
substance  for  the  vasodilatation  produced  in  the 
chronically  sympathectomized  ear  of  the  rabbit  by 
stimulation  of  the  sensory  great  auricular  nerve  is 
neither  histamine  nor  acetylcholine  (123)  but  is 
probably  adenosine  triphosphate  (122),  the  presence 
of  which  has  been  demonstrated  in  nerve  roots  (121). 


Innervation  of  the  Blood  Vessels  of  the  Skin 
in  Different  Areas 

The  problem  is  to  define,  for  different  areas  of 
skin,  the  existence  and  range  of  action  of  vasocon- 
strictor and  vasodilator  fibers.  This  has  been  most 
fully  investigated  in  the  human  limbs,  particularly 
in  the  upper  limbs,  and  the  innervation  here  will  be 
first  described. 

the  human  hand  and  fingers.  In  the  cold  subject, 
the  blood  flow  through  the  hand  is  very  small,  often 
less  than  1  ml  per  100  ml  per  min.  When  the  subject 
is  warmed,  either  in  a  hot  cabinet  (143)  or  by  im- 
mersing the  legs  in  stirred  water  at  44  C  (89),  the 
blood  flow  increases  to  about  30  ml  per  too  ml  per 
min,  this  being  part  of  the  general  response  by  which 
the  body  attempts  to  lose  heat.  Although  abundant 
cholinesterase  is  found  in  the  arteriovenous  anastomo- 
ses of  the  fingers,  and  although  Lewis  &  Pickering 
(143)  obtained  evidence  in  cases  of  Raynaud's  dis- 
ease for  the  activity  of  vasodilator  nerves,  the  increase 
in  blood  flow  in  normal  persons  can  be  entirely  ac- 
counted for  by  a  reduction  in  the  activity  of  vaso- 
constrictor nerves;  several  careful  investigations  have 


CIRCULATION    THROUGH    THE    SKIN 


l339 


failed  to  detect  any  contributions  from  vasodilator 
nerves.  Thus  Pickering  (161)  during  body  heating 
found  equal  rates  of  heat  elimination  from  the  two 
hands,  the  ulnar  nerve  conveying  part  of  the  sym- 
pathetic supply  to  one  hand  having  been  blocked. 
In  a  more  sensitive  test,  Arnott  &  Macfie  (15)  meas- 
ured the  heat  elimination  from  the  fifth  fingers  during 
body  heating.  The  sympathetic  supply  to  one  was 
entirely  interrupted  by  ulnar  nerve  block,  but  the 
rates  of  heat  elimination  were  equal.  Warren  et  al. 
(185)  found  that  paravertebral  block  of  the  sym- 
pathetic outflow  increased  rather  than  decreased  the 
blood  flow  through  the  hand  of  a  heated  subject. 
Gaskell  (87)  compared  the  rates  of  blood  flow  through 
the  two  hands  by  venous  occlusion  plethysmog- 
raphy, which  is  probably  the  most  accurate  method. 
He  heated  the  subject,  and  then  blocked  on  one 
side  near  the  elbow  the  radial,  ulnar,  and  median 
nerves  which  probably  convey  the  great  majority 
of  sympathetic  fibers  to  the  hand.  This  caused  no 
alteration  in  the  rate  of  blood  flow.  Roddie  et  al. 
(172)  found  no  difference  between  the  rates  of  blood 
flow  through  the  two  hands  in  similar  experiments 
in  which  the  nerve  block  on  one  side  preceded  the 
body  heating;  this  eliminated  the  possibility  that  in 
GaskelTs  experiments  (87)  a  stable  chemical  vaso- 
dilator substance  was  released  by  sympathetic  nerves 
before  they  were  blocked.  The  most  probable  ex- 
planation of  these  observations  is  that  in  the  ade- 
quately heated  subject  there  is  a  complete  cessation 
of  activity  in  the  vasoconstrictor  nerves  to  the  hand, 
and  no  activity  in  vasodilator  nerves.  The  less  prob- 
able alternative  is  that  in  the  hand  of  a  heated  subject 
there  is  a  balance  of  vasoconstrictor  and  vasodilator 
activity,  and  that  the  vessels  are  unaffected  when  both 
activities  are  abolished  by  nerve  block. 

Although  there  is  no  evidence  for  the  participation 
of  vasodilator  nerves  in  the  response  to  body  heating 
in  normal  persons,  a  vasodilatation  dependent  on  an 
intact  sympathetic  nerve  supply  may  accompany 
the  sweating  in  the  hand  which  is  provoked  by  emo- 
tional stress.  The  direct  and  immediate  effect  of 
emotion  is  to  reduce  the  blood  flow  through  the  hand 
(2)  by  increasing  the  activity  in  vasoconstrictor  nerves. 
If,  however,  the  emotional  stress  is  continued,  as  by 
mental  arithmetic,  the  vasodilatation  consequent  on 
sweating  may  outweigh  the  constriction  even  in 
normal  persons,  and  in  persons  suffering  from  ex- 
cessive sweating  the  vasodilatation  may  be  very 
large  indeed  (10),  the  flow  rising  from  5  to  over 
30  ml  per  100  ml  per  min  (fig.  10). 


B.P.  (mm 
118/76 

Hg) 

Arithmetic 

120/76 

134/82 

I 
ml  /mm) 

1 

\ 

0 
0 

1      /             *4 

_1 

1 

S 

0 

T3 
O 
O 

-co 

L 

\        Hand 
Forearm 

30 


20 --5. 


10 


0  Minutes  10 

fig.  10.  Results  showing  the  marked  increase  in  hand  blood 
flow  (•)  during  mental  arithmetic  in  a  hyperhidrotic  subject. 
There  was  little  change  in  the  forearm  blood  flow  (O)  or 
arterial  blood  pressure.  Plethysmograph  temperature  36  C. 
[From  All  wood  et  al.  (10).] 

the  human  forearm.  Both  vasoconstrictor  nerves, 
and  nerves  which  directly  or  indirectly  cause  vaso- 
dilatation (vasodilator  nerves)  regulate  the  circula- 
tion through  the  skin  of  the  forearm.  Of  these,  the 
vasodilator  nerves,  first  described  by  Grant  &  Holling 
(100),  are  by  far  the  more  important.  The  role  of  the 
two  sets  of  nerves  is  clearly  displayed  during  the 
response  of  total  forearm  blood  flow  to  general  body 
heating. 

This  response  has  recently  been  shown,  by  several 
methods,  to  be  confined  to  the  skin,  the  muscle  cir- 
culation remaining  unchanged.  Thus  Edholm  et  al. 
(71)  found  that  intensive  iontophoresis  of  adrenaline, 
sufficient  to  arrest  the  circulation  in  the  skin  of  the 
forearm,  prevented  the  normal  increase  in  total 
forearm  blood  flow  with  body  heating.  Barcroft  et  al. 
(20)  found  that  when  a  person  is  heated  the  total 
blood  flow  through  the  calf  of  the  leg,  measured 
plethysmographically,  increases,  but  that  through 
the  muscle,  measured  by  a  heated  thermocouple 
method,  does  not;  the  increase  must  have  been  in  the 
skin.  The  rate  of  clearance  of  radioactive  sodium 
from  muscle  is  unchanged  or  reduced  (154).  Roddie 
et  al.  (170)  found  that  during  general  body  heating 
there  was  a  gradual  increase,  from  an  initial  40  to 
72  per  cent  to  a  final  85  to  99  per  cent,  in  the  oxygen 
saturation  of  the  blood  in  the  superficial  veins  of  the 
forearm  predominantly  draining  skin,  but  no  change 
in  the  deep  veins  mainly  draining  muscle  (fig.  11); 
the  changes  in  the  superficial  blood  closely  paralleled 
the  increase  in  total  forearm  blood  flow  in  the  op- 
posite arm. 


i  34o 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  1 1 .  The  effect  of  body  heating  and  of  change  of  posture 
on  the  oxygen  saturation  of  deep  and  superficial  forearm  venous 
blood.  The  black  rectangle  indicates  the  period  of  general  body- 
heating.  The  intervals  between  the  dotted  lines  represent  the 
periods  during  which  the  subject's  legs  were  passively  raised. 
O,  Left  forearm  blood  How,  ■  oxygen  saturation  of  superficial 
venous  blood  in  right  forearm;  •,  oxygen  saturation  of  deep 
venous  blood  in  right  forearm.  [From  Roddie  el  al.  (170).] 

On  warming  a  rather  cold  subject,  the  blood  flow 
through  the  forearm,  and  hence  through  the  skin  of 
the  forearm,  increases  in  two  steps  (171).  The  first 
increase,  from  about  2  to  about  4  ml  per  100  ml  per 
min,  is  of  the  same  order  of  size  as  the  increase  which 
follows  block  of  the  superficial  nerves  to  the  forearm, 
and  may  be  assumed  to  be  due  to  withdrawal  of 
vasoconstrictor  activity.  The  subject  is  by  now  com- 
fortably warm.  If  body  heating  is  continued,  there 
is  a  further  increase  in  forearm  flow  from  4  to  10  to 
1 5  ml  per  1 00  ml  per  min.  This  is  accompanied  by 
sweating.  The  total  forearm  blood  flow  and  the  oxygen 
saturation  of  the  blood  from  superficial  veins  now  far 
exceed  the  levels  seen  after  cutaneous  nerve  block. 
Blocking  the  cutaneous  nerves  at  this  stage  causes  the 
forearm  blood  flow  to  fall  to  about  the  level  seen  in 
an  unheated  subject  (72).  Without  block,  the  blood 
flow  through  the  skin  of  the  forearm  is  now  very  large 
indeed;  Edholm  el  al.  (71 )  give  a  figure  of  165  ml  per 
100  ml  of  forearm  skin  per  min,  but  do  not  claim 
that  this  is  more  than  an  approximate  figure.  The 
sweating  can  be  prevented  and  the  vasodilatation 
delayed  by  the  injection  of  atropine  into  the  brachial 
artery  before  the  heating  starts.  Fox  &  Hilton  (81) 
have  found  that  during  sweating  there  is  a  fivefold 
increase  in  the  bradykinin-like  activity  in  the  per- 
fusate of  the  subcutaneous  tissue  of  the  forearm,  and 
that  a  bradykinin-formintj  enzyme  is  present  in 
sweat.    Bradykinin    is    a    very    powerful    vasodilator 


substance.  Injected  into  the  human  brachial  artery 
it  is  more  powerful,  per  molecule,  than  acetylcholine 
or  histamine,  or  indeed  any  other  known  substance 
(80).  It  is  suggested  (81)  that  the  vasodilatation  in 
the  skin  of  the  human  forearm  is  produced  in  the  main 
by  bradykinin  resulting  from  sweat  gland  activity, 
itself  provoked  by  cholinergic  sympathetic  nerves. 

In  the  region  of  the  wrist  there  must  be  a  transi- 
tion from  the  vasoconstrictor  control  of  the  hand 
vessels  to  the  predominantly  vasodilator  control  of 
the  forearm  vessels.  The  site,  sharpness,  and  varia- 
bility or  constancy  of  the  demarcation  have  not  been 
defined. 

other  areas  of  the  human  body.  The  innervation 
of  the  foot  has  been  less  completely  examined  than 
that  of  the  hand,  but  as  far  as  is  known,  the  pattern 
is  similar.  Elsewhere,  our  knowledge  is  fragmentary 
and  incomplete.  In  the  upper  arm,  calf  of  leg,  and 
thigh  (36)  the  pattern  of  vasomotor  innervation  is 
like  that  of  the  forearm,  there  being  a  weak  vasocon- 
strictor innervation  operating  when  the  subject  is 
cold,  and  a  more  powerful  vasodilator  innervation, 
probably  associated  with  sweat  gland  control,  which 
operates  when  the  subject  is  hot.  Vasodilator  control 
is  also  dominant  in  the  forehead  and  chin,  and  cutane- 
ous vasodilatation  accompanies  sweating  in  these 
areas;  vasoconstrictor  control  is  important  in  the 
glabrous  portion  of  the  lips,  and  in  the  skin  of  the 
nose  (78,  79). 

the  skin  of  animals.  Apart  from  the  paws  (138),  the 
skin  of  the  limbs  of  cats  and  dogs  lacks  eccrine  sweat 
glands.  In  these  species,  heat  vasodilatation  results 
from  the  reduction  in  the  activity  of  vasoconstrictor 
nerves,  and  there  is  no  evidence  for  vasodilator 
nerves  (77,  102). 

late  effects  of  sympathetic  denervation.  Goltz 
&  Freusberg  (97)  noted  that  the  freshly  denervated 
leg  of  the  dog  was  warmer  than  its  fellow,  but  that 
the  difference  does  not  persist.  It  has  since  been 
shown  by  several  groups  of  workers  (18,  23,  101,  145, 
184,  190)  that  the  blood  flow  in  a  limb  several  weeks 
after  sympathectomy  differs  little  from  the  preopera- 
tive value.  The  blood  flow  in  both  hands  and  feet 
reaches  its  highest  value  about  the  second  day  after 
the  operation,  and  then  declines  steeply  during  the 
next  few  days  (fig.  9).  In  the  hand,  the  decline  in  flow- 
is  equally  rapid  whether  a  preganglionic  section  or  a 
postganglionic  section  with  ganglionectomy  has  been 
performed  (184).  In  the  forearm  (63)  the  maximum 


CIRCULATION    THROUGH    THE    SKIN 


1341 


flow  is  seen  on  the  day  of  the  operation,  and  the 
decline  is  faster  than  in  the  hand;  the  extent  to  which 
the  vessels  of  muscle  and  skin,  respectively,  contribute 
to  these  changes  has  not  been  defined. 

The  cause  of  the  change  in  the  vessels  which  leads 
to  the  return  of  blood  flow  to  near  the  normal  level  is 
not  known.  The  denervated  vessels  develop  an  in- 
creased sensitivity  to  adrenaline  and  other  vasoac- 
tive agents  (46,  74)  and  this  develops  at  a  rate  which 
closely  parallels  the  decline  in  blood  flow  (22).  In- 
creased sensitivity  of  chronically  sympathectomized 
vessels  has  been  demonstrated  in  the  finger  to  ad- 
renaline injected  intravenously  (178),  and  in  the 
hand  to  both  adrenaline  and  noradrenaline  injected 
intra-arterially  (fig.  14).  Whether  the  return  of  tone 
is  due  to  an  increased  sensitivity  of  the  vessels  to 
unknown  circulating  pressor  substances,  or  to  an 
intrinsic  change  in  the  muscle  of  the  vessel  wall,  or 
to  an  effect  of  surviving  accessory  sympathetic  fibers 
is  not  decided. 

LATE    EFFECTS    OF    TOTAL    DENERVATION.    "While    loss 

of  sympathetic  supply  causes  the  corresponding  fingers 
to  be  in  general  warmer  than  they  otherwise  would 
be,  loss  of  all  nerve  supply  causes  the  corresponding 
fingers  to  be  in  general  colder  than  they  otherwise 
would  be.  And,  since  with  combined  loss  of  both 
motor  and  sympathetic  supply  the  digits  remain 
warm,  it  seems  that  sensory  nerve  loss  must  be  an 
important  factor  in  determining  the  persistent  cold- 
ness in  cases  of  mixed  nerve  lesions"  (Lewis  & 
Pickering,  144).  The  extent  to  which  the  coldness  of 
denervated  fingers  depends  on  the  loss  of  sensory  as 
opposed  to  sympathetic  innervation  has,  however, 
been  questioned  (62),  and  limbs  normal  except  for 
muscular  paralysis  are  colder  than  normal  (144).  The 
most  conspicuous  abnormality  in  the  behavior  of  the 
circulation  in  denervated  digits  is  the  great  reduction, 
under  normal  circumstances,  in  the  vasodilator 
response  to  cold. 

Reflex  Control  of  Blood  Vessels  of  the  Skin 

The  blood  flow  through  the  digits  can  be  varied 
through  a  very  wide  range  by  the  activity  of  the 
sympathetic  vasoconstrictor  nerves.  At  the  upper  and 
lower  extremes  of  the  range  the  blood  flow  is  normally 
fairly  steady  from  minute  to  minute.  At  intermediate 
levels,  such  as  are  normally  found  in  comfortably 
warm  subjects,  the  flow  usually  fluctuates,  rising  and 
falling  by  20  per  cent  or  more  several  times  a  minute. 
The   fluctuations   are   abolished    bv   division   of  the 


sympathetic  nerves,  occur  simultaneously  in  the 
digits  of  all  limbs,  and  are  often  associated  with 
simultaneous  changes  in  heart  rate  (41,  42,  45).  The 
frequency  of  the  constrictions  is  greater  when  the 
flow  is  near  the  lower  than  when  it  is  near  the  upper 
end  of  its  range,  and  the  size  and  pattern  of  the  varia- 
tions van,-  considerably  in  different  individuals.  The 
functional  significance  of  the  fluctuations  is  not 
known;  their  occurrence  makes  desirable  the  use  of 
repeated  rather  than  single  observations  in  estimates 
of  the  skin  circulation  in  the  extremities.  They  are 
not  found  in  the  skin  of  the  forehead  (117). 

Very  little  is  known  about  the  reflex  responses  of 
skin  other  than  that  in  the  extremities,  but  such  evi- 
dence as  is  available  indicates  that  the  responses, 
if  present,  are  comparatively  small  (85,    116). 

body  temperature  regulation.  The  skin  is  a  main 
route  for  loss  of  heat  from  the  body,  and  by  far  the 
most  important  route  capable  of  adjustment  by  the 
temperature-regulating  center.  The  heat  lost  from  the 
surface,  whether  by  conduction,  convection,  radiation, 
or  the  evaporation  of  sweat  must  be  transported  to 
the  skin,  and  because  of  the  low  thermal  conductivity 
of  body  tissue,  the  transport  is  mainly  in  the  circu- 
lating blood. 

Gibbon  &  Landis  (8g)  found  that  if  one  arm  was 
immersed  in  water  at  42.5  C  to  44.6  C  the  temperature 
of  the  fingers  of  the  opposite  hand  started  to  rise  in  5 
to  10  min,  and  reached  32  C  in  g  to  16  min.  If,  how- 
ever, (fig.  12)  under  similar  conditions,  the  circula- 
tion in  the  immersed  arm  was  arrested  (with  brief 
releases)  by  a  pneumatic  cuff  for  the  first  35  min  of 
immersion,  the  rise  in  temperature  of  the  fingers  of 
the  opposite  hand  was  delayed  until  7  to  10  min 
after  the  final  release  of  the  cuff  (that  is  42-45  min 
from  the  start  of  immersion),  and  the  fingers  reached 
32  C  11  to  16  min  after  the  release.  The  response  in 
the  fingers  evidently  depends  on  the  return  to  the 
body  of  hot  blood  from  the  immersed  part,  rather 
than  on  the  stimulation  of  peripheral  receptor  organs. 
This  conclusion  is  confirmed  by  the  finding  that 
rapid  intravenous  infusions  of  hot  saline  are  able  to 
provoke  vasodilatation  in  the  hand  by  a  mechanism 
independent  of  any  surface  heating  ( 1 7g).  The  central 
receptor  mechanism  is  sensitive  to  the  addition  of  as 
little  as  1  to  2  Calories  of  heat  to  the  body,  or  to  an 
amount  of  heating  sufficient  to  raise  the  sublingual 
temperature  by  0.15  C  (88). 

The  temperature  of  surface  receptors  is,  however, 
of  some  importance  in  the  reflex  regulation  of  the  skin 
circulation.    Kerslake    &    Cooper    (129)    found    that 


'34-1 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  12.  The  right  arm,  with  the 
circulation  off,  was  immersed  in  hot 
water  at  42.8-44.3  C  at  the  38th  min. 
There  was  no  dilatation  in  the  left 
second  (Z.2 )  or  left  fourth  (Z.4)  finger 
until  the  circulation  was  released  at  the 
76th  min.  [From  Gibbon  &  Landis 
(89)-] 


18 


16 


10 


CIRCULATION    OFF 
RT   ARM   IN   BATH    428- 443 C 


30 


50 

MINUTES 


70 


90 


heating  the  trunk  or  both  legs  with  radiant  heat 
caused  a  substantial  (2-fold  or  3-fold)  increase  in  blood 
flow  through  the  hand,  with  a  latency  of  only  10  to 
15  sec;  this  was  too  short  a  time  for  a  mechanism 
depending  on  the  return  of  hot  blood  to  the  heat- 
regulating  center.  Furthermore,  on  heating  the  legs 
the  response  was  unaffected  when  cuffs  around  the 
thighs  were  inflated  to  200  mm  Hg  to  arrest  the  circu- 
lation (fig.  13).  In  this  case  the  vasodilatation  there- 
fore appears  to  depend  on  afferent  information 
conveyed  by  nerves  from  the  heated  skin.  The  response 
to  heating  the  legs  disappears  after  bilateral  lumbar 
sympathectomy,  and  in  persons  with  unilateral 
sympathectomy  it  is  obtained  on  heating  the  normal 
but  not  the  sympathectomized  leg  (57).  It  is  not  yet 
certain  whether  the  afferent  nerves  traverse  the 
sympathetic  ganglia,  or  whether  sympathectomy 
modifies  the  response  by  altering  the  conditions  at 
somatic  nerve  thermoreceptors.  Stimulating  the 
intact  lumbar  sympathetic  chain  or  its  cut  central 
end  causes  vasoconstriction  in  the  hand,  but  it  is  not 
known  whether  the  stimulated  afferent  fibers  are 
from  the  skin  or  from  the  viscera  (58). 

As  mentioned  earlier,  the  effector  side  of  the  tem- 
perature regulation  reflex  is  mediated  in  the  hand  by 
adjusting  vasoconstrictor  activity,  and  in  the  forearm 


mainly  by  adjusting  vasodilator  activity.  The  reduc- 
tion in  vasoconstrictor  activity  is  not  simultaneous 
in  all  areas;  the  individual  fingers  often  dilate  asyn- 
chronously, and  the  foot  often  dilates  many  minutes 
after  and  less  completely  than  the  hand  (162).  The 
vessels  in  warm  skin  dilate  sooner  than  those  in  corre- 
sponding areas  of  cold  skin. 

Exposure  of  part  of  the  body  to  cold  causes  changes 
in  the  circulation  in  other  areas  by  two  mechanisms. 
There  is  a  rapid  transient  reflex  vasoconstriction,  due 
to  stimulation  of  afferent  nerves  (160),  and  a  longer 
lasting  vasoconstriction  due  to  cooled  blood  returning 
to  the  heat-regulating  center  (160,  181).  The  cooling 
effect  on  the  temperature  of  the  body  core  of  exposure 
of  limbs  to  cold  is  usually  restricted  by  local  vasocon- 
striction. This  limits  the  quantity  of  cooled  blood 
returning  to  the  core.  Furthermore  the  efficient  ar- 
rangements for  exchange  of  heat  between  arteries  and 
veins  in  the  limbs  (25,  26)  reduce  the  cooling  effect 
of  the  blood.  On  the  other  hand,  the  temperature  of 
the  blood  that  does  return  may,  at  the  start  of  its 
journey,  be  30  C  or  more  below  that  of  the  core, 
while  from  a  heated  region  the  blood  can  hardly 
start  its  return  at  a  temperature  more  than  7  to  8° 
above  that  of  the  core.  Further,  cold  may  sometimes 
be   sufficiently   severe   to   cause   cold   vasodilatation, 


CIRCULATION    THROUGH    THE    SKIN 


'343 


• 


OCIRCULATION     OCCLUDED-    NO    HEAT 
©HEAT-CIRCULATION      OCCLUDED 
•  HEAT-  NO    OCCLUSION 


60      ^.---....e  120 


SECONDS 


fig.  13.  Changes  in  hand  blood  flow  during  heating  of  the 
front  of  the  legs.  Each  curve  is  the  mean  of  three  runs.  [From 
Kerslake  &  Cooper  (129).] 

and  while  this  is  in  progress  the  heat  loss  may  be 
several  times  greater  than  the  heat  gain  during 
exposure  to  heat. 

When  a  nude  person  is  chilled,  the  temperature  of 
the  skin  and  the  loss  of  heat  from  it  fall  to  much  lower 
levels  over  the  limbs,  and  particularly  the  hands  and 
feet,  than  they  do  over  the  head,  neck,  and  trunk. 
This  difference  is  partly  accounted  for  by  the  more 
vigorous  vasoconstriction  in  the  skin  of  the  limbs,  and 
partly  by  the  more  favorable  opportunities  in  the 
limbs  for  economizing  heat  loss  by  exchange  of  heat 
between  arteries  and  veins.  Thus  there  are  poor 
defenses  against  heat  loss  from  the  head  and  trunk, 
and  these  regions  are  particularly  dependent  on 
clothing  for  insulation.  The  loss  of  heat  from  the 
uncovered  head  may  be  very  large  (85),  amounting 
to  about  one-half  the  resting  heat  production  of  the 
body  when  the  ambient  temperature  is  —  4  C. 

emotion.  In  the  middle  ranges  of  flow,  the  circulation 
through  the  hand  is  often  very  sensitive  to  slight  emo- 
tional stimuli;  it  may  suffer  a  considerable  transient 
reduction,  lasting  a  minute  or  more,  when  a  person 
enters  the  room,  if  a  remark  is  made  or  a  question  in 
mental  arithmetic  posed  (2),  or  if  there  is  an  unex- 
pected noise.  For  this  reason  it  is  important  to  reduce 
disturbance  to  a  minimum  in  experiments  in  which 
the  blood  flow  to  the  hand  (or  foot)  is  measured.  A 


more  prolonged  emotional  stimulus,  such  as  is  pro- 
vided by  mental  arithmetic  for  10  min  under  trying 
conditions,  causes  in  persons  with  hyperhidrosis  and 
in  some  normal  persons  an  increase  in  the  blood  flow 
through  the  hand;  this  is  associated  with  emotional 
sweating  (10).  All  these  responses  are  prevented  by 
division  of  the  sympathetic  nervous  outflow.  It  is, 
however,  possible  that  during  more  severe  emotional 
upsets,  the  circulation  through  the  skin  may  be 
affected  by  adrenal  gland  activity.  In  the  forearm, 
the  circulation  through  the  skin  is  little  affected  by 
the  emotional  stress  of  mental  arithmetic  (76). 

fainting.  In  posthemorrhagic  fainting  the  blood  flow 
through  the  hand  was  found  by  Barcroft  &  Edholm 
(21)  to  be  more  reduced  than  would  be  expected 
from  the  fall  in  arterial  blood  pressure.  This  indicated 
vasoconstriction  in  the  hand.  Other  observations  have 
indicated  little  change  or  vasodilatation.  It  seems  very 
probable  that  the  response  is  a  variable  one,  de- 
pending perhaps  on  the  degree  of  associated  emo- 
tional sweating.  Little  is  known  about  the  precise 
changes  in  blood  flow  in  other  areas  of  skin. 

general  sensory  stimuli.  Transient  reduction  in 
hand  or  finger  blood  flow  has  been  described  in  re- 
sponse to  a  great  range  of  mildly  unpleasant  stimuli 
such  as  immersing  another  part  of  the  body  in  cold 
water  (160),  pinching  (2),  or  inflating  a  pneumatic 
cuff  around  the  arm.  On  the  other  hand,  Lynn  & 
Simeone  (146)  were  unable  to  provoke  reflex  vaso- 
constriction in  anesthetized  dogs  by  electrical  stimu- 
lation or  by  distention  of  the  femoral  vein. 

response  to  a  deep  inspiration.  After  a  deep  in- 
spiration there  is  a  transient  decrease  in  finger  volume 
(38,  94).  The  size  of  the  arterial  pulsations  diminishes 
and  the  rate  of  blood  flow  falls  sometimes  to  a  very 
low  level  (116,  189).  The  blood  flow  can  be  seen  to 
slow  in  the  capillary  loops  of  the  nail  bed  (153).  The 
blood  flow  is  similarly  transiently  decreased  in  the 
hands  and  feet  (138)  but  not  in  the  more  proximal 
parts  of  the  limbs.  The  response  is  lost  after  nerve 
block  or  sympathectomy. 

Gilliatt  (90)  found  that  the  vasoconstrictor  response 
in  the  finger  could  be  elicited  by  a  sufficiently  fast 
and  deep  expansion  of  the  lungs,  whether  brought 
about  by  passive  inflation  or  voluntary  inspiration. 
It  did  not  follow  obstructed  inspiratory  or  expiratory 
efforts,  nor  deep  expiration.  The  response  has  been 
observed  in  the  fingers  and  toes  of  persons  with  a 
complete  break  in  the  functional  continuity  of  the 


■:544 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


spinal  cord  above  the  level  of  the  sympathetic  outflow 
to  the  hands  (91),  and  in  these  cases  the  response 
appears  to  be  a  purely  spinal  reflex.  At  least  some  of 
the  afferent  fibers  must  enter  the  cord  below  the 
second  thoracic  roots.  The  receptors  and  the  precise 
nature  of  the  effective  stimulus  have  not  been  identi- 
fied. The  reflex  may  be  responsible  for  the  reduction 
in  the  blood  flow  through  the  hands  in  hyperventila- 
tion (2),  but  its  functional  significance  is  unknown. 

RESPONSE   TO  DISTENTION   OF  THE   BLADDER.   Distention 

of  the  bladder  causes  a  constriction  of  the  blood 
vessels  of  the  skin,  and  elsewhere,  by  a  spinal  reflex. 
The  response  was  first  described  by  Guttman  & 
Whitteridge  (111)  in  patients  with  complete  trans- 
verse section  of  the  spinal  cord  and  in  whom  the 
isolated  cord  was  undamaged.  With  sections  above 
the  level  of  the  second  lumbar  outflow  there  was 
constriction  in  the  skin  of  the  feet  and  legs;  with  high 
section  there  was  also  constriction  in  the  hands.  The 
response  may  be  sufficient  to  raise  the  arterial  pres- 
sure, and  to  lead  to  consequent  reflex  adjustments  in 
that  part  of  the  circulation  innervated  by  the  brain 
and  upper  part  of  the  spinal  cord.  It  is  important 
when  making  observations  on  the  skin  circulation 
to  start  with  the  subject's  bladder  empty,  and  to  re- 
empty  it  before  it  becomes  uncomfortably  full. 

hypoglycemia.  The  blood  flow  is  increased  through 
the  hand  and  the  forearm  in  insulin  hypoglycemia 
(3).  The  increase  in  the  forearm  is  partly  in  the  skin, 
and  mediated  by  an  active  vasodilator  mechanism 
(11),  probably  associated  with  sweating.  Injection  of 
an  adequate  dose  of  atropine  into  the  brachial  artery 
reduces  the  blood  flow  through  the  forearm,  but  does 
not  affect  that  through  the  hand  (13). 

posture.  Changes  in  body  posture  cause  complex 
changes  and  reactions  in  the  circulation,  but  if  the 
inclination  to  the  horizontal  of  the  observed  limb  re- 
mains unchanged  the  net  effect  is  that  the  circulation 
through  the  hands  (27)  and  fingers  and  toes  (131  )  is 
little  changed.  By  contrast,  as  a  single  arm  or  leg  is 
raised  above  the  horizontal,  the  posture  of  all  other 
parts  remaining  unchanged,  the  rate  of  blood  flow 
through  the  digits  is  progressively  diminished  (174, 
191)  and  in  all  dependent  positions  the  blood  flow  is 
slightly  increased  (174).  The  digital  pulse  volume  is 
greater  in  the  raised  limb,  and  less  in  the  dependent 
limb,  than  it  is  in  a  horizontal  limb  (96).  This  is  a  strik- 
ing example  of  the  way  in  which,  under  some  circum- 
stances,   blood    flow    and    pulse    volume    may    even 


change  in  opposite  directions,  although  in  other 
circumstances  their  changes  may  correspond  closelv 
(42). 

RESPONSES     TO     BARORECEPTOR     STIMULATION.      Present 

evidence  suggests  that  the  blood  vessels  of  the  skin 
are  largely,  and  perhaps  entirely,  excused  from  par- 
ticipation in  baroreceptor  reflexes. 

Low  pressure  baroreceptor s.  Unidentified  low  pressure 
baroreceptors  within  the  thorax  can  be  stimulated 
by  raising  the  legs  of  a  recumbent  subject  and  allow- 
ing part  of  the  blood  they  contain  to  flow  into  the 
central  venous  pool,  or  by  breathing  through  a  narrow 
tube  which  restricts  air  flow  and  causes  intrathoracic 
pressure  transients  of  +30  to  — 20  mm  Hg  to  be  set 
up.  Such  stimulation  causes  a  reflex  dilatation, 
brought  about  by  reduction  in  vasoconstrictor  nerve 
activity,  in  the  blood  vessels  of  the  voluntary  muscle 
of  the  forearm,  but  no  change  in  the  resistance  to 
flow  through  the  hand  or  through  the  skin  of  the 
forearm  (173). 

Systemic  arterial  baroreceptors.  The  decisive  animal 
experiments,  in  which  observations  have  been  made 
on  a  perfused  isolated  innervated  limb,  while  the 
baroreceptors  have  been  stimulated  in  various  ways 
(sec  119),  have  dealt  either  with  whole  limbs  or 
skinned  limbs.  There  do  not  appear  to  have  been 
anv  decisive  experiments  dealing  with  the  skin  as 
such.  In  the  human,  in  experiments  in  which  bilateral 
arterial  compression  caused  increases  in  heart  rate 
and  arterial  blood  pressure  (and  was  thereby  shown 
to  affect  the  baroreceptors),  the  vascular  resistance 
through  the  hand  remained  unchanged  (168). 


ACTION  OF  HUMORAL  AGENTS  ON  THE 
BLOOD    VESSELS    OF    THE    SKIN 

The  action  of  drugs  on  the  skin  has  been  recently 
reviewed  by  Herxheimer  (118).  Only  substances  of 
ph\  siological  importance  will  be  considered  here. 
Their  direct  local  action  is  best  tested  by  a  steady 
intraarterial  infusion.  The  dose  is  adjusted  to  the 
volume  of  tissue  to  which  it  will  be  distributed,  and 
it  is  usually  so  small  that  any  returning  to  the  general 
circulation  causes  a  negligible  disturbance  of  arterial 
pressure  and  of  the  blood  vessels  elsewhere.  By  measur- 
ing the  blood  flow  in  the  contralateral  limb  as  well 
.is  in  the  infused  limb  general  disturbances  of  the 
circulation  can  be  detected  and  can  be  allowed  for 
since  these  normally  affect  the  limbs  symmetrically. 

The   effect   of  humoral    agents   released    into    the 


CIRCULATION    THROUGH    THE    SKIN 


1345 


40  -S 


20 


Adrenaline 

Noradrenaline                / 
/ 

c 
0 

/ 

/ 
/ 
/ 

/ 

^7 

0 
0 

> 

tn 

c 

-  <u 

0^ 

■"''                  Bejore__ -^ 

Q- 

T>V                            ^ 

^ 

C 
<-3 

/              p       ^"""^ 

51 

<7 

1/ 

MCj/min 

1                 1 

pg/min 
1                                  1                 1 

64 


16 


_1_ 
64 


16 


fig.  14.  The  mean  percentage 
reduction  in  the  rate  of  blood  flow  in  1 3 
hands,  tested  before  and  after  sym- 
pathectomy, in  response  to  infusions  of 
adrenaline  and  noradrenaline  at  various 
rates  into  the  brachial  artery.  The 
effects  of  general  disturbance  of  the 
circulation  have  been  eliminated  by 
referring  the  blood  flow  to  the  simul- 
taneously measured  blood  flow  in  the 
opposite  hand.  Noradrenaline  has  a 
greater  constrictor  effect  than  adrena- 
line in  normally  innervated  hands.  After 
sympathectomy  the  response  to  both 
substances  is  augmented.  [From  Duff 
(64)0 


general  circulation  is  tested  by  intravenous  infusion. 
The  rate  should  ideally  follow  the  normal  pattern  of 
secretion  but,  in  the  general  absence  of  exact  knowl- 
edge of  this,  steady  infusion  is  best  employed  (g)  and 
is  much  superior  to  a  sudden  injection.  The  effect 
on  the  skin  or  any  other  part  of  the  peripheral  circu- 
lation depends  on  a  combination  of  direct  local 
action  and  of  general  circulatory  disturbance  involv- 
ing changes  in  arterial  pressure  and  vasomotor 
control,  and  probably  changes  in  the  concentration 
of  other  humoral  agents  in  the  arterial  blood. 

Adrenaline  and  Noradrenaline 


subcutaneously  both  substances  cause 
1  pallor,  and  iontophoresis  of  adrenaline 
virtually  to  arrest  the  circulation  through 
.  Injected  into  the  brachial  artery  in  very 
both  substances  (22)  cause  a  reduction  in 
through  the  hand  (fig.  14).  There  is 
of  the  low  pressure  capacity  vessels, 
veins,  as  well  as  of  the  resistance  vessels 


Injected 
intense  loca 
can  be  used 
the  skin  ( 7 1 
small  doses, 
blood  flow 
constriction 
presumably 

(93)- 

During  the  infusion  of  either  substance  intra- 
venously at  20  fig  per  min  there  is  a  severe  reduction, 
and  sometimes  nearly  complete  arrest,  of  the  blood 
flow  through  the  hands.  After  adrenaline  injection, 
the  flow  usually  increases  for  a  time  to  above  the 
resting  level  (182)  and  there  is  often  a  flushing  of  the 
face  (17,  103).  No  such  increase  is  seen  in  sym- 
pathectomized  hands,  or  after  intravenous  nor- 
adrenaline, or  either  substance  given  intra-arterially 
(182). 


Histamine 

Pricked  into  the  skin  histamine  causes  a  local  wheal 
and  a  reddening  of  the  skin  or  flare  extending  for  a 
radius  of  3  to  4  cm  (139).  The  temperature  of  the  skin 
is  only  slightly  increased  in  the  region  of  the  flare 
(61,  139)  and,  although  the  content  of  blood  is  greatly 
increased,  the  increase  in  the  flow  is  modest.  Infused 
into  the  brachial  artery,  histamine  has  a  dilator 
effect  at  all  doses  tested  (fig.  15)  and  the  skin  becomes 
deeply  flushed.  The  flush  does  not  always  cover  all 
parts  of  the  hand,  and  this  illustrates  a  general 
difficulty  with  intra-arterial  infusions.  The  injected 
material  may  not  become  thoroughly  mixed  with  the 
arterial  blood  at  the  site  of  injection,  and  the  artery 
may  not  be  the  exclusive  supply  to  the  area  of  tissue 
examined.  Further,  the  pattern  of  distribution  may 
varv  with  changes  in  the  circulation. 


Acetylcholine 

This  acts  as  a  powerful  dilator  to  the  blood  vessels 
of  the  hand  (fig.  15),  but  so  rapid  is  its  destruction  in 
the  blood  stream  that  for  equal  effect  on  the  blood 
flow  through  the  hand  the  dose  into  the  brachial 
artery  must  be  about  one  thousand  times  as  great 
as  that  into  the  radial  artery  (65). 

5-Hydroxytryptamine  ( Serotonin ) 

When  infused  into  the  brachial  artery  at  the  rate 
of  1  fig  per  min  or  more,  this  causes  a  reduction  in 
the  rate  of  flow  of  blood  through  the  hand,  but  the 
volume  of  the  part  increases  because  of  edema  forma- 


1346  HANDBOOK    OF    PHYSIOLOGY  -^  CIRCULATION    II 


fig.  15.  The  effect  on  forearm  and 
hand  blood  flow  of  various  doses  of 
acetylcholine  and  histamine  injected 
over  i-min  periods  into  the  brachial 
artery  of  four  normal  subjects.  Con- 
tinuous line:  injected  side;  dotted  lines: 
control  side.  Doses  in  jig.  [From  Duff 
et  al.  (65).] 


40 


E 
§ 


ACh,  hand 

AD. 

16 

256 

4000 

- 

.,-.  -.••■.■•• 

R.B.C. 


5    M-  10 

Minutes 


Minutes 


tion,  and  the  skin  becomes  flushed  and  petechial 
hemorrhages  appear;  thus  the  vessels  controlling 
flow  are  constricted,  and  those  responsible  for  color 
are  dilated  (169).  On  the  other  hand,  the  low  pressure 
capacity  vessels  as  a  whole  are  rendered  less  disten- 
sible (93),  so  the  reaction  of  those  responsible  for  color 
appears  not  to  be  typical  of  the  low  pressure  vessels 
as  a  whole. 

Adenosine  Triphosphate 

Injected  intra-arterially  in  man,  magnesium 
adenosine  triphosphate  causes  a  great  increase  in  the 
blood  flow  through  the  hand,  and  is  nearly  as  ef- 
fective as  an  equal  weight  of  histamine  (68).  A  dose 
of  1  mg  per  min  into  the  brachial  artery  raises  the 
blood  flow  in  the  hand  to  an  average  value  of  34  ml 
per  100  ml  of  hand  per  min.  Adenosine  triphosphate 
may  be  the  transmitter  substance  released  from 
sensory  nerve  endings  causing  antidromic  vaso- 
dilatation (122). 


Bradykinin 

Detailed  information  is  not  yet  published  but  it 
appears  that,  per  molecule  of  injected  substance, 
bradvkinin  has  a  more  potent  vasodilator  effect  than 
any  other  tested  substance  (80). 


Carbon  Dioxide 

Breathing  mixtures  containing  high  concentrations 
of  carbon  dioxide  has  a  complex  effect  on  the  circu- 
lation, with  great  disturbance  of  vasomotor  regulation. 
The  local  effect  of  carbon  dioxide,  as  seen  when  a 
hand  is  immersed  in  a  saturated  solution  of  the  gas 
(60)  or  when  carbon  dioxide  mixtures  are  injected 
subcutaneously  (61),  is  entirely  vasodilator.  The 
effect  has  not,  however,  been  quantitatively  defined 
in  terms  of  the  response  to  various  tensions  of  the 
gas  in  the  tissues. 

Vasopressin 

Infused  intravenously  this  causes  an  initial  vaso- 
constriction in  the  hands,  which  diminishes  as  the 
infusion  continues  ( 1 33)- 

Oxytocin 

Injected  intravenously  in  man  this  may  cause 
flushing.  Injections  of  500  units  intravenously  or 
50  units  into  the  brachial  artery  cause  the  blood 
flow  through  the  hand  to  double  for  a  few  minutes. 
With  repeated  doses,  by  either  route,  the  response 
diminishes  (134).  The  vasodilator  effect  of  oxytocin 
is  balanced  by  one-twentieth  of  the  number  of  units 
of  vasopressin. 


CIRCULATION    THROUGH    THE    SKIN 


'347 


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'3' 


1 6. 


17' 


'9' 


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67.  Duff,  F.,  A.  D.  M.  Greenfield,  and  R.  F.  Whelan. 
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75.  Felder,  D.,  E.  Russ,  H.  Montgomery,  and  O.  Horwitz. 
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76.  Fencl,  V.,  Z.  Hejl,  J.  Jirka,  J.  Madlafousek,  and 
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77.  Folkow,  B.,  J.  Frost,  K.  Haeger,  and  B.  Uvnas.  The 
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78.  Fox,  R.  H.,  R.  Goldsmith,  and  D.  J.  Kidd.  Cutaneous 
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88.  Gerbrandv,  J.,  E.  S.  Snell,  and  \V.  I.  Cranston.  Oral 
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!95°- 

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124. 

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Holton,  F.  A.,  and  P.  Holton.  The  capillary  dilator 
substance  in  dry  powders  of  spinal  roots;  a  possible  role  of 
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nerve  endings.  J.  Physiol.,  London  126:  124,  1954.  142 

Holton,  P.  The  liberation  of  adenosine  triphosphate  on 
antidromic    stimulation    of   sensory    nerves.    J.    Physiol.,  143 

London  145:  494,  1959. 

Holton,  P.,  and  W.  L.  M.  Perry.  On  the  transmitter 
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CIRCULATION    THROUGH    THE    SKIN 


'35' 


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169.  Roddie,  I.  C,  J.  T.  Shepherd,  and  R.  F.  VVhelan.  The 
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171.  Roddie,  I.  C,  J.  T.  Shepherd,  and  R.  F.  VVhelan.  The 
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Research  3:  581,  1955. 


CHAPTER    40 


Circulation  in  skeletal  muscle 


HENRY    BAR CROFT 


Sherrington  School  of  Physiology,  St.  Thomas  Hospital 
Medical  School,  London,  England 


CHAPTER     CONTENTS 

Basal  Tone 
Automaticity 

Automaticity  in  Human  Muscle  Vessels 
Pressure-Flow   Relations    in    Muscle    Vessels    Deprived    of 

Automaticity 
Critical  Closing  Pressure 
Local  Temperature 
The  Problem  of  Structure  and  Function 
Nervous  Control 

Sympathetic  Vasoconstrictor  Nerves 

Effect    of   sympathetic    vasoconstrictors    upon    resistance, 
blood  volume,  and  capillary  filtration  in  skeletal  muscle 
vessels 
Chemical     transmission    at    sympathetic     vasoconstrictor 

nerve  endings  in  skeletal  muscle 
Effect    of   stimulation    of   the    arterial    baroreceptors    on 

skeletal  muscle  vessels  in  the  dog 
Effect  of  stimulation  of  the  arterial  baroreceptors  on  the 

circulation  in  human  skeletal  muscle 
Effect  of  receptors  in  a  low  pressure  area  in  the  cardio- 
pulmonary system  on  the  sympathetic   vasoconstrictor 
tone  in  human  skeletal  muscle 
Impulse  frequency  in  sympathetic  vasoconstrictor  fibers 
Sympathetic  Vasodilator  Nerves 

Chemical   transmission   at  sympathetic   vasodilator  nerve 

endings  in  skeletal  muscle 
Activation    of  sympathetic    vasodilator   fibers   to   skeletal 

muscle  by  hypothalamic  stimulation 
Sympathetic  vasodilator  fibers  to  human  skeletal  muscles 
Do  Posterior  Root  Fibers  Affect  Muscle  Blood  Flow? 
Effect  of  the  Temperature-Regulating  Center  on  the  Circula- 
tion in  Muscle 
Role  of  Sympathetic  Fibers  to  Muscle  in  Exercise 
Action  of  Sympathomimetic  Substances 
Noradrenaline 
Adrenaline 

Effect  of  Adrenaline  on  the  Circulation  in  Skeletal  Muscle 
During  Exercise 
Reactive  Hyperemia 
Exercise  Hyperemia 


few  will  deny  that  analytical  study  of  the  physiology 
of  the  circulation  in  skeletal  muscle  began  in  the 
Institute  of  Physiology  at  Leipzig.  The  paper  bears 
the  name  of  Gaskell  (108),  but  it  was  Carl  Ludwig 
who  suggested  the  problem  and  who  probably  did 
many  of  the  experiments.  In  Gaskell's  Obituary 
Notice  written  by  Langley  (137)  we  read — "At  this 
time  Ludwig's  laboratory  was  much  the  most  im- 
portant school  of  physiological  research  in  Germany 
or  elsewhere.  It  attracted  students  from  all  parts  of 
the  world.  All  the  work  was  planned  by  Ludwig, 
who  had  an  almost  unerring  sense  of  the  lines  of 
work  which  would  yield  profitable  results.  To  this 
the  success  of  the  school  was  mainly  due.  Its  popu- 
larity was  increased  by  the  method  of  procedure 
adopted  by  Ludwig.  This  has  been  described  by  T. 
Lauder  Brunton  who  was  with  Ludwig  in  1869-70. 
The  experiments  were  carried  out  by  Ludwig  with 
the  pupil  as  an  assistant,  Ludwig  wrote  the  paper 
and  then  published  it,  occasionally  as  a  conjoint 
work,  but  usually  in  the  name  of  his  pupil.  As  I  have 
heard  from  Gaskell  the  method  was  the  same  in  his 
time." 

Be  that  as  it  may,  let  us  turn  to  the  experiments 
themselves — "On  the  changes  of  the  blood  stream  in 
muscles  through  stimulation  of  their  nerves."  By  a 
simple  graphical  method  venous  outflow  was  recorded 
from  the  extensor  group  of  muscles  of  an  unanesthe- 
tized  dog.  The  changes  in  outflow  were  determined 
during  and  after  tetanic  stimulation  of  the  crural 
nerve.  From  a  typical  record,  such  as  that  seen  in 
figure  2  (top),  six  phases  could  be  discerned  during 
sustained  contraction :  a)  an  initial  spurt  due  to 
squeezing  of  the  veins  by  the  muscles;  b)  decrease  in 
flow  caused  to  some  extent  by  mechanical  compres- 
sion of  the  vessels  by  the  contracted  muscle;  c)  in- 


'353 


■354 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


FIG.  I.   Walter  Holbrook  Gaskell,  1847-1914. 

crease  in  flow;  then,  following  contraction;  d)  a 
check  in  the  rate  of  the  stream  while  the  veins  re- 
filled; e)  a  further  large  increase  in  flow;  and  finally 
/)  gradual  restoration  of  the  flow  to  the  resting  rate. 
It  is  interesting  to  compare  Gaskell's  record  with 
that  seen  in  figure  2  (bottom),  which  was  made  by 
Kramer  &  Quensel  (131)  50  years  later.  They  deter- 
mined the  venous  outflow  of  the  dog's  gastrocnemius 
with  a  hot-wire  anemometer.  Kramer  and  his 
colleagues  recognized  the  following  changes  in  out- 
flow during  maximal  tetanic  stimulation  of  the  motor 
nerve:  a)  an  initial  peak  due  to  expression  of  blood; 

b)  decrease  in  flow  due  to  mechanical  compression; 

c)  increase  in  flow;  then,  after  relaxation,  d)  transitory 
decrease  while  the  vessels  refilled;  e)  hyperemia 
reaching  the  maximum;  /)  restoration  of  the  flow 
to  the  resting  rate.  The  agreement  between  Gaskell's 
and  Kramer's  records  is  remarkable,  the  main  dif- 
ference being  that  the  postexercise  flow  was  greater 
in  Gaskell's  experiment.  Presumably  in  his  experi- 
ment the  muscle  had  contracted  more  powerfully 
during  stimulation. 

So  much  for  tetanic  contraction.  Figure  22  shows 
the  changes  during  rhythmic  contraction.  The  record 
is  from  another  experiment  of  Kramer's  (132).  The 
motor  nerve  to  the  gastrocnemius  was  stimulated  for 
1  sec  every  alternate  sec  for  5  min.  Venous  outflow- 
increased  rapidly  during  the  first  minute  to  reach  a 
steady  level.  Further  increase  in  outflow  occurred 
immediately  after  the  exercise  because  the  stream 
was  no  longer  checked  repetitively  by  mechanical 
compression.  Then  after  a  few  seconds  it  subsided  to 
the  resting  rate. 

In  man  the  changes  in  flow  in  the  forearm  muscles 


during  strong  sustained  contraction  were  determined 
by  Grant  (113),  who  recorded  the  rate  of  the  blood 
flow  by  venous  occlusion  plethysmography.  An  ex- 
cellent description  of  the  method  has  been  published 
by  Greenfield  (114).  Grant's  subject  gripped  an  iron 
bar  as  hard  as  possible  for  1  min.  There  was  a  small 
increase  in  flow  during  the  exercise  and  a  large  one 
afterward.  The  vasodilatation  during  contraction  was 
not  conspicuous  because  of  compression  of  the  vessels 
I iv  the  contracted  muscle.  As  soon  as  the  muscle 
relaxed,  compression  ceased  and  then  blood  flowed 
rapidly  into  the  veins. 

During  strong  contraction  of  the  human  gastroc- 
nemius soleus  the  effect  of  mechanical  compression 
of  the  muscle  vessels  may  stop  the  flow.  For  example, 
when  one  is  standing  tiptoe  on  the  ball  of  one  foot, 
supporting  the  whole  weight  of  the  body  by  contrac- 
tion of  the  calf  muscles,  the  blood  flow  in  these 
muscles  is  probably  arrested.  This  was  inferred  from 
records  of  the  changes  in  temperature  in  these  muscles 
made  while  the  subject  was  standing  on  tiptoe  (28). 
The  length  of  time  one  can  stand  tiptoe  on  one  leg 


MINUTES 


fig.  a.  Top:  Changes  in  venous  outflow  from  the  extensor 
group  of  muscles  of  the  dog*s  leg,  during  (R-R)  and  after 
tetanic  stimulation  of  the  crural  nerve.  [From  Gaskell  (108).] 
Bottom:  Changes  in  the  venous  outflow  from  the  gastrocnemius 
muscle  of  the  dog  recorded  during  (R-R)  and  after  tetanic 
stimulation  of  the  sciatic  nerve.  [From  Kramer  &  Quensel 
O3O.] 


CIRCULATION    IN    SKELETAL    MUSCLE 


'355 


4-0  - 


20 


RHYTHMIC  EXERCISE 

1 

1 

1 

-c      j 

iiiiMiHi 

^     ! 

ill          '  1 

—      1 

E             | 

1                        1     '  \ 

O            ' 

\ 

—            1 

1                         1  \ 

1 

E             1 

1 

II  \ 

1  i 

I  1     '■  1  1  '  '                               !  CALF^ 

I 

1  1                                                 1  FLOW 

1 

Minutes 

10 


IE 


fig.  3.  Diagrammatic  representation  of  changes  in  blood  flow 
in  the  calf  muscles  of  the  human  leg  during  strong  rhythmic 
contraction.   [From  Barcroft  &  Dornhorst  (19).] 


resting  value.  At  speeds  of  from  4  to  8  mph  there  was 
no  further  increase  in  the  size  of  the  peak  post- 
exercise  flow,  but  the  flow  returned  to  the  resting  rate 
more  and  more  slowly  as  the  speed  increased. 

These  opening  paragraphs  recall  the  circulatory 
changes  in  muscle  that  take  place  during  the  per- 
formance of  its  most  important  function — namely, 
contraction.  The  mechanism  of  the  hyperemia  of 
exercise  is  not  yet  understood  and  it  is  the  most 
important  problem  in  this  field.  Besides  dealing  with 
the  hyperemia  of  exercise  this  article  must  refer  to 
many  other  matters.  For  example,  we  shall  have  to 
deal  with  the  basal  tone  of  the  vessels,  and  with  their 
nervous  regulation,  their  responses  to  adrenaline,  and 
so  forth.  It  will  be  convenient  to  refer  first  to  these 
general  matters,  and  afterward,  with  such  knowledge 
as  a  background,  to  return  to  the  central  problem  of 
the  hyperemia  of  exercise. 


is  not  curtailed  by  previous  arrest  of  the  circulation 
in  the  thigh.  That  is  to  say,  the  circulation  in  the  calf 
is  of  no  functional  significance  in  tiptoe  standing,  an 
observation  in  accord  with  the  fact  that  the  gastroc- 
nemius soleus  arrests  its  own  circulation  when  stand- 
ing on  tiptoe  (28).  During  this  exercise  intramuscular 
pressure  in  the  calf  does  not  exceed  about  50  mm  Hg 
(1 19),  so  that  it  seems  likely  that  the  blood  supply  to 
the  muscle  is  stopped  by  nipping  of  its  vessels. 

The  circulation  in  the  calf  muscles  behaves  quite 
differently  during  weak  sustained  contraction.  Then 
there  is  marked  hyperemia.  The  effect  of  the  vaso- 
dilatation predominates  (28).  The  behavior  of  the 
circulation  during  the  sustained  contraction  of  other 
human  muscles  also  depends  upon  the  force  of  their 
contraction  and  the  extent  to  which  vasodilatation 
overcomes  the  effect  of  mechanical  compression  (67, 
141,  142,  145). 

When  human  muscles  contract  rhythmically,  each 
strong  contraction  checks  the  hyperemia  (19).  This 
is  shown  in  figure  3.  In  running,  blood  flow  through 
the  calf  must  be  intermittent;  free  flow  through 
widely  dilated  vessels  when  the  muscles  are  relaxed 
must  alternate  with  partial  or  perhaps  complete 
arrest  of  the  circulation  during  contraction. 

Black  (36)  has  investigated  the  effect  on  the  post- 
exercise  blood  flow  of  walking  at  different  speeds 
from  1  to  8  mph.  The  subject  wore  a  light  celluloid 
plethysmograph  on  his  calf.  The  distance  covered  was 
130  yards.  Up  to  4  mph  the  size  of  the  immediate 
peak  postexercise  blood  flow  was  directly  propor- 
tional to  the  speed.  The  flow  returned  rapidly  to  its 


BASAL    TONE 

Skeletal  muscle  vessels  exhibit  a  very  pronounced 
basal  tone.  In  this  respect  they  differ  from  the  vessels 
of  the  skin,  or  at  any  rate  from  the  A-V  anastomoses 
in  the  skin.  Lofving  &  Mellander  (143)  found  that 
the  resistance  to  flow  in  acutely  denervated  cat 
muscles  can  be  decreased  by  80  to  85  per  cent  by  the 
close  arterial  injection  of  supramaximal  amounts  of 
acetylcholine  or  ATP;  the  resistance  in  the  denervated 
paw  can  only  be  decreased  by  20  to  50  per  cent. 

The  action  of  a  circulating  vasoconstrictor  sub- 
stance has  often  been  invoked  to  explain  the  strong 
basal  tone  in  muscle  vessels.  If  this  were  so  then  con- 
strictor substances  such  as  noradrenaline,  adrenaline, 
serotonin,  angiotonin,  and  vasopressin  should  act 
more  powerfully  in  muscle,  where  basal  tone  is  strong, 
than  in  the  skin  where  basal  tone  is  weak.  However 
Lofving  &  Mellander  (143)  have  shown  that  many 
constrictor  substances  act  more  powerfully  on  the 
skin  vessels  of  the  paw  than  on  skeletal  muscle  vessels. 
They  concluded  that  the  basal  tone  in  muscle  vessels 
cannot  be  due  to  the  action  of  adrenaline,  noradren- 
aline, serotonin,  angiotonin,  or  vasopressin  since 
muscle  vessels  did  not  respond  more  sensitively  to 
any  of  these   agents. 

Human  muscle  vessels,  too,  exhibit  strong  basal 
tone.  Vascular  resistance  in  the  normal  forearm  is 
about  the  same  as  that  in  the  chronically  sym- 
pathectomized  forearm  (73)  and  in  both  it  decreases 
to  about  one-tenth  in  severe  exercise  (113).  If  the 
smooth   muscle   coats   of  these  vessels   were   to   stop 


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CIRCULATION    II 


contracting  spontaneously  peripheral  resistance  and 
arterial  blood  pressure  might  well  fall  to  a  danger- 
ously low  level.  Our  very  lives  must  depend  upon  the 
maintenance  of  basal  tone  in  the  vessels  of  the  skeletal 
muscular  system. 

Automaticity 

This  may  be  illustrated  by  experiments  on  the  cat. 
Folkow  &  Lofving  (97)  recorded  the  effect  of  lowering 
and  then  raising  the  arterial  pressure  upon  the  blood 
flow  through  the  muscles  of  the  leg  and  the  following 
results  have  been  calculated,  approximately,  from 
one  of  their  experiments: 


ABP 

120 

50 

50 

120 

120 

F 

7 

2.6 

3-8 

15 

7 

PRU 

17 

'9 

13 

8 

'7 

When  the  arterial  pressure  was  suddenly  lowered 
from  1 20  to  50  mm  Hg  the  resistance  to  flow  in- 
creased slightly  from  1  7  to  19  units,  probably  because 
of  elastic  recoil  of  the  vessels.  Now  over  the  next 
few  minutes,  arterial  pressure  being  still  50  mm  Hg, 
vascular  resistance  gradually  fell  from  19  to  13  units 
indicating  a  gradual  reduction  in  smooth  muscle  tone. 
When  the  arterial  pressure  was  suddenly  restored  to 
120  mm  the  resistance  fell  from  13  to  8  units,  due  to 
stretching  of  the  relaxed  vessels.  In  the  course  of  the 
next  few  minutes  the  resistance  rose  again  from  8  to 
1 7  units,  its  initial  value,  indicating  a  gradual  restora- 
tion of  smooth  muscle  tone.  In  short,  lowering  the 
arterial  pressure  was  soon  followed  by  decrease  in 
basal  tone  and  vice  versa. 

An  even  more  striking  example  of  automaticity  is 
shown  in  another  of  Folkow's  (89)  experiments. 
Clamping  the  carotid  arteries  was  followed  by  a  rise 
in  arterial  pressure  from  100  to  150  mm  Hg;  blood 
flow  in  the  denervated  muscular  portions  of  the  hind 
parts  rose  initially  but  soon  returned  to  its  initial 
level.  In  spite  of  the  rise  in  arterial  pressure,  the  lumen 
of  the  muscle  vessels  must  have  decreased. 

The  explanation  of  automaticity  is  not  yet  com- 
plete. Plain  muscle  responds  to  stretch  by  increased 
contraction.  Bayliss  (35)  pointed  out  the  significance 
of  this.  In  a  well-known  experiment  he  recorded 
volume  changes  in  the  dog's  hind  leg  before,  during, 
and  after  splanchnic  nerve  stimulation.  He  notes: 
"As  the  arterial  pressure  rises  the  limb  is  distended 
passively,  but  instead  of  merely  returning  to  its 
original  volume  when  the  blood  pressure  has  come 
down  again  it  constricts  much  below  its  previous 
level  and  only  gradually  returns."   He  thought  this 


was  probably  because  the  plain  muscle  of  the  arterial 
walls  had  responded  to  stretch  by  contraction.  How- 
ever, other  factors  may  be  involved.  It  will  be  re- 
membered that  when  in  one  of  Folkow's  experiments 
described  above  the  arterial  blood  pressure  was 
raised  the  flow  remained  constant  and  the  lumen  of 
the  vessels  became  smaller.  In  that  case  the  stimulus 
cannot  have  been  simply  stretching  the  vessel  walls 
if  by  that  is  meant  a  maintained  elongation  of  the 
smooth  muscle  fibers.  Nor  can  the  vasoconstriction 
have  been  due  to  the  lowering  of  metabolite  concen- 
tration due  to  more  rapid  flow — in  this  experiment 
the  flow  did  not  increase.  Perhaps  some  of  the  capil- 
lary bed  shut  down  so  that  the  same  total  quantity 
of  blood  flowed  faster  through  a  restricted  area. 
Further  work  is  needed  on  the  fundamental  signifi- 
cance of  automaticity. 

Pressure-flow  relations  in  muscle  depend  a  good 
deal  on  the  condition  of  the  animal.  As  this  dete- 
riorates in  the  course  of  an  experiment,  automaticity 
declines  and  the  effect  of  alteration  in  arterial  pres- 
sure upon  muscle  blood  flow  becomes  more  pro- 
nounced. 


Automaticity  in  Hit 


Muscle  lessels 


Experiments  by  Greenfield  &  Patterson  (115)  show 
that  human  vessels  constrict  when  they  are  stretched. 
The  forearm  was  enclosed  in  a  plethysmograph,  for 
measuring  the  rate  of  flow,  modified  so  that  pressures 
of  —50  and  —  150  mm  Hg  could  be  applied  for  30  sec 
to  the  enclosed  limb  segment.  Immediately  after  the 
release  of  the  negative  pressure  forearm  blood  flow- 
was  decreased;  the  vessels  must  therefore  have  con- 
stricted. The  vessels  in  the  calf  respond  in  the  same 
way  to  stretching  (60).  Blair  and  others  (38)  re- 
corded the  oxygen  saturation  changes  in  blood  from 
the  skin  and  from  the  muscle.  When  suction  was 
applied  oxygen  saturation  rose  at  once  in  the  blood 
from  the  skin  and  muscle,  due  to  distention  of  the 
vessels.  This  can  be  seen  in  figure  4.  However,  by  the 
end  of  the  first  few  minutes  of  suction,  oxygen  satura- 
tion of  the  blood  from  both  skin  and  muscle  had  re- 
turned to  its  initial  value  or  was  even  less;  thus  the 
vessels  had  contracted  to  their  initial  size  or  even 
smaller.  So  much  for  the  facts.  Since  the  circum- 
ferential size  of  the  vessels  was  not  increased,  and 
may  have  been  decreased,  the  authors  thought  that 
the  response  could  not  be  explained  simply  by  stretch- 
ing. 

Stretching  the  vessels  of  normal,  sympathectomized, 
and  chronicallv  denervated  forearms  bv  venous  con- 


CIRCULATION    IN    SKELETAL    MUSCLE 


[357 


gestion  instead  of  by  suction  is  also  followed  by  con- 
striction of  the  resistance  vessels  (157). 

Pressure-Flow  Relations  in  Muscle  Vessels 
Deprived  of  Automaticity 

Folkow  &  Lofving  (97)  investigated  pressure-flow 
relations  in  maximally  dilated  muscle  vessels  in 
which  automaticity  had  been  abolished  by  perfusing 


100 


fig.  4.  Results  showing  that  stretching  of  the  forearm 
vessels  causes  contraction.  Oxygen  saturations  of  blood  samples 
from  a  superficial  (O)  and  a  deep  (•)  forearm  vein  after  general 
body  heating.  During  the  time  represented  by  the  black 
rectangle  the  subject's  legs  were  passively  raised.  During  the 
period  between  the  vertical  lines  the  forearm  was  exposed  to  a 
pressure  50  mm  Hg  below  atmospheric.  [From  Blair  el  at. 
(39)-] 


them  with  dextran-Tyrode  solution.  Their  results  are 
summarized  in  figure  5.  Figure  5A  (continuous  curve) 
shows  the  pressure  flow  relations  when  the  arterial 
pressure  was  increased  stepwise,  the  venous  pressure 
being  maintained  at  zero.  The  curve  is  convex  to 
the  pressure  axis  indicating  vascular  distention  as 
the  pressure  increased,  until  further  distention  is 
prevented  by  the  connective  tissue  and  the  develop- 
ment of  edema.  In  Figure  5A  (broken  line)  are  seen 
the  results  when  the  mean  intravascular  pressure 
was  kept  constant  at  50  mm  Hg,  and  the  perfusion 
pressure  was  increased  by  increasing  the  arterial 
pressure  above  and  decreasing  the  venous  pressure 
below  the  mean  value.  The  relation  between  the 
perfusion  pressure  and  the  flow  is  then  linear.  This 
is  as  would  be  expected  since  the  distending  force, 
and  hence  the  resistance  to  flow  remain  constant  at 
all  values  of  the  perfusion  pressure.  Finally  in  Figure 
5B  is  seen  the  effect  of  raising  arterial  and  venous 
pressures  together  by  equal  increments  so  that  the 
perfusion  pressure  remains  constant  while  mean 
pressure  increases.  It  will  be  seen  that  the  greater 
the  mean  pressure  the  larger  is  the  flow  correspond- 
ing to  a  given  difference  in  the  perfusion  pressure. 
This  follows  because  an  increase  in  the  mean  pres- 
sure distends  the  vessels  and  decreases  intravascular 
resistance.  When  the  mean  pressure  is  high  the  ves- 
sels are  almost  maximally  distended  and  resist  further 
distention  like  rigid  tubes. 

Critical  Closing  Pressure 

When  the  arterial  supply  to  the  cat's  muscles  was 
occluded  in  an  animal  in  good  condition  the  arterial 
pressure  did  not  level  out  at  a  value  specific  for  the 


FLOW  ML/MIN 


%  INCREASE  OF  FLOW 

-|=90 

*580  FjSO 

P.30 
f=60 
P,20 


fig.  5.  Perfusion  of  the  calf  of  the  cat's 
leg  with  dextran-Tyrode  solution.  Vessels 
maximally  dilated.  Arterial  pressure,  Pa; 
venous    pressure,    Pv;    perfusion    pressure, 

p         p         D  Pa  +  Pv 

Pa  —  Pv  =  Pn;  mean  pressure, ' = 

2 

Pmi.     For    further    explanation    see    text. 

[After  Folkow  &  Lofving  (96).] 


1358 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


prevailing  vascular  tone  (97),  that  is  to  say,  not  when 
the  muscle  vessels  exhibited  automaticity.  On  the 
contrary,  the  arterial  pressure  always  fell  to  within 
a  few  mm  Hg  of  zero.  During  the  occlusion  basal 
tone  must  have  decreased,  as  was  manifested  after- 
wards by  reactive  hyperemia.  Observations  in  man 
confirm  this.  After  arrest  of  the  circulation  in  the 
upper  arm,  intrabrachial  arterial  pressure  and  pres- 
sure in  the  antecubital  vein  fall  progressively  till 
eventually  intra-arterial  sinks  below  intravenous 
pressure.  This  is  explained  by  progressive  loss  of 
intravascular  tone,  without  however  the  reflux  of 
venous  blood,  which  is  prevented  by  the  action  of  the 
venous  valves  (48). 

Using  a  pressure  plethysmograph,  Burton  & 
Yamada  (48)  found  that  the  vessels  of  a  segment  of 
the  forearm  did  close  critically  after  reduction  of  their 
transmural  pressure.  About  half  the  tissue  in  their 
forearm  plethysmograph  must  have  been  muscle. 
Further  work  is  needed  on  critical  closing  pressure  in 
healthy  muscle. 

Local  Temperature 

Not  enough  is  known  about  the  effect  of  local 
temperature  on  the  blood  flow  through  muscle. 
Blood  flow  appears  to  decrease  progressively  when  the 
cat's  hind  limb  with  paw  tied  off  is  cooled  from  40  C 
to  25  C.  Further  cooling  is  accompanied  by  increase 
in  flow  which  at  10  C  generally  exceeds  that  at  40  C 
(155).  This  is  not  so  in  the  limb  that  has  been  treated 
with  cyanide:  blood  flow  diminishes  as  the  tempera- 
ture falls,  owing  to  diminution  in  the  fluidity  of  the 
blood  (155). 

In  man  the  average  forearm  blood  flow  when  the 
limb  was  in  water  at  45  C  was  1  7.6  ml  per  100  ml  per 
min.  When  the  water  was  13  C  forearm  flow  was 
0.5  ml.  However,  these  experiments  tell  us  little 
about  the  effect  of  local  temperature  on  human 
muscle  blood  flow  (20).  Forearm  blood  flow  in- 
creases as  the  temperature  of  the  surrounding  water 
is  lowered  from  18  C  to  o  C;  the  dilatation  is  mainly 
in  the  muscles  as  it  takes  place  after  the  circulation 
in  the  skin  has  been  arrested  by  adrenaline  electro- 
phoresis.   Further  work   in   this   lield   is  needed. 


THE  PROBLEM  OF  STRUCTURE  AND  FUNCTION 

The  arrangement  of  blood  vessels  in  striated 
muscle  was  studied  by  Spalteholtz  (173)  and  de- 
scribed  as   follows    by    Krogh    (134).    "The   arteries 


supplying  a  muscle  branch  freely,  and  between  the 
branches  there  are  very  numerous  anastomoses 
forming  a  primary  network.  Into  the  meshes  of  this 
net  small  arteries  are  given  off  at  regular  intervals, 
and  these  again  anastomose  freely,  forming  a  second- 
ary cubical  net  of  great  regularity.  From  the  threads 
of  this  network  the  arterioles  branch  off,  generally 
at  right  angles  to  the  muscle  fibers  and  at  very  regular 
intervals  (of  about  1  mm  in  the  warm-blooded  ani- 
mal), and  these  arterioles  finally  split  up  into  a  large 
number  of  capillaries  running  along  the  muscle  fibers 
and  in  the  main  parallel  to  them  but  with  numerous 
anastomoses,  forming  long  narrow  meshes  about  the 
fibers.  The  capillaries  unite  into  venules  intercalated 
regularly  between  the  arterioles,  and  the  whole 
system  of  veins  reproduces  and  follows  almost  ex- 
actly that  of  the  arteries.  All  the  veins  down  to  the 
smallest  branches  are  provided  with  valves  allowing 
the  blood  to  flow  in  the  direction  of  the  heart  only." 

The  number  of  capillaries  per  square  millimeter 
transverse  section  of  striated  muscle  is  related  to  the 
metabolic  activity  of  the  animal.  Krogh  found  400 
per  mm2  of  muscle  in  the  cod,  1350  in  the  horse,  2630 
in  the  dog,  and  the  number  in  the  smallest  mammal 
he  thought  would  be  more  than  4000.  Assuming  a 
figure  of  2000  for  the  number  of  capillaries  per  square 
millimeter  of  human  muscle  he  calculated  that  the 
total  length  of  all  the  capillaries  in  all  the  skeletal 
muscles  of  a  man  would  be  equal  to  a  distance  of  two 
and  a  half  times  round  the  earth,  and  he  estimated 
that  when  all  these  capillaries  were  open  their  surface 
area  would  be  6300  m-\ 

Certain  experimental  findings  are  difficult  to 
explain  on  the  basis  of  the  classical  description  of 
skeletal  muscle  vessels.  For  example,  stimulation  of 
the  vasoconstrictor  nerves  to  the  dog's  hind  legs  is 
accompanied  by  decrease  in  muscle  blood  flow,  by 
decrease  in  oxygen  consumption  of  the  muscle  and 
surprisingly  by  a  rise  in  oxygen  saturation  of  the 
venous  blood  (154).  Pappenheimer  thought  that  the 
blood  must  have  been  directed  through  A-V  shunts 
whose  surface  area  available  for  Oa  exchange  was 
small.  Issekutz  (127-129)  came  to  the  same  conclu- 
sion. Then,  again,  increase  in  muscle  blood  flow  is 
accompanied  by  decrease  in  oxygen  consumption 
during  sympathetic  vasodilator  nerve  stimulation 
(126),  but  by  increase  in  Oo  consumption  during 
inhibition  of  sympathetic  vasoconstrictor  tone  (169). 
As  figure  6  shows,  hypothalamic  stimulation  is  accom- 
panied by  increase  in  venous  outflow  from  muscle 
but  the  clearance  of  Xal131  from  muscle  does  not 
alter.  To  explain  such  results  it  has  been  suggested 


CIRCULATION    IN    SKELETAL    MUSCLE 


!359 


2CO 

/ 

ISO 

/ 

%  BLOOO  FLOW 

o 

SO 

SO 
O 

CLEARANCE   % 

200 

30 

fig.  6.  Radio-iodide  clearance  and  blood  flow  in  the 
gastrocnemius:  Nal131  injected  intra-arterially.  Results  show 
that  hypothalamic  stimulation  increases  muscle  blood  flow  but 
does  not  alter  Nal131  clearance.  O — Stimulation  of  the  hypo- 
thalamic vasodilator  pathway;  5  trials,  4  cats.  [From  Hyman 
el  al.  (126).] 

the  stimulation  of  the  vasodilators  shifts  the  flow 
from  nutritional  to  nonnutritional  (A-V  shunt) 
channels. 

Intravenous  infusions  of  adrenaline  increase  the 
rate  of  the  blood  flow  through  muscle  without  affect- 
ing the  rate  of  Na24  clearance  (151).  This  too  has 
been  attributed  to  the  opening  of  A-V  shunts  (18). 
A-V  anastomoses  have  been  invoked  to  explain  the 
circulatory  changes  in  muscle  during  hypothermia 
(61)  and  to  account  for  the  very  small  A-V  02  dif- 
ference in  resting  muscle  (31). 

Zweifach  (181 J  claims  that  he  has  seen  blood 
short-circuitin  g  through  "thoroughfare  vessels"  in 
skeletal  musc'e,  and  Redish  et  al.  (161)  have  pub- 
lished photomicrographs  of  A-Y  shunts  in  human 
skeletal  muscle.  However,  most  anatomists  deny  the 
existence  of  A-V  anastomoses  in  skeletal  muscle 
(43).  The  perfusion  of  skeletal  muscles  with  fluids 
containing  minute  plastic  spheres  shows,  moreover, 
that  no  sphere  of  30  /*  diameter  or  over  traverses  the 
denervated  gastrocnemius  of  the  dog,  though  one- 
fifth  of  the  stream  goes  through  vessels  of  20  n  diam- 
eter. These  vessels  may  be  large  capillaries  (66,  159). 

Barlow  et  al.  (32,  33),  having  failed  to  find  A-V 
shunts  in  muscle,  have  suggested  another  explanation 
of  the  action  of  adrenaline  on  the  muscle  circulation. 
They  found  that  muscle  contains  two  entirely  sepa- 
rate circulations,  one  to  the  skeletal  muscle  fibers, 
the  other  to  the  connective  tissue.  According  to  these 
authors  adrenaline  increases  the  rate  of  flow  through 
the  nutritional  vessels  as  is  shown  plethysmographi- 
cally.  However,  it  has  little  effect  upon  the  rate  of 
flow  in  the  connective  tissue  where,  in  most  experi- 


ments, the  Xa24  is  located,  so  that  the  rate  of  Na24 
clearance  is  scarcely  altered. 

Folkow  (93)  and  Mellander  (149)  are  using  the 
following  scheme  for  the  muscle  circulation.  After 
large  "windkessel  vessels,"  which  transform  pulsatile 
into  fairly  steady  flow,  come  "resistance  vessels," 
consisting  of  two  variable  sets — precapillary  (pre- 
dominantly the  arterioles)  and  postcapillary  (mainly 
the  small  veins).  These  vessels  determine  the  resist- 
ance to  flow  and  also  affect  the  hydrostatic  capillary 
pressure  and  therefore  the  filtration  rate.  The  "sphinc- 
ter" vessels  are  a  specialized  section  of  the  smallest 
precapillary  resistance  vessels.  These  vessels  can 
cause  intermittent  closing  of  the  capillaries  and  they 
regulate  the  size  of  the  capillary  surface  area  ex- 
posed to  the  blood  flow  and  available  for  blood- 
tissue  fluid  exchange.  Then  there  are  "capacitance 
vessels"  (mainly  the  veins)  in  which  minor  changes 
in  tone,  too  small  to  affect  the  resistance  signifi- 
cantly, will  have  a  large  effect  upon  the  circulating 
blood  volume  available  for  the  heart.  Lastly  there 
are,  of  course,  the  "exchange  vessels"  or  true  capil- 
laries for  the  direct  exchange  of  substances  between 
the  blood  and  tissue  fluids;  they  are  devoid  of  smooth 
muscle  cells. 

Further  work  is  necessary  to  reconcile  the  function 
of  the  vascular  bed  in  muscle  with  its  structural  ar- 
rangement. 


NERVOUS  CONTROL 

Skeletal  muscle  vessels  exhibit  strong  intrinsic 
basal  tone  and  correspondingly  weak  nervous  control. 
Their  smooth  muscle  is  supplied  by  sympathetic 
vasoconstrictor  and  vasodilator  fibers,  though  the 
belief  that  these  act  reciprocally  is  no  longer  tenable. 
Nor  is  there  at  present  any  convincing  evidence  that 
muscle's  sensory  innervation  has  any  effect  on  its 
vessels,  either  by  antidromic  impulses  or  by  axon 
reflexes. 

Sympathetic  Vasoconstrictor  Xerves 

These  have  been  found  in  the  cat,  dog,  hare,  mon- 
key, and  in  man,  in  fact  in  all  mammals  so  far  in- 
vestigated [for  literature  see  29,  92].  The  evidence 
for  their  existence  in  animals  is  conclusive.  It  may  be 
of  some  interest  to  refer  briefly  to  the  proof  of  their 
presence  in  man  (21,  29).  It  is  as  follows.  The  rate 
of  the  blood  flow  in  the  upper  muscular  parts  of  both 
forearms    was    measured    plcthysmographically    and 


>36° 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


found  to  be  equal.  Radial,  median,  and  ulnar  nerve 
blocks  were  performed  in  one  arm,  above  the  elbow, 
and  the  rate  of  the  blood  flow  doubled  in  that  limb. 
Nerve  blocks  did  not  affect  the  rate  of  the  blood  flow 
in  the  sympathectomized  forearm.  Therefore  the 
doubling  of  the  flow  in  the  normal  forearm  must 
have  been  due  to  blocking  sympathetic  vasocon- 
strictor fibers.  Whereabouts  were  the  vessels  supplied 
by  these  fibers?  Nerve  block  doubled  forearm  blood 
flow  after  the  circulation  in  the  skin  had  been  arrested 
by  adrenaline  electrophoresis.  Therefore  the  release 
of  vasoconstrictor  tone  was  deep  to  the  skin,  probably 
in  the  skeletal  muscles.  Other  authors  have  confirmed 
this  (166).  It  is  interesting  to  note  that  brachial 
plexus  block  is  followed  by  an  even  greater  increase 
in  forearm  flow  (23).  Release  of  vasoconstrictor  tone 
in  all  muscles  would  increase  the  circulation  through 
the  skeletal  muscular  system  by  1.5  liter  per  min — the 
increase  in  severe  exercise  is  far  greater,  about  20 
liter  per  min  (21).  Sympathetic  vasoconstrictor  tone 
is  also  present  in  the  resting  muscle  of  the  cat  (13), 
dog  (10),  and  man  (21),  and  probably  in  the  muscle 
vessels  of  all  other  mammals. 

EFFECT  OF  SYMPATHETIC  VASOCONSTRICTORS  UPON 
RESISTANCE,  BLOOD  VOLUME,  AND  CAPILLARY  FILTRA- 
TION in  skeletal  muscle  vessels.  So  far  we  have  seen 
that  the  vasoconstrictor  fibers  in  muscle  can  increase 


the  resistance  to  flow.  They  can  also  reduce  capillary 
filtration  and  increase  venous  constrictor  tone.  A 
beautiful  preparation  shown  in  figure  7  has  been 
developed  by  Mellander  (149)  for  simultaneous  re- 
cording of  these  effects.  These  studies  will  be  briefly 
described.  They  concern  the  effects  of  stimulation 
of  the  abdominal  sympathetic  chain  upon  the  cir- 
culation in  the  hind  parts  of  the  cat — almost  the  whole 
of  the  cat  distal  to  the  fifth  lumbar  vertebra.  This 
part  of  the  cat  consisted  of  skin,  muscle,  and  bone  in 
the  proportions  of  1:4:1.  The  circulation  through 
bone  could  be  neglected  and  the  hind  parts  could  be 
regarded  as  a  "combined  skin-muscle  region,"  a 
few  experiments  with  rather  similar  results  were 
made  on  skinned  hind  parts  or  "muscle  regions." 
Figure  8  shows  a  typical  tracing.  The  arterial  in- 
flow pressure  was  maintained  constant,  by  means 
of  a  screw  clip,  at  120  mm  Hg.  Atropine  was  given 
to  exclude  the  action  of  the  vasodilator  fibers.  The 
abdominal  sympathetic  was  stimulated  for  periods  of 
1  min,  indicated  by  the  signal  marker,  at  the  dif- 
ferent frequencies  shown  on  the  tracing.  The  tracing 
also  shows  the  corresponding  changes  in  the  volume 
of  the  hind  parts,  which  were  enclosed  in  a  plethysmo- 
graph  communicating  with  a  piston  recorder.  During 
stimulation  the  hind  parts  shrank  rapidly  at  first 
and  then  more  slowly.  The  initial  rapid  shrinking, 
shown  bv  an  almost  vertical  downstroke  of  the  lever, 


KYMOGRAPH 


VOLUME  PISTON  RECORDER 


GADDUM   RECORDER 


PLETHYSMOGRAPH 


SYMP.   CHAINS 


TO  INF.   MESENT   ART 


TO  INF.  CAVAL  VEIN 
FROM    CAVAL  VEIN 


HEATING  PAD 


fig.  7.  Preparation  used  by  Mellander  to  investigate  the  effect  of  sympathetic  vasoconstrictor  nerve 
stimulations  upon  vascular  resistance,  blood  volume  and  capillary  filtration  rate  in  skeletal  muscle 
vessels.  [After  Mellander  (149).] 


CIRCULATION    IN    SKELETAL    MUSCLE  1 36 1 


•  • 
* 
Art. blood  pressure 

• 

Frequency  of 
sJirri/sec 

Change  of  volume     g, 

ml 

-2 

-4 

-6- 


..-  * 

0.25        0.5           1 

2 

'4 
■» 

;z 

6 

8                  16 

^7^ 3^ 

—yr-~ 

-v  -  V  \( 

====2 

-8 

-10 

Colcul.decreose 

of  capill.  pressure 

mmHg 

Blood  flow             «oC  I 
ml/min                      0tl 

Signal 

Time  20  sec                  , 

2             2            4 

* 

5  • 

3t= 

6 

Ui 

■ 

1                   1 

10                 15 

1 

™m 

fig.  8.  Typical  tracing  obtained  by  Mellander  using  the  preparation  shown  in  fig.  7.  For  further 
explanation  see  text.  [After  Mellander  (149).] 


was  a  measure  of  the  decrease  in  the  volume  of  blood 
in  the  hind  limbs,  mainly  due  to  contraction  of  the 
venules.  The  subsequent  slower  shrinkage,  indicated 
by  the  dotted  sloping  lines,  was  a  measure  of  the 
rate  of  loss  of  tissue  fluid.  Below  the  record  of  the 
volume  changes  are  shown  the  corresponding  changes 
in  capillary  pressure;  these  were  calculated  after  the 
experiment  and  will  be  referred  to  later.  Below  this 
again  we  see  the  changes  in  the  venous  outflow  from 
the  hind  parts,  the  rate  of  flow  is  proportional  to  the 
height  of  the  record.  At  the  beginning  of  the  experi- 
ment the  venous  pressure  was  adjusted,  by  raising 
or  lowering  the  venous  outflow  cannula,  so  that  the 
volume  of  the  hind  parts  remained  constant.  It 
will  only  be  necessary  to  consider  the  change  in  the 
circulation  produced  by  sympathetic  nerve  stimula- 
tion at  2,  8,  and  16  impulses  per  sec.  Typical  results 
are  shown  in  table  i .  The  data  obtained  from  the 
tracing  are  shown  by  the  figures  in  italic,  namely 
the  arterial  blood  pressure  (line  i);  the  capacitance 
changes  (initial  rapid  shrinkage,  line  8);  the  rate  of 
loss  of  tissue  fluid  (slow  continuous  shrinkage,  line 
12)  and  the  rate  of  the  venous  outflow  (line  2). 

It  will  be  convenient  to  consider  first  the  changes  in 
resistance  due  to  the  effect  of  the  vasoconstrictors  in 
the  precapillary  and  postcapillary  vessels,  that  is 
mainly  on  the  arterioles,  and  to  a  smaller  extent  on 
the  venules.  Maximal  vasoconstriction  was  produced 
by  stimulation  at  frequencies  of  16  per  sec  or  more. 


The  outflow  decreased  from  60  to  10  ml  per  min 
(line  2),  a  reduction  of  50  ml  (line  3)  which  can  be 
regarded  as  100  per  cent  maximal  (line  4).  This 
corresponds  to  a  6-fold  increase  in  resistance  (line  5), 
an  increase  of  from  2  to  12  P.R.  units  (line  6). 

However  the  maximum  possible  physiological 
impulse  frequency,  as  we  shall  see,  is  probably  not 
more  than  6  to  10  per  sec.  The  changes  recorded 
using  a  frequency  of  8  per  sec  are  therefore  of  par- 
ticular interest.  The  blood  flow  from  the  hind  parts 
was  reduced  from  60  to  about  13  ml  (line  2),  a  reduc- 
tion of  about  47  ml  (line  3),  a  response  corresponding 
to  g4  per  cent  of  the  maximal  (line  4)  and  to  a  four- 
and-a-half-fold  increase  in  resistance  (line  5).  These 
figures  correspond  to  a  reduction  in  the  rate  of  flow 
in  the  hind  parts  from  8.5  ml  per  100  ml  hind  part 
per  min  to  1.85  ml  per  100  ml  per  min  (hind-part 
volume  700  ml). 

We  must  now  refer  to  the  effects  of  stimulating  the 
vasoconstrictor  nerves  upon  the  volume  of  blood 
in  the  vessels  of  the  hind  parts.  The  maximal  effect 
was  obtained  at  a  frequency  of  8  per  sec.  At  this 
frequency,  6.25  ml  were  expelled  by  venous  contrac- 
tion (table  1 :  line  8).  According  to  this  the  amount  of 
blood  that  could  be  expelled  by  venous  contraction 
from  the  whole  of  the  skin  and  the  entire  skeletal 
muscular  system,  tissues  weighing  half  as  much  as 
the  whole  body,  would  be  only  4.5  per  cent  of  the 
animal's   blood   volume.    But   of  course   it   must   be 


1362 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


table  i .  Changes  in  the  Circulation  and  Tissue  Fluid 
Volume  in  the  Hind  Limbs  of  the  Cat  During 
Stimulation  of  the  Sympathetic  Vasoconstrictor  Nerves 


Before 
Stimu- 
lation 

After  1  min  Stimulation  at 
the  Following  Frequences 

2 

8 

Max 

Physiol 

16 

Max 

1  ABP,  mm  Hg 

120 

1 20 

120 

120 

2   Blood  flow  from  hind  parts, 

60 

40 

'3 

IO 

ml/min 

3  Decrease    in    blood    flow, 

20 

47 

5° 

ml/min 

4  Decrease  in  flow  as  %  max 

40 

94 

IOO 

decrease 

5   Increase  in  resistance 

«x 

4]2 

6 

6  Resistance,  PRU 

■2 

3 

9 

12 

7   Percentage    shortening    of 

35 

plain    muscle    in    resis- 

tance vessels 

8  Decrease   in   blood   volume 

O 

5 

ea 

e\i 

of  hind  parts,  ml 

9  Decrease  in  blood  volume 

80 

IOO 

100 

of  hind  parts  as  %  of  max 

10  Blood   loss   as   %   of  total 

25 

33 

33 

blood  in  hind  parts 

1 1    Percentage     shortening     of 

20 

plain  muscle  in  venules 

and  veins 

12   Slow  decrease  in  volume  of 

O 

2 

5 

6V2 

hind  parts,  ml 

13  Decrease  in  capillary  BP, 

5 

10 

15 

mm  Hg 

14  Approximate  capillary  BP, 

24 

]9 

14 

9 

mm  Hg 

remembered  that  skin  and  resting  muscle  are  rela- 
tively avascular  tissues  and  only  contain  14  per  cent 
of  the  blood  volume.  Measurements  of  the  volume 
of  blood  in  the  hind  parts,  by  a  radioisotopic  method, 
showed  that  they  contained  about  20  ml  of  blood. 
Of  this,  6.25  ml,  that  is  33  per  cent,  was  expelled  by 
sympathetic  activity.  If  the  sympathetic  could  expel 
33  per  cent,  the  same  proportion,  from  the  splanchnic 
area  which  contains  a  relatively  enormous  amount 
of  blood,  it  is  clear  that  this  mechanism  would  be  of 
great  importance. 

But  let  us  return  to  table  1  and  to  Mellander's 
results.  It  will  be  seen  that  at  2  per  sec  hind-part 
blood  volume  is  reduced  by  80  per  cent  of  the  maxi- 
mal (line  9)  and  that  resistance  is  not  reduced  by  80 
per  cent  until  the  impulse  frequency  has  been  in- 
creased to  8  per  sec  (line  4). 


To  account  for  the  changes  in  resistance  and  hind- 
part  blood  volume  found  during  maximal  electrical 
stimulation  Mellander  has  calculated  that  the  inter- 
nal circumferences  of  an  "average  arteriole"  and  an 
"average  venule"  would  have  to  decrease  by  35  per 
cent  and  20  per  cent,  respectively.  This  would  happen 
if  the  smooth  muscle  coat  in  both  arterioles  and  ven- 
ules shortened  by  20  per  cent.  In  the  case  of  the 
arteriole,  owing  to  the  protrusion  inwards  of  the 
inner  wall  layers  (99),  this  would  reduce  the  internal 
circumference  not  by  20  per  cent  but  by  about  35 
per  cent. 

Table  1,  line  12,  shows  the  effect  of  sympathetic 
chain  stimulation  on  transcapillary  fluid  movement. 
During  stimulation  tissue  fluid  entered  the  capillaries 
and  drained  away,  the  amount  being  related  to  the 
impulse  frequency.  The  greater  the  impulse  frequency 
the  more  must  capillary  pressure  have  fallen.  The 
precapillary  vessels  must  have  constricted  both 
absolutely  and  relatively  more  than  the  postcapillary 
vessels.  The  discrepancy  must  have  increased  as  the 
frequency  increased.  The  falls  in  capillary  pressure 
corresponding  to  the  different  impulse  frequencies 
were  determined  as  follows.  In  a  control  experiment 
venous  pressure  was  decreased  by  a  known  amount 
by  lowering  the  venous  cannula,  and  the  rate  at 
which  fluid  drained  from  the  tissues  out  of  the  hind 
parts  was  recorded.  From  this  the  rate  at  which  fluid 
entered  the  capillaries  per  1  mm  drop  in  capillary 
pressure  was  calculated.  This  was  the  absorption 
coefficient.  Knowing  both  this  and  the  rate  of  entry  of 
fluid  into  the  capillaries  recorded  during  the  stimula- 
tion at  the  different  impulse  frequencies,  the  cor- 
responding falls  in  capillary  pressure  could  be  cal- 
culated. These  are  shown  in  lines  13  and  14  and  in 
the  tracing  in  figure  8. 

Another  interesting  point  is  that  at  the  end  of  2-min 
stimulation  the  absorption  of  tissue  fluid  ceases. 
Nevertheless  during  maximal  physiological  sympa- 
thetic stimulation  for  2  min  the  volume  of  tissue  fluid 
draining  out  of  the  hind  parts  is  almost  as  much  as 
that  expressed  from  the  capacitance  vessels  (lines  8 
and  12). 

Folkow  &  Mellander  (98)  have  developed  a  tech- 
nique for  investigating  the  effect  of  a  procedure  upon 
the  capillary  surface  area.  Maximal  stimulation  of 
the  sympathetic  vasoconstrictors,  they  find,  closes 
many  precapillary  sphincters  and  reduces  the  capil- 
lary surface  area  to  about  one-third  under  conditions 
where   blood   flow   is  decreased   to  about   one-sixth. 

CHEMICAL     TRANSMISSION     AT     SYMPATHETIC     VASOCON- 
STRICTOR NERVE  ENDINGS  IN  SKELETAL  MUSCLE.   Folkow 


CIRCULATION    IN    SKELETAL    MUSCLE 


'363 


I   -    SYMPATHETIC   CHAIN 
DIVIDINO    PLANE 


fig.  9.  Preparation  used  for  investi- 
gating the  effect  of  stimulation  of  the 
baroreceptors  on  muscle  blood  flow. 
[After  Folkow  et  al.  (101).] 


&  Uvnas  (ioq,  104)  have  shown  that  the  transmitter 
is  probably  noradrenaline.  It  is  not  adrenaline.  Proof 
of  this  was  obtained  in  cats  given  Dibenamine.  Other 
procedures  excluded  the  action  of  the  vasodilator 
fibers.  After  giving  Dibenamine,  stimulation  of  the 
vasoconstrictors  caused  only  weak  contraction  or 
none  at  all.  Injections  of  noradrenaline  likewise 
caused  weak  contraction  or  had  no  effect.  On  the 
other  hand,  injections  of  adrenaline  caused  marked 
vasodilatation  in  the  muscle.  From  such  results 
Folkow  and  Uvnas  concluded  that  the  vasocon- 
strictor nerve  endings  in  the  muscles  of  the  cat  (102) 
and  dog  (104)  might  have  released  noradrenaline 
but  they  had  not  released  adrenaline.  For  a  proper 
account  of  these  beautiful  experiments  and  for  the 
literature,  their  papers  should  be  consulted.  Nor- 
adrenaline has  not  yet  been  positively  identified  in 
the  venous  effluent  collected  from  a  muscle  vein 
during  vasoconstrictor  nerve  stimulation. 

EFFECT  OF  STIMULATION  OF  THE  ARTERIAL  BARO- 
RECEPTORS ON   SKELETAL  MUSCLE   VESSELS  IN   THE   DOG. 

Folkow  et  al.  (101)  have  shown  that  the  sympathetic 
vasoconstrictor  fibers  are  solely  responsible  for  medi- 
ating the  baroreceptor  reflex.  Their  proof  is  as  follows. 
Figure  9  shows  the  preparation  of  the  hind  parts  of 
one  dog  (the  recipient)  which  were  perfused  from 
another  dog  (the  donor);  changes  in  blood  pressure 
and  in  hormone  concentration  in  the  upper  part  of 
the  recipient's  body  could  not  affect  the  circulation 


in  its  hind  legs.  The  venous  outflow  from  the  hind 
legs,  mainly  from  the  muscles,  was  recorded,  as 
was  that  from  an  area  of  the  hind-leg  skin.  The  re- 
sults are  seen  in  figure  10.  Reduction  of  the  blood 
pressure  in  the  recipient's  carotid  sinuses,  by  carotid 
occlusion,  caused  vasoconstriction  in  both  muscle 
and  skin.  After  section  of  the  abdominal  sympathetic 
nerves  neither  carotid  occlusion  nor  stimulation  of 
the  carotid  sinus  .terve  had  any  effect  whatsoever. 
Dorsal  root  fibers  could  not  have  been  implicated. 
They  could  have  mediated  vasodilatation,  as  acetyl- 
choline injections  did.  And  they  were  still  in  good 
physiological  condition  because  vasodilatation  was 
recorded  in  the  skin  when  the  dorsal  roots  were  stimu- 
lated (101).  In  other  experiments  the  vasoconstrictor 
action  of  the  abdominal  sympathetic  chains  was 
blocked  by  Dibenamine.  Clamping  the  carotids  no 
longer  caused  vasoconstriction  in  the  legs.  Although 
the  sympathetic  vasodilator  pathway  remained  in- 
tact there  was  no  sign  of  reciprocal  innervation.  On 
the  other  hand,  vasoconstriction  in  the  legs  following 
carotid  occlusion  was  normal  after  the  dilator  fibers 
had  been  blocked  by  atropine  (104).  Folkow  and  his 
colleagues  concluded  that  the  effect  of  stimulation  of 
the  arterial  baroreceptors  on  the  blood  flow  in  muscle 
must  be  mediated  solely  by  inhibition  of  activity  in 
the  sympathetic  vasoconstrictor  fibers. 

EFFECT  OF  STIMULATION  OF  THE  ARTERIAL  BARORE- 
CEPTORS   ON     THE     CIRCULATION     IN     HUMAN     SKELETAL 


1364 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


mmHg. 


FIG.  10.  Results  obtained  with  the 
preparation  shown  in  fig.  9.  Sympathec- 
tomy abolished  the  action  of  the  carotid 
sinuses  upon  the  skin  and  muscle  of  the 
hind  limb.  [After  Folkow  et  al.  (101).] 
Note  that  an  increase  in  saphenal  blood 
flow  records  downward. 


DONOR 


RECIPIENT 


SAPHENAL 
BLOOD  FLOW 


CAVAL  OUTFLOW 

SIGNAL 

TIME   6OSEC 


1.5:  OCCLUSION    COMMON   CAROTIDS 

2.4.6.8:    STIMULATION    RIGHT  SINUS   NERVE 
3.7.9:       INTRA-ARTERIAL     INJECTION    0-2>ig    ACh 


muscle.  Folkow  and  others  (54)  recorded  the  effect 
of  stimulation  of  the  carotid  sinus  nerve  in  five  pa- 
tients during  block  dissections  of  the  neck  performed 
for  the  treatment  of  cancer.  Stimulation  at  40  per 
sec  elicited  maximal  effects.  Mean  blood  pressure 
and  pulse  amplitude  fell  promptly,  there  was  a  slight 
increase  in  forearm  flow,  implying  considerable 
vasodilatation,  which  was  probably  of  nervous  origin. 
Nevertheless  it  is  unlikely  that  arterial  pressure 
changes  in  the  carotid  sinuses  in  man  have  much 
effect  on  the  sympathetic  tone  in  human  muscle 
vessels  for  the  following  reasons.  Stretching  the  ca- 
rotid sinuses  by  applying  subatmospheric  pressure  to 
the  outside  of  the  neck  causes  bradycardia  and  fall 
in  arterial  pressure — signs  of  stimulation  of  the 
baroreceptors — but  vascular  resistance  in  the  fore- 
arm is  unaltered  (81).  Compression  of  the  carotid 
arteries,  followed  by  fall  of  the  carotid  arterial  pres- 
sure to  20  mm  Hg  causes  tachycardia,  hyperpnea, 
and  rise  in  brachial  arterial  pressure — signs  of  de- 
creased baroreceptor  activity — but  forearm  vascular 
resistance  is  unaltered  (163).  Although  strong  stimula- 
tion of  the  carotid  sinus  nerve  causes  reflex  vaso- 
dilatation in  human  muscle  quite  large  changes  in 
the  transmural  pressure  in  the  carotid  sinuses  do  not 
seem  to  have  any  effect  on  the  vascular  resistance 
in  human  muscle. 

EFFECT  OF  RECEPTORS  IN  A  LOW  PRESSURE  AREA  IN 
THE  CARDIO-PULMONARY  SYSTEM  ON  THE  SYMPATHETIC 
VASOCONSTRICTOR    TONE    IN    HUMAN    SKELETAL    MUSCLE. 


The  evidence  for  this  important  reflex  is  as  follows 
(39,  164,  167,  168).  Raising  the  legs  of  a  recumbent 
subject  increases  the  forearm  blood  flow.  It  does  not 
have  this  effect  in  the  sympathectomized  forearm. 
The  dilatation  is  reflex.  Raising  the  legs  after  the  cir- 
culation in  them  has  been  arrested  has  no  effect 
upon  forearm  blood  flow.  The  reflex  is  elicited  by  a 
shift  of  blood  from  the  legs  into  the  trunk.  Raising 
the  legs  has  scarcely  any  effect  on  arterial  blood 
pressure  We  have  already  seen  that  in  man  neither 
stretching  the  carotid  sinuses  (81)  nor  reducing  the 
blood  pressure  in  them  (163)  affects  the  tone  of  blood 
vessels  of  the  forearm — so  it  seems  very  unlikely 
that  their  discharge  frequency  would  be  affected 
by  the  very  small  change  in  arterial  pressure  which 
follows  raising  the  legs.  On  the  other  hand,  raising 
the  legs  increases  the  central  venous  pressure.  It 
seems  then  reasonable  that  rise  in  pressure  on  the 
venous  side  stretches  structures  in  the  cardiopul- 
monary system  and  so  stimulates  low  pressure  re- 
ceptors which  reflexly  increase  forearm  blood  flow. 
This  conclusion  is  supported  by  the  finding  that  blood 
flow  in  the  normally  innervated  forearm  increases 
when  the  thoracic  vessels  are  stretched  by  negative 
pressure  breathing  (39).  When  the  thoracic  contents 
are  repetitively  stretched  by  rapid  alternating  positive 
and  negative  intrathoracic  pressure  changes  forearm 
blood  flow  is  trebled  or  quadrupled  (163). 

The  low  pressure  receptors  act  reflexly  by  altering 
sympathetic  vasoconstrictor  tone  in  the  muscles. 
This  has  been  deduced  from  the  following  observa- 


CIRCULATION    IN    SKELETAL    MUSCLE 


'365 


uons.  Raising  the  legs  increases  forearm  blood  flow 
but  it  has  no  effect  on  blood  flow  in  the  hand,  which 
has  very  little  muscle.  The  increase  in  forearm  flow 
is  accompanied  by  increase  in  oxygen  saturation  of 
the   blood   draining   from   the  forearm   muscles   but 
there  is  no  change  in  the  oxygen  saturation  of  the 
blood    draining    from    the    forearm    skin.    Therefore 
the  vasodilatation  in  the  forearm  must  be  in  the  mus- 
cles. As  mentioned  previously,  the  reflex  is  mediated 
by  the  sympathetic  nerves  as  it  is  absent  in  sympa- 
thectomized   forearms   and   after  deep   nerve   block. 
Atropinization   of  the  forearm  does  not  weaken   it. 
Therefore  vasodilator  fibers  do  not  seem  to  be  impli- 
cated, and  it  is  probably  due  to  decrease  in  the  dis- 
charge frequency  in  the  vasoconstrictor  fibers  (167). 
This  low  pressure  receptor  reflex  in  skeletal  muscle 
vessels  may  function   so  as   to  reduce   the  effect   of 
alterations    in    venous    pressure    upon    the    arterial 
blood  pressure.  The  effect  of  an  increase  in  venous 
pressure    and    cardiac    output    on    arterial    pressure 
would  be  reduced  because  of  reflex  vasodilatation  in 
the  muscles.  Conversely  reflex  constriction  in  skeletal 
muscles  would  tend  to  maintain  arterial  blood  pres- 
sure after  a  fall  in  venous  pressure  and  cardiac  output. 
After   major   operations   forearm    blood    flow   is   de- 
creased for  several  days  (1 10).  This  may  be  due  to  a 
low  pressure  receptor  reflex  induced  by  hemorrhage 
and  decreased  venous  pressure.   The  importance  of 
low  pressure  receptor  reflexes  in  man  may  be  related 
to  the  upright  posture. 

IMPULSE  FREQUENCY  IN  SYMPATHETIC  VASOCONSTRIC- 
TOR fibers.  Folkow  (90)  has  also  investigated  the 
impulse  frequency  in  the  vasoconstrictor  fibers  to 
skeletal  muscle — postganglionic  C-fibcrs.  He  con- 
cluded that  whereas  in  somatic  fibers  the  maximum 
discharge  frequency  may  reach  50  per  sec  the  maxi- 
mum frequency  in  the  vasoconstrictors  to  muscle 
hardly  ever  exceeds  6  to  10  per  sec,  and  normal 
sympathetic  tone  is  maintained  at  a  discharge  fre- 
quency of  only  about  1  per  sec.  The  experiments 
forming  the  basis  of  this  statement  are  most  elegant. 
The  preparation  is  seen  in  figure  1 1  and  a  typical 
result  in  figure  12.  Atropine  was  given  to  block  the 
action  of  the  vasodilator  fibers.  Venous  outflow  from 
the  isolated  muscles  of  one  cat's  leg  was  recorded 
before,  during,  and  after  i-min  periods  of  stimulation 
of  the  abdominal  sympathetic  chain  at  frequencies 
increasing  stepwise  from  0.5  to  20  per  sec.  As  the 
frequency  was  increased  the  reductions  of  the  blood 
flow  became  greater  and  were  maximal  at  a  fre- 
quency of  16  per  sec.  After  stimulations  at  frequencies 


BLOOD  REINFUSED 


STIMULATION 

OF 
SYMPATHECTIC 


VENOUS  DRAINAGE 
OF   MUSCLES 


OCCLUDE    CAROTIDS 


BLOOD   PRESSURE 


PARTIAL  OCCLUSION 
OF  AORTA  TO  KEEP 
PERFUSION  PRESSURE 
CONSTANT 


BLOOD   PRESSURE 


fig.  1 1 .  Preparation  used  by  Folkow  to  investigate  the 
impulse  frequency  in  sympathetic  vasoconstrictor  fibers.  [After 
Folkow  (90).] 

below  7  or  so  per  sec  the  blood  flow  returned  rapidly 
to  its  initial  value,  but  its  restoration  became  more 
and  more  delayed  after  stimulations  at  progressively 
higher  frequencies.  Folkow  then  turned  his  attention 
to  the  venous  outflow  from  the  leg  muscles  of  the 
opposite  side  of  the  cat,  the  side  on  which  the  abdomi- 
nal sympathetic  chain  was  still  intact;  maximal 
physiological  stimulation  of  the  vasoconstrictor  fibers 
(only)  was  induced  by  clamping  both  carotid  and 
vertebral  arteries.  The  vagi  had  been  cut.  The  possi- 
bility of  adrenaline  secretion  had  been  eliminated 
and  arterial  inflow  pressure  into  the  leg  was  kept 
constant  by  tightening  a  screw  clip  on  the  abdominal 
aorta.  The  reduction  in  flow  during  carotid  and 
vertebral  occlusion  and  the  rate  of  its  restoration 
afterward  were  then  compared  with  the  reductions 
in  flow  and  subsequent  rates  of  restoration  that  had 
been  obtained  during  and  after  electrical  stimulation 
of  the  peripheral  end  of  the  cut  abdominal  sympa- 
thetic chain.  The  comparison  showed  that  maximal 
physiological  stimulation  of  the  vasoconstrictors  (by 
occlusion  of  the  arterial  supply  to  the  head)  caused 
changes  in  muscle  blood  flow  closely  resembling  those 
recorded  during  and  after  electrical  nerve  stimulation 
at  6  to  8  per  sec.  Blood  flow  during  stimulation  at  6 
to  8  per  sec  was  reduced  by  80  per  cent  of  the  maxi- 
mal reduction  recorded  during  maximum  electrical 
stimulation  at  16  per  sec. 


[    ;M.  HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 

BLOOD   PRESSURE 


fig.  12.  Results  obtained  with  the 
preparation  seen  in  fig.  i  i  showing  that 
maximum  physiological  frequency  in  vaso- 
constrictor fibers  to  the  leg  muscle  is  about 
6-8  per  sec.  [After  Folkow  (90).]  I,  2, 
carotid  occlusion;  ;j,  sympathectomy.  4. 
0.5  stim./sec;  5,  !  stim./sec;  6,  2  stim./ 
sec;  7,  4  stim./sec;  8,  6  stim./sec;  9,  10 
stim.  sec;  10,  15  stim./sec;  II,  20  stim./ 
sec.  For  further  details  see  text. 


mmHg 

190 

150 

SIGNAL 

TIME   30SEC 

BLOOD 

FLOW 

mmHg 

180 

140 

Sympathetic  Vasodilator  Nerves 

Folkow  &  Uvnas  (102)  noticed  that  after  Dibena- 
mine,  stimulation  of  the  abdominal  sympathetic 
chain  caused  marked  vasodilatation  in  the  cat's 
hind  limbs.  The  reason  was  sought  in  a  later  paper 
(103).  What  kind  of  fibers  had  they  been  stimulating? 
Were  they  true  sympathetic  fibers?  To  decide  this 
they  extirpated  dorsal  root  ganglia  Lj  to  L5  on  one 
side  and  allowed  10  to  14  days  for  the  sensory  fibers 
to  degenerate.  However,  this  did  not  diminish  the 
vasodilator  response  in  the  legs  during  stimulation 
of  the  abdominal  sympathetic  chain.  From  this  and 
other  elegant  experiments  they  concluded  that  the 
increase  in  blood  flow  must  be  due  to  stimulation  of 
none  other  than  sympathetic  vasodilator  fibers. 
That  being  so  they  then  investigated  the  where- 
abouts of  this  vasodilatation  in  the  hind  parts. 
Stimulation  of  the  abdominal  sympathetics  did  not 
increase  flow  in  the  saphenous  vein  draining  the  skin, 
on  the  other  hand  the  flow  from  the  vena  cava  drain- 
ing skinned  hind  parts,  with  the  paws  tied  off,  did 
increase  very  greatly.  They  concluded  that  the  in- 
crease must  have  been  in  the  muscles.  Other  investi- 
gators had  shown  that  the  skeletal  muscles  of  the  dog 
are  supplied  by  sympathetic  vasodilator  fibers  (47). 

CHEMICAL  TRANSMISSION   AT  SYMPATHETIC  VASODILATOR 

nerve  endings  in  skeletal  muscle.  These  are  cho- 
linergic. Folkow  et  al.  (96)  showed  this  in  cats  given 
Dibenamine  to  block  the  action  of  sympathetic  vaso- 
constrictor fibers.  They  noticed  that  the  vasodilator 
response  to  stimulation  of  the  abdominal  sympa- 
thetic chain  was  much  reduced  by  atropine.  Atropine 
did  not  reduce  the  vasodilator  action  of  adrenaline 
or  of  histamine.  If  the  abdominal  sympathetic  vaso- 
dilator fibers  were  cholinergic,  they  argued,  the 
vasodilatation  should   be  potentiated   after  inactiva- 


tion  of  cholinesterase  by  eserine.  It  was  difficult  to 
test  this  because  the  combination  of  Dibenamine  and 
eserine  caused  almost  maximal  vasodilatation  in  the 
hind  legs.  Positive  results  were  obtained  in  only  a 
few  experiments.  Nor  could  they  test  the  effect  of 
the  venous  effluent  on  the  eserinized  leech  muscle 
because  there  were  no  leeches  in  Sweden.  However 
the  results  of  tests  made  with  extracts  of  the  venous 
effluent  upon  the  cat's  blood  pressure  and  upon  the 
frog's  rectus  muscle  showed  beyond  any  doubt  that 
sympathetic  vasodilator  nerve  stimulation  did  re- 
lease acetylcholine.  Folkow  &  Uvnas  (105)  could 
find  no  evidence  for  the  existence  of  adrenergic 
vasodilators  to  muscle  vessels  in  the  cat.  In  the  dog 
too  these  vasodilator  fibers  are  cholinergic  (46). 

ACTIVATION  OF  SYMPATHETIC  VASODILATOR  FIBERS 
TO  SKELETAL    MUSCLE    BY  HYPOTHALAMIC  STIMULATION. 

Eliasson  et  al.  (78)  were  the  first  to  show  that  stimula- 
tion of  the  hypothalamus  activated  the  sympathetic 
vasodilator  fibers  to  muscle  blood  vessels.  These 
fibers  must  have  been  solely  responsible  as  the  re- 
sponse was  abolished  by  minute  doses  of  atropine  or 
by  section  of  the  abdominal  sympathetic  chains. 
Figures  1  ;  and  14  show  the  preparation  and  a  typ- 
ical result.  As  hypothalamic  stimulation  caused  con- 
striction in  the  skin  and  intestines,  tachycardia, 
constriction  of  the  spleen,  and  dilatation  of  the  pupils, 
they  thought  that  activation  of  the  vasodilator  fibers 
to  the  skeletal  muscles  must  be  part  of  the  reaction  of  a 
state  of  emergency  in  which  a  sudden  increase  in 
muscle  blood  flow  is  often  needed  for  muscular  activ- 
ity. Further  studies  have  since  been  made  on  the 
central  connections  of  these  fibers  (2-4,  79,  139,  140). 

SYMPATHETIC  VASODILATOR  FIBERS  TO  HUMAN  SKELETAL 

muscles.    Observations   on    man    suggest    that   these 


CIRCULATION    IN    SKELETAL    MUSCLE 


1367 


LIGATURE 


fig.  13.  Preparation  used  for  investigating  the  effect  of 
hypothalamic  stimulation  in  the  skin  and  skeletal  muscle  of  the 
dog's  hind  limb.  [After  Eliasson  el  at.   (78).] 

fibers  exist  and  are  activated  during  fainting  and 
emotional  stress.  During  fainting,  the  vasovagal 
syndrome,  induced  experimentally  by  hemorrhage, 
the  arterial  blood  pressure  falls  precipitously  but 
blood  flow  in  the  forearm  increases.  There  must  be 
marked  vasodilatation  in  the  forearm  (24).  This 
vasodilatation  is  absent  in  sympathectomized  fore- 
arms and  is  mediated  by  sympathetic  fibers.  It  is 
probably  in  the  skeletal  muscles,  although  this  has 
not  yet  been  examined  with  the  Hensel  needle,  or  by- 
observations  of  the  changes  in  oxygen  saturation 
of  the  blood  draining  from  the  deep  forearm  veins, 
or  by  inducing  faints  in  subjects  after  arresting  most 
of  the  circulation  in  the  forearm  skin  by  adrenaline 
electrophoresis.  Is  the  vasodilatation  due  to  inhibition 
of  sympathetic  vasoconstrictor  tone  or  to  activation 
of  sympathetic  vasodilator  fibers?  It  is  difficult  to 
devise  a  satisfactory  experiment  to  decide  which  is 
responsible.  During  the  faint  the  average  blood 
flow  in  six  nerve-blocked  forearms  was  less  than  that 
in  six  normally  innervated  forearms.  Therefore  it 
seems  likely  that  vasodilator  fibers  were  activated 
(22).  However,  in  the  cat  simple  inhibition  of  vaso- 


constrictor tone  causes  fall  in  arterial  blood  pressure 
accompanied  by  increase  in  muscle  blood  flow  (Fol- 
kow,    personal    communication). 

It  is  worth  noting  that  the  vasodilatation  in  muscle 
in  fainting  is  probably  large  enough  to  be  mainly 
responsible  for  the  fall  in  blood  pressure  and  so  for 
loss  of  consciousness  (24). 

Vasodilators  to  human  muscle  are  probably  acti- 
vated in  emotional  stress.  Wilkins  and  Eichna  found 
that  calf  blood  flow  increased  when  a  subject  was 
given  a  mental  arithmetic  problem  which  took  him 
about  15  sec  to  solve.  They  thought  that  this  vaso- 
dilatation was  mediated  both  by  the  sympathetic 
nerves  and  by  adrenaline  secretion  (179).  Others 
have  studied  the  effect  on  forearm  blood  flow  of 
harassing  subjects  with  mental  arithmetic  problems 
for  several  minutes.  They  have  shown  with  the  Hen- 
sel needle  that  the  vasodilatation  is  in  the  forearm 
muscles  (44,83,  111),  and  that  the  response  is  re- 
duced, though  not  abolished  by  atropine,  so  that 
it  is  probably  mediated  to  some  extent  by  activity 
in  vasodilator  fibers  (16,  42). 

Blair  et  al.  (37)  frightened  subjects  by  telling  them 


BLOOD   PRESSURE 

160 

mmHg   140 

I20 


MUSCULAR 
BLOOD  FLOW 


LEFT  HIND  LIMB 


SIGNAL 
TIME  6OSEC 


CUTANEOUS 
BLOOD  FLOW 


RIGHT  HIND  LIMB 


SIGNAL 
TIME  60  SEC 


fig.  14.  Results  obtained  with  the  preparation  shown  in  fig. 
13.  Stimulation  of  part  of  the  hypothalamus  caused  vaso- 
dilatation in  the  skeletal  muscles  and  vasoconstriction  in  skin  of 
the  hind  limb.  Section  of  the  lumbar  spinal  cord  did  not  abolish 
these  effects  which  were  mediated  by  the  sympathetic  chains. 


i368 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Minutes 

fig.  15.  Results  showing  that  active  cholinergic  vasodilator 
nerves  to  human  muscle  contribute  to  the  vasodilatation  in  the 
forearm  muscles  during  stress.  Open  circles:  hand  blood  flow. 
Solid  circles :  forearm  blood  flow.  During  the  time  represented  by 
the  rectangle  it  was  suggested  to  the  subject  that  he  was  suffering 
from  severe  blood  loss.  [Blair  et  al.  (39).] 

that  they  were  suffering  from  severe  blood  loss. 
In  one  experiment,  the  result  of  which  is  illustrated 
in  figure  15,  forearm  blood  flow  rose  from  8  to  50 
ml  per  min,  while  hand  blood  flow  was  not  affected. 
In  another  subject  oxygen  saturation  of  blood  drain- 
ing from  muscle  rose  from  20  to  65  per  cent.  In  six 
subjects  the  vasodilator  responses  to  a  wide  variety 
of  stimuli  were  found  to  be  reduced  by  atropinization 
of  the  forearm.  They  concluded  that  activation  of 
cholinergic  vasodilator  nerves  to  human  muscle  con- 
tributed to  the  vasodilatation  in  the  forearm  muscles 
during  stress. 


Do  Posterior  Root  Fibers  Affect  Muscle  Blood  Flow? 

There  is  no  important  evidence  of  any  efferent  path- 
way via  the  posterior  roots  to  animal  or  human  muscle 
vessels.  These  fibers  certainly  play  no  part  in  the 
arterial  baroreceptor  reflex  which  is  mediated  solely 
by  sympathetic  vasoconstrictor  fibers  (101),  and 
they  play  no  part  in  hypothalamic  vasodilatation 
which  is  mediated  solely  by  sympathetic  vasodilator 


fibers  (78).  In  man,  too,  sympathectomy  of  the  limbs 
completely  abolishes  all  known  vascular  responses 
of  central  origin. 

There  remains  the  question  of  whether  or  not 
axon  reflexes  from  sensory  endings  in  muscle  influ- 
ence the  vessels.  If  so,  then  stimulation  of  the  posterior 
roots  should  cause  "antidromic"  vasodilatation  in 
muscle.  Celander  &  Folkow  (56)  investigated  the 
effect  on  paw  flow  and  muscle  flow  of  stimulation 
of  the  peripheral  cut  ends  of  L5-S2.  There  was 
marked  vasodilatation  in  the  paw  but  no  effect  on 
the  circulation  in  muscle.  Nor  was  there  any  change 
in  the  flow  through  muscle  when  the  small  C-fibers 
were  selectively  stimulated  by  heating  the  sciatic 
nerve.  They  concluded  that  axon  reflexes  in  muscle 
were  of  very  little  significance. 

Effect  of  the  Temperature-Regulating  Center 
on  the  Circulation  in  Muscle 

It  is  well  known  that  rise  in  body  temperature  re- 
leases sympathetic  vasoconstrictor  tone  in  the  paws. 
However  the  temperature-regulating  center  has 
very  little  influence  on  the  circulation  in  muscle. 
Folkow  et  al.  (100)  heated  the  cat's  hypothalamus  by 
diathermy  and  recorded  marked  cutaneous  vaso- 
dilatation, but  there  was  no  change  in  the  venous 
return  from  the  skinned  hind  parts.  In  man,  Edholm 
et  al.  (75)  recorded  marked  increase  in  flow  in  the 
forearm  during  body  heating,  but  this  was  absent 
in  the  opposite  forearm  in  which  the  cutaneous  cir- 
culation had  previously  been  arrested  by  adrenaline 
electrophoresis.  This  has  been  confirmed  by  observa- 
tions of  muscle  flow  made  with  the  Hensel  needle 
(15)  and  by  measurements  of  the  oxygen  saturation 
of  blood  obtained  from  veins  draining  muscle  (165). 
Body  heating  which  causes  sweating  and  rise  in 
mouth  temperature  does  not  increase  blood  flow  in 
skeletal  muscle. 

Role  of  Sympathetic  Fibers  to  Muscle  in  Exercise 

Gaskell  (108,  iog)  at  first  thought  that  vasodilator 
nerves  were  responsible  for  the  vasodilatation  In 
muscle  in  exercise,  but  later  he  realized  that  the  ac- 
tion of  metabolites  was  more  important  (107).  There 
is  strong  evidence  that  the  hyperemia  of  exercise  is 
due  to  the  action  of  a  local  mechanism  which  is 
triggered  by  the  process  of  contraction.  For  example, 
Hilton  (120)  and  others  showed  that  the  muscular 
contractions  and  vasodilatation  elicited  by  motor 
nerve  stimulation  are  both  completely  abolished  by 


CIRCULATION    IN    SKELETAL    MUSCLE 


[369 


20 

FOREARMS 

• •       Normal 

c 
E 

I] 

"e 

O 
O 

V 

I  10 

-  \ 

5 

0 

_J 

Li. 

\ 

D 
O 
O 

_J 

m 

O 

1 

10 


Minutes  after  exercise 


fig.  16.  Results  showing  vasodilatation  in  normal  and 
sympathectomized  muscle  after  exercise.  Ordinate  gives 
increase  in  blood  flow  above  normal  level.  [After  Grant  (113).] 

curare.  Curare  does  not  paralyze  vasodilator  nerve 
endings  so  that  the  vasodilatation  must  have  been 
due  to  the  contractile  process.  Muscles  given  atro- 
pine, and  then  stimulated,  vasodilate  quite  normally 
in  spite  of  cholinergic  vasodilator  nerve  block  (11, 
106).  Dogs  are  normally  active  after  extirpation  of 
both  sympathetic  chains  (53)  and  human  beings  with 
sympathectomized  limbs  walk  and  cycle  and  take 
all  forms  of  normal  exercise.  Before  lumbar  sympa- 
thectomy a  policeman  ran  380  yards  in  65  and  61 
sec;  99  days  after  sympathectomy  he  did  it  in  60 
and  61.5  sec  (H.  Barcroft  and  J.  S.  Paddle,  un- 
published observation).  Figure  16  shows  that  in  a 
sympathectomized  forearm  the  blood  flow  rose  19 
ml  per  100  ml  per  min  after  clenching  a  bar  hard  for  1 
min,  in  a  normal  forearm  the  blood  flow  rose  only 
18  ml  (113).  Such  findings  show  that  the  sympathetic 
vasodilators  were  not  responsible  for  muscle  vaso- 
dilatation in  any  of  these  activities. 

However,  there  is  no  doubt  that  in  exercise  sympa- 
thetic impulse  discharge  to  skeletal  muscular  system 
may  alter.  Blair  el  al.  (41)  recorded  blood  flow  in 
both  forearms  and  harassed  a  subject  to  do  his  best 
to  exercise  one  of  them  in  which  voluntary  movement 
had  been  paralyzed  by  a  curare-like  substance. 
The  subject's  strenuous  efforts  were  accompanied 
by  vasodilatation  in  both  his  forearms.  As  this  was 
equal  in  the  two  sides,  they  concluded  that  the  spe- 
cific vasodilator  fibers  to  a  specific  muscle  group  are 
not  activated  during  activation  of  the  motor  nerves 
to  the  group  in  question. 


In  other  experiments  the  circulatory  changes  in 
the  forearm  were  recorded  while  subjects,  who  were 
recumbent,  performed  bicycling  exercises  with  their 
legs.  During  these  exercises  arterial  blood  pressure 
rose  and  forearm  blood  flow  decreased  so  that  vascu- 
lar resistance  in  the  forearm  increased.  This  vaso- 
constriction was  still  present  when  the  cutaneous 
nerves  were  blocked  but  it  was  absent  after  deep 
nerve  block.  It  was  mediated  by  the  sympathetic 
fibers  to  muscle  vessels.  Since  it  was  not  affected  by 
previous  atropinization  of  the  forearm  it  must  have 
been  due  to  activation  of  the  vasoconstrictor  fibers. 

There  then  is  a  paradox.  The  vasodilators  were 
activated  when  the  subject  tried  hard  to  exercise  his 
paralyzed  forearm,  but  it  was  the  vasoconstrictors 
that  were  activated  during  the  bicycling  experiments. 
Can  this  be  explained  as  follows?  In  the  bicycling 
experiment  the  vasoconstriction  was  probably  a 
manifestation  of  generalized  vasoconstriction  of  the 
resistance  and  capacitance  vessels,  involving  the 
splanchnic  area  too,  and  providing  blood  for  the 
large  increase  in  output  necessary  to  supply  the  active 
legs.  In  this  exercise  the  effect  of  activation  of  the 
vasodilator  fibers  may  have  been  overpowered  by 
much  stronger  activation  of  the  constrictors.  On  the 
other  hand,  when  an  emotionally  stressed  subject 
begins  exercise  the  combined  actions  of  the  vaso- 
dilator nerves  and  the  local  factor  would  be  expected 
to  cause  more  than  usually  rapid  vasodilatation  in 
his  active  muscles. 

ACTION    OF    SYMPATHOMIMETIC    SUBSTANCES 

Noradrenaline 

Given  intra-arterially,  in  animals  or  man,  nor- 
adrenaline constricts  muscle  vessels  in  all  effective 
doses  (27,  29,  55,  59,  94,  117,  178).  Given  intrave- 
nously in  animals  its  constrictor  action  may  be  over- 
come by  the  rise  in  blood  pressure;  if  this  is  prevented 
(59)  or  obviated  (55)  the  muscle  vessels  constrict. 
In  man,  at  the  beginning  of  an  intravenous  noradren- 
aline infusion,  there  may  be  a  transient  vasodilatation, 
and  after  this  the  flow  settles  down  at  about  the  initial 
rate  for  the  rest  of  the  infusion  period;  reflex  vaso- 
dilatation of  sympathetic  nervous  origin  usually 
masks  noradrenaline's  direct  constrictor  action 
(25,  178)- 

Adrenaline 

The  literature  contains  numerous  references  to  the 
effect    of  adrenaline   on    the   circulation    in   skeletal 


'37° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


muscle  (see  1 16,  147).  Many  of  the  results  are  difficult 
to  interpret.  Artificial  perfusion  pumps,  often  used  in 
these  studies,  must  have  damaged  the  blood  and, 
because  of  the  release  of  vasodilator  substances, 
basal  tone  in  the  muscle  vessels  may  be  weakened 
(91).  About  the  use  of  artificial  pumps  Folkow  (91) 
says  "The  present  experiments  indicate  that  slight 
interference  with  the  blood  supply  may  damage  the 
blood  cells  with  release  of  substances  that  consider- 
ably depress  the  tone  of  the  vascular  smooth  muscles 
and  their  reactions  to  different  types  of  stimuli. 
The  mere  passage  of  normal  arterial  blood  through  a 
pump  device  of  the  type  generally  used  in  the  per- 
fusion experiments  releases  these  substances  in  con- 
centrations big  enough  to  depress  the  vascular  tone. 
The  rougher  the  handling  of  the  blood  the  bigger 
will  their  effect*  be  ....  The  substance  (or  substances) 
is  contained  in  the  blood  cells,  probably  in  the  eryth- 
rocytes, and  is  rapidly  destroyed  while  passing  the 
lungs,  even  when  present  in  big  concentrations  .... 
It  must  be  a  very  potent  vasodilator  agent,  as  the 
erythrocytes  of  only  0.5  mm3  blood  contain  amounts 
enough  to  elicit  a  well-defined  vasodilatation  .... 
All   these  characteristics   are   typical   also   for  ATP. 

"It  should  be  stressed,  that  most  blood  pump 
devices  are  very  unsuitable  for  a  study  of  the  reactions 
of  the  blood  vessels,  as  their  vascular  smooth  muscles 
rapidly  loose  their  tone  and  reactivity  to  most  kinds 
of  influences  due  to  the  fact  that  big  amounts  of 
vasodepressor  agents  are  then  released  from  the 
formed  elements  of  the  blood.  .  .  ."  These  remarks 
apply  to  the  cat  (Folkow,  personal  communication). 

Besides  being  observed  during  pump  perfusion, 
the  action  of  adrenaline  was  usually  studied  after 
the  hormone  had  been  given  rapidly  by  single 
injection,  so  that  there  was  not  enough  time  for  the 
resulting  action  on  the  vessels  to  reach  a  steady 
state. 

Dale  &  Richards  (63,  64),  in  two  classic  papers, 
showed  that  small  doses  of  adrenaline  cause  vaso- 
dilatation in  the  denervated  muscles  of  the  cat's 
hind  limb. 

Clarke  (57,  58)  gave  adrenaline  by  intra-arterial 
infusion.  His  records  of  the  venous  outflow  from  the 
skinned  limb  of  the  cat  show  that  it  had  a  biphasic 
effect — vasodilatation  followed  by  vasoconstriction. 
The  vasodilator  effect  has  been  attributed  to  libera- 
tion of  acetylcholine  (174,  175),  but  this  has  been 
denied.  Celander  (55)  recorded  the  changes  in 
venous  outflow  from  the  denervated  muscle  of  the 
cat's  hind  leg.  Close  intra-arterial  infusion  of  adren- 
aline at  0.04  fig  per  kg  per  min  had  no  effect  (fig.  1  7 A) ; 


0.07  fig  per  kg  per  min  caused  a  large  transient 
dilatation  accompanied  by  a  small  sustained  one 
lasting  till  the  end  of  the  infusion  (fig.  17C);  0.13 
fig  per  kg  per  min  caused  the  initial  transient  vaso- 
dilatation followed,  in  this  case,  not  by  sustained 
vasodilatation  but  by  sustained  constriction  (fig. 
175).  Whether  the  initial  transient  vasodilatation 
was  followed  by  small  sustained  vasodilatation  or  by 
sustained  vasoconstriction  was  a  matter  of  dosage.  As 
to  the  explanation  of  this  paradox  Celander  says: 
"It  is  hard  to  conceive  that  the  direct  effect  of  /-adren- 
aline on  the  smooth  muscle  cells  of  the  muscular  blood 
vessels  at  a  low  dosage  should  be  relaxation  while  the 
same  substance  on  the  same  substrate  at  a  higher  dos- 
age would  bring  about  a  constriction.  It  seems  more 
reasonable  to  assume  that  the  dilator  action  of 
/-adrenaline  is  an  "indirect"  one  and  that  its  disap- 
pearance at  a  higher  dosage  of  /-adrenaline  is  related 
to  the  'direct'  constrictor  action  of  /-adrenaline.  In 
that  case  the  dilatation  would  be  due  to  the  mobiliza- 
tion of  a  vasodilator  factor  released  by  /-adrenaline 
in  the  surrounding;  skeletal  muscle  cells  with  a  sec- 
ondary influence  on  the  smooth  muscles  of  the  blood 
vessels."  The  author  thought  that  the  sustained  vaso- 
dilatation was  a  phenomenon  which  should  be  looked 
upon  more  as  a  "metabolic"  action  of  adrenaline 
than   as  a  direct  "motor"   action.    He  also   thought 


BLOOD 
PRESSURE 


MUSCULAR 
BLOOD  FLOW 

SIGNAL 
TIME-30SEC 


fig.  17.  Effects  on  muscular  blood  flow  of /-adrenaline  given 
intra-arterially.  Perfusing  blood  pressure  120  mm  Hg.  Body 
weight  2.5  kg.  A:  I -A  infusion  /-adrenaline  0.04  jig/kg/min. 
B.  I -A  infusion  /-adrenaline  0.13  jig/kg/min.  C:  I-A  infusion 
/-adrenaline  0.07  jig/kg/min.  For  further  details  see  text. 
[From  Celander  (55).] 


CIRCULATION    IN    SKELETAL    MUSCLE 


■37' 


that  the  "after-dilatation"  seen  after  the  larger  infu- 
sions (fig.  1  -]B)  might  well  be  due  to  the  action  of 
some  carbohydrate  metabolite  diffusing  slowly  from 
the  skeletal  muscle  cells.  This  substance  was  perhaps 
lactic  acid  as  Lundholm  (144)  had  suggested. 

Celander  (55)  also  recorded  the  changes  in  venous 
outflow  during  intravenous  adrenaline  infusions. 
Arterial  pressure  in  the  cat's  legs  was  kept  constant  by 
adjusting  a  screw  clip  on  the  lower  abdominal 
aorta.  The  general  picture  was  the  same — initial 
transient  vasodilatation  followed  by  smaller  sus- 
tained vasodilatation  or  by  constriction  according 
to  the  infusion  rate.  There  was  one  important  dif- 
ference. Far  greater  amounts  of  adrenaline — about 
five  times  as  much — had  to  enter  the  leg  before  the 
sustained  vasodilatation  gave  place  to  constriction. 
In  the  case  of  intravenous  infusions  the  local  con- 
strictor action  of  adrenaline  was  believed  to  have 
been  opposed  by  the  vasodilator  action  of  a  substance 
liberated  into  the  general  circulation.  Celander 
thought  this  substance  was  perhaps  lactic  acid  from 
the  other  muscles. 

Celander's  (55)  investigation  also  included  the 
changes  in  venous  outflow  caused  by  unilateral 
splanchnic  nerve  stimulation.  Here,  too,  arterial 
pressure  in  the  leg  was  kept  from  rising  by  tightening 
a  screw  clip  placed  proximally.  Stimulation  at 
frequencies  of  1  to  6  per  sec  (corresponding  to  bi- 
lateral splanchnic  stimulation  at  0.5-3/sec)  caused 
sustained  vasodilatation  in  the  skeletal  muscles. 
Further  increase  in  the  frequency  was  accompanied 
by  progressively  less  vasodilatation.  The  results  may- 
have  been  complicated  by  liberation  of  substances 
from  the  liver;  but  they  are  interesting  because  it  is 
via  the  splanchnic  nerves  that  the  suprarenal  gland 
receives  its  natural  stimulus. 

The  human  experiments  on  the  biphasic  and  other 
actions  of  adrenaline  on  muscle  vessels  are  of  par- 
ticular interest.  To  quote  Lewis  (138),  "It  is  perhaps 
impossible  to  measure  the  relevant  quantities  so 
precisely  in  man  as  in  animals  that  are  reduced  by 
anaesthesia  to  perfect  stillness  and  control.  The 
disadvantage  is  offset,  however,  in  other  directions. 
It  is  the  reaction  in  man  himself  of  which  we  par- 
ticularly require  knowledge.  Moreover,  in  human 
experiments  the  nutrient  fluids  bathing  the  limb  are 
those  natural  to  the  limb  and  to  the  reaction,  and 
this  has  not  always  been  the  case  in  animal  experi- 
ments. Our  observations  are  undertaken  upon  the 
unanaesthetised  subject,  the  body  as  a  whole  is 
healthy  and  undisturbed,  the  general  circulation  is 
perfect,  conditions  rarely,  if  ever,  realised  in  animal 


experiment,  and  yet  probably  essential  to  an  eluci- 
dation of  the  full  truth  where  such  a  delicate  reaction 
is  concerned." 

The  subject  is  given  a  continuous  infusion  of  saline 
into  the  brachial  or  femoral  artery  throughout  the 
experiment.  When  appropriate  the  syringe  contain- 
ing the  saline  is  replaced  by  another  containing  the 
same  saline  solution  to  which  adrenaline  has  been 
added.  The  subject  does  not  know  whether  syringes 
contain  adrenaline  or  not.  Thus  when  adrenaline 
is  given,  changes  in  forearm  or  calf  blood  flow  can 
safely  be  attributed  to  the  adrenaline  itself;  neither 
the  saline  nor  emotional  stress  can  be  responsible 
(29).  Soon  after  the  beginning  of  an  intra-arterial 
adrenaline  infusion  blood  flow  in  the  muscular  part 
of  the  limb  increases  abruptly,  reaching  a  peak  in 
about  1  min.  From  the  peak  the  flow  subsides  abruptly 
to  a  little  above  the  initial  level  at  which  it  remains 
for  the  rest  of  the  infusion  period.  The  vessels,  as 
it  were,  "yawn" — they  open  wide  and  close.  This 
initial  transient  vasodilatation  occurs  at  the  begin- 
ning of  infusions  at  rates  varying  from  about  0.00 1 
to  2.0  Mg  per  min.  The  biphasic  pattern  of  the  re- 
sponse is  very  striking  (177).  When  the  rate  of  the 
infusion  is  increased  stepwise,  each  increase  in  rate 
is  accompanied  by  its  own  transient  initial  vaso- 
dilatation (29).  Intra-arterial  infusion  of  very  large 
amounts  of  adrenaline,  far  above  the  physiological 
range,  causes  sustained  vasoconstriction. 

As  figure  18  shows,  the  initial  biphasic  transient 
dilatation  is  also  the  first  response  of  the  muscle 
vessels  of  man  to  infusions  of  adrenaline  given  by  the 
intravenous  route.  The  subsequent  residual  sus- 
tained vasodilatation  is  larger  than  that  recorded 
during  intra-arterial  infusions  (29,74,  J  77)-  Thus 
in  the  forearm  an  intravenous  infusion  at  10  jug  per 
min  is  accompanied  by  an  initial  fivefold  increase 
in  flow  after  which  the  rate  subsides  to  about  double 
the  initial  value  for  the  remainder  of  the  infusion 
period  (5,29,  178).  That  both  the  initial  transient 
and  the  subsequent  smaller  sustained  vasodilatation 
take  place  in  the  skeletal  muscle  has  been  shown  by 
records  taken  with  a  Hensel  needle  implanted  in  the 
calf  muscles  (14,  26).  This  is  seen  in  figure  19. 

There  is  then  a  close  resemblance  between  the 
action  of  adrenaline  on  the  vessels  of  the  skeletal 
muscle  of  man  and  of  animals.  The  mechanism  of 
the  initial  transient  vasodilatation  and  of  the  later 
sustained  one  is  plainly  of  great  fundamental  signifi- 
cance. It  will  be  convenient  to  consider  first  the  na- 
ture  of  the   initial    biphasic   effect  which   is  such   a 


1372 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


SALINE 

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fig.  1 8.  Results  show  the  effect  of  an  intravenous  infusion  of 
adrenaline  in  man  on  forearm  blood  flow.  The  initial  large 
transient  and  later  smaller  sustained  vasodilatation  are  due  to 
the  action  of  adrenaline  on  the  blood  vessels  in  the  skeletal 
muscles. 


constant    and    conspicuous    response    of    the    vessels 
in  the  muscles  of  the  calf  and  forearm. 

During  the  initial  vasodilatation  blood  flow  in- 
creases about  fivefold.  The  main  resistance  vessels, 
the  arterioles  and  precapillary  sphincters  must  be 
widely  dilated.  This  is  in  accordance  with  micro- 
scopic observations  made  by  Hartman  &  Walker 
( 1 1 8)  on  the  tibialis  anticus  of  the  cat.  Small  doses  of 
adrenaline  dilated  arterioles,  capillaries,  and  venules. 
In  man  this  dilatation  is  not  dependent  on  nervous 
connections.  It  occurs  after  nerve  block,  after  sympa- 
thectomy, and  in  completely  denervated  limbs  (29, 
177).  It  must  be  due  to  the  local  action  of  adrenaline 
in  the  skeletal  muscles.  This  might  be  a  direct  action 
on  the  plain  muscle  of  the  arterioles  or  a  metabolic 
action  due  to  products  of  carbohydrate  metabolism 
released  by  the  action  of  adrenaline  on  the  skeletal 
muscle  fibers.  That  the  action  of  adrenaline  is  direct 
rather  than  metabolic  is  shown  by  the  following  ob- 
servations. In  the  first  place,  the  initial  vasodilatation 
is  not  accompanied  by  any  rise  in  venous  blood 
lactate,  which  may  even  fall,  so  it  is  not  likely  that 
there    is   a    rise   in    the   concentration   of  anv    other 


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fig.  19.  Simultaneous  records  of  the  changes  in  blood  flow  in  calf  of  the  leg  (plethysmograph)  and 
in  the  muscles  of  the  calf  of  the  leg  iHensel  needle)  recorded  in  six  experiments  before,  during,  and 
after  the  intravenous  infusion  of  adrenaline.  [After  Barcroft  el  al.  (26).] 


CIRCULATION    IN    SKELETAL    MUSCLE 


'373 


metabolite  from  the  skeletal  muscle  fibers  (17). 
Secondly,  a  perfectly  normal  initial  vasodilatation 
has  been  recorded  in  a  patient  whose  muscles,  owing 
to  an  inborn  error  of  metabolism,  contained  no 
phosphorylase,  so  that  the  vasodilatation  was  prob- 
ably not  due  to  any  product  of  glycolysis  (146,  170; 
also  H.  Barcroft  and  B.  McArdle,  unpublished  ob- 
servation). It  seems  reasonable  to  conclude  that  the 
initial  vasodilatation  is  not  due  to  the  action  of 
adrenaline  on  carbohydrate  metabolism  in  the 
skeletal  muscle  fibers,  and  that  it  probably  is  due  to 
the  direct  action  of  adrenaline  on  the  plain  muscle 
of  the  arteriolar  walls. 

Now  we  must  consider  the  second  part  of  the  bi- 
phasic  initial  transient  vasodilatation — the  rapid 
return  of  the  flow  from  the  peak  toward  the  resting 
level.  Allwood  &  Ginsburg  (7)  and  de  la  Lande  & 
Whelan  (136)  have  shown  that  this  is  due  to  a  direct 
constrictor  action  of  adrenaline  on  the  muscle  vessels. 
It  can  be  partially  or  completely  prevented  by  adre- 
nergic blocking  agents,  as  is  shown  in  figure  20.  That  is 
to  say  adrenaline  causes  first  vasodilatation  in  muscle 
almost  immediately  followed  by  vasoconstriction, 
which  can  be  prevented  by  a  blocking  agent.  The 
question  now  arises  as  to  whether  the  vasodilator  and 
vasoconstrictor  phases  of  the  initial  transient  vaso- 
dilatation take  place  in  the  same  vascular  bed,  or  is 
the  opening  of  one  set  of  vessels  soon  followed  by  the 
closing  of  another  set  in  parallel?  A  little  considera- 
tion of  the  extent  of  the  changes  in  flow  shows  that 
the  initial  vasodilatation  and  the  ensuing  vasocon- 
striction must  both  take  place  in  the  same  set  of 
vessels.  Suppose,  as  often  happens,  the  flow  before 
the  beginning  of  the  infusion  was  3  ml  per  min. 
Then  constriction  in  one  bed  could  not  reduce  the 
flow  by  more  than  the  preinfusion  rate  of  3  ml.  In 
fact  typical  flows  before,  at,  and  after  the  initial 
transient  vasodilatation  may  be  3,  15,  6  ml,  respec- 
tively. That  is,  constriction  may  reduce  the  flow  by 
9  ml,  i.e.,  by  three  times  the  total  preinfusion  rate. 
Plainly  this  could  only  happen  if  the  vessels  had  first 
dilated  so  that  they  could  be  constricted  to  this 
extent. 

It  is  well  known  that  the  action  of  adrenaline  on  a 
piece  of  smooth  muscle  can  be  biphasic  (45).  It  is 
highly  probable  that  the  vasodilator  and  constrictor 
phases  of  the  initial  transient  vasodilatation  are 
both  due  to  a  direct  biphasic  action  of  adrenaline  on 
the  smooth  muscle  coat  of  the  arterioles  of  the  skeletal 
muscle  vessels.  This  would  be  in  accordance  with 
the  fact  that  vasodilatation  invariably  comes  before 
constriction  and  that  in  any  given  infusion  the  sizes 


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Adrenaline  l.V. 

For 

1       r 

►0]                     10  //g/min 

r 1 r ' 

0- 

1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 — 1 

Minutes 

fig.  20.  Results  showing  that  the  rapid  return  of  the  forearm 
blood  flow  from  the  initial  peak  towards  the  resting  rate  during 
adrenaline  infusions  is  due  to  a  direct  vasoconstrictor  action  on 
the  muscle  blood  vessels.  Open  circles:  before  chlorpromazine. 
Solid  circles:  after  chlorpromazine.  [From  de  la  Lande  &  Whelan 

(136).] 

of  the  vasodilatation  and  vasoconstriction  are  usually 
equal.  If  the  inhibitory  and  excitatory  actions  of 
adrenaline  were  to  take  place  in  different  parts  of 
the  same  vascular  bed,  i.e.,  in  the  arterioles  and 
venules,  it  seems  less  likely  vasodilatation  would  so 
closely  relate  to  constriction  in  both  time  and  extent. 
It  is  very  difficult  to  imagine  that  the  main  resistance 
could  shift  from  the  arterioles  to  the  venules.  It  is 
generally  believed  that  adrenaline  does  constrict 
arterioles. 

We  must  now  turn  to  the  smaller  sustained  vaso- 
dilatation that  follows  the  large  initial  transient  one. 
Similar  sustained  vasodilatation  in  muscle  would  be 
expected  to  accompany  a  continuous  release  of  adren- 
aline from  the  adrenal  glands.  It  will  be  recalled  that 
Celander  (55)  observed  sustained  vasodilatation 
during  intra-arterial  adrenaline  infusions  and  at- 
tributed it  to  the  action  of  lactic  acid  liberated  by  the 
metabolic  action  of  adrenaline  in  the  skeletal  muscle 
fibers.  Intra-arterial  infusions  of  adrenaline  in  man 
are  also  accompanied  by  local  release  of  lactic  acid 
(6)  and  the  small  sustained  vasodilatation  in  such 
infusions  may  be  due  to  an  indirect  metabolic  action 
of  adrenaline  on  the  skeletal  muscle  fibers.  The  evi- 
dence so  far  available  shows  that  the  sustained  vaso- 
dilatation in  man  is  rather  larger  during  intravenous 
than  during  intra-arterial  infusions  (29,  74,  177). 
Celander  (55)  found  the  same  in  animals  and  thought 
that  it  was  because  during  intravenous  infusions  the 


1374 


HANDBOOK    OF    I'lIVSK ,\ 


CIRCULATION    II 


muscle  vessels  were  dilated  not  only  by  locally 
liberated  lactic  acid  but  also  by  lactic  acid  liberated 
from  other  muscles  into  the  general  circulation. 
Many  experiments  have  been  done  on  man  to  try 
to  explain  why  the  sustained  vasodilatation  is  larger 
during  intravenous  infusions  than  it  is  during  intra- 
arterial ones.  It  is  not  due  to  rise  in  arterial  blood 
pressure,  nervous  reflexes  (29,  177),  histamine  forma- 
tion (153),  or  secretion  of  the  pituitary  (135).  It  is 
probably  explained  by  the  fact  that  during  intrave- 
nous infusions  the  concentration  of  adrenaline  re- 
mains constant  independently  of  the  rate  of  flow, 
whereas  the  concentration  varies  reciprocally  with  the 
rate  of  flow  during  intra-arterial  infusions.  The  large 
sustained  vasodilatation  typical  of  an  intravenous 
adrenaline  infusion  can  be  obtained  too  during  an 
intra-arterial  infusion,  if  the  rate  of  infusion  of  the 
hormone  is  gradually  increased  so  as  to  keep  its 
concentration  constant  (143a). 

Effect  of  Adrenaline  on  the  emulation  in 
Skeletal  Muscle  During  Exercisi 

It  is  often  stated  that  adrenaline  dilates  muscle 
blood  vessels  in  exercise.  So  far  as  I  am  aware  there 
is  no  evidence  that  it  actually  does  so.  The  idea  is 
often  accepted  as  part  of  Cannon's  Emergency 
Theory  of  the  function  of  the  autonomic  nervous 
system.  So  far  as  I  can  find,  Cannon  himself  never 
suggested  it  (49-52).  On  the  other  hand,  why  are 
the  plain  muscle  coats  of  the  arteries  in  the  skeletal 
muscles  specialized  so  that  they  are  rapidly  dilated 
by  adrenaline?  Is  this  of  any  teleological  value  in  the 
cat  or  man?  Or  was  it  of  value  in  some  extinct  an- 
cestor? Or  is  it  just  a   coincidence? 

A  few  minutes  after  the  beginning  of  long-lasting 
repetitive  stimulation  of  the  motor  nerve  to  the  dog's 
gastrocnemius,  the  oxygen  saturation  of  the  venous 
blood  draining  from  the  muscle  sinks  to  its  lowest 
point  to  rise  again  later.  This  is  because  of  delay  in 
the  rate  of  opening  of  the  vessels.  If  in  the  exercising 
animal  adrenaline  secretion  helped  to  open  the  ves- 
sels, the  provision  of  oxygen  and  disposal  of  waste 
products  would   be  facilitated. 

When  exercise  begins  the  blood  pressure  rises, 
sympathetic  impulse  discharge  increases,  and  metab- 
olite concentration  in  the  muscle  mounts  up.  It 
would  be  very  difficult  to  devise  an  experiment  in  the 
cat,  dog,  or  human  to  determine  the  extent  to  which 
the  initial  dilatation  of  the  muscle  vessels  was  in 
fact  due   to   the  action  of  adrenaline. 

In  man,  emotional  stress  at  the  beginning  of  exer- 


cise may  be  accompanied  by  adrenaline  secretion 
(16).  This  would  be  expected  to  cause  an  initial 
transient  vasodilatation  throughout  the  entire  skele- 
tal muscular  system.  In  active  muscles  the  vessels 
would  be  rapidly  dilated  and  the  constrictor  phase 
of  the  initial  biphasic  response  might  well  be  blocked 
b)  the  action  of  the  mounting  concentration  of  metab- 
olites. In  animal  experiments  the  constrictor  action 
of  adrenaline  is  blocked  if  muscles  are  active  (150). 
In  other  muscles  which  were  not  contracting  the 
constrictor  part  of  the  biphasic  response  would  mani- 
festly be  of  use  as  it  would  prevent  useless  and  waste- 
ful hyperemia.  To  quote  from  August  Krogh  (134), 
"Speculations  such  as  these,  though  admittedly- 
loose,  are  sometimes  very  useful.  Sooner  or  later  an 
opportunity  offers  of  putting  them  to  the  test.  It  is, 
of  course,  very  gratifying  to  find  them  confirmed,  but 
generally  they  are  even  more  useful  when  they  turn 
out  to  be  wrong,  because,  in  that  case,  they  serve  to 
discover  at  what  point  the  reasoning  went  astray  and 
to  guide  it  back  into  a  channel  which  may  possibly 
lead  it  onward.  The  problems  of  physiology  are  so 
complicated  that,  to  put  it  tersely,  one  cannot  expect 
to  be  able  to  reason  correctly  from  the  facts  for  more 
than  5  min  at  a  stretch." 

Apart  from  the  beginning  of  exercise  is  the  question 
of  the  action  of  adrenaline  on  the  vessels  later  on 
(sustained  vasodilator  action).  It  is  known  that  adren- 
aline continues  to  be  secreted  in  severe  exercise  in 
man  (82),  but  because  of  the  very  strong  action  of 
metabolites  its  effect  on  the  vessels  would  be  ex- 
pected to  be  negligible.  This  is  in  accordance  with 
the  results  of  experiments.  In  dogs,  Cannon  et  al. 
(49)  found  that  the  amounts  of  work  that  dogs 
could  do  to  exhaustion  on  a  treadmill  was  neither 
prolonged  by  previous  injection  of  adrenaline  nor 
shortened  by  previous  adrenalectomy.  In  man  Dorn- 
horst  &  Whelan  (68)  found  that  the  postexercise 
"blood  debt"  was  not  diminished  when  the  exercise 
was  performed  during  an  infusion  of  adrenaline. 


REACTIVE    HYPEREMIA 

Reactive  hyperemia  can  be  induced  in  skeletal 
muscle  vessels.  Hilton  ( 1 20)  recorded  it  in  the  cat's 
isolated  gastrocnemius.  Following  temporary  arrest 
of  the  circulation  through  this  muscle,  achieved  by 
clamping  the  artery  for  30  sec,  the  increase  in  blood 
flow  was  as  great  as  that  recorded  after  30  sec  of 
maximal  tetanic  contraction,  but  after  ischemia  the 
flow  subsided  more  quickly.  Folkow  &  Lofving  (97) 


CIRCULATION    IN    SKELETAL    MUSCLE 


'375 


found  that  temporary  occlusion  of  the  circulation 
through  the  cat's  hind  limb  (paw  tied  off)  was 
followed  by  reactive  hyperemia.  As  the  condition 
of  the  animal  deteriorated,  basal  tone  diminished  and 
reactivity  of  the  vessels  decreased.  Reactive  hyperemia 
in  skeletal  muscles  is  soon  lost  when  they  are  per- 
fused with  saline. 

It  is  generally  agreed  that  reactive  hyperemia 
takes  place  independently  of  nervous  connections. 
Bayliss  (35)  thought  that  the  relaxation  of  the  vessels 
during  reactive  hyperemia  was  due  to  lengthening  of 
the  plain  muscle  because,  during  the  period  of  ar- 
rested circulation,  the  fibers  were  no  longer  subjected 
to  the  stimulus  of  stretch.  Lewis  ( 1 38)  denied  this 
because  reactive  hyperemia  followed  circulatory 
arrest  by  venous  occlusion,  during  which  the  smooth 
muscle  of  the  arterial  walls  was  still  distended  by 
the  arterial  blood  pressure.  He  did  numerous  ex- 
periments leading  him  to  the  conclusion  that  the 
response  was  due  to  the  action  of  a  histamine-like 
vasodilator  substance  the  concentration  of  which, 
in  the  tissue  fluids,  increased  during  the  ischemic 
period.  Folkow  et  al.  (95)  and  Emmelin  &  Emmelin 
(80)  found  that  reactive  hyperemia  occurred  quite 
normally  in  the  limbs  of  animals  in  which  the  action 
of  injected  histamine  had  been  completely  blocked  by 
antihistaminics.  Therefore,  they  concluded  that  the 
response  was  probably  not  due  to  the  action  of  a 
histamine-like  substance.  Guyton  et  al.  (62)  showed 
that  reactive  hyperemia  cannot  be  due  to  the  action 
of  accumulated  CO  2.  Ventilating  dogs  with  20  per 
cent  CO 2  was  not  accompanied  by  any  vasodilatation 
in  the  legs.  On  the  other  hand,  reduction  of  the 
oxygen  saturation  of  the  blood  to  30  per  cent  doubled 
the  rate  of  the  blood  flow.  Guyton  et  al.  thought  that 
oxygen  deficiency  might  well  be  one  of  the  causes  of 
reactive  hyperemia. 

Most  studies  of  reactive  hyperemia  in  muscle  in 
man  have  been  made  in  the  forearm  or  calf  using 
venous  occlusion  plethysmography.  However,  one 
must  alwavs  remember  that  the  blood  flows  recorded 
by  this  method  are  not  those  in  the  skeletal  muscle 
only,  but  include  also  the  blood  flow  through  the 
skin. 

In  man  as  in  animals  (120),  the  longer  the  period 
of  arrest  lasts  the  greater  is  the  subsequent  hyperemia 
in  the  forearm  ( 1 58) ;  the  increase  is  mainly  in  the 
duration  of  high  flows,  the  peak  value  being  relatively 
little  increased.  Reduction  of  the  arterial  pressure 
during  the  period  of  arrest  and  of  the  stimulus  of 
stretch  may  be  partlv  responsible  for  the  loss  of 
vascular  tone   (156).    Exposing   the  forearm  to  sub- 


atmospheric  pressure  and  thus  '"packing"  it  with 
blood  before  arresting  the  circulation  lessens  the  fall 
of  intravascular  pressure  during  the  period  of  oc- 
clusion. As  in  animals,  so  in  the  human  forearm, 
antihistamines,  such  as  tripelennamine,  mepyramine, 
and  antazoline  when  introduced  into  the  brachial 
artery  do  not  diminish  the  reactive  hyperemia  that 
follows  3  min  of  circulatory  arrest,  although  they 
completely  abolish  the  increase  in  flow  brought 
about    by    the    intra-arterial    injection    of   histamine 

(70- 

Apart  from  histamine,  various  chemical  causes, 
such  as  anoxia,  have  been  suggested  to  explain  reac- 
tivity in  man.  Lewis  (138)  says,  "'It  is  manifest  that 
neither  deficiency  of  oxygen  nor  an  accumulation 
of  carbon  dioxide  or  other  weak  acid  in  the  blood 
that  is  within  the  vessels  can  possibly  form  the  direct 
stimulus;  were  that  so  the  reaction  would  always  be 
fleeting,  the  blood  being  at  once  replaced  by  the  flood 
of  the  reactive  hyperaemia."  Certainly  the  vessels 
would  be  filled  with  fresh  blood  almost  instantly,  but 
does  it  follow  that  the  reaction  would  be  fleeting? 
After  sudden  removal  of  the  stimulus  how  fast  in 
fact  would  the  vessels  contract?  Some  kinds  of  plain 
muscle  respond  to  stimulation  rather  slowly.  Further 
experiments  are  needed  on  this  important  point. 
McNeill  (148)  showed  that  during  the  second  minute 
of  a  reactive  hyperemia  in  the  forearm  the  oxygen 
saturation  of  the  venous  blood  in  the  antecubital 
vein  may  rise  transiently  to  well  above  the  resting 
value.  The  effect  is  seen  in  figure  21.  The  reason  for 
this  transient  rise  in  venous  oxygen  saturation,  as 
McNeill  showed,  was  that  oxygen  consumption  re- 
turned to  the  resting  level  more  promptly  than  did 
the  blood  flow;  this  corresponded  to  a  transient  de- 
crease in  utilization.  Return  of  the  blood  flow  to  the 
pre-occlusion  level  may  have  lagged  behind  restora- 
tion of  the  circulation  a)  because  of  the  presence  of  a 
nonoxidizable  metabolite,  or  b)  because  the  vessels 
simply  could  not  contract  fast  enought  to  keep  pace 
with  the  rapid  fall  of  the  concentration  of  some 
oxidizable  vasodilator  metabolite.  Further  work  is 
necessary  on  this  topic. 

Dornhorst  &  Whelan  (68)  showed  that,  after  a 
short  period  of  arrest  of  the  circulation  in  the  calf, 
the  rate  at  which  the  blood  flow  during  the  subse- 
quent reactive  hyperemia  returns  to  initial  levels  is 
exponential;  i.e.,  a  straight  line  is  obtained  when  log 
flow  is  plotted  against  time  (compare  fig.  24Z?).  The 
significance  of  this  fact  is  not  clear.  In  other  experi- 
ments, using  a  pressure  plethysmograph,  they  studied 
the  effect  on  reactive  hyperemia  of  reduction  of  the 


'376 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


100 


1  2  3 

Minutes 

fig.  2i.  Results  showing  that  after  circulatory  arrest 
(vertical  lines)  the  oxygen  saturation  in  the  venous  blood  rises  to 
above  the  initial  value.  Oxygen  consumption  (open  circles) 
returns  to  the  resting  level  more  quickly  than  the  blood  flow 
(filled  circles).  [From  McNeil  (148).] 

arterial  pressure.  The  resting  rate  of  flow,  post- 
ishemic peak  and  "area  under  curve"  or  "blood 
debt"  were  all  much  reduced,  but  this  was  not  so 
for  the  exponential  rate  of  restoration  of  the  flow. 
They  concluded  that  the  flow  could  not  depend  on 
the  local  concentration  of  some  metabolite,  the  re- 
moval of  which  depended  critically  on  the  rate  of  the 
blood  flow.  They  say  "the  facts  were  compatible  with 
the  concept  of  a  metabolite  diffusing  out  of  the  tissues 
with  a  concentration  gradient  which  effectively 
limits  its  rate  of  removal  when  the  blood  flow  is 
above  some  small  value,  or  of  a  metabolite  oxidized 
at  a  rate  dependent  on  its  concentration  and  inde- 
pendent of  the  local  oxygen  tension  when  this  ex- 
ceeds some  low  figure."  The  significance  of  this 
finding  is  not  yet  known.  Another  relevant  experi- 
ment was  performed  by  Blair  et  al.  (41).  They  studied 
the  blood  flow  in  the  forearm  after  5  min  circulatory 
arrest.  Coincident  with  the  release  of  the  circulation 
the  brachial  artery  was  compressed  digitally  for  5 
min  to  prevent  the  blood  flow  from  rising  above  the 
resting  level.  Release  of  the  artery  was  not  followed 
by  any  reactive  hyperemia.  They  concluded  that  it 
was  not  necessary  to  have  an  increase  in  blood  flow 
alter   circulatory    arrest    to   "repay"    the    "debt"    in- 


curred during  this  procedure.  It  would  be  interesting 
to  compare  the  oxygen  debt  incurred  during  the 
circulatory  arrest  with  the  subsequent  oxygen  repay- 
ment. So  far  as  I  am  aware  this  has  not  been  done, 
because  of  technical  difficulty.  [However,  see  (180).] 
It  is  certainly  worth  recalling  that  reactive  hy- 
peremia in  totally  denervated  forearms  is  just  as 
great  as  in  normal  ones  (72).  Indeed,  owing  to  the 
withering  of  the  muscles  the  response  per  100  ml  is 
far  greater  in  the  denervated  forearm.  Can  reactive 
hyperemia  be  due  to  ischemia  of  the  plain  muscle  of 
the  arterial  tree? 


EXERCISE    HYPEREMIA 

Active  muscles  must  get  oxygen  from  the  air.  To 
this  end  total  ventilation  increases,  heart  rate  is 
speeded  up,  and  muscle  blood  vessels  dilate.  We 
still  do  not  know  for  certain  the  mechanism  of  any 
of  these  responses.  The  hyperpnea  that  we  can  see 
and  the  tachycardia  that  we  can  feel  and  record  have 
attracted  more  attention  than  the  deeply  hidden 
dilatation  of  the  muscle  vessels.  We  still  seem  a  long 
way  from  understanding  the  cause  of  the  hyperemia 
of  exercise.  I  recall  some  sentences  of  my  father's. 
"Let  us  then  jot  down  such  information  as  is  forth- 
coming in  the  hope  that  the  points  at  issue  may  be 
taken  up  one  by  one  by  future  workers,  and  that  one 
day  systematic  work  may  be  done  on  the  subject. 
I  say  'jot  down'  rather  than  'put  together'  because 
to  make  any  sort  of  story  from  such  unsatisfactory 
material  would  be  quite  unwarrantable"  (30). 

Let  us  first  "jot  down"  some  points  about  the 
hypothesis  that  exercise  hyperemia  is  caused  by 
anoxia  of  the  vascular  tree.  It  is  certainlv  worth 
noting  that  the  rate  at  which  muscle  blood  vessels 
open  may  be  as  fast  after  simple  arrest  of  the  circu- 
lation as  during  exercise.  Eichna  &  Wilkins  (77) 
found  that  the  peak  forearm  flow  after  5  min  of  simple 
circulatory  arrest  was  as  large  as  that  after  5  min 
combined  circulatory  arrest  and  rhythmic  exercise. 
Dornhorst  &  Whelan  (68)  recorded  a  peak  flow  of 
about  20  ml  per  100  ml  calf  per  min  after  2  min 
ischemia;  after  2  min  rhythmic  exercise  the  same  post- 
exercise  peak  flow  was  recorded.  Hilton  (120)  noted 
that  the  flow  from  the  cat's  gastrocnemius  after  30 
sec  ischemia  was  the  same  as  that  after  30  sec  exercise. 
True,  the  mechanisms  of  ischemia  and  exercise  are 
not  really  comparable,  but  further  work  is  necessary 
to  see  if  ischemia  opens  the  vessels  as  fast  alone  as 
when   combined   with   exercise.    If  so,   we  must   ask 


CIRCULATION    IN    SKELETAL    MUSCLE 


'377 


whether  the  smooth  muscles  of  the  arterial  tree 
relax  simply  because  their  oxygen  is  taken  away 
by    the    active    skeletal    muscle    fibers. 

The  experiments  of  Kramer  and  his  colleagues 
(131-133,  160)  have  helped  a  great  deal  to  establish 
the  effect  of  exercise  on  the  circulation  and  metab- 
olism of  muscle.  The  dog's  gastrocnemius  muscle  was 
stimulated  indirectly  via  its  nerve.  The  rate  of  its 
venous  outflow  was  recorded  continuously  by  an 
optical  method  in  milliliters  per  minute  as  also  were 
the  arterial  blood  pressure  and  the  oxygen  saturations 
of  both  arterial  and  venous  blood;  in  some  experi- 
ments blood  lactate  was  estimated.  From  these,  the 
relations  between  work  done,  blood  flow,  oxygen 
consumption,  and  lactate  output  were  calculated. 
Figure  22  is  from  an  experiment  of  Kramer's  in 
which  the  sciatic  nerve  was  stimulated  maximally 
at  310  impulses  per  sec  for  1  sec  every  alternate  sec. 
The  findings  are  relevant: 

/)  At  the  beginning  of  exercise  venous  blood 
oxygen  tension  fell  abruptly  to  reach  a  "low"  after 
about  1  min.  Blood  flow  rose  exponentially  to  reach 
a  steady  value  in  about  1  min.  If  the  resting  vessels 
were  opened  wide  by  acetylcholine  then  oxygen 
usage  jumped  up  to  the  steady  state  as  soon  as  the 
exercise  began. 

These  facts  may  be  interpreted  as  follows.  As  soon 
as  exercise  begins  there  is  an  immediate  demand  for 
oxvgen,  the  supply  of  blood  being  quite  inadequate, 
tissue  oxygen  tension  falls  to  a  very  low  level.  This  is 
reflected  in  the  low  oxygen  saturation  of  the  venous 
blood,  and  possibly  also  in  the  gradual  relaxation 
of  the  plain  muscle  of  the  arterial  tree.  As  vasodilata- 
tion proceeds  and  oxygen  supply  improves  venous 
oxygen  saturation  rises  somewhat. 

2)  During  the  steady  state,  blood  flow,  work  done, 
and  rate  of  oxygen  consumption  are  linearly  related. 
This  is  seen  in  figure  23.  During  submaximal  exercises 
the  muscle  gets  all  the  oxygen  it  wants  (or  almost). 
Opening  the  vessels  still  more  with  acetylcholine 
does  not  increase  the  oxygen  consumption.  It  is  not 
clear  from  these  exeriments  whether  the  blood  flow 
was  linearly  related  to  the  decrease  in  venous  blood 
oxygen  tension.  It  seems  very  significant  indeed  that 
the  rate  of  the  blood  flow  is  linearly  related  to  the 
rate  of  oxygen  consumption.  Further  work  is  needed 
to  see  how  it  is  related  to  tissue  oxygen  tension. 

3)  Immediately  after  moderate  exercise  extra 
oxygen  usage  stops  in  a  muscle  the  vessels  of  which 
are  opened  maximally  with  acetylcholine.  When  the 
circulation  is  normal,  oxygen  consumption  and  blood 
flow  rapidly  subside  exponentially,  oxygen  consump- 


z 

o 

cr 

3 


%,    ARTERIAL 
VENOUS 


-10 
ML/MIN 


5 
Q 


□ 
O 

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MINUTES 
fig.  22.  Results  obtained  by  Kramer  and  his  colleagues. 
Top:  records  from  which  blood  flow,  oxygen  saturation,  and 
oxygen  consumption  were  obtained.  Rhythmic  stimulation 
between  the  vertical  lines.  Note  the  remarkable  rise  in  the 
venous  oxygen  saturation  after  the  end  of  exercise.  Bottom:  re- 
sults calculated  from  records  like  those  shown  above.  [After 
Kramer  et  at.  (132).] 

tion  falling  a  little  more  rapidly  than  blood  flow. 
The  behavior  of  the  venous  O2  saturation  is  interest- 
ing. Immediately  after  exercise  stops,  it  rises  tran- 
siently to  a  peak  and  then  subsides  again  to  a  low 
level  from  which  it  recovers  only  very  slowly.  The 
reason  for  the  immediate  postexercise  peak  may  be 
as  follows.  The  demand  for  oxygen  being  soon  satis- 
fied, the  arterial  tree  is  no  longer  anoxic  and  its 
plain  muscle  starts  to  contract.  But  the  rate  of  con- 
traction cannot  keep  pace  with  the  fall  off  in  demand 
for  O-i.  Hence  O2  saturation  rises.  It  is  not  clear 
why,  later  on,  the  postexercise  venous  blood  oxygen 
saturation  subsides  from  the  peak  to  a  level  almost 
as  low  as  in  exercise,  and  from  which  recovery  to  the 
pre-exercise  level  takes  place  only  very  gradually. 
Since  at  this  time  the  rate  of  the  blood  flow  is  de- 
creasing, it  is  plain  that  blood  flow  cannot  be  in- 
versely related  to  venous  blood  oxygen  tension.  To 
be  able  to  explain  this  odd  finding  would  be  to  gain 
much  insight  into  the  mechanism  of  exercise  hyper- 
emia. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


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WORK     PERFORMED    AS     °/c     MAXIMUM 

fig.  23.  Results  showing  that  blood  flow  and  oxygen  con- 
sumption in  the  dog's  gastrocnemius  muscle  were  proportional 
to  the  work  done  during  rhythmic  contraction.  [From  Kramer 
el  al.  (132).] 

So  much  for  Kramer's  experiments.  It  is  worth 
recalling  that  Barger  el  al.  (31)  in  their  experiments 
on  the  regulation  of  the  circulation  in  exercise  in 
the  normal  clog  also  concluded,  though  from  less 
direct  evidence,  that  muscle  blood  flow  and  oxygen 
consumption  were  directly  related. 

It  is  worth  noting  that  in  hyperthyroid  subjects 
the  postexercise  blood  flow  following  a  standard 
exercise  is  much  increased  (1).  Here  again  an  ex- 
planation might  take  us  to  the  very  center  of  the 
mechanism  of  exercise  hyperemia. 

But  now  we  must  "jot  down"  some  results  which 
make  it  difficult  to  picture  a  relationship  between 
tissue  oxygen  tension  and  blood  flow.  Let  us  begin 
with  experiments  by  Dornhorst  &  Whelan  (68). 
They  studied  the  effect  of  reduction  of  femoral  arterial 
blood  pressure  on  postexercise  hyperemia  in  the  calf 
muscles.  The  effective  arterial  pressure  could  be 
halved  by  means  of  a  pressure  plethysmograph. 
Figure  24  shows  a  typical  result.  After  the  arterial 
pressure  was  reduced  by  one-half,  the  postexercise 
hyperemia  flows  and  "blood  debt"  were  lowered  but 
the  hyperemia  was  not  prolonged.  The  changes  in 
the  peripheral   vascular  resistance   of  the  calf  were 


exactly  similar  to  those  found  in  the  limb  with  normal 
blood  pressure.  Thus,  if  postexercise  hyperemia 
depended  on  the  local  concentration  of  a  metabolite, 
its  removal  or  destruction  could  not  depend  on  the 
rate  of  blood  flow  nor  could  its  oxidation  depend  upon 
local  oxygen  tension.  They  concluded  that  for  post- 
exercise hyperemia,  as  for  reactive  hyperemia  (see 
above),  the  vasodilatation  could  be  due  to  an  intra- 
cellular metabolite  the  removal  of  which  from  the 
tissue  of  the  vessel  wall  is  limited  more  criticallv  by 
its  diffusion  gradient  than  by  the  rate  of  blood  flow 
through  the  vessel  lumen.  Such  a  metabolite,  they 
suggested,  would  be  deactivated  primarily  by  intra- 
cellular oxidation. 

Holling  &  Verel  (125)  studied  the  effect  of  lowering 
the  effective  arterial  pressure  on  the  forearm  blood 
flow.  Arterial  pressure  was  lowered  by  elevating  the 
forearm.  There  was  a  linear  relation  between  pressure 
and  flow.  Peripheral  vascular  resistance  did  not 
change.  Compensation  for  reduction  of  perfusion 
pressure  by  vasodilatation  did  not  occur.  Oxygen 
tension  in  the  elevated  forearm  was  reduced  as 
shown  by  the  polarograph,  but  oxygen  uptake  was 
unaltered  because  of  increased  utilization.  Their 
findings  did  not  support  the  concept  that  metabolism 
of  resting  muscle  played  a  prominent  role  in  the 
regulation  of  its  blood  flow.  In  line  with  this,  Blair 
et  al.  (40)  showed  that  compression  of  the  brachial 
arterv  for  5  min  beginning  at  the  end  of  1  min 
rhythmic  exercise  of  the  forearm  muscles  altogether 
abolished  postcontraction  hyperemia.  They  concluded 
that  it  was  not  necessary  to  have  an  increase  in  blood 
flow  after  exercise  to  "repay"  the  "debt"  incurred  in 
exercise.  This  agrees  with  their  observations  following 
postocclusive  (reactive)  hyperemia  (see  above). 
However,  by  supplying  the  tissues  with  an  excess  of 
blood,  postexercise  hyperemia  does  return  the  tissues 
to  the  resting  state  more  quickly  than  does  the  resting 
flow. 

If  oxygen  lack  of  the  arterial  tree  opens  the  vessels 
in  exercise,  then  asphyxiating  skeletal  muscle  should 
cause  hyperemia.  Bayliss  (34),  however,  found  that 
the  blood  flow  through  the  denervated  hind  limb 
did  not  alter  when  the  arterial  blood  was  made 
asphyxial.  Yerzar  (176)  studied  the  effect  of  ven- 
tilating the  cat  with  8  to  1  o  per  cent  oxygen  on  the 
gaseous  metabolism  of  the  gastrocnemius  muscle. 
Partial  asphyxia  of  the  muscle  greatly  reduced  its 
rate  of  oxygen  consumption  but  had  no  effect  on  the 
rate  of  the  blood  flow.  The  venous  blood  seldom 
became  less  than  30  per  cent  saturated  with  oxygen, 
nevertheless  tissue  oxvgen  tension  in  regions  farthest 


CIRCULATION    IN    SKELETAL    MUSCLE 


'379 


60  1 20       O  60 

TIME      IN      SECONDS 


I20 


fig.  24.  Results  showing  that  reduction  of  the  arterial  blood 
pressure  did  not  affect  the  resistance  changes  in  the  muscle 
vessels  of  the  calf  of  the  leg  after  exercise.  Solid  circles:  average 
of  1 2  runs  in  six  subjects  with  pressure  in  plethysmograph 
raised  67  cm  H;0.  Open  circles:  average  of  12  control  runs  on 
the  same  subjects.  A:  simple  scale;  B:  semilogarithmic  scale. 
[From  Dornhorst  &  Whelan  (68). j 

from  capillaries  could  not  have  been  far  from  zero. 
Others  have  found  that  venous  blood  from  exercising 
muscles  seldom  contains  less  than  6  vol  per  cent 
oxygen  (12,  31),  and  that  muscle  oxygen  tension 
may  be  very  low.  For  example,  during  tetanic 
stimulation  of  the  cat's  soleus  oxygen  saturation  of  the 
myoglobin  falls  from  90  to  50  per  cent  (152).  Rough- 
ton  has  kindly  told  me  that  this  corresponds  to  a  fall 
in  muscle  oxygen  tension  of  from  about  40  to  5  mm 
Hg  (F.  J.  W.  Roughton,  personal  communication). 
Ehrlich  (76)  too,  who  measured  the  reduction  of 
alizarin  blue,  found  that  muscles  reduce  very  ac- 
tively. 

But  what  about  the  effect  of  really  low  arterial 
blood  oxygen  tensions  on  muscle  flow?  The  trouble 
is  that  these  kill  the  heart.  It  is  true  that  Fleisch  el  a/. 
(86),  who  perfused  hind  legs  with  blood  artificially 
ventilated  with  3  per  cent  oxygen,  did  not  find  much 
dilator  effect.  But  their  preparation  had  lost  basal 
tone  and  was  probably  widely  dilated  before  the 
effect  of  rarefied  oxygen  was  tested.  Because  of  the 
damage  done  to  the  blood  of  the  cat  by  pumps  (91) 
the  experimenter  who  wishes  to  test  the  effect  on 
muscle  blood  flow  of  complete  reduction  of  the  blood 
is  faced  with  a  very  awkward  technical  problem.  In 
dogs  Guyton  ct  al.  (62)  recorded  some  vasodilatation 
in  the  hind  legs  when  the  oxygen  tension  of  the  blood 
perfusing  them  was  reduced  to  30  per  cent.  We  do 
badly  need  a  study  of  the  effect  on  muscle  blood  flow 
and  gaseous  metabolism  of  progressive  reduction 
in  02  tension  of  the  arterial   inflow  right  down  as 


far  as  zero.  It  will  be  recalled  that  Hilton  &  Eicholtz 
(124)  found  that  ventilating  the  animal  with  N2 
was  accompanied  by  a  large  increase  in  coronary 
blood  flow.  Results  have  not  yet  appeared  on  the 
effect  of  ventilating  the  animal  with  N2,  on  the  hy- 
peremia of  exercise,  nor  on  the  effect  on  the  hypere- 
mia of  exercise  of  reducing  arterial  oxygen  tension 
down  to  zero. 

So  much  for  oxygen  lack.  It  was  Gaskell's  (107) 
idea  that  muscle  blood  vessels  were  opened  by  vaso- 
dilator metabolites  liberated  from  the  skeletal  muscle 
fibers.  It  was  he  who  first  painted  the  arteries  of  the 
frog's  mylohyoid  with  1:10,000  lactic  acid  and  ob- 
served the  vasodilatation.  However,  lactic  acid  is 
probably  not  responsible  for  exercise  hyperemia. 
Exercise  is  accompanied  by  the  usual  hyperemia  in 
muscles  that  have  been  poisoned  with  moniodoacetic 
acid  to  prevent  the  formation  of  any  lactic  acid 
(112,  162).  Exercise  is  accompanied  by  hyperemia 
in  patients  whose  muscles,  owing  to  congenital 
absence  of  phosphorylase,  are  unable  to  form  lactic 
acid  (146,  170).  And  there  are  awkward  differences 
between   blood   flow   and   lactic   acid   time  relations 

(i33)- 

Fleisch   &   Sibul    (85)   found   that  neutral   lactate 

had  no  dilator  effect.  That  of  injected  lactic  acid 
they  thought  to  be  due  to  its  pH.  Other  substances 
which  caused  vasodilatation  in  concentrations  of 
Mo  to  *300  ml  Per  m'  blood  were  methylglyoxal, 
Na-pyroracemic  acid,  acetaldehyde,  acetates,  sodium 
acetoacetate,  salts  of  fatty  acids,  and  adenosine 
phosphate.  Their  actions  were  additive.  Fleisch  & 
Weger  (88)  investigated  the  action  of  fructose 
1  ,6-diphosphate,  dihydroxyacetaone  phosphate,  phos- 
phoglyceric  acid,  phosphopyruvic  acid,  phospho- 
glycerol,  and  creatine  phosphate  on  the  blood 
vessels  of  the  cat's  hind  leg.  All  were  inactive  or 
weakly  dilator.  However,  their  results  were  not  of 
much  quantitative  value  because  they  used  pump 
perfusion  and  worked  with  a  preparation  that  had 
lost  basal  tone. 

Gaskell  (107)  had  suggested  that  CO  2  might  be  a 
factor  and  while  Bayliss  (35)  showed  that  it  had  a 
vasodilator  action  Krogh  (134),  Fleisch  (86)  and 
others  have  shown  that  its  effect  is  too  weak  to  be  of 
much  significance. 

Fleisch  &  Sibul  (85)  thought  that  the  additive 
effect  of  carbohydrate  metabolites  might  be  con- 
siderable because  of  their  reduction  of  the  pH.  But 
Gollwitzer-Meier's  (112)  determinations  of  the  pH 
changes  in  the  venous  effluent  of  the  exercising 
gastrocnemius  of  the  dog  did  not  support  this  hypoth- 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


esis.  Moreover,  as  we  have  seen,  exercise  hyperemia 
occurs  in  muscles  poisoned  with  moniodoacetic  acid 
although  their  pH  probably  increases  (112). 

All  workers  are  agreed  as  to  the  great  vasodilator 
power  of  ATP  and  its  related  compounds  in  animals 
(88,  162,  171)  and  man  (70).  And  several  have  sug- 
gested that  it  is  concerned  with  exercise  hyperemia. 
In  fact  the  amount  of  ATP  in  muscle  is  probably- 
reduced  in  exercise  because  of  conversion  to  ADP. 
As  we  have  seen  the  rate  of  the  blood  flow  in  muscle 
closely  parallels  the  rate  of  its  oxygen  usage.  But  so 
far  as  I  know  there  is  no  relation  between  muscle 
02  consumption  and  the  rate  at  which  ATP  or  ADP 
leaks  out  of  the  muscle  fiber. 

Dawes  (65)  suggested  that  potassium  might  be 
partly  responsible  for  the  hyperemia  of  exercise.  This 
was  based  on  the  finding  that  intra-arterial  injection 
of  5000  ^g  of  potassium  into  the  pump-perfused 
muscles  of  the  dog's  hind  legs  caused  some  vasodilata- 
tion. Once  more  attention  is  being  focused  on  potas- 
sium. Kjellmar  (130)  found  that  postcontraction 
hyperemia  in  the  cat's  gastrocnemius  muscle  was 
accompanied  by  a  rise  in  the  potassium  concentra- 
tion in  the  venous  effluent.  Intra-arterial  infusions  of 
small  amounts  of  potassium  caused  vasodilatation. 
But,  and  this  is  important,  infusions  of  amounts  far 
bigger  than  those  found  during  exercise  cause  con- 
striction. Tetanus  of  the  cat's  muscle  during  the 
potassium-induced  constrictor  phase  was  no  longer 
followed  by  hyperemia,  although  injected  vaso- 
dilator agents  induced  vasodilator  responses.  This 
suggests  that  the  hyperemia  of  exercise  may  be  at 
least  partly  due  to  the  action  of  potassium  ions.  I  do 
not  know  whether  the  rate  at  which  K  leaves  the 
skeletal  muscle  fibers  is  related  to  their  rate  of  oxygen 
consumption.  We  have  seen  how  closely  blood  flow 
is  related  to  oxygen  consumption  and  to  the  work 
done. 

Anrep  and  others  (8,  9,  1 1 )  found  that  blood  from 
active  muscles  contained  histamine  and  that  during 
contraction  the  amount  of  histamine  in  muscle  di- 
minished. Fleisch  &  Weger  (87)  repeated  their 
experiments  and  concluded  that  the  loss  of  histamine 
was  due  to  the  fact  that  the  condition  of  the  animals 
had  deteriorated.  In  man,  active  muscles  do  not 
release  a  vasodilator  substance,  or  if  they  do  it  does 
not  survive  a  single  passage  through  the  lungs.  The 
performance  of  leg  exercise  is  not  accompanied  by 
any  change  in  the  vascular  resistance  of  the  nerve- 
blocked  forearm  (42). 

Bradykinin  has  recently  come  very  much   to  the 


lore.  Hilton  (123)  has  shown  that  it  is  not  implicated 
in  the  mechanism  of  exercise  hyperemia. 

In  exercise  muscle  blood  flow  may  increase  ten- 
fold. Peripheral  vascular  resistance  in  the  muscle 
must  have  fallen  to  one-tenth  of  its  normal  value  and 
the  principal  resistance  vessels,  usually  considered  to 
be  the  arterioles,  must  be  widely  dilated.  This  dilata- 
tion results  from  the  action  of  metabolites  produced 
either  in  the  arterial  tree  itself  or  in  the  surrounding 
skeletal  muscle  fibers  or  in  both.  The  question  arises, 
if  metabolites  from  the  skeletal  muscle  fibers  are 
involved,  by  what  mechanism  do  they  cause  relaxa- 
tion of  the  multilayered  arteriolar  plain  muscle 
coat?  The  following  points  seem  relevant: 

1)  It  is  not  hard  to  imagine  that  vasodilator 
metabolites  from  the  tissue  fluids  could  quickly 
diffuse  through  the  arteriolar  walls.  A  good  example 
of  diffusion  through  thick  tissues  is  that  of  a  dental 
anesthetic,  which  in  a  short  time  seeps  from  the  sub- 
cutaneous tissue  of  the  gum  through  the  maxillary 
bone  into  the  tooth  socket.  Diffusion  of  metabolites 
through  minute  arterioles  might  well  be  very  rapid 
indeed. 

2)  Schretzenmayr  (172)  made  the  curious  dis- 
covery that  contractions  of  the  skeletal  muscles  in  the 
lower  part  of  the  cat's  leg  are  followed  by  increase 
in  the  diameter  of  the  femoral  artery  in  the  inguinal 
region.  Figure  25  illustrates  this.  Since  this  increase 
in  diameter  was  not  abolished  by  denervation,  but 
was  by  painting  the  vessels  with  phenol,  he  thought 
that  it  must  be  an  axon  reflex  from  the  active  muscles 
to  the  arterial  walls.  Fleisch  (84)  confirmed  this  in 
the  dog  and  showed  that  intra-arterial  injections  of 
acetic    acid,    of    various    intermediary    products    of 


30  SEC 


fig.  25.  Exercise  of  the  leg  muscles  by  stimulation  of  the 
sciatic  nerve  (A,  between  the  arrows)  caused  dilatation  of  the 
femoral  artery  proximal  to  the  muscle.  After  curare  neither 
stimulation  of  the  sciatic  {B)  nor  of  the  muscle  (C)  had  any 
effect   on   the   diameter  of   the  femoral   artery.    [From   Hilton 

(122)-] 


CIRCULATION    IN    SKELETAL    MUSCLE 


I38. 


muscle  metabolism,  of  histamine  and  especially  of 
acetylcholine  all  were  followed  by  widening  of  the 
femoral  artery. 

Hilton  (121,  122)  compared  the  effects  of  a  variety 
of  drua;s  and  procedures  on  postcontraction  hyperemia 
and  on  the  postcontraction  dilatation  of  the  femoral 
artery.  The  actions  of  drugs  on  these  two  processes 
resembled  each  so  closely  as  to  suggest  strongly  that 
they  had  a  common  mechanism.  He  noted  also  that 
the  dilator  response  traveled  slowly  along  the  wall 
of  the  artery  at  about  10  cm  per  sec.  Intra-arterial 
injections  into  the  muscle  of  acetylcholine,  histamine, 
bradykinin,  and  nicotine  were  all  followed  by  intra- 
and  extramuscular  arterial  vasodilatation.   However 


intra-arterial  injection  of  ATP  causes  only  intra- 
muscular vasodilatation;  he  did  not  think  that  ATP 
could  be  concerned  with  the  dilator  response  which 
accompanies  muscular  contraction  (125). 

5)  D'Silva  &  Fouche  (69)  found  that  shunting 
the  blood  from  the  artery  to  the  vein  causes  widening 
of  the  artery  proximally.  They  think  that  the  dilata- 
tion of  the  artery  in  exercise  may  not  be  due  to 
metabolites  but  to  a  change  in  the  rate  of  flow. 

4)  It  seems  important  to  bear  in  mind  that  muscle 
blood  flow,  work  done,  and  oxygen  consumption  are 
closely  related,  though  we  do  not  understand  the 
nature  of  the  underlying  mechanism. 


REFERENCES 

1.  Abramson,  D.  I.,  and  S.  M.  Fierst.  Peripheral  vascular 
responses  to  exercise  in  the  hyperthyroid  state.  J.  Clin. 
Invest.  20:  517,  1941. 

2.  Abrahams,  V.  C,  and  S.  M.  Hilton.  Active  muscle 
vasodilatation  and  its  relation  to  'flight  and  fright' 
reactions  in  the  conscious  animal.  J.  Physiol..  London 
140:  16P,  1958. 

3.  Abrahams,  V.  C,  S.  M.  Hilton,  and  J.  L.  Malcolm. 
Sensory  input  to  the  hypothalamic  and  mesencephalic 
regions  subserving  the  defence  reaction.  J.  Physiol.,  London 
149:  45P,  1959. 

4.  Abrahams,  V.  C,  S.  M.  Hilton,  and  A.  Zbrozvna. 
Active  muscle  vasodilatation  elicited  by  mesencephalic 
stimulation.  Its  relation  to  the  defence  reaction.  J. 
Physiol.,  London  148:  32 P,  1959. 

5.  Allen,  W.  J.,  H.  Barcroft,  and  O.  G.  Edholm.  The 
action  of  adrenaline  on  the  blood  vessels  in  human 
skeletal  muscle.  J.  Physiol.,  London  105:  255,  1946. 

6.  Allwood,  M.  J.,  and  A.  F.  Cobbold.  Lactic  acid  release 
by  intra-arterial  adrenaline  infusions  before  and  after 
dibenyline,  and  its  relationship  to  blood  flow  changes  in 
the  human  forearm.  J.  Physiol.,  London  157:  328,  1961. 

7.  Allwood,  M.  J.,  and  J.  Ginsburg.  The  effect  of  dibeny- 
line on  the  vascular  response  to  the  sympathomimetic 
amines  in  the  forearm.  J.  Physiol.,  London  147:  57P,  1959- 

8.  Anrep,  G.  V.,  and  G.  S.  Barsoum.  Appearance  of 
histamine  in  the  venous  blood  during  muscular  con- 
traction. J.  Physiol.,  London  85:  409,  1935. 

9.  Anrep,  G  V.,  G.  S.  Barsoum,  M.  Talaat,  and  E. 
Wieninger.  Further  observations  on  the  release  of 
histamine    by    skeletal    muscles.    J.    Physiol.,    London    96: 

->4°.  '939- 

10.  Anrep,  G.  V.,  A.  Blalock,  and  A.  Samaan.  Effect  of 
muscular  contraction  upon  blood  flow  in  skeletal  muscle. 
Proc.  Roy.  Soc.,  London,  B.   114:  223,  1934. 

11.  Anrep,  G.  V.,  and  E.  von  Saalfeld.  The  blood  flow 
through  skeletal  muscle  in  relation  to  its  contraction.  J. 
Physiol.,  London  85:  375,  1935. 

12.  Assmussen,   E.   and  M.   Nielsen.   Cardiac  output  during 


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156.  Patterson,  G.  C.  The  role  of  intra-vascular  pressure  in 
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■949.  P-   >3- 


CHAPTER     41 


The  hepatic  circulation1 


STANLEY  E.  BRADLEY 


Department  of  Medicine,  Columbia  University  College  of  Physicians 
and  Surgeons,  and  Presbyterian  Hospital,  New  York  City 


CHAPTER    CONTENTS 

Anatomy 
Methodology 
Direct  Methods 

I  lepatic  and  splanchnic  blood  Hows 

Hepatic  and  splanchnic  blood  volumes 

Hepatic  and  splanchnic  blood  pressures 
Indirect  Methods 

Hepatic  blood  flow 

Splanchnic  blood  volume  and  transit  time 
Normal  Parameters  of  the  Hepatic  Circulation 
Hepatic  Blood  Flow 

Splanchnic  Vascular  Pressures  and  Resistances 
Splanchnic  Blood  Volume 
Primary  Determinants  of  Hepatic  Blood  Flow  and  Volume 
Cross  Section 

Path  Length  and  Distributional  Pattern 
Viscosity 

Volume  and  Distensibility 
Secondary    Determinants   of  Hepatic    Hemodynamic    Adjust- 
ments 
Neural  Determinants 
Neurohumoral  Determinants 

Epinephrine  and  norepinephrine 

Acetylcholine 

Autonomic  blockade 
Local  Biochemical  Determinants 

Oxygen 

Carbon  dioxide 

Histamine 
Physical  Determinants 

Intra-abdominal  pressure 

Gravity 

Respiration 

Exercise 


1  The  preparation  of  this  report  was  aided  by  a  grant  from 
The  Heart  and  Lung  Foundation,  New  York  City.  It  is  sub- 
mitted in  honor  of  Chester  S.  Keefer  and  the  Golden  Anni- 
versary of  the  Evans  Memorial  Department  of  Clinical  Re- 
search, Boston    Massachusetts. 


Hepatic  Circulatory  Integration  and  Dysfunction 
Hepatosystemic  Interrelationships 
Hepatosplanchnic  Interrelationships 


a  voluminous  literature  testifies  convincingly, 
and  sometimes  eloquently,  to  the  importance  of  the 
hepatic  circulation  in  the  body  economy  of  verte- 
brates. The  volume  and  composition  of  the  blood 
perfusing  the  liver  are  undoubtedly  major  deter- 
minants of  hepatocellular  function.  The  maintenance 
of  the  hepatic  parenchymal  "milieu  interieur"  with 
essential  nutrients  and  the  delivery  of  raw  materials 
from  the  gut  and  other  parts  of  the  body  to  the  liver 
for  processing  depends  directly  upon  the  blood 
supply.  In  even  the  lowest  vertebrates  the  liver  lies 
in  the  path  of  all  the  vessels  draining  the  splanchnic 
viscera,  thus  potentially  controlling  the  total  splanch- 
nic venous  outflow  (85).  The  splanchnic  vasculature 
as  a  whole  must  be  considered  therefore  an  integral 
part  of  the  hepatic  circulatory  system.  The  liver  is 
influential  in  affecting  general  cellular  metabolism 
and  homeostasis  only  to  the  extent  to  which  it  can 
modify  the  chemical  structure  of  the  blood  coming  to 
it.  A  copious  flow  of  blood  is  required  for  this  purpose 
and  the  resultant  anatomical  arrangements  and 
size  of  the  hepatic  vasculature  appear  to  confer  upon 
the  liver  an  important  place  in  cardiovascular  dy- 
namics. 

Quantitative  evaluation  of  the  circulatory  physiol- 
ogy of  the  liver  and  the  other  splanchnic  viscera  has 
proved  extremely  difficult  owing  to  the  inadequacies 
of  the  methods  available,  to  uncertainties  arising 
from  species  differences,  and  to  the  lack  of  data  ob- 
tained simultaneously  to  provide  information  regard- 
ing the  behavior  of  the  remainder  of  the  circulatory 


1387 


i388 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


system.  Measurements  of  cardiac  output  and  arterial 
blood  pressure  are  required  to  determine  whether 
changes  in  hepatic  hemodynamics  are  produced  by 
local  vasomotor  activity  or  by  passive  changes  in 
response  to  alterations  in  the  perfusing  pressure. 
Data  on  the  correlated  behavior  of  other  vascular 
beds  aid  also  in  delineating  the  mechanism  of  in- 
tegration and  in  placing  the  role  of  the  splanchnic 
bed  in  proper  perspective.  Responses  seem  to  differ 
between  the  various  vertebrate  species  either  because 
effective  drug  dosage  levels  and  the  intensities  of  the 
various  stimuli  used  are  not  comparable  or  because 
the  physiological  mechanisms  are  fundamentally 
dissimilar.  More  data  are  needed  to  determine  which 
of  these  alternatives  is  responsible  for  many  phenom- 
ena. Meanwhile,  interpretation  of  the  behavior  of 
the  hepatic  circulation  in  one  species  (in  man  for 
instance),  on  the  basis  of  the  known  behavior  in 
another  (such  as  dog)  must  be  made  with  caution. 
Methodology  is  a  major  stumbling  block.  Regardless 
of  species,  the  hepatic  circulation  is  difficult  to  ap- 
proach and  surgical  procedures  of  some  kind  are 
usually  necessary.  As  a  result  the  method  of  measure- 
ment may  modify  or  interfere  with  the  response 
under  study.  Coniinuous  observations  over  any  ex- 
tended period  or  repeated  examinations  at  long 
intervals  may  be  impossible  owing  to  deterioration 
of  the  preparation  or  to  the  ultimate  irreversible 
damaging  effects  of  mensuration  itself.  All  these  dif- 
ficulties may  be  laid  to  the  inaccessibility  and  com- 
plex   arrangement    of   the    hepatic    vasculature. 


ANATOMY 

Recent  investigations  have  contributed  impor- 
tantly in  characterizing  the  structural  patterns  of 
the  hepatic  vascular  inflow  and  outflow  systems. 
A  variety  of  techniques  has  been  employed.  The 
injection  of  plastic  masses  and  colored  materials  of 
various  kinds  into  the  hepatic  artery,  portal  vein, 
and  hepatic  veins  has  been  used  with  increasing  skill 
and  efficacy  (97,  120,  148,  205,  214).  Careful  re- 
constructions by  the  wax  plate  method  or  by  photo- 
graphic procedures  have  resulted  in  a  new  appraisal 
of  the  arrangement  of  minute  hepatic  vessels  relative 
to  the  parenchymal  cells.  Modern  methods  of  micro- 
dissection have  been  less  frequently  used,  but  direct 
observation  of  the  quartz-rod  transilluminated  liver 
in  living  animals  has  played  an  important  part  in 
providing  information  on  the  anatomy  and  behavior 
of  the  sinusoids  (185,  270,  299).  A  large  number  of 


careful  gross  dissections  of  the  splanchnic  vascular 
bed  has  resulted  in  more  reliable  statistical  data  on 
the  various  types  of  arrangements  of  the  hepatic 
artery  and  portal  vein  (120,  145,  214).  Although 
anatomical  facts  are  of  vital  importance  in  the  inter- 
pretation of  functional  data,  it  must  be  emphasized 
that  a  priori  inference  regarding  functional  signifi- 
cances on  the  basis  of  structure  alone  may  be  very 
hazardous. 

The  character  of  the  venous  and  arterial  inflow- 
tracts  is  particularly  susceptible  to  misinterpretation. 
The  cross  section  of  the  hepatic  artery  is  much  smaller 
than  that  of  the  portal  vein  in  a  ratio  of  approxi- 
mately one  to  five — suggesting  that  arterial  inflow 
is  roughly  one-fifth  of  the  portal  venous  inflow.  Since 
this  conclusion  has  found  some  justification  in  the 
measurement  of  blood  flows,  it  has  served  to  encour- 
age further  speculation.  Cross-sectional  area  alone  is 
not  a  good  indication  of  relative  flows  in  the  absence 
of  data  on  pressures  and  resistances,  and  it  is  not 
surprising,  therefore,  to  find  on  further  study  that 
the  only  generalization  regarding  the  relationship 
between  arterial  and  venous  inflow,  which  seems  per- 
missible at  present,  is  that  they  tend  to  show  a  degree 
of  reciprocity.  Anatomically  the  two  systems  differ 
greatly. 

The  portal  venous  system  drains  the  vascular  beds 
of  the  spleen,  pancreas,  stomach,  large  and  small 
intestines,  and  the  mesenteries.  Each  of  these  beds 
presents  certain  unique  features  that  cannot  be  dis- 
missed simply  because  they  are  not  immediately 
concerned  with  the  hepatic  circulation.  The  volume 
of  blood  flowing  into  the  portal  vein  and  the  pressure 
maintained  upon  the  blood  in  the  portal  vein  are 
determined  to  a  large  extent  by  the  resistances  to 
arterial  perfusion  within  each  of  these  portal  units. 
The  dynamics  of  portal  hepatic  inflow  are  therefore 
bound  up  intimately  with  the  behavior  of  extra- 
hepatic  splanchnic  circulation. 

The  arteries  giving  rise  to  the  extrahepatic  splanch- 
nic vasculature  include  a  large  array  of  major 
branches  that  spring  directly  from  the  aorta  or  from 
the  celiac  axis  in  a  rather  bewildering  variety  of 
patterns  recently  described  in  detail  by  several 
anatomists.  [See  (214)  for  survey.]  In  general 
there  is  an  abundance  of  collateral  anastomoses  out- 
side the  organs  supplied,  but  exceptions  to  this  tend- 
ency abound  and  surgeons  must  proceed  warily  in 
ligating  any  large  branch  without  prior  demon- 
stration of  the  area  of  supply. 

The  terminal  vessels  are  equally  diverse,  ranging 
from   the   well-muscled   end   arterioles    (penicilli)   in 


I  HE    Hl'.l'AHC    CIRCULATION 


'3^9 


the  spleen  to  the  thin  freely  anastomosing  mucosal 
arterioles  in  the  gastrointestinal  tract  (22,  39,  184, 
227,  317)-  It  seems  probable  that  the  major  point 
of  splanchnic  vascular  resistance  lies  in  these  vessels, 
but  arteriovenous  (A-V)  anastomoses  between  mu- 
cosal arteries  and  veins  appear  to  be  numerous. 
There  is  evidence  (22)  that  blood  may  be  diverted 
through  these  channels  principally  as  a  result  of 
changes  in  capillary  resistance  rather  than  active 
changes  in  A-V  cross  section. 

The  capillary  nets  that  drain  into  the  various  tribu- 
taries of  the  portal  vein  are  also  highly  variable.  In 
the  gastric  and  mesenteric  beds  (22,  317)  thorough- 
fare channels  (A-V)  may  provide  direct  routing  of 
blood  from  the  arterioles  to  the  venules,  the  degree 
of  capillary  filling  outside  the  A-V  capillary  depending 
upon  selective  "sphincteric"  action.  Similar  vessels 
have  been  described  in  the  spleen.  Here  the  capillary 
system  is  made  more  than  usually  complex  by  the 
presence  of  a  venous  sinusoidal  system  which  has 
been  the  cause  for  much  disagreement  (184,  227). 
The  presence  of  capillary  sphincters  and  A-V  channels 
elsewhere  also  remains  disputed,  since  it  is  possible 
that  the  phenomena  described  may  be  artifactitious. 
Muscular  tissue  is  not  obviously  present  in  the  capil- 
laries or  at  the  sites  of  the  so-called  "sphincters." 
Capillary  vasomotion  and  the  closure  of  sphincters 
may  therefore  be  attributable  to  changes  in  intra- 
luminal pressure  secondary  to  arteriolar  activity 
rather  than  local  contractions.  Capillary  nets  could 
contribute  importantly  to  frictional  resistance  through 
mechanisms  such  as  these,  but  further  anatomical 
investigation  is  necessary.  In  addition,  it  must  be 
shown  more  satisfactorily  that  the  manipulation  of 
tissues  prior  to  or  during  microscopic  examination 
is  not  responsible  for  the  changes  observed. 

The  portal  vein  enters  the  hilum  of  the  liver  in 
close  relationship  to  the  hepatic  artery  and  the 
emerging  common  bile  duct.  It  is  a  rather  weakly 
muscled  vessel,  most  of  the  muscle  fibers  being  ar- 
ranged longitudinally  with  a  sparse  coat  of  circular 
muscle  (65).  The  structure  of  the  portal  vein  sug- 
gests limited  distensibility  and  easy  collapsibility. 
Numerous  communications  between  the  portal 
vein  and  the  systemic  veins  have  been  demonstrated 
by  a  variety  of  techniques.  Edwards  (119)  has  shown 
(by  roentgenography  and  dissection  after  injection 
of  a  barium  sulfate  suspension  into  the  femoral  veins 
of  three  cadavers)  that  the  most  important  connec- 
tions are  to  be  found  in  man  at  the  retroperitoneal 
surfaces  of  the  abdominal  viscera,  in  the  pelvis, 
and   in   the  mediastinum.   Even  in  normal   persons, 


the  portal  system  fills  with  radiopaque  material 
introduced  in  this  way.  The  anastomoses  are  rela- 
tively small  and  are  probably  of  no  importance  in 
determining  portal  venous  pressure.  They  play  a 
more  prominent  role  when  portal  venous  inflow  is 
blocked.  In  dogs  and  other  vertebrates  in  which 
mesenteries  are  better  developed  than  in  man  such 
retroperitoneal  links  appear  to  be  lacking  (85). 

At  its  entrance  into  the  porta  hepatis,  the  portal 
vein  displays  a  relatively  uniform  and  constant  ar- 
rangement which  contrasts  sharply  with  the  dis- 
orderly configuration  of  the  hepatic  arterial  supply. 
According  to  Gilfillan  (145)  the  portal  vein  is  nearly 
always  formed  behind  the  head  of  the  pancreas  at  the 
level  of  the  second  lumbar  vertebra  by  the  union  of 
the  splenic  and  superior  mesenteric  veins  to  course 
directly  in  the  hepatoduodenal  ligament  to  the  hilum. 
The  hepatic  artery  (or  arteries),  on  the  other  hand, 
is  highly  variable  in  its  origin,  course,  anastomoses 
within  the  gastrohepatic  ligament,  and  relation  to 
the  portal  vein.  Within  the  liver,  the  venous  and 
arterial  inflow  tracts  assure  a  fairly  regular  pattern 
of  distribution  and  relationships.  At  the  hilum  the 
blood  vessels  and  bile  ducts  do  not  penetrate  the 
capsule  of  the  liver  but  are  carried  in  a  sheath  of 
connective  tissue  derived  from  it  which  accompanies 
them  in  all  their  ramifications  as  the  portal  tract. 
Recent  studies  of  vascular  casts  have  demonstrated 
that  the  external  fissuring  or  lobation  of  the  liver  is 
not  precisely  followed  by  the  vascular  and  ductal 
system  (173,  214).  Instead  the  vessels  are  distributed 
to  the  right  or  left  lobar  segments  which  are  sepa- 
rated by  an  avascular  sagittal  cleavage  plane  inter- 
secting the  visceral  surface  of  the  liver  along  a  line 
drawn  from  the  fossa  of  the  inferior  vena  cava  through 
the  gallbladder.  These  "vascular  lobes"  are  divided 
into  segments  which  are  distinct  and  easily  separable 
in  plastic  corrosion  casts.  Communications  between 
the  right  and  left  hepatic  arteries  or  between  their 
branches  may  be  found  within  the  liver  (148)  but 
appear  to  be  uncommon,  at  least  in  man  (84,  205). 
The  portal  venous  system  appears  to  have  a  similar 
and  parallel  arrangement  with  even  fewer  intra- 
hepatic anastomoses. 

The  finer  branches  of  the  portal  vein  and  hepatic 
artery  communicate  indirectly  through  a  capillary 
network  which  appears  to  furnish  the  blood  supply 
to  the  bile  duct  and  other  tissues  in  the  portal  tract 
(97,  120,  148,  185,  205,  214,  270,  299).  The  small 
hepatic  artery  lies  close  to  the  portal  vein  in  all  the 
vertebrate  species  studied.  Arterioportal  anastomoses 
resembling  rungs  of  a  ladder  have  been  described  by 


'39° 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


some  workers  (185,  270,  299) — and  denied  by  others 
(84) — in  the  frog,  rat,  mouse,  rabbit,  and  guinea 
pig  (not  in  the  cat  or  man)  close  to  the  terminal 
arborizations  in  the  portal  tract.  Three-dimensional 
reconstruction  studies  on  the  basis  of  injections  of 
dyes  or  colloids  by  a  large  number  of  workers  now 
seem  to  warrant  the  view  that  terminal  branches  of 
the  hepatic  arteries  as  well  as  of  the  portal  vein 
give  rise  to  the  sinusoids  in  various  mammals  and 
amphibia  (84,  97,  102,  120,  148,  185,  205,  214,  270, 
299).  It  is  possible  that  these  findings  apply  in  general 
to  most  vertebrates  but  additional  studies  of  the 
comparative  anatomy  of  the  finer  hepatic  vessels  are 
needed.  The  axial  vein  in  the  portal  space  appears  to 
give  rise  to  smaller  radicles  which  then  course  paral- 
lel to  the  parent  vessel,  usually  in  the  same  direction, 
giving  off  branches  that  penetrate  a  so-called  "'limit- 
ing plate"  of  parenchymal  cells  to  enter  the  sinusoids. 
Small  branches  leading  directly  into  the  sinusoid 
may  also  spring  from  the  axial  portal  vein.  The  capil- 
lary network  fed  by  the  hepatic  arterioles  gives  rise 
to  the  sinusoids  and  by  its  link  to  the  portal  vein 
provides  an  arterioportal  anastomosis  through  which 
the  portal  venous  distribution  may  be  supplied  by 
the  arterial  inflow;  or  the  reverse  could  occur.  It  is 
difficult  to  be  certain  in  the  welter  of  conflicting 
claims,  but  it  does  seem  likely  that  the  sinusoids  con- 
stitute the  most  important  region  of  terminal  ar- 
teriolar distribution  rather  than  the  portal  tract  and 
supporting  tissues.  The  hepatic  arterioles  may  join 
the  terminal  portal  veins  where  they  enter  the  sinus- 
oids, or  they  may  enter  the  sinusoids  directly  at  any 
point  between  the  portal  tract  and  the  central  veins 
The  junction  of  the  arterial  and  portal  venous  streams, 
therefore,  apparently  occurs  chiefly  (if  not  entirely) 
under  most  circumstances  at  or  within  the  sinusoid 
and  perhaps  to  some  extent  within  the  capillary  net- 
work in  the  portal  tracts.  At  this  level  the  vessels 
appear  to  have  very  thin  walls  containing  little  if 
any  muscle  tissue.  Sphincters  are  described  at  the 
point  of  entry  into  the  sinusoid  because  closure  of 
the  vessels  in  a  manner  suggesting  sphincteric  action 
has  been  observed  microscopically  in  transilluminated 
livers  of  living  animals.  Apparently  muscular  sphinc- 
ters have  not  been  detected  by  histological  techniques. 
The  point  of  emergence  of  a  small  capillary  from  a 
larger  muscular  arteriole  in  the  portal  space  has 
been  construed  by  Elias  (120)  as  a  sphincter.  Certainly 
distinct  muscular  sphincters  do  not  seem  to  be  demon- 
strable  within    the    sinusoidal    system   proper. 

The  structure  of  the  hepatic  lobule  and  the  rela- 
tionship between  the  parenchyma  and  the  capillaries 


or  sinusoids  has  long  been  the  subject  of  spirited 
discussion,  and  disagreement  that  is  not  yet  settled. 
In  recent  years,  Elias  and  his  associates  have  taken 
issue  with  the  view  that  the  liver  is  a  complex  tubular 
gland  modified  by  extensive  coalescence  and  reorga- 
nization to  form  a  tightly  packed  mesh  of  cells  bathed 
on  all  sides  by  the  blood  in  the  sinusoids.  They  have 
called  attention  to  the  dominance  of  long  rows  of 
cells,  one  cell  thick,  in  sections  of  mammalian  livers 
and  the  paucity  of  cylindrical  cross  sections  such  as 
one  might  expect  in  a  tubular  organ.  Careful  three- 
dimensional  reconstructions  indicate  that  the  liver 
may  be  considered  a  cell  mass  penetrated  by  a  net- 
work of  tubular  sinusoids  separated  by  interconnect- 
ing cellular  sheets  or  plates,  one  cell  thick  in  mammals 
and  certain  birds,  usually  two  cells  thick  in  all  other 
vertebrates.  A  tubular  layer  of  parenchymal  cells 
encloses  the  portal  tracts  as  a  limiting  plate  which  is 
pierced  by  the  terminal  branches  of  the  portal  vein 
and  hepatic  artery.  The  limiting  plate  can  be  traced 
along  the  tract  to  the  surface  of  the  liver  where  it 
passes  out  to  lie  under  the  capsule.  There  may  be 
several  such  subcapsular  (seemingly  concentric) 
limiting  plates  or  none.  The  openings  into  the  central 
vein  are  so  numerous  that  a  clear-cut  limiting  plate  is 
not  demonstrable  but  a  similar  lamina  does  appear 
about  the  sublobular  vein  and  layer  branches  of  the 
hepatic  veins.  These  studies  have  not  definitely  ruled 
out  the  possibility  that  the  liver  is  basically  a  closely 
conglutinated  tubular  structure  in  lower  forms,  with 
flattening  and  realignment  of  the  cells  into  single 
cell  layers  in  the  mammals.  Indeed,  a  tubular  con- 
struction is  demonstrable  when  increased  sinusoidal 
pressure  increases  the  spaces  between  the  laminae 
and  seems  to  fragment  them  (121).  Rappaport 
(237)  and  his  associates  have  attributed  the  usual 
microscopic  picture  to  the  character  of  the  basic 
hepatic  unit  which  they  believe  to  be  an  "irregular 
berry-like  parenchymal  mass  situated  around  the 
trio  of  terminal  branches  of  portal  vein,  hepatic 
artery,  and  bile  duct,  growing  out  from  a  small  portal 
triad  and  mainly  running  perpendicularly  to  the 
central  vein.  The  hepatic  unit  occupies  adjacent 
parts  of  neighboring  hexagonal  fields  and  extends 
from  the  central  vein  of  one  hexagon  to  the  central 
vein  of  another."  All  sections  of  such  a  structure 
would  tend  to  be  tangential  and  would,  they  claim, 
yield  a  preponderance  of  longitudinal  sections. 

Regardless  of  the  ultimate  outcome  of  this  argu- 
ment it  is  evident  that  sinusoids  are  cylindrical  or 
saccular  vessels  closely  encased  in  a  kind  of  highly 
flexible   plastic   sheathing   that  must   operate   to   in- 


THE    HEPATIC    CIRCULATION 


[39' 


flucnce  their  behavior.  They  radiate  from  the  portal 
tracts  and  converge  upon  the  central  veins,  produc- 
ing the  appearance  in  section  of  hexagonal  "lobules" 
that  are  centered  upon  the  central  vein.  This  appear- 
ance is  apparently  attributable  to  the  degree  of  filling 
of  the  peripheral  vessels  between  the  portal  tracts, 
since  it  has  been  shown  that  elevation  of  hepatic 
venous  pressure  or  reduction  in  portal  venous  pres- 
sure changes  the  configuration  of  the  lobule  to  one 
centered  upon  the  portal  tracts  as  a  result  of  relative 
distension  of  the  vessels  running  between  the  central 
veins  (121).  The  walls  of  the  sinusoids  are  composed 
of  thin  endothelial  cells,  possibly  [as  Knisely  et  al. 
(185)  claim]  all  capable  of  active  phagocystosis, 
though  this  question  is  not  yet  settled.  There  is  no 
evidence  of  muscular  tissue  and  the  endothelium  is 
usually  closely  attached  to  the  parenchymal  cells.  A 
narrow  perisinusoidal  fluid-filled  (plasma?)  space 
(Disse)  observed  on  many  occasions  by  light  micros- 
copy has  been  clearly  delineated  by  the  electron 
microscope  (30,  126,  i6g).  Numerous  relatively 
large  fenestrations  in  the  sinusoidal  endothelium 
may  permit  the  plasma  to  come  into  direct  contact 
with  the  hepatic  cells.  Both  luminal  and  the  canalic- 
ular surfaces  of  the  parenchymal  cells  are  markedly 
increased  by  folds  and  microvilli.  The  space  between 
the  endothelium  and  the  polygonal  cells  is  apparently 
no  greater  than  0.5/1  and  it  may  be  filled  with  an 
amorphous  material  resembling  basement  mem- 
brane rather  than  plasma.  Since  the  extravascular 
space  is  so  narrow,  the  sinusoidal  closure  must  in- 
volve displacement  and  apposition  of  the  surrounding 
cell  plates. 

The  hepatic  venous  drainage  system  begins  in  the 
colander-like  thin-walled  central  veins  that  empty 
into  the  muscular  sublobular  veins.  In  certain  re- 
spects the  central  veins  appear  to  be  passive  sumps 
not  strictly  separable  from  the  parenchyma  and  not 
unlike  a  large  receiving  sinusoid.  Opening  and 
closure  of  sinusoids  at  the  point  of  entry  into  the 
central  vein  have  been  described  by  workers  using 
transillumination  techniques  (186),  but  definite 
structural  evidence  of  muscular  sphincters  seems  to  be 
lacking.  In  contrast  the  muscle  coats  of  the  "sub- 
lobular" and  other  hepatic  veins  appear  to  be  en- 
tirely adequate  for  this  purpose.  Gibson  (143)  finds 
that  sinusoids  empty  only  into  the  central  veins  al- 
though Deysach  (107)  has  claimed  that  sinusoids 
may  occasionally  enter  the  larger  hepatic  venules 
directly  as  "sluice  channels"  which  may  bypass  the 
central  venous  sumps.  Gibson  believes  these  vessels 
are  really  central  veins  and  he  agrees  with  Deysach 


in  viewing  the  point  of  passage  through  the  thick 
muscular  wall  as  a  site  at  which  contraction  could 
interfere  with  flow.  In  the  dog,  contraction  of  the 
musculature  can  throw  the  large  as  well  as  the  small 
hepatic  veins  into  corrugated  folds  that  could  con- 
ceivably block  outflow  completely  (287).  The  extent 
of  this  musculature  appears  to  vary  greatly  in  dif- 
ferent species,  but  it  appears  to  be  weak  and  rela- 
tively unimportant  in  man  (132,  143).  The  dis- 
tribution of  the  hepatic  veins  and  their  tributaries 
results  in  an  intimate  interdigitation  with  the  system 
of  portal  tracts.  The  finer  radicles  course  at  acute 
angles  or  perpendicular  to  the  portal  tracts  from 
which  they  are  derived.  There  is  no  evidence  of  seg- 
mentation or  lobation  as  there  is  in  the  arrangement 
of  the  portal  tracts.  Except  in  animals  with  deeply 
fissured  and  lobated  livers,  the  hepatic  veins  freely 
cross  the  "avascular  plane"  separating  the  hepatic 
segments  to  bind  the  liver  into  a  single  vascular  mass. 
The  system  empties  into  the  inferior  vena  cava  by 
three  or  more  terminal  branches  just  below  the  dia- 
phragm or  within  the  "caval  tunnel"  where  the  in- 
ferior vena  cava  is  closely  applied  to  or  incorporated 
in  the  posterior  surface  of  the  liver.  In  certain  species 
(notably  the  dog  and  diving  mammals)  the  muscular 
coat  of  the  hepatic  vein  becomes  more  prominent 
and  forms  a  sphincteric  ring  at  the  orifice  into  the 
vena  cava.  The  preponderance  of  the  inferior  portion 
of  the  ring  may  serve  as  a  "sling"  to  pull  up  the  lower 
lip  of  the  opening  into  a  valvelike  ridge. 

A  lymphatic  drainage  system  runs  parallel  to  the 
vascular  inflow  and  outflow  tracts,  to  communicate 
at  the  hilum  and  at  the  junction  of  the  hepatic  veins 
and  inferior  vena  cava  with  larger  trunks  that  ul- 
timately carry  the  lymph  through  the  local  lymph 
nodes  to  the  cisterna  chyli  or  thoracic  duct  (85).  A 
rich  network  of  lymph  vessels  lies  about  and  within 
the  walls  of  the  draining  vessels  and  beneath  the 
capsule  of  the  liver,  but  there  is  little  evidence  for 
lymphatic  capillaries  within  the  parenchyma.  It  is 
possible  that  the  perisinusoidal  space  is  the  terminus  a 
quo  of  the  lymphatics.  A  more  definite  point  lies  in 
fluid-filled  spaces,  the  so-called  spaces  of  Mall, 
found  in  close  proximity  to  the  portal  tracts,  between 
the  limiting  plate  and  the  connective  tissue  making 
up  the  bulk  of  the  tract.  Arrangements  of  cells  and 
channels  resembling  very  small  lymph  nodes  are 
described  or  pictured  at  many  points  within  these 
nets  and  a  rich  lymphopoietic  layer  is  found  beneath 
the  capsule  of  the  liver  in  some  of  the  lower  verte- 
brates. Erythropoietic  tissue  may  also  occur  in  adult 


1 392 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


forms,  though  it  is  usually  more  prominent  in  fetal 
livers  (120). 

The  liver  is  a  remarkably  malleable  organ,  the 
adjoining  organs  molding  its  surface  and  determining 
its  shape.  Changes  in  the  filling  of  the  stomach  in  the 
dog,  for  example,  induce  considerable  alteration  in 
the  configuration  of  the  portion  of  the  liver  lying  in 
contact  with  it.  The  influence  of  these  deformations 
on  the  local  hepatic  circulation  does  not  seem  to 
have  been  studied.  It  is  likely  that  only  the  more 
superficial  parts  of  the  liver  are  involved  and  that 
resistance  to  flow  is  increased  in  the  compressed 
regions.  The  liver  appears  to  be  equally  plastic 
when  interference  with  outflow,  as  in  congestive 
heart  failure,  results  in  an  elevation  in  vascular  dis- 
tending pressures.  Presumably  the  marked  hepatic 
enlargement  involves  stretching  of  lamellae,  canalic- 
uli,  and  the  connective  tissue  framework  (121). 
To  what  extent  the  distortion  affects  the  degree  and 
distribution  of  resistance  to  blood  flow  remains  un- 
determined. Certainly,  if  the  distortion  is  long  main- 
tained, persistent  change  in  architecture  occurs  and 
fibrosis  develops. 


METHODOLOGY 

The  structure  and  location  of  the  hepatic  vascular 
bed  and  its  tributaries  indicate  at  once  the  physical 
difficulties  of  quantitative  evaluation  of  hepatic 
hemodynamics  and  the  variety  of  measurements 
required.  Among  the  latter  the  following  appear  to 
be  particularly  important:  a)  determination  of  the 
minute  volumes  of  blood  flowing  into  and  out  of  the 
liver,  including  flows  through  the  various  compo- 
nents of  the  splanchnic  bed;  b)  measurement  of  the 
volume  of  blood  within  the  hepatic  vascular  bed  and 
the  contributory  vessels  of  the  splanchnic  viscera; 
and  c)  measurement  of  the  blood  pressure  in  the 
arteries,  the  hepatic  veins,  and  at  the  points  of  junc- 
tion between  the  different  streams  in  the  portal  vein 
and  the  sinusoids.  Given  these  data,  a  complete 
analysis  of  the  local  determinants  of  flow  and  integra- 
tion is  possible.  Until  recently,  most  hepatic  hemo- 
dynamic parameters  have  been  measurable  only  by  a 
direct  approach  invoking  considerable  traumatic 
manipulation  and  interference  with  normal  function. 
Various  indirect  methods  are  now  under  study  in 
many  laboratories  which  appear  to  provide  a  means  of 
measuring  local  blood  pressure  and  hepatoportal 
blood  flows  and  volumes  in  intact  animals  and  man 
without  operation  or  anesthesia. 


Dirrct  Methods 

HEPATIC    AND    SPLANCHNIC    BLOOD    FLOWS.    Blood    flow 

through  the  hepatic  artery,  the  portal  vein,  and  he- 
patic veins  has  been  measured  directly  in  experimental 
animals  for  many  years  by  a  number  of  devices.  The 
Ludwig  stromuhr  has  been  replaced  by  the  thermo- 
stromuhr  and  more  recently  by  the  rotameter  and 
other  types  of  flowmeter  (67).  These  methods  re- 
quire isolation  of  the  artery  or  vein  for  insertion  or 
application  of  the  measuring  device.  Additional 
surgery  is  required  to  obtain  a  value  for  hepatic 
venous  outflow  by  difference  between  the  flows 
through  the  inferior  vena  cava  above  and  below  the 
entry  of  the  hepatic  veins  or  as  the  retrograde  flow 
through  the  inferior  vena  cava  (above  the  renal 
veins)  after  ligation  at  the  level  of  the  diaphragm. 
Trauma,  anesthesia,  manipulation,  hemorrhage,  and 
loss  through  collateral  channels  all  contribute  to 
the  errors  inherent  in  these  procedures.  Nevertheless, 
they  possess  the  great  advantage  of  the  direct  ap- 
proach. 

The  so-called  "collection  methods"  are  equally 
direct  but  somewhat  easier  to  use  and  more  accurate, 
at  least  with  respect  to  the  measurement  of  hepatic 
venous  outflow  and  portal  venous  inflow.  Here  the 
outflow  is  collected,  rapidly  measured,  and  then 
returned  to  the  systemic  circulation.  Thus,  portal 
venous  inflow  may  be  measured  as  the  outflow  from 
the  severed  splenic  vein  following  splenectomy  and 
temporary  occlusion  of  the  portal  vein  close  to  the 
liver  (204).  Blalock  &  Mason  (35)  introduced  under 
local  anesthesia  a  blind  brass  cannula  with  lateral 
openings  via  the  right  external  jugular  vein  of  the 
dog,  the  superior  vena  cava,  and  right  atrium  into 
the  inferior  vena  cava  where  balloons  affixed  to  the 
cannula  could  be  inflated  temporarily  at  points  above 
and  below  the  entry  of  the  hepatic  veins  during 
withdrawal  of  the  total  venous  outflow.  More  re- 
cently, Selkurt  (264)  has  measured  hepatic  venous 
outflow  in  dogs  by  a  similar  technique  after  shunting 
blood  from  the  hind  portions  of  the  animal  via  an 
external  circuit  from  the  femoral  veins  to  an  external 
jugular  vein,  with  ligation  of  the  inferior  vena  cava 
below  the  hepatic  veins,  and  collection  of  hepatic 
venous  blood  from  above  by  a  special  cannula. 
Although  this  method  requires  general  anesthesia 
and  abdominal  surgery,  inclusion  of  blood  from  the 
lower  portion  of  the  vena  cava  is  avoided  and  a  period 
of  complete  obstruction  of  flow  from  the  hind  por- 
tions, with  attendant  circulatory  disturbances,  is 
circumvented. 


THE    HEPATIC    CIRCULATION 


'393 


Changes  in  local  blood  flow  and  velocity  may  be 
detected  by  instruments  recently  developed  upon  the 
principle  of  the  "thermostromuhr."  Grayson  (155) 
and  his  associates  have  used  a  tiny  copper-constantan 
thermocouple  and  heating  wire  implanted  in  the 
liver  for  this  purpose.  The  measured  loss  of  heat  to 
the  tissues  appears  to  be  a  linear  function  of  tissue 
thermal  conductivity  and  blood  flow.  The  first  of 
these  variables  may  be  determined  as  a  constant  for 
each  liver  after  cessation  of  circulation;  changes  in  the 
second  can  then  be  computed  in  percentage  terms 
from  changes  in  conductivity.  The  unit  may  be  left 
in  place  indefinitely  and  measurements  made  as 
desired  after  healing  of  the  wound  through  which  the 
leads  emerge.  Movement  of  blood  can  be  assessed 
only  in  a  collar  of  tissue  approximately  0.5  cm  long 
and  0.3  cm  in  diameter  within  the  immediate  vicin- 
itv  of  the  embedded  thermocouple.  Although  total 
flow  cannot  be  measured,  the  instruments  provide  a 
satisfactory  means  of  following  either  acute  or  chronic 
adjustments  in  small  animals.  A  somewhat  similar 
device  has  been  introduced  by  Grabner  &  Neumayr 
(151 )  for  the  purpose  of  estimating  blood  flow  through 
a  hepatic  vein.  A  tiny  thermistor  affixed  to  the  tip 
of  a  Cournand  catheter  is  heated  several  degrees 
above  the  temperature  of  the  blood  after  insertion 
into  an  hepatic  vein.  Any  change  in  temperature  of 
the  element  is  directly  related  to  a  change  in  the 
velocity  of  the  blood  flow  in  the  immediate  vicinity 
of  the  ''pickup,"  or  to  the  actual  volume  of  flow  if 
the  calibre  of  the  vein  is  constant.  Movements  of 
the  catheter  tip  with  respiration,  reversal  in  the 
direction  of  flow,  scar  formation,  proximity  of  large 
vessels,  and  changes  in  hepatic  blood  temperatures 
may  jeopardize  the  validity  and  usefulness  of  the 
method,  but  it  does  possess  the  advantage  of  detecting 
rapid  and  transient  alterations. 

The  transillumination  method  (185,  270,  299), 
discussed  above  in  connection  with  the  delineation 
of  the  finer  anatomy  of  the  liver,  has  proved  valuable 
in  defining  the  character  of  blood  flow  through  the 
terminal  radicles  of  the  hepatic  artery  and  portal 
vein.  The  technique  invokes  careful  exposure  of  the 
liver  in  anesthetized  or  pithed  animals  with  as  little 
trauma  and  blood  loss  as  possible.  A  quartz  rod, 
provided  with  a  conduit  through  which  warm  Ring- 
er's solution  may  bathe  the  tissue  examined,  must 
be  inserted  under  the  edge  of  the  liver.  The  liver 
edge  transilluminated  by  light  conducted  through 
the  quartz  rod  may  then  be  examined  microscopi- 
cally at  high  magnification.  Respiratory  movements 
of  the  liver  can  be  prevented  in  the  anesthetized  ani- 


mals by  the  introduction  of  100  per  cent  oxygen 
through  a  catheter  placed  in  the  trachea.  Fluores- 
cence microscopy  and  transillumination  with  ultra- 
violet light  following  injection  of  fluorescent  materials 
permit  somewhat  better  visualization  of  the  blood 
stream  within  the  sinusoids  and  of  the  movement  of 
the  materials  from  the  blood  into  the  parenchymal 
cells  and  bile  canaliculi  (153).  Dyes  and  particulate 
substances  have  been  used  similarly  to  follow  flow  in 
visible  light.  The  conditions  under  which  observations 
must  be  made  are  obviously  unphysiologic  and  limit 
the  extent  to  which  generalizations  may  be  adduced. 
Local  extraneous  factors  such  as  changes  in  tissue 
tension,  the  direct  effects  of  immobilizing  and  han- 
dling the  liver,  the  influence  of  foreign  materials  and 
fluids  within  the  abdominal  cavity,  as  well  as  the 
effects  of  anesthesia,  prolonged  immobilization  of 
the  body  in  an  abnormal  position,  and  the  limited 
area  available  to  study  combine  to  make  interpreta- 
tions most  uncertain.  When  considered  in  relation 
to  information  obtained  by  other  methods,  however, 
studies  of  the  transilluminated  liver  may  be  most 
helpful  and  revealing. 

Studies  of  the  perfusability  of  the  isolated  liver 
have  also  contributed  to  the  knowledge  of  the  he- 
patic circulation,  though  here  again  interpretation  in 
terms  of  the  intact  animal  and  the  circulatory  system 
as  a  whole  must  be  made  with  caution.  The  prepara- 
tion of  the  liver  in  investigations  of  this  kind  has 
varied  widely.  At  one  extreme  the  liver  is  handled 
with  greatest  care  to  avoid  prolonged  interruption 
of  blood  flow  either  by  perfusing  the  liver  in  situ  or 
by  rapid  transfer  from  the  living  animal  to  the  per- 
fusion apparatus  where  it  is  maintained  under  con- 
ditions as  closely  as  possible  approximating  those 
in  situ  (10,  25,  61,  83,  277).  The  contributions  of  the 
arterial  and  venous  inflow  to  total  outflow,  the 
character  of  intrahepatic  adjustments,  and  the  re- 
sponse to  an  array  of  controlled  pressure-flow  states 
impossible  to  impose  in  the  intact  animal  may  be 
precisely  evaluated  in  the  isolated  perfused  liver. 
Techniques  have  steadily  improved  with  the  de- 
velopment of  more  effective  anticoagulation,  oxy- 
genation, and  surgery.  At  the  other  extreme,  the 
liver  is  removed  at  a  varying  time  after  death  and 
perfused  with  different  foreign  substances,  ranging 
from  saline  to  kerosene  (1 1 1 ).  Intrahepatic  resistances 
and  the  interplay  of  the  inflow  systems  at  different 
pressures  have  been  evaluated  by  this  means.  Kero- 
sene oil  has  been  used  by  Dock  ( 1 1 1 )  because  it  is 
confined  to  the  vascular  channels  and  does  not  dif- 
fuse, as  saline  solutions  do,  into  extravascular  tissues 


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CIRCULATION    II 


to  interfere  with  perfusability.  As  noted  above,  the 
injection  of  colored  plastic  semisolid  substances  aids 
in  defining  functional  relationships  between  vascular 
structures  as  well  as  their  anatomic  arrangements. 
The  extent  to  which  streams  of  different  color  inter- 
mingle or  fill  a  given  portion  of  the  vascular  bed 
points  to  dynamic  relations  that  may  be  important 
in  life. 

Radiopaque  injection  masses  have  been  used  in 
both  living  and  "dead-'  livers  in  order  to  visualize 
the  vascular  tree  by  X  ray  (22,  84,  148).  Daniel  & 
Prichard  (102)  have  used  microangiography  to 
study  portal  venous  flow  in  rats,  cats,  guinea  pigs, 
rabbits,  and  goats.  Contrast  substance  is  injected 
rapidly  into  an  omental  or  intestinal  vein  and  serial 
radiographs  taken  thereafter  at  a  rate  of  one  or  two 
per  sec  over  a  9-  to  1 2-sec  period  or  motion  pictures  by 
high-speed  cinefluorography  (144).  The  dispersion 
of  the  radiopaque  material  in  the  blood  stream,  the 
distribution  of  portal  inflow  to  the  hepatic  segments, 
and  the  time  of  blood  movement  may  be  determined 
graphically  in  this  manner.  Although  there  are  ob- 
vious drawbacks  (anesthesia,  immobilization,  the 
presence  of  a  foreign  material  in  very  high  concen- 
tration, and  manipulation  of  the  gut),  certain  hemo- 
dynamic effects  can  be  examined  only  by  this  method. 

Radiographic  methods  of  studying  the  portal 
venous  system  have  also  proved  of  value  diagnosti- 
cally.  Roentgenograms  taken  at  the  operating  table 
immediately  after  injection  of  a  concentrated  solution 
of  Diodrast  (85)  (70% — 12  to  40  ml,  depending  on 
the  size  of  the  patient)  or  Urokon  (70% — in  similar 
dosage)  into  a  tributary  of  the  portal  vein  have  been 
helpful  in  determining  the  extent  of  collateral  cir- 
culation or  the  point  of  venous  obstruction  in  patients 
with  portal  venous  hypertension.  Percutaneous 
splenoportal  venography  (15,  314)  permits  visualiza- 
tion of  the  splenic  and  portal  veins  in  anesthetized 
patients  and,  when  rapid  serial  radiography  is  em- 
ployed, the  character  of  blood  flow  and  vascular 
filling  can  be  made  out.  Diodrast  or  Urokon  may  be 
injected  directly  into  the  spleen  through  a  long  17- 
or  18-gauge  needle  that  is  inserted  through  the  skin 
under  local  anesthesia.  In  most  patients,  subjected 
to  this  procedure,  the  spleen  is  palpable  and  the 
needle  may  be  placed  obliquely  into  the  body  of  the 
spleen,  or  it  may  be  introduced  through  the  ninth 
intercostal  space  at  the  midaxillary  or  posterior 
axillary  line.  The  contrast  substance  leaves  the  spleen 
almost  at  once  and  may  be  detected  radiographically 
within  one  or  two  seconds  in  the  portal  vein  and  its 
branches.    The    procedure    is    somewhat    hazardous, 


since  intraperitoneal  bleeding  often  occurs  and 
splenic  infarcts  may  develop.  Severe  hemorrhage  has 
been  reported. 

Of  even  greater  potential  danger  is  a  new  variant 
of  the  technique  of  splenoportal  venography  de- 
scribed by  Bierman  and  his  associates  (32),  who 
introduce  a  needle  through  the  liver  into  the  portal 
vein.  However,  they  report  that  no  serious  complica- 
tions developed  following  or  in  the  course  of  1 44 
transhepatic  portal  venipunctures  in  73  seriously 
ill  patients.  Under  local  anesthesia,  while  the  patient 
holds  his  breath,  they  insert  a  special  large-gauge 
styletted  needle  at  a  point  1  cm  below  the  xiphoid 
process  and  1  cm  to  the  right  of  the  midline  to  a  depth 
of  12  cm.  The  obturator  is  then  removed  and  the 
needle  is  slowly  withdrawn  during  application  of 
gentle  suction  until  there  is  free  flow  of  blood,  indi- 
cating that  the  laterally  placed  orifice  lies  in  a  vessel. 
A  small  ureteral  catheter  or  polyethylene  tubing 
may  be  threaded  through  the  needle  into  the  vein 
and  left  in  place  for  a  prolonged  period  after  the 
needle  has  been  withdrawn.  A  contrast  medium 
such  as  Diodrast,  Urokon,  or  Neo-Iopax  (sodium 
acetrizoate,  iodopyracet,  or  sodium  iodomethamate) 
may  be  injected  through  the  needle  or  catheter. 
In  a  number  of  instances,  the  hepatic  vein,  inferior 
vena  cava,  or  hepatic  artery  have  been  visualized. 
Zeid  ft  al.  (314)  have  had  a  similar  experience.  A 
more  recent  development  which  employs  the  costal 
intra-osseous  route  appears  to  be  considerably  safer 
(262).  The  injection  of  contrast  material  directly 
into  the  medullary  cavity  of  a  lower  rib  results  in 
visualization  of  veins  in  the  vertebral,  intercostal, 
azygos,  and  hemiazygos  drainage  system.  In  con- 
tradistinction to  splenoportal  venography,  which 
reveals  portal  collateral  channels  in  the  presence  of 
portal  hypertension,  intraosseous  venography  permits 
detection  of  systemic   venous  collaterals. 

HEPATIC  AND  SPLANCHNIC  BLOOD  VOLUMES.  The  vol- 
ume of  blood  in  the  liver  and  the  splanchnic  bed 
may  also  be  estimated  by  radiographic  and  injection 
techniques.  The  relative  mass  of  the  hepatic  vascula- 
ture has  been  evaluated  qualitatively  from  veno- 
grams and  arteriograms,  and  from  the  volume  of 
plastic  casts  of  vascular  tree.  Measurement  of  the 
liver  opacified  by  contrast  medium  or  delineated 
after  inflation  of  the  stomach  or  colon  with  gas  is  also 
theoretically  possible  (300).  Changes  in  the  size  of 
the  spleen  have  been  followed  radiographically 
(20)  and  interpreted  in  terms  of  displacement  or 
filling  with  blood.  Unfortunately,  the  extent  of  vascu- 


THE    HEPATIC    CIRCULATION 


'395 


lar  filling  by  contrast  substance  or  injection  mass  is 
most  uncertain,  and  the  assumptions  required  in  esti- 
mating volume  from  X-ray  shadows  are  of  dubious 
validity.  Nevertheless,  further  exploration  in  this 
direction  may  prove  fruitful. 

Changes  in  the  volume  of  spleen  and  liver  may  be 
more  accurately  measured  plethysmographically  in 
animals,  but  the  fixation  of  the  organ  and  the  sur- 
gical handling  required  seriously  impair  the  validity 
of  the  values  obtained  (132).  These  devices  permit  a 
rough  estimation  of  engorgement  or  disgorgement  of 
the  liver  during  vascular  adjustments,  but  they 
provide  no  information  on  the  absolute  volume  of 
blood  in  the  liver.  The  same  difficulties  are  encoun- 
tered in  studies  of  the  volume  or  weight  of  the  iso- 
lated liver  (10,  25,  61,  203)  or  spleen  (163,  287). 
Measurement  of  the  volume  of  blood  retained  in  or 
expelled  from  the  liver  or  splanchnic  bed  as  a  whole 
may  also  be  made  on  the  basis  of  the  difference  in 
blood  inflow  and  outflow  during  a  period  of  shifting 
volume. 

It  has  proved  extremely  difficult,  also,  to  deter- 
mine the  absolute  volume  of  blood  in  the  liver  or 
spleen  and  their  tributaries  by  the  direct  approach. 
With  excision,  blood  runs  off  into  the  systemic  veins 
and  is  lost.  Surgery  in  living  animals,  with  care  to 
block  inflow  and  outflow  tracts  simultaneously  and 
to  avoid  trauma  that  might  induce  physiologic  re- 
distribution of  blood,  is  required  to  obtain  reliable 
values.  The  quantity  of  blood  may  then  be  evaluated 
by  extraction  of  hemoglobin  and  calculation  of  blood 
volume  from  the  hematocrit  of  arterial  blood.  A 
serious  difficulty  arises  at  this  point  because  the  hema- 
tocrit in  the  capillaries  and  sinusoids  may  differ 
greatly  from  that  in  large  vessels.  Radioisotope  label- 
ing of  plasma  (I131-labeled  human  serum  albumin, 
Cr51  tagging  of  plasma  proteins,  T-1824  bound  to 
plasma  proteins)  and  of  red  cells  (P3'2,  Cr51)  has  proved 
helpful  in  surmounting  this  obstacle.  Recovery  of 
the  isotope  is  relatively  easy  and  blood  volume  can 
be  calculated  on  the  basis  of  the  radioactivity  per 
unit  volume  of  arterial  plasma  and  red  cells.  Allow- 
ance must  be  made  for  the  possible  uptake  of  radio- 
isotope by  the  liver  cells  or  lymph.  Though  these 
jmethods  (106,  175,  181)  provide  approximate  values 
for  hepatic  blood  volume  in  steady  states,  changes  in 
the  same  animals  cannot  be  obtained. 

HEPATIC  AND  SPLANCHNIC  BLOOD  PRESSURES.  Blood  pres- 
sure has  been  measured  directly  in  the  intra-abdominal 
veins  after  laparotomy  in  animals  and  man  (85). 
Opening  the  abdomen  may  bring  about  changes  in 


pressure  gradients  independently  of  the  effects  of 
anesthesia  and  surgery,  but  on  the  whole  these 
measurements  are  acceptable  and  revealing,  par- 
ticularly when  analyzed  in  terms  of  simultaneous 
measurements  of  arterial  pressure  and  blood  flow. 
Pressure  measurements  may  be  made  in  unanes- 
thetized  subjects  by  percutaneous  splenic  or  hepatic 
puncture  (15,  17,  32).  Atkinson  &  Sherlock  (17) 
found  a  statistically  linear  correlation  between  intra- 
splenic  pressure  and  portal  venous  pressure  over  a 
wide  range  in  24  patients.  With  transhepatic  punc- 
ture of  the  portal  vein  (32)  reliable  records  may  be 
obtained  that  possess  an  advantage  over  intrasplenic 
pressure  tracings  in  showing  phasic  or  respiratory 
fluctuations  that  are  damped  out  in  the  splenic 
pulp  spaces.  Portal  venous  pressure  has  also  been 
estimated  on  the  basis  of  pressure  in  large  readily 
accessible  collateral  veins  in  the  abdominal  wall  of 
patients  with  portal  venous  obstruction.  Though 
this  approach  may  yield  valid  figures  for  the  subject 
under  study,  it  is  not  feasible  in  the  normal  and 
does  not  yield  values  of  general  application.  Care 
must  be  taken  to  refer  all  values  to  the  same  reference 
plane,  preferably  at  the  level  of  the  right  atrium 
determined  radiologically.  Many  workers  use  a  level 
5  cm  posterior  to  the  angle  of  Louis  as  the  reference 
plane  in  human  subjects;  and  in  general  this  is  quite 
satisfactory,  though  it  appears  to  be  a  less  dependable 
guide  to  the  level  of  the  right  atrium  than  the  plane 
10  cm  anterior  to  the  back  (246).  Changes  in  pressure 
are  usually  of  particular  interest  and  the  importance 
of  the  zero  reference  plane  is  not  often  stressed,  since 
the  accuracy  of  pressure  differences  is  not  affected 
by  it.  When  absolute  values  obtained  by  different 
groups  of  workers  are  compared,  however,  apparent 
discrepancies  are  encountered  that  may  be  due  to 
inexact  definition  of  the  reference  point. 

The  development  of  venous  catheterization  tech- 
niques by  Cournand,  Richards,  and  their  associates 
(98,  246)  has  opened  up  a  new  approach  to  the  study 
of  intravascular  pressures.  The  insertion  of  a  long 
radiopaque  ureteral  catheter  deep  into  the  venous 
system  under  fluoroscopic  control  is  atraumatic,  rela- 
tively simple,  and  safe.  The  catheter  is  introduced 
under  local  anesthesia  into  a  vein  in  the  antecubital 
fossa  (preferably  lying  at  the  medial  aspect)  in  human 
subjects  and  into  a  jugular  vein  in  dogs.  It  is  then 
threaded  into  the  right  atrium  and  inferior  vena  cava. 
A  curved  tip  makes  manipulation  and  control  of 
direction  possible  but  at  the  same  time  interferes 
with  passage,  since  it  may  cause  the  catheter  to  move 
in    unintended    directions   or    to   catch    at    valvelike 


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shelves,  such  as  the  Eustachian  "valve"  in  the  right 
atrium  at  the  point  of  entry  of  the  inferior  vena  cava. 
With  experience  it  is  usually  possible  to  maneuver 
the  catheter  tip  past  these  obstacles  and  into  the  de- 
sired vessel.  Human  subjects  can  assist  in  this  opera- 
tion by  making  voluntary  movements  of  the  arms, 
shoulders,  neck,  and  trunk  or  by  deep  breath  holding, 
thus  shortening,  lengthening,  or  straightening  the 
venous  channels  in  accommodating  the  passage  of 
the  catheters.  Untrained  dogs  must  be  anesthetized 
and  external  movement  of  the  body  employed  as  an 
aid.  Rappaport  (77)  has  described  a  device  for 
"guided  catheterization"  which  can  be  used  to  bend 
the  tip  of  the  catheter  after  it  is  placed  close  to  the 
orifices  of  the  hepatic  veins.  The  angulation  obtain- 
able permits  catheterization  of  an  hepatic  vein  from 
below,  an  approach  which  is  impossible  with  the 
Cournand  catheter  owing  to  the  relatively  fixed 
obtuse  angle  of  its  tip.  In  at  least  1000  catheterizations 
of  the  hepatic  veins  in  man  in  several  laboratories 
not  a  single  fatality  has  occurred  despite  the  fact 
that  many  subjects  were  seriously  ill.  This  good 
record  is  undoubtedly  attributable  to  the  fact  that 
the  right  heart  is  not  entered  and  thus  a  dangerous 
source  of  arrhythmia  is  avoided.  The  use  of  a  rela- 
tively soft  catheter  is  advisable  even  though  it  makes 
manipulation  more  difficult.  Excessive  buckling  or 
coiling  should  be  guarded  against,  since  knots  can 
be  tied  in  the  catheter.  Indeed,  a  knot  in  a  catheter 
which  included  the  chorda  tendinae  of  the  tricuspid 
valve  has  been  observed  in  the  dog.  The  procedure  is 
therefore  not  without  hazard  and  should  always  be 
used  cautiously  with  the  catheter  under  direct  ob- 
servation throughout.  In  man,  a  vein  draining  the 
right  lobe  is  easiest  to  enter;  in  the  dog,  a  vein  drain- 
ing the  left  lobe.  Since  these  lobes  are  the  largest 
hepatic  lobes  in  man  and  dog,  the  catheter  can  be 
inserted  to  a  depth  that  permits  reliable  measure- 
ments   of   intrahepatic    venous    pressure. 

Taylor  &  Myers  (286)  have  shown  that  thrusting 
the  catheter  deep  into  the  liver  and  obstructing  the 
hepatic  vein  provides  a  means  of  measuring  portal 
venous  pressure.  Occlusion  is  assured  by  introducing 
the  catheter  until  it  buckles  slightly  within  the  he- 
patic vein.  The  '"occluded  hepatic  venous  pressure" 
theoretically  reflects  the  pressure  transmitted  from 
the  portal  vein  or  venules  through  a  stationary  column 
of  blood  extending  from  the  tip  of  the  catheter.  The 
outflow  tract  obstructed  is  probably  quite  large, 
presumably  consisting  of  a  "wedge"  of  convergent 
hepatic  venules,  sublobular  veins,  and  sinusoids  into 
which    both    hepatic    arterioles    and    portal    venules 


empty.  The  hepatic  venous  "end  pressures"  therefore 
may  mirror  the  mean  pressure  attained  when  flows 
into  and  out  of  the  obstructed  area  have  reached 
equilibrium  and  may  more  closely  approximate 
sinusoidal  pressures  than  portal  venous  pressure. 
The  small  gradient  of  pressure  between  the  portal 
vein  and  the  sinusoids  probably  accounts  for  the  good 
agreement  with  the  portal  venous  and  intrasplenic 
pressures  reported  by  a  number  of  workers  (76,  135, 
244)- 

Indirect  Methods 

Hepatic  venous  catheterization  has  also  proved  of 
major  importance  in  the  development  of  indirect 
methods  for  the  appraisal  of  the  hepatic  circulation. 
Accurate  measurement  of  changes  in  the  blood  as  it 
passes  through  the  liver  makes  it  possible  to  apply 
the  Fick  principle  in  the  estimation  of  flow,  to  study 
hepatic  clearances,  and  to  follow  the  dilution  of 
isotopes  within  the  splanchnic  blood  volume.  Since 
hepatic  blood  flow  and  hepatic  arteriovenous  dif- 
ferences can  be  determined  simultaneously,  hepatic 
removal  of  various  substances  from  the  blood  can 
be  subjected  to  analysis.  Under  appropriate  condi- 
tions maximal  hepatocellular  activity  can  be  em- 
ployed as  a  means  of  approximating  the  mass  of 
tissue  perfused  by  blood  in  order  to  permit  more 
precise  definition  of  ischemia,  hyperemia,  and  re- 
distribution. On  the  basis  of  such  analyses,  more 
sophisticated  clearance  techniques  have  been  de- 
veloped that  may  circumvent  venous  catheterization. 
The  blood  volume  in  the  splanchnic  bed  and  the 
distribution  of  flow  and  volume  have  been  adduced 
from  studies  of  the  time  required  for  the  movement  of 
tracers  such  as  I131  human  serum  albumin  across  the 
splanchnic  bed,  in  relation  to  flow.  These  approaches 
have  been  opened  up  in  the  past  15  years  and  are 
already  yielding  a  rich  harvest  of  new  information 
regarding  hepatic  hemodynamics. 

hepatic  blood  flow.  The  hepatic  blood  flow  can  be 
estimated  indirectly  by  three  somewhat  different 
methods.  In  one  the  total  quantity  of  some  substance 
removed  from  or  added  to  the  blood  each  minute 
by  the  liver  is  determined  and  divided  by  the  hepatic 
arteriovenous  concentration  difference,  i.e.,  the 
amount  removed  from  or  added  to  each  milliliter 
of  blood  perfusing  the  liver.  In  a  second  procedure, 
the  percentile  disappearance  of  some  substance 
more  or  less  completely  cleared  from  the  blood  per- 
fusing  the  liver  is  measured  and  hepatic  blood  flow 


THE    HEPATIC    CIRCULATION 


1397 


computed  as  that  percentage  of  the  blood  volume. 
And,  finally,  flow  may  be  estimated  from  the  extent 
of  dilution  of  a  known  quantity  of  some  tracer  by 
total  outflow  during;  a  measured  period  of  time. 
Obviously,  the  validity  of  all  measurements  depends 
upon  a  number  of  assumptions  which  are  difficult 
to  verify.  Nevertheless,  suitable  test  substances  have 
been  found  and  adequate  evidence  of  reliability  has 
been  forthcoming  to  warrant  qualified  acceptance 
of  much  of  the  data  set  out  in  the  literature. 

Clearance  and  extraction  techniques.  A  variety  of  dye- 
stuffs  has  been  employed  in  the  development  of  con- 
stant infusion  clearance  and  extraction  techniques 
beginning  with  bromosulfophthalein  (BSP  or  Brom- 
sulfalein)  in  1945  (49),  and  more  recently  employing 
tetrachlor-tetraiodo-fluorescein  (rose  bengal)  (258), 
and  a  tricarbocyanine  dye,  indocyanine  green  (238, 
304).  The  hepatic  removal  of  these  substances  can  be 
estimated  with  reasonable  accuracy  from  the  rate  of 
infusion  if  it  may  be  assumed  that  a)  disappearance 
from  the  blood  depends  solely  upon  hepatic  ex- 
traction, and  b)  changes  in  plasma  concentration 
can  be  taken  into  account  simply  by  multiplying 
the  change  in  concentration  (AP)  by  the  plasma  vol- 
ume (PV).  Subtracting  (rising  level)  or  adding 
(falling  level)  this  product  (in  milligrams  per  min- 
ute) and  the  infusion  rate  yields  a  value  for  hepatic 
removal.  The  hepatic  arteriovenous  difference  is 
measured  as  the  difference  between  concentrations 
in  samples  of  blood  obtained  from  a  peripheral  artery 
and  an  hepatic  vein  at  the  same  time.  As  a  rule  these 
values  are  derived  by  interpolation  at  the  midpoint 
between  successive  samples  in  order  to  allow  for 
simultaneous  correction  for  changing  levels.  A 
number  of  additional  assumptions  must  be  made  in 
accepting  this  procedure  including  c)  that  a  sample 
of  blood  from  any  hepatic  vein  is  representative  of 
the  total  mixed  hepatic  venous  drainage;  and  d)  that 
the  presence  of  the  catheter  does  not  affect  represent- 
ative sampling.  Numerous  thoroughgoing  investi- 
gations have  elucidated  each  step  and  in  doing  so 
have  contributed  importantly  to  knowledge  of  hepa- 
tocellular function. 

