*

A k.'

Presented to the
library of the

LMYHRSITY OF TORONTO

C

Arthur Axler

PHYSIOLOGY AND BIOCHEMISTRY
IN MODERN MEDICINE

I'.Y

.1. J. R. MACLEOD, M.lv

PKOFK.ssoK 0» PHYSIOLOGY in thk i nivkksity or TOKONTO, Tl . ruKMt

PB0FES80B OK PHYSIOLOGY IN ihk Wl

CI.KVKIANI), OHIO

Assisted by Roy <;. Peabce, B.A., M.D.
Director of the Cardiorespiratory Laboratory of Lakeside BoepitaL

Cleveland, < >lii<>

AND BY OTHERS

SECOND KDTTTON

\\ l ill . ll I i 8TRATION8, 1NCLI DING
n PLATES l\ COLORS

BT LOUIfi
c \ mushy COMPANY
1919

Copyright, 191S, 1919, Bv C. V. Mosby Company

3^

Press of

C. V. Mosby Company

St. Louis

TO

M. \\ . \l

PREFACE TO SECOND EDITION

Tin- opportunitj has been taken in this - od edition to elimins

typographical errors and to alter the wording in certain cha

there was ambiguity of statement in the Brat edition.

eonraging reception afforded the \ < ► 1 1 1 m*- has fully confirmed the auth<

conviction thai modern acquaintance with physiology i> fundamental

tn Bound medical and surgical praeti<

.1. .1 R M v i

Toronto, Canada.
1919.

PREFACE TO FIRST EDITION

The necessity of allotting the various subjects of the medical eurrie-
ilium to different periods, so thai the more Btrictly scientific subj<
are completed in the earlier years, has the greal <li- that the

student, being no longer in touch with laboratory work, fails to employ
the scientific knowledge with full advantage in the solution <»f his elin-
ical problems. He is apt to regard tin- first two or tlr in the

laboratory departments as inconsequential in comparison with tin- sup
posedly more practical instruction offered during the subsequent clinical
years. He is taught by his laboratory instr tors
and to correlate the observed facts, so that he may !><• enabled to <1-
conclusions as to the manner <>t' working of the various fui the

animal body in health, and before proceeding to his clinical b1 he

is required to show s proficiency in scientific knowh
recognized that this must serve as the basis upon which his l
of disease is i<> be built When the clinic is ed, however, the nv I

hi|n of the scientist arc not infrequently cast
of disease is nought for largely bj the empirical meth<
endeavor to see and examine innumerabl<
according to the grouping of the signs and h
the prescribed methods of experiei - • mucl

much has to he seen during the clinical years, '1

thought to iIk1 nature of the functional disturb Mr

fur the Bymptoms; he fails to realize tl

VI PREFACE

lial difference between the condition broughl aboul in his patient by
some pathological lesion, and thai which may be produced in the labora-
tory by experimental procedures, by drugs or by toxins. It, must of
course be recognized thai just as the science of medicine originated by
the grouping of symptoms into more or less characteristic diseases for
which the most favorable method of treatment had to be discovered by
experience, so must a certain part of the medical training be more or
less empirical but it should at the same time be realized that such a
method is only a means to an end, and that the real understanding of
disease can be acquired only when every abnormal condition is inter-
preted as a primary or secondary consequence of some perverted bodily
function, and when the training in observation and the inductive method
is carried from the laboratory into the clinic.

It is a constant experience of clinical instructors who would employ
scientific methods of instruction, that they find the students not only
indifferent to an analysis of their cases from the functional standpoint,
but also that they are too inadequately prepared in fundamental phys-
iological knowledge, to make the analysis possible. The student may
have a superficial acquaintance with the main facts of physiological science
but have failed to acquire the enquiring habit of mind which will en-
able him, through reflection, comparison, and personal research, to ap-
ply the knowledge in practical medicine and surgery.

For this lack of correlation between the laboratory and clinical stud-
ies, the clinical instructors are not alone responsible. The laboratory
courses are frequently given without any attempt bein^ made to show
the student the bearing of the subject in the interpretation of disease,
or to train him so that in his later years he may be able to adapt the
methods of investigation which he learned in the laboratory, to the study
of morbid conditions. It is self-evident that (without any knowledge
of disease) the extent to which the student in the earlier years of the
course could be expected to appreciate the clinical significance of what
he learns in the laboratory is limited, but this should not deter the in-
structor from indicating whenever he can, the general application of
s.-icntific knowledge in the interpretation of diseased conditions. But
the chief remedy of the evil undoubtedly lies partly in the continuance
of certain of the laboratory courses into the clinical years, and partly
in the study of medical literature in which the application of physiology
and biochemistry in the practice of medicine is emphasized.

Notwithstanding the sufficient number of excellent textbooks in phys-
iology available to the medical student, there is none in which partic-
ular emphasis is laid upon the application of the subject in the routine
practice of medicine. In the presenl volume the attempt is made to

I'Ki r\t i

inni such a waul, by reviewing those portions of pi

chemistry which experiei has shown to be

clinical investigator. The wort is not intended to '■

either for the regular textbooks in physiology, or for I

pathology. It is supplemental-} to Buch volume* 11 d< ike

'I"' modern test in Functional pathology, with ..

diseased condition, and then pr >ed to analyze the possibl

consequences of the disturbances of function which this exhibil
if deals with the present-day knowledge of human physiology in
as this can be used in a general way to advance the m
disease. In a Bense it is therefore an advanced text in physi
those aboul to enter upon their clinical instruction, and
time, a review for those of a maturer clinical experience wl
to seek the physiological interpretation of d

In attempting to fulfil these requirements, it has been deemed •
tial to go hack to the fundamentals of the subject, and to exp!
simply as possible the physical and physicochemical principles u-
which so large a pari of physiological knowledge depends P

may I onsidered as an application of the known la-

physics and chemistry to explain the functions of living matt
only after tin' extent to which this application can be made has
appreciated, that the knowledge may be used to Berve as th< foui
upon which a superstructure of clinical knowledge can be built

In order thai the volume mighl be maintained
has been necessary to selecl certain parts of the subje< I
emphasis, the hasis of selection being the dej i which our 1

clearly shows the value of the application of physiological method
of observation and of thoughl in the study of diseased conditions T
has not keen done to the extent of omitting the apparently
parts, for these have keen treated in sufficient detail to link I
together so as to preserve a logical continuity, and show- the 1
one field of knowledge on another. There are howi
of the science, particularly the physiology i
special senses, and of reproduction, for which application in t! •
fields of medicine and surgery is limited, and
omitted entirely. It lias keen judged thai tlii-
trary selection is justified on the ground thai tin
physiology covers these sub
for whom on the other hand, 1

Bible within ike limits of such a volume as this w M
chemistry, no attempt is made to review tl
characteristic tests of the various chemical
sues and fluids This is nlreadv sufli.-i.it'

VI 11 PREFACE

biochemistry, and in t lie numerous manuals oh clinical methods. Bio-
chemical knowledge I8 treated rather from the physiologist's stand-
point, as an integral pari of his subject, particular attention, neverthe-
less, being paid to the far-reaching applications of this latest depart-
ment of medical science, in the elucidation of many obscure problems
of clinical medicine, such as those of diabetes, nephritis, acidosis, goiter
and myxedema. To make the volume of value to those who may not
have had time or opportunity to familiarize themselves with the techni-
cal methods of the physiologist and biochemist as used in the modern
clinic, a certain amount of space is devoted to a brief description of the
methods that appear at present to be receiving most attention, and to
be of greatest value.

Finally, it should be mentioned that the principles of serum diagnosis
and therapy are omitted, since these belong to a highly specialized science
requiring an intensive training of its own.

In the hope that the volume may be instrumental in arousing sufficient
interest to stimulate a more intensive study of the various subjects
which it introduces, a brief bibliography is given at the end of each
section. The references selected are to papers that are more partic-
ularly known to the author; they are not necessarily the most impor-
tant publications on the subject, but are often chosen because of the
useful reviews of previous work contained in them, rather than because
of their own originality. Some of the papers, however, are referred to
as authority for statements of fact which may arouse in the reader a
desire to ponder for himself the evidence upon which these are based.
The references are usually divided into two groups, "monographs" and
"original papers," and it is only occasionally that specific reference is
made to the former in the context. The original papers, on the other
hand, are referred to by numbers. "With the general field of the subject
so well covered by such excellent textbooks as Bayliss' "Principles of
General Physiology," Stewart's, Howell's, Starling's, and Halliburton's
"Human Physiologies," and Leonard Hill's ""Recent and Further Ad-
vances in Physiology," the author has felt free to pick and choose from
the monographs and original papers, topics that are ordinarily passed
over cursorily in the textbook, and when this has been done, the refer-
ences are somewhat more extensive. Such is the case for example in
the chapters relating to the chemistry of respiration, to the metabolism
of carbohydrates and fats, to the problems of dietetics and growth, to the
physicochemieal basis of neutrality regulation in the animal body, and to
the action of en/.ymes.

Acknowledgment is gratefully made for the assistance and advice
in the preparation of the book, particularly to Doctor P. G. Pearce. for
the contribution of several chapters. 1o which his name is attached, and

I'REFAI I

for which he is entirely responsible; and to Doctor E I
criticisms, after patienl perusal of the unfinished n
inestimable value in its final revision. Acknowledgment
to Doctor l\. \V. Scuti and Professor I' K Lloyd, for valual iticism

and advice, and to tin- former for a chapter on I Appli

tion of Electrocardiographs." To Ifise Achsa I' M I I thor

owes a <jreat dclit of trratitude for tic thorough and painstaking way in
which she prepared the mannscript for the ] • r her

tiring endeavors to have the spelling and punctuation in conformity
with Webster's Dictionary. For assistance in tl eparation >>f I
index thanks arc due to Miss Marian Armour and Mrs M
and for permission to use certain of tin figures and illustratioi
various authors and publishers who granted it. For th<
agemenl and careful execution of the presswork, the author wia
thank the publishers, whose courteous and friendly dealings have alwi

made the work easier.

J. J. i; m \

University of Toronto,
Toronto, Canada.

CONTENTS

P \i;t i

THE I'llVsn OCHEMICAL BASIS OF PUYSIOLOOK AL

PROCESSE

EBAL CONSIDERATIONS

The Laws "t" Solution, 3; Qas Laws,

for Measuring Osmotic P 9a •■'. pa, 7; P

CB \i'Ti i: !i

Kmi PRE88URE ' '"M 'i

Measurement l.v Depression of Frees

fusion, and allied Pi in Physiological M ' 1.

('II LPTEB III

Electric I'oNhiiTivuv. Dissociation, and I . .

Biological Applications, 1'.'.

CH \l'l 1 K 1\

Tin; Principles Involved in thi

Tit r.il.l.- A.i.iity and alkalinity, 22
23; M:i~> action, 23; application to 1
26; application in Determining the Real

CH LPTEB v

Tin Principles Envol> d> in tub U

The Electric Met! od, 29 : The Ind

CH \ITI B \ I

Reoulati

Buffer Bui -• - M«> .«

alkalinity, 1 1 : Til ral ion Mel II ■ s ■

Methods, i»'>.

<'H MTI1C VII

"it»s

Charactei istii Properl

51 ; Tj ndall Phenomenon, ">l ; R

ties, .".."> ; Brownian M

Xll CONTENTS

CHAPTEB VI II page

Colloids (Cont'd) 60

Suspensoitls and Emulsoids, 60 j Gelatinization, 61 ; [mbibition, 62; Action of
Electrolytes Oil Colloids, 0.'! ; Proteins as Colloids, (>:*,; Surface Tension, 64;
Adsorption, <>.">; Everyday Reactions Depending on Adsorption, 66; Conditions
Influencing or Influenced by Adsorption, i>7 ; Physiological Processes Depending

On Adsorption, 69.

CHAPTEB IX

Ferments, ok Enzymes 71

The Nature of Enzyme Action, 72; Properties of Enzymes, 7H ; Reversibility
of Enzyme Action, 77; Specificity of Enzyme Action, 79; Peculiarities of
Enzymes, 80; Types of Enzyme, 81; Enzyme Preparations, 82; Conditions for
Enzymic Activity, 82

PART II
THE CIRCULATING FLUIDS

CHAPTER X

Blood: Its General Properties (By R. G. Pearce) 85

Quantity of Blood in the Body, 85; Water Content, 86; Proteins, 87; Fer-
ments and Antiferments, 89.

CHAPTER XI

Tin; Blood Cells (By R. (i. Pearce) 91

lud Blood Corpuscles, or Erythrocytes. 91; Origin, 92; Rates of Regeneration,

93; Hemolysis, 95; Leucocytes, 96; Blood Platelets, 97.

CHAPTER XII

Blood Clotting 98

Visible Changes in the Blood During Clotting;, 98; Methods of Retarding
clotting. 99; Nature of the Clotting Process, 101; Influence of Calcium Salts,
10.".; Influence of Tissues, 104.

CHAPTER XIII

Blood Clotting (Cont'd) • 106

Theories of Blood Clotting, 106; Intravascular Clotting, 107; Measurement of
the Clotting Time, 1|IS: Blood Clotting in Various Physiological Conditions, LlOj
Blood clotting in Disease, 111; Hemorrhagic Diseases, 112; Thrombus Forma-
tion, 113.

CHAPTER XIV

Lymph Formation and Circulation 115

General Considerations, 115; Experimental Investigations, 118; Edema, L20.

P VRT Ml
PIR< i i VTION OF 1 III! BLOOD

«'ii \ri i.i; ■•

Blooo i'

The Mean \i tei ial Blood r • m

Spring Man"! 120 : < finical M

OH \lTi.i: \\ I

The Factors Conci rni d in \i un

Pumping A «• t i« r th«' Heart, 134; Periph

Blood in the Body, 135; Effect! Hemorrh
ity of the Blood, 1 10; Elasticity

CHAPTEB \\ II

Till ACTION OK Till. HEART

The Pumping Action of the Heart, Ml: tnl
Comparison of the < (urves, i Is.

ill M'TIK Will
Tin: PUMPING ACTION OF Till II CONT1

Contour of the [ntracardial Pn 151; V<

Auricular Curve, 153; The Mechanism oi
154; The Heart Bounds, 157; <
Blectrophonogran - . I 58.

CHAPTER XIX

Tin: NUTRITION OF Tin: HEART

B] I Supply, lfil : Perfusion of the Hi

t i. hi of the Heart in Bitu, l<ii : bV latiooahip <>r tl ■ •
Perfusion Fluid in Cold-bl led and Warm-bl

CH M'N B ■•

Physiology of the Heabtbi vi

< )ii^in aiwl Propagation of tl
^ . - 1 1 i . • Hypothesis, 172
Physiological < liaracti rial

ill MTI B XXI

I'm sun .h,\ 01 THE II

__: i 1 1 and Propagation of t1
tag Tissue in the M ian Hi

''ii \r.
Pirrsioi ik.\ oi phe ii
Mode of Propaj
Ventricles, 191 j -

tiirlcs and Auricli

XIV CONTENTS

CHAPTER Will page

The Bloodflow in the Arteries 198

The Pulses, 198; General Characteristics, 198; Hate of Transmission of Pulse
Waves, 198; Contour of the Pulse Curve, 200; Velocity Pulse, 1200; Palpable
Pulse, 202; Analysis of the Curve, 202; The Dicrotic Wave, 203; Causes of
Disappearance of the Pulse in the Veins, 205.

CHAPTER XXIV

Bate op Movement of the Blood in tee Blood Vessels 206

Velocity of Flow, 206; Mass Movement of the Blood, 208; The Visceral Blood-
flow in Man, 212; Work of the Heart, 212; Circulation Time, 213; Movement
of Blood in the Veins, 214.

CHAPTER XXV

The Control of tub Circulation 216

Nerve Control, 217; Vagus Control in the Cold-blooded and the Mammalian
Heart, 217; Tonic Vagus Action, 221; Afferent Vagus Impulses, 222; Mechan-
ism of Vagus, 224; Termination of the Vagus Fibers in the Heart. 225; Sym-
pathetic Control, 227.

CHAPTER XXVI

The Control of the Circulation (Cont'd) 229

Nerve Control of Peripheral Resistance, 229; Detection of Vasomotor Fibers
in Nerves, 231; Origin of Vasomotor Nerve Fibers, 2."»2 ; Vasomotor Nerve
Centers, 235; Independent Tonicity of Blood Vessels, 236.

CHAPTER XXVII

The Control of the Circulation (Cont'd) 237

Control of the Vasomotor Center, 237; Hormone Control, 237; Nerve Control.
238; Pressor and Depressor Impulses, 239; Reciprocal Innervation of Vascular
Areas, 243; Influence of Gravity on the Circulation. 214.

CHAPTER XXVIII

Peculiarities of Blood Supply in Certain Viscera 247

Circulation in the Brain, 247; Anatomical Peculiarities, 247; Physical Condi-
tions of Circulation, 249; Vasomotor Nerves, 252; Intracranial Pressure, 253;
Circulation through the Lungs, 25.1; Circulation through the Liver. 255; The
Coronary Circulation, 257.

CHAPTER XXIX

('link '.\ i, Applications of Certain Physiological Methods 259

Electrocardiograms, 259; The Ventricular Complex, 262.

CHAPTER XXX

Clinical Applications op Certain Physiological Methods (Cont'd) .... 266
Electrocardiograms of the More Usual Forms of Cardiac Irregularities, 266;
Sinus Arrhythmia, 266; sinus Bradycardia, 266; The Extrasystole, 266; Parox-
ysmal Tachycardia, 269; Auricular Fibrillation, 269; Auricular Flutter, 269;
Heart-block, 270.

CH M'li i:
Clinical Applica

Polysphygmograms, 273 ; \
Pulse Tracings, 278 : tbnoi mal I '

CU \i'Tii; XXXII
Clinical ai-im.i. i pions of Certain P
Measurement of the Mass Movemenl
282; Clinical Conditions Which Affecl the i

CHAPTEB XXXIII

Shock

(iiu\ it\ shock, 287 ; Hemorrhi _ -

Shock, 288; Nervous 81 k. 289; fi

vestigation of Shock, 289 ; Treatment
295.

PART IV
RESPIRATION

CH LPTEB .\X.\I\

Respiration

The Mechanics Lration, 299 ; P

-W ; Bespiratory Tracing T [ntrapleural

on Bl 1 Pressure, ."■

CHAPTEB -\.\.\\
The Mb hanics or Besptrati - r.-> i;. o. p

Variations in Dead Space, Besidual Air and the Mi
Various Physiological and Pathological C

CHAPTEB WW I
The Mecb Bi bptrai i Bi i;. i

The Mechanism of thi •
The Movements of the Bibs, ;l">: The \ I
319 : The Action >>i' the Diapl
meats "" the I

CHAP1 WYii

The Control of Bi bpir >

The B ij

i'U W ! ..Will

Tin. Control or Bespih
Bormons Control •
Arterial Bloo< .

». in Venom

\ \ I CONTEXTS

CHAPTER XXXIX page

The Control of Respiration (Cont'd) (By R. G. Pf.arce) 344

Estimation of the Alveolar Cases. ::44 : Method for Normal Subjects, 345;
Clinical Method. 347.

CHAPTER XL

The Control of Respiration (Cont'd) 349

The Nature of the Respiratory Hormone, 349; Relationship between CO., of
Inspired Air and Pulmonary Ventilation, 350; Possibility that (XX Specifically
Stimulates the Center, 352; Relationship among Acidosis, Alveolar CO. and
Respiratory Activity, .'!."i4.

CHAPTER XLI

The Control of Respiration (Cont'd) 356

The Constancy of the Alveolar C02 Tension under Normal Conditions, 256 ;
Sensitivity of the Center to Changes in the CO, Tension of the Alveolar Air,
357; Alveolar C02 Tension during Breathing in a Confined Space, 357, in
Rarefied Air, 360, and in Apnea, 362.

CHAPTER XLII

The Control of Respiration (Cont'd) 366

The Effect of Muscular Exercise on the Respiration, 356.

CHAPTER XLIII

The Control of Respiration (Cont'd) 371

Pii iodic Breathing. .".71; Types of Periodic Breathing, 371; Causes of Periodic
Breathing, 372.

CHAPTER XLIV

Respiration beyond the Lungs 378

Transportation of Gases by the Blood, 379; Transportation of Oxygen, 379;
Dissociation Curve, 383; Difference between Curves of Blood and Hemoglobin
Solution, 383; Rate of Dissociation, 3S6; Dissociation Constant, 388.

CHAPTER XLV

Respiration beyond the Lungs (Cont'd) 390

Means by Which the Blood Carries the Gases, 390; Oxygen Requirement of
the Tissues, 393; Mechanism by Which the Demands of the Tissues for Oxy-
gen Are Met, 397.

CHAPTER XLVI

The Physiology of Breathing in Compressed Air and in Rarefied Air . . . 399
Mountain Sickness, 399; Compressed Air Sickness (Caisson Disease), 402;
Practical Application in Treatment, 406.

CHAPTER XLVII

The Circulatory and Respiratory Changes Accompanying: Muscular Exercise 410
Mechanical Factor. 410; Nervous Factor, 412: Hormone Factor, 413.

PART V
DIGESTION

CH WTl.i: \I.\ III

EBAL PHYSIOLOGY 01 nil In.

Microscopic Changes during Activity, 418 ; M<
Ohangea during Activity, 421; <'..iitr,,i of Olai
Control, 423.

CH U'Ti.i: xu \

PHYSIO] THI DlOl

Hormone Control, 125 : N< « *. . 1 1 1 r . . ]

CHAPTEB I.

PHYSIOLOGY Of THE DIOBSTTVI GLANDS (CONT'D)

N'ormal Conditions of Secretion, 130; Norma -

lion of Gastric Juice, 132; The [ntestinaJ Bi 141.

CHAPTEB I.I

The Mechanisms of Digestion iu

Mastication, 444; Deglutition, it."; The < ':irh .. Bpl
449.

CHAPTEB Ml

T 1 1 k Mechanisms of Digestion C

Movements of the Stomach, 451; Chan the M

of the Stomach Movements on Kmpt;

156; Control of the Pyloric Sphincter, 156; BaJ theft

158; Influence <>r Pathological Conditions on tl
tomv. 161.

CH M'Ti l; I. in

Tin: Mechanisms of Dig ....

Movements <>t" the [nteal
Movements of the Large [nt<
Movements, 170.

ill \I'TIK I.l\
HtJNGEB a.M< All-:

Hanger Con! racl h, 471 ; B<

tions, 171 : Hunger during Starvation,

17''..

(MI \ I'll B LI

KEMICA1 P

tion iii tin- Stomach, K
Amount and Bom
Milk in the Stomach, 488.

XV111 CONTENTS

CHAPTEB LV] page

Biochemical Processes of Digestion (Cont'd) 489

Digestion in the Intestines, 4S!i; Pancreatic Digestion, 489; The Bile, 492;
Chemistry of Bile, 194.

CHAPTER LVII

Bacterial Digestion in the Intestine 499

Bacterial Digestion of Protein, 501 ; Botulism, 503.

PART VI
THE EXCRETION OF URINE

CHAPTER LVIII

The Excretion of Urine (By R. G. Pearce) 507

Structure of Kidney, 507; Mechanism of the Excretion of Urine, 510; Theories
of Renal Function, 511; Diuretics, 51S; Albuminuria, 519; Influence of the
Nervous System on the Secretion of Urine, 519.

CHAPTER LIX

The Amount, Composition and Character of t{he Urine (By R. G. Pearce) . 521
Amount, 522; Specific Gravity, 522; Depression of Freezing Point, 523; Re-
action, 524; Solid Constituents, 525.

PART VII
METABOLISM

CHAPTER LX

Metabolism 534

Energy Balance, 5.'!5 ; Methods for Measuring Energy Output, 536; Normal
Values, 538; Influence of Age and Sex, 541; Influence of Diseases, 542;
The Material Balance of the Body, 543; Methods for Measuring Output, 543;
Calculation of the Results 544.

CHAPTER LXI

The Carbon Balance 547

Respiratory Quotient, .117; Influence of Diet, 547; Influence of Metabolism,
549; Magnitude "f the Respiratory Exchange, 550; Influence of fiody Tem-
perature, 551.

CHAPTER LXII

\ Clinical Method for Determining the Respirator? Exchange in Man (By

R. G. Pearce) 554

The Valves, 555; Tissot Spirometers, 556; Douglas Bag, 558; Ealdane Gas-
analysis Apparatus, 559; Calculations, 562.

'II M'TI.K I. Mil

Starvation

Excretion ol \in

Bzeretion of Pui

570; Nitrogenous Equilibrium, 571 ; IV

CH M'l'i i: IAIV
Nitkition and Growth . .

The Pood Factor of Growth, 574; Rclationshi]
Maintenance of Life, 57 I.

CB M'Tl.i; l.w

Nutrition ins Growth (Cont'd)

Relationship of Carbohydrates and I
Factors, or Vitamines, 584; Relationship of]

CH M'TI .l{ l.\\ I

Dietetics

Calorie Requirements, 588; The Protein Rcquin
Factors, 593 : Dig* stibilitj and Palatal ility,

CHAPTEB l.w II

The Metabolism of Protein

[ntroductory, 595; Chemi8try of Protein and of i

CHAPTEB l.W III

Fmk METABOLISM Of PROTEI

A hi i in • Acids in tin' Blood and l

CHAPTEB I..MX

The Metabolism ok Protein Com ';•

KihI Products of Protein Metabolii

fluence of Acidosis on Ammonia-urea Ratio, 616; Infl

i i;i area Ratio, 617; P(

CH M'Tl.i: i \\

Till \l I LBOl I8M oh PRO! i in I ■ • '"--'

Creatine and Creatinine, 622; I
62 i ; [nfluen t F I, A

ell \rn B ia.m

Tin Mi iTABOl I ...

rjndetermined Nitrogen and 1' ■ ■ >

and Glyeuronat

CH \r ri B I AMI

CrIO Arm v\i> nil l'i RI]

mieal Nature of the Pui
G staining Purine and Pyrimidiw Ra*
ii ■■. al Body, 63*
undei Various pi .

XX CONTENTS

CHAPTER LXXIII PAGE

Uric Acid and the Purine Bodies (Cont'd) 643

Source of Endogenous Purines, 643; Influence of Various Physiological Con-
ditions, of Drugs, and of Disease on the Endogenous Uric-acid Excretion,
647 J Uric Acid of Blood, 648.

CHAPTER LXXIV

Metabolism of the Carbohydrates 052

Capacity of the Body to Assimilate Carbohydrates, 652; Assimilation Limits,
652; Saturation Limits, 654; Digestion and Absorption, 050; Sugar Level in
the Blood, 057; Value of Blood Examinations in Diagnosis of Diabetes, 059;
Relationship Between Blood Sugar and the Occurrence of Glycosuria, 660.

CHAPTER LXXV

Metabolism of the Carbohydrates (Cont'd) 662

Fate of Absorbed Glucose, Gluconeogenesis, 662; Storage of Sugar, 662;
Sources of Glycogen, 662; Gluconeogenesis in Normal Animals, 667.

CHAPTER LXXVI

Metabolism of the Carbohydrates (Cont'd) 669

Fate of Glycogen, 669; Regulation of the Blood Sugar Level, 671; Nerve
Control and Experimental Diabetes, 672 ; Nervous Diabetes in Man, 674 ;
Hormone Control and Permanent Diabetes, 676; Utilization of Glucose in
Tissues, 677; Relation of the Pancreas to Sugar Metabolism, 678; Diabetes
and the Ductless Glands, 678; Diabetic Acidosis or Ketosis, 683; Starvation
Treatment, 684.

CHAPTER LXXVII

Fat Metabolism 686

Chemistry of Fatty Substances, 686; Digestion of Fats, 690; Absorption of
Fats, 691.

CHAPTER LXXVIII

Fat Metabolism (Cont'd) 696

Pal of Blood, 696; Methods of Determination, 696; Variations in P.lood Fat,
697; Depot Fat, 700; Fat in the Liver, 701.

CHAPTER LXXIX

Fat Metabolism (Cont'd) 707

Production of Fatty Acid Out of Carbohydrate, 707; Method by Which the
Fatty Acid is Broken Down, 709.

CHAPTER LXXX

Control of Body Temperature and Fever 714

Variations in Body Temperature, 714; Factors in Maintaining the Body Tem-
perature, 71") ; Control of Temperature, 719: Fever, 721; Causes, 721; Changes
in the Body during Fever, 723; Beat regulating Center, 725; Significance of
Fever, 726.

PART VII!
THE ENDOCRINE ORGANS I >R Dl I TL GL iNDS

CHAPTEB I.X.WI

The Endocrini Ob 3, ob i > ; •

Methods of Investigation ; 7 G Cori

732; Adrenalectomy, :

CHAPTEB I.X.WI I

Adrenal Gland (Cont'd)

Variations in Phys J Acth

of the Gland, 738; Epinephrini I ntent of th

Method, 743; Adrenalemia, ~\~>: Am

docrine Organs, 7 16.

CHAPTEB I. WWII!

Thykoid ani) Parathyroid Glands

Structural Belationship, 749; Thyroid Gland,
Experimental Thyroidectomy, 752 ;
with Other Endocrine Org . 757; Paratl
roidectoiny, 758; Belationship with Other End<

CHAPTEB I. XXXIV

l*rniTAi;Y BODY

Structural Belationships, 762; Functions, 764; C
Belationship with Other Endocrh

CHAPTEB I. WW

The Pineal Gland am. mi Gonads ■

Pineal Gland, 776 : Gons Is or tl
of the Male, 77"'' : < leneral

PART IX
TIIK CENTRAL NERVOl - SI STEM

CHAPTEB I. WW 1

Tin; EVOI k Tilt: ~

(HAITI B I. .WWII

Pbopi kiiis or Each P

i; oeptor, 7-- icritie and
parate -

(II \I'TI K 1 WW III
Tin: PSOPERI I

The Nerve Network,
Tin- Nerve i

XXI 1 CONTENTS

CHAPTER LXXXIX

Reflexes of the Spinal A.nimal usjd Spinal Shock 803

Spinal Shock in Laboratory Animals, 803 j Spinal Shock in Man, 800; Cause
of Spinal Shock. 807.

CHAPTER XC

Physiological Properties op the Simple Reflex Arc ... 809

Latent Period, 809j Grading of Intensity, 809; After-effect, 810; Summation,
S10; Irreversibility of the Direction of Conduction, 810; Refractory Period,
811; Successive Defeneration, 813.

CHAPTER XCI

Reciprocal [nnervation 814

Reciprocal [nhib'ition, Ml; Action of Strychnine and Tetanus Toxin, 819.

CHAPTER XCII

Interaction Among Reflexes 821

Integration of Allied Reflexes, 822; Integration of Antagonistic Reflexes,
824; Other Factors Which Determine Occupancy of Final Common Path, 824;
Irradiation, 826.

CHAPTER XCIII

The Tendon Jerks ; Sensory Pathways in Spinal Cord 828

The Tendon Jerks, 828; Afferent Spinal Pathways, 830.

CHAPTER XCIV

Effects of Experimental Lesions of Various Parts of the Nervous System . 835
Anterior Roots, 835; Posterior Roots, 836; Spinal Cord, and Brain Stem, 839;
Medulla, 839; Corpora Quadrigemina, 840; Removal of the Cerebral Hemi-
spheres, 840.

CHAPTER XCV
Cerebral Localization S43

Ablation of the Motor Centers, S43 ; Stimulation of the Motor Centers, 844;
Clinical Observations, 849.

CHAPTER XCVI

Cerebral Localization (Cont'd) 850

Sensory Centers, 850; Sense Centers, 851; Association Areas, 852.

CHAPTER XCVII
ditional and Unconditional Reflexes 856

CHAPTER XCVIII

Higher Functions of ■ Cerebrum en Man; Aphasia S00

Psychopathological Applications, s<;l\

CHAPTER XCI2

Functions of the Cerebelli m 865

Localization of Function, 867; Circumscribed Extirpation, 869; Clinical Ob-
servations, 870.

•-Ill

•HAITI B 0

The < i heb! i.i.i m \-i' i n, Bi m< ibci lah i
ociation between th- Eye Movement

< HAITI. K <M

Tin. ,\i roNOMic Nebvoi System

era] Plan of Construction, ^77; Thoracicolui
tem Proper, vs" ; Bulbosaci al Outl
Avii Reflexes, vv;: Functioni ■ • Autonomic N<
the Autonomic Bystem, 885.

[LUSTRATIONS

no.

1. Diagram of osmometer

-. Hematoorite

3. Plasm.. lysis in cells from Tradescantia <h». <>l<.r

i. Apparatus for measurement of the deprest 11

5. Diagram of conductivity sella

•;. Wheatstone Bridge for the meaauremenl . .

7. Diagram t.> show type of electrodes ised in •

'.». < 'hurt of tint- I in coloi i uit-i ri«-

(Color Plate. I

v Diagram of apparatus for the meaauremenl ll ion

i". Diagram of apparatus for saturating bl 1 and t

ll. Van Slyke's apparatus i"r measuring the 00

blood plasma

li'. (Jltramicroacope -lit type) for tin- examinatioi olloidal

1.".. To Bhow diffusion into gelatin of a <r \ -t :il!. ■: :

of a colloid stain

14. Diagram from W. Ostwald showing the relai

colloidal disporsoids compared with a red blood an

anthrax bacillus

i". Capillary analysis of eolloids

16. Diagram to show structure of gels

17. Diagram to illustrate surf.a -inn

iy. Traube's stalagmometer

I1.'. Diagram of tin' graphic coagulometer

20. Coagulometer

21. Mercury manometer and > i Lraa 1 magnet,

torial blood pressure in n laboratory experii

22. The arterial blood pressure r rded with a mercury i

ing) along with a tracing of th<

23. Hiirthle's spring manometer

24. \ i torial pressure recorded bj

26 Diagram based on experiments on

moan blood pi at diff(

26. Apparatus for measuring the arterial bl<
l'7. Effect of cutting the vagus
28. Eff< stimulating th<

Mood pressure

l'!». Effect of stimulation of the lefl spl

sure

."A The effect of rapid and slon hen

."•1. Diau'ra'ii ..r" . xperirn.nt to

elasticity of the all

.".I". Diagram of ^

XXVI ILLUSTRATIONS

FIG. PAGE

33. Optical records of intraventricular pressure 147

34. Superimposed pressure curves after being graduated 149

35. Von Frank's maximal ami minimal valve, which is placed in the course of

the tube between heart and mercury manometer 152

36. Diagram to show the positions of the cardiac valves 155

37. Diagram showing the position of the cardiac chambers and valves during

presystole and during the sphymic period 156

38. Electrophonograms along with intraventricular pressure curves from three

different experiments 159

39. One form of apparatus for recording tracings from an excised heart . . 163

40. Volume curve of ventricles of cat (lower curve) in a heart lung perfusion

preparation 169

tl. Heart and cardiac nerves of Limulus polyphemus 173

42. Heart -block produced by applying clamp 175

43. Tracing of contraction of ventricle, showing the effect of the local appli-

cation of heat to the auricle . 175

t I. Frog heart showing the position of the first and second ligatures of Stannius 176

45. Effects of stimuli of increasing strength on skeletal and cardiac muscle to

illustrate the "all or nothing" principle in the latter 177

46. The effects of successive stimuli on skeletal and cardiac muscle to show the

prominence of the staircase phenomenon, or treppe, in the latter . . 178
17. The effects of successive stimuli and of tetanizing stimuli on skeletal muscle

and cardiac muscle 179

48. Myograms of frog's ventricle, showing effect of excitation by break induc-

tion shocks at various moments of the cardiac cycle 180

49. Heart of tortoise as suspended 183

50. Dissection of heart to show auriculoventricular bundle 184

51. Photograph of model of the auriculoventricular bundle and its ramifications,

constructed from dissections of the heart 184

52. Diagram of an auricle showing the arrangement of the muscle bands; the

concentration point; and the outline of the node 186

53. Diagram to show the general ramifications of the conducting tissue in the

heart of the mammal 186

54. Diagram to illustrate the development and spread of the wave of negativity

in a strip of muscle (curarized sartorius) when stimulated at the end . 188

55. Simultaneous electrocardiograms to show the cause for extrinsic deflections 190

56. Diagram of experiment by Lewis showing the times at which the excitation

wave appeared on the front of the heart 194

."7. Diagram of Chauveau 's drnmograph 200

.IS. Diagram to show principle of Pitot's tubes for measuring velocity pulse . . 201

60. Dudgeon's Bphygmograpn 201

61. Pulse tracing (sphygmogram) taken by Bphygmograph 202

62. Forms of apparatus for measurement of blood -velocities 207

63. Plethysmograph for recording volume changes in the hand and forearm . 210

64. Simultaneous tracings from auricle and ventricle of turtle's heart . . . 218

65. Effect of vagus stimulation on heart of turtle 218

66. Tracing to show thai vagus stimulation may diminish transmission from

auricles to ventricles 219

II. 1. 1 STRAT101

no.
ii7. Tracing to .show thai va

auricles to ventricles

88. Diagram to show the innervatioi bean in tl

Plate, i .'

69. Frog heart tracing showing the action

70. Schematic representation of the innorvati f thi

(Color Plate. I

71. Tracings showing the effects on the hi

stimulation of the sympathetic nerves prior union with I
vagus nerve BM

72. Roy's kidnej oncometer

7.".. Pall of Ii1(m„i pressure from excitation of the deprea

71. Tlic effect of Btrong stimulation (heal the skin i

terial blood pressure and respiratory -

75. Diagram showing the probable arrangi of th<

76. Aortic blood pressure, showing the eff

77. Tracing to -how the eff< _ ity on rial blood pr
7s". The effeel of gravity on the aortic pressure after

<<>r«I in the upper dorsal region

79. Schema to show the relations of the Pacchionian I

so. Trmin^ showing simultaneous recoi the art. -rial M 1 preaSUI

venous pressure, the intracranial j tin- pr

sinuses

81. Electrocardiographic apparatus as made by I

terials Co

82. Noinial electrocardiogram

B3. Electrocardiogram (dog) taken simultaneously witl in«l
ventricle

84. Records of electrocardiogram and movement

that when the apex is warmed a typical T-wave app f ^

wave in the opposite direction appearing when ts

B5. sinus bradycardis

86. Auricular extrasystole

87. Ventricular extra* rising in the ?
38. Ventricular extrasystole arising in the l>-ft i

89. Paroxysmal tachycardia

90. Auricular fibrillation

91. Auricular flutter

92. Delayed eonduetion

l'artial dissociation

94. Complete dissociation

'.'.">. PolyBphygmograph ....

Normal jugular tracing

•■7 Bedui ■ i tracings from carotid,

the general relationsl
98 PolysphyjrmoB ncludlnc

99. Delayed conduction time

ion. Dropped beat

101. Premature beats extra

-
-

XXVI 11 ILLUSTRATIONS

PIG. PAGE

lm'. Paroxysmal tachycardia 278

103. Auricular flutter 279

L04. Auricular flutter _ 279

L05. Auricular fibrillation 280

10(3. Showing the appearance of the blood vessels in the ears of a rabbit in

a state of deep shock. (Color Plate.) 290

L07. Diagram showing amounts of air contained by the lungs in various phases

of ordinary and of forced respiration 301

'108. Pneumograph 303

109. Body plethysmograph for recording respiration 30-4

110. Effect of abdominal and chest breathing on the pulse and blood pressure

of man 308

111. First dorsal vertebra, sixth dorsal vertebra and rib. Axis of rotation shown

in each case 316

111'. Lower half of the thorax from the 6th dorsal to the 4th vertebra, seen

from the front 318

113. Intercostal muscles of 5th and 6th spaces 319

114. Hamberger 's schema to demonstrate the functional antagonism of internal

and external intercostals 319

115. Schema to demonstrate that the function of the internal intercar-

tilaginous intercostals is identical with that of the external in-
terosseous intercostals 320

116. Diagram to show the effect of high and low positions of the diaphragm

on the costal angle 322

117. Diagram to show the effect of clinical displacements of the diaphragm

on the costal angle 323

118 Diagram to show cuts required for isolation of the phrenic center . . . 328
119. Diagram to show certain positions in the medulla and upper cervical

cord, where sections may be made without seriously disturbing the

respirations 329

L20. Diagram to show where cuts are made to isolate the chief respiratory

center from afferent impulses 330

L21. Diagram showing principle for measurement of the tension of CO, in blood 338
L22. The gas analysis pipette for the microtonometer shown in Fig. 123 . . . 339

123. Microtonometer, to be inserted into a blood vessel ,. 339

124. Apparatus for collection of a sample of alveolar air by Haldane's method 340

125. Fridericia's apparatus for measuring the CO, in alveolar air 341

126. Curves to show the relationship between the 02 and CO, tensions in alveolar

air and arterial blood 341

127. Same as Fig. 126, except that in this case the tension of CO, in the

alveolar air was experimentally altered 342

128. Arrangement of meters ami connections of Pearcc's method for measure-

ment of C02 of alveolar air in normal subjects 346

L29. Curve showing the respiratory response to CO, in the decerebrate cat . . 351

130. Tensions of 02 and COj in alveolar air ai different altitudes 361

I'M. Curves showing variations in alveolar <:as tensions after forced breath-
ing for two minutes 364

132. Various types of periodic breathing 372

II. 1. 1 SI ic\

no.

I I. Quantitative record of breath

-' em, in diameter

134. Barcrofl 'a tonometei foi d

by hemoglobin or blood

L35. Bareroft'a differential bl I gaa man

136. Barci ofl blood ^':i> manor

137. Typical dissociation curve. (Color I'

138. Average dissociation cui

139. Dissociation curves of hemoglobin

it". 1 tissocial ion cui \ ea of human bl I . . .

III. Curves Bhow ing relativi

influenced by temperaturi and i

i 12. Curve of < '< > tension in blood

1 13. Cells of parol i'l gland Bho

ill. Parotid gland of rabbit in varying ~ t ; • t .

145. Diagrammatic representation of the inn<

in the dog. i « !oloi Plate

146. Pancreatic acini Btained with hematoxylin

117. Three preparations of pancreatic acini -•

I 18. Diagram showing minial

a double layeT of mucous

1 19. Typical curve retion i

on mastication of palatable f I for

150. Cubic centimeters

and milk

151. Digestive power of the jui

column digested in M. • • ' , with <

L52. Loop of intestine after tying off th<
the middle porl ion and retui i

153. The changes \\lii<-h take place in the

the Bofl palate, the epigli

ge Of SW.-lllnW illL'

154. Schematic outline <>f ii ach

155. I diagrams ol outline and posil

taken on man in thi

impregnated \\iih bismuth Bubnitra
L56. i >u; linca of I he ahadovt b cast ' .■

• r feedii I with I

ir.7. Section of thi tomach

gl\ t'li mi i hree diffi • • ntlj

158. Outlim

after i'. ■ ding W itll ■

159. < nr\ ea to show the

small int.

160. Apparatus for recoi lit

161. 1 diagrammatic repi

162. Intestinal cont rai tions » a«<

t ion of bol li vngi

\xx ILLUSTRATIONS

FIG. PAGE

lti.:. The effect of excitation of both splanchnic nerves on the intestinal

contractions 467

164. The effect of stimulation of right vagus nerve on the intestinal

contractions 468

lii.">. Diagram of time it takes for a capsule containing bismuth to reach the

various parts of the large intestine 469

166. Diagram of method for recording stomach movements 472

167. Tracing of the tonus rhythm of the stomach three hours after a meal . . 473

168. Tracings from the stomach during the culmination of a period of vigorous

gastric hunger contractions 473

169. Showing augmentation of the knee-jerk during the marked hunger con-

* i actions 475

170. Diagram of the uriniferous tubules, the ,'arteries, and the veins of

the kidney 508

171. Cross section of convoluted tubules from kidney of rat 509

172. Diagram of blood supply of Malpighian corpuscle and of convoluted

tubules in amphibian kidney 515

173. Nerve supply of the kidney 520

174. Respiration calorimeter of the Eussell Sage Institute of Pathology,

Bellevue Hospital, New York 536

175. Chart for determining surface area of man in square meters from weight

in kilograms and height in centimeters according to formula . . . 540

176. Diagram of Atwater-Benedict respiration calorimeter 543

177. Nose clip, face mask, and mouthpiece 555

178. Diagram of respiratory valves 556

179. The Tissot spirometer 557

180. The Douglas bag method for determining the respiratory exchange . . 558

181. Haldane gas apparatus and Pearce sampling tube 559

182. Curve constructed from data obtained from a man who fasted for thirty-

one days 567

183. Curves of growth of rats on basal rations plus the various proteins indicated 576

184. Curves of growth of rats on basal rations plus the proteins indicated . . 577

185. Photographs of rats of same brood on various diets 579

186. Vividiffusion apparatus of J. J. Abel 607

187. Curves showing the amount of amino nitrogen taken up by different tis-

sues after the cutaneous injection of amino acids 608

188. Curves showing the concentration of amino-acid nitrogen in the blood dur-

ing fasting and protein digestion 609

189. Curves showing the percentage of glucose in blood after a constant injec-

tion of an 18 per cent solution into a mesenteric vein 658

190. Arrangement of apparatus for recording contractions of a uterine strip,

intestinal strip, or ring, etc 740

191. Tracing showing the effect of epinephrine on the intestinal contractions

and on the arterial blood pressure 741

192. Arrangement of apparatus for perfusion of the vessels of a brainless frog 742

193. Microphotographs of thyroid gland of dog 751

194. Cretin, nineteen years old 7<j4

195. Case of myxedema before and after treatment '55

196. Drawing from a photograph of a mesial sagittal section through the pitui-

tary gland <>f a human fetus in"

II. I

no.

197. Tracing showing the action ol pil I

blood pi • isure in :i dog

L98. Tracing showing the

its effeel <>ii ill I pi

199. Showing the appearai

200. Sand of :i person affected w itii

201. Diagram showing gradual evolution o

anemone, and i arthwoi m

202. Diagram of aen item "i" -■

ganglion, sabeeophageal ganglioi . eso|
203 Schema of Bimple reflex are

204. Thermoesthesiometer

205. Cold spots and heal Boots ol an an

206. Diagram to show axon refl< ry nen

207. Arborization of collaterals from the posterior

of the posterior horn

208. Normal <-<-ll from the anterior horn, stained to ss . . 799

209. Pari of an anterior cornual cell from th<

Bhow neurofibrils

210. I.i\ii!ur nerve cells oxamined by the nltramii

211. Tracing from the hind limb of :i spinal

ments produced by applying stii ;li at •

212. Becord from myograph connected with the

213. Diagram Bhowing the muscles and nervei

vat ion

L'lt. Beciprocal innervation ....

215. Sherrington's diagram illustrating the mechan

216. Diagram showing the reflex ares involved in
l'1 7. Showing region of body of dog from which

218. Diagram Bhowing tl nental arrai the s<

219. Outer aspecl of tli" brain <>t the chimp

220. Three seetions through different pa *'•-'

221. The location of the chief motor and sensoi

• - ..t' the human braia ....
i-'i'L'. Footprints after destruction of tb< " '

223. I diagrams to represent r< -

dorsal \ lew of the righl ha
scheme of snbdivitiioi

224. Schema of the parts mammalian

225 and 226. The inferolateral and tl »■

indicating certaii
The semieircular canals of tl '■

three planes of
8 Diagram Illustrating the diff<

of the volunl I involunl

l'l''.'. Diagrnm of Ihe -• n ' -

Coloi Plat<
Diagram show ing thi
■

XXX11 ILLUSTRATIONS

PIG. PACK

231. Diagram showing the manner in which a preganglionic fiber, emanating

from the spinal nerve by the white ramus communicans, connects in
a ganglion of the sympathetic chain with a nerve cell, the axon of
which then proceeds as the postganglionic liber by way of the gray
ramus communicans back to the spinal nerve, along which it travels
to the periphery. (Color Plate.) 880

232. Diagram showing the main parts of the autonomic nervous system to be

used along with Fig. 229. ( Color Plate.) 882

I'."..".. Schematic representation of the involuntary nervous system. (Color Plate.) 884

PHYSIOLOGY AND BIOCHEMISTRY
IN MODKRN MEDICINE

PART I

THE PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL

PROCESSES

CHAPTER I
GENERAL « 0NSIDERATIO1

The work of the physiologisl consists, in larf t, in as

whal extenl the known laws of physics and chemistry
in explaining the phenomena of lit'.-. 11. gatl
house of physical and chemical knowledge wi
interpretation of the various mechanisms thai w
pose the Living machine, and having added to tins k

it on for use by those who ar< ncerned in th<

disease.

Many of tin1 most importanl steps in the ad

knowledge in r ill years have depended upi

hitherto unknown physical or chemical law, or upon th<

some accurate method for the measurement

which these or previously known laws d<

van't Hoff, Arrhenius, and Ostwald of th<

were Boon followed by important obe

the movemenl of fluids and dissolv<

branes; the discos eriea of Hardy, \\

colloids and of the phenomena

explaining many hitherto inexplic

ferments; the die x

of the electro mol ive for

termine the actual

1

2 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

fluids, and to explain the general ion of the electric currents which ac-
company muscular, nervous, and glandular activity.

It would be out of place here to devote much space to a detailed ac-
count of such matters. They belong more properly in the domain of
general than in that of human physiology. General physiology is con-
cerned with the study of the essential nature of the vital processes;
whereas human physiology is merely a branch of the subject in which
special attention is devoted to the application of the truths of general
physiology to the working of the human machine. For the physician
and surgeon a knowledge of human physiology is as essential as is a
knowledge of the construction of a piece of machinery for the engineer
who attempts its repair, but obviously to acquire this knowledge the
fundamental principles of general physiology must first of all be under-
stood. For these reasons the introductory chapters are devoted to a
brief review of the most important of the physicochemical principles
upon which the working of the cell depends.

From the viewpoint of the physical chemist the cell consists of an
envelope of more or less permeable material inclosing a dilute solution
of crystalline substances in which colloid matter is suspended. It con-
tains, in other Avords, a solution of crystalloids and colloids, in which
these are in a state of equilibrium with each other. This equilibrium is
readily altered by various influences that may act on the cell, and the
resulting changes manifest themselves outwardly by alterations in the
shape and volume of the cell — growth and motion; by the extrusion of
some of its contents — secretion; or by the propagation to other parts of
the cell, or its processes, of the state of disturbed equilibrium — nervous
impulse. Besides the activities that are dependent upon physicochem-
ical changes, purely chemical processes go on in the cell. Many of
these consist in the breakdown and oxidation of complex unstable organic
molecules, a process identical with that occurring in combustion outside
the cell. Others involve the building up, stage by stage, of complex
substances out of the elements or out of simpler molecules. Chemical
transformations occur in the cell which, in the chemical laboratory, re-
quire the most powerful rea gents and physicochemical forces, either the
strongest of acids, alkalies, oxidizing agents, etc., or extreme degrees
of heat, electrical energy, etc. But this is not all, for in the cell these
chemical transformations are capable of being guided to a very remark-
able degree of nicety so as to produce intermediate products that are
used for some special purpose either by the cell that produced them or,
after transportation by the blood, etc., by cells in other parts of the
organism.

It is customary to speak of the cell as a chemical laboratory, but it

I.\

is more than this; it is a laboral
in-lit of the chemist l>nt directed in the I
many activities by a guiding hand which
to man. Chemical transformations thai

the greatest skill pro, 1 withoul appa ifficulty in I

what are these changes due w I al is l

gents and forces, and what is the dii

in their varied activities) To these, which

lions of genera] physiology, the reply n

are the ferments or enzymes, and that the dii

through the susceptibility of enzymic acti\

ronmenl in which the enzymes are acting. In mat

can be explained on a physicochemical depei

known laws of mass action or surfac lion; ii

pend on purely chemical changes in

in reaction or the accumulation of chemical sul

poisons on the enzj me. Bui 1 1 ■

on influences which as yel arc quite unknown to tl •

such as the changes in cell activity thai can be

nerve impulse.

These preliminary remarks will serve to indicate ti
which we musl firsl occupy our attention. Tl
chemical nature of saline solutions
ture of enzyme action. The knowledge which

to be of value, not only 1 anse it will help

of the workings of the normal healthy cell, bul

it will indicate possible causes for derangemenl in cellul

Buggesl rational means bj which we may

THE PHYSICOCHEMICAL LAWS OF SOLUTION

The 0«l La

Three fundamental princip
for an understanding of the nati
we take a quantity of anj
called a '-Mam molecule or I
actly 22.4 liters at
that, as we compn
same proportion as the volume din
proportional to it- pn

4 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

pari of their volume a1 0 C. for every degree C. that their temperature

is raised.* •

The pressure of a gas is measured by connecting a pressure gauge or
manometer with the vessel which contains the gas. Now, it is plain
that if the 22.4 liters, which is the volume occupied by a gram-molecular
quantity, were compressed so as to occupy a volume of 1 liter, its pressure
would be 22.4 times that of 1 atmosphere, or 22.4 x 760 mm. Hg — the
temperature remaining constant. Under these conditions we must im-
agine that the molecules of gas are crowded together by the compression,
and if we further conceive of these molecules as being in constant mo-
tion, then we can understand why the pressure should increase just in
proportion as we confine the space in which they can move.

One other property of gases must be borne in mind — namely, their
tendency to diffuse from places where the pressure is high to places
where it is low until the pressure is the same throughout.

OSMOTIC PRESSURE

These fundamental facts regarding the behavior of gases suggested
to van't Hoff the hypothesis that molecules of dissolved substances must
behave in a similar manner to those of gases. To put this hypothesis to
the .test, it is necessary that we have some method for measuring the
pressure of dissolved molecules. We can not, as in the case of a gas,
use an ordinary manometer, for this, would measure only the pressure
of the solvent on the walls of its container and would tell us nothing of
the pressure of the dissolved molecules. "We must use some filter or
membrane that will allow the molecules of the solvent but not those of
the dissolved substance to pass through it. It is evident that if such a
filter is placed, for example, between a solution of sugar in water and
water alone, the molecules of the latter will diffuse into the solution
until this has become so diluted that the pressure of the dissolved mol-
ecules, is equal on both sides of the membrane. Such a membrane is
called semipermeable; the diffusion of molecules through it is called
osmosis, and the pressure which is generated, the osmotic pressure. If
we prevent the water molecules from actually diffusing by opposing
a pressure which is equal to that with which they tend to diffuse through
the membrane, Ave can tell the magnitude of the osmotic pressure (Fig. 1).

In applying these facts to test the hypothesis that molecules in solution

*This implies that at -273° C. the gas would occupy no volume. P.efore this temperature is
reached, however, the liquefaction of the gas sets in. The temperature -273° C. is known as absolute
zero. An observed temperature plus 273° is called the absolute temperature. Another way of stat-
ing the above law is t that the volume- is directly proportional to the temperature.
At 273° C. the volume of a gas at 0° C. would be doubled, or if expansion were prevented the
pressure would be doubled.

obey the same lav

permeable membrane which ia rigid
and which forma pari of the wal
manometer. 1 £ \\ e place in Mich an osm<
molecular weight in grama of Borne rob
solvent, a Bo-called -ram molecular Bolution, •
gas laws are to apply, the osmotic p
liters of a gaa compressed to the volumi
it should equal 22 t 760 nun. Hg AJtl
able technical difficulties in making a semi]
strong enough to withstand such a p

'W-'M'.ihSi

r:

w

1 I >ia( I'he

le membr;
r, and W i
the

:rr.

-

plished, ami the fundamental princip
lished that substances in solution i

Further proof that the gas lawa ap]
showing that tli.' osmotic i>: ■
portional t<> the ci
ami t.» the absolute temp '

sures, which states that t '•
or <liss.»l\ ed molecu es) is the sum of 1
ucnl «>t* tli.- mixture would
npied 1>\ the mixtt

6 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

Since the osmotic pressure is analogous to the pressure of a gas and
is therefore proportional to the molecular concent ration (i.e., number
of molecules in unit space), it follows that a semipermeable membrane
can be used to determine the relative concentration of two solutions of
the same substance. When a watery solution of some substance is
placed in an osmometer that is surrounded by a similar but more dilute
solution, -water molecules will diffuse into the osmometer until the pres-
sure is equal on the two sides of the semipermeable membrane; that is,
the water Avill pass from the solution having a lower osmotic pressure
into the solution having the higher pressure. When two solutions have
the same osmotic pressure, they are said to be isotonic; when that of one
is greater than that of the other, it is hypertonic; and when less, hypotonic.

Biological Methods for Measuring Osmotic Pressure

A practical biological application of these principles can very readily
be made if, instead of a rigid semipermeable membrane such as that
figured in the diagram, we employ one that is extensible and takes the
form of a closed sac ; then as diffusion of water occurs the sac will either
distend when it contains a stronger solution than that outside, or shrivel
or crenate when the reverse conditions obtain. Many animal and veg-
etable protoplasmic membranes are semipermeable, including the en-
velope of red blood corpuscles. Thus, if we examine blood corpuscles
under the microscope and add to them a saline solution of higher os-
motic pressure than blood serum, they will visibly diminish in size and
become irregular in shape; whereas if the solution is of lower osmotic
pressure, they will distend. If no change occurs, the osmotic pressure of
the cell contents must equal that of the saline solution in which the cells
are immersed, from which it is clear that Ave can readily determine the
magnitude of the osmotic pressure if Ave know the strength of the
saline solution.

Instead of measuring the individual cells under the microscope, Ave can
measure the space they occupy in the fluid in which they are suspended.
For this purpose a portion of the suspension is placed in a graduated
tube of narrow bore, whieh is rotated in a horizontal position by a cen-
trifuge after being closed at one end. The graduation at which the
upper edge of the column of cells stands after centrifugirig is a measure
of the relative amount of cells and fluid in the suspension. Having
Pound this value for cells suspended in an isotonic solution, as for blood
corpuscles in blood serum, we may then proceed to ascertain it for the
same cells suspended in an unknown solution; if we find thai the cells
occupy a greater volume, the saline solution must have an osmotic pres

LAWS

Biire th.it is lower than thai of Berum in ap
readings on the tube in the two and i

The above apparatus, called a hematocrite I g 2
tensively used in the collection of data i
pressures of diflferenl physiological fluids.

Hemolysis

Another way for determining the relal

ferenl solutions i sists in placing equal ami

bl I in a series of test tubes containi

and after allowing the tubes to Btand for some tin - in tvl

them taking <>f the blood corpuscles urt l

isotonic or hypertonic \\ ith the contenl
will Bettle to the bottom of the tube and tl
untinted with hemoglobin, but in solutions which are d
the sediment will be less distincl ami ilu- su]

Fig. 2.- Hi-mat... i ite. Th< pra

at which tin- corpus

! in which l

By noting I the l<»w esl concentration
i he solul ions in \\ lii'-li the corpusc
Bupernatanl ilni<l colorless, and 2 the Iur
the corpuscles when they settle leave th<
determine the limiting concentratioi
stances. Thus, with bullock's 1>I<><"! the tol
Hamburger :

a

•

KNO

n ica

K M |

C II 0

1 •

• Ml coon

MBSO,.

711:

1

8 PHYSIC0CHEM1CAL BASIS OF PHYSIOLOGICAL PROCESSES

The mean of these limiting concentrations is the critical concentration
and indicates the strength of each solution that can be added to blood
-without causing any damage to the corpuscles. This critical concen-
tration is not, as migh.1 at first sight be imagined, the same as that
which is isotonic with the contents of the corpuscles, but distinctly
below it. The reason for this becomes apparent if we observe the be-
havior of corpuscles suspended in an isotonic solution which is then
gradually diluted. As dilution proceeds, the corpuscles distend, until at
last their envelopes burst and the hemoglobin is discharged. The lim-
iting concentrations of a given salt vary for different corpuscles; thus,
the concentration of sodium chloride solution that just causes laking of
frog's blood corpuscles is 0.21 per cent, of human blood 0.47 per cent,
and of horse blood 0.68 per cent. It is the strength of the corpuscular
envelope rather than variations in the osmotic pressure of the contents
that is responsible for these differences.

The above described method of hemolysis, as it is called, can not be
used for comparisons of osmotic pressure in cases in which the solution
contains substances which alter the permeability of the corpuscular
envelop; for example, it can not be used when urea, or ammonium
salts, or certain toxic bodies are present. This very fact is, however,
put to a useful purpose in ascertaining whether a given substance does
have a damaging influence on the corpuscular envelope by finding whether
hemolysis occurs when we suspend the corpuscles in a solution that is
isotonic with the corpuscular contents. AVe can further determine the
degree of this toxic influence by estimating by color comparisons
(colorimetry) the amount of hemoglobin that has diffused out of the
corpuscles.

Plasmolysis

An analogous method for determining osmotic pressure is that of
plasmolysis, in which the behavior of certain plant cells is observed
microscopically while they are in contact with solutions of different
strengths. When the surrounding solution is isotonic with the cell
contents, the latter fill the cell and extend up to the more or less rigid
cell wall (A in Fig. 3) ; but when the solution is hypotonic, the cell
contents become detached from the cell wall at one or more places —
plasmolysis' (B and C). The semipermeable membrane in this case is
therefore not the cell Avail but the layer of protoplasm on the surface
of the cell contents. The method can be used only for detecting solu-
tions thai are hypertonic, for with those that are hypotonic the cells
merely become turgid and exert more pressure on the more or less
rigid cell wall. Many of tin- conclusions that have been drawn from

].\

results obtained by the plasmol;

question, becausi no r< gai d

of the cell to adsorb imbibe w i I

Tlir methods of hemolysis ;i
investigation <>!' manj problems in i
toxic fluids, Buch ;i-> snal
the hemolytic i»<>w er has pro\ • •<! of \ alut
aging influence on other ■•••IK than bli

vsis have also been es] ially valuable in workii

by which, cellular toxins j:

under which this action may be count

M cai
wall; /\ tin

•

antibodies. Furtherm it i« m that

animal body, either intra »H

be tested by the above methods in

with the body fluids. It a hyp.

in the abstraction of wain- from the tis

solution will cause the water conl

has recently been taken of thi

solutions in the treatmenl of w< B

strong saline solutions, an outflov

.•.•lis thai border on the wound, at

infection the defensive substai i

CHAPTER II
OSMOTIC PRESSURE (Cont'd)

Measurement by Depression of Freezing Point

The limitations in the use of the plasinolytic and hemolytic methods
in the precise measurement of the osmotic pressure of the body fluids
have rendered it necessary to find some physical method that will be
generally applicable. Because of technical difficulties, it is impracticable
to measure the pressure directly by employing an osmometer, so that
some indirect method, depending on a readily measurable physical prop-
erty which varies in proportion to the osmotic pressure of the dissolved
substances, must be used. Fortunately, one such exists in the property
which dissolved substances have in lowering the temperature at which
the pure solvent solidifies; the freezing point of pure water, for example,
is lowered when substances are dissolved in it, and the extent of this
lowering, with certain reservations which will be explained later (page
16), is proportional to the molecular concentration of the solution and
independent of the chemical nature of the substance dissolved. This
lowering of temperature is designated by the Greek letter A, and to
measure it a thermometer is used which is not only extremely sensitive
but in which the level of the mercury column can be adjusted so that it
stands at a convenient level on the scale corresponding to the freezing
point of whatever solvent was used in making the solution under investi-
gation (Beckmann's thermometer) (Fig. 4). The exact position on
the scale of this thermometer at which the pure solvent freezes having
been ascertained, the observation is repeated with the solution whose
osmotic pressure is to be determined.