All  these  agents  are  apparently  transferred  from 
blood  to  bile  by  fundamentally  similar  mechanisms. 
The  character  of  BSP  removal  has  been  the  most  in- 
tensively studied  but  the  data  available  on  rose  bengal 
and  indocyanine  green  suggest  that  they  move  by  the 
same  pathways,  since  indocyanine  green  interferes 
with  hepatic  uptake  of  BSP  (304)  and  BSP  with 
uptake  of  rose  bengal  (177,  212).  Considerable  evi- 
dence (45,  59,  75,   177,  212,  305,  306,  312)  supports 


the  view  that  BSP  is  removed  from  the  blood  by  a 
dual  mechanism  that  involves  a)  accumulation  or 
"storage"  of  the  dye  within  the  polygonal  cells  in  a 
higher  concentration  than  in  the  plasma,  and  b) 
transfer  by  a  limited  transport  system  from  plasma  to 
bile.  Analysis  of  the  biochemical  mechanisms  of 
further  subsidiary  processes  and  of  the  physiological 
concomitants  is  far  from  completion,  but  it  seems  not 
unlikely  that  both  storage  and  transfer  require  energy 
expenditure  and  depend  upon  enzymatic  catalysis. 
Uptake  into  storage  apparently  proceeds  only  when 
the  plasma  concentration  is  rising  and  for  a  period 
after  stabilization  until  equilibration  is  complete. 
Whether  BSP  moves  into  the  bile  only  from  the  so- 
called  "storage  space,"  directly  from  the  blood  to  the 
bile  canaliculi,  or  by  both  routes  remains  unsettled. 
Rose  bengal  appears  to  be  handled  in  much  the  same 
fashion  and  may  indeed  be  visualized  by  fluorescent 
microscopy  as  it  accumulates  in  high  concentration 
within  the  parenchymal  cells.  Intercellular  accumula- 
tion of  indocyanine  green  has  not  been  proved  but 
seems  probable  in  view  of  the  rapidity  with  which  it 
disappears  from  the  blood  relative  to  its  output  in 
the  bile  (304).  The  limit  imposed  upon  removal  by 
the  transfer  maximum  or  Tm-  results  in  reduced 
extraction  by  the  liver  as  arterial  plasma  concentra- 
tions rise  and  makes  it  preferable  to  maintain  levels 
close  to  1  or  2  mg  per  cent  in  order  to  assure  suffi- 
ciently large  differences  between  peripheral  and 
hepatic  venous  concentration  for  accurate  measure- 
ments. Even  at  higher  levels,  however,  hepatic 
removal  accounts  almost  exclusively  for  the  disap- 
pearance of  these  substances  from  the  blood. 

Considerable  confusion  has  resulted  from  failure 
to  use  such  words  as  "removal,"  "extraction,"  and 
"recovery"  with  precision.  "Removal"  may  be 
defined  either  as  the  amount  of  dye  removed  from 
the  blood  each  minute  (the  usage  employed  in  this 

2  Unfortunately  the  term  Lm  has  been  applied  by  Mason 
et  al.  (208)  to  maximal  hepatic  removal  of  BSP.  Maximal 
transfer  is  determined  by  liver  mass  and  the  abbreviation, 
Lm,  is,  therefore,  justified  to  some  extent.  Nevertheless,  trans- 
fer is  a  functional  phenomenon  that  may  be  affected  without 
change  in  liver  mass  by  substances  competing  for  the  same 
system,  by  various  inhibitors  (such  as  deoxycholic  acid  or 
Benemid  in  the  case  of  BSP),  and  by  fever  or  hepatic  disorders 
(74,  306).  For  this  reason  use  of  "Tm"  to  refer  to  the  "transfer 
maximum"  seems  preferable  and  in  keeping  with  usage  in 
other  fields  (280).  Of  even  greater  importance  is  the  fact  that 
Lm  as  determined  by  Mason  (208)  and  others  6285,  295) 
includes  movements  of  dye  into  storage  as  well  as  transfer 
from  blood  to  bile.  Hence  in  referring  to  a  more  discrete  (albeit 
complex  and  multifarious)  activity  Tm  appears  to  be  the  more 
suitable  term. 


i398 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


paper)  or  as  the  total  amount  which  has  appeared 
in   the   bile  over  a   period   of  time — usually  several 
hours  and  usually  expressed  as  a  percentage  of  the 
total    dose    administered.    The    latter    is    also    often 
referred  to  as  "recovery"  but  may  be  confused  with 
"extraction,"   a   term  correctly  applied   to  the  per- 
centage  of  dye   removed   from   the    blood   perfusing 
liver  and  calculated  as  the  ratio  between  the  arterial- 
hepatic    venous    concentration    difference    and    the 
peripheral  arterial  or  venous  concentration.  Hepatic 
extraction  must  be  computed  on  the  assumption  that 
the  arterial  concentration  is  a  measure  of  the  concen- 
tration in  the  blood  perfusing  the  liver  by  way  of  both 
the  hepatic  artery  and  portal  vein  from  which  ex- 
traction has  occurred  to  account  for  the  concentra- 
tion  found    in    the   hepatic   venous   blood.    For   this 
reason  due  allowance  must  be  made  for  splanchnic 
circulation  time  when  rapid  changes  are  occurring. 
Perhaps  the  most  serious  confusion  has  arisen  in 
discussions  of  extrahepatic  removal  of  BSP.  When  the 
plasma  level  was  maintained  at  a  constant  level  in 
the  dog  at  about  i  mg  per  cent,  the  extraction  of  BSP 
averaged  34  ±  (sd)  12  per  cent  (282),  in  association 
with  removal  rates  of  from  0.57  to  i.g8  mg  per  min. 
No  more  and  usually  much  less  than  10  per  cent  of 
the  amount  removed  per  minute  could  be  ascribed 
to  extrahepatic   loss,   when   direct   measurements  of 
hepatic  uptake  of  BSP  were  made  in  the  anesthetized 
dog  (41,  305).  Following  hepatectomy,  however,  the 
plasma  level  may  fall  by  25  or  35  per  cent  from  a  level 
of  1   mg  per  cent   1    hour  after  a  single  intravenous 
dose,   an  observation  which  has  been  claimed    (87, 
88,   302)   to  indicate  a   proportionately  large  extra- 
hepatic contribution  to  removal.  The  confusion  here 
stems  from  comparing  two  fundamentally  different 
removals;  one,  the  percentage  of  the  total  removal 
rate  per  minute  attributable  to  extrahepatic  tissues; 
the  other,  the  percentage  change  in  plasma  concen- 
tration over  the  course  of  1   hour.  If  the  dog's  circu- 
lating plasma  volume  following  hepatectomy  can  be 
taken  as  800  ml,  then  a  30  per  cent  fall  in  BSP  from  a 
concentration  of  1.0  mg  per  cent  to  0.7  mg  per  cent 
in  the  course  of  1    hour  would  entail  a  total  loss  of 
2.4  mg  or  0.04  mg  of  BSP  per  min,  approximately  5 
per  cent  of  the  expected  removal  of  1 .0  mg  per  min. 
This  figure  does  not  differ  greatly   from  those  ob- 
tained  by  direct  measurement  and   it  may  be  con- 
cluded that  extrahepatic  loss  is  negligible  under  most 
circumstances.  The  failure  to  escape  from  the  vascu- 
lature may  be  attributed  to  the  fact  that  all  three 
dyes   are   almost  completely   bound    by   the   plasma 
proteins    (49,    258,    304).    Neither    rose  bengal  nor 


indocyanine  green  enters  the  urine  (258,  304), 
whereas  Bromsulfalein  is  excreted  by  the  kidney  in 
amounts  equaling  0.06  to  2.0  per  cent  of  the  total 
dose  (49,  60,  88,  220,  232,  275,  311).  Since  disap- 
pearance from  the  blood  depends,  therefore,  almost 
exclusively  upon  the  liver,  hepatic  removal  per  minute 
may  be  computed  from  the  rate  of  infusion  (plus  or 
minus,  respectively,  the  amount  removed  from  or 
added  to  the  plasma  volume,  i.e.,  AP  X  PV).  This 
conclusion  is  not  vitiated  by  failure  to  "recover" 
more  than  60  to  80  per  cent  of  a  dose  of  BSP  from 
the  bile  nor  is  indocyanine  green  necessarily  prefer- 
able because  97.7  per  cent  of  a  single  dose  appears 
in  the  bile.  The  total  recovery  is  a  measure  of  the 
extent  to  which  other  excretory  pathways  are  ac- 
cessible and  of  the  time  allowed  for  collection.  It 
does  not  throw  light  upon  the  movement  into  other 
tissues. 

The    incomplete    recovery    of   BSP    does    suggest, 
however,   that   BSP  may  undergo  alteration   in   the 
body    and    that,    as    a    consequence,    calculation    of 
hepatic  removal  may  be  erroneous.  Brauer  and  his 
associates  (60,  188)  have  shown  that  BSP  from  the  bile 
of  the  cat,  rat,  sheep,  and  chicken  can  be  separated 
into  four  fractions  by  column  chromatography  having 
the  same  absorption  spectra.   Recent  work  (45,  93, 
105,    165,    178,    211)    indicates    that    the   chromato- 
graphic fractions  are  conjugates  of  BSP  formed  in  the 
liver  by  combination  with  glutathione  at  the  sulfhy- 
dryl  group  (GSH),  with  the  release  of  bromine.  Since 
GSH  is  confined  to  the  cells,  conjugation  must  occur 
intracellularly.    In    addition    to    various    isomers    of 
BSP-GSH,      BSP-cysteinyl-glycine      conjugates      are 
formed,     presumably    by    enzymatic     hydrolysis    of 
BSP-GSH,   since  free  glutamic   acid   appears  simul- 
taneously in  the  bile.  There  is  at  present  no  evidence 
that  conjugation  is  essential  to  transfer  or  storage  of 
BSP  (178).  Indeed,  free  BSP  appears  in  the  bile  and 
both  rose   bengal   (189)   and   indocyanine   (304)  are 
excreted   without   any  evidence  of  conjugation.   All 
the  biliary  BSP  conjugates  have  been  found  in  the 
blood  of  man  and  dog  indicating  escape  from  cells. 
This  movement  into  the  blood  occurs  chiefly  within 
the  liver  and  does  not  interfere  with  the  calculation 
of  estimated    hepatic    blood    flow    (EHBF)    since    it 
affects   the  computation  of  both   hepatic   extraction 
and  removal  to  the  same  extent  and  thus  cancels  out. 
Enterohepatic  circulation   (198,    199,   224)  of  dye  is 
similarly  of  no  concern  provided  hepatic  venous  con- 
centration does  not  exceed  the  arterial  concentration 
and   provided  portal  venous  blood  does  not  bypass 
the   liver  via   collateral   pathways.    In   any  case,   in- 


THE    HEPATIC    CIRCULATION 


'399 


testinal  absorption  of  BSP,  though  it  does  occur,  does 
not  seem  to  result  in  a  significant  difference  between 
portal  venous  and  arterial  concentrations.  Whether 
derived  from  intestinal  contents  or  from  hepatic 
cells,  BSP  conjugate  displays  the  same  spectral 
properties  as  standard  BSP,  but  its  extinction  coeffi- 
cient appears  to  be  slightly  different  ( 1 88).  The  error 
so  produced  also  tends  to  cancel  out.  A  larger  error 
may  result  from  conjugation  that  occurs  elsewhere 
in  the  body,  as  in  the  kidney  ('252).  However,  BSP 
conjugate  from  this  source  seems  to  contribute  in- 
significantly to  the  blood  level,  even  in  hepatec- 
tomized  dogs  with  prolonged  maintenance  of  very 
high  plasma  BSP  concentrations.  BSP  conjugate  ac- 
counted at  most  for  10  per  cent  (1.0  mg  per  cent)  of 
the  plasma  BSP  concentration  45  min  after  adminis- 
tration, with  plasma  levels  falling  from  17  to  10  mg 
per  cent,  in  two  dogs  studied  by  Rosenau  and  his 
associates  (252). 

The  most  important  drawback  in  the  use  of  BSP, 
rose  bengal,  and  indocyanine  green  for  the  measure- 
ment of  hepatic  blood  flow  lies  in  the  impossibility 
of  sampling  a  mixture  of  all  the  venous  blood  draining 
from  the  liver.  The  liver  is  a  large  organ  in  which 
nonuniform  perfusion,  inequalities  in  tissue  activity, 
and  heterogeneity  of  bile  formation  may  be  induced 
at  any  time  by  a  large  number  of  extraneous  factors. 
Nevertheless,  many  workers  (77,  146,  232,  275)  have 
failed  to  find  any  significant  difference  between  con- 
centrations of  BSP  in  blood  taken  from  different 
hepatic  veins  in  the  same  animal,  provided  peripheral 
plasma  levels  are  kept  constant  and  comparable. 
Differences  observed  by  others  (49,  118)  may  be 
ascribed  to  changing  concentrations  or  to  sampling 
difficulties.  Careful  control  is  especially  important 
during  withdrawal  of  blood  through  the  catheter  in 
an  hepatic  vein  (62,  118,  146,  257).  Diaphragmatic 
movements  result  in  displacement  of  the  tip  of  the 
catheter  by  pressing  the  liver  down  and  in  doing  so 
predispose  to  retrograde  suction  of  blood  from  the 
inferior  vena  cava.  In  the  dog,  contraction  of  the 
hepatic  venous  musculature  seems  occasionally  to 
block  venous  outflow  from  the  liver  without  inter- 
ference with  reflux.  Since  this  phenomenon  occurs 
infrequently  and  erratically,  it  is  extremely  difficult 
to  appraise  quantitatively.  Edwards'  (118)  failure  to 
observe  it  in  three  experiments  is  therefore  not  sur- 
prising. As  he  notes,  hasty  sampling  may  result  in 
dilution  by  residual  "washout"  saline  infusion 
trapped  in  the  catheter  and  veins.  Care  must  be 
taken   to   avoid   wedging   the   catheter   deep    in   the 


hepatic  vein  in  order  to  avoid  any  stimulus  to  hepatic 
venous  contraction  or  interference  with  outflow. 

Of  special  importance  is  the  fact  that  obstruction  by 
the  wedged  catheter  may  affect  portal  venous  inflow 
preponderantly  so  that  the  sample  obtained  consists 
largely  of  blood  originating  in  the  hepatic  artery. 
Sapirstein  &  Reininger  (257)  have  reported  values 
for  sodium  />-aminohippurate  (PAH)  concentration 
in  "wedged"  hepatic  venous  samples  during  mesen- 
teric venous  infusion  of  PAH  that  suggest  such  a 
possibility.  Although  their  results  may  be  explained 
by  nonuniform  distribution  of  PAH  attributable  to 
"streamlining,"  a  recent  paper  by  Brauer  et  al.  (62) 
brings  forward  new  evidence  supporting  the  idea  of 
interference  with  portal  venous  inflow  by  the  catheter. 
These  workers  have  injected  S'i5-labeled  BSP  into 
the  portal  vein  or  hepatic  artery  as  a  means  of  dif- 
ferentiating arterial  and  venous  components  in  the 
outflow.  With  the  former,  radioactivity  remained 
much  lower  in  the  hepatic  vein  than  in  the  femoral 
artery,  whereas  radioactivity  rose  promptly  in  the 
hepatic  vein  and  remained  higher  than  in  the  femoral 
artery  when  BS:i5P  was  injected  into  the  hepatic 
artery.  This  phenomenon  would  not  affect  determina- 
tion of  BSP  extraction  if  BSP  were  removed  to  the 
same  extent  from  hepatic  arterial  and  portal  venous 
inflows.  Andrews  and  his  associates  (14)  have  claimed 
that  extraction  is  in  fact  more  complete  when  BSP 
is  infused  into  the  hepatic  artery  than  when  it  is  given 
by  the  portal  vein  in  perfused  canine  livers.  Other 
workers  (62,  83)  have  failed  to  confirm  this  observa- 
tion, however,  and  in  a  variety  of  critical  studies  have 
found  little  difference  in  efficiency  of  extraction  be- 
tween the  two  routes.  Nevertheless,  the  uncertainties 
inherent  in  hepatic  venous  sampling  call  for  caution 
in  interpretation  and  should  be  acknowledged  by 
referring  to  the  measure  as  "estimated  hepatic  blood 
flow"  or  EHBF. 

The  best  evidence  that  clearance  and  extraction 
techniques  with  constant  infusion  yield  valid  estimates 
of  hepatic  blood  flow  has  been  obtained  from  simul- 
taneous measurements  by  direct  methods.  Selkurt 
(264)  found  that  the  BSP  method  overestimated 
flow  by  7.3  per  cent  on  the  average  when  total 
hepatic  venous  outflow  was  measured  by  collection 
and  reinfused  in  274  comparisons  in  14  experiments. 
Similar  results  have  been  obtained  by  Shoemaker 
(275)  and  by  Drapanas  and  his  associates  (114)  using 
other  direct  methods.  Changes  in  blood  flow  follow- 
ing hemorrhage  or  transfusion  were  accurately  re- 
flected in  values  for  EHBF.  In  view  of  unavoidable 
trauma  and   blood   loss   that   would   enhance  extra- 


1400 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


hepatic  escape  of  the  dye  during  these  procedures, 
the  agreement  is  remarkably  good.  Although  these 
comparisons  have  been  limited  to  Bromsulfalein 
there  is  no  reason  to  suppose  that  rose  bengal  and 
indocyanine  green  would  not  prove  equally  reliable. 

Of  all  the  clearance  materials  at  hand,  BSP  appears 
at  present  to  be  clearly  superior.  Rose  bengal  as  ob- 
tained commercially  is  a  mixture  of  several  chro- 
matographically  separable  components  some  of  which 
appear  to  be  less  readily  cleared  than  others.  Though 
this  defect  is  not  important  so  long  as  hepatic  extrac- 
tion is  determined,  it  may  be  troublesome.  Composi- 
tion varies  from  lot  to  lot  with  a  resultant  unpre- 
dictable irregularity  in  extraction  and  removal  rate. 
The  availability  of  I13I-labeled  rose  bengal  (91,  213) 
simplifies  analysis  but  does  not  compensate  for  the 
other  difficulties.  Indocyanine  green  is  most  attrac- 
tive for  many  reasons.  It  is  easily  and  accurately 
measured  in  the  plasma;  it  is  not  conjugated,  and  it 
does  not  enter  the  urine  nor  move  perceptibly  from 
the  plasma  into  any  tissue  other  than  the  liver.  Un- 
fortunately, it  is  unstable  on  standing  in  aqueous 
solutions,  and  may  prove  unsuitable,  therefore,  for 
constant  infusion.  The  chemical  determination  of 
Bromsulfalein  offers  certain  difficulties,  since  it  is 
difficult  to  remove  the  dye  from  the  plasma  proteins 
and  to  eliminate  interfering  materials  present  in  the 
blank.  It  is  possibly  this  factor  that  accounts  for 
Sherlock's  (273)  finding  [which  others  (48,  77,  78) 
have  failed  to  confirm]  that  values  for  EHBF  tended 
to  be  excessively  high  when  plasma  BSP  concentra- 
tions were  less  than  1  mg  per  cent.  Even  a  small 
error  in  the  determination  of  arterial  and  hepatic 
venous  concentrations  may  produce  a  large  error  in 
the  A-V  difference.  In  any  case,  interference  by 
substances  in  the  ""blank"  can  be  avoided  for  all 
practical  purposes  by  appropriate  dilution  and  use  of 
the  Beckman  DU  spectrophotometer. 

A  variety  of  other  agents  has  been  employed  for 
determining  EHBF  but  none  has  won  wide  accept- 
ance. Galactose  has  been  found  to  be  metabolized 
by  the  liver  alone  with  sufficient  rapidity  to  permit 
accurate  measurement  of  extraction  and  computation 
of  hepatic  removal  at  levels  too  low  for  significant 
urinary  loss  (293).  Metabolic  changes  may  interfere 
importantly,  however.  Alcohol  has  been  suggested 
for  use  in  the  same  manner  but  more  recent  work 
(191)  has  shown  that  it  may  be  removed  actively  by 
tissues  other  than  the  liver.  Finally  the  role  of  the 
liver  as  the  major  site  of  urea  formation  has  been 
exploited  in  the  measurement  of  hepatic  blood  flow. 
Urinary  urea  excretion  has  been  taken  as  equal  to  the 


rate  of  hepatic  synthesis  and  divided  by  the  amount 
of  urea  added  to  each  milliliter  of  blood  perfusing  the 
liver  (the  hepatic  venous-arterial  urea  concentration 
difference)  to  yield  values  for  EHBF  that  agree  with 
those  obtained  by  the  BSP  method  (217).  The  diffi- 
culties of  analysis,  correction  for  urinary  delay,  and 
maintenance  of  a  steady  state,  militate  against  its 
routine  use.  Bromsulfalein  appears  to  be  relatively 
innocuous.  Anaphylactic  reactions  are  exceedingly 
rare  (283)  and  occasional  febrile  responses  appear 
to  be  due  to  contamination  during  preparation. 
Intense  local  inflammation  follows  extravasation  of 
BSP  into  the  tissues. 

Single  injection  techniques.  The  hepatic  ''clearance" 
of  any  substance  removed  exclusively  by  the  liver  may 
be  computed  from  the  change  in  plasma  concentra- 
tion with  time,  following  intravenous  administration 
of  a  single  dose.  Here  the  word  "'clearance"  has  been 
used  in  a  somewhat  different  sense  than  that  out- 
lined above.  In  renal  physiology  the  term  applies 
to  the  amount  of  any  material  excreted  in  the  urine 
per  minute  relative  to  its  concentration  in  each 
milliliter  of  plasma.  This  ratio  has  the  dimensions  of 
volume  and  is  equivalent  to  the  volume  of  plasma 
that  would  have  been  " "cleared"  completely  of  the 
substance  in  question,  if  it  had  been  completely  ex- 
tracted from  each  milliliter.  But  the  clearance  (195) 
may  also  be  computed  from  the  falling  plasma  con- 
centration following  intravenous  administration  of  a 
single  dose  provided  a)  the  disappearance  follows  a 
simple  exponential  decay  function : 

(when  Co  is  the  initial  concentration,  C\  the  concen- 
tration at  time  t,  and  k  is  the  disappearance  constant), 
and  b)  the  plasma  volume  of  distribution  (V)  is 
known.  In  this  case  clearance  is  equal  to  the  product 
of  V  and  k,  since  /.  is  equal  to  the  fraction  of  the 
volume  that  is  completely  cleared.  The  constant  k 
is  also  often  referred  to,  rather  confusingly,  as  the 
"fractional  clearance."  In  the  estimation  of  hepatic 
blood  flow  by  "single  injection"  it  is  necessary  to 
find  substances  that  are  removed  by  the  liver  alone 
with  almost  100  per  cent  efficiency,  that  are  dis- 
tributed within  a  determinable  volume  of  distribu- 
tion and  that  may  be  used  for  repeated  determina- 
tions. If  a  radioisotope  could  be  employed  as  such, 
or  as  a  label  for  the  ideal  test  material,  changes  in 
plasma  radioactivity  might  be  followed  by  external 
monitoring  (over  the  thigh,  for  example),  thus 
eliminating  the  objectionable  features  of  the  "con- 


THE    HEPATIC    CIRCULATION 


I  40  I 


stant  infusion"  technique  which  includes  repeated 
blood  sampling,  hepatic  venous  catheterization,  and 
prolonged  intravenous  infusion. 

The  remarkable  phagocytic  activity  of  reticuloen- 
dothelial cells  situated   in   the   liver  and  splanchnic 
bed  early  suggested  the   possibility   that   particulate 
substances  in  colloidal  suspension  might  be  removed 
with  sufficient  efficiency  to  permit  the  development 
of  single    injection    techniques    dog,    272).    Various 
agents  in  colloidal  suspension  including  carbon,  iron, 
gold,  chromium  phosphate,  polyvinylpyrrolidine,  and 
denatured  plasma  protein  have  been  studied  inten- 
sively by  many  workers  (33,  109,  1 10,  272,  296,  316). 
In   general   it  appears  that   phagocytic   removal   by 
the  R-E  cells  within   the  liver  and  spleen  depends 
upon    particle   size,    "saturation,"    splanchnic    blood 
flow,  body  temperature,  and  the  obscure  factors  that 
determine  preferential  removal  (55,  56,  316).  Of  these, 
particle  size  seems  to  be  critical  though  difficult  to 
define.   Large  particles  (100  A  or  larger)  are  taken 
up  more  actively  than  small  ones;  addition  of  plasma 
to  the  suspension  prior  to  administration  appears  to 
enhance  removal,  possibly  by  increasing  the  bulk  of 
small  particles  with  a  protein  coating  like  that  ob- 
served directly  by  Knisely  et  al.  (185)  prior  to  phago- 
cytosis by  KupfTer  cells.  The  majority  of  studies  in 
intact  animals  and  man  have  involved  the  administra- 
tion of  P32-labeled  chromium  phosphate,  radioactive 
gold    (Au198)    and    heat-denatured    plasma    albumin 
labeled  with  I131  (33,  231,  242,  296).  From  80  to  100 
per  cent  of  a  single  dose  of  each  of  these  agents  has 
been  shown  to  accumulate  in  the  liver  and  spleen 
and  each  yields  a  disappearance  curve  that  can  be 
resolved  into  two  or  more  simple  exponential  func- 
tions.   The    values    in    plasma    radioactivity   do   not 
usually  fall  to  zero  but  tend  to  flatten  into  a  straight 
line  on  semilogarithmic  paper.  This  phenomenon  has 
been  attributed   to  the  very  slow  removal  of  small 
particles  which  represent  only  a  minute  fraction  of 
the  dose.  In  practice  the  values  obtained  by  extrap- 
olating the  "tail"  of  the  curve  back  to  zero  time  are 
subtracted  from  the  initial  figures  to  obtain  a  disap- 
pearance curve  which  is  usually  a  single  exponential 
that  can  be  evaluated  simply  in  terms  of  the  disap- 
pearance half-time  (t\  =): 

k  .  2.303  log  C0/.5C0    _   .693 

'2  y2 

taking  any  value  on  the  curve  as  C0  and  lv«.  as  the 
time  required  thereafter  for  the  concentration, 
plotted  semilogarithmically,   to  fall  to  half  C0.    The 


value  for  k,  i.e.,  the  fractional  clearance,  is  usually 
multiplied  by  the  total  plasma  volume  to  yield  a 
figure  for  EHBF.  Colloidal  chromium  phosphate  is 
difficult  to  prepare  with  a  suitable  range  of  particle 
size  and  is  now  little  used.  Radioactive  gold  and 
iodine  are  7-emitters  and  their  disappearance  may  be 
followed  by  external  counting. 

Perhaps  the  most  serious  difficulty  with  the  single 
injection  techniques  lies  in  choosing  the  "volume  of 
distribution,'    (Y)    to   which    the    hepatic    fractional 
clearance  may  be  referred  (108).  Although  the  plasma 
volume  is  usually  employed,  a  substantial  fraction  of 
the  plasma  volume  within  the  splanchnic  bed  from 
which  clearance  has  occurred  cannot   be   included. 
The  "volume"  concerned  is  presumably  one,  too,  in 
which   admixture    is   instantaneous   and   throughout 
which  the  same  concentration  prevails  at  any  mo- 
ment. Attempts  have  been  made  to  correct  for  "mix- 
ing   time"    by    including    a    nondiffusible    dye,    like 
T-1824,  with  the  test  close,  but  the  corrections  have 
proved     relatively     insignificant     and      have      been 
deemed  unnecessary.  Attempts  to  compute  V  have 
proved  less  successful,  especially  following  trauma  or 
blood  loss.  Many  workers  use  the  volume  of  dilution 
calculated  from  the  intercept  at  zero  time  obtained 
by  extrapolation  of  the  disappearance  curve;  others 
simply  report  values  for  k,  or  use  the  plasma  volume 
less  a  fraction  held  in  the  splanchnic  vessels.  Another 
problem  arises  from  the  assumption  that  hepatic  ex- 
traction is  nearly  complete.   In  early  studies  (296), 
values  of  70  to  90  per  cent  were  reported  for  col- 
loidal Au198,  but  more  recently  reported  figures  (231) 
range  from  30  to  70  per  cent,  accounting  perhaps  for 
lower  values  for  EHBF.  Changes  in  the  composition 
and   properties  of  gold  colloids  commercially  avail- 
able may  be  responsible  for  this  phenomenon.   Al- 
though heat-denatured  serum  proteins  labeled  with 
I131  appear  to  be  extracted  very  efficiently  and,  as  an 
added     advantage,     are    ultimately    eliminated     by 
normal   metabolic   processes,   they  have  found   little 
use  in  large  part  because  I131  rose  bengal  and  indo- 
cyanine  green  have  proved  more  attractive  (19,  183, 
213).   Both   I131  rose   bengal  and   indocyanine  green 
disappear  rapidly  and  exponentially  from  the  blood 
and,  since  neither  is  lost  in  the  urine  nor  taken  up  in 
significant    quantity    by    extrahepatic    tissues,    both 
may  be  used  to  measure  EHBF  by  the  single  injection 
technique.     Nevertheless,    uncertainty     remains    re- 
garding the  character  of  the  volume  of  distribution 
from  which  the  dyes  disappear,   the  constancy    and 
magnitude  of  extraction  under  all  circumstances,  and 
the  part  played   by  different  mechanisms  in  deter- 


I  J.I  l_> 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


mining  the  fractional  clearance.  Studies  of  BSP 
disappearance  and  of  I131  rose  bengal  accumulation 
in  the  liver  indicate  the  possibility  of  reflux,  of  inter- 
play between  coupled  reservoirs  and  transfer  systems, 
and  of  secondary  derangements  (e.g.,  saturation  and 
competition)  that  may  lead  to  error  (45,  122,  177, 
212,  312). 

Dilution  techniques.  A  third  indirect  approach  to 
estimation  of  hepatic  (or  splanchnic)  blood  flow 
depends  upon  measurement  of  the  dilution  of  a  known 
quantity  of  some  tracer  within  the  hepatic  circulation 
over  an  accurately  measured  time  period.  In  essence, 
these  procedures  are  adaptations  of  the  Hamilton- 
Stewart  method  for  the  measurement  of  cardiac 
output  and  the  Kety-Schmidt  method  for  cerebral 
blood  flow.  For  the  first,  which  has  been  developed 
by  Reichman  and  his  associates  (239),  I131-labeled 
human  serum  albumin  (HSA)  is  injected  into  the 
spleen  and  the  concentration  curve  followed  either 
a)  over  the  liver  by  external  counting  with  approxi- 
mate correction  for  background,  or  b)  in  hepatic 
venous  outflow  collected  continuously  at  a  constant 
rate  with  sampling  at  regular  intervals.  Analysis  of 
the  hepatic  venous  radioactivity  curve  (as  in  the 
analysis  of  pulmonary  arterial  concentrations  for 
determination  of  cardiac  output  by  the  "dye  method") 
yields  a  value  for  the  average  hepatic  venous  activity- 
resulting  from  dilution  of  the  injectate  by  splanchnic 
blood  flow  during  the  time  chosen.  The  tracer  in- 
jected into  the  spleen  appears  to  travel  as  a  compact 
"bolus"  in  the  splenic  venous  blood  though  a  frac- 
tion (significant  in  20  %  of  human  subjects)  may  be 
left  behind  in  the  subcapsular  tissues.  Delayed  entry 
into  the  splanchnic  bed  with  "trailing"  may  result 
from  slow  uneven  injection.  The  amount  actually 
injected  and  diluted  within  the  hepatic  blood  flow 
can  be  computed  as  the  product  of  the  radioactivity 
in  the  peripheral  blood  at  equilibrium  (taken  at  10 
min  after  injection)  and  the  total  blood  volume  deter- 
mined separately.  This  quantity  divided  by  the  cal- 
culated "average  hepatic  venous  radioactivity" 
yields  a  value  for  the  total  splanchnic  outflow  during 
the  period  of  analysis.  Uncertainties  arising  from  re- 
circulation, nonuniform  mixing,  determination  of  the 
quantity  of  Im-HSA  injected,  and  possible  pooling, 
together  with  the  difficulties  involved  in  intrasplenic 
injection,  limit  the  usefulness  of  this  method.  A  similar 
procedure  has  yielded  satisfactory  results  in  the  dog 
with  injection  of  iodinated  albumin  and  Cr5J  (labeled 
erythrocytes)  into  the  portal  vein  (278). 

Application  of  the  Kety-Schmidt  technique  has 
been  suggested  by  a  number  of  students  (176,   288). 


The  average  arterial-hepatic  venous  concentration 
difference  during  equilibration  following  the  intra- 
venous administration  of  substances  freely  diffusible 
throughout  the  liver  and  splanchnic  bed,  such  as 
radioactive  krypton,  water  labeled  with  deuterium  or 
tritium,  or  4-amino  antipyrine,  may  be  divided  into 
the  average  hepatic  venous  concentration  at  equilib- 
rium to  obtain  a  value  for  splanchnic  blood  flow  per 
unit  mass  of  splanchnic  tissue.  Sapirstein  (256)  claims 
that  the  distribution  within  the  body  of  such  uni- 
formly diffusible  tracers  shortly  after  injection  is 
determined  by  the  distribution  of  cardiac  output  and 
thus  indicative  of  local  flow  as  a  fraction  of  output. 
According  to  this  view,  if  radioactive  potassium 
chloride  is  given  to  an  experimental  animal  and 
allowed  sufficient  time  to  pass  through  the  heart  and 
lungs  to  the  tissues  of  the  body,  and  if  the  animal  is 
killed  before  appreciable  venous  drainage  and  re- 
circulation have  occurred,  the  K.4-  content  of  the 
various  organs  can  be  used  to  evaluate  the  pattern 
of  flow  distribution.  Periods  of  time  ranging  from  5  to 
60  sec  before  death  in  the  rat  or  20  to  120  sec  in  the 
dog  do  not  appear  to  affect  the  results  (except  for  the 
brain),  presumably  because  venous  K4-  content  is 
much  smaller  than  the  arterial  levels  during  these 
periods  and  because  recirculation  does  not  begin  to 
contribute  for  about  30  sec.  Although  the  drawbacks 
of  such  a  procedure  are  obvious,  interesting  and  help- 
ful information  may  be  obtainable  by  this  means 
alone. 

SPLANCHNIC    BLOOD    VOLUME    AND    TRANSIT    TIME.     The 

volume  of  blood  within  the  splanchnic  bed  and  the 
mean  splanchnic  circulation  time  may  also  be  meas- 
ured by  an  adaptation  of  the  dilution  methods  (50, 
94).  Comparison  and  careful  timing  of  the  moment- 
to-moment  changes  in  arterial  and  hepatic  venous 
concentrations  during  the  period  of  equilibration 
following  injection  of  some  substance  which  is  con- 
fined to  the  vascular  bed,  such  as  I131  HSA,  affords  a 
measure  of  both  the  total  quantity  of  tracer  distributed 
within  the  splanchnic  bed  at  equilibrium  and  the 
time  required  for  passage  from  artery  to  the  point  of 
venous  sampling.  Thus  the  amount  of  tracer  entering 
the  splanchnic  bed  between  its  first  appearance  in  the 
arterial  blood  (sampled  from  a  brachial  or  femoral 
artery)  and  the  point  of  equilibrium  (defined  as 
agreement  between  arterial  and  venous  concentra- 
tions within  the  limits  of  analytical  error  over  a 
period  of  30  sec  or  longer)  is  equal  to  the  product  of 
the  total  splanchnic  blood  flow  and  the  average 
arterial  radioactivity   (.7)  during  that  period   (/,,,  in 


THE    HEPATIC    CIRCULATION 


i4°3 


sec).  The  amount  leaving  is  the  product  of  the  blood 
flow  and  the  average  hepatic  venous  radioactivity 
(F)  at  the  same  time.  Since  blood  flow  can  be  meas- 
ured by  the  BSP  method  and  average  arterial  and 
venous  radioactivities  can  be  obtained  by  "integrated 
sampling"  the  amount  of  tracer  distributed  within  the 
splanchnic  bed  is  easily  determined  following  intra- 
venous injection  of  I131  HSA  and  divided  by  the 
arterial  concentration  at  equilibrium  (Aeq)  to  yield  a 
value  for  splanchnic  blood  volume: 


SBV  = 


(A-V)x  EHBF  x  te 


(A.a) 


where  EHBF  is  expressed  in  milliliters  of  blood  flow 
per  second.  Since  splanchnic  blood  volume  is  equal  to 
the  product  of  the  hepatic  blood  flow  per  second  and 
the  mean  splanchnic  circulation  time  (MCT)  in 
seconds, 


it  follows, 


SBV  -"  EHBF  x    MCT 


MCT'^^L- 


(A.a) 


It  will  be  recognized  that  the  Hamilton-Stewart  and 
Kety-Schmidt  methods  alluded  to  above  are  applica- 
tions of  the  same  principle  which  has  been  treated  at 
greater  length  mathematically  by  Stephenson  and 
others  (284,  315).  [See  also  Chapters  18  and  19  of 
this  Handbook^  Radioactive  phosphate  or  chromium- 
labeled  erythrocytes  have  been  used  to  determine 
splanchnic  red  cell  mass  and  erythrocyte  circulation 
time  (94).  Any  other  relatively  nondiffusible  sub- 
stance should  yield  equally  reliable  results,  provided 
the  major  assumptions  upon  which  the  method  is 
based  are  valid. 

All  the  difficulties  implicit  in  the  measurement  of 
hepatic  blood  flow  pertain  with  equal  force  to  the 
determination  of  the  splanchnic  blood  volume.  Of 
added  importance  is  the  assumption  of  "representa- 
tive hepatic  venous  sampling,"  because  the  distribu- 
tion of  tracer  within  splanchnic  blood  flow  varies 
from  time  to  time  during  equilibration,  appearing 
first  in  the  hepatic  arterial  inflow  and  later  in  other 
parts  of  the  bed.  Thus  the  various  splanchnic  pathways 
must  be  represented  within  each  outflow  tract  to  an 
equivalent  degree.  In  view  of  the  anatomical  arrange- 
ments and  the  data  yielded  by  study  of  circulation 
time  (see  below)  this  assumption  seems  to  be  valid 
in  normal  man  and  animals.  Local  changes  within 
the  liver  will  certainly  interfere  and  the  effects  of 


streamlining  (to  be  dealt  with  later)  may  also  in- 
troduce inequalities  by  predisposing  to  predominance 
of  splenic  and  gastrointestinal  vascular  routes  within 
the  left  and  right  hepatic  venous  outflows,  respectively. 
The  fact  that  similar  values  are  obtained  with 
sampling  from  right  and  left  lobes  suggests  that  this 
possibility  is  not  important,  but  further  work  is 
necessary  to  settle  the  matter.  Uniform  and  diffused 
admixture  of  tracer  throughout  all  the  blood  filling 
the  splanchnic  blood  vessels  must  have  been  com- 
pleted by  the  "equilibrium  time."  Since  equilibra- 
tion appears  to  be  attained  within  3  min  or  less,  it 
seems  most  unlikely  that  volumes  of  blood  held  rela- 
tively motionless,  in  contact  with  but  not  actively  a 
part  of  the  circulating  blood,  are  included  in  the 
final  value.  Tracer  undoubtedly  must  find  its  way 
into  the  splenic  pulp,  but  largely  by  diffusion  rather 
than  by  active  mixing,  thus  probably  accounting  for 
the  lack  of  change  in  splanchnic  blood  volume  (SBY) 
noted  following  splenectomy.  For  this  reason  the 
value  should  be  referred  to  as  the  "circulating 
splanchnic  blood  volume."  Although  the  term  specif- 
ically indicates  the  volume  of  whole  blood,  the  tracer 
usually  employed  (I131  HSA)  is  actually  distributed 
within  the  plasma.  Blood  volume  must  therefore  be 
computed  from  the  estimated  plasma  volume  and 
the  arterial  hematocrit.  But  the  latter  is  not  strictly 
applicable  because  the  phenomena  of  "lamination" 
and  "plasma  skimming"  result  in  a  lower  hematocrit 
in  blood  flowing  through  the  capillaries  than  in 
arterial  blood.  The  resulting  error  may  be  relatively 
large  and  must  be  borne  in  mind  in  interpreting 
shifts,  particularly  in  association  with  a  changing 
hematocrit.  Simultaneous  determinations  of  red  cell 
mass  and  plasma  volume  should  yield  a  more  accurate 
estimate  of  the  total  volume,  though  measurement  of 
the  red  cell  mass  is  undoubtedly  more  seriously  limited 
by  the  difficulty  of  complete  admixture.  Blood  flow 
and  volume  must  remain  relatively  constant  during 
the  period  of  determination — at  least  10  min — to 
permit  estimation  of  hepatic  blood  flow.  Owing  to 
the  limits  of  accuracy  imposed  by  the  analytical 
procedures,  blood  flow  must  not  be  so  large  relative  to 
volume  as  to  minimize  critically  the  difference  be- 
tween the  mean  values  for  arterial  and  hepatic 
venous  radioactivities.  Experiments  with  model  sys- 
tems in  which  the  blue  dye,  T-1824,  has  been  used 
have  demonstrated  the  validity  of  the  method  pro- 
vided flow  per  minute  is  not  greater  than  three  times 
the  volume  (63).  A  higher  ratio  may  be  compatible 
with  sufficiently  accurate  measurement  of  the  arterio- 


H°4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


venous  difference  when  radioactive  tracers  are  used 
(234).  For  the  splanchnic  bed  the  actual  ratio  is 
much  lower,  approximating  unity  under  most  cir- 
cumstances. A  more  serious  problem  is  loss  of  tracer 
en  route  either  into  the  interstitial  fluid  or  into  col- 
lateral channels  that  bypass  the  liver.  The  first 
possibility  is  usually  not  very  important.  The  second 
does  not  affect  the  measurement  in  normal  subjects, 
but  with  cirrhosis  and  other  conditions  leading  to  the 
development  of  a  collateral  circulation  measurement 
may  be  impossible.  This  consideration  applies  with 
equal  force  to  evaluation  of  the  "mean"  circulation 
time. 

An  accurate  analysis  of  the  time  required  for  blood 
to  move  through  the  splanchnic  bed  requires  de- 
termination of  tracer  levels  in  artery  and  hepatic 
vein  at  i-sec  or  2-sec  intervals  owing  to  the  rapidity 
of  the  change  which  must  be  followed  (303).  The 
development  of  satisfactory  means  of  doing  this  by- 
Wheeler  (303),  Tornvall  (290),  and  their  associates 
has  made  it  possible  to  apply  and  to  extend  analyses 
of  transit  times  worked  out  in  the  course  of  a  study 
of  urine  formation  (51).  Since  blood  must  be  drawn 
through  a  catheter  there  is  distortion  of  the  concentra- 
tion curve  by  the  velocity  differential  produced  by 
laminar  flow  (215,  274).  This  factor  may  be  allowed 
for  by  sampling  arterial  and  hepatic  venous  blood 
at  the  same  rate  through  catheters  having  the  same 
dimensions.  Wheeler's  collection  technique  involves 
the  use  of  a  30-foot  length  of  polyethylene  tubing 
into  which  the  blood  is  drawn  together  with  droplets 
of  mercury  to  break  up  the  column  of  blood  and  to 
prevent  streamlining.  Since  the  tubing  has  a  uniform 
calibre  and  since  withdrawal  is  carefully  timed,  seg- 
ments of  tubing  containing  blood  collected  during 
successive  i-sec  intervals  can  be  heat  sealed  and  cut 
off  as  separate  "timed"  segments  for  determination 
of  I131  activity,  after  removal  of  the  mercury  droplets 
by  centrifugation.  Tornvall's  device  consists  of  a 
magazine  of  50  U-shaped  channels,  each  with  a 
capacity  of  3  ml,  arranged  in  a  carrier  that  auto- 
matically fills  each  channel  in  succession,  at  i-sec  to 
2-sec  intervals,  as  blood  is  withdrawn  at  a  constant 
rate.  It  is  possible  to  apply  values  so  obtained  in  the 
construction  of  a  frequency  distribution  of  arterial- 
hepatic  venous  transit  times.  The  effluent  from  a 
system  of  tubes  draining  a  reservoir  describes  a 
frequency  distribution  of  transit  times  from  reservoir 
to  sampling  site  when  the  reservoir  tracer  concentra- 
tion is  suddenly  set  at  some  arbitrary  level  (taken  as 
1 00  7c)  at  zero  time.  Changes  in  reservoir  (or  arterial) 
concentration  are  reflected  in  distortions  in  the  effluent 


(or  venous)  concentration  curve  which  may  be  taken 
into  account  by  sequential  comparison  and  graphic 
integration.  Although  hepatic  arterial  and  mesen- 
teric vasculatures  are  undoubtedly  characterized  by 
markedly  different  mean  circulation  times,  there  is 
so  much  dispersion  and  overlap  between  these  and 
other  splanchnic  beds  that  separation  of  specific 
populations  has  proved  impossible.  Nevertheless,  the 
method  affords  a  more  precise  indirect  approach  to 
an  understanding  of  the  intrasplanchnic  distribution 
of  flow  and  volume  than  any  other  now  available. 


NORMAL    PARAMETERS    OF    THE    HEPATIC    CIRCULATION 

Although  methodology  is  now  far-advanced,  a 
reliable  quantitative  description  of  the  hepatic  and 
splanchnic  circulation  at  rest  in  man  and  experi- 
mental animals  is  still  a  major  desideratum.  Un- 
certainty results  from  all  the  technical  difficulties 
already  noted.  In  addition,  the  control  or  "resting 
state"  is  extremely  difficult  to  define  and  is  perhaps, 
like  the  "normal,"  a  relatively  meaningless  concept. 
The  splanchnic  circulation  (hence,  the  hepatic  out- 
flow) serves  at  one  and  the  same  time  the  demands  of 
viscera  engaged  in  a  diversity  of  metabolic  activities 
and  the  needs  of  the  cardiovascular  system  as  a 
whole.  The  establishment  of  a  steady  state  referable 
to  each  of  these  factors  would  be  almost  impossible 
and,  in  any  case,  of  limited  applicability.  For  this 
reason  it  has  seemed  preferable  to  abstract  suitable 
"control"  approximations  from  the  literature  and  to 
consider  these  as  the  basis  for  a  reasonable  appraisal 
of  what  may  be  characterized  as  the  "reference 
state." 


Hepatic  Blood  Flow 

Of  necessity,  data  obtained  in  studies  of  man  and 
dog  must  dominate  the  picture.  Although  the  hepatic 
circulation  has  been  investigated  extensively  in  the 
cat,  rat,  mouse,  rabbit,  and  other  species,  the  in- 
formation obtained  has  been  largely  qualitative;  of 
considerable  importance  in  elucidating  physiologic 
and  pathologic  adjustments,  of  but  inferential  value 
quantitatively.  Systematic  exploration  of  the  field  of 
comparative  physiology  with  the  methods  at  hand 
would  be  most  rewarding.  In  both  man  and  dog, 
the  figures  for  hepatic  blood  flow,  portal  venous  and 
sinusoidal  pressures,  and  splanchnic  blood  volume 
range  widely.  In  91  apparently  normal  fasting  human 
subjects,    studied    resting    in    recumbency,    the    BSP 


THE    HEPATIC    CIRCULATION 


1405 


method  yielded  a  mean  value  of  1530  ±  (sd)  300  ml 
per  min  (48),  which  appears  to  be  fairly  representa- 
tive  [and   certainly   not   differing   significantly  from 
the    figures    published    by   other   workers   using   the 
same  or  other  methods  (33,  78,  231,  242,  273,  296)]. 
The    wide    range   observed    suggests   a   considerable 
variation  in  flow  that  is  also  evident  (though  by  no 
means  to  the  same  extent)  during  the  course  of  a 
single  study  in  the  same  subject.   For  the  dog,   the 
values  obtained  by  different  workers  differ  much  more 
significantly  (37,  90,  129,  232,  275,  282).  To  a  large 
extent    the    disagreement   may    be    ascribed    to    dif- 
ferences   in    preparation,    anesthesia,    and    surgical 
manipulation.  Anesthesia  appears  to  be  particularly 
difficult  to  control,  since  it  may  be  associated  with  a 
varying     degree     of     hypercapnia     with     resultant 
splanchnic  vasoconstriction.  Light  barbiturate  anes- 
thesia appears  to  produce  no  change  in  splanchnic 
hemodynamics  in  man  so  long  as  the  plasma  carbon 
dioxide    tension    is    kept    constant    (123).    Artificial 
respiration    with    various    mechanical    devices    pre- 
disposes to  hypercapnia  in  man  and  it  may  be  assumed 
that  this  is  also  true  of  the  dog.  Hence,  it  seems  reason- 
able to  accept  the  mean  values  for  EHBF  obtained 
in  unanesthetized  dogs  by  Pratt  (232),  Bollman  (37), 
Fisher  (129),  and  their  co-workers  of  43.6  ml,  42.5 
ml,  and  45  ml  per  kg  body  wt  per  min,  respectively, 
as  the  best  available  estimates.  As  in  man,  variance  is 
relatively  large   (in  Fisher's  series,  for  example,  the 
standard  deviation  was  ±9.3   ml/ kg   body  wt/min) 
and  a  similar  variation  is  observed  during  the  course 
of  a  single  study.  The  values  for  EHBF  are  not  cor- 
related with  body  size  in  man  as  they  are  in  the  dog, 
presumably  because  the  range  of  variation  in  body 
size  in  man  is  so  much  less  than  in  the  dog  and  be- 
cause a  correlation  may  be  obscured  by  other  factors 
responsible  for  variance  in  "resting"  EHBF.  Dobson 
&  Jones  (1 10)  have  reported  mean  values  for  hepatic 
blood  flow  (chromic  phosphate  method)  in  the  un- 
anesthetized rabbit,   rat,   mouse   (0.74,    1.2,   and    1.4 
ml/ml  liver/ min,   respectively)   in  rough  agreement 
with  those  for  man  and  dog.  Similar  values  have  been 
reported  also,  in  terms  of  body  weight,  for  sheep  and 
cattle  (138,  260). 

Splanchnic  J  'oscular  Pressures  and  Resistances 

The  figures  available  for  arterial  and  venous  pres- 
sures and  for  pressure  differentials  in  different  species 
also  indicate  close  similarities  though  a  definitive  and 
systematic  investigation  remains  to  be  done.  In 
every  series  the  values  range  so  widely  that  inter- 


species differences  are  apparently  insignificant  (17,  ;_\ 
76,  135,  244,  286,  314).  This  variation  may  be  ex- 
plained largely  by  the  technical  difficulty  of  establish- 
ing strictly  comparable  "zero  reference  planes," 
states  of  "resting  normality,"  and  laboratory  condi- 
tions. Nevertheless,  mean  arterial  pressure  may  be 
taken  as  approximately  100  mm  Hg  in  both  man  and 
dog,  portal  venous  pressure  as  10  mm  Hg,  and  central 
(or  atrial)  venous  pressure  as  o.  Since  portal  and 
wedged  hepatic  venous  pressure  in  dog  and  man 
behave  in  the  same  way  and  attain  the  same  levels, 
the  value  for  sinusoidal  pressure  of  8.5  mm  Hg  com- 
puted for  the  dog  by  Friedman  &  Weiner  (135)  as 
the  midpoint  between  wedged  hepatic  and  wedged 
portal  venous  pressures  may  be  accepted  also  for 
man.  The  pressure  gradients  therefore  are  90  mm 
Hg  between  artery  and  portal  vein,  91.5  between 
hepatic  artery  and  sinusoids,  1.5  between  portal 
vein  and  sinusoids,  and  8.5  between  sinusoids  and  the 
right  heart. 

The  resistances  that  determine  these  drops  in 
pressure  between  the  arteries  and  veins  can  be 
evaluated  only  when  the  distribution  of  blood  flow 
is  known.  Exact  figures  are  not  available  but  most 
workers  (though  not  all)  tend  to  accept  the  view  that 
hepatic  arterial  inflow  is  approximately  one-half 
portal  venous  inflow  (132).  If  this  is  the  case  and  if 
resistances  may  be  computed  as  the  ratio  between 
pressure  drop  (given  above)  and  flow  per  second 
(1530  ml  in  man  and  550  ml  in  the  dog)  multiplied 
by  a  factor — 1332 — to  obtain  figures  in  absolute 
units  (dynes  cm-5  sec),  the  following  values  for  re- 
sistances within  the  splanchnic  bed  would  obtain  in 
man  and  dog  (10  kg): 


Arterial  sinusoidal  (hepatic  arterio- 
lar— R,) 

Arterial  portal  venous  (splanchnic 
arteriolar — R2) 

Portal  venous  sinusoidal  (portal  ven- 
ular— R3) 

Sinusoidal  inferior  vena  cava  (post- 
sinusoidal — Rt) 


Man  Dog 

14,630  48,750 

7200  24,000 

1 20  400 

450  1510 


The  interrelationship  between  resistances  is  com- 
plicated by  the  fact  that  the  splanchnic  circulation 
consists  of  a  combination  of  resistances  both  in 
series  and  in  parallel  (fig.  1).  The  computation  of 
any  component  requires  a  precise  information  re- 
garding the  distribution  of  total  blood  flow  as  well 
as  pressure  gradients.  Any  attempt  to  infer  behavior 
of  a  given  resistance   from  values  for   the   pressure 


1406 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  I.  The  hepatic  and  splanchnic  cir- 
cuits. The  vascular  resistances  in  the  splanch- 
nic bed  (A)  are  shown  here  in  diagrammatic 
form  (B).  The  resistances  indicated  are  the 
determinants  of  sinusoidal  and  portal  venous 
pressures  and  of  flows  through  the  portal 
vein  and  hepatic  artery.  In  addition  to  the 
hepatic  arteriolar  resistance  {R\),  colic, 
mesenteric,  pancreatic,  gastric,  and  splenic 
arteriolar  (/?;),  portal  venular  (/?,)  and  post- 
sinusoidal  (R,)  resistances,  a  fifth  resistance 
lying  in  direct  communication  between  the 
portal  vein  and  inferior  vena  cava  (the  col- 
lateral resistance)  is  shown  as  a  dotted  line. 
It  may  be  seen  that  the  resistance  pattern 
resembles  that  of  the  Wheatstone  bridge, 
though  the  electrical  analogy  must  not  be 
taken  too  literally.  The  total  splanchnic 
resistance  (RT)  may  be  expressed  (44)  in 
terms  of  its  constituent  resistances  as  follows 
(omitting  the  collateral  resistance) : 


RIRZ 


R,R3 


+  R. 


R,+R2+R3 

[Reprinted  from   (43)   with  permission   of  the 
publishers.] 


Inf   V.C. 


*2 

Splanchnic 
arter:    'i- 
PORTAL  V         resist 


AORTA 


gradient  alone  is  fraught  with  the  danger  of  serious 
error.  If  the  values  above  are  correct,  it  is  evident 
that  the  resistance  to  outflow  from  the  liver  and  the 
portal  venous  bed  is  a  fraction  of  inflow  resistance. 
It  may  be  inferred  therefrom  that  relatively  small 
absolute  changes  in  Rf  and  R*  would  influence  portal 
venous  and  sinusoidal  pressure  markedly,  and  in 
doing  so,  affect  the  volume  of  blood  distending  the 
portal  and  hepatic  vasculature. 

Splanchnic  Blood  Volume 

The  balance  between  input  and  outlet  resistances 
and  the  "capacity"  of  the  vasculature  together 
presumably  determine  splanchnic  blood  volume  and 
the  pressures  under  which  the  vessels  are  distended. 
The  relative  contribution  of  each  is  difficult  to  assess 
not  only  during  change  but  also  in  the  basal  reference 
state.  The  total  circulating  splanchnic  blood  volume 
(regional  dilution  method)  in  both  dog  and  man  at 
rest  amounts  to  approximately  20  per  cent  of  the 
total  blood  volume,  within  a  wide  range  attributable 
both  to  technical  and  physiologic  factors  (43,  44,  50, 
106,  175,  181).  Of  this,  the  bulk  appears  to  be  held 
within  the  large  veins  (for  details  see  below),  though 
an  important  moiety  is  lodged  within  the  sinusoids  of 
the  liver  and  the  spleen.  The  intrinsic  capacity  of 
this  variegated  system  at  any  pressure  thus  depends 
upon  the  elasticity  of  muscular  veins  and  the  counter- 


forces  operating  to  compress  or  distend  the  intra- 
abdominal viscera  and  their  vasculatures. 

Muscular  contraction  may  quickly  modify  the 
former,  whereas  the  introduction  of  food,  water,  and 
air  into  the  gastrointestinal  tract  and  the  movement 
of  fluid  across  the  cell  walls  may  change  the  latter 
very  slowly.  It  is  difficult,  under  the  circumstances, 
to  establish  satisfactory  reproducible  control  values. 
Moreover,  the  pressures  acting  in  the  different  parts 
of  the  bed  are  effective  in  proportion  to  diameter, 
in  accord  with  Laplace's  law  (70)  so  that  a  much 
greater  pressure  rise  is  necessary  to  increase  sinusoidal 
volume  than  to  produce  the  same  increment  in 
venous  volume.  Insufficient  data  are  available  to 
permit  quantitative  evaluation  of  this  factor  in  dif- 
ferent regions  and  to  give  proper  importance  to 
venous  and  capillary  pressure  levels. 

The  cross-sectional  distribution  of  the  vessels, 
containing  the  blood,  figures  importantly  not  only 
in  determining  the  average  distensibility  but  also  in 
fixing  the  average  hematocrit  and  the  composition 
of  the  splanchnic  blood  volume.  Lamination  of 
flowing  blood  results  in  a  lower  hematocrit  in 
capillaries  than  in  large  vessels,  owing  to  the  relatively 
large  volume  of  plasma  in  the  layer  immediately 
adjacent  to  the  vessel  wall.  Sequestration  of  blood 
with  sluggish  turnover  may  lead  to  accumulation  of 
red  cells,  however,  and  to  a  higher  hematocrit  than 
in  the  large  vessels.  The  hematocrit  of  the  circulating 


THE    HEPATIC    CIRCULATION 


1407 


splanchnic  blood  volume  of  the  dog  has  been  proved 
to  average  79.4  =b  8.9  per  cent  of  the  simultaneously 
determined  arterial  hematocrit  (94).  Splenectomy 
does  not  significantly  affect  the  value,  presumably 
because  the  tracer  is  not  dispersed  throughout  the 
spleen.  Since  circulating  SBV  is  computed  on  the 
basis  of  the  arterial  hematocrit  it  is  evident  that  the 
value  is  overestimated  by  the  extent  to  which  the 
splanchnic  hematocrit  differs  from  the  arterial  and 
underestimated  by  failure  to  include  stagnant  splenic 
blood.  Nevertheless,  the  magnitude  of  the  value 
indicates  at  once  that  the  splanchnic  reservoir  can 
contribute  significantly  in  systemic  circulatory  homeo- 
stasis by  mobilizing  a  large  volume  of  blood  to  repair 
deficits  in  the  peripheral  circulating  volume  or  by 
expanding  to  accommodate  an  excess  that  might 
threaten  cardiac  stability. 

At  present,  methodology  undoubtedly  figures  most 
prominently  as  a  cause  for  contemporary  figures 
denoting  hepatic  circulatory  variance.  Active  vascular 
adjustments  must  also  play  an  important  role  in 
producing  the  variability  observed  in  measurements 
of  flows,  pressures,  and  volumes  at  "rest"  in  view  of 
the  abundant  evidence  of  muscular  tissue  and  mus- 
cular activity  in  influencing  flow  and  volume.  The 
same  fundamental  mechanisms  are  involved  in  the 
circulatory  changes  observed  during  "acute"  re- 
sponses to  various  stimuli  and  stresses.  Alterations  in 
vascular  dimensions  and  elastic  properties  and  in 
hemodynamic  patterns  arise  primarily  from  the 
varied  interplay  of  vasoconstriction,  closure,  or  col- 
lapse of  vessels,  and  rearrangement  of  vascular  path- 
ways, but  numerous  additional  extraneous  factors 
exert  a  vital  modifying,  integrating,  and  directive 
influence.  Among  the  latter  it  is  necessary  to  consider 
neural  mechanisms,  humoral  agents,  and  external 
physical  forces  that  are  imposed  by  abdominal 
muscular  contraction,  tissue  tension,  gravity,  respira- 
tory movements,  and  the  like. 


PRIMARY  DETERMINANTS  OF  HEPATIC   BLOOD 
FLOW  AND    VOLUME 

Cross  Section 

Since  blood  flow  and  volume  are  functions  not 
only  of  the  driving  and  distending  pressures  but  also 
of  the  dimensions  of  a  vasculature,  splanchnic  vascular 
anatomy  may  be  considered  an  immediate  de- 
terminant of  hepatic  hemodynamics.  Structure,  as 
such,    however,    is    not    constant    in    its    physiologic 


implications  nor  is  it  particularly  helpful  in  indicating 
the  control  reference  state  because  death  and  dissec- 
tion result  in  disarrangement  of  the  delicate  balances 
that  depend  upon  tissue  turgor  and  muscle  contrac- 
tion. Nevertheless,  anatomic  data  may  help  in  sug- 
gesting the  points  at  which  resistance  to  flow  should 
be  most  marked.  Mall's  (206)  careful  measurements 
ol  the  dimensions  and  numbers  of  vessels  within  the 
liver  and  splanchnic  bed  can  still  be  used,  more  than 
half  a  century  after  their  publication,  as  a  basis  for 
computing  sites  of  resistance.  Assuming  that  each 
successive  category  of  vessels  gives  rise  to  a  new  sys- 
tem of  resisting  conduits  in  parallel,  the  cross  section 
of  each  conduit  progressively  diminishing  to  the  level 
of  the  capillaries;  the  frictional  resistances  to  flow 
at  each  level  may  be  computed  from  Poiseuille's 
law  of  fluid  flow  through  capillary  vessels  in  parallel 
as  follows: 


-L+-L+J- 
R,       R2       R3 


where  RT  is  the  total  resistance  imposed  by  any 
category  of  parallel  branches  and  Ru  R2,  R3,  ■  ■  ■  are 
the  resistances  imposed  by  each  constituent  branch. 
Since  resistance  in  each  branch  varies  inversely  as 
the  fourth  power  of  its  radius  (r)  and  directly  as  its 
length  (7)  and  the  viscosity  (jj)  of  the  perfusate: 

and  if  the  average  radius  (r)  is  used : 

RT    vl    or  Rr-JF* 

where  n  is  the  number  of  vessels  in  each  category. 
Changes  in  the  values  for  viscosity  and  length  con- 
tribute negligibly  to  the  change  in  total  resistance  as 
the  vessels  narrow  and  increase  in  number.  The 
values  presented  by  Mall  for  the  number  of  branches 
and  for  the  average  cross  section  at  each  level  indicate 
that  (i/nr  )  reaches  a  maximum  in  the  smallest 
arterial  branches  (or  arterioles)  in  the  liver,  spleen, 
stomach,  and  intestines.  It  may  be  inferred,  therefore, 
that  arteriolar  resistance  plays  a  preponderant  role 
in  determining  splanchnic  and  hepatic  inflow.  Be- 
yond this  point  in  both  the  portal  venous  and  hepatic 
venous  systems,  values  for  (i/nr  )  fall  to  very  low 
figures  though  slight  increases  do  occur  at  the  level 
of  the  smallest  portal  venular  branches  and  the 
sinusoids.  No  evidence  of  a  significant  postsinusoidal 
resistance  may  be  adduced  from  these  data,  though 


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CIRCULATION    II 


the  wedged  hepatic  venous-central  venous  pressure 
differential  gives  proof  to  its  operation  while  the 
thick  throttling  musculature  of  the  small  hepatic 
veins  (in  the  dog,  at  least)  suggests  a  mechanism  for 
its  production.  The  musculature  of  the  arterioles 
also  indicates  an  apparently  adequate  basis  for 
variation  noted  in  intrahepatic  or  splanchnic  re- 
sistances and  blood  flows.  Nevertheless,  other  factors 
enter  the  equation  and  under  certain  circumstances 
contribute  effectively  in  changing  the  total  vascular 
cross  section  independently  of  vasomotor  activity. 

Collapse  of  vessels  secondary  to  changes  in  trans- 
mural pressure  may  result  in  the  redistribution  of 
resistances  and  in  the  reduction  of  the  number  and 
diameter  of  the  units  perfused  at  any  level.  Much 
work  in  recent  years  (149,  162,  226,  307)  indicates 
that  perfusing  pressure  and  blood  flow  are  linearly 
correlated  only  above  20  to  40  mm  Hg  in  the  maxi- 
mally dilated  vascular  beds  of  the  isolated  hind  limb 
of  the  dog.  At  lower  pressures  the  pressure-flow  curve 
is  sigmoid  with  a  positive  intercept  on  the  pressure 
axis.  Green  and  his  associates  (162)  have  suggested 
that  vascular  compliance  may  produce  the  convexity 
to  the  base  and  the  positive  pressure  intercept  at  zero 
flow,  the  perfused  vessels  decreasing  in  cross  section 
and  number  as  the  distending  pressures  are  lowered 
with  increasing  resistance  in  consequence.  This  phe- 
nomenon has  been  extensively  studied  by  Burton 
and  his  associates  (70-72)  who  attribute  it  to  an 
inherent  vascular  instability  that  develops  as  the 
product  of  the  intraluminal  pressure  and  the  radius 
falls  below  the  "tension"  in  the  wall.  At  this  point, 
that  of  "critical  closing  pressure,"  collapse  occurs  and 
the  vessel  "shuts  down."  The  mural  tension  is  at- 
tributed to  the  interplay  of  elastic  tension  or  tissue 
resistance  to  stretch,  active  tension  generated  by 
muscular  contraction,  and  interfacial  tension  arising 
from  the  surface  forces  between  blood  and  the  "un- 
wettable"  intima.  A  significant  correlation  noted 
between  critical  closing  pressure  and  resistance  to 
flow  in  various  preparations  (including  the  perfused 
ear  of  the  rabbit,  intact  dogs  with  extracorporeal 
circulation,  the  human  hand  during  changes  in 
transmural  pressure)  has  been  interpreted  as  evidence 
that  the  arterioles  are  chiefly  concerned.  The  linear 
relationship  between  high  pressures  and  flows  ob- 
served by  Whittaker  &  Winton  (307),  Pappenheimer 
&  Maes  (226),  and  others  (70,  71)  indicates  non- 
distensibility  of  the  resistance  vessels  and  appears  to 
be  a  result  of  maximal  dilatation  in  their  experiments. 
Levy  (194),  Folkow  &  Lofving  (131),  and  others 
(166)  have  shown  that  the  resistance  vessels  are  freely 


distensible  over  a  wide  range  of  pressures  produced  by- 
equal  increments  in  both  arterial  and  venous  pressures, 
less  so  when  arterial  pressure  alone  is  raised  and  more 
obviously  with  a  rise  in  venous  pressure  alone;  pro- 
vided the  bed  is  denervated  and  before  local  adjust- 
ments obtrude.  Thus  resistance  to  flow  through  an 
extremity  may  be  diminished  by  raising  the  in- 
travascular  pressure   and   increased    by   lowering   it. 

Studies  by  Brauer  el  al.  (57),  Trapold  (292),  and 
Selkurt  it  al.  (269)  indicate  that  critical  closing  pres- 
sures may  also  be  defined  for  the  vasculatures  of  the 
liver  and  intestines.  All  have  used  isolated  denervated 
tissues  perfused  in  vitro  over  a  wide  range  of  pressures. 
Brauer  el  al.  (57)  obtained  a  sigmoid  relationship 
between  perfusion  pressure  and  flow  through  the 
isolated  rat  liver  perfused  via  the  portal  vein  alone. 
They  found  an  increment  in  resistance  below  pressures 
of  5  to  10  mm  Hg  apparently  attributable  to  closure 
of  a  significant  proportion  of  vessels  that  occurred  in 
association  with  impairment  in  bile  formation.  Pres- 
sure-flow relationships  were  evaluated  by  Trapold 
(292)  and  Selkurt  et  al.  (269)  in  the  vessels  of  isolated 
loops  of  small  intestine.  Both  observed  linearity 
between  60  and  1 50  mm  Hg,  convexity  to  the  pressure 
axis  at  about  60  mm  Hg  or  lower,  and  a  tendency  for 
flattening  at  higher  pressures.  The  zero  flow  in- 
tercept on  the  pressure  axis  was  16  mm  Hg.  They 
interpreted  these  findings  as  evidence  of  "critical 
closing"  at  low  pressures  and  of  distension  with 
diminishing  resistance  as  pressure  was  increased.  All 
three  groups  noted  the  changes  in  critical  closing 
pressure  (rising  with  vasoconstriction  and  falling  with 
dilatation)  observed  by  Burton  and  his  co-workers 
(70-72)  during  vasomotor  activity  produced  by 
drugs  and  anoxia,  and  attributed  by  them  to  a 
change  in  "active  tension."  In  normally  innervated 
beds  or  in  carefully  prepared  tissues,  however,  the 
correlation  between  critical  closing  pressure  and  the 
level  of  vasomotor  tone  did  not  appear  to  be  readily 
demonstrable  and  free  distensibility  was  not  ap- 
parent (250).  Indeed,  additional  evidence  suggests 
that  stretch  of  the  vessel  wall  by  a  rise  in  intravascular 
or  transmural  pressure  may  actually  elicit  a  reactive 
contraction  of  the  smooth  muscle,  that  prevents  dis- 
tension and  that  may  even  reduce  cross  section. 

The  possibility  that  intraluminal  tension  might 
determine  vascular  tone  in  this  manner  was  raised 
by  W.  M.  Bayliss  in  1902  as  an  explanation  for  his 
observations  that  transient  occlusion  of  the  femoral 
artery  was  followed  immediately  in  the  denervated 
limb  by  hyperemia,  and  that  a  sharp  rise  in  intra- 
luminal  pressure   elicited   an   increase   in   "tone"   of 


THE    HEPATIC    CIRCULATION 


1409 


isolated  arterial  segments.  Owing  to  the  questionable 
application  of  these  observations  to  the  situation  in 
intact  animals  and  the  uncertain  role  of  local  vaso- 
active materials,  the  "myogenic  theory  of  tone" 
was  not  readily  accepted,  but  recent  work  by  Folkow 
and  others  appears  to  have  put  it  upon  a  sounder 
basis.  Folkow  &  Lofving  (131)  worked  with  the 
denervated  hind  limb,  skin,  and  mesenteric  arterial 
bed  in  anesthetized  cats,  dogs,  and  rabbits.  They 
found  that  lowering  the  arterial  pressure  for  as  short  a 
period  as  3  to  5  sec  by  arterial  or  aortic  occlusion 
produced  dilation,  whereas  raising  the  pressure  by 
bilateral  carotid  occlusion  for  20  to  60  sec  elicited  a 
vasoconstriction.  Neither  anoxia  nor  hypercapnia 
altered  the  response.  Denervation  apparently  elim- 
inated neither  vascular  tone  nor  responsiveness  to 
vasoactive  drugs  such  as  acetylcholine,  epinephrine, 
norepinephrine,  serotonin,  vasopressin,  and  angioten- 
sin. From  these  results  and  from  direct  study  of 
isolated  arteries  and  minute  blood  vessels  Folkow 
concluded  that  ''vascular  tone"  is  created  by  a 
rhythmic  unsynchronized  activity  of  the  smooth 
muscle  of  the  resistance  vessels.  Conclusive  demon- 
stration of  myogenic  autoregulation  within  the  mesen- 
teric vasculature  has  proved  somewhat  difficult, 
though  Johnson  (180)  has  been  successful  in  finding 
it  in  2 1  of  26  experiments.  The  response,  he  observed, 
was  not  eliminated  by  infusion  of  enough  procaine 
to  block  a  possible  local  autonomic  reflex  arc  and 
did  not  appear  to  depend  upon  a  change  in  tissue 
fluid  content,  oxygen  consumption,  or  lactic  acid 
production.  The  use  of  a  suitable  perfusion  system 
and  enough  time  to  permit  recovery  from  surgery, 
venous  cannulation,  and  denervation  may  have  been 
important  in  Johnson's  success  in  demonstrating  the 
phenomenon.  Study  of  pressure-flow  relationships 
in  the  portal  venous  drainage  tract  has  been  less 
clear  cut  in  showing  evidence  of  myogenic  mainten- 
ance of  tone.  Although  the  data  obtained  by  Riecker 
(250)  with  perfusion  of  the  canine  liver  via  the  portal 
vein  in  situ  are  not  marred  by  the  effects  of  the  trauma 
and  disorganization,  inevitable  during  excision  and 
study  in  vitro,  they  exhibit  considerable  variance; 
opposing,  on  the  one  hand,  the  view  that  the  porto- 
hepatic  vasculature  is  a  simple,  passive  elastic  svstem 
and  failing  to  support,  on  the  other  hand,  intrinsic 
control  of  vascular  cross  section. 

Although  the  data  indicate  that  closure  by  col- 
lapse may  occur  in  the  hepatic  and  splanchnic  vascula- 
ture, the  role  of  a  definite  critical  closing  pressure 
remains  uncertain.  Confusion  arises  particularly  in 
connection  with  the  character  of  closure.  According 


to  the  myogenic  theory,  the  "unstretched  radius" 
is  reached  after  the  complete  contraction  of  elastic 
recoil  and  is  therefore  zero.  In  this  view,  closure 
consists  in  a  concentric  constriction,  but  it  may  also 
be  regarded  as  collapse  to  form  a  closed  slit  from 
some  finite  value  for  the  unstretched  radius.  Since 
critical  closing  has  apparently  escaped  direct  observa- 
tion, it  is  impossible  to  say  which,  if  either,  state 
obtains.  The  fact  (70)  that  the  pressure  at  which 
closure  occurs  does  not  differ  from  that  at  which  the 
vessels  re-expand  (critical  opening  pressure)  favors 
the  first,  at  least  so  far  as  the  resistance  vessels  are 
concerned.  There  is  ample  evidence  that  the  critical 
opening  pressure  for  the  large  veins  greatly  exceeds 
their  critical  closing  pressure.  A  response  similar  to 
that  of  the  large  veins — and  slit  formation  on  closure — 
seems  more  likely  also  at  the  level  of  the  tenuous 
venular  channels  and  capillaries  and  at  arteriovenous 
communications.  However,  the  liver  plates  must 
move  with  expansion  or  deflation  of  the  sinusoids  to 
impose  special  plastic  properties  quite  unlike  those 
characteristic  of  other  capillary  nets.  Critical  closing 
pressures  in  the  depth  of  a  lobe  probably  differ 
markedly  from  those  characteristics  of  sinusoids  close 
to  the  surface  not  only  because  deformation  must 
affect  the  periphery  more  easily  but  also  because  the 
distance  from  the  afferent  vessels  is  shorter  in  the 
central  regions.  No  matter  what  the  mechanism  of 
closure  may  be,  it  effectively  changes  resistance  to 
flow  by  reducing  the  vascular  cross  section.  In  addi- 
tion, the  distribution  of  collapse  may  affect  the  re- 
sistance by  altering  the  mean  length  of  the  resisting 
circuits. 

Path  Length  and  Distributional  Pattern 

Resistance  is  directly  related  to  path  length  and 
though  the  length  of  the  conduit  contributes  much 
less  to  frictional  loss  of  the  energy  head  at  any  level 
than  does  the  radius,  it  figures  importantly  in  the 
total  resistance  from  artery  to  vein.  Arteriovenous  or 
veno-venous  shunting  is  the  most  obvious  means  of 
shortening  the  vascular  bed.  Arteriovenous  anas- 
tomoses (A-V)  occur  prominently  in  the  wall  of  the 
stomach  (22,  39)  and  may  be  operative  elsewhere  in 
the  gastrointestinal  tract,  but  there  is  little  evidence 
that  they  are  significant  hemodynamically.  Even 
when  the  capillaries  of  the  perfused  stomach  are 
completely  blocked  with  starch  granules,  no  more 
than  5  per  cent  of  the  total  flow  passes  through  the 
A-V  anastomosis.  Few  or  none  are  demonstrable  in 
the   liver  though   Prinzmetal   et    al.    (233)   have   re- 


1410 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


ported  that  glass  spheres  up  to  180  n  in  diameter 
may  be  recovered  from  hepatic  venous  effluent  fol- 
lowing injection  into  the  portal  vein.  In  contrast, 
Gordon  et  al.  (150)  obtained  much  smaller  values  with 
a  method  based  upon  the  established  relationship 
between  perfusate  surface  tension,  minimal  perfusing 
pressures,  and  the  largest  radius  in  a  system  of  tubes. 
They  found  that  portal  to  hepatic  vein  "anastomoses" 
did  not  exceed  24  n  in  diameter  and  hepatic  A-V 
anastomosis  ranged  from  18  to  26  ii  in  the  rat  and 
rabbit.  The  former  are  probably  the  hepatic  sinusoids 
proper;  the  latter,  the  A-V  anastomosis  reported  by 
Wakim  &  Mann  (299)  and  Seneviratne  (270).  With 
respect  to  the  data  obtained  with  glass  beads,  they 
note  that  the  method  "yields  remarkable  results  in 
that  every  organ  investigated  by  this  means  has  been 
shown  to  have  very  large  A-V  anastomoses."  What- 
ever the  merits  of  this  dispute,  vascular  anastomoses 
do  not  seem  to  play  a  large  part  in  determining 
hepatic  hemodynamics.  Possibly  they  operate  in 
establishing  distributional  patterns  of  flow  but  even 
here  cross  section  and  path  length  per  se  appear  to 
be  more  important. 

The  characteristic  patterns  of  the  pathways  by 
which  blood  travels  through  the  capillary  beds  within 
the  hepatic  and  splanchnic  vasculature  are  imperfectly- 
understood.  There  is  now  fairly  general  agreement 
that  capillaries  themselves  possess  no  intrinsic  capacity 
for  contractility  or  for  autoregulation  of  flow  and 
volume  within  them.  Chambers  &  Zweifach  (82) 
claim  that  capillary  nets  are  characterized  by  con- 
tinuously active  and  well-marked  "thoroughfare  chan- 
nels" or  "A-V  capillaries,"  which  pass  more  or  less 
directly  from  the  arterioles  to  the  draining  veins  and 
from  which  the  bulk  of  the  capillaries  take  origin. 
According  to  these  workers,  the  proximal  portion  of 
the  central  channel  is  encircled  by  muscle  cells  and 
is  to  be  regarded  as  a  junctional  arteriole  or  "met- 
arteriole"  which  gives  rise  to  even  less  well-muscled 
"precapillary"  vessels  or  "precapillary  sphincters" 
controlling  inflow  cross  section.  This  arrangement 
has  been  described  with  what  seems  complete  validity 
in  the  mesenteries  (82,  317)  but  does  not  seem  to  be 
typical  of  capillary  nets  in  other  tissues  (154)  [see 
also  Chapter  27  of  this  volume].  Active,  more  or 
less  rhythmic,  alternating  dilatation  and  contraction 
or  so-called  "vasomotion"  has  also  been  observed  in 
the  terminal  arterioles  by  time-lapse  photography. 
Xot  all  workers  have  been  successful  in  convincing 
themselves  of  the  validity  of  vasomotion  but  all 
seem  in  agreement  regarding  the  phenomenon  of 
"intermittency"  or  transient  nonperfusion  of  a  frac- 


tion of  any  given  capillary  bed.  Flow  ceases  or  capil- 
laries empty  completely  and  remain  so  for  a  time, 
then  flow  resumes  without  apparent  cause.  During 
hyperemia  nearly  every  capillary  visualized  will  be 
active.  Ischemia  seems  to  reduce  the  number  of 
active  capillaries  as  well  as  to  diminish  flow  through 
those  remaining  in  function.  This  phenomenon  has 
been  repeatedly  observed  (185,  225,  270,  299,  317) 
in  the  hepatic  sinusoidal  system  as  well  as  in  the 
capillary  beds  of  the  mesenteric  distribution,  the 
pancreas,  and  the  spleen.  Of  course,  the  capillaries 
accessible  to  direct  visualization  are  an  infinitesimal 
fraction  of  the  total  and  probably  not  a  representative 
or  random  sampling.  Intermittency  probably  occurs 
during  normal  life  and  may  be  involved  in  altering 
actively  the  total  resistance  to  flow,  but  it  seems  not 
unlikely  that  it  is  an  expression  of  capillary  instability 
resulting  from  a  critical  reduction  in  distending  pres- 
sures by  "path-length  resistance." 

Innumerable  routes  of  various  lengths  may  be 
followed  by  the  blood  from  the  aorta  to  the  hepatic 
vein.  On  the  arterial  side,  the  gastric,  mesenteric,  and 
colic  vessels  are  particularly  long  and  variable  with 
interconnection  by  arcades  that  may  serve  to  equalize 
input  pressures  and  flows.  The  hepatic  and  splenic 
arteries  are  shorter  and  more  direct  but  path  length 
varies  nonetheless  because  hilar  entry  results  in  short 
routes  in  the  more  central  regions  and  longer  ones 
by  way  of  the  parenchymal  tissues  situated  at  the 
periphery.  The  same  configuration  applies  to  the 
hepatic  portal  inflow  tract  but  here  the  low  pressure 
head  and  the  minimal  cross-sectional  resistance  ap- 
pear to  confer  greater  importance  upon  path  length 
as  a  determinant  of  energy  loss.  Daniel  &  Prichard 
(10 1,  102)  claim  that  portal  blood  does  not  always 
perfuse  the  entire  liver  for  this  reason.  They  used 
rapid  serial  angiography  as  a  means  of  assessing 
distribution  of  flow  following  injection  of  Thorotrast 
into  a  mesenteric  vein  in  cats,  rabbits,  guinea  pigs, 
pigs,  and  goats.  The  contrast  medium  was  usually 
found  to  move  freely  into  the  portal  vein  and  its 
branches,  then  into  the  sinusoids,  opacifying  the 
organ  diffusely  with  sharp  definition  of  its  profile, 
and  finally  into  the  hepatic  veins  and  inferior  vena 
cava.  In  a  few  rats  and  kittens,  a  "restricted  intra- 
hepatic circulation"  was  demonstrable  with  failure  of 
the  Thorotrast  to  fill  the  outermost  ramifications  of 
the  portal  vein,  with  an  irregular  and  patchy  opacifi- 
cation limited  to  the  central  tissues  and  with  filling 
of  only  those  segments  of  the  hepatic  veins  which  lie 
relatively  near  the  hilum.  This  phenomenon  could  be 
induced  by  stimulation  of  the  hepatic  nerves  and  by 


THE    HEPATIC    CIRCULATION 


I4I 


partial  hepatectomy  suggesting  the  possibility  that 
neurovascular  mechanism  is  invoked.  Although  the 
contrast  substance  appeared  to  move  more  rapidly 
into  the  hepatic  veins  with  the  "restricted"  pattern, 
no  evidence  of  veno-venous  shunting  could  be  ad- 
duced. Circulation  time  estimated  in  this  way  is  not  a 
reliable  guide  to  the  actual  velocity  of  the  blood.  Any 
reduction  in  the  volume  of  blood  held  in  the  vessels 
would  reduce  the  transit  time  without  necessarily 
affecting  flow.  The  rise  and  fall  of  Thorotrast  concen- 
tration in  the  entering  blood  must  also  be  taken  into 
account  as  well  as  the  extent  of  dilution  by  arteriolar 
inflow.  Blood  flow  was  not  measured  and  it  is  impos- 
sible to  say  whether  the  alteration  in  portal  inflow  was 
associated  with  a  compensatory  change  in  hepatic 
arteriolar  resistance.  The  phenomenon  suggests  that 
the  peripheral  sinusoids  which  can  be  examined 
directly  and  in  which  intermittency  has  been  observed 
may  be  peculiarly  susceptible  to  shifts  in  the  pattern 
of  perfusion.  It  is  probable  that  the  same  considera- 
tions are  applicable  to  intermittency  in  mesenteric 
and  splenic  vessels.  Determination  of  the  distribution 
of  circulation  (or  transit)  times  across  the  splanchnic 
bed  in  the  dog  (303)  indicates  that  separate  popula- 
tions of  path  lengths  (e.g.,  hepatic  arterial,  splenic, 
and  mesenteric  channels)  overlap  markedly,  each 
possessing  very  short  and  very  long  routes.  Hence  the 
effect  of  special  distribution  patterns  within  any  one 
circuit  (such  as  the  hepatic)  would  have  little  detect- 
able influence  upon  the  composition  of  draining  blood. 
The  fact  that  BSP  transfer  remains  relatively  constant 
over  a  wide  range  of  flow  suggests  that  parenchymal 
cells  are  uniformly  perfused  under  most  circumstances 
(305)- 

I  'iscosity 

The  equation  of  vascular  resistance  with  the  num- 
ber, cross  section,  and  length  of  the  arterioles  alone 
implies  that  blood  flows  freely  without  turbulence  as 
an  ideal  Newtonian  fluid  in  accord  with  Poiseuille's 
law.  In  reality,  of  course,  blood  is  a  highly  complex 
and  heterogenous  suspension  of  red  cells  in  a  colloidal 
solution  of  proteins.  Much  evidence  indicates  that  its 
viscosity  is  altered  by  the  character  of  the  conduit,  by 
perfusing  pressure,  and  by  flow  (202).  Although  there 
is  little  reason  to  believe  that  critical  velocities  are 
frequently  exceeded  in  any  portion  of  the  splanchnic 
vasculature,  turbulence  may  be  induced  by  respira- 
tory and  body  movements  which  check  the  flow  of 
blood  and  give  rise  to  transient  vortices  and  eddies. 
Turbulence  may  also  arise  during  arterial  pulsation 


with  a  tendency  for  the  blood  to  move  backward,  even 
in  the  capillaries,  during  diastole.  Laminar  flow  re- 
sults in  inward  movement  of  red  cells  and  accumula- 
tion about  the  axis  presumably  owing  to  nonuniform 
distribution  of  the  shearing  force  across  the  lumen  of 
the  vessel  and  to  shear  rate  dependence  of  plasma 
viscosity  (202,  301).  However,  this  process  appears 
to  be  inconsistent,  so  that  turbulence  of  a  sort  always 
occurs  and  produces  a  "mixed  flow."  Both  the  cell- 
free  zone  of  plasma  and  the  high  velocity  differential 
next  to  the  vessel  walls  permit  "slippage"  and  result 
in  a  lower  than  expected  viscosity  in  vessels  of  small 
diameters  where  the  volume  of  "plasma-lining"  is 
proportionately  larger.  From  this  layer  is  derived  the 
plasma  which  enters  capillaries  by  the  process  of 
plasma-skimming  observed  in  the  hepatic  sinusoids 
and  mesenteric  capillaries  by  Knisely  (185)  and 
others  (225,  270,  299).  Consequently,  the  blood 
perfusing  capillaries  may  vary  widely  in  viscosity  as 
well  as  hematocrit  with  resultant  irregularities  that 
are  not  readily  resolved  in  hemodynamic  analysis. 
The  development  of  turbulence  under  various  cir- 
cumstances and  the  effects  of  anomalous  viscosity 
complicate  matters  still  more. 

With  turbulence,  a  more  complete  admixture  of 
blood  results.  Thus  the  blood  entering  the  arteries 
from  the  heart  has  undergone  a  thorough  stirring  and 
may  be  regarded  as  having  a  relatively  uniform  com- 
position. Within  the  large  veins,  lamination  results 
in  an  unequal  mixing  of  converging  streams  of  vary- 
ing composition  so  that  "representative  sampling" 
from  the  inferior  vena  cava,  for  example,  may  be 
difficult  or  impossible.  Similarly,  "layering"  may  oc- 
cur in  the  portal  vein  and  give  rise  to  nonuniform 
distribution  within  the  liver,  of  blood  coming  from 
the  gastrointestinal,  pancreatic,  and  splenic  veins. 
This  possibility,  first  broached  by  Glenard  in  1890, 
was  given  experimental  support  by  studies  of  Serege, 
who  found  that  India  ink  injected  into  the  splenic 
vein  of  dogs  was  carried  preferentially  to  the  left  lobe 
of  the  liver.  Later,  Bartlett  et  al.  (24)  found  that 
absorption  of  copper  sulfate  from  the  stomach  and 
duodenum  of  dogs  resulted  in  deposition  preponder- 
antly in  the  left  lobe  and  that  absorption  from  the 
ileum  led  to  deposition  in  the  right.  Gopher  &  Dick 
(95)  observed  "stream  lines"  in  the  canine  portal  vein 
directly  with  transillumination  following  injection  of 
trypan  blue  into  various  portal  tributaries.  Perhaps 
the  most  convincing  evidence  of  "bilaterality  of 
portal  flow"  was  reported  in  1945  by  Hahn  et  al.  (168). 
These  workers  injected  radioactive  phosphorus  as 
orthophosphate    into    the    splenic    vein,    mesenteric 


I  41  2 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


vein,  or  jugular  vein  of  dogs  after  placing  loose  liga- 
tures around  the  portal  vein,  hepatic  artery,  and 
inferior  vena  cava.  After  approximately  3  sec  the 
ligatures  were  tied  and  the  liver  removed  immedi- 
ately, transverse  sections  cut  and  "wet  ashed,"  and 
radioactivity  determined  on  the  measured  aliquots. 
After  injection  into  the  jugular  vein,  the  radioactivity 
was  found  uniformly  distributed  through  the  liver 
from  right  to  left.  Three-quarters  of  the  radioactivity 
appeared  in  the  left  side  of  the  liver  after  injection  into 
the  splenic  vein,  and  approximately  the  same  pro- 
portion appeared  on  the  opposite  side  after  injection 
into  the  mesenteric  vein.  Each  observation  was  made 
but  once,  under  anesthesia,  with  the  abdomen  open 
and  after  extensive  manipulation  of  the  viscera. 
Hence,  application  of  these  data  to  the  situation  in 
man  is  most  uncertain.  Nonetheless,  there  has  been  a 
tendency  among  clinicians  to  explain  the  distribution 
of  pathology  in  human  hepatic  disease  on  this  basis. 

Barnett  &  Cochrane  (23)  have  recently  pointed 
out  the  importance  of  species  and  individual  anatomic 
peculiarities  in  altering  lamination.  Experiments  on  a 
model  system  proved  helpful  in  evaluating  these 
effects  of  branching  and  convergence  of  tributaries 
upon  the  distribution  of  streamlines  at  varying  rates 
of  flow  with  different  perfusates.  For  branches  like 
those  at  the  hilum  of  the  liver,  they  found  that  the 
chance  that  particles  in  the  major  trunk  "remote 
from  the  branch  would  pass  into  it  are  greater  with 
increasing  viscosity  and  decreasing  width  of  the 
branch,"  the  angle  of  outflow  having  little  significance 
at  the  rates  of  flow  usually  prevailing.  Thus,  for  a 
fluid  like  blood,  small  branches  would  seem  likely  to 
be  perfused  by  a  fairly  representative  sample  of  the 
total  inflow.  "Moreover,  the  manner  of  formation  of 
the  portal  vein  is  important.  Where  it  is  formed  by  a 
tributary  joining  a  straight  main  vein  (Y)  particles 
are  more  likely  to  pass  across  the  portal  vein  when  the 
rate  of  flow  in  the  tributary  is  large  and  its  diameter 
small.  The  converse  is  true  where  the  portal  vein  is 
formed  by  the  symmetrical  union  (Y)  of  a  major  and 
minor  tributary,  unless  the  rate  of  flow  in  the  minor 
tributary  is  very  high.  In  both  types  of  junction  more 
crossing-over  of  the  streams  occurs  when  the  angle  of 
union  is  larger  than  when  it  is  acute." 

Although  these  considerations  are  of  importance  it 
is  probable  that  local  movements  of  vessels  are  of 
even  greater  significance  in  determining  the  extent 
to  which  the  blood  streams  commingle  in  the  portal 
vein  in  the  intact  animal  and  man.  In  the  anesthetized 
dog  secured  in  the  dorsirecumbent  position,  with  the 
abdomen    open    and    respiratory    movements    mini- 


mized, it  is  not  surprising  that  lamination  may  be 
detected  in  the  inferior  vena  cava  (132).  And  even 
under  these  circumstances  Cole  and  his  associates 
(89)  found  that  I131-labeled  rose  bengal  was  uniformly 
distributed  in  the  liver  following  injection  into  four  of 
the  different  divisions  of  the  portal  vein  draining  the 
spleen,  small  intestine,  cecum,  and  colon  of  the  dog.  In 
intact  man  and  dog  it  has  proved  a  much  more  elu- 
sive phenomenon.  Portal  venography  by  intrasplenic 
injection  of  contrast  substance  has  usually  failed  to 
show  much  evidence  of  "physiological  bilaterality." 
Streamlining  or  a  filling  defect  in  the  shadow  of  the 
portal  vein  at  the  point  of  entry  of  the  superior  mes- 
enteric vein  attributable  to  lateral  filling  by  radio- 
lucent  blood  from  the  mesenteric  vein  has  been 
reported  (15,  116)  but  it  is  by  no  means  a  constant,  or 
even  a  frequent  observation.  Indeed,  Patrassi  and  his 
colleagues  (229)  claim  that  injection  of  contrast  sub- 
stances into  the  spleen  tends  rather  to  make  the  right 
lobe  more  opaque  than  the  left.  In  addition,  they 
found  no  significant  difference  between  the  transit 
times  from  spleen  to  each  of  the  two  lobes  when  small 
amounts  of  sodium  para-aminohippurate  or  red  blood 
cells  labeled  with  radioactive  phosphorus  were  in- 
jected into  the  spleen  of  human  subjects.  Similar 
studies  in  dogs  yielded  the  same  results.  Incomplete 
portal  venous  admixture  may  therefore  be  regarded 
as  a  potential  but  unlikely  result  of  the  viscous 
properties  ot  blood.  Hemodynamically  it  is  important 
chiefly  with  respect  to  the  movement  of  red  cells  and 
variation  of  hematocrit  within  the  splanchnic  and 
hepatic  vessels. 

Volume  and  Distensibility 

The  potential  volume  of  the  vasculature  which 
houses  the  "circulating  blood"  of  the  splanchnic  bed 
may  be  analyzed  dimensionally  with  the  data  pub- 
lished by  Mall  (206)  which  have  already  been 
employed  in  determining  the  major  points  of  vascular 
resistance.  Using  data  for  the  length  of  vessels  in  the 
mesenteric  circuit  from  the  work  of  Schleier  (261), 
and  estimates  of  vascular  lengths  in  the  liver,  the 
total  volume  of  each  vascular  category  may  be  com- 
puted as  for  cylinders.  The  internal  volume  of  hepatic 
and  mesenteric  arterial  inflow  tract  in  a  dog  of 
"medium  size"  (liver  weight — ca.  175  g)  was  found 
by  this  means  to  amount  to  4.1  ml;  the  mesenteric 
and  portal  venous  systems,  42.6  ml;  the  sinusoids, 
32.3  ml;  and  the  hepatic  venous  outflow  tract, 
4 1. 1  ml.  Thus  the  arteries  accounted  for  some  3.3  per 
cent  of  the  total,  the  sinusoids  and  mesenteric  capil- 


THE    HEPATIC    CIRCULATION 


1413 


laries  foi-27.5  per  cent,  and  the  veins  for  the  remainder 
or  69.2  per  cent.  Assuming  that  the  gastric,  colic, 
and  pancreatic  vessels  hold  no  more  than  twice  the 
amount  in  the  mesenteric  vessels,  and  omitting  the 
spleen,  the  splanchnic  bed  in  Mall's  "dog"  held  a 
total  of  153  ml  or  28.5  per  cent  of  the  blood  volume 
of  an  animal  weighing  7  kg  (taking  the  liver  weight 
and  blood  volume  as  2.5  per  cent  and  7.7  per  cent, 
respectively,  of  body  weight).  Since  the  total  values 
compare  favorably  with  those  yielded  by  other 
methods,  the  figures  indicating  distribution  of  volumes 
may  be  regarded  as  equally  valid  in  pointing  to  a 
predominance  of  the  veins  in  determining  the  volume 
of  blood  contained  within  the  liver  and  the  splanchnic 
bed  at  rest.  As  noted  above,  the  veins  of  the  splanchnic 
bed  are  generously  supplied  with  muscle  and  it  may 
be  surmised  that  their  capacity  is  subject  to  change 
by  venomotor  activity. 

The  obvious  constriction  or  dilatation  of  veins — 
including  those  of  the  splanchnic  vasculatures — in 
response  to  chilling,  tapping,  warming,  or  various 
injurious  manipulations  indicates  clearly  the  ability 
of  the  venous  musculature  to  alter  the  calibre  and 
length  of  the  veins  (132).  The  mechanisms  by  which 
venous  smooth  muscle  effects  these  changes,  the 
integration  and  function  of  circular,  spiral,  and  longi- 
tudinal fibers  in  different  veins,  and  the  patterns  of 
contraction  and  relaxation  are  most  obscure.  Zweifach 
(317)  and  others  (132)  have  reported  spontaneous 
"intermittent  activity"  not  only  in  the  arteries  and 
arterioles  of  the  mesenteries  but  also  in  the  small 
venules,  with  cycles  of  alternate  filling  and  emptying 
that  appear  to  be  irregular,  unpredictable,  and 
independent  of  the  innervation.  Similar  fluctuations 
have  been  observed  by  Knisely  and  his  associates 
(185)  at  the  level  of  the  central  veins  and  sinusoids  in 
the  liver,  presumably  secondary  to  activity  of  the 
well-muscled  sublobular  veins.  The  mass,  configura- 
tion, and  extent  of  the  hepatic  venous  musculature 
ranges  widely  among  species  and  is  apparently 
capable  of  a  corresponding  range  of  constrictive 
action,  from  complete  sphincteric  throttling  at  in- 
numerable points  throughout  the  total  drainage  net 
to  a  modest  reduction  in  capacity.  Unfortunately, 
quantitative  data  are  lacking  and  even  the  qualita- 
tive studies  are  so  incomplete  and  fragmentary  that 
it  is  impossible  at  present  to  assess  the  pattern  and 
extent  of  change  at  different  levels  in  a  variety  of 
species. 

Spontaneous  vasomotion  appears  to  be  randomly 
distributed,  involved  in  strictly  local  shifts  in  volume 
but  not  in  sweeping  changes  that  move  blood  between 


major  units  of  the  cardiovascular  system.  Studies 
based  upon  measurements  of  circulating  splanchnic 
blood  volume  (regional  dilution  of  I '"-labeled  HSA) 
indicate  that  large  changes  in  SBV  may  occur  in  the 
course  of  normal  circulatory  adjustments.  In  man,  for 
example,  both  tilting  into  the  upright  position  and 
exercise  in  recumbency  have  been  found  to  induce 
splanchnic  vasoconstriction  with  a  fall  in  hepatic 
blood  flow  and  splanchnic  blood  volume  (42).  It  is 
not  yet  clear  if  a  fall  in  distending  pressure  secondary 
to  a  more  marked  increase  in  the  gastrointestinal  and 
splenic  inflow  resistance  than  in  hepatic  venous  out- 
flow resistance,  or  if  an  active  reduction  in  venous 
capacity  is  responsible.  The  fact  that  splanchnic 
denervation  interferes  with  the  response  to  tilting 
suggests  that  venoconstriction  may  be  essential.  Even 
if  capacity  is  affected  by  venomotor  activity,  however, 
the  extent  of  filling  still  depends  upon  the  level  of 
distending  pressure  and  upon  the  manner  in  which 
distensibility  is  altered  by  "stretch"  itself. 

The  arrangement  of  collagenous  tissue  in  the  ad- 
ventitia,  of  muscle  in  the  media,  and  of  elastic  tissue 
in  the  inner  layers  of  vessels  appears  to  result  in  an 
elastic  behavior  resembling  that  of  three  springs  in 
parallel,  the  weakest  representing  the  elastic  tissue; 
the  intermediate,  muscle;  and  the  stiffest,  collagen. 
Interconnections  and  viscous  changes  in  muscle  and 
elastic  tissue  complicate  the  effort  to  devise  a  truly 
representative  model  (31,  241)  [see  also  Chapters 
24  and  26  of  this  volume].  The  stretch  or  volume- 
pressure  response  curve  yielded  by  isolated  vessels 
proves  to  be  concave  to  the  pressure  axis  at  low  pres- 
sures, linear  over  an  intermediate  range,  and  finally 
convex  at  high  pressures,  suggesting  that  vascular 
distensibility  is  dominated  initially  by  muscle,  then, 
by  elastic  tissue  and,  finally,  by  collagen  and  fibrous 
tissue,  as  stretching  occurs.  Such  a  sigmoid  curve  has 
been  obtained  for  canine  splanchnic  veins  under  a 
variety  of  conditions  in  situ  (4,  7).  The  inflections 
occur  at  quite  different  pressures  than  they  do  in  the 
aorta  in  conformity  with  the  differences  in  structure. 
The  concavity  to  the  pressure  axis  and  flattening 
occur  at  a  much  lower  pressure  (at  about  40  cm  saline 
as  opposed  to  140  mm  Hg  for  the  aorta)  indicating 
dominance  of  fibrous  tissue  in  the  vein.  A  more 
marked  increase  in  splanchnic  venous  distensibility 
is  evident  at  physiologic  pressures  during  the  vaso- 
constrictive action  of  catecholamines,  presumably 
because  smooth  muscle  contributes  more  importantly 
under  these  circumstances.  At  lower  pressures  (below 
15  cm  saline),  or  when  constriction  results  in  a  very 
low  venous  cross  section,  distensibility  seems  to  de- 


1 4i4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


crease  because  of  the  operation  of  Laplace's  law. 
After  a  period  of  time  at  high  pressures  the  stretched 
vein  does  not  return  at  once  to  the  control  volume 
when  distending  pressures  are  lowered  to  the  control 
but  assumes  temporarily  a  new  larger  "zero  volume." 
The  viscous  element  which  is  responsible  for  this 
phenomenon  is  particularly  difficult  to  explain.  To 
some  extent  it  may  be  referred  to  architectural  ad- 
justments such  as  slippage  or  uncoiling  of  intertwined 
elements,  but  all  tissues  in  the  wall,  under  sufficiently 
prolonged  stress,  are  subject  to  a  kind  of  viscous  flow. 
Alexander  (4,  5,  7)  has  encountered  the  same  prob- 
lem in  a  somewhat  different  form  in  the  course  of  a 
study  of  splanchnic  venous  distensibility  in  anesthe- 
tized dogs.  Volumes  of  blood  were  injected  by  a  motor- 
driven  syringe  at  constant  rates  (10 — 250  ml  min) 
into  the  vein  draining  a  loop  of  ileum  isolated  with 
all  collateral  vessels  and  nerves  ligated  and  cut. 
Simultaneous  arterial  and  venous  pressure  measure- 
ments permitted  direct  determination  of  pressure- 
volume  relationships.  By  this  means  two  types  of 
distensibility  were  evident;  /)  rapid  elastic  expansion 
yielding  the  expected  sigmoid  pressure-volume  curve 
during  the  injection  of  relatively  small  volumes  of 
blood  and,  2)  an  additional,  more  slowly  developing 
distention  increasingly  apparent  at  slower  injection 
speeds.  Alexander  attributes  the  latter  phenomenon 
to  viscous  creep  and  refers  to  it  as  "delayed  com- 
pliance." Apparently,  it  is  a  continuously  changing 
factor,  possibly  arising  from  the  operation  of  multiple 
viscoelastic  units  arranged  in  series  with  the  other 
components.  Whatever  the  mechanism,  delayed 
compliance  may  be  of  major  importance  in  deter- 
mining splanchnic  vascular  pooling  at  any  distending 
portal  venous  pressure. 


SECONDARY    DETERMINANTS    OF    HEPATIC 
HEMODYNAMIC    ADJUSTMENTS 

Although  the  dimensions  and  the  physical  proper- 
ties of  all  parts  of  the  splanchnic  vascular  bed  are 
primarily  responsible  for  its  over-all  hemodynamic 
character,  both  circulatory  stability  and  rearrange- 
ment are  mediated  by  essential  secondary  mecha- 
nisms. Neural,  humoral,  and  physical  agents  are 
demonstrably  involved  in  the  maintenance  of  the 
"reference"  state  and  in  the  production  of  appropriate 
patterns  of  response.  Change  in  any  one  of  these 
factors  elicits  adjustments  in  all  the  others  that  must 
also  be  taken  into  account.  A  rich  innervation  assures 
integration    and    spread    of    vascular    adjustments. 


Whether  neural  activity  is  also  responsible  for  the 
tone  of  vascular  smooth  muscle  remains  uncertain. 
Xo  matter  how  defined,  tone  is  not  clearly  dependent 
upon  a  continuous  release  of  neural  impulses.  A  very 
slow  and  indetectable  discharge  rate  might  be  in- 
volved, but  local  factors,  chemical  and  physical,  still 
seem  to  take  precedence  over  and  replace  neural 
regulation  under  certain  circumstances.  Neurohu- 
moral transmitters,  such  as  epinephrine,  norepineph- 
rine, and  acetylcholine  may  also  have  considerable 
importance,  contributing  by  local  release  in  the 
maintenance  of  tone  observed  following  denervation, 
for  example,  or  by  release  into  the  circulation,  in 
systemic  integrations.  Other  local  biochemical  factors 
that  must  be  considered  to  participate  include  oxygen, 
carbon  dioxide,  hydrogen  ion,  and  metabolites  like 
histamine  or  serotonin.  Among  the  physical  deter- 
minants are  to  be  numbered  intra-abdominal  pres- 
sure, gravity,  intestinal  motility,  and  the  changes 
associated  with  respiration  and  body  movements. 

Neural  Determinants 

The  nerves  of  the  liver,  gall  bladder,  and  bile  ducts 
form  a  plexiform  structure  made  up  of  numerous 
small  ganglia  with  a)  the  anterior  hepatic  plexus 
(derived  from  the  left  portion  of  celiac  plexus  and  the 
right  abdominal  branch  of  the  left  vagus)  immeshing 
the  hepatic  artery,  and  b)  the  posterior  hepatic  plexus 
(derived  from  the  right  portion  of  the  celiac  plexus 
and  the  branches  of  the  right  vagus  that  traverse  the 
celiac  plexus)  investing  the  portal  vein  and  bile  duct 
(8,  190,  253).  Ganglia  required  for  parasympathetic 
synapses  are  not  present.  The  spleen  receives  its  supply 
almost  entirely  from  the  celiac  plexus  possibly  with 
some  contribution  by  the  left  phrenic  nerve.  Like  the 
liver,  the  spleen  receives  no  parasympathetic  com- 
ponent (53,  294).  Throughout  the  splanchnic  bed 
bundles  of  nerves  accompany  blood  vessels  in  their 
distribution  to  the  tissues.  Within  the  walls  of  the 
larger  arteries  subsidiary  plexuses  are  arranged  in  a 
more  or  less  orderly  manner.  An  outer  plexus  in  the 
adventitia,  a  deeper  plexus  between  adventitia  and 
media,  and  a  plexus  within  the  muscular  media  have 
been  recognized.  The  complexity  of  these  networks 
becomes  progressively  less  marked  in  the  vessel  walls 
as  caliber  diminishes  until  at  the  capillars'  level  it  i^ 
difficult  or  impossible  to  find  any  evidence  of  specific 
innervation.  The  close  association  of  vagal  and  sym- 
pathetic fibers  in  many  regions  does  not  imply  an 
association  in  controlling  vascular  smooth  muscle. 
Indeed  the  reverse  seems  to  be  true  for  vagal  fibers 


THE     HEPATIC    CIRCULATION 


1415 


clearly  innervate  the  smooth  muscle  of  gastrointestinal 
tract,  biliary  tract,  and  pancreatic  ducts  (including 
secretory  cells),  but  none  has  been  traced  to  the  blood 
vessels  (8,  190,  249,  253).  The  innervation  of  the  blood 
vessels  within  the  splanchnic  viscera  appears  to  be 
derived  exclusively  from  the  sympathetic  venous 
system.  Moreover,  all  the  sympathetic  efferent  path- 
ways are  now  believed  to  be  vasoconstrictive  in  ac- 
tivity. 

Recent  work  (80)  strongly  supports  the  view  that 
neither  sympathetic  nor  dorsal  root  vasodilator  fibers 
run  to  the  splanchnic  vasculature.  The  appearance  of 
vasodilation  evident  in  a  rise  in  splanchnic  blood  flow 
with  no  blood  pressure  change,  or  in  the  face  of  a 
reduction  in  blood  pressure,  is  therefore  to  be  referred 
to  ''diminished  vasoconstrictive  tone."  Although  this 
conclusion  is  not  universally  acceptable,  it  must  be 
admitted  that  a  great  weight  of  evidence  gives  it 
strong  support.  Direct  stimulation  of  the  splanchnic 
nerves,  the  hepatic  plexus,  or  splenic  nerve  by  a 
tetanizing  current  induces  only  a  vasoconstrictive 
response  in  vivo  or  in  situ  which  may  be  expressed  by 
diminished  blood  flow,  by  a  tendency  for  the  liver 
and  spleen  to  contract,  by  diminished  cross  section  of 
intrahepatic  vessels  under  direct  observation,  and  by 
peripheral  ischemia  of  the  liver  evident  in  micro- 
radiographic  studies  (11,  20,  25,  102,  104,  132,  161, 
204,  270,  299).  Variation  in  the  extent  of  this  response 
appears  to  be  referable  to  differences  in  species  studied 
and  in  the  techniques  employed,  but  the  general 
agreement  upon  its  qualitative  features  is  unmistak- 
able. In  contrast,  stimulation  of  the  vagus  produces 
little  or  no  obvious  change  in  intrahepatic  or  splanch- 
nic resistance  under  similar  circumstances  (11,  104, 
161,  270).  Richins  (248)  has  claimed  that  vasodilation 
may  occur  in  the  pancreas  during  stimulation  of  the 
celiac  plexus  after  cutting  the  splanchnic  nerves  in 
the  cat,  because  "quick-freezing"  the  pancreas  during 
this  period  and  careful  preparation  of  microscopic 
sections  of  the  tissue  reveal  larger  cross  sections  of  the 
arterioles  and  veins.  This  method  is  obviously  open  to 
question  because  it  requires  the  assumption  that 
fixation  and  preparation  of  the  tissues  for  study  do 
not  affect  the  state  of  the  vessels  which  obtains  at  the 
moment  of  freezing.  Somewhat  stronger  support  for 
active  cholinergic  hepatic  vasodilation  under  special 
conditions  has  been  put  forward  by  Grayson  and  his 
associates  (147,  157).  These  workers  have  attributed 
increments  in  hepatic  blood  flow,  measured  by  inter- 
nal calorimetry  in  intact  unanesthetized  rats  and 
rabbits,  during  increments  in  arterial  pressure  pro- 
duced by  infusion  of  epinephrine  or  by  transfusion  of 


rat  blood,  to  reflex  vasodilation  because  the  response 
could  be  blocked  by  section  of  the  right  vagus,  celiac 
neurectomy,  atropine,  and  hexamethonium.  They 
could  not  compute  the  changes  in  hepatic  vascular 
resistance,  however,  and  it  seems  more  likely  that  the 
failure  for  blood  flow  to  change  after  neural  blockade 
during  the  rise  in  blood  pressure  is  the  result  of  active 
vasoconstriction.  In  this  view,  an  intact  innervation 
maintains  flow  by  minimizing  or  blocking  the  funda- 
mental vasoconstrictive  response  rather  than  by 
inducing  vasodilation.  In  fact,  Grayson  and  Ginsburg, 
like  manv  other  workers,  have  found  that  stimulation 
of  the  cut  distal  end  of  the  vagus  has  no  effect  upon  the 
hepatic  circulation. 

The  undeniable  fact  of  abdominal  pain  clearly 
indicates  the  presence  of  afferent  pathways  mediating 
visceral  perception.  Within  and  about  the  vessels  of 
the  splanchnic  bed,  myelinated  and  nonmyelinated 
fibers  may  be  found  ending  freely  in  a  fine  meshwork 
or  in  Pacinian  corpuscles.  The  first  seem  to  accompany 
the  vessels  closely,  branching  dichotomously  at  each 
bifurcation  and  losing  their  myelin  sheaths  distal  to 
the  last  branching.  A  filmy  plexus  of  nonmyelinated 
nerves  about  the  vessels  extends  into  the  avascular 
portions  of  the  mesenterv,  onto  the  visceral  perito- 
neum covering  the  intestines  and  bladder,  and  into  the 
substance  of  the  liver  and  kidney.  Sheehan  (271) 
found  that  small  nerve  ganglion  cells  appear  in  this 
network  at  wide  intervals  and  concluded  that  single 
fibers  "branch  and  anastomose  in  a  true  network 
arrangement."  Fine  twigs  may  be  seen  occasionally 
issuing  from  the  plexus  to  end  freely  among  the  en- 
dothelial cells.  Since  they  are  demonstrable  after 
removal  of  the  splanchnic  sympathetic  chain  and  the 
vagi,  they  are  presumably  somatic  in  origin  and  pos- 
sibly responsible  for  visceral  sensations.  Perhaps  the 
most  prominent  and  clearly  definable  afferent  nerve 
endings  associated  with  the  splanchnic  vasculature 
are  the  Pacinian  corpuscles.  These  structures  vary 
considerably  in  size  and  shape,  ranging  from  easily 
visible  ovoid  bulbs  (1.0  by  0.6  mm  in  diameter)  to 
end  bulbs  measuring  only  8  by  4  n.  Typically  the 
Pacinian  corpuscle  is  composed  of  a  relatively  thick, 
laminated  capsule  with  a  central  core  through  which 
the  main  afferent  nerve  runs  to  its  termination.  It 
lies  embedded  in  the  vessel  walls  particularly  in  the 
pancreas,  lymph  nodes,  and  mesenteries  or  in  the 
surrounding  connective  tissue  and  fat,  usually  ar- 
ranged with  the  long  axis  parallel  to  the  vessel.  The 
number  of  corpuscles  varies  from  species  to  species, 
widely  distributed  and  common  in  the  cat,  but  almost 
absent  in  the  mesentery  of  the  dog,  rabbit,  mouse. 


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CIRCULATION    II 


and  man  (251).  Electrophysiologic  studies  (139,  141) 
indicate  that  Pacinian  corpuscles  in  the  skin  and 
mesenteries  are  sensitive  to  pressure  changes.  The 
spontaneous  outflow  of  impulses  in  large  afferent 
fibers  in  the  splanchnic  nerve  seem  to  derive  in  the 
main  from  the  Pacinian  corpuscles.  Gammon  & 
Bronk  (139),  recording  impulses  from  the  peripheral 
end  of  the  splanchnic  nerve  and  its  branches  in  cats, 
found  group  discharges  synchronous  with  systolic  ar- 
terial pressure  peaks.  During  constant  perfusion  a 
sustained  discharge  was  observed.  Sarnoff  &  Yamada 
(259)  have  suggested  that  Pacinian  corpuscles  may 
mediate  the  changes  in  arterial  pressure  noted  during 
manipulation  of  the  splanchnic  vessels,  but  recent 
work  (40)  indicates  that  extrasplanchnic  baroreceptors 
are  involved  and  that  mesenteric  pressure  receptors  do 
not  contribute  significantly,  at  least  in  species  other 
than  the  cat.  Nevertheless,  afferent  impulses  originat- 
ing in  these  areas  may  be  implicated  in  local  and 
central  reflex  arcs  of  importance  to  hepatic  circulatory 
adjustments. 

Impulses  passing  from  the  splanchnic  bed  by  all 
these  afferent  routes  evidently  pass  directly  to  the 
central  venous  system.  Central  representation  of 
afferent  fibers  from  the  abdomen  has  been  explored 
by  a  variety  of  methods.  Bain  et  al.  (18)  found  that 
stimulation  of  the  central  end  of  the  divided  splanch- 
nic causes  pupillary  dilatation  that  is  due  to  inhibi- 
tion of  the  oculomotor  nucleus  and  not  to  change  in 
blood  pressure,  release  of  adrenaline,  or  activity  of 
somatic  afferent  fibers,  since  it  occurs  after  transection 
of  the  spinal  cord  between  the  fifth  and  sixth  thoracic 
roots.  Using  this  method  as  a  means  of  detecting 
splanchnic  afferent  impulses  they  found  that  splanch- 
nic afferents  enter  the  cord  from  the  sympathetic 
chain  via  the  rami  and  the  dorsal  roots.  No  synaptic 
junctions  seem  to  occur  in  the  dorsal  roots  or  in  the 
lateral  sympathetic  ganglia  which  resemble  those  for 
sympathetic  afferents  in  the  sympathetic  ganglia. 
According  to  Downman  (113),  stimulation  of  these 
fibers,  in  both  cats  and  dogs,  evokes  detectable  changes 
in  cerebral  action  potentials  within  the  trunk  areas  of 
somatic  sensory  representation,  viz,  contralateral 
area  I  and  both  contralateral  and  ipsilateral  area  II. 
The  distribution  and  latency  of  the  responses  elicited 
by  centripetal  stimulation  of  the  splanchnic  nerve  do 
not  differ  from  those  elicited  by  stimulation  of  a  body- 
wall  nerve.  Amassian  (9)  reported  similar  cortical 
representation  of  visceral  afferent  impulses  in  the 
rabbit,  monkey,  dog,  and  cat  with  maximal  primary 
cortical  responses  in  the  trunk  region  of  contralateral 
areas  I  and  II,  with  ipsilateral  representation  in  area 


II  for  the  cat  alone.  The  lack  of  correlation  between 
the  number  of  receptors  and  the  intensity  of  responses 
suggests  that  splanchnic  afferent  projection  may  be 
but  partially  derived  from  Pacinian  bodies.  In  addi- 
tion, the  projection  to  somatovisceral  areas  in  the 
cortex  raises  additional  doubt  whether  Pacinian 
corpuscles  are  primarily  concerned  in  vascular  read- 
justments rather  than  visceral  sensation.  The  path- 
ways through  the  cord  have  been  mapped  out  to  some 
extent  by  Aidar  et  al.  (2)  who  found  that  action 
potentials  were  detectable  in  the  cat  to  levels  as  high 
as  the  thalamus.  Faster  impulses  course  through  the 
ipsilateral  fasciculus  and  nucleus  gracilis,  internal 
arcuate  fibers,  and  contralateral  medial  lemniscus  to 
reach  the  thalamus.  Slower  impulses  ascend  in  the 
lateral  spinothalamic  tracts.  These  findings  have  been 
confirmed  by  Gardner  et  al.  (140)  in  studies  of  cortical 
projections  of  fast  visceral  afferent  impulses  in  the 
cat  and  monkey.  Since  section  of  the  dorsal  funiculi 
does  not  always  abolish  cortical  potentials  evoked  by 
stimulation  of  the  splanchnic  nerve  they  suggest  that 
additional  pathways  are  followed.  The  anatomical 
basis  for  reflex  regulation  of  the  hepatic  and  splanch- 
nic circulation  is  clearly  evident  in  these  studies.  The 
status  of  a  controlling  "vasomotor  center"  for  the 
splanchnic  bed  is  most  obscure  and  it  cannot  be  said 
with  certainty  that  discrete  splanchnic  vasomotor 
representation  is  detectable  within  the  cortex.  Never- 
theless, the  cortical  representation  of  visceral  sensory 
and  motor  functions  that  may  involve  vascular  smooth 
muscle  seems  to  imply,  on  the  one  hand,  a  measure  of 
influence  upon  splanchnic  vascular  changes  by  cortical 
activity  directly,  or,  on  the  other,  a  reflection  of 
visceral  circulatory  adjustments  in  cortical  function. 

Reflex  responses  almost  certainly  occur  within  the 
splanchnic  and  hepatic  vasculature,  although  they 
are  extremely  difficult  to  characterize.  Axon  reflexes, 
involving  afferent  nerves  like  those  responsible  for  the 
vasodilation  of  the  "flare"  in  the  skin  during  the 
"triple  response,"  are  not  demonstrable  (80).  The 
phenomenon  of  "autoregulation"  of  hepatic  blood 
flow  is  possibly  an  exception  but,  as  noted  above,  a 
local  stretch-and-response  myogenic  balance  may  be 
responsible  (180).  Expansion  of  the  portal  venous 
chamber  may  also  elicit  what  Yamada  &  Burton 
(313)  have  referred  to  as  a  "veni-vasomotor  reflex" 
characterized  by  arteriolar  vasoconstriction  proximal 
to  the  site  of  venous  distention.  Mesenteric  arteriolar 
constriction  observed  during  an  elevation  in  portal 
venous  pressure  (268)  may  be  explained  on  this  basis 
but,  here  again,  retrograde  elevation  of  pressure  to  the 
level  of  the  arterioles  with  the  slowing  of  flow  cannot 


THE    HEPATIC    CIRCULATION 


[4I7 


be  eliminated  as  a  cause  for  myogenic  activation  (180). 
The  possibility  that  elevated  hepatic  venous  pressure 
may  induce  reflex  constriction  in  the  hepatic  arterioles 
and  portal  venules  should  be  investigated.  Similarly, 
conclusive  demonstration  of  reflex  changes  mediated 
through  spinal  or  corticothalamic  centers  via  visceral 
afferent  and  efferent  arcs  is  needed.  There  is  little 
doubt  that  disturbance  of  splanchnic  and  hepatic 
vessels  or  stimulation  of  the  central  ends  of  the  cut 
splanchnic  nerves  can  give  rise  to  marked  changes  in 
systemic  hemodynamics.  In  both  man  and  experi- 
mental animals  traction  on  the  mesenteric  vessels  is 
associated  with  a  striking  fall  in  arterial  blood  pressure 
provided  the  nerve  supply  is  intact  (230,  291),  whereas 
splanchnic  nerve  stimulation  results  in  transient 
arterial  hypertension  (141).  The  mechanisms  of  these 
reactions  have  not  been  subjected  to  detailed  analysis 
and  it  is  impossible  at  present  to  evaluate  them  in 
terms  of  venous  return,  peripheral  vascular  resistances, 
and  local  splanchnic  and  hepatic  hemodynamics. 
The  splanchnic  vasculature  also  undergoes  changes 
that  appear  to  arise  reflexly  from  other  parts  of  the 
cardiovascular  system,  such  as  the  carotid  sinuses  and 
great  veins,  but  the  usual  difficulties  in  interpretation 
arise  in  connection  with  widespread  and  simultaneous 
circulatory  adjustments  in  the  remainder  of  the  body. 
Perhaps  the  venoconstriction  with  increased  carotid 
sinus  tension  and  the  venodilation  during  a  fall  in 
carotid  sinus  tension,  or  during  distension  of  the  in- 
ferior vena  cava  noted  by  Alexander  (4,  5)  in  isolated 
innervated  segments  of  the  mesenteric  veins,  may  be 
regarded  as  reasonably  clear-cut  evidence  of  reflex 
action,  but  even  here  uncertainty  must  remain  re- 
garding myogenic  and  humoral  factors.  Since  the 
venodilator  response  is  abolished  by  section  of  both 
vagi,  these  reservations  seem  ill-founded  and  a  reflex 
with  an  afferent  pathway  via  the  vagal  trunks  may  be 
postulated.  Certainly  afferent  pathways  from  other 
parts  of  the  body  seem  to  be  capable  of  activating 
visceral  neural  outflow  and  visceral  vascular  responses 
to  peripheral  stimulation.  Heating  or  chilling  the 
skin,  a  rise  of  pressure  in  the  carotid  sinus,  distention 
of  the  inferior  vena  cava,  and  stimulation  of  the 
central  end  of  the  severed  sciatic  nerve  have  all  been 
shown  to  elicit  changes  in  the  splanchnic  vasculature 
(4,  5,  132).  The  blushing  or  blanching  of  the  gastric 
or  rectal  mucosa  during  emotional  responses  (156, 
192)  also  suggests  that  cortical  activity,  mediated  by 
pathways  that  begin  in  the  cortical  motor  projection 
of  the  splanchnic  autonomic  system,  may  affect  the 
splanchnic  and  hepatic  circulation. 


Neurohumoral  Determinants 

Confusion  regarding  the  neural  determinants  of 
flows  and  volumes  within  the  splanchnic  vessels  is 
inevitable  not  only  because  responses  are  so  complex 
but  also  because  so  little  is  known  about  the  structure 
and  function  of  the  neurovascular  units.  Several  types 
of  nerve  endings  and  receptors  in  vascular  smooth 
muscle  have  been  postulated  to  account  for  the  varied 
responses  to  neural  stimulation,  to  neurohumoral 
transmitters,  and  to  blocking  agents,  but  too  little  is 
known  with  assurance  to  permit  the  formulation  of  a 
fully  satisfactory  explanation.  Recent  work  (161) 
suggests  that  norepinephrine  alone  is  released  from 
the  nerve  endings  in  the  splanchnic  vessels,  and  that 
receptors  (J3)  responsive  to  circulatory  epinephrine 
are  present  in  the  mesenteric,  splenic,  and  hepatic 
vessels.  Reserpine  appears  to  be  capable  of  releasing 
norepinephrine  from  splanchnic  nerves,  whereas  the 
circulating  amine,  released  by  the  adrenal  medulla  or 
introduced  extraneously,  can  replenish  the  depleted 
store  (69).  Dopamine,  the  immediate  precursor  to 
norepinephrine,  accounts  for  more  than  95  per  cent  of 
the  catecholamine  demonstrable  in  the  liver,  jejunum, 
and  colon  where  it  appears  to  occur  to  a  large  extent 
in  nonneural  tissue  (263).  In  the  spleen  and  the 
pancreas,  norepinephrine  and  epinephrine  are  found 
in  approximately  equal  amounts  as  in  adrenergic 
nerves.  The  large  local  supply  of  dopamine  may  imply- 
that  it  has  an  action  of  its  own.  Acetylcholine  has  been 
found  in  large  amounts  in  the  spleens  of  some  species 
(100)  in  accord  with  some  evidence  for  cholinergic 
vasodilator  receptors  in  the  splenic  vessels.  The  inter- 
play of  all  these  factors  in  any  single  neurovascular 
reaction  is  extremely  difficult  to  follow,  especially  in 
view  of  differences  in  responsiveness,  independent 
myogenic  reactivity,  and  innervation  within  what 
Folkow  (130)  has  referred  to  as  the  "series-coupled" 
and  "parallel-coupled  circuits"  of  the  hepatic  and 
splanchnic  vasculature.  Study  of  the  pattern  of  re- 
sponse to  individual  chemical  agents  may  ultimately 
clarify  the  mechanism  of  these  responses  and  throw- 
light  upon  the  local  and  systemic  role  of  the  hormones 
themselves. 


EPINEPHRINE    AND    NOREPINEPHRINE.     To    what    extent 

the  circulating  catecholamines  participate  in  vaso- 
motor adjustments  remains  uncertain.  Neural  activity 
appears  to  exert  a  profound  and  selective  action, 
effectively  controlling  splanchnic  vasomotor  function 
without  need  for  an  adjuvant  (79,  130).  The  total 
range  of  control  by  direct  sympathetic  innervation  is 


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HANDBOOK    OF    I'llVMOI.DCV 


CIRCULATION     II 


also  much  more  impressive  than  that  of  the  adrenal 
medulla.  Stimulation  of  the  constrictor  nerve  fibers  to 
i In-  spleen,  for  example,  causes  marked  contraction  at 
rates  as  low  as  one  impulse  every  other  second, 
whereas  large  doses  (5  /ug/kg/min)  of  the  medullary 
amines  fail  to  cause  more  than  40  per  cent  contraction 
of  the  denervated  spleen  and  an  even  smaller  maximal 
response  is  produced  by  stimulation  of  the  adrenal 
medullae.  Celander  (79)  has  concluded  therefore  that 
motor  control  of  smooth  muscle  in  blood  vessels  is 
dominated  by  the  neural  component.  A  corresponding 
predominance  of  the  adrenal  medullary  hormones 
might  apply  to  the  sympathetic  control  of  various 
metabolic  processes.  In  emergency  situations,  more- 
over, it  is  possible  that  circulating  hormones  may  have 
greater  importance  in  determining  vascular  responses. 
Both  epinephrine  and  norepinephrine  are  clearly 
vasoconstrictor  at  all  dosage  levels  in  the  perfused 
liver  (12,  13,  25,  81,  132).  In  the  early  work  adren- 
aline, known  to  be  a  mixture  of  /-epinephrine  and 
/-norepinephrine,  was  used.  Fortunately,  the  effect  of 
epinephrine  appears  to  dominate  the  vascular  re- 
sponse to  the  mixture  and  the  findings  of  the  earlier 
studies  do  not  differ  substantially  from  those  carried 
out  more  recently  with  /-epinephrine  alone.  The 
published  data  are  often  difficult  to  evaluate  owing  to 
the  rapidity  with  which  a  succession  of  shifts  occurs 
after  introduction  of  the  drugs.  In  part,  the  changes 
may  be  attributed  to  the  rearrangements  involved  in 
passing  from  one  state  to  another.  Thus  hepatic 
venous  outflow  may  increase  transiently  as  the  liver 
shrinks  with  a  reduction  in  intrahepatic  blood  volume, 
although  inflow  may  fall  and  remain  depressed. 
Differences  in  dosage  are  also  obviously  responsible 
for  certain  variants  and  may  indeed  give  rise  to  ir- 
regularities in  response  pattern  as  the  plasma  con- 
centration of  the  amine  rises  abruptly  and  then  tails 
off  following  injection,  reaching  some  parts  of  the 
vasculature  early  in  high  concentration,  others  later 
after  dilution  within  the  vessels.  Finally,  the  physio- 
logic state  of  the  organ,  whether  liver,  spleen,  or  in- 
testine, is  especially  important.  Congestion  and  in- 
creased resistance  to  perfusion  arising  from  various 
causes,  chiefly  on  deterioration  with  time,  may  greatly 
modify  the  response.  With  due  allowance  for  all  these 
considerations,  however,  both  drugs  appear  to  in- 
crease resistance  to  flow  through  the  perfused  hepatic 
(12,  13,  25,  81,  132),  mesenteric  (132,  269),  and 
splenic  (132)  arterioles  and  to  diminish  the  vascular 
capacity  by  venoconstriction  and  splenic  contraction 
in  all  species.  The  facts  are  consistent  with  the  pres- 
ence of  a-receptors  mediated  by  norepinephrine  (161). 


The  moderate  vasodilation  that  may  occur  in  the 
perfused  mesenteric  circuit,  but  not  in  the  hepatic 
vessels,  following  the  vasoconstrictive  response  to 
epinephrine  may  be  regarded  as  evidence  that  [1- 
receptors  occur  in  the  former  and  not  in  the  latter, 
though  the  role  of  secondary  changes  with  gut  activity 
or  of  balanced  shifts  within  the  liver  is  not  easily 
determined.  Little  information  regarding  the  dis- 
tribution of  resistance  and  volume  changes  and  the 
relative  intensities  of  smooth  muscle  contraction  be- 
tween the  different  beds  or  even  within  the  same  one 
may  be  gleaned  from  these  data. 

In  the  intact  animal,  the  responses  are  even  more 
varied  and  complex,  but  the  interplay  of  local  circuits, 
pressures,  and  over-all  cardiovascular  adjustments 
may  be  made  out  more  readily.  The  early  work  (132) 
on  mammals  yielded  data  generally  consistent  with 
the  conclusion  that  epinephrine  gives  rise  to  an  eleva- 
tion in  arterial  and  portal  venous  pressure  in  asso- 
tion  with  a  reduction  in  splenic  and  hepatic  volume, 
and  diminished  hepatic  venous  outflow.  All  these 
changes  are  in  accord  with  those  observed  in  the 
isolated  systems  and  suggest,  furthermore,  that  a  more 
marked  increase  may  develop  in  the  hepatic  vascular 
resistances  than  in  mesenteric  or  splenic  to  account 
for  the  rise  in  portal  venous  pressure  (1,  29,  47,  68, 
104,  125,  142,  157,  159,  160,  163,  203,  2io,  223,  281). 
Recent  studies  (1,  29,  47,  68,  125,  142,  157,  159,  160, 
223,  281)  indicate  that  norepinephrine  may  behave 
similarly.  With  greater  detail  and  precision,  however, 
interpretation  has  become  somewhat  more  dubious. 
In  the  first  place,  it  is  now  clear  that  epinephrine  is 
essentially  vasodilator  in  its  total  systemic  effect, 
physiologic  doses  producing  no  change  or  even  a  fall 
in  arterial  mean  pressure.  Changes  in  flow  must  be 
equated  with  mean  pressures  and  cannot  be  taken 
alone  as  evidence  for  vasodilation  or  vasoconstriction. 
Furthermore,  much  of  the  published  material  relates 
to  the  pattern  of  response  observed  after  a  single  dose 
of  the  drug  that  induces  a  succession  of  conflicting 
local  and  reflex  adjustments  in  which  the  assignment 
of  cause  and  effect  may  be  quite  impossible.  With 
constant  infusion  of  epinephrine  in  unoperated, 
unanesthetized  man  (47),  dog  (142),  and  rat  (157), 
hepatic  venous  outflow  has  been  found  to  increase. 
Since  the  increment  in  flow  exceeded  or  was  out  of 
phase  with  the  increment  in  arterial  mean  pressure 
in  the  studies  of  man  (0.10  jug  epinephrine  kg  min 
for  30  min — BSP  method)  and  dog  (0.25  /ug/kg/min 
for  1  min — blood  flow  velocity  measured  by  implanted 
"thermistorsonde")  it  may  be  concluded  that  over-all 
splanchnic  vascular  resistance  decreased  during  these 


THE    HEPATIC:    CIRCULATION 


1419 


experiments.  In  the  rat,  however,  the  rise  in  hepatic 
blood  flow  appeared  to  be  less  than  the  rise  in  arterial 
pressure  indicating  a  local  vasoconstriction  less  than 
that  elsewhere  in  the  body.  Perhaps  the  differences 
in  results  are  attributable  to  differences  in  the 
dosage — the  lower  doses  inducing  vasodilation  of  the 
mesenteric  arterioles  by  stimulation  of  /3-receptors. 
Certainly  if  portal  venous  pressure  rises  together  with 
hepatic  blood  flow,  as  it  seems  to  in  man  (187),  it  is 
possible  that  mesenteric  vasodilation  dominates  the 
circulatory  pattern,  masking  a  moderate  degree  of 
intrahepatic  vasoconstriction.  Whether  a  reflex  me- 
diated through  the  central  nervous  system  also  con- 
tributes (21)  remains  uncertain.  Norepinephrine,  in 
contrast,  is  clearly  vasoconstrictor  but  as  with  epineph- 
rine, nothing  is  known  about  its  effect  upon  the 
individual  components  in  the  intact  hepatic  and 
splanchnic  bed.  The  data  available  are  too  frag- 
mentary and  unreliable  to  permit  even  a  tentative 
synthesis. 

Direct  visual  examination  of  the  vessels  within  the 
splanchnic  bed  gives  further  support  to  the  view  that 
medullary  amine  usually  tends  to  evoke  a  complex 
vasoconstrictive  response.  Seneviratne  (270)  and 
Wakim  (299)  agree  in  reporting  that  epinephrine 
applied  directly  to  the  surface  of  both  the  mammalian 
and  amphibian  liver  produces  contraction  of  the 
sinusoids,  presumably  as  a  result  of  constriction  of 
hepatic  arterioles  and  portal  venules.  No  obvious 
effect  upon  the  visible  portal  and  hepatic  veins  was 
evident,  however.  A  similar  response  was  observed 
when  the  drug  was  injected  into  the  portal  vein. 
Interestingly,  when  the  drug  was  given  via  the  vena 
cava,  the  response  was  delayed  and  then  replaced  by 
"overactivity  of  the  circulation  in  the  whole  liver, 
both  as  to  number  of  active  sinusoids  and  as  to  en- 
gorgement and  rate  of  flow  of  blood  in  them."  Similar 
responses  have  been  reported  in  the  gastrointestinal 
tract  (132).  Serial  angiography  also  yields  evidence  of 
intrahepatic  vasoconstriction  in  rat,  rabbit,  cat,  dog, 
and  the  monkey  (101).  Intraportal  injection  of  ad- 
renalin (10-20  ,ug)  resulted  in  changes  like  those 
produced  by  stimulation  of  the  splanchnic  nerves — 
i.e.,  a  reduction  in  the  number  of  fine  vessels  demon- 
strable by  the  circulating  contrast  medium  together 
with  an  inconsistent  diminution  in  calibre  of  the  larger 
portal  vessels.  Daniel  &  Pritchard  (101)  noted  further 
that  "the  rapid  transhepatic  passage  of  the  portal  flow 
which  was  observed  after  administration  of  adrenaline 
was  associated  in  some  but  not  all  experiments  with  a 
change  in  the  distribution  of  the  contrast  medium 
within  the  liver.  .  .  .   Frequently  there  was  evidence 


of  an  unequal  distribution  of  the  blood  flow  within 
the  liver,  illustrating  that  a  differential  use  was  being 
made  by  the  portal  venous  blood  of  the  various  path- 
ways  through  the  liver."  Much  more  work  is  required 
to  sort  out  the  data  available  and  to  evaluate  by  more 
precise  methods  the  pattern  of  flow  and  pressure 
redistribution  throughout  the  splanchnic  bed  during 
the  action  of  epinephrine  and  norepinephrine. 

acetylcholine.  Little  consistent  change  appears  in 
the  isolated  perfused  splanchnic  circulation  following 
the  administration  of  acetylcholine  regardless  of  the 
method  employed  in  its  evaluation.  Bauer  et  al.  (25) 
were  unable  to  obtain  a  definite  response  in  the 
perfused  liver  of  the  dog,  cat,  or  goat.  If  the  "arterial 
tone"  was  "high"  an  intra-arterial  injection  of  ace- 
tylcholine appeared  to  produce  a  relaxation  com- 
parable to  that  induced  by  histamine.  Relatively 
small  doses  intra-arterially,  however,  acted  upon  the 
perfused  goat's  liver  somewhat  like  adrenaline,  that 
is,  "arterial  and  portal  tone  were  increased,  liver 
volume  diminished,  and  outflow  practically 
unchanged.  .  .  .  this  effect  of  acetylcholine  was  of  the 
parasympathetic  type,  in  that  it  was  completely 
abolished  by  atropine,  which  left  those  of  adrenaline 
and  histamine  unchanged."  Chakravarti  &  Tripod 
(81)  found  that  acetylcholine  produced  an  easily 
detectable  effect  upon  the  circulation  through  the 
perfused  liver  if  adrenaline  were  added  to  the  per- 
fusate in  order  to  provide  a  "vasoconstricted  state" 
in  which  a  vasodilator  action  could  be  more  easily 
elicited.  Unlike  adrenaline  or  histamine,  acetylcholine 
had  no  action  when  injected  into  the  portal  vein. 
Andrews  et  al.  (13)  reported  results  similar  to  these. 
In  most  of  their  studies  of  the  perfused  canine  liver, 
acetylcholine  in  doses  ranging  from  0.35  to  15.0  ng 
injected  into  the  hepatic  artery  produced  no  change  in 
arterial  inflow,  and  a  fall  in  both  portal  inflow  and 
hepatic  outflow  with  a  rise  in  volume;  but  when  adren- 
aline (0.1  fig  per  ml)  was  added  to  the  perfusate 
acetylcholine  raised  the  arterial  inflow  and  slightly 
decreased  portal  venous  inflow  with  a  rise  in  both 
total  outflow  and  volume.  When  injected  into  the 
portal  vein,  acetylcholine  produced  the  same  response 
as  that  produced  by  intra-arterial  injection  but  10  to 
1 5  times  the  amount  was  required  for  an  equivalent 
effect.  Administration  of  eserine  equalized  the  re- 
sponse to  arterial  and  venous  administration  indicat- 
ing that  the  difference  might  be  due  to  greater  de- 
struction of  acetylcholine  in  the  portal  vessels.  They 
interpreted  their  results  as  indicating  a  weak  vaso- 
constrictive response  in  the  portal  vein  and  hepatic 


1420 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


vein  with  little  or  no  action  upon  the  arterial  circuit. 
Acetyl-/3-methylcholine  chloride  and  carbaminoyl 
chloride  had  a  similar  but  longer  action  and  did  not 
produce  different  responses  depending  upon  the  route 
of  administration,  possibly  because  neither  is  readily 
destroyed  by  hepatic  esterases.  In  subsequent  studies 
of  the  effect  of  acetylcholine  on  the  perfused  hepatic 
vasculature  of  the  monkey,  cat,  and  rabbit,  the  same 
group  (12)  was  impressed  by  the  difficulty  of  obtaining 
reproducible  responses  for  "the  vascular  responses 
showed  considerable  variation  not  only  from  species 
to  species  but  also  from  time  to  time  in  the  same 
animal."  Similar  equivocal  results  have  been  obtained 
in  studies  of  isolated  gut  (27).  Indeed,  Bean  &  Sidky 
(27)  have  adduced  evidence  that  the  increase  ob- 
served in  blood  flow  through  a  perfused  intestinal 
loop  is  attributable  to  the  release  of  vasoactive  ma- 
terials locally  rather  than  to  a  direct  effect  upon  the 
vasculature.  In  the  case  of  the  spleen,  acetylcholine 
does  seem  to  have  a  direct  effect  at  least  insofar  as 
strips  of  splenic  muscle  are  concerned  (53). 

In  his  initial  studies  in  191 8,  Reid  Hunt  found  that 
the  liver  of  the  intact  dog  shrank  following  intravenous 
administration  of  small  doses  but  expanded  with 
larger  ones.  A  similar  response  was  noted  by 
McMichael  (210)  in  the  cat;  the  reduction  in  volume 
coincided  with  a  fall  in  portal  venous  pressure  and 
arterial  pressure.  In  a  similar  study  of  the  dog,  Katz 
&  Rodbard  (182)  also  noted  that  acetylcholine  caused 
an  isolated  fall  in  portal  venous  pressure  that  occurred 
at  approximately  the  same  time  as  a  fall  in  arterial 
pressure  and  a  rise  in  peripheral  venous  pressure. 
Portal  venous  flow  (Ludwig  stromuhr)  tended  to 
follow  the  portal  venous  pressure  but  did  not  fall  to 
the  same  extent  as  arterial  pressure,  suggesting  the 
development  of  mesenteric  arteriolar  dilatation.  In 
more  recent  studies,  the  results  also  suggest  that 
vasodilatation  may  occur  in  the  liver  though  a  change 
inflow  has  not  been  seen  on  direct  observation  (299). 
Using  implanted  devices  to  measure  flow,  Ginsburg 
&  Grayson  (147)  and  Gersmeyer  &  Gersmeyer  (142) 
report  an  increase  in  hepatic  venous  outflow  in  rats 
and  dogs  during  intravenous  infusion  of  acetylcholine. 
Since  arterial  pressure  fell  at  the  same  time,  intra- 
hepatic resistance  must  have  diminished.  An  increase 
in  the  volume  of  the  gut  and  in  mesenteric  and  gastric 
outflow  has  been  noted  by  other  workers  (132,  219). 
The  increment  in  hepatic  blood  flow  cannot  be  ex- 
plained entirely  on  this  basis,  however,  since  Ginsburg 
&  Grayson  (147)  found  that  hepatic  blood  flow  in- 
creased in  the  rat  even  when  portal  drainage  was 
diverted  from  the  liver.  The  spleen  in  the  intact  dog 


apparently  changes  little  in  volume  with  a  slight 
augmentation  in  arterial  inflow  despite  arterial  hy- 
potension (164,  223). 

Although  the  reactions,  outlined  above,  to  acetyl- 
choline in  the  isolated  and  intact  hepatic  vasculature 
are  obviously  equivocal,  a  change  of  some  kind  does 
seem  to  occur.  This  fact  is  a  little  difficult  to  square 
with  the  absence  of  cholinergic  innervation  of  the 
splanchnic  and  hepatic  vessels  and  with  the  lack  of 
any  response  to  vagal  neurectomy  and  stimulation. 
Cholinergic  activity  is  definitely  important  in  the 
function  of  the  gastrointestinal  musculature  and  of 
the  glands  of  the  biliary  tract  and  pancreas.  Hence, 
it  is  possible,  as  Bean  &  Sidky  (27)  have  suggested, 
that  secondary  release  of  substances  acting  locally 
upon  the  blood  vessels  may  be  implicated.  Brandon 
&  Rand  (53)  and  Burn  &  Rand  (6g)  have  recently- 
brought  forward  a  more  attractive  hypothesis  that 
acetylcholine  may  release  norepinephrine  from  stores 
in  the  tissues  (in  the  nerves  or  chromaffin  cells)  which 
may  be  depleted  by  reserpine  or  neural  degeneration 
and  replaced  by  an  infusion  of  norepinephrine.  The 
variability  of  the  results  reported  by  many  workers 
may  well  be  explained,  in  part  at  least,  by  variation 
in  the  stores  initially  available  and  in  the  depletion  of 
the  neurotransmitter  during  the  preparation  of  the 
tissues  for  study.  Stimulation  of  the  adrenal  medulla 
and  a  general  systemic  response  must  also  be  taken 
into  account  in  the  interpretation  of  the  effect  of 
acetylcholine  upon  the  hepatic  circulation  in  the 
intact  animal. 

autonomic  blockade.  Autonomic  denervation  and 
chemical  interference  with  autonomic  activity  have 
proved  extremely  helpful  in  the  study  of  neurovascular 
function.  As  knowledge  has  accumulated,  however, 
the  complexities  of  the  problem  have  become  in- 
creasingly apparent.  Surgical  denervation  is  neces- 
sarily limited  by  the  inaccessibility,  diversity,  and 
versatility  of  the  nerve  supply.  A  remarkable  array  of 
autonomic  blocking  agents  is  now  available  and  grow- 
ing in  number  and  variety  with  each  year.  Unfortu- 
nately, the  supply  has  outrun  the  laborious  and 
gradual  gathering  of  information  regarding  mode  and 
site  of  action.  Most  of  these  substances  interfere  with 
both  sympathetic  and  parasympathetic  function, 
most  produce  confusing  side  effects  unrelated  to  the 
splanchnic  adrenergic  blockade.  Few  have  been 
studied  with  special  attention  to  the  effects  upon 
hepatic  inflow  and  outflow  tracts.  Since  this  is  not  the 
place  to  embark  upon  a  detailed  examination  of  the 
mechanisms  of  adrenergic  and  cholinergic  blockade, 


THE    HEPATIC    CIRCULATION 


I  42  I 


these  matters  will  not  be  considered  here.  Interfer- 
ence with  autonomic  transmission,  no  matter  how 
produced — whether  by  competition  for  receptor  sites, 
by  depletion  of  stored  transmitters,  by  changes  in 
membrane  permeability  or  polarization,  by  change  in 
synthesis  or  degradation,  or  even  by  surgery — makes 
possible  a  more  meaningful  appraisal  of  the  relative 
importance  of  neural,  humoral,  and  local  circulatory 
determinants. 

Denervation  by  any  method  does  not  seem  to  pro- 
duce significant  change  in  the  blood  flow  in  any  part 
of  the  splanchnic  and  hepatic  vascular  bed.  Mesen- 
teric vasodilation,  increased  hepatic  blood  flow,  and 
partial  splenic  contraction  have  been  reported  shortly 
after  section  of  the  splanchnic  nerves,  splenic  nerve, 
and  lumbodorsal  sympathectomy,  but  these  reactions 
seem  to  be  temporary  (132).  Wilkins  and  his  associates 
(310)  have  found  that  the  EHBF  was  definitely  higher 
and  splanchnic  vascular  resistance  "significantly" 
lower  in  13  patients  with  hypertensive  vascular  disease 
2  weeks  after  the  Smithwick  procedure.  In  six  patients 
studied  4  to  6  months  later,  EHBF  had  returned  to 
control  values.  Circulating  splanchnic  blood  volume 
has  also  been  found  to  increase  after  sympathectomy 
(42).  High  spinal  anesthesia  induces  a  fall  in  EHBF 
that  may  be  accounted  for  by  the  coincidental  fall  in 
blood  pressure  in  the  absence  of  change  in  resting 
splanchnic  resistance  (201).  Section  of  the  vagus  has 
no  obvious  effect  (147). 

Hexamethonium  appears  to  be  capable  of  blocking 
cholinergic  transmission  within  autonomic  ganglia 
though  it  does  not  block  the  response  to  sympathetic 
nerve  stimulation  (92,  133,  245).  During  ganglionic 
blockage,  blood  flow  through  the  splanchnic  bed 
decreased  in  dog  and  man  only  to  the  extent  to  which 
arterial  pressure  was  reduced.  The  circulating 
splanchnic  blood  volume,  in  contrast,  was  found  to 
expand  significantly  in  the  dog  in  the  absence  of 
detectable  change  in  portal  venous  or  sinusoidal 
pressures  (92).  These  data  are  consistent  with  the  view 
that  basal  arteriolar  cross  section  in  the  splanchnic 
and  hepatic  beds  at  rest  does  not  depend  exclusively, 
if  at  all,  upon  the  integrity  of  the  autonomic  nerve 
supply.  Such  a  statement  does  not  imply  that  no 
change  occurred  in  the  vascular  smooth  muscle. 
Whatever  change  in  tone  that  may  have  occurred  was 
evidently  not  sufficient  to  result  in  dilatation  of  the 
arterioles.  It  has  been  suggested  that  the  contrasting 
arteriolar  and  venous  reactions  can  be  explained  on 
the  basis  of  Laplace's  law,  the  difference  in  radii 
accounting  chiefly  for  the  relative  effectiveness  of  the 
distending  pressures  at  each  level. 


After  administration  of  adrenergic  blocking  drugs 
(ergotamine,  Dibenzyline,  Dibenamine,  Ilidar),  epi- 
nephrine, norepinephrine,  and  neural  stimulation 
fail  to  induce  the  usual  arteriolar  vasoconstriction  in 
the  liver,  gastrointestinal  tract,  or  spleen  (159-161, 
223).  Norepinephrine  appears  to  elicit  little  or  no 
change  of  any  kind  under  these  circumstances, 
whereas  epinephrine  now  causes  vasodilation  in  the 
mesenteric  and  splenic  vessels.  The  effect  of  neural 
stimulation  is  also  reversed  to  some  extent  in  the  gut 
and  spleen.  Both  are  without  any  demonstrable  effect 
upon  the  liver.  These  findings  have  been  interpreted 
as  evidence  for  vasodilator  /3-receptors  in  the  mesen- 
teric and  splenic  arterioles.  Since  study  of  the  behavior 
of  the  veins,  with  special  reference  to  their  volume 
capacity,  has  not  been  made  during  adrenergic  block- 
ade, it  is  impossible  to  say  whether  these  findings 
apply  in  general  to  the  other  vascular  levels  in  each 
coupled  system.  It  is  also  difficult  to  be  certain  whether 
dilation  is  an  active  or  passive  process  or  whether  it 
involves  the  participation  of  other  substances  pro- 
duced locally  in  response  to  epinephrine.  There  is  no 
doubt  that  general  blockade  at  any  level  is  associated 
with  a  much  more  marked  interference  with  vascular 
responses  than  is  evident  in  the  reversal  of  responses  to 
epinephrine.  Although  the  hemodynamic  pattern  at 
rest  is  not  materially  affected,  any  shift  in  position, 
imposition  of  stress,  or  environmental  change  unmasks 
a  serious  loss  of  capacity  to  make  corrective  adjust- 
ments. Tilting  into  the  upright  position,  for  example, 
results  in  a  sharp  drop  in  arterial  pressure  without 
eliciting  the  normal  compensatory  change  in  splanch- 
nic vascular  resistance.  Pooling  of  blood  within  the 
splanchnic  veins  actually  enhances  the  tendency  to 
circulatory  collapse  (42).  Neural  and  neurohumoral 
mechanisms  may  not  be  essential  to  maintenance  of 
the  resting  state  but  they  are  clearly  necessary  for 
coordination  in  systemic  responses. 

Local  Biochemical  Determinants 

Changes  in  blood  flow  result  in  corresponding 
changes  in  the  delivery  of  oxygen  and  essential  nu- 
trients to,  and  in  the  removal  of  metabolites  from,  the 
tissues.  Moreover,  the  associated  activity  of  smooth 
muscle,  the  distention  or  deflation  of  capillaries,  the 
alterations  in  interstitial  pressure  and  in  lymphatic 
drainage  all  impinge  directly  upon  the  cells.  Meta- 
bolic processes  are  certainly  affected  by  the  secondary 
shifts  in  exchange  and  in  the  milieu  interieur  and  by 
the  neurohumoral  agents  themselves  concerned  in 
these  responses.  In  consequence,  vasoactive  materials 


I4'22 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


oi  various  kinds,  for  the  most  part  still  uncharacter- 
ized,  are  released  locally  to  play  a  more  or  less  essen- 
tial role  in  determining  the  pattern  of  circulatory 
adjustments.  Since  these  materials  rarely  enter  the 
blood  in  amounts  sufficient  for  detection  it  is  extremely 
difficult  to  evaluate  their  contribution.  Tissue  gas 
exchange  is  an  exception  because  oxygen  and  carbon 
dioxide  content  of  the  blood  entering  and  leaving  the 
tissues  is  easily  measured,  but  the  influence  of  other 
agents  must  be  studied  indirectly. 

oxygen.  Even  assessing  the  role  of  the  blood  gases  is 
dillicult  because  it  cannot  be  said  with  any  certainty 
how  oxygen  and  carbon  dioxide  concentrations  are 
distributed  within  the  capillary  network.  The  abun- 
dance of  intercommunications  makes  it  likely  that  a 
relatively  uniform  admixture  of  blood  occurs.  Never- 
theless, the  gradient  between  artery  and  vein  must 
be  reflected  in  a  similar  tissue  differential  so  that 
vessels  like  those  on  the  periphery  of  the  hepatic 
lobules  contain  more  highly  oxygenated  blood  than 
those  entering  the  central  veins.  Hypoxia,  per  se,  seems 
to  have  relatively  little  effect  upon  the  hepatic  circula- 
tion. Hypoxia  does  result  in  the  rapid  deterioration  of 
the  perfused  liver  with  the  development  of  obvious 
swelling  and  decreased  perfusibility,  but  whether 
these  changes  are  to  be  ascribed  to  active  vascular 
changes  or  to  cellular  swelling  alone  does  not  seem  to 
have  been  subjected  to  systematic  study  (132). 
Torrance  (291)  found  no  evidence  of  any  change  in 
intrahepatic  resistance  to  flow  (internal  calorimetry) 
in  anesthetized  rabbits  after  complete  occlusion  of  the 
arterial  and  venous  inflow  tracts  for  2  min.  More 
prolonged  (2  hours)  ischemia  of  the  liver  in  anesthe- 
tized, splenectomized  dogs  by  occlusion  of  the  hepatic 
artery  and  diversion  of  the  portal  inflow  via  an  ex- 
ternal shunt  to  the  jugular  vein  produces  a  complex 
splanchnic  vascular  response,  according  to  Selkurt 
(265,  266).  He  found  that  arterial  blood  flow  dropped 
to  66  per  cent  of  control  on  restoration  of  hepatic 
perfusion  in  association  with  a  rise  in  intrahepatic  and 
a  fall  in  mesenteric  resistances  that  together  resulted 
in  a  marked  increase  in  portal  venous  pressure.  This 
work  indicates,  as  does  that  of  Torrance  (291),  that 
"reactive  hvperemia"  does  not  develop  in  the  liver 
and  it  agrees  with  the  more  recent  findings  of  Fischer 
el  al.  ( 1  28)  in  showing  hepatic  arteriolar  constriction. 
Seneviratne  (270)  has  noted  sinusoidal  dilatation 
after  1  hour  of  airway  obstruction  in  mice  and  rats 
but  in  this  instance  carbon  dioxide  retention  cannot  be 
eliminated  as  the  cause.  Of  course,  prolonged  hypoxia 
also    elicits    widespread    compensatory    adjustments 


in  the  systemic  circulation  in  which  the  hepatic  and 
splanchnic  bed  might  be  expected  to  participate  and 
which  may  produce  changes  opposed  to  those  resulting 
from  its  action  locally.  Thus,  perfusion  of  the  mesen- 
teric vasculature  in  an  isolated  innervated  segment  of 
a  dog's  intestine  with  hypoxic  blood  resulted  in  vaso- 
dilation and  increased  flow  (26),  in  line  with  Selkurt's 
observations  following  protracted  anoxia.  When  the 
animal  was  allowed  to  breath  a  low  oxygen  mixture, 
however,  reflex  mesenteric  vasoconstriction  developed 
to  a  degree  commensurate  with  the  arterial  oxygen 
content.  Mesenteric  and  portal  venous  distensibility 
also  decreases  under  these  circumstances  and  it  may 
be  presumed  that  reflex  venoconstriction  contributes 
to  the  development  of  portal  venous  hypertension  and 
results  in  a  reduction  in  splanchnic  blood  volume 
during  hypoxia. 

carbon  dioxide.  The  effect  of  hypercapnia  is  par- 
ticularly dillicult  to  follow  owing  to  interference  by 
an  array  of  striking  concomitant  adjustments  that 
include  hyperventilation,  peripheral  vasodilation, 
hypertension,  tachycardia,  and  an  increase  in  cardiac 
output  (247).  To  circumvent  these  obstacles,  the 
splanchnic  hemodynamic  effects  of  elevated  arterial 
carbon  dioxide  tensions  were  studied  by  Epstein  and 
his  associates  (123)  in  normal  human  subjects  during 
light  general  anesthesia  with  thiopental  and  nitrous 
oxide.  Arterial  carbon  dioxide  tension  could  be  main- 
tained at  a  constant  level  (Paco,  =  56  mm  Hg  on  the 
average)  by  mechanically  controlled  respiration  with 
an  appropriate  gas  mixture  following  neuromuscular 
blockade  with  succinylcholine.  Under  these  circum- 
stances, interference  with  the  response  by  an  increase 
in  ventilation  could  be  eliminated.  Nevertheless,  the 
over-all  response  appeared  to  be  inconsistent  and 
erratic;  mean  arterial  pressure  rising  in  six  subjects, 
falling  in  two,  and  not  changing  in  five  in  association 
with  a  fall  in  EHBF  in  nine  but  with  little  or  no  change 
in  EHBF  in  four.  Splanchnic  vascular  resistance 
always  increased,  however,  EHBF  changing  in  accord 
with  the  balance  between  the  perfusing  pressure  and 
resistance.  Since  blood  flow  tended  to  fall,  the  splanch- 
nic vasoconstriction  appeared  usually  to  be  somewhat 
in  excess  of  that  elsewhere  in  the  body.  Circulatine; 
splanchnic  blood  volume  also  decreased  significantly 
in  ten  subjects  and,  since  hypercapnia  has  been  found 
to  increase  portal  venous  pressure,  the  change  may  be 
interpreted  as  evidence  of  constriction  of  splanchnic 
veins.  The  vasoconstrictive  response  is  probably 
mediated  through  the  central  nervous  system,  since 
several  investigators  (132,  216)  have  found  that  in- 


THE    HEPATIC    CIRCULATION 


1423 


creased  carbon  dioxide  tension  in  the  blood  perfusing 
splanchnic  blood  vessels  including  those  of  the  liver, 
intestines,  and  spleen,  elicits  an  arteriolar  and  venous 
constrictive  response  only  if  the  splanchnic  nerve 
supply  is  intact.  After  denervation,  an  elevation  in 
PaCo,  regularly  induces  vasodilation.  Evidently  this 
reflex  pathway  is  relatively  unaffected  by  cholinergic 
blockade  and  by  light  general  anesthesia.  Whether 
sufficiently  high  concentrations  of  carbon  dioxide 
could  overcome  the  opposing  reflex  activity  and  dilate 
the  vessels  directly  remains  unsettled,  although  Brick- 
ner  et  al.  (66)  have  shown  that  mesenteric  vasodilation 
may  occur  in  the  intact  animal  breathing  gas  mix- 
tures that  contain  more  than  8  per  cent  carbon  di- 
oxide. Splenic  contraction  induced  by  hypercapnia 
appears  to  involve  activity  of  both  splanchnic  nerves 
and  adrenals  (235).  Further  work  is  required  to 
elucidate  the  role  of  adrenergic  mediators,  the  re- 
distribution of  blood  within  the  splanchnic  bed,  and 
changes  in  the  partition  of  hepatic  inflow  during 
hypercapnia.  In  addition,  the  effect  of  carbon  dioxide 
released  locally  by  metabolizing  tissues,  in  amounts 
too  small  to  affect  the  vasomotor  centers,  deserves 
investigation. 

histamine.  There  is  no  doubt  that  carbon  dioxide  is 
added  to  the  blood  perfusing  the  tissues  and  that  it  is 
present,  therefore,  in  varying  concentrations  which 
are  certainly  in  excess  of  those  in  the  arterial  blood  at 
the  capillary  level.  Various  other  vasoactive  materials 
also  appear  at  approximately  the  same  site,  though 
relatively  little  is  known  regarding  the  mechanisms 
and  character  of  their  release.  Electrolyte  shifts  and 
the  production  of  hydrogen  ion  may  be  particularly 
important  though  very  little  is  known  about  the  part 
they  play  in  the  regulation  of  the  microcirculation. 
Another  vasoactive  substance  which  appears  in  high 
concentration  in  all  the  tissues  served  by  the  splanch- 
nic circulation  is  histamine  (127).  Although  it  has 
excited  intense  interest  and  extensive  study  for  more 
than  a  half  century,  the  function  of  histamine  remains 
puzzling  and  controversial.  Its  action  upon  the  hepatic 
and  splanchnic  circulations  has  received  special  atten- 
tion. As  early  as  1899,  it  was  discovered  that  a  striking 
engorgement  of  the  liver  occurs  in  the  dog  during 
anaphylactic  shock,  and  not  long  afterward  the  same 
phenomenon  was  observed  following  introduction  of 
histamine  into  the  portal  vein  (132).  Since  hepatic 
venous  outflow  decreased  during  engorgement  of  the 
liver,  it  was  suggested  that  contraction  of  the  venous 
musculature  might  act  as  a  throttle  mechanism  to 
occlude  the  hepatic  veins  in  the  dog.  Dale  (25)  and 


others  (12,  132)  have  confirmed  these  results,  Dale 
showing  that  the  response  could  be  eliminated  by- 
slitting  the  hepatic  veins  of  the  perfused  liver.  More- 
over, hepatic  swelling  proved  to  be  less  marked  or 
absent  altogether  in  animals  like  the  cat,  goat,  or 
monkey  that  have  thinly  muscled  hepatic  veins.  A 
diminution  in  portal  inflow  as  well  as  in  hepatic 
venous  outflow  also  points  to  the  development  of  in- 
creased resistance  to  perfusion.  All  these  findings, 
together  with  the  fact  that  histamine  causes  contrac- 
tion of  the  spleen  in  most  animals  (132),  point  to 
vasoconstriction  as  the  predominant  effect.  Else- 
where in  the  body,  however,  histamine  causes  striking 
arteriolar  vasodilation,  and  in  intact  animals  the  net 
effect  appears  to  be  vasodilator  also  in  the  splanchnic 
bed.  An  increase  in  EHBF  in  the  face  of  arterial  hy- 
potension has  been  observed  in  man  after  intramus- 
cular injection  of  histamine  phosphate  (47).  In  tin- 
anesthetized  dogs,  moreover,  Gersmeyer  &  Gersmeyer 
(142)  have  found  that  the  velocity  (thermistor)  of 
portal  venous  blood  flow  increased  sharply,  although 
portal  venous  pressure  rises  very  little  as  arterial  and 
inferior  vena  caval  pressures  fall.  Since  it  seems  likely 
from  what  has  been  said  above  that  outflow  resistance 
is  increased,  the  increments  in  portal  pressure  [which 
are  quite  marked  in  other  studies  (308)]  and  blood 
flow  are  most  reasonably  explained  on  the  basis  of 
mesenteric  vasodilation  in  excess  of  augmented  intra- 
hepatic resistance.  It  is  equally  possible  that  hepatic 
arteriolar  dilatation  occurs.  More  precise  and  detailed 
information  obtained  under  properly  controlled 
conditions  is  needed  to  evaluate  the  simultaneous 
changes  in  splanchnic  resistances  and  in  venous 
capacity.  The  data  at  hand  are  in  accord  with  growing 
evidence  that  "histamine  may  actively  dilate  arterioles 
at  the  same  time  that  it  actively  constricts  veins" 
(167)  not  only  as  a  result  of  a  direct  action  upon  the 
vessels  but  also  as  a  secondary  result  of  adrenal  medul- 
lary discharge  (134,  228,  297).  It  is  also  possible  that 
the  action  of  many  other  substances  is  mediated 
through  histamine  release   (228). 

Still  another  substance  released  locally  is  serotonin, 
or  5-hydroxytryptamine,  which  has  been  identified 
and  extensively  studied  in  recent  years.  Selkurt  (269) 
reports  that  it  behaves  like  norepinephrine  in  causing 
vasoconstriction  within  the  isolated  mesenteric  vessels 
of  the  dog  but  little  is  known  about  its  effect  upon  the 
intrahepatic  resistances  or  upon  the  volume  of  blood 
held  within  the  total  splanchnic  bed,  liver,  or  spleen. 
A  steadily  growing  list  of  similar  activating  agents, 
including  a  miscellany  of  amines  and  peptides  pro- 
duced during  tissue  injury,  is  making  manifest  the 


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CIRCULATION    II 


inadequacy  of  current  concepts  of  cardiovascular 
regulation  and  stimulating  numerous  new  investiga- 
tions of  the  hepatic  circulation. 

Physical  Determinants 

Neural,  neurohumoral,  and  local  chemical  influ- 
ences operate  for  the  most  part  reactively  to  alter 
vascular  perfusion  and  content  by  changing  arteriolar 
cross  section  and  venous  distensibility.  As  such  they 
mediate  adjustments  but  do  not  actually  produce 
them.  In  contrast,  external  physical  forces  to  which 
the  abdominal  viscera  are  exposed  affect  the  hepatic 
and  splanchnic  vessels  directly,  frequently  eliciting 
corrective  or  compensatory  responses  in  which  all  the 
mechanisms  discussed  above  are  called  into  play. 
Movements  and  gaseous  distention  of  the  gastroin- 
testinal tract  compress,  stretch,  and  variously  deform 
the  mesenteric  vasculature  with  resultant  change  in 
flow  and  volume  that  must  affect  the  delivery  of  blood 
to  the  liver  by  the  portal  vein.  To  what  extent  shifts 
within  the  mesenteric  circuit,  repartitioning  of  the 
total  hepatic  inflow,  and  redistribution  of  the  splanch- 
nic blood  volume  depend  upon  activity  of  the  mus- 
culature of  the  gut  remains  uncertain.  These  problems 
are  dealt  with  at  length  in  Chapter  42  but  must  be 
touched  upon  here  in  order  to  indicate  the  potential 
importance  of  extravascular  forces  upon  the  hepatic 
blood  supply.  In  this  instance  a  reciprocal  relationship 
obtains  in  that  digestion,  absorption,  and  the  other 
functions  of  the  gastrointestinal  tract  depend  in  turn 
upon  the  integrity  of  the  mesenteric  vasculature. 
Moreover,  the  integrated  function  of  the  liver  and 
intestine  hinges  upon  movement  of  absorbed  material 
through  the  portal  system  to  the  liver.  Exercise  and 
respiration  also  impinge  directly  upon  the  hepatic 
circulation  by  raising  intra-abdominal  pressure  and 
often  by  changing  the  position  of  the  body.  Both 
activities  are  associated  with  widespread  cardiovas- 
cular changes  affecting  all  parts  of  the  body.  The 
splanchnic  vasculature  participates  in  these  reactions 
but  it  may  actually  be  more  markedly  influenced 
directly  by  the  associated  physical  effects. 

intra-abdominal  pressure.  The  roughly  cylindrical 
container  holding  the  abdominal  viscera  and  their 
vasculatures  is  almost  completely  muscular  and 
capable  of  actively  increasing  the  pressure  within  the 
peritoneal  cavity.  Moreover,  the  gastrointestinal 
system  is  periodically  filled  with  fluids,  solids,  and  gas, 
which  occupy  space  and  raise  the  pressure.  As  long 
as  the  pressures  distending  the  vessels  are  in  excess 


of  the  circumambient  pressures,  there  is  little  effect 
upon  the  resistance  to  flow  or  upon  the  forces  con- 
ducive to  blood  flow.  When  the  external  pressure 
equals  or  exceeds  the  intraluminal  pressure,  by  an 
amount  determined  by  the  elastic  properties  of  the 
vessel,  instability  develops  and  collapse  occurs  at 
some  critical  pressure,  provided  the  contents  can  be 
displaced.  Any  pressure  increment  is  uniformly  dis- 
tributed throughout  the  abdomen,  and  blood,  not 
being  compressible,  must  move  from  an  area  of  high 
pressure  to  one  of  low  pressure  to  permit  collapse  of 
those  vessels  in  which  the  intraluminal  pressure  is 
less  than  the  external  pressure.  This  occurs  most 
readily  at  the  diaphragm,  across  which  the  usual 
pressure  drop  is  augmented.  It  may  be  inferred  that 
with  a  rise  in  intra-abdominal  pressure,  blood  in  the 
veins  close  to  the  diaphragm  is  expressed  and  the 
vessels  collapsed,  thus  producing  a  dam  at  the  point 
of  outlet.  Since  the  arterial  perfusing  pressure  is  little 
affected,  blood  continues  to  pour  into  the  system, 
but  with  the  cessation  of  outflow,  pressures  gradually 
rise  and  inflow  begins  to  diminish.  When  the  local 
pressure  at  the  point  of  collapse  exceeds  the  critical 
opening  pressure,  outflow  is  restored  and  a  new  equi- 
librium established.  Whether  the  expected  increase 
in  resistance  so  induced  would  tend  to  result  in  pool- 
ing  of  blood  within  the  splanchnic  circuit  in  the  face 
of  the  forces  operating  to  prevent  distention  must 
depend  upon  the  relationship  between  the  distribu- 
tion of  resistances  and  pressure  gradients  within  the 
bed.  Little  information  is  available  on  which  one  may- 
base  further  speculation.  Increased  intra-abdominal 
pressure  has  been  found  to  reduce  hepatic  blood 
flow  in  man  and  experimental  animals  (47,  221), 
but  precise  localization  of  the  sites  of  increased  re- 
sistance and  the  character  of  volume  capacity  changes 
have  not  been  satisfactorily  settled. 

gravity.  Gravitational  force  is  also  constantly  opera- 
tive in  affecting  intravascular  pressures  within  the 
abdomen.  Change  of  position  results  in  a  change  in 
the  hydrostatic  pressure  at  every  point  in  the  vascula- 
ture by  means  of  an  addition  or  subtraction  of  a 
column  of  blood,  the  height  of  which  depends  upon 
the  elastic  properties  of  the  vascular  system.  In  com- 
puting the  hydrostatic  head  at  any  point  in  the  vessels, 
it  is  customary  to  take  the  center  of  the  right  atrium 
as  the  zero  base  line  in  recumbency.  All  pressures 
above  that  level  in  the  supine  position  are  negative 
with  reference  to  it,  and  all  below  are  positive.  With 
a  shift  in  position,  the  levels  at  which  pressure  in  the 
arteries  and  veins  remains  unchanged  mav  be  taken 


THE    HEPATIC    CIRCULATION 


1425 


as  the  zero  reference  planes  for  the  respective  sys- 
tems. In  man,  the  arterial  zero  reference  plane  lies 
at  the  level  of  the  diaphragm  immediately  after  tilt- 
ing into  the  upright  position,  with  moderate  change 
thereafter  during  vasomotor  adjustments  (309). 
Thus  the  elastic  properties  of  the  vasculature  are 
such  as  to  maintain  the  arterial  pressure  relatively 
constant  at  the  level  of  the  diaphragm;  pressures  at 
points  above,  falling,  and  below,  rising,  solely  by  the 
weight  of  the  column  of  blood  lying  between  each 
point  and  the  zero  reference  level.  The  imposed  blood 
column  does  not  reach  to  the  level  of  the  uppermost 
body  surface,  e.g.,  the  top  of  the  head,  because  the 
closed  elastic  container  exerts  an  attractive  force  in 
supporting  that  portion  of  the  blood  above  the  refer- 
ence plane.  A  similar  elastic  buffering  of  hydrostatic 
shifts  occurs  in  the  veins.  In  both  dog  (86)  and  man 
(309)  the  venous  side  of  the  circulation  is  divided 
dynamically  by  cardiac  activity  into  two  separate 
hydrostatic  compartments  each  with  a  separate 
zero  reference  plane.  The  immediate  hydraulic 
changes  with  change  of  position  are  minimized  on 
both  the  arterial  and  venous  side  and  little  immediate 
change  in  hemodynamics  occurs  in  dog  or  man. 
Within  a  few  seconds  after  assumption  of  the  head-up 
position,  however,  the  blood  pressure  does  tend  to 
fall  and  the  heart  rate  to  speed.  Widespread  vaso- 
constriction quickly  checks  the  decline  in  arterial 
pressure.  The  splanchnic  vasculature  partakes  in  this 
general  response,  since  it  has  been  observed  that 
splanchnic  blood  flow  (EHBF)  decreases  significantly 
in  man  during  orthostasis  (99).  This  change  is  im- 
paired in  hypertensive  patients  following  lumbodorsal 
sympathectomy  (310).  Circulating  splanchnic  blood 
volume  is  also  reduced  in  the  upright  position  pre- 
sumably as  a  result  of  reflex  alteration  in  the  splanch- 
nic vascular  capacity  (42).  Further  work  is  needed 
to  define  these  changes  in  experimental  animals. 

respiration.  The  intra-abdominal  pressure  figures 
prominently  in  a  more  active  sense  as  one  of  the  forces 
involved  in  determining  changes  in  splanchnic 
blood  flow  during  respiration.  Evaluation  of  the 
changes  in  pressure  gradients  and  flows  during  the 
respiratory  cycle  is  complicated  by  the  difficultv  of 
defining  precisely  what  takes  place  in  general  terms. 
The  number  of  factors  involved  and  the  variety  of 
combinations  possible  under  different  circumstances 
makes  generalization  extremely  hazardous.  Even  the 
dynamics  of  quiet  breathing  in  recumbency  in  man 
can  vary  from  time  to  time  and  from  person  to  person, 
depending  upon  the  individual  pattern  of  abdominal 


and  thoracic  muscular  interplay,  fatigue,  extent  of 
gastrointestinal  and  bladder  filling,  apprehension 
and  the  state  of  consciousness,  muscular  development, 
pulmonary  or  cardiac  dysfunction,  blood  volume, 
and  many  other  variables.  It  is  to  this  irregularity 
that  a  remarkable  diversity  of  opinion  must  be  at- 
tributed (64,  132). 

The  fact  that  pressure  within  the  thorax  tends  to 
be  lower  than  atmospheric  pressure  during  inspira- 
tion and  somewhat  higher  during  expiration  is  self- 
evident;  the  question  that  is  difficult  to  answer  is  how 
and  to  what  extent  this  phasic  change  in  pressure  is 
transmitted  to  the  splanchnic  vasculature.  With 
descent  of  the  diaphragm  during  inspiration  the  vis- 
cera are  forced  into  the  abdominal  cavity,  the  vascu- 
lar bed  subjected  to  shortening  and  buckling,  and  the 
liver  and  spleen  compressed  to  some  extent  as  they 
are  thrust  out  of  the  thorax.  During  expiration  shifts 
in  the  opposite  direction  must  occur.  In  association 
with  these  changes,  opposing  changes  in  intra-abdom- 
inal and  thoracic  pressure  probably  occur  in  such  a 
way  as  to  increase  the  pressure  gradient  between 
abdomen  and  thorax  during  inspiration  and  to  re- 
duce it  during  expiration.  In  the  main,  these  in- 
ferences find  support  in  the  experimental  record  but 
they  must  be  modified  under  many  conditions. 
For  example,  it  is  possible  for  contraction  of  the 
abdominal  muscles  during  expiration  and  relaxation 
during  inspiration  to  counter  the  usual  effect  easily 
and  to  produce  a  reversed  pattern.  Indeed  with 
maximal  or  laborious  breathing  in  man,  this  seems 
to  be  the  rule  (73).  In  the  upright  position  the  super- 
imposed hydrostatic  pressure  changes  also  have  an 
effect.  As  noted  above,  the  intra-abdominal  pressure 
under  these  circumstances  is  governed  to  some  extent 
— modified,  of  course,  by  muscular  tone  and  activity — 
by  the  hydrostatic  forces  and  the  shift  in  arterial 
and  venous  zero  reference  planes.  The  weight  of  the 
upper  abdominal  viscera  may  be  supported  in  part 
by  the  retractive  forces  of  the  thorax  and  its  contents 
and,  with  impeded  diaphragmatic  excursion,  an 
abdominal  component  in  the  respiratory  pattern 
may  figure  more  prominently.  The  magnitude  and 
direction  of  thoracico-abdominal  pressure  shifts 
may  have  direct  bearing  upon  blood  flow  into  or 
out  of  the  splanchnic  vasculature  or  upon  the  quan- 
tity of  blood  held  within  it  at  any  moment.  This  is 
so  because  collapse  of  the  large  draining  venous 
channels  may  increase  resistance  to  flow  more  than 
the  rise  in  the  pressure  gradient  tends  to  enhance  it. 
This  point  has  been  much  debated  and  still  remains 
unsettled.   On  the  one  hand,  Holt   (174)   and  Duo- 


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CIRCULATION    II 


marco  &  Rimini  (117)  believe  that  reduction  in 
venous  cross  section  at  the  level  of  the  diaphragm 
and  within  the  superior  vena  cava  will  impede  return 
of  blood  to  the  heart  during  inspiration.  Thus,  radio- 
micrographic  studies  in  the  rat  indicate  that  hepatic 
outflow  may  be  more  rapid  during  expiration  (58). 
This  thesis  has  been  vigorously  disputed,  on  the  other 
hand,  by  the  group  with  Wiggers  in  Cleveland  which 
has  included  Opdyke  (222),  Alexander  (3),  and 
Brecher  (64).  These  workers  have  shown  that, 
though  venous  collapse  may  increase  resistance  with 
an  increased  pressure  drop  at  the  diaphragm,  there 
is  nonetheless  an  inspiratory  increase  in  return, 
provided  the  tendency  to  venous  collapse  is  not  ex- 
aggerated by  marked  changes  in  the  gradient,  and 
provided  alteration  in  the  timing  of  phasic  changes 
does  not  predispose  to  "depletion"  of  the  venous 
chamber  with  resultant  collapse.  Both  groups  are 
probably  correct,  however,  in  view  of  the  manner 
in  which  the  response  may  be  altered  by  extraneous 
factors,  such  as  respiratory  rate,  position,  and  body 
size.  During  inspiration  under  ordinary  circumstances 
the  blood  held  in  the  hepatic  venous  tree  and  the 
inferior  caval  system  flows  out  somewhat  more 
rapidly  than  inflow  so  that  venous  return  is  initially 
augmented — and  splanchnic  outflow  increased.  The 
accompanying  compression  of  outflow  channels  and 
the  rise  in  intra-abdominal  pressure  would  operate 
to  reduce  inflow  so  that  net  flow  might  change  very 
little,  rise  or  fall,  depending  upon  the  duration  and 
frequency  of  the  inspiration  phase.  Direct  observation 
as  well  as  measurement  of  flow  bears  out  this  con- 
clusion, at  least  for  the  dog.  The  increased  outflow 
resistance  may  actually  conduce  to  portal  venous 
pooling  (3),  again  depending  upon  the  interplay  of 
all  the  other  factors  concerned.  It  may  actually  be 
rather  difficult  to  define  splanchnic  flow  and  volume 
under  these  circumstances  because  the  '"depleting" 
phase  of  inspiration  may  be  followed  by  filling  during 
expiration  not  only  from  the  arterial  side  but  also  by 
retrograde  flow  from  the  right  atrium  into  the  hepatic 
venous  chamber  as  angiographic  studies  have  shown. 
The  effect  of  anatomic  and  dimensional  differences 
requires  further  study. 

exercise.  The  effect  of  exercise  must  be  determined 
to  a  large  extent  by  the  manner  in  which  it  affects 
respiratory  activity,  intra-abdominal  pressure,  and 
gas  exchange  as  well  as  by  release  of  various  vaso- 
active agents.  In  quietly  resting  human  subjects  in 
recumbency,  exercise  (alternate  leg  raising)  induces  a 
significant  reduction  in  both  hepatic  blood  flow  and 


splanchnic  blood  volume  presumably  as  a  result  of 
vasoconstrictive  activity  (298).  Reallocation  of 
splanchnic  blood  volume  seems  to  occur  quickly 
and  may  indeed  play  a  role  in  the  maintenance  of 
cardiac  output  prior  to  the  establishment  of  a  new 
equilibrium.  When  blood  pressure  rises,  the  fall 
in  splanchnic  blood  flow  may  not  occur  in  spite  of 
vasoconstriction.  This  phenomenon  has  been  ob- 
served in  dogs  (superior  mesenteric  arterial  flow- 
measured  by  thermostromuhr)  exercised  on  a  tread- 
mill (172).  Possibly  there  was  a  similar  absence  of 
change  in  EHBF,  in  the  face  of  an  increment  in  he- 
patic temperature,  in  three  normal  human  subjects 
studied  by  Graf  (152).  The  Bromsulfalein  clearance  is 
of  questionable  value  in  evaluating  the  effect  of  exer- 
cise, since  BSP  extraction  tends  to  increase  in  associa- 
tion with  a  rise  in  hepatic  arteriovenous  oxygen 
difference  (34,  200).  Barcroft  and  his  associates  (20) 
found  that  exercise  (running)  caused  a  significant 
splenic  contraction  in  dogs  and  cats,  which  tended  to 
persist  in  proportion  to  the  duration  and  severity  of 
exertion.  A  definite  pattern  of  response  of  splanchnic 
arteriolar  and  venous  constriction  can  be  made  out 
but,  in  view  of  the  varied  and  opposing  forces  that 
are  brought  into  play  during  exertion,  a  diversity 
of  responses  is  probably  the  rule  in  normal  life. 

HEPATIC  CIRCULATORY  INTEGRATION 
AND  DYSFUNCTION 

Hepatosystemic  Interrelationships 

The  participation  of  the  hepatic  and  splanchnic 
circulation  in  general  systemic  reactions  is  usually 
diflicult  to  detect  and  to  delineate.  The  changes  ob- 
served during  exercise,  assumption  of  the  upright 
position,  and  respiration  have  been  noted  above 
because  they  entail  a  direct  effect  upon  the  intra- 
abdominal vasculature.  In  addition,  any  tendency 
for  cardiac  output  or  arterial  pressure  to  fall  or  to 
rise  is  associated  with  concomitant  changes  in  hepatic 
blood  flow  and  splanchnic  blood  volume.  In  the 
main,  these  adjustments  appear  to  provide  for  con- 
tinued perfusion  of  the  liver  without  undue  inter- 
ference with  corrective  responses  elsewhere  in  the 
body  to  restore  the  status  quo  ante.  Owing  to  the  com- 
plexities of  the  splanchnic  circuitry,  however,  the 
precise  mechanisms  of  local  adjustments  are  usually 
obscure.  Little  or  no  information  is  available  regard- 
ing minor  shifts.  More  is  known  about  adjustments  in 
such  extreme  disorders  as  circulatory  collapse  and 
congestive  heart  failure.  Unfortunately,  the  need  for 


THE     HEPATIC    CIRCULATION 


[427 


anesthesia  in  the  experimental  study  of  shock  in- 
troduces an  additional  variable.  General  anesthesia 
with  nitrous  oxide,  thiopental,  or  pentobarbital  does 
not  seem  to  affect  EHBF  and  SBV  provided  gas 
exchange  is  carefully  controlled  (123,  124).  Reactions 
may  differ  with  the  agent  employed  [splenic  volume 
is  increased,  for  example,  by  barbiturates  and  de- 
creased by  ether  (132)]  and  more  carefully  controlled 
studies  are  necessary  to  evaluate  the  effects  of  dif- 
ferent dosage  levels  and  anesthetic  planes.  Anesthetic 
drugs  also  act  like  autonomic  "blockers"  to  diminish 
responsiveness  so  that  data  collected  in  experimental 
studies  may  not  be  strictly  relevant  to  the  clinical 
state.  Studies  in  man  have  been  helpful  for  this  reason, 
though  complete  control  is  impossible.  The  hepatic 
circulatory  changes  of  congestive  heart  failure  have 
been  investigated  only  in  man  and,  though  the  data 
are  of  great  value,  reliable  evaluation  must  wait  upon 
definitive  studies  of  the  condition  produced  experi- 
mentally in  laboratory  animals. 

The  effects  of  hemorrhage  have  been  most  ex- 
tensively explored.  In  the  anesthetized  (pentobarbital) 
dog  and  rat,  splanchnic  blood  flow  and  volume  de- 
crease during  and  following  blood  loss  (136,  137, 
179,  243,  267).  Blood  flow  appears  to  diminish  in 
proportion  to  the  fall  in  arterial  pressure.  A  transient 
vasoconstriction  may  occur  but  the  general  tendency 
appears  to  be  rather  in  the  direction  of  moderate 
vasodilation,  particularlv  affecting  the  hepatic  ar- 
terioles. Mesenteric  arteriolar  constriction  may  de- 
velop after  prolonged  hemorrhagic  hypotension  (96, 
136)  and  may  even  be  enhanced  by  the  administra- 
tion of  norepinephrine,  but  there  is  no  evidence  that 
it  is  effective  in  sustaining  arterial  pressure  (193). 
Portal  venous  pressure  usually  falls,  too,  presumably 
as  a  result  of  both  the  shift  in  the  balance  between 
input  and  output  resistances  (central  venous  pressure 
also  falls)  and  the  drop  in  arterial  pressure.  Splanch- 
nic blood  volume  decreases  more  than  the  total 
blood  volume  (137,  243).  The  reduction  in  distend- 
ing pressure  is  probably  a  major  determinant  of  the 
shift,  but  venoconstriction,  demonstrable  in  isolated 
preparations  (6),  must  play  a  part  also  and  un- 
doubtedly accounts  for  the  continued  reduction  in 
splanchnic  blood  volume  following  restoration  of 
blood  volume  at  a  time  when  portal  venous  pressure 
tends  to  rise.  Certainly,  splenic  contraction  occurs 
in  most  species  (132).  The  splanchnic  venous  reservoir 
evidently  participates  as  a  whole  in  homeostatic 
compensations  by  actively  transferring  blood  into 
the  central  veins  and  sustaining  the  "circulating  blood 
volume."  This  response  continues   to   be  detectable 


even  in  the  terminal  irreversible  phase  (137,  243). 
How  and  to  what  extent  anesthesia,  adrenal  medul- 
lary discharge  and  neural  activity  contribute  to  or 
modify  hepatic  vasomotor  adjustments  remains  un- 
settled. Studies  of  changes  during  hemorrhage  in 
human  volunteers  suggest  that  splanchnic  vaso- 
constriction may  be  more  prominent  in  the  absence 
of  anesthesia  (28). 

A  definite  vasoconstrictive  pattern  is  clearlv  charac- 
teristic of  congestive  heart  failure  in  patients  with 
various  cardiac  diseases  (236).  In  this  situation, 
EHBF  has  been  found  to  be  reduced  to  the  same  ex- 
tent as  cardiac  output  despite  maintenance  or  even 
elevation  of  the  arterial  blood  pressure,  indicating 
vasoconstriction  no  greater  than  that  elsewhere  in 
the  body  and  certainly  much  less  than  that  occurring 
in  the  kidney.  A  uniform  contraction  of  hepatic  and 
splanchnic  arterioles  probably  occurs  without  much, 
if  any,  change  in  postsinusoidal  or  portal  venular 
resistance,  since  wedged  hepatic  venous  pressure  did 
not  differ  from  the  free  hepatic  venous  pressure  by 
more  than  2  mm  Hg  according  to  Rapaport  and  his 
associates  (236).  Circulating  splanchnic  blood  volume 
is  disproportionately  increased  by  cardiac  failure, 
at  least  in  those  patients  in  whom  atrial  and  wedged 
hepatic  venous  pressure  is  elevated.  There  is  no  evi- 
dence at  present  of  either  splanchnic  venoconstriction 
or  venodilation  and  it  is  necessary  to  conclude,  for 
the  moment,  that  the  distention  is  passive.  The  se- 
questration of  a  larger  portion  of  the  blood  volume 
in  the  splanchnic  bed  may  effectively  reduce  the  load 
imposed  upon  the  heart  and,  in  so  doing,  serve  as  a 
compensatory  device.  The  large  volume  of  blood 
within  the  splanchnic  veins  is  an  ever-present  hazard, 
however,  for  exertion,  violent  respiratory  movements, 
or  increased  intra-abdominal  pressure  may  displace  a 
large  volume  of  blood  from  the  abdomen  and  throw 
an  additional,  and  perhaps  an  overwhelming,  burden 
upon  the  heart  at  almost  any  time.  More  data  are 
needed  to  evaluate  this  possibility  and  to  assess  the 
role  of  the  hepatic  vasculature  in  the  pathogenesis 
and  therapy  of  congestive  heart  failure  and  other 
cardiovascular  disorders. 

Hepatosplatulmic  Inter) elationships 

The  interdependence  of  the  liver  and  the  gastro- 
intestinal tract  is  self-evident.  Digestion  and  absorp- 
tion depend  upon  normal  biliary  secretion,  while  the 
enterohepatic  circulation  of  bile  salts  and  the  release  of 
secretin,  in  turn,  determine  bile  flow  and  composition. 
Water,  electrolytes,  and  various  organic  compounds 


[428 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


move  rapidly  from  the  gut  into  the  portal  venous 
blood  and  are  carried  directly  to  the  liver.  Since  the 
bulk  of  the  blood  bathing  the  parenchymal  cells 
comes  from  the  portal  vein,  and  since  the  sinusoidal 
walls  are  completely  permeable  to  large  molecules 
(209),  the  extracellular  tissue  fluid  of  the  hepatic 
parenchyma  must  vary  much  more  widely  in  com- 
position, osmolarity,  and  acidity  than  interstitial 
fluid  elsewhere  in  the  body.  Cellular  function  is 
undoubtedly  influenced  by  the  milieu  interieur  as  a 
whole  as  well  as  by  certain  active  ingredients  in  it. 
The  gastrointestinal  tract  may  be  said  to  control  the 
chemical  environment  of  liver  cells  not  only  by  its 
absorptive  activity  but  also  by  its  oxygen  consump- 
tion, for  the  liver  must  be  content  with  the  leavings  of 
the  gut.  Owing  to  the  difficulty  of  sampling  portal 
venous  blood,  little  is  known  about  the  fluctuations 
in  the  chemical  composition  of  portal  venous  blood 
and  their  impact  upon  hepatocellular  function.  Much 
more,  but  still  too  little,  is  known  about  the  manner 
in  which  portal  venous  pressures  may  be  affected  by 
the  interplay  between  hepatic  and  splanchnic  re- 
sistances. 

The  behavior  of  portal  venous  blood  flow  and  pres- 
sure under  normal  conditions  has  been  discussed  at 
length  above  and  the  pattern  of  partition  will  be 
covered  in  another  chapter.  Since  there  is  a  lack  of 
data  on  the  distribution  of  flow  and  pressures  through- 
out the  total  hepatosplanchnic  vasculature,  the  rela- 
tive importance  of  pre-  and  postportal  vein  resistances 
cannot  be  clearly  defined.  The  fact  that  portal  venous 
inflow  usually  accounts  for  some  two-thirds  to  three- 
quarters  of  the  hepatic  venous  outflow  points  to  domi- 
nance by  the  preportal  resistances  (35,  37,  115, 
132,  204,  255).  The  rise  in  portal  venous  pressure 
during  the  action  of  epinephrine  may  be  ascribed 
therefore  largely  to  mesenteric  (subsuming  under 
this  term  the  total  preportal  bed)  vasodilation,  the 
fall  with  norepinephrine  to  mesenteric  vasoconstric- 
tion. Vasopressin  (103,  142,  308)  has  also  been 
found  to  be  a  most  effective  agent  in  lowering  portal 
venous  pressure  in  man  and  dogs  by  contraction  of 
the  mesenteric  arterioles  in  association  with  a  reduc- 
tion in  hepatic  blood  flow.  The  resulting  rearrange- 
ment of  pressure  gradients  may  result  in  a  fall  in 
sinusoidal  pressure,  so  that  the  much  weaker  hepatic 
arteriolar  constriction  may  be  effectively  countered 
by  the  rise  in  arteriosinusoidal  pressure  difference 
and  hepatic  arterial  inflow  actually  increased  (171). 
There  is  relatively  little  evidence  of  an  actively 
maintained    balance    between    arterial    and    portal 


venous  flow  to  the  liver,  although  the  arrangement  of 
resistances  noted  above  does  lead  to  an  apparent 
reciprocity  when  one  or  the  other  inflow  is  predomi- 
nantly affected  (36,  158).  Ligation  of  the  portal  vein 
is  thus  immediately  followed  by  an  increase  in  hepatic 
arterial  inflow,  up  to  100  per  cent  above  control,  and 
hepatic  arterial  ligation  has  a  similar  effect  upon 
portal  venous  flow,  but  the  increment  fails  to  restore 
total  flow  to  the  control  level  (158,  254).  Perhaps 
subsequent  changes  in  tissue  function  set  in  train 
delayed  corrective  adjustments  that  assure  adequate 
perfusion,  but  local  mechanisms  to  provide  immedi- 
ately for  reciprocity  seem  to  be  lacking.  Indeed, 
portal  venous  pressure  may  be  persistently  reduced 
after  hepatic  arterial  ligation  so  that  an  increment  in 
portal  inflow  fails  to  make  up  the  deficit  in  perfusion. 
A  similar  phenomenon  has  been  encountered  in 
patients  with  cirrhosis  (52)  where  parenchymal 
cellular  damage  and  extensive  fibrosis  have  grossly 
deformed  the  architecture  of  the  liver  and  its  vascula- 
ture. The  blood  flow  through  the  cirrhotic  liver  is 
significantly  reduced  by  attenuation  of  the  total 
vascular  bed  and  by  compression  and  distortion  of 
the  hepatic  venous  outflow  tract.  The  resultant  ele- 
vation in  sinusoidal  and  portal  venous  pressure  is 
often  combined  with  a  fall  in  plasma  albumin  con- 
centration. Portal  venous  hypertension  appears  to 
be  the  primary  event  responsible  for  increased  move- 
ment of  fluid  across  capillary  and  sinusoidal  walls 
and  for  the  formation  of  ascites.  Secondary  cir- 
culatory, humoral,  and  renal  changes  are  also  essen- 
tial features  [see  (16)  and  (196)  for  a  recent  examina- 
tion of  this  problem].  The  portal  venous  pressure 
may  be  markedly  diminished  by  portacaval  anasto- 
mosis, in  association  with  a  significant  fall  in  hepatic 
blood  flow  that  tends  to  persist  without  any  evi- 
dence of  hepatic  arteriolar  dilatation.  Hepatic  venous 
oxygen  concentration  is  well  below  normal  in  cir- 
rhotic patients  and  it  falls  still  lower  after  establishment 
of  a  portacaval  shunt,  indicating  further  that  hepatic 
arterial  and  portal  venous  inflows  are  not  neces- 
sarily correlated.  The  relative  independence  of  the  two 
vascular  supplies  may  indeed  contribute  in  the  patho- 
genesis and  perpetuation  of  cirrhosis  (289). 

Under  normal  resting  conditions  the  gastroin- 
testinal vasculature  could  conceivably  determine 
hepatic  function  through  its  domination  of  sub- 
strate supply,  but,  in  fact,  the  hepatic  blood  supply 
appears  to  be  adjusted  to  the  metabolic  requirements 
of  the  body  as  a  whole.  Digestion  and  absorption, 
as  such,  do  not  affect  hepatic  blood  flow.  Ingestion 


THE     HEPATIC    CIRCULATION 


I429 


of  protein,  possibly  carbohydrates,  but  not  fat,  is 
followed  by  the  development  of  hepatic  hyperemia 
in  man  (54,  152,  200,  240).  Reininger  &  Sapirstein 
(240)  have  found  that  hepatic  blood  flow  increases 
in  rats  after  a  protein  meal,  in  proportion  to  the  rise 
in  cardiac  output  and  blood  flow  to  other  tissues 
that  occurs  at  the  same  time.  Similar  changes  in 
systemic  and  hepatic  circulation  have  been  de- 
tected in  man  during  febrile  reactions  to  pyrogenic 
agents  (46,  152,  170)  in  association  with  increased 
total  oxygen  consumption.  Liver  temperature  rises 
after  protein  feeding  and  during  fever  (152),  pre- 
sumably as  a  result  of  augmented  hepatocellular 
metabolism.  When  hepatic  oxygen  consumption  is 
increased  by  thyrotoxicosis,  EHBF  does  not  change 
appreciably  (218).  According  to  Bondy  and  others 
(38)  uncontrolled  human  diabetes  is  not  associated 
with  a  significant  change  in  EHBF,  although  Lips- 
comb &  Crandall  ( 1 97)  have  observed  high  values 
in  diabetic  dogs.  A  definite  increment  in  EHBF  has 
been  observed  in  dogs  also  during  hyperglycemia 
produced  by  glucagon  administration  and  hypogly- 
cemia produced  by  insulin  (112,  276,  279).  Epi- 
nephrine release  may  be  involved  in  the  latter  and 
must,  indeed,  be  weighed  in  the  evaluation  of  hepatic 
hyperemia,  whatever  its  cause.  Sympathoadrenal 
activation  is  an  unlikely  participant,  however,  in  the 
action  of  /-hydrazinophthalazine  which  has  been 
found  (207)  to  elicit  a  pattern  of  circulatory  and 
metabolic  adjustments,  in  every  respect  like  that 
produced  by  pyrogen,  except  that  body  temperature 
does  not  rise.  If  the  expansion  in  splanchnic  blood 
volume  during  the  action  of  hydralazine  in  dogs  is 
typical  of  the  hepatic  hyperemic  reaction  in  general, 
it  may  be  concluded  that  vascular  smooth  muscle  is 
uniformly  affected  with  simultaneous  arteriolar  and 
venous  dilatation.  Moreover,  the  tendency  for  ar- 
terial pressure  to  fall  to  low  levels  in  these  conditions 
may  be  the  result  of  interference  with  venous  return 
by  "splanchnic  pooling."  Hyperemic  responses  de- 
serve careful  study  not  only  for  the  light  that  may  be 
cast  upon  normal  hepatosplanchnic  interrelation- 
ships but  also  for  better  understanding  of  derange- 
ments in  integration  that  may  be  involved  in  the 
production  of  hepatic  disorders. 


Throughout  the  foregoing  discussion  attention 
has  been  directed  chiefly  to  the  local  and  systemic 
factors  that  may  determine  hepatic  blood  flow  in 
health  and  disease.  Admittedly  the  account  is  sketchy 


owing  to  inadequacies  of  the  author  and  the  space 
available.  An  effort  has  been  made  to  cover  in  some 
detail  the  elements  of  hepatic  and  splanchnic  hemo- 
dynamics. The  role  of  the  preportal  systems  in  the 
spleen,  gastrointestinal  tract,  and  pancreas  have 
been  alluded  to  frequently  but  it  has  been  difficult  to 
give  these  factors  the  weight  they  deserve,  chiefly 
because  the  evidence  available  is  so  fragmentary  and 
questionable.  As  noted  at  the  outset,  methodology- 
must  take  first  rank  as  a  cause  for  uncertainty.  Dif- 
ficulty in  generalization  arises  also  from  dependence 
upon  data  drawn  from  but  one,  or  too  few,  experi- 
mental animal  species;  from  acute  responses  tram- 
meled by  unphysiologic  conditions  of  anesthesia, 
restraint,  and  surgery;  and,  finally,  from  portions, 
rather  than  the  totality  of  any  reaction.  Emphasis 
has  been  placed  upon  correlation  of  structure  and 
function.  For  this  reason,  among  others,  the  arteriolar 
resistances  have  been  stressed  as  determinants  of 
flow  and  pressure  gradients.  The  volume  of  blood 
contained  within  the  vasculature  has  been  assigned 
chiefly  to  the  large  veins  and  translocations  or  re- 
arrangement of  content  ascribed,  therefore,  to 
alterations  in  venous  smooth  muscle  function  and 
inlet-outlet  balance.  Neither  of  these  inferences  is 
invalidated  by  the  possibility  touched  upon  at  several 
points,  that  extravascular  influences  may  dominate 
more  slowly  developing  changes.  Tissue  turgor,  fibro- 
sis, extravascular  cellular  or  fluid  infiltration,  and 
distortion  by  compression  or  traction  may  affect 
vascular  path  lengths  and  numbers,  as  well  as  cross 
sections,  with  a  corresponding  effect  upon  resistance 
and  volume  capacity.  Much  remains  to  be  learned 
about  the  dynamics  of  flow  in  sinusoidal  capillaries 
and  it  is  possible  that  conventional  explanations 
will  ultimately  prove  inadequate.  The  hepatic  vascu- 
lature and  the  splanchnic  reservoir  proximal  to  it 
participate  in  systemic  circulatory  reactions,  but  the 
evidence  suggests  that  maintenance  of  hepatocellular 
function  has  priority  and  that  homeostatic  adjust- 
ments operate  solely  to  produce  a  state  that  does  not 
actively  impair  over-all  compensation,  without  adding 
much  to  it.  Perhaps  the  shift  of  blood  from  the 
splanchnic  bed  is  helpful  but  the  data  cannot  be  con- 
strued to  favor  conclusively  an  active  rather  than  a 
passive  role.  The  liver  is  undoubtedly  essential  to 
metabolic  activity,  but  the  role  of  the  hepatic 
circulation  in  metabolic  homeostasis  remains  to  be 
elucidated.  In  this  direction,  hepatic  circulatory 
physiology  may  stand  upon  the  threshold  to  signifi- 
cant discoveries. 


'43« 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


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76.  Canter,  J.  W.,  W.  S.  Rosenthal,  and  I.  D.  Baronofskv. 
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The  effect  of  levarterevol  (L-norepinephrine)  on  hepatic 

blood  flow  in  the  normal,  anesthetized  dog.  ./.  Pharmacol. 

Exptl.    Therap.    1  10:    398-402,    1954. 

Smythe,  C.  McC,  H.  O.  Heinemann,  and  S.  E.  Bradley. 

Estimated  hepatic  blood  flow  in  the  dog.  Effect  of  ethyl 

alcohol    on    it,    renal    blood    flow,    cardiac    output    and 

arterial  pressure.  Am.  J.  Physiol.    172:  737-742,    1953. 

Stecher,  J.    L.    Fatal   reaction   to  sulfobromophthalein. 

New  Engl.  J.  Med.  261:  963,    1959. 

Stephenson,  J.  L.  Theory  of  the  measurement  of  blood 

flow  by  the  dilution  of  an  indicator.  Bull.  Math.  Biophys. 

10:  1 17-121,  1948. 

Taleisnik,  S.  Liver  mass  determination  by  Bromsulfalein 

in   partially   hepatectomized   rabbits.    Gastroenterology   29: 

64-70,  1955- 

Taylor,  W.  J.,  and  J.  D.  Myers.  Occlusive  hepatic 
venous  catheterization  in  the  normal  liver,  cirrhosis  of 
the  liver  and  noncirrhotic  portal  hypertension.  Circulation 

i3:368-38°.  '956- 

Thomas,  W.  D.,  and  H.  E.  Essex.  Observations  on  the 
hepatic  venous  circulation  with  special  reference  to  the 
sphincteric  mechanism.  Am.  J.  Physiol.  158:303-310,  1949. 
Thompson,  A.  M.,  H.  M.  Cavert,  N.  Lifson,  and  R.  L. 
Evans.  Regional  tissue  uptake  of  D2O  in  perfused  organs : 
rat  liver,   dog   heart  and  gastrocnemius.   Am.  J.  Physiol. 

!97:  897-902,  1959- 

Tisdale,  W.  A.,  G.  Klatskin,  and  W.  W.  Glenn.  Portal 
hypertension  and  bleeding  esophageal  varices;  their  occur- 
rence in  the  absence  of  both  intrahepatic  and  extrahepatic 
obstruction  of  the  portal  vein.  New  Engl.  J.  Med.  261  :  209- 
218,  1959. 

Tornvall,  G.,  and  L.  Johansson.  Liver  circulation  in 
man  as  studied  by  means  of  dilution  curves.  A  method 
using  catheterisation  technique.  Acta  Med.  Scand.  1 54  ■ 
491-500,  1956. 

Torrance,  H.  B.  Liver  blood  flow  during  operations  on 
the  upper  abdomen.  J.  Roy.  Coll.  Surgeons,  Edinburgh  2: 
216-228,  1957. 

Trapold,  J.  H.  Effect  of  ganglionic  blocking  agents  upon 
blood    flow    and    resistance    in    the    superior    mesenteric 
artery  of  the  dog.  Circulation  Research  4:  718-723,   1956. 
Tygstrup,  N.,  and  K.   Winkler.  Galactose  blood  clear- 
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1-9,  1958. 

Utterback,  R.  A.  The  innervation  of  the  spleen.  J.  Comp. 
Neurol.  81  :  55-68,  1944. 

Verschure,  J.  C.  M.  Clinical  use  of  measurements  of 
clearance  and  maximum  capacity  of  the  liver.  Acta  Med. 
Scand.    142:   409-419,    1952. 

Vetter,  H.,  G  Grabner,  R.  Hofer,  A.  Neumayr,  and 
O.  Parzer.  Comparison  of  liver  blood  flow  values  esti- 
mated by  the  Bromsulphalein  and  by  the  radiogold 
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CIRCULATION    II 


299.  Wakim,  K.  G.,  and  F.  C.  Mann.  The  intrahepatic  circu- 
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300.  Walk,  L.  Roentgenologic  determination  of  the  liver 
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301.  Wells,  R.  E.,  Jr.,  and  E.  W.  Merrill.  Shear  rate  de- 
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302.  Werner,  A.  Y.,  and  S.  M.  Horvath.  Measurement  of 
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1958. 

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306.  Wheeler,  H.  O.,  J.  I.  Meltzer,  and  S.  E.  Bradley. 
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313.  Yamada,  S.,  and  A.  C.  Burton.  Effect  of  reduced  tissue 
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316.  Zilversmit,  D.  B.,  G.  A.  Boyd,  and  M.  Brucer.  The 
effect  of  particle  size  on  blood  clearance  and  tissue  dis- 
tribution of  radioactive  gold  colloids.  J.  Lab.  Clin.  Med. 
40:  255-260,  1952. 

317.  Zweifach,  B.  W.  Direct  observation  of  the  mesenteric 
circulation  in  experimental  animals.  Anal.  Record  120: 
277-291,  1954. 


&^r^A 


CHAPTER     42 


The  flow  of  blood  in  the  mesenteric  vessels' 


EUGENE    GRIM  Department  oj  Physiology,  University  of  Minnesota,  Minneapolis,  Minnesota 


CHAPTER     CONTENTS 

Magnitude  of  Total  Mesenteric  Blood  Flow 
Partition  of  Total  Blood  Flow 

Major  Organs 

Individual  Tissues 

Vessels  of  Different  Sizes 
Mesenteric  Blood  Volume 
Factors  Affecting  the  Blood  Flow  and  Its  Distribution 

Stomach 

Intestine 

Pancreas 

Spleen 

Mesenteric  Circulation  as  a  Whole 
Relation  of  Blood  Flow  to  Function  of  the  Mesenteric  Organs 


the  mesenteric  circulation  is  usually  considered  to 
be  that  part  of  the  systemic  circulation  which  sup- 
plies the  stomach,  small  intestine,  large  intestine, 
pancreas,  and  spleen.  These  organs  receive  blood 
from  all  the  branches  of  the  celiac  (except  the  hepatic 
proper),  the  superior  mesenteric,  and  the  inferior 
mesenteric  arteries.  They  are  not  drained  directly 
into  the  venous  system  as  are  most  organs,  but  into 
the  portal  vein  from  which  the  blood  passes  through 
a  second  set  of  capillaries  in  the  liver  before  entering 
the  inferior  vena  cava. 

Because  of  the  peculiar  anatomy  of  this  venous 
drainage  system,  the  flow  of  blood  in  the  mesenteric 
vessels  may  be  altered  profoundly  by  factors  which 
do  not  act  directly  on  these  vessels  but  rather  change 
the  resistance  of  the  hepatic  vasculature.  This  poses  a 
problem  for  the  investigator  who  uses  the  intact 
animal  as  the  most  "physiological"  subject  for  study. 

1  This  chapter  was  written  during  the  tenure  of  a  U.  S. 
Public  Health  Service  Senior  Research  Fellowship   (SF-161). 


Great  care  must  be  exercised  in  the  interpretation  of 
the  results  of  such  studies,  particularly  when  they 
disagree  with  those  from  investigations  on  the  iso- 
lated mesenteric  organs. 

The  mesenteric  circulation  as  such  has  not  pre- 
viously been  the  subject  of  a  comprehensive  review, 
although  it  has  been  considered  in  a  subsidiary 
fashion  in  reviews  on  the  total  splanchnic  blood  flow 
by  such  authors  as  La  Croix  (92)  and  Bradley  (21). 
Even  the  standard  textbooks  of  physiology,  in  which 
can  be  found  sections  devoted  to  the  circulation 
through  the  heart,  brain,  lungs,  kidneys,  liver,  and 
skeletal  musculature,  contain  few  statements  con- 
cerning the  circulation  through  the  mesenteric 
organs. 

In  part,  the  cause  of  this  is  the  relative  scarcity  of 
quantitative  information  on  the  subject  and  the 
many  instances  in  which  different  investigators  have 
published  contradictory  results.  For  the  same  reasons 
many  of  the  statements  that  follow  should  be  taken 
as  tentative.  This  review  might  be  better  viewed  as 
indicating  guide  lines  for  future  research  rather  than 
as  a  definitive  dissertation. 


MAGNITUDE    OF   TOTAL    MESENTERIC   BLOOD    FLOW 

The  total  flow  of  blood  through  the  mesenteric 
system  can  be  most  directly  determined  by  measuring 
the  flow  through  the  portal  vein.  Since  there  has 
been  no  suitable  method  for  this  measurement  in  the 
human,  all  the  available  quantitative  information 
has  been  obtained  in  experimental  animals,  especially 
the  dog. 

One  of  the  earliest  measurements  of  portal  venous 
flow  was  made  by  Burton-Opitz   (30)   as  a  part  of 


1439 


1440 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


what  probably  remains  to  this  day  the  most  complete 
study  of  the  flow  of  blood  through  the  mesenteric 
organs.  He  placed  a  stromuhr  in  the  portal  veins  of 
dogs  anesthetized  with  ether  and  obtained  a  mean 
blood  flow  divided  by  the  mean  body  weight  of  14.3 
kg  of  19  ml  per  min  per  kg.  His  animals  had  relatively 
low  arterial  blood  pressures,  the  average  being  about 
100  mm  Hg,  and  a  normal  mean  portal  vein  pressure 
of  1  1  mm  Hg. 

In  several  subsequent  studies  made  with  thermo- 
stromuhrs,  values  between  16  and  20  ml  per  min  per 
kg  were  obtained.  These  include  Grab  et  al.  (59), 
Soskin  et  al.  (128),  Grodins  et  al.  (71),  and  Grindlay 
et  al.  (70).  Some  of  the  dogs  used  were  unanesthetized; 
others  were  anesthetized  with  such  agents  as  ether, 
chloralose,  or  sodium  pentobarbital.  Arterial  blood 
pressure  was  given  only  in  the  report  of  Grab  et  al., 
the  mean  being  100  mm  Hg. 

These  investigations  were  performed  with  in- 
struments which  have  since  been  severely  criticized, 
the  stromuhr  because  it  introduces  a  flow  resistance 
into  the  vessel  in  which  it  is  placed  and  the  thermo- 
stromuhr  for  a  variety  of  reasons  [see,  for  example, 
Gregg  (68)]. 

MacLeod  &  Pearce  (97)  cannulated  the  thoracic 
vena  cava  of  ether-anesthetized  dogs,  occluding  it 
above  and  below  the  entrance  of  the  hepatic  veins 
with  balloons,  and  collected  the  outflow  before  and 
after  portal  vein  ligation.  The  mean  total  liver  outflow 
in  animals  with  an  arterial  blood  pressure  of  about 
140  mm  Hg  was  44  ml  per  min  per  kg.  This  was 
reduced  by  60  per  cent  upon  portal  vein  occlusion, 
indicating  that  the  usual  flow  through  the  latter  was 
about  26  ml  per  min  per  kg.  Blalock  &  Mason  (17) 
used  a  somewhat  similar  technique  in  unanesthetized 
dogs  to  measure  the  hepatic  venous  outflow  im- 
mediately after  hepatic  arterial  ligation  and  ob- 
tained a  mean  value  of  24  ml  per  min  per  kg. 

Electromagnetic  flowmeters  have  been  placed  on 
the  portal  vein  by  several  groups  of  investigators. 
Stewart  et  al.  (129)  and  Drapanas  et  al.  (41)  found 
the  mean  portal  flow  to  be  25  ml  per  min  per  kg  at 
arterial  pressures  of  about  140  mm  Hg.  Green  et  al. 
(66)  obtained  a  lower  value,  1  7  ml  per  min  per  kg, 
but  the  mean  arterial  pressure  of  their  animals  was 
only  slightly  above  100  mm  Hg. 

Direct  measurements  of  portal  venous  flow  by 
cannulation  and  collection  of  the  blood  was  made 
by  Heimburger  et  al.  (75).  They  obtained  a  mean 
value  of  30  ml  per  min  per  kg;  however,  since  they 
collected   the   blood   by   gravity    thus   producing   an 


unphysiological,  negative  pressure  in  the  portal  vein, 
it  seems  likely  that  this  value  is  too  high. 

The  highest  value  for  portal  venous  flow  has  been 
reported  by  Sapirstein  (114).  He  injected  radio- 
potassium  and  radiorubidium  into  both  rats  and 
dogs  and  observed  that  the  concentration  of  these 
isotopes  in  all  organs  except  the  brain  remained 
nearly  constant  for  a  period  of  approximately  10  to 
60  sec  after  injection.  He  concluded  that  the  ex- 
traction ratios  for  these  substances  must  necessarily 
be  the  same  for  all  the  organs,  and  hence  that  the 
fraction  of  injected  isotope  found  in  any  organ  was 
equal  to  the  fraction  of  the  cardiac  output  passing 
through  the  organ.  By  adding  the  isotope  contents 
of  the  organs  drained  by  the  portal  vein,  Sapirstein 
found  that  20  per  cent  of  the  cardiac  output  passed 
through  them,  a  value  which  agrees  well  with  the 
findings  of  the  previous  workers.  However,  when 
Sapirstein  converted  this  value  to  units  of  flow  per 
unit  body  weight,  he  obtained  34  ml  per  min  per  kg. 
The  discrepancy  arises  from  the  fact  that  his  dogs 
were  small  (6-8  kg)  and  had  a  mean  cardiac  output 
by  the  K42-dilution  technique  of  170  ml  per  min  per 
kg.  In  the  larger  animals  used  by  most  investigators 
(12-20  kg)  the  cardiac  output  is  usually  about  125 
ml  per  min  per  kg,  20  per  cent  of  which  is  25  ml  per 
min  per  kg. 

The  discrepancies  among  portal  venous  flows  ob- 
tained by  various  workers  would  seem  in  large  part 
to  have  been  due  to  differences  in  arterial  pressures 
rather  than  to  the  measurement  procedures.  The 
workers  who  found  values  of  about  25  ml  per  min 
per  kg  studied  dogs  having  arterial  pressures  of 
about  130  mm  Hg,  while  those  who  observed  18  or 
19  ml  per  min  per  kg  used  animals  with  pressures 
of  about  100  mm  Hg.  It  would  appear  that  the  portal 
venous  blood  flow  in  dogs  of  10  to  20  kg  body  wt 
having  a  "normar'  arterial  pressure  of  130  mm  Hg 
is  about  25  ml  per  min  per  kg.  This  is  equivalent  to 
about  20  per  cent  of  the  cardiac  output  or  approx- 
imately 350  to  450  ml  per  min  in  a  15-kg  animal.  It 
does  not  seem  that  this  value  is  too  much  affected  by 
anesthesia  with  a  variety  of  agents. 

A  very  few  measurements  of  total  portal  flow  in 
other  species  can  be  found  in  the  literature.  Sapirstein 
and  co-workers  (109,  113,  133)  in  three  separate 
studies  found  the  portal  flow  in  rats  anesthetized  with 
sodium  pentobarbital  to  be  14,  16,  and  20  per  cent 
of  the  cardiac  output.  Fegler  &  Hill  (44)  using  a 
thermodilution  technique  in  sheep  obtained  a  very- 
high  portal  flow  of  31  per  cent  of  the  cardiac  output; 
however,    as    they    pointed    out,    members    of    this 


FLOW    OF    BLOOD    IN     MESENTERIC    VESSELS 


I44I 


species  are  exceedingly  sensitive  to  abdominal  trauma. 
In  the  human,  portal  flow  is  usually  estimated  on  the 
assumption  (from  studies  with  the  dog)  that  two- 
thirds  to  three-fourths  of  the  total  hepatic  flow  as 
determined  by  the  Bromsulfalein  technique  (800- 
850  ml/min  m2)  is  derived  from  the  portal  vein.  On 
this  basis,  the  portal  venous  flow  is  530  to  640  ml  per 
min  per  m2,  somewhat  less  than  20  per  cent  of  the 
cardiac  output. 


PARTITION    OF  TOTAL   BLOOD    FLOW 

Major  Organs 

Two  investigators,  Burton-Opitz  and  Sapirstein, 
have  measured  the  blood  flow  through  all  the  major 
mesenteric  organs.  The  former  measured  gastric 
flow  (29)  by  placing  a  stromuhr  in  the  gastrosplenic 
vein,  ligating  the  pancreatic  and  splenic  branches. 
Ligation  of  the  gastroduodenal  and  pyloric  veins 
presumably  forced  all  the  gastric  venous  drainage 
through  anastomotic  channels  into  the  stromuhr. 
He  obtained  a  mean  flow  of  0.25  ml  per  min  per  g 
of  stomach  in  dogs  with  a  mean  arterial  pressure  of 
85  mm  Hg.  In  another  group  of  animals  (27)  he 
placed  the  stromuhr  in  the  common  mesenteric  vein 
thus  obtaining  the  blood  flow  through  all  the  intestine 
except  the  duodenum  which  is  drained  by  the  pan- 
creaticoduodenal vein.  At  a  mean  arterial  pressure 
of  slightly  less  than  100  mm  Hg,  the  mean  flow  was 
0.31  ml  per  min  per  g  of  intestine.  His  measurements 
of  pancreatic  blood  flow  (31)  were  more  difficult  to 
make  as  this  organ  is  supplied  and  drained  by  num- 
erous vessels.  He  placed  the  stromuhr  in  the  gastro- 
duodenal artery,  ligated  the  right  gastroepiploic 
artery,  and  so  obtained  the  flow  through  the  superior 
pancreaticoduodenal  artery.  This  vessel  supplies  the 
body  of  the  pancreas  and  a  portion  of  the  duodenum. 
The  head  of  the  pancreas  receives  arterial  blood  by 
way  of  the  inferior  pancreaticoduodenal,  a  branch  of 
the  cranial  (superior)  mesenteric,  and  the  tail  of  the 
organ  by  way  of  branches  of  the  splenic  artery.  In 
two  animals  he  was  able  to  separate  the  body  of  the 
pancreas  from  the  duodenum  and  so  obtained  the 
pancreatic  flow  alone.  The  mean  flow  was  0.8  ml 
per  min  per  g  at  1  10  mm  Hg.  To  measure  the  splenic 
blood  flow,  Burton-Opitz  placed  the  stromuhr  in  the 
splenic  vein  (28).  In  10  animals,  he  obtained  a 
mean  flow  of  0.58  ml  per  min  per  g  at  an  arterial 
pressure  of  98  mm  Hg. 

From    Burton-Opitz'    data,    the    weights    of    the 


stomach,  intestine,  pancreas,  and  spleen  in  a  15-kg 
dog  can  be  estimated  as  250,  500,  50,  and  70  g, 
respectively.  The  total  blood  flows  through  the  same 
organs  would  be  60,  155,  40,  and  40  ml  per  min, 
respectively,  and  the  partition  of  the  total  mesenteric 
flow  about  20,  55,  13,  and  13  per  cent.  In  Sapirstein's 
study  (114)  the  partition  of  blood  flow  was  determined 
directly.  He  obtained  values  of  13,  72,  8,  and  7  per 
cent  for  the  same  organs. 

The  discrepancies  in  these  two  sets  of  data  may 
be  due  to  one  or  more  of  several  factors.  As  stated 
earlier,  Sapirstein's  dogs  were  much  smaller  than 
those  of  Burton-Opitz.  In  the  former  the  weight  of 
the  intestines  was  greater  in  relation  to  the  weights 
of  the  other  mesenteric  organs  than  in  the  latter. 
Further,  Sapirstein's  dogs  were  anesthetized  with 
sodium  pentobarbital  and  presumably  had  arterial 
pressures  30  to  40  mm  Hg  higher.  Finally,  the  meas- 
urement techniques  used  may  have  resulted  in  er- 
roneous values  for  one  or  more  organs  in  the  study. 
It  is  possible  that  the  resistance  offered  by  the  stro- 
muhr to  the  intestinal  venous  outflow  may  have 
caused  Burton-Opitz  to  underestimate  the  propor- 
tion of  the  total  flow  that  passed  through  the  gut. 
On  the  other  hand,  Sapirstein's  method  may  result 
in  either  an  underestimate  or  an  overestimate  of 
flow  through  an  organ.  His  assumption  that  con- 
stancy of  isotope  content  with  time  in  all  organs  im- 
plies identical  extraction  ratios  is  not  wholly  justified. 
It  is  probably  not  too  much  in  error  as  the  extraction 
ratio  for  radiopotassium  in  the  first  few  seconds  after 
injection  is  nearly  one  for  all  organs.  However,  isotope 
constancy  can  be  observed  in  the  presence  of  different 
extraction  ratios  if  the  potassium  ion  concentrations 
of  the  organs  differ,  as  they  do. 

In  order  to  compare  the  data  of  Burton-Opitz 
and  Sapirstein  for  any  one  organ  with  data  obtained 
by  other  investigators,  it  is  desirable  to  express  the 
flows  per  unit  weight  of  organ.  Also,  an  attempt  must 
be  made  to  normalize  the  values  to  some  kind  of 
average  animal.  For  Burton-Opitz'  results  this  can 
be  done  by  correcting  to  an  arterial  pressure  of 
1 30  to  1 40  mm  Hg,  assuming  that  the  flow  increases 
linearly  with  arterial-venous  pressure  difference. 
The  following  values  are  thus  obtained :  stomach, 
0.4;  intestine,  0.4;  pancreas,  1.0;  and  spleen,  0.8 
ml  per  min  per  g  of  tissue.  Sapirstein's  values  for  the 
same  organs  are  0.4,  0.7,  1.0,  and  0.6,  respectively. 
These  values  were  obtained  by  taking  the  cardiac 
output  to  be  170  ml  per  min  per  kg.  If  Sapirstein's 
distribution  is  applied  to  1 5-  or  20-kg  animals  with 
a  cardiac  output  of  125  ml  per  min  per  kg,  his  values 


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HANDBOOK    OF    PHYSIOLOGY    ^   CIRCULATION     II 


would  all  be  reduced  by  some  25  per  cent;  that  is, 
with  the  exception  of  the  intestine,  they  would  be 
lower  than  those  of  Burton-Opitz. 

Of  the  other  workers  who  have  measured  gastric 
blood  flow,  Boenheim  (18)  collected  the  venous 
drainage  directly  and  obtained  a  mean  flow  of  0.26 
ml  per  min  per  g  at  the  very  low  arterial  pressure 
of  60  mm  Hg.  Lim  et  al.  (94)  perfused  with  a  donor 
dog  an  isolated  surviving  stomach  and  collected  the 
venous  outflow  to  find  a  mean  value  of  0.34  ml  per 
min  per  g  at  a  perfusion  pressure  of  100  mm  Hg. 
Recently,  Salmon  et  al.  (112)  used  a  method  similar 
to  that  of  Boenheim's  in  dogs  with  blood  pressures  of 
130  to  150  mm  Hg  and  obtained  a  mean  flow  of 
0.37  ml  per  min  per  g. 

The  literature  contains  widely  varying  values  for 
the  blood  flow  through  the  intestines.  Selkurt  et  al. 
(119)  measured  mesenteric  venous  outflow  in  dogs 
anesthetized  with  sodium  pentobarbital  and  having 
pressures  of  1 30  mm  Hg  or  more.  They  found  a  mean 
flow  of  8.7  ml  per  min  per  kg  body  wt  which  is 
equivalent  to  about  0.2  ml  per  min  per  g  organ. 
In  a  later  study  with  a  rotameter,  Selkurt  (120) 
obtained  flows  50  per  cent  or  higher,  but  no  body- 
weights  were  given  so  direct  comparison  cannot  be 
made. 

A  large  number  of  measurements  of  venous  outflow 
from  segments  of  small  intestine  have  been  made  in 
the  writer's  laboratory  in  the  past  few  years.  These 
were  innervated  and  denervated  segments,  in  situ, 
in  dogs  weighing  1 2  to  20  kg,  anesthetized  with 
sodium  pentobarbital  and  having  arterial  pressures 
of  1  20  to  1 50  mm  Hg.  Although  there  was  a  large 
variation  in  values  from  segment  to  segment,  the 
mean  flows  were  about  0.6  ml  per  min  per  g,  being 
slightly  higher  in  the  upper  jejunum  than  in  the 
lower  ileum.  These  values  were  obtained  with  a 
venous  pressure  of  zero.  When  the  venous  pressure 
was  elevated  to  10  mm  Hg,  the  flow  was  generally 
reduced  by  10  to  15  per  cent. 

Brodie  and  co-workers  (23,  24)  measured  the 
blood  flow  through  small  intestinal  segments 
plethysmographically  and  obtained  a  mean  value  of 
0.4  ml  per  min  per  g.  Neely  &  Turner  (103)  used  a 
somewhat  similar  technique,  measuring  weight 
changes  following  venous  occlusion  to  find  0.28  ml 
per  min  per  g.  Results  of  such  studies  as  these  two 
must  be  considered  in  light  of  the  prompt  rise  in 
intestinal  vascular  resistance  which  follows  an  acute 
rise  in  venous  pressure  [see,  for  example,  Selkurt  & 
Johnson  (122)  and  Johnson  (85)]. 

Selkurt  et  al.  (121)  artificially  perfused  segments  of 


ileum  and  obtained  flows  with  an  arterial-venous 
pressure  difference  of  130  mm  Hg  of  about  0.25  ml 
per  min  per  g.  This  is  much  lower  than  flows  ob- 
tained with  similar  preparations  in  this  writer's 
laboratory.  In  our  early  work,  very  low  flows  were 
frequently  obtained;  however,  more  normal  flows  of 
0.5  to  0.6  ml  per  min  per  g  were  usual  in  later  ex- 
periments. The  cause  of  the  vasoconstriction  in 
intestinal  segments  which  follows  arterial  cannulation 
is  not  known  to  this  writer,  but  it  seems  to  be  generally 
prevented  by  topical  application  of  procaine  at  the 
site  of  the  cannulation.  This  vasoconstriction  can  at 
times  be  so  intense  as  to  reduce  blood  flow  to  less 
than  0.05  ml  per  min  per  g. 

Geber  (54)  has  recently  placed  an  electromagnetic 
flowmeter  on  cannulae  placed  in  the  arterial  circuit 
of  segments  of  dog's  intestine  and  obtained  very 
high  flows.  His  values  were  duodenum,  1 .38;  jejunum, 
0.98;  ileum,  0.82;  and  colon,  0.73  ml  per  min  per  g. 
It  is  difficult  to  believe  that  these  values  are  not  falsely 
high.  If  correct,  the  intestinal  venous  outflow  would 
be  equal  to  or  greater  than  the  total  portal  venous 
flow  as  measured  by  most  workers.  It  is  possible  that 
Geber  trimmed  the  mesentery  from  the  intestinal 
segments  before  weighing  them.  In  some  animals, 
this  would  reduce  the  segment  weight  by  25  to  50 
per  cent,  and  thus  result  in  high  estimates  of  the 
perfusion  rates. 

Several  investigators  have  attempted  to  measure 
the  blood  flow  through  the  cranial  mesenteric  artery 
of  the  dog.  Trapold  (132)  using  a  Shipley  rotameter 
and  Deal  &  Green  (38)  using  an  electromagnetic 
flowmeter  found  flows  in  the  range  of  10  to  60  ml  per 
min,  the  average  being  less  than  2  ml  per  min  per  kg 
body  wt.  This  is  a  surprisingly  low  value;  with  the 
exception  of  the  flow  through  the  relatively  small 
caudal  mesenteric  artery,  the  cranial  artery  supplies 
the  same  tissues  as  are  drained  by  the  common  mesen- 
teric vein.  It  is  possible  that  manipulation  of  the 
mesenteric  artery  may  result  in  vasoconstriction  just 
as  does  cannulation  of  the  intestinal  arteries.  Cull 
et  al.  (36)  obtained  higher  flows  in  the  cranial  mesen- 
teric artery  (120  ml/min  in  dogs  of  unspecified 
weights),  but  these  are  still  significantly  lower  than 
would  be  expected.  Grodins  et  al.  (71)  used  a  thermo- 
stromuhr  to  obtain  mesenteric  artery  flows  of  a 
more  expected  value  of  1 2  ml  per  min  per  kg.  Meyer 
(100)  ligated  the  gastroduodenal  and  caudal  mesen- 
teric arteries  and  collected  venous  outflow  from  that 
part  of  the  gut  supplied  by  the  cranial  artery  (je- 
junum, ileum,  and  proximal  portion  of  the  colon). 
He   obtained   flows   of  the   same   order   as   those   of 


FLOW    OF    BLOOD    IN    MESENTERIC    VESSELS 


H43 


Grodins,  180  to  190  ml  per  min  from  tissue  averaging 
370  g  in  weight  (0.5  ml/ min  g). 

The  studies  on  pancreatic  blood  flow  have  not 
generally  supplied  sufficient  information  to  permit 
calculation  of  the  flows  per  unit  organ  weight; 
hence  comparison  with  the  values  of  Burton-Opitz 
and  Sapirstein  are  difficult.  Babkin  &  Starling  (6) 
perfused  the  superior  pancreaticoduodenal  artery 
from  a  heart-lung  preparation  and  collected  the 
venous  outflow  in  dogs  under  morphine  and  chloralose 
anesthesia.  They  did  not  separate  the  pancreas  from 
the  duodenum.  In  one  experiment  they  observed  a 
control  flow  of  100  ml  per  min  and  in  another  30 
to  40  ml  per  min.  No  animal  or  organ  weights  were 
given.  Gayet  &  Guillaume  (52,  53)  measured  the 
outflow  from  the  superior  pancreatic  vein  in  dogs  and 
obtained  resting  values  of  20  to  25  ml  per  min  in 
animals  of  unspecified  weight.  Bennett  &  Still  (14) 
placed  a  stromuhr  in  the  superior  pancreatico- 
duodenal vein  of  dogs  of  8  to  9-kg  body  wt.  Various 
anesthetic  agents  were  used:  sodium  barbital,  sodium 
amytal,  and  chloralose.  They  separated  the  pancreas 
from  the  duodenum  and  estimated  that  they  were 
measuring  the  drainage  of  about  one-half  of  the 
organ.  The  mean  flow  was  6.2  ml  per  min.  This  is  of 
the  order  of  0.5  to  0.6  ml  per  min  per  g  of  tissue. 

Grindley  et  al.  (69)  used  a  thermostromuhr  to 
measure  splenic  blood  flow  in  unanesthetized  dogs. 
They  obtained  a  mean  value  of  95  ml  per  min  which 
is  50  per  cent  higher  than  that  observed  by  Burton- 
Opitz.  Ottis  et  al.  (104)  employed  electromagnetic 
flowmeters  in  dogs  anesthetized  with  sodium  pento- 
barbital and  observed  flows  of  about  30  ml  per  min 
in  dogs  of  approximately  the  same  weight.  While 
this  is  much  lower  than  observed  by  Burton-Opitz, 
it  is  in  better  agreement  with  the  findings  of  Sapir- 
stein. It  is  important  to  note  that  in  expressing  splenic 
blood  flows  per  unit  weight  of  organ,  care  must  be 
exercised  in  the  definition  of  the  organ  weight. 
Burton-Opitz  found  the  spleen  of  his  etherized  dogs 
to  weigh  about  5  g  per  kg  body  wt.  postmortem.  As 
is  well  known,  the  spleen  in  animals  anesthetized 
with  pentobarbital  weigh  three  to  four  times  this, 
and  Burton-Opitz'  value  of  0.8  ml  per  min  per  g 
would  accordingly  be  reduced  to  0.2  or  0.25  ml  per 
min  per  g. 

An  attempt  has  been  made  to  summarize  all  this 
data  and  to  choose  mean  values  which  it  is  hoped 
approximate  the  situation  in  the  intact  dog;  these 
are  shown  in  table  1 . 


table  1.  Blood  Flow  Through  Mesenteric  Organs  of  a 
15-kg  Dog  Having  an  Arterial  Blood  Pressure 
of  Approximately  130  mm  Hg 


Weight,  g 

Blond  Flow 

Organ 

ml  min,  g  organ 

mJ/min 
animal 

%  of  total 

Stomach 
Intestine 
Pancreas 
Spleen 

250 
500 

5° 

70*    (25ot) 

035 

°-5 

0.8 

0.7*  (0.2 f) 

90 

250 

40 

50 

20 
60 
10 
IO 

*  Weight  and  flow  in  ether  anesthesia.  f  Same  in  pento- 

barbital anesthesia. 


Individual  Tissues 

Since  the  arterial  supply  and  venous  drainage  of 
any  tissue  of  a  complex  organ  is  by  way  of  thousands 
of  microscopic  vessels,  the  usual  direct  methods 
cannot  be  employed  to  measure  tissue  blood  flow. 
Instead,  one  must  resort  to  methods  based  on  the 
Fick  principle. 

Shore  et  al.  (125),  in  a  study  of  the  secretion  of 
basic  drugs  by  canine  gastric  mucosa,  found  that 
the  clearance  rates  of  drugs  having  a  pK  of  5  or 
greater  were  equal  and  maximal  for  all  the  drugs 
tested.  They  concluded  that  this  maximal  value  was 
equal  to  the  mucosal  blood  flow.  By  measurement  of 
the  concentration  of  drug  in  the  gastropyloric  venous 
blood,  they  further  discovered  that  the  maximal 
clearance  was  about  two-thirds  of  the  total  gastric 
blood  flow;  that  is,  approximately  two-thirds  of  the 
total  flow  passed  through  the  secreting  portion  of  the 
mucosa.  Schanker  et  al.  (116)  determined  the  clear- 
ance of  one  of  the  same  drugs,  aniline,  by  the  rat 
stomach  to  be  75  ml  per  hour.  On  the  basis  of  Sapir- 
stein's  findings,  the  total  gastric  blood  flow  in  rats 
of  the  same  size  is  140  to  150  ml  per  hour.  Thus,  a 
minimum  of  one-half  the  total  flow  passes  through 
the  secreting  mucosa. 

Two  different  techniques  have  been  employed  by 
workers  in  this  writer's  laboratory  to  obtain  a  reason- 
ably complete  analysis  of  the  distribution  of  blood 
flow  through  the  tissues  of  the  canine  small  intestine. 
Lindseth  (95)  employed  glass  microspheres  of  12  /u 
in  diameter  labeled  with  Na24  in  dogs  anesthetized 
with  sodium  pentobarbital.  After  the  injection  of  a 
small  quantity  of  the  spheres  into  an  intestinal  artery, 
the  segment  supplied  by  that  artery  was  removed 
and  separated  into  its  component  tissues:  mucosa, 
submucosa,  muscularis,  and  mesentery.  The  frac- 
tion of  the  injected  spheres  in  each  tissue  was  de- 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


termined  by  counting  the  isotope.  Since  the  spheres 
were  too  small  to  lodge  in  any  arteriovenous  vessels 
except  the  capillaries,  this  fraction  should  represent 
the  proportion  of  the  total  blood  flow  which  passed 
through  the  capillaries  of  that  tissue.  For  fasted  ileal 
segments  the  proportions  were  mucosa,  38  per  cent; 
submucosa,  8  per  cent;  muscularis,  22  per  cent;  and 
mesentery,  15  per  cent.  The  remaining  17  per  cent 
passed  through  vessels  larger  than  12  /x  in  diameter. 
The  flows  in  milliliters  per  minute  per  gram  of  tissue 
were  mucosa,  0.42;  submucosa,  0.34;  muscularis, 
0.48;  and  mesentery,  0.69.  For  fasted  jejunal  seg- 
ments, the  distribution  and  flows  per  gram  of  tissue 
were  not  significantly  different,  except  that  the  total 
blood  flow  was  somewhat  higher,  the  difference 
passing  through  arteriovenous  channels  larger  than 
12  xx. 

The  other  method  was  employed  by  Rayner  et  al. 
(107)  in  dogs  under  morphine  analgesia  and  by 
Weiner  (137)  in  dogs  under  pentobarbital  anesthesia. 
Segments  of  fasted  ileum  were  artifically  perfused 
with  blood  containing  deuterium  oxide  for  short 
periods  of  time.  On  the  assumption  that  the  kinetics 
of  distribution  of  isotopic  water  is  blood-flow  limited, 
the  perfusion  rate  for  each  tissue  was  calculated  from 
its  isotopic  content  at  the  end  of  the  perfusion  period. 
In  milliliters  per  minute  per  gram  of  tissue,  Rayner 
et  al.  obtained  the  following  flows:  mucosa,  0.38; 
submucosa,  0.56;  muscularis,  0.66;  and  mesentery, 
0.23.  Weiner  found  0.42,  0.50,  0.51,  and  0.16  for 
the  same  tissues. 

Comparison  of  the  results  obtained  with  the 
microsphere  and  with  the  D20  methods  in  pento- 
barbital-anesthetized  animals  shows  the  major 
discrepancy  to  be  in  the  estimation  of  flow  through 
the  mesentery.  It  seems  most  likely  that  the  D20 
technique  underestimates  flow  through  this  fatty 
tissue.  The  higher  submucosal  flow  obtained  with 
the  latter  technique  may  indicate  that  some  D>0 
exchange  occurs  across  the  walls  of  arteriovenous 
bridges  which  abound  in  that  tissue. 

Vessels  of  Different  Sizes 

Many  histological  studies  have  demonstrated  that 
the  arterioles  and  venules  of  the  mesenteric  organs 
are  connected  by  vessels  varying  from  true  capillaries 
with  a  diameter  of  10  ju  or  less  to  arteriovenous  bridges 
or  throughfares  with  diameters  in  the  range  10  to 
20  xx  to  true  arteriovenous  anastomoses  having 
diameters  in  excess  of  20  xt.  The  distribution  of  organ 
blood  flow  to  these  different-sized  channels  has  been 
investigated  in  only  a  very  few  instances. 


Walder  (135)  estimated  the  flow  through  arterio- 
venous anastomoses  in  the  artifically  perfused  human 
stomach  by  measuring  the  perfusion  rate  before  and 
after  presumably  blocking  all  the  capillaries  with 
starch  granules.  On  this  basis,  he  concluded  that  the 
proportion  of  the  total  flow  passing  through  arterio- 
venous anastomoses  was  about  5  per  cent. 

Lindseth  (95)  measured  the  blood  flow  through 
arteriovenous  vessels  of  different  sizes  by  injecting 
small,  known  numbers  of  radioactive  spheres  of 
different  diameters  into  the  arterial  supply  of  the 
canine  intestine.  He  employed  spheres  with  mean 
diameters  of  12,  20,  and  44  /x.  Measurement  of  the 
number  of  such  spheres  which  passed  through  the 
organ  into  the  venous  blood  permitted  him  to  calcu- 
late the  partition  of  the  total  blood  flow  among  the 
arteriovenous  channels  of  the  three  sizes.  He  found 
that  essentially  no  44  xx  spheres  passed  through  in 
either  the  jejunum  or  ileum;  3  to  4  per  cent  of  the 
blood  flowed  through  vessels  having  diameters  be- 
tween 20  and  44  /x;  and  24  per  cent  in  the  jejunum 
and  14  per  cent  in  the  ileum  passed  through  vessels 
1 2  to  20  xx  in  diameter.  Thus,  in  the  fasting  canine 
intestine,  the  fraction  of  the  total  blood  flow  which 
passes  through  true  arteriovenous  anastomoses 
(vessels  greater  than  20  /x  in  diameter)  is  very  small. 
However,  a  quite  significant  fraction  may  flow 
through  arteriovenous  bridges  and  hence  bypass  the 
capillaries. 

The  finding  that  such  a  small  fraction  of  the  blood 
passes  through  channels  larger  than  20  xx  is  in 
agreement  with  results  of  investigations  by  Gordon 
et  al.  (58).  These  workers  estimated  the  size  of  the 
largest  arteriovenous  channels  in  the  intestine  of  rats 
and  rabbits  anesthetized  with  sodium  pentobarbital 
by  determining  the  minimum  pressure  required  to 
force  mercury,  air,  or  kerosene  through  the  vascula- 
ture of  these  organs.  They  concluded  that  the  intes- 
tines contain  no  vessels  larger  than  25  xx  in  diameter. 

Several  investigators  have  injected  large  quantities 
of  glass  microspheres  into  the  arteries  supplying  one 
of  the  mesenteric  organs  and  determined  the  max- 
imum size  of  the  spheres  which  passed  through. 
Sherman  &  Newman  (124)  did  this  in  the  stomach 
and  duodenum  of  the  dog  and  recovered  some 
spheres  as  large  as  100  to  180  it.  Prinzmetal  (106) 
reported  spheres  of  160  to  37011  in  the  splenic  vein 
of  dogs  studied  in  the  same  way.  Walder  (134)  made 
a  more  complete  study  and  used  much  smaller 
quantities  of  spheres  in  the  artificially  perfused  human 
stomach.  He  found  the  diameter  of  the  largest 
spheres  to  pass  through  were  1 40  ll  and  of  the  mean 


FLOW    OF    BLOOD    IN    MESENTERIC    VESSELS 


'445 


iooju.  The  fraction  of  injected  spheres  which  passed 
through  was  not  determined  in  these  investigations. 


MESENTERIC    BLOOD    VOLUME 

Attempts  to  measure  the  volume  of  blood  in  the 
mesenteric  organs  of  the  dog  are  complicated  by  the 
presence  of  the  spleen,  the  quantity  of  blood  in  this 
organ  varying  greatly  with  the  nature  of  the  anes- 
thetic agent.  Further,  since  its  hematocrit  is  much 
higher  than  that  of  the  body  as  a  whole,  estimates  of 
mesenteric  blood  volume  from  the  distribution  of 
labeled  red  cells  can  be  expected  to  be  too  high  and 
those  made  with  labeled  plasma  constituents  too  low. 
A  correct  value  can  be  obtained  only  if  both  red  cell 
and  plasma  volume  are  measured  simultaneously. 

Although  such  a  direct  study  has  not  been  made, 
it  is  possible  to  approximate  the  mesenteric  blood 
volume  by  combining  the  results  of  several  different 
investigations.  One  of  the  most  pertinent  of  these  is 
Johnstone's  (87).  He  placed  ligatures  around  the 
esophageal-gastric  junction  and  the  rectum  of  dogs 
anesthetized  with  sodium  pentobarbital,  and  in- 
jected P'i2-labeled  red  cells.  After  a  5-min  mixing 
period,  he  clamped  the  celiac  axis,  mesenteric  arteries, 
and  portal  vein,  simultaneously.  By  analyzing  these 
organs  for  P32,  he  found  that  they  contained  22  per 
cent  of  the  injected  red  cells. 

To  calculate  the  blood  volume  from  this  observa- 
tion, the  hematocrit  of  the  mesenteric  organs,  es- 
pecially the  spleen,  must  be  known.  Allen  &  Reeve 
(2)  determined  both  the  red  cell  and  plasma  volume 
of  spleens  from  pentobarbital-anesthetized  dogs. 
They  found  the  blood  volume  to  be  4  to  10  per  cent 
of  the  total  body  blood  volume  and  the  hematocrit 
1.7  times  that  of  the  large  vessels.  The  ratio  of  the 
large  vessel  hematocrit  to  that  of  the  whole  body  is  a 
variable  quantity  as  pointed  out  by  Baker  &  Reming- 
ton (7);  however,  in  dogs  anesthetized  with  pento- 
barbital like  those  of  Allen  and  Reeve,  Reeve  et  al. 
(108)  found  the  ratio  to  be  about  0.9;  that  is,  the 
splenic  hematocrit  would  be  about  50  per  cent  greater 
than  that  of  the  whole  body.  The  dogs  of  Allen  and 
Reeve  were  only  lightly  anesthetized  and  other 
studies  have  shown  that  the  spleen  in  more  deeply 
anesthetized  animals  may  contain  more  than  10 
per  cent  of  the  total  blood  volume.  A  reasonable 
estimate,  though,  would  be  that  the  spleens  of  dogs 
anesthetized  with  pentobarbital  have  10  per  cent  of 
the  total  blood  volume  and  15  per  cent  of  the  total 
red    cell    mass.    Combining    this    with    Johnstone's 


observations,  the  other  mesenteric  organs  would 
contain  7  per  cent  of  the  body's  red  cells  and,  as- 
suming their  hematocrit  to  be  about  the  same  as  the 
body's,  7  per  cent  of  the  total  blood  volume.  Thus, 
the  mesenteric  organs  would  hold  1 7  per  cent  of  the 
total  blood  volume,  or  about  15  ml  per  kg  body  wt 
in  dogs  under  pentobarbital  anesthesia.  Under  ether 
anesthesia,  with  the  spleen  essentially  empty  of 
blood,  this  value  would  drop  to  nearly  7  per  cent 
(6  ml/kg).  In  unanesthetized  animals,  the  volume 
should  be  between  these  two  extremes.  Friedman 
(49)  has  shown  that  the  spleens  of  unanesthetized 
mice  contains  about  one-half  as  much  blood  as  those 
of  animals  under  pentobarbital  anesthesia. 

Horvath  et  al.  (82)  used  the  "exclusion  technique" 
of  Delorme  and  co-workers  (39)  to  determine  the 
volume  of  blood  in  the  mesenteric  organs  plus  the 
liver.  They  found  this  to  be  21  per  cent  of  the  total 
blood  volume,  6  per  cent  in  the  hepatic,  6  per  cent 
in  the  splenic,  and  9  per  cent  in  the  mesenteric 
artery  beds.  Most  of  their  experiments  were  with 
I131-labeled  albumin  and  hence  probably  gave  under- 
estimates of  the  blood  volume,  particularly  of  the 
splenic  artery  distribution.  Their  findings  do  not, 
therefore,  disagree  significantly  with  the  estimate 
given  above. 

Measurement  of  the  volume  of  blood  contained  in 
the  minute  vessels  of  some  of  the  mesenteric  organs 
was  made  by  Gibson  et  al.  (55)  in  dogs  under  light 
morphine  narcosis.  These  workers  determined  both 
the  red  cell  and  plasma  content  of  the  drained  organs 
and  found  the  stomach  and  intestine  to  contain  0.04 
ml  blood  per  g  tissue  and  the  spleen  0.5  ml  per  g. 
The  blood  volume  of  organs  of  the  rat  was  determined 
by  Everett  et  al.  (43)  with  Fe59-labeled  cells  and 
I131-labeled  plasma  in  quick-frozen  animals.  For  the 
small  intestine  they  obtained  a  blood  content  of 
0.034  ml  per  g  and  for  the  spleen,  0.17  ml  per  g 
Rieke  &  Everett  (in)  made  similar  measurements 
with  rats  under  pentobarbital  anesthesia  and  found 
0.047  ml  per  g  of  intestine  and  0.32  ml  per  g  of 
spleen. 

If  the  minute  vessels  of  the  stomach  and  intestine 
contain  about  0.04  ml  per  g  of  blood,  these  organs 
in  a  1 5-kg  dog  would  contain  about  30  ml  of  blood, 
2-3  in  the  intestine.  Thus,  a  dog  not  too  deeply  anesthe- 
tized with  pentobarbital  would  have  a  total  mesen- 
teric blood  volume  of  some  200  to  250  ml,  60  per 
cent  of  which  would  be  in  the  spleen,  10  to  15  per 
cent  in  the  minute  vessels  of  the  other  organs,  and 
the  remaining  25  to  30  per  cent  in  the  large  gastric 
and  intestinal  vessels.  This  partition  as  well  as  the 


I446  HANDBOOK    OF    PHYSIOLOGY  -~  CIRCULATION    II 


total   volume  can,   of  course,   vary   greatly   in   both 
physiological  and  pathological  states. 


FACTORS  AFFECTING  THE  BLOOD  FLOW 
AND  ITS  DISTRIBUTION 

Stomach 

Stimulation  of  the  splanchnic  nerves  decreases  the 
blood  flow  through  the  gastric  vessels.  This  has  been 
demonstrated  by  Burton-Opitz  (29)  in  the  ether- 
anesthetized  dog,  by  Lim  et  al.  (94)  in  the  blood- 
perfused  canine  stomach,  by  Thompson  &  Vane 
(131)  in  cats  anesthetized  with  chloralose,  and  by 
Walder  (134)  in  Ringer-perfused  human  stomachs. 
Friesen  &  Hemingway  (51),  using  a  calorimetric 
method,  showed  that  the  mucosal  flow  decreased 
during  sympathetic  stimulation  in  unanesthetized 
dogs.  In  the  rat,  Schnitzlein  (117)  observed  blanching 
of  the  gastric  mucosa  during  splanchnic  stimulation 
and  Arabehety  et  al.  (5)  found  engorgement  following 
block  or  section  of  the  same  nerves.  The  latter  ob- 
servations, it  should  be  emphasized,  are  of  the 
mucosal  blood  volume  and  do  not  necessarily  demon- 
strate that  the  blood  flow  through  this  tissue  is  de- 
creased by  sympathetic  stimulation. 

Care  should  be  exercised  in  the  interpretation  of 
the  many  observations  of  changes  in  mucosal  color, 
labeled  red  cell  content,  India  ink  density,  etc. 
produced  by  nervous  stimulation  or  drug  administra- 
tion. Blanching  may  well  occur  without  significant 
change  in  the  blood  flow  or  even  in  face  of  an  in- 
creased blood  flow.  Engorgement  may  accompany  an 
increase  in  flow  resistance,  especially  if  that  occurs  as 
a  consequence  of  venular  constriction.  Such  observa- 
tions can  properly  be  taken  as  indicating  changes  in 
blood  volume  only. 

Many  of  the  investigations  cited  above  (18,  94, 
131,  134)  have  shown  that  the  influence  of  epineph- 
rine on  the  gastric  circulation  is  quite  similar  to  that 
of  splanchnic  stimulation.  In  addition,  Henning 
et  al.  (76)  using  an  acetylene  clearance  method 
observed  an  apparent  reduction  in  human  mucosal 
blood  flow  in  response  to  administration  of  sympatho- 
mimetic drugs.  Peters  &  Womack  (105)  found  that 
epinephrine  produced  mucosal  blanching  in  the  dog. 
They  also  injected  glass  microspheres  into  the  arterial 
supply  and,  finding  more  large  spheres  in  the  venous 
outflow  than  in  control  studies,  concluded  that  adren- 
aline dilated  arteriovenous  anastomoses.  This  latter  is 
not  in  agreement  with  the  findings  of  Walder  (135), 


who  concluded  that  the  increase  in  arteriovenous 
anastomotic  flow  was  due  only  to  increased  resistance 
in  the  capillary  system  rather  than  anastomotic 
dilation.  Miller  &  Haszczyc  (101  )  found  that  epineph- 
rine reduced  the  number  of  blood-filled  capillaries 
in  biopsy  specimens  from  human  gastrostomies. 
Dolcini  et  al.  (40)  made  similar  observations  in  the 
rat.  Schnitzlein  (117)  observed  mucosal  engorgement 
in  rats  given  ergotoxine  to  block  adrenergic  influences, 
although  the  same  drug  in  Walder's  (134)  exper- 
iments did  not  alter  the  perfusion  rate  significantly 
from  control  values. 

Burton-Opitz  (29),  Lim  et  al.  (94),  Boenheim  (18), 
Friesen  &  Hemingway  (51)  all  found  little  or  no 
effect  of  vagal  stimulation  on  gastric  blood  flow 
unless  peristaltic  activity  appeared,  in  which  case 
blood  flow  declined.  Schnitzlein  (117)  did  observe 
mucosal  engorgement  in  the  rat  with  vagal  stimula- 
tion. He  also  found  that  the  application  of  acetyl- 
choline to  the  gastric  muscularis  produced  contrac- 
tions and  mucosal  blanching.  Necheles  et  al.  (102) 
found  that  acetylcholine  usually  produced  vasocon- 
striction in  Ringer-perfused  rat  stomachs.  It  was 
stated  that  this  was  not  the  consequence  of  increased 
motor  activity,  although  the  latter  was  not  recorded. 
Walder  (134)  reported  that  acetylcholine  in  some 
cases  reduced  and  in  others  increased  the  rate  of 
perfusion  through  human  stomachs.  He  made  no 
comments  concerning  motor  activity. 