A gram-molecular solution in water (having therefore an osmotic pres-
sure of 170,240 mm. Hg) has a freezing point that is 1.86° C. lower than
that of pure water. This is known as the "freezing point constant,"
and it varies for different solvents, being 3.9 for acetic acid and 4.9
for benzene. If an unknown watery solution is found to have a freez-
ing point that is A° C. lower than that of water, its osmotic pressure

... .Axl7.024 _

will equal — ^-^ mm. Hg.

10

DTK I!.

II

The depression of the freezing points p

fluids has been compared, '1 bjecta in

osmotic pressure is a property which changes under
and pathological conditions, and to find out
pressures of the fluids in contacl with a d
forces alone can l><' held responsible for th<
through it from one fluid to the other.

The Role of Osmosis, Diffusion, and Allied Processes in Physiological

Mechanisms

An account of some <>!' the investigations in which
methods have I n used will illustrate their value

\

J

< ;

I

Pig, a. \
solution is pi

, in then
tin- men

•
thertnooM ter ii vai
thin placed in

mechanism involved in I
stances through cell membri
intestine, in the formation of
ploying physical methods in
always mos1 n<

12 I'HYSICOCIIEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

chemist works with pure solutions, while the physiologist has to use
fluids thai are always complicated and frequently very variable in com-
position. We must simplify the problem as far as possible by having
clearly before us the exact nature of the biological problem which a com-
parison of physicochemical values, such as osmotic pressure, may ena-
ble us to elucidate, and we must consider the other physical forces
which may assist or modify the particular one we arc investigating.

In the physical experiments described above, the semipermeable mem-
brane may be conceived of as composed of pores of such a size that
they permit only the smallest of molecules — those of water — to pass
through them. Semipermeable membranes with larger pores may, how-
ever, exist — that is, membranes which permit water molecules and mole-
cules of simple chemical substances to pass, but hold back those com-
posed of large complex molecules. Such a semipermeable membrane
would alloAV the saline constituents but not the proteins of blood serum
to pass. It is, however, no longer semipermeable towards all of the dis-
solved substances, and the process of diffusion through it is more gener-
ally designated as one of dialysis than of osmosis.

Since the passage of dissolved molecules through membranes de-
pends upon the principle of diffusion, its rate will be proportional to
the osmotic pressures of the solutions on the two surfaces of the mem-
brane and to the size of the molecules, small molecules diffusing more
quickly than large ones. Suppose a membrane permeable to sodium
chloride and water is placed between two fluids containing sodium
chloride in solution, but in greater concentration in one of them than
in the other: the sodium chloride will diffuse from the stronger to the
weaker solution, and water will diffuse still more quickly (because its
molecules are smaller) in the opposite direction, until the number of
sodium-chloride molecules in a given volume of solution is equal on
Imtli sides of the membrane. For a time, therefore, the volume of the
stronger solution will increase. The differences which exist in the dif-
fusibility of dissolved molecules are analogous to those which have
long been known to exist in the diffusibility of gases, but the relation
between rate of diffusibility and molecular weight is not so simple as
the ratio between these two quantities in gases. These relationships,
however, indicate several further possibilities in the explanation of the
mechanism of exchange of substances through membranes, and must not
be overlooked, as they often are, in the interpretation of physiological
phenomena. An excellent review of the possible conditions is given
by Starling in his "Human Physiology."4 For example, let us suppose
the substances on the two 'sides of a semipermeable membrane, such
as the peritoneal, to be different in diffusibility, as cane sugar,

won<

which does qoI readily diffusi

quickly; tl smotic flow will take place from th<

tion to tl ane sugar even when the sodium ch

than the sugar. In such a case, water n
having the higher osmotic pressure Na<
this is lower I sugar .

Furthermore, the simple laws of osmoe
five influence of the membrane toward certain
becoming dissolved or adsorbed in r
others. Many membram

(e. £.. rubber membranes in contact with pyrid

and it is probable that such a property

a not unimportanl role in tin- transferei animal

membranes Kahlenberg

These few conditions which may modify the dir<
flow, are indicated here to show how i> ich pit and

how careful we musl be no1 to assume that.
ferred through a li\i 1 1 <_r membrane contrary to the simpler la
mosia ami diffusion, it must involve the
from those operating in dead membranes

Another force comes into operation under certain c<
that of filtration. 'I 'his i-. ;! purely mechanical pi ich m<

cules are forced through the pi I a filter

aces in pressure on its two si ■

We are now in a ]>o->iti.in to consider in how far I
forces explain certain physiological problen -

1. Is tin absorption, into tin b
tinal walls, of substana < in thi

dependent up,,,, tin pi ■/ filtration,

absorption of weak solutions of highly diflfu
very largely a matter of osmosis and din*
into the blood because of osmotic i . but *

narily come into plaj ry elearlj

servations. 1 1' a pi t* int<

two ligatures on it. and the isolated lo<
taining the same saline constituenl
Berum, or better b1 ill. w ith son
will l»e found after some time thai
into the blood : the contet

l»loo«l, e\ en though the OSmot

the same on both sides of lie membrj • v

The intestinal membrj

14 PHYSICOCHEMICAL basis of physiological processes

substances a permeability which varies, not at all with the physical
(liffusibility of the substance, bui with its value from a physiological
standpoint. Thus, sodium sulphate and sodium chloride diffuse through
ordinary membranes with about equal facility, and yet if a solution con-
taining these two salts is placed in the intestine, the chloride will be
absorbed into the blood much more quickly than the sulphate. Sodium
sulphate in watery solution diffuses through a membrane fifteen times
more quickly than cane sugar, but from the intestinal lumen, cane
sugar is absorbed ten times more quickly than sodium sulphate. If.
however, the vitality of the epithelium is destroyed, as by first of all
bathing it with a solution of sodium fluoride, then the sulphate and
chloride will be absorbed at an equal rate.

Although diffusion and osmosis can not therefore play any significant
role in the normal process of absorption from the intestine, we must
not entirely discount them ; under certain circumstances, these physical
forces may assert their influence as, for example, when concentrated
saline solutions are present. Such solutions will attract water from the
blood, and, other things being equal, more will be attracted the less
permeable the epithelium happens to be towards the saline employed.
Sulphates and phosphates will attract more water than chlorides or
acetates. This property of the saline solutions to attract water coun-
teracts the natural tendency for the water to be absorbed, and the
large volume of fluid stimulates peristalsis.

2. Do the physical processes of filtration, diffusion and osmosis suf-
fice lo account for the production of urine ~by the kidneys? Under normal
conditions the molecular concentration of the urine, as determined by
the depression of freezing point, is considerably greater than that of
the blood. This indicates that excretion must have occurred contrary
to the laws of osmosis ; in other words, that the renal cells must have
compelled dissolved molecules to be transferred from the blood to the
urine, although the difference in osmotic pressure would cause them to
pass in the opposite direction. This force, sometimes called for want
of a better name "vital activity," must depend on the operation of
processes that are quite distinct from those of diffusion, etc.; but that
they are necessarily of a nonphysical nature (e. g., vital) is less probable
than that they depend on some physical process the nature of which our
present knowledge does not permit us to understand.

By comparing the osmotic pressures of urine and blood, attempts
have been made to measure the work done by the kidney in the produc-
lion of urine. Thus, it has been found that A for normal urine (human)
is about 1.8, and for blood about 0.6, from which it may be calculated
that in the production of 1 kilogram of urine 150 kilogrammeters of

MOTK r*Rl 1",

work are expended. Bui thai such compe

sure of blood and urine are fallaciou

the kidney is evidenced, uol alone by tl

tions, bu1 also by the fad thai und< circui

copious diuresis the osmotic pressure of tl e ui ii •

lower than thai of the Mood. Thai opp

indicates thai differences in osmotic pr<

can Bignify little it" anything regarding the work • !•

For some time after the application of osmotic p
to the study of biological problems, it was tl

of a in urine might 1 f clinical valui

especially in one kidney as compared with the other For ,; ><me

a was determined in samples of ur moved from each

catheterization. The tests of renal efficiency based on tl
tion of potassium iodide, phenolphthaleii
of much greater value.

3. Is the formation of lymph purely n pi
pressure of normal Lymph is nearly always somewhal
blood serum, although occasionally it lias h.
higher. Physical proi rach as filtration, might I

to accounl for its formation under m <liti«.i^ Bui

Bider the excessive production of lymph that
hilar activity or following tin- injection o
"lymphagogues," it is no1 so easj to explain tl
terms, although some interesting attempts have b<
those that are wedded to the mechanistic
marked increase in lymph flow which occurs
exercise or glandular activity has been attributi
ing such processes large molecules become brok
in tin- cell protoplasm, so that the osmotic |
is attracted into the the cell until the latter I
process of filtration into 'If ing lympl

page ll"

There are Beveral other phj -
tion which 1 1 1 i *_r 1 1 1 be considered in Ihe
instances w ill suffice tn illustral

t In- in ha\ e tn be considered

thai

eaual t

the kuliirv in pi

CHAPTER III
ELECTRIC CONDUCTIVITY, DISSOCIATION, AND IONIZATION

The osmotic pressure is not infrequently found to be considerably
greater than that expected from the strength of the solution. Although
A of a gram-molecular watery solution of cane sugar (342 gm. to the liter)
is 1.86 (see page 10), that of sodium chloride (58.5 gm. to the liter) is
considerably greater. If the hypothesis regarding the relationship of
molecular concentration to osmotic pressure is to hold good, it becomes
necessary to explain this apparent inconsistency; one must account for
a greater number of dissolved units than is represented by the actual
number of dissolved molecules (i.e., weight of dissolved substances).

It was observed that the power to conduct the electric current— electric
conductivity — in the case of solutions (e. g., of sugar) which have an
osmotic pressure that corresponds to the weight of dissolved substances
is practically nil, whereas the conductivity of those solutions which give
higher osmotic pressure is quite pronounced. Arrhenius made the hy-
pothesis that the conductivity depends on the splitting of molecules into
two or more portions or ions, each of which carries either a positive or a
negative electric charge, and that it is only when such dissociation occurs
that the electric current can be conducted through the solution, the ions
serving as it were as floats carrying the electric current. When sodium
chloride is dissolved in water, it splits into Na carrying a positive charge
and CI carrying a negative charge, or Na + Cl-, as it is written; on the
other hand, when sugar is dissolved, the molecules remain unbroken and
no electric charges are set free.

Substances which thus dissociate are called electrolytes, and those which
do not, nonelectrolytes. When the electric current is passed through a
solution of electrolytes, the ions which carry a positive charge move to
the electrode or pole by which the current leaves the solution — that is, in
the same directions as the current; and since this electrode is called the
cathode, these are called cations. Hydrogen and the metals belong to
this group. The ions carrying a negative charge go in the opposite direc-
tion, against the current — that is, towards the electrode by which the cur-
rent enters, or the anode; they are therefore called anions. They include
oxygen, the halogens and the acid groups, such as S0.1; C03, etc.

It must be understood that this dissociation into ions is already present
in the solution before any electric current passes through it, the ions

16

RLECTRIC < ONDl I 1 i\ ll V. I) 17

being however uniformly distributed tl
thai ili«' negath e charges of the anioi
charges of the cations. The electric curr<
conic cluii <n'd, the one positively, the oth<
tive force is exerted on the ions of oppoe t<
lively charged ions to migrate towards the i>
positively charged, towards the negativi
of t 1m- ions thai endows the solution with conducti

In water, or in a solution of a nonelectrolyte, moli 1 1 1 1 •• non-

electrolyte exisl thus:

II 0 II 0 II 0

II 0 II 0 II <»

II 0 II 0 H,0

In a solution of an electrolyte, the molecules split into ions I

\a CI- Na CI Na CI-
\a el Na CI- Na CI-

\a CI \- CI- Na CI-

When an electric currenl passes through a solution
tin- ions tend i<» arrange themselves tl

Cathode

An

\a V

\

("1

CI

l

\a \.:

V

CI

CI

1

\a V

\'a

CI

CI

CI

It follows from the above considerations tl
stanct in solution will <l> i>> ml on tfu </•
tion. Furthermore, if v. ime thai in

phenomena are concerned, each ion behaves in thi
cule, tlifii it follows thai the electrical nal

tn tl jctenl to w liicli the ■ »-- 1 n < > t

peel it to I"' from the amounl <>f substance actual!

In the Determination of the Conductiviu
use Btandard conditions of depth and width i
currenl is passed, and t<> ha\ •• bod
is thru know n i u
being the conducth it;
centimeter cube, w ould ofl
sides of the cube actii

is

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

ally made in a cylindrical vessel of hard glass I from soft glass enough
alkali might be dissolved to affect the results), the electrodes being circu-
lar plates of platinum firmly cemented at a known distance from each
other (Fig. 5).* This conductivity cell, as it is called, is connected
with, a suitable electric apparatus for measuring the resistance offered

w s:

Fig. 5.-— Diagram of conductivity cells. The platinum discs are represented by the thick
hlack lines. They are held in position by thick-walled glass tubes, through which they are
connected with the terminals by platinum wires. (From Spencer.)

by the solution to the passage of an electric current (Wheatstone Bridge)
(see Fig. 6). The resistance is of course inversely proportional to the
conductivity.

As a saline solution is progressively diluted, its specific conductivity
naturally decreases (since there are now fewer molecules between the

Fig. d. — Wheatstone IJridge for the measurement of electric resistance: a-b, bridge wire; c,

the movable contact.

two opposite faces of the centimeter cube, and the space between ions or
molecules is increased). This result will not, however, tell us whether
the salt itself is undergoing any alteration in conducting power as a con-
sequence, for example, of greater dissociation. To ascertain this we must

'This distance is determined not by direct measurement but by calculation from results obtained
by testing the actual resistance of a solution whose specific resistance is accurately known.

I l.Ii I RI4 < ONDU< Tl\ II V, OlfcKOl I -

obtain figures relating to the quanl I

we multiply the specific conductivity by it
which contains I gram-equivalent (see page 22

which represents the« < lucting power oi quival< i

known as the equivalent or molecular t

the sign a. When ii is determined for pro dilute

a gradually increases, indicating thai I

as a conductor im n i with dilution, I"

extenl of this increase is found i<» I ome •

proceeds. By plotting the values of the molecule
i\>' dilutions as a curve, the value at infinite dilul
by extrapolation. 'Plus value is repr< c.

Now, lei us see how these facts bear out the
tii ii i. According to this hypothesis the conductivity d<
ber nf imis (see page IT . and since it is al a maximum Illa-

tion, //" valut a •- must represent tin total
duced by the dissociation of t gran

dilution. I f, therefore, we divide a by \ we obtain a val
which must represent the degree to which th<
various dilutions a1 which A is measured. Prom whal 1
garding the osmotic pressure of similar solutions, it
value a could also be calculated by finding th<
pression of freezing poinl a is greater than would 1"
number of dissolved molecules. An a matte
thai practically identical values are obtained many

furnishing almosl incontrovertible proof in supp<
hypothesis. In the cases of weak ;i<i< Is and bases, ii
a value, called the dissociai istant K which

tive values nf ,i at all dilutions. Since the activil
is dependenl upon the number of 1 1 and < »ll
by dissociation, it follows that it must be p 8 [1

necessary to postpone a consideration of the ;■!':•
until we have studied mass n pag<

Biological Applications. The practical val kn

not bo much on any dired simple applic
explaining physiological pnx
which it has iu enabling us to ui
other phy8icochemical factors concerned in p
out a clear comprehension i
impossible to consider Buch problei

•In ol

gram r.|iir.

20 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

of enzymes (mass action, etc.), the occurrence of electric cm-rents during
the physiological activity of muscles, glands, and nerves, ;m<l the all-
important question of the reaction or H-ion concentration of the body
fluids.

Before proceeding to show how these facts concerning the nature of
solutions are applicable to the study of physiological processes, it may be
well to indicate one or two instances in which measurements of electrical
conductivity and of dissociation have direct physiologic value. The circu-
lation time of the bloodttow through an organ can be determined by first
finding the electrical resistance of a short piece of the vein of the organ,
and then observing the change in resistance which is produced wrhen the
conductivity of the blood in the vein is altered by the arrival in it of
saline injected into the artery. The interval elapsing between the injec-
tion into the artery and the changes in resistance in the vein obviously
equals the circulation time (G. N. Stewart).

The same investigator has used measurements by electrical conductiv-
ity to study the passage of electrolytes out of the red blood corpuscles into
the serum. Under normal conditions the blood serum has a certain elec-
trical conductivity equal to that of a 0.9 per cent sodium-chloride solution.
The conductivity of the defibrinated blood is only about one-half that of
serum, because it contains corpuscles which are nonconductors and there-
fore obstruct the free passage of the ions, just as a suspension of quartz
powder in a sodium-chloride solution lowers the conductivity of the lat-
ter. If anything occurs therefore to occasion a passage of the saline con-
tents of the corpuscles through their walls into the serum, an increase in
the electric conductivity will be produced. The value of this method in
the investigation of changes in permeability of the red corpuscles is de-
pendent on the fact that such migration of electrolytes out of the cor-
puscles may occur before any of the less diffusible hemoglobin itself has
escaped. The rise in conductivity precedes the hemolysis (see page 7).

Although determinations of the specific conductivity of blood and urine
under various pathological conditions have also been made, the results
have not been found to possess any diagnostic value or clinical signifi-
cance. Measurements of the electric conductivity of blood have, how-
ever, been used by Wilson7 and by Priestley and Haldane8 to detect the
degree of dilution when large quantities of water are ingested.

Another application of conductivity measurements in biochemistry has
been made in studying the digestive action of proteolytic enzymes (Bay-
liss). The general action of the enzymes is to break the large undisso-
ciated molecules of the higher proteins (albumin, casein, etc.), into
smaller molecules (amino acids, etc.), which are partly ionized. As diges-

I I.I i IKK I 0ND1 « I l\ II \ . DIKKOI'I \

lion proceeds, therefore, the conducth it;
gressively increases, ;ni<l is a measure of th<
Applications of tin dissociation hypol in i>!

explanation of such phei lena as tl

during muscular, glandular, and nen i I i

the application are nol as yel sufficiently understood I

tempting to <h» more than indicate the

problems are being im estigated. I

currenl of action of muscle maj be explained in I

hypothesis. To 'I" so we must delve a little further into pi ;•

ical research, when we shall find thai th(

cerning ionized molecules that musl I"- of import

our problem. The firsl is thai th intribution which

the equivalenl (or molecular conductivity o olution
of the other ion with which it is associated; ami th.

differ « siderably in their conducting power. 3

K , \'a.. ('|/, \< i ', carry charges of th.- Bame magnitude, • .

not conduct t<> thr same degree, thej musl m<

through the solution. We are driven, therefori

exposed to the same electric force, different ions have diffi

tics: that is to Bay, when an electric currenl p.isv.^ throuj

an electrolyte, the positively charged ions mo

differeni rate from thai at which the negativelj i

towards the a !<■. Confirmation of this conclusion is

ination of the concentration changes around th.- tw
electrolytic cell. The actual velocity ch ion •

experimental means.

•Thus Tar;:
same ratio a>. their chemical equivsh

CHAPTER IV

THE PRINCIPLES INVOLVED IN THE DETERMINATION OF THE
HYDROGEN-ION CONCENTRATION

TITRABLE ACIDITY AND ALKALINITY

All acids have one property in common — namely, that they contain
hydrogen — and when the acid becomes neutralized, it is this element
which becomes replaced by some other cation. Evidently, then, the
strength of an acid is proportional to the number of displaceable hydro-
gen atoms which it contains. It may contain other hydrogen atoms
which are so bound up in the molecule that they do not become displaced
when an alkali is mixed with the acid. For example, in organic acids
like acetic, CH3COOH, it is only the H atom attached to the COOH
group, but not those attached to the CH3 group, that is replaceable. It
must therefore be possible to prepare for every acid a solution having
exactly the same neutralizing power as that of any other acid; that is,
the same volume of solution must be required in each case to neutralize
a given quantity of alkali, the point of neutralization being judged by
the change in color of indicators. As a standard a gram-molecular solu-
tion of an acid with one displaceable H ion, such as hydrochloric, is
chosen. This we call a "normal acid" (N). To prepare a normal solu-
tion of acids having two displaceable IT atoms, such as H2S04, we can not
however use a gram-molecular quantity, but must take one-half of it;
and similarly in the case of those with three H atoms, such as H3P04,
a one-third gram-molecular solution will be a normal acid solution. For
practical purposes, use is very generally made of solutions that are some
fraction of the normal, e. g., tenth or decinormal (written N/10), or hun-
dredth or centinormal (N/100).

In a similar way, alkaline solutions can be prepared, a normal alkali
being one which exactly corresponds in strength with a normal acid
(i.e., can exactly neutralize it). Now, the characteristic of alkalies is
that they produce in solution "OH" or hydroxy] ions; so that the process
of neutralization must consist in the union of the H ions of the acid with
• the OH ions of the alkali to form water: KOH + HC1 = = KC1 +H20. We
can, therefore, prepare normal solutions of alkalies by dissolving in 1
liter of water such quantities of alkali (in grams) as will yield the Oil
required to read with the available hydrogen in normal acid solutions.

22

BYDR<

Actual Degree of Acidity or AlkalimU
method of titration a normal solution oi
as hydrochloric, is no stronger than a normal
such as acetic or lactic. It requ
it. But the normal solution of tl
more toxic, dissolves metals more readily, and in
and physiological properties acts much more quick!} I
so thai the titrabh acidity or alkali

of the a.-id or alkali, or the actual dec I It

in this connection that the dissociation hypol

that the degree to which the acid I mes die

remainder <»t' the molecule will dctermini

Tht' question is, how arc we to measure the latfc

which we may measure is that known

accelerate reactions, such as the splitting of I ll 0

glucose and levulose, which otherwise would

page 75 . It' then the real Btrength of an acid •

of dissociation which it undergoes, ''^

power should correspond with those represents

ties of the acids in equivalenl concentration

actually the case is shown in the following table, in whi

of various acids are give ►mpared with ll< 1. which •

ACID

at

u

IH'I

Dichloracel ic

Monochloracetic

Forntie

Acetic

0.4:

It will be evidenl that, it" we could measure tl ■
II ions in a solution that is, of II ions thai
w e should have a faithful index of its
has been rendered possible by the applici I
chemical principles namely
force. Since the objed of this volun
for the various methods thai are used in modern i

essary for us to review the main principle: hall

see that they apply, no1 only in the n
hut in many other physiological p

BfMl Action

When material part in

posing while others Bre

24 PHYSICOCHEMICAL basis of physiological processes

condition is reached in which the changes in one direction are exactly
offset by those in the other. An equilibrium is said to have become estab-
lished between the reacting substances. Bearing in mind that the ions
and molecules entering into these reactions are constantly moving about
and coming in contact with one another, it is easy to see that if we were
to add an additional quantity of one kind of molecule or ion, there would
be a change all along the line until a new equilibrium was established.
If, on the other hand, Ave were to remove one kind of molecule or ion
as fast as it is formed, the equilibrium could never be established, and
the reaction would proceed until all of this material had disappeared.
The natural rate at which any chemical reaction proceeds is dependent
upon a number of conditions, such as chemical affinity, temperature,
catalysis, and concentration. Of these conditions that of concentration
is most readily measured. If we maintain all of the conditions other
than that of concentration unchanged, and designate this combined in-
fluence as K (constant), we shall find that the speed of the reaction is
proportional to the molecular concentration of the reacting substances
(i. e., the number of gram-molecular weights per liter). In other words,
the speed with which two "substances, a and b, unite to form other sub-
stances, c and d, will be expressed by the equation,

k (a)x(b) <=» k' (c)x(d);*

which means that, when the reaction is complete, the composition of

the mixture will be dependent upon the ratio between k and k". Since

however these are both constants, their quotient is also constant (K), and

(a) x (b)
we have the equation, , . -r^r- = K, indicating that no matter how

(c) x (d)

the concentrations a, b, c, and d are varied, reaction will take place in

one direction or the other until the concentrations have become adjusted

so that K remains unchanged.

As an example of the application of these laws, let us take the reaction

which occurs between alcohols and organic acids to form the substance 5

called esters — a reaction which is analogous to that between mineral

alkalies and acids to form neutral salts, and which is of special interest

to us because it is the reaction involved in the splitting of animal fats.

The equation for the reaction is:

C,H,OH + CILCOOH ?^ C9HeOOCCHa + H.O.
(ethyl (acetic (ethyl acetate,

alcohol) acid) an ester)

Or expressed according to the law of mass action:

[C2HrpH] x [CH3COOH]

LC,H0OOCCH3] x [ILO]

K.

*Thc brackets indicate that gram molecular quantities are used.

HYDRi

Now it 1^ clear thai if we increi ! 1 < » in thi

in order thai K may remain unchanged < II < »< • < < II
the substances which form the oumerator of ti
or both these changes musl occur. A- a i
the above, both of these adjustments I
down, it iniiM thereby increase tin- concenl

Since in aqueous solutions the reaction juts in the pi

of water, it is evidenl that the tendency for a:

water is to break down into alcohol and ami. and th all

reactions in the bodj Quids in which water enters inl

Physiological Applications. The application i
in the explanation of biochemical pro
the reactions which enzymes or ferments art
of the same general nature as thai represented ah
of their activities arc usually the substances on th< side
in which no water molecules appear i.e., they are hydi
Enzymes merely accelerate the reaction
with a mixture of the substances on either sid< of th<

• In is tn .- elerate the production of a sufficienl c

on the other Bide, until the equilibrium poinl

an enzyme present in pancreatic juice, call<

breakdown of such esters as neutral fat, which consists mic

alcohol, glycerol, combined with the fatty acids palmitic C II '''"'11 .

stearic c || COOB and oleic CTB COOH :

'■II ',11 I M OH

(tin- neutral fat,

tri-r

Under ordinarj conditions the reaction pi a until

neutral t'at has become decomposed because

water, hut if we start with a mixture of I I With

just enough water to permit the enzymi I

■ I in the opposite direel ion i e., bo thai Bon
s\ nthesized. This is called the •

l '• cause "i' the universal pr
versible reactions could nut alone I"

sis of neutral fat or of similar BUD81 I

way by which synthesis could occur under tl •
if the Bubstance produ ^ w ith 1

site of the read ion i a boob as I

precipitation of the SUD8tai

\ elope of BOme inert mat. rial I-, • ■ ■

26 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

occurs in the epithelium of the intestine out of the fatty acid and glycerol
absorbed from the intestinal contents, it is possible that the last men-
tioned process occurs. In other cases the substance may be carried
away by the blood or lymph or urine as fast as it is formed.

The Law of Mass Action as Applied to the Measurement of H-ion
Concentration. — Let us now return to the reaction or H-ion concentration
of substances in solution. As the standard of neutrality, pure water is
chosen. Let us consider, then, how the laws- of mass action can be
applied in order to enable us to determine the H-ion concentration of
pure water. It has been stated above that chemically pure water is in-
capable of conducting the electric current. This however is not strictly
the case, for it conducts to a very slight degree. According to the dis-
sociation hypothesis, it must therefore be represented as containing
molecules of H,0 and ions of H- and OH -, and according to that of mass
action there must be a balanced reaction between the molecules and ions
represented thus:

H.O<=>H • + OH • oiJ FTjTVi ~ = K.

Since the concentration of H- and OH- is extremely small, there must
always be such an overwhelming preponderance of H20 molecules that
no changes in the concentration of H- and OH • will be capable of appre-
ciably affecting the concentration of H20 ; in other words, one may omit
the denominator of the equation and write it [H-] x [OH-] = K. If
then we know the value of K, it will only be necessary to measure the
concentration of either H- or OH- in order to express in numerical terms
the reaction of the solution. It has been found that the value of K is
about lxlO14,* and since the concentrations of H- and OH- are nec-
essarily equal in pure water, it follows that [H] = [OH] = \'lxlO"14,
i. e., each ion has a concentration of 1 x 10"7. This means that water con-
t.iins approximately 1 gram mol. each of H- and OH- ions, or 1 gram
H- and 17 grams OH- ions, in 10 7 or 10.000,000 liters. A consequence
of the above law is that no matter how much the concentration of one
ion is increased by adding another substance, the solution must still
contain some of the other ion. Tims, in acid solutions eon. H- must
increase and con. OH- must decrease in such proportion that the two
multiplied together equals about 1 x 10 ll. The H-ion concentration can
be used there fore to crprrss Hie reaction of neutral, acid and alkaline
solutions.

In place of water, let us substitute decinormal hydrochloric acid

*The sign 10"" is simply a convenient way of expressing the degree of dilution. It gives the
number of times the value standing in front of it must be multiplied by 10 in order to find the.
.degree of dilution.

HYDROG1 \ |. 27

"I .\ IK 'I thai is, a hj drochloric acid -■
of the molecular weighl «>r hydrochl cid in

liter of water. At this dilution HC1 is 91 p<

t!i«' II ion concenl rati ,r <*,, ,-is ir i itten

or, in mathemal ical notal ion, 9.1 I'1

Mi thod of I' ■■■ I To '• "i'l the

several figures t<> express C ... as has Keen done abo

• In ! a scheme by which only one figuri l

ignated by Ph, is Pound by subtracting from the i

the figure standing behind I11 the common logarithm •

pressing the normality of the acid.* In a decinormal II"

therefore, we must subtracl from the po

which is .96 ascertained from logarithm tabl< 1 "I T

another example: decinormal acetic acid is dissociate

tent of 1.3 per cent; CH is therefore 0.0013 normal, or 1.3x1

the logarithm of 1.3 is .11, P„ equals 3 .11, •■ 2 -

The only objection to the use of tl onenl Ph aa

the B-ion concentration is that it inc in magn

becomes less; this is because the negati
garded. As stated above, it is usual t<» express tl
.is well as acids in terms of Ch, or Ph, becaus
concentration of II ions than of <'II ioi - A. 0.1 NaOB s
per cenl dissociated; therefore the "OH" ion is

equivalents n|| per liter . and since the produd 1 Oil'

concentrations must always equal 1" I 20 I

the II ion increases in concentration, the "'11 i<»u m
crease. ESxpressed according t<> the above Bchemt SM \ KaOIl

solution gives PH L3.06; thus, 0.084 B.4xl08;
and this subtracted from the power 2 1.08 P 14.14

L3.06 as PH.##

similar]}. I\, of "'.1 \ Ml HO solution is 11.286 It*
1 } per cent ; therefore the solution contaii
HO i.e., M L0 P 0 l 16 2 B54 P 14.1

11.286.1

'"It !■

ihai number
Ih.iti I'm", bul l v

■

tTIlr

0

L>s PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

Application of the Law of Mass Action in Determining the Real
Strength of Acids or Alkalies. — \Ye have seen that it is the degree of
dissociation upon which the real strength of an acid depends and that
this varies with dilution (page lit). The equilibrium between the un-
dissociated and dissociated molecules may therefore be shifted in either
direction by changing the concentration; in other words, the process of
dissociation is a reversible reaction, and may be represented as
AB±5A' + B\ The law of mass action must apply in such a ease, and
as a matter of fact it has been found that a constant can be calculated,
which is known as the dissociation constant.* It is an expression of the
inherent ability of the acid to dissociate into ions, and is therefore the
best measure of the strength of the acid. This is strictly the case for all
of the weaker acids, but strong mineral acids (and bases) do not give
a satisfactory constant, so that the comparison must not be made between
them and weaker ones. That the dissociation constant expresses the rela-
tive strength of organic acids can be shown by comparing its value with
that of the rate at which cane sugar is inverted (see page 23), this being
proportional to the concentration of the H ions present. K for some or-
ganic acids is : Acetic, 0.000018 ; Formic, 0.000214 ; Benzoic, 0.00006 ; Sal-
icylic, 0.00102.

*The equation is — — p-^r- r= K, where it is supposed that in volume V of the solution there is

1 gram-equivalent of electrolyte, and that the degree of dissociation is a; the quantity of undis-
sociated electrolyte stated in a fraction of a gram-equivalent will he la, and the quantity of each
ion a. To illustrate, let us take acetic acid in various dilutions:

V

0.994

2.02
15.9
18.1

a

Kx 10:

0.004

1.62

0.00614

1.88

0.0166

1.76

0.0178

0.78

I MAT I BR V

THE PRINCIPLES INVOLVED l\ THE MEAS1 REMEN1 OF THE
HYDROGEN l<»\ < ON( ENTRATION I

THE METHODS OF MEASUREMENT

The Electric Method

In order to understand the principle of il •
measuring the II ion concentration, il is nee

said < cerning the factors governing the development of electric i

rents in chemical batteries. There may be a furtl

knowledge in connection with th<

which occurs during physiological activity, as in

When a metal is immersed in a solution of
tendency to give off ions into the solution. 9 lar ioi
already presenl in this solution, and these, by t;
tend to oppose the passage of the i
force with which the metal sends oul its ions into th<
tin electrolytic solution /■ h' this [ual t<» tl

sure of the metallic ions in the solution, there will
generated, but it' it is greater or less than ih<
metallic ion, an electric currenl will beset up. When tl
Bure is the greater, the metal will become n<
ions carrj positive charges into the boIuI

when tl smotic pressure is ir than the N..luti.>ii

will have a positive charge, owing t<> th<
from the solution.

Because of .1 called

from the metal can uot travel an} n
charged mass of metal, bo that fron
impossible for us to lead off an :

must form a circuit. Tin- is done n tl 7

connecting side tubes coming fron
mediate vessel containing ution

uecting the metals by wires l •
same metals in soluti

rent w ill be "ate, I,

30

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

equal and in opposite directions to each other. I >u the other hand, should
the concentration of the metallic ion in the solutions be unequal, the
electromotive force will How from the one electrode to the other, and
the pressure with which it flows will be equal to the difference in con-
centration of the two solutions. This is the principle of a concentration
cell, and if we know the concentration of one of the solutions composing
it, and then proceed to measure the electromotive force, we can obtain
the concentrations of the other solution by difference. To do this we
must employ a formula which takes into consideration the relation be-
tween the potential and the concentration of the solution.

The potential of an unknown electrode composed of a metal in con-
tact with a solution of one of its salts may also be determined by making
it one pole of a battery of which the other pole is composed of a stand-
aid electrode of unchanging known potential. An electrode of the latter

^y

Fig. 7. — Diagram to show type of electrodes used in studying electromotive force. The
metal in each electrode is connected (through a glass tube) with a platinum wire, to which
the apparatus for measurement of the voltage is connected. The metal dips into a solution
contained in the electrode vessel and filling the side tube. The latter dips into an inter-
mediate vessel containing saturated KG solution. The currents flow through the circuit under
the following conditions: (1) dissimilar metals dipping into the same fluid; (2) similar metals
dipping into different fluids; (3) dissimilar metals dipping into different fluids.

type can most readily be made by bringing pure mercury in contact
with a saturated solution of calomel (Hg2Cl2) in normal potassium chlo-
ride solution. Under suitable conditions (i. e., when the circuit is com-
pleted), a potential of -i 0.560 v. is developed in this so-called calonnl
electrode* — that is, positive ions of mercury are deposited on the mercury
from the calomel solution at this pressure. Suppose that we connect a
calomel electrode, through the intermediation of some solution which

•The calomel electrode consists of a suitably shaped glass vessel containing pure mercury, con-
nected by means of a platinum wire with a conductor, and filled with a saturated, solution of pure
mercurous chloride in normal KG solution up to such a level that it also (ills a side tube connected
with a vessel containing a saturated solution of potassium chloride. Into this vessel also runs a
similar side tube from the unknown electrode. By having an excess of undissolved calomel in the
solution in the calomel electrode its saturated condition is maintained during the chemical changes
which accompany the production of the electric current.

HYDROO

will serve as a good conductor, with another el
trodes being also connected bj wires with electrical a]
measuring the total potential of the battery; then by addJ
to or subtracting this value from the total potential
sign of the unknown electrode we can tell the potential
electrode.

We have discussed these principles of electrochemisti
form the basis upon which depends the Btandard method the deter-

mination of the H-ion concentration of fluids. Suppose
thai in place of using a metal in the construction <>:
use an electrode consisting <>t' a layer of pure hydro
with a solution in which are free II ions: then the rate ;it whiel II

fi'.S^

J pf^-l 3-"V --,f

+© +

-Diagram ol foi thi

rent k<"|" ' ated in the batten
lion, and the II ele< trode) or ■ ■

:-i the bi idffe w ire, w >" i e i h<
liri.l«<- win- from an accumulat
nt at various :

S"i' n~i ill

become added to the solution from the II !.v ,.ik-,n from

•

pend on the concentration of II ions in Bolution. I

hydrogen electrode fulfilling the abo

employ some means by which a layer "t" hydrogen may !••

fortunately this can be done by taking advanta

Bpongy platinum possesses of absorbing larg It

is also necessary to keep an atmosphi H

fluid.

As is tli.' case «'t" the simpler cells
types \\lii<-li we mighl use for measurii
erated in tin* unknov n • - 1 * • « ■ t rode n •

:!L' PHTSICOCHEMICAL BASIS OF I'll YSIOUHJICAL I'HOCKSRKS

hydrogen electrodes, of which one contains a solution of known H-ion
concentration, and the other the solution in which this is unknown;
and a cell of which one electrode is a standard calomel electrode and
the other, a hydrogen electrode containing the unknown solution.

The exact arrangement of the apparatus in which the calomel elec-
trode is used will be seen in the accompanying sketch. The hydrogen
electrode, it will be noticed, is a very small V-shaped tube, in which is
suspended a platinum wire coated with spongy platinum and dipping
into a solution which nearly fills the tube. The space above the solution
is -filled with pure hydrogen. This and the calomel electrode are con-
nected with suitable electric measuring instruments, and the circuit is
completed by connecting the two electrodes by means of an intermediate
vessel containing a saturated solution of potassium chloride. This con-
necting solution is used because it has been found that the electric cur-
rents set up at the contact between different solutions are so small that
they can be disregarded.*

As outlined above, the hydrogen electrode is that which is used to
determine the H-ion concentration of blood, the particular point about
it, in comparison with the apparatus used for simpler solutions, being
that the hydrogen is not changed in the course of the experiment. This
precaution is to prevent the carbon dioxide of the blood from being
"washed out" of it by a frequently changing atmosphere of hydrogen.
Many inaccuracies in the earlier results obtained by this method were
due to the removal of carbon dioxide, which, as we shall see later, is
one of the chief acids contributing to the H-ion concentration of blood.

The Indicator Method

As pointed out in a previous chapter (page 22), the method of titra-
tion for acidity or alkalinity in Avhich a standard solution of alkali or
acid is added until a certain change in the color of a suitable indicator
is detected, does not afford any information regarding the H-ion con-
centration actually present in the solution. It tells us the total con-
centration of available acid or base, both dissociated and undissociated.
By modification of the method of procedure, however, we may also use
indicators for determining the H-ion concentratioii. The principle of
this method depends on the fact that there are certain dyes which
•liange quite distinctly in tint with very slight changes in the H-ion
concentration, so that if we use dyes which possess this property at a
point near that of neutralit}r (i. e., between PH6.5 and PH8), Ave can es-

*A description of the technic for measuring the electric potential developed by the cell would
be out of place here. Suffice to say that the strength of the current is compared with that of a
current of known strength furnished by a normal cell, the comparison being made by a bridge wire
F, a capillary electrometer II being employed to detect the direction and degree of current.

HYDRO*!

timate the II -ion concentration of the bod} flui
accuracy, provided certain precautions are taken I
disturbing influence which the protein and ^tlts in these flui
mi tin' color change.

To understand this use of indicators, it is importanl to in mi

thai one solution reacting neutral to one indicator H

concentration which differs very marked]} from thai i
tion reacting neutral to another indicator. This is
read to differenl II ion concentral \ tlution thai

phenolphthalein has a Pa of aboul 9, wh< ntral I

ange lias a I'm of aboul 4. rl'liis can 1"- very clearly
a solution of phosphoric acid with decinormal alkali. After
amounl of alkali has been added it will be noticed that methyl
changes from red to yellow, bul after it has changed
alkaline as judged by this indicator, it still remains distinctly
wards phenolphthalein shows no red tint even thou,
more alkali is added. The methyl orange is. tin
sive i<» weak acids such as remain after the greater p
phoric acid has been neutralized by the alkali.

The scries of indicators which has been empl<
given in the accompanying table, along with the I'm limits through wl
they change in color.

List or [kdii

CHF.MICAL NAMK

COMMON

SAMF,

Thymol Bulfon phthalein

id ran^c)
Tctrri liromo phenol sul-
d phthalein

Orthn r.irlwxy benzene

aao di methyl

aniline
Ortho carboxy I

nzo <li prop] 1

aniline
l »i bromo ortho en

sulfon phthalein

Di bromo thymol soli

phthalein
Phenol suit" ii phthalein
Ortho ereaol solfon

phthalein
Thymol sulfon phtha]

above)
Ortho ereaol phthalein

Thymol blue

Brom pi
blue

Mi thyl

purple
blue

■

Thr<.f dyw n:

34 PHYSICOCHF.MICAL RASIS OF PHYSIOLOGICAL PROCESSES

Briefly stated the method for measuring the Il-ion concentration con-
sists in preparing a series of solutions containing known concentrations
of 11-ion — that is to say, of known PH — and adding to each solution an
equal amount of an indicator which exhibits easily distinguishable
chanties in tint at H-ion concentrations approximating those believed
to be present in the unknown solution. The same indicator is added to
the unknown solution, which is then placed side by side with the stand-
ards to find with which of them it most closely matches. The series
of solutions of known H-ion concentration is prepared by mixing fif-
teenth normal solutions of Na2HP04 and KH,P04 in varying propor-
tions as given in the following table:

Preparation ok Standard Solutions
The solutions are mixed in the proportions indicated below to obtain the desired Pn:*

Ph 6.4 6.6 6.8 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 8.0 8.2 8.4

Primary Potas. 73 63 51 37 32 27 23 19 15.8 13.2 11 8.8 5.6 3.2 2.0

Phos., c.c.
Secondary Sodium 27 37 49 63 68 73 77 81 84.2 86.8 89 91.2 94.4 96.8 98.0

Phos., c.c.

(From Levy, Rowntree and Marriott.)

* Standard phosphate mixtures are prepared according to Sorensen's directions as follows:
1/15' mol. acid or primary potassium phosphate. — 9.078 grams of the pure recrystallized salt
(KII2PO4) are dissolved in freshly distilled water and made up to 1 liter.

1/15 mol. alkaline or secondary sodium phosphate. — The pure recrystallized salt (NaoHPO.1. 12H20)
is exposed to the air for from ten days to two weeks, protected from dust. Ten molecules of water
of crystallization are given off and a salt of the formula! Na2ilPOj .2H;() is obtained; 11.876 grams
of this are dissolved in freshly distilled water and made up to 1 liter. The solution should give a
deep rose red color with phenolphthalein. If only a faint pink color is obtained, the salt is not
sufficiently pure.

The indicator method is extremely accurate when used with pure
solutions of acids, but, as mentioned above, it is apt to be inaccurate, at
least with most indicators, when protein or inorganic salts are pres-
ent in the solution, and of course it is quite unusable with colored
fluids such as blood. In order to overcome these difficulties, the
dialysis method has recentl}- been evolved. It consists in placing the
fluid — blood, for example — in a dialyser sac composed of celloidin and
about as large as a small test tube. The sac is placed in a wider test
tube of hard glass containing an isotonic solution of sodium chloride
that has been carefully tested to ascertain that it is strictly neutral.
The amount of blood or serum required for this method is only 2 or
3 c.c, and the amount of salt solution placed outside the sac should be
about the same. It takes only from five to ten minutes for dialysis to
occur. The celloidin sac is then removed, a few drops of the indicator
are thoroughly mixed with the dialysate, and the tube compared with
the series of standards until the corresponding tint is matched. This
indicates the H-ion concentration in the dialysate. The tints produced
by using sulphonephenolphthalein are reproduced as nearly as possible

p« I Ph ' V, 7Z R. 7 i

■■

IC

w w

w w w W

9

PhT-5 PH7-6 pM7-7 r p^ .

BYDR0G1

in Hi.- accompanying chart. The II i"ii concentral
solution is thai of the tinl with which it n - in il i

It might be thoughl thai this method would I"- inaccu
the loss of carbon dioxide from the blood. By actual experiment, 1 •
ever, it lias been Pound that, it' the blood is collected with
cautions, the error is negligible. The method is, tl
one clinically.

The following table gives the hydrogen-ion cone
read ion of the body fluids.

Ki.rii>

I'H

Ki.nn

Blood

Urine

Balh a

Gastric juice (adult) 0.9

1 . stric juice I Lufa i

Pancreatic juice (dog

Small intestinal contents

Small intestinal Content S I infl

Bile from liver

Bile from gall bladder

Perspiration

Perspiration

Tears

7.1

6.0 M . ■

Ps

1.6 :' ii'1

5.0 Pericardia] fluid

B.3 A< 7.1

Vitreous hut
:.] ' ten al fluid

7. \ Amniotic tlui<l 7.1

7.1 Amniotic fluid
l..-. Milk (hun :
7.1'

Milk .
Mill

VV. M. I II \ 1.

CIIAPTRR VI

THE REGULATION OF NEUTRALITY IX THE ANIMAL BODY

AND ACIDOSIS

Nothing is more constant in the animal economy than t lie H-ion con-
centration (CH) of the fluids which bathe the tissues. This regulation
is fundamentally of a physicochemical nature, depending on the inter-
action of alkalies with acids, of which carbonic and phosphoric acids
and the proteins are the most important.* When different amounts of
acids or alkalies are added to water, the range of variation in H ion is
very extensive, whereas in blood the range is very limited indeed, not
extending beyond PH7 and PH7.52 (i. e., CH never goes above that of a
0.000,000,1 N solution or below that of a 0.000,000,03 N solution). In
other words blood can withstand considerable additions of acid or al-
kali without much change.

Buffer Substances. — The chemical reactions upon which this remark-
able constancy in reaction depends have been explained by Lawrence
J. Henderson.10 The fundamental equations are as follows:

M.HPO, + HA = MH,PO, + MA, and
MHC03 f HA = H2C6n 4 MA,
when M = a basic radicle, and A, an acid radicle.

Now it has been discovered that weak acids, like carbonic and phos-
phoric, possess the remarkable property of maintaining the reaction
constant when they are present in a- solution which also contains an
excess of their salts. Under these circumstances the concentration of
ionized hydrogen is almost exactly equal to the product of the dissocia-
tion constantt of the acid (see page 10) multiplied by the r;itio be-
tween free acid and salt; in other words,

[HA]
H-=KXtBAT

If carbonic acid is present in a solution of bicarbonates so that there

*Aceorrling to circumstances, proteins may act either as acids or as alkalies. They are there-
fore called amphoteric.

fThe ionization constant has already been referred to as a figure which expresses the tendency
of a weak acid or base to dissociate in an aqueous solution. "It expresses the proportion in which
the nondissociated part is capable of existing in the presence of its ions," and therefore is a gauge
of the strength. The dissociation constant amounts to about 0.000,000,5 for carbonic acid; that is,
the dissociation of H0CO3 into II ■-!- 1 K'< >:;' at room temperature will be such that the concentra-
tion of H-ion equals a 0.000,000,5 N solution.

36

are equivalenl quantities of fre< H,CO I bicarl

— the II ion concentration will be exactly I the -I

constant of carl ic acid; therefor* 0.000,000,5 N P 6.31

five times the value of neutrality, .1 \ P 7 : l

times as much free carbonic acid as bicarboni I \ theo the I!

concentration will be fifty times that of neutrality, i. • *. —

0.000, ,5 0.000,005 P 5.3] ; if ther. ten tin

acid than bicarbonate, the II ion concentration will be one-half thai

neutrality, i. e., =rj 0.000,000,5 0.000,000,05 P 7 '

if twenty times less, one fourth P 7.6 . Since a

bicarbonate is actually presenl in blood enough to yield fron

< 'n_- per LOO c.c. of blood see page 391 . and th<

undergoes fluctuations which ar< only trivia] when compared with tl

which have I □ chosen in the above examples, it is clear thai

be very little change in the H-ion concentration of the blood in com] i
with tho variations which would occur were no bicarbonate present.

Another weak acid which acts like carbonic in maintaini -

ity is acid phosphate .MM I'11 . and for the Bam< □ namely. |

its dissociation constanl is of similar magnitude to the II ;"':

tration. Although the hi 1 plasma itself contains much less pho

than bicarbonate, the 1 i-.^n<-- contain a considerable amount, which

ahles them to maintain their neutrality. This on of 1

phosphates is styled the buffer action, meaning that it mp

dowil the effect oil the H imi e. .1 icell t fat ion which addit

alkalies would otherwise have. As pointed oul by I '•
better word to use would be "tampon action." sine,. th<
actually soak up much of the added II or OH' io - [1
to the fluids of the higher animals, but is widely

throu ghoul nature; for example, in th< n and in the flui

organisms and animalcules see I. J Hendersoi

Although the actual reaction by which neutrality is m.
purely of a physicochemical natui
made so thai the acid and b ibstan<

supplied and those produced bj the react
quires Tl e ii r ■ ^i)>i>1<i is parti}

The exogenous Bource is the basic and in

food; and although we do nol ordinarily
of these substances i maj d

persistent udniinistration
endogenous source dcpei

38 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

of acids such as carbonic, phosphoric, lactic, and sulphuric, and of
alkalies such as ammonia. Amphoteric substances, like amino acids and
proteins, may functionate either as acids or as alkalies. Whatever may
be its source, a considerable reserve of alkali is undoubtedly available
in the animal organism. This required store of alkali appears to be
automatically liberated as a result of the physicochemical process.

The removal is affected by three pathways: (1) through the lungs
gaseous carbonic acid is eliminated; (2) through the kidneys, the fixed
acids; and (3) through the intestines, some of the phosphoric acid.

Carbonic acid is produced in large amounts in the normal process of
metabolism, and is excreted in a gaseous condition by the lungs. Varia-
tion in its excretion is the most important mechanism for controlling
temporary eliavges in CH- In order to make this clear, it may be well to
revert for a moment to the physicochemical equation by which carbonic
acid is enabled to maintain neutrality. This may be written: CH =

rr rtr\

molecular ratio ^ tmA • The ratio may be increased either bv adding
J\arlL(J3

fi'ce carbonic acid to the blood (as by causing an animal to respire some
of the gas), or by the addition of some other acid (e. g., oxybutyric, as in
diabetes) which will decompose some of the NaHC03 and produce
H2C03. The increase which these changes would cause in GH of the
blood is prevented by the remarkable sensitivity of the respiratory cen-
ter to changes in CH. An increase which is much less than can be
measured by physicochemical means stimulates the center, causing in-
creased pulmonary ventilation, so that the carbonic acid is immediately
eliminated through the lungs. This elimination does not stop when the

old level of carbonic-acid concentration is reached, but proceeds until

"FT CO

the original ratio tt * is again attained in the blood, and CH is

NaHC (J?.

restored exactly to its original value. If it stopped at the old C02 con-
centration, the ratio would be too high because there is less NaHCO,.

THE THEORY OF ACIDOSIS

Although these considerations indicate that variations may occur in
the bicarbonate content of the blood without any significant change in
Ch, they also show that the bicarbonate content must be a criterion of
the acid-base balance of the blood, and probably of the body fluids in
general. As pointed out by Van Slykc,12 bicarbonate represents the ex-
cess of base which is left over after all the fi.rrel acids have been neu-
tralized. It represents the base that is available for the neutralization of
any excess (.)' such acids that may appear — a measure of the reserve of
"buffer substance" or, more specifically, the alkaline reserve of the body.

Under normal conditions the amounl of NaHCO

constant (amounting to 50-65 vols, per cent < 0 ivhen

it indicates thai an excess of fixed acid musl !><• p

by Van Slyke and others to constitul nition * —

namely, fla condition in which the concentration of bia in th*»

blood is reduced below the normal level." I

for any reason should no1 respond promptly enough to an ii in

the molecular ratio , . and <\ nsequently l

condition is called uncompensated acidosis, but if the center »nd

m> that Ch is Ik'M constanl although NaHt 1 1 condition

is .ill.' Of ' "//'/" flSati '/ acidosis.

For practical reasons, therefore, the study of pathological acidoe
pends on an estimation of the bicarbonate content of the bl<
it is simpler to carry oul and is of equal valui plasma. \V

plasma is obtained by removing 1>I 1 from a vein of the arm and c

trifuging immediately oul of contacl with air (so thai CO, i aol be

lust from it it contains approximately 60 vols, per cent I (l

we know that the partial pressure of CO, in M 1 is equal to 42 mm. Hg

scertained from determinations of the alveolar ' 0 set 14),

we can calculate how much of the 60 vols per cent must be in simple
solution by application of the law of solution of gas in a liquid
336). It has been found thai plasma at body temperature and at
mm. Hg atmospheric pressure dissolves 0.54 ... bo thai

42
12 mm. it will dissolve =^x 100x0.54 I vols 1 nbing

[H,CO 1

the figures to our equation we

NfaHCO
This definition of acidosis leaves oul 1 all conditions thai m

raise the ratio v the addition of U.CO, wit mp BinR

\all< ( >

any of the NaHt It > . such, for exampl<

carbonic acid is presenl in the blood plasu

l i i are nol infrequenl in both health and dis<

ditions the above definition ie sufficiently <-<>u W

we come to Btudy th ntrol of the respiral

an increase in the ratio v ,,

actual increase in «',, ran be produced bj eaush

• n ii

\.iiieO» K ,

1 1 .
K .i ■ : j

40 PHYSUOClir.MICAI; BASIS OF PHYSIOLOGICAL PROCESSES

containing an excess of CO, — a true acidosis, but one for which no place
is found in the above definition.

Nevertheless, Van Slyke's definition has a veal value, because it em-
phasizes the importance of a determination of the bicarbonate as a cri-
terion of the degree of the forms of acidosis usually met with in disease.
The bicarbonate under such conditions may become reduced either be-
cause of the appearance of improperly oxidized fatty acids, like /?-oxy-
butyric and acetoacetic, when carbohydrate metabolism is upset as in
diabetes or starvation, or because the acids produced by a normal
metabolism are inadequately eliminated by the kidneys, as in nephritis.

Accordingly, if the respiratory mechanism and increased mass move-
ment of the blood (for an increase in CH accelerates this also) should

IT CO,
fail to eliminate CO, quickly enough so as to keep the Tjr^ ratio at

one twentieth, then CH will rise. This is not likely to happen until a

large part of the NaHC03 has been used up, so that an estimation of that

actually present must be a reliable index of the proximity to this

condition.

A sustained increase in CH is incompatible with life. The NaHC03 is

the buffer, the factor of safety which prevents its occurrence. Although

it is only in arterial blood (i. e., after elimination of excess of CO, by

TT Co
the lungs has been accomplished) that constancy in the ratio tt<^a~

NaHCOo
can be expected, it is fortunate, for practical reasons, that venous blood

collected during muscular rest and without stasis should be only slightly

different.

"When acids are added to the blood, they will first of all be neutralized

by the "buffers" of the plasma — namely, NaHC03 and protein, as Ave

have seen. But this is only the first line of defense against acidosis, for

buffer substances present in the corpuscles may also be used. This intra-

corpuscular reserve of alkali is mobilized partly by transference of K

and Na from corpuscle to plasma, but mainly by that of HC1 from the

plasma into the corpuscle, so releasing base in the former to combine

with the added acid (e. g., H,C03), according to the equation:

H,C03 + NaCl +± NaHCO, f HC1. The HC1 on entering the corpuscle

reacts with phosphates according to the equation: HC1 + NaJTPO, ^±

NaH,P04 + NaCl. This is a particularly important detail of the buffer

action of the blood, for it shows us how the phosphates of the corpuscles

are rendered available for neutralizing acids added to the plasma, where

there are practically no phosphates. Indeed the transference of acid

through the corpuscular envelope indicates that the same sort of thing

must go on with the oilier cells of the body, so that the plasma, itself

rather poor in buffer substances, has all those of the body at its disposal.

THE MEASUREMENT OF THE RESERVE ALKALINITY

1. Titration Methods

There are several methods by which the kal in .

may l>c measured. The Bimplesl in theory <-"i
standard acid must be added t<> a measured quantil
order to reach the aeutral pohil as judged by change in tint
indicator. The indicators emplo} ed
change their tints ;ii Minn concentrations tl
of neutrality (i. e., at a high CH or Iom I' To bring th

poinl of neutrality the added alkali will 1 d to neutral i

bicarbonate of the plasma, bul other acid-bindii -
This will give us a false iinptvssiun of the acid-bin<
plasma, since, at the normal Ch of tin- blood, pr< I
tn anything like tin' extenl they do at higher deg I \

objection to the method is thai the proteins in1
9 of tin- indicators.

The objections can be removed by determining the end p
metrically <»r by indicators thai change tint at aboul P 7
practical way is 1<> determine the change in Ch produced by
known volume of standard arid to blood plasma. I
in Ch will then be greater the less the alkaline I

metric method irregularities thai mighl be
of carbonic arid in the blood to start with
the < '< » from the plasma after adding i 'I

therefore consists in mixing 1 c c. plasma with 2 c
separating runnel, which is then
after which the fluid is transferred to a hyd
measured see pag< In normal blood this - P

In acidosis, where there is a depleted alkali
will cause a much greater change in C« in diab<
or luw er.

The technic involved in the abo> e meth<
routine clinical work. For such purp< -
and Rom nt ree maj be emploj ed.

Tin M i thod op Levy R At

lonsol" -lass of aboul 2
powdered ru utral potassium oxalal
immediately stoppered and placed on i

the bl 1 are then placed ii

and allowed to stand for !;'

42 PHYSICOCHKMICAL BASIS OF PHYSIOLOGICAL PROCESSES

layer of plasma to separate on the surface (this prevents laking of the
blood during the subsequent addition of acid or alkali). The blood in
the first tube is used for the determination of the normal H-ion. In
each of the next three tubes are added respectively 0.1, 0.2 and 0.3 c.c.
N/50 HC1, and to the last three, similar quantities of N/50 NaOH. After
inverting the tubes so as to mix the contents, the blood in each is trans-
ferred to celloidin sacs and the CH determined according to the method
described elsewhere (page 32).

The tubes are noted in which a change in tint from that of the normal
blood is evident, and the results are expressed as the c.c. of N/50 HC1
or NaOH which must be added to blood to change its Ch. Thus, the
alkali buffer is the c.c. of N/50 NaOH which can be added to 2 c.c. of
blood without change of CH of the dialysate, and the acid buffer the c.c.
of N/50 HC1.

The method suffers from the following drawbacks:

1. Very small quantities of acid and alkali are employed.

2. It is often difficult to tell just exactly when a slight difference in
tint has been produced.

3. Even with the precautions described above, it is impossible to be
sure that the amount of C02 in the different samples of blood is the same,
which means, of course, that some bloods will, on this account alone, be
able to bind more alkali than others.

The Method of Van Slyke. — A method based on somewhat the same
principle, but which is more accurate because it meets the above objec-
tion, is that suggested by Van Slyke, Stillman and Cullen.14 Plasma is
freed of C02 by placing it in a vacuum, and is then mixed with an equal
volume of N/50 HC1 (or NaOH) and the CH determined by the electric
method (see page 29). In the case of normal blood, after such an addi-
tion of acid, a practically normal CH will be found, whereas in the blood
of cases of acidosis it will be very distinctly increased (i.e., PH lower).

2. CO^-combining Power

The above objections to the titration of blood plasma or dialysate
with standard solutions of acids are removed if we measure the com-
bining poAver of the blood alkali towards carbonic acid itself at normal
blood reaction. This may be done either in blood immediately after its
removal from the animal or in blood that has been first of all saturated
outside the body with carbonic acid at a partial pressure equal to that
existing in the body. Since for practical reasons venous blood must be
used — in the clinic at least — the former of these methods suffers from
the fault Hint varying amounts of carbonic acid will be added to the
blood during its passage through the tissues, and the error thereby

ACID

incurred will become greatlj ag
duced in drawing the specimen for analysis Bui thi
this method has no1 been extensi ely emplo
Slyke, is the technical difficulty of making the nee

It is most satisfactory to colled venous bl I

a1 leasl of muscular resl so thai thei i CO oul

venous stasis, and to centrifuge withoul permitting sideral

of carbonic acid. The latter precaution is nec<
migration of acid radicles, e.g., HC1, from plasma ii I
tin' ('(>.. of iIip former is increased, and in the n on when the

C03 is decreased, [f the COa in the blood w< I I &me durii

trifuging as it is in the body, the separate plasma would no1
same amount of alkali i. e., iis reserve alkalinity would I •
Although tl retically, therefore, centrifuging should !"■ p I in

l"i({. 10. — Diagram of a
l" ads m tin- bottle cond<
filled with expired air, si
rotated so that tin- hluo.i a film o

an atmosphere containing the same partial pr< CO

the body (i. e., the alveolar air skx : _■ 144 this im-

practicable for genera] use, and is unnec

B] mini of blood is prevented bj allowing it to tlow

very slowly 'Without anj suction . It is mixed in t1 ith

powdered (neutral potassium oxalat< enough to i

solution with the blood . and immediately delivered i1 '

tube under paraffin oil, which by floating on I

fi ee diffusion of CO to the outside air e\ en the.

more I 0 than wain- . To mix the Mood with tl

should be moved backward and forward Beveral

shaken.

A itrr cenl rifuging, aboul 3
w ith < '< >. al the Bame tension as in al> i

44

MIYSinx llKMIt'AI. BASIS OF PHYSIOLOGICAL PKOCKSSKS

is done by placing the plasma in a separating funnel of 300 c.c. capacity,
laying the funnel on its side and displacing the air in it by alveolar air
secured by quickly making as deep an inspiration as possible through
the tube and bottle containing glass beads (Fig. 10). The glass beads
remove excess of water vapor from the air. The tunnel must be restop-
pered before the end of the expiration, so that no outside air enters. It
is then rotated, for about two minutes, in such a way that the plasma
forms a film on its walls. If il is necessary to postpone the saturating
of the plasma, this should be pipetted off from the corpuscles and pre-
served in hard <ilass tesl tubes coated with paraffin. From ordinary i>-lass

Fig. 11. — \ it n Slyke's apparatus fur measuring the COi-coinbining power of blood in blood plasma.

For description, see context.

enough alkali is soon dissolved out to vitiate the results. After saturation
of the plasma with C02, the funnel is placed in the upright position and
the plasma allowed to colled in the narrow portion, after which 1 c.c.
is removed with an accurate pipette and analyzed for C02.

The analysis may be done by using either the Van Slyke or the Hal-
dane-Barcr oft apparatus. Tin Van Slyke method is as follows:

The apparatus is filled to the top of the graduated tube with mercury
(Pig. 11) by raising the mercury reservoir /•', care being taken thai
/> and /•-' are also rilled. One c.c. of the C02-saturated plasma is then de-

livered into .1 which has been rinsed oul with ' I I

and the stopcock / turned so that I

reservoir /'. the plasma rung into /: b il

procedure is repeated with 1 e.c. watei h in all o

and anally 0.5 <-.<• of 5 per cenl H,SO is Bucked in,

is turned off. The reservoir /•' is then li all

of the mercury, but none of the l»l 1. to run oul ol B I

is thus produced in /» and C.

As the level of the mercury falls in /; and C, the plasma
It'iitly.' because il is exposed to a vacuum. To bi
< 0 have been dislodged Prom the solution, the appar
several times. To ascertain how much CO //

is now tur I so as to bring C and E into communical

lowering the reservoir the fluid in ( to run /'

Stopi k // is thereafter turned so as to conned C and D

voir raised so that the mercury runs into C as far i CO, 1

lected in tlic burette will permil it to go. After bring

mercury in /•' to correspond to that in the burette, I

this stands is read. l\ gives the c.c. of CO, lil

Under the above conditions normal plasma bii

its volume of CO,; therefore, since the total capacity

e c . tlif mercury should stand a1 0.31 n the bui i

measurement it is necessary to allow for the CO, 1

in the water, etc., as well as for barometric p

This is best done by the use of a table based on t

1 0 under the various conditions obtaining, whicl

Slyke's paper."

Tin Haldai ■ 5 croft apparatus that is i
analysis is show n in Fig. 136, : CO

water is placed in the bottle and the l

■ ^

thai

rub
licr i

n ihr tlni.l iii the

limb.

\wtli

bag until •

. he lirinlit at
l>r<

The •
that tin

krpt constant, thi

■
till the I lu«M Ol

46 PHYSI.COCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

The bottle is then connected with the manometer with the precautions
described elsewhere in this volume. When temperature conditions have
been allowed for, saturated tartaric acid is mixed with the plasma solu-
tion and the gas evolved measured by the displacement of the fluid in the
manometer. The apparatus may also be used with blood in place of
plasma. In this case, however, it is necessary that the oxygen be removed
before adding the tartaric acid. This precaution is necessary, since acid
can dislodge some of the 0, from hemoglobin. The blood is therefore first
of all hiked with ammonia containing some saponin, then shaken with
0.25 c.c. saturated potassium ferricyanide solution, and finally with the
saturated acid solution. If blood is used, the estimations must be made
on strictly fresh blood, since on standing the C02-combining power
greatly deteriorates.

3. Indirect Methods

There are several other methods by which the alkaline reserve may be
measured. These include:

1. Determination of the Tension of COL> in Alveolar Air (page 344).—
Since this method is employed more particularly in investigating the
hormone control of the respiratory center, we shall defer a description
of it until later. The alveolar CO., tension corresponds to the C02 ten-
sion in arterial blood and this is proportional to the alkaline reserve as
determined by Van Slyke's method as is proved by the fact that the ratio,

plasma CO, . , . » .-,

, , ~,~ " : — , is satisiactorilv constant.

alveolar CO, tension

2. The Measurement of the Acid Excretion by the Kidney. — As might
be expected, the acid-base equilibrium of the body may also be gauged by
measurement of the acid excretion of the urine, in which the acids are
contained partly in combination with ammonia or a fixed base, and partly
in a free state. We shall first of all consider the methods of acid
excretion and then examine the evidence showing that the total acid
excretion is proportional to the alkaline reserve as measured by the
above described methods.

Excretion of Acid in Combination with Ammonia. — The production
of ammonia is essentially an endogenous process, and when excessive
quantities of acid make their appearance in the organism, the fixed alkali
may not be sufficient to neutralize it all, so that ammonia, derived from
the breakdown of amino acids (page 616) , instead of being converted
into urea is employed to neutralize the excess of acid. Most workers
have in this way explained the very large ammonia excretion that has
long been known to occur in such conditions as diabetic acidosis. Some
recent workers are, however, inclined to question the significance of

ammonia in this connection, believing thai th<

cretion is, like the acetone bodies them

metabolism. Be this as it may, il

for neutralizing acid in disi although it □

factor in tlir maintenance of neutrality under I [1

a factor of Bafety, in thai it helps to care for an inc

the normal mechanism of the body is o

Excbetion of Phosphates. The more permam ity

depends on the excretion of phosphates by the kidi

erning this process is i sactly I 1 in

connection with carbonic ac.id. In the one case il
C02, and in the other, the fixed phosphoric acid tl
reaction. The ratio between the acid Baits of phosph< lid, Mil 1

and til-' alkaline salts, M III*'', in blood is approxim but in

the mine this ratio varies according to the amounl of H ioi
!><• eliminated from the blood. In other words, a defin
phoric acid i^ enabled to carry variable amounts of II ion
by causing the amount of alkali excreted in combination with it
come altered. For example, in the form of MH,PO amounl

1'", obviously carries ou1 more II ion than when it
M BP04. The adjustment between these 1 the

kidney. We may a rdingly measure tin' amounl of alkal I by

the organism by finding how much standardized alkali m

a given quantity of urine until the reaction obtaii

since the latter value is constant, the titration can be done simplj
titrating the urine with an indicator Buch as gulph< "in.

which changes tint at aboul Ph of blood.

A more serviceable indicator t<> use, howe

cause its end poinl is BUCh that when human mine just r Tail

to it that is, when the titrable add approacl

ing power of the plasma iv ,-it its maximum

ammonia excretion by the urine is eero Vai 9 [1

therefore, to use this indicator, because it hap

poinl situated for a reaction which is well

trality, and which is reached in urine when tl •

acid-combining power and no ammonia is bein 'ion

purposi - \> the « 1 1 combining p"

Bhould, therefore, '"■ a proportionate ii

titrable acidity of the urii

Although a genera] parallelism •■•
diabetes, i tc . there is no Btri<
therefore 1 n tried of comparii ith

48 physicochemical basis of physiological processes

tin- excretion rate of acid as determined by an application of Ambard's
equation for chlorides and urea, and with curiously satisfactory results
(Fitz and Van Slyke). This equation is:

Blood concentration = < slant \ vAr^- vc; where I) is the excretion

rate, W the body weight, and C the concentration of excretory prod-
net in 1 lie urine. For the present purpose D is therefore the number of
c.c. of N/10 alkali (or acid) required to bring the urine to the neutral
point of phenolphthalein plus the NIL expressed as c.c. of an N/10 solution,
for the twenty-four hours, and C is e.c. of N 10 alkali and of N/10 NH3
pei' liter of urine. If we assume that the acid accumulation in the blood
is proportional to the fall of the plasma C02 figure below the maximal
figure of 80, the above equation becomes:

Retained acid = 80 - plasma C02 = constant xXTxFVtl

For practical purposes it is best to make the necessary analysis on a
sample of urine collected over a period of one to four hours, and to col-
lect the blood for determination of its reserve alkalinity in the middle
of this period. The twenty-four-hour rate of excretion is then computed
(D) from the analysis.

The value calculated by the above equation has been found to agree
with that of the C02-combining power of the plasma to within 10 vol-
umes per cent, except when bicarbonate is being taken by the person.
when the blood bicarbonate is much higher than indicated by the urine.

3. Determination of Alkali Retention. — Another valuable criterion of
the alkaline reserve is the amount of alkali required to change the re-
action of the urine. In health the CH of the urine varies from
0.000,016 N (PH = 4.8) to about 0.000,000,035 N (P„ = 7.46) with a mean
of about 0.000,001 N (PH = 6). These extremes are rarely overstepped
in disease, but frequently the average is considerably different, In car-
dio-renal disease, for example, the mean acidity may be approximately
0.000,005 N (PH = 5.3), or five times the normal value. A certain de-
gree of acidosis is therefore common enough in this condition — a fact
which has indicated the advisability of administering sodium bicarbon-
ate. It has been found that 5 grams or less of soda, given by mouth to
a normal person, causes a distinct diminution in the CH of the urine,
whereas in pathologic cases it may be necessary to i>ive more than 100
grams before a similar effect is observed (L. J. Henderson and Palmer15
and Sellards").

For this very large holding back of alkali, the organism and not the
kidney is responsible. This is indicated by the fact that, when the
administration of alkali is discontinued, the acidity of the urine soon

regains its old l<-\ el, although new \i aller d

the Ch of the urine will immediately be I" I

that for tli<- moderate de( i acidosis '-"111111011 in chr

properly controlled administration of Boda is
tageous treatment.

CHAPTER VII
COLLOIDS

Substances -which can be obtained in the crystalline state and which,
when in solution, are capable of readily diffusing through membranes,
are designated as crystalloids, and are to be distinguished from another,
larger group of substances not having these characteristics or having
them only in very minor degree — the colloids. In every field of chem-
istry the properties of colloids have been studied extensively during
recent years, but in no field more than in that which covers the chem-
istry of biological fluids and tissues, into whose composition colloids
enter much more extensively than crystalloids. The subject of colloidal
chemistry has indeed become so extensive that an attempt to do more
than indicate some of the most important characteristics of colloids
would take us far beyond the limitations of this book. The far-reaching
applications of the subject in physiology and medicine are only begin-
ning to be realized.

The term ''colloid," or "colloidal," does not refer to a class of chemical
substances, but rather to a state of matter which is quite independent
of the chemical composition of the substance. "We are familiar with
more colloids in the organic than in the inorganic world, yet they are
plentiful in both, and the same substance may at one time be colloidal
and at another noncolloidal. Indeed, under appropriate conditions prob-
ably all substances may assume the colloidal state — not solids and liq-
uids alone, but gases as well. It is mainly with liquids, however, that
we are concerned in biochemistry.

CHARACTERISTIC PROPERTIES

The distinction between molecular* and colloidal solutions is a rela-
tive one. Suppose, for example, that we take a piece of gold in water
and divide it up into smaller and smaller parts. At a certain stage, the
particles will be so fine that they will remain in suspension and be in-
visible by ordinary means. They are then said to be in the colloidal
state. If we divide them further until they become molecules of gold,
a molecular solution Avill be obtained. In the colloidal state, there are

'Molecular solutions include those of nonelectrolytes, such as sugar, and electrolytes, such as
inorganic salts. /

50

t w i» distinct phases in i lie solutioi .

between the two, because of tl

ticle, is an enormous surfaci

and at tlic interface beta een th< the pi

depend on surfac< . surface tens

developed, and are responsible for the peculiar |

solutions as compared with those of molecular

therefore, be Btj led honwg< in I

which we have hitherto been concerned with,

r>ct\\ ecu these i w o groups of solutions is an interim i
susp s' 'as suspensions of quartz or carbon, or oil i

sides being turbid in transmitted light, the Bolutioi

means of the ultramicroscope i atain partic I

rated by filtration from the fluid they are

case of many emulsions in which the parti

through the filter pores by changing their shap

centrifuged suspensions may also separate inl

though this can be greatly hindered by the addition o ling

substance such as gelatin or certain bodies 1

tive action i as peptone, prol

True Colloidal Solutions

1. The Solution Is More or Less Turbid. Frequently th

nized by holding the solution in a thin-walled - rt a

dark background, bul the turbidity may 1

for its detection the use of the Tyndall phenomenon. 1

to all in the effect of a beam of sunlight let in through a small a]

into an otherwise darkened room. In the coura

.lust particles, which are invisible in an equally illumi

come visible, and thus render very distinct tl

If a colloidal solution contained in a glas iral-

lel sides, is held in th w such a beam,

will be Been in the Liquid, which is qoI tl • with n

Focused artificial lighl may be employed for ii

The lighl that is sent OUt at righl an-_

which means that the particles reflecting th< r than

the mean wave length of the light f< •* 3

Btood that the individual particli

visible t<> the naked eye by the beam, although i

often he seen |i\ USlIlg !' I luillil:

scope combined w ith suitable m;

2. Colloids Do Not Readily Diffuse, i

52

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

are half filled with a 5 per cent solution oi' pure gelatin or a 1 per cent
solution of pure agar, and, after the jelly is set, the solution under
examination is poured on the surface; or, when it is of high spe-
cific gravity, the tube of gelatin, etc., is placed mouth downwards in
the solution. In the case of colloidal solutions very little if any diffu-
sion into the gelatin or agar will occur, even after several days; whereas
true molecular solutions will diffuse for a considerable distance. When
colored solutions are used, the diffusion can readily he recognized by
visual inspection (see Fig. 13), but when they are colorless, the presence
or absence of diffusion must be determined by removing the column
of gelatin or agar and dividing it into slices of equal size, which are
then examined chemically for the substance in question.

A further test is afforded by the failure of colloids to diffuse through
membranes (dialysis). This was the method originally used by Thomas
Graham to distinguish between molecular and colloidal solutions. The
solution under examination is placed in a dialyzer, which is then im-
mersed in a wide vessel containing the pure solvent. The older forms

Fig. 12. — Ultraniicroseope (slit type) for the examination of colloidal solutions. The arrange-
ment of diaphragms, etc., in this form removes the absorptive effects of the surfaces of the glass
vessel or slide used to contain the colloidal solutions.

of dialyzer consisted in general of a bell-shaped glass vessel closed be-
low with parchment paper, but more recently so-called diffusion sacs
have been adopted. These consist of pig or fish bladders or of col-
lodion sacs. The latter are made by placing some collodion dissolved
in ether in a test tube, which is then tilted so that the collodion runs
out except for a thin layer which remains adherent to the walls. When
the collodion has set, the sac can be removed after loosening it by allow-
ing a little water to flow between the sac and the walls of the test tube.
The sac containing the colloidal solution is then suspended in water
or some of the solvent used in preparing the colloidal solution, care
being taken that the menisci of the fluids inside and outside of the sac
stand at the same level. Sometimes, especially when collodion sacs are
used, some colloid may at first diffuse through, but if the outer fluid
(the dialysate) is renewed and the dialysis allowed to proceed, this
ceases.

i OLLOIDS

When a fluid solution exhibits both <>f t]
Tyndall phenomenon and indiffusibilitj , th<
being in a true colloidal state, bul there are sub
red or protein solutions of certain strengths, wlii<-li i
slighl diffusibility in a dialyzer bul not Bhov the Tyndall
Substances of this group constitute transitional
,-itnl colloidal solutions, and to determine their ti

■

Barj to employ i cfined t!

lilt rat ion. etc., which can nol be described hi

3. The Size of Colloidal Particles. It wil
property upon \\ hich the abo> e rn<
of the particle. Particles « hich can still b<
are called microns. They hi

0 1 1 nun or in-'!.

are invisible microscopically

54

PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

tion, but are still visible when the ultramicroscopic illumination is
used, are called submicrons. They have a dimension between 0.1 fx and
1 /i/x (0.000,001 mm.),* and they constitute the colloids. Particles smaller
than 1 fx/x are called amicrons, this term being used to include the mol-
ecules and ions present in molecular solutions. (The amicron of hydro-
gen is, for example, computed to be 0.067 to 0.159 /*/*, and that of water
vapor, 0.113 /x/x.) This classification of dissolved substances according
to the size of the particles and molecules shows the relationship of one

SubmicrcmS

U/U.U

IOAA

1Q

Colloidal <i°><i-

Ma&Yi^itQtion r.'t.ooo.ooo

/W\CTOY\S

naa^'VicoAiow 1:3533

Fig. 14. — Diagram from W. Ostvvald showing the relative size of various particles and colloidal
dispersoids compared with a red blood corpuscle and an anthrax bacillus.

class of substances to others. An idea of the relative sizes of colloidal
particles and molecules in comparison with such familiar objects as a
blood corpuscle and an anthrax bacillus is given in Fig. 14. The fluid
in which the "particle" is suspended is called the dispersion medium, or
i eternal phase, and the particle itself the dispcrsoid, or infernal phase.
It is the enormous development of surface which determines the dif-

V — 0.001 mm., and n/i = 0.000,001 mm.

I 01

ince in ill" properties of a colloidal Bolutioi
rion of the Bame Bubstance l •
Bolution of platinum | prepared by al

• ••■II platinum electrodes in and p im in

depends on the fad that the bu tinum in I

has I n increased many million times. When th<

still greater and the particles gain the bu

due to Burface development become Bup]

centration in unit volume become tuated '!"■ ■■

cut t.n osmotic pressure, difrusibilitj

whether ions, molecules or particles, but

much more pronounced when the die

and others when they are small. In other words, the pi

surface, such as those of surface tension bcc p

only when the dispersoids have the properl in ma

the dispersoids 1 me molecular in size, they manifest tl

characteristic of true solutions.

4. Electric Properties of Colloids, fcfosl colloids carry i which

may be either positive or negative toward the dispersion medium. B<>th
crystalloids and colloids therefore carry

case, however, the charge does not reveal itself until the mol
solution have become dissociated, when each ioi of

opposite Bign (see t »;i >_-•.• 16), whereas in the
loid particle usually carries a charge which is alwi
positive or negative. Colloids may ther<
and negative, according to the charges which tin
a third group in which the charge may be eith<
cording to the nature of the dispersion medium.

A colloid not carrying a charge to begin with can b<
by the action of electrolytes, for I
aa well as those of inert powders ended in in-

fluenced by the charges present in the i"iis of tl I urn.

The II- and < >H' ions an •daily liab

particles of inert powders in bus]

a positive charge when the water in \\h

Bed, and a negative charge when i1 is mad< alkali] I

be said that suspensions st po\>

in w ater • g eha coal, cellulos

• »r congo red, etc. are •■

ide l ferrum dialysatum and Berum ;

tioi senious Bulphide at

Bolution, and strum globulin in n< I

56

PHYSICOCHKMICAL BASIS OF PHYSIOLOGICAL PROCESSES

To ascertain the nature of the charge various methods may he em-
ployed, of which the following are important:

1. The method of electrophoresis. The colloid solution is placed in a
U-tube, each side of which carries a platinum electrode dipping into the
solution. After a strong continuous electric current has been allowed
to pass for some time through the solution, it will be found that the
colloid collects at the anode (where the current enters) when it is a
negative colloid (since unlike electric charges attract each other), and
at the cathode when it is positive. In the case of colored solutions, the
migration can be readily seen, but otherwise it may be necessary to ana-
lvze the solution at the two poles.

Pig. 15. — Capillary analysis of colloids. Strips of filter paper, after being suspended with
the lower ends dipping into colloidal solutions. Those on the right hand were positive colloids,
which did not rise in the strips, but formed a sharp line of demarcation at the lower end on
account of precipitation. Those on the left hand were negative colloids. (From W. Ostwald.)

2. The method of capillary analysis. For this purpose a long strip of
filter paper is arranged vertically over the solution, with its loAver end
dipping into it. In the case of negative colloids the colloid, as well as
the dispersion medium, rises uniformly on the strip of paper (it may be
to a height of 20 cm.) ; whereas with positive colloids the dispersion
medium alone rises, the colloid itself doing so only to a wry slight ex-
tent, but becoming so highly concentrated at the interface between the
solution and the paper that it coagulates on the end of the strip of paper,
where it forms a sharp line of demarcation (Fig. 15).

3. The method of mutual precipitation of colloids. When a positive

COLIXHDS

and a negative colloid are mixed in Buch |

charges are neutralized, precipitation usually i

we can tell tli«' nature of the electric chi if an unki

its behavior when a colloid of known electric Bign if

example, it' ferric hydroxide (positive causes .1 i ipil

when it is added to an unknown colloidal solution, the el<
i)!' the Latter musl be negative; if it does nol i»i««-i 1 «i v
hydroxide, but does so with arsenious sulphidi
posil i\ ••.

5. Brownian Movement. Like tin- parti. -Irs in fin.- mechanical

si"iis. those "t' colloidal solutions, (.v] i.-i 1 1 \- when •

microscopically, exhibit the so-called Brownian movements,

I. >'.'ii described as "dancing, 1 1 < « j ► j > i 1 1 i_r and Bkippii I •

occur in straighl lines, which are suddenly changed in >;

are quite independent of external sources of energy, Buch

temperature (although tiny become quicker as tl

siiliitii.ii is raised . earth vibrations, chemical <•!

charge of the colloid. The mo\ ements I"- le a apid the sma

particles, and they become sluggish as •

creases. Addition of electrolytes decreases the movemenl \<\ caus .

particles to clump together. The density and visc<

si.Hi medium, the electric charge >>( the dispersoid ami

Brownian movements, arc the forces which operal

sedimentation of the particles in a colloidal solution.

6. Osmotic Pressure. As one of the distinguishing pi
loids we have seen that their diflfusibility, as in'

lies, is extremely slow when compared with thai

This does nol mean, however, that colloids are

diffusibility if lefl long enough. Indeed th<

movemenl indicates that such diffusion >"

Bhould lie possible, by the application of the same prii

w hich govern molecular Bolutioi

Inane , in measure the osmol ic pr<

.Man.\ studies "f the osmotic property
undertaken, especially bj th..>e v ho

that tin lloids of hi I serum Berum albumin and

ate aii osmotic pressure I f this Bhould

ii\ for tl wnotic

pressure BUch as that supplied l>.\ the
the various physiologic pi
through cell membranes as in tin
For measuring the osmotic

58 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

to those already described (page 4) can be employed. Most of the
recent work has been done either with collodion sacs, or with unglazed
clay cnps impregnated with some gel, such as silica or gelatin. When
such an osmometer, filled with some colloidal solution (like a solution of
pure albumin) and provided with a vertical glass tube, is placed in an
outer vessel containing water, the fluid will be seen to rise in the ver-
tical tube, the height to which it rises being proportional to the osmotic
pressure.

But the observed pressure does not necessarily give us the osmotic
pressure of the pure colloid, for to this, even when highly purified, there
is almost certain to be attached a considerable amount of inorganic
salt, which may be responsible for the osmosis. It has indeed been
maintained by some observers that electrolytes form an integral part
of certain colloids, being bound to them perhaps by adsorption (see
page 65), and that they are essential to the maintenance of the colloidal
state. In any case, since electrolytes are always present, the osmotic
pressure of the pure colloid can be measured only when means are
taken to discount their influence. Several devices have been used, of
which the following may be mentioned:

1. Addition to the fluid outside the osmometer of a percentage of
salt equal to that found by chemical analysis to be present in the col-
loid. (This method is untrustworthy.)

2. The use of a limited quantity of fluid on the outside of the osmom-
eter so that equality of saline content soon becomes established, by
diffusion, in the fluids on the two sides of the membrane.

3. The use of a membrane which is permeable to electrolytes but
not to colloids.

Even when the greatest care is taken in its measurement, the osmotic
pressure of a given colloid has been found to vary considerably not
only according to the method used in its preparation, but also accord-
ing to the amount of mechanical agitation (shaking, stirring, etc.) to
which the colloid solution has been subjected. Regarding the influ-
ence of the method of preparation, it was found in one series of experi-
ments that albumin that had been repeatedly washed (but still con-
tained considerable ash) gave no osmotic pressure, whereas another
preparation that had been purified by crystallization twice (and con-
tained much less ash) had a pressure of 3.38 mm. Hg. According to
these results the ash content of the colloid is not fundamentally re-
sponsible for its osmotic pressure. As to the influence of mechanical
agitation, the osmotic pressure of a gelatin solution is increased by
shaking, while that of a solution of egg albumin is decreased.

The property upon which the osmotic pressure depends is undoubtedly

the state of dispersion of the colloid particles, and until

the factors which may influence this, mei

of colloids can scarcely I"- of yerj much value

property has Bome physiologic bearing

loids have in restoring the blood pre« ill .

Further e\ idence thai i be osmol i<- pr<
significance thai it has in the case of molecular boIuI

the Pad thai tl Bmotic pressure is only approxin oal

to the concentration «>t' the Bolution; it may either ii

relatively to the Btrength of the solution. Temp<

a differenl influence on the osmotic pressure Loids I that wl

it has "ii the osmotic pressure of molecular Boluti< atly

has an influence which persists after the solution is ;

original level.

The influei of added Bubstances on the osmotic ]»

solutions is of considerable interesl to the biol

ease of molecular solutions this is purely additive, in I

loids ili>' added substance may al one time cause the osmoti

increase, a1 another, to decrease. It lias been found that th<

pressure of gelatin solutions at firsl d< then rapidly inc

the H-ion concentration is raised. The addition of alkali inci

osmotic pressure until a maximum is reached, beyond whicl

fall. Both ac'nN and alkalies lessen the osmotic pr< bu-

miii. Electrolytes always decrease the osmotic pi

albumin solutions, and the dej to which the;

depends on the uature of the cation and anion con

In the order of their depressing influence tl •

sri\ es:

Eeavy metals > alkaline earths > alkalies
and the anions:

SO > CI • NO Br I

The influence of a given electrolj te vi
tion of the colloid, a fad which mu-
ni this field.

CHAPTER VIII
COLLOIDS (Cont'd)

SUSPENSOIDS AND EMULSOIDS

According to whether colloids form solutions that are more or less
viscid than the suspension medium, they are divided into emulsoids and
suspensoids. Examples of the former class are silicates and gelatin, and
of the latter,' dialyzed iron and arsenious sulphide. The following char-
acteristics are used to distinguish between suspensoids and emulsoids:

1. Measuring the time it takes, at a standard temperature, for a given
volume of the fluid to flow out of a standard pipette (10 c.c.) shows the
viscosity to be, roughly, inversely proportional to the time of outflow. In
the case of suspensoids the viscosity is no different from that of the
dispersion medium alone, and does not vary much when the solution is
cooled. The viscosity of emulsoids even in very dilute solutions is, on
the other hand, considerably greater than that of the dispersion medium
itself, and it becomes greatly increased by cooling.

2. Suspensoids are much more readily coagulated by the addition of
electrolytes than emulsoids. This is particularly true when water is
the dispersion medium (so-called hydrosols), and when electrolytes hav-
ing a polyvalent ion (such as Al or Mg.) are employed. Thus, practically
all suspensoids are coagulated in the presence of 1 per cent of alum.
which has no influence on emulsoids. We shall return to this phase of
our subject later on.

The division of colloids into emulsoids and suspensoids is more or less
arbitrary, since one class may be changed into the other, the determining
factor being the water content of the dispersoid. The water content of
suspensoids is low (lyophobe), while that of emulsoids is high. By
changing the relative amounts of water and solid of which a colloidal
solution is composed, the nature of the dispersoid may be changed. If
the water is diminished, the dispersoid behaves as a suspensoid and be-
comes readily precipitated. The practical importance of this fact is
that ii explains the salting out of proteins — a process extensively used
in their separation. Ordinarily these behave as emulsoids, but the addi-
tion of salt raises the osmotic pressure of the dispersion medium, and
thus attracts water from the dispersoids, with the result that they come

60

I III. I .

iii lirli;i\ e aa suspensoids, and i
trolytes.

Another property of emulsoids of biological in
tection which they can afford ag the precipil

electrolytes on suspensoids. If a colloidal solul
a trace of gelatin, the subsequent additioi
produce qo precipitation. The explanation of tl
becomes distributed as ;i film on the Buspensoid pari
converl ing them into emulsoids.

Gelatinization

One of the besl kno\* □ property
tion, which has an interesting bearing on many pn
After the gel has set, an enormous quired I

any water Prom it, indicating thai the '
tinuous phase but must be enclosed in sresicli
material.

A> a gelatin solution cools, tl
light, bul the very fine particles which
Boon increase in number and -
their Brov nian iu»\ ements and adl
felt-like threads throughout the solul \

\\urk <it' the more Bolid phas<
being inclosed in the dk

1 1'. as in the a< mpanj ing diagi am, I

Bented by \\ hite and the dispersoid in
tin- two in a Buspensoid is as in .1, and thai
any of the dispersion medium ii /•'. I

G2 PHTSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

cause the more fluid phase to penetrate the more solid. If the gel is
treated with reagents like formaldehyde, the liquid can be readily pressed
out. This occurs during fixation for histological purposes.

Imbibition

Closely related to gel formation is the process of imbibition — the
power of taking up large quantities of water without actually forming
liquid solutions. Besides gelatin the dried tissues of plants and animals
exhibit the phenomenon, and it is undoubtedly of importance in many
physiologic processes such as growth and the passage of water into
cells, etc. The materials present as vacuoles in plant cells attract water
from the environment of the cell by imbibition, and thus exert on the
cell Avail a pressure which, acting along with the osmotic pressure,
maintains the turgor of the cell. The initial growth of pollen is also
dependent upon imbibition, and important observations on this process,
under varying conditions, are likely to furnish us with useful informa-
tion concerning the significance of imbibition in connection with growth
of cells in general.

By measuring the rate of increase in length of long, narrow strips of
gelatin placed in Petri dishes containing solutions of varying composi-
tion, the factors that influence the imbibition process can be quantita-
tively investigated. Working in this way, F. II. Lloyd17 has found that
for all acids there is a certain concentration (about N/320 H,S04) which
induces a maximum rate of swelling, and another, much weaker
(N/2800 H,S04), in which the rate of swelling is even less than in pure
water. In higher concentrations of acid than N/320, the gelatin at first
swells very quickly, but the rate slows off so that it soon comes to be
less than that with intermediate concentrations. Regarding alkalies,
at high concentrations the effect is similar to that of acids. Salts alone
seem to repress the swelling below that of water. It should be pointed
out that the concentrations of acid and alkali in the above observations
are much greater than those that could occur in the animal body. The
experiments recall the attempts made some years ago by Martin Fischer
to explain edema as due to excessive imbibition of water by the pro-
teins of the tissues because of increased acidity of the blood and tis-
sue fluids. That imbibition might possibly play some role in such
processes is not denied, but Fischer disregards entirely the now well-estab-
lished facts that hydrogen-ion concentration is one of the most constant
properties of the blood, that very Ioav concentrations of acid may dimin-
ish rather than increase imbibition, and that it is manifested only in
the absence of inorganic salts.* Moreover, the fluid in edema can often

'Determinations of tin.1 hydrogen-ion concentration <>f the blood recently published from Fischer's

laboratory do not inspire confidence.

I ..I

be drained off by holloa needles, and it i

of the blood to another, neither of which pro

if imbibition were th< tial Factor eon< I

;i «_r.-i i t i->t this hypothesis should be demanded, il might

utter failure of the therapeutic measure

are recommended to combal the edema.

Action of Electrolytes on Colloids apaii
pressure . It has been stated above that the bich a « - * ► 1 1 « »

particle assumes may 1"' neutralized by a charj

ried by an ion present in the die □ medium Tl lion

of the electric chai - 3 coagulation of the Busp

the emulsoids. Of the positive and negati which

trolytes dissociate, the one producing tl gulation which

opposite in sign to the electric charge of the colloidal

A quantity of electrolyte which is capable of produ
cipitation when added all at once to suspei soida ill 1><-
added in Bmall quantities al a time. This phenom< hich

known to be exhibited when toxins ;m<l antitoxins are n
probably owing to the fad that precipitation depends on inequality
irregular distribution of electric charges, a condition which b<

ablished when the electrolyte is suddenly added, bul
is gradually added. The particles in the latter ease becom<
acclimated to the electric charges introduced by tl lition

electrolyti

Proteins as Colloids. The most prominent colloids in tl t bio

chemistry are the proteins. On account •
however, pertain factors intervene which
their behavior very difficult. As we shall Bee later, pr<
up of combinations of amino acids, each of whicl MI

and acid groups COOH . The various amino aci
in protein by il • I OOH of one uniting with the Ml r, with

the elimination of water thus CO OH II !1N xn

r< N >ll groups arc left oncombined A
of these oncombined radicles, the prot<
will exhibit faintly acid or basic or neutral
example, a sail will be formed by union with th< Ml
dissociate into the anion of the acid at
with alkalies union will occur with thi ' ' " ': :
dissociating will form a small cation ■

complex anion. We maj the
posil i\ e or a negath e elect ri

64 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

the fluid in which it is dissolved, so thai the reaction towards other
colloids and towards electrolytes will vary.

One feature of proteins of importance in this connection is that known
as the isoelectric point, at which the protein exists with a maximum of
electrically neutral molecules. This point is reached by adding acid 1<>
a protein solution. The acid represses the dissociation of the protein
acting as an acid, and therefore diminishes the number of free hydrogen
ions; and at the same time it combines with the NH2 groups and neutral-
izes the basic characteristics. The alteration in electric charge thus in-
duced alters the water-absorbing powers of the protein and therefore
all of the properties which Ave have seen to be associated therewith
(page 63).

SURFACE TENSION

Before we consider a very important property of colloids known as
adsorption, by means of which they are able to perform many reactions
that do not conform with the laws of mass action, it will be well to

B.

Fig. 17. — Diagram to illustrate surface tension. The rings A and B inclose soap films in
which a very fine loop of silk is suspended. In A it is loose but in B, where the him inclosed
in the loop has been broken, it is drawn into a circle by the tension of the soap film. (From
Bayliss.)

say a few words concerning' the physical phenomenon upon which this
depends — namely, surface tension. The creation of this force is due
to the fact that, Avhereas the molecules within a liquid are subjected to
equal forces of attraction on all sides, at the surface these forces act on
one side of the molecules only, and therefore tend to pull them inwards.
This causes the surface to pull itself together so as to occupy the least
possible area, and it is this force which constitutes surface tension.
The surface behaves as if stretched. There are various simple experi-
ments that reveal the presence of surface tension. If a film is made on
a loop of wire by dipping it in soap solution, a fine silk thread can be
floated in the film, so that it forms a loop that is quite loose. If the
portion of the film inside the loop is destroyed by touching it with filter
paper, the film will break in the loo]), which will now be pulled into a
circular shape by the tension of the film around it (Fig. 17).

For the measurement of surface tension, various methods are used.

-

The si/'' of drops of liquid falling from an orifice

face tension; the larger the drops, tl iter thi l

the number of drops obtained by allowing a liquid to dro

ard orifice in a given time is counted, we have a mea

tension. A.ccoun1 tnusl of course also be taken of the sp<

of the liquid. The instrument used for this purpo

stalagmometer Fi'_r. Is . Another method depends <>n the

the heighl to which a fluid rises in ;i capillary tub<

Burface tension (and inversely on the diameter of th<

difference in the heights to which two liquids rise in capillary tu

known bore permits us to compare their Burl

is known for tine of the solutions, ii can b ermined

Besides existing between liquid and air, Burface tension a
the interface between two immiscible Liquids, and at tl

l-'ili. IS. — Tra;;'
drops formed in
one for bl I and other viscous fl

pended Bolid particles and liquid, as in colloidal solutions

we have Been, the Burfac< interface is enorn I in

these solutions, a very greal Burfai rg) is present, foi th [ual

to the surface tension multiplied by the Burface

ADSORPTION

The Burface tension between liquid and ranic

Bubstances are dissolved in the liquid, bul is Blightlj i when i:

Btanic salts are dissolved The dc

-ding to the organic Bubstance dissolved. I with

bile salts, upon which fad the well-known M
of bile in urine is based Bet

lit! PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

solid (iinl liquid, the surface tension is always lowered l>u dissolving sub-
stances in the liquid. Now, at the interfaces ltd ween solid particles and
liquid there must be a local accumulation of free surface energy, which
will be equal to the surface tension multiplied by the surface (inter-
face) area. A constant tendency exists for such free energy to be de-
creased and, since dissolved substances have this effect, they will become
concentrated at the interface. This is known as the principle of Willard
Gibbs, and it is of fundamental importance to the biochemist, because
on it depends the phenomenon known as adsorption, which in the case
of colloidal solutions may therefore be denned as the local concentra-
tion or condensation of dissolved substances at the interface between
the two phases. The amount of substance concentrated at the interface
can be calculated by a formula which takes into account the concentra-
tion of the dissolved substance, the temperature, and the surface tension
at the interface (the Gibbs formula). After absorption has occurred, vari-
ous reactions of a chemical, electrical or purely physical nature (e. g., dif-
fusion) may follow at a rate which depends on the amount of the
condensation.

Every-day Reactions Which Depend on Adsorption

1. Decolorization of liquids by charcoal. That no chemical reaction oc-
curs in such a case is readily shown by the ease with which the pigment
can be extracted from the charcoal.

2. Adsorption of gases by such solids as charcoal and spongy platinum.
In these cases there must be great condensation, even a liquefaction of the
gas, during which heat must be evolved. By absorbing oxygen and hydro-
gen, spongy platinum causes these gases to combine and form water. The
hemoglobin of blood may take up oxygen by a similar process.

3. Formation of solid surface films on solutions of protein, saponin, etc.
The condensation may lead to coagulation, which explains why, if the
froth produced by beating the white of an egg is allowed to stand, it can
not be again beaten into a froth, the albumin having gone out of solution
by surface coagulation.

An interesting phenomenon depending on the surface tension occurs
when the protoplasmic contents of a ciliated infusorian is pressed out in
water. A new membrane forms on the protoplasm because of surface con-
centration of all constituents which lower surface energy. By application
of the principle of Willard Gibbs, A. B. Macallum18 concludes that not only
adsorption, as exhibited in a colloidal solution, but also the local accumula-
tions of material often seen in cells, are associated with changes in sur-
face energy. His conclusions are based largely on microscopic studies
of various forms of cell exhibiting different degrees and types of activity,

. Ml I ...

;ni<l ingeniously Btaincd for potassium b; tanitrite B

;i means the potassium Btaius intense black. In • ■ I i cal

accumulations of potassium occur either near the int<

clear and the chlorophyl-containing parts of the cell or

under a portion of the cell wall from which later a protrusion g

t.» form the firsl Btage in conjugation. The outgrowth from the cell,

as well as the accumulation of potassium, ma) I"- the result

Burface tension. In unicellular animal organisms, Buch i 11a,

much less potassium is p . being confined to th< ilia,

which Macallum believes indicates thai the structures are produced

an outcome of low Burface tension.

In the cells of higher animals, deposits of potassium are a]
in striated muscle, for example, tl • or in a zone at each •

doubly refractive band and immediately adjaci singly •

tive hand. Changes in surface tension, associated with <-l. get
distribution of potassium, are believed bj man} I iponsible

muscular contraction. In nerves and nerve cells, potassium

trated al the axon and at the surfaces of tn Us. [nterestii

in. ns are offered to explain the relationship among cha - in surf
tension al the terminations of axons \\ oapses, terminations in •.
muscle cells brought about by the uerve impulse acting as a
electric potential. Surface condei sation of potassium hi
observed al the lumen border of gland cells pan .1 on the lu-

men Burface of the cells of the renal tubuh - Such observat
in what way surface tension may !>.• railed into play to coi I cellular
activities. The field is new and almost unexplored, but the • ilready
much to indicate that surface energy • I important role in the

performance of many cellular activity

Conditions That Influence or Are Influenced by Adsorption

Electric Changes. Besides mere eon
into play to assist or retard adsorption. One of 1
these is electrical. Most Bolids when |
a negative cl if electricit ae a p l •

the Willard Oibbs law, a constant tendency will
to be diminished by the neutralization of tl

ir by deposition on the intei
electric charge of oppi by the action «>f tl

Charcoal in suspension in wat

[f colloidal iron, which has a positive cht

will become deposited on the charcoal, as will also tl ■

inorganie salt. On account >>( electric adsorptii bile

68 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

salts arc adsorbed much more freely than they would lie if the process
depended solely on surface condensation; that is, if the Gibbs formula is
used to calculate the adsorption, it will give values that are much below
those actually found.

If the dissolved substance and the particles both have the same electric
sign, adsorption will not occur. Filter paper, for example, has a nega-
tive charge and can not therefore adsorb a negative dye such as congo
red (as shown by the depth to which it becomes stained) ; whereas it
readily adsorbs night blue, which is positively charged. If the negative
charge of the paper is lowered, it becomes capable of adsorbing some of
the negative congo red. This can be effected either by placing the paper
in alcohol or by adding inorganic salts (NaCl) to the water with which
it is in contact. The positive-charged ions of Na, produced by dissocia-
tion, neutralize some of the negative charge on the paper, and allow a
certain amount of adsorption of the negative-charged congo red to oc-
cur. As would be expected, acids and alkalies are capable of greatly
altering the electric charges by the H and OH ions which they contribute.

Chemical Forces. — If the nature of the phase at the surface of which
adsorption occurs is such that it can enter into chemical combination
with the substance adsorbed, reactions will occur that do not obey the
laws of mass action. By adsorption, reactions of a certain type may be
encouraged over other reactions, even although the necessary reacting
substances may be present in the solution (specific adsorption). The
adsorbing substance itself is not, however, usually susceptible of chem-
ical change even when it exists as very minute particles, as in the case of
colloidal solutions. Nevertheless, adsorption may accelerate chemical
reactions by bringing together in concentrated form substances of high
chemical reactivity. In such cases the adsorbing substance itself does
not enter into the chemical reaction, and can be recovered at the end
in an unchanged condition. It acts as a catalyst (page 72). As we
shall see later, enzymes act in this way — i. e., their rate of reaction is
controlled by adsorption.*

The distinguishing feature of such adsorption phenomena is that a
curve of the reaction (drawn by plotting amount of chemical change

'Another instance of the influence of surface energy on the course of chemical reactions is seen
in the accelerative influence of charcoal on such reactions as the oxidation of formic acid, glycerol,
etc. Surface tension may also cause retardation of chemical reactions, as is seen in the turbidity

M
(due to the separation of chloroform) which gradually develops when a . Na»C03 solution is

M i

mixed with a ' chloral hydrate solution. The surface remains clear, because surface energy has

prevented the reaction.

An important effect of surface tension on chemical reactions is also seen in the relationship
between it and the absorption coefficient of gases (volume of gas dissolved by unit volume of
liquid). The lower the surface tension, the greater the solubility of the gas. Oxygen and nitrogen
are, for example, much more soluble in alcohol, hydrocarbons or oil than in water. This shows
the futility of attempting to prevent the loss of gases from fluids such as blood by covering them
with oils or hydrocarbons.

againsl concentration of reacting substa bola,

thai the laws of mass action (pa( In

order t<> be able t<> determine whether Borne particular for

ample, a fermentation process, or 1 1 e i bt -1

ia caused by adsorption, we tnusl compare iti
cording to the same principles, with the typical ad A

formula maj be used h natructing the curves In arrh • hi-.

formula, two facts have to be remembered: I Aa adsorptioi

and less and le8s <>f the free energy on the adsorbii

in In' neutralized, the reaction slows off, until equilibrium i

Tin- iimn- dilute tin' solul ion, I eater i^ ' r

tents tu lir adsorbed, which means thai it" a is th<

adsorbed from a certain solution, then, from a Bolution of I

Btrength, Bomewhal less than 2 a will be adsorbed i.e., <« multipl

by some rool of 2. Although the formula is one l • • ■ I < • 1 1 •_•■ i 1 1 lt to ti

known as parabolic, it must no1 be assumed thai on which

happens tn txiv.' such a parabolic curve (such as the combination I 0

with hemoglobin under certain conditions

dependent on adsorption.

It must be understood thai although the Bubsti
from a Bolution by adsorption is no longer capable of contributing
conductivity or the osmotic pressure of the Bolution, i*
nut so firmly fixed that it can not be bcI tree again by purely mcchan
means, as by constanl dilution of the fluid. It' charcoal which i
Borbed sugar is placed in a dialyzer made of incur

which allow BUgar bul UOl charcoal to pass thl r will

gradually be removed if the dialyzer is immersed in runnii A

certain equilibrium exists between the Bubsi idsorb*

Bubstance still remaining in Bolution. It" tl nin-

ishing by dialysis, the adsorption compound must break do

tain the equilibrium. It is clear, hov

will be extremely slow. The ability ol

removal bj washing is taken advauti - bj nature in holding

foodstuffs in the soil.

Physiological Processes Depending on Adsorption

Instances in which adsorption undoubl
part in physiological proi

1. The action of en/\ I 7 1

*_'. The combination of toxin with antitoxin
of adsorption rather than those of i
portant to note that w hen ti •

70 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

cessive quantities to diphtheria antitoxin, more toxin is neutralized than
when the toxin is all added at once. A similar phenomenon can also be
observed by adding filter paper to congo red, more of the pigment being
adsorbed when the paper is added in small quantities than when added
all at once. The explanation is that relatively more adsorption of a
given substance occurs from a dilute than from a strong solution (cf.
page 69).

3. The sensitizing of leucocytes by opsonins, as well as the subsequent
ingestion of bacilli by the sensitized leucocytes, both of which follow the
course of an adsorption reaction.

4. The formation of adsorption compounds, such as the inorganic salts
and proteins and the complex lecithin compounds that can be extracted
from egg yolk or brain tissue. In such compounds the laws of chemical
proportion no longer hold, and properties may be exhibited that are quite
different from those of either one of its components. When yolk of egg
is extracted with ether, for example, a compound of lecithin with vitellin
goes into solution, although vitellin itself is quite insoluble in ether.*
There can be no doubt that adsorption compounds of this character are
very abundant in living cells, and that they are constantly being formed
and broken down.

*By mixing solutions of egg albumin, congo red and a dye called fustic in the presence of
alum, the colloidal particles of which each is composed run together to form larger colloidal ag-
gregates, which l>v ultramicrosconic examination can be seen to be composed of a red. a yeliow
and a green colloidal particle. The attractive force holding the particles together is electric in
this case.

CHAPTER IX

PBRMBNI - OB ENZYME

< toe of the mosl b1 rikii '_r developn
istry concerns the nature of enzyme action. markal

the facta that have been bronghl to light tl

py one engaged in the Btndy of life pi
of thai study may be to know something

• occupying the attention of inv< in this In this

chapter a brief survey will be given of Borne i
tempi will In- made at completeness, and only wl
Bake of example will reference 1"' made to individual I
action.

The discovery by Buchner that an enzyme can 1"
cells which is capable of instantly bringing about tl •

tation of dextrose solutions has 1 a responsibl

modern advance. Formerly, yeast cells were belies
alcoholic fermentation as a result of their growth: it
a life phenomenon, or "vital process " Not we ki
produce an intracellular ferment or endo-enzyme* to which i1
properties are due and which can acl apai
It is no great Btretch of imagination to think of all ch<
mediate, i by cellular activity as due to a similar mechanism, and tl
has led to the hypot thai all pi

the animal ami plant are caused by enzyn
day we knew only of the extracellular enzymi
the digestive ferments), thai is
cells, but Becreted from them and acting
we must recognize intracellular enzym<
in thp protoplasm of the cell Bui •• •■ m
carry as too far. Without further ;
that the riddle i is thus Boh i

\ •■■ • sample of »1 which

Ruppoaed to pla) in the animal economy i
protein. I >lj tic enzym<

the animal an. I plai ' !'■; I

*Th< •'"i"

72 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

plex protein molecule is split up to render it absorbable from the intes-
tine, and the tissues appropriate from the blood those of the degradation
products that they require for the construction of protoplasm, which,
later, they decompose so as to utilize the energy which the organism
demands. All these processes are believed to be the work of enzymes.

The Nature of Enzyme Action

The changes brought about by enzymes can also be accomplished by
ordinary chemical means, but these have often to be of a very energetic
nature to accomplish what the enzyme can so quickly and quietly
perform.

It is the custom to regard enzymes as catalysts. A catalyst is a sub-
stance which accelerates (or retards) a chemical reaction which in its
absence could proceed at a different (usually slower) pace. The action
of catalysts has been aptly likened to that of a lubricant. A weight
placed at the top of an inclined plane, so held that the weight only slowly
slips doAvn, has its velocity greatly increased if its under surface be
oiled. The oil accelerates the action but does not affect the ultimate
result. Catalysts do not combine with the final products of the reaction,
these being, as a rule, the same as they would have been had no catalyst
been added. Another characteristic is the tremendous amount of chem-
ical change which even a trace of catalyst can induce. There are many
examples of catalysts in the inorganic world, among which may be cited
the action of spongy platinum on hydrogen peroxide. This substance
normally tends to decompose into water and oxygen, but if a small
amount of spongy platinum is added to it, the decomposition is greatly
accelerated: H202 = H20 + 0.

A very good example of the action of an inorganic catalyst is that of
the hydrogen ion on cane sugar, or other disaccharides, in the presence
of water. It accelerates the hydrolysis. Cane sugar solution at room
temperature does not indeed, in sterile solution, undergo any appreciable
hydrolysis, but at 100° C. it does, which leads us to believe that, though
inappreciable, the action also occurs at room temperature. By adding
a little hydrochloric acid, or other acid not having an oxidizing effect
on sugar, we greatly accelerate the hydrolysis because of the hydrogen
ions present in the acid solution. Within certain limits the rate of hy-
drolysis is proportional to the amount of catalyst present.

Enzymes, like other catalysts, produce their action when present in
very small amounts (e. g., sucrase can hydrolyze 200,000 times its weight
of cane sugar; diastase can convert starch to sugar in a dilution of
1-1,000,000) and there is a distinct relationship between the amount of
enzyme prescnl and the rate of the reaction. The final product of the

n km

reaction is, however, tin- Bame ;it whatever rate il

enzyme does nol appear in the final product* M

diastase can be found unaltered in amounl

their action. This is determined bj adding a

(thai is, of material tn be acted <»n . when the

;i'_r;iin in the usual way. The Bame is no doubl tru<

though as yel it can actually be proved for only I.

therefore, may I"- defined as catalysts produced by li

The Properties of Enzymes

Although enzymes are exampli i 'litiit mai

ties thai appear t<» differ i"i< >in those of inorganic c 11 ill.

therefore, 1"' advisable in considering m quality I in

catalysts ami enzymes, for by ibis method a much clei
tlic nature of enzyme action can 1'-' gained Bayliss l

that are Btrictly peculiar t<i enzyn ■ shall

1. Most enzymes an remarkably specific in tl
ganic catalysts <n-< very much /■ Thus, in th<

which bring about inversion of disaccharides, this sp< sific irly

shown. There is a s| ial enzyme for each "t" tin- three >\

maltose, lactose ami cane siiLrar and one i
another.

Still more Btrikingly is this specificil inzyme

in the fad that certain enzymes, Buch as zymasi
will act only on bodies having a certain configuration, tl
their Bide chains arranged in a certain wa} Tl
of dextrose ■< and 8 which differ from each
• that the Bide chains are arranged in differenl i
tion f«> the centra] chain of carbon atoms This form a is

called stereoisomerism because the two bodi<
i lighl t" an equal degree in opposite din
of these hut ool on the other, ami th« r innum<

same kin. I. [ndeed, of all bodies that ■ nl\

one is found in living cells and it is on this variety

in animals .-an act. A similar specificil

their pharmacological action.
Specificity <>t" action is explained bj -
d the Bubstrate ami th.
place the enzyme must p
rately w ith that of the subsl

h.ck ami ke\ ; the key mu

operate. The .p. eificitj d i

74 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

relationship between enzymes and inorganic catalysts, for on the one
hand there are several enzymes which do not exhibit this property, and
on the other, there are inorganic catalysts which do. For example,
lipase, the fat-splitting enzyme of pancreatic juice, decomposes not only
fats but to a greater or less degree a number of bodies of the same gen-
eral build (esters), and tyrosinase can decompose, not tyrosin alone,
but all phenol compounds. Conversely, the hydrogen ion — to the pres-
ence of which acids owe their catalytic powers — can decompose the ordi-
nary esters (that is, of acids containing the carboxyl or COOH group)
but it has no action on the sulphonic esters. However, enzymes are cer-
tainly much more specific in their action than inorganic catalysts.

2. Temperature does not influence catalysis and enzyme action in the
same way. As the temperature is raised in the case of inorganic catalysts,
the reaction becomes about doubled in rapidity for each rise of 10° C,
whereas in the case of enzymes it becomes increased up to a certain opti-
mum temperature, beyond which, as the temperature rises, the reaction is
first slowed and then disappears altogether.

This peculiarity of enzymes as compared with inorganic catalysts need
not in itself disprove the analogy between the two, because enzymes do
not form true, but colloidal solutions. Colloidal solutions, as we have
seen, are really fine suspensions of ultramicroscopic particles ; there is no
splitting into ions of the dissolved substance, as is the case with true
(molecular) solutions, but the colloid is suspended in the water or other
solvent to form a heterogeneous system (page 51), on which account
the surface area of the menstruum is enormously increased. Rise in
temperature alters the extent of the surface area, and thereby intro-
duces an influence which progressively opposes catalysis.

Although inorganic catalysts in molecular solution show no optimum
temperature but increase in activity in proportion as the temperature is
raised, inorganic colloidal catalysts may show an optimum temperature.
Thus, spongy platinum shows an optimum temperature in its action on a
mixture of hydrogen and oxygen. It has therefore been suggested that
it is because they are colloids that enzymes exhibit this property.

3. Inorganic catalysts frequently carry ttir reaction to a further stage
than that attained by the action of enzymes. For example, acid breaks
down the protein molecule much more completely than do the proteolytic
enzymes. This difference is perhaps explained by the fact that enzymes
are retarded in their activities when there comes to be a certain accumu-
lation of the products of the reaction present. The final stages in the
reaction may become so slow as to be almost, inappreciable. This de-
crease in activity is partly due to a union hoi ween the enzyme and the
products of its activity.

FERMENTS, OR ENZY Ml

t I in vi locity constant in ti ■ <is un-

changed throughout th( reaction, whereas in tl
conn s i it) ■ or gn <it, ,• ,/„• //,, y,

changed by catalytic action, it is, of com

in concentration bo thai less and less of it remains to be 1

implies thai there are fewer molecule

catalysl to act on and consequently thai the amounl anil

ot time is progressively less, At any momenl
catalysis will 1).- proportional to the amounl
left. To understand this we must refer back to whal we ha
mass action. It' we suppose thai two sul i. and B react 1

two other substances C and 1>. then, by the law of m
tic.ii will nol go "ii to completion bul will stop when ;i certain equilibrium
is reached. The reaction can 1"- represent
A I'.. -•!' i). which means thai it proc al a rate i»;
the reacting molecules. In Bomi 3 this reaction g until

A or Bhas practically disappeared (thai is, the equilibrium point is v<

■■ the righl of the equation . as is tl in the i'

sugar:

C12HM0 H" 'II 0 I II

Taking place as it does in an
little tendency for this reaction to '-ro in the opp
versible action' (page 25 . the onlj thing which will influei
velocity is the concentration of cane sugar; in other words, th<
of the reaction a1 anj moment will depend solely on thi
C, of the materia] still left undecomposed. This cai
means of an equation.*

The value of siidi an equation is that it giv<

ing the amount of inversion that would OCCUr in each nnit •

cane sn'_rar were kept in constanl entratioiL When,

it is stated that K for a particular strength i actin

solution is 0.002, this means that when volume, ■

•If x be the

■

KC Dal
the rr/irt:
calculus,

m that 5x ti

mcth

|

thin permiltii
timet

A-

76 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

temperature are constant in a gram-molecular solution of sugar, 0.002
"•rain-molecule of sugar -would be inverted the first minute and 0.002
gram each succeeding minute, provided we could keep the solution con-
stantly a gram-molecular one, that is, provided we could add sugar just
as quickly as it becomes inverted.

At first sight it may appear of little practical importance to determine
K. In our present discussion concerning the nature of enzyme action,
it is however of great value for, whereas with inorganic catalysis K is
really of constant value, with enzyme action it is not so. Thus, when
cane sugar is inverted by sucrase — an enzyme present in the intestine
and in yeast — the constant gradually rises; for most other unimolecular
reactions mediated by enzymes it gradually falls; for example, the action
of trypsin on proteins.

Where there is a great excess of substance to be acted on, in compari-
son with the amount of enzyme present, it will be found that a more
const ant value than K is obtained when we compute the absolute amount
of substance decomposed in a given time. In such a case, too, the
amount of change in a given time will be proportional to the amount of
enzyme present, indicating that some sort of combination between en-
zyme and substrate must be the first step in the fermentative process.
This fact has been noticed by us in connection with the hydrolysis of
glycogen in the liver. When there is an excess of glycogen present, the
amounts which disappear in equal intervals of time after death, are the
same ; when, on the contrary, there is not much glycogen, the amount
which disappears gradually declines, but, if K be computed by the above
equation, it is constant.

To make these facts clear it may be well to pause for a moment to
consider an illustration. The conditions obtaining when there is a large
excess of substrate over enzyme may be compared to those governing
the removal of a pile of bricks from one place to another by a number of
men. The. pile of bricks represents the substrate ; the men, the enzyme.
If each man works up to his capacity, it is plain that the number of
bricks transferred in a given time will not depend at all on the size of
the pile to be transferred. When, however, the pile of bricks gets small,
though the same number of men continue to work the number of bricks
transferred in a given time falls off, because the men interfere with one
another's activities in securing their loads from the pile. When a similar
stage is arrived at in enzyme processes, we have to use the velocity con-
stant to show how much work could be done by the enzyme if the amount
of substrate were maintained of constant amount.

In the large volume of recent work which has been done with the
object of discovering the cause of these variations in the velocity con-

77

st.uit iii the case of enzymes, four important «•< »i i « I i t i < ■
nixed: l sibilitj ; 2 gi adual d<

liinatioii of the enzyme with products "t" th<

Of these four influences the onlj hi<-li could bi

for an increase in the activity of the enzyme in this

process the enzyme by its action produc . which

its own activity. In Bome casi
invertase on cane sugar these are acid bodies, ;i u.
acidity favoring the action "t" this enzyme.

The other influences all tend to retard the
lower the value of K. Negative autocatalj

produces products which interfere with itivity. Gradual d<

tion of the enzyme and its union with the product '.ill

manifestly also decrease its power. '1*1 • plenty i

both <>l" these processes may occur.

Reversibility of Enzyme Action

Bui the mosl important »>t' all the ca
activity is undoubtedly reversibilii n, which

tin- law of mass action (page 25 . If we t
r, the equation is :

CH CH CI il ll.o-. . i |

•livl but) rati

The equilibrium point is ool bo near the i»< >^it i« .n of com]

- in the case of the inversion o
tendency for tin- bodies produced l>\ the hydrolvs
the original Bubstanees is quite marked, bo thai the react

end before all the ethyl butyrate lias been d iposed

before the equilibrium point is reached, there will i
Bively increasing opposition to the breakdown
que which, when enzymes are used to

velocity constant, as determined b) the
fall as the reaction proceeds < n a m

and butyric acid there is \<-v\ bIo^i syntl
again lipase accelerates the pro t indt

u ithin a short time. Ethyl butyral
periments because, on account of its od< r
Thus, if the alcohol and acid be mi
luit if some lipase be added, it \\ ill i
action of lipase lias also been dem<

J8 PHYSICOCHEMICAL BASIS OF PHYSIOLOGICAL PROCESSES

It should be clearly understood that pure catalysts, such as the hydro-
gen ion, in accelerating a reaction like the above, do so equally in both
directions, so that the position of equilibrium remains unchanged. En-
zymes may, however, cause this position to change because of their form-
ing intermediate combinations.

The reverse phase of certain reactions is probably the cause of at least
some of the synthetic processes which occur in the annual body. A great
difficulty in accepting such a view, however, is the fact that the equilib-
rium point of all liydrolytic reactions, in the presence of an excess of
water, is so near complete hydrolysis that very little synthesis can be
possible. That is true so long as the substance synthesized is soluble,
but if it is nearly insoluble in water, or if it is immediately removed
from the site of the reaction by diffusion, or in any other way, then it is
obvious that it will go on being synthesized by the reaction. Thus, in the
intestine neutral fat is hydrolyzed by pancreatic lipase into fatty acid
and glycerin, which are absorbed into the epithelium, where they again
come under the influence of intracellular lipase. This latter will tend to
accelerate the synthesis of neutral fat from the fatty acid and glycerin
until the equilibrium point of the system (fat acid + glycerin <^ neutral
.fat + H,0) is again reached; but this point, although it is near the right
hand of the equation, will really never be reached for the reason that the
neutral fat, as quickly as it is formed, will become deposited in insoluble
globules in the protoplasm and thus be removed from the equation. In
support of this view it has been found that lipase is present in intestinal
mucosa after all traces of adherent pancreatic juice have been washed
away. By similar reactions the fat of the tissues becomes decomposed to
fatty acid and glycerin and passes out of the blood when the concentra-
tion of fat in this fluid falls below a certain level. Provided one of the
substances synthesized is insoluble or can in some other way be removed
from the reaction, it is plain that, even though the equilibrium point is
very near to that of complete hydrolysis, yet the reversion will be suf-
ficient to do all that is required of it.

Results such as the above have prompted many to conclude that it is
by such reversible action that all synthetic processes occur in the living
organism. But the demonstrable synthesis of an ester must not be taken
as evidence that all other syntheses are explainable on the same basis.
For example, we have seen above that in the case of cane sugar the equi-
librium point in the equation is so near that of complete hydrolysis, that no
measurable amount of cane sugar is formed when dextrose and levulose are
allowed to act on each other, and that cane sugar does not appear
when sucrase is added to the mixture. If instead of sucrase we take
another of the sugar enzymes — namely, maltase, which accelerates the

I I KM , .1

decomposition of maltose into \\\<> molecules of .
ever, evidence of synthesis as a resull of the acccleratioi
reaction. To understand th< ilts we musl rememh

dextrose is a mixture of two si I a bj

two molecules >>\ <i dextrose condense thai i with

i>\ a molecule <»t' water maltose is Formed, l>ut when two mo

of ii dextros ndense isomaltose resull

as to whether nudtast is really responsible for the

molecules to maltose, ii being claimed by some tliat tins is

by another enzyme, emulsine. If tins were true it would i illy

minimize the important E reversible action as a factor in celluh

thesis. The latesl evidence goi show, ho

and not emulsine thai is responsible in the above

Evidence, both direcl and indirect, is als imulatii -

show that enzymes may accelerate the Byntl >f j » i-« » t

of direcl evidence we have: 1 the retardation of the dig<
of trypsin, etc., which sets in after the process hi
and 2 the recommencemenl <<\ a digestive |
end. if the products of the digestion are removed by dial
means. .\s direct evidence may be cited the formation
products when pepsin is added to concentrated Boluti
and the diminution in the number of small molecules, as judg
urements of electrical conductivity, when trypsin is added I
nets of tryptic digestion of caseinogen. Protamine a sim]
tein lias also been found to be produced when trypc
a mollusc was added i" a tryptic d E the •

significance of these facts in connection with the mel
amino ai«l< will be evident when w< me I idy this snl>

Specificity of Enzyme Action

Although in all of the above features of enzyme action l
contradicl the vievt thai they are catalyl : agents, 1

iliarity which at first Bighl Beems nnintf rpr.-t ah •

This is with regard t>> their often remarkabh
as we have sen, maltase '-an hydrolyze malt'
posed of two o-dextrose molecules . hut i

This means that mere diflf<

molecules is Bufficienl t<> alter the infl
such different aid uol influence t;

•Wr I . .