In  the  studies  already  referred  to  by  Lim  et  al., 
Thompson  and  Vane,  and  Walder,  histamine  caused 
a  vasodilation  in  the  stomach.  Cutting  et  al.  (37) 
also  observed  increased  gastric  blood  flow  in  cats 
with  this  compound.  Richards  et  al.  (no),  using  a 
calorimetric  method,  found  that  histamine  increased 
mucosal  flow  in  the  human  stomach.  In  contra- 
distinction, Necheles  et  al.  (102)  could  observe  no 
effect  of  histamine  in  their  Ringer-perfused  rat 
stomachs;  and  Boenheim  (18)  reported  a  decrease  in 
etherized  dogs,  although  the  arterial  pressures  of  his 
animals  were  very  low.  Peters  &  Womack  (105) 
observed  a  marked  increase  in  the  mucosal  content 
of  arterially  injected  starch  granules  and  India  ink 
during  histamine  administration  in  the  dog.  Miller 
&  Haszczyc  (101)  also  saw  an  increase  in  filled  capil- 
laries in  human  mucosa  as  a  consequence  of  the 
drug.  Kimbel  et  al.  (90),  on  the  other  hand,  found  a 
marked  decrease  in  the  P32-labeled  red  cell  content 
of  the  gastric  mucosa  of  polycythemic  patients  given 
histamine. 

The  influence  of  several  other  chemicals  on  gastric 
blood  flow  has  also  been  studied.  Cutting  et  al.  (37) 


FLOW    OF    BLOOD    IN    MESENTERIC    VESSELS 


1447 


found  that  pilocarpine  increased  flow  in  the  cat. 
Bishton  (16)  made  a  similar  observation  in  guinea 
pigs  when  the  pilocarpine  was  administered  topically. 
Schnitzlein  (117)  saw  mucosal  engorgement  in  the 
rat  under  the  influence  of  this  drug.  Lim  et  al.  (94) 
observed  little  effect  of  Pitressin  in  their  perfused 
preparation,  but  both  Cutting  et  al.  and  Boenheim 
(18)  found  a  decrease  in  flow  under  the  influence  of 
this  hormonal  preparation.  Lim  et  al.  found  that 
sodium  nitrite  and  Cutting's  group  that  erythrol 
tetranitrate  increased  flow.  Dolcini  and  co-workers 
(40)  observed  an  increase  in  the  gastric  mucosal 
content  of  arterially  administered  India  ink  in  the 
rat  given  serotonin  or  5-hydrox\  tryptophan. 

Salmon  et  al.  (112)  demonstrated  that  cooling  the 
dog  stomach  to  15  C  reduced  the  blood  flow  to  30  to 
40  per  cent  of  control.  Heating  was  shown  by  Cut- 
ting's group  to  have  the  opposite  effect. 

Richards  et  al.  (1 10)  found  that  a  variety  of  emo- 
tional states,  anxiety,  tension,  resentment,  all  in- 
creased flow  in  the  human  gastric  mucosa  as  evi- 
denced by  the  increase  of  heat  uptake  by  the  luminal 
surface.  Wolf  &  Wolff  (138)  made  an  extensive  study 
of  color  changes  (i.e.,  blood  volume  changes)  in  a 
human  gastrostomy.  There  was  an  increase  in  redness 
following  administration  of  histamine,  alcohol,  beef 
juice,  acetylmethylcholine,  exposure  to  local  warm- 
ing, during  discussion  of  food  and  coincident  with 
evidence  of  hostility.  Blanching  occurred  during 
fear,  sadness,  discouragement,  exposure  to  cold,  and 
after  administration  of  epinephrine,  ergotamine,  or 
Pitressin. 

Intestine 

It  is  generally  agreed  that  stimulation  of  the 
splanchnic  nerves  causes  vasoconstriction  in  the 
intestine.  As  early  as  1899,  Bayliss  &  Starling  (11) 
demonstrated  that  such  stimulation  decreased  the 
volume  of  intestinal  segments.  Burton-Opitz  (27) 
observed  a  reduction  in  mesenteric  venous  flow  in 
etherized  dogs  without  a  significant  increase  in  portal 
vein  pressure,  thus  showing  that  mesenteric  resistance 
was  increased.  Deal  &  Green  (38)  measured  flow  in 
the  cranial  mesenteric  artery  and  the  appropriate 
pressures  in  dogs  anesthetized  with  pentobarbital 
in  order  to  determine  intestinal  vascular  resistance. 
Although  their  control  flows  were  abnormally  low 
(less  than  0.1  ml 'min  g  of  tissue),  they  found  an 
increase  of  50  per  cent  in  resistance  during  splanchnic 
stimulation.  Both  Celander  (34)  and  Kock  (91) 
determined    venous    outflow    from  jejunal    loops    in 


vagotomized  cats  under  pentobarbital  or  chloralose- 
urethan  anesthesia  and  also  found  that  splanchnic 
stimulation  reduced  the  flow. 

Bulbring  &  Burn  (25)  observed  a  reduction  in 
intestinal  volume  in  plethvsmographic  studies  with 
etherized,  adrenalectomized  dogs  and  cats  during 
stimulation.  After  administration  of  ergotoxine,  the 
same  procedure  produced  an  increase  in  volume. 
Atropine  did  not  block  the  dilation  phase,  and  they 
concluded  that  the  splanchnic  nerves  contained  some 
noncholinergic  vasodilator  fibers  as  well  as  the  vaso- 
constrictor elements.  Deal  and  Green  also  found  that 
the  sympatholytic  agent,  Ilidar,  sometimes  reversed 
the  constrictor  effect  of  splanchnic  stimulation  and 
that  atropine  had  no  influence  on  the  reversal. 
Folkow  et  al.  (47)  in  their  studies  on  cats  concluded 
that  the  vasodilator  fibers  could  not  be  adrenergic 
either  and  hence  that  there  were  probably  no  splanch- 
nic vasodilators.  They  thought  that  the  vasodilation 
seen  during  splanchnic  stimulation  after  ergotamine 
or  Dibenamine  was  probably  due  to  relaxation  of  the 
intestinal  smooth  muscle. 

The  primary  effect  of  both  epinephrine  and  nor- 
epinephrine on  the  intestinal  vasculature  seems  to 
be  the  same  as  that  of  splanchnic  stimulation. 
Schwiegk  (118)  found  epinephrine  to  decrease  both 
arterial  and  venous  flow  in  dogs  anesthetized  with 
chloralose.  In  cats,  also  anesthetized  with  chloralose, 
Clark  (35)  found  that  epinephrine  in  all  concentra- 
tions reduced  intestinal  venous  outflow.  Folkow  et 
al.  (47)  observed  vasoconstriction  in  the  cat  with 
both  epinephrine  and  norepinephrine,  as  also  did 
Kock  (91).  Grayson's  group  (61-64),  using  a  calori- 
metric  method,  demonstrated  that  both  compounds 
produced  vasoconstriction  in  the  mucosa  and  muscle 
of  human  ileostomies  and  colostomies.  Binit  et  al. 
(15)  observed  an  increase  in  the  resistance  of  the 
mesenteric  arterial  bed  upon  intra-arterial  injection 
of  epinephrine  in  the  dog  under  chloralose  anesthesia. 
Green  and  co-workers  (38,  65)  in  their  studies  on 
mesenteric  artery  flow  in  dogs  anesthetized  with 
pentobarbital  found  that  both  compounds  caused  a 
several  hundred  per  cent  increase  in  resistance. 
Selkurt  et  al.  (121)  observed  a  reduced  flow  through 
artificially  perfused,  denervated  ileal  segments  under 
the  influence  of  both  substances.  Bohr  et  al.  (19) 
used  the  Zweifach  preparation  of  the  rat  mesoap- 
pendix  to  show  that  epinephrine  and  norepinephrine 
were  both  constrictors  whether  administered  intra- 
venously or  topically.  Although  these  workers  found 
epinephrine  the  more  potent  compound,  all  the 
other  investigators  (47,  65,  91)  who  compared  the 


'44-8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


two  substances  in   the  dog  and  the  cat  found  nor- 
epinephrine to  be  the  more  potent  (see  below). 

Two  groups  of  workers  (65,  118)  have  observed  a 
secondary  increase  in  blood  flow  in  the  dog  intestine 
following  the  primary  vasoconstriction  due  to  epineph- 
rine administration,  although  in  the  cat,  Folkow  et 
al.  (47)  could  find  the  constrictor  effect  only.  Several 
studies  (35,  47,  65)  have  shown  that  only  vasodilation 
occurs  with  epinephrine  if  given  after  such  substances 
as  ergotoxine,  Dibenamine,  or  Ilidar.  These  same 
substances  are  capable  of  blocking  the  constrictor 
effect  of  norepinephrine  but  do  not  reverse  it. 

Not  all  the  results  of  investigations  of  volume  or 
weight  changes  of  the  intestine  under  the  influence  of 
epinephrine  and  norepinephrine  agree  with  the 
findings  on  blood  flow.  Woods  et  al.  (139),  Goetz 
(57)  and  MacLean  et  al.  (96)  all  found  that  epineph- 
rine caused  a  primary  reduction  in  volume  followed 
by  a  secondary  increase.  The  latter  observed  a  de- 
crease in  weight  with  norepinephrine.  Opposed  to 
these  are  the  observations  of  Biilbring  &  Burn  (25), 
Goetz  (57),  with  small  doses,  and  Burn  &  Hutcheon 
(26)  that  epinephrine  increased  the  volume  oi  in- 
testinal segments  of  dogs  and  cats.  As  Folkow  (48) 
has  stated,  these  discrepancies  might  well  be  ex- 
plained by  the  possibility  that  the  smooth  muscle 
relaxing  effects  of  epinephrine  result  in  a  decreased 
transmural  pressure  in  the  intestinal  vessels  which  for 
small  doses  of  the  drug  overbalance  its  usual  con- 
strictor effects.  Aside  from  this  possibility,  it  remains 
highly  questionable  whether  or  not  intestinal  vascular 
resistance  changes  can  be  deduced  from  variations  in 
the  volume  of  the  organ. 

The  influence  of  the  parasympathetic  portion  of 
the  autonomic  nervous  system  on  the  intestinal 
vasculature  is  not  completely  clear.  Celander  & 
Folkow  (32)  observed  an  increase  in  intestinal  blood 
flow  in  the  cat  as  a  part  of  the  depressor  response  to 
sinus  nerve  stimulation.  Since  this  disappeared  after 
ergotamine,  they  concluded  that  there  were  no 
dilator  fibers  involved  and  that  the  increase  in  flow 
was  the  consequence  of  a  reduction  in  constrictor 
tone.  The  parasympathetic  mediator,  acetylcholine, 
does  seem  to  cause  vasodilation,  as  shown  by  the 
just-mentioned  workers,  as  well  as  by  Binit  et  al. 
(15)  and  by  Bean  &  Sidky  (13).  The  latter  took  great 
care  to  separate  the  effects  of  the  compound  on  the 
vasculature  and  the  visceral  smooth  muscle  and 
showed  that  the  increase  in  blood  flow  appeared 
before  the  augmentation  of  motor  activity.  The 
increase  in  blood  flow  was  abolished  or  reversed  by 
vigorous  segmental  contractions.  Howe\  er,  one  note 


of  caution  should  be  made  regarding  all  three  of 
these  studies.  All  were  performed  with  perfused 
preparations  and  it  may  be  that  the  control  blood 
flows  were  abnormally  low  as  is  so  frequently  the 
case  with  perfused  intestinal  segments.  Although 
adequate  control  data  are  not  given  in  any  instance, 
estimations  from  Bean  and  Sidky's  results  indicate 
that  their  preparations  may  have  had  an  abnormally 
high  constrictor  tone.  Care  should  be  exercised, 
therefore,  in  concluding  that  acetylcholine  has  a 
dilator  effect  in  the  intact  normally  perfused  in- 
testine. 

It  seems  reasonable  to  conclude  that  splanchnic 
nerve  stimulation,  and  administration  of  the  adrener- 
gic substances,  epinephrine  and  norepinephrine, 
produce  vasoconstriction  in  the  intestine,  presumably 
by  excitation  of  alpha  adrenergic  constrictor  re- 
ceptors as  reviewed  by  Green  &  Kepchar  (66a). 
The  usual  secondary  dilation  observed  after  epineph- 
rine injection  and  especially  the  primary  dilation 
seen  when  epinephrine  is  administered  following 
Ilidar  or  ergotamine  blockade  indicates  the  presence 
of  beta  adrenergic  dilator  receptors  as  well.  This 
offers  an  explanation  of  the  lesser  constrictor  potency 
of  epinephrine  since  this  compound,  unlike  nor- 
epinephrine, stimulates  both  the  constrictor  and 
dilator  receptors.  The  small  increase  in  flow  which 
occurs  during  splanchnic  stimulation  after  admin- 
istration of  Ilidar  or  ergotamine  seems  more  likely 
to  be  explained  by  intestinal  smooth  muscle  relaxa- 
tion, or  by  mechanical  distention  of  blood  vessels 
due  to  a  rise  in  blood  pressure,  than  by  stimulation  of 
the  beta  dilator  receptors.  It  is  highly  questionable 
whether  the  vagus  has  any  influence  on  the  intestinal 
circulation  other  than  that  secondary  to  augmenta- 
tion of  motor  activity.  Acetylcholine  probably  has  a 
dilator  effect  but  unequivocal  proof  of  this  in  the 
intact  intestine  is  not  available. 

The  influence  of  other  chemical  compounds  on  the 
intestine  may  be  summarized  as  follows.  Biilbring  & 
Burn  (25)  found  histamine  to  produce  a  slight  vaso- 
dilation, as  did  Binit  et  al.  (15).  In  this  writer's 
laboratory,  on  the  other  hand,  this  compound  has 
been  found  to  produce  constriction  fairly  consistently 
in  artificially  perfused  intestinal  segments.  Both 
Selkurt's  group  (121)  and  Bohr  and  his  colleagues 
(19)  found  serotonin  to  be  an  intestinal  vasocon- 
strictor. The  latter  also  found  Pitressin  to  be  a  con- 
strictor of  intestinal  surface  vessels. 

Vasodilation  has  been  produced  by  isopropylnor- 
epinephrine  in  the  hands  of  Green  et  al.  (65),  by 
curare  in  a  study  by  Elwell  &  Bean  (42),  by  adenosine 


FLOW    OF    BLOOD    IN    MESENTERIC    VESSELS 


1449 


triphosphate  in  the  investigations  of  Selkurt  et  al. 
(121)  and  of  Binit  et  al.  (15),  and  by  topically  applied 
procaine  in  Grayson's  research  (61)  on  human  mu- 
cosal blood  flow.  Grayson  also  observed  that  cooling 
a  limb  caused  dilation  in  the  colostomy  mucosa 
whereas  heating  the  body  produced  constriction,  the 
direction  of  the  changes  being  opposite  to  those  in 
the  skin.  Trapold  (132)  found  that  several  ganglionic 
blocking  agents  caused  a  small  decrease  in  resistance 
to  flow  in  the  mesenteric  artery  bed,  although  this 
must  be  interpreted  in  light  of  the  fact  that  his  control 
flows  were  abnormally  low. 

Sidky  &  Bean  (12,  126)  used  their  isolated  in- 
testinal segment  preparation  to  investigate  the  effects 
of  variations  in  the  concentration  of  the  respiratory- 
gases  in  the  perfusion  fluid.  They  found  that  hyper- 
capnia  and  hypoxia  resulted  in  an  increase  in  blood 
flow;  hypocapnia  resulted  in  vasoconstriction.  Brick- 
ner  et  al.  (22)  determined  the  total  mesenteric  flow 
less  that  through  the  spleen  in  dogs  breathing  gas 
mixtures  containing  various  percentages  of  C02. 
With  less  than  5  per  cent  C02,  the  circulatory  changes 
were  minor;  at  levels  of  5  to  16  per  cent,  there  was  a 
significant  decrease  in  mesenteric  resistance. 

Intestinal  blood  flow  is  profoundly  influenced  by 
motor  activity.  Anrep  et  al.  (4)  perfused  loops  of  dog 
intestine  and  observed  a  decrease  in  venous  outflow 
during  muscular  contractions.  Sidky  &  Bean  (127) 
in  their  studies  of  artificially  perfused  intestinal  seg- 
ments found  that  early  in  a  contraction  arterial  inflow 
decreased  and  venous  outflow  increased,  with  venous 
pressure  sometimes  exceeding  arterial  pressure.  If 
the  contractions  were  rhythmic  and  of  short  dura- 
tion, they  could  augment  the  flow.  If  the  duration  of 
a  contraction  was  longer,  the  flow  through  the  seg- 
ment would  decrease  as  a  consequence  of  the  fall  in 
arterial  inflow.  As  expected,  these  effects  were  more 
pronounced  the  stronger  the  contractions. 

Lawson  &  Chumley  (93)  showed  that  increases  in 
intraluminal  pressure  to  values  below  30  mm  Hg 
caused  a  temporary  decrease  in  blood  flow  followed 
by  recovery  to  control  values.  At  higher  pressures 
only  a  partial  recovery'  was  noted.  Recovery  was  not 
observed  in  segments  placed  in  plaster  casts  or  treated 
with  procaine,  and  denervation  was  without  in- 
fluence. They  concluded  that  the  stretching  of  the 
gut  wall  initiated  a  vasodilation  mediated  through 
intrinsic  nerve  networks. 

Selkurt  et  al.  (121)  have  investigated  the  relation 
between  blood  flow  through  an  artificially  perfused 
denervated  ileal  segment  and  the  arterial-venous 
pressure  difference.  They  found  the  relationship  to 


be  slightly  curvilinear,  convex  toward  the  pressure 
axis,  with  a  positive  intercept  on  that  axis  of  about 
15  mm  Hg.  Since,  as  already  pointed  out,  their 
observed  flows  at  normal  arterial-venous  pressure 
differences  were  quite  low,  some  caution  must  be 
exercised  in  applying  their  results  to  the  normal 
situation.  However,  Johnson  et  al.  (84)  found  a 
similar  intestinal  pressure-flow  relationship  in  the 
totally  perfused  dog,  although  with  higher  flows  for 
any  given  pressure. 

Selkurt  &  Johnson  (122)  and  Johnson  (85)  ob- 
served that  the  effect  of  increasing  intestinal  venous 
pressure  was  to  produce  a  rise  in  vascular  resistance 
in  the  mesenteric  bed.  They  concluded  that  the  re- 
sistance changes  were  not  dependent  on  nervous 
mechanisms  but  suggested  that  the  elevation  of 
venous  pressure  induced  a  myogenic  response  in  the 
resistance  vessels. 

Johnson  (86)  also  investigated  the  influence  on 
flow  resistance  of  partial  occlusion  of  an  intestinal 
artery.  In  70  per  cent  of  the  cases  the  resistance  de- 
creased with  arterial  pressure  reduction.  He  con- 
cluded that  this  autoregulation  of  intestinal  blood 
flow  was  not  clue  to  a  local  reflex  but  rather  was  the 
consequence  of  a  myogenic  response  of  the  vascular 
smooth  muscle. 

Occlusion  of  the  mesenteric  artery  also  has  an 
effect  on  the  systemic  circulation,  causing  a  rise  in 
arterial  blood  pressure.  Sarnoff  &  Yamada  (115) 
observed  large  increases  in  blood  pressure  in  the  cat 
and  concluded  that  this  effect  was  dependent  upon 
reflexes  initiated  by  receptors  in  the  abdominal 
organs,  particularly  in  the  pancreas.  In  this  species, 
they  considered  such  reflexes  more  important  than 
those  originating  in  the  carotid  sinus  and  aortic 
arch.  Boyer  &  Scher  (20)  observed  smaller  pressure 
changes  in  the  same  animal  and  concluded  that 
there  was  no  evidence  for  the  presence  of  baroceptors 
in  the  mesenteric  artery,  and  that  the  rise  in  systemic 
arterial  pressure  was  due  only  to  mechanical  diver- 
sion of  the  blood  away  from  the  abdominal  viscera. 
Heymans  et  al.  (79)  performed  similar  studies  with 
the  dog  and  decided  that  the  general  blood  pressure 
rise  was  a  purely  hemodynamic  effect  due  to  the 
exclusion  of  an  important  arterial  vascular  area  and 
did  not  indicate  the  existence  of  abdominal  baro- 
ceptors. Selkurt  &  Rothe  (123)  performed  similar 
studies  in  both  dogs  and  cats.  The  results  with  cats 
agreed  with  the  findings  of  Sarnoff  and  Yamada. 
Those  obtained  from  dogs  led  the  authors  to  con- 
clude, in  agreement  with  Heymans,  that  splanchnic 
baroceptor  activity  in  that  species  is  slight. 


1 45° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Herrick  et  al.  (78)  measured  blood  flow  through 
the  cranial  mesenteric  artery  of  unanesthetized  dogs 
with  a  thermostromuhr  during  treadmill  exercise  and 
found  that  the  flow  was  essentially  unchanged  despite 
an  increase  in  arterial  blood  pressure,  indicating  an 
intestinal  vasoconstriction.  Barcroft  &  Florey  (9) 
observed  exteriorized  preparations  of  colonic  mucosa 
of  dogs  during  exercise.  Early  in  the  period  mucosal 
pallor  was  evident  but,  as  the  exercise  continued, 
the  color  returned  to  normal. 

Several  workers  (50,  60)  have  attempted  to  study 
the  influence  of  various  emotional  states  such  as 
depression,  anxiety,  fear,  etc.,  on  human  intestinal 
blood  flow  by  making  inferences  from  observations  on 
the  degree  of  mucosal  engorgement  in  colostomies. 
The  possible  errors  inherent  in  such  inferences  have 
already  been  alluded  to. 

Pancreas 

The  information  available  on  the  influence  of 
nervous  stimulation  and  of  drugs  on  pancreatic 
circulation  is  scanty.  Both  Anrep  (3)  and  Gayet  & 
Guillaume  (52)  showed  a  reduction  in  venous  outflow 
as  a  consequence  of  splanchnic  stimulation.  The 
effect  of  vagal  stimulation  is  not  quite  so  clear.  Anrep 
concluded  that  the  vagus  carried  neither  constrictor 
nor  dilator  fibers  to  the  pancreas.  Gayet  and  Guil- 
laume consistently  found  a  marked  increase  in  blood 
flow  during  vagal  stimulation. 

Gayet  &  Guillaume  (52),  Maltesos  &  Watson 
(98),  Jones  (88),  and  Bennett  &  Still  (14)  all  ob- 
served an  increase  in  blood  flow  when  secretin  was 
administered,  in  contradistinction  to  Weaver  (136), 
who  could  find  no  change  in  venous  outflow.  J  ones 
found  that  the  rise  in  flow  was  a  function  of  splanchnic 
vasomotor  tone  and  could  be  quite  small  when  the 
tone  was  high.  Because  Bennett  and  Still  observed  a 
secretin-induced  rise  in  blood  flow  only  when  the 
pancreatic  duct  pressure  increased,  they  proposed 
that  the  apparent  vasodilator  action  of  the  hormone 
was  not  due  to  a  direct  effect  on  the  vasculature  but 
was  the  consequence  of  a  reflex  initiated  by  the  rise 
in  ductal  pressure  during  secretion.  They  concluded 
that  a  truly  "vasodilation-free"  secretin  may  be 
prepared. 

Recently,  Holton  &  Jones  (80)  used  a  photoelectric 
technique  to  measure  blood  content  changes  in  the 
pancreas  and  found  that  acetylcholine,  histamine, 
secretin,  and  pancreozymin  all  produce  vasodilation, 
whether  or  not  secondary  to  a  rise  in  ductal  pressure 
is  not  clear. 


Spleen 

In  most  of  the  investigations  on  the  splenic  circula- 
tion, attention  has  been  directed  toward  changes  in 
the  volume  of  the  organ  rather  than  the  blood  flow 
through  it.  Adrenergic  stimulation  causes  a  marked 
decrease  in  volume  in  dogs  and  cats.  As  shown  by 
Celander  (33)  in  cats  under  chloralose  anesthesia, 
sympathetic  stimulation  is  more  potent  in  this  regard 
than  epinephrine,  which  in  turn  is  several  times  more 
effective  than  norepinephrine.  Others,  such  as  Ahl- 
quist  et  al.  (1)  and  Holtz  et  al.  (81)  have  demon- 
strated that  epinephrine  is  also  more  effective  than 
norepinephrine  in  the  dog.  Many  other  compounds 
produce  splenic  contraction;  ephedrine,  pituitrin, 
histamine,  acetylcholine,  and  amyl  nitrite.  Anesthetic 
agents  also  exert  a  profound  influence;  as  shown  by 
Hausner  and  co-workers  (74),  ether  causes  a  reduc- 
tion in  size  and  various  barbiturates  a  marked  en- 
largement over  that  of  the  waking  animal.  Hahn 
et  al.  (72)  reported  that  spleens  taken  from  dogs 
anesthetized  with  pentobarbital  weighed  four  times 
those  from  etherized  animals.  Almost  any  change  in 
the  environment  which  can  produce  a  sympathetic 
discharge  in  the  animal  causes  splenic  contraction. 
Thus,  Hargis  &  Mann  (73)  and  Barcroft  and  co- 
workers (8,  10)  observed  this  in  waking  dogs  sub- 
jected to  a  loud  noise,  tail  pinching,  hemorrhage, 
exercise,  or  exposure  to  cold.  The  first  mentioned 
workers  thought  that  most  of  these  responses  were 
reflex,  since  they  occurred  so  rapidly  and  were  not 
observed  after  denervation.  Barcroft  and  Elliott, 
however,  did  find  contraction  of  the  denervated  spleen 
after  a  loud  noise,  although  it  was  delayed  and 
progressed  slowly.  One  of  the  few  maneuvers  which 
increases  splenic  volume  is  feeding. 

A  number  of  investigators,  for  example,  Glaser 
et  al.  (56),  have  concluded  that  the  spleen  is  not  an 
important  blood  storage  organ  in  the  human  body, 
and  hence  does  not  change  volume  as  markedly  as 
in  the  dog  or  cat. 

With  regard  to  factors  influencing  the  splenic  blood 
flow,  Burton-Opitz  (28)  found  that  stimulation  of  the 
splanchnic  nerve  or  any  of  the  fibers  of  the  splenic 
plexus  caused  a  reduction  in  blood  flow  through  the 
splenic  vein.  Green  and  co-workers  (67,  104)  studied 
this  in  more  detail  and  found  that  splanchnic  stimula- 
tion of  short  duration  decreased  arterial  inflow  but 
temporarily  increased  venous  outflow,  thus  accounting 
for  the  reduction  in  volume  of  the  organ.  They  also 


FLOW    OF    BLOOD    IN    MESENTERIC    VESSELS 


1451 


showed  that  epinephrine  and  norepinephrine  had  a 
similar  effect,  with  the  former  being  more  potent. 
Phenoxybenzamine  reversed  the  inflow  reduction,  and 
reduced  the  increase  in  venous  outflow  and  the  volume 
change.  Acetylcholine  and  methacholine  increased 
arterial  and  venous  flow  and  slightly  increased  organ 
volume,  these  effects  being  blocked  by  atropine. 
This  observation  is  in  agreement  with  that  of  Hunt 
(83),  but  at  variance  with  those  of  Ferguson  et  al. 
(45)  and  of  Fleming  &  Parpart  (46)  who  observed 
arteriolar  constriction  in  the  mouse  spleen  with 
topical  application  of  acetylcholine  as  well  as  epineph- 
rine, norepinephrine,  and  histamine.  An  extensive 
investigation  by  Grindlay  and  co-workers  (6g)  with 
thermostromuhrs  in  unanesthctized  dogs  showed  that 
a  loud  noise  resulted  in  a  temporary  increase  in 
venous  outflow  while  having  no  effect  on  arterial 
inflow,  thus  accounting  for  the  usual  volume  reduc- 
tion of  the  organ.  They  also  found  that  both  arterial 
and  venous  flow  rose  after  feeding  and  fell  after 
hemorrhage  in  agreement  with  volume  changes. 
1  Hiring  exercise  both  flows  increased.  Since  splenic 
volume  decreases  during  exercise,  this  provides  a 
good  example  of  the  danger  inherent  in  assuming 
that  the  direction  of  volume  change  of  an  organ 
indicates  the  direction  of  flow  change. 

Mesenteric  Circulation  as  a  Whole 

The  influence  of  nervous  stimulation  or  drug 
administration  on  the  mesenteric  circulation  as  a 
whole  must  for  the  most  part  be  inferred  from  a 
synthesis  of  the  effects  of  these  factors  on  the  separate 
organs.  Most  studies  in  the  intact  animal  have  been 
on  the  total  splanchnic  flow  with  no  separation  of 
this  into  its  hepatic  arterial  and  portal  venous  com- 
ponents. Even  where  the  portal  flow  is  determined 
separately  care  must  be  exercised  in  the  interpreta- 
tion of  the  results,  since  the  factor  under  study  may 
alter  the  portal  flow  by  affecting  hepatic  resistance 
and  have  no  effect  on  mesenteric  resistance.  Only 
when  measurement  of  the  portal  flow  is  accompanied 
by  determination  of  the  mesenteric  arterial-venous 
pressure  difference  is  it  possible  to  infer  the  effects 
of  the  factor  on  the  mesenteric  circulation,  and  even 
then  the  effect  may  not  be  direct;  for  example,  a 
passive  dilation  of  mesenteric  vessels  due  to  a  rise  in 
portal  venous  pressure  as  a  consequence  of  a  hepatic 
resistance  increase  or  the  contrary  myogenic  vaso- 
constriction studied  by  Selkurt  and  Johnson.  One 
such   study    in    which   pressures   were    recorded,    al- 


though mesenteric  resistances  were  not  calculated,  is 
that  of  Katz  &  Rodbard  (89).  Another  pertinent 
investigation  is  that  of  McMichael  (99).  The  results 
of  these  workers  are  considered  below  with  a  sum- 
mary of  what  seems  to  be  the  best  evidence  to  the 
present  time  on  the  factors  affecting  blood  flow 
through  the  separate  mesenteric  organs. 

There  is  general  agreement  that  splanchnic  stim- 
ulation increases  the  resistance  to  blood  flow  through 
the  mesenteric  circuit.  Most  results  indicate  that  the 
effect  of  norepinephrine  and  the  primary  effect  of 
epinephrine  are  similar,  with  norepinephrine  the 
more  potent  of  the  two  except  in  the  spleen.  In  gen- 
eral, epinephrine  has  a  secondary  dilator  effect  which 
is  the  only  consequence  of  its  administration  following 
treatment  with  various  sympathetic  blocking  agents. 
Katz  and  Rodbard,  and  McMichael  found  that 
epinephrine  first  increased  then  decreased  mesenteric 
resistance.  It  might  be  noted  that  adrenergic  stim- 
ulation may  result  in  a  temporary  increase  in  portal 
venous  flow  despite  the  primary  rise  in  resistance, 
because  such  stimulation  evokes  splenic  contraction 
and  the  discharge  of  its  stored  blood. 

Vagal  stimulation  probably  has  little  if  any  sig- 
nificant influence  on  the  mesenteric  blood  flow, 
except  insofar  as  flow  is  changed  secondary  to  an 
increase  in  motility  in  the  stomach  and  gut.  Because 
the  results  of  studies  with  acetylcholine  are  contra- 
dictory with  all  organs  except  the  intestine,  and  there 
their  validity  may  be  questioned,  much  the  same 
conclusion  must  be  drawn  for  this  factor  for  the 
present. 

Pitressin  seems  to  have  a  constrictor  effect  in  most 
of  the  mesenteric  organs.  Again  the  data  of  Katz  and 
Rodbard,  and  of  McMichael  confirm  this  for  the 
mesenteric  circuit  as  a  whole.  Since  serotonin  seems 
to  be  a  constrictor  in  the  intestine,  and  since  the 
major  part  of  the  mesenteric  flow  passes  through  this 
organ,  the  effect  of  this  hormone  on  the  circulation 
as  a  whole  is  probably  the  same.  The  influence  of 
histamine  on  the  gastric  circulation  seems  to  be 
dilatory;  however,  its  effect  on  the  other  organs  is  not 
so  clearly  established.  Katz  and  Rodbard's  data 
indicate  little  change  in  the  over-all  flow  resistance  in 
the  mesenteric  organs  under  the  influence  of  this 
compound;  the  dilation  in  the  stomach  may  be 
balanced  by  constriction  elsewhere.  Finally,  one 
physiological  maneuver,  exercise,  seems  to  cause 
vasoconstriction  in  all  the  mesenteric  circulation 
except  in  the  spleen. 


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CIRCULATION    II 


RELATION    OF    BLOOD    FLOW    TO    FUNCTION 
OF   THE    MESENTERIC    ORGANS 

The  influence  of  the  blood  flow  on  the  function  of 
the  mesenteric  organs  seems  to  be  clearly  established 
in  only  one  respect;  namely,  that  a  certain  minimum 
flow  is  essential  for  the  maintenance  of  the  integrity 
of  the  cells.  Whether  or  not  the  alimentary  activities, 
secretion,  absorption,  and  motility,  of  the  stomach, 
intestine,  and  pancreas  require  an  augmentation  of 
the  blood  supply  above  the  basal  level  is  the  subject 
of  conflicting  evidence,  although  most  of  the  admit- 
tedly scanty  evidence  indicates  that,  necessary  or  not, 
there  is  an  increase  in  blood  flow  through  these  or- 
gans after  the  ingestion  of  a  meal. 

Herrick  et  al.  (77),  in  thermostromuhr  studies  in 
the  unanesthetized  dog,  observed  that  1  to  2  hours 
after  taking  a  meal  the  cranial  mesenteric  artery  flow 
was  increased  to  50  to  60  per  cent  above  control. 
Since  there  were  increases  of  similar  magnitude  in 
flows  through  the  femoral  and  carotid  arteries  at  the 
same  time,  they  concluded  that  digestion  caused  a 
general  increase  in  cardiac  output  rather  than  a  shift 
of  blood  supply  from  other  regions  of  the  body  to  the 
abdominal  viscera.  Reininger  &  Sapirstein  (109) 
used  their  K42  method  to  demonstrate  that  there  was 
a  similarly  uniform  increase  of  about  30  per  cent  in 
blood  flow  to  all  parts  of  the  body  of  the  rat  after 
feeding. 

Brodie  and  co-workers  (23,  24)  measured  the 
oxygen  uptake  by  segments  of  canine  small  intestine 
and  observed  a  30  per  cent  increase  during  absorp- 
tion of  dilute  salt  solutions  and  a  60  per  cent  increase 
during  absorption  of  protein  solutions.  They  reported 
similar  rises  in  blood  flow,  but  this  must  be  interpreted 
in  light  of  their  use  of  the  plethysmograph  to  make 
the  measurements.  Lindseth  (95)  determined  both 
total  intestinal  segment  flow  and  its  partition  among 
the  individual  tissues  in  anesthetized  fasted  and  fed 
dogs.  In  upper  jejunal  segments,  feeding  produced  no 
significant  change  in  total  venous  outflow  but  caused 
a  diversion  of  the  flow  through  the  mesentery  to  the 
capillaries  of  the  mucosa  and  submucosa.  In  the 
ileum,  there  was  a  25  to  30  per  cent  increase  in  total 
flow,  almost  all  of  which  went  to  the  muscle,  there 
being  essentially  no  change  in  that  through  the 
absorbing  mucosa.  He  also  found  no  significant  altera- 
tion in  the  fraction  of  the  total  flow  which  passed 
through  arteriovenous  anastomoses. 

Numerous  attempts  have  been  made  to  determine 
the  relation  between  blood  flow  and  secretion  by  the 


gastric  mucosa.  Thompson  &  Vane  (131)  in  their 
studies  with  the  perfused  cat  stomach  observed 
parallel  changes  in  secretory  rate  and  blood  flow  as 
a  consequence  of  sympathetic  stimulation,  epineph- 
rine administration,  and  celiac  arterial  infusion  of 
histamine,  and  concluded  that  secretion  could  be 
directly  influenced  by  changing  blood  flow.  Lim 
et  al.  (94),  on  the  other  hand,  in  similar  studies  with 
the  dog  found  that  histamine-induced  secretion  could 
occur  in  face  of  a  falling  blood  flow.  Further,  sodium 
nitrite  increased  the  blood  flow  without  initiating 
secretion.  Cutting  et  al.  (37)  observed  increases  in 
both  parameters  in  the  cat  when  given  histamine  or 
pilocarpine.  Pituitrin  decreased  blood  flow  and 
volume  secretion  but  had  little  if  any  effect  on  the 
amount  of  acid  produced.  Warming  the  stomach  or 
the  administration  of  erythrol  tetranitrate  increased 
flow  without  stimulating  secretion.  Finally  it  has 
been  noted  that  vagal  stimulation  which  induces 
secretion  has  little  or  no  effect  of  the  total  blood  flow 
through  the  stomach  although  it  does  cause  mucosal 
engorgement.  There  seems  little  doubt  that  the  parie- 
tal cells  must  require  an  increase  in  oxygen  supply 
during  secretion.  There  are,  however,  a  number  of 
ways  by  which  this  can  occur  without  alteration  in 
the  total  gastric  blood  flow.  Oxygen  extraction  can 
rise,  although  the  work  of  Peters  &  Womack  (105) 
indicates  that  such  is  not  the  case  in  the  dog  in  re- 
sponse to  histamine  injection  or  vagal  stimulation. 
Other  possibilities  include  shifts  of  flow  from  arterio- 
venous anastomotic  channels,  from  other  tissues, 
or  from  other  regions  of  the  stomach  to  the  fundic 
mucosa.  Experiments  to  measure  the  distribution  of 
blood  flow  to  the  different  tissue  and  arteriovenous 
channels  in  the  basal  and  in  the  secretory  states  are 
needed.  It  is  the  mucosal  flow  that  is  of  real  signifi- 
cance and  it  may  not  vary  in  the  same  manner  as 
the  total  flow.  On  the  basis  of  the  evidence  presently 
available  reasonable  conclusions  seem  to  be  that 
agents  which  decrease  gastric  blood  flow  below  the 
basal  level  prevent  or  at  least  markedly  reduce 
secretion,  that  increased  blood  flow  does  not  of  itself 
initiate  or  augment  secretion,  and  that  whether  or 
not  secretion  is  necessarily  accompanied  by  an  in- 
crease in  total  gastric  blood  flow  cannot  be  answered 
definitely. 

The  investigations  on  the  relation  of  pancreatic 
secretion  to  blood  flow  have  been  critically  reviewed 
recently  by  Tankel  &  Hollander  (130).  They  pointed 
out  the  contradictory  nature  of  the  evidence  presently 


FLOW    OF   BLOOD    IN    MESENTERIC    VESSELS 


'453 


available  and  stated  that  it  does  not  warrant  the 
conclusion  that  pancreatic  secretion  is  dependent 
on  the  blood  supply,  except  that  a  minimum  flow  is 
required  to  maintain  cellular  activity  and  provide 
fluid  for  secretion. 

The  relation  between  motor  activity  and  blood 
flow  in  the  stomach  and  intestine  have  been  referred 
to  earlier.  Vigorous  contractions,  such  as  are  pro- 
duced by  vagal  stimulation,  cause  a  reduction  in 
blood  flow.  On  the  other  hand,  a  reduction  in  blood 
flow   may,    as   suggested   by   Celander    (34),   be   re- 


sponsible   for    the    usually    observed    inhibition    of 
motility  during  sympathetic  stimulation. 

The  best  general  conclusion  seems  to  be  that  there 
is  as  yet  no  clearly  established  demonstration  that 
the  mesenteric  organs  need  an  augmentation  of  their 
basal  blood  supply  to  perform  their  alimentary  func- 
tion. It  seems  clear  that  these  organs  receive  their 
proportionate  share  of  the  general  rise  in  cardiac 
output  which  follows  feeding,  but  whether  this  is 
coincidental  or  to  satisfy  an  essential  requirement  is 
debatable. 


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91.  Koch,  N.  An  experimental  analysis  of  mechanisms  engaged 
in  reflex  inhibition  of  intestinal  motility.  Acta  Physiol.  Scand. 
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92.  LaCroix,  E.  Splanchnic  circulation.  Ada  gastro-enterol. 
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93.  Lawson,  H.,  and  J.  Chumley.  The  effect  of  distention  on 
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1940. 

94.  Lim,  R.,  H.  Necheles,  and  T.  Ni.  The  vasomotor  reactions 
of  the  (vivi-perfused)  stomach.  Chinese  J.  Physiol  1  :  381, 
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95.  Lindseth,  E.  Vascular  Flow  Patterns  in  the  Tissues  of  the  Dog 
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i960. 

96.  MacLean,  L.,  E.  Brackney,  and  M.  Visscher  Effects  of 
epinephrine,  norepinephrine  and  histamine  on  canine 
intestine  and  liver  weight  continuously  recorded  in  vivo. 
J.  Appl.  Physiol.  9:  237,  1956. 

97.  MacLeod,  J.,  and  R.  Pearce.  The  outflow  of  blood  from 
the  liver  as  affected  by  variations  in  the  condition  of  the 
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98.  Maltesos,  C,  and  R.  Watson.  Durchblutung  und 
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Arch   ges.  Physiol.  241  :  516,  1939. 

99.  McMichael,  J.  The  portal  circulation.  I.  Action  of 
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London  75  :  241 ,  1932. 

100.  Meyer,  M.  Hemodynamic  Studies  of  Endotoxin  Shock  in  the 
Dog  (Ph.D.  Thesis).  Minneapolis:  Univ.  of  Minnesota, 
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101 .  Miller,  E.,  and  V.  Haszczyc.  Gastric  mucosal  capillaries 
in  the  human.  A.M. A.  Arch.  Surg.  73:  465,  1956. 

102.  Necheles,  H.,  R.  Frank,  W.  Kaye,  and  E.  Rosenman. 
Effect  of  acetylcholine  on  the  blood  flow  through  the 
stomach  and  legs  of  the  rat.  Am.  J.  Physiol.  114:  695,  1936. 

103.  Neely,  W.,  and  M.  Turner.  Measurement  of  blood  flow 
in  kidney  and  isolated  segments  of  intestine.  J.  Appl. 
Physiol.  14:37,  1959. 

104.  Ottis,  K,  J.  Davis,  and  H.  Green.  Effects  of  adrenergic 
and  cholinergic  drugs  on  splenic  inflow  and  outflow 
before  and  during  adrenergic  blockade.  Am.  J.  Physiol. 
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105.  Peters,  R.,  and  N.  Womack.  Hemodynamics  of  gastric 
secretion.  Ann.  Surg.  148:  537,  1958. 

106.  Prinzmetal,  M.  Arterio-venous  anastomoses  in  the  liver, 
spleen  and  lungs.  Am.  J.  Physiol.  152  :  48,  1948. 

107.  Rayner,  R.,  L.  MacLean,  and  E.  Grim.  Intestinal  tissue 
blood  flow  in  shock  due  to  endotoxin.  Circulation  Research 
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108.  Reeve,  E.,  M.  Gregersen,  T.  Allen,  and  H.  Sear 
Distribution  of  cells  and  plasma  in  the  normal  and 
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109.  Reininger,  E.,  and  L.  Sapirstein.  Effect  of  digestion  on 


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Richards,  C,  S.  Wolf,  and  H.  Wolff.  The  measure- 
ment and  recording  of  gastroduodenal  blood  flow  in  man 
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55'.  '94'2- 

Rieke,  W.,  and  N.  Everett.  Effect  of  pentobarbital 
anesthesia  on  the  blood  values  of  rat  organs  and  tissues. 
Am.  .1.  Physiol.  188:  403,  1957. 

Salmon,  P.,  W.  Griffin,  and  O.  Wangensteen.  Effect  of 
intragastric  temperature  changes  upon  gastric  blood  flow. 
Proc.  Soc.  Exptl.  Biol.  Med.  101  :  442,  1959. 
Sapirstein,  L.  Fractionation  of  the  cardiac  output  of  rats 
with  isotopic  potassium.  Circulation  Research  4:  689,  1956. 
Sapirstein,  L.  Regional  blood  flow  by  fractional  distribu- 
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of  arterial  pressure  from  abdominal  receptors  with  special 
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Pharmacol.  Exptl.  Therap.  120:528,  1957. 
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Selkurt,  E.,  R.  Alexander,  and  M.  Patterson.  Role  of 
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120.  Selkurt,  E.  Splanchnic  hemodynamics  as  influenced  by 
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"3- 
114. 

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116. 

117. 
118. 

"9 


126. 


127. 


128. 


129. 


130. 


i3»- 


133- 

134 
'35- 

■  36. 

137 

138 
139 


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'95'- 

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Soskin,  S.,  H.  Essex,  J.  Herrick,  and  F.  Mann.  Mecha- 
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Stewart,  J.,  J.  Stephens,  M.  Leslie,  B.  Portin,  and  W. 
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Thompson,  J.,  and  J.  Vane.  Gastric  secretion  induced  by 
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CHAPTER     43 


The  renal  circulation 


EWALD    E.    SELKURT 


Department  of  Physiology,  Indiana  University 
School  of  Medicine,  Indianapolis,  Indiana 


CHAPTER      CONTENTS 

Functional  Architecture  of  the  Renal  Circulation 

Arterial  System 

Venous  System 

Glomerular  Circulation 

Juxtaglomerular  Complex 

Blood  Supply  to  the  Medullary  Zones 

Renal  Lymphatic  System 
Nerve  Supply  to  the  Kidney :  Anatomical  Aspects 

Extrinsic  Nerves 

Intrinsic  Innervation 
Distribution    of   Osmotic    Constituents    in    the    Kidney:   The 

Countercurrent  Hypothesis 
Renal  Blood  Volume:  The  Intrarenal  Hematocrit 
Metabolic  Aspects 

Oxygen  Utilization 

Heat  Production 
Pressure  Gradients  in  the  Renal  Vascular  Circuit 

Pressure  Gradients 

Critical  Closure;  Yield  Pressure 

Intrarenal  Pressure 
Measurement  of  Renal  Blood  Flow 

Methods 

Critique  of  the  Clearance  Method 

Renal  Blood  Flow  Values 
Extrinsic  Regulation  of  Renal  Blood  Flow 

Neurogenic  Control 

Humoral  Control;  Pharmacologic  Agents 
Anatomy  of  the  Renal  Circulation 

History 

Mechanism  of  Autoregulation 
Present  Status  of  the  Trueta  Juxtamedullary  Shunt 

Morphological  Evidence 

Functional   Evidence;   Interpretations   Based   on   Clearance 
Rate 

Role  of  the   Medullary   Circulation   in   Diuresis   and    Anti- 
diuresis 
Response  of  Renal  Blood  Flow  in  Physiological  Stress 

Exercise 

Posture  and  Orthostatic  Hypotension 

Renal  Hypoxia  and  Ischemia 


Hypercapnia  and  Acidosis 
Hemorrhagic  Hypotension  and  Shock 
Concluding  Remarks 


the  introduction  of  the  concept  of  the  counter- 
current  osmotic  multiplier  system  to  the  kidney  by 
Wirz  el  al.  (345-349)  as  a  means  of  explaining 
urinary  concentration  and  dilution  has  apparently 
initiated  a  phase  of  re-evaluation  of  classical  renal 
functional  concepts  which  promises  to  be  far  reaching 
in  scope.  Recent  critical  reviews,  while  pointing  out 
gaps  in  our  knowledge,  have  nevertheless  opened  up 
exciting  vistas  and  new  pathways  for  research  (169, 
171,  289,  314)-  The  countercurrent  concept  rests 
rather  firmly  on  findings  in  the  rat  and  hamster; 
however,  significant  anatomical  differences  in  the 
kidneys  of  the  dog  and  man  require  that  this  hypoth- 
esis be  intensively  tested  in  these  and  other  species. 
Only  about  one-eighth  of  the  nephrons  of  the  human 
kidney  appear  to  have  the  long  medullary  loops  of 
Henle  requisite  for  the  mechanism  (245).  Most  lie  in 
the  cortex,  and  have  straight,  short,  thin  segments,  or 
indeed,  none  at  all  (fig.  1).  The  dog,  however,  has 
long  loops  and  long,  thin  medullary  segments,  yet 
its  kidneys  are  not  remarkably  different  from  those  of 
the  human  in  concentrating  power. 

The  renal  circulation  has  been  found  to  play  a 
unique  and  important  role  in  the  composite  picture  of 
the  countercurrent  mechanism.  Knowledge  of  the 
distribution  of  blood  to  the  cortex  and  medulla  has 
assumed  pre-eminent  importance.  Older  ideas  have 
had  to  be  revised.  The  vasa  recta,  considered  originally 
as  a  medullary  shunt  by  Trueta  et  al.  (311),  assume 


H57 


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CORT 


--PAP  D 


fig.  I.  Anatomical  distribution  of  nephron  types  in  the  hu- 
man kidney.  CORT.:  cortex;  O.ST.:  outer  stripe  or  band; 
O.Z.:  outer  zone  of  medulla;  INST.:  inner  stripe  or  band; 
MED.:  medulla;  IN.Z. :  inner  zone  of  medulla;  PAP.D.:  pap- 
illary duct.  [After  Peter  (245).] 

new  importance  as  the  vascular  counterpart  of  the 
countercurrent  system  of  the  nephrons.  Longley  et  al. 
(191)  look  upon  the  vasa  recta  as  retia  mirabilia 
conjugata  (similar  to  the  retia  mirabilia  of  the  swim 
bladder  of  fishes),  especially  endowed  to  function  as  a 
countercurrent  multiplier  system.  Recent  studies 
(166,  309)  have  shown  that  the  flow  of  blood  through 
these  vessels  appears  to  be  significantly  slower  than 
through  the  cortical  circulation,  apparently  a  func- 
tional adaptation  to  the  optimal  operation  of  the 
countercurrent  mechanism. 


The  question  of  the  possible  role  of  the  phenomenon 
of  the  autoregulation  of  the  renal  circulation  in  the 
countercurrent  system  has  been  raised.  Speculatively, 
it  would  appear  undesirable  for  rapid  fluctuations  in 
blood  flow  to  occur  through  the  zone  of  hypertonicity, 
and  the  over-all  constancy  of  renal  blood  flow  may 
thus  be  an  adaptation  to  insure  stability  in  this  system. 

This  article  will  include  largely  the  developments 
in  renal  circulatory  physiology  since  Homer  Smith's 
review  in  1940  of  The  Physiology  of  Renal  Circulation 
(286).  This  era  has  seen  the  ascendancy  of  the 
clearance  method  for  measurement  of  renal  blood 
flow,  the  waxing  and  waning  of  the  Trueta  juxta- 
medullary  shunt  mechanism,  the  development  of  a 
growing  interest  in  the  mechanism  of  renal  circulatory 
autonomy,  and  the  unfolding  of  the  countercurrent 
hypothesis  of  kidney  function  with  important  implica- 
tions for  the  renal  circulation. 


FUNCTIONAL  ARCHITECTURE   OF  THE 
RENAL  CIRCULATION 

Limitation  of  space  precludes  the  consideration  of 
the  anatomy  of  the  renal  circulation  on  the  broad 
comparative  basis  that  it  warrants.  Rather,  major 
emphasis  will  be  placed  on  the  salient  features  of 
circulation  in  the  dog,  the  species  in  which  a  significant 
proportion  of  the  functional  studies  have  been  made, 
with  appropriate  references  to  other  species,  especially 
human,  when  needed  for  full  development  of  a  given 
topic. 

Arterial  System 

Major  distribution  of  the  renal  artery  in  the  dog  is 
shown  in  figure  2  [from  plastic  injection  corrosion 
studies  of  von  Kiigelgen  et  al.  (322)].  Figure  3  shows 
division  of  the  interlobar  artery  into  primary, 
secondary,  and  tertiary  arcuate  arteries,  from  which 
spring  the  interlobular  arteries.  The  afferent  arterioles 
usually  supply  only  one  glomerulus,  but  rarely  may 
branch  to  supply  2  to  4  glomeruli  with  a  total  of 
200,000  per  kidney.  This  is  compared  to  estimates 
ranging  from  600,000  to  1,700,000  in  each  human 
kidney  (213,  216,  318). 

specialized  arterial  circuits.  Spanner  (290,  291), 
Trueta  et  al.  (311),  Baker  (6),  and  von  Ki'igelen  & 
Passarge  (323)  have  found  peculiarly  coiled  vessels 
(which  arise  from  the  interlobar  arteries)  in  the  renal 
sinus  of  dog,  cat,  and  human.  These  spiral  vessels, 


THE    RENAL    CIRCULATION 


1459 


ventr. 


fig.  2.  Horizontal  section  through  the  dog  kidney.  RI  and 
RII.  renal  artery  and  primary  branches;  Arc  I  and  Arc  II: 
primary  and  secondary  arcuate  arteries;  IL:  interlobar  artery; 
ILl:  interlobular  artery;  Caps:  capsular  artery,  U:  aorta.  [After 
von  Kiigelgen  et  al.  (322).] 

100  to  150  ii  in  diameter,  form  a  plexus  which  supplies 
the  calycine  mucosa  and  the  renal  papilla  (fig.  4). 
Baker  contends  that  they  anastomose  with  the  vasa 
recta.  It  is  important  to  emphasize  that  these  vessels 
participate  with  the  vasa  recta  system  (vide  infra)  in 
supplying  blood  to  the  papillary  zone  containing  the 
tips  of  the  loops  of  Henle,  the  site  of  maximal  osmotic 
concentration.  Their  long,  coiled  length  delivers  blood 
into  the  vasa  recta  system  at  low  pressure  (6).  Arterio- 
arterial  anastomoses  occur  in  this  system,  an  exception 
to  the  usual  pattern  of  end  arteries  found  in  the 
divisions  of  the  renal  artery. 


Venous  System 

Deferring  discussion  of  the  glomerular  and  capillary 
circulation,  attention  is  directed  to  the  venous 
system  in  figure  5.  Note  the  sparsity  of  interlobular 
veins  relative  to  the  interlobular  arteries  (a  ratio  of 
20  to  1).  Their  function  appears  to  be  to  connect  the 
superficial  and  deep  venous  systems  of  the  cortex  (V. 
corticalis  superficialis  and  V.  corticalis  profunda), 
into  which  the  capillaries  drain.  The  upper  fifth  of 
the  cortex  appears  to  be  an  "arterial-free'"  zone  (af 
in  fig.  5),  so  that  the  upper  glomeruli  are  overlayed  by 
only  venous  channels  (stellate  veins,  superficial 
cortical  veins),  and  prevenous  capillaries  (cortex 
corticis).  Puncture  of  glomeruli  for  this  reason  has 
been  unsuccessful  in  the  dog.  A  "venous-free"'  zone 
(vf)  also  exists,  free  of  cortical  veins  (superficial  and 
deep),  and  occupied  only  by  occasional  interlobular 
veins. 

venous  sinuses;  veno-venous  anastomoses.  Venous 
sinuses  or  sinusoids  lying  in  the  connective  tissue 
adjacent  to  the  pelvis  of  the  human  kidney  were 
observed  by  Spanner  (290,  291)  and  by  Barrie 
et  al.  (12).  Spanner  described  them  as  isolated 
accumulations  of  large  venous  plexi  arranged  super- 
ficially along  the  walls  of  the  minor  calyces  of  the 
renal  pelvis.  Trueta  el  al.  also  described  in  the  same 
zone  of  the  human  kidney  many  vessels  of  large  caliber 
which  unite  interlobar  veins  (veno-venous  anasto- 
moses). These  vessels  lie  closely  adjacent  to  the  outer 
surfaces  of  the  walls  of  the  calyces  of  the  renal  pelvis, 
and  the  capillaries  of  the  pelvic  mucosa  drain  into  this 
complex  system.  They  may  offer  a  clue  to  the  phenom- 
enon of  pyelovenous  backflow  sometimes  seen  after 
retrograde    pyelography.    Veno-venous    anastomoses 


fig.  3.  Scheme  of  the  finer  arterial  supply 
of  the  dog  kidney,  gl:  Glomerulus  with  vas 
afferens.  [After  von  Kiigelgen  et  al.  (322).] 


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CORTEX 


fig.  4.  The  medullary   and   papillary  blood  supply  of  the 
kidney.  [After  Baker  (6).] 

are  common  in  the  dog  kidney  between  interlobar 
veins,  between  arcuate  veins,  and  between  stellate  and 
arcuate  veins  (322). 

arteriovenous  anastomoses.  The  venous  sinusoids 
have  been  described  as  the  site  of  numerous  arterio- 


venous anastomoses  in  the  human  kidney  by  Spanner. 
Barriet  et  at.  (12)  believe  that  such  arteriovenous 
connections  occur  between  the  aforementioned 
spiral  arteries  and  the  sinusoids,  the  latter  emptying 
presumably  into  the  interlobar  veins,  but  admit  that 
open  communications  between  the  spiral  arteries  and 
the  sinusoids  are  extremely  difficult  to  demonstrate. 
Trueta  et  at.  have  disputed  Spanner's  findings,  and 
Baker  (6)  found  only  an  insignificant  number  in 
confirmation  of  Trueta.  Nor  could  von  Kiigelen 
et  at.  (322,  323)  and  Christensen  (54)  find  them  in 
the  dog  kidney. 

In  summary,  arterio-arterial  and  veno-venous 
anastomoses  occur  commonly  in  the  kidneys  of  man 
and  dog.  Although  arteriovenous  anastomoses  prob- 
ably  exist,  their  occurrence  is  infrequent.  Func- 
tionally, direct  A-V  shunting  of  blood  must  therefore 
be  negligible,  and  blood  passes  generally  through  a 
capillarv  circuit  (cortical  peritubular  plexus  or 
medullary  vasa  recta  system).  In  confirmation, 
Piiper  &  Schiirmeyer  (249)  found  that  the  intact 
dog  kidney  passed  only  1.5  per  cent  of  19  n  wax 
spheres  injected  into  the  renal  artery,  0.3  per  cent 
of  30  n,  and  0.08  per  cent  of  38  ^  size.  Denervation, 
and  injection  of  KCN,  novacaine,  and  histamine  did 
not  influence  the  results.  Although  Simkin  et  at. 
(283)  recovered  glass  spheres  up  to  440  m  in  size  from 
the  renal  vein  of  excised  human  kidneys,  they  did  not 
indicate  what  portion  these  represented  of  the  total 
injected. 

venous  valves  and  valvelike  structures.  These 
have  been  described  by  von  Kugelgen  et  at.  (320-322) 
in    the   dog,   swine,    and   human   kidney.    They   are 


V.s  fellah. 


fig.  5.  The  blood  supply  of  the  cortex,  in- 
cluding the  venous  system,  a/:  Arterial-free 
zone  of  the  cortex;  vf:  vein-free  zone  of  the 
cortex.  [After  von  Kugelgen  et  at.  (322).] 


V.  corti  calis 
superficial/! 


/cortical  is 
profunda 
V.  interlobularis 


V.interlobans 


THE    RENAL    CIRCULATION 


I  46  I 


located  in  the  renal  vein  at  its  entrance  to  the  vena 
cava,  and  in  the  main  branches  of  the  renal  vein  (the 
latter  not  as  a  rule  in  man).  They  are  found  also  at 
the  orifices  of  the  interlobar  veins,  arcuate  veins,  and 
occasionally  just  before  the  opening  of  the  capsular 
(stellate)  veins  into  the  interlobular  veins. 

Koester  el  al.  (162)  have  found,  in  both  human  and 
dog  kidneys,  structures  in  the  veins  which  might  act 
as  effluent  constrictions,  which  they  described  in 
terms  of  "stenoses"  and  '"sinusoidal  cushions." 
Stenoses  are  common  at  the  ostia  of  smaller  tributaries 
entering  interlobar  veins  in  the  human  kidney.  They 
seem  to  be  composed  of  a  dense  collagenous  framework 
lined  with  endothelium;  usually  muscle  is  present  as 
a  proliferation  of  the  media  of  the  vessel.  In  the  dog, 
stenoses  appear  occasionally  along  the  course  of  the 
interlobars  and  primary  tributaries  to  the  renal  vein; 
however,  they  are  present  primarily  at  the  con- 
fluence of  arcuates  with  interlobars  and  of  the 
interlobular  with  arcuates. 

At  the  confluence  of  arcuates  with  one  another  to 
form  an  interlobar  vein  in  the  human  kidney,  the 
sinusoidal  cushions  usually  appear,  sometimes  at 
the  confluence  of  the  interlobulars  with  arcuates. 
These  structures  characteristically  contain  venous 
sinuses  (which  connect  with  interlobular  and  medul- 
lary veins)  in  the  connective  tissue  matrix.  These 
structures  are  often  interlaced  with  smooth  muscle. 
Their  appearance  is  said  to  resemble  erectile  tissue 
(162).  In  the  dog,  they  are  less  extensive  and  lie 
primarily  close  to  the  arcuate-interlobar  junction. 
Smooth  muscle  in  the  cushions  of  this  species  is  very 
inconspicuous  or  absent. 

It  is  worthy  of  emphasis  that  the  aforementioned 
structures  are  not  valves  in  the  sense  of  those  found  in 
systemic  veins,  although  many  of  those  pictured  by 
von  Kiiglegen  et  al.  (320,  321)  exhibit  a  cusplike 
organization.  In  any  event,  their  designation  as 
"effluent  constrictors"  at  present  best  describes  their 
function,  although  the  functional  significance  is  hard 
to  assess.  The  relatively  high  pressure  found  in  the 
arcuate  veins  of  dogs  (24  mm  Hg)  by  Swan  el  al. 
(302)  appeared  to  give  functional  evidence  of  a  point 
of  increased  resistance  at  the  arcuate-interlobar 
junction.  When  the  catheter  was  withdrawn  into  the 
interlobar  vein,  pressure  decreased  immediately  to  7 
mm  Hg.  Brun  et  al.  (41)  found  wedged  catheter 
pressures  averaging  18  mm  Hg  in  the  human  kidney; 
the  pressure  in  the  renal  vein  averaged  5.6  mm  Hg. 
It  was  concluded  that  the  wedged  renal  vein  pressure 
equalled  arcuate  venous  pressure  and  hence  very  near 
to   the   pressure   in   the   peritubular   capillaries   and 


interlobular  veins.  According  to  Koester  et  al.  (162), 
the  effluent  constrictors  keep  the  kidney  "functionally 
distended"  with  fluids;  they  state  also  that  these 
structures  cause  smaller  vessels  of  the  vascular  system 
(venous  channels?)  to  widen  in  bore,  reducing 
resistance  to  blood  flow.  The  logic  of  this  can  be 
doubted  since  this  at  best  would  only  compensate  for 
the  initial  resistance  imposed.  Nor  is  this  supported  by 
physiological  studies  in  which  venous  pressure  has 
been  experimentally  elevated  (119,  122,  123,  233, 
273,  281,  32g),  under  which  circumstance  over-all 
renal  resistance  in  fact  increases,  possibly  by  a 
"venous-arteriolar"  reflex. 

Glomerular  Circulation 

The  studies  of  Boyer  (29),  Elias  et  al.  (82),  Hall 
(125,  126),  Johnston  (154),  and  Kurlz  &  McManus 
( 1  70)  show  that  the  glomerular  capillaries  are  not 
simple  loops,  but  form  a  freely  branching,  anastomotic 
network  (fig.  6).  More  specifically,  larger  through 
channels  exist  with  an  associated  capillary  network 
of  smaller  anastomotic  channels.  Hall  has  suggested 
that  this  may  afford  a  structural  basis  for  the  skim- 
ming of  plasma  relatively  freed  of  cells  into  the  net- 
work of  small  capillaries,  while  the  greater  mass  of 
blood  cells  directly  and  rapidly  flows  through  the 
lobule  to  the  efferent  arterioles  as  an  axial  stream. 


fig.  6.   Glomerular   capillary  supply,   showing   anastomotic 
connections.   [After  Elias  (82).] 


1462 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  7.  Electron  microscope  reconstruction 
of  the  glomerular  filtering  membranes.  [After 
Hall  (125).] 


INTRACAPILLARY     SPACE 
(LUMEN) 


LAMINA   FENESTRATA 
(LINING  NETWORK). 


PODOCYTE 
(COVERING    CELL) 


EXTRACAPILLARY    SPACE 
(CAPSULAR    SPACE) 


This  may  facilitate  the  filtration  process  by  slowing 
flow  and  reducing  turbulence. 

Figure  7  shows  a  sectional  diagram  of  the  struc- 
tures forming  the  filtration  apparatus  as  developed 
by  electron  microscopy  (125).  The  pores  in  the  capil- 
lary endothelium  (.05  fi  thick)  (lamina  fenestrata) 
are  too  large  (0.1  /x)  to  restrain  the  plasma  constitu- 
ents. Rather,  they  expose  the  ultrafiltration  mem- 
brane, the  lamina  densa,  to  the  free  flow  of  plasma 
by  removing  the  endothelial  cytoplasmic  barrier. 

Although  the  lamina  densa  (glomerular  basement 
membrane),  0.1  n  thickness,  exhibits  differences  in 
stratification  (244),  it  is  probable  that  it  is  a  homoge- 
nous layer;  pores  that  have  been  noted  are  probably 
artifactual.  It  appears  to  be  the  limiting  membrane 
for  restraint  of  plasma  proteins  and  cells. 

The  podocytes  (foot  cells)  of  the  visceral  layer  of 
Bowman's  capsule  rest  on  the  lamina  densa  with 
thousands  of  foot  processes  (pedicels).  Hall  has  sug- 
gested that  they  may  play  an  important  part  in  the 
regulation  of  filtration.  The  space  between  the  pedicels 
may  be  narrow  enough  ( 1 00  A)  to  be  a  limiting  dimen- 
sion in  restriction  of  plasma  proteins  ("slit  pore"). 
Hall  suggested  that  the  foot  processes  may  be  nar- 
rowed or  widened  thereby  exposing  a  greater  or  lesser 
area  of  basement  membrane,  although  a  mechanism 
by  which  such  changes  could  be  brought  about  has 
not  so  far  been  proposed.  However,  it  is  conceivable 
that  changes  in  caliber  of  the  capillaries  as  a  function 
of  internal  pressure  (vis  a  tergo)  may  alter  the  spacing 
of  the  pedicels.  Using  as  a  basis  the  observations  on 
the  frog  glomerulus,  Elias  et  al.  (82)  described  another 
possible  method  of  regulation.   They  observed  that 


the  position  of  the  glomerular  blood  channels  is  not 
constant  and  undergoes  changes  (e.g.,  transverse 
displacement)  in  relation  to  the  foot  processes.  Thus, 
a  group  of  pedicels  may  be  active  while  a  blood 
channel  is  located  under  them,  and  later  at  rest 
(when  that  blood  channel  has  shifted  to  a  new  loca- 
tion). 

The  permeability  of  the  filtering  membrane  of  the 
kidney  has  been  repeatedly  studied  by  determining 
the  renal  plasma  clearance  of  molecules  of  varying 
sizes.  Wallenius  (326),  for  example,  by  fractional 
hydrolysis  of  dextran,  produced  and  separated  sub- 
stances with  a  wide  range  of  molecular  sizes  and 
shapes  and  examined  the  facility  with  which  they 
passed  into  the  urine  (fig.  8).  He  calculated  that  the 
pore  radius  in  the  dog  glomerular  membrane  may 
range  from  18  A  to  50  A.  These  findings  are  in  accord 
with  the  anatomical  evidence.  The  findings  of  Gie- 
bisch  et  al.  (100)  are  in  essential  agreement.  The 
ratio  of  dextran  clearance  to  circulation  clearance 
fell  markedly  at  a  molecular  weight  of  ca.  50,000. 

Juxtaglomerular  Complex 

Two  structural  entities  at  the  vascular  pole  of  the 
glomerulus,  the  juxtaglomerular  apparatus  and 
macula  densa,  have  been  thought  to  be  related  in 
some  way  to  the  control  of  blood  pressure  or  salt 
balance  and  thus  to  be  concerned  with  renal  hyper- 
tension (310).  One  of  these,  the  juxtaglomerular 
apparatus  (JGA),  is  a  thickening  of  the  media  of  the 
afferent  glomerular  arterioles  (polkissen)  (fig.  9). 
The  cells  of  the  JGA  become  swollen,  afibrillar  in 


THE    RENAL    CIRCULATION 


1463 


I0( 

> 

L_ 

60 

\ 

± 

\ 

0 

W 

40 

5? 

0  \ 

0 
O 

■\  8 

0 

n 

MOLECULAR,    WEIGHT    x  l|o-3 

1 

0                       2 

0                        30                       40                        50 

fig.  8.  The  relationship  of  the  molecular 
weight  of  dextran  to  percentage  filtered.  [After 
VVallenius  C326).] 


fig.  9.  The  juxtaglomerular 
complex  of  the  kidney.  JGA: 
juxtaglomerular  apparatus  (Pol- 
kissen) ;  MD :  macula  densa  of 
distal  convoluted  tubule.  [Cour- 
tesy of  B.  S.  Garber  (unpub- 
lished).] 


appearance,  and  contain  granules  (periodic  acid- 
Schiff  reaction)  which  vary  in  amount  in  various 
forms  of  experimental  hypertension  and  with  varia- 
tions in  sodium  intake.  Pathological  states  which 
produce  renal  ischemia,  such  as  the  crush  syndrome, 
cause  similar  changes  and  are  accompanied  by  in- 
crease in  blood  pressure  (no).  A  role  in  the  regulation 
of  autonomy  has  been  invoked  for  this  structure  (121, 


274,  281,  308,  330).  In  general,  when  the  kidney  is 
exposed  to  hypertensive  blood  pressures,  the  granu- 
larity decreases;  if  the  blood  pressure  is  decreased,  the 
granularity  tends  to  increase.  Tobian  (310)  feels  that 
these  cells  act  as  "stretch  receptors,"  changing  their 
rate  of  secretion  inversely  with  degree  of  stretch  of  the 
walls  of  the  arterioles. 

The  changes  in  granularity  in  the  JGA  cells  are 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


related  to  extractable  renin  or  its  precursor.  It  is  now 
conceived  that  renin  is  an  inhibitor  of  an  antihyper- 
tensive function  of  the  kidney  ( 163).  An  explanation  of 
hypertension  caused  by  renal  ischemia  would  be  as 
follows:  if  the  renal  artery  is  constricted,  the  JGA 
cells,  being  stretched  less,  would  increase  the  secretion 
of  renin.  This  would  then  inhibit  the  cells  subserving 
the  antihypertension  function  of  the  kidney,  and 
systemic  blood  pressure  would  rise. 

The  cells  are  also  influenced  by  electrolytes.  A  diet 
low  in  sodium  increases  granulation  in  dogs,  cats,  and 
rats  (both  intact  and  hypophysectomized).  Increase 
in  salt  intake  decreases  granularity  (310).  Although  a 
complex  interrelationship  with  the  adrenal  cortex 
is  probable,  a  simpler  explanation  offered  by  Tobian 
is  that  a  low  salt  intake  favors  a  decrease  in  blood 
volume,  reduced  blood  pressure,  and  decreased 
stretch  of  the  JGA  cells  (increased  secretion).  A  high 
salt  diet  would  have  the  opposite  effect.  On  the  basis 
of  the  above  scheme,  a  decreased  sodium  diet  should 
ultimately  result  in  increased  blood  pressure,  based 
upon  the  increased  granularity  of  the  JGA.  This  may 
indeed  be  a  compensatory  mechanism  to  maintain 
blood  pressure  in  the  face  of  lowered  blood  pressure 
resulting  from  decreased  plasma  and  extracellular 
volumes  caused  by  low  sodium  intake. 

The  other  structure  of  importance  is  a  portion  of 
the  distal  convoluted  tubule  near  the  vascular  pole, 
the  macula  densa.  McManus  (194-196)  has  suggested 
that  the  JGA,  macula  densa,  and  associated  struc- 
tures be  together  called  the  juxtaglomerular  "com- 
plex." This  epithelial  plaque  appears  to  have  a 
reversed  polarity  from  the  rest  of  the  tubule,  in  the 
sense  that  the  Golgi  apparatus  is  between  the  nucleus 
and  the  attached  pole  of  the  cell,  (contiguous  to  the 
vasculature),  rather  than  between  the  nucleus  and  the 
lumen.  The  suggestion  made  by  McManus  (196)  and 
supported  by  Garber  el  al.  (98)  was  that  these  cells 
abstracted  from  the  contents  of  the  lumen  and  trans- 
mitted this  material  to  the  cells  of  the  arterioles.  It  is 
relevant  to  point  out  that  a  site  of  active  sodium  re- 
absorption  is  found  in  the  vicinity  of  the  distal  con- 
voluted tubule.  It  has  been  suggested  that  the  JGA 
and  macula  densa  form  a  regulatory  system  capable 
of  responding  to  osmotic  pressure  changes  (and 
possibly  hydrostatic  pressures),  in  turn  modifying 
glomerular  filtration  in  a  self-regulatory  manner. 
This  interesting  hypothesis  needs  experimental 
verification,  particularly  in  view  of  the  contention 
by  de  la  Pefia  &  de  Castro  (70)  that  structures  re- 
sembling the  macula  densa  were  found  in  apposition 
to  efferent  arterioles  in  the  human  kidney.  It  is  worthy 


of  note  that  afibrillar  cells  containing  granules,  similar 
to  those  in  the  afferent  arterioles,  have  been  noted  in 
efferent  arterioles   (194). 

Blood  Supply  to  the  Medullary  Zones 

Edwards  (79)  has  described  two  types  of  efferent 
arterioles  which  exist  in  the  juxtamedullary  zone  of 
the  human  kidney.  One  out  of  four  to  five  glomeruli 
has  a  "corticomedullary"  efferent  arteriole  to  capil- 
laries of  the  juxtamedullary  parenchyma  (fig.  10). 
The  others  (about  180,000  per  human  kidney) 
have  long,  descending  arterioles  (arteriolae  rectae 
spuriae).  These  go  on  to  the  capillaries.  One  type 
forms  networks  around  the  tubules,  the  other  goes 
on  to  the  vasa  recta  system  (fig.  1 1).  The  venae  rectae 
return  to  the  arcuate  veins. 

Note  in  table  1  the  greater  total  muscle  volumes 
in  the  medullary  efferent  arterioles  as  compared  with 
the  cortical.  The  total  volume  of  muscle  in  the  wall 
of  the  afferent  and  efferent  arterioles  was  0.124  ml 
and  in  the  medulla  0.169  ml  (79).  Christensen  (54) 
found  the  diameters  of  the  juxtamedullary  vasa 
efferentia  of  the  dog  kidney  about  the  same  as  those 
in  the  cortical  vasa  efferentia,  contrary  to  the  findings 
of  Trueta  et  al.  (311)  who  state  that  the  caliber  of  the 
juxtamedullary  efferent  arterioles  greatly  exceeds  the 


Interlobular ...    s. 


\ 
k 


Corhcal 
Eff.  arteriole 


Corhco- medullary 
Eff.  arteriole 


^8i 


s 


5> 


Medullary 
Eff.  arteriole 


fig.  10.  The  blood  supply  of  the  juxtamedullary  zone.  [After 
Edwards  (79).] 


THE    RENAL    CIRCULATION 


[465 


Capsule 


Cortex 


Outet  zone 
of  medulla 


Inner  zone 
of  medulla 


fig.  11.  The  vasa  recta  system  of  the  kidney.  (Courtesy  of 
A.  A.  Maximov  &  VV.  Bloom,  Textbook  of  Histology.  Philadel- 
phia: Saunders,  1957.) 


cortical  efferents.  The  impression  is  definitely  gained 
that  the  arterioles  supplying  the  medullary  zone  are 
not  low-resistance  vessels  as  originally  suggested  by 
Trueta,  but  appear  to  be  sites  that  could  offer  con- 
siderable resistance  to  blood  flow,  thus  resulting  in  a 
significant  drop  in  pressure  gradient.  One  would 
anticipate  on  this  basis  that  hydrostatic  pressure  in 
the  vasa  recta  system  would  be  very  low  were  it  not 
for  the  relatively  high  venous  pressure  found  in  the 
arcuate  veins.  Gottschalk  &  Mylle  (112)  and  Wirz 
(347),  by  direct  puncture  of  cortical  peritubular 
capillaries  in  the  rat,  found  an  average  of  ca.  1 6  mm 
Hg  (range:  14.0  to  20.0  mm  Hg),  which  is  well  below 
the  oncotic  pressure  of  the  plasma  protein  when  one 
considers  that  glomerular  filtration  concentrates  the 
protein.  If  this  applies  to  the  vasa  recta,  it  would  be 
favorable  for  optimal  operation  of  the  countercurrent 
system.  The  water  abstracted  from  the  collecting 
ducts  moves  into  the  vasa  recta  because  of  the  gradient 
of  chemical  potential  established  by  the  colloid  os- 
motic pressure  of  the  plasma  proteins. 

Direct  connections  from  the  arcuate  arteries  into 
the  medullary  zone  (arteriolae  rectae  verae)  have 
been  found  in  dog  and  man  (18,  54,  217,  221,  311) 
but  appear  to  be  rare.  Likewise,  Ludwig's  arterioles, 
branches  from  the  afferent  arterioles  in  the  cortico- 
medullary  zone  passing  directly  into  the  medullary 
peritubular  capillaries,  are  very  infrequent  in  the 
dog,  cat,  and  man.  They  are  very  rare  (295)  in  the 
rat  kidney.  Oliver  (236)  and  More  &  Duff  (217)  did 
not  find  them  in  normal  human  kidneys. 


Renal  Lymphatic  System 

A  greater  lymphatic  system  (cortical)  exists,  and 
there  is  a  lesser  (medullary)  system  which  follows  the 


table    I .   Averaged  Measurements  in  Microns  of  Cortical  and  Medullary  Arterioles  per  Kidney 
and  the  Total  Volume  in  cm3  of  the  Muscle  Composing  Their  Walls1 


Arteriole 

Afferent 
Efferent 


Total  Xo. 


I ,000,000 
820,000 


Length  per 
Arteriole 


277 
200 


Total  Length 
Cortex 

277,000,000 
164,000,000 


External  Diam.        Luminal  Diam. 


26 
16 


13 

12 


Total  Muscle 
Vol.  in  cm3 


O.II 

O.OI4 


Medulla 

Efferent                         180,000                         600                         108,000,000  33  18  0.065 

1st  brs.-3                       540,000                         400                         216,000,000  24  14  0.064 

2nd  brs.-6                 1,080,000                         300                         324,000,000  15  9  0.04 

1  Specimen  calculation  such  as  was  used  to  obtain  the  muscle  volume  given  in  the  last  column  of  the  above  table. 
Afferent  arteriole:  w  X   132  X  277,000,000  =    147,087,000,000  ^i3  =   total  volume 

7r  X  6.52  X  277,000,000  =  37,1 18,000,000  m3  =   lumen  volume 

Total  volume  less  lumen  volume  =   109,989,000,000  m3  =  0.11  cm3  [After  Edwards  (79).] 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


course  of  the  vasa  recta  (251).  They  begin  blindly 
in  two  locations:  closely  adjacent  to  the  capsules  of 
cortical  glomeruli  and  beneath  the  mucosa  of  the 
papilla  (fig.  12).  The  cortical  lymphatic  capillary 
networks  do  not  have  a  functional  relationship  to 
the  glomeruli.  There  is  apparently  no  entry  (248). 

The  lymphatics  from  the  cortex  with  an  inter- 
lobular course  drain  toward  the  arcuate  vessels. 
Those  from  the  medulla,  draining  the  vasa  recta,  join 
the  cortical  branches  at  the  arcuate  level,  then  pass 
out  with  the  interlobar  vessels  toward  the  renal  pelvis. 
After  converging  at  the  hilum  of  the  kidney,  they 
course  as  perivascular  channels  to  the  cysterna  chyli 
and  thoracic  duct  (230,  261).  Valves  appear  to  be 
lacking  in  the  lymphatics  of  the  renal  parenchyma 
but  are  present  in  the  large  trunks  of  the  renal  sinus. 

Figures  for  the  volume  of  lymph  produced  by  the 


fig.  12.  The  black  threadlike  lines  indicate  the  greater  and 
lesser  lymphatic  systems  of  the  human  kidney.  The  arrows  show 
the  probable  direction  oflymph  flow;a:  capsule;  b:  interlobular 
vein;  c:  interlobular  artery;  d:  glomerulus;  e:  arcuate  artery;/: 
arcuate  vein,  »:  interlobar  artery;  h:  interlobar  vein;  i:  papilla. 
[After  Rawson  (251).] 


kidney  are  scarce.  Single  capsular  lymphatics  of  the 
dog  yield  flows  of  ca.  1  ml  per  hour  (176,  177,  304). 
An  estimate  from  the  data  of  Schmidt  &  Hayman 
(266)  yields  a  total  of  ca.  7  ml  per  hour  per  kidney. 

Available  anatomical  evidence  indicates  that  the 
capsular  lymphatics  join  with  the  cortical  and  medul- 
lary lymphatics.  Lymph  flow  increases  when  the 
kidney  is  subjected  to  osmotic  diuretics  (106,  230, 
266).  It  is  enhanced  by  ureteral  obstruction.  Pyelolym- 
phatic  backflow  is  evidenced  by  the  fact  that  dye  has 
been  shown  to  move  from  the  pelvis  into  the  lymphat- 
ics with  increased  intrapelvic  pressure.  Elevation  of 
renal  venous  pressure  in  the  dog  by  1 4  to  35  cm  results 
in  approximately  3-fold  to  5-fold  increase  in  lymph 
flow  (123,  177).  Marked  increase  in  lymphatic  pres- 
sure accompanies  venous  obstruction  (157).  Elevation 
of  arterial  pressure  does  not  markedly  increase  lymph 
flow  from  hilar  vessels:  0.023  ml  per  min  at  58  mm 
Hg  to  0.039  ml  Per  mm  at  '57  mrn  Hg  (124). 

It  is  of  considerable  interest  that  the  lymph  is  high 
in  sodium,  chloride,  and  urea  content  compared  to 
plasma  and  thoracic  duct  lymph  (176,  304).  LeBrie 
&  Mayerson  (176)  have  found  Na  and  CI  concentra- 
tions of  162  and  140  per  liter,  respectively,  compared 
to  145.7  anc'  1 10.5  in  the  plasma,  and  145.6  and  1  2  1 .3 
in  the  thoracic  duct  lymph.  Interestingly,  the  K 
content  does  not  differ  significantly.  These  findings 
support  the  countercurrent  hypothesis,  for  it  is  to  be 
expected  that  these  concentrations  will  be  elevated 
as  a  result  of  the  contribution  of  the  medullary 
lymphatics  which  drain  the  papillary  zone  of  hyper- 
osmolarity  of  the  kidney.  K.  is  not  a  significant  con- 
tributor to  this  hyperosmolarity  (267).  This  is  further 
supported  by  the  low  glucose  content  of  this  fluid 
relative  to  plasma  (304),  suggesting  an  important 
source  beyond  the  proximal  convoluted  tubules. 
An  interesting  avenue  of  investigation  of  the  counter- 
current  mechanism  thus  appears  to  be  afforded  by  a 
study  of  the  renal  lymphatics. 

The  renal  lvmph  protein  concentration  averages 
2.9  g  per  100  ml  as  compared  to  5.83  g  per  100  ml  for 
the  plasma  proteins  (177).  Evidently  the  renal  lym- 
phatics subserve  an  important  function  for  operation 
of  the  countercurrent  system  by  draining  off  excessive 
protein  filtered  by  the  vasa  recta,  which  might  other- 
wise accumulate  in  the  interstitial  spaces  of  the  me- 
dulla. Removal  of  such  protein  would  act  to  maintain  a 
more  favorable  gradient  of  movement  of  interstitial 
fluid  into  the  vasa  recta,  attracted  by  the  relatively 
higher  oncotic  pressure. 


THE    RENAL    CIRCULATION 


I467 


fig.  13.  Renal  plexuses  of  the  human  kidney,  anterior  aspects.  1  :  Hypogastric  nerves.  2:  Middle 
spermatic  and  ureteric  nerve.  3 :  R.  spermatic  artery.  4 :  Renal  branch  from  sup.  hypogastric  plexus. 
5:  Lumbar  splanchnic  nerve.  6:  Sup.  ureteric  nerve.  7:  Communication  between  renal  plexus  and 
spermatic  nerve.  8:  Small  renal  ganglion.  9:  Renal  branch  from  lumbar  sympathetic  trunk.  10:  Post, 
renal  ganglion.  1 1  :  Aorticorenal  ganglion.  12  :  Communication  between  suprarenal  and  renal  plexuses. 
1  3  Right  coeliac  ganglion.  14:  R.  phrenic  nerve.  15:  Post,  vagal  trunk  and  coeliac  di  v.  i6:Ant.  vagal 
trunks.  17:  Esophagus.  18:  L.  phrenic  nerve.  19:  Greater  (thoracic)  splanchnic  nerve.  20:  Lesser 
(thoracic)  splanchnic  nerve.  21  :  Lowest  (thoracic)  splanchnic  nerve.  22:  Sup.  mesenteric  ganglion. 
23:  Post,  renal  ganglion.  24:  Intermesenteric  nerves.  25:  Renal  branches  from  lower  ends  of  inter- 
mesenteric  nerves.  26 :  Lumbar  sympathetic  trunk.  27  :  L.  ureter.  28 :  Inf.  mesenteric  plexus.  29 :  Sup. 
hypogastric  plexus.  [After  Mitchell  (211).] 


NERVE  SUPPLY  TO  THE  KIDNEY:  ANATOMICAL  ASPECTS 

Extrinsic  Nerves 

It  is  generally  agreed  that  the  major  nerve  supply 
to  the  kidney  has  its  origin  largely  from  the  twelfth 
thoracic  to  the  second  lumbar  ganglia  of  the  sym- 
pathetic nervous  system  in  man  (51),  and  in  the  dog 
from  T4  through  L2,  but  most  abundantly  from 
T10  through  T12  (31).  Relative  to  its  size,  the  kidney 
receives  a  more  profuse  and  widespread  supply  than 
almost  any  other  viscus.  Mitchell  (211)  has  written 
comprehensively  on  the  anatomical  aspects  of  the 
nerve  supply  to  the  human  kidney,  with  an  extensive 
historical  review,  and  with  good  anatomical  illustra- 
tions to  which  the  reader  is  referred.  Christensen 
el  a/.   (55)   have  given  a  detailed  description  of  the 


innervation  of  the  cat  kidney.  The  renal  nerves  of 
the  human  kidney  are  derived  from  the  following: 

celiac  plexus.  The  renal  branches  arise  from  the 
celiac  or  aorticorenal  ganglia,  and  contain  sympa- 
thetic and  almost  certainly  parasympathetic  fibers. 
Most  investigators  feel  that  the  posterior  vagal  trunk 
supplies  the  kidney  via  the  celiac  plexus,  although 
several  have  indicated  that  it  may  pass  directly  to  the 
renal  plexus  (fig.  13). 

thoracic  splanchnic  nerve.  The  greater  (superior 
thoracic)  splanchnic  nerve  occasionally,  and  the 
lesser  (middle  thoracic)  splanchnic  nerve  almost 
invariably  send  direct  filaments  to  the  aorticorenal 
ganglion  or  renal  plexus,  while  the  least  (inferior 
thoracic)  splanchnic  nerve  ends  in  the  renal  plexus. 


1468 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


lumbar  splanchnic  NER\ES.  Direct  branches  to  the 
renal  plexus  may  arise  both  from  the  first  and  second 
lumbar  ganglia,  or  from  the  adjacent  portions  of  the 
sympathetic  trunk.  These  branches  are  inconsistent, 
especially  the  ones  from  the  second  lumbar  ganglion. 
When  present,  they  join  the  posterior  root  of  the 
renal  plexus  often  close  to  the  terminations  of  the 
lowest  splanchnic  nerve,  and  sometimes  they  end  in 
the  posterior  renal  ganglia. 

intermesenteric  nerves.  The  renal  branches  from 
the  upper  parts  of  the  intermesenteric  nerves  run 
almost  directly  to  the  renal  hilum.  The  uppermost 
ones  are  associated  with  those  arising  from  the  celiac 
plexus  and  occasionally  from  the  superior  mesenteric 
ganglion,  and  those  a  little  lower  down  are  connected 
with  the  origins  of  the  superior  spermatic  nerves. 

Other  branches  originate  from  the  lower  ends  of 
the  intermesenteric  nerves  or  from  the  superior 
hypogastric  plexus  (presacral  nerve).  Except  near 
their  terminations  they  are  separate  from  the  other 
renal  nerves;  they  communicate  with  the  superior 
and  middle  spermatic  nerves,  and  are  apparently 
distributed  mainly  to  the  renal  pelvis  and  upper 
ureter.  Mitchell  suggests  that  the  ureter,  renal  pelvis, 
and  renal  collecting  tubules  may  receive  their  para- 
sympathetic supply  via  these  nerves  through  the 
caudal  (pelvic  splanchnic)  rather  than  cranial  (vagal) 
outflow. 

The  various  renal  nerves  unite  in  a  plexiform 
manner  around  the  renal  artery.  Xo  filaments  of  any 
size  lie  anterior  to  the  vein  or  posterior  to  the  pelvis, 
and  the  plexus  splits  into  subsidiary  plexuses  which 
accompany  the  branches  of  the  renal  artery  into  the 
kidney.  A  few  filaments  accompany  the  superior  and 
inferior  renal  capsular  veins.  All  nerves  of  the  plexus 
do  not  cluster  intimately  around  the  renal  artery,  but 
several  approach  only  the  branches  of  this  vessel  in 
the  actual  hilum  of  the  kidney.  Both  preganglionic 
and  postganglionic  nerve  fibers  exist  in  the  renal 
plexus.  The  renal  nerves  and  plexus  form  multiple 
intercommunications  with  many  other  autonomic 
nerves  and  plexuses. 

Ganglia  of  varying  size  are  invariably  located  in 
the  plexus,  and  the  posterior  renal  ganglion  is  the 
largest  and  most  constant.  Many  of  the  ganglia  are 
of  microscopic  size;  these  are  more  numerous  in 
infantile  kidney  specimens,  although  not  absent  in 
adult  kidneys. 

Intrinsic  Innervation 

Mitchell  (212)  has  emphasized  the  difficulties 
involved  in  the  differential  staining  of  intrinsic  nerve 


fibers;  reticular  fibers  are  especially  troublesome  and 
caution  must  be  exercised  in  properly  separating 
them  from  the  nerves.  Errors  of  interpretation  have 
resulted  from  improper  identification.  The  following 
description  is  largely  from  Mitchell  and  based  upon 
the  innervation  in  man. 

The  main  renal  plexus  divides  into  large  bundles 
which  accompany  the  branches  of  the  renal  artery 
into  the  kidney,  giving  off  interlobar,  arcuate,  and 
interlobular  nerves  corresponding  to  the  divisions  of 
the  artery.  They  may  lie  adjacent  to  the  arteries  or  be 
imbedded  in  the  adventitia;  some  spread  out  in  the 
adventitia  and  media,  but  others  leave  the  vessels  to 
run  between  the  tubules.  The  nerve  fibers  in  the 
adventitia  do  not  all  end  in  the  artery,  but  may 
re-emerge  into  the  perivascular  space.  Definite  nerve 
filaments  or  endings  were  not  found  in  the  intima  of 
any  of  the  renal  vessels,  and  no  fine  nerve  plexuses 
were  detected  around  the  peritubular  capillaries.  The 
fibers  are  unmyelinated,  according  to  Mitchell. 

nerve  supply  to  cortex.  Nerve  fibers  are  much 
more  common  in  the  cortex  than  in  the  medulla,  and 
probably  more  frequent  among  the  convoluted 
tubules.  They  are  derived  from  the  small  bundles  of 
nerve  fibers  associated  with  the  interlobular  arteries. 
At  irregular  intervals  strands  detach  themselves  from 
the  parent  bundles  and  pass  between  the  tubules 
where  they  are  connected  by  occasional  anastomoses, 
and  filaments  may  be  traced  to  the  limits  of  the 
cortex. 

Many  fibers  appear  to  end  as  free,  fine,  beaded 
filaments  on  the  basement  membranes  or  between  the 
tubular  cells.  Others  give  off  short  side  branches  which 
end  in  globular  or  fusiform  swellings.  Endings  have 
been  seen  on  the  basement  membranes  and  between 
the  cells,  but  the  presence  of  intracellular  endings  is 
doubtful.  This  aspect  has  been  controversial:  some 
workers  believe  that  nerve  fibers  may  end  within  the 
tubular  cells  (133,  161). 

The  glomeruli  receive  offshoots  from  the  inter- 
lobular nerves  and  other  filaments  which  are  derived 
from  adjacent  interlobular  nerve  bundles.  These 
offshoots  run  alongside  afferent  arterioles,  and  wind 
around  them  in  a  spiral  fashion,  supplying  these 
vessels.  Knoche  (161)  has  demonstrated  a  terminal 
reticulum  on  the  specialized  cells  of  the  juxtaglomeru- 
lar apparatus  (polkissen  cell).  Filaments  proceed  to 
the  glomerulus,  and  Mitchell  contends  that  the 
resultant  strands  fade  away  on  the  capsule  or  may 
end  in  a  small  series  of  slight  varicosities.  Dark 
staining  strands  (Romane's  stain)  have  been  seen 
within  the  glomeruli,  but  identification  as  nerves  was 


THE    RENAL    CIRCULATION  1 469 


not  absolutely  positive.  Knoche,  on  the  other  hand 
(using  Bielschowsky-Gros  stain),  described  a  promi- 
nent terminal  reticulum  surrounding  the  glomerular 
capillaries.  Since  there  are  presumably  no  contractile 
elements  of  the  smooth  muscle  type  in  the  glomerular 
zone,  the  role  of  these  nerve  fibers  becomes  highly 
problematical.  He  also  found  nerve  filaments  around 
the  efferent  arterioles.  Harman  &  Davies  (133)  saw 
nerve  endings  in  the  perivascular  tissue  of  the  glomeru- 
lus, and  hypothesized  an  afferent  function  for  them. 

Knoche  also  described  a  prominent  reticulum 
surrounding  the  complex  made  up  of  the  macula 
densa,  the  polkissen,  Goormaghtigh's  "cell  aggre- 
gate" and  paravascular  and  paraportal  cell  clumps, 
and  suggested  that  together  they  formed  a  receptor- 
effector  zone  to  adjust  glomerular  filtration  to  the 
variations  in  blood  pressure. 

medullary  nerve  supply.  Comparatively  few  nerve 
fibers  pass  into  the  medulla  as  compared  with  the 
cortex,  and  most  of  these  are  located  in  the  boundary 
zones.  They  reach  the  medulla  largely  through 
offshoots  from  the  nerve  bundles  alongside  the  arcuate 
arteries,  and  by  accompanying  the  arteriolae  rectae 
spuriae.  A  point  of  control  of  the  vasa  recta  system 
could  reside  here. 

renal  afferents.  Beyond  the  possibility  of  pres- 
soreceptors in  the  field  of  the  juxtaglomerular  cell 
groups,  the  renal  tissue  is  generally  nonsensitive  to 
afferent  stimulation.  Swelling  gives  renal  pain  via 
stretch  of  the  capsule,  which  has  pain  afferents.  It  is 
said  that  some  afferent  sensory  function  is  localized  in 
the  papillary  tissue  and  in  the  pelvis. 


distribution  of  osmotic  constitutents  in  the 
kidney;  the  countercurrent  hypothesis 

The  osmotic  constituents  of  the  kidney  are  arranged 
so  that  they  are  isotonic  with  blood  in  the  cortex, 
then  rise  to  three  to  four  times  this  concentration  at 
the  tip  of  the  papilla.  VVirz  et  al.  (345)  have  demon- 
strated by  a  cryoscopic  method  (disappearance  of  ice 
crystals  as  observed  by  a  polarizing  microscope)  that 
points  of  equal  osmotic  pressure  form  shells  concentric 
to  the  tip  of  the  papilla  (fig.  14),  and  are  parallel  to 
the  interzonal  boundary.  The  important  osmotic 
constituents  are  sodium,  chloride,  and  urea,  as 
revealed  by  the  analysis  of  Ullrich  &  Jarausch  (312) 
(figs.  15  and  16),  and  supported  by  the  findings  of 
Schmidt-Nielsen  &  OTJell  (267). 

A    uniform    distribution    of   osmotic    constituents 


max.  700 


IsotoniscfiO 


fkj.  14.  Distribution  of  osmotic  constituents  in  the  kidney 
(hamster).  A.Z.:  outer  zone  of  medulla:  I.Z.:  inner  zone  of 
medulla.  [After  Wirz  et  al.  (345).] 


between  the  loops  of  Henle,  vasa  recta,  and  collecting 
tubules  has  been  proved  by  micropuncture  (346, 
348)  in  the  hamster  and  rat  (fig.  17)  [Gottschalk  & 
Mylle  (1 13)-]  The  "hairpin"  loop  arrangement  of  the 
loops  of  Henle  and  vasa  recta  has  been  the  basis  for 
the  formulation  of  the  countercurrent  multiplier 
system  concept  for  urinary  concentration  and  dilution 
(132).  (For  discussion  of  this  principle  as  applied  to 
kidney  function,  see  131,  169,  171,  259,  289,  314.) 

Briefly,  the  principle  of  the  countercurrent  system 
as  it  applies  to  the  medullary  loop  of  Henle  system  is 
as  follows:  sodium,  by  an  active  process,  and  chloride, 
as  the  result  of  an  electrochemical  gradient  thus 
established,  are  believed  to  be  transported  out  of  the 
relatively  water-impermeable  ascending  limb  of  the 
loop  of  Henle  into  the  interstitium  of  the  medulla 
until  a  gradient  of  ca.  200  mOsm  per  kg.  H20  has 
been  established  (fig.  17).  This  single  effect  is  multi- 
plied as  the  fluid  of  the  thin  part  of  the  descending 
limb  comes  into  osmotic  equilibrium  with  the  inter- 
stitial fluid  by  diffusion  of  water  out  (and  probably 
by  the  diffusion  of  some  NaCl  into  the  descending 
limb),  thus  raising  the  osmolarity  of  the  fluid  rounding 
the  hairpin  loop  into  the  ascending  limb.   The  in- 


'47° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


100- 
jrmol/ml 


Jrin 

ostnol 

Hz-Konz 

^imol/mJ. 

2,  IS 

13 

1,66 

es 

1.73 

31 

1,66 

90 

20 


13 
32 


umol/ml 
too  - 


Urin 
osmol  ZVKonz. 
^mol/ml 
62 


112 
356 
212 


fig.  15.  Na  and  CI  concentration  in  kidney  tissue  (Mmole/ml  of  tissue  fluid,)  in  hydropenic  (solid 
lines)  and  diuretic  idashed  lines)  dogs.  To  the  right  are  the  osmotic  pressures,  and  Na  and  CI  concen- 
trations of  bladder  urine  taken  shortly  before  the  tissue  analysis.  [(After  Ullrich  &  Jarausch  (312).] 


125.5 
106 


creased  concentration  here,  also  raising  that  in  the 
interstitium  now  favors  further  movement  of  fluid  out 
of  the  descending  limb,  further  increasing  concen- 
tration, and  so  on. 

In  this  fashion,  an  increasing  osmotic  gradient  is 
established  in  the  direction  of  the  tip  of  the  papilla, 
and  yet  at  no  level  is  there  much  osmotic  difference 
among  the  luminal  fluid,  interstitial  fluid,  and  blood. 
The  collecting  ducts  in  the  presence  of  pituitary 
antidiuretic  hormone  (ADH)  are  believed  to  be  water 
permeable  and  somewhat  Na-impermeable  (net 
transport  small,  although  there  may  be  diffusion 
into  and  active  transport  out).  This  results  in  diffusion 
of  water  out  of  the  collecting  ducts  into  the  hyper- 
osmotic medullary  interstitium,  and  ultimately  into 
the  vasa  recta  to  be  carried  away  until  fluid  in  the 
collecting  ducts  becomes  correspondingly  concen- 
trated. The  role  of  the  vasa  recta  will  be  dealt  with  in 
greater  detail  below. 

The  view  is  currently  favored  that  ADH  <icts  in  a 
permissive  fashion  to  let  water  diffuse  out  of  the 
nephron,  perhaps  altering  the  size  of  the  "pores" 
in  the  base  of  the  cells  of  the  tubular  epithelium. 
Figures  18  and  19  illustrate  the  operation  of  the 
countercurrent  system  in  the  concentrating  and 
diluting  kidney.  In  the  concentrating  kidney  (fig.  18) 
ADH  restores  the  hypotonic  urine  in  the  distal  con- 
voluted tubule  to  isotonicity  by  permissive  (passive) 
loss  of  water  and  then  permits  its  concentration  to 
hypertonicity  in  the  collecting  duct.  In  the  diluting 


kidney,  the  distal  convoluted  tubule  and  collecting 
duct  remain  impermeable  to  water,  and  the  urine 
remains  hypotonic. 

Mechanisms  relating  to  salt  and  water  handling  in 
the  proximal  convoluted  tubule,  though  highly 
important  in  a  bulk  sense,  will  not  be  dealt  with  here 
(see  279).  Sodium  is  probably  actively  reabsorbed 
here,  with  water  following  passively. 


RENAL   BLOOD   VOLUME; 

THE    INTRARENAL    HEMATOCRIT 

The  renal  blood  volume  has  been  estimated  in 
three  ways:  /)  by  reconstructions  of  the  vascular  bed 
and  from  these  estimation  of  the  volume;  2)  by  the 
product  of  mean  transit  time  of  erythrocytes  and 
plasma  and  the  mean  volume  flow;  and  3)  by  an 
injection  of  labeled  erythrocytes  (Cr51,  P32)  and 
labeled  albumin  (T-1824,  I131)  with  subsequent 
analysis  of  distribution  in  selected,  homogenized 
tissue  samples.  Measurement  of  hemoglobin  content 
has  also  served  to  assess  erythrocyte  volume. 

By  reconstruction  techniques,  Weaver  el  al.  (332) 
computed  the  following  distribution:  4.5  ml  per  100 
g  of  kidney  in  arteries,  4.1  ml  per  100  g  in  cortical 
veins,  and  2.6  ml  per  100  g  in  subcortical  veins,  with 
about  2  ml  per  100  g  undetermined,  distributed 
somehow  among  glomerular  capillaries,  efferent 
arterioles,    peritubular    capillaries,    and    medullary 


THE    RENAL    CIRCULATION 


1471 


Gewebsflussigk. 
800  - 


fig.  16.  Urea  distribution  in  the  dog  kidney  during  hy- 
dropenia  {upper  curves)  and  diuresis  (lower  curves).  [After  Ullrich 
&  Jarausch  (312).] 

vasculature  for  a  total  of  13.0  per  100  g  of  kidney. 
The  interstitial  fluid  volume  also  averaged  13.0  ml 
per  100  g  tissue  (303).  Hematocrit  of  kidney  fluid 
drained  from  vein  and  artery  was  27.0  per  cent  com- 
pared to  the  systemic  hematocrit  of  ca.  43  per  cent; 
this  probably  represented  a  combination  of  blood  and 
"diluting"  fluid  (interstitial  fluid).  On  the  other  hand, 
Morgan  (219)  placed  a  dog  kidney,  continuously- 
pressured  with  blood  from  a  carotid  artery  in  a  cham- 
ber filled  with  saline  solution  and  intermittently 
stopped  flow  and  expressed  blood  from  the  vessels 
(largely  from  the  vein)  by  increasing  the  fluid  pres- 
sure within  the  chamber.  These  samples  showed  hem- 
atocrit values  only  slightly  lower  than  arterial  blood. 
The  expressed  volume  represented  an  average  of  11.3 
per  cent  of  the  kidney  weight.  Using  Weaver's  data 
for  proportions,  venous  blood  volume  would  be  54 


per  cent  of  the  total.  As  to  whether  or  not  Morgan's 
samples  contained  more  than  venous  blood  would 
depend  upon  the  figure  accepted  for  renal  blood 
volume.  All  injection  methods  yield  values  of  20  ml 
or  more  of  blood  per  100  g  of  kidney. 

Computation  of  blood  volume  from  the  product  of 
mean  transit  time  and  minute  flow  yields  values  of 
20  to  24  ml  per  100  g  of  kidney  (66,  183,  185,  188) 
with  a  kidney  hematocrit/large  vessel  hematocrit  ratio 
of  ca.  0.90.  Transit  time  for  red  cells  (t,.)  through  the 
kidney  is  slightly  faster  than  plasma  (tp),  e.g.,  tc  = 
6.4  and  tp  =  7.6  sec  (tc/tP  =  0.83  ±  5)  (183).  The 
question  as  to  whether  this  small  difference  in  transit 
time  supports  the  idea  of  red-cell  shunting  is  de- 
batable. However,  Morgan  (219)  has  advanced  a 
cogent  mathematical  argument  to  show  that  a 
kidney/systemic  hematocrit  ratio  as  high  as  0.83 
could  be  enough  to  account  for  passage  of  significant 
amounts  of  cell-rich  blood  through  shunting  channels. 
Hemorrhage  with  lowered  blood  pressure  did  not 
influence  the  renal  hematocrit  (188)  nor  did  KCN 
toxicity,  which  eliminates  autoregulation  of  the  flow 
(234).  Hence  the  intrarenal  hematocrit  is  not  related 
to  this  phenomenon,  a  fact  which  argues  against  the 
cell-separation  hypothesis  of  Pappenheimer  &  Kinter 
(240). 

The  third  method  tends  to  yield  the  largest  volumes, 
averaging  27  ml  per  100  g  of  kidney  (84,  99,  182,  186, 
240).  The  hematocrit  ratio  averages  20  per  cent, 
slightly  less  than  half  of  the  systemic  hematocrit  ratio. 
It  appears  reasonable  to  assume  that  this  method 
measures  extravascular  volume  to  a  certain  degree, 
accounting  in  the  main  for  the  difference  from  other 
methods.  During  the  editing  of  this  chapter  a  pre- 
liminary note  has  come  to  the  author"  s  attention 
(249a)  in  which  it  is  claimed  that  washing  out  the 
renal  vasculature  yields  a  renal  hematocrit  part  way 
between  those  given  by  the  homogenate  method  and 
the  mean  transit  time  method. 

The  distribution  of  cells  and  plasma  in  various 
zones  of  the  kidney  appears  in  table  2  (186). 

The  findings  of  Emery  et  al.  (84)  are  in  essential 
agreement  with  the  above  with  one  exception:  the 
papillary  hematocrit  is  47  per  cent  of  the  large  vessel 
hematocrit;  but  this  value  is  extremely  variable  in 
both  groups  of  data,  and  may  reflect  the  fact  that 
this  critical  anatomical  zone  is  supplied  from  two 
sources,  the  vasa  recta  and  the  spiral  arteries. 

Lilienfield  et  al.  (184)  point  out  that  no  significant 
difference  in  hematocrit  exists  between  outer  and 
inner  cortex.  This  is  interpreted  as  evidence  against 
the  cell-separation  hypothesis  for  autoregulation  of 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


CORTEX 


fig.  17.  Distribution  of  osmotic  con- 
stituents in  tubules  and  vasa  recta  sys- 
tem of  rats,  indicating  sites  of  active 
and  passive  sodium,  urea,  and  water 
transport.  The  numbers  represent  hypo- 
thetical osmolarity  values.  No  quanti- 
tative significance  is  to  be  attached  to 
the  number  of  arrows  and  only  net 
movements  are  indicated.  [After 
Gottschalk  &  Mylle  (113).] 


TRANSPORT 

Active 

Possive 

SODIUM 

■» 

CO 

UREA 

=5 

'-'.) 

WATER 

-* 

OUTER  ZONE 
OF   MEDULLA 


fig.  18.  Role  of  ADH  in  urine  concentra- 
tion and  dilution  in  the  countercurrent  system. 
In  the  concentrating  kidney,  ADH  acts  in  a 
permissive  manner  to  facilitate  water  removal 
from  the  distal  convoluted  tubule  and  collect- 
ing tubule  (white  arrows)  into  the  zone  of  hyper- 
osmolarity.  (Active  sodium  transport  indicated 
by  heavy  black  arrows.)  Water  and  sodium  ex- 
changes in  the  vasa  recta  system  are  indicated 
as  passive  processes.  The  question  mark  at  the 
descending  limb  of  the  loop  of  Henle  indicates 
uncertainty  as  to  the  mechanism  which  initiates 
the  countercurrent  exchange.  [After  Wirz 
(349)-] 


renal  blood  flow  (240),  because  plasma  stripping  in 
the  interlobular  arteries  should  lead  to  progressive 
hemoconcentration.  The  hemoglobin  content  of  the 
cortical  capillaries  was  found  to  be  below  that  of  the 
arterial  blood  hemoglobin,  as  measured  by  oximeter 
techniques  (165).  Emery  et  al.  stoutly  support  the 
hypothesis  by  attributing  the  low  hematocrit  to  axial 
streaming  of  cells  in  the  many  small  vessels  of  the 
outer  cortex.  How  this  would  fit  into  a  concept  of 
autoregulation  by  changes  created  in  blood  viscosity, 
and  thus  changes  in  vascular  resistance  (240),  be- 
comes  difficult    to   envision.    The   somewhat    higher 


values  in  the  inner  cortex  and  outer  medulla  may 
reflect  the  hematocrit  of  larger  vessels  in  this  region. 

Although  Emery  et  al.  believe  that  the  low  medul- 
lary hematocrit  is  further  evidence  of  plasma  strip- 
ping, it  could  be  equally  well  explained  by  escape  of 
labeled  protein  from  the  vasa  recta  into  the  inter- 
stitial spaces,  a  view  supported  by  Swann  et  al.  (303). 

In  dogs,  autoradiographs  appear  to  show  a  higher 
concentration  of  I131-labeled  albumin  in  the  renal 
papilla  than  in  other  regions  of  the  kidney  (174). 
If  a  mechanism  were  to  operate  here  to  concentrate 
plasma  albumin  above  normal  levels,  this  could  lead 


THE    RENAL    CIRCULATION 


!473 


FIG.  19.  The  countercurrent  mechanism 
during  diuresis  (absence  of  ADH  action). 
[After  VVirz  (349).] 


table   2.   Distribution  of  Cells  and  Plasma  in  Zones  of  the  Kidney 


Outer 
Cortex 

Inner 
Cortex 

Outer 

Medulla 

Inner 
Medulla 

Outer 
Papilla 

Inner 

Papilla 

Whole 
Kidney 

Cr5'  RBC                    Mean 

5-5 

6.9 

10.4 

6.3 

3-6 

3-5 

7-2 

S.E. 

±0.5 

±0.7 

±1.4 

±0.8 

±1 .1 

±1 .0 

±0.8 

I131  Albumin                Mean 

■22.8 

24.0 

30-7 

34-6 

37 -o 

38-5 

25.6 

S.E. 

±1.1 

±1.2 

±1.1 

±2.2 

±3-i 

±2.5 

±0.8 

Vascular  vol. 

28.3 

3° -9 

41. 1 

4°- 9 

40.6 

42.0 

32.8 

Tissue  hematocrit 

19-4 

22.3 

25-3 

'5-4 

8.8 

83 

21  -9 

Tissue  hematocrit 

43 

50 

56 

34 

20 

18 

49 

Arterial  hematocrit 

All  values  as  ml/100  g.         [After  Lilienfield  el  at.   (,186).] 


to  an  erroneous  impression  of  a  larger  volume  of 
distribution  for  those  substances  which  are  bound  by 
albumin.  It  is  noteworthy  that  red  cell  volumes  per 
gram  of  tissue  are  very  similar  in  the  medulla  and 
the  outer  cortex  (84),  so  that  the  low  apparent  hema- 
tocrit in  the  medulla  is  the  result  of  the  large  "ap- 
parent" albumin  space. 

Confirmation  of  the  high  concentration  of  albumin 
in  the  loops  of  the  vasa  recta  would  lead  to  the  in- 
teresting possibility  of  a  countercurrent  system  for 
accumulation  of  albumin  in  the  papillary  portion 
of  the  loops.  High  concentration  of  albumin  here 
would  aid  the  rapid  net  transport  of  water  from  the 
interstitial  space  into  the  zone  of  elevated  oncotic 
pressure,  facilitating  removal  by  the  vascular  system. 
The  countercurrent  exchange  of  water  would  begin 
at  the  juxtamedullary  portion  of  the  vasa  recta  by 
movement  of  water  across  to  the  ascending  venae 
rectae.   The  high  interstitial  content   of  protein,   as 


revealed  by  analysis  of  lymph  (177)  and  the  slow 
apparent  flow  of  plasma  through  the  vasa  recta 
system  [T-1824  transit  time  of  27.7  sec  in  the  medulla 
as  compared  to  2.5  sec  in  the  cortex  (166)]  are  in 
support  of  this  hypothesis. 

Recently,  strong  evidence  of  a  countercurrent 
system  for  water  has  been  advanced  by  Morel  et  al. 
(218).  They  compared  the  kinetics  of  distribution  of 
Na22  and  tritiated  water  in  the  kidneys  of  oliguric 
hamsters.  The  concentration  of  the  tracer  in  tissue 
samples  removed  at  graded  levels  from  cortex  to 
papilla  was  measured.  Na'22  showed  uniform  distribu- 
tion in  less  than  2  min,  but  the  turnover  of  water  in 
the  deepest  regions  of  the  kidney  was  not  complete  in 
10  min.  This  they  attributed  to  the  passage  of  water 
across  the  descending  and  ascending  branches  of  the 
loops  of  Henle  and  vasa  recta.  Thus,  the  osmotic 
gradients  of  the  hairpin  system  may  supply  the  trigger 


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CIRCULATION    II 


mechanism  for  the  removal  of  water  and  concentra- 
tion of  albumin  in  the  vasa  recta  loops. 


METABOLIC     ASPECTS 

Oxygen  Utilization 

The  renal  venous  blood  contains  considerably  more 
oxygen  than  does  venous  blood  from  other  tissues. 
The  resulting  small  A-Y  oxygen  difference  [1.7  vol  % 
in  man  (287),  and  ca.  3.0  vol  %  in  the  dog  and  cat] 
remains  constant  over  a  wide  range  of  renal  blood 
flows  (66,  74,  102,  164,  180,  181,  317),  although  it 
may  change  at  very  low  rates  of  flow.  Thus,  oxygen 
consumption  (normally  .08  to  o.  10  ml/g/min  in  the 
dog)  is  related  to  flow,  so  that  when  flow  is  reduced 
as  in  shock  (74)  the  organ  ordinarily  does  not  increase 
its  extraction  but  apparently  suffers  curtailment  of 
oxidative  metabolism.  As  Pappenheimer  &  Kinter 
(240)  have  pointed  out,  the  kidney  behaves  in  a  sense 
as  a  " flow-limited"  tissue.  The  "cell-separation" 
theory  proposed  by  them  has  attempted  to  reconcile 
the  paradox  of  high  renal  venous  oxygen  saturation 
and  flow  limitation.  If  the  majority  of  the  red  cells 
coursed  through  hypothetical  shunts,  then  blood  of 
low  erythrocyte  count,  low  in  oxygen,  would  supply 
the  tubular  cells  with  a  barely  adequate  supply  of 
oxygen.  If  flow  were  impaired,  oxygen  supply  would 
become  insufficient,  unless  the  blood  flow  could  be- 
come redistributed  to  supply  the  tubular  cells. 

Levy  (178)  has  brought  evidence  to  bear  against 
this  hypothesis  by  showing  that  when  additional 
oxygen  was  made  available,  the  extraction  of  oxygen 
still  remained  constant  over  a  wide  range  of  blood 
flows,  unattended  by  alteration  of  intrarenal  hemato- 
crit. In  addition,  2 ,4-dinitrophenol  was  found  to 
increase  the  renal  oxygen  extraction  very  signifi- 
cantly without  altering  the  intrarenal  hematocrit 
ratio.  This  implied  that  the  capillarv  blood  perfusing 
the  renal  tubules  must  not  be  virtually  desaturated 
at  normal  or  even  at  moderately  reduced  flows. 

An  alternative  ingenious  explanation  was  offered 
by  Levy  for  the  apparent  flow  limitation  (179),  based 
upon  the  earlier  observation  of  Longley  et  al.  (190). 
The  latter  showed  that  krypton85  attained  equilibrium 
very  slowly  between  the  circulatory  system  and  the 
renal  medulla.  If  these  findings  implied  that  krypton 
diffused  from  arterial  to  venous  limbs  of  the  medullary 
capillary  circuits,  it  might  be  that  oxygen  would 
also  diffuse  across  this  path.  Experimental  verification 
appeared  to  be  offered  by  the  simultaneous  injection 


of  highly  oxygenated  blood  and  blood  containing 
methemoglobin-labeled  red  cells  into  the  renal  artery. 
Analysis  of  renal  vein  blood  showed  that  the  peak  of 
elevated  oxygen  tension  arrived  slightly  ahead  of  the 
labeled  cells  (1.25  ±  0.97  sec).  Since  the  erythrocytes 
represent  the  portion  of  the  blood  that  passes  through 
the  kidney  most  rapidly,  it  was  concluded  that  some 
of  the  oxygen  must  diffuse  from  the  vascular  system 
and  re-enter  at  some  point  downstream.  The  likely 
site  for  this  operation  is  between  the  upper  arterial 
and  venous  limbs  of  the  vasa  recta.  In  support  of  this 
is  the  fact  that  oxygen  pressure  of  the  renal  venous 
blood  is  always  higher  than  that  of  the  urine  (253). 
This  could  be  explained  by  supposing  that  urine  in 
the  collecting  tubules  tends  to  equilibrate  with  blood 
of  low  oxygen  tension  in  the  vasa  recta  before  enter- 
ing   the    pelvis. 

The  implication  of  this  is  that  the  medullary  zone 
of  the  kidney  and  particularly  the  region  of  the  papilla 
would  be  a  zone  of  decreased  oxygen  tension  com- 
pared to  the  cortex.  The  low  hematocrit  here  would 
further  compromise  the  oxygen  supply  (84,  166,  184). 
Lastly,  volume  flow  in  the  medulla  has  been  measured 
by  an  ingenious  intrarenal  photoelectric  technique 
and  found  to  be  small,  21.8  ml  per  min  per  100  g 
compared  to  400  ml  per  min  per  100  g  in  the  cortex 
(166). 

But  the  operation  of  the  countercurrent  system 
does  not  demand  increased  oxygen  utilization  by  the 
cells  of  the  medulla.  Ullrich  (314)  has  summarized 
the  result  of  a  number  of  Warburg  tissue-slice  studies 
made  in  the  guinea  pig,  dog,  and  cat.  The  average 
values  are  as  follows  in  cubic  millimeter  per  milli- 
gram of  dry  tissue  per  hour:  cortex,  21.3;  outer 
medulla,  15.1;  inner  medulla,  6.2.  A  representative 
experiment  made  on  guinea  pig  kidney  tissue  by 
Grupp  &   Hierholzer  (115)  appears  in  figure  20. 

These  findings  would  support  the  conclusion  that 
the  important  structures  of  the  inner  medulla  (loops 
of  Henle  and  collecting  ducts)  do  not  have  important 
energy  requiring  functions.  Ullrich  &  Pehling  (313) 
have  shown  that  tissue  slices  of  the  outer  medulla  of 
the  dog  kidney  increased  their  oxygen  uptake  as  a 
linear  function  of  NaCl  concentration  in  the  bath. 
While  oxygen  uptake  of  the  outer  medulla  was 
stimulated  by  addition  of  200  /jm  NaCl  per  ml,  this 
produced  only  a  slight  depression  of  oxygen  uptake  by 
slices  from  the  cortex  and  inner  medulla.  It  is  the 
outer  medullary  zone  that  contains  the  portion  of  the 
ascending  thick  limb  of  the  loop  of  Henle  where  the 
active  sodium  pump  appears  to  be  located,  based  on 
the   puncture   studies.    However,   evidence  of  active 


THE    RENAL    CIRCULATION 


H75 


Rinden- 
Morkzone 


cmm/mg  Tmc/tengemcM 
\Verbrautfi 


10  30  50  70 

Zeif  in  Min  uteri 


fig.  20.  Oxygen  utilization  (mm3/ 
mg  tissue  dry  weight)  in  various  zones 
of  the  guinea  pig  kidney.  [After  Grupp 
&  Hierholzer  (115).] 


sodium  reabsorption  in  the  collecting  tubules  has 
been  recently  adduced  by  microcatheterization  (140). 
This  process  probably  involves  an  ion-exchange 
mechanism  with  K  and  NH4  akin  to  that  operating 
in  the  distal  convoluted  tubule  (315). 

Heat  Production 

Grupp  et  al.  (116,  11  7)  have  calculated  that  a  dog 
kidney  of  average  weight  of"  40  g  and  an  average 
surface  of  6.0  cm2  produces  ca.  8  cal  per  min  (0.18 
cal/g/min).  Fregler  (95)  found  an  average  of  0.52 
cal  per  g  per  min  (0.29-0.78).  By  insertion  of  small 
thermistor  probes  to  varying  depths  into  the  dog 
kidney,  Ochwadt  &  Schmier  (232)  and  Grupp  & 
Janssen  (117)  were  able  to  compare  the  temperature 
difference  at  varying  depths  from  the  surface  of  the 
kidney  to  the  renal  arterial  blood.  The  distribution  of 
the  temperature  gradient  appears  in  figure  21.  Note 
the  highest  values  in  the  cortex,  a  drop  at  the  cortico- 
medullary  junction,  and  a  secondary  increase  in  the 
medulla.  Since  differential  flow  effects  could  compli- 
cate the  picture,  heat  production  was  measured  by 
Janssen  &  Grupp  (151)  in  kidneys  in  which  the  circu- 
lation was  stopped  for  1  to  3  min.  In  these,  the  cortex 
averaged  0.162  C  above  arterial  blood,  and  in  the 
medulla,  0.113  C,  confirming  the  above  trend. 

The  higher  heat  production  in  the  cortex  is  related 
to  its  higher  metabolism.  The  dip  in  the  gradient 
at  the  corticomedullary  junction  could  be  explained 
by  the  more  direct  influence  of  the  large  vessels  lying 
in  this  zone,  reflecting  systemic  temperature.  The 
temperature  gradient  correlates  only  roughly  with  that 
of  oxygen  utilization.  If  flow  in  the  medulla  is  indeed 
as  slow  as  the  measurement  of  Kramer  et  al.  (166) 
would  indicate,  heat  storage  could  be  a  factor  in  the 
relatively  higher  temperature  in  the  medulla. 

Grupp    &   Janssen    (117)    have   related    the   heat 


turnover  of  the  kidney  to  the  blood  flow  by  the  for- 
mula: turnover  (per  sec)  =  K-i/F[(0R  —  dA)/(6v  — 
9a)],  where  F  is  the  flow  (ml  min);  K  is  a  constant 
based  on  the  timing  and  the  specific  heat  of  kidney 
tissue  and  blood;  8R  is  the  temperature  within  the 
renal  tissue;  0A  is  the  temperature  in  the  renal  artery; 
and  8V  is  the  temperature  in  the  renal  vein. 

The  mean  trend  is  shown  in  figure  22.  Above  a 
flow  of  2  ml  per  g  per  min,  the  turnover  is  directly 
related  to  flow.  Below  this  value,  turnover  slows 
noticeably  and  becomes  quite  independent  of  flow. 
Environmental  factors  (conduction,  etc)  must  now 
have  a  greater  effect  than  flow  on  heat  removal. 


PRESSURE  GRADIENTS  IN  THE 
RENAL  VASCULAR  CIRCUIT 

Pressure  Gradient 

Ideal  circumstances  for  analysis  of  pressure  gradi- 
ents in  the  renal  vascular  circuit  would  require  direct 
micropuncture  of  representative  segments  of  the  ves- 
sels. The  only  mammal  in  which  this  has  been  done 
for  analysis  of  pressure  is  the  rat  (1 12,  347),  and  then 
only  in  the  peritubular  capillaries  of  the  cortical 
tubules.  Coupled  with  this  were  measurements  of 
intratubular  (proximal)  pressure.  The  results  appear 
in  table  3.  Wirz  (347)  reported  data  from  1  7  anes- 
thetized male  rats  which  were  in  excellent  agreement: 
in  proximal  tubules,  14.8  mm  Hg  (to  22);  in  5  of 
these  animals,  postglomerular  capillary  pressure  was 
17.4  ±  2.6  mm  Hg.  Using  Winton's  (343)  estimate 
that  glomerular  pressure  is  65  per  cent  of  arterial 
pressure,  the  following  gradient  probably  exists  in 
the  rat:  mean  arterial  pressure,  100  mm  Hg;  glomeru- 
lar capillary,  65  mm  Hg;  peritubular  capillary  pres- 
sure,  16  mm  Hg;  and  renal  vein  pressure,  2.0  mm 


Hg  (in). 


1476 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


0.1 


0 


Ri 

ode 

nzon  e 

Rinden-Mark- 

M 

ark 

Z  0 

n  e 

Zone 

obere 

untere 

°c 

• 

oj 

.1j 

• 

• 

o 

• 

• 
• 

o 

• 
• 

• 

• 

• 
• 

• 
• 

• 
• 

0,2 

• 
• 

• 

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• 

• 

• 

• 

m 

•• 
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• 

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* 

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Abstand  von  N/erenoberfldche 


_l_ 


8 


10 


1Z 


It 


16  mm 


fig.  21.  Zonary  temperature  gradients  in  the  dog  kidney  (ordinate:  AT  compared  to  arterial  blood; 
abscissa:  depth  from  kidney  surface  in  mm).  Rindenzone:  cortical  zone;  Rinde-Markzone:  juxta- 
medullary  zone;  obere  Markzone:  upper  medullary  zone;  untere  Markzone:  deep  medullary  zone. 
[After  Janssen  &  Grupp  (151).] 


5,0 

f,0 

3,0- 

2,0 

1,0 


\ 

E 

*-* 

1 

1 

Warme- 

-  Turnover 

in  sec 

20 


to 


60 


80 


100 


fig.  22.  Heat  turnover  in  sec  (abscissa)  related  to  renal  blood 
flow  in  ml/g/min    (ordinate).  [After  Grupp  &  Janssen  (117).] 

Swann  (342)  has  postulated,  based  in  part  on 
estimates  and  in  part  on  direct  measurement  of 
intrarenal,  arcuate  vein,  and  renal  vein  pressure, 
the  hydrostatic  pressures  which  probably  exist  in  the 
dog  kidney.  The  estimates  appear  in  figure  23.  The 
relatively  high  capillary  pressures,  compared  to  that 
of  the  rat,  may  be  due  to  the  higher  intrarenal  pres- 
sure recorded  in  the  dog,  16  to  26  mm  Hg,  compared 
to  an  average  of  10  mm  Hg  in  the  rat. 


Critical  Closure;   Yield  Pressure 

The  term  "critical  closing  pressure"  (CCP)  was 
introduced  by  Burton  (46)  in  his  analysis  of  the  physi- 
cal factors  controlling  the  equilibrium  of  small  blood 
vessels.  Critical  closing  pressure  is  defined  as  the 
arterial  pressure  in  a  local  vascular  bed  at  which 
flow  through  the  area  becomes  zero.  When  flow  is 
plotted  against  pressure,  there  is  a  positive  intercept 
on  the  pressure  axis  when  flow  is  zero.  It  has  been 
suggested  that  CCP  is  dependent  on  vasomotor  tone, 
and  hence  can  be  used  as  an  index  of  this  tone.  Its 
relation  to  intrarenal  tissue  pressures  becomes  of 
interest  in  connection  with  the  latter's  role  in  the 
phenomenon  of  autoregulation  of  renal  blood  flow. 

Measurements  of  the  so-called  CCP  for  the  kidney 

o 

have  been  made  in  cats  by  Yamada  &  Astrcim  (4, 
352),  and  in  dogs  by  Hinshaw  et  al.  (141).  The  tech- 
nique involves  perfusion  of  the  in  situ  or  isolated 
organ  by  pump  or  from  a  reservoir  at  stready  pres- 
sures. Arterial  and  venous  pressure  are  measured 
with  optical  manometers  or  electromanometers. 
Venous  outflow  is  recorded.  The  decay  gradients  of 
pressure  and  flow  are  recorded  during  brief  occlusion 
for  an  arbitrary  period  lasting 2  to  2.5  min  as  employed 

O 

by  Yamada  and  Astrom  or  until  pressures  have 
plateaued  (Hinshaw  et  al.)  and  flow  has  stopped. 
At  the  end  of  this  time,  arterial   (Pa,)  and   venous 


THE    RENAL    CIRCULATION 


•477 


fig.  23.  Estimates  of  hydrostatic  pressures  (mm  Hg)  in 
the  dog  nephron  and  associated  vasculature  [After  Swann 
(342,  discussion).] 

(PV()  pressures  are  measured,  and  the  A-V  difference 
calculated. 

In  15  experiments  on  the  kidney  (nerves  intact) 
(352),  PAf  averaged  12.0  ±  4.1  (sd)  mm  Hg,  and 
Pvt ,  5.0  ±  2.9.  The  PAf  —  Pv,  difference  was  7.0 
±  3.6  mm  Hg.  Another  series  (4)  agreed  very  closely. 
The  minimum  arterial  pressure  for  flow  (Pa,),  in 
this  situation  corresponding  to  critical  closing  pres- 
sure, was  of  the  same  order  of  magnitude  as  the 
"yield  pressure"  in  the  dog  (7-14  mm  Hg)  (120, 
258,  271,  282). 

Arterial  pressure  flow  (PA()  (preferred  to  CCP 
because  of  the  probability  of  inherently  different 
connotation)  and  PA(  —  PV|  can  be  experimentally 
varied  under  a  variety  of  circumstances.  The  values 

table  3.  Relation  Between  Intratubular  and  Peritubular 
Capillary  Pressure  in  Unmanipulated  Kidneys 


Pressure  Measured 

No.  of 
Rats 

Avg.  of  Meas- 
ured Values, 
mm  Hg 

Avg.  of  Ad- 
justed Val- 
ues*, mm  Hg 

Intratubular 

21 

13.8 

13.8 

Small  capillary 

1 1 

14.2 

14.0 

Large  capillary 

8 

20.4 

,8.7 

Unclassified  capillary 

7 

.6.7 

'5-4 

*  Adjusted  for  rat  differences  by  the  statistical  technique 
of  disproportionate  subclass  numbers  in  the  analysis  of 
variance.         [After  Gottschalk  &  Mylle   (112).] 


are  lowered  by  nerve  section  and  ganglionic  block- 
ing agents.  They  are  increased  during  the  reflex 
response  to  carotid  occlusion  and  noradrenaline 
intra-arterial  injections  and  to  cooling  (352). 

The  role  of  tissue  pressure  is  of  importance,  particu- 
larly as  influenced  by  the  renal  venous  pressure  and 
the  possibility  of  a  venous-arteriolar  reflex.  It  was 
found  that  when  pressure-time  curves  were  deter- 
mined at  venous  pressures  of  15  to  60  mm  Hg  (4), 
that  PA(  and  PVf  became  identical  in  8  of  12  cases, 
and  in  the  remaining  4  ranged  from  2  to  6  mm  higher 
than  venous  pressure  (Pv)  at  the  end  of  2  to  2.5  min 
of  occlusion. 

The  PAf  at  elevated  venous  pressure  was  never 
greater  than  the  sum  of  the  control  PAf  and  the  applied 
venous  pressure,  implying  a  lack  of  increase  in  vaso- 
motor tone  as  the  result  of  increasing  venous  pressure, 
and  arguing  against  a  venous-arteriolar  reflex. 

Identical  pressure  at  the  elevated  venous  pressure 
implies  that  the  distensible  resistance  vessels  have 
increased  their  caliber  or  in  some  manner  permitted 
the  pressure  to  equilibrate.  In  the  four  cases  with  con- 
sistently higher  PA(  an  explanation  of  "prevailing 
high  vasomotor  tone  alone  or  in  combination  with  an 
initially  high  intrarenal  pressure"  was  offered.  In 
any  event,  Astrom  believes  that  the  interstitial  pres- 
sure in  the  kidney  is  more  important  than  the  vaso- 
motor tone  as  a  determinant  of  the  PAf  and  the 
PA(  —    PVf  difference. 

Hinshaw  et  al.  (141)  related  the  apparent  CCP  to 
tissue  pressure  changes  in  dog  kidneys.  Stabilized 
values  following  clamp  of  inflow  and  after  cessation 
of  flow  were  1 . 7  mm  Hg,  for  PA  —  Pv  pressure  dif- 
ference, and  2.9  mm  Hg  for  tissue  pressure.  The 
correspondence  of  values  led  them  to  the  conclusion 
that  the  A-V  pressure  differences  were  the  result  of 
the  tissue  pressure;  the  somewhat  higher  value  for  the 
tissue  pressure  indicated  incomplete  transmission  of 
pressure  across  the  walls  of  the  vessels.  At  any  rate,  the 
manifest  CCP  could  be  accounted  for  by  the  tissue 
pressure,  they  believed.  If  so,  then  the  active  vaso- 
motor tone  would  be  negligible  in  the  kidney  under 
these  experimental  conditions.  This  conclusion  held 
for  kidneys  in  situ  (nerves  intact)  as  well  as  their 
pump-lung-kidney     preparations. 

The  conclusion  reached  by  Astrom  was  that  CCP 
in  the  kidney  in  the  sense  employed  by  Burton  need 
not  be  assumed  and  that  the  PA(  more  appropriately 
should  be  considered  as  a  yield  pressure,  that  pressure 
needed  to  start  flow  against  the  compressing  effect 
of  the  interstitial  pressure.  It  should  be  added  here 
that  the  term  "yield  pressure"  as  originally  employed 


1478 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


for  the  kidney  circulation  by  Selkurt  (271)  connoted 
an  element  of  the  viscous  properties  of  the  blood 
looked  upon  as  a  fluid  manifesting  plastic  flow. 

Intrarenal  Pressure 

Such  pressures  have  been  obtained,  with  minor 
variations  in  technique  among  various  investigators, 
by  insertion  of  small-gauge  needles  (no.  24-27)  into 
the  renal  substance  to  varying  depths,  introduction 
of  small  volumes  of  saline  (0.1-1.0  mm3)  through 
the  needle  tip,  and  reading  the  stabilized  pressure 
with  low  volume-displacement  manometers.  What 
this  pressure  represents  is  debatable  and  probably 
cannot  be  interpreted  as  interstitial  pressure  in  the 
classical  sense.  De  Langen  (71)  has  reviewed  the 
vagaries  of  renal  interstitial  pressure  measurement. 
The  small  pool  of  fluid  immediately  surrounding  the 
tip  of  the  needle  probably  represents  pressure  from 
damaged  blood  vessels,  tubules,  glomeruli,  and  lym- 
phatics. Since  it  best  reflects  changes  in  venous  pres- 
sure, it  would  appear  that  these  vessels  are  the  usual 
sites  of  entry.  Swann  et  al.  (302)  have  shown  that 
intrarenal  pressure  and  arcuate  vein  pressure  are 
equal  (coefficient  of  correlation  0.85)  in  a  range  of 
intrarenal  pressures  of  6  to  73  mm  Hg. 

Although  in  the  strictest  sense  this  should  perhaps 
only  be  called  "needle"  pressure,  a  designation  pre- 
ferred by  Winton  (343),  Gottschalk  (in,  112)  has 
chosen  to  call  it  interstitial  pressure.  Others  have 
designated  it  as  "intrarenal  pressure"  (IRP),  a  term 
preferred  here  in  the  belief  that  it  reflects  directly  or 
indirectly  renal  interstitial  pressure  as  a  part  of  the 
integrated  pressure  which  is  recorded  by  the  needle- 
puncture  technique.  Renal  interstitial  pressure  has 
been  considered  to  be  the  resultant  of  a  number  of 
component  factors:  a)  intravascular  pressure  and 
volume,  b)  glomerular  filtrate  and  urine  volume,  c) 
external  renal  capsule  elasticity,  d)  Bowman's  capsule 
volume  and  elasticity,  and  e)  stroma  rigidity. 

Winton  (340-342)  has  employed  an  indirect  method 
to  measure  intrarenal  pressure,  which  he  has  defined 
as  a  pressure  exerted  in  all  directions  throughout  the 
substance  of  the  organ,  tending  to  obliterate  collapsi- 

table  4.  Intrarenal  Pressure  (mm  Hg)  in  Dog  Kidney 


Xo.  of 

Mean 

Range 

Animal: 

Montgomery  et  al.  (215) 

26 

IO-58 

42 

Swann  et  al.   (300) 

25 

■°-59 

I  I 

Gottschalk  (1 11) 

16 

12-25 

8 

Miles  &  DeVVardener  (206) 

21 

8-35 

'5 

Winton  (343) 

21 

"-45 

23 

ble  structures  such  as  peripheral  parts  of  tubules  and 
venules.  In  isolated  dog  kidneys,  intrarenal  pressure 
was  taken  to  approximate  ureteral  pressure  when  the 
latter  was  elevated  to  a  degree  which  caused  a  de- 
crease in  urine  flow. 

Needle  pressures  for  the  dog  kidney  are  summarized 
in  table  4. 

Gottschalk  found  the  IRP  somewhat  lower  in 
smaller  animals  (rats,  guinea  pigs,  rabbits,  and  cats), 
averaging  10  mm  Hg  (4-19)  in  65  animals,  a  value 
equal  to  that  found  in  dogs  by  Winton  when  he 
employed  his  indirect  method  (340). 

FACTORS  WHICH  MODIFY  INTRARENAL  PRESSURE.  Relation 

between  venous  pressure  and  IRP.  When  venous  pressure 
was  raised  by  graded  compression  of  the  renal  vein  in 
12  rats,  rabbits,  and  dogs,  the  IRP  was  not  affected 
until  venous  pressure  approached  the  pre-existing 
intrarenal  pressure,  which  then  began  to  rise  (111). 
At  renal  venous  pressures  above  20  mm  Hg,  IRP 
followed  venous  pressure  very  closely  and  was  at  most 
1  or  2  mm  Hg  more  than  venous  pressure  through  a 
range  exceeding  100  mm  Hg.  The  results  of  Swann 
et  al.  (300)  in  the  dog  were  very  comparable,  except 
that  IRP  started  at  a  higher  control  value  (25  mm 
Hg). 

Relation  of  ureteral  pressure  and  intrarenal  pressure. 
Increased  ureteral  pressure  probably  increases  IRP 
by  compressing  the  intrarenal  veins  (111).  In  12 
rabbits  and  dogs  elevating  the  ureteral  pressure  to  15 
and  30  mm  Hg  raised  the  IRP  from  a  control  average 
of  10  mm  Hg  to  averages  of  14  and  19  mm  Hg, 
respectively.  Elevating  ureteral  pressure  to  50  mm 
Hg  increased  IRP  from  a  control  value  of  8  to  2 1  mm 
Hg  in  11  rabbits  and  from  12  to  27  mm  Hg  in  4 
dogs.  Ureteral  pressure  is  about  half  as  effective  as 
venous  pressure  in  elevating  IRP. 

Arterial  pressure  influence  on  intrarenal  pressure.  Results 
of  different  investigators  are  quite  discordant.  Winton 
(341)  in  a  range  of  80  to  100  mm  Hg  found  no  con- 
sistent change  in  IRP  by  the  indirect  method.  The 
other  workers  used  needle  punctures.  Gottschalk 
(111)  observed  no  effect  until  mean  arterial  pressure 
was  reduced  below  40  mm  Hg,  when  IRP  fell 
abruptly.  Miles  &  DeWardener  (206)  found  that  as 
mean  arterial  pressure  was  decreased  from  1 20  to  20 
mm  Hg  in  dogs  by  clamping  the  aorta,  IRP  fell  from 
27  to  10  mm  Hg.  Hinshaw  et  al.  (143-145)  also  found 
IRP  varied  with  arterial  pressure  in  the  zone  of 
autoregulation.  Swann  et  al.  (301)  found  the  best 
correlation;  a  plot  of  IRP  against  arterial  pressure 
exhibited   a   coefficient   of  correlation   of  0.85,   and 


THE    RENAL    CIRCULATION 


1479 


showed  that  IRP  was  related  to  mean  arterial  pres- 
sure (PA)  as  follows:  IRP  =  g.4  +  .22  PA  .  Thus, 
when  arterial  pressure  increased  1  mm  Hg,  IRP 
increased  0.22  mm  Hg. 

Other  factors:  a)  location  of  needle  tip.  Gottschalk 
compared  needle  pressure  in  the  cortex  versus  the 
medulla.  In  rats  and  rabbits  there  was  no  significant 
difference.  In  dogs,  repeated  determinations  were 
more  variable,  but  there  were  no  consistent  differ- 
ences in  deep  and  superficial  measurements.  VVinton 
(343)  has  recorded  a  much  higher  IRP  in  the  medulla 
than  in  the  cortex  (fig.  24).  This  may  have  particular 
significance  in  interpretation  of  the  countercurrent 
system  (vide  infra). 

b)  Decapsulation.  Miles  &  DeWardener  (206)  found 
no  difference  in  IRP  as  the  result  of  decapsulation. 
Nor  did  differences  appear  as  IRP  was  increased  by 
osmotic  diuresis  (mannitol),  elevation  of  venous  pres- 
sure, and  increase  in  perfusion  pressure  after  KCN 
elimination  of  renal  circulatory  autonomy.  VVinton 
and  Swann  reported  a  reduction  of  IRP  to  about  one- 
half  as  the  result  of  decapsulation  (342).  Although  the 
latter  results  seem  most  logical,  the  former  investiga- 
tors emphasize  the  necessity  of  care  in  handling  to 
avoid  decreases  in  IRP  due  to  vasoconstriction,  and 
the  need  for  an  adequate  recovery  period  before 
measurements  are  made.  The  significance  of  the 
change  of  IRP  with  decapsulation  will  be  considered 
further  below  in  relation  to  the  problem  of  renal 
circulatorv    autonomv. 


"1 


40 


NEEDLEX^0* 
PRESSURE 
mm  Hg 


**?£-■ 


URETER  PRESSURE   ram  H9 


O  S  IO  15  20  25  30         35 

fig.  24.  Needle  pressures  in  medulla  and  cortex  of  the  dog 
kidney  related  to  ureter  pressure.  The  straight  diagonal  line 
represents  perfect  correlation.  [After  VVinton  (343).] 


Intrarenal  pressure  and  the  countercurrent  system.  Reduc- 
tion in  urine  volume  and  electrolyte  output  of  the 
kidney  as  the  result  of  increase  in  venous  and  ureteral 
pressure  are  well-known  phenomena  (127,  273,  277, 
279).  Increases  in  intrarenal  pressure  could  favor 
reduction  in  urine  volume  in  several  ways:  pressure 
on  the  collecting  ducts  would  slow  movement  of  urine 
in  this  segment  and  favor  removal  of  water  molecules 
to  the  zone  of  hyperosmolarity,  operationally  domi- 
nated by  ADH.  Secondly,  compression  of  the  vasa 
recta  would  slow  the  flow  of  blood  and  favor  uptake 
of  water  into  the  hyperoncotic  zone.  Finally,  a  high 
interstitial  pressure  could  favor  inward  flow.  If  the 
observation  of  Winton  (fig.  24)  that  IRP  is  higher 
in  the  medulla  than  in  the  cortex  can  be  confirmed, 
particularly  specific  and  effective  mechanism  would 
exist. 

The  mechanism  underlying  decreased  excretion  of 
electrolytes  is  more  complex,  involving  among  other 
factors  alterations  in  load  offered  to  the  tubules  re- 
sulting from  changes  in  filtration  rate  brought  about 
by  venous  and  ureteral  pressure  elevation  (127,  273, 
277.  279)- 


MEASUREMENT  OF  RENAL  BLOOD   FLOW 

Methods 

Both  direct  and  indirect  methods  have  been  em- 
ployed. Direct  methods  employ  flowmeters  of  various 
types  which  record  either  arterial  inflow  or  venous 
outflow.  These  include  the  following:  thermostroh- 
muhr  or  direct-recording  strohmuhr  (Ludwig  type); 
rotameter;  bubble  flowmeter;  electromagnetic  flow- 
meter; direct  venous  outflow  (cylinder  and  stop- 
watch). The  indirect  methods  are  an  application  of 
the  renal  clearance  principle.  This  is  based  on  the 
clearance  (C)  ratio:  C  =  11'  P,  in  which  U  is  the 
urinary  concentration  in  mg  per  ml.,  V  is  the  minute 
urine  volume,  and  P  is  the  plasma  concentration 
(usually  systemic  vein)  in  mg  per  ml.  [For  method- 
ology, including  the  use  of  clearance  techniques,  see 
(272,  288).] 

The  plasma  clearance  of  inulin  (Clu)  has  been 
universally  proved  to  be  solely  by  glomerular  filtra- 
tion. In  dog  and  other  mammals  (except  anthropoids) 
the  clearance  of  creatinine  (CCr)  is  also  a  measure  of 
filtration    rate. 

The  requisite  for  the  clearance  of  a  substance  to 
measure  plasma  flow  is  that  it  be  entirely  removed 
(or  nearly  so)  from  the  plasma  in  one  transit  through 


[480 


HANDBOOK    O  I-     1'HYSIOLOGY 


CIRCULATION    II 


the  kidney.  This  is  verified  by  examination  of  the 
concentration  in  the  renal  vein  (I,).  Such  can  be 
related  to  the  renal  arterial  plasma  concentration 
1  1)  as  the  extraction  ratio  E:  E  =  (Ac  —  Vc)/Ac. 
Hence,  if  Vc  =  o,  E  will  equal  1 .0.  E  is  less  than  unity 
to  the  extent  that  the  material  is  not  removed  by 
urinary  excretion.  It  is  clear  that  if  the  clearance  is 
divided  by  the  extraction  ratio  (C/E),  the  resultant 
quotient  will  yield  the  total  renal  plasma  flow  (RPF). 

UV 


RPF 


Ac-Vc 


This  formula  is  an  expression  of  the  Fick  principle, 
for  if  P  be  taken  as  Ac  (systemic  venous  plasma  con- 
centration equal  to  renal  arterial  plasma  concentra- 
tion), we  have: 

UV 


RPF' 


Ac 


UV 


Ac~vc 


% 


table  5.  Renal  Extraction 

of  Dwdrast  and  PAH 

Investigators 

Animal 

Mean 

Range 

/. 

Diodrast 

White  (338) 

Dog 

O.74 

O.61-O.85 

Corcoran  el  at.  (59) 

Dog 

O.84 

O.79-O.96 

Hemingway  &  Schweitzer 

Dog 

o-73 

O.62-0.87 

(■37) 

Study  &  Shipley  (298) 

Dog 

0.74 

O.66-0.81 

Kinter  &  Pappenheimer 

Cat 

°-73 

O.63-O.92 

(160) 

Josephson  et  at.   (152) 

Man 

°-73 

O.70-O.79 

Bergstrom  et  al.  (16) 

Man 

0.74 

0.58-O.86 

h 

'.  PAH 

Selkurt  (269) 

Dog 

0.74 

O.64-O.94 

Phillips  et  al.   (247) 

Dog 

0.87 

O.83-O.91 

Thompson  et  al.  (305) 

Dog 

o-75 

O.51-O.90 

Ascheim  et  al.  (3) 

Dog 

0.82 

O.75-O.90 

Kinter  &  Pappenheimer 

Cat 

0.85 

0.78-0.93 

(160) 

Warren  et  al.  (327) 

Man 

0.90 

0.85-1 .00 

Bradley  &  Bradley  (32) 

Man 

°-93 

O.90-O .94 

Cargill  (49) 

Man 

0.90 

O.83-O.93 

Maxwell  et  al.  (198) 

Man 

0.92 

O.88-O.97 

Josephson  el  al.  (153) 

Man 

0.89 

O.85-O.92 

Bergstrom  et  al.  (16) 

Man 

0.90 

O.88-O.93 

In  order  to  obtain  total  renal  blood  flow,  the  hemato- 
crit  measurement  of  the  blood  is  introduced : 


RBF= 


E ( l-hemot  ) 


or 


UV 


(Ac-Vc)  < l-hemat) 


Several  substances  are  so  efficiently  removed  by 
combined  processes  of  glomerular  filtration  and  active 
tubular  (proximal)  transport  (secretion)  at  low  plasma 
concentrations,  that  the  renal  vein  concentration  is 
very  low  (i.e.,  extraction  nearly  complete,  and  E 
close  to  unity).  These  include  Diodrast  (D)  and/>-ami- 
nohippurate  (PAH)  (287,  288).  Then  CD  or  CPAh  is 
nearly  equivalent  to  plasma  flow.  The  fact  that  ex- 
traction is  not  complete  is  interpreted  as  indicating 
that  a  small  fraction  of  blood  does  not  perfuse  ex- 
cretory tissue:  this  would  include  capsule  and  inert 
supportive  tissue,  medullary  tissue  (loops  of  Henle, 
collecting  ducts),  calycine  mucosa,  and  pelvis.  On 
this  basis,  Smith  has  referred  to  this  as  the  "effective" 
plasma  or  blood  flow. 

A  considerable  amount  of  study  has  been  made  of 
the  extraction  ratios  of  Diodrast  and  PAH.  A  repre- 
sentative group  of  findings  is  shown  in  table  5. 

Although  ED  and  £pAH  seem  comparable  in  the 
dog,  £PAH  is  more  efficient  in  man  than  ED  .  This  was 
particularly  the  experience  of  Bergstrom  et  al.  (16) 
who  made  simultaneous  comparisons  (EPAB  =  0.90; 
Ely  =  0.74).  Differences  in  kinetics  of  erythrocyte  to 
plasma  shift  for  PAH  ma\    lie  involved,  and    this  is 


probably  less  important  for  man  than  the  dog.  A 
factor  to  be  considered  is  that  the  animal  work  has 
done  largely  under  anesthesia,  while  the  human  sub- 
jects were  unanesthetized. 

The  Fick  principle  can  be  employed  with  any  sub- 
stance cleared  by  the  kidney  which  shows  a  measura- 
ble A-V  difference.  Obviously,  the  smaller  the  A-V 
difference,  the  more  prone  to  error  the  calculation 
will  be.  Thus,  phenol  red,  urea,  mannitol,  and  inulin 
have  been  employed,  but  have  considerably  smaller 
A-V  differences  than  Diodrast  and  PAH. 

the  nitrous  oxide  method.  This  is  an  adaptation  of 
the  method  employed  for  the  measurement  of  cerebral 
blood  flow  and  involves  inhalation  by  the  subject  of 
nitrous  oxide,  and  uptake  from  the  blood  by  the 
kidney.  The  Fick  principle  is  employed  (58,  68). 


N20 


100V,  ,-. 
f'(A* 


VJdt 


RBFS„0  is  the  blood  flow  per  100  g  kidney  tissue 
per  minute  as  measured  by  N20  uptake;  VcV-S  is 
the  kidney  uptake  of  N20  per  g  tissue  during  the  time 
from  O  to  /'  (time  of  blood-tissue  equilibrium);  and 
Ac  and  Vc  are  arterial  and  renal  venous  concentra- 
tions, respectively,  which  finally  become  equal  at 
time  I'.  S  is  the  partition  coefficient  between  blood 
and  tissue  (assumed  to  be  unity  in  this  instance). 


1  III-:     RENAL    CIRCULATION 


I481 


The  method  yields  an  average  of  3.2  ml  per  min 
per  g  kidney  weight  in  anesthetized  dogs  (58)  and  in 
man  (68).  Comparison  of  this  method  with  a  direct 
method  ( bubble  flowmeter)  in  the  do?  under  various 
physiological  conditions  shows  that  the  two  yield 
flow  values  which  are  not  significantly  different  (58). 
An  obvious  advantage  is  that  the  nitrous  oxide  method 
can  be  employed  during  conditions  of  anuria.  A 
similar  application  using  radioactive  krypton  (Kr85) 
has  been  employed  during  anuria  (40). 

Critique  of  the  Clearance  .Method 

CRITERIA  FOR  APPLICATION  OF  CLEARANCE.  Some  of  the 

criteria  which  must  be  met  in  order  for  the  clearance 
of  a  substance  such  as  Diodrast  or  PAH  to  measure 
accurately  renal  plasma  flow  are:  a)  change  of  volume 
of  blood  in  passage  is  negligible  (i.e.,  urine  and  lymph 
flow  not  excessive),  b)  concentration  of  substance  in 
blood  is  constant,  or  the  rate  of  change  of  concentra- 
tion is  uniform  for  midpoint  collection,  <)  rate  of 
urine  flow  should  be  sufficiently  large  and  constant 
so  that  it  may  be  representative  of  the  urine  in  the 
nephrons,  d)  the  substance  should  not  be  formed  or 
altered  in  the  kidney,  e)  all  blood  in  the  renal  vein 
should  pass  through  the  kidney  (and  not  enter  via 
shunts). 

FACTORS    WHICH    MIGHT    INVALIDATE    THE    CLEARANCE 

method,  a)  Oliguria  or  marked  fluctuations  in  urine 
flow  such  as  might  accompany  rapid  changes  in  blood 
pressure.  If  there  is  stagnation,  or  rapid  fluctuation 
of  the  urine  flow  in  the  nephrons,  the  collected  sample 
will  not  reflect  the  true  excretion,  and  the  midpoint 
plasma  sample  will  lack  validity.  b)  Rapid  changes  in 
plasma  concentration,  preventing  establishment  of 
equilibrium  among  blood,  interstitial  fluid,  tubular 
cells,  and  tubular  urine,  c)  Renal  storage  of  substance 
in  tubular  cells  or  interstitial  fluid,  d)  Storage  of  sub- 
stance in  the  erythrocytes  in  excess  of  the  plasma 
concentration,  so  that  its  simple  outward  diffusion 
through  the  plasma  adds  appreciably  to  the  amount 
actually  carried  by  the  plasma  leading  to  an  errone- 
ous plasma  flow  figure,  e)  Impairment  of  the  PAH 
tubular  transfer  mechanism,  leading  to  an  erroneously 
low  plasma  flow  figure. 

ADEQUACY  OF  Cd  AND  CPAH  AS  MEASUREMENT  OF  RENAL 

plasma  flow.  Under  stabilized  conditions  that  fulfill 
the  criteria  explained  previously,  good  correspond- 
ence of  clearance  to  direct  methods  is  obtained. 
Selkurt  (269)  found  that  BFPAH  averaged  91  per  cent 


of  the  simultaneously  measured  direct  blood  flow 
(venous  outflow  method).  The  difference  was  at- 
tributable to  incomplete  extraction  of  PAH.  Conn 
&  Markley  (57)  compared  renal  blood  flow  in  anes- 
thetized dogs  as  measured  indirectly  by  the  Fick 
principle  (PAH  clearance)  to  blood  flow  measured 
directly  by  bubble  flowmeter.  The  ratio  of  indirect 
to  direct  values  averaged  1.025.  Employment  of  the 
Fick  principle  corrects  for  incomplete  extraction  and 
yields  total  blood  flow.  Schwalb  et  al.  (268)  made  a 
similar  comparison  and  found  a  ratio  ot  1.06  ± 
0.17.  But  after  the  kidney  was  poisoned  with  Na 
fluoride,  the  agreement  did  not  hold.  Then  flow 
measured  by  the  bubble  flowmeter  was  often  much 
higher  than  that  measured  by  PAH  clearance.  Since 
the  use  of  the  Fick  method  should  correct  for  incom- 
plete extraction  due  to  impairment  of  the  PAH  secre- 
tory mechanism,  the  authors  believed  that  PAH  was 
stored  in  the  kidney  (possibly  in  the  tubular  cells) 
so  that  excretion  (I'V)  was  low,  relative  to  the  ap- 
parent removal. 

Reubi  et  al.  (255)  compared  simultaneous  Fick 
plasma  flows  for  PAH,  mannitol,  endogenous  creati- 
nine, and  thiosulfate.  For  example,  the  ratio  between 
Cpah ;'£pAH  and  CM/EM  varied  between  1 .54  and 
0.645.  Disparities  were  further  exaggerated  by  in- 
jection of  epinephrine  and  histamine  causing  rapid 
transients  in  blood  pressure  and  urine  flow.  Suggested 
causes  for  the  discrepancies  were:  differences  in  the 
extraction  and  blood  flow  in  separate  kidneys;  intra- 
renal  extraction;  conjugation  or  breakdown  of  PAH, 
mannitol,  creatinine,  and  thiosulfate;  removal  of  part 
of  the  substances  from  the  kidney  through  lymphatic 
vessels,  thus  bypassing  the  renal  vein;  changes  in 
the  permeability  of  the  red  cells  to  the  test  substances; 
or,  finally  analytical  difficulties.  Balint  &  Fekete  (8) 
found  great  disparities  between  direct  blood  flow  and 
the  Fick  method  (C'pah,  £pah)  in  hemorrhagic  hypo- 
tension, hemorrhagic  shock,  and  shock  from  pyloric 
obstruction  in  dogs.  The  indirect  method  was  always 
lower  by  varying  degrees  than  the  direct  method. 

Since  errors  are  compounded  by  the  analysis  of 
Reubi  et  al.,  it  would  be  more  desirable  to  compare  the 
indirect  methods  against  a  direct  method  in  tests  for 
fidelity  under  experimental  conditions.  Under  cir- 
cumstances of  rapidly  changing  blood  flow  resulting 
from  nerve  stimulation  or  action  of  vasoactive  drugs, 
as  has  been  suggested,  the  clearance  method  may  not 
accurately  follow  direct  flow.  Study  &  Shipley  (298) 
found  excellent  agreement  between  the  Fick  method 
(Diodrast)  and  direct  flow  (rotameter  in  renal  vein) 
during  control  conditions.  During  stimulation  of  the 


[  (,'lj 


HANDBOOK    OP     II I  YSIOI.OGY 


CIRCULATION     II 


renal  nerves,  resulting  in  a  53  per  cent  reduction  in 
direct  flow,  the  calculated  RBF  was  from  1  to  70 
per  cent  of  the  true  values  because  of  reduction  in 
mine  How  and  incomplete  excretion  (UV).  All  calcu- 
lated flows  exceeded  the  direct  flows  on  cessation  of 
stimulation  as  stored  urine  was  washed  out.  They 
emphasized  the  need  to  correct  for  possible  shifts  of 
Diodrast  (or  PAH)  from  erythrocytes  to  plasma  during 
the  venous  sampling.  To  the  extent  that  this  occurs, 
the  Eu  or  £PAH  will  be  vitiated,  and  the  Fick  applica- 
tion inaccurate.  Phillips  et  al.  (247)  have  given  meth- 
ods for  correction  of  PAH  shift.  Whole  blood  extrac- 
tion eliminates  errors  incurred  by  the  shift  from  cells 
to  plasma,  and  Bergstrom  et  al.  (16)  have  found 
the  use  of  radioactive  Diodrast  (containing  I131) 
particularly  helpful  in  this  respect.  The  possibility  has 
been  examined  that  opening  of  vascular  shunts  not 
perfusing  excretory  tissue  might  occur  following  nerve 
stimulation  or  drug  action  and  invalidate  the  clear- 
ances. Epinephrine  (0.1  /xg)  in  rabbits  caused  the 
£PAH  to  fall  to  negative  values  in  seven  of  nine  cases 
[average  for  the  seven,  —  26.6  c1  (214)].  This  was 
restored  in  10  to  40  min.  The  negative  values  have 
been  explained  by  a  return  to  the  venous  outflow 
of  stored  PAH  (interstitial  fluid  of  papillary  zone?). 
Injections  of  Thorotrast  in  these  pictured  the  possi- 
bility of  juxtamedullary  shunting  of  blood.  Ephedrine 
produced  a  similar  picture  in  cats  [India  ink  injection 
(189)],  but  Lofgren  points  out  that  the  picture  of 
cortical  ischemia  and  medullary  filling  could  result 
from  congestion  of  the  vasa  recta  following  contrac- 
tion of  venous  effluent  constrictors,  rather  than  from 
opening  of  a  bypass  and  increased  flow.  Mover  et  al. 
(222)  employed  sciatic  stimulation  and  epinephrine 
in  dogs  and  rabbits.  With  sciatic  stimulation,  blood 
flow  decreased  ca.  36  per  cent,  but  renal  venous  blood 
never  became  arterialized,  as  the  original  Trueta 
shunt  operation  would  demand.  In  fact,  the  A-V  oxy- 
gen difference  actually  increased.  India  ink  distributed 
fairly  equally  throughout  cortex  and  medulla  after 
nerve  stimulation.  The  rabbit  kidney  after  epineph- 
rine, however,  appeared  to  confirm  the  appearance 
of  cortical  ischemia  and  subcortical  injection.  But  the 
latter  does  not  necessarily  mean  increased  medullary 
flow.  Epinephrine  and  histamine  caused  a  maximum 
decrease  of  E,,XH  of  only  1  1 .4  per  cent  in  the  human 
kidney  (254). 

In  an  interesting  experiment  Cargill  (48)  infused 
human  serum  albumin  into  patients.  EPAH  invariably 
decreased  significantly,  even  as  CPAH  increased. 
C\n  rose  proportionally  to  (.',.  ul  ,  so  that  the  filtered 


fraction  remained  constant.  These  results  could  readily 
be  explained  by  increased  shunting  of  blood  through 
the  medullary  vasa  recta  system. 

EXTRACTION     RATIO     AS    A     TEST    OF    VALIDITY     OF    THE 

clearance  method.  The  extraction  ratio  has  been 
one  of  the  measurements  which  yields  insight  into 
the  efficacy  of  the  tubular  transfer  process  or  the 
adequacy  of  tubular  vascular  perfusion.  It  is  reduced 
during  shunting  of  blood  away  from  the  tubular 
secretory  sites,  or  as  the  result  of  actual  impairment 
of  the  transport  mechanism.  Some  of  the  physiological 
and  pathological  conditions  in  which  renal  extraction 
has  been  evaluated  follow. 

£pAH  is  not  reduced  by  abdominal  compression 
which  elevates  control  venous  pressure  from  ca.  6  mm 
Hg  to  18  mm  Hg  (32).  This  lack  of  effect  on  £PAH 
may  be  due  to  the  probability  that  transmural  renal 
venous  pressure  would  not  be  changed  by  this  maneu- 
ver (329).  Werko  et  al.  (334)  found  no  change  in 
£PAH  during  the  renal  ischemia  induced  by  tilting. 
£PAH  may  be  normal  or  only  slightly  impaired  in 
essential  hypertension.  A  series  examined  by  Reubi 
&  Schroeder  (254)  averaged  0.84,  including  one  of 
69.8.  CargilPs  (49)  series  of  hypertensive  patients 
including  those  with  nephrosclerosis  averaged  0.79 
(0.58-0.91).  The  lowered  values  are  associated  with 
reduction  of  CHAH  below  300  ml  per  min.  In  anemia, 
there  is  only  a  slight  decrease  of  the  ratio  (256,  305). 
In  nine  observations  on  subjects  with  no  renal  pathol- 
ogy but  in  congestive  heart  failure,  Merrill  (202) 
found  only  two  below  0.85  (0.64,  0.63);  Edelman 
et  al.  (78)  reported  an  average  of  0.90  (0.88-0.91) 
in  ten  congestive  heart  failure  subjects. 

In  nephritis  there  may  be  considerable  reduction 
in  the  extraction  ratio.  Bradley  et  al.  (33)  obtained 
values  for  £PAH  ranging  from  0.58  to  0.76  in  six  sub- 
jects with  chronic  glomerulonephritis.  It  may  be 
supposed  that  in  the  course  of  disorganization  of  the 
renal  vascular  pattern,  channels  are  established  in 
which  blood  flows  from  the  artery  to  vein  without 
exposure  to  functional  tubular  tissue  (abnormal  shunts 
or  destroyed  excretory  tissue).  Marked  reduction  in 
£PAH  (as  low  as  0.034  and  0.106)  was  noted  with 
tubular  damage  resulting  from  carbon  tetrachloride 
poisoning  (284).  £PAH  decreased  during  acidemia 
which  developed  during  the  apnea  of  diffusion  respira- 
tion in  dogs  (27).  The  control  EPAH  of  0.86  at  pH 
7.4  decreased  to  0.53  at  7.05. 

Renal  ischemia  and  anoxic  damage  resulting  from 
hemorrhagic   shock  will   impair  extraction.   Twenty 


THE    RENAL    CIRCULATION 


1483 


minutes  of  renal  ischemia  in  dogs  resulted  in  a  reduc- 
tion in  £pAH  from  0.74  to  0.59  (269).  Control  flow 
(Cpah)  which  gave  91  per  cent  of  the  simultaneous 
direct  blood  flow  measurement  decreased  to  30 
per  cent  of  the  direct  flow  as  a  consequence  of  ische- 
mia. Recovery  occurred  in  85  min.  After  2  hours  of 
ischemia  (246),  £pAH  (control,  0.90-0.94)  was  reduced 
to  0.1 1   to  0.43. 

Phillips  et  al.  (247)  found  adequate  extraction  of 
PAH  until  renal  plasma  flow  was  reduced  below  7 
ml  per  min  during  hemorrhagic  hypotension  and 
then  clearances  no  longer  reflected  plasma  flow 
accurately.  Corcoran  &  Page  (62)  stated  that  CD  did 
not  have  value  as  a  measure  of  plasma  flow  during 
severe,  prolonged  hypotension,  nor  immediately 
after  restoration  of  blood  pressure  by  transfusion. 
Diodrast  clearance  fell  progressively  on  repeated 
hemorrhage  and  transfusion,  until  in  some  instances 
negative  extraction  values  were  obtained  (as  low   as 

—  1 .59  compared  to  control  of  0.757).  C*n  transfusion, 
an  "over-shooting"  of  clearances  beyond  the  control 
was  observed  during  the  early  stages  as  a  result  ot 
washing  out  of  material  accumulated  in  the  interstitial 
fluid  and  stagnant  urine  during  hypotension.  Selkurt 
(270)  compared  CPAH  with  a  direct  blood  flow  method 
in  dogs  during  hemorrhagic  hypotension  and  shock. 
/;-Aminohippurate  clearance  virtually  ceased  during 
hypotension  (60-40  mm  Hg)  as  direct  flow  fell  to  1  1 
per  cent  of  control.  On  transfusion,  although  direct 
flow  was  rapidly  restored  to  near  control,  blood  flow 
calculated  from  CPAH  averaged  only  39  per  cent  of 
direct  flow,  as  the  result  of  anoxic  tubular  impairment. 
£PAH  during  hypotension  was  low  and  variable  with 
numerous  negative  extraction  values  (range,  —0.750 
to  0.543  during  a  90  min  period  at  60  mm  Hg,  and 

—  1.50-0.285  during  45  min  at  40  mm  Hg).  After 
transfusion,  £VAH  partially  recovered,  averaging 
0.406  (0.03-0.69)  compared  to  the  control  of  0.73. 
Clearly  the  hypotensive  anoxia  had  invalidated  the 
CpAH  clearance  as  a  measure  of  plasma  flow  probably 
because  of  consequent   tubular  damage. 

The  negative  extraction  during  hypotension  has 
been  explained  as  the  result  either  of  back  diffusion  of 
PAH  from  the  lumina  of  damaged  nephrons  into 
venous  blood  (270),  or  of  absorption  into  the  renal 
venous  blood  of  PAH  accumulated  during  the  period 
of  hypotension  and  impaired  urinary  excretion  (62). 
Again,  this  may  be  PAH  concentrated  in  the  vasa 
recta  and  interstitial  fluid  in  proximity  (counter- 
current  mechanism),  and  will  thus  imply  continued, 


table  6.  Clearance  Data  in  Mammals  and 

Renal  Blood  Flow  in  Dog 


Per  g  K\V 
ml  min 


Ci„ 


CpAH 


Per  kg  Body  Wt 
ml,  m  in 


Cln  Cpah 


Per  i.7)  m- 
BSA  ml  min 


Cln       CpAH 


A.    Clearance  Data  in  Mammals* 


Rat 

o-75 

2-75 

6.00 

22.0 

7° 

253 

Rabbit 

0.66 

2.50 

3.12 

18.2 

87 

5' 2 

Dog 

0.62 

1. 91 

4.29 

■3-5 

146 

460 

Man 

0.46 

2 -33 

'■97 

10. 0 

118 

600 

B.    Renal  Blond  Flow  in  Dog\ 

RPP        RBF 

RPF 

RBF 

RPF 

RBF 

Unanesthetizedf 
Anesthetized§ 

2.08 
1.89 

3.80 
3-4° 

■2-5 
13.0 

22.7 
23-4 

463 

845 

K.W  =  kidney  weight,  BSA  =  body  surface  area. 
*  [From  Smith    (287).]  f  (From    Handbook    of   Circulation, 

WADC  Tech.  Rpt.  59-593,  '959)  X  220  Observations; 
direct  venous  outflow;  urea,  phenol  red,  and  PAH  extrac- 
tion. §58  observations;  (pentobarbital  and  chloralose) : 
direct   venous   outflow,   rotameter,    and   bubble   flowmeter. 

but  reduced,  perfusion  of  the  medullary  zone,  with 
cortical    ischemia. 

Renal  Blood  Flow  Values 

Data  have  been  culled  from  two  important  sources 
in  the  summary  presented  in  table  6.  It  will  be  noted 
that  the  dog  appears  to  have  the  lowest  CPAh  per 
gram  kidney  weight.  The  rat's  value  for  CPAh  is  least 
per  1 .73  m-  body  surface  area,  increasing  progressively 
in  the  series  to  the  value  in  man.  The  dog  has  the 
highest  filtration  rate  (CIn)  relative  to  the  effective 
plasma  flow  (C'pah),  giving  a  filtration  fraction  (FF)  of 
0.32.  In  man  this  is  0.20. 

In  summary,  as  Smith  has  repreatedly  stressed,  the 
clearance  methods  yield  adequate  information  on 
renal  hemodynamics  only  under  conditions  of  relative 
stability  of  flow.  They  cannot  accurately  follow  rapid 
changes  of  blood  flow,  and  changes  in  pathological 
states  (e.g.,  shock  kidney)  seriously  handicap  their 
utility. 


EXTRINSIC   REGULATION   OF  RENAL  BLOOD    FLOW 

A  eurogenic  Control 

The  thoracolumbar  sympathetic  supply  is  a  rich 
source  of  vasoconstrictor  fibers  for  the  kidneys.  The 


1484 


HANDBOOK    OF    PHYSIOLOGY 


ClkCILATION    II 


vagus  apparently  contains  no  vasomotor  fibers  to  the 
kidney,  and  no  evidence  exists  for  vasodilator  fibers 
in  this  circuit.  Hence,  the  vasomotor  status  of  the 
kidney  is  maintained  by  variations  in  vasoconstrictor 
tone. 

the  question  of  renal  autonomy.  Considerable 
controversy  has  revolved  around  the  question  of 
whether  or  not  a  continued  flow  of  impulses  passes 
to  the  arterioles,  or  whether  such  regulation  is  absent 
in  the  basal  state,  to  be  invoked  only  in  emergency 
states  of  heightened  sympathetic  nervous  system 
activity.  Early  investigators,  working  in  anesthetized 
animals,  appeared  to  demonstrate  a  "denervation 
hyperemia."  In  view  of  the  fact  that  ample  evidence 
exists  that  morphine,  ether,  chloroform,  urethane,  and 
pentobarbital  anesthesia  depress  renal  blood  flow 
to  varying  degrees,  probably  due  to  enhanced  activity 
of  the  sympathetic  system  and  adrenal  medulla,  it  is 
understandable  that  removal  of  the  neurogenic  source 
of  renal  vasoconstrictor  activity  would  result  in  a 
relative  hyperemia,  e.g.,  with  unilateral  denervation. 
Earlier  work  in  this  area  has  been  reviewed  by  Smith 
(287)  and  Carstensen  &  Holle  (51). 

When  clearance  techniques  are  employed  in 
trained,  unanesthetized  dogs,  which  have  recovered 
well  from  the  effects  of  surgical  denervation  of  one 
kidney,  or  denervation  and  transplantation  of  one 
organ,  function  is  equal  in  the  experimental  and  con- 
trol kidneys.  This  includes  concordance  of  glomerular 
filtration  rate  (creatinine  or  inulin  clearance),  plasma 
flow  (Diodrast  or  PAH  clearance),  and  indeed,  diure- 
tic  activity   and   electrolyte  excretion    (17,   35,    139, 

197.   257>   299)- 

Carstensen  &  Holle  (51)  performed  sympathetec- 

tomies  at  the  levels  of  the  first  and  second  lumbar 
vertebrae  (Li  and  L2)  in  patients  suffering  with 
arteriosclerotic  obliterans  and  endarteritis  obliterans. 
Clearances  of  phenolsulfonphthalein  (PSP),  creati- 
nine, and  PAH  were  measured  before  and  after  the 
operation.  Although  individual  results  were  quite 
variable,  the  average  changes  were  not  significant: 
endogenous  creatinine  clearance  for  glomerular 
filtration  rate  (GFR),  127  ±  42  before;  136  ±  59, 
after;  PAH  clearance,  340  ±67  before;  366  ±  92 
after.  Unilateral  sympathectomy  (from  T8  to  Li, 
and  greater  and  lesser  splanchnics)  in  patients  with 
essential  hypertension  did  not  increase  blood  flow 
on  the  operated  side  (104),  and  both  kidneys  re- 
sponded by  an  equal  reduction  in  flow  after  Adrenalin 
administration. 

Smith   et  al.    (285)   demonstrated   in   normal,   un- 


operated  human  subjects  that  spinal  anesthesia  up 
to  T5  or  higher  did  not  produce  renal  hyperemia  as 
measured  by  the  Diodrast  clearance,  nor  did  it  have 
any  other  consistent  effect  on  the  renal  circulation. 
They  concluded  that  the  renal  blood  flow  is  normally 
determined  by  autonomous,  intrinsic  activity  of  the 
renal  arterioles  and  is  not  dependent  upon  the  tonic 
activity  in  the  sympathetic  pathways,  which  show 
continued  action  potentials  (263). 

It  must  be  emphasized  that  despite  its  inherent 
autonomy  of  circulation,  the  kidney  will  respond  with 
vasoconstriction  during  enhanced  activity  resulting 
from  direct  electrical  stimulation  of  the  renal  nerves 
in  the  dog,  rabbit,  cat,  and  rat  (81,  148,  167,  222, 
298,  319);  this  is  reversed  by  a  variety  of  sympatholytic 
drugs  (81,  319).  Studies  of  blood  distribution  in  the 
rabbit  kidney  supplemented  with  India  ink  injection 
techniques,  revealed  that  the  resulting  ischemia  was 
largely  cortical,  and  that  the  blood  supply  to  the 
medullary  zones  was  not  noticeably  altered  (25). 
Houck  (148)  examined  the  effect  of  electrical  stimu- 
lation of  the  renal  nerves  of  anesthetized  dogs  on 
blood  flow  (PAH  clearance),  filtration  rate  (creatinine 
clearance),  and  Tm  (tubular  maximum)  of  PAH  and 
glucose  (G).  By  relating  filtration  rate  to  unit  of 
tubular  excretory  tissue  (filtration/TmPAH),  and 
reabsorptive  tissue  (filtration/TmG),  and  the  per- 
fusion of  active  tubules  with  blood  (RBF/TmPAH  , 
it  was  discerned  that  regions  of  ischemia  were  pro- 
duced, with  random  closure  of  nephrons.  This  was 
verified  by  the  distribution  of  India  ink  injected  into 
the  renal  artery.  The  evidence  was  that  the  effects 
resulted  predominantly  from  constriction  of  the  af- 
ferent arterioles.  Blood  was  not  shunted  from  the 
cortex  to  the  medulla.  Study  &  Shipley  (298)  also 
believe  the  effects  are  largely  on  the  afferent  arterioles. 
They  too  found  no  evidence  of  shunting. 

Strong  afferent  stimulation  (acute  tracheal  com- 
pression, sudden  clamping  of  an  upper  or  lower 
extremity,  and  sciatic  nerve  stimulation  (25,  65, 
66) )  likewise  caused  renal  vasoconstriction  on  a 
reflex  basis.  Pain  caused  by  intense  cold  stimulation 
of  the  hand,  or  pressure  headaches,  resulted  in  de- 
creased clearance  of  Diodrast  and  of  inulin  to  a  lesser 
degree  (filtration  fraction  increased),  while  blood 
pressure  increased  (35 1 ) . 

More  subtle  reflex  mechanisms  have  been  dis- 
cerned. Bladder  distention  in  chloralosed  cats  gave 
reflex  increases  in  blood  pressure;  apparently  the 
kidney  participated  in  the  vasoconstriction  as  mani- 
fested by  decreases  in  volume  (229).  Bilateral  splanch- 
nectomy    abolished     the     viscerovascular     response. 


THE    RENAL    CIRCULATION 


I48; 


An  ureterorenal  reflex  was  described  by  Hix  (146). 
When  a  catheter  distended  the  ureter  in  the  dog, 
ipsilateral  plasma  flow  and  GFR  decreased.  The 
afferent  stimulus  facilitated  further  decrease  in  these 
functions  during  emotional  stimulus.  Anesthetization 
of  the  ureter  or  surgical  denervation  abolished  the 
reflex.  The  physiological  significance  of  such  viscero- 
vascular  reflexes  is  not  apparent;  but  it  can  be  sug- 
gested that  the  circumstances  evoking  the  reflex 
(bladder  distention,  ureteral  irritation)  are  such  that 
cessation  of  urine  production  would  be  beneficial, 
at  least  temporarily. 

CENTRAL    NERVOUS    SYSTEM    (CNS)    CONTROL    OF    RENAL 

blood  flow.  Evidence  exists  that  a  representation  of 
control  of  the  renal  circulation  exists  in  the  cerebral 
cortex.  Smith  (286)  in  1940  presented  an  example  of 
psychogenic  renal  vasoconstriction,  as  evidenced  by  a 
marked  decrease  in  the  Diodrast  clearance;  the  inulin 
clearance  decreased  only  slightly,  so  that  FF  increased. 
Meehan  recently  has  confirmed  the  observation  that 
emotional  states  will  cause  a  decrease  in  renal  plasma 
flow  (PAH  clearance)  (200).  Cort  (66)  observed 
reduction  of  A-V  oxygen  and  carbon  dioxide  differ- 
ences in  the  cat  kidney  during  stimulation  of  the 
supraorbital  cortex,  signifying  reduction  in  flow. 
Hoff  et  al.  (147)  acutely  stimulated  two  cortical  foci 
in  cats  on  the  right  and  left  anterior  sigmoid  gyri,  or 
applied  more  diffuse  chronic  stimuli  to  the  rostral 
surface  of  the  cranium.  Ischemia  of  the  renal  cortex 
(revealed  by  India  ink  injection)  resulted,  with  little 
effect  on  the  renal  medulla.  When  denervated,  the 
kidney  was  passively  engorged  as  the  blood  pressure 
rose.  Chronic  stimulation  for  a  number  of  days  led  to 
tubular  degeneration  as  a  result  of  the  continued 
ischemia. 

Wise  &  Ganong  (350)  stimulated  the  hypothala- 
mus, pons,  and  medulla  oblongata  of  pentobarbital- 
ized  dogs  with  chronically  implanted  electrodes. 
Effects  on  glomerular  filtration,  and  excretion  of  water 
and  electrolytes  were  studied.  Influence  on  GFR  was 
variable:  stimulation  of  the  dorsal  medulla  just  lateral 
to  the  midline  led  to  a  rise  in  blood  pressure  with  an 
associated  decline  in  GFR  and  urine  volume,  abol- 
ished by  renal  denervation.  Stimulation  of  an  area  in 
the  obex,  in  and  near  the  area  postrema,  led  to  a  rise  in 
GFR  and  urine  volume,  without  significant  change  in 
blood  pressure.  Other  points  stimulated  in  the  brain 
stem  (medulla,  pons,  midbrain,  and  posterior  hypo- 
thalamus) had  no  effects  on  GFR  and  electrolyte 
excretion,  even  though  some  stimuli  caused  changes 
in  blood  pressure. 


Thus,  the  CNS  control  of  the  renal  circulation  is 
intimately  wrapped  up  in  the  general  problems  of 
higher  regulation  of  the  cardiovascular  system.  As 
these  become  worked  out,  better  insight  into  renal 
control  will  eventuate  (241). 

Humoral  Control ;  Pharmacologic  Agents 

adrenergic.  /-Epinephrine  and  arterenol  (levartere- 
nol,  norepinephrine)  are  both  active  vasoconstrictors 
of  the  renal  vasculature.  The  comparative  potency, 
and  the  site  of  action  is  not  entirely  settled,  depending 
upon  technique  employed,  e.g.,  indirect  clearance 
techniques  with  intravenous  injection,  or  direct  flow 
studies  with  intra-arterial  injection.  The  latter 
method,  employed  by  Spencer  et  al.  (292)  has  an 
obvious  advantage  in  that  local  effects  can  be  ob- 
served without  demonstrable  alteration  of  systemic 
pressure.  Flow  measurement  was  made  with  an  elec- 
tromagnetic flowmeter  in  dogs.  Table  7  shows  the 
effect  of  the  same  dosage  of  epinephrine  and  arterenol 
as  measured  by  the  volume  of  blood  shunted  from  the 
kidney.  Only  at  a  10  ng  dose  is  the  difference  signifi- 
cant, and  at  this  dose  epinephrine  appears  to  be  the 
more  effective. 

Werko  et  al.  (335)  compared  the  effects  on  clear- 
ances (CIn  and  CPAH)  done  in  man.  The  substances 
were  given  in  approximately  the  same  dosage  during 
two  experimental  periods,  following  control.  An 
attempt  to  assess  the  differential  site  of  action  was 
made  by  application  of  the  formula  of  Gomez  (105) 
for  calculation  of  regional  vascular  resistance.  The 
average  values  appear  in  table  8. 

As  Spencer  et  al.  found,  the  differences  between  the 
action  of  these  two  adrenergic  drugs  are  not  great,  and 
here  arterenol  appears  to  be  the  more  effective.  For 
both,  the  greatest  degree  of  resistance  change  was  in 
the  afferent  arterioles.  Maxwell  et  al.  (199)  injected 
1.0  to  1.5  mg  of  epinephrine  intramuscularly  in 
human  subjects,  and  noted  a  decrease  of  13  per  cent 

TABLE  7.  Effect  of  Epinephrine  and  Arterenol  on 
Renal  Blood  Flow  in  the  Dog 


Dose, 

No.  of 
Paired 
Observa- 
tions 

Avg.  m!  of  Blood 
Shunted  by: 

Mean  Difference 
/-Epinephrine  Arterenol 

*g 

Epineph- 
rine 

Arterenol 

Avg. 

24-5 
u-3 
68.3 

SE 

P 

I 

3 

10 

9 
9 

10 

58.5 
69.8 

217.O 

33-8 

58 -4 
148.7 

21  .2 
IO.6 
18.4 

°-3 
0.36 

0.005 

[After  Spencer  et  al.   (292).] 


i486 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


table  8.   Comparative  Effects  of  Epinephrine  and  Arterenol  on  Human  Renal  J  'aseular  Dy 


namies 


Vascular  Resistanct 

in  Dynes-  sec  -cm"5 

Cid 

RPF 

FF 

VK 

RAa 

RAe 

RV 

Total  resistance 

X  10' 

X  10' 

X  W 

X  10' 

Control 

"5 

665 

0.18 

IOO 

2.71 

I  .60 

2.89 

7-19 

Arterenol  20.4  pg/min 

in 

498 

O.22 

121 

5-42 

2.13 

3-73 

1 1 .27 

Control 

128 

660 

O.iq 

IOO 

2-53 

1.92 

2.88 

7-33 

Epinephrine  24.5  pg/min 

129 

553 

O.23 

"3 

4.04 

2.29 

3-54 

9-85 

[After  Werko  et  at.  (335)] 


in  CIn  and  40  per  cent  in  RPF;  FF  increased  by  39 
per  cent.  Also  employing  Gomez'  calculation,  they 
computed  that  the  greatest  resistance  increase  was  in 
the  venular  and  venous  component,  and  suggested 
that  this  contributed  significantly  to  the  kidney  vol- 
ume increase  that  had  been  noted  some  time  ago 
from  epinephrine,  the  so-called  "paradoxical  ex- 
pansion" of  Richards  and  Plant.  The  work  of  Mehrizi 
and  Hamilton  (201)  in  the  dog  kidney  has  confirmed 
this  conclusion  for  arterenol.  Note  that  in  the  data  of 
Werko  et  al.  (table  8),  RAe  (efferent  arteriolar  resist- 
ance) and  RY  (venous  resistance)  increased  equally 
after  epinephrine,  and  the  change  was  most  pro- 
nounced in  RAa  (afferent  arteriolar  resistance). 

Studies  were  made  in  which  measurements  of 
TmG  and  TmpAH  were  combined  in  the  dog  and 
human  (149,  208).  In  the  dog,  the  ratio  GFR  TmG 
decreased  significantly,  due  to  over-all  reduction  in 
filtration  rate  in  each  glomerulus,  rather  than  nephron 
shutdown,  according  to  Houck  (149).  But  Mills 
et  al.  (208)  state  that  GFR  and  TmG  decrease  together 
with  epinephrine  and  arterenol,  implying  nephron 
closure;  this  might  be  anticipated  with  higher  dosage. 
In  the  human,  the  dosage  employed  (0.243  /ig  kg  min 
of  epinephrine,  0.321  fig  kg  min  of  arterenol)  caused 
no  significant  alteration  of  GFR  or  TraPAH,  although 
RBF  fell  to  63  per  cent  of  control.  Changes  in  EPAH 
were  never  observed  by  several  groups  of  workers. 

sympathomimetic  drugs.  Several  sympathomimetic 
substances  have  been  studied  for  comparative  effects 
on  renal  blood  flow  (5,  1 14,  293).  None  of  a  series  of 
rapidly  acting  vasodepressors,  such  as  isoproterenol 
and  ethylarterenol,  injected  into  the  renal  artery  of 
dogs  (flow  measured  by  electromagnetic  flowmeter) 
induced  vasoconstriction  (114,  293).  Epinephrine, 
tried  in  this  series,  caused  the  most  potent  constric- 
tion. The  amylbutyl  and  isobutylamine  derivatives  of 
arterenol,  even  in  quite  large  doses,  were  devoid  of 
any  renal  vasomotor  action  despite  the  fact  that  they 


exhibited  definite  vasodepressor  actions  on  the  sys- 
temic circulation.  It  was  concluded  that  the  renal 
circulation  does  not  exhibit  sympathetic  inhibitory 
receptors. 

Aviado  et  al.  (5)  grouped  a  number  of  drugs  into 
four  categories,  based  upon  effects  observed  in  the  dog 
kidney  by  intrarenal  arterial  or  systemic  intravenous 
injection.  Direct  flow  was  measured  by  rotameter. 
Type  A:  Drugs  which  are  capable  of  constricting  renal 
vessels  when  injected  into  the  renal  artery  or  when 
given  intravenously:  levarterenol,  epinephrine,  phen- 
vlephrine,  metaraminol,  methoxamine,  and  nephazo- 
line.  Type  B:  Drugs  which  constrict  when  injected 
into  the  renal  artery  but,  when  injected  intravenously, 
constriction  is  not  always  encountered :  ephedrine, 
phenylpropanolamine,  hydroxyamphetamine,  and 
compound  45-50.  Type  C:  These  have  no  important 
actions  when  injected  into  the  artery.  When  injected 
intravenously,  renal  blood  flow  is  increased  because 
of  their  systemic  pressor  effect :  methamphetamine, 
pseudoephedrine,  amphetamine,  pholedrine,  methyl- 
aminoheptane,  tuaminoheptane,  mephentermine,  and 
phenylpropylmethylamine.  Type  D:  Drugs  that  have 
a  local  dilator  action;  when  they  are  injected  intra- 
venously, renal  blood  flow  is  decreased  as  a  result  of 
arterial  depressor  action:  isoproterenol,  nylidrin, 
isoprophenamine,  methoxyphenamine,  and  cyclo- 
pentamine.  Spencer  (293)  reported  a  weak  constrictor 
action  by  isoproterenol,  but  this  was  not  encountered 
in  the  above  series  because  smaller  doses  were  used. 

A  similar  analysis  of  various  sympathomimetic 
drugs  on  renal  hemodynamics  has  been  made  recently 
by  Milhetal.  (210),  employing  clearance  in  normoten- 
sive  and  hypotensive  drugs.  In  this  series,  mephen- 
termine had  the  least  effect  on  GFR  and  RBF,  and 
methoxamine   the  greatest. 

ganglionic  blocking  agents.  Ganglion-blocking 
drugs  interfere  with  the  reflex  adjustments  of  the 
circulation.  They  block  the  vasoconstrictor  pathways 


THE    RENAL    CIRCULATION 


I487 


which  control  peripheral  resistance  and  venous  return 
and  hence  prevent  the  rise  in  blood  pressure  which 
results  from  such  maneuvers  as  clamping  the  carotids, 
cutting  the  pressoreceptor  nerves,  the  Valsalva  maneu- 
ver, and  the  cold  pressor  test.  Essentially,  they  elimi- 
nate efferent  nervous  influences  which  keep  blood 
pressure  up.  The  fall  in  blood  pressure  which  results 
from  their  administration  may,  in  part,  be  due  to 
decrease  in  cardiac  output.  Peripheral  vasodilatation 
and  increased  flow  may  occur,  e.g.,  in  the  limbs,  in 
the  presence  of  a  fall  in  blood  pressure,  or  at  least 
in  the  absence  of  a  rise.  There  appears  to  be  little  or 
no  direct  effect  on  the  vasculature.  Responses  of  the 
splanchnic  organs,  including  the  kidney,  may  be  quite 
different:  decreased  blood  pressure  is  accompanied  by 
decrease  in  flow. 

Hexamethonium  chloride.  Mover  et  al.  (225)  gave  2 
to  5  mg  per  kg  (iv)  and  observed  an  average  drop 
of  1 38  to  97  mm  Hg  in  the  blood  pressure  in  20  dogs 
anesthetized  with  pentobarbital  or  chloralose.  Glo- 
merular filtration  rate  showed  no  change  (46-45 
ml  min),  RPF  decreased  from  182  to  1  72  ml  per  min, 
and  FF  varied  from  0.26  to  0.28.  Renal  vascular 
resistance  (RVR)  decreased  from  0.57  to  0.48,  and 
TmG  showed  little  alteration  (161 -155  mg/'min). 

In  patients  (220),  with  a  greater  fall  in  blood  pres- 
sure at  the  dosage  used,  blood  pressure  fell  to  66 
per  cent  of  control.  CIn  decreased  to  78  per  cent,  and 
CTpah  was  maintained  at  98  per  cent  of  control,  signify- 
ing decrease  in  RYR.  One  must  consider  the  possibil- 
ity that  renal  autonomy  may  account  for  this,  rather 
than  dilatation  due  to  drug  action.  In  another  series, 
in  normotensive  and  hypertensive  patients  (209), 
blood  pressure  decreased  to  80  to  85  per  cent  of  con- 
trol following  dosage  of  5  to  75  mg.  In  half  no  change 
or  actual  increase  in  RVR  occurred,  so  that  GFR  and 
RPF  were  reduced  at  the  time  of  maximum  decrease  of 
blood  pressure.  In  the  other  half,  RYR  decreased  so 
that  GFR  and  RPF  were  maintained  despite  the  fall 
in  blood  pressure.  There  was  no  effect  on  EPAS. 

Arjonad  (trimethaphan  camphorsulfonate)  has  a 
greater  depressing  effect  on  renal  function  (GFR  and 
RPF)  than  hexamethonium,  due  to  greater  reduction 
of  blood  pressure  (227);  RYR  is  not  significantly 
altered  in  normals.  In  patients  with  nephrosclerosis 
(243)  CpAH  ,  originally  reduced,  tended  to  be  main- 
tained despite  a  fall  in  blood  pressure  to  40  to  50  per 
cent  of  control;  C?in  was  noticeably  reduced.  The 
intensity  of  renal  vasoconstriction  in  dogs,  produced 
by  clamping  the  aorta  or  limb  trauma,  was  relieved 
by  Arfonad  blockade  (26). 

Other    blocking    agents.    Pendiomid    (azamethonium 


chloride),  administered  to  patients  with  no  vascular 
disease  at  the  rate  of  2  to  6  mg  per  min  for  several 
hours  (avg  250  mg  over  3  hours),  caused  blood  pres- 
sure to  fall  from  97  to  71  mm  Hg.  Renal  blood  flow 
decreased  in  about  the  proportion  of  the  decline  in 
blood  pressure,  with  no  significant  change  in  RVR 
(228).  Ecolid  (chlorisondamine)  in  hypertensives 
shows  maintained  renal  blood  flow  despite  significant 
fall  in  blood  pressure  (77).  Tetraethylammonium 
bromide  is  a  renal  vasoconstrictor,  according  to  Aas 
&  Blegen  ( 1 )  as  revealed  by  the  more  marked  fall  in 
Cpah  than  systemic  pressure.  Priscoline  (tolazoline), 
state  Young  et  al.  (353),  is  a  vasodepressor  and  a  renal 
constrictor  both  in  humans  and  dogs.  Marked  decre- 
ment in  GFR  occurs,  along  with  somewhat  lesser 
decrease  in  RPF,  and  they  believe  the  major  site  of 
action  is  on  the  afferent  arterioles.  After  denervation 
of  the  kidney,  Priscoline  has  no  effect,  and  Young 
and  his  group  suggest  that  the  drug  causes  afferent 
arteriolar  stimulation  via  the  sympathetic  innervation. 
Ilidar  (azapetine)  directly  injected  into  the  renal 
artery  has  no  effect  up  to  a  dose  of  3  mg;  above  this, 
it  is  a  constrictor  (292).  Regitine  (phentolamine) 
is  both  vasodepressor  and  vasodilator  in  dogs  (226) 
at  infusion  rates  of  3  mg/kg  for  over  5  min  RBF 
increased  from  307  to  341  ml  per  min,  despite  a  de- 
cline in  blood  pressure  from  134  to  102  mm  Hg. 
Dibenzyline  (phenoxybenzamine)  was  injected  into 
one  renal  artery  of  the  dog,  followed  by  infusion  of 
arterenol  systemically.  Marked  decrease  in  GFR 
and  RPF  occurred  in  the  untreated  kidney,  but  not 
in  the  treated  kidney  (129).  Dibenamine  (N,n'- 
dibenzyl-B-chloroethylamine  hydrochloride)  caused 
definite  remission  of  enhanced  vasomotor  tone  result- 
ing from  hemorrhage  in  dog  (34),  but  did  not  alter 
the  outcome  of  hemorrhagic  shock. 

other  vasoactive  drugs.  Apresoline  (hydralazine)  is 
a  vasodepressor  which  reduces  vascular  resistance  in 
the  kidney.  It  is  not  a  ganglionic  blocker,  but  its  exact 
mechanism  of  action  is  unknown,  although  it  has  been 
suggested  that  it  may  antagonize  neurohumoral  sub- 
stances (such  as  serotonin,  pherantosin,  and  angio- 
tensin) which  are  believed  to  affect  blood  pressure. 
Table  g  shows  its  effects  in  normal  subjects  and  acute 
nephritics  (dosage,  0.2-2.5  mg/kg,  orally). 

While  improving  normal  blood  flow,  Apresoline 
unaccountably  increased  vascular  resistance  of  the 
nephritics,  despite  a  fall  in  systemic  pressure.  That 
hypertension  per  se  was  not  basic  to  this  response  is 
shown  by  the  effects  in  essential  hypertensives  studied 
by  Gjorup  &  Hilden  (101).  While  mean  blood  pres- 


1488 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


table  9.  Effect  of  Apresoline  on  Renal  Hemodynamu  s 

in  Normal  and  Nephritic  Humans 

GFR    RPF    RBF      FF      PA      RVR 

A  oi  mat 


[idol  V 

'35 

560 

872 

-44 

92 

0. 108 

After 

i  1  1 

665 

1 1 16 

Xephritic 

• '  73 

74 

0.067 

Ui-I'oi  i- 

95 

594 

928 

.  164 

126 

0.150 

After 

60 

456 

7'7 

.  1  20 

99 

0.197 

[After  Etteldorf  et  al.   (86).] 

table  10.  Effects  of  Serotonin  on  Renal  Hemodynamu  * 
in  the  Unanesthetized  Dog 


Dose 

GFR 

ml/min 

Urine  Vol. 
ml,  min 

RPF 

ml/min 

P 

Before 

After 

Before 

After 

Before 

After 

5 

72 

71 

3-2 

3-3 

226 

227 

10 

74 

74 

3-5 

■•7 

227 

238 

>o.  10 

15 

73 

64 

3-9 

1 .0 

225 

257 

<o.05 

20 

73 

57 

3-» 

0.4 

225 

270 

<o.oi 

25 

73 

54 

4.1 

°-3 

226 

2  75 

<O.OI 

[After  Spinazzola  &  Sherrod  (294).] 

sure  changed  from  137  to  1 16  mm  Hg,  CPAH  increased 
from  343  to  429  ml  per  min.  The  dosage  was  com- 
parable to  die  above  series.  Interestingly,  the  vaso- 
constrictive effect  of  exercise  (in  patients  with  mitral 
stenosis)  is  counteracted  by  Apresoline  (337). 

Serotonin  (5-hydroxytryptamine),  an  extremely 
interesting  compound  produces  hyperemia  in  the 
kidney  (64,  294)  and  has  a  striking  antidiuretic 
activity.  Spinazzola  &  Sherrod  (294)  have  studied 
the  effects  of  graded  increase  in  dosage  in  unanesthe- 
tized dogs  (table  10).  Blood  pressure  showed  no 
significant  changes.  Although  decrease  in  GFR  con- 
tributes to  the  antidiuresis,  some  other  mechanism 
may  be  involved  (stage  2).  Emanuel  et  al.  (83),  on 
the  contrary,  find  that  direct  infusion  into  the  renal 
artery  in  dosage  of  10  /zg  to  100  ng  per  min  increased 
vascular  resistance. 

Miscellaneous.  Histamine  has  an  unpredictable 
action  on  renal  blood  flow  (287).  The  best  work  ap- 
pears to  be  that  of  Blackmore  et  al.  (22)  who  adminis- 
tered 2.5  /zg  per  kg  per  min  for  2  hours  to  dogs. 
Glomerular  filtration  rate  was  constant  during  the 
infusion,  even  though  blood  pressure  fell  slowly 
(never  below  75  mm  Hg).  Control  RBF  was  360.5 
ml  per  min  (sd,  21.5);  after  1  hour,  466.5  (±37.3); 
2  hours,  487.8;  (±39.2);  recovery,  434. 1  (±34.2). 
Bradykinin  increases  direct  blood  flow  in  the  dog 
kidney  (g),  in  the  face  of  decreases  in  systemic  blood 
pressure. 


Morphine  sulfate  (30  mg  kg)  results  in  significant 
reductions  in  CPAH  in  dogs,  while  Cln  stays  constant. 
Blood  pressure  declines  slightly  but  active  vasocon- 
striction is  indicated  (7). 

Xanthine  derivatives.  In  man,  theophylline  (ami- 
nophylline)  and  caffeine  increase  filtration  rate. 
After  a  brief  and  variable  increase  in  CD  ,  this  suffers 
a  sustained  decrease  (287).  The  initial  rise  is  associ- 
ated with  an  increase  in  cardiac  output.  Parephvllin 
(diethylaminoethyltheophylline)  has  no  effect  on  GFR 
and  RBF  in  dogs.  In  man,  an  initial  decrease  in 
GFR  and  CPAH  was  noted  (187),  then  a  slight  in- 
crease in  20  to  40  min.  Filtration  fraction  showed  no 
change,  and  blood  pressure  changes  were  not  signifi- 
cant. In  patients  in  heart  failure,  GFR  and  CPAH 
paradoxically  decreased. 

ANESTHETIC  AGENTS  AND  RENAL  BLOOD   FLOW.    Several 

reviews  on  the  subject  (242,  275,  287)  have  pointed  out 
that  all  general  anesthetic  agents  significantly  dimin- 
ish renal  plasma  flow,  glomerular  filtration  rate,  and 
water  and  electrolyte  excretion  if  there  is  sufficient 
depth  of  anesthesia.  During  light  anesthesia,  blood 
flow  through  the  skin  and  muscles  of  the  extremities 
may  be  increased  (242)  with  vasoconstriction  in  the 
splanchnic  area,  which  may  include  the  kidney,  so 
that  a  redistribution  of  blood  occurs.  During  pro- 
longed or  deep  anesthesia,  flow  through  skin  and 
muscles,  as  well  as  in  the  splanchnic  bed,  decreases. 

The  effects  of  anesthetic  agents  are  complex,  for 
other  factors  are  introduced  which  modify  the  kidney 
function  beyond  the  direct  action  of  the  anesthetic 
agent  itself.  Possible  changes  in  systemic  arterial  and 
venous  pressure  would  modify  renal  blood  flow.  The 
sympathetic  system  is  stimulated  to  produce  en- 
hanced neurogenic  effects.  Catecholamine  output  goes 
up  in  turn  causing  further  vasoconstriction.  In  deep 
narcosis,  effects  of  hypoxia  and  hypercapnia  enter 
the  picture  because  of  respiratory  depression  or  airway 
obstruction.  In  terms  of  the  water  and  electrolyte 
picture,  changes  occur  in  endocrine  output  (e.g.,  en- 
hanced activity  of  the  pituitary-adrenal  axis,  and  in- 
creased ADH  output  from  the  neurohypophysis). 
Finally  the  kidney's  ability  to  correct  acid-base  dis- 
turbances may  be  impaired. 

Pentobarbital  anesthesia.  During  relatively  short 
periods  of  action,  no  consistent  change  in  inulin  and 
Diodrast  clearances  or  TmD  were  noted  with  dosage 
of  30  mg  per  kg  (61).  When  the  duration  of  action  of 
pentobarbital  sodium  and  sodium  barbital  was  in- 
creased to  5  hours  by  Glauser  &  Selkurt  (103),  there 
was  18  per  cent  decrease  in  CPAh,  with  no  change  in 


THE    RENAL    CIRCULATION 


I489 


GFR  (CCr)  so  that  FF  increased  an  average  of  24  per 
cent.  TiripAH  was  only  slightly  depressed. 

Ether;  cyclopropane.  Craig  et  al.  (67)  have  shown  that 
light  ether  and  cyclopropane  anesthesia  (stage  III, 
plane  1 )  in  dogs  produced  no  significant  alteration  in 
PAH  or  creatinine  clearance,  but  in  deep  anesthesia 
(stage  III,  plane  3)  depression  of  function  occurred; 
the  PAH  and  creatinine  clearances  were  reduced  to 
53  ±  8.9  per  cent  and  48  ±  7.7  per  cent,  respectively, 
of  the  values  observed  during  light  anesthesia,  despite 
maintenance  of  blood  pressure.  The  clearances  re- 
turned substantially  to  normal  when  the  animal  was 
allowed  to  recover  to  stage  III,  plane  1 .  The  reduction 
was  attributed  to  afferent  arteriolar  constriction. 

Coller  et  al.  (56)  studied  the  action  of  ether  and 
cyclopropane  on  a  series  of  humans,  but  their  results 
were  complicated  by  accompanving  surgery.  How- 
ever, four  with  ether  showed  no  significant  change 
in  renal  blood  flow  (based  on  C0)  or  glomerular 
filtration  (Cm) ;  one  showed  no  change  in  blood  flow- 
but  had  a  marked  decrease  in  GFR;  two  showed  de- 
creases in  both  blood  flow  and  glomerular  filtration. 
Under  cyclopropane,  two  showed  little  or  no  decrease 
in  RBF,  yet  both  showed  significant  decreases  in 
glomerular  filtration.  In  two  others,  all  renal  function 
was  markedly  reduced,  but  these  cases  were  compli- 
cated by  accompanying  shock.  Burnett  et  al.  (45) 
reported  that  in  eight  patients  during  ether  anes- 
thesia maintained  in  stage  III,  plane  2,  mannitol 
clearance  was  reduced  by  2 1  per  cent,  and  CPAH  by 
39  per  cent,  with  a  resultant  increase  in  FF  of  25  per 
cent.  In  seven  patients  receiving  cyclopropane,  these 
changes  were  —31,  —  52  and  +35  per  cent,  respec- 
tively. It  is  entirely  probable  that,  according  to  the 
work  of  Miles  &  DeVVardener  (205),  the  reductions  in 
RBF  resulting  from  ether  and  cyclopropane,  when 
they  occur,  are  on  a  neurogenic  reflex  basis.  Renal 
vascular  resistance  increased  in  dogs  inhaling  cyclo- 
propane, but  in  denervated  kidneys  there  was  no 
effect.  With  ether,  an  actual  fall  in  RVR  occurred  in 
the  denervated  kidney,  evidently  a  local  dilatory 
mechanism.  This  was  confirmed  when  ether  was  in- 
jected in  the  renal  arterial  flow  measuring  circuit 
(rotameter);  RVR  again  decreased,  due  to  active 
vasodilatation. 


AUTONOMY  OF  THE  RENAL  CIRCULATION 

History 

In  the  preceding  sections  devoted  to  extrinsic  regu- 
lation of  renal  blood  flow  (neurogenic  and  humoral), 


the  underlying  thread  of  circulatory  autonomy  was 
revealed  occasionally.  Rein  (252),  in  1931  while 
studying  regional  blood  flow  in  dogs  during  changes 
in  systemic  arterial  pressure,  was  struck  by  the  relative 
constancy  of  the  renal  blood  flow  as  compared  to  other 
tissues.  Unna  (316),  employing  the  Rein  thermo- 
strohmuhr,  confirmed  these  observations  and  con- 
cluded: "Es  kann  die  Nierendurchsblutung  unab- 
hangig  von  arteriellen  Druck  reguliert  werden." 
Hartman  et  al.  (1  35)  and  Opitz  &  Smyth  (238)  demon- 
strated that  this  obtained  under  circumstances  of 
reflex  alteration  in  blood  pressure  (carotid  sinus  nerve 
stimulation,  carotid  clamping)  and  carbon  dioxide 
inhalation  in  kidneys  that  had  been  denervated,  im- 
plying an  intrinsic  mechanism.  Enger  et  al.  (85)  found 
evidence  of  autoregulation:  partial  clamping  of  the 
renal  artery  brought  renal  flow  down,  but  in  a  short 
time  there  followed  a  partial  restoration  of  flow. 
Forster  &  Maes  (91)  studied  the  effects  of  elevation 
of  mean  arterial  pressure  on  the  clearance  of  jfr-amino- 
hippurate  (PAH)  and  creatinine  in  rabbits  whose 
kidneys  had  been  denervated  and  whose  adrenal 
glands  had  been  demedullated.  They  too  found  that, 
when  blood  pressure  was  elevated  by  neurogenic 
mechanisms  resulting  from  clamping  of  the  carotid 
arteries,  these  clearances  were  remarkably  constant. 

Selkurt  (271)  plotted  the  response  of  blood  flow  in 
dogs  to  progressive  decrement  of  effective  perfusion 
pressure  (A-V  difference)  by  lowering  arterial  pressure 
(aortic  compression)  in  a  "pressure-flow"  relation- 
ship. This  was  concave  to  the  pressure  axis  in  a  range 
of  14  to  117  mm  Hg  with  flow  relatively  independent 
of  pressure  at  the  higher  range,  but  decreasing  below 
ca.  80  mm.  Results  were  essentially  the  same  in  the 
intact  as  in  the  denervated  kidney.  Hemorrhage  ap- 
peared to  abolish  the  concavity  of  the  pressure-flow 
relationship.  It  was  not  manifested  in  the  dead  kidney. 
The  zero  flow  intercept  on  the  pressure  abscissa 
averaged  14  mm  Hg,  a  minimal  yield  pressure  for 
movement  of  blood  through  the  vascular  circuits. 
Selkurt  et  al.  (274)  further  analyzed  the  pressure-flow 
relationship  of  PAH  and  creatinine  clearance  and 
found  that  glomerular  filtration  rate  manifested  good 
constancy  in  a  range  of  90  to  180  mm  Hg.  This  im- 
plied that  one  possible  factor  in  "renal  autonomy," 
a  change  in  vascular  resistance  due  to  changes  in 
blood  viscosity  incurred  by  filtration  at  the  glomeruli, 
could  be  ruled  out.  Calculations  of  regional  vascular 
resistance  strongly  suggested  that  the  afferent  ar- 
terioles were  an  important  point  of  control. 

Shipley  &  Study  (282)  confirmed  and  extended 
these  observations  by  examining  the  renal  blood  under 
conditions   of  elevation   of  perfusion   pressure   by   a 


1490 


HANDBOOK    OF    PHYSIOLOGY 


CIRCl'LATION    II 


pump  into  hypertensive  ranges.  Above  ca.  200  mm  Hg, 
renal  blood  flow  by  rotameter  increased  with  in- 
creases in  perfusion  pressure  to  280  mm  Hg  so  that  a 
limit  to  the  regulatory  mechanism  was  reached  at 
about  200  mm.  Yet  GFR  remained  constant  at  the 
higher  pressures.  DeWardener  &  Miles  (73)  con- 
firmed the  sigmoid  nature  of  the  pressure-flow  curve 
at  high  pressures  and  extended  the  observations  on 
the  effect  of  hemorrhage.  The  pressure-flow  curve 
during  hemorrhage  fell  markedly  below  the  control 
curve  and  assumed  approximate  linearity;  the  sus- 
tained vasoconstriction  had  apparently  impaired  or 
abolished  the  autoregulation.  Likewise,  prolonged 
perfusion  (4-5  hours)  also  was  found  to  impair  auto- 
regulation. 

Mechanism  of  Autoregulation 

Possible  mechanisms  which  might  account  for  auto- 
regulation have  been  explored  in  several  reviews 
(280,  343,  344).  Mechanisms  suggested  were:  a) 
"metabolic  theory"  or  reactive  hyperemia  theory;  b) 
intrarenal  vascular  reflex  control;  c)  changes  in  vis- 
cosity of  blood  as  a  factor  in  changes  in  renal 
resistance,  the  ''viscosity  theory,"  as  exemplified  by 
the  cell  separation  theory  of  Pappenheimer  &  Kinter 
(240);  d)  the  "tissue-pressure"  theory,  in  which 
changes  in  arterial,  venous,  and  ureteral  pressures 
in  varying  degrees  create  changes  in  intrarenal  pres- 
sure, which  in  turn  affect  blood  flow;  and  e)  the 
"myogenic  theory"  or  vasoconstrictor  theory,  whereby 
active  changes  in  the  smooth  muscles  of  the  arterioles 
(afferent),  in  response  to  changes  in  intraluminal 
pressure,   regulate  flow. 

the  "metabolic  theory."  This  was  suggested  by 
Selkurt  (280)  as  a  possible  explanation  for  the  re- 
duced vascular  resistance  manifested  in  the  kidney 
with  moderate  reduction  in  perfusion  pressure.  In- 
creased production,  or  reduced  removal,  or  both,  of 
(hyperemia-producing)  metabolites  resulting  from 
the  impaired  flow  and  hypoxia,  might  cause  the  ob- 
served vascular  dilatation.  Typically,  flow  drops  im- 
mediately on  decrease  in  pressure,  but  improves  in  30 
sec  to  1  min  (120,  258).  When  pressure  is  released,  an 
"overshoot"  occurs,  which  restores  in  30  sec  to  1  min. 
More  difficult  to  explain  is  the  increased  resistance 
which  develops  when  pressure  is  suddenly  raised.  If 
one  speculates  that  a  base-line  production  of 
metabolites  is  the  case  for  the  kidney,  then  an  immedi- 
ate increase  in  flow  as  pressure  is  raised  might  rapidly 
wash  out  metabolites  responsible  for  the  resting  caliber 


of  the  resistance  vessels,  resulting  in  a  net  reduction  in 
caliber.  A  similar  possibility  has  been  considered  by 
Haddy  et  al.  (124). 

Some  support  for  a  metabolic  mechanism  was 
offered  by  the  finding  that  kidneys  perfused  by  pump 
with  hypoxic  venous  blood  demonstrated  hyperemia 
(278),  but  the  possibility  of  preformed  metabolites  in 
the  venous  blood  which  might  dilate  the  renal  ar- 
terioles must  be  held  open.  As  earlier  mentioned,  the 
peculiar  flow-limited  characteristic  of  the  kidney  may 
make  it  more  susceptible  to  hypoxic  states.  Perhaps 
stronger  support  was  the  demonstration  by  Sarre  & 
Ansorge  (262)  that  the  dog  kidney  exhibited  "re- 
active hyperemia"  to  short  bouts  (1—5  min)  of  clamp- 
ing of  the  renal  arteries.  The  responses  were  usually 
modest,  but  in  two  instances  flow  increased  by  1 50 
and  1 73  per  cent.  Flow  was  restored  to  normal  in 
these  cases  in  about  5  min.  Since  a  venous  outflow 
method  was  used,  filling  of  the  organ  could  not  have 
been  the  apparent  cause  of  the  elevated  flow  on  resto- 
ration of  arterial  pressure.  It  is  known  that  the  pH  of 
the  cortical  substance  decreases  by  0.3  to  0.4  pH 
units  during  partial  clamping  of  the  renal  artery 
(237),  indicating  accumulation  of  metabolites. 
Spencer  (293)  has  more  recently  demonstrated  reac- 
tive hyperemia  in  the  kidney  after  brief  ischemia;  flow, 
measured  with  a  square-wave  electromagnetic  flow- 
meter, was  increased  in  dogs  after  brief  clamping  of 
the  renal  artery.  Contrarily,  Grupp  &  Heimpel  (118) 
more  often  observed  small  reductions  in  flow  measured 
in  dogs  both  by  direct  arterial  inflow  and  venous  out- 
flow following  1  to  7  min  of  ischemia.  In  5  of  26  dogs 
an  increase  averaging  16  per  cent  (maximum,  32%) 
was  seen.  Yamada  &  Astrom  (352)  did  not  observe 
reactive  hyperemia  in  the  kidneys  of  cats  after  brief 
ischemia.  Since  abundant  evidence  exists  that  the 
kidney,  after  more  prolonged  ischemia,  releases 
pressor  material,  the  complexity  of  this  interesting 
problem  is  evident.  The  duration  of  ischemia  looms 
as  an  important  variable. 

intrarenal  reflexes.  Extrinsic  reflexes  are  not 
necessary  for  the  manifestation  of  autonomy,  and  no 
afferents  from  renal  baroreceptors  or  chemoreceptors 
exist  according  to  Page  &  McCubbin  (239).  But  the 
presence  of  intrarenal  autonomic  ganglia  were  ap- 
parently confirmed  pharmacologically:  nicotine  and 
dimethylphenylpiperazinium  iodide  (DMPP)  stimu- 
lated ganglia  and  caused  the  discharge  of  pressor 
amines.  Page  and  McCubbin  have  suggested  this  as  a 
possible  mechanism  in  autoregulation.  Since  ganglio- 
plegic  and  sympatholytic  agents  have  been  said  to 


HIE    RENAL    CIRCULATION 


1491 


eliminate  the  mechanism  of  homeostasis  [Brull  et  al. 
(38)],  the  possibility  of  such  an  intrarenal  reflexogenic 
mechanism  should  be  weighed,  although  possible 
afferent  pathways  resembling  an  axon  reflex  (den- 
dritic mechanoreceptors  or  stretch  receptors)  remain 
to  be  demonstrated.  The  results  of  Brull  et  al.,  who 
argued  for  an  intrarenal  reflex  mechanism,  were  some- 
what sporadic  and  complicated  by  the  fact  that  some 
of  their  perfusion  pressures  after  drug  treatment  were 
high  enough  to  exceed  the  normal  range  of  autonomy. 
Intrarenal  sympatholysis  with  Dibenzyline  (331)  and 
phentolamine  (124),  tested  by  abolishing  the  vasocon- 
striction produced  by  DMPP,  did  not  abolish  auto- 
regulation. 

Procaine  injected  directly  into  the  renal  artery  will 
abolish  autoregulation,  but  this  could  be  an  effect 
directly  on  the  smooth  muscle  of  the  arterioles.  How- 
ever, Waugh  &  Shanks  (331)  claimed  that  with  pro- 
caine concentration  of  only  50  ng  per  100  ml  of 
perfusate,  anesthesia  of  intrarenal  nervous  elements 
was  achieved  without  concomitant  removal  or  ap- 
preciable depression  of  vascular  smooth  muscle  re- 
sponses to  direct  stimuli.  This  prevented  the 
vasoconstrictor  response  of  DMPP,  but  the  prepara- 
tion remained  sensitive  to  small  doses  of  epinephrine 
or  barium  chloride.  When  pressure  was  elevated  by  50 
per  cent,  flow  increased  only  13  per  cent.  Further- 
more, yohimbine,  an  adrenergic  blocking  agent,  in 
concentrations  which  caused  nearly  complete  intra- 
renal sympatholysis  (as  judged  by  blockade  of  large 
test  responses  to  the  ganglionic  stimulant  DMPP  and 
to  epinephrine)  did  not  depress  autoregulation  (331)- 

Twenty  times  greater  perfusate  concentrations  of 
procaine  (0.1  g/100  ml)  were  shown  by  Waugh  and 
Shanks  to  abolish  autoregulation.  In  a  typical  experi- 
ment, renal  flow  increased  64  per  cent  per  50  per  cent 
increase  in  arterial  pressure.  The  intense  renal  vaso- 
constriction normally  evoked  by  intra-arterial  injec- 
tions of  1  /ig  epinephrine  and  2.5  mg  of  barium 
chloride  was  largely  prevented  by  the  higher  concen- 
trations of  procaine.  It  is  likely  that  results  obtained 
by  Ochwadt  (233)  and  Weiss  et  al.  (333)  with  com- 
parable dosage  of  procaine  are  also  the  result  of 
marked  direct  depression  of  smooth  muscle  activity. 

In  summary,  the  intricacies  of  distinguishing  be- 
tween abolition  of  an  intrarenal  neurogenic  com- 
ponent and  direct  effects  on  smooth  muscle  by 
pharmacological  agents  are  apparent.  It  would 
appear,  nevertheless,  that  the  evidence  offered  by 
Waugh  and  Shanks  weighs  heavily  against  a  nervous 
component. 


the  viscosity  theorv.  Foremost  proponents  of  this 
theory  are  Pappenheimer  &  Kinter  (159,  160,  240) 
with  their  cell  separation  hypothesis,  championed 
by  Winton  (343,  344).  The  details  are  so  well  known 
that  only  a  brief  review  is  necessary.  In  this  theory,  the 
interlobular  arteries  and  afferent  arterioles  act  as 
vessels  specially  developed  to  promote  plasma 
skimming  and  stripping.  Streamlining  of  erythrocytes 
leaves  a  core  of  cells  to  supply  the  outer  cortical 
glomeruli.  A  gradient  of  red  cell  concentration  would 
develop,  with  low  cell  hematocrit  in  the  deep 
glomeruli,  and  high  hematocrit  in  the  outer  cortical 
glomeruli.  They  suppose  that  the  red  cells  after 
traversing  the  glomeruli  and  efferent  arterioles  have 
access  to  special  through  channels  communicating 
directly  to  interlobular  veins,  leaving  a  plasma-rich 
component  of  the  blood  to  supply  the  peritubular 
vascular  bed. 

Pappenheimer  and  Kinter  believe  that  the  above 
scheme  offers  an  explanation  for  the  low  dynamic 
hematocrit  of  the  kidney,  since  the  red  cells  move 
through  the  hypothetical  shunts  faster  than  the 
plasma,  so  that  the  instantaneous  hematocrit  of  the 
total  renal  blood  content  would  be  less  than  the  ar- 
terial hematocrit  value.  Support  for  this  was  offered 
by  the  experimental  demonstration  in  cats  that  low- 
ered arterial  pressure  (less  streamlining,  hence  less 
cell  separation)  showed  higher  intrarenal  hematocrit. 

Autoregulation  is  brought  about  by  the  change  in 
viscosity,  increasing  in  turn  resistance  to  blood  flow 
resulting  from  hemoconcentration  as  the  blood  pro- 
ceeds to  the  outer  cortex.  Such  a  mechanism  could 
keep  total  flow  constant  as  a  function  of  the  level  of 
arterial  pressure.  Added  facets  that  are  important 
are  as  follows:  reduction  in  hematocrit  of  the  per- 
fusing fluid  caused  remission  of  autoregulation,  and 
development  of  a  linear  P:F  relationship,  as  the 
theory  would  demand  (160).  Implicit  in  the  theory  is 
that  a  gradient  of  filtration  rate  should  occur  based 
on  the  hematocrit  distribution,  i.e.,  the  inner 
glomeruli  receiving  the  higher  volume  of  plasma 
should  have  the  higher  filtration  rate.  A  mechanism 
for  autonomy  of  glomerular  filtration  rate  is  offered, 
for  with  reduced  blood  pressure  less  stripping  would 
occur,  so  that  peripheral  glomeruli  would  have  a 
relative  increase  in  filtration  rate,  despite  the  increase 
in  the  inner  glomeruli. 

Incomplete  extraction  of  PAH  and  Diodrast  in  dog 
and  man  (0.75  to  0.9  respectively),  which  decreases 
under  a  variety  of  experimental  conditions,  is  ex- 
plained by  the  fact  that  blood  passing  through  shunts 
is  unavailable  for  extraction.  The  separation  process, 


'492 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


for  example,  becomes  less  efficient  in  the  kidnevs  of 
anesthetized  animals,  thus  leading  to  correspondingly 
lower  extraction  ratios.  With  lowered  hematocrit, 
more  plasma  passes  through  the  hypothetical  shunt 
circulation,  bypassing  the  tubular  elements.  A  reduc- 
tion in  extraction  ratio  to  60  per  cent  of  control  value 
was  noted  under  this  circumstance  (160). 

The  peculiarities  of  oxygen  supply  to  the  kidney, 
resulting  from  the  implications  of  this  hypothesis,  have 
been  discussed  earlier.  In  brief,  the  peritubular  circu- 
lation is  supplied  with  a  cell-poor  component  of  blood, 
and  the  oxygen  saturation  in  blood  leaving  the 
actively  metabolizing  tissue  of  the  kidney  may  be  far 
lower  than  in  the  renal  vein.  This  was  proposed  as  the 
basis  for  the  flow-limited  nature  of  the  organ  despite 
high  venous  oxygen  content,  a  proposal  challenged  by 
Levy  (178,   179). 

The  provocative  cell-separation  theory  has  served  a 
useful  purpose  in  stimulating  a  sizable  amount  of  re- 
search. From  this  has  grown  a  considerable  body  of 
data  which  has  challenged  several  of  the  fundamental 
precepts  of  Pappenheimer  and  Kinter.  These  facts 
are  summarized : 

/)  In  the  first  instance,  the  hypothetical  short 
shunt  from  the  efferent  arterioles  to  interlobular  vein, 
bypassing  the  peritubular  capillaries,  has  never  been 
anatomically  demonstrated.  While  the  vasa  recta 
circuit  might  conceivably  function  in  this  role,  it  is  a 
long  circuit  with  a  slow  circulation  and  is  low  in 
erythrocytes,  not  cell-rich  as  the  hypothesis  demands. 
In  all  probability,  less  than  10  per  cent  of  the  total 
renal  blood  flow  passes  through  this  circuit,  based 
upon  the  extraction  ratio  of  PAH  (256),  and  the  flow 
estimates  of  Kramer  el  al.  (166);  hence  its  role  in 
autoregulation  is  dubious. 

2)  Studies  of  cell-plasma  transit  time  show  no 
great  differences  in  speed  of  red  cell  transit  compared 
to  labeled  albumin,  hence  do  not  favor  the  idea  of 
preferential  shunting. 

3)  Studies  of  distribution  of  erythrocytes  through 
the  zones  of  the  kidney  reveal  no  increase  in  concen- 
tration from  outer  medulla  to  cortex. 

./)  Autoregulation  can  persist  with  anemia  (305, 
330)  or  with  perfusion  of  kidneys  with  cell-poor  fluids, 
e.g.,  dextran  (143,  306,  308,  330,  331,  333).  But  in 
support  of  Pappenheimer  &  Kinter  (240),  Haddy  el 
al.  ( 1 24)  saw  no  autoregulation  in  kidneys  perfused 
with  dextran.  Autoregulation,  when  initially  present, 
has  been  shown  by  Waugh  and  Shanks  to  disappear 
after  perfusion  of  the  kidney  with  dextran  for  variable 
periods  of  time.  Of  considerable  interest  is  the  finding 
that  a  plasma  factor  is  needed  in  order  to  maintain 


satisfactory  autoregulation  (330)  and  may  explain 
some  of  the  differences  in  results. 

5)  The  cell-separation  hypothesis  must  necessarily 
advocate  differential  filtration  in  glomeruli  at  different 
levels,  highest  in  the  juxtamedullary,  lowest  in  the 
peripheral.  From  this  a  "splay"  in  the  TmG  titration 
curve  could  be  expected,  whereby  nephrons  attached 
to  glomeruli  with  high  filtering  capacity  would  be 
saturated  first,  those  with  low  filtration  last.  No  such 
splay  was  observed  in  anemic  dogs  ( 1 58)  and  humans 
(256),  indicating  that  all  nephrons  are  saturated  ap- 
proximately simultaneously. 

6")  When  few  or  no  red  cells  are  present  in  arterial 
blood  the  proportion  of  plasma  flowing  through  the 
preferential  channels  should  increase  with  increasing 
pressure,  and  hence  EPAiI  and  ED  should  decrease  in 
anemic  animals  at  the  higher  flow  of  elevated  pressure 
(159).  This  was  found  to  be  the  case  in  cats.  According 
to  Kinter  and  Pappenheimer,  this  would  not  occur 
when  red  cells  are  present  because  the  tendency  for 
plasma  flow  through  the  shunts  to  increase,  owing  to 
the  distensibility  factor,  would  be  counteracted  by 
more  efficient  plasma  skimming.  On  the  other  hand, 
Thompson  el  al.  (305)  found  no  significant  effect  on 
£PAH  of  variations  in  blood  pressure  in  either  normal 
or  anemic  dogs. 

7)  The  appearance  curves  of  PAH  in  the  urine  of 
normal  and  anemic  subjects  are  superimposable, 
suggesting  no  difference  in  traversal  pathway  (256). 

In  summary,  the  numerous  weighty  arguments 
which  have  ben  raised  in  opposition  to  the  cell- 
separation  hypothesis  appear  to  necessitate  abandon- 
ment of  this  theory  as  being  important  in  explaining 
renal  autonomy,  although  Winton  (344)  has  taken 
the  view  that  it  may  be  a  participating  mechanism  in 
the  over  all  phenomenon. 

tissue  pressure  theory.  Advocates  of  this  theory 
must  of  necessity  demonstrate  an  increase  in  IRP  as 
arterial  perfusion  pressure  is  elevated.  Such  evidence 
has  been  offered  by  Hinshaw  et  al.  (141 -144)  for  the 
isolated  kidney-lung-pump  preparation.  Representa- 
tive experiments  are  shown  in  figure  25  (143).  It  is 
seen  that  stabilization  of  flow  coincides  with  an  abrupt 
rise  in  IRP  at  ca.  80  mm  Hg.  Although  flow  with 
dextran  is  higher,  because  of  lower  viscosity,  the 
same  relationship  prevails.  In  another  study  (142), 
it  was  shown  that  kidney  weight  increased  with  pres- 
sure, 0.6  g  per  10  mm  Hg  rise  before  onset  of  auto- 
regulation (range  40  to  80  mm)  and  only  0.3  g  per 
100  mm  Hg  after.  Thurau  &  Kramer  (307),  as  well 
as  Scher  (265),  observed  a  weight  increase  with  sudden 


THE  RENAL  CIRCULATION 


1493 


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RENAL  ARTERY  PRESSURE  (  mmHq  ) 

fig.  25.  Renal  circulatory  autonomy  in  the  dog  as  a  func- 
tion of  tissue  pressure  (needle  puncture).  Symbols  4A  and  4C 
represent  curves  obtained  with  blood  perfusions  before  and 
after  4%  dextran  (4B).  [After  Hinshaw  et  al.  (143).] 

increase  in  pressure.  It  was  concluded  that  the  auto- 
regulation  occurred  because  of  increased  accumula- 
tion of  extravascular  fluid  resulting  from  enhanced 
filtration  at  high  pressure,  which  compressed  low 
pressure  vessels.  Significantly,  blood  volume  estimated 
from  mean  transit  time  (T-1824  X  mean  blood  flow) 
was  shown  to  decrease  slightly  at  pressures  in  the 
range  100-200  in  the  autoregulating  kidney  (188), 
but  volume  increased  in  the  K.CN  poisoned  kidney. 
Hence  the  weight  change  is  likely  due  largely  to  ex- 
travascular fluid  accumulation. 

Analysis  of  regional  resistance  changes  has  been 
attempted  by  Hinshaw  et  al.  (145),  on  the  basis  of 
certain  assumptions.  The  first  was  that  a  stabilized 
ureteral  pressure  after   occlusion   was  a   measure  of 


the  Bowman's  capsule  extravascular  pressure.  Then, 
glomerular  capillary  pressure  should  equal  this  pres- 
sure plus  the  plasma  oncotic  pressure  (20  mm  Hg 
in  this  series).  Another  assumption  was  that  intra- 
renal  venous  pressure  (postperitubular  capillary  seg- 
ment) was  equal  to  tissue  pressure  (IRP),  (which  has 
been  shown  to  be  correct  for  the  arcuate  veins  at 
elevated  venous  pressure)  plus  the  plasma  oncotic 
pressure.  The  authors  have  formulated  the  regional 
resistances  as  follows  [reprinted  with  permission  from 
Hinshaw  et  al.  ( 1 45)] : 

PRE -GLOMERULAR    SEGMENT 
=  RA-UP- COP 


POST -GLOMERULAR      SEGMENT 

(a)  EFFERENT     ARTERIOLAR     SEGMENT 

UP-TP 

F 

(b)  post- peritubular  capillary  segment 

(venous  segment) 

_  tp  -i-  cop  -rv 

f 

RA=  RENAL    ARTERY    PRESSURE  UP"  URETERAL    PRESSURE 

TP.  TISSUE    PRESSURE  COP 'COLLOID     OSMOTIC     PRESSURE 

RV-  ORIFICE    RENAL    VENOUS     PRESSURE 

Autoregulation  was  shown  to  persist  during  occlu- 
sion of  the  ureters  (144),  as  indeed  it  does  during 
venous  pressure  elevation  (119,  123,  281).  The  above 
estimates  of  regional  resistance  are  applicable,  then, 
to  the  autoregulation  manifested  during  ureteral 
occlusion  in  the  isolated  perfused  kidney.  In  a  range 
of  100  to  191  mm  Hg  renal  arterial  pressure  the  fol- 
lowing average  changes  occurred :  preglomerular 
resistance,  —4  per  cent;  postglomerular,  +101  per 
cent  (in  the  latter  value,  most  is  attributable  to  the 
postperitubular  capillary  segment).  Under  these  spe- 
cial circumstances,  afferent  arteriolar  control  seems 
unimportant,  and  it  is  the  influence  of  increased 
IRP  on  compressible  postglomerular  vessels  that 
appears  to  dominate. 

Although  this  hypothesis  is  ingenious  in  its  applica- 
tion, the  special  circumstance  of  the  measurements 
will  make  it  difficult  to  apply  to  the  normally  func- 
tioning kidney.  It  is  well  to  recall  that  the  fundamental 
precept,  i.e.,  that  IRP  varies  with  arterial  pressure, 
has  not  been  uniformly  accepted  by  all  investigators. 

If  the  above  hypothesis  is  correct,  decapsulation  of 
the  kidney  should  have  a  significant  influence  on  the 
autoregulatory  mechanism.  In  this,  investigators  are 
not  in  agreement.  Bounous  et  al.  (28)    after  careful 


I  I'll 


HANDBOOK    OF    PHYSIOLOGY- 


CIRCULATION    II 


decapsulation  procedures,  found  that  autoregula- 
tion  was  indeed  abolished  (fig.  26).  Haddy  et  al.  (124) 
illustrate  several  experiments  which  offer  support  of 
this:  two  pressure-flow  curves  are  more  linear  after 
decapsulation  than  before.  But  Miles  &  DeWardener 
(206)  found  no  difference  between  the  IRP  of  the 
control  and  that  of  the  decapsulated  kidney.  Elevation 
of  IRP  by  mannitol  diuresis  and  elevation  of  venous 
pressure  caused  approximately  equal  increases  in 
IRP  in  the  decapsulated  kidney  and  in  the  paired 
control.  In  an  extreme  situation,  following  K.CN 
treatment  and  elevation  of  perfusion  pressure  by 
pump  to  300  mm  Hg,  IRP  increased  ca.  100  mm  Hg 
in  both  control  and  decapsulated  kidneys. 

In  summary,  the  tissue  pressure  theory  is  attractive 
in  some  respects,  but  since  it  concerns  a  purely  phvsi- 
cal  mechanism  it  is  hard  to  square  with  the  lack  of 
autoregulation  in  kidneys  treated  with  procaine, 
KCN,  and  papaverine,  in  the  oil-perfused  kidney,  or 
even  in  dead  kidneys.  Implicitly,  it  dispenses  with 
the  need  for  afferent  arteriolar  control,  but  a  con- 
siderable body  of  evidence  supports  the  possibility  of 
such  control. 

the  myogenic  theory.  The  principal  evidence  for 
this  theory  comes  from  the  behavior  of  the  renal  blood 
flow  during  rapid  changes  in  perfusion  pressure.  An 
example  taken  from  the  work  of  Semple  & 
DeWardener  (281)  appears  in  figure  27.  Flow  was 
measured  with  an  electromagnetic  flowmeter.  Note 


I60> 


5CV 
PV 


30SEC   -v- 


fig.  26.  Effect  of  decapsulation  on  autoregulation  in  the  dog. 
C:  control;  V:  bilateral  section  of  cervical  vagosympathetic 
chains  in  the  neck;  S:  renal  denervation;  I):  renal  decapsula- 
tion. [After  Bounous  et  al.  (28).] 


fig.  27.  Renal  circulatory  adjustment  following  sudden  in- 
crease in  arterial  perfusion  pressure  i/J.)i  PI':  renal  venous 
pressure.  [After  Semple  &  DeWardener  (281).] 


the  immediate  "overshoot"  of  flow  as  pressure  is 
raised,  followed  by  return  to  a  flow  level  somewhat 
below  the  control  within  60  sec,  and  then  stabilization 
at  the  control  flow  but  at  a  pressure  some  50  mm  Hg 
higher  than  during  the  control.  On  occasion,  rhythmic 
rapid  fluctuations  in  flow  were  observed  after  pressure 
elevation  before  stabilization  occurred,  a  "hunting" 
phenomenon. 

When  the  elevation  was  done  in  progressive  steps, 
the  overshoot  was  proportional  to  the  pressure  eleva- 
tion, but  returned  in  each  instance  to  approximate 
the  control  level  [see  fig.  28  (308)].  It  is  of  interest 
that  the  levels  of  flow,  reached  instantaneously  after 
pressure  change,  fall  on  a  curve  describing  the 
pressure-flow  relationship  in  the  same  kidney  after 
paralysis  of  smooth  muscle  activity  with  papaverine 
(x x  in  the  figure). 

Likewise,  when  pressure  was  dropped  in  steps,  flow 
decreased  immediately  in  a  passive  manner,  but  in 
30  to  60  sec  readjusted  to  the  previous  level  [fig.  29 
(120)].  In  this  series,  constancy  of  flow  was  main- 
tained down  to  70  mm  Hg,  then  fell  off  rapidly. 

Thurau  &  Kramer  (307)  have  analyzed  in  an  in- 
teresting fashion  the  correlation  of  total  blood  flow, 
superficial  (cortical  peritubular)  capillary  blood  con- 
tent, and  weight  change  in  response  to  rectangular 
pressure  increments.  The  results  are  illustrated  in 
figure  30.  Capillary  blood  content  was  measured  by 
an  "infrared  reflectometer'"  technique.  Note  the 
typically  instantaneous  overshoot  of  flow  as  pressure 
is  increased,  followed  by  stabilization.  (Allowance 
must  be  made  for  the  possibility  that  an  overshoot 
artifact  by  the  rotameter  may  contribute  to  the  initial 
rise.)  This  appears  to  be  a  function  of  the  initial  tonus 


THE    RENAL    CIRCULATION  1 495 


300 -- 


ZOO    mmHg  300 


fig.  28.  Immediate  and  stabilized  relationship  of  renal 
blood  flow  to  perfusion  pressure.  [After  Thurau  &  Kramer 
(308).] 


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fig.  29.  Immediate  and  stabilized  response  of  renal  blood 
flow  to  decrease  in  perfusion  pressure.  O:  Immediate  flow;  •: 
stabilized  flow;  X  :  immediate  response  to  restoration  of  pressure, 
then  return  to  control  ( •)  cluster,  at  upper  end  of  curve.  The 
numbers  indicate  sequence  of  response.  [After  Grupp  et 
al.  (120).] 


of  the  vascular  smooth  muscle;  when  low,  overshoot 
was  greater  than  when  tonus  was  high.  The  capillary 
volume  increases  transiently  during  the  phase  of 
overshooting  (increase  is  with  downward  deflection  of 
the  galvanometer)  accompanying  the  initial  passive 
expansion  of  arteries  and  arterioles  as  pressure  is 
suddenly   increased.    Then,    as   total   flow   settles   to 


BLOOD  PRESSURE 


BLOOD  FLOW 


GALV. 
DEFLECTION 


WEIGHT 


120 

fig.  30.  Immediate  and  delayed  adjustment  to  rectilinear 
increase  in  blood  pressure — renal  blood  How,  superficial  corti- 
cal blood  volume  (galvanometer  deflection) — and  kidney 
weight.  (Downward  deflection  of  galvanometer  indicates  in- 
crease in  volume.)  Weight  change  is  an  approximation  of  trend. 
[After  Thurau  &  Kramer  (307).] 

lower  levels  after  the  onset  of  the  myogenic  contrac- 
tion, capillary  content  decreases  somewhat. 

Upon  decrement  of  pressure,  flow  decreases  mark- 
edly below  the  control,  indicative  of  the  contracted 
state  of  the  resistance  vessels.  Then  normal  flow  is 
slowly  restored  as  the  myogenic  response  recedes. 
Capillary  blood  content  during  this  decrement  in 
flow  also  decreases  significantly,  then  is  restored  as 
total  flow  rises. 

The  weight  change  may  show  a  triphasic  response 
in  experiments  with  more  prolonged  stages:  a)  an 
initial  rapid  increment  as  blood  surges  into  the  re- 
laxed vessels;  b)  a  transient  drop  as  the  myogenic  re- 
sponse occurs;  and  c)  a  secondary  rise.  The  last  may 
be  the  result  of  increased  transudation  of  fluid  through 
the  capillaries  at  the  elevated  pressure  and  increased 
flow. 

The  dynamic  reactivity  implied  in  these  fairly- 
rapid  adjustments  corresponds  to  the  type  of  reac- 


1 4g6 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


tivity  anticipated  from  the  smooth  muscle  of  the 
vasculature.  That  a  vital  phenomenon  is  involved  is 
supported  by  the  action  of  a  number  of  agents  known 
to  impair  smooth  muscle  activity:  papaverine  will 
eliminate  autoregulation  (306,  308),  as  will  K.CN 
(188,  207,  233)  and  theophylline  (121).  Procaine  has 
been  cited  earlier.  Certain  anesthetics,  such  as  numal 
(120,  121)  and  chloralhydrate  (330)  impair  auto- 
regulation as  will  ethanol  (260). 

Both  cooling  and  perfusion  of  the  kidney  with  oil 
remove  autoregulation  (328,  330).  Hemorrhage  de- 
presses autoregulation  (73,  271,  331).  Anoxia  created 
by  perfusion  of  the  kidney  with  perfusion  fluid  [20  9i 
plasma-80  %  polyvinylpyrollidone  (PVP)-Locke's  solu- 
tion] subjected  to  helium  rather  than  oxygen  appeared 
to  impair  autoregulation  somewhat;  flow  increased 
more  with  pressure  increments  than  with  comparable 
increments  during  the  control  (331 ). 

It  is  well  to  point  out  that  autoregulation  may  be 
impaired  in  another  manner  and  may,  in  part,  ex- 
plain the  apparent  loss  of  response  in  hemorrhage. 
Under  this  circumstance  and  with  adrenaline  and 
hypertonic  fluid  infusions,  the  smooth  muscle  of  the 
vasculature  becomes  highly  tonic,  and  responses  to 
increments  in  pressure  become  much  reduced  (307). 
Then  the  pressure-flow  curve  becomes  convex  to  the 
pressure  axis  and  resembles  the  pressure-flow  curves 
obtained  in  the  hind  limb  and  other  organs,  which 
usually  have  a  higher  resistance  than  the  kidney. 

aberrant  resltlts.  Several  investigations  may  be 
cited  in  which  typical  autoregulation  was  not  ob- 
served, but  in  which  pressure-flow  curves  were  linear 
or  convex  to  the  pressure  axis.  This  includes  the  work 
of  Ohler  et  al.  (235)  in  the  rat.  Indications  of  a  high 
degree  of  vascular  tone  are  seen  in  the  low  flows  in 
many  preparations  and  the  high  flow  intercepts  on  the 
pressure  axis.  It  will  be  recalled  that  others  have  re- 
ported the  more  common  concave-to-pressure-axis 
curve  in  the  rat  (333),  indicating  autoregulation. 

Likewise,  the  work  of  Langston  et  al.  (172,  173) 
manifested  a  convex-to-pressure-axis  relationship  of 
flow  in  dogs.  Again,  flow  per  gram  of  tissue  was  low 
(less  than  2  ml  min  g)  at  normal  pressure,  suggesting 
a  highly  tonic  preparation.  The  high  pressure  inter- 
cept for  flow  also  suggested  this.  In  the  first  report 
(172)  flow  appeared  to  be  only  about  10  ml  per  min 
(total  per  kidney)  at  60  mm  Hg.  In  the  second  report 
(173),  in  the  control  series,  the  zero  flow  intercept 
lay  between  20  and  40  mm  Hg;  flow  at  100  mm  Hg 
in  most  preparations  was  less  than  1 .5  ml  per  min  per 
g.  Furthermore  the  method  of  perfusion  suggested  the 


possibility  of  a  source  of  technical  error.  The  kidney 
was  perfused  via  an  isolated  segment  of  aorta  at  the 
level  of  the  renal  artery.  Hardin  et  al.  (130)  used  a 
similar  technique,  and  found  the  same  convex  rela- 
tionship. However,  when  they  carefully  tied  small 
lumbar  arteries  leaving  this  segment  of  the  aorta,  the 
pressure-flow  curve  assumed  the  more  commonlv 
found  contour,  concave  to  the  pressure  axis  (fig.  31). 

SIGNIFICANCE  OF  THE  MYOGENIC  RESPONSE.    Bayliss  (  I  3), 

a  number  of  years  ago,  called  attention  to  a  myogenic 
response  to  sudden  changes  in  pressure  both  in  de- 
nervated  organs  and  segments  of  artery  (carotid),  and 
attributed  it  to  alterations  in  tonus  of  smooth  muscle 
in  the  arteries  in  response  to  change  in  tension. 
Wachholder  (324)  studied  isolated  segments  of  equine 
carotid,  and  observed  contractions  following  sudden 
increases  in  pressure  occurring  with  a  latency  of 
usually  10  to  20  sec  (8  sec  was  the  shortest).  The  con- 
traction phase  lasted  20  to  60  sec.  Burgi  (44)  utilized 
bovine  mesenteric  artery  segments,  but  saw  distinct 
responses  in  only  23  per  cent  of  his  tests;  weak  re- 
sponses occurred  in  9  per  cent,  and  in  12  per  cent  the 
response  had  so  great  a  latency  that  it  was  deemed 
questionable;  56  per  cent  showed  no  response. 

Folkow  (89,  90)  has  placed  the  suggestion  of  Bayliss 
and  others  on  a  firmer  footing.  His  experiments, 
utilizing  the  dog  hind  limb  preparation,  under  condi- 
tions which  apparently  controlled  possible  neurogenic 


350 

'■Sr 

300 

1    7 

•  LUMBAR    ARTERIES    occluded 

250 

X 

•  LUMBAR     ARTERIES    patent 

E 
E 

200 

UJ 

"0: 

150 

3 

CO 

to 

UJ 

■  (Z 
0. 

1.0  J 

-—~7 

100 

8^/ 

""7 

50 

.9 

FLOW 

m  l/mln 

0  25  50  75  OO  125  150  175         200 

fig.  31.  Perfusion  pressure  as  a  function  of  rate  of  blood  flow 
through  both  kidneys  of  a  dog  before  and  after  occlusion  of  the 
lumbar  arteries.  Numbers  are  renal  vascular  resistance  in  mm 
Hg/ml/min.  (After  Hardin  et  al.  (130).] 


THE    RENAL    CIRCULATION 


'497 


and  humoral  factors,  gave  support  to  the  myogenic 
theory,  and  he  concluded  "Vascular  tone  is  in  its 
basic  origin  myogenic,  though  strongly  influenced  by 
external  factors." 

That  this  property  of  the  smooth  muscle  of  the  kid- 
ney arterioles  is  typical  of  smooth  muscle  elsewhere 
is  shown  by  the  work  of  Bozler  (30).  Isolated  segments 
of  ureter  were  subjected  to  sudden  increases  in  in- 
ternal pressure.  This  created  electrical  potentials 
which  produced,  at  first,  local  responses;  if  the  poten- 
tial was  strong  enough,  a  conducted  response  resulted. 
He  found  that  the  greater  the  pressure,  the  steeper 
was  the  local  potential  change  and  the  shorter  the 
delay  for  the  onset  of  conduction.  Bulbring  (43)  has 
shown  that  stretch  of  smooth  muscle  cells  of  the  taenia 
coli  acted  as  a  stimulus  for  increased  myogenic  auto- 
maticity,  and  that  the  element  of  the  smooth  muscle 
cell  sensitive  to  stretch  was  closely  combined  with  the 
properties  of  the  tension-producing  element. 

The  group  of  investigators  that  support  the 
myogenic  theory  to  explain  autoregulation  of  the 
kidney  favor  the  afferent  arteriole  as  the  site  of  regula- 
tion. More  specifically,  the  myocytes  of  the  juxta- 
glomerular apparatus  appear  to  be  a  likely  point  of 
control  (274,  331).  In  conclusion,  the  myogenic 
theory  seems  most  attractive  as  an  explanation  of 
autoregulation  of  the  renal  circulation,  but  it  is  likely 
that  acceptance  of  one  theory  to  the  exclusion  of  some 
of  the  others  would  be  an  oversimplification.  The 
challenging  prospect  remains  to  integrate  properly 
the  several  possibilities  into  a  unified  concept  which 
might  operate  in  the  intact,  unanesthetized  animal  in 
normal  circulatorv  homeostasis 


PRESENT  STATUS  OF  THE  TRUETA 
JUXTAMEDULLARY  SHUNT 

It  was  postulated  by  Trueta  et  al.  (311)  that  diver- 
sion of  renal  blood  from  its  usual  cortical  route  to  the 
"less  resistant  and  more  capacious  medullary  circuit" 
(198)  (probably  not  true  by  currently  known  facts) 
was  a  physiologic  mechanism  which  was  involved  in  a 
number  of  abnormal  circulatory  states.  These  in- 
cluded reflex  anuria,  anuria  associated  with  incom- 
patible blood  transfusion,  crush  injury,  blackwater 
fever,  etc.,  Pitressin  inhibition  of  water  diuresis,  the 
renal  ischemia  of  shock  or  that  induced  by  fright  or 
adrenaline,  in  the  reduction  in  tubular  excretion 
following  protracted  renal  ischemia,  and  in  the  genesis 
of  essential  hypertension. 

These  investigators  had  reported  that  during  renal 


ischemia  the  arterial  pulse  may  be  seen  in  the  renal 
vein,  and  that  the  renal  venous  blood  may  acquire  an 
arterial  color.  It  was  their  belief  that  the  juxtamedul- 
lary  glomeruli  and  vasa  recta  circuit  may  afford 
veritable  shunts  between  the  renal  artery  and  vein  "... 
a  diversion  of  blood  from  the  cortex,  the  most  active 
part  of  the  kidney,  to  the  medullars-  pathway,  with  a 
possible  increased  speed  of  flow  through  these 
channels." 

Such  shunts  should  therefore  cause  a  reduction  in 
renal  oxygen  A-V  difference.  Furthermore,  this  would 
shunt  blood  away  from  the  zone  ol  greater  metabolic 
activity  in  the  cortex  to  the  juxtamedullary  vasa  recta 
and  loop  of  Henle  system,  with  less  efficient  perfusion 
of  the  proximal  tubular  secretory  sites.  This  should 
cause  a  decrease  of  ED  or  £PAH  with  an  increase,  or 
no  necessary  decrease,  in  total  blood  flow  as  measured 
by  direct  methods  or  perhaps  by  the  Fick  method. 
Finally,  if  shunts  open  which  bypass  glomeruli,  £In 
should  decrease  without  a  decrease  in  blood  flow,  or 
should  decrease  more  markedly  than  blood  flow 
(assuming  continued  adequacy  of  filtration  pressure). 

Morphological  identification  of  the  shunt  should  be 
possible  with  injections  of  India  ink,  Prussian  blue,  or 
radiopaque  material  such  as  Thorotrast.  The  Trueta 
evidence  consisted  mainly  of  appearance  of  India  ink 
or  Thorotrast  in  higher  concentration  in  the  juxta- 
medullary region  when  injected  intravascularly  during 
sciatic  nerve  stimulation  or  epinephrine  action.  But 
great  care  must  be  exercised  in  attempts  to  interpret 
rate  or  volume  of  flow  by  appearance  of  the  injection 
mass.  Thus,  contraction  of  venous  effluent  constrictors 
could  give  the  appearance  of  congestion  of  the  medul- 
lary circuit,  in  the  face  of  an  actual  reduction  of  flow. 
Incomplete  filling  due  to  faulty  injection  could  give 
the  appearance  of  vasoconstriction  in  the  cortex. 

Morphological  Evidence 

Injection  studies  have  been  controversial,  being 
interpreted  either  in  favor  of  the  original  hypothesis  or 
against  it.  This  has  been  largely  a  matter  of  interpreta- 
tion of  what  are  often  quite  similar  pictures. 

Montague  &  Wilson  (214),  correlating  Thorotrast 
injection  studies  with  clearance  data  (£PAH)  in  rabbits, 
believed  they  saw  evidence  of  a  juxtamedullary  shunt 
after  epinephrine  injection.  This  was  accompanied 
by  marked  decreases  in  EFxn  (mostly  negative,  and 
averaging  —  26.6^).  Herdman  &  Jaco  (138)  par- 
tially constricted  one  renal  artery  of  rabbits,  and  in- 
jected India  ink  3  days  to  5  weeks  later.  They  found 
the  ink  chiefly  in  the  inner  cortex  and  juxtamedullary 


1498 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


zone,  suggesting  the  diversion  of  blood  accompanying 
cortical  ischemia.  Tracheal  occlusion  in  rabbits  (92) 
caused  paling  of  the  kidney  and  decrease  in  volume. 
Sections  of  innervated  kidneys  removed  at  the  height 
of  anoxia  showed  anemia  of  the  cortical  portions.  In 
the  denervated,  there  was  no  such  "diversion"  of  flow, 
but  it  was  possible  to  produce  it  in  these  by  injections 
of  epinephrine.  Arcadi  &  Farman  (2)  state  that  in 
rabbits,  blood  was  diverted  almost  exclusively  to  the 
cortical  circuit  by  pilocarpine  and  magnesium  sulfate 
injection  and  most  prominently  by  water  diuresis. 
Dehydration,  on  the  other  hand,  caused  the  accumula- 
tion of  ink  in  the  medulla.  The  findings  of  Kuhlgatz 
(168)  in  rats  were  very  similar  with  respect  to  the 
findings  on  diuresis  and  dehydration.  Mover  et  al. 
(222,  223)  although  finding  uniform  distribution  of 
India  ink  in  dog  and  rabbit  kidneys  during  sciatic 
stimulation,  nevertheless  report  cortical  ischemia  and 
subcortical  accumulation  of  ink  after  injection  of  0.2 
mg  of  epinephrine  into  the  rabbit,  but  this  finding  does 
not  have  to  be  interpreted  as  demonstrating  the  open- 
ing of  medullary  shunts. 

Insull  et  al.  ( 1  50)  have  pointed  out  that  an  adequate 
filling  pressure  is  needed  for  validity  of  the  injection 
methods.  When  Prussian  blue  was  injected  into  fresh 
rabbit  kidneys  at  a  pressure  of  50  cm  HoO,  good 
filling  of  the  entire  kidney,  including  cortex,  was  ob- 
served; at  25  cm  HoO,  filling  of  the  juxtamedullary 
glomeruli  and  vasa  recta  only  occurred. 

In  some  experiments  involving  sciatic  stimulation, 
stimulation  of  the  perirenal  plexus,  or  hemorrhage, 
the  juxtamedullary  glomeruli  were  uniformly  stained, 
while  the  peripheral  glomeruli  were  not.  This  oc- 
curred only  when  renal  blood  flow  was  low.  They  in- 
terpreted this  as  regional  cortical  ischemia  but  not  as 
increased  flow  through  the  medulla. 