■

80 PHYSICOCHEMICAL BASIS OP PHYSIOLOGICAL PROCESSES

explain the cause of the difference. This has been done on the basis
either that enzymes are colloids or that the active (catalytic) group of
the enzyme is attached to a colloid molecule. Before a substance can
be acted on, it must combine with the colloid, which it does by the proc-
ess of adsorption (sec page 65). This can occur, however, only when
there is a harmony between the adsorbing substance and the substance
adsorbed. Instances of the specificity of adsorption have already been
given.

In support of this view it has been found that of the two proteases,
a and fS, in the spleen, one is adsorbed but not the other when a solu-
tion containing them is shaken with Kieselguhr. Furthermore, when
solutions of invertase are shaken with certain inert powders, the in-
vertase is adsorbed by some of them but not by others. In strong sup-
port of the adsorption hypothesis is also the fact that the same mathe-
matical laws as apply in the process of adsorption are obeyed in the
ratio which exists between the activity of an enzyme and its concen-
tration in the solution.

To sum up, then, catalysis as exhibited by enzymes involves three
processes: (1) contact between the enzyme and the substrate, which will be
dependent on their rates of diffusion; (2) adsorption between them, which
will depend on their configurations (cf. the lock and key simile) ; and
(3) the chemical change which itself probably takes place in two stages.
In connection with the third process, it is probable that an initial com-
pound of a definite chemical nature is first formed, followed by the
hydrolytic or other chemical change, after which the enzyme group
becomes free.

It is very significant in this connection to note that in their solubil-
ities there exists a distinct relationship between the ferments and the
substrates on which they react. Thus, trypsin is very soluble in water
and acts on water-soluble proteins; lipase is soluble in fat solvents.

Certain Peculiarities of Enzymes

Notwithstanding the very strong case that is made out for the cata-
lytic hypothesis, there are certain facts which many find it difficult to
make conform with such a view. One of these is that dextrose can
undergo three distinct and separate types of decomposition according
to the enzyme allowed to act on it. These are alcoholic fermentation,
butyric acid fermentation and lactic acid fermentation. It is difficult
to see how simple catalytic action can be responsible for all three results.
The enzyme must not only initiate the changes but also direct their
course.

Another peculiarity is thai when certain enzymes — e.g., rennin, pep-

PI i:\li NT8, OR Bl

sin. etc. are Inoculated in animals, they caus<

appear in the I » 1 < »< »< I of the inoculated animal. Thu en antirennin

sfniiii is added i<» milk it greatly hinders clotti

addition of rennin. It is probable thai powerful antienzyme

duced in the animal body for the purpose of protecting th<

attack by enzymes. It is on accounl of the pr<

thai intestinal parasites can exist in the i 1 the immunity

From digestion which the mucosa of th< itinal I

is believed to be due to the Bame cause. Bui ti doubt

regarding this claim. Fresh pancreatic juice when ii

empty intestine < 1 i -_r i • s t -, its walls. When f I is present in the ii I

tine it evidently prevents digestion of the walls by diverting ti
to itself.

Types of Enzyme

Saving learned something aboul the genera] nature

• may QOW turn our attention I rtain details that have a ]>;

importance. In the first place, with regard to nomenclature, in the

earlier work cadi newly discovered enzyme received a which \

often quite inappropriate. .Many of these names ai

pepsin, trypsin, ptyalin, etc., bu1 it is now- customar the

enzyme according to the Bubstance on which it acl I is is d

by replacing the last part of the name of the Bubsl >n by the

termination -ase for example, the enzyme which inverts ma I " I * * « 1

maltase . <>r bj merely adding -ase to the name i

upon thus, the enzyme which hydrolyzea glycogen is called |

Mfosl of the enzymes in the animal body

es and are classified according to the chemical na1

Btrate on which they work. Thus, we havi
1. The amylases accelerating the hydrolysis of pol

ptyalin (in saliva , amylopsin (in pancreatic juic< .

liver , <1 in malt

'_*. The inveriates accelerating hydrolya
ase, lactase and sucrase in sue, mis entericus

:'.. The proti inan - accelerating hj
iin gastric j u i<-.- . trypsin (in pancreatic juic<
proteinase

1 The Upasi » accelerating disruption
i in pancreatic juice . inl • acellular Ii]

.1 rginast accelerat ing hyd
nithin. i intracellular .

82 PHYSICOCHEMIOAL BASIS OP PHYSIOLOGICAL PROCESSES

6. Urease — accelerating hydrolysis of urea to ammonium carbonate
(in many microorganisms and in the soy bean).

7. Glyoxylase — converting glyoxals into lactic acid (page 666).
Other enzymes accelerate oxidative processes and are called oxidases

and peroxidases. Others bring about the displacement of an amino
group by hydroxyl (desamidases). Others cause coagulation (coagula-
tive ferments), e.g., thrombin, rennin. One of the enzymes present in
succus entericus acts by converting the zymogen (trypsinogen) into the
enzyme (trypsin).

Enzyme Preparations

So far it has been impossible to prepare enzymes in a pure state al-
though, being colloidal in nature, they are readily precipitated or ad-
sorbed along with, other colloids.

Since most enzymes exist in cells, it is necessary to break up the cells
in order to isolate the enzyme. This is done in various ways. By one
method the cells are ground in a mortar with fine sand, then made into
a paste with infusorial earth (Kieselguhr), the paste enclosed in stout
canvas and placed under an hydraulic press at about 300 atmospheres
pressure ; a clear fluid separates and this contains the enzymes. An-
other way is to freeze the tissue with liquid air and grind it in a steel
mortar by means of a machine, ^till another and less expensive method,
and one which we have found most useful for organs and tissues, con-
sists in reducing the tissue to a pulp and, after sieving it to get rid of
connective tissue, etc., spreading the pulp on glass plates and drying
in a slightly warmed, dry air current. The scales of dried material are
then ground in a paint mill with toluene, and the resulting suspension
filtered ; the powder which remains on the filter, after thorough washing
with toluene, is dried and kept for future use. The toluene removes all
the fatty substances, so that when shaken with water, etc., the enzymes
dissolve.

Conditions for Enzymic Activity

Reactions brought about by intracellular enzymes are very readily
inhibited when there comes to be a certain accumulation of their prod-
ucts of action. Thus, yeast ceases to ferment sugar when the alcohol
has accumulated to a certain percentage. This action is partially due
to a toxic action of the alcohol on the cell, which paralyzes its power of
absorbing the substance to be acted on by the intracellular enzyme. If
these products be not in some way removed, they will ultimately kill
the cell and stop the fermentation. AVe have seen above how the ac-
cumulation of products may interfere with the activities of enzymes in

■ ■

other ways in which the enzyme does not

li\ the fad thai it resumes ita original activities on

products.

Bnzymes, both intracellular and extracellulai
wards the i 1 1 1 » i lt .- » i j i < - composition of the medium in which
ing. For the intracellular enzymes this is what
we bear in mind the profound influence "i" inorganic gaits
beal and on cell growth and division. This influei • I

reaction acidity, etc. on the life of the <-'-ll is bo pronounce

some observers to believe thai al rmal cell multiplication in '

as in tin' case of tumor formation, is due t.. cha a the

composition of the tissue fluids. Bxtracellula
Busceptible to the influence of inorganic ^.ilt s bul

towards the reacti E the Bolution. In terms of modei

we may say thai the concentration of II- and OH' ions has a profound
influence on the activities of enzymes. Mosl of the eni

iinal bodj perform their action mally in the presence

cess «>r OH' ions, thai is. in faintly alkaline redaction. Indeed tin- onlj
exception of importance i" iliis is the pepsin of gastric juice, which i
mally arts in an acid medium. An \ of either OH' ll

inhibits tin- activity <>!' tin- enzyme ami usuallv destroys it perma
The activities of enzymes air also influenced by Light, man}
being destroyed by sunlight; cells Buch as microorganisms
affected.

Before being secreted the <li'_r<-sti\.' enzym Us whi

produce them as inactive precursors called I

in resting gland cells are "t' this nature. Tin- activation
or its conversion into tin- enzyme, occurs after it hat

this has been isidered as another aid t<> <i

Sometimes the activation does nol occur until the

some distance along tin- gland duct, as in tin

enzyme of pancreatic juice. Till it reaches the intestiiv

trypsinogen tin- zymogen . l>nt it is hei

like bod} produced by tin- i il epitheliun

PHYSICOCHEMICAL REFERKM i

bfonogi aphs and 0 I ' ■

Bayliss, W. M.: Principli

Llip, .1. C: Physical Chemistry, II

ed, -. 191 1.
M. ci. n. lun. .i. 8.: Phj lical I I

Press, 1917
t&tarling, E. II.: Principle*

84 PHYSICOCHEMICAL RASIS OP PHYSIOLOGICAL PROCESSUS

Kahlenberg, L.: Jour. Physical Chem., 190G, x, 141.
sReid, i:., Weymouth: Jour. Physiol., 1898, aacii, lvi.
7 Wilson, T. M.: Am. Jour. Physiol, 1905, xiii, 150.
sHaldane, J. S., and Priestley, J. G.: Jour. Physiol., 191(5, 1, 29G; Priostlcv, J. G:

Ibid., p. 304.
sClark, W. M., and Lubs, H. A.: Jour. Bacteriology, 1917, ii, 1 and 109.
LoHenderson, L. J.: The Excretion of Acid in Health and Disease, Earvey Lectures,

J. B. Lippincott Co., 1915, x, 132.
"Henderson, L. J.: The Fitness of the Environment. Macmillan, X. Y., 1913.
>-V;in Slyke, D. D.: Jour. Biol. Chem., 1917, xxx, 289, 347.
"Levy, B. L., and Rowntree, L. G.: Arch. Int. Med., 1916, xvii, 525.
"Cull'en, G. E.: Jour. Biol. Chem.. 1917, xxx, 369.

1- 'Palmer, W. W., and Henderson, L. J.: Arch, Int. Med., 1913, xii, 153.
isSellards, A. W.: The Principles of Acidosis and Clinical Methods for Its Study,

Harvard University Press, Cambridge, 1917.
i"Lloyd, F. H.: Private communication.
'vMacallum, A. B, : Surface Tension and Yital Phenomena. University of Toronto

Studies, Xo. 8, 1912; also Ergebnisse der Physiologie, 1911, ii, 598.
isBayliss, W. M.: Enzymic Action, ed. 2. Monographs in Biochemistry, Longmans,
Green & Co.

PART II

THE BLOOD AND THE LYMPH

CHAPTER X

BLOOD: ITS GENERAL PROPERTIES
r.v R. G. Peabce, B.A., M.D.

The blood, being the carrier of the nutritive and wi ibstai

the body's metabolism, must at one time <»r another contain all t;
terials which compose the ti^ms in addition to those which an iliar

to the blood itself. It is a very complex fluid, ami all <>; institw

are nut fully known. Structurally it is composed of water in which are
dissolved various gases ami organic ami inorganic bodies, the c
and platelets.

THE QUANTITY OF BLOOD IN THE BODY

The nmst accurate method <>t' determining the volume of M 1 in

the body is bj bleeding and subsequently washing <>ut the bl from
the vessels and then estimating the amounl of hemoglobin in the tol
fluid (Welcher's method . This method employed in the
criminals who had been decapitated gave the weighl of the bl<
7.7 and 7.2 per cent of the body weight. Bloodless methods for del
mining the total volume of blood are based upon the principle of add

ing a definite quantity of a known substai to the circulation ai

estimating its concentration in a sample of blood withdrawn from

bodj Bhortly afterward. It' the Bubstance can not lea

ami dues not cause tliiid tn be withdrawn from the tis the total quantity

of blood in the body can be calculated from

injected Bubstance in the blood. The must accurate method*

this principle are Haldane and Smith's, in which carbon n

is inhaled in a given amount ami the carbon mon

Bequentlj determined colorimetrically ; and Keitl

aghty's, which employs vital re. I. a dye of lo

remains long enough in the bod) )■■ be ihn

blood, and its entration in the pla •

86 THE BLOOD AND THE LYMPH

by comparing with a suitable" standard mixture of dye and serum. These
methods give the total amount of blood in the body as from 5 to 8.8 per
cent of its weight. Meek has recently developed a method in which gum
acacia is used. After mixing with the blood, the concentration of this
substance is determined from the calcium content. Being colloid, none
of the gum leaves the blood vessels.

The newer methods have shown that the volume of the circulating
fluid is maintained fairly constant in spite of influences tending to alter
it. The body accomplishes this by drawing upon the reserve fluid in
the tisvsues and by varying the rate of water excretion, particularly
through the kidneys. Years ago the doctrine of an increased amount of
blood in the body (plethora) gave rise to the therapeutic use of bleeding.
Especially Avas this thought to be useful in conditions which we now
recognize as chronic hypertension, and which show no increase in blood
volume. Indeed variation in blood volume is not common, although
plethora may occur in polycythemia, chlorosis, and anemias, and there
may be a temporary reduction in the amount of blood in diseases in
which there is a great depletion of water, as in Asiatic cholera, and fol-
lowing very severe hemorrhage.

While the total quantity of the blood in the body does not vary greatly,
the concentration of its various constituents is subject to distinct change.
The volume percentages of the corpuscles and the plasma can be approx-
imately determined by allowing oxalated blood to sediment or by cen-
trifuging in a graduated cylinder by the use of the hematocrit. Such
methods are not very reliable, but may yield some important information.
Normally 45 to 50 per cent of the volume of blood is composed of cor-
puscles. It varies more or less directly with the number of red blood
colls.

THE WATER CONTENT OF THE BLOOD

Since the blood plasma is essentially a watery solution, some idea of
its water content can be obtained by a determination of the specific
gravity. The most accurate method for accomplishing this is to deter-
mine directly the weight of a given volume of blood and compare it
with the weight of the same volume of water. Since this method re-
quires a rather large amount of blood, indirect methods using smaller
•amounts have been devised. One of these (Hammerschlag's) uses a
solution of chloroform and benzol of a specific gravity of about 1.050,
in which a drop of blood is suspended by delivering it cautiously from
;i pipette bent at right angles near its tip. If the drop sinks, chloroform
is added; if it rises, benzol is added until the drop remains suspended.

BLOOD : I i

The Bpecific gravity of the benzol-chloroform mixl

and this value is Bupposed to gh •• th< ■<!.

The Bpecific gravity of the blood determined in tin
t ween 1 040 and 1 .065. It is some •■ i al
after exercise; it is Blightly lower duri day I

the variation in individuals is considerable Th< • which

in the sj ific gravity of the blood in disease are chiefly due tioi

in the percentage of protein, since the Ball

tively fixed. It is only when greal chai ir in t;

of the noncolloidal salts that they markedly a

Prom ,,(| to 92 per cenl of the plasma and From 59 2
corpuscles consisl of water. Of the whole blood, from I
by volume or aboul 55 per cenl by weight cons
40 to 30 | t by volume or 15 per cent by weight

puscles.

THE PROTEINS OF THE BLOOD

The plasma obtained by centrifuging the blood rendered not
Mi- by oxalates, hirudin or other means

per < - « - t 1 1 of coagulable proteins. These proteins a min,

Berum globulin, and fibrinogen. Thej can be
by tin' nse of acids and neutral sails. Their proportion ■
ferent conditions, bu1 is approximately

Fibrinogen ....0.1

'•iilin

•mi albumin

The amount of fibrinogen is subject to th<

Fibrinogen

The l( oluble of the bl 1 p fibril

almost freed of it by hal tion with Bodim lh a

small amounl cid It is precipit • in ti

of blood coagulation

anmunt of fibrin which it product

Scrum Globulin ami Serum Albumin
Globulin ordinarily defim

and albumins as b.-in It -

serum globulin and albumin
lin obtained b\ dialysis can

88 THE BLOOD AND THE LYMPH

a suitable amount of water, which makes the salt adherent to the pre-
cipitate a weak saline solution. In neutral or acid solutions it is coag-
ulated by heat at about 75° C. But it does not act as an individual pro-
tein, since a portion of it is precipitated by dialysis or by carbon diox-
ide. Probably serum globulin really consists of two or more proteins.

The serum albumin remaining in solution after saturation with am-
monium sulphate likewise does not represent a chemical entity. It is
possible by carefully heating the solution of serum albumin to distin-
guish three separate coagulation temperatures. This fact has been in-
terpreted as meaning that the serum albumin consists of at least three
closely related proteins.

Since the refractive index of the blood depends primarily upon the
amount of protein present, it has been taken as a means of determining
variations in the concentration of the proteins. It has been found that
the concentration of the blood proteins \raries somewhat; during ex-
ercise it is increased probably because of the taking up of water by
the tissues, and during profuse bleeding it is diminished because
large amounts of fluid are being added to the blood from the lymph,
which is relatively poor in proteins. The ingestion of considerable
amounts of salts has been found to reduce the concentration of the blood
proteins for a short time. In pathological conditions, as in diabetes, when
rapid changes in the body weight due to alterations in the diet are oc-
curring, changes in the fluid content of the blood are often observed.
Likewise in edema caused by faulty renal function, there may be a re-
tention of fluid in the blood before there is any indication of edema. The
hydremic condition of the blood can therefore be considered as a useful
diagnostic aid in determining the water metabolism.

The relative concentration of the proteins of the blood is also of some
interest, especially since in some diseases a considerable amount of
blood protein is lost. By refractrometric methods it is possible to sep-
arate the globulin and albumin fractions. Normally the total proteins
range between 6.7 and 8.7 per cent, of which the albumins lie between
4.05 and 7.7 per cent, and the globulins between 1 and 2.54 per cent, In
some diseases, as in chronic nephritis, pneumonia, and syphilis, the
total proteins of the blood are decreased and the relative amount of
serum globulin is increased On the other hand, in many mild infections
and chronic septic conditions the globulin fraction may be increased
with no change occurring in the total protein content.3

Our knowledge of the origin and the function of the blood proteins is
quite unsatisfactory. Previous to the discovery of amino acids, the
building stones of the proteins, in the blood it was thought that the
nitrogenous nutrients were converted somehow into blood proteins dur-

BL : ITS '.INI RAL I'ROI'I

ing or immediately followii
canal, and thai the tissue cells nourii

tein. It is nu« known that the amino

thetized into blood proteins after their absorption from the <\
-■in. The blood proteins are radically « I i

tein S tbstai - \\ hich retard or «1"

1 1 « » t alter the relationship « • n. i -> t i 1 1 «_r between tl
blood. This fad indicates that the Berum pi

independent of the nitrogenoui tabolism i un-

doubtedly maintain the viscosit blood and

its neutrality. Attempts i" localize the

proteins have nol 1 d successful. There rin-

ogen is formed for the most part in the tie

(liver . It is quite possible that the blood own |

as <i" other t from the amino acids il co I

THE FERMENTS AND ANTIFERMENTS OF THE BLOOD

The blood plasma contains many Hi' the ferments * in tl.

The nature of these ferments has been the subj< ny in>

tions in recent years, primarily because i1 i en found I

intimately connected with the problems of immunity.

Among the ferments ih<- following have been demoi 1 in I

blood:

Proteases arc probably presenl normally in the human M 1

in small amounts, but thej are found in largt

blood corpuscles. A protein foreign to the body it' it

blood ordinarily produces no untoward syi

tion following the first by Borne days will product

ing known as anaphylaxis. This fact has led to tl

the injection of any foreign protein int<

the appearance therein >>\ specific |

the Bt range protein int<> its derival

pov the body to produce sp<

of much research and debate, and \

nanc} . for cancer, and

phenomenon; He beli<

ransc the ' ■•'• of p s that bril

ferments w hose duty
investigators fail t.» find the
Abderhalden, and believe tl
of digesting

90 THE BLOOD AND THE LYMPH

from the digestive juices (Boldyreff). Some investigators fail to confirm
the claim that the proteolytic activity of the blood serum is increased under
the above conditions.

Blood contains an antiferment known as antitrypsin. This can be
removed from the blood serum by several substances, among which are
kaolin, colloidal iron and starch. Serum thus treated shows strong pro-
teolytic activity and autodigestion will occur. In this case there can be
no question of the specific origin of proteases. Abderhalden believes
that the ferments of the blood of the pregnant woman are able to digest
the placental tissue. Human placental tissue has the ability of absorb-
ing antitrypsin and it is very questionable as to whether the test pro-
posed by Abderhalden is due to the new formation of ferments or to
the removal of the antitrypsin and the action of the protease normally
present in the blood.

Nuclein ferments are capable of decomposing nucleic acid and purins
into the simpler bodies.

Lipases have been demonstrated in the blood.

Amylase. — The presence of starch-splitting ferments in the blood was
first shown by Magendie in 1841, and later Bernard showed that gly-
cogen or starch injected into a vein produced glycosuria. Since then
it has been proved conclusively that diastatic enzymes are normally
present in the blood and lymph. The source of these enzymes has given
rise to much speculation. Some observers believe that they are derived
from the amylopsin of the pancreatic secretion, while others believe that
they are manufactured by the liver. Ligature of the pancreatic ducts
is said to increase the amount of amylase, while removal of the pan-
creas may (Carlson and Luckhart) or may not (Schlesinger) increase
the amylase of the blood. In some forms of experimental diabetes the
amylase of the blood has been found increased, and this is the case in
human diabetes (Myers and Killian). If this is true, a cause for the
inability of the diabetic to store up glycogen is found. In impairment
of renal function, there is usually an increase in the blood amylase and
a decrease in the urine amylase. This has been suggested as being of
diagnostic value.

The blood contains a feeble glycolytic enzyme capable of destroying
glucose. It is claimed that this power is reduced in diabetics (Lepine).

Catalase is found in the blood and tissues generally. It has the power
of liberating oxygen from hydrogen peroxide without any accompany-
ing oxidation process. Its physiological significance is not known. It
is said that the amount of catalase is increased during excitement and
exercise, and is decreased in conditions where the body's activity is
lowered. Its determination is clinically unimportant at present.

' II ATI ER XI

BLO< >D THE BLOOD CELL

Bl h\ <.. P] \i;- : . T. A . MH

THE RED BLOOD CORPUSCLES. OR ERYTHROCYTES

The most prominenl function of the bl
tissues It owes this property chiefly to the red bio

-•nt in large aumbei - 5, ,000 pei c d m

are biconcave discs, having a diameter of aboul 7 7. l
structed out of a framework composed largely of lipoidal mal
the meshes of which i^ deposited a substance call*

which the remarkable oxygen-carrying power <>t' the bl 1

ther tin- manner by which the red •■•■ll carries its henn _

intimate structure of the cell itself is accurately known. I

monly believed that the hemoglobin is held enmeshed in

(ii- stroma, or encased in the cell membrane. One thing

ever, thai the union of hemoglobin with il '. i*

a fairly Btrong one, since mere fragmentation

liberate tin- hemoglobin. The fad that the framework •

amount of lipoidal Bubstances enables tl

shape ami is responsible for their chara

Hemoglobin is a very «•< >ni ]>l<x substance be
conjugated proteins Bj chemical means it c
Bimple «_rli»liulin ami .i pigment hematin \\

pletely saturated, oxygen is pi I in hemog in th<

of two atoms of oxygen i « » one atom of iron Pet<
oxygen can In- carried by hemoglobin containi
molecular weight of the molecule being ab<
thereof Barcrofl and I' V 1 i

iron in the molecule w ould rep
of th<- molecule. The corpusculai
t200 squai i m< tera Tl ■

able for the absorpti

ihm'Ics pass in single file througl I

Since tin- amounl of ■ ■ aren which ihe bl<
it s hemoglobin content, it is

92 THE BLOOD AND THE LYMPH

methods of determining the approximate amount present. The amount
of hemoglobin present in a quantity of blood is usually determined
eolorimetrieally by comparing the color of the blood with standard col-
ors which correspond to known strengths of hemoglobin. In normal
persons the amount of hemoglobin varies greatly at different ages, and
in order to determine "whether or not a given blood contains more or
less hemoglobin than normal, it is imperative to consider the age. The
greatest variations oecur between birth and the sixteenth year. After
the sixteenth year the blood in males usually contains a larger amount
than that in females (Williamson4). Instruments used in determining
the amount of hemoglobin should be standardized to give the value in
grams hemoglobin per 100 c.c. of fluid.

The amount of hemoglobin which is present in each corpuscle in
terms of normal is therefore of some clinical interest. This relation of
the number of red cells to the amount of hemoglobin is known as the
color index and is computed as follows: The average red count in man
is 5,000,000 to the c.mm., and the average minimal amount of hemo-
globin is taken as 13.88 grams in 100 c.c. of blood (=80, Sahli; =90.
Miescher; =86, Plesch; and 110, Tallquist methods). These relative
values give a color index of one. The percentage of normal red cells
divided by the percentage of normal hemoglobin present gives the
color index.

The Origin of the Red Blood Cells

In fetal life the spleen and the liver are generally believed to be re-
sponsible for the formation of the red blood cells. In extrauterine life
this function is taken over by the red bone marrow. In the primitive
condition all red blood cells are supposed to be nucleated. In extra-
uterine life the nuclei of the red cells are lost, and nonnucleated forms
are alone present in the blood stream. In fetal life and in certain path-
ologic conditions, the rate of blood formation is so rapid that some
nucleated cells appear in the blood. The normal response of the body
to a loss of red blood corpuscles consists in an increased activity of the
blood-forming eells of the red bone marrow. It is not easy to follow
the course of the regeneration of the red corpuscles or to discover the
mechanism of their formation in the bone marrow, since this tissue pre-
sents a mixture of cells which are precursors of the varied corpuscles
found in the blood and the identity of which can not be determined.

Recently new methods of: staining blood for microscopic examina-
tion have allowed more detailed study to be made on the site and
method of blood cell formation. "When fresh unfixed blood is treated
with solutions of various dyes, such as brilliant cresyl blue, polychrome

Tin r.i OOD Mir.

methylene blue or neut pal red, an <»t i

in Borne '•'•lis in the form "i

give :i reticulated appearance to the corpuscles I

arc nunc abundanl in infants' blood and in pi

vere anemia or hemolytic jaundice than in normal l>l<"

taken as evideni E tin1 youth <•!' tin- red '•••II ;i

tive proci since the number of the reticulated

in ihr blood is nunc or less directly prop

activities <»t' the bone marrow, enumeration of the reticulated •

of clinical importance in anemias. In conditions in whii

been made plethoric by the transfusion of blood, it h

the number '>t* reticulated cells is decreased; the bone ma:

animals also shows ;i marked reduction in reticulated •

The diminished rate of hi 1 cell formation Bometime

transfusions may l"- explained by assuming that the Btimulus wl

awakens the formation of red cells in the bone marro

made subnormal on the injection of'red cells into the blood, an<

the formation of red cells is depressed Small trai -

fore preferable to large ones in cases in which tin- n

linn is greatly impaired. By means of li\in>_r cull

r«>w the different Btages «'t' the development of th<

true red corpuscles may be studied Towei and Herm Somi

has been gathered from such Btudies which poii ts to

in place of the red cells being cells which have l< r nuc

the current teaching, they are rather cells which de

bud and escape into the circulation as true red cells The nu

red cell and the v>-<\ nucleated corpuscle of the bird are ti

intranuclear activity and arc morphologically identical.

Rates of Regeneration of Erythr.

Microscopic examination of the hi 1 durii

\>-i\ cells shows the presence of nucleated I

in the blood have therefore been taken as an i

blood regeneration. The evid upon which tl

however, is hardly complete, Bince cl

cell formation may be responsibli

bone marrow is considered the 1 cell

that an abnormal increase in the red bone

increased red cell formation |

about the new formation unnt

max he an important '

large number of red cells in oondil

04 THE BLOOD AND THE LYMPH

oxygen in the inspired air, as in life at high altitudes, or a difficulty in
its absorption through the lungs, as in congenital heart disease.

The red cells produced following hemorrhage and in simple anemia
contain less than the normal amount of hemoglobin, but their shape and
size are approximately normal, and few nucleated cells are present. In
the regeneration of red cells -which is found in pernicious anemia, we
find the cells containing an unusually large amount of hemoglobin.
The red cells in this disease have abnormal forms, many being large,
with or without a nucleus, and containing, basic staining granules.
This type of blood cell formation is due to degenerative changes.

The Fate of the Erythrocytes

The length of life of the red blood cell is unknown. Estimates based
ii] ton the daily excretion of bile pigments are not reliable, since Hooper
and Whipple have shown that the pigments, in part at least, arise from
pigments which the liver has made' in excess of its needs for the manu-
facture of hemoglobin, and which, not being needed, are excreted."'
There is no question hoAvever that every erythrocyte sooner or later
undergoes disintegration, a process formerly thought to be ushered in
by the ingestion of the red blood cell by a phagocyte in the spleen or
in a hemolymph gland, the hemoglobin of the disintegrated cell being set
free and carried to the liver, where it is broken up into hematin, which
the body stores for future use, and into bile pigments, which are ex-
creted. Rous and Robertson6 fail to find evidence that this process
occurs in man to an extent sufficient to account for the normal destruc-
tion of the blood cells. However they have recently found another and
unsuspected method for blood destruction in all animals thus far
studied — namely, the disintegration of the blood cells by fragmentation
while they are circulating, without loss of their hemoglobin. These
fragmented cells are found most frequently in the spleen. They believe
that the small ill-formed cells, known as microcytes and poikilocytes,
observed in severe experimental anemias, are due not to the fact that
they are produced by the bone marrow, but rather to the fact that the
marrow in its anemic condition is not able to produce a resistant ery-
throcyte, and fragmentation therefore takes place too readily. A sim-
ilar condition may exist in the severe anemias of man and account for
the general high resistance of the red cells found in the blood of these
patients, inasmuch as the weak cells are generally fragmented very soon
after they are formed. Long ago Ehrlich stated that the microcytes
and poikilocytes of anemia are the result of fragmentation of the cells
in the circulating blood, but he believed that this fragmentation was a

I III i:i.i»ol» il ll.

purposeful division in order to increase the total kuH

cells. The ultimate fate of the red ■••■ll fragmenl »wn. I-

reasonable t<> suppose that the fragmented bil

are carried to tin- liver, where the hemoglobin is ti

hematin and l»il<- pigments.

Hemolysis

Another method of red blood cell destruction, which
not take place normally, is by hemolysis. The natu
tion of the hemoglobin with the stroma of the red eel .
marked, is no1 definitely known. Thai il is not mer<
Bac is shown by the fad thai the '•••11 may be <-ut into hits withi
hemoglobin being set free. In some manner the hemoglobin
ically bound with the Btroma of the red ••••II. I hich it c

freed by a number of physicochemical and chemical
ess is known as hemolysis, and the substances which bring it
known as hemolytic agents. The manner in which tin
the release of hemoglobin from the blood is quite \ati>-<!

1 1" the osmotic pressure of the plasma is lowered by « 1 i 1 1 1 1 i •
Bure within the corpuscle remains high, and water is absorbed
cell. If this absorption is sufficient, the cell ruptures and the hem< -•
is discharged. For this reason it is necessary in diluti

solutions of salt having an osmotic pressure equal to tl

hi 1 to proteel the red <-<'ll from hemolysis. This is

a 0.9 per '•'•nt solution of sodium chloride Betti
however, by using either Ringer's solutioi

per cenl CaCl„ and 0.03 per cenl KC1 or I ke's solution

NaCl, 0.024 per cenl CaCl . 0.042 per cenl K( ' 0.01 0
\'al !< !( I and 0 1 per cenl gli s<

In normal corpuscles hemolysis occurs I small it in -

tions containing aboul 0 12 per cenl odium chl li

diseases the fragility of the corpus

The membrane and Btroma of the erythi
terial which is soluble in alcohol
Addition of these agents to the 1»1<»<><1 brinfi
ably by dissolving the li|><»i<lal material
occurs with saponin is similar in tj
lipoids, tin- compound being Boluble in v

The hemolytic properl • rum, whether I

normally presenl w hen the blo<
ln> produced artificially by the injection
subjed of great il

06 THE BLOOD A.ND TTTF. LYMPH

of clinical medicine. The hemolytic serum produced by the injection

of foreign corpuscles owes its activity to two substances. The one
called the amboceptor, or immune body, is specific against the type
of cell injected and is increased during immunization. The second
body is the complement; it is nonspecific, and is not increased dur-
ing immunization. Complement is destroyed by heating the serum for
mie hour at 55° C, leaving the amboceptor alone present. Corpuscles
placed in such serum are not hemolyzed until complement either from
fresh immune or from nonimmune serum is added.

The serum of animals possessing natural hemolytic properties towards
the corpuscles of other animals likewise owes its effect to the joint action
of amboceptors and complement.

Ordinarily the serum from animals of one species does not exhibit
hemolytic properties to blood from another animal of the same species.
In unusual cases, however, the serum of an animal will produce hemol-
ysis of the corpuscles of an animal of the same species. Such sera are
said to possess isohemolysins. The fact is of great importance in the
transfusion of blood from one individual to another.

The cause of the acute hemolysis which occurs in the disease parox-
ysmal hemoglobinuria is not known. It is probably due to the presence
of a hemolytic substance which unites with the blood corpuscles at
temperatures below the normal body temperature, since the attack fol-
lows exposure to cold, and blood from patients subject to the condition
may be hemolyzed in vitro by cooling and subsequently heating it.

LEUCOCYTES

There are a number of varieties of white cells in the blood. These are
differentiated from one another by their shape, staining properties, and
the granules in their protoplasm. AVe may divide them into two main
groups — nongranular mononuclear cells and granular polynuclear cells.

The nongranular mononuclear cells are termed lymphocytes. Two va-
rieties are differentiated, the small and the large.

The small mononuclear leucocyte makes up from 23 to 28 per cent
of the total leucocytes and the large mononuclear, from 2 to 4 per cent.

The polynuclear leucocytes are divided into three groups according
to whether their granules stain with basic, neutral or acid stains. The
leucocytes that stain with basic dyes, or the basophile cells, are very
few, making up less than one per cent of the total count. LikeAvise the
acid-staining granular cells, acidophile, are few, comprising from 2 to
4 per cent of the total count. The most numerous are the neutrophiles.

Till I l.

or the polynuclear leuci with neutral-stainii I

comprise from Bfl to To | i of the total com •

Another type of white ••••II is known as th<
it was supposed to represent an intermedial
and polynuclear cells. Probably Buch transitions do
transitional leucocyte is related to the mononuclear ■

The polynuclear <-••! U originate in the bone n
reason have been termed myeloid cells. rom c<

the bone marrov termed myeloblasts, which arc nongranular and c
tain a large nucleus. In the course of development the cha
granules appear, and the nucleus remains round and later b<
tabulated. These intermediate forms died myel<

nuclear cells originate in the lymphatic tis if the body.

The leucocytes possess the ability to make ameboid moven
tu • foreign particles which may be presented to them. <>n

count of this latt.-r ability they are commonly called phi a I

the process of inflammation the leuc< semble at the spot wl

the Beat of the injury or infection, and remove th<
or necrotic tissue bj ingesting and digesting it.

It is not definitely known whether »>r not the lymphi
tion as phagocytes. Other functions besid<

, ascribed to the white cells, but they are not as
cepted. The number of leucocytes in the blood is subject I

siderable variation. They normally numbe

per c mm. At the heighl of digestion and aft

there is usually a small increase, and under pathological

especially in infectious diseases, this I. S

infections u the polymorphonuch while othei

the lymphocytes. The t\

fully know n, nor are the function

The Blood Platel-

These are small oval particles about 3 p in diameter, w

in large numb< i c mm in the hi 1 I

po^ed to be formed Mom partich sm which

off from the l.i '""1 cells in the I marrow

and chemical propeii understood,

very important role in tho llation of the bloi

CHAPTEE XII
BLOOD: BLOOD CLOTTING

On leaving the blood vessels, the blood clots so as to form a ping,
which assists in preventing further hemorrhage. The clotting must
therefore be considered as a protective mechanism against excessive
draining of blood out of the organism. When the wounded vessels
are small, the clotting, along with constriction of the damaged vessels
and the formation in them of thrombi containing large numbers of
platelets, serves to effect complete stoppage of the hemorrhage even
though the blood pressure may not have become materially reduced.
The greater loss of blood from larger vessels causes the arterial pressure
to fall, and this enables the clot to stiffen and seal the wound before
the pressure again rises. When the clotting power of the blood is
subnormal, life is endangered by even trivial wounds ; under these
conditions the smallest surface scratch may continue to bleed exces-
sively in spite of whatever local treatment js applied. The most ex-
treme degree of this condition occurs in hemophilia, a disease which
is characterized by a most interesting family history — namely, that
although it affects only certain of the male members of a family,
yet it is transmitted from generation to generation by the female side
alone. The disease has existed in certain of the royal families of
Europe for many generations, which has made it possible by con-
sulting the genealogic trees to demonstrate the infallibility of this
law of inheritance.

The clotting of the blood is also either depressed or increased in a
variety of physiologic and pathologic conditions. We shall, however,
defer further consideration of these until we have learned something
of the nature of the factors which are responsible for the process itself.

The Visible Changes in the Blood During Clotting"

In' a few minutes after it leaves the blood vessels, the blood forms a
jelly-like clot, which adheres to the walls of the container in Avhich the
blood is collected and soon becomes so solid that the vessel may be
inverted without spilling any of the blood. Clotting is now said to be
complete. The clot soon begins to contract, and as it does so, drops of
clear fluid or serum become expressed and float on the surface of the

98

B1 I

clol or collect betv een it ami |
Bome t ime t he » - 1 « * t breaks aw aj
in the serum. The latter may l"- p

opalescent, partly because of the p
cause of leucocytes which have m i oul i

their pov< er of diapedesi

1 1' a drop of freshly --h ■< 1 blood lined

will be observed thai the firsl Btep in clottii
of fine threads radiating from t"<-i. which
platelets. The fine threads are called fibr I

as to form ;ni interlacing meshwork which
corpuscles and leucocytes. B3 the the ultrami<

Howell1 and others have observed thai the fibrin
thrombin to oxalated plasma is really deposited in t;

stalline needles "fibrin needles" which 1 >•*<•< *iii •
as they increase rapidly in numbers Although the
consists therefore in the conversion of a hydr< -
page t-11 . it is a unique process solution of the \>\

esponsible for the formation of the fibrin (fibril
colloidal solutions, be precipitated in a variety of ways, bul »nly

when the conditions are favorable for M 1 clotting thai fibrin 1

and therefore fibrin threads, are formed. The blood •
forms a structureless gel when it clots Howell).

Methods of Retarding Clotting of Drawn Blood

To understand the nature of the clotting p

are res] sible for its occurrence, it is advantaf

conditions Bomewhal by getting rid of I i corp

the other formed elements of the M I and tl

which tip suspended in living blood nam< 1

separation of blood into corpuscles and plasma is rendi

by sedimentation or l>\ centrifu

inhibil or greatly delay the clotting p 1

purpose are numerous \ of tl 1

I 1 Keeping tin- blood at a temperatui

point. This method is. however,

immediately receh ''-I into narrow

t ii it- kepi most Btrictly at the low level. I

other slowly clotting bloods, the n

tions. 2 I.' ceivii bl i thi

inila. coated w ith a 1.

'••<! This method il imp<

100 THE BLOOD AND THE LYMPH

transfuse blood without making a vessel-to-vessel anastomosis. (3) Mix-
ing the blood with, chemicals that are capable of removing the calcium
from solution. Such reagents are potassium or sodium oxalate (in a con-
centration of 0.1 per cent after mixing), and sodium fluoride and sodium
citrate (2 per cent solution, with one part of the solution to four parts
of blood). (4) Mixing the blood with certain neutral salts, particularly
the sulphates of sodium and magnesium (one part of 27 per cent solution
of magnesium sulphate mixed with four parts of blood). Blood thus
treated is known as "salted blood," and the plasma separated by centri-
fuging, as "salted plasma." Clotting is readily induced by adding watei
to the salted blood or plasma, and in this way diminishing the concen-
tration of the salts. (5) The addition to blood of one of a class of sub-
stances known as antithrombins. Leech extract or the purified substance
separated from it, known under the trade name of "hirudin," and sub-
stances present in blood removed from animals after they have been
injected with peptone solutions, are examples.

The methods which have just been described are those applied to blood
after it has left the blood vessels. Another interesting group of anti-
coagulants prevent clotting only when injected into the Mood vessels of
the living animal. The most powerful example of this group is snake
venom, certain varieties of which can prevent clotting in the dosage of
%00 of a milligram for each kilogram of body weight. Similar but much
less potent effects are produced by the injection of several proteolytic
enzymes, but most attention has been paid to the effect of commercial
peptone injected in solution intravenously in the proportion of 0.3 gram
to each kilogram of body weight, Blood subsequently removed up to about
half an hour or more does not clot, and as Ave have already seen, if added
to blood from another animal, materially retards clotting. This group of
intra vitam anticoagulants is particularly interesting, since none of the
substances belonging to it is capable of preventing clotting of blood
when mixed with this after it has been shed. Their action therefore
obviously depends on the production of some substance in the body,
probably, as we shall see later, in the liver, since they fail to act after
the removal of this organ from the circulation (see page 111).

The time of clotting varies greatly according to the conditions under
which the blood is collected and the animal from which it is derived.
Human blood, for example, received into a test tube from a puncture
through the skin may clot at any time within three or ten minutes, five
minutes being taken as an average time for blood kept at a temperature
of about 20° C. This time may be considerably shortened by increasing
the extent of foreign material with which the blood comes into contact,
and more particularly by whipping the blood with a bunch of twigs or

BLOOD CLO 1"1

w ires. In this latter case, I clot d<

manner, bnt the fine threads of fibrin

ing behind the blood Berum with tin pp

The fibrin removed in this way may then be
Berum. The -••nun and corpuscles now
is iisc<l for many physiological purposes Clottii
ated by allowing the blood to flov ovei exposed I
evidently added to it from the tissues whicl
process, this influence being particularly marked in tl
of the lower vertebrates Winn the blood

eived through a cannula inserted directly into :i •
injury to the walls as possible, it very slowly cl< ill, bu1

does bo it' the blood is allowed ti» come i
tissues, or if it is mixed with tissue extract eh a- I
Clotting is considerably accelerated by warming t;
l>licntioii of a cloth or tampon well wrung out with 1
saline to a wounded Burface is a mosl efficient m< j I

orrhage from vessels too small to ligi

The Nature of the Clotting Process

Plasma obtained by centrifuging hi 1 thai has bet

clotting by one of the foreg - methods can be made to clol

the inhibiting influence; for example, in i l«''l plasma by warm

blood tn room temperature, in Baited plasma by dilul
an equal volume of water, and in decalcified plasma 1>\ addii
••ii-nt amounl of soluble calcium Ball combine with all I

oxalate and Leave a small trace of calcium Ball

The first question coi rns thi

it is furnished b) comparing the composition of I •••■■« 1 pi

• if Berum. Though both of these fluids contain the pi

and globulin, in approximately the same

contains another protein not unlike globulin in most

hut distinguished from typical globulin in tl

half-saturation with sodium chloride, in which

ble, and is more readil '

of the plasma with Bodium chloride, equal

rated Bodium chloride solution arc n

fibrinogen, as the Bubstancc is called

the tube by centrifuging and is

half saturated sodium ehlori<

siihnl in weak saline solution

bonate . will then be found to

102 THE BLOOD AND THE LYMPH

The next question concerns the nature of the conditions that cause the
fibrinogen to clot. When a fibrinogen solution is mixed with a few drops
of blood serum, a clot usually forms, which however is not the case when
plasma is added or when the serum is heated before adding it. Because
a small quantity of serum is capable of causing the clotting of a large
quantity of fibrinogen solution or plasma, it is supposed that the active
substance present in it is of the nature of a ferment — fibrin ferment or
thrombin. It must be pointed out, however, that there is considerable
doubt whether this active body is really of the nature of a ferment or
enzyme. For example, although heated serum does not cause clotting,
thrombin, prepared from serum by the method about to be described, in
the absence of inorganic salts can withstand even a boiling temperature.
Moreover, true enzymes are characterized by the fact that, like other
catalytic agents, a very minute quantity can effect a change in an indef-
inite amount of substance without the enzyme becoming used up in the
process (page 72). When thrombin is allowed to act upon a fibrinogen
solution, on the other hand, it is said that only a fixed amount of fibrin
can be formed when a small amount of thrombin is added. Neither does
this amount increase when the time of reaction is prolonged.

Wha'tever may be the significance of the foregoing facts, it is impor
taut to know that the clotting substance, thrombin, can be isolated from
blood serum in a tolerably pure condition. For this purpose blood
serum is allowed to stand under a large volume of alcohol for a week or
two; the precipitate is then collected and rubbed up with water, which
extracts the thrombin from it, leaving the serum protein in a coagulated
state. The resulting watery solution of thrombin may be further pre-
cipitated by alcohol, the precipitate washed in alcohol and redissolved
in water, yielding ultimately a solution which exhibits very marked co-
agulating powers when added to plasma or fibrinogen solution. Throm-
bin shows most of the protein reactions but it is not coagulated by heat.
As would be expected, a considerable quantity of thrombin remains
adherent to the fibrin formed in the process of clotting, and Howell8
describes a very useful method by which it can be separated from fibrin
and preserved in a dry condition. Briefly stated, this method consists
in allowing washed fibrin to stand overnight under eight per cent
sodium-chloride solution, which dissolves the thrombin. The resulting
extract is then mixed with an equal volume of acetone, which throws
down a precipitate containing the thrombin. To preserve it, the precip-
itate is collected on a number of small filter papers, which are subse-
quently opened out and dried by exposure to a current of cold air before
an electric fan. When the thrombin solutions are desired, the dried pre-
cipitates are extracted with a little water.

111..

Thrombin d«"'s no1 •• v i^i in blood plasmi
glass tube is inserted into an artery ant blood

<•oli.il, the precipitate after standi) eld no throi ibin

when triturated with water. Quite clearly, then

produced ;it the time the bl I clots, and 1 1 1 « - qui

it produced froml It will !>•• remembered that, wh<
amined under the microscope during the <•!< »t 1 1
threads are Been to Btarl from t'"<-i which corresp*
Lets. It would appear therefore thai the tin-.. ml. in tn
Borne Bubstance thai is shed forth from the platelets duri

tegration which they undergo shortly after the bl i

Btance is called prothrombin. The platelets or their

megacaryocytes of red bone marrow, are probably i I I

for clotting may occur in the complete al n it

appears to come from the leu< ytes. Prothrombin apj illy

in the fluid used to perfuse red bone marrow outside the bod) I>:i'
and Drinker0).

To Bum up whal we have bo far 1 « • .• » t ■ I. it may I

process «>i' clotting starts with the disintegration of blood
probably of leucocytes, as a resull of which there is shi
plasma a Bubstance "•ailed prothrombin, which immediately

omes activated or converted into thrombin. The ,; mbin ti
tacka a protein present in plasma called fibr t in

thread-like form the insoluble protein, fibrin. Hut this doei
plete the history, for al leasl two other important

play; tin • is the presence "f soluble calcium salts, and tl

of peculiar Bubstances «i*-iix •-«! from the tissues out

and called thromboplastic Bubstanci thromboplastin H SV<

must now consider the action of these two

The Influence of Calcium Salts. \ x plained, tl.

Boluble calcium Balta are necessarj for clotl
Bervation that tin- process is entirely p
blood is mixed with Boluble oxalati
mighl I"- made on the Bcore that tin
That Buch is nol the ease is indicated by tl

•

blood or plasma is dialyzed agaiiiHl phys
the soluble oxalate has been removi
immediately Buperveni
question arises as t,. how tl • nun i.

1 thai it is concerned in •

2 that it is i.. [1

.•an quite readil) be si ..w p thai

104 THE BLOOD AND THE LYMPH

that the calcium acts; for example, clotting occurs when purified throm-
bin is added to dialyzed oxalate blood or plasma or to a pure solution of
fibrinogen. Citrates prevent clotting by forming calcium citrate, which
all hough soluble does not ionize in solution. It is the free calcium ions
that are important. The action of the fluoride is somewhat mysterious,
for it has been found that to produce clotting in fluoride plasma the sim-
ple addition of calcium chloride will not suffice; thrombin itself must be
added as well. Some authors assert, however, that if the calcium chlo-
ride is added cautiously to "fluoride" blood, it will induce clotting
(Rettger). In any case it appears that the fluoride does something more
than precipitate the calcium; possibly it prevents the breaking up of
platelets and leucocytes.

The Influence of the Tissues. — As already stated, when slowly clotting
blood, like that of a bird, is collected through a sterile glass tube into a
thoroughly clean vessel and immediately centrifuged, the plasma will
often remain indefinitely unclotted. If an extract of some tissue, such
as muscle, is added, however, the plasma immediately clots. To a much
less degree, the same phenomenon is exhibited by mammalian plasma
when it is collected in a similar manner. From these observations the
conclusions may be drawn that the tissues furnish some substance as-
sisting in the clotting process, and that this substance is also formed
from certain elements present in mammalian but not present in avian
blood. The absence of platelets from the latter blood suggests that
these must be the source of the activating substance in mammalian blood.
It is plain that this tissue factor in clotting is of importance in hasten-
ing the process when an animal is wounded.

Before attempting to formulate an hypothesis that will explain the
process of clotting, it is necessary to call attention to one other impor-
tant fact. This refers to the presence in blood of a substance that pre-
vents clotting and is hence called ant (thrombin. Antithrombin is pres-
ent in normal blood, for a given specimen of pure fibrinogen will clot
less rapidly when mixed with serum to which some oxalated plasma has
been added than with an equal amount of the same serum correspond-
ingly diluted with a solution of soluble oxalate. A striking increase
in the concentration of antithrombin in blood can be brought about by
rapidly injecting a solution of commercial peptone into the blood ves-
sels fifteen to thirty minutes before bleeding. The peptonized blood or
plasma will remain fluid for many hours, if not indefinitely. That the
failure of this blood to clot depends on the presence of some anticlotting
substance, and not upon the absence of one of the necessary clotting sub-
stances (fibrinogen, thrombin, etc.), is evidenced by the fact that the
addition of some of it to a mixture of thrombin and fibrinogen inhibits

in 0

igulation, which it do< do, ho

to 80 ' and filtered i '■
antagonistic action ia quantitative in tl.
the peptone-plasma inhibits the actio

>urce of antithrombin in the bodj ap]
the liver, for it has been found: I thai pept»
from which the liver has been removed doe
be formed I tenney and Minol 2 thai pe]

portal vein cans.- antithrombin to appear in tl
idly than when the injection ia made into a
when the liver ia perfused outside the b( ith a :

taining peptone, antithrombin accumulates in

A fluid containing a high
by the Bo-called salivary gland at the head •
tion of tin* fluid ia to prevenl clotting of tl
may continue to such it withoul intei
ing leechea for medicinal purposes it is I

and thoroughly with water bo thai all tri
be removed; otherwise the bleeding may continm

Practical use ia made of this effecl of the 1 h t(» pr

outside tlif body, or it may be used to inhibit c

experiments where <-l<»ttiiii_r would othei with t;

- : for example, in < ■ i circulation •
experiments in vividiffusion 7 l

head ia cul off and extracted either with -
chloroform, which ■ other proteina from th<

in<; a strong antithrombin, known under
At temperaturea aboul thai of the body the acti

itly augmented. In animals li] mammals in \vl

of antithrombin is small, this ma> be in
idity <>f the blood Howell Blood contj
made t" '•!<•) 1>\ the addition <>t' thrombii

CHAPTER XII]
BLOOD: BLOOD CLOTTING (Cont'd)

THEORIES OF BLOOD CLOTTING

Attempts to link all the foregoing facts together in the form of a
simple theory have not so far been entirely successful. All agree that
the fibrin is derived from fibrinogen by the action of thrombin, the points
in dispute being those which concern the origin of the thrombin and
the mode of action of the calcium and thromboplastic substances. The
theory most widely accepted in Europe is that of Morawitz, according
to which the thrombin exists in living blood in an inactive state called
thrombogen (prothrombin), which becomes converted into thrombin by
the simultaneous action on it of soluble calcium salts and of thrombo-
plastic substances furnished by the tissue cells in general and by the
cellular elements of the blood platelets and leucocytes. According to
this view the thromboplastic substance, aided by the presence of calcium
ions, converts thrombogen (prothrombin) to thrombin. It acts there-
fore as a kinase and is called thrombokinase. The fundamental fact of
this theory, then, is that kinase is necessary for the union of the cal-
cium with prothrombin — a fact, however, which is challenged by HoAvell,
who states that prothrombin may be converted to thrombin by the action
of calcium ions alone. This investigator believes that the thrombo-
plastic substance acts not as a kinase but because it neutralizes anti-
thrombin, which is constantly present in the blood, and the function of
which is to prevent the calcium from uniting with the prothrombin to
form thrombin. Howell's theory in his own words is as follows: "In
the circulating blood we find as constant constituents fibrinogen, pro-
thrombin, calcium salts and antithrombin. The last named substance
holds the prothrombin in combination and thus prevents its conversion
or activation to thrombin. When the blood is shed, the disintegration
of the corpuscles (platelets) furnishes material (thromboplastin) which
combines with the antithrombin and" at the same time liberates more
"prothrombin; the latter is then activated by the calcium and acts on
the fibrinogen." Antithrombin can also prevent the action of thrombin
on fibrinogen. As already pointed out, the thromboplastin can be de-
rived from the blood itself in the mammals, but only from the tissues
in the lower vertebrates. It is interesting to note that the thromboplastin

can I"- extracted from the i

belong i" the class of phosphatids, beii . if

not identical w ith, kephalin II- ell).

Intravascular Clottii.

The practical applical ion of thi
manner in which 1 1 1 « - blood is maintained in a t!'ii«l
vessels, and the disturbance of tliis function ci

ting. A< rding to the one theory, 1 1 1 « - blood is mar

absence from it of anj considerable quantil

to tin- other, by the presence in il of an amount of an1 ifli

eienl to prevenl the union of calcium with protl 1

is maintained even when large amounts of thrombin urn,

which contains this substance, are injected int< We

••an Iwsi explain the immunity <>t' the bl 1 to the action of thrombin

der these circumstances ;^ being due to the i' n it

of antithrombin in amounts sufficient to prevent the action of thr
on fibrinogen, for, as stated above, it is claimed b) Howell
thrombin lias this influence as well as that of p ting ti •

of prothrombin into thrombin.
Intravascular clotting may be brought about bj

1 Mechanical damage t" the lining of the 1»1 !

plication of a ligature, for example, the damaged <

covered by a clot, which gradually becomes firmei

spread up thr M^-rl t < . the next branch 2 l

Bubstances in the blood. Emboli, for example

to form at tin- places where thej stick, nam<

Clotting is also a frequenl occurrence when tin

tin- cardiovascular tube, ami it maj occur under imp

conditions causing the condition known \

••stiiiL' variety of intravascular clottii

nous injectioi ctracl - ll-rich

lymph glands or testes Wooltlridg* Bj

acid ami digestion with peptoi •

extracts which, when dissolved in alkali

u l.i r clotting effect
phorus, it is probable that th<
i nucleoalbumin Their action mi
thrombin, according to Elowell'a tl
bokinasi ding to M

\- a matter of fact, h(
pletcly explained by either 1 I

108 THE BLOOD AND THE LYMPH

frequent injections of small amounts of the above material are made,
instead of intravascular clotting, a delay in the coagulation time is
likely to occur. Indeed, repeated injections of small amounts may en-
tirely remove the clotting power of the blood. The readiness with which
this so-called "negative phase" appears, seems to depend on the nutri-
tive condition of the animal at the time of injection. If a large dose is
injected into a fasting dog, for example, thrombosis is confined to the
portal area, whereas if it is injected into a recently fed animal, the
thrombosis is universal throughout the vascular system. The develop-
ment of the negative phase is undoubtedly dependent upon some reac-
tion on the part of the living cells of the organism, since it does not occur
on the addition of similar substances to blood outside the body. The
reaction is, indeed, akin to that by which immune bodies in general are
produced. For example, a toxin injected in large amount has a cer-
tain toxic effect, but in repeated small doses with intervening intervals
it leads to the production of an antitoxin. So with the substance in
question; a large dose injected at one time causes a positive effect — clot-
ting— but smaller doses frequently injected, the opposite effect — want of
clotting. It is probable, as suggested by Starling, that more intensive
study of the conditions causing intravascular clotting will throw con-
siderable light on the general question of the production of immunity.

Measurement of the Clotting Time

To measure the clotting time of drawn samples of Mood, several con-
ditions must be observed. These have been tabulated by Addis11 as
follows:

1. The specimens of blood must always be obtained by exactly the
s;inie technic. It would introduce serious errors to compare the clot-
ting1 time of one specimen of blood received from an incision of the
skin (ear lobe) with that of another collected in a syringe by veni-
pnneture.

2. The temperature conditions must always be the same. Probably
25° C. is the best temperature to use. Higher temperatures are unsuit-
able for two reasons: first, because during its collection the blood will
have become cooled to about or below this point, and time would be con-
sumed in raising it higher; and second, because the lime of coagulation
is more and more shortened for each degree1 that the temperature is
raised, this acceleration becoming especially pronounced for tempera-
tures above 25° C. Quite apart from the liability to incur errors inci-
dent to measurement of shorter periods of time, observations at higher
temperatures necessitate most rigorous adherence to a fixed temperature
of the water bath. Temperatures much below 25° C. arc unsuitable, be-

Km

cause the clottii udual

w hen it i ura

Tin- blood musl ;ilw ;i\ b be eo in tin

ae iii oontacl with the Bame kind and amount

To this it max be added thai the receiving
clean; an) trace of old blood elol ni nun i-

a '.'a i list.

I The end point mus1 be sharp. I-
difficulties are met with in making pi |

greatly t<» be desired thai differenl ii

form method. For experimental pui l

.M • • i n 1 1 ■ 1 1 } i .- 1 1 1 T is no doubl the I <1 it h.-is the adde<

giving a graphic record of th< rvatioi

(Fig, 19 shows the principle of the method
through a standard cannula (C into a tube / •"• cm. lot

i

I

■ In. hall. I'

internal diameter; and a loop 2 mm.

copper wire /' . which is 8 cm. long and m. in

lowed to fall gentl) into the blood

of the w ire is articulated w ith the shoi t

poised thai w hen the Btop R . which

position, is released, the w in

• >n the blood in tin- tub< I

a w riting point, w hich is made to it

So long as the blood is unc

is released and a vert

the loop Bticks on the blood and 1 1

For clinical purpo
is lis.-. |. the method of 1 1

•Am. Jour.

110 THE BLOOD AND THE LYMPH

2 or 4 e.C. of the blood in ;i wide tube (of 21 mm. diameter) that has
been cleaned by a bichromate-acid mixture. The period that elapses
between the moment of the entry of fluid into the syringe and that at
which the elot has become firm enough so that the tube can be inverted
without spilling any blood, is taken as the clotting time. Since the blood
docs not come in contact with exposed tissues, it takes from 20 to 60
minutes to clot by this method.

For routine clinical examination of blood taken from a skin wound
Brodie and Russel's method11 is most satisfactory. This consists in
principle in observing a drop of blood, under the low power of the
microscope, while a fine current of air is gently blown against it at
regular intervals in a tangential direction. Until clotting sets, in, the
individual corpuscles move freely in a circular direction, but as soon
as clotting begins they move in masses which soon tend to become fixed
so that, although they move somewhat when the air impinges on them,
they immediately return to their original position when the current
is discontinued. When clotting is complete, the air current merely

Fig. 20. — Coagulometer. The drop of biood is placed on the lower end of the glass cone and
the air stream is directed against it from the side tube shown by the black dot. The apparatus
is placed on the stage of the microscope and the drop observed by the low power.

presses on the corpuscles at one point. By this method the clotting
time averages five minutes. A convenient apparatus for this method is
that of Boggs, which is shown in Fig. 20. It consists of a truncated
cone of glass, projecting into a moist chamber provided with a tube on
the side so arranged that when air is blown into the chamber, it strikes
the drop of blood placed on the end of the cone tangentially.

Blood Clotting in Certain Physiologic Conditions

Besides the experimental conditions already enumerated as changing
the clotting time in the blood of laboratory animals, special mention
must be made of the influence of epinephrine injections, of conditions
supposed to cause a hypersecretion of this hormone, of the emotions,
and of hemorrhage.

Epinephrine added to drawn blood does not affect the clotting time.,
but if small amounts are injected intravenously or even subcutaneously,
a marked decrease occurs (Cannon and Gray; cf. Cannon, loc. cit.) .
Larger injections may have the opposite effect, and intermediate amounts

BLOOD CI/) 111

may cause al Brs1 a prolongation at

'I'h. iilta b ith larger do • related to 1 1

repeated doses of relatively large amounts nephrine in nay

v.. greatly retard coagulation aa to make the animals p emo«

philic. It was further found b) Cannon and hi eph

rine doea not influence the clotting time when injected int<

from which the abdominal viscera have been r< n

by ligation i>t' the inferior vena cava and the abdominal In tl

of the influence which destruction of liver cells

form, etc. is known t<> have in lengthening clottii ould -■

reasonable to i lude that it must be through th

rine develops its clotting effect

Stimulation of the splanchnic nervet l i

and it would appear thai this action depends on the resulting li
cretion of epinephrine (page 746 for it is n Mowing stim

tiuii of the nerves in animals from which the adr<
excised Cannon and Mendenhall). The interesting n is m

by Cannon that the Bhorter clotting time observed in animals
Btrong emotions of frighl or fear may also I"- due to th<
of epinephrine which this worker believi

Blood Clotting in Disease

With the factors concerned in the process - i>i»'-d in n

not surprising thai the underlying causes respoi Bible for d<
ficienl clotting of l»l<»(>d in diseased conditions
intravascular clots thrombi are little understood. H

ell's theory "i" the nature of the process, which is tl
the presenl time, abnormal clotting mighl be due
causes: I .1 diminisht <l amount I

hepatic n-lls are greatly damaged, as in :
phosphorus and in Buch dis< ite yellow

fever. In man} cases of chronic cirrhosis >>r the l
have shown, the blood also clol
It Bhould be pointed oul thai it is no1 s,, much th<
increased in Buch c as the tin I 'hat

is affected.

I ncy in /" '. In th nditinn

neonatorum," undoubted benefil is d-

ut* hi 1 Berum or h> din el blood I

bin <>r prothrombin is thus fun

i Since tl

In.th blood cells and tissue cells, il d<><

1 1L' THE BLOOD AND THE LYMPH

could ever occur. Certain observers, however — Morawitz, for example —
lay great stress on this as an important factor in hemorrhagic diseases.

4. An excess of antithrombin. The undoubted increase in Ibis substance
that can be brought about experimentally by injecting hirudin or pep-
tone into animals, has stimulated careful search for a similar increase in
the blood in clinical conditions in which abnormal blood clotting is one
of the symptoms I Whipple10). Antithrombin is said to be increased in
septicemia, pneumonia, miliary tuberculosis, etc.

5. A deficiency of calcium ions. Although at one time it was supposed
that this might be responsible for the feeble clotting in hemophilia, it
has not been found, after very extensive trials, that- the exhibition of
Ca salts in any way relieves the condition. It is said, however, that the
slow coagulation seen in obstructive jaundice is decidedly shortened by
treatment with calcium salts.