The  conclusions  of  Block  et  al.  (24)  and  Kahn  rt  a/. 
(156)  are  similar.  Block  et  al.  tried  stimulation  of  renal 
nerves  in  rabbits,  clamping  of  the  artery,  injection  of 
constrictor  agents,  and  sciatic  nerve  stimulations. 
They  concluded  that  a  pale  cortex  and  a  medulla 
filled  with  blood  were  not  evidence  that  blood  was 
flowing  largely  through  the  medulla:  the  medulla 
may  be  congested  even  though  flow  has  stopped.  Kahn 
et  al.  found  during  sciatic  stimulation  in  the  rabbit  a 
normal  distribution  of  ink  in  8  of  1 1  animals.  In  3, 
however,  the  peripheral  cortex  had  no  ink,  and  the 
juxtamedullary  glomeruli  and  the  medullary  vessels 
were  well  filled. 

In  summary,  the  rabbit  kidney  during  various  types 
of  strong  afferent  stimulation  or  during  epinephrine 
action   mav   demonstrate   a   cortical    ischemia,    with 


maintained  flow  in  the  medulla.  This  cannot  be 
interpreted  as  diversion  of  flow  to  the  medulla,  and 
particularly  not  as  increased  flow  through  this  zone. 
Nevertheless,  the  anatomical  evidence  of  a  dual  circu- 
lation is  good,  and  there  is  some  good  functional 
evidence  of  this. 

Daniel  et  al.  (6g)  have  made  excellent  serial  angio- 
grams in  cats  and  dogs  which  follow  the  progress  of 
Thorotrast  through  the  kidney.  The  material  passes 
very  rapidly  through  the  cortex,  but  the  diffuse 
shadow  of  the  medulla  persists  long  after  the  veins 
have  emptied,  demonstrating  a  much  slower  per- 
fusion of  the  vasa  recta  system  of  the  medulla.  This 
conforms  with  the  studies  of  Kramer  et  al.  (166)  who 
used  a  photoelectric  technique.  They  bring  evidence 
that  the  role  of  the  medullary  vasa  recta  system  may  be 
unique  in  connection  with  the  role  of  the  counter- 
current  system,  and  the  dilution  and  concentration  of 
the  urine.  Other  evidence  is  at  hand  in  support  of 
this,  and  will  be  taken  up  in  a  later  section. 

Functional  Evidence;  Interpretations 

Based  on  Clearance  Data 

Scher  (264)  used  a  heated-thermocouple  technique 
in  dogs,  rabbits,  and  cats,  one  thermocouple  being 
placed  in  the  cortex  and  the  other  in  the  medulla. 
Although  quantitative  interpretations  must  be  made 
cautiously,  focal  flow  paralleled  total  renal  blood  flow 
during  action  of  epinephrine  and  arterenol,  acetyl- 
choline, and  stimulation  of  periarterial  plexus. 

The  clearance  data  are  concerned  mainly  with 
changes  in  A-V  oxygen  difference,  and  in  £PiH  and 
Eln.  Mover  et  al.  (223),  during  marked  reduction  in 
flow  (—46%)  resulting  from  prolonged  sciatic  stimu- 
lation in  dogs,  found  the  A-V  oxygen  difference  in- 
creased from  1.7  to  3.3  vol  per  cent;  in  rabbits,  from 
3.1  to  6.8  vol  per  cent  in  a  group  in  which  venous 
flow  was  measured,  and  3.5  to  9.2  vol  per  cent  in  a 
venipuncture  group.  With  epinephrine,  resulting  in 
increased  blood  pressure  and  reduced  flow  (as  much 
as  70%  reduction)  in  rabbits,  A-V  oxygen  increased 
as  much  as  313  per  cent.  Other  investigtions  de- 
tected no  significant  alteration  of  oxygen  extraction 
in  dogs  or  man  during  epinephrine  injection  ( 1 49,  224, 

254)- 

Epinephrine  in  dogs  gave  no  evidence  of  a  medul- 
lary shunt,  since  £PAH,  ECT,  extraction  of  oxygen  and 
TmG  did  not  significantly  decrease  in  presence  of 
moderate  to  marked  decrease  in  GFR,  urine  flow, 
and  RBF  (149).  Mover  &  Handley  (224)  observed  no 
reduction  in  EPXH  in  dogs,  but  TmG  decreased  due  to 


THE    RENAL    CIRCULATION 


'499 


table    1 1 .  Effect  of  Albumin  Infusion  on  Renal  Function  in  Man 
\-75  S  dlb.  (300  ml)  infused  in  10-24  m'"l 


U.    Inn 

After 

';  Increase 

Cln 

CpAH 

Total 
KM 

EpAB 

Med. 
RPF 

Cln 

CpAH 

Total 
RPF 

I  I'M! 

Med. 
RPF 

Ci» 

CPAH 

Total 
RPF 

Med. 
RPF 

Normal 

l65 

863 

1044 

82.7 

181 

189 

I  I  23 

1586 

71.2 

463 

'4 

3' 

52 

256 

Normal 

112 

741 

820 

9O.4 

79 

124 

IOOI 

1280 

78-3 

279 

1 1 

35 

56 

354 

Normal 

130 

638 

788 

8l  .O 

■5° 

I38 

764 

1250 

6l  .O 

486 

6 

20 

59 

324 

Hypertension 

IO9 

375 

429 

87-3 

54 

112 

491 

662 

74-3 

'7' 

3 

3' 

54 

316 

Hypertension 

IOO 

542 

*57 

82.5 

"5 

IO3 

693 

938 

73-7 

245 

3 

27'5 

43 

213 

Hypertension 

36 

■45 

250 

58.O 

105 

39 

154 

353 

43 -6 

'99 

8 

6 

42 

190 

Chronic  nephritis 

56 

265 

4'3 

64.O 

148 

32 

24O 

533 

45' 

293 

-43 

-9.0 

29 

198 

Nephrotic  synd. 

66 

444 

493 

90.0 

49 

1 10 

757 

IOIO 

75  0 

253 

67 

70 

205 

5'6 

Avg. 

86 

26.5 

67 -5 

296 

Total  RPF  (total  renal  plasma  flow)  =   (Cpah/Epab)' 100. 
Cpah-         [After  Cargill  (48).] 


Med.  RPF  (medullary  renal  plasma  flow)  =  Total  RPF  — 


glomerular  closure  during  epinephrine  and  arterenol 
infusion.  Epinephrine  and  histamine  caused  a  de- 
crease in  ispAH  of  only  1 1 .4  per  cent  at  the  maximum 
in  the  human  (254).  Tilting,  with  resultant  increased 
sympathetic  activity  as  evidenced  by  reduction  in 
RPF  (CPAH  £pah)j  induced  no  change  in  £PAH  (39)- 
An  interesting  exception,  and  at  present  the  only 
type  of  positive  evidence  of  increased  flow  through 
the  medullary  circuit,  is  supplied  by  Cargill  (48)  on 
the  effects  of  iv  administration  of  serum  albumin  on 
renal  function  of  human  subjects  in  water  diuresis. 
The  results  are  summarized  in  table  1 1 .  Note  that 
■Epah  decreased  and  the  calculated  medullary  plasma 
flow  increased  from  no  to  298  ml  per  min.  Michie 
et  al.  (204)  have  supplied  excellent  confirmation  of 
these  results.  In  their  studies,  the  constancy  of  TmG 
and  TmpAH  suggested  that  no  nephrons  were  shut 
off  as  RPF  increased  up  to  200  per  cent.  They  sug- 
gested that  this  was  due  to  opening  of  intrarenal 
shunts  without  diversion  of  cortical  blood.  Barker  et 
al.  (11)  concur  with  the  observations  of  Michie  et  al. 
They  found  also  that  A-V  oxygen  decreased  by  30  to 
40  per  cent  as  the  total  renal  blood  flow  increased,  a 
fact  consonant  with  the  above  interpretation. 


Role  of  the  Medullary  Circulation 
in  Diuresis  and  Antidiuresis 

The  Oxford  workers  originally  suggested  juxta- 
medullary  diversion  of  blood,  with  diminished  filtra- 
tion and  greater  reabsorption  of  water  in  the  thin 
segment,  as  a  mechanism  explaining  the  antidiuretic 
action  of  Pitressin,  spontaneous  changes  in  urine  flow 
in  the  erect  and  supine  position,  during  emotional 


excitation,  and  in  other  circumstances  involving 
endogenous  ADH  secretion.  The  medullary  diversion 
of  blood  was  first  proposed  as  an  explanation  of  anti- 
diuresis  by  Frey  (96)  in  1934. 

From  this  it  has  been  assumed  by  Maxwell  et  al. 
(198)  that  changes  in  EPAH  should  accompany  diure- 
sis. This  was  not  the  case  in  a  series  of  human  sub- 
jects presented  by  them  with  a  range  of  urine  flow 
from  0.68  to  19.7  ml  per  min.  £]>AH  remained  within 
a  normal  range  of  0.88  to  0.96.  However,  their  ob- 
servations of  entire  diuretic  cycles  were  few.  Further- 
more, inhibition  of  water  diuresis  with  doses  of 
Pitressin  as  high  as  2000  to  5000  milliunits  per  hour 
caused  no  significant  alteration  in  EPAH,  Ein,  and 
A-V  oxygen  difference. 

The  application  of  the  intrarenal  photoelectric 
technique  for  measuring  regional  dye  transit  time 
(T-1824)  has  disclosed  interesting  new  facts  about 
this  mechanism.  The  technique  as  applied  by  Kramer 
et  al.  (166,  309)  is  shown  in  figure  32.  Normally, 
mean  transit  time  averages  27.7  sec  for  the  medulla, 
and  2.5  sec  for  the  cortex  of  the  canine  kidney.  When 
the  perfusion  pressure  was  elevated  (carotid  sinus  de- 
nervation and  vagal  block  by  narcosis,  or  by  pump), 
medullary  transit  time  was  markedly  reduced,  while 
cortical  transit  time  and  total  renal  blood  flow  (ro- 
tameter) remained  constant.  With  this,  urine  volume 
increased  noticeably.  Two  representative  experiments 
appear  in  table  12  (308).  From  such  evidence,  they 
conclude  that  the  juxtamedullary  glomeruli  and  the 
vasa  recta  system  do  not  demonstrate  autoregulation 
of  flow.  (It  is  possible  that  enhanced  perfusion  of  the 
medulla  at  higher  pressure  via  shunts  of  other  types, 
e.g.,   the  spiral   arteries,   arteriolae  rectae  verae,   or 


1500 


IIAMlBi  )(  iK    OF    I'HYSIOI  OCA- 


CIRCULATION    II 


Kobe/ 


Rinden- 
Refleklomeler 


Y\^j Photozelle 


R 

Harnabfluss 


fig.  32.   Method  for  measuring  cortical  and  medullary  cir- 
culatory transit  time.  [After  Kramer  el  al.  (166).] 

table  12.  Effect  of  Increased  Perfusion  Pressure  on 
Regional  Transit  Time  of  the  Kidney 


Renal  Art. 
Pressure 
mm  Hg 


Med.  Trans. 

Time  (tpM) 

sec 


Cortical 

Trans.  Time 

U.,R)  sec 


tPM 
1PR 


Blood  Flow 
ml/g/min 


Urine  Vol. 
ml/min 


Experiment 


'°5 
■95 
205 


16.5 

12. 1 

1 1 .2 


4.2 
4-5 
4-5 


0.25 
2.50 
3-5° 


Experiment  1 1 


140 

32-3 

3' 

IO.4 

4.1 

0.30 

l65 

27-5 

3-3 

8-3 

4.0 

o-75 

210 

22.9 

3-i 

7-4 

4-3 

2.25 

[After  Thurau  et  al.   (308).] 

Ludwig's  arterioles,  could  produce  this  effect.)  The 
total  volume  flow,  they  contend,  is  small  relative  to 
total  flow,  and  is  within  the  error  of  the  method  of 
measurement.  Nevertheless,  it  suffices  to  "washout" 
the  osmotic  gradient  established  in  the  critical  long 
vasa  recta  loops  and  accompanying  loops  of  Henle  in 
the  papillary  zone.  With  this,  the  mechanism  for 
concentration  of  the  urine  becomes  limited;  and 
diuresis  ensues.  Selkurt  (276)  has  shown  that  this 
type  of  diuresis  is  accompanied  by  enhanced  sodium 
excretion. 

In  support  of  this  hypothesis  are  the  effects  of  water 
diuresis  and  ADH  action  (fig.  33).  Note  the  marked 
decrease  in  medullary-plasma  transit  time  (tpM) 
with  diuresis,   and   the  return  during  ADH   action. 


These  effects  are  thought  to  be  the  result  of  changes  in 
blood  viscosity  brought  about  during  water  diuresis 
(decreased  concentration  of  albumin  and  cells  in  the 
vasa  recta)  or  increased  ADH  action.  It  will  be  re- 
called that  with  water  diuresis,  lack  of  ADH  activity 
permits  the  urine  to  remain  hypotonic:  the  osmotic 
gradient  is  dissipated  and,  with  it,  no  concentration 
of  blood  constituents  occurs:  blood  viscosity  decreases, 
and  transit  time  is  reduced.  The  vasopressor  activity 
of  ADH  (arginine-vasopressin)  may  conceivablv  be 
involved  in  regulation  of  blood  flow  in  this  circuit. 

The  critical  point  of  change  in  t,,M  occurs  when 
Cosm  —  V  —  o,  as  revealed  in  two  representative 
experiments  in  figure  34.  When  free  water  clearance 
(Ch2o)  begins,  T„M  reaches  a  rather  constant,  minimal 
value. 

The  failure  of  Maxwell  et  al.  (198)  to  note  changes 
in  £pAH  with  diuresis  and  antidiuresis  may  have  oc- 
curred because  the  above  changes  in  flow  are  small 
enough  not  to  be  discernible  in  the  normal  range  of 
variation  of  the  EpXH  measurement. 

An  explanation  of  the  results  of  Goodyer  et  al.  ( 108, 
log)  may  fall  into  line  with  the  above  findings.  During 
nonshocking  hemorrhage  during  which  arterial 
pressure  was  kept  constant,  sodium  excretion  declined 
in  the  absence  of  measurable  changes  in  glomerular 
filtration  rate  or  renal  plasma  flow.  (Data  on  urine 
volume  were  not  supplied,  but  this  must  certainly 
have  declined.)  Measurement  of  intrarenal  hematocrit 
led  them  to  conclude  that  intrarenal  redistribution  of 
blood  flow  may  have  occurred,  involving  diversion  of 
plasma  to  cell-poor  capillaries  (or  to  lymphatic 
spaces).  This  could  involve  the  above  mentioned  vasa 
recta  mechanism,  and  obviouslv  would  be  the  con- 
verse of  the  above  cited  experiments  involving  in- 
creased renal  perfusion  pressure. 

In  summary,  a  newly  recognized  and  important 
function  of  the  vasa  recta  system  as  a  counterpart  of 


?r 


I' 

ml/min 
80r      1 


few 


-  *: 


sec 
80 

Wasserdiurese 

nachADH 

tpMs* 
"/Posm 

y  ■ 

/     & 

60 
'  W 

9(1 

^\ 

"        "  0  2  3  CStd. 

fig.  33.  Mean  medullary  transit  time  of  T-1824  (tpM) 
during  diuresis  and  after  ADH;  U/P„sm:  osmolar  concentration 
ratio  of  urine  to  plasma;  GF:  glomerular  filtration.  [After 
Thurau  et  al.  (309).] 


THE    RENAL    CIRCULATION 


I  50I 


80 

sec 
60- 


W 


20 


0%  s 

\° 

0 

-  a. 
1- 

4 

ml/min 

rH20  "•— 

-*Ch2o  ' 

2 

fig.  34.  Mean  transit  time  during 
diuresis  and  antidiuresis  as  a  function  of 
CHoO  (water  concentration);  T§20:  os- 
motic water  deficit,  i.e.,  below  equilib- 
rium point.  [After  Thurau  et  al.  (309).] 


the  loop  of  Henle  in  the  countercurrent  system  is  indi- 
cated, and  this  becomes  the  modern  role  of  the  former 
Trueta  juxtamedullary  shunt. 


RESPONSE  OF  RENAL  BLOOD   FLOW 
TO  PHYSIOLOGICAL  STRESS 


The  dog  and  man  differ  significantly  in  the  response 
of  the  renal  blood  flow  to  exercise.  The  canine  kidney- 
shows  a  considerable  amount  of  autonomy  of  circula- 
tion during  exercise  to  a  degree  which  results  in  sig- 
nificant reduction  in  blood  flow  in  man.  Blake  (23) 
exercised  dogs  on  a  treadmill  at  the  rate  of  2.5  mph 
for  40  min  and  observed  no  significant  changes  in 
Cpah  and  C'cr-  In  one  of  three  dogs  tested,  when  "emo- 
tional" stimulus  was  superimposed  (a  loud  horn), 
Cpah  decreased  from  161  to  137  ml  per  min,  then  re- 
turned. CCr  did  not  change.  Greater  effects  were  noted 
on  sodium  excretion,  which  decreased  during  the 
emotional  response.  Carlin  et  al.  (50)  ran  their  dogs 
at  5.6  to  io  mph  on  a  150  grade  for  7  to  20  min;  pulse 
rate  was  often  over  160  per  min,  and  respiratory 
rate,  over  300  per  min.  Yet  there  was  no  change  in 
Cpah  or  CIn,  and  sodium  excretion  did  not  change  sig- 
nificantly. 

Recumbent  human  subjects  pedaling  the  equiva- 
lent of  0.5  kg  weight  at  60  cycles  per  min,  which 
doubled  their  resting  oxygen  consumption,  showed  a 
20  per  cent  reduction  in  RPF,  while  GFR  remained 
unchanged,  as  did  £PAH  (42).  Sodium  excretion  de- 
creased by  20  per  cent.  Chapman  et  al.  (52)  worked 
their  normal  male  subjects  on  a  treadmill  for  16-min 
periods.  The  following  decreases  in  CPAH  were  noted : 
at  3.0  mph  at  o  grade,  6  per  cent;  3.0  mph  at  5  per 
cent  grade,  17  per  cent;  at  3.5  mph  at  10  per  cent 
grade,  25  per  cent  below  resting  control.  Work  was 


continued  for  another  16-min  period,  with  the  follow 
ing  decreases:  15,  27,  and  35  per  cent,  respectively. 
Recovery  was  incomplete  after  40  min.  In  a  subse- 
quent study  (53),  the  above  results  were  confirmed 
and,  in  addition,  the  work  period  (3  mph  at  j'~, 
grade)  was  prolonged  to  3  hours;  during  the  second 
and  third  hours,  CPAh  decreased  no  more  than  it  had 
during  the  first  hour  (  —  18.510  —33.7  %  below  control). 
Recovery  occurred  in  about  an  hour.  Radigan  & 
Robinson  (250)  observed  that  exercise  (3  mph  on  a  5  ' . 
grade)  produced  a  42  per  cent  decrease  in  RPF,  but 
the  Cln  did  not  change  when  the  environmental  tem- 
perature was  cool  (21  C);  when  the  work  was  done 
in  a  hot  environment  (50  C),  C'In  decreased  by  16.5 
per  cent,  with  a  36  per  cent  decrease  in  CPAH.  In 
another  study,  subjects  who  had  run  the  440-yard 
dash  at  full  speed  had  reductions  of  18  to  54  per  cent 
below  control  in  CD,  and  exhibited  also  decrease  in 
CIn  (10).  The  apparent  blood  flow  remained  reduced 
for  10  to  40  min  postexercise. 

Harpuder  et  al.  (134)  compared  different  grades  of 
work  in  different  postures  on  CPAH.  Light  work  (3500 
kg-m)  in  the  erect  or  sitting  position  had  no  significant 
effect.  At  ca.  4800  kg-m,  CPAH  decreased  to  0.85  ± 
.08  of  control  in  the  supine,  as  compared  to  0.69  ±  .04 
in  the  erect  position.  At  9120  kg-m  in  the  erect  posture, 
the  reduction  was  0.55  ±  .10.  At  the  peak  of  exer- 
cise, blood  pressure  had  risen  from  1 14/72  to  164/82 
mm  Hg,  and  heart  rate  from  64  to  1 42  per  min.  They 
point  out  that  with  a  normal  renal  blood  flow  about 
1  liter  per  min  (2o'<'  of  the  cardiac  output),  a  saving 
of  0.5  liter  per  min  is  made  available  for  the  circula- 
tion of  active  tissues.  White  &  Rolf  (339)  similarly- 
analyzed  the  effects  of  running  exercise  With  brief 
maximum  exercise,  RPF  decreased  to  20  per  cent  of 
control,  and  under  extreme  conditions  they  predicted 
that  almost  1  liter  per  min  of  blood  was  made  available 
or  the  active  tissues. 

The  cardiac  patient  shows  more  marked  renal  re- 


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CIRCULATION    II 


sponses  to  exercise  than  the  normal  subject.  A  degree 
of  exercise  (recumbent)  on  a  bicyle  ergometer  which 
had  no  influence  on  normal  subjects  (70  kg-m  min) 
had  the  effects  shown  in  table  13  on  cardiac  patients 
[Werko  et  al.  (336)].  Patients  were  grouped  into  cate- 
gories based  on  heart  size  [Group  A,  512  ml  m-  BSA; 
Group  B,  796  ml/m2  (no  right  heart  failure) ;  Group 
C,  807  ml  per  m2  (with  right  heart  failure)].  Note 
particularly  reduction  in  RBF,  percentage  of  cardiac 
output,  and  increase  in  renal  vascular  resistance.  The 
work  of  others  is  in  support  of  this  (94,  155,  203). 
Evidently  heart  failure  lays  additional  stress  on  com- 
pensatory mechanisms.  When  exercise  is  added,  more 
intense  neurogenic  and  hormoral  influences  serve  in 
shunting  blood  away  from  the  kidney. 

The  kidney  may  not  suffer  as  much  as  might  be 
anticipated  during  the  curtailment  of  flow  in  exer- 
cise, at  least  in  heart  disease,  in  view  of  the  findings 
of  Bishop  et  al.  (21).  They  have  discovered  that  the 
A-V  oxygen  difference  of  the  kidney  of  the  cardiac  pa- 
tient may  increase,  during  exercise,  in  apparent  con- 
tradiction to  the  generally  accepted  "flow-limited" 
characteristic  of  its  circulation.  The  renal  A-V  oxygen 
in  12  cardiac  patients  (mostly  rheumatic  heart  disease 
but  none  in  congestive  heart  failure),  averaged  2.03 
vol  per  cent;  this  increased  to  a  mean  of  3.31  vol  per 
cent  during  exercise.  In  one,  an  increase  to  12.40  vol 
per  cent  was  recorded. 


Posture  and  Orthostatic  Hypotension 

In  normal  young  males,  CPAh  in  the  sitting  position 
is  0.91  ±  .04  of  that  recorded  with  the  subject  supine; 
in  the  erect  position,  it  is  0.85  ±0.14  (242).  Tilting  of 
the  subject  from  the  horizontal  similarly  produces  re- 
duction in  glomerular  filtration  rate,   e.g.,    127-120 


to  98-93  ml  per  min  (6o°  tilt),  recovering  to  126,  1 1  7, 
and  1 12  ml  per  min  (39). 

Motionless  standing,  or  tilting  of  the  subject  lying 
quietly  on  a  tilt-table,  leads  to  progressive  venous 
stagnation,  reduced  cardiac  output,  and  neurogenic 
vasoconstriction  until  the  cerebral  circulation  becomes 
inadequate,  at  which  point  syncope  occurs. 

When  tilting  is  done  in  increments  from  horizontal 
to  60 °,  RPF  and  C,„  progressively  decrease;  this  is 
more  marked  when  reflex  compensatory  mechanisms 
are  good,  as  manifested  by  well-sustained  blood 
pressure,  than  when  blood  pressure  is  not  sustained 
and  fainting  is  imminent  (36,  60,  72,  286,  334).  Pa- 
tients prone  to  orthostatic  hypotension  in  particular 
manifest  the  latter  responses  (36).  £PAH  usually  is  not 
altered  (36,  334).  Filtration  fraction  tends  to  increase, 
suggesting  predominantlv  efferent  arteriolar  constric- 
tion (60,  287). 

Two  different  types  of  responses  are  shown  in  table 
14.  In  table  14  A,  compensation  was  good,  and  arterial 
blood  pressure  was  well  maintained.  In  B,  in  a  patient 
subject  to  orthostatic  hypotension,  renal  blood  flow 
"opened  up"  as  syncope  ensued. 

The  type  of  response  seen  in  table  14  B  was  also 
shown  during  fainting  produced  by  cuffing  the  lower 
appendages,  plus  venisection  (up  to  500  ml)  (72).  In 
all  cases,  when  blood  pressure  fell,  CPAh  decreased 
but  the  calculated  renal  vascular  resistance  decreased. 
Thus,  the  kidney  participates  in  the  more  widespread 
splanchnic  vasodilatation  which  occurs  during  syncope 

(14)- 

It  is  of  interest  that  the  medullary  flow  increases  in 
the  subject  (table  14  B)  during  the  failure  of  vascular 
compensation.  Although  this  type  of  calculation  of 
medullary  flow  must  be  accepted  with  some  reserva- 
tion, the  data  suggest  that  vascular  resistance  de- 
creases more  markedlv  in  the  medullary  circulation, 


table    1 3.   Effect  of  Exercise  on  Renal  Hemodynamics  in  Cardiac  Patients 


Brachial  BP 
mm  Hg 

Cardiac 
Index 

Cln 

ml/min 

CPAH 

ml/min 

FF 

% 

RPF 

ml,  min 

%  Cardiac 
Output 

R  dynes-sec 
cm5 

( 

jroup  A 

N  =  26  C 

N=i4  E 

9°-9 
+6.2 

3-59 

+  .07 

108  7 
-2-5 

( 

404.8 
-485 
iroup  B 

27.8 
+3-' 

731 
-90 

12.2 
-3-4 

IO5.6 

+  22.9 

N=7  C 
N=7  E 

97-7 
+ 10.2 

2. 1 1 
+0.86 

76.3 
-4.0 

( 

216.4 
-36.8 

~iroup  C 

34-9 
+3-4 

398 

-71 

10.8 
-3-4 

183.0 
+  24.8 

N=7  C 
N=7  E 

96-3 

+5-4 

i-94 
+0.26 

83.0 
-8.0 

204.6 
-23-7 

43-3 
+2.6 

403.6 
-48.O 

1 1  .2 
-1.8 

'99-7 

+65  -7 

[After  Werko  et  al.   (336). 


THE    RENAL    CIRCULATION 


I5°3 


table    14.   Effect  of  Tilting  on  Renal  Vascular  Compensation  in  Man 


Position 


Cln 

ml  min 


CpAH 

ml  min 


RPF" 

ml  min 


Medullary6 
Flow  ml/min 


Pac 

mm  Hg 


Trued  FF 


Epah 


RKe 


A.   Adequate  cardiovascular  compensation' 

Horizontal 

141 

588 

620 

32 

94 

0.227 

O.96 

.091 

30  degree 

109 

543 

573 

28 

116 

0.190 

0.88 

.  121 

45  degree 

77 

235 

262 

27 

104 

O.327 

0.90 

.238 

Horizontal 

'52 

766 

79° 

24 

98 

°'93 

o-97 

•°75 

B.   Ina 

ienuate  cardiovascular  comi 

'icnsation* 

Horizontal 

69 

354 

5'4 

160 

92 

0. 140 

0.63 

.108 

15  degree 

62 

34" 

515 

'74 

77 

0. 120 

0.68 

.090 

25  degree 

66 

358 

580 

222 

57 

0. 1 10 

°-59 

■059 

30  degree 

54 

293 

425 

132 

45 

0.130 

0.68 

.064 

■  RPF  =  Cpah/Epah-         ''Medullary  flow:  RPF  —  Cpah-         cPa  in  Part  B  calculated  from  diastolic  pressure  +  '3  pulse 
pressure.         dTrue  FF   ==    Ci„/RPF.         'Hemat.  40%   (assumed);  RK   =    (Pa   -    PV)/RBF,   in  mm  Hg/ml/min.         '[After 


VVerko  et  at.  (334).]         «[After  Brodwall  (36).] 

supporting  the  notion  of  differential  blood  flow  to 
cortex  and  medulla. 

VVerko  et  al.  (334)  found  little  increase  in  the  renal 
A-V  oxygen  difference  during  tilting,  so  that  renal 
oxygen  consumption  tended  to  decrease.  The  subject 
in  table  14  A  showed  a  decrease  from  25  ml  per  min 
to  10  ml  per  min  at  a  45°  tilt,  but  this  was  the  greatest 
change  in  the  series.  The  data  thus  support  the  con- 
cept of  the  flow-limited  nature  of  the  renal  circula- 
tion. 

Renal  Hypoxia  and  Ischemia 

hypoxia.  Analysis  of  the  response  of  renal  blood  flow- 
to  hypoxic  states  has  been  complicated  by  the  varied 
techniques  and  experimental  conditions  employed, 
and  the  varying  degrees  of  hypoxia.  Thus,  the  whole 
organism  may  be  expected  to  show  a  different  re- 
sponse than  the  isolated  organ  to  hypoxia  (278). 
Ischemia  presents  not  only  the  problem  of  reduced 
oxygen  supply,  but  also  of  accumulation  of  metabolites 
in  the  organ. 

Caldwell  et  al.  (47)  gave  to  subjects  oxygen  intakes 
as  low  as  9.3  per  cent  for  periods  of  5  to  17  min.  No 
consistent  effects  in  CPAh  and  CTn  were  observed; 
blood  pressure  only  occasionally  showed  a  slight 
tendency  to  increase.  Berger  et  al.  (15)  experimentally 
reduced  arterial  oxygen  tension  from  ca.  97  mm  Hg 
to  ca.  50  mm  Hg  in  humans.  CPAh  increased  by  an 
average  of  13  per  cent  (  —  5.2  to  +22.8)  with  no  sig- 
nificant change  in  CIn  or  blood  pressure.  Acute  ex- 
posure of  dogs  to  simulated  altitudes  of  18,000  feet 
(79.4  mm  Hg  partial  pressure  of  oxygen)  and  24,000 
feet  (61 .6  mm  Hg  oxygen)  caused  an  increase  in  renal 
plasma   flow   at    18,000  feet,   but   this  generally  de- 


creased below  ground  level  values  at  24,cco  fee 
(193).  The  seal,  when  subjected  to  10  per  cent  oxygen 
or  asphyxia,  reacts  with  a  significant  decrease  in  RPF 
and  GFR  (192),  accompanied  by  marked  slowing  of 
the  heart  and  increases  in  blood  pressure.  It  would 
appear  that  mild  hypoxic  states  unaccompanied  by 
systemic  reflex  vascular  alterations  manifest  a  slight 
renal  hyperemia,  but  more  severe  hypoxic  states  or 
asphyxia  trigger  vasoconstrictor  reflexes  in  which  the 
kidney  participates.  Other  experimental  approaches 
confirm  this.  Bing  &  Knudsen  (19)  by  direct  observa- 
tion of  the  mouse  kidney  noted  blanching  (cortical 
ischemia)  to  occur  in  the  range  of  6.5  to  10.5  vol  per 
cent  oxygen  in  the  inspired  air  (average  7  vol  %), 
with  arterial  oxygen  tension  at  42  per  cent  of  control. 
It  was  concluded  that  a  reflex  was  involved,  with 
centers  sensitive  to  hypoxia  in  the  spinal  cord,  for  it 
persisted  after  cord  section  at  T4,  but  was  lost  with 
renal  denervation.  It  is  likely  that  the  medullary 
centers  activated  by  impulses  from  the  chemoreceptors 
in  the  carotid  sinus  and  aortic  arch  would  also  par- 
ticipate. 

acute  renal  ischemia.  Numerous  experiments  have 
been  made  in  which  the  duration  of  ischemia  has  lasted 
from  several  minutes  to  3  and  4  hours.  Short-term 
occlusion  results  in  rather  transient  hemodynamic 
effects,  while  longer  ischemia  involves  varying  degrees 
of  tubular  damage  which  must  be  taken  into  account 
in  interpreting  clearance  data.  Short  bouts  (10-20 
min)  produce  small  but  variable  effects  with  rapid 
recovery.  No  change  in  blood  flow  (246),  or  small  de- 
creases (76,  269),  or  even  increases  (87)  have  been 
reported.  Since  brief  ischemia  has  been  reported  to 
cause  reactive  hyperemia  (262,  293)  and  when  clear- 


1504 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


anccs  arc  used  a  washout  •"overshoot"  could  occur 
(62,  298),  some  reasons  for  the  variability  can  be  per- 
ceived. 

Thirty  minutes  of  ischemia  (unilateral)  in  dogs  (76) 
resulted  in  a  fall  in  CPAH  and  C,„  to  less  than  50  per 
cent  of  control,  but  recovery  occurred  in  30  min.  No 
significant  change  in  EFAS  occurred,  indicating  con- 
tinued authenticity  of  the  clearance.  Following  45 
min  of  ischemia,  CPAH  and  CIn  were  still  much  reduced 
1 35  min  after  release,  but  now  the  validity  of  the 
clearance  could  be  questioned  because  of  possible 
tubular  damage.  Unquestionably,  2  hours  of  ischemia 
results  in  marked  and  persistent  reduction  of  £pAH 
(control  0.90-0.94,  to  o.  1 1-0.43)  (246). 

The  mechanism  of  the  persistent  ischemia  is  of 
great  interest.  One  speculation  is  that  prolonged 
clamping  of  the  artery  results  in  the  excessive  produc- 
tion and  accumulation  of  pressor  substances  which  act 
locally  (269).  Other  possible  factors  should  be  con- 
sidered. A  locally  activated,  persisting  reflex,  either 
intrarenal  (93)  or  caused  by  mechanical  compression 
of  the  arteries  and  intramural  nerve  fibers,  could  be 
involved.  It  is  noteworthy  that  renal  artery  blockade 
does  not  have  the  same  effect  as  venous  blockade. 
Neely  &  Turner  (231)  found  that  renal  blood  flow  in 
the  dog  kidney  (direct  method)  after  1  hour  of  uni- 
lateral occlusion  of  the  artery  was  reduced  to  44  per 
cent  of  control  immediately  after  release,  but  was  re- 
stored to  79  per  cent  1  hour  later.  Venous  occlusion 
for  30  min  resulted  in  a  decrease  to  58  per  cent  of  con- 
trol and  blood  flow  remained  at  this  value  1  hour 
later.  Combined  occlusion  of  artery  and  vein  also 
resulted  in  poor  recovery  of  flow.  With  venous 
occlusion,  a  persistent  weight  increase  occurred;  but 
with  combined  artery  and  vein  occlusion  the  weight 
was  constant,  so  that  congestion  of  the  kidney  did  not 
appear  to  be  the  answer.  The  possibility  of  intra- 
vascular thrombosis  was  raised. 

With  prolonged  ischemia,  tubular  damage,  uremia, 
and  death  in  renal  failure  is  the  outcome.  Hamilton 
et  al.  (128)  found  that  anesthetized  dogs  with  the 
right  kidney  previously  removed  uniformly  survived 
2  hours  of  clamping  of  the  left  renal  artery,  and  some 


survived  ischemia  of  3  to  4  hours.  When  the  kidney 
was  cooled  to  5  to  17  C,  percentage  survival  was  im- 
proved even  with  longer  periods  of  ischemia,  because 
of  greatly  reduced  cellular  metabolism  (20). 

The  pattern  of  recovery  of  renal  clearance  following 
2  hours  of  clamping  of  the  remaining  kidnev  after 
unilateral  nephrectomy  in  the  clog  is  nicely  shown  in 
the  work  of  Friedman  et  al.  [table  15  (97)]. 

It  can  be  seen  that  the  clearances  lose  their  validity 
for  measuring  plasma  flow  because  of  tubular  damage, 
revealed  by  the  low  £PAh  and  reduced  TmPAH.  When 
plasma  flow  is  estimated  by  the  Fick  application,  al- 
though reduced  to  less  than  half  of  control  3  hours 
after  ischemia,  blood  flow  is  fairly  well  restored  in  24 
hours.  The  low  CCr  is  probably  the  result  of  continued 
back  diffusion  of  creatinine,  so  that  the  FF  has  little 
meaning  for  some  time  after  ischemia. 

Hypercapnia  and  Acidosis 

Dowds  et  al.  (75)  studied  the  effects  of  progressive 
hypercapnia  in  anesthetized  dogs  rebreathing  from  a 
spirometer  flushed  with  pure  oxygen  to  prevent 
hypoxia.  During  about  2.5  hours,  the  carbon  dioxide 
content  of  the  inspired  air  increased  to  an  average  of 
16.8  vol  per  cent  (13.5-19.9).  This  was  accompanied 
by  a  marked  increase  in  respiratory  rate.  Arterial 
blood  carbon  dioxide  increased  from  35  vol  per  cent 
to  an  average  peak  of  52.8  vol  per  cent.  Heart  rate 
slowed  and  blood  pressure  declined  about  10  per  cent 
below  the  control.  In  this  range  of  carbon  dioxide  in- 
crease, C'pah  and  C'cr  did  not  change  remarkably;  if 
anything  they  decreased  with  the  fall  in  blood  pres- 
sure. Brooker  et  al.  (37)  subjected  dogs  to  30  per  cent 
carbon  dioxide  in  oxygen  for  30-min  periods.  All  dogs 
became  acidotic,  with  decreased  urinary  output.  Blood 
flow  decreased  to  an  average  of  45  per  cent  of  control 
(25  to  64 %  ).  Renal  resistance  increased  from  0.68  to 
1. 1  7  mm  Hg  per  ml  per  min,  despite  a  fall  of  blood 
pressure  to  93  per  cent  of  control.  In  similar  experi- 
ments, Stone  et  al.  (296)  studied  the  effects  on  intact 
and  pharmacologically  denervated  kidneys  of  anes- 
thetized dogs.  With  carbon  dioxide  inhalation,  blood 


table    15.   Effects  of  2-Hour  Renal  Ischemia 


1  "rural 

;    t  hours 

24  hours 

5-8  days 

2  weeks 

3  monlhs 

CCr  (ml/min) 

59 

1  -9 

8.6 

13-5 

12.7 

63.O 

Cpah  (ml/min) 

182 

5- 

27.9 

44-7 

62.5 

174.O 

FF 

Ep  Ml 

Gp  mi    Epah  (ml/min) 

0.320 
0.66 

276 

0.470 
0.048 
108 

0.400 
0 . 1 42 
196 

0 .  209 
0 .  263 
170 

0.203 
0.327 
191 

O.366 
O.84 
208 

TmpAH   (mg/min) 

.3.8 

1  .4 

3'7 

3-23 

6.0 

[After  Friedman  el  al .   (97).] 


THE    RENAL    CIRCULATION 


I5°5 


pH  decreased  from  ca.  7.45  to  7.10.  Respiration  rate 
tripled,  but  blood  pressure  fell  slightly.  Renal  blood 
flow  showed  an  average  reduction  to  24.3  per  cent  of 
control  (range  11-45%)  at  tne  er,d  °f  tne  30-min 
inhalation  period.  This  was  accompanied  by  oliguria 
or  anuria.  Denervation  of  the  kidney  apparently  pre- 
vented the  marked  decrease  in  flow  observed  in  the 
intact  kidney  and  urine  production  continued.  The 
authors  concluded  that  the  increased  renal  vascular 
resistance  was  a  reflex  component  of  a  more  gen- 
eralized vasoconstrictor  response  to  high  carbon 
dioxide.  Franklin  et  al.  (93)  by  the  visual  "blanching" 
technique  in  rabbits  inspiring  gas  mixtures  of  in- 
creased carbon  dioxide  content  (up  to  25  %)  saw 
blanching  (cortical  ischemia)  when  the  blood  carbon 
dioxide  content  had  increased  to  140  per  cent  of  con- 
trol. The  response  was  abolished  by  nerve  section, 
confirming  the  reflex  nature  of  the  phenomenon. 

Hvpercapnia  is  an  important  factor  contributing  to 
the  marked  reduction  in  renal  flow  which  results 
during  diffusion  respiration  (297).  In  this,  with  re- 
spiratory arrest  resulting  from  excess  anesthetic  action 
or  curare,  oxygen  is  taken  into  the  lungs  by  the  con- 
tinued removal  of  the  gas  from  the  alveoli  by 
hemoglobin  uptake  in  the  pulmonary  circulation. 
Breathing  of  pure  oxygen  for  1  hour  prior  to  onset  of 
respiration  arrest  is  essential  ("denitrogenation"). 
Blood  content  of  carbon  dioxide  rises  progressively, 
since  it  is  not  removed  by  the  quiescent  lungs.  After 
30  min  of  apnea,  blood  flow  had  decreased  to  28  per 
cent  of  the  control.  Blood  pressure  had  fallen  an  aver- 
age of  23  mm  Hg  during  this  time  and  renal  resistance 
increased  by  230  per  cent.  In  a  denervated  series 
(nerve  block),  these  changes  in  renal  blood  flow  and 
resistance  were  restored  to  the  decreasing  control 
trend.  Again,  a  central  origin  of  the  renal  ischemia 
was  predicated.  Bohr  et  al.  (27),  although  demon- 
strating a  lessened  trend  for  CPAH  to  decrease  in  the 
denervated  kidney,  nevertheless  observed  significant 
decreases  (PAH  to  38  %  of  control  with  blood  pressure 
decrease  from  1 16-95  mm  Hg).  Therefore,  circulatory 
pressor  substances  must  be  released  in  greater  amounts 
to  contribute  to  the  vasoconstriction. 

It  seems  reasonable  to  conclude  that  the  reduction 
in  renal  blood  flow  during  hvpercapnia  and  acidosis 
is  centrally  mediated.  It  is  nevertheless  surprising 
that  in  none  of  these  investigations  was  there  recorded 
an  increase  in  blood  pressure.  From  the  reported 
facts  it  would  appear  that  the  preponderant  effect  of 
hvpercapnia  and  the  accompanying  acidemia  was  a 
reflex  increase  in  renal  vascular  resistance  in  the  face 
of  an  actual  fall  in  arterial  blood  pressure,  a  con- 


comitance of  events  difficult  to  reconcile.  It  may  be 
that  anesthesia  alters  the  normal  response.  Also,  it 
must  be  kept  in  mind  that  the  direct  peripheral  vascu- 
lar action  of  carbon  dioxide  is  dilatory  (e.g.  on  vessels 
of  skeletal  muscle),  which  action  may  become  pre- 
ponderant. This  does  not  preclude  the  possibility  that 
other  tissues,  such  as  the  kidney,  respond  only  by  con- 
striction. 

Hemorrhagic  Hypotension  and  Shock 

HEMORRHAGE    AND   HEMORRHAGIC   SHOCK.   Acute 

hemorrhage  provokes  responses  in  the  renal  circula- 
tion which  are  typical  of  general  compensatory  mecha- 
nisms set  into  play,  viz.  reflex  vasoconstriction,  and 
shunting  of  blood  to  other  tissues  in  order  to  com- 
pensate for  low  blood  flow.  In  the  case  of  the  kidney, 
if  blood  loss  is  great  enough,  this  means  shutdown  of 
renal  excretory  function  which,  if  prolonged,  might 
have  serious  consequences  to  the  organism.  Moreover, 
a  prolonged  period  of  anoxic  hypotension  will  impair 
the  function  of  the  tubular  epithelium,  adding  to  the 
problem  of  shock  the  probability  of  renal  failure  and 
uremia. 

Following  acute  hemorrhage,  the  kidney's  circu- 
lating autonomy  aids  in  reestablishing  flow.  Heine- 
mann  et  al.  (136)  bled  anesthetized  dogs  1.3  to  3.9 
per  cent  of  body  weight;  blood  pressure  fell  by  5  to  59 
mm  Hg  to  levels  91  to  51  per  cent  of  mean  control 
values.  Renal  blood  flow  (based  on  CPAh)  decreased 
more  than  the  blood  pressure,  signifying  vasoconstric- 
tion. In  four  representative  experiments,  RBF  de- 
clined from  16. 1  ( 1 5.6—16.6)  to  4.5  (0.3-10.5)  ml  per 
kg  per  min.  In  three  animals,  while  hypovolemia  and 
hypotension  were  maintained,  blood  flow  was  re- 
stored autonomously  to  16.5  (11. 7-19. 5)  ml  per  kg 
per  min  in  25  to  70  min.  Goodyer  &  Jaeger  (107) 
found  similar  responses  to  moderate  hemorrhage  in 
anesthetized  dogs,  followed  by  restoration  of  flow. 
Denervated  kidneys  showed  a  lesser  decrease  after 
hemorrhage  than  the  paired  intact  kidney,  but  both 
showed  compensatory  restoration,  indicating  that  the 
autonomy  is  intrinsic.  Dibenzyline  selectively  injected 
into  one  renal  artery  reduced  its  responsiveness  to 
hemorrhage  compared  to  the  control  side  (129). 

Phillips  et  al.  (247)  found  that  rapid,  massive  hemor- 
rhage in  anesthetized  dogs  was  accompanied  by  almost 
complete  cessation  of  RBF  (CPah/£pah)-  If  hemor- 
rhage was  not  too  great,  arterial  pressure  rose  as  the 
result  of  extrarenal  vasoconstriction,  and  renal  blood 
flow  was  restored  but  at  a  figure  less  than  before 
hemorrhage.  In  the  recovery  phase,  the  kidney  ap- 


1506 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


peared  to  be  favored  at  the  expense  of  the  rest  of  the 
circulation.  The  cycle  could  be  repeated  with  addi- 
tional hemorrhages.  Ultimately,  peripheral  vasocon- 
striction failed  to  maintain  an  adequate  systemic 
pressure,  and  renal  plasma  flow  and  glomerular  filtra- 
tion fell  to  low  values.  It  was  inferred  that  at  this 
stage  afferent  arteriolar  vasoconstriction  closed  the 
renal  circulation  in  an  effort  to  maintain  circulation 
to  vital  centers.  In  view  of  the  possible  unreliability 
of  the  Fick  method  (CPAB/EPAB)  during  hypotension 
and  shock  according  to  Balint  &  Fekete  (8),  this  in- 
terpretation may  not  be  warranted.  The  indirect 
method  gave  them  much  lower  values  than  did  the 
direct,  giving  the  erroneous  impression  of  marked  in- 
crease in  renal  vascular  resistance  and  marked  de- 
crease in  the  renal  fraction  of  the  cardiac  output. 

Corcoran  &  Page  (62)  induced  hemorrhagic  shock 
in  anesthetized  dogs  by  controlled  bleeding  to  main- 
tain pressure  at  about  60  mm  Hg  for  70  min,  followed 
by  transfusion.  This  cycle  was  repeated  two  or  three 
times.  Clearances  (CD  or  Cin)  decreased  to  zero  or 
nearly  so  during  hypotension.  Repeated  reduction 
and  restoration  of  blood  pressure  led  ultimately  to  a 
permanent  reduction  in  renal  blood  flow.  Since  this 
phenomenon  occurred  in  dogs  with  denervated  kid- 
neys, it  was  suggested  that  the  reduced  function  was 
the  result  of  appearance  in  the  blood  of  vasoconstrictor 
substances.  Again,  caution  must  be  exercised  in  inter- 
pretation because  of  the  unreliability  of  indirect 
methods. 

Selkurt  (270)  noted  the  persistence  of  a  small  flow 
of  blood  through  the  kidneys  of  anesthetized  dogs 
(direct  venous  outflow)  subjected  to  hemorrhage  of 
2  to  5  per  cent  of  body  weight  to  bring  blood  pressure 
to  consecutive  60  and  40  mm  Hg  pressure  stages, 
held  90  and  45  min,  respectively.  Clearances  could 
not  be  followed  because  of  extreme  oliguria  and 
anuria.  Renal  vascular  resistance  (calculated  from 
direct  flow)  was  not  excessively  increased  early  in  the 
60  mm  Hg  pressure  stage  period  [experimental/ 
control  =  avg.  1.15  (0.73-2.07)],  possibly  because  of 
operation  of  renal  autonomy.  But  at  the  end  of  the 
period  at  40  mm,  the  ratio  averaged  3.04  (1.53-6. 15). 
Enhanced  vasoconstrictor  activity  as  the  result  of 
additional  hemorrhage,  plus  increased  release  of  cir- 
culating pressor  materials,  such  as  catecholamines 
(325)  or  serotonin  (63),  could  have  accounted  for  the 
enhanced  vasoconstriction. 

On  transfusion,  renal  vascular  resistance  returned 
almost  to  control  value,  but  increased  again  second- 
arily  as  normovolemic  shock  developed.  Terminally, 
this  was  as  great  as  4.7  times  the  control    Because  of 


variable  degrees  of  tubular  damage,  the  clearances  of 
PAH  and  creatinine  could  not  be  relied  upon  for 
accurate  measurement  of  plasma  flow  and  GFR  after 
transfusion. 

tourniquet  and  traumatic  shock.  Allowing  for  the 
time  factor  and  sequences  of  events,  the  changes  in- 
duced in  renal  function  by  tourniquet  shock  in  dogs 
are  much  the  same  as  observed  after  hemorrhage. 
Corcoran  el  al.  (63)  applied  leg  tourniquets  tight 
enough  to  block  venous  return  but  not  necessarily 
arterial  inflow.  RPF  and  GFR  progressively  fell  until 
at  90  min  they  were  25  per  cent  of  control.  Blood 
pressure  decreased  about  25  per  cent,  with  increased 
hematocrit  ratio.  On  release  of  the  tourniquet  which 
had  been  in  place  for  200  min,  blood  flow  might  re- 
cover for  a  time,  then  decline  again  if  shock  ensued. 
With  development  of  shock  ED,  which  had  remained 
normal,  declined  to  0.50.  Because  flow  decreased 
somewhat,  even  in  the  denervated  kidney,  the  vaso- 
constriction must  have  been  partly  of  humoral  origin. 
Increased  release  of  serotonin  was  considered  as  a 
possibility.  Catecholamine  output  could  have  been 
enhanced. 

The  effects  of  tourniquet  application  and  limb 
crushing  in  anesthetized  dogs  was  studied  by  Eggleton 
et  al.  (80),  the  tourniquets  being  left  in  place  for  4  to  5 
hours.  On  release,  blood  pressure  fell  and  urine  flow- 
ceased.  With  gum  acacia  infusion  to  restore  pressure, 
the  creatinine  clearance  still  remained  about  one- 
third  of  control.  The  basis  for  the  reduced  creatinine 
clearance  was  not  satisfactorily  explained,  but  afferent 
impulses  to  vasomotor  centers,  and  release  of  humoral 
substances  which  might  be  vasoconstrictor  to  the 
kidney  could  be  considered  as  possibilities.  Back 
diffusion  through  damaged  tubules  did  not  appear 
likely  under  the  circumstances  of  their  experiment. 
Fleming  &  Bigelow  (88)  made  direct  visual  observa- 
tions of  cortical  blood  flow  of  kidneys  with  crushing 
injury  to  the  hind  legs.  They  saw  agglutination  of  the 
cells  in  vessels  of  20  to  30  ju  size  as  large  clumps  In 
capillaries,  the  clumps  were  seen  intermittently  ob- 
structing the  lumen,  often  causing  stasis  or  even  ap- 
parent reversal  of  flow. 

traumatic  injuries  in  man.  Lauson  el  al.  (175)  re- 
ported renal  function  studies  in  shock  of  varied  etiolo- 
gies in  man  but  mostly  resulting  from  hemorrhage 
and  skeletal  trauma.  Keeping  in  mind  the  limitations 
of  the  clearance  methods  for  measurement  of  blood 
flow  and  filtration  rate  under  the  unfavorable  condi- 
tions that  apply  in  shock,  general  conclusions  emerge 


THE    RENAL    CIRCULATION 


I507 


which  are  consonant  with  the  findings  in  the  experi- 
mental animal.  Filtration  rate  rapidly  declined  at  a 
mean  arterial  pressure  of  60  mm,  and  often  ceased  en- 
tirely between  40  and  50  mm  Hg.  Estimated  blood 
flow  was  drastically  reduced,  and  calculated  renal  re- 
sistance was  high.  The  renal  fraction  of  the  cardiac 
output  was  much  below  the  normal  range,  but  the 
criticism  of  Balint  &  Fekete  (8)  must  be  kept  in  mind. 
Despite  this,  and  its  autonomy  under  or  during 
such  circumstances,  it  is  tempting  to  conclude  that  the 
renal  circulation  in  man  is  subordinate  to  the  welfare 
of  the  body  as  a  whole. 


CONCLUDING  REMARKS 

The  kidney  is  an  organ  characterized  by  a  high 
volume  of  blood  flow  resulting  in  a  narrow  A-V  oxy- 
gen difference  despite  a  high  rate  of  oxygen  utiliza- 
tion. The  A-V  oxygen  difference  tends  to  remain 
constant  in  the  face  of  minor  fluctuations  in  flow,  but 
at  very  low  rates  of  flow,  an  increase  in  the  A-V  oxy- 


gen difference  has  been  observed  by  several  investi- 
gators. The  remarkable  autonomy  of  the  renal 
circulation  may  be  an  adaptation  to  insure  steady  de- 
livery of  oxygen  to  the  renal  tissue. 

The  constancy  of  flow  appears  to  be  desirable  for 
another  reason.  The  countercurrent  system  for  the 
concentration  and  dilution  of  the  urine  operates 
optimally  with  constant  blood  flow.  When  this  has 
been  experimentally  altered  (e.g.,  increased  flow 
through  the  medullary  circuits)  the  osmotic  stratifica- 
tion in  the  vasa  recta  and  loop  of  Henle  system  has 
been  dissipated,  and  concentrating  power  impaired. 

Indications  are  that  a  countercurrent  multiplier 
system  for  concentration  of  serum  albumin  exists  in 
the  vasa  recta,  a  mechanism  which  would  aid  inter- 
stitial fluid  uptake  and  removal  into  the  systemic 
circulation.  The  interesting  interrelationship  of  the 
vasa  recta  system  to  the  loop  of  Henle  system  in  the 
role  of  water  and  salt  absorption  merits  much  further 
study,  particularly  in  the  direction  of  quantitative 
measurement  of  regional  flow  (cortical  versus  medul- 
lary), and  the  factors  which  alter  it. 


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I!    Willi!    1!   Ik       ill         I'll1!    -,11    ll    !   II.  \ 


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I509 


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95.  Fregler,  G.  Measurement  of  renal  blood  flow  and  heat 
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108.  Goodyer,  A.  V.  N.,  L.  R.  Mattie,  and  A.  Chetrick. 
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no.  Goormagtigh,  N.  The  renal  arteriolar  changes  in  the 
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ill.  Gottschalk,  C.  W.  A  comparative  study  of  renal  inter- 
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148.  Houck,  C.  R.  Alteration  of  renal  hemodynamics  and 
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149.  Houck,  C.  R.  Alterations  in  renal  hemodynamics  and 
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HANDBOOK    OK    PHYSIOLOGY 


CIRCULATION    II 


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kreislaufes.  Pfliigers  Arch.  ges.  Physiol.  268:  188,  1959. 

308.  Thurau,  K,  and  K.  Kramer.  Weitere  Untersuchungen 

zur    myogenen   Natur    der  Autoregulation    der   Nieren-  327- 

kreislaufes.  PJliigers  Arch.  ges.  Physiol.  269:  77,  1959. 

309.  Thurau,  K.,  P.  Deetjen,  and  K.  Kramer.  Hamodynamik 
des  Nierenmarks :  Wechselbeziehung  zwischen  vascularem 

und  tubularem  Gegenstromsystem  bei  arteriellen  Druck-  328. 

steigerung,    Wasserdiurese,     und     osmotischer     Diurese. 
Pfliigers  Atch.  ges.  Physiol.  270:  270,  i960.  329- 

310.  Tobian,  L.  Interrelationship  of  electrolytes,  juxtaglomer- 
ular cells  and  hypertension.  Physiol.  Rers.  40:  280,  i960. 

311.  Trueta,  J.,  A.  E.  Barclay,  P.  M.  Daniel,  K.J.  Frank-         330. 
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312.  Ullrich,  K.  J.,  and  K.  H.  Jarausch.  Untersuchungen  331. 


zum  Problem  der  Harnkonzentrierung  und  Verdiinnung. 
Uber  die  Verteilung  der  Electrolyten  (Na,  K,  Ca,  Mg, 
anorg.  Phosphat),  HarnstofT,  Aminosaiiren  und  exogenen 
Kreatinin  in  Rinde  und  Mark  der  Hundeniere  bei 
verschiedenen  Diuresezustandcn.  Pfliigers  Arch.  ges.  Physiol. 
2°2:537.  1956- 

Ullrich,  K.  J.,  and  G.  Pehling.  Aktiver  Natrium  Trans- 
port und  Saucrstoffverbrauch  in  der  aiisseren  Markzone 
der  Niere.  Pfliigers  Arch.  ges.  Physiol.  267:  207,  1958. 
Ullrich,  K.  J.  Das  Nierenmark:  Stuktur,  Stoffwechsel, 
und  Funktion.  Ergeb.  Physiol,  u  Exptl.  Phaimakol.  50:  433, 

'959- 

Ullrich,   K.  J.    Uber  die   Funktion  des   Nierenmarkes. 

Deut.  Med.  Wochschr.  84:  1  197,  1959. 

Unna,    K.    Artericller   Druck   und   Nierendurchblutung. 

Pfliigers  Arch.  ges.  Physiol.  235:  515,  1935. 

Van  Slyke,  D.  D.,  C.  P.  Rhoads,  A.  Hiller,  and  A.  S. 

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blood  flow,  renal  oxygen  consumption,  and  diuresis.  The 

mechanism  of  urea  excretion.  Am.  J.  Physiol.    109:  336, 

1934- 

Vimtrup,  B.  Number,  shape,  structure  and  surface  area 

of  glomeruli  in  man  and  animals.  Am.  ./.  Anat.  41  :  123, 

1928. 

von    Bubnoff,    M.,   D.    Hoffman,    E.    Schmid,   and    R. 

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Pathol.  Pharmakol.  224 :  443,  1 955. 

von  Kiigelgen,  A.,  and  H.  Greinemann.  Die  Klappen  in 

den  menschlichcn  Nierenvenen,  besonders  an  der  Miin- 

dung  der  Nierenbeckenvenen.  Z.  Zellforsch.,  47  :  648,  1958. 

von    Kugelgen,    A.,    and    S.    Zuleger.    Nachweis    von 

Venenklappen   in    der   Niere   von    Hund,    Schwein   und 

Mensch.  Z.  Zellforsch.  47:  327,  1958. 

von  Kugelgen,  A.,  B.  Kuhlo,  W.  Kuhlo,  and  J.  Otto. 

Die  Gefassarchitektur  der  Niere.  Stuttgart :  Thieme,  1 959. 

von  Kugelgen,  A.,  and  E.  Passarge.  Das  Nierenbeckan- 

gefassystem    als    extraglomenularer    Blutweg.    Z.    Anat. 

Entwicklungsgeschiclite  122:86,  i960. 

Wachholder,  K.  Haben  die  rhythmischen  Spontankont- 

raktionen   der   Gefasse  einen  nachweisbaren  Einfluss  auf 

den  Blutstrom?  Pfliigers  Arch.  ges.  Physiol.  190:  222,   1921. 

Walker,  W.  F.,  M.  Sheretettin  Zileli,  F.  W.  Reutter, 

W.    C.    Shoemaker,    D.    Friend,    and    F.    D.    Moore. 

Adrenal  medullary  secretion  in  hemorrhagic  shock.  Am. 

J.  Physiol.  197:  773,  1959. 

Wallenius,  G.  Renal  clearance  of  dextran  as  a  measure  of 

glomerular    permeability.    Acta    Soc.    Med.    Upsalien.    59: 

Suppl.  4,  1 -9 1,  1954. 

Warren,  J.,  E.  Brannon,  and  A.  Merrill.  A  method  of 

obtaining  renal  venous  blood  in  unanesthetized  persons 

with  observations  on   the  extraction  of  02  and  sodium 

/>-aminohippurate.  Science  100:  108,  1944. 

Waugh,  W.  H.  Flow  as  a  function  of  arterial  pressure  in 

the  oil-perfused  kidney.  Circulation  Research  6:  107,  1958. 

Waugh,  W.  H.,  and  W.  F.   Hamilton.   Increased  una1 

venous  pressure  and  extrarenal  pressure  on  renal  vasculai 

resistance.  Circulation  Research  6:  116,  1958. 

Wauch,   W.    H.    Myogenic   nature  of  autoregulation   of 

renal    blood    flow    in    the    absence    of   blood    corpuscles. 

Circulation  Research  6:  363,  1958. 

Waugh,  W.   H.,  and  R.   G.   Shanks.   Cause  of  genuine 


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autoregulation  of  the  renal  circulation.  Circulation  Research 
8:  871,  i960. 

332.  Weaver,  A.  N,  C.  T.  McCarver,  and  H.  G.  Swann. 
Distribution  of  blood  in  the  functional  kidney.  J.  Exptl. 
Med.  104:  41 ,  1956. 

333.  Weiss,  C,  H.  Passow,  and  A.  Rothstein.  Autoregulation 
of  flow  in  isolated  rat  kidney  in  the  absence  of  red  cells. 
Am.  J.  Physiol.   196:  1  1  15,  1959. 

334.  Werko,  L.,  H.  Bucht,  and  B.  Josephson.  The  renal 
extraction  of  PAH  and  oxygen  in  man  during  functional 
changes  of  the  circulation.  Scand.  J.  Clin.  &  Lab.  Invest. 

[1:  32I>  !949- 

335.  Werko,  L.,  H.  Bucht,  B.  Josephson,  and  J.  Ek.  The 
effect  of  nor-adrenaline  and  adrenaline  on  renal  hemo- 
dynamics and  renal  function  in  man.  Scand.  J.  Clin.  & 
Lab.  Invest.  3:  255,  1951. 

336.  Werko,  L.,  E.  Varnauskas,  H.  Eliasch,  J.  Ek,  H. 
Bucht,  B.  Thomasson,  and  J.  Bergstrom.  Studies  on  the 
renal  circulation  and  renal  function  in  mitral  valvular 
disease.  I.  Effect  of  exercise.  Circulation  9:  687,  1954. 

337.  Werko,  L.,  E.  Varnauskas,  J.  Ek,  H.  Bucht,  B. 
Thomasson,  J.  Bergstrom,  and  H.  Eliasch.  Studies  on 
the  renal  circulation  and  renal  function  in  mitral  valvular 
disease.  II.  Effect  of  Apresoline.  Circulation  9:  700,   1954. 

338.  White,  H.  L.  Observations  on  the  behavior  of  Diodrast 
in  the  dog.  Am.  J.  Physiol.  130:  454,  1940. 

339.  White,  H.  L.,  and  D.  Rolf.  Some  effects  of  exercise  and 
of  some  other  influences  on  the  renal  circulation  in  man. 
Am.  J.  Physiol.  152:  505,  1948. 

340.  Winton,  F.  R.  Intrarenal  pressure.  J.  Physiol. ,  London  78: 

9p.  1933- 

341.  Winton,  F.  R.  The  influence  of  changes  in  the  arterial 
pressure  on  the  intrarenal  pressure  in  the  isolated  mam- 
malian kidney.  J.  Physiol.,  London  87:  18P,  1936. 


342.  Winton,  F.  R.  Intrarenal  pressure  and  renal  blood  flow. 
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Macy,  Jr.  Found,  p.  51,  1951. 

343.  Winton,  F.  R.  Pressures  and  flows  in  the  kidney.  Modern  views 
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344.  Winton,  F.  R.  Present  concepts  of  the  renal  circulation. 
A.M. A.  Arch.  Internal  Med.  103:  495,  1959. 

345.  Wirz,  H.,  B.  Harcitav,  and  W.  Kuhn.  Lokalization  des 
Konzentrierungs-prozessen  in  der  Niere  durch  directe 
Kryoskopie.  Helv.  Physiol,  et  Pharmacol.  Acta  9:  196,  1951. 

346.  Wirz,  H.  Der  osmotische  Druck  des  Blutes  in  dern  Nieren- 
papillae.  Helv.  Physiol,  et  Pharmacol.  Acta  1 1  :  20,  1 953. 

347.  Wirz,  H.  Druckmessung  in  Kapillaren  und  Tubuli  der 
Niere  der  Ratte.   Helv.  Physiol,   et  Pharmacol.  Acta   13:  42, 

■955- 

348.  Wirz,  H.  Der  osmotische  Druck  in  den  corticalen  Tubuli 
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■956- 

349.  Wirz,  H.  Die  Niere  als  Regulator  des  osmotischen  Druckes 
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350.  Wise,  B.  L.,  and  W.  F.  Ganong.  Effect  of  brain-stem 
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i960. 

351.  Wolf,  G.  A.  Effect  of  pain  on  renal  function.  Research 
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352.  Yamada,  S.  I.,  and  A.  Astrom.  Critical  closing  pressure 
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353.  Young,  W.  G.,  Jr.,  J.  S.  H.  Harris,  and  W.  C.  Sealy. 
Production  of  neurogenic  afferent  renal  vasoconstriction 
in  humans  and  dogs  by  2-benzyl-4,5-imidazoline  HC1 
(Priscoline).  J.  Appl.  Physiol.  3:  77,  1950. 


CHAPTER      44 


Blood  supply  to  the  heart 


DONALD    E.    GREGG 
LLOYD    C.    FISHER 


Department  of  Cardiorespiratory  Diseases,  Walter  Reed  Army  Institute 
of  Research,  Walter  Reed  Army  Medical  Center,  Washington,  D.  C. 


CHAPTER    CONTENTS 

Functional  Anatomy 

The  Myocardium 

Coronary  Arteries 

Myocardial  Arterioles  and  Capillaries 

Myocardial  Veins 

Collateral  Circulation 

Congenital  Anomalies 

The  Cardiac  Nerves 

Lymphatic  Drainage  of  the  Heart 
Preparations    and    Methodologies    of  Special    Interest   in    the 
Study  of  the  Heart  and  Its  Coronary  Circulation 

Preparations 

Coronary  Flow  Methods  (Animals) 

Coronary  Flow  (Man  and  Animals) 
Distribution  of  Myocardial  Blood  Flow- 
Arterial  Circuit 

The  Venous  Circuit 

Possible  Use  of  Left  Coronary  Artery  Flow  Together    with 
the  Chemical  Composition  of  Coronary  Sinus  Blood  as  an 
Index  of  Left  Ventricular  Metabolism 
Physical  Determinants  of  Coronary  Flow 
Determinants  of  Normal  Myocardial  Metabolism 
Basal  Data 
Response  of  the  Coronary  Circulation  to  Various  Stimuli 

Resting  State 

Reactive  Hyperemia 

Heart  Rate 

Heart  Doing  No  External  Work 

Ventricular  Volume  or  Fiber  Length 

Blood  Pressure 

Chemical  Composition  of  the  Blood 

Transfusion 

Anemia 

Nervous  Influences 

Hormones 

Exercise  and  Excitement 

Valvular  Disease 

Hypertensive  Cardiovascular  Disease 

Heart  Failure 

Hemorrhagic  Shock 

Hypothermia 

Hyperthermia 

Summary 
Drugs  Versus  the  Coronary  Circulation 


Coronary  Artery  Disease 

Natural  Responses  of  the  Normal  but  Overstressed  Portion  of 

the  Myocardium 
Coronary  Artery  Collateral  Circulation 


FUNCTIONAL    ANATOMY 

the  historical  knowledge  of  the  heart's  integral 
blood  supply  parallels  knowledge  of  the  broader  scope 
of  the  cardiovascular  system  in  toto.  Thus  commenc- 
ing with  Galen's  designation  of  the  term  "coronary 
arteries,"  it  nevertheless  remained  for  Harvey  (1645) 
to  show  accurately  that  channels  existed  in  the  walls 
of  the  heart  for  its  own  nourishment.  Interarterial 
anastomoses  were  demonstrated  by  Lower  in  1671 
using  fluid  injection  techniques,  and  in  1 704  the 
ventricular  branches  of  the  coronary  arteries  were 
visualized  by  a  corrosion  technique  introduced  by 
Ruysch.  Connections  between  the  arteries  and  the 
cardiac  cavities  were  shown  in  1 706  by  Vieussens 
using  saffron  injections  into  the  coronary  arteries,  and 
between  the  cardiac  veins  and  the  cardiac  chambers 
in  1  708  by  Thebesius  using  air  injected  through  the 
coronary  sinus.  That  these  cavitary  communications 
were,  in  fact,  different  channels  was  not  well  docu- 
mented until  the  twentieth  century  when  phylo- 
genetic  studies  by  Grant  (142),  and  mammalian 
studies  by  Wearn  (382)  established  the  existence  of 
intramyocardial  trabeculae  and  sinusoids  which 
separated  the  veins  (Thebesian)  from  the  arterial 
circuit  (arterioluminal),  and  contributed  their  own 
communications  (arterio-sinusoidal)  to  the  cavities. 
The  more  recent  introduction  of  radiographic  tech- 
niques (84,  352)  for  visualization  of  coronary  arteries 
in  intact  humans  and  animals,  or  in  pathologic  speci- 
mens (18,  37,  338),  and  of  cast-digestion  techniques 
(18,  172,  173,  190-192,  258)  for  permanent  reproduc- 


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CIRCULATION    II 


lions  of  normal  and  pathologic  channels  have 
further  advanced  and  clarified  the  interarterial  and 
transarterial  communications  and  their  branches.1 

The  Myocardium 

ventricles.  Gross  dissection  studies  (108,  153,  232) 
reveal  a  rather  consistent  and  orderly  arrangement  in 
mammals  with  quantitative  differences  overshadowed 
by  qualitative  similarities.  Every  muscle  fascicle 
originates  from  the  fibrous  rings  at  the  base,  the  super- 
ficial fibers  descending  toward  and  penetrating  the 
apex  to  form  the  vortex  spirals,  and  then  looping 
upward  as  the  deeper  fibers  which  ascend  along  the 
endocardial  surface  to  reinsert  in  the  annulus  fibrosis. 
Thus,  the  two  ventricles  are  encompassed  by  figure- 
of-eight  bands  of  muscle  with  origins  and  insertions 
at  the  base  and  a  fulcrum  at  the  apex.  The  muscular 
interventricular  septum  receives  part  of  these  fascicles 
while  an  intermediate  layer  encircles  only  the  left 
ventricle,  also  adding  to  the  septum. 

There  are  probably  no  true  cleavage  planes  between 
isolated  fascicles  but,  rather,  the  ventricle  represents 
a  single  muscle  mass  dividing  and  branching  into 
intercommunicating  fascicles.  In  any  one  plane,  how- 
ever, the  fibers  are  more  or  less  constant,  the  epicardial 
fibers  running  perpendicular  to  the  endocardial 
fibers  at  any  given  point. 

atria.  Nearly  all  fibers  arise  and  insert  into  the  A-V 
rings,  but  some  fibers  merge  and  disappear  on  the 
muscular  coats  of  the  great  veins. 

Interatrial  fibers  form  the  septal  areas  while  the 
auricles  and  pectinate  regions  are  largely  intra-atrial 
fascicles.  There  are  two  simple  layers — an  inner 
horizontal  and  an  outer  vertical — bound  by  much 
intertwining  interdigitation. 

1  :i  >\ducting  system.  Commencing  with  the  sino-atrial 
node  at  the  superior  vena  cava  and  right  atrium, 
specialized  myomeric  conducting  tissue  traverses  the 
right  side  of  the  interatrial  septum  to  the  locus  of  the 
atrioventricular  node  (153,  399).  The  latter  is  situated 
on  the  atrial  side  of  the  base  of  the  tricuspid  valves' 
medial  leaflet,  above  the  coronary  sinus  and  between 

1  No  attempt  has  been  made  to  give  a  complete  bibliography 
which  would  involve  consideration  of  many  thousands  of  publi- 
cations. Except  for  an  occasional  lead  article,  the  older  work  is 
considered  by  referring  to  some  40  to  50  reviews,  monographs, 
and  symposia.  Direct  but  incomplete  reference  is  made  to  the 
more  recent  work  not  covered  in  such  summaries.  By  this 
means,  most  of  the  important  work  in  the  field  can  be  found  by 
the  interested  reader  although  direct  reference  may  no!  In- 
made  to  it. 


the  limbus  fossa  ovalis  and  the  medial  leaflet.  From 
the  A-V  node,  the  bundle  of  His  penetrates  the  fibrous 
A-V  ring  and  runs  in  the  posterior  membranous 
interventricular  septum,  branching  into  the  right  and 
left  bundles  at  this  site  or  in  the  upper  muscular 
septum.  The  right  bundle  branch  is  solitary  in  its 
course  through  the  septum  to  the  base  of  the  modera- 
tor band,  while  the  left  bundle  subdivides  into  many 
branches.  The  terminations  of  each  bundle  form  many 
fine  fasciculi  intimately  applied  to  the  endocardium 
before  merging  with  the  contractile  myocardium. 

Coronary  Arteries 

The  course  and  distribution  of  the  major  coronary 
arteries  in  all  mammalian  subgroups  is  remarkably 
similar  and  intergroup  differences  are  less  pronounced 
than  intragroup  variations.  The  basic  anatomic  pat- 
terns are  thus  comparable  from  the  smallest  to  the 
largest  mammals,  i.e.,  from  rodents  to  whales  (63, 
78,  142,  298). 

There  are  two  coronary  arteries,  right  and  left, 
arising  respectively  from  the  right  anterior  and  left 
anterior  aortic  sinuses  of  Valsalva.  The  ostia  are 
situated  above  the  reflections  of  the  semilunar  valves, 
the  right  coronary  in  man  being  35 °  to  the  right,  and 
the  left  coronary  650  to  the  left  of  the  anteroposterior 
axis  of  the  body  (258). 

left  coronary  artery.  This  vessel  courses  in  epi- 
cardial areolar  tissue  anteriorly  and  to  the  left  in  the 
auriculoventricular  groove,  between  the  pulmonary 
artery  and  the  left  auricular  appendage,  and  bifur- 
cates into  the  anterior  descending  and  circumflex 
branches  (fig.  1).  These  two  branches  are  quite  con- 
stant in  all  species,  the  bifurcation  occurring  1  to  1.5 
cm  (84,  1 89-191,  258)  from  the  ostium  in  man,  and 
2-4  mm  in  dogs  and  smaller  mammals  (36,  64,  153, 
290).  In  dogs  and  rabbits,  but  not  in  man,  monkeys, 
or  higher  primates  (63,  64,  78,  172,  173,  189,  258),  a 
septal  artery  arises  just  prior  to,  at,  or  not  uncom- 
monly, just  beyond  the  bifurcation  on  the  descendens 
or  circumflex,  in  that  order.  Small  branches  from  the 
left  coronary  artery  are  frequently  present  passing  to 
the  pulmonary  conns  and  left  atrium,  and  in  the 
rabbit,  branches  from  both  left  and  right  coronary 
arteries  supply  the  major  portion  of  the  vasa  vasorum 
of  the  pulmonary  artery  (351).  A  third  primary 
division  has  also  been  described  arising  between  the 
above  and  supplying  the  anterior  left  ventricle  (348). 
The  anterior  descendens  follows  the  anterior  inter- 
ventricular sulcus  toward  the  apex  and  is  of  variable 
length,  terminating  prior  to,  at,  or  beyond  the  apex. 


BLOOD    SUPPLY    TO    THE    HEART 


I5!9 


fig.  I.  Vinylite  cast  of  a  human  heart.  Anterolateral  aspect 
of  left  ventricle  following  digestion  of  muscle.  M.P.A.  =  main 
pulmonary  artery;  R.A.  =  right  atrium;  L.A.D.  =  left  anterior 
descending  coronary  artery;  L.C.  =  left  circumflex  coronary 
artery;  G.C.V.  —  great  cardiac  vein,  P.I.I'.  =  posterior  inter- 
ventricular vein.  [From  James  (191).] 

In  humans  it  terminates  40  per  cent  of  the  time  at  the 
apex,  and  in  60  per  cent,  ascends  2  cm  or  more  in  the 
posterior  longitudinal  sulcus,  while  in  rabbits  it 
rarely  reaches  the  apex  (64,  84,  153,  191,  258).  It  is 
covered  by  bridges  of  ventricular  myocardium  for 
most  of  its  course  (292).  There  are  from  two  to  seven 
ventricular  branches,  the  large  left  ventricular 
branches  coursing  over  the  anterior  surface  toward  the 
apex,  the  small  right  ventricular  branches  crossing  the 
interventricular  groove  to  supply  a  narrow  band  of 
muscle  and  to  anastomose  with  right  coronary 
branches.  Anastomoses  exist  with  anterior  ventricular 
branches  of  the  left  circumflex  coronary  artery  and 
at  the  apex,  with  the  latter's  marginal  branch  and 
the  posterior  descending  artery  whether  of  circumflex 
or  right  coronary  origin  (18,  189,  191,  258,  337). 
Septal  branches  penetrate  deeply  from  the  underside 
of  the  vessel  all  along  its  course  in  the  anterior  sulcus. 


In  humans,  primates,  and  pigs,  these  branches  are  not 
supported  as  in  dogs  and  rabbits  by  an  individual 
septal  artery  arising  from  the  main  left  coronary  or 
origin  of  the  descendens.  A  fairly  constant  branch  to 
the  pulmonary  conus  region  exists  in  most  species. 

The  left  circumflex  follows  the  auriculoventricular 
groove  to  the  left,  coursing  under  the  left  auricular 
appendage  and  terminating  at  a  variable  distance 
from  the  posterior  longitudinal  sulcus.  It  is  largely  an 
epicardial  vessel,  surrounded  by  areolar  and  adipose 
tissue,  and  rarely  covered  by  muscular  loops  (292).  In 
dogs  it  almost  always  reaches  or  crosses  the  crux  of  the 
posterior  sulcus,  terminating  as  the  posterior  descend- 
ing artery,  whereas  in  pigs  (64,  289)  it  rarely  does  so. 
In  man,  higher  primates,  and  rabbits,  the  vessel 
usually  ends  at  the  obtuse  margin  (63,  78,  191,  258). 
An  average  of  three  anterior  ventricular  branches  and 
three  atrial  branches  occurs  in  man  and  dogs  (36, 
64),  the  former  coursing  to  the  apex  to  anastomose 
with  the  anterior  descendens  branches.  Posteriorly, 
communications  exist  with  the  right  coronary  either 
from  the  posterior  descendens  or  the  marginal 
branches.  In  the  dog  a  branch  of  the  left  circumflex  at 
the  posterior  crux  passes  deep  to  supply  the  A-V  node 
and  His  bundle  (172,  173). 

right  coronary  artery.  The  main  right  coronary 
artery  arises  from  a  single  ostium  in  its  aortic  cusp, 
but  not  infrequently,  especially  in  dogs  and  primates, 
smaller  ostia  of  accessory  branches  are  also  present 
(63,  258,  290).  The  right  coronary  passes  anteriorly 
behind  the  pulmonary  artery  and  follows  the  respec- 
tive auriculoventricular  groove  to  the  right  (acute) 
margin  of  the  heart.  In  dogs  and  rabbits  it  usually 
terminates  here  as  the  marginal  branch,  whereas  in 
pigs  and  man  it  invariably  (93  %)  reaches  the  posterior 
crux  to  become  the  posterior  descending  artery  (64, 
191,  289).  In  its  course  it  gives  off  an  average  of  three 
atrial  branches,  one  of  which,  the  dorsal  (posterior) 
right  atrial  artery,  is  the  major  supply  to  the  S-A 
node  in  man  and  dog  (172,  190),  and  three  to  five 
right  ventricular  branches.  Posteriorly,  in  man  and 
pigs,  a  branch  to  the  A-V  node  is  given  off  at  the 
crux,  corresponding  to  the  branch  from  the  circum- 
flex in  dogs  (172,  189,  190,  246,  258,  399).  A  constant 
branch  to  the  pulmonary  conus  frequently  arises  from 
an  accessory  ostium. 

Although  it  is  evident  that  the  course  and  distribu- 
tion of  the  coronary  arteries  is  basically  similar  in  the 
various  species  mentioned,  the  ramifications  are  such 
as  to  permit  a  breakdown  into  patterns  of  dominance. 
Thus,  in  all  species,  the  entire  anterior  and  lateral 
left  ventricle  is  supplied  by  the  left  coronary  branches, 


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CIRCULATION    II 


and  the  free  right  ventricular  wall  by  the  right 
coronary  artery.  The  most  variable  area  is  posterior, 
and  it  is  by  virtue  of  the  communication  of  the  poste- 
rior descending  artery  with  either  the  left  or  right 
coronary  artery,  or  both,  that  the  designation  "domi- 
nant" pattern  has  arisen  (18,  37,  84,  153,  258,  348). 
Hence,  dogs  are  universally  left  coronary  dominant, 
the  left  circumflex  branches  supplying  the  posterior 
left  and  right  ventricles,  the  posterior  septum  and 
A-V  node.  This  pattern  is  the  least  common  in  man 
and  pigs,  approximating  20  per  cent  of  cases  in  the 
former.  Pigs  are  generally  right  coronary  dominant, 
while  man,  both  living  and  autopsied,  and  the  higher 
primates  manifest  this  pattern  half  of  the  time  and  a 
balanced  circuit  in  approximately  a  third  (37,  63, 
84,  153,  348).  In  the  perfused  human  heart,  however, 
this  pattern  of  dominance  is  not  found  (370). 

The  secondary  divisions  of  the  major  coronary 
branches  in  man  are  consistently  different  over  the 
two  ventricles,  the  branches  of  the  anterior  descendens 
and  left  circumflex  arising  at  acute  angles  and  cours- 
ing to  the  apex,  while  those  of  the  right  coronary 
arise  at  right  angles  and  course  toward  the  anterior 
interventricular  sulcus  (191).  The  terminal  branches 
are  likewise  different;  those  over  the  left  ventricle  are 
perpendicular  to  the  epicardial  course,  while  those 
over  the  right  ventricle  are  parallel.  Once  the  arteries 
penetrate  the  myocardium,  they  lose  their  tortuosity 
and  linearly  follow  the  muscular  grain  in  a  plane 
between  the  superficial  and  deep  muscle  layers  (153, 
191,  258). 

The  functional  supply  to  the  conducting  tissue 
bears  further  comment  since  it  has  been  shown  in 
man  and  dogs  that  mortality  and  morbidity  are  in- 
creased when  ligation  of  vessels  includes  septal  and 
nodal  arteries  (5,  61,  246).  Of  the  three  atrial  branches 
from  each  coronary  artery,  the  cristal  branch  of  the 
dorsal  right  atrial  artery  is  the  major  supply  to  the 
S-A  node  in  man  (60-70%)  and  dogs;  rich  anastomo- 
ses exist  with  the  ventral  left  atrial  artery  in  75  per 
cent  of  dogs  whereas,  in  man,  this  latter  vessel  is  the 
major  supply  to  the  S-A  node  in  40  per  cent  (1  53,  1  72, 
173,  189,  190,  399).  In  rats  and  dogs  (172,  174),  and 
possibly  in  man,  anastomoses  with  extracardiac  ves- 
sels are  readily  shown  at  the  junction  of  the  superior 
vena  cava  and  right  atrium.  Rats  have  a  dual  blood 
supply  to  the  heart,  the  atrial  and  S-A  nodal  vessels 
stemming  from  cardiaco-mediastinal  branches  of  the 
internal  mammary  and  subclavian  arteries,  while  the 
ventricles,  A-V  node,  and  parts  of  the  atria  are  sup- 
plied by  the  coronary  arteries. 

Recent  vinylite  cast  techniques  have  shown  a 
consistent  artery  to  the  region  of  the  A-V  node  arising, 


BRANCH      TO 
AV    NODE 


R.  CORONARY  A 


LEFT    ANT  DESC. 
CORONARY   A. 


POST 
DESC. 
CORONARY 
A. 


fig.  2.  Drawing  of  the  blood  supply  of  the  normal  human 
interventricular  septum.  Note  the  preponderance  of  supply  by 
the  left  anterior  descending  coronary  artery  and  the  U-turn  of 
the  posterior  right  coronary  artery  which  gives  off  the  branch 
to  the  atrioventricular  node.  [From  James  (189).] 

in  man,  from  that  coronary  artery  which  crosses  the 
posterior  crux  (189-191,  246).  Thus,  in  80  percent, 
this  was  the  right  coronary,  the  left  in  10  per  cent,  and 
from  both  in  another  10  per  cent.  In  100  per  cent  of  a 
large  series  in  dogs  (246),  a  similar  vessel  arose  at  the 
crux  from  the  left  circumflex  coronary.  This  vessel, 
variously  named  the  posterior  septal  artery  and  ramus 
septi  fibrosi,  courses  along  the  base  of  the  interatrial 
septum  and  penetrates  the  annulus  fibrosus  to  supply 
the  His  bundle  and  upper  interventricular  septum 
(246,  399)  (fig.  2).  In  its  course  it  freely  anastomoses 
with  atrial  vessels,  predominantly  the  dorsal  left 
atrial  artery  and,  from  below,  the  anterior  septal 
arteries. 

The  interventricular  septum  receives  its  blood  sup- 
ply from  the  anterior  septal  artery  and  penetrating 
branches  of  the  anterior  and  posterior  descending 
arteries  (36,  172,  173,  189,  190,  246,  258).  The  former 
is  well  developed  in  dogs  but  in  man  and  higher 
primates  it  is  somewhat  vestigial,  although  easily 
identified  as  the  first  and  largest  branch  of  the  anterior 
descendens. 

The  anterior  branches  in  man  are  40  to  80  mm  in 
length,  supply  the  anterior  two-thirds  to  three-fourths 
of  the  septum,  and  penetrate  near  the  right  ventricular 
side  remaining  under  the  right  ventricular  endo- 
cardium  before   terminating  deeper   in   the  septum. 


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I  52  I 


The  posterior  branches  are  shorter,  up  to  15  mm;  they 
supply  the  posterior  one-third  of  the  septum  and 
anastomose  with  the  anterior  branches.  In  dogs,  how- 
ever, the  anastomoses  are  deficient  and  the  large 
anterior  septal  artery's  superior  and  inferior  divisions 
supply  the  central  portion  of  the  upper  two-thirds  of 
the  septum  including  the  moderator  band  and  lower 
His  bundle  (36,  64,  246,  290,  399).  The  more  distal 
bundle  branches  are  supplied  by  the  penetrating 
vessels. 

coronary  blood  volume.  Available  information  re- 
garding coronary  blood  volume  (artery  through 
coronary  vein  content)  is  incomplete  and  quite  ap- 
proximate. In  humans,  at  postmortem,  average  values 
in  both  sexes  range  from  about  2  to  6  ml  per  100  g 
heart  weight  (310).  In  the  arrested  dog  and  cat  heart 
and  isolated  beating  dog  heart,  values  approximate  6 
to  8  ml  per  100  g  heart  muscle  (129). 

Myocardial  Arterioles  and  Capillaries 

As  the  superficial  arteries  penetrate  the  myo- 
cardium, they  bifurcate  or  trifurcate  disproportion- 
ately so  that  the  parent  vessel  and  diameter  grow 
gradually  smaller  while  the  daughter  vessels  narrow- 
rapidly,  terminating  in  the  capillary  network  (294, 
295).  The  deeper  arterioles  lose  the  internal  elastic 
membrane  and  subendothelium  present  in  the  more 
superficial  layers  and  contain  a  single  layered  intima 
and  a  media  one  to  two  muscle  layers  thick.  As  the 
arteriole  narrows,  its  muscularis  becomes  discontinu- 
ous and  the  muscle  cells  decrease  in  frequency  with 
increasing  distance  from  the  arteriole.  This  latter 
vessel,  the  metarteriole,  is  continuous  at  its  distal  end 
with  the  simple  endothelial  tube  characterizing  the 
capillary.  A  group  of  one  or  more,  usually  three,  mus- 
cle cells  at  the  proximal  end  of  a  capillary  constitutes 
a  sphincter  and  denotes  the  precapillary. 

Recent  studies  have  suggested  that  the  myocardial 
capillaries  are  not  all  functional  at  all  times  as  was 
previously  believed  (294,  295).  It  has  been  shown  that 
the  metarterioles  and  precapillary  sphincters  can 
close  off  the  capillary  lumen.  Thus,  during  sphincteric 
contractions,  the  nucleus  of  the  endothelial  cell  under- 
lying the  sphincter  becomes  rounded  and  is  forced 
into  the  lumen  of  the  vessel  thereby  occluding  it.  Dur- 
ing relaxation  and  in  those  regions  where  there  are  no 
sphincters,  the  nucleus  is  flattened  along  the  wall  and 
the  lumen  is  open.  The  demonstration  of  nerve  fibers 
accompanying  the  vessels  in  the  areolar  connective 
tissue  and  terminally  "splaying''  to  surround  the 
myocardial  cells  and  sphincters,  and  the  absence  of 


any  such  supply  to  "true"  capillaries,  lends  support 
to  a  changing  dynamic  state  of  capillary  patency  and 
function.  Moreover,  the  demonstration  of  anastomotic 
connections  between  arterioles,  metarterioles,  pre- 
capillaries, and  venules  in  both  man  and  dogs  suggests 
arteriovenous  shunting  as  an  integral  component  of 
the  myocardial  capillary  circulation. 

In  the  newborn  human  and  rabbit  there  is  approxi- 
mately one  myocardial  capillary  per  four  myocardial 
fibers,  corresponding  to  4,000  capillaries  per  mm2  of 
tissue  (382).  In  the  human  adult  the  ratio  of  capillaries 
to  fibers  approaches  1:1,  while  the  capillary  concen- 
tration approximates  3,000  to  4,000  per  mm2  of  tissue, 
both  values  being  fairly  constant  over  a  wide  age  span 
(6,  125,  382).  The  capillary  diffusing  area  per  cm3  of 
tissue  averages  1,145  cm2  m  children,  and  1,184  cm2 
in  adults  (6).  An  analysis  of  tissue  from  various  ven- 
tricular areas  reveals  similar  capillary  densities  and 
surface  areas  for  the  human  left  ventricle,  right  ven- 
tricle, and  papillary  muscle,  whereas  the  interventric- 
ular septum  shows  a  decrease  in  both  these  parameters. 
While  the  maximum  diffusing  distance  is  calculated 
to  be  8  /u  in  all  of  the  above  areas,  that  to  the  con- 
ducting system  proper  is  appreciably  greater. 

In  contrast  to  the  septal  myocardium,  there  is  a 
scanty  capillary  supply  to  the  A-V  node  and  His 
bundle  in  sheep  and  cattle  (125).  Capillaries  and 
conducting  fibers  are  not  intimately  connected  and 
are  often  separated  by  wide  spaces  of  connective  tissue. 
In  the  His  bundle,  capillaries  are  located  outside  the 
dense  band  of  fibers  with  the  central  nuclei  far  from 
the  source  of  blood.  Other  investigations  in  dogs  and 
humans  have  shown  a  well-developed  system  of  sinu- 
soids anastomosing  with  capillaries,  veins,  and  arteries 
which  traverse  the  annulus  fibrosus  and  supply  the 
A-V  node  and  common  bundle  (365,  366). 

Exchange  of  metabolites  in  myocardial  capillaries 
has  received  anatomic  amplification  and  clarification 
by  electron  microscopic  techniques  (iii,  270,  286). 
The  endothelial  cells  form  a  continuous  capillary  and 
arteriolar  lining  without  any  evidence  of  intercellular 
or  intracellular  pores.  Many  vesicles  or  caveolae  are 
concentrated  under  the  cell  membranes  facing  both 
the  capillary  lumen  and  pericapillary  spaces,  and  are 
believed  to  represent  continuous  invagination  and 
pinching  off  of  the  plasma  membrane  which  then 
crosses  the  cell  and  liberates  nutrients,  metabolites, 
and  other  materials  (1  1  1,  270,  286).  Injected  colloidal 
gold  particles  have  been  photographed  concentrating 
along  the  luminal  side,  engulfed  and  transported 
across  the  cell  in  vesicles,  and  finally,  phagocytized  by 
macrophages  in  the  pericapillary  spaces.  This  trans- 
port  mechanism  has   been  variously  termed   "pino- 


1522 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


cytosis"  (286)  and  "cytopempsis"  (270),  the  latter 
being  preferred  since  it  does  not  imply  actual  utiliza- 
tion of  the  transported  substances  by  the  endothelial 
cell. 

Myocardial  I  'etm 

There  are  twice  the  number  of  venous  as  arterial 
channels  in  the  heart,  their  density  in  the  left  ventricle 
greatly  exceeding  that  of  the  right  (191),  and  they 
have  been  subdivided  into  superficial  and  deep  cir- 
cuits (153,  365,  366).  The  superficial  left  ventricular 
veins  parallel  the  arterial  branches  and  course  toward 
the  base  of  the  heart  to  empty  into  the  great  cardiac 
vein  anteriorly,  and  its  continuation  in  the  left  auric- 
uloventricular  groove,  the  coronary  sinus,  poste- 
riorly. The  latter  empties  into  the  right  atrium  in  the 
posterior-inferior  interatrial  septum  located  between 
the  medial  end  of  the  inferior  vena  cava  and  A-V 
ring,  and  receives  subsidiary  trunks  up  to  its  orifice 
(183).  The  anterior  cardiac  veins  drain  the  right 
ventricle  and  are  smaller,  frequently  solitary,  trunks 
which  empty  individually  into  the  right  atrium  just 
above  the  A-V  valves  (153). 

The  deeper  venous  circuit  has  communications 
with  both  atrial  and  ventricular  cavities  via  Thebesian 
and  sinusoidal  channels  (153).  Myocardial  sinusoids 
or  trabeculae  are  especially  rich  in  the  ventricular 
walls  and  maintain  communications  with  arterioles, 
capillaries,  venules,  and  the  heart  cavities  (64,  153, 
189,  191,  365,  366)  These  sinusoids  are  lined  by  a 
single  layer  of  endothelium  and  range  from  40  to  75  ji 
in  dogs,  and  60  to  90  jx  in  newborn  humans  in  the 
septal  myocardium.  In  dogs  and  pigs  there  is  a  mas- 
sive formation  of  sinuses  in  the  left  ventricular  wall 
communicating  with  the  cavity  (64). 

Collateral  Circulation 

As  noted  earlier  (vide  supra),  intercoronary  anasto- 
moses were  first  demonstrated  by  Lower  using  a 
watery  injection  of  dye,  and  in  1803  von  Haller  re- 
ported on  the  extracardiac  communications  of  the 
coronary  arteries,  utilizing  the  same  techniques  (153, 
382).  The  latter  were  principally  channels  from  the 
base  of  the  pulmonary  artery  and  veins,  root  of  the 
aorta  and  venae  cavae,  and  other  basal  (usually 
atrial)  vessels,  to  vessels  in  the  intrapericardial  re- 
flections. These  vessels  are  largely  from  the  internal 
mammary  artery  via  the  pericardiacophrenic  branch, 
but  communications  also  exist  with  the  bronchial 
arteries. 

In  lower  vertebrates  the  blood  supply  to  the  heart 


is  nearly  all  extracardiac  in  origin,  whereas  the  rat 
maintains  a  dual  supply  of  both  intracardiac  and 
extracardiac  origin.  In  normal  mammalian  hearts  the 
extracardiac  communications  are  of  the  order  of  small 
arterioles  and  capillaries  and  are  anatomically  and 
physiologically  insignificant. 

Intracardiac  coronary  anastomoses  in  human 
hearts  and  those  of  various  laboratory  animals  have 
been  the  subject  of  numerous  pathologic  and  experi- 
mental investigations  during  the  past  decade.  Col- 
lateral arterial  communications  in  normal  hearts  have 
been  anatomically  divided  into  those  stemming  from 
the  same  major  coronary  artery,  i.e.,  intracoronary, 
and  those  between  the  right  and  left  coronary- 
branches,  i.e.,  intercoronary  (18,  258).  All  mammalian 
species  show  some  intercoronary  anastomoses,  espe- 
cially over  the  anterior  left  ventricle,  while  inter- 
coronary anastomoses  vary  appreciably  between 
species,  the  dog's  being  fairly  vvell  developed,  the 
pig's  poorly,  and  man's  quite  variable;  the  greater 
proportion  occurring  in  the  muscular  interventricular 
septum  (18,  189). 

Functional  collateral  channels,  as  opposed  to 
anatomic  communications,  have  been  defined  for 
mammalian  hearts  as  those  above  40  tx  in  diameter, 
i.e.,  those  which  do  not  traverse  a  capillary  bed  (37, 
38,  338).  High  viscosity  fluids  do  not  penetrate  vessels 
below  40  /x  and,  utilizing  this  technique  or  those  with 
graduate  spheres  above  35  tx,  6  to  g  per  cent  of  normal 
human  hearts  have  adequate  collateral  channels  (38, 
2gi,  411).  Conversely,  latex  casts  have  shown  lux- 
uriant anastomoses  ranging  from  20  to  350  /x  in  all 
normal  hearts  and  in  all  myocardial  areas  below  the 
subepicardial  layer  of  muscle  (18).  Thus,  while  the 
experimental  and  pathophysiological  approaches  to 
this  problem  will  be  more  fully  discussed  in  a  later 
section,  the  disparity  between  the  functional  state, 
i.e.,  its  physiologic  competency,  and  the  nonfunctional 
state,  i.e.,  its  anatomic  patency,  becomes  more  obvious 
and  the  reason  for  the  designation  of  the  coronary 
arteries  as  "end  arteries"  more  apparent  (153,  404). 

While  the  above  discussion  has  dealt  mainly  with 
arterial  collaterals,  venous  collateral  channels  freely 
communicate  over  the  surface  of  the  heart  (153),  in- 
cluding those  between  the  anterior  cardiac  veins  of 
the  right  ventricle  and  the  left  ventricular  coronary 
sinus  system.  Extracardiac  communications  of  the 
cardiac  veins  are  not  uncommon  especially  in  lower 
mammals,  and  are  usually  related  to  the  persistence 
of  the  left  caval  or  cardinal  veins.  In  the  pig,  large 
communications  may  exist  between  the  hemizygous 
vein  and  the  great  cardiac  vein,  the  latter  also  having 
substantial  epicardial  connections  with  the  anterior 


BLOOD    SUPPLY    TO    THE    HEART 


'523 


cardiac  veins  (64).  Of  greater  concern,  however,  is  the 
existence  of  communications  between  the  ventricular 
cavities  and  the  trabecular  sinusoids  via  the  The- 
besian, arterioluminal,  and  arteriosinusoidal  vessels 
(153).  Although  dyes  and  particulate  matter  have 
been  recovered  from  ventricular  myocardium  follow- 
ing intracavity  injections  (153),  this  has  only  occurred 
experimentally  with  a)  high  ventricular  end-diastolic 
perfusion  pressures,  b)  congenital  aortic  and  pulmonic 
valvular  atresia  with  intact  septa,  and  c)  in  the  ar- 
rested heart  or  one  in  which  the  heart  stopped  before 
its  removal.  As  a  result  of  simple  pressure  differentials, 
the  dye  or  particle  moves  into  the  myocardium,  while 
for  the  same  dynamic  reasons  only  the  reverse  could, 
and  indeed  does,  occur  in  the  actively  beating  heart 
(i53.  404)- 

Congenital  Anomalies 

Variations  in  the  course  and  number  of  nutrient 
vessels  to  the  myocardium  are  not  uncommon  and, 
as  with  other  organ  systems,  are  usually  of  no  physio- 
logic concern.  However,  the  acceptance  of  the  clinical 
syndrome  of  the  aberrant  left  coronary  artery  as  part 
of  a  group  of  congenital  coronary  arteriovenous 
fistulae,  and  its  recent  physiologic  documentation,  has 
prompted  this  brief  digression  into  those  embryologic 
and  phylogenetic  ramifications  relating  to  the  coro- 
nary arteries. 

The  lowest  orders  of  vertebrate  hearts  have  no  well- 
defined  myocardial  blood  supply.  Thus,  the  single- 
chambered  ventricle  of  the  lamprey  nourishes  its 
myocardium  via  extensive  intramyocardial  sinusoids 
in  direct  communication  with  the  ventricular  cavity 
(142).  The  arterial  supply  to  vertebrate  orders  below 
reptiles  arises  from  cranial  and  caudal  vessels  coursing 
through  the  cardiac  ligaments.  Reptilia  maintain  a 
single  cranial  supply  of  vessels  which  are  related  to  the 
fishes'  epibranchial  and  hypobranchial  vessels,  the 
latter  disappearing  and  moving  caudally  with  the  loss 
of  the  gills  (8). 

Mammalian  coronary  arteries  arise  from  primordial 
buds  in  the  truncus  arteriosus  during  the  5th  week  of 
gestation.  At  this  time,  the  endocardial  cushions  and 
longitudinal  ridges  are  also  forming,  respectively 
dividing  the  heart  and  truncus  into  two  channels.  The 
heart  has  been  actively  beating  and  forcing  blood 
through  the  systemic  circulation  since  the  3d  week, 
and  the  heart  itself  is  nourished  by  the  sinusoido- 
luminal  channels  (8,  101,  140).  In  the  fetal  rabbit, 
endothelial-lined  trabecular  spaces  spiral  toward  the 
surface  forming  capillaries  and  epicardial  vessels.  The 


latter  join  with  venous  cords  growing  caudally  in  the 
epicardium  from  the  sinus  venosus  to  form  the  first  of 
the  myocardial  vessels.  Arterial  buds  form  a  few  days 
later  and  spread  as  a  solid  column  of  cells  to  the 
bulbus  cordis,  with  subsequent  extensions  and  branches 
to  the  lateral  areas.  As  these  epicardial  arteries 
enlarge,  the  sinusoids  decrease  in  size  by  a  condensa- 
tion and  compression  of  the  myocardial  cortex,  finally 
becoming  capillaries  (140).  In  lampreys  and  lower 
fishes,  and  in  certain  human  congenital  anomalies, 
this  condensation  does  not  occur,  the  spongy  trabecu- 
lar network  remaining  undisturbed  (141,  382).  In 
higher  fishes  and  mammalia  there  is  an  outer,  con- 
densed, capillary-containing  layer  supplied  by  epi- 
cardial vessels,  and  an  inner  trabecular  layer  with 
retained  cavitary  communications.  Thus,  the  varia- 
tions in  the  number  and  site  of  the  coronary  ostial 
anlagen  will  determine  the  final  origin  of  the  coronary 
arteries,  while  variations  in  the  epicardial  course  and 
degree  of  myocardial  condensation  may  determine  the 
eventual  communications.  These  anomalies  have 
recently  been  presented  as  follows  (101). 

a)  Coronary  arteries  arising  from  the  aorta  and 
supplying  the  heart  in  normal,  albeit  variable,  fashion 
without  abnormal  communications.  This  includes 
those  with  single  ostia  and  single  coronary  arteries, 
common  sinus,  accessory  ostia,  and  ostia  elsewhere  in 
the  aorta.  In  a  recent  large  series,  such  anomalies  oc- 
curred in  52  cases  of  18,950  autopsies  for  an  incidence 
of  2.75  per  1,000  (4).  Reviews  of  single  coronary 
arteries  in  man  have  stressed  the  absence  of  clinical 
symptoms  except  those  related  to  associated  cardio- 
vascular anomalies  (4,  308,  350).  However,  the 
anomalous  distribution  seems  to  predispose  to  early 
sclerotic  changes  and  myocardial  infarction,  the 
average  age  of  death  in  adults  being  45  years.  In  one 
series  (308),  all  cases  of  myocardial  infarction,  fibrosis, 
or  ischemia  were  related  to  the  absence  of  a  left 
coronary  artery,  i.e.,  the  presence  of  a  single  right 
coronary  artery. 

b)  Coronary  arteries  supplying  blood  to  grossly 
abnormal  hearts  in  which  congenital  pulmonary  or 
aortic  atresia  exists  in  conjunction  with  intact  ven- 
tricular septa  and  intact  A-V  valves.  Ventricular 
blood  is  forced  from  the  cavities  via  myocardial 
sinusoids  which  anastomose  in  the  epicardium  with 
the  coronary  arteries.  This  type,  fortunately,  is  rare. 

c)  Coronary  arteries  distributing  blood  abnormally. 
These  may  be  via  left-to-right  arteriovenous  shunts 
into  the  right  heart  chambers,  cardiac  veins,  or  pul- 
monary artery,  or  via  arterioluminal  shunts  into  the 
left  heart  chambers  (fig.  3). 


1524  HANDBOOK    OF    PHYSIOLOGY  -^  CIRCULATION    II 


Atretic  HV. 


fig.  3.  Anomalous  coronary  artery  commu- 
nications: A:  retrograde  flow  from  right  ven- 
tricular cavity  to  epicardial  coronary  arteries 
via  myocardial  sinusoids  in  presence  of  pul- 
monic (or  aortic)  atresia  with  intact  ventricular 
septum  and  competent  auriculoventricular 
valves.  B:  composite  illustration  of  aortic 
communication  with  the  cardiac  chambers  via 
the  coronary  arteries.  C:  communication  of  the 
aorta  with  the  pulmonary  artery  via  aber- 
rantly coursing  coronary  arteries.  D:  anoma- 
lous origin  of  the  left  coronary  artery  from  the 
pulmonary  artery.  [From  Edwards  (101).] 


ronary a 


Congenital  coronary  arteriovenous  fistulae  have 
been  demonstrated  in  humans  at  thoracotomy,  or 
preoperatively  utilizing  angiocardiography  and  coro- 
nary arteriography  (104,  356).  While  gasometric 
analyses  may  suggest  a  left-to-right  shunt  similar  to 
septal  defects  or  a  patent  ductus  arteriosus,  ausculta- 
tory findings  have  more  often  suggested  the  latter. 
Clinical  symptoms  and  signs,  present  in  half  the 
cases,  reflect  a  high  output  congestive  failure,  the 
shunts  averaging  40  per  cent  of  the  cardiac  output 
(356).  The  embryologic  defect  is  probably  a  per- 
sistence of  myocardial  sinusoids  although  the  large, 
sometimes  aneurysmal,  dilatation  and  veinlike  thin- 
ning of  the  arterial  wall  is  a  "common  feature  to  all 
arteries  proximal  to  an  arteriovenous  shunt,"  and 
may,  therefore,  be  a  secondary  rather  than  a  primary 
alteration  (101).  A  recent  review  now  totals  71  cases 
(104). 

The  anomalous  left  coronary  artery  has  recently 
become  a  subject  of  increasing  clinical  and  physio- 


logic interest,  not  only  because  it  is  the  most  common 
of  the  congenital  coronary  artery  aberrations  and 
readily  diagnosed  with  modern  clinical  techniques, 
but  also  because  of  the  controversy  concerning  the 
direction  of  blood  flow  in  the  aberrant  vessel.  There 
have  been  over  60  cases  reported  in  various  reviews  on 
this  anomaly,  approximately  one-fourth  occurring  in 
adults  in  whom  an  apparent  attenuation  of  the  patho- 
physiologic process  is  manifested.  As  the  truncus  is 
dividing  into  aorta  and  pulmonary  artery  (5th  week  of 
gestation),  the  primordial  coronary  ostial  buds  have 
already  been  established  and  the  growth  of  solid 
arterial  cords  has  commenced  (8,  6g)  (fig.  4).  The 
predominant  finding  of  normal  and  equal-sized 
aortae  and  pulmonary  arteries  strongly  implicates  a 
malposition  anteriorly  of  the  left  coronary  artery  as 
the  primary  developmental  defect,  but  the  occurrence 
of  hypoplastic  aortae,  in  rare  cases,  does  not  negate 
the  possibility  of  an  abnormal  division  of  the  truncus 
arteriosus. 


BLOOD    SUPPLY    TO    THE    HEART 


'525 


AORTIC     VALVE 


TRUNCUS    ARTERIOSUS 
NORMAL 


LEFT    CORONARY 
ARTERY 


ANOMALOUS 


PULMONARY  VALVE 


fig.  4.  Diagrammatic  representation  of  the  normal  and  the  anomalous  origin  of  the  left  coronary 
artery  following  torsion  and  division  of  the  truncus  into  aorta  and  pulmonary  artery.  [From  George 
&  Knowlan  (127).] 


The  anatomic  abnormality  was  first  described  for 
an  aberrant  right  coronary  artery  in  1886  (101).  At 
that  time,  the  suggestion  of  reversal  of  flow  in  the 
aberrant  vessel  was  postulated  because  of  the  tortuous, 
dilated  nature  of  the  arteries  involved  and  a  simple 
reflection  on  the  pressure  differential  between  the  two 
circuits.  The  anatomic  aberration  of  the  left  coronary 
was  described  in  ign  and  the  clinical  syndrome  of 
infarcts  in  1933  (101).  Electrocardiograph  findings 
suggest  a  recent  anterior  or  anterolateral  myocardial 
infarction  (58,  69,  10 1,  127,  210),  while  angiocardiog- 
raphy or  cine-angiocardiography  reveals  a  normal 
right  ventricle  and  pulmonary  artery  and  a  dilated, 
thinned  left  ventricle  without  evidence  of  filling  of  the 
left  coronary  artery  from  the  pulmonary  artery;  retro- 
grade aortography  reveals  a  dilated  right  coronary  and 
late  filling  of  the  left  coronary  (from  right  coronary 
collaterals).  The  aberrant  artery  in  both  adults  and 
infants  is  a  thin-walled  veinlike  vessel  with  an  atro- 
phied media.  Grossly  visible  right-to-left  coronary 
anastomoses  were  present  in  27  per  cent  of  the  adult 
specimens. 

Using  pathologic  specimens  and  surgical  observa- 
tions, but  without  definitive  physiologic  data  for 
support,  Edwards  earlier  proposed  a  hypothesis 
sustaining  the  concept  of  retrograde  flow  and  refuting 
that  of  antegrade  flow  from  the  pulmonary  artery 
(101).  Physiologic  proof  of  the  retrograde  nature  of 


flow  in  the  aberrant  left  coronary  has  been  presented 
at  thoracotomy  in  a  preoperatively  diagnosed  2}/%- 
month-old  child  (325).  Prior  to  ligation  of  the  vessel 
at  its  origin  from  the  pulmonary  artery,  the  pressure 
in  the  left  coronary  artery  was  30/15  mm  Hg,  rising 
to  75  mm  Hg  systolic  distally  after  occlusion,  while  a 
simultaneous  pulmonary  artery  mean  pressure  was  25 
mm  Hg.  Arterial  saturations  in  the  corresponding 
vessels  were  100  and  76  percent,  respectively.  A  post- 
ligation  rise  of  30  mm  Hg  systolic  pressure,  and  a 
decreased  paradoxical  bulge  of  the  left  ventricular 
infarct  area,  as  blood  now  traversed  rather  than 
shunted  away  from  the  myocardial  bed,  lends  final 
support  to  the  retrograde  flow  thesis.  In  contrast  to 
the  invariably  fatal  outcome  within  the  first  year  of 
life,  this  patient  is  alive  and  asymptomatic. 

The  Cardiac  Nerves 

The  nerve  supply  to  the  heart  is  mediated  through 
the  cardiac  plexuses  located  above  the  base  and  be- 
tween the  aortic  arch  and  tracheal  bifurcation  (397). 
Vagal,  sympathetic,  and  dorsal  root  fibers  intermingle 
and  tend  to  lose  their  identity  as  they  decussate  into 
right  and  left  halves  before  entering  the  pericardium. 
Functionally,  however,  they  are  best  divided  into 
sensory  and  autonomic  functions. 

The  sensory  afferent  fibers  originate  in   thoracic 


1526 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


dorsal  ganglia.  They  are  largely  unmyelinated  in  their 
myocardial  course  (153,  397),  and  supply  the  pain- 
sensitive  areas  in  the  pericardium,  connective  tissue, 
adventitia,  and  walls  of  the  heart,  terminating  as  fine 
beaded  nerve  fibers  and  loops  similar  to  those  in  the 
skin  and  skeletal  muscle.  Sensory  axons  traveling  in 
sympathetic  plexuses  and  through  the  lower  two 
cervical  and  upper  four  thoracic  sympathetic  ganglia 
complete  the  afferent  limb  of  the  pain  reflex.  In  both 
man  and  dog,  ablation  of  the  stellate  and  upper  four 
thoracic  ganglia,  or  upper  four  dorsal  thoracic  spinal 
roots,  completely  blocks  the  pain  pathway  (397 ). 
These  neurons  send  fibers  via  the  posterior  spinal 
roots  which  synapse  in  the  posterior  spinal  horn  with 
secondary  fibers  running  in  the  spinothalamic  tracts 
and  terminating  in  the  posterior-ventral  nucleus  of 
the  thalamus  (fig.  5).  While  connections  to  the  cortical 
somatic  sensory  areas  exist,  these  only  modify  the 
reaction  to,  rather  than  the  perception  of,  cardiac 
pain. 

The  autonomic   innervation   includes   both  an  af- 


ferent and  efferent  vagal  and  sympathetic  supply. 
Vagal  parasympathetics  are  mediated  by  the  cardiac 
plexus  and  stem  from  both  right  and  left  vagi  and  the 
recurrent  laryngeal  nerves.  A  large  portion  of  both 
afferent  and  efferent  fibers  is  distributed  to  the  great 
vessels  superior  to  the  heart,  while  the  greatest  part  of 
the  remainder  supply  the  interatrial  septum  and  the 
sino-atrial  and  A-V  nodal  areas  (12,  76,  153,  368, 
397).  The  large  number  of  fibers  in  the  latter  areas 
contrasts  with  the  paucity  of  fibers  supplied  to  the 
atrial  muscles  via  atrial  arteries  and  the  even  smaller 
number  found  in  the  ventricles.  Using  veratrum  alka- 
loids, only  the  left  coronary  artery  system,  i.e.,  the  left 
ventricle,  has  been  found  to  contain  afferent  vagal 
ganglia  which  contribute  to  the  Bezold-Jarisch  reflex 
while,  conversely,  no  efferent  vagal  supply  is  present 
in  either  ventricle  (12,  76,  368).  The  sympathetic 
efferent  discharge  is  largely  to  ventricular  muscle  and 
coronary  arteries  and  contains  both  cardiomotor 
and  vasomotor  fibers,  while  atrial  efferents  are  pre- 
dominantly to  the  S-A  node  and  are  cardio-accelera- 


SUP 

CERVICAL   GANGLION!^ 


MIDDLE 

CERVICAL   GANGLIONJ 


UPPER    SENSORY 
NEURON     IN 
SPINOTHALAMIC 
TRACT 


LEG 


PARAVERTEBRAL      CHAIN    OF 
SYMPATHETIC     GANGLIA 

DIRECT    THORACIC 
CARDIAC     NS. 

OCCASIONAL    CONNECTING 
RAMUS      TO 


SPINOTHALAMIC       TRACT 


fig.  5.  Illustration  of  the  cardiac  nerves  and  their  central  communications.  Parasympathetic  ef- 
ferent and  afferent  fibers  from  the  vagus  and  recurrent  nerves  join  the  cardiac  plexuses  at  the  base  of  the 
heart.  [From  White  (397).] 


BLOOD    SUPPLY    TO    THE    HEART 


1527 


tor.  Since  staining  techniques  have  been  notably  poor 
in  differentiating  vagal  and  sympathetic  terminals, 
most  of  the  available  functional  neural  anatomy  stems 
from    physiologic    and    pharmacologic    observations 

(12,    76). 

Lymphatic  Drainage  of  the  Heart 

The  myocardial  lymphatics  arise  at  the  periphery  of 
the  capillaries  and  drain  into  deep  and  superficial  lym- 
phatic plexuses.  They  lie,  respectively,  immediately 
subjacent  to  the  endocardium  and  epicardium,  the 
former  draining  toward  the  surface  to  join  in  the 
formation  of  lymphatic  trunks.  The  vessels  course  in 
the  anterior  and  posterior  longitudinal  sulci  and  con- 
dense to  form  left  and  right  common  trunks.  The  left 
trunk  passes  between  the  pulmonary  artery  and  left 
atrium,  and  the  right  behind  the  pulmonary  artery, 
both  terminating  in  the  "cardiac  Kmph  node."  This 
node  is  well  delineated  in  the  dog  and  is  regularly 
found  between  the  innominate  artery  and  superior 
vena  cava  (86,  287  I. 

Recent  studies  have  indicated  a  pathologic  simi- 
larity between  experimentally  induced  myocardial 
fibrosis  secondary  to  chronic  obstruction  of  the  com- 
mon lymph  trunks  and  idiopathic  endocardial 
fibroelastosis  or  endomyocardial  fibrosis  (261). 


PREPARATIONS    AND    METHODOLOGIES    OF    SPECIAL 
INTEREST    IN    THE    STUDY    OF    THE    HEART 
AND    ITS    CORONARY    CIRCULATION 

Many  of  the  various  preparations,  procedures,  and 
instruments  have  been  considered  in  previous  reviews 
(7,  10,  136,  146,  149,  152,  153,  299,  384,  400). 

Preparations 

The  coronary  circulation  has  been  studied  with  the 
heart  in  various  degrees  of  deviation  from  the  normal 
state.  These  preparations  include  the  heart-lung,  the 
isolated  heart,  and  the  open  or  closed-chest  animal  or 
human  with  anesthesia.  The  use  of  the  nonworking 
isolated  perfused  heart  by  Langendorff  in  1895  (221) 
and  by  Porter  (293),  in  which  arterial  inflow  and 
venous  outflow  could  be  measured,  laid  the  ground- 
work for  our  understanding  of  the  coronary  circula- 
tion. An  early  bottleneck  to  the  study  of  the  coronary 
circulation  in  the  isolated  heart  was  the  lack  of  an 
efficient  means  of  oxygenating  the  blood.  The  isolation 
of  the  heart  connected  to  its  lungs  (215),  and  subse- 


quent use  of  this  preparation  by  many  others  (10) 
contributed  extensively  to  our  knowledge  of  the  heart 
and  coronary  circulation.  There  are  many  variations 
of  this  procedure  but,  in  general,  the  heart  and  lungs 
are  removed  in  such  a  way  that  the  cerebral  circula- 
tion and  the  vagal  and  sympathetic  nerves  remain 
connected  to  the  heart  while  the  venous  return,  car- 
diac output,   ventricular  volume,   heart  rate,   aortic 
and   pulmonary   resistances,    atrial,    ventricular   and 
arterial  pressures,  and  the  chemical  composition  of  the 
blood  can  be  separately  altered  and  controlled  and 
even  cardiac  biopsies  made.  Early  in  its  use,  Morawitz 
&  Zahn  (272)  developed  a  cannula  for  insertion  into 
the  coronary  sinus  via   the  right  atrium.  The  flow 
through  it  was  presumed  to  quantitate  total  venous 
return  from  the  vessels  of  the  heart.  Although  this 
idea  was  later  shown  not  to  be  true,  the  investigation 
was   important   for   it   enabled   the  experimenter   to 
study  the  coronary  sinus  fraction  of  coronary  venous 
outflow  not  only  in  the  isolated  heart  but  also  in  the 
heart  beating  in  situ.  An  artificial  lung  was  substituted 
by  Evans  et  al.  in  1934  (107),  and  since  then  the  de- 
velopment of  such  devices  and  preparations  has  been 
rapid,  permitting  total  coronary  venous  flow  measure- 
ment and  fractionation  of  coronary  sinus  drainage  and 
noncoronary  sinus  drainage  in  the  working  and  non- 
working  isolated  heart.  Some  of  the  better  arrange- 
ments are  as  follows:  a)  Coronary  venous  drainage  is 
pumped    through   an   oxygenator   into    the   coronary 
arteries,  b)  The  heart  is  isolated  in  a  manner  similar 
to   the  classical   heart-lung  preparation  except   that 
instead  of  returning  the  blood  to  the  right  atrium  and 
through  the  lungs  to  the  left  atrium,  the  left  ventricle 
usually  discharges  its  blood  through  a  resistance  into  a 
reservoir  from  which  it  returns  to  the  left  atrium.  This 
is   a   closed   system  except   for   the  escape  of  blood 
through  the  coronary  vessels  into  the  right  heart  which 
receives  no  other  blood  (335).  This  coronary  venous 
blood  may  be  ejected  through  the  pulmonary  artery 
and  collected,  or  it  can  be  separated  into  coronary 
sinus  and  non-coronary  sinus  fractions  by  coronary 
sinus  cannulation.  In  either  case  the  blood  goes  into 
the  venous  system  of  a  donor  dog  whose  arterial  system 
is  connected  to  the  reservoir,  c)  The  isolated  beating 
heart  doing  no  external  work  but  with  its  nerves  and 
cerebral  circulation  intact  may  be  studied  within  the 
chest  of  dog  (or  man)  by  directing  systemic  venous 
return  through  a  pump  oxygenator  into  the  aorta,  thus 
bypassing  the  heart.  Total  coronary  venous  drainage 
can  be  measured  in  the  pulmonary  artery  or  it  can  be 
fractionated   by   also  collecting  separately  coronary 
sinus  flow.  The  effect  of  systolic  and  diastolic  ventricu- 


1 528 


HANDBOOK    OF    PHYSIOLOGY    ^  CIRCULATION    II 


lar  distention  on  cardiac  energetics  and  coronary  flow 
can  also  be  gauged  (in  the  dog)  by  inserting  into  the 
left  ventricle  a  balloon  inflated  to  different  degrees  of 
fullness  (328).  The  blood  may  be  oxygenated  by 
passing  it  through  a  mechanical  oxygenator  system,  an 
autogenous  lung,  or  through  a  donor,  human  or 
animal.  It  is  believed  that  isolated  hearts  generally  are 
in  varying  degrees  of  failure  (performance  character- 
istics less  than  those  of  a  normal  heart  within  the  chest) 
and  that  this  can  be  prevented  by  a  continued  inter- 
change of  its  blood  with  that  of  a  supporting  dog  or 
human.  The  latter  arrangement  has  been  used  by 
Sarnoff  (335)  and  by  Garcia-Ramos,  Rosenblueth, 
and  their  associates  (126,  313).  A  possible  explanation 
for  this  phenomenon  is  the  loss  of  myocardial  cate- 
cholamines in  the  isolated  heart  preparation  and  its 
replenishment  by  the  cross-perfusion  technique  (201). 
In  any  case,  in  these  varying  types  of  isolated  hearts 
doing  work,  the  coronary  vascular  bed  is  largely  di- 
lated, for  the  coronary  flow  is  greatly  increased  and 
the  coronary  A-V  oxygen  difference  greatly  decreased 
over  the  values  for  hearts  working  within  the  chest. 
Finally,  it  is  of  considerable  interest  that  the  heart 
beat  and  carbohydrate  metabolism  of  the  isolated  dog 
heart  can  be  maintained  for  prolonged  periods  by  per- 
fusion of  the  coronary  circulation,  not  with  blood,  but 
with  gaseous  oxygen  (55). 

Wiggers  (796)  was  one  of  the  first  to  study  the  hemo- 
dynamics of  the  coronary  circulation  and  energetics 
of  the  heart  beating  and  working  in  situ  in  the  anes- 
thetized open-chest  dog,  in  which  the  coronary  vessels 
were  naturally  perfused  from  the  aorta.  By  right  heart 
bypass,  the  extracoronary  sinus  venous  drainage  can 
be  quantitated.  In  this,  systemic  venous  return  by- 
passes the  right  atrium  and  ventricle  into  a  reservoir 
from  which  it  is  pumped  into  the  peripheral  portion 
of  the  pulmonary  artery.  The  coronary  venous  drain- 
age can  be  collected  by  a  tube  in  the  right  atrium  or  in 
the  central  portion  of  the  divided  pulmonary  artery 

(309)- 

While  in  some  of  these  preparations  the  coronary 
circulation  is  naturally  perfused  from  the  aorta  at  its 
prevailing  pressure,  for  many  investigations  it  is 
desirable  to  have  coronary  artery  perfusion  at  constant 
controlled  flow  rates  or  at  constant  perfusion  pressures, 
or  both,  the  pressures  being  different  from  the  pre- 
vailing aortic  pressure.  Various  expedients  have  been 
devised  to  achieve  these  ends.  The  simplest  arrange- 
ment is  to  connect  the  peripheral  end  of  a  coronary 
artery  or  a  branch  to  a  blood  reservoir  at  an  appro- 
priate elevation  so  that  it  drains  into  the  artery  by 
gravity  (249).  In  another  arrangement,  air  expansion 


chambers  are  used  to  permit  constant  pressure  per- 
fusion (153).  Similarly,  one  end  of  a  pump  may  be 
connected  to  a  local  arterial  source  and  the  other  end 
of  the  pump  to  the  coronary  artery.  Either  the  per- 
fusion pressure  or  flow  rate  can  be  varied  separately. 
For  more  complicated  systems,  pump  or  pump 
oxygenator  systems  such  as  already  indicated  for 
right  heart  and  total  heart  bypass  are  used,  in  which 
the  coronary  perfusion  pressure  is  constant.  These  ap- 
proaches have  the  important  advantage  that  they 
enable  the  investigator  to  study  separately  the  periph- 
eral and  myocardial  factors  that  regulate  flow.  As  a 
further  separation  of  those  peripheral  parameters 
which  determine  flow  and  metabolism  in  the  myo- 
cardium, the  coronary  arteries  of  the  isolated  heart, 
heart-lung  preparation,  and  of  the  open-chest  dog, 
may  be  perfused  at  constant  pressure  or  flow  rate, 
first  while  the  heart  is  beating,  and  then  while  it  is  in 
prolonged  diastole  as  the  result  of  stoppage  from  pro- 
longed cervical  vagal  stimulation  or  intracoronary 
injection  of  acetylcholine,  potassium  chloride  or 
citrate  (17,  249,  311,  323). 

Finally,  with  the  advent  of  methodologies  not  re- 
quiring use  of  anticoagulants  or  the  insertion  into  a 
vessel  of  a  flow  metering  device,  reasonably  satis- 
factory measurements  have  been  made  in  the  resting 
and  active  dog  (159,  212)  and  the  resting  human 
(92.  3r9)- 

Coronary  Flow  Methods  (Animals) 

phasic  flow.  These  were  designed  with  the  hope  of 
analyzing  the  factors  affecting  coronary  flow  which 
are  too  rapid  in  action  to  be  studied  effectively  by 
mean  flow  measurements.  They  record  the  instan- 
taneous flow  at  the  point  of  their  insertion  into  a  blood 
vessel.  The  vascular  bed  of  the  heart  is  made  up  not 
only  of  vessels  within  the  myocardial  wall,  but  also  of 
vessels  lying  on  the  surface  of  the  heart.  Since  the 
change  in  mean  vessel  bore  during  a  cardiac  cycle  in 
the  superficial  vessels  (in  which  the  flow  measurement 
is  made)  is  presumably  different  from  that  of  the 
deeper  vessels,  such  a  device  measures  a  combination 
of  "intramural"  and  ''extramural"  flow.  It  does  not, 
therefore,  necessarily  indicate  correctly  the  intramural 
flow  at  all  times.  Comparison,  however,  of  the  arterial 
blood  pressure  with  the  flow  in  late  diastole  in  such 
recordings  is  the  only  means  known  to  the  author  by 
which  change  in  the  active  vasomotor  state  of  the 
coronary  bed  can  be  estimated  when  the  coronary 
arteries  are  naturally  perfused  from  the  aorta. 

Some   of  the   major   earlier   phasic   flow   methods 


BLOOD    SUPPLY    TO    THE    HEART 


!529 


which  were  used  on  isolated  hearts  or  anesthetized 
animals  have  been:  a)  estimation  of  the  phasic  dif- 
ference between  the  central  and  peripheral  coronary 
pressure  curves  during  a  cardiac  cycle  (151,  153); 
b  )  the  recording  of  movement  of  the  free  end  of  a 
bristle  mounted  in  the  wall  of  a  tube  of  fixed  diameter 
through  which  coronary  flow  occurs  (302);  c)  meas- 
urement of  cooling  by  air  of  a  heated  platinum  wire 
mounted  in  the  neck  of  a  bottle  partially  filled  with 
blood,  the  lower  part  of  which  is  connected  to  the 
coronary  circulation  (10);  d)  measurement  of  cyclic 
movement  of  various  foreign  substances  (toluene, 
mercury  droplet)  inserted  into  a  coronary  artery  (10); 
e)  recording  of  the  small  pressure  drop  in  a  pressurized 
air-blood  chamber  as  blood  flows  from  the  base  of  the 
reservoir  into  a  coronary  artery  (93,  153);/)  measure- 
ment of  the  lateral  pressure  difference  above  and 
below  an  area  of  constriction  (orifice)  in  a  metal  tube 
inserted  into  a  coronary  artery  (153);  g)  recording  of 
the  upstream  and  downstream  pressure  difference  in 
a  metal  tube  inserted  into  the  coronary  sinus  (196). 

Finally,  the  electromagnetic  flowmeter  has  been 
successfully  applied  to  the  coronary  circulation  in  the 
dog  (217,  395).  A  square-wave  type  of  electromag- 
netic flowmeter  has  been  found  quite  useful  in  coro- 
nary flow  studies  in  open-chest  sacrifice  dogs  (81 ),  but 
because  of  their  necessary  size,  they  have  not  yet  been 
chronically  implanted  on  the  coronary  arteries.  The 
sine-wave  type  can  be  miniaturized,  and  flow  trans- 
ducers of  aspirin-tablet  size  or  smaller  have  been  suc- 
cessfully applied  for  periods  of  weeks  to  the  right 
coronary  artery,  the  main  left  coronary  artery  and  its 
major  branches,  of  the  conscious  and  active  dog  (212). 
For  further  discussion  of  flowmeters  see  Chapter  38 
in  this  Handbook. 

mean  flow.  The  most  accurate  measurement  of  mean 
coronary  venous  outflow  is  by  its  collection  in  a 
graduate,  and  of  coronary  arterial  inflow  by  reading 
the  graduations  on  a  calibrated  reservoir.  More 
sophisticated  devices  have  been  developed  and  applied 
to  dog  and  man.  Some  of  the  more  important  in  the 
dog  are:  a)  timing  visually  or  photoelectrically  the 
passage  of  an  air  bubble  through  a  glass  tube  of  known 
length  and  volume  which  is  placed  between  the  cut 
ends  of  a  coronary  artery  through  which  flow  is  being 
measured  [bubble  flowmeter  (90)];  b)  recording  the 
position  of  a  '"float"  in  a  vertical  tapered  tube  through 
which  coronary  blood  is  flowing  [rotameter  (153, 
345)];  c)  recording  the  temperature  difference  of  two 
thermojunctions  mounted  in  a  plastic  sleeve  of  con- 
stant cross  section  through  which  coronary  blood  is 


flowing  (thermostromuhr — though  its  ultimate  re- 
liability in  many  circumstances  has  been  questioned) 
(153);  d)  recording  the  heat  clearance  or  the  tempera- 
ture difference  of  a  reference  cold  thermocouple  and 
an  electrically  heated  thermocouple  inserted  into  the 
myocardium  ( 14;^ ). 

Coronary  Flow  (Man  and  Animals) 

Variations  of  the  Fick  principle  and  coronary  cine- 
angiography have  been  used  to  attack  the  coronary 
blood  flow  problem  in  man.  The  first  major  advance 
came  with  the  use  of  nitrous  oxide  inhalation  for 
determining  blood  flow  draining  into  the  coronary 
sinus.  As  compared  to  direct  measurement  of  coronary 
blood  flow,  the  method  [see  previously  cited  reviews: 
(35,  92,  154,  319)]  shows  a  reasonable  accuracy,  and 
in  humans  has  furnished  almost  all  our  information 
regarding  coronary  blood  flow.  Another  variation  of 
the  Fick  principle  has  been  used  to  estimate  myo- 
cardial blood  flow  in  the  animal  and  in  man.  Studies 
in  the  rat  and  dog  have  indicated  that  when  intra- 
venous slug  injections  of  the  radioisotopes  K42  or  Rb8B 
are  made,  the  following  occurs:  the  isotopes  have  a 
large  volume  of  distribution  within  the  myocardium, 
and,  for  at  least  1  min  after  a  single  intravenous 
injection  of  the  isotope,  their  coronary  venous  drain- 
age is  negligible  compared  with  their  initial  deposi- 
tion; the  extraction  ratios  of  the  heart  and  whole  body 
for  the  isotope  are  identical.  By  determining  cardiac 
output  by  means  of  this  isotope  injection,  and  at  the 
same  time  determining  the  fraction  of  the  injected 
isotope  taken  up  by  the  myocardium  (animal  sacrifice 
and  direct  counting)  within  this  minute,  it  is  possible 
to  estimate  total  myocardial  blood  flow  in  the  dog 
and  rat  (185,  234,  330).  By  comparing  the  isotope 
concentrations  in  different  myocardial  areas,  the 
regional  flow  distribution  can  also  be  estimated.  These 
results  could  have  a  reasonable  accuracy.  The  obsta- 
cles, however,  to  the  use  of  such  a  method  in  man 
without  coronary  sinus  catheterization  are  formidable. 
While  the  isotope  is  being  infused  intravenously  at  a 
rate  designed  to  keep  a  constant  arterial  concentration, 
it  might  be  possible  to  estimate,  by  radiation  detection 
over  the  precoidium  and  by  direct  counts  on  the 
blood,  the  increments  in  myocardial  Rb86  content  and 
its  concentration  in  the  coronary  sinus  blood.  How- 
ever, the  isotope  extraction  at  different  coronary 
blood  flow  rates  is  not  constant  (reported  extractions 
vary  from  40  to  70%)  and  may  vary  with  duration  of 
the  perfusion.  As  yet,  these  difficulties  have  not  been 
resolved  (245,  274). 


'53° 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


The  indicator  dilution  technique  for  coronary  blood 
flow  in  man  is  based  on  the  fact  that,  when  cardiac 
output  is  being  estimated  by  means  of  a  device  placed 
over  the  precordium  to  pick  up  the  specific  activity  of 
a  tracer  substance  such  as  I131  following  rapid  intra- 
venous injection,  the  curve  produced  during  the  first 
circulation  of  the  radioactivity,  in  addition  to  having 
two  well-defined  peaks  representing  passage  of  radio- 
activity through  the  right  and  left  sides  of  the  heart, 
respectively,  may  also  have  a  third  small  peak  closely 
following  that  attributed  to  left  ventricular  activity. 
This  appears  at  a  time  which  could  represent  myo- 
cardial blood  flow  (343,  381  ).  Unfortunately,  because 
of  an  insufficient  time  lag,  it  is  difficult  to  differentiate 
the  peak  of  precordial  radioactivity  related  to  myo- 
cardial flow  from  other  rapid  changes  in  precordial 
activity,  such  as  that  resulting  from  the  preceding 
passage  of  blood  through  the  left  side  of  the  heart,  or 
that  due  to  subsequent  recirculation  from  the  most 
rapid  noncoronary  circuits  (252).  Until  the  true 
coronary  precordial  peak  in  radioactivity  can  be  more 
sharply  defined,  it  is  difficult  to  place  reliance  on  data 
obtained  with  this  method  as  representing  coronary 
flow.  A  variation  of  the  application  of  the  isotope 
dilution  technique  to  the  problem  arises  from  the 
observation  in  both  humans  and  dogs  that  concentra- 
tion curves  of  radioactivity  recorded  over  the  heart, 
following  rapid  intravenous  injection  of  small  boluses 
of  I131,  have  slower  disappearance  rates  than  those 
obtained  by  sampling  directly  from  a  peripheral 
artery,  such  as  the  femoral  (260),  the  difference  being 
due  presumably  to  the  coronary  flow. 

Finally,  special  techniques  have  been  developed 
for  selective  catheterization  of  individual  coronary 
arterial  branches  in  intact  closed-chest  dogs  and 
unanesthetized  human  subjects  by  means  of  special 
catheters  which  permit  intracoronary  injection  of 
radiopaque  materials  and  roentgenological  visualiza- 
tion of  the  coronary  vessels  (352,  393).  Coronary  cine- 
angiography is,  at  the  present  time,  in  a  somewhat 
embryonic  stage  of  development  as  a  research  or 
diagnostic  method.  Perfusion  with  the  media  in  ap- 
propriate volume  and  concentration  apparently  does 
not  result  in  development  of  anginal  pain,  EGG  evi- 
dence of  myocardial  ischemia,  or  photographic  evi- 
dence of  coronary  vasoconstriction.  However,  funda- 
mental hazards  in  the  application  of  this  technique 
lie  in  the  possibility  of  inadvertent  mechanical  occlu- 
sion of  a  coronary  artery  with  the  catheter  tip  and  the 
known  moderate  vasodilator  and  cardiotoxic  proper- 
ties of  the  contrast  media.  From  an  investigative  point 
of  view,  coronary  arteriography,  even  when  recorded 


continuously  by  motion  picture  photography  of  the 
fluorescent  screen,  does  not  provide  a  measure  of 
coronary  flow  and  vascular  resistance.  Such  data  can, 
however,  provide  evidence  of  change  in  size  and 
number  of  visible  arterial  vessels  after  administration 
of  various  physiological  and  pharmacological  agents. 
In  the  presence  of  a  constant  blood  pressure,  such 
changes  would  indicate  local  changes  in  the  vasomo- 
tive  states  although  it  cannot  be  currently  determined 
whether  these  alterations  are  active  or  passive.  In 
addition,  it  is  used  to  study  the  existence  of  and  change 
in  intercoronary  arterial  collateral  channels  in  life, 
since  the  origin  and  distribution  of  collateral  channels 
as  small  as  100  ju  can  be  well  demonstrated.  From  a 
diagnostic  point  of  view,  selective  opacification  of 
individual  coronary  arteries  provides  information  on 
the  length  and  exact  location  of  partial  and  complete 
occlusive  lesions  in  major  vessels  as  small  as  1  mm  in 
diameter. 


DISTRIBUTION    OF    MYOCARDIAL    BLOOD    FLOW' 

Arterial  Circuit 

As  blood  is  ejected  from  the  left  ventricle,  it  simul- 
taneously enters  both  coronary  ostia  and  flows  via  the 
epicardial  coronary  arteries  to  their  respective  myo- 
cardial beds.  By  direct  measurement  in  open-chest 
dogs,  the  left  coronary  and  right  coronary  arterial 
inflow  approach  85  and  15  percent,  respectively  ( 1 53)- 
The  same  relationship  also  exists  in  the  dog  heart-lung 
preparation  and  perfused,  fibrillating  heart,  lending 
physiologic  support  to  the  anatomically  designated 
left  coronary  artery  dominance  in  dogs.  While  the 
direct  measurement  of  coronary  arterial  distribution 
in  man  is  unknown,  coronary  arteriography  in  un- 
anesthetized patients  has  demonstrated  variations  in 
volume  of  the  various  coronary  arterial  beds  which 
correspond  quite  well  with  postmoitem  anatomic 
studies  (84). 

Utilizing  the  bubble  flowmeter  (90)  in  both  open- 
and  closed-chest  acute  experiments  in  dogs,  an  average 
left  coronary  inflow  of  65  ml  per  100  g  left  ventricular 
tissue  per  minute  was  found  with  no  significant  dif- 
ference between  the  two  groups.  The  left  circumflex 
was  found  to  supply  an  average  of  40  per  cent,  and  the 
anterior  descendens  about  26  per  cent  by  weight  of  the 
left  ventricle.  Similar  values  have  been  obtained  with 
rotameters  and  in  the  intact  unanesthetized  dog  with 
electromagnetic  flowmeters.  Figures  for  the  contribu- 
tion of  the  anterior  septal  artery  flow  in  the  dog  can 


BLOOD    SUPPLY    TO    THE    HEART 


I531 


be  estimated  by  observing  the  decrease  in  total  left 
coronary  inflow  after  occlusion  of  the  septal  artery  or 
by  direct  cannulation  (265  and  Gregg,  unpublished 
observations).  In  either  method,  the  volume  of  flow 
is  from  11  to  21  per  cent  of  total  left  coronary  flow. 

Radioactive  cations  (Na22,  K42,  Mg2S,  Rb86,  Fe56) 
and  anions  (P32,  I131)  and  D20  have  been  applied  to 
the  coronary  circulation  as  a  means  of  determining 
distribution  of  blood  and  plasma  flow,  and  metabo- 
lism of  the  involved  myocardial  bed.  Tissue  uptake 
and  turnover  rates  of  the  radioactive  substances  have 
revealed  a  heterogeneous  myocardial  distribution  (21, 
122,  1 97,  234,  244,  245).  All  left  ventricular  areas  in- 
cluding base,  apex,  septum,  and  free  walls  have  a  50  to 
100  per  cent  higher  uptake  and  turnover  rate  than 
the  right  ventricle  and  atria.  In  descending  order  of 
activity  are  the  right  ventricle,  left  atrium,  right 
atrium,  His  bundle  and,  lastly,  the  sino-atrial  and 
atrioventricular  nodes.  In  most  instances,  the  myo- 
cardial uptake  is  nearly  instantaneous  since  a  plateau 
is  reached  after  a  single  systemic  circulation  and, 
thereafter,  remains  relatively  constant  with  only- 
minor  differences  between  the  20-sec  and  10-min 
determinations.  D20  similarly  reaches  equilibrium 
between  plasma  and  tissue  water  after  a  single  circula- 
tion and  can  also  be  calculated  within  10  to  20  sec 
following  injection  (197). 

Radio-rubidium  (Rb'*6)  has  been  found  to  be  the 
most  versatile  for  myocardial  flow  determinations 
because  of  its  long  half-life  (T1 2  =  19.5  days),  rapid 
myocardial  uptake  (in  exchange  for  intracellular 
potassium),  and  relatively  fixed  myocardial  extraction 
despite  varying  arterial  concentrations  (230,  245).  In 
addition  to  the  tissue  concentrations,  Rb86  and  Na22 
and  D20  have  been  used  for  coronary  blood  flow 
determinations,  and  in  those  instances  where  checks 
against  a  standard  reference  method  (i.e.,  N20  and 
flowmeters)  were  done,  good  correlations  were  ob- 
tained (274).  Flow  values  vary  from  0.4  to  1.6  ml 
per  g  per  min,  with  an  average  of  0.7  to  1 .0  ml  per  g 
per  min  for  dog  and  man,  while  in  rats  values  four 
times  this  have  been  found,  supposedly  related  to  the 
four-fold  greater  energy  output  of  the  rodent  myo- 
cardium, i.e.,  1 .00  joules  per  g  per  min  versus  0.27 
joules  per  g  per  min  (185). 


The  Ye, 


Circuit 


In  addition  to  the  regional  differences  in  rate  of  up- 
take, there  also  exists  a  concentration  gradient  be- 
tween the  endocardial  and  epicardial  surfaces,  the 
former  having  the   higher  uptake   and    turnover  of 


radioactive  cations  (244).  The  disparity  is  most 
marked  in  the  right  ventricle  since  the  concentration 
of  Thebesian  vessels  is  highest  in  this  chamber,  and 
also,  a  favorable  pressure  gradient  exists  for  blood  to 
flow  from  the  myocardium  to  the  cavities  during 
systole.  It  has  therefore  been  argued  that  this  is  sup- 
portive evidence  for  utilization  of  the  deep  vascular 
communications  of  the  heart.  The  role  played  by  the 
deep  vascular  structures,  however,  is  probably  quite 
small  for  several  reasons.  Balance  studies  in  which  an 
attempt  was  made  to  measure  coronary  inflow  and 
outflow  simultaneously  with  rotameters  in  the  super- 
ficial coronary  vessels  of  the  open-chest  dog  have 
shown  that  a)  coronary  sinus  flow  ceases  when  both 
the  right  and  left  coronary  arteries  are  occluded  with 
the  heart  beating  in  situ;  b)  the  left  coronary  artery 
accounts  for  all  but  5  to  10  per  cent  of  coronary  sinus 
outflow;  c)  80  to  85  per  cent  of  left  coronary  inflow  is 
reflected  in  the  coronary  sinus  outflow  while  some  of 
the  remainder  is  accounted  for  by  the  anterior  cardiac 
veins;  d)  90  per  cent  or  more  of  the  right  coronary 
inflow  drains  via  the  anterior  cardiac  veins;  and 
e )  there  is  no  evidence  of  significant  Thebesian  drain- 
age of  the  right  coronary  system  (153).  These  studies 
in  the  open-chest  dog  are  technically  quite  difficult 
and  although  recovery  is  usually  of  the  order  of  80  to 
85  per  cent  (300),  comparison  of  total  coronary  inflow 
with  outflow  in  the  superficial  veins  is  subject  to 
considerable  error.  At  the  same  time,  in  other  experi- 
ments following  acute  coronary  sinus  ligation  it  was 
observed  that  although  the  lateral  wall  of  the  left 
ventricle  was  markedly  congested,  portions  of  the 
interventricular  septum  showed  less  evidence  of  con- 
gestion. This  observation  of  20  years  ago  was  not  fol- 
lowed up  until  recently  when  it  was  found  that  the 
portion  of  left  coronary  inflow  (about  15%)  not  re- 
covered in  the  coronary  sinus  could  be  largely  ac- 
counted for  by  the  fact  that  a  portion  of  the  left 
anterior  atrial  artery  flow  drains  into  the  left  atrium, 
and  that  most  of  the  septal  artery  and  some  branches 
of  the  left  descendens  artery  which  perfuse  the  septum 
drain  into  the  right  ventricular  cavity  (265,  266).  The 
finding  concerning  drainage  of  the  left  atrial  coronary 
flow  is  in  line  with  observations  with  an  illuminated 
cardioscope  in  humans  and  dogs  at  the  time  of  cardiac 
surgery,  that  very  small  streams  of  dark  blood  can  be 
seen  entering  the  left  atrium  but  not  the  left  ventricle 

(53)- 

The  deep  drainage  channels  could  have  an  im- 
portant functional  role  if  they  served  as  arterial 
channels  from  the  left  ventricular  cavity  to  the  myo- 
cardium   during    coronary    artery    constriction    or 


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CIRCULATION     II 


occlusion,  or  as  venous  channels  for  the  whole  myo- 
cardium in  the  presence  of  extensive  superficial  vein 
constriction  or  occlusion.  Regarding  the  first  situation, 
although  essentially  complete  occlusion  of  the  coro- 
nary arteries  in  human  beings  has  been  found  at 
autopsy  (227),  the  presence  or  extent  of  development 
of  extracardiac  arterial  collaterals  is  not  known.  In 
addition,  with  temporary  functional  separation  of  one 
or  both  coronary  arteries  from  the  aorta,  no  blood 
flow  from  the  ventricles  into  the  superficial  coronary 
venous  system  can  be  demonstrated  and  the  hearts  do 
not  survive  (153).  When  dye  is  injected  into  the  right 
ventricle  in  acute  experiments,  extensive  capillary 
injection  on  the  surface  of  both  ventricles  occurs  if 
right  ventricular  pressure  is  artificially  made  to  exceed 
left  ventricular  pressure  (153).  Although  this  could 
have  occurred  through  the  Thebesian  channels  of  the 
interventricular  septum  (265),  the  anterior  cardiac 
veins  were  not  excluded  as  a  portal  of  entry  for  the 
dye.  Regarding  the  second  situation,  with  acute 
closure  of  all  grossly  visible  anterior  cardiac  veins  or 
of  the  coronary  sinus,  or  both,  a  considerable  reduction 
in  right  and  left  coronary  inflow  occurs  (153).  Al- 
though the  heart,  following  acute  closure  of  both  the 
coronary  sinus  and  anterior  cardiac  veins,  becomes 
exceedingly  hemorrhagic  and  progressively  weaker, 
such  hearts  may  survive  up  to  2  hours.  Dogs  in  which 
both  superficial  venous  systems  have  been  chronically 
occluded  in  a  two-stage  operation  have  survived  for 
periods  of  months.  However,  that  significant  drainage 
occurs  through  such  a  route  could  not  be  verified, 
since,  at  postmortem  examination,  these  hearts 
exhibited  numerous  superficial  cardiac  veins  of  con- 
siderable size  which  were  not  previously  apparent,  and 
several  large  extracardiac  venous  anastomoses,  the 
aggregate  cross  section  of  which  was  estimated  to  be 
adequate  for  venous  drainage  of  the  entire  heart  ( 1 53). 
Until  the  intracardiac  and  extracardiac  arterial  and 
venous  collaterals  which  appear  with  coronary  arterial 
or  venous  ligation  have  been  excluded  as  flow  chan- 
nels, any  conclusion  regarding  the  utilization  of  deep 
coronary  venous  drainage  channels  in  diseased  hearts 
is  difficult  to  reach. 


Possible  Use  of  Left  Coronary  Artery  Flow  Together 
with  the  Chemical  Composition  of  Coronary  Sinus 
Blood  as  an  Index  of  Left  Ventricular  Metabolism 

It  is  not  possible  to  quantitate  accurately  the 
metabolism  of  the  right  ventricle  in  dog  (or  man) 
because  its  superficial  anterior  cardiac  veins  have 
many  exits  into  the  right  atrium  and  their  contained 


blood  is  grossly  contaminated  by  blood  from  the  left 
coronary  artery.  However,  a  large  drainage  of  the 
left  myocardium  occurs  into  the  coronary  sinus  and 
the  latter  is  accessible.  Hence,  the  question  of  whether 
the  chemical  composition  of  coronary  sinus  blood 
together  with  left  coronary  inflow  can  be  used  as  an 
index  of  quantitative  changes  in  metabolism  of  the 
left  ventricle  is  a  very  practical  and  important  con- 
sideration because  of  the  widespread  use  by  the  basic 
experimenter  and  the  clinical  investigator  of  these 
measurements  for  this  purpose.  To  justify  such  usage, 
experimental  evidence  must  show,  first,  that  most  of 
left  coronary  inflow  drains  into  the  coronary  sinus 
and  that  the  latter  is  not  significantly  contaminated 
by  drainage  from  the  right  coronary  artery  and, 
second,  that  its  chemical  composition  approximates 
that  portion  of  the  blood  coming  from  the  left  coronary 
artery  which  does  not  flow  through  the  coronary 
sinus. 

In  the  open-chest  dog  in  which  no  great  effort  is 
made  to  avoid  obstruction  at  the  ostium,  the  per- 
centage recovery  in  the  coronary  sinus  of  left  coronary 
inflow  varies  from  64  to  83  per  cent  in  any  one  dog, 
and  shows  little  variation  from  dog  to  dog  (153)-  By 
use  of  a  special  cannula  which  collects  all  the  blood 
draining  into  the  coronary  sinus  without  obstruction 
to  any  of  its  veins,  the  percentage  of  left  coronary 
artery  inflow  recovered  in  the  coronary  sinus  is  quite 
high  (80-90  %)  and  reasonably  constant  during  the 
induction  of  a  variety  of  physiological  variables  and 
drug  injections  (300).  In  the  open-chest  dog,  the 
right  coronary  artery  contributes  not  more  than  2  to  3 
per  cent,  or  1  to  2  ml  per  min,  to  the  coronary  sinus 
flow,  and  this  only  occasionally.  This  has  been  deter- 
mined by  observing  minimal  changes  in  coronary 
sinus  flow  when  the  right  coronary  artery  is  clamped 
in  the  presence  of  an  elevated  right  ventricular  pres- 
sure from  pulmonary  artery  stenosis,  when  right 
coronary  artery  clamping  is  superimposed  on  a  pre- 
existing occlusion  of  the  left  coronary  artery  (153), 
and  by  observing  only  minimal  changes  in  the  optical 
density  of  coronary  sinus  blood  following  massive 
injection  of  Evans  blue  dye  into  the  right  coronary 
artery  (300). 

The  investigation  of  whether  the  coronary  sinus 
fraction  of  blood  is  representative  in  chemical  compo- 
sition of  total  left  coronary  venous  return  started  with 
the  experiments  of  Evans  &  Starling  in  1913  (106)  and 
has  continued  to  the  present  time.  Actually,  investiga- 
tions during  this  period  did  not  directly  attack  the  prob- 
lem (158).  In  these  experiments,  the  effect  of  increased 
right   ventricular   pressure  was  determined   on   flow 


BLOOD    SUPPLY    TO    THE    HEART 


'533 


and  oxygen  content  of  coronary  sinus  blood  and  of  the 
remaining  coronary  venous  blood  including  that 
from  the  right  coronary  artery.  Obviously,  these  ob- 
servations are  germane  only  to  the  problem  of  whether 
an  increase  in  right  ventricular  metabolism  asso- 
ciated with  increased  right  ventricular  pressure  is 
reflected  in  the  coronary  sinus  blood  (195,  264).  This 
might  not  be  expected  because  of  the  very  small 
drainage  of  right  coronary  flow  into  the  coronary 
sinus.  These  experiments  are  certainly  not  germane 
to  the  problem  of  whether  the  two  coronary  venous 
drainage  fractions  from  the  left  coronary  artery  have 
the  same  chemical  composition,  for  such  measure- 
ments were  not  made. 

This  question  for  the  left  myocardium  has  been 
answered  by  simultaneously  and  continuously  meas- 
uring, under  different  circumstances,  left  coronary 
artery  flow,  and  the  flow  and  oxygen  content  of  the 
two  coronary  venous  fractions  derived  from  the  left 
coronary  artery.  In  these  experiments,  the  systemic 
venous  return  bypassed  the  right  heart,  and  the  right 
coronary  artery  was  generally  clamped.  The  oxygen 
uptake  calculated  on  the  basis  of  left  coronary  artery 
flow  times  the  difference  between  the  arterial  and 
coronary  sinus  oxygen  content  agrees  quite  well  with 
the  oxygen  uptake  based  on  the  sum  of  the  respective 
volume  flows  and  the  oxygen  content  of  the  two  left 
coronary  venous  drainage  fractions.  This  is  effected 
by  a  combination  of  a  generally  lower  oxygen  content 
in  the  coronary  sinus  and  a  considerably  greater 
coronary  sinus  flow  (300).  Hence,  in  the  open-chest 
dog  a  combination  of  left  coronary  artery  flow  and 
coronary  sinus  arteriovenous  oxygen  difference  gives 
a  reasonably  precise  value  for  uptake  of  oxygen  by 
the  left  ventricle. 

From  data  such  as  these  it  has  been  reasonably- 
assumed  that  measurement  of  coronary  sinus  flow 
could  be  substituted  for  left  coronary  inflow  and, 
together  with  the  coronary  sinus,  A-V  oxygen  differ- 
ence could  also  serve  as  an  index  of  metabolic  events 
in  the  left  myocardium  of  man  and  beast.  The  authors, 
however,  in  no  way  recommend  this  procedure. 
Although  widely  used  in  man,  it  has  never  been 
demonstrated  that  the  flow,  composition,  and  sources 
of  coronary  sinus  blood  fulfill  the  requirements  as  laid 
down  and  found  to  exist  in  the  dog.  [Actually  in 
early  experiments  with  the  isolated  dog  heart  sig- 
nificant right  coronary  artery  drainage  into  the 
coronary  sinus  was  demonstrated  (92).]  In  addition, 
accurate  measurement  of  coronary  sinus  flow  is 
extremely  hazardous  whether  done  indirectly  by 
means  of  the   nitrous  oxide  method   or  directly   by 


cannulation.  In  the  first  case  there  is  the  ever  present 
danger  of  contamination  with  right  atrial  blood.  In 
the  second  instance,  without  knowledge  of  the  in- 
vestigator, coronary  sinus  flow  may  be  reduced  1 >\ 
shrinkage  and  partial  closure  of  the  sinus.  This 
diminishes  only  slightly  the  left  coronary  inflow, 
which  now  drains  preferentially  by  the  anterior 
cardiac   veins. 


PHYSICAL    DETERMINANTS    OF    CORONARY     FLOW 

Coronary  flow  is  related  to  the  pressure  difference 
(effective  pressure)  between  the  central  coronary 
artery  (identical  to  aortic  pressure)  and  the  right 
atrium  divided  by  the  sum  of  the  viscous  resistances 
to  flow  in  the  epicardial  portion  of  the  artery  and  in 
the  peripheral  coronary  bed.  Viscous  resistance  to 
flow,  aside  from  change  in  hematocrit,  is  mainly 
governed  by  the  mean  caliber  of  the  coronary  vascular 
bed.  Since  the  arterial  resistance  is  negligible,  the 
mean  coronary  diameter  and,  hence,  flow  are  con- 
trolled by  the  effective  intravessel  pressure  and  by  two 
peripheral  mechanisms,  i.e.,  active  changes  in  the 
state  of  the  small  mass  of  intramural  smooth  muscle 
built  into  the  coronary  vessels,  and  the  mechanical  or 
passive  effect  on  flow  exerted  during  ventricular 
systole  by  the  large  muscle  mass  around  the  coronary 
vessels. 

Insight  into  the  complexity  of  the  integrating  action 
of  central  and  peripheral  flow  determinants  has  been 
obtained  from  the  recording  of  the  peripheral  coro- 
nary pressure  and  the  phasic  or  moment-to-moment 
changes  in  coronary  inflow  and  outflow  in  the  epi- 
cardial arteries  and  veins  (151,  153,  158,  212,  301). 
These  curves  were  obtained  from  the  open-chest  dog 
and  from  the  resting  unanesthetized  dog  some  days 
postoperatively,  after  implanting  an  electromagnetic 
flowmeter  on  the  left  coronary  artery  (fig.  6).  At  the 
onset  of  isometric  contraction  of  the  left  ventricle  in 
the  unanesthetized  dog,  there  is  an  abrupt  decrease  in 
left  coronary  inflow  and,  although  at  times  backflow 
may  appear,  a  considerable  forward  flow  generally 
persists  throughout  systole.  With  the  rise  in  aortic 
pressure,  forward  flow  increases  initially  and  rapidly, 
only  to  decrease  to  a  new  intermediate  level  in  late 
systole.  With  the  onset  of  isometric  relaxation, 
coronary  flow  increases  significantly,  peaking  at 
early  diastole  and  then  declining  progressively.  These 
demarcations  of  flow  are  much  less  obvious  in  the 
right  coronary  inflow  pattern,  which  roughly  re- 
sembles the  prevailing  aortic  pressure  curve.  The  flow 


[534 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


AORTIC    PRESS 


LEFT    COR     FLOW 


CARDIAC    OUTPUT 


105  mm  Hq    MEAN 


225  ml/min 

90  ml/IOOg/min 

2  8  ml/HEART 

BEAT 


3000    ml/mm 

37  ml/HEART 

BEAT 


HEART     RATE    80 

fig.  6.  Reproduction  of  a  retrace  of  an  original  record  taken 
in  the  conscious  dog,  14  days  postoperative,  showing  phasic 
aortic  blood  pressures  recorded  by  a  strain  gauge  connected  to 
a  chronically  implanted  aortic  catheter,  and  phasic  left  coronary 
artery  flow  and  stroke  cardiac  output  by  electromagnetic  flow- 
meters chronically  implanted,  respectively,  on  the  main  left 
coronary  artery  and  ascending  aorta.  (Unpublished  observa- 
tions.) 

patterns  just  indicated  for  the  conscious  dog  are 
similar  to  those  in  the  open-chest  dog  except  that  in 
the  left  coronary  artery  of  the  latter,  systolic  flow  is 
minimal  and  backflow  is  usually  present  during  iso- 
metric contraction  (153). 

The  flow  patterns  of  the  left  coronary  artery  are  a 
complex  of  events  happening  in  the  total  distribution 
of  flow  in  the  left  myocardium  and  a  small  portion  of 
the  right  ventricle.  Regional  variations  of  flow  pattern 
might  be  expected  based  on  anatomical  and  func- 
tional differences  in  the  areas  supplied.  Flow  patterns 
of  the  main  left  coronary  and  its  circumflex  and 
descendens  branches  are  essentially  similar.  Phasic 
flow,  however,  in  the  left  anterior  atrial  artery  shows 
a  forward  flow  in  both  systole  and  diastole  with  the 
flow  pattern  resembling  an  aortic  pressure  pulse  (349). 
About  40  per  cent  of  this  arterial  flow  (5  '"<  of  left 
circumflex  flow)  drains  into  the  left  atrium  (266). 
Patterns  of  flow  through  the  canine  septal  artery  are 
not  available.  It  would,  however,  be  predicted  that 
the  pattern  would  differ  from  that  in  the  circumflex 
and  descendens  by  having  a  much  smaller  systolic 
flow  since  this  artery  has  essentially  no  epicardial 
component.  Most  of  the  flow  in  this  very  small  artery 
drains  into  the  right  ventricle  (265). 

The  finding  of  a  significant  and  variable  coronary 
flow  during  systole  in  the  left  coronary  artery  of  the 
unanesthetized  dog  deserves  further  comment.  In  the 


past,  the  view  based  on  work  in  the  open-chest  dog 
has  been  that  flow  in  the  left  coronary  artery  is  very 
small  during  systole,  that  it  does  not  vary  significantly 
with  different  dynamic  conditions,  and  that  it  can 
be  accounted  for  largely  on  the  basis  of  radial  en- 
largement of  the  epicardial  vessels  and  their  filling 
during  ventricular  contraction  (153).  This  meant 
that  events  in  systole  could  be  and  were  largely  ig- 
nored and  that  the  only  important  considerations  for 
regulation  of  left  coronary  flow  were  happenings 
during  diastole.  Recent  work  using  chronically  im- 
planted electromagnetic  flowmeters  indicates  that 
although  the  coronary  flow  in  systole  in  the  unanesthe- 
tized dog  at  rest  can,  at  times,  be  rather  small,  in 
many  dogs  it  may  approximate  30  per  cent  of  that 
during  diastole.  In  the  presence  of  mild  exercise,  it 
does  not  appreciably  increase,  but  following  release  of 
coronary  artery  occlusion,  and  during  excitement  and 
chronic  stimulation  of  the  cardiac  sympathetic  nerves, 
the  volume  of  systolic  flow  increases  300  to  400  per 
cent,  as  does  the  diastolic  flow,  the  ratio  between  the 
two  remaining  about  the  same  (139,  212,  301 ).  Finally, 
in  irreversible  hemorrhagic  shock,  late  in  the  period 
of  spontaneous  cardiovascular  decay  after  blood 
reinfusion,  the  systolic  flow  may  approach  that  during 
diastole  for  an  equivalent  time  interval,  and  eventually 
the  flow  pattern  may  resemble  somewhat  the  prevail- 
ing aortic  pressure  pulse  with  most  of  the  coronary 
flow  occurring  in  systole  rather  than  in  diastole  ( 1 59)- 
The  proper  explanation  of  these  findings  awaits 
future  experimentation  (fig.   7). 

The  preceding  account  indicates  that  the  coronary 
bed  has  a  fluctuating  resistance  to  flow.  Flow  curve 
inspection  shows  the  obvious  importance  of  left 
ventricular  contraction  in  controlling  coronary  flow, 
because  during  systole  left  coronary  flow  is  reduced 
while  coronary  sinus  flow  is  increased.  The  increase 
in  coronary  sinus  flow  suggests  that  ventricular  con- 
traction acts  to  aid  coronary  flow  by  massaging  blood 
through  its  wall;  the  reduction  in  coronary  inflow  sug- 
gests that  it  acts  to  throttle  coronary  flow.  The 
answer  depends  upon  the  relative  changes  of  inflow 
and  outflow  volume  during  systole.  Unfortunately, 
this  is  impossible  to  determine  because  of  the  incom- 
plete and  variable  drainage  of  the  left  coronary  artery 
through  the  coronary  sinus.  However,  actual  meas- 
urements in  the  left  coronary  artery  of  the  open-chest 
dog  show  that  the  peripheral  coronary  maximal 
systolic  and  minimal  diastolic  pressure  values  approxi- 
mate 80  20  mm  Hg,  and  inflow  is  cut  off  at  these 
pressure  levels  when  the  left  coronary  artery  is  per- 
fused through  its  distal  end  under  constant  pressure. 


BLOOD    SUPPLY    TO    THE    HEART  1 535 


BLOOD 
PRESS 
mm   Hg 

® 

19 

21 

© 

CIRC. 

COR 

FLOW 

ml/min 

0 

/W-l_  P* 

FLOW 

STROKE 
VOLUME 

ml 

Hr 

AzA. 

A^i_A 

fig.  7.  Reproduction  of  retraces  from  an  original  record  taken  in  a  resting  unanesthetized  dog 
some  days  postoperative  showing  the  effect  of  irreversible  hemorrhagic  shock  on  phasic  blood  pressure 
and  phasic  stroke  left  circumflex  coronary  flow,  using  a  strain  gauge  and  electromagnetic  flowmeter 
as  in  fig.  6.  A — early;  B — midway;  C — late  in  the  period  of  spontaneous  hemodynamic  decay  fol- 
lowing reinfusion.  (L'npublished  observations.) 


In  the  right  coronary  artery,  the  contour  and  time 
relations  of  the  peripheral  coronary  pressure  curve 
are  similar  but  the  values  for  systole  and  diastole  and 
for  the  cut-off  of  flow  are  considerably  lower  ( 1 53). 

Separation  and  quantitation  of  the  determinants 
of  coronary  flow  lying  within  the  myocardial  wall, 
i.e.,  the  vascular  and  extravascular  muscle,  are  of 
extreme  importance.  Various  methods  have  been 
proposed  and  used,  but  they  have  been  only  partially 
successful.  The  problem  of  determining  the  relation- 
ship of  blood  flow  to  active  vasomotor  changes, 
irrespective  of  whether  the  effect  on  the  intrinsic 
muscles  of  the  coronary  vessels  is  mediated  through 
the  blood  stream  or  is  secondary  to  metabolic  changes 
in  the  surrounding  myocardium,  is  especially  difficult. 
It  is  not  known  how  much  coronary  flow  might  change 
with  a  given  change  in  coronary  perfusing  pressure 
without  an  associated  active  change  in  the  vasomotor 
state  of  the  bed.  Determination  of  active  variations  in 
vasomotor  tone  in  the  coronary  bed  is  further  compli- 
cated by  uncontrollable  mechanical  factors.  Varia- 
tions may  occur  in  the  respective  durations  of  systole 
and  diastole  during  which  the  rates  of  flow  per  unit 
of  time  may  be  quite  different  and  thus  obscure  any 
active  vasomotor  changes. 

By  analysis  of  phasic  inflow  curves,  however, 
change  in  the  vasomotor  state  can  be  separately  and 


roughly  estimated.  A  critical  point  on  a  coronary 
inflow  curve  is  selected  in  late  diastole,  at  which 
time  the  rate  of  change  of  the  volume-elastic  and 
myocardial  compression  forces  is  presumed  to  be 
minimal  (153)-  At  this  point,  extravascular  forces  are 
at  a  minimum,  the  rate  of  flow  reflecting  the  vaso- 
motor state  of  the  coronary  bed,  and  the  ratio  of  the 
aortic  pressure  to  the  simultaneously  existing  rate  of 
flow  is  then  determined.  A  shift  in  the  diastolic  ratio 
is  taken  to  represent  active  constriction  or  dilatation 
of  the  coronary  bed  (41,  146).  It  has  also  been  sug- 
gested that  change  in  the  extravascular  compressing 
force  during  systole  can  be  estimated  by  comparing 
the  diastolic  ratio  with  the  ratio  of  blood  pressure  to 
coronary  flow  at  a  point  in  late  systole  when  extra- 
vascular support  is  maximal  and  flow  reflects  the 
combined  effect  of  myocardial  compression  and  the 
existing  vasomotor  state  (146).  At  this  time,  the  rate  of 
change  of  the  volume-elastic  and  myocardial  com- 
pression forces  is  presumed  to  be  minimal.  Use  of 
such  a  systolic  point  has  as  yet  no  experimental 
verification. 

The  problem  of  determining  the  magnitude  of 
extravascular  support  has  been  approached  in  differ- 
ent ways.  It  has  been  suggested  that  intramural 
pressure  can  be  used  as  a  measure  of  extravascular 
compression,  and  attempts  have  been  made  to  quanti- 


>536 


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CIRCULATION    II 


tate  the  pressure  developed  within  the  wall  of  the  left 
ventricle  during  systole  and  to  use  it  as  a  measure  of 
extravascular  support.  To  do  this,  pressure  pulses 
have  been  recorded  from  a  myocardially  imbedded 
vessel  (or  myocardial  fluid  pocket  connected  to  a 
recording  manometer).  However,  experimental  work 
indicates  that  although  these  pressures  may  indicate 
directional  changes  in  extravascular  compression, 
they  are,  in  part,  artifactually  produced  and,  hence, 
do  not  approximate  the  correct  values  for  intramural 
pressure  (153). 

A  method  recently  developed  has  given  some  in- 
formation on  this  point  (323).  Continuous  measure- 
ments are  made  in  the  open-chest  dog  while  the  left 
coronary  artery  is  perfused  with  blood  under  a  con- 
stant pressure.  First  it  is  done  in  the  beating  heart, 
and  then  during  ventricular  asystole  induced  by 
vagal  stimulation,  or  by  disconnecting  an  external 
pacemaker  which  drives  the  ventricles  (complete 
atrioventricular  heart  block  having  been  surgically 
produced  previously).  By  either  means,  the  mechani- 
cal effects  of  ventricular  contraction  are  largely 
removed.  Induction  of  ventricular  asystole  by  vagal 
stimulation  always  increases  immediately  (within 
1  sec)  left  and  right  coronary  inflow.  Thus,  ventricu- 
lar contraction  acts  to  impede  coronary  flow  through 
the  ventricular  wall.  The  extent  of  the  rise  of  flow  is 
taken  to  represent  the  magnitude  of  the  mechanical 
or  passive  factors  limiting  coronary  flow.  The  mag- 
nitude of  this  mechanical  throttling  effect  on  cor- 
onary flow  during  systole  normally  varies  from 
31  to  300  per  cent  and  averages  about  50  per 
cent.  The  new  flow  level  represents  that  state  of 
coronary  dilatation  related  to  the  condition  of  the 
intrinsic  smooth  muscle  of  the  coronary  vessels  at 
the  prevailing  coronary  pressure.  The  relative  con- 
tribution of  extravascular  and  intravascular  re- 
sistance to  an  increase  of  coronary  flow  has  been 
tested  under  the  different  conditions  of  increasing 
heart  rate,  decreased  arterial  blood  oxygen  satura- 
tion, aortic  constriction,  transfusion,  and  drug  injec- 
tions. In  all  instances,  the  major  portion  of  a  flow 
increase  is  through  active  dilatation  and  not  through 
reduction  in  extravascular  resistance.  The  largest 
reduction  (40  % )  in  extravascular  resistance  is  from  a 
decrease  in  arterial  oxygen  saturation  (155,  236). 


DETERMINANTS  OF  NORMAL  MYOCARDIAL   METABOLISM 

The  ability  of  the  heart  to  do  work  depends  basi- 
cally on  its  biochemical  activity  leading  to  muscular 


contraction.  Cardiac  muscle  has  been  found  to  have 
basic  chemical  patterns  similar  to  those  of  other 
muscle.  The  catabolism  of  fat,  carbohydrate,  and  pro- 
tein produces  free  energy,  about  half  of  which  is 
dissipated  as  heat  and  half  is  captured  as  phosphate- 
bond  energy  which  is  used  for  muscle  cell  work  and 
for  various  anabolic  activities  such  as  synthesis  of 
glycogen,  lipids,  proteins,  and  enzymes.  These  cata- 
bolic  and  anabolic  reactions  proceed  simultaneously 
under  the  influence  of  a  complex  system  of  enzymes, 
coenzymes  (from  the  vitamin  B  complex),  and 
hormones. 

Coronary  sinus  catheterization  studies  in  man  and 
dog  have  indicated  that  the  heart  is  able  to  choose  its 
fuel  from  a  variety  of  foodstuffs.  These  include 
mainly  glucose,  lactate,  pyruvate,  fatty  acids  (non- 
esterified)  and,  to  a  lesser  extent,  acetate,  ketone 
bodies,  and  amino  acids.  To  determine  their  quanti- 
tative contribution  to  the  energy  production  of  the 
heart,  i.e.,  its  oxygen  consumption,  measurements 
have  been  made  of  their  cardiac  extraction  (coronary 
artery — coronary  sinus  difference),  their  total  uptake 
[coronary  flow  X  (coronary  artery — coronary  sinus 
difference  of  substance)],  and  the  myocardial  respira- 
tory quotient  (coronary  sinus — arterial  carbon  dioxide 
difference;  coronary  artery — coronary  sinus  oxygen 
difference).  Excellent  correlation  has  been  demon- 
strated between  the  myocardial  respiratory  quotient 
and  the  myocardial  uptake  of  substance.  The  extent 
to  which  each  substrate  contributes  to  the  energy 
requirement  of  the  heart  in  vivo  is  influenced  by  its 
concentration  (above  threshold)  in  arterial  blood.  In 
addition,  the  state  of  nutrition  of  the  organism  mark- 
edly influences  the  kind  of  substrate  used  for  energy 
production  of  the  heart.  Under  postprandial  condi- 
tions, or  after  glucose  infusion,  myocardial  metab- 
olism is  mainly  glucose,  lactate,  and  pyruvate,  since 
its  respiratory  quotient  approximates  0.9  with  a  high 
extraction  of  carbohydrate  and  a  negligible  uptake  of 
amino  acids.  Even  the  substitution  of  5  to  10  per  cent 
oxygen  for  the  normal  2  1  per  cent  in  the  inspired  air 
does  little  to  change  carbohydrate  uptake  by  the 
normal  heart.  During  overnight  fasting,  the  heart 
derives  much  of  its  energy  from  fat,  as  indicated  by  a 
myocardial  respiratory  quotient  of  0.80  with  a  low 
extraction  and  uptake  of  carbohydrate.  With  pro- 
longed fasting,  the  extraction  coefficient  for  carbo- 
hydrate practically  disappears,  those  for  fatty  acids 
and  ketones  are  maximal  and  the  respiratory  quotient 
is  0.70.  As  regards  the  uptake  of  oxygen,  the  coronary 
A-V  oxygen  differences  in  man  vary  linearly  with  the 
arterial  oxygen  content  through  a  range  from  mild 


BLOOD    SUPPLY     TO     1  UK    HEART 


[537 


anemia  to  marked  polycythemia  so  that  the  myo- 
cardial extraction  coefficient  (A-V),  A  is  constant. 

In  addition  to  patterns  of  myocardial  metabolism  in 
the  normal  heart,  other  metabolic  changes  have  been 
reported  in  some  pathological  and  diseased  states. 
Patients  with  heart  failure  and  decreased  cardiac 
work  due  to  valvular  disease  show  an  increased  carbo- 
hydrate uptake  by  the  heart  with  a  normal  extraction 
of  lactate  and  pyruvate  and  increased  glucose  exti  ac- 
tion. The  heart  in  the  patient  with  diabetes  appears 
to  derive  most  of  its  energy  from  fat  even  in  mild 
cases  with  a  postabsorptive  respiratory  quotient  ol 
about  0.7  and  an  increased  uptake  of  fatty  acids  and 
a  decreased  carbohydrate  uptake. 

Thus,  the  heart  demonstrates  broad  flexibility  in 
the  utilization  of  substrate  for  energy  production 
without  a  change  in  work  performance  or  work 
capacity.  This  makes  it  largely  independent  of  fluctua- 
tions in  its  chemical  environment.  There  is  no  evi- 
dence that  substrate  lack  occurs  in  any  clinical 
situation  to  the  extent  that  it  embarrasses  the  cardiac 
work  capacity.  Similarly,  the  metabolic  disturbances 
such  as  diabetes  mellitus  which  alter  the  fuel  mixture 
available  to  the  heart  do  not  also  alter  cardiac  func- 
tion. It  is,  however,  well  to  defer  detailed  considera- 
tion of  other  data  because  an  interpretation  must  be 
based  on  the  assumption  that  oxidation  of  foodstuffs 
to  carbon  dioxide  and  water  is  the  sole  factor  in  the 
determination  of  the  myocardial  respiratory  quotient 
and  of  the  myocardial  extraction  and  uptake  of  these 
compounds  including  oxygen.  Without  doubt,  stor- 
age of  and  or  conversion  into  other  compounds  is 
occurring  concurrently,  and  these  activities  are 
expecially  prominent  in  the  presence  of  a  changing 
cardiac  level  of  activity  or  changing  levels  of  blood 
substrate  (16,  32,  33,  74,  1 16,  133,  169,  278,  279). 


BASAL  DATA 

In  the  resting  state,  the  coronary  data  for  dog  and 
man  agree.  With  the  left  ventricular  cardiac  work 
index  approximating  3.0  to  4.6  kg-m,  left  coronary- 
flow  approximates  72  to  85  ml  per  100  g  of  left 
ventricle  per  min  (118,  153,  307).  In  the  anesthetized 
open-chest  dog,  values  as  high  as  600  ml  per  100  g 
left  ventricle  per  min  have  been  recorded  when  the 
left  heart  has  been  stressed  by  a  combination  of 
catecholamine  injection  and  aortic  constriction  (344). 
Left  coronary  flow  values  in  the  unanesthetized  dog 
during  maximal  natural  stresses  are  not  yet  available 
but  during  moderate  treadmill  exercise  and  following 


excitement,  the  coronary  flow  has  approximated 
that  in  the  open-chest  dog  (212).  As  indicated  under 
physical  determinants  of  coronary  flow,  the  frac- 
tionation of  the  volume  flow  between  systole  and 
diastole  is  somewhat  variable,  but  in  the  left  coronary- 
artery  of  the  unanesthetized  dog  the  systolic  volume 
flow  very  often  approximates  25  to  30  per  cent  of  the 
diastolic  flow  under  semibasal  conditions,  as  well  as 
during  excitement,  exercise,  and  reactive  hyperemia 

(i59a)- 

In  the  anesthetized  dog,  the  circulation  time  from 
the  central  coronary  artery  to  the  coronary  sinus 
approximates  4.5  sec  (260).  In  normal  patients,  the 
coronary  transit  time  (with  I131  injection)  varies  from 
6.5  to  1 1  sec.  Exercise  and  nitroglycerin,  which  in- 
crease coronary  flow  (nitrous  oxide  method),  decrease 
the  transit  time  (increased  coronary  flow  velocity) 
while  the  Valsalva  maneuver,  which  increases  the 
circulation  time,  decreases  coronary  flow  (135). 

Flow  values  for  the  right  coronary  artery  in  a  good- 
sized  open-chest  dog  approximate  10  to  15  ml  per 
min.  In  the  resting,  unanesthetized  dog,  the  values 
are  similar  (unpublished  observations).  The  volume  of 
systolic  flow  generally  exceeds  the  diastolic  volume 
flow  for  an  equivalent  time  period  and  very  often  ex- 
ceeds total  diastolic  flow  (153,  and  unpublished  obser- 
vations). Values  per  gram  of  myocardium  and  the 
flow  responses  to  natural  stresses  of  everyday  life  are 
not  known. 

Although  each  ventricle  can  remove  essentially  all 
oxygen  from  the  coronary  blood  in  its  passage  through 
the  myocardium,  normally,  for  the  left  ventricle 
(also  the  right),  about  two-thirds  is  extracted  with  an 
arteriovenous  difference  of  1  1  to  14  ml,  and  a  coro- 
nary sinus  value  of  5  to  6  ml.  This  extraction  changes 
little,  i.e.,  less  than  10  to  20  per  cent  with  increased 
stress  (except  following  catecholamine  injection, 
anoxia,  and  anemia,  in  which  it  decreases),  indicating 
that  the  oxygen  supply  is  well  balanced  with  metabolic 
demands  (208). 

Oxygen  uptake  per  100  g  left  ventricle  (coronary 
flow  X  coronary  A-V  02  difference)  is  8  to  10  ml 
per  min  in  the  open-chest  dog,  the  anesthetized  closed- 
chest  dog  with  normal  blood  pressure  and  cardiac 
output,  and  in  the  resting  unanesthetized  dog  and 
human.  Maximum  values  calculated  in  the  open- 
chest  dog  approximate  60  ml  per  100  g  per  min.  In 
the  unanesthetized  active  dog  under  the  influence  of 
mild  exercise  and  excitement,  values  are  not  avail- 
able. 

With  present  poor  methodology,  separation  of  oxy- 
gen usage  between  systole  and  diastole  can  only  be 


'538 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


made  by  measuring  oxygen  uptake,  first  in  the  beating 
heart  during  repetitive  systoles  and  diastoles,  and  then 
in  the  relaxed  heart  or  during  prolonged  diastole, 
thus  obtaining  the  oxygen  usage  during  systole  by 
difference.  Estimation  of  the  metabolism  of  the  myo- 
cardium in  the  absence  of  a  heart  beat,  that  is  during 
prolonged  diastole,  has  been  made  in  the  vagus-ar- 
rested heart  (see  section  on  Physical  Determinants  of 
Coronary  Flow).  The  oxygen  saturation  of  the  arterial 
blood  and  coronary  sinus  blood  is  also  measured 
continuously.  This  permits  left  coronary  arteriovenous 
oxygen  difference  as  well  as  coronary  inflow  to  be 
measured  continuously,  first  in  the  beating  heart  and 
then  in  the  stopped  heart  until  a  new  equilibrium  is 
established,  usually  within  20  to  25  sec  (155,  156, 
249).  As  coronary  inflow  rises  immediately  with 
asystole,  the  oxygen  saturation  of  blood  in  the  coro- 
nary sinus  also  rises,  thus  greatly  reducing  the  coro- 
nary arteriovenous  oxygen  difference.  Calculations 
in  many  experiments  show  that  as  the  result  of  the 
combination  of  an  increased  coronary  flow  and  a 
decreased  coronary  arteriovenous  oxygen  difference, 
the  oxygen  usage  per  100  g  of  left  ventricle  per  min 
decreases  from  the  average  control  level  of  8. 1  ml  in 
the  working  beating  heart  to  2.3  ml  in  the  resting 
heart,  or  to  30  per  cent  of  the  control.  This  oxygen 
consumption  in  diastole  is  about  one-third  that  in 
systole  for  an  equivalent  time  period  (249). 

Attention  is  also  directed  to  the  values  for  oxygen 
usage  obtained  in  the  same  type  of  preparation  but  in 
which  the  external  work  of  the  heart  is  reduced  to 
zero  by  other  means.  In  the  potassium-stopped  heart, 
the  oxygen  usage  of  2  ml  during  diastole  is  about  the 
same  as  in  vagal  asystole.  In  the  beating  heart  emp- 
tied by  suction  and  hemorrhage,  and  in  the  heart 
with  induced  ventricular  fibrillation,  the  oxygen 
usages  of  3.4  and  3.8  ml  are  much  greater  (249)  (see 
the  paragraphs  under  Heart  Rate  for  more  detailed 
consideration). 

The  metabolism  of  the  heart  is  predominantly 
aerobic.  With  abrupt  vagal  stoppage,  however,  during 
constant  pressure  perfusion  of  the  coronary  arteries, 
an  excess  of  oxygen  (oxygen  debt)  over  that  in  the 
asystolic  state  is  taken  up  by  the  heart  from  the  onset 
of  asystole  to  the  time  of  appearance  of  the  final 
resting  metabolism.  This  volume  of  oxygen,  which 
is  quite  small  (estimated  as  8%  compared  to  the 
maximum  oxygen  debt  for  an  equivalent  weight  of 
skeletal  muscle  of  man),  might  be  greater  in  a  heart 
working  to  capacity.  Whether  under  prolonged  hy- 
poxia the  anaerobic  component  of  myocardial  metab- 


olism   can    be    extended    has    not    been    determined 

(]55)- 

As  in  any  muscle,  the  mechanical  efficiency  of  the 
left  ventricle  is  estimated  by  dividing  its  external 
work  by  the  difference  between  its  oxygen  consump- 
tion during  activity  and  during  its  resting  state.  Pub- 
lished data  (31)  which  indicate  efficiency  approxi- 
mating 10  to  20  per  cent  in  the  normal  heart  include 
only  the  first  two  measurements.  Since  the  resting 
metabolism  is  considerable  and  variable,  and  such 
values  are  generally  not  available,  interpretation  of 
the  relation  of  cardiac  work  to  oxygen  uptake  is  diffi- 
cult. 


RESPONSE    OF    THE    CORONARY    CIRCULATION 
TO    VARIOUS   STIMULI 

The  information  has  been  obtained  from  the  un- 
anesthetized  dog  and  man  and  from  the  anesthetized 
open-  or  closed-chest  dog. 


Resting  Stalt- 
As  already  pointed  out,  the  levels  of  coronary  flow 
and  oxygen  usage  of  the  myocardium  are  quite 
fluctuant,  varying  greatly  with  the  different  types  of 
preparation  and  the  prevailing  stimuli.  For  values  of 
coronary  flow  and  myocardial  metabolism  representa- 
tive of  the  basal  or  resting  state,  selection  of  data  in 
the  dog  and  man  must  be  restricted  to  those  in  which 
the  systemic  arterial  blood  pressure,  cardiac  index, 
cardiac  work  index,  heart  rate,  and  body  oxygen 
uptake  roughly  approximated  those  figures  for  the 
resting  state.  In  the  abnormal  or  diseased  state  in 
human  beings,  data  have  been  restricted  to  those  in 
which  systemic  blood  pressure,  cardiac  index,  cardiac 
work  index,  and  heart  rate  approximate  values  re- 
garded as  acceptable  for  the  basal  state  when  there 
was  no  known  reason  for  it  to  be  elevated.  These 
criteria  exclude  a  considerable  volume  of  published 
work,  especially  in  man.  While  most  of  the  data 
comparing  left  coronary  flow  to  the  oxygen  usage 
per  100  g  left  ventricle  per  min,  for  the  resting  state 
in  man  and  dog,  have  been  obtained  by  the  N20 
method,  the  excellent  correlation  of  A-V  oxygen  dif- 
ferences yielded  by  this  method  with  those  from  the 
more  precise  methods  used  on  the  dog  supports  the 
accuracy  of  the  former  when  properly  used. 


BLOOD    SUPPLY    TO    THE    HEART 


[539 


Reactive  Hyperemia 

Reactive  hyperemia  is  considered  to  be  the  excess 
blood  flow  (over  the  control  flow  that  normally  would 
have  occurred)  following  release  of  a  coronary  artery 
occlusion.  The  coronary  bed  is  extremely  reactive  to 
the  stimulus  of  anoxia.  After  release  of  temporary 
occlusion  of  a  coronary  artery,  even  for  as  short  a 
time  as  2  to  3  sec,  left  coronary  arterial  flow  increases 
almost  immediately  in  the  isolated  heart,  heart- 
lung  preparation,  the  anesthetized  open-chest  dog, 
and  the  unanesthetized  dog  (66,  67,  147,  301).  The 
augmented  flow  exists  throughout  systole  and  diastole. 
The  flow  response  occurs  without  necessarily  any 
change  in  blood  pressure  or  heart  rate  and  before  any 
impairment  of  myocardial  contraction  occurs  in  the 
area  rendered  ischemic.  Beyond  30  to  60  sec  of  occlu- 
sion, the  area  bulges  during  systole  (153)-  Depending 
upon  the  duration  of  the  occlusion,  the  peak  flow 
response  (100-300%  of  control  flow)  does  not  usually 


occur  immediately  upon  release  of  the  occluded 
coronary  artery,  but  reaches  a  maximum  some  time 
during  the  first  half  minute  of  reactive  hyperemia  and 
may  last  up  to  4  min  (fig.  8).  The  volume  of  reactive 
hyperemia  blood  flow,  its  duration  and  peak  flow 
values  increase  with  lengthening  periods  of  left 
circumflex  arterial  occlusion  up  to  120  sec.  The 
theoretical  blood  flow  "debt"  (control  blood  flow  X 
duration  of  occlusion)  seems  to  be  always  greatly  over- 
paid (average  2 1 9  c'<  )  in  the  presence  of  periods  of 
occlusion  lasting  from  5  sec  to  180  sec.  The  reactive 
hyperemia  responses  in  skeletal  muscle  vascular  beds 
are  similar  (222)  except  that  the  blood  flow  debt  is 
variably  over-  or  underpaid  (410).  In  other  vascular 
beds,  such  as  the  superior  mesenteric  artery,  this  re- 
sponse is  much  smaller  than  in  the  myocardium;  in 
the  renal  (150),  it  is  essentially  nonexistent. 

The  presence  of  reactive  hyperemia  has  not  been 
satisfactorily  explained.  Its  purpose  must  be  to  supply 


,200 


£  100- 


E 
£89 


HEART    RATE   =    162 


90 


82 


88 


<o 
ouj    60 


30   SEC 
"OCCLUSION       ]/    R  H.B.F 


43  7 


□  z     24 

O  Ld 

3?      12 

m  x 

°       0 


p         ART    BLOOD  =  19.8  VOL  % 

">     COR   SINUS       56                                       |          y^~ 

_______                     13.0  cc   0 

>-fa— -i**"^ 

5.6 

tA 


24r 


16 


6  2 


0     DEBT     31  cc 


11.8  cc 


6  2 


SECONDS 


30  60  90  120  150  180 

fig.  8.  Diagrammatic  redrawing  of  arterial  blood  pressure  (upper  tracing),  left  coronary  blood 
How  (next  lower  tracing),  and  coronary  sinus  oxygen  saturation  (third  tracing  down),  before,  during, 
and  after  release  of  30  sec  of  left  coronary  artery  occlusion  in  the  open-chest  dog.  Lowest  curve  repre- 
sents Oj  consumption  of  left  myocardium  (flow  times  A-V  O2)  in  ml/min,  calculated  from  above 
experimental  data.  Arrows  A  and  B  represent,  respectively,  beginning  and  end  of  measurements  of 
reactive  hyperemic  blood  flow  (RHBF)  and  its  average  A-V  02  difference  used  in  calculation.  [From 
Coffman  &  Gregg  (67).] 


i54" 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION     II 


the  metabolic  needs  accumulated  during  the  anoxic 
period.  The  large  increase  in  systolic  as  well  as  dia- 
stolic flow  within  the  first  few  seconds,  before  there  is 
time  for  a  change  in  myocardial  contractility,  in- 
dicates that  massive  active  vasodilation  has  taken 
place  which  overcomes  systolic  flow  resistance.  With 
a  longer  period  of  occlusion,  there  must  be  considered 
the  possibility  of  flow  through  arteriovenous  shunts 
and  through  vessels  probably  near  the  epicardial 
surface,  whose  surrounding  myocardium  is  now  "tired" 
and  does  not  so  strongly  oppose  flow. 

The  oxygen  consumption  during  myocardial  re- 
active hyperemia  is  measured  by  determining  the 
left  coronary  artery  blood  flow  (rotameter)  and  the 
difference  in  oxygen  saturation  of  the  arterial  and 
coronary  sinus  blood  (measured  continuously  with 
an  optical  densitometer).  The  theoretical  oxygen 
"debt"  (control  oxygen  consumption  X  duration  of 
left  coronary  artery  occlusion)  is  overpaid  for  15-  and 
30-sec  but  slightly  underpaid  for  10-sec  occlusions 
(67).  The  rate  of  oxygen  consumption  during  the 
increased  blood  flow  period  is  greater  than  in  the 
control  state,  showing  that  the  myocardium  has  been 
stimulated  to  take  up  more  oxygen.  The  basic  hy- 
pothesis governing  the  calculation  of  the  oxygen 
"debt"  in  these  studies  is  somewhat  erroneous,  for  the 
oxygen  in  the  blood  in  the  coronary  vascular  bed 
during  arterial  occlusion,  the  metabolic  rate  during 
the  circulatory  stasis,  and  changes  in  cardiac  work  are 
not  considered.  As  further  evidence  that  the  myo- 
cardium develops  an  oxygen  deficit,  i.e.,  that 
anaerobic  metabolism  occurs,  it  has  been  found  that 
lactic  acid  increases  in  the  coronary  sinus  blood, 
often  in  comparison  to  pyruvic  acid  levels  following 
the  period  of  anoxia  (67).  These  observations  have 
been  confirmed  in  the  unanesthetized  dog  with  the 
aid  of  chronically  implanted  (3-14  days  postoperative) 
electromagnetic  flowmeters  and  coronary  sinus 
sampling  tubes  (280). 

The  contracting  myocardium  can  withstand  much 
shorter  periods  of  arterial  occlusion  and  oxygen 
deficit  than  resting  skeletal  muscle,  and  repays  its 
oxygen  "debt"  with  an  increased  blood  flow  but  with  a 
decreased  A-V  oxygen  difference. 

Heart  Rate 

Early  reports  indicated  that  myocardial  oxygen 
usage  increases  in  the  heart-lung  and  isolated  heart 
when  heart  rate  spontaneously  changes  or  when  it  is 
increased  by  warming  the  sinus  node  or  by  driving  the 
heart   electrically,   but   the  evidence   was  conflicting 


concerning  the  effect  of  rhythm  of  the  heart  on  coro- 
nary blood  flow.  In  the  above  preparations,  increase 
in  heart  rate  either  increases,  decreases,  or  does  not 
affect  coronary  flow  do).  More  recent  investigations 
with  somewhat  better  techniques  and  methodologies 
confirmed  this  finding  of  correlation  of  oxygen  usage 
with  heart  rate  in  these  preparations  and  showed  a 
higher  energy  cost  of  external  work  at  the  faster  heart 
rate  (369).  The  oxygen  observations  were  extended 
to  the  empty  heart  beating  in  the  open-chest  dog 
(249).  In  the  latter  preparation,  electrically  induced 
ventricular  tachycardia  after  section  of  the  bundle  of 
His  (23,  236,  355)  or  electrically  induced  auricular 
tachycardia  at  rates  somewhat  higher  than  those 
naturally  occurring  generally  increases  aortic  blood 
pressure,  cardiac  output,  and  cardiac  work,  while  the 
stroke  volume  and  stroke  work  decrease  (225). 
Simultaneously,  minute  coronary  flow  and  oxygen 
usage  increase,  coronary  resistance  decreases,  oxygen 
extraction  is  unchanged,  but  the  coronary  flow  and 
oxygen  consumption  per  beat  decrease  (23).  Com- 
parable results  were  obtained  in  normal  human 
subjects  with  atropine-induced  cardio-acceleration 
(137)  and  in  the  anesthetized  closed-chest  dog  with 
electrically  induced  auricular  tachycardia,  except 
that  systemic  blood  pressure,  cardiac  output,  and 
cardiac  work  did  not  rise  (256).  Since  acceleration  of 
of  the  heart  means  proportionally  greater  time  per 
beat  and  per  minute  in  systole  than  in  diastole,  and 
since  in  systole  coronary  flow  is  less  than  in  diastole, 
it  would  be  anticipated  that  increased  heart  rate  per 
se  should  reduce  coronary  flow.  Since  it  does  not,  it 
must  be  that  increased  flow  is  due  to  arteriolar  dilata- 
tion resulting  from  the  increased  metabolic  activity. 
Actual  measurements  indicate  that  as  heart  rate 
increases,  extravascular  resistance  rises  but  intra- 
vascular resistance  falls  to  a  greater  extent,  indicating 
a  fall  in  net  coronary  resistance  (236).  The  same  trend 
of  flow  and  oxygen  usage  per  beat  and  per  minute 
also  occurs  at  the  faster  heart  rate  when  minute 
cardiac  work  is  held  constant  or  when  comparisons 
are  made  at  the  same  level  of  stroke  work.  This  means 
that  cardiac  acceleration  can  augment  the  energy 
metabolism  of  the  myocardium  without  manifesta- 
tion of  the  extra  energy  as  work  (23,  225).  Data  on 
alteration  in  the  coronary  circulation  following  a 
naturally  occurring  change  in  heart  rate  are  limited 
to  the  observation  of  increased  coronary  flow  with 
increased  heart  rate  (92).  Hence,  the  value  of  these 
observations  in  relation  to  natural  changes  in  heart 
rate  arising  from  local  changes  in  the  circulation  of 


BLOOD  SUPPLY  TO  THE  HEART 


■541 


the   sinus   node   naturally   occurring   remains   to   be 
determined. 

In  the  open-chest  dog,  various  arrhythmias,  either- 
occurring  naturally  or  induced  by  electrical  means, 
by  mechanical  stroking  of  the  heart,  or  by  aconite 
application,  significantly  reduce  systemic  blood  pres- 
sure and  coronary  flow  when  the  irregularity  is 
marked  or  the  rate  rapid  (above  190  per  min)  (72, 
387).  These  arrhythmias  include  incomplete  heart 
block,  premature  auricular  and  ventricular  systoles, 
auricular  fibrillation  and  flutter,  auricular  and  ven- 
tricular tachycardia. 

Heart  Doing  Xo  Externa!  Work 

Knowledge  of  the  metabolic  state  of  the  heart 
doing  no  external  work  is  important  because:  a) 
ventricular  fibrillation  and  asystole  are  frequent 
experimental  and  clinical  occurrences;  b)  in  the 
empty  beating  heart  or  the  asystolic  arrested  heart, 
the  magnitude  of  oxygen  utilization  could  seriously 
affect  the  potential  for  normal  external  efficiency  of 
the  myocardium;  c)  with  the  advent  of  open-heart 
surgery  one  must  be  certain,  in  the  hearts  made 
dynamically  quiescent  by  means  of  cardiac  bypass, 
ventricular  fibrillation,  or  ventricular  arrest,  that  the 
metabolic  requirements  are  met  by  the  available 
oxygen  and  myocardial  damage  does  not  occur. 

The  relative  length  of  time  the  A-V  node  and  myo- 
cardium can  withstand  complete  ischemia  and  still 
function  normally  on  return  of  their  blood  supply 
has  been  studied  in  dogs  whose  hearts  were  maintained 
on  an  extracorporeal  circulation.  Myocardial  anoxia 
(by  clamping  the  coronary  inflow)  leads  to  somewhat 
earlier  damage  to  the  myocardial  muscle  than  to  the 
conducting  system,  for  after  80  to  90  min  of  anoxia, 
blood  pressure  cannot  be  maintained  on  removal  of 
the  heart  from  the  extracorporeal  circulation,  while 
conduction  is  normal  after  as  much  as  100  min  of 
anoxia.  The  former  is  due  to  development  of  an 
unusual  firmness  of  the  left  ventricular  muscle  which 
is  not  reversible  upon  reperfusion  of  the  heart  (65). 
At  the  same  time,  ventricular  distensibility,  as  re- 
vealed by  ventricular  pressure-volume  curves,  is 
sharply  reduced  (161).  If  ventricular  fibrillation  is 
induced  without  maintenance  of  coronary  flow,  myo- 
cardial substances  such  as  adenosine  triphosphate 
and  glycogen  (which  are  maintained  with  coronary 
perfusion)  fall  progressively  within  15  to  30  min  and 
are  partially  resynthesized  upon  reinstitution  of 
perfusion  (288).  The  oxygen  usage  has  been  deter- 
mined  for   the   left   ventricle,    the   external  work   of 


which  has  been  reduced  to  zero  by  four  different 
procedures — vagal  stimulation,  intracoronary  po- 
tassium injection,  ventricular  fibrillation,  and  hemor- 
rhage combined  with  suction  to  give  an  empty  but 
beating  heart.  Results  have  been  rather  variable  for 
the  same  procedure  in  the  hands  of  different  investi- 
gators and  generally  one  investigator  has  used  only 
two  of  the  procedures.  For  example,  the  values  for 
oxygen  usage  for  100  g  myocardium  during  fibrilla- 
tion vary  from  3.7  to  14.6  ml,  in  the  empty  beating 
heart  from  1.5  to  3.5  ml,  during  vagal  asystole  from 
0.8  ml  to  3.7  ml,  intracoronary  potassium  injection 
from  1.4  to  2.5  ml  (17,  22,  26,  29,  179,  192,  249, 
268,  288,  369).  However,  comparing  the  four  pro- 
cedures in  the  same  series  of  experiments  using  the 
open-chest  dog,  the  oxygen  uptake  per  100  g  left 
ventricle  in  the  working  heart  is  8  to  10  ml  per  min, 
the  resting  metabolism  (absence  of  heart  beat,  cardiac 
output,  and  arterial  blood  pressure)  during  cardiac 
arrest  by  vagal  stimulation  or  potassium  injection, 
approximates  2.5  ml  per  100  gleft  ventricle  per  min,  or 
about  25  to  30  per  cent  of  that  at  the  prior  working 
level  (249).  The  metabolism  of  the  nonworking  (but 
slowly  beating)  heart  obtained  by  rapid  exsanguina- 
tion  is  about  3.4  ml,  and  of  the  fibrillating  heart  3.8 
ml.  Where  measured,  oxygen  values  were  the  resultant 
of  a  simultaneous  coronary  flow  increase  and  coro- 
nary A-V  oxygen  decrease.  Although  the  relative 
values  may  hold,  too  much  stress  should  not  be  placed 
on  the  absolute  values.  While  the  various  determi- 
nants of  each  are  probably  still  largely  unknown, 
knowledge  is  sufficient  to  indicate  that  each  should 
be  widely  variable.  For  example,  values  for  the  empty 
beating  heart  are  grossly  affected  by  the  prevailing 
heart  rate;  values  for  the  fibrillating  heart  depend 
upon  the  type  and  frequency  of  fibrillation  and  upon 
the  ventricular  diastolic  size  (268);  values  for  the 
vagus-arrested  heart  or  following  removal  of  an 
artificial  pacemaker  are  not  affected  by  ventricular 
systolic  or  diastolic  size  but  vary  greatly  with  the 
previous  level  of  metabolism  in  the  working  heart. 
With  a  large  elevation  of  myocardial  metabolism  by 
intracoronary  artery  injection  of  epinephrine  or 
norepinephrine,  the  values  are  especially  high  and 
may  equal  50  per  cent  of  those  in  the  control  state 
(249)- 

I  entmular  I  olume  or  Fiber  Length 

Correlation  of  the  left  ventricular  diastolic  or 
systolic  fiber  length  (volume  of  a  ventricle),  or  ven- 
tricular tension,  with  the  coronary  flow  and  oxygen 


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usage  has  been  the  subject  of  many  serious  and  ex- 
cellent investigations,  but  largely  with  the  use  of  the 
isolated  heart.  The  hypothesis  that  the  oxygen  used 
during  ventricular  systole  is  largely  determined  by 
ventricular  diastolic  volume  but  not  by  ventricular 
tension  has  been  in  vogue  for  many  years.  In  1927, 
Starling  &  Visscher  (354)  showed  that  myocardial 
oxygen  consumption  correlated  with  the  changing 
diastolic  ventricular  volume  to  the  point  of  diminished 
stroke  volume  from  excessive  ventricular  distention, 
but  that  the  oxygen  consumption  of  the  heart  had  no 
relation  to  its  systolic  volume.  In  isolated  strips  of 
mammalian  myocardium,  the  oxygen  consumption  at 
rest  increases  significantly  as  the  muscle  length  is 
extended,  but  the  tension  developed  as  a  result  of 
lengthening  has  a  negligible  effect  on  the  oxygen 
usage  (396).  Recently,  others  have  shown  an  excellent 
correlation  of  oxygen  usage  and  diastolic  volume  in 
the  excised  beating  or  fibrillating  heart  with  perfused 
coronary  arteries  (269).  These  observations  also 
apply  to  the  heart  beating  within  the  chest.  For 
example,  following  partial  constriction  (by  means 
of  a  snare)  of  the  pulmonary  artery  or  the  aorta 
central  to  the  two  coronary  ostia,  the  oxygen  usage  of 
both  ventricles,  and  the  blood  flow  in  right  and  left 
coronary  arteries,  are  increased,  even  the  flow  in 
systole  being  considerably  augmented  in  the  right 
coronary  artery  (153).  However,  in  the  excised  heart 
or  the  heart  in  situ  which  has  been  stopped  by  cervical 
vagal  stimulation  or  potassium  injection,  this  relation 
does  not  hold.  Here  large  changes  in  the  volume  of 
blood  within  the  ventricular  cavities  can  occur  with- 
out alteration  of  the  oxygen  consumption  (249,  268). 
This  observation  ties  in  with  the  fact  that  in  the 
open-chest  dog  the  working  heart's  oxygen  usage  and 
its  coronary  flow  are  not  determined  by  the  filling 
pressure  (atrial  pressure)  or  the  end-diastolic  pressure 
or  volume,  for  at  any  given  filling  pressure  the  oxygen 
and  coronary  flow  can  vary  widely  (46,  47).  In  ex- 
periments in  which  the  isolated  beating  heart  with 
perfused  coronary  arteries  has  been  made  to  contract 
isovolumetrically  or  isobarically,  the  myocardial 
oxygen  consumption  is  best  correlated  with  peak 
systolic   pressure   or   systolic   volume    (269). 


that  in  the  right  atrium  into  which  the  coronary 
blood  drains  approximates  o  to  8  mm  Hg.  It  would  be 
expected  that  elevation  of  systemic  venous  or  right 
atrial  pressure  would  decrease  both  right  and  left 
coronary  inflow.  However,  the  influence  of  these 
pressures  on  coronary  flow  is  difficult  to  study  for  the 
changes  induced  in  them  lead  to  other  cardiodynamic 
alterations.  An  approach  to  the  problem  has  been 
made  by  studying  the  effect  of  constriction  or  ligation 
of  the  coronary  venous  drainage  system  on  coronary 
inflow.  With  the  heart  beating  in  situ,  mild  elevation 
of  pressure  in  the  coronary  veins  draining  the  left 
coronary  artery  by  coronary  sinus  constriction  may 
decrease  only  slightly  coronary  inflow  and  increase 
coronary  A-V  oxygen  difference.  Acute  coronary 
sinus  closure  causes  congestion  of  the  left  ventricle 
(but  not  of  the  right  ventricle,  atria,  or  a  portion  of 
the  interventricular  septum),  a  greatly  elevated  venous 
pressure  in  the  coronary  sinus  and  great  cardiac  vein 
often  approximating  or  exceeding  aortic  systolic 
pressure  (153),  but  the  flow  reduction  in  the  left 
coronary  artery  or  its  major  branches  is  only  moder- 
ate, averaging  8  per  cent  in  10  dogs.  However,  the 
venous  outflow  measured  simultaneously  in  several 
major  anterior  cardiac  veins  increases  greatly.  Simi- 
lar responses  occur  when  the  major  venous  drainage 
channels  of  the  right  heart,  the  anterior  cardiac 
veins,  are  occluded  in  acute  experiments;  right  coro- 
nary inflow  decreases  from  o  to  63  per  cent,  averaging 
21    per  cent  in  eight  different  experiments  (1 53)- 

In  acute  experiments,  pulmonary  artery  constric- 
tion in  the  presence  of  previous  ligation  of  the  anterior 
cardiac  veins  still  causes  a  significant  augmentation 
of  right  coronary  inflow.  Finally,  occlusion  of  both 
the  coronary  sinus  and  all  grossly  visible  anterior 
cardiac  veins  reduces  inflow  further,  but  the  hearts 
generally  survive  and  coronary  inflow  increases  with 
increased  load.  Even  with  chronic  ligation  of  the 
anterior  cardiac  veins  and  the  coronary  sinus,  the 
peripheral  coronary  venous  pressure  returns  toward 
normal  within  30  days  (1 53). 

From  these  observations,  it  does  not  seem  likely 
that  a  considerable  elevation  of  right  atrial  pressure 
will  influence  significantly  coronary  inflow  in  the 
normal  heart. 


Blood  Pressure 

coronary'  venous  pressure.  The  venous  pressure  in 
the  great  cardiac  vein  of  the  anesthetized  dog,  with 
or  without  open  chest,  approximates  (10-15)7(0-5) 
mm  Hg  (153);  the  values  for  the  coronary  sinus  and 
anterior  cardiac  veins  are  considerably  lower,  while 


coronary  arterial  pressure.  The  mechanisms  con- 
cerned in  alterations  of  coronary  flow  following  acute 
elevation  or  depression  of  central  coronary  pressure 
have  been  only  partially  elucidated.  Before  con- 
sidering the  effect  of  coronary  perfusion  pressure  on 
coronary  flow,  attention  is  called  to  the  experimental 


BLOOD    SUPPLY    TO    THE    HEART 


1543 


fact  that  in  the  presence  of  a  declining  coronary 
perfusion  pressure,  coronary  flow  ceases  even  when 
coronary  perfusion  pressure  is  still  sizeable,  an  ob- 
servation also  made  in  the  renal  and  mesenteric  beds 
(150)  (see  values  under  Physical  Determinants  of 
Coronary  Flow).  Coronary  inflow  (right  or  left 
coronary  artery)  immediately  increases  throughout 
the  cardiac  cycle  with  a  rising  perfusion  pressure  and 
decreases  with  a  falling  perfusion  pressure  in  all 
preparations  studied. 

In  both  right  and  left  hearts,  however,  there  is  no 
set  relationship  between  coronary  flow  and  change  in 
central  coronary  perfusion  pressure,  the  effect  on 
flow  of  a  given  pressure  change  varying  from  zero  to 
a  maximum.  The  degree  of  change  and  its  duration 
will  depend  upon  the  extent  of  passive  and  active 
changes  in  resistance  within  the  myocardium  asso- 
ciated with  the  alteration  of  perfusion  pressure.  In 
the  heart  doing  no  external  work  (empty,  beating, 
or  fibrillating),  the  change  in  coronary  flow  is  sizeable 
with  moderate  change  in  coronary  perfusion  pressure, 
but  various  relationships  are  observed.  The  resistance 
may  be  semilogarithmic  (80,  283,  341),  i.e.,  it  de- 
creases with  increasing  flow,  or  at  the  highest  flow 
rates  resistance  may  be  constant  or  may  increase. 
Associated  changes  in  resistance  in  the  coronary  bed 
can  be  demonstrated  when  the  vessels  are  perfused  at 
various  pressures  with  the  cardiac  work  kept  con- 
stant or  not  varying  greatly.  In  the  open-chest  dog, 
there  is  a  rapid  and  marked  change  in  coronary 
flow  within  a  few  seconds  following  change  of  the 
perfusion  pressure.  The  induced  change  in  coronary 
flow  may  remain  for  some  time  (1  to  2  min)  or  it 
may  return  toward,  to,  above,  or  below  the  control 
flow  level,  thus  showing  large  resistance  changes  in 
the  coronary  vascular  bed  (89,  158,  249,  315).  A 
similar  autoregulation  of  blood  flow  in  the  presence  of 
a  mechanically  induced  change  in  perfusion  pressure 
has  been  observed  in  other  regions  such  as  the  kidney 
(363)  and  skeletal  muscle  (353). 

It  is  not  surprising  that  in  these  various  situations, 
most  of  which  are  highly  abnormal,  a  variable  rela- 
tion of  pressure  to  flow  exists.  It  is  believed  that  these 
changes  represent  automatic  shifts  in  the  size  of  the 
coronary  vascular  bed  and  in  vascular  resistance 
(passive  and  active  blood  vessel  changes)  which 
serve  to  meet  the  metabolic  needs  of  the  myocardium. 
Whether  they  are  related  to  the  oxygen  supply  and 
demand,  to  the  relative  amount  of  metabolites  washed 
away,  or  to  some  other  control,  is  not  known. 

One  of  the  largest  changes  in  coronary  flow  from 
altered    coronary   perfusion    pressure    occurs   during 


aortic  constriction  with  the  heart  beating  and  working 
in  situ.  In  general,  in  such  instances  in  which  a  change 
in  coronary  flow  resulting  from  alteration  of  coronary 
perfusion  pressure  is  associated  with  a  change  in 
ventricular  stress  (ventricular  size  or  systolic  pres- 
sure, or  both),  the  coronary  A-V  oxygen  is  the  same 
or  increased  slightly  while  the  oxygen  consumption 
changes  considerably  in  the  same  direction  as  the 
flow.  Since  the  heart  rate  (generally  fast)  does  not 
alter  greatly,  both  stroke  coronary  flow  and  stroke 
coronary  oxygen  usage  show  large  increases. 

The  oxygen  uptake  of  a  heart  in  the  open-chest  dog 
performing  external  work  can  apparently  be  altered 
by  changing  abruptly  or  gradually  the  level  of  a 
constant  coronary  perfusion  pressure  by  5  to  35  mm 
Hg  for  periods  up  to  several  minutes.  The  apparent 
oxygen  uptake  of  the  left  ventricle  increases  signifi- 
cantly when  coronary  perfusion  pressure  increases. 
When  coronary  perfusion  pressure  decreases,  oxygen 
uptake  decreases.  This  change  in  oxygen  uptake  by 
the  myocardium  associated  with  the  opposite  change 
in  coronary  A-V  oxygen  occurs  in  the  presence  of  a 
constant  arterial  blood  pressure,  heart  rate,  stroke 
volume,  and  cardiac  work.  Similarly,  in  isolated 
hearts  not  performing  external  work,  the  change  in 
coronary  flow  from  alteration  of  coronary  perfusion 
pressure  is  counterbalanced  by  a  shift  in  the  coronary 
A-V  oxygen  in  the  opposite  direction,  but  the  oxygen 
uptake  is  changed  significantly  especially  at  the 
higher  levels  of  coronary  perfusion  pressure.  As  yet, 
experimental  testing  has  not  been  able  to  ascribe 
this  apparent  change  in  oxygen  uptake  to  an  arti- 
factual  happening  (158,  and  unpublished  observa- 
tions on  the  isolated  heart).  These  findings,  which 
have  been  confirmed  (7),  would  seem  to  make  suspect 
various  observations,  especially  in  the  isolated  heart, 
in  which  perfusion  pressure  has  been  varied. 

Many  observers  have  reported  that  a  given  increase 
in  work  of  the  heart,  produced  by  raising  aortic 
pressure  (aortic  clamp)  while  holding  cardiac  output 
constant,  results  in  a  much  higher  coronary  flow  and 
oxygen  usage  per  minute  and  per  beat  than  when  a 
similar  increase  in  cardiac  work  is  effected  by  ele- 
vating cardiac  output  through  increased  venous 
return  at  a  constant  aortic  blood  pressure  (208). 
This  discrepancy  between  the  relative  oxygen  costs  of 
pressure  and  flow  work  is  observed  in  the  isolated 
heart  as  well  as  in  the  dog  with  a  complete  circulation. 
In  experiments  with  the  isolated,  supported  heart 
with  a  constant  heart  rate,  an  increase  in  left  ven- 
tricular work,  by  augmenting  cardiac  output  while 
at  the  same  time  lowering  aortic  pressure  by  aortic 


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CIRCULATION    II 


clamp  release,  results  in  a  large  increase  in  cardiac 
work  associated  with  a  decrease  in  oxygen  usage 
(334).  These  observations  taken  together  stress  the 
importance  of  the  aortic  pressure  and  of  the  develop- 
ment of  tension  by  the  heart  in  the  control  of  oxygen 
utilization. 

Chemical  Composition  of  the  Blood 

The  chemical  composition  of  the  blood  and  tissue 
fluids  within  the  myocardium  has  been  found  to  be  of 
great  importance  in  determining  the  volume  of 
coronary  flow. 

asphyxia.  Asphyxia,  in  which  the  carbon  dioxide 
content  of  the  blood  increases  and  the  oxygen  con- 
tent decreases  simultaneously  from  cessation  of 
breathing,  is  accompanied  by  a  large  increase  in 
coronary  inflow  in  the  anesthetized  dog.  Within  30 
to  60  sec  after  cessation  of  respiration,  the  flow  in  both 
systole  and  diastole  increases,  averaging  about  200 
per  cent,  and  this  occurs  before  any  significant  change 
in  aortic  pressure  or  heart  rate  ( 1 47 ). 

hypoxia.  When  the  oxygen  content  of  fully  saturated 
arterial  blood  of  normal  hematocrit  is  decreased  by 
exposing  it  to  successive  mixtures  of  oxygen  and 
nitrogen,  containing  progressively  less  oxygen  (100% 
O2  down  to  5  %  02),  the  resultant  arterial  hypoxia 
induces  profound  increases  (200-300  %)  in  coronary 
arterial  inflow  in  both  systole  and  diastole  in  the 
fibrillating  heart,  isolated  heart,  heart-lung  prepara- 
tion, and  anesthetized  dog,  but  the  oxygen  consump- 
tion is  not  changed  (26,  113,  147,  167,  182).  In  the 
anesthetized  dog,  as  the  arterial  oxygen  saturation 
decreases,  the  coronary  A-V  oxygen  difference  and 
coronary  sinus  oxygen  content  are  decreased  as  the 
oxygen  extraction  increases.  For  example,  starting 
with  a  control  coronary  sinus  oxygen  content  of  4.2 
vol  per  cent  and  saturation  of  20  per  cent,  the  coro- 
nary A-V  oxygen  difference  may  be  decreased  to  3 
vol  per  cent  and  the  coronary  sinus  oxygen  to  1  vol 
per  cent,  while  the  oxygen  extraction  may  be  in- 
creased to  95  per  cent.  Similar  findings  are  reported 
in  man  (181).  Eventually,  heart  rate,  blood  pressure, 
and  cardiac  output  may  be  elevated,  presumably 
from  the  marked  increment  of  cardiac  contractility 
arising  from  stimulation  of  the  sympathetic  nervous 
system  (408)  since  anoxia  has  only  a  depressant 
effect  on  the  completely  isolated  heart  (242).  The 
increase  in  coronary  flow  precedes  any  change  in 
these   parameters  and   maximal  coronary  dilatation 


occurs  when  the  arterial  saturation  falls  to  about  20 
per  cent  of  normal. 

Since  the  flow  effects  of  systemic  anoxia  produced 
by  artificial  respiration  with  air  and  nitrogen  and  of 
local  myocardial  anoxia  by  underperfusion  or  by 
cyanide  injection  (147)  into  the  coronary  artery 
are  similar,  it  is  concluded  that  they  all  depend  upon 
the  anoxia  produced,  and  probably  upon  the  presence 
of  this  anoxia  in  the  myocardium.  Since  the  blood 
pressure  does  not  change  and  the  ratio  of  pressure  to 
flow  increases  throughout  the  cardiac  cycle,  it  is 
also  concluded  that  anoxia  causes  a  relaxation  of  the 
walls  of  the  coronary  vessels.  To  what  extent  this  is 
active,  that  is,  a  direct  effect  on  smooth  muscle  of  the 
coronary  vessels,  and  to  what  extent,  if  any,  extra- 
vascular  support  has  been  lowered,  cannot  be  as- 
certained by  these  experiments.  By  using  the  technique 
already  described  of  prolonged  vagal  stoppage  of  the 
heart  for  separation  and  fractionation  of  flow  deter- 
minants, coronary  perfusion  with  saturated  blood 
has  been  compared  to  perfusion  with  somewhat 
unsaturated  blood.  The  resulting  flow  increase  in  the 
beating  heart,  in  the  latter  instance,  is  shown  to  be 
about  equally  divided  between  a  decreased  extra- 
vascular  compression  and  an  active  vessel  relaxation 

(158)- 

The  ultimate  cause  of  the  decrease  in  coronary 
vascular  resistance  in  the  presence  of  hypoxemia  is 
not  known,  but  it  could  arise  from  a  direct  action  of 
low  arterial  oxygen  content  of  the  blood  on  the  smooth 
muscle  of  the  coronary  vessels  (182)  or  from  hypoxia 
of  the  myocardium.  To  differentiate  these  possi- 
bilities, open-chest  experiments  have  been  made 
on  fibrillating  dog  hearts,  involving  coronary  per- 
fusions with  blood  at  varying  levels  of  saturation  and 
at  high  perfusion  pressures  which  increased  the  coro- 
nary flow  until  coronary  sinus  blood  became  relatively 
rich  in  oxygen  (26).  In  the  presence  of  a  quite  high 
coronary  perfusion  pressure,  considerable  lowering  of 
arterial  oxygen  content  (to  10  vol  per  cent)  does  not 
increase  coronary  flow.  An  increase  in  flow  occurs 
only  at  coronary  sinus  oxygen  levels  less  than  5.5 
vol  per  cent.  Since  the  coronary  sinus  oxygen  content 
probably  closely  reflects  tissue  oxygen  content,  this 
finding  suggests  that  arterial  oxygen  content  is  not 
critical  in  the  regulation  of  coronary  flow  but  that 
coronary  vasodilation  in  hypoxemia  is  related  to 
myocardial  hypoxia  (myocardial  oxygen  content). 
Finally,  experiments  are  reported  in  which  the  coro- 
nary arteries  of  the  isolated  heart  are  perfused  with  a 
fully  saturated  hemoglobin  solution  whose  oxygen 
content  is  varied  by  dilution.  In  this  situation,  as  the 


BLOOD    SUPPLY    TO    THE    HEART 


1 545 


oxygen  content  was  varied  from  18  vol  per  cent  down 
to  2  vol  per  cent  by  dilution  with  Ringer-Lockc\ 
solution,  the  coronary  flow  increased  although  the 
intravascular  oxygen  tension  at  the  level  of  the 
arterioles  was  kept  constant  (164). 

metabolites.  The  mechanism  whereby  hypoxia 
operates  to  increase  coronary  flow  remains  obscure. 
Presumably,  metabolites  accumulate  but  their  nature 
and  possible  effectiveness  are  unknown.  Experiments 
dealing  with  this  problem  in  which  an  extracorporeal 
circulation  of  blood  is  used  must  be  cautiously  evalu- 
ated. Dog  blood  contains  potent  vasoconstrictor  and 
vasodilator  substances.  The  red  cells,  especially, 
contain  a  potent  vasodilator  substance  (adenosine 
triphosphate).  This  and  other  substances  are  readily- 
made  active  by  hemolysis  resulting  from  minute 
mechanical  trauma  and  agitation  (60).  In  the  heart- 
lung  preparation,  coronary  flow  generally  progres- 
sively increases  as  the  experiment  continues,  and 
substances  accumulating  in  the  coronary  venous 
blood  were  originally  thought  to  cause  vasodilatation 
when  reinfused  into  the  coronary  arteries  (17). 
Hilton  &  Eicholtz  (182),  however,  could  not  confirm 
this  in  the  isolated  heart,  for  replacement  of  the  blood 
that  had  circulated  for  some  time  by  fresh  defibrinated 
blood  did  not  significantly  alter  flow. 

It  is  not  clear  whether  or  not  vasodilator  substances 
exist  in  the  coronary  sinus  blood  of  the  heart  beating 
within  the  chest  in  sufficient  concentration  to  alter 
coronary  blood  flow.  In  recent  experiments,  blood 
draining  normal,  hypoxic,  or  overperfused  (perfusion 
pressure  considerably  greater  than  aortic  pressure) 
hearts  has  been  oxygenated  in  a  dog  lung  or  on  a 
screen  and  perfused  at  a  controlled  pressure  through  a 
rotameter  into  a  test  coronary  artery  of  the  same  or 
second  dog,  or  unoxygenated  coronary  sinus  blood 
has  been  perfused  into  an  isolated  beating  frog  heart. 
These  experiments  have  failed  to  demonstrate  sub- 
stances having  vasoactive,  inotropic,  or  chronotropic 
properties  in  the  coronary  sinus  blood  (193).  On  the 
other  hand,  injection  of  coronary  sinus  blood  obtained 
during  cardiac  sympathetic  nerve  stimulation  causes 
a  moderate  coronary  dilatation  at  the  same  blood 
pressure  and  heart  rate  (277). 

Intracoronary  injection  of  intermediate  metabolites 
will  increase  coronary  blood  flow.  Histamine,  metabo- 
lites such  as  adenosine,  adenylic  acid,  and  breakdown 
products  of  nucleic  acids  increase  coronary  flow  in 
the  perfused  heart,  the  human  heart-lung  preparation 
and  heart  in  situ  (10,  277).  However,  it  has  never  been 
demonstrated   that   the  concentration   of  these  sub- 


stances increases  within  the  myocardium  during 
anoxia  or  increased  effort  of  the  heart.  Studies  on 
relative  coronary  vasodilator  potency  show  that 
adenine  is  relatively  inactive,  while  adenosine  tri- 
phosphate and  adenosine  diphosphate  have  approxi- 
mately four  times  the  potency  of  adenosine  mono- 
phosphate, adenosine,  and  uridine  triphosphate 
(406,  407).  In  addition  to  vasodilator  properties, 
some  of  the  purine  and  pyrimidine  derivatives  have 
been  demonstrated  to  have  positive  inotropic  action 
in  the  normal  and  failing  heart  (52).  It  is  not  sur- 
prising, therefore,  that  in  the  open-chest  dog  with 
constant  pressure  perfusion  of  the  coronary  arteries, 
some  of  these  substances  (ATP  and  UTP)  with 
inotropic  and  vasodilator  properties  also  increase  the 
myocardial  oxygen  consumption  (407).  However, 
since  the  elevation  in  coronary  blood  flow  is  greater 
than  that  necessary  to  meet  the  increased  oxygen 
demand,  i.e.,  the  coronary  A-V  oxygen  is  decreased 
considerably,  the  action  of  such  compounds  is  prob- 
ably largely  on  the  coronary  vessels,  and  only  second- 
arily on  metabolic  rate. 

Although  it  has  not  been  possible  to  demonstrate 
in  the  coronary  sinus  blood  substances  having  vasoac- 
tive, chronotropic,  or  inotropic  properties,  this  does 
not  necessarily  rule  out  an  active  role  of  metabolites 
in  regulating  coronary  flow.  As  pointed  out  by  Berne 
(28),  although  adenosine  and  adenine  nucleotides  are 
not  recoverable  in  the  coronary  sinus,  derivatives  of 
adenosine  such  as  inosine  and  hypoxanthine  appear 
in  the  coronary  sinus  blood  during  periods  of  myo- 
cardial hypoxia,  and  vasoactive  concentrations  of 
adenosine  added  to  coronary  arterial  blood  are  re- 
coverable in  the  coronary  sinus  only  as  inosine  and 
hypoxanthine.  Thus,  the  possibility  should  be  enter- 
tained that  in  hypoxia,  myocardial  nucleotides  give 
rise  to  adenosine  which  diffuses  out  of  cardiac  cells, 
induces  vasodilatation,  but  is  deaminated  and  split 
before  separation   from   the   blood   can   be   effected. 

acidosis  and  alkalosis.  In  the  isolated  heart  or  heart- 
lung  preparation,  acidosis  induced  by  administering 
C02  or  lactic  acid  dilates  the  coronary  blood  vessels, 
for  coronary  flow  may  increase  ( 1 82 )  despite  a  marked 
reduction  in  the  rate,  output,  arterial  blood  pressure, 
and  contractile  force  of  the  myocardium  (273).  In  an 
intact  preparation  in  the  presence  of  severe  respiratory 
acidosis  (from  C02  administration),  or  a  fixed  acidosis 
(from  infusion  of  HC1  solution),  coronary  flow  in- 
creases (114),  remains  constant  (134),  or  decreases 
(go,  147),  while  systemic  dynamics  (blood  pressure, 
heart    rate,    and    cardiac    output)    are    not    largely 


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CIRCULATION    II 


changed.  In  contrast  to  its  direct  depressant  effect 
on  the  isolated  perfused  heart,  a  C02  concentration 
in  the  respired  air  of  the  open-chest  dog  of  at  least  8 
per  cent  has  a  stimulating  influence  on  the  myocar- 
dium for  the  contractile  force  may  not  be  lowered  and 
myocardial  function  curves  are  not  depressed  (267). 
Presumably,  this  arises  from  its  stimulating  influence 
on  the  sympatho-adrenal  system  since  acidotic  heart 
failure  in  the  heart-lung  preparation  can  be  reversed 
by  administration  of  sympathomimetic  amines.  The 
divergent  results  with  hypercapnia  may,  therefore, 
merely  express  the  variable  weighting  of  the  antago- 
nistic effects  on  the  intact  animal  circulation,  of  a 
direct  depressant  effect  on  the  myocardium  and 
smooth  muscle  of  the  coronary  vessels,  and  of  an 
indirect  stimulating  effect  on  the  same  structures 
through  the  sympatho-adrenal  system.  In  the  intact 
dog,  hypocapnia  (arterial  C02  less  than  35  vol  per 
cent)  is  without  effect  on  systemic  and  coronary 
hemodynamics  and  the  ventricular  function  curve  is 
unaltered  (1 14,  267). 

In  the  isolated  heart  doing  no  work,  alkalosis  in- 
duced by  varying  the  bicarbonate  concentration  of 
the  perfusing  solution,  or  following  CO»  administra- 
tion, depresses  inotropic  and  chronotropic  cardiac 
activities  but  increases  coronary  flow.  These  changes 
in  cardiac  function  are  effected  only  when  the  pH  of 
the  perfusate  is  altered  (248).  Sodium  bicarbonate 
infusion  in  the  intact  anesthetized  dog  stimulates 
both  systemic  and  coronary  hemodynamics.  In  the 
presence  of  an  essentially  constant  heart  rate  and 
arterial  blood  pressure,  and  a  marked  increase  in 
cardiac  output,  the  coronary  flow  and  oxygen  usage 
per  minute  and  per  heart  beat  are  elevated  consider- 
ably (134).  The  mechanisms  concerned  are  not 
known.  Nor  has  it  been  established  whether  these 
effects  of  acidosis  and  alkalosis  on  the  coronary  cir- 
culation in  the  intact  dog  arise  from  changes  in  pCO>, 
HC03,  or  from  the  resulting  change  in  pH,  since  in  no 
instance   has   the   pH   been   separately  controlled. 

potassium,  calcium.  There  has  not  been  sufficient 
experimentation  to  determine  the  role,  if  any,  of  the 
electrolytes  in  regulating  the  coronary  circulation. 
Increased  potassium  concentration  (150%)  in  the 
blood  perfusing  the  fibrillating  heart  of  the  Langen- 
dorff  preparation  increases  coronary  flow,  while 
larger  intracoronary  concentrations  in  the  open- 
chest  dog  also  produce  similar  increases  (88).  In  the 
heart-lung  preparation,  isolated  heart,  or  heart  within 
the  chest,  very  large  potassium  concentrations  suffi- 
cient to  arrest  the  heart  reduce  coronary  inflow  (249, 


259).  In  the  latter  instance,  the  oxygen  usage  is  also 
greatly  reduced  as  a  result  of  a  decreased  flow  and 
oxygen  extraction.  In  the  open-chest  dog,  upon  the 
addition  of  pharmacological  amounts  of  Ca  gluconate, 
coronary  flow  and  oxygen  consumption  increase  and 
oxygen  extraction  decreases  without  much  change  in 
blood  pressure  and  heart  rate  (115). 

Transfusion 

Augmentation  of  ventricular  load  by  increasing 
venous  return,  and,  hence,  circulating  blood  volume 
through  infusion  has  a  clinical  counterpart  in  the  load 
placed  upon  the  human  heart  by  transfusion  or  by  an 
aortacaval  fistula.  During  transfusion,  systolic  and 
diastolic  heart  size,  ventricular  stroke  volume  and 
stroke  work,  atrial  and  ventricular  end-diastolic 
pressures  and  arterial  blood  pressure  all  increase  as 
the  heart  rate  slows  considerably.  When  the  coronary 
arteries  are  perfused  at  a  constant  pressure  or  with  a 
normal  pulsatile  aortic  pressure,  an  increase  in  the 
cardiac  output  or  cardiac  work  through  augmentation 
of  venous  return  to  the  heart  beating  in  situ  augments 
moderately  the  coronary  flow  and  oxygen  usage  per 
minute  and  per  heart  beat  while  the  aortic  pressure 
rises  (46,  90,  152,  153).  The  increasing  coronary  flow 
is  partially  explainable  on  a  mechanical  basis  since 
the  slowing  of  the  heart  should  increase  coronary 
flow  per  beat  and  per  minute  by  increasing  the  dia- 
stolic time  period  during  which  coronary  flow  is 
greater.  The  coronary  flow  and  oxygen  are  used 
economically,  for  the  ratio  of  stroke  cardiac  work  to 
stroke  oxygen  consumption  increases.  However,  it 
has  been  repeatedly  shown  in  the  denervated  heart 
and  heart-lung  preparation  that  coronary  arterial 
inflow  and  coronary  sinus  outflow  are  reduced  some- 
what or  unchanged  by  alterations  in  cardiac  output 
as  long  as  the  resistance  against  which  the  ventricles 
contract  is  unaltered  (10).  These  findings  have  been 
extended  to  the  open-chest  dog  in  which  coronary 
flow  and  oxygen  usage  may  not  change  or  may  rise 
only  slightly  in  the  presence  of  a  constant  arterial 
blood  pressure  and  marked  increase  in  cardiac  out- 
put (46).  In  the  isolated  supported  heart,  the  coronary 
flow  and  oxygen  usage  per  minute  and  per  heart 
beat  can  be  made  to  decrease  in  response  to  a  lowering 
of  arterial  blood  pressure,  achieved  by  release  of  an 
aortic  constriction  during  the  augmentation  of  cardiac 
output  which  follows  an   increase   in   venous  return 

(334)- 

Since  the  average  individual  is  transfused  only  on 

rare  occasions,  it  is  not  known  whether  such,  informa- 


BLOOD    SUIM'LY    TO     THE    HEART 


r547 


tion  can  be  used  to  explain  happenings  in  the  coro- 
nary circulation  of  the  normal  heart  exposed  to  the 
stresses  of  everyday  life.  At  least,  in  the  latter  instance 
the  systemic  dynamics  are  quite  different  from  those 
listed  above  as  occurring  with  transfusion.  For  ex- 
ample, in  exercise  and  excitement,  while  the  heart 
rate  increases  greatly  and  the  duration  of  systole 
decreases,  cardiac  size  may  decrease  and  stroke 
volume  and  atrial  and  ventricular  diastolic  pressures 
may  undergo  only  limited  changes. 


Anemia 

The  coronary  system  participates  actively  in  the 
circulatory  adjustments  to  anemia.  For  hemoglobin 
values  of  10  g  or  more,  the  systemic  circulation  is 
essentially  unaltered  and  the  compensation  of  the 
coronary  system  to  the  decreased  oxygen-carrying 
capacity  is  similar  to  that  with  hypoxia,  i.e.,  an 
increased  coronary  flow  without  change  in  oxygen 
uptake.  When  the  hemoglobin  values  reach  6  to  8  g, 
the  response  of  the  systemic  circulation  is  manifested 
by  tachycardia,  increased  cardiac  output  and  cardiac 
work,  and  a  fall  in  peripheral  resistance.  The  coronary 
flow  may  now  triple;  coronary  venous  blood  may 
contain  less  than  2  vol  per  cent  oxygen,  the  coronary 
arteriovenous  oxygen  difference  may  be  4  ml  or  less, 
and  oxygen  uptake  may  be  considerably  increased. 
The  increase  in  coronary  flow  is  related  in  part  to  the 
decreased  blood  viscosity,  and  in  larger  part  to  the 
active  dilatation  associated  with  myocardial  hypoxia, 
which  in  turn  arises  from  the  low  hematocrit  and 
from  the  increased  metabolism.  Ultimately,  myo- 
cardial failure  will  occur  in  severe  anemia  when  the 
coronary  vessels  have  approached  maximal  dilatation 
and  cannot  further  compensate  for  the  decreased 
oxygen-carrying  capacity  of  the  blood  either  by 
increased  flow  or  by  increased  oxygen  extraction.  In 
the  presence  of  coronary  stenosis  associated  with 
anemia,  the  effect  of  coronary  arteriolar  dilatation  in 
increasing  flow  is  minimized  by  the  high  fixed  resis- 
tance of  the  stenotic  artery,  and  myocardial  depression 
and  failure  occur  at  lesser  degrees  of  anemia  (31,  57). 

Very  little  information  is  available  regarding  the 
coronary  circulation  in  the  presence  of  polycythemia 
vera.  The  expanded  red  cell  mass  has  been  associated 
with  a  considerable  reduction  in  coronary  blood  flow 
and  an  increased  oxygen  extraction  without  change 
in  oxygen  usage.  Allocation  of  these  changes  to  an 
enhanced  oxygen-carrying  capacity  or  to  a  viscosity 
effect  has  not  been  made  (305). 


Xarvits  Influences 

The  control  of  the  coronary  circulation  by  para- 
sympathetic and  sympathetic  nerves  has  been  the 
subject  of  intensive  investigation  and  dispute.  Many 
experiments,  however,  have  been  interpreted  with 
difficulty  since  cardiac  output  and  cardiac  work  were 
not  determined,  and  heart  rate  and  arterial  blood 
pressure  which  affect  coronary  flow  and  oxygen 
usage  varied  widely  (go,  187,  340,  405).  There  is 
some  evidence  to  indicate  that  the  over-all  nature  and 
extent  of  neural  cardiogenic  control  is  some  degree  of 
coronary  vasoconstriction  since  a)  an  outstanding 
characteristic  of  the  isolated  heart  or  heart-lung 
preparation  is  a  very  high  coronary  blood  flow  and 
low  myocardial  oxygen  extraction,  and  b)  in  chronic 
dogs  the  procedure  of  pericoronary  denervation 
results  in  a  relative  increase  in  coronary  flow  and 
decrease  in  oxygen  extraction  (43).  For  the  most  part, 
the  nervous  system  influences  on  the  coronary  cir- 
culation have  been  studied  by  observing  the  coronary 
flow,  oxygen  usage,  and  contractility  responses  fol- 
lowing electrical  stimulation  or  severance  of  the 
nerves.  Although  such  procedures  are  not  paralleled 
by  normal  occurrences  in  the  animal,  the  observed 
responses  are  presumed  to  indicate  the  functions 
which  the  nerves  are  capable  of  exercising  in  the 
intact  animal.  Further  difficulty  in  interpretation 
arises  from  the  fact  that  the  specific  effects  upon  the 
heart  muscle  and  on  the  coronary  vascular  system 
are  largely  experimentally  inseparable  and  only  the 
net  effect  can  be  observed.  Differences  in  methods 
and  preparations  are  additional  variables  which  may 
account  for  the  discordant  results  of  different  in- 
vestigators. 

vagus.  Recent  studies  of  the  effect  of  the  vagus  nerves 
on  the  heart  have  gradually  clarified  our  view  of  their 
effect  on  the  coronary  circulation.  Early  evidence 
indicated  that  the  vagus  nerves  contain  both  dilator 
and  constrictor  fibers  (401).  That  the  vagus  exerts  a 
vasoconstrictor  effect  is  based  on  observations  that 
abolition  of  the  parasympathetic  pathways  in  the 
heart-lung  preparation  (by  mechanical  and  chemical 
means)  results  in  augmentation  of  heart  rate  or 
coronary  flow,  while  stimulation  of  the  peripheral 
ends  of  the  cut  vagi  decreases  coronary  flow  (10). 
The  evidence  that  it  exerts  a  vasodilator  effect  arises 
from  the  observation  that  in  the  fibrillating  heart  with 
coronary  arteries  perfused  with  blood  under  a  con- 
stant pressure,  vagal  section  usually  decreases  coro- 
nary inflow   but  vagal  stimulation   usually   increases 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


coronary  inflow  (206).  It  would  seem  unlikely  that 
the  vagus  would  act  as  a  vasoconstrictor  since  its 
chemical  transmitter,  acetylcholine,  is  a  coronary 
vasodilator. 

Such  studies,  of  course,  do  not  define  the  action  of 
the  vagi  in  the  intact  animal.  In  the  open-chest  dog 
with  the  heart  rate  maintained  at  a  constant  value 
by  an  electric  pacemaker,  section  of  these  nerves  or 
stimulation  of  their  cut  ends  does  not  usually  evoke 
significant  change  in  coronary  inflow,  coronary 
sinus  flow  (orifice  meter,  bubble  flowmeter,  rotam- 
eter),  or  in  coronary  A-V  oxygen  difference,  while 
blood  pressure  and  cardiac  output  are  essentially 
unchanged  (83,  go,  236,  339).  In  all  preparations, 
ventricular  contractility  is  usually  not  changed  (367). 
These  observations  are  in  accord  with  the  apparent 
lack  of  vagal  fiber  distribution  to  the  ventricular 
myocardium  (54,  262).  At  times,  vagal  stimulation 
(378)  has  been  observed  to  cause  reduction  in  cardiac 
output,  blood  pressure,  and  coronary  inflow,  an 
effect  which  was  abolished  by  atropine.  Although 
this  effect  is  ascribed  by  the  authors  to  a  negative 
inotropic  effect  of  vagal  stimulation  on  the  ventricular 
muscle,  it  could  also  have  resulted  from  diminution  of 
vigor  of  atrial  contraction  thus  reducing  ventricular 
filling,   a   finding  of  different   investigators   (336). 


sympathetic.  Stimulation  of  the  stellate  ganglion  or 
its  cardiac  branches  in  the  anesthetized  open-chest 
dog  or  in  the  unanesthetized  resting  dog  increases 
mean  flow  in  both  right  and  left  coronary  arteries 
(83,  139,  153).  This  augmentation  lasts  for  minutes 
and  persists  long  after  any  augmentation  of  heart 
rate  or  blood  pressure  (if  such  occurs)  has  returned 
to  normal.  Figure  9  is  a  response  of  the  left  circumflex 
flow  obtained  with  an  electromagnetic  flowmeter  in  a 
resting  unanesthetized  dog  a  few  days  after  probe 
implantation.  In  this  dog,  in  which  the  left  stellate 
ganglion  had  been  previously  disconnected  from  the 
thoracic  sympathetic  chain  and  spinal  nerves  to 
eliminate  peripheral  effects  of  excitation,  stimulation 
of  the  common  ansa  subclavia  initially  and  transiently 
decreases  coronary  flow  throughout  the  cardiac  cycle 
without  change  in  blood  pressure  or  heart  rate.  Within 
a  few  seconds,  at  an  unchanged  blood  pressure  but 
increased  heart  rate,  mean  coronary  flow  increases  as 
the  result  of  an  increase  in  diastolic  flow  and  in  spite 
of  a  depression  of  systolic  flow  with  appearance  of 
backflow.  Almost  immediately,  thereafter,  coronary 
flow  increases  greatly  throughout  the  entire  cardiac 
cycle,  with  the  disappearance  of  backflow.  This 
pattern  of  response  to  stellate  stimulation  may  occur 
with  or  without  spontaneous  elevation  of  blood  pres- 


STELLATE    G.   STIM. 


RECOVERY 


BLOOD 
PRESS 


MEAN  COR 
FLOW/MIN 


SYST.  COR 
FLOW/MIN 


MEAN   COR.  FLOW 
SYST  COR    FLOW 


fig.  9.  Reproduction  of  sections  from  a  continuous  record  in  a  conscious  dog  a  few  days  postopera- 
tive, showing  effect  of  left  stellate  ganglion  stimulation  on  phasic  arterial  blood  pressure  and  stroke 
left  circumflex  coronary  inflow  using  a  strain  gauge  and  electromagnetic  flowmeter  as  in  fig.  6. 
Connections  of  stellate  to  sympathetic  chain  severed  at  time  of  operation.  [Granata  el  al.  (139).] 


BLOOD  SUPPLY  TO  THE  HEART 


'549 


sure  and  heart  rate,  or  when  the  aortic  blood  pressure 
(in  open-chest  dogs)  is  artificially  controlled  and 
compensated  to  the  control  level.  This  indicates  that 
the  factors  of  heart  rate,  blood  pressure,  and  work 
are  not  indispensable  to  the  natural  mechanism 
through  which  the  flow  increase  is  mediated.  The 
major  portion  of  the  flow  increase  is  related  to  acti\<- 
dilatation  since  blood  pressure  does  not  necessarily 
rise.  The  net  flow  increase  rests  in  part,  however,  on  a 
mechanical  basis,  for  the  duration  of  systole  (in  which 
flow  is  less  than  in  diastole)  is  reduced  and  thus,  at 
the  same  heart  rate,  the  period  of  time  occupied  by 
diastole  (in  which  rate  of  flow  is  greater),  is  increased 
considerably.  About  30  per  cent  of  the  flow  increase 
is  estimated  to  be  due  to  this  shortening  of  systolic 
and  lengthening  of  diastolic  time  per  beat  or  per 
minute  (93).  Concurrently,  left  ventricular  oxygen 
usage,  cardiac  output,  and  cardiac  work,  either  per 
minute  or  per  heart  beat,  increase  while  the  systolic 
and  diastolic  dimensions  of  the  heart  decrease.  Since 
the  blood  pressure  and  heart  rate  do  not  necessarily 
change  during  the  flow  increase,  while  duration  of 
systole  shortens,  the  stroke  coronary  flow  does  not 
correlate  with  pressures  developed  by  the  ventricle 
or  with  directional  trends  in  ventricular  tension 
calculated  thereon. 

The  evidence  is  well  founded  that  stimulation  of  the 
sympathetic  nerves  to  the  heart  aids  greatly  in  main- 
taining and  augmenting  the  rate  and  contractility  of 
the  heart,  as  shown  by  improvement  in  the  atrial  and 
ventricular  function  curves  from  any  given  atrial, 
ventricular  end-diastolic  pressure  (263,  336),  or  fiber 
length,  and  in  the  gradient  of  the  aortic  pressure  and 
stroke  volume  curves  (11,  153,  211).  In  no  experiment 
has  coronary  inflow  been  found  to  increase  without 
experimental  evidence  of  increased  vigor  of  contrac- 
tion, increased  cardiac  work,  and  metabolism.  The 
mechanism  by  which  this  is  accomplished  has  not 
been  completely  identified.  The  possibility  that 
adrenal  secretion  is  responsible  for  the  cardiac  stimu- 
lating effect  has  been  largely  discounted  experi- 
mentally (153)-  The  facts  that  a)  administration  of 
acetylcholine  to  an  atropinized  heart  results  in  libera- 
tion of  an  adrenaline-like  substance  (186);  /;)  that 
this  substance  is  also  normally  present  in  heart  ex- 
tracts (376);  and  c)  that  stimulation  of  cardiogenic 
sympathetic  fibers  sets  free  an  adrenaline-like  sub- 
stance (284,  346),  all  support  the  view  that  a  dominant 
role  is  played  by  myocardial  catecholamines. 

The  experiments  of  Eckstein  et  al.  (93)  offer  evi- 
dence that  this  process  is  very  wasteful,  for  the  increase 
in  the  work  of  the  heart  is  not  essential  to  the  asso- 


ciated increase  in  coronary  inflow.  Stimulation  of  the 
accelerator  nerves  in  the  open-chest  dog  produces  an 
increase  in  vigor  of  contraction,  cardiac  output, 
cardiac  work,  coronary  blood  flow,  and  oxygen  con- 
sumption. However,  simultaneous  nerve  stimulation 
and  inflation  of  a  left  auricular  balloon  to  reduce  the 
external  work  of  the  heart  below  the  control  value  is 
likewise  followed  by  increased  vigor  of  contraction, 
increased  coronary  flow  and  increased  oxygen  con- 
sumption. Thus,  the  adrenaline-like  substance  re- 
leased by  nerve  stimulation  would  appear  to  increase 
oxygen  consumption  directly. 

The  preceding  observations  do  not  preclude  the 
possibility  that  the  major  influence  of  the  sympathetic 
cardiac  nerves  may  be  to  exert  a  direct  vasomotor 
influence  on  the  coronary  vessels,  the  initial  temporary 
coronary  vasoconstriction  which  invariably  occurs 
being  overpowered  by  metabolic  dilator  influences 
associated  with  the  type  of  stimulation.  It  is,  however, 
most  difficult  to  establish  and  identify  conclusively, 
by  experimental  means,  the  separate  effects  of  nervous 
influences  upon  the  myocardium  and  coronary  vessels 
because  the  physiological  functions  of  these  structures 
are  so  intimately  related  that  their  individual  re- 
sponses can  be  secondarily  modified,  each  by  the 
other.  In  the  innervated  fibrillating  heart,  stellate 
stimulation  at  times  decreases  coronary  flow,  while 
nerve  section  increases  coronary  flow  (206).  Recent 
evidence  indicates  the  existence  and  functional  im- 
portance of  coronary  vasomotor  fibers  the  action  of 
which  in  previous  investigations  was  presumably 
obscured  because  of  a  nonselective  type  of  nerve 
stimulation  (199,  358).  As  other  workers  have  shown, 
excitation  of  high  threshold  postganglionic  (stellate 
or  inferior  cervical)  cardiosympathetic  fibers  with 
high  voltage  and  high  frequency  stimulation  causes 
profound  alterations  in  myocardial  metabolism  which 
could  not  be  prevented  by  ergotamine  or  atropine. 
However,  appropriate  stimulation  of  preganglionic 
fibers,  using  low  voltage  and  low  frequency,  leads 
either  to  coronary  vasoconstriction  (decreased  coro- 
nary flow  and  blood  pressure  and  increased  coronary 
A-V  oxygen  without  alteration  in  oxygen  consump- 
tion), or  to  coronary  vasodilation  (increased  coronary 
flow,  decreased  coronary  A-V  oxygen  without  blood 
pressure  elevation  and  without  alteration  in  cardiac 
metabolism).  The  magnitude  and  importance  of  these 
direct  vasomotor  effects  remain  to  be  determined. 
In  the  author's  laboratory,  preliminary  attempts  have 
failed  to  demonstrate  these  direct  vasomotor  influences 
of  the  cardiac  sympathetic  fibers  in  the  unanesthe- 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


tized  dog  with  a  chronically  implanted  electromag- 
netic flowmeter  on   the  coronary  artery. 

To  the  author's  knowledge,  the  existence  of  a 
tonic  action  on  the  coronary  circulation  of  the  intact 
animal,  attributable  to  the  parasympathetic  and 
sympathetic  nerve  fibers,  has  never  been  demon- 
strated, the  section  of  these  nerves  in  the  open-chest 
dog  leading  only  to  nonspecific  changes.  Study  of  this 
problem  should  be  made  through  the  application  to 
the  coronary  circulation  of  recent  techniques  for 
coronary  neurectomy  and  extrinsic  cardiac  denerva- 
tion on  chronic  dogs  (43,  71). 

reflex  control.  Our  knowledge  of  the  role  of  the 
central  nervous  system  in  regulation  of  the  coronary 
circulation  in  health  and  disease  is  sufficient  to  war- 
rant discussion  but  is  certainly  insufficient  to  draw 
firm  conclusions.  This  arises  from  a  lack  of  proper 
experiments  in  which  studies  of  both  the  reflexes  and 
the  coronary  hemodynamic  responses  have  been 
simultaneously  made.  A  proper  demonstration  de- 
pends on  the  observations  that  the  vagus  and  sym- 
pathetic nerves  to  the  heart  are  tonically  active  as 
far  as  coronary  blood  flow  regulation  is  concerned,  or 
can  be  made  so  by  the  induction  of  adequate  stimuli 
arising  either  within  the  heart  or  peripherally. 

Different  observations  support  the  view  that  there 
are  receptors  in  the  distribution  of  the  canine  left 
coronary  artery.  Injection  of  veratridine  into  a  left 
coronary  artery  (but  not  the  right  coronary),  going 
only  to  the  left  ventricular  muscle  and  in  amounts 
insufficient  to  affect  the  systemic  circulation  upon 
direct  injection  into  the  left  ventricle,  causes  an 
abrupt  fall  in  blood  pressure  and  heart  rate  (76,  77). 
( lirculatory  depression  which  may  follow  selective 
augmentation  of  central  coronary  pressure  near  the 
left  coronary  orifice  and  the  initial  part  of  the  cle- 
scendens  artery,  or  which  may  occur  during  coronary 
sinus  occlusion,  is  relieved  by  vagal  section  (132,  187, 

285). 

The  evidence  is  equivocal  that  flow  in  one  coronary 
artery  can  be  influenced  reflexively  and  adversely  by 
impulses  arising  in  another  occluded  coronary  artery. 
Various  supportive  observations  suggest  that  noxious 
intercoronary  reflexes  can  be  made  to  occur:  a) 
Ligation  of  a  coronary  artery  is  stated  to  cause  reflex 
spasm  or  vasoconstriction  in  the  other  coronary  artery 
resulting  in  fatal  ventricular  fibrillation  (231).  This 
is  presumed  to  be  abolished  by  bilateral  vagosym- 
pathetic blockade  (228).  The  infarction  after  coronary 
ligation  is  increased  with  vagal  stimulation  and  is 
prevented  by  local  anesthesia  of  the  vessel  wall  at  the 


site  of  the  ligature  (220,  223).  b)  In  the  anesthetized 
closed-chest  dog  with  visualization  of  the  coronary 
artery  bed  by  cinefluorography  after  injection  of  a 
radiopaque  dye,  selective  embolization  (lycopodium 
spores)  of  a  coronary  artery  branch  results  in  a  marked 
decrease  in  size  of  the  nonembolized  coronary  artery 
bed  and  in  coronary  sinus  flow  (165).  On  the  other 
hand,  a)  West  et  al.  (392),  using  techniques  similar  to 
those  of  Guzman,  failed  to  find  evidence  of  reflex 
coronary  vasoconstriction  following  coronary  em- 
bolization. /))  In  the  open-chest  dog,  following  liga- 
tion of  the  right  or  left  coronary  artery,  the  coronary 
flow  (rotameter)  rises  and  resistance  falls  in  the  un- 
occluded  coronary  artery,  such  flow  augmentation 
presumably  resulting  from  an  anatomical  and  func- 
tional overlap  of  the  right  and  left  coronary  arteries 
(153,  282,  377).  c)  In  the  unanesthetized  resting  dog, 
some  days  after  implantation  of  an  electromagnetic 
flowmeter  on  the  main  left  coronary  artery  or  a  major 
arterial  branch,  temporary  (10-30  sec)  occlusion  of  a 
left  coronary  artery  branch  results  either  in  no  change 
or  an  increase  in  blood  flow  in  the  artery  in  which 
flow  is  being  measured  ( L.  C.  Fisher,  unpublished  obser- 
vations). It  must  be  remembered  that  these  experiments 
with  negative  results  follow  considerable  dissection  of 
the  coronary  arteries,  and  actually  represent  con- 
ditions which  deviate  extensively  from  the  normal 
nerve  state.  Thus  they  do  not  rule  out  the  possibility 
of  reflex  coronary  vasoconstriction  occurring  in  small 
localized  regions  of  the  myocardium  after  coronary 
occlusion. 