One thing stands out prominently in connection with the whole problem,
and that is the close relationship of the blood platelets to the clotting
process. Prom these cells are derived, according to Howell, not only the
prothrombin but also, as from other cells, thromboplastin. It is not sur-
prising therefore to find that decided alterations in the platelet count
occur in cases of faulty blood clotting, and that local accumulations of
these elements within the blood vessels, produced by their clumping to-
gether or agglutinating, is followed by a formation of local clots, as in
thrombosis.

Hemorrhagic Diseases

In many of the so-called hemorrhagic diseases (acute leucemia and
aspastic anemia) and in the hemorrhagic varieties of diphtheria and
smallpox, the platelet count drops from its normal of between 200,000
and 800,000 per cubic millimeter to well below 100,000, and indeed in
these conditions it is frequently difficult to find any platelets. Samples of
blood clot outside the body within the normal time, but the clot is soft
and usually fails to retract in the normal manner. It is on account of
this, rather than slow clotting that the hemorrhage continues, so that in
appraising the gravity of the symptom it is best to measure not the clot-
ting time but the time that it takes for bleeding to cease from a small
skin wound, as in the lobe of the ear. This can be very accurately done
by applying blotting paper at regular intervals to the puncture (Duke17).

The most interesting and at the same time the most mysterious of all
conditions in which blood clotting is interfered with is hemophilia. The
clotting time is longer than normal, but even after the clot forms, bleed-
ing is likely to continue because the clots are very readily displaced. Bo.th
clotting time and bleeding time are increased. So far no change in the

Bi i 11:

clotting factors of the blood has been <!•

corpuscles and the platelets are normal in nun

cium salts are normal, and, as Bowel] hi

antithrombin. < me significant fai

thromboplastin or of its active ingredient, kephalii

clotting time of tin- blood when it is removed bj I

menl with this observation it has been found that

much in..!-.- rapidly, indeed sometimes in the usual •

flow over cu1 or damaged tissue ami s,, become mi: ith thi

tin. These facts taken together would Beem to i

must lie in a deficiency in prothrombin, and

from the platelets, which however arc nol «!• ■! in nun,

further assume that these elements have und

change preventing their disintegration. An accompanying in

their agglutinating properties would at the same tim<

ure in hemophilia to clump together at the site of 1

to block the smaller vessels with thrombi; I

time even alter clotting has iurred.

Thrombus Formation

The lirst formed portion of a thrombus is paler than l
ause it contains excessive numbers of platelets
that it is by a'_r,_rlut inatiuu of these inl hich tl

blood vessels and by disintegrati g thrombin and th-

plastin, that the dotting starts. This platelet agglutination i:
from stagnation in the bloodflow, <•!• from rougheni
vessel walls. Stagnation may \«- due eitl failure of tl

as a whole as in heart < ii^. ■■ \,, local physical alt.

cular tube, Betting up conditions in which eddj curr<

Is of hi 1 an- formed, BUCh as will I.,

Buddenly become wider, as in var
sudden bend of large \ eins The flrsl
lowed by one ..t* a darker color, which ftlU
anastomotic branch. Similar s1 tion m
tion < • .- 1 u ^ . ■ ■ 1 bj lodgm< iboli in t;

bodies in tine suspension, bacteria, etc
very small ami o particularly in the

ami lung's. The small thrombi
spreads into the larger vea

in th agulabilit) of the bl W

Bible that excessive amo

this neutralizes the antithrombin in I»1<»<m1 m

114 TIIR BLOOD AND THE LYMPH

replaced by fresh blood before clotting ensues, or it may be that sub-
stances derived from the inflamed tissue cause the platelets to aggluti-
nate. The increased clotting often observed after the injection of hemo-
lytic agencies (foreign sera, snake venom, etc.) may also be due to
platelet agglutination. Like the thrombosis following embolism, the
clotting occurs at first in the capillaries, the initial thrombi containing
masses of platelets along with skeletons of blood corpuscles and cells
from the blood-forming organs.

CHAPTER XIV

LYMPH F< »i;m a l [( >N AND < IK< i I \ I !•

GENERAL CONSIDERATIONS

Lymphatics are modified veins. Th<
onic life aa buds of endothelium, which arc t •
embryo in the sixth week of development. The
curs from the internal jugular vein, and the endi
come hollow and join together, forming tir>t a pl<
a Bac, from which again lymphatic \
out in invade the akin <>t" the head, neck, thoi
the deep Btructu the head. The - ultim

groups of lymph glands. At a later similar :

certain <>i* tin1 abdominal veins, forming a retro]
grow out tin- lymphatics of tin- abdominal ami, •
thr thoracic viscera. A similar pair i
veins supplying thr lymphatics for tin- Bkin of t!
walls. Tin- retroperitoneal and iliac inn b<

the jugular sac by means of the thoracic duct l
no \al\rs in tin- lymphatic i thai the wl

jected either from the thoracic duel or from I
thai tin- superficial and deep lymphatics are pi
of vessels.

Anatomists have succeeded in tracin
many parts of the body. This knowled

connection with the spread of infectioi bun-

danl in the skin, the intestine, and
from the muscle bundles, from the hepatic lobuli
the connecth e t issue between 1
ami from the central u<

The l\ mphatics ha\ e thi
to absorb Bubstanci I

show that this absorption mi
into the peritoneal <-a\ ity, tl
blood vess< -; i lymphatic*

Btance inject* -1 True boIu!

116 THE BLOOD AND THE LYMPH

are taken up by special large cells showing phagocytic powers, and trans-
ferred to the lymphatics — for example, those of the diaphragm. A sim-
ilar selective absorption is well known in the ease of the villi of the in-
testine, where fat passes into the lacteals and carbohydrates into the
blood. It appears as if lymphatic adsorption, both of solid materials
and of solutions, requires the cooperation of phagocytic cells.

The newer conception of the lymphatics as a closed system is at vari-
ance with the older one, in which they were supposed to get smaller and
smaller, and their walls less and less complete until ultimately they
faded off into the tissue spaces. These, however, bear no closer relation-
ship to lymphatics than they do to blood capillaries. The tissue spaces
include all the minute spaces between the fibers and cells of the con-
nective tissues and between the parenchyma of the organs and the great
serous cavities of the body (pleural, peritoneal), as well as specially
developed tissue spaces, forming the subarachnoid spaces of the brain,
the scala vestibuli and tympani of the cochlea and the anterior chamber
of the eye. The fluids in these spaces — the tissue fluids — are quite dif-
ferent from the lymph in the lymphatics both in composition and in
function. Indeed, the tissue fluids are among the most varied of all
the fluids of the body. The spaces may themselves become linked to-
gether so as to form a circulatory system, which is quite independent of
the lymphatics. This is particularly the case in the brain, where the tis-
sue spaces surrounding every individual nerve cell extend into the sub-
arachnoid area, where they drain into the cerebral sinuses through the
arachnoidal villi, which exist as lace-like projections of the arachnoid
into the dural sinuses, being covered by a layer of mesothelial cells spe-
cially abundant at the tips of the villi, where they form cell nests. Ob-
servations of the passage of substances in solution by these pathways
have been made by injecting potassium ferrocyanide and citrate of iron
into the subarachnoid and subdural spaces and afterwards detecting
the presence of the salts by mounting sections in acid media, so as to
permit prussian blue to develop. Ordinarily the precipitate is found in
or near the villi, but after cerebral anemia it forms in the tissue spaces
that surround the nerve cells.

There are therefore three fluids concerned in the transference of food
materials and gases between the gastrointestinal apparatus and lungs
and the tissue cells — namely, the blood plasma, the tissue fluids, and the
lymph. The tissue fluid, being in contact with the tissue elements, serves
as their immediate nutritive fluid, and it is the function of the blood and
lymph to maintain it of proper composition. Everything must be trans-
ferred to and from the tissue cells through the tissue fluid, making it

LYMPH H 11"

therefore in mail) ways the im.st important

In the tissue cella themselves there \a also tl c fluid in

colloids and crystalloids thai enter into tin- comp

are dissolved. This can be removed from cells onl> In ni<

sucli as grinding with fine sand in ■ mortj a--

to a pressure of several thousand atmospheres in a li

press This is known as tl The ul1

[stuffs occurs between the tissue fluids and th<
the •■•■li membrane. The extent and charact
on man} circumstances, Borne affecting i li «• cell wall,
and other properties of the two fluids. Obvious!
circulation is to maintain the tissue fluids
blood plasma serving to carry food materials and d
them ■ see page 380 . but being as in the o|

moval of effete products bj the lymph. The lym]
the blood is both purveyor and scavenger.

The above description of the lymphatics is not in

l»\ anati. mist-,, certain of wh believe thai the lymphatic

from tissue spaces and are consequently much mo

appear to be from injected s] imens

instruction models, made from serial sectii
in which the lymphatics frequently app< dated

visible connections. The failure of injectii

iimter parts of BUCh a lympliat in the emhr

the discontinuity of spaces, which is. ho
level opment.

The manner of absorption of injected t!ui<ls
port the view that the lymphatic lirectlj

sue Bpaces When all the Btruetn a pa-

main artery or vein, injected pois i*hich

sueh as the nerve centers, develop their
tad animal e.g., strychnine Similarly, v
ylene blue are injected into th<
appear in the urine long before the lymph

ilts indicate the pathway of absorption I
the lymph \ • Through this 1.

•■ slowly, hut can be
tion When colored solutions sucl I
Bubcutaneously, howei
lymphatics maj ultimately occur,

•organisms

118 THE BLOOD AND THE LYMPH

EXPERIMENTAL INVESTIGATIONS

It has proved a most difficult problem to gain any exact knowledge
of the production of lymph by experimental means. Starling, some years
ago, in repeating many of the experiments of older physiologists in the
light of the newer facts of physical chemistry, added much that is of
interest, and it is chiefly with his work that we will concern ourselves
here.

The unequal lymph supply of different regions of the body is strik-
ingly demonstrated by comparing the lymph flow from the lymphatics
of the leg with that from the thoracic duct. No lymph flows from the
former unless the muscles are thrown into activity or the blood is pre-
vented from leaving the limb by ligaturing all the veins. Changes in the
arterial blood pressure do not affect the flow. On the other hand, a great
increase in the flow from the thoracic duct can readily be induced by
disturbances in the blood supply. Obstruction of the portal vein, for
example, immediately increases the lymph flow four or five times because of
venous congestion in the intestinal capillaries, whilst a still greater
increase — perhaps tenfold — is induced by obstruction to the inferior vena
cava, which raises the capillary pressure in both the liver and the intes-
tines. After ligation of the hepatic lymphatics (at the hepatic pedicle),
obstruction of the vena cava no longer causes the outflow of lymph to
increase, indicating that the lymph in the last mentioned experiment
must have come from the hepatic lymphatics.

These results, so far as they go, could be satisfactorily explained on
the basis that lymph formation is a filtration process, that is, a process
dependent upon difference in mechanical pressure between the blood
capillaries and the tissue spaces. The lymphatics would then serve as
channels to return this fluid to the blood vessels through the thoracic
duct. The difference in the magnitude of the increased lymph flow from
increase in capillary pressure in different regions would be dependent
on the permeability of the filter, the capillaries of the limbs being much
less permeable than those of the intestine, and particularly of the liver.
Another fact in conformity with this view concerns the composition of
the lymph from the two regions, that from the limb lymphatics being
poor in protein, whereas that from the thoracic duct does not fall far
behind the blood plasma in this regard.

Although filtration may explain the considerable increase in lymph
flow produced by extreme changes in capillary pressure, it by no means
suffices to explain lymph formation under less abnormal conditions.
When a muscle or a gland is at rest, it produces practically no lymph.

I J Mill rOBMAI l' I IK' 1 19

hut during activity tin- il<»u I mes mai I in not be explaii

by filtration, bnl may !"• a tinted for by a physico

namely, osmosis. The energy required for ti
cell is produced bj chemical <•! . whereby large mole*

broken down into numerous small' i i smaller mol<

then discharged int., the surrounding tis>uc fluids, the osmotic
of which they iner< with the consequence that

a from the plasma in the blood capillarii i i

increases the volume of ti>>n.- fluid, which is then drained
lymphatics I e increase in molar i tration will ale

tissue juices, tending to make the '•••II Bwell up by absorhii
In gland cells this water is immediately extruded I

water of the secretion (seepage J'_'l .

An analogous method of lymph formation is not confined '<> situ
where the capillaries are relatively impermeable, for il
tin- liver, the lymph flow from which is greatly increased by the in
tion of hih' sabs ,\ similar process no doubt results from mu«
activity, although in this ease the tissue spaces must form a continn

-in of their <>un, there being, a r<lin«_r to mi ithorities, no

lymphatic

Considerable u has been taken in the Btimulat I which

certain chemical Bubstances have on th< etion of lymph from

thoracic duct. Th< called l>im.j>lnh; belong

crystalline ami colloidal. Of the former, glucose, urea, and Bodium
chloride in hypertonic solution, are the l>«^t known. 81 -
their action as dependent upon an increase in the osmotic pi
the blood. This attracts water into the blood from ti
ami leads tu an hydremic plethora, with a consequent u ipil-

larj ■ sure. It' the blood pressure is lowered by hemoi
the hypertonic Bolution is injected, little stimulation "t" lymph fl

•us, l ause there is no available fluid in I

plethora. This observation does not, how<

tl xplanation, becau many other disturbai

hemorrhage

Tl (illui<lal lymphagogues include watery exti

sues of leeches, era} fish, and mua

\ probably acl by damaging tin- endothelium «'f tl
that filtration occurs mon Although th

more particularly on the lymphatics of tl
apparent on the skin capillaries, produi
tnation of Mi nettle rasl

120 THE BLOOD AND THE LYMPH

EDEMA

With such an imperfect knowledge concerning the physiology of
lymph formation, it is not surprising that the causes of excessive accu-
mulation of fluid in and between the tissue elements should he little un-
derstood. All of the conditions which have been mentioned as capable
of causing an increased secretion of lymph — such as increase in capillary
pressure, hydremic plethora, action of poisons on the endothelium — are
likely to cause edema if the lymphatics of the part are simultaneously
obstructed. To produce in animals edema of the subcutaneous tissues
like that observed clinically, it is, however, necessary that'the vascular
disturbance be accompanied either by local damage to the capillary
endothelium, such as is produced by arsenic or uranium; or by a gen-
eral toxemic condition, such as is set up by nephritis. "When large
amounts of saline solution are injected intravenously, extensive ex-
travasation of fluid may occur into the liver, peritoneum and intestinal
lumen, without any subcutaneous edema.

Clinical edemas are of at least three types:

1. The inflammatory edemas, in which the fluid permeates the cells of
the inflamed area and does, not shift to other parts of the body under
the influence of gravity.

2. The nephritic edemas, in which the fluid is more or less loose in the
subcutaneous tissues and readily changes its position, and which is
accompanied by excess of water in the blood with a corresponding in-
crease of sodium chloride ; the percentage concentration of sodium chlo-
ride in the blood remains unchanged, but that the other constituents
diminished.

3. Cardiac edemas, which are also hypostatic, but are unaccompanied
by changes in the relative amount of water and sodium chloride in the
blood.

The second and third varieties of edema may of course be more or
less present together, for the kidneys are likely to become secondarily
affected during venous stasis.

The salt retention in nephritic edema is very significant. As ex-
plained elsewhere, it is revealed by comparing the daily output of so-
dium chloride by the urine with the concentration of this salt in the
blood. Less salt is eliminated than would be the case in a normal in-
dividual Avith the same percentage of salt in the blood. Tn many cases
also edema can be diminished by withholding salt from the food. Widal
and Javal have conclusively shown the relationship of retention of water
in the body, as judged by variations in body weight, to the hydremic
condition, as judged by the refractive index of the blood serum, and

LYMPH rOBM \ I 121

to the amounl <>i salt in the diet, A

w ater usually

a result of giving salt, the bodj - • • i *_r 1 1 1 may ii c

kilograms 10 to 15 pounds within a <\

ance of puffines

The cause of the edema during sail retention is no -i'-wlit clo
lated to the action "t" lymphagogues. In a normal person

tion of salt is immediately followed bj excretion of th<
the kidney. Where the kidneys are diseased, ;i
tained in the blood, raising its osmotic pr< and i

from the tissue fluids. This leads I the imbil

being used to replace thai lo I im the But all ti

lymphagogues do not, when presenl in i in the M I

patients, necessarily cause edema ; un

considerably withoul any such effect. The different action ally

attributed to inequality in the diffusibility of the tv italloid

animal membranes, Bodium chloride diffusing much

area.

It is liinst important to note thai the fluid in edema
tissues and cin be drained away !>y the insertion <>f tubes Th<

absolutely no evidence in Bupporl of the claim o Fiscl

edema is due t<» imbibition of water \>\ the « •« »1 1 « ■ i < 1 -- "t' tl l

question has been fully dis

BLOOD AND LYMPH REFERENi ES

M • ogi aphs

'Howell, u . II ;

•star! ii.: Human Phya

Row< . \ ii \,rcb. Int. Med., 191 i
iWillianu

Tower and Herm:
• l;

rfintler, G rt. .i..»ir. lied., 191!

MImw.I1, \\ . !:

•••I K !

i>, • ■
w

1 1.
ad MendcnhaJI

• II. .«. II, \\. ll

-
Whipple, <.. H : \

■ il \ "

I' ' \V. W \r. I

PART III

THE CIRCULATION OF THE BLOOD

CHAPTER XV

BLOOD PRESSUKi;

The object of the circulation is to maintain through the tissues a sup-
ply of blood that is adequate to meet their demands for nutriment and
oxygen and to remove the effete products of their metabolism. The de-
mands vary according to the activities of the tissue, being particularly
variable in the case of such tissues as the muscular and the glandular.
In studying the physiology of the circulation Ave have therefore to bear
in mind two aspects of the problem: (1) the cause for the continuous
bloodfloAV, and (2) the mechanism by which alterations in this bloodflow
are brought about.

If Ave open an artery Ave shall find that the blood escapes from it
under such a pressure that it is thrown to a height of about six feet,
that its outflow is proportional to the size of the artery, and that it pul-
sates. If, on the other hand, we open a vein, Ave shall find that the
blood Avells out without any A^ery evident pressure, and that it Aoavs
in a continuous stream, its outfloAv being the same in a unit of time as
that of the artery, provided the tAvo A^essels are the only ones supplying
the particular area. The general conditions governing the bloodfloAv
arc the same as those governing the Aoav of fluid through any system of
tubes. For example, in the city Avater mains it is knoAvn to every one
that the rate of outfloAv from any part of the system depends finally on
tAvo fact Mrs : (1) the difference in pressure at the beginning and end of
the system, and (2) the caliber of the tube at the outlet. We may in-
crease the outflow either by raising the pressure at the beginning of the sys-
tem, the caliber of the outlet meanwhile remaining constant, or by main-
taining the pressure constant but increasing the caliber of the outlet.

In the circulation of the blood, the difference in pressure at the be-
ginning and end of the circulation is furnished by the pumping action
of the heart, and the alteration of the caliber of the outlet is provided
for by the constriction or dilatation of the blood vessels. These simple
physical principles indicate the direction which a study of the circulation

122

BIXX)D E'RI 12 :

should take. Thej indicate thai our I

mean blood pressure, h<>\\ it is maintain)

vary. After we have learned tl then ;

particular examination of the mechanism oi pump thai

heartbeat; then finally we may pi < amine tl

pro by which the caliber of tl mtrolled

THE MEAN ARTERIAL BLOOD PRESSURE

The firsl prerequisite to the investigation i b! 1 pn

any other physical problem, is that ould p< by

which it can be quantitatively measured. The eai
plish this was made by the English scientist, th< !.'•
little over a century after Harvey published his accoui I

tinii of the hi I Hales connected a glass tube ni • in length ■■

vered artery of a Inns.-, the '•"in tion I two being m

by means "t' a piece of brass pipe joined t" tin- windpipe
substitute for rubber tubing. He Pound on untying the lig I

Py that tin- hi 1 P08e in tin- tube to a hri-_r'' '

inches above the level <>t' the lefl ventricle "t" the heart, and thai
at full heigh 1 it rose ami fell with each pulse through a <li-'
three or four inchi -

Mercury Manometer Tracin

l • somewhal crude bul very significant experiment oi I! rly

iilish.'d tin- existence of tin- enormous pressure al which th<
made t.. circulate through the arteries. To r<
investigation <>t' the factors on which this preat
r> to invenl some mi nvenient mei

hut this was nut a mplished until a centurj lat.T, when l

plied the er, which Ludwig subsequei

that tracings mighl he taken (Pig 21

I laving h a tracii sho\i n in l ' g 22,

hnw it nia\ I I in the Btud} "t" blood !• !

must do is t" im BMure the a> erage licighl

-ure: the mean art ''1 1 •

distance multiplied bj i\\<>. because the distanci
eury lias moved up in 'lie limb "f the manoi
ing point is onlj

boul 13 5 t imes hea^ ier than nn e<
measuremenl mi multiplied i

124

THE CIRCULATION OF THE BLOOD

our result in terms of the height to which the blood pressure could raise
a column of blood.

In arteries of approximately the same size, the mean arterial blood
pressure does not markedly vary in different mammals. Thus, in the
carotid artery of the dog it averages about 110 to 120 mm. Hg, in that
of the eat about 105 to 115 mm., in the rabbit from 90 to 105 mm., in
the sheep about 150 mm., in the horse aboul 200 mm., and in man SOme-

rig. 21. — Mercury manometer and signal magnet, arranged for recording the mean arterial
blood pressure in a laboratory experiment. The pressure bottle (R) is filled with anticoagulating
fluid and is connected by tubing with the manometer (M), the cannula for the artery (U) briny
connected with the T-piece (J). By this arrangement it is possible to flush out the tubing
when clotting interferes with the experiment. (From Jackson— Experimental Pharmacology.)

where between 120 and 140 mm. The pressure varies in different parts
of the vascular system, being greatest in the aorta and least in the small-
est arterioles but the fall in pressure — the pressure gradient — does not
become very pronounced until the arterioles have become so small that
it is no longer possible to insert a cannula into them; thus, the mean

|il.4>4>l>

1 •_•:.

hi 1 pressure in the renal <>r femoral

in the •

It' we examine tl" contour i which the i

shall tin. 1 that it exhibits two typea ■ and

observe the animal while the tracing is being tal shall thai

. Willi ..

the former arc «:i m^.- 1 l>\ the i
tions ;ui observation \\lii<-h immediately

trustworthiness of the method, for it will b< ;' that

the heartbeal produces an eflfecl on blood

thai of the respiratioi 0 ilty in

1 to the relative signifieaii f the wn

126

THE CIRCULATION OF TTTK lU.OOn

Spring- Manometer Tracings

The cause of tins inaccuracy depends on the inertia of the mercury,
an inertia which is so great that the sudden changes of pressure produced
by each heartbeat are not able to overcome it, whereas the much less
significant but more prolonged pressure changes produced by each respi-
ration develop their full effect on the mercury. These facts led investi-
gators to seek for instruments in which the inertia error is eliminated,
with the result that they invented what are known as spring manometers.

an"'''"!ii»
Fig. 23. — Hiirthle's spring manometer.

Many forms of this instrument have been devised, but for our pur-
pose it is necessary to describe the principle of only the simplest and
most efficient — the Hiirthle manometer. As shown in Fig. 23, it consists
of a variety of tambour, which differs from the ordinary tambour in two
important particulars: (1) the chamber is made as small as possible, and
(2) it is covered not with an elastic membrane but with one of leather or of
thin fluted metal. These two precautions are taken in order to avoid spuri-
ous wraves set up on account of elastic recoil. Such errors are further
reduced by filling the* tubing and chamber of the tambour with a fluid
so as to eliminate the elastic recoil of air.

rn,>

Fig. 24. — Arterial pressure recorded by a spring manometer. The effect of weak excitation of
the vagus is seen during the period marked by the signal m. (From Dubois.)

Before the tracing taken with the spring manometer can be em-
ployed for quantitative measurements, it must obviously be graduated
according to some scale. This is accomplished immediately before or
after the experiment by connecting the manometer through a T-piece
with a pressure bottle, which can be raised or lowered to a specified
height, and with a mercury manometer. The displacement of the writing
point of the spring manometer corresponding to each 10 mm. ITg of
pressure is then written on the tracing.

Itl I!:i sM Id

12'

The tracings taken with Buch a manomete
quite different From those with the mercury mi I

that now the cardiac \\ ledlj the more pronounced, tl

tory, being comparatively inconspicuous. Tin pn in the

instead ol being tank Bteady, undei rable

during each heaii beat.*

Examination of tliis tracing gives us accurate
the l'l«'(»«i pressure both between the heartbeat
an<l during them Bystolic. I' give
dead Load <>i' 1 1 » < - circulation that is, the pre

lent as well as the liin Load thai is superadded to this b;

h

160 „

N\?

L me of

or 5 TUL IC PRE 5 S UPC

120

XJ \7~"

V N J r f\

I me of

line of nX'A

MEAN PRESSURE

D/ASTOUC — ~vU
Press u/e wj

PULSE PRESSURE
7"fy* cf/Efe rence tetrveen
S YS TOL IC

30

D/A 5 TOL IC PRE 3 3 1 R£
\C

0

' ' — — E%

H A

c V ^ ft

1 ■ . . ' .

■

This diffi en called th< /<• • it

amount somewhere a 1 > « > : , an. ii_r I: we ta to a

spring ma er from differenl parts of tl rial tr<

that, as we travel towards the periphery. the pi
and leas marked, until finally by the time the capilla

almosl entirely <li~ This decline in the pn

mon i to be dependent in<" . fall in

in diastolic i In

th.- diastolic pressure rema nt all

rial '

th- I.

• .

128 THE CIRCULATION OF THE BLOOD

Clinical Measurements

The methods of blood-pressure measurement in man have recently
become so perfected that the results are almost as accurate as those ob-
tained in laboratory animals by direct measurement through the use of
cannula inserted into the vessels. Both the systolic and the diastolic
pressure can lie measured with equal facility and accuracy. Since the
technic for making the systolic measurements was described at a much
• '.nlier date than that for the diastolic, it has until recently been the
habit with a great part of the medical profession to be satisfied with
systolic readings alone. This is most unfortunate, because the knowledge
which such information gives us is incomparably inferior to that which
ran be obtained by gauging the diastolic pressure. Until we have learned
more about the dynamics of circulation, it would be profitless to go
into any details as to the reasons for this statement, but it will soon
become self-evident. Suffice it for the present to state that the diastolic
pressure is the more important because it gives us the load which the ves-
sels and aortic valves must constantly hear, and the resistance which must
be overcome prior to the "opening of these valves at the beginning of
systole. Moreover, it helps us to gauge the peripheral resistance.

The first step in the technic of blood-pressure measurements in man
is the placing of an armlet or cuff around the arm or leg. This armlet
consists of a rubber bag at least 12 cm. broad and covered on its outer
surface by cloth or leather. The bag is connected by tubing with a pres-
sure gauge and a pump. The pressure gauge may be either an ordinary
mercury manometer or one of the numerous gauges built on the aneroid
principle that are now on the market (Fig. 26). For measuring the
1)1 ood pressure in the vessels of the upper extremities, the armlet should
be applied around the fleshy part of the upper arm and for the lower
limbs around the thigh. For accurate reading of both pressures the
folloAving procedure should be followed. Having applied the armlet, the
pulse is palpated at the radial artery, and the pressure in the arm-
let then raised until the pulse can no longer be felt, at which moment
the pressure in the manometer is noted. The cuff is then slowly
decompressed and the pressure noted at which the pulse reappears.
These two readings of systolic pressure should be close together, but
they will not usually agree exactly for reasons which will be explained
immediately. They give us the palpatory systolic index, as it is called.
The pressure is now lowered about 15 mm. Hg, and a stethoscope is
placed in front of the bend of the elbow over the artery and as close up
to the cuff as possible. With each heartbeat a distinct sound like a pistol
shot will be heard. The decompression is now continued slowly, and as
the pressure falls the sounds will be heard to become louder and prob-

">!' I'KI

ably Bomewhal murmurish in qual ty. At a cert
character of the sound will Buddenl) i much l<

murmurish quality ii' presenl will suddenly disappea I
responds to tli«' < 1 i : i •- 1 « > 1 i « • pn which is now read off from

manometer.

It must be remembered thai below this point,
cuff is further ound is still heard in th<

does not entirely disappear until th< sure has become quite lov

point of final disappearance is, ho BigniJ I '-utT is

-

now entirely decompressed, and Bhould I •

mi thai the circulation in the pi the arm beloi

normal.

The above readings should i illed by

tion, in which the methods emplo slight!) n w

■ hoscopc at the bend ot Lbo^i thi

a little alio\ e the pre> ioush det< rmi
sound is clearly heard. Tl
sound disappears Tins poinl i

130 THE CIRCULATION OF THE BLOOD

the auditory systolic index. It will be found to give a systolic pressure
a little higher than thai obtained by palpation of the artery at the wrist.
The sound being now absent, the pressure in the cuff is lowered until
the sound reappears, and the point at which this occurs should almost
exactly correspond to that at which the sound was found to disappear.
If the palpatory systolic index is not below the auditory, it indicates
that some error has been made in the application of the apparatus, and
that the reading of the diastolic pressure will be unreliable. The usual
source of error is in the position of the stethoscope. If readjustment of
this does not bring the two indices into proper relationship, the auscul-
tatory method can not be relied upon for either systolic or diastolic
readings.

In case of failure of the auscultatory method, we have to fall back upon
the palpatory method for measurement of the systolic pressure; and for
measurement of diastolic, we must use the method known as the oscillatory,
which until recent years was the only one known for gauging the dias-
tolic pressure. This consists in observing the oscillation of the indicator
of the pressure gauge ; as the pressure in the cuff falls gradually from
below the systolic pressure, these oscillations will be observed to increase
in amplitude, until they reach a maximum beyond which with lower
pressure they rapidly decline. The pressure in the cuff at the moment
when the oscillations are at the maximum represents the diastolic pres-
sure. With a mercury instrument it is obviously difficult to employ this
method, but with a modern spring instrument it can with a little practice
be used with great accuracy and will serve as a valuable check on the
diastolic reading as taken by the auscultatory method.

The procedure may be altered in various ways, there being only one pre-
caution to bear in mind ; namely, that the pressure in the cuff should not be
applied continuously for more than a few moments of time, for if this
is done for long periods, not only will it interfere with the accuracy
of the reading, but it may cause considerable discomfort to the patient.

There are several conditions affecting the accuracy of the readings by
each method which it is well to bear in mind. ' These have been investi-
gated by MacWilliam,1 Leonard Hill,2 and Erlanger.3 With regard to
the systolic pressure the most important of these are as follows: (1) The
compression cuff should be a wide one (12 cm.), and it should never be
applied so that there is any chance of its compressing the artery against
a bony surface. This precaution is necessary, since it has been found that
much less pressure is required to obliterate any perceptible pulse beloAV
the armlet when the artery is flattened against some hard structure than
when it is uniformly compressed in the tissues in which it lies. (2) Dis-
crepancies are often noted between the systolic readings on compres-

Ill l>

simi ; 1 1 m 1 decompression of tl

decompi ession ;it a low er pi i

compression, the difference being mosl n

is done quickly. Thia difference is owing to tl

the pulse does no1 reach the forearm until ;i!l tl
<list« -lulfii w ith l>l<>'..| ■■•II dis

readinga taken Prom different limbs; thus, it
thai the systolic preasure in the ]<■<; is higher thai
when the observed person is in the horizontal position l
are mosl commonly ol ! in patients

on or thickened arl l the p

water-hammer variety, and the greate tolic pn

ins t.. depend on dif
ieal conditions cone in the transmission •

w ave t«i the the t w .» exl remitii

The reason for tin' discrepancies in
doubt that the hardening is likely t<> be more pronounced in t;
sels of the thigh than in those of the arms. Winn a
compressed it doea not collapse uniformly thj
completely <•!« >^.-. 1 bul its walls come togetl middl

••hinks still vniain at the Bidea The hi 1 continu*

these chinks, and a very coi l»ly higher p •• in the cuff

quired to obliterate them. That this is probably the c

is supported by the observation that, although in sucl

doea oo1 disappear in the \< if the t"""t a1 the Ban

doea at the wri8t, a distinct change is nevertheless i"

pulse "t" the i"""t at a cuff pressure equal t«> tl

in the wrist. In a patient showing a s

upper arm ami l!»s mm. for the leg, at llii mm. th

although nol obliterated, becanK it down in volui I

•• it persisted at a small volume with little all n unti

ifftcient to obliterate it. h is s.u.i • •
and decompression of the hardened
crepancy in tin- Byatolic readings D ff<
also Bometimea observed in normal individuals, particul
cular exercise, but for t hese n

While palpating the radial a it wi

• e in the cufl aduall |

pulse iner • ibly until a

This ' heha\ n-r of tl I

sph ■ I ' I • -

significance that th<

132 Till: CIRCULATION OF THE BLOOD

at which a sound first comes to be heard by Listening over the artery
at the elbow.

With regard to the diastolic pressure, there has been some controversy
as to whether it is more accurately gauged by the oscillatory or the aus-
cultatory method. If both methods are employed it will usually be found
that the oscillatory gives a higher reading than the auscultatory. The
concensus of opinion seems to be that the latter method is the more accu-
rate, and certainly it is the easier to apply, for with the oscillatory
there is often great difficulty in deciding just exactly when the maximum
oscillation occurs.

The strongest evidence supporting the conclusion that the auscultatory
readings are more reliable than the oscillatory has been gained by ex-
periments with an artificial schema, consisting of a vide glass tube rep-
resenting the armlet, filled with Ringer's solution* and closed at both
ends by rubber stoppers pierced by tubes. These tubes are connected
with a recently excised artery, which therefore runs from end to end
inside the wide tube. Through tubing connected with the artery a
pulsatile flow of oxygenated Ringer's solution is made to flow at vary-
ing pressures, which are indicated by valved manometers (see page 152).
The pressure in the wide tube is also measured by a manometer, and
it is caused to vary by a suitable compressor. By comparing the be-
havior of the artery with the pulsating movement of a spring manom-
eter connected with the wide tube, under different degrees of pressure
inside and outside the artery, it has been observed that the maximal
oscillation occurs when the artery is actually somewhat flattened be-
tween the pulse beats; that is, it occurs at an outside pressure above
the diastolic pressure, at 'which of course the vessel should retain its
circular shape. When a stethoscope is applied to the tube leading
from the artery just beyond the wide tube, in the above described
model sounds similar to those in the arm are heard with each pulsa-
tion. While the pressure is being gradually lowered from above the
obliteration point, these sounds become first audible as soon as a cer-
tain amount of fluid is forced through the compressed area at each pulse
(the systolic index), and they become louder and often murmurish in
quality as the decompression is proceeded with, until a pressure is reached
at which they suddenly become less intense and change in character. At
this moment it will be observed by watching the artery that the external
pressure is no longer capable of producing any flattening of the vessel
between pulses. Evidently, therefore, the change of sound corresponds
exactly to the diastolic pressure (Mac William).

*RinKcr'^ solution is vised so that the artery may he preserved as nearly as possible in a living
condition. This is important, since tin- elastic properties change when the arterial walls die.

I-.I I'lil

It should be clearly understood thai i1 i>> the
duces the sound, I »u t ccurrence and

upon the intra-arterial pressure existing during the diastolic pi
The cause of the Bound has been shown to depend on tin- p
a water-hammer in th<- blood vessels below 1 1n- compression
langei B .1 water-hammer is meant the

are caused by suddenly stopping the Aom of water in a tube W

sudden pressur curs in tubes »\iili elastic walls, I

into vibration and bo produce a sound. In the taking

measurements, ;i^ above described, when the pressure in th<- cuff -

tween Bystolic and diastolic, the volume <>f the '•••in will

increase abruptly with each heartbeat ;m<l thus permil

volume of Bwift-flowing l>l«»<»<l i(. enter the resl of the

the cuflP. When 1 1 1 i -> quickly moving column of blood comes int<

• with the stationary blood filling the uncompressed .
cuff, it will become immediately checked, and thus distend il
wall with unusual violence and set it into vibration.

CHAPTER XVI

TIIK FACTORS CONCERNED IN MAINTAINING THE

BLOOD PRESSURE

Having become familiar with the principles of the methods by which
blood-pressure measurements are made, the next problem is to examine
into the causes which operate to maintain the pressure. Two of these
causes may be considered as fundamental, sinee without them no such
pressure could exist. These are: (1) the pumping action of the heart,
and (2s) the peripheral resistance — that is, the resistance to outflow of
blood from the ends of the arterial system. Less essential though im-
portant factors are: (3) the volume of blood in the blood vessels, (4)
the viscidity or viscosity of the blood, and (5s) the elasticity of the
walls of the vessels. We shall now proceed to examine the experimental
evidence which indicates the relative importance of each of these factors.

1. The Pumping Action of the Heart

Changes produced in the mean arterial blood pressure by alteration
in the pumping action of the heart are most strikingly demonstrated by
observing this pressure after cutting or during stimulation of the vagus
nerves. As will be explained later (page 217), impulses conveyed
through these nerves to the heart make the beats slower and weaker.
These impulses are constantly acting in the heart, so that when both
vagus nerves are cut, the beats become more frequent and stronger,
with the result that the mean arterial pressure rises considerably. A
lesser degree of this effect can usually be obtained by cutting the vagus
nerve on one xide (Fig. 27). If now the peripheral end of a cut vagus
nerve is stimulated, as by applying an electric current to it. the heart will
either stop beating altogether or become very much slowed, with the result
that the mean arterial blood pressure will fall, in the former case almost to
zero and in the latter, to a level corresponding to the degree of slowing
of the heart (Fig. 28).

2. The Peripheral Resistance

T<» demonstrate the influence of peripheral resistance on mean arte-
rial blood pressure, the mosl striking experiment is performed by cut-
ting or stimulating the greal splanchnic nerve. In this nerve impulses,

134

lUo.ii. i-i:

which are called \ .i> instrictor be<

blood vessels, are transmitted t«» tl

The vessels art- under th< I influ< •• impu

when the nerves thai transmil them i ed, th<

tlniN offer less resistan el movement of 1 >I « •* •■ 1

produ I on the mean arterial blood pr<

splanchnic nerv< a marked and sudden fall, which is im-

mediatel} om it' the peripheral end i

stimulated artificial In ,-l ^n-j tlii^ experiment to pn

relationship between peripheral resistance and the mean ait. rial !»'

i

it in u-t be remembered thai it i> not entirely c
the results observed on the mean il blood | m cut!

itimnlating the nerve ma) be in p cplaim

in the total capacity of thi
the nen es, li om b) stimu them.

3. The Amount ot Blood In the Bi>

Tl tei ed bj hemorrl

Biich I'l i » i

I bearing, but

136

THE CIKCILATION OF THE BLOOD

To appreciate the significance of the results, it is important to bear in
mind that the total volume of lh< blood constitutes from 5 to 7 per cent
of the weight of the animal. This fact has been determined partly by
postmortem, and partly by antemortem measurements. In the post-
mortem method, the total amount of blood is determined by collecting the
blood while bleeding the animal to death and then washing out the
vessels with saline solution until the escaping fluid is no longer tinged
with red. The amount of blood contained in the saline solution is estimated
by colorimetric methods (see page 92), and is added to that of the blood

Uwi i. Ous. <♦ AbSC'&S

Fig. 28. — Effect of stimulating the peripheral end of the right vagus on the arterial blood

pressure.

directly collected. In the antemortem method some substance that does not
diffuse through vessel walls or become quickly destroyed is added to the
blood. By determining the concentration of this substance in a speci-
men of blood, the volume with which it has become mixed can readily be
calculated. Acacia has recently been found suitable for this purpose
(Meek), but the best known work (of Ealdane) was done by causing the
animal to inspire a known amount of carbon monoxide. This combines
with the hemoglobin of the blood (see page 401) to displace an equal
quantity of oxygen. By determining the difference between Hie volume

I'.l I'KI

of ca pbon mono* ide in t In- blood b<

calculate with Imu much I •!«■<>• 1 the known ii
carbon monoxide must hi
differenl animals; in the <l" blo< ><\

of tli.- body \\ eight, and in man, ab

/ .n the blood

: bleeding 1 1' a large art< moral,

TiH*t «rAfruitsA

the pressure will shou sn immediate l»ut i

■ that w <• li:i\ c suddenly de< I

hand onlj a small arti a * eii

at first produce no • nn the 1>I<»<«I

considerable amount of bl< - been pen

T<> I u. ma) st.it.- ti

kilogram of l""l rht do<

moval of a Becond porl i"

i:;s

THE CIRCFLATION OF 1HF. BLOOD

blood per kilogram removed averaging about 6 mm. Hg, until after 20
to 25 c.c. of blood per kilogram have been removed, when a more rapid
fall in pressure sets in (Downs'). When the pressure reaches the level
of from 20 to 30 mm. Hg. the danger limit is reached, for there now
supervenes a train of symptoms known as "'shock.'' and the chances for the
animal's recovery become uncertain. That the removal of the first por-
tion of blood, if this removal is slow enough, does not influence the blood
pressure, indicates that some adjustment has occurred in the vascular
system to hold up the pressure in spite of the loss of blood. This adjust-
ment is believed to consist in vasoconstriction.

Time in Sees &.
Abscissa

Fig. 30. — The effect of rapid and slow hemorrhage on the arterial blood pressure. Between
the second and third pieces of tracing an interval of two minutes elapsed.

Recovery from hemorrhage is remarkably rapid, the original volume of
blood being restored within a few hours. The chances of recovery de-
pend upon the amount of blood lost. A loss equal to 2 or 3 per cent of
the body weight can almost always be recovered from in laboratory ani-
mals, and in the case of man there is reason to believe that recovery
may occur after as much as 3 per cent of the body weight has been lost.
The recovery of blood pressure is brought about partly by a transfer
of fluid from the tissues to the blood. This abstraction causes a drying
out of the tissues, which soon excites an extreme degree of thirst. The
dilution of blood by fluid derived from the tissues occurs very rapidly.
as can be shown by comparison of the hemoglobin content, or the number
of blood corpuscles, in samples of blood removed immediately before

OOD I'RI

and immediate!) after ;i hemoi I

hemorrhagic blood dedl)

diluting fluid contains a lower conc<

the blood plasma. The dilution bl I is ind( that

hemolysis occurs, the plasma beii tinctly tii I.

I [emorrhagi I he hj drog<

blood plasma, and diminishes the ston alkali, bo thi

iliti tain amounl he blood • '-r . i

ran i ter rise in i he hj i ion <-<'ix-

The deficiency in the I.I I elements produ I by the dilul

Red by the manufacture of i rpuscles in tl !>nt

this pi ■■ ii a liberally fed animal tak

nit'iit, and while it is going on microscopic examination of the I>I'»<.<1 will
al the pi • of immatur rpusc

1 reful studies of U 1 regeneration following the removal oi I

successive days, of 25 per cent of the blood, have shown thi in

starving animals the total amounl of hemoglobin p

globin multiplied by the volume of blood slowly rec Whi|

ami Hooper . Recovery is greatly hastened by feeding with fl<

even with gelatin. Removal of the spleen or the establishn

ary fistula does not interfere with the recovery.

Incidentally it will be advantageous t nsider here the effects of

transfusion. I are very different according to the nature of the fluid

used for transfusion. Three transfusion fluids have I n inv<

I blood itself, (2 physiological saline solution see pi
physiological saline solution containing viscid Bubstances such

The effects are also verj different i trding to whether I

injected into animals with normal l»l 1 pressur ■ into those wl

blood ire has been lowered by preceding hem

When I'l I is injected into animals with normal I>1"<..1 pr<

will very soon cause the pressure to rise, and as the injection is ma

tained the rise may continue until the press

or more above its normal level. It" the injection is

r, a sudden fall of pressui
right side of the heart, [f the injection is nol
blood pressure after 1 >«i n lt maintain.-. I for n
level.

Inject ion of saline into a normal animal, it' in

at all on the hi 1 if m< >idly ii will

slightly, but t<> n much than t;

t' is injected M uH
crated In

140 THE CIRCULATION OF THE BLOOD

continuance of the saline injection, the blood pressure returns very
rapidly to its old level. The most striking result of such experiments is
the enormous volume of saline solution which can be slowly injected
without perceptibly affecting the pressure. The question is, Where does
the fluid go? If the urinary outflow is examined, a ceil a in increase will
usually be observed, but never by any means sufficient to account for
the disappearance of the injected saline. If we open the abdominal cav-
ity, Ave shall find that a considerable transudation of the saline into the
peritoneal cavity has occurred, and that the liver is conspicuously edem-
atous. A certain degree of edema is also usually evident in the tissues
of the extremities.

Still more interesting and important, from a practical standpoint, are
the results obtained by injecting the above solutions into animals
•whose blood pressure has been lowered by a previous hemorrhage. If
the blood removed during the hemorrhage is defibrinated (see page 101),
and then reinjected into the animal, it will bring the blood pressure al-
most but not quite back to its original level, which will then be fairly
well maintained. If, on the other hand, saline solution instead of blood
is injected, the restoration of blood pressure (with an amount of saline ■
equal to that of the removed blood) will amount only to about three-
quarters of the extent to which it had fallen. This partial recovery is,
moreover, maintained for a short time only, after which the pressure
approaches the level to which it was reduced by the hemorrhage.

These observations raise two important practical questions: (1) Why
is saline relatively ineffective in the restoration of pressure? and (2)
Why is the restored pressure not maintained1?

The answers to these questions brings us to a consideration of the next
of the factors concerned in the maintenance of the blood pressure,
namely, the viscosity of the blood.

4. The Viscosity of the Blood

The importance of this factor arises from the fact that facility of flow
in a tube is inversely proportional to the viscosity of the fluid and
directly proportional to the driving pressure to which it is subjected —
that is, to the difference in pressure between two points in the tube.
If therefore the output of the heart remain constant, but the viscos-
ity of the blood be decreased by a saline injection, the facility of flow
will be increased and the pressure decreased. This fact can easily
be shown experimentally in a model by causing gum solutions of various
concentrations to be driven through a i>lass tube by means of a small
piston pump delivering a constant amount of fluid into the tube with

141

each in"', emcnt. All hough the oul

must remain constant, the ure in the tubing \\ ill

to the 'ii Bolutioi I I

Ti rring i >ults to an animal blood

lowered by hemorrhage, it has been fou
taining a Buffieienl amount of gum tin i" i

ity aboul equal to that of blood, are injected, th<
pressure in re I as well as ii would hi n had blood itself i

jected A 7 per cenl Bolution of gum acacia almosl fulfi
iin-n ts, but unfortunately tliis Bolution » • » » i » t -- 1 i 1 1 -^ a slightl} mount

of calcium than it is safe to inject into ai
may. however, be removed l>. i itly neutralizing
sodium hydroxide, neutral red being used ;^ an indie
calcium becomes precipitated as phosphate. The mucilafi
Pharmacopeia, ili!ut<'<l five times \\ith water, makes ~
linn of gum acacia. A 6 per cenl Bolution of gelal

to 100 l es a viscosity similar to that of 1>I 1, but on i

the possible presence of tetanus Bpores such solutions m i

fully sterilized before injection, and the pi

a decrease in viscosity. The injection quantil

solutions equal to thai of blood lost by a hemorrh; a

the blood pressure bach to its original height and hold it I

hour or so.

Viscosity is. 1 > ••, qo1 the only property
which their desirab t depends, 'ri-
als) iii.s into play. By injecting saline Bolution containin

amount of a colloid bucI rch, which g

vise '-lit ha osmotic pressure bl 1

temporarily recovers after transfusion, does not malntaii
the same way as w ith solutions containing gum i l

between a Btarch solution ami i gum o

moti.e pressure, the eff< w hicl

retion of urine, as can bi
ureters during the injection into anil

alon • of saline containing tin K w

first two fluids diun produced, but not with tl

i that the osmotic ;
of v rom the blood into the urin

incut of thia pn on tin- bh

counteract the filtration pn by which the ur

Although the urinary ir w ill

142 ttii: circulation of the nr.oon

the colloids in recovering the blood pressure, 1 lio conditions controlling
it reveal the mechanism by which the passage of fluid from the blood
vessels into the tissues is prevented when solutions of correct composi-
tion are injected. Normally the protein content of the blood plasma is
higher than that of the tissue lymph, so that there is a continual attrac-
tion of water from the tissues to the blood — an attraction which is nor-
mally balanced by filtration going in the opposite direction. When the
filtration pressure in the blood vessels exceeds the difference existing
between the osmotic pressure of their contents and thai of the tissue
fluids, water will pass into the tissue spaces. When the blood is diluted,
as by the injection of saline solution, the osmotic pressure of the colloids
in a given volume becomes lowered and, the filtration pressure remaining
constant, fluid passes into the tissue spaces. Of course these explanations
rest on the assumption that the walls of the blood vessels consist of a
membrane which is permeable to crystalloids but impermeable or nearly
so to colloids.

Another important property of the transfused saline solution to con-
sider is its hydrogen-ion concentration. This value increases in the blood
left in the body after hemorrhage, and injection of sodium chloride solu-
tion aggravates the acidosis; addition of NaHC03 so as to make a 0.2
M solution restores the correct PH, and at the same time restores the
lost buffer influence (Milroy7.) These observations are of interest in the
light of the recent discovery of Cannon that a condition of acidosis, as
judged by the C02-combining poAver of the blood, is present in shock,
and that the development of this condition can often be guarded against
by bicarbonate injections.

5. Elasticity of Vessel Walls

The elasticity of the vessel walls is essential to the maintenance of the
diastolic pressure. If the walls presented no elasticity but were rigid,
blood pressure would fall to zero between the heartbeats. This fact can
xery readily be shown by a simple physical model consisting of a pump
to represent the heart, connected through a T-piece with two tubes, one
of which is elastic, the other rigid. The free end of each tube is con-
tracted to a narrow aperture representing the peripheral resistance, and
either tube may be shut off from the pump by means of a stopcock (see
Fig. 30). Each tube should also be connected with a mercury manom-
eter. If now the stopcocks are arranged so that the fluid passes into
the rigid tube while the pump is in action, it will be found that with
each stroke of the pump the pressure in the tube rises considerably, but
that it f;il Is to zero between the strokes. If now the stopcocks are turned
so that the flow is through the elastic tube, the action of the pump being

11 :

meanw hile k i-i »t up, it \\ ill be found

is maintained ;it a height which in dcpendci

the i>imi|) is operating, and 2

The quicker the action of the pump and t; her tl ■

lower the fall of pressure between the beal

The physical explanation of this result is clearly that the fluid
the elastic tube when the wave <>f p into i' imp

distends tin- walls of the tul • that when the pi imp

tched elasl c n the <-"liiiim o

and maintain the pressure We may saj that the (
vessel walls store up Borne <>t' the systolic pre
t he blood during diastole.

-

Ti insiderations would lead us to ''\i t thai pati<

find arteries Bhould exhibil a lower diastolic pressure than norma] |
sons, which, however, is nol usually th<

Buffer from an increase in the resistance t<> the fl< <\ 1 in I iph-

ery. The pressure pulse in these pati<

On the other hand, when the vessel walls 1»< me m

elastic, as in certain ci aneurism, the pres

below the aneurism is distinctly less than that <>!
sels of i he same pal ient.

CHAPTER XVII

THE ACTION OF THE .HEART

Having studied the methods for measurement and the main factors con-
cerned in the maintenance of the arterial blood pressure, we may now pro-
ceed to study in greater detail the two most important of these ; namely, the
action of the heart, and the peripheral resistance.

The heart action has to be studied from two viewpoints, the physical
and the physiological. From the physical viewpoint we have to study
the heart as the pump of the circulation. We must see how it acts so as
to raise the pressure of the blood within it, and how the valves operate
so as to direct the bloodflow always in one direction. We must also ex-
plain the causes of certain secondary physical phenomena, such as the
heart sounds which accompany the heart action, and of certain secondary
changes in pressure produced in the other thoracic viscera by each heart-
beat. From the physiological viewpoint we must investigate the conditions
responsible for the constant rhythmic activity of the heart and the con-
trol to which this is subjected through the nervous system.

THE PUMPING ACTION OF THE HEART

When the heart is viewed in the opened thorax of an animal kept alive
by artificial respiration and lying in the prone position, it can be noted
that with each contraction the ventricles become smaller and harder, that
the apex tends to rise up a little, so that if the thorax were intact it
Mould press more firmly against the walls, and that it rotates slightly
from left to right, but does not move nearer the base of the heart. If
the auriculoventricular groove is carefully observed, it will often be
noted that it moves slightly toward the apex with each systole, whereas
the base of the heart itself, where it is attached to the large vessels, re-
mains fixed. The auricles can often be seen to contract and relax before
the ventricles.

The most noteworthy results of this inspection are that during sys-
tole the apex of the heart does not move toward the base, but that
the auriculoventricular groove moves slightly toward the apex. That
these same movements occur in the intact animal can be shown by the
very simple experiment of pushing two long steel knitting needles

1-44

i is

through the I ic walla into th<

thai it i>i- tie apes of t 1

I fulcra ;tt ti t wall,

and it' the movements of their 01 I by ti

hi* the heart, are observed, the) will 1»- fi>un<l to
made on I posed heart.

Mm e particular im esl ignl ii
uf the hearl ca> it \ during »le and dij

making measurements ctions across tl

these conditions P01 such put I in dii ly "1»

tained, bul for the heart in Bystole iT
artificial means of injecting the heart with ln»t chrom
just before the death ••!' the animal. Tl 1 chron
muscle tu contracl and maintains it in tl ndition. 1

tin's.' investigations is. however, not <>t* much practical im]

Although it is im.v, common knowledge thai the direction of tl .
uf the liliiinl is from the veins to the arteri< it may b<

consider for a momenl th< pal principle of the m< I

William Harvey sue ided in making tliis discovery. Ii

partly anatomic, parti; rimental. He pointed oul thai tin

the veins, and of the auricles to which they lead, are very thin, \.
thus.' of the arteries and ventric ry thick, and he

in the veins the blood musl flow gently from the I

rt, tu which the valves in tl • ad thai in tl

it must be propelled by pulses with each systole through

ards the tissues by tin- contraction of the walls
experimental Bupport for this hypothesis he furnished parti)
j, veins and arteries leading r from ti

erving the resulting distension or collapse of 1 1
calculation of the amount 0 od which must be expel
venl gh en period of t in

Harv< '- d
in»t much added to until exp 1 metl

the

and compared. Until Buch a
■ible ti> h ite the mechanism by which t! •

the heart eai iti< ted v» ith I

function, or to descrilx •
in : 3 during the variot

It is for the pin
cha that int diac p

146

TFIF. CIRCULATION OF Til!'. lil.OOD

Intracardiac Pressure Curves

The earliest method for taking such curves consisted in introducing
into the cardiac chambers and the blond vessels of the horse, so-called
cardiac sounds. These consisted of a more or less rigid tube furnished at
one end with a little elastic bag or ampulla and connected at the other
with a tambour, by means of rubber tubing. One of these little bags
was placed in one of the ventricles, another in the auricle or aorta, the
tube being inserted in the former case through one of the large veins at
the root of the neck; in the latter case through the carotid artery. The
intracardiac pressure curves obtained in this way marked a great ad-
vance over the methods that had previously been used to study the events
of the cardiac cycle, but they were so faulty in comparison with tracings

Fig. 32. — Diagram of Wiggers' optical manometer. The wide glass tube (A) (connected
with the ventricle, etc.) is connected with a brass cylinder (B) provided with a stopcock ((.').
the lumen of which comes in apposition with a plate (a) having a small opening in it. The
freedom of communication between B and o is regulated by the position of the tap. Above a is
a segment capsule (b) 3 mm. in diameter and covered by rubber dam. This carries a small
mirror (C) fastened so that it pivots on the chord side of the capsule. Above the capsule is
arranged an inclined mirror, from which a strong beam of light is reflected on to the mirror
(c) on the capsule. This beam thru travels back and the mirror (£) is adjusted so that it
impinges on a moving photographic plate. The slightest movements of the small mirror (C)
are thus greatly magnified.

taken by more modern methods that it is not worth while considering
them any further here.

The physical errors involved in the use of the older instruments were
due mainly to the elastic recoil of the membranes, etc., used in their
construction. A great improvement in technic was afforded by the use
of the spring manometer of Iliirthle (sec page 126), which was connected
with one of the heart cavities by a cannula filled before insertion with
some antieoagulant fluid. The cavity of the tambour was made as small
as possible, and either left empty or filled with the anlieoagulating fluid.

I III \< TION OP Till III \l;r

i r

A searching investigation into tin- physical principles involved in ti
ing records of sudden changes in pressure bj such instruments has, how-
ever, shown tli.it considerable ••inns are incurred, the inertia of the

moving m;i^ of fluid in the tubing and the □ Bsity of using levers in

order to secure records being responsible for mosl of them cf. V*
gers). Their elimination has recently been achieved by usin<_r ,-i so-called
optical manometer, one of which (Wiggers' is shown in the accom-
panying figure. It consists of a wide 'jlass tube .1. connected above with
a hollow brass cj linder /»'. provided with a stopcock C, the lumen of which
tapers from below upward till it assumes tin' same diameter as an ap
ture in the segmenl capsule l>, above it thai is. a capsule cu1 away at one
end -which is :\ mm. in diameter ami covered with rubber 'lam. By ad-
justment of this stopcock the piils.-it ions of the fluid in .1 ami B can be
damped to a greater or less extenl before they are transmitted into the

Fig. .'.! Optical records of intraventricular pressure; a-!, auricular systole; bd. prespuygi
period; >'•/. sphygmic period; after f. diastole. Instrument trying dc{

were employed in taking the curves. (From Wigl

segmenl capsule. A small piece of celluloid carrying a tiny mirror r<

on the rubber dam, being pivoted on the chord side of the capsule A
mirror is attached to the capsule with its plane so adjusted that the
image of a strong lighl placed at some distance from it is focused on the
little mirror carried by the celluloid. The ray reflected from the little
mirror ami again reflected from the larger mirror is adjusted s,

impinge upon a moving photographic plane travelling at a uniform ratl-
in a suitably constructed photographic apparatus. By the us< I such

an apparatus the chief errors encountered by the use of the older in-
struments are eliminated, because there is no moving m;is> of fluid and
there are no levers to set up spurious vibrations. Curves -••cured by

the use of this instrument are shown in I

Two objects must he kept in view in analyzing the curves 1 Cui

obtained from the different cavities may he compared in order to de-
termine the exact moment during the cardiac cycle at which BUCh p

148 THE CIRCULATION OF THE I'.LOOD

sure changes occur as must serve to produce opening or closing of the
various valves; and (2) the contour of the curves obtained from each
cavity may be examined in order to find out exactly how the pressure
in that particular cavity is behaving.

Comparison of the Curves

Before using the curves for ascertaining the relative pressure in the
differenl cavities, they must be graduated according to some scale, for
it is clear that by the use of instruments like those we have been describ-
ing, the absolute pressure value of each curve will vary according to the
construction of the instrument (thickness of membrane, etc.), and in-
deed instruments of varying degrees of resistance must be employed in
taking curves from places having such different pressures as exist in
the auricles and ventricles. The graduation is, however, a very easy
matter, and consists, as already explained (page 126), in connecting the
instrument by means of a T-piece with a mercury manometer and a pres-
sure bottle and then marking on the tracing, the points corresponding to
each 10, 20 or 50 millimeters of increase of pressure, as the case may be.

To ascertain the time relationship between the opening and the closing
of the auriculoventricular valve, the tracings should be taken from the
right auricle and the right ventricle, and to ascertain the same with re-
gard to the semilunar valve, from the left ventricle and the aorta.*

By comparing the curves it is now an easy matter to ascertain the
exact moment at which the pressure in the one cavity comes to equal
that in the other. This moment, read on the accompanying time tracing,
will obviously indicate that at which the particular valve is just about to
open or close. From the results of such experiments, the curves may be
superimposed as in Fig. 34.

In the first place let us compare the curves from the right auricle and
/< utricle. The curves begin at the very end of diastole, and they show
that a distinct increase in pressure is occurring in both auricle and ven-
tricle and lasting about 0.05 second. This is of course caused by auric-
ular systole, and since it occurs in both cavities, it indicates that the
passage between them, the auriculoventricular orifice, must be open.
The ventricular curve then suddenly shoots away beyond the auricular
because of the onset of systole in the ventricle, and the point at which
the two curves begin to separate indicates the moment at which the
auriculoventricular valves close. From this time on until ventricular
systole has given place to diastole, (about 0.2 second), the auricle is

*The connections v itli the heart may lie made by pushing long cannulx down the large veins or
arteries, or in the case of the ventricles by inserting a cannula with a sharp point directly through
the wall of the ventricle.

1 II! V IF I HI II

ther< Bhut off from thi I

which the tw o ca\ ities at ■ ighl i

tricular valves open is indicated l>> I
Saving thus determined tl
of the auriculoventricular valv< i maj i
intraventricular pressure curve with thai taken fromtl

ry calibration corrections, this eur\'e ha* i

in its true relationship to the ventricular curve Bepim
end of diastole, we find that the aortic pn
above that of the ventricles, indicating that the Bemilui

closed; ;in<l it will I bserved thai the inti tricular p

•. ,.: *

Ventricular

Polls*

m

,V1

■ icl»

IOU

^A£rto

I

^-

1J

\ Auricle *s-^

•

zi
Si

.- »
< <

3

irt

■

iound of heart

3

s

. .'IKIS

Ol

■<:

OJ

M

oa

I
the T

the beginning ■'•• doea not rise sufficiently I

appreciable inl 0.04 Becoi d

alo ventricular \ alves; thai is 1

il.tr b; h tin- \ en1 1'

• riod during which the ventricle bj
sufficient amounl of pressure in the fluid
the semilunar \ ;il\ i

and it 1ms I- pularly »';ill«-.l '

in physiological Ian

shall u- last i) m in i

150 THE CIRCULATION OF THE BLOOD

After the aortic valves have been opened, it will be observed that the
pressure in the ventricles is just a little above that in the aorta, and that
it continues so during the whole of ventricular systole. When diastole
sets in, the pressure in the ventricles quickly falls, and a point is soon
reached at which equality of pressure in ventricle and aorta is again
attained. This corresponds to the moment of the closure of the semi-
lunar valves. The pressure in the ventricle, although now rapidly fall-
ing, takes a little time before it has fallen low enough to permit the
auricular valves to open. Here again, then, the ventricle is a closed cavity,
and we have what is known as the postsphygmic period.

I HAPTER XVIII
THE PI MPING A' TK >N I 'I THE HEART I ont'd

THE CONTOUR OF THE INTRACARDIAC CURVES

The Ventricular Curve

rrom an analysis of tli utour of each curve, further ii

points are broughl to light The ventricular cun e in the diagram allu

li<>\\ ii as having a flal top or plateau. B
of the more modern, optically recording, instruments i1
thai this plateau becomes displaced by ;i peak if every ; ition is

taken to prei ent dulling dov n of the pressure changes in tl ■
as l.\ opening wide the stopcock in the instrument I
is, however, by do means a sharp one, bo thai we may fitlj ibe th<-

contour "t' the ventricular curve during the Bphygmic peri(
ing of a rising portion, almosl continuous with the curve during
sphygmic period, ;i summit and then a declining po , which is usually
Blower than the ascending. The practical value arising from a stud]
curves li<'s in the insighl which they •_: i \ < ■ us into the nature
of the cardiac pump They Bhow ns thai tin- impulse which the ventr
gives tu the moving mass of l»l*»«»»l in the aorta is a sudden rather thi

tained one The column "f l>h><».l in the aorta is a 1 1 1 i •_: 1 1 1 \ thing
i!iu\<\ and it would appear as it' a sustained broughl to 1 •■

it during the Bphygmic period would be far more efficienl in !»•
about an adequate movemenl of the blood than a Budden ,:• Ii

a heav) Lrat<' a bIon sustained pressure is
sudden bloM

l • is further <>f inl
that there is \ erj little indication of an;
at the moment during which the semilunar

erthcless, \<y close Bcrutinj ii <-.m usually
change in the direction of t h<
open and similarly thai the mom<

i>> a Bharper bend in the cui v< is a matt
thai thi ontour of the cu iring I

partly "D the de
•l\ on th'

152

THE CIRCl'LATION OF THE BLOOD

In the case of the right ventricle the contour of the curve also depends
on the degree of resistance to the bloodflow through the pulmonary
circuit. The top of the curve becomes broader when the initial tension
is high, and more rounded when there is a high pulmonary resistance.

Another point of interest in connection with the ventricular curve is
that early in diastole il descends below the titie of zero pressure, indicating
that a negative or suction pressure must exist in the ventricle at this
time. It will be further observed, however, that this subatmospheric
pressure exists for only a very short time. The auriculoventricular
valves being opened, a similar negative pressure is also present in the
auricular tracing. Were we to depend on such records alone for evidence
of the actual existence of this negative pressure in the heart, objection
might be taken to the conclusion on the ground that it was due to the

to manometer

max valve

mm valve

to heart

Fig. 35. — Von Frank's maximal ami minimal valve, which is placed in the course of the
tube between heart and mercury manometer. By turning the stopcocks, it may be used as a
maximum, minimum, or ordinary manometer (central tubes open). (From Starling.)

sudden recoil to which the instrument is subjected at the beginning of
diastole. It is necessary therefore to control these observations by the
use of an entirely different method. This consists in connecting the
heart with a valved mercury manometer (see Fig. 35). This instru-
ment does not of course record any sudden changes of pressure in the
cardiac cavity, but in obedience to changes in pressure the mercury slowly
moves in the direction in which the valve permits it to move. Such an
instrument, with the valve opening towards the heart, is called a minimal
manometer, and after it has been connected with the ventricle, it will be
found that a negative pressure of perhaps 40 or 60 mm. Hg is recorded.
Evidently, then, the negativi pressure does actually exist in the ventricle
during some phase of the cycle, and the question arises as to whether it
is of importance in connection with the pumping action of the heart. At
first sight, considering the heart as an elastic structure, we might con-

i in i-i \iri\-. \- i

ceive thai the negative pressure would

just ,is it racks water in ;m ordinary ball syrini i

will, however, show thai this conclusion is untenable, parti} b<

negath e pressure exists in the

partly because it \\<>ul<l have to "i" >wly movii imn of

I'l I in the thin walled veins, with the resull thai it would

<>f thea to come together rather than produce a mov<

blood contained in them. The negative pr<

therefore be of much consequence in attracting I nous blood ii

ventricle.

Several factors maj i perati produce thi

among which ma} be mentioned the Budden opening <>nt of the I

the ventricles :it the beginning of diastole, the n il of I

which hi mes compressed in the In-art walls during

turgescence of the walls of the ventricles produced by tin* sudden inr
• if blood into the coronary vessels at the beginning I

pro< tend to cause an opening oul of the walls of the venti

a consequenl increase in the capacity of their cavitii

The Auricular Curve

ESxaminati f the intraauricular pressure curv< is of particular in-

ni-<' of the relationship which it 1 a tracing tal the

movements in the jugular vein at the ro neck n tj

This jugular pulse curve, as it is called, is produced mainly by
changes of pressure occurring in the auricle, from which it <liftv
the relative heighl <>t" the various waves B _ iduating the intra
auricular pressure curve bj the method described abo

ictly the magnitude in the changes of pr< g during

cardiac cycle. This obvious!} can t">t be done with a tracing
the jugular vein, although qualitatively the tracii
changi ccurring in the aurich

< >n examining the auricular pressure cun
finil that after the w if presystole, wl ich

with that mi the intraventricular curve
in a peak aim the beginning "t" t;

cun e then rapidly tally ind<

Bure, and alowlj rises throughout th.
tin- momenl o the auriculo

again ami th< tr runs parallel with I

. used to designate tin- •
similar wi hown "n the jugu

154 THE CIRCULATION OF THE BLOOD

lettering is more or less arbitrary, we must accept it because of its gen-
et;!] usage in all work of this kind.

As to the causes of the waves. .1, is of course caused by auricular systole
or presystole; C, occurring as it does at the beginning of the period of
ventricular systole, is caused by the bulging into the auricle of the closed
auriculoventricular valve. The floor of the auricle, in other words, at
this moment becomes somewhat elevated and imparts to the blood which
is resting upon it a slight wave of pressure, which is transmitted along
the veins for a considerable distance. The succeeding depression is
marked x, and the negative pressure which it indicates is probably due
to the co-operation of three forces, all tending to increase the auricular
capacity: (1) the diastole of the walls of the auricle; (2) the descent
of the auriculoventricular groove, thus tending to open out somewhat
the folds in the walls of the auricle; and (3), no doubt most important of
all, the tendency of the thin-walled auricles to become dilated as a result
of the sudden diminution in intrathoracic pressure produced at each heart-
beat by the discharge of blood from the heart and intrathoracic blood
vessels into those of the rest of the body. All thin-walled structures
in the thoracic cavity, the auricles included, will expand to take up the
extra room created in the thoracic cavity. Similar negative heart pulses,
as they are called, can be observed with each systole in the lungs and
in the esophagus.

THE MECHANISM OF OPENING AND CLOSING OF THE VALVES

When physical valves open and close as a result of the changes in pres-
sure on their two surfaces, a certain amount of fluid must succeed in
passing the valve flaps before these become perfectly closed. But there
is every reason to believe that such is not the case in the heart, the flaps
of both the auriculoventricular and the semilunar valves being already
completely closed before pressure conditions entailing a possible regur-
gitation of blood through them become established.

Auriculoventricular Valves

During diastole the flaps of the auriculoventricular valves are hanging
down into the ventricle and floating in a half-open position in the blood,
which is meanwhile accumulating in the chamber. This position is de-
pendent upon the operation of two opposing forces on the valve flaps:
the pressure of the blood flowing from the auricle on their upper aspects,
and reflected waves of pressure from the walls of the ventricle on their
under aspects (centripetal reflux). When presystole occurs, the pres-
sure of the auricular stream momentarily increases, thus slightly dis-
tending the wall of the meanwhile relaxed ventricle and after a moment's

I III l-l Ml'l

iy causing t he reflect< d omc n .v

same time the muscular fibers in th< laps (I

contrad and make the flaps
being thai the valve takes up a i«>-,iti..n r thai

systole Buddenlj stops, the reflexed wi ill pe

of time longer than the auricular whirl,

the elastic nature of the ventricular wall,
with perfecl opposition nol merel) al thci s bul

Biderable distance along their upper

When \ entricular systol< ly rif.

which i-> broughl suddenly to bear on the under Burfi
closed valves is to cause them t<» vibrate and t" b

inwhile anchored down ; > i > « I pr< I from ihi[>;

auricle by the chorda? tendinea?. There is reason to
musculi papillares to which the tached bej

utsel "f ventricular Bystole indeed Blightly
pagi md thus keep the chorda? taul \

contraction of these muscles becomes mort

tightening of the choi down the

so thai progressivel proportio their up]

• in-' opposed Meanwhile the auriculov<
coming ne 1 down on account of 1

of the auriculoventriculai

Semilunar Vah

The mechai ism im olved in tl
Bomeu hat diffcn nt. It 1
tube, the pressure and

•'ilid Ul

L56

'HE CIBC1 LATION OP THE lU.ool.

can be demonstrated l>\ observing the Mow through a wide tube of water in
which are suspended lycopodium spores. By placing in the tube small
In-ill tubes so arranged that one open end lies near the periphery and
die other near the center, it can be seen thai the differences in pressure
are such as to cause the fluid to Mow from periphery to axis (centripetal
eddies).

If the benl tubes are used to study the conditions of flow in 8 tube which
suddenly becomes wider, it will be found thai where the wide portion
starts centripetal eddies are se1 up, which tend to carry the spores into

I lie axis of the st renin, where their velocity [g greatly inere;ise(|. \ow

these are the conditions obtaining ;ii the beginning of the large arteries

S.a.-D.V.

D.a.-S-v.

Pig, Diagran liowing lh< position "I i he cardial chambei and valvi during |>rei !olc

I '.v. ) and 'In nil pi I. I r'i om Landoi

of the heart, the orifice into the ventricles being constricted, while al
the sinus valsalvae the vessels are dilated. A centripetal vortex must be
• I up in the sinus, tending to throw the valve flaps into ;i closed posi
lion, which, however is prevented by the Mood rushing between them
from the ventricles. They thus take up ;i mid position and vibrate in
the stream. When the efflux from the ventricle stops ;it the end of sys-
tole, the reflux, lasting for s nioinrni longer and being now unopposed,
immediately closes the valves, in which position they are then maintained
by the greater pressure on their upper surfaces.

The position of I he \;d\es relative lo Ihr events of the c;irdi;ic cycle is

show n in Pigs. 36 and 37.

mi i OP Til

THE m:\> i BOI v

I )iirn ' .1111 |)l if lli.'

Call I"' li' ;u >\ li\ ;i|>|il

.ii the beginning of \ ■
opex heat ; tl ' the heginti

t lit till

\ third Hound much
horl i line after i he second I ■ ■ tudy tho <
t he Bounds i he \ ibi at ion - w hieh tin
alongside cardiac i i mem

oh ■ '

Can < "i Bound

I : li.i . lm 11 round t hai i in' |

one high pitched nnd 1 1 i hei of a dull < I

■lir\ .-.I to I"- 1 1" i eault of \ ibral ioi up in th<

nli»\ nil riculiir vnlvi I i hei in I he I • I • •« •« 1 in tin

Niiddeii in systolic pressure The • 1 1 1 1 1 clement on th<

is undoubtedly of museulnr 01 igin 'I
as follows I Win n the nuriculovcntriculnr valv<
closing properly either bj di or bj pusl loop o

h pitched quality disappears, and not I
■ound accompanies tho <lnll bruit produced '
In a heart that lias b< [loss bj an ii

api n in ai '-I but Btill bcatini <lwll i

tho ound still continues to be heard for a bIio

lusclo prodix ound i

•II I !

\\ fii Mini 1 111 ■ inn' |" -i in

I

■•.in readily bo shov n to b< >\ U\ I

of the semilunar \ ah i i"|i thi

them, and tl

till IIS1HII IS fill

immediately «lisa|>i f tho '

tho apex, and il
vented from <•!•.

158 THE CIRCULATION OF THE BLOOD

passing a wire down the carotid artery. The third sound, although audi-
ble only in some individuals, can nevertheless be shown to exist by the
electrophonograph, and since it occurs at the time when the aurieulo-
ventricular valves open, it is believed to depend upon the sudden inrush
of blood from auricles to ventricles.

The greatest importance of the sounds is in the clinical diagnosis of val-
vular and other lesions of the heart, When a valve leaks, for examine,
the blood escapes past it under great pressure, and is ejected into a mass
of blood at low pressure, these being conditions which are well known
to create sounds or bruits. By examining the exact relationship of such
bruits to the normal heart sounds, deductions can be drawn concerning
the condition of the various valves.

Record of Heart Sounds

The heart sounds have been graphically recorded by transmitting them
through a stethoscope to a microphone placed in circuit with a string
galvanometer (electrophonograms). Through this circuit passes a cur-
rent the strength of which depends on the resistance offered by the
microphone, and consequently to the number and amplitude of the
vibrations of the sounds transmitted to it through the stethoscope.
There are several objections to this method. One of these is depend-
ent on the varying distance of the heart from the chest Avail, which
causes many of the sound vibrations to be lost before they reach the
stethoscope; another, on adventitious sounds arising from contracting
muscles, the impact of the heart against the chest wall, etc., and still
another on unequal resonation by the air in the neighboring portions of
lungs. To investigate the problem more thoroughly, Wiggers,37 using
anesthetized animals, has recorded the sounds by carefully stitching to
the heart (exposed through a small opening in the pericardium) a lever.
the end of which was attached to a "transmitter" consisting of a
small capsule covered with rubber dam. The transmitter was connected
by rubber tubing to a "recorder" consisting of another small capsule carry-
ing on its membrane (made of rubber cement) an eccentrically placed small
mirror, on to which a beam of light was thrown. The movements of the
beam of light reflected from the mirror, and caused by the sound vibra-
tions, were photographed. Mechanical vibrations set up in the apparatus
itself were largely eliminated by a side opening on the recorder, and the
effect of outside sounds minimized by surrounding the recorder by a
ventilated glass housing.

Although this apparatus is not free from faults due to inherent vibra-
tion frequency and resonance, the records secured by it are valuable in
showing the exad relationship of the sounds to the events of the cardiac

ill! rr\ni\<; \-

cycle. The \ ibi from the tw<

tin. ii tlir aorta / -

five to thirteen irregular vibrations, usually in I

composed of two small vibrations, the middl<

tionit, and the third of n varving numbei mail \

■

duration of the sound is

from 0 V\ n conij

160 THE CIRCULATION OF THE BLOOD

lar pressure curve, the initial vibrations occur 0.01 second prior to the rise
in pressure, the main vibrations reaching their greatest amplitude before
the sphygmic period begins, and the final vibrations occurring during
the early part of the sphygmic period and therefore just before the aortic
pressure has reached its height. The main vibrations therefore occur
<luring the descending limb of the R wave of the electrocardiogram (be-
ginning 0.01 second before its completion), the small preliminary vibra-
tions occurring during the ascending limb. When taken from the aorta,
the record of the first sound is somewhat different, there being no initial
vibrations and the main ones being of greater frequency and reaching
their maximum earlier than those taken from the ventricle. The sub-
sequent vibrations are also larger, especially when the aortic pressure
is high (Fig. 38).

The record of the second sound at the ventricle is much simpler and
usually of less amplitude than the first, consisting of two to six vibrations
lasting 0.015 to 0.056 second. They begin a short time after the ventricu-
lar pressure begins to fall, approximately at the dicrotic, notch of the aortic
curve, being completed in from 0.015 to 0.025 second after the bottom
of the notch. Their relationship to the T wave is variable. Taken from
the aorta, the record of the second sound shows vibrations of greater
amplitude and of a greater frequency than that from the ventricle.

CHAPTER XIX
THE M TRITK >N OF THE HE MM

THE BLOOD SUPPLY

In cold blooded animals, such as the I
by blood soaking into it Prom the heart chambi hich i?

form definite cavities as in the mammalian heart, bul an inl

men! of muscular tissue. In the hearts of higher animal
lature is supplied bj Bpecial arteri( coronar igh a •

amount of blood may still pass directly from the card
the musculature through the veins of Thebesiu

The relative importance of the various branches of tl >nary a '•

in maintaining an adequate nutrition of the heart lias l n Btudi<

observing the effect of occlusion of one or more of them W T P •
Occlusion of t 1m- circumflex branch of the left coronar} artery
arrest <>f the heartbeal in aboul v" per cent i
usually accompanied bj fibrillary contraction. Occlusii the ri

coronary arrested the ventricular contraction in about 20 per cent
the cases. Smaller branches may i eluded without any evid

change in the heartbeat.

These results indicate thai the capillary areas supplied !
of the coronary artery <h> n«.t freely anastomose with mother, l

are more or N-ss terminal arteries; that is. each branch supplies a dist
region of the cardiac muscle If oi > of the smaller bi
nary is occluded, although there is no imme< stoppaj

■ mi- time the area supplied by that branch usualh
gain indicating that collateral
ished I' is interesting, hoi
that anatomic studies have shown thai -tain amount

CCUr hrtv. pillar: 01 hrali.-i

• huit, from the above observations, that no adequate
becomi i through tins anastomosi

PERFUSION OF HEART OUTSIDE THE BODY

In order that the blood supply through I
ai lcipiat i-l\ maintain tl mnl nutrit

HiL' THE CIRCULATION OF THE BL06t>

conditions must be fulfilled. The recognition of these conditions lias
been accomplished by observations on the excised heart, for it lias been
Pound thai if they are fulfilled tlie mammalian heart can be made to beat
in perfectly normal fashion for several hours after its removal from

the animal's body. Indeed certain ma iiima I ia 11 hearts, such as that of the
rabbit, may be made to beat for Several days outside; the body. We ma\
Consider the essential conditions of the blood supply under four headings:

(1) the temperature; (2) the oxygen supply; (3) the pressure; and (4)

the chemical com posit ion. Successful perfusion may be performed with

artificial saline solutions (e. g., Locke's), but it is simplest in investigating

the relative importance of the above conditions to start the heart pel'
fusion with defibrinated blood.

After bleeding an anesthetized animal, such as a dog or a cat, until

no more blood can be removed, the blood is defibrinated and filtered

through gauze to remove the fibrin. The thorax of the dead animal is
then quickly opened, ligatures placed around the main arteries springing
from the arch of the aorta, a cannula with its end pointing toward the
heart inserted into the descending thoracic aorta, and the Latter cut
across below the point of insertion of the cannula. The heart is then
quickly removed from the thorax and an artificial saline solution
(Locke's) allowed to run into the aortic cannula through a side lube,
until all the blood has been washed out from the coronary vessels. Dur-
ing this operation the heart may develop a few beats even though the
solution is quite COOl. The aortic cannula is now connected with a bottle

containing the defibrinated blood diluted with Locke's solution and
broughl to body temperature by immersion in a water-bath. By means
of a suitably regulated air pressure exerted on the surface of the diluted
blood in the bottle, this is forced through an outlet at tin1 fool of the
bottle into tubing which runs to the aortic cannula. The fluid tints finds

its way into the coronary vessels; for in passing toward the heart in the

aorta il will close the semilunar valves and force its way under pressure

into tin' coronary vessels, subsequently escaping by the coronary sinus into

the righl auricle. Yvvy soon after the perfusion is started the heart

begins to beat vigorously and regularly, thus offering a suitable prepara-
tion upon which to lest the first three mentioned conditions necessary
for the nutrition id' the cardiac inuscnlat lire (Fig. 39).

If the temperature of the solution is allowed to fall considerably, the
heat becomes much slower, and if the cooling is proceeded with, the heart

will after a while cease beating altogether. If the pressure is lowered,

the beat will mil necessarily become slower but \\-vy much feebler, and

will soon cease. In general it may be said that the temperature of the

solution affects the rate of the beat, and the pressure affects its Strength,

runnel {refilling
& air vent )

Stock solution
' Diluted blood*-
a salt solution)

Metal pan
- Hot water bath

oxygen or
comprened air

i
mrl

1G4 THE CIRCULATION OF THE BLOOD

It is, however, obvious that in perfused preparations changes in pres-
sure are likely to cause alterations in rate as well as in force, unless
great care is taken to keep the heart itself as warm as the perfusion
fluid.

The importance of an adequate pressure in the coronary vessels has
been clearly brought out in certain experiments in which the beat has
been maintained for a short time by establishing a pressure in the cor-
onary vessels by means of indifferent fluids or gases. Thus, if oxygen
gas is allowed to pass through the vessels under pressure, the heart will
beat for a short time, and the same result has been observed even when
mineral oil or mercury has been perfused under pressure (Sollmann).

The necessity for an adequate oxygen supply is very readily demon-
strated. If the darker blood ejected from the right auricle with each
heartbeat is transferred immediately to the perfusion bottle, the heart-
beat will soon become feeble and irregular, to be readily restored to
normal when this dark blood is shaken up with air or oxygen.

By artificial perfusion in the manner above described, the automatism
of the heart may be restored many hours after death. Partial restora-
tion, confined. to the auricles or to that part of the ventricles lying im-
mediately adjacent to the large blood vessels, can also be accomplished
in the heart of man several days after death, provided death has not
been caused by some acute toxic infection such as diphtheria or septice-
mia. The Russian physiologist Kuliabko, has succeeded in restoring for
over an hour the normal beat of the heart of a three-months-old boy
twenty hours after death from double pneumonia, but here again the
pulsation returns only in certain parts of the heart. As will be pointed
out, the remarkable resistance of the heart muscle displayed in these
experiments has been taken as an argument in favor of the myogenic
hypothesis for automatic rhythmic power of cardiac muscle, the argu-
ment being that nervous structures could not live so long a time after
death. The fallacies in this argument are discussed elsewhere.

RESUSCITATION OF THE HEART IN SITU

A suitable intracoronary pressure is a sine qua non for the mainte-
nance of the heartbeat, and this is a fact of great clinical significance,
for it indicates that any attempts to resuscitate a dead animal are cer-
tain of failure unless the method is such as will bring a nutrient fluid
under a certain pressure to bear on the coronary arteries. Injection of
fluid, even of defibrinated blood, into a vein will obviously fail to ful-
fill this condition, for the perfusion must be made into an artery so that
the fluid is carried down the aorta and thence into the coronary arteries.

■i III. M TRITION OP l Hi Hi Mil 165

The practical question, in so far as resuscitation of the heartbeal is
concerned, i^ therefore, //""■ can wt get tl>< n< >■> ssary fluid under pt
sure into II" beginning of II" aorta? Even if we were to transfuse fluid
under considerable pressure into the aorta through the carotid artery,
it would mainly follow tin- large vessels leading away from the ln-art.
only a Fraction ofil reaching the beginning of the aorta. To compel the
iluiil to pass towards the hearl we musl introduce some obstruction to
its passage peripherally. This can be done by the injection of a consid-
erable dose of epinephrine I adrenaline in normal saline Bolution through
tin' needle of a hypodermic syringe inserted into the tubing leading
from the burette or pressure bottle to the cannula in the carotid arte
An the perfusion fluid is running in, the epinephrine injection is quickly
made, artificial respiration and cardiac massage being meanwhile prac-
ticed. In the majority of animals it will be found that complete res-
toration of the normal blood pressure can be effected by this method,
[ndeed by performing the resuscitation under aseptic conditio! s, some
animals may be permanently resuscitated so far as the circulation is
concerned, although the nervous structures, even after a few minutes
of "death," never reacquire their normal condition.

The epinephrine acts mainly by constricting the small arterioles and
thus directing the bloodflow towards the heart, bul partly also by a direct
stimulating action on the cardial- muscle. It does not, however, con-
tract the coronary vessels; on the contrary, it is said to cause tl
slightly to dilate.

THE RELATIVE IMPORTANCE OF THE VARIOUS CONSTITUENTS

OF THE PERFUSION FLUID

We can study the chemical conditions necessary for resuscitation
of the heartbeat by observing the beal of an artificially perfused hearl
while solutions of differenl chemical composition are being perfi
through the coronary vessels. At the outset we are im] i with the

fact that for successful resuscitation the organic constituents t the
nutrient fluid are of trivial importance compared with the inorganic

constituents. "With a solution containing the proper proportion of in-

janic salts, and of course an adequate supply of oxygen, the heart
o\ a rabbit, for example, may he made to continue beating i'"r -
days, h is tine that it will heat longer if some of the organic con-
stituents of the blood plasma, particularly carbohydral
hnt on the inorganic constituents aloni ability to beal a truly

remarkable.

166 THE CIRCULATION OF Till. BLOOD

Observations on Cold-Blooded Heart

The earlier experiments Cor the investigation' of the chemical condi-
tions necessary for the maintenance of the heartbeat were performed

on the heart of the frog or turtle. By perfusing either of llicse hearts
with physiological sodium-chloride solution, it was observed that though
the beat might continue for some time, yet it gradually grew feebler
and feebler, until at last it ceased altogether with the heart muscle
in a condition of extreme relaxation or diastole. If small proportions
of potassium and calcium salts (as chloride) were added to the sodium-
chloride solution, the beat was much better maintained. Doctor Sidney
Ringer proved that the optimum concentration to produce efficient and
prolonged contraction for the heart of the frog or terrapin is as follows:
potassium chloride, 0.03 per cent; calcium chloride, 0.025 per cent.
The effectiveness of the solution was also found to be increased by the
addition of 0.003 per cent of sodium bicarbonate. This acts as a buf-
fer substance (page 36), holding the hydrogen-ion concentration at a
constant level. More recent work has shown that the hydrogen-ion con-
centration of the perfusion solutions is of considerable importance in
determining the efficiency of the beat, but the optimum is not the same
for the hearts of different kinds of animal, and indeed it may differ
for different parts of the same heart.

The question naturally arises as to the relative importance of each
of the above salts; or rather, we should say, cations, since the anion,
chlorine, is the same for all of them. The function of the sodium chlo-
ride in the solutions is twofold: (1) to endow the solution with the
proper osmotic pressure (see page 4) ; and (2) to perform the special
role of the sodium ion in the origination and maintenance of the auto-
matic beat. The latter function of Na can be shown by observing the behav-
ior of strips cut out from the ventricle of the turtle heart and placed
in solutions of correct osmotic pressure but containing no sodium chlo-
ride— isotonic solutions of cane sugar, for example. They soon cease
to beat, but if a small amount of sodium chloride is added to the cane
sugar solution, rhythmic contractions return. The role of the ceilciuni
ions is almost entirely a pharmacological one. If a strip of turtle ven-
tricle which has been made to cease beating by immersion in isotonic
sugar solution is placed in a weak solution of calcium chloride before
it is transferred to sodium chloride solution, the spontaneous contrac-
tions will return earlier and continue for a longer time. On the other
hand, if more than the correct amount of calcium salt is present in the
solution, the beats will soon be found to become smaller and smaller
in amplitude, because relaxation does not properly occur between them,
and ultimately they will cease altogether with the ventricle in a condition

II! I III I

ctreme contraction, called calcium I

nia\ also be shown l>\ attempting to pc ith !»'•

serum from which the calcium has been removed Idition

sn.liuiii oxalate which precipitates il i

li BOOH C( ' . I'Ut ran 1 1 .nlily be made

adding a Blight calcium chloride

The potassium ions do nol appear, li] i I •- i ■ i n i and sodium, I

absolutely essential for x 1 » • - tnaintenai >f tin- heartbeat; al

heart of the turtle will beat for a long time when perfused with a solu-
tion containing only sodium and calcium The explanation

lit need not, however, necessarily \»- that potassium is an u
constituent "t' th<' perfusion fluid, for it may well depend on the
there is a Bufficienl Btore of potassium 1«>.-K.-.1 ..
to supply the requirements of the heart mu ir tins ion for at ■

as long as the heat unuM continue under lircumstances In any

-

know that potaasium has a profound influ<
beat, for when the proportion of it in the perfusion fluid i* incr<

beat I mes • ery bIov and th<- tone of the hearl i diminished

that is, it becomes mely relaxed tho

amounl is further increased, will verj soon come to a standstill h

• at I \ dilated or diastolic position.

The st riking antagonism displayed by these inorganii
the heartbeat has led Borne investigati • thai

sponaible for the rhythmic activity of the heart dependa on son
of chemical union occurring between the inorganic cati<

ibstani t' the heart. Union of calcium with ti

gubstance will lead t<> Bystole 01 conl »nion i

or potassium will lead t<> relaxation or <liast..

Observations on Mammalian Heart

Investigation of the efficiency
I mammalian heart has shown that the p
must be somewhat different from that u
I mighl be expected, the niosl efficient pi

in the l>l 1 serum of the particular animal v

fused Basing his proportions upon I

i Histitiniits of mammalian hi

inorganic Bolution "t" the ;" • » 1 1 « * x >. • * a

dium chloride, 0 9 i" Icium

chloride, 0.042 ] ■! sodium
\\ ; en " I »ock lution
under i>r<

168 THE CIRC1 I-ATION OP THE BLOOD

ture, efficient heating can be maintained for many hours. More recently
a solution known as Tyrodc's is commonly used. It contains a small amount
of magnesium and of phosphates. Although undoubtedly superior for
some perfused preparations, such as the intestine, it does not seem to be
in any way superior to Locke's for the perfusion of the heart. The bicar-
bonates and phosphates in these solutions endow them with a liydrogen-ion
concentration near that of the blood (slightly on the alkaline side of
neutrality), and at the same time they act as buffer suhstances.

As already pointed out, the organic constituents of such perfusion
fluids do not appear to he relatively of nearly so much importance as
the inorganic. Nevertheless it appears that a small percentage (0.01
per cent) of glucose does materially improve the nutritive qualities of
the solution, and it has moreover been shown that after a while the con-
centration of glucose in the perfusion fluid distinctly decreases. This
docs not of itself necessarily mean that the glucose is actually utilized
by the heart muscle: it might he stored away in it as glycogen. That
some consumption of carbohydrate does however occur in the heart has
been demonstrated by measuring the intake of oxygen and the output
of carbon dioxide through the lung's of an isolated heart-lung prepara-
tion perfused outside the body with defibrinated blood. By experiments of
this type the attempt has been made to show that the heart of diabetic
animals loses the power of burning glucose as compared with the hearts
of normal animals. While the experiments are very suggestive, the
results do not as yet justify us in claiming that in the latter disease the
power of burning glucose in the tissues has been materially depressed.

The concentration of hydrogen ions in the perfusion fluid has an im-
portant influence on cardiac efficiency. We also know that the most
convenient method for changing the hydrogen-ion concentration of such
fluids is by altering their tension of carbon dioxide (see page 354). In
a heart-lung preparation,* such alteration in carbon-dioxide tension can
very readily be brought about by altering the percentage of this gas in
the air with which the lungs are ventilated. To measure the efficiency
of the heartbeat in such an experiment, it is convenient to enclose the
organ in a cardioplethysmograph, the tracing of which will tell us the
degree to which the heart is contracted or relaxed, as well as the output
of blood per minute. By increasing the tension of carbon dioxide, it
has been found in such experiments that the dilatation of the ventricle
is encouraged, so that the heart with each beat discharges a larger quan-
tity of blood (Fig. 40). When defibrinated blood is used the optimum

*A heart-lung preparation is one in which both heart and lungs arc perfused outside the body,
the vessels being suitably connected to maintain a continuous circulation.

IKIIIm\ 01 Ml! II

pressui e or tension "!' carbon 'li<>
.iikI l'» per '••lit •-!' ;iii atmosphi

That tin- effecl <■!' carbon dioxide in
heart betv een I dependent upon I

centration of the perfusion fluid has l"'«'!i Bhown

ilts iii experiments with perfusion fluids I h diflf< • I anti-

tities of weak nonvolatile acids hav< added. I

?*■

■-• ►- •>••*- ■» »«

.>, . .

l

I

■V-.u '-»■

J"i i_

'j

■

. ■

•

of practical importance because of the light which I

lardiac failure following upon conditions in which I
removal <>\ carbon dioxide from th<
• tilation of the lungs Yandell II son has

gica :k may !"•. partly al least, d

"washing out" of carbon ili<'\i'l<- from ti .1 by the d;

often incident to the administration of

CHAPTER XX

THE PHYSIOLOGY OF THE HEARTBEAT

THE ORIGIN AND PROPAGATION OF THE BEAT— THE PHYSIO-
LOGICAL CHARACTERISTICS OF CARDIAC MUSCLE

The origin and propagation of the heartbeat are studied on the excised
heart of a frog or turtle, or on the mammalian heart by perfusing it
under suitable conditions, which have already been described. The results
obtained on the cold-blooded heart apply more or less directly to the
warm-blooded. In the first place it is clear that the rhythmic contrac-
tility of the heart is not at all dependent upon the central nervous sys-
tem, for if it were so, the excised heart could not continue beating. This
fact does not, however, necessarily imply that the beating power is in-
dependent of nervous structures, for in the heart itself an extended net-
work of nerve cells and connecting nerve fibers can readily be demon-
strated. It might quite well be the case that the rhythmic beat is de-
pendent upon the transmission to the muscle fibers of the heart of
impulses generated in the nerve cells and transmitted along the nerve
fillers of this local nervous system. Such is the neurogenic hypothesis of
the heartbeat.

On the other hand, it may be that these nervous structures are not at
all responsible for the origination of the beat, but serve merely as sta-
tions on the pathway of the nerve impulses, transmitted to the heart
from the central nervous system along the vagus and sympathetic nerves,
for the purpose of altering the rate of the heartbeat so as to adjust it
to the requirements of blood supply in the various parts of the body. In
such a case the rhythmic power would reside in the muscular tissues of
the heart — that is, each cardiac muscular cell would have the power,
not merely like skeletal muscle of contracting in response to a stimulus
transmitted to it, but also of originating that stimulus within itself.
This is the myogenic hypothesis. Much controversy has raged around
these two hypotheses and although space will not permit a detailed study
of the question, it will be necessary, on account of the great importance of
the subject from the physiological standpoint, briefly to review the main
arguments of each school of thought.

There is no piece of evidence offered by the advocates of either tin*
neurogenic or (lie myogenic hypothesis that can, taken singly, be con-

170

THE PHY81 \ ■ 171

sidered as absolutel) conclusive AlthouRl

at firsl sighl appear t<> be conclusiv< . • •

subjected to a closer scrutiny It is o

evidence for and against each view thai we shall In- in a

to any conclusion, and • then it will be plain thai

be only tentath •

Myogenic Hypothesis

Taking firsl of all the evidence in Buppoii of the my< g
the following Btanda oul mosl prominently:

1 The heaii beats in the embryo chick b< any n<
grown into it. and no1 only this, bul if porl

moved from the embryo and placed in l»l 1 plasma, ontinue

ting for many days It has also been observed tl a1 may

off from this mass of cardiac muscle and undergo multi]
differentiation, so a^ to produce isolated musch a which exhibit

rhythmic contractility. The rebuttal on the part
ihis apparently unassailable « - x i « that, i

bryonic muscle cells may exhibil the power of rhythmic i

does nut mean thai the fully developed muscle i arily 1

such power. In the eary stag inic development, il

evidenl thai the functions which in the fully developed animal .
to various Bpecial organs and ti should be performed b

having Beveral such functions in common. The muc
for example, maj to Btarl with be power no1

tracting bul also of initiating the contraction. It maj
tly nervous in character and that only later, when the di
mmmated, does the power of rhythmic contractioi
gated to the nervous element and tl..
muscle itself.

2 The aervous structure in the I aaj be damaged -
chanical means or by drugs withoul apparently int< with
power of rhythmic contract i

it is possible to d ml a c< nsid< i amoui I

withoul a: the beat, and in all auin

of atropine, w hich pai the p

nervous bj stem m •• page 22< ml in I

tricle in such h<

I n. I>\

and although a few n<
withoul virtue

made to contract rhythmically !•> p<

172 THE CIRCULATION OF THE BLOOD

solution under pressure and starting the healing by application of elec-
trica] stimuli. Isolated strips of ventricular muscle, in which also no
nervous element can be demonstrated, may under favorable conditions
be caused to beat quite regularly it' supplied with proper nutrient fluid.
The rebuttal of this evidence is twofold: In the first place, skeletal mus-
cle itself under certain conditions, such as exposure to solutions con-
taining an excess of phosphate (Biedermann's), may exhibit rhythmic
contractility, especially on cooling, which indicates that exhibition of rhyth-
mic power in isolated portions of cardiac muscle need not mean that under
ordinary conditions such power is responsible for the normal heartbeat.
In t lie second place, it is pointed out that although we can not reveal
their presence by present-day histologic methods, this is not conclusive
evidence that the heart-muscle fiber may not possess some nervous struc-
tures capable of functioning as nerve cells.

The heart even of mammals can be made to continue beating for sev-
eral days after excision from the body. The nerve cells, as we know them
in the central nervous system at least, can not, on the other hand, be
made to functionate for more than a few hours after death. Therefore,
it is argued, the heartbeat in surviving mammalian hearts can not de-
pend on the nervous structures. The argument is however easily refuted:
on the one hand, Ave do not know that the nerve structures situated
peripherally in the heart muscles are of the same viable nature as those
composing the central nervous system; and, on the other, the survival
of the heart may in itself be sufficient to maintain around the nerve cells
embedded in it a nutrient environment which is much more physiological
than that which Ave can supply in artificial perfusions of surviving
nervous tissues.

4. Circumstantial but nevertheless strong evidence is furnished by
the fact that many other varieties of involuntary muscle are endowed
with rhythmic contractility; thus, the muscle of the intestines, of the
ureters, of the bladder, of the uterus, of the blood Aressels of certain
animals, and of the lymph vessels in the so-called lymph hearts, main-
tain rhythmic contractility after isolation from the animal body. The
rhythmic power seems in certain of these cases to be independent of
nervous control.

Neurogenic Hypothesis

In favor of this hypothesis the following evidence is offered:
1. The heart of certain animals — of Limulus, the king-crab, for exam-
ple, is definitely dependent for its rhythmic contractility upon neigh-
boring nervous structures. The heart of this animal is a tubular sac-
culated organ, and along its dorsal surface there runs Longitudinally a

'Mil. I'll

iii pai t direcl l;> t«> the a n< 1 in p J l R<

m<>\ al of this n

heartbeat ; 1 1 1 « - heart

skeletal muscle, Id appraising the

noted that although by Btimulal

heart •■an be i»i I, the <"in racti(

it i> not rhj thmii
the various physiolo properl tnuscli

if. I it \\ ill !»'• found that in all --i' thi

muscle behaves, not li irl mus animals, but lil

of skeletal muscle. This evidenci . while

that the heart «'!' Limulus depends for ita rhythmic
boring nei ictures - not .1 the assumption that tlii> will 1"'

• -• in the I ' animals having differenl pi

2 The disposition <»t' the nervi uctures in tl

the fi"L.r and turtle, I he deg

.

rhythmic po the diffei

rhythmic power i^ manifested by the Minis and the
•ri<-lr at the IuiIIiun arteriosus. In the formi
structu prominent ; in the lal I

be d<
In i : place, it may merelj

atrud ■ 'I the >l«'\ elopn mic p

The unequal rhythmic powers may depend primarily
iu Btructure of the muscle fibers th<
hown

I
. loped »n an<l their i

ular ; in Bhort, tl h-Ii more eml

■

I a jury hai turn fl

acter, it would no

174 THE CIRCULATION OF THE BLOOD

prove))." But it is likely that 1 lie majority of the jury would vote
in favor of the myogenic hypothesis. Probably the safest viewpoint to
take at the present time is that the power of rhythmic contraction is
inherent in the cardiac muscle fibers, being most highly developed in
those of the venous end of the heart, and least developed in those of
the arterial end. Such a conclusion does not deny. to the nervous struc-
tures of the heart the power under certain conditions of also assuming
rhythmic activity. In one case at least — namely, the heart of Limulus —
we know that this is so. For some reason in this animal the cardiac
muscle fiber has lost its inherent rhythmic power, and is now dependent
for its activities upon rhythmic nervous discharges transmitted to it
from the neighboring nerve cords, a condition which is paralleled in
the higher animals in the innervation of the respiratory muscles. The
respiratory center rhythmically discharges impulses to the muscles, which
are quiescent in the absence of these impulses.

The Pacemaker of the Heart and Heart-block

In a volume of this nature, devoted primarily to the practical appli-
cation of physiology, the discussion of these problems may seem a little
out of place, but that this is not the case is seen when we consider that
the experiments upon which the various points of evidence depend
bring to light facts of the very greatest importance in the study of the
physiology of the heartbeat. One fact which stands out prominently
is that the greatest rhythmic power resides in the basal portion of the
heart — that is, in what corresponds, in the more primitive hearts, to the
sinus venosus.

Although the muscle of the entire heart possesses rhythmic power, it
does not do so to an equal degree; in the sinus the rhythmic power is
extraordinarily developed, while in the bulbus arteriosus it is scarcely
recognizable. This observation suggests the possibility that the sinus
may dominate the heartbeat — that it may be the "pacemaker" for the
heart as a whole. The most natural method for demonstrating such a
possibility would be to observe the effect on the heartbeat of some block
between the sinus and the rest of the heart. Such a block can be intro-
duced in the heart of cold-blooded animals by local compression around
the various junctions. If a thread is tied around the sinoauricular
junction, the sinus will go on beating uninterruptedly, but the auricles
and ventricles — that is, the greater part of the heart below the ligatures
—will cease beating, sometimes entirely (Stannius' ligature). After a
while, however, the heart below the ligature will usually begin to beat,
but at a rhythm which is slower than, and independent of, that of the
sinus.

'1111 l'HYSHU.<*

The • menl can \»- still I.. •

shaped clamp Qi ell'a clamp h' this ia app
can be pinched either a1 the Binoauricular junction ilo-

ventricular, it will \«- found that, .

I lllci

I

pinched, the portion of i !>«• hearl below fails to beat quickly
above the clamp Fig J'- Thia is known as partial heart
the degree of tin- block is indicated by the numerical ex to 1,

:: to 1. 1 to l. etc., meaning that tin- sinus is beating either V
quickly as tin' ventricle, or three times, <>r four tim<

■

Similar conditions of heart bl<
the cardi

Further evidence that tl ua doiuii ;t in I

176 THE CIRCULATION OF Till: BLOOD

cold-blooded animals is Furnished by observing the effects of local heat-
ing or cooling of the various parts of the heart. In all rhythmically
acting structures it is well-known that heat increases the rate of the
rhythm and cold depresses it. If we locally warm the region of the
sinus, as by holding a heated wire near it the whole heart will immedi-
ately beat quicker; but if we locally heat the tip of the ventricle, no
alteration of rhythm will be observed to occur (Fig. 43).

The establishment of the fact that the sinus dominates the heartbeat
— that it is the pacemaker of the beat — raises the question as to how the
impulse originated at this place is transmitted over the rest of the
heart, and here again a neurogenic and a myogenic hypothesis have to
be considered. Before going into this question, however, it will be well
for us to consider briefly the manner of response of cardiac muscle
fiber to a stimulus, because the behavior of cardiac muscle under such
conditions is considerably different in many regards from that of skel-
etal muscle, and it is to these differences that many of the peculiar
alterations in the beat observed after interfering with the conducting
structures between the sinus and the rest of the heart, are to be ex-
plained.

The Physiological Characteristics of Cardiac Muscle

It is necessary to bring the heart into a quiescent state in order to
investigate the properties of its musculature. This is accomplished by
the application of the Stannius ligature between the sinus and the auri-

1....]

Fig. 44. — Frog heart showing the position of the first and second ligatures of Stannius
(Hedon): r, auricles; 2, sinus; 3, ventricle. It is the first ligature which brings the heart
to standstill.

cles (Fig. 44). After tightening the ligature the auricles and ventricles
become quiescent, and by observing the effects produced by the appli-
cation of electric or other stimuli we can compare the behavior of the
cardiac muscle with thai of skeletal muscle similarly stimulated. This
comparison is made because of the assistance which it offers in compre-
hending the properties of cardiac muscle. As a matter of fact, recent
investigations have shown that the differences between the two types of
muscle are not fundamental, since under certain conditions the one may

Till* I'll II KT

177

made i" behm «• I i K • - the othi l
ence or absence of anastomosifi In

I. When eleel i i<- Rtimuli of \ ar\ .
muscle, the c etion •

tin- strength <>i' 1 1 1 • - latter until this has l>ec(
tlif maximal response I4- ••li«,iic.| in cardiac m
an entirelj different result is obtained, for tl
produces anj response at all, prod that is mi

height of contraction is the same as it would hi
stronger Btimulus been applied. Expressing th t in u-' i

w »■ may saj thai in cardiac mus

■

.

>m<;/ i letal, iIk- «•!'•'

traction, is pi ional to tl tioi

times know 11

I f maximal Btimu

• ime to tal mu

sik ■ • 1 1 1 1 _r stimuli; il about '

w ti if)i for Borne coi
each stimulus
first few con trad

ilra

178

THE (IKCI'LATION OF THE MEOOD

staircase with gradually diminishing steps will be produced. If we repeat
this observation with cardiac muscle, we shall find that the staircase
phenomenon or treppe, as it is called, is very pronounced ; and moreover,
in obedience to the all or nothing principle, the treppe is obtained in
cardiac muscle whatever may be the relative strengths of the stimuli
applied to the heart, provided always that all of them are effective;
whereas in the case of skeletal muscle it can be demonstrated only pro-
vided the stimuli are of equal strength (Fig. 46).

3. If an effective stimulus is applied to a skeletal muscle while in process

Skeletal muscle

Cardiac muscle

Fig. 4C>. — The effects of successive stimuli on skeletal and cardiac muscle to show the prominence
of the staircase phenomenon, or treppe, in the latter. (From T. G. Brodie.)

of contraction, as in Kflpu.i„o to a preceding stimulus, the second stimulus
prolongs the contraction produced by the first one. If, however, the second
stimulus is applied during the latent period* of the first one, it will have no
effect — that is, the muscle during this period is refractory.! From these
results it follows that stimuli succeeding each other during the contraction
period will, in the case of skeletal muscle, cause a continuous contraction, or
tetanus, as it is called, because the contraction produced by each stimu-
lus will add itself to that of its predecessor before any trace of relax-
ation has set in. If, however, the second stimulus is applied so late in
the contraction period of the first that time is not available for the latent

*By "latent period" is meant the period after the moment of application of a stimulus during
which no effect of that stimulus is observed.

tBy "refractory period" is meant the time following the application of a stimulus during which a
second stimulus develops less than its full effect or no effect at all.

•III! I'HYSIOI.O Till

.■•I to expend itaelf, then <>l<\ iousl;
curred before the elfe

anus w ill be incomplete I ill be

panying tracings I ig IT

■

•

-

In tl •
different, for //"

eoni i .- thai stimul

duced bj a pre* ioua stimulus I

1M)

THE CIRCULATION OF I'lIF F.FOOh

have one until the muscle lias reached the full extent of its contraction
ami is about to relax. Since a latent period must supervene upon the
application of this second stimulus, it follows that no complete fusion of
the contractions is possible. Complete tetanus therefore, does not occur
in cardiac muscle, however frequently the stimuli may be applied (Fig.

47).

The refractory phase is a property of extreme importance in under-
standing many of the peculiar irregularities observed in cardiac action.
If we observe the effect of stimuli applied at varying periods after the

pig. 48. — Myograms of frog's ventricle, showing effect of excitation by break induction
shocks at various moments of the cardiac cycle. The line O indicates the commencement of
all the beats during which the shock is sent in. It will be noted that in /, 2 and J, the heart
is refractory to the stimulus. The signals indicate the moments at which the stimuli were ap-
plied. From 4 to 8 the heart reacts by an extrasystole, after a delay, which is progressively less
the later in diastole the stimulus enters, as shown by the sections shaded obliquely to make them
more conspicuous. The extrasystolcs increase in height from 4 to 8, each being followed by
a compensatory pause. ("From Fuciani's Unman Physiology.)

termination of the refractory phase of a previous stimulus, Ave shall find
that the height of the extra contraction is directly proportional to the
time after the end of the refractory period at which it is applied. If a
stimulus is applied at the very beginning of diastole, the extra contrac-
tion will he small, whereas if it is applied at the end of diastole, the
extra contraction will be at least as high as thai <>f the preceding. It
may he higher hecanse of the treppe.

PHYSIO 1*1

These obsen ations enable
plying

pha ' • Durii

tory, in) effect is produced by th< • b Btimulut
extra systoles \ •. 1 1 i • ■ 1 1 are pi ely mo ter in

diastole the} occur, follow the application i h stimuli,

suit- ... far exactly like those obtained \\\\\i a qu Bui

.-unit In- r phenomenon now becomes evident; namely, I ollowing •
extra Bystole there is :i compensator} pause in the action of I
of such duration that, when the nexl natural I"
practically al the same time .is it would ha irred

stimulus been applied. This will !>.• apparenl from th<
diagram Fig I 8

|- should !'<• noted thai the refractor} period atly <limi:

raising the temperatui the heart, rndeed, und<

and with Btrong stimulation it may be possible to produce an aim
compli ■ ■ tanus

The importance of knowing the above fad that

enabled to explain the peculiar manner in which the ventricle
to stiiiluli transmitted to it from the sinus and tin* auricle Tl •■ m
lature of the auricle and ventricle of the mammalian heart •
continuous Bheet, but is 31 ted by b Bpace at the auriculov<
junction, across which, in specially organized structures, tl •
auricle is transmitl tricle. Sometin timuli

frequent that the ventricular muscle is unable to res
lus transmitted t" it. with the result that marked irregularities in c

■timi mi ISO . In this wa\ certain of th<

larities ol i in man ran be explained. Thus, the Bo-callod

• minus is due to ever} second beat ;

• is therefi aerally weaker than the p

ma I beats, and it is ;ilm"st always followed b} .1 rum;.
the inters

iond beat is diminished it

CHAPTEB XXI

THE PHYSIOLOGY OF THE EEARTBEAT (Cont'd)

THE ORIGIN AND PROPAGATION OF THE BEAT IN THE

MAMMALIAN HEART

As h;is been shown in tlic preceding chapter, there is no doubt thai
in the cold-blooded heart the beat originates at the sinus venosus, whence
it spreads to the rest of the heart. Very strong evidence has also been
presented to indicate that the beating power is inherent in the muscle
fiber itself and independent of nervous structure. This would suggest the
further possibility that the structures through which the beat is propa-
gated arc the muscle fibers and not the nerve fibers — in other words,
that the propagation of the heartbeat, like its origination, is myogenic
rather than neurogenic. Direct proof of this hypothesis is readily fur-
nished by numerous experiments, among which may be mentioned mak-
ing interdigitating cuts across the heart, or excising a ribbon of ven-
tricular muscle by an incision simulating the walls of Troy. In both
these cases the beat will be found to travel from one end of the muscular
band to the other, although it is evident that all the nerves proceeding
from base to apex of the heart must have been severed. Of course this
evidence is not irrefutable, for it might be argued that there are nerv-
ous structures disposed in the form of a plexus continuously all over the
heart, and that some branches of the plexus remain uncut in the above
experiments. It is only in the heart of Limulus that undoubted evidence
exists that the beat is transmitted by nerves, but as Ave have seen, this
heart in all its properties is probably the proverbial exception which
proves the rule. The balance of evidence stands in favor- of the view
that the propagation of the beat over the cold-blooded heart is myogenic
and not neuros;enic.

■ ^>

CONDUCTING TISSUE IN MAMMALIAN HEART

When we at I cm pi to investigate the problems of the origin and propa-
gation of the beat in the warm-blooded heart, many experimental diffi-
culties of course face us. In overcoming these, the first thing Ave must
do is to establish tin1 structural relationship between cold-blooded and
warm-blooded hearts. In the embryo of both classes of animals the

182

nil i-m.-K.i.

t arises as tii> lied eardi

diverticula jttom ou1 from the walla of this tub<

In t he comparath ely simple
siti" the auric

more or less <\ idenl e\ en in the full
in 1 1 1 • - the auricli - 1 1g i'1 ; bul in t li-

mammalia it is impossible bj superficial examination
remains of the primith iia<- tub< M

ti"»ns duri have, ho show n thai il

jtructu I of t i

nt from that of tlr irt, and d

TH

as would indicate n<>t onlj thai it is derived from

tube, bul ;iIm> thai it is the main pathway which

transmitted.

I his primil much ;

giona than in others, 1 1 * • - firsl portion
known ;is the of S

This Btructui >und .it ti

ttiin on the riu'lit Ride and
of peculiar small primitive cells and fil
a bum iliar t.

w here, near the union of the •

184

THE CIRCULATION OF THE BLOOD

valve, it bifurcates so as to send a branch down each side of the septum
immediately below the endocardium. Each main branch, as it proceeds
downward on the septum, divides up into an intricate system of smaller
branches, which become reflected over the inner surface of the ventricles,
where their existence has been known for sonic time as the so-called

Fig. SO. — Dissection of heart to show auriculoventricular bundle (Keith); 3, the beginning of
the bundle, known as the A-V node; _', the bundle dividing into two branches; 4, the branch run-
ning on the right side of the interventricular septum. (From Howell's Physiology.)

Fig. 51. — 1'hotograph of model of the auriculoventricular bundle and its ramifications, con-
structed from dissections of the heart (Miss De Witt). All of the branches in the left ventricle
arc not included. (From Howell.)

Purhinje fibers. The filters ultimately end in dose association with the
papillary muscles. The node and main bundle and the two branches
before they have begun to divide are surrounded by fibrous tissue, and
they seem to have a liberal blood supply. It is of interest that they con-
tain a high percentage of glycogen. In the human heart the auriculo-

1111 III'.

• ricular node and bundle m< ul 15 niiu .
J in in. in u idth.

The real <•!' the tissue i n the auricles and venti

in nature, although other inections lil<<- th<

bundle have been described by

/ ral . runs bel w een the righl auri<

the righl ventricle.

Another, bul much Bmaller, n similar embryonic card

more recently been discovered bj l\«iili ;ni<l Flack in
the auricle which correspond anatomically t<> tin

cold-blooded animals that is, in the area lyii
ings of ' he venae cava; and ai ound tl Po be

explicit, tliis tissue lies "in the buIcus terminalia j
formed by the junction <>r the upper Burfaci
with the Buperior \ ena ca^ a. "' Tl

is mon r leas club-shaped, the blunl end of il iub

shown in the accompanying figure Fig 52 [1

that there is no direcl connection visible b.-tu .•.•!! th< -

auriculoventricular nodes Pig 5 ;

Another anatomic fa< in the a mpanyii

the disposition of the muscular li:

bundles in ;i peculi n-shaped manner from a point im-

mediately below the sinoauricular n< •«!.• t.» all p

the right auricle. This poinl has I n called I •»»*•

.v the termination of the venae cava?, the muscle fibi
or less circularly .

Saving become familiar wiili the disposition in the mi
uf the j>riiniti\ <• cardiac tissue, along which in the heart
animals we knov that the heartbeat spreads, we may nov p

• hat this tissue
origination and propagation of the beat in the

igin <>t" the beal in .i i
it is of course impossible to tell wl

i. lu>\\ ever, it « ill contin
dies it u ill be observed 1
ricular ii, and pai

Biderable tin

ultii){iim i is situ.ii< il in i

sinoauricular nod< Tl • ' I i th<
tracting do< a i

which the beat

• uf the am

186

THE CIRCULATION OP THE BLOOD

longest time after death. Although the observation does not enable us
to determine exactly where the heartbeat originates, yet it makes it
very probable that this is somewhere in the auricles; a conclusion which
is borne out by many other pieces of evidence, such as those obtained by

Fig. 52. — Diagram of an auricle showing the arrangement of the muscle bands; the concen-
tration point (C.P.); and the outline of the S.A. node {S.A.N. ). The diagram is to scale, and
illustrates by the circles and connecting dotted lines the method of leading off by paired contacts
and the subsequent orientation. (From Thomas Lewis.)

, Auricular appendage
.--Sinoauricular node

Auriculoventricular node
Auriculoventricular bundle

Right a left ventricular
bundles

-Musculi papillares

Fig. 53.— Diagram to show the general ramifications (if the conducting tissue in the heart of
the mammal. Jt will be observed that there is none of this tissue between the sinoauriculo- and
auriculoventricular nodes.

the study of polysphygmograms (page 273), of electrocardiograms (page
266), and of observations on the heart during heart-block (page 270).
Our problem therefore narrows itself down to determining the exact
point of the right auricle at which the beat originates.

l III PH\ ill HI 1-7

SITE OF ORIGIN OF THF BEAT

The working hypothesis from which w<
problem is thai the beal orig in the ! t<>

[»ul this to the ■■ irious methods have 1 1 \\

or < ling "i- injuring tin- node and nol

Such procedu eatly affi

produce no change when applied i«» other pari I »■

termination of tin comparative rhythmic i"

diflfere the auricular walls. II I in tl

from the region of the i n »< l.-. Determination

ometric <• u r\ es of the relal ion of tl

impulse 1 1 nil t h. ^<- methods the resull

in the sinoauricular node, bu1 on
tance in connection \\ ith the ii
man. it is particularly with the resull of the third
that \\ >• w ill concern «>ir

Evidence Furnished by Studying the Current of Action Which

Accompanies the Heartbeat

start with, it is .-ssriitial that w >- ma ith

nethods employed Th<
follov s w | en a • ction p

mediately preceded by a change in electrical pol
detected bj means • 1\ anometi I with 1

ailed nonpolarizable electro I

and must nol \ ibl

to p i nerallj in use toda;

Einthovi n. h <\ from 1 1

ployed in physical laboratories in that tin
through a foil of w in
Bilverized quartz thread ^i^ i in tl

.■xists between tin- two opp
The Btring is thus surrounded on all • j innui

ending betv e< n tin- tun: v.

small, p tring, it wi

OM n. ami tli. - ith tl

W ill cans.- the
st i ■ light, ami i*

ted on .i mo\ in _
suitable holdi I
in plac<

1SS

'NIK CIKCt'LATION OF Till-: BLOOD

trie currents set up by the contact of metal with the saline constituents
of the muscle juices.

If avc connect a galvanometer by means of nonpolarizable electrodes
with two parts of a denervated muscle (the curarized sartorius of the
frog), it will be found that a current is sot up whenever a wave of con-
traction passes over the muscle from one end to the other. The part
which first contracts becomes electrically negative to the rest of the muscle,
l»ut as the wave of contraction passes along it, the "negativity" de-
creases at the end at which the wave started until, when the wave has
reached the middle of the strip, neither end of the muscle shows any
difference in potential, so that the string comes back to a position of
rest. However, as the contraction wave reaches the farther end of the
muscle, this lead in turn becomes negative, and the string swings in the

d If-

Fig. 54. — Diagram to illustrate the development and spread of the wave of negativity in a
strip of muscle (curarized sartorius) when stimulated at the end (/'). The shaded portions show
the position of the negativitv. The portion of the curve drawn by the deflections of the galvanom-
eter at each stage are shown at the right (a, b, c, and d) . (After Lewis.)

opposite direction (Fig. 54). From this comparatively simple experiment
it can be seen that a muscular contraction wave arises at the electrode which
is negative first, and that the movement of the string of the galvanometer is
most marked — that is, the deflection is greatest — when the two electrodes
are applied at the extreme ends of the muscle. When they are brought
closer together, the initial deflection becomes much less marked; in other
words, the amplitude of the negative wave is greatest when the time
interval between the receipt of the excitation at the two contacts is
greatest.

The application of these facts t" the study of the initiation of the heat
in the auricle requires that we should consider another proposition:
namely, if a pair of contacts are arranged in the center of a circular
sheet of muscle and the edge of this sheet is stimulated at different

Mil I'll

i he amplitude "i deflection
pair <•: etH « ill t

points of stimulation, for under 1 1
itesl possible difTe

the wave to reach eacl ntacl

Bearing I principles in mind, we may i

I When tv <> eh applied ;it difl

ricle, the amplitudi

In I bj each heartbeal i« .vhen the lit

trodes m the iricular i make I

movemenl of the string musl be pi iphed in the n

described, the resulting tracing being called '■

the experiments with the circular sheet of m lluded to

thai the Rtimulus i<» produce this resull musl havt
borhood of ' he nod< 2 I f one elect

her electrode is moved aboul from i»'
auricle, the deflection being noted
on the node ^n ill always be found to I
This, however, will nol !»•■ the I both ele

..ii other parts of tl><- auricli

\ shall Bee immediately, the current

In-art may be re 'ded bj connecting a galvam

of the body; for exampli the righl fore limb and I

limb. <>n the eleel liogram thus obtained a

of w hich, «-all<'<l the P wi ly be

rHiiiractn.n of the auricli -_' If

■us with thus.' obtained during

sed by applying ele stimulation to

found that the ele the

normal curve onlj when the stimulated
the Binoaurieular nod< In other
applied to the sinoauricular node tl
When the appendix <>r th<
diHtorted although the other w

\ B taking eh
<>n the auricle and i
limb lead tal
the tin

lship t>. tin' r

■

190

Tin: < n;< i lation ok tiii: blood

when one electrode is over the upper end of the sinoauricular node, and
thai in other regions of the auricle it always appears at a later interval.
Further details on this subject will be found in the papers by Eyster and
Meek8 and in Lewis monographs.

Frequently, in taking electrocardiograms from different parts of the auricle, it is
found tli.it cci tain of the curves show small waves of positivity below the line of equal
potential preceding the main wave of negativity. These initial deflections are most
marked when both the electrodes are far removed from the sinoauricular node — for ex-
ample, when they are placed on the auricular appendix; but they are never present when

Fig. 55. — Simultaneous electrocardiograms to show the cause for extrinsic deflections. The
upper curves are from the appendix and the lower ones from lead II. The chief or intrinsic
deflection (Tn) is seen to disappear in the right-hand appendix electrocardiogram, because the
base of the appendix has been crushed. The extrinsic deflection (Ex) remains, as do the ven-
tricular deflections (J1 J"-). (From Lewis.)

one of the electrodes is placed on the sinoauricular node itself. In other words, curves
taken from leads at a distance from the sinoauricular node are more or less composite
in form, being made up partly of the main deflection due to the arrival of the excitation
and partly of the secondary deflections dependent upon extrinsic influences acting on
the electrodes; that is, the electrode picks up electric discharges from distant areas of
muscle while these are in a condition of contraction (Fig. 55). From these considera-
tions it follows that the intervals between the intrinsic and extrinsic deflections
should be longest in leads that are farthest from the node, and gradually become
less as one of the contacts approaches the node, until over this structure the ex-
trinsic deflection is no longer recorded. Such has been found to be the case. (Lewis.)