Changes  in  coronary  blood  flow  which  might  result 
from  extracardiac  stimuli  would  be  of  great  clinical 
interest,  and  their  demonstration  might  aid  in  eluci- 
dating the  mechanism  of  the  relationship  between 
angina  pectoris  and  its  various  incitants,  such  as 
eating,  abdominal  distention,  cold,  and  exercise.  The 
claim  is  made  that  many  diverse  afferent  stimuli  affect 
the  coronary  circulation.  Prolonged  experimental 
neurosis  in  monkeys  produced  by  conflicting  condi- 
tioned reflexes  or  selected  brain  stimulation  can  pro- 
duce ECG  changes  identical  to  those  of  human 
ventricular  ischemia  (250).  Stimulation  of  many 
afferent  nerves,  distention  of  the  stomach,  gall  bladder 
and  esophagus,  and  cutaneous  pain,  all  are  presumed 
to  decrease  coronary  flow  in  the  anesthetized  dog, 
while  elevation  of  cerebral  blood  pressure  and  carotid 
sinus  pressure  decreases  coronary  flow  in  the  inner- 
vated heart-lung  preparation  (blood  pressure  and 
heart  rate  kept  constant)  (153).  In  these  experiments, 
the  recording  devices  and  data  were  generally  in- 
sufficient  to   establish   that  no  changes  occurred   in 


BLOOD    SUPPLY    TO    THE    HEART 


'Sj1 


heart  rate,  cardiac  output,  blood  pressure,  length  of 
systole  and  diastole,  each  of  which  could  alter  cardiac 
metabolism,  work  and  coronary  flow  separately  or  in 
combination.  Actually,  in  experiments  with  adequate 
flow  methods,  a)  increase  in  intragastric  or  intrabiliary 
tension  gives  a  variable  flow  response  (bubble  flow- 
meter and  rotameter)  but  always  in  the  same  direction 
as  the  blood  pressure  change  (90,  285,  405);  b)  dermal 
contact  with  ice  water  in  the  anesthetized  dog  fails  to 
produce  reflex  constriction  of  the  coronary  arteries 
(24,  347).  The  sight,  smell,  and  ingestion  of  food  and 
tilting  the  head  down  all  increase  coronary  flow 
(electromagnetic  flowmeter)  concurrently  with  an 
augmented  heart  rate  and  blood  pressure  (301).  It  is 
therefore  unreasonable  to  maintain,  as  has  been  done, 
that  such  agents  have  caused  active  vasoconstriction 
or  vasodilatation  in  the  coronary  bed  and  that  such 
changes  are  necessarily  largely  controlled  through 
nervous  reflexes.  This  is  especially  so  since  in  each 
experiment  the  effects  of  the  stimuli  were  not  generally 
tested  after  as  well  as  before  the  cutting  of  the  car- 
diac nerves. 

Thus,  while  reflexes  to  the  coronary  circulation  from 


the  heart  or  extracardiac  visceral  structures  certainly 
do  exist  and  may  be  important  in  normal  physiology 
and  pathological  physiology,  we  must  wait  for  the 
future  to  show  their  exact  function. 


Hormones 

norepinephrine  and  epinephrine.  Since  the  generally 
accepted  theory  of  autonomic  nerve  transmission  is 
based  on  the  liberation  of  acetylcholine  and  epineph- 
rine-like  substances,  the  coronary  flow  effects  with 
these  agents  are  of  particular  interest  in  connection 
with  coronary  innervation. 

The  action  of  epinephrine  on  the  coronary  blood 
flow  has  been  investigated  extensively.  In  most  dog 
preparations,  including  the  fibrillating  heart  (27), 
heart-lung  preparation  (179),  the  open-chest  dog  (82, 
83,  1 12,  146),  and  the  unanesthetized  dog  a  few  days 
postoperative  to  flowmeter  implantation  (301), 
intracoronary  artery  injection  of  epinephrine  and 
norepinephrine  increases  coronary  blood  flow.  In 
the  latter  two  preparations,  their  effect  on  the  coro- 


6  fiq    EPINEPHRINE   I  V 
CONTROL  ]  12  ! 


16  SEC 


RECOVERY 


i 

/H. 

/^ 

90 
123 
197 
2  2 
162 
35 


120 
120 
196 
1.6 

163 
33 


J\A 

/"N/\ 

114 
114 
119 
1.0 
90 
29 


fig.  10.  Reproduction  of  sections  from  original  record  taken  in  a  conscious  resting  dog  some  days 
postoperative,  showing  the  effect  of  rapid  intravenous  injection  of  6  /xg  epinephrine  on  phasic  arterial 
blood  pressure  and  stroke  left  circumflex  How,  using  a  strain  gauge  and  electromagnetic  flowmeter 
as  in  fig.  6.  [Rayford  el  a/.   (301).] 


■552 


HANDBOOK    OF    PHYSIOIcx.Y 


CIRCULATION    II 


nary  flow  pattern  is  similar  to  the  sustained  effect 
obtained  during  stimulation  of  cardiac  accelerator 
nerves,  i.e.,  an  increased  blood  flow  throughout  the 
cycle  (fig.  10).  In  all  animal  preparations,  as  well  as 
in  man,  myocardial  contractility  is  increased  to  a 
marked  degree  as  indicated  by  the  intensity  of  fibril- 
latory  movements  in  the  fibrillating  heart,  by  de- 
pression of  the  isometric  and  systolic  portions  of  the 
phasic  inflow  curve  in  the  dog,  and  by  an  increase  in 
myocardial  contractile  force  as  measured  by  a  strain 
gauge  arch  in  man  and  animal  (131).  Both  intra- 
venous and  intracoronary  artery  injections  increase 
cardiac  oxygen  consumption,  in  the  first  instance  by 
increasing  coronary  flow  and  decreasing  coronary 
A-V  oxygen  difference  (112),  in  the  second  instance 
by  increasing  coronary  flow  and  increasing  coronary 
A-V  oxygen  difference  (27).  This  occurs  even  in  the 
vagus-stopped  heart  (249).  With  very  small  doses, 
coronary  inflow  may  increase  without  any  change  in 
blood  pressure  or  heart  rate  and  with  increased  coro- 
nary A-V  oxygen  difference.  With  larger  doses,  as 
the  systemic  effects  of  the  substance  (increased  aortic 
blood  pressure,  cardiac  output,  and  changing  heart 
rate)  become  evident,  the  coronary  and  metabolic 
effects  are  exaggerated  (90). 

From  the  preceding  it  can  be  seen  that  there  is 
general  agreement  that  these  substances  produce 
coronary  vasodilatation.  The  flow  increase  is  the  net 
result  of  an  augmented  extravascular  support  tending 
to  decrease  coronary  flow,  a  metabolic  dilator  effect 
tending  to  increase  coronary  flow  and  any  direct 
effect  the  compounds  may  have  on  the  coronary 
vessels.  There  is,  however,  disagreement  and  con- 
fusion regarding  the  respective  magnitude  of  each 
separate  effect.  There  is  little  doubt  that  with  the 
larger  doses,  most  of  the  flow  increase  is  due  to  the 
large  increase  in  myocardial  metabolism.  However, 
one  point  of  view  has  it  that  these  substances  are 
primarily  coronary  vasoconstrictors,  their  vasodilator 
action  arising  secondarily  from  a  hypoxic  state  of  the 
myocardium  as  a  result  of  their  stimulating  effect  on 
the  myocardial  metabolism.  The  evidence  for  this  is 
that  epinephrine  causes  an  initial  and  transient  de- 
crease in  coronary  flow  in  the  fibrillating  heart  and 
in  the  beating  heart  (as  does  cardiac  sympathetic 
nerve  stimulation).  Elevation  of  extravascular  support 
as  a  cause  of  the  early  impediment  to  flow  here  ap- 
parently does  not  occur  since  intramyocardial  pres- 
sure does  not  rise  in  the  fibrillating  heart  (27),  and 
extravascular  resistance  falls  somewhat  in  the  vagus- 
stopped  heart  (236).  Unfortunately,  since  the  duration 
of  the  period  of  constriction  is  so  fleeting  and  the  flow 
effect  so  mild,  the  view  is  very  difficult  to  document. 


acetylcholine.  Acetylcholine,  intra-arterially,  in- 
creases coronary  blood  flow  in  the  dog  in  the  fibril- 
lating heart  and  in  the  heart-lung  preparation  (10). 
In  the  open-chest  dog,  intravenous  injection  of  acetyl- 
choline decreases  aortic  pressure  and  coronary  flow, 
and  increases  heart  rate  as  a  result  of  a  decreased 
systemic  peripheral  resistance  (339).  Intracoronary 
artery  injection  of  effective  doses  of  this  hormone,  and 
also  intravenous  injection  (provided  the  blood  pres- 
sure is  mechanically  compensated  by  an  aortic  clamp 
and  the  heart  electrically  driven  following  surgical 
induction  of  an  A-V  heart  block),  increases  consider- 
ably left  coronary  inflow  and  coronary  sinus  flow, 
and  decreases  the  left  ventricular  function  curve  (90, 
339,  405).  If  the  intracoronary  dose  is  properly  chosen, 
this  response  occurs  without  a  significant  effect  on  the 
systolic  blood  pressure,  heart  rate,  systolic  'diastolic 
time  interval,  cardiac  output,  cardiac  work,  but  the 
myocardial  oxygen  consumption  per  minute  and  per 
heart  beat  increases.  The  increased  coronary  flow  is 
completely  abolished  by  atropine  (405).  Since  the 
mechanical  and  metabolic  factors  which  could  in- 
fluence coronary  flow  are  thus  excluded,  the  increase 
in  coronary  flow  represents  a  true  coronary  vasodila- 
tation (see  fig.  13).  The  relation  between  myocardial 
oxygen  consumption  and  left  ventricular  work  is  not 
changed.  Consequently,  the  induced  depression  of 
myocardial  contractility  or  work  per  unit  of  filling 
pressure  is  not  associated  with  any  change  in  myo- 
cardial efficiency  (work  per  unit  of  oxygen  consump- 
tion). 

thyroid.  The  myocardium  participates  in  the  in- 
crease in  oxygen  consumption  characteristic  of  all 
body  tissues  in  thyrotoxicosis  (398).  This  hyper- 
metabolism is  accompanied  by  an  increase  in  coronary 
blood  flow,  a  decrease  in  coronary  vascular  resistance, 
and  an  increase  in  oxygen  consumption  per  minute 
and  per  beat.  Since  there  is  an  increase  in  oxygen 
usage  per  beat,  cardiac  oxygen  utilization  is  pre- 
sumably related  not  only  to  the  increase  in  heart 
rate  but  to  the  general  hypermetabolism  of  the  myo- 
cardium as  well  (230,  317). 

Hypothyroidism  in  man  has  been  shown  to  be 
associated  with  a  reduction  in  heart  rate,  cardiac 
output,  arterial  blood  pressure,  and  body  oxygen 
usage.  In  vitro  studies  of  experimentally  induced 
hypothyroidism  have  demonstrated  a  reduction  in 
oxygen  consumption  of  the  myocardium  (130).  Con- 
trolled experimental  inactivation  of  the  thyroid  by- 
use  of  I131  in  the  dog  leads  to  standardized  changes  in 
the  systemic  circulation  (342).  In  addition,  coronary 
sinus  flow  (N20  method)  and  left  ventricular  oxygen 


BLOOD    SUPPLY    TO    THE    HEART 


'553 


consumption  are  reduced.  Atropine  raises  each  of  these 
parameters  fas  well  as  the  heart  rate)  to  normal. 
These  experiments  are  difficult  to  interpret.  Howevei , 
since  the  stroke  coronary  flow  and  stroke  coronary 
oxygen  usage  are  unaffected  by  hypothyroidism,  the 
reduced  flow  and  oxygen  consumption  are  probably 
related  in  part  to  the  altered  myocardial  metabolism. 

pitressin.  There  is  agreement  that  Pitressin  increases 
resistance  to  flow  in  the  coronary  circulation  (146, 
153,  218,  384).  In  the  revived  human  heart  perfused 
by  the  Langendorff  method,  and  in  the  perfused  dog 
heart  in  ventricular  fibrillation,  Pitressin  decreases 
coronary  flow.  In  the  open-  (146)  or  closed-chest  dog, 
coronary  inflow  decreases,  the  reduction  occurring 
throughout  the  cardiac  cycle  in  the  presence  of  an 
increased  central  coronary  pressure  and,  sometimes,  a 
mild  reduction  in  heart  rate.  Selective  angiography 
demonstrates  visible  vasoconstriction  of  the  superficial 
coronary  arterial  tree  (see  fig.  13)  (393).  Although  it 
seems  reasonably  sure  that  this  hormone  decreases 
coronary  flow  by  a  direct  constrictive  action  on  the 
coronary  bed,  simultaneous  studies  have  not  been 
made  of  the  associated  work  and  metabolism,  and  the 
possibility  of  a  reduced  metabolic  influence  has  not 
been  ruled  out.  If  Pitressin  has  a  direct  action  on  the 
coronary  vessels,  presumably  it  acts  at  the  arteriolar 
level.  This  is  so  since  in  the  isolated  perfused  rabbit 
heart  (1  76)  Pitressin  does  not  change  the  intracellular 
and  extracellular  Na  and  K  values.  If  resistance 
increased  at  the  venules  or  distal  end  of  the  capillaries, 
one  might  expect  an  increase  in  the  extravascular 
space. 

Exercise  and  Excitement 

Most  of  the  information  thus  far  considered  is 
based  upon  observations  obtained  from  the  resting 
human  and  the  anesthetized,  open-chest  dog.  It  is  not 
known  to  what  extent  it  applies  to  normal  situa- 
tions, since  the  information  has  been  obtained  either 
under  conditions  far  removed  from  normal,  as  the 
result  of  insults  from  anesthesia,  surgery,  and  trauma 
in  the  last  situation,  and  hence,  it  does  not  contain 
information  from  normal  humans  and  animals  as  to 
the  regulation  of  the  coronary  circulation  exposed  to 
the  stresses  of  everyday  life  such  as  exercise,  excite- 
ment, and  positional  changes.  For  example,  in  exercise 
and  excitement,  the  heart  rate  is  greatly  increased. 
It  is  disturbing  that  in  only  two  of  all  the  conditions 
of  stress  in  which  heart  rate  increases,  in  the  open- 
chest  dog,  do  the  stroke  coronary  flow  and  stroke 
coronary  oxygen  increase.  These  are  in  thyrotoxicosis 


and  with  cardiac  sympathetic  nerve  stimulation.  In 
the  others,  stroke  coronary  flow  and  stroke  coronary 
oxygen  decrease.  This  would  mean  that  coronary  flow 
and  oxygen  usage  are  completely  limited  by  the 
heart  rate.  For  example,  if  the  heart  rate  is  tripled, 
coronary  flow  can  only  be  increased  three  times.  It  is 
difficult  to  conceive  that  the  heart  works  in  this  way, 
but  rather  that  additional  mechanisms  can  also 
increase  the  coronary  flow  per  heart  beat. 

Accordingly,  considerable  effort  has  been  ex- 
pended to  make  appropriate  measurements  in  the 
normal  state.  It  is  not  to  be  expected  that  new  pa- 
rameters of  control  will  necessarily  exist  in  these 
stresses  imposed  by  everyday  life,  but  it  is  possible  that 
their  weighting  will  be  quite  different.  Early  observa- 
tions indicated  that  in  man  (240)  and  in  the  dog 
(105)  left  coronary  flow  and  myocardial  oxygen 
consumption  increased,  while  the  coronary  arterio- 
venous oxygen  showed  little  change.  More  recently,  an 
appropriate  flowmeter  has  been  applied  to  the 
coronary  system  of  an  essentially  normal  animal. 
Initially,  it  was  believed  that  no  flowmeter  would 
operate  properly  if  applied  directly  to  the  ventricle 
on  the  surface  of  the  heart  because  of  its  violent 
motion.  Therefore,  in  large  dogs  a  systemic  artery, 
either  the  carotid  or  internal  mammary,  was  anasto- 
mosed by  a  nonsuture  technique  to  the  left  circumflex 
coronary  artery  branch  so  that  a  flowmeter  could 
later  be  mounted  on  it  in  a  quiescent  region  off  the 
surface  of  the  heart.  Angiograms  and  postmortem  ex- 
amination of  the  hearts  indicated  the  patency  of  the 
anastomoses  and  the  normalcy  of  the  other  coronary 
vessels  and  the  myocardium.  Of  y^  dogs,  6  died  of 
technical  errors  on  the  table  or  shortly  thereafter, 
3  died  of  thrombosis  at  the  site  of  the  anastomosis,  2  to 
1 3  days  postoperative.  The  remaining  24  dogs  were 
sacrificed  1  2  to  24  months  later.  Prior  to  sacrifice  an 
electromagnetic  flowmeter,  modeled  after  that  of 
Kolin  (217),  was  placed  on  the  anastomosed  internal 
mammary  artery  and  the  coronary  blood  flow  meas- 
ured daily  for  periods  up  to  2  months.  Zero  blood 
flow  was  obtained  when  desired  by  temporarily 
occluding  the  flow  by  means  of  a  special  rubber  pneu- 
matic cuff  placed  around  the  internal  mammary 
artery  just  distal  to  the  flow  transducer  at  the  time  of 
its  implantation  (171). 

These  preliminary  experiments  in  1958  were 
encouraging.  Electromagnetic  flowmeters  of  the 
sine-wave  type,  but  greatly  modified  and  improved 
from  the  standpoint  of  miniaturization,  sensitivity, 
stability,  and  ruggedness,  were  constructed  (212a). 
The  flow  probes  used  on  the  left  coronary  artery  were 
necessarily  somewhat  smaller  than  an  aspirin  tablet, 


'554 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


since  the  maximum  space  available  for  implantation 
on  the  main  left  coronary  approximates  2  to  2.5  mm. 
A  large  electromagnetic  flowmeter  implanted  on  the 
ascending  aorta  (or  pulmonary  artery)  gave  simul- 
taneous cardiac  output  per  heartbeat.  For  phasic 
arterial  pressure  a  plastic  tube  filled  with  heparin 
was  implanted  in  the  aorta  just  beyond  the  aortic 
flow  transducer. 

Strips  of  record  in  figure  1  1  illustrate  the  flow 
through  the  left  circumflex  artery  anastomosed  to  the 
internal  mammary  artery  in  a  large  greyhound  at 
standing  rest,  and  running  on  a  treadmill  at  1  2  mph 
on  a  5  per  cent  grade  for  3  min  (mild  to  moderate 
exercise  for  such  a  dog).  As  the  heart  rate  almost 
triples,  the  mean  coronary  flow  also  triples.  Despite 
this,  stroke  coronary  flow  does  not  increase  but 
decreases  mildly.  The  fact  that  the  stroke  coronary 
flow  did  not  increase  with  exercise  cannot  be  ascribed 
to  increased  resistance  through  the  much  longer 
anastomosed  circuit  because  tests  in  acute  experi- 
ments showed  that  coronary  flow  was  the  same  in 
the  long  and  short  circuits  up  to  levels  of  about  650 
ml  per  min  (344).  Similar  flow  changes  during 
exercise  occur  in  the  main  left  coronary  artery  and 
in  the  descendens  and  circumflex  branches  without 
anastomosis  (212).  This  suggests  that  the  coronary 
flow  is  limited  by  the  heart  rate.  It  is  expected  (as 
yet  without  proof)  that  with  quite  heavy  exercise, 
the  coronary  flow  per  heart  beat  will  rise. 


The  coronary  flow  response  to  varying  degrees  of 
excitement  is  quite  different  from  that  to  exercise. 
In  the  experiment  illustrated  (fig.  12),  a  dog  at  rest 
underwent  spontaneous  excitement.  As  the  heart 
rate  increases  from  98  to  250  beats  per  min,  but 
without  change  in  mean  blood  pressure,  the  left 
circumflex  coronary  flow  increases  from  94  to  344 
ml  per  min,  and  despite  the  shortened  diastole 
during  which  most  of  the  coronary  flow  occurs,  the 
coronary  flow  is  more  than  tripled.  In  contrast  to  the 
response  in  exercise,  however,  stroke  coronary  flow- 
increases  from  1.0  to  1.3,  this  occurring  during  systole 
and  diastole.  Later,  as  a  moderate  increase  in  blood 
pressure  occurs,  the  stroke  coronary  flow  is  approxi- 
mately tripled.  Similar  flow  responses  to  excitement 
have  been  observed  in  the  main  left  coronary  artery 
with  or  without  a  large  blood  pressure  change.  These 
experiments  indicate  that  the  heart  is  able  to  obtain 
an  increased  coronary  flow  during  excitement  not 
only  because  of  the  increased  number  of  heartbeats, 
but  also  because  of  an  increased  flow  per  heartbeat. 

\'alvular  Disease 

It  is  difficult,  if  not  impossible,  to  duplicate  human 
valvular  disorders  experimentally  because  of  lack  of 
methodologies  to  assess  accurately  the  degree  of 
insufficiency  and  stenosis  in  both  man  and  beast,  to 
measure  the  coronary  blood  flow,  and  to  make  the 


REST 


(STANDING) 


180 

120 

60 

0 


•"-I 


EXERCISE 


RECOVERY 


5    SEC 


fo 


l\ 


10   SEC 


20   SEC 


5  SEC 


: 


M 


HYPEREMIA 

m 
(5  SEC   OCCLUSION) 


HEART 
RATE 

MEAN 
FLOW 

STROKE 
COR   FLOW 


80 
45.5 
0.57 


172 


54  7 


0.32 


214 
70.5 
0.33 


220 

110.7 

0  48 


146 


108 


0.74 


89 


45 


0.51 


fig.  1 1.  Reproduction  of  sections  of  records  taken  from  an  exercising  dog  showing  phasic  coronary 
flow  obtained  by  an  electromagnetic  flowmeter  mounted  on  an  internal  mammary  artery  anasto- 
mosed to  the  left  circumflex  coronary  artery.  Anastomosis  performed  1 7  months  earlier  and  flow 
probe  implanted  7  weeks  before.  Large  greyhound  at  standing  rest,  running  3  min  on  treadmill  at 
10  mph,    recovery,  5-sec  occlusion  of  anastomosis    to   observe    reactive  hyperemia.   [Khouri  ft  al. 

(212).] 


79 
108 
1.37 


BLOOD    SUPPLY    TO    THE    HEART 


1 555 


SPONTANEOUS  EXCITEMENT 
CONTROL  I  25  SEC 


HEART 
RATE 


MEAN 
ART    B   P 


MEAN  COR 
FLOW/MIN 


STROKE  COR 
FLOW  (cc) 


DIASTOLIC 
FLOW/MIN 


SYSTOLIC 
FLOW/MIN 


98 
115 
94 
1.0 
76 


250 
122 
314 
13 
258 
56 


117 
137 
340 
29 
276 
64 


77 
126 
200 
2.6 
177 
23 


72 
113 
74 
10 
66 
85 


fig.  1 2.  Reproduction  of  sections  from  a  continuous  record  in  a  conscious  dog  some  days  post- 
operative, showing  effect  of  excitement  on  mean  arterial  blood  pressure  and  stroke  left  circumflex 
flow,  using  strain  gauge  and  electromagnetic  flowmeter  as  in  fig.  6.  [Rayford  et  al.  (301).] 


experiments  of  a  long-term  chronic  nature.  It  is  not 
known,  therefore,  what  application  to  the  clinical 
situation  can  be  made  of  present  experiments. 


AORTIC  STENOSIS,  PULMONARY  HYPERTENSION,  PUL- 
MONARY    EMPHYSEMA     AND     COR     PULMONALE.    In     the 

past,  the  coronary  effects  of  stenosis  of  the  aortic 
valves,  cor  pulmonale,  pulmonary  emphysema,  and 
pulmonary  hypertension  associated  with  mountain 
sickness  have  not  been  studied  in  humans,  largely  for 
lack  of  an  adequate  method.  Our  information  on 
these  events  thus  comes  largely  from  the  dog. 

In  experiments  with  the  isolated  heart,  elevation  of 
right  ventricular  pressure  by  constriction  of  the 
pulmonary  artery  or  elevation  of  left  ventricular 
pressure  by  aortic  constriction  (coronary  perfusion 
pressure  kept  constant)  has  been  demonstrated  to 
cause  a  reduction  in  blood  flow  to  the  myocardium 
of  the  right  and  left  heart,  respectively  (153,  205). 
The  flow  decrease  is  attributed  to  the  dominant 
effect  of  the  direct  mechanical  inhibitive  action  of  the 
increased  vigor  of  the  heart  or  the  establishment  of 
an  unfavorable  pressure  gradient  for  right  coronary 
drainage  or  both.  In  studies  of  the  isolated  supported 
dog  heart,  when  coronary  perfusion  pressure  (aortic) 
is  kept  constant,  elevation  of  the  resistance  to  right 


ventricular  output  (an  increase  in  cardiac  work) 
does  not  affect  total  coronary  outflow  (313).  This 
means  that  either  the  heart  is  performing  the  work 
much  more  economically  or  there  is  a  large  safety 
factor  in  the  oxygen  to  be  extracted.  The  latter  is,  of 
course,  true  in  the  isolated  heart  in  which  the  ex- 
traction may  be  only  20  per  cent,  but  in  the  normal 
heart  no  such  wide  margin  of  safety  is  available, 
extraction  being  of  the  order  of  75  per  cent.  Therefore, 
it  remains  to  be  seen  whether  this  dissociation  of 
cardiac  work  and  coronary  flow  in  the  isolated  heart 
applies  to  a  normal  situation. 

Acute  elevation  of  right  ventricular  pressure  by 
pulmonary  artery  constriction  in  the  open-chest  dog 
with  constant  heart  rate  is  followed  by  a  maintained 
increase  up  to  4  hours  in  systolic  as  well  as  diastolic 
blood  flow  in  the  right  coronary  artery  in  the  presence 
of  the  same  or  some  lowering  of  the  aortic  or  central 
coronary  artery  pressure.  In  addition,  venous  outflow 
in  the  anterior  cardiac  veins  increases  greatly  (1 53). 
During  the  sustained  response,  both  right  ventricular 
work  and  metabolism  increase,  the  former  being  a 
result  of  the  increased  pulmonary  arterial  pressure 
and  a  small  decrease  in  cardiac  output,  the  latter 
elevation  resulting  from  a  combination  of  an  increase 
in  right  coronary  flow  and  a  greater  oxygen  extrac- 


1556 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


tion  from  the  right  coronary  blood.  A  high  degree  of 
coronary  dilatation  has  obviously  occurred  since 
right  coronary  artery  flow  has  increased  throughout 
the  cardiac  cycle  (especially  in  systole),  in  the 
presence  of  the  same  or  a  lower  central  coronary 
arterial  pressure  (153).  The  mechanisms  responsible 
cannot  be  identified  with  certainty.  They  could  be 
the  opening  of  closed  or  partially  closed  capillaries 
and  arterioles,  the  increased  passage  of  blood  through 
arteriovenous  shunts,  or  increased  metabolism.  It  is 
probably  not  explainable  on  the  basis  of  myocardial 
hypoxia,  since,  if  the  right  coronary  flow  is  increased 
300  to  400  per  cent  by  a  constant  but  very  high 
infusion  pressure,  the  flow  increases  still  further  when 
right  ventricular  pressure  is  elevated.  Regardless, 
however,  of  the  mechanism  of  coronary  flow  increase, 
elevation  of  right  ventricular  pressure  can  also  be 
shown  to  have  a  flow-reducing  effect  antagonistic  to 
the  flow-promoting  mechanisms.  In  the  presence  of 
an  adequately  maintained  central  coronary  pressure, 
the  sustained  flow  increase  and  decrease  are  preceded 
and  followed  by  transient  periods  of  flow  reduction 
and  elevation.  The  initial  temporary  decrease  in  flow 
is  attributed  to  the  dominant  influence  of  augmented 
extravascular  mechanical  compression  on  the 
coronary  vessels.  The  subsequent  appearance  of  a 
sustained  increased  flow  observed  shortly  thereafter 
indicates  that  the  effect  of  coronary  dilatation  has 
exceeded  the  flow  reducing  effect  of  increased  extra- 
vascular  compression.  The  immediate  and  transient 
flow  increase  following  abrupt  lowering  of  intra- 
ventricular pressure  is  a  rough  index  of  the  extent  to 
which  flow  had  previously  been  retarded  by  aug- 
mentation of  extravascular  compression. 

Concurrent  with  the  elevation  of  right  coronary 
flow,  left  coronary  flow  and  its  drainage  into  the 
coronary  sinus  are  significantly  elevated  (153,  196). 
The  increase  might  be  of  significant  magnitude  to  be 
determined  in  human  subjects  in  the  presence  of  an 
elevated  right  ventricular  pressure,  although  this  has 
not  been  found  (312).  It  might  be  conjectured  that 
the  source  of  a  portion  of  this  increased  left  coronary 
blood  is  increased  flow  through  the  ventricular 
septum,  much  of  which  normally  drains  into  the  right 
ventricular  cavity  but  which,  because  of  high  right 
ventricular  pressure,  might  be  diverted  into  the 
coronary  sinus  (265). 

Such  responses  of  flow  and  metabolism  in  the 
right  myocardium  to  elevation  of  its  cavity  pressure 
are  not  peculiar  to  it.  Elevation  of  left  ventricular 
pressure  by  an  aortic  constriction  central  to  the 
coronary  ostia,  i.e.,  between  the  aortic  valves  and 
coronary    ostia    to    stimulate    aortic    stenosis,    gives 


trends  for  coronary  flow  and  myocardial  metabolism 
of  the  left  ventricle  identical  to  those  found  in  the 
right  ventricle  (1 53). 

These  maintained  changes  in  the  coronary  circula- 
tion could  well  be  the  early  response  in  the  human 
being  to  gradual  moderate  stenosis  of  the  correspond- 
ing valves. 

aortic  insufficiency.  In  patients  with  aortic  in- 
sufficiency and  lacking  disease  of  the  coronary  ostia 
or  arteries,  the  presence  of  chest  pain  resembling  that 
due  to  myocardial  ischemia  is  generally  assigned  to  a 
reduction  in  coronary  blood  flow,  this  arising  pre- 
sumably from  a  reduction  of  the  mean  aortic  or 
central  coronary  diastolic  pressure.  In  the  open-chest 
dog  reversible  aortic  regurgitant  flow  has  been 
accurately  produced  without  valve  injury,  metered 
and  controllably  varied,  while  at  the  same  time 
metering  cardiac  output.  Aortic  regurgitant  flows  in 
excess  of  the  dog's  resting  cardiac  output  resulted  in  a 
marked  decrease  of  effective  cardiac  output,  a  rise  of 
peripheral  resistance  and  left  ventricular  end-diastolic 
pressure,  and  a  marked  depression  of  the  left  ventricu- 
lar pressure  curve  without  significant  change  in  mean 
left  atrial  pressure.  No  coronary  flows  were  measured 
(390).  In  early  experiments  in  the  open-chest  dog  in 
rather  poor  condition  (144,  153)  reversible  aortic 
insufficiency  (umbrella-type  aortic  valve  expanders) 
sufficient  to  lower  aortic  diastolic  pressure  decreases 
mean  left  coronary  flow  as  a  resultant  of  an  increased 
systolic  flow  and  a  markedly  reduced  diastolic  flow. 
On  the  other  hand,  Foltz  et  al.  (119),  from  measure- 
ments on  anesthetized  dogs  two  or  three  days  after 
the  aortic  cusps  had  been  torn,  found  a  considerable 
increase  in  coronary  flow  and  myocardial  oxygen 
usage.  This  latter  finding  has  been  confirmed  by 
Wegria  in  acute  experiments,  and  West  in  chronic 
dogs  (386,  394).  In  patients  with  reduced  diastolic 
pressure,  wide  pulse  pressure  and  varying  degrees  of 
left  ventricular  enlargement,  those  without  angina  or 
failure  have  normal  coronary  hemodynamics;  those 
with  angina  have  a  reduced  coronary  flow  and  cardiac 
oxygen  usage;  and  those  in  failure  have  an  increased 
coronary  flow  and  oxygen  usage  (constant  coronary 
A-Y  oxygen  difference)  (303).  Such  observations  are 
difficult  to  interpret  because  of  their  small  number, 
the  lack  of  adequate  control  data,  and  the  possibility 
of  complicating  disease  of  coronary  ostia  or  arteries, 
or  both. 

mitral  stenosis.  The  general  hemodynamic  effects 
from  mitral  stenosis  include  increased  wedge  pressure, 
pulmonary  arterial  pressure,  right   ventricular  work, 


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1557 


and  decreased  systemic  blood  pressure,  cardiac  index, 
and  cardiac  work  index.  In  small  groups  of  human 
subjects,  a  normal  or  decreased  coronary  blood  flow 
has  been  reported  (216).  In  a  large  group  of  females, 
the  above  systemic  changes  have  been  found  to  be 
associated  with  a  decrease  in  left  ventricular  coronary 
blood  flow,  increased  coronary  oxygen  extraction, 
and  decreased  left  ventricular  oxygen  utilization  per 
unit  of  myocardium,  as  compared  with  normal 
females  but  not  as  compared  with  normal  males 
(321).  This  depression  of  the  left  coronary  circulation 
in  the  presence  of  a  lowered  activity  of  the  left 
ventricle  would  be  expected.  Acceptance  of  these 
data,  although  in  line  with  those  previously  reported 
in  the  intact  dog  (118),  should  possibly  be  deferred 
until  previous  work  indicating  that  the  left  coronary 
circulation  in  the  female  is  maintained  at  a  con- 
siderably higher  level  than  in  the  male  (320)  is 
confirmed. 

mitral  insufficiency.  Mitral  regurgitation  has  been 
experimentally  produced  in  the  open-chest  dog  by 
permitting  blood  to  flow  externally  from  the  left 
ventricular  apex  through  a  flowmeter  into  the  left 
atrium  during  systole.  Such  controlled  regurgitant 
flows,  up  to  three  times  the  resting  cardiac  output, 
are  tolerated  with  only  slight  or  mild  alterations  of 
effective  cardiac  output,  aortic,  left  atrial  and  left 
ventricular  pressures,  total  peripheral  resistance,  and 
the  effective  left  ventricular  function  curves  (45).  In 
anesthetized  open-chest  dogs,  acute  mitral  insuffi- 
ciency of  variable  severity,  produced  by  means  of  an 
umbrella-type  valve  spreader  so  as  to  allow  a  partial 
or  incomplete  return  of  the  aortic  flow  to  its  control 
level,  results  in  a  moderate  increase  in  coronary  blood 
flow  and  myocardial  oxygen  usage  and  a  reduced 
efficiency.  Presumably,  the  left  ventricle  expends  a 
significant  amount  of  energy  in  regurgitating  blood 
into  the  left  atrium  during  mitral  insufficiency  (388). 
No  comparable  studies  of  this  nature  are  available  in 
humans. 

aortic  coarctation.  With  simulation  of  clinical 
coarctation  by  acute  mechanical  constriction  of  the 
thoracic  aorta  just  beyond  the  left  subclavian  artery, 
venous  return  to  the  heart  by  way  of  the  inferior  vena 
cava  is  decreased  but  compensatory  flow  through 
various  branches  of  the  aortic  arch  may  increase, 
with  a  resultant  maintained  cardiac  output  and 
elevated  left  ventricular  work  load.  With  greater 
aortic  constriction,  the  net  cardiac  output  decreases, 
causing  the  cardiac  work  to  decrease.  In  either  case, 
the  coronary  dilatation  and  increased  flow  arise  in 


large  part  from  active  changes  in  the  bore  of  the 
coronary  bed  related  to  the  metabolic  demands,  and, 
in  part,  passively  from  the  increased  blood  pressure 
and  moderately  decreased  heart  rate  (90,  207).  The 
cardiac  oxygen  consumption  is  increased  much  more 
by  this  augmentation  of  pressure  work  than  with  an 
equal  increase  of  volume  work  following  transfusion 
(335).  No  chronic  studies  of  aortic  coarctation  have 
been  made  because,  owing  to  development  of  col- 
lateral circuits,  the  aorta  may  be  first  partially  and 
then  completely  constricted  at  the  arch  without 
permanent  development  of  hypertension  proximal  to 
the  occlusion.  In  human  coarctation  not  much 
change  is  reported  in  coronary  flow  and  oxygen 
uptake,  but  this  might  be  expected  because  systemic 
pressure  is  only  mildly  elevated  (31).  However,  if  true, 
the  deviation  might  be  explained  by  the  fact  that  in 
these  hearts,  which  are  hypertrophied,  there  are 
fewer  capillaries  per  unit  of  muscle  to  carry  the  oxygen 
and  flow. 


Hypertensive  Cardiovascular  Disease 

An  exception  to  the  general  picture  of  coronary 
compensation  to  increased  systemic  stress  appears  to 
be  the  response  of  the  chronically  hypertensive  heart. 
In  essential  hypertension,  with  a  normal  cardiac 
output  and  elevated  systemic  blood  pressure,  the 
coronary  flow  and  oxygen  consumption  per  100  g 
myocardium  are  unaltered  while  coronary  resistance 
increases.  This  increased  resistance  is  shared  with  the 
renal  and  cerebral  circulations.  Since  these  hearts  are 
generally  hypertrophied,  total  coronary  flow  and 
oxygen  usage  are  probably  increased.  This  deviation 
is  explainable  if  it  is  assumed  that  such  hearts  with 
known  coronary  artery  disease  have  an  increased 
amount  of  perfused  fibrotic  tissue  (31,  316). 

Heart  Failure 

Although  the  underlying  mechanisms  for  various 
types  of  heart  failure  may  be  different,  the  basic 
hemodynamic  manifestations  of  cardiac  failure  are 
similar  from  causes  such  as  congestive  heart  failure, 
anemia,  anoxia,  hemorrhagic  shock,  myocardial 
infarction,  hyperthyroidism,  and  beriberi.  Experi- 
mentally, such  hearts  exhibit  depressed  Starling  or 
ventricular  function  curves  (increased  ratio  of  end- 
diastolic  ventricular  volume  or  ventricular  filling 
pressure  to  stroke  work),  and  show  the  characteristic 
optimum  beyond  which  further  stretching  reduces 
the  force  of  contraction  and  leads  to  myocardial 
failure.  In  acute  heart  failure  in  the  open-chest  dog, 


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CIRCULATION    II 


with  progressive  deterioration  of  the  right  myocardium 
from  pulmonary  artery  stenosis,  the  changes  in 
coronary  flow  and  oxygen  usage  per  minute  and  per 
beat  may  be  in  the  same  direction  (increase)  as  those 
described  for  the  nonfailing  right  myocardium,  but  of 
lesser  magnitude  (see  section  on  Valvular  Disease). 
If  the  heart  failure  is  severe  enough,  extravascular 
compression  can  become  dominant  over  any  active 
coronary  dilatation  from  metabolic  processes,  and 
coronary  flow  and  oxygen  usage  may  be  normal  or 
decrease,  with  the  oxygen  extraction  at  times  reaching 
go  per  cent  (153)-  The  coronary  circulation  in  the 
heart,  failing  with  severe  aortic  stenosis,  undergoes 
similar  changes  (Gregg,  unpublished  data).  When 
acute  heart  failure  and  chronic  congestive  failure 
simulating  the  human  condition  are  induced  by 
surgical  complete  heart  block,  changes  in  left  coronary 
flow  and  ventricular  oxygen  consumption  also  rather 
closely  parallel  alterations  in  the  reduced  left  ventricu- 
lar work  (355).  In  each  instance,  the  mechanical 
efficiency  of  the  myocardium  drops,  the  total  energy 
of  liberation  (oxygen  consumption)  being  fairly  well 
maintained,  but  the  work  falls  off.  The  isolated 
mammalian  heart  or  heart-lung  is  also  characterized 
by  deterioration  of  mechanical  efficiency  and  on  the 
same  basis  (74,  243).  In  chronic  left  heart  failure 
due  to  rheumatic,  arteriosclerotic,  and  hypertensive 
heart  disease,  the  coronary  circulation  apparently 
responds  by  a  slight  increase  in  oxygen  usage  through 
maintenance  of  the  left  coronary  flow  and  an  in- 
creased coronary  A-V  oxygen  difference.  This 
corresponds  with  the  changes  indicated  for  the  right 
heart  in  an  early  stage  of  failure.  As  is  true  for  the 
heart-lung  or  isolated  heart,  such  hearts  have  con- 
siderable difficulty  in  transforming  released  energy 
into  realizable  work.  Studies  of  the  coronary  circula- 
tion in  high-output  failure  from  excessive  transfusion 
or  a  chronic  aorta-caval  fistula  are  not  available.  In 
the  anesthetized  open-chest  dog,  however,  an  acute 
arteriovenous  fistula  sufficient  to  increase  cardiac 
output  and  cardiac  work  causes  considerable  aug- 
mentation of  stroke  coronary  flow  and  stroke  coronary 
oxygen  even  in  the  presence  of  a  sizeable  decrease  in 
arterial  blood  pressure  (389). 

When  acute  heart  failure  induced  by  pulmonary 
artery  constriction  has  advanced  to  the  stage  where 
systemic  blood  pressure  is  low,  left  ventricular  size  is 
small,  right  ventricular  size  is  large,  and  release  of 
the  constriction  does  not  restore  ventricular  working 
capacity,  then  the  use  of  arterial  transfusion  with  a 
pump  temporarily  promotes  functional  recovery  of 
the  heart  (increase  in  arterial  and  coronary  perfusion 


pressure,  coronary  flow,  cardiac  output,  cardiac  work, 
and  myocardial  vigor,  decrease  in  cardiac  size  and 
coronary  A-V  oxygen  difference).  Veno-arterial 
pumping  accentuates  and  makes  more  permanent 
these  beneficial  changes.  Since  an  increase  in  coronary 
flow  invariably  precedes  recovery  of  the  heart,  it 
suggests  that  it  is  a  primary  stimulus  through  an 
effect  on  myocardial  metabolism  for  increased 
ventricular  performance  and  decrease  in  heart 
size  (14). 

Postmortem  specimens  from  human  patients  may 
show  myocardial  edema  (increased  water,  Na  and  CI 
content  per  unit  of  myocardium)  in  the  presence  of 
congestive  heart  failure,  acute  infarction,  and  ischemic 
areas.  Very  often,  however,  previous  drug  administra- 
tion, together  with  agonal  and  postmortem  changes, 
makes  interpretation  difficult.  The  isolated  dog  heart 
does  not  develop  edema  when  directly  perfused  from 
a  donor  dog,  but  increased  myocardial  water  content 
is  found  after  acute  cardiac  injury  (over-distended 
ventricle),  excessive  perfusion  pressure,  increased 
coronary  venous  pressure,  and  by  perfusion  with 
blood  from  a  disposable  bag  oxygenator  system.  It 
occurs  spontaneously  in  the  failing  heart-lung  prepa- 
ration and  in  chronic  heart  failure  produced  experi- 
mentally by  thoracocaval  constriction,  pulmonary 
stenosis,  and  tricuspid  insufficiency,  separately  or 
together.  The  mechanism  or  mechanisms  involved  are 
unknown,  but  in  these  chronic  preparations,  elevation 
of  right  atrial  pressure  seems  to  be  a  major  pathogenic 
factor  in  its  formation.  Whether  its  presence  con- 
tributes to  abnormal  cardiac  function  or  whether  its 
prevention  or  reversal  is  a  therapeutic  objective  in 
the  management  of  heart  disease  is  a  moot  question 
(329.  409 )• 

Hemorrhagic  Slunk 

Standardized  oligemic  shock  in  dogs  is  characterized 
during  the  hypotensive  phase  by  a  decrease  in 
cardiac  output,  systemic  blood  pressure,  cardiac 
work,  stroke  volume  and  stroke  work,  and  by  an 
increase  in  heart  rate  and  an  adequate  central  venous 
pressure.  Coronary  flow  and  coronary  resistance 
are  greatly  decreased  but  the  coronary  flow  fraction 
of  cardiac  output  is  increased  (102).  Coronary  flow  is 
generally  greater  and  the  resistance  generally  less  than 
can  be  accounted  for  by  a  simple  decline  in  arterial 
blood  pressure  (281).  At  the  same  time,  the  oxygen 
uptake  decreases  and  the  coronary  arteriovenous 
oxygen  difference  is  generally  unchanged  (166).  The 
coronary  response  to  sustained  hypotension  through 


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1559 


spinal  anesthesia  or  injection  of  procaine  and  Etamon 
is  similar  (168).  With  partial  or  complete  restoration 
to  normal  systemic  blood  pressure  by  reinfusion 
(intra-arterial  and  intravenous  routes  are  equally 
effective)  (56,  361),  coronary  flow  is  greater  and  flow 
resistance  is  less  than  at  an  equivalent  arterial  blood 
pressure  in  the  preshock  state. 

The  fact  that  early  in  the  hypotensive  phase  neither 
ventricular  end-diastolic  pressure  nor  atrial  pressure 
rises  indicates  that  the  functional  capacity  of  the 
heart  is  adequate  for  the  work  performed.  However, 
that  myocardial  depression  or  failure  is  partially 
responsible  for  the  hemorrhagic  shock  syndrome  is 
suggested  by  different  observations,  a)  After  prolonged 
hypotension,  there  may  be  evident  cardiac  dilatation 
and  elevated  left  and  right  atrial  pressures  with  the 
heart  eventually  proceeding  to  ventricular  fibrillation 
or  standstill  (331).  With  spontaneous  cardiovascular 
decay  after  reinfusion,  the  atrial  pressure  may  be  at  a 
normal  or  elevated  level  despite  large  cardiac  output 
reduction  (402).  b)  During  prolonged  oligemic 
hypotension,  as  the  animal  starts  to  take  up  blood 
from  the  reservoir  to  maintain  its  falling  blood 
pressure,  the  atrial  pressure  may  rise  to  very  high 
levels  (163).  Gross  and  microscopic  evidence  of 
myocardial  injury  appears  in  both  reversible  and 
irreversible  shock.  Such  myocardial  depression  could 
be  caused  by  an  insufficient  coronary  flow  during 
either  the  hypotensive  or  the  post-hemorrhagic 
periods.  The  high  coronary  flow  during  the  restora- 
tion period  would  seem  to  preclude  an  inadequate 
coronary  flow  as  an  adequate  explanation.  During 
the  hypotensive  period,  the  actual  coronary  flow  is 
greatly  curtailed.  The  problem  is  whether  the 
associated  sizeable  reduction  in  coronary  resistance 
is  sufficient  to  permit  enough  blood  to  reach  the 
myocardium  to  prevent  it  from  failing.  In  some 
instances,  at  least,  this  loss  of  myocardial  contrac- 
tility is  consequent  upon  an  insufficient  coronary 
flow,  since  the  relation  of  atrial  pressure  to  cardiac 
size  can  be  reversed  by  increasing  left  coronary  flow 
mildly  with  a  pump,  without  change  in  either  the 
hypotension  or  blood  volume  (331). 

The  work  just  discussed  has  been  largely  restricted 
to  studies  in  experimental  animals  exposed  to  anes- 
thesia, surgery,  and  varying  amounts  of  traumatic 
insult.  More  proper  studies  might  be  conducted  in 
intact  conscious  dogs;  this  is  possible  with  methodology 
now  available.  This  type  of  study  has  been  made  with 
the  use  of  modified  and  improved  electromagnetic 
flowmeters  which  were  chronically  implanted  on  the 
left  coronary  artery  as  well  as  the  aorta  and  various 


systemic  arteries  (159).  The  experiments  confirm 
previous  findings  that,  of  all  the  arterial  beds,  only 
the  coronary  shows  a  decreased  vascular  resistance 
during  hemorrhagic  irreversible  shock,  and  add  new 
information  regarding  the  compensatory  behavior  of 
the  left  coronary  vascular  bed.  The  coronary  pressure- 
flow  ratio  moderately  increases  during  hemorrhage, 
progressively  decreases  during  the  hypotensive  period 
as  the  coronary  flow  increases  spontaneously,  and  is 
temporarily  restored  during  the  reinfusion.  During 
the  irreversible  period,  in  which  the  coronary  flow  is 
fairly  well  maintained,  the  pressure-flow  ratio  again 
drops.  The  resistance,  however,  to  coronary  flow  is 
somewhat  less  during  the  period  of  spontaneous  decay 
than  during  the  initial  hypotensive  period.  These 
pressure-flow  changes  may  have  their  explanation  in 
certain  characteristic  changes  in  the  coronary  flow 
pattern.  The  phasic  flow  pattern,  initially  some  dis- 
tance above  the  zero  flow  line  throughout  the  cardiac 
cycle,  moves  closer  to  the  zero  flow  line  during 
hemorrhage,  and  backflow  may  appear  during 
systole.  The  magnitude  of  the  flow  pattern,  however, 
increases,  indicating  increased  vigor  of  contraction. 
As  the  hypotensive  period  progresses,  flow  is  re- 
established in  systole  and  increased  somewhat  in 
diastole.  Following  reinfusion,  and  late  in  the  period 
of  spontaneous  hemodynamic  decay,  the  flow  pattern 
may  resemble  somewhat  the  prevailing  aortic  pres- 
sure pulse  with  the  systolic  flow  equal  to  or  exceeding 
the  diastolic  flow.  The  mechanisms  whereby  coronary 
systolic  flow  is  thus  preferentially  enhanced  are  not 
known. 


Hypothermia 

The  circulatory  and  metabolic  adjustments  of  the 
heart  during  hypothermia  have  been  partially 
explored  (87).  When  the  body  temperature  is  dropped 
from  37  C  to  20-28  C,  by  immersion  hypothermia  or 
by  cooling  the  systemic  arterial  blood  flow,  the 
associated  changes  that  occur  which  tend  to  reduce 
the  coronary  flow  are  a  diminution  in  blood  and 
muscle  temperatures,  cardiac  output,  heart  rate, 
cardiac  work,  and  oxygen  usage  by  the  heart,  an 
increased  blood  viscosity  and  a  greatly  lengthened 
period  of  ventricular  systole.  The  coronary  A-V 
oxygen  difference  remains  about  normal  or  decreases 
(103,  128,  175,  180,  322).  Opposing  these  factors  are 
the  relaxation  of  the  major  coronary  vessels,  which  is 
known  to  occur  with  hypothermia,  and  dilatation  of 
the  coronary  bed  caused  by  the  hypotension  per  se 
(25,    177).    As    a    resultant    of   these    determinants, 


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coronary  flow  is  decreased  at  low  temperature. 
However,  the  per  cent  reduction  in  cardiac  output  is 
greater  than  that  in  coronary  flow,  which  results  in  an 
increase  in  the  coronary  fraction  of  cardiac  output  at 
temperatures  of  25  to  26  C  (103,  322).  There  is  little 
change,  a  decrease,  or  an  increase  in  peripheral 
resistance  in  the  coronary  bed,  whereas  in  the  systemic 
bed  an  increase  in  peripheral  resistance  invariably 
occurs  (1  77,  322).  A  constant  or  increasing  mechanical 
efficiency  is  usually  observed  in  the  open-  or  closed- 
chest  dog  (128,  175)  although  it  has  been  reported  to 
fall  (103,  198).  Similarly,  in  the  heart-lung  prepara- 
tion or  isolated  heart,  the  mechanical  efficiency  is 
fairly  constant  when  cardiac  work  per  beat  (same 
stroke  volume  and  arterial  blood  pressure)  and 
heart  rate  are  constant  (15).  Myocardial  function 
appears  to  be  adequate  and  myocardial  hypoxia  not 
to  exist  (198).  However,  many  hearts  are  apparently 
not  too  far  from  failure  because  if  total  venous  inflow 
occlusion  (which  decreases  coronary  flow  close  to 
zero)  is  now  added  to  permit  open  cardiotomy, 
myocardial  failure  supervenes,  as  evidenced  by- 
elevation  in  mean  right  atrial  pressure  and  post- 
mortem findings.  This  trend  can  be  reversed  by 
perfusion  of  the  coronary  system  with  small  volumes 
of  oxygenated  blood  (239). 

Hyperthermia 

The  systemic  dynamic  changes  resulting  from 
elevation  of  body  temperature  by  fever  or  external 
application  of  heat  (hot  baths,  diathermy)  are  quite 
similar  in  man  and  dog,  are  well  documented,  and 
include  considerable  elevation  of  heart  rate,  blood 
pressure,  cardiac  output,  right  and  left  ventricular 
work,  a  decreased  peripheral  resistance  and  a  con- 
stant stroke  volume  and  stroke  work.  The  little 
information  available  on  the  associated  coronary 
changes  indicates  that  a  large  elevation  of  body 
temperature  (up  to  105  F)  by  means  of  diathermy, 
in  the  closed-chest  dog,  increases  considerably 
coronary  blood  flow,  myocardial  oxygen  usage, 
coronary  A-V  oxygen  difference,  increases  mildly  the 
stroke  coronary  oxygen  usage,  decreases  external 
efficiency,  and  leaves  unchanged  the  stroke  coronary 
flow  and  coronary  resistance  (257).  In  open-chest 
dogs  with  an  initial  hypotensive  systemic  blood 
pressure,  diathermy  has  no  effect  on  coronary  flow 
(253).  In  the  heart-lung  preparation,  when  the 
myocardium  is  warmed,  coronary  flow  and  oxygen 
usage  are  increased;  but  they  are  not  when  the 
coronary  blood  is  warmed  (10). 


Summary 

Over  the  years,  the  basic  mechanisms  affecting 
coronary  flow  and  oxygen  usage  have  been  related 
experimentally  to  various  parameters,  and  the  state- 
ment is  often  made  that  there  is  one  controlling  or 
unifying  influence  for  coronary  flow  per  heart  beat 
and  also  one  for  oxygen  usage  of  the  left  myocardium 
per  cardiac  cycle,  a)  Directional  changes  in  stroke 
coronary  flow  correlate  with  stroke  coronary  oxygen 
usage.  This  is  so,  however,  because  normally  most 
oxygen  is  removed  from  the  coronary  blood  and  the 
level  of  coronary  sinus  oxygen  is  usually  fairly  con- 
stant under  stress,  i.e.,  it  does  not  change  more  than 
10  to  15  per  cent.  In  those  instances  in  which  the 
coronary  arteriovenous  oxygen  difference  increases 
or  decreases  by  this  amount,  it  does  not  greatly 
affect  the  relation  of  coronary  flow  to  oxygen  usage 
since  the  change  is  very  small  relative  to  the  magni- 
tude of  the  coronary  flow  change,  but  this  does  not 
document  a  functional  correlation  between  these 
parameters,  b)  The  stroke  coronary  flow  and  stroke 
coronary  oxygen  correlate  fairly  well  with  the  stroke 
work  under  a  variety  of  conditions  of  changing 
systemic  stress,  but  it  is  possible  to  so  regulate  experi- 
ments that  the  response  of  the  coronary  circulation  is 
dissociated  from  stroke  work,  c)  The  exceptions  to 
the  usual  correlation  of  stroke  work  and  coronary 
oxygen  usage  constitute  a  group  of  conditions  in 
which  the  outflow  channels  of  the  two  ventricles  have 
been  restricted  in  some  manner.  In  these,  one  can 
show  excellent  correlation  of  the  stroke  coronary  flow 
and  oxygen  usage  with  the  mean  systolic  arterial 
blood  pressure  alone,  or  with  the  product  of  the 
systolic  blood  pressure  and  the  duration  of  systole, 
the  so-called  "tension-time  index."  However,  experi- 
ments in  the  unanesthetized  dog  during  exercise  and 
excitement  do  not  always  support  this  view.  In 
addition,  there  is  quite  a  list  of  determinants  that 
have  been  thought  to  be  fundamental.  Attempts 
have  been  made  to  relate  coronary  flow  and  oxygen 
usage  to  the  mean  arterial  blood  pressure,  ventricular 
filling  pressure  or  mean  atrial  pressure,  ventricular 
diastolic  volume  or  fiber  length,  tension  within  the 
ventricular  wall,  oxygen  tension  of  the  arterial  blood, 
oxygen  tension  within  the  myocardium,  action  of 
local  metabolites  or  vasodilating  substances.  Possibly, 
the  best  correlation  of  all  should  be  with  the  reduction 
of  cytochrome  oxidase  and  the  needs  of  the  hydrogen 
transport  system.  Probably  no  final  answer  is  avail- 
able. Final  decision  as  to  whether  any  of  these 
determinants  of  coronarv  flow  or  oxygen  usage  are 


BLOOD    SUPPLY    TO    THE    HEART 


1561 


primary  or  empirical  must  await  the  necessary 
measurements  under  normal  conditions  of  stress 
without  anesthesia  or  surgical  insult. 


DRUGS    VERSUS    THE    CORONARY    CIRCULATION 

The  pertinent  literature  has  been  reviewed  (7,  13, 
49-  68.  145.  '53.  209,  238,  275,  384,  413).  Con- 
sideration will  be  given  here  only  to  the  effects  of  a 
few  selected  drugs  on  the  coronary  circulation  in  the 
normal  state  and  in  the  presence  of  coronary  artery 
disease. 

Drugs  may  be  effective  in  altering  the  normal  and 
collateral  myocardial  blood  supply  by  a  direct  effect 
on  the  vasomotor  state  of  the  vessels,  by  an  increase 
or  decrease  in  central  blood  pressure,  by  myocardial 
stimulation  or  depression,  by  a  change  in  the  cardiac 
workload  through  extracardiac  phenomena,  or  by 
electrolyte,  pH  or  gaseous  alterations  of  the  blood 
perfusing  the  coronary  bed.  It  is  interesting  to  know 
whether  a  drug  affects  the  extravascular  and  intra- 
vascular resistances  of  the  coronary  bed,  but  it  is 
more  important  to  know  its  effect  upon  the  supply  of 
oxygen  to  the  myocardium,  the  oxygen  used  by  the 
myocardium,  and  the  efficiency  of  the  heart  in  the 
use  of  its  oxygen  for  the  work  performed.  In  addition, 
a  pharmacological  agent  may  be  able  to  improve  the 
oxygen  utilization  for  external  work  of  the  heart 
without  an  increase  in  coronary  blood  flow  or  oxygen 
extraction. 

In  order  to  properly  evaluate  an  agent,  the  follow- 
ing information  is  necessary:  a)  coronary  blood  flow, 
b)  arteriovenous  oxygen  difference  across  the  coronary 
bed,  c)  blood  pressure,  d)  cardiac  output,  e)  myo- 
cardial contractility,  and  /)  heart  rate.  From  these 
data,  the  myocardial  oxygen  availability  and  usage, 
cardiac  work  and  efficiency  can  be  calculated. 

Few  drugs  have  been  completely  studied.  The 
pharmacologic  agents  will  be  considered  from  the 
standpoint  of:  a)  the  effects  of  therapeutic  or  poten- 
tially therapeutic  drugs  on  the  normal  myocardium 
undergoing  normal  or  excessive  stress,  and  b)  the 
effects  of  nontherapeutic  drugs  on  the  normally 
stressed  myocardium.  In  the  normal  and  hyper- 
tensive heart,  the  ganglionic  blockers  such  as  hexa- 
methonium  decrease  both  cardiac  work  and  myo- 
cardial oxygen  availability  but  not  the  oxygen  usage 
(73,  162).  Nitroglycerin  has  no  apparent  direct  effect 
on  the  amount  of  free  energy  released  with  each 
contraction  of  the  myocardium  either  before  or  after 
partial  coronary  artery  occlusion,  but  rather  reduces 


hemodynamic  workload  by  a  decrease  in  left  atrial 
filling  pressure  (75).  Experiments  in  dogs  with 
sodium  nitrite  or  nitroglycerin  injected  into  the  left 
coronary  artery  show  that  the  coronary  arteries  and 
their  small  branches  dilate  (fig.  13)  (393),  and  that 
the  flow  increases  greatly  in  both  systole  and  diastole 
and  in  the  presence  of  a  decreased  central  coronary 
pressure,  cardiac  output,  cardiac  work,  a  constant 
heart  rate  and  only  a  slight  decrease  in  the  systolic: 
diastolic  ratio.  Hence,  the  conclusion  is  inescapable 
that  these  drugs  exert  a  vasodilating  action  on  the 
coronary  vessels  (41).  This  could  arise  from  a  direct 
effect  of  the  drug  on  the  coronary  vessels  since  cardiac 
metabolism  is  not  increased  (decreased  coronary 
A-V  oxygen  difference  and  increased  coronary  flow) 
(94,  333).  Experiments  in  normal  man  with  nitro- 
glycerin, however,  show  an  increased  coronary  blood 
flow  with  an  increased  myocardial  oxygen  uptake 
(constant  coronary  A-V  oxygen  difference  and 
increased  coronary  flow),  decreased  cardiac  work  and 
decreased  cardiac  efficiency  (42).  Furthermore,  in 
patients  with  coronary  artery  disease,  this  drug  does 
not  increase  coronary  flow  while,  with  a  steady 
oxygen  extraction,  it  decreases  cardiac  work  (de- 
creased blood  pressure  and  cardiac  output)  (138). 
These  data  raise  the  old  question  of  the  applicability 
of  knowledge  obtained  in  normal  animal  or  human 
studies  to  the  diseased  states.  If  these  studies  should 
be  confirmed  in  patients  during  anginal  attacks,  other 
theories  for  the  action  of  nitroglycerin  must  be  con- 
sidered. One  theory  holds  that  nitroglycerin  blocks 
the  anoxia-inducing  effect  of  the  catecholamines  on 
the  heart  (296),  but  an  antiadrenergic  action  could 
not  be  demonstrated  for  this  drug  (94).  One  might 
postulate  that  a  decrease  in  cardiac  work  secondary 
to  the  decrease  in  blood  pressure,  in  the  presence  of  a 
stable  oxygen  consumption,  may  be  helpful  to  the 
myocardium  despite  a  calculated  decrease  in  myo- 
cardial efficiency.  Present  calculations  include  only- 
evaluation  of  the  external  efficiency  of  the  heart.  If 
such  hearts  are  using  all  the  oxygen  they  could 
extract  at  a  given  workload,  then  a  decrease  in  this 
work,  at  the  same  level  of  oxygen  consumption,  might 
be  beneficial. 

With  the  xanthines  mean  coronary  flow  is  increased, 
this  being  the  net  result  of  a  marked  increase  during 
diastole  and  a  decrease  during  systole  which  occurs 
in  the  presence  of  a  normal  or  mildly  decreased  blood 
pressure  and  without  significant  change  in  cycle 
length  or  systolic: diastolic  ratio.  Visually,  the  heart 
shows  increased  vigor  and  its  metabolism  and  work 
are   increased    (41).    Nikethamide   acts   similarly    by 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  13.  Effects  of  coronary 
arterial  injection  of  Pitressin, 
nitroglycerin,  and  acetylcholine 
in  the  anesthetized  dog.  Catheter 
in  the  first  part  of  the  anterior 
descendens  branch  (left  lateral 
view).  Radiopaque  material  in- 
jected in  all  cases  5  cc.  A  :  control 
angiogram  (BP  150/115;  HR  90) 
before  Pitressin.  B:  (BP  145/115; 
HR  85)  1  min  after  Pitressin  in- 
jection (0.008  units/kg).  C:  con- 
trol angiogram  (BP  175/125; 
HR  75).  D:  (BP  165/115  HR 
78)  after  nitroglycerin  injection 
(5  MgAg).  E:  control  (BP  177/ 
115;  HR  84).  F:  (BP  170/117; 
HR  84)  immediately  after  acetyl- 
choline injection  (0.04  MgAg). 
[Modified  after  West  &  Guzman 
(393)0 


increasing  the  oxygen  available  to  the  myocardium 
but  at  the  expense  of  an  increased  oxygen  usage  and 
cardiac  work  (91).  It  would  probably  be  preferable 
to  increase  the  oxygen  availability  without  stimulation 
of  myocardial  oxygen  metabolism,  as  has  been  shown 
for  nitroglycerin  and   papaverine   in   animal   studies 


(75,  117,  214).  Hydralazine,  which  may  precipitate 
anginal  attacks  in  hypertensive  patients,  possesses 
what  are  usually  considered  the  desired  properties 
for  a  coronary  vasodilator:  it  increases  coronary 
blood  flow,  increases  oxygen  availability,  and  does 
not  alter  the  oxygen  uptake  of  the  myocardium  (316). 


BLOOD  SUPPLY  TO  THE  HEART 


1563 


It  would  appear  that  our  concepts  of  the  "ideal" 
agent  for  coronary  artery  disease  must  be  revised. 

Information  is  confusing  regarding  the  coronary 
effects  of  khellin,  a  drug  used  in  the  eastern  Medi- 
terranean regions  since  ancient  times  in  renal  colic 
and  ureteral  spasm.  Interest  in  its  possible  cardiac 
effect  arose  as  the  result  of  the  discovery  that,  orally 
or  intravenously,  it  acts  for  many  hours  as  an  ex- 
tremely potent  coronary  vasodilator  in  the  heart-lung 
preparation  and  in  the  heart  in  situ.  In  the  doses 
used,  it  has  no  effect  on  the  general  blood  pressure 
and  does  not  increase  the  oxygen  requirements  of 
the  heart,  i.e.,  it  acts  only  to  relax  the  intrinsic  smooth 
muscle  of  the  coronary  arterioles  (153).  However, 
others  (109)  did  not  find  it  effective  on  the  coronary 
or  systemic  circulation  of  the  anesthetized  dog. 

There  is  little  doubt  that  digitalis  augments 
ventricular  contractility  and  the  peripheral  circulation 
(48,  314).  However,  in  normal  human  subjects, 
strophanthus  apparently  has  a  deleterious  effect 
since  it  decreases  cardiac  work  and  efficiency  without 
altering  coronary  flow,  oxygen  supply,  or  usage  of 
the  myocardium  (31).  Conversely,  in  the  patient  with 
congestive  heart  failure,  it  has  a  salutary  effect  by 
acting  to  increase  cardiac  work  and  efficiency  without 
using  more  oxygen  or  altering  the  coronary  circula- 
tion. This  is  another  case  in  which  the  action  of  a 
drug  is  entirely  different  in  the  normal  subject  from 
what  it  is  in  the  diseased  subject. 

Ever  since  Favarger  (110),  in  1887,  claimed  that 
excessive  tobacco  smoking  produced  coronary  vaso- 
constriction which,  repeated  over  many  years, 
gradually  resulted  in  organic  heart  disease,  tobacco 
has  been  considered  an  important  cause  of  coronary 
disease.  The  alterations  of  the  ECG  (T-wave  depres- 
sion and  sagging  of  the  S-T  segment)  and  of  the  BCG 
in  the  normal  heart,  or  the  heart  with  coronary 
arterial  disease,  that  follow  inhalation  of  tobacco 
smoke  or  administration  of  nicotine,  have  been 
generally  thought  to  result  either  from  coronary- 
arterial  constriction  or  from  an  increase  in  the  work 
of  the  heart  beyond  the  capacity  of  the  coronary 
arteries  to  supply  the  necessary  metabolic  require- 
ments of  the  myocardium.  Observations  on  the 
normal  heart  of  the  anesthetized  dog  do  not  support 
this  view.  Intracoronary  nicotine  injection  greatly 
increases  myocardial  contractility,  and  in  dogs  pre- 
treated  with  Dopa,  nicotine  increases  considerably 
the  myocardial  catecholamine  concentration  (202). 
The  circulatory  responses  to  administration  of 
cigarette  smoke  or  nicotine  generally  include  elevation 
of  heart  rate,  blood  pressure,  cardiac  output,  cardiac 


work,  left  coronary  flow,  myocardial  oxygen  usage, 
and  a  decrease  in  coronary  vascular  resistance.  The 
coronary  oxygen  extraction  may  be  decreased,  and 
often  the  oxygen  usage  may  be  transiently  unchanged 
or  decreased  (213).  These  responses  can  all  be  blocked 
by  injection  of  tetraethylammonium  chloride.  These 
effects  parallel  those  observed  with  epinephrine 
injection  and  are  presumably  related  to  its  release. 
The  response  to  nicotine  of  the  coronary  flow,  in  dogs 
with  coronary  insufficiency  from  coronary  arterial 
ligation  or  gradual  coronary  artery  narrowing,  is 
considerably  less  than  in  dogs  with  normal  coronary 
arteries  (20);  in  the  isolated  atherosclerotic  rabbit 
heart,  it  decreases  coronary  flow  (364).  In  normal 
man,  earlier  findings  indicate  that  cigarette  smoking 
increases  coronary  blood  flow  and  heart  rate,  and 
decreases  coronary  vascular  resistance  in  the  presence 
of  reduced  systemic  dynamics,  whereas  in  patients 
with  coronary  artery  disease,  smoking  causes  no 
appreciable  change  in  coronary  flow  and  myocardial 
oxygen  consumption  in  the  presence  of  increased 
heart  rate,  blood  pressure,  cardiac  output,  and  cardiac 
work  (304).  This  suggests  that  the  electrocardio- 
graphic changes  observed  during  smoking  are  the 
result  of  a  relatively  deficient  oxygen  supply  to  the 
myocardium  in  the  presence  of  increased  oxygen 
needs  (increased  cardiac  work).  Later  reports  from 
the  same  laboratory  indicate,  in  subjects  both  normal 
and  with  coronary  artery  disease,  that  smoking 
increases  heart  rate,  blood  pressure,  and  left  ventricu- 
lar work  but  does  not  alter  coronary  flow  or  cardiac 
oxygen  usage  (306).  Decision  as  to  the  action  of 
smoking  and  nicotine  in  human  subjects  must  be 
deferred  until  the  various  neurohumoral  responses 
evoked  are  better  understood  and  better  methodology 
is  available. 

Certain  agents  which  increase  coronary  blood  flow 
will  not  be  discussed  because  of  the  scant  information 
available.  Isoproterenol,  histamine,  antihistamines, 
heparin,  Dicumarol,  ethanol,  5-hydroxytryptamine, 
Amplivix,  and  RA-8  increase  coronary  flow  in  animal 
preparations  (62,  200,  224,  238,  299,  384).  Reports 
are  conflicting  regarding  Metrazol,  quinidine, 
quinine,  and  morphine  (299,  318,  384).  Only  two 
drugs,  Pitressin  and  angiotensin,  decrease  coronary 
blood  flow  without  a  decrease  in  central  blood 
pressure  (150). 

For  clinical  use  in  angina  pectoris,  drugs  are 
evaluated  in  patients  by  methods  involving  their 
ability  to  alter  the  electrocardiographic  response  to 
an  exercise  test  or  by  drug-placebo  (double  blind) 
studies  (70,   157).  The  selection  of  patients  for  these 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


trials  is  very  difficult  due  to  the  variability  of  the 
disease  and  its  response  to  many  extraneous  factors. 
Nitroglycerin  remains  the  only  universally  preferred 
treatment.  Other  agents,  including  the  long-acting 
nitrates,  have  received  some  favorable  but  also  many 
unfavorable  reports.  The  mode  of  action  of  the  mono- 
amine oxidases  is  unknown  although  the  clinically 
beneficial  but  toxic  iproniazid  has  been  demonstrated 
to  increase  coronary  flow  and  depress  cardiac  con- 
traction in  isolated  hearts  (160).  Anticholesterol 
agents  and  thyroid  are  used  in  the  hope  of  decreasing 
the  atherosclerotic  process,  but  long-term  studies  are 
needed  to  assess  their  value.  However,  study  of 
hyperthyroid  patients  shows  that  their  myocardial 
oxygen  utilization  is  increased  more  than  would  be 
expected  from  the  increased  heart  rate  (3 17)- 

Table  1  is  a  compilation  of  data  concerning  the 
action  of  the  vasopressor  agents  most  commonly  used 
in  cardiogenic  shock.  Since  most  of  these  studies  were 
performed  in  normal  animals  or  man,  the  question 
again  arises  whether  the  information  can  be  applied 
to  the  diseased  state.  Against  such  application  is  the 
demonstration  that  drugs  may  act  differently  in  a 
normal,  as  compared  to  a  failing  heart,  i.e.,  mephen- 
termine  may  exert  a   myocardial  oxygen-conserving 


effect  in  failing  animal  hearts  but  an  oxygen-wasting 
action  in  normal  hearts  (391).  Since  the  etiology  of 
cardiogenic  shock  is  undetermined  (decreased  pe- 
ripheral resistance,  or  myocardial  failure  or  both), 
controversy  exists  regarding  its  treatment.  The 
question  concerns  whether  an  agent  should  be  used 
which  not  only  increases  coronary  flow  and  blood 
pressure  (methoxamine),  but  also  stimulates  the 
myocardium  and,  therefore,  increases  myocardial 
oxygen  consumption  (epinephrine,  levarterenol, 
metaraminol,  and  mephentermine)  (13,  237).  It 
appears  that  clinical  results  favor  the  latter  concept, 
for  levarterenol  has  met  with  the  most  success.  Also, 
in  animal  studies  the  vasopressor  agents  which  stimu- 
late myocardial  contractility  and  lower  atrial  pressure 
are  more  beneficial  to  the  "failing"  heart  (332). 
However,  methoxamine  has  been  shown  to  be  of 
use  for  increasing  the  blood  pressure  and  coronary 
flow  in  hemorrhagic  shock  in  animals,  and  also  in 
cardiogenic  shock  in  patients  (13).  A  useful  agent  for 
cardiogenic  shock  should  increase  coronary  flow, 
stimulate  myocardial  contractility,  and  raise  the 
blood  pressure  and  cardiac  output,  but  should  not 
increase  myocardial  oxygen  consumption  in  relation 
to  its  workload.  It  was  pointed  out  above  that  myo- 


table   1.  Pressor  Agents  Used  in  Cardiogenic  Shock* 


Drug 

Route 

Blood 
Pressure 

Systolic 
Diastolic 

Heart 
Rate 

Myo- 
cardial 

I'mM  r   ci] 

Con- 
traction 

Coro- 
nary 
Blood 
Flow 

Myo- 
cardial 

o2 

Uptake 

Coro- 
nary 
A-V  C: 
Differ- 
ence 

Cardiac 
Output 

Cardiac 
Work 

Cardiac 
Effi- 
ciency 

Total 
Periph- 
eral Re- 
sistance 

Right 
Atrial 
Pres- 
sure 

Epinephrine 

1.  V. 

+  /- 

+  (±) 

(+) 

(+) 

(+) 

(-1 

+ 

+ 

(-) 

— 

(Adrenaline) 

I.  c. 

(+) 

c+) 

(+) 

(+) 

Levarterenol 

I.  V. 

+  /  + 

-<±) 

(+) 

(+) 

(+> 

(-) 

-(±) 

+  (+.) 

(-) 

+ 

(-) 

(Levophed) 

I.  c. 

(+) 

(+) 

(+) 

(+) 

Ephedrine 

1.  V. 

I.  c. 

+/o 

+ 

(±) 

(+) 

+  (±) 

+ 

- 

Metaraminol 

I.  V. 

+  /  + 

_ 

(+) 

(+> 

o(±) 

+ 

+ 

(-) 

(Aramine) 

I.  c. 

(+) 

(+) 

Mephentermine 

I.  V. 

+  /  + 

— 

(+) 

(+) 

(+) 

(-) 

0(±) 

+ 

(-) 

+  (0) 

(") 

(Wyamine) 

I.  c. 

(+) 

<+) 

Phenylephrine 

I.  V. 

+  /+ 

— 

(+) 

(  +  ) 

± 

+ 

+ 

+  t 

(Neosynephrine ) 

I.  c. 

(+) 

(+) 

Methoxamine 

I.  V. 

+  /  + 

— 

(0) 

(+) 

(-) 

(-) 

(+) 

(+) 

(Vasoxyl) 

I.  c. 

(O) 

(0) 

*  Results  in  man.  Figures  in  parentheses  indicate  if  dogs  react  differently  or  if  only  dog  results  are  available. 
Key:  I.  V.  =  intravenous;  I.  C.  =  intracoronary ;  +  =  increase;  o  =  no  change;  —   =  decrease;  ±   =  variable  effects  or 
conflicting  data;  t  =  venous  pressure. 


BLOOD    SUPPLY    TO     THE    HEART 


1^6 


3»3 


cardial  contractility  and  oxygen  consumption  may  be 
dissociated.  Such  drugs  may  be  available  but  more 
experimental  proof  is  necessary. 


CORONARY    ARTERY    DISEASE 

The  basic  pathological  lesion  in  coronary  artery 
disease  is  the  atheroma  which  eventually  leads  to 
narrowing  or  occlusion  of  the  coronary  artery  lumen 
by  progressive  intimal  thickening,  intimal  ulceration, 
hemorrhage  or  superimposed  thrombosis.  Thrombosis 
on  an  arteriosclerotic  basis  (43%),  arteriosclerosis 
with  and  without  infarction  (41%),  and  intramural 
hemorrhage  (8'c),  also  presumably  on  an  arterio- 
sclerotic basis,  account  for  about  go  per  cent  of 
coronary  artery  lesions  (379).  Coronary  artery 
narrowing  or  occlusions  are  limited  to  the  three 
main  coronary  arteries  (50  '"< )  and  their  primary 
branches  (50%),  and  are  almost  entirely  epicardial 
(100).  The  lesions  are  localized,  segmental,  and 
multiple  (avg.  2.5/heart),  and  70  per  cent  occur 
within  3  to  4  cm  of  the  coronary  ostia  (39,  184). 
As  a  result  of  this  occlusive  process,  the  myocardial 
circulation  is  reduced  to  a  variable  degree,  depending 
upon  the  nature  and  extent  of  the  lesion  and  the 
extent  to  which  intercoronary  artery  collateral 
development  takes  place.  Serious  consequences  occur 
when  the  extent  of  the  former  is  large  or  the  latter 
mechanism  fails  to  compensate  for  the  ischemic 
changes  produced  by  the  atherosclerotic  process. 
The  following,  singly  or  together,  may  then  take 
place:  angina  pectoris,  myocardial  infarction, 
mechanical  failure,  or  sudden  death. 

Since  Heberden's  classic  description  in  1  768  of  the 
syndrome  of  angina  pectoris,  much  effort  by  medical 
investigators  has  been  directed  toward  this  problem. 
While  there  are  some  dissenting  voices  (297),  general 
consideration  indicates  that  the  production  of  pain 
arises  from  stimulation  of  sensory  cardiac  nerve 
endings  which,  in  turn,  arises  from  imbalance  in  the 
heart  between  supply  and  demand  of  oxygen.  Sensory 
nerve  endings  of  the  heart  (and  aorta)  are  present  in 
the  myocardium,  endocardium,  and  epicardium, 
and  in  the  adventitia  of  the  coronary  arteries.  Their 
associated  neurones  converge  in  the  periarterial 
plexus  of  the  coronary  arteries,  continue  through  the 
superficial  and  deep  cardiac  plexuses  and  course  in 
the  middle  and  inferior  cardiac  nerves  to  join  the 
corresponding  cervical  ganglia  of  the  sympathetic 
chain.  These  centrally  bound  fibers  then  descend  to 
the  upper  thoracic  ganglia  and  reach  their  cells  in  the 


spinal  ganglia  by  passing  through  the  white  rami 
communicantes  into  the  first  thoracic  and  upper  4  or 
5  intercostal  nerves.  They  cross  to  the  opposite  spino- 
thalamic tract  and  course  through  the  brain  stem  to 
the  thalamus  (397,  401). 

From  the  preceding,  it  is  obvious  that  pain  could 
be  relieved  in  different  ways:  by  raising  the  cerebral 
level  or  threshold  for  pain  perception,  by  attenuation 
of  factors  in  the  environment  that  lead  to  stimulation 
of  the  cardiac  pain  end  organs,  by  the  induction  of 
proper  coronary  vasodilatation.  However,  the  physio- 
logical evaluation  of  angina  pectoris,  and  of  the 
effects  of  medical  and  surgical  therapy  on  it,  is 
limited  to  study  of  the  relief  of  the  angina  of  effort  in 
cases  where  attempts  are  made  to  delete  the  sub- 
jective element  of  pain,  and  to  the  measurement  in 
equivocal  cases  of  the  coronary  flow  response  to 
vasodilator  drugs  such  as  nitroglycerin  to  determine 
the  ability  of  the  coronary  bed  to  dilate  on  demand. 
The  latter  is  predicated  upon  the  experimental 
finding  in  advanced  coronary  artery  disease  of 
fixation  of  the  coronary  flow  when  challenged  by 
nitroglycerin  (44).  Whether  the  ability  of  a  drug  to 
diminish  anginal  episodes  or  to  improve  the  electro- 
cardiographic response  in  exercise  is  an  objective 
measure  of  positive  benefit  to  a  stressed  myocardium 
is  still  debatable.  This  is  so  because  it  is  not  known 
to  what  extent  the  influence  of  the  physiology  of 
sensation  on  angina  has  been  removed,  and  the 
assumption  must  necessarily  be  made  that  the  electro- 
cardiographic response  correctly  indicates  myocardial 
hypoxia  or  ischemia. 

As  yet,  experimental  studies  directly  attacking  the 
problem  of  coronary  atherosclerosis  have  not  been 
productive  in  elucidating  the  mechanism  of  or 
prevention  of  the  lesion.  However,  the  functional 
consequences  and  compensatory  physiological  re- 
sponses to  controlled  experimental  coronary  con- 
striction and  occlusion,  or  to  the  loss  of  functional 
myocardial  areas  in  acute  and  chronic  animals,  have 
been  extensively  investigated. 

No  standardizable  preparation  with  coronary 
artery  constriction  or  occlusion  similar  to  that  of  the 
human  has  been  worked  out  for  the  experimental 
animal.  Naturally  occurring  or  experimentally 
induced  coronary  lesions  (dog  and  rabbit)  are  similar 
in  many  respects  to  the  human  lesions,  but  the 
endothelium  remains  intact  and  ulceration  and 
thrombus  formation  do  not  occur.  For  acute  or 
chronic  experiments,  an  artery  may  be  tied  off 
abruptly  and  completely  or  partially,  by  inserting  a 
probe  between  the  artery  and  suture  (98),  or  acute 


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(and  at  times  chronic)  preparations  can  be  made  by 
the  intracoronary  artery  injection  of  lvcopodium 
spores  (392)  or  plastic  microspheres  (2,  34).  More 
gradual  constriction  of  the  lumen,  however,  may 
reduce  the  incidence  of  ventricular  fibrillation, 
minimize  infarction,  and  augment  collateral  develop- 
ment. The  introduction  of  intracoronary  clots,  the 
induction  of  coronary  thrombosis  by  electrical  means 
(194,  327),  the  application  to  the  artery  of  adjustable 
Goldblatt  clamps,  irritant  rings  or  bands  of  cellophane 
or  bakelite,  osmotic  clamps,  or  swelling  casein  rings, 
can  all  ultimately  lead  to  complete  coronary  artery 
occlusion  (123,  362,  375).  Unfortunately,  by  none  of 
these  methods  can  the  time  of  complete  occlusion  be 
known  in  vivo,  nor  could  the  per  cent  reduction  in 
flow  be  predicted  even  if  the  extent  of  local  reduction 
in  vessel  lumen  were  known.  As  in  other  vessels,  the 
effectiveness  of  a  given  localized  constriction  in 
reducing  flow  may  be  large  or  small  and  will  vary  in 
inverse  relation  to  the  peripheral  resistance  of  the 
vascular  bed  and  lumen  of  the  constricted  segment, 
and  in  direct  relation  to  the  flow  velocity,  blood 
viscosity,    and   axial   length   of  the   constricted   area 

(153)- 

The  hearts  of  persons  afflicted  with  the  clinical 
signs  and  symptoms  of  coronary  artery  disease,  or  of 
animals  in  which  coronary  insufficiency  has  been 
experimentally  induced,  generally  present  a  dual 
problem.  The  area  of  the  heart  with  a  normally 
functioning  coronary  arterial  system  carries  much, 
if  not  most,  of  the  burden  of  metabolism  and  work  of 
the  poorly  nourished  myocardium,  in  addition  to  its 
own.  If  the  handicapped  area  of  myocardium  is 
large,  then  the  normal  portion  of  the  myocardium  is 
heavily  loaded  and  stressed  in  its  efforts  to  carry  the 
total  performance  of  the  heart.  In  the  remaining  area 
of  the  myocardium,  i.e.,  that  handicapped  by 
sclerosed  vessels,  or  vessels  not  carrying  a  normal 
supply  of  oxygen  to  the  myocardium,  the  supply  of 
blood  and  oxygen  is  too  small. 

Natural  Responses  oj  the  Normal  but  Overstressed 
Portion  of  the  Myocardium 

If  the  ligation  or  constriction  of  a  coronary  artery 
is  severe  enough,  useful  function  is  lost  within  1  min 
in  the  myocardium  fed  by  it,  since  the  muscle  mass 
which  was  shortening  during  systole  now  bulges  and 
lengthens  (359).  The  fact  that  the  area  lengthens 
rather  than  shortens  during  systole  does  not  mean 
that  the  area  is  not  viable,  but  rather  that  although 
attempting  to  shorten,  the  force  it  exerts  is  so  weak  as 


to  be  overbalanced  by  the  intraventricular  pressure 
which  distends  it.  Since,  as  will  be  discussed  later, 
the  collateral  flow  does  not  increase  for  some  hours, 
any  early  natural  cardiac  compensation  must  occur, 
not  by  improvement  of  the  circulation  in  the  affected 
area,  but  through  enhanced  action  of  the  normal 
myocardium  which  is  not  involved.  Loss  of  contract- 
ing blocks  of  muscle  following  coronary  artery 
occlusion  not  only  reduces  the  total  myocardial  force 
available  for  raising  intraventricular  tension,  but 
some  of  this  pressure  is  spent  in  stretching  the  ischemia 
area  and  thus  is  lost  for  expelling  blood  into  the  aorta. 
The  immediate  consequences  of  this,  producing  a 
hypodynamic  ventricle,  are  a  reduction  in  left 
ventricular  systolic  pressure,  aortic  pulse  pressure, 
systolic  and  diastolic  pressures,  duration  of  systole, 
and,  especially,  stroke  volume  and  stroke  work.  In 
this  situation,  left  coronary  inflow  decreases  con- 
siderably (120,  385).  However,  within  a  few  minutes, 
the  normal  portion  of  the  heart  may  put  into  opera- 
tion compensatory  mechanisms  by  means  of  which 
dynamic  conditions  are  largely  restored  to  normal, 
provided  the  normal  myocardium  is  in  a  good 
responsive  condition.  In  this  situation  of  increased 
cardiac  work  per  unit  of  functioning  myocardium, 
coronary  flow,  arteriovenous  oxygen  difference,  and 
metabolism  of  the  left  ventricle  increase.  The  increase 
in  oxygen  uptake  is  equal  to,  and  at  times  can  be 
much  more  than,  that  lost  by  the  deletion  of  non- 
contractile  muscle. 

However,  not  all  hearts  react  as  well  because  the 
viable  portion  of  the  myocardium  may  not  initially 
respond  to  stretch,  or  the  same  lack  of  response  may 
occur  later  after  an  initial  salutary  response.  This  has 
been  especially  studied  in  dog  hearts  in  which  inter- 
ference with  the  coronary  circulation  has  been  by 
coronary  ligature,  or  by  intracoronary  injection  of 
plastic  microspheres  (2,  33).  This  leads  to  acute  or 
progressive  heart  failure  associated  with  profound 
hypotension,  decreased  cardiac  output  and  stroke 
volume,  and  the  clinical  signs  and  symptoms  of  a 
shock-like  state  similar  to  that  which  occurs  following 
the  loss  of  blood  or  plasma.  The  clinical  inference 
that  this  is  due  to  supervention  of  local  coronary 
spasm  or  peripheral  circulatory  failure  has  not 
received  experimental  support.  Most  evidence  indi- 
cates that  no  primary  insufficiency  of  tfie  resistance  or 
capacity  vessels  exists,  nor  even  any  noxious  reflex  to 
which  the  cause  of  shock  could  be  attributed,  nor  does 
such  shock  arise,  apparently,  from  reflex  coronary 
constriction  in  the  nonoccluded  coronary  artery  (57, 
153,  233,  254).  The  experiments  of  Kuhn  et  at.  (219) 


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1567 


could,  however,  be  interpreted  differently.  There  are 
many  reasons  to  favor  the  view  that  in  this  situation, 
circulatory  failure  not  due  to  severe  irregularity  of 
the  heart  beat  is  due  successively  to:  a)  defection  of 
useful  contractions  in  the  ischemic  area,  b)  a  loss  of 
contractile  energy  through  expansion  of  the  affected 
area  and  d)  failure  of  the  still  viable  fractions  to 
compensate  adequately. 

Since  protracted  hypotension  can,  at  times,  lead  to 
myocardial  damage  and  failure,  and  since  experi- 
mentally the  coronary  collateral  flow  varies  passively 
with  the  systemic  blood  pressure,  attempts  have  been 
made  to  improve  such  hearts  experimentally  and 
clinically  by  drugs  and  a  venoarterial  perfusion. 

The  state  of  the  heavily  stressed  normal  myo- 
cardium could  be  improved  with  drugs  either  by 
increasing  its  oxygen  supply  or  by  using  the  available 
oxygen  more  economically.  The  major  mechanism 
for  increasing  the  oxygen  supply  is  by  increased 
coronary  flow  since,  normally,  the  oxygen  is  largely 
extracted  from  blood  passing  through  the  myo- 
cardium. The  drugs  would  have  to  promote  coronary 
flow  in  the  heavily  loaded  normal  myocardium  in 
which  oxygen  usage,  coronary  flow,  and  coronary 
A-V  oxygen  difference  are  already  at  a  high  level. 
Whether  any  drug  has  the  desired  type  of  dilatation 
(active  myocardial  vessel  relaxation,  decreased  extra- 
vascular  compression,  minimal  increase  in  metab- 
olism and  cardiac  work,  minimal  effect  on  other 
vascular  beds),  and  whether  it  also  increases  ventricu- 
lar efficiency  remains  to  be  determined.  In  the  normal 
dog,  drugs  such  as  papaverine,  nitroglycerin,  epineph- 
rine, aminophylline,  Coramine,  and  khellin  augment 
the  myocardial  coronary  flow  and  oxygen  supply,  but 
generally  at  a  considerable  expense  to  the  heart 
through  decreased  coronary  sinus  oxygen  (with 
nitroglycerin  coronary  sinus  oxygen  is  increased), 
and  increased  cardiac  work  and  metabolism.  In 
normal  man,  sublingual  nitroglycerin  leads  to  an 
increased  myocardial  oxygen  usage  (increased 
coronary  flow  and  constant  coronary  A-V  oxygen 
difference),  with  little  or  no  change  in  cardiac  output 
and  cardiac  work,  and  with  a  decreased  efficiency 
(42).  In  patients  at  rest,  with  coronary  artery  disease, 
coronary  flow  is  normal.  Following  nitroglycerin, 
coronary  flow  and  oxygen  usage  are  unchanged  but 
systemic  blood  pressure,  cardiac  work,  and  cardiac 
output  are  reduced;  hence,  coronary  resistance  is  not 
changed  while  efficiency  is  decreased  (138).  It  would 
thus  seem  that  the  dilator  capacity  of  the  coronary- 
tree  with  coronary  artery  disease  is  exhausted.  The 


mechanism  whereby  nitroglycerin  relieves  pain  is  not 
that  of  general  coronary  dilatation  and  is  unknown. 

The  incidence  of  cardiogenic  shock  complicating 
acute  myocardial  infarction  has  been  reported  as  1 2 
per  cent,  and  mortality  associated  with  this  com- 
plication may  be  in  excess  of  80  per  cent  (3,  121). 
Vasopressor  drugs  have  been  widely  employed  in 
this  situation  (see  table  1  for  details).  The  improve- 
ment that  occurs  in  the  human  heart  with  drugs  such 
as  neosynephrine  and  norepinephrine,  in  the  presence 
of  coronary  insufficiency  and  infarction,  arises 
because  of  a  good  dynamic  response  in  the  normal  but 
overstretched  myocardium.  This  presumably  aug- 
ments the  coronary  collateral  flow  by  increasing  the 
coronary  perfusion  pressure  and  by  making  the  heart 
smaller  (see  section  on  coronary  collaterals). 

Although  the  use  of  vasopressor  agents  may 
reduce  mortality  in  myocardial  infarction  with 
shock,  at  least  half  fail  to  respond.  In  such  patients, 
extracorporeal  circulatory  support  is  being  tried 
whereby  blood  is  pumped  from  a  convenient  vein  to 
an  artery  (14,  357).  The  major  objective  is  to  produce 
a  sustained  increase  in  aortic  pressure  and,  hence,  an 
increase  in  coronary,  cerebral,  and  other  important 
regional  circulations,  and  yet,  without  an  increase  in 
left  ventricular  work  that  might  cause  further  cardiac 
deterioration.  Conclusive  evidence  of  the  benefit  of 
this  procedure  has  not  yet  been  obtained.  In  dogs 
subjected  to  coronary  embolization,  use  of  a  closed- 
chest  extracorporeal  circulation  with  blood  transfer 
from  the  veins  to  the  abdominal  aorta  has  been 
effective  in  restoring  central  aortic  pressure  only  if 
the  aorta  is  occluded  beyond  the  pump  (219). 

Coronary  Artery  Collateral  Circulation 

PREPARATIONS  AND  METHODOLOGIES  FOR  COLLATERAL 

flow  in  animal  and  man.  Most  studies  have  been 
prophylactic  in  nature,  i.e.,  a  potential  stimulus  has 
been  applied  to  the  normal  coronary  circulation 
without  interruption  of  coronary  flow  to  determine 
whether,  following  subsequent  coronary  artery  ob- 
struction, the  coronary  collateral  flow  will  be  in- 
creased. In  only  a  few  instances  has  the  effect  on 
collateral  flow  of  different  variables  been  studied  some 
time  after  creation  of  coronary  insufficiency.  It  is 
unfortunate  that  a  standardized  preparation  of 
coronary  insufficiency  has  not  been  generally  em- 
ployed since  this  is  the  situation  existing  in  man  with 
coronary  artery  disease. 

The  experimental  tools  for  study  of  the  collateral 
circulation  leave  much  to  be  desired.  In  the  experi- 


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mental  animal,  these  are  concerned  with  measure- 
ments of  the  effects  of  various  prophylactic  and, 
occasionally,  postcoronary  occlusion  procedures  on 
the  electrocardiogram,  mortality,  size  of  infarcts, 
exercise  tolerance,  the  coronary  artery  pressure  be- 
yond a  region  of  coronary  artery  occlusion  (the 
so-called  peripheral  coronary  pressure),  and  finally, 
on  the  injectable  and  functional  collaterals  in  the 
presence  of  coronary  insufficiency  or  occlusion.  All 
are  difficult  to  evaluate  because  of  the  considerable 
variability  in  the  size  of  the  naturally  occurring 
collateral  circulation.  The  latter  difficulty  can  be 
significantly  reduced  but  not  eliminated  by  using 
only  animals  showing  large  T-wave  inversion  and 
S-T  segment  depression  during  temporary  coronary 
artery  ligation.  Experimental  indications  are  that  the 
size  of  the  injectable  collateral  bed  and  the  level  of 
the  peripheral  coronary  pressure  correlate  well  with 
direct  collateral  flow  measurements  (95).  The  latter 
measurement  has  been  widely  used  and  has  given 
considerable  information  (9,  15:3).  The  collateral 
flow  (retrograde  or  backflow)  is  determined  by 
collecting  the  volume  of  blood  flowing  externally 
from  a  tube  inserted  into  the  peripheral  end  of  a 
centrally  occluded  coronary  artery.  This  is  flow- 
before  it  has  passed  through  a  capillary  bed,  i.e.,  it  is 
fully  oxygenated,  and  is  presumably  somewhat  too 
large  because,  in  the  measurement,  it  drains  against 
atmospheric  pressure  whereas,  functionally,  the 
collateral  blood  must  flow  against  the  peripheral 
coronary  resistance  beyond  the  occlusion.  Collateral 
flow  can  also  be  measured  under  selected  circum- 
stances as  it  enters  the  myocardium,  or  after  it  has 
passed  through  a  capillary  bed  and  appears  in  the 
coronary  sinus.  This  can  be  done  when  extracardiac 
tissue  with  a  vascular  stalk  has  been  previously 
applied  to  the  heart  to  stimulate  collateral  develop- 
ment. The  collateral  inflow  can  be  measured  acutely 
in  the  open-chest  dog  by  interposing  a  rotameter  in 
the  vascular  stalk,  or  chronically  by  applying  an 
electromagnetic  flowmeter  to  the  extracardiac  arterial 
pedicle.  The  collateral  contribution  to  the  coronary 
sinus  is  estimated  by  measuring  the  decrease  in  sinus 
flow  after  clamping  the  potential  extracardiac  source 
of  collateral  flow. 

Recent  investigations  indicate  caution  in  the  use  of 
the  directly  measured  collateral  flow.  0)  Rb86 
clearance  studies  estimate  collateral  flow  as  two  to 
three  times  the  directly  measured  backflow,  thus 
suggesting  that  in  addition  to  functioning  inter- 
arterial  channels,  other  vessels  communicate  with  the 
ischemic  zone  at  the  arteriolar  and  capillary  levels 


(235,  247).  This  method,  however,  cannot  be  used  for 
estimating  changes  in  collateral  flow  because  of  the 
unknown  and  variable  extraction  ratio  of  this  sub- 
stance in  the  ischemic  area,  b)  The  small  portion 
(possibly  15%)  of  left  coronary  artery  inflow  not 
recoverable  in  the  coronary  sinus  or  anterior  cardiac 
veins  has  been  largely  accounted  for  by  drainage  of 
the  septal  artery  and  some  branches  of  the  left 
descendens  into  the  right  ventricular  cavity  (265). 
Thus,  in  the  presence  of  coronary  artery  occlusion, 
some  blood  might  perfuse  portions  of  the  septum 
retrogradely  during  systole  when  the  pressure  gradient 
might  be  favorable. 

Tests  of  coronary  collateral  function  in  life  in  the 
normal  and  diseased  heart  of  man  have  been  largely 
restricted  to  monitoring  changes  in  the  electro- 
cardiogram to  exercise  tolerance  and  angina  and, 
after  death,  to  injection  of  the  coronary  collateral 
circulation  at  autopsy  with  opaque  viscous  material 
(338).  In  those  individuals  with  an  occluded  coronary 
artery  ramus  and  undergoing  a  coronary  operation, 
it  would  appear  feasible  to  use  as  an  index  of  collateral 
flow  the  coronary  pressure  beyond  the  occlusion, 
which  can  be  measured  by  simple  needle  insertion. 
This  technique  used  so  successfully  in  animals  has  not 
been  attempted  in  man.  Finally,  coronary  angio- 
graphic studies  by  Sones  (352),  and  others,  have 
demonstrated  collaterals  in  both  normal  and  ab- 
normal hearts.  Whether  this  technique  has  a  future 
in  the  study  of  the  development  and  regression  of 
collaterals  and  atheromatous  lesions  remains  to  be 
seen  (184). 

From  the  preceding  it  can  be  seen  that,  because  of 
our  poor  methodology,  and  especially  because  the 
direct  or  indirect  measurement  of  collateral  flow  has 
not  as  yet  been  made  in  man,  objective  evidence  of 
positive  benefit  to  the  heart  cannot  come  primarily 
from  observations  after  experimental  or  surgical 
maneuvers  or  coronary  surgery  in  man,  but  must 
come  from  the  effect  of  various  procedures  on  coronary 
collateral  function  in  other  animals. 

NATURAL    RESPONSES    OF    THE    CORONARY    COLLATERAL 

circulation.  The  natural  responses  of  the  coronary 
circulation  of  animals  during  experimental  coronary 
artery  constriction  and  occlusion,  which,  presumabh  , 
also  happen  in  the  heart  of  man,  have  been  studied 
extensively. 

Considerable  reduction  in  the  lumen  of  a  coronary 
artery  can  occur  with  minimal  or  no  permanent 
change  in  coronary  flow.  This  is  so  because  the 
coronary  resistance  to  flow  measured  beyond  a  point 


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1569 


of  occlusion  (by  ligation)  of  a  left  coronary  artery 
branch  is  considerable,  being  about  30  20  mm  Hg, 
and  the  central  coronary  resistance  is  quite  low  (153). 
The  effect  of  a  central  constriction  on  coronary  flow 
is  a  function  of  how  much  the  resistance  imposed  by- 
it  is  in  relation  to  the  resistance  in  the  coronary  bed. 
When  the  flow  to  the  bed  is  reduced  by  central 
constriction,  the  peripheral  vessels  dilate  as  a  result 
of  the  associated  ischemia  and  the  flow  may  tend  to 
increase,  the  combined  result  of  which  will  be  a  new 
equilibrium.  Hence,  since  the  peripheral  resistance  in 
the  coronary  bed  is  constantly  changing  and  will  be 
decreased  by  the  anoxia  induced  by  the  central 
constriction,  and  since  the  effect  on  flow  of  any  central 
constriction  of  lumen  is  a  function  of  how  much  that 
resistance  is,  in  relation  to  peripheral  resistance,  no 
predictions  can  be  made  as  to  the  effect  on  blood 
flow  when  the  coronary  artery  is  constricted  by  known 
amounts.  Since  the  peripheral  resistance  is  relatively 
high,  generally  sizeable  reductions  in  lumen  are 
necessary  before  inflow  decreases.  Thus,  the  reduction 
of  lumen  of  a  coronary  vessel  may  be  of  little  func- 
tional importance  to  the  vascular  bed  supplied  by 
that  vessel  when  the  rate  of  flow  is  normal  or  some- 
what low,  but  the  same  constriction  can  seriously 
limit  flow  to  the  same  bed  just  at  the  time  when  the 
requirements  of  the  latter  are  greatest  and  flow  would 
otherwise  be  much  greater  (153).  Obviously,  how- 
ever, this  compensatory  dilatation  of  the  coronary  bed 
in  the  presence  of  constriction  of  its  central  coronary 
artery  has  a  limit,  and  flow  through  it  will  ultimately 
fall  significantly.  In  part  because  of  this,  the  heart 
has  a  remarkable  ability  to  retain  viability  of  its 
muscle  beyond  a  constriction,  and  significant  changes 
in  the  electrocardiogram  do  not  occur  until  coronary 
inflow  is  reduced  approximately  70  per  cent  (383). 

Studies  have  been  made  of  how  quickly  such  an 
ischemic  area  with  its  potential  collateral  supply  of 
oxygen  becomes  nonviable.  Admittedly,  tests  for 
viability  are  crude.  However,  if  the  criteria  used  are 
an  absence  of  local  action  currents,  failure  of  local 
conduction,  and  lack  of  movement  in  the  presence  of 
generalized  ventricular  fibrillation,  then  viability 
does  not  usually  continue  beyond  an  hour,  although 
occasionally  the  presence  of  local  action  currents  and 
excitability  may  persist  from  2l  2  to  7  hours  (403). 
The  return  of  normal  myocardial  function  has  been 
studied  also  after  reinstitution  of  coronary  flow  in  dog 
hearts  maintained  anoxic  for  prolonged  periods  on  an 
extracorporeal  circulation.  Hearts  maintained  anoxic 
for  up  to  100  min  can  maintain  their  blood  pressure 
on  removal  from  the  extracorporeal  circulation  (65). 


Within  1  min  after  occlusion  of  a  left  coronary 
artery  branch,  the  intracoronary  pressure  beyond  this 
point  drops  to  about  30  20  mm  Hg  and  useful 
function  is  lost,  for  the  muscle  now  lengthens  during 
systole  of  the  left  ventricle  (359).  When,  however, 
the  peripheral  end  of  this  ligated  coronary  artery  is 
permitted  to  bleed  externally,  collateral  arterial 
blood  appears  immediately,  averaging  about  3.0  ml 
per  min  for  about  50  g  of  potentially  infarcted  myo- 
cardium, and  this  blood  can  be  shown  to  come  from 
the  other  nonoccluded  coronary  arteries  (153).  The 
collateral  communications  are  largely  in  the  epicardial 
areas  (40).  Probably  not  more  than  2.4  ml  of  this 
blood  (containing  0.5  ml  oxygen)  would  perfuse  the 
myocardial  bed  if  the  collateral  flow  were  not  per- 
mitted to  bleed  externally.  This  is  because  of  the 
peripheral  resistance  existing  beyond  the  point  of 
occlusion  and  averaging  20  or  so  mm  Hg.  That  most 
of  this  calculated  collateral  flow  actually  traverses 
the  capillary  bed  is  evidenced  by  the  fact  that  the 
electrocardiogram  improves  when  the  collateral  flow 
is  not  permitted  to  bleed  externally  (96,  g8). 

Most  of  these  hearts  with  occlusion  of  a  major  left 
coronary  artery  branch  die  within  a  number  of 
hours.  For  example,  experimental  ligation  of  the  left 
circumflex  coronary  artery  may  give  mortalities  of 
70  per  cent  or  more  (170).  Other  hearts  are  more 
fortunate,  for  if  they  survive  the  first  few  hours,  then, 
for  some  completely  unknown  reason,  within  12 
hours  collateral  flow  starts  to  rise,  doubling  within  2 
days,  and  within  3  to  4  weeks  it  may  approximate  40 
to  100  per  cent  of  normal  inflow  into  that  coronary 
artery.  Almost  all  the  collateral  flow  comes  from  the 
unoccluded  coronary  arteries.  The  myocardial  fibers 
which  were  lengthening  early  after  occlusion  now 
shorten  in  systole.  Concurrently,  the  peripheral 
coronary  pressure  increases  to  values  somewhat  less 
than  the  normal  central  coronary  pressure  and  the 
myocardium  shortens  during  systole  (153). 

MEANS  OF  EXPERIMENTALLY  CHANGING  COLLATERAL 
FLOW  EARLY   AFTER   CORONARY   OCCLUSION.    The   level 

of  collateral  flow  with  its  oxygen  content  is  estimated 
to  be  about  40  per  cent  of  that  calculated  as  necessary 
to  maintain  indefinitely  the  viability  of  this  myo- 
cardium, since  the  oxygen  uptake  of  50  g  of  a  heart 
with  perfused  coronary  arteries  at  rest  and  doing  no 
external  work  approximates  1.2  ml,  as  compared  to 
the  immediately  available  collateral  oxygen  supply  of 
0.5  ml  (249).  Hence,  it  is  important  to  try  to  increase 
immediately  this  collateral  flow  or  backflow.  Except 
for  one  report  on  the  positive  effect  of  nitroglycerin 


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CIRCULATION    II 


(229),  this  level  of  backflow  has  not  been  made  to 
increase  for  8  to  1  o  hours  by  drugs  or  by  any  known 
physiological  means,  such  as  increased  heart  rate, 
increased  flow  in  the  other  coronary  arteries,  in- 
duction of  hypoxia  or  hypoxemia  in  the  other  coronary 
arteries  (204).  Why  the  collateral  flow  remains  fixed, 
why  the  anastomoses  function  as  a  set  of  inert  tubes, 
and  why  they  do  not  exhibit  vasomotion  or  participate 
in  the  vasodilatory  response  of  the  normal  coronary 
bed  are  not  known.  This  situation  contrasts  with  the 
rapid  development  of  collaterals  in  other  vascular 
beds  such  as  the  femoral  and  carotid  arteries  (153). 

This  retrograde  flow  can,  however,  be  greatly 
reduced  by  excessive  stretch  of  the  myocardium  and 
reactive  hyperemia  in  the  other  nonoccluded  coro- 
nary artery  branches.  The  improvement  that  occurs 
with  drugs  such  as  neosynephrine  and  norepinephrine 
in  the  human  heart  in  the  presence  of  coronary 
insufficiency  and  infarction  could  result  from  an 
increase  in  the  oxygen  supply  to  regionally  ischemic 
muscle  (337),  and  from  augmentation  of  the  col- 
lateral flow  through  increase  of  the  coronary  per- 
fusion pressure  and  a  smaller  heart  size.  Spasm  of  the 
coronary  arteries  with  diminished  blood  flow  is  also 
frequently  invoked  to  explain  the  onset  of  episodes  of 
angina  pectoris  and  of  reduction  in  collateral  flow. 
However,  no  firm  conclusion  can  yet  be  drawn  as  to 
whether  flow  in  one  coronary  artery  can  be  in- 
fluenced reflexly  and  adversely  by  impulses  arising 
from  an  intra-  or  extracardiac  source  (see  the  section 
on  Reflexes). 

Lysis  of  coronary  thrombi  induced  experimentally 
can  be  observed  to  follow  fibrinolytic  therapy. 
Whether  this  will  change  the  evolution  of  early 
myocardial  infarction  and  result  in  salvage  of  ischemic 
tissue  without  collateral  development  has  not  yet 
been  determined  (276). 


collateral    stresses    to    which    the    hearts    have    been 
previously  exposed. 

Evidence,  largely  from  the  classical  work  of  Zoll 
et  al.  (411),  indicates  that  the  incidence  of  injectable 
coronary  artery  collaterals  is  quite  small  in  normal 
human  hearts,  but  is  greatly  increased  in  the  presence 
of  coronary  artery  constriction  or  occlusion.  There  is 
also  evidence  in  different  species  that  nature  adopts 
prophylactic  measures  to  protect  some  hearts  against 
subsequent  coronary  artery  occlusion.  The  coronary 
vessels  appear  to  be  capable  of  setting  up  or  enlarging 
anastomoses  between  themselves  without  the  stimulus 
of  coronary  occlusion  or  insufficiency.  Presumably, 
this  is  due  to  some  form  of  antecedent  stress.  In  these 
hearts,  stresses,  some  known  but  mostly  unknown, 
prophylactically  enhance  the  potential  collateral 
circulation  without  the  stimulus  of  coronary  occlusion 
or  constriction.  These  are  exemplified  in  man  by  the 
increase  in  the  incidence  of  the  injectable  coronary 
arterial  collateral  bed  in  the  presence  of  hypertrophy, 
valvular  disease,  cor  pulmonale,  anemia,  and  prob- 
ably high  altitude  (38,  412;  also  Rotta,  personal 
communication).  This  is  exemplified  in  the  pig  by  an 
increase  in  the  injectable  collaterals  in  the  presence  of 
anemia  (39,  412),  and  in  the  dog  by  an  increase  in 
both  the  injectable  and  functional  collaterals  in  the 
presence  of  high  altitude  (Rotta,  unpublished  ob- 
servations), and  transfused  anemia  (97).  No  good 
experimental  evidence  exists,  however,  to  indicate 
that  physical  exercise  per  se  augments  prophylacti- 
cally the  collateral  flow  as  measured  in  a  normal 
coronary  artery  immediately  after  its  occlusion. 
The  injectable  coronary  collateral  bed,  however,  is 
stated  to  increase  in  exercised  rats  (360).  Individuals 
who  escape  serious  consequences  from  coronary 
occlusion  may  well  be  those  whose  collaterals  have 
been  previously  expanded  by  such  means. 


RESPONSE  OF  THE  CORONARY  COLLATERAL  CIRCULATION 
TO     NATURALLY     OCCURRING     PROPHYLACTIC     STIMULI. 

As  indicated  earlier,  the  intercoronary  arterial  com- 
munications are  generally  small  in  normal  man, 
fewer  than  10  per  cent  having  anastomoses  with 
diameters  of  40  p.  or  more  (39).  However,  others  using 
corrosion  and  injection  techniques  found  anastomoses 
of  greater  size  and  with  greater  frequency  (18,  226, 
371).  The  coronary  arterial  tree  of  the  pig  is  strikingly 
similar  to  that  of  man  (96,  289),  while  in  the  dog  the 
anastomoses  are  larger  and  more  frequent.  These 
differences  in  collateral  function  might  be  explained 
on  a  technical  basis  or  as  fundamental  species  varia- 
tions; however,  they  could  be  related  to  the  types  of 


MEDICAL,  PHYSIOLOGICAL,  AND  SURGICAL  ATTEMPTS  TO 
IMPROVE  THE  CORONARY  ARTERY  COLLATERAL  CIRCU- 
LATION prophylactically.  Either  before  or  after 
establishment  of  coronary  insufficiency,  it  should  be 
possible  to  improve  the  state  of  the  heart  of  dog  or 
man  by  augmentation  of  the  coronary  artery  col- 
lateral circulation  which  naturally  functions,  by 
retrograde  perfusion  of  the  ischemic  coronary  bed 
with  arterial  blood,  or  by  elevation  of  the  ventricular 
fibrillation  threshold.  In  man,  in  addition,  positive 
and  subjective  benefit  could  arise  through  psychogenic 
effects  which  are  not  necessarily  related  to  the  heart. 
Chronic  experiments  have  produced  no  good 
evidence  to  indicate  that  any  drug  promotes  collateral 


BLOOD  SUPPLY  TO  THE  HEART 


'57' 


flow  or  reduces  the  size  of  infarcts  produced  by  subse- 
quent coronary  artery  ligation  (380,  404).  The  alleged 
favorable  effect  on  survival  of  the  use  of  drugs  such  as 
papaverine  or  quinidine  is  better  explained  by  their 
known  action  in  raising  the  fibrillation  threshold  and 
in  reducing  myocardial  excitability  (384). 

The  capable  experimental  coronary  surgeon  has 
been  able  to  improve  considerably  on  the  state  of 
such  hearts.  Much  of  the  advancement  in  the  surgical 
and  physiological  fields  has  arisen  from  the  pioneer 
investigations  and  stimulus  of  Beck  (19,  50,  255). 
The  procedures  used  include  section  of  the  cardiac 
sympathetic  nerves  (178),  induction  of  myocardial 
hypoxia  by  various  manipulations  of  the  coronary 
venous  system  or  by  a  coronary  fistula  (19,  79,  95, 
158),  production  of  mechanical  and  chemical 
pericarditis  between  the  epicardium  and  pericardium 
to  use  the  extracardiac  anastomoses  (19,  178), 
application  of  extracardiac  tissue  to  the  heart  (271, 
324,  372,  373),  internal  mammary  artery  ligation 
(99),  sham  operations  (1,  19,  85),  coronary  endarterec- 
tomy  (241,  326),  and  coronary  artery  bypass  (171 ). 

Many  of  these  procedures  in  the  experimental 
animal  are  of  positive  benefit  to  the  heart  and  give 
immediate  or  sustained  protection  against  subsequent 
ligation  of  a  major  coronary  artery  ramus.  Ligation 
of  a  major  ramus  of  the  left  coronary  artery  causes 
about  a  70  to  90  per  cent  mortality  within  the  first 
1  to  2  hours,  and  chronically  there  is  considerable 
infarction  (95).  When  partial  or  complete  occlusion  of 
the  coronary  sinus  precedes  coronary  artery  ligation, 
or  when  a  portion  of  the  coronary  bed  is  perfused  in 
retrograde  fashion  by  connecting  the  coronary  sinus 
to  an  artery,  the  immediate  mortality  is  reduced  con- 
siderably. With  the  exception  of  section  of  cardiac 
sympathetic  fibers  and  internal  mammary  artery 
ligation,  most  other  procedures — chronic  coronary 
venous  maneuvers,  application  of  various  chemical 
and  mechanical  irritants,  separately  or  in  combina- 
tion, and  application  of  extracardiac  tissue  to  the 
heart,  generally  lead  to  a  significant  reduction  in 
mortality  and  infarction  (there  are,  however, 
exceptions)  (124).  There  is  an  increase  in  the  in- 
jectable and  functional  collaterals  with  the  chronic 
coronary  venous  maneuvers  and  with  the  application 
of  mechanical  and  chemical  irritants  to  the  heart. 
The  level  of  collateral  flow,  5  to  12  ml  in  most  in- 
stances, considerably  exceeds  the  control  retrograde 
flow  of  3  ml  with  acute  artery  ligation  alone.  Accord- 
ingly, it  is  deduced  that  these  surgical  maneuvers 
give  sustained,  and  in  the  case  of  the  coronary  venous 
maneuvers,  immediate  protection  against  ligation  of  a 


major  coronary  artery  branch.  The  retrograde  flow  in 
the  chronic  experiments  equals  or  exceeds  that 
estimated  to  be  necessary  to  maintain  viability. 

Cardiac  benefit  from  these  procedures  could  arise 
from  retrograde  flow  of  blood  from  the  superficial 
veins  through  the  capillary  bed,  from  development  of 
intra-  and  extracardiac  collaterals,  or  from  elevation 
of  the  ventricular  fibrillation  threshold,  thus  giving 
nature  time  to  develop  additional  collaterals  to 
sustain  the  heart.  There  are  no  critical  experiments 
to  prove  that  with  the  acute  coronary  venous  maneu- 
vers, protection  against  fibrillation  and  death  is 
supplied  by  blood  flowing  in  a  retrograde  direction 
from  coronary  vein  to  capillary  to  ventricular  cavity. 
Acute  perfusion  of  the  coronary  sinus  with  arterial 
blood  at  or  near  aortic  blood  pressure,  or  acute 
ligation  of  the  coronary  sinus,  results  in  venous  con- 
gestion of  the  left  heart  with  an  increased  coronary 
venous  pressure,  at  times  equal  to  the  aortic  pressure, 
a  diffuse  myocardial  hemorrhage  (with  the  exception 
of  the  septum  which  remains  pink  in  color),  and  a 
sizeable  reduction  in  left  coronary  inflow  and  cardiac 
output.  When  the  peripheral  portion  of  the  occluded 
coronary  artery  is  permitted  to  bleed  externally,  the 
measured  backflow  is  of  highly  reduced  blood  and  the 
volume  is  increased  greatly  (to  15  ml  or  more)  over 
that  which  occurs  with  acute  coronary  artery  ligation 
alone  (153).  It  is  very  important  to  know  that  this 
blood  can  be  shown  to  have  traversed  the  capillary 
bed  of  the  occluded  coronary  artery  in  a  reverse 
direction.  However,  proof  is  lacking  that,  when  the 
ligated  coronary  artery  is  not  permitted  to  bleed 
externally,  flow  from  the  superficial  coronary  veins  is 
diverted  through  the  capillary  bed  of  the  left  myo- 
cardium and  then  into  the  left  ventricular  cavity. 
Actually,  the  development  of  extreme  myocardial 
embarrassment,  together  with  the  fact  that  most  of 
left  coronary  artery  inflow  and  the  blood  entering  the 
coronary  sinus  from  the  shunt  can  now  be  recovered 
in  the  anterior  cardiac  veins  of  the  right  ventricle 
(153),  offers  not  quite  certain  evidence  that  the  deep 
ventricular  drainage  channels  are  not  used.  However, 
the  high  values  for  venous  pressure  in  the  coronary 
sinus  and  the  augmentation  of  peripheral  vascular 
pressure  and  retrograde  flow  which  appear  in  the 
left  coronary  artery  immediately  after  left  coronary 
venous  ligation  decrease  after  a  time  interval  (up  to 
30  days)  to  values  only  slightly  above  normal  (153). 

The  observation  that  these  procedures  can  elevate 
the  ventricular  fibrillation  threshold  suggests  but 
does  not  prove  that  this  is  a  major  mechanism  of 
protection.  In  hearts  with  chronic  application  of  these 


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CIRCULATION    II 


various  latter  maneuvers,  protection  in  large  part, 
and  in  many  instances,  is  probably  afforded  by  the 
augmented  collateral  circulation.  For  example,  with 
an  aorta-coronary  sinus  shunt,  the  backflow  of  i  o  to 
12  ml  of  arterial  blood  exceeds  that  calculated  to  be 
necessary  for  viability  and  persists  for  at  least  a  year 
and  even  after  loss  of  function  of  the  shunt  (95).  But 
since  most  hearts  following  coronary  artery  ligation 
die  within  24  hours,  since  the  usual  retrograde  flow 
observed  with  these  procedures  is  not  large,  and  since 
sham  operation  involving  manipulation  of  the  heart 
at  times  increases  collateral  flow  or  gives  sustained 
protection  against  coronary  occlusion,  or  both,  the 
possibility  must  be  entertained  that  there  may  be  no 
specific  effect  of  some  of  the  maneuvers;  they  may 
act  by  raising  the  ventricular  fibrillation  threshold 
thus  giving  time  for  collaterals  to  develop. 

In  some  procedures  that  apply  extracardiac  tissue 
to  the  heart,  such  as  a  pedical  skin  flap  (271),  or  an 
internal  mammary  artery  ligation  (99)  or  its  myo- 
cardial implantation  (324),  the  collateral  flow  does 
not  increase.  These  studies,  however,  are  incomplete. 
Further  work  should  be  done  to  determine,  in 
addition  to  the  usual  arterial  collateral  flow  measure- 
ments, whether  blood  actually  flows  from  the  extra- 
cardiac  tissue  through  the  capillary  bed  of  the 
myocardium  into  the  coronary  sinus  or  other  coronary 
venous  outflow  channels.  Despite  some  positive  find- 
ings, no  firm  conclusion  can  be  drawn  (372,  373). 

ATTEMPTS  TO  IMPROVE  THE  COLLATERAL  CIRCULATION 
AFTER     CORONARY     ARTERY     OBSTRUCTION     IN     ANIMALS 

and  man.  As  already  indicated,  immediate  or  early 
augmentation  of  the  coronary  collateral  circulation, 
beyond  that  occurring  naturally  following  marked 
coronary  constriction  or  occlusion,  has  not  been 
demonstrated.  Neither  experimental  estimation  of  a 
favorable  delayed  or  chronic  collateral  response 
(decrease  in  infarct  size  and  increased  injectable 
collateral  bed  or  collateral  flow)  to  drugs  has  been 
demonstrated  (379,  412).  However,  the  following 
evidence  of  positive  benefit  has  been  reported :  a) 
Treadmill  exercise,  when  added  to  a  pre-existing 
coronary  insufficiency,  appears  to  increase  the 
collateral  flow  to  a  level  greater  than  with  coronary 
constriction  alone  (98).  b)  In  the  presence  of  aneroid- 
induced  chronic  left  coronary  insufficiency  and 
epicardectomy,  the  addition  of  a  mammary  artery 
implant  or  application  of  an  Ivalon  sponge  is  stated  to 
greatly  extend  the  survival  time  of  the  dog  and  to 
increase  the  functional  communications  of  the 
ischemic   bed    with   the   left   ventricular   cavity   and 


extracardiac  arteries.  This  benefit  does  not  follow  the 
use  of  cardiopneumopexy  or  the  applications  of 
various  other  irritants  to  the  myocardium  (374).  c) 
Experimental  attempts  have  been  made  to  improve 
the  blood  supply  to  the  normal  heart  and  the  heart 
with  infarction  (intracoronary  injection  of  plastic 
microspheres)  by  altering  the  time  of  arrival  of  the 
arterial  pressure  pulse  so  that  the  systolic  pulse 
arrives  during  diastole,  the  period  of  greater  flow  (59, 
188,  203).  The  procedure  is  reported  to  greatly 
reduce  the  mortality  rate  from  the  myocardial  in- 
farction and  to  increase  the  injectable  collateral  bed. 
d)  When  a  pulmonary  artery  to  left  atrial  shunt  is 
added  to  an  already  existing  chronic  occlusion  of  the 
left  circumflex  branch,  coronary  angiograms  and 
vinyl  acetate  casts  show  a  more  rapid  collateral 
filling  and  a  greater  vascularity,  respectively,  than 
following  coronary  artery  occlusion  alone  (30). 

Most  of  the  procedures  designed  to  promote 
collateral  development,  including  the  sham  opera- 
tion, have  been  applied  to  the  heart  of  man  suffering 
from  coronary  artery  disease.  All  appear  to  increase 
to  some  extent  the  work  and  exercise  tolerance  and  to 
decrease  cardiac  pain  (19,  178,  374).  The  summary  of 
over  600  patients  on  whom  the  Beck  operation  was 
performed  may  serve  as  an  example  (51).  These 
observations  are  not  necessarily  explained  on  the 
same  basis  of  the  improvement  in  the  collateral 
circulation  of  the  dog  which  follows  such  procedures. 
This  is  because  in  the  dog  most  surgery  precedes 
coronary  artery  ligation  and  is  designed  to  promote 
collaterals  in  the  presence  of  a  normal  coronary 
circulation,  whereas,  in  the  human,  surgery  follows 
coronary  artery  occlusion  and  is  designed  to  promote 
collateral  circulation  after  the  coronary  insufficiency 
has  been  naturally  established.  In  man,  hypoxia,  the 
greatest  known  vessel  dilator,  and  a  natural  stimulus 
to  collateral  development,  has  already  been  working 
for  many  months.  Since  human  coronary  surgery 
which  follows  coronary  occlusion  has  as  yet  little 
counterpart  in  animal  experiments,  attempts  should 
not  be  made  to  interpret  these  human  coronary 
experiments  on  a  physiological  basis. 

The  explanation  of  the  results  in  man  is  not  clear. 
Patients  treated  surgically  by  epicardial  phenoliza- 
tion,  poudrage,  cardiopneumopexy,  and  bilateral 
internal  mammary  artery  ligation,  although  showing 
marked  relief  of  angina,  do  not  show  electrocardio- 
graphic improvement  or  an  increase  in  coronary  flow, 
or  a  decrease  in  coronary  vascular  resistance  following 
nitroglycerin  (44).  Undoubtedly,  some  subjects  are 
protected  and  live  longer  because  of  the  known  experi- 


BLOOD  SUPPLY  TO  THE  HEART 


1573 


mental  fact  that  handling  the  heart  raises  the  ventricu- 
lar fibrillation  threshold.  Some  may  be  improved  by 
procedures  such  as  de-epicardialization  which  could 
obliterate  the  afferent  pathways  for  pain.  However, 
results  of  the  sham  operation  of  Adams  (1)  and 
Dimond  (85),  involving  only  a  skin  incision,  strongly 
suggest  that  much  of  the  positive  benefit  is  on  a 
psychogenic  basis. 

Coronary  endarterectomy  which  has  been  applied 
to  man  is  on  a  sound  physiological  basis  and  its 
purpose  is  entirely  different  from  the  preceding.  The 
surgeon  directly  reestablishes  coronary  flow  through 
the  original  coronary  artery  by  removing  its  athero- 
sclerotic plug.  It  does  not  require  collateral  develop- 
ment and  should  be  effective  provided  there  exists  a 
gross  coronary  insufficiency  of  blood  beyond  the 
obstruction,  provided  the  vessel  remains  patent  and 
thrombi  do  not  form,  and  provided  there  are  no 
sizeable  atherosclerotic  lesions  beyond  the  region  of 
the  occluded  coronary  artery.  It  is  quite  doubtful 
that  these  criteria  can  be  met  (182).  Preliminary 
experiments  with  the  use  of  endarterectomy  for 
coronary  occlusion  were  apparently  initially  favorable 
to  the  patients,  relieving  their  angina,  and  improving 
their  electrocardiograms  and  work  tolerance  (241, 
326).  However,  most  of  these  patients  have  died,  and 
no  evidence  is  available  that  at  autopsy  the  endarter- 
ectomized  artery  has  remained  patent.  Many  more 
operations  will  have  to  be  performed  to  establish  the 
possible  merit  of  this  procedure  in  humans. 

Finally,  bypass  of  a  length  of  an  occluded  coronary- 
artery  by  anastomosis  of  its  peripheral  patent  end  to  a 
systemic  artery  has  not  yet  been  attempted  in  man. 


In  dogs,  a  nonsuture  anastomosis  by  intima-to-intima 
contact  between  the  left  coronary  artery  and  the  left 
internal  mammary  artery  has  been  highly  successful 
(171).  In  almost  all  the  dogs  (24  of  33),  the  anasto- 
moses have  been  demonstrated  to  be  patent  and 
without  myocardial  infarction  as  evidenced  by  gross 
observation,  angiography,  and  measurement  of 
coronary  blood  flow  through  the  anastomosis  up  to 
the  time  of  dog  sacrifice  (12-24  months  after  opera- 
tion). Other  technical  achievements  in  this  area 
include  chronic  anastomoses  of  two  branches  of  the 
left  subclavian  artery  to  the  peripheral  and  central 
ends,  respectively,  of  the  left  circumflex  coronary,  the 
central  end  of  the  main  left  coronary  being  tied 
(unpublished  observations),  and  end-to-end  anasto- 
mosis of  the  central  end  of  the  main  left  coronary 
artery  to  the  peripheral  end  of  the  left  subclavian 
artery  (251).  Since  anastomosis  of  a  coronary  artery 
branch  to  a  systemic  artery  is  almost  always  successful 
in  the  dog  in  which  the  anastomosed  vessels  are  only 
2  to  3  mm  diameter,  there  should  be  no  difficulty  at 
all  in  the  human  heart  in  which  the  coronary  artery 
branches  have  a  much  greater  diameter.  This  proce- 
dure might,  therefore,  have  an  application  in  the 
creation  of  a  permanent  new  blood  supply  in  the 
presence  of  coronary  artery  disease  in  man.  One 
should  not,  however,  overlook  a  probably  late  com- 
plication to  successful  coronary  endarterectomy  or 
coronary  bypass  in  man.  In  the  presence  of  such  a 
large  new  blood  supply,  the  existing  collateral  flow 
will  disappear.  If  another  coronary  occlusion  subse- 
quently occurs,  the  patient  will  be  in  difficulty, 
having  lost  his  collaterals. 


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4'- 

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47 


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50. 


51' 


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i58o 


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CIRCULATION    II 


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369.  Van  Citters,  R.  L.,  W.  E.  Ruth,  and  K.  R.  Reismann. 


Effect  of  heart  rate  on  oxygen  consumption  of  isolated 
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Vasko,  J.  S.,  and  D.  C.  Sabiston.  A  study  of  predomi- 
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Vastesaeger,  M.  M.,  P.  P.  Van  Der  Straeten,  J. 
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Vidone,  R.  A.,  J.  L.  Kline,  M.  Pitel,  and  A.  A.  Liebovv. 
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Vineberg,  A.,  and  T.  D.  Deliyannis.  Myocardial  nu- 
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Von  Euler,  U.  S.  Presence  of  a  sympathomimetic  sub- 
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Wang,  H.  H.,  C.  W.  Frank,  D.  M.  Kanter,  and  R. 
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vol.  11. 


yd 


CHAPTER     45 


Maternal  blood  flow  in  the  uterus  and  placenta1 


S.    R.    M.    REYNOLDS  Department  of  Anatomy,  University  of  Illinois  College  of  Medicine,  Chicago,  Illinois 


CHAPTER  CONTENTS 

Comparative  Anatomy  of  Uteri 

Angiogenesis  in  the  Uterus 

Vascular  Connections  of  the  Uterus 

Functional  Implications  of  Venous  Drainage 

Comparative  Anatomy  of  the  Placenta 

Types  of  Placentas 

Placental  Structure  and  Placental  Exchange 

Vascularity  and  Accommodation  of  the  Products  of  Conception 

Menstruation 

Hormones  and  the  Uterine  Vasculature 

Uterine  Contraction  and  Blood  Flow 

Body  Posture  and  Uterine  Contractility 

Estrogen  and  Uterine  Blood  Vessels 

Uterine  Innervation 

Pregnancy  and  the  Uterine  Circulation 


among  the  several  orders  of  mammals,  no  organ 
in  the  body  is  more  varied  in  form  and  size  than  the 
uterus.  One  may  not  properly  speak  of  "the  uterus" 
as  an  organ  in  which  identical  physiological  activities 
take  place  in  the  fulfillment  of  the  purpose  for  which 
a  uterus  exists.  True,  the  uterus  permits  implantation 
of  fertilized  blastocysts,  accommodates  the  products 
of  conception  for  a  normal  span  of  development,  and 
then  delivers  to  the  outside  world  an  organism  or 
organisms  that  can  survive.  Specialized  adaptations 
exist  among  mammals  in  the  form  and  function  of 
the  various  uterine  and  placental  types.  Such  varia- 
tions in  uterine  and  placental  structures,  coupled 
with  specialized  variations  in  cyclic  activity,  serve  to 
render  them  quite  different  from  one  another  while 
achieving  a  common  goal,  namely,  the  production 
of  living  offspring. 

As  a  student  of  physiology,  man  tends  to  be  an- 


1  Prepared  and  typed  under  USPHS  Grant  RG  4728. 


thropocentric;  he  employs  many  kinds  of  animals 
exhibiting  many  types  of  mechanisms  but,  while  ex- 
amining comparative  basic  processes,  he  hopes  to 
understand  himself.  It  is  necessary,  therefore,  that 
insofar  as  present  knowledge  permits,  the  several 
types  of  form  and  function  be  considered. 


COMPARATIVE  ANATOMY  OF  UTERI 

It  is  axiomatic  in  developmental  biology  that 
ontogeny  repeats  phylogeny.  This  is  to  say,  as  one 
passes  from  species  A  to  species  Z  there  are  grades  of 
morphological  complexity  that  can  be  seen.  Similarly, 
in  the  development  of  species  Z,  all  or  most  of  the 
essential  elements  of  species  A,  B,  C,  D,  .  .  .  Z  are 
observable  in  transition  from  a  simple  type  to  a 
complex  type  of  structure.  Although  this  is  an  over- 
simplification of  the  situation,  it  is  generally  true  and 
it  is  as  easily  demonstrable  for  the  uterus  as  with  any 
organ  in  the  body  [Reynolds  (198)]. 

Like  so  many  viscera  of  the  body,  the  uterus  may  be 
characterized  as  starting  as  paired  symmetrical  tubes, 
part  of  the  mullerian  duct  system.  In  monotremes 
(e.g.,  Echidnae),  marsupials  (e.g.,  Marsupialae),  and 
some  rodents  (e.g.,  Leporidae)  at  least,  two  uteri 
remain  separate  throughout  life,  arising  cephalad  at 
the  caudal  end  of  the  fallopian  tube  and  terminating 
caudally  with  independent  cervical  openings  in  the 
vagina.  In  other  species,  the  caudal  ends  of  the  ducts 
fuse  mesially  to  form  a  single  cervical  opening  in  the 
vagina.  Examples  of  this  are  seen  in  certain  rodents 
(e.g.,  Mus  rattus  and  norvegicus),  carnivores  (e.g., 
Canis),  ungulates  (e.g.,  Ovis,  Bovis,  and  Equidae) 
and  many  others.  Continuing  the  extent  of  mesial 
fusion  to  the  ultimate  degree,  the  primates  normally 
have   a   single  uterus,   which   receives  two  fallopian 


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HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


tubes,  and  a  cervix.  These  several  types  of  uteri  are 
recognized  as  the  uterus  duplex,  the  uterus  bicornis, 
and  uterus  simplex;  the  latter  representing,  para- 
doxically, the  most  complicated  organization  of  all, 
being,  as  it  is,  the  fusion  of  paired  simple  ducts  into  a 
single  complex  organ.  Just  as  increasing  degrees  of 
complexitv  of  organization  may  be  seen  throughout 
the  phyla  so,  in  the  development  of  the  uterus  simplex, 
all  the  transitional  stages  of  development  from  the 
duplex  to  the  simplex  form  are  recognized.  Persistence 
of  incompletely  formed  uteri  as  malformations 
sometimes  complicates  the  parturitional  process.  No 
one  has  produced  experimentally  arrested  fusion  or 
partial  development  of  the  uterus  simplex,  probably 
for  the  simple  reason  that  no  studies  of  experimental 
teratogenesis  have  been  made  in  primates. 

Since  the  several  classes  of  uteri  have  in  common  an 
orderly  and  progressively  more  complex  organiza- 
tion, one  might  anticipate  that  there  would   be  an 


FIG.  I.  Comparative  types  of  uteri  from  the  uterus  duplex  to 
the  uterus  simplex  found  in  various  mammals:  .-1,  monotreme 
[Echidna  aculeala);  B,  marsupial  (Didelphis  virginiana);  C,  rodent 
(rabbit);  D,  carnivore  (dog);  E,  ungulate  (mare);  /•',  primate 
(Macacus  rhesus).  [After  Rudolph  and  Ivy,  taken  from  Reynolds 
(198)-] 


orderly  and  progressively  more  complex  organization 
of  the  vasculature  of  the  uterus  among  different 
animals.  So  there  is. 


ANGIOGENESIS    IN    THE    LTERUS 

All  organogeny  takes  place  around  a  primary 
\  ascular  organizational  pattern  [Evans  (71)].  Blood 
vessels  begin  as  a  diffuse  capillary  network,  some 
channels  of  which  become  more  and  more  prominent, 
larger  and  structurally  more  complex  as  arterial  and 
venous  pathways  come  into   being   [Thoma   (233)]. 

Why  this  is  so  is  not  clear,  although  Thoma  has 
postulated  that  the  process  is  governed  in  part  by  the 
hemodynamic  load  imposed  upon  certain  parts  of  the 
delicate  capillary  system.  As  these  pathways  become 
more  defined,  they  give  rise  to  still  further  differ- 
entiation of  more  peripheral  branches.  The  sizes  and 
angles  of  these  branches  are  related  to  certain  physical 
relationships  that  were  first  laid  down  by  Hess  (105) 
on  thermodynamic  grounds,  and  first  given  substance 
experimentally  by  Reynolds  (197)  in  the  developed 
vascular  tree.  However,  more  than  simple  hemody- 
namics is  involved,  since  Price  (177)  has  shown  that 
organogenesis  can  take  place  in  tissue  culture  only  if 
a  semisolid  medium  is  used,  but  not  if  a  liquid  medium 
is  employed.  Thus  the  dependence  or  role  of  vascular 
development  as  a  contributory  mechanism  to  or- 
ganogenesis is  seen  to  be  unessential  for  primary 
organization,  but  to  be  essential  for  subsequent  devel- 
opment. 


VASCULAR    CONNECTIONS    OF    THE    UTERUS 

The  common  vascular  denominator  for  all  uteri  is 
the  pattern  of  vascular  supply  of  blood  to,  and  drain- 
age of  blood  from,  the  uterus.  This  was  certainly  seen 
by  Aristotle,  by  Vesalius,  and  by  Hunter.  It  was  not 
stressed  as  a  vascular  complex,  apparently,  until  the 
early  part  of  this  century  by  Byron  Robinson  (211). 
This  author  compared  in  different  species  the  vascular 
circle  that  starts  in  the  aorta  by  way  of  the  anterior 
division  of  the  internal  iliac  arteries  on  each  side,  or 
may  arise  in  common  with  the  vaginal,  umbilical,  or 
middle  rectal  arteries.  The  uterine  arteries  descend 
in  the  fat  at  the  base  of  the  broad  ligament  and,  going 
between  the  layers  of  that  ligament,  pass  to  the  uterus, 
following  a  tortuous  course.  They  run  along  the 
mesial  sides  of  the  uterus,  giving  off  branches  to  the 
bodv  of  the  uterus  along  the  way.  At  the  cephalic  end 


UTERINE  BLOOD  FLOW 


1587 


fig.  2.  Arrangements  of  arte- 
rial and  venous  pathways  to 
uterus  simplex  (left)  and  uterus 
duplex  (right).  The  "circle"  of 
the  arterial  pathway  is  shown  as  a 
continuous  pathway  from  the 
aorta,  ovarian  artery,  uterine 
artery,  hypogastric  artery  (uterus 
simplex),  femoral  artery,  and 
aorta.  A  similar  circle  exists  in 
the  venous  connections.  [After 
Byron  Robinson  (211).] 


of  the  uterus,  the  arteries  anastomose  with  a  branch  of 
the  ovarian  artery,  one  on  each  side.  The  uterine 
arteries  supply,  therefore,  part  of  the  vagina,  the 
uterus,  and  fallopian  tubes  on  each  side. 

Since  the  ovarian  arteries  arise  from  the  aorta  just 
below  the  renal  arteries,  it  will  be  seen  that  there  is, 
indeed,  a  large  communicating  arterial  circle  supply- 
ing the  uterus  on  each  side  of  the  midline.  In  the  case 
of  partial  or  complete  uterine  fusion  during  develop- 
ment there  is  further  connection  of  the  finer  arterial 
branches  from  both  sides  in  the  body  of  the  uterus 
[Faulkner  (77,  78)].  The  arcuate  arteries  of  the  uterus 
lie  in  the  zona  vascularis  in  the  myometrium.  Myomas 
in  the  smooth  muscle  of  the  uterus  are  singularly 
deficient  in  blood  supply  (see  fig.  3)  [Faulkner  (77), 
Holmgren  (1 13)]. 

We  observe  in  this  arrangement  that  the  uterus 
simplex  is  supplied  from  two  primary  arterial  sources, 
on  each  side,  and  that  where  the  form  of  the  uterus 
permits,  there  is  free  union  between  these.  It  is  possible 
to  see  that  the  uterus,  which  increases  along  with  its 
blood  vessels  many  times  over  in  size  during  gestation, 
is  assured  of  a  reasonably  large  and  constant  head  of 
arterial  pressure  at  all  times. 

The  morphology  of  the  venous  drainage  of  the 
uterus  is  equally  important  for  the  physiological 
changes  that  take  place  in  the  uterus  and  its  circula- 
tion. The  uterine  veins,  without  valves,  arise  from 
within  the  tissues  of  the  uterus  and  enter  the  broad 
ligament   at   numerous   points   in   increasingly   large 


venous  channels  as  smaller  ones  have  united  along 
the  way.  However,  there  are  four  main  venous  paths 
of  exit  from  the  uterus  [Bieniarz  (31)].  In  the  common 
laboratory  animals,  the  veins  of  the  broad  ligaments 
unite  and  form  rather  uncomplicated  plexuses  in  the 
broad  ligament  [Reynolds  ( 1 98)]  receiving  veins  from 
the  uterus  along  the  way.  The  parametrial  veins  join 
with  ovarian  veins  to  drain  blood  toward  their  point  of 
entrance  into  the  inferior  vena  cava  on  the  right  side 
and  the  renal  vein  on  the  left  side. 

As  with  many  parts  of  the  venous  system,  the 
drainage  connections  are  complex,  rather  than  dia- 
grammatically  simple  as  is  commonly  believed.  In 
the  primate,  these  relations  are  more  complicated 
than  in  the  usual  laboratory  animals.  For  example,  in 
the  broad  ligament  of  primates,  there  is  an  extensive 
pampiniform  plexus,  having  multiple  connections 
with  the  pudendal  veins,  the  several  rectal  plexuses, 
the  internal  iliac  veins,  and  inferior  vena  cava.  Not 
only  may  uterine  blood  move  toward  the  heart 
through  the  inferior  vena  cava,  but  through  the 
internal  and  superficial  epigastric  veins  to  the  mam- 
mary and  internal  costal  veins  as  well.  Blood  may 
also,  if  pressure  within  or  upon  the  venous  system 
requires  it,  flow  to  the  ascending  lumbar  veins,  by 
way  of  segmental  connections,  to  the  azygous  and 
hemiazygous  veins. 

The  ovarian  vein  enlarges  greatly  during  pregnancy 
[Borell  &  Fernstrom  (38),  Hodgkinson  (no)].  There 
is  much  current  interest  in  this  subject,  first  stressed 


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CIRCULATION    II 


fig.  3.  Arterial  pattern  of  uterus.  Cleared  preparation.  One 
small  myoma  on  right  side.   [From  Faulkner  (77).] 

by  Davidsohn  (64)  many  years  ago.  Further  assurance 
of  venous  return  exists  by  way  of  multiple  venous 
connections  to  the  vertebral  vein  system,  as  Batson 
(27,  28)  has  emphasized  (see  also  Jeffcoate  (117). 
The  ovarian  "vein"  in  part  is  in  reality  the  tubo- 
ovarian  pampiniform  plexus  which  pours  blood  into 
the  inferior  vena  cava  from  the  right  side,  or  the 
renal  vein  on  the  left.  Other  interconnections  exist, 
also.  However,  sudden  occlusion  of  the  inferior  vena 
cava  can  cause  separation  of  the  placenta  [Mengert 
et  al.  (150)].  Donnelly  (66)  relates  noninduced  pla- 
cental separation  to  gross  abnormalities  of  the 
placenta. 

All  in  all,  within  the  uterus  itself  and  in  the  venous 
systems  of  the  abdominal  cavity  and  body  wall,  there 
are  abundant  intercommunications,  so  that  oppor- 
tunity for  obstruction  to  the  venous  drainage  of  uterine 
blood  is  minimized.  Barcroft  &  Rothschild  (21) 
emphasized  this  with  regard  to  the  rabbit;  Bieniarz 
(31)  has  stressed  it  in  relation  to  the  human.  Oughtred 
&  Reynolds  (165)  demonstrated  the  operation  of  the 


collateral  abdominal  and  somatic  venous  systems  in 
the  dog  when  the  inferior  and  superior  vena  cava 
were  blocked  at  various  levels. 


FUNCTIONAL    IMPLICATIONS    OF    VENOUS    DRAINAGE 

Problems  that  arise  from  malfunctioning  of  the 
venous  system  are  recognized.  In  general,  they  are 
twofold.  In  animals  having  an  erect  posture,  at  least 
in  the  human,  pelvic  congestion  which  is  correctable 
by  operative  procedures  is  known  [Taylor  (230), 
Curtis  et  al.  (58)].  These  contribute  to  endocrine 
disorders  and  a  variety  of  clinical  entities.  The  second 
group  of  functional  disorders  is  related  to  distribution 
of  the  vascular  loads  upon  the  circulatory  system  in 
late  pregnancy  [Bieniarz  (30)].  When  the  placenta  in 
the  human  is  implanted  high  in  the  uterus,  drainage 
by  way  of  the  ovarian  pathways  predominates.  When 
this  happens,  albuminuria,  hypertension,  and  even 
toxemia  frequently  occur.  A  continuous  discharge  of 
several  hundred  milliliters  of  blood  per  minute  into 
the  vena  cava  or  renal  vein  may  complicate  renal  and 
adrenal  blood  flow,  Bieniarz  (31)  postulates.  Ligation 
of  the  vena  cava  above  the  renal  veins  affects  renal 
function  and  possibly  adrenal  gland  activities  as  well 
[Karaev  (126)].  When,  on  the  other  hand,  the  pla- 
centa is  implanted  low  in  the  uterus  simplex,  placenta 
praevia  and  hemorrhage  more  commonly  occur 
[Bieniarz  (30)].  The  former  condition  is  more  frequent 
in  primigravidas,  the  latter,  in  multiparas. 

Although  ovarian  vein  physiology  has  been  im- 
plicated by  deduction  in  the  incidence  of  toxemia 
[Bieniarz  (30)],  other  mechanisms  are  suspect,  also. 
Placental  ischemia  as  a  factor  is  considered  by  Page 
(168).  Saito  (214)  produced  toxemic  signs  in  animals 
with  human  placental  extracts  and  this  is  said  to  be 
an  allergic  reaction  by  Lin  ( 136)  who  sensitized  rats  to 
placental  tissue  by  injection  of  placental  tissue  5 
months  before.  However,  killing  of  the  fetuses  in 
hypertensive  rats  leads  to  lowering  of  blood  pressure 
[Page  (166)].  Examining  the  problem  experimentally, 
Ogden  et  al.  (162)  placed  Goldblatt  clamps  on  uterine 
arteries  in  pregnant  rabbits  and  observed  that  pro- 
gressive hypertension  developed  promptly.  This  was 
relieved  by  removal  of  the  clamps.  Grollman  (87) 
observed  that  induced  hypertension  in  rats  is  reduced 
by  normal  pregnancy,  but  not  by  pseudopregnancy. 
(See   below   discussion    of  the   placenta   as   an   A-V 


fig.  4  (facing  page).  The  uterine  drainage  system  during  pregnancy  (sagittal  view).  Different 
visceral  and  parietal  venous  drainage  routes  are  shown  in  different  colors.  [Reprinted  by  permission 
from  Bieniarz    (31).] 


Cranial  caval  vein 

Thoracoabdominal  network 

Intercostal  veins 

Internal  mammary  vein 

Caudal  caval  vein 
Portal  vein 

Epigastric  superficial  vein "^Ka% 

Epigastric  internal  vein 


\ Dural  and  cerebral  sinuses 

') 
J) 

y 

SI 

J^V- Vertebral  vein  system 

Segmental  communications 

,IAJ7       "  rt8      I  Thoracic  longitudinal 

lf.Ql left     \  veins 

Tubo-ovarian  pampiniform 
plexus 

S}\  Caudal  caval  vein 

Ascending  lumbar  vein 
Mesenteric  inferior 

^t\  VI  -A Sacral  vein 

\WJjjf~  |~  "  ~ Superior  rectal 

Medial  rectal     j  plexuses 
Inferior  rectal    I 
Pudendal  vein 


Caudal  caval  system. 

Uterovenal  visceral  circulation. 

Portal  circulation. 

The  anterior  parietal  abdomino-thoracal  communications. 

Retroperitoneal  and  retropleural  communications  to  the  cranial  caval  system. 

Vertebral  vein  system  to  the  cerebral  sinuses. 


fig.  4.    See  legend  on  facing  page. 


UTERINE    BLOOD    FLOW 


I  591 


Vertebral  plexus +0 brain 


anas+omosi 
por  ro-ovaric 
«<evtra 


fig.  5.  The  uterine  drainage  in  ad- 
vanced first  pregnancy,  with  predomi- 
nantly high  fundal  drainage  through  the 
pampiniform  plexuses  and  ovarian  veins 
toward  the  kidneys,  and  through  visceral 
and  segmental  communications,  toward 
the  portal  circulation,  vertebral  plexus, 
and  brain.  [Reprinted  by  permission 
from  Bieniarz  (31).] 


fig.  6.  Anterior  and  posterior 
view  of  the  uterus  with  the  venous 
vascular  patterns  visible  during 
cesarean  section  and  with  regions 
of  placental  location.  U,  upper; 
M,  middle;  L,  lower  portion  of 
uterus.  [Reprinted  by  permission 
from  Bieniarz  (31).] 


Annul os  view 

shunt.)  A  more  comprehensive  discussion  of  this 
subject  will  be  found  elsewhere  [Reynolds  (198)].  It 
should  be  noted  that  there  is  no  logical  reason  why 
either  the  ovarian  vein  hypothesis  or  the  placental 
ischemia  hypothesis  as  an  etiological  factor  excludes 
the  other. 

The  above  assertion  of  morphological  and  clinical 
facts  makes  it  clear  that  the  change  and  distribution  of 
blood  flow  within  and  from  the  pregnant  uterus  is 
governed  in  part  by  the  site  of  placental  implantation, 
in  part  by  the  change  in  size  of  the  uterus,  and  in  part 
by    the    increase    in    quantity    of  functional    uterine 


POSIlStOK    VIEW 


tissue  during  pregnancy.  Local  or  regional  blood  flow 
is  associated  with  the  supply  of  blood  to  the  uterine 
tissues  and  especially  to  the  placenta. 


COMPARATIVE  ANATOMY  OF  THE  PLACENTA 

As  with  the  above  discussion  of  the  uterus,  it  is 
necessary  to  recognize  that  there  is  a  wide  array  of 
placental  forms.  Although  Mossman  (158)  has  de- 
scribed these  forms  and  noted  their  arrangements 
throughout  the  several  orders  of  mammals,  insufficient 


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CIRCULATION    II 


emphasis  has  been  laid  upon  the  demands  which 
these  several  arrangements  impose  on  the  circulation. 
Further,  just  as  there  are  differences  in  gross  mor- 
phology, so  there  is  still  further  sanation  in  the  micro- 
circulatory  organization  of  the  various  types  of 
placentas.  The  generally  recognized  distinctions  in 
this  regard  are  those  of  Grosser  (88)  who  classifies 
placentas  on  the  basis  of  the  number  and  type  of  tissue 
layers  interposed  between  the  maternal  and  fetal 
bloods.  The  beauty  of  this  system  is  that  tilings  fall 
neatly  into  place.  For  example,  the  epitheliochorial 
type  of  placenta  suggests  that  in  general  there  are 
six  layers  of  tissue  (maternal  endothelium,  connective 
tissue,  and  epithelium  apposed  to  layers  of  fetal 
epithelium,  connective  tissue,  and  endothelium).  The 
simplest  hemochorial  placenta  has  only  fetal  epithe- 
lium, connective  tissue,  and  endothelium  between 
the  two  bloods.  Intermediate  between  these  two  ex- 
tremes are  the  syndesmochorial  (lacking  maternal 
epithelium)  and  the  endothelial  chorial  (lacking  the 
maternal  connective  tissue  and  epithelium). 

To  complicate  the  apparent  simplicity  of  this 
system,  there  is  no  phylogenetic  relationship  between 
the  several  types  of  placentas.  Some  rodents  and 
primates  have  hemochorial,  and  ungulates  have 
epitheliochorial  and  syndesmochorial  types  of  pla- 
centas. Carnivores  do  not  fit  into  an)'  one  group. 
More  disturbing  to  the  simple  view  of  Grosser  (88) 
that  a  neat  classification  of  placental  types  exists 
which  is  based  on  their  microcirculatory  relationships 
is  the  fact  that  careful  re-evaluations  by  placentolo- 
gists  in  recent  years  suggest  that  structural  changes 
take  place  throughout  the  life  span  of  the  placenta; 
the  morphology  is  not  uniformly  constant  with  regard 


to  the  tissues  mentioned  above  [Amoroso  (4),  Huggett 
&  Hammond  (116)].  Amoroso  has  enumerated  a 
wide  range  of  types  and  patterns  of  changes  of  vascular 
arrangements,  not  only  in  commonly  used  laboratorv 
animals  but  in  unusual  ones  as  well.  It  is  found  that 
capillaries  "migrate"  into  intraepithelial  locations. 
One  does  not  find  any  critical  limitation  of  effective- 
ness in  the  transfer  of  metabolites  across  the  various 
"types"  of  placentas  in  terms  of  growth  and  survival 
of  fetuses. 


TYPES    OF    PLACENTAS 

Just  as  there  are  distinguishing  microscopic  mor- 
phological and  physiological  differences  in  the  pla- 
centas of  the  various  species,  there  are  wide  differences 
in  the  forms  of  placentas  [Mossman  (158)].  Apparently 
the  simplest  form  is  the  discoidal  placenta,  represent- 
ing a  single  structure.  This  is  seen  in  such  widely 
different  species  as  hamsters,  mice,  rats,  rabbits, 
guinea  pigs,  and  humans,  to  name  a  few.  The  opposite 
extreme  is  seen  in  the  placental  structures  of  sheep, 
goats,  cows,  mares,  and  many  other  species,  all  un- 
gulates. In  these,  each  developing  embryo  has  a 
complement  of  twenty  or  more  discrete  discoidal 
placental  parts,  called  cotyledons,  each  supplied  by  a 
branch  from  one  or  two  umbilical  arteries  and  drained 
by  a  vein  that  ultimately  enters  one  of  two  umbilical 
veins.  These  cotyledons  have  vascular  connections 
with  others  and  lie  scattered  throughout  the  entire 
interior  surface  of  the  uterus. 

Other  types  of  placentas  exist.  In  rhesus  monkeys 
there  are  two  discoidal  placentas,  one  lying  on  the 


fig.  7.  Sodium  transfer  during  preg- 
nancy across  placentas  of  four  different 
types.  [From  Flexner  &  Gellhorn   (8i).j 


MOM    No  TRANSFERRED/GM    PLACENTA/HR 
AT    MIODLE    OF   9TH    TENTH    OF    GESTATION 


SOW 


GOAT 


FETAL  SIDE 


MATERNAL   SIDE 


GUINEA     RABBIT         RAT  MAN 

PIG 


FETAL  SIDE 


<s> 


MATERNAL    SIDE 


EPITHELIO- 
CHORIAL 


SYNDESMO 
CHORIAL 


ENDOTHELIO- 
CHORI AL 


HEMO- 
CHOR  IAL 


UTERINE    BLOOD    FLOW 


1593 


0  4  0.5  0.6  0.7 

PERIOD  OF  GESTATION  IN  TENTHS  OF   TOTAL 


-100 


fig.  8.  Transfer  rate  of  sodium  during  gestation  in  six  species.  [From  Flexner  &   Gellhorn  (81).] 


ventral,  the  other  on  the  dorsal  aspect  of  the  interior 
of  the  uterus.  However,  only  one  of  these  receives  the 
umbilical  vessels  and  is  called,  therefore,  the  primary 
placenta.  The  secondary  placenta  receives  its  vessels 
from  continuations  of  a  number  of  umbilical  vessel 
branches  on  the  chorioallantoic  surface  of  the  primary 
placenta  that  pass  between  the  amnion  and  chorion 
laeve  to  the  secondary  placenta,  rather  like  the  con- 
nection between  the  cotyledons  of  the  ungulate 
placenta. 

The  "unitary"  structure  of  the  fully  developed 
discoidal  placenta,  of  the  human,  rhesus  monkey, 
and  other  species  is  the  cotyledon  [Wilkin  (245)]. 
This  is  a  vascular  unit  which  is  fetal  (see  further 
discussion  below).  By  implication,  the  maternal 
placental  structures  are  fitted  to  the  cotyledon.  In  a 
sense  they  are.  The  decidual  plate  with  its  septa  blocks 
off  smaller  areas  of  the  fetal  portion  of  the  placenta  as 
ridges  or  folds  of  tissue  about  a  number  of  the  cotyle- 
dons. However,  the  ridges  of  the  septa  do  not  make 
connection  with  the  fetal  tissues  in  a  way  that  makes 
discrete,  unitary  compartments,  or  chambers.  The 
maternal  vascular  compartments  interconnect  deep 
in  the  placenta  beneath  the  chorioallantoic  plate  of 
the  placenta,  so  that  there  is  a  continuum  of  the 
maternal  vascular  area.  The  entire  area  is  spoken 
of  as  a  maternal  lake  or  intervillous  space.  To  the 
extent  that  there  is  continuity,  this  is  true,  but  there 
are  innumerable  attachments  of  fetal  vessels  covered 
with  chorionic  tissue  to  the  basal  part  of  the  placenta 
in  the  lake  on  the  decidual  plate  and  on  the  septa 


[Wilkin  (245)].  The  crypts  or  pockets  between  septal 
folds  become  more  numerous  as  pregnancy  advances. 

In  early  pregnancy,  isolated  lakes  of  maternal  blood 
in  the  trophoblast  merge  and  fuse  as  one  may  imagine 
pockets  of  gas  in  aging  cheese  might  fuse  to  form 
larger  pockets.  This  involves  the  entire  syncytial 
trophoblast  in  the  area  of  implantation,  embedded  in 
the  decidua  basalis.  As  the  placenta  enlarges  and 
undergoes  morphogenesis  and  the  uterus  enlarges 
pari  passu,  the  characteristics  of  the  placenta  change 
until  it  is  complete  in  form,  after  the  fourth  month  of 
pregnancy.  Only  a  small  proportion  of  the  interior  of 
the  uterine  surface  then  is  involved.  Zonary  placentas 
completely  surrounding  the  fetus  are  found  in  some 
species.  These  and  still  other  patterns  of  gross  struc- 
ture and  vascular  arrangements  have  been  described 
by  Mossman  (158)  and  by  Amoroso  (5). 

Because  there  is  such  a  variety  in  the  types  of 
placentas  and  since  these  undergo  important  struc- 
tural changes  during  pregnancy,  a  physiologist  who 
measures  uterine  blood  flow  during  pregnancy  may 
not  properly  speak  of  blood  flow  except  as  the  latter 
relates  to  an  evolving  set  of  morphological  relation- 
ships with  respect  to  a  given  form  of  placenta.  It  is 
to  be  borne  in  mind  also  that  the  largest  part  of  the 
gravid  uterus  is  not  associated  with  the  placenta;  it, 
too,  must  be  supplied  with  blood.  There  are,  in  a 
sense,  two  uterine  blood  flows,  one  to  the  placenta  in 
its  various  forms,  the  other  to  the  uterine  tissues  which 
are  undergoing  enormous  growth,  stretching  and 
change  of  shape.  To  measure  total  uterine  blood  flow 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  9.  Circumferential  arteries  of  nonpreg- 
nant rabbit  uterus.  These  anastomose  with 
each  other  laterally  and  supply  the  uterine 
wall.  [From  Reynolds  (199).] 


tells  what  the  circulatory  load  of  the  gravid  uterus 
is  on  the  maternal  cardiovascular  system  but  it  fails 
to  tell  how  this  is  related  to  supplying  fetal  needs, 
on  one  hand,  and  uterine  tissue  needs,  on  the  other. 


among  many  types  of  placentas.  In  this  way,  it 
becomes  possible  to  account  for  the  occurrence  of 
fetal  erythrocytes  in  the  maternal  blood  and  vice 
versa  (see  below). 


PLACENTAL  STRUCTURE  AND  PLACENTAL  EXCHANGE 

Flexner  and  associates  [Flexner  &  Gellhorn  (81), 
see  Reynolds  (198)]  have  found  wide  differences  in 
the  rates  of  transfer  of  given  electrolytes  across  various 
types  of  placentas.  Thus,  in  the  ninth  decile  of  gesta- 
tion the  transfer  of  Xa  is  0.026  mg  per  hour  per  gram 
of  placenta  in  the  so-called  epitheliochorial  placenta 
and  6  to  8  mg  per  hour  per  gram  of  placenta  in  the 
hemochorial  placenta.  Intermediate  rates  of  transfer 
are  found  in  the  syndesmochorial  and  endothelio- 
chorial  placentas.  Although  it  is  believed  by  some 
that  Grosser's  classification  of  placental  types  has 
outlived  its  usefulness  [cf  Amoroso  (6)],  it  is  possible 
that  the  classification  expresses  a  general  tendency 
toward  morphological  organization  and  functional 
capability  that  is  not  entirely  negated  by  dwelling  on 
details  of  isolated  microscopic  fields  either  in  the 
several  types  of  placentas  or  in  any  one  placenta.  One 
may  accept  the  fact  that  diere  are  differences  in 
morphology,  but  these  are  not  sharply  defined  either 
within  one  placenta  at  various  stages  of  pregnancy  or 


VASCULARITY    AND    ACCOMMODATION    OF    THE 
PRODUCTS    OF    CONCEPTION 

The  adaptation  of  the  vasculature  of  the  nonpreg- 
nant uterus  to  the  changes  of  gravidity  is  met  in 
various  ways  in  the  several  types  of  uteri:  through 
growth  and  enlargement  of  the  blood  vessels  [Orsini 
(164),  Wermbter  (241),  Schwarz  &  Hawker  (218)] 
and  by  physical  rearrangement  of  blood  vessels  as 
the  uterus  enlarges  and  changes  the  spatial  orienta- 
tion of  the  uterine  blood  vessels,  especially  as  the 
uterus  is  finally  stretched  in  the  latter  part  of  preg- 
nancy. In  all  nonpregnant  uteri  numerous  arteries 
are  tortuous,  coiled,  or  undulating  [Ramsey  (180)]. 
These  tortuosities  in  the  blood  vessels  permit  their 
extension  to  accommodate  in  part  the  increase  in 
size  of  the  uterus.  In  sheep,  one  or  two  of  the  uterine 
arteries  approach  each  cotyledon.  The  vessels  divide 
into  five  or  six  trunks  and  pursue  a  tortuous  course 
in  the  submucosa  before  dividing  again  and  entering 
the  cotyledon  [Barcroft  &  Barron  (19)].  The  early 
pattern  of  these  structures  seems  not  to  change  during 


fig.  10  (facing  page).  Distribution  of  fetal  arteries  and  veins  to  cotyledons  of  placenta  of  Pere 
David's  deer.  Note  that  arteries  and  veins  are  of  about  equal  size  and  number,  indicating  about 
equally  rapid  flows  of  blood  in  them.  1.  Three  injected  cotyledons.  Nearly  natural  size.  2.  Section 
through  middle  of  placentome.  Masson  stain.  Natural  size.  3.  Drawing  of  three  injected  villi,  re- 
moved from  placentome.  Central  vessels  of  the  villus  and  the  intraepithelial  capillary  network  are 
shown.  4.  Section  through  fetal  zone  of  placentome  showing  stem  villus  and  to  vessels.  X50.  Left 
and  right,  thin  strands  of  maternal  connective  tissue  from  which  epithelium  is  removed.  [From  Harri- 
son &  Hamilton  (95).  Courtesy  Cambridge  University  Press.] 


fig.  10.  See  legend  on  facing  page. 


UTERINE    BLOOD    FLOW 


'597 


pregnancy  except  that  the  uterus  is  distended  as 
pregnancy  advances  and  increases  steadily. 

Harrison  &  Hamilton  (95)  have  demonstrated 
especially  well  the  relation  of  maternal  and  fetal 
blood  vessels  to  each  other  in  a  deer.  (See  below  for 
discussion  of  the  fetal  blood  vessels  in  the  hemochorial 
placenta.) 

In  the  monkey,  as  the  endometrium  becomes 
thinner  because  the  uterus  is  distended  by  the  con- 
ceptus,  the  arteries  become  extended  and  the  number 
of  arterial  connections  with  the  intervillous  spaces 
increases  by  development  of  smaller  branches.  Sub- 
sequently, the  ends  of  adjacent  vessels  coalesce  to 
form  terminal  dilations  from  which  a  single  opening 
with  a  large  accumulation  of  lining  cells  passes 
through  the  basal  decidual  plate  into  the  maternal 
lake  of  blood  [Ramsey  (183)].  In  the  human,  similar 
arrangements  exist  [Lundgren  (137)].  Arterio-arterial 
shunts  in  the  uterus  exist  among  these  vessels  [Heckel 
&  Tobin  (100),  Reynolds  (199)].  As  pregnancy 
advances,  the  number  of  arterial  openings  into  the 
villous  lake  decreases  substantially.  Uterine  blood 
vessels,  along  with  all  other  tissues  of  the  uterus,  grow 
by  hypertrophy  and  hyperplasia  of  their  component 
parts  during  pregnancy  [Reynolds  (198)].  The  cause 
of  this  is  partly  hormonal,  partly  the  result  of  disten- 
tion of  the  tissues.  Hormones  and  distention  interact 
to  effect  the  growth  response  of  the  uterus  during 
pregnancy  (198). 


For  many  reasons,  therefore,  the  physiologist  who 
would  study  blood  flow  would  be  well  advised  to 
appreciate  the  complexity  of  structural  and  functional 
factors  involved  in  the  uterus  in  different  functional 
states. 

The  adaptation  of  the  uterine  vasculature  to  the 
uterus  during  pregnancy  has  been  especially  well 
studied  in  the  rabbit  [Reynolds  (199)],  which  is 
typical  of  the  uterus  duplex  and,  with  some  modifi- 
cations, to  the  uterus  bicornis.  A  certain  parallel 
exists  also  with  changes  that  occur  in  pregnancy  in  the 
uterus  simplex  [Ramsey  (187)]. 

In  the  rabbit,  the  vascular  system  of  the  uterus 
consists  of  large  vascular  channels  which  intercom- 
municate freely,  both  longitudinally  along  the  meso- 
metrial  border  of  the  uterus  and  circularly  along  the 
length  of  the  uterus.  This  is  well  shown  by  Orsini 
(164)  in  the  hamster.  Of  these  large  channels,  the 
mesometrial  arcuate  vein  is  concerned  primarily  with 
draining  the  region  of  the  uterus  to  which  placental 
sites  are  attached.  The  lateral  arcuate  veins  on  each 
side  of  the  uterus  drain  the  larger  part  of  the  uterine 
wall.  Each  of  these  vascular  beds  is  supported  by  the 
same  incoming  arteries  and  drained  by  the  veins  of 
the  broad  ligament.  The  implication  of  such  an  ar- 
rangement is  clear.  If,  due  to  distention,  the  blood 
flow  is  reduced  in  one  area  (i.e.,  the  peripheral  vas- 
cular resistance  increases),  the  flow  of  blood  to  the 


ARTERIES 


MARGIN  OF  INTERVILLOUS  SPACE 


■ 

A 

i 

/ 

TERMINAL  SAC 


ARCUATE  ARTERY 


PERITONEAL  SURFACE 


[B]  6th  WEEK 


a 

3-d  WEEK 


MARGIN  OF  INTERVILLOUS  SPACE 


BASE  OF  ENOOMETRIU 


PERITONEAL  SURFACE 


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MARGIN  QF  INTERVILLOUS  SPACE   , 


SPIRAL  ARTERY 

(PARTIALLY 

UNCOILED) 


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SP  pal  ajjter.  [uncoiled; 


MARGIN  OF  INTERVILLOUS  SPACE 


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ARCUATE  ARTERY 


ff]l9">  WEEK 


fig.   1 1 .   Pattern  of  arterial  supply  to  basal  plate  of  the  monkey  placenta  at  different  stages  of 
pregnancy.  [Permission  of  Ramsey  (181).] 


1598  HANDBOOK    OF   PHYSIOLOGY  ^  CIRCULATION    II 

VEINS 


ARCUATE  VEIN 


fig.    12.   Pattern  of  veins  draining  basal  plate  of  placenta  in  the  monkey  at  various  stages  of 
pregnancy.  [Permission  of  Ramsey  (181).] 


other  vascular  bed  increases  so  that  it  receives  a  larger 
portion  of  the  incoming  arterial  blood  to  the  uterus. 


MENSTRUATION 

The  morphological  and  physiological  mechanisms 
of  menstruation  have  been  the  subject  of  considerable 
interest,  particularly  since  precise  knowledge  of 
uterine  rhythmic  cycles  was  first  established  some 
forty  years  ago.  Reviews  on  the  subject  in  a  modern 
context  began  to  appear  when  Hartman  (96)  dis- 
cussed the  subject  of  intermenstrual  bleeding. 
Bartelmez  (23)  gave  us  the  first  comprehensive  re- 
view of  the  subject,  however,  and  this  was  extended 
and  revised  in  the  light  of  later  information  by 
Reynolds  (196),  by  Smith  &  Smith  (222)  and  by 
Kaiser  (124).  Since  that  time,  remarkably  little 
attention  has  been  directed  to  the  problem. 

In  the  uteri  of  certain  but  not  all  primates  there  are 
numerous  coiled  arterioles  in  the  endometrium  [Daron 
(62),  Dalgaard  (59),  Kaiser  (121),  Bartelmez  (26)] 
which  are  demonstrable  in  conventional  tissue  sec- 
tions [Kaiser  (121)].  These  arterioles  undergo  in- 
crease in  coiling  throughout  the  menstrual  cycle, 
reaching  maximum  development  prior  to  menstrua- 
tion [Daron  (62),  Kaiser  (121)].  Van  Wagenen  (237) 
notes  that  it  is  vasoconstriction  of  these  vessels  [not 
coiling,  as  commonly  supposed  (61)]  which  causes 
ischemia.  Then,  due  to  hormonally  induced  changes 
within  the  tissues  [Smith  &  Smith,  (222)],  there  is 
loss  of  tissue  fluid  and  thinning  or  regression  of  the 


endometrium,  and  this  results  in  congestion  and 
stasis  of  blood  in  the  coiled  vessels  [Markee  (144)]. 
Subsequently,  the  superficial  layers  of  the  en- 
dometrium degenerate,  slough  off  in  an  irregular  but 
spreading  manner  as  menstruation  takes  place. 
Sloughing  begins  when  the  endometrium  is  about 
one-half  of  the  peak  thickness  prior  to  the  end  of  the 
cycle.  Bleeding  is  by  capillary  seepage,  by  reflux 
venous  hemorrhage  [Markee  (144),  Daron  (63), 
Bartelmez  (22)],  and  occasionally  by  brief  arterial 
spurting  of  blood  [Markee  (144)]-  Menstruation 
begins  in  localized  areas  and  extends  to  others  to 
involve  the  entire  area  [Strassman  (228),  Phelps 
( 1  72)].  A  role  of  arteriovenous  shunts  in  the  menstrual 
process  is  both  alleged  [Schlegel  (216),  Dalgaard 
(59)]  and  denied  [Bartelmez  (24)],  but  the  evidence 
at  hand  seems  to  favor  the  former  view  [see  Hertig 
&  Rock  (104)].  The  physiological  effect  of  coiling  the 
arterioles  of  the  uterus  can  hardly  be  different  from 
that  of  coiling  of  vessels  in  the  ovary  and  the  testicle. 
Here,  it  lowers  the  blood  pressure  to  the  tissues  beyond 
the  coil   [Reynolds   (200),   Waites   &   Moule   (240)]. 

Since  menstruation  has  been  shown  to  be  asso- 
ciated with  local  hemodynamic  changes  within  the 
tissues  concerned,  some  investigators  have  attempted 
to  induce  profound  hemodynamic  disturbances  with  a 
view  to  causing  uterine  bleeding.  This  has  been  done 
[Van  Wagenen  &  Zuckerman  (238),  Markee  et  a!. 
(145)]  but  not  invariably  so  [Emmel  et  al.  (69)].  The 
effect  of  cord  transection  depends  upon  a  proper 
effective  estrogen  level. 

The  critical  factors  in  determining  what  manipula- 


UTERINE    BLOOD    FLOW 


'599 


tions  or  hormone  treatments  will  produce  menstrua- 
tion are  related  to  the  nature  of  the  vasculature  of  the 
endometrium.  This  is  affected  by  the  previous 
menstrual  history  of  the  organism  since  each  cycle 
brings  about  some  residual  changes  through  growth  of 
the  vascular  tree  which  persist  to  affect  the  next 
cyclic  bleeding  [Phelps  (173)]. 

In  addition  to  the  idea  that  changes  in  the  uterine 
vasculature  affect  and  modify  the  menstrual  process, 
Smith  (220)  and  Smith  &  Smith  (221)  hold  to  the 
view  that  a  toxic  substance  is  produced  within  the 
endometrium,  secondary  to  the  premenstrual 
ischemia,  and  that  this  toxin  leads  to  the  breakdown 
of  the  tissues  and  the  ensuing  menstrual  discharge. 

Prostigmin,  a  vasodilating  substance,  has  been 
shown  to  cause  uterine  bleeding  in  nonpregnant 
women  [Soskin  et  al.  (223)],  but  not  in  pregnant 
women.  Kaiser  (123)  failed  to  observe  a  similar 
response  in  the  rhesus  monkey.  This  drug  also  failed 
to  affect  estrogen-induced  hyperemia  in  endometrial 
ocular   transplants   in    the   rabbit    [Kaiser    (125)]. 

In  the  nonpregnant  endometrium  of  both  rabbits 
and  monkeys,  there  are  rhythmic  constrictions  and 
dilations  of  the  minute  vessels  which  are  independent 
of  the  nervous  system  [Markee  (142,  144)].  Under  the 
influence  of  estrogen  there  is  persistent  hyperemia  of 
the  endometrium  [Pompen  (176),  Markee  (143)]. 
The  significance  of  the  rhythmic  vascular  changes, 
both  as  to  cause  and  as  to  function,  are  unknown. 
They  are,  apparently,  unique  to  endometrial  vessels, 
although  estrogens  do  have  profound  effects  on 
somatic  minute  vessels  [see  Reynolds  (198)],  especially 
integumentary,  in  rabbits  and  humans  [Reynolds  & 
Foster  (206,  208)],  and  in  the  nasal  mucosa  [Mac- 
kenzie (139)],  as  well.  The  retinal  circulation  is  also 
modified  in  women,  manifesting  itself  by  scotomata 
that  change  in  position  with  change  in  posture  [Evans 
(72)];  this  is  marked  in  the  last  half  of  the  menstrual 
cycle. 

Of  importance  to  the  vascular  architecture  in  the 
endometrium  is  the  seldom  emphasized  fact  that  the 
tissue  in  which  these  structures  lie  is  loose  and  spongy. 
The  vascular  elements  are  developed  out  of  all  pro- 
portion to  the  immediate  vascular  needs  of  the  tissue 
[Reynolds  (196)].  It  is  clear  that  the  vascular  arrange- 
ment is  adapted  to  the  future  needs  of  supplying  and 
invading  the  implanting  trophoblast  [Hasner  (98), 
Bartelmez  (25)].  This  instance  is  not  unique  in 
developmental  biology  where  nature  has  repeatedly- 
contrived  to  anticipate  future  needs  by  prior  organi- 
zation of  mechanisms.  When  a  trophoblast  fails  to 
develop,  the  complex  vascular  structure  ot  the  endo- 
metrium breaks  down  since  it  cannot  be  maintained 


in  the  face  of  the  requirements  of  cyclic  endocrine 
activity  in  which  ovulation  is  the  focal  point  of  the 
pattern.  This  endometrial  cycle  occurs,  even  though 
ovulation  may  not  occur.  Moreover,  most  uteri, 
even  including  those  of  some  primates  [Kaiser  (120), 
Hamlett  (93),  Goodman  &  Wislocki  (85)],  do  not 
manifest  endometrial  sloughing  even  though  they 
exhibit  microscopic  bleeding;  instead,  the  endometrial 
vessels  undergo  an  ebb  and  flow  of  cyclic  growth  and 
regression  unaccompanied  by  profound  menstrual 
process.  In  either  event,  the  local  vasculature  changes 
cyclically.  In  some  species,  such  as  rats,  hamsters, 
and  guinea  pigs,  the  cyclic  occurrence  of  localized 
areas  of  hyperemia  within  the  uterus  is  evident  (see 
below) . 


HORMONES  AND  THE  UTERINE  VASCULATURE 

The  endometrial  hyperemia,  indeed  the  entire 
uterine  hyperemia,  that  occurs  periodically  has  a 
metabolic  basis  under  endocrine  control.  Estrogen 
augments  the  amount  of  acetylcholine  found  in  the 
uterus  [Reynolds  (193,  203)]  and  in  the  nasal  mucosa 
as  well  [Reynolds  &  Foster  (207)].  However,  it  was 
later  found  that  it  is  the  change  in  cholinesterase 
which  accounts  for  this  [Everett  &  Sawyer  (73), 
Herschberg  (103)].  It  is  also  reported  that  the  hypere- 
mia is  associated  with  alterations  in  the  amount  of 
histamine  or  histamine-like  substances  in  the  uterus 
[Kaiser  (122)].  It  appears  that  one  can  only  say  that 
there  is  a  change  in  vasoreactive  tissue  constituents 
under  the  influence  of  estrogen  and  it  is  probable  that 
more  than  one  substance  is  involved. 


UTERINE  CONTRACTION  AND  BLOOD   FLOW 

The  circulation  in  the  uterus,  like  that  in  all  mus- 
cular viscera,  functions  in  the  face  of  contraction  and 
relaxation  of  the  muscular  components  of  the  organ. 
It  must  serve  with  great  efficiency  as  the  uterus  under- 
goes great  change  in  size  and  shape  during  pregnancy. 
The  consequences  of  contractions,  growth,  and  dis- 
tention upon  blood  flow  in  the  uterus  require  con- 
sideration. Certainly,  clamping  of  the  blood  supply 
to  the  uterus  elicits  uterine  contractions,  as  Rorhrig 
showed  many  years  ago  [see  Reynolds  (198)].  In 
this  respect,  myometrium  is  no  different  from  intestine 
or  other  smooth  muscle.  More  delicate,  however,  is 
the  observation  that  low  arterial  blood  pressure  is 
associated  with  an  increase  in  frequency  and  ampli- 
tude of  uterine  contractions  [Kunisima  (132),  Robson 


i  Goo 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION 


fig.  1 3.  Schematic  representation  of  arterial 
supply  to  portions  of  uterus  simplex  (monkey, 
human).  [From  Reynolds  (.196).] 


Spiral  Artery 
Venous  Lake 

Gland 

Capillary  bed 
Basal  Artery 

Radial  Artery 
Arcuate  Artery. 

Arcuate  Vein 
Peripheral  Artery 


Functtonal 
ENDOMETRIUM 

Basal 

Myo-Endometnal 
border 

MYOMETRIUM 


&  Schild  (212)],  while  an  induced  higher  blood 
pressure  has  an  opposite  effect.  Ahlquist  &  Wood- 
bury (2)  found  in  cats  that  when  intrauterine  pressure 
reaches  60  to  70  mm  Hg,  uterine  blood  flow  virtually 
ceases.  This  is  reminiscent  of  the  report  by  Moir 
(156)  that  when  intrauterine  pressure  exceeds  arterial 
blood  pressure,  a  woman  feels  ischemic  uterine  pain. 
It  may  be  that  myometrial  smooth  muscle  acts  in 
concert  with  that  of  the  uterine  blood  vessels  them- 
selves. In  myometrial  studies,  adrenaline  and  nor- 
adrenaline cause  decreased  uterine  blood  flow  in 
rabbits  and  guinea  pigs,  associated  with  uterine  con- 
tractions [Dornhorst  &  Young  (67)],  but  an  action  on 
uterine  blood  vessels  was  not  eliminated.  The  conse- 
quence of  strong  uterine  contractions  on  the  systemic 
circulation  are  shown  by  the  fact  that  undulatory 
changes  in  arterial  blood  pressure  occur  as  the  post- 
partum uterus  contracts  [Franklin  (82)]. 

For  many  years,  speculation  existed  concerning 
the  effect  of  uterine  contractions  on  the  flow  of  blood 
in  the  placenta  of  the  human.  Two  possibilities 
existed:  a)  that  the  contraction  squeezes  blood  out  of 
the  placenta  as  water  may  be  squeezed  out  of  a 
sponge  [Kermauner  (128),  Grosser  (89,  90)],  and 
b)  that  as  the  intervillous  space  pressure  builds  up, 
veins  are  at  first  occluded,  then  pressure  increases  in 
the  intervillous  space  as  it  increases  in  the  amniotic 
cavity  [Keiffer  (127),  Wagner  (239),  Pryztowski 
(179)].  Meanwhile,  blood  remains  in  the  placenta  to 
meet  the  needs  of  maternal-fetal  exchange  during 
uterine  contraction.  There  is  now  no  doubt  that  the 
second  view  is  correct.  This  was  suggested  indirectly 
by  the  work  of  Woodbury  et  al.  (250)  and  shown 
clearly  by  Woodbury  et  al.  (251 ),  Alvarez  &  Caldeyro 


Barcia  (3),  Caldeyro  Barcia  (50),  and  by  Pryztowsky 
(179)  in  women  and  by  Ramsey  et  al.  (188) 
n  monkeys. 


BODY  POSTURE  AND  UTERINE  CONTRACTILITY 

Perhaps  the  most  telling  observation  about  the 
effect  of  uterine  circulation  on  uterine  contractions  is 
the  observation  made  in  women  that  a  change  in 
posture  modifies  the  quality  of  uterine  contractility. 
When  a  woman  in  late  pregnancy  or  in  labor  lies  on 
her  back,  uterine  contractions  of  a  given  frequency 
and  intensity  (i.e.,  change  of  intrauterine  pressure) 
are  seen  [Williams  (246),  Caldeyro  Barcia  et  al.  (51)]. 
When  she  assumes  a  semireclining  posture,  or  turns 
on  her  side,  the  contractions  become  slower  and  more 
intense.  With  a  view  to  studying  the  role  of  compres- 
sion of  the  inferior  vena  cava  in  the  recumbent 
position,  pressures  were  recorded  simultaneously  in  a 
woman  in  the  lower  and  upper  parts  of  the  vena 
cava  [Caldeyro  Barcia  et  al.  (51)].  The  weight  of  the 
gravid  uterus  on  the  retroperitoneal  surface  caused  a 
disassociation  of  the  venous  pulse  pressures  in  the  two 
parts  of  the  vein;  with  the  woman  on  her  side,  the 
venous  pulse  waves  became  synchronous,  and  the 
quality  of  uterine  contractions  changed. 


ESTROGEN  AND  UTERINE  BLOOD  VESSELS 

Another  indication  of  the  relation  between  uterine 
contractility  and  uterine  blood  flow  lies  in  the  ob- 
servation  that,    following   estrogen   withdrawal,    the 


UTERINE  BLOOD  FLOW 


l60I 


EMBARAZO    NORMAL   DE   TERMINO 
PARTO  INDUCIDO  PITOCIN  l/V    p^    U.  por   min 


EMBARAZO    NORMAL    DE    TERMINO 
PARTO  INDUCIDO    PITOCIN    l/V  ,-?rn  U.  por  min 


DECUBITO        DORSAL 
mmHg  f£\ 


N.510 


^VAjf^VENA 


DECUBITO 
mmHg 
30 


200 
LATERAL    DERECHO 


ILIACA 

PRESION 
AMNIOTICA 

VENA  CAVA 


W  SUPERIOR 


PRESION 
ARTERIAL 


minulos 


N.510 

VENA 
ILIACA 


PRESION 
AMNIOTICA 

VENA  CAVA 
SUPERIOR 

PRESION 
ARTERIAL 


!  minutos 


fig.  14.  Effect  of  body  position  on  pressure  in  the  iliac  vein,  superior  vena  cava  during  late 
pregnancy  and  arterial  blood  pressure.  .4.-  on  back.  Note  bimodal  pressure  peaks.  B:  on  side.  Note 
single  simultaneous  pressure  peaks  in  upper  and  lower  vena  cava,  synchronous  with  acme  of  uterine 
contractions  and  lower  systolic  blood  pressure.  [Permission  of  Caldeyro  Barcia  el  al.  (51).] 


uterus  becomes  less  hyperemic  and  gradually  loses  its 
contractility  [Reynolds  (191)].  Within  an  hour  after 
estrogen  is  injected  there  is  an  intense  hyperemia 
[Markee  (142),  Pompen  ( 1  76)].  Twelve  or  more  hours 
later  the  myometrium  becomes  active  [Reynolds 
(190)].  Beginning  activity  depends  upon  synthesis  of 
actomyosin  in  the  uterus  [Csapo  (57)];  this  is  related 
to  a  rise  of  aerobic  metabolism  of  the  uterus  [MacLeod 
&  Reynolds  (140)].  There  seems  to  be  an  assumption 
that  this  is  solely  in  the  smooth  muscle  of  the  myo- 
metrium. It  is  possible,  however,  that  smooth  muscle 
in  the  uterine  blood  vessels  is  equally  estrogen- 
dependent;  this  has  not  been  investigated.  Certainly, 
with  prolonged  estrogen  withdrawal  the  blood  vessels 
of  certain  parts  of  the  uterine  vasculature  show  a 
reversible  hyaline  degeneration  [Okkels  &  Engle 
(163),  Kahn  &  Laipply  (.119)].  All  parts  of  the  vas- 
culature are  not  equally  affected.  The  very  first 
effect  of  estrogen  on  the  uterine  vasculature  is  to 
cause  capillary  dilation  [Pompen  (176),  Fagin  & 
Reynolds  (74)].  Its  role  in  affecting  the  larger  vessels 
seems  to  have  attracted  very  little  attention  although 
stilbestrol  raises  the  arterial  pressure  in  female  but  not 
in  male  rats  [Hill  (106)]. 

When  estrogen  given  to  rabbits  is  combined  with 


progesterone  in  relatively  massive  doses,  profound 
hyperemia  of  the  uterus  cccurs  [Gillman  (84)]. 
Extensive  sloughing  of  the  endometrium  results. 
Estrogen  alone  increases  capillary  permeability 
[Hechter  et  al.  (99)]  which  is  associated  during  the 
first  6  hours  with  an  increase  in  the  relative  wet 
weight  of  the  uterus  of  ovariectomized  rats.  Later  the 
relative  dry  weight  increases  progressively  to  a  maxi- 
mum about   24  hours  after   the  injection   [Astwood 

(13)]- 

The  mechanism  of  the  estrogen-induced  hyperemia 

is  indicated  by  the  fact  that  estrogen  increases  the 
acetylcholine-content  of  rabbit  uteri  within  1  hour 
[Reynolds  (193)],  and  its  concentration  in  the  uterus 
changes  during  pregnancy  [Reynolds  &  Foster  (205)]. 
One  group  of  workers  failed  to  confirm  the  response 
in  rabbits  [Emmens  et  al.  (70)]  for  unknown  reasons. 
Even  so,  estrogen  seems  to  affect  the  acetylcholine  of 
the  uterus  by  altering  its  cholinesterase  content 
[Herschberg  (103),  Sawyer  &  Everett  (215),  Everett 
&  Sawyer  (73)].  Pompen  (176),  it  will  be  recalled, 
found  that  the  uterus  in  situ  does  not  become  hypere- 
mic under  estrogen  if  atropine  is  administered.  Kaiser 
(125),  however,  failed  to  observe  this  if  the  endo- 
metrium is  transplanted,  and  without  an  innervation. 


I  t  >(  12 


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CIRCULATION    II 


Sturgis  (229)  found  that  anything  which  alters 
uterine  blood  flow  in  the  monkey  may  affect  the  rate 
of  fluid  formation  in  the  uterine  lumen  (glandular 
secretion?).  This  lead  has  never  been  followed  up, 
or  studied  in  relation  to  endometrial  physiology  or 
cytology. 

In  the  absence  of  large  amounts  of  estrogen,  but 
not  in  ovariectomized  rabbits  or  guinea  pigs,  the 
capillaries  of  the  endometrium  exhibit  a  rather  rapid 
rhythmic  blanching  and  blushing  [Markee  (141, 
142)].  This  phenomenon  is  unrelated  to  myometrial 
activity.  Since  capillaries  lack  contractile  elements, 
it  must  be,  therefore,  a  manifestation  of  arteriolar 
activity. 


UTERINE    INNERVATION 

There  is  a  rich  sympathetic  innervation  to  the  uterus 
[Reynolds  (198),  Krantz  (130)].  The  parasympathetic 
innervation  is  limited,  so  far  as  is  known,  to  the  region 
of  the  cervix.  Despite  the  nerve  supply,  a  uterus  which 
is  denervated  by  transplantation  to  the  ventral  peri- 
toneal wall  possesses  all  the  normal  nongravid  re- 
activity of  the  uterus  in  situ  [Reynolds  &  Kaminester 
(209)].  This  is  not  to  say  that  the  innervation  is  with- 
out effect  upon  the  vasculature  [Reynolds  &  Kami- 
nester (210)].  Rather,  the  hormones  are  independent 
of  the  innervation  in  their  action  on  the  uterus.  Cer- 
tainly, fright  causes  vasoconstriction,  but  it  is  possible 
that  this  is  a  hormonal  effect  of  blood-borne  epineph- 
rine [Markee  (142)].  Few  data  exist  which  suggest, 
much  less  show,  what  the  normal  role  of  the  vasomotor 
innervation  to  the  uterus  is.  The  existence  of  vaso- 
motor nerves,  however,  as  entities  separate  from  the 
nerves  which  supply  the  myometrial  smooth  muscle 
has  been  amply  shown  [Medowar  (149)].  Vasodilator 
fibers  may  exist  since  cholinergic  sympathetic  fibers 
to  the  uterus  seem  to  have  been  demonstrated,  as 
well  as  adrenergic  ones  [Burn  (46)].  Moreover, 
atropine  has  been  seen  to  reduce  the  hyperemic  effect 
of  estrogen  on  the  uterus  in  situ  [Pompen  (176)]  but 
not  in  denervated  endometrial  transplants  in  the  eye 
[Kaiser  (125)]. 


PREGNANCY  AND  THE  UTERINE  CIRCULATION 

Pregnancy  imposes  an  array  of  special  requirements 
upon  the  uterine  circulation.  These  are,  as  mentioned 
above,  responses  to  growth  of  the  conceptus  and 
spatial  adjustments  that  are  of  great  magnitude. 


At  the  outset  of  pregnancy,  the  uterine  hyperemia 
of  estrus  gives  way  to  a  quality  in  the  circulation  in 
the  uterus  prior  to  implantation  and  for  a  time  after 
which  renders  the  uterus  bluish  in  appearance  as  if 
the  circulation  were  turgid.  This  is  seen  with  the 
uterus  in  situ  [Barcroft  &  Rothschild  (21)]  and  in 
ocular  grafts  [Neumann  (160)].  Aside  from  the 
generalized  uterine  hyperemia  referred  to  above, 
localized  hyperemia,  more  marked  in  some  parts  of 
the  endometrium  than  in  others,  has  long  been  known 
and  suspected  to  be  related  to  implantation.  This  was 
reported  in  the  human  by  His  (108),  Ilitschmann  & 
Adler  (109),  Strahl  &  Beneke  (227),  Delporte  (65), 
Teacher  (231),  Falkiner  &  Fleming  (76),  and  Wilkin 
(242).  More  refined  examination  of  this  in  controlled 
experiments  on  animals  awaited  the  work  of  Bacsich 
&  Wyburn  (15-17)  in  the  guinea  pig  and  more  re- 
cently in  the  rat  [Williams  (246),  Holmes  &  Davis 
(112)]  and  hamster  [Orsini  (164)].  Perhaps  the  most 
remarkable  instance  of  localized  implantation  is  found 
in  the  South  African  shrew,  Elephantulus  myurus 
jamesoni,  which  has  a  uterus  duplex.  This  species 
sheds  dozens  of  ova  at  each  ovulation;  all  become 
fertilized  but  only  two  become  implanted,  one  in 
each  uterus  in  a  region  of  remarkable  vascular  de- 
velopment   [van   der   Hoist    &    Gillman    (115)]. 

The  meaning  of  the  above  relationships  is  being 
studied  by  Boving  (36,  37).  Implantation  occurs  in 
the  vicinity  of  a  single  capillary  loop  lying  beneath 
the  endometrial  epithelium.  Attachment  (in  the 
rabbit)  takes  place  when  the  abembryonic  pole  of  the 
blastocyst  develops  a  sticky  substance  that  is  lacking 
over  the  embryonic  pole.  This  substance  is  related  to  a 
gradient  of  alkalinity  occurring  within  the  blastocyst 
and  is  associated  with  the  differential  in  production  of 
metabolites  between  the  embryonic  pole  and  the 
abembryonic  pole  of  the  blastocyst.  The  concept  is 
that  the  blood  flowing  through  the  capillary  loop 
removes  C02  about  as  fast  as  it  is  produced,  leaving 
behind  on  the  surface  of  the  blastocyst  a  calcium- 
proteinate  residue  that  is  sticky.  Carbonic  anhydrase 
is  present  in  high  concentration  in  the  endometrium 
[Lutwack-Mann  &  Laser  (138)].  The  epithelium  of 
the  endometrium  breaks  down  when  attachment 
occurs  [Boving  (37)]-  In  intraocular  transplants  in 
rats,  trophoblast  causes  a  breakdown  of  capillaries 
[Grobstein  (86)]  as  it  does  in  the  endometrium 
[Mossman  (158)]. 

From  this  time  until  the  period  of  uterine  conver- 
sion (see  above),  when  the  pregnant  uterus  changes 
from  spheroidal  to  an  elongating  form,  the  uterine 
vasculature    undergoes    enlargement    and    its    blood 


UTERINE  BLOOD  FLOW 


l6o3 


fig.  15.  Local  vasodilating 
action  of  estrogen  in  endome- 
trium of  guinea  pig.  A,  anti- 
mesometrial,  B,  lateral;  C,  mes- 
ometrial.  [From  Bacsich  & 
Wyburn  (15).] 


volume  increases  [Orsini  (164),  Reynolds  (199)] 
coinciding  with  die  period  of  most  rapid  uterine 
enlargement.  From  this  time  until  near  term,  there  is 
a  period  of  diminished  blood  in  the  vascular  bed 
until  term,  when  a  period  of  partial  hemostasis 
supervenes  [Barcroft  &  Rothschild  (21),  Reynolds 
(192,  196)].  These  changes  are  supported  by  studies 
of  bits  of  transplanted  endometrium  to  the  anterior 
chamber    of    the    eye    [Neumann    (160),    Krichesky 

('30]. 

When  the  uterus  is  in  situ,  the  blood  vessels  over  the 
conceptus  give  evidence  of  hypertrophy  and  the 
tortuous  course  of  the  uterine  arteries  progressively 
changes  as  they  straighten  out  [Reynolds  (199)]. 
This  is  associated  with  local  distention  of  the  tissues 
by  the  conceptus.  Distention  is  a  factor  in  uterine 
hypertrophy  [Reynolds  (198)].  The  veins,  showing  no 
initial  tortuosities,  can  only  adapt  by  growth,  stretch- 
ing, and  proliferation.  In  the  uterus  duplex,  the 
vessels  in  the  interconceptus  sites  show  no  such 
changes.  Only  as  the  spheroidal  conceptuses  enlarge 
and  encroach  upon  the  interconceptus  sites  do  the 
blood  vessels  there  become  involved  in  extension  and 
stretching.  These  processes  continue  until  a  phase  of 
maximum  spheroidal  size  is  attained.  At  this  time, 
vessels  that  have  been  crowded  from  about  each 
conceptus  toward  the  interconceptus  sites  lie  close 
together;  those  that  lie  around  a  conceptus  are 
stretched  and,  in  any  one  area,  sparse.  Within  a  very- 
short  period  of  time  (in  the  order  of  hours),  the  rapidly 
enlarging  conceptus  breaks  out  of  its  spheroidal 
shape  as  it  pushes  along  the  uterine  lumen  into  less 
distended  regions  of  the  uterus.  When  this  happens, 
the  vessels  of  the  interconceptus  region  slip  with  the 
tissues  in  which  they  lie  over  the  conceptus,  much  as  a 
stocking  is  slipped  up  a  leg.  After  this,  the  enlargement 
of  the  conceptus  is  solely  by  elongation,  without 
further  increase   in   diameter.   This   elongation   con- 


tinues until  shortly  before  term,  at  which  time  a  second 
limit  of  distention  is  reached  and  stress  is  placed  upon 
the  circulation  for  a  second  time.  In  any  event,  at  a 
time  when  fetal  growth  and  demands  upon  the  cir- 
culation are  great,  the  uterine  blood  vessels  merely 
become  rearranged  so  as  to  minimize  the  hemo- 
dynamic work  of  the  maternal  circulatory  system  in 
supplying  the  uterus  and  its  contents. 

How  is  blood  flow  in  the  uterus  modified  as  these 
changes  take  place?  By  measuring  local  circulation 
times  [Reynolds  (194,  199)],  it  has  been  found  that  as 
the  spheroidal  conceptus  enlarges  there  is  a  progres- 
sive decline  in  the  circulation  rate  until  the  time  of 
conversion.  Just  prior  to  conversion,  there  is  a  pro- 
found hemostasis  in  the  tissues  about  a  conceptus. 
Upon  release  of  tissue  tension  by  the  act  of  conversion, 
a  sudden  increase  in  local  circulation  rate  takes  place, 
approaching  that  observed  at  the  start  of  pregnancy. 
As  gestation  nears  its  end,  there  is  a  second  decline  in 
blood  flow  concomitant  with  the  longitudinal  stretch- 
ing of  the  uterus  prior  to  parturition. 

The  flow  characteristics  described  above  relate  to 
the  flow  in  the  maternal  vessels  of  the  uterine  wall, 
not  to  the  other  part  of  the  uterine  circulation,  which 
goes  to  the  placenta.  Here,  there  must  be  adequate 
flow  at  all  times,  otherwise  the  fetus  will  be 
endangered.  No  objective  study  has  been  made  of  the 
manner  by  which  this  is  accomplished,  but  it  has  been 
speculated  that  the  governing  factor  is  the  changing 
shape  of  the  pregnant  uterus  combined  with  tension 
in  the  uterine  tissues  [Reynolds  (195)].  Blood  flow  is 
reduced  to  the  tissues  of  the  uterus  which  are  most 
concerned  with  change  of  shape  in  order  to  accommo- 
date products  of  conception,  and  at  the  same  time 
blood  is  directed  toward  the  placenta,  since  both 
parts  of  the  system  are  supplied  by  the  same  arteries  at 
the  border  of  the  mesometrium.  This  is  to  say  that  as 
the   peripheral   vascular   resistance   increases   in   one 


1604 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


_RPI _, 


fig.  16.  Injected  arteries  of  rabbit  uterus  on  12th  day  (/), 
16th  (2),  20th  (3,  side  view;  ,/,  antimesometrial  view),  22nd 
(5  and  6)  24th  (7  and  <?)  of  gestation.  Note  diminishing  in- 
jectibility  of  blood  vessels  as  uterus  reaches  maximum  spheroidal 
distention  on  day  22.  [From  Reynolds  (199). 

part  of  a  common  vascular  bed,  flow  to  the  other  area 
is  favored,  since  the  peripheral  vascular  resistance 
there,  while  unchanged,  is  relatively  less  than  in  the 
first  area.  Study  of  the  vascular  rearrangements  in  the 
pregnant  monkey  uterus  show  that  a  comparable 
pattern  of  vascular  arrangements  occur  in  the  uterus 
simplex  [Gillespie  et  al.   (83),  Ramsey  (187)]. 

Physiologists  have  long  been  concerned  with  uterine 
blood  flow.  Barcroft  and  his  associates  measured 
total  uterus  blood  volumes  and  blood  flows  in  the 
uterus  of  the  rabbit  throughout  pregnancy  [Barcroft 
et  al.  (20),  Barcroft  &  Rothschild  (21)].  It  was  found 
that  both  increase  but  in  dissimilar  patterns.  From  a 
content  of  about  2  ml  at  the  outset  of  pregnancy  in  the 
rabbit,  the  uterine  blood  volume  increases  to  more 


than  30  ml  by  day  27,  whereupon  it  declines  50  per 
cent  in  the  next  3  days.  The  blood  flow  increases  to 
two  peaks  of  30  ml  per  min  on  the  20th  and  27th 
days  (gestation  31  days),  with  the  decline  in  total 
blood  flow  to  less  than  20  ml  on  day  24.  It  will  be 
seen  that  the  local  deprivation  of  blood  in  uterine 
tissues  described  in  the  regional  studies  above  were 
reflected  also  in  the  total  blood  flow'  [Reynolds  (192)]. 
Page  (167),  using  an  indirect  method  of  reasoning 
based  on  facts,  shows  that  in  the  ninth  month  of 
pregnancy  in  women  there  is  a  decline  of  nearly  one- 
half  in  uterine  blood  flow. 

The  turnover  of  blood  in  the  pregnant  rabbit  uterus 
based  on  the  flow  divided  by  the  volume,  shows  a 
progressive  increase  from  about  60  per  cent  turnover 
on  the  1  2th  day  of  pregnancy  to  1  75  per  cent  turnover 
on  day  20  with  a  sustained  75  to  85  per  cent  turnover 
after  uterine  conversion.  Comparing  the  turnover 
characteristics  with  the  factors  of  uterine  growth  and 
distention,  one  sees  how  affected  by  or  related  to  these 
factors  the   uterine  circulation    is  [Reynolds   (192)]. 

Recent  studies  have  been  directed  toward  the  meas- 
urement of  total  uterine  blood  flow  in  sheep  and 
humans.  These  have  been  of  three  types.  In  the  sheep 
and  humans,  arterial  and  venous  blood  sampling  and 
application  of  the  Fick  principle  have  been  used.  In 


30 

c  c  s/min 
cc  s 

• 

<7 

A 

20 

10 

'\ 

days 


fig.  17.  A:  blood  flow  (x)  and  blood  volume  (•)  in  rabbit 
uterus  during  pregnancy.  B:  percentage  turnover  of  blood  (•) 
related  to  uterine  growth  (stippled  area)  and  intrauterine 
pressure  (x).  [From  Reynolds  (192),  based  in  part  on  Barcroft 
et  al.  (20).] 


UTERINE    BLOOD    FLOW 


[605 


Case    N  821 


mmHg 


minutes 


-  90 


10 


15 


20 


25 


30 


3T 


TD- 


TT 


To 


fig.  18.  Effect  of  uterine  contraction  in  women  on  maternal  circulation.  Uterine  pressure  is 
shown  on  two  sensitivity  scales  (0-100  mm  Hg;  0-20  mm  Hg  to  show  effect  of  tonus  in  latter  record 
on  vena  cava  pressures,  superior  vena  cava,  and  retrohepatic).  Note  decrease  in  inferior  caval  pres- 
sure as  uterus  contracts  when  tonus  is  high  but  not  when  tonus  is  low.  Note  bradycardia  during 
contraction.  (Permission  of  Bieniarz  el  al.,  XXI  Int.  Cong.  Physiol.  Sciences,  Buenos  Aires,  Aug. 
'959-) 


the  ewe,  continuous  monitoring;  of  uterine  blood  flow 
in  a  uterine  artery  has  been  done  with  an  electro- 
magnetic flow  meter.  The  third  method  involved  in- 
jection of  radioactive  sodium  into  the  intervillous 
spaces  and   measuring  the  disappearance   rate. 

Metcalfe  el  al.  (154)  found  by  use  of  a  modified 
Fick  principle  (142)  that  the  blood  flow  to  the  non- 
gravid  uterus  in  sheep  and  goats  is  25  ml  per  min. 
Slightly  more  than  half  way  through  pregnancy  on 
the  80th  day,  the  flow  increases  to  200  ml  per  min. 
At  term,  flow  is  more  than  1  liter  per  min,  a  sub- 
stantial increase  in  blood  flow  for  an  organ.  The 
surface  area  of  the  fetal  portion  of  the  human  placenta, 


it  may  be  noted  parenthetically,  is  estimated  to  be 
about  15  m2  [Christoffersen  (53)];  the  increase  in 
placental  villous  surface  area  throughout  pregnane}- 
is  described  by  Wilkin  &   Bursztein  (245). 

Metcalfe  et  al.  (153)  have  related  the  increase  in 
blood  flow  as  observed  by  them  and  others  to  the 
fetal  demand,  in  the  rabbit,  human,  and  ungulate 
(sheep,  goat).  The  relations  are  summarized  as 
follows : 


Rabbit 

Human 

Ungulate 

Uterine  blood  flow  per 

•25 

156 

283 

kilogram  fetal  weight 

(ml/kg/min) 

i6o6 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


(Retrohepatic 
Region  ) 

INFERIOR         ° 

VENA   CAVA    80 

PRESSURE    40 

(Retrouterine     - 
Region) 

80 


Case  N. 889 


AMNIOTIC 

FLUID 
PRESSURE 


FEMORAL    120-(-| 
ARTERY 


PRESSURE 


80 


to\ 


fig.  19.  Blocking  of  inferior  (retrouterine)  vena  cava  with  strong  uterine  contraction.  Note 
fall  of  arterial  blood  pressure  as  venous  pressure  rises.  [Permission  of  Caldeyro  Barcia  el  al.  (51). 
See  fig.  14.] 


The  above  differences  in  maternal  hemodynamic 
work  are  not  related  to  the  oxygen  utilization  of  the 
fetus,  as  shown  by  the  same  authors: 


Uterine  oxygen  consump- 
tion per  kilogram  fetal 
weight  (ml/kg/min) 


Rabbit  Human        Ungulate 

8.3  7.4  8.9 


The  syndesmochorial  placenta  in  terms  of  uterine 
work  to  supply  a  given  weight  of  placenta  appears 
to  be  far  less  efficient  than  the  hemochorial  type  of 
placenta. 

On  admittedly  less  sure  grounds,  observations  on 
human  uteri  have  been  made.  Techniques  of 
sampling,  numbers  of  subjects,  assumptions  regarding 
uterine  weights  and  other  uncertainties  all  contribute 
to  the  interpretation  of  the  data,  and  a  number  of 
workers  have  entered  into  this  uncertain  field.  These 
reports  are  discussed  by  Metcalfe  et  al.  (152).  In 
their  series,  13  single  fetus  pregnancies  were  studied. 
They  found  the  blood  flow  to  be  of  the  order  of  500 
ml  per  min  and  the  O2  consumption  of  the  uterus  and 
its  contents,  25  ml  per  min.  In  one  twin  pregnancy, 
both  values  were  about  doubled.  It  appears  that  the 
fetal  load,  or  drain  upon  the  uterus,  may  be  a  kev 


factor  in  determining  how  much  blood  flows  to  the 
uterus.2  This  is  shown  bv  the  following  data: 


Single 

Twin 

Uterine  blood  flow 

460 

I  150 

Uterine  02 

25 

48 

Uterine  CO» 

20 

47 

Uterine  RQ 

O.80 

0 

If  this  is  for  nonidentical  twin  pregnancies  [not  stated 
by  Metcalfe  et  al.  (153)],  the  result  is  understandable: 
there  are  two  placentas  to  be  supplied.  If  there  were 
but  one  placenta,  the  results  with  respect  to  blood 
flow  are  less  clear.  Romney  et  al.  (213)  have  added 
data  in  the  human  also. 

With  respect  to  the  increase  in  uterine  blood  flow, 
Ramsey  et  al.  (188)  have  pointed  out,  it  is  about  half 
as  great  as  the  increase  in  maternal  renal  blood  flow 
during  pregnancv. 

The  problem  of  the  utero-placental  circulation  as  a 

2  Since  this  review  was  written,  an  important  paper  (H. 
Wulf.  Der  Gasaustausch  in  der  reifen  Plazenta  des  Menschrn. 


Z.  Geburlshilfe  u.  Gynakol.    152: 


-134,    1962)  with  extensive 


literature  review  on  gas  exchange  in  the  placenta  has  been 
published.  While  dealing  mainly  with  gas  exchange,  it  discusses 
the  causes  (including  anatomical  and  physiological)  of  utero- 
umbilical  oxygen   and  carbon  dioxide  tension   gradients. 


UTERINE  BLOOD  FLOW 


1607 


physiological  burden  on  the  circulation  led  Burwell 
(47-49)  to  regard  it  as  an  arteriovenous  shunt.  The 
blood -volume  increase  of  the  human  uterus  that 
occurs  is  reported  by  Caton  et  al.  (52).  The  effect  on 
the  maternal  heart  rate,  cardiac  output,  and  blood 
volume  are  comparable  to  the  effect  of  a  major  arterio- 
venous shunt  in  the  cardiovascular  system.  In  the 
latter  part  of  pregnancy  increases  are  seen  in  resting 
heart  rate,  cardiac  output,  circulation  rate  and  blood 
volume  [Hamilton  (91),  Palmer  &  Walker  (169)]. 
In  the  last  few  weeks  of  pregnancy  there  begins  to  be  a 


z  4 


"  i!60  h 
1180 


-: x  /  \ 

• — • 

^  UTERINE    CONTRACTION 

MINUTES  __ 

^__ 1  //  ET^a 


10 


20 


60 


90 


fig.  20.  Average  uterine  blood  flow  at  term  in  uterus  of  ewe. 
The  time  scale  does  not  refer  to  the  duration  of  uterine  con- 
tractions or  to  the  duration  of  the  decrease  in  flow.  Although 
recordings  were  taken  continuously,  for  the  reason  of  space 
economy  only  one  single  contraction,  with  two  blood  flow 
readings,  is  given  for  each  rate  of  oxytocin  infusion.  In  early 
labor,  uterine  contractions  occurred  every  8-10  min  and  lasted 
for  about  20-25  sec.  Each  contraction  was  accompanied  by  a 
decrease  in  flow.  When  the  rate  of  oxytocin  was  doubled,  con- 
tractions occurred  every  4-5  min  and  lasted  for  35-40  sec,  and 
the  flow  was  more  reduced.  With  a  further  increase  in  the 
infusion  rate,  the  contractions  lasted  for  45-60  sec  and  the 
reduction  in  flow  was  more  marked.  Note  the  rebound  in  flow 
during  uterine  relaxation.   [Assali  et  al.    (10).] 


decline  in  each  of  these  as  maternal  oxygen  consump- 
tion increases.  The  cause  of  these  declines  is  not 
known,  but  one  is  reminded  of  the  profound  uterine 
ischemia  seen  in  rabbits  (vide  supra)  toward  the  end 
of  pregnancy.  The  concept  of  the  gravid  uterus  actin? 
as  an  A-V  shunt  was  first  set  forth  in  1938  [Burwell 
(49)]  and  supported  by  the  later  studies  cited  above. 
The  most  recent  summary  is  by  Burwell  (47).  The 
circulatory  load  as  a  pathophysiological  mechanism 
upon  the  circulation  after  birth  when  the  A-V  shunt 
is  removed  has  drawn  the  attention  of  Schwarz  (217) 
and  the  ischemia  of  the  parturient  uterus  noted  by 
Thoma  (234). 

Assali  et  al.  (7,  8)  were  the  first  investigators  to 
catheterize  the  uterine  vein  in  women  for  the  purpose 
of  withdrawing  blood  samples  that  could  be  employed, 
when  combined  with  simultaneous  arterial  samples, 
to  use  the  Fick  principle  (nitrous  oxide)  in  estimating 
uterine  blood  flow.  Studying  women  in  normal  preg- 
nancy, Assali  et  al.  (9)  found  that  the  flow  was  15  ml 
per  100  g  of  tissue  per  min.  This  value,  approximating 
150  ml  per  min,  is  surely  low  (see  above).  However, 
with  the  same  method,  they  observed  a  decrease  to 
9  ml  per  1 00  g  of  tissue  per  min  in  the  first  24-hour 
postpartum  period.  Before  commencing  these  studies, 
Assali  (7)  reviewed  and  criticized  methods  used 
previously. 

A  new  departure  in  measurement  of  uterine  blood 
flow  was  reported  by  Assali  et  al.  (10)  who  monitored 
blood  flow  in  a  uterine  artery  of  the  pregnant  ewe 
with  an  electromagnetic  flowmeter  during  spontane- 
ous and  induced  labor.  Uterine  contractions,  spon- 
taneous or  induced,  were  accompanied  by  a  significant 
decrease  in  blood  flow  which  was  more  or  less  pro- 
portional to  the  strength  of  the  contraction.  During 


Pr«-  1 

pactum^ 
delivery 


6  7  8 

DAY  POST-PARTUM 


10 


-/>- 


14 


fig.  21.  Average  uterine  blood  How 
obtained  during  the  puerperium  in  the 
ewe.  Delivery  of  the  placenta  occurred 
between  day  1  and  day  2.  Note  the 
precipitous  fall  in  flow  which  occurred 
after  the  expulsion  of  the  placenta.  The 
progressive  decrease  during  the  post- 
partum period  coincided  with  uterine 
involution.  [Assali  et  al.  (10).] 


i6o8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


AMNIOTIC 


fig.  22.  Identical  pressures  in  amniotic 
fluid  and  intervillous  space  of  placenta  in  the 
monkey  with  the  uterus  contracted  or  relaxed. 
[Permission  of  Ramsey  et  at.  (,i  88.] 


5  10 

C-772  138  DAYS 

AMNIOTIC 
Average  tonus  16 

Average  amplitude    18  8 


I.  VS. 
Average    tonus  4  I 

Average  omplitude:20  8 


fig.  23.  Failure  of  India  ink  to  reach  a  sinus 
structure  at  margin  of  monkey  placenta.  [Per- 
mission of  Ramsey  (185).] 


fig.  24.  Injected  lymphatics  in  uterus  of  a 
nearly  mature  rhesus  monkey.  Note  paucity  in 
superficial  endometrium.  (From  Wislocki  & 
Dempsey.  Anal.  Record  75:  341,  1939.) 


M  vometrium' 


uterine  relaxation,  reactive  hyperemia  set  in.  After 
labor,  there  was  a  precipitous  fall  in  uterine  blood 
flow  which  declined  gradually  with  subsequent  uterine 
involution. 

The  action  of  oxytocic,  vasopressor,  and  vaso- 
depressor drugs  on  postpartum  uterine  blood  flow- 
was  studied  by  the  same  method  [Assali  et  al.  (11)]. 
Both  natural  and  synthetic  oxytocics  in  large  doses 


cause  an  initial  rise,  followed  by  a  marked  decline  in 
uterine  artery  blood  flow.  Epinephrine  produces  no 
significant  change  in  uterine  blood  flow,  although 
norepinephrine  increases  the  diastolic  pressure  and 
mean  blood  flow.  Apresoline  (a  sympatholytic  agent) 
increases  blood  flow  substantially. 

In  a  study  of  uterine  blood  flow  and  uterine  metabo- 
lism in  women,  Assali  et  al.    (12)   report  that  blood 


UTERINE  BLOOD  FLOW 


1609 


fig.  25.  Pattern  of  distribution  of  radiopaque  dye  injected 
into  aorta  by  way  of  femora]  artery  in  the  monkey  pregnant 
for  1 1 1  days.  Serial  radiographs  taken  at  3 - '  2 _  4,  5,  and  6  sec 
after  start  of  injection.  Insert  at  lower  left  is  of  marked  out 
portion  of  picture  above,  enlarged  4  times.  The  arrows  indicate 
spurts  of  dye  in  the  intervillous  space.  SA,  spiral  arteries  of 
endometrium;  HA,  hypogastric  artery;  (7.4,  uterine  artery; 
RA,  renal  artery.  [Permission  of  Ramsey  f  1 88 ).] 

flow  values  determined  by  the  electromagnetic  flow- 
meter and  the  nitrous  oxide  method  were  in  good 
agreement.  Uterine  blood  flow  increases  from  50  ml 
per  min  in  the  10th  week  of  gestation  to  190  ml  per 
min  at  the  30th  week.  The  flow  of  blood  per  unit  of 
uterine  tissue  was  determined  to  be  relatively  constant 
throughout  pregnancy.  The  rate  of  increase  in  the 
rate  of  blood  flow  and  oxygen  consumption  of  the 
"uterus"  exceeds  that  of  the  fetus;  it  is  surmised  that 
the  placenta  absorbs  the  difference. 


A  number  of  studies  of  placental  blood  flow  in 
women  have  been  reported.  Browne  &  Veal  (44)  were 
the  first  to  use  the  injection  of  \a-4  for  this  purpose. 
They  injected  it  into  the  intervillous  space  of  normo- 
tensive  and  hypertensive  women  and  estimated  in  the 
former  a  flow  of  600  ml  per  min;  in  the  latter,  about 
200  ml  per  min.  Similar  differences  were  found  in 
the  uptake  of  Na24  in  the  myometrium  by  Johnson  & 
Clayton  (1 18).  Variations  in  growth  of  the  conceptus 
and  associated  changes  in  shape  of  the  uterus  affect 
markedly  uterine  and  placental  blood  flow  [Browne 
(43)].  After  fetal  death,  the  placenta  cannot  be 
localized  by  the  Na'-4  method;  placental  blood  flow 
must  decrease  substantially.  In  later  pregnancy,  the 
placental  flow  of  the  maternal  blood  exceeds  by 
three  times  the  flow  necessary  to  maintain  the  fetus. 
The  work  of  Browne  (43)  likewise  suggests  that  as 
maternal  blood  pressure  diminishes  in  normal  pa- 
tients, placental  blood  flow  increases  by  some  en- 
hancing mechanism,  perhaps  the  A-V  shunt  of 
Burwell.  This  is  presumed  to  be  a  protective  mecha- 
nism, analogous  to  a  renal  shunt  type  of  mechanism. 
L^  The  intervillous  space  pressure  is  equal  to  that  of 
amniotic  fluid  pressure  or  very  close  to  it  [Alvarez  & 
Caldeyro  Barcia  (3),  Pryztowski  (178),  Hellman 
et  al.  (102)].  Interestingly,  fetal  capillary  blood 
pressure  in  the  placenta  is  considerably  higher 
[Reynolds  (202)].  It  is  probably  the  association  of 
several  factors  that  permits  the  escape  of  fetal  blood 
constituents  into  the  intervillous  space,  and  into 
maternal  blood.  One  is  the  high  fetal  capillary  blood 
pressure  just  noted.  Another  is  the  progressive  thinning 
of  the  trophoblast  layer  as  the  placenta  ages,  with 
loss  of  the  cytotrophoblast  layer  and  with  the  capil- 
laries coming  to  lie  next  to  the  thin  syncytium.  Still 
another  is  the  ever  diminishing  size  of  the  villi  as  they 
increase  in  number.  Combined,  these  factors  permit 
some  escape  of  fetal  erythrocytes  into  the  maternal 
circulation  [Naesland  (159),  Mengert  et  al.  (151), 
Bromberg  et  al.  (42)].  Maternal  erythrocytes  do  not 
normally  enter  the  fetal  circulation  [Mittelstrass  & 
Horst  (155)]-  How  the  exchange  of  water  and  other 
substances  occurs  between  the  maternal  circulation 
where  the  pressure  is  low  and  the  fetal  circulation, 
where  the  pressure  is  high,  has  been  considered 
theoretically  by  Wilkin  (243,  244).  Under  certain 
conditions,  simple  diffusion  occurs;  under  others,  the 
process  depends  upon  active  transport  mechanisms 
[Huggett  &  Hammond  (116)]. 

The  connection  between  maternal  uterine  blood 
and  amniotic  fluid  is  still  a  moot  question,  despite 
intensive  study.  That  there  is  a  rapid  and  voluminous 


l6l0  HANDBOOK    OF    PHYSIOLOGY    ^CIRCULATION    II 


fig.  26.  Pattern  of  distribution  of  India  ink 
in  monkey  placenta  perfused  by  way  of  the 
aorta.    [Permission   of  Ramsey    (183).] 


■> 


interchange  is  not  questioned  [Flexner  &  Gellhorn 
(80),  Hellman  et  al.  (101),  see  Reynolds  (198)  for 
review].  It  was  shown  long  ago  [Paton  et  al.  (170)] 
that  the  volume  of  amniotic  fluid  in  any  species  is 
nearly  constant  at  any  given  stage  of  normal  preg- 
nancy [Hammond  (94),  Reynolds  (198),  Lell  (134), 
Wislocki  (249),  McCafferty  (146)].  Although  some 
amniotic  fluid  surely  passes  from  the  fetus  to  the 
amniotic  sac  [Reynolds  (201)],  water  passes  by  an 
extraplacental  route  as  well  [Paul  et  al.  (171)].  More- 
over, maternal  emboli  of  amniotic  fluid  detritus  are 
known  to  occur  [Bachman  (14)].  Sfameni  (219)  has 
reviewed  the  lymphatic  circulation  in  the  vascular 
relations  between   the  mother  and  fetus.   The  theo- 


retical aspects  of  the  subject  are  reviewed  by  Plentl 
(174,  175)  and  McCance  &  Dickinson  ( 1 47). 

Knowledge  of  the  manner  by  which  maternal 
blood  reaches  the  placenta  has  received  much  study 
in  recent  years.  Maternal  blood  reaches  the  placenta, 
of  course,  by  endometrial  branches  of  the  uterine 
arteries.  Blood  is  drained  from  the  placenta  by  endo- 
metrial branches  of  the  uterine  veins.  These  are 
largely  anatomical  studies  based  upon  injection  of 
India  ink  or  other  media  into  the  aorta  or  the  femoral 
vein  followed  by  sections  and  study  of  the  injected 
regions  [Ramsey  (181)];  by  injection-corrosion  prep- 
arations; and  by  serial  radiography  [cf  Ramsey  et  al. 
(188)].  Direct  injections  of  uterine  vessels  of  excised 


PRIMARY  PLACENTAL''' 


•  Totol  orteries  7 


SECONDARY  PLACENT, 


C-750-  I23days 


o  Total  veins   19 


•  Total  arteries  10 


o  Total  veins  18 


fig.  27.   Total  arterial  and  venous   openings  in  the  placenta  of  the  monkey  in  Lite  pregnancy. 
[Permission  of  Ramsey   (184).] 


UTERINE    BLOOD     FLOW 


l6l  I 


pregnant  uteri  have  also  been  made.  Evidence  shows 
that  the  blood  enters  the  intervillous  space  of  the 
placenta  in  spurts  and  diffuses  into  relatively  localized 
areas  where,  circulating  about  the  placental  villi, 
it  leaves  the  spaces  by  nearby  veins.  However,  simul- 
taneous blood  samples  from  different  parts  of  the 
intervillous  space  yield  the  same  blood  oxygen  levels 
[McGaughey  et  a!.  (148)].  There  is  no  appreciable 
Spanner  type  of  circulation  toward  the  chorial  plate 
and  then  to  the  margin  of  the  placenta  where  it  is 
carried  off  through  a  marginal  sinus.  The  latter 
structure  does  not,  in  fact,  exist.  There  are  veins  that 
drain  various  parts  of  the  margin  of  the  placenta  but 
veins  also  drain  the  basal  plate  and  the  septa  as  well. 

The  number  of  vessels  supplying  the  placenta  has 
received  recent  attention.  The  number  of  arteries 
emptying  into  the  placenta  in  late  pregnancy  per  unit 
area  is  less  than  at  an  earlier  time  [Boyd  (41)].  The 
number  of  arterial  openings  into  the  human  inter- 
villous space  is  about  300  for  25,000  mm-  at  term  and 
about  1 20  for  6000  mm2  in  the  fourth  month.  More- 
over, the  lumens  of  the  arterioles  are  much  reduced  in 
size  by  an  accumulation  of  intimal  tissue  near  the 
orifice  [Ramsey  (184)].  In  elephantulus,  each  pla- 
centa is  supplied  by  three  small  arterioles  [van  der 
Horst  (114)].  The  number  of  veins  draining  the 
placenta  is  about  double  that  of  the  arteries  [Ramsey 
(182,  186)].  Radiographic  (serial)  studies  of  the 
entry  of  blood  into  the  placenta  are  reported  in 
monkeys  [Ramsey  et  al.  (188)]  and  women  [Borell  et 
al.  (38,  40),  Fernstrom  (79),  Hormann  (111),  Hart- 
nett  (97)]. 

The  question  of  the  pathway  of  maternal  bood 
flow  vis-a-vis  the  fetal  blood  flow  in  the  hemochorial 
placenta  has  received  consideration.  Barcroft  &  Bar- 
ron (18,  19),  Wimsatt  (248),  and  Mossmann  (158) 
incline  to  the  view  that  incoming  maternal  arterial 
blood  (oxygenated)  encounters  incoming  fetal  blood 
(reduced)  and,  running  parallel  to  the  point  at  which 
the  streams  part,  the  maternal  blood  gives  up  oxygen 
to  the  fetal  blood  along  the  way.  Noer  (161)  has 
shown  this  to  be  true  in  an  artificial  model  when 
acid  ions,  dyes,  and  dextrose  are  used.  To  apply  the 
principle  of  countercurrent  flow  to  the  hemochorial 
placenta,  as  Spanner  (224,  225)  has  done,  is  in  error, 
as  a  number  of  observations  show  [Stieve  (226), 
Ramsey  (183,  185),  Fernstrom  (79),  Borell  et  al.  (39), 
Hilleman  (107),  Kladetzky-Haubrich  (129)].  It  does 
not  apply  in  the  labyrinthine  placenta  of  the  rat 
[Hamilton  &  Boyd  (92),  B0e  (32,  33)]  or  hamster 
[Adams  &  Hilleman  (1)],  or  in  the  placenta  of  the 
sow  [Amoroso  (4)]. 


Extensive  studies  of  the  arrangements  of  fetal 
cotyledons  and  of  the  blood  vessels  within  them  have 
been  made.  The  gross  vascular  arrangement  in  the 
hemochorial  placenta  shows  the  cotyledon  to  be  a 
tuft,  arising  from  a  single  stem  artery.  It  sends  an- 
choring branches  to  the  basal  plate.  Free  villi  are 
given  off  from  the  anchoring  villi  and  from  recurrent 
free  villi  that  pass  toward  the  chorionic  plate  from 
the  anchoring  sites  [Wilkin  (244),  Crawford  (54)]. 
Gross  relations  are  described  by  Falkiner  (75),  Earn 
&  Nicholson  (68),  Crawford  (56),  ten  Berge  (232), 
Thoyer-Rogart  &  Harris  (235),  Vernete  &  Esteba- 
Caballera  (236),  Lemtis  (135),  Danesino  (60,  61), 
and  La  Have  (133).  One  author  claims  the  fetal 
vessels  are  densest  near  the  decidual  plate  [ten  Berge 
(232)],  but  this  is  denied  by  Beker  &  van  Steenis  (29) 

Vasculature  of  human  chorionic  villi 
(after   BfJe) 


Superficial  capillary   network 


Paravascular  network 


fig.    28.    Schematic    representation    of  major    and    minute 
vessels  in  villus  of  human  placenta.  [Permission  of  B0e  (33).] 


l6l2 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


and  Crawford  (56).  Within  die  fetal  villus,  the  es- 
sential vascular  arrangement  is  one  of  a  large  plexus 
rather  than  a  series  of  simple  capillary  networks 
[Crawford  (56),  B0e  (33-35)]. 

In  concluding  a  review  of  the  maternal  blood  flow 
in  the  uterus  it  is  appropriate  to  note  that  where  the 
pregnant  uterus  is  concerned,  the  fetal  circulation 
cannot  properly  be  separated  from  the  uterine  cir- 


culation. They  are  a  complex  and  in  a  sense  a  single 
unit,  one  affecting  the  other  in  the  developing  changes 
that  take  place.  The  conceptus  affects  uterine  growth 
and  all  that  that  entails,  while  at  the  same  time  the 
uterus  affects  the  development  of  its  contents.  The 
complexity  of  the  relationships  between  uterine 
growth,  vascularity,  and  fetal  development  are  re- 
viewed elsewhere  in  this  context  (203). 


REFERENCES 

1.  Adams,  F.  W.,  and  M.  H.  Hilleman.  Morphogenesis  of 
vitelline  and  allantoic  placentae  of  the  golden  hamster 
(Cricetus   auratus).   Anal.   Record    108:   363-384,    1950. 

2.  Ahlquist,  R.  P.,  and  R.  A.  Woodbury.  Influence  of 
drugs  and  uterine  activity  upon  blood  flow.  Federation 
Proc.  6:  305,  1947. 

3.  Alvarez,  H.,  and  R.  Caldevro  Barcia.  Fisiopatologia 
de  la  contraccion  uterina  y  sus  aplicaciones  en  la  clinica 
obstetricia.  Segundo  Congreso  Latino-Americano  de  Obstetricia 
y  Ginecologia.  Brazil,  1954. 

4.  Amoroso,  E.  C.  The  vascular  relations  in  the  placenta  of 
the  sow.  Quoted  by  Huggett  and  Hammond,  116.  J. 
Physiol.,  London  18:  1,   1947. 

5.  Amoroso,  E.  C.  The  Physiology  of  Reproduction  (3rd  ed.), 
edited  by  A.  S.  Parkes.  New  York:  Longmans,  vol.  2,  1952. 

6.  Amoroso,  E.  C.  The  biology  of  the  placenta.  Trans. 
5th  Conf.  on  Gestation,  edited  by  C.  Villee.  New  York: 
Josiah  Macy,  Jr.,  Found.,   1959,  pp.   15-72. 

7.  Assali,  N.  S.  Measurement  of  uterine  blood  flow  and 
uterine  metabolism.  I.  Critical  review  of  methods.  Am. 
J.  Obslet.  Gynecol.  66:  3-10,  1953. 

8.  Assali,  N.  S.,  R.  A.  Douglass,  Jr.,  W.  W.  Baird,  D.  B. 
Nicholson,  and  R.  Suyemoto.  Measurement  of  uterine 
blood  flow  and  uterine  metabolism.  II.  The  techniques  of 
catheterization  and  cannulation  of  the  uterine  veins  and 
sampling  of  arterial  and  venous  blood  in  pregnant  women. 
Am.  J.  Obstet.  Gynecol.  66:  11 -17,  1953. 

9.  Assali,  N.  S.,  R.  A.  Douglass,  Jr.,  W.  W.  Baird,  D  B. 
Nicholson,  and  R.  Suyemoto.  Measurement  of  uterine 
blood  flow  and  uterine  metabolism.  Am.  J.  Obslet.  Gynecol. 
66:  248-253,  1953. 

10.  Assali,  N.  S.,  A.  Dasgupta,  A.  Kolin,  and  L.  Holms. 
Measurement  of  uterine  blood  flow  and  metabolism.  V. 
Changes  during  spontaneous  and  induced  labor  in  un- 
anesthetized  pregnant  sheep  and  dogs.  Am.  J.  Physiol. 
614-620,  1958. 

1 1.  Assali,  N.  S.,  K.  Dasgupta,  and  A.  Kolin.  Measurement 
of  uterine  blood  flow  and  metabolism.  VI.  Effects  of 
oxytocin,  vaso-pressor  and  vaso-depressor  drugs  on  the 
blood  How  to  the  post  partum  uterus  of  unanesthetized 
sheep.  Am.  J.  Obstet.  Gynecol.  78:  313-321,  1 959. 

12.  Assali,  N.  S.,  L.  Raurama,  and  T.  Peltonen.  Measure- 
ment of  uterine  blood  flow  and  uterine  metabolism.  VIII. 
Uterine  and  fetal  blood  flow  and  oxygen  consumption  in 
early  human  pregnancy.  Am.  J.  Obstet.  Gynecol.  79 :  86- 
98,  i960. 

13.  Astwood,  E.  B.  Six-hour  assay  for  quantitative  deter- 
mination of  estrogen.  Endocrinology  23:  28-31,    1938. 


14.  Bachman,  C.  Maternal  pulmonary  embolism  by  amniotic 
fluid  (editorial).  .4m.  J.  Obstet.  Gynecol.  43:  164-165,  1942. 

15.  Bacsich,  P.,  and  G.  M.  Wyburn.  Observations  on  the 
oestrous  cycle  of  the  guinea  pig.  Proc.  Roy.  Soc,  Edinburgh 

60 :  33-39.  '94°. 

16.  Bacsich,  P.,  and  G.  M.  Wyburn.  Cyclic  variations  in  the 
vascular  architecture  of  the  uterus  of  the  guinea  pig. 
Trans.  Roy.  Soc,  Edinburgh  60:  79-86,   1940. 

17.  Bacsich,  P.,  and  G.  M.  Wyburn.  Hormonal  analysis  of 
the  cyclic  variations  in  the  vascular  architecture  of  the 
uterus  of  the  guinea  pig.  Trans.  Roy.  Soc,  Edinburgh  60: 
465  (part  II),  1940-1941. 

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test  for  early  pregnancy.  J.  Am.  Med.  Assoc.  114:  2090- 
2091,  1940. 

Spanner,   R.   Mutterlicher  und  kindlicher  Kreislauf  der 
menschlichen  Placenta  und  seine  Strombaknen.  Z.  Anal. 
Entwicklungsgeschichte   105:    163-242,    1935. 
Spanner,  R.  Circulation  of  the  human  placenta.  Am.  J. 
Obstet.  Gynecol.  71  :  350-362,   1956. 

Stieve,  H.  Uber  den  Abfluss  des  Blutes  aus  dem  inter- 
villosen  Raum  der  menschlichen  Placenta.  Vorlaulige 
Mitteilung.  Z.  Gyndkol.  64:  1570-1582,  1940. 
Strahl,  R.,  and  R.  Beneke.  Ein  jungen  menschlicher  Em- 
bryo Wiesbaden.  Wiesbaden:  Bergmanon,  1910,  p.  292. 
Strassman,  P.  Placenta  praevia.  Arch.  Gyndkol.  67:  112- 
275,  1902. 

Sturgis,  S.  H.  Method  for  obtaining  uterine  fluid  from 
the  monkey:  effect  of  pilocarpine,  atropine,  physiological 
salt  solution  and  adrenalin.  Endocrinology  31  :  664-672, 
1942. 

Taylor,  H.  C,  Jr.  Pelvic  pain  based  on  a  vascular  and 
autonomic  nervous  system  disorder.  Am.  J.  Obstet.  Gynecol. 
67:  1177-76,  1954. 

Teacher,  J.  H.  On  the  implantation  of  the  human  ovum 
and  the  early  development  of  the  trophoblast.  J.  Obstet. 
Gynaecol.   Brit.  Empire  31:   166-217,    '  924- 
Ten  Berge,  B.  S.  Capillaraktion  in  der  Placenta.   Arch. 
Gyndkol.    186:  253-256,    1955. 

Thoma,   R.   Der  mittlere  Durchflussmenge  der  Arterien 
des    Menschen    als    Funktion    des    Gefassradius.    Pfliigers 
Arch.  ges.  Physio/.,   194:  385-406,   1922. 
Thoma,   H.   Ischaemia  of  the   parturient  uterus.   Am.   J. 
Obstet.  Gynecol.   15:853-857,   1928. 

Thoyer-Rocart,  J.,  and  A.  Martin.  A  study  of  fetal 
circulation  in  the  placenta  by  iniection  of  synthetic  resins. 
Gynecol,  el  Obstet.  55:  255-256,   1956. 

Vernete,  G.,  and  J.  Estaba-Caballera.  A  study  of  the 
morphology  of  the  premature  placenta.  Acta  Ginecol., 
Madrid  5  :  48 1 ,  1 954. 

Van  Wagenen,  G.  Uterine  bleeding  of  monkeys  in  re- 
lation to  neural  and  vascular  processes:  spinal  transection 
and  menstruation.  Am.  J.  Physiol.  105:  473-486,  1933. 
Van  Wagenen,  G,  and  S.  Zuckerman.  Uterine  bleeding 
of  monkeys  in  relation  to  neural  and  vascular  processes: 
II.  Spinal-cord  transection  and  the  oestrin-level.  Am.  J. 
Physiol.    106:  416-422,   1933. 

Wagner,  G.  A.  Der  intervillose  Raum.  Arch  Gyndkol.  137: 
699-708,  1929. 

Wattes,  G.  M.  H.,  and  G.  R.  Moule.  Blood  pressure  in 
the  internal  spermatic  artery  of  the  ram.  J.  Rcprod.  and 
Fertility  1  :  223-229,   i960. 

Wermbter,  F.  Uber  den  Umbau  der  Uterusgefasse  in 
verschiedenen  Monaten  der  Schwangerschaft  erst-  und 
mehrgebarender  Frauen  unter  Beriicksichtigung  des 
Verhaltcns  der  Zwischemubstanz  der  Arterienwande. 
Virchow's  Arch,  pathol.  Anal.  257:  249-283,  1925. 
Wilkin,  P.  Some  aspects  of  the  vascularization  of  the 
human  endometrium  during  the  luteal  phase  of  the  men- 
strual cycle.  Bull.  soc.  roy.  beige,  gynecol.  obstet.  25:  402-412, 
'955- 


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243.  Wilkin,  P.  Study  of  physical  factors  determining  pla- 
cental permeability.  Bull,  federation  soc.  gynecol.  el  obstH. 
langue  franf.  9:  33,  1957. 

244.  Wilkin,  P.  Morphogenese.  In:  Le  Placenta  Humain,  edited 
by  P.  Snoeck.  Paris:  Masson,  1958,  pp.  60-67. 

245.  Wilkin,  P.,  and  M.  Bursztein.  Quantitatise  study  of  the 
development  of  placental  exchange  surface  during  preg- 
nancy. Bull,  federation  soc.  gynecol.  et  obstet.  langue  franc.  9: 

37-  >957- 

246.  Williams,  E.  A.  Abnormal  uterine  action  in  labor.  J. 
Obstet.  Gynaecol.  Brit.  Empire  59:  635-641,   1952. 

247.  Williams,  M.  F.  The  vascular  architecture  of  the  rat 
uterus  as  influenced  by  estrogen  and  progesterone.  Am. 
J.  Anat.  83:  247-308,    1948. 


248.  Wimsatt,  W.  A.  The  placentation  of  a  vespertilionid  bat, 
Myotis  lucifugus  lucifugus.  Am.  J.  Anat.  77:  1-52,  1945. 

249.  Wislocki,  G.  B.  On  the  volume  of  the  fetal  fluids  in  sow 
and  cat.  Anat.  Record  63:   183-192,   1935. 

250.  Woodbury,  R.  A.,  W.  F.  Hamilton,  and  R.  Torpin. 
The  relationships  between  abdominal,  uterine  and  ar- 
terial pressures  during  labor.  Am.  J.  Physiol.    121:  640- 

649.  '938- 

251.  Woodbury,  R.  A.,  W.  F.  Hamilton,  B.  E.  Abreu,  and 
R.  Torpin.  Effects  of  posterior  pituitary  extracts,  oxytocin 
(pitocin)  and  ergonovine  hydracrylate  (Ergotrate)  on 
uterine,  arterial,  venous  and  maternal  effective  pressures 
in  pregnant  humans.  J.  Pharmacol.  Exptl.  Therap.  80: 
256-263,  1944. 


CHAPTER     46 


The  fetal  and  neonatal  circulation 


MAUREEN    YOUNG  Department  of  Medicine,  St.  Thomas's  Hospital,  London,  England 


CHAPTER      CONTENTS 

The  Fetal  Placenta 

Implantation 

Placentation  and  Placental  Function 
Early  Development  of  the  Cardiovascular  System 

Peripheral  Circulation 

The  Heart 

Congenital  Malformation 
Course  of  the  Circulation  of  the  Fetus 

Regional  Blood  Flow 

Hepatic  Blood  Supply  and  the  Ductus  Venosus 
Fetal  Heart 

Heart  Rate.  Regulating  Mechanisms 

Cardiac  Output 
Arterial  Blood  Pressure 

Systemic  Pressure 

Pulmonary  Artery  Pressure 

Development     of    the     Cardiovascular     Reflexes     and     the 
Responses  to  Asphyxia  and  Hormones 
Fetal  Placental  Blood  Flow 

Effective    Perfusion    Pressure.    Resistance    of   the    Placental 
Circulation 

Umbilical  Blood  Flow 

Oxygen  Environment  and  Requirements  of  the  Fetus 
Influence  of  Hypoxia  and  Asphyxia  on  the  Fetus 

Hemoglobin 

Blood  Flow- 
Oxygen  Consumption 

Heart  Rate  During  Reduction  in  Maternal  Placental  Blood 
Flow 
Changes   in   Fetal   Circulation   at   Birth   and   in   the   Neonatal 
Period 

Umbilical  Cord;  Ductus  Venosus 

Fetal  Channels  in  the  Thorax 

Pulmonary    Vascular    Resistance,    Arterial    Pressure,    and 
Blood  Flow 

The  Heart 

Systemic  Pressure;  Cardiovascular  Reflexes,  and  Peripheral 
Resistance 

Viability 

Congenital  Heart  Disease 


thirty  years  have  passed  since  the  inspiration  and 
eloquence  of  Sir  Joseph  Barcroft  gave  the  functional 
development  of  the  cardiovascular  system  its  place 
in  circulatory  physiology.  In  the  intervening  vears 
histochemical  techniques  and  the  electron  microscope 
have  shown  how  complex  is  the  placental  structure 
between  the  maternal  and  fetal  circulations:  advances 
in  knowledge  of  transport  mechanisms  and  the  use  of 
isotopically  labeled  compounds  begin  to  clarify  the 
active  processes  occurring  within  this  structure:  the 
pathways  of  the  circulation  "in  utero,"'  in  both  the 
placenta  and  the  fetus,  and  the  changes  of  the  latter 
at  birth,  have  been  confirmed :  studies  of  the  develop- 
ment of  the  regulatory  mechanisms  of  the  fetal  circula- 
tion have  been  extended  into  the  neonatal  period 
(70,  83);  finally,  obstetricians  and  pediatricians  have 
accumulated  circulatory  information  on  the  human 
infant  which  demonstrates  the  value  and  limitations 
of  applying  observations  from  one  species  to  another. 
Detailed  reviews  have  been  written  on  each  of  these 
subjects  both  from  the  historical  viewpoint  and  that  of 
comparative  physiology:  it  falls  to  this  chapter  to  do 
justice  to  the  main  facts  with  particular  reference  to 
the  higher  mammals  and  to  the  human  infant. 

In  acute  experiments  on  the  fetus  with  an  intact 
placental  circulation,  the  possibilities  of  departure 
from  the  physiological  state  are  even  more  numerous 
than  in  the  grown  animal.  Understanding  of  the  precise 
influence  of  the  disturbances  due  both  to  the  anesthetic 
and  to  removal  from  the  uterine  environment  awaits 
the  development  of  intrauterine  techniques  such  as  the 
chronic  implantation  of  electrodes  and  catheters. 
Many  workers  have  tried  to  minimize  these  disturb- 
ances by  working  on  the  fetus  delivered  into  a  saline 
bath  at  37  C;  however,  particular  attention  must  be 
paid  to  the  position  of  the  fetus  in  relation  to  the 
placenta;    further,    interference    with    the    maternal 


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placental  blood  flow  and  therefore  the  internal  en- 
vironment of  the  fetus,  consequent  upon  the  retraction 
of  the  cut  uterine  muscle  around  the  uterine  vessels, 
still  occurs.  In  the  sheep,  on  which  many  of  the 
studies  have  been  made,  the  uterine  muscle  is  not  so 
reactive  to  mechanical  stimuli  as  the  uterus  of  the 
rabbit,  the  guinea  pig,  or  the  monkey  and  man. 
Spasmolytics  have  not  been  used  to  prevent  this  re- 
sponse of  the  uterine  muscle.  The  local  application 
of  procaine  or  papaverine  is  used  to  prevent  spasm  of 
the  umbilical  vessels  during  cannulation  or  sampling 
of  blood,  but  these  maneuvers  are  best  carried  out  on 
the  abdominal  trunks  of  the  vessels,  which  are  less 
contractile,  or  on  the  placental  tributaries,  in  order 
not  to  interfere  with  the  main  blood  flow. 

Barcroft's  (25)  theme  that  it  is  dangerous  to  argue 
from  species  to  species  about  the  relative  stage  of 
physiological  development  in  utero  and  at  birth  is 
most  applicable  to  a  consideration  of  the  cardiovascu- 
lar system.  It  will  become  apparent  that,  in  the  spe- 
cies which  have  been  most  extensively  studied,  func- 
tional development  does  not  depend  upon  gestational 
age  but  corresponds  most  nearly  to  the  requirements 
of  the  newly  born  when  it  is,  however,  never  so  ad- 
vanced as  in  the  adult. 


THE    FETAL    PLACENTA 

Implantation 

What  forces  compel  the  fertilized  ovum  to  satisfy 
its  high  nutritive  requirements  in  the  superficial 
layers  of  the  endometrium?  Or  does  the  endometrial 
epithelium  have  the  power  to  attract  inert  particles 
the  size  of  the  7-day  human  blastocyst  (106)?  What 
are  the  mutual  relationships  between  the  trophoblast 


and  the  endometrium  once  contact  between  the  two 
has  been  established?  Both  the  anatomical  and  ex- 
perimental aspects  of  implantation  are  beautifully 
described,  for  many  species,  by  Hamilton  et  al. 
(102)  and  by  Boyd  &  Hamilton  (45).  Under  normal 
conditions  the  blastocyst  in  utero  implants  at  a  defi- 
nite size,  at  a  prescribed  time,  and  in  special  sites 
(43);  the  presence  of  progesterone  is  essential  hut  the 
mechanism  of  its  action  is  unknown  (148).  Fawcett 
et  al.  observe  that,  "the  individual  potentialities  of  the 
ovum  and  uterine  mucosa  should  not  be  thought  of  as 
mutually  exclusive  but  mutually  supporting  and 
neither  is  "chiefly"  responsible  for  implantation" 
(94).  These  potentialities  may,  however,  be  observed 
quite  independently :  the  mouse  ovum,  once  it  has 
reached  a  certain  size,  is  capable  of  implanting  ran- 
domly in  extrauterine  sites  such  as  the  anterior  cham- 
ber of  the  eye  and  the  abdominal  cavity,  regardless 
of  the  sex  of  the  host.  The  trophoblast  causes  extra- 
vasation of  blood  in  these  sites  before  cellular  inva- 
sion has  taken  place  and  the  substance  responsible 
must  be  actively  penetrating,  for  secondary  implan- 
tation sites  start  to  proliferate  in  the  macaque  before 
any  erosion  of  the  uterine  surfaces  (191)  and,  in  the 
human,  congestion  also  appears  on  the  opposite  side 
of  the  uterus  to  the  site  of  implantation  (105).  The 
active  substance  may  be  a  product  of  metabolism 
of  the  dividing  blastocyst,  even  carbon  dioxide  itself; 
or  it  may  be  chorionic  gonadotropin,  known  to 
appear  first  at  the  time  of  implantation.  Evidence 
for  a  penetrating  action  of  chorionic  gonadotrophin 
is  suggested  by  perfusion  experiments  on  full-time 
human  placentas;  citrate  metabolism  is  enhanced  by 
estradiol  only  when  chorionic  gonadotrophin  is  also 
added  to  the  perfusing  fluid  (180).  The  initial  re- 
sponses of  the  endometrium  may  also  be  observed  in 


Fetal   Capillary 


I  v  1 

Epithelio-  Maternal     Syndesmo-      Maternal     Endothelio-  Haemo- 

chorial  Tissues       chorial  Capillary      chorial  chorial 

fig.  I.   Histological  types  of  placenta  arranged  to  emphasize  the  progressive  breaking  down  of  the 
barrier  between  the  maternal  and  fetal  circulations.  [Redrawn  by  Amoroso  (8).] 


Maternal      Haemoendo- 
Blood  thelial 


THE     FETAL    AND    NEONATAL    CIRCULATION 


[621 


»  J&I3 


the  absence  of  a  fertilized  ovum.  In  the  rat,  but  not 
in  the  guinea  pig,  the  endometrium  is  able  to  implant 
inert  objects,  such  as  glass  beads  the  size  of  the  blasto- 
cyst normally  implanted  (36).  Electrical  and  me- 
chanical stimulation  of  the  pregnant  rat  uterus  can 
produce  the  formation  of  a  maternal  placenta,  iden- 
tical in  structure  with  the  decidua  of  pregnancy; 
these  deciduomata  may  bleed  into  the  uterine  cavity 
and  the  early  normal  extravasation  of  blood  in  the 
endometrium  is  therefore  probably  not  dependent 
upon  the  fetal  trophoblast   (125,   170). 

The  implanted  blastocyst  probably  receives  its 
nourishment  for  a  short  time  from  the  glycogen, 
lipid,  and  other  materials  stored  in  the  stromal 
cells  of  the  uterine  mucosa  which  have  become  en- 
larged by  the  decidual  response;  in  some  ruminants 
the  mucosa  secretes  uterine  milk  for  this  purpose.  The 
formation  of  the  true  placenta,  containing  the  fetal 
and  maternal  circulations  is  due  to  a  balance  in  activ- 
ity of  the  fetal  trophoblast  and  maternal  decidua;  any 
disturbance  in  this  balance  may  result  in  the  rejection 
of  the  blastocyst  or  nonspecific,  even  malignant, 
growths.  Progesterone  and  estrogen  are  required  for 
placental  and  fetal  development,  the  ovary  and 
placenta  itself  contributing  to  the  production  of  these 
hormones  to  varying  extents  in  the  different  species 
(10):  an  adequate  placenta  may  develop  in  the  per- 
itoneal cavity  and  viable  infants  be  delivered  at  lap- 
arotomy (81);  it  has  been  shown  in  the  mouse  and  the 
cat  that  the  fetus  is  not  necessary  for  the  development 
of  the  placenta  (11,  141). 

Placentation  and  Placental  Function 

Amoroso  (8)  describes  fully  the  structure  of  the 
tissue  which  separates  the  fetal  from  the  maternal 
blood  streams  in  mammalian  placentas,  following  the 
classification  of  Grosser  (100)  modified  by  Mossman 
(138).  Figure  1  demonstrates  how  this  scheme  is 
based  on  the  number  of  tissue  lavers  between  the  two 


fig.  2.A:  section  through  a  villus  from  a  human  placenta 
of  9  weeks  gestation.  (X  7,040.)  The  surface  projections  and  a 
bulbous  promontory  are  illustrated.  In  the  apical  part  of  the 
syncytium  some  large  vacuoles,  filled  with  granular  material, 
are  seen.  These  are  interpreted  as  absorption  vacuoles  formed 
by  pinocytosis.  They  are  different  from  the  smaller  vesicles  with 
homogenous  centers  which  are  thought  to  be  ergastoplasmic. 
B:  section  through  a  thin  portion  of  a  human  villus  from  a 
placenta  delivered  at  term.  (X  10,110.)  There  are  well-de- 
veloped microvilli  on  the  surface  of  the  syncytium.  Beneath  the 
syncytium  is  a  zone  of  lighter  cytoplasm.  Such  a  zone  has  been 
shown  to  be  continuous  with  residual  Langhans  cells.  The  base- 
ment membranes  are  present,  separated  by  a  space  in  which 
collagenous  fibrils  can  be  seen.  Beneath  the  second  of  these  is 
the  endothelium  of  a  fetal  capillary.  [From  Amoroso  (9).] 


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circulations.  The  "thinner"  placentas  start  with 
six  cell  layers  between  the  maternal  and  fetal  blood, 
as  in  the  epitheliochorial  placenta,  and  there  is  a 
progressive  breakdown  of  tissue  during  development 
which  chiefly  involves  the  three  maternal  layers. 
Figure  2A  and  B  shows  that,  even  after  the  number 
of  cell  layers  has  been  determined  in  the  human 
placenta,  there  is  a  further  reduction  in  depth  of  the 
remaining  tissue.  The  thickness  of  this  placental 
"barrier"  will  be  one  of  the  factors  influencing  the 
rate  of  transfer  of  substances,  such  as  the  respiratory 
gases,  water,  and  electrolytes,  dependent  upon 
simple  diffusion  for  their  transfer;  but  most  of  the 
exchanges  between  the  mother  and  fetus  will  take 
place  by  active  transport,  and  the  composition  of  the 
cytoplasm  rather  than  the  depth  of  the  barrier  is 
likely  to  be  the  more  important  factor  (63,  143); 
the  evidence  suggests  that  placental  tissue  has  a  high 
oxygen  consumption,  10  ml  per  kg  per  min,  probably 
higher  than  the  fetus  itself  (17,  111).  Histochemical 
techniques  have  identified  the  cytoplasmic  content  of 
the  cells  with  a  variety  of  proteins,  enzymes,  lipids, 
and  carbohydrates  (8,  190);  the  cytoplasmic  structure 
is  transient,  and  changes  as  the  functional  capacity  of 
the  fetal  metabolic  processes  develop  during  gestation 
(181).  The  varying  structure  of  the  barrier  in  different 


«.'.  '■■/-•.■.■-^J'.^*.' 