CHAPTER XXII

Till. PIH SIOLOGY OF THE HEAR*] BE \ I I

THE ORIGIN AND PROPAGATION OF THE EEAT (Cont'd) —

FIBRILLATION

Mode of Propagation in the Auricles

Prom the mass of evidence we have little doubl that tl
originates in the sinoauricular node, and the <i"'
as tu lit.w the beal is propagated over the remaindi
into tli<- ventricles. Regarding ti Ration

auricles, two possibilities exist: I it ma) Bpread uniforml)
muscular tissu.- of the auricular wall until it reach
uiar node, or 2 there may be laid down between th< auricul

the auriculoventricular node a special strand of highly cond
It is no argumenl ngainsl this second possibility thai
have been unable by histological methods to differentiate any suel

ttl! I

There i^ considerable practical importance attached
these questions, particularly with I to t h.- caui

of cardiac arrhythmia, Buch, for example, as that kno*
Tims, it is evident that if the beat is transmitted uniform!)
muscular tissue of the auricle, then the whole auricle will bav<

•.-.1 before the beal 1 ched the auriculoventriculai

which it is then transmitted t<. tin- ventricles On tl

■ should travel between th<- two nodes i
then the impulse will have arrived at the auriculovei
tin- auricle has coi Is a mal I is

.is to \\ hich of these two >

vidence Beem rmer

uniforml) the musculai

The methods emp d atta<

the \m th..sr described abo

the other tin- indin cl In I
placed on the aurii
auricular node The I \\ 1» i«*li th<

<-<»ir -h pair u hich is ]»•

192 Till CIRCULATION OF THE BLOOD

rately determined Erom the galvanometric record. The exact distance be-
tween the contact and the sinoauricular node is then measured and from
the data the average transmission time is estimated. From his results
Lewis' concludes thai the transmission rates are uniform from the node
to all parts of the auricle, a\ it li the exception of the superior vena cava.
in which the rate is considerably lower. One thousand millimeters per
second represents very fairly the average rate at which the excitation
wave travels. On the other hand, Eyster and Meek8 state that the wave
is propagated throughout the sinus node, and that it spreads to the
contiguous vena? cava? and to the auriculoventricular node with con-
siderable rapidity, reaching the mouth of the superior vena cava in 0.01
second, whereas its passage to the auricle itself takes 0.02 second. There is
therefore a delay in the passage of the wave to the auricle, which indi-
cates that the excitation must spread to the auriculoventricular node be-
fore involving the right atrium. These authors conclude that "this leads
to the inevitable conclusion that the cardiac impulse spreads to the ven-
tricle and to the right auricle by different paths, and does not pass to
the ventricle through the auricle, as ordinarily stated."

In the second, or indirect, method, the onset of the negative wave from
different leads in the auricle is compared against a standard. For the
standard Eyster and Meek have used the record of the mechanical sys-
tole of the auricle, but the interpretation of the result is extremely dif-
ficult on account of the rate at which the changes are occurring. Lewis,
on the other hand, has used the standard electrocardiogram for purposes
of comparison.

Mode of Propagation of the Beat to the Ventricles

After reaching the auriculoventricular node, the beat is transmitted to
the ventricles along the auriculoventricular bundle — a fact which has been
most clearly demonstrated by the experiments on // cart-block. We have al-
ready seen (page 174) that although each chamber of the heart of a
turtle or frog has a rhythm of its own, this is much more pronounced at
the venous end of the heart, and when the transmission of the beat to the
ventricles from the auricles is obstructed or blocked, as by compression
or partial cutting at the auriculoventricular junction, the ventricles,
after coming to a standstill for a time, subsequently contract with a
rhythm which is entirely independent of that of the auricles.

In the mammalian heart the same results may be obtained by arrang-
ing a clamp so that it compresses practically nothing but the auriculo-
ventricular bundle (Erlanger.) If the compression is extreme, the
rhythm of the ventricles is finite independent of that of the auricles, but
if it is only partial, the ventricular systoles follow regularly every sec-

I 111 fir. \ 01 i HI in IBTBJ a l

ond, third, or fourth auricular contraction, i rach a eompleto

partial heart-block has been instituted, tin- clamp ii rem t will

usually be found thai the heart-block disapp< and the auri
ventricular contractions fall back into their usual sequence The im-
portance of tliis discovery, apart from its physiological in
the fad thai it is exactly duplicated in <

tracing of the radial artery is compared with »f the jugulai

iu certain types of heaii disease, it will be found thai tin- auric
ing two or three times more quickly than the venti In man]

thesi - it has I a t*iiiunl on autopsy that definite lesions often

litic iu nature involve the auriculoventricular bundle, In
however, such lesions have no1 been disc mes the bun<

is v,, severely diseased thai the block is complete, the venti
tracting quite independently of the auricle Stokes-Adams Bynd
In Buch cases it is assumed thai the 1 » « - ; 1 1 originates in the uninjured p
of the bundle below the seat of the block. It should be pointed "ut h<
however, thai all cases of slow pulse in the arterii not i rily

dependenl upon heart-block, but may depend upon a slow l..
auricle itself. This is called bradycardia.

9 imetimes after complete destruction of the auriculoventricular bun-
die the heat continues to he transmitted to the ventricle, and con
this transmission has sometimes been observed to he upset by l< not

affecting the bundle. The explanation of both of th< ceptional

suits almosl certainly is that the righl lateral connection described

•_r'- 1M the main pathway of transmission for t>

TIm- facility of conduction through the auriculoventricular bundle

suhjeet to alteration hy the impulses passing to it ah.

particularly the left vagus. I! can also be altered bj certain dr
especially digitalis ami Btrophanthin. The clear demi ion that it is

along this bundle that the heat is transmitted is strong evidence i'
of tli.- myogenic hypothewa 1T1 concerning tin

heai-the.it. hut it does not m ly disprove the m

. for histological investigation lias shown that tin- bun<
surrounded by an intimate plexus of nerve fib<

Spread of the Beat in the Ventricle

After the impulse lias been transmitted by the bui
tricles, it Bpn the many branches into whicl

the two main divisions of this huinl rate,

ventricular musculatn

ruination of these brand • papillarj m

contrad before -t "t" Ihe mnselo of ti

194

THE CIRCULATION OF THE BLOOD

significance in connection with their function of tightening the chorda1
tendineae so as to prevenl any bulging of the flaps of the auriculoven-
tricular valve into the auricles when, at the beginning of the presphygmic
period, the high intraventricular pressure is brought to bear on their
under surfaces. After starting at this point in the ventricle, the con-
traction wave seems to spread farther through the ventricular muscle at
a fairly uniform rate.

Investigation of this problem by means of the galvanometer has been
technically a very difficult matter, and the details of the researches by
Lewis and his pupils have not as yet been published in full. According
to the preliminary communications at hand, however,3'1 it appears that,

Fig. 56. — Diagram of experiment by Lewis showing the times at which the excitation wave
appeared on the front of the heart relative to the upstroke of R in lead II. R.A., right appen-
dix; D.B.L., descending branch of left coronary artery. (From Thomas Lewis.)

when nonpolarizable electrodes are placed at various parts of the outer
aspect of the ventricle, and comparison made of the moments at which
the cardiac impulse arrives, as judged by the appearance of the excita-
tion wave relative to R in a standard electrocardiogram, it has been
Pound that the time of arrival bears no relationship to the anatomic ar-
rangement of the muscle bundles of the ventricle. It arrives early and
simultaneously over an area of the surface near the anterior attachment
of the wall of the right ventricle. It arrives late at the base of the right
ventricle and in the part near the posterior intraventricular groove.
Histological examination lias shown that the branches of the right division
of the auriculoventricular bundle are most closelv connected with the

ill I'll, M

place w here the ai ri\ i hat d

obtained from tin- left ventricle, bu n the) lependcnt uj

relationship of the part to the Pnrkinje til" l

FIBRILLATION OF THE HEART

Ventricles

'I'lif e> <-n Bpread of the w a-, i I ion o

the uniform excitabilitj of the muscular fibers If
lar til'tis. or bundles "t' I tabilit;

others, then, when the Btimulua I atracl arrives, it will not p
a oniform contraction of neighboring bundles, and ccord
the cardiac musculature will '-ri\<- place t.» a confused mo I in \\ 1

each pari of the In-art is contracting independent^ of tl •

Uation, or delirium cordis, as it is called, can be p
variety of experimental methods, rach, for exam] timulat

the ventricles with induced electric Bho r bj

branch of the coronary artery, or by the injection of lycopodium

circulation, or by mechanical stimulation of thi
in the region of the auriculoventricular bundle.

Fibrillation of the ventricles is undoubtedly a common
in man, for of course the confused movements make the venl - in-
capabh ting on the <-<>iitfnts of the In-art. It is

which can probably never I"- recovered from in the higher anims
it is of ii .'■ thai the ease with which it is s.-t up .

application of an electric stimulus va a marked in <li'

<-iit animals, and thai in those hearts in which fibrillation can I
ited only with difficulty, •■ can usually i

•t by meai cold and then allowing it U

dministration pinephrim * the I

this way, thai of the ral been found t.i be most r< ila-

tion ; then in order come thi

I od pea t : 1 1 tin- hi

affected Fibrillation utricle is uiulou

death in mosl >. Cut

■ 1 that, w In
alternating current produces ventricular fibril
tin* lower animals, at least in t;
doI do
in produced by a u

• ly. ho

196 THE CIRCULATION OF THE BLOOD

the central nervous system, so that the method of applying stronger cur-
rents, even were it feasible to do so quickly enough, would be of no
therapeutic value in removing fibrillation.

The disappointing results that have followed the repeated attempts
to resuscitate persons killed accidentally by electric shocks is undoubt-
edly dependent upon the fact that in the heart of man it is impossible
to bring back the normal beat after the ventricles have been thrown into
fibrillation. Fibrillation of the ventricle is also the cause of the sudden
cardiac failure occurring when blood clots or emboli cause a blockage
of the coronary circulation (it is sometimes the cause of angina pec-
toris, for example). It must also be remembered in clinical practice
that mechanical stimulation of the ventricles may produce fibrillation, so
that in attempted resuscitation by cardiac massage care should be taken
not to apply this too vigorously.

Auricles

Although ventricular fibrillation is seldom recovered from, it has been
clearly shown in recent years that fibrillation of the auricles is relatively
common and that it is by no means immediately fatal. Indeed it is one
of the most common of the chronic cardiac disorders in man. Auricular
fibrillation can be produced experimentally by the application of a
strong electric stimulus to the auricles. If, however, a weaker stimulus
is applied, the auricles do not go into typical fibrillation, but come to
beat at a very rapid and regular rate, perhaps three or four hundred a
minute. This condition is called "auricular flutter," and is quite fre-
quently observed in the clinic.

The influence of auricular fibrillation and flutter- on the beat of the ven-
tricle is an extremely important one in connection with the irregular-
ities of the heart observed in man, and this influence in most cases is
explained by considering (1) the narrowness of the path (in the auric-
uloventricular bundle) along which the impulses have to travel, and (2)
the varying conditions of excitability of the ventricular muscle, depend-
ing upon the existence of the refractory phase (page 180).

In auricular flutter, when three or four hundred impulses per minute
are passing along the bundle to the ventricle, the contraction produced
by the first one will scarcely have started before the second and imme-
diately succeeding ones arrive, so that the ventricle will beat at a rate
that is much less than that of the auricle, and a condition simulating
heart-block Mill become established. The characteristic feature which
distinguishes this from true heart-block, however, is the fact that the
ventricular rate is above normal, whereas in true heart-block the rate
is much below normal. By means of the electrocardiogram or by

•mi PHI

polysphygroographic tracing

ting \\ ith |" ilarity all

In auricular fibrillation I y « ill

gular rate to the impulses transmitted
contractions, if examined by the methods al

Further details of the met hi
will be ; later

CHAPTER XXI 1 1
THE BLOODFLOW IX THE ARTERIES

THE PULSES

Returning to the physical laAvs that govern the circulation of the blood,
"\ve may now consider the temporary changes produced in the bloodfloAV
in the arteries by each systolic discharge. These changes go under the
general term of the pulses, of "which three may be distinguished: (\)
the pressure pulse, or the pulsatile increase of pressure produced by
each heartbeat (see page 127) ; (2) the velocity pulse, or pulsatile accel-
eration of velocity; and (3) the palpable pulse, or the pulsatile expansion
of the Avails of the blood vessels produced by the sudden change of blood
pressure in their interior. The general characteristics of the three
pulses are the same, certain features being however more pronounced
in one than in another.

General Characteristics

Rate of Transmission of Pulse Wave. — The rate of transmission of
the pulse wave can be determined by taking simultaneous tracings of
the pulses from two far distant parts of the arterial system along with
accurate time-tracings. From records (cf. Fig. 98) taken from the apex or
the carotid and radial arteries Ave can determine how long it takes for
the beginning of the pulse wave to travel to the radial artery from the
point in the aorta from whieh the carotid artery springs. We shall find
that it takes about one-tenth of a second, which, considering the length
of the artery involved, Avould Avork out as a transmission Aelocity of
about seATen meters per second or about seA'enteen miles an hour. The
pulse therefore travels along the blood A-essels at a much greater speed
than the blood itself is moving, this being, as Ave shall see immediately,
about 0.5 meters per second in the larger blood A-essels.

The pulse is a Avave of sudden increase in pressure and velocity pass-
ing along a stream whieh is floAving in the same direction Avith a cer-
tain more permanent pressure and velocity. A simple physical experi-
ment may serve to make this clear: If the first of a row of billiard balls
be tapped Avith the cue, the end balls Avill fly off Avhile the others are
moving slowly along in the direction of the stroke. Bach ball becomes
accelerated by the ball behind it, and imparts ils influence to the ball

I'.IS

I lit ,

in front. In other w ords, a pulsati
by a pulsatile change in ;

b polae wave going in the lame directioi
eolomn of tlui<l can also be illu I
down a Btreani when a atone is thrown ii to it.

The U ngth of >'"• uch ti

rh <■-! at the periphery of th<

red from the beginnii Ti

ber, for it is a common mistake to think <>t' tl
one. The determination of the length of the pub*
following equation: L YT. wher< I. equals thi
wave, V i' city of transmission, ai d T ita d n

in the artery. Under ordinary circumstances L would usually
from ■"- 25 to A 5 metei

The rate of transmission of the pulse
rigidity of the walls of the arteries To undersl why ti

it -vx ill l»f w.-ll for a momenl to consider the physical condil
upon which the pulse wave de] I

tube with th<- nozzl< large syringe, with each m<

ton a wave of pressure will be transm
which it will travel at such a high ty thai it will i

end of the tube almost instantaneously, and ii
flow of fluid from I ■ the tube with each c

pump will l>t \ equal to thai ted by the d

piston It", on the other hand, an ••' 1. ii

found thai the Budden ii i
the pump causes a distention of the wall
i wave at a readil surabh

ible the tube
of the tube will continue

incut of the pump. Whal happens in the ,:il»- will
the fluid is that the portion which is imn
uini distention and, being elastic, I

>il and thus • -<'il pi •

^ult. pressun
that tra\ el bl me tn a stop tw

tra\ el distally act on ii«l in

and by temporarily raisii

sel w all, until the i
(ion it is clear thai th<

• he longer « ill it '
riul t" 1 1

200

THE CIRCULATION OF THE BLOOD

Alteration in the rate of transmission of the pulse wave in the arter-
ies of man depends entirely upon an application of these principles.
When the arteries become hardened in old age, the rate of transmission
of the pulse wave is markedly increased. The pulse is also transmitted
more rapidly in the vessels of the lower extremities than in those of the
upper, since in the former the blood vessels are somewhat more rigid.
Delay in the transmission of the pulse wave is further observed as one
of the signs of aneurism in a vessel; as is well known, aneurism of the
subclavian artery on one side causes a delay of the pulse on that side
that is perceptible to the fingers.

The Contour of the Pulse Curves

For more particular study of the exact contour of the pulse wave, and
especially for determining the time relationships of the secondary waves,

Fig. 57. — Diagram of Chauveau's dromograph. a, tube for introduction into the lumen of the
artery, and containing a needle or vane, which passes through the elastic membrane in its side
and moves by the impulse of the blood current; c, graduated scale for measuring the extent of
the oscillations of the needle.

a large variety of methods of varying degrees of accuracy have been
elaborated for each kind of pulse.

Those devised for measuring the pressure pulse have already been de-
scribed (see page 127), and for the other pulses they are as follows:

Velocity Pulse. — Much ingenuity has been displayed in the elabora-
tion of methods for recording the velocity pulse. In one of these the
artery is cut across and the ends attached to a tube, into the lumen
of which projects a paddle or vane articulated with a light lever, which
passes through its wall (see Fig. 57). The vane floats in the blood
stream, and the outer end of the lever to which it is attached is con-
nected with some device to record its movements, which vary with the
velocity of bloodflow (hemodromograph). Another method consists in
the application of the instrument known as Pitot's tube used by phys-
icists. This consists of a horizontal tube having two side tubes, each of

1 1 1 1 I i I

201

which is conn<

inside tin- horizontal tube, v.

sn that the inner <-ii'l of one of 1

a

j

c

D

■

'/

» '.

*>*

;

Btream, and record
duced by the Budd

202 THE CIRCULATION OF THE BLOOD

other — the distal lube — being bent down stream, records merely lateral
pressure. A photographic record of the movement of the iluid in the
two tubes gives the velocity pulse (see Fig. 58). For physiologic pur-
poses the form of apparatus used is constructed as shown in Fig. 59.

Palpable False. — To secure a record of the palpable pulse, the so-
called spliygmograph is employed, although a tambour having a button
in the center which is made to press on the artery may also be em-
ployed. The commonest form of spliygmograph is that known as
Dudgeon's (Fig. 60). It consists of a small button connected with a
spring, the movements of which are transmitted and magnified by means
of a S3rstem of levers connected with a writing point arranged so as
to inscribe its movements on a moving surface.

The Analysis of the Curve

The general contour of the pulse waves taken by any of the above
methods are in general very much the same. The pressure and velocity

Fig. 61. — Pulse tracing (sphygmogram) taken by spliygmograph. a d, the period of the pulse
curve; b, the primary; c, the dicrotic wave. Time marked in fifths of a second. (From Prac-
tical Physiology.)

pulse curves are, however, not usually taken for the purpose of observ-
ing the contour of the wave but rather for measuring the difference in
pressure or velocity actually produced during each pulse. It is a record
of the palpable pulse that is usually employed for studying the contour
of the wave and the presence of secondary waves. A record of the pal-
pable pulse wave (Fig. 61) shows two separate waves on the descending
limb of the main wave. If a large number of similar pulse curves are
taken from different individuals or from the same individual under
different conditions, it will be found that of these two waves the second
one is by far the more constant; and if the waves are timed in relation-
ship to the heart sounds, this second wave always occurs immediately
after the second sound, allowance, of course, being made for the time
required for the pulse to be transmitted from the heart to the artery
from which the pulse tracing is being taken. If the observation is
made very carefully, it can indeed be; shown that the second sound cor-
responds exactly to Hie notch which precedes this wave. The waves that

I 111. «)\\ |\ 1 HI. AICi

precede this notch can not be related to d

tin- heart Evidently, then, th< iry pu

equal significance, by far the must important being that which

immediately after tin- Becond sound, called tl

•h in front of it being called the dicrotic no \ econd

waves urring before the dicrotic . 1 1 1 •-« I j

ur <>ii the ascending limb of the main pulse ' • sometii

do, they are « • ; i II • * » L anacr Vi the di<

called postdu

The relative importance of the dicrotic, in comparison with tl..
dicrotic ami postdicrotic waves, is furtl •
it alone is Been on a Bo-called hemataugram, which

tained by allowing a fine stream of M 1. escaping from a pinhoh

in the -\\ a 1 1 of an artery, to impinge upon a movii _ of white blot-
ting paper. That such a tracing Bhowa a dicrotic but no s ndary wa

indicates thai only the former is presenl in the bl

that the "tip londary waves must be produced bj some

arising either in the elastic tissue of the walls of the blood

in the elastic propertii the instruments used for taking the p

tracing.

The Dicrotic Wave. Because of its obviously gri rnifican

shall first of all consider the exact cause of tin- dicrotic wave and

h preceding it. Theoretically, two possible - niigl * lain

the wave: either it is due to some secondary wave set up at I
or it is dependent upon wa- lected from the periphery of t;

culation hack along the blood Btream, just sondary wavi

fleeted from the walk of a tub of water when a stone is thrown in the

center. In considering this s ml possibility, we art

the assumption thai at the ends of th<- arterial ra then

stance to the onward movemenl of blood, Tl [uent brand

which ' urs when the arteriole '.pillar

i many opportunitii ction of pull

rt, hut these waves must be reflected at such varying
the art. -rial system thai there can be little opportunity
come added together so ;is m a wavi

make itself p tible in the blood flowing in the

wa\ relatively bo small and they occur ich different timi

the lift result «>t" their addition, s«> •
wavi oncerned, must 1>.- practically nil. Notv
Biderations, it is possible thai under - i uses

of high arterial tension, certain of th»> pred

ma\ be 'hif d> tin- a!

204 THE CIRCULATION OF THE BLOOD

Thai the dicrotic is not a reflected wave is clearly established by the
fad that if the distance between the dicrotic wave and the main pulse
wave is measured at different points of tbe arterial stream, it will al-
ways be found to be the same, which obviously would not be the case
were the dicrotic wave reflected. If, for example, we were to examine
the contour of the wave produced by throwing a stone into a tub of
water, we should find that near the edge the secondary wave was very
close to the main wave, whereas near the center the secondary wave
would occur much later.

Our problem therefore narrows itself down to an investigation of
the cause for the dicrotic wave at the central end of the circulation. It
occurs, as we have seen, immediately after the beginning of diastole.
That it can not be due to anything taking place in the ventricle itself is
evidenced by the fact that such a wave is absent from an intracardiac
pressure curve (see page 151), although it is present in the very begin-
ning of the aorta. Now, the only structures existing between those two
points which could be held responsible for this wave are the semilunar
valves — a conclusion which is sustained by the fact that, if the aortic
valves are rendered incompetent by hooking them back, or if the pulse
beat is examined in patients suffering from an aortic insufficiency, it
will be found that the dicrotic wave is not nearly so evident as usual.

To understand how the valves are responsible for the production of the
wave, the mechanical changes occurring at the root of the aorta must
be clearly understood (see page 155). The stretching of the elastic walls
of the aorta which occurs with each systolic outrush of blood is fol-
lowed by a powerful and sudden contraction of the stretched walls,
and the pressure thus brought to bear on the column of blood in the aorta
tends to impel it both forward and backward. The forward movement
adds itself to the wave of increased pressure already produced by the
ventricular contraction. The backward component travels as far as the
semilunar valve, from which it is reflected, and now proceeds peripher-
ally along the blood stream during the time at which the original pres-
sure pulse is declining. It therefore imprints itself on the pulse trac-
ing as a separate wave, and does so all the more markedly when the
decline in the main pulse wave is rapid, as in cases in which the periph-
eral resistance is low, but fails to be prominent when, on account of
a high peripheral resistance, the decline in the main pulse wave is tardy.
This explanation coincides exactly with the well-known clinical fact
that the dicrotic wave is conspicuous in pulses of low tension, but ill
marked or absent in pulses of high tension.

One point remains to be considered, and that is the cause for the
sudden decline in the main wave at the cessation of the ventricular out-

'Mil:!

put, for, it mighl I"- s.u.l in

pressure Dear the heart, w hei
the pressure between I

•In- elastic recoil of the I

usually is thai the Budden >■■

ventricle .'it tin- <-n<l of the Bph; period «••

to 1"- produced in the M 1 ;it the beginnii

reflux of blood towards the heart, th< I

bulg closed valves, and 2 to produce thi

l . while tlui'l is tl<>\\ ing under pn
denly arrested by turning a Btopcock, it i> p

I to bIkw that a negative w a up in

Btopcock, and thai this negative i
depending on th<- elasticit Is.

Causes for Disappearance of the Pulse in the Veins

The disappearai of the pulse in the capilli

absence in the veins we have already Been t<

influeni •) lasticity of the vessel walls and the r

anci I ' accounl of these tw<

blood during bj - ed up t<> .1 during di

tched vessi -
through tn the veins, either because tl
marked, or because the
dilatation . In patients with hardened art<
als after taking nitrite, which dilates the i
nut) come through at the peripherj and appear in t! i

called the peripheral venous p ind it

guished from the cenl ral
at the I the neck, i

transmission of the auricular
blood in the veins. If a pulse is
doubl . whether it i^ peripheral i tral in

moved by local
ia peri phi • will disappear on I

it is central, on

CHAPTER XXIV

THE EATE OF MOVEMENT OF THE BLOOD IN THE

BLOOD VESSELS

Since the object of the circulation is to maintain an adequate move-
ment of blood in the tissues and capillaries, it is evident that besides
measuring the pressure of bloodflow, we should also measure the rate
of its movement, or, a.s it is often called, the mean velocity. This measure-
ment may be undertaken either for a given vessel or for a complete
vascular area, such, for example, as that of one of the viscera or one
of the extremities — the mass movement of the blood. Or instead of
measuring the mean velocity we may desire to know how long it takes
for a particle of blood to traverse a given vascular area. Such a meas-
urement is called the circulation time; it does not at all tell us how long
it takes for all the blood to pass through the given area, but only, as
stated, the time required for the circulation of a fraction of the blood
through a particular field.

VELOCITY OF FLOW IN A VESSEL

Special methods have been devised for the measurement of each of
these three velocities. For the measurement of the velocity of flow
through a main artery or vein, methods similar to those employed by
hydraulic engineers are employed ; that is to say, the volume of blood,
in cubic centimeters, which passes a given point is measured for ;
given time, and the result divided by the cross section of the vessel at
the point of observation. The result gives us the mean lineal velocity.
To measure the outflow of blood in a given time, the simplest method
would be to cut across the vessel and collect the blood in a graduate,
but obviously in this method an error would be introduced, because
cutting the vessel would loAver the peripheral resistance and remove the
natural obstruction to the flow present in the intact animal. Moreover,
the hemorrhage would in itself introduce a disturbing factor on account
of the loss of circulating fluid.

To make such measurements of any value, it is obviously necessary to
retain the peripheral resistance. For smaller vessels 1 his can be done
by introducing in the course of the artery a long glass lube bent in the

20G

nl M((\ i \li

207

Bhape "i the letter II '•>• merelj alia t<»

bleed into b graduated tube and seeini the blood columi

tn tr.-i\ el from one ei This mel i I

value in measuring the velocity of flom from small
\>-iii^ coming from glands and muscles For larf

muhr is employed. There are numerou tromuhr; I

Bhown in the diagram Ludwig'c Pig. 62 \ liull»s

united above, and com ted below with tubes that open flush with the

surface of ;i brass disc This is pivoted at its center with another similar

platform also having flush w itli the surface the opening

nected with the <-ut ends of tin' artery or vein. In a certain p

tli«' platform, the tubes from the artery <>r vein are <

those of the bulbs, bo thai the blood can i1<>\\ from one end of ,; •

'

* 1

( I

;.

■

•i(jtl thr

i on l

fluiih

•lood
id.

through tin' Imllis to the other end. To us< strumei I

mal bulb is filled with <>il and the peripheral one with pin

The clip is then removed from the central end of ti

flows in and «li- the oil, which in turn d

peripheral end of the artt i • \\

the tube joining the two bulbs, the instruim thai

the oil is broughl bac in into ti

being effected bo quickly that 1 1

flow 'i'; pci ition is I in tli

Count ii - juratel) the numb<

number of rei olut ioi h bj ti

208 THE CIRCULATION OF TllE BLOOD

centimeters the amount of blood that has flowed through the instrument
in a definite unit of time. This gives us the volume flow and, if the
result is divided by the cross section of the vessel in square centimeters,
we obtain what is known as 1he mean lineal velocity. Many modifica-
tions have been made of this instrument, but it is unnecessary to go into
them here.

The general result of such measurements has been to show that the
lineal velocity is inversely proportional to the cross section of the vesisel
at the point of observation. It is obvious that the volume of blood
flowing out of the heart to the aorta in a given time is exactly equal
to that flowing into it by the vena cava, and likewise that the volume
flowing into an organ is exactly equal to that which flows out. Conse-
quently the lineal velocity will be inversely proportional to the sec-
tional area of the vessel. The principle is the same as that which gov-
erns the velocity of flow of a stream: when the bed is narrow, the cur-
rent is swift, but it becomes sluggish when the bed is wide. If the
arteries were of the same caliber as the veins, the mean velocity of the
bloodflow through the two would be the same, but actually it is much
greater in the arteries because the lumen of these at a given point in the
circulation is only from one-third to one-half that of the corresponding
vein.

It must be understood that we are dealing above with the mean
velocity in a unit of time, and that there must be considerable alteration
with each systole and diastole, constituting the velocity pulse (page 200).
The degree of this alteration with each velocity pulse is much less at
the periphery of the circulation than near the heart. As the periphery
is reached, the flow becomes more uniform. It must further be re-
membered that, although the mean velocity depends essentially upon
the area of the vascular bed, yet it is subject to considerable variations
as a result of changes either in the force or rate of the heartbeat or
in the facility of outflow from the ends of the arterial system — that is,
changes in peripheral resistance.

It is usually stated that the mean lineal velocity in the carotid artery
is about 300 millimeters per second; and in the jugular vein, about 150
millimeters; whereas in the capillaries, where the total area of the
vascular bed has become enormously increased, being perhaps some 800
times that of the aorta, the velocity of flow is only about half a milli-
meter per second.

MASS MOVEMENT OF THE BLOOD IN A VASCULAR AREA

Methods. In considering the bloodflow or mass movement of the olood
in the different regions of the body, it is usually more practical to

BATE <»K M0\

nut tin- mean lineal
blood, I >i it rather li"\\ many cubic
the pari per 100 grai

nenta may 1"- i ■ i .- 1 • 1 « - in n \ m iel i

and one rein to the part, the Btromuhr n
it ma) be inserted in either I - - - 1 i ^ 1 1 i

measuring '!!<■ mass movemenl of M 1 tl •

the liver, ilii-> is indeed the only method that can be

>muhr being inserted either in th urse of tl

]>ati«- arteries, or, i still, in the jus! :

of the hepatic \rin, the vena cavs being shut utT for a i

the liver and the heart and the M I, as it \\><

allowed < Heel in the Btromuhr. For "t:

••, methods which <ln n<»t involve any with the 1>1<

may be employed ' h f these is th<

\ rgan, Buch kidney, is enclosed in a p

mograph (see page 230 and \\ 1 1 i 1 < • a

iribed on a quickly revolving drum, the Idenly

with the result thai the kidney volume expands in proportion

mass of bl 1 flowing into it. When tl

tain degree, the clamp is removed and the bloodflow i

sue its course It is then an easj matter, by graduating tl

mograph, to determine how many cubic centime

flowed into the organ in the given tin I avoid Beriou

in the tissue, the clamp musl be applied to the vein for only tl

od of time Tins method may also be employed for i
bloodflow through the extremities Thus, it" the arm
plethysmograph l"i'_r 63 and a band encircling the arm i

plethys graph is tightei to constrict th<

terit rate at « InVli tin- volu m w ithin I

expands will correspond to tl.. which M 1 is flowii

Hewlett
Por the purpose of i I flow through the upp

emities, a much d ^

St( art Tl depends on the principle that, pi
•u the thorax »■» the hands "r U el i
w hieh h< I
proportional

■ |y for the method, tl

■
if the temperature in tl
ature

210

THE t'IK( ll.ATlox ()K THE BLOOD

lose heat to the environment until the outflowing or venous blood is at
exactly the same temperature as the environment; for example, if the
hand is placed in water that is a little cooler than that of the blood,
and the temperature of the blood in one of the large veins of the hand
is measured, it will be found to be the same as that of the water in the
water-bath.

To measure the rate of flow, therefore, we must ascertain: (1) how
much heat has been given out by the part to the water surrounding it
in a given time, and (2) the difference in temperature of the inflowing
(arterial) and outflowing (venous) blood. We measure the amount of

Fig. 63. — Plethysmograph for recording volume changes in the hand and forearm. By observ-
ing the rate with which t lie volume increases when the arm is compressed, the mass movement of
the blood can be determined. (From Jackson.)

heat given out to the water in calories, a calorie being the amount of
heat required to raise 1he temperature of 1 c.c. of water from 0° C.
to 1° C. Suppose, for example, a hand were placed in 3,000 c.c. of
water at 33° C, and that after ten minutes the temperature had risen
to 33.5° C, then the amount of calories given out would be 3,000x0.5=
1500. Since calories equal cubic centimeters multiplied by change in
temperature, it follows that if we divide the figure representing them by
the actually observed difference in temperature between inflowing and
outflowing blood, the result must equal the number of cubic centimeters
of blood that has flowed through the part. The temperature of the in-
flowing blood has been found to be practically identical with that of the

mouth mull-!

hi I. an all

water during the i ime t lial I

tails of i he teeli m| • i

sai<l Ik

uothii nn I

l'i C and 50 < w itli .1

pacit\ . \\ itli douhli
\\ itli somi insula) iiiL- iii-

Results. R< arcliiifs I mlts obtained with tl

found thai the blood supply fori rrams

\ iac< measured h muhr mel I

'_'! c c. : intestine, 71 e.c; spleen, -
vem ii\ er, total, v 1 c.c ; brain, 1

roid gland, 51 The large bl I supp

of the kidnej he mosl si ril

I '•■ the u the calorimeter method the M lfl<

and of a health} young man has b<

of hand per minuti
gram less for the left, The footflov is onlj third t

that of ilm hand per 1(|" c hich

ow ing to Hi.

bone in the hand. The a\ e

vidua! under ordinarj eonditii I from tin

l»ut it is , dinarih sensiti

environment in which the subjecl i n livii

he measuremenl In < In idual, w hen t

1 the flow mi t he 1 ighl

hand 1 10.1;

11 it v - • . 1 •_» 1 C, 18

influent

i should i -mall

rounded h
patients short!}
fall; 1

clinic will be alluded

■

only tl •

tation

212 TIIK CIRCULATION OF THE BLOOD

circulation is more or less reciprocal with that at the periphery, an
increase in the one place being accompanied by a corresponding de-
crease in the oilier.

The Visceral Bloodflow In Man

The visceral bloodflow in man can be measured indirectly in the case
of the lungs, either, (1) by finding the quantity of oxygen absorbed by the
blood during an interval of time that is less than that required for the
blood to travel once round the circulation (60 seconds) and comparing
this with the oxygen content of samples of arterial and venous blood, or (2)
by causing a person to breathe a known quantity of nitrons-oxide gas and
then finding the concentration of this gas in the blood after leaving the
lungs. In the former method the difference in oxygen percentage be-
tween arterial and venous blood will be less for a given absorption of
oxygen from the alveoli the more rapid the circulation of blood through
the lungs, and in the latter method for the absorption of a given amount
of nitrous oxide, the less will be the concentration of this gas in the
blood the more rapid the circulation. Obviously these estimations must
be made only over periods of time, less than that taken for any of
the blood to complete one circuit of the circulation.

The methods are admittedly only approximate, but the results are of
much interest, mainly because of the indication they give us as to the
amount of blood pumped out by the ventricle with each heartbeat, or
during a given period of time. The results have been found to vary
considerably; thus, one author (Krogh) places the output of blood per
minute as between 2.3 and 8.7 liters, which would correspond, at a
pulse rate of 70, to an output per heartbreat of from 40 to 120 c.c. An
immediate and very marked increase has been found to occur during
muscular work. By comparing the bloodflow through the hand with
that through the lungs, an estimate can be formed in a given individual
as to the relative magnitude of the peripheral and visceral moieties of
blood. Interesting results, which will be referred to later, have been
obtained from such measurements.

The Work of the Heart

Meanwhile it is of interest to note that we may calculate from the
ventricular output of the blood the amount of work that the heart is doing
in maintaining the circulation. Of course the calculation is again only
approximate, since we have to assume certain figures. If we assume that
in a 70-kilogram man the quantity of blood is 4,200 c.c. (see page 85),
and that it takes about one minute for all the blood to complete a cir-
culation, then the work performed by the left ventricle in one minute

II «-) \H»\ IMIM >n I 111

will be equal to thai done in raising thi
heighl ponding t" the mean pr<

millimeters of mercury, which would i
column "t* blood 1,755 meters high l " IT".", nun l>

meter , tin- work «l<>n.- I>v th<> lefl ventricli
kilogram-meters in one minute, or in tw< Four h<

00 kilogram meters. The v. ork done by the rigl
about one-third thai of the left, this being aboul tin
sures in the two chambers The total work of the I

■ aboul 14000 kilogram meters This pep Is an enormoi

of work; indeed it has been computed that it is
of 70 kilograms to aboul twice the heigl
v York. The work thus expended in forci
capillaries 1 omes converted 1>.\ friction in the small bl

•. the heat equivalent of the above amount of work tx

aboul 350 color 1

THE CIRCULATION TIME

The circulation time, or the time taken by a drop of bl 1

between two points in the circulation, can n labo I

animals by a variety of methods, all depending on the pri
how long it takes for a drop of Borne substance injected into an
appear in the corresponding vein. For example, to determine tl
taken for a drop of blood to pass from the jugular vein int<
artery in a rabbit, a solution of methylene blue in isotonic saline is in-
jected into the former vessel and the moment i
tin- walls of the artery determined b) a stop-watch. It" the walls ,
thick to admil of the employmi this method, a \ iolution

sodium chloride may be substituted for the methyleni
ment of its appearance at another poii lulation d< I

ing tl itrical conductivity of the

ductivity of a blood v< la partly on I

trolytes in the blood flowing through it. tin- mon
solution, appears will be ind I b\ a

I '

1 1 ich methods, it has I.. • ,ml tl

circulation is ven short compared with that of tl
In a rahl.it it is usually a little less than I

• 1 dog of about 12 kil
it is computed to 1"- about I

filiation tiiin> iii BUcIl

L'l I THE CIRC1 LiATlON OF THE BLOOD

and more susceptible than that of the Lungs to different conditions of
temperature. In a dog in which the pulmonary circulation lime was
about 8.5 seconds, that of the spleen was about 11 seconds, and of the
kidney about 17. 5 seconds. The shortesl circulation time of all is of
course thai in the coronary artery, bu1 that through the retina can not fall
far behind it.

To determine tin total circulation linn-, we must know: ( 1 ) the average
amount of blood passing by each pari in a given time, and (2) the average
circulation time of each part. Prom such computations, which however
are obviously subject to considerable error, it has been reckoned that the
total circulation time in man must lit1 somewhere between 1 and 1.25
minutes.

MOVEMENT OF BLOOD IN VEINS

Before leaving this part of our subject, a few words may be said con-
cerning the forces cone* rn< <l in the movement of blood in the veins from
the capillaries to the heart. By the time that the venules are reached,
owing to friction in the capillaries the blood will have lost most of the
force imparted to it by the heart action. Nevertheless, this remaining
vis a tcrgo must be considered as the basic cause for the movement of
the venous blood near the periphery. As the venules get larger, two
other factors come into play: the massaging influence of the muscles,
and the valves of the veins. By the movements of the muscles the veins
which lie between will be rhythmically compressed, and this will tend to
cause the blood to be moved forward and backward in them, the back-
ward movement being' however prevented by the operation of the valves.
When the tonicity of the muscles is subnormal, as in conditions of ill
health, the absence of this massaging action permits the blood to stag-
nate in the veins, especially in those of the lower extremities in upright
animals, with the consequence that the veins become dilated, particularly
just above the valves, thus causing the condition known as varicose veins.

As the thorax is approached, two other factors become operative: the
aspirating influence of the thorax during inspiration, and the negative
intraventricular pressure (sec page L52). There is no doubt -that the
former of these is of considerable importance in maintaining the venous
return near the heart, for although the change of pressure induced by in-
spiration amounts to only 5 millimeters of mercury, yet it acts so
slowly that it produces a considerable influence. The aspirating effect
of the ventricle at the beginning of diastole is, however, of no sig-
nificance in attracting blood to the heart, for although, as "\ve have seen,
it may be considerable, ye1 it lasls for so short a time thai it: could not

rcome the inertia i
the \ <■ pi • Miurc did

more than a small amount i
collapsible \\ alia of I i
i < t\\ arda the heart.

CHAPTER XXV
THE CONTROL OF THE CIRCULATION

The available blood in the body is parceled out to the various organs
and tissues according to their relative activities, and, since these vary
from time to time, the question arises as to the nature of the mechanism
or mechanisms involved in bringing about this adjustment. Two possible
methods of increasing the supply are: an increase in the mass movement
of all the blood in circulation, and a reciprocal adjustment of the resistance
to the flow in different vascular areas brought about by vasodilatation
in one and vasoconstriction in others. Both of these methods might
operate together.

Two agencies can be thought of as responsible for bringing about
the above changes: (1) chemical substances or- hormones, present in
the blood, and (2) the nervous system.

The influence of chemical substances, or hormones, (page 729) in the
control of the circulation is undoubtedly an important one, and of those
known at the present time two groups may be mentioned: (1) sub-
stances which alter the hydrogen-ion concentration of the blood, and
(2) so-called pressor and depressor substances, produced either by duct-
less glands, such as the adrenal, or by the activity of tissues. An in-
crease in hydrogen-ion concentration of the blood not only affects' the
heartbeat (see page 168), but causes a marked dilatation of the blood
vessels, so that both the central and the peripheral changes will be such
as to encourage an increased flow of blood through the active organs
or viscus. Thus, during muscular activity of the leg muscles there will
be a tendency to an increase in the hydrogen-ion concentration of the
blood as a whole, resulting in a greater cardiac activity and a greater
outrush of blood through the aorta, and at the same time the vessels of
the acting muscle will have become especially dilated because of the
production by the active muscles either of lactic acid or of carbonic acid.
The active muscle also produces such substances as imidazole, which
have a powerful vasodilating action. Such substances arc sometimes
called depressor.

Though the hormone control of the circulation is undoubtedly of great
importance, it is probably much less so than that exercised through the
nervous system, and here again the control is centered partly in the

216

Ill

In-art and partly in thi
heart is effected ll

'•i^r.i mi the bl Ih, till

The activity of tl
motor impul e disci
inu' from the \ arious r
active, \\ «• must Biippose thai rtin
afferent impulses t-. be tri
Upon W hich thej a<-t in
lion and a 1 «•<•.- 1 1 dilatation <>t" t i
perhaps a constriction of tin- bl I

THE NERVE CONTROL OF THE HKA! \T

The VagQfl Control

With regard to the cot
alread that the ctrtth

heart t«> quicken and the arterial bl I

stimulation of the peripheral •
come bIom ed, if n<»t rtopped all
I ' ■•• thr more detailed in

irt, it is i
imenl w hich, for <»1>\ rious

a COld-blooded animal. BUCl

be performed in mammals pro> id(
The general effect of the vagus in
although apparent dif
portal ' he differenl pai

gation of the heartbi

The Cold Blooded Heart I
turtle nerve h •

■
tract

in the a< iii|»an\ ;•

is a w eakening of 1 1
the ventricle I
Buricular b<
mw hile t!
\
it would seem •

2 1 8

THE CIRCULATION OF THE i'.LUOD

but strengthens the ventricular beat. It is clear, however, that the
strengthening of the ventricular beat is merely due to the fact that the
cavity has become better filled with blood during diastole as a result of
the slowing of the auricle. These results indicate, then, that with weak
stimulation the vagus exerts its direct influence only on the auricle. If

Fig. 64. — Simultaneous tracings from auricle and ventricle of turtle's heart. Between the crosses
the vagus was stimulated, with the effect that the auricular beat diminished in force but not in
frequency, while the ventricular beats were practically unaffected. (From Howell's Physiology.)

the stimulation is strong enough both auricles and ventricles cease to
beat altogether, and if the stimulus is maintained, the inhibition may go
on for a very long time (Fig. 65).

Usually, even though the stimulus is maintained the heart begins to

Fig. 65. — Effect of vagus stimulation on heart of turtle. Note the after effect of augmentation.

beal again after a time, at first only occasionally but gradually more
rapidly. This is known as escapement, and it indicates that the energy
pent uj> in the bearl during the vagus inhibition has at last overcome
the inhibiting influence of the nerve, which is meanwhile becoming
fatigued. All of these results could be quite satisfactorily explained on
the assumption that the action of the vagus is confined to the sinus,

which, it will be reu

heart Then

the rhythm of the venti icl< It i

from thes< ts thai I

fi II it II pint I

' In 1 1 lil </

Besides affeel i 1 1 ur I

a control <>n tl
;i partial block is institute >\ in the lu
t w een tin- auric i i \ pnti

auricular beal and may i
the tracing reproduced in I U

lmw .-\ it. that und( in conditions t;

rather than deei

H .1H»^H\M\\\\l\M,\i\r.i\\mmi\u\^,,,>i;''

I he

i ricular junction ;
that w hen .1 clamp

• he \ enl ricl< '■■*•!

usual stimulation

I"-. te distinctly dowed, m

respond to the auricula

uenl l

ted ti
j important w ..
ahortlj II

■

220

Till: CIRC1 I.ATION OF THE BLOOD

auriculoventricular junction and on the ventricle remains. After the
atropinization, vagus stimulation delays the transmission of beat from
auricle to ventricle and shortens the time of each beat in the ventricle.
Tt Mas further found that by the local application of atropine various
parts of the ventricle can be rendered irresponsive to the influence of
the vagus and the effects of this nerve on the form of the cardiogram
modified at will. These results have an important bearing in the in-
terpretation of the cause of the T-wave of the electro-cardiogram
which will be referred to later. Mines' results show that the proba-
ble explanation is that the T-wave is due to the greater duration of the
excitatory state at the base than at the apex, for by altering the relative
duration of this state at base and apex by the above methods, he could
cause the T-wave to appear or disappear.

The direct excitability of the heart muscle to external stimuli is also
depressed during vagus stimulation. This effect is, however, not evi-

I'ig. 67. — Tracing lo show that vagus stimulation may facilitate transmission from auricles to
ventricles. It shows the effect of right vagus stimulation on heart-block produced in the turtle by
a clamp. Upper tracing records ventricle; lower tracing, auricles. Weak faradization of the right
vagus nerve beginning at A affected the degree of block only at T > when a lengthened period
between auricular contractions caused a single ventricular contraction. At B stronger faradiza-
tion of the same nerve produced marked slowing of the auricles, in consequence of which the block
disappeared and the ventricles contracted after each auricular contraction. Block reappeared when
the rate again became rapid. Initial auricular rate = 36 per minute. (From Garrey.)

dent in the case of all hearts, but is seen in those of certain fishes (e. g.,
the eel).

The Mammalian Heart. — The action of the vagus on the mammalian
heart may be investigated either by exposing the heart and connecting
the auricles and ventricle's with specially designed recording levers
I myocardiograph), or if we desire to study the influence on the heart as
a whole, by taking a blood-pressure tracing from one of the large arteries
by means of a spring manometer. The results are in general similar to
those observed on the frog or turtle heart, the main effects being de-
veloped on the auricle. Considerable differences are found in the effect
on the heart as a whole in different animals, particularly with regard to
the facility with which escapement occurs. In the dog when the vagus

is continuous!) Rtimulated, I
long time, \\ hereas in th<
by escapement. It' thi

quently !"• obsei ed in ti
iii!_' vagus stimulation it
still remaining inhibited

I f t 1 1 • - si imulation of lh<
animal w hose blood pri
only quickly • ir, bul w ill usual >

because of the asphyxia w lii<-li
inhibition Tl •• asph} xia n
blood an<l this Btimulati a both '
action I6fi l

fad thai during vagus inhibition tl
improved

As an outcome
nerve arts mainly on the sinoauricuh
auriculovent ricular bund
described above on tin- cold b
right vagus always causes s|.,
and the ventricular beats, but stimulal
observed to have bul little infl
ma} produce a condition oi
plied tn the auriculoventricular 1»
block, then during Btimulal ii
complete There is, hov
Auences, .-it leasl in tl
considerably on the \ enl i icl< infl
as the of the <■

ill <>!•<!• i.-lllol^

die, it is most BUitabli

utricular beats when I
application of artificial
traction produced bj
stimulation of t1

|>ass This.- ,\
<-itl may !•

triclea w hen uu-
the left \ agui

i n found I

Tonic Villus Action

I i

222 THE CIRCULATION OP THE KUxm

increases when the continuity of the vagus nerve is broken either by
cutting or by freezing a portion of nerve (Fig. 26). The effed is usually
inconspicuous when one nerve only is cut, but in most mammals il be-
comes quite marked when both arc cut. Change in the heart rain pro
dneed by muscular effort is much more gradual in animals with marked
vagus tone, such as hunting dogs, than in those with little vagus lone, as in
domestic rabbits. The degree of vagus tone therefore bears a relation-
ship to the staying power of the animal for prolonged muscular effort.
It is usually ill developed in cold-blooded animals. It is quite marked
in the case of man, as is evident on observing the heartbeat before and
after giving a sufficient dose of atropine to paralyze the termination of
the vagus in the heart.

The exact location of the nerve cells thai form the center of discharg-
ing impulses along the vagus fibers to the heart can not be made out
with certainty, but they are no doubt part of the great motor nucleus
(ambiguus), from which arise the fibers not only of the vagus but of
the glossopharyngeal nerve. The tone of this vagus center is almost
without doubt dependent upon the constant transmission to it along tlie
sensory or afferent fibers of impulses coming from various portions of
the body. According to the strength or number of these impulses, the
tone may be increased or diminished, thus altering the rate of the- heart.
It is possible of course that the tone can be maintained, independently
of the afferent impulses, by the action on the center of chemical meta-
bolic products or hormones produced in the cells or carried to them in
the blood. We know at least that, like the respiratory center, that of
the vagus is excitable by such hormones as the hydrogen-ion concen-
tration of the blood. The tonicity of the vagus center is, however, mainly
dependent upon the passage to it of afferent impulses, and as evidence
for this conclusion may be cited the observation that, after section of
most of the afferent nerves to the medulla (as by cutting the spinal cord
high up in the cervical region), subsequent section of the tAvo vagi does
not produce anything like the usual degree of change in the heart rate.

The Afferent Vagus Impulses. — The afferent vagus impulses may come
from practically any part of the body, having been first discovered by
the simple experiment of tapping the abdomen of the frog with the han-
dle of a scalpel, when slowing of the heart rale is observed. Cutting the
vagi abolishes the reflex, (similar cardiac inhibition is produced by me-
chanical stimulation of the tail or gills of an eel. Tn mammals stimula-
tion of the central end of any sensory nerve usually slows the heart,
though sometimes the opposite effect occurs. The pulmonary branches
of the vagus are pai-ticularly sensitive in producing reflex inhibition,
and distinct results are usually obtained: by stimulation of the termina-

I III .

tions "i* the fifth n<

:is by inhaling ammonia

rags in the phai

:is when :i Substance

nerves of the Rhdominnl

nis center, as is seen in irril I

aeh such aa urs in gasl riti» r

by violent stimulation "i" tl

men, or by irritation of the senso

ehanical or because of die

t-nt vagus stimulation is obtained bj

the • 3 • i; i c tlomotor ■

in some individual

Through which of these affei
stimuli arc transmitted to tl

tuiio, can not be said, although it

In considering the cause for an ol
must nt' course bear in mind

irred, nol through the . but l

center. Thus, when tin- heaii b mes qui<

to diminution in tin- vagus tone
along tl.-- bj mpathetic nen •
reflex action through the augi
mental conditio! been clei

nerves are eul and the peripheral end •
o as to hold the heaii at aboul
■ •i" eertaii ry nen es ma} ca i •

sympathetic control <»t* the heart]
important than control through t;

it in. -ans that the BCtUS
must : it the

of th<- \ ;i epondi

vation it it inaur*

ample, for anj quick

i bout n omptl

moment that the s\ mi
wititic influei
u hen the knee joint •'•

illljMlls. IIMllll' ■»**• **

the same moment inl
muaclcfi • Nl-I

224 THE CIRCULATION OF THE BLOOD

Several possibilities have to be kepi in mind when we attempt to
determine the exciting cause for an observed change in the heart rate in
ma>}. Thus, a slowing of the rate may be due to mechanical stimulation
of the vagus trunk, as in pressure on the nerves by a tumor or aneurism
in the neck. That such mechanical irritation may stimulate the vagus
is easily demonstrated in many individuals by applying pressure to the
vagus where it lies in the neck in front of the sixth cervical vertebra.
Such pressure sometimes produces so profound an inhibition of the heart
that temporary loss of consciousness occurs. It is often an unsafe ex-
periment to perform.

Change in the heart rate in man may be caused by direct stimulation
of the vagus center, as by the presence of a tumor or a blood clot in the
medulla, or by the action on the center of some unusual hormone in the
blood. A general increase in intracranial pressure also stimulates the
vagus center. The slowing of the heart which occurs in asphyxia might
be due either to the action of hormones (hydrogen-ion concentration)
in the blood as the result of the asphyxia, or to the increased intra-
cranial pressure. That the latter is the more important cause is shown
by the fact that, if the rise in blood pressure is prevented by connecting
an artery with a mercury valve, — that is, with a tube dipping into a
cylinder of mercury to a depth corresponding to the normal blood
pressure, so that when the pressure tends to rise the blood escapes, —
the slowing of the heart is not observed. The excitability of the afferent
vagus fibers in the lungs is greatly increased during the earlier stage
of chloroform administration.

Finally it should be pointed out that, although we have no voluntary
control of the activity of the vagus center, its activities are subject
in great variation as a result of impulses transmitted from centers higher
up in the cerebrospinal axis. It is by the operation on the vagus center of
such impulses that changes in heart rate occur during emotional ex-
citement, fright, etc. The increased heart rate in muscular exercise is
probably dependent upon a number of causes, such as the irradiation of
the motor impulses on to the cardiac centers (see page 412), the rise in
temperature and changes in the hydrogen-ion concentration of the blood,
etc.

Mechanism of Action of Vagus on the Heart. — Physiologists have nat-
urally been curious as to the exact manner in which the vagus nerve
brings about inhibition of heart action. Similar inhibition as a result
of stimulation of efferent nerves exists in the case of the dilator fibers
to the bloo.l vessels (pa^e 234) and the sympathetic nerve to the intes-
tine (page 407). Inhibition of voluntary muscles can be produced only
through the central nervous svstem by stimulation of afferent nerves

left Ant i

.ftiqht An!

inic
foitai

nouron

Inf Vena cava

Bi dd

i Jr ,„ •< f» '

Sympathetic fibre* - tfo/ted ///

I III I

[ ■ . 1 L-' « - "II I '

for the inhibitory

.-ml Hi" a CUl

the anterior ro<

of tin- latter w lnii thej
ration \\ h i«li folio

still produce inhibition o
therefore be the factor u] hich t!

is dependent. This l.a\ es l
tli." hearl tructurea in

rendered inhibitory in natui

lias been conaidei ab ■
must be occurring in tin- I
practically nothing that i- definiti
ever, is that tin- electrical
trodea from two portions of the auricl
take th«' same direction \\ hen t i
it takes when the motor nei
lat. -.1 A positive instead of n negati
Bince a negative variation is alv

breakdou □ changes n i g in th<

contraction, it is assumed tl
illation of the vagus mut»1 ind
a building up, or anabolic pn

• ul. I fit in >tly \\ i t li •

been held in standstill ime tii

er after the inhibition

• nis to ha •

inhibition produced b]
heart, bo that v

The Manner of Termination of the VagU Fibers in ioart

siilij.-.-t i- able pi

In approachii
■ s tih.-i > belong
• -

periphi • al I
which ganglionic medul
.•••Us. become conm

exisl '*■

known for I long ' in
junction, at tl i

22G

THE CIRCULATION OF THE BLOOD

auriculoventricular junction. The function of the ganglia is to serve as
cell stations on the course of the vagus nerves. (Fig. 68.)

Nicotine is a drug which in certain concentrations, if applied locally
to sympathetic ganglia, specifically paralyzes the synapses between the
ends of the preganglionic fibers and the cells from which the post-
ganglionic fibers arise. If this drug is applied in a 1 per cent solution
to the heart, stimulation of the vagus trunk no longer produces inhibi-
tion, but if the stimulus is applied to a portion of the heart known as

^-a^A e$i4*t& tT$-*t£**>t*svoi-

^<itfc4 t^ictd off -*t£&o££*xc-

bii<Arvu(A.

il/w*~-UAAft/y-s'i M

Fig. 69. — Frog heart tracing showing the action of nicotine. The vagus trunk was stimulated
as indicated. In the normal (lower) tracing inhibition occurs hut after nicotine (second tracing)
no inhibition follows. Stimulation of the crescent in the next two lines still is followed by inhibi-
tion. The final effects of the drug are shown in the last two (upper) tracings. (From Jackson.)

the white crescentic line, inhibition still occurs, because at this point the
postganglionic nerve fibers come near to the surface and therefore are
stimulated (Fig. 69). On the other hand, atropine is a drug which
paralyzes the postganglionic fibers, so that after its application to the
heart inhibition can not be produced by stimulating either the vagus
trunk or the white crescentic line. Pilocarpine and muscarine are drugs
which have an action exactly opposite or antagonistic to that of atro-

rledulla

oblongata

N XI

Cervical 1

Accessory n
to trape2ius.

Spinal
medulla -
{cord)

Ram!
communican-

tes going to
Symp gang,
(preganglionic
Ansa

iu be la via
(Annului of

Vieussem '

Thoracic
nerves

N I

Postganglionic
are a

ti.VI

N.X

Jugular ganglion (Gang
Depressor
(Sensory) Sep*

Nodosum ganglion (c I
■Inhibitory cranial BVtotK

Superior cervical ganglion

OescenCing sympathetic fibers
- Cervical vago-symc •

Subclavian
art.

ctrodes (si.-
heart Augmentat.

-

Electrodes
(Acceleration, or

augmentation ot heart '

•I HI ■

pine; that is, the} Btim
slow ing and possibl) an i

In the mammalian I

-ns ii«t • pi oc< -••! 'In eel
be shown histological
< >n the other hand, the
I »i • to tin- auriculo> i

turea are abundanl i - *

results w hich follow Btimulatioi
influence which the nen •
the majority of i' I

vagus i^ likely to produce slov
stimulation of tin- lefl vagus is more I
partial heart-block.

< »ii account of tin- differ*
lating the vagus, some air horiti<
contain four kinds of ;
each kind <>t' influence \\ hich tl
ences are, it will In- remembered, on I
propagation of the heartbeat, an. I
!• is, however, almosl certainly unn<
tinn, for the results can be
ferenl dec "' stimulation

exacl part of the ln-art to which tl

ample, when the right vagus m
I nly a diminution in thi

•

their rate, indicating thai I
the auricular «i alls and i
is increased a little, then both i
indicating thai the Btimulus
culature directlj and I

Tin- Sympathetic Control

Tin mpat I 1 as

being exactly opp<
the tih'-rs of thi

y arise in the mamm
upper thoracic portion of tl

ponding spinal i
the sympathi ain, up

rvical ganglis \
til-.

228

THE CIRCULATION OK THE I'.LOOI)

as postganglionic fibers, proceeding to the hearl through branches com-
ing off from the stellate ganglion itself, or From the ansa subclavii <>r

interior cervical ganglion. (Fig. 70). hi cold-blooded animals, such as
the frog, the sympathetic fibers run up to the upper end of the cervical
sympathetic and join the vagus immediately after it leaves the cranial
cavity. They then proceed along with this uerve — forming the vago-
sympathetic— to the heart. The effect of stimulation is shown in Fig. 71.
The sympathetic nerve differs from the vagus in that a much longer la-
tent period elapses before its influence becomes effective, and this persists
for a much longer period after the stimulus is withdrawn. If the vagus

U\j\jMimmn

a ii ii i ii

\J VJ vj U VJ M

-n-wvtmuvvv mvvvivwhU-wuM**4*-yuM*>+vMVAM4VH4Vmumv*-v^»4^

A.

»nu>UIU>l>»t»UMMll»M'>»Mlt><l>»n>>HW^Vt*^»l*UU>»U>>ll<M«i^l>»>l>t>>l>>'>>>ll<»iM4-tV>->>t>ni>UUIUtVHVH»M4<^HU

B.

Fig. 71. — Tracings showing the effects on the heartbeat of the frog resulting from stimulation of
the sympathetic nerves prior to their union with the vagus nerve. (From Brodie.)

and sympathetic are stimulated at the same time, as by exciting the vago-
sympathetic in the frog, the first effect observed is that of the vagus
usually folloAved, after removal of the stimulus, by the sympathetic ef-
fect. If the stimulus is maintained for a long time, so that the vagus
becomes fatigued, escapement Avill occur earlier than with pure vagus
stimulation, and augmentation may become apparent. The sympathetic
influence is, however, never so strong as that of the vagus. The two
nerves are therefore not antagonistic in the sense that the one neutralizes
the effect of the other; but when both are stimulated, the heart responds
first to the vagus and later to the sympathetic.

I llAl'l l.i; XXVI
THE < • >NTR< »I. OF l III: I UN i LAT1

THE NERVE CONTROL OF THE PERIPHERAL KKSISTA*.

As already explaii ed, 1
takes place through I
fibers "ii the musculatun
impulses like those in tin n a

nervt itaining such fibi

dergo dilatation
ulated artificially, coi
lator impulses <l" not ap]
be tonic, bo that the cuttii
tln-ir stimulation, however,
are contained in mosl

their p
condition of the 1>1<m><1

Methods for the Detection of Constriction .on

everal methods, varying with t;
be used for i

<l! Ills;

Bernard on the M 1 i

this is held \\ ith a light I
eorr< ling side

* w ill Bpring in*
ma! inspect ion is us
ing lilntation

! in thi

\ ■

is oik

or foot w

part ri

dom thfOUgl

t \> 1 1 1 \Y i

280

THE CIRCULATION OF THE BLOOD

distinct rise in temperature will be observed when the sciatic nerve Of the
corresponding limb is cut. The application of this principle in deter-
mining the mass movement of blood by the amount of heat given off from
the hands or feet has already been explained.

Other methods depend upon observation of the outflow of blood from
the veins of the part. A simple application of this method can be used in
t hr ease of the ear of the rabbit. If the tip of the ear is cut off, bleeding
under ordinary circumstances is only very slight, but if the cervical
sympathetic is cut, it becomes quite marked, slowing down again or
even stopping entirely when the peripheral end of the nerve is stimu-
lated. By making measurements of the volume of the outflow of blood
from a vein by this method, the extent of constriction or dilatation can

tube to recorder

enclosed
membrane

Fig. 72. — Roy's kidney oncometer. (From Jackson.)

be followed quantitatively. Vasodilatation also causes changes in the
character of the venous flow, the usually continuous flow becoming pul-
satile and the color of the blood brightening. Comparison of the pressures
in the arteries and the veins of a part is also often of value in the detec-
tion of changes in the caliber of the blood vessels, for, of course, the
greater the difference in pressure between the two manometers, the
greater must be the resistance offered to the flow.