.    '■^■.,\irV-:-              Maternal      artery            :;*. 

v           '                 •   '   * 

•2>"~ 

1M                  ...,„/¥/..  . 

Maternal  vein          feS&y,  ■'■..■ 

r:...\vC\ 

Muscular  coat 

fig.  3.  Arrangement  of  blood  vessels  in  the  placentome  of 
the  sheep  placenta.  [Redrawn  by  Amoroso  (8)  after  Barron.] 


species  has  been  a  constant  target  for  speculation  and 
probably  represents  adaptations  concerned  with 
differences  in  intermediary  metabolism  and  the  re- 
quired rate  of  growth  of  the  fetus. 

In  the  hemochorial  placenta,  in  which  the  maternal 
endothelium  is  absent,  vesicles  of  maternal  plasma 
may  be  transported  across  the  trophoblastic  cells  into 
the  fetal  blood  stream;  these  vesicles  are  formed  by  a 
fusion  of  the  microvilli  of  the  syncytium,  or  pinocyto- 
sis  (128),  and  probably  enable  the  transfer  of  whole 
protein  molecules,  possibly  those  responsible  for  the 
passive  immunity  of  the  fetus  (22,  64).  Other  special 
mechanisms  occur  in  the  pregnant  uterus  for  trans- 
ferring materials  to  the  fetus;  the  fetal  membranes  in 
the  rabbit  are  able  to  transfer  immune  proteins,  se- 
creted by  the  uterine  glands  (46)  and  the  endometrial 
cups  of  the  pregnant  mare  secrete  gonadotrophin  (9). 

Finally,  the  functional  capacity  of  any  placenta 
will  also  depend  upon  the  maternal  and  placental 
blood  flows.  In  most  animals  the  number  of  chorionic 
villi  and  the  placental  weight  increase  rapidly  after 
implantation  and  reach  a  maximum  while  the 
fetus  is  differentiating  and  before  the  major  increase 
in  weight  gain  (25).  The  opportunity  for  exchange 
between  the  two  circulations  will  be  limited  by  the 
efficiency  of  these  chorionic  villi,  the  disposition  of  the 
maternal  and  fetal  blood  vessels  in  relation  to  each 
other,  and  the  blood  flows  on  either  side  of  the  pla- 
cental barrier.  Bumm  (48)  suggested  that  a  counter- 
current  flow  mechanism  might  exist  to  facilitate  ex- 
change across  the  barrier  in  the  human  placenta,  and 
Mossman  (137)  demonstrated  that  suitable  anatomical 
arrangements  of  the  blood  vessels  were,  in  fact,  to  be 
found  in  the  ground  squirrel  and  in  the  rabbit.  Figure 
3  shows  the  probable  direction  of  the  two  blood 
streams  in  the  sheep;  fetal  blood,  passing  through  the 
chorionic  vessels  has  the  opportunity  of  exchanging 
with  the  maternal  arterial  blood  before  leaving  in  the 
umbilical  vein  for  the  fetus.  Similar  arrangements 
exist  in  all  species  with  a  labyrinthine  placenta  (8). 
In  the  hemochorial  placenta  of  the  primate  the  prin- 
ciple of  countercurrent  flow  is  insured  functionally: 
the  maternal  arteries  enter  the  intervillous  space 
through  funnel-shaped  openings,  and  the  blood  is 
projected  up  to  the  base  of  the  chorionic  villi  to  ex- 
change with  fetal  blood  leaving  for  the  umbilical  vein 
(153).  There  has  been  much  controversy  over  this 
circulation  through  the  years  but  recently  elegant 
radiological  demonstrations  by  Borell  et  al.  (38)  in  the 
human,    and    by    Ramsey    (153)    in    the    macaque 


THE    FETAL    AND    NEONATAL    CIRCULATION 


l62  ; 


monkey,  leave  little  doubt  that  there  is  a  blood  flow 
mechanism  in  these  placentas  which  approaches  the 
efficiency  of  the  countercurrent  methods  (31). 


EARLY    DEVELOPMENT    OF    THE 
CARDIOVASCULAR    SYSTEM 

Streeter's  label  for  the  fetus  as  a  whole,  "Open 
for  business  during  alterations'"  is  most  readily  ex- 
tended to  the  cardiovascular  system:  this  is  the  first 
organ  system  to  reach  a  functional  state  in  the  embryo, 
it  supplies  all  the  embryonic  tissues  and  undergoes 
rapid  and  extensive  alterations  during  the  develop- 
ment of  the  organs. 

Peripheral  Circ illation 

Again,  Hamilton  et  al.  provide  a  detailed  account 
of  the  morphology  of  the  development  of  the  mam- 
malian cardiovascular  system  (102).  But,  what  deter- 
mines the  appearance  of  isolated  endothelial  cords, 
first  in  the  yolk  sac  area,  and  then  in  the  embryo, 
with  the  eventual  formation  of  diffuse  plexuses? 
Why  do  lumina  develop  in  these  cords  and  why  do 
larger  channels  form?  What  is  responsible  for  the 
elaboration  of  the  neighboring  mesenchyme  into 
the  tunica  media  and  adventitia?  Why  does  the  heart 
form  and  become  differentiated  to  direct  the  blood 
through  these  channels?  None  of  these  questions  can 
be  fully  answered  but,  following  the  study  of  the  his- 
togenesis of  the  arteries  in  the  chick  embryo,  Hughes 
discusses  the  many  factors  which  can  influence  the 
development  of  blood  vessels  (113).  The  primitive 
endothelial  network  is  formed  before  the  circulation 
begins  and  is  determined  by  genetic  factors:  in  con- 
trast, the  development  of  the  main  vessels  within  the 
capillary  network  is  dependent  upon  a  circulation 
and  the  dynamic  relationship  between  the  structure 
of  vessels  and  the  rate,  direction  and  pressure  of 
blood  within  them  is  probably  acquired  early  in  em- 
bryonic life.  There  are  no  hemodynamic  measure- 
ments with  which  to  substantiate  this  statement,  but 
the  classical  relation  between  function  and  structure 
is  to  be  found  in  Benninghof  and  Spanner's  descrip- 
tion of  the  acardiac  fetus  with  a  normal  twin  (35); 
all  the  arteries  of  the  acardiac  fetus,  including  the 
aorta  and  common  carotid,  possessed  the  structure 
of  peripheral  muscular  vessels  because  they  were 
physiologically    peripheral    arteries    of    the    normal 


Premature- 30w«(«  9* 


Full  Term  3e-do««ks  3  months 


x  COLLAGEN      •  ELASTIN        oELASTIN+COLLAGEN 
fig.   4.   The  pattern  of  fibrous  protein  distribution   in   the 
major  vessels  of  the  human  infant  at  30  weeks  gestation,  full 
term,  and  3  months  post  partum  (Cleary,  unpublished). 

twin,  whose  heart  circulated  the  blood  in  both  fetuses. 
The  mammalian  ductus  arteriosus,  on  the  other 
hand,  is  a  particular  example  of  a  muscular  artery 
joining  two  adjacent  elastic  arteries.  The  adult  pattern 
of  fibrous  protein  distribution  is  present  by  30  weeks 
in  the  major  vessels  of  the  human  fetus  (fig.  4) ;  elastin 
exceeds  collagen  in  the  thoracic  aorta  but  the  propor- 
tion of  each  is  reversed  in  the  abdominal  aorta.  The 
percentage  of  elastin  increases  to  a  maximum  3 
months  after  delivery. 

The  capillary  networks  are  coarse  in  young  em- 
bryos and  become  more  delicate  and  numerous  dur- 
ing development,  but  at  different  times  in  the  various 
tissues  (142,  152)  and  it  would  be  instructive  to  cor- 
relate the  degree  of  vascularization  with  the  oxygen 
requirements  of  the  organs.  The  richness  of  distribu- 
tion of  the  capillary  bed  will  be  of  special  importance 
in  the  lungs,  brain  and  cardiovascular  system  of  the 
prematurely  born  and  postmature  young. 

The  Heart 

Ebert  et  al.  describe  the  initial  phases  in  heart 
formation,  from  experimental  evidence  in  the  chick 
and  rat  embryos  (87,  96).  In  the  prestreak  embryo 
the  capacity  for  heart  formation  is  widely  distributed 
and  pulsating  cardiac  muscle  may  develop  in  tissue 
culture  of  peripheral  and  posterior  regions  of  the 
blastoderm:  later,  this  capacity  is  more  restricted  and 
is  finally  limited  to  two  definite  regions  which  sub- 
sequently fuse  in  the  head  process  stage  embryo. 
In  vitro  these  cells  will  develop  into  a  rounded  mass 
of  cardiac  muscle  and  the  onset  of  contractility  is 
swift  and  associated  with  the  appearance  of  glycogen, 
but  not  with  definite  mvofibrils  or  cross  striations. 


[624 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


But  the  morphogenesis  of  heart  chambers  can  only 
take  place  "in  embryo"  demonstrating,  again,  the 
probable  importance  of  spacial  factors  in  develop- 
ment; striated  myofibrils  are  present  by  the  time  the 
contractile  activity  is  sufficient  to  circulate  the  blood. 
Ebert  (86)  has  shown  by  immunochemical  techniques 
that  cardiac  myosin,  similar  to  that  found  in  the 
adult,  is  widely  distributed  in  the  very  early  embryo 
and  that  the  restriction  of  the  heart-forming  area 
during  development  is  accompanied  by  a  limitation 
of  the  synthesis  of  this  specific  protein  and  the  com- 
mencement of  the  capacity  for  synthesis  in  these 
areas.  These  facts  do  not  explain  the  first  appearance 
of  myosin  or  actin,  the  origin  of  the  nonpropagated 
contractions  which  begin  in  the  ventricles,  or  the 
probable  dependence  of  the  developing  cardiac  mus- 
cle metabolism  chiefly  upon  anaerobic  glycolysis 
(>77)- 

Congenital  Malformation 

A  knowledge  of  the  metabolic  processes  responsible 
for  embryonic  differentiation  would  provide  the 
foundation  for  a  better  understanding  of  the  causes 
of  congenital  malformation  and  help  to  enable  their 
prevention.  In  human  pediatrics,  congenital  ab- 
normalities appear  in  1  per  cent  of  all  live  births 
(162)  and  now  contribute  to  20  per  cent  of  the  neo- 
natal deaths  in  countries  where  the  infant  death  rates 
are  low  (185);  malformation  of  the  cardiovascular 
system  is  second  to  malformation  of  the  nervous  sys- 
tem in  causing  this  mortality.  The  causes  of  congenital 
abnormality  may  be  genetic  but  are  chiefly  due  to 
environmental  factors  (147)  and  there  is  a  wealth  of 
descriptive  information  on  the  influence  of  a  wide 
variety  of  experimental  procedures  and  chemical 
substances  which  are  teratogenic  (119);  each  is  usu- 
ally effective  at  a  certain  stage  of  development  and 
may  influence  the  organogenesis  of  one  or  a  number 
of  the  systems.  Abnormalities  of  the  cardiovascular 
system  in  human  infants  are  mainly  associated  with 
the  rubella  virus:  in  the  experimental  animal  meta- 
bolic inhibitors  and  nutritional  deficiencies  of  the 
mother,  especially  of  the  vitamins,  may  produce 
abnormalities;  the  high  concentration  of  riboflavin 
in  fetal  blood  and  the  transfer  mechanism  which 
exists  in  the  placenta  for  this  vitamin  is  probably 
related  to  its  high  requirements  in  fetal  metabolism 
(131).  Acute  anoxaemia,  due  to  maternal  exposure 
to  carbon  monoxide  gas  is  known  to  be  teratogenic 
in  the  human  infant  (115)  but  chronic  hypoxia, 
though  it  may  be  effective  in  animals  (119),  is  diffi- 


cult to  establish  as  teratogenic  in  the  human.  The 
incidence  of  congenital  malformation  of  the  cardio- 
vascular system  is  no  greater  in  infants  born  to  women 
living  at  high  altitudes  than  it  is  at  sea  level  (147), 
demonstrating  that  the  adaptive  processes  enabling 
life  at  lower  oxygen  tension  also  ensures  an  adequate 
oxygen  supply  in  developing  tissues.  Another  aspect 
of  chronic  hypoxia,  reduction  in  maternal  placental 
blood  flow,  probably  has  most  important  conse- 
quences for  the  infant  in  such  conditions  as  toxemia 
of  pregnancy:  in  animals  a  reduced  maternal  placen- 
tal blood  supply  causes  "runting"  and  the  over-all 
size  of  the  fetus  is  small,  but  there  appear  to  be  no 
definite  congenital  abnormalities  (132);  this  may 
possibly  be  explained  by  the  reduction  in  supply  of 
nutritive  material  without  any  alteration  in  balance 
of  the  essential  constituents.  These  epidemiological 
and  etiological  facts  cannot,  yet,  explain  why  only 
5  to  30  per  cent  of  the  infants,  born  of  mothers  in- 
fected with  rubella  during  the  first  trimester,  de- 
velop malformations  of  the  cardiovascular  system 
(95)  or  why  the  disturbance  of  organogenesis  presents 
itself  in  diverse  forms.  For  example,  why  does  normal 
but  misplaced  growth  of  the  large  blood  vessels 
occur?  What  stimulates  growth  of  the  septum  secun- 
dum causing  premature  closure  of  the  foramen  ovale 
and  why  is  there  too  little  reabsorption  of  the  septum 
spurium  leaving  Chiari's  net  (144)? 


COURSE    OF    THE    CIRCULATION    IN    THE    FETUS 

The  probable  course  of  the  fetal  circulation  in  the 
mammal,  once  the  major  channels  have  developed, 
is  illustrated  in  figure  5.  The  most  arterial  blood 
circulates  from  the  placenta,  in  the  umbilical  vein, 
to  the  liver  which  it  perfuses;  this  blood  leaves  the 
hepatic  vein  to  join  venous  blood  from  the  caudal 
part  of  the  body  in  the  inferior  vena  cava.  In  some 
species,  notably  the  human,  the  monkey,  and  the 
sheep,  a  proportion  of  the  blood  in  the  umbilical 
vein  short-circuits  the  liver  and  passes  straight  into 
the  inferior  vena  cava  through  the  ductus  venosus. 
As  it  enters  the  heart  the  inferior  caval  stream  is 
divided  by  the  crista  dividens  of  the  foramen  ovale 
(fig.  6) ;  most  of  the  blood  flows  straight  into  the  left 
auricle,  where  it  mixes  with  a  small  volume  of  pul- 
monary venous  blood  and  passes  into  the  left  ven- 
tricle, whence  it  is  pumped  mainly  to  the  head  and 
upper  extremities.  A  smaller  stream  of  inferior  caval 
blood  is  directed  to  the  right  auricle,  mixes  with  ve- 
nous  blood   from   the  coronarv  sinus  and   from   the 


UMBILICAL 
VEIN 


THE    FETAL    AND    NEONATAL    CIRCULATION  1 625 

s.v.c. 


fig.  5.  Fetal  circulation  and  probable  course  of  the  blood 
through  the  fetal  heart.  [After  G.  S.  Dawes  (Bell  el  al.  Textbook 
of  Physiology  and  Biochemistry,  5th  ed.,  1961).] 

upper  part  of  the  body,  carried  by  the  superior  vena 
cava,  and  passes  into  the  right  ventricle;  most  of  this 
blood  short-circuits  the  lungs,  through  the  ductus 
arteriosus,  and  passes  to  the  descending  aorta  to  sup- 
ply the  lower  extremities  or  become  oxygenated  in  the 
placenta. 

The  presence  of  the  ductus  arteriosus  and  the 
foramen  ovale  and  their  functional  significance, 
allowing  the  two  ventricles  to  work  in  parallel,  did 
not  escape  William  Harvey:  "Thus,  in  the  embryo, 
while  the  lungs  are  idle  and  devoid  of  activity  or 
movement,  as  though  they  did  not  exist,  Nature  uses 
the  two  ventricles  of  the  heart  as  one  for  the  trans- 
mission of  the  blood."  Harvey  used  the  fetal  circula- 
tion to  support  his  general  thesis  of  the  circulation  of 
the  blood.  Barclay  et  al.  (27)  review  the  history  of  the 
anatomical  evidence  for  the  present  concept  of  the 
fetal  circulation :  Sabatier,  nearly  two  hundred  years 
ago,  observed  that  the  foramen  ovale  did  not  lie  be- 
tween the  two  atria,  but  at  the  junction  of  the  two 
venae  cavae  with  the  left  auricle,  and  directed  the 
inferior  caval  blood  into  the  left  auricle;  it  was  he  who 


CRISTA 
OIVIOENS 


PULMONARY 
VEINS 


I.V.C. 


VALVE  OF 

FORAMEN 

OVALE 


fig.  6.  Diagram  of  the  great  veins  to  show  that  in  the  fetus 
the  inferior  vena  caval  blood  divides  into  two  streams,  one  of 
which  enters  the  right  atrium  while  the  other  passes  through 
the  foramen  ovale  into  the  left  atrium.  [From  Dawes  (66).] 

first  suggested  the  figure-of-eight-like  course  for  the 
circulation  shown  in  figure  5.  Shortly  afterwards, 
Wolf  also  found  that  the  two  atria  were  not  in  com- 
munication with  each  other,  that  the  inferior  vena 
cava  lay  between  them  with  openings  in  each,  and 
that  the  relationship  of  these  communications  was 
such  that  the  major  portion  of  the  inferior  caval 
stream  would  pass  into  the  left  auricle.  It  was  not 
until  1939  that  the  pathways  of  the  inferior  and  su- 
perior caval  streams,  in  the  chest  and  heart,  were 
actually  observed  in  the  sheep  by  Barclay  et  al.,  using 
rapid  serial  radiography  following  the  injection  of 
radiopaque  substances  (26).  Similar  observations  have 
been  made,  most  elegantly,  in  the  full-time  human 
infant  by  Lind  and  Wegelius  who  were  able  to  make 
the  injections  and  perform  the  angiocardiography  be- 
fore the  first  breath  (129).  The  latter  have  also  con- 
firmed the  functional  relationship  between  the  venae 
cavae  and  the  atria  in  early  nonviable  infants  at  thera- 
peutic abortion. 

Regional  Blood  Flow 

Was  Sabatier  correct  in  suggesting  that  the  brain  is 
supplied  by  the  most  arterial  blood?  How  much  mix- 
ing is  there  of  the  superior  and  inferior  caval  blood 
in  the  right  auricle?  How  much  pulmonary  venous 
blood  is  added  to  the  inferior  caval  blood  in  the  left 
atrium?  Huggett,  who  was  the  first  to  carry  out  ex- 
periments on  the  living  fetus  with  an  intact  placental 
circulation,  found  that  the  oxygen  content  of  the 
carotid  artery  exceeded  that  of  the  umbilical  artery 
in  goats  (112);  Barcroft  observed  a  10  to  20  per  cent 


1626 


I!  Will','  II  >k     Ml       I  •  I  I  -i  Ml  il  I  >,,\ 


CIRCULATION    II 


100 


FORAMEN 
OVALE 


BODY 


L  HEART 


70 


130 


130 


R  HEART 


100 


■200- 


4-70- 

v    m  i/- 


DUCTUS 
ARTERIOSUS 

fig.  7.  To  show  that  both  sides  of  the  fetal  heart  work  in 
parallel;  the  approximate  volume  of  blood  flow  through  the 
principal  vessels,  in  the  lamb,  is  indicated  in  ml/kg/min. 
(From  G.  S.  Dawes.  Changes  in  the  circulation  at  birth.  Brit. 
Med.  Bull.  17:  149,  1 961.) 

difference  in  saturation  in  favor  of  the  carotid  artery 
in  the  sheep  (25).  Everett  and  Johnson  injected 
labeled  phosphorus  into  the  superior  or  the  inferior 
vena  cava  and,  from  its  partition  in  the  left  and  right 
atria,  were  also  in  favor  of  the  Sabatier  hypothesis 
(91).  Evidence  which  suggests  that  the  upper  half 
of  the  body  may  require  a  better  oxygen  supply  is 
provided  by  Spratt  who  added  metabolic  inhibitors 
to  the  developing  chick  embryo  in  vitro;  he  concluded 
that  the  developing  nervous  system  depended  pri- 
marily upon  oxidative  metabolism,  in  contrast  with 
the  heart  which  depended  chiefly  upon  anaerobic 
glycolysis  (177).  It  was  also  shown,  by  tissue  slice 
technique  in  the  sheep  that  the  requirements  of  the 
brain  per  gram  of  tissue  increased  during  the  last 
third  of  gestation  but  that  the  proportional  oxygen 
uptake  of  the  brain  per  kg  of  body  weight  remained 
constant,  at  about  five  times  the  adult  value  (53). 

Eranko  and  Karvonen,  however,  could  find  no 
difference  in  the  number  of  hemopoietic  foci  between 
the  lower  and  upper  limb  bone  marrow  of  fetuses 
which  might  be  expected  if  the  oxygen  tensions  of 
the  two  bloods  were  different  (90).  Dawes  and  his 
colleagues  observed  that  the  oxygen  content  of  the 
carotid  artery  only  exceeded  that  of  the  umbilical 
artery  by  6  per  cent,  when  both  were  sampled  simul- 
taneously, in  the  lamb  (76)  and  the  monkey  fetus 
(71);  greater  differences  were  observed  following 
hemorrhage,  constriction  of  the  umbilical  cord,  or 
hypoxia,  especially  in  young  fetuses  (68).  These  ob- 
servers also  approached  the  problem  more  quan- 
titatively by  estimating,  simultaneously,  the  oxygen 
content  of  the  blood  in  the  two  venae  cavae  and, 
after  the  two  streams  have  mixed,  in  the  pulmonary 


trunk  in  the  sheep  at  term.  Similar  analyses  were 
applied  to  the  three  other  positions  in  the  fetal  cir- 
culation where  blood  of  differing  oxygen  content 
meet,  namely  the  upper  part  of  the  inferior  vena 
cava,  the  left  atrium  and  the  junction  of  the  ductus 
arteriosus  with  the  descending  aorta.  From  these 
measurements  they  were  also  able,  by  making  certain 
assumptions,  to  calculate  the  blood  flow  in  all  the 
principal  vessels  as  a  fraction  of  the  cardiac  output 
(fig.  7) :  they  concluded  that  the  similarity  of  the  oxy- 
gen content  of  the  blood  supplying  the  upper  and 
lower  extremities  could  easily  be  accounted  for. 
Measurements  of  the  regional  blood  flows  and  oxygen 
utilizations  are  needed  to  prove  the  hypothesis  that 
the  course  of  the  circulation  in  the  fetus  is  designed  to 
ensure  the  supply  of  the  most  arterial  blood  to  the 
brain  and  coronary  circulation. 

The  blood  flow  through  the  various  fetal  organs 
and  through  the  placenta  will  vary  both  quantita- 
tively and  relatively  to  one  another  during  growth, 
and  this  theme  has  been  well  developed  by  Barcroft 
(25)  and  Barron  (28).  What  are  the  relative  propor- 
tions of  the  cardiac  output  which  perfuse  the  fetus 
and  the  placenta?  What  is  the  magnitude  of  the  pul- 
monary blood  flow  during  development?  Barcroft  & 
Kennedy  (24)  found  the  relative  distribution  of  the 
blood  between  the  fetus  and  the  fetal  placental  cir- 
culation in  the  sheep  to  change  during  growth  in 
such  a  manner  that  when  the  embryo  was  young,  the 
greater  part  of  its  blood  volume  was  in  the  placenta; 
halfway  through  gestation,  when  the  placenta  had 
reached  its  full  size,  the  position  was  reversed  and  the 
amount  of  blood  in  the  placenta  remained  constant 
while  that  in  the  fetus  increased.  The  anatomical 
limit  having  once  been  set,  the  rate  of  turnover  of  the 
blood  in  the  placenta  will  become  increasingly  im- 
portant and  the  fetal  heart  does  not  "keepe  holiday" 
(William  Harvey)  but  has  an  increasing  responsibil- 
ity to  meet  the  demands  of  growth;  the  increase  in 
cardiac  output  and  vasomotor  tone  will  ensure  the 
gradual  rise  in  arterial  pressure  upon  which  the 
umbilical  blood  flow  will  depend.  Barcroft  (25)  esti- 
mated that  at  least  50  per  cent  of  the  combined  car- 
diac output  perfused  the  placenta  in  the  goat  and 
in  the  sheep  near  term,  and  Dawes  el  al.  (76)  cal- 
culated a  figure  of  57  per  cent.  How  this  proportion 
changes  during  gestation  is  not  known.  Cineradio- 
graphic  observations  in  the  sheep  (26)  and  human 
infant  (129)  suggest  that  the  blood  flow  through  the 
fetal  lungs  is  a  small  proportion  of  the  combined 
cardiac  output  during  intrauterine  life.  Since  the 
development    of    blood    vessels    is    dependent    upon 


THE     FETAL    AND    NEONATAL    CIRCULATION 


i  *  >->  7 


genetic  and  environmental  factors  as  well  as  the 
pressure  within  them,  the  fact  that  the  great  vessels 
do  enlarge  and  the  pulmonary  vascular  bed  does 
increase  must  mean  that  there  is  an  increasing  vol- 
ume of  flow  during  intrauterine  life;  however,  it  is 
not  known  whether  the  proportion  of  this  blood  flow 
to  the  total  cardiac  output  changes  or  remains  con- 
stant during  development.  Dawes  et  al.  (76)  have 
estimated  that,  in  the  near  term  sheep  fetus,  about  10 
per  cent  of  the  combined  ventricular  output  perfuses 
the  lungs. 

Hepatic  Blood  Supply  and  the  Ductus  Venosus 

The  liver  is  probably  supplied  by  the  most  oxy- 
genated blood  in  the  body;  the  umbilical  vein  carries 
well-oxygenated  portal  blood  from  the  placenta 
and  a  hepatic  branch  leaves,  before  the  ductus  veno- 
sus, to  supply  the  left  lobe  of  the  liver,  nearly  two- 
thirds  of  the  whole  organ.  The  volume  of  this  flow 
is  large,  representing  over  50  per  cent  of  the  cardiac 
output  (since  the  umbilical  blood  flow  is  about  57% 
of  the  cardiac  output  in  the  lamb  and  probably  only 
a  small  proportion  passes  through  the  ductus  veno- 
sus), and  the  oxygen  tension  is  unlikely  to  be  greatly 
reduced  by  mixture  with  hepatic  arterial  blood. 
Emery  (89)  found  more  hemopoietic  foci  in  the  right 
side  of  the  liver  than  in  the  left  and  degenerative 
changes  are  observed  more  frequently  on  the  right 
side  of  the  liver  at  autopsy  in  stillborn  infants  and 
following  neonatal  deaths  (101).  It  is  possible  that  the 
reduction  in  oxygen  supply  to  the  liver,  following 
birth,  is  a  factor  in  the  development  of  physiological 
icterus  (178). 

The  presence  of  a  ductus  venosus  is  not  universal 
but  it  is  patent  in  the  lamb  and  monkey  and  in  the 
human  infant  at  term  (27,  71,  129);  at  the  junction 
with  the  umbilical  vein,  the  vessel  possesses  a  muscular 
sphincter,  which  is  innervated  by  postganglionic 
branches  of  the  vagus  nerve.  Cineangiography  sug- 
gested to  Barclay  et  al.  (26)  that  only  a  small  propor- 
tion of  the  umbilical  venous  blood  flow  passed  through 
the  ductus  venosus  in  the  lamb  but  no  direct  meas- 
urements have  yet  been  made.  It  has  been  suggested 
that  the  sphincter  closes  in  response  to  a  rise  in  um- 
bilical venous  return  to  the  heart  (155);  conversely 
it  may  regulate  hepatic  blood  flow  itself  or  the  placen- 
tal blood  flow  since  the  main  resistance  to  the  um- 
bilical blood  flow  resides  in  the  liver.  A  large  flow 
through  the  ductus  venosus  would  ensure  a  good 
supply  of  arterialized  blood  to  the  head  but  the  fact 
that  a  ductus  venosus  is  not  always  present  suggests 


that  no  special  mechanism  exists  for  supplying  the 
brain  with  the  most  arterialized  blood.  Experimental 
occlusion  of  the  ductus  venosus  in  the  mature  lamb, 
caused  no  significant  change  in  arterial  blood  pres- 
sure, heart  rate,  or  carotid  arterial  0>  saturation 
(12).  Rostral  to  the  ductus  venosus  the  umbilical 
vein  continues  as  the  portal  sinus  and  joins  the  portal 
vein  where  arterialized  and  venous  blood  meet  in 
unknown  quantities. 


FETAL    HEART 


The  development  of  activity  in  the  mammalian 
heart  has  been  observed  in  hanging  drop  cultures  of 
whole  embryonic  rat  vesicles  (96) :  the  earliest  con- 
tractions occurred  in  the  left  ventricle  and  were  fol- 
lowed by  a  slower  rhythm  in  the  right  ventricular 
tube;  when  the  two  ventricles  joined  the  left  became 
the  pacemaker.  The  auricles  beat  a  little  later  and  the 
sinus  venosus  last,  finally  bringing  the  ventricular 
rhythm  under  their  control  at  an  early  stage  in  de- 
velopment. 

Recording  of  the  electrical  activity  of  the  heart 
in  utero  has  not  been  frequently  attempted  in  experi- 
mental animals  but  would  provide  both  fundamental 
knowledge  of  the  development  of  the  propagated 
impulse  and  enable  the  fetal  heart  rate  to  be  counted 
with  minimal  disturbance  during  growth.  The  im- 
pulse is  large  enough  to  record  in  rabbit  and  guinea 
pig  fetuses,  15  g  in  weight  (32,  133).  Recording  of  the 
ECG  of  the  human  fetal  heart  in  utero,  using  leads 
placed  in  the  mother's  vagina  or  rectum,  or  on  her 
abdomen  has  been  employed  for  many  years  to 
monitor  the  heart  rate,  particularly  during  difficult 
labors  (127);  the  method  is  not,  however,  widely 
used  and  it  is  possible  that  the  electrophonocardio- 
graph  will  be  simpler  and  less  subject  to  interference 
from  the  maternal  heart  (175).  Electrocardiograms 
obtained  from  human  infants  at  Cesarean  section 
show  all  the  deflections  characteristic  of  the  adult  as 
early  as  the  second  month;  in  the  full-term  infant 
there  is  a  small  right  ventricular  preponderance 
corresponding  to  the  slightly  greater  relative  weight 
of  this  ventricle  at  birth.  The  left  ventricle  starts  to 
exceed  the  right  3  months  after  birth  and  by  6  months 
of  age  the  deflections  are  usually  identical  with  those 
of  the  adult;  this  is  due  both  to  growth  of  the  left 
ventricle  and  to  involution  of  the  right  ventricle 
(121).  The  T  wave  is  frequently  of  low  amplitude  at 
birth  and  becomes  negative  shortly  afterward  (178); 
the  sign  may  be  reversed  again  by  the  administration 


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CIRCULATION    II 


of  adrenaline  and  the  observers  attributed  this  to  a 
rise  of  pulmonary  arterial  pressure. 

Heart  Rate.  Regulating  Mechanisms 

In  the  smaller  animals  systematic  correlation  of 
the  fetal  heart  rate  with  age  has  not  been  frequently 
made  and  when  the  uterus  is  opened  the  data  may  be 
questionable  on  account  of  cooling  and  hypoxia 
(189).  In  the  guinea  pig  and  the  rabbit  the  heart 
rate  has  been  counted  from  ECG  records  taken  with 
the  uterine  wall  intact  and  the  maternal  abdomen 
opened  under  saline  at  37  C  (133);  the  heart  rates  in 
both  increased  from  160  to  320  per  min  during  20  to 
67  days  in  guinea  pig  and  25  to  31  days  in  the  rabbit 
fetuses,  but  the  range  was  wide,  possibly  on  account 
of  intrauterine  hypoxia.  The  maternal  heart  rates 
also  varied  widely  and  within  the  same  range  as  the 
full-term  fetus.  In  the  guinea  pig  fetus  a  slight  slow- 
ing occurred  when  the  uterine  wall  was  incised  and 
allowed  to  contract  around  the  large  vessels  supply- 
ing the  placenta.  In  the  rabbit  fetus  postmaturity 
did  not  influence  the  heart  rate  (134).  The  heart 
rate  of  the  monkey  fetus  at  Cesarean  section  is  140 
to  1  70  beats  per  min  (71 ). 

Barcroft  and  colleagues  (25)  counted  the  lamb 
heart  rate  in  utero  with  a  stethoscope  and  found 
that  it  increased  during  the  first  two-thirds  of  preg- 
nancy to  150  beats  per  min  and  thereafter  fell  slowly 
to  128  beats  per  min  at  term;  in  a  larger  series  in 
which  the  heart  rates  were  obtained  from  blood 
pressure  tracings,  the  rate  rose  throughout  gestation 
to  about  200  beats  per  min  at  term  (39).  The  ewe 
heart  rate  is  normally  100  to  120  per  min.  In  two 
studies  in  humans  the  fetal  heart  rate  was  also  ob- 
served to  be  faster  in  midfetal  life,  156  per  min,  than 
just  before  birth,  when  the  average  was  142  per  min. 
These  differences  are  small,  however,  and  probably 
not  significant;  in  one  study  the  counts  were  made 
with  a  stethoscope  (1  76)  and  in  the  second  from  ECG 
recordings  (192). 

The  pattern  of  changes  in  fetal  heart  rate  in  utero 
will  be  determined  by  the  rate  of  development  of  the 
pacemaker  rhythm  and  the  onset  of  subsequent  vagal 
restraint.  The  anatomical  pathways  of  the  parasym- 
pathetic system  are  laid  down  early,  and  vagal  fibers 
may  be  observed  in  the  A-V  bundle  in  a  6-weeks- 
old  human  fetus  (184),  before  the  inhibitory  response 
of  the  isolated  cardiac  muscle  to  acetylcholine  is  ob- 
served (194).  Vagal  tone  is  not  apparent  in  utero  or 
subsequently  in  the  guinea  pig,  rabbit,  or  cat:  the 
full-term  fetal  heart  rates  are  the  same  as  in  the  adult, 


and  in  the  cat  the  heart  rate  is  uninfluenced,  in  both 
the  newborn  and  the  adult,  by  section  of  the  vagus 
nerves  (114);  the  latter,  however,  is  not  particularly 
good  evidence.  Vagal  tone  was  considered  by  Bar- 
croft and  colleagues  (25)  to  be  present  in  the  sheep 
fetus  toward  term,  for  they  found  that  bilateral  sec- 
tion of  these  nerves  increased  the  heart  rate;  this, 
however,  was  not  confirmed  by  Born  et  al.  (39). 
Stimulation  of  the  peripheral  cut  end  of  the  vagus 
nerve  will  cause  bradycardia  in  the  sheep  fetus  half- 
way through  gestation,  though  the  heart  will  re- 
spond to  intravenous  acetylcholine  earlier  (74). 
The  isolated  fetal  heart  is  very  sensitive  to  acetyl- 
choline but  it  is  not  possible  to  correlate  this  with  the 
age  of  the  fetus  (19).  The  influence  of  atropine  on 
fetal  heart  rates  and  a  comparison  with  its  action  in 
the  adult  of  the  same  species  is  practically  unknown; 
late  in  intrauterine  life  atropine  in  the  fetal  circula- 
tion causes  an  acceleration  of  the  fetal  guinea  pig 
heart  (97).  In  the  pregnant  woman  atropine  in  the 
maternal  circulation  ( 1 1  o)  abolishes  asphyxial  fetal 
bradveardia,  but  there  is  no  evidence  for  its  influence 
on  the  normal  heart  rate  nor  independent  evidence 
for  its  placental  transfer. 

The  sympathetic  pathways  are  known  to  be  laid 
down  early  in  development  in  the  kitten  and  the  hu- 
man fetus  (44,  103);  the  lamb  heart  is  able  to  acceler- 
ate in  response  to  intravenous  adrenaline  two-thirds 
of  the  way  through  the  gestation  period  and  at  term 
the  sensitivity  of  the  fetal  heart  is  little  different  from 
that  of  the  adult  in  both  the  sheep  (74)  and  the  rabbit 
(70) ;  earlier  observers  frequently  found  a  decreased 
sensitivity  and  this  was  possibly  due  to  anoxia  (194). 
Again,  the  isolated  heart  is  sensitive  to  adrenaline 
and  noradrenaline  and  there  is  no  correlation  with 
the  age  of  the  fetus  (19). 

Cardiac  Output 

Fetal  cardiac  output  was  measured  in  the  goat 
both  cardiometrically  and  using  the  Fick  principle 
by  Barcroft  and  his  colleagues  (25);  they  estimated 
that  it  increased  from  1 1 3  ml  per  kg  body  weight  per 
min  at  89  days  of  age  to  193  ml  per  kg  body  weight 
per  min  at  150  days,  full  term.  Dawes  et  al.  (75)  cal- 
culated that  the  cardiac  output  of  both  ventricles  in 
the  lamb  at  term  was  235  ml  per  kg  per  min,  know- 
ing the  umbilical  blood  flow  and  estimating  that  it 
formed  about  57  per  cent  of  the  combined  cardiac 
output.  Assali  et  al.  (17)  made  similar  calculations 
in  human  fetuses  of  9  to  28  weeks  gestation  and  found 
the  cardiac  output  to  be  200  ml  per  kg  per  min; 


THE     FETAL    AND    NEONATAL    CIRCI   LATION 


[629 


their  assumptions  a)  that  the  umbilical  blood  flow  is  a 
constant  fraction  of  the  cardiac  output  during  this 
period  of  rapid  growth,  and  h)  that  the  umbilical 
blood  flow  forms  the  same  proportion  of  the  cardiac 
output  in  both  the  human  and  in  the  sheep  fetus  have, 
to  date,  no  foundation. 


ARTERIAL    BLOOD    PRESSURE 

Systemic  Pressure 

The  rate  of  increase  in  systemic  arterial  pressure 
during  gestation  varies  among  the  species  and  the 
final  values  at  term  correspond  most  nearly  to  the 
requirements  of  the  newly  born:  for  instance,  in  the 
helpless  newborn  of  the  rat  and  rabbit  the  mean  pres- 
sure in  the  carotid  artery  is  only  30  mm  Hg  after  21 
and  31  days  of  gestation,  respectively  (49,  70);  the 
newborn  kitten  and  puppy  are  also  born  with  ar- 
terial pressures  of  30  mm  Hg  after  67  days  (114) 
while  the  active  guinea  pig  is  born  with  an  arterial 
pressure  of  50  mm  Hg  after  a  similar  time  in  utero. 
Arterial  pressures  of  60  to  70  mm  Hg  are  observed  in 
the  newborn  lamb  and  kid  following  147  days  ges- 
tation (25),  and  in  the  newborn  human  babe  after 
an  intrauterine  life  of  twice  this  duration  (196). 
The  rhesus  monkey  has  a  mean  arterial  pressure  of 
about  55  mm  Hg  at  birth  after  160  days  gestation 
(71).  An  increase  in  arterial  pressure  during  intra- 
uterine life  must  assist  in  increasing  the  umbilical 
blood  flow  and  the  opportunity  for  exchange  between 
the  mother  and  fetus;  however,  this  is  only  one  means 
of  meeting  the  increasing  demands  of  growth,  and 
the  potentialities  of  the  placental  and  fetal  tissues 
vary  among  the  species  (98). 

The  course  of  the  rise  in  arterial  blood  pressure 
during  intrauterine  life  is  shown  in  figure  8  for  the 
lamb.  It  is  impossible  to  assess  the  relative  parts 
played  by  alterations  in  cardiac  output  and  the  de- 
velopment of  vasomotor  tone  in  contributing  to 
these  changes.  After  about  90  days  gestation  in  the 
lamb,  when  the  arterial  pressure  rises  more  rapidly, 
the  heart  rate  continues  to  increase  but  no  cardiac 
output  measurements  are  available;  Barcroft's  (25) 
results  in  the  goat  suggest  that  there  may  be  an 
increase  in  cardiac  output  in  relation  to  body  weight 
from  go  days  onward  and,  as  the  umbilical  blood 
flow  in  the  lamb  decreases  in  relation  to  body  weight 
during  the  same  period,  the  mean  body  blood  flow  is 
probably  increased.  However,  the  cardiac  output  at 
term  is  greater  per  kg  of  body  weight  than  in  the 


adult  and  the  low  arterial  pressure  may  be  accounted 
for  by  a  low  peripheral  resistance:  as  will  be  seen, 
this  low  resistance  is  probably  due  to  low  tonic  ac- 
tivity of  both  nervous  and  chemical  regulating  mecha- 
nisms. 

Pulmonary  Artery  Pressure 

In  utero,  before  the  lungs  are  inflated  with  air 
there  is  no  good  reason  why  the  pulmonarv  vascular 
resistance  should  be  widely  different  from  the  vascu- 
lar resistance  elsewhere  in  the  growing  fetus.  Ardran 
et  al.  (13)  find  in  the  lamb  that  the  pressure  in  the 
left  pulmonary  artery  is  about  5  mm  Hg  higher  than 
that  in  the  carotid  artery,  which  suggests  that  the 
vascular  resistance  in  the  lungs  before  birth  is  pos- 
sibly slightly  higher  than  the  combined  resistance  of 
the  fetal  tissues  and  the  placenta;  this  has  recently 
been  confirmed  by  Assali  et  al.  (16).  In  keeping  with 
these  observations  are  the  findings  that  the  thickness 
of  the  walls  of  the  two  ventricles  is  approximately  the 
same  during  development,  with  a  slight  preponder- 
ance of  the  right  over  the  left,  in  the  lamb  and  in  the 
human  infant  at  birth  (66). 

Development   of  the   Cardiovascular   Reflexes  and  the 
Responses  to  Asphyxia  and  Hormones 

The  anatomical  pathways  for  the  cardiovascular 
reflexes  are  laid  down  early  in  development  in  both 
the  human  fetus  (44)  and  in  the  cat  (103),  but,  as 
predicted  by  Barcroft,  though  the  machinery  is 
ready  it  may  not  be  functional  and  the  stage  of 
gestation    at   which   the   cardiovascular   reflexes   are 


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fig.  8.  Systemic  blood  pressure  of  fetal  lambs,  under 
dialurethane  (o)  or  pentobarbitone  (•)  anesthesia.  [From 
Dawes     (66).] 


1630 


HANDBOOK    (J1-     I'HYSIOI.OOY 


CIRCULATION     II 


operative  varies  among  the  species.  The  earlier 
work  is  described  by  Barcroft  (25)  and  the  later  by 
Dawes  and  his  colleagues  (39,  70,  71,  74). 

The  responses  to  asphyxia  and  to  the  intravenous 
administration  of  hormones  have  been  most  gener- 
ally used  to  determine  the  activity  of  the  cardio- 
vascular system  in  the  fetus:  the  low  resistance  of  the 
placenta,  the  low  arterial  oxygen  tension,  and  the 
fetal  course  of  the  circulation  must  also  influence  the 
final  operation  of  the  reflexes.  Quantitative  data  are 
difficult  to  obtain  when  both  the  peripheral  and  cen- 
tral mechanisms  have  not  yet  reached  a  steady  rela- 
tionship with  each  other.  However,  in  the  lamb,  the 
steeper  rise  in  arterial  pressure  which  occurs  from 
90  days  onward  approximately  coincides  with  the 
development  of  increasing  responsiveness  to  asphyxia, 
as  judged  by  the  rise  in  arterial  pressure  and  heart 
rate  (39) :  further,  the  removal  of  sympathetic  tone, 
following  the  injection  of  a  ganglion-blocking  agent 
such  as  hexamethonium  causes  a  greater  fall  of 
blood  pressure  toward  term.  The  tone  of  the  vasomo- 
tor mechanisms  is  probably  not  fully  developed  at 
birth  for  the  mean  arterial  pressure  is  about  40  mm 
Hg  lower  than  in  the  adult  sheep.  In  the  rabbit, 
cat,  and  dog,  with  low  arterial  pressures  at  term,  the 
vasomotor  mechanisms  are  probably  still  less  de- 
veloped at  birth  (70,  1 14). 

The  pattern  of  the  response  of  the  developing 
cardiovascular  system  to  asphyxia  alters  with  gesta- 
tional age.  The  bradycardia  which  follows  either  the 
occlusion  of  the  umbilical  cord  or  the  administration 
of  low  oxygen  tensions  to  the  mother  is  probably 
brought  about  in  a  variety  of  ways.  In  the  early  fetus 
of  all  species  cardiac  slowing  is  delayed,  it  is  due  to 
the  direct  effect  of  the  hypoxia  on  the  pacemaker 
and  is  the  cause  of  the  ensuing  hypotension;  this 
depression  of  the  pacemaker  is  the  final  cause  of 
death  at  any  age  when  hypoxia  is  prolonged.  Later  in 
development,  a  transient  bradycardia  of  swift  onset 
is  observed,  which  is  due  to  stimulation  of  the  medul- 
lary vagal  center;  later  still,  this  slowing  is  succeeded 
by  a  tachycardia,  due  to  stimulation  of  the  medullary 
sympathetic  center.  This  response  is  enhanced  by 
cutting  the  vagus  nerves.  The  third  type  of  brady- 
cardia is  reflex  in  origin  and  occurs  in  response  to 
the  rise  in  blood  pressure  when  vasomotor,  baro- 
receptor,  and  chemoreceptor  activity  is  developed; 
the  bradycardia  seen  in  the  fully  developed  lamb  or 
human  fetus  is  probably  reflex  in  origin  provided  the 
asphyxia  is  of  short  duration.  It  is  noteworthy  that 
prolonged  asphyxia  or  hypoxia  reduces  the  heart 
rate  to  between  60  to  80  beats  per  min  in  most  species; 


this  rate  is  sustained  for  varying  periods  before  ar- 
rhythmia occurs.  Both  the  tachycardia  and  the 
reflex  bradycardia  during  asphyxia  may  be  enhanced 
by  the  activity  of  the  adrenal  medulla  (54).  Bradv- 
cardia  is  also  the  primary  response  to  hypoxic  stimu- 
lation of  the  chemoreceptors  in  the  adult  animal  (60, 
61);  however,  if  the  brain  is  also  hypoxic,  tachycardia 
usually  results  from  hypoxia  of  these  areas  and  this 
tachycardia  is  enhanced  it  their  oxygen  supply  is 
increased. 

Quantitative  data  relating  the  oxygen  saturation 
of  the  fetal  blood  at  which  the  changes  in  heart  rate 
take  place  in  utero  have  been  provided  in  the  near- 
term  lamb  by  Born  et  til.  (39),  and  by  Reynolds  & 
Paul  (161).  These  observers  are  not  entirely  in 
agreement  with  each  other;  both  administered 
nitrogen  containing  low  concentrations  of  oxygen  to 
the  mother  under  barbiturate  anesthesia.  Born  el  al. 
delivered  their  lambs  by  Cesarean  section  and  ob- 
served an  increase  in  heart  rate  and  blood  pressure 
during  the  administration  of  7.5  to  5.0  per  cent  oxy- 
gen to  the  mother  which  caused  the  fetal  carotid 
arterial  oxygen  saturation  to  fall  to  50  to  35  per  cent; 
bradycardia  did  not  occur  until  the  arterial  oxygen 
saturation  was  below  20  per  cent  for  some  minutes 
(fig.  9).  Reynolds  and  Paul's  lambs  were  kept  in 
utero  and  blood  pressures  and  blood  samples  were 
obtained  from  branches  ot  the  umbilical  vessels 
exposed  through  a  small  uterine  incision.  Their 
results  were  not  so  clear  cut  for  fetal  tachycardia  or 
bradycardia  might  be  observed  following  the  ad- 
ministration of  13  per  cent  and  10  per  cent  oxygen 
to  the  mother  and  6  per  cent  oxygen  usually  caused 
fetal  bradycardia;  it  is  to  be  noted  that  the  adminis- 
tration of  13  per  cent  oxygen  reduced  the  arterial 
oxygen  saturation  to  30  per  cent,  a  figure  which  was 
obtained  by  Born  et  til.  with  much  lower  oxygen  mix- 
tures. In  the  guinea  pig,  also  anesthetized  with 
Nembutal,  the  administration  of  10  per  cent  oxygen 
to  the  mother  caused  a  slight  fall  in  fetal  heart  rate, 
during  the  last  third  of  gestation,  while  6  per  cent 
oxygen  always  caused  marked  bradycardia  (97,  133). 

The  absence  of  cardiac  acceleration  in  response  to 
asphyxia  early  in  gestation  is  not  due  to  the  inability 
of  the  young  heart  to  increase  its  rate,  for  it  will 
respond  to  adrenaline  early  in  development:  in  the 
lamb  the  heart  is  more  sensitive  to  adrenaline  than 
are  the  peripheral  vessels  for  tachycardia  occurs  at  a 
time  when  the  increase  in  pressure  is  relatively  small; 
later  the  rise  in  blood  pressure  is  greater  and  the 
increase  in  heart  rate  diminished,  due  to  the  de- 
velopment of  baroreceptor  reflex  activity  (74)-  Acetyl- 


THE    FETAL    AND    NEONATAL    CIRCULATION 


I  63  I 


fig.  9.  Response  of  the  fetal  heart  rate  and  arterial  pressure 
in  the  lamb  during  hypoxia.  The  rise  in  blood  pressure  is  accom- 
panied by  a)  tachycardia  during  the  administration  of  10' ",  <  > 
to  the  mother,  b)  bradycardia  during  ventilation  with  6%  Oj. 
[From  Born  et  at.  (39)-] 


choline  also  causes  bradycardia  and  hypotension 
early  in  gestation.  Dawes  and  his  colleagues  consider 
that  the  range  of  effectiveness,  per  kg  of  body  weight, 
of  those  autonomic  drugs  does  not  differ  from  60  to 
160  days  in  the  lamb,  and  is  about  the  same  as  in 
the  adult  for  both  the  lamb  and  the  fetal  rabbit  (70, 
74).  In  the  lamb  at  term,  with  ventilation  established, 
adrenaline  and  noradrenaline  cause  a  greater  rise  in 
blood  pressure  following  occlusion  of  the  umbilical 
cord,  when  the  low  resistance  circuit  of  the  placenta 
is  absent.  Equal  doses  of  these  drugs  are  also  more 
effective  when  injected  into  the  femoral  vein  and  pass 
straight  to  the  left  side  of  the  heart  and  to  the  coro- 
nary circulation,  than  after  injection  into  the  jugular 
vein  when  the  drug  has  first  to  traverse  the  lungs. 
Since  suprarenal  venous  blood  enters  the  inferior 
vena  cava,  there  will  be  the  possibility  of  a  rise  in 
the  fetal  blood  pressure  and  an  increase  in  the  placen- 
tal blood  flow  during  stress;  the  effectiveness  of  sym- 
pathomimetic amines  liberated  during  the  stress  of 
asphyxia  in  the  fetus  may  be  limited  by  the  reduced 
responsiveness  of  the  cardiovascular  system  during 
asphyxia  (195).  The  adrenal  glands  and  accessory 
organs  contain  a  pressor  substance  early  in  develop- 
ment in  the  sheep  (54)  and  in  the  human  infant 
(186).  It  is  also  known  that  sympathomimetic  amines 
are  released  into  the  adrenal  veins  during  asphyxia 
by  about  90  days  gestation  in  the  sheep;  this  libera- 
tion is  due  to  the  direct  action  of  asphyxia  on  the 


adrenal  medulla.  The  splanchnic  nerves  do  not 
take  part  in  the  release  until  shortly  before  term. 
It  is  perhaps  significant  that  noradrenaline  predomi- 
nates for  its  pressor  activity  is  the  greater  and  the 
stimulating  action  on  metabolism  apparently  more 
effective  than  that  of  adrenaline  in  the  young  animal 
(136). 

The  catecholamine  concentration  of  human  fetal 
heart,  kidney,  and  lung  during  the  first  trimester 
was  found  to  be  roughly  similar  to  that  in  adult 
organs  though  the  brain  contained  much  smaller 
concentrations  than  in  the  adult  (99);  again,  norepi- 
nephrine predominated  suggesting  its  early  appear- 
ance at  sympathetic  nerve  endings,  but  no  dopamine 
was  found  in  any  tissue  studied.  5-Hydroxytrypta- 
mine  is  found  in  the  blood  platelets  of  the  fetal  guinea 
pig  two-thirds  of  the  way  through  gestation  and  is 
still  lower  than  the  adult  at  term  (174);  the  brain 
levels,  however,  approximate  to  those  of  the  adult 
at  term  (120).  The  high  estrogen  and  progesterone 
content  of  fetal  blood  (4)  may  influence  both  cardio- 
vascular development  and  the  responses  of  the  vessels. 
The  action  of  many  other  pharmacological  substances 
on  the  fetus  has  been  reviewed  recently  (20). 

The  importance  of  cardiovascular  regulating 
mechanisms  to  the  fetus  in  utero  is  questionable; 
asphyxia  and  hemorrhage  are  probably  the  only 
stresses  which  the  fetus  encounters.  The  responses  to 
hemorrhage  have  not  been  frequently  studied  and 
Mott  suggests  that  they  might  possibly  be  a  better 
indication  of  the  homeostatic  capacity  of  the  fetal 
circulation  than  the  response  to  asphyxia  since  the 
fetus  is  more  resistant  to  hypoxia  than  the  adult 
(140). 


FETAL  PLACENTAL  BLOOD  FLOW 

Effective  Perfusion  Pressure.  Resistant  e  0] 
the  Placental  Circulation 

The  effective  perfusion  pressure  across  the  fetal 
placental  circulation  increases  as  the  arterial  pressure 
rises  with  gestational  age.  Figure  10  shows  some  com- 
parative values  for  umbilical  arterial  and  venous 
pressure  measurements  in  the  lamb  (25).  Reynolds  & 
Paul  (160)  have  observed  umbilical  venous  pressures 
as  high  as  35  mm  Hg  in  the  lamb  at  term;  the  reason 
for  this  rise  in  umbilical  venous  pressure  may  be  re- 
lated to  an  increased  resistance  to  flow  in  the  fetal 
liver,  through  which  most  of  the  umbilical  blood 
passes    during    development.    The    sphincter    of   the 


1632 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


1     "T" 

1 

SO 

— 

•  Umbilical  art 
0  Umbilical  veir 

>ry 

1 

1 

00 

X 

E 
B 

< 1 

u 

3 
to 

• 

< 

1 

» 
• 

• 

u 

Pu 

1 

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20 

1 

4 

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j 

i 

0 

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1 

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i 

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1 

<x 

1       < 

) 

1  ( 

> 

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0 

Fetal  age -days 

1 .                   1 

50  70  90  110  130  150 

fig.  10.  Pressures  in  umbilical  veins  and  arteries  at  successive 
fetal  ages  in  the  lamb.  [From  Barcroft  (25).] 

ductus  venosus  may  regulate  this  pressure  and  thus 
both  placental  and  hepatic  blood  flows  in  this  species. 

From  figure  10  it  can  be  seen  that  the  pressure  drop 
across  the  placenta  is  about  40  mm  Hg  in  the  lamb  at 
term  and,  in  comparison,  the  pressure  drop  in  the 
systemic  circulation  is  of  the  order  of  60  mm  Hg;  since 
about  60  per  cent  of  the  cardiac  output  goes  to  the 
placenta  the  resistance  in  the  fetal  placental  circula- 
tion is  about  half  that  of  the  fetal  systemic  circulation. 
The  resistance  in  the  fetal  liver  is  still  lower  than  in  the 
placenta  for  the  greater  part  of  the  umbilical  blood 
flow  traverses  this  organ  with  a  pressure  fall  of  only 
20  mm  Hg.  No  arteriolar  regulating  mechanism  has 
been  described  in  the  chorionic  villi  but  B0e  (37)  has 
demonstrated,  in  the  human  placenta,  the  existence 
of  a  shunt  mechanism  within  the  villous  circulation 
which  may  possibly  open  up  during  asphyxia  and 
increase  the  fetal  placental  reserve.  The  walls  of  the 
capillaries  in  the  chorionic  villi  have  neither  smooth 
muscle  nor  a  nerve  supply,  but  in  teased  specimens 
their  endothelium  has  been  observed  to  undergo 
spontaneous  rhythmic  movements  and  to  be  con- 
stricted by  histamine  and  acetylcholine  (179). 

When  the  placenta  has  reached  its  maximum 
weight  in  the  lamb,  at  80  days  gestation,  the  pressure 
drop  across  the  placenta  is  25  mm  Hg;  during  the  last 
third  of  intrauterine  life  this  pressure  drop  only  in- 
creases by  a  further  15  mm  Hg  while  the  umbilical 


140 


50 
MM  HG. 
AORTIC  -UV    PRESSURE 

fig.  1 1 .  Pressure  How  curves  for  the  fetal  placental  circula- 
tion at  90,  115,  and  140  days  gestation  in  the  sheep.  [From 
Dawes  (69).] 

blood  flow  is  increasing  tenfold.  From  pressure-flow 
measurements  in  the  umbilical  circulation  (fig.  11) 
Dawes  concludes  that  the  increase  in  flow  is  chiefly 
brought  about  by  a  decrease  in  placental  vascular 
resistance;  at  the  end  of  term  no  further  decrease  in 
resistance  occurs  and  the  increasing  flow  is  dependent 
on  the  rising  pressure  gradient  (69). 

Umbilical  Blood  Flow 

Umbilical  blood  flow  has  been  measured  in  the 
sheep  fetus  the  most  frequently  and  by  a  variety  of 
methods.  Cooper  el  at.  (56)  used  the  venous  occlusion 
plethysmograph  (see  fig.  12)  and  found  that  the  blood 
flow  per  kg  of  fetal  weight  ranged  from  250  ml  per 
min  at  60  days  gestation  to  about  1 30  ml  per  min  at 
term,  147  days.  The  actual  flows  and  their  decrease 
in  relation  to  body  weight  are  in  good  agreement 
with  the  later  observations  of  Acheson  el  al.  (1)  using 
the  same  technique  but  a  different  breed  of  sheep 
(fig.  13).  Reynolds  et  al.  (158)  made  a  few  measure- 
ments of  the  blood  flow  in  the  umbilical  artery 
in  the  lamb  by  cineangiography  and  concluded  that 
there  was  no  reduction  in  relation  to  body  weight  at 
the  end  of  term;  this  suggests  that  the  fall  in  blood 
flow  using  the  plethysmograph  may  be  an  artifact 
due  to  the  greater  sensitivity  of  the  umbilical  vessels 
at  this  time.  In  the  guinea  pig  the  venous  occlusion 
plethysmograph  gave  values  of  45  to  108  ml  per  kg 
per  min,  with  no  tendency  to  change  as  the  fetal 
weight  increased  (172):  the  arterial  pressure  is  lower 


THE    FETAL    AND    NEONATAL    CIRCULATION 


1633 


Soft  rubber 
seal 


To  volume 
recorder 


Perspex  curtain      Perspex  window 
hanging  into  /for  direct 

saline  to  /  observation  of 

make  fluid  seal  /  umbilical  vessels 


Pneumatic 
bag  for 
compression 
of  cord 


Umbilical 
cord 


Electric  lamp 


Tinned  brass  tank 
fig.  12.  Section  through  a  fetal  plethysmograph  at  the 
point  of  entry  of  the  umbilical  cord.  The  umbilical  cord  lies  on 
a  gently  curved  perspex  strip.  [From  A.  D.  M.  Greenfield.  A 
foetal  plethysmograph.  J.  Phyiiol.,  London  108:  158  (Fig.  2), 
1949] 


J00 

O 

-s 

0 

< 

0 

ui 

a 

5? 

-1 

O 

u. 

^•Oy 

0 

UJ 

200 

.  0 
0 
0 

• 

X^-^j5 

<■ 

UJ 

0: 

m~ 

0 

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0  c* 

7 — -^^    °  0  --^ 

-l< 

vrc---:^5~~~ 

too 

-31 

3 

• 
GESTATION  AGE     (DAYS) 

0  , 

fig.  13.   Umbilical   blood   flow   in   the   lamb,   per   kg   body 

weight  during  gestation.  [Data  of  K.  E.  Cooper  el  al.  (O ) 

G.  H.  Acheson  el  al.  (• ).]  The  thin  continuous  curved  line 

indicates  the  weight  increase  per  cent  per  day.  [From  Acheson 
el  al.   (1).] 

than  in  the  sheep  and  the  pressure  gradient  between 
artery  and  vein  is  likely  to  be  smaller  and,  assuming 
that  the  vascular  resistances  are  similar,  this  will 
account  for  the  lower  placental  blood  flow.  When 
these  umbilical  blood  flow  rates  are  compared  with 
growth  curves  it  is  observed  that  5.5  liters  of  blood 
are  required  to  lay  down  1 .0  g  of  fetal  tissue  in  the 
sheep,  as  compared  with  only  1.3  liters  in  the  guinea 
pig,  (98).  Using  an  electromagnetic  flowmeter  Assali 
et  al.  (17)  found  the  umbilical  arterial  flow  in  nine 
human  fetuses  of  12  to  28  weeks  gestation  to  range 
between  94  and  127  ml  per  kg  per  min.  It  is  remark- 
able that  vessels  so  contractile  as  those  in  the  cord 
have  yielded,  on  the  whole,  reproducible  results. 
Each  worker  has  been  most  aware  of  the  experimen- 


tal errors  involved  in  his  measurements.  Dawes  & 
Mott  (72)  also  point  out  that  the  venous  occlusion 
plethysmograph  has  a  disadvantage  in  the  present 
application,  for  when  the  umbilical  vein  is  temporarily 
occluded  the  return  to  the  heart  must  be  reduced; 
they  found  that  a  velodyne  flowmeter,  providing  a 
direct  measure  of  flow,  inserted  into  the  vein  in  the 
abdomen  gave  results  which  were  higher  than  those 
obtained  by  the  plethysmograph. 

The  umbilical  blood  flow  may  be  increased  at  the 
end  of  term  in  the  lamb  by  reducing  the  fetal  ar- 
terial oxygen  saturation  (39).  This  is  probably  mainly 
due  to  the  rise  in  arterial  pressure  caused  by  the  re- 
sponse of  the  fetal  vasomotor  center  to  the  altered 
chemical  composition  of  the  blood.  Reynolds  &  Paul 
(160)  found  that  no  rise  in  umbilical  venous  pressure 
accompanied  the  rise  in  umbilical  arterial  pressure 
and  suggested  that  the  tone  of  sphincter  of  the  ductus 
venosus  was  decreased  in  response  to  the  increased 
umbilical  venous  flow.  The  injection  of  adrenaline 
into  the  femoral  or  jugular  vein  of  the  fetus  causes  an 
increase  of  umbilical  blood  flow  which  is  proportional 
to  the  rise  in  arterial  blood  pressure  (74)  (fig.  14). 
Isolated  umbilical  vessels  are  very  sensitive  to  the 
vasoconstrictor  action  of  adrenaline  and  these  results 
suggest  that  the  hormone  is  destroyed  before  it  reaches 
the  umbilical  vessels;  no  figures  are  available  to 
show  how  the  hormone  influences  the  resistance  in 
the  placenta.  The  umbilical  blood  flow  is  reduced 


100 


80 


60 


40 


20 


§5 

o 


-  o 
o 


.0 
h  E 

"o 

V 


O 


•o 


O    o° 

•  cfo 


o 


Increase  of  systemic  blood  pressure  (%) 
l l I i i i l_ 


20  40  60 

fig.  14.  Increase  in  umbilical  blood  flow  following  the  in- 
jection of  adrenaline  (•)  or  noradrenaline  (O)  in  the  mature 
fetal  lamb.  [From  Dawes  el  al.  (74).] 


1634 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


when  the  arterial  pressure  falls  following  the  injec- 
tion of  hypotensive  drugs  such  as  acetylcholine  and 
hexamethonium  into  the  fetal  circulation  (74)  and 
following  severe  hvpoxaemia  of  10  to  1 r,  min  duration 
(69)- 


Oxygen  Requirements  and  Environment  of  the  Fetus 

Primarily  dependent  upon  the  maternal  placental 
circulation,  the  fetal  heart  provides  an  umbilical 
blood  flow  which,  under  normal  conditions,  main- 
tains a  steady  oxygen  consumption  of  4  to  6  ml  per 
kg  body  weight  per  min  in  both  the  lamb  during  the 
last  half  of  gestation  ( 1 )  and  in  the  human  fetus  of  9 
to  28  weeks  gestation  (17):  this  represents  an  oxygen 
consumption  in  relation  to  weight  comparable  with 
the  adult  and  the  constancy  is  remarkable  in  view  of 
the  changing  oxygen  utilization  of  the  various  organs, 
and  their  varying  weights  in  relation  to  each  other, 
during  development.  Huckabee  et  al.  ( 1 1  1 )  point 
out  that  without  a  knowledge  of  the  anaerobic  metab- 
olism of  the  fetus  it  is  impossible  to  obtain  an  accurate 
estimate  of  the  energy  requirements  of  growth  from 
the  quantity  of  oxygen  consumed  alone;  however, 
there  is  no  good  evidence  for  anaerobic  metabolism 
in  the  normal  fetus  for  blood  lactate  levels  are  com- 
parable with  the  adult  (71).  Huckabee  et  al.  also 
point  out  that  the  metabolic  rate  of  the  fetus,  if  it 
were  known,  is  not  synonymous  with  the  metabolic 
rate  required  for  the  life  and  growth  of  the  fetus  and 
the  metabolic  needs  of  the  placenta  must  be  included. 
These  observers  found  in  the  goat,  as  did  Assali  et  al. 
(17)  in  the  human,  that  the  oxygen  consumption 
of  the  pregnant  uterus  was  about  10  ml  per  kg  per 
min;  the  calculations  were  made  lrom  uterine  blood 
flow  and  A-V  O2  differences.  But,  while  Assali  et  al. 
consider  the  placenta  to  have  a  greater  oxygen 
consumption  than  the  fetal  tissues,  Huckabee  et  al., 
from  uterine  oxygen  utilization  measurements  after 
fetal  death,  suggest  that  this  may  be  the  reverse; 
the  latter  estimate  of  fetal  oxygen  consumption,  as 
approximately  10  ml  per  kg  per  min,  would  agree 
with  determinations  of  the  minimal  oxygen  consump- 
tion of  the  newborn  lamb.  However,  Dawes  and 
Mott  have  shown  that  such  a  high  oxygen  consump- 
tion is  characteristic  of  the  newborn  only  and  is 
attained  at  different  ages  in  the  different  species; 
further,  they  have  demonstrated  that  this  increase  in 
oxygen  consumption  is  not  dependent  upon  the  raised 
arterial  oxygen  saturation  following  the  establishment 
of  respiration  for  it  does  not  occur  in  immature  lambs 


delivered    by   Cesarean   section   and   artificially  ven- 
tilated (72). 

What  is  the  oxygen  environment  of  the  fetal  tissues 
in  utero?  Recently,  Misrahy  et  al.  (135)  have  measured 
the  oxygen  availability  (a02)  in  fetal  brain  and  kid- 
ney, in  a  number  of  species  under  Nembutal  anes- 
thesia. Nondiffusion  limited  polarographic  elec- 
trodes, too  n  in  diameter,  with  a  circumferential 
recording  surface,  2  mm  in  width,  were  inserted  into 
the  tissues,  with  little  disturbance  of  the  uterine  wall; 
the  aO;  ranged  between  18  per  cent  and  30  per  cent 
of  the  diffusion  current  in  air,  corresponding  to  30 
to  45  mm  Hg  O2  and  was  similar  to  the  maternal 
tissue  oxygen  tensions  measured  in  the  same  manner. 
Misrahy  el  al.  consider  these  readings  to  represent 
the  rate  of  oxygen  transport  between  the  capillaries 
and  the  active  cells.  The  tension  of  oxygen  in  the 
arterial  blood  of  the  fetus  is,  however,  probably  con- 
siderably lower  than  that  in  the  maternal  blood.  It  is 
difficult  to  assess  the  values  for  arterial  oxygen  satura- 
tion in  utero  for  when  the  uterus  is  opened  and  um- 
bilical vein  samples  collected  the  placental  circulation 
is  impaired  to  an  unknown  extent.  Westin  (187)  has 
shown,  by  hysterophotography,  that  the  oxygen 
saturation  of  the  fetal  blood  is  probably  high  in  14 
to  18  week  human  fetuses  for  the  skin  is  pink  and  the 
umbilical  vein  arterial  in  color  in  utero,  and  Dawes 
and  his  colleagues  ( 1 ,  39)  have  observed  arterial 
oxygen  saturations  as  high  as  74  per  cent  in  the  lamb 
near  term.  In  the  human  at  term,  blood  collected  from 
the  choriodecidual  space  by  placental  puncture  has 
been  reported  to  have  a  mean  pO>  of  38  mm  Hg; 
the  p()j  in  umbilical  vein  blood  is  probably  10  mm 
lower  (31).  These  results  in  the  human  should,  how- 
ever, be  regarded  with  reserve  for  there  is  no  means 
of  knowing  whether  the  sample  of  blood  obtained 
comes  from  the  choriodecidual  space  or  a  uterine 
vein. 

How  is  equality  of  oxygen  availability  to  the  fetal 
and  adult  tissues  attained  in  spite  of  the  low  arterial 
oxygen  saturation  in  the  former?  The  mechanisms 
appear  to  be,  for  the  most  part,  similar  to  the  adult 
response  to  low  arterial  oxygen  saturations.  First, 
the  fetal  blood  has  a  greater  affinity  for  oxygen  than 
the  maternal  blood;  this  is  a  property  of  the  fetal 
hemoglobin  and  its  environment  in  the  red  cells 
which  enables  fetal  blood  to  leave  the  placenta  with  a 
greater  oxygen  saturation  than  the  maternal  blood 
at  low  oxygen  tensions.  The  factors  involved  in  the 
transfer  of  0>  and  CO»  between  the  maternal  and 
fetal  circulations  are  clearly  outlined  by  Barron  & 
Meschia  (30)  and  Bartels  et  al.  (31).  Second,  there  is  a 


THE    FETAL    AND    NEONATAL    CIRCULATION 


l635 


steady  rise  in  the  blood  hemoglobin  in  fetuses  of  all 
species  during  gestation.  Most  are  born  with  levels 
which  are  higher  than  that  of  the  mother  (29)  and 
erythropoietic  concentration  is  known  to  be  high  in 
the  cord  blood  of  many  species  (6,  41).  Third,  the 
average  blood  flow  through  the  fetal  tissues  is  high. 
This  has  not  been  compared  with  the  adult  values 
for  each  individual  tissue  but  estimates  of  the  fetal 
cardiac  output  in  the  lamb  are  high,  as  already  de- 
scribed and  amount  to  an  average  tissue  flow  of 
about  120  ml  per  kg  per  min,  which  is  at  least  twice 
the  flow  in  the  adult  sheep.  These  cardiac  output 
measurements  have  been  calculated  indirectly  from 
umbilical  blood  flow  measurements  and  the  dis- 
tribution of  blood  within  the  fetus  with  an  open  chest 
and  are,  therefore,  probably  an  underestimate. 
Approximate  calculations  for  the  human  fetus  also 
suggest  that  the  average  body  blood  flow  is  high. 

INFLUENCE   OF   HYPOXIA    AND    ASPHYXIA 
ON    THE    FETUS 

The  effects  of  a  prolonged  reduction  in  oxygen 
supply  have  been  observed  in  fetuses  born  to  mothers 
at  high  altitude  and  the  possibility  of  hypoxia  as  a 
cause  of  congenital  malformation  has  already  been 
discussed :  experimentally  the  influence  of  acute  hy- 
poxia, produced  by  maternal  breathing  of  low- 
oxygen  gas  mixtures  has  been  studied  the  most 
frequently.  The  results  of  true  asphyxia  may  be  ob- 
served during  marked  impairment  of  the  maternal 
placental  circulation  or  the  mechanical  obstruction 
of  the  umbilical  vessels. 

Hemoglobin 

The  possibility  of  a  rise  in  blood  hemoglobin 
concentration,  in  response  to  a  reduced  oxygen 
supply,  first  attracted  the  attention  of  Joseph  Bar- 
croft  (25)  who  correlated  the  fetal  hemoglobin  level 
with  the  percentage  saturation  of  the  umbilical  vein 
blood  with  oxygen,  in  the  lamb  at  term.  This  idea 
has  proved  most  controversial  clinically  (118,  182), 
particularly  because  subsequent  investigators  did  not 
heed  Barcroft's  warning  concerning  the  difficulties  of 
collecting  a  good  specimen  of  umbilical  vein  blood, 
and  his  awareness  of  the  variety  of  conditions  which 
might  bring  about  rapid  changes  in  the  oxygen  satu- 
ration of  cord  blood.  Neither  the  oxygen  saturation 
of  the  blood  in  the  umbilical  vessels  at  birth,  nor 
the  total  level  of  hemoglobin  in  the  blood  and  the 
relative  proportion  of  fetal  hemoglobin,  contributing 


to  this,  have  proved  to  assist  in  the  interpretation  of 
either  the  extent  or  duration  of  any  impairment  of 
the  intrauterine  environment.  However,  it  is  now 
certain  that  fetal  hemopoietic  tissues  can  respond 
when  oxygen  availability  is  reduced  for  the  young 
born  to  llamas  at  15,000  ft  have  higher  blood  hemo- 
globin concentrations  than  those  born  at  sea  level 
(150).  It  is  interesting  to  speculate  on  this  response 
at  altitude  in  the  fetus:  as  described,  erythropoietic 
concentration  is  high  in  cord  blood  at  sea  level  and 
may  represent  the  fetal  response  to  low  arterial  oxy- 
gen tensions  despite  the  adequate  availability  of 
oxygen  to  the  majority  of  fetal  tissues;  adult  hemo- 
poietic tissue,  however,  will  also  respond  at  25,700  ft 
(7,830  m)  when  the  arterial  oxygen  tension  is  reduced 
to  33  mm  Hg  (151),  a  value  which  is  normal  for  the 
fetus.  Born  et  al.  have  shown  that  fetal  hemoglobin 
concentrations  increase  during  acute  hypoxia  in  the 
lamb,  which  suggests  that  red  cells  may  have  been  re- 
leased from  the  spleen  or  there  may  only  have  been  a 
loss  of  plasma  to  the  extracellular  space  (39). 

Blood  Flow 

It  is  doubtful  if  the  possibility  of  increasing  the 
tissue  and  placental  blood  flow  in  response  to  a  re- 
duction in  oxygen  supply  is  significant  in  the  fetus: 
in  the  lamb,  younger  than  60  days  of  gestational  age, 
both  umbilical  and  tissue  blood  flows  will  probably 
fall  since  there  are  no  reflex  mechanisms  to  elevate 
the  blood  pressure  and  the  depleted  oxygen  supply 
will  cause  bradycardia.  Later,  when  the  cardio- 
vascular reflexes  begin  to  be  developed,  a  rise  in 
arterial  pressure  and  carotid  and  umbilical  blood 
flow  is  observed  in  response  to  asphyxia  or  low  oxy- 
gen tensions;  these  responses  occur  when  the  fetal 
arterial  oxygen  saturation  is  reduced  to  50  to  35 
per  cent,  following  the  administration  of  7.5  to  5.0  per 
cent  oxygen  in  nitrogen  to  the  mother  (39).  The 
increase  in  carotid  and  umbilical  blood  flows  prob- 
ably occurs  at  the  expense  of  the  blood  supply  to  the 
major  portion  of  the  body,  for  it  is  unlikely  that  the 
cardiac  output  increases:  there  is  no  experimental 
evidence  to  support  this  statement,  but  it  is  known  that 
hypoxia  does  not  increase  the  cardiac  output  in  the 
newborn  lamb  (57);  this  lack  of  response  is  possibly 
related  to  the  very  high  cardiac  output  at  this  time, 
for  the  fetal  cardiac  output  at  term  is  at  least  twice 
that  of  the  adult  per  kg  body  weight.  The  decrease 
in  oxygen  consumption  of  the  hind  quarters  in  the 
lamb  during  hypoxia  may  be  evidence  for  peripheral 
vasoconstriction. 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


12  - 


100 


fig.  15.  Oxygen  consumption  per  kilogram  body  weight  at 
different  arterial  oxygen  saturations.  (•)  Fetal  lambs;  (©) 
lambs  less  than  1  day  old;  (o)  lambs  1-10  days  old  after  the 
rise  in  minimal  oxygen  consumption  (95ro  confidence  limits 
are  shown);  horizontal  lines  indicate  the  range  of  observations. 
[From  Cross  el  al.  (57).] 


Oxygen  Consumption 

The  fetus  has  a  third  mechanism  of  defense  at 
low  oxygen  tensions,  that  of  lowering  its  oxygen  con- 
sumption. Cross  et  al.  have  shown  that  this  occurs 
when  the  umbilical  arterial  oxygen  falls  to  50  per  cent 
saturation  in  the  lamb,  and  the  effect  increases  as  the 
arterial  oxygen  tension  is  reduced  still  further  (57) 
(fig.  15).  The  fall  in  oxygen  utilization  may  be  due 
primarily  to  the  decrease  in  blood  flow  to  the  majority 
of  tissues,  as  discussed  above,  for  it  is  accompanied 
by  an  accumulation  of  lactic  acid  and  depletion  of 
tissue  glycogen  stores  (171).  It  would  be  interesting 
to  know  if  the  tissue  temperature  falls  as  it  does  in  the 
adult  when  the  blood  flow  and  oxygen  supply  are  re- 
duced to  muscle  (169).  A  reduction  in  oxygen  con- 
sumption with  low  arterial  oxygen  tensions  is  not 
readily  demonstrated  in  the  adult  animal,  for  the 
cardiac  output  increases  and  the  heart  is  liable  to 
sudden  failure  before  low  oxygen  tensions  are  reached 
(1).  The  inability  of  the  fetal  cardiac  output  to  in- 
crease, and  the  capacity  of  the  heart  to  continue  to 
beat  during  asphyxia,  must  be  important  for  survival 
during  birth. 

The  oxygen  consumption  of  newborn  animals,  at 
their  neutral  temperature,  increases  after  birth  at 
intervals  which  vary  with  the  species  (67,  72).  In 
the  lamb,  the  minimal  oxygen  utilization  is  trebled 


within  24  hours  of  delivery  to  correspond  with  the 
metabolic  requirements  of  its  surface  area,  and  usu- 
ally no  shivering  occurs  (72):  this  recently  acquired 
increase  in  oxygen  consumption  is  not  well  main- 
tained when  the  arterial  oxygen  saturation  is  lowered. 
Hill  has  also  observed  that  the  increase  in  oxygen 
consumption  without  shivering,  in  response  to  a 
low  environmental  temperature,  is  particularly  sus- 
ceptible to  hypoxia  (107). 

Heart  Rate  During  Reduction  in  Maternal 
Placental  Blood  Flow 

The  influence  of  asphyxia  on  the  fetal  heart  rate 
in  utero  and  its  relationship  to  the  degree  of  reduc- 
tion in  maternal  placental  blood  flow,  or  the  short- 
term  placental  reserve,  has  important  practical 
applications.  The  physiology  of  the  response  of  the 
fetal  cardiovascular  system  to  asphyxia  has  already 
been  discussed.  It  is  generally  agreed  that  tachy- 
cardia is  the  first  indication  of  intrauterine  asphyxia 
at  term  in  the  human  infant  (108),  and  in  the  lamb. 
Born  et  al.  observed  that  tachycardia  did  not  occur  in 
the  lamb  until  the  umbilical  arterial  oxygen  satura- 
tion was  reduced  to  50  to  35  per  cent,  during  the 
administration  of  7.0  to  5.5  per  cent  oxygen  to  the 
maternal  sheep;  bradycardia,  most  usually  associated 
with  intrauterine  asphyxia,  was  not  observed  until 
the  oxygen  saturation  reached  20  per  cent  (39). 
The  influence  of  the  accumulation  of  carbon  dioxide, 
occurring  in  asphyxia,  is  not  known.  The  time 
course  of  both  the  cardiac  acceleration  and  slowing 
observed  experimentally  and  clinically  is  very  vari- 
able, depending  upon  the  rate  of  onset  and  degree 
of  asphyxia  induced,  the  existing  oxygen  environ- 
ment and  the  previous  asphyxial  history.  For  in- 
stance, a  sustained  acceleration  is  readily  observed 
as  the  tension  of  oxygen  administered  to  the  maternal 
animal  is  gradually  lowered,  but  it  is  only  transient 
when  nitrogen  is  inspired  by  the  mother  or  when 
the  cord  is  tied;  frequently  acceleration  does  not 
precede  the  bradycardia  in  the  latter  circumstances. 
Hon  (108)  has  described  two  time  courses  for  fetal 
bradycardia  in  the  human  infant  during  labor:  the 
one,  which  he  describes  as  physiological,  occurs  fol- 
lowing a  uterine  contraction  and  most  usually  in 
vertex  presentations;  the  heart  slows  briefly  and 
recovers  swiftly  within  15  sec.  The  second,  which 
Hon  calls  pathological,  has  a  longer  time  course  and 
is  considered  to  be  possible  evidence  of  previous 
asphyxia  or  a  permanent  reduction  in  uterine  blood 
flow.   An   example  of  the   influence   of  limiting  the 


THE     FETAL    AND    NEONATAL    CIRCULATION 


I&37 


Intra-  uterine 


Uterus  open 


22 


24 


26 


1       2      3      4      S      6  20 

Time  (mln) 

fig.  16.  In  the  guinea  pig,  of  54  days  gestation,  a)  the  fetal 
heart  slows  when  the  uterus  is  opened;  h)  marked  fetal  brady- 
cardia occurs  following  the  maternal  injection  of  noradrenaline 
only  after  the  uterine  wall  is  opened.  [From  Martin  &  Young 
(■33)-] 

blood  supply  to  the  fetus  upon  the  susceptibility  to 
further  asphyxia  as  shown  in  figure  16;  after  the 
uterine  wall  was  opened,  to  expose  the  fetus,  the 
uterine  muscle  contracted  away  from  the  incision 
around  the  uterine  blood  vessels,  and  cardiac  slowing 
could  be  produced  with  a  smaller  dose  of  vasocon- 
strictor substance  in  the  maternal  circulation  than 
when  the  fetus  was  in  utero. 

Reduction  in  the  uterine  blood  flow  giving  rise  to 
these  various  patterns  of  fetal  heart  rate  changes  may 
be  brought  about  in  many  ways.  It  follows  the  injec- 
tion of  either  hypotensive  (82,  194)  or  vasoconstrictor 
(34)  drugs  into  the  maternal  circulation;  the  effect 
will  be  reversible  or  not  according  to  the  dose  given 
and  the  duration  of  action  of  the  pharmacological 
substance.  Uterine  blood  flow  may  be  markedly 
reduced  temporarily,  by  adrenaline  or  noradrenaline 
in  the  maternal  circulation,  and  this  may  be  one 
reason  for  the  poor  placental  transfer  of  noradrenaline 
which  has  been  observed  (168).  In  the  guinea  pig  the 
uterine  blood  vessels  become  sensitized  to  the  action 
of  adrenaline  as  gestation  proceeds  and  following  the 
administration  of  both  estrogen  and  progesterone 
(133).  It  is  possible  that  there  is  a  reduction  in  ma- 
ternal placental  blood  flow  before  conversion  of  the 
uterus  from  the  spherical  to  oval  shape  (154,  157). 

The  influence  of  uterine  contraction  on  the  fetal 
heart  rate  has  been  most  extensively  studied  and  de- 
pends upon  the  duration  of  the  contraction,  its  fre- 
quency and  upon  the  intrauterine  pressure  developed 
(7,  15,  109).  It  is  probable  that  the  first  effect  of  any 


uterine  contraction  will  be  to  upset  the  functional 
countercurrent  mechanism  which  enables  the  mater- 
nal arterial  blood  in  the  intervillous  space  to  reach 
the  base  of  the  chorionic  villi  and  enable  final  ar- 
terialization  of  the  umbilical  venous  blood.  Hendricks 
et  at.  (104)  have  made  simultaneous  recordings  of  the 
intra-amniotic  and  intervillous  pressures  in  the  hu- 
man and  consider  the  sequence  of  events  on  the 
maternal  side  of  the  placenta  to  be  complicated  be- 
fore the  oxygen  supply  to  the  fetus  is  impaired  during 
a  contraction.  They  observed  the  pressures  in  the 
intervillous  pool  and  the  amniotic  cavity  to  be  about 
equal,  both  when  the  uterus  was  relaxed  and  during 
systole;  the  increase  in  the  intervillous  pressure  lagged 
behind  the  intra-amniotic  pressure  rise  during  con- 
traction. It  is  suggested  that  the  intervillous  volume  is 
slightly  reduced  during  the  early  phase  of  contrac- 
tion; but  once  the  intra-amniotic  pressure  exceeds 
that  in  the  uterine  vein,  venous  drainage  will  cease 
and  the  intervillous  volume  become  expanded  as 
the  arterial  inflow  continues.  The  oxygen  supply, 
though  slowed,  may  continue  for  a  considerable  time 
during  contraction,  and  the  spongy  structure  of  the 
placenta  and  the  large  venous  sinuses  allows  local 
pressure  differences  to  be  distributed  and  prevent 
retroplacental  hemorrhage.  The  increased  pressure 
in  the  intervillous  space  will  be  transmitted  to  the 
fetal  vessels  and,  added  to  a  reduced  oxygen  supply, 
there  will  be  a  reduction  in  umbilical  blood  flow 
as  the  resistance  increases.  Reynolds  &  Paul  (159) 
observed  in  the  lamb,  in  utero,  that  rhythmic  con- 
tractions of  low  intensity  which  caused  a  rise  of  intra- 
amniotic  pressure  of  about  5  mm  Hg  caused  an 
equal  rise  in  fetal  blood  pressure  but  no  change  in 
heart  rate:  manual  pressure  on  the  uterus  or  the 
application  of  weights,  from  1  kg  upward,  caused 
a  rise  of  arterial  pressure  in  the  fetus  which  exceeded 
the  rise  in  amniotic  pressure;  this  was  asphyxial  in 
origin  and  accompanied  by  bradycardia.  Strong 
contractions  induced  by  Pitocin,  which  raised  the 
intra-amniotic  pressure  more  than  10  mm  Hg,  gave 
similar  vascular  responses  in  the  fetus   (15,    159). 

The  quantitative  relationship  between  reduction 
in  maternal  placental  blood  flow  and  the  appearance 
of  fetal  bradycardia  has  been  supplied  in  the  sheep 
by  Adams  et  al.  (2);  no  change  in  fetal  heart  rate  was 
observed  until  the  uterine  blood  flow,  measured  with 
an  electromagnetic  flowmeter,  was  reduced  to  about 
one-third  of  the  control  level  following  the  injection 
of  adrenaline  into  the  maternal  circulation.  This 
relationship  was  readily  predicted  from  the  heart 
rate  changes  occurring  during  the  administration  of 


i638 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION     II 


low  oxygen  tension  mixtures  to  the  mother  in  both 
the  sheep  and  the  guinea  pig  (39,  133)-  It  appears 
that  there  is  no  species  difference  for  the  sensitivity 
of  the  fetal  heart  to  hypoxia  in  utero.  Hon  has  also 
described  intermittent  fetal  bradycardia  during  de- 
livery which  he  considered  to  be  unrelated  to  altera- 
tion in  placental  blood  flow  and  due  to  either  com- 
pression of  the  cord  (109)  or  medullary  asphyxia. 
The  bradycardia  during  cord  compression  had  a 
long  time  course,  but  swift  physiological  brady- 
cardia was  frequently  observed  in  vertex  presenta- 
tions and  could  be  related  to  the  degree  of  cervical 
dilatation  and  was  possibly  caused  by  the  rise  in 
intracranial  pressure.  This  is  an  old  clinical  observa- 
tion and  Harvey  Gushing  also  observed  bradycardia 
in  adult  animals  during  experimental  asphyxia  of 
the  medulla  (59). 

The  great  ability  of  the  fetus  to  survive  asphyxia 
is  still  not  understood  (139,  171)  and  it  is  not  known 
whether  the  ultimate  damage  to  the  tissues  is  mainly 
due  to  the  absence  of  oxygen  and,  therefore,  the 
supply  of  energy,  or  to  the  fall  in  pH  as  the  lactic 
acid  accumulates.  Whittam  (188)  has  shown  that 
anoxic  fetal  kidney  slices  maintain  their  potassium 
content  better  than  adult  tissue  and,  if  this  is  true 
for  both  the  heart  and  the  brain,  it  possibly  explains 
the  maintenance  of  their  excitability  and  activity 
for  long  periods  during  asphyxia.  Mott  stresses  the 
importance  of  the  maintenance  of  a  circulation  during 
anoxia  so  that  glucose,  from  the  liver  glycogen,  may 
be  supplied  to  all  the  tissues,  and  lactic  acid  removed 
(139):  liver  glycogen  is  partially  mobilized  during 
anoxia  and  the  brain  and  heart  both  suffer  a  large 
reduction  in  glycogen  content;  in  the  young  fetus 
total  lactate  production  can  be  accounted  for  by  the 


loss  of  carbohydrate  from  the  heart.  The  survival 
time  of  the  fetal  heart  is  directly  related  to  its  carbo- 
hydrate stores  which  are  larger  than  those  of  the  adult 
(fig.  17);  these  reserves  may  be  depleted  by  repeated 
episodes  of  hypoxia  which  may  have  a  cumulative 
effect. 


CHANGES    IN    THE    FETAL    CIRCULATION    AT    BIRTH 
AND    IN    THE    NEONATAL    PERIOD 

Umbilical  Curd:  Ductus  Venosus 

The  detailed  structure  of  the  umbilical  cord  varies 
widely  among  the  species,  but  all  the  arteries  and 
veins  have  thick  muscular  walls  and  lack  a  nerve 
supply  (27);  the  horse  and  rabbit  have  separate 
sphincters  in  the  region  of  the  umbilical  ring  (194). 
The  isolated  umbilical  and  placental  vessels  are  very 
reactive:  constriction  occurs  in  response  to  cooling, 
stretching,  or  handling,  the  presence  of  the  sympa- 
thetic autonomic  drugs  in  the  perfusion  fluid  and 
high  oxygen  tensions;  relaxation  occurs  in  the  pres- 
ence of  low  oxygen  tensions  and  high  CO-;  tensions. 
Rogers  (163)  observed  the  phenomenon  of  "pressure 
spasm,"  a  complete  but  temporary  occlusion  follow- 
ing an  increased  and  sustained  perfusion  pressure; 
this  response  to  pressure  is  also  observed  in  dener- 
vated  systemic  vessels  (33).  Following  a  natural  birth 
there  will,  therefore,  be  many  factors  combining  to 
ensure  an  effective  closure  of  the  umbilical  vessels. 
Intrauterine  asphyxia  might  be  expected  to  impair 
the  effectiveness  of  these  stimuli  and,  recently,  it 
has  been  observed  that  the  cord  continues  to  pulsate 
for  long  periods  in  infants  following  a  difficult  de- 
livery (80). 


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STAGE    OF     GESTATION 


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fig.  17.  Cardiac      glycogen      in       different 
species  before  and  after  birth.  [From  Sheliev 

(171).] 


THE    FETAL    AND    NEONATAL    CIRCULATION 


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fig.  18.  Ventilation  of  the  lungs  of  a  mature  fetal  lamb 
caused  the  mean  left  atrial  pressure  to  rise  above  the  pressure 
in  the  inferior  vena  cava  (IVC) ;  occlusion  of  the  umbilical 
cord  caused  the  IVC  pressure  to  fall.  Both,  therefore,  contribute 
to  the  rapid  reversal  of  the  pressure  gradient  across  the  foramen 
ovale,  resulting  in  its  closure  after  birth.  (Modified  from  G.  S. 
Dawes.  Changes  in  the  circulation  at  birth.  Brit.  Med.  Bull. 
17:  152,  1961.) 

The  mechanism  for  the  functional  closure  of  the 
ductus  venosus  is  unknown  but  it  is  important  that 
this  should  take  place  early  in  neonatal  life.  The 
formation  of  an  Eck  fistula,  with  the  portal  blood 
short-circuiting  the  liver,  passing  through  the  portal 
sinus  and  straight  into  the  inferior  vena  cava,  might 
explain  the  hypoglycemia  and  icterus  which  some- 
times occurs  in  the  neonatal  period,  especially  in  pre- 
mature infants.  Cardiac  catheterization  through  the 
umbilical  vein  depends  upon  anatomical  patency  of 
the  ductus  venosus;  there  is  evidence  that  it  is  either 
closed  or  absent  in  about  30  per  cent  of  newborn 
infants  (167).  However,  when  the  ductus  venosus  is 
patent  it  may  be  visualized  by  radiopaque  sub- 
stances up  to  12  days  after  birth  (146). 

Fetal  Channels  in  the  Thorax 

The  first  breath  initiates  the  changes  in  course  of 
the  blood  streams  in  the  heart:  expansion  of  the  lungs 
decreases  the  resistance  in  the  small  vessels  and  the 
resulting  increase  in  pulmonary  blood  flow  raises 
the  left  atrial  pressure  above  that  in  the  inferior  vena 
cava,  closing  the  foramen  ovale  functionally  (fig.  18); 
this  closure  is  assisted  by  the  fall  in  the  inferior  vena 
caval  pressure  due  to  the  temporarily  reduced  venous 
return  to  the  heart,  following  occlusion  of  the  um- 
bilical vessels.  The  whole  volume  of  inferior  caval 
blood  now  joins  the  superior  caval  blood  in  the  right 


atrium  to  maintain  the  high  pulmonary  blood  flow. 
As  a  result  of  the  reduced  pulmonary  vascular  re- 
sistance the  pulmonary  arterial  pressure  falls  below 
the  systemic  level  and  blood  flow  through  the  ductus 
arteriosus    is    diminished. 

The  radiological  studies  in  the  sheep  and  the  hu- 
man infant  (26,  129),  at  first  suggested  that  when 
respiration  is  off  to  a  flying  start  the  functional  clos- 
ure of  both  the  foramen  ovale  and  the  ductus  ar- 
teriosus is  immediate.  However,  anatomical  closure  is 
not  complete  for  some  weeks  and  there  is  evidence 
that  blood  may  flow  through  both  these  channels, 
probably  intermittently,  for  about  a  fortnight  after 
birth;  this  is  demonstrated  in  the  angiocardiographic 
studies  and  in  dye  dilution  curves  which,  in  normal 
babies,  are  characteristic  of  pathological  states  with  a 
patent  ductus  (149).  More  direct  evidence  for  a 
patent  ductus  with  a  left-to-right  shunt  has  been 
obtained  in  mongol  (117)  and  in  normal  infants  (3); 
during  cardiac  catheterization  it  was  found  that  blood 
obtained  from  the  pulmonary  artery  contained  more 
oxygen  than  that  collected  from  the  right  auricle 
and,  in  addition,  the  pulmonary  arterial  pressures 
were  higher  than  expected.  Dawes  and  his  colleagues 
have  measured  this  flow  in  the  lamb  and  find  it  con- 
siderable (76).  Blood  flowing  through  the  wide  open 
ductus  arteriosus  creates  no  murmurs,  but  as  the 
vessel  constricts  there  is  turbulence  of  the  swiftly 
flowing  stream  and  murmurs  attributed  to  this  can 
be  heard  in  both  the  sheep  (76)  and  the  human  in- 
fant (50).  The  direction  of  this  shunt  may  be  from 
left  to  right  or  right  to  left  according  to  the  relative 
pressures  in  the  pulmonary  and  aortic  trunks.  Follow- 
ing expansion  of  the  lungs,  the  pulmonary  arterial 
pressure  falls  relative  to  the  systemic  pressure  and 
there  is  the  possibility  of  a  left-to-right  shunt;  if  this 
occurs,  the  work  of  the  left  heart  will  be  increased 
but,  during  recirculation  of  the  blood  through  the 
lungs,  there  is  a  further  opportunity  for  oxygen  up- 
take which  is  advantageous  when  the  ventilation  is 
poor.  During  asphyxia  or  crying  the  pulmonary  ar- 
terial pressure  rises  and  may  exceed  the  systemic 
pressure  causing  the  possibility  of  a  right-to-left 
flow  again,  when  the  lower  half  of  the  body  will 
probably  receive  blood  of  a  lower  oxygen  content 
than   the   upper   half  (88). 

The  wall  of  the  ductus  arteriosus  has  a  sphincter- 
like structure  and  the  musculature  a  poor  nerve 
supply.  In  the  lamb  fetus  the  lumen  is  nearly  as 
large  as  the  pulmonary  artery  and  descending  aorta 
and  the  blood  flow  through  it  approximately  one- 
third  of  the  combined  output  of  the  two  ventricles  (76) ; 


1640 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


LEFT    ATRIUM 

LEFT  PULMONARY 
FLOW 


PULMONARY 
VASCULAR 
RESISTANCE 


MINUTES    FROM     DELIVERY  90 


fig.  ig.  Changes  in  the  circulation  on  ventilating  the 
fetal  lung:  a)  artificial  positive  pressure  ventilation  of  the  lungs 
caused  a  large  fall  of  pulmonary  vascular  resistance,  an  increase 
in  pulmonary  flow  and  a  fall  in  pulmonary  artery  pressure. 
b)  Temporary  occlusion  of  the  ductus  arteriosus  caused  a  rise  in 
femoral  pressure  and  a  fall  in  pulmonary  pressure  and  flow, 
showing  that  blood  had  been  flowing  from  the  aorta  into  the 
pulmonary  trunk.  The  figures  35  and  79  indicate  the  carotid 
arterial  Os%  saturation.  (From  G.  S.  Dawes.  Changes  in  the 
circulation  at  birth.  Brit.  Med.  Bull.   17:   151,  1 96 1 . ) 

with  the  reduction  in  pulmonary  arterial  pressure 
the  flow  is  diminished  and  the  wall  constricts.  Closure 
of  the  ductus  is  not  dependent  upon  its  nervous  con- 
nections and  will  occur  following  inflation  of  the 
lungs  provided  the  oxygen  tension  is  high  and,  like 
the  umbilical  vessels,  it  will  dilate  when  the  blood 
oxygen  tension  is  low  (27,  40);  constriction  can, 
however,  occur  during  asphyxia  and  this  may  be  due 
to  the  release  of  sympathetic  amines.  The  responses 
of  the  ductus  arteriosus  and  the  cord  vessels  are  com- 
mon to  all  unstriped  muscle,  and  the  exemption  of 
the  neighboring  aorta  and  pulmonary  artery  is  due 
to  the  preponderance  of  elastic  fibers  in  the  tunica 
media  of  the  latter  vessels. 

In  the  fetal  lamb  in  utero  the  right  atrial  pressure 
is  1  to  1 1  2  cm  H2O  higher  than  the  left  atrial  pressure 
(fig.  18).  This  pressure  difference  occurs  because 
the  pulmonary  venous  return  to  the  left  auricle  is 
small  and  only  about  one-ninth  of  that  returning  to 
the  right  side  of  the  heart;  75  per  cent  of  the  inferior 
caval  blood  is  directed  bv  the  valve  of  the  foramen 


ovale  and  redistributes  the  venous  return  to  maintain 
the  left  ventricular  output  and  systemic  and  placental 
blood  flows.  Following  inflation  of  the  lungs  the  de- 
crease in  pulmonary  vascular  resistance  enables  the 
pulmonary  blood  flow  to  treble  and  as  the  interatrial 
pressure  difference  is  reversed  the  foramen  oval  closes 
(77);  Dawes  and  his  colleagues  consider  that  clamp- 
ing the  cord  before  the  first  breath,  thus  reducing 
temporarily  the  inferior  caval  flow,  might  be  sufficient 
to  lower  the  right  atrial  pressure  and  assist  closure  of 
the  foramen  ovale.  However,  maintenance  of  its 
closure  will  depend  upon  the  increased  pulmonary 
venous  return.  In  small  animals  the  preponderance  of 
left-over-right  atrial  pressure  is  difficult  to  demon- 
strate within  the  first  24  hours  of  birth,  but  develops 
during  the  subsequent  days  and  weeks;  the  main- 
tenance of  this  pressure  difference  which  is  observed 
throughout  life  is  probably  the  combined  influence  of 
filling  and  elasticity  of  the  two  ventricles. 

Pulmonary  Vascular  Resistance,  Arterial 
Pressure,  and  Blood  Flow 

The  way  in  which  the  first  breath  initiates  the  re- 
duction in  pulmonary  vascular  resistance  is  not  yet 
fully  explained.  Using  a  density  flowmeter,  Dawes 
et  al.  measured  the  blood  flow  in  the  left  pulmonary 
artery  of  lambs  delivered  by  Cesarean  section;  follow- 
ing positive  pressure  ventilation  with  air,  oxygen,  or 
nitrogen  they  observed  a  three-  to  fourfold  increase  in 
pulmonary  blood  flow,  a  decrease  in  arterial  pressure 
and  calculated  a  tenfold  decrease  in  pulmonary  vascu- 
lar resistance  (13,  78).  Distention  of  the  lungs  with 
warm  saline  was  not  found  to  increase  the  pulmonary 
blood  flow  and  no  change  in  circulatory  pattern 
probably  takes  place  during  respiratory  effects  in 
utero  when  amniotic  fluid  is  known  to  enter  the 
lungs  (65).  Dawes'  conclusion  that  the  decrease 
in  pulmonary  vascular  resistance  was  primarily 
due  to  the  mechanical  factors  associated  with  ventila- 
tion was  questioned,  recently,  by  Cook  et  al.  (55) 
following  observations  in  newborn  lamb  preparations 
in  which  the  two  lungs  were  ventilated  separately 
and  the  pulmonary  vessels  perfused  at  a  constant 
pressure;  alveolar  hypoxia  and  hypercapnia  caused 
vasoconstriction  in  the  pulmonary  circulation  which 
was  more  marked  than  that  observed  in  the  adult  lung 
(84)  and  ventilation  with  nitrogen  alone  gave  variable 
results — possibly  on  account  of  differences  in  local 
( !(  )_.  tension.  Recent  observations  have  shown  that 
both  an  increase  in  arterial  and  alveolar  pOL>  and  a 
reduction  in  pCOj  contribute  toward  the  increase  in 


THE    FETAL    AND    NEONATAL    CIRCULATION 


I  641 


50 


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ui 

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AGE    IN     DAYS 


5  15  25  35 

fig.  20.  Right  ventricular  systolic  pressure  in  15  puppies 
during  the  first  5  weeks  of  neonatal  life.  [From  Rudolph  el  al. 
(166).] 

pulmonary  blood  flow  at  the  onset  of  pulmonary 
ventilation  in  the  lamb;  similar  changes  in  blood 
chemistry,  and  vasodilator  drugs,  also  increase  blood 
flow  in  the  unexpanded  fetal  lung  (73)  which  would 
suggest  that  a  decrease  in  vascular  resistance  is  not 
necessarily  due  to  uncoiling  of  vessels  as  suggested  by 
Reynolds  (156).  Once  started,  the  increase  in  blood 
flow  itself  together  with  the  raised  left  atrial  blood 
pressure  may  help  to  maintain  a  low  pulmonary 
vascular  resistance  as  it  does  in  the  adult  lung  (42). 
Pulmonary  vascular  resistance  has  been  calculated  in 
the  human  infant  at  birth  and  during  the  first  3  weeks 
of  life  from  measurements  of  the  pulmonary  artery 
pressure  and  cardiac  output,  determined  by  the  Fick 
principle  (164).  Within  a  few  hours  of  delivery  the 
pulmonary  vascular  resistance  is  about  550  dynes  per 
sec  per  cm-s  in  comparison  with  an  assumed  fetal 
value  of  8,000  dynes  sec  cm-5.  This  neonatal  value 
is  still  considerably  higher  than  that  found  in  the 
older  infant  and  the  adult,  but  is  already  much  less 
than  the  systemic  vascular  resistance;  it  declines  to 
the  adult  level  by  6  months  of  age  by  which  time 
the  walls  of  the  pulmonary  arterioles  are  reduced  in 
thickness  (62).  The  lung  blood  volume  does  not 
change  immediately  following  this  large  drop  in  re- 
sistance (66)  but  a  considerable  increase  has  been 
demonstrated  within  the  first  24  hours  of  life  in  the 
guinea  pig  (92). 

The  pulmonary  arterial  pressure  is  reduced  by 
about  a  half  to  approximately  35  mm  Hg  during 
the  immediate  postnatal  period  in  both  the  lamb 
and  the  human  infant,  and  in  the  puppy  (165,  166). 
The  final  reduction  in  pressure  occurs  gradually  over 


the  following  weeks  (fig.  20).  The  thickness  of  the 
walls  of  the  two  ventricles  is  nearly  equal  in  the 
fetus  with  a  slight  preponderance  of  the  right 
chamber:  while  the  pulmonary  vascular  resistance 
and  arterial  pressure  are  falling  and  the  systemic 
vascular  resistance  and  pressure  are  rising  in  the 
newborn  period,  the  right  ventricular  wall  decreases 
in  thickness  and  the  left  ventricular  wall  increases  in 
thickness;  in  the  human  infant  these  changes  are 
nearly  completed  within  the  first  month  of  life  (121). 

The  Heart 

The  immediate  changes  in  heart  rate  in  the  human 
infant  following  a  normal  birth  are  variable  and 
transient  (173).  In  the  lamb  delivered  by  Cesarean 
section  the  heart  rate  slows  when  the  cord  is  clamped 
(66):  this  may  be  reflex  in  origin  for  the  arterial 
pressure  is  raised,  but  may  also  be  due  to  the  direct 
effect  of  asphyxia  on  the  pacemaker;  the  bradycardia 
is  followed  by  tachycardia  once  respiration  and 
oxygenation  of  the  blood  are  established.  During  the 
first  2  days  after  birth  the  heart  rate  of  the  human 
infant  is  usually  lower  than  in  utero,  about  120 
beats  per  min,  and  rises  during  the  first  week  of 
life  (14,  21,  198).  The  temporary  bradycardia  is 
possibly  the  combined  effect  of  the  low  body  tempera- 
ture during  this  period  (52)  and  the  residual  effect 
of  perinatal  asphyxia.  In  the  newborn  kitten  and 
puppy  the  heart  rate  varies  widely,  ranging  from 
180  to  260  per  min  during  the  first  15  weeks  of  life 
(114).  The  heart  rate  of  the  newborn  monkey  is 
205  ±  20  (sd)  beats  per  min  (1 16). 

The  heart  volume  has  been  measured  radiologically 
in  the  human  infant  (124)  and  found  to  have  an 
average  value  of  48  ml  in  55  infants  on  the  day  of 
birth;  during  the  first  hour  of  life  there  was  an  in- 
crease in  volume  with  a  return  to  the  immediate 
postnatal  level  within  3  hours.  During  the  subsequent 
4  days  of  life  the  volume  diminished  by  25  per  cent 
and  thereafter  increased;  the  decrease  in  heart  size 
was  more  pronounced  in  premature  babies.  These 
early  changes  in  heart  volume  and  the  enlargement 
of  the  heart  which  occurs  following  birth  asphyxia 
(51)  need  to  be  made  simultaneously  with  other 
circulatory  measurements,  for  a  better  understanding 
of  the  events  taking  place. 

Cardiac  output  measurements  in  newborn  human 
infants  by  the  dye  dilution  technique  (149)  and  using 
the  Fick  principle  (3)  provide  a  very  wide  range  of 
values  180  to  850  ml  per  min,  which  is  probably  ex- 
plained by  the  patency  of  the  fetal  channels;  this  is  a 


1642 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Cord  clamped   after  3  mm  _^* 

J< 


Cord  clamped  immediately 


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Cord  clamped  during  delivery 


AGE  (hr  ) 


I  2  3  4         24 

fig.  21.  Three  representative  records  of  the  changes  in  the 
systolic  pressure  of  normal  babies  during  the  first  24  hours  of 
life.  [From  Ashworth  &  Neligan  (14).] 


factor  which  must  influence  all  but  the  cardiometer 
results  in  animals,  which  also  have  their  inherent 
disadvantages.  The  average  cardiac  output  of  the 
human  infant,  540  ml  per  min,  corresponds  to  a 
value  of  180  ml  per  kg  per  min  and  is  about  double 
the  value  in  the  adult  per  kg  body  weight;  the  cardiac 
index  is  2.5  liters  per  min  per  m2.  Assuming  a  new- 
born heart  rate  of  140  per  min,  the  stroke  volume 
will  be  approximately  4  ml.  It  may  be  noted  that  if 
the  estimates  of  cardiac  output  in  utero  are  correct, 
200  ml  per  kg  per  min  (17),  the  value  does  not  change 
in  the  neonatal  period  and  no  increase  in  oxygen 
consumption  is  observed  (58).  On  the  other  hand, 
there  is  evidence  for  an  increase  in  cardiac  output 
following  birth  in  the  lamb:  Cross  et  al.  (57)  made 
calculations  using  the  Fick  principle  and  obtained 
values  of  325  ±  30  ml  per  kg  per  min,  which  com- 
pared with  the  near  term  intrauterine  estimate  of 
235  ml  per  kg  per  min  for  both  ventricles;  a  single 
ventricle  has  therefore  increased  its  output  three- 
fold. This  increase  may  be  the  response  to  the  raised 
oxygen  consumption  which  occurs  in  the  lamb  at 
birth  or  it  may  be  the  expression  of  the  better  measure- 
ments which  are  possible  after  birth. 

Systemic  Pressure,  Cardiovascular  Reflexes 
and  Peripheral  Resistance 

When  the  changes  in  systemic  arterial  pressure  at 
delivery  are  measured,  a  discrepancy  exists  between 
the  lamb  and  the  human  baby;  namely,  a  small 
transient  rise  of  pressure   is  observed   following   the 


initiation  of  ventilation  or  occlusion  of  the  cord  in 
the  lamb  (66)  while,  remarkably,  in  the  human 
infant  no  change  of  pressure  is  seen  (183,  196).  There 
are  many  possible  explanations  for  this  difference: 
first,  the  different  types  of  maternal  placental  circu- 
lation; second,  the  influence  of  contraction  of  the 
uterine  muscle  on  this  circulation;  and  third,  the 
alteration  of  distribution  of  blood  between  the 
placenta  and  fetus  before  the  arterial  measurements 
are  made.  The  arterial  pressure  measurements  in 
lambs  have  all  been  made  on  fetuses  delivered  by 
Cesarean  section  and,  as  the  sheep  uterus  is  not  very 
reactive  to  surgery,  the  maternal  and  consequently 
the  fetal  placental  circulations  are  probably  not 
greatly  impaired.  When  the  lamb  is  delivered  vagin- 
ally the  maternal  placental  blood  flow  is  not  reduced 
during  labor  and  does  not  decrease  until  separation 
of  the  placenta  some  hours  after  delivery  of  the  fetus 
(15).  The  temporary  rise  in  pressure  observed  is 
therefore  probably  due  to  the  removal  of  the  low 
resistance  circuit  of  the  placenta,  and  a  small  rise  in 
arterial  pressure  following  cord  occlusion  has  also 
been  observed  in  the  rhesus  monkey  delivered  by 
Cesarean  section  (71).  In  the  adult  animal  the  reduc- 
tion of  a  circulating  bed  even  of  the  same  resistance 
as  the  total  vascular  bed,  raises  the  arterial  blood 
pressure  (23).  In  the  human,  contraction  of  the  uterus 
during  labor  probably  reduces  both  the  maternal  and 
fetal  placental  blood  flow  and  therefore  much  of  the 
low  resistance  circuit  of  the  placenta  is  gradually 
removed  before  the  arterial  pressure  measurements 
are  made  as  the  cord  is  tied.  Other  hemodynamic 
factors,  such  as  the  relative  distribution  of  blood 
between  the  fetus  and  the  placenta  and  the  relative 
proportions  of  the  cardiac  output  which  traverse 
the  placenta,  might  also  influence  any  change  in 
systemic  pressure  at  birth.  In  the  lamb,  at  term,  only 
1 5  per  cent  of  the  total  blood  volume  is  to  be  found 
in  the  placenta  and  60  per  cent  of  the  cardiac  output 
traverses  this  vascular  bed.  The  human  placenta 
contains  30  per  cent  of  the  total  circulating  blood 
volume  at  term  (173),  but  the  portion  of  the  cardiac 
output  perfusing  it  is  not  known. 

Ashworth  &  Neligan  (14)  have  used  the  con- 
ventional inflatable  cuff  and  manometer  and  a 
sensitive  pulse  indicator  to  measure  the  arterial 
pressure  in  the  newborn  infant's  arm,  and  report 
marked  changes  in  systolic  pressure  within  the  first 
24  hours  of  life.  The  initial  pressures,  within  2  min 
of  delivery,  ranged  from  1 16  to  52  mm  Hg  and  there 
was  subsequently  a  fall  of  up  to  54  mm  Hg  (fig.  21); 
delay  in  clamping  the  cord  postponed  this  fall,  but 


THE    FETAL    AND    NEONATAL    CIRCULATION 


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40  SO  I20  160 

fig.  22.  Arterial  blood  pressures  before  ( )  and  after), ) 

birth,  showing  the  continuous  course  of  the  rise  with  increasing 
age,  in  the  rabbit,  cat,  sheep,  and  monkey.  (Modified  from 
G.  S.  Dawes.  Changes  in  the  circulation  at  birth.  Brit.  Med. 
Bull.  17:  150,  1 96 1.) 

did  not  influence  its  magnitude.  It  is  tempting  to 
suggest  that  the  wide  range  of  initial  pressures  is  due 
to  varying  degrees  of  asphyxia  during  birth,  but  no 
proof  exists  for  this  explanation.  The  pressures  rise 
gradually  during  the  second  day  of  life  and  during 
the  subsequent  weeks. 

Once  the  temporary  interruptions  of  parturition 
are  over,  the  mechanisms  which  have  been  responsible 
for  the  gradual  rise  in  arterial  pressure  throughout 
gestation  will,  probably,  be  extended  into  the  neo- 
natal period:  these  mechanisms  are,  however,  likely 
to  be  modified  by  the  different  internal  environment 
of  the  young  free  animal,  as  compared  with  the 
fetus,  and  by  many  other  factors  which  will  vary 
with  the  species;  orthostatic  factors  and  the  mode  of 
life  will  be  among  these.  The  rate  of  rise  in  arterial 
pressure  is  rapid  in  small  animals  and  the  mean  pres- 
sure is  about  doubled  during  the  first  6  weeks  of  life, 
approaching  the  adult  level;  in  the  sheep  and  monkey 
the  rise  is  slower  (fig.  22).  In  the  human  infant,  who 
has  been  a  repeated  subject  for  blood  pressure  meas- 
urements, the  rise  is  slow  during  the  first  9  months 
of  life  (fig.  23)  and  continues  well  into  adolescence 
and  throughout  adult  life  (194).  [But  see  also  (193). 
Ed.] 

The  newborn  is  a  more  satisfactory  experimental 
subject  than  the  fetus  for,  under  experimental  condi- 
tions, an  established  respiration  provides  a  more 
constant  internal  environment  than  the  placental 
circulation.  The  differences  between  the  cardio- 
vascular responses  of  newborn  and  adult  animals  are 
of  a  quantitative  rather  than  a  qualitative  nature: 


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fig.  23.  Mean  arterial  blood  pressures  at  birth  and  during 
the  first  few  months  of  life  in  normal  infants.  [From  Holland  & 
Young,  Brit.  Med.  J.  2:  1331,  1956.] 


in  the  newborn  monkey  there  is  evidence  for  func- 
tional baroreceptor  and  chemoreceptor  activity, 
yet  bradycardia  and  hypotension  still  follow  acute 
hypoxia  (71).  In  the  young  growing  rabbit  (70,  83), 
kitten,  and  puppy  ( 1  1  4)  a  gradual  increase  in  vasocon- 
strictor tone  in  the  systemic  circulation  can  be 
demonstrated  by  the  responses  to  asphyxia  and  to  the 
injection  of  hexamethonium.  Downing's  (83)  observa- 
tions show  that  the  threshold  for  baroreceptor  stimu- 
lation in  young  rabbits  is  about  40  mm  Hg. 
Hutchinson  el  al.  (11 4)  have  also  demonstrated  in  the 
newborn  kitten  and  puppy  that  the  carotid  sinus- 
cardiac  center  mechanism  will  respond  to  a  rise  in 
pressure  but  not  to  a  fall.  These  findings  may  be  ex- 
plained by  Landgren's  (126)  observations  that  40 
mm  Hg  is  just  within  the  recording  range  of  the 
baroreceptors;  any  stimulus  which  raises  the  pressure 
will  elicit  a  response,  especially  if  the  pulse  pressure 
is  also  increased  (85),  but  a  further  fall  will  be  in- 
effective. As  the  resting  arterial  pressure  rises  and 
approaches  the  maximum  sensitivity  range  of  the 
baroreceptors,  85  to  100  mm  Hg,  the  reflexes 
become  more  active;  for  instance,  following  the  injec- 
tion of  adrenaline  the  percentage  decrease  in  heart 
rate  increases  in  relation  to  the  percentage  rise  in 
blood  pressure  in  the  growing  rabbit  and  kitten.  The 
direct  action  of  adrenaline  on  the  heart  could  only 
be  demonstrated  in  the  youngest  animals  following 
doses  so  small  that  the  blood  pressure  did  not  rise 
sufficiently  to  elicit  a  reflex  bradycardia.  In  contrast, 
the  young  kitten  heart  was  found  to  be  more  sensitive 
to  acetylcholine  than  the  peripheral  vessels;  with 
small  doses  a  marked  bradycardia  accompanied  the 
fall    in    blood    pressure    in    the    kitten,    while    reflex 


1644 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


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Gestation  age    in    days 


fig.  24.  Increase  in  distensibility  of  fetal  lamb  lungs  with 
age.  A:  tidal  air/peak  intratracheal  pressure  =  distensibility; 
B:  distensibility  per  kg  body  weight  plotted  against  age.  [From 
Dawes  (66).] 


mechanisms  are  not  very  active  in  the  newborn  infant 
(197).  The  physiological  activity  of  the  vasomotor 
sympathetic  mechanism  to  the  skin  blood  vessels  is, 
however,  well  developed  at  birth  and  quite  compa- 
rable with  that  of  the  adult — a  fact  which  was  dem- 
onstrated clearly  by  Day  (79)  who  showed,  by 
conductivity  measurements,  that  the  circulatory  re- 
sponses to  changes  in  environmental  temperature  were 
as  effective  as  in  the  adult  in  maintaining  body  tem- 
perature. These  observations  have  recently  been  am- 
plified by  Briick  (47). 

Renal  blood  flow  appears  to  be  low  in  the  sheep 
fetus  (5)  and  the  newborn  infant  (173)  when  com- 
pared with  the  adult  on  a  body  weight  basis;  PAH 
clearance  was  used  in  these  measurements  but  nothing 
is  known  of  the  secretory  capacity  of  the  tubules  for 
this  substance.  Unilateral  renal  artery  stenosis,  with 
fatal  arterial  hypertension  of  180  mm  Hg,  has  been 
observed  in  a  newborn  infant  ( 1 30)  suggesting  that 
the  renin-hypertensinogen  mechanism  is  active  early 
in  life  in  man  and  may  account  for  the  hypertension 
above  the  lesion  with  coarctation  of  the  aorta. 

Viability 


tachycardia  followed  the  hypotension  occurring  with 
comparable  doses  in  the  adult. 

In  the  newborn  monkey,  the  carotid  sinus  reflexes 
are  functional  and  occlusion  of  the  carotid  arteries 
has  been  shown  to  cause  a  rise  in  the  arterial  pressure, 
which  is  abolished  by  cutting  the  carotid  sinus  nerves 
(71) :  but  acute  anoxia  causes  a  fall  in  arterial  pressure 
suggesting  that  the  vasomotor  center  itself  is  not  very 
active:  there  was,  however,  a  rise  in  arterial  pressure 
in  the  fetus  in  response  to  asphyxia.  In  the  newborn 
baby  the  mean  arterial  pressure  is  about  40  mm  Hg 
below  the  mean  pressure  of  the  adult  and  the  avail- 
able evidence  shows  that,  once  the  immediate  read- 
justment of  birth  are  complete,  there  is  a  low  periph- 
eral resistance  (196);  the  cardiac  output  per  kg  of 
body  weight  is  about  double  that  of  the  adult,  the 
blood  flow  to  the  extremities  is  likewise  double  and 
the  cerebral  blood  flow  is  high  (123).  Low  tonic 
activity  of  both  the  chemical  and  reflex  regulating 
mechanisms  are  probably  concerned,  and  the  develop- 
ment of  these  will  probably  contribute  relatively 
more  to  the  gradual  rise  in  arterial  pressure  during 
growth  than  the  cardiac  output,  which  declines  in 
relation  to  body  weight.  Recently,  records  of  arterial 
blood  pressure  changes  during  replacement  trans- 
fusions, when  the  blood  volume  was  reduced  rapidly 
by    10  per  cent,   demonstrated   that   the   baroceptor 


Viability,  in  its  narrowest  sense,  may  be  considered 
as  the  capacity  of  the  newborn  to  establish  correct 


200 


150 


100 


50 


1 38  days  gestation  age 


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Pulmonary  arterial  perfusion  pressure  (mm  Hg) 
I 1 ■  ■ 1 1 

0  10  20  30  40  50 

fig.  25.   Perfusion    of    isolated    lungs    of   two    fetal    lambs, 

mature,  above;  nonviable,  below.  Pressure  flow  diagrams  were 

constructed  before  ventilation  (o)  and  about  15  min  later  (•). 

Following  ventilation,  there  is  a  large  decrease  of  pulmonary 

vascular  resistance  in  the  mature  lamb  and  almost  no  change 

in  the  premature.  [From  Dawes  (66).] 


THE    FETAL    AND    NEONATAL    CIRCULATION 


'645 


pulmonary  ventilation  and  perfusion  to  provide  full 
oxygenation  of  the  blood  in  order  to  maintain  the 
necessary  oxygen  supply  to  the  body  tissues;  it  is, 
therefore,  closely  linked  with  lung  development 
which  occurs  relatively  late  in  intrauterine  life. 
Most  of  the  quantitative  data  relating  this  develop- 
ment to  length  of  gestation  are,  again,  supplied  by 
Dawes  and  his  colleagues  in  the  lamb  fetus.  At  90 
days  of  age  fluid  starts  to  collect  in  the  alveolar 
spaces  of  the  lungs  (93).  Shortly  afterward  the  dis- 
tensibility  of  the  lungs  begins  to  increase  so  that,  at 
a  given  inflation  pressure,  older  lambs  obtain  more 
tidal  air  per  kg  body  weight  (fig.  24);  ventilation 
also  starts  to  cause  a  decrease  in  pulmonary  vascular 
resistance  and  there  is  a  larger  blood  flow  for  the  same 
perfusion  pressure  (fig.  25).  By  110  days  gestational 
age,  about  28  to  30  weeks  on  the  human  scale,  arti- 
ficial ventilation  can  raise  the  arterial  oxygen  satura- 
tion to  95  per  cent  and  independent  existence  is 
possible;  in  the  nonviable  premature  this  cannot  occur 
and  death  is  due  to  asphyxia. 

The  development  of  many  other  physiological 
mechanisms  must  also  influence  the  successful  opera- 
tion of  ventilation  and  perfusion  of  the  lung  tissues. 
Among  these  will  be  the  level  of  the  arterial  blood 
pressure,  closure  of  the  foramen  ovale  and  ductus 
arteriosus,  and  the  presence  of  sufficient  surface 
active  substance  to  prevent  collapse  of  the  expanded 
alveoli  (145);  Avery  &  Mead  (18)  have  found  the 
surface  activity  of  lung  extracts  from  premature 
infants  to  be  only  one-third  of  that  from  normal 
full-time  lungs. 

Congenital  Heart  Disease 

The  transition  from  the  fetal  to  the  adult  course  of 
the  circulation  may  not  take   place   because  of  in- 


herent congenital  abnormality  or  be  protracted  on 
account  of  a  difficult  labor  and  the  ensuing  asphyxia. 
Rowe  (164)  gives  a  concise  account  of  the  physical 
signs  and  the  physiology  of  both,  together  with  the 
possibilities  of  their  treatment  (122).  The  physio- 
logical disturbances  accompanying  congenital  mal- 
formations may  be  divided  into  three  groups:  /)  a 
left-to-right  shunt  through  a  patent  ductus  arteriosus, 
2)  the  retention  of  a  fetal  type  of  flow  through  both 
ductus  arteriosus  and  foramen  ovale,  and  3)  simple 
intracardiac  arteriovenous  shunts.  Only  the  first 
group  have  normal  arterial  oxygen  saturations. 

The  physical  signs  of  congenital  heart  disease  are 
frequently  difficult  to  distinguish  from  the  transient 
abnormalities  due  to  respiratory  disturbances  at 
birth;  Rowe  also  divides  these  infants  into  three  main 
groups.  In  the  first  are  those  who  do  not  breathe 
readily  at  birth  and  who  have  a  murmur  due  to 
patency  of  the  ductus  arteriosus:  Burnard  (51)  has 
observed  a  midsystolic  murmur  in  70  per  cent  of 
such  infants,  and  considers  it  due  to  swift  turbulent 
flow  through  a  ductus  only  partially  constricted  on 
account  of  asphyxia;  the  direction  of  this  flow  will 
depend  upon  the  relative  pressures  in  the  pulmonary 
and  aortic  trunks.  Lind  &  Wegelius  (129)  have 
angiocardiographic  evidence  for  delayed  closure  of 
the  ductus  arteriosus  following  asphyxia  neonatorum. 
In  the  second  group,  apnea  may  develop  suddenly 
following  normal  respiration  of  a  few  hours  to  4  weeks 
duration;  a  loud  continuous  murmur,  due  to  a  left- 
to-right  shunt  through  the  opened  ductus  arteriosus 
is  heard.  The  third  group  of  premature  infants,  with 
classical  respiratory  distress  syndrome  have,  on  ac- 
count of  the  high  lung  resistance,  a  pulmonary  ejec- 
tion click  to  the  second  heart  sound;  during  the 
recovery  phase  a  midsystolic  sound  is  also  heard  as 
the  ductus  arteriosus  narrows. 


REFERENCES 


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CIRCULATION    II 


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THE     FETAL    AND    NEONATAL    CIRCULATION 


1647 


59 


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61 


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167.  Rudolph,  A.  M.,  J.  E.  Drorbaugh,  P.  A.  M.  Auld, 
A.  J.  Rudolph,  A.  S.  Nadas,  C.  A.  Smith,  and  J.  P. 
Hubbell.  Circulation  in  the  respiratory  distress  syndrome. 
Pediatrics  27:  551,  1 96 1 . 

168.  Sandler.  M.,  C.  R.  J.  Ruthven,  S.  F.  Contracter,  C. 
Wood,  R.  T.  Booth,  and  J.  H.  M.  Pinkerton.  Trans- 
mission of  noradrenaline  across  the  human  placenta. 
Nature  197:  598,  1963. 

169.  Scholander,  P.  Experimental  Studies  on  Asphyxia  in  Animals. 
Oxygen  Supply  to  the  Human  Foetus.  C.I.O  M.S.  Symposium. 
Oxford:  Blackwe.ll,  1959,  p.  267. 

170.  Selye,  H.,  and  T.  McKeown.  Studies  on  the  physiology 
of  the  maternal  placenta  in  the  rat.  Proc.  Roy.  Soc.  London, 
Ser.  B.  119:  1,  1935-36. 

171.  Shelley,  H.  J.  Glycogen  reserves  and  their  changes  at 
birth  and  in  anoxia.  Brit.  Med.  Bull.  17:  127,  1961. 

172.  Shepherd,  J.  T.,  and  R.  F.  Whelan.  The  blood  flow  in 
the  umbilical  cord  of  the  foetal  guinea  pig.  J.  Physiol., 
London  115:1 50,  1 95 1 . 

173.  Smith,  C.  A.  The  Physiology  of  the  Newborn  Infant  (3rd 
ed.).  Oxford:  Bla<  kwell  Sci.  Publ.,  1959,  p.  122. 

174.  Smith,  S.  E.,  R.  S.  Stacey,  and  I.  M.  Young.  5-HT  con- 
centrations in  the  gut  and  platelets  of  the  developing 
guinea  pig.  Chem.  Pharm.  In  press. 

175.  Smythe,  C.  N.,  and  J.  L.  Farrow.  Present  place  in 
obstetrics  for  foetal  phonocardiography  and  electro- 
cardiography. Brit.  Med.  J.  2:  1003,  1958. 

176.  Sontag,  L.  W.,  and  T.  W.  Richards.  Soc.  Res.  Child., 
Devel.  Monog.  3,  1938,  p.  4. 

177.  Spratt,  N.  T.  Nutritional  requirements  of  the  early  chick 
embryo.  Biol.  Bull.  99:  120,  1950. 

178.  Stern,  L.,  and  J.  Lind.  Cardiovascular  disease:  perinatal 
circulation.  Ann.  Rev.  Med.   11:   113,   i960. 

179.  Ten  Berge,  B.  S.  Capillair-activitie  in  placenta-vlokken: 
de  invloed  van  histamine  en  acetylcholine;  de  invloed 
ophet  beloop  van  de  zwangerschap.  Ned.  Tijdschr.  Geneesh. 

99 :  3556,  1955- 

180.  Troen,  P.,  and  E.  E.  Gordon.  Perfusion  studies  of  the 
human  placenta.   I.  Effect  of  estradiol  and  human  cho- 


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CIRCULATION    II 


rionic  gonadotropin  on  citric  acid  metabolism.  J.  Clin. 
Invest.  37:  1516,  1959. 

181.  Villee,  C.  A.  The  intermediary  metabolism  of  human 
foetal  tissues.  Cold  Spring  Harbor  Symp.  Quant.  Biol,  ig: 
186,  1954. 

182.  Walker,  J.,  and  A.  C.  Turnbull.  Oxygen  Supply  to  the 
Human  Foetus.  C.I. O. M.S.  Symposium.  Oxford:  Blackwell, 

1959.  P-  '55- 

183.  Wallgren,  G.,  P.  Karlberg,  and  J.  Lind.  Studies  of 
the  circulatory  adaption  immediately  after  birth.  Acta 
Paediat.  49:  843,  i960. 

184.  Walls,  E.  W.  Development  of  specialized  conducting 
tissue  of  human  heart.  J.  Anal.  81  :  93,  1947. 

185.  Warkany,  J.  Congenital  malformations  and  pediatrics. 
Pediatrics  19:725,  1957. 

186.  West,  G.  B.,  D.  M.  Shepherd,  R.  B.  Hunter  and  A.  R. 

MacGregor.  The  functions  of  the  organs  of  Zuckerkandl. 
Clin.  Sci.  12:  317,   1953. 

187.  Westin,  B.  Technique  and  estimation  of  oxygenation  of 
the  human  foetus  in  utero  by  means  of  hystero-photography. 
Acta  Paediat.  46:  117,  1957. 

188.  Whittam,  R.  Sodium  and  potassium  movements  in 
kidney  cortex  slices  from  newborn  animals.  J.  Physiol., 
London  153:358,  i960. 

189.  Windle,  W.  F.  Physiology  of  the  Foetus.  Philadelphia: 
Saunders,  1940. 


190.  Wislocki,  G.  B.,  and  E.  W.  Dempsey.  The  chemical 
histology  of  the  human  placenta  and  decidua  with 
reference  to  the  mucopolysaccharides,  glycogen,  lipids 
and  acid  phosphatase.  Am.  J.  Anat.  83:  1,  1948. 

191.  Wislocki,  G.  B.,  and  G.  L.  Streeter.  Placentation  of 
the  macaque  (Macaca  mulatta)  from  the  time  of  implan- 
tation until  the  formation  of  the  definitive  placenta.  In: 
Contribution  to  Embryology.  Washington :  Carnegie  Inst.  27 : 
',  I938. 

192.  Wong,  M.,  and  D.  E.  Cassels.  The  foetal  electrocardio- 
gram A.M. A.  J.  Diseases  Children  99:  4,  ig6o. 

193.  Woodbury,  R.  A.,  M.  Robinow,  and  W.  F.  Hamilton. 
Blood   pressure  studies   on   infants.   Am    J.    Physiol.    122: 

472.  '938- 

194.  Young,  I.  M.  The  uterine,  placental  and  foetal  circula- 
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by  R.J.  S.  MacDowall.  London:  Dawson,  1956,  vol.  2, 
p.  184. 

195.  Young,  I.  M.  Some  observations  on  the  mechanism  of 
adrenaline  hypernoea.  J.  Physiol.,  London  137:  374,  1957. 

196.  Young,  I.  M.  Blood  pressure  in  the  newborn  baby.  Brit. 
Med.  Bull.  17:1 54,  1 96 1 . 

197.  Young,  I.  M.,  and  D.  C  Cottom.  (To  be  published.) 

198.  Young,  I.  M.,  and  W.  W.  Holland.  Some  physiological 
responses  of  the  neonatal  arterial  blood  pressure  and 
pulse  rate.  Brit.  Med.  J.  2:  276,  1958. 


CHAPTER     47 


The  flow  of  blood  through  bones  and  joints 


WALTER    S.    ROOT  Department  of  Physiology,  College  of  Physicians  and  Surgeons,  New  York  City 


CHAPTER    CONTENTS 

Bones 

Long  Bones 

Vertebrae 

Flat  Bones 

Nerve  Supply  of  Bone 

Blood  Flow  in  Bone 

Oxygen  in  the  Blood  of  Bones 

Intramedullary  Pressure 

Temperature  of  Bone  Marrow 
Joints 

The  Blood  Supply 

The  Nerve  Supply 

Blood  Flow  Through  Joints 

Nervous  Control  of  Joint  Blood  Vessels 


bone  must  not  be  thought  of  as  an  inert  substance, 
but  rather  as  one  of  the  highly  specialized  tissues  of 
the  body,  consisting  of  active  cells  which  respond 
promptly  to  physiological  demands  upon  the  skeletal 
and  hematopoietic  systems.  The  cells  are  sensitive  to 
nutritional  and  functional  processes,  and  differ  in 
their  reactions  from  those  of  other  tissues  only  because 
of  the  rigidity  and  stability  of  the  intercellular  de- 
posits of  mineral  salts. 

Contrary  to  general  belief,  bone  is  a  relatively 
vascular  tissue  (68).  This  concept  is  borne  out  by  the 
rapidity  with  which  substances  injected  into  bone 
marrow  appear  in  the  general  circulation  (105,  106). 
Large  infusions  can  be  administered  in  a  short  time 
(4),  and  this  route  of  giving  fluid  has  been  useful  in 
dealing  with  infants  (43)  and  in  treating  patients  in 
conditions  of  hemorrhage  and  shock  (101). 

BONES 

The  anatomical  features  of  the  vascular  system  in 
bones  are  classified  as  long  bones,  flat  bones,  or 
vertebrae. 


Long  Bones 

Most  studies  of  the  long  bones  have  been  made 
upon  the  femur  or  the  tibia-fibula.  The  long  bones 
receive  blood  from  three  sources:  a)  the  nutrient 
artery  or  arteries  entering  the  bone  in  the  shaft,  b) 
blood  vessels  entering  the  ends  of  the  bone,  and  c) 
blood  vessels  penetrating  the  periosteum  (fig.  1). 

Radiological  observations  in  which  the  arteries  are 
injected  with  radiopaque  substances  show  that  the 
principal  nutrient  artery  of  the  femur  traverses  the 
cortex  inclined  toward  the  knee  (16).  No  branches 
are  given  to  the  cortex  in  the  nutrient  canal.  On 
entering  the  medulla,  the  artery  divides  into  ascend- 
ing and  descending  limbs  which,  with  few  subdivi- 
sions, pass  to  either  end  of  the  bone.  In  general,  larger 
arteries  are  visualized  as  sharply  defined  and  tortuous 
channels  in  the  proximo-distal  axis,  and  are  com- 
paratively few  in  number. 

Medullary  arteries  can  be  traced  to  the  meta- 
physeal region  where  they  break  up  into  numerous 
fine  vessels  which  join  across  the  line  of  union  at  the 
epiphyseo-metaphyseal  synostosis  with  others  derived 
from  the  epiphyseal  arteries  (fig.  2).  Arterial  twigs 
from  the  main  medullary  arteries  can  be  seen  to  pass 
more  or  less  transversely  toward  the  endosteal  aspect 
of  the  compactum  where  they  recurve  and  course  for 
a  short  distance  in  the  peripheral  medullary  zone. 
Here  they  anastomose  with  one  another,  and  give  rise 
to  fine  vessels  which  pierce  the  endosteal  face  of  the 
compactum  and  arborize  irregularly  in  the  inner 
cortical  zone  (16). 

There  has  been  some  difference  of  opinion  con- 
cerning the  vascular  supply  to  the  metaphyseal  re- 
gion. Thus,  Weinmann  &  Sicher  (111)  state  that  the 
nutrient  artery  supplies  the  central  part  of  the  meta- 
physis,  its  more  peripheral  parts  being  fed  by  meta- 
physeal arteries  derived  from  the  periosteum.  On  the 


1651 


rfea 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


PRINCIPAL  NUTRIENT 
ARTERY  AND  VEIN 


PERIOSTEAL  CAPILLARIES  - 
IN  CONTINUITY  WITH  ' 
CORTICAL  CAPILLARIES 


other  hand,  Trueta  &  Harrison  (107) 
believe  that  in  the  adult  human  femur 
the  nutrient  artery  does  not  reach  the 
metaphyseal  region  which  is  wholly  sup- 
plied by  metaphyseal  arteries.  Studies 
on   rabbit  embrvos  and  young  rabbits     metaphyseal  arteries 

AND  TERMINALS  OF  THE 

indicate  that  in  the  earliest  stages  of  de-    medullary  arterial 

SYSTEM  ^«^ 

velopment  the  metaphysis  receives  blood 
only  from  the  nutrient  artery.  Later, 
metaphyseal  arteries  derived  from  the 
periosteum  take  over  the  supply  of  the 
peripheral  region,  the  extent  of  the  area 
supplied  bv  them  increasing  progres- 
sively (85). 

The  arteries  supplying  the  proximal 
part  of  the  femur  and  the  acetabulum 
are  the  lateral  femoral  circumflex,  the 
medial  femoral  circumflex,  the  obtu- 
rator, the  superior  gluteal,  the  inferior 
gluteal,  the  first  perforating  artery,  and 
the  nutrient  artery  of  the  femur  (62). 
Branches  of  these  enter  the  head  and 
neck  of  the  femur  through  small  foram- 
ina, or  enter  by  way  of  the  fovea  cen- 
tralis, or  are  carried  to  the  head  of  the 
femur  in  the  ligamentum  teres. 

In  children  the  foveal  vessels  assume 
a  small  role  in  supplying  blood  to  the 
femoral  head  (108,  114).  When  these 
arteries  do  penetrate  to  the  ossification 
center  they  are  probably  supplemen- 
tary (62).  In  the  adult  the  foveal  ar- 
teries are  larger  and  usually  nourish  the 
femur.    Apparently,    arteries   enter   the 

femoral  head  through  the  ligamentum  section.  [From  Brookes  (13).] 
teres  in  the  majority  of  cases  (108,  1  14), 
but  this  supply  is  supplementary   to  the  vital  supply 
from  the  capital  arteries  (62). 

All  investigators  have  emphasized  the  importance 
of  the  capital  branches  of  the  medial  femoral  circum- 
flex artery  for  the  nutrition  of  the  femoral  head  (109). 
The  terminal  branches  enter  the  femoral  head  at  the 
articular  rim,  just  posterior  to  the  superior  and  in- 
ferior poles  of  the  femoral  neck.  Most  investigators 
have  found  that  the  superior  posterior  branches  are 
larger  and  more  numerous  than  the  inferior  posterior 
arteries.  Usually,  no  arteries  enter  the  femoral  head 
or  neck  anteriorly  (109).  The  nutrient  artery  cannot 
be  traced  past  the  marrow  cavity  (62). 

Vessels  enter  the  distal  end  of  the  femur  through 
three  groups  of  foramina:  supracondylar,  condylar, 
and  intercondylar  (99).  In  each  some  10  to  35  for- 


END-ARTERIAL 
TERMINALS 


VENOUS  SINUSOIDS  V 
.--'METAPHYSEAL  VEINS 


MEDULLARY 
SINUSOIDS 


INTERFASCICULAR 
CAPILLARIES  IN  MUSCLE 


CENTRAL  VENOUS 
CHANNEL 


LARGE  EMISSARY  VEIN 


TRANSVERSE  EPIPHYSEAL 
VENOUS  CHANNEL 


fig.  i .   Diagram  of  vascular  organization  of  rat  tubular  bone   in    longitudinal 


amina  are  present.  Condylar  arteries  perforate  the 
cortex  and  ramify  within  the  spongiosa.  Terminal 
branches  of  the  middle  geniculate  arteries  pass 
through  the  intercondylar  foramina  and  are  distribu- 
ted to  the  central  parts  of  the  epiphysis.  Rami  arising 
from  the  superior,  lateral,  and  middle  geniculate 
arteries  pass  through  the  anterior  and  posterior 
supracondylar  nutrient  foramina,  and  are  distributed 
to  the  distal  end  of  the  diaphysis.  The  generous  vascu- 
lar supply  explains  the  lack  of  ischemic  necrosis  after 
fractures  of  the  lower  end  of  the  femur. 

The  blood  supply  to  the  cortex  or  compactum  of 
long  bones  runs  in  longitudinal  canals  known  as 
Haversian  canals.  In  man  the  canals  vary  from  25  to 
125,  averaging  50  yu  in  diameter,  but  larger  ones  are 
also  seen  (70).  Although  these  canals  run  longitudi- 


FLOW    OF    BLOOD    THROUGH    BONES    AND    JOINTS 


1653 


Periosteal  arteriole 
and  venae  comitantes' 
Periosteal 
capillaries 


Medullary 
artery 


Cortical 
-x" capillaries 

Endosteal 
capillaries 

Medullary 
sinusoids 


Central 
enous  sinus 


fig.  2.  The  blood  vascular  organization  of  diaphyseal  tu- 
bular bone  represented  diagramatically  in  transverse  section. 
[From   Brookes    (14).] 


fig.  3.  A  longitudinal  section  of  cortical  bone  showing  the 
anastomosing  and  branching  Haversian  canals.  The  com- 
municating canals  between  the  Haversian  canals  are  demon- 
strated. [From  Jaffe   (70).] 

nally,  they  do  not  run  vertically  for  more  than  short 
distances  soon  deviating  from  a  straight  line.  The 
canals  form  a  continuously  anastomosing  and  ramify- 
ing network  (fig.  3).  Beneath  the  articular  cartilage 
at  the  upper  and  lower  ends  of  a  bone,  the  canals  run 
transversely  to  the  long  diameter  of  the  bone.  Near 
the  surface  of  the  bone,  Haversian  canals  communi- 
cate with  the  canals  of  the  ground  lamellae  which 
open  to  the  external  surface  of  the  bone,  and  the 
innermost  canals  lead  into  the  medullary  cavity.  Re- 


cently the  term  "macrocanalicular  system"  has  been 
used  to  refer  to  the  system  in  mineralized  tissue  which 
is  made  up  of  Haversian  and  anastomosing  Volkmann 
spaces  (68).  It  is  generally  stated  that  one  or  two 
capillaries  are  present  in  an  Haversian  canal  (79).  A 
single  endothelial  tube  surrounded  by  a  slight 
adventitia  has  been  described  in  Volkmann's  canals. 

Lexer  (86)  had  emphasized  the  role  of  the  periosteal 
arteries  in  bone  nutrition,  but  more  recent  studies 
indicate  that  the  periosteal  circulation  may  be  scanty 
(20),  periosteal  arteries  being  found  rarely  or  only 
with  difficulty  (i).  Also,  the  notion  of  a  periosteal 
arterial  penetration  of  compact  bone  has  recently 
been  rejected  as  a  result  of  microradiographic  analy- 
sis in  the  rabbit  ( 16),  and  in  the  rat  and  human  fetus 
(13,  14).  This  opinion  is  further  strengthened  by  a 
study  of  nonischemic  adult  tubular  bone  (15).  Ac- 
cording to  certain  investigators  (13-16),  normal 
diaphyseal  blood  flow  is  centrifugal,  that  is,  passing 
from  the  medullary  arterial  system  outward  through 
the  cortex  into  the  periosteal  and  interfascicular  capil- 
laries of  muscle.  Drainage  of  compact  bone  is  effected 
either  by  way  of  periosteal  capillaries  or  through 
medullary  sinusoids  and  the  central  venous  channel. 
Apparently,  the  vascular  systems  of  bone  and  peri- 
osteum are  united,  but  only  at  the  capillary  level. 
This  would  explain  the  survival  of  outlying  bone  cells 
seen  by  Marneffe  (88)  in  rat  diaphysis  nourished  by 
the  periosteum  alone.  It  also  provides  a  basis  for  the 
development  of  a  collateral  circulation  as  found  in 
Johnson's  experiments  in  dogs  (72). 

The  obliquity  of  Haversian  canals  has  been  noted 
by  Cohn  &  Harris  (29)  and  others.  Brookes  (13), 
studying  rat  femora  and  tibiae  as  a  whole,  was  able 
to  show  how  cortical  vascular  obliquity  is  in  opposing 
senses  at  either  end  of  a  long  bone,  the  two  regions 
meeting  by  abrupt  directional  changes.  In  the  adult 
human  tibia  this  change  takes  place  at  the  inferior 
metaphysis  and  may  well  be  a  factor  in  the  delayed 
healing  of  fractures  at  this  site,  where  a  rich  venous 
outflow  would  predispose  to  recurrent  hematoma 
formation. 

It  seems  likely  that  the  normal  arterial  supply  to 
cortical  capillaries  is  mediated  by  medullary  end 
arteries.  This  conception  is  supported  by  the  findings 
of  Eletto  (42)  who  noted  the  lack  of  anastomoses  be- 
tween branches  of  the  principal  nutrient  artery  in  the 
medulla.  It  would  help  to  explain  the  occurrence  of 
irregular  bone  cell  necrosis  in  the  cortex  produced  by 
the  injection  of  particulate  suspensions  (75,  76),  or  by 
interruption  of  the  principal  nutrient  artery  (10). 
Epiphyses  also  seem  to  contain  discrete  circumscribed 


ib-,4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


vascular  zones  with  little  functional  overlap,  the  ob- 
struction of  which  on  either  arterial  or  venous  sides 
is  a  factor  in  osteochondritis  juvenilis  (19). 

The  role  of  the  periosteum  in  bone  regeneration 
and  the  incorporation  of  blood  vessels  from  the 
periosteal  vascular  network  during  bone  growth  in 
width  can  still  be  accepted  in  that  the  vitality  of  the 
osteogenic  layer  of  young  periosteum  is  maintained 
by  the  osteogenic  capillary  layer  fed  by  periosteal 
arteries  (54). 

As  visualized  radiographically,  the  venous  system 
differs  somewhat  from  the  arterial  system.  Thus,  a 
solitary  longitudinal  channel  of  wide  caliber  in  an 
approximately  central  medullary  position  can  be 
traced  from  one  end  of  a  bone  to  the  other.  Since  this 
central  canal  lacks  a  muscular  tunica  media  (88),  it 
may  properly  be  called  a  central  venous  sinus  in  the 
medulla  (16).  At  the  trochanteric  fossa  the  central 
venous  channel  is  joined  by  tributaries  from  the  lesser, 
third,  and  greater  trochanter  as  well  as  by  a  vessel 
p.issing  down  the  neck  from  the  head  of  the  femur. 
The  central  vein  is  joined  by  the  principal  nutrient 
vein  a  short  distance  below  the  nutrient  canal  and 
passes  characteristically  as  a  single  vessel  down  to  the 
inferior  metaphysis  where  it  anastomoses  with  an 
ascending  branch  of  the  middle  geniculate  vein. 
Sometimes  it  divides  into  two  stems  at  the  mid-shaft 
level.  The  central  venous  channel  has  numerous 
transverse  branches  radiating  toward  the  endosteum 
and  these  drain  the  sinusoids  of  the  medulla.  An 
endosteal  line  marking  the  junction  of  the  medullary 
sinusoids  with  the  cortical  capillaries  can  be  seen. 

Branemark  (11),  who  has  been  able  to  visualize 
bone  circulation  in  the  living  rabbit,  states  that  the 
bone  marrow  arteriole  divides  dichotomously  into 
capillaries.  These  run  to  sinusoids  which  are  sometimes 
hexagonal,  sometimes  spindle  shaped.  Sinusoids  may 
unite  to  form  sinusoidal  systems.  The  sinusoids  are 
drained  by  venules  into  collecting  venules  which 
empty  into  the  central  veins.  The  sinusoids  vary 
rhythmically  in  their  degree  of  dilation.  Blood  cells 
may  bypass  a  sinusoid  by  flowing  through  a  shunting 
capillary  directly  into  a  venule.  In  some  instances, 
cells  appear  to  hug  the  vessel  wall  of  one  half  of  a 
sinusoid  apparently  without  disturbing  flow  in  the 
other  half.  Capillaries  stemming  from  marrow  ar- 
terioles enter  the  Haversian  canals  to  supply  endos- 
teal parts  of  diaphyseal  bone.  The  capillaries  then 
swine;  back  into  the  marrow  to  empty  into  sinusoids 
or  directly  into  collecting  venules.  Blood  flow  in  bone 
capillaries  is  fairly  steady,  and  the  velocity  of  flow  is 
higher  than  in  marrow  capillaries. 


In  the  pigeon,  "transitional  capillaries"  (37,  38) 
connect  the  arteries  to  the  venous  sinusoids.  The 
capillary  link  is  extremely  circumscribed,  and  it  is  not 
until  the  venous  sinusoidal  anastomoses  are  reached 
that  the  blood  spreads  out  in  lacing  and  interlacing 
vessel  tufts,  thence  to  be  directed  from  the  tuft-like 
branchings  into  larger  and  larger  vessels  eventually  to 
enter  the  central  longitudinal  vein  almost  at  right 
angles. 

There  seems  little  doubt  that  the  extensively  dis- 
tributed, spacious,  thin-walled  venous  sinusoids  nor- 
mally form  the  principal  functioning  vascular  bed  for 
the  actively  circulating  blood  in  marrow,  i.e.,  they 
correspond  to  the  capillaries  of  other  organs. 

In  pigeons  in  which  the  marrow  is  made  hypo- 
plastic by  starvation,  one  can  see,  between  the  fat 
spaces,  well-outlined  and  clearly  defined  channels 
which  constitute  a  most  extensive  system  of  capil- 
laries (37).  Many  of  these  appear  to  be  nonpatent  and 
functionally  dormant  as  far  as  the  active  blood  circu- 
lation is  concerned.  These  capillaries  come  off  the 
venous  sinusoids  by  way  of  conical  openings,  and  seem 
to  be  continuous  with  them.  They  are  not  capillaries 
in  the  sense  of  an  arteriovenous  transition,  but  instead 
extend  from  venous  channel  to  venous  channel;  they 
are  intersinusoidal.  The  same  intersinusoidal  semi- 
collapsed  channels  have  been  reported  in  the  marrow 
of  the  ribs  of  the  white  rat  138),  and  are  believed  to  be 
present  in  the  dog  (40). 

Three  theories  as  to  the  nature  of  the  circulation  in 
adult  marrow  have  been  advanced :  a)  by  Rindfleisch 
(98)  who  believed  that  the  blood  spaces  are  lined  by 
parenchvma  alone  and  have  no  endothelial  cells;  b) 
Langer  (81),  on  the  other  hand,  thought  of  the  mar- 


Spinal 
branches 


Ddrsc^i 
medial  a. 


Aorta- 


Calcified 
spongiosum 

Cartilaginous 


Anterolateral  a. 


fig.  4.  Diagram  of  a  transverse  section  through  the  mid- 
body  of  the  vertebra  of  a  six-month-old  fetus.  [From  Ferguson 
(46).] 


FLOW  OF  BLOOD  THROUGH  BONES  AND  JOINTS 


165 


00 


row  as  an  entirely  closed  vascular  system;  and  c) 
Bunting  (18)  pictured  vessels  lined  with  epithelium, 
but  with  openings  at  various  points  communicating 
directly  with  the  medullary  parenchyma.  A  survey  of 
the  literature  indicates  no  general  agreement  among 
those  who  have  studied  the  subject. 

I  'a librae 

In  the  lumbar  and  thoracic  regions  the  aorta  gives 
off  paired  segmental  arteries.  These  penetrate  the 
anterior  groups  of  spinal  muscles  and  continue  pos- 
teriorly in  the  horizontal  plane  to  pass  on  either  side 
of  the  vertebral  body  and  lie  in  direct  contact  with 
the  anterior  and  lateral  wall  of  this  structure  (fig.  4) 
to  which  small  branches  are  contributed  (56).  Each 
artery  gives  off  a  large  branch  in  the  trough  formed 
by  the  vertebral  body  and  the  transverse  process. 
This  branch  traverses  the  intervertebral  foramen  and 
divides  into  three  terminal  arterioles  (113).  One  of 
these  passes  to  the  posterior  surfaces  of  the  two  adja- 
cent vertebral  bodies.  A  second  runs  to  the  spinal 
cord  and  its  meninges.  The  third  supplies  the  pos- 
terior vertebral  processes  and  surrounding  soft 
structures. 

The  first  branch  mentioned  above  divides  within 
the  spinal  canal,  one  terminus  running  upward  and 
medially  across  the  posterior  surface  of  the  vertebral 
body  under  the  posterior  spinal  ligament,  to  enter  a 
foramen  about  the  center  of  the  body.  The  other 
terminus  runs  downward  and  medially  to  a  similar 
entrance  in  the  center  of  the  body  of  the  next  distal 
vertebra.  Thus,  there  are  four  diagonal  arteries,  two 
from  each  side  converging  to  enter  the  center  of  the 
posterior  surface  of  each  vertebra,  either  through  a 
common  foramen  or  through  separate  foramina.  The 
arterioles  may  coalesce  or  remain  separate  before 
radiating  to  all  parts  of  the  centrum  (113).  The  main 
dorsal  vertebral  artery  and  the  right  and  left  antero- 
lateral arteries  appear  to  end  in  the  middle  of  the 
developing  osseous  spongiosa.  No  arterial  branches 
can  be  demonstrated  beyond  the  center  of  the  verte- 
bral body.  Irregular  vascular  canals  can  be  seen  in 
the  spongiosa  and  a  diffuse  network  of  thin-walled 
channels  is  present  in  the  surrounding  cartilaginous 
zone.  Very  small  vessels  perforate  the  cartilaginous 
plate  and  tiny  capillary  channels  permeate  the  can- 
nulus  fibrosa.  The  branches  to  the  cord  anastomose 
freely  with  the  anterior  and  posterior  spinal  arteries 
which  lie  on  the  respective  surfaces  of  the  cord  ex- 
tending from  within  the  skull  to  the  end  of  the  cord. 
The   pedicles,    transverse   processes,   articular   facets, 


and  lamina  have  a  good  arterial  blood  supply  through 
the  anastomosing  branches  of  the  posterior  rami  from 
the  paired  segmental  arteries  (46).  Similar  anatomical 
arrangements  are  true  for  the  cervical  vertebrae  (56). 

The  intervertebral  disc  tissues  appear  to  offer  an 
important  focus  for  degeneration  as  they  are  always 
farthest  from  the  arterial  supply  (46). 

Each  lumbar  vertebral  body  is  drained  by  four 
main  venous  trunks.  Two  leave  the  body,  one  on 
either  side  from  an  anterolateral  position  at  a  level 
just  above  the  midline;  two  emerge  as  paired  vessels 
from  the  bony  foramen  in  the  center  of  the  posterior 
vertebral  wall  (110).  The  two  posterior  veins  empty 
at  once  into  the  anterior  longitudinal  meningo- 
rhachidian  veins  of  the  posterior  external  plexus. 
Direct  connection  with  the  corresponding  lumbar 
veins  is  made  through  the  spinal  rami  of  the  latter. 
The  two  anterolateral  veins  from  the  vertebral  body 
empty  directly  into  the  lumbar  veins.  The  lumbar 
veins  passing  horizontally  are  in  direct  communica- 
tion with  three  great  longitudinal  or  vertical  venous 
systems:  a)  posteriorly  with  the  posterior  external 
venous  plexus  which  extends  vertically  within  the 
spinal  canal,  external  to  the  spinal  cord  membranes; 
b)  with  the  azygos  or  hemiazygos  systems,  and  c)  with 
the  inferior  vena  cava. 

Within  the  vertebral  body  the  two  posterior  and 
the  two  anterolateral  veins  meet  to  form  a  large 
reservoir.  Although  these  veins  have  the  usual  venous 
structure  beyond  the  vertebral  periosteum,  the  wall 
structure  is  replaced  by  a  limiting  membrane  of 
flattened  endothelial  cells  within  the  body.  Radiating 
peripherally  from  the  central  venous  basin  are  many 
irregular  columnar  spaces  which  occupy  approxi- 
mately forty  per  cent  of  the  entire  vertebral  body. 
The  more  peripheral  parts  of  the  venous  spaces  con- 
tain within  their  lumens  a  very  large  proportion  of 
hematopoietic  tissue,  together  with  reticuloendo- 
thelial elements.  Hematopoietic  tissue  is  occasionally 
found  within  the  lumen  of  the  central  venous  space 
(no). 

Flat  Bones 

The  mandible  appears  to  be  the  flat  bone  concern- 
ing which  the  most  information  is  available.  The 
periosteum  and  outer  circumferential  portions  of  the 
osseous  mandible  are  supplied  by  such  adjacent 
arteries  as  the  facial,  submental,  inferior  alveolar, 
mylohyoid,  mental,  masseric,  lateral  pterygoid,  medial 
pterygoid,  temporal  and  sublingual  branch  of  the 
lingual  (36).  One  or  more  nutrient  foramina  passing 


,(>-,<> 


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CIRCULATION    II 


through  the  marrow  space  are  evident  above  the 
genial  tubercle,  and  multiple  small  foramina  are 
usually  seen  in  the  small  triangular  area  on  the  inner 
face  of  the  ramus  below  the  mandibular  notch  and 
above  or  on  the  endocondylar  and  endocoronoid 
ridges. 

Within  the  mandibular  canal  the  inferior  dental 
artery  gives  rise  to  blood  vessels  which  pass  upward 
toward  the  alveolar  border  (28).  Some  vessels  pass 
toward  the  lower  border,  but  these  are  few  in  number. 
The  lower  border  of  the  mandible  is  supplied  mainly 
by  periosteal  vessels.  The  inferior  dental  artery  within 
the  mandibular  canal  is  surrounded  by  numerous 
vessels,  presumably  venae  comitantes. 

Some  eleven  areas  of  cortical  bone  are  recognized 
(36),  the  regions  being  based  upon  the  direction  of 
the  canals  in  the  Haversian  mesh.  There  is  little  evi- 
dence of  the  presence  of  lacunae  or  canaliculi  in  the 
adult. 

Nerve  Supply  of  Bone 

Perhaps  the  most  complete  and  careful  study  of  the 
innervation  of  bone  has  been  carried  out  by  Kuntz  & 
Richins  (78).  According  to  their  study  the  absence  of 
any  nerve  fibers  not  in  close  proximity  to  blood 
vessels,  in  preparations  in  which  excision  of  the  dorsal 
root  ganglia  had  resulted  in  degeneration  of  the  af- 
ferent fibers,  leads  to  the  conclusions:  a)  that  the 
parenchymatous  tissue  of  the  bone  marrow  is  devoid 
of  direct  afferent  innervation,  and  />)  that,  in  prep- 
arations of  normally  innervated  bone  marrow,  un- 
myelinated fibers  which  exhibit  no  obvious  relation- 
ships to  blood  vessels  represent  unmyelinated  afferent 
fibers  or  the  unmyelinated  terminal  portions  of 
myelinated  ones. 

afferent  fibers.  The  conception  of  some  sensory 
innervation  of  the  bone  marrow  is  supported  by  the 
common  clinical  observation  that  puncture  of  bone 
gives  rise  to  pain,  and  the  finding  that  many  afferent 
fibers  in  bone  fall  within  the  caliber  range  of  the 
pain-conducting  fibers  is  in  full  agreement  with  this 
view.  Schleicher  (100)  noted  that  when  blood  plasma 
was  infused  into  the  sternum  a  sharp  pain  was  felt 
about  the  infusion  area  when  the  pressure  of  the  in- 
coming fluid  was  greater  than  the  intramedullary 
pressure.  In  many  persons  with  multiple  myeloma 
and  metastatic  bone  lesions,  distinct  bone  pain  is  asso- 
ciated with  sudden  straining  or  coughing  (94).  It  is 
possible  that  the  sudden  elevation  of  intramedullary 
pressure  shown  to  result  from  such  effort  results  in 


distortion  of  the  arteries  and  arterioles  bearing 
sensory  nerves  and  that  this  produces  pain. 

When  the  sympathetic  nerve  fibers  are  caused  to 
degenerate  by  removing  the  appropriate  sympathetic 
ganglia,  afferent  fibers  are  found  running  to  blood 
vessels.  They  are  present  in  relationships  which  indi- 
cate that  they  are  also  connected  with  receptors  im- 
bedded in  the  parenchyma  of  the  marrow  (78).  Foa 
(47,  48)  suggests  that  the  afferent  fibers  may  play  a 
part  in  the  reflex  regulation  of  functional  activity  of 
bone  marrow,  and  Chiray  et  al.  (24)  have  shown  that 
the  intramedullary  injection  of  certain  substances  will 
produce  reflex  changes  in  blood  pressure. 

efferent  fibers.  The  relation  of  the  sympathetic 
innervation  to  bone  circulation  has  been  studied 
either  by  sectioning  or  stimulating  sympathetic  fibers. 
It  seems  clear  that  cutting  sympathetic  fibers  causes 
vasodilation  and  hyperemia  (39,  40,  48,  60),  and  that 
stimulation  produces  vasoconstriction  (39,  48,  60, 
1 12). 

Hurrell  (69)  has  traced  nerve  fibers  into  and  along 
Haversian  canals  of  adult  bone  into  two-thirds  of  the 
thickness  of  the  shaft  of  a  cat's  femur.  Some  end 
blindly  in  the  bone  matrix;  others,  in  close  connection 
with  osteocytes.  He  suggests  tentatively  that  the  nerve 
fibers  found  may  be  the  two  ends  of  a  reflex  arc 
governing  bone  growth  and  maintenance.  In  this  con- 
nection Coppo  (31)  has  reported  a  decrease  in  the 
percentage  of  ash,  and  a  modification  of  its  composi- 
tion, 8  to  1  5  davs  after  denervation  of  bone.  Neverthe- 
less, all  experiments  on  animals  have  shown  that  uni- 
lateral sympathectomy  by  itself  has  no  observable 
effect  on  bone  growth  (3,  21).  The  results  obtained 
from  experiments  on  the  effect  of  sympathectomy  on 
the  healing  of  fractures  are  equivocal.  Some  investi- 
gators have  found  healing  to  be  accelerated  (30), 
whereas  others  have  seen  no  effect  (89).  According  to 
Corbin  &  Hinsey  (32),  bones  and  joints  are  not  sup- 
plied with  nerves  having  specific  trophic  functions. 

Blood  Flow  in  Bone 

The  circulation  in  bone  is  sufficient  to  supply  the 
normal  variations  of  physiological  processes,  but  often 
fails  to  respond  to  the  extreme  insults  of  trauma  or 
infection.  The  delayed  union  of  comminuted  bumper 
fracture  of  the  tibia,  and  the  extensive  involvement  of 
the  shaft  of  the  long  bones  in  osteomyelitis  are  classi- 
cal examples.  In  situations  where  end  arteries  are 
present,  as  at  the  metaphyseal  side  of  the  epiphyseal 
plate,    infarction    is    common.    Aseptic    infarction    is 


FLOW    OF    BLOOD    THROUGH    BONES    AND   JOINTS 


1657 


found  in  nutritional  diseases  such  as  scurvy  and 
rickets,  and  septic  infarction  with  abscess  formation 
in  tuberculosis  and  other  forms  of  bacteremia  (23). 

Arterial  blood  from  the  terminal  arborizations  in 
the  cortex,  derived  from  the  medullary  arterial  sys- 
tem, empties  into  a  vascular  lattice  contained  in  the 
canals  of  Havers  and  Volkmann  (16).  Here  the  circu- 
lation is  probably  very  sluggish  and,  besides  move- 
ment up  and  down  the  diaphysis,  blood  may  be 
shifted  into  either  medulla  or  periosteum  depending 
upon  functional  variations  in  opposing  muscles  and 
hematopoietic  activity  in  the  marrow.  According  to 
Branemark  (11)  blood  flow  in  bone  capillaries  is 
fairly  steady  and  the  velocity  is  greater  than  in  mar- 
row capillaries.  Externally,  the  vascular  lattice  of  the 
cortex  connects  with  the  osteogenic  capillary  layer; 
internally,  with  the  medullary  sinusoids.  The  former 
route  to  the  systemic  veins  is  direct  and  probably 
drains  most  of  the  blood  circulating  in  the  cortex.  The 
latter  route  is  indirect,  through  the  sinusoids,  into  the 
central  venous  sinus,  and  thence  via  the  nutrient  vein 
at  the  bone  extremities  into  periarticular  veins  (16). 

Lamas  et  al.  (80)  have  pointed  out  that  a  relatively- 
slow  blood  flow  in  bone  should  be  expected,  since 
none  of  the  three  functions  of  long  bones,  mechanical 
support  of  the  body,  storage  of  calcium  salts,  and 
hematopoiesis,  needs  a  rapid  circulation.  In  this  con- 
nection, it  may  be  noted  that  the  arrangement  of 
blood  vessels  within  bone  favors  a  slow  circulation. 
Thus,  the  nutrient  artery  describes  many  curves 
before  entering  bone  and  after  dividing  into  ascend- 
ing branches  which  run  through  the  marrow,  it  ends 
in  wide  blood  spaces  close  to  the  epiphyses.  These 
blood  spaces  are  in  close  contact  with  thin-walled 
veins  of  wide  caliber.  This  arrangement  of  blood 
vessels  reduces  the  pressure  and  speed  of  circulation 
in  the  arteries,  and  enables  the  vein  to  carry  sub- 
stances quickly  away  from  the  blood  spaces:  hence 
the  efficacy  of  therapeutic  injections  into  marrow. 

Few  quantitative  studies  of  blood  flow  through 
bone  have  been  made,  [ones  (73),  who  studied  the 
uptake  rate  of  a  radioactive  colloid  which  is  highly 
selected  by  marrow  cells,  found  a  minimal  circula- 
tion through  the  red  marrow  in  the  rabbit  amounting 
to  7  per  cent  of  the  circulating  blood  volume  per  min. 
A  corresponding  value  for  man  would  be  about 
300  ml. 

The  blood  flow  through  human  bone  has  been 
studied  by  measuring  the  rate  of  clearance  of  I131  from 
bone  marrow  (94).  Xo  apparent  correlation  was 
found  between  marrow  clearance  rates  and  hemo- 
globin level,  leucocyte  count,  body  temperature,  or 


blood  pressure.  The  intravenous  injection  of  hexa- 
methonium  bromide,  a  ganglionic  blocking  agent, 
reduced  the  clearance  rate  of  marrow,  and  this  ap- 
pears to  be  directly  related  to  the  fall  in  blood  pres- 
sure. Conversely,  the  injection  of  Paredrine  resulted  in 
a  distinct  increase  in  the  clearance  rate  from  the 
marrow,  presumably  as  a  result  of  the  sympathomi- 
metic action  of  the  drug.  A  decreased  flow  through 
the  perfused  tibia  of  the  dog  can  be  produced  by 
stimulating  sympathetic  nerve  fibers  or  by  adding 
Adrenalin  to  the  perfusion  fluid   (39). 

Plethysmographic  measurements  of  blood  flow 
through  the  normal  humerus  of  man  have  been  made 
by  Edholm  et  al.  (41).  They  report  a  blood  flow 
through  the  nutrient  artery  of  0.5  to  1.0  ml  per  100  ml 
of  bone  per  min.  They  point  out  that  this  value  may 
represent  only  half  the  total  flow,  for  the  periosteal 
vascular  supply  is  not  included.  They  calculate  on  the 
basis  of  these  measurements  that  the  total  skeletal 
blood  flow  should  be  74.5  ml  per  min,  although  they 
concede  that  this  is  bound  to  be  an  underestimation, 
for  bones  with  an  active  marrow  are  more  vascular 
than  the  humerus.  The  above  measurements  are  much 
lower  than  the  values  of  3.5  to  41  ml  per  100  g  bone 
per  min  found  in  perfusion  experiments  using  the 
tibia  of  the  dog  (40). 

hyperemia.  Blair  (7)  has  suggested  that  alternating 
ischemia  and  hyperemia  maintain  normal  bone  calcifi- 
cation and  aid  healing  after  a  fracture.  In  this  con- 
nection it  should  be  noted  that  hyperemia  has  long 
been  thought  to  be  the  physiological  basis  for  localized 
deossification.  Thus,  Leriche  &  Policard  (83)  state: 
"If  by  any  process  whatever,  the  activity  of  the  circu- 
lation is  increased  in  the  vicinity  of  bone,  the  latter 
becomes  rarefied."  Also,  Greig  (52)  has  written: 
"Every  trauma  of  bone  is  followed  by  a  reactionary 
local  hyperemia,  and  every  disease  resulting  in  bone 
rarefaction  or  decalcification  is  accompanied  by  a 
more  or  less  copious  and  prolonged  increase  of  the 
arterial  and  capillary  circulations."  De  Lorimer  et  al. 
(87)  interpret  their  radiological  studies  showing  areas 
of  bone  rarefaction  as  being  the  result  of  localized 
reflex  hyperemia.  They  believe  this  may  be  produced 
by  trauma  even  of  minor  degree  as  in  simple  contu- 
sions, sprains,  or  overenergetic  physical  therapy,  or 
by  infection  or  neoplasms. 

Although  the  above  statements  seem  to  rest  more 
on  logic  than  on  observable  facts,  it  seems  clear  that 
vascular  resorption  of  bone  is  related  to  definite  circu- 
latory changes.  Thus,  Miller  &  cle  Takats  (91),  who 
carried  out  plethysmographic  studies  of  blood  flow  on 


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CIRCULATION    II 


1 2  patients  suffering  from  painful  osteoporosis  follow- 
ing injury,  found  an  increased  blood  flow  amounting 
to  5  to  60  per  cent  in  the  affected  limb.  Also,  in  severe 
inflammatory  processes  an  actual  coalescence  of 
several  Haversian  canals  takes  place,  the  bony  parti- 
tion between  them  disappearing  with  the  formation 
of  large  spaces  in  bone  containing  numerous  blood 
\  essels  and  considerable  vascular  granulation.  The 
process  is  not  confined  to  the  Haversian  system,  but 
also  involves  the  spongy  tabeculae.  The  marrow  also 
becomes  extremely  vascularized,  as  a  result  of  the 
proliferation  of  the  existing  vessels  (71). 

reduction  of  blood  supply.  According  to  Haslhofer 
(58)  the  richness  of  anastomoses  in  long  bones  pre- 
vents bone  infarction  even  when  the  blood  supply  to 
the  nutrient  artery  is  interrupted.  On  the  other  hand, 
Axhausen  &  Bergmann  (2)  present  clinical  instances 
of  aseptic  bone  necrosis  which  they  ascribe  to  interrup- 
tion of  local  blood  supply.  Also,  Phemister  (96,  97) 
has  published  radiographic  and  pathologic  descrip- 
tions of  lesions  which  he  considers  to  be  the  result  of 
marrow  infarction. 

Since  the  production  of  bone  and  marrow  infarcts 
in  animals  was  generally  considered  impossible  by 
conventional  means,  earlier  investigators  resorted  to 
extensive  stripping  procedures  or  to  the  production  of 
multiple  small  emboli  designed  to  occlude  large  num- 
bers of  capillaries.  Thus,  Brunschwig  (17)  attempted 
to  produce  infarction  of  the  marrow  of  the  femur  in 
dogs  by  stripping  the  entire  periosteum  and  simulta- 
neously cutting  the  nutrient  artery.  Despite  this  ex- 
tensive trauma,  no  evidence  of  infarction  was  seen  in 
adult  dogs.  Among  the  injection  experiments  are 
those  of  Wollenberg  (115)  who  injected  talc  into  the 
femoral  artery  of  dogs  and  observed  areas  of  necrosis 
in  metaphyses  and  epiphyses.  Bergmann  (6),  on  the 
other  hand,  could  find  no  changes  in  epiphyses,  al- 
though he  saw  widespread  necrosis  of  cortical  bone 
after  the  injection  of  particles  of  silver  suspended  in 
gum  arabic,  and  Kistler  (75-77)  could  find  no  in- 
farcts following  ligation  of  the  nutrient  artery  of  the 
femur  in  rabbits.  However,  the  injection  of  suspen- 
sions of  charcoal  in  acacia  and  of  masses  of  aggluti- 
nated bacteria,  under  unmeasured  but  admittedly 
high  pressure,  produced  areas  of  necrosis  in  the  center 
of  the  metaphyses. 

Huggins  &  Wiege  (65)  seem  to  have  been  the  first 
to  report  changes  following  occlusion  of  the  nutrient 
artery  only.  In  both  mature  and  immature  rabbits 
ligation  of  the  nutrient  vessels  to  the  femur  was  fol- 
lowed in  all  instances  by  infarction  of  the  marrow. 


Although  in  a  few  cases  there  was  some  periosteal  and 
endosteal  reaction  above  the  operative  site,  no  evi- 
dence of  bone  infarction  was  found.  In  a  recent  study 
Brookes  (12)  has  shown  that  occlusion  of  the  princi- 
pal nutrient  canal  of  the  femur  in  day-old  rabbits 
produces  an  initial  shortening,  followed  by  equaliza- 
tion, and  then  a  final  absolute  shortening  of  3  per  cent 
in  the  occluded  femur. 

Variations  in  nutrition  of  the  growth  cartilage  will 
cause  shortening  or  lengthening  of  long  bones.  Thus, 
interruption  of  the  medullary  arteries  and  diversion 
of  blood  to  the  growth  cartilage  presumably  will  ac- 
count for  the  increased  growth  rate  observed  in  long 
bones  affected  by  a  variety  of  conditions,  such  as 
fractures,  chronic  infections,  and  tumors  (45).  Occlu- 
sion of  the  nutrient  canal  may  result  in  diversion  of 
blood  into  the  epiphyseal  and  metaphyseal  arteries, 
with  possible  ischemia  of  the  diaphysis.  It  is  probable 
that  while  collateral  circulation  is  developing  in  the 
bone  extremities,  a  diminution  in  the  femoral  blood 
supply  to  the  growth  cartilages  occurs,  thus  account- 
ing for  the  growth  lag  of  occluded  femora  noted  by 
Brookes  (12)  in  the  first  30  days.  With  the  establish- 
ment of  a  collateral  circulation  by  means  of  anasto- 
moses between  the  metaphyseal  arteries  and  the 
principal  nutrient  artery,  blood  flow  near  the  growth 
cartilage  is  increased  bringing  about  equalization  in 
the  length  of  occluded  and  normal  femora  in  the 
intermediate  growth  phase.  In  the  final  phase,  120  to 
150  days,  a  relative  decrease  in  the  nutrition  of  the 
growth  cartilages  must  occur  to  account  for  the  3.7 
per  cent  retardation  in  femoral  growth  seen  at  ma- 
turity. The  reason  for  this  is  not  clear.  However,  it 
seems  probable  that  towards  the  end  of  growth  the 
collateral  circulation  is  not  quite  able  to  furnish  the 
same  quantity  of  blood  to  die  medullary  artery  as 
when  the  nutrient  artery  is  also  available  as  a  supply 
channel  (12).  These  results  may  be  compared  with 
the  evidence  of  bone  lengthening  after  fractures  in 
children  (22)  in  whom  presumably  the  same  local 
vascular  mechanism  is  active  that  determined  the 
growth  curve  of  occluded  femora  in  rabbits. 

It  is  generally  thought  that  the  disturbances  on  the 
venous  side  produced  by  obliterating  the  vein  accom- 
panying the  nutrient  artery  is  slight,  because  of  the 
profuse  venous  drainage  at  the  bone  extremities  (57) 
and  at  the  surface  of  the  diaphysis  (16). 

Oxygen  in  the  Blood  of  Bones 

Ham  (53)  has  shown  by  measurements  in  the  dog's 
radius  that  bone  cells,  if  they  are  to  survive,  can  gen- 


FLOW    OF    BLOOD    THROUGH    BONES    AND    JOINTS 


'659 


erally  be  no  farther  than  100  n  from  a  nutrient  vessel. 
Actually  few  quantitative  measurements  of  the  oxy- 
gen content  of  the  blood  circulating  through  bone 
have  been  made,  and  these  have  been  concerned  with 
the  blood  taken  from  marrow.  Thus,  Grant  &  Root 
(51)  punctured  the  humerus  of  unanesthetized  dogs 
and  determined  the  oxygen  saturation  and  tension  in 
the  first  0.15  ml  of  blood  removed.  The  oxygen  satu- 
ration of  bone  marrow  blood  is  similar  to  that  of  blood 
drawn  from  the  jugular  vein.  The  oxygen  contents 
and  capacities,  and  the  hematocrit  values  decrease  to 
about  the  same  extent  in  jugular  and  bone  marrow 
blood  after  a  30  per  cent  hemorrhage,  and  recovery 
takes  place  at  the  same  rate.  Similar  studies  have  been 
carried  out  on  normal  man  and  patients  suffering 
from  anemia  and  polycythemia  vera  (5,  102),  and  pa- 
tients with  primary  and  secondary  polycythemia 
(59).  The  oxygen  saturation  of  marrow  blood  was 
found  to  be  similar  to  that  of  normal  man;  that  of 
polycythemic  individuals  appears  to  be  greater  than 
normal. 

The  factors  controlling  the  oxygen  tension  and 
oxygen  supply  to  "erythrogenic  nests"  are  not  well 
understood.  It  is  likely  that  the  oxygen  consumption 
of  these  growing  cells  is  one  consideration,  and  that 
the  quantity  and  partial  pressure  of  oxygen  in  the 
blood  perfusing  the  area  constitutes  another  factor. 
The  bulk  of  marrow  blood  appears  from  histological 
evidence  to  be  contained  in  the  venous  sinusoids.  It 
seems  reasonable  to  think  that  most  of  the  mature 
erythrocytes  found  in  the  sample  obtained  by  needle 
puncture  are  derived  from  the  sinusoids.  Presumably 
the  erythrogenic  nests  are  in  diffusion  equilibrium 
with  the  blood  in  the  sinusoids  even  though  the 
growing  erythroid  cells  may  be  sealed  off  from  the 
sinusoids  as  proposed  by  Doan  (37,  38). 


Intramedullary  Pressure 

The  pressure  within  the  medullary  canal  has  been 
measured  in  various  bones  in  different  animals  by  a 
number  of  investigators.  In  animals,  such  as  the  dog 
and  cat,  it  varies  between  20  and  1 15,  averaging  some 
50  mm  Hg  (8,  60,  74,  82).  According  to  Petrakis  (95), 
the  pressures  in  the  marrow  of  patients  without 
marrow  disease  are  uniformly  low.  Thus,  in  the 
sternum  the  pressures  were  approximately  atmos- 
pheric, ranging  from  2/0  to  17/15  mm  Hg.  Tocantins 
&  O'Neill  (106)  report  intramedullary  pressures  of 
50  to  120  mm  H20  (3.7-8.9  mm  Hg)  in  the  human 
sternum.  Petrakis  (95)  notes  that  human  marrow 
pressures  are  lower  than  those  seen  in  lower  animals, 
and  suggests  that  the  difference  may  be  attributed  to 
the  effects  of  anesthesia.  The  pressures  measured  in 
the  region  of  the  diaphysis  are  said  to  be  definitely 
higher  than  those  found  near  the  epiphyses  (fig.  5) 
(103). 

Marrow  pressure  records  show  a  definite,  but  small, 
pulse  pressure  (60,  74,  82,  103).  This  observation  may 
be  of  practical  importance,  for  Miles  (90)  reports 
that  the  absence  of  such  fluctuations  in  pressure  in  the 
femoral  head  of  patients  indicates  necrosis  of  this 
structure. 

In  addition  to  changes  in  pulse  pressure,  records  of 
marrow  pressure  show  rhythmic  fluctuations  corre- 
sponding to  respiration  (fig.  5)  (60,  103).  Also,  slower 
rhythmic  variations  in  pressure,  presumably  Traube- 
Hering  waves,  are  sometimes  seen  (8). 

Rasgone,  Vater,  and  Marbarger  (see  74)  concluded 
that  the  marrow  behaves  as  a  semiclosed  cavity  and 
that  changes  in  intramedullary  pressure  are  dependent 
upon  the  volume  of  blood  within  the  marrow  cavitv. 
When  the  venous  return  is  obstructed,  the  mean 
pressure  of  the  marrow  increases  and  the  pulse  pres- 


100 


0 

x 

5 


50 


RESP 


DIAPHYSIS  EPIPHYSIS 

FEMUR 


fig.  5.  Bone  marrow  pres- 
sure in  diaphysis  and  epiphysis, 
and  respiration  rate  recorded 
simultaneously  in  the  dog.  [From 
Stein  (103).] 


Il 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


sure  decreases  (8,  103),  whereas  occlusion  of  the 
arterial  supply  to  the  bone  decreases  both  mean  and 
pulse  pressures  (8,  60,  103).  Fracture  of  both  sides  of 
the  femur  causes  the  intramedullary  pressure  to  fall 
to  zero  (8).  Kaiser  and  his  co-workers  (74)  demon- 
strated a  direct  correlation  between  altitude  and  a 
fall  in  marrow  pressure  in  dogs,  and  experimentally 
confirmed  the  fact  that  the  marrow  cavity  acts  as  a 
semiclosed  cavity. 

This  conception  is  supported  by  the  study  of 
Petrakis  (95)  who  showed  that  the  Valsalva  maneuver 
in  man  produces  a  rise  in  systemic  venous  pressure, 
thus  reducing  the  venous  outflow  from  the  marrow 
cavity  and  causing  an  increase  in  marrow  pressure 
and  a  decrease  in  pulse  pressure.  Human  marrow 
pressure  varies  with  respiration  and  body  position. 
Thus,  sternal  pressures  were  found  to  be  near  or 
below  atmospheric  pressures  in  recumbent,  nonleu- 
kemic  patients,  and  to  vary  with  the  respiration.  The 
more  distal  iliac  sites  did  not  respond  to  the  respira- 
tory effects  of  forced  breathing,  but  required  the  more 
strenuous  effects  of  the  Valsalva  effort  or  of  coughing 
to  evoke  changes.  The  higher  pressures  obtained  in 
the  iliac  crest  are  presumably  a  result  of  die  erect 
position  of  man.  The  effects  of  changes  in  body  posi- 
tion and  of  alterations  in  respiration  on  marrow 
pressures  indicate  that,  under  conditions  of  normal 
activity,  intramedullary  pressure  varies  considerably 
and  is  passively  aflected  by  changes  in  venous  pres- 
sure resulting  from  these  activities. 

In  this  connection,  it  is  interesting  to  note  that  in- 
creasing the  blood  volume  by  the  intravenous  infu- 
sion of  large  quantities  of  saline  causes  a  gradual  in- 
crease of  marrow  pressure  (8).  On  the  other  hand,  a 
decrease  in  blood  volume  produced  by  hemorrhage 
causes  a  slow  fall  in  medullary  pressure  (60). 

Although  marrow  pressure  does  not  ordinarily  re- 
flect changes  in  mean  systemic  arterial  pressure  (74), 
decapitated  cats  and  cats  with  acute  spinal  injury 
have  low  femoral  arterial  pressures  and  do  show  low 
marrow  pressures  (60).  Chronic  "spinal"  cats,  in 
which  the  systemic  pressure  has  returned  to  the  levels 
seen  before  the  spinal  cord  was  cut,  had  bone  marrow 
pressures  similar  to  those  found  in  unoperated  animals. 
Stimulation  of  the  cut  peripheral  end  of  either  vagus 
nerve  produced  the  usual  slowing  of  the  heart  and  fall 
in  svstemic  pressure.  This  was  associated  with  a  re- 
duction in  bone  marrow  pressure.  Changes  in  marrow 
pressure  induced  by  stimulation  of  the  central  ends 
of  the  cut  vagi  or  of  the  central  end  of  the  cut  femoral 
or  sciatic  nerve,  or  by  making  an  incision  in  the  ab- 
dominal  wall,   were   small    and   unpredictable.    The 


increase  in  systemic  arterial  pressure  produced  bv 
occluding  both  carotid  arteries  was  associated  with  a 
rise  in  marrow  pressure. 

Stimulation  of  the  cut  peripheral  end  of  the  ab- 
dominal sympathetic  chain  isolated  from  its  connec- 
tions with  the  spinal  cord  produced  a  fall  in  marrow 
pressure  within  the  femur.  A  similar  reduction  in 
marrow  pressure  of  the  mandible  occurs  when  the 
peripheral  end  of  the  cut  cervical  sympathetic  cord  is 
stimulated.  The  fall  in  marrow  pressure  caused  by 
excitation  of  sympathetic  nerve  fibers  has  been  used 
to  trace  the  pathway  by  which  such  fibers  reach 
specific  bones  (1 12). 

To  determine  whether  the  sympathetic  innervation 
of  the  marrow  vessels  is  constantly  influenced  by  tonic 
impulses,  the  abdominal  sympathetic  chain  of  one 
side  was  removed  with  strict  aseptic  precautions. 
Several  days  after  recovery  from  the  operation,  simul- 
taneous measurement  of  the  marrow  pressures 
showed  no  difference.  However,  when  the  experiment 
was  repeated  using  cats  made  decerebrate  by  ligating 
both  common  carotid  arteries  and  the  basilar  artery, 
the  pressure  in  the  denervated  femur  was  found  to  be 
25  mm  Hg  higher  than  its  innervated  control  (60). 

Stimulation  of  the  peripheral  end  of  the  cut  splanch- 
nic nerve  produced  the  usual  prolonged  rise  in  femoral 
arterial  pressure,  whereas  the  marrow  pressure  of  the 
femur  was  greatly  reduced  (fig.  6)  and  recovered 
only  as  the  systemic  pressure  returned  to  the  control 
value  (60).  The  same  phenomena  can  be  reproduced 
by  the  intravenous  injection  of  Adrenalin  (fig.  7) 
(8,  60,  82).  The  Adrenalin  effect  can  be  reversed  by 
the  prior  injection  of  Hydergine  (60).  Other  drugs 
which  produce  an  increase  in  systemic  pressure  and  a 
reduction  in  marrow  pressure  are  norepinephrine 
(60),  Pituitrin  (8,  82),  Neo-Synephrine  (8),  Syneph- 
rine  (8),  and  tyramine  (8). 

A  rise  in  systemic  blood  pressure  with  a  simulta- 
neous increase  in  marrow  pressure  is  produced  by  the 


fig.  6.  Effect  of  stimulating  the  peripheral  end  of  the  cut 
splanchnic  nerve  on  the  femoral  arterial  pressure  (upper  record) 
and  the  marrow  pressure  (lower  record)  in  the  femur  of  the 
cat.    [From  Herzig  &  Root   (60).] 


FLOW    OF    BLOOD    THROUGH    BONES    AND    JOINTS 


[66l 


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fig.  7.  Effect  of  injecting  in- 
travenously 1  ml  of  1  150,000 
Adrenalin  on  the  femoral  ar- 
terial pressure  (upper  record) 
and  the  marrow  pressure  (lower 
record)  in  the  femur  of  the  cat. 
[From  Herzig  &   Root   (60).] 


administration  of  ephedrine  (82),  Benzedrine  (8,  60), 
ergotamine  tartrate  (8)  or  nicotine  (8).  A  reduction 
in  both  systemic  and  marrow  pressure  follows  the  in- 
jection of  histamine  (8,  82),  acetylcholine  (8),  sodium 
nitrate  (8),  and  amyl  nitrite  (60). 

Patients  with  leukemia  and  multiple  myeloma  dif- 
fer from  nonleukemic  patients  in  having  elevated 
mean  marrow  pressures  and  increased  pulse  pressures 
(95).  In  patients  with  acute  leukemia  in  whom  the 
highest  pressures  are  found,  dicrotic  notches  are  pres- 
ent in  the  pulse  waves  suggesting  a  lowered  pe- 
ripheral resistance  in  the  marrow  circulation.  The 
degree  of  anemia  could  not  be  correlated  with  the 
mean  pressures,  nor  with  the  pulse  pressures  in  the 
marrow.  The  pressure  data  confirm  the  increased 
vascularity  in  the  marrow  in  some  forms  of  leukemia 
as  demonstrated  by  the  clearance  of  I131  from  the 
marrow  (94). 

Temperature  of  Bone  Marrow 

This  subject  is  of  some  importance,  for  it  is  generally 
believed  that  hematopoiesis  requires  the  maintenance 
of  a  high  bone  marrow  temperature  (33).  According 
to  Huggins  et  al.  (64),  the  more  centrally  placed 
bones  of  the  extremities,  the  cranial  bones  and  the 
sternum  in  the  rat,  rabbit,  and  pigeon  have  tempera- 
tures similar  to  that  of  the  peritoneal  cavity,  whereas 
the  temperature  of  the  peripheral  bone  marrow  of  the 
extremities  may  be  lower  by  4  to  8  C  or  more.  In 
adult  man  the  red  marrow  is  exclusively  limited  to 
the  bones  of  the  body  trunk  and  head  as  well  as  the 
proximal  portions  of  the  limbs  (92).  Chemical  ac- 
tivity of  the  marrow  does  not  affect  the  thermal  con- 
dition appreciably.  On  the  other  hand,  the  heat  of 
muscular  activity  of  the  limbs  increases  marrow 
temperature. 

Huggins  &  Blocksom  (63)  showed  that  an  increase 


in  bone  marrow  temperature  of  the  outlying  bones 
led  to  the  replacement  of  yellow  by  red  marrow.  They 
found  a  close  correlation  between  the  development  of 
cellular  marrow  and  a  temperature  level  similar  to 
that  of  the  deep  peritoneal  cavity.  However,  they  were 
uncertain  whether  this  is  a  primary  effect  upon  tissue 
metabolism,  or  a  secondary  vasomotor  effect. 

Petrakis  (93),  who  studied  the  temperature  in  the 
sternum,  iliac  crest,  tibia,  spinous  process,  and  verte- 
bral body  of  ten  patients,  found  temperatures  ranging 
from  that  of  the  rectum  in  the  vertebral  body  mar- 
row, to  4  C  below  this  in  other  bones.  He  interprets 
this  to  mean  a  lack  of  precise  temperature  regulation 
in  hematopoietically  active  bone  marrow.  No  corre- 
lation was  found  between  temperature  and  cell  type. 

JOINTS 

Gardner's  excellent  review  (50)  should  be  con- 
sulted for  general  information  concerning  the  physi- 
ology of  movable  joints. 

The  Blood  Supply 

According  to  Davies  (34)  little  has  been  added  to 
the  first  description  of  the  circulus  vasculosus  by 
William  Hunter  (66)  who  in  1743  wrote:  "All  around 
the  neck  of  the  bone  there  is  a  great  number  of 
Arteries  and  Veins  which  ramify  into  smaller  Branches 
and  communicate  with  one  another  by  frequent 
Anastomoses  like  those  of  the  mesenterv.  This  might 
be  called  the  Circulus  vasculosus,  the  vascular  border  of 
the  Joint." 

At  the  articular  margins,  the  capillaries  form  deli- 
cate anastomosing  loops  comparable  in  pattern  with 
those  seen  in  the  mesentery.  The  blood  supply  of  the 
synovial  membrane  and  capsule  communicate  freely 
with  the  periosteal  and  epiphyseal  supply;  hence,  the 


1 66a 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


shaft  of  the  bone  forms  one  nutritional  unit,  and  the 
joint  cavity  and  adjoining  epiphysis  form  another. 
For  this  reason,  Harris  (55)  uses  the  term  circulus 
vasculosis  arliculi  et  epiphyseos  to  emphasize  the  nutri- 
tional interdependence  of  the  joint  and  the  epiphysis. 

The  venous  drainage  has  received  little  attention. 
According  to  Testut  (104),  Sappey  described  the 
veins  as  characterized  by  frequent  anastomoses, 
tortuosities,  and  varicosities.  Testut  remarks  on  their 
voluminous  nature.  Occasional  valves  are  seen  in  the 
large  veins,  even  in  the  more  superficial  parts  of  the 
synovial  membranes. 

The  delicate  nature  of  the  synovial  membrane  and 
its  blood  supply  is  indicated  by  the  fact  that  small 
extravasations  of  blood  into  the  joint  cavity  are  often 
found  in  animals,  and  some  extravasation  follows 
such  a  simple  procedure  as  puncture  of  the  joint  (35). 

The  Nerve  Supply 

Chief  among  the  features  of  the  synovial  membrane 
is  its  sensitivity  to  pain.  Localization  is  often  not 
highly  accurate.  To  what  degree  the  synovial  mem- 
brane responds  to  other  sensations,  such  as  tension  or 
pressure,  is  uncertain.  Medullated  and  nonmedullated 
nerves  entering  the  joint  with  the  blood  vessels  form  a 
plexus  in  the  synovial  membrane.  The  nonmedullated 
fibers  in  large  part  innervate  the  blood  vessels  and  are 
probably  of  sympathetic  origin.  The  effects  of  sympa- 
thectomy on  the  vascular  supply  of  joints  remains 
obscure,  and  in  view  of  the  paradoxical  effects  re- 
corded by  Engel  (44)  they  need  investigation.  The 
synovial  membrane  shows  an  abundance  of  free  nerve 
endings  presumably  subserving  pain;  end  organs 
possibly  concerned  with  proprioceptive  impulses  are 
variously  described  as  Ruflini,  Golgi,  Mazzoni, 
looped  or  knotted  types.  Pacinian  corpuscles  are  not  a 
characteristic  feature  of  the  synovial  membrane. 
Gardner  (49)  failed  to  find  them,  and  Davies  (34) 
confirms  this. 

Blond  Flow  Through  Joints 

Attempts  have  been  made  to  determine  the  blood 
flow  through  joints  by  measuring  the  intra-articular 
temperature  (61),  by  the  application  of  the  plethysmo- 
graph  to  a  knee  segment  (9),  by  using  a  bubble  flow- 
meter (25),  and  by  means  of  an  electromagnetic 
flowmeter  (26,  27). 

In  adult  anesthetized  dogs  weighing  9.5  to  31  k", 
the  blood  flow  through  the  knee  joint  amounts  to  1.5 
to  7.0  ml  per  min  (26).  The  temperature  of  the  joint 
must  be  markedly  raised  to  obtain  a  measurable  in- 


crease in  flow,  changes  of  10  C  having  little  effect. 
Even  a  high  external  temperature  of  60  to  65  C  in- 
creases the  blood  flow  only  1 5  to  57  per  cent.  Rapid 
cooling  of  the  joint  with  ice  packs  causes  the  flow  to 
decrease  and  remain  fairly  constant  at  half  that  of  the 
control.  However,  sometimes  the  flow  falls,  rises,  and 
then  falls  again;  this  is  a  type  of  behavior  also  de- 
scribed for  skin  vessels  exposed  to  low  temperatures 
(84).  Removal  of  the  ice  packs  is  followed  by  a  slow 
return  of  blood  flow  to  the  control  level,  partly  owing 
to  the  delay  in  returning  to  the  normal  temperature. 
Nevertheless,  a  delay  in  the  return  of  blood  flow  also 
occurs  when  the  joint  is  quickly  restored  to  the  control 
temperature. 

According  to  Horvath  &  Hollander  (61),  joint 
blood  vessels  dilate  in  response  to  cold  and  constrict 
when  exposed  to  heat.  This  finding  is  not  supported 
by  the  work  of  Hunter  &  Whillams  (67)  who  used  the 
same  technique.  The  latter  found  that  joint  tempera- 
ture fell  when  their  subject  was  exposed  to  cold,  and 
this  they  attributed  to  a  reflex  superficial  vasodilata- 
tion resulting  in  a  short  period  of  excessive  heat  loss. 
On  the  other  hand,  Cobbold  &  Lewis  (26)  believe 
the  decrease  in  intra-articular  temperature  on  expo- 
sure to  cold  is  the  result  of  the  constriction  of  joint 
vessels.  In  their  plethysmographic  study  of  blood  flow 
through  the  knee  segment,  Bonney*/ a/.  (9)  found  that 
cooling  the  area  resulted  in  a  decrease  in  blood  flow, 
and  heating  produced  the  reverse  effect.  Since  they 
found  a  similar  decrease  in  flow  when  the  circulation 
to  the  skin  of  the  segment  was  suppressed  by  Adrenalin 
iontophoresis,  and  further  observed  that  after  this 
procedure  cooling  no  longer  decreased  the  blood  flow, 
Bonney  et  al.  suggest  that  a  different  reaction  to  cool- 
ing may  occur  in  articular  than  does  in  superficial 
vessels.  The  direct  measurement  of  flow  by  Cobbold 
&  Lewis  (26)  does  not  support  this  view.  These  in- 
vestigators believe  that  the  results  reported  by  Bonney 
et  al.  are  complicated  by  the  presence  of  other  tissue 
such  as  muscle. 


Nervous  Control  of  Joint  Blood  J'essels 

The  innervation  of  joints  has  been  fully  reviewed 
by  Gardner  (50).  The  blood  vessels  of  the  knee  joint 
receive  vasoconstrictor  fibers  by  way  of  the  articular 
nerves.  Section  of  these  increases  blood  flow  some 
50  per  cent  above  the  resting  level  (27).  Stimulation 
of  the  peripheral  cut  end  of  this  nerve  produces  vaso- 
constriction and  a  decreased  blood  flow.  When  the 
carotid  arteries  were  occluded  below  the  carotid  sinus, 
the  usual  increase  in  systemic  pressure  was  seen,  but 


FLOW    OF    BLOOD    THROUGH    BONES    AND    JOINTS 


1663 


no  change  in  outflow  from  the  joint  was  observed. 
Repetition  of  carotid  occlusion  after  sympathectomy 
always  produced  an  increase  in  flow.  Lowering  of 
systemic  pressure  by  hemorrhage  results  in  a  decrease 
in  joint  blood  flow  which  may  cease  if  the  blood  loss 
is  great  enough. 


The  vasoconstrictor  action  of  Adrenalin,  measured 
as  a  decrease  in  blood  flow  (27),  can  also  be  produced 
by  means  of  Noradrenalin.  Such  effects  are  seen  in 
both  innervated  and  denervated  vessels.  Acetylcholine 
has  a  marked  vasodilator  action  on  innervated  and 
denervated  vessels. 


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93.  Petrakis,  N.  L.  Temperature  of  human  bone  marrow. 
J.  Appl.  Physiol.  4:  549,  1952. 

94.  Petrakis,  N.  L.,  S.  P.  Masowedis,  and  P.  Miller.  The 
local  blood  flow  in  human  bone  marrow  in  leukemia  and 
neoplastic  diseases  as  determined  by  the  clearance  rate 
of  radio-iodide  (I131).  J.  Clin.  Invest.  32:  952,  1953. 

95.  Petrakis,  N.  L.  Bone  marrow  pressures  in  leukemic  and 
non-leukemic  patients.  J.  Clin.  Invest.  33:  27,  1954. 

96.  Phemister,  D.  B.  Changes  in  bones  and  joints  resulting 
from  interruption  of  circulation.  I.  General  considerations 
and  changes  resulting  from  injuries.  Arch.  Surg.  41  :  436, 
1940. 

97.  Phemister,  D.  B.  Changes  in  bones  and  joints  resulting 
from  interruption  of  circulation.  II.  Non-traumatic  lesions 
in  adults  with  bone  infarction ;  arthritis  deformans.  Arch. 
Surg.  41:  1455,   1940. 

98.  Rindfleisch,    G.    E.    Ueber    Knochenmark    und    Blut- 


bildung.  Arch,  nukroskop.  Anal.  u.  Entwicklungsmach.   17:1, 
21,   1880. 
99.   Rogers,  W.  M.,  and  H.  Gladstone.  Vascular  foramina 
and  arterial  supply  of  the  distal  end  of  the  femur.  J.  Bone 
and  Joint  Surg.  32A:  867,   1950. 

100.  Schleicher,  E.  M.  On  the  "conical  openings"  in  the 
wall  of  venous  sinusoids  and  their  relation  to  the  so-called 
erythrogenic  capillaries  in  the  bone  marrow  of  man. 
Anat.  Record  95:  379,    1946. 

101.  Schnall,  M.  D.,  and  R.  J.  Heffernan.  Intrasternal  in- 
fusions in  obstetrical  hemorrhage.  Am.  J.  Surg.  68:  44, 
'945- 

102.  Schwartz,  B.  M.,  and  D.  Stats.  Oxygen  saturation  of 
sternal  marrow  blood  in  polycythemia  vera.  J.  Clin. 
Invest.   28:  736,    1949. 

103.  Stein,  A.  H.,  H.  C.  Morgan,  and  F.  C.  Reynolds.  Varia- 
tions in  normal  bone  marrow  pressures.  J.  Bone  and  Joint 
Surg.  39A:  1  1  29,   1957. 

104.  Testut,  L.  Vaisseaux  et  nerfs  des  tissues  conjonctifs  fibreux, 
sereux,  et  osseux.  Anatomie  et  physiologic.  (These  d'agregation.) 
Paris  :  Masson,    1 880. 

105.  Tocantins,  L.  M.  Rapid  absorption  of  substances  in- 
jected into  bone  marrow.  Proc.  Soc.  Exptl.  Biol.  Med.  45: 
292.  '94°- 

106.  Tocantins,  L.  M.,  and  J.  F.  O'Neill.  Infusion  of  blood 
and  other  fluids  into  the  circulation  via  the  bone  marrow. 
Proc.  Soc.  Exptl.  Biol.  Med.  45:  782,  1940. 

107.  Trueta,  T.,  and  M.  A.  M.  Harrison.  The  normal  vas- 
cular anatomy  of  the  femoral  head  in  adult  man.  J.  Bone 
and  Joint  Surg.  35B:  442,   1953. 

108.  Tucker,  F.  R.  Arterial  supply  to  the  femoral  head  and 
its  clinical  importance.   J.   Bone  and  Joint  Surg.   31B:  82, 

■949- 

109.  Vereby,  K.  Die  Blutversorgung  des  Femurkopfes.  Anat. 
Anz.  93:  225,    1942. 

1 10.  Wagner,  G.,  and  E.  P.  Pendergrass.  Intrinsic  circula- 
tion of  the  vertebral  body.  Am.  J.  Roentgenol.  27:  818,  1932. 

111.  Weinmann,  J.  P.,  and  H.  Sicher.  Bone  and  Bones.  Funda- 
mentals of  Bone  Biology.  London:  Kimpton,  1947. 

112.  Weiss,  R.,  and  W.  S.  Root.  Innervation  of  the  vessels 
of  the  marrow  cavity  of  certain  bones.  Am.  J.  Physiol.  197: 

1255.  '959- 

113.  Willis,  T.  A.  Nutrient  arteries  of  the  vertebral  bodies. 
J.  Bone  and  Joint  Surg.  31  A:  538,  1949. 

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developing  femoral  head  and  neck.  Surg.  Gynecol.  Obstet. 
77:61,  1943. 

1 1 5.  Wollenberg,  G.  A.  Die  aseptische  Knochennecrose  und 
ihre  Bedeutung  fur  die  Knochen-  und  Gelenkchirurgie. 
Acta  Chir.  Scand.  60:  369,   1926. 


CHAPTER     48 


Dynamics  of  the  pulmonary  circulation 


ALFRED    P.    FISHMAN 


Department  of  Medicine,  Columbia  University, 
College  of  Physicians  and  Surgeons,  New  York  City 


CHAPTER      CONTENTS 

The  Growth  of  Ideas 

Bridge  Between  Two  Ventricles 
Role  in  External  Respiration 
Analysis  of  Pulmonary  Hemodynamics 
Alveolar-Capillary  Gas  Exchange 
Comparative  Physiology 

Experimental  Animals  and  Test  Preparations 
Functional  Anatomy 
Blood  Vessels 

Overlap  of  distensibility  and  resistance  characteristics 

Large  pulmonary  vessels 

Small  muscular  pulmonary  vessels 

Capillaries 
Extravascular  Smooth  Muscle 
Systemic  Blood  Supply  of  the  Lung 
Venous  Admixture 
Pulmonary  Vasomotor  Nerves 
Pulmonary  Blood  Flow 
Normal  Values 

Uneven  Pulmonary  Blood  Flow 
Pulmonary  Vascular  Pressures 
Recording 

Hydrostatic  Reference  Level 
Pulmonary  Arterial  Pressure 
Pulmonary  Venous  and  Left  Atrial  Pressures 
Pulmonary  Arteriovenous  Pressure  Gradient 
Pulmonary  Wedge  Pressures 
Influence  of  Intrathoracic  Pressure  on  Pulmonary  Vascular 

Pressure 
Transmural  Versus  Luminal  Pressures 
Pulmonary  Blood  Volume 

Measurement  of  Pulmonary  Blood  Volume 

Stewart-Hamilton  :  indicator  dilution 

Newman:  exponential  downslope 

Bradley:  equilibration  curves 
Changes  in  Pulmonary  Blood  Volume 

Lung  volumes 

Mechanics  of  breathing 

Radioactive  tracers 

Miscellaneous 
Normal  Values  for  Pulmonary  Blood  Volume 


Variations  in  Pulmonary  Blood  Volume 

Partition  of  Pulmonary  Blood  Volume 
Hemodynamic  Interrelations 

Distensibility  and  Resistance 

Distensibility  arid  Capacity :  Pressure -Volume  Relationships 

Resistance:  Pressure-Flow  Relationships 

Meaning  of  Pulmonary  Vascular  Resistance 

Practical  Recognition  of  Pulmonary  Vasomotricity 

Blood  Flow  Through  Each  Lung  Separately 

Critical  Closure 

Potential  and  Kinetic  Energy 
Pulmonary  Capillary  Circulation 

Pulmonary  Capillary  Pressure 

Rate  of  Pulmonary  Capillary  Blood  Flow- 
Nature  of  Pulmonary  Capillary  Blood  Flow 

Size  of  Pulmonary  Capillary  Bed 

Pulmonary  Capillary  Blood  Volume 

Resistance  and  Distensibility 

Time  Spent  by  Blood  in  Pulmonary  Capillaries 

Pulmonary  Capillary  I  lematocrit 

Transcapillary  Exchange 
Miscellaneous  Hemodynamic  Phenomena 

Pulmonary  Arterial  Pulse-Wave  Velocity 

Pulmonary  Circulation  Time 
Influence  of  Respiration  on  Pulmonary  Circulation 

Spontaneous  Breathing 

Inllation  of  the  Lungs 

Positive  Pressure  Breathing 

Negative  Pressure  Breathing  (Pleural) 

Negative  Pressure  Breathing   (Intrapulmonary) 

Cough 

Prolonged  Expiration 

Forced  Expiration  (Valsalva) 
Occlusion  of  a  Pulmonary  Artery 
Effects  of  Exercise  on  Pulmonary  Circulation 

Pulmonary  Blood  Flow 

Blood  Flow  and  Oxygen  Uptake 

Arteriovenous  Oxygen  Difference 

Pulmonary  Vascular  Pressures 

Pulmonary  Blood  Volume 

Pulmonary  Vascular  Resistance 
Miscellaneous  Mechanical  Influences 

Heart  Rate 


1667 


1 668 


HANDEOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


"Bronchomotor  Tone" 

Mechanical  Compression  (Atelectasis) 

Hypertonic  Solutions 
Pulmonary  Vasomotor  Activity 

Respiratory  Gases 

Acute  Hypoxia 

Chronic  Hypoxia 

Acute  Hyperoxia 

Acute  Hypercapnia 

Acute  Acidosis 

Alveolar  Hypoventilation 

Pulmonary  Vasomotor  Reflexes 

Pulmonary  Vasomotor  Waves 
Effect  of  Drugs 

Predominantly  Passive  Effects 

Pulmonary  Vasoconstrictors 

Pulmonary  Vasodilators 
Cardiopulmonary  Disorders 

Pulmonary  Arterial  Hypertension 
Restricted  vascular  bed 
Increase  in  pulmonary  blood  flow 
Increase  in  pulmonary  venous  pressure 
Pulmonary  arterial  vasoconstriction 

Cor  Pulmonale 

Pulmonary  Edema 

Pulmonary  Hypotension 

Pulmonary  Arteriovenous  Fistula 

Pulmonic  Stenosis 

Pulmonic  Valvular  Insufficiency 


(242).  By  this  arrangement,  the  lung  is  equipped  to 
operate  efficiently  over  a  wide  range  of  metabolic  ac- 
tivities: the  enormous  expanse  of  alveolar-capillary 
surface  is  capable  of  increasing  during  activity  (346) 
and  the  geometric  distribution  of  airways  and  blood 
vessels  favors  the  continued  balance  of  alveolar  venti- 
lation and  pulmonary  capillary  perfusion  even  during 
strenuous  exertion  (7).  Finally,  governing  the  coordi- 
nated performance  of  this  respiratory  apparatus  is  a 
complicated  system  of  ventilatory  and  circulatory 
controls;  these  succeed,  despite  the  phasic  and 
asynchronous  nature  of  the  ventilation  and  circula- 
tion, in  stabilizing  the  gaseous  composition  of  the 
alveolar  gas  and  in  ensuring  adequate  perfusion  of 
the  gas-exchanging  surfaces. 

In  addition  to  participating  in  external  respiration, 
the  pulmonary  circulation  also  performs  several  me- 
chanical functions  as  a  consequence  of  its  architecture 
and  location.  Thus,  as  the  bridge  between  the  two 
sides  of  the  heart,  it  is  in  a  position  to  serve  as  a 
reservoir  of  blood  for  the  left  ventricle  and  to  control 
left  ventricular  output  by  varying  the  pulmonary 
venous  return  (183).  .Similarly,  as  a  consequence  of 
their  position  at  the  outlet  of  the  right  ventricle,  the 
smaller  pulmonary  vessels  constitute  a  filter  for  sys- 
temic venous  particles  of  all  kinds,  including  the 
normal  formed  elements  of  the  blood  (1). 


the  pulmonary  circulation  is  part  of  an  elaborate 
tonometric  system  for  external  respiration;  it  exists 
for  the  perfusion  of  the  lungs  rather  than  for  their  nu- 
trition. And,  as  a  consequence  of  its  anatomical  dispo- 
sition with  respect  to  the  pulmonary  airways  and  air 
spaces,  the  lung  operates  as  a  respiratory  organ 
rather  than  as  an  air  sac. 

The  lung  appeared  in  the  vertebrate  phylum.  In 
principle,  it  is  designed  to  bring  a  thin  stream  of 
venous  blood  into  gaseous  equilibrium  with  a  large 
volume  of  alveolar  gas;  however,  in  construction  and 
in  efficiency,  it  varies  from  class  to  class.  Thus,  in  the 
amphibia — vertebrates  which  bridge  the  gap  between 
the  water  and  the  land — the  lung  resembles  a  large 
bulla  (fig.  1 ) ;  this  inefficient  construction  apparently 
suffices  for  the  low  metabolic  requirements  of  the 
amphibia  for  oxygen.  At  the  other  extreme  is  the 
complex  lung  of  the  large  and  vigorous  terrestrial 
vertebrates;  in  such  a  lung,  septation  and  alveolation 
have  created  a  porous  structure,  composed  mainly  of 
myriads  of  microscopic  air  spaces;  suspended  in  the 
walls  of  these  tiny  air  spaces  are  the  pulmonary  capil- 
laries to  which  the  pulmonary  arterial  tree  delivers 
the  entire  right  ventricular  output  for  arterialization 


fig.  1.  Alveolar  structure  of  the  frog  lung.  Each  lung  con- 
sists of  a  large  central  cavity  surrounded  by  numerous  small 
chambers  of  varying  size.  The  alveolar  walls  are  outlined  by 
the  vessels  which  they  contain.  (Prepared  in  collaboration  with 
H.  O.  Heinemann.) 


DYNAMICS    OF    PULMONARY    CIRCULATION 


.669 


fa 


r 


h 


fig.  2.  Structure  of  the  heart  according  to  Leonardo  da  Vinci 
(98).  The  diagram  shows  the  (nonexistent)  pores  in  the  ven- 
tricular septum,  an  essential  component  of  the  Galenical  con- 
cept of  the  motion  of  the  blood. 

In  recent  years,  the  biological  role  of  the  pulmo- 
nary circulation  and  lungs  has  been  emphasized 
(294).  For  example,  the  pulmonary  vascular  endo- 
thelium seems  to  contribute  enzymes,  such  as  lipo- 
protein lipases,  to  the  perfusing  blood  (1).  Mast  cells, 
which  are  abundant  in  the  lungs  of  many  species,  are 
believed  to  add  a  wide  variety  of  substances,  including 
heparin,  histamine,  hyaluronic  acid,  and  serotonin 
(230).  Finally,  the  walls  of  the  pulmonary  blood  ves- 
sels and  pulmonary  tissue  may  also  neutralize  certain 
endogenous  substances  (e.g.,  serotonin)  which  could 
exert  noxious  effects  if  they  gained  access  to  the  left 
heart  and  systemic  circulation  (158). 


THE    GROWTH   OF   IDEAS 

The  large  pulmonary  vessels  were  known  to 
Herophilus  of  Alexandria  in  the  fourth  century,  B.C. 
(228).  But  not  until  the  time  of  Harvey  (1578-1667) 
did  dispassionate  evidence  begin  to  establish  the 
structure  and  function  of  the  pulmonary  circulation 
(90,  91,1  79).  For  convenience,  the  origins  and  growth 
of  the  modern  ideas  will  be  sketched  under  four  sepa- 
rate headings:  a)  the  appreciation  and  proof  that  the 
pulmonary  vascular  tree  constitutes  a  closed  circuit 
between  the  right  and  left  hearts,  b)  the  awareness 
that  the  lungs  are  concerned  with  external  respira- 
tion, <)  the  systematic  analysis  of  pulmonary  hemo- 
dynamics, and  d)  the  coordinated  description  of 
alveolar-capillary  gas  exchange.  While  such  a  presen- 
tation of  the  growth  of  ideas  has  the  advantage  of 
brevity,  its  lack  of  historical  detail  ignores  foretellers 


such  as  Ibn  Xafis  (291),  Servetus  (91),  and  Mayow 
(144),  whose  clairvoyance  could  only  be  appreciated 
retrospectively;  it  also  exaggerates  the  contributions 
of  the  "'finishers,"  whose  discoveries  crowned  the 
concepts  and  efforts  of  others. 

Bridge  Between  Two  Ventricles 

In  Harvey's  time,  Galenical  misconception  (fig.  2) 
and  philosophic  speculation  still  predominated.  Al- 
though some  of  Harvey's  predecessors  and  contempo- 
raries had  realized  that  there  were  no  ventricular 
pores  by  which  right  ventricular  blood  could  bypass 
the  lungs  and  that  the  pulmonary  artery  was  too 
large  to  serve  only  as  a  nutrient  vessel,  their  preoccu- 
pation with  the  idea  of  the  vascular  system  as  the 
generator  of  essential  spirits  blinded  them  to  the 
motion  of  the  blood  in  the  vessels.  For  Harvey,  the 
idea  of  the  pulmonary  circulation  as  a  bridge  between 
the  two  ventricles  was  an  essential  component  of  his 
theory  of  the  unidirectional  circulation  of  the  blood; 
he  verified  his  theory  by  direct  experiment  and  pro- 
posed "porosities"  as  the  final  links  between  the 
arteries  and  veins  (195).  In  1661,  a  few  years  after 
Harvey's  death,  Malpighi  provided  the  final  proof  of 
pulmonary  vascular  continuity  by  visualizing  the 
passage  of  blood  from  the  pulmonary  arteries  to  the 
veins  by  way  of  the  pulmonary  capillaries  (280). 

Role  in  External  Respiration 

Harvey  was  concerned  solely  with  the  mechanical 
aspects  of  the  circulation  of  the  blood.  His  concept 
did  not  deal  with  the  prevalent  notions  about  the 
role  of  the  lungs  either  as  a  source  of  material  for  the 
generation  of  the  vital  spirit  or  as  a  refrigerating 
device  to  control  the  innate  heat  of  the  heart  (166). 
Two  years  after  Harvey's  death,  Lower  (fig.  3),  using 
Hooke's  new  respiration  pump,  showed  that  blood 
became  arterialized  as  it  passed  from  the  right  to  the 
left  side  of  the  heart  (172).  The  idea  that  ingredients 
of  air,  rather  than  air  itself,  were  the  basis  of  external 
respiration  had  to  await  new  developments  in  chemis- 
try and  in  physics.  A  century  was  to  pass  before:  a) 
Black  ( 1 788—1867),  Lavoisier  (1743-1794),  and 
Rutherford  (1 753-1814)  identified  the  three  respira- 
tory gases;  b)  Lavoisier  proved  that  oxygen  rather 
than  air  was  essential  for  life;  and  c)  Lavoisier  and 
Laplace  likened  respiration  to  combustion  (90,  91, 
144).  Indeed,  not  until  the  mid-nineteenth  century 
was  it  appreciated  that  combustion  occurred  in  the 
tissues  rather  than  in  the  lungs  and  that  hemoglobin 


167O  HANDBOOK    OF    PHYSIOLOGY    ^    CIRCULATION    II 


fig.  3.  Richard  Lower  (163 1-1691).  In  his  book,  Tractatus 
De  Corde,  he  described  his  experiments  with  Hooke's  respiration 
pump.  These  experiments  proved  that  venous  blcod  becomes 
arterialized  in  traversing  the  lungs  and  that  bleed  absorbs  a 
vital  chemical  substance  from  the  air  (172). 


was  involved  in  the  transport  of  oxygen  from  the  lungs 
to  the  tissues  (90a,  144). 

Analysis  of  Pulmonary  Hemodynamics 

Although  certain  aspects  of  the  regulation  of  the 
pulmonary  circulation — such  as  the  influence  of  the 
respiration — were  under  experimental  scrutiny  by  the 
middle  of  the  eighteenth  century  (180),  the  system- 
atic study  of  pulmonary  hemodynamics  could  not 
begin  without  practical  methods  for  measuring  pul- 
monary vascular  blood  pressures  and  flow  (189,  433). 
These  became  available  about  a  century  later:  pul- 
monary arterial  pressures  were  first  measured  in  the 
laboratory  of  Carl  Ludwig  (fig.  4)  in  the  i85o's,  by 
using  the  recording  mercury  manometer  in  open-chest 
dogs  (27);  shortly  thereafter,  more  elaborate  measure- 
ments were  made  in  the  intact  horse  (90a,  91).  In 
1870,  A.  Fick  (fig.  4)  pointed  out  how  measurements 
of  respiratory  gas  exchange  could  be  used  to  calculate 
the  volume  rate  of  pulmonary  blood  flow  (130).  But, 
without  ready  access  to  mixed  venous  blood,  the 
direct  Fick  principle  offered  little  promise  of  becoming 
a  popular  method  for  measuring  the  pulmonary  blood 
flow  in  either  the  intact  animal  or  man. 


fig.  4.  Pioneers  in  hemodynamic  measurements.  Left:  Carl  Ludwig  (1816-18951  introduced 
graphic  recording  of  blood  pressure  in  1847.  Right:  Adolph  Fick  (1829-1901),  student  of  Ludwig, 
in  1870  described  the  use  of  respiratory  gas  exchange  for  the  measurement  of  cardiac  output  in  intact 
animal  or  man.  [After  Rothschuh  (361).] 


DYNAMICS   OF    PULMONARY   CIRCULATION 


1671 


During  the  next  seventy  years,  a  wide  variety  of  in- 
genious experimental  preparations  and  new  tech- 
niques were  used  to  gain  information  about  the  remote 
pulmonary  circulation:  a)  artificial  experimental 
conditions  were  devised  to  control  some  respiratory 
and  circulatory  parameters  so  that  others  could  be 
measured  (40,  1 57) ;  b)  high-fidelity  manometric  sys- 
tems were  invented  and  used  to  register  the  details  of 
the  pulmonary  vascular  pressure  pulses  (183);  c) 
cannulae  were  placed  during  open  thoracotomy  so 
that  pulmonary  arteriovenous  pressure  gradients 
could  be  measured  in  the  closed-chest  animal  imme- 
diately after  operation  (225) ;  d)  angiostomy  cannulae 
were  devised  so  that  pulmonary  vascular  blood  pres- 
sures could  be  recorded  at  will  in  intact,  unanesthe- 
tized  animals  (183,  187);  and  e)  indirect  methods 
were  developed  for  the  estimation  of  the  pulmonary 
blood  flow  in  intact  animals  or  man  (see  Chapter  1  7). 

This  three-quarters  of  a  century  of  steady  progress 
underwent  sudden  acceleration  in  the  logo's.  In  1929, 
Forssmann  demonstrated  on  himself  that  a  catheter 
could  be  safely  threaded  by  way  of  a  peripheral  vein 
into  the  right  heart  (142);  shortly  thereafter,  Klein 
measured  the  pulmonary  blood  flow  by  the  direct 
Fick  principle  in  man  (90a).  By  World  War  II,  the 
stage  was  set  for  Cournand,  Richards,  and  their  co- 
workers to  begin  their  systematic  studies  of  the  pul- 
monary circulation  in  man  under  natural  conditions 
(92).  And,  since  the  ig4o's,  right  heart  catheterization 
has  been  used  for  the  sampling  of  mixed  venous  blood, 
for  the  injection  of  contrast  material  and  test  sub- 
stances into  the  pulmonary  circulation,  and  for  the 
recording  of  blood  pressures  from  the  right  side  of 
the  heart;  the  technique  has  also  provided  access  to 
the  venous  effluent  from  special  organs  and  regions 
of  the  body  and  has  led  to  the  techniques  of  left  heart 
catheterization. 


Alveolar-Capillary  Gas  Exchange 

As  indicated  previously,  the  pulmonary  circulation 
is  predominantly  built  for  alveolar-capillary  gas  ex- 
change. Up  to  the  turn  of  the  present  century,  the 
precise  nature  of  alveolar-capillary  gas  exchange  was 
unclear;  particularly  uncertain  was  the  mechanism 
by  which  oxygen  traversed  the  alveolar-capillary 
interfaces:  some  held  that  oxygen  was  secreted  by  the 
alveoli  (177);  others  maintained  that  diffusion  alone 
was  involved  (10).  The  issue  was  finally  settled  in 
favor  of  diffusion  by  August  and  Marie  Krogh  (243). 
These  studies  by  the  Kroghs  also  paved  the  way  for 


measuring  the  rate  of  pulmonary  capillary  blood  flow 
using  soluble,  inert  gases  as  tracer  substances  (343). 

To  complete  the  picture  of  the  coordinated  circula- 
tory-respiratory mechanism  for  external  gas  exchange 
(fig.  5),  more  had  to  be  learned  of  the  physiological 
behavior  and  of  the  physicochemical  properties  of  the 
blood.  To  this  end,  Barcroft  (fig.  6)  provided  pre- 
cise experimental  information  concerning  the  dis- 
sociation of  oxyhemoglobin  (9);  L.  J.  Henderson 
(fig.  6)  and  his  collaborators  analyzed  blood  as  a 
physicochemical  system  and  defined  its  role  in  the 
exchange  of  the  respiratory  gases  between  the 
atmosphere  and  the  tissues  (201,  297). 

The  regulation  of  alveolar-capillary  gas  exchange 
came  under  serious  experimental  scrutiny  in  the 
1940's.  In  1946,  Euler  &  Liljestrand  (125)  proposed 
that  the  local  concentration  of  the  respiratory  gases 
within  the  lung — a  function  of  local  ventilation- 
perfusion  relationships — might  regulate,  in  turn,  the 
distribution  of  the  pulmonary  blood  flow;  the  many 
experiments  subsequently  performed  by  others  to  test 
this  hypothesis  (132)  will  be  considered  later  in  this 
chapter.  Interest  in  alveolar-capillary  gas  exchange 
was  also  stimulated  in  the  1 94o's  from  another  direc- 
tion, i.e.,  from  the  practical  exigencies  of  aviation 
medicine  in  World  War  II;  from  this  practical  interest 
developed  theoretical  models,  quantitative  formula- 
tions, and  graphic  representations  which  have  not 
only  helped  to  resolve  old  problems  in  alveolar- 
capillary  gas  exchange  but  also  to  point  up  new  ones 
(267,  327,  345). 


COMPARATIVE    PHYSIOLOGY 

There  are  exceedingly  few  hemodynamic  measure- 
ments in  the  nonmammalian  vertebrates.  In  the 
fishes  and  sharks,  the  mean  blood  pressure  in  the 
ventral  aorta  (to  the  gills)  is  of  the  order  of  30  mm  Hg; 
as  blood  traverses  the  gills,  blood  pressure  drops  to 
reach  a  slightly  lower  level  in  the  dorsal  (systemic) 
aorta  (57). 

This  arrangement  of  the  circulation  in  the  fishes  is 
unfavorable  for  the  systemic  circulation.  The  hemo- 
dynamic situation  of  the  systemic  circulation  begins 
to  improve  in  the  Amphibia  and  Reptilia  in  which  the 
pulmonary  artery  is  separate  from  the  aorta  and  over- 
rides a  functionally  single  ventricle.  Among  the 
Reptilia,  pulmonary  arterial  blood  pressures  have 
been  measured  in  the  turtle  (352)  and  in  the  snake 
(222).  In  both  of  these  species,  the  patterns  of  blood 


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CIRCULATION    II 


BLOOD     FLOW      X     HbOg    CAPACITY 
DIFFUSING         CAPACITY 

fig.  5.  Nomogram  illustrating  the  respiratory  and  circulatory  interplay  involved  in  delivering 
an  adequate  supply  of  oxygen  to  the  arterial  blood.  The  dashed-line  rectangle  represents  the  situa- 
tion at  rest;  the  solid-line  rectangle  represents  the  situation  during  exercise.  At  rest,  this  subject  has 
an  oxygen  requirement  (VuJ  of  250  nil/min.  Starting  in  the  left  upper  quadrant,  and  moving  from 
quadrant  to  quadrant  in  a  counterclockwise  direction,  Vo,  is  shown  to  be  met  by  a  cardiac  output  of 
5  liters/min,  an  oxygen  capacity  of  20  ml/ 100  ml,  a  Hb  flow/capillary  area  of  5  and  a  diffusing 
capacity  of  20  ml/min/mm  Hg.  Also  pictured  are  the  corresponding  arteriovenous  differences  in 
oxygen  content  and  saturation  of  blood  (A-V  AO?),  as  well  as  the  mean  alveolar-capillary  diffusing 
gradient  for  oxygen  (mean  A  alveolar-capillary  Po2).  During  exercise,  as  the  oxygen  requirement 
increases  (Vo«  =  1250  ml/min),  these  variables  undergo  appropriate  change.  A  similar  nomogram 
could  be  constructed  for  oxygen  uptake  in  the  tissues.  [Based  on  Barcroft  (9)  and  Lilienthal  el  al. 
(266).] 


■-    NORMAL 
—    EXERCISE 


pressure  are  qualitatively  similar:  the  systolic  pres- 
sures in  the  pulmonary  and  systemic  circulations  are 
identical;  the  pulmonary  arterial  diastolic  pressure  is 
lower  than  the  systemic  arterial  diastolic  pressure,  due 
to  the  presence  of  a  spiral  valve  between  the  systemic 
artery  and  the  ventricle  (352).  In  the  turtle,  the  pul- 
monary arterial  pressure  is  of  the  order  of  35/12 
(352).  When  systemic  vascular  resistance  increases, 
blood  is  diverted  through  the  ventricular  septal 
defect  to  the  pulmonary  circulation  (443). 


The  ventricular  septum  is  complete  and  the  two 
circulations  are  entirely  separate  in  the  homeothermic 
mammals  and  birds.  Among  the  mammals  and  birds, 
pulmonary  arterial  pressures  have  been  measured  in 
a  wide  variety  of  species  including  man,  dog,  cat, 
guinea  pig  (114),  chicken  (352),  and  calf  (199).  In 
the  chicken  and  calf,  the  pulmonary  arterial  pressure 
is  generally  of  the  same  order  of  magnitude  as  in  the 
clog,  cat,  and  man,  i.e.,  of  the  order  of  20  to  30  mm 
Hg  systolic  and   10  to   12  mm  Hg  diastolic;  in  the 


DYNAMICS    OF    PULMONARY    CIRCULATION 


'673 


J^iA*tZ&u 


fig.  6.  Joseph  Barcroft  (1872-1947)  (left)  and  Lawrence  J. 
Henderson  (1878-194.;)  (right)  photographed  in  September 
1936.  (Courtesy  of  D.  B.  Dill.) 

guinea  pig,  it  is  somewhat  lower  ( 1 14),  whereas  in  the 
pig,  horse,  cow,  and  steer  it  is  often  considerably 
higher  (112,  199J. 

The  pulmonary  blood  flow  has  also  been  measured 
in  various  conventional  and  unconventional  labora- 
tory animals  including  the  goat  (10),  the  horse  (446), 
and  the  cow  (112,  199).  Although,  in  general,  the 
larger  species  have  the  larger  pulmonary  blood  flows, 
there  is  no  consistent  interspecies  relationship  be- 
tween pulmonary  blood  flow  on  the  one  hand  and 
either  body  surface  area  or  weight  on  the  other  (22). 
Whether  the  disparities  represent  real  biological  dif- 
ferences, or  the  inadequacies  of  weight  and  body  sur- 
face area  as  standards  of  reference,  or  artifacts  arising 
from  trying  experimental  situations,  remains  to  be 
decided. 

EXPERIMENTAL    ANIMALS    AND    TEST    PREPARATIONS 

The  normal  pulmonary  circulation  has  only  been 
studied  in  a  few  dogs  and  humans.  Instead,  most  of  the 
observations  have  been  made  on  the  pulmonary  cir- 
culations of  anesthetized  animals,  of  artificial  prep- 
arations, and  of  patients  with  heart  and  lung  disease. 

Each  of  these  three  categories  is  a  major  deviation 
from  normal :  the  use  of  anesthetized  animals  succeeds 
admirably  in  excluding  the  elements  of  anxiety  and 
cooperation;    but    its    substitutes,    instead,    blunted 


vasomotor  responses  and  changing  levels  of  metabo- 
lism, respiration,  and  circulation  (257).  Artificial 
preparations,  such  as  isolated  vascular  rings  or  iso- 
lated lungs,  certainly  allow  remarkable  control  of 
mechanical  parameters  and  may  uncover  influences 
which  are  obscured  in  the  intact  organism;  but,  by 
severing  nervous  connections,  by  failing  to  pass  pul- 
monary blood  through  other  vital  organs,  and  by 
depending  on  abnormal  perfusates,  impaired  nutrient 
circulations,  deteriorating  heart  and  lungs,  and  ab- 
normal gas  exchange,  they  may  introduce  not  only 
discernible — but  also  hidden — artifacts  (95,  141,  183). 
Finally,  while  the  study  of  patients  with  heart  and 
lung  disease  may  be  revealing  to  physicians  who  are 
attempting  to  gain  insights  into  the  mechanism  of 
heart  strain  and  failure,  the  results  from  these  "ex- 
periments of  nature"  can  rarely  be  used  to  predict 
the  behavior  of  the  normal  pulmonary  circulation, 
since  both  heart  and  lung  disease  tend  to  exaggerate 
the  influence  of  mechanical  factors  and  to  alter  the 
structure  of  the  pulmonary  blood  vessels. 

"Species  difference"  is  a  standard  apology  for 
atypical  responses  of  the  pulmonary  circulation  to 
diverse  stimuli  (95).  Occasionally,  the  basis  for  this 
excuse  is  a  distinctive  morphological  characteristic 
(72,  171,  199).  For  example,  the  small  muscular  pul- 
monary arteries  of  the  rabbit  contain  much  thicker 
media  than  do  the  corresponding  vessels  of  rat,  cat, 
and  man  (fig.  7).  It  is  easy  to  imagine  that  contraction 
of  such  hypertrophied  muscle  could  evoke  the 
"gnarly"  distortion  of  the  rabbit's  vascular  tree  which 
follows  the  infusion  of  large  quantities  of  norepineph- 
rine (61);  on  the  other  hand,  it  is  somewhat  more 
difficult  to  imagine  such  an  intense  vascular  response 
in  species  with  muscle-poor  precapillary  vessels. 

Species  difference  may  reside  in  physiological  as 
well  as  in  anatomical  peculiarities  (218).  For  exam- 
ple, the  rabbit  is  notoriously  vagotonic,  whereas  the 
cat,  dog,  and  man  are  generally  regarded  as  sympa- 
thotonic;  moreover,  the  pulmonary  circulation  of  the 
rabbit  also  appears  to  be  more  susceptible  to  the 
effects  of  pharmacological  agents,  such  as  histamine, 
than  is  the  pulmonary  circulation  of  the  dog  (442). 
Such  anatomical  and  physiological  peculiarities  occur 
throughout  the  animal  kingdom,  complicating  the 
transfer  of  information  from  one  species  to  another 
(95.  239>  352)- 

FUNCTIONAL    ANATOMY 

The  dependent  position  of  the  pulmonary  circula- 
tion— within  the  lung  and  thorax  on  the  one  hand, 


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CIRCULATION    II 


60 

^ 
^ 

M 

v 
v 

53 

V^v                    PULMONARY 

49 

xx                    ARTERY 

•V 

44 

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Id 

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v        COW,    PIG      v                          \ 

vx_Z 1 \ 

*•<«.     MAN                 ^«0                \ 

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220  176 

OF     VESSELS 


fig.  7.  Relationship  between  vascular  calibers  and  medial  thickness  in  different  species.  Both  the 
small  pulmonary  arteries  and  the  small  pulmonary  veins  are  well  developed  in  the  guinea  pig,  cat, 
calf,  and  pig.  On  the  other  hand,  in  man  and  in  the  rabbit,  only  the  arterial  muscle,  and  in  the  rat 
only  the  venous  muscle,  is  well  developed.  [Redrawn  after  Takino  (392).] 


and  between  the  two  ventricles  on  the  other — subjects 
it  to  a  variety  of  mechanical  influences.  Consequently, 
the  following  appraisal  of  the  functional  anatomy  of 
the  pulmonary  circulation  will  take  into  account  not 
only  those  features  of  the  vascular  tree  which  deter- 
mine pulmonary  vascular  distensibility  and  resistance 
to  perfusion  but  also  the  extravascular  structures 
which  may,  under  appropriate  conditions,  modify  or 
obscure  the  natural  properties  of  the  pulmonary 
vessels  (288). 

Unless  expressly  indicated,  the  anatomical  descrip- 
tions which  follow  derive  largely  from  the  examination 
of  the  lungs  of  normal  man  at  sea  level.  It  is  likely 
that,  in  most  respects,  the  generalizations  about  struc- 
ture, and  particularly  about  the  relationships  between 
structure  and  function,  apply  almost  as  well  to  the 
cat  and  to  the  dog.  However,  much  more  has  to  be 
learned  before  the  generalizations  from  normal  man 
at  sea  level  can  be  applied  directly  either  to  other 
test  animals,  such  as  the  rabbit  and  the  cow,  or  to 
normal  native  residents  at  high  altitudes,  or  to  sea 
level  residents  with  abnormal  pulmonary  vessels  or 
parenchyma  (99,  392). 

Blood  Vessels 

OVERLAP  OF  DISTENSIBILITY  AND  RESISTANCE  CHARAC- 
TERISTICS. In     the     systemic     circulation,     the     term 


"arteriole"  is  synonomous  with  "resistance"  vessel. 
Characteristically,  the  systemic  arteriole  has  a  heavy 
coat  of  circular  smooth  muscle  and  a  high  ratio  of 
wall  thickness  to  lumen  diameter.  With  respect  to 
size,  ''systemic  arteriole"  generally  refers  to  vessels  of 
300  to  400  fi  or  less,  depending  on  the  organ  in  which 
they  are  found  (50).  On  the  other  hand,  in  the  low- 
pressure  pulmonary  circulation,  the  anatomical 
counterpart  of  the  systemic  arteriole  does  not  exist. 
This  lack  of  sphincteric  precapillary  vessels  has  several 
implications:  a)  that  other  small  vessels  may  con- 
tribute appreciably  to  the  pressure  drop  between  the 
pulmonary  artery  and  veins;  b)  that  the  small  pul- 
monary vessels  may  also  serve  as  storage  vessels, 
changing  caliber  passively  with  the  pulmonary  blood 
volume;  and  c)  that  under  appropriate  conditions, 
each  of  the  small  vascular  segments  may  constitute 
the  dominant  pulmonary  vascular  resistance  to 
blood  flow. 

large  pulmonary  vessels.  The  pulmonary  artery 
rapidly  subdivides  into  terminal  branches  which 
have  thinner  walls  and  wider  bores  than  the  cor- 
responding branches  of  the  systemic  arterial  tree.  The 
media  of  the  main  pulmonary  artery  is  about  half 
as  thick  as  that  of  the  aorta;  the  elastic  fibers  are 
short  and  far  less  orderly  than  in  the  aorta  (198). 
The  smooth  muscle  appears  to  insert  on  the  elastic 


DYNAMICS    OF    PULMONARY    CIRCULATION 


■675 


fibers,  suggesting  an  arrangement  capable  of  con- 
trolling either  the  pressure  of  the  wall  on  its  contents 
or  the  volume  of  blood  contained  within  the  large 
vessel  (198).  In  general,  the  structure  of  the  large 
vessels  seems  better  suited  for  varying  their  distensi- 
bility  than  their  geometry;  nonetheless,  the  possibility 
exists  that  constriction  of  large  vessels  may  also  effect 
pulmonary  vascular  resistance  to  blood  flow  (126). 

In  the  normal  human  lung  the  pulmonary  arteries 
are  end-arteries,  continuing  without  branching  to  the 
level  of  the  first  alveoli  in  the  walls  of  the  respiratory 
bronchioles  (292,  421).  Unfortunately,  too  little  is 
known  of  the  pattern  of  branching  to  serve  as  a  re- 
liable basis  for  predicting  the  distribution  of  resistance 
along  the  length  of  the  pulmonary  vascular  tree 
(140,  169,  205).  The  arterial  portion  of  the  pulmonary 
circulation  lies  adjacent  to  the  bronchial  tree;  indeed, 
in  the  region  of  the  respiratory  bronchiole,  arterial 
bifurcations  straddle  the  airway  (117).  Consequently, 
the  arterial  branches  are  more  susceptible  to  passive 
distortion  by  the  conducting  airways  than  are  the 
venous  branches  which  are  situated  at  the  periphery 
of  the  lobule. 

The  pulmonary  veins  are  end-veins  (421).  Their 
musculo-elastic  components  are  more  irregularly 
dispersed  than  those  of  the  corresponding  pulmonary 
arteries;  their  media  contain  more  collagenous  fibers. 
At  the  entry  of  the  veins  into  the  left  atrium,  exten- 
sions of  cardiac  muscle  become  incorporated  into 
the  venous  walls.  The  suggestion  has  been  made  that 
under  certain  experimental  conditions,  these  muscular 
extensions  may  act  as  "throttles"  (56,  121,  392,  394). 

small  muscular  pulmonary  vessels.  From  the  point 
of  view  of  vasomotor  activity,  three  concepts  are 
generally  held:  /)  vascular  smooth  muscle  is  pre- 
requisite for  active  change  in  caliber;  2)  during  a 
change  in  vasomotor  tone,  the  small,  muscle-con- 
taining vessels  are  the  site  of  changed  resistance;  and 
j)  the  thicker  the  media,  the  more  apt  is  the  vessel  to 
constrict,  the  less  apt  is  it  to  undergo  passive  dilation, 
and  the  more  likely  is  it  to  offer  appreciable  resistance 
to  perfusion  (59,  141). 

The  anatomical  characteristics  of  the  small  muscu- 
lar pulmonary  vessels  are  illustrated  in  figure  8.  The 
upper  half  of  this  figure  depicts  the  structure  of  ex- 
ceedingly small  (30  n)  pulmonary  vessels:  in  neither 
the  pulmonary  "arteriole"  or  venule  is  smooth 
muscle  discernible;  by  way  of  contrast,  the  coat  of 
smooth  muscle  in  the  systemic  arterioles  is  readily 
apparent.  The  lower  half  of  this  figure  contrasts  a 
small    pulmonary    artery    and    a    small    pulmonary 


vein — each  about  50  ^  in  diameter — with  a  systemic 
arteriole  of  approximately  the  same  size;  pulmonary 
arterioles  of  this  size  are  to  be  found  at  the  level  of 
the  alveolar  ducts  and  alveoli,  buried  in  pulmonary 
tissue  (118).  It  may  be  seen  that  the  pulmonary 
arteriole  contains  only  a  thin  rim  of  smooth  muscle; 
in  the  corresponding  pulmonary  venule  of  55  /j,  no 
smooth  muscle  can  be  recognized;  on  the  other  hand, 
the  systemic  arteriole  contains  a  thick  media.  It  is 
difficult  to  imagine  the  pulmonary  vessels  shown  in 
figure  8  as  the  sites  of  intense  vasoconstriction. 

Somewhat  better  suited  for  vasomotor  activity 
are  the  larger  precapillary  vessels.  These  "small 
muscular  arteries"  range  from  100  to  1000  n  in 
diameter  (403),  contain  well-formed  media,  and  lie 
adjacent  to  the  respiratory  bronchioles.  They  are 
usually  separated  from  the  pulmonary  tissue  by 
perivascular  lymph  spaces  and  their  muscular  coats 
thin  as  they  proceed  peripherally  to  the  vicinity  of 
the  alveolar  ducts.  From  these  muscular  vessels,  the 
pulmonary  arterioles  generally  arise  at  right  angles 
so  that  the  configuration  of  muscle  at  their  origins 
often  appears  sphincteric  (118,   196). 

The  corresponding  venules  of  100  to  1000  y.  lie 
at  the  periphery  of  the  lobule.  And,  in  contrast  to 
the  small  muscular  arteries,  smooth  muscle  is  either 
poorly  organized  or  absent  and  the  elastic  fibers  are 
irregular  and  indistinct.  Consequently,  even  pul- 
monary veins  up  to  1000  /*  in  diameter  seem  to  be 
poorly  equipped  for  vasomotor  activity. 

capillaries.  At  the  alveolar  border,  the  precapillary 
vessel  subdivides  to  form  a  racemosing  network  of 
capillary  segments  sandwiched  between  adjacent 
alveolar  walls  (fig.  9,  insert)  (292).  Whether  these 
capillaries  lie  free  between  the  alveoli  or  indent 
them — a  structural  distinction  relevant  to  estimates 
of  pericapillary  pressure — is  uncertain. 

The  capillary  circulation  has  certain  distinctive 
features:  a)  each  of  these  capillary  segments  is  ap- 
proximately 10  to  14  p  in  length  and  7  to  9  n  in 
diameter  (422);  b)  except  in  congested  lungs  the  red 
cells  pass  through  in  single  file  (fig.  9);  c)  the  capillary 
networks  in  different  parts  of  the  lung  differ  with 
respect  to  the  length,  caliber,  and  number  of  con- 
stituent vessels  (162,  292);  d)  "pores,"  presumed  on 
physiological  grounds  to  exist  in  the  pulmonary 
capillary  wall,  have  not  been  seen  by  electron  mi- 
croscopists;  e)  chemical  analyses  have  failed  to  settle 
if  the  capillary  wall  is  predominantly  aqueous  or 
lipoid  in  nature  (375);  /)  there  appear  to  be  neither 
contractile  cells  around   the  capillaries  nor  smooth 


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eem 


fig.  8.  Structure  of  small  pre-  and  postcapillary  vessels.  Upper  half.  Comparison  of  a  30  fi  pre- 
capillary vessel  (left)  and  postcapillary  vessel  (center)  with  systemic  arterial  branches  (right)  of  the  same 
size.  The  pulmonary  pre-  and  postcapillary  vessels  are  structurally  similar;  they  are  strikingly  differ- 
ent from  the  systemic  arterial  branches.  Lower  half.  Comparison  of  a  57  11  pulmonary  artery  (left)  and 
a  corresponding  pulmonary  vein  (center  with  systemic  arteriole  (right)  of  the  same  size.  Muscle  cannot 
be  identified  in  the  vein,  ec,  endothelial  cells;  ef,  elastic  libers;  ™,  smooth  muscle;  iem,  internal  clastic 
membrane;  eem,  external  elastic  membrane;  ac,  alveolar  capillaries.  (Elastic  tissue  stain.  585  X) 
[Courtesy  of  E.  R.  Weibel  (132).] 


muscle  in  the  capillary  walls.  Without  such  con- 
tractile elements,  it  is  unlikely  that  the  capillaries 
can  contract  actively  in  the  conventional  manner  of 
muscle-containing  vessels  (400);  on  the  contrary, 
capillary  lumens  are  more  apt  to  be  passively  nar- 
rowed by  swelling  of  endothelial  cells,  by  perivascular 
transudates  (114),  by  raised  alveolar  pressures  (351), 
and  by  the  pushes  and  pulls  of  adjacent  structures 

(397)- 

According  to  Weibel,  the  "typical"  alveolus  in 
man  is  more  like  the  cell  of  a  honeycomb  than  a 
sphere    (422).    It    measures    approximately    200    to 


250  fi  in  diameter.  Each  alveolus  is  lined  by  a  con- 
tinuous epithelium  (40  to  65  m,u  thick)  which  changes 
its  submicroscopic  appearance  upon  appropriate 
stimulation  (276,  375).  In  the  human  lung  approx- 
imately 300  million  alveoli  are  juxtaposed  to  ap- 
proximately the  same  number  of  capillary  segments. 
After  the  age  of  8  years,  an  increase  in  the  size  of  the 
lung  seems  to  involve  an  increase  in  the  dimensions 
of  existing  alveolar-capillary  units  rather  than  in 
their  number  (422). 

The  thickness  of  the  alveolar-capillary  interface  is 
of  the  order  of  285  to  640  rn.fi  (375):  not  all  of  the 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1677 


fig.  9.  Electron  microphotograph  of  human  lung.  The  red 
cells  (RBC)  are  shown  passing  single  hie  through  a  pulmonary 
capillary  (CAP)  between  adjacent  alveoli  (ALV).  19,370  X. 
[Courtesy  of  Dr.  Councilman  Morgan.]  Insert:  Network  of  cap- 
illaries in  the  walls  of  the  sacculi  alveolares.  330  X-  [From 
Miller  (292).] 


70  m2;  at  three-quarters  of  the  total  lung  capacity  it 
increases  further  (to  the  order  of  90  m2)  (422). 


Extr avascular  Smooth  Muscle 

Pulmonary  smooth  muscle  is  contained  not  only 
in  the  vessels  but  also  in  the  tracheobronchial  tree 
and  in  the  pulmonary  tissue.  In  man,  the  neatly 
organized  tracheobronchial  smooth  muscle  continues 
down  to  the  mouths  of  the  alveoli  (fig.  10)  where  it 
is  in  a  position  to  influence  passively  the  pressure  in 
the  alveoli  and,  thereby,  the  caliber  of  the  capillaries 
in  the  alveolar  walls  (8,  196).  Although  parenchymal 
smooth  muscle  is  apparently  plentiful  in  the  amphi- 
bian and  reptilian  lung  (220,  236),  and  in  patients 
with  chronic  pulmonary  disease  (265),  the  quantity 
and  arrangement  of  this  parenchymal  smooth  muscle 
in  the  normal  human  lung  is  unknown.  Nonetheless, 
because  of  its  close  association  with  the  elastic  network 
of  the  lung,  parenchymal  smooth  muscle  may  con- 
ceivably affect  vascular  calibers  directly  by  con- 
tiguity and,  indirectly,  by  changing  the  pulmonary 
lung  volume  and  distensibility.  Moreover,  since  the 
musculo-elastic  system  of  the  lung  is  nourished  by  the 
bronchial  arteries,  the  possibility  exists  that  agents 
which  reach  the  lungs  by  way  of  the  systemic  circu- 
lation may  change  pulmonary  vascular  dimensions 
through  their  effects  on  extravascular,  rather  than 
intravascular,  smooth  muscle. 


alveolar  surface  is  ordinarily  used  for  gas  exchange; 
nor  is  all  of  the  capillary  circumference  in  contact 
with  alveolar  wall  (196).  The  portion  of  the  available 
capillary  surface  which  is  actually  used  appears  to 
vary  with  the  total  lung  volume,  the  degree  of  capil- 
lary filling  and  the  size  of  the  alveoli.  At  a  volume 
corresponding  to  three-quarters  of  the  total  lung 
capacity,  the  capillary  network  occupies  60  per  cent 
of  the  alveolar  surface  and  the  capillary  blood  volume 
is  of  the  order  of  200  to  250  cm3  (422). 

Over  the  years,  anatomical  measurements  of  the 
capillary  surface  area  have  provided  exceedingly 
variable  results:  values  have  ranged  from  50  m-  to 
140  m2  (132).  Some  of  this  discrepancy  is  undoubtedly 
attributable  to  methodological  differences  (143),  to 
the  uncertainties  of  reconstructing  the  lung  on  the 
basis  of  small  sections,  and,  particularly,  to  the  failure 
to  specify  the  lung  volume  at  which  the  measure- 
ments were  made.  The  recent  measurements  by 
Weibel  indicate  that  at  the  resting  position  of  the 
lung,  the  capillary  surface  is  of  the  order  of  50  to 


Systemic  Blood  Supply  of  the  Lung 

In  the  normal  human  and  canine  lung,  the  bron- 
chial arteries  arise  from  intrathoracic  systemic 
arteries  and  deliver  oxygenated  blood  to  the  walls 
of  the  tracheobronchial  tree,  the  supporting  frame- 
work of  the  lungs  and  the  walls  of  the  pulmonary 
arteries  and  veins  (133).  Accordingly,  they  are 
nutrient  arteries.  In  contrast  to  pulmonary  arteries 
of  equal  caliber,  the  bronchial  arterial  walls  are 
thick  and  their  innervation  is  plentiful.  In  the  normal 
lung,  bronchial  venous  blood  drains  largely  into  the 
azygous  veins  but  some  also  enters  the  pulmonary 
veins  (263,  445). 

The  quantity  of  blood  carried  to  the  lungs  by  the 
bronchial  arteries  is  difficult  to  measure  precisely; 
the  complexity  of  the  problem  may  be  inferred  from 
the  wide  variety  of  experimental  approaches  which 
have  been  attempted  in  both  dog  and  man  (93,  133 
214,  368).  Nonetheless,  despite  inevitable  differences, 
the  results  of  these  diverse  trials  suggest  that  the 
bronchial  arterial  flow  ordinarily  constitutes  only  an 


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HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  10.  Schematic  representation  of 
the  disposition  of  smooth  muscle  in  the 
terminal  portions  of  the  respiratory 
tree.  The  cut  muscle  appears  as  small 
nodular  structures  of  various  sizes  and 
shapes;  it  ends  at  the  mouths  of  the 
alveoli.  [After  Baltisberger  (8).] 


«r  •* 


t  ft.  J       i .    rvs   To*     *"  \  x. 


exceedingly  small  fraction  of  the  cardiac  output  and 
that  the  effect  of  the  bronchial  circulation  on  the 
behavior  of  the  normal  pulmonary  circulation  is 
negligible.  The  evidence  for  the  latter  conclusion  is 
of  three  general  types:  /)  the  difficulty  encountered 
by  anatomists  in  finding  bronchial-pulmonary  ar- 
terial communications  in  the  normal  human  or 
canine  lung  except  by  elaborate  injection  techniques 
(421);  2)  the  measurements  in  the  dog  during  arti- 
ficial perfusion  of  the  lungs  which  indicate  that  the 
normal  bronchial  arterial  flow  is  of  the  order  of  1 
to  2  per  cent  of  the  cardiac  output  (55,  423);  and 
3)  the  measurements  in  intact  man  which  indicate 
that  the  normal  bronchial  arterial  blood  flow  is  too 
small  to  be  measured  by  conventional  techniques 
(139,   152).  It  should  be  noted  that  under  some  ex- 


ceedingly artificial  experimental  circumstances,  the 
bronchial  circulation  in  the  dog  has  been  found  to 
exert  an  appreciable  hemodynamic  effect  on  the 
pulmonary  circulation  (95).  However,  because  of  the 
unusual  experimental  conditions,  these  results  seem 
to  indicate  the  ultimate  potential  of  the  bronchial 
circulation  rather  than  its  actual  performance  in  life. 
The  systemic  blood  supply  of  the  lung  undergoes  a 
remarkable  proliferation  in  various  disorders  of  the 
heart  and  lungs  (79,  98,  133,  263) :  old  vessels  enlarge 
and  become  tortuous;  new  vessels  appear  and  join 
with  the  old  to  form  bizarre  Medusaean  patterns. 
Moreover,  in  contrast  to  the  normal  lung,  in  which 
precapillary  communications  between  the  two  circu- 
lations are  difficult  to  demonstrate  (292,  420),  the 
enlarged     precapillary     anastomoses     between     the 


DYNAMICS    OF    PULMONARY    CIRCULATION  1 679 


NORMAL 


NUTRIENT 


© 


BRONCHIECTASIS 


PA 

C2) 


HEMODYNAMIC? 


TETRAD 


©PA 


COi 


RESPIRATORY  ? 


® 


PROXIMAL 
BV 


0  mm  Hg      5  mm  Hg 


NORMAL 


10  mm  Hg     5  mmHg 


RIGHT    HEART     FAILURE 


fig.  1 1 .  Pulmonary  collateral  circula- 
tion. Upper  half:  The  arterial  portion.  A: 
usual  nutrient  function;  B:  expansion  to 
constitute  a  hemodynamic  burden,  as  in 
diffuse  suppurative  disease;  C:  participa- 
tion in  external  respiration  when  systemic 
arterial  hypoxemia  coexists  with  inade- 
quate pulmonary  arterial  blood  flow. 
Lower  half:  The  venous  portion.  D:  usual 
emptying  of  proximal  bronchial  veins;  E: 
alternate  emptying  of  proximal  bronchial 
veins  when  right  atrial  pressures  exceed 
left  atrial  pressures.  [After  Fishman  (133).] 


pulmonary    and    systemic    circulations    are    grossly 
visible  (264). 

The  proliferation  generally  does  not  affect  the 
entire  collateral  circulation  in  a  uniform  manner 
(fig.  11).  Thus,  in  the  portion  of  the  lung  which  lies 
adjacent  to  an  area  of  pulmonary  inflammation,  as 
well  as  in  the  lung  with  a  severely  compromised 
pulmonary  arterial  blood  supply,  it  is  the  arterial 
portion  of  the  collateral  circulation  which  expands; 
on  the  other  hand,  the  venous  portion  of  the  collateral 
circulation  undergoes  the  more  striking  expansion  in 
certain  types  of  pulmonary  emphysema  and  in  mitral 
stenosis  (263).  If  the  expanded  collateral  circulation 
becomes  sufficiently  large — as  in  diffuse  suppurative 


disease  of  the  lung  (263) — it  may  carry  large  volumes 
of  blood,  and  transmit  systemic  blood  pressures,  to 
the  point  of  constituting  a  hemodynamic  burden  on 
the  pulmonary  circulation. 

It  should  be  noted  that  as  the  collateral  circulation 
proliferates,  the  difficulties  in  measuring  the  rate  of 
collateral  blood  flow  also  grow.  Particularly  trouble- 
some, from  the  technical  point  of  view,  are  the 
multiple  origins  of  the  collateral  arterial  branches  on 
the  one  hand  and  the  alternate  venous  outlets  on  the 
other  (fig.  1 1).  Indeed,  on  account  of  this  anatomical 
arrangement,  it  is  difficult  to  measure  volumetrically 
the  total  collateral  blood  flow  even  in  the  open-chest 
dog    in    which    the    heart    and    thoracic   vessels   are 


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CIRCULATION    II 


exposed  for  cannulation.  Another  problem  is  the 
prediction,  on  a  priori  grounds,  of  the  hemodynamic 
behavior,  i.e.,  the  blood  flow,  the  driving  pressure, 
and  the  resistance  to  perfusion  of  anastomotic  channels 
which  vary  so  in  length,  caliber  and,  possibly,  in 
tone.  However,  one  anatomical  aspect  of  the  ex- 
panded collateral  arterial  circulation  does  lend  itself 
to  physiological  exploitation:  the  precapillary  anas- 
tomoses make  it  possible  to  measure  that  part  of 
the  collateral  arterial  inflow  which  reaches  the  gas- 
exchanging  surfaces  of  the  lung  and  is  available  for 
respiratory  gas  exchange,  i.e.,  the  "effective"  col- 
lateral blood  flow  (31,  139). 

I  'enous  Admixture 

In  the  normal  pulmonary  circulation  a  small 
quantity  of  venous  blood  traverses  anatomical  chan- 
nels to  bypass  the  gas-exchanging  surfaces  of  the 
lungs,  thereby  reducing  the  oxygen  tension  of  periph- 
eral arterial  blood.  This  shunt  has  diverse  anatomical 
origins:  bronchial  veins,  anterior  cardiac  veins, 
Thebesian  veins,  portal  veins,  mediastinal  veins  and 
pulmonary  arteries;  in  normal  man  and  dog  the 
volume  of  shunted  blood  is  generally  considered  to 
be  of  the  order  of  2  per  cent  of  the  cardiac  output 

(13.  23>  349)- 

In  the  rabbit  and  guinea  pig,  arteriovenous  chan- 
nels have  been  seen  on  the  surface  of  the  transil- 
luminated  lung  (219).  In  the  dog,  the  evidence  for 
such  shunts  is  less  direct  and  there  is  considerable 
dispute  concerning  their  size  (349).  Two  types  of 
observations  favor  a  large  size:  /)  glass  spheres,  up 
to  500  fi  in  diameter,  reach  the  left  heart  following 
injection  into  the  pulmonary  artery  (322) ;  2)  radi- 
opaque material,  forcefully  injected  through  the 
side  vent  of  a  wedged  pulmonary  arterial  catheter, 
traces  a  cine-angiographic  course  suggestive  of  short- 
circuits  (331).  Opposed  is  the  experimental  evidence 
that  these  channels  are  closer  to  25  n  than  to  500  n 
in  diameter  (38,  167,  349).  A  reasonable  interpreta- 
tion of  the  disparate  results  in  the  dog  is  that  the 
experimental  conditions  determine  the  degree  of 
patency  of  these  channels  and  that  ordinarily  these 
channels  are  virtually  closed  (95). 

The  situation  is  somewhat  more  tenuous  for  the 
human  lung:  on  the  one  hand,  large  glass  spheres 
(up  to  500  n  in  diameter)  also  traverse  the  isolated 
human  lung  (322);  on  the  other,  is  the  inability  of 
painstaking  histological  examination  to  disclose  the 
channels  (421)  and  the  failure  of  physiological  meas- 
urements to  obtain  the  high  values  for  venous  ad- 


mixture which  would  be  consistent  with  the  presence 
of  large,  patent  channels  (23).  If  arteriovenous  chan- 
nels do  exist  in  the  normal  human  lung,  they  seem  to 
allow  very  little  blood  flow  under  ordinary  conditions. 
The  small  anatomical  shunt  in  the  normal  animal 
or  man  stands  in  marked  contrast  to  the  large  size 
which  it  may  achieve  in  certain  clinical  states,  such 
as  congenital  right-to-left  intracardiac  shunts  and 
pulmonary  hemangiomatosis  (155,  226).  Appreciable 
shunting  has  also  been  demonstrated  in  those  patients 
with  cirrhosis  of  the  liver  who  develop  portal-pul- 
monary venous  communications  (63). 

Pulmonary  \'asomotor  Nerves 

There  is  no  doubt  about  either  the  existence  of 
pulmonary  vasomotor  nerves  or  their  ability  to 
change  pulmonary  vascular  calibers  when  appro- 
priately stimulated;  only  their  physiological  meaning 
can  be  questioned  (96,  382). 

The  pulmonary  vasomotor  nerves  have  been  most 
intensively  studied  in  the  dog:  both  vasodilator  and 
vasoconstrictor  fibers  have  been  identified  in  the 
upper  sympathetic  chain  and  in  the  vagus  nerves 
(95).  Because  of  the  complicated  intermingling  of 
these  fibers — not  only  with  each  other  but  also  with 
bronchial  and  cardiac  fibers — electrical  stimulation 
often  fails  to  separate  vagal  from  sympathetic  effects 
on  the  one  hand,  and  vasomotor  from  bronchomotor 
and  cardiac  effects  on  the  other  (95). 

For  comprehensive  reviews  of  pulmonary  and 
pulmonary  vascular  innervation  the  reader  is  referred 
elsewhere  (96,  267).  A  few  aspects  are  particularly 
relevant  to  considerations  of  pulmonary  hemody- 
namics: a)  the  large  pulmonary  arteries  and  veins 
are  more  richly  innervated  than  their  smaller  counter- 
parts (81,  147,  392);  b)  the  muscular  arteries  and 
arterioles  are  more  richly  innervated  than  the  cor- 
responding veins  and  venules  (392);  c)  nerve  endings 
reach  the  medial  and  subendothelial  layers  of  the 
large  arteries  and  veins  (392);  d)  sensory  nerves  and 
receptors  have  been  identified  in  the  airways  and  in 
the  large  pulmonary  arteries  and  veins  (6,  80) ;  e ) 
the  bronchial  arteries  are  more  richly  innervated 
than  any  other  pulmonary  vessels  (292);  and  /)  the 
nerve  supply  to  the  bronchi  exceeds  that  of  the  pul- 
monary vessels  (392). 

As  a  pharmacological  device  for  estimating  the 
concentration  of  adrenergic  nerve  endings  in  the 
different  parts  of  the  pulmonary  vascular  tree,  Euler 
&  Lishajko  (126)  compared  the  concentrations  of 
norepinephrine  in  the  central  and  in  the  peripheral 


DYNAMICS    OF    PULMONARY    CIRCULATION 


l68l 


portions  of  the  human  pulmonary  vascular  tree.  In 
keeping  with  the  anatomical  evidence  for  a  pre- 
dominant distribution  of  nerves  to  the  larger  pul- 
monary vessels,  they  found  that  the  large  pulmonary 
vessels  (of  the  dog  and  cow)  contain  larger  quantities 
of  norepinephrine  than  do  the  small  pulmonary 
vessels.  The  greater  concentration  of  nerves  in  the 
region  of  the  large  pulmonary  vessels  is  consistent 
with  the  notion  that  the  pulmonary  vascular  bed  is 
better  innervated  for  tensing  its  large  vessels  than  for 
shrinking  the  caliber  of  its  small  ones  (403).  However, 
this  attractive  idea,  which  is  based  on  anatomical 
observations,  is  inconclusive  on  several  accounts: 
a)  the  display  of  an  abundant  innervation  provides 
no  measure  of  either  the  number  or  the  nature  of  the 
impulses  which  the  nerves  transmit;  b)  consecutive 
muscular  segments  of  a  single  pulmonary  vascular 
unit  may  be  differently  affected  by  a  stimulus  (95) ; 
and  c)  because  of  its  mixed  embryological  origin  in 
endoderm  and  mesoderm,  pulmonary  vascular  in- 
nervation may  possess  subtle,  and  as  yet  undisclosed, 
features. 


PULMONARY    BLOOD    FLOW 

In  subjects  with  a  normal  heart  and  circulation, 
the  pulmonary  blood  flow,  the  pulmonary  capillary 
blood  flow  and  the  output  of  each  ventricle  (the 
cardiac  output)  represent  virtually  identical  quan- 
tities. In  previous  chapters  of  this  book,  the  cardiac 
output  is  considered  with  respect  to  its  measurement 
(Chapter  17)  and  control  (Chapters  15  and  16);  the 
present  section  will  confine  itself  to  resting  measure- 
ments of  pulmonary  blood  flow,  leaving  for  subse- 
quent sections  the  pulmonary  capillary  blood  flow 
and  the  behavior  of  the  cardiac  output  during 
exercise. 

Normal  Values 

For  the  sake  of  comparison,  cardiac  output  in  man 
is  generally  expressed  per  square  meter  of  body  sur- 
face area  (cardiac  index):  in  one  representative 
study,  the  average  cardiac  index  of  a  group  of  basal, 
postprandial,  supine  human  adults  was  3.12  liters/ 
min/m2  (sd  ±0.40);  the  corresponding  oxygen  uptake 
of  this  group  was  138  ml  min/m2  sd  ±14  (87). 
Unfortunately,  even  in  adults,  body  surface  area  is 
not  an  ideal  standard  of  reference;  it  becomes  even 
less  reliable  when  subjects  of  different  age,  sex,  and 
body    build     are    compared,     since    the    •'normal" 


values  have  been  derived  from  a  select  portion  of  the 
adult  population.  In  the  unanesthetized  dog,  the 
cardiac  output  per  minute  is  of  the  order  of  150 
ml  per  kg  (12).  It  should  be  emphasized  that  there 
are  exceedingly  few  such  measurements  on  the  un- 
anesthetized dog  and  the  values  which  do  exist  are 
far  from  consistent  (303). 

Excitement  (discomfort  or  anxiety)  may  artificially 
increase  the  "basal"  cardiac  output.  This  fact  has 
been  illustrated  by  measurements  on  the  unanesthe- 
tized dog  prior  to,  and  following,  treadmill  exercise: 
the  resting  cardiac  output,  while  awaiting  the  start 
of  treadmill  exercise,  was  higher  than  the  resting 
cardiac  output  after  the  exercise  was  finished  (12). 
Excitement  may  continue  to  operate  during  the  test 
periods.  Fortunately,  there  are  objective  criteria 
which  can  be  used  to  detect  the  existence  of  disturb- 
ing emotional  influences;  these  include  tachycardia, 
a  high  respiratory  exchange  ratio  of  the  expired  gas, 
a  high  oxygen  uptake,  and  a  high  pH  of  systemic 
arterial  blood  (136).  Transient  episodes  of  emotional 
stress  are  apt  to  introduce  appreciable  errors  into 
steady-state  measurements  of  flow,  particularly  by 
the  Fick  principle  (412,  439);  on  the  other  hand, 
sustained  excitement  will  artificially  increase  the 
cardiac  output.  In  the  latter  instance,  the  normality 
of  the  cardiac  output  can  be  appraised  by  comparison 
with  the  simultaneously  measured  oxygen  uptake 
(fig.  12).  Ordinarily,  the  arteriovenous  difference 
for  oxygen  is  of  little  help  in  such  an  appraisal  since 
its  variations  at  rest  approximate  the  limits  of  analytic 
error  (e.g.,  average  of  38.4  sd  ±6.3  ml  per  liter 
(334))- 


Uneven  Pulmonary  Blood  Flow 

The  pattern  of  distribution  of  the  right  ventricular 
output  throughout  the  lung  has  been  examined  in 
several  different  ways:  a)  direct  inspection  of  the 
pulmonary  blood  vessels;  b)  fractional,  or  continuous, 
analysis  of  the  alveolar  component  of  expired  air; 
c)  bronchospirometry  or  regional  sampling  of  alveolar 
air;  d)  external  scintillation  counting  following  the 
breathing  of  radioactive  gases;  and  e)  the  use  of 
conceptual  models  to  explain  actual  respiratory 
gas  exchange. 

Direct  inspection  of  the  lung  for  the  determination 
of  the  pattern  of  the  pulmonary  blood  flow  has  been 
practiced  for  at  least  90  years  (54)-  Three  types  of 
observations  have  been  made:  /)  the  examination  of 
the  surface  of  the  exposed  lung  in  the  living  animal 
(21,  105,  419),  2)  the  postmortem  examination  of  the 


1 68a 


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CIRCULATION    II 


excised  lung  following  the  injection  of  tracer  materials 
(323,  405),  and  3)  roentgenography,  including 
angiocardiography  (202).  These  approaches  are  all 
qualitative  but  have  clearly  established  two  features 
of  the  pulmonary  circulation :  the  distribution  of  the 
pulmonary   blood   flow   is  ordinarily   quite   uniform 


but  that  it  may  be  drastically  modified  by  appro- 
priate stimulation  (fig.  13);  structural  abnormalities 
are  prepotent  over  physiological  influences  in  deter- 
mining the  course  taken  by  the  blood  (427).  The 
direct  observations  have  also  been  used  to  account 
for  a  variety  of  otherwise  inexplicable  clinical  phe- 


•        • 


♦     ♦ 


•  •  •    ..    mr   i 


••      •  ♦ 


•Supine 
+  Upright 


OXYGEN    UPTAKE    (cc/min) 


400  800  1200  1600  2000 

pig.  12.  Relationship  between  oxygen  uptake  and  cardiac  output  at  rest  (supine),  during  supine 
exercise,  and  during  upright  exercise.  The  diagonal  line  (at  the  far  left)  is  based  on  the  method  of 
least  squares  and  represents  spontaneous  variations  in  the  cardiac  output  in  56  normal  subjects  at 
rest.  This  line  lies  to  the  left  of  the  exercise  data  and  has  a  steeper  slope.  For  any  given  oxygen  uptake, 
the  cardiac  output  is  lower  during  upright  exercise  than  during  supine  exercise.  [After  Reeves  el  al. 
(336)-] 


2400 


2800 


fig.  13.  Variations  in  the  distribution  of  the  pulmonary  blood  flow.  For  each  experiment,  filtered 
India  ink  was  injected  into  a  marginal  ear  vein  of  an  unanesthetized  rabbit  loosely  restrained  in  its 
normal  body  position.  .4.-  uniform  distribution  of  the  India  ink;  B:  "patchy'  distribution  following 
introduction  of  a  cardiac  catheter  into  the  right  ventricle  via  the  right  external  jugular  vein  (local 
procaine  anesthesia).  [After  Tuller  el  al.  (405).] 


DYNAMICS    OF    PULMONARY    CIRCULATION 


l683 


nomena,  including  the  bizarre  "'butterfly"  shadows 
of  pulmonary  edema  (202)  and  the  maintenance  of 
the  virtually  normal  oxygenation  of  peripheral  arterial 
blood  in  patients  with  atelectasis  and  pneumonia  (85). 

Much  more  relevant  to  the  performance  of  the 
lung  in  gas  exchange  is  the  distribution  of  the  pul- 
monary capillary  blood  with  respect  to  alveolar 
volume,  alveolar  ventilation,  and  pulmonary  diffusing 
surfaces.  In  the  normal  lung,  these  parameters  are 
ordinarily  quite  precisely  balanced  (131,  145,  427); 
in  disease,  the  upsets  may  be  quite  striking  (58). 
Two  approaches  are  in  popular  use  for  relating  pul- 
monary capillary  perfusion  to  alveolar  ventilation: 
the  determination  of  the  pattern  of  change  in  the 
alveolar  composition  of  a  respiratory  gas  (284)  and 
of  the  respiratory  exchange  ratio  (428)  during  a 
single  expiration;  the  determination  of  the  rate  of 
increase  in  the  peripheral  arterial  oxygen  saturation 
(314)  and  tension  (131)  during  oxygen  breathing. 
It  has  been  pointed  out  elsewhere  that  each  of  these 
approaches  has  its  own  uncertainties  (428). 

The  comparison  of  blood  flow  through  different 
parts  of  the  lungs  has  generally  involved  either 
bronchospirometry  or  regional  sampling  of  alveolar 
gas.  Bronchospirometry  has  been  particularly  fruitful 
in  comparing  the  perfusion  of  the  two  lungs;  thus, 
simultaneous  measurements  of  the  uptake  of  each 
lung  separately  have  disclosed  that  ordinarily  each 
lung  receives  a  share  of  the  cardiac  output  which  is 
proportional  both  to  its  gas  volume  (29)  and  to  its 
ventilation  (203).  Accordingly,  in  man,  the  right 
lung  receives  55  per  cent  of  the  cardiac  output  (135); 
this  fraction  is  decreased  when  the  subject  turns  on 
his  side  so  that  the  left  lung  is  down  (29). 

Bronchospirometric  comparisons  of  oxygen  uptake 
have  also  disclosed  that  gravity  rearranges  the 
distribution  of  the  blood  flow  within  each  lung:  as 
the  human  subject  stands,  the  oxygen  uptake  of  the 
lower  lobes  increases  at  the  expense  of  the  upper 
lobes,  indicating  a  preferential  distribution  of  blood 
flow  to  the  lower  lobes;  the  change  in  the  pattern  of 
the  blood  flow  occurs  even  though  the  distribution  of 
ventilation  is  little  altered  by  the  change  in  posture 
(286).  It  should  be  noted  that  the  use  of  broncho- 
spirometry to  detect  changes  in  regional  blood  flow 
presupposes  that  all  parts  of  the  lungs  are  breathing 
the  same  inspired  mixture;  when  different  parts  of 
the  lungs  are  given  different  inspired  gas  mixtures  to 
breathe,  the  procedures  and  calculations  grow  much 
more  complicated  since  all  of  the  variables  in  the 
Fick  equation — instead  of  only  the  oxygen  uptake — ■ 
have  to  be  determined  (135,  221,  410). 


Hemodynamic  measurements  (247)  and  analyses 
of  alveolar  gas  have  been  consistent  with  the  broncho- 
spirometric measurements.  For  example,  the  alveolar 
gas  analyses  have  shown  that:  a)  the  oxygen  tension 
of  the  upper  lobes  exceeds  that  of  the  lower  lobes 
(285,  330);  b)  the  carbon  dioxide  tension  of  the  upper 
lobes  is  less  than  that  of  the  lower  lobes  (284,  330, 
388),  and  c)  the  respiratory  exchange  ratio  of  the 
upper  lobes  exceeds  that  of  the  lower  lobes  (428). 
All  these  observations  are  consistent  with  the  clinical 
belief  that  high  oxygen  tension  in  the  apices  of  the 
lungs,  resulting  from  inadequate  perfusion  with 
respect  to  ventilation,  is  responsible  for  the  apical 
localization  of  pulmonary  tuberculosis  (344).  They 
also  indicate  that  if  intrapulmonary  baroreceptor 
mechanisms  for  rearranging  pulmonary  blood  flow  do 
exist  at  the  pulmonary  bases,  they  are  easily  over- 
whelmed by  the  mechanical  effects  of  gravity. 

The  combination  of  xenon133  and  external  counting 
was  originally  used  to  estimate  the  distribution  of 
inspired  air  (32,  234).  Subsequently,  oxygen15  (107) 
and  then  oxygen'Mabeled  carbon  dioxide  (427)  were 
introduced  to  relate  the  distribution  of  the  perfusion 
to  the  distribution  of  the  inspired  air.  In  addition  to 
confirming  that  in  the  seated  normal  subject  the 
lower  lobes  are  much  better  perfused  than  the  upper 
(8:1)  (428),  these  studies  also  expressed,  in  quantita- 
tive terms,  the  spectrum  of  ventilation-perfusion 
ratios  which  exist  in  the  lungs  of  upright  normal 
man,  and  showed  how  the  ratios  gradually  convert 
from  high  to  low  values  as  the  base  of  the  lung  is 
approached.  Moreover,  although  these  inhomoge- 
neities  have  inevitable  consequences  for  the  gas 
tensions  in  the  regional  alveoli  and  capillaries,  they 
were  shown  to  have  little  significance  for  the  efficiency 
of  the  lung  in  oxygen  uptake  or  carbon  dioxide  output. 
Finally,  the  intrapulmonary  distribution  of  air  and 
blood  was  demonstrated  to  become  much  more 
uniform  when  the  normal  subject  assumed  the  supine 
position  or  when  mechanical  influences,  such  as 
anatomical  restriction  of  the  lower  pulmonary 
vascular  bed  by  congestion  and  fibrosis,  counteracted 
the  tendency  of  gravity  to  direct  blood  to  the  lower 
lobes  in  the  upright  position  (107). 

Because  the  normal  lung  is  too  inhomogeneous 
and  too  complicated  to  be  treated  in  simple  mathe- 
matical terms,  conceptual  models  of  alveolar-capillary 
gas  exchange  have  been  adopted  as  practical  tools 
for  assessing  the  adequacy  of  pulmonary  capillary 
perfusion.  One  particularly  useful  model  has  been 
the  homogeneous  "ideal"  lung,  a  figurative  lung  to 
which  actual  inhomogeneities  can  be  referred   (266, 


[684 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


PULMONARY 
ARTERY 


SYSTEMIC 
ARTERY 


60- 

X 

- 1 

Va 
Q 

7 

i 
1 
5 

Va       1 

vV1 

— i 1 —  ■  I 

E    40  -1 

-  ~\ 

o 

MIXED    VENOUS 

BLOOO 

Va     5 

< 

1 

20  - 

INSPIRED 

-* — m- — i— 

0 

1 f— 

— 1 — 

Pa 

— (— 

°2 

mrr 

— y 

Hg 

— 

CAS    ■>. 

— 1 1 1 

40 


60 


80 


VENOUS   ADMIXTURE 

fig.  14.  Model  of  the  lungs.  Any  inhomogencity  of  ventilation  and  perfusion  is  represented  as 
"virtual  venous  admixture."  Pulmonary  arteriovenous  shunts  appear  as  •'anatomical  venous  ad- 
mixture." According  to  this  model,  the  alveolar-arterial  difference  in  oxygen  tension  may  be  sub- 
divided into  three  components:  diffusion,  virtual  venous  admixture,  and  anatomical  venous  ad- 
mixture. As  indicated  in  the  text,  this  is  an  oversimplification.  [After  Briehl  &  Fishman  (51).] 

327,  345):  the  standard  tactic  is  to  express  deviations 
from  homogeneity  in  terms  of  their  effect  on  the 
alveolar-arterial  differences  in  oxygen  tension  ("A-a 
gradient").  By  partitioning  the  A-a  gradient  into 
three  components  (fig.  14),  it  is  possible  not  only  to 
identify  the  venous  admixture  component,  but  also 
to  separate  it  into  anatomical  and  "virtual"  portions; 
the  "virtual"  venous  admixture  is  then  an  expression 
of  the  inhomogeneity  of  pulmonary  capillary  perfusion 
with    respect    to    other    gas-exchanging    parameters 

(14.  23,  51). 

The  picture  which  has  emerged  from  this  type  of 
approach  is  illustrated  in  figure  15:  alveoli  which 
are  excessively  perfused  for  their  ventilation  (VA/Q 
<  0.8)  contribute  to  the  virtual  venous  admixture; 
those  which  are  perfused  but  nonventilated  (VA/Q. 
=  o)  appear  as  anatomical  venous  admixture;  those 
which  are  excessively  ventilated  for  their  perfusion 
(VA/Q.  >  0.8)  contribute  to  the  "physiological"  dead 
space,  the  "alveolar"  dead  space,  and  to  the  alveolar- 
arterial  gradient  for  carbon  dioxide  (347*  377)- 

While  this  model  is  the  basis  of  much  of  contempo- 
rary thinking  about  the  distribution  of  blood  flow 
with  respect  to  gas  exchange,  it  is  known  to  be  inade- 
quate on  several  practical  and  theoretical  accounts: 
a)  the  fractionation  of  A-a  gradient  is  technically 
difficult  and  apt  to  be  imprecise,  especially  in  patients 
with  diffuse  pulmonary  disease;  b)  the  model  does 
not  recognize  other  inhomogeneities,  e.g.,  between 
perfusion  and  diffusing  capacity  or  between  stroke 
output  and  pulmonary  capillary  blood  volume,  which 


100 


120 


140 


160 


fig.  15.  Hypothetical  distribution  of  alveolar  ventilation- 
perfusion  ratios  (VA/Q)  within  the  normal  human  lung.  Values 
for  VA/Q  range  from  zero  at  the  mixed  venous  blood  point 
(perfusion  but  no  ventilation)  to  infinity  at  the  inspired  air 
point  (ventilation  without  perfusion).  According  to  this  model, 
the  VA/Q  ratio  of  each  alveolus  fixes  its  respiratory  exchange 
ratio  (R)  as  well  as  its  gas  tensions  (Pan„,  Pa02,  and  PacoJ. 
[Based  on  Riley  &  Cournand  (345)  and  Rahn  (327).] 

consequently  appear  as  imbalances  between  ventila- 
tion and  perfusion  (319,  413);  and  c)  basic  assump- 
tions, such  as  the  type  of  statistical  distribution  of 
ventilation-perfusion  ratios  among  the  alveoli  may 
be   erroneous   (128). 

In  practice,  the  mixing  formula  shown  in  figure 
16  is  generally  applied  to  data  obtained  during 
ambient  air  breathing  to  determine  the  total  venous 
mixture,  i.e.,  the  sum  of  the  anatomical  and  the 
virtual;  by  repeating  the  measurements  during 
high-oxygen  breathing,  the  virtual  component  is 
minimized  so  that  the  venous  admixture  consists 
almost  entirely  of  the  anatomical  component   (23). 


DYNAMICS    OF    PULMONARY    CIRCULATION 


l685 


PULMONARY 
ARTERY 


SYSTEMIC 
ARTERY 

(Cq) 


Qs        ca  _  cc 

Q  Cy    —     Cc' 

fig.  16.  Schematic  representation  of  the  lung  to  illustrate 
the  components  of  the  venous  admixture  and  the  calculation  of 
the  venous  admixture  as  a  fraction  of  the  cardiac  output. 
Q,  =  venous  admixture  (anatomical  plus  "virtual");  Q  = 
cardiac  output;  Ca,  Cc,  C;  =  oxygen  content  of  arterial,  end- 
capillary,  and  mixed  venous  blood,  respectively.  Furthermore, 
by  administering  enriched-oxygen  mixtures,  the  total  venous 
admixture  (Qs/Q)  can  be  subdivided  into  its  anatomical  and 
"virtual"  portions. 

Attempts  have  also  been  made  to  measure  anatomical 
venous  admixture  in  other  ways,  e.g.,  the  simultaneous 
intravenous  injection  of  T-1824  and  KrS5;  unfor- 
tunately, such  methods  are  most  reliable  when  the 
anatomical  venous  admixture  is  large,  i.e.,  greater 
than  1 5  per  cent  of  the  cardiac  output  (155). 

In  recent  years,  relationships  between  pulmonary 
capillary  perfusion  and  other  gas-exchanging  param- 
eters have  been  clarified  in  many  different  ways: 
a)  the  determination  of  alveolar-arterial  gradients 
for  nitrogen  (67,  232);  b)  the  quantification  of  the 
role  played  by  parameters  other  than  ventilation  and 
perfusion  in  determining  virtual  venous  admixture 
(319);  c)  the  comparison  of  anatomical  dead  spaces 
with  physiological  and  alveolar  dead  spaces  (347, 
377);  d)  the  analysis  of  the  pulmonary  elimination 
of  intravenously  injected  radioactive  tracers  (173); 
and  e)  by  the  creation  of  new  and  more  elaborate 
models  (52,  131).  With  the  growth  of  understanding 
of  these  interplays  has  come  the  fuller  appreciation 
of  the  extent  to  which  they  may  affect  conventional 
tests  of  pulmonary  performance  and  calculations  of 
pulmonary  resistance. 


PULMONARY    VASCULAR    PRESSURES 


Recording 

The  characteristics  of  adequate  manometric  systems 
as  well  as  the  limitations  of  the  cardiac  catheter  in 


reproducing  the  intravascular  and  intracardiac 
pressure  pulses  are  considered  elsewhere  in  this 
volume.  However,  it  should  be  emphasized  that 
with  modern,  hi-fidelity  recorders  and  manometers, 
it  is  generally  the  catheter  attached  to  sensing  ele- 
ment, rather  than  the  manometric  system,  which 
limits  the  capacity  of  the  apparatus  to  duplicate 
faithfully  the  pressure  pulse.  It  is  also  noteworthy 
that  even  though  blood  pressure  recorded  from  the 
end  of  a  catheter  in  the  pulmonary  artery  is  suffi- 
ciently exact  for  most  physiologic  purposes,  it  fails  to 
measure  the  lateral  pressure  in  the  vessel  by  a  small, 
but  variable,  amount. 


Hydrostatic  Reference  Level 

For  the  measurement  of  absolute  pressures  within 
the  thorax,  correction  is  made  for  the  hydrostatic 
pressure  difference  between  the  intrathoracic  site 
from  which  pressure  is  being  recorded  and  the  exter- 
nally-placed sensing  element  of  the  manometer 
(169).  For  this  purpose,  the  plane  of  the  sensing 
element  is  set  in  relationship  to  both  the  heart  and 
to  some  thoracic  landmark.  In  practice,  different 
hydrostatic  zero  levels  have  been  adopted :  most 
popular  are  levels  5  cm  below  the  angle  of  Louis 
(253)  and  10  to  12  cm  above  the  tabletop  (103). 
While  the  different  reference  levels  do  complicate 
the  comparison  of  data  from  different  laboratories, 
each  is  a  perfectly  reliable  standard  for  comparing 
consecutive  measurements  in  a  single  animal. 

Several  uncertainties  creep  into  the  use  of  fixed 
external  references  to  obtain  absolute  values  of 
intrathoracic  blood  pressures,  particularly  in  patients 
who  are  dyspneic  from  cardiac  or  pulmonary  disease. 
Thus,  in  subjects  with  large  hearts  or  unusual  con- 
figurations of  the  chest,  it  may  be  difficult  to  estimate 
precisely  the  difference  between  the  external  reference 
plane  and  the  intracardiac  site  of  reference  (253); 
moreover,  even  in  normal  subjects,  the  heart  changes 
position  during  each  cardiac  cycle.  Consequently,  it 
seems  reasonable  to  view  pulmonary  vascular  and 
intracardiac  pressures  which  are  measured  in  this 
way  as  accurate  only  to  within  a  few  mm  Hg. 

Unfortunately,  many  intuitively  attractive  solutions 
to  the  problem  of  "zeroing"  are  not  feasible:  the 
tip  of  the  cardiac  catheter,  as  localized  by  X  ray, 
cannot,  per  se,  serve  as  the  zero  reference  plane;  nor 
is  it  a  simple  matter  to  "zero"  an  intracardiac 
manometer  which  is  built  into  the  tip  of  a  cardiac 
catheter.  Nonetheless,  despite  these  difficulties  in- 
herent in  the  choice  of  reference  levels  for  absolute 


1 686  HANDBOOK    OF    PHYSIOLOGY    v-~    CIRCULATION    II 


fr/V  A, 
i  \ !  V  \  I 

hi    ijiiMii    y      \ 


fig.  17.  Simultaneous  aortic  (AO)  and  pulmonary  arterial  (PA)  pressure  pulses  recorded  from  a 
human  subject  with  a  normal  circulation  during  open  thoracotomy.  The  arrows  indicate  the  be- 
ginning of  ejection  and  the  end  of  protodiastole  in  the  aorta  and  pulmonary  artery.  (Paper  speed, 
25  mm/sec  on  left;  75  mm/sec  on  right.  Interval  between  time  lines,  0.04  sec.)  [After  Braunwald 
etal.  (47).] 


values,  any  of  these  reference  levels  will  suffice  for 
consecutive  measurements  in  a  single  experiment. 


Pulmonary  Arterial  Pressure 

With  minor  differences,  the  contour  of  the  pul- 
monary arterial  pulse  mirrors  that  at  the  root  of  the 
aorta:  as  may  be  seen  in  figure  17  (47),  the  pul- 
monary arterial  pressure  pulse  is  small  in  amplitude 
as  compared  to  the  aortic  pulse  and  characteristically 
displays  a  rapid  rise  to  a  rounded  peak  during  systole, 
a  brisk  small  incisura  and  a  gradual  decrease  in 
pressure  during  diastole  (182,  225).  The  "classical" 
pulmonary  arterial  curves  are  more  apt  to  be  recorded 
in  pulmonary  hypertensive  states  than  in  pulmonary 
normotensive  states;  at  the  lower  levels  of  pulmonary 
arterial  pressure,  distorting  artifacts  are  exceedingly 
common.  Not  shown  are  the  corresponding  records 
of  the  velocity  of  the  blood  flow:  in  contrast  to  the 
pressure-velocity  relationships  in  the  aorta,  the 
pulmonary  arterial  pressure-velocity  curves  are 
quite  similar:  the  velocity  of  blood  flow  in  the  pul- 
monary artery  lags  slightly  behind  the  pulmonary 
arterial   pressure    (156). 

Ordinarily,  the  pulmonary  arterial  mean  pressure 
in  man  (87),  dog  (303),  cat  (132),  and  the  rabbit 
(239)  averages  one-fifth  to  one-sixth  that  in  the 
systemic  circulation.  In  man,  the  level  of  the  pul- 
monary arterial  pressure  seems  to  increase  slightly 
with  age  (101).  There  is  no  fixed  relationship  between 
the  pressures  in  the  two  circuits.  In  man,  before  the 
onset  of  systole,  the  pulmonary  arterial  pressure  is 
of  the  order  of  7  to  12  mm  Hg;  during  systole  it 
rises  abruptly  to  20  to  30  mm  Hg;  the  corresponding 


mean  pressure  is  of  the  order  of  12  to  15  mm  Hg 
(87,  103).  In  the  dog,  pulmonary  arterial  pressures 
tend  to  be  somewhat  higher,  so  that  a  mean  pressure 
of  20  mm  Hg  is  not  unusual  (187). 


Pulmonary  Venous  and  Left  Atrial  Pressures 

Blood  pressures  have  been  recorded  directly  from 
the  left  atrium  and  pulmonary  veins  in  dog  (187) 
and  man  (45,  92,  299).  The  pulmonary  venous 
pressure  pulse  is  a  record  of  left  atrial  events,  indi- 
cating that  the  pulmonary  arterial  pressure  pulse  has 
been  damped  out  by  the  small  pulmonary  vessels. 
As  in  the  systemic  veins  and  right  atrium,  the  a,  c,  and 
v  waves  are  clearly  defined  (187);  but,  in  contrast 
to  the  right  heart,  the  summit  of  the  v  wave  is  usually 
the  highest  part  of  the  pressure  pulse,  and  pressure 
variations  during  the  cardiac  cycle  are  greater  in  the 
left  atrium  and  pulmonary  veins.  Thus,  in  both  the 
unanesthetized  and  anesthetized  dog,  pulmonary 
venous  pressures  during  a  single  cardiac  cycle  range 
between  3  and  12  mm  Hg  (187).  In  intact,  unanes- 
thetized man  the  mean  left  atrial  pressure  is  of  the 
order  of  4  to  5  mm  Hg  (47).  Although  physiologic 
observations  (121)  arc  accumulating  to  support 
the  anatomic  impression  (56,  392)  that  the  pulmonary 
venous-left  atrial  junctions  can  act  as  sphincters, 
final  proof,  in  the  form  of  suitably  recorded  pulmo- 
nary venous-left  atrial  pressure  gradients  or  differences 
between  the  contours  of  the  pulmonary  venous  and 
left  atrial  pressure  pulses  have  as  yet  not  been  pub- 
lished. 

Until  recently,  measurements  of  left  atrial  and 
pulmonary  venous  pressures  in  intact  animals  were 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1687 


confined  to  dogs  fitted  with  angiostomy  cannulae 
(150,  225);  in  recent  years,  these  pressures  have 
been  measured  in  both  intact  animal  and  man  by 
every  conceivable  route:  right  heart  catheterization 
in  patients  with  congenital  atrial  defects,  direct 
cardiac  puncture,  transbronchial  puncture,  trans- 
thoracic puncture,  and  intracardiac  transseptal 
puncture  (45,  299). 

Pulmonary  Arteriovenous  Pressure  Gradient 

In  man,  cat,  and  dog,  the  pressure  drop  across  the 
pulmonary  vascular  bed  is  of  the  order  of  one-tenth 
of  the  pressure  drop  across  the  systemic  circulation. 
The  pulmonary  arterial-left  atrial  pressure  gradient 
is  maximal  early  in  systole  (fig.  18);  it  decreases  late 
in  systole  and  may  even  approach  zero  if  diastole  is 
sufficiently  prolonged  (182).  Unfortunately,  since 
both  the  pulmonary  arterial  and  pulmonary  venous 
pressure  pulses  have  different  origins  (right  and  left 
sides  of  the  heart,  respectively),  it  is  not  possible  to 
predict  the  shape  of  the  pressure  pulses  of  the  inter- 
vening vascular  bed  from  the  pulmonary  arterial- 
pulmonary  venous  pressure  gradient. 

Pulmonary   Wedge  Pressures 

The  pulmonary  arterial  wedge  pressure  is  recorded 
by  advancing  a  cardiac  catheter  until  its  tip  occludes 
a  terminal  branch  of  the  pulmonary  artery;  flow  then 


fig.  18.  The  pulmonary  vascular  pressure  gradient.  Upper 
curve:  record  of  the  pulmonary  arterial  pressure  pulse  of  an  un- 
anesthetized,  unoperated  dog;  blood  pressure  35/12  mm  Hg, 
mean  20  mm  Hg.  Lower  curve :  record  of  the  pulmonary  venous 
pressure  pulse;  blood  pressure  2  to  12  mm  Hg.  Middle  curve: 
differential  manometer  record  of  pulmonary  arterial  minus 
pulmonary  venous  pressure,  i.e.,  the  gradient  of  pressure  driving 
blood  through  the  pulmonary  vascular  system.  [After  Hamilton 
(182).] 


stops  in  the  vascular  segment  beyond  the  tip  of  the 
catheter:  the  pressure  transmitted  by  the  intervening 
static  column  of  blood  presumably  approximates 
closely  the  pressure  in  the  first  communicating 
pulmonary  veins  in  which  flow  persists.  Pulmonary 
venous  wedge  pressure  is  recorded  by  impacting  a 
catheter  (passed  retrograde)  in  a  pulmonary  vein. 

Originally  (200),  it  was  believed  that  the  wedged 
pulmonary  arterial  pressure  could  be  used  as  a  meas- 
ure of  pressure  in  the  pulmonary  capillary  bed.  It  is 
now  clear  that  the  wedged  arterial  catheter  registers 
more  remote  events,  i.e.,  events  in  the  large  pulmonary 
veins  and,  unless  the  "throttles"  actually  operate,  in 
the  left  atrium  (83).  In  both  dog  and  man — with 
normal  pulmonary  circulation  or  with  pulmonary 
venous  congestion — the  mean  pulmonary  arterial 
wedge  pressure  and  the  mean  left  atrial  pressure  are 
nearly  identical  (83).  In  the  normal  animal  and  man, 
the  level  of  the  arterial  wedge  pressure  is  of  the  order 
of  5  to  9  mm  Hg  (103);  in  patients  with  pulmonary 
venous  congestion  from  mitral  stenosis,  it  parallels  the 
left  atrial  and  pulmonary  venous  pressure. 

The  validity  and  meaning  of  the  arterial  wedge 
pressure  have  been  the  subjects  of  considerable  debate 
(26).  Various  criteria  have  been  adopted  for  deciding 
if  a  wedge  pressure  is  a  reliable  measure  of  the  level  of 
the  left  atrial  pressure;  these  include  higher  pulmonary 
arterial  mean  and  diastolic  pressures  than  the  re- 
corded wedge  pressure,  the  withdrawal  of  fully  oxy- 
genated blood  from  the  impacted  catheter,  the  snap  of 
the  catheter  as  it  is  withdrawn  from  the  wedge  posi- 
tion and  a  characteristic  configuration  of  the  wedge 
tracing  (83,  103).  No  single  one  of  these  criteria  en- 
sures a  reliable  measure  of  left  atrial  pressure, 
particularly  when  pressure  is  changing  rapidly  (26). 
Indeed,  even  when  all  criteria  are  met,  the  left  atrial 
pressure  may  be  poorly  transmitted  due  to  a  faulty 
wedge  position  of  the  catheter  (fig.  19)  (22). 

The  use  of  the  arterial  wedge  pressure  as  a  measure 
of  the  level  of  left  atrial  pressure  is  on  sounder  footing 
than  its  use  to  record  the  contour  of  the  left  atrial 
pressure  pulse.  Only  in  states  of  pulmonary  venous 
congestion  is  the  wedge  catheter  apt  to  reproduce 
cyclic  events  in  the  left  atrium  (83,  113).  Interpreta- 
tion of  changes  in  contour  is  particularly  troublesome 
when  artifacts  are  present;  these  artifacts  tend  to  be 
most  pronounced  during  exercise  and  deep  breathing. 

Blood  pressure  falls  in  the  pulmonary  artery  distal 
to  an  occlusive  balloon  and  assumes  the  nondescript 
character  of  a  wedge  pressure  (fig.  20)  (49,  42).  The 
level  of  this  distal  pulmonary  arterial  pressure 
corresponds  to  that  in  the  left  atrium  and  fluctuates 


1 688  HANDBOOK    OF    PHYSIOLOGY     ■*■     CIRCULATION    II 


fig.  19.  Various  positions  of  the  "wedged"  catheter  redrawn  from  pulmonary  wedge  arterio- 
grams. A:  the  catheter  is  wedged  in  an  artery  which  is  slightly  smaller  than  the  catheter  tip;  the 
lumen  of  the  artery  is  in  direct  line  with  the  lumen  of  the  catheter.  B:  the  catheter  is  wedged  at  a 
bifurcation  of  an  artery  of  the  same  size  as  the  catheter  tip.  C:  the  tip  of  the  catheter  impinges  against 
the  wall  of  a  sharply  angulated  artery.  D:  The  catheter  is  wedged  at  a  point  where  the  artery  divides 
into  three  or  more  branches.  E:  the  catheter  is  incompletely  wedged.  The  injected  dye  regurgitates 
around  the  catheter  outlining  the  artery  proximal  to  the  catheter  tip.  Positions  A,  B,  and  D  are 
favorable  for  recording  wedge  pressure;  positions  C  and  E  are  not.  [After  Bell  el  al.  (22).] 


with  changes  in  the  left  atrial  pressure.  The  tracing 
shows  no  left  atrial  or  pulmonary  venous  events  but 
does  display  respiratory  swings. 

Pulmonary  venous  wedge  pressures  have  also  been 
recorded  in  the  dog  (435),  in  normal  human  subjects 
(84,  248),  and  in  patients  with  atrial  septal  defects.  In 
the  normal  dog  the  pulmonary  venous  wedge  pressure 
approximates  mean  pressure  in  the  pulmonary  artery 
(435)  '■>  m  patients,  with  pulmonary  hypertension,  the 
pulmonary  arterial  mean  pressure  is  much  higher 
than  the  pulmonary  venous  wedge  pressure,  pre- 
sumably due  to  the  interposed  high  vascular  resistance 
(84). 

In  brief,  neither  the  pulmonary  arterial  wedge 
pressure  nor  the  pulmonary  venous  wedge  pressure 
provides  a  measure  of  the  pulmonary  capillary 
pressure.  However,  with  care  and  under  appropriate 
circumstances,  the  pulmonary  arterial  wedge  pres- 
sure does  provide  an  approximate  measure  of  the 
pulmonary  venous,  and  usually,  of  the  mean  left 
atrial  pressure;  it  can  then  be  used  to  estimate  the 
driving  pressure  across  the  entire  pulmonary  vascular 
bed  and  to  calculate  the  resistance  to  perfusion  offered 
by  the  small  pulmonary  vessels. 


Influence  of  Intrathoracic  Pressure  on  Pulmonary 
Vascular  Pressure 

Pressure  in  an  intrathoracic  vessel  is  not  a  simple 
concept.  In  order  for  such  a  pressure  to  have  meaning, 
it  must  be  related  to  a  reference  level,  i.e.,  atmospheric 
or  pleural  pressure.  If  the  manometer  which  records 
the  pressure  is  balanced  against  atmospheric  pressure, 
all  pressure  changes  within  the  thorax  arising  from  the 
ventilation — for  example,  a  cough  (fig.  2  1 ) — will  be 
immediately  propagated  across  the  walls  of  the  pul- 
monary vessels  and  heart  to  the  incompressible  blood 
which  they  contain;  the  intrathoracic  pressure  changes 
will,  therefore,  be  registered  as  an  integral  part  of 
the  pressure  pulse.  However,  pressures  recorded  in 
this  way  ("luminal"  pressures)  provide  no  measure 
of  the  pressure  which  distends  the  vessels  ("trans- 
mural" pressures) :  during  a  cough,  while  the  pressure 
recorded  by  a  manometer  balanced  against  atmos- 
pheric pressure  rises  precipitously,  a  manometer 
balanced  against  pleural  pressure  shows  that  the 
transmural  pressure  has  remained  virtually  unchanged 
(190). 

Values  for  the  pleural  pressures  have  been  obtained 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1689 


in  various  ways,  including  direct  measurements  from 
gas  pockets  and  balloons  within  the  pleural  or 
mediastinal  spaces  (82)  and  indirect  estimates  from 
the  esophagus   (287).   It  is  generally  conceded  that 


mm 
Hg 


20  r 
10 
0 


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20rl 

10 
0 


BEFORE 


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AFTER 


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fig.  20.  Effect  of  occluding  the  right  pulmonary  artery  on 
blood  pressures  distal  and  proximal  to  the  occlusive  balloon. 
Before  occlusion,  blood  pressures  are  identical  in  the  main  and 
right  pulmonary  arteries.  After  occlusion,  the  distal  pressure 
falls  to  the  level  of  pulmonary  wedge  pressures  (left  atrial 
pressure),  pressure  in  the  main  pulmonary  artery  proximal  to 
the  balloon  increases  by  approximately  5  mm  Hg.  ( Unpub- 
lished observations  of  M.  Brandfonbrenner,  A.  Himmelstein, 
G.  M.  Turino,  and  A.  P.  Fishman.) 


even  the  direct  methods  may  fail  to  provide  precise 
measurements  of  the  pressures  which  are  operating 
at  the  surface  of  the  particular  pulmonary  vessels 
under  consideration:  the  pressure  within  the  pleura 
may  not  be  entirely  uniform  (82,  127);  the  extramural 
pressures  along  the  length  of  the  vascular  tree  may 
differ  from  segment  to  segment  and  from  the  pleural 
pressure,  depending  on  the  location  of  the  segment, 
i.e.,  intrapericardial,  intrapulmonary,  or  juxta- 
alveolar.  The  use  of  indirect  measures,  which  provides 
reliable  measures  of  pleural  pressures  in  some  experi- 
mental and  clinical  conditions,  fails  in  others  (287). 

Transmural  \ersus  Luminal  Pressures 

During  each  respiratory  cycle,  the  changing  pleural 
pressures  (fig.  22)  affect  all  intrathoracic  vessels  except 
those  apposed  to  alveoli.  Consequently,  for  the 
alveolar  capillaries,  the  pressure  which  determines 
their  caliber,  i.e.,  transmural  pressure,  is  customarily 
calculated  as  the  difference  between  (estimated) 
intracapillary  and  alveolar  pressure;  the  transmural 
pressure  of  all  other  vessels  is  calculated  as  the  differ- 
ence between  the  luminal  and  the  pleural  pressure 
(fig.  23)  (61,  233).  The  practical  difficulties  in  esti- 
mating perivascular  pressure  from  pleural  pressure 
have  been  indicated  above;  pericapillary  pressures 
also  have  an  element  of  uncertainty  because  of  the 
prospect  that  tissue  forces,  such  as  alveolar  surface 
tension,  may  decrease  pericapillary  pressure  to  sub- 
atmospheric  levels. 

Depending  on  the  purpose  of  the  observation, 
pulmonary  vascular  pressures  are  referred  either  to 
atmospheric    or    to    pleural    pressure.    Considerable 


fic.  21.  Differential  pressure  record  of  a  "cough."'  The  lowest  tracing  is  from  a  mouthpiece  into 
which  a  forcible  expiration  was  made.  The  middle  record  is  that  of  luminal  systemic  arterial  pressure. 
The  upper  record  is  a  differential  record  of  the  middle  minus  the  lower  record.  The  mouthpiece 
record  is  assumed  to  show  pressure  changes  nearly  identical  with  intrathoracic  pressure  changes; 
the  differential  record  indicates  the  stresses  which  the  intrathoracic  arteries  undergo.  [After  Hamilton 
etal.  (190).] 


169O  HANDBOOK    OF    PHYSIOLOGY    "-    CIRCULATION    II 

T.M. 


M 


IPP 


I  !  lilt    i:  i  ll!l  I  !  1,1    lltlil'l    I  "1  I'  I 

bJ"***"1* -kJ 


I    Hi!  I  !: 


REST-  21%    02 


fig.  22.  Effects  of  breathing  5'  < 
CO2  and  of  exercise  on  the  pleural 
pressures  (IPP)  and  esophageal  pres- 
sures (EP)  of  a  human  subject.  All 
pressures  are  in  mm  Hg.  [After  Fishman 
et  al.  (132).] 


IPP 


""''! — T- 


confusion  has  arisen  from  the  indiscriminate  use  of 
transmural  pressures  for  luminal  pressures  in  the 
calculation  of  pulmonary  vascular  resistance.  It 
should  be  emphasized  that  as  long  as  left  atrial  pres- 
sure exceeds  alveolar  pressure,  the  measurement  of 
the  driving  pressure  across  the  lung  requires  only  the 
simultaneous  measurements  of  luminal  pulmonary 
arterial  and  venous  pressures — no  matter  what  the 
intrathoracic  pressure  may  be. 


PULMONARY  BLOOD  VOLUME 

The  pulmonary  vasculature  constitutes  a  distensible 
reservoir,  interposed  between  the  right  and  left  heart. 
The  volume  of  blood  which  it  contains  is  of  interest 
on  three  separate  accounts:  /)  the  mechanical  be- 
havior of  the  lungs;  2)  the  efficiency  of  gas  exchange; 
and  j)  the  sustained  return  of  pulmonary  venous 
blood  to  the  left  heart.  In  large  part,  the  volume  of 
blood  contained  in  the  lungs  at  any  instant  is  de- 
termined passively  by  the  balance  between  pulmonary 
inflow,  i.e.,  between  the  output  of  the  two  ventricles; 
it  is  also  influenced  considerably  by  the  ventilation. 
Whether  an  element  of  self-control  is  also  provided  by 
pulmonary  vasomotor  activity,  particularly  on  the 
part  of  the  veins  (305)  or  of  hypothetical  venous 
sinuses  (381),  is  uncertain. 


fig.  23.  Difference  between  luminal  pressures  (referred  to 
atmosphere)  and  transmural  pressures  (referred  to  perivascu- 
lar pressure)  along  the  length  of  the  pulmonary  vascular  tree. 
The  shaded  area  represents  the  luminal  pressure.  In  the  capil- 
laries (PC),  which  are  exposed  to  alveolar  pressure,  the  luminal 
and  transmural  pressures  are  virtually  identical.  On  the  other 
hand,  in  the  pulmonary  artery  (PA)  and  vein  (PV),  the  trans- 
mural pressure  exceeds  the  luminal  pressure  by  the  pleural 
(perivascular)  pressure. 

Measurement  of  Pulmonary  Blood  Volume 

For  convenience,  the  methods  for  measuring  pul- 
monary blood  volume  may  be  sorted  according  to 
whether  they  are  designed  to  measure  the  pulmonary 
blood  volume  or  a  change  in  pulmonary  blood 
volume. 

In  the  isolated  lung  or  in  thoracotomized  animals, 
the  pulmonary  blood  volume  is  available  for  direct 
mensuration  (293,  384);  but,  because  of  the  surgical 
manipulations  and  the  drastic  experimental  condi- 
tions, the  measured  volume  may  differ  considerably 


DYNAMICS    OF    PULMONARY    CIRCULATION 


l6gi 


from  the  volume  which  prevails  under  more  natural 
conditions.  In  intact  animal  or  man,  indicator-dilu- 
tion techniques  have  been  commonly  used  to  approxi- 
mate the  size  of  the  pulmonary  blood  volume. 

stewart-hamilton:  indicator  dilution.  This  is  an 
indicator-dilution  method  (fig.  24)  which  entails  the 
introduction  of  a  test  substance  into  the  venous  side 
of  the  circulation  and  the  registration,  from  a  systemic 
artery,  of  its  changing  concentration  with  time  (18, 
hi,  184).  This  application  was  first  proposed  by- 
Stewart  (184),  who  held  that  the  product  of  the  flow 
and  the  appearance  time  of  the  injected  substance  is 
a  measure  of  the  capacity  of  the  bed  through  which 
the  flow  takes  place;  this  idea  was  shared  by  Blumgart 
and  Weiss  (184).  Hamilton  and  collaborators  (186) 
showed  that  the  mean  circulation  time  rather  than 
the  shortest  circulation  time  should  be  used  to  calcu- 
late the  volume  of  blood  in  the  vascular  bed  between 
the  point  of  injection  and  the  point  of  sampling.  In  a 
simple  model,  in  which  the  entire  stream  passes  the 
points  of  injection  and  of  sampling,  the  idea  that  the 
product  of  the  flow  and  the  mean  circulation  time 
measures  the  intervening  volume  is  not  only  ac- 
ceptable intuitively,  but  has  also  been  checked  in 
models  (186)  and  proved  mathematically  (444). 
Since  the  mean  circulation  time  is  approximately  the 
time  ordinate  corresponding  to  the  center  of  gravity 
of  the  time-concentration  curve  (fig.  25A),  the  substi- 
tution of  the  median  for  the  mean  circulation  time 
may  introduce  considerable  error  into  the  calcula- 
tion (184). 

The  injection  into  the  venous  circulation  coupled 


with  sampling  from  a  peripheral  artery  defines  only  a 
"central  blood  volume";  its  limits  are  wide  and  vague: 
it  includes  not  merely  the  blood  volume  between  the 
needles,  but  also  the  volume  of  blood  contained  in  the 
other  branches  of  the  venous  and  arterial  trees  having 
equivalent  circulation  times.  It  is  a  virtual  volume 
which  corresponds  to  an  anatomical  volume  only 
under  ideal  conditions:  if  mixing  of  blood  and  tracer 
is  complete  and  uniform,  if  the  system  contains  neither 
stagnant  nor  sequestered  blood  and  if  there  are  no 
preferential  channels  which  are  operating  to  short- 
circuit  the  system.  The  use  of  mathematics  to  con- 
struct a  continuous  infusion  curve  from  the  single  in- 
jection curve  involves  identical  premises  and  does  not 
make  the  measurement  of  the  pulmonary  blood  vol- 
ume any  more  definitive.  The  continuous  infusion  of 
a  tracer  substance  into  the  central  circulation  does 
provide  an  alternate  approach  for  measuring  the 
pulmonary  blood  flow  and  central  blood  volume 
(fig.  25B)  (444);  however,  as  in  the  case  of  the  single 
injection,  the  results  promise  to  be  less  precise  for 
volume  than  for  flow  (444). 

When  the  test  substance  is  injected  into  a  peripheral 
vein  (instead  of  into  the  pulmonary  artery),  the  cen- 
tral blood  volume  includes  the  whole  cardiac  blood 
volume.  Many  different  radiological  techniques  have 
been  applied  to  the  measurement  of  the  cardiac 
blood  volume  in  dog  and  man  (151).  Despite  theoreti- 
cal reservations  of  various  kinds — such  as  the  diffi- 
culty in  separating  the  contribution  of  cardiac  cavities 
and  walls  to  the  radiographic  picture  of  the  heart — 
the  radiographic  cardiac  volume  in  dogs  was  found  to 
correspond,  within  10  per  cent,  to  the  directly  meas- 


Jt 


.6.4  mg/Lit 


< 
tr 

t- 


o 

z 
o 
o 


20 


I  0     - 


INJECT  E  D 
TIME 
Av      CONC 
6  0 


14.11 
I  5    sec 


m  g 


FLOW    = 


CB  V 


I  1.70    mg/Lit 
14.11 


11.70     x 
MCT 


I  5 
1 1  sec 


=  4.82 
Lit/min 


4.82 
60 


x    I  I      =     880     ml 


SECONDS 


fig.  24.  Concentration-time  curve  inscribed  by  densitometer  through  which  peripheral  arterial 
blood  was  drawn  at  a  constant  rate  following  injection  of  T-1824  into  the  pulmonary  artery  of  a 
normal  human  subject.  At  t  =  o,  the  indicator  was  injected.  The  calibration  marks  at  the  top  of  the 
record  indicate  that  a  deflection  of  1  cm  is  equal  to  a  concentration  of  6.4  mg  of  dye  per  liter  of 
blood.  From  such  a  record,  the  pulmonary  blood  flow,  the  mean  circulation  time  (MCT),  and  the 
central  blood  volume  can  be  calculated  as  shown. 


[692 


HANDBOOK    OF    PHYSIOLOGY     ">    CIRCULATION    II 


40r 


10        15 
Seconds 

fig.  25.  Schematic  representations  of  concentration-time  curves  following  injection  of  indicator 
into  central  circulation.  A:  single  injection  curve.  Recirculation  of  indicator  occurs  at  arrow.  The 
dashed  lines  illustrate  likely  extremes  of  extrapolation  of  the  downlimb  to  zero  during  the  first  cir- 
culation of  indicator.  The  shaded  arrow  represents  the  relative  difference  between  the  two  esti- 
mates of  blood  flow  based  on  the  two  extrapolations.  The  vertical  lines  fi  and  £2  represent  the  two 
estimates  of  mean  transit  time  based  on  the  two  extrapolations.  If  recirculation  occurs  earlier,  so  that 
the  shape  of  the  downlimb  is  uncertain,  considerable  errors  may  be  introduced  by  the  extrapolation. 
B:  constant  injection  curve.  The  times  at  which  the  indicator  just  appears  and  recirculates  are  identi- 
cal with  those  in  panel  A.  The  dashed  lines  represent  likely  extrapolations  to  a  plateau  concentra- 
tion. The  shaded  area  between  Pmax-i  and  Pmax-s  represents  the  difference  between  estimates  of 
area  above  the  extrapolated  buildup  concentration  curves.  The  problem  of  recognizing  the  point  of 
recirculation  is  the  same  as  for  the  single  injection  curve  of  panel  A.  [After  Zierler  (444).] 


10         15 
Seconds 


ured  volumes  (184);  moreover,  following  epinephrine 
overdosage,  the  radiographic  cardiac  volume  was 
found  to  constitute  an  unusually  large  fraction  of  the 
central  blood  volume  (151,  184).  By  substituting 
cineradiography  of  the  opacified  intracardiac  volumes 
for  conventional  radiography,  the  precision  of  the 
radiographic  approach  has  been  greatly  enhanced 
(73,  170,  367);  this  modification  promises  a  reliable 
measure  of  the  volumes  of  the  individual  chambers  in 
normal  man  and  dog.  It  remains  to  be  seen  if  precise 
measurements  of  this  type  can  also  be  made  in  pa- 
tients with  pulmonary  congestion  and  cardiomegaly. 
Recently,  the  central  blood  volume  has  been  ex- 
perimentally narrowed  to  the  pulmonary  blood  vol- 
ume by  the  use  of  two  catheters — one  in  the 
pulmonary  artery  and  the  other  in  the  left  atrium. 
Once  placed,  the  catheters  have  been  put  to  different 
uses:  a)  for  injecting  a  tracer  substance  into  the  pul- 
monary artery  and  for  sampling  from  the  left  atrium 
(246,  293),  and  b)  for  injecting  tracer  substances  into 
both    the    pulmonary    artery    and    left    atrium,    and 


sampling  from  the  brachial  artery,  thereby  determin- 
ing the  mean  pulmonary  arterial-left  atrial  transit 
time  (106,  278).  Although  the  second  of  these  ap- 
proaches was  designed  to  circumvent  the  theoretical 
possibility  of  incomplete  mixing  in  the  left  atrium,  the 
values  for  the  pulmonary  blood  volume  by  both  ap- 
proaches have  been  not  only  similar,  but  also  sur- 
prisingly low. 

newman:  exponential  DOvvNSLOPE.  The  time-con- 
centration  curve  of  injected  substance  typically  has  a 
descending  exponential  limb.  According  to  Newman 
(304),  the  slope  of  this  line  measures  the  volume  of  a 
model  through  which  water  is  perfused  if  there  is 
instantaneous  and  complete  mixing  of  injected  dye 
and  perfusate.  If  several  chambers  are  perfused  in 
series,  the  slope  indicates  the  volume  of  the  largest. 
Assuming  that  the  lung  volume  is  the  largest  of  those 
concerned  in  the  circulation,  Newman  used  the  slope 
to  obtain  a  measure  of  the  pulmonary  blood  volume. 
In  1932,  Hamilton  et  al.  (186)  had  evolved  an  equa- 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1693 


tion  similar  to  that  of  Newman,  but  rejected  the  idea 
that  the  volume  term  in  that  equation  could  stand 
for  a  significant  physiological  volume  because,  in  the 
physiological  circuit,  there  is  neither  instantaneous 
nor  complete  mixing  of  dye  with  all  of  the  blood  in 
either  heart  or  lungs.  It  now  seems  that  the  1932  view 
is  correct  (1 1 1,  283,  417). 

bradley:  equilibration  curves.  The  method  origi- 
nally devised  by  Bradley  et  al.  for  the  estimation  of 
splanchnic  blood  volume  (41)  has  been  applied  by 
others  to  the  estimation  of  the  pulmonary  blood  vol- 
ume (326).  The  method  entails  the  determination  of 
the  amount  of  tracer  substance  contained  in  the  sys- 
tem at  equilibrium  (cardiac  output  X  arteriovenous 
difference  X  equilibration  time)  divided  by  the 
equilibration  concentration  of  tracer.  From  the  point 
of  view  of  application  to  the  lungs,  the  most  vul- 
nerable part  of  the  equation  is  the  arteriovenous 
difference.  Experiments  with  models  have  shown  that, 
in  contrast  to  the  splanchnic  circulation,  the  pul- 
monary circulation  is  not  suited  for  this  type  of 
equilibration  method  (46).  Consequently,  it  is  difficult 
to  place  much  confidence  in  the  measurements  in  man 
which  find  that  all  three  methods — the  Stewart- 
Hamilton,  Bradley,  and  Newman — provide  com- 
parable values  for  the  pulmonary  blood  volume 
(326),  particularly  when  there  are  other  theoretical 
and  practical  reasons  to  expect  discrepancies  ( 1 1  1 ) . 

Changes  in  Pulmonary  Blood  Volume 

Many  different  approaches  have  been  used  to  detect 
a  change  in  pulmonary  blood  volume.  They  include: 
a)  lung  volumes,  b)  mechanics  of  breathing,  c)  radio- 
active tracers,  d)  teeter  board. 

lung  volumes.  In  normal  subjects  the  vital  capacity 
is  less  in  the  supine  than  in  the  upright  position.  Al- 
though part  of  this  decrease  may  reflect  a  change  in 
the  position  and  tone  of  the  diaphragm  (296,  388), 
an  increase  in  the  pulmonary  blood  volume  also  seems 
to  be  involved  since  measures  which  interfere  with 
systemic  venous  return  to  the  lungs  minimize,  or 
prevent,  the  decrease  in  vital  capacity  (188). 
Clinically,  a  low  vital  capacity  is  found  in  pulmonary 
congestion  (406).  However,  in  such  patients,  par- 
ticularly if  pulmonary  venous  hypertension  has  been 
prolonged  and  severe,  the  lung  volumes  may  be  more 
encroached  upon  by  pulmonary  edema  and  fibrosis 
than  by  an  expanded  pulmonary  blood  volume  (238, 
378). 


mechanics  of  breathing.  Pathologists  have  long  been 
aware  that  the  chronically  congested  lung  is  a  stiff 
lung  (415).  In  1934,  Christie  and  Meakins  showed  by 
measurements  of  pleural  pressure  in  vivo  that  the 
chronically  congested  lung  requires  a  greater  dis- 
tending force  than  the  normal  lung  (287).  Since  then, 
more  elaborate  ways  of  measuring  and  expressing 
pulmonary  distensibility,  such  as  "compliance" 
(change  in  lung  volume  per  unit  change  in  pleural 
pressure)  have  come  into  general  use  for  the  study  of 
both  acute  and  chronic  pulmonary  congestion;  for 
the  sake  of  safety  and  expediency,  and  at  some  sacrifice 
of  accuracy,  esophageal  pressures  have  been  substi- 
tuted for  pleural  pressures  (fig.  26)  (287). 

The  effects  of  acute  pulmonary  engorgement  on 
pulmonary  distensibility  have  been  examined  in  ani- 
mals (35,  146)  and  in  man  (33,  406).  Such  studies 
have  shown  that  pulmonary  venous  hypertension  has 
a  considerably  greater  effect  in  reducing  pulmonary 
compliance  than  does  either  pulmonary  arterial 
hypertension  or  an  increase  in  pulmonary  blood  flow 
(35);  moreover,  a  decrease  in  vital  capacity  parallels 
a  decrease  in  pulmonary  compliance  (406).  But  these 
studies  have  also  clarified  some  of  the  uncertainties 
which  attend  the  use  of  a  change  in  compliance  as  a 


TIDAL 

VOLUME 

ml 


ESOPHAGEAL  PRESSURE 
cm  H20 


200 


60 


25 


20 


03 


COMPLIANCE 

2U 

cm   H20 

WORK  AGAINST 

NON -ELASTIC 

RESISTANCE 

(%) 

WORK    OF 

BREATHING 

Kq  m 

lit    VE 

fig.  26.  Comparison  of  the  pulmonary  pressure-volume  dia- 
gram of  a  normal  subject  with  that  of  a  patient  with  severe 
pulmonary  congestion  due  to  mitral  stenosis.  In  the  congested 
lung,  the  compliance  (AV/AP)  is  approximately  a  third  of 
normal  and  the  resistance  to  air  flow  is  normal.  If  pulmonary 
congestion  is  accompanied  by  edema  of  the  airways  ("cardiac 
asthma"),  both  the  increased  resistance  to  air  flow  and  the 
stiffer  lungs  contribute  to  the  inordinate  work  of  breathing. 
[After  Turino  &   Fishman   (406).] 


1 694 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


qualitative  measure  of  the  state  of  the  pulmonary 
blood  volume:  an  increase  in  pulmonary  interstitial 
fluid  during  acute  pulmonary  venous  hypertension 
may  be  indistinguishable  from  associated  increase  in 
pulmonary  blood  volume  (378);  the  discrepancies 
between  esophageal  pressure  and  pleural  pressure 
are  exaggerated  in  the  supine  position  since  medi- 
astinal contents  compress  the  esophagus  to  yield 
artificially  high  values  for  pleural  pressures;  changes 
in  the  lung  volume  may,  per  se,  affect  apparent  pul- 
monary distensibility  (287). 

Despite  the  limitations  of  methodology  and  the  un- 
certain distinction  between  an  expanded  pulmonary 
blood  volume  on  the  one  hand  and  its  consequences 
on  the  other,  pulmonary  mechanics  in  pulmonary  con- 
gestion continues  to  attract  attention  on  several  physio- 
logical accounts.  For  example,  mechanical  work  and 
energy  cost  of  moving  congested  lungs  has  proved  to 
be  abnormally  high;  moreover,  in  some  obscure  way, 
stiff  lungs  seem  to  set  the  characteristic  breathing  pat- 
tern (rapid  frequency,  small  tidal  volume)  of  pulmo- 
nary congestion   (177,   406). 

radioactive  tracers.  Change  in  the  radioactivity 
of  a  portion  of  the  lung  field  after  the  intravenous 
administration  of  a  radioactive  tracer  has  been  used 
as  a  measure  of  the  change  in  pulmonary  blood  vol- 
ume under  various  experimental  conditions  (271, 
425).  The  validity  of  this  approach  rests  heavily  on 
the  assumption  that  the  external  detector  continues 
to   survey  an   unchanged   geometry   throughout   the 


control  and  test  periods.  It  is  difficult  to  prove  that 
this  assumption  is  fulfilled  in  experiments  which  in- 
volve either  respiratory  maneuvers  or  changes  in  body 
position  (425). 

miscellaneous.  Some  experiments  require  only  the 
recognition  of  a  change  in  thoracic  (instead  of  pul- 
monary) blood  volume.  For  such  experiments,  the 
critically  balanced  teeter  board  has  served  as  a  useful 
device  to  detect  a  shift  in  the  center  of  gravity  of  the 
body  as  blood  is  displaced  from  one  end  of  the  body 
to  the  other  (fig.  27)  (86,  154,  395).  Also,  the  "cardio- 
pneumogram''  has  provided  an  approach  to  the 
changes  in  thoracic  blood  volume  during  each  cardiac 
cycle  (185). 

Normal  Values  for  Pulmonary  Blood  J'olume 

It  is  meaningless  to  use  the  central  blood  volume — 
with  its  vague  boundaries  and  its  potential  for  internal 
rearrangement — as  a  measure  of  the  pulmonary  blood 
volume  as  long  as  the  test  substance  is  injected  into  a 
peripheral  vein  (184,  307).  The  first  step  to  narrow 
the  boundaries  of  the  central  blood  volume  was  the 
pulmonary  arterial  injection  of  the  test  substance 
(coupled  with  peripheral  arterial  sampling) ;  under 
these  conditions,  the  central  blood  volume  approxi- 
mates 20  to  25  per  cent  of  the  total  circulating  blood 
volume  (224,  249,  250).  The  second  step  was  to  couple 
the  pulmonary  arterial  injection  either  with  sampling 
from  the  left  atrium  or  with  the  injection  of  a  second 


Fig.  27.  The  teeter  board  for  detect- 
ing shifts  in  regional  blood  volumes. 
The  records  show  that  during  acute  hy- 
poxia (.4)  the  position  of  the  center  of 
gravity  of  the  body  remains  unchanged; 
on  the  other  hand,  during  the  infusion 
of  noradrenaline  (B),  the  center  of 
gravity  shifts  cephalad.  CAL  =  cali- 
bration by  placing  a  200-gram  weight  at 
the  angle  of  Louis.  [After  Fritts  el  al. 
(■54)-] 


DASH-POT 
DAMPER 


COUNTER- 
WEIGHT 


SPRING 


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KYMOGRAPH 


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vfy  iM^0mmmmmimiiiimmmmmmmn 


START 
NOR-ADRENALINE 


t  t 

5  MINUTES  STOP 

NOR-ADRENALINE 


DYNAMICS    OF    PULMONARY    CIRCULATION 


l69c 


tracer  into  the  left  atrium.  By  these  techniques,  the 
pulmonary  blood  volume  is  of  the  order  of  10  per 
cent  of  the  total  circulating  blood  volume  (106,  246, 

293)- 

It  is  surprising  how  closely  the  latter  indicator-dilu- 
tion value  of  10  per  cent  in  intact  man  corresponds  to 
the  more  direct  measurements  in  animals,  i.e.,  dog, 
rabbit,  and  rat  (293).  The  indicator-dilution  value  of 
10  per  cent  also  coincides  with  estimates  based  on 
pulmonary  vascular  dimensions  in  the  dog  (169). 

Variations  in  Pulmonary  Blood  Volume 

The  pulmonary  blood  volume  increases  under  a 
heterogenous  group  of  conditions  (fig.  28) :  a)  an  in- 
crease in  pulmonary  blood  flow  (224,  250);  b)  infla- 
tion of  an  antigravity  suit  (33);  c)  negative  (pleural) 
pressure  breathing  (397) ;  d)  the  assumption  of  the 
supine  position  (381);  e)  systemic  vasoconstriction 
from  a  variety  of  causes  (64,  154,  186,  372);  /)  im- 
mersion in  water  (188);  g)  clamping  of  the  pul- 
monary veins  (114);  and  h)  left  ventricular  failure 
and  mitral  stenosis  (238). 

Conversely,  a  decrease  in  pulmonary  blood  volume 
occurs  during  venesection  and  reduced  cardiac  output 
(184),  positive  pressure  breathing  and  the  Valsalva 
maneuver  (44),  systemic  vasodilatation  from  warming 
(369,  381)  and  the  assumption  of  the  upright  posture 
(247,381). 

Partition  of  Pulmonary  Blood  I  'olume 

One  particularly  hazy  aspect  of  the  pulmonary  cir- 
culation   is    the    pattern    in    which    the    pulmonary 


arteries,  capillaries,  and  veins  share  the  pulmonary 
blood  volume  under  natural  conditions,  and  the  wax- 
in  which  this  pattern  is  modified  either  by  physiologi- 
cal stimuli  or  by  disease.  A  few  beginnings  have  been 
made:  anatomical  measurements  in  the  dog  suggest 
that  the  capacity  of  the  pre-  and  postcapillary  pul- 
monary vascular  segments  is  approximately  the  same 
(169);  observations  on  the  isolated  lung,  while  failing 
to  define  precise  anatomical  boundaries,  have  suc- 
ceeded in  disclosing  how  the  pulmonary  blood  volume 
may  be  reapportioned  in  response  to  mechanical  in- 
fluences (124,  315,  317,  324)  and  to  special  stimuli 
(116,  305).  However,  there  is  no  obvious  way  to  ap- 
ply these  experimental  observations  to  the  arrange- 
ment of  the  pulmonary  blood  volume  in  life. 


HEMODYNAMIC  INTERRELATIONS 

Distensibility  and  Resistance 

In  previous  sections,  pulmonary  blood  flow,  vol- 
ume and  pressures  were  considered  separately.  The 
analysis  of  their  interplay  is  a  much  more  complicated 
matter.  Generally  speaking,  the  aim  of  such  an 
analysis  is  to  relate  the  static  and  dynamic  properties 
of  the  pulmonary  vascular  tree  to  its  architecture  and 
to  the  structure  of  its  walls.  Until  recently,  investiga- 
tors were  preoccupied  with  the  model  of  the  pul- 
monary circulation  which  pictured  it  as  the 
hemodynamic  analog  of  an  electrical  d-c  circuit  and 
which  viewed  the  pulmonary  blood  flow  as  though  it 
were  continuous  and  steady  (169);  for  testing  this  con- 
ceptual model,  the  isolated  lung  seemed  ideal  on  the 


mm 
Hg 
2 


UP 
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LEG      RAISING 
mmHg  MI  H 

DOWN  80_ 


'■^ih^^h^Mm^^^ 


SUPINE       EXERCISE 
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UP  DOWN 

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fig.  28.  Effects  of  leg  raising  and  supine  exercise  on  pulmonary  arterial  blood  pressure.  Leg  raising. 
In  the  normal  subject  (upper  left),  leg  raising  is  without  appreciable  effect  on  the  pulmonary  arterial 
pressure ;  in  the  patient  with  tight  mitral  stenosis  (upper  right),  leg  raising  elicits  a  considerable  in- 
crease in  pressure.  Supine  exercise.  In  normal  subject  (lower  left),  exercise  increases  pulmonary  arterial 
pressure  by  a  few  mm  Hg;  in  the  patient  with  tight  mitral  stenosis  (lower  right),  the  increase  in  pressure 
is  much  more  striking.  [After  Turino  &  Fishman  (406).] 


1696 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


fig.  29.  Continuous  records  of  pulmonary  arterial  pressure 
(P)  and  flow  (Q)  from  a  closed-chest,  unanesthetized  dog. 
Blood  pressure  was  recorded  through  a  polyvinyl  tube  (encased 
in  nylon)  inserted  through  the  wall  of  the  main  pulmonary 
artery  about  1  cm  distal  to  pulmonic  valve.  Blood  flow  was  re- 
corded by  an  electromagnetic  flow  meter  (modified  Kolin 
type)  placed  proximal  to  the  bifurcation  of  the  main  pulmo- 
nary artery.  Tubing  and  wires  placed  surgically  and  led  to  out- 
side between  scapulae.  For  calibration  of  flow  meter,  snares 
around  right  and  left  pulmonary  arteries  were  tightened  to 
arrest  pulmonary  arterial  flow.  (Courtesy  of  L.  Fisher  and 
D.  E.  Gregg.) 

assumption  that  it  simulated  the  geometry  and  dis- 
tensibility  of  the  pulmonary  circulation  in  vivo. 
Within  the  last  few  years,  investigators  have  begun  to 
take  a  more  realistic  view  of  the  pulmonary  circula- 
tion, recognizing  that  hemodynamic  events  within  it 
vary  from  instant  to  instant  and  that  phasic  differ- 
ences between  pressure  and  flow  (fig.  29)  are 
important;  in  order  to  treat  these  phasic  events,  they 
have  resorted  to  a  model  based  on  electrical  a-c 
theory  (71,  177,  438).  However,  for  the  moment,  this 
approach  is  handicapped  by  the  technical  difficulties 
of  recording  pulsatile  pulmonary  blood  flow,  espe- 
cially in  living  systems  (153,  237). 

Distensibility  and  Capacity: 
Pressure- 1  olume  Relationships 

Because  of  the  manner  in  which  the  pulmonary 
circulation  is  incorporated  into  the  lung,  the  term 
"pulmonary  vascular  distensibility"  is  a  composite 
one :  it  connotes  not  only  the  elastic  properties  of  the 
vascular  walls  but  also  the  tone  of  their  smooth 
muscle,  the  perivascular  air  pressures,  the  effects  of 
hidden  forces  such  as  alveolar  surface  tension  (78, 
312),  the  presence  of  excessive  interstitial  fluid  (239), 
and  the  mechanical  distortions  of  adjacent  pulmonary 


tissues  (146).  As  in  the  systemic  circulation,  the  dis- 
tensibility characteristics  are  customarily  expressed 
as  the  change  in  vascular  volume  per  unit  change  in 
transmural  pressure.  However,  in  contrast  to  the 
systemic  circulation,  the  small  precapillary  vessels 
are  thin-walled  and  easily  distensible,  thereby  con- 
tributing to  the  pressure-volume  characteristics  of  the 
pulmonary  arterial  tree  (350).  This  participation  of 
the  pulmonary  '"resistance"  vessels  in  the  "capaci- 
tance" function  of  the  pulmonary  circulation  is  of 
hemodynamic  significance:  for  example,  without 
pulmonary  arteriolar  sphincters,  a  larger  fraction  of 
the  right  ventricular  stroke  volume  is  apt  to  escape 
from  the  pulmonary  arterial  tree  during  and  just 
after  each  systole  than  from  the  systemic  arterial  tree 
(240);  also,  during  bradycardia  the  pulmonary  ar- 
terial pressure  may  fall  to  the  level  of  pulmonary 
venous  pressures  (187). 

The  distensibility  characteristics  of  the  pulmonary 
circulation,  and  of  its  individual  segments,  have  been 
determined  under  a  wide  variety  of  experimental 
conditions,  using  greatly  different  types  of  prepara- 
tions. These  studies  have  led  to  certain  generaliza- 
tions: a)  the  pressure-volume  characteristics  of  the 
entire  vascular  tree  (fig.  30)  and  of  the  large  pul- 
monary  vessels   resemble   those   of  a   large   systemic 


vein  (148,  211, 


290);  b)  as  in  other  distensible 


structures,  the  blood  pressure  at  any  volume  is  higher 
when  the  system  is  being  filled  than  when  it  is  being 
emptied  ("hysteresis,"  "delayed  compliance,"  "stress- 


50-- 


fig.  30.  Pressure-volume  relationship  of  the  pulmonary 
vascular  bed  in  the  dog.  To  construct  this  curve,  blood  was 
withdrawn  at  10-sec  intervals  after  initially  elevating  pressure 
in  the  system  to  approximately  60  mm  Hg.  [After  Sarnoff  & 
Berglund  (371 ).] 


DYNAMICS    OF    PULMONARY    CIRCULATION  1 697 


relaxation")  (318,  337,  371);  c)  the  pulmonary  venous- 
left  atrial  segment  is  less  distensible  than  the  systemic 
venous-right  atrial  segment  (87,  272,  309);  d)  the 
successive  segments  of  the  pulmonary  vascular  tree 
differ  considerably  in  distensibility  [the  veins  and 
arteries  are  more  distensible  than  the  capillaries  ( 1 24, 
318)];  and  e)  although  the  aorta  and  pulmonary 
artery  are  of  approximately  the  same  caliber  in  life, 
the  range  of  maximum  distensibility  for  the  pul- 
monary artery  (10  to  40  mm  Hg)  is  much  lower  than 
for  the  aorta  (182).  Unfortunately,  measurements  of 
pulmonary  vascular  distensibility  in  intact  animal  or 
man  have  not  yet  become  practical  or  reliable  (71, 

293)- 

These  generalizations  about  pulmonary  vascular 
distensibility  help  to  explain  some  physiological 
features  of  the  pulmonary  circulation.  For  example, 
the  small  pulse  pressure  in  the  pulmonary  artery 
seems  to  be  a  consequence  of  both  the  marked  distensi- 
bility of  the  pulmonary  arterial  tree,  which  prevents 
a  considerable  rise  in  pressure  as  the  right  ventric- 
ular stroke  volume  is  ejected,  and  the  low  pul- 
monary vascular  resistance,  which  allows  more  blood 
to  escape  from  the  pulmonary  arterial  tree  during 
each  systole  and  causes  the  pressure  to  fall  earlier 
during  systole  (102,  182).  The  greater  distensibility 
of  the  pulmonary  than  the  systemic  arterial  tree  also 
helps  to  account  for  the  slower  velocity  of  the  pulse 
wave  in  the  pulmonary  artery  (250  cm/sec)  than  in 
the  aorta  (300  cm/sec). 

The  unusual  distensibility  of  the  small  pulmonary 
vessels,  i.e.,  of  the  pulmonary  "resistance"  vessels 
affects  their  hemodynamic  behavior.  For  example, 
as  the  pulmonary  blood  volume  is  expanded  (251, 
437),  small  pulmonary  vessels  share  in  this  increase, 
leading  to  an  increase  in  their  transmural  pressures, 
passive  dilatation  of  their  lumens  and  a  decrease  in 
their  resistance  to  blood  flow;  since  the  arterial, 
capillary  and  venous  portions  of  the  small  pulmonary 
vessels  have  different  capacities  and  pressure-volume 
characteristics,  the  increase  in  pulmonary  blood  vol- 
ume will  not  be  equally  apportioned  among  these 
vascular  segments.  Moreover,  the  distensibility  char- 
acteristics and  capacities  are  such  that  at  low  pul- 
monary vascular  volumes  and  pressures,  each  in- 
crement in  blood  volume  will  raise  the  blood  pressure 
less,  and  passively  dilate  the  vessels  more,  than  at 
high  levels.  This  hemodynamic  behavior  is  particu- 
larly relevant  to  those  experiments  in  which  an  under- 
standing of  the  passive  characteristics  of  the 
pulmonary  vascular  tree  and  of  its  segments  is  pre- 
requisite for  interpreting  a  change  in  calculated  pul- 


monary vascular  resistance  in   terms  of  pulmonarv 
vasomotor  activity  (69,  101). 

Resistance:  Pressure-Flow  Relations/u/n 

It  has  been  noted  above  that,  for  the  sake  of  ex- 
pediency, flow  through  the  pulmonary  circulation  is 
conventionally  treated  as  though  it  were  steady.  Ac- 
cordingly, and  by  analogy  with  Ohm's  law,  the  ratio 
of  the  drop  in  mean  pressure  across  the  pulmonarv 
circulation  (AP)  to  the  mean  blood  flow  (Q)  is  used 
as  a  measure  of  pulmonary  vascular  resistance.  This 
idea  of  resistance  is  unambiguous  when  applied  to 
rigid  tubes  perfused  by  a  homogeneous  fluid  flowing 
in  a  laminar  stream:  under  these  special  conditions, 
the  plot  of  AP  against  Q,  is  linear  and  passes  through 
the  origin,  i.e.,  it  is  predictable  and  interpretable  in 
physical  terms.  Complexities  are  introduced  when 
these  concepts  are  extended  to  the  pulmonary  (as 
well  as  to  the  systemic)  circulation:  the  vascular  bed 
is  a  nonlinear,  visco-elastic,  frequency-dependent 
system  perfused  by  a  complicated  non-Xewtonian 
fluid;  moreover,  the  flow  is  pulsatile  so  that  inertial 
factors,  reflected  waves,  pulse  wave  velocity,  and  in- 
terconversions  of  energy  become  relevant  considera- 
tions (156,  277).  In  such  a  system,  resistance  varies 
with  pressure  and  flow;  plots  of  AP  against  Q,  are  not 
linear  and  do  not  pass  through  the  origin  (61,  169, 
175).  And,  as  the  result  of  the  many  different  active 
and  passive  influences  which  may  affect  the  relation- 
ship between  AP  and  Q,  the  term  "resistance"  is 
bereft  of  its  original  physical  meaning:  instead  of 
representing  a  fixed  attribute  of  blood  vessels,  it  has 
assumed  physiological  meaning  as  a  product  of  a  set 
of  circumstances. 

table  i.  Representative  Values  for  a  Normal  Human 
Subject  in  the  Basal  State 

Pulmonary  blood  flow  6.0     liters/min 

3.1      liters/min/m2  BSA 


Pulmonary  blood  pressures 

s/d.m 

Right  atrium 

3/2. 2 

mm  Hg 

Right  ventricle 

20/0 

mm  Hg 

Pulmonary  artery 

20/9,15 

mm  Hg 

Pulmonary  wedge 

6 

mm  Hg 

Left  atrium 

7/3.5 

mm  Hg 

Pulmonary  vascular 

O.I* 

R  units 

resistance 

*  Calculated  from  the  data  in  this  table:  R  =    (15  —  5)/ 
(6000/60)    =    0.1    R   units.  t  R   units   express   calculated 

resistance  as  mm  Hg/(ml/sec);  to  convert  to  C.G.S.  units 
(dynes  sec  cm-5),  the  value  in  R  units  is  multiplied  by  1328. 


i6g8 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Meaning  of  Pulmonary  Vascular  Resistance 

Generally  speaking,  the  pulmonary  circulation — 
which  receives  the  same  blood  flow  as  the  systemic 
circulation  at  one-fifth  the  blood  pressure — is  a  low- 
resistance  circuit.  In  the  normal  pulmonary  circula- 
tion, the  pulmonary  vascular  resistance  is  ordinarily 
of  the  order  of  o.  i  to  0.3  R  units  (table  1).  But  in 
evaluating  data  for  resistance,  at  least  three  separate 
problems  are  involved:  /)  the  precise  measurement 
of  the  parameters  invoked  in  the  equation  for  re- 
sistance, i.e.,  pressure  drop  across  the  pulmonary 
vascular  bed  divided  by  the  rate  of  pulmonary  blood 
flow;  2)  the  decision  as  to  whether  a  change  in  calcu- 
lated resistance  means  a  change  in  pulmonary  vascu- 
lar caliber;  and  3)  the  interpretation  of  a  change  in 
caliber  in  terms  of  the  mechanism  which  effected  it, 
i.e.,  vasomotor  or  passive  (61,  132). 

With  respect  to  the  values  substituted  in  the  equa- 
tion for  resistance,  it  is  self-evident  that  calculations 
of  pulmonary  vascular  resistance,  which  are  to  be 
meaningful  in  vasomotor  terms  or  even  in  terms  of 
vascular  caliber,  presuppose  accurate  measurements 
of  blood  flow  and  pressures.  Under  certain  stressful 
conditions,  such  as  exercise,  acute  hypoxia,  and  acute 
hypercapnia,  heightened  respiratory  excursions  com- 
plicate the  precise  measurement  of  pressures,  and  pul- 
monary blood  flow  is  easily  miscalculated.  Moreover, 
Permutt  and  co-workers  have  recently  likened  the 
pulmonary  vessels  to  a  series  of  Starling  valves  and 
warned  against  blind  faith  in  the  left  atrial  (or  pul- 
monary venous)  pressure  as  a  measure  of  pulmonary 
outflow  pressure.  In  particular,  they  have  stressed 
that  any  situation  in  which  alveolar  pressure  exceeds 
pulmonary  venous  pressure,  by  creating  a  discon- 
tinuity in  pressure  between  the  capillaries  and  the 
pulmonary  veins,  invalidates  the  use  of  the  pulmonary 
venous  pressure  for  the  calculation  of  total  pulmonary 
vascular  resistance  (315,  354).  Accordingly,  just  as  the 
studies  of  West  et  al.  (427)  suggest  a  spectrum  of 
ventilation-perfusion  relationships  in  the  lung  of  up- 
right man,  the  model  of  Permutt  et  al.  (unpublished 
observations)  suggests  a  distribution  of  the  de- 
terminants of  resistance  to  perfusion,  depending  on 
the  relationships  of  pulmonary  arterial,  left  atrial,  and 
alveolar  pressures  in  the  different  parts  of  the  upright 
lung.  The  precise  relationships  between  the  normal 
imbalances  between  ventilation  and  perfusion  on  the 
one  hand,  and  the  interplay  of  alveolar  and  pul- 
monary vascular  pressure  on  the  other,  remain  to  be 
elucidated. 

With  respect  to  the  second  problem,  i.e.,  the  equa- 


tion of  a  change  in  calculated  pulmonary  vascular 
resistance  to  a  change  in  pulmonary  vascular  calibers, 
there  are  at  least  two  different  types  of  enigmas.  One  is 
the  possibility  that  a  change  in  "anomalous  viscosity," 
which  is  customarily  disregarded,  may  masquerade 
as  a  change  in  caliber  (197,  260,  430);  since  this 
source  of  confusion  is  most  apt  to  become  appreciable 
when  pulmonary  blood  flow  drops  to  exceedingly  low 
levels,  the  practice  of  ignoring  it  seems  reasonable  as 
long  as  levels  of  pulmonary  blood  flow  are  of  the  same 
order  of  magnitude  as  that  ordinarily  encountered 
in  vivo.  The  other  is  the  equivocal  anatomical  mean- 
ing of  a  change  in  caliber,  since  a  change  in  geometry 
may  arise  not  only  from  a  change  in  the  diameters  of 
patent  vessels  but  also  a  change  in  the  number  of 
parallel  paths  which  are  being  perfused  (267). 

Finally,  before  pulmonary  vasomotricity  can  be 
invoked,  it  is  axiomatic  that  all  conceivable  passive 
mechanisms  for  affecting  vascular  calibers  (table  2) 
be  taken  into  full  account.  One  such  passive  mecha- 
nism, particularly  likely  during  artificial  ventilation, 
is  the  mechanical  distortion  of  the  vessels  by  adjacent 
lung  tissue  at  abnormal  lung  volumes  (397)-  Another, 
more  universal,  source  of  confusion  is  an  undetected 
change   in   transmural   pressure   operating   subtly   to 

table  2.  Factors  Conceivably  Involved  in  a  Change 
in  Pulmonary  Vascular  Resistance 

MECHANICAL    (PASSIVE) 

Passive  cardiocirculatory  effects 

1 .  Back  pressure  from  left  atrium  or  pulmonary  veins 

2.  Change  in  pulmonary  blood  flow 

3.  Change  in  pulmonary  blood  volume 

4.  Bronchial  collateral  circulation 

a)  Nutrition  of  nerves,  ganglia,  and  smooth  muscle 

b)  Patency  of  collateral  circulation 
Passive  respiratory  effects 

1 .  Change  in  alveolar  pressures 

a)  Tone  of  bronchial  smooth  muscles 
bl  Secretions  of  bronchial  glands 

c)  Alveolar  surface  tensions 

2.  Change  in  intrathoracic  pressures 

3.  Tone  of  interstitial  smooth  muscle 

4.  Pericapillary  edema 

VASOMOTOR    (ACTIVE) 

Originating  from  without  the  lungs 

1.  Autonomic  nervous  system  (including  systemic  chemo- 

receptors) 

2.  Catecholamines 
Originating  within  the  lungs 

1.  "Critical"  closure  of  small  muscular  vessels 

2.  Intravascular  chemoreceptors 

3.  Chemical  stimuli  (directly  on  vascular  muscle) 

4.  Deranged  vascular  metabolism 

5.  Local  reflexes 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1699 


200- 


150- 


P  vs  R 
Q   vs  R 


R    mmHg/ml/min 
-I 1 1- 


FiG.  31.  Passive  changes  in  pulmonary'  vascular  resistance 
(R)  at  different  pulmonary  arterial  pressures  (P)  and  at  dif- 
ferent pulmonary  blood  flows  (Q).  Pulmonary  venous  pressure 
remains  constant  throughout.  As  How  and  pressure  decrease, 
resistance  increases.  [Based  on  Edwards  (119).] 


which  would  be  expected  to  obtain  were  it  not  for  the 
stimulus  (fig.  32);  and  b)  the  continuous  registration 
of  the  pressure  gradient  across  the  pulmonary  vascu- 
lar tree  and  of  the  systemic  blood  pressure,  before 
and  after  the  injection  of  a  pharmacological  agent 
into  the  pulmonary  artery  (fig.  33). 

The  use  of  pressure-flow  points  to  recognize  vaso- 
motor activity  requires  that  the  passive  pressure  gra- 
dient-flow relations  be  known  or  predictable.  It  is 
difficult  to  compare  the  published  relationships  in  the 
pulmonary  with  those  in  the  systemic  circuit  because 
conventionally  the  data  do  not  cover  the  same  range. 
Pressure-flow  plots  for  systemic  beds  include  zero 
pressure  and  zero  flow,  while  the  conventional  presen- 
tation of  pulmonary  data  start  with  "normal"  pressure 
and  flow  and  plot  the  fractional  excess  of  one  against 
the  fractional  excess  of  the  other.  Qualitatively,  the 


modify  vascular  caliber  and  resistance.  For  example, 
an  increase  in  transmural  pressure — arising  from  an 
increase  in  either  pulmonary-  arterial  or  left  atrial 
pressure — passively  widens  the  vessels  and  decreases 
their  resistance  (fig.  31);  conversely,  a  drop  in  trans- 
mural pressure  increases  vascular  resistance  (36,  69, 
366).  Consequently,  a  change  in  resistance  is  not  a 
reliable  sign  of  pulmonary  vasomotricity  when  trans- 
mural pressures  change.  Indeed,  at  different  levels  of 
transmural  pressure,  calculated  resistance  may  re- 
main unaltered  even  though  pulmonary  vasomotor 
tone  has  altered  considerably  (61).  Considerations 
such  as  these  have  had  two  major  effects  on  experi- 
mental design  and  interpretation:  a)  many  have 
urged  that  the  use  of  ohmic  resistance  be  abandoned 
in  favor  of  more  straightforward  presentation  of 
pressures  and  the  corresponding  flows,  and  b)  others 
have  insisted  on  stringent  experimental  criteria,  such 
as  constant  flow  (fig.  31 ),  left  atrial,  alveolar  and  intra- 
pleural pressures  before  interpreting  a  change  in 
pulmonary  arterial  pressure. 

Practical  Recognition  of  Pulmonary  Vasomotricity 

Dissatisfaction  with  the  use  of  calculated  resistance 
(a  ratio)  to  detect  an  active  change  in  vascular  caliber 
has  encouraged  the  use  of  graphic  representations 
which  relate  blood  flow  to  the  pressure  gradient  that 
effects  it  (70).  For  example,  the  recognition  of  pul- 
monary vasomotor  activity  has  been  attempted  bv: 
a)  the  comparison  of  experimentally  determined  pul- 
monary vascular  pressure-flow  points,  obtained  after 
applying   a   stimulus,   with    the   pressure-flow   curve 


20    -- 


10    -- 


2  I  %  0 . 


0     HI (- 


3.5 


4.5 


5.5 


0.3 


0.  I    -- 


E      / 


12 


•/.  0.  © 


EXERCISE 


21  V.   0. 


3.5 


4.5 
Lit/min 


55 


fig.  32.  Detection  of  a  decrease  in  pulmonary  vascular  cali- 
ber from  pulmonary  arterial  flow-pressure  curves  and  from 
pulmonary  vascular  flow-resistance  curves.  For  these  curves, 
mild  exercise  was  used  to  increase  pulmonary  blood  flow  pas- 
sively and  acute  hypoxia  was  used  as  the  test  stimulus.  A.  Dur- 
ing exercise,  pulmonary  arterial  pressure  increased  as  blood 
flow  increased;  during  acute  hypoxia,  an  equivalent  increase 
in  pressure  occurred  without  an  appreciable  increment  in 
blood  flow.  B.  During  exercise,  calculated  resistance  decreased; 
conversely,  during  acute  hypoxia,  calculated  resistance  in- 
creased even  though  blood  flow  (and  presumably  all 
other  respiratory  and  circulatory  parameters)  remain  un- 
changed. [Based  on  Fishman  et  al.  (132).] 


1700 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


PA 


MM  HG 
20 


LP 


10  SEC 


M$tm 


sxmmmmm 


fig.  33.  Blood  pressures  in  the  pulmonary  artery,  pulmonary  vein,  and  aorta  following  the  in- 
jection of  5  mg  of  acetylcholine  into  the  pulmonary  artery  of  a  human  subject  during  open  thora- 
cotomy. The  time  of  injection  is  indicated  by  the  upright  arrow.  (Unpublished  observations  of  A.  G. 
Jameson  and  A.  P.  Fishman.) 


lower  portion  of  the  pulmonary  arterial  pressure-flow 
curve  in  the  rabbit  (416),  the  dog  (119,  252,  434), 
and  man  (89)  resembles  that  of  systemic  beds:  an 
increase  in  pressure  is  associated  with  a  parabolic 
increase  in  flow;  the  inscribed  curve  is  convex  to  the 
pressure  axis.  The  upper  portion  of  the  pulmonary 
plot  shows  an  opposite  inflection  which  does  not  ap- 
pear in  systemic  beds.  Quantitatively,  the  pulmonary 
and  systemic  arterial  curves  differ  not  only  in  the  level 
of  the  arterial  pressure  but  also  in  the  large  increments 
in  blood  flow  evoked  by  slight  increments  in  pul- 
monary arterial  pressure  (at  constant  left  atrial  pres- 
sure). 

Curves  depicting  the  relationship  between  the 
driving  pressures  and  flow  are  difficult  to  establish 
for  either  intact  dog  or  man  since  it  is  impractical  to 
increase  pulmonary  blood  flow  without  simultaneously 
modifying  the  behavior  of  the  respiration,  the  heart, 
and  the  systemic  circulation.  However,  Lategola  has 
succeeded  in  drawing  a  passive  pressure-flow  curve 
for  the  pulmonary  vascular  tree  of  the  intact  dog, 
using  values  obtained  in  the  course  of  graded  occlusion 
of  the  pulmonary  arterial  tree  by  balloon-tipped 
catheters  (252).  This  curve  appears  as  the  solid  line 
in  figure  34.  The  shape  of  this  curve  is  generally  in- 
terpreted as  showing  that:  a)  as  flow  increases,  re- 
sistance decreases;  and  b)  beyond  a  transition  phase 
(AQ  of  approximately  250  per  cent),  resistance  be- 
comes constant.  Moreover,  the  length  of  the  gently 
sloping  portion  of  the  curve  is  regarded  as  a  measure 
of  the  maximum  calibers,  both  of  the  patent  vessels 
and  of  those  available  to  open  in  parallel;  the  start 
of  the  steeply  ascending  portion  is  thought  to  occur 
when  the  system  begins  to  behave  as  though  it  were 
comprised  of  rigid  tubes  (89,  252).  It  should  be  noted 
that  while  the  general  shape  of  the  pressure-flow  rela- 
tionship seems  beyond  cavil,  the  precise  levels  of  flow 
at  which  the  tubes  appear  to  become  rigid  are  not  as 


300- 

200- 

< 

< 

100- 

0  - 

3o 

A  6   % 

1                  1 

100 


200 


300 


fig.  34.  Relationship  between  pulmonary  blood  flow'  and 
pulmonary  arterial  pressure  in  dog  and  man.  Note  that  the 
origin  represents  normal  or  control  levels  (not  zero  levels)  of 
both  pressure  and  flow.  The  line  is  redrawn  after  Lategola 
(•252)  and  is  based  on  data  obtained  during  graded  occlusion 
of  the  pulmonary  artery  tree  in  the  dog.  The  shaded  area  rep- 
resents corresponding  measurements  in  normal  man  during 
balloon  occlusion  of  one  pulmonary  artery  both  at  rest  and 
during  mild  exercise  (42).  The  individual  points  represent 
observations  on  human  subjects  during  supine  exercise.  Open 
circles:  mild  exercise  (382);  solid  triangles:  graded  exercise  (149); 
open  triangles:  mild  exercise  after  pneumonectomy  (89). 

convincingly  established  (281)  and  the  final  slope 
must  be  considered  in  the  assessment  of  constancy  of 
resistance. 

Superimposed  on  the  pressure-flow  curve  of  the 
dog  is  a  shaded  envelope  which  includes  the  points 
obtained  during  similar  occlusion  of  a  pulmonary 
arterv  in  man  (42);  in  order  to  exceed  the  increments 
in  blood  flow  obtainable  at  rest,  the  human  subjects 
performed  mild  leg  exercise  during  the  occlusion  of 
one  pulmonary  artery.  It  may  be  seen  that  the  en- 
velope of  human  points  closely  follows  the  horizontal 


DYNAMICS    OF    PULMONARY    CIRCULATION 


I  70I 


portion  of  the  dog's  pressure-flow  curve;  un- 
fortunately, in  this  study,  sufficiently  high  flows  to 
define  the  steep  portion  of  the  curve  were  not 
achieved.  However,  the  original  measurements  by 
Cournand  and  co-workers  on  human  subjects  after 
pneumonectomy  (open  triangles)  suggest  that  the  rest 
of  the  human  pressure-flow  curve  may  also  resemble 
that  of  the  dog  (89).  More  observations  in  both  man 
and  dog  at  higher  levels  of  flow  are  obviously  needed; 
unfortunately,  patients  with  congenital  left-to-right 
shunts,  who  may,  from  a  priori  considerations  of  their 
large  pulmonary  blood  flows,  appear  to  be  logical 
candidates  for  such  measurements,  are  usually  found 
to  be  unsuitable  for  pressure-flow  curves  because  of 
complicating  pulmonarv  vascular  disease  and  ana- 
tomical defects  which  preclude  precise  measurements 
of  pulmonary  blood  flow. 

There  are  three  interesting  side  lights  to  the  curve 
illustrated  in  figure  34.  The  first  is  the  difference 
between  this  parabolic  curve  of  the  normal  subject 
and  the  linear  relationship  between  pressure  and 
flow  which  has  been  described  for  patients  with  ab- 
normal vascular  beds  (132);  this  difference  suggests 
that  those  animal  or  isolated-lung  experiments  which 
find  a  linear  relationship  between  pulmonary  arterial 
pressure  and  flow  may  be  dealing  with  abnormal,  or 
overfilled,  lungs  (132).  The  second  is  the  relationship 
between  the  sharp  inflection  of  the  curve  and  the 
maximum  diffusing  capacity;  it  has  yet  to  be  estab- 
lished whether  maximal  dilatation  of  the  pulmonary 
capillary  bed,  i.e.,  the  achievement  of  the  maximum 
diffusing  capacity,  coincides  with  the  abrupt  increase 
in  the  pulmonary  arterial  pressure  (267,  407).  The 
third  deals  with  the  use  of  graded  exercise  to  construct 
the  pressure-flow  curve  in  intact  animal  or  man.  It 
may  be  seen  that  during  mild  to  moderate  exercise  in 
man,  the  pressure-flow  points  overlap  those  obtained 
during  graded  occlusion  in  the  dog;  during  heavier 
exercise,  the  coincidence  of  human  and  animal  points 
is  not  as  exact.  These  discrepancies  raise  the  possi- 
bility that  strenuous  exertion  may  sufficiently  alter 
passive  determinants,  i.e.,  transmural  pressures  and 
left  atrial  pressure,  to  invalidate  the  use  of  such  exer- 
cise for  the  construction  of  a  reference  curve  which  is 
supposed  only  to  depict  the  uncomplicated  conse- 
quence of  increasing  flow  on  pressure  (132).  On  the 
other  hand,  the  use  of  mild  to  moderate  exercise  for 
this  purpose  seems  valid  on  several  scores:  a)  the 
mean  left  atrial  pressure  (104)  and  mean  pleural 
pressures  are  little  affected  by  light  exercise  (132), 
b)  the  pressure-flow  curses  obtained  during  light 
exercise  and   the  passive  curves  obtained   from  iso- 


lated lungs  are  quite  similar  (119,  416),  and  c)  the 
exercise  points  correspond  to  those  obtained  during 
graded  occlusion  of  the  pulmonary  artery  (42,  53, 
101). 

The  second  way  of  identifying  pulmonary  vasocon- 
striction is  particularly  applicable  to  the  use  of 
pharmacological  agents;  it  has  the  advantage  of  circum- 
venting many  of  the  restrictions  outlined  for  steady- 
state  measurements.  It  involves  (fig.  33)  the  single 
injection  of  a  pharmacological  agent  into  the  pul- 
monary circulation  of  the  intact  animal  or  man  and 
the  continuous  registration  of  the  pressure  drop  across 
the  lungs,  the  heart  rate,  and  the  systemic  blood  pres- 
sure during  the  single  pulmonary  circulation,  i.e., 
before  recirculation.  In  this  way,  the  effect  of  the 
agent  appears  as  a  change  in  pulmonary  arterial 
pressure  before  flow  can  change  and  before  the  agent 
can  affect  the  systemic  circulation  (187).  An  alternate 
way  of  accomplishing  the  same  end  for  steady-state 
experiments  is  the  continuous  infusion  of  an  agent, 
e.g.,  acetylcholine  (192,  441)  which  is  destroyed 
within  the  lungs  during  the  course  of  a  single  circula- 
tion. 

Blood  F/ozv  Through  Each  Lung  Separately 

After  application  of  a  unilateral  stimulus,  such  as 
hypoxia  (135),  or  the  unilateral  infusion  of  acetylcho- 
line (89),  the  partition  of  flow  between  the  two  lungs 
is  a  measure  of  the  relative  resistances  of  the  two  sides 
since  the  pressure  gradient  across  the  lungs  is  identical 
on  the  two  sides.  Although  the  idea  of  using  one  lung 
in  this  way,  as  a  control  for  the  other,  is  intuitively- 
attractive,  the  experiments  are  generally  technically 
difficult,  particularly  if  bronchospirometry  is  involved. 

Critical  Closure 

Small  muscular  blood  vessels  of  the  systemic  circu- 
lation are  believed  to  be  inherently  unstable  so  that 
they  are  inclined  to  spring  shut — concentrically  and 
completely — when  their  intraluminal  pressure  drops 
below  a  critical  value.  This  "critical  closing  pressure'1 
has  been  proposed  as  a  measure  of  the  tone  of  vascular 
smooth  muscle,  i.e.,  of  vasomotor  activity:  the  level 
of  the  "critical  closing  pressure"  increases  as  wall 
tension  increases  and  as  the  size  of  the  vessel  decreases. 
Critical  closing  pressure  is  manifested  experimentally 
by  the  arrest  of  flow  despite  an  appreciable  perfusion 
pressure.  By  similar  reasoning,  the  muscular  small 
vessels  spring  open  when  "critical  opening  pressures" 
are  exceeded  (60,  165). 


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CIRCULATION    II 


The  concept  of  critical  opening  and  closure  has 
been  invoked  to  account  for  certain  puzzling  responses 
of  the  pulmonary  circulation  (429).  These  include  the 
exceedingly  gradual  increase  in  pulmonary  arterial 
pressure  during  graded  exercise  (267),  the  relative 
stability  of  the  pulmonary  arterial  blood  pressure 
during  hemorrhage  (160),  and  the  pressure  gradient 
between  the  pulmonary  artery  and  left  atrium  as  the 
left  atrium  falls  below  7  mm  Hg  (36,  366). 

However,  it  is  more  difficult  to  prove  the  operation 
of  critical  opening  and  closure  of  small  vessels  in  the 
pulmonary,  than  in  the  systemic,  circulation.  The 
difficulties  are  of  several  different  kinds:  a)  mechanical 
influences,  e.g.,  local  changes  in  transmural  pressure, 
may  open  and  close  vessels  independent  of  vasomotor 
activity;  b)  the  effects  of  anomalous  viscosity  are  apt 
to  be  more  pronounced  and  to  simulate  changes  in 
vascular  calibers  in  a  low-pressure  circulation;  c)  the 
pulmonary  arterioles  are  thin-walled,  wide-lumened 
and,  in  general,  poorly  constructed  to  spring  shut; 
d)  there  are  generally  alternate,  and  equally  con- 
vincing mechanisms  to  account  for  pulmonary  vascu- 
lar behavior  (272);  and  e)  experiments  specifically 
designed  to  look  for  signs  of  critical  closure  have  not 
always  been  able  to  find  them  (273,  434). 

At  present,  the  experimental  evidence  for  critical 
opening  and  closure  of  small  pulmonary  vessels — a 
vasomotor  phenomenon — is  inconclusive.  If  the  phe- 
nomenon does  occur,  it  seems  to  do  so  when  the 
pressure  gradient  between  the  pulmonary  artery  and 
left  atrium  is  exceedingly  low,  i.e.,  of  the  order  of  1 
to  2  mm  Hg  (42);  moreover,  it  does  not  seem  to  affect 
equally  all  small  vessels  of  comparable  dimensions 
(273,  366).  In  general,  transmural  pressures  are  more 
apt  to  be  involved  in  the  closure  and  opening  of  small 
pulmonary  vessels  than  is  vasomotor  activity.  It 
would  be  of  interest  to  examine  such  closed  pul- 
monary vessels  to  see  if  their  lumens  are  slits  (mechani- 
cal collapse)  or  circles  (concentric  obliteration  by 
vasoconstriction ) . 

Potential  and  Kinetic  Energy 

Mechanical  energy  is  imparted  by  the  right  ven- 
tricle to  the  blood  perfusing  the  pulmonary  circulation 
in  two  forms,  kinetic  and  potential  energy.  At  rest, 
the  kinetic  energy  factor  in  the  pulmonary  circulation 
is  of  the  order  of  10  per  cent  or  less  of  the  total;  on 
the  other  hand,  both  in  normal  subjects  during  exer- 
cise and  in  patients  with  pulmonic  stenosis  or  left- 
to-right  shunts,  the  kinetic  energy  factor  may  increase 
to  over  50  per  cent  of  the  total  (320,  338). 


The  usual  calculation  of  resistance  deals  only  with 
the  drop  in  potential  energy  (pressure)  across  the 
system.  It  does  not  take  into  account  the  fact  that 
as  blood  courses  down  the  pulmonary  vascular  tree, 
part  of  the  kinetic  energy  is  reconverted  to  pressure 
energy  as  the  area  of  the  bed  increases;  a  small  frac- 
tion is  dissipated  as  heat  arising  from  the  friction  of 
blood  flow  (20).  In  experimental  pulmonic  valvular 
insufficiency,  the  unusually  rapid  blood  flow  and 
turbulence  in  the  pulmonary  artery  may  produce  a 
drop  in  pressure  across  the  pulmonic  valve  (123). 

These  considerations  suggest  that  at  rest,  when  the 
kinetic  energy  factor  is  small  and  of  the  same  order  of 
magnitude  in  the  pulmonary  arteries  and  veins,  the 
drop  in  potential  energy  (pressure)  between  the 
pulmonary  arteries  and  veins  provides  a  rough  meas- 
ure of  the  decrease  in  mechanical  energy  across  the 
pulmonary  vascular  bed;  on  the  other  hand,  in 
normal  subjects  during  exercise,  and  in  patients  with 
cardiac  abnormalities  characterized  by  large  stroke 
volumes  and  rapid  rates  of  pulmonary  blood  flow, 
the  pressure  gradient  across  the  pulmonary  circula- 
tion does  not  provide  an  adequate  measure  of  the 
mechanical  energy  delivered  to  the  system. 


PULMONARY    CAPILLARY    CIRCULATION 

Pulmonary  Capillary  Pressure  (Pc) 

Since  a  direct  method  for  measuring  Pc  pressures 
is  not  available,  the  level  of  the  Pc  pressure  is  generally 
estimated  from  the  pulmonary  arterial  diastolic 
pressure  on  the  one  hand,  and  the  mean  left  atrial 
pressure,  on  the  other.  In  the  normal  subject  these 
limits  set  the  mean  Pc  pressure  at  approximately  10 
mm  Hg. 


Rate  of  Pulmonary  Capillary  Blood  Flow  (Q,c) 

In  the  normal  animal  or  man  the  rate  of  pulmonary 
capillary  blood  flow  is  virtually  identical  with  the 
right  ventricular  output;  in  left-to-right  shunts  or 
extensive  collateral  arterial  circulations,  Qc  exceeds 
the  right  ventricular  output.  An  earlier  chapter  has 
analyzed  the  methods  used  to  measure  the  cardiac 
output.  Of  special  interest  to  the  present  section  is 
the  use  of  inert  soluble  gases  not  only  to  measure  the 
rate  of  pulmonary  capillary  blood  flow  in  man  but 
also  to  explore  the  nature  of  the  pulmonary  capillary 
flow.  Throughout  this  section  it  will  be  assumed  that 
physiological   measurements  of  pulmonary  capillary 


DYNAMICS    OF    PULMONARY    CIRCULATION 


'7°3 


flow  need  not  be  measuring  only  the  flow  through 
anatomic  pulmonary  capillaries.  The  physiologic 
measurements  may  also  be  including  the  flow  through 
other  small  pulmonarv  vessels  that  participate  in  the 
uptake  of  the  inert  gas.  However,  this  distinction  be- 
tween the  anatomic  and  the  physiologic  pulmonary 
capillary  is  more  meaningful  with  respect  to  relating 
the  gas-exchanging  characteristics  of  the  small  pul- 
monary vessels  to  their  hemodynamic  behavior  than 
with  respect  to  the  measurement  of  the  cardiac 
output. 

The  principle  underlying  the  use  of  inert  gases  to 
measure  pulmonary  blood  flow  was  enunciated  by 
Bornstein  in  1910  (343).  Unfortunately,  he  chose  an 
insoluble  gas,  i.e.,  nitrogen,  as  the  test  gas.  In  191  2, 
Krogh  &  Lindhard  (240)  substituted  the  soluble 
inert  gas,  nitrous  oxide,  for  nitrogen  and  devised  an 
experimental  protocol,  involving  respiratory  maneu- 
vers, to  obtain  the  values  needed  for  the  equation, 

Qc  =  vw>n,,o-FaN!0 

in  which  Qc         =  pulmonary    capillary    blood    flow 

per  minute 
VN;0    =  volume     of    N>0     absorbed     per 

minute  (BTPS) 
XN2O   =  Ostwald's  coefficient  of  solubility 

of  nitrous  oxide  in  blood  at  37  C 
FaN20    =  mean  fraction  of  N2O  in  alveolar 

gas  during  the  test  (BTPS). 
Since  the  coefficient  of  solubility  (X)  is  constant, 
the  variables  involved  in  the  calculation  of  the  flow 
are  two:  /)  the  volume  of  N20  absorbed  per  minute 
(VN!o);  and  2)  the  mean  alveolar  fraction  of  N2O 
during  the  test  (Fav,,,)-  Subsequently,  it  was  shown 
that  there  are  several  practical  limitations  to  the 
Krogh  and  Lindhard  method;  these  include:  a)  the 
need  to  complete  the  test  before  recirculation  of  the 
test  gas;  in  normal  man  the  pulmonary  recirculation 
time  is  of  the  order  of  1 1  ±  3  sec  (74,  343);  b)  the 
difficulty  in  obtaining  simultaneous  measurements  of 
the  different  variables  involved  in  the  equation;  c) 
the  dilemma  of  distinguishing  the  uptake  of  the  gas 
by  the  pulmonary  tissues  from  the  uptake  by  the 
pulmonary  capillary  blood;  and  d)  the  unsubstanti- 
ated use  of  "correction  factors"  (273,  343).  Despite 
these  reservations,  the  inert-gas  methods  do  provide 
accurate  measurements  of  pulmonary  capillary  blood 
flow  (Qc)  in  resting  subjects  if  proper  precautions 
are  taken.  However,  during  exercise  and  in  chronic 
pulmonary  disease  they  become  less  reliable.  The 
current   consensus    appears    to    be    that    despite    the 


attractive  simplicity  of  these  tests,  their  most  reliable 
use,  even  in  resting  patients  with  normal  lungs,  is  for 
consecutive  measurements  of  Qc. 

Interest  in  the  use  of  soluble,  inert  gases  to  measure 
pulmonary  capillary  blood  flow  lagged  once  the  direct 
Fick  and  Stewart-Hamilton  methods  were  stand- 
ardized into  clinically  useful  techniques.  However,  it 
revived  when  Lee  and  DuBois  substituted  the  body 
plethysmograph  for  the  spirometer  to  measure  the 
rate  of  uptake  of  nitrous  oxide:  this  ingenious  mod- 
ification of  the  Krogh  and  Lindhard  method  promised 
not  only  to  provide  the  usual  measure  of  the  rate  of 
capillary  blood  flow  per  minute  but  also  of  the  rate 
of  flow  at  any  instant  (254).  Unfortunately,  there  are 
practical  difficulties  inherent  in  the  use  of  the  bodv 
plethysmograph  for  the  measurement  of  instantaneous 
flow.  These  limitations  have  led  to  the  development 
of  modified  plethysmography:  techniques  in  man 
(37,  418)  and  a  modified  cardiopneumographic 
method  in  the  dog  (185,  298). 

A  ature  of  Pulmonarv  Capillary  Blood  Flow 

Whether  pulmonary  capillary  flow  is  steady  or 
pulsatile  is  critical  for  the  understanding  of  both 
pulmonary  hemodynamics  and  gas  exchange  (275, 
319).  For  example,  if  the  linear  velocity  of  the  blood 
flow  through  the  alveolar  capillaries  were  to  vary 
during  the  cardiac  cycle  without  compensatory 
changes  in  other  parameters,  e.g.,  diffusing  capacity 
and  capillary  blood  volume,  the  equilibration  between 
alveolar  gas  and  capillary  blood  might  well  be  dis- 
turbed (143). 

A  standard  of  reference  for  assessing  the  nature  of 
the  pulmonary  capillary  blood  flow  is  the  prevalent 
idea  that  blood  flow  through  the  systemic  capillaries 
is  ordinarily  continuous  and  devoid  of  major  oscilla- 
tions from  the  mean.  This  idea  is  consistent  with  two 
features  of  the  systemic  circulation:  a)  the  interplay 
between  arterial  distensibility  and  arteriolar  re- 
sistance, so  that  the  systemic  "windkessel"  maintains 
flow  during  diastole;  and  b)  the  varying  path  lengths 
between  the  root  of  the  aorta  and  the  capillaries.  Of 
these  two  influences,  the  windkessel  effect  is  held  to 
be  the  more  important. 

It  is  much  more  difficult  to  predict  the  nature  of 
the  pulmonary  capillary  flow.  On  the  one  hand, 
marked  surges  of  capillary  flow  following  systole 
(pulsatile  flow)  might  be  expected  to  occur  on  at 
least  two  accounts:  /)  the  relatively  small  capacity  of 
the  pulmonary  arterial  tree  as  compared  to  the 
systemic  arterial  tree;  and  2)  the  relatively  low  re- 


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CIRCULATION    II 


sistance  of  the  small  precapillary  vessels  (102).  On 
the  other  hand  is  the  fact  that,  somewhere  en  route  to 
the  pulmonary  veins,  the  pulmonary  arterial  pressure 
pulse  is  damped  out  so  that  the  pulmonary  venous 
pressure  pulse  ordinarily  reflects  only  left  atrial 
events.  The  problem  then  devolves  into  deciding  the 
degree  to  which  the  flow  pattern  in  the  pulmonary 
capillaries  resembles  the  pattern  of  instant-to-instant 
changes  in  the  pulmonary  vascular  pressure  gradient 
and  of  flow  in  the  pulmonary  artery. 

If  it  is  assumed  that  the  pattern  of  pulmonary 
capillary  blood  flow  is  uniform  throughout  the  lung, 
direct  inspection  of  the  surface  capillaries  of  the  lung 
should  afford  some  insight  into  the  nature  of  the 
pulmonary  capillary  flow.  In  1733,  while  examining 
the  exposed  frog  lung,  Stephen  Hales  observed  that 
not  only  was  blood  "sensibly  accelerated  at  each 
svstole  in  the  finest  capillaries,  but  also  in  their  cor- 
responding capillary  veins,  tho'  not  in  their  larger 
trunks"  (178).  This  was  the  first  declaration  that 
pulmonary  capillary  flow — at  least  in  the  frog — was 
pulsatile.  However,  200  years  later,  observations  on 
transilluminated  lung  of  the  cat  indicated  that  the 
pattern  of  capillary  flow  in  the  mammalian  lung  was 
distinctly  different  from  that  of  the  amphibian  lung; 
thus,  instead  of  pulsatility,  YVearn  and  co-workers 
stressed  intermittency,  a  phenomenon  attributable  to 
the  opening  and  closing  of  pulmonary  precapillary 
vessels  (419).  The  rarity  of  pulsatile  flow  in  the  sur- 
face capillaries  of  the  mammalian  lung  has  since  been 
confirmed  by  others  (21). 

Opposed  to  these  direct  observations  on  the  mam- 
malian lung  are  the  results  obtained  by  plethysmo- 
graphic  techniques  in  man  (37,  254,  418).  Not  only 
do  they  picture  pulmonary  capillary  flow  as  regularly 
and  vigorously  pulsatile,  but  they  also  depict  a  flow 
pattern  in  the  pulmonary  capillaries  which  corre- 
sponds more  closely  to  the  instantaneous  changes  in 
the  blood  pressure  gradient  across  the  lungs  than  to 
the  flow  pulse  in  the  pulmonary  artery  (fig.  29) 
(270).  Moreover,  unless  one  postulates  species 
differences  among  mammals,  these  results  in  man 
also  challenge  the  notion  that  examination  of  the 
surface  capillaries  of  the  lung  is  a  useful  index  of  the 
pattern  of  flow  in  the  bulk  of  the  pulmonary  capil- 
laries. 

Even  though  the  majority  of  the  plethysmographic 
studies  agree  that  pulmonary  capillary  blood  flow  is 
pulsatile  in  man,  they  are  not  entirely  consistent 
with  respect  to  the  form  of  the  capillary  flow  pulse. 
For  example,  not  only  do  the  published  records 
differ  with  respect   to  the  amplitude  of  peak  flow, 


but  they  also  display  different  contours  for  the  flow 
pulse:  some,  but  not  all,  the  records  indicate  that 
flow  is  interrupted  for  much  of  each  cardiac  cycle; 
often,  pulmonary  capillary  blood  flow  seems  to 
reverse;  finally,  the  reported  flow  patterns  generally 
vary  from  beat-to-beat.  Undoubtedly,  at  least  part  of 
this  variability  is  attributable  to  practical  difficulties 
inherent  in  the  plethysmographic  techniques  (342). 
In  addition,  as  may  be  gleaned  from  figure  35,  in- 
accuracies are  inescapable  in  the  matching  and 
analvsis  of  the  air  and  nitrous  oxide  records. 


ECG 


AIR 


© 


-kv_X 


feo%N20        -vi 

(20%   02  \/*S^ 


4.5   — 


1.5   — 


D1 


18  — 
12 
6   — 


fig.  35.  The  pattern  of  the  pulmonary  capillary  blood  flow 
according  to  the  pncumocardiographic  (A)  and  plethysmo- 
graphic (B  and  C)  methods.  From  above  downward,  the  elec- 
trocardiogram (ECG),  the  air  record  (AIR),  the  nitrous  oxide 
record  (8o*>c  NjO,  20%  O.),  the  difference  between  the  air 
record  and  the  nitrous  oxide  record  (VN„0),  and  the  rate  of 
pulmonary  capillary  blood  flow  (Qc)  in  liters  per  minute.  A: 
actual  pneumocardiograms  obtained  from  an  anesthetized, 
curarized  dog  during  arrested  respiration.  Mechanical  events 
are  eliminated  in  the  process  of  point-by-point  subtraction  of 
the  nitrous  oxide  pneumocardiogram  from  the  air  pneumo- 
cardiogram,  yielding  a  record  of  instantaneous  changes  in  air- 
way pressures  due  only  to  the  volumes  of  nitrous  oxide  removed 
by  the  perfusing  blood  (VN-,0).  Differentiation  of  the  volume- 
uptake  record  provides  a  record  of  the  rate  of  uptake  of  nitrous 
oxide  and,  therefore,  of  the  pulmonary  capillary  blood  flow 
(Qc)-  Except  for  the  unexplained  dip  in  the  Qc  record,  pulmo- 
nary capillary  flow  appears  to  be  continuous  and  largely  con- 
fined to  the  systolic  portion  of  the  cardiac  cycle.  B  and  C: 
hypothetical  plethysmographic  records  to  compare  strongly 
pulsatile  but  continuous  capillary  flow  (B)  with  weakly  pulsa- 
tile but  continuous  capillary  flow  (C).  Not  illustrated  is  the 
possibility  of  interrupted  capillary  flow,  i.e.,  that  capillary  flow- 
may  actually  stop  (drop  to  zero)  for  part  of  each  cardiac  cycle. 
[After  Morkin   el   al.    (298).] 


DYNAMICS    OF    PULMONARY    CIRCULATION 


'7°5 


Size  o]  Pulmonary  Capillary  Bed 

Although  the  extent  of  the  pulmonary  capillary 
bed  in  a  living  subject  cannot  be  expressed  in  absolute 
units,  a  change  in  area  can  be  detected  from  con- 
secutive measurements  of  the  pulmonary  diffusing 
capacity.  Such  measurements,  using  either  oxygen  or 
carbon  monoxide  as  the  test  gas  have  shown  that: 

a)  not  all  of  the  available  area  is  in  use  at  rest;  and 

b)  the  capillary  area  involved  in  gas  exchange  in- 
creases progressively  under  a  variety  of  circum- 
stances, e.g.,  exercise.  The  major  mechanism  involved 
in  increasing  the  area  is  an  increase  in  transmural 
pressure  (357).  The  precise  way  in  which  this  distend- 
ing pressure  is  increased  varies  from  circumstance  to 
circumstance.  Thus,  in  some  conditions,  an  increase 
in  capillary  blood  volume  is  involved;  in  others,  the 
perivascular  pressures  may  decrease;  at  high  lung 
volumes,  the  capillaries  may  even  be  passively- 
stretched.  As  expected  from  theoretical  considera- 
tions, the  diffusing  capacity  is  little  affected  by 
changes  in  pulmonary  blood  flow;  only  when  pul- 
monary blood  flow  is  severely  curtailed  does  the 
diffusing  capacity  decrease  (358,  407).  Pneumo- 
nectomy generally  (143),  but  not  invariably  (89)  de- 
creases the  diffusing  capacity. 

The  maximum  diffusing  capacity  is  of  interest  as 
a  measure  of  the  maximum  available  pulmonary 
capillary  area.  It  has  been  suggested  that  this  max- 
imal value  is  reached  at  a  level  of  blood  flow  which 
corresponds  to  the  steep  inflection  of  the  flow-pressure 
curve  (fig.  34).  However,  the  experimental  support 
for  this  hypothesis  is  inconclusive  (348). 

Pulmonary  Capillary  Blood  Volume  (Q.,.) 

On  the  basis  of  measured  differences  between  the 
rates  of  reaction  of  carbon  monoxide  with  hemoglobin 
solutions  at  different  oxygen  tensions,  and  the  calcu- 
lation of  the  average  time  spent  by  blood  in  traversing 
the  pulmonary  capillaries,  the  volume  of  blood  in  the 
pulmonary  capillaries  of  the  normal  resting  subject 
was  originally  calculated  to  be  of  the  order  of  60  to 
75  ml  (364,  365);  during  severe  exercise,  Qc  increased 
somewhat  (to  approximately  90  to  100  ml)  (223, 
364).  More  recent  measurements  and  calculations  of 
the  same  type  have  raised  the  value  of  the  resting 
Qc  to  approximately  100  ml,  both  for  the  normal 
subject  (15,  244)  and  for  the  patient  with  mitral 
stenosis  (15).  At  present,  there  is  no  way  to  decide 
how  much  of  the  reported  variability  is  artificial 
(143,  365)  and  how  much  is  a  consequence  of  either 


\ 

1.5  en 


O  to 
_1  0: 


-    200 


TTTTTTTfTTf 


PRE  CAPILLARY 


1  T  1   1  1  1  1  1  1 

POSTCAPILLAR  Y 


fig.  36.  Hypothetical  relationship  between  blood  pressure 
(solid  line,)  and  cross-sectional  area  (shaded)  in  the  pulmonary 
vascular  bed  of  the  dog.  The  blood  pressure  is  represented  as 
per  cent  of  initial  value.  Vascular  diameters  at  key  points  are 
indicated  by  asterisks.  According  to  this  schema,  the  major  drop 
in  blood  pressure  occurs  in  the  region  of  the  pulmonary  capil- 
laries (shaded  spike).  [Based  on  Schleier  (373).] 

biological  differences  between  subjects  or  the  effects 
of  the  breathing  maneuvers  which  are  part  of  the 
tests  (244).  A  variety  of  agents  and  procedures  seem 
to  be  capable  of  passively  altering  Qc  (262). 

In  the  dog,  anatomical  measurements  suggest  that 
the  pulmonary  capillaries  may  contain  10  per  cent 
of  the  total  volume  of  blood  between  the  right  ven- 
tricle and  left  atrium,  i.e.,  of  the  order  of  1.2  per  cent 
of  the  total  circulating  blood  volume  (169).  For  the 
human  lung,  Weibel  found  that  Qc  varies  with  the 
lung  volume  and  with  the  degree  of  capillary  filling. 
In  his  preparation,  which  involved  negative  (pleural) 
pressure  inflation  of  the  lung  and  fixation  in  formalin 
vapor,  Qc  was  150  to  200  ml,  i.e.,  approximately 
twice  the  volume  obtained  by  physiological  measure- 
ments. Part  of  the  difference  between  the  anatomical 
and  physiological  measurements  may  be  the  degree  of 
inflation  of  the  lung  (422). 


Resistance  and  Distensibility 

How  much  of  the  pulmonary  vascular  resistance  to 
perfusion  lies  in  the  pulmonary  capillary  bed  is  a 
matter  of  opinion  (66).  The  prevalent  notion  is  that, 
under  ordinary  conditions,  the  resistance  function 
resides  in  the  small,  muscular  precapillary  vessels. 
On  the  other  hand,  calculations  of  resistance  based 
on  anatomical  measurements  and  assumptions  have 
raised  the  possibility  that  a  large  part  (up  to  half)  of 


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CIRCULATION    II 


the  pressure  drop  across  the  pulmonary  vascular  bed 
may  occur  in  the  capillaries  (fig.  36)  (373).  Con- 
sistent with  the  latter  view  are  some  physiological 
observations  on  the  isolated  lung  (318).  While  such 
calculations  and  observations  cannot  define  the  major 
site  of  pulmonary  vascular  resistance  under  natural 
conditions,  they  do  emphasize  that  the  evidence 
favoring  the  precapillary  segments  is  not  on  firm 
footing. 

Under  certain  circumstances,  the  capillaries  do 
become  the  major  site  of  pulmonary  vascular  re- 
sistance. The  most  common  circumstance  is  the 
artificial  increase  in  alveolar  pressure  in  the  course  of 
positive  pressure  breathing  (191,  306).  It  is  also 
possible  to  imagine  such  a  role  for  the  capillaries  in 
those  natural  circumstances  in  which  the  left  atrial 
pressure  happens  to  fall  below  alveolar  pressures. 
Such  a  condition  presumably  exists  in  the  apical 
alveoli  of  the  upright  human  subject  and  is  exag- 
gerated when  the  standing  subject  takes  a  deep 
breath. 

In  isolated  lungs  perfused  at  physiological  levels 
of  blood  pressure,  the  pulmonary  capillaries  appear  to 
be  less  distensible  than  the  larger  pulmonary  vessels 
(124).  However,  physiologically  meaningful  measure 
ments  of  the  distensibility  characteristics  of  the 
pulmonary  capillaries  are  difficult  to  obtain  for  a 
variety  of  technical  reasons,  including  the  inacces- 
sible location  of  the  capillaries,  the  difficulty  of 
making  static  measurements  under  in  vivo,  dynamic 
conditions,  the  difficulty  in  reproducing  the  natural 
capillary  pressures  in  experimental  preparations,  and 
the  uncertainty  concerning  the  distensibility  charac- 
teristics of  the  pericapillary  tissues  because  of  the 
propensity  of  the  isolated  lung  to  develop  pulmonary 
edema. 

Time  Spent  by  Blood  in  Pulmonary  Capillaries 

Stephen  Hales  seems  to  have  been  the  first  (1733) 
to  pay  serious  attention  to  the  rate  at  which  blood 
flows  through  the  pulmonary  capillaries;  coupling 
direct  observation  with  simple  arithmetical  calcula- 
tion, he  estimated  this  rate  to  be  approximately  1.4 
mm  per  sec  in  the  frog  lung  (1  78).  Curiously  enough, 
the  elaborate  techniques  of  the  twentieth  century 
(cine-microphotography  with  lamp  black  as  a  tracer 
in  the  exposed  lung)  have  provided  similar  values  for 
the  cat  (1   to  2  mm/sec)  (414). 

The  latter  observations  on  the  cat  are  the  only 
direct  observations  on  the  time  spent  by  particles  in 
the  pulmonary  capillaries   (o.  1    sec).   All   other  esti- 


mates represent  calculations  and  assumptions  based 
on  measurements  of  alveolar  capillary  gas  exchange. 
The  most  commonly  cited  values  are  those  of  Rough- 
ton,  based  on  the  kinetics  of  the  combination  of 
carbon  monoxide  and  hemoglobin  in  man.  Originally, 
this  approach  indicated  that,  on  the  average,  a  unit 
of  blood  spends  approximately  three-quarters  of  a 
second  in  gas  exchange  in  the  pulmonary  capillary 
at  rest,  and  somewhat  less  during  exercise  (364); 
subsequent  refinements  in  methodology  have  sug- 
gested that  the  contact  time  at  rest  may  be  a  little 
longer,  i.e.,  of  the  order  of  1  sec  (223,  317,  365). 
Other  calculations,  based  on  the  analysis  of  the 
alveolar-arterial  oxygen  gradient  have  yielded  lower 
values:  0.18  sec  in  the  dog  (295)  and  0.23  to  0.5  sec 
in  resting  man  (295,  396);  however,  theoretical  con- 
siderations suggest  that  this  approach  tends  to  under- 
estimate the  time  of  contact  (318).  Finally,  anatomical 
considerations  have  led  to  the  low  contact  time  of 
0.1  sec  (301).  At  first  encounter,  this  is  a  discouraging 
span  of  values.  But,  in  view  of  the  wide  variations  in 
methodology,  assumptions,  and  types  of  calculations, 
this  range  of  about  0.1  to  1.0  sec  in  resting  man  is 
surprisingly  small  and,  when  duly  weighed,  the 
generally  accepted  value  of  three-quarters  of  a  sec 
to  1  sec  at  rest  seems  quite  reasonable.  Obviously 
lacking  are  simultaneous  measurements  of  contact 
time  by  the  physiological  methods  and  by  direct 
observation  of  the  exposed  lung  in  the  same  animal 

(143)- 

The  time  spent  by  a  unit  of  blood  in  the  pulmonary 

capillary  depends  on  various  hemodynamic  influences. 
Paramount  among  these  is  the  relationship  between 
the  stroke  output  of  the  right  heart  and  the  pulmonary 
capillary  blood  volume;  in  resting  man  these  two 
values  are  of  the  same  order  of  magnitude.  Another 
determining  influence  is  the  nature  of  the  pulmonary 
capillary  blood  flow:  pulsatile  pulmonary  capillary 
flow  causes  some  red  cells  to  spend  less  time  in  the 
pulmonary  capillaries  than  others.  Finally,  values 
based  on  alveolar-capillary  gas  exchange  and  the 
rate  of  combination  of  test  gases  with  hemoglobin 
may  misjudge  actual  contact  times;  for  example, 
actual  time  would  be  expected  to  differ  from  calcu- 
lated time  if,  as  is  customarily  done,  the  calculations 
assume  that  the  hematocrit  of  pulmonary  capillary 
blood  is  identical  with  that  of  blood  sampled  from 
large  systemic  vessels  (143,  317). 

These  theoretical  considerations  may  have  practical 
meaning.  Ordinarily,  the  time  spent  by  each  unit  of 
blood  in  the  pulmonary  capillary  is  more  than  ample 
for  complete  oxygenation,   both  at  rest  and  during 


DYNAMICS    OF    PULMONARY    CIRCULATION 


I707 


exercise.  However,  it  is  conceivable  that,  under 
certain  pathological  conditions,  such  as  those  which 
involve  a  huge  pulmonary  blood  flow  through  a 
curtailed  pulmonary  vascular  bed,  the  contact  time 
may  be  too  brief.  Indeed,  an  inadequate  contact 
time  has  been  invoked  to  account  for  peripheral 
arterial  hypoxemia  in  resting  patients  with  multiple 
pulmonary  emboli  and  in  exercising  patients  with 
"alveolar-capillary  block"  (359)-  However,  such 
explanations  are  not  entirely  convincing  since,  in 
most  of  these  pathologic  states,  other  equally  con- 
vincing explanations  for  peripheral  arterial  hy- 
poxemia, e.g.,  opening  of  pulmonary  arteriovenous 
shunts,  also  exist. 

Pulmonary  Capillary  Hematocrit 

In  the  1930's,  Fahraeus  and  Lindquist  pointed  out 
that  blood  flowing  in  capillary  tubing  has  a  greater 
ratio  of  plasma  to  red  cells  than  does  blood  in  wider 
streams  (18).  Since  then,  it  has  been  repeatedly  shown 
that  the  hematocrit  of  blood  in  many  organs  is  less 
than  in  the  large  vessels  which  enter  and  leave  them. 
The  lung  appears  to  be  no  exception:  measurements 
of  the  hematocrit  of  blood  obtained  from  whole  organ 
homogenates  (161)  as  well  as  comparisons  of  transit 
time  of  tagged  red  cells  and  plasma  (332)  indicate 
that  the  small  vessel  hematocrit  is  regularly  lower 
than  that  of  the  large  vessels,  ranging  from  1 7  per 
cent  less  at  rest  to  13  per  cent  less  during  exercise. 
This  difference  may  affect  not  only  the  hemodynamic 
behavior  of  the  pulmonary  capillary  circulation  but 
also  measurements  of  alveolar-capillary  gas  exchange, 
such  as  the  pulmonary  diffusing  capacity  for  carbon 
monoxide,  and  derivative  values,  such  as  the  time 
spent  by  blood  in  the  pulmonary  capillary  and  the 
pulmonary  capillary  blood  volume  (143,  318). 

Transcapillary  Exchange 

Until  recently,  considerations  of  the  transcapillary 
movements  of  water  and  electrolytes  emphasized 
their  bulk  transfer  and  dealt  largely  with  the  balances 
between  hydrostatic  and  oncotic  pressures  (Starling's 
law  of  capillary  exchange).  Recognizing  that  the 
pulmonary  capillaries  were  unique  in  being  "bathed 
in  air  rather  than  in  water,"  such  considerations  of 
bulk  transfer  were  sufficient  to  account  for  the  normal 
"dry"  lungs  as  well  as  the  "wet"  lungs  of  clinical 
pulmonary  edema.  Within  the  last  few  years,  trans- 
capillary exchange  by  diffusion  has  also  been  taken 
into    serious   account    (76).    Still    incomplete    is    the 


definition  of  the  role  of  the  pulmonary  lymphatics 
with  respect  to  the  water  which  escapes  into  the 
pulmonary  interstitium  and  alveoli. 

Certain  aspects  of  the  transcapillary  exchange  of 
water  seem  well  established.  For  example,  the  osmotic 
pressure  of  the  plasma  colloids  (expressed  figuratively 
as  an  "oncotic  pressure")  of  approximately  25  mm  Hg 
normally  suffices  to  prevent  bulk  loss  of  fluid  from 
the  pulmonary  capillaries,  even  in  the  hydrostatically 
dependent  portions  of  the  lung.  Also,  while  trans- 
capillary molecular  exchange  rates  by  diffusion  may 
be  of  the  order  of  the  cardiac  output,  no  net  fluid 
transfer  occurs.  Ethanol  and  injected  carbon  dioxide 
behave  like  isotopic  water.  As  expected,  the  indi- 
cator-dilution curves  for  T-1824  (which  does  not 
leave  the  capillaries)  and  for  water  (which  undergoes 
rapid  to-and-fro  transcapillary  exchange)  are  quite 
different  (76).  Indeed,  labeled  water  resembles  the 
inert  gases  in  behaving  as  though  the  barrier  did  not 
exist. 

Quite  unexpected  is  the  similarity  between  the 
T-1824  indicator-dilution  curve  and  the  correspond- 
ing curves  for  urea  and  for  the  highly  diffusible 
phosphate,  potassium,  sodium,  and  chloride  ions 
(16,  77,  360).  Virtual  identity  of  these  curves  has 
been  interpreted  to  mean  that:  a)  in  contrast  to  the 
enormous  pulmonary  volume  of  distribution  of 
sodium  and  chloride  at  equilibrium  (134),  the  volume 
of  dilution  available  to  urea  and  to  the  diffusible 
ions  during  a  single  circulation  is  confined  either  to 
the  strict  pulmonary  vascular  volume  or  to  the  pul- 
monary vascular  volume  plus  an  additional,  circum- 
scribed perivascular  volume  into  which  these  sub- 
stances diffuse  and  then  promptly  return,  and  b) 
because  of  the  ready  permeability  of  the  barrier 
(probably  the  basement  membrane)  to  water  as  well 
as  its  relative  impermeability  to  ions  and  urea,  the 
barrier  is  aqueous  rather  than  lipid  in  nature. 


MISCELLANEOUS    HEMODYNAMIC    PHENOMENA 

Pulmonary  Arterial  Pulse-Wave   Velocity 

The  pulse-wave  velocity  is  related  to  relative, 
rather  than  to  absolute,  distensibility  (see  Chapter 
24).  Estimates  of  the  speed  at  which  the  pulse  wave 
travels  along  the  length  of  the  pulmonary  arterial 
tree  vary  considerably.  The  discrepancies  are  at- 
tributable to  three  causes:  inadequate  methodology; 
the  experimental  difficulty  of  controlling  the  hemo- 
dynamic influences  which  modify  the  speed  of  the 


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CIRCULATION    II 


pulse  wave,  e.g.,  initial  volume  or  diastolic  pressure; 
and  species  differences  in  distensibility.  Thus,  one 
set  of  values  for  the  pulmonary  arterial  pulse-wave 
velocity  in  the  rabbit  averages  200  cm  per  sec  (124); 
this  method  is  based  on  measurements  of  pulmonary 
vascular  distensibility  and  capacity.  On  the  other 
hand,  much  lower  values  (83  cm  sec)  have  been 
calculated  by  an  alternate  approach  which  involves 
the  registration  of  phase  shifts  of  a  single  harmonic 
component  of  the  pulse  wave  as  it  traverses  a  known 
distance  (140a).  Similarly,  in  the  dog,  mean  velocities 
have  averaged  250  cm  per  sec  in  one  studv  (311) 
and  400  cm  per  sec  in  another  (225).  Finally,  in  man, 
kymographic  studies  have  indicated  a  velocity  of 
200  cm  per  sec  in  the  main  pulmonary  artery  and 
275  cm  per  sec  in  the  peripheral  branches  (71).  It 
should  be  noted  that  each  of  these  methods  has  its 
own  peculiar  problems:  thus,  some  are  troubled  by 
the  need  for  the  precise  measurement  of  in  vivo 
distances  between  points  on  the  pulmonary  artery 
(71,  225);  others  have  to  overcome  the  difhcultv  of 
attempting  static  measurements  under  dynamic  con- 
ditions of  flow  (124). 

Because  of  the  practical  limitations  and  assump- 
tions involved  in  the  experimental  approaches,  none 
of  these  values  seem  to  offer  more  than  an  order  of 
magnitude.  However,  with  a  single  exception  (225), 
they  are  consistent  with  the  notion  that  the  pulse- 
wave  velocitv  in  the  distensible  pulmonarv  arterial 
tree  is  somewhat  less  than  in  the  aorta. 

Pulmonary  Circulation  Tune 

Measurements  of  circulation  times  are  in  common 
clinical  use  for  the  recognition  of  heart  failure.  This 
use  depends  on  the  arrival  of  a  test  substance  at  a 
chosen  site  in  sufficient  concentration  to  be  detected; 
the  value  obtained,  i.e.,  the  ''appearance  time,"  is 
related,  in  a  complex  way,  to  the  mean  circulation 
time  used  for  the  calculation  of  central  blood  volume 
(184,  313).  It  is  clear  that  the  precise  value  for  cir- 
culation time  will  be  influenced  not  only  by  technical 
peculiarities,  e.g.,  by  rate  of  injection,  nature  of  the 
test  substance,  and  sensitivity  of  the  detector,  but 
also  by  physiological  events.  For  example,  if  the 
pulmonary  circulation  lies  between  the  sites  of  in- 
jection and  sampling,  an  increase  in  its  blood  volume 
will  dilute  the  test  substance  excessively  and  delay 
its  recognition  at  the  test  site.  It  is,  therefore,  not 
surprising  that  values  for  circulation  times  from 
different  laboratories  are  frequently  inconsistent. 

One  study  in  the  dog  (Stewart  principle)  found  the 


total  circulation  time  to  be  approximately  1 1  sec, 
and  the  pulmonary  circulation  time  to  average 
approximately  half  of  the  total  (184).  Other  studies 
indicate  that  the  pulmonary  circulation  time  (pul- 
monary artery  to  vein)  is  somewhat  less,  i.e.,  about 
3  to  4  sec  (306,  329).  The  circulation  time  for  red 


INCREASED    PRESSURE  DECREASED    PRESSURE 

IN     L  IN     T 


fig.  37.  Two-chamber  model  to  illustrate  the  effects  of  vary- 
ing pressures  around  a  collapsible  rubber  tube  on  its  dimen- 
sions. The  tube  (a,  c,  b)  runs  through  one  rectangular  chamber 
(T-T)  and  is  exposed  for  a  limited  extent  (c)  to  the  pressure 
of  the  other  chamber  (L).  In  .-1  and  B,  the  two  ends  of  the  per- 
fusing system  (a,  b)  are  outside  of  the  chambers;  in  C  and  D, 
the  entire  system  is  contained  within  chamber  T-T.  For  the 
sake  of  clarity,  only  A  has  been  lettered;  the  arrow  in  each 
figure  indicates  the  chamber  subjected  to  a  change  in  pressure 
and  the  direction  of  change.  A :  the  pressure  in  chamber  L  is 
greater  than  atmospheric,  the  pressure  in  chamber  T-T  is 
atmospheric.  The  aspect  of  the  tube  exposed  to  L  is  collapsed. 
B:  the  pressure  in  chamber  T-T  is  less  than  atmospheric;  the 
pressure  in  L  is  atmospheric.  The  whole  length  of  tube  within 
chamber  T-T  is  increased  in  diameter;  the  portion  exposed  to 
L  is  less  dilated  than  the  remainder  of  the  tube.  C  and  D :  two 
different  but  equivalent  conditions.  As  long  as  the  reservoirs 
are  contained  within  chamber  T-T,  the  same  effect  is  obtained 
by  balancing  positive  pressure  in  L  against  atmospheric  pres- 
sure in  T-T  (C)  or  by  balancing  atmospheric  pressure  in  L 
against  negative  pressure  in  T-T  (D).  In  either  case,  the  result 
is  identical  with  that  illustrated  in  .4.  By  analogy,  this  model 
suggests  that:  /)  when  alveolar  pressure  \L)  is  raised  (.1),  the 
transmural  pressure  of  adjacent  vessels  (c)  is  decreased;  2)  the 
situation  of  two  reservoirs  (pulmonary  arterial  and  venous 
pressures)  outside  of  the  pleural  cavity  (B)  corresponds  to 
negative  (pleural)  pressure  inflation  as  well  as  to  normal 
respiration;  3)  when  pleural  pressure  is  decreased  {B),  the 
transmural  pressures  of  larger  vessels  are  increased  more  than 
those  of  the  capillaries,  and  ./>  the  situation  of  two  reservoirs  in 
the  pleural  cavity  (C  and  D)  is  a  physical  identity  with  positive 
pressure  inflation.  [Based  on  Quincke  &   Pfeiffer  (324).] 


DYNAMICS    OF    PULMONARY    CIRCULATION 


I709 


cells  is  less  than  that  of  the  plasma  [cell  transit  time 
plasma  transit  time  =  0.91  ±  .05  (310)].  In  man, 
the  total  (systemic  plus  pulmonary)  circulation  time 
is  of  the  order  of  15  to  18  sec  (184).  Approximately, 
one  quarter  to  one  third  of  the  total  time  is  spent  in 
traversing  the  pulmonary  circulation;  the  circulation 
time  between  the  right  ventricle  and  the  pulmonary 
capillaries  is  estimated  to  be  2  to  3  sec  (87).  Despite 
the  many  measurements  of  the  pulmonary  circula- 
tion time,  both  in  normal  subjects  and  in  patients 
with  cardiopulmonary  disorders,  there  is  still  an 
inadequate  fund  of  information  concerning  the  pre- 
cise pulmonary  vascular  pathways  traversed  by  the 
test  substance  between  the  sites  of  injection  and 
sampling  (75). 


INFLUENCE    OF    RESPIRATION    ON 
PULMONARY    CIRCULATION 

In  the  pulmonary  circulation,  blood  pressures, 
volume,  and  flow  change  during  each  breath.  The 
precise  nature  of  these  changes  has  been  debated  for 
two  centuries  (50,  324).  Nonetheless,  many  aspects 
remain  unsettled  largely  because  of  the  technical 
difficulties  involved  in  simultaneously  recording 
transient  respiratory  and  circulatory  events  in  the 
intact  animal  or  man. 

The  attempts  to  circumvent  the  technical  diffi- 
culties have  created  problems  of  their  own:  a)  the 
recourse  to  simplifying  physical  models  (fig.  37) 
and  artificial  preparations  has  led  to  dubious  gener- 
alizations about  natural  breathing  (61,  354);  b) 
the  experimental  control  of  some  respiratory  in- 
fluences at  the  expense  of  others,  has  tended  to 
exaggerate  the  physiological  importance  of  some 
parameters  while  denying  others — such  as  the  degree 
and  type  of  inflation — their  full  due  (215,  380);  and 
c)  complicated  experimental  designs  have  created 
artificial  situations  in  which  the  usual  calculation  of 
pulmonary  vascular  resistance  either  does  not  apply 
or  is  very  difficult  to  translate  into  terms  of  pul- 
monary vascular  dimensions  (315,  354). 


Spontaneous  Breathing 

During  inspiration,  as  pleural  pressure  becomes 
more  negative,  luminal  pressure  (referred  to  atmos- 
phere) decreases.  On  the  other  hand,  transmural 
pulmonary  arterial  pressures — systolic,  diastolic,  and 
mean — increase.  During  expiration,  these  changes  are 
reversed. 


There  is  no  unanimity  concerning  the  mechanisms 
responsible  for  the  increase  in  pulmonary  arterial 
transmural  pressure  during  inspiration.  Most  certain 
is  an  increase  in  pulmonary  blood  flow,  arising  from 
the  decrease  in  intrathoracic  pressure  and  from  the 
increase  in  systemic  venous  return  which  it  promotes 
(17,  49);  much  more  equivocal  is  a  reduction  in  the 
outflow  from  the  pulmonary  vascular  bed  so  that  the 
pulmonary  blood  volume  is  increased  (225,  253). 
Such  a  combination  of  increased  inflow  and  reduced 
outflow  would  imply  pulmonary  vascular  distension 
and,  hence,  a  decrease  in  pulmonary  vascular 
resistance. 

However,  there  are  experimental  results  which  do 
not  fit  this  picture:  a)  under  some  circumstances,  in- 
spiration has  been  found  to  increase — rather  than  to 
decrease — pulmonary  vascular  resistance  (49,  1 1 5, 
309);  b)  measurements  of  transmural  atrial  pressures 
suggest  that  the  pulmonary  veins  empty  uninterrupt- 
edly during  inspiration  (187);  and  e)  experiments  on 
models  and  dogs  indicate,  that,  under  circumstances 
which  promote  an  unusual  emptying  of  the  extra- 
thoracic  veins,  the  veins  may  collapse  during  inspira- 
tion as  they  enter  the  thorax,  thereby  preventing  an 
increase  in  venous  return  (308). 

At  least  part  of  the  divergent  opinions  about  the 
effects  of  inspiration  on  the  pulmonary  circulation 
seem  to  arise  from  failure  to  take  full  cognizance  of  the 
experimental  setting:  during  an  ordinary  quiet 
breath,  pulmonary  blood  flow  and  volume  do  appear 
to  increase;  if  resistance  does  change,  the  change  is 
small  (354).  Moreover,  collapse  of  extrathoracic  veins 
is  not  apt  to  occur  under  ordinary  physiological  cir- 
cumstances even  though  it  may  conceivably  occur  in 
the  resting  subject  who  is  breathing  with  enormous 
tidal  volumes  (354). 

As  long  as  fluctuations  in  intrathoracic  pressure 
are  small  and  venous  return  to  the  right  heart  remains 
ample  throughout  the  respiratory  cycle,  the  pulmo- 
nary arterial  pressure  pulses  are  fairly  uniform.  How- 
ever, in  clinical  conditions  associated  with  low 
systemic  venous  return,  in  chronic  pulmonary  disease 
(fig.  38),  during  exercise  and  during  voluntary  deep 
breathing,  marked  swings  do  occur  in  the  pulmonary 
arterial  pressure  pulses.  These  reflect  not  only  the 
swings  in  intrathoracic  pressure  but  also  changes  in 
blood  flow,  volume,  and  resistance  (187,  253). 

During  natural  expiration,  the  filling  of  the  right 
heart  is  decreased  as  intrathoracic  pressures  approach, 
or  even  exceed,  caval  pressures;  the  pattern  described 
for  inspiration  is  reversed.  In  patients  with  pulmonary 
disease,  in  whom  expiration  has  become  an  active 


I  7IO 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION'     II 


fig.  38.  Blood  pressures  re- 
corded from  the  pulmonary 
artery  (PA)  and  right  atrium 
(RA)  during  quiet  breathing  in 
a  patient  with  chronic  bronchitis 
and  emphysema. 


30    [— 
mm    Hg 


20 


5 
0 


PA 


I  0     — 


MMjuW 


M 


M 


RA 


process,  venous  return  to  the  thorax  may  become  ob- 
structed as  positive  intrathoracic  pressures  are  im- 
posed on  central  venous  pressures.  However,  until  the 
systemic  venous  valves  (in  the  external  jugular,  sub- 
clavian, axillary,  and  femoral  veins)  become  incompe- 
tent from  central  venous  congestion,  the  rise  in  central 
venous  pressure  is  not  transmitted  to  the  peripheral 
systemic  veins.  Therefore,  during  a  forced  expiration, 
peripheral  venous  pressure  rises  only  gradually,  rep- 
resenting the  gradual  filling  of  a  distensible  system 
which  is  obstructed  at  its  thoracic  venous  outlet. 


of  the  pulmonary  vascular  bed  (397);/)  the  balance 
of  alveolar,  pleural,  left  atrial,  and  pulmonary  ar- 
terial pressures  which  is  required  to  make  calculated 
changes  in  resistance  meaningful  (354);  and  g)  the 
probable  insignificance  of  alveolar  surface  tension  in 
determining  pulmonary  vascular  resistance  during 
either  positive  (intrapulmonary)  or  negative  (pleural) 
pressure  inflation  of  the  lungs  (398).  This  list  also 
serves  to  emphasize  the  fallibility  of  extrapolating 
from  artificial  inflation  of  the  lung  to  spontaneous 
breathing. 


Inflation  of  the  Lungs 

In  1 87 1,  Quincke  and  Pfeiffer  reported  that  positive 
(intrapulmonary)  inflation  of  the  lungs  decreases  the 
pulmonary  blood  volume  and  increases  the  resistance 
to  flow  (324).  Since  then,  physiologists  have  debated — 
on  the  basis  of  a  wide  variety  of  experiments,  models, 
animal  preparations,  and  intact  animals — whether 
resistance  to  perfusion  increases  as  the  lungs  are  in- 
flated and  if  positive  pressure  inflation  exerts  the  same 
effects  as  negative  (pleural)  pressure  inflation  (39, 
431).  It  now  seems  that  the  discordant  results  were  to 
be  expected  because  of  the  nature  of  the  experiments 
and  of  the  models  (62).  The  principal  bases  for  dis- 
agreement seem  to  have  been:  a)  the  uncertain  mean- 
ing of  the  model  under  study  (354);  b)  the  failure  to 
distinguish  between  transmural  pressure  and  luminal 
pressure  in  determining  vascular  calibers  (61);  c)  the 
mechanical  increase  in  resistance  at  exceedingly  low 
lung  volumes,  possibly  due  to  kinking  or  collapse  of 
small  vessels  (61);  d)  the  mechanical  increase  in  re- 
sistance at  high  degrees  of  pulmonary  distension  as 
resistance  vessels  are  stretched  (354);  e)  the  influence 
of  the  pressure-volume  behavior  of  the  lung,  and  of 
its  enclosed  pulmonary  vasculature,  on  the  resistance 


Positive  Pressure  Breathing 

In  the  isolated  lung,  or  in  the  open-chest  animal, 
inflation  of  the  lung  from  the  collapsed  position  is 
associated  with  an  initial  decrease  in  resistance  as  the 
lung  is  moderately  inflated,  followed  by  an  increase 
in  resistance  as  the  lung  is  distended  further  (62). 
Such  U-shaped  curves  have  been  taken  to  represent: 
a.)  a  decrease  in  resistance  to  blood  flow  as  vessels  in 
the  collapsed  lungs  are  unkinked  and  opened  (62), 
followed  by  h)  an  increase  in  resistance  due  to  both  a 
decrease  in  transmural  distending  pressure  as  alveolar 
pressures  increase  (191,  215)  and  mechanical  distor- 
tion of  the  resistance  vessels  at  the  high  lung  volumes 

(2I5>  397)- 

In  the  closed-chest  animal,  positive  pressure  breath- 
ing affects  the  pulmonary  circulation  by  increasing 
alveolar  pressure  and  impeding  systemic  venous 
return  to  the  lungs:  the  systemic  venous-right  atrial 
pressure  gradient  is  decreased,  thereby  decreasing  the 
filling  of  the  right  ventricle  and  right  ventricular  out- 
put (87,  253);  the  volume  of  the  heart  and  pulmonary 
vessels  decreases.  As  a  result  of  the  combination  of  a 
decreased  right  ventricular  output  and  a  sustained 
left  ventricular  output,  the  pulmonary  blood  volume 


DYNAMICS    OF    PULMONARY    CIRCULATION 


I7II 


V*TI ON 


fio.  39.  Schematic  representation  of  the  influence  of  positive  pressure  breathing  on  the  right 
ventricular  (RV)  and  systemic  arterial  (BA)  pressures  of  a  normal  human  subject.  The  mask  pressure 
(M)  appears  above  the  pressure  pulses.  All  pressures  are  in  mm  Hg.  During  inflation,  as  mask  (and 
pleural)  pressures  increase,  the  pulse  pressure  in  the  right  ventricle  progressively  decreases;  con- 
comitantly, the  systemic  arterial  pulse  pressure  increases.  During  expiration,  the  reverse  occurs.  The 
prompt  return  of  the  mask  pressure  to  ambient  pressure  accounts  for  the  ability  of  expiration  to  com- 
pensate for  the  inspiratory  deficit  in  blood  flow.  [After  Richards  el  al.  (340). 


decreases  (395)  and  the  pulmonary  vascular  resist- 
ance increases  (49).  Although  the  imposed  pressure 
raises  pulmonary  vascular  luminal  pressures  the  trans- 
mural pressures  are  virtually  unaffected  (253),  and 
the  pressure  gradient  along  the  length  of  the  pulmo- 
nary vascular  tree  remains  essentially  unchanged 
(187,  256).  The  circulatory  changes  arising  from  the 
imposed  pressure  reverse  promptlv  once  the  lungs 
are  vented  to  atmosphere  (fig.  39). 

In  systemic  hypotensive  states,  positive  pressure 
breathing  may  precipitate  circulatory  collapse  if 
compensatory  mechanisms  are  insufficient  to  sustain 
the  venous  return  to  the  right  heart  (49).  Not  only 
are  the  output  of  the  right  heart  and  the  pulmonary 
blood  volume  reduced,  but  the  normal  balance  be- 
tween alveolar  perfusion  and  alveolar  ventilation  is 
also  upset  so  that  portions  of  the  lung  become  ex- 
cessively ventilated  with  respect  to  perfusion  (160). 

A  variety  of  mechanical  devices  are  in  common  use 
for  intermittent  positive  pressure  breathing  (426). 
Their  effects  on  the  circulation  are  functions  of  the 
degree  and  duration  of  the  cyclic  swings  which  they 
induce  in  intrathoracic  pressure.  The  cardiac  output 
generally  falls  (11)  in  proportion  to  the  mean  increase 
in  intrathoracic  pressure;  in  practice,  the  cardiac  out- 
put may  be  kept  at  control  levels  by  using  cycling 
devices  which  operate  to:  a)  inflate  the  lungs  gradu- 
ally to  peak  pressure;  b)  decompress  the  lungs  sud- 
denly by  venting  them  to  atmosphere;  and  c)  allow  a 
longer  period  of  exposure  to  atmospheric  pressure 
than  to  positive  pressure. 

Negative  Pressure  Breathing  (Pleural) 

As  pressure  around  the  collapsed  isolated  lung  is 
artificially  decreased,  its  resistance  to  perfusion  de- 
creases (61,  354).  The  changes  in  resistance  which 
accompany  further  inflation  of  this  type  are  unsettled. 


Thus,  some  have  found  only  a  continuing  decrease  in 
resistance  as  the  lung  is  expanded  by  progressive 
decrements  in  "pleural  pressure"  (62);  others  have 
found  U-shaped  curves  in  which  the  initial  drop  in 
resistance  as  the  lung  begins  to  expand  (pleural  pres- 
sure —  5  to  —  10  cm  H^O)  is  succeeded  by  an  increase 
in  resistance  as  the  pleural  pressure  decreases  further 
(pleural  pressure  —10  to  —25  cm  H20)  (354,  397). 
The  nadir  in  resistance  occurs  at  half-maximal  lung 
volume. 

The  mechanisms  proposed  to  account  for  these 
divergent  results  are  enlightening.  The  initial  de- 
crease in  resistance — to  which  all  agree — has  been 
attributed  to  either  an  increase  in  transmural  pressure 
or  to  the  unkinking  of  "gnarly"  vessels  (61 ).  Different 
explanations  have  been  used  to  account  for  the  di- 
vergent results  at  high  levels  of  inflation:  those  who 
find  a  continued  drop  in  resistance  ascribe  it  to  the 
continued  increase  in  transmural  pressure  as  "pleural" 
pressure  drops  (62);  those  who  find  that  resistance 
finally  increases  believe  that  at  lung  volumes  exceed- 
ing 50  per  cent  of  maximal,  mechanical  distortion  of 
the  pulmonary  vessels — a  function  of  lung  volume 
rather  than  of  transmural  pressure — is  involved  (354, 
397).  While  these  studies  leave  unsettled  the  question 
of  the  behavior  of  the  pulmonary  vascular  resistance 
as  the  lung  is  progressively  inflated,  they  do  serve  as 
a  reminder  that  the  transmural  pressures,  which  ac- 
count satisfactorily  for  passive  changes  in  caliber  at 
moderate  degrees  of  inflation,  may  be  supplanted  by 
other  mechanical  influences,  e.g.,  stretching  or  col- 
lapse, in  determining  vascular  calibers  at  extreme 
inflation  or  deflation. 

Negative  Pressure  Breathing  (Intrapulmonary) 

"Snorkel"   breathing  is  characterized   by  a  lower 
pressure  within  the  lungs  than  around  the  body  (49)- 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


4  OH 


I00| 
60 


fig.  40.  Effects  of  a  prolonged  forced  expiration  on  systemic  arterial  pressures  {upper  tracing)  and 
right  ventricular  {lower  /racing)  pressures  in  a  patient  with  chronic  pulmonary  emphysema  and 
fibrosis.  Ten  seconds  after  the  start  of  expiration  (solid  arrow),  the  amplitude  of  the  RV  pressure 
pulse  begins  to  increase,  after  several  beats,  there  is  a  progressive  rise  in  the  femoral  arterial  systolic, 
diastolic,  and  pulse  pressures.  This  suggests  that  as  the  flow  of  blood  into  the  thorax  is  impeded,  the 
volume  of  the  peripheral  venous  reservoir  slowly  increases  until  the  venous  pressure  becomes  suffi- 
ciently great  again  to  increase  the  right  heart  filling  and  output,  in  spite  of  the  continued  elevation 
of  the  intrathoracic  pressure.  During  the  succeeding  inspiration  (hollow  arrow),  a  further  augmenta- 
tion of  the  right  ventricular  pulse  pressure  occurs  (last  four  beats).  [After  Lauson,  el  at.  (253).] 


i! 


IIIIIIIIIIIIMMIIHIIIIIMMIim|N|||»l|IU}H 

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lUwMwi1 


BA 


O  -20 

20 


h, 


OES 

fig.  41.  Effect  of  the  Valsalva  maneuver  on  brachial  arterial  pressure  (BA)  and  "transmural" 
pulmonary  arterial  pressure  (dPA).  The  changes  in  intrathoracic  pressure,  measured  as  the  esopha- 
geal pressure  (OES),  indicate  the  onset,  duration,  and  end  of  the  expiratory  effort.  All  pressures  are 
in  mm  Hg.  The  overshoot  in  the  systemic  arterial  response  following  the  Valsalva  maneuver  is 
ascribed  to  reflex  vasoconstriction.  On  the  other  hand,  the  pattern  of  change  in  pulmonary  arterial 
pressure  is  attributed  to  mechanical  events,  i.e.,  to  alterations  in  venous  return  and  right  ventricular 
output.  [After  Lee  et  at.  (255).] 


At  the  start  of  negative  (intrapulmonary)  pressure 
breathing  the  systemic  venous  return  to  the  lungs 
and  the  pulmonary  blood  volume  increase  (49).  In 
contrast  to  positive  pressure  breathing,  the  negative 
intrapulmonary  pressures  distend  the  intrapulmonary 
vessels  (256).  At  the  small  lung  volumes,  associated 
with  continuous  negative  pressure  breathing,  atelec- 
tasis may  develop. 

Cough 

During  a  cough,  pressure  referred  to  atmosphere 
rises  simultaneously  and  equally  in  the  thorax 
(fig.  21),  abdomen,  and  cerebrospinal  canal  (190). 
The  increase  in  pressure  (which  may  transiently  reach 


levels  of  1 50  mm  Hg)  does  not  strain  the  intrathoracic 
(255)  or  abdominal  or  cerebrospinal  vessels,  and  does 
not,  per  se,  affect  the  pressure  gradient  which  drives 
blood  along  the  pulmonary  vascular  tree.  However, 
it  is  propagated  to  the  peripheral  arterial  tree  where 
it  causes  a  marked  increase  in  the  transmural  distend- 
ing pressure  (190). 

Prolonged  Expiration 

During  a  prolonged  expiration  (fig.  40),  the  ampli- 
tude of  the  pulmonary  arterial  (and  right  ventricular) 
pressure  pulse  first  decreases  and  then  gradually  in- 
creases; the  systemic  arterial  blood  pressures  undergo 
a  similar  pattern  of  change.  This  sequence  has  been 


DYNAMICS    OF    PULMONARY    CIRCULATION 


ni3 


interpreted  as  reflecting  the  gradual  increase  in 
peripheral  venous  blood  volume  and  pressure  during 
the  sustained  expiration  until  adequate  filling  of  the 
right,  and  then  the  left,  heart  is  restored  (187,  253). 

Forced  Expiration  (Valsalva) 

The  effects  of  the  Valsalva  maneuver  (forced  ex- 
piration against  a  closed  glottis  or  a  column  of  water 
30  to  40  cm  high)  (fig.  41 ),  has  been  more  intensively 
studied  in  the  systemic  circulation  than  in  the  pulmo- 
nary circulation  (255).  Shortly  after  the  start  of  the 
maneuver,  the  distending  pulmonary  arterial  pressure 
falls  abruptly  as  the  filling  pressure  of  the  heart  is 
reduced  by  the  increased  intrathoracic  pressure  (187, 
253);  it  remains  low  during  the  period  of  strain.  Upon 
release  of  the  expiratory  effort,  pulmonary  arterial 
mean  and  pulse  pressures  "overshoot"  the  prestrain 
level,  but  to  a  lesser  extent  than  in  the  systemic 
arteries.  During  the  maneuver,  considerable  quanti- 
ties of  blood  may  be  displaced  from  the  thorax  to  the 
periphery  (253).  The  systemic  arterial  overshoot 
seems  to  involve  a  combination  of  an  increased 
cardiac  output  and  vasoconstriction;  although  some 
believe  that  these  same  mechanisms  are  involved  in 
the  pulmonary  arterial  overshoot,  the  evidence  for 
pulmonary  vasoconstriction  is  much  more  tenuous 
than  for  systemic  vasoconstriction  (255). 


OCCLUSION    OF    A    PULMONARY    ARTERY 

In  principle,  occlusion  of  larger  and  larger  portions 
of  the  pulmonary  arterial  tree  provides  a  simple  tool 


BEFORE 


LEFT 


RIGHT 


DURING 


I 

£ : 

' 

J._;jt"'- 

E=Si5P 

-  1"  '■ 

fig.  42.  Effect  of  complete  occlusion  of  one  pulmonary  artery 
on  ipsilateral  oxygen  uptake.  Before  inflation  of  the  occlusive 
balloon  in  the  right  pulmonary  artery  (left  panel),  both  lungs 
share  almost  equally  in  the  oxygen  uptake.  The  middle  panel 
shows  the  occlusive  balloon,  inflated  with  Diodrast,  positioned 
at  the  end  of  a  cardiac  catheter  in  the  right  pulmonary  artery. 
After  complete  occlusion,  the  oxygen  uptake  by  the  right  lung 
ceases.  [After  Fishman  et  al.  (139J.J 


for  testing  the  passive  effects  of  an  increase  in  pulmo- 
nary blood  flow  on  pulmonary  arterial  pressures 
(fig.  34)  and  pulmonary  vascular  resistance.  In  the 
open-chest  dog,  graded  occlusion  of  the  pulmonary 
vascular  tree  is  easily  performed  (194).  The  situation 
is  much  more  complicated  in  the  closed-chest  dog  or 
man  in  whom  balloon-tipped,  venous  catheters  are 
guided,  under  fluoroscopic  control,  into  a  pulmonary- 
artery;  in  this  experimental  situation  additional  tech- 
niques, such  as  bronchospirometry,  are  required  to 
establish  the  degree  of  occlusion  which  has  been 
accomplished  (fig.  42). 

In  wondrous  contrast  to  the  catastrophic  effects 
occluding  the  pulmonary  vascular  tree  by  emboli,  in- 
flation of  a  balloon  in  one  pulmonary  artery  is  entirely- 
innocuous:  the  metabolic  rate,  the  total  cardiac  out- 
put, the  systemic  arterial  and  left  atrial  blood  pres- 
sures, and  the  heart  rate  remain  unchanged;  the  total 
ventilation  rarely  increases  by  more  than  10  per  cent 
(53,  101).  However,  even  this  slight  change  in  total 
minute  ventilation  helps  to  adapt  the  alveolar 
ventilation  to  the  altered  pulmonary  capillary  per- 
fusion (390). 

The  first  studies  of  the  pulmonary  circulation  fol- 
lowing occlusion  of  one  pulmonary  artery-  were  made 
in  1876  on  the  open-chest  dog  (132).  These  indicated 
that  the  pulmonary  arterial  pressure,  measured 
proximal  to  the  site  of  occlusion,  increased  by  50  per 
cent  following  interruption  of  the  blood  flow  to  one 
lung.  Subsequently,  a  similar  procedure  in  other 
open-chest  animals  found  lesser  increases,  ranging  from 
zero  in  the  rabbit  ( 1 25)  to  20  per  cent  in  the  cat  ( 1 25). 
More  puzzling  than  these  divergent  results  in  the  dif- 
ferent species  is  the  fact  that  in  the  intact  dog,  oc- 
clusion of  one  pulmonary  artery  by  a  balloon-tipped 
catheter  has  also  produced  variable  effects:  on  the 
one  hand  are  results  indicating  that  pulmonary  ar- 
terial pressure  remains  essentially  unchanged  (68, 
101);  other  results  indicate  an  increase  in  pressure  of 
the  order  of  33  per  cent  (252,  259).  However,  since 
none  of  the  experiments  in  the  dog  verified  the  degree 
of  pulmonary  arterial  occlusion  produced  by  the  in- 
flated balloon,  it  seems  reasonable  to  assume  that  in- 
flation of  the  balloon  was  not  equally  successful  in 
producing  complete  occlusion  in  the  different  dogs, 
and  that  the  larger  increments  in  pulmonary  arterial 
pressure — i.e.,  of  the  order  of  33  per  cent  (252,  259) — 
represent  the  more  complete  occlusions. 

In  man  the  results  have  been  more  consistent:  after 
complete  occlusion  of  one  pulmonary  artery,  the 
pulmonary  arterial  pressure  (primarily  systolic) 
proximal  to  the  occlusion  increases,  the  pulmonary- 


i7i4 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


blood  volume  on  the  patent  side  also  increases,  the 
pulmonary  circulation  time  decreases  and  the  pul- 
monary vascular  resistance  decreases  (42,  101).  Be- 
cause of  the  configuration  of  the  trachea  in  the  dog, 
the  completeness  of  the  unilateral  interruption  of 
blood  flow  is  more  readily  checked  by  bronchospi- 
rometry  in  man  (fig.  42);  when  the  right  ventricular 
output  has  been  shown  to  be  completely  diverted  to 
one  lung  in  man,  the  pulmonary  arterial  pressure  has 
been  found  to  increase  by  30  to  40  per  cent  (5  to 
7  mm  Hg),  and  the  calculated  resistance  to  fall  to  40 
or  50  per  cent  of  the  initial  value  (42,  53,  101).  The 
increase  in  pulmonary  arterial  pressure  seems  en- 
tirely attributable  to  the  passive  consequences  of  an 
augmented  pulmonary  blood  flow  and  volume. 


EFFECTS  OF  EXERCISE  ON  PULMONARY  CIRCULATION 

Exercise  is  a  practical  expedient  for  increasing  pul- 
monary blood  flow.  However,  by  comparison  with 
unilateral  occlusion  of  one  pulmonary  artery,  it  suffers 
the  disadvantage  of  simultaneously  evoking  changes 
in  the  ventilation,  in  the  performance  of  the  heart, 
and  in  a  variety  of  circulatory  parameters. 

Experimentally,  dog  and  man  have  been  exercised 
in  various  different  ways:  electrical  stimulation, 
ergometer,  push-pedal,  and  treadmill.  The  workload 
imposed  by  the  exercise,  as  well  as  the  efficiency  with 
which  the  exercise  is  performed,  varies  with  the  type 
of  exercise,  the  position  in  which  it  is  performed,  and 
the  familiarity  with  the  exercise  (7,  12).  For  practical 
reasons,  the  work  load  is  generally  inferred  from  the 
increase  in  oxygen  uptake  rather  than  measured 
directly  (216). 

Pulmonary  Blood  Flow 

The  first  measurements  of  the  cardiac  output 
during  exercise  were  made  by  foreign  gas  methods 
(240).  Since  then,  with  few  exceptions  (3),  the  foreign 
gas  methods  have  been  superceded  by  indicator- 
dilution  methods  and  by  applications  of  the  Fick 
principle. 

For  accuracy,  the  use  of  the  Fick  method  during 
exercise  requires  that  the  oxygen  uptake  at  the  mouth 
provide  a  precise  measure  of  the  oxygen  uptake  by- 
pulmonary  capillary  blood,  and  that  the  pulmonary 
arteriovenous  oxygen  difference  be  constant.  These 
criteria  are  most  apt  to  be  satisfied  when  respiration 
and  circulation  become  stable,  i.e.,  when  minute 
ventilation,   respiratory   exchange  ratio,   oxygen  up- 


take, heart  rate,  arteriovenous  oxygen  difference,  and 
cardiac  output  no  longer  vary  with  time.  Unfortu- 
nately, all  these  parameters  do  not  stabilize  simulta- 
neously (108,  109,  136).  Thus,  the  oxygen  uptake  at 
the  mouth,  and  the  arteriovenous  oxygen  difference 
mav  level  off  after  1  min  of  heavy  exercise  (up  to  1200 
ml  min  nr),  whereas  the  respiratory  exchange  ratio 
and  the  ventilation  require  much  longer  to  reach  a 
plateau.  As  long  as  the  respiratory  gas  exchange  is 
unstable,  it  is  difficult  to  be  sure  that  the  measure- 
ment of  the  oxygen  uptake  at  the  mouth  provides  a 
reliable  value  for  the  numerator  of  the  Fick  equation, 
i.e.,  of  the  oxygen  taken  up  by  blood  perfusing  the 
pulmonary  capillaries.  On  the  other  hand,  when 
both  the  respiration  and  circulation  become  stable — 
usually  within  3  min  in  normal  subjects  performing 
light,  supine  exercise  (O2  uptake  up  to  400  ml  min/ 
m'2) — the  prospect  of  an  accurate  measurement  of 
pulmonary  blood  flow  is  increased  (212).  Obviously, 
during  heavy  exercise  (O2  uptake  greater  than  1000 
ml  min  m2),  it  may  become  difficult  to  achieve  a 
steady  state;  indeed,  as  exhaustion  is  approached,  the 
Fick  method  may  become  completely  unreliable.  It 
is  apparent  that  these  considerations  do  not  support 
the  practice  of  applying  the  Fick  principle  to  the 
measurement  of  the  cardiac  output  during  brief 
periods  of  heavy  exercise  (108,  109).  It  would  be  re- 
assuring if  this  use  of  the  Fick  principle  were  validated 
by  another  independent  method,  such  as  the  Stewart- 
Hamilton,  which,  in  principle,  requires  a  briefer 
steady  state. 

Blood  Flow  and  Oxygen  Uptake 

In  the  unanesthetized  dog  (12)  and  in  normal  man 
(104,  149,  335),  an  increment  in  oxygen  uptake  (AY0„) 
of  100  ml  is  usually  associated  with  an  increment  in 
cardiac  output  (AQ.)  of  600  to  800  ml.  However,  both 
lower  (101,  109,  258)  and  higher  (101  )  ratios  of  AQ. / 
AVo,  have  also  been  observed.  One  likely  explanation 
for  at  least  part  of  the  variability  is  that  different 
degrees  of  approach  to  the  '"basal"  state  were  achieved 
prior  to  exercise  in  the  different  studies:  it  has  been 
shown  that  in  those  studies  in  which  a  serious  attempt 
is  made  to  achieve  a  basal  pre-exercise  state,  the 
ratio  AQ/AVoj  may  even  exceed  1  liter  of  cardiac 
output  per  100  ml  of  oxygen  uptake  (132);  conversely, 
when  a  nonbasal  state  exists  prior  to  the  exercise,  the 
ratio  AQ./AV0„  may  fall  below  600  ml  (109).  This 
point  is  emphasized  by  the  solid  line  of  figure  12, 
which  indicates  that  for  a  given  level  of  oxygen  uptake 
the  cardiac  output  during  excitement  is  higher  than 


DYNAMICS    OF    PULMONARY    CIRCULATION 


!7I5 


during  exercise;  this  effect  may  continue,  to  an  un- 
predictable degree,  during  mild  exercise. 

In  heart  failure  the  ratio  AQ/AV02  is  often  abnor- 
mally low,  i.e.,  less  than  600  ml  increase  in  flow  per 
100  ml  increase  in  oxygen  uptake.  A  sti  iking  dissocia- 
tion between  AQ,  and  AV0,  follows  the  exhibition  of 
dinitrophenol,  so  that  the  cardiac  output  continues 
at  basal  levels  even  though  oxygen  uptake  increases 
tremendously  (216). 

Arteriovenous  Oxygen  Difference 

The  pulmonary  arteriovenous  oxygen  difference 
increases  during  exercise.  However,  in  contrast  to  the 
roughly  linear  relation  between  cardiac  output  and 
oxygen  uptake  during  graded  exercise,  the  relation 
between  the  arteriovenous  oxygen  difference  and 
oxygen  consumption  is  clearly  hyperbolic  (109,  382). 
Whether  the  oxygen  requirements  of  the  tissue  are  met 
predominantly  by  an  increase  in  cardiac  output  or  by 
a  greater  extraction  of  oxygen  from  each  unit  of  blood 
perfusing  the  tissues  seems  to  depend,  at  least  in  part, 
on  the  type  of  exercise,  the  body  position  in  which  the 
exercise  is  performed,  and  the  ambient  temperature 
(7,  336).  Parenthetically,  it  is  of  interest  that  during 
graded  exercise  (up  to  2000  ml/min/m2)  trained  and 
untrained  subjects  increase  cardiac  output  and  widen 
arteriovenous  differences  for  oxygen  in  an  identical 
fashion  (149). 

Pulmonary  Vascular  Pressures 

Because  of  the  difficulty  in  measuring  intrathoracic 
pressures,  pulmonary  vascular  pressures  are  conven- 
tionally referred  to  atmosphere.  In  only  one  study 
were  they  also  referred  to  esophageal  pressures  (109); 
this  study  suggested  that  conventional  luminal  pres- 
sures tend  to  underestimate  slightly  the  transmural 
pressures.  Before  considering  the  change  in  pulmo- 
nary artery  pressure  during  exercise,  it  is  relevant  to 
recall  that:  a)  pulmonary  vascular  pressures  are 
difficult  to  measure  accurately  during  exercise  since 
respiratory  swings  are  marked  and  the  records  are 
apt  to  be  distorted  by  artifacts,  and  b)  especially 
during  severe  exercise,  shifts  in  mid-position  of  the 
lung  and  changes  in  compliance  confuse  the  recogni- 
tion of  the  mechanisms  involved  in  a  change  in  pres- 
sure (109). 

Until  a  few  years  ago,  because  of  the  practical 
difficulties  in  measuring  small  changes  in  pressure 
during  exercise,  it  was  uncertain  if  light  (supine) 
exercise   elicited   an   increase   in   pulmonary   arterial 


pressure  (104,  208,  346).  Indeed,  an  appreciable 
increase  was  believed  to  occur  only  at  levels  of  exer- 
cise which  tripled  the  cardiac  output  (89).  However, 
recent  refinements  in  manometric  methods,  coupled 
with  the  substitution  of  continuous  pressure  recording 
for  the  tedious  process  of  measuring  and  integrating 
individual  pressure  pulses,  have  established  that  the 
pulmonary  arterial  pressure  increases  (by  3-5  mm  Hg) 
even  during  light  supine  exercise  (132,  370,  383). 

The  behavior  of  the  pulmonary  arterial  pressure 
during  light  exercise  is  quite  stereotyped  (fig.  28) :  at 
the  start  of  the  exercise,  the  (luminal)  pulmonary 
arterial  pressure  increases  abruptly  by  3  to  5  mm  Hg. 
As  exercise  is  continued,  a  plateau  is  reached,  gener- 
ally 1  to  2  mm  Hg  less  than  peak  values  (132,  382). 
The  increase  in  systolic  pressure  exceeds  the  increase 
in  diastolic  pressure.  As  a  rule,  the  higher  the  pre- 
exercise  level  of  the  pulmonary  arterial  pressures,  the 
higher  the  values  reached  during  exercise.  Immedi- 
ately after  the  exercise,  the  pulmonary  arterial  pres- 
sure often  falls  below  control,  resting  values  (iog,  132, 
382). 

The  pulmonary  arterial  flow-pressure  points  ob- 
tained by  different  investigators  during  graded  exer- 
cise are  superimposed  on  the  pressure-flow  line  of 
figure  34.  At  the  lower  grades  of  exercise,  the  points 
fall  along  the  flow-pressure  curve  obtained  in  the 
course  of  progressive  curtailment  of  the  pulmonary 
vascular  bed  by  balloon-occlusion.  At  the  higher 
grades  of  exercise  the  pulmonarv  arterial  pressure  at 
any  given  level  of  blood  flow  tends  to  exceed  the 
corresponding  pressure  during  balloon-occlusion. 

Direct  measurements  of  the  left  atrial  pressure 
during  exercise  in  intact  man  or  dog  have  not  been 
reported.  On  the  other  hand,  in  dogs  exercised  by 
electrical  stimulation  of  the  extremities,  the  left  atrial 
pressure  remains  unchanged  (125);  unfortunately,  the 
level  of  exercise  in  these  experiments  is  unknown.  In 
man  the  slight  increments  of  the  pulmonary  arterial 
pressure  during  mild  exercise  suggest  that  if  the  left 
atrial  pressure  does  increase,  the  increase  cannot 
exceed  a  few  mm  Hg.  The  pulmonary  ''wedge"  pres- 
sure is  unaffected  by  mild  exercise  but  may  increase 
slightly  during  severer  exercise  (104). 

Pulmonary  Blood  Volume 

There  is  considerable  indirect  evidence  to  indicate 
that  the  pulmonary  blood  volume  increases  during 
supine  exercise:  the  central  blood  volume  increases 
(48,  101),  the  pulmonary  compliance  decreases  (279), 
and,  except  for  the  muscles  (250),  the  regional  blood 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


volume  decrease  (48).  However,  such  evidence  ap- 
plies only  to  the  steady  part  of  the  exercise;  more 
difficult  to  ascertain  is  the  pattern  of  change  in  the 
pulmonary  blood  volume  from  the  start  to  the  finish 
of  the  exercise.  In  this  regard,  the  most  convincing  clue 
is  the  characteristic  sequence  of  changes  in  the  pulmo- 
nary arterial  pressure  (fig.  28);  this  pattern  is  con- 
sistent with  an  abrupt  increase  in  the  pulmonary  blood 
volume  at  the  start  of  the  supine  exercise,  a  gradual 
stabilization  at  below-peak  values  as  exercise  is  con- 
tinued, and  a  prompt  fall  to  below  resting  values 
when  exercise  is  arrested  (iog,  132).  How  the  in- 
creased blood  volume  is  apportioned  among  the 
different  vascular  segments  of  the  lung  is  unknown; 
however,  the  pulmonary  capillaries  apparently  share 
in  the  increase  (364). 

Pulmonary  Vascular  Resistance 

The  calculated  pulmonary  vascular  resistance  either 
remains  unaltered  (iog)  or,  more  often,  decreases 
(101,  346)  during  light  to  moderate  (supine)  exercise. 
Although  it  is  generally  believed  that  the  decrease  in 
calculated  resistance  at  these  levels  of  exercise  repre- 
sents both  the  widening  of  patent  pulmonary  vessels 
and  the  opening  of  closed  vessels  (208,  241,  346),  the 
particular  mechanisms  which  are  responsible  for  this 
change  in  vascular  geometry  remain  speculative. 
Three  reasonable  alternatives  come  to  mind :  active 
pulmonary  vasodilatation,  passive  dilatation  by  the 
decrease  in  pleural  pressure,  or  passive  dilatation  by 
the  increase  in  luminal  pulmonary  arterial  blood 
pressure.  Of  the  three  alternatives,  the  passive  increase 
in  pulmonary  arterial  luminal  (and  transmural)  pres- 
sure seems  sufficient — without  invoking  vasomotric- 
ity — to  account  for  the  widening  and  opening  of  the 
pulmonary  vessels  at  these  low  grades  of  exercise  (187). 

During  heavy  exercise,  as  the  pulmonary  blood 
flow  is  more  than  tripled,  the  pulmonary  vascular 
resistance  (calculated  on  the  basis  of  an  assumed  left 
atrial  pressure)  is  described  as  becoming  constant 
(252).  As  pointed  out  previously,  the  pulmonary 
vascular  tree  is  then  pictured  as  behaving  as  though  it 
were  comprised  of  "rigid  tubes";  the  "rigid  tubes," 
in  turn,  are  envisaged  as  wide-open,  low-resistance 
vessels  with  elastic  fibers  stretched  to  tighten  their 
collagen  "jackets"  (187).  Generally  speaking,  the 
calculations  of  pulmonary  vascular  resistance  during 
heavy  exercise  on  the  basis  of  pulmonary  arterial 
pressure  and  flow  (fig.  34)  are  consistent  with  this 
view.  However,  this  interpretation  of  calculated 
resistance  is  handicapped   by  the  lack  of  assurance 


concerning  the  simultaneous  behavior  of  the  left 
atrial  pressure,  the  pulmonary  blood  volume  and  the 
pleural  pressures.  Indeed,  without  information  about 
these  critical  parameters,  the  ratio  of  pulmonary 
arterial  pressure  to  pulmonary  blood  flow  during 
heavy  exercise  may  represent  either  an  increase  or  a 
decrease  in  pulmonary  vascular  resistance.  Finally,  as 
indicated  previously,  not  only  may  the  kinetic  energv 
in  the  pulmonary  artery  exceed  the  potential  energy 
at  high  rates  of  pulmonary  blood  flow,  but  intercon- 
versions  of  potential  and  kinetic  energy  are  bound  to 
occur  along  the  length  of  the  pulmonary  vascular  tree 
(20).  Consequently,  during  heavy  exercise,  even  the 
ratio  of  the  pulmonary  vascular  pressure  gradient 
(potential  energy  gradient)  to  the  pulmonarv  blood 
flow  need  not  provide  a  reliable  index  of  pulmonary 
vascular  dimensions. 


MISCELLANEOUS    MECHANICAL    INFLITENCES 

Heart  Rate 

In  normal  dog  and  man,  speeding  up  of  the  heart 
rate  by  atropine,  is  ordinarily  without  appreciable 
effect  on  pulmonary  vascular  blood  pressures  or  blood 
flow  (424);  in  some  instances  the  cardiac  output  may 
increase  by  40  to  50  per  cent  (168).  In  patients  with 
"tight"  mitral  stenosis,  even  the  slight  increment  in 
cardiac  output  induced  by  atropine  may  suffice  to 
precipitate  pulmonary  edema  by  elevating  pulmonary 
venous  and  pulmonary  capillary  pressures. 

Slowing  of  the  heart  has  been  produced  by  vagal 
stimulation  in  dogs:  as  the  heart  rate  drops  to  one- 
half  or  one-third  of  the  initial  value,  the  cardiac  out- 
put falls  and  the  pulmonary  venous  pressure  rises 
(65).  A  similar  combination  of  bradycardia,  low 
cardiac  output,  and  high  pulmonary  venous  pressure 
also  occurs  when  intracranial  pressure  is  considerably 
increased;  in  this  case,  the  occurrence  of  pulmonary 
edema  is  often  potentiated  by  left  ventricular  failure 
from  intense  systemic  vasoconstriction.  Measures 
which  prevent  the  bradycardia  or  left  ventricular 
overwork  also  protect  against  the  pulmonary  edema 
of  increased  intracranial  pressure  (65). 


"Bronclwmotor  Tone" 

This  colloquialism  refers  to  a  state  of  partial  con- 
traction of  bronchial  smooth  muscle  (95,  132,  351). 
An  increase  in  "bronchomotor  tone"  may  conceivably 
affect  pulmonary  vascular  dimensions  in  at  least  three 


DYNAMICS    OF    PULMONARY    CIRCULATION 


'7'7 


different  ways:  /)  by  mechanical  distortion  of  the 
pulmonary  arterial  tree  and  of  the  large  pulmonary 
veins  which  lie  adjacent  to  the  tracheobronchial  tree; 
2)  by  raising  intra-alveolar  pressure  to  compress  the 
pulmonarv  capillaries  and  to  increase,  thereby,  their 
resistance  to  perfusion;  and  j)  by  increasing  the 
"elastance"  of  the  lung  (ig,  305,  351 ),  i.e.,  the  elastic 
forces  which  are  developed  during  each  respiratory 
cycle.  Many  experimental  (95,  305)  and  clinical 
observations  attest  to  the  capacity  of  the  bronchial 
smooth  muscle  to  undergo  drastic  changes  in  tone  in 
response  to  appropriate  stimulation;  this  severe  type 
of  bronchospasm  poses  no  problem  in  recognition. 
More  troublesome  is  the  prospect  that  subtle  changes 
in  "bronchomotor  tone"  mav  escape  detection  (351). 
As  a  general  approach,  bronchomotor  tone  may 
reasonably  be  considered  to  remain  unchanged  during 
the  course  of  an  experiment  if:  a)  clinical  evidences  of 
bronchial  obstruction  or  dyspnea  do  not  appear;  b) 
the  ventilatory  pattern  remains  unchanged;  and  c) 
the  mechanical  properties  of  the  lungs  remain  un- 
altered (132,  153).  When  the  nature  of  the  experiment 
precludes  such  clinical  and  experimental  stability, 
decision  as  to  the  influence  of  altered  bronchomotor 
tone  on  pulmonary  hemodynamics  falls  to  the  experi- 
menter. 


Following  complete  collapse,  only  10  to  15  per  cent 
of  the  cardiac  output  perfuses  the  collapsed  lung  (316). 

Several  different  ways  have  been  used  to  trace  the 
sequential  changes  in  perfusion  following  bronchial 
obstruction :  the  change  in  peripheral  arterial  oxygen- 
ation (316),  the  change  in  "venous  admixture'"  (23) 
and  angiography  (85).  Although  not  entirely  con- 
sistent (5),  the  results  seem  to  indicate  that  within  an 
hour  after  the  bronchial  obstruction,  the  blood  flow 
to  the  nonventilating  lung  is  apt  to  decrease  by  30  to  40 
per  cent  (316).  In  time,  the  blood  flow  to  the  non- 
ventilating  lung  decreases  further;  up  to  a  month  may 
be  required  for  nearly  all  mixed  venous  blood  to  be 
excluded  from  the  atelectatic  lung  and  for  systemic 
arterial  oxygenation  to  return  toward  normal  values 
(85).  By  way  of  contrast,  the  spontaneous  restoration 
of  systemic  arterial  oxygenation  in  patients  with 
pneumonia  or  pneumothorax  is  more  often  a  matter 
of  days  than  of  weeks. 

The  observation  has  been  made  that  the  pulmonarv 
collateral  circulation  may  proliferate  in  atelectatic 
areas.  However,  the  strong  possibility  exists  that 
complications  of  atelectasis,  such  as  pulmonary  infec- 
tion, rather  than  the  mechanical  collapse,  per  se,  are 
responsible  for  the  expanded  collateral  circulation 
(316). 


Mechanical  Compression  (Atelectasis) 

It  is  well  known  that  mechanical  factors  influence 
the  caliber  of  the  pulmonary  blood  vessels  and  their 
resistance  to  blood  flow.  For  example,  at  a  given 
hydrostatic  pressure  head,  moderately  inflated  lungs 
contain  more  blood  (wider  vascular  calibers)  than  do 
either  collapsed  or  markedly  distended  lungs  (146); 
similarly,  pneumothorax  not  only  decreases  the  air 
content  of  the  lungs  but  also  shrinks  the  vascular 
calibers  (380). 

Atelectasis  is  generally  believed  to  affect  the  pulmo- 
nary circulation  by  mechanical  compression.  It  has 
been  produced  experimentally  by  bronchial  obstruc- 
tion (85,  94),  pneumothorax  (380)  and  sustained 
hypoventilation  (359).  The  changes  following  bron- 
chial obstruction  have  been  most  intensively  studied: 
following  complete  occlusion  of  a  bronchus,  gas  is 
absorbed  at  a  rate  set  by  the  composition  of  the  gas, 
the  surface  area  and  the  rate  of  perfusion  of  the  af- 
fected area  (94).  As  the  gas  content  of  the  lung  de- 
creases, the  mechanical  compression  of  the  pulmo- 
nary blood  vessels — particularly  of  the  capillaries  in 
the  collapsed  alveoli — diverts  the  blood  flow  from  the 
atelectatic  to  the  unaffected  parts  of  the  lung  (85,  380). 


Hypertonic  Solutions 

A  particularly  puzzling  phenomenon  has  been  the 
occurrence  of  pulmonary  arterial  hypertension  fol- 
lowing the  injection  of  hyperosmotic  solutions,  e.g., 
20  per  cent  sodium  chloride,  into  a  peripheral  vein 
(28).  Different  mechanisms  have  been  proposed  to 
account  for  this  pressor  response,  including  selective 
constriction  of  the  superior  pulmonary  veins  at  their 
entry  into  the  left  atrium  (120).  Recently,  microscopic 
examination  has  shown  that  intravascular  red-cell 
agglutination  occurs  after  the  injection  of  highly  con- 
centrated salt  and  sugar  solutions,  raising  the  possi- 
bility that  luminal  obstruction,  rather  than  vasocon- 
striction, may  underlie  the  pulmonary  pressor  response 
to  hypertonic  solutions  (333,  376). 


PULMONARY    VASOMOTOR    ACTIVITY 

It  has  been  shown  in  a  previous  section  that  the 
pulmonary  circulation  is  equipped  with  vascular 
smooth  muscle  and  nerves,  and  that  the  pulmonarv 
circulation  has  the  ability  to  vasoconstrict  and  to 
vasodilate.  Much  more  difficult  to  decide  is  whether 


1 718 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


this  capacity  for  vasoconstriction  is  actually  used  by 
the  intact  animal  under  natural  conditions:  the 
strength  of  such  a  decision  depends  on  the  degree  to 
which  all  conceivable  passive  influences  on  the  pulmo- 
nary circulation  have  to  be  appraised  and  found 
wanting.  And  the  list  of  potential  passive  influences 
is  apt  to  be  longer  for  experiments  performed  under 
natural  conditions  than  under  contrived  experimental 
conditions  (387). 

Recognizing  that  final  proof  of  the  operation  of 
pulmonary  vasomotor  activity  under  natural  condi- 
tions is  difficult  to  obtain,  there  is,  nonetheless, 
reasonable  evidence  to  indicate  that  it  does  occur; 
this  evidence  is  of  two  types:  /)  the  response  of  the 
pulmonary  circulation  to  acute  hypoxia  and  to  acute 
acidosis  and  2)  the  occurrence  of  pulmonary  vaso- 
motor reflex  activity.  More  uncertain  is  the  occurrence 
of  pulmonary  vasomotor  waves. 

Respiratory  Gases 

The  first  experiments  devoted  to  the  effects  of  the 
respiratory  gases  on  the  pulmonary  circulation  were 
concerned  with  asphyxia.  Although  these  experiments 
did  show  that  asphyxia  elicited  pulmonary  hyperten- 
sion, they  made  no  attempt  to  distinguish  which  of 
the  respiratory  gases  was  responsible  for  the  rise  in 
pressure.  Thirty  years  later,  acute  hypoxia,  per  se, 
was  shown  to  be  capable  of  eliciting  pulmonary 
hypertension  in  the  anesthetized  dog  (132).  There- 
after, interest  in  the  respiratory  gases  was  episodic 
until  1946,  when  Euler  and  Liljestrand  demonstrated 
that  acute  hypoxia  and  acute  hypercapnia  evoked  an 
increase  in  pulmonary  arterial  pressure  in  the  anesthe- 
tized cat  and  that  this  pressor  response  occurred  in 
the  face  of  an  unchanged  or  a  decreased  left  atrial 
pressure  (125,  268).  Although  these  experiments  were 
inconclusive  in  some  respects — e.g.,  the  lack  of  meas- 


urement of  pulmonary  blood  flow  or  peripheral 
arterial  oxygen  saturation  or  pH —  they  constituted 
a  landmark  in  the  study  of  the  pulmonary  circulation 
because  of  the  clairvoyant  hypothesis  which  they  sug- 
gested and  the  subsequent  work  which  they  stimu- 
lated. The  hypothesis  consisted  of  three  parts:  /)  that 
a  change  in  the  composition  of  the  inspired  gas  is 
capable  of  eliciting  an  increase  in  resistance  and  that 
this  increase  in  resistance  stems,  in  turn,  from  pulmo- 
nary vasoconstriction;  2)  that  this  vasoconstriction  is 
mediated  by  local  vasomotor  responses  rather  than 
by  reflexes  involving  the  extrapulmonary  portions  of 
the  autonomic  nervous  system;  and  3)  that  the  vaso- 
motor effects  of  the  respiratory  gases  serve  to  adjust 
alveolar  perfusion  to  alveolar  ventilation.  Subsequent 
experiences  have  done  more  to  supply  and  clarify 
details  than  to  alter  the  general  structure  of  the  hy- 
pothesis; in  particular,  they  have  distinguished  be- 
tween the  effects  of  acute  hypoxia,  acute  hypercapnia, 
and  respiratory  acidosis  on  the  pulmonary  circulation. 

Acute  Hypoxia 

A  reduction  in  the  fraction  of  oxygen  in  the  inspired 
air — generally  below  1 2  per  cent — has  elicited  an  in- 
crease in  pulmonary  arterial  pressure  in  every  species 
in  which  it  has  been  tested  (132).  In  the  intact,  un- 
anesthetized  animal  and  man  this  pressor  response 
generally  occurs  when  the  oxygen  saturation  of 
peripheral  arterial  blood  drops  below  80  per  cent 
(136).  The  associated  increase  in  mean  pressure  is  of 
the  order  of  4  to  8  mm  Hg  (fig.  43)  (300).  Only  a 
small  part  of  this  increase  in  pressure  is  attributable  to 
an  increase  in  pulmonary  blood  flow:  during  the 
breathing  of  a  10  per  cent  oxygen  mixture  the  in- 
crease in  flow  rarely  exceeds  30  per  cent  (132).  Since 
the  usual  passive  determinants  of  pulmonary  vascular 
pressure — pulmonary    blood    volume    (154),    ventila- 


fic.  43.  Effect  of  acute  hypoxia  on 
pulmonary  arterial  pressure.  During 
acute  hypoxia,  the  systolic,  diastolic, 
and  mean  blood  pressures  increase.  The 
heart  rate  also  increases  and  respiratory 
fluctuations  in  the  luminal  pressures 
(referred  to  atmosphere)  become  more 
marked. 


H.P. 
H 


A       A       A       A       r\        A 
\J   KJ    Sj    V  \J 

21%     op 


30 

5- 

0 


W^£ 


12%    o2 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1719 


Mixed 
Venous  P02 

Pulmonary 
Venous  P02 

mm  Hk 

mm  Hg 

40 

100 

3° 

105 

3° 

45 

35 

35* 

table  3.  Representative  Oxygen  Tensions  oj  Precapillary 
and  Postcapillary  Pulmonary  I  'essels  During 
I  'at  urns  Experimental  Circumstant  es 


Rest;  ambient  air 
Moderate  exercise;  ambient  air 
Bilateral  hypoxia;  12%  02 
Unilateral  hypoxia;  5%  O: 

*  Pulmonary  venous  P,,„  on  the  opposite  side,  i.e.,  the 
hyperoxic  side,  exceeds  100  mm  Hg. 

tion  (132),  and  left  atrial  pressure  (125,  303) — 
undergo  too  little  change  to  affect  the  level  of  pulmo- 
nary arterial  pressure,  the  increase  in  the  blood  pres- 
sure gradient  across  the  lungs  is  generally  acknowl- 
edged to  involve  an  active  increase  in  pulmonary 
vascular  resistance,  i.e.,  vasoconstriction. 

In  essence,  the  evidence  for  vasoconstriction  during 
acute  hypoxia  falls  into  three  categories  (132):  /)  the 
disproportionate  increase  in  the  pressure  gradient 
across  the  lung  with  respect  to  the  increment  in 
pulmonary  blood  flow  (fig.  32)  (132);  .' )  the  redistri- 
bution of  the  pulmonary  blood  flow  in  favor  of  the 
high-oxygen  lung  during  unilateral  hypoxia  (209, 
328,  408);  and  2)  the  vasodilator  effects  of  infused 
acetylcholine  during  bilateral  (153)  and  unilateral 
(go)  hypoxia.  Despite  this  cumulative  evidence,  not 
all  are  convinced  that  acute  hypoxia  elicits  pulmo- 
nary vasoconstriction  (353).  However,  although  the 
evidence  against  pulmonary  vasoconstriction  is  not 
very  substantial,  it  does  serve  to  recall:  a)  that  the 
magnitude  of  the  changes  in  pulmonary  vascular 
blood  pressure  is  small;  b)  the  possibility  that  subtle 
extraneous  influences,  such  as  constriction  of  the 
extravascular  smooth  muscle  may  mimic  vasocon- 
striction; and  c)  that  the  effects  of  acute  hypoxia  on 
the  pulmonary  circulation  are  easily  overwhelmed 
by    known    mechanical    influences,    such    as   gravity 

('32)- 

The  particular  vascular  segment,  or  segments,  in- 
volved in  the  pulmonary  vasoconstriction  has  been 
sought  in  many  ways.  At  the  moment,  the  experi- 
ments performed  under  exceedingly  artificial  condi- 
tions favor  postcapillary  vasoconstriction.  On  the 
other  hand,  experiments  in  intact  animals  with  di- 
nitrophenol  (which  selectively  lowers  precapillary 
oxygen  tension)  have  demonstrated  precapillary  vaso- 
constriction (Bergofsky  et  al.,  unpublished  observa- 
tions). No  evidence  has  yet  been  adduced  to  indicate 
that  pulmonary  venous-left  atrial  junctions  constrict 
during  hypoxia.  The  opinion  of  the  author  is  that 


both  the  precapillary  small  vessels  and  the  post- 
capillary small  vessels  can  constrict  if  exposed  to  a 
sufficient  degree  of  hypoxia  (132).  An  idea  of  the 
oxygen  tensions  which  exist  in  the  pre-  and  post- 
capillary segments  under  various  conditions  is  given 
in  table  3. 

The  notion  that  the  small  pulmonary  muscular 
vessels,  regardless  of  location,  constrict  when  exposed 
to  a  sufficiently  intense  hypoxic  stimulus  implies  that 
during  ambient  air  breathing  the  hypoxic  mixed 
venous  blood  may  set  the  tone  (albeit  slight)  of  the 
pulmonary  ''arterioles"  and,  thereby,  the  level  of  the 
pulmonary  arterial  pressure;  this  tonic  effect  would 
presumably  be  heightened  during  exercise  (as  mixed 
venous  blood  becomes  more  unsaturated)  unless  the 
arterioles  were  passively  widened  by  mechanical 
influences.  The  experiments  involving  hypoxia  by 
airway  are  also  complicated.  In  these,  the  prospect 
exists  that  the  hypoxic  mixture  may  affect  the  pre- 
capillary as  well  as  the  postcapillary  segments;  none- 
theless, the  postcapillary  segments  would  be  more 
drastically  affected  because  mixed  venous  blood  is 
ordinarily  low  in  oxygen  tension.  Finally,  vasocon- 
striction of  either  segment  could  account  for  some 
rearrangement  of  the  pulmonary  blood  flow  in  pa- 
tients with  maldistribution  of  air  and  blood  even 
though  mechanical  influences  would  be  expected  to 
be  prepotent. 

Several  other  aspects  of  the  pressor  response  to 
acute  hypoxia  warrant  special  emphasis:  <;)  the  in- 
crease in  vascular  resistance  in  the  isolated  perfused 
lung — which  is  devoid  of  neurohumoral  influences,  of 
a  collateral  circulation,  and  of  extrapulmonary  re- 
flexes— indicates  that  hypoxia  acts  locally,  i.e.,  either 
by  a  direct  chemo-effect  on  the  vessel,  or  by  way  of  an 
intrapulmonary  reflex,  rather  than  by  way  of  extra- 
pulmonary controls  (116,  305);  b)  the  persistence  of 
the  pressor  response  after  ergotamine  and  atropine 
favors  a  direct  rather  than  a  reflex  action  (116,  125); 
c)  severe  hypoxia  or  anoxia,  as  commonly  used  in  the 
isolated  lung  or  in  artificial  preparations,  may  not 
represent  the  same  biochemical  stimulus  to  vascular 
smooth  muscle  as  tolerable  levels  of  hypoxia  in  animal 
or  man  (132);  d)  the  pulmonary  vasoconstriction 
evoked  by  hypoxia  has  to  be  reconciled  with  the  fact 
that  hypoxia  dilates  most  intact  vascular  beds,  con- 
stricts isolated  vessels,  and  dilates  the  placental 
vessels  (137);  e)  the  biochemical  mechanism  by  which 
acute  hypoxia  causes  smooth  muscle  to  constrict  has 
not  been  elucidated  (116);/)  the  catecholamines  are 
not  involved  in  the  pressor  response  to  moderate 
hypoxia  (163);  andjj)  the  vasoconstriction  evoked  by 


I  720 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


© 


© 


ONE    YEAR    RESIDENT 
NATIVE    RESIDENT  (".-}      =      NATIVE      "SEROCHE' 


fig.  44.  Schematic  representation  of 
respiratory  and  circulatory  measure- 
ments of  man  at  altitude  (14,900  feet). 
The  horizontal  line  in  each  panel  rep- 
resents a  typical  sea-level  value.  [Based 
on  Rotta  et  at.  (362).] 


cog 

mm    Hq 


SATURATION 
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HEMOGLOBIN 

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20- 

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80- 
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1  ~ 

J     j» 

• 
'     )  1          1 

CARDIAC 

HEART 

PULMONARY 

SYSTEMIC 

INDEX 

RATE 

ARTERY 

ARTERY 

MEAN 

MEAN 

PRESSURE 

PRESSURE 

acute  hypoxia  is  easily  overcome  by  mechanical  in- 
fluences, such  as  gravity  (2). 

Chronic  Hypoxia 

Chronic  hypoxia  and  hypoxemia  are  regular  fea- 
tures of  life  at  high  altitudes.  At  the  Fifth  Annual 
Conference  on  Research  in  Emphysema,  held  at 
Aspen,  Colorado,  June  15-18,  1962,  Pefialoza,  Sime, 
Banchero,  and  Gamboa  enlarged  upon  the  earlier 
observations  of  Hurtado  and  co-workers  at  Moro- 
cocha  (Peru)  (altitude  of  14,900  feet,  atmospheric 
oxygen  tension  of  80  mm  Hg)  (fig.  44)  (362).  They 
confirmed,  on  the  basis  of  right  heart  catheterization 
in  38  native  residents  of  Morococha,  that  mild  pulmo- 


nary hypertension  (of  the  order  of  41  15,  28  mm  Hg) 
coexisted  with  normal  cardiac  output  (average  of 
3.71  1/min/m2)  and  with  normal  pulmonary  wedge 
pressure  and  heart  rate.  During  strenuous  supine 
exercise  (four-  to  fivefold  increase  in  oxygen  uptake), 
the  doubling  of  blood  flow  (from  3.65  to  7.49  1  min/ 
m2)  was  associated  with  a  doubling  of  the  pulmonary 
arterial  pressure  (from  41/15,  29  to  77/40,  60).  In 
resting  subjects,  the  breathing  of  35  per  cent  oxygen 
(or  the  infusion  of  acetylcholine)  reduced  the  pulmo- 
narv  arterial  pressures  somewhat  (by  20  to  25  per 
cent)  but  not  quite  to  normal  sea  level  values.  Restudy 
of  1  1  altitude  dwellers  after  two  years  at  sea  level  dis- 
closed that  the  blood  gases,  the  respiration,  and  the 
circulation  had  returned  to  virtually  normal  sea  level 


DYNAMICS    OF    PULMONARY    CIRCULATION 


[72  1 


values  at  rest  but  that  the  increment  in  pulmonary 
arterial  pressure  during  exercise  was  still  excessive  for 
the  increment  in  blood  flow. 

Penaloza  et  al.  also  found  that  young  children  (1-5 
years  of  age),  born  and  raised  at  altitude,  had  more 
marked  pulmonary  hypertension  (of  the  order  of 
58/32,  45  mm  Hg)  than  older  children  (of  the  order 
of  41/18,  28  mm  Hg)  and  adults;  in  this  respect, 
the  youngsters  at  altitude  differed  strikingly  from 
their  counterparts  at  sea  level  who  achieved  normal 
pulmonary  arterial  pressures  during  the  third  to  sixth 
month  of  life. 

Pulmonary  hypertension  and  right  ventricular  en- 
largement are  characteristic  not  only  of  acclimatized 
man  but  also  of  acclimatized  cattle  (199).  Malaccli- 
matization  to  altitude  results  in  "mountain  sickness," 
both  in  man  and  in  animals.  Although  mountain 
sickness  is  not  a  distinct  clinical  entity,  at  least  two 
different  types  have  been  identified,  i.e.,  "brisket 
disease"  in  cattle  and  "seroche"  in  man  (table  4); 
both  seem  to  originate  in  alveolar  hypoventilation. 
Seroche  is  manifested  by  polycythemia,  easy  fatiga- 
bility, and  respiratory  distress  during  exertion;  its 
physiological  hallmarks  are  severe  hypoxemia,  hyper- 
capnia,  polycythemia,  and  pulmonary  hypertension 
(9,  362).  Removal  of  the  native  suffering  from  seroche 
to  sea  level  results  in  a  prompt  clinical  improvement 
and,  within  2  months  at  sea  level,  in  return  of  blood 
gases,  circulation,  and  respiration  at  rest  to  virtually 
normal  values  except  for  a  slight  residual  pulmonary 
hypertension  (Penaloza  et  al.).  On  the  other  hand, 
the  clinical  picture  of  brisket  disease  is  dominated  by 
the  consequences  of  severe  pulmonary  hypertension 
and  cor  pulmonale,  i.e.,  by  severe  right  ventricular 
failure,  functional  tricuspid  insufficiency,  and  de- 
pendent edema  of  the  brisket.  Although  the  clinical 
pictures  of  seroche  and  brisket  disease  overlap  some- 

table  4.  Chronic  Mountain  Sickness  in  Cattle  and  in  Man* 

Cattle  Man 

SYNONYM  BRISKET  DISEASE  SEROCHE 

Altitude  8,000  to  1,200  ft.  >  12,000  ft. 

Prepotent  Pulmonary  vaso-         Severe  hypoxemia 

mechanism  constriction  and  hypercapnia 

Major  conse-  Severe    pulmonary     Polycythemia;    mod- 

quences  hypertension;  erate  pulmonary 

cor  pulmonale  hypertension 

Clinical  Congestive  heart        CNS  disturbances; 

disability  failure  lassitude,  fatigue, 

dyspnea 

*  Based  on  observations  of  Hecht  et  al.  (199). 


what,  hypoxemia  and  polycythemia  are  far  less 
striking  in  the  animals  than  in  man  (table  4). 

At  least  part  of  the  severe  pulmonary  hypertension 
of  brisket  disease  is  attributable  to  the  sphincteric 
construction  of  the  small  precapillary  pulmonary 
vessels  in  cattle;  presumably  this  anatomical  arrange- 
ment not  only  affords  unusual  intrinsic  resistance  to 
blood  flow  but  also  effects  an  intense  pulmonary 
precapillary  vasoconstriction  in  response  to  mild 
hypoxia  (199).  It  is  not  yet  settled  if  postcapillary 
events  (left  heart  failure,  constriction  of  the  pulmonary 
veins,  or  "throttles")  are  also  involved  in  severe 
brisket  disease. 

Thick  pulmonary  precapillary  vessels  are  also  found 
in  native  residents  at  high  altitudes.  Thus,  the  small 
precapillary  vessels  are  thicker  than  their  counter- 
parts at  sea  level  and  smooth  muscle  extends  further 
down  the  pulmonary  vascular  tree  at  altitude  than  at 
sea  level.  This  medial  hypertrophy  of  the  pulmonary 
precapillary  vessels  suggests  that  the  pulmonary 
hypertension  of  man  at  altitude  originates  in  morpho- 
logic changes  as  well  as  in  vasomotor  activity  (Arias- 
Stella  and  Saldana,  unpublished  observations). 

Acute  Hvperoxia 

Enrichment  of  the  inspired  air  with  oxygen,  or  the 
substitution  of  100  per  cent  oxygen  for  air,  is  without 
appreciable  effect  on  the  normal  pulmonary  circula- 
tion (132).  This  lack  of  effect  is  consistent  with  the 
notion  that  the  resistance  vessels  of  the  normal  pulmo- 
nary circulation — despite  the  normal  unsaturation  of 
mixed  venous  blood — ordinarily  have  little  "tone." 
On  the  other  hand,  oxygen-rich  mixtures  have  been 
shown  to  partially  relieve  pulmonary  hypertension  of 
chronically  hypoxic  and  hypoxemic  animals  and  man 
(132,  164,  389).  The  effectiveness  of  oxygen-rich  mix- 
tures as  pulmonary  vasodilators  in  hypoxemic  states 
has  led  to  the  use  of  oxygen-rich  mixtures  to  relax 
hypertonic  pulmonary  vascular  smooth  muscle  in 
nonhypoxemic  states.  However,  there  is  no  apparent 
reason  to  suspect  that  hvperoxia  will  dilate  pulmo- 
nary vessels  which  are  not  hypoxemic. 

Acute  Hypercapnia 

At  first  encounter,  the  published  accounts  of  the 
effects  of  breathing  5  to  10  per  cent  C02  in  air  on  the 
pulmonary  circulation  are  utterly  confusing.  Un- 
doubtedly, part  of  the  confusion  arises  from  the  failure 
to  take  into  account  the  peculiarities  of  the  different 
preparations  and  experimental  conditions.  The  situa- 
tion is  improved  by  sorting  the  results  according  to 


i  72  a 


HANDBOOK    OF    PHYSIOLOGY     -"    CIRCULATION     II 


♦  Q  •    2  87    L/min 

pH-   7  38  

L    Ac  "    10   mgm    V. 


Q  ■    2  94   L/min 
pH  -7  21 
L  Ac   ■    56  mgm   °/. 


fig.  45.  A  continuous  record  of  the  pulmonary  arterial  (PA)  and  left  ventricular  (LV)  blood 
pressures  in  the  dog  prior  to,  and  during,  an  infusion  of  0.3  M  lactic  acid.  The  arrow  above  the 
pressure  tracing  indicates  the  start  of  the  infusion.  The  values  for  cardiac  output  (Ql,  blood  pH  and 
blood  lactate  concentration  (L  Ac)  on  the  left  were  obtained  during  the  control  period;  those  on  the 
right  are  after  3  min  of  the  infusion.  Time  lines  occur  at  i-sec  intervals;  the  duration  of  the  entire 
record  is  3  min  15  sec.  [Unpublished  records  of  Bergofsky  et  at.  (24).] 


four  categories:  isolated  lungs,  unilateral  hypercapnia, 
controlled  ventilation,  and  spontaneous  ventilation 
(132).  But,  even  though  results  tend  to  be  consistent 
within  each  category,  the  differences  between  cate- 
gories may  be  quite  striking.  Thus,  in  spontaneously 
breathing  animals  and  man,  acute  hypercapnia  is 
generally  without  effect  on  pulmonary  hemodynamics 
(132);  conversely,  in  anesthetized  animals  which  are 
being  passively  ventilated,  acute  hypercapnia  usually 
increases  pulmonary  vascular  resistance  (24).  Recent 
observations  have  suggested  a  basis  for  this  disparity: 
for  example,  during  anesthesia  and  controlled  CO2 
breathing — when  the  ventilatory  response  to  inspired 
CO2  is  limited  by  the  apparatus — respiratory  acidosis 
is  common;  on  the  other  hand,  during  spontaneous 
breathing — when  the  increase  in  ventilation  is  quite 
marked — respiratory  acidosis  is  ordinarily  mild.  In 
the  next  section  it  will  be  shown  that  severe  acidosis 
increases  pulmonary  vascular  resistance.  Accordingly, 
the  effects  of  breathing  CO2  on  the  pulmonary  circula- 
tion appear  to  depend  on  the  degree  of  acidosis  which 
it  produces. 

Acute  Acidosis 

For  a  long  while,  observations  on  the  isolated  lung 
(1 16,  305)  and  on  the  lungs  perfused  in  situ  (423)  led 
to  the  opinion  that  acidosis  played  no  role  in  the 
regulation  of  the  pulmonary  circulation.  Recently,  this 
view  was  challenged  by  experiments  on  similar 
preparations  which  not  only  indicated  that  acute 
acidosis  is  capable  of  eliciting  an  increase  in  pulmo- 
nary vascular  resistance,  but  also  suggested  that  it 
might  be  involved  in  the  pulmonary  vascular  response 


to  acute  hypoxia  (269).  That  acidosis  can  also  elicit 
an  increase  in  the  pulmonary  vascular  resistance  in 
the  intact  anesthetized  dog  is  shown  in  figure  45;  in 
these  animals,  the  pressor  response  seems  to  arise 
from  pulmonary  vasoconstriction  and  to  depend  upon 
the  degree  of  acidosis  rather  than  upon  specific 
anions  (24,  30).  It  should  be  noted  that  this  constrictor 
effect  of  acidosis  on  pulmonary  vascular  smooth  mus- 
cle stands  in  marked  contrast  to  the  inhibitory  effects 
of  acidosis  on  systemic  vascular  smooth  muscle  (402). 
Another  use  of  alkali  and  amine  buffer  has  been  to 
test  the  idea  that  acidosis  may  underlie  the  pulmonary 
arterial  pressor  response  to  acute  hypoxia  (269).  This 
idea  could  not  be  substantiated  in  normal  man  (24). 
Instead,  the  conclusion  was  reached  that  acute 
hypoxia  and  acute  acidosis  constitute  independent 
stimuli  for  pulmonary  vasoconstriction;  however,  it  is 
conceivable  that  in  subjects  with  regional  hypoventi- 
lation, the  two  separate  stimuli  may  act  synergistically 
to  divert  pulmonary  blood  flow  to  the  well-ventilated 
portions  of  the  lung  (24). 

Alveolar  Hypoventilation 

Alveolar  hypoventilation  may  be  uniform,  as  in 
patients  with  kyphoscoliosis  or  extreme  obesity  (25), 
or  spotty,  as  in  chronic  bronchitis  and  emphysema. 
During  ambient-air  breathing,  the  designation  "alveo- 
lar hypoventilation"  implies  a  combination  of  alveolar 
hypoxia  and  hypercapnia;  the  state  achieves  clinical 
significance  when  sufficiently  severe  to  produce  sys- 
temic arterial  hypoxemia  and  respiratory  acidosis  (138). 
Experimentally,  it  has  been  deliberately  induced  by 
artificial  underventilation  during  general  anesthesia 
(359).  Largely  on  the  basis  of  such  experiments,  it  has 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1/2  3 


been  claimed  that  alveolar  hypoventilation  elicits 
pulmonary  arterial  hypertension  not  only  by  wa\  of 
acute  hypoxia  but  also  by  an  hypothetical  "alveolo- 
vascular  reflex."  Since  mechanical  underventilation 
of  the  lungs  involves  an  element  of  mechanical  col- 
lapse of  alveoli  as  well  as  a  change  in  the  alveolar  gas 
composition,  the  operation  of  this  special  alveolar 
reflex  is  difficult  to  prove.  Nonetheless,  this  hypotheti- 
cal reflex  is  consistent  with  the  consensus  that  pulmo- 
nary vasomotor  effects  of  acute  hypoxia  (by  airway) 
are  independent  of  systemic  arterial  hypoxemia  (204). 

Pulmonary  Vasomotor  Reflexes 

The  plentiful  supply  of  autonomic  nerves  to  the 
lungs  and  of  nerve  fibers  to  the  pulmonary  blood 
vessels  has  stimulated  the  search  for  direct  evidence 
of  pulmonary  reflex  activity.  This  search  has  dis- 
closed that  numerous  afferent  vagal  fibers  and  baro- 
receptor  endings  exist  in  the  large  pulmonary  arteries, 
that  the  impulse  activity  of  the  pulmonary  barorecep- 
tor  fibers  varies  with  the  pulsatile  blood  pressure  in 
the  pulmonary  artery  and  that  the  receptors  are  active 
at  the  usual  levels  of  pulmonary  arterial  pressure  (80). 
On  the  other  hand,  since  the  efferent  limbs  have  not 
yet  been  traced  either  to  their  conjunction  with  affer- 
ent limbs  or  to  their  endings  in  effector  cells,  the 
proof  of  their  existence  consists  entirely  of  indirect 
physiologic  observations,  e.g.,  systemic  vasodilation  as 
pulmonary  arterial  pressure  increases  (6). 

The  pulmonary  circulation  is  believed  to  participate 
in  a  wide  variety  of  mechano-  and  chemoreflexes 
(207,  393).  Some  of  these  hypothetical  reflexes  are 
conceived  to  be  purely  local,  e.g.,  pulmonary  veno- 
arteriolar  (6,  101,  231,  409)  or  alveolar-vascular 
(359);  these  local  reflexes  are  inaccessible  for  direct 
appraisal.  Much  more  tangible  are  the  remote  reflexes. 

Three  types  of  remote  reflexes  have  been  exten- 
sively studied.  The  first  is  a  reflex  from  the  pulmo- 
nary vessels  to  the  systemic  circulation.  With  rare 
exception  (261),  this  type  of  reflex  has  been  ''depres- 
sor" in  nature,  evoking  bradycardia  and  systemic 
arterial  hypotension  in  response  to  a  wide  variety  of 
stimuli;  the  stimuli  have  included  an  increase  in  static 
pressure  at  either  end  of  the  pulmonary  vascular  tree 
or  along  its  whole  length  (6,  110),  chemoreflexes  of 
different  kinds  (99),  and  pulmonary  vascular  hypo- 
thermia (159)- 

The  second  type  of  remote  reflex  is  a  combined  or 
chain  reflex  from  the  pulmonary  arteries  to  the  small 
pulmonary  vessels  on  the  one  hand  (4,  32 1 )  and  to  the 
respiratory  apparatus  on  the  other  (432).  With  few 


exceptions  (101),  such  a  reflex  has  customarily  been 
invoked  to  account  for  the  dramatic  clinical  syndrome 
which  follows  multiple  pulmonary  emboli,  i.e.,  the 
pulmonary  hypertension,  the  rapid  shallow  breathing, 
the  bronchoconstriction,  and  the  decrease  in  periph- 
eral arterial  oxygenation  (227).  However,  many  of  the 
links  in  this  reflex  chain  reaction  remain  speculative. 
More  precisely  defined,  but  much  less  meaningful 
with  respect  to  function,  are  the  chemoreflex  path- 
ways which  connect  the  pulmonary  arterial  tree  with 
the  respiratory  apparatus  (99). 

The  third  type  of  remote  reflex  runs  from  the 
reflexogenic  areas  of  the  carotid  arterial  bifurcations 
and  aortic  arch  to  the  pulmonary  circulation  (206). 
To  create  the  proper  experimental  setting  for  the 
demonstration  of  these  feeble  reflexes,  Daly  and  Daly 
were  obliged  to  resort  to  the  "vasosensory  controlled 
perfused  living  animal"  preparation  in  which  the 
pulmonary  and  systemic  circulations  could  be  sepa- 
rately controlled.  In  this  special  preparation,  intense 
pressor  stimulation  of  the  systemic  baroreceptors 
evoked  pulmonary  vasodilatation;  perfusion  of  the 
carotid  chemoreceptors  with  hypoxic  or  venous  blood 
(during  interrupted  bronchial  arterial  flow)  evoked 
pulmonary  vasoconstriction  (96).  The  authors  are 
careful  to  point  out  that  the  elaborate  controls  re- 
quired to  demonstrate  the  existence  of  these  reflex 
pathways  obscure  the  meaning  of  these  reflexes  for  the 
live,  intact  organism  (95). 

Pulmonary  Vasomotor  Waves 

Rhythmic  oscillations  in  systemic  arterial  blood 
pressure  (Traube-Hering-Mayer  waves)  were  first 
described  toward  the  close  of  the  nineteenth  century 
(404).  Although  the  consensus  since  then  has  favored 
the  view  that  these  systemic  waves  reflect  the  rhythmic 
activity  of  the  medullary  vasomotor  center,  not  always 
has  irradiation  from  the  respiratory  to  the  vasomotor 
center  been  excluded.  Most  often,  the  Traube- 
Hering-Mayer  waves  have  been  encountered  in  ab- 
normal or  deteriorating  experimental  preparations; 
even  in  the  same  preparation  the  pattern  of  the  waves 
tends  to  vary  with  respect  to  frequency  and  to  ampli- 
tude (229). 

Infrequently,  the  swings  in  systemic  arterial  blood 
pressure  were  found  to  be  associated  with  swings  in 
pulmonary  arterial  blood  pressure  (125).  And,  on 
rare  occasion,  the  pulmonary  arterial  swings  occurred 
either  without  (379),  or  with  barely  perceptible  (125), 
systemic  arterial  waves.  In  these  few  instances,  other 
passive  effects  were  not  entirely  excluded. 


•7*4 


II  \M>HOOK    OF    I'HYsioI  (  IGY 


CIRCULATION    II 


mmHq      H.  F 
80 


10  SEC 


PA 

40 


li  I L 

WW 


mmm 


10  SEC 

t  i 


I  20 
BA 
80 

40 


fig.  46.  Spontaneous  rhythmic  fluctuations  in  pulmonary  arterial  blood  pressure  in  a  young 
woman  with  primary  pulmonary  hypertension.  The  pulmonary  arterial  systolic  pressure  is  identical 
with  the  systolic  pressure  in  the  right  ventricle.  The  pulmonary  arterial  pressure  waxes  and  wanes. 
Each  cycle  is  1 10  sec  long;  the  pulmonary  arterial  systolic  pressure  ranges  from  57  to  74  mm  Hg;  the 
diastolic  pressure  ranges  from  26  to  36  mm.  The  pressure  changes  are  not  accompanied  by  parallel 
changes  in  heart  rate.  The  brachial  arterial  pressure  is  somewhat  low.  The  slow  cyclic  variations  in 
pulmonary  arterial  pressure  have  no  counterparts  in  the  systemic  blood  pressure.  (Unpublished 
observations  by  A.  P.  Fishman  and  A.  G.Jameson.) 


Recently,  a  pulmonary  arterial  rhythm,  unaccom- 
panied by  fluctuations  in  systemic  arterial  blood  pres- 
sure, was  observed  in  an  unanesthetized  woman  with 
primary  pulmonary  hypertension  (fig.  46).  In  this 
subject,  systemic  hypotension  coexisted  with  pulmo- 
nary hypertension,  a  combination  which  presumably 
favors  the  occurrence  of  isolated  pulmonary  arterial 
pressure  waves  in  the  experimental  animal  (379). 
However,  while  it  is  intuitively  attractive  to  accept 
the  pulmonary  arterial  waves  in  this  subject  as  a 
manifestation  of  a  central  vasomotor  rhythm  — super- 
imposed by  the  central  nervous  system  on  local  pulmo- 
nary vascular  controls — the  probability  remains  that 
the  fluctuations  in  pulmonary  arterial  pressure  may 
merely  reflect  the  passive  consequences  of  rhythmic 
changes  in  systemic  hemodynamics  (125). 


EFFECTS    OF    DRUGS 

Interests  in  the  pharmacology  of  the  pulmonary 
circulation  differ:  at  one  extreme  is  the  use  of  drugs  to 
display  the  capacity  of  the  pulmonary  vessels  to 
undergo  a  change  in  "tone";  this  has  led  to  the  stuck 
of  isolated  perfused  lungs  and  vascular  rings.  At  the 
other  extreme  is  the  effect  of  a  particular  drug  on  the 
pulmonary  circulation  under  natural  conditions;  this 
has  involved  the  study  of  the  unanesthetized  intact 
animal  or  man  in  whom  the  ventilation,  circulation, 
and  the  coordinating  neurohumoral  systems  are  all 


intact.  Between  these  extremes  are  many  shades  of 
interest  which  are  not  always  defined  or  self-evident 
from  the  experimental  protocols. 

It  is  generally  difficult,  in  intact  animal  and  man, 
to  separate  the  direct,  local  vasomotor  effects  of  a 
drug  on  the  pulmonary  circulation  from  its  indirect, 
passive  effects  originating  from  afar,  i.e.,  in  the 
systemic  circulation,  the  left  heart  or  the  ventilation. 
Theoretically,  this  distinction  should  be  easily  made 
if  the  pharmacological  agent,  such  as  acetylcholine, 
is  rapidly  destroyed  by  contact  with  blood  (122): 
minute  quantities  of  acetylcholine  are  infused  into  a 
peripheral  vein  or  into  the  pulmonary  artery  at  a  rate 
carefully  adjusted  to  avoid  the  classical  circulatory 
picture  of  systemic  vasodilatation  and  cardiac  inhibi- 
tion; the  action  of  the  drug  is  then  presumed  to  be 
confined  to  the  pulmonary  circulation.  During  this 
venous  or  pulmonary  arterial  titration  with  acetyl- 
choline, steady-state  measurements  are  made,  not 
only  of  pulmonary  blood  flow  and  pressures,  but  also 
of  other  relevant  respiratory  and  circulatory  param- 
eters (153). 

Of  more  universal  applicability  is  the  procedure  of 
injecting  a  drug  into  the  pulmonary  artery  while  re- 
cording blood  pressures  simultaneously  from  the 
pulmonary  artery,  the  pulmonary  vein  (or  left 
atrium),  and  a  systemic  artery  as  the  drug  traverses 
the  pulmonary  circulation  (fig.  33)  (150,  187).  At 
first,  the  use  of  this  approach  required  open  thora- 
cotomy for  the  cannulation  of  the  pulmonary  vessels 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1725 


(225).  However,  the  gradual  progression  from  angios- 
tomy  cannulae  (187)  to  combined  right  and  left 
heart  catheterization  (92)  has  made  it  feasible  to 
record  simultaneously  the  blood  pressures  at  both 
ends  of  the  pulmonary  circulation  as  well  as  the  blood 
pressure  in  a  systemic  artery  in  the  intact,  unanesthe- 
tized  animal  and  man. 


Predominantly  Passive  Effects 

Certain  familiar  drugs  seem  to  affect  the  pulmo- 
nary circulation  of  the  intact  animal  or  man  pre- 
dominantly by  way  of  the  systemic  circulation. 
Cardinal  examples  are  the  effects  of  digitalis  and 
quinidine  in  subjects  with  left  heart  failure:  digitalis 
reduces  the  pulmonary  hypertension  of  left  heart 
failure  by  improving  myocardial  performance;  quini- 

30--" 


20-- 


10  - 


15 
10 
5 

.16-- 
.08-- 


-  PA 

» 

-i  - 

P  "wedge" 

T_.__. 

~2 

r" 

L"I  : 

_T_ 

J 

Rp 

■  V 

^ 

-N 

AMBIENT 
AIR 

HYPOXIA 

(So02:74%) 

NE 

(20-67,ug7min) 

fig.  47.  Comparison  of  the  effects  of  acute  hypoxia  and  of 
infusing  norepinephrine  on  pulmonary  vascular  pressures  and 
resistance.  PA  =  mean  pulmonary  arterial  pressure; 
P  "WEDGE"  =  mean  pulmonary  arterial  wedge  pressure; 
Rp  =  mean  pulmonary  vascular  resistance.  The  solid  circles 
represent  the  average  values  for  the  group  of  13  normal  sub- 
jects; the  vertical  bars  represent  the  range.  During  hypoxia,  the 
increase  in  pulmonary  arterial  pressure  was  not  associated  with 
an  increase  in  "wedge"  pressure;  during  norepinephrine  infu- 
sion, an  increase  in  pulmonary  arterial  pressure  was  invariably 
associated  with  an  increase  in  "wedge"  pressure.  Accordingly, 
calculated  resistance  increased  during  hypoxia  and  decreased 
during  norepinephrine  infusion.   [After  Goldring  et  at.   (163).] 


dine,  on  the  other  hand,  improves  the  emptying  of 
the  left  heart  by  decreasing  systemic  vascular  resist- 
ance rather  than  by  a  direct  action  on  the  myocard- 
ium (87,  129). 

The  effects  of  epinephrine  on  the  pulmonary  circu- 
lation have  long  been  disputed,  primarily  because  of 
the  occurrence  of  simultaneous  changes  in  both  the 
systemic  and  pulmonary  circulations  (97,  187,  436). 
However,  granting  that  a  direct  pulmonary  vasocon- 
stricting  effect  can  be  demonstrated  in  special  prep- 
arations (355),  in  the  intact  animal  the  increase  in 
pulmonarv  arterial  pressure  evoked  by  epinephrine 
is  almost  exclusively  a  consequence  of  passive  back 
pressure  from  the  left  heart  and  systemic  circulation 
(187).  Indeed,  in  the  dog,  excessively  large  doses  of 
epinephrine  reproduce  the  sequence  elicited  by  the 
intracisternal  implantation  of  fibrin  (64,  372),  in- 
cluding pulmonary  hypertension  and  pulmonary 
edema  from  left  heart  failure.  And,  consistent  with 
the  prepotent  effects  of  epinephrine  on  the  systemic 
circulation  in  the  dog,  is  the  observation  that  in  the 
turtle  (single  ventricle),  intravenous  epinephrine  in- 
creases systemic  vascular  resistance  without  affecting 
pulmonary  vascular  resistance  (443). 

Levarterenol  (/-norepinephrine)  also  elicits  an  in- 
crease in  pulmonary  arterial  pressure.  As  in  the  case  of 
epinephrine,  the  capacity  for  pulmonary  vasoconstric- 
tion can  be  demonstrated  by  special  techniques  (355)- 
However,  in  intact  man,  the  increase  in  pulmonary 
arterial  pressure  elicited  by  levarterenol  is  predomi- 
nantly, if  not  exclusively,  passive,  i.e.,  secondary  to  an 
increase  in  left  atrial  pressure  (fig.  47)  (163). 

Histamine  elicits  a  complex  series  of  ventilatory  and 
circulatorv  effects.  In  the  isolated  lung,  it  elicits 
vasoconstriction  (442);  the  intensity  of  this  response 
varies  with  the  species,  dose,  and  preparation.  In 
intact  man,  tolerable  doses,  which  are  sufficient  to 
elicit  systemic  hypotension,  are  without  discernible 
effect  on  pulmonary  hemodynamics;  whether  tolera- 
ble doses  are  inadequate  to  provoke  pulmonary  vaso- 
constriction, or  whether  vasoconstriction  does  occur 
and  is  neutralized  by  some  concomitant  passive 
effects,  remains  unsettled  (4).  Finally,  the  induction  of 
severe  systemic  hypotension  in  the  dog  by  large 
quantities  of  histamine  is  associated  with  passive 
pulmonary  hypotension  (100). 

Pulmonary  I  asoconstrictors 

The  systemic  circulation  is  far  more  sensitive  to  the 
usual  vasoconstrictor  agents  than  is  the  pulmonary 
circulation.  However,  a  host  of  apparently  unrelated 


HANDBOOK   OF    PHYSIOLOGY    ^    CIRCULATION    II 


substances  have  been  categorized  as  pulmonary  vaso- 
constrictors. These  include  serotonin  (5-hydroxy- 
tryptamine)  (34,  302,  356)  adenosine  triphosphate 
(4),  small  quantities  of  hypertonic  saline  (28),  bacte- 
rial endotoxins  (245)  and  alloxan  (4). 

Serotonin,  which  has  captured  physiological  and 
clinical  imaginations  on  many  different  accounts,  is 
also  generally  held  to  be  a  uniquely  effective  pulmo- 
nary arterial  and  venous  vasoconstrictor  (43,  227). 
The  evidence  rests  largely  on  animal  experiments 
(4,  366)  and  on  the  behavior  of  isolated  lungs  (158) 
since  "safe"  doses  in  intact  man  are  without  discerni- 
ble pulmonary  vascular  effect  (193).  At  first  en- 
counter, the  disprepancies  between  the  effects  of 
serotonin  in  animals  and  man  might  be  attributed  to  a 
"species"  difference;  however,  even  this  refuge  is  un- 
certain because  of  the  diffuse  and  bizarre  effects  of 
serotonin:  a)  its  tendency  to  produce  "temporary  em- 
boli,'' so  that  an  increase  in  pulmonary  arterial  pres- 
sure and  an  increase  in  pulmonary  vascular  resistance 
may  arise  from  transient  occlusion  of  small  pulmo- 
nary vessels  as  well  as  from  vasoconstriction  (235),  b) 
its  bronchoconstricting  effects  (366),  c)  its  respiratory 
and  Bezold-like  circulatory  effects  in  the  intact  animal 
(193),  and  d)  the  discrepancies  between  the  doses  of 
serotonin  used  in  the  different  experiments.  Finally, 
the  ineffectiveness  of  tolerable  closes  of  serotonin  as  a 
pulmonary  vasoconstrictor  in  man  is  consistent  with 
the  lack  of  pulmonary  hypertension  in  patients  with 
serotonin-secreting  tumors  (399). 

Aside  from  their  apparent  proclivity  for  the  venous 
side  of  the  pulmonary  circulation,  these  pharmaco- 
logical pulmonary  "vasoconstrictors"  have  little  in 
common.  For  example,  in  contrast  to  serotonin  and 
alloxan,  endotoxin  requires  contact  with  blood  to  be- 
come effective  (4).  Moreover,  hypertonic  saline  (333, 
376),  as  well  as  serotonin,  has  been  shown  to  conglu- 
tinate  red  cells  (235).  It  is  clear  that  much  remains 
unknown  about  these  pulmonary  vasoconstrictors. 

Pulmonary  Vasodilatm  1 

Interest  in  pulmonary  vasodilators  has  been  stimu- 
lated both  by  the  clinical  need  for  therapeutic  agents 
to  relieve  pulmonary  hypertension  and  the  physio- 
logic concern  with  pulmonary  vasomotor  tone.  Aviado 
(4)  has  sorted  the  substances  which  have  been  tested 
into  five  groups:  /)  musculotropics  (aminophylline); 
2)  parasympathomimetics  (acetylcholine);  3)  sym- 
pathomimetics (isoproterenol);  -/.)  adrenergic  blockers 
(tolazoline);  and  5)  ganglionic  blockers  (hexa- 
methonium).    A   good   number   of  these   have    been 


used  to  treat  systemic  hypertension,  indicating  the 
complex  hemodynamic  changes  which  may  be  ex- 
pected to  complicate  the  interpretation  of  their 
effects  on  the  pulmonary  circulation.  It  is  also  note- 
worthy that  none  have  yet  found  a  place  in  the  treat- 
ment of  pulmonary  hypertension,  and  that,  except 
for  acetylcholine,  none  have  provided  any  fresh 
insights  into  the  regulation  of  the  pulmonary  circula- 
tion. 

Acetylcholine  has  achieved  clinical  pre-eminence 
as  a  pulmonary  vasodilator.  This  reputation  arises 
largely  from  recent  experiences  with  pulmonary 
hypertensive  patients  since  previous  studies  on  intact 
animals,  artificial  preparations  and  normal  man  have 
been  contradictory  (132).  As  mentioned  previously, 
the  experiments  which  have  adduced  evidence  for  a 
pulmonary  vasodilating  effect  of  acetylcholine  have 
exploited  the  rapid  destruction  of  acetylcholine  by 
the  cholinesterases  of  the  blood  to  restrict  the  action 
of  acetylcholine  to  the  pulmonary  circulation  (122, 
401).  The  experiments  have  involved  either  a  single 
injection  of  acetylcholine  into  the  venous  circulation 
or  pulmonary  artery  (187,  192,  441),  or  a  continuous 
infusion  of  acetylcholine  into  the  pulmonary  arterv 
at  a  rate  (0.5  mg/min)  insufficient,  at  least  by  con- 
ventional tests,  to  affect  either  the  lungs,  the  respira- 
tion, the  left  heart,  or  the  systemic  circulation  (153). 
The  evidence  that  acetylcholine  elicits  pulmonary 
vasodilatation  includes:  a)  a  decrease  in  the  pressure 
gradient  across  the  lungs  in  pulmonary  hypertensive 
subjects  in  whom  the  pulmonary  vessels  are  pre- 
sumably hypertonic  (192,  282,  441);  b)  a  partial  or 
complete  reversal  of  the  anticipated  increase  in 
calculated  pulmonary  vascular  resistance  during 
acute  hypoxia  (153);  c)  the  prevention  of  the  increase 
in  unilateral  resistance  during  unilateral  hypoxia  by 
the  infusion  of  acetylcholine  on  the  hypoxic  side 
(go);  and  d)  a  decrease  in  the  peripheral  arterial 
oxygenation  of  patients  with  supposed  ventilation- 
perfusion  abnormalities  (383).  The  last  effect  is 
generally  believed  to  reflect  the  diversion  of  mixed 
venous  blood  to  hypoventilated  portions  of  the  lungs 
as  local  hypoxic  vasoconstriction  is  relieved  by  the 
acetylcholine;  however,  alternate  explanations  such 
as  the  opening  of  arteriovenous  shunts  or  atelectasis 
have  also  been  proposed.  It  has  been  indicated 
elsewhere  that  while  these  experiments  on  man  are 
consistent  with  a  pulmonary  vasodilating  effect  of 
acetylcholine,  they  are  not  entirely  convincing  (132). 

Other  vasodilator  substances  and  autonomic  block- 
ing agents  (including  spinal  anesthesia)  have  also 
been  used  in  the  attempt  to  elicit  pulmonary  vaso- 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1727 


dilation,  especially  in  pulmonary  hypertensive  sub- 
jects (4,  369,  386).  Granting  that  these  agents  are 
often  capable  of  relieving  pulmonarv  arterial  hvper- 
tension,  it  has  yet  to  be  shown  that  their  hypotensive 
effect  represents  pulmonary  vasodilation. 


CARDIOPULMONARY    DISORDERS 

Pulmonary  Arterial  Hypertension 

According  to  the  range  of  normal  values  described 
earlier  in  this  chapter,  pulmonary  arterial  hyper- 
tension exists  when  pulmonary  arterial  pressures 
exceed  approximately  30/18  mm  Hg.  Even  such 
mildly  hypertensive  levels  have  been  found  to  strain 
the  heart  if  continued  for  a  lifetime  (363).  Moreover, 
subjects  with  "high-normal"  pulmonary  arterial 
pressures  at  rest  often  become  pulmonary  hyper- 
tensive when  blood  flow  is  increased  acutely,  as  by 
occlusion  of  a  pulmonary  artery  (68)  or  by  exercise 
(132);  the  latter  observations  suggest  that  pulmonary 
arterial  hypertension  occurs  frequently  in  the  course 
of  daily  activities  once  pulmonary  arterial  pressures 
reach  "high-normal"  levels  at  rest. 

The  causes  of  pulmonary  arterial  hypertension 
may  be  conveniently  sorted  into  four  categories. 
Three  of  these  are  mechanical  (passive) :  reduction 
in  the  extent  and  distensibility  of  the  pulmonary 
vascular  bed,  increase  in  pulmonary  blood  flow,  and 
increase  in  pulmonary  venous  pressure;  the  fourth 
is  vasoconstriction  (active).  Before  considering  these 
mechanisms  separately,  it  should  be  noted  that 
pulmonary  hypertension  is  more  often  the  conse- 
quence of  a  complex  interplay  of  mechanisms  than 
of  any  single  influence  operating  independently. 
Moreover,  in  patients  with  cardiopulmonary  dis- 
orders, it  is  generally  easier  to  single  out  the  pre- 
potent mechanism  than  to  try  to  quantify  the  relative 
contributions  of  all  the  mechanisms  that  could  con- 
ceivably  be  involved    (88). 

restricted  vascular  bed.  In  normal  animal  and 
man,  almost  two-thirds  of  the  lungs  have  to  be  re- 
moved before  pulmonary  arterial  pressures  reach  hy- 
pertensive levels  (89,  252).  By  way  of  contrast,  there 
are  many  pulmonary  diseases  which  surreptitiously 
reduce  the  number  and  caliber  of  small  pulmonary 
vessels  and  modify  the  distensibility  of  the  remaining 
vessels,  so  that  even  a  normal  pulmonary  blood  flow 
is  associated  with  marked  pulmonary  hypertension. 
Examples   of  such   diseases   are   pulmonary   emboli, 


pulmonary  arteritis,  interstitial  fibrosis  and  granu- 
loma, bullous  emphysema,  and  "primary  pulmonary 
hypertension"  (341).  The  architecture  of  the  thorax 
may  also  limit  the  capacity  and  expansibility  of  the 
pulmonary  vascular  bed :  thus,  in  subjects  with  severe 
kyphoscoliosis,  the  combination  of  a  dwarfed  pulmo- 
nary vascular  bed  and  an  adult  cardiac  output 
predisposes  to  pulmonary  hypertension  (25). 

increase  in  pulmonary  blood  flow.  It  has  been 
indicated  previously,  that  in  the  normal  pulmonary 
circulation,  the  cardiac  output  has  to  be  tripled 
before  pulmonary  hypertensive  levels  are  reached 
(8g).  In  patients  with  congenital  cardiac  defects  and 
left-to-right  shunts,  pulmonary  hypertension  may 
occur  even  at  lower  blood  flows  because  of  anatomical, 
and  possibly  functional,  changes  in  the  vessels.  An 
especially  interesting  situation  obtains  in  patients  in 
whom  both  the  pulmonarv  and  systemic  circulations 
communicate,  as  in  the  reptilian  heart,  with  the  left 
ventricle.  In  this  case,  the  partition  of  the  left  ven- 
tricular output  between  the  two  circulations  is  a 
function  of  their  relative  resistances:  in  time,  if 
pulmonary  vascular  resistance  to  perfusion  increases, 
the  pulmonary  blood  flow  will  diminish  even  though 
the  level  of  pulmonary  hypertension  remains  un- 
changed (440). 

INCREASE    IN    PULMONARY   VENOUS    PRESSURE.    The    tWO 

previous  causes  of  pulmonary  arterial  hypertension 
are  unrelated  to  the  level  of  the  pulmonary  venous 
pressure.  But,  in  the  1 30  years  since  James  Hope,  it 
has  become  common  knowledge  that  pulmonary 
venous  hypertension  leads  to  pulmonary  arterial 
hypertension  (213).  Etiologically,  pulmonary  arterial 
hypertension  of  this  type  generally  originates  either 
in  mitral  valvular  disease  or  left  heart  failure.  In 
dogs  with  acute  or  subacute  (up  to  ten  months) 
mitral  stenosis,  the  increment  in  pulmonary  arterial 
pressure  appears  to  be  a  direct  consequence  of  back 
pressure:  as  pulmonary  venous  pressure  and  pulmo- 
nary blood  volume  increase,  the  pulmonary  capillary 
and  arterial  pressures  also  rise,  but  not  to  the  same 
degree  as  the  pulmonary  venous  pressure;  since  the 
decrease  in  the  pressure  gradient  is  associated  with  an 
unchanged  cardiac  output,  the  calculated  pulmonary 
vascular  resistance  decreases  (176).  Clinical  counter- 
parts of  this  experimental  situation  are  rare  but  do 
occur;  they  are  characterized  by  complete  restoration 
of  the  pulmonary  arterial  blood  pressure  to  normal 
as  the  pulmonary  venous  hypertension  is  relieved. 
The    more    common    clinical    situation    is    one    in 


1728 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


which  the  pulmonary  arterial  pressure  is  inordinately 
high  for  the  level  of  the  pulmonary  venous  pressure, 
the  pulmonary  blood  volume  is  not  abnormally 
large,  and  relief  of  the  pulmonary  venous  hypertension 
does  not  completely  restore  the  pulmonary  arterial 
pressure  to  normal  levels.  In  such  patients,  the 
persistence  of  pulmonary  arterial  hypertension  after 
relief  of  the  back  pressure  is  attributable  to  secondary- 
effects,  i.e.,  to  anatomical  changes  in  the  lungs  and 
vessels,  possibly  abetted  by  constriction  of  the  small 
pulmonary  arteries   (238). 

One  prevalent  notion  about  chronic  pulmonary 
venous  hypertension  is  that  it  elicits  "protective" 
vasoconstriction  of  pulmonary  precapillary  vessels. 
Although  it  is  self-evident  that  pulmonary  arterial 
hypertension  must  occur  if  sufficient  forward  flow  is 
to  continue  in  the  face  of  pulmonary  venous  hyper- 
tension, the  teleological  advantage  of  pulmonary 
precapillary  vasoconstriction  is  not  entirely  clear: 
heightened  "arteriolar"  tone  would  increase  the 
pressure  work  of  the  right  heart  and  only  reduce 
capillary  blood  pressure  if  it  succeeded  in  reducing 
the  pulmonary  capillary  blood  flow.  Teleologically, 
the  prevention  of  undue  filtration  pressures  in  the 
pulmonary  capillaries  would  be  more  economically 
accomplished  by  quieting  the  heart  rather  than  by- 
increasing  the  right  ventricular  work.  Indeed,  the 
inability  to  resolve  the  question  of  protective  vaso- 
constriction again  emphasizes  that  pulmonary  vaso- 
motor activity  is  exceedingly  difficult  to  recognize 
in  the  abnormal  pulmonary  circulation,  particularly 
when  structural  changes  have  extended  beyond  the 
vessels  into  the  surrounding  lung. 

PULMONARY    ARTERIAL    VASOCONSTRICTION.    In    normal 

dog,  cat,  and  man,  pulmonary  arterial  vasocon- 
striction rarely  evokes  more  than  a  mild  pulmonary 
hypertension.  On  the  other  hand,  in  cattle,  con- 
traction of  the  sphincteric  pulmonary  arterioles 
often  effects  dramatic  increases  in  pulmonary  arterial 
pressure  (199).  This  correlation  between  vascular 
structure  and  the  intensity  of  the  pulmonary  vascular 
response  raises  the  prospect  that  pulmonary  vascular 
disease  may,  by  thickening  vascular  media,  enable 
the  small  muscular  vessels  to  contract  with  unusual 
vigor.  However,  this  ingenious  notion  has  yet  to  be 
critically  tested  (181). 

Cor  Pulmonale 

Pulmonary  hypertension  attracts  clinical  attention 
when  it  causes  the  right  heart  to  enlarge  (dilate  or 


BRONCHITIS 

AND 
EMPHYSEMA 


/ 


\ 


RESTRICTED 

PU  LMONARY 

VASCULAR     BED 


ALVEOLAR 
HYPOVENTILATION 


\ 


/ 


PU  LMONARY 
H  Y  PERTENSION 


COR 
PULMONALE 


HEART 
FAILURE 


fig.  48.  The  evolution  of  cor  pulmonale  and  right  heart 
failure  in  chronic  pulmonary  emphysema.  Alveolar  hypo- 
ventilation contributes  to  pulmonary  hypertension  by  way  of 
hypoxia  and  respiratory  acidosis:  hypoxia  elicits  pulmonary 
vasoconstiiction,  polycythemia,  hypervolemia,  increased  blood 
viscosity,  and  increased  cardiac  output;  acidosis  elicits  pulmo- 
nary vasoconstriction. 

hypertrophy)  or  to  fail.  The  term  cor  pulmonale  is 
generally  reserved  for  right  ventricular  enlargement 
which  originates  either  in  diffuse  pulmonary  disease 
or  in  ineffective  performance  of  the  chest  bellows.  As 
a  rule,  pulmonary  hypertension  underlies  cor  pul- 
monale; in  some  types  of  lung  disease,  particularly 
those  associated  with  hypoxemia,  the  abnormal 
pressure  work  of  the  right  heart  may  be  supple- 
mented by  an  abnormally  high  cardiac  output,  i.e., 
flow  work  (89,  339,  341). 

It  has  become  clear  that  the  genesis  of  cor  pul- 
monale is  to  be  sought  in  the  mechanisms  which 
ordinarily  determine  the  normal  pulmonarv  arterial 
pressure;  only  the  combinations  and  the  prepotent 
influences  differ.  For  example,  in  diffuse  interstitial 
diseases  of  the  lung  (e.g.,  "alveolar-capillary  block") 
anatomic  changes  in  pulmonary  vessels  and  paren- 
chvma  operate  without  benefit  of  increased  flow  or 
hypoxia.  On  the  other  hand,  in  the  concentric  alveolar 
hypoventilation  of  extreme  obesity,  respiratory 
paralysis  or  kyphoscoliosis,  hypoxia  and  respiratory 
acidosis  elicit  pulmonary  hypertension  in  subjects 
with    normal    lungs.    Finally,    in    the   most   common 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1729 


fig.  49.  Dye-dilution  curve  inscribed 
by  densitometer  from  peripheral  artery 
following  injection  of  Evan's  blue  dye 
(T-1824)  into  the  pulmonary  artery. 
The  upper  curve  is  normal.  The  short 
appearance  time  and  abnormal  initial 
deflection  of  the  lower  curve  are  charac- 
teristic of  pulmonary  arteriovenous 
shunts. 


cause  of  cor  pulmonale,  i.e.,  chronic  bronchitis  and 
emphysema,  a  combination  of  anatomic  changes, 
hypoxia  and  acidosis  are  involved :  destruction  of 
alveolar  capillaries  sets  the  stage  by  restricting  the 
pulmonary  vascular  bed,  generally  without  evoking 
pulmonary  hypertension;  the  picture  is  completed  by 
disturbances  of  alveolar  ventilation  and  perfusion — 
usually  incidental  to  an  acute  bronchitis — which 
superimpose  the  vasoconstriction  of  hypoxia  and 
respiratory  acidosis  on  the  structural  changes  (fig.  48) 
(34')- 

It  is  clinically  and  physiologically  important  to 
recognize  the  occurrence  of  right  heart  failure  in 
patients  with  cor  pulmonale.  Prior  to  heart  failure, 
the  enlarged  right  ventricle  functions  normally:  it  is 
filled  by  an  atrial  inflow  pressure  of  a  few  mm  Hg,  it 


empties  approximately  half  of  its  volume  during  each 
ejection  and  it  increases  its  output  during  exercise  in 
accord  with  metabolic  requirements.  The  first  signs 
of  right  ventricular  failure  generally  appear  during 
exercise:  as  ventricular  emptying  is  compromised, 
the  mean  filling  pressure  increases  to  abnormal  levels 
(7-10  mm  Hg)  and  the  increase  in  cardiac  output  is 
no  longer  commensurate  with  the  increase  in  oxygen 
uptake  (341  ). 

Pulmonary  Edema 

In  1878,  Welch  produced  pulmonary  edema  in 
rabbits  by  either  ligating  the  aorta  or  compressing 
the  left  ventricle.  He  attributed  the  pulmonary  edema 
to  the  pulmonary  congestion  and  pulmonary  venous 


BEFORE   VALVULOTOMY 


AFTER   VALVULOTOMY 


NK 


to  M  M  U  U  M  A 


MM 

Hg 

-18O 


40 


J    0 


vL^UUUUUUUuU^ 


fig.  50.  Blood  pressures  recorded  during  open  thoracotomy  in  a  patient  with  pulmonic  stenosis. 
Before  valvulotomy.  Marked  right  ventricular  hypertension  coexists  with  systemic  hypotension.  The 
pulmonary  arterial  pressure  pulse  is  vibratory.  After  valvulotomy.  The  right  ventricular  pulmonary 
hypertension  has  been  considerably  relieved.  The  pulmonary  arterial  pressure  has  increased  and  the 
pressure  pulse  is  characteristic  of  pulmonic  insufficiency.  [After  Himmelstein,  el  al.  (210).] 


'-  ;o 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


hypertension  which  followed  the  induced  (transient) 
imbalance  between  the  outputs  of  the  two  ventricles 
(411). 

Since  then,  many  other  experimental  procedures 
have  been  used  to  produce  pulmonary  edema: 
vagotomy,  vagal  stimulation,  intravenous  infusion  of 
fluid,  left  heart  failure,  increase  in  intracranial 
pressure,  exhibition  of  epinephrine,  and  exhibition  of 
ammonium  chloride  (411)-  These  share  a  common 
denominator:  an  excessively  high  pulmonary  venous 
and  capillary  pressure.  Accordingly,  they  are  con- 
sistent with  Welch's  hypothesis;  and,  the  origin  of 
the  pulmonary  edema  which  these  procedures  effect 
is  to  be  regarded  in  the  light  of  Starling's  law  of 
transcapillary  exchange  (1  74). 

It  would  be  misleading  to  imply  that  an  inordinate 
filtration  pressure  in  the  pulmonary  capillaries 
underlies  all  types  of  experimental  and  clinical 
pulmonary  edema.  For  example,  the  pulmonary 
edema  caused  by  a-naphthylthiourea  does  seem  to 
depend  on  an  increase  in  capillary  permeability 
(114);  an  increase  in  capillary  permeability  has  also 
been  postulated  to  account  for  the  bilateral  pulmonary 
edema  which  follows  the  injection  of  a  starch  sus- 
pension into  a  lobar  pulmonary  artery  (227).  How- 
ever, continued  emphasis  on  hemodynamic  balances 
promises  to  be  rewarding  for  several  reasons:  a)  the 
usual  forms  of  pulmonary  edema  do  seem  explicable 
in  terms  of  the  usual  determinants  of  transcapillary 
exchange  of  water,  solutes,  and  colloids,  i.e.,  in  terms 
of  Starling's  law  (174,  385,  411);  b)  many  earlier 
types  of  so-called  "'neurogenic"  pulmonary  edema 
disappeared  when  subjected  to  analysis  in  terms  of 
conventional  hemodynamic  parameters  (64,  372); 
<  )  uncertainties  as  to  the  precise  mechanisms  involved 
in  special  types  of  pulmonary  edema  are  bound  to 
prevail  until  elusive  parameters,  such  as  capillary 
pressure,  volume,  and  permeability  on  the  one  hand, 
and  the  role  of  the  lymphatics  on  the  other,  can  be 
precisely  measured  and  defined  in  quantitative  terms 
(325);  and  d)  mysterious  influences  should  only  be 
given  credence  when  the  local  hemodynamic  and 
physicochemical  mechanisms  operating  across  capil- 
lary walls  have  been  taken  into  full  account,  and  found 
wanting  (217). 

Pulmonary  Hypotension 

During  bleeding  to  the  point  of  systemic  arterial 
hvpotension  as  well  as  during  traumatic  and  his- 
tamine shock,  the  circulating  blood  volume,  the 
cardiac    output,    and    the    central    venous    pressures 


decrease  (100,  289,  391).  However,  despite  the  pro- 
gressive decline  in  systemic  arterial  and  left  atrial 
blood  pressures,  the  pulmonary  arterial  pressure 
tends  to  stabilize  at  approximately  two-thirds  of  its 
initial  value.  This  stability  presumably  involves  the 
gradual  closure  of  portions  of  the  pulmonary  vascular 
tree  as  intraluminal  pressures  in  these  areas  fall.  As  a 
result  of  the  preferential  closure  of  certain  portions  of 
the  pulmonary  vascular  tree  during  systemic  hypo- 
tension, the  affected  portions  of  the  lungs  become 
excessively  ventilated  for  their  perfusion,  leading  to 
an  appreciable  arterial-alveolar  difference  in  carbon 
dioxide  tension  (of  the  order  of  8  mm  Hg)  and  to  the 
creation  of  an  "alveolar  dead  space."  Restoration  of 
the  circulating  blood  volume  raises  the  pulmonary 
arterial  pressure  to  supracontrol  values  even  though 
slight  systemic  arterial  hypotension  persists  (160). 

Pulmonarx  Arteriovenous  Fistula 

The  surgical  production  of  a  pulmonary  arterio- 
venous anastomosis  is  associated  with  a  decrease  in 
systemic  arterial  oxygenation  and  in  pulmonary 
arterial  (mean)  pressure.  The  subsequent  course  of 
the  experimental  animal,  as  well  as  the  natural 
history  of  the  human  subject  with  a  pulmonary 
arteriovenous  fistula  (155),  is  determined  by  the  size 
of  the  shunt  and  the  degree  of  systemic  arterial 
hypoxemia  which  it  effects.  If  systemic  hypoxemia  is 
sufficiently  marked,  a  considerable  polycythemia  will 
ensue  leading,  in  turn,  to  an  increase  in  the  viscosity 
of  the  blood,  an  increase  in  the  resistance  to  blood 
flow  through  the  usual  resistance  vessels  and  the 
diversion  of  more  and  more  of  the  right  ventricular 
output  through  the  low-resistance  shunt  (fig.  49). 

Pulmonic  Stenosis 

A  hindrance  to  the  exit  of  blood  from  the  right 
ventricle  occurs  commonly  as  a  congenital  cardiac 
malformation;  either  the  valve  or  the  infundibulum 
or  the  main  pulmonary  artery  may  be  the  seat  of  the 
stenosis.  Experimentally,  stenosis  of  the  pulmonary 
artery  has  been  produced  in  different  ways  (12).  In 
all,  severe  narrowing  of  the  lesion  is  necessary  before 
the  right  ventricle  becomes  strained. 

In  the  absence  of  an  abnormally  large  blood  flow 
across  the  pulmonary  valve,  the  physiologic  hallmark 
of  pulmonic  stenosis  is  right  ventricular  hypertension 
coupled  with  a  systolic  blood  pressure  gradient 
between  the  right  ventricle  and  pulmonary  artery 
(fig.  50).  In  acute  animal  experiments,  a  constriction 


DYNAMICS    OF    PULMONARY    CIRCULATION 


1 731 


of  the  pulmonary  arterial  lumen  of  at  least  40  per 
cent  is  needed  to  raise  systolic  pressure  appreciablv 
in  the  right  ventricle;  greater  degrees  of  constriction 
are  needed  to  produce  right  ventricular  failure,  i.e., 
dilatation  of  the  right  heart,  abnormally  high  end- 
diastolic  pressures  in  the  right  ventricle,  and  tri- 
cuspid regurgitation  (12).  Parenthetically,  it  may  be 
noted  that  pulmonic  stenosis  is  an  excellent  physio- 
logical tool  for  stimulating  the  proliferation  of  the 
pulmonary  collateral  arterial  circulation  (263,  264). 

Pulmonary  I  'alvular  Insufficiency 

Pulmonary  valvular  insufficiency  has  been 
produced  experimentally  in  dogs  (123)  and  during 
remedial  cardiac  surgery  in  man  (fig.  50).  After 
avulsion  of  the  valve,  not  only  does  the  pulmonary 
arterial    diastolic    pressure    fall    to    right-ventricular 


diastolic  levels,  but  a  systolic  right  ventricular- 
pulmonary  arterial  pressure  gradient  may  also  appear. 
This  gradient  is  a  consequence  of  unusually  rapid  and 
turbulent  flow  during  systole  rather  than  of  pulmonic 
stenosis  (123). 

Pulmonic  insufficiency  is  generally  regarded  as  a 
benign  lesion :  in  dogs,  performance  on  the  treadmill 
as  well  as  end-diastolic  pressures  in  the  right  ven- 
tricle remains  normal  after  months  of  exercise  and 
despite  right  ventricular  systolic  pressures  approxi- 
mating 100  mm  Hg  (12).  However,  pulmonic  in- 
sufficiency may  bring  the  heart  closer  to  the  brink  of 
its  reserve  so  that  an  additional  lesion,  e.g.,  tricuspid 
insufficiency  may  precipitate  overt  heart  failure  (12). 
Whether  the  cardiac  reserve  is  sufficient  to  tolerate 
pulmonary  valvular  insufficiency  for  a  lifetime,  or 
only  for  a  few  years,  remains  to  be  established. 


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1738 


II  WDI'.i  ii  >K     '  '1      l'in  Ml  H  i  ii. -i 


CIRCULATION    II 


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separate  perfusion  of  systemic  and  pulmonary  circulation 

in  dog.  Am.  J.  Physiol.  191  :  453,  1957. 

424.  Weissler,  A.  M.,  J.  J.  Leonard,  and  J.  V.  Warren. 
Effects  of  posture  and  atropine  on  the  cardiac  output. 
J.  Clin.  Invest.  36:  1656,  1957. 

425.  Weissler,  A.  M,  B.  H.  McCraw,  and  J.  V.  Warren. 
Pulmonary  blood  volume  determined  by  a  radioactive 
tracer  technique.   J.   Appl.   Physiol.    14:  531,    1959. 

426.  Werko,  L.  The  influence  of  positive  pressure  breathing 
on  the  circulation  in  man.  Acta  Med.  Scant! .  Suppl.   193, 

■947- 

427.  West,  J.  B.,  C.  T.  Dollery,  and  P.  Hugh-Jones.  The 
use   of  radioactive   carbon   dioxide   to   measure   regiona  1 


417. 


418. 


4>9- 


420. 


421 


422. 


423- 


428. 

429- 
43° 

431- 

432- 
433' 
434- 

435- 

436- 

437- 

438. 
439- 


440. 


441 


442. 


443- 


blood  flow  in  the  lungs  of  patients  with  pulmonary  dis- 
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West,  J.  B.,  K.  T.  Fowler,  P.  Hugh-Jones,  and  T.  V. 
O'Donnell.  The  measurement  of  the  inequality  of  ventila- 
tion and  of  perfusion  in  the  lung  by  the  analysis  of  single 
expirates.  Clin.  Set.  16:549,  1957. 

Wezler,  K.,  and  W.  Sinn.  Das  Stromungsgesetz  des 
Blutkreislaufes.  Ar-jieiniitlrl-Porsch.  J  Beihejt.  3:  1953. 
Whittaker,  S.  R.  F.,  and  F.  R.  Winton.  Apparent 
viscosity  of  blood  flowing  in  isolated  hindlimb  of  dog,  and 
its  variation  with  corpuscular  concentration.  J.  Physiol., 
London  78:339,  1933. 

Whittenberger,  J.  L.,  M.  McGregor,  E.  Berglund, 
and  H.  G.  Borst.  Influence  of  state  of  inflation  of  the 
lung  on  pulmonary  vascular  resistance.  J.  Appl.  Physiol. 
15:  878,  i960. 

Whitteridge,    D.    Multiple   embolism   of  the   lung   and 
rapid  shallow  breathing.  Physiol.  Revs.  30:475,  1950. 
Wk.gers,    G.   J.    The   regulation   of  the   pulmonary   cir- 
culation. Physiol.  Revs.  I  :  239,  1 92 1. 

Williams,  M.  H.,  Jr.  Relationships  between  pulmonary 
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Wilson,  R.  H.,  W.  Hoseth,  and  M.  Dempsey.  The  inter- 
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Witham,  A.  G,  J.  W.  Fleming,  and  W.  L.  Bloom.  The 
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Wmmersley,  J.  R.  The  mathematical  analysis  of  the 
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Air  Develop.  Center  Tech.  Rept.  WADC-Tr 56-61 4,  1958. 
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Wood,  P.  The  Eisenmenger  Syndrome  or  pulmonary 
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2:70'.  755.  ]958- 

Wood,  P.,  E.  M.  Besterman,  M.  K.  Towers,  and  M.  B. 
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INDEX 


Index 


[£    LIBRAR 

^V   MASS. 


Abdominal  pressure 
venous  pressure,   1123 

Absorption 

general  formulation,  961 
injury  and,  994 

extracellular  pathway,    1065- 1066 
intracellular    pathway,    1 065-1066 
pathways,  discussion  of,  1 066 

Acetabulum 

arteries  of,  1652 

Acetate  ion 

arteriolar  size  and,  948 
entrance  rate  into  muscle,  1 1 38 

Acetylcholine 

arterial  diameter  and,  807 
as  coronary  vasodilator,  1548 
as  neuromuscular  transmitter,   1366 
atrophine  antagonism,  1552 
blood  flow  and,  953 
cardiac  effects,  1552 
coronary  circulation  and,  1562 
cutaneous  blood  How  and,  1 346 
distribution  in  abdominal  viscera,  141 7 
gastric  blood  flow  and,  1446 
hepatic  blood  flow  and,  1419 
in  uterus,  estrogen  and,  1599 
intestinal  blood  flow  and,  1448 
joint  blood  flow  and,   1663 
mesenteric  blood  flow  and,   1451 
pancreatic  blood  flow  and,   1450 
pressure-flow  and,  952 
pulmonary  vascular  pressures  and,  1700 
release  of  norepinephrine  by,   1420 
secretion  in  arteriovenous  anasto- 
moses, 1256 
segmental  resistance  and,  952 
skeletal  muscle  blood  flow  and,  1 364 
skin  circulation  and,   1 334,   1 345 
smooth  muscle  potential  and,  1 155 


splanchnic  circulation  and,   1419 

splenic  blood  flow  and,  1450-1451 

vascular  capacity  and,  953 

vascular  effects  of,  972 

vascular  volume  and,  955 

venodilator  responses,  1094 
Acetylsalicylic  acid 

bradykinin  release  and,   1242 

erythromelalgia  and,  1242 
Acidosis 

acute,  pulmonary  resistance  and,   1722 

renal  blood  flow  and,  1504 
Adipose  tissue 

fat  metabolism  in,  1 175 
Acrocyanosis 

basic  defect  in,   1 231 -1232 

characterization,  1230 

detailed  description,  1231 

differential  diagnosis,  123 1 

pathology,  1231 

picture  of,  1230 

sympathectomy  in,  1232 

symptoms,  1230 

vascular  mechanisms  in,  1231 
Actinomyosin 

as  contractile  system,  871 
Adenosine  triphosphate 

intestinal  blood  flow  and,  1448-1449 

skin  circulation  and,   1346 

vasodilatation  and,  1338 
Adenylic  acid 

pressure-volume  relations  and,   1085 

venodilator  responses,  1094 
ADH :  see  Antidiuretic  hormone 
Adipose  tissue 

nature  of,  1 173 
Adrenaline:  see  Epinephrine 
Adrenergic  agents 

'747 


action  on  vascular  beds,  949 
venoconstrictor  responses,  1 094 
Adrenergic  blocking  agents 

hepatic  circulation  and,   1421 
Adrenocortical  hormones 
atherosclerosis  and,  1201 
filtration  coefficients  and,  999 
lipid  metabolism,  iaoi 
Adrenocorticotropic  hormone 

fat  mobilization  and,  1174-1175 
Adventitial  cells:  see  Rougct  cells 
Aging 

aorta  and,  875 

arterial  distensibility  and,  808,  876 

arterial  ratio  of  radius  to  wall  thickness 

and,  876 
arterial  retraction  and,  813 
arterial  stretch  and,  876 
blood  pressure  regulation  and,  876 
blood  vessel  wall  stiffness  and,  809 
collagen  fibers  and,  868 
decrease  of  hysteresis  with,  877 
elastic  tissue  and,  86g 
peripheral  vascular  disease  and,    12 17 
serum  cholesterol  level  and,   11 98 
smooth  muscle  degeneration  and,  875 
vascular  smooth  muscle  and,  872,  875 
venous  valves  and,  882 
wall  thickness  and,  813 
Albumin 

appearance  in  lymph,  1043 
binding  of  fatty  acids,    1 1 78 
capillaries  permeability  to,    1013 
concentration  in  human  plasma,  974 
disappearance  from  plasma,  1043 
egg,  molecular  sieving  of,  1017 
extra-  and   intravascular   masses,    1042 
infusion,  renal  function  and,   1499 
in  lymph,  1042 


i748 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


in  lymph  and  plasma,  1063 

urea  and,  1064 
molecular  weight,  974 
osmotic   pressure-concentration  curves, 

972 

osmotic  pressure  due  to,  974 

permeability   of  muscle   capillaries   to, 
1013 
Alcohol 

hepatic  blood  How  and,  1400 
Aldosterone 

shock  and,  1 1 16 
Alexander,  R.  S. 

The   peripheral   venous   system,    1075- 
1098 
Alkali  metal  ions 

ionic  radii,  1 137 

relative    entrance    rates    into    muscle, 
.138 

relation   ion  size   to  electric   field   mo- 
bility, 1 138 
Alloxan  diabetes 

atherosclerosis  and,  1201 

lipid  metabolism  in,  1201 
Altitude 

circulatory    and    respiratory    measure- 
ments and,  1 720 
Alveoli 

capillary  gas  exchange,    167  1 

hypoventilation 

alveolovascular  reflexes,  172 3 
in  chronic  bronchitis,    1722 
in  various  conditions,  1722 

pressure,     transmural     vessel     pressure 
and,  1 708 

relationship  to  capillaries,   1676 

structure  of,  1676 

ventilation,  determination  of,    1682 

ventilation-perfusion  ratios,  1684 
Ammonium 

ionic  radii  of,  1 137 

mobility  in  electric  field,   11 38 

relative  diameter,   1  1  38 
Ammonium  ion 

entrance  rate  into  muscle,  1 138 
Amniotic  fluid 

maternal  uterine  blood  and,   1609 

pressure,  placental  pressure  and,    1608 
Amyl  nitrite 

splenic  blood  flow  and,  1450 
Amyloid  disease 

proteins  of  edema  fluids  in,  982 
Analogue  computer  techniques 

differentiation,  841 
Anaphylactic  shock 

blood  and  lymph  in,  1059 

lymphatic  system  in,  1058 
Anesthesia 

blood  vessel  dilation  and,  900 

hepatic  blood  flow  and,  1405 


mesenteric  blood  flow  in,   1443 

plasma  K  response  to  epinephrine  and, 
1 152 

renal  blood  flow  and,   1488 
Angina  pectoris 

causes  of,  1550 

origin  of  pain,  1 565 

response  to  drugs,  1564 

treatment  of,  1572 
Angiogenesis 

general  aspects,  1 258 

in  transparent  chamber,  1259 
Angiotensin  (angiotoninl 

plasma  Na  concentration  and,   1153 

skeletal  muscles  and,  1355 

vascular  volume  and,  955 
Aniline 

clearance  by  rat  stomach,  1443 
Anions 

vascular   smooth   muscle    tension    and, 

1 '59 
Anoxia 

capillary  filtration  coefficients  and,  9Q8 
capillary  permeability  and,  997 
collateral  development  and,  1  260 
coronary  blood  vessels  and,  1544 
effects  on  fetus,   1635-1638 
fetal  blood  flow  and,   1635 
fetal  hemoglobin  and,  1635 
fetal  resistance  to,    1638 
filtration  coefficients  and,  989 
intermittent   claudication   and,    1217 
muscle  blood  flow  and,  1378 
pulmonary    edema    and,  1053 
reactive  hyperemia  and,  1375 
Anterior  pituitary  hormones 
atherosclerosis  and,  1 202 
cholesterol  metabolism  and,   1  202 
lipid  metabolism  and,   1 202 
Anticipation 

venous  pressure  and,    1090 
Antidiuresis 

mean  regional  transit  time,  water  con- 
centration and,  1 50 1 
renal  medullary  circulation  in,   1499 
Antidiuretic  hormone 

permeability   of  collecting   ducts    and, 

1470 
urine  concentration  and,  1472 
Antipyrine 

capillary  clearance  blood  flow  and, 

1023 
diffusion  of,  1002 
Aorta 

abdominal 

arterial  flow  pulse  in,  849 
backflow  component,  852 
circumference,  846 
flow  pulses,  852 
mean  peak  flow,  846 
phase  relationships,  851 
resonant  flow  wave,  851 


acetylcholine  and,  1700 

aging  and,  875 

analogy  to  nylon  stocking,  806 

arch 

blood  distribution  of,  849 

pressoreceptors  of,  875 
ascending 

blood  flow  and,  845,  859 

circumference,  846 

diastolic  flow  curve,  845 

flow  pattern,  859 

flow  pulse  through,  845 

hemodynamics  in,  845,  846,  859 

mass-acceleration  effects,  846 

mean  peak  flow,  846 

mean  peak  velocity,  846 

pressure-flow  relationship,  846 

velocity  profile,  845 
as  reservoir,  799,  824-835 
baroreceptor  in,  874 
blood  distribution  in  arch,  851 
branches  of,  flow  in,  852 
central  pulse  contour,  824-826 
diastole,  backflow  and,  847 
distensibility 

measurement,  801-814 

pressure  volume  curves  and,  8 1 2 
electrical  analogue,  820 
electrolyte  levels  in,   1 141 
extension-release  of,  877 
foam  cell  in,  1  170 
function  as  conduit,  814-824 
functions  of,  799 

histological  considerations  of,  804-806 
hysteresis  loop,  802-804 
length,  pulsatile  changes  in,  813 
muscle  contraction  in,  807 
Na  and  K  of,  1  1 4 1 
phase  relationships  in,  772 
physiology,  799-838 
pressure  differences  with  ventricle,  781- 

782 
pressure-flow  relations  in,  820 
pressure  pulse  compared  to  pulmonary, 

1686 
pressure  pulses,  reconstruction  of  com- 
parative values,  825 
pressure-volume  diagram  in,  875 
pressure-volume     diagram,      muscular 

arteries  and,  879 
pulse  at  various  positions,  829 
pulse   contour  in,   Valsalva   maneuver 

and,  831 
reflected  waves  in,  827 
resonance 

exit  tubes  and,  827 

femoral  system  and,  828 

in  visceral  arteries  and,  829 

mode  of,  828 

origin  of,  829 

requirements  for,  827 

standing  waves  in,  826-829 
resonating  system  and,  827-828 


■749 


response  of  related  rings,  807 
response  to  stretch,  873 
simulated,  flow  velocity  curve,  822 
tension-length  curve,  801-802 
thoracic 

arterial  flow  pulse  in,  849 

blood  flow  in,  860 

circumference,   846 

distensibility  modulus,  813 

mean  peak  flow,  846 

mean  peak  velocity,  846 

pressure-flow  values,  823-824 

pressure-volume  diagram,  873 

pressure-volume    relationships,    812- 
813 

stretch  curves  of,  802,  811 

stretch-release  curves,  812 
vaso  vasorum  in,  884 
wall  thickness,  pulsatile  changes  in,  813 
Aortic  flow 
axial 

pressure  difference  and,  847 

pulse  in,  845 
computer  solution  to,  847 
curves,  82 1 

at  rest,  773 

during  sympathetic  stimulation,  773 

in  exercise,  772 

pressure  and,  772 

stroke  volume  and,  82 1 
ductus  arteriosus  and,  861 
during  exercise,  846 
measurements  in,  800 
pattern,  820 

pressure  changes  and,  82 1 
piessure   relationship  in  values,  848 
pulse  in,  845 
pulse,  in  stenosis,  859 
relationships  in,  849 
see  also  Aorta;  Cardiac  output 
Aortic  regurgitation 
aortic  flows  and,   1  556 
backflow  wave  in,  860 
brachial  pulse  contour  in,  831-832 
discussion  of,  860 

left  ventricular  ejection  pulse  and,  860 
flow-pressure  gradient  in,  860 
myocardial  ischemia,    1556 
reversible  aortic  insufficiency,   1 556 
Aortic  stenosis 

aortic  arch  pressure  and,  860 
elevated  ventricular  pressure  and,  1555 
flow  curve  and,  860 
flow  pulse  in,  859 
stroke   volume   and   compensatory 
mechanisms,  860 
Apresoline :  see  Hydralazine 
Aramine :  see  Metaraminol 
Arbacia  egg 

filtration  coefficients  in,  992 
Arfonad:  see  Trimethaphan  camphor  - 

sulfonate 
Arrhythmias 


coronary  blood  flow  and,   [541 
effectiveness  of  heart  and,   11 04 
Arterial  disease 

chronic,   vasoconstrictor  mechanism, 

1237 
obliterative,   vascular  dilatability   and, 

1223 
occlusive,  pain  in,  12 18 
vasoconstrictor   mechanisms    in    acute, 

1236 
Arterial  spasm 

basis  for  improvement,   1237 
elastic  recoil  and,  1237 
possible  role  of  serotonin,   1237 
Arterial  system 

abnormal,  communications,   1256 
analogy  approach,  844 
experimental  testing  of,  850 
frequency  response,  characteristics, 

848-849,  851 
gas  embolism,  skin  circulation  and, 

1337 
harmonics  of,  818-821 
harmonics,  phase  lag  and,  817 
low-pass  filtered  hydraulic  supply,  847 
nonpassive  network,  843 
physical  properties,  841 
pressure -pulse  augmentation,  848-849 
resonant  frequency,  848-849 
resonant-network  model,  847,  850 
resonant  wave  amplitude,  848-849 
segmentation  of,  843 
size  range,  841 

transient,  response  method,  844 
transmission  line  model,  849,  851,  852 
values  of  elements,  843 
windkessel    model,    electrical    analogue 
of,  848 
Arteries 

anatomy  of  central  and  peripheral,  880 

arcuate  patterns,  905 

arrangement  of  longitudinal  muscles  in, 

878 
arteriolar    branch   enlargement    at   ori- 
gin, 896 
branches,  angles  of,  896 
changes  after  extirpation,  801 
collateral,  wall  structure  in,   1 268 
contraction 

propulsion  of  blood  and,  871 

relaxation  of,  and,  87 1 
distensibility 

age  and,  808,  875 

in  living  vessels,  804 

muscle  contraction  and,  806 
elastic 

anatomy,  877 

characteristics  of,  873 

discussion,  863-877 

distensibility,  873 

hysteresis  in,  879 

interaction  of  elements,  876 

mechanical  behavior,  878 


model  of,  876 

pressure-volume  diagrams,  879 

role  of  smooth  muscle,  877 

schema  of  behavior,  876 

tension  muscles  in,  874 

visco-elastic  and  plastic  behavior,  877 
evaluation  of  status,  1223 
excised,  stretched  rings,  802 
from  red  pulp  of  spleen  ampulla,  912 
harmonics,  factors  affecting,  820 
length  and  diameter  changes  of,  813 
length  changes,  H 1  j 
ligation,    after    sympathectomy,     limb 

temperature  and,  1264 
major 

function  of,  799 

histology,  804 

loss  of  blood  pressure  in,  801 

physiology,  799-838 
mediation  of  reflex  vasospasm,   1236 
muscular 

anatomy,  877 

discussion,  872,  877-880 

hysteresis  in,  879 

mechanical  behavior  of,  878,  879 

pressure-volume  diagrams,  879 

schema  of  behavior,  879 

smooth  muscle  in,  880 

stress-relaxation  in,  872 

structure,  877 
muscle  ring,  response  to  loading,   1084 
nutrient 

ligation,  marrow  infarction  and,  1658 

physiology,  1677 
peripheral 

pulse  contours,  828 

vascularization  of  wall,  885 

vasa  vasorum  of,  885 
precapillary  branch,  camera-lucida 

drawing  of,  898 
pressure-volume  diagram,  873,  879 
ratio  of  radius  to  thickness,  age  and,  876 
resonance  in,  826 

ring  and  longitudinal  muscle  arrange- 
ment, 878 
ring  muscles  of,  873 
spasm  of,  myogenic  factor,  1236 
spontaneous    rhythmical    contractions, 

898 
standing  waves  in,  826 
stretch 

age  and,  876 

hysteresis  loop,  802 
tension  muscles  of,  873 
valves,  structure,  781 
vascular  tone,  source  of,  1409 
vasa  vasorum  in,  885 
wall  thickness  of,  812 
Arterioles 

arcuate  systems  of,  896 
identification  of,  909 
receptor  sites  for  blood  flow  control,  949 
terminal,  contractions  in,  899 


i?5c 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


terminal,  definition,  891 
terminal,  vasomotion  of,  897 
vasomotion  in,  8g6,  900 
Arterioportal  anastomoses 

in  liver,  922 
Arteriovenous  anastomoses 
abnormal  description,   1 256 
blood  How  and,  1261 
body  temperature  and,  921 
classification,  1251 

collateral  circulation   and,    1257,    1261 
compared  to  A-V  bridges,  92 1 
criteria,  909 
factors  affecting,  972 
graphic  reconstruction,  1253 
in  cochlea,  916 
in  conjunctiva,  908-910 
in  ilial  submucosa,  907 
in  lungs,  880 

in  panniculus  carnosus,  902 
in  rabbit  ears,  92 1 
in  skeletal  muscle,  902,   1358 
in  stomach,  905 
in  submucosal  plexus,  906 
in  tongue,  1254 
in  various  tissues,  921 
microcirculation  and,  899 
nor  m,  il 

development,  1254 

distribution,  1252 

factors  affecting,  1 255 

fate,  1254 

function,  1252 

role,  1256 

size,  1252 

structure,  1252 
opening  of,  blood   flow  and,    1257 
precapillary,  1251 
spontaneous  rhythm,  92  1 
structure,  880,  92 1 
temperature  regulation  and,  922 
traumatic  or  surgically  induced,    1257 
wall  structure,  880 
Arteriovenous  bridges 
blood  flow  in,  918 
compared  to  arteriovenous  anasto- 
moses, 92 1 
description,  918 
Arteriovenous  communications 
cutaneous  arterial  spider,   1256 
fistula,  musical  qualities  of,  859 
fistula,  traumatic,  1257 
in  rabbit  ear,  1255 
in  spleen,  912 

normally  occurring,   1252-1256 
surgically  induced,  1257 
Arteriovenous  pathways 

antimesenteric    area,    anastomoses    in, 

905 
arcuate   patterns   in   terminal   vascular 

bed,  897 
definitions,  891 


in  bat  wing,  895-898 

in  bulbar  conjunctiva,  908-910 

in  cochlea,  915-918 

in  hamster  cheek  pouch,  900 

in  lung,  913-915 

in  mesentery,  900 

in  myocardium,  903-904 

in  rabbit  ear,  898-goo 

in  skeletal  muscle,  900-903 

in  skin,  904 

in  spleen,  g  10-9 13 

in  stomach  and  intestine,  go4-go8 

structure  of  in  terminal  vascular  beds, 

895-923 

techniques  for  microscopic  observation 
of,  892-895 

through  terminal  vascular  beds,  923 
Artificial  membranes 

filtration  coefficients  through,  992 
Artificial  perfusion 

pressure    gradients,    resistance    change 
and,  1089 
Artificial  respiration 

lymph  flow  and,  1052 
Ascites 

liver,  lymphatics  and,  1051 
Atherogenesis 

chickens  and,  1201 

cholesterol-induced,  1201 

cholesterol-induced  corticoids  and, 
1202 
Atherogenic  diets 

thyroid  activity  and,  1  200 
Atheromatous  lesion 

accumulation  of  lipophages,   1 1  70 
Atherosclerosis 

/-epinephrine  and,  1202 
Atheroma 

derivation  of  constituents,  1188 

lipid  constituents,  1 188 
Atherosclerosis 

adipose  tissue  and,    11 73- 1175 

adrenocortical  activity  and,   1201 

alloxan  diabetes  and,   1 201 

anterior  pituitary  hormones  and,   1 202 

basic  vascular  lesions,    1 1  g8 

blood  clotting  and,   ii8g-iigo 

blood  lipids  and,   11 87-1 189 

chickens 

production  of,  1201 
sex  differences,  1204 

coronary  heart  disease  and,   1 1 98 

complications,  11 98 

definition,  1 167,  1 197 

diabetes  and,  1 187,  1200 

diet  and,  1 171-1 172 

dietary  fats  and,  1 167 

elastic   tissue  and,    1168 

emotional  factors  and,    1  198 

emotional  stress  and,   1208 

etiology  of,  1 1 67 

experimental 


hyaluronidase  and,  1202 

in  rabbit,  1  i6g 
factors  affecting,  Ii8g 
fat    absorption,    digestion    and,     1 1 72- 

"73 

feeding  patterns  and,  1207 
foam  cells  and,  1 168 
heredity  and,  1205-1206 
hormones  and,  1 197-1205 
hypertensive  patients  and,   1169 
hypothyroidism  and,  1  187 
ingestion  of  food  and,  1 171 
initial  lesion,  1 168 
insulin  and,  1200 
interplay  of  factors,   1208 
lipid  metabolism  and,   1 167-1190 
lipoprotein  diffusion  and,  1046 
metabolic  disturbance  in,   1197 
pathogenesis,  1 168-1 1  7 1 
pathology,  1  168 
physical  activity  and,  1206 
serum  cholesterol  level  and,  1 197 
serum  lipids  and,   11 75-1 180 
sex  differences,    1 203-1 204 
sex  hormones  and,   1203 
special  manifestations,  1 188 
species  differences,  1 205 
strain  differences,  1205 
stress  and,  1206-1208 
thrombus  formation  and,   1 189 
Atria 

contraction,  valve  closure  and,  781 
filling 

changes  of  venous  return  and,  786 

during  ventricular  systole,  786 

factors  controlling,  787 

pericardium  and,  7g3 

ventricular  contraction  and,  788,  794 

X  wave  and,  786 
function  of,  769 
left  and  right  compared,  789 
muscle  fascicles,  1518 
myocardial  fibers  in,   1518 
pressures 

characteristics,  776 

complex  graphical  analysis  of,    1 1 1 8 

drop  after  contraction,  776 

lymph  flow  and,  1052 

pulmonary  edema  and,  1052 

recording  of,  776 

V  point,  776 
X  point,  776 

Y  point,  776 
Z  point,  776 

role  of,  768 

system,  steady -state  oscillation,  844 

systole,  functions,  787 

systolic  reserve  volume,  786 

volume,  783-786 

at  different  stages  of  cardiac  cycle, 

785 
difficulties  of  determining,  785 


INDEX 


■751 


exercise  and,  786 
terminology,  785 
under  various  conditions,  782 
various  activities  and,  785-786 
Atrioventricular  valves 

asynchrony  in  closure,  790 
closing,  775 

mechanism  of  closure,  780 
movement  of,  781 
passive  movements  of,  779 
structure,  780 
Atrium,  left 
pressure  in 

acute  left  heart  failure  and,  1  120 
acute  right  heart  failure  and,  1121 
lung  edema  and,  991 
relation  to  right  at  birth,  1640 
venous  pressure  and,  1 1 18-1 1 19 
Atrium,  right 
pressure  in 

acute  left  heart  failure  and,  1 1 20 
acute  right  heart  failure  and,  1 121 
blood  transfusion  and,  1 1 1 4 
blood  volume  and,  1 1 14 
cardiac  decompensation  and,  1 1 1 7 
cardiac  output  and,  1 105 
congestive  heart  failure  and,   11 16 
disease  and,  1710 
drugs  and,  1 564 
exercise  and,  1 1 13 
heart  recompensation  and,  1 1 17 
hemorrhage  and,  1 1 1 4 
muscular  exercise,  1 1 1 3 
myocardial  damage,  1 1 15 
open  chest  and,  11 15 
peripheral  venous  pressure  and,  1 127 
rapid  transfusion  and,  1 1 1 3 
relation  to  left  at  birth,    1640 
shock  and,  1  1 14 

simplified  graphical  analysis  of,  11 03 
sympathetic    stimulation    and,    1112 
vasomotor  tone,  1 1 1 3 
venous  collapse  and,  1 107 
venous  pressure  and,   1 1 26 
venous  return  and,   Ilia 
Atropine 

estrogen-induced  hyperemia  and,   1601 
intestinal  blood  flow  and,  1^-17 
resistance  in  vascular  bed  and,   948 
skin  blood  flow  and,   1340 
Autonomic  nervous  system 

anatomical  arrangement,  1723 
blockade,  hepatic  circulation  and,  1420 
distribution  of,  1526 
fat  mobilization  and,  1 1 75 
myogenic  activity  and,  880 
Autoregulation 

myogenic  theory,  946 
perfusion  pump  schema  for,  943 
Axon  reflex 

capillary  pressure  and,  996 


femoral  artery  and,  1  380 

Bader,  H. 

The   anatomy    and    physiology   of   the 
vascular  wall,  865-889 
Barcroft,  H. 

Circulation   in   skeletal   muscle,    1353- 
■385 
Baroreceptors 

extrasplanchnic,  141 6 

in  young  animals,  1643 

reflex,  in  skeletal  muscle  vessels,    1363 

stimulation 

skeletal  muscle  blood  flow,   1363 
skin  circulation  and,    1344 
Basal  data 

flow  values  for,  1537 
left  ventricle,  1537 
Bat  wing 

arteriovenous  pathways,  920 
blood  flow  in  capillary  bed,  895 
microcirculation  in,  894,  895 
Bernoulli  effect 

description  of,  779 
Bernoulli's  theorem 

applied  to  flowmeters,  1296 
Bier's  spots,  1 225 
Bile 

lymph  transport  and,  1045 
release    of   alkaline    phosphatase    from 
intestinal  mucosa  and,  1047 
Bile  acids 

enterohepatic  cycle  of,  1  180 
formation  from  cholesterol,  1 1  79 
formation  of,  1 180 
sequestrants,  characterization,  1186 
Birds 

protein  osmotic  pressure  in,  975 
Bladder  distention 

skin  circulation  and,  1 344 
Blood 

chemical  composition  of,  1544 

cells,  injury  with  perfusion  pumps,  1370 

clots,  relation  to  thrombi,   1 190 

clotting,  thrombosis,  1189-1190 

coagulation 

anaphylaxis  reaction,  1059 
dietary  fat  and,  1  189 
serum  lipids  and,  1  168 
propulsion  by  arteries,  871 
transfusion 

cardiac  output  and,  1 1  14 
right  atrial  pressure  and,   11 14 
venous  return  and,  1 1 14 
velocity,  measurement  of,  1302 
viscosity 

apparent  flow  and,  938 
apparent  in  vivo  and  in  vitro,   940 
pressure-flow  relationships  and,  940 
Blood  brain  barrier 

capillary  permeability  and,  1013 
Blood  flow 


acetylcholine  and,  953 
arterial 

arcades,  906 

oxygen  saturation  and,   1 1 25 
perfusion  pressure  and,  936 
pressure,     extravascular,     effect    on, 

94',  1378 
systemic,  845-854 
arteriovenous 

anastomoses  and,  899,  1261 
difference    pressure    and,    937,    938 
autoregulation  of,  880,  943 
A-V  bridges  in,  918 
axial,  842,  1295 

equation  for,  842 
blood-tissue  exchange  and,    1019,   1023 
capillary 

clearance  and,  1023 
contractility  and,  923 
gas  exchange  time,  1 706 
measurement  of,  1702 
nets,  896,  897,  898,  899,  900 
permeability,  1019-1024 
pressure  and,  969 

rate,  hemodynamic  influences,    1706 
value  of,  1702,  1706 
changes  in  velocity,  839 
collateral  development  and,  1 260 
critical  closing  pressure,  1408 
debt,  repayment  of,  1539 
determination     of    vascular     behavior 

from,  957 
edema  and,  969 
extramural,  1528 
flow -pressure  curves,  1700 
heart-lung  preparation,  1527 
inflection  of  wall  and,  1 298 
laminar,  parabolic  velocity  profile,  1295 
lateral  pressure  and,  941,   1378 
lowered    impedance    in    small    artery 

and,  853 
mean   transit   time,   perfusion   pressure 

and, 954 
metabolic  control,  1024 
nonlaminar  flow  rules,  858 
oxygen  consumption,  blood  flow,  tem- 
perature and,  1022 
perfusion  pressure  and,  943,  954 
phasic,  1528 

methods,  1528- 1529 
pressure  relationships,  1408 
pulsatile 

arterial  inflow,  956 
in  peripheral  arteries,  1296 
in  pulmonary  vessels,  855-856 
in  systemic  arteries,  845-854 
in  systemic  veins,  854-855 
methods    of   measurement,    839-841 
rigid  and  distensible  tubes,  814-816 
receptors   for   control    in   muscle,    949 
relation    to    pressure,     equations    814, 
88o,  951 


175^ 


HANDBOOK    OF    PHYSIOLOGY 


IJIRCILATION    II 


spontaneous    rhythmical    contractions, 
898 

temperature,     O2     consumption     and, 
1022 

thermal  conductivity  and,  1287 

through  distensible  tube,  824 

through  rigid  system,  824 

vasoconstrictor   fiber   stimulation    and, 
971 

vasomotion  and,  926 

vascular  behavior  and,  935 

venous 

collapsibility  and,  1080 
pressure  and,  1 1 26 
system  and,  1079 

venovasomotor  reflex,  1 282 

see  also  Circulatory  autoregulation 
Blood  flow  measurements 

Aschofl   and   Wever  ring  element  for, 
1285 

bubble  flowmeter,  1 280-1 281,  1530 

capillary,  1 706 

cerebral  blood  flow,  1290 

collateral  circulation,  1270 

computer  techniques  and,  840-841 

dilution  methods,  1291 

discussion  of  role,   Reynold's  numbers 
and,  131 1 

drop  chamber,  1278 

during    venous    occlusion    plethysmog- 
raphy, 1282 

dye  studies,  precautions,  1 399 

electrolytic  polarization,  1321 

electromagnetic-induction  principle, 

^V^-lV%  '53° 
instruments  for,  1278-1287 
isotopes  and,  1530 
mathematical  relation 

to  resistance,  939 

to  pressure,  939 
methods,  839-841,  1278-1287 

based  on  Ludwig's  principle,   1278- 
1279 

clearance  techniques,  1397 

extraction  techniques,  1397 
nitrous  oxide  method,  1 290 
nuclear  magnetic  resonance,  1321 
outflow  measurement,  1279-1280 
photoelectric  plethysmography,  1283 
plethysmography,  1281 -1283 
Prandtl's  theory,  1311 
pulse  plethysmography,  1 283 
regional    determinations,     1022,     1290- 

1293 
RCA    5734   transducer,    discussion   of, 

1308 
Reins  thermostromuhr,  1 283-1285 
schema  of  direct -recording   flowmeters 

1279 
strain-gauge  occlusion  technique,   1282 
tachograph,  1283 
thermal  methods,  1 283- 1 287 


traveling  markers,  1320 
ultrasonic  flowmeters,  1318 
venous  outflow  collection,  1278 
see  also  Flowmeters 
Blood  flow,  regional 
aorta,  800 
ascending  aorta  and,  845,  859 

zero  drift,  840 
ascending   vs.   thoracic   aorta,   847 
bone,  1 656- 1 658 
carotid  artery  flow,  853 
conjunctival  capillaries,  908 
descending  thoracic   aorta  in,  860 
gastric,  1443 

factors  affecting,  1446 

muscosa,  blood  flow  in,  1443 

mucosal  secretion  and,  1452 

tetranitrate  and,  1447 
hand 

emotion  and,  1339 

heating  of  legs  and,  1 343 

vessel  innervation  and,    1339 
Ilidar,  intestine  and,  1447 
intestine,  1443 

intrauterine  pressure  and,  1600 
mesenteric  circulation,  hematocrit  and 

blood  volume,  1445 
pancreas,  1441 -1443 

factors  affecting,  1450 

pancreozymin,  1450 

secretion  and,  1452 
placental,    functional    implications    of 

venous  drainage,  1588 
splanchnic 

effect  of  dopamine  on,  141 7 

factors  affecting,  1429 

method,  1392 
splenic,  1443 

epinephrine  and,  955 

factors  affecting,  1450 

sympathetic    stimulation    and,    955 
stria  vascularis,  9 1 7 
systemic    arterial    differential    pressure 

flowmeter  and,  345 
through  portal  vein,  1439 
umbilical 

epinephrine  and,  1633 

factors  influencing,  1633 

in  lamb,  1633 

in  man,  1633 

in  sheep,  1632-1634 

norepinephrine  and,  1633 
uterine 

electrolyte  exchange,  1594 

-pinephrine,  effects  on,  1637 

norepinephrine,  1637 
see  also  Cerebral  blood  flow;  Cutaneous 
blood   flow;   Hepatic    blood   flow; 
Pulmonary     blood     flow;     Renal 
blood  flow;  Skeletal  blood  flow 
Blood  pressures 
age  and,  1643 


aortic 

cardiac  output  and,  1534 
coronary  flow  and,  1534 
flow  during  exercise  and,  846 

arterial 

blood  flow  and,  1378 
bone  blood  flow  and,  1657 
cerebral  venous  outflow  and,  946 
intrarenal  pressure  and,  1478 
lateral  pressure,  flow  and,  941 
mesenteric  artery,  occlusion  of,   1449 
myocardial  damage  and,  1 1 1 6 
portal  venous  flow  and,  1440 
serotonin  and,  1089 
skeletal  muscle  blood  flow  and,  1357 
uterine  contractions  and,  1599 
values  for,  1714 

arteriovenous  difference 
blood  flow  and,  937,  938 
intestinal  blood  flow  and,  1449 

atheroma  formation  and,  1208 

basal  tone  and,  1 356 

bone   medullary  canal,   pressure,    and, 
1 660- 1 66 1 

brachial     artery,     Valsalva    maneuver 
and,  171 2 

brachial  pulse  and,  831 

capillary,  962-972 

changes 

after  birth,  1642 
during  birth,  1642 

coronary  flow 

coronary  sinus  oxygen  saturation 

and, 1539 
epinephrine  and,  1551 
stellate    ganglion    stimulation    and, 
1548 

determination     of     vascular     behavior 
from,  957 

diastolic,  vessel  wall  tension  and,   1 139 

differentials,   equation  for,    1 297 

digital,  response  to  noradrenaline,  1229 

drugs  and,  1564 

exercise,  846 

hyperemia  and,  1378 

extracellular  Na  and  K  and,  1 154 

fall,  collateral  development  and,   1260 

flow  relations 

Acetylcholine  and,  952 

and    simultaneous   measurement    of, 

840 
source  and,  844 

hemorrhagic  shock  and,   1535 

histamine  and,  970 

in  bone  marrow,  1659 
adrenaline  and,  1661 
nerve  stimulation  and,    1660 

in    digital    arteries,    temperature    and, 
968 

lactic  acid  and,  1722 

lateral 

principles  of,  1300 


I  Mil   \ 


!753 


simultaneous    measurement    of,    840 

uses  of,  1300 
leg  blood  flow  and,  1 356 
loss  in  major  arteries,  801 
mathematical  relation 

to  flow,  937,  939 

to  resistance,  939 
mean  circulatory 

compared  to  mean  systemic  pressure, 
1109 

measurements  of,  1 1 09 
mean  systemic 

acute  left  heart  failure  and,  1 1 20 

acute  right  heart  failure   and,    1 1 2 1 

blood  volume  and,  1 109,  1 1 10 

congestive   heart    failure    and,     iiiti 

definition,  1107,  11 09 

factors  affecting,  1 1  1 1 

value,  1 1 09 

vasomotor  tone  and,  1 1 10 

venous  return  curve  and,  1 109-1 1 10 
plasma  Na  and,  1 152 
positive  pressure  breathing   and,    1 7 1 1 
potassium  changes  and,  1 153 
pressure-pulse  contour  and,  832 
regulation 

age  and,  876 

Na  transfer  and,  1 153 
relation  to  flow,  equations,  814 
sodium  and  potassium 

sodium  changes  and,  1 153 
systemic,  altitude  and,  1720 
vasomotion  and,  926 
vascular  behavior  and,  935 
vessel  wall  structure  and,  1 269 
volume    relationships,    blood    injection 

and  withdrawal,  1085 
wall  stress  and,  875 

see    also    Capillary    pressure;    Venous 
pressure 
Blood  tissue  exchange 

blood  flow  and,  1019,  1023 
capillary  permeability  and,  1019 
of  ions,  1 02 1 
small  molecules,  1021 
Blood  vessels 

alpha  receptor  in,  949 
automaticity  of 

in  man,  1 356 

physiological  condition  and,  1356 
basal  tone  of,  1 355 
beta  receptor  in,  949 
cochlear    perilymph,    endolymph    and, 

9'7 
delta  dilator  receptors  in,  949 
denervated 

adrenaline  and,  1341 
noradrenaline  and,  1341 
different  types,  872-883 
dilated,  distensibility  pattern,   1084 
distensibility     and    resistance    charac- 
teristics, 1674 


excised,  tension-length  curves,  804 

function,  865 

gamma  dilator  receptors  in,  949 

innervation  of,  1338 

self-differentiation,  1 258 

small,  relation  to  lymphatic  capillaries, 

'°37 
Blood  vessel  walls 

active  transport  in,  883 

aldosterone  and,  1 202 

anatomical  elements,  866 

anatomy  of,  865 

arrangement   of  muscle   fibers  in,   806 

basal  tone,  880 

derivation,  880 

myogenic  activity  and,  880 

wall  tension  and,  880 
changes  in  Raynaud's  syndrome,   1227 
collagen  fibers  in,  868 
collagen  tissue,  866,  868 

hysteresis,  868 

irreversible  elongation,  868 

maximal  extension  and,  868 

maximal  tensile  strength,  868 

safety  factor,  868 

stress  and,  865 

structure,  868 
diffusion  in,  883 

diffusion  limit  for  nutrition,  883 
elastic  tissue,  866,  869 

aging  and,  869 

function  of,  869 

hysteresis,  868 

irreversible  elongation,  868 

maximal  extension,  868 

maximal  tensile  strength,  868 

structure,  869 
elements  of,  866-872 
endothelium  of,  868 

cement  and,  883 
estrogens  and,  1204 
extensibility 

elastic  modulus  and,  808 

measure  of,  811 

muscle  contraction  and,  807 

of  structural  elements,  805 
fetal,  elastin-collagen  distribution,  1623 
ground  substance  of,  868 
hormones  and,  1 1 99 
interaction  of  elements  in,  876 
location  of  vasa  vasorum,  885 
lumen  diameter  and  wall  thickness,  866 
lymphatics  of,  886 
model  of,  883 

muscle  of,  arterial  spasm  and,  1236 
network  of  structures,  805 
nutrition,  883-886 

hypertension  and,  886 

lymphatics  and,  886 
of  central  and  peripheral  arteries,  880 
of  venous  system,  881 
oxygen  uptake,  1198 


physiology  of,  865 
properties  of,  866 
qualities,  due  to  in  series  arrangement 

of  elements,  867 
relaxation  of,  1544 
ring  muscles  in,  869-870 
sodium  transport  in,  884 
species  differences,  1 198 
stiffness,  aging  and,  809 
stress,  formula,  865 
structure 

pressure  and,  1269 

relation  to  stretch  hysteresis,  803 
tension 

hydrostatic  pressure  and,  881 

in  veins,  882 

loading  and,  1084 

muscles  in,  869-870 

pressoreceptors  and,  874 
vascularization,  885,  886 

in  peripheral  arteries,  885 
vasa  vasorum  penetration,  885 
venous,  arterial  supply,  885 
see  also  Vascular  smooth  muscle;  Endo- 
thelium 
Blood  volume 

atrial  pressure  and,  1 1 22 
capillary,  total  blood  volume  and,  1705 
cardiac  output  and,  1  1 14 
cardiovascular  dynamics,  1 122 
determination     of    vascular     behavior 

from,  957 
estimation  of  change,  954 
expanded,    capillary    pores    and,    1053 
extrinsic  influences,  954 
factors  affecting,  954 
maximal  effect,  1361 
mean  systemic  pressure  and,  1 109,  1 1 10 
mesenteric,  1445 
muscle  circulation  vasoconstrictors  and, 

1361 
perfusion  pressure  and,  954 
pulsatile  changes  in,  956 
regional,  shifts  in,  1694 
regulation,  lymphatic  return  and,  1042 
resistance  to  flow  and,  956 
right  atrial  pressure  and,  11 14 
vascular 

beds  in,  953-954 

behavior  and,  935 
venous   return   and,    11 10,    11 14,    11 22 

curves  and,  1 1 10,  1 122 
ventricular  outputs  and,  1 1 2 1 
Body  build 

coronary  atherosclerosis  and,  1 206 
Body  position 

uterine  contractility  and,  1600 
venous  pressure  during  pregnancy  and, 
1601 
Body  size 

hepatic  blood  flow  and,  1405 
Body  temperature 


1754 


HANDBOOK    OF    PHYSIOLOGY 


CIRCl'LATION    II 


arteriovenous  anastomoses  and,  92  1 
cutaneous  circulation  and,  1342 
regulation,   skin  circulation  and,    1341 

Body  temperature 

role  of  skin  anastomoses,  1 326-1327 
skin  blood  flow  and,  1 339 

Bone 

bone  marrow  temperature,  1661 
content  of  human  limbs,  1327 
cortical,  Haversian  canals,  1653 
erythrogenic   nests,   oxygen   supply   to, 

1659 

intramedullary  pressure,  1 659-1 661 
marrow,  blood  pressure  in,   1659,   1660 
medullary  canal  pressure,  1659 
blood  pressure  and,  1 660-1 661 
blood  volume  and,  1659- 1660 
factors  affecting,  1660 
Valsalva  maneuver  and,  1660 
nerve  supply,  1 656 
oxygen  content  of  blood,  1658- 1659 
tubular,    vascular   organization,    1652, 

1653 

vascularity  of,  1651 

vertebra,  diagram,  1654 
Bone  blood  flow 

arterial  pressure  and,  1657 

capillaries  in,  1654 

in  man,  1657 

quantitative  measures,  1657 
Bone  circulation 

efferent  fibers,  1656 

flat  bones,  1655- 1656 

hyperemia,  in  handling,  1657 

infarction  in,  1656- 1657 

long  bones,  1 651 -1655 

reduction  of,  1658 

resorption  and,  1657 

vertebrae,  1655 
Bone  marrow 

afferent  fibers,  1656 

oxygen  saturation  of  blood  in,  1659 

temperature  of,  1661 
species  difference,  1661 
Brachial  artery,  dimensions  and  flow,  849 

pulse 

contour  in,  Valsalva  maneuver  and, 

831 
pressure  change  in,  826 
Bradykinin 

capillary  permeability  and,  1061 

release,   acetylsalicylic   acid   and,    1242 

skin  circulation  and,  1346 

vasodilatation  and,  1340 
Brecher,  G.  A. 

Functional  anatomy  of  cardiac  pump- 
ing. 759-798 
Bretschneider  Pitot  meter 

principle  and  formula  for,  1301 

see  also  Flowmeters 
Brisket  disease  see  Mountain  sickness 


Bristle  flowmeters :  see  Flowmeters 
Brodie  Trendelenburg  test 

description,  1223 
Broemser  s  differential  sphygmograph 

discussion  of,  1 299 

principle  of,  1302 
Bi  omosulfophthalein 

conjugation  of,  1398 

extrahepatic  removal  of,  1 398 

metabolism  of,  1398 

removal  from  blood,  1397 

transfer  from  blood  to  bile,  1397 

value  in  clearance  studies,  1 400 
Bromide 

entrance  rate  into  muscle,  1 1 38 
Bronchi 

diameter   in   relation   to    bronchial  ar- 
teries, 1  266 
Bronchial  arteries 

diameter    in    relation    to    diameter    of 
bronchi,  1 266 

flow 

collateral  vessels,  1679 
pulmonary  arterial  relationships, 
1678 

nutrient,  1677 
Bronchiectasis 

pulmonary  collateral  circulation,   1679 
Bronchitis 

pulmonary   artery   pressure   and,    1710 

right  atrium  pressure  and,  1  7 1  o 
Bronchomotor  tone 

bronchospasm,  1 7 1 7 

effects  of,  1 7 1 6 

elastance  of,  1 7 1 7 
Bubble  flowmeter:  see  Flowmeters 
Bulbar  conjunctiva 

microcirculation  in,  893,  908 
Bundle  of  His 

discussion  of,  15 18 
Burch,  G.  E. 

Peripheral    vascular    diseases — diseases 
other  than  atherosclerosis,  12 15- 

IJ49 
Burns 

capillary  permeability  and,  1061 
lymph 

composition  and,  1061 
flow  and,  1061 
protein  in,  985,  1061 
lymphatic  system  and,  1061 
porosity  of  capillary  wall  in,  1000 
protein 

in  interstitial  fluid,  985 
of  lymph  and  plasma,  1061 
vasoconstrictor  substance  produced, 
1 06 1 

Caffeine 

renal  lymph  flow  and,  1058 
Calcium 


arteriolar  size  and,  948 
entrance  rate  into  muscle,  11 38 
mobility  in  electric   field,   11 38 
relative  diameter  of  ion,  1 1 38 
smooth  muscle  tension  and,   1  1 57 
vascular 

effects  of,  972 

resistance  and,  1158 

smooth   muscle   tension    and,    1157- 
1158 
vasoconstriction  and,  1 158 
Calcium  chloride 

mean    activity    coefficients,     in    given 
solution,  1  137 
Calorimetry 

of  skin,  as  measure  of  blood  flow,  1327 
Capacitance 
definition,  820 
relation  to  effect  of  change  in  resistance, 

1 1 08 
terminal  vascular  beds,  935-957 
Capillaries 

arterial,  description,  899 
bed 

collaterals  to,  diagram  of,  936 

density,  oxygen  diffusion  and,  1020 
blood  and  lymph,  morphology,  1062 
blood  flow  in,  goo 

nets,  896,  897 
caliber  changes,  899 
contraction,  923,  924 

blood  flow  and,  923 
count  in  muscle,  1019 
definition  of,  892 
density,  conducting  tissue  of  heart  and, 

152 1 
description  of,  9 1  o 
diagram  of  average  limits,  985 
filtration  coefficients  of,  988-1000 
function  of,  880 

adsorbed  protein,  994 
growth  of,  899 
in  skeletal  muscle,  902 
injured,  filtration  coefficients  and,  995 
interendothelial  junction,  1012 
intramural,  in  venous  walls,  885 
limb,  protein  of  capillary  filtrate,  982 
membranes,  filtration  coefficients 

through,  992 
mesenteric 

effects  of  various  substances  on,  998 

filtration  coefficients  of,  998 

fluid  exchange,  996 
microaneurysm  in  diabetes,  1 200 
muscles  in,  1358 
nets,  blood  pressure  in,  896,  897 
origin  in  various  tissues,  920 
para-circulations,  986 
pores  of,  1002,  1 01  1 
pore  size 

calculation,  1005 


1 755 


diffusion  and,  1003 

effective  radius,  1002 

hydrodynamic  flow  and,  1003 

in  various  areas,  1006,  1043 
"pore  stretching",  1053 
pore  structure,  101 1 
porosity  of  injured  wall,  999 
protein  passage  through,  986 
stasis 

permeability  to  protein  and,  997 

pressure  and,  997 

steps  leading  to,  995 
stoppage  of  flow  in,  880 
structure,  880 

in  lungs,  1676 

in  muscle,  1009 

regional  differences,  1013-1018 
transitional,  in  pigeon  bone,   1654 
"true",  1 52 1 
venous,  leaks  in,  1014 
walls 

exchange  of  substances  through,  961- 
1024 

filtration  and  absorption,  961-962 
Capillary  filtrate 
circulations  of,  986 
production  of,  986 
protein  content,  982,  985 
volume  formed,  987 
see  also  Lymph;  Interstitial  fluid 
Capillary  permeability 
anoxia  and,  997,  1053 
arterial  disappearance  curves  and,  ioog 
blood  brain  barrier  and,  1013 
blood  flow  and,  971,  1 01 9-1 024 
blood-tissue 

exchange  and,  1019 

permeability  and,  1023 
burns  and,  1061 

comparison  with  blood-tissue  permea- 
bility, 1023 
definition,  gg2 
dilatation  and,  1059 
factors,  1 06 1 
histamine  and,  1059 
hypoxemia,  systemic  and,  998 
in  liver,  1050 
in  various  organs,  1012 
leaks  and,  1014 
lipid-insoluble    molecules    and,     1007, 

1013 
lipid-soluble  molecules,    1 01 8-1 01 9 
local  hypoxemia  and,  998 
lymph  formation  and,  1040 
molecular  sieving  and,  1005 
natural  mediators,  1061 
osmotic  pressure,  flux  rate  and,  1010 
pinocytosis  and,  1017 
platelets  and,  995 
protein  and,  in  stasis,  997 
respiratory  gases  and,  1018 


substance  produced  in  shock  and,  1060- 

106 1 
sympathetic  stimulation  and,  1 362 
tissue  metabolism  and,  gg7 
traumatic  shock  and,  1 05g 
urea  and,  1064 
uterine,  estrogen  and,  1601 
Capillary  pressure 
blood  flow  and,  g6g 
dependence    on    venous    and    arterial 

pressures,  g6g 
direct  measurement,  g64 
direct  methods,  requirements,  g63 
epinephrine  and,  g68 
factors  affecting,  g66,  g72 
nitration  coefficients  and,  ggi 
fluid  exchange  and,  988 
functional  changes  of,  g68 
histamine  and,  996 
hydrostatic  and  isogravimetric,  990 
hyperemia  and,  968 
hypertension  and,  968 
injury  and,  gg6 
in  kidney,  g65 
in  lungs,  g66 
in  nets,  8g6,  897 
in  retina,  966 
in  various  species,  965 
methods  of  measurement,  962 
osmotic    pressure    of    plasma    proteins 

and,  963,  965 
pressure  gradient  and,  965 
protein  osmotic  pressure  and,  9gi 
postglomerular,  g66 
Raynaud"s  disease  and,  g68 
spatial  relation  of  capillary  bed  to  heart 

and,  g67 
stasis  and,  gg7 
suction  forces,  g66 
sympathetic  stimulation,  g7 1 
temperature  and,  g68 
variability  of,  g66 
vasodilatation  and,  g68 
venous  pressure  and,  g68 
Carbohydrate 

absorption  and  metabolism  of,  1 1 7 1 
Carbonate 

entrance  rate  into  muscle,  1 1 38 
Carbon  dioxide 

capillary  filtration  coefficients,  gg8 

cerebral  blood  flow  and,  946 

filtration  coefficients  and,  997 

heart  and,  1545 

mesenteric    filtration    coefficients    and, 

igg8 
pleural   and  esophageal  pressures  and 

i6go 
reactive  hyperemia  and,  1375 
skin  circulation  and,  1346 
Cardiac  blood  supply 
basal  data,  1537-1538 
capillaries 


density  in  adults,  1521 

density  in  newborn,  152 1 
functional  anatomy,  1517-1527 
methodology  of  study,  1527-1530 
preparation  for  study,  1527-1530 
see  also  Coronary  blood  flow 
Cardiac  cycle 

apex  cardiogram,  777-779 

atrial  pressures,  776 

attempts  at  empirical  time  correlations, 

777 
circulatory  system  cyclical  events  and, 

779 
composite  graph,  778 
description  of,  770 
diastole  and  systole,  770 
electrocardiogram,  777 
intraventricular-  streaming,  772 
isometric  contraction,  770 
isovolumetric 

relaxation,  773 

ventricular  contraction,  770 
position  changes  of  great   vessels,    766 
pressure  and  flow  effects  during,  769- 

775 
pressure-volume  phase  relationships, 

774 
protosystolic  phase,  779 
scheme,  770 
time  intervals,  770,  791 

between  valvular  motions,  7go 
vibrocardiogram  (apex  cardiogram), 

777-779 
Cardiac  decompensation 

cardiac  output  and,  1 1 1 7 

right  atrial  pressure  and,   1 1 1 7 

venous  return  and,  1 1 1  7 
Cardiac  lymph 

cardiac  work  and,  1055 

composition,  1055 

flow  rates,  1 055 

obstruction,  ECG  changes,  1055 
Cardiac  muscle  contractility 

coronary  blood  flow  and,  I54g 

drugs  and,  1564 
Cardiac  nerves 

autonomic  innervation,  1526 

central  communications,  1526 

plexi 

autonomic  fibers,  1526 
division  of,  1525 

see  also  Autonomic  nervous  system 
Cardiac  output 

acute  left  heart  failure  and,  1120 

acute  right  heart  failure  and,  1121 

altitude  and,  1720 

aortic 

flow  during  exercise,  846 

pressure,    coronary    flow    and,     1534 

at  birth,  1641 

blood 


1756 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


transfusion  and,  1  1  1 4 

volume  and,  1 1 14 
cardiac 

decompensation,  1 1 1  7 

tamponade  and,  1 1 05 
change  in  resistive  load  and,  1103 
closed-chest  massage,  761-762 
congestive  heart  failure  and,  1 1 16 
drugs  and,  1564 
exercise,  846,  1 1  1  3 
feeding  and,  1452 
fetal,  1628 

anoxia  and,  1635 
heart 

failure  and,  17 15 

recompensation  and,  1 1 1  7 
hemorrhage  and,  1 1 14 
hypoefTective  heart  and,  1 104 
limiting  factor,  761 
local  oxygen  utilization  and,  1 1 26 
magnitude,  987 
massage,  closed-chest,  761-762 
muscular  exercise,  1 1 1 3 
myocardial 

damage,  1 1 1 5 

infarction,  1 1  15 
open  chest  and,   1105,   11 15 
oxygen  uptake  and,  1682 
pressure  on  outside  and,  1 104 
rapid  transfusion  and,  1 1 1 3 
right  atrial  pressure  and,  I  105 
shock  and,  1  1  14 

simplified  graphical  analysis  of,  1 103 
sympathetic  stimulation  and,  1 1 12 
values  for,  1720 
vasomotor  tone,  1 1 1 3 
vascular  resistance  and,  1 1 18 
venous  return  and,  1 1 1  2 
Cardiac  output  curves 
cardiac 

load  and,  1 104 

tamponade  and,  1 1 05 
closed-chest  animals  and,  11 03 
factors  affecting,  11 04,  11 05 
heart  effectiveness  as  a  pump  and,  1 104 
open -chest 

effects,  1 1 04 
venous  return,  1 1 1 1 

curves  and,  1 1 03,  1 1 05 
Cardiac  pumping 

development  of  concept,  759 
electrocardiogram  and,  777 
extracardiac  structures  and,  761 
functional  anatomy,  759-798 
mechanical  analogues,  760 
Cardiogenic  shock 
discussion  of,  1564 
drug  action  on,  1 564 
pressor  agents  and,  15(14 
vasodepressor  drugs,  1 567 
Cardiovascular  dynamics 


analysis 

of  decompensation,  1 1  1 7 
of  recompensation,  1 1 1 7 

blood  volume  and,  1 1 10,  1 122 

left  ventricular  weakening  and,  1 120 

myocardial  infarction  and,  1 1 15 

open  chest  and,  1 1 15 

rapid  transfusion  and,  1 1  14 

right   ventricular   weakness   and,    1121 

shock  and,  1 1 14 

simultaneous  analysis  of  right  and  left, 
1119 

sympathetic  stimulation  and,  1 1 1 2 

see  also  Vascular  hydraulics 
Cardiovascular  reflexes 

development  of,  1629 
Cardiovascular  system 

development  of,  1623-1624 
factor  affecting,  1624 

fetal,  species  differences,   1620 
Carnivores 

uterus  in,  1585 
Carotid  artery 

arterial  flow  pulse  in,  849 

dimensions  and  flow,  849 

flow  patterns,  853 

muscle  tension,   electrolytes  and,    11 46 

pulse-pressure  change  in,  826 

stress-relaxation  curves  of,  872 
Carotid  sinus 

blood  pressure  responses,  1094 

pressoreceptors  of,  874,  875 

response,  in  young  animals,  1643 

stimulation  by  noradrenaline,  874 
Cartilage 

growth,  blood  supply  and,  1 658 
Castelli  principle 

definition  of,  1 306 
Cat 

blood  pressure,  age  and,  1643 

capillary  blood  pressure  in,  965 

heartbeat  at  birth,  1641 

protein  osmotic  pressure  in,  965 

pulmonary  vessels  in,  1674 
Catch  mechanism 

definition,  871 
Catecholamines 

coronary  heart  disease  and,  1181 

distribution  in  abdominal  viscera,  1417 

of  blood,  in  Raynaud's  syndrome,  1229 

vasomotor  adjustments  and,  141 7 

see    also    Norepinephrine;    Epinephrine 
Catheter 

wedged,  position  of,  1688 
Cattle 

hepatic  blood  flow  in,  1405 

mountain  sickness  in,  1721 
Causalgia 

characterization,  1233 

classification,  1233 

initiating  factors,  1234 

major  and  minor,  1234 


neural  elements  in,  1 235 

pain  in,  1234 

pathogenesis,  1234 

reflex  elements  in,  1235 

sympathectomy  in,  1235 

thalamic  dysfunction  in,  1235 

theories,  1235 

treatment,  1234 

vasomotor  changes,  1234 

X-ray  studies,  1234 
Celiac  plexus 

innervation  of  kidney,  1467 
Cell  volume 

dependence  on  Na,  1 136 
Central  nervous  system 

cardiac  nerves,  communication,  1526 

circulatory,  autoregulation 
neural  control,  946 
tissue  CO2  tension  and,  946 

intracapillary  oxygen  pressure,  1021 

reactive  hyperemia  and,  1329 
Cerebral  blood  flow:  see  Section  1,  vol.  3, 
ch.  70-71 

adrenergic  response,  951 

4-aminoantipyrine,  I2gi 

arterial  pressure  and,  946 

autonomic  reflex  in,  946 

autoregulation,  942 

carbon  dioxide  and,  946 

cerebrospinal  fluid  and,  941 

cholinergic  response,  951 

dilution  studies,  1  292 

discussion  of,  1291 

epinephrine  and,  950 

inadequacies,  1 292 

nitrous  oxide  method,  1290-1291 

oxygen  and,  946 

radioactive  krypton  and,  129 1 

requirements  for,  1 292 
Cerebrospinal     fluid     pressure 

cerebral  blood  flow  and,  941 
Cesium 

entrance  rate  into  muscle,  1 1 38 

ionic  radii,  1 137 

mobility  in  electric  field,  1 1 38 

relative  diameter,  1 1 38 

vascular  muscle  tension  and,  1 146 
Chemical  injury 

capillary  filtration  coefficients,  998 

mesenteric  capillaries  and,  996 
Chicken 

lipid    metabolism    and    atherosclerosis 
in,  1  201 

lipoprotein  pattern  in,  1203 

sex  hormones,  atherosclerosis  and,  1 204 
Cholesterol 

absorption,  inhibition  of,  1186 

biosynthesis,  inhibition  of,  1 186 

conversion  to  bile  acids,  1 1 79 

degradation,  promotion  of,  1 1 86 

disposal  of,  1 1 79 

increased  tissue  removal  of,  1 187 


INDEX 


i/57 


mechanism  of  lowering,  i  187 
metabolism 

anterior  pituitary  hormones,  1  202 

emotional  stress  and,  1 208 

epinephrine  and,  1202 

physical  activity  and,  1206 

sex  hormones  and,  1 203 

species  differences,  1205 

strain  differences,  1205 

stress  and,  1206 

thyroid  function  and,  1 199 
saturated  fats  and,  1 183-1 184 
synthesis  of,  1 1 79-1 180 
Cholinesterase 

in  uterus,  estrogen  and,  1599 

binding,  protein  osmotic  pressure  and, 

977 

distribution  in  kidney,  1469 

entrance  rate  into  muscle,  1 138 

in  organs  and  tissues,  1 141 
Chloride  space 

aorta,  1 1 4 1 

bladder,  1141 

stomach,  1 141 

uterus,  1 1 4 1 

vascular  tissue,  1141 
Chlorisondamine 

renal  blood  flow  and,  1487 
Chlorothiazide 

in  treatment  of  hypertension,  1 142 
Chlorpromazine 

adrenaline  response  of  blood  flow  and, 

'373 
Cholestyramine 

mechanism  of  action,  1 186 
Chronic  pancreatitis 

description,  1200 
Chylomicrons 

characterization,  1 1 76 

direct  diffusion  of,  1 1 76 

lymph  in,  1044 

of  pinocytosis,  1044 
Circulation 

analyses  of 

algebraic,  1 102 
graphical  1 1 02 
history  1 1 02 

changes    on    ventilation    of  fetal    lung, 
1640 

deep  drainage  channels,    1 531-1532 

factor  relationships  within  circuit,  1 101 

hemodynamics,  865 

hepatic  and  systemic  relationships,  1426 

hydrostatic  considerations,  1425 

in    fetus    and,    1624-1627,    1638-1645 

neonatal,  1638- 1 645 

of  submucosal  plexus,  906 

open  chest  and,  1 1 15 

pairing  of  arterial  and  venous,  920 

preferential  channel,  go8 

pressure  gradient  in,  965 

schema,  1 100 


splenic,  species  differences  in,  913 
sympathetic  vasoconstrictor  nerves  and, 

1362 
time 

methodology,  1708 
values  for,  1537,  1708 
Circulatory  arrest 

nervous  changes  and,  1225 

oxygen  consumption  in  muscle  during, 

'376 
oxygen  saturation  of  venous  blood,  1376 
recovery  after,  1225 
results  of,  1225 

vasoconstrictor    and    vasodilator    sub- 
stances and,  1 225 
Circulatory  autoregulation 
collaterals  and,  947 
discussion  of,  1 543 
feedback  loop,  945 
general  concept,  945 
tissue  oxygen  tension,  945 
hydrogen  ion  concentration  and,  946 
mechanisms  responsible,  944 
nervous  system  and,  946 
physical  factors,  947 
pressure-flow  relationships,  1543 
see  also  Blood  flow 
Circulus  vasculosus 
description,  1661 
Circumflex  artery 
branches,  1519 
distribution  of,  1 5 1 9 
Cirrhosis 

hepatic  lymph  and,  1051 
Cistera  chyli 

definition,  1036 
Clip  needle 

definition,  840 
Coarctation  of  aorta 

blood  flow  and,  856,  862 
cardiac 

O2  consumption,  1557 
output  and,  1557 
changes    in    flow    contours    and,    858 
experimental,  856-858 
flow-pressure  relationships,  862 
left  ventricular  workload,  1557 
murmur  and,  856 
Cochlea 
blood 

velocity  in  vessels  of,  g  1 8 
vessels  of,  917 
microcirculation  in,  915 
spiral 

ligament,  small  vessels  in,  915 
prominence,    species    differences    in 
circulation,  gi6 
Cold 

acclimatization  to,  1334 

as    stress,     atherosclerosis     and,     1208 

prolonged  exposure  to,  1335 


vasodilator  response  to,  in  skin,  1 333 

venoconstrictor  responses,  1094 
Cold  vasodilatation 

acclimatization  to,  1334 

innervation  and,  1334 

skin  circulation  and,  1331 

total  denervation  and,  1341 
Collagen  diseases 

classification,  1237 

vasoconstrictor  mechanisms,  1237 
Collagen  fibers 

aging  and,  868 

as  safety  factor,  868,  880 

compared  to  elastic  tissue,  868 

extensibility  of,  805 

in  arteries,  873 

in  scleroderma,  1238 
Collagen  tissue 

contribution    to    pressure-volume    dia- 
gram, 873 

description,  868 

elastic 

behavior  of,  868 

visco-elastic  behavior  of,  868 
Collateral  circulation 

after  arterial  occlusion,  1 260 

arterial  versus  venous,  1267 

arteriovenous  fistulas  and,  1261 

blood  flow  measurement,  1270 

chemical  factors  and,  1 263 

definition,  1257 

denervation  and,  1 263 

development  of,  1 260 

effects  of,  1 268 

experimental  alteration,  1569 

functional  changes,  1522 

hormones  and,  1265 

increase,  1572 

factors  affecting,  1572 
ligation    of   pulmonary    vessels    and, 
1267 

lung  in,  1 26 1 

lysis  of  vascular  tone  and,  1 263 

measurement,  1 268 

neural  factors,  1262 

outstanding  problems,  1271 

rate  of  development,  1 266 

regression,  1 267 

structure  of  vessels,  1 268 

terminology,  1259 

types  of  vessels,  1 259 

venous  channels,  1522 
Compliance,  arterial 

definition,  820 

discussion  of,  842 
Conductance 

definition,  841 

perfusion  pressure  and,  954 
Congenital  anomalies 

cardiovascular  defects 

backflow  wave  and,   in  aortic  valve 
closure,  860 


1758 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


classification,  1645 
effectiveness  of  heart  and,  1 1 04 
heart,  1624 
signs  of,  1645 
types  of,  1523 
Congestive  heart  failure 

cardiac  output  and,  1 1  lb 

fluid  retention,  1 1 16 

mean  systemic  pressure,  1  1 16 

renal  output  and,  1 1 16 

restriction  of  fluid  and  salt  in,  1 1 1 7 

right  atrial  pressure  and,  1 1 16 

sodium  retention  and,  1 057 

venomotor  activity  in,  1095 

venous  pressure,  1057,  11 16 

venous  return  and,  11 16 
Conjunctiva 

arteriovenous  anastomosis  in,  908 

vasomotion  in,  909 
Conrad,  Margaret  C. 

Resistance    (conductance)    and    capac- 
itance    phenomena     in     terminal 
vascular  beds,  935-960 
Constant-pressure  flowmeters 

discussion  of,  1 303 
Contour  rule 

definition,  858 
Convective  acceleration 

definition,  1296 
Cooling 

gastric  blood  flow,  1447 
Cor  pulmonale 

acute  bronchitis  and,  1729 

alveolar-capillary  block  and,  1728 

chronic  bronchitis  and,  1 728-1729 

elevated  ventricular  pressure  and,  1555 

emphysema  and,  1729 

kyphoscoliosis  and,  1728 

origin  of,  1728 

pulmonary  hypertension  and,  1728 

right  heart  failure  and,  1 729 
Coronary  arterial  occlusion 

bypass,  1573 

coronary  blood  flow  and,  1539 

experimental    alteration    of    collateral 
flow,  1569 

improved  collateral  circulation,  1572 

mortality,     anatomical     location    and, 

!569 
possible  treatments,  1572 
sinus  oxygen  saturation  and,  1 539 
Coronary  arteries 

adjustment  to  anemia,  1547 
anatomical  division  of,  1522 
anomalous  communications,  1524 
anterior  descendents,  1518 
arrangement  in  myocardium,  1520 
basic  anatomic  patterns,  1518 
branches  of,  1518,  1519,  1520 
catheterization,  1530 
circumflex  branch,  1519 
collateral  circulation,  1522 
congenital  anomalies,  1523 


construction,  ECG  changes  and,  1569 

C02  and  lactic  acid,  1545 

course  of,  15 18 

distribution,  15 18 

dominance  pattern,  1520 

estimation  of,  1535 

functional 

anatomy,  1517 

supply  to  conducting  tissue,  1520 
hemoglobin  levels  and,  1547 
in  hypoxemia,  1544 
insufficiency,  collateral  circulation 

studies  and,  1567 
left,  15 18 

phasic  flow,  1534 

receptors  in,  1550 
ligation 

local  anesthesia  and,  1550 

vagal  stimulation  and,  1550 
major  branches,  1520 
normal  and  anomalous  origins,  1525 
occlusion  of,  1532 

experimental,  1565 
origin  and  distribution,  15 1 9 
pressure,  augmentation  and  circulatory 

depression,  1550 
pressure,  perfusion,  1535,  ■ 541-1543 
relaxation  of  walls,  1544 
right,  1519 

secondary  divisions  of,  1520 
sensitivity  to  anoxia,  1539 
species 

differentiation,  15 19 

variation,  1523 
terminal  branches,  1520 
vasomotion,  1552 
vasomotor  tone,  1535 
Coronary  atherosclerosis 
body  build  and,  1 206 
effectiveness  of  heart  and,  1 1 04 
heart  disease  and,  1 198 
personality  and,  1206 
Coronary  blood  flow 
acetylcholine,  1552 
acidosis  and,  1545 
action  of  hormones,  1 55 1 
active  vasomotor  changes  and,  1535 
adenosine,  1545 
adenylic  acid,  1545 
adrenergic  response,  951 
alkalosis  and,  1545 
angina,  cardiac  failure  and,  1556 
aortic 

arch  pressure  and,  855 

insufficiency,  1556 

pressure,  cardiac  output  and,  1534 
arterial  saturation-critical  point,  1544 
arteriovenous  oxygen  difference,  1 536 

as  index  of  metabolic  rate,  1539 

myocardial  extraction  coefficient 
and,  1536 
asphyxia  and.  1544 


augmentation,  1548 

autonomic  control,  1547 

autoregulation,  1543 

backflow,  1533 

basal  data,  1537 

bicarbonate  concentration  and,  1546 

blood  pressure  and,  1539,  1548 

epinephrine  and,  1551 
blood  viscosity  and,  1547 
calcium  and,  1546 
cardiac 

cycle  and,  1533,  1548 

muscle  contractility  and,  1549 

output  and,  1546 
cholinergic  response,  951 
circulation  times,  1537 
collateral  circulation,  1567,  1568,  1570 

drugs,  1567 

establishment  of,  1570 

extracardiac  vessels,  1520,  1522 

functional  channels,  1522 

intracardial  vessels,  1522 

measurement  of,  1271,  1568 

natural  responses  of,  1568 

primary  location,  1569 

prophylactic  stimuli  and,  1570 
coronary  artery  disease  and,  1565- 1573 
determinants  of,  1533 
drugs  and,  1561,  1564 
dye-dilution  studies,  1292,  1530 
elevated  ventricular  pressure  and,  1555 
epinephrine  and,  950 
excitement  and,  1554-1555 
exercise  and,  1553-1554 
extra-  and  intravascular  resistance  and, 

extracardiac  stimuli  and,  1550 

extravascular  support,  1535 

factors  affecting,  1554 

Fick  principle  and,  1529 

flow    values    in    right    ventricle,    1537 

heart  rate  and,  1540,  1554 

hemorrhagic  shock  and,  1535 

histamine,  1545 

hypercapnia,  1546 

hyperthermia  and,  1560 

hypocapnia,  1546 

hypoxia  and,  1544 

in  animals,  1529 

in  aortic  coarctation,  1557 

increased  work  of  heart,  1543 

inflow  curves,  853 

influence  of  systemic  pressure,  1542 

in  heart  failure,  1558 

in  hemorrhagic  shock,  1558 

in  hypothermia,  1559 

in  male  and  female,  1 557 

in  man,  1529 

in  mitral  insufficiency,  1557 

in  mitral  stenosis,  1557 

in  myocardium,  1533 

in  resting  state,  1538 


INDEX 


1759 


insufficiency,  correction  for,  1570 
intermediate  metabolites  and,  1545 
left 

drainage  of,  1534 

excitement  and,  1534 

in    irreversible    hemorrhagic    shock, 

■534 
mild  exercise  and,  1534 
occlusion  and,  1534 
patterns,  1534 
stimulation    of   cardiac    sympathetic 

nerves  and,  1534 
variance    with    dynamic    conditions, 

!534 

ventricular  pressure  and,  855 
measurement,  855,  1535,  1553 

dilution  methods,  1291-1293 

isotopes,  1529 

mean  flow,  1529 

nitrous  oxide  method,  1291 

rotameter  measurement  of,  1291 
metabolites,  1545 

myocardial  distribution  of,    1 530- 1 533 
nicotine,  1563 
nucleic  acids,  1545 
oxygen  and,  945 

uptake,  1533,  1537 
phasic  flow,  1528 
physical   determinants   of,   841,    1533- 

"536 
Pitressin  and,  1553 
potassium  and,  1546 
pulmonary     artery     constriction     and, 

"542 
purine  derivatives,  1545 
pyrimidine  derivatives,  1545 
reflex  control  of,  1 550 
resistance  changes  and,  1 544 
respiratory  acidosis,  1545- 1546 
response  to  anoxia,  1 539 
retrograde  flow,  1570 

ventricular  fibrillation  threshold  and, 

'57' 
sodium  bicarbonate  infusion,   1546 
sodium  cyanide  and,  945 
species  variation,  15 19-1523 
stellate  ganglion  stimulation  and,    1  ",4.'! 
stimulation  of,  1548- 1549 
stimuli  and,  1 538-1561 
studies  on,  1527 
systemic  pressure  and,  1542 
thyroid  influence  upon,  1552 
tonic    activity    of    autonomic    nervous 

system,  1550 
vagus  and,  1547 
vascular 

hydraulics  of,  853 

pressures  and,  853 
vasoconstrictors,  1 545 
vasodilators  and,  1545,  1561 
venous  occlusion,  1542 
ventricular 


metabolism,  1532 
muscle  activity  and,  1534 
tension,  1 541  -1542 
work  of  heart  and,  1 549 
see  also  Cardiac  blood  supply 
Coronary  blood  volume,  1521 
Coronary  heart  disease 
atherosclerosis,  1 1  g8 
catecholamines  and,  1181 
factors  associated  with,  1 188 
personality  profile  and,  1 181 
Coronary  sinus 
blood 

as  index  of  metabolic  changes,   1532 
arteriovenous  oxygen  difference,  1533 
chemical  composition,  1532 
chronotropic  effects  of,  1545 
inotropic  effects  of,  1545 
vasodilator  substances  in,  1545 
flow,    contribution    of   right    coronary 

artery,  1532 
pressure  in,  1542 
Coronary  vessels 

extravascular  mechanical   compression 

and,  1556 
percentage  of  cardiac  output,  762 
ventricular 

distensibility,  763 
function  and,  762 
Corticoids 

cholesterol-induced  atherogenesis  and, 
1202 
Cortisone 

collateral  circulation  and,  1265 
Cough 

differential  pressure  record  of,  1689 
Cournand  catheter 

blood  flow  and,  1287 
Cow 

pulmonary  vessels  in,  1674 
Cranial  mesenteric  artery 
blood  flow  through,  1442 
flow,  feeding  and,  1452 
Creep 

definition,  1084 
description  of,  803 
Critical  closing  pressure 
blood  flow  and,  1408 
definition,  880 
muscle  vessels  and,  1357 
role  of,  1409 
use  of  term,  941 
Curare 

vascular  smooth  muscle  and,  1380 
Cutaneous  blood  flow 
acetylcholine  and,  1346 
adrenergic  response,  951 
atropine  and,  1340 
cholinergic  response,  951 
epinephrine  and,  950,  1345 
factors  affecting,  1 220-1 222 
heat  loss  and,  1 333 


histamine  and,  1346 

humoral  agents  and,  1344 

immersion  time  and,  1331 

measurement,  1284,  132  7- 1328 

mental  arithmetic  and,  1339 

nervous  control  of,  1 337 

norepinephrine  and,  1 345 

posture  and,  1 340 

relation  to  pressure,  951 

sweating  and,  1340 

sympathectomy  and,  1338 

temperature  and,  1330 

thermal  conductivity  and,  1287 

total,  1220,  1328 

venous  oxygen  saturation  and,  1 336 
Cutaneous  blood  vessels 

action  of  humoral  agents  on,  1344- 1346 

arrangement  of,  1 326-1 327 

innervation  of,  1338-1341 

nervous  control  of,  1 337— '  344 

physical  disturbances  and,  1 329-1 337 

reactions  to  injury,  1 336-1 337 

reflex  control  of,  1 341 -1344 

transmural  pressure  and,  1 330 

vasomotor  nerves,  1 337—1 338 
Cutaneous  circulation 

acetylcholine  and,  1334,  1345 

adenosine  triphosphate  and,  1 346 

adrenaline  and,  1345 

anastomoses,  1326 
function,  1327 
per  square  centimeter  of  surface  area, 

'3*7 
arterial  gas  embolism  and,  1337 
arteriovenous  anastomoses,  1 326 

local  cooling  and,  1333 
autoregulation  in,  944 
baroreceptor  stimulation  and,  1344 
bladder  distention  and,  1344 
body  temperature  regulation  and,  1 341, 

1342 
bradykinin  and,  1346 
capillary  blood  pressure  in,  965 
carbon  dioxide  and,  1346 
cold  vasodilatation,  1331 
color  of  the  skin  and,  1328 
critical  closing  pressure  and,  1330 
deep  inspiration  and,  1343 
determination  of  the  adequacy  of,  1219 
emotion  and,  1343 
evaluation  by  sympathetic  innervation, 

1223 
fainting  and,  1 343 
frostbite  and,  1335 
general  sensory  stimuli  and,  1343 
gravitational  effects,  1221 
heat  loss,  1333,  1334 
histamine  and,  1334,  '345 
humoral  agents  and,  1 344 
hypoglycemia  and,  1 344 
hypothalamic  stimulation,  1367 
immersion  foot  and,  1  335 


1760 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


local  temperature  and,    1 330-1 336 

noradrenaline  and,  1345 

osmotic    pressure    of   plasma    proteins 
in,  965 

oxytocin,  1 346 

Pitressin,  1346 

posture  and,  1344 

reactions  to  injury  and,  1 336 

reflex  control  of,  1341 

serotonin  and,  1345 

sympathetic  denervation  and,  1 340 

temperatures,  1330 
of  the  skin  and,  1 328 

transmural  pressure  and,  1330 

trench  foot  and,  1 335 

triple  response,  1336 

total  denervation  and,  1341 

ultraviolet  light  and,  1336 

white  reaction,  1 336 
Cutis  marmorata 

characterization,  1233 
Cyanide 

glomerular  capillary  permeability  and, 

999 
Cyclopropane 

renal  blood  flow  and,  1489 
Cytopempsis 

definition,  884,  1066,  1522 

Damping 

central  pulse  contour  and,  829 
electrical,  841 
mechanical,  841 
Darcy  equation 

for  viscous  flow  of  fluids,  991 
DCA 

hypertension  and,  1 142 
K  and, 1142-1 143 
Na  and,  1 1 42 

Na  and  K  of  aorta  in,  1 150 
Na  and  K  measurements  in,  1 150 
intracellular  Na  and,  1 150 
Denervation 

collateral  circulation  and,  1263 
cutaneous  heat  loss  and,  1 334 
total 

cold  vasodilatation  and,  1341 
skin  circulation  and,  1341 
Denison,  A.  B.,  Jr. 

Pulsatile    blood    flow    in    the    vascular 
system,  839-864 
Density  flowmeter:  see  Flowmeter,  Dawes 
Dermatomyositis:    see    Collagen    diseases 
Desoxycorticosterone  acetate :  see  DCA 
Dextran 

appearance  in  lymph,  1043 

effective  osmotic  pressures  in  capillaries, 

994 
in  lymph  and  plasma,  1 063 
molecular  sieving  of,  1014 
molecular  weights 


permeability  coefficients  and,  1 05 1 
renal  nitration  and,  1463 
Diabetes  mellitus 

atherosclerosis  and,  1187,  1200 
capillary  microaneurysm  and,  1200 
lipid  metabolism  and,  1 200 
peripheral  vascular  disease  and,  1 2 1 7 
Diaphragm 

pressure  in  lymphatic  plexus,  1065 
Dibenamine 

intestinal  blood  flow  and,  1447 
Diet 

fat  in,  blood  coagulation  and,  1 189 
foodstuffs  comprising,  1171 
serum 

cholesterol  and,  1182 
lipids  and,  1 186 
Differential 

manometer,  natural  frequency,  1 299 
pressure,  measurement,  840 
transformer,  description,  1307 
Diffusion 
coefficient 

molecular  radius  and,  1001 
osmotic    and    frictional    forces    and, 
1001 
Fick's  formulation,  1000 
free,  1000 

general  principles,  1000 
glucose,  1001 

hydrodynamic  flow  and,  1002 
nutrition  of  vessel  walls  by,  883 
pore 

dimensions  and,  1002 
size  and,  1002,  1003 
raffinose,  1009 
restricted,  1001 
factors  in,  1001 
simultaneous  flow  and,  1005 
through  porous  membranes,  1001 
transcapillary 

lipid-insoluble  molecules  and,  1007- 

1008 
quantitation,  1009 
water,  pore  size  and,  1 004 
Digitalis 

congestive  heart  failure  and,  1 1 1 7 
Diodrast 

renal  extraction  of,  1480 
Diuresis 

countercurrent  mechanism  in,  1473 
mean  regional  transit  time,  water  con- 
centration and,  1 50 1 
renal  medullary  circulation  in,  1499 
Diuretics 

renal  lymph  flow  and,  1058 
Dog 

adrenergic  control  of  renal  blood  flow, 

1485 
heartbeat  at  birth,  1641 
hepatic  blood  flow  in,  1405 
renal 


arterial  system,  1459 
circulation  compared  to  man,  1501 
clearance  in,  1483 
Donnan  effect 

protein  osmotic  pressure  and,  976 
Donnan  equilibrium 

in  biological  systems,  1 1 38 
Drop  recorders 

disadvantages  of,  1278 

primary  use  of,  1278 
"Dry"  lungs 

definition,  1052 
Ductus  arteriosus 

aortic  flow  and,  861 

closure,  1639 

compensation  by  left  ventricle,  861 

direction  of  flow,  1639 

flow  through,  861 

murmur  envelope  and,  861 
Ductus  venosus 

closure  of,  1639 
Dye  clearance 

through  skin,  acetylcholine  and,  953 
Dynamic  stretches 

definition,  867 

Ear 

arteriovenous  anastomosis  in,  1 252 
Ecolid :  see  Chlorisondamine 
Edema 

blood  flow  and,  969 

formation,  hypoxemia  and,  998 

histamine  and,  970 

interstitial  fluid  pressure  and,  980 

kidney  function  and,  1057 

left  atrial  pressure  and,  991 

pulmonary 

lymphatics  and,  1051 
lymph  flow  and,  1052 

traumatic  shock  and,  1060 

venous  pressure  and,  969 
EHBF :  see  Splanchnic  blood  flow 
Elastic  arteries 

distensibility  of,  873 

models,  875 

pressure-volume  diagram,  873 

response  to  stretch,  871 

stress-relaxation  in,  872 

tension-length  diagram,  873 

tension  muscles  in,  model  of,  874 
Elastic  incompleteness 

definition,  867 
Elastic  material 

behavior  with  stretch,  866 
Elastic  modulus 

applied  stress  and,  808 

as  measure  of  extensibility,  808 

initial  arterial  diameter  and,  808 

static  versus  dynamic,  81 1 

wall  stiffness  and,  809 
Elastic  tissue 

aging  and,  869 


INDEX 


I  761 


contribution  to  pressure-volume 

diagram,  873 
description,  869 

elastic  behavior  of,  868 

extensibility  of,  805 

function  in  blood  vessels,  869 

in  thoracic  aorta,  873 
plastic  behavior  of,  868 

recruitment  of  fibers  in,  876 

stress-strain  relation,  805 

structural    arrangement,    with   smooth 
muscle,  873 

visco-elastic  behavior  of,  868 
Elastic  tubes 

internal  pressure  to  radius,  939 
Elasticity 

definition,  866 

description  of,  866 

properties  of  blood  vessels,  866 
Electrocardiogram 

after  lymphic  obstruction,  1 055 

cardiac  pumping  and,  777 

fetal,  1627 

for  division  of  cardiac  cycle,  775 
Electrochemical  gradients 

ions  and,  1 138 
Electrolytes 

mean  activity  coefficients,  1 137 

of  vascular  tissue,  1141 

placental  exchange  of,  1594 

relative  entrance  rates,  1 1 38 

renal 

artery  pressure  and,  1 1 48 
vein  flow  and,  1 148 
Electromagnetic -induction  principle:  see 

Flowmeters,  electromagnetic 
Emotional  stress 

atherosclerosis  and,  1 208 

cholesterol  metabolism  and,  1208 

gastric  blood  flow,  1447 

intestinal  blood  flow  and,  1450 

lipid  metabolism  and,  1208 

skin  circulation  and,  1343 

vasodilators  to  human  muscle  and,  1367 
Endothelium 

active  transport  through,  883 

contraction  of,  924 

description,  868 

diffusion  through,  883 

permeability,  11 98 

see  also  Blood  vessel  walls 
Energy  production 

discussion  of,  1536 
Enzymes 

concentration  in  lymph,  1047 

transportation  via  lymph,  1047 
Ephedrine 

cardiac  hemodynamics  and,  1564 

cardiac  lymph  flow  and,  1055 

splenic  blood  flow  and,  1450 
Epinephrine 

arterial  diameter  and,  807 


atherosclerosis  and,  1202 
biphasic  action 

in  man,  1371 

in  muscle  circulation  1373 
biphasic  transient  dilatation  and,  1371 
blocking  of,  by  chlorpromazine,  1373 
blood  pressure 

coronary  flow  and,  1551 

in  bone  marrow  and,  1 66 1 
bone  medullary  pressure  and,  1660 
capillary  pressure  and,  968 
cardiac 

hemodynamics  and,  1564 

lymph  flow  and,  1055 

oxygen  consumption,  1551 
cardiovascular  response  to,  141 8 
cholesterol  metabolism  and,  1202 
coronary 

blood  flow  and,  1551 

vasomotion  and,  1551-1552 
cutaneous  blood  flow  and,  1345 
direct  and  indirect  effects,  1370 
effect  in  various  vascular  beds,  950 
fat  mobilization  and,  1175 
filtration  coefficients,  999 
gastric  blood  flow  and,  1446 
intestinal  blood  flow  and,  1447 
isolated  aortic  rings  and,  807 
joint  blood  flow  and,  1663 
K  efflux  and,  1 156 
lipid  metabolism  and,  1202 
mean  systemic  pressure  and,  1  1 1 1 
mesenteric  blood  flow  and,  1451 
muscle 

blood  flow  and,  948,  1359 

venous  outflow  and,  1371 
neuromuscular  transmission  and   1363, 
peripheral  resistance  and,  1 1 1 1 
plasma  K,  anesthesia  and,  11 52 
postpartum    uterine    blood    flow    and, 

1608 
rate   of  injection,    venous   return   and, 

1 1 1  1 
renal  blood  flow  and,  1485 
residual    sustained   vasodilatation   and, 

1371 
resistance  in  vascular  bed  and,  948 
segmental  resistance  and,  951 
sensitivity  to  lymphatic  system,   1040 
skeletal  muscles  and,  1355 

blood  flow,  1370,  1372 

circulation  and,  1369 

circulation,  exercise  and,  1374 
skin 

capillaries  and,  904 

circulation  and,  1345 
splenic  blood  flow  and,  955,   1450 
stretch  curves  for  aorta  and,  802 
total  systemic  effect,  1418 
vascular 


changes  due  to,  g6g,  970-971 
volume  and,  955 

venous  return  curves  and,  1 1 10 
Epiphyses 

blood  supply  of,  1653 
Ergotamine 

intestinal  blood  flow  and,  1447 
Ergotoxine 

gastric  blood  flow  and,  1446 
Erythermalgia :  see  Erythromelalgia 
Erythrocytes 

filtration  coefficients,  992 
Erythrol 

gastric  blood  flow  and,  1447 
Erythromelalgia 

acetylsalicylic  acid  and,  1242 

cutaneous  pain  fibers  and,  1242 

description,  1241 

diagnosis  of,  1 242 

mechanism  of,  1241 

symptoms,  1241 

temperature  changes  and,  1241 

vasodilation  and,  1241 
Esophageal  pressure 

carbon  dioxide  and,  1690 

exercise  and,  1690 
Essential  hypertension 

definition,  875 

smooth  muscle  tension  and,  875 
Estrogens 

as  vasodilating  agents,  1603 

blood  vessel  walls  and,  1204 

uterine 

acetylcholine  and,  1599 
blood  vessels  and,  1600-1601 
histamine  and,  1599 

uterus  and,  1 600-1601 

vascularity  of  endometrium  and,   1599 
Ether 

renal  blood  flow  and,  1489 
Excitement 

coronary  blood  flow  and,  1555 
Exercise 

adrenaline  and,  1374 

aortic  flow  and,  846 

pressure-flow  curves  and,  772-773 

arterial  transmission  line  and,  852 

atherosclerosis  and,  1206 

capillary  blood  volume,  1705 

cardiac  output,  11 13 

cholesterol  metabolism  and,  1 206 

circulation,  skeletal  muscle  and,    1374 

coronary 

atherosclerosis  and,  1207 
blood  flow  and,  1554 

ejection  pulse  and,  845 

heart  and,  846 

hepatic  circulation  and,  1426 

hyperemia,  1355,  1368,  1376,  1380 
pH  and,  1379 

intestinal  blood  flow  and,  1449 

lipid  metabolism  and,  1206 


1762 


HANDBOOK    OK    I'HYMULOGY 


CIRCULATION    II 


lymph 

How  and,  1050 

protein  from  contracted  muscle  and, 

985 
mechanism  of  effect 

on  cardiac  output,  1 1  13 
on  right  atrial  pressure,  1 1 1 3 
on  venous  return,  1 1 1 3 
muscle 

blood  flow  and,  1355 
metabolism  and,  1377 
venous  oxygen  saturation  and,   1377 
oxygen    uptake,    cardiac    output    and, 

1682 
pleural  and  esophageal  pressures  and, 

1690 
postexercise  blood  flow  and,  1355 
protein,  in  interstitial  fluid,  985 
pulmonary 

circulation,  exercise  and,  1672 
vascular  resistance  and,  1699 
vessel  oxygen  tension  and,   1 7 1 9 
wedge  pressures  and,  966 
renal  blood  flow  and,  1501 
resistance  changes  in  muscle  and,  1379 
right  atrial  pressure  and,  1  1 13 
running,  blood  flow  in  legs  and,   1 355 
skeletal   muscle   blood   flow  after  sym- 
pathectomy and,  1369 
splenic  blood  flow  and,   1451 
sympathetic 

fibers  to  muscle  and,  1368 
impulses  to  muscle  and,  1369 
venoconstrictor  responses,  1094 
venous  return   and.    1078,    11 13,    1125 

cardiac  output  and,  1113 
ventricular  volumes  during,  783 
Extensibility  modulus 

relation  to  elastic  modulus,  808 
Extracardiac  stimuli 

types  of,  1550 
Extracellular  space 

blood  pressure  changes  and,  1 153 
ratio  to  total  water,  1 141 
volume,  chloride  measurement  of,  1 140 
Extracellular  fluid  volume 

inulin  measurements  of,  1 140 
Extraendothelial  cells 
development  of,  899 
Extraction 

definition,  1397,  1398 
Eye 

arrangement    of    lymphatics    in,    1038 
superficial  vascular  pattern 
nasal  quadrant,  909 
temporal  quadrant,  909 

Factor  P :  see  Pain  factor 

Fainting 

neurogenic,  venodilatation  in,   T094 
skeletal   muscle   blood   flow   and,    1367 
skin  circulation  and,  1343 


venous  return  and,  1 123 
Familial  hypercholesterolemic  xanthoma- 
tosis 
description  of,   1  205 
Fat 

content  of  human  limbs,   1327 
digestion  and  absorption,  1 172 
metabolism 

in  adipose  cells,  1 175 

insulin  and,  1  1  74 

liver  and,  1 1 78 
mobilization 

autonomic  nervous  system,  1  1 75 

hormones  and,  1174-1175 
synthesis  in  intestinal  mucosa,  1  173 
Fats 

chemical  composition,   1171 
Fatty  acids 

binding  to  albumin,  1 178 
classification,  1183 
essential,  man  and,  1 183 
food  sources,  1 1 83 
free 

characterization,  1 1 78 

of    plasma,    relation    to    diet,     1 1 78 
long-chain,  absorption,  1045 
of  diet,  cholesterol  and,  1 182 
Feeding 

cardiac  output  and,  1452 

cranial    mesenteric    artery    flow    and, 

'43- 
splenic  blood  flow  and,  1450 
Felch,  \V.  C. 

Lipid  metabolism  in  relation  to  physi- 
ology   and    pathology    of   athero- 
sclerosis, 1 1 67- 1 195 
Femoral  artery 

arterial  flow  pulse  in,  849 
dimensions  and  flow,  846 
resonance  in,  828 
Femur 

arteries  of,  1652 
foveal  arteries  and,  1652 
Fetuin 

role  in  fetal  osmotic  pressure,  975 
Fetus 
blood 

flow,  anoxia,  hypoxia  and,  1635 
oxygen  saturation,  1634 
pressure  in,  1629-1631 
volume  in  relation  to  placenta,  1626 
bradycardia  in,  1630 
brain,  oxygen  availability  in,  1634 
cardiac  output,  1628 
cardiovascular  reflexes  in,  1 629 
circulation 

changes  on  respiration,  1640 
course  of,  1 624-1 627 
factors  controlling,  1623 
peripheral,  1623 
diagram  of  great  veins,  1625 


ductus  venosus  in,  1627 

elastin — collagen  in  blood  vessels,  1623 

erythrocytes,    entrance    into    maternal 
circulation,  1609 

factor    enhancing   oxygen    availability, 
1634 

heart,  1627-1629 

adrenaline  and,  1630 
diagram,  1626 

hemoglobin  in,  1635 

hepatic  blood  supply,  1627 

hypoxia,  asphyxia  and,   1635-1638 

liver,  oxygen  supply  to,  1627 

lung  development  in,  1645 

noradrenaline  in,  1631 

oxygen  consumption  of,  1634 
organs  and,  1623 

oxygen  requirements  of,  1634 

plethysmograph  of,  1633 

pressures  in  umbilical  vessels,  1632 

pulmonary  artery  pressure,  1629 

regional  blood  flow,  1625 

relationship  between  oxygen  saturation 
and  consumption,  1 636 

resistance  to  anoxia,  1638 

systemic  pressure,  1629 

vascularization,  1623 

vertebral  diagram,  1654 

weight 

fetal  blood  flow  and,   1605 
uterine    oxygen    consumption    and, 
1606 
Fever 

hepatic  blood  flow  and,  1429 
Fibrillation 

intensity  of,  1552 

phasic  inflow  curve,  1552 
Fibrinogen 

concentration   in   human   plasma,    974 

molecular  weight,  974 
Fibroblasts 

filtration  coefficients,  992 
Fick  principle 

cerebral  blood  flow,  1 290 

general  formula,  1291-1292 

nitrous  oxide  method,  1290 
Fick's  diffusion  formulation,  1000 
Filler  voltage 

definition  of,  13 17 
Filtration 

general  formulation,  961 

injury  and,  994 

pressure,  pulmonary  edema  and,   1053 
Filtration  coefficients 

adrenocortical  hormones  and,  999 

adsorbed  plasma  protein  and,  994 

capillary  pressure  and,  991 

discussion  of  term,  991 

epinephrine  and,  999 

factors  affecting,  988,  998 

injured  capillaries  and,  995 

injury  and,  994 


INDEX 


1763 


membranes,  various,  992 

mesenteric  capillaries,  factors  affecting, 

998 

methods  of  measurement,  990 

of  capillaries,  g88-iooo 

of  tissues,  988-1000 

pore  size  and,  1002 

range  for  capillaries,  99-2 

species  differences,  992 

temperature  and,  993 

tissue  asphyxia  and,  997 

venous  pressure  and,  989 
Filtration   constant :  see  Filtration  coeffi- 
cients 
Filtration  rate 

glucose,  1 006 

hydrostatic  pressure  in  capillaries  and, 

990 
isogravimetric   capillary   pressure   and, 

990 
raffinose,  1006 
sucrose,  1006 
urea,  1006 

venous  pressure  and,  978,  989 
Fingers 

innervation  of  skin  blood  vessels,   1 338 
Fisher,  L.  C. 

Blood  supply  to  the  heart,    151 7-1584 
Fishman,  A.  P. 

Dynamics   of  the    pulmonary   circula- 
tion, 1667-1743 
Flat  bones 

blood  supply  to,  1655 
Flowmeters 

applicability,  1296 

based  on  pressure  differences,  1 296 

Bernoulli's    theorem,     application    in, 

1296 
bristle,  1305-131 1 

Holzlohner  and  Bergmann,    1306 
modified  for  large  arteries,   1309 
schematic    diagram    of    bristle    and 

pendulum,  1305 
standard  transducer-tube,  1309 
Broemser   and   Reissinger's  cannula, 

1298 
Broemser's  differential  sphygmograph, 

1302 
bubble,  1 280,  1 530 
calibration  of,  1 294 
Dawes,  1280 

differential  pressure,  845,  1300 
equations  for,  1297 
friction  device,  1297 
pulsatile  flow  and,  1297 
direct  recording,  1279 
electromagnetic 

a-c      modification     of,      1 313- 1 314, 

1530 
calibration  of,  1314 
coronary  blood  flow  and,  1533 
d-c  procedure,  1 313 


diagram,  1  3  1  2 

Faraday's    induction    law    in,     131 2 

-induction  principle,  1311-1318 

Kolin,  1313,  1 316 

laminar  flow  in,  131 2 

magnet  size,  1315 

magnetic  field  strength,   1315 

square  wave,  840,  1313 

transformer  emf,  1  3 1 5 

zero  changes,  13 16 
electroturbinometer,  1 304 
frequency  characteristics,  1 296 
Gaddum  venous  outflow,  1  278 
Hensel's  needle,  1286 
Lauber's  venturi  cannula,  1  297 
Ludwig's  stromuhr,  1279 

Pavlov's  modification,  1279 

silicone  filled,  1  279 
mechano-electric  transducer  tube,  1308 
natural  frequency,  I2g6 
orifice 

constriction  of,  1 299 

principle,  1299 
pendulum,  1305-131 1 
Pitot  meter,  1300 

Cybulski's  modification  of,   1302 

variations  of,  1 300 
Pitot  '"torpedo",  1301 
Prandtl's  tube,  1301 
pressure  differentials,  1297 
principles,  840 
properties  of,  840 

registration  of  pressure  differences,  1 294 
requirements,  839 
response    to    velocity    profile    changes, 

I295 
Reynolds  number  and  turbulence,  1295 
rotameter,  1 303-1304,  1530 

of  Shipley  and   Wilson,    1304 
Schroeder's  differential — pressure,  1 299 
sensitivity,  1295 
square-wave,  1 3 1 7 

circuits,  1318 

magnet  sleeve  units,  1 3 1 8 
theory,     constriction     and     operation, 

1 294- 1 32 1 
thermal      conductivity      measurement, 

1285 
transducer-tube 

of  Laszt  and  Miiller,  1 3 1  o 

of  Miiller,  1310 
traveling  markers,  1320 
turbulence,    velocity    profile    in,     1295 
types  of,  840 
ultrasonic,  131 8-1 320 
venturimeter    of    original    type,     1 298 
Wretlind,  for  ascending  aorta,  1 300 
see  also  Blood  flow  measurement 
Fluid  exchange 

capillary  blood  pressure  and,  988 
mesenteric  capillaries  and,  996 
Fluid  flow 


electrical  analogues  of,  842 

in  elastic  tube,  842 

in  rigid  tube,  842 
Fluid  movements 

symbols  of  factors,  962 
Fluid  retention 

congestive  heart  failure  and,  1 1  16 

venous  return  curve  and,  1 1 16 
Food 

hepatic  blood  flow  and,  1429 

ingestion,    metabolic   consequences  of, 
1171 

splanchnic  blood  volume  and,  1406 
Food  fat 

body  fat  and,  1  172 
Foot 

anastomoses  per  square  centimeter    of 
surface  area,  1327 

innervation    of  skin    blood    vessels    in, 

'34° 
percentage    composition    by    volume, 

■327 

skin  circulation,  local  temperature  and, 

■33' 
Foramen  ovale 

closure  of,  1639 
Forced  expiration 

definition  of,  1713 

overshoot,  1  713 

Valsalva  maneuver.  1 7 1 3 
Forearm 

blood    flow,    body    heating    and,    1339 

innervation  of  skin  blood  vessels,   1339 

percentage    composition     by     volume, 

i327 

volume  changes,  1093 
Fourier 

analysis,  of  pulse  wave,  817 

series,  physiologic  meaning,  845 
Frank's  formula 

assumptions  necessary,  833 
Frequency  characteristics 

pulsatile  flow  and,  1296 
Friedman,  Constance  L. 

Effects    of    ions    on    vascular    smooth 
muscle,  1 1 35-1 166 
Friedman,  S.  M. 

Effects    of    ions    on    vascular    smooth 
muscle,  1 1 35-1 166 
Frog 

capillary  blood  pressure  in,  965 

lung  structure,  1668 

osmotic  pressure  of  plasma  proteins,  965 
Frostbite 

peripheral  vascular  disease  and,    1 2 1 7 

skin  circulation  and,  1335 
Fry's  method 

formula  for,  1 302 

measurement  of,  1302 
Functional  residual  capacity 

definition,  782 


764 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


in  the  intact  organism,  784 
measurement  of,  785 
Fused  quartz  rod 

for  studies  of  microcirculation,  893 

Galactose 

for  hepatic  blood  flow,  1 400 
Galletti,  P.  M. 

Functional  anatomy  of  cardiac  pump- 
ing,  759-798 
Globulins 

ft,  osmotic  pressure-concentration 

curves,  972 
ft  concentration  in  human  plasma,  974 

y> 

concentration  in  human  plasma,  974 
molecular  weight,  974 
osmotic  pressure-concentration 
curves,  972 
osmotic  pressure  due  to,  974 
Globulin  permeability  factors 

in  lymph,  1061 
Glomeruli 
capillary 

permeability,  cyanide  and,  999 
pressure  in,  965 
filtration,   osmotic   pressure   of  plasma 

proteins  and,  976 
juxtaglomerular  complex,   14*14 
granularity,  1463 
renin  and,  1464 
membranes 

electron  microscopy,  1462 
molecular  sieving  in,  1017 
podocytes  and,  1018 
pore  size,  1462 
Glucose 

capillary  permeability  to,  1013 
diffusion  of,  1001-1002,  1010 
diffusion  rates,  1012 
filtration  rate,  1006 

permeability   of  muscle   capillaries   to, 
1013 
Gravity 

hepatic  circulation  and,  1424 
Green,  H.  D. 

Resistance    (conductance)    and    capac- 
itance     phenomena     in     terminal 
vascular  beds,  935-960 
Greenfield,  A.  D.  M. 

The  circulation  through  the  skin,  1  525 

1351 

Gregg,  D.  E. 

Blood  supply  to  the  heart,    151 7-1 584 

Grim,  E. 

The   flow   of  blood   in   the   mesenteric 
vessels,  1439- 1456 

Guinea  pig 

capillary  blood  pressure  in,  965 
cardiac    glycogen    before    birth,     1638 
osmotic  pressure  of  plasma  proteins,  965 


protein  osmotic  pressure  in,  965 
pulmonary  vessels  in,  1674 
Guyton,  A.  C. 

Venous  return,  1 099-1 133 

Haddy  technique 

application  of,  1089 
Hair  growth 

cutaneous  circulation  and,  12 19 
Hamster  cheek  pouch 

microcirculation  in,  892,  900 
vascular 

network,  901 
pattern,  goi 
Hand 

anastomoses   per  square  centimeter  of 

surface  area,  1327 
blood     vessels,     pressure-volume     dia- 
grams of,  878 
innervation  of  skin  blood  vessels,   1338 
percentage    composition     by     volume, 

1327 
plethysmograph  for,  1282 
skin     circulation,     local     temperature 
and,  1 33 1 
Hashim,  S.  A. 

Lipid  metabolism  in  relation  to  physi- 
ology   and    pathology    of    athero- 
sclerosis, 1 1 67-1 195 
Heart 

anatomical  components,  763 
as  a  pump,  761 
effectiveness,  1 1 04 
left  ventricle,  844 
pressure-suction,  789 
reciprocating,  760 
rotary,  760 
backflow,  mechanisms  preventing,  780 
catheterization,  1671 
cineangiography,  1530 
conduction  system,  764,  1584 
configuration  changes,  764 
da  Vinci,  1669 
development  of,  1623 
diastole  and  systole 
measurement  of,  1538 
values  for,  1538 
diastolic 

capacity,  definition,  783 
reserve  volume,  definition,  782 
differences     between     right     and     left 

cardiac  cavities,  789-791 
effectiveness,  load  pumped  against  and, 

1 104 
efficiency,  drugs  and,  1564 
electrical-mechanical     event     relation- 
ships, 777 
end  arteries  in,  1522 
end -diastolic  level,  784 
end-systolic  volume,  782,  784 
epicardium,  anatomy,  792 
fetal,  1627-1629 


noradrenaline,  effect  of,  1631 

sensitivity  to  adrenaline,  1 630 
filling  pressure,  1104 
function,  simultaneous  analysis  of  right 

and  left,  1 1 19 
functional  anatomy  of,  759,  798,   1517 
glycogen,  before  birth,  1638 
hypereffectiveness  of  factors,  1 104 
hypertrophy,  effectiveness  of  heart  and, 

1 104 
hypothetical    ejection    curve    for,    821 
interventricular  septum,  blood  supply, 

1520 
left,  compared  to  right  heart,  789 
lymphatics,  1527 
lymphatic  plexuses  in,  1054 
macroscopic  structures,   762-769 
mechanical 

analogues,  760 

efficiency,  761 

properties,  761 
Myomeric    conducting    tissue,     151 8 
muscle  :  see  Myocardium 
orifice  relationships,  764 
oxygen  tension  and,  946 
oxygen  uptake,  1 541 -1543 

cardiac  arrest  and,  1541 

fibrillation  and,  1541 
oxygen  utilization,  1538 

aortic  pressure  and,  1543- 1544 

myocardial   tension  and,     1 543-1 544 

vagal-arrest  and,  1538 
papillary  muscles,  structure  of,  780 
pericardium :  see  Pericardium 
phase  relationships,  775 
recompensation  of,  1 1  1 7 

cardiac  output  and,  1117 

right  atrial  pressure  and,  1  1  1  7 

venous  return  and,  1 1  1  7 
response    to    increased    outflow    resist- 
ance, 844 
right,  compared  to  left  heart,  789 
role  of,  760 

schematic  representation  of,  777 
size,  stroke  volume,  systolic  peak  and, 

832 
skeleton  of,  763 
structure,    according    to    Leonardo    da 

Vinci,  1669 
sympathetic    nerves,    stimulation    and, 

'549 
tamponade,  cardiac  output  curves  and, 

1105 
teratogenic  factors,  1624 
unilateral  disturbance,  analysis  of,  1 1  18 
ventricles,     fiber     arrangement,      1 5 18 
vinylite  cast  of,  1519 
volume 

blood,  per  minute,  761 
changes  at  birth,  1641 
Heartbeat 

augmented  rates,  775 


INDEX 


65 


central  venous  pressure  and,  1  1  24 

development  of,  1627 

venous  return  and,  1  1  24 
Heart  disease 

compensatory  mechanisms,  1566 

O;  uptake,  1566 

valvular 

effectiveness  of  heart  and,    1 1 04 
elevated   ventricular   pressure,    1554 

valvulitis,  lymph  How  and,  1054 

vasodepressor  drugs  in,  1 567 
Heart  failure 

cardiac  work,  1558 

congestive,  analysis  of,  1 1 16 

coronary  stenosis,  1547 

discussion  of,  1557 

experimental,  1 566 

extras  ascular  compression,  1 558 

hemodynamic   manifestations  of,    1557 

in  severe  anemia,  1547 

left 

cardiac  output  and,  11 20 

atrial  pressures  and,  1 120 

mean  pulmonary  pressure  and,  1 1 20 

mean   systemic    pressure    and,    1 1 20 

venous  return  and,  1 1 20 

myocardial  mechanical  efficiency,  1558 

proteins  of  edema  fluids  in,  982 

right 

cardiac  output  and,   1  1  2  1 

atrial  pressures  and,  1 121 

mean  pulmonary  pressure  and,  1 12 1 

mean   systemic    pressure    and,    1 1 2  1 

pulmonary  collateral  circulation, 

l679 
venous  return  and,  1 121 

Starling  curves  in,  1557 
Heart  murmurs 

axial  velocity,  858 

critical 

internal  diameter  and,  858 
velocity,  858 

envelope,  definition,  858 

examples,  859 

general  rules,  858 

moaning,  systolic,  859 

musical,  origin,  859 

nonlaminar  flow,  856,  858 

normal,  856 

recording  of,  856 

sea  gull,  definition,  859 

shape,  definition,  858 

turbulence,  858 
Heart  rate 

acceleration,   energy   metabolism   and, 

'54° 
altitude  and,  1720 
aortic  flow  during  exercise  and,  846 
augmented,  phase  relationships,  775 
birth  and,  1641 

coronary  blood  flow  and,   1540 
diastolic  oscillations  and,  827 


drugs  and,   1564 

exercise  and,  846 

fetal 

maternal  placental   blood   flow  and, 

1636 
regulating  mechanisms,  1628 
slowing  with  uterine  opening,   1637 

in  exercise  and  excitement,   1553 

pressure  augmentation,  827 

rapid,  limit  to  cardiac  output,  761 

stroke  coronary  flow  and,   1554 

uniform,  pulse  pressure  wave  and,  817 

vascular  resistance  and,  1540 

velocity  of  pulse  wave   foot  and,   818 

ventricular  filling  and,  775 
Heart  work 

aging  and,  875 

chemical  patterns  of,  1 536 

coenzymes,  1536 

drugs  and,  1564 

enzymes,  1536 

glycogen,  1536 

hormones,  1536 

index,    values    in    left    ventricle,    1537 

lipids,  1536 

protein,  1536 
Hematocrit 

pulmonary  capillary 
during  exercise,  1707 
during  rest,  1  707 

splanchnic  versus  arterial,  1 407 
Hemodromograph 

definition  of,  1306 
Hemoglobin 

in  fetus,  1635 

levels,  effects  of,  1547 

X,  molecular  sieving  of,  10 17 
Hemorrhage 

cardiac  output  and,  1 1 14 

right  atrial  pressure  and,  1 1 14 

splenic  blood  flow  and,  1 451 

venous  return  and,  1 1 1 4 

ventricular  outputs  and,  1 121 
Hensel  needle :  see  Flowmeters 
Heparin 

anaphylactic  shock  and,  1059 

anaphylaxis  release  and,  1059 
Hepatectomy 

BSP  removal  and,  1398 
Hepatic  blood  flow 

acetylcholine  and,  1 41 9 

adrenergic  response,  951 

alcohol  as  measure,  1 400 

cholinergic  response,  951 

cirrhosis  and,  1428 

clearance    and    extraction    techniques, 

1397 
cross  section  and,  1407 
dilution  techniques.   1402 
direct  method  for,  1 392 
distributional  pattern,  1409 
epinephrine  and,  950,  141 8 


factors  affecting,  1405 
Fick  principle  and,  1396 
galactose  as  measure,  1400 
in  dog,  1405 
in  man,  1405 

measured   by    R-E   cell   activity,    1401 
merits  of  various  dyes,  1400 
path  length,  1409 
perfusion  studies  of,  1 393 
single    injection    technique    and,    1401 
thermostromuhr  and,  1393 
transillumination  and,  1393 
under  control  conditions,  1404 
viscosity,  141  1 

volume    and    distensibility    and,     1412 
Hepatic  circulation 
anatomy,  1 388-1 392 
autonomic  blockade,  1420 
bilaterality  of  portal  flow,  1411 
blood 

flow  and  volume,  1407-1414 

pressure  and,  1 395 

volume  in,  1 394 
capillary  nets  and,  1 389 
catheterization  of,  1396 
collaterals  in,  1  268 
critical  closing  pressures  in,    1408 
denervation  and,  1421 
diagram,  1406 
differentiation   of  venous   and   arterial 

now,  1399 
distributional  pattern,  1409 
dye  studies,  precautions,    1399 
dysfunction,  1426-1429 
hemorrhage,  effect  on,  1427 
hemodynamic 

adjustments,  1414-1426 

parameters,  1392 
hyperemia 

factors  affecting,  1429 

foods  ingested  and,  1429 
importance,  1387 

inflow,  arteriolar  resistance  and,   1407 
integration,  1 426-1 429 
intraosseous  venography,  1394 
local    biochemical    determinants,    1421 
lymph  and,  1391 
methodology,  1 392-1 404 
neural  determinants,  14 14-141  7 
neurohumoral  determinants,  141 7 
normal  parameters,  1404- 1407 
physical  determinants,  1424 
portal  venipunctures  and,  1394 
radiopaque  injection  masses.  1394 
reciprocity  of  venous  and   arterial  in- 
flows. 1388 
reflex  regulation  of,  1416 
response  to  epinephrine.   14 18 
sinusoids  in,  1390 
splanchnic  interrelationships,   1427 
systemic  interrelationships,    1426 
turbulence  in,  1 4 1  1 


1766 


HANDBOOK    OF    PHYSIOLOGY 


CIKOI'LATION    II 


veins  of,  1 39 1 

sphincter  in,  1391 
venous 

catheterization,  1395 

outHow  measurement,  1 392 
viscosity,  1411 
volume 

arterial  inflow  tract,    1412 

flow  distensibility  and,    141-' 
Hepatic  lymph 

formation  of,  1050 
pathways,  1050 
protein 

concentration,  1050 

distribution.  1050 
rate  of  flow,  1051 
volume,  1050 

in  relation  to  plasma,  1051 
Hereditv 

atherosclerosis,  1 205- 1 206 
lipid  metabolism  and,  1205 
Hexamcthonium  chloride 

renal  blood  flow  and,  1487 
High  altitude 

cardiac  output,  1720 
children  and,  1  72  1 
exercise,  1 720 
Histamine 

as  a  lymphagogue,  1059 
capillary 

permeability  and,  1059,  1061 

pressure  and,  996 
cutaneous  blood  flow  and,  1346 
edema  and,  970 
effects  of,  1 725 
gastric  blood  flow  and,  144b 
hepatic  circulation  and,  1423 
in  lymph,  1047 

intestinal  blood  flow  and,  1448 
pancreatic  blood  flow  and,  1450 
reactive    hyperemia    and,     1329,    1375 
skin  circulation  and,  1334,  1345 
smooth  muscle  potential  and,  1155 
species  difference  in  action,  1059 
splenic  blood  flow  and,  1450 
total  systemic  effect,   1423 
vascular 

changes  due  to,  969 

pressures  and  interstitial,  970 
venoconstrictor  responses,   1094 
wheal  test,  1223 
Histodynamics 

principles,  1258 
Historical  development 

concepts,  pulmonary  circulation,    [670 
contributors,  1670 
Barcroft,  1673 

Fick,  1670 
Henderson,  1673 

Lower,  1670 
Ludwig,  1670 
Hormones 


atherosclerosis  and,  1  199 

collateral  circulation  and,  [265 

estrogen  and,  1 600-1  bo 2 

lipid  metabolism  and,  1  199 

pregnancy  and,  1602-1612 
Hoyer-Grosser  canal 

description,  1252 
1  [yaluronic  acid 

»m-1s,  diffusion  and,  1021 
I  lyaluronidase 

experimental  atherosclerosis  and,   1202 
Hydralazine 

postpartum    uterine    blood    flow    and, 
1608 

renal  blood  flow  and,  1487 
I  [ydraulic  impedance 

definition  of,  843 

discussion  of,  843-844 
Hydraulic  reactance 

definition,  844 

equation  for,  844 

in  pressure-flow  diagram,  844 
Hydrochloric  acid 

mean  activity  coefficient,  in  given  solu- 
tion, 1 137 
Hydrochlorothiazide 

hypertension  and,  1  1  42 
Hydrodynamic  conductivity :  see 

Filtration  coefficients 
Hydrodynamic  transcapillary  flow 

of  water,  pore  size  and,  1004 
Hydrogen  ion 

entrance  rate  into  muscle,  1 1 38 

mobility  in  electric  field,  1138 

relative  diameter,  1 1 38 
Hydrogen  ion  concentration 

capillary  filtration  coefficients,  998 

change,   vascular  resistance  and,    n  59 

exercise  hyperemia  and,  1379 

filtration  coefficients  and,  997 

membrane  permeability  and,  1  159 

mesenteric,  filtration  coefficients  of,  998 

vascular   smooth   muscle   tension    and, 

1  1581 '59 
1 1\  dropenia 

urea  distribution  in  kidney  and,    1 47 1 
Hydrostatic  pressure 

peripheral  venous  pressures  and,  1127 
venous  pressure  and,  1 1 26 
Hypercapnia 

central,  venoconstrictor  responses,  1094 
hepatic  circulation  and.   1422 
intestinal  blood  flow  and,  1449 
renal  blood  flow  and,  1504 
Hyperemia 

capillary  pressure  and,  968 
coronary  blood  flow  and,  1554 
exercise,  1355,  1368 
anoxia  and,  1376 
blood  pressure  and,  1378 
bradykinin  and,  1380 
ischemia  and,  1376 


lactic  acid  and,  1379 

metabolites  and,  1378 

skeletal    muscle    circulation,     1376- 
1380 
prolonged    insufficiency    of  circulation 

1,  1330 

reactive 

anaerobic  metabolism,  1540 

arteriovenous  shunts  and,  1540 

blood  flow  and,  1376 

blood  pressure  and,  1539 

centra]  nervous  system  and,  1329 

definition,  1539 

explanation  for,  1539 

heart  rate  and,  1539 

histamine  and,  1329 

in  skeletal  muscle,  1374-1376 

in  skin,  1329 

lactic  acid  levels,  1540 

length   of  occlusion   time   and.    1539 

magnitude  of,  944 

mechanism  of,  944 

oxygen  consumption  during,  1540 

oxygen  debt  and,  1540 

size  and  duration,  1329 

temperature  and,  1329 

volume  of  blood  flow,  1539 

vascular  events  during,  1375 
Hypertension 

acute,  Na  and  K.  in,  1  151 
capillary  pressure  and,  968 
chronic 

brachial  pulse  in,  832 

measurement  of  Na  and  K  in,   1 150 
damping  of  incisura  and,  832 
electrolytes  in  vascular  tissue  and,  1 150 
lipoprotein  diffusion  and,  1046 
Na  as  primary  etiological  factor,    1  143 
relation  of  Na  and  K,    1142,    1143 
venous  pressure  and,  1224 
r«    also  Blood  pressures 
Hyperthermia 
diathermy,  1560 
see  also  Fever 
Hyperthyroidism 
cardiac  effects,  1552 
cholesterol  metabolism  and,  1199 
Hypertonic  solutions 

action  of,  1717 
Hypoglycemia 

skin  circulation  and,  1344 
Hypoproteinemia 

protein  concentration  in  extravascular 

fluids,  985 
protein    in    interstitial    fluid    and,    985 
Hypotension 

acute,  Na  and  K  in,  1 151 

chronic,  measurement  of  Na  and  K  in, 

1  150 
hemorrhagic,    renal    blood    flow    and, 

■5°5 
Hypothalamic  stimulation 


1767 


effect  on  skin  and  muscle  circulation, 

■367 

skeletal    muscle   blood   flow   and,    1359 

Hypothermia 

discussion  of,  1559,  1560 
effectiveness  of  heart  and,  1 104 

Hypothyroidism 

atherosclerosis  and,  1  187 
cholesterol  metabolism  and,  1  199 

Hypoxemia 

capillary  permeability  and,  998 
local  edema  formation  and,  998 

I  [ypoxia 

cardiac  contractility,  1544 
discussion  of,  1544 
effects  on  fetus,  1635- 1638 
endothelial  proliferation  and,   1259 
fetal  blood  flow  and,  1635 
filtration  coefficients  and,  997 
hepatic  circulation  and,  1422 
intestinal  blood  flow  and,  1449 
myocardial  nucleotides  and,  1545 
pulmonary 

arterial  pressure  and,  1053,  1718 
vascular  pressure  and,  1  725 
vascular  resistance  and,  1725 
vessel  oxygen  tension,  17 19 
regional  blood  volume  and,  1694 
renal  blood  flow  and,  1503 
vascular  effects  of,  972 
vasoconstriction,  17  19 
venoconstrictor  responses  and,  iog4 

Hysteresis 

decrease  with  age,  877 

in  elastic  and  muscular  vessels,  879 

in    elastic    vessels,    dependence    upon 

stretch  velocity,  877 
in  excised  vessels,  803 

Hysteresis  loop 
definition,  867 

Ileum 

vascular  pattern,  907 
Iliac  artery 

arterial  flow  pulse  in,  849 

circumference,  846 

mean  peak 
flow,  846 
velocity,  846 
Immersion  foot 

description,  1335 

skin  circulation  and,  1335 
Index  finger 

anastomoses   per  square  centimeter  of 
surface  area,  1327 
Indicator  dye 

concentration-time  curve,  1 69 1 ,  1692 

dilution  curve,  1729 
Indocyanine  green 

removal  from  blood,   1  397 

transfer  from  blood  to  bile,  1397 

value  in  clearance  studies,  1400 


Inert  ance 

definition,  820 

formula  of,  841 
Inferior  metaphysis 

blood  supply  of,  1653 
Inflammation 

capillary  stasis  in,  995 
Infusions 

effects    on    protein    and    lymph    flow, 
1043-1044 
Inhibitory  permeability  factor,  IPF,  1061 
Injury 

capillary 

permeability  and,  995 
pressure  and,  996 

filtration  coefficients  and,  989 

mechanical,  skin  circulation  and,   1336 
Inlet  length 

definition,  1  296 
Insulin 

atherosclerosis  and,  1  200 

fat  metabolism  and,  1  1  74 

lipid  metabolism  and,  1200 
lnterarterial  anastomoses 

functional  anatomy,  151 7 
Intercellular  cement 

increased  intracapillary  pressures  and, 

■°53 
Intermesenteric  nerve 

innervation  of  kidney,  1468 
Intermittent  claudication 

basic  requirements,  1217 

definition,  1217 
Interstitial  fluid 

bound  and  free  water  and,  978 

circulation  of,  986 

distribution,  978-979 

movement  of  dye  in,  979 

protein 

circulation  of,  1041 
osmotic  pressure,  984 

proteins  of,  982-1007 
Interstitial  fluid  pressure 

breaking  point,  981 

chronic  studies  of,  981 

cutaneous,  980 

description,  977 

edema  and,  980 

factors  affecting,  979 

in  kidney,  982 

in  various  body  parts,  980 

muscle,  980 

null  point  method,  979 

subcutaneous,  980 

"tissue  pressure",  977-982 

venous  congestion  and,  980 
Interstitial  pressure 

histamine  and,  970 
Interstitial  resistance 

skin  in,  979 
Interventricular  system 

blood  supply  to,  1520 


Intervertebral  discs 

blood  supply  to,  1655 
Intestinal  mesentery 

blood  flow  in,  1443-1444 
Intestine 

blood  flow,  1443-1444 
autoregulation  of,  944 
factors  affecting,  1447 
through,  1441,  1442,  1443 

blood  volume  in,  1445 

circulation  of  villi,  907 

electrolyte  levels  in,  1 141 

fat  synthesis  in,  1  173 

in  vasomotor  receptors,  1448 

microcirculation  in,  904 

muscularis,  blood  flow  in,  1 443-1 444 

segments,  blood  flow  through,  1442 

submucosa,  blood  flow  in,  1 443-1 444 

villi,  circulation  in,  907 
Intra-abdominal  pressure 

hepatic  circulation  and,  1424 
Intraluminal  pressure 

intestinal  blood  flow  and,  1449 
Intramural  flow 

discussion  of,  1528 
Intrauterine  pressure 

blood  How  and,  1600 
Inulin 

disappearance  from  plasma,  1008 

permeability 

of  capillary  to,  1013 
of  muscle  capillaries  to,  1013 
Inulin  space 

extracellular  space  and,  1  141 

in  bladder,  1141 

in  stomach,  1  141 

in  uterus,  1  141 

in  vascular  tissue,  1  141 
Iodine 

protein-bound  transport  in  lymph, 
1049 
Ions 

activity,  1 1 3  7 

alkali  metal,  ionic  radii,   1 137 

blood-tissue  exchange  of,  1021 

definition,  1  136 

hydrated  size,  1 137 

methods  of  studying  effects,  1  139-1 142 

mobility,  1 137 

properties,  1 1 36 

relative  diameters,  1 138 

mobility  in  electric  field,  size  and,  1 138 

symbols  for  concentration  and  activity, 

"37 
IPF:  see  Inhibitory  Permeability  Factor 
Iron 

transport  in  lymph,  1048 
Ischemia 
renal 

blood  flow  and,   1503 
hemodynamics  and,  1504 


1 768 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Ischemic  neuritis 

description,  12 18 
Isogravimetric  capillary  pressure 

definition,  990 
Isolation 

atherosclerosis  and,  1208 
Isometric 

contraction 

coronary  blood  flow  and.  [533 

relaxation 

coronary  blood  Bow  and.   1533 
I  sopropyl  norepinephrine 

intestinal  blood  How  and,   1448 
Isoproterenol 

vascular  volume  and,  955 

Joint  blood  vessels 

blood  pressure  and,  1662 
nervous  control  of,  1662 
Joints 
blood 

How,  1662 
supply,  1 661 -1662 
nerve  supply,  1 662 

nervous  control  of  blood  vessels,    1662 
Jugular  vein 

volume  distensibility,  1 083 
Juxtaglomerular  apparatus   (JGA):  see 
Kidney 

Katz,  L   N. 

The    role    of    endocrines,    stress,    and 
heredity  on  atherosclerosis,   1 197— 
1  213 
Khellin 

coronary  effects  and,  1563 
Kidney 

arrangement  of  lymphatics  in,  1038 
A-V  oxygen  difference,  1474 
blood  volume,  1470- 1474 
countercurrent  mechanism,   1472 
distribution     of    osmotic    constituents, 

1469 
function 

albumin  infusion  and,  1499 
edema,  lymph  flow  and,  1057 
renal  lymph  and,  1058 
glomerular   filtration   of  dextran,    1463 
heat  production,  1475 
hydrostatic  pressures  in  nephron,   1477 
interstitial  pressure,  1478 
intrarenal      pressure      (IRP),      factors 

affecting,  1478 
intratubular  and  peritubular  capillar) 

pressures,  1476 
juxtaglomerular  complex,   [462 

electron  micrograph,  14*13 
lymph 

circulation,  [466 
production  in,  1466 
metabolism,  1474- 1475 
nephron  types,  1458 


nerve  supply,  1467- 1469 
output 

congestive    heart    failure    and,    11 16 

in  myocardial  damage,  1  1  1 6 
oxygen  utilization,  1 474 

blood  flow  and,  1474 

in  various  zones,  147", 
pathological  changes  in  ureter  ligation, 

.058 
pressure  gradients  in  various  areas,  1475 
safety  valve  mechanism  of  lymph,  1058 
urea    distribution    during    hydropenia, 

1471 
volume  changes  with  resistance  change, 

955 
zonary  temperature  gradients,  147b 
Kirchoff's  current  law- 
statement  of,  849 
Knee 

blood  flow  through,  1662 
Kramer.  K 

Methods    of    measuring     blood    flow, 
'277-1324 

Lacteals 

definition,  1036 
Lactic  acid 

blood  pressures  and,  1722 

exercise  hyperemia  and,  1379 

heart  and,  1545 
Lamb 

fetal,  systemic  blood  pressure  in,   1  b _■  ct 

umbilical  blood  flow  in,  1633 
Laminar  flow- 
discussion  of,  1295 

Poiseuillc's  law,  1  295 

velocity   distribution    form,    1 295 
Landis,  E.  M. 

Exchange    of   substances    through    the 
capillary  walls,  961-1034 
Leg 

filtration  coefficients  for,  992 
Leukemia 

medullary  pressure  and,  1661 
Leukocytes 

filtration  coefficients,  992 
Leukotaxine 

capillary  permeability  and,  1061 
Levophed :  see  Norepinephrine 
Liebow,  A.  A. 

Situations    which    lead    to    changes    in 
vascular  patterns,    1251-1276 
Limb  fluids 

protein  in,  985 
Lipase 

transport  in  lymph,  11147 
Lipid-insoluble  molecules 

permeability   of  muscle   capillaries   to, 
1013 

restricted  diffusion  of,  1010 

transcapillary  movement,  1007 

transcapillary  movement  of,  1008- 1009 


Lipid  metabolism 

adrenocortical  activity  and,  1201 

alloxan  diabetes  and,  1201 

anterior  pituitary  hormones,  !  202 

atherosclerosis  and,  1167-1190 

caloric  intake  and,  1207 

definition,  1 167 

diabetes  mellitus  and,  1200 

emotional  stress  and,  1208 

epinephrine  and,  1202 

heredity  and,  1  205 

hormones  and,  1 1 99 

in  chickens,  1  201 

insulin  and,  1200 

physical  activity  and,  1206 

sex  hormones  and,  1203 

stress  and,  1206 
Lipid-soluble  molecules 

capillary  permeability,  1018 
Lipids 

absorption  of,  1045,  1 1 73 

circulation  of,  in  women,   1  203 

description,  1  167 

lymph  transport  of,  1044 

mobilization,  hormones  and,   1 1  74 

rate    of   movement    from    blood,    1044 
Lipophage 

derivation  of,  1 1  70 
Lipoproteins 

a,  974 

oa-acid  glycoprotein,  974 

(3,  974 

/3i-lipid  poor  euglobulin,  974 

ft-metal  combining,  974 

characterization,  1  1  76 

classification,  11 76 

interconversion,  11 78 

molecular  surface,  1177 

schematic  conception  of,  1  177 
Lithium 

entrance  rate  into  muscle,  1  138 

ion  diameters,  1138 

ionic  radii.  1 137 

mobility  in  electric  field,   11 38 

relative  diameter,  1 138 
Livedo  reticularis 

basic  defect  in.  1233 

blood  vessel  changes  in,   1233 

characterization,  1  232 

classification,  1232 

picture  of,  1232 

primary,  description,  1233 

secondarv,  description  1233 
Liver 

arrangement  of  lymphatics  in,  1038 

autoregulation  in,  944 

blood  volume  in,  1445 

BSP  transfer,  1397 

cellular  arrangement  in,  1390 

clearance  tests,  equation  for,  1400 

fat  metabolism  and,  1178 

in  arterioportal  anastomoses,  922 


INDEX 


I769 


in   capillary   permeability,    1050 
lymphatic  pathways,  1050 
reactive  hyperemia  in,  1422 
sinusoids,  structure  of,  1391 
volume  of  blood  in,  1395 
see  also  Hepatic  circulation  and  Hepatic- 
blood  flow 
Lm 

definition,  1397 
Local  acceleration 
definition,  1296 
Lochner,  W. 

Methods    of    measuring     blood     flow, 
1277-1324 
Long  bones 

central  venous  sinus.   1654 
circulation  in,  1651 

marrow,  1654 
cortical  arteries,  1652 
medullary  arteries  of,  1651 
periosteal  circulation  of,  1 653 
sinusoids,  1654 
sources  of  blood,  1651 
vascular  supply  of  metaphyseal  region, 

1651-1652 
venous 

sinusoids  in  marrow,  1654 
system,  1654 
Low-pass  inverse  feedback 

definition  of.  1317 
Low-frequency  manometers 

definition  of,  1 303 
Low-pressure  receptors 

sympathetic     vasoconstrictor     tone     in 
muscles  and,  1 364 
Ludwig's  principle 

variations  of,  1279 
Lungs 

anatomical  structure,  1668 
arteriolar  diameters,  914 
A-V  pathways  in,  914 
capillary 

permeability  in,  1018 
pressure  in,  966 

pressure,  osmotic  pressure  and,  991 
structure  in,  1676 
surface  area,  10 18 
collateral  circulation  in,  1261.   1266 
Tetralogy  of  Fallot.  1 262 
rate  of  development,  1266 
fetal 

blood  flow  in,  1641 
distensibility,  1644 
frog,  alveolar  structure,  1668 
human,  electron  micrograph  of,    1677 
ideal 

application  of,  1683 
limitations  of,  1683 
microcirculation  in,  913 
model  of,  1684,  1685 

"ideal",  1683 
phylogenetic  development,  1668 


pressure -tiow  diagrams  before  and  after 

ventilation,  1644 
rate  of  development,    1266 
smooth  muscle  in,   1678 
transcapillary  exchange,  1 707 
"tropism"  of  collaterals,  1265 
Lupus  erythematosus:  see  Collagen  disease 
Lymph 

absorption 

by  diaphragmatic  lymphatics,  1065 

extracellular  pathway,  1065 

intracellular  pathway,  1065 

of  substances  by,  1 064 
albumin  in 

infusion  and,  1042 

relation    to    plasma    albumin,     1063 
atherosclerosis  and,  1046 
B12  in,  1048 
blood   volume    regulation    and,    1042- 

1044 
chylomicrons  in,   1044 
circulation,  magnitude,  987 
coagulation,  1048 

fibrinogen  and,  1048 

prothrombin  level  and,  1048 

vitamin  K  and.  1048 
composition,  1041 

from  right  duct,  1052 
dextran  in,  relation  to  plasma  dextran, 

1063 
disappearance 

of  phospholipids,  1045 

of  triglycerides,  1045 
drainage,  urine  concentration,  1058 
enzymes  and,  1047 
exchange   of  substances   with   plasma, 

1 040- 1 042 
extravascular  pool,  protein  and,    1041 
factors  affecting  protein  content,   1041 
fatty  acid  absorption  and,  1045-1046 
histaminase  activity  of,  1047 
histaminolytic  activity  of,  1047 
iron 

content  of,  1 049 

transport  in,  1048 
lipase  transport  in,  1047 
lipid  absorption  and,  1045 
lipoproteins  of,  1044 
methods  of  study,  1035- 1036 
molecular  sieving  of  dextran  in.    1014 
pericapillary  filtrate  and,  1037 
phospholipid 

ratio  to  lipid  diet  and,  1046 

transport,  1046 
plasma 

exchange  and,  1040 

protein-equilibration,  1042 
pore  concept  and,  1040 
pressure  gradient,  1037 
protein-bound  iodine  in,  1049 
protein 

circulation  and,  1041 


compared    to    intravascular    protein, 

987 

concentration  of,  985 

in  various  conditions,  985 

movement,  1040 

regional  differences,  982 

relation  to  plasma,  1046 
return  to  general  circulation,  1063 
shock  and,  1 058-1 061 
Starling  hypothesis  and,  1040 
steroids  and,  1045 
tissue  fluid  and,  1037-1038 
transport 

effect  on  bile,  1045 

function,  1044-1050 

of  nucleotides,  1049 

of  various  substances  in,    1044- 1050 
urea,  and  albumin  content,  1064 
volume  flow,   before  and  during  infu- 
sion, 1042 
Lymph  flow 

anaphylactic  sensitization  in,  1059 
artificial  respiration  and,  1052 
atrial  pressure  and,  1052 
burns  and,  1061 
edema 

kidney  function  and,  1057 

production  and,  1060 
EKG  and,  1055 
infusions  and,  1043 
postural  proteinuria  and,   1057 
pulmonary  edema  and,  1052,  1054 
renal 

backflow,  in  renal  disease,  1058 

capsular,  1056 

compared  with  urine  flow,    1056 

diuretics  and,  1058 

factors  affecting,  1056 

venous  pressure  and,  1056 
traumatic  shock  and,  1060 
valvulitis  and.   1054 
vasodilatation  and,  968 
Lymphatic  system 

anaphylactic  shock  in,  1058 
anatomical 

arrangement,  1527 

dissection,  1036 
as  a  homeostatic  mechanism,  1035 
basement  membrane  in,  1062,  1066 
cannulation,  1036 
definition,  1036 

development  and  structure,  1036 
direct  venous  connections,    1039 
distribution  in  tissues,  1038 
endothelium,  specificity,  1037 
histological  study,  1062 
isotopes  in  studies  of,  1036 
liver,  1391 

ascites  and,  1051 
lymphatic  return  and,  1042 
main    trunks,    anatomic    arrangement, 
1038 


i77" 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


methods  of  study,  1035 

of  myocardium,  1 054 

of  uterus,  1608 

origin  and  drainage,  1527 

permeability   compared   to   capillaries, 

1062 
plexuses 

density  of,  1038 

dI  heart.  T054 

pressure    in,    diaphragm    and,    1065 
pressure,  1037 

increased  venous  pressure  and,   1038 

respiration  and,  1 038 
pulmonary 

anastomotic  connections,  1052 

anatomical  arrangement,  1051 

edema  and,  1051 
radiopaque    dyes    in    studies   of,     1036 
regional,  signilicance,  1049 
renal,  1466 

anatomy.  1055 

obstruction,  1058 

pyelonephritis  and,  1058 

"safety  valve"  mechanism,   1058 
response  to  trauma,  1040 
retention  of  substances,  1062 
right  lymph  duct 

composition  of  lymph,  1052 

origin  of  contents,  1051 
sensitivity  to  epinephrine,  1040 
shock  in,  1058 
shunts  in,  1063 
terminology,  1036 
thoracic  duct,  1050 

location,  1039 

rate  of  flow,  1 050 

structure,  1039 

valve  system,  1039 
transport 

function,  1044 

lipid,  1044 
valves  in,  1037 

variability  of  structures,  1039 
venous 

origin,  1037 

pressure  and,  1037 
Lymphatic  permeabilitv 

anatomical    structures    important     in, 

1064 
colloidal     particles,     factors     involved, 

1 06 1  - 1 066 
concepts,  1066 

intraluminal  pressure  and,  1064 
"leaky  pump"  concept,  1066 
potential  physical  openings,  1 065 
size  limitation,  1064 
stigmata,  stomata  and,  1065 
test  substances  for,  1064 
theories  of,  1065 
"toxic"  effect  of  urea,  1064 
Lymphatic  vessels 
capillaries 


in  myocardium,  1054 

relationship   to   small   blood   vessels, 

'°37 
contractility  of,  1039- 1040 
development   and   structure   of,    1036- 

1037 
distribution  of,  1038- 1039 
in  heart  valves,  1054 
permeability  pattern  in,   1062 
protein  leakage,  1 062-1 063 
shock  and,  1050- 1058,  1 058-1 061 
Lymphedema 

lymph  and  interstitial  protein   in,  986 

Macrocanalicular  system 

definition,  1653 
Maculadensa:      see      Glomeruli,      juxta- 
glomerular complex 
Magnesium 

arteriolar  size  and,  948 

entrance  rate  into  muscle,  1 138 

ion  diameters,  1 1 38 

mobility  in  electric  field,  1  138 

relative  diameter,  1 1 38 

smooth  muscle  tension  and,  1 158 

vascular 

resistance,  1  158 

smooth    muscle    tension    and,     1 1 57  — 
1 158 
vasodilatation  and,  1158 
Magnet-coil  current 

heat  production  and,  13 17 
Malnutrition 

proteins  of  edema  fluids  in,  982 
Mammals 

protein  osmotic  pressure  in,  975 
Man 

aortic  resonance  in,  826 
arteriovenous  anastomosis  in  ear,   1 252 
automaticity  in  blood  vessels,  1356 
axillary    artery,    tension    muscles,    869 
bile  acid  formation  in,  1  180 
biphasic  action  of  adrenaline,  1371 
birth 

cardiac  index  at,  1642 
cardiac  output  at,  1641 
changes  in  systolic  pressure  at,   1642 
heartbeat  at,  1641 

pulmonary    vascular    resistance    at, 
1 64 1 
blood 

lipids  and  atherosclerosis,  1187 
supply    to    interventricular    septum, 

1520 
vessels  in  cochlea,  915 
blood  flow 
in  foot,  1340 
in  forearm,  1339 
in  hand,  1338 
bone  blood  flow  in,  1657 
brachial  pulse  in,  831 
capillaries  of  labyrinth,  915 
capillary 


blood  pressure  in,  965 

networks  of  the  cochlea,  916 
cardiac  glycogen  before  birth,  1638 
circulation 

skeletal  muscle,  1363 

through  skin,  1325 
electron  micrograph  of  lung,  1677 
essential  fatty  acids  and,  1 1 83 
extension-release  curves  of  aorta,  877 
filtration  coefficients  for  tissues,  992 
flow  pulses  in,  859-862 
hepatic  blood  flow  in,  1405 
heredity  and  atherosclerosis,  1205 
interstitial  fluid  pressure  in,  980 
lipoproteins  in,  1  177 
medullary  pressure  in,  1660 
mountain  sickness  in,  1721 
nephron  types  in  kidneys,  1458 
osmotic    pressure    of    plasma    proteins 

in.  965 
patterns  of  circulating  lipids,  1203 
placental  histology,  1621 
plasma  components,  974 
pressure-volume  diagram  in  aorta,  875 
protein 

content  of  plasma,  974 

osmotic  pressure  in,  965,  973 
pulmonary 

artery  in,  1674 

blood  flow,  1697 

blood  pressures,  1697 

vascular  resistance,  1697 

vein  in.  1674 
renal  blood  How 

in  infants,  1644 

trauma  and,  1506 
renal  circulation 

adrenergic  control,  1 486 

compared  to  dog,  1501 
renal  clearance  in,  1483 
skeletal  muscle  innervation,  1 364,  1 366, 

>367 
stimulation    of    arterial    baroreceptors 

in,  1363 
studies  on  bulbar  conjunctiva,  894 
sympathetic  vasoconstrictor  nerves  in, 

■359 
tissue  composition  of  veins,  881 
umbilical  arterial  flow  in,   1633 
\  in\  lite  cast  of  heart,  1519 
Mandible 

arterial  supply  to,  1655 
Mannitol 
renal 

artery  pressure  and,  1 1 48 
lymph  flow  and,  1058 
vein  flow  and,  1  148 
Marsupials 

uterus  in,  1585 
Mayerson,  H.  S. 

The  physiologic  importance  of  lymph, 
io35-'°73 


INDEX 


1771 


Mechanical  compression  atelectasis 

angiography,  1717 

experimental,  1 7 1  7 

venous  admixture,  1 7 1 7 
Mechanical  pumps 

classification,  760 
Membrane 

manometers,  definition  of,  1 303 

permeability,  ions  and,  1  137 

potentials,  ions  and,  1 1 38 
Menstruation 

mechanisms  of,  1 598 

role   of  arteriovenous  shunts   in,    1598 

scotomata  and,  1599 
Mephentermine 

cardiac  hemodynamics  and,  1564 
Mercury- 
renal  lymph  flow  and,  1058 
Mesenteric  artery 

pressure-diameter  diagrams  of,  878 
Mesenteric  blood  flow 

adrenergic  response,  95 1 

arteriovenous  anastomoses  and,  1444 

blood  volume,  1445- 1446 

cholinergic  response,  951 

epinephrine  and,  950 

factors    influencing,     1 446-1 452 

function  and,  1452- 1453 

magnitude,  1 439-1 441 

organ  function  and,  1452 

partition,  1 441 -1445 

to  major  organs,  1441 

to  vessels  of  different  sizes,  1 444 
Mesenteric  circulation 

capillary  blood  pressure  in,  965 

factors  affecting,  1451 

function,  preferential  channels  and,  919 

organs  included,  1439 

osmotic  pressure  of  plasma  proteins  in, 

965 

pressure  gradient  in,  964 

pressure-volume  relations,  1085 
Mesentery 

camera-lucida  outline  of  capillaries,  919 

microcirculation  in,  900 

veins,  plastic  cast,  1077 
Metabolites 

exercise,  hyperemia  and,  1378 
Metabolism 

disease  and,  1537 

of  tissues,  venous  return  and,  1 1 25 
Metaraminol 

cardiac  hemodynamics  and,  1564 
Metarteriole 

definition,  892 

description,  919 

vasomotion  in,  925 
Methacholine 

splenic  blood  flow  and,  1451 
Methodology 

acute  pulmonary  engorgement,  1693 

cardiopneumogram,  1694 


compliance,  1693 

mechanics  of  breathing,  1 693 

mercury  injection,  1036 

pulmonary 

arterial  hypertension,  1693 
distensibility,  1693 
venous  hypertension,  1693 

radioactive  tracers,  1694 

teeter  board,  1694 
Methoxamine 

cardiac  hemodynamics  and,  1 564 
Microcirculation 

alternate  routes  in,  895 

arteriovenous  anastomoses,  899 

bat  wing,  895 

bulbar  conjunctiva,  908 

chambers,  893 

cochlea,  915 

definition,  891 

description,  1 263 

hamster  cheek  pouch,  goo 

intestine,  904 

lung,  9 1 3 

mesentery,  900 

myocardium,  903 

preferential  channel,  908 

rabbit  ear,  898 

removable-top  chamber  for,  893 

skeletal  muscle,  900 

skin,  904 

spiral  ligament,  916 

spleen,  910 

stomach,  904 

stria  vascularis,  916 

thoroughfare  channel,  918 
Mitral  insufficiency 

discussion  of,  1557 

experimental  mitral  regurgitation,  1557 

ventricular  function  curves,  1557 
Mitral  stenosis 

cardiac  index,  1557 

cardiac  work  index,  1557 

discussion  of,  1 556 

lymph  flow  and,  1055 

pulmonary 

arterial  pressure,  exercise  and,  1695 
hypertension,  1727 
pressure-volume  diagram,  1693 
Mitral  valve 

closure  interval,  7go 

opening  interval,  79° 

structure,  780 
Moat  chamber 

for  studies  of  microcirculation,  893 
Model 

arterial,  windkessel,  847 

pressure  applied  around  tube,  1708 

tension  muscles  and  elastic  tissue,  874 
Molecular  sieving 

diffusion,  restricted  and,  1005 

rate  of  filtration  and,  1005 


regional  differences,  1013 
theory  of,  1005 
Molecules,  small 

blood-tissue  exchange,  102 1 
Mollusk  smooth  muscle 

catch  mechanism  in,  871 
Monkey 

blood  pressure,  age  and,  1643 
cardiac  glycogen  before  birth,  1638 
carotid  sinus  response  in,  1644 
heart  beat  at  birth,  1641 
Monoamine  oxidase 

in  Raynaud's  syndrome,  1229 
of  digital  arteries,  1229 
Monotremes 

uterus  in,  1585 
Mountain  sickness 

syndrome  of,  1721 
Mouse 

hepatic  blood  flow  in,  1405 
interstitial  fluid  pressure,  980 
Muscle  pump :  see  Pumps 
Muscular  activity :  see  Exercise 
Myocardial  damage 

arterial  pressure  and,  1 1 16 
cardiac  output,  1  1 1  5 
infarction 

after  coronary  ligation,  1550 

cardiac  output  and,  1  1 15 

effectiveness  of  heart  and,  1 104 

right  atrial  pressure  and,  1 1 15 

venous  return  and,  1 1  1 5 
ischemia,  viability  and,  1569 
renal  output  and,  1 1 16 
right  atrial  pressure,  1 1  1 5 
vasoconstriction  and,  1 1 16 
venous  return,  1 1 15 
Myocardium 

aerobic  metabolism,  1538 
anoxia 

discussion  of,  1541 

effects  of,  1 54 1 

ventricular  distensibility,  1541 

ventricular  fibrillation,  1541 
arterioles 

anatomical  structure,  152 1 

discussion  of,  1 52 1 
atrial,  768-769 

architecture  of,  768 

classification,  768 
blood  flow 

distribution  of,  1530 

methods  for  determination    1 530 

venous  circuit,  1531 
capillaries,  functional  activity,    1521 
capillary 

density,  1521 

distribution,  903 

exchange  of  metabolites,  1521 
cardiac  failure  and,  1537 
changes  of,  1536 
chemical  patterns  of,  1536 


1772 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


chordae  tendineae,  function,  764 

coenzymes,  1536 

composition  of,  762 

contractile  force,  CO2  and,  1546 

deep 

bulbospiral  muscle,  arrangement,  767 

drainage  channels,  1 53 1 

sinospiral  muscle,  arrangement,  767 
determinants    of   normal    metabolism, 

1 536- 1 537 
diabetes,  1537 
energy  production,  1536 
enzymes,  1536 
glycogen,  1536 
hormones,  1536 

ischemia  and  normal  function,  1541 
lipids,  1536 

lymphatic  supply,  1054 
mechanical  efficiency  of,  1 538 
metabolism  and,  1536 

disease,  1537 

epinephrine  and,  1541 

norepinephrine  and,  1541 
metarteriole,  actions  of,  1 52 1 
microcirculation  in,  903 
muscle 

arrangement  in  ventricles,  768-769 

fascicles,  1518 
myocardial  respiratory  quotient,  1536 
oxygen  debt,  1538 
oxygen  uptake 

coronary  dilatation,  1567 

during  cardiac  arrest,  1541 

during  fibrillation,  1541 

in  working  heart,  1541 
precapillary  sphincter,  actions  ot,  1521 
protein,  1536 
respiratory  quotient,  1536 
schematic  arrangement  of  muscle  fibers, 

768 
sinusoids  in,  functional  anatomy,  1517 
spiral  muscle  arrangement,  767 
superficial  bulbospiral  muscle,  arrange- 
ment, 767 
superficial  muscle  layers,  765 

ventricular  contraction  and,  765 
trabeculae,  functional  anatomy,  1517 
veins 

density  of,  1522 

distribution  of,  1522 
ventricular,  765-768,  1518 

architecture  of,  765 

arrangement,  768-769 

classification  of  muscles,  766 

evolution  of,  766 

fascicles,  15 18 

in  left  ventricle,   1538 
vessels,  nerve  supply  to,  1 52 1 
vortex  spirals,  1518 
Myocarditis 

effectiveness  of  heart  and,  1 104 


Myoglobin 

capillary  permeability  to,  10 13 
molecular  sieving  of,  1017 
permeability   of  muscle   capillaries   to, 
1013 

Natriuretic  drugs 

hypertension  and,  1 142 
Negative  pressure  breathing 

intrapulmonary,  1 7 1 2 

pleural,  171 1 
Neomycin 

cholesterol  levels  and,  1 187 
Nephrosis 

proteins  of  edema  fluids  in,  982 
Neuromuscular  transmission 

sympathetic 

vasoconstrictors  to  skeletal  muscle, 

■363 
vasodilators  in  skeletal  muscle,  1 366 
Newborn 

respiration,    course    of    blood    streams 
and,  1639 
Nicotine 

catecholamines  and,  1563 
Nitrate 

entrance  rate  into  muscle,  1 138 
Nitrites 

venodilator  responses,  1094 
Nitroglycerin 
action  of,  1 567 

coronary  circulation  and,  1562 
Nitrous  oxide 

saturation  curves,  1291 
Nodulus  arantii 

description,  781 
Nonlaminar  flow 

murmurs  and,  858-859 
Norepinephrine 

arterial  diameter  and,  807 

as  neuromuscular  transmitter,  1 363 

blood  pressure  rise  and,  1 155 

bone  medullary  pressure  and,  1660 

cardiac  oxygen  consumption,  1552 

carotid  sinus  stimulation  by,  874 

coronary 

blood  flow  and,  1552 
vasomotion,  1 552 
cutaneous  blood  flow  and,  1345 
distribution  in  pulmonary  tree,  1680 
effects  of,  1725 
fat  mobilization  and,  1 1 75 
intestinal  blood  flow  and,  1447 
mesenteric  blood  flow  and,  145 1 
plasma 

K  and, 1 1 52 
Na  and,  1 152,  1 153 
potentiation  by  K,  1  146 
pulmonary  vascular  pressure  and  resist- 
ance and,  1725 
regional  blood  volume  and,  1694 
resistance  in  vascular  bed  and,  948 


skeletal  muscles  and,  1355 

circulation  and,  1369 
skin  circulation  and,  1345 
splanchnic  circulation  and,  141 7 
splenic  blood  flow  and,  1  450 
total  systemic  effect,  141 9 
vascular 

effects  of,  969,  970-971 
volume  and,  955 
venous 

constriction  due  to,  1086 
distensibility  and,  iog3 
Normotension 

damping  of  incisura  and,  832 
Nucleotides 

transport  in  lymph,  1049 
Nutrient  exchange 

between  maternal  and  fetal  circulation, 
1609 

Oliguria 

renal  blood  flow  and,  1481 
Open  chest 

cardiac  output  and,  1  1  15 
right  atrial  pressure  and,  1 1 1 5 
venous  return  and,  1 1 1 5 
Orifice  flowmeter 

principle  and  discussion  of,  1298 
use  in  veins,  1 299 
Orthostatic  hypotension 

renal  blood  flow  and,  1502 
Osler-Weber-Rendu  disease 

description,  1256 
Osmometer 

description  of,  973 
Osmotic  equilibrium 

description,  1 136 
Osmotic  flow 

osmotic  pressure  and,  1006 
Osmotic  pressure 

calculated  experimentally  and  on  Don- 
nan  theory,  977 
capillaries,  dextran  and,  994 
concentration  curves  for  plasma  pro- 
teins, 972 
dependence  on  Na,  1 1 36 
due  to  urethan  and  urea,  1018 
factors  determining,  1 136 
osmotic  flow  and,  1006 
physicochemical  aspects  of  protein,  976 
plasma   proteins,   glomerular   filtration 

and,  976 
protein 

anion  binding  and,  977 
concentration  and,  975 
Donnan  effect,  976 
factors  affecting,  973 
fetal,  975 

filtration  rate  and,  989 
in  various  species,  965 
measurement,  972 
of  human  plasma,  973 


INDEX 


'773 


of  interstitial  fluid,  984 
predicted  and  actual,  977 
reduced,  adaptation  due  to,  974 
species  differences,  975 

relation  to  temperature  and  concentra- 
tion, 1 136 

renal  lymph  and,  1057 
Osmotic  reflection  coefficient 

definition,  1006 

factors  influencing,  1007 
Ovarian  arteries 

origin  of,  1587 
Oxygen 

arterial  saturation,  blood  How,  11 25 

availability,  fetal,  1635 

blood-tissue  transport  of,  1019 

cerebral  blood  flow  and,  946 

consumption 

measurement  of,  1540 
muscle,  blood  flow  and,  1377 
oxygen  saturation  and,  1636 
relation  of  fetal  and  placental,  1634 

coronary  blood  flow  and,  945 

debt,  repayment  of,  1540 

exchange,  maternal  and  fetal  blood, 
161 1 

filtration  coefficients  and,  997 

local  utilization 

cardiac  output  and,  1 1 26 
venous  return  and,  1 1 26 

mesenteric,  filtration  coefficients  of,  998 

of  skin  blood,  as  measure  of  blood  flow, 

'327 
pressure,  intracapillary  in  brain,  1020 
pulmonary  capillary  permeability  and, 

1018 
steady-state  radial  diffusion  of,  in  tis- 
sues, 1020 
tension,   tissue,  arterial  occlusion   and, 

126 1 
uptake 

cardiac  output  and,  1682,  1 7 1 4 
values  for,  1720 
Oxytocic  drugs 

postpartum  uterine  blood  flow  and, 
1608 
Oxytocin 

skin  circulation  and,  1346 

Pacinian  corpuscles 

pressure  mediation  and,  141 6 

structure  and  function,  141 5 
Paddle  flowmeter 

discussion  of,  1 307-1 308 
Pain 

origin  of,  1565 

visceral,  neural  mechanism,  1415 
Pain  factor 

description,  1 2  1 8 
Palm 

anastomoses   per  square  centimeter  of 
surface  area,  1327 


Pancreatic  secretion 

blood  flow  and,  1452 
Panniculus  carnosus 

arteriovenous  anastomoses  in,  902 
Pappenhcimer,  J .  R. 

Exchange  of  substances  through  the 
capillary  walls,  961-1034 
Para-amino  hippuric  acid 

renal  extraction  of,  1 480 
Paramyosin 

as  plastic  element,  871 
Parasympathetic  nervous  system 

inhibition,  effectiveness  of  heart  and, 
1 104 

innervation 

of  splanchnic  viscera,  14 15 
of  uterus,  1 602 

intestinal  blood  flow  and,  1448 

lack  of  control  of  venous  tone,  1077 

stimulation,  effectiveness  of  heart  and, 
1 104 

vasodilator  nerves  cholinergic  to  mus- 
cle, 1368 
Pathology 

progressive  valvular  fibrosis,  1054 
Pendulum  flowmeter 

principle  and  discussion  of,  1306 
Perfusion  pressure 

arterial  flow  and,  936 

blood 

flow  and,  954 
volume  and,  954 

conductance  and,  954 

mean  transit  time  and,  954 
Perfusion  pumps 

blood  cell  injury  and,  1370 
Periarteritis  nodosa:  see  Collagen  diseases 
Pericardium 

anatomy  of,  7g2 

atrial  filling  and,  793 

filling  by  heart,  793 

function  of,  791-794 

histology,  792 

plastic  behavior  of,  7g2 

pressure,  cardiac  cycle  and,  793 

pressure-volume  curve,  792 

reserve  power  of  heart  and,  794 
Perimysium 

capillary  bed  of,  902 
Peripheral  circulation 

carbon  dioxide  and,  11 25 

laboratory  procedures  for  examining, 
1224 
Peripheral  vascular  diseases 

circulatory  arrest  and,  1 224-1 225 

classification  of,  1 225-1 226 

clinical  approach,  12 16-1224 

definition,  12 15 

malfunction  in  general,  12 16 

mechanisms  in,  1226-1242 

patient's  history,  1 2 1 7 

symptoms  of  arterial  disease,  12  1  7 


trophic  changes  in,  12 18 

vasoconstrictor,  1226-1 241 

vasodilative,  1241-1242 
Peripheral  venous  system 

anatomical  considerations,  1075-1079 

assessment  of  venomotor  activity,  1 087- 
1094 

hemodynamic  relations,  1081 

physiological  characteristics  of,  1079- 
1087 

venomotor  responses,  1094-1095 
Peritoneal  cavity 

absorption  of  particles  from,  1065 
Personality  profile 

coronary  atherosclerosis  and,  1206 

heart  disease  and,  1  181 
Perthes  test 

description,  1224 
Phase-sensitive  demodulation 

definition,  13 15 
Phenoxybenzamine 

muscle  blood  flow  and,  948 

splenic  blood  flow  and,  1451 
Phenylephrine 

bone  medullary  pressure  and,  1660 

cardiac  hemodynamics  and,  1564 

pressure-volume  relationships  and.  1085 
Phlebothrombosis:  see  Thrombophlebitis 
Physical  activity :  see  Exercise 

Pig 

pulmonary  vessels  in,  1674 
Phillips,  J. 

Peripheral  vascular  diseases — diseases 
other  than  atherosclerosis,  1 2 1 5- 

1249 
Phosphate 

entrance  rate  into  muscle,  1 1 38 
renal  lymph  flow  and,  1058 
Phospholipids 

dietary  sources,  1 1 72 
transport,  total  lipid  transport  and, 
1046 
Pick,  R. 

The  role  of  endocrines,  stress,  and  he- 
redity on  atherosclerosis,  1 197— 
1213 
Pigeon 

transitional  capillaries  in  bone,  1654 
Pilocarpine 

gastric  blood  flow  and,  1447 
Pinocytosis 

definition  of,  1522 
of  chylomicrons,  1044 
Pituitary  hormones 

blood  volume  in  relation  to  fetal,  1626 
bone  medullary  pressure  and,  1660 
circulation,  1592 

arterial  supply,  1597,  161 1 
sheep,  1622 
venous  drainage,  1598 
comparative  anatomy  of,  1 591 -1592 
cotyledons,   vascular  arrangements   in, 
1597.  l6l! 


'774 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


countercurrent  flow  in,  1622 
fat  mobilization  and,  1  174 
fetal,  1 620- 1 623 

capillary  blood  pressure,  1609 

pressure  flow  curves,  1632 
function,  1622 

hemochorial,  deficiency,  1606 
India  ink  injection  of,  1608,  1610 
intervillous  space  pressure,  1609 
maternal  blood  and,  1610 
oxygen  consumption  of,  1622,  1634 
Pitressin 

coronary  circulation  and,  1562 

effects  of,  1553 

effects  upon  Na  and  K,  1553 

gastric  blood  flow  and,  1447 

intestinal  blood  flow  and,  1448 

mesenteric  blood  flow  and,  1451 

plasma  Na  concentration  and,  1 153 

skin  circulation  and,  1346 
pituitrin,  splenic  blood  flow  and,  1450 
pressure,  amniotic  fluid  pressure  and, 

placental  1608 
radiopaque  injections  of,  1 609 
structure,  1592,  1594 

arterial  and  venous  openings  in,  1610 

changes  in  pregnancy,  1593 

exchange  of  substances  and,   1594 

unitary,  1593 
syndesmochorial,  deficiency,  1606 
types,  1 592- 1 594 

histological,  1620 

uterine  work  necessary,  1606 
Placental  blood  flow 
fetal,  1 63 1 -1 635 

resistance  in,  163 1 
maternal,  effects  of  reduction,  1636 
uterine  contractions  and,  1600 
Placental  exchange 
factors  affecting,  1622 
mechanisms  of,  1622 
sodium,  in  various  species,  1592,  1593 
structure  and,  1594 
Plasma 

albumin,  in  relation  to  lymph  albumin, 

1063 
dextran,  in  relation  to  lymph  dextran, 

1063 
exchange,  lymph  and,  1040 
human,  components  of,  974 
potassium,  epinephrine,  anesthesia  and, 

1 152 
proteins 

capillary  pressure  and,  963 

glomerular  filtration  and,  976 

in  man,  974 

osmotic  pressure  of,  962-977 

relation  to  lymph,  1046 
urea,  albumin  content  and,  1064 
Plasma  skimming,  898 
Plasmin 


capillary  permeability  and,  1061 
Plastic  material 

behavior  with  stretch,  866 
Plasticity 

definition,  867 

description  of,  803,  866,  867 

properties  of  blood  vessels,  866 
Platelets 

capillary  permeability  and,  995 
Plethysmograph  pulses 

factors  affecting,  957 
Plethysmography 

modifications  of,  1281 

principle  of,  1281 
Pleural  pressure 

carbon  dioxide  and,  1690 

exercise  and,  1690 

measurement  of,  1 688-1 689 
Podocytes 

molecular  sieving  and,  1017-1018 
Poikilotherms 

protein  osmotic  pressure  in,  975 
Poiseuille's  law 

blood  flow  to  organs,  865 

modified  for  collapsible  tubes,  1080 
Poiseuille's  equation 

origin  of,  963 
Pore  concept 

lymph  formation  and,  1040 

see  also  Capillaries;  Pores 
Portal  vein 

anatomy  and  distribution,  1389 

flow 

arterial  pressure  and,  1440 
in  various  species,  1440 

through  blood  flow,  1439 
Positive  pressure  breathing 

cardiac  output  and,  171 1 

circulatory  collapse  and,  171  1 

intermittent  positive  pressure  breathing, 
171 1 

intrathoracic  pressure,  171 1 

pulmonary  blood  flow  and,  17 10 

pulmonary     vascular    resistance     and, 
1 7 10-17 1 1 

systemic  hypotensive  states,  1  7 1  1 
Posture 

cutaneous  blood  flow  and,  1340 

renal  blood  flow  and,  1502 

skin  circulation  and,  1344 

see  also  Body  position 
Potassium 

arteriolar  size  and,  948 

blood  pressure  and,  1 155 

entrance  rate  into  muscle,  1 138 

exercise  hyperemia  and,  1380 

extracellular,  blood  pressure  and,  11 54 

hypertension  and,  1142-1143 

in  various  tissues,  1 141 

ionic  radii,  1 137 

mobility  in  electric  field,  1 138 

peripheral  vascular  resistance  and,  1 149 


potentiation  of  norepinephrine,  1 1 46 
radioactive 

blood  to  tissue  permeability,  1023 

capillary  permeability  to,  1023 

flow  distribution  pattern  and,  1402 

relative  diameter,  1 1 38 

spontaneous  muscle  activity  and,  1 156 

vascular   smooth   muscle   tension    and, 

1142-1157 
vasoconstrictor  effect,  1 149 
vasodilation  and,  1380 
Potassium  hydroxide 

mean  activity  coefficients,  1 137 
Potassium  transport 
efHux 

epinephrine  and,  11 56 
membrane  potentials,  1156 
smooth  muscle  tension  and,  1 156 
Precapillary  sphincter 
definition,  892 
function,  900 
Pregnancy 

arterial  supply  to  placenta  and,  1597 
circulating  lipids  in,  1203 
ovarian  vein  and,  1587 
placental  structure  and,  1593 
uterine 

arterial  injection  during,  1604 
blood  flow  and,  1 593-1 594,  1603, 

1609 
blood  flow  and  volume  during,  1604 
circulation  and,  1602 
vasculature  and,  1594,  1603 
venous  drainage  and,  1588,  1598 
venous  pressure,  body  position  and, 
1601 
Pressoreceptors 
anatomy  of,  874 
blood  pressure  and,  875 
relation  to  surrounding  tissue,  874 
structure  and  location,  874 
Pressure-volume  curves 

aorta  compared  to  muscular  arteries, 

879 
arteries 

elastic,  879 
muscular,  879 
contractile  state  of  smooth  muscle  and, 

873 
drugs  and,  1085 
in  mesenteric  artery,  878 
in  vivo,  in  hand,  878 
pulmonary 
normal,  1693 
mitral  stenosis  and,  1693 
veins,  882 
Primates 

uterus  in,  1585 
Priscoline :  sec  Tolazoline 
Procaine 

intestinal  blood  flow  and,  1448-1449 


INDEX 


1775 


Progressive  systemic  sclerosis:  see  Sclero- 
derma 
Pro-PF/IPF  system 

definition,  1061 
Prostigmin 

uterine  bleeding  and,  1599 
Protein 

absorption 

and  metabolism  of,  1  1  7 1 
from  interstitial  fluid,  983 
circulation  of,  986 
circulation  in  lymph,  982,  987 
concentration,  osmotic  pressure  and, 

975 
estimates  of  molecular  weight,  973 
exchangeable  mass  of  interstitial  fluid, 

984 
hepatic  blood  flow  and,  1429 
in  extracapillary  fluids,  982 
in  interstitial  fluid,  984 
in  lymph,  985 

leakage,  infusions  and,  1043 -1044 
osmotic  pressure,  capillary  blood  pres- 
sure and,  991 
passage  through  capillary  wall,  986 
rate  of 

lymph  circulation,  987 

movement  from  blood,    1 044-1 045 
Proteinuria 

postural,  lymph  flow  and,  1057 
Psychic  stimulation 

venoconstrictor  responses,  1094 
Pulmonary  arterial  pressure 
acute 

left  heart  failure  and,  1 120 

right  heart  failure  and,  1 121 
age  and,  1686 
altitude  and,  1720 
blood  flow  and,  1696 
exercise  and,  1695 
flow-pressure  relationships 

in  exercise  and,  1701 

transmural  pressures,  1701 
hydrostatic  reference  level,  1685 
hypertension,  1727 
hypoxia  and,  1053,  1 71 8,  1725 
in  disease,  17 10 
in  man,  1697 
in  neonatal  period,  1641 
lactic  acid  and,  1722 
luminal  pressure,  1688 
primary  pulmonary  hypertension  and, 

1724 
mean  values,  1686 
norepinephrine,  1725 
recording,  1685 
transmural  pressures,  1688 
values  for  low  oxygen  saturation,  1 7 1 8 
Valsalva  maneuver  and,  1 7 12 
vascular  resistance  and,  1699 
Pulmonary  artery 

acetylcholine  and,  1 700 


creep  in,  805 

occlusion,  pressure  changes,  1689 
pressure  pulse  compared  to  aorta,  1686 
stretch  curve  of,  805 
wall,  inertance  and  resistance  in,  843 
Pulmonary  bed 

capillary  pulsatile  flow  in,  856 
Pulmonary  blood  flow 
acetylcholine  and,  1 726 
acute  acidosis  and,  1722 
acute  hypercapnia,  17 18,  1721 
alveolar-capillary 

gas  exchange,  167 1 

interface,  1676 
alveolar  gas  analysis,  1683 
analytical  determinations,  1670 
anesthetics  and,  1673 
appearance  time,  1 708 
arterial  pressure  and,  1696 
arteriovenous 

oxygen  difference,  1714,  1 7 1 5 

pressure  gradient,  1687 

shunts,  indicator  dilution  curves  in, 

1729 
as  a  filter,  1668 
as  a  reservoir,  1668 
blood  vessels,  1674 
bradycardia  and,  17 16 
capillary 

blood  volume,  1705 

Fick  method,  1703 

flow  rate,  1702,  1703,  1706 

gas  exchange  in,  1706 

pneumocardiographic  recording, 
1704 

plethysmography  recording,  1704 

pressure,  1702 

Stewart-Hamilton  methods,  1703 
changes  at  birth,  1641 
chronic  hypoxia  and,  1720 
circulation  time,  1708 
comparative  physiology  of,  167 1 
critical  closing  pressure,  1701 
critical  opening  pressures,  1701 
distribution  pattern  in  lung,  1 681  -1682 
drugs  and,  1724,  1725 
during  expiration,  1709 
during  inspiration,  1709 
epinephrine  and,  1725 
excitement  and,  1681 
exercise  and,  i6gg,  1 714 
experimental  studies,  1673 
Fick  principle,  17 14 
flow-pressure  curves,  1 700 
forced  expiration  and,  1 7 1 3 
functional  anatomy,  1673 
gravity  effects,  1683 
heart  rate  and,  1716 
high  altitude  and,  1720 
high  Oj  content,  1721 
hypertension  and,  1  727 
in  individual  lungs,  1701 


in  man,  1697 

in  spontaneous  breathing,  1709 

inspired  air  distribution,  1683 

intrapulmonary 

baroreceptors,  1683 

inflation,  1710 
in  vessels,  excluding  organs,  1293 
intrathoracic  pressure,  1709 
hypoxia  and,  1699,  1718,  1720 
kinetic  energy,  1702 
left  ventricle  and,  1 293 
luminal  pressure  in,  1709,  1710 
lung  inflation  and,  17 10 
measurement  of,  1714 
negative  (pleural)  pressure  inflation 

and,  1 7 1  o 
non-Newtonian  fluid,  1697 
normal  values,  1681 
oxygen  uptake,  17 14 
plethysmography,  1704 
positive  pressure  inflation,  17 10 
potential  energy,  1702 
pressure-volume  characteristics,  1696 
prolonged  expiration  and,   17 12 
pulmonary 

artery  occlusion,  1  7 1 3 

efficiency,  1683 
pulse-wave  velocity,  1 707 
reflex  activity  and,  1723 
respiration,  1 709 
respiratory 

acidosis,  1722 

gases,  1 718 

gas  exchange,  17 14 
right  ventricular  ejection  pulse  and,  855 
species  difference,  1673 
Stewart-Hamilton  method,  1703,  1714 
thoracic  aorta,  1293 
"tight"  mitral  stenosis,  1716 
transmural  pressure,  1699,  1701,   1709, 

1710 
types  of  reflexes,  1723 
values  for,  1681-1685,  1714 
valves  of,  1 70 1 
valvular  insufficiency,  1 73 1 
vascular  pressures,  17 15 
vascular  resistance,  1697,  17 16 
venous  admixture,  1 680 
wedge  pressures,  1687 
Pulmonary  blood  vessels 
arteries 

as  end  arteries,  1675 

distribution,  1675 

pulse  control,  1686 

pulse -wave  velocity,  1697 
arteriovenous  fistula,  1730 
capacity,  1696 
capillaries 

distensibility  of,  1705 

resistance  in,  1705 

smooth  muscle,  1675 

structure  of,  1675 


776 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


circulation  in,  1675 
capillary  bed 

maximum  diffusing  capacity,  1705 
measurement  of,  1705 
size  of,  1 705 

transmural  pressure,    1  705 
delayed  compliance,  1696 
distensibility,  1696 
hysteresis,  1696 

pulmonary  "resistance"  vessels,  1696 
stress  relaxation,  1696 
veins,  1675 

structure  of,  1675 
venules,  structure  of,  1675 
Pulmonary  blood  volume 
changes  in,  1693 
estimation 

Bradley  equilibration  curves,  1693 
Newman  exponential  downslope 
equation,  1692 
in  exercise,  171 5 
lung  volumes,  1693 
measurement  of,  1691,  1692 
methodology,  1693 
normal  values,  1694 
partition  of,  1695 
pulmonary  arterial  pressure  and,  1715- 

1716 
Stewart-Hamilton  method,  1691 
variations  in,  1695 
Pulmonary  circulation 

acetylcholine  and,  1700,  1726 
arterial    occlusion,    171 3-1 714 

ipsilateral  oxygen  uptake  and,  1  7 1 3 
blood  volume,  1690- 1695 
capillary- 
circulation,  1 702-1 707 
hematocrit,  effect  on  gas  exchange, 

1707 
hematocrit,  values  for,  1 707 
perfusion,    alveolar   ventilation    and, 

1682 
pressure,  1052 

pressure,  wedge  pressure  and,  1688 
cardiopulmonary  disorders,    172  7- 1731 
collaterals,  1265-1266,  1268,   1679 

development  of,  1267 
comparative  physiology,  1671-1673 
drugs  and,  I  724-1  727 
dynamics  of,  1667-1731 
exercise  and,  1714-1716 
functional  anatomy,  1673-1 681 
growth  of  ideas  about,  1669—167 1 
hemodynamic 

interrelations,  1695- 1702 
phenomena,  1 707-1 709 
interplay  with  respiration,  1672 
large  vessels 

anatomical  structure,  1674 
subdivision  of,  1674 
measurement  of  collaterals  in,  1271 
mechanical  influences  on,  1716-1717 


oxygen  tensions  representative  in,  17 19 
pressure-volume  relationship,  1696 
respiration  and,  1 709-1 713 
serotonin  and,  1725- 1726 
test  preparations  for,  1673 
vascular 

bed,  blood  pressure  and,  1705 

distensibility,  1696 

pressure  gradient,  1687 
vasoconstriction 

in  acute  hypoxia,  1 7 1 9 

site  of,  1 7 1 9 
vasoconstrictors  and,  1701,  1726 
vasodilators  and,  1726 
vasomotion,  1699,  171 7-1 724 

passive  mechanism,  1698 

pulmonary  vasomotricity,  1698 
vasomotor 

activity,  1  7 1  7 

control,  1680 

nerves,  anatomical  arrangement, 
1680 

reflexes,  autonomic  nerve  supply, 

1723 

waves,  pulmonary  arterial  pressure 

and,  1723 
waves,  pulmonary  arterial  rhythm, 

1724 
waves,  Traube-Hering-Mayer  waves, 

■723 

venous  pressure 

left  atrial  events  and,  1686 
measurement  of,  1686 
values  for,  1686 

venous  return,   left  ventricular  output 
and,  1 1 18-1 1  ig 
Pulmonary  edema 

anoxia  and,  1053 

atrial  pressures  and,  1052 

capillary  "pore  stretching"  and,  1053 

causes  of,  1 730 

experimental,  1729 

filtration  pressure  and,  1053 

lymph  flow  and,  1054 

"neurogenic",  1730 

pathogenesis  of,  1054 

Starling's  law,  1730 

Welch's  hypothesis,  1  730 
Pulmonary  emphysema 

cor  pulmonale  and,  1728 

prolonged     forced     expiration,     blood 
pressure  and,  1 7 1 2 

pulmonary   artery   pressure   and,    17 10 

right  atrial  pressure  and,  1  710 

right  heart  failure,  1 728 
Pulmonary  hypertension 

arterial  pressure  and,  1724 

bullous  emphysema,  1727 

causes  of,  1727 

elevated  ventricular  pressure  and,  1 555 

granuloma,  1727 

interstitial  fibrosis,  1727 


left  heart  failure,  1  727 

lymph  flow  and,  1052 

mitral  stenosis,  1727 

mitral  valvular  disease,  1727 

primary  pulmonary  hypertension,  1727 

pulmonary 

arterial  vasoconstriction,  1728 

arteritis,  1727 

blood  flow  and,  1727 

capillary  filtration  pressure,  1728 

emboli,  1727 

venous  hypertension,  1727 

venous  pressure  and,  1727 
restricted  vascular  bed,  1727 
Pulmonary  hypotension 

alveolar  dead  space  and,  1730 
causes  of,  1 730 
Pulmonary  vascular  resistance 
anomalous  viscosity,  1698 
blood  flow  and,  1699 
calculation  of,  1 698 
exercise  and,  1699 
factors  involved,  1698 
hypoxia  and,  1725 
in  human  infant  at  birth,  1641 
initial  breath  and,  1640 
in  man,  1697 
norepinephrine,  1725 
pulmonary  arterial  pressures  and,  1699 
see  also  Vascular  resistance 
Pulmonic  valve 

closure  interval,  790 
compared  to  aortic  valve,  855-856 
differential  pressure  across,  855-856 
experimental  stenosis,  1 730 
incompetence,   blood   pressures   and, 

1729 
opening  interval,  790 
Pulse  energy  absorption 

instances  of,  852 
Pulse  plethysmography 

discussion  of,  1 283 
Pulse  technique 

discussion  of,  1 3 1 9 
Pulse  wave 

aortic  and  pulmonary  compared,   1686 
arterial,  distribution  of,  849 
brachial 

aortic  regurgitation  and,  831 

in  chronic  hypertension,  832 

varying  levels,  831 
central 

contour,  821 

stroke  volume  and,  833 
contour 

central  and  peripheral,  825 

characteristics,  830 

diastolic,  832 

incisural  vibration,  832 

modification,  824 

pressure  and,  832 

slope  of  pressure  rise,  830 


INDEX 


'777 


systolic  peak,  832 

systolic  profile,  825 
derivation  of  Bramwell  and  Hill  equa- 
tion, 816 
factors  affecting,  819 
Fourier  analysis  of,  817 
normal  and  pathological,  859 
origin  of,  815 

phase  lag  with  fluid  displacement,  817 
propagation 

hypothermia  and,  827 

resonance,  826 

standing  waves,  826 
secondary  causes,  839 
systolic  length  and,  817 
velocity 

diastolic  pressure  relation  and,  817 

heart  rate  and,  818 

of  various  parts,  819 

stiffness  modulus  and,  819 
wall  distensibility  and,  815 
Pumps 

characteristics,  to  duplicate  ventricular 

contraction,  800 
kinetic,  760 

positive  displacement,  760 
reciprocating,  definition,  760 
rotary,  760 

volume,  left  ventricle  as,  844 
Purine  derivatives 

inotropic  effects  of,  1 545 
Purkinje  cells 

function,  763 
Pyelonephritis 

renal  lymphatic  pressure  and,  1058 
Pyrimidine  derivatives 
inotropic  effects  of,  1545 

Q  wave 

interval,  790 

Rabbit 

blood  pressure,  age  and,  1643 
cardiac  glycogen  before  birth,  1638 
ear 

arteriovenous  communications,   1 255 

microcirculation  in,  898 

plexus  of  regenerated  vessels  in,  921 
hepatic  blood  flow  in,  1405 
pulmonary  vessels  in,  1674 
renal  clearance  in,  1483 
uterine    vasculature,    pregnancy    and, 

'597 
Race 

peripheral  vascular  disease  and,   12 17 
Radial  flow 

equation  for,  842 
Raffinose 

diffusion  of,  1002,  1009,  1010 

filtration  rate,  1006 

permeability   of  muscle   capillaries   to, 
1013 


Rapela,  C.  E. 

Resistance   (conductance)   and  capaci- 
tance phenomena  in  terminal  vas- 
cular beds,  935-960 
Rat 

capillary  blood  pressure  in,  965 
hepatic  blood  flow  in,  1405 
mesoappendix 

circulation  of,  920 
for  studies  of  microcirculation,  894 
osmotic  pressure  of  plasma  proteins  in, 

965 

protein  osmotic  pressure  in,  965 

pulmonary  vessels  in,  1674 

renal  clearance  in,  1483 
Raynaud's  syndrome 

basic  defect,  1227,  1229 

blood  catecholamines  in,  1229 

capillarioscope  studies  in,  1228 

capillary 

changes  in,  1228 
pressure  and,  968 

changes  in  hands,  1227 

clinical  characteristics,  1226 

diagnosis  of,  1226 

differential  diagnosis,  1231 

digital  blood  pressure  and,  1229 

evidence  for  local  defect,  1228 

localization  of  lesions,  1226 

mechanisms  in,  1227 

monoamine  oxidase  in  digital  arteries, 
1229 

secondary  characteristics,  1 230 

sensitivity  to  cold  in,  1228 

symptoms,  1226,  1227 

sympathectomy  in,  1228 
Reactance  flow  patterns 

definition,  853 
Rein's  thermostromuhr 

principle  and  discussion  of,  1283 
Remington,  J.  W. 

The  physiology  of  the  aorta  and  major 
arteries,  799-838 
Renal  artery 

arterial  flow  pulse  in,  849 

circumference,  846 

mean  peak 
flow,  846 
velocity,  846 
Renal  blood  flow 

abdominal  aortic  pressure  and,  852 

acidosis  and,  1504 

adrenergic 
control,  1485 
response,  951 

anesthetic  agents  and,  1488 

apresoline  and,  1488 

autonomy  of,  1 484 

calculated  from  clearance  data,  1 480 

cholinergic  response,  951 

CNS  control  of,  1 485 

computation  of,  854 


critique  of  clearance  method,  1481 
dominant  hydraulic  elements,  852 
epinephrine  and,  950 
exercise  and,  1501 

in  cardiac  patients,  [502 
extrinsic  regulation  1483-1489 
factors  affecting,  1482 
ganglionic  blocking  agents,  i486 
heat  turnover  and,  1476 
hemorrhagic  hypotension  and,  1505 
hypercapnia  and,  1504 
hypoxia,  ischemia  and,  1503 
in  vessels,  excluding  organs,  1293 
in  young  animals,  1644 
measurement  of,  1479- 1483 
neurogenic  control,  1 483 
nitrous  oxide  method,  1 480 
orthostatic  hypotension  and,  1502 
posture,  1502 

renal  clearance  principle  and,  1479 
response  in  physiological  stress,   1501- 

'5°7 
shock  and,  1505 
sympathomimetic  drugs,  1  486 
tourniquet  and,  1506 
traumatic 

injuries  in  man  and,  1506 

shock  and,  1506 

vascular  compensation  in  man,  tilting 

and,  1503 

Renal  circulation 

anatomy,  1 489-1 497 

arterial  system,  1458 

dog,  1459 
arteries,  volume  of  muscle  in  wall,  1465 
arteriovenous  anastomoses,  1460 
autoregulation,  947 

cell  separation  hypothesis,  1491 

decapsulation,  1494 

factors  impairing,  1 496 

in  vascular  beds,  944 

intrarenal  reflexes,  1490 

mechanism  of,  1490 

metabolic  theory,  1490 

myogenic  theory,  1494,  1496 

perfusion  pressure  and,    1494,    1495, 
1496 

tissue  pressure  theory,  1492,  1493 

viscosity  theory,  1491 
capillary  pressures  in,  965 
cell  separation  hypothesis,  1492 
cortical,  1460 

critical  closing  pressure,  1 476 
distribution  of  cells  and  plasma,  1473 
distribution  of  osmotic  constituents, 

1 469-1 470,  1472 
functional  architecture,  1458- 1466 
glomerular,  1461 
intrarenal  hematocrit,  1470 
juxtamedullary  zone,  1464 
medullary 

and  cortical  transit  time,  1500 


1778 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


and  papillary  blood  supply,  1460 
in  antidiuresis,  1499 
in  diuresis,  1499 

perfusion  pressure  and  regional  transit 
time,  1500 

pressure  gradients,  1475-1479 

regional  resistance  changes,  1 49*3 

sinusoidal  cushions,  1461 

stenoses,  definition,  1461 

to  medullary  zones,  1464 

Trueta  juxtamedullary  shunt,   1497- 
1501 

vasa  recta  system,  1 465 

venous 

sinuses,  1459 
system,  1459 
valves,  1460 

veno-venous  anastomoses,  1459 
Renal  clearance 

factor  affecting  extraction  ratio,  1 482 

in  mammals,  1483 
Renal  disease 

pyelolymphatic  backflow  in,  1058 
Renal  lymph 

capsular,  components,  1 056 

colloid  osmotic  pressure  and,  1057 

composition,  1055,  1466 
compared  to  plasma,  1056 
venous  pressure  and,  1057 

flow  rate,  1055 

glucose  concentration,  1 055-1 056 

protein  concentration,  1056 

production,  1466 

renal  injury  and,  1058 

sodium  concentration,  1056 

source  of,  1055 

urea  concentration,  1 055-1 056 
Renin 

juxtaglomerular  complex  and,  1464 
Reserpine 

splanchnic  circulation  and,  141 7 
Reservoir,  arterial 

reconstruction  of  extensibility  response 
in,  816 
Resistance 

theoretical  discussion  of,  841 

see  also  Vascular  resistance 
Resistance  flow  patterns 

definition,  853 
Resonance 

explanation,  826 

model  for,  826 
Resonant  wave 

definition,  847 

function  of,  852 
Respiration 

central  venous  pressure  and,  1 124 

deep  inspiration,  venoconstrictor 
responses,  1094 

fetal,  circulation  changes,  1640 

forced  expiration,  17 13 

in  newborn,  course  of  blood  and,  1639 


inspiration,  hepatic  circulation  and, 

1426 
pulmonary  circulation  and,  1672 
right  ventricular  stroke  volume,  785 
vena  cava!  flow  and,  857 
ventricular  stroke  volume  and,  784 
see   also    Negative    pressure    breathing; 
Positive  pressure  breathing 

Respiratory  acidosis 
effects  of,  1545-1546 

Respiratory  gases 

capillary  permeability  and,   1018 

Rest 

aortic  flow  curve  at,  773 
coronary  blood  flow  and,  1554 
oxygen  uptake,  cardiac  output  and, 

1682 
pulmonary  vessel  oxygen  tension  and, 

■7>9 
Reticuloendothelial  cells 

blood  flow,  phagocytic  action  and,  1401 
Retina 

capillary  pressure  in,  966 
Reynolds  number 

critical  value  and  inlet  length,  1296 
Reynolds,  S.  R.  M. 

Maternal  blood  flow  in  the  uterus  and 
placenta,  1 585-1618 
Rheoplethysmography 

of  digital  flow,  1220-1222 
Rheumatic  fever:  see  Collagen  diseases 
Rheumatoid    arthritis:   see   Collagen   dis- 
eases 
Rodents 

uterus  in,  1585 
Root,  VV.  S. 

The  flow  of  blood  through  bones  and 
joints,  1651-1665 
Rose  bengal 

removal  from  blood,  1397 

transfer  from  blood  to  bile,  1 397 

value  in  clearance  studies,  1 400 
Rouget  cell 

capillary  contractility  and,  923 

function,  923 

smooth  muscle  cells  and,  924 
Rubella  virus 

cardiovascular  abnormalities  and,  1624 
Rubidium 

entrance  rate  into  muscle,  1 138 

ion  diameters,  1 1 38 

ionic  radii  of,  1  137 

mobility  in  electric  field,  1 1  38 

relative  diameter,  1 1 38 
Rutin 

vascular  effects  of,  972 

Sartorius  muscle 

weight,  Na  and,  1  136 
Scleroderma 

blood  vessels  and,  1239 

characterization,  1238 


organs  involved,  1239 

picture  of,  1  238 

Raynaud's  phenomena  and,  1239 

skin  pathology  in,  1238 

vascular  signs,  1 239 

see  also  Collagen  diseases 
Scotomata 

menstrual  cycle  and,  1599 
Secretin 

pancreatic  blood  flow  and,  1450 
Semilunar  valve 

closure 

backflow  wave  and,  in  congenital  ste- 
nosis, 859-860 
interval,  790 

opening  interval,  790 

passive  movements  of,  779 
Sensory  afferent  fibers 

distribution,  1526 

origin,  1 525-1 526 
Septal  defects 

aortic  blood  flow,  857 

pulmonary  blood  flow  and,  857 

ventricular  ejection  pulses  and,  857 
Seroche:  see  Mountain  sickness 
Serotonin 

arterial  and  venous 
effects,  1094 
pressures  and,  1088 

capillary  permeability  and,  1061 

effects  of,  1726 

gastric  blood  flow  and,  1447 

hepatic  circulation  and,  1423 

intestinal  blood  flow  and,  1448 

mesenteric  blood  flow  and,  1451 

possible  role  in  arterial  spasm,  1237 

renal  hemodynamics  and,  1488 

skeletal  muscles  and,  1355 

skin  circulation  and,  1345 

vascular  changes  due  to,  969 

vessels  affected  by,  951 

venoconstrictor  responses,  1094 
Serum 

permeability  of  mammalian  muscle 
capillaries  to,  1013 
Serum  albumin 

disappearance  from  plasma,  1008 
Serum  cholesterol 

aging  and,  1 198 

atherosclerosis  and,  1 1 97 

diet  and,  1 182 

dietary  cholesterol  and,  1 184 

lowering 

by  dietary  means,  1 1 85 
mechanism,  1 185 

neomycin  and,  1 187 

thyroxin  and,  1186-1187 
Serum  lipids 

atherosclerosis  and,  11 75-1 180,  1 187 

chain  length  of  dietary  fat  and,  1 183 

classification,  1 1 75 

description,  1 1 75 


INDEX 


'779 


dietary 

fatty  acids  and,  1 182 
manipulation  and,  1 186 

diseases  affecting,  1 180 

factors  influencing,  1 180-1 187 

melting  point  of  dietary  fat  and,  1 1 83 

"normal"  level,   1181 

origins  of,  1 179 

sex  and,  1 181 

stress  and,  1 181 

unsaturation  of  dietary  fat  and,  1  183 
Serum  lipoproteins 

atherosclerosis  and,  1046 
Sex 

peripheral  vascular  disease  and,  1 2 1 7 

serum  lipids  and,  1  1 8 1 
Sex  hormones 

atherosclerosis  and,  1 203 

cholesterol  metabolism  and,  1 203 

lipid  metabolism  and,  1203 
Sheep 

blood  pressure,  age,  and,  1643 

blood  vessels  of  placenta,  1622 

cardiac  glycogen  before  birth,  1638 

hepatic  blood  flow  in,  1405 
Shock 

aldosterone  and,  1 1  16 

cardiac  output  and,  1  1  14 

hemorrhagic 

coronary   flow,   blood   pressure   and, 

'535 

discussion  of,  1558 

myocardial  depression  and,  1559 

oligemic  shock,  1558 

02  uptake,  1558 
irreversible 

cardiac  output  and,  1 1 14 

right  atrial  pressure  and,  1 1 14 

venous  return  and,  1114 
lymphatic  system  in,  1058 
renal  blood  flow  and,  1505 
right  atrial  pressure  and,  1 1 14 
tourniquet 

renal  blood  flow  and,  1506 

"toxic  factor"  in,  1060 
venous  return  and,  1 1 14 
Skeletal  muscle 

autoregulation,  tissue,  945-946 
contraction 

blood  flow  and,  1354 

intermittent  claudication  and,  12 17 
interstitial  fluid  pressure,  980 
man 

fluid  pressure  in,  980 

sympathetic  vasoconstrictor  tone  in, 

sympathetic  vasodilator  fibers,  1366- 
1367 
metabolism,  exercise  and,  1377 
percentage  composition  by  volume, 
1327 


percentage  of  parts  of  human  limbs, 

1327 
relative  entrance  rates  of  electrolytes, 

1138 
spontaneous  activity,  K  and,  1 156 
tetanic  contraction,  blood  flow  and, 

'354 
Skeletal  muscle  blood  flow 
adrenaline  and,  1359 
adrenergic  response,  951 
after  arterial  occlusion,  944 
after  sympathectomy, 

effect  of  exercise,   1 369 
anoxia  and,  1376 
arterial  pressure  and,  1357 
cholinergic  response,  951 
cholinergic  vasodilator  nerves  and,  1368 
contraction  and,  1 354 
epinephrine  and,  948,  950,   1370,   1372 
exercise  and,  1354,  1355 
hypothalamic  stimulation  and,    1359 
in  fainting,  1367 
in  dog,  1 36 1 

local  temperature  and,  1358 
oxygen  consumption  and,  1377 
perfusion  pressure  and,  943 
phenoxybenzamine  and,  948 
posterior  root  fibers  and,  1368 
preparation  for  study  of  baroreceptors, 

■3°3 
radioiodine  clearance  in,  1359 
receptors  for  control,  949 
sympathetic  stimulation  and,  948 
sympathetic  vasoconstrictor  nerves  and, 
1362 
Skeletal  muscle  circulation 

arteriovenous  anastomoses  in,  902 
autoregulation  in,  944 
basal  tone,  1 355-1 358 

of  vessels  in,  1355 
capillaries 

fine  structure  in,  101  1 

structure  of,  1009-101 3 
capillary 

counts,  1019,  1358 

distribution  in,  902 
exercise,  adrenaline  and,  1374 
function,  1 358-1 359 
hyperemia 

exercise,  1 376-1 380 

reactive,  1374-1376 
hypothalamic  stimulation,  1367 
microcirculation  in,  900 
nervous  control,  1359-1369 
oxygen  consumption  and  work,  1378 
passage  of  red  cells  in  capillary   from, 

9°3 
pattern  of  vessel  arrangement,  901 
preparation  for  study,  1360 
pressure-flow  relations,  automaticity 

and,  1357 
reactive  hyperemia  in,  944,  1374 


resistance  changes,  exercise  and,  1379 

resistance  of  vascular   bed,   vasoactive 
agents  and,  948 

scheme  for,  1359 

structure,  1358- 1359 

sympathetic 

impulses  to,  exercise  and,  1369 
vasoconstrictor  nerves  and,  1 359- 

■365.  '366 
vasodilator  nerves  and,  1366 
sympathomimetic  substances  and, 

'369-'374 
temperature -regulating  center  and, 

1368 
vasoconstrictors  and,  1355,  1359 
venous  oxygen  saturation  after  exercise, 

'377 
vessel  stretch  and,  1357 
weight,  Na  and,  1 136 
Skeletal  muscle  vessels 
A-V  shunts  and,  1358 
blood  volume  and,  1360 
capillary  filtration  in,  1360 
critical  closing  pressure  and,  1357 
resistance  of,  1 360 
stimulation  of  arterial  baroreceptors, 

1363 
structure  and  function,  1358 
sympathetic 

vasoconstrictors  and,  1360 

vasodilator  nerves  and,  1 366 
sympathomimetic  substances  and,  1369 
to  fibers  and  to  connective  tissue,  1 359 
Skin 

blood  vessels  of,  1 326 
color,  1328 

blood  flow  and,  1328 

temperature  and,  1220 
dermis,  capillary  bed  of,  904 
fluid  pressure  in,  980 
innervation  of,  1 338 
interstitial  fluid  pressure,  980 
mechanism  of  vasodilatation  in  ani- 
mals, 1340 
microcirculation  in,  903 
pathology  in  scleroderma,  1238 
percentage  composition  by  volume, 

1327 
percentage  of  parts  of  human  limbs, 

1327 
reactive  hyperemia  and,  1329 
resistance  in  interstitial,  979 
temperature  of,  1 328 

blood  flow  and,  1328 

color  and,  1220 

local  temperature  and,  1332 
vasoconstrictor  sympathetic  nerves  in, 

■337 
venous  oxygen  saturation  in,  1336 
see  also  Cutaneous 
Sleep 

venodilator  responses,  1094 


1780 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


Smooth  muscle 

characteristics,  870 
conduction  in,  870 
degeneration,  aging  and,  872 
hyporesponsiveness   to  drugs,   Na  gra- 
dient and,  1 145 
mechanical  properties,  872 
pressure-volume  diagrams  for,  873 
response  to  stretch,  870 
spontaneous  activity,  880 
tension 

K  and,  1 145 

K  efflux  and,  1 156 

membrane  potential  and,  1 155 

Na  and,  1 144 

Na  gradient  and,  1 145 

spike  activity  and,  1  157 

tonus  and,  1 156 
see  also  Vascular  smooth  muscle 
Sodium 

blood  pressure  and,  1 155 

deficiency,  signs,  1 1 43 

distribution  in  kidney,  1469 

entrance  rate  into  muscle,  1 1 38 

extracellular,  blood  pressure  and,  11 54 

in  bladder,  1 141 

in  stomach,  1 141 

intake,  juxtaglomerular  granules   and, 

1464 
in  uterus,  1 141 
in  vascular  tissue,  1 141 
ion  diameters,  1 1 38 
ionic  radii,  1 137 
mobility  in  electric  field,  1 138 
muscle  weight  and,  1 136 
radioactive,    clearance    as    measure    of 

blood  flow,  1328 
relative  diameter,  1 138 
relation  to  hypertension,  1142 
serum  level,  vascular  muscle  tension, 

"47 
smooth  muscle  tension  and,  11 44,  1145 
space,  in  organs  and  tissues,  1  141 
vascular  smooth  muscle  tension  and, 
[142-1157 
Sodium  chloride 
diffusion  of,  1010 
diffusion  rates,  1012 
permeability  of  muscle  capillaries  to, 

1013 
renal 

artery  pressure  and,  11 48 
lymph  flow  and,  1058 
vein  flow  and,  1 1 48 
Sodium  cyanide 

coronary  blood  flow  and,  945 
Sodium  hydroxide 

mean  activity  coefficients,  1 1 37 
Sodium  nitrite 

gastric  blood  flow,  1447 
Sodium  transport 

blood  vessel  walls  in,  884 


influx 

in  blood  vessel  wall,  884 
in  frog  skin,  884 

placental,  in  various  species,  1592-1593 
Spannmuskeln :  see  Vascular  smooth 

muscle 
Species  differences 

atherosclerosis  sex  hormones  and,   1204 

cholesterol  feeding  and,  1 205 

vascular  caliber  and  medial  thickness, 
1674 
Spencer,  M.  P. 

Pulsatile  blood  flow  in  the  vascular  sys- 
tem, 839-864 
Splanchnic  blood  volume 

determination,  1406 

factors  affecting,  1406 

measurements  of,  1402,  1403 

splenectomy  and,  1403 
Splanchnic  circulation 

acetylcholine  and,  141 9 

blood  transit  time,  1402 

diagram,  1406 

hepatic  interrelationships,  1428 

inflow,  arteriolar  resistance  and,  1407 

man  and  dog,  1405 

neurohumoral  determinants,  1417 

parasympathetic  fibers  and,  1415 

pressures  in,  1 405 

reflex  regulation  of,  141 6 

resistances  in,  1 405 
Splanchnic  stimulation 

intestinal  blood  flow  and,  1447 

mesenteric  blood  flow  and,  1451 

pancreatic  blood  flow  and,  1450 
Splanchnic  viscera 

innervation  of,  141 5 
Spleen 

arrangement  of  lymphatics  in,  1 038 

blood  flow,  1 44 1,  1443 
factors  affecting,  1450 

blood  volume  in,  1445 

microcirculation  in,  910 

removal,  splanchnic  blood  volume  and, 

■4°3 

species  differences  in  circulation,  913 

theories  of  circulation,  910 

vascular  connections  in,  912 

vascular  volume  changes  in,  955 
Stable  loop 

definition,  867 
Standing  waves 

explanation,  826 
Static  stretch 

definition,  867 
Stellate  ganglion 

stimulation,  1548 

arterial  blood  pressure,  1548 
coronary  inflow  and,  1548 
Steroids 

absorption  of,  1 045 
Stewart-Hamilton  method 


cardiomegaly,  1692 

central  blood  volume,  1691 

mean  circulation  time,  i6gi 

pulmonary  congestion,  1692 
Stomach 

blood  flow,  1441,  1442,  1443 
factors  affecting,  144^ 

blood  volume  in,  1445 

clearance  of  aniline,  1443 

electrolyte  levels  in,  1  141 

microcirculation  in,  904 
Strain  differences 

cholesterol  feeding  and,  1205 
Stress 

atherosclerosis  and,  1 206-1208 

cholesterol  metabolism  and,  1206 

cutaneous  blood  flow  and,  1339 

epidemiology  of,  1 1 8 1 

heart  rate  and,  1553 

lipid  metabolism  and,  1206 

serum  lipids  and,  1 181 

stroke   coronary   oxygen   increase   and, 

1553 
Stress-relaxation 

behavior,  in  various  arteries,  872 

definition,  1084 

description  of,  803 

reversibility,  803 
Stretch  curve 

contribution  of  structural  elements,  806 

muscle  contraction  and,  807 
Stroke  volume 

aorta  flow  during  exercise,  846 

calculated,    compared    to    Fick   proce- 
dure, 834-835 

calculation,  833-835 

central  pressure  pulse  and,  833 

exercise,  846 

indirect  calculations,  834 

relation  to  diastolic  capacity,  784 

right  ventricular,  spontaneous  respira- 
tion and,  785 

under  various  conditions,  782 
Subcutaneous  tissue 

fluid  pressure  in,  980 

interstitial  fluid  pressure,  980 

percentage   of  parts   of  human   limbs, 
1327 

percentage  composition  by  volume, 

'327 
Subclavian  artery 

pressure  pulse  contour,  831 
Sucquet-Hoyer  canal 

description,  1252 
Sucrose 

blood  to  tissue  permeability,  1023 

capillary  permeability,  1023 

diffusion  of,  1002,  1010 

disappearance  from  plasma,  1008 

filtration  rate,  1006 

permeability  of,  1023 

muscle  capillaries  to,  1013 


[78i 


Suction 

definition,  787 
Sulfate 

entrance  rate  into  muscle,  1 138 
Sulfuric  acid 

mean  activity  coefficients,  11 37 
Sweat 

evaporation,  vasodilatation  and,  1337 
Sweating 

cutaneous  circulation  and,  12 19 
skin  blood  flow  and,  1340 
Sympathetic  nervous  system 

collateral  circulation  and,  1262 

coronary  blood  flow  and,  1548 

direct  action  on  heart,  1549 

fibers  of  variable  intensity,  1549 

fibrillating  heart,  1549 

inhibition,   effectiveness  of  heart   and, 

1 104 
innervation 

of  kidney,  1467 
of  splanchnic  viscera,  14.15 
of  uterus,  1602 
vasoconstrictor  fibers 

arteriovenous  anastomoses  and,  1255 
circulation  and,  1362 
impulse  frequency  in,  1365,  1366 
impulses   to   skeletal   muscle   vessels, 

1365 
in  skin,  1337 
skeletal  muscle  circulation,  1359- 

'365 

tissue  fluid  volume,  1362 
vasodilator  fibers 

arteriovenous  anastomoses  and,  1255 

in  skin,  1337 

skeletal  muscle  circulation,  1366 
venous  tone  and,  1077 
Sympathetic  stimulation 
aortic  flow  curve  and,  773 
bone  medullary  pressure  and,  1660 
cardiac  output,  1 1 12 
effectiveness  of  heart  and,  1 104 
gastric  blood  flow  and,  1446 
heart  and,  1549 
muscle  blood  flow  and,  948 
resistance  in  vascular  bed  and,  948 
right  atrial  pressure  and,  1 1 12 
segmental  resistance  and,  952 
small  vessel  pressure  and,  971 
splenic  blood  flow  and,  955,  1450 
venous 

pressure  and,  970 

return  and,  1 1 1 2 
ventricular  and  lung  volumes  and,  783 
Sympathectomy 

cutaneous  blood  flow  and,  1338 
extremity  temperature  after  arterial 

ligation  and,  1264 
skin  circulation  and,  1340 
thrombophlebitis  and,  1240 
vessel  spasm  and,  1237 


Sympathomimetic  substances 

skeletal  muscle  circulation  and,   1369- 

'374 
synephrine,  bone  medullary  pressure 
and,  1660 
Synovial  membrane 

sensitivity  to  pain,  1662 
Systolic  reserve  volume 
definition,  782 

Temperature 

arteriovenous  anastomoses  and,  1 255 

blood  pressure  and,  968 

capillary  blood  pressure  and,  966,  968 

changes 

erythromelalgia  and,  1241 

in  acrocyanosis,  1230-1231 

in  livedo  reticularis,  1233 

Raynaud's  syndrome  and,  1226 
circulation  arrest  and,  1224 
cutaneous 

blood  flow  and,  1330 

circulation  and,  12 19 
filtration  coefficients  and,  988-989,  993 
hand,  sympathectomy  and,  1331 
local 

muscle  blood  flow  and,  1358 

skin  circulation  and,  1330 
of  extremity 

arterial  ligation  and,  1264 

sympathectomy  and,  1264 
of  skin,  as  measure  of  blood  flow,  1327 
reactive  hyperemia  and,  1329 
regulating  center,  muscle  circulation 

and,  1368 
skin  capillaries  and,  904 
vasoconstriction  and,  1094 
vasomotion  and,  927 
Tendon 

percentage  composition  by  volume, 

'327 
percentage  of  parts  of  human  limbs, 

'3-7 
Tension-length  relationship 

theoretical  distensibility 

calculated  moduli,  81  1 
Tension  muscles 

blood  pressure  and,  875 

connections,  869-870 

description,  869-870 

essential  hypertension  and,  875 
Tension-time  index 

definition,  1560 
Terminal  impedance 

energy  transference  of,  852 
Terminal  vascular  beds 

capacitance,  935-957 

in  submucosa  and  muscle,  906 

resistance,  935-957 
vessel  and,  936-950 

vessel  structure  in,  895 
Tetraethylammonium  chloride 


effect  on  catecholamines,  1563 
Tetralogy  of  Fallot 

pulmonary   collateral   circulation   and, 
1262,  1679 
Thebesian  vessels 

concentration  of,  1531 

functional  anatomy,  1517 
Thermal  conductivity 

measurement,  1 285 

of  skin,  blood  flow  and,  1327,  1329 
Thermal  methods 

principle  of,  1 283 
Thermistors 

blood  flow  and,  1287 
Thermocouples 

blood  flow  and,  1287 
Thermoregulation 

arteriovenous  anastomoses  and,  1256 
Thermostromuhrs 

disadvantages  of,  1 284 

temperature  profile,  1  284 
Thiourea 

renal 

artery  pressure  and,  1148 
vein  flow  and,  1 148 
Thoracic  splanchnic  nerve 

innervation  of  kidney,  1467 
Thrombophlebitis 

acute,  1239 

symptoms,  1  240 
sympathectomy  and,  1240 
vasospasm  in,  1240-1241 

migratory,  definition,  1240 

peripheral  vascular  disease  and,  1217 

phlebothrombosis  and,  1239-1240 

plethysmograph  pulses  in,  957 

vasoconstrictor  mechanisms  and,  1239 
Thrombosis 

atherosclerosis  and,  1189 

blood  clotting  and,  1 189-1 190 

mechanism  of,  1189 
Thrombotic   thrombocytopenic    purpura: 

see  Collagen  diseases 
Thrombus 

blood  clots  and,  1 190 

structure,  1  igo 
Thyroid 

activity,  atherogenic  diets  and,   1200 

fat  mobilization  and,  1175 
Thyroxin 

cholesterol  levels  and,  1 186-1 187 
Thyrotoxicosis 

heart  rate  and,  1554 

stroke  coronary 
flow  and,  1553 
oxygen  usage  and,  1553 
Tilting 

renal  blood  flow  and,  1503 
Tissue  pressure:  see  Interstitial  fluid  pres- 
sure 


1782 


HANDBOOK    OF    PHYSIOLOGY  ^  CIRCULATION    II 


Tm 

definition,  1397 
Tobacco 

cardiac  effects,  1 563 

coronary  disease  and,  1563 
Tolazoline 

renal  blood  flow  and,  1487 
Tongue 

arteriovenous  anastomoses  in,  1 254 
Toxemia  of  pregnancy 

ovarian  vein  physiology  and,  1 588 

placental  ischemia  and,  1588 
Transformer  component 

definition,  1315 
Transfusion 

effects  of,  1546 

rapid 

cardiac  output  and,  1 1 1 3 
right  atrial  pressure  and,  1 1 13 
venous  return  and,  1 1 13 
Transillumination 

with  fused  quartz  rod,  893 
Transmural  pressure 

calculation,  1689 
Traumatic  shock 

capillary  permeability  and,  1059 

lymph  flow  and,  1060 

participation  of  the   lymphatic  system 
and,  1059 

renal  blood  flow  and,  1506 

vasoconstrictor  substance  and,  1060 

see  also  Shock 
Traveling  markers 

dye,  1320 

gas  bubbles,  1320 

radiopaque  material,  1320 

tagged  corpuscles,  1320 
Trench  foot 

skin  circulation  and,  1335 

stages  of,  1 335 
Tricuspid  valve 

closure  interval,  790 

flow  pulse  at,  862 

opening  interval,  790 

pulse  wave  at,  862 

regurgitation,  differential  pressure 
method,  862 

structure,  780 
Trimethaphan  camphorsulfonate 

renal  blood  flow  and,  1487 
Trousseau  syndrome :  see  Thrombophlebi- 
tis, migratory 
Trueta  juxtamedullary  shunt 

functional  evidence,  1498 

morphological  evidence,  1497 
Tumors 

origin  of  blood  vessels  in,  1 265 
Tyramine 

medullary  pressure  and,  1660 


Ultraviolet  light 

skin  circulation  and,  1336 
Umbilical  vessels 

artery 

pulse-wave  velocity  and  rate  in,  819 
stress-relaxation  curves  of,  872 

closure  of,  1638 

pressures  in,  1632 
Ungulates 

uterus  in,  1 585 
Uranium-nitrate  injury 

renal  lymph  and,  1058 
Urea 

blood  to  tissue  permeability,  1023 

capillary 

clearance  blood  flow  and,  1023 
permeability,  1023 

concentration  in  lymph,  1064 

diffusion  of,  1002,  ioio,  1012 

distribution  in  kidney,  1469 

filtration  rate,  1006 

osmotic  transients  due  to,  1018 

permeability  of,  1023 

muscle  capillaries  to,  1013 

renal  lymph  flow  and,  1058 
Ureter  ligation 

pathological  changes  in  kidney,  1058 
Urethan 

osmotic  transients  due  to,  1018 
Urine 

concentration,  ADH  and,  1472 

formation 

countercurrent  system,  1479 
intrarenal  pressure  and,  1479 
Uterine  blood  flow 

accommodation  of  embryo  and,   1594- 

'598 
changes  during  pregnancy,  1604 
contractions  and,  1599 
drugs  and,  1637 
during  labor,  1607 
during  puerperium,  1608 
fetal  load  and,  1606 
fetal  weight  and,  1605 
postpartum,  1607 
pregnancy  and,  1603,  1607,  1609 
total,  methods,  1604,  1605 
uterine  shape  and,  1603 
Uterine  circulation 

accommodation  of  embryo  and,   1594- 

1598 
arrangement,  in  various  types,  1587 
arterial 

injection  during  pregnancy,  1604 

pattern  of,  1588 

supply,  in  simplex,  1600 
arteries 

course  of,  1586 

menstruation  and,  1598 
comparative,  1586 
estrogen  and,  1600- 1602,  1603 
hormones  and,  1599 


implantation  and,  1602 

in  nonpregnant  rabbit,  1594 

pregnancy  and,  1594,  1602,  1603,  1604 

vascular  connections  of,  1586- 1588 

vascularity,  1598-1599 

venous  drainage,  1 587 
Uterine  contractions 

arterial  blood  pressure  and,  1 599 

blood  flow  and,  1599 

compression,    inferior   vena   cava   and, 
1600 

maternal  circulation,  1605 

placental  blood  flow  and,  1600 

venous  pressure  and,  1606 
Uterine  milk 

function  of,  1621 
Uteroplacental  circulation 

as  arteriovenous  shunt,  1606 
Uterus 

accommodation  of  embryo  and,   1594- 

1598 
angiogenesis  in,  1586 
arterio-arterial  shunts  in,  1597 
basic  function  of,  1585 
bicornus,  definition,  1586 
comparative  anatomy  of,  1585- 1586 
comparative  types,  1586 
contractility 

blood  flow  and,  1 599-1600 

body  posture,  1600 
duplex,  definition,  1586 
electrolyte  levels  in,  1 141 
endometrium,  vascularity  of,  1599 
estrogen  and,  1 600-1 601 
hyperemia  due  to  hormones,  1601 
innervation  of,  1602 
lymphatics  of,  1608 
menstruation  and,  1598- 1599 
oxygen  consumption,  fetal  weight  and, 

if  Mill 

pregnant,  radiopaque  injections  of, 
1609 

role  in  implantation,  162 1 

simplex,  definition,  1586 

work  of  supplying  various  types  of  pla- 
centa, 1606 

Vagal  stimulation 

gastric  blood  flow  and,  1446 
mesenteric  blood  flow  and,  145 1 
pancreatic  blood  flow  and,  1450 

Vagus  stimulation 

vasomotor  activity,  1 547 

Valsalva  maneuver 

aortic  pulse  contour  in,  831 
brachial  arterial  pressure,  1712 
brachial  artery  pulse  contour  in,  831 
pulmonary  arterial  pressure  and,  1  7 12 

Valves 

arterial,  781-782 
atrioventricular,  780-781 
forward  work  of,  847 


INDEX 


'783 


function  of,  779 

in  lymphatic  vessels,  1054 

removal,  blood  pressures  before  and 

after,  1729 
time  intervals  between  motions,  790 
venoatrial  junction,  780 
Valvula  Eustachii 
description,  780 
Valvula  Thebesii 

description,  780 
van  Itallie,  T.  B. 

Lipid  metabolism  in  relation  to  physi- 
ology and  pathology  of  athero- 
sclerosis, 1 167— 1 1 95 
van't  Hoff's  law 
deviations,  975 

physiological  significance  of,  975 
protein  osmotic  pressure  concentration 
curve  and,  973 
Vasa  recta 

function  of,  1057,  1458 
Vasa  vasorum 
classification,  885 
flow  resistance,  886 
function  of,  883 
interna,  description  of,  885 
location,  885 
pressure  and  flow  in,  886 
types,  885 

vessel  wall  penetration,  885 
Vasa  venarum 
anatomy  of,  1076 
drainage  of,  885,  1076 
in  vascular  disease,  1076 
Vascular  beds 

analysis  of  behavior,  935 
autoregulation,  944 

definition,  942 
blood  volume  in,  953-954 
capacity,  methods  of  studying,  953 
compensation  for  pressure  change,  ter- 
minology, 942 
extravascular  pressure  and  pressure- 
flow  relationships,  941 
flow  in,  epinephrine  and,  950 
interpretation  of  behavior,  957 
pressure-flow  relations,  936 
autoregulation  and,  942 
methods,  936 
normal  plots,  937 
mathematical  relationships,  937 
venous  pressure  and,  941 
resistance  vessels 

autoregulation  of,  941 
chemical  effects  on,  948 
extrinsic  control,  948 
segmental  resistances  in,  950-953 
extrinsic  agents  and,  951 
perfusion  pressure  and,  95 1 
venous  pressure  and,  951 
Vascular  behavior 


interpretation  of,  957 
malfunction,  12 16 
physical  examination  and,  12 18 
simple  clinical  tests  of,  1 2 1 8 
Vascular  capacity:  see  Vascular  beds, 

blood  volume  in 
Vascular  hydraulics 

arterial  system,  blood  flow  in  branches, 

852 
axial  flow,  842 
compliance,  842 
dilatability  tests  of,  1222 
distensibility,  time  dependency  in  elas- 
tic behavior  and,  1084 
distensible  tubes,  pulsatile  flow  in,  815 
elements  of,  841-845 
flow  source,  pressure  source  and,  844 
future  considerations,  794 
hydraulic  impedance,  843-844 
inertance,  841-842 
principles  of,  io7g 
problems   of  pulsatile   flow   in   flexible 

tubes,  800 
radial  flow,  842-843 
resistance,  841 

total  flow  in  elastic  pipe,  equation,  843 
Vascular  resistance 

active  pulmonary  vasodilatation,    17 16 

arteriolar,  hepatic  inflow  and,  1407 

calcium,  magnesium  and,  1 158 

cardiac  output  and,  1 1 18 

changes  in  organ  volume  and,  955 

circulatory  effects  of,  1 1 18 

collagen  "jackets",  1716 

definition,  820 

during  exercise,  17 16 

hypoxia  and,  1 544 

mathematical  relation 

to  flow,  939 

to  pressure,  939 
muscle  circulation  vasoconstrictors  and, 

1 36 1 
passive  pulmonary  dilatation,   17 16 
peripheral 

major  site  of,  895 

measurement  of,  1 139 

potassium  and,  1 149 

venous  return  and,  1 107,  1 108 
postcapillary  increase,  results  of,  956 
precapillary  increase,  results  of,  956 
pH  change  and,  1 159 
potential  energy  gradient,  17 16 
resistance  vessels,  936 

terminal  vascular  beds  and,  936-950 
terminal  vascular  beds,  935-957 
total  peripheral,  drugs  and,  1564 
vasomotor  activity,  1 7 1 6 
venous 

blood  flow  and,  1 1 26 

pressure  and,  11 26 

return  and,  1  r  18 
see  also  Pulmonary  vascular  resistance 


Vascular  smooth  muscle 
adrenaline  and,  1373 
aging  and,  872-875 
arrangement,  806,  870 

plastic   and  contractile   mechanisms, 
87. 
autonomic  nervous  system,  87 1 
catch  mechanisms,  871 
collagen  fibers  as  safety  factor,  880 
conduction  in,  870 
contractility,  927 
contraction  of,  870,  87 1 

arterial  distensibility  and,  806 
creep  in,  805 
curare  and,  1380 

elastic,  viscoelastic,  and  plastic  be- 
haviors, 868 
elasticity  of  veins  and,  882 
excitation  in,  870 
extensibility  of,  805 
extracellular  ions,  water  and,  1 140 
extracellular  space  of,  1 157 
functional  syncytium  of,  870 
intracellular  ions,  water  and,  1140 
in  veins,  881 

ions  and,  methods  of  studying,  1 1 39 
longitudinal,  in  arteries,  1268 
measurement  problems  in,  11 42 
methods  of  studying  ion  effects,  1139- 

1 142 
modifying   properties   of  collagen   and 

elastic  tissue,  872 
oxygen  lack  and,  1 1 25 
pressure-flow  relations  and,  870 
properties,  870 
response  to  stretch,  870 
ring  muscles,  description  of,  870 
shift  from  plastic  to  viscoelastic  be- 
havior, 871 
spontaneous  pendular  rhythm  and,  870 
stress-relaxation  of,  872 
structure  of,  869 
tension 

anions  and,  1 1 59 

Ca  and  Mg  and,  1 157 

cell  volume  and,  1 160 

changes  of  milieu  and,  1 139 

diastolic  blood  pressure  and,  1 1 39 

factors,  1 160 

K  and,  1 1 45,  1 1 46 

K  infusion  and,  1 149 

measurement  of,  1 1 40 

Na  and,  1 144,  1 154 

Na  and  K  in,  1 151 

Na  gradient  and,  1 145 

Na  infusion,  1 147 

permeability  to  Na  and,  1 160 

pH  and,  1 158 

ratio  of  K  and  Na,  1 1 47 

role  of  ions  in,  1 142-1 159 

sodium  and,  1 147 

water  and,  1 154 


1784 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


tension  muscle,  869 
description  of,  870 

types  of,  869 

see  also  Blood  vessel  walls 
Vasculitis 

description  of,  1238 

see  also  Collagen  diseases 
Vasoconstriction 

disease  syndromes,  1 226 

evidence  for,  1 7 1  g 

oxygenation  of  blood  and,  1125 

plasma  Na  and  K  and,  1154 

veins 

factors  affecting,  1094 
temperature  changes  and,  1095 
Vasodepressor  drugs 

in  heart  disease,  1567 

postpartum  uterine  blood  flow  and, 
1608 
Vasodilatation 

adenosine  triphosphate  and,  1338 

axon  reflex  pathway,  1338 

bradykinin  and,  1340 

capillary  pressure  and,  968 

erythromelalgia  and,  1241 

factors  affecting,  1094 

ganglionic  blockers  and,  1561 

hypertonic  solutions  and,  1 148 

lymph  flow  and,  968 

nitroglycerin  and,  1561 

oxygenation  of  blood  and,  1 1 25 

potassium  and,  1380 

reflex,  12 19,  1223 

sodium  and,  1 1 47 

sodium  nitrite  and,  1561 
Vasomotion 

active  and  passive,  925 

active,  environment  and,  926 

anesthesia  and,  925 

arterioles  in,  900 

blood  flow  and,  926 

blood  pressure  and,  926 

definition,  8g2,  925,  928 

fluid  exchange  and,  926 

function,  928 

in  arterioles,  904 

in  conjunctiva,  909 

internal  pressure  of  vessels  and,  927 

ionic,  active,  925 

irregular  activity,  925 

metarterioles  in,  925 

of  arteriovascular  vessels,  896 

of  terminal  arterioles,  897 

receptors,  in  intestine,  1448 

rhythmical  activity,  925 

venous  pressure  alterations  due  to,  927 
Vasomotor  tone 

arteriovenous  difference,  pressure,  blood 
flow  and,  937,  938 

cardiac  output,  113 

right  atrial  pressure,  1 1 13 

mean  systemic  pressure  and,  1 1  1  o 


myogenic  theory,  1409 
venous  return,  1 1 13 
see  also  Venomotor  activity 
Vasopressin 

skeletal  muscles  and,  1355 
Vasospasm 

plethysmograph  pulses  in,  957 
Vasospastic  claudication 

definition,  1 2 1 7 
Veins 

action  of  skeletal  muscle  upon,  882 

arcuate  patterns  of,  897,  905 

arterial  pulsation  in,  883 

as  reservoirs,  1078 

capacity  of,  1078 

central,  reservoir  function,  787 

circular  muscle  in,  881 

collapse 

blood  flow  and,  1080 

elevated  abdominal  pressure  and, 
1 1 23 

hemodynamic  significance,  1080 

hydrostatic  shifts  and,  1082 

right  atrial  pressure  and,  1 1 07 

venous  return  and,  1123 
collapsibility,  function,  1082 
composition  of,  881 
constricted 

distensibility  pattern,  1084,  1086 
constriction  due  to  levarterenol,  1086 
distensibility  of,  1082 

standardization  need,  1085 

noradrenaline  and,  1093 
distensibility  pattern,  1084,1086 

repeated  stretch  and,  1085 
elastic-muscular  system  of,  88 1 
elongation 

spiral  twist  and,  1083-1084 

volume  change  and,  1083 
large,  contribution  to  blood  reservoir, 

't>79 
location  of  vasa  vasorum  in,  885 
longitudinal  muscle  in,  881 
mechanical  properties,  882 
morphological  differences  in  wall 

structure,  952 
muscular  arrangement  in,  881 
nature  of  constriction,  1086 
occlusion,  afterdrop,  1 283 
phasic  pressure  changes  in,  1082 
physiological  characteristics,  1079 
plastic  properties  of,  1 085 
postural  effects  upon,  881 
pressure  alterations  due  to  vasomotion, 

927 
pressure  changes  due  to  anticipation, 

1090 
pressure  -volu  me 
curves  from,  1083 
diagrams,  882 
proportion  of  circulating  blood  in,  900 


radial  distention,  volume  change  and, 

1083 
repeated  stretch  and,  1085 
restoration   of  collapsed   to   cylindrical 

shape,  1 082-1 083 
spontaneous  pressure  waves,  928 
stretch  curves  obtained,  1084 
stress  relaxation,  1085 
structure  of,  881 
structural  support,  883 
tone 

parasympathetic  nerves  and,  1077 

sympathetic  control  of,  1077 
valves,  1077 

aging  and,  882 

function,  1078 

insufficiency  and,  882 

pumping  action,  882 

structure  of,  882 
valvular  competence,  1077 
vasomotion  in,  926 
venospasms,  1086 
venovenous  reflexes,  1095 
wall  structure  in,  881 
wall  tension  in,  882 
Velocity  inductance 
definition  of,  1303 
Velocity  resistance 

definition  of,  1303 
Vena  cava 

distensibility,  collagen  fiber  recruit- 
ment and,  882 
inferior,  compression,  uterine  contrac- 
tions, and,  1600 
superior,  pulsatile  flow  in,  856 
Venivasomotor  reflex 

definition,  141 6 
Venomotor  activity 

adrenergic  response,  1087 
assessment  of,  1087 
congestive  heart  failure  and,  1095 
direct  observation  of,  1087 
distensibility  by  volume  increment, 

1 092-1093 
inferences  from  venous  pressure,  1 087 
in  various  species,  927 
in  vitro  studies,  1087 
measurement  of  pressure  gradients, 

1088 
plethysmography  and,  1091 
psychic  stimulation  and,  1089 
pulse  methods,  1090 
summary  of,  1094 

venous  distensibility  patterns  and,  1091 
venomotor  index,  1 092 
Venous  blood  flow 

body  acceleration  and,  854 
peripheral  venous  pressures  and,  1 127 
phasic  variations,  854 
postural  changes  and,  854 
pulsatile  flow,  854 
systemic,  854-855 


INDEX 


>785 


vena  caval 

atrial  contraction  and,  854 

heart's  action  and,  854 
normal  respiration  and,  855 

oscillatory  pressure  gradient,  854 
pressure  gradient  in,  854 

respiration  and,  857 
Venous  circuit 

methods  for  determination,  1531 
Venous  congestion 

central,  venous  pressure  and,  1031 
interstitial  fluid  pressure  and,  980 
peripheral  venous  pressure  and,  1081 
protein  concentration  in  extravascular 

fluids,  985 
protein,  in  interstitial  fluid,  985 
Venous  pressure 

abdominal  pressure  and,  1 1 23 

anticipation  and,  1090 

body  position  and,  in  pregnancy,  1601 

capillary  pressure  and,  968 

central 

heart  beat  and,  1 1 24 

peripheral  venous  pressure  and,  1 08 1 

respiration  and,  1 1 24 

venous  congestion  and,  1081 
changes,  venous  return  and,  1 1 24 
clinical  evaluation  from,  1224 
cold  and,  logo 
coronary,  values  for,  1542 
composition,  renal  lymph  and,  1057 
congestive  heart  failure  and,  1057 
edema  and,  969,  1 240 
factors  affecting,  972,  11 26 
filtration  and,  977 

coefficient  and,  989 

rate  and,  978,  989 
fluid  absorption  and,  982 
human  forearm  volume  and,  1093 
hypertension,  1224 
intrarenal  pressure  and,  1478 
left  atrial  pressure  and,  1 1 1 8- 1 1 1 9 
lymph  flow,  969 
lymphatic  pressure  and,  1 037 
measurements  in  an  occluded  segment, 

1089 
peripheral 

hydrostatic  pressure  and,  1 127 

right  atrial  pressure  and,  1 127 

venous  congestion  and,  1081 

venous  flow  and,  1 127 
pulmonary,  elevation,  lymph  flow,  and, 

1052 
pulse  methods,  1090 
renal  lymph  flow  and,  1056 
serotonin  and,  1088 
sympathetic  stimulation  and,  970 
transverse    muscle    in    veins    and,    882 
uterine  contractions  and,  1606 
venous  return  and,  1 1 26 
venous  system  and,  1079 
Venous  return 


acute  left  heart  failure  and,  1 1 20 
acute  right  heart  failure  and,  1 1 2 1 
arterial  resistance  and,  1 1 08 
bilateral  femoral  A-V  fistulae  and,  1 108 
blood 

transfusion,  1 1 14 

volume  and,  1 1 10,  1 1 14 
cardiac  decompensation,  1 1 1 7 
cardiac  output  and,  1 100,  1 1 12 

curves  and,  1103-1105,  1111-1118 
central  pulsation  and,  11 24 
circuit  analysis  applied  to,  1100-1102 
classical  analysis,  1 102-1 103 
complex  graphic  analysis  of,  1 1 1 8-1 122 
congestive  heart  failure  and,  1 1 1 6 
definition,  1099 
exercise  and,  1 1 13 

external  pressure  on  heart  and,  n  04 
factors  affecting,  1 1 22-1 1 26 
factors  regulating,  1100 
fainting  and,  1 1 23 
heart,  recompensation  and,  1 1 1 7 
hemorrhage  and,  1 1 1 4 
local  oxygen  utilization  and,  1 1 26 
mean  systemic  pressure  and,  1 109 
muscular  exercise,  1 1 13,  1 125 
myocardial  damage,  1 1 15 
opening  the  chest,  1 1 15 
peripheral  resistance  and,  1 107,  1 108 
pressure  gradient  for,  1 107 
principles  of  circuit  analysis,  1 100 
pulmonary  analysis  of,  1 1 18 
rapid  transfusion  and,  1 1 1 3 
rate  of  epinephrine  injection  and,  1 1 1 1 
rectification  phenomenon  and,  1 1 25 
right  atrial  pressure   and,    11 06,    11 10, 

1 1 12 
shock,  irreversible  and,  1 1 14 
simplified  graphical  analysis,  1 103- 

1 1 18 
statement  of  problem,  11 00 
studied  with  external  perfusion  circuit, 

1 106 
sympathetic  stimulation,  1 1 12 
systemic  pressure  and,  1 1 09 
tissue  metabolism  and,  1 1 25 
vascular  resistance  and,  1 1 1 8 
vasomotor  tone,  1 1 1 3 
venous 

collapse  and,  1 123 

pressures  and,  11 26-1 127 

pump  and,  1 122 

resistance  and,  1 108 

return  curves  and,  1 105-1 1  1 1 
ventricular  output  and,  1100,  11 20 
see  also  Pulmonary  venous  return 
Venous  return  curves 

blood  volume  and,  1 1 10,  1 122 
cardiac  output  curves  and,   1103,   11 05 
epinephrine  and,  1 1 10 
factors  affecting,  1 1 1 1 


fluid  retention  and,  1 1 16 
mean  systemic  pressure  and,  1 109-1 1 10 
method  of  recording,  1 1 05 
normal,  1 1 06 

normal,   methods  of  establishing,    1107 
Venous  system 

blood  flow  and,  1079 
disease,  symptoms  of,  1218 
evaluation  of  status  of,  1 223 
flow  in  systemic  veins,  854 
peripheral 

innervation,  1076 

pressure,  central  venous  pressure 
and,  1 08 1 

structure,  1075 
streamlining  in,  772 
Ventricle,  left 

ability  to  maintain  entire  circulation, 

791 
as  pressure  pump,  790 
as  volume  pump,  790 
changes  in  wall  after  birth,  1641 
deceleration  of  blood  rate,  845 
linear  acceleration  of  blood,  845 
output,  pulmonary  venous  return  and, 

1 1 1 8-1 1 19 
pressure,  lactic  acid  and,  1722 
pressure-volume  curves,  762 
rapid-filling  interval,  790 
Ventricle,  right 

ejection  pulse,  form,  855 
pressure,  778,  779,  791 

positive  pressure  breathing  and,  1  71 1 
rapid-filling  interval,  790 
systole,  function  of,  791 
Ventricles 

asynchrony  in  systole,  790 
blood  flow  velocity  in,  772 
changes  after  birth,  791 
compared  with  piston  pump,  784 
comparison  of  left  and  right,  790 
configuration  changes,  765 
diastolic  suction,  functional  residual 

capacity  and,  7go 
distensibility,  coronary  vessels  and,  763 
ejection  pulses 

comparison  of,  857 

during  deceleration,  846 

exercise  and,  845 

repair  of  congenital  septal  defect 
and,  857 
equilibration  of  left  and  right,  1120 
expenditure  of  energy,  847 
filling,  786-788 

by  atrial  contraction,  774 

forces  responsible  for,  788 

nature  of  vis  a  fronte,  789 

rapid  and  slow,  774 

sequence,  854-855 

suction  and,  788 

vis  a  tergo  and  vis  a  fronte,  788 
function,  coronary  vessels  and,  762 


1786 


HANDBOOK    OF    PHYSIOLOGY 


CIRCULATION    II 


functional  residual  capacity,  788 

gross  dissection  studies  of,  1518 

metabolism,  methods,  1532 

output 

blood  volume  and,  1 121 
comparison  of  two  sides,  1 1  ig 
hemorrhage  and,  1121 
venous  return  and,  1 1 20 

pressure  differences  with  aorta,  781-782 

pressure  in,  during  contraction,  771 

rapid  and  reduced  ejection,  772 

septal   flow,    extravascular   mechanical 
compression  and,  1556 

stroke  volume 

respiration  and,  784 
variations,  784 

systolic  suction,  787 

volume,  782-785 

correlation  of  terms,  784 
lung  volume  and,  783 
pertinent  terminology,  782 
relationship  to  body  weight,  789 
under  various  conditions,  782 
various   activities   and,   782-785 
Ventricular  contraction 

atrial  filling  and,  788,  794 

premature,  781 

valve  closure  and,  780-781 
Venturi  meter 

principles  of,  1 297,  1 298 
Venules 

leaks  in,  1014 
Vertebrae 

blood  supply  to,  1655 
Vertebral  arteries 

distribution,  1655 
Vibrocardiogram 

cardiac  cycle  and,  777 


Vis  a  fronte 

analysis  of  venous  return,  1 102 

definition,  854 

schematic  representation,  856 
Vis  a  tergo 

analysis  of  venous  return,  1 102 
Visco-elasticity 

application  of  term,  803 

behavior  with  stretch,  866 

definition,  867 

description  of,  866 

elastic  tissue  property,  805,  866,  877 

illustration,  867 

smooth  muscle  property,  866,  872,  878, 
879 

tendon,  lack  of,  805 

time-dependent,  in  umbilical  artery, 
819 

vessel  compliance  and,  820 
Viscous  flow  patterns 

definition,  853 
Vitamin  B12 

transport  in  lymph,  1048 

Water 

bound  and  free  in  interstitial  fluid,  978 

diffusion  rates,  1012 

hydrodynamic  flow  and  diffusion  of, 

1004 
in  bladder,  1 141 
in  stomach,  1 141 
in  uterus,  1 141 
in  vascular  tissue,  1 141 
permeability   of  muscle   capillaries   to, 

1013 
ratio   to  extracellular  space,    1141 
relation  to  sodium  hypertension,    11 43 
splanchnic  blood  volume  and,  1406 


Wedge  pressure 

use  of,  1687 

values  for,  1687 
Wetterer,  E. 

Methods  of  measuring  blood  flow, 
1277-1324 
Wiedeman,  Mary  P. 

Patterns  of  the  arteriovenous  pathways, 

89'~933 
Windkessel 

analogue  of  arterial  system,  825,   847, 

848,  873 
definition,  873 
Windkessel  model 
arterial  system 
discussion  of,  847 
pressure-flow  relationship,  847 
Work 

blood   flow,   oxygen  consumption   and, 
'3/8 
Wyamine :  see  Mephentermine 

X  wave 

atrial  filling  and,  786 
Xanthines 

effect  on  heart,  1561 

Y  wave 

opening  of  atrioventricular  valves  and, 
787 
Yield  pressure 

definition,  1477 
Young's  modulus 

definition   809 

Zinc  sulfate 

mean  activity  coefficients,  1 1 37 


tllRlKHl 


111