For experimental purposes, however, the standard method is that
known as the pletkysmographic. For this purpose the organ or tissue is
enclosed in a so-called plethysmograph or volume recorder, the prin-
ciple of which will be clearly seen by consultation of the accompanying
diagram of one adapted for tbe kidney (Fig. 72). Any increase de-
tected by this means in the volume of the part must be due cither to

'

'

■

,11

an increase in blood i!"
action or to a local vasodil
curs We car do! t.-n from th<
chfl a i ■ • - .- i 1 1 > reapon8ibl(

bj simultaneously o
falls w hen the volumi
ing to the pari must have b<
blood pressure remaii
means thai the M I

Methods for the Detection of Vasomotor I in N- : , ■ Trunks

1 1 \\ I- \\ -isli in find "ut through whi '»r

area is Bupplied \\ itli

l" 'I by the us<

effecl produced on th<

lating tli-- peripheral end

t'n. us it lias been found thai 1 1 i

tributed bo thai those having

mainly in m>. ■• trim'

in - trunks, hi

lilicrs arc aboul equal. N

istrictor fibers are i he

ami those containing i

ipani nen e to the submaxill
external genitalia.
It must l.c clearly und<

preponderate in one of
also present. In the cen ical -
ling to tl i
■i readilj
of these parts u hen I ;
similarly, even in I
siipph ing tin

the rostrictor til-

efted of the latter i

thai p. ir. i

fibei

nic nerve

The pr<

I chorda t \ m

strat.-. I
A

232 THE CIRCULATION OF THE BLOOD

ture of both kinds of vasomotor fibers is the sciatic. If the hind limb of
a dog is placed in a plethysinograph and simultaneously a record of the
mean arterial" blood pressure taken, it will be found on cutting the sciatic
nerve that the volume of the limb increases, whereas the blood pressure
remains practically constant. Before placing the limb in the plethysmo-
graphy the muscles must of course be paralyzed by means of curare;
otherwise muscular contractions would confuse the result. If the
peripheral end of the cut nerve is now stimulated, vasoconstriction "will
readily be observed. So far, then, the results demonstrate the presence
of vasoconstrictor nerve fibers alone.

To demonstrate the presence of vasodilators a different procedure is
necessary. This is based on the following facts: (1) The vasodilator
nerve fibers degenerate more slowly than the vasoconstrictor; (2) they
are less depressed in their excitability by cooling the nerve; and (3) they
are more sensitive to weak slow faradic stimulation than the vasocon-
strictor fibers. Accordingly, if we cut the sciatic nerve two or three
days before the actual experiment, and then, while observing the volume
of the limb, proceed to stimulate the half-degenerated nerve with feeble
electric stimuli of sIoav frequency we shall usually observe a dilatation
of the limb instead of constriction; and even if we cool a stretch of a
freshly cut nerve before applying the stimulus, the same result will
often be obtained.

The Origin of Vasomotor Nerve Fibers

Having seen how the presence of vasomotor fibers may be detected in
peripheral nerves, we must now proceed to trace them back to their
origin from the central nervous system. The method for doing this con-
sists, in general, in observing the effect on the blood vessels produced by
cutting or stimulating the various nerve roots through which the fibers
might pass on their way to the nerve trunks. As a result of such obser-
vations it has been found that all of the vasoconstrictor fibers emanate
from the spinal cord in the region between the level of the second thoracic
and that of the second or third lumbar spinal roots, but from nowhere
else in the cerebrospinal axis. Section of the spinal cord below the level
of the second lumbar spinal roots produces no change in the volume of
the hind limb, provided the muscles be thoroughly curarized, nor docs
stimulation of the lower end of the enl spinal cord have any effect. If
the last two thoracic or the first two lumbar spinal roots are stimulated,
however, evidence of vasoconstriction will be obtained.

The restriction of the origin of vasoconstrictor fibers to the above-
mentioned regions of the spinal cord indicates thai in proceeding to
the mixed nerve trunks they must travel along special nerve paths.

I II

Th< • pro id< d

The

I iy w ;i\ of t i

the neighboring bj m]

desci ii- 1 a irding to thi

come into contact w ith tl

which they may pi

ri\ ea at Bom< glion, in

around one of th<

then continm

to the spinal n«-r\ .■ be

!.. the p"int w here il •
cell, it is medulla ted and is
the n< sell, it is nonm< dullat

■■•■ -77

lion in

ell «;ni

the ganglion ot

■

tinll
till- .

applicat ion

i'lT. i

t In- il ill W I

;)ionic

lionic 1
H hiti- r;i in 1 :il :i In.

■

■

Ml f

234 THE CIRCULATION OP THE BLOOD

roots. Tho thoracic fibers pass down the sympathetic chain, which they leave by the
great splanchnic nerves. The lumbar fibers form the lesser or abdominal splanchnic
nerves. As preganglionic fibers, therefore, these fibers are carried by the greater and
lesser splanchnic nerves into the abdomen, where the former comes into close relation-
ship with the suprarenal gland's, giving off a branch to the suprarenal ganglion. The
main course of the nerve is continued on to the solar plexus, in the various ganglia of
which most of the preganglionic fibers end by synapsis, the postganglionic fibers then
proceeding along the blood vessels to the vessels of the abdominal viscera. (See also
page S70).

Vasodilator fibers have a more varied origin than vasoconstrictor, and
they run an entirely different course. Vasodilator impulses may he
transmitted by fibers arising from practically any level of the cerebro-
spinal axis, not only by the motor roots, but by the sensory as well.
Thus, they pass out of the spinal cord in the posterior sacral roots to
enter the nerves of the hind limbs, as has been demonstrated by observ-
ing an increase in the volume of the curarized limb during electrical
stimulation of the exposed rootlets. The apparent inconsistency of these
observations with the well-known law concerning the direction of the
impulses contained in the posterior spinal roots is explained by assum-
ing that the dilator impulses are transmitted along the ordinary sensory
fibers, since there are no efferent fibers in these roots. They are impul-
ses which go against the ordinary stream (antidromic). In support of
this explanation it is of importance to note that at their termination
near the skin many sensory fibers split into several branches, some of
which run to blood vessels, and others to receptor organs (page 797).
Stimulation of the latter branches may cause dilatation of the local blood
vessels nearby, indicating that impulses must be transmitted up to the
point at which the branching occurs and then down the vascular branch,
this result being obtained even after the main trunk of the nerve has
been cut above the division.

For the blood vessels of the anterior extremity, the vasodilator impulses are similarly
transmitted through the posterior spinal roots of the lower cervical region of the spinal
cord. The vasodilator fibers to the abdominal viscera are transmitted with the splanchnic
nerves, but they may also be derived from the posterior spinal roots, for it has been
found that stimulation of posterior roots in the splanchnic area causes dilatation in the
intestine (Bayliss). Vasodilator fibers are also contained in the cranial nerves, par-
ticularly the seventh and the ninth, being distributed in the former nerve to the an-
terior portion of the tongue and the salivary glands, and in the latter to the posterior
portion of the tongue and the mucous membrane of the floor of the mouth. The vaso-
dilator fibers for the mucous membrane of the inside of the cheeks and nares have their
course in the cervical sympathetic, being distributed to the buccofacial region in the
branches of the fifth cranial nerve.

There is evidence to show that the vasodilator libers, like the vasoconstrictor, become
connected by synapsis with nerve cells somewhere in their course. In the case of the
vasodilator fibers in the chorda tympani and nervi erigentes, such cell stations have
been clearh demonstrated in the liilus of the submaxillary gland in the former nerve

Ill:

nii'l in j lj^ • .

■ •>- il n • •» .-1

i.. which thi
then

til..

The Vasomotor Ni

1 ' if next problem
nervous Bystem, and find tl
the nerve centers from w hich tl

stenee of both \
is no adequate e^ idei
the latter, v. e mnsl confii e oui
Tli. it two levels in 1 1

ler of the Bpinal <l. and 2 in thi

oblongata.

The spinal, or as the}
cent re represented b

ter in the thoracic portion i
g] ionic vi strictor fibers abo

location of the nen «• cells comp

nol as j et 1 ii definitely made oul I

the vagus center s< e Rai I

Bcend in the lateral columi

iund the cells of the Bubsidii
horns.

The experimental i • idi i ce w hich ii
subsidiary centers is quite d< I

1"\>. ■ ical region below t! •

\\ itli the moi ements of t! e dia]

found); . because '
\ • ■ daj b, ho

I r after this has occurrt tl, tl
down • rtebral canal,

indicating that th<

ill.- pathw n\ !
ha\ e been broughl ah<

ni independcnl •
fore demons!

themselvt <

• Tilt

puis

236 THE CIRC1 I. ATI ()X OF THE BLOOD

arrive, then a hitherto dormant power of tonic activity becomes devel-
oped in the subsidiary centers.

Independent Tonicity of Blood Vessels

Even after complete disconnection of the spinal cord from the blood
vessels, as by cutting of the splanchnic nerve to the abdomen or abla-
tion of that portion of the lower spinal cord from which the fibers to
the hind limb arise, the disconnected blood vessels, although at first
completely dilated, may later reacquire an independent tone of their
own, indicating therefore, that they must possess some neuromuscular
mechanism which can act independently of the nerve centers, and which
may be stimulated to activity by the presence of hormones in the blood.
The hormone was at one time thought to be epinephrine (see page 745).

Epinephrine control is indicated in the effect produced upon arterial
blood pressure by stimulation of the great splanchnic nerve. Careful
analysis of the curve, shown in Fig. 29, shows that the rise is both im-
mediate and delayed ; that is, the curve mounts immediately, then flat-
tens out a little, and then assumes a further rise. This delayed response
seems to depend upon the excretion of epinephrine into the blood, for it
does not occur when the suprarenal veins are occluded, and is much de-
layed by temporarily clamping the suprarenal veins on the same side
as that on which the splanchnic nerve is stimulated. It has been stated
by certain observers that, after occlusion of the adrenal veins, there is
a downward tendency, of the blood pressure, which however develops
with extreme slowness; and that a distinct elevation of blood pressure
follows the removal of a clamp temporarily placed on the adrenal veins.
This rise is pronounced if the splanchnic nerve is stimulated during the
occlusion of the veins. It must of course be understood that the imme-
diate rise in blood pressure following splanchnic stimulation is caused by
vasoconstriction in the splanchnic area itself, as is evidenced by the
fact that it does not occur, or is only very faint, when the abdominal
blood vessels are ligated prior to the stimulation of the splanchnic nerve.
Even after ligation of the adrenal veins and of the blood vessels of the
splanchnic area, stimulation of the splanchnic nerve may still cause a
slight rise in arterial blood pressure, possibly because some fibers may
run from the splanchnic to vascular areas not situated within the realm
of the splanchnic nerve- for example, the blood vessels of the lumbar
muscles.

CHAPTKH XXVII

I ill. I ONTROL "l I ill. I li;. i I

CONTROL OF THE VASOMOTOR I

The acth itiea of tl>«' \ a
mones and partly bj afferenl imp .

The Hormone Control

As u ith t In- respirator} cenl
concentration of the blood. When ti
\ asoconsl rictor pari of I ! •
thai the blood \ easels ar<
ing, .!• criterion "t' h) d
carbon tli<»\i<l«- in the l»l I

• • the relationship bj iani

in the carbon-dioxide tension broughl nal

breathe atmospheres containing
s«.ii' Thus, if a decerel
containing 5 per «,«,nt or a

lira in the arterial blood

•In- liy<li-"
by tin fad thai a similai
\ enous inj«'<-t ion of a

.it.

Ilisti-.nl of iiij<-<-t .

in the muscli animal i'

supply. When a d

atmosphei

aboul

this latenl period in 1 1

carbon dioxide is inspi

Ik- produced in thi

is important to

employ ed -
which the reaull
tion caus<

238 THE CIRCULATION OF THE BLOOD

some time, but the explanation that has usually been given has been that
it is due to a direct effect of oxygen want on the center.

The sensitivity of the medullary center towards the hydrogen-ion is
many times greater than that of the subsidiary centers in the spinal
cord. If an animal is kept alive by artificial respiration for some time
after cutting the cervical spinal cord, the subsidiary vasomotor centers
will, as "\ve have seen, gradually acquire a tonic action, and the lowered
blood pressure will gradually rise again. If, when this has been attained,
the animal is made to breathe an atmosphere rich in carbon dioxide, a sud-
den rise in blood pressure will occur, but to produce it a very much
greater percentage of this gas must be inspired than when the pathway
between the chief and subsidiary centers is intact. Whereas 5 per cent
carbon dioxide is sufficient to cause a rise of pressure in an animal hav-
ing its chief vasomotor center, it takes 25 per cent and upward to pro-
duce a like effect on a spinal animal; and similarly, although 2 c.c. of
N/15 lactic acid will stimulate the chief vasomotor center, it takes 5 c.c.
of N/2 to excite the spinal-cord centers.

The Nerve Control

However important hormones may be in maintaining a tonic stimula-
tion of the center, the more sudden changes in activity are mainly
brought about by afferent nerve impulses. The afferent impulses are
of two classes: (1) those causing a rise in blood pressure, called
pressor, and (2) those causing a fall in blood pressure, called depressor.
The effect produced on the arterial blood pressure by stimulation of
either pressor or depressor fibers is usually more or less evanescent,
especially in the case of the depressor fibers; and when the change fol-
lowing stimulation of the nerve passes off, the blood pressure always
returns to its former level. This indicates that the afferent impulses do
not affect the tonic control which the vasomotor center exereises on the
blood vessels. It has, therefore, been assumed by Porter10 that there are
really two kinds of A-asomotor centers: one concerned merely in the
bringing about of temporary reflex changes, the other concerned in the
maintenance of the vascular tone. It may be that the activities of the
former are primarily dependent upon afferent impulses, and the latter,
upon hormones. Justification for this view has been found in observa-
tions made on the effects of stimulation of pressor and depressor fibers
in animals under the influence of curare or alcohol. With the former
drug, stimulation of a nerve containing a preponderance of pressor or
depressor fibers produces double its usual effect, but the mean level of
the blood pressure apart from this effect remains unchanged. With the
latter drug (alcohol), on the other hand, the reflex response entirely

i 111

disappears, althoui
h;is passed <>IT, and
and the refit hanisi

identical.

\' the presenl stape
Btndy the effect "i* Btimulal
\ aaoreflex centei 3uch ii;
Borj uen e of the body, and H
ut* both kinds of fib

Pressor and Depressor Impulses. I ><
in the cardim <l< pi
as an independent nen e trunk
the Buperior larj ngeal, tl i

\ agns trunk, to I
the depressor is bound up w ith '
times !"■ Beparab 'I '•;■ i

I iiil: the cause of tl
is the eliminatioi

imultaneous Btimul
either by cutting both

mulatioo
an animal
incn
one of the abdominal \ i«

w • •
bj a si -

rial lil 1 pi •

• •

240 I in CIRCl NATION OP 1 BE BLOOD

abdominal discus becomes diminished evidence of general vasoconstric-
tion. .Bui when the sensory nerve is stimulated with extremely weak
faradic shocks, an entirely different result is likely to be obtained;
namely, a fall of blood pressure and an increase in volume of the limb
or visens. indicating that in this manner we have stimulated depressor
liters. By careful experimentation with quantitatively graduated elec-
trical stimuli, it has been found by Martin and others17 that on stimu-
lating an afferent nerve with weak shocks, a fall in blood pressure is
the first effect to be observed, and that this becomes more and more
marked as the strength of the stimuli is increased, until a certain opti-
mum is reached, after which the fall in blood pressure becomes less evi-
dent. When a certain strength of stimulation is exceeded, a rise instead
of a fall occurs. After this point additional increase in stimulation causes
more and more marked elevation of blood pressure through a very long
range of stimuli.

Stimulation of two afferent nerves at the same time usually produces
a greater reflex vasomotor change than the stimulation with an equiva-
lent strength of current of either nerve alone. That is to say, the effect
produced by stimulating the central end of both sciatics simultaneously
will be greater than that produced by stimulating either alone with double
the strength of stimulus.

As has been stated above, the reflex change in blood pressure is often
quite transitory in nature, although the stimulation of the pressor nerve is
maintained. "When this decline has occurred, the pressor reaction can
often be renewed by shifting the stimulation to a second nerve. These
facts concerning the greater efficacy of combined stimulation of several
nerves are of considerable importance in connection with the general
question of reflex changes in blood pressure. For instance, many of the
pressor fibers found in the sciatic nerve are connected with the receptors
that mediate the sensations of the skin. When these receptors are
stimulated, as by heat or cold, reflex changes in blood pressure occur
(pressor reaction), (Fig. 74), and it is important to remember that
localized stimulation of the skin is less efficient in bringing about such
vascular changes than stimulation applied over large areas, even when
the local stimulus is intense and the general stimulus mild in character.
•I i imping into a moderately cold bath will cause a much greater rise in
arterial blood pressure than plunging the hand into ice cold water.

Mechanism of Action of Pressor and Depressor Impulses. — When Ave
consider the exact mechanism by which these afferent impulses operate,
we have to bear in mind four possibilities: the reflex fall produced by
stimulation of. a depressor afferent fiber may be due either to a stimula-
tion of the vasodilator pari of the center or to an inhibition of the tone

(.t the

caused

the vasoconstrictor

the \ asodilator pi I \

sIlOU II tO or. Mil-. Jit

HuL+ftiU

for the inhibition ol
Withoul

imple
tained, the exp<
lation which results
parti} iii..\ al

242

THE C1RCILATION OF THE BLOOD

stimulation. The volume of the hind limb of a curarized and vagotomized
rabbit increases when the central end of the cardiac depressor nerve is
stimulated. In order to determine whether this dilatation is due solely
to the removal of vasoconstrictor tone, the above experiment was repeated
on a rabbit in which the sympathetic chain had been cut below the level
of the second lumbar spinal roots. By such an operation all the vaso-
constrictor fibers to the vessels of the hind limb are severed, but the
vasodilator fibers, since they emanate through the sacral sensory roots,
are left intact. It was nevertheless found on stimulating the depressor
nerve that dilatation of the hind limb still occurred, thus indicating

Fig. 75. — Diagram showing the probable arrangements of the vasomotor reflexes.

A. Muscle of arteriole.

D. Vasodilator nerve fiber terminating on A and inhibiting its natural tonus, as indicated by -
sign.

C. Vasoconstrictor fiber also ending in A, but exciting it ( + )• These two kinds of fiber arise
from the dilator center (DC) and the constrictor center (CC) respectively.

F. Afferent depressor fiber, dividing into two branches, one of which (-) inhibits the con-
strictor center, while the other (+) excites the dilator center causing dilatation of the arteriole and
fall of blood pressure.

R. Pressor fiber exciting CC and inhibiting DC, and therefore causing vasoconstriction and rise
of blood pressure.

a, b, c, and d represent the synapses of the pressor and depressor branches with the efferent
neurons. (From Bayliss.)

that stimulation through vasodilator fibers must have taken place. Con-
versely, in another experiment, instead of the sympathetic chain, the
spinal cord was cut below the level of the second lumbar segment, thus

ering the dilator '
stimulation caused the \ ol in
an inhibition of <-"ii-'

Reciprocal Innervation of Vascular Area*

It must imt be imagini >l i I
•curring in oi •
the body. On the contrary

its in the I'l 1 supply to diff< I

example, more I>1<><><1 is required bj

■ t. and this is insured l.\ di
with reciprocal constriction of th<

• of the relatively
dilatation during digest h e acl

rtriction of tin' other \ that 1

essitating a more po>n erful
the mean pressure. After 1
as n role fall bo much as the diasl
sure pulse therefoi >mes g

applied to the \ w ith ei

thai is throM a on them, w eak<
the brain.

A ample of reciprocal action

in muscular ■ Tl ■

th«. istii>-t. The !■ ■

■ entirely at least a
l>y hormo

gen-ion i centration ill,

local irritants t<> tin-

menU set in the same

ficial and perha]

tion of those < \

of skin similarly i "<*!

dilatation elae* hen I
the body, such
ran be Bhon ii. i •
ipplied

Ex]

! bj nui i
ulnr ner

■ •

-II THE CIRCULATION OP THE BLOOD

sure (Loven reflex). Similarly when the centra] end of one of the sen-
sory roots of the leg of a dog is stimulated, there is a rise in arterial
blood pressure and an increase in the volume of the limb.

THE INFLUENCE OF GRAVITY ON THE CIRCULATION

If the arterial blood pressure is measured in the arm and leg in a man
standing erect, a difference corresponding to the hydrostatic effect of
gravity will be found between the two readings. In comparison with
the high pressure normally existing in the arteries, this difference is.
however, of little significance. On the other hand, in the veins, Avhere
the average pressure is low, gravity would cause serious embarrassment
to the circulation of blood were it not for the valves and the forces
which move the blood beyond them (page 214).

In erect animals the part of the circulation in which blood might stag-
nate as a result of gravity is the splanchnic area. Were such stagna-
tion to occur, the blood would not be returned to the right heart, so
that the arteries would not receive sufficient blood to maintain an ade-
quate circulation, particularly in the vessels of the brain.

Simple experiments devised by Leonard Hill19' 2S illustrate these prin-
ciples. When a snake, for example, is pinned out on a long piece of
wood and an opening made opposite the heart, this organ can be seen
to fill adequately with blood as long as the animal is maintained in the
horizontal position. When placed vertically, however, the heart be-
comes bloodless. If now the tail end of the animal is placed in a cylinder
of water so as to overcome the effect of gravity, the heart will be seen
to fill again with blood. Evidently in such an animal there is no mechan-
ism to compensate for gravity.

If a domestic rabbit with a large pendulous abdomen is held in the
vertical tail-down position, stagnation of blood in the splanchnic ves-
sels occurs to such an extent that in from fifteen to twenty minutes the
animal dies from cerebral anemia. If an abdominal binder is first of all
applied, the vertical position will not have the same consequences. This
experiment illustrates clearly the possible evil effects that gravity may
produce in animals in which no mechanism exists to compensate for it.

Placing an animal such as a dog under lighl ether anesthesia in the
vertical tail-down position produces an immediate fall in arterial blood
pressure, as shown in the tracing (Fig. 76), followed by a certain de-
gree of compensation even while the animal is si ill in the erect position.
The extenl to which this compensation occurs varies with the depth of
the anesthesia. If the experiment is repeated after administering a large
dose of chloroform, not only will the initial fall he much greater, but

I III

subsequent compensation \\ ill b<

th.'si- facts in tl

Leonard I lill has ^1
pensating mechanism I

■

2 the t"ii>- of the splanchn
rlir respirator} movei
tor <-;in be readih shou n h
inal wnlls in :in .

I \ ■

till"

animal is nov ;

246

THE CIRCULATION OF THE BLOOD

to the zero line and the animal soon dies (Fig. 78). The influence of the
third factor is not so great as of the other two, but can be shown by the
increased respiratory activity which is likely to develop in the vertical

Fig. 78. — The effect of gravity on the aortic pressure after division of the spinal cord in the

upper dorsal region. By placing the animal in the vertical feet-down posture, the pressure fell

almost to zero, but on returning it to the horizontal posture, the circulation was restored. (From
Leonard Hill.)

tail-down position, the anemic condition of the respiratory center being
no doubt the cause of the increased respiration.

i I! ATI ,||

PECULIARITIES OP BL I SUPPLY I

Up to the
from i ral point oi

p, in which the
liar requirements of blood
incased as it is in the rigid craniun
expand as a result
hand, we know thai tl i

erably from time to time
which Buch changes are brougl I In

• •illation is peculiai
organ by two \ easels,

and in the <>tli-T. onder 1"\\ p v.

tionship of these I

the coronary and puln
ti"ii "ii a nut highly

THE CIRCULATION IN THE BRAIN

Anatomical Pecnli

tailment o
by the exist \v.

and tl ■

the bl I supplj of tl •'*

as the 'l'"_r. the four main
In man, 1

I in tl •

the ••'•Mi rai > . ti ■ **at

is to lo*» Do!

brand

t-> the pia d '>u« mailer bra

ulii'-h freely *ue.

248

THE CIRCULATION OF THE BLOOD

The venous blood is collected by the small, very thin-walled and valve-
less cerebral veins. These run together to form larger veins dis-
charging info the sinuses, the openings into which are kept patent by
t lie arrangement of dura mater around the orifices. The sinuses exist
between the dura and skull and are so constructed that they can not
be compressed, particularly those at the base of the brain. From them
the blood is conveyed mainly to the internal jugular vein, some of it
however escaping by the anastomoses existing between the cavernous
sinus and the opththalmic veins, and by the venous plexus of the spinal
cord. The most striking peculiarities of the veins are their patulous con-
dition and the absence of valves, so that any change in the blood pres-
sure in the internal jugular vein must be immediately reflected in that of
the venous sinuses. This explains why compression of the abdomen

Fig. 79. — Schema to show the relations of the Pacchionian bodies to the sinuses: d, d, Folds
of the dura mater, inclosing a sinus between them; v.b., the blood in the sinus; a, the arachnoidal
membrane; p, the pia mater; Pa., the Pacchionian body as a projection of the arachnoid into the
blood sinus. (From Howell's Physiology.)

causes venous blood to flow from an opening made in the longitudinal
sinus.

In considering the cerebral circulation, another factor that must be
borne in mind is the presence of cerebrospinal fluid. This is contained
in the subarachnoid spaces of the brain and spinal cord, these spaces, in
the case of the brain, being often considerably enlarged to form the
cisternae. The cerebrospinal fluid is also present in the ventricles of the
brain, which it will be remembered communicate with the subarachnoid
spaces through the foramen of Magendie, etc. It is unlikely that the
cerebrospinal fluid is of much importance in connection with the control
of the blood supply to the brain tissue. It may be merely a lubricating
fluid; at least it is so small in amount (60 to 80 c.c. in man) as to be
apparently of little value in bringing about an alteration in brain volume.

PI CI LIARI

Although Dormall;
ulated undei

Under these conditions in man
200 '■ ■■ a da} or mi
The fluid is apparently

ill.- pathu a\ H by M 1 1 1 • - 1 1 tin

noid Bpace are obstructed, it colli i

hydrocephalus. I Fnd<

rapid, an Rhown experimentally b} th<

saline is absorbed « hen it is in

absorption is belies <-<\ to |

arc minute sac like protrusi

\cii. »us sinus Tl e mem

Muiil is extremely thin at l

Physical Conditions ot Circulation

1 "i accounl of these anatomical peculia
trolling tin' circulation of bl

from ' ' ibtaining in an

exception of the bones. In othei

dilatation or constriction of ti

diminution of the volume "t" t i

in volume is evidently imp<

the rigid cranium in which it [i

poinl <»f view w e musl

jecting into a ci'_ri'l • lied with

these conditions it i- <<h\ ious 1 1

contract inn- dilate v. ithoul son

the contents of tin- cranial

ime hai <■ thoughl that tl i
of the spinal cord mig I
tents, bul the relative!} small
the small! the openi

flu- lack of experimental

spinal fluid in tl
diction to such a \ iev I !
not contracl

* siniulta
such as the sm.i

that it is only

in."- in the calilx

250 THE CIRCULATION OF THE BLOOD

to see how such reciprocal dilatation and constriction could be of any
advantage except perhaps in causing certain areas to receive more
blood than others. A reciprocal relationship might also exist between
adjacent arterioles as well as between arterioles and veins; when, for
example, the arm center becomes active, it is conceivable that its
arterioles might dilate at the same moment that those of a neighboring,
less active center become constricted. Alterations obviously might oc-
cur without causing any perceptible change either in the volume of the
brain as a whole or in the condition of venous flow.

In consideration of these factors, most observers are agreed that the
total volume of blood in the brain must be constant at all times (Monro
and Kellie doctrine). Alteration of blood supply can, however, still be
brought about by changes in the velocity with which the blood traverses
the vessels. When more blood is required in the brain to supply the
increased metabolism which we must presume accompanies heightened
mental activity, it is not accomplished as in other parts of the body by
an increase in the capacity of the vessels as compared with those of
other vascular .areas, but by a hurrying up of the circulation through
vessels whose caliber remains unaltered.

The main factors determining the velocity of bloodfloiv through the
brain must, therefore, be dependent upon changes occurring elsewhere
in the vascular system, a conclusion for which there is abundant experi-
mental evidence. Of the many ingenious methods that have been de-
vised to secure this evidence, we will cite but one in this place. Records
are taken of changes in: (1) the venous blood pressure of the brain by
connecting a cannula either with the vein immediately after leaving the
skull or, better still, with the torcular Herophili; (2) the brain volume,
by connecting a very sensitive receiving tambour with a trephine hole
in the cranium so that its open end lies against the pia mater.* Al-
though, as we have seen, while incased in the rigid cranium the brain
volume can not change to any degree, yet this will occur when a
portion of the cranium is removed, so that pulsations correspond-
ing to those in the blood vessels will be observed; (3) the circula-
tory conditions elsewhere in the body, by taking arterial and
venous pressures and plethysmograms. The results in a normal an-
imal show the following points (see Fig. 80): (1) The tracings of
the arterial blood pressure (A), the brain volume (C) and the intra-
cranial venous pressure (C) have exactly the same contour — that is,
the respiratory and the cardiac waves in all three of them are identical.
The venous blood as it flows into the jugular veins also pulsates in

"This receiving tambour really consists of a brass tube of the same diameter as the trephine
hole, into which it is tightly fitted. The brass tube is closed at its inner end by thin rubber membrane,
and its outer end is connected with the receiving tambour.

i \i:iiii

■

in. is,, M with the a-.

temie venom m is imi

of the sii if the brain and in I

;i mpanyini ii g \

the brain which can not b<

elsewhere in th<
suit is importanl
ntrol i

raking into 1

hut alao *

252 THE CIRCULATION OF THE BLOOD

we must conclude that changes in blood supply depend on changes in
the velocity of the bloodflow, and thai such alterations in velocity are
dependent upon changes occurring in the aortic and more especially
in the vena-cava pressure. When the aortic pressure rises, more blood
will flow into the cerebral arteries and move along them at an increased
velocity, the increased pressure probably causing a moderate degree
of passive dilatation, to allow extra room for which the numerous
small cerebral veins become compressed. This compression of the veins
probably does not obstruct the greater Mow <>\' blood through them, be-
cause, taken as a whole, they are ordinarily much more capacious than
need be. On the other hand, if the aortic pressure should remain con-
stant, but that in the vena cava increase, then there would be obstruc-
tion to the passage of blood in the intracranial arteries, and conse-
quently a diminished velocity of flow.

Vasomotor Nerves

It might be inferred that, since the bloodflow through the cerebral
vessels is mainly dependent on vascular conditions elsewhere in the
body, there would be no need, as in the vessels of other vascular areas,
for vasomotor fibers. Histologists have, however, discovered the pres-
ence of such fibers, and it has become necessary for the physiologist to
find out if they are really of importance in connection with the regula-
tion of the blood supply to the brain. Even if it is admitted that the
arterioles could not contract or expand as a whole without producing
local changes in venous pressure or cranial volume, it is yet of course
always possible, as has already been pointed out. that one set of arte-
rioles might contract at the same moment that another set expanded.

That the vessels can undergo a process of constriction has been shown
by experiments in which the volume of outflow from the vessels of
the brain was measured in perfused preparations of brain. When
epinephrine was added to the perfusion fluid, curtailment of outflow
was observed to occur (Wiggers). Since this drug causes constriction of
vessels only when these are supplied with constrictor fibers (see page
7:'>ii \ the conclusion may be drawn that the cerebral blood vessels do
contain such nerve fibers. Nevertheless, the local vasomotor control of
the cerebral blood vessels can not have the significance in connection
with changes in blood supply that it has for other vascular areas (Hill
and Maeleod20). No doubt nerve fibers are present in the cerebral
blood vessels, and presumably under certain conditions they are capable
of causing the blood vessels to undergo alterations in caliber, but it is
impossible to set of what real valut (his can bt under normal conditions.

II CI LIABI1

Intracranial Pre.s. .

I tae word more with
that is, the pressure in t! i
Under ordinary condil
laries, and maj be m<
a tul'i' Bcrev ed into tin- cranium as <i'
ary from 0 mm. Hg in i

dog pois <1 by Btrychnine It

pressioi] <>t' th.- \ eina of I he

pressure, bul also in pathnloj

new groM th in the brain, if it o<

is destroy ed, exerts pressure on all pari

cavity, bul this pressure m

tin- cranial «•< »nt «nt s. for the fal

porl a part of it. thus directii
pathwa; The Btructun I the ba
the veins <>t' < lalen ami the S3 1\ i.
way. It' th»- pressure is rapidly applied
out the cranial <-i.iit.-nK. in buc!
culatory in origin, sin.-.- immediatelj
tin- intracranial pressure i^ nol foum

Tin- major symptom*
anemia of the medulla obl<

applied locally in tin- hull. a f a

very Bmall foreign bodj or only trivial l
destroy lit".-, ot of pressure t:

which <-as<-. mi a« tint •'!' the BUpp

larger growth is required to affect th<
produced by blocking of I
causes th.- greatesl rise in intn

dulla, 1 an- brain 1^ dri

linst the occipital
pre« that ■

the symptoms of acute
tical l Leonard 1 1 1

common practice Tl

to the soil!- ! COl

CIRCULATION THROUGH THE I N
Tin- pulmonary

11 the

254 THE CIRCULATION OP THE BLOOD

in Ihe pulmonary arteries does not amount to more than about 20 mm.
Ilg, or about one-sixth of that of the systemic arteries, the peripheral
resistance in the blood vessels of the lungs is much less than that of
the body in general. This lower resistance is owing partly to the large
diameter of the arterioles and the small amount of muscular fibers in
their walls, and partly to the fact that the capillaries are held con-
stantly in a somewhat dilated condition on account of the subatmos-
pheric pressure in the thorax (see page 306).

Another peculiarity of the pulmonary circulation is that the caliber
of the vessels is to a very large extent dependent upon the changes
that occur in the intrathoracic pressure with each inspiration and ex-
piration. They become dilated on inspiration and contracted on ex-
piration. The extent to which these respiratory changes affect the
amount of blood contained in the lungs, is very considerable. At the
height of inspiration it is computed that a little more than eight per
cent of the whole blood in the body is contained in the lungs, whereas
on expiration it diminishes to between five and seven per cent.

A third peculiarity is that the pulmonic blood vessels are not sup-
plied with vasomotor nerve fibers — at least with such as can readily be
demonstrated. It is said that, when the pulmonary vessels are per-
fused and the outflow measured, a diminution in the latter is found to
occur when epinephrine is added to the injection fluid — a result which
is, however, denied by certain investigators. Changes in the bloodflow
have not been observed to occur when the vagus or sympathetic nerve
fibers running to the lungs are stimulated. In short, the conclusion
which we must draw is much the same as that for the blood vessels
of the brain — namely, that although, as a result of the epinephrine ex-
periment, we must admit that a vasomotor supply may possibly be
present, yet it is one which can be of no significance under normal
conditions.

When there is obstruction to the outflow of blood from the left ven-
tricle, as, for example, in cases of high aortic pressure, the blood is not
entirely discharged with each beat of the left ventricle, and therefore
dams back through the left auricle into the lungs. On account of the
marked distensibility of the pulmonary capillaries, a large amount of
this blood may collect there and thus make the lungs serve as a kind of
reservoir of the heart. When the capacity of this reservoir has, how-
ever, been overstepped, an increased peripheral resistance will come to
be offered to the movement of blood in the pulmonary arteries, the
pressure in which will consequently rise and sooner or later interfere
with the discharge from the right ventricle, causing as a result a stag-
nation of blood in the systemic veins, and a consequent increase in vol-

imp teh \ is

obviously also Bup<

left \ fiit ricle tu t In- left

CIRCULATION THBOUOB THK I .IV)

liver is the onlj
arterial blood, the former i
by way of the capacio
by the Btrikinglj -a he]

small ainiitiiit of blood which is ««U

and the biliary ducts, noi
the portal vein until the
point the two blood streams mi;
away by the Bublobuli

Methods of Ii on

l Btudj the relative im
ply, and also to im estig
the must sat iry method I

in volume flow rather than in th<
ume-flow measurement lias been i

207 to the hepatic
flow iif blood Prom the i
inth.w vessels intact, and then \
tiuii to the Aral rtromuhr

bloodflow or hi I pn

the entering vessels, and a
of the lh'\\ in both \ • •
measure the outfli
below the

d of th< \ a belov

placed around this

thread the vena "m

hepatic \ eina is n
flows iittu 0]
•
from tl •

clip on th< mti

the tl .ml tl

and \\ hen

256 THE CIRCULATION OF THE BLOOD

and the receiver tilted up so thai the 1»1 1 Hows at low pressure back

into the circulation. The receiver being of known capacity, the length
of time it takes the blood to fill it as determined by the piston recorder,
furnishes us with the necessary data from which to calculate the rate
of flow. The receiver is chosen of such a size that it takes only a few
seconds to fill, the diversion of blood into it not causing any material
fall in arterial pressure. The observations are repeated frequently.

Results. — By the use of these methods it has been found that the total
mass movement of blood to the liver of the dog varies between 1.46 and
2.40 C.C. per second for 100 grams of liver. Considerable changes may
occur in the arterial pressure without affecting the liver flow. When
the hepatic artery is occluded, the flow diminishes by about 30 per
cent, or conversely, when the portal vein is obstructed but the hepatic
artery left intact, by about 60 per cent, indicating that about one-third
of the total bloodflow through the liver is contributed by the hepatic
artery and two-thirds by the portal vein. Some blood, however, gains
the liver through anastomotic channels between it and the diaphrag-
matic veins.

The relative supply by the two vessels is subject to various condi-
tions. That through the hepatic artery, for example, may be very con-
siderably altered on account of vasoconstriction in this vessel, for its
Avails can easily be shown to be liberally supplied with vasoconstrictor
fibers carried by the hepatic plexus. This can be demonstrated by
the rise in blood pressure which occurs in a branch of the hepatic artery
during stimulation of the plexus. On the other hand, alterations in the
bloodflow in the portal vein can not be brought about by active con-
striction or dilatation of the intrahepatic branches of this vessel, no
active vasomotor fibers having been demonstrated by stimulation of
the hepatic nerves, although, as in the case of the brain and lung blood
vessels, a certain amount of constriction may occur under the influence
of epinephrine.

The bloodflow through the portal vein is dependent on changes oc-
curring at either end of the distribution of the vessel, that is, changes
occurring in the liver itself or in the intestine. Of these factors the lat-
ter is no doubt the more important, an increase not only in portal blood
pressure but also in portal bloodflow being readily produced by dila-
tation of the splanchnic blood vessels; for example, as the result of sec-
tion of the splanchnic nerve. Alterations in portal bloodflow brought
about by changes in the caliber of the vessels in the liver itself are
partly dependent upon changes in the branches of the hepatic artery.
Let us consider briefly how this may be broughl about. At the point
where the portal and hepatic arteries come together — that is, at the in-

I'l i i II MCI l

trahepatic capillai

equal, which mean* that

live tissue, the brand

t<> the blood tl«'\\ in'_r thro

tin- hepatic arterioles,

tor nei freat variation in I

changes \\ ill affect th<- d

tis^iif in w hich the artei ioh

thin-walled branches of the portal veil

of 'his tissu.- becomefl

in tin' hepatic artery, the p<

i tin- bloodflovt along then
striction occurs in the hepatic
tissue becomes diminished, the

them more readilj Macleod and R. O. 1J 1.

• Ifiir. • in Bupporl '»t' the abo> >

(low of I'l 1 I'miii the liver I 1 duri

patic plexus. The firsl effed is an ii
soon returns to its original amount, even l
plexus is k<-|>t up during the I

Mow must indicate either thai th<
not been maintained, or that it hat
bj a compensatory increase in tl
a in ;i 1 1 #■ i- of fact, \\ «• know that I

he hepatic pies
tion of the connective tissue in \\lii<-li l
tu such :ni extent, as i t of 1 1

permil the I'l 1 t.> flow thn

aae in outflow immediately
plexus, is in. doubt
the hepatie vessels, ;m<l it
organs during stimulation •

THE CORONARY CIRCULATU'*-

\\ ■ i 'u.lii-.i

w itli |
Us t.. Btlld) I
2 \\ hether thi
nt' the
JiVir

111 i ' ■' i • - 1 1 i • I i V i i

258 THE CIRCULATION OF THE BLOOD

movement of blood in 1 lie coronary vessels- namely, at the beginning
of systole, and again at the beginning of diastole. Nevertheless the
pressure pulse has the same contour in the coronary as in the systemic
circulation. (W. T. Porter.22) During systole the intramural branches
of the coronary artery are compressed and the blood pressed out of
them. This emptying of the vessels favors the flow of blood through
the heart walls.

Regarding the presence of coronary vasomotor nerves, there is at pres-
ent a certain amount of doubt. When strips of the coronary artery are
suspended in a solution of epinephrine, they undergo relaxation instead
of contraction. On the assumption that the action of epinephrine on
blood vessels is the same as that of stimulation of the vasoconstrictor
fibers, this result has been taken as evidence of the absence of such
fibers and the possible presence of vasodilator fibers. A somewhat
similar type of experiment has been performed by injecting epineph-
rine into the fluid used to perfuse the excised mammalian heart,
with the result that, when such injections are made into a heart that
is not beating, evidence of vasoconstriction is obtained, whereas when
injected into a beating heart, dilatation occurs. This latter result
may, however, be owing to the action of the epinephrine in stimulating
the cardiac contractions. Other observers, however, deny that the in-
jection of epinephrine into the coronary circulation has any influence
upon the outflow of the perfusion fluid. Taking the result of these
observations as a whole, we may at least conclude that epinephrine
does not produce the same marked vasoconstriction that it produces in
other blood vessels — a fact, which, as already stated, may be taken
advantage of in bringing about the rise in coronary pressure that is
necessary for successful resuscitation of the heart.

Attempts to demonstrate the presence of vasomotor fibers by electrical
stimulation of the vagus or sympathetic nerve have yielded results which
are quite inconclusive, although some observers assert that the vagus*
nerve carries vasoconstrictor fibers to the coronary vessels, and that
the sympathetic carries vasodilator.

CHAPTER \.\l\

I LINK \l. Al-I'i .1' \ l IONS OF I i.im UN PH

mi: i BODS-

In the follow ing chapl
us.- of the electrocardiogram, of pol
measurements. This is done to
employed for the accurate u

ELECTROCARDIOGRAMS

To obsen e I be electrical i -ita-

tion wave over the heart from aui
to place the electrodes directly on th<
may follow the electrical change bj
to the rarfa< E the body. Prom such i

remely importanl facts conci
in;i\ 1" tained. In order \>> mak<

left eh placed In a solution i

porous jars, immersed in larj
/nS( )t and sine terminals. ; \ ■

be used. By manipulation
connected with the el< in tin

right arm and l< no ; lead 2, inn

nml left !• - Through lead 1 . I
t»r thai produced d

he current will
lead :>, it \\ ill pass main
Wheil any par

ed thai the b1 i ing
renl - from il

movements of the
introducii

* V

1
!

260

'i'ii

CIRCULATION OK Till: BLOOD

quired amount of current, called the compensating current, to bring the
string shadow back to the zero or midposition. In order that the rec-
ord obtained may be quantitative in character, it is further necessary
that the movemenl of the siring be standardized. This is done by as-
certaining to what extent the string moves when a current of known
voltage is senl through it and by altering the tension of the string so that
one millivolt of current causes an excursion of one centimeter of the
string shadow on the photographic plate. It would take us beyond the

Fig. 81. — Electrocardiographic apparatus as made by the Cambridge Scientific Materials Co. Con-
tact electrodes are shown, but the immersion electrodes described in the context are preferable.

confines of this volume to go in any greater detail into the technie in-
volved in taking electrocardiograms, hut it may be said that this is by
no means difficult, provided the instructions which are supplied with
the instrument arc carefully followed. In practice the taking of elec-
trocardiograms is indeed quite a simple matter, and the extremely im-
portant informal ion which they give us concerning the mechanism of
the heartbeat and the evidence of myocardial disease should make their
employment a universal practice in all cardiac clinics. Some of these
clinical applications are described elsewhere (page 266).

What particularly
<//•<//// in 'i normal . h

three w avea abo> e 1 1
They have been l<
and in all Buch Is m In

line of zero potei tial ind
the apex. The exacl ■ ■
simultaneous!} \\ itli I
changes occurring in the

i.

ha\ e been secured by 1

how ii in Fig - i

ventricular
It w ill !>«• obs< I

traction of th<
sent in th<

lion of tl
ami dill
the presph\ gniio

■

262

TIIE CIRCULATION OP THE BLOOD

Although such comparisons give us considerable insight into the cause
of several of the waves, there yet remain certain peculiarities of the
electrocardiogram to be considered. These are: (1) the cause of the
slight positive wave, Q; (2) the cause of the positive wave, S; (3) the
cause for the period of equal potential at the base and apex during ven-
tricular systole indicated by the portion of the curve between S and T;
(4) the cause for the negative wave, T. To solve these problems it is
necessary to compare electrocardiograms taken from the surface of the
body with those from electrodes placed directly on the base or apex of
the ventricle of the exposed heart.

Fig. 83. — Electrocardiogram (dog) taken simultaneously with curves from auricle and ven-
tricle. It will be observed that wave P slightly precedes auricular systole and that wave R occurs
just before the presphygmic period starts in the ventricle. (From Lewis.)

The Ventricular Complex

In view of the nature of the electric change which occurs in a strip
of denervated muscle when a wave of contraction passes along it (page
188), the simplest interpretation of the ventricular part of the above
curve is that the contraction must pass into the ventricle at a little dis-
tance from the base, thus causing the latter, for a moment of time, to be
positive to the rest of the ventricle, and accounting for the slight down-
ward wave, Q. Immediately after this the base of the ventricle becomes
negative to the apex, giving us the marked upward wave, R, which
however lasts for but a short period of time, being followed by an inter-
val during which the base and apex are of the same electrical potential
(horizontal part of wave between R and T). Finally the base again be-
comes negative to the apex, thus accounting for the smaller upward

wave, T. The

follow ing K. is

n i n i •

plai Winn el<

directly on the baa
ind tli
which is obtained fron
passes along it : n is dij
may be interpn I indicatii

the base and ends
t i in • * suggested for • i •■ i
proceeds to the ap< i final]

tion of the muscular fib<
with the bend of the li p
though th<- explai ation
logical fad that thi develo]

has been shown by obsen ii
cured through electrodes pi
exposed ventricle i'1 1

:planation whicl
preaenl time

tinuancr of

<i}>< t. To '• i\ this h\ p. •

be to Bee w hetl
such as that of the t'i

- up the contraction p
l-as.-. This can be do
the ventricular electrode

• beating in Ring
tion.

pa in the ■

l •

•
Purkinji
thei tuld 1"

■

264

'NIK CIRCULATION OF THE BLOOD

eie*'1

t/u<a*

\pjjjko**A£jcL

A. — Normal

B. — Apex cooled

T

1 <s'' *']

j ■

C. — Apex wanned

Fig. 84. — Records of electrocardiogram and movement of ventricle of frog showing that when
the apex is warmed a typical T-wave appears in place of a wave in the opposite direction appear-
ing when the apex is cooled. (From Mines.)

undoubtedly in com i

-, , .

inten al, as it la called, ii
travel from the unoauricular to th<
In delayed transmission tins interva

ously alfl uditions ot" heari

uhir flutter will !><• immediate!}

interpretation of abnormalities in I

of the curve is, however, i

undertaken unless curves from the tl

will be found that the correspondii

one another in detail; for exam]

in lead 2, although sometimes it is more p

upright in normal individuals in cur

infrequently un erted in those of '•

in tliosi' from lead l The Q-R-S

curves from lead :>'. These variations

relative preponderance of the musculature

tricles, i"<»r it is evidenl thai the amount i patl

w a\ lict w een tin- two leads will

CHAPTER XXX

CLINICAL APPLICATIONS OF CERTAIN PHYSIOLOGICAL

METHODS (Cont'd)

CLINICAL APPLICATIONS OF ELECTROCARDIOGRAPHY

The Electrocardiogram in the More Usual Forms of Cardiac

Irregularities

By R. W. Scott

The principle of the application of the string galvanometer to the
study of cardiac irregularities has been indicated. It is our object here
to outline some of the more common forms of irregular heart action,
with a brief description of the abnormalities in the electrocardiogram
resulting therefrom. For the sake of comparison a normal electrocar-
diogram is shown in Fig. 82. The cause and relationship of the various
deflections have been explained (see page 262).

Sinus Arrhythmia. — This irregularity is seen commonly in children
and young adults, and is without pathologic significance. The electro-
cardiogram presents the normal deflections and shows by the varying
spaces between the P deflections that the cardiac impulse has been gen-
erated at slightly irregular intervals.

Sinus Bradycardia. — The electrocardiogram in a simple case of sinus
bradycardia is usually normal, except that the deflections occur at an
unusually slow rate (Fig. 85). This indicates that the cardiac impulse
is built up at a slow rate, but when generated it evokes a normal auric-
ular and ventricular contraction.

The Extrasystole. — The extrasystole may be either auricular or ven-
tricular in origin. Occasionally a rare type is seen in which the im-
pulse arises in the junctional tissues between the auricle and ventricle.
When the focus of impulse production is at or near the sinoauricular
node, the resulting electrocardiogram complexes are practically normal.
If, however, the seat of impulse formation is removed from the S-A
node, the P deflection may be distorted or actually inverted, followed
by a normal Q-R-S-T complex (Fig. 86).

In the case of ventricular extrasystole, the cardiac impulse originates
in either the right or the left ventricle. This abnormal site, together

2GG

i I INK'AI. M-I'l.K

Ml

-A.

I

T

(X

P IP f

rv

■

T

>./'■

9

1

268

Tilt: CIKCI'I.ATIOX OF T1IK BUH)I>

with the path which the impulse takes, produces a much greater differ-
ence of electric potential than is seen in the normal electrocardiogram.
When the impulse arises in the right ventricle near the base, the prin-

Fig. S9. — Paroxysmal tachycardia. Auricular origin. Note that the P deflection falls back on. T.

Rate 200 per, minute.

cipal R deflection is upwards in both leads 1 and 2. Arising near the
apex, the principal R deflection is up in lead 1 and down in lead 2. Two
extra systoles both arising in the right ventricle are shown in Fig. 87.

k

1

■R

n

"\

-\

i\

■ " " ■ " *

- ■ ■

%

-R

1 "J is

I 1

J

■w""1"^^*

^ j,^

*%^**^w

f

-I

H

r

3

\

1

k. . — •.

{

1

{

. r1

— t

Fig. 90. — Auricular fibrillation. Leads 1, 2, 3. Note the coarse fibrillation waves between the
R peaks, and the absence of any B deflections in relation to R. Also the unequal spacing of the R
deflections.

In the case of the left ventricle, a basal impulse gives a downward
principal deflection in lead 1 and up in lead 2. When the aberrant fo-
cus is located near the apex of the left ventricle, the principal deflee-

I I INK \l vi-ri.i. mo

tion i^ dou ii in both leads 1 and

t\ i tole 11.

.•in extras} Btole originati

Paroxysmal T;uhv.ardi:i
interval I i the I ! i

eardia th< da normally show

tion of T and the succeeding P l
ular origin, the P deflection m
focus of impulse production is loe
auricular node. Rarely the
taken during the paroxysm maj shoi
simulating isolated ventriculai

Auricular Fibrillation I
tion shows three distinctive fcaturt

l Al.si -n. r the P deflection;

J The \ ••utricular eompli Q R S I

quence and may vary in li<-i'_rlit.

The | small irregul

ventricular complexes A typical
Pig 90

The dependen if the P

indicated page 261 It*

for by th«- fact thai the individual mil

independently of one another,

traction while others are

contract ion of tin- auricle as a w I •

The multiple impulses from th<
pics and e> oke a conl raction )'• •« a

stati contraction pcfn

\ entricular responses w ill •
\ entricular complexes in the • •
heighl of the K deflectio
by tin- superimposition

i ivit \ . These small \

.• more or l< -
parate oscillatioi

Auncular Flutter \
cardiograph, and il

<•nii.liti.ui without •

rtions are usually rl

from 2

ncgat t'-'v nognti

270

T1IK CIKM TI.ATInX <)K Till-: BLOOD

origin of the auricular impulse (when arising from some other source
than the S-A node the impulse is said to be ectopic). Usually a regular
succession of P deflections can be traced throughout the record (Fig.
91).

Since it is impossible for the ventricle to respond to all the impulses
coming from the auricles, a condition of partial heart-block obtains
(2:1 — 3:1 — 4:1, etc.). The ventricular complexes will occur regularly
except when a 3:2 rhythm exists.

Fig. 91. — Auricular flutter. Auricular rate 300. Ventricular rate 80. Note the inversion of the P

deflections.

Usually the ventricular complexes are such as to indicate that the
stimulus arose in the auricle (supraventricular). The height of the
individual deflections Q-R-S-T may vary, depending on the predominance
of a right or left ventricular hypertrophy.

Tig. 92. — Delayed conduction. Note the normal appearance of the electrocardiogram except for
the prolongation of the P-R interval, which measures .23 seconds.

Heart-block. — There are three degrees of severity in heart-block: (1)
delayed conduction, (2) partial dissociation, and (3) complete dissocia-
tion.

Any one of these conditions may be present in the same patient at
successive intervals.

Delayed Conduction. — When the conducting tissues of the heart are
so affected as to cause an abnormal prolongation of the P-R interval,
the condition is called delayed conduction. The ventricles respond to
each stimulus originating at the sinus node, but the time required for the
impulse to pass through the conducting tissues is longer than normal.

clink \\. \i-i

I ti ;t simple <-ns<- 1 ;

but w hen the P-R i

gthened bej ond 1 1"
92

l'\l;l ! \i I I In*

ventric • jpond to the impuJ
time, hut occasionally tail to do bo, whi
beat." Tl

complex, >li«'\\ ing thai the aui
luit that the ventriclea failed to i
the sinoauricular node l

: i 1

the auricles beat ii d
(»f the •
Q R 9 T I
made ont w hen the

272 THE CIRCULATION OF THE BLOOD

the auricle will happen to contract during ventricular systole, causing a
distortion of the ventricular complex by the superimposition of a P
deflection. Except when this occurs the Q-R-S-T complex is the normal
supraventricular type. The P deflections occur more frequently than
the Q-R-S-T complex, showing that the auricles are beating more often
than the ventricles. The auricular rate in the average case of complete
heart-block is about 72, while the ventricular rate is much slower (35
to 40).

• \ 11

I II \l-l I

I LINK \i. M'l'i.n \i [( i;i UN I'll

METHODS I

POLYSPHYGMOGRAMS

Venous Pulse Tracings, [i
technic is usuall} follou ed: i
with liis head Blightlj raised !•;
receh er tliistlr funne
■ •I* the neck. This li«-s imm<
The Btj !•• of the ambou mal

amount of fricl i"ii OD the

can aol 1"' interpreted withoul
the button of a i ng tambo

and the Bt} le of its r rding I

drum in the same perpendicula

Tracings ahould be taken w ith
speed and before « 1 i-t u i-l mh lt th<

they sliuiilil be I to il

tationai
permil of accur

should alwaj b I
ihown in

interpret tl •

pill-

thi> is done «'ii the radial
in fronl <>t' it

.r..,t

• m of the puis
Tl
ginning "t" the Bph
ing <»t" the semilum

■ alignment
the sponding

wave i . which
auriculo> entricu

»mall

274

THE CIRCULATION OF TOE BLOOD

The auricular wave (ft) occurs one-fifth of a second in front of c, and
may now be ascertained by measuring off this distance in front of c.
This is line 1.

The distance on the radial pulse tracing from the beginning of the
upstroke to the dicrotic notch is ascertained. The distance between these
is the sphygmic period (E).

Fig. 95. — Polysphygmograph. This instrument records in ink on glazed paper two simul-
taneous tracings, i. e., radial pulse and one other, such as carotid, jugular, apex beat, etc., in addi-
tion to the time tracing. The ink tracings are both more convenient and permanent than smoked
paper tracings. The clockwork operates at variable speeds, permitting the taking of protracted
records at different speeds.

The same distance is measured off on the venous tracing from c. Line
5 will be found to fall just before a small wave (v), which is due to the
sudden opening of the tricuspid valves. This practically coincides with
the dicrotic notch on the radial pulse tracing. Sometimes a little wave

3*v

\

\l^L

k

\ — \

I'ig. 96. — Normal jugular tracing. The spacing below shows the duration of the a-c interval.

(From 1;.. P. Carter.)

occurs on the upstroke of wave v just where line 5 falls. This co-
incides with the closure of the semilunar valves. The distance between it
and wave v corresponds to the postsphygmic period.

The cause for the depression (marked x) following c will readily be
understood by referring to the intraauricular curve (Fig. 97), to which,
as already explained, the venous pulse tracing is qualitatively similar.

The riae in the cm

the auricle with l>l"".l i

open, allow inuF t he U I to tall inl

■ •

and auri

• !c of the ventri. I

T ■ interprel the cardiogran
radial and apex beat with l>"th writu
and the other directions described ui
The following poinl

od

J

l_t_>

:

276 Till CIR< i LATION OF THE BLOOD

1. The beginning of the sphygmic period (E) (line 5).

2. The end of the sphygmic period (E) (line 5).

3. The auricular wave.

4. The beginning of ventricular systole (difference between 1 and 4
equals presphygmic interval).

f>. The opening of auriculoventricular valves (lowest point in tracing).

The exact momenl at which the hearl sounds are heard can usually
be indicated on the tracing.

It is important to make certain that the button of the tambour is ac-
curately over the apex beat, since otherwise a depressed or negative
wave may he inscribed at ventricular systole.

Simultaneous Arterial Pulse Tracings. — The velocity of the transmis-
sion of the pulse wave is calculated by measuring the time between the
systolic rise in the carotid and in 1he radial arteries, tracings of which
are taken by applying one receiving tambour to the carotid artery and
another to the radial artery.

Abnormal Pulses
The following is a brief description of the main character of abnormal

pulses:

The Ventricular Pulse. — In this no "a" waves are present in the
jugular tracing, the heart action being either regular or irregular. In
the former case, the absence of the "a" waves may depend on: (1) over-
filling of the right auricle, (2) increase in the heart rate, or (3) complete
heart-block associated with auricular fibrillation. When the heart is
irregular, the absence of the "a" waves signifies auricular fibrillation.

Delayed Conduction and Heart-block. — This causes a change in the
time relationship of the "a" and "c" waves in the jugular curve. When
the heart-block is of the first degree, the "a-c" interval merely becomes
lengthened, but when it is of such degree that the normal impulse some-
times fails to be conveyed along the auriculoventricular bundle, isolated
"a" waves can be detected. In the higher degrees of heart-block there
are regularly recurring "a" waves having no constant time relationship
to the "c" waves. For the purpose of exact analysis of the curves in
suspected enses of delayed conduction, it is often advantageous to draw
vertical lines below the tracing representing the beginning of auricular
and ventricular systole. This has been done in the tracing reproduced
in Fig. 99.

The line joining these two verticals indicates the conduction time
or "a-c" interval. When it exceeds one-fifth of a second, there is
delay in the conduction time.

.\ tracing show ing a lug
Sinus Arrhythmia i
irregular, bul t i

\\ i 1 1 1 the usual tin

in the "a" ••■" ii U

^[A/^A^- V4

',', s

1

Sinus Bradycardia. I
sinus; the " a <•" ii ten al is normal

•ally P ■_ l]

Premature Beats. I
origin. In tl

ilarly throughout, bu1 ti i

k -

■ ••Ii it Ii (hi

Tills is «il..

• ■
follow ed h

278

THE CIRCULATION OF THE BLOOD

site of origin of the premature beats can be determined only by careful

measurement of the distances between the various beats of the ventricle.

"Whenever an irregularity repeats itself and the duration of one cycle

of the arrhythmia accurately corresponds to another, the irregularity

Fig. 101. — Premature beats (extrasystoles) ventricular in origin at PB. Compare the duration of
the intervals marked A and B' with those marked C and D. (From E. P. Carter.)

may be due to: (1) premature auricular or ventricular contractions;
(2) the occasional occurrence of dropped beats (a failure of ventricular
response) ; or (3) a high degree of heart-block with a wide variation in
the ventricular response. The important point to note here is that, no
matter how irregular such a tracing may appear, if the irregularity re-
peats itself it can not be due to auricular fibrillation.

Tig. 102. — Paroxysmal tachycardia. The paroxysms start at xx following normal beats and
lasting for seven beats. The clue to "a," which falls with "v" after the first premature contrac-
tions, is found in the initial beat of the new rhythm. (From E. P. Carter.)

Paroxysmal Tachycardia. — When the rate of a regular pulse is sud-
denly altered but the change in rate bears a simple ratio to the previous
rhythm, the change may be due to (1) premature ventricular contrac-
tions which do not reach the radial, or (2) to the sudden development

oi a ''••• o in "ii" heai
ratio beta een the -'•■ and 1
appc
-^iiis during v. lii'-li •
ariable time, Buch i I
i •■ tracing in raefa a

,. |v |v- |^ 1

Auricular Flutter, i;

of t Iun cardiac condition \\ it!
Bphygmogram or the i icardiogram l

two types, one made up of r;t|>i<!, r leas

thai are paired w ith a constant

■r . . * — -w » *

~*^*»~m-*0 -w^i— w«^

iMi^j^iiiU

j .j

r

/\ I

\-

\ I of th<

condition, ao thai tl
may be I 1:4. 1

tion tl i

280

THE CIRCULATION OP THE BLOOD

radial pulse may be regular or irregular. The cause for the failure of
every auricular beat to travel to the ventricle during auricular flutter
is partly the refractory condition of the bundle, and partly the refrac-
tory phase of ventricular contraction. The bundle may be considered
as a narrow bridge which will transmit the impulses across it only at a
certain rate. If the impulses arrive too rapidly, only some of them can
cross the bridge, and even of those that do cross, a limited number only
will find the ventricle in a condition of excitability because of the re-
fractory period (see page 178). Tracings showing auricular flutter arc

w-

^K.>^\.\lV\\ . V

.1"' ".'.V-.

-x *"'.'-'

*v •.; ;

-/ 1\ ,*'.*."?.

:$*&■

■ : v'"'

.'■'.-'.>,v

-.;;■'-•* m

-," *w i.'" '.

:•'*••"■"••

\fv\^«k\fc* \ \ \ \

\

\

_\

v%

H

V

M

s

\\

wy

•j*

V

H

y

Fig. 105. — Auricular fibrillation. Note the absence of all "a" waves from the jugular tracing, the
marked irregularity of the radial pulse, and the occurrence of "c" and "v" during the sphygmic
period. (From E. P. Carter.)

given in Figs. 103 and 104. In one of them the radial pulse is regular;
in the other, irregular.

Auricular Fibrillation. — The contractions of the auricle, as already ex-
plained, are entirely irregular, so that the jugular tracings show an en-
lire absence of all "a" waves, the radial tracing being characterized by
the complete absence of a dominant rhythm and by great variation in the
length of the individual beats from one cardiac cycle to the next. This
irregularity does not repeat itself, and the long pauses are not simple
multiples of the shortest pause. Tracings from a case of auricular
fibrillation are shown in Fig. 105.

CHAPTER II

CLINK ai. APPLICATIONS OF < I

METHODS I nt'd

THE MEASUREMENT OF THE MASS MOVEMENT OF THE BLOOD

Method. The apparatus used for tl ■,.,,.

a v.'ssri containing a known quantity
mometer from which a change of U mp

lentigrade can be read. Ii. ord<
the loss of heal betv • ■• a th< el and I

double, the Bpace between being stuffed
the is closed \\ ith a thicl

it for the hand or fool and for the thermon
with which t.. keep the \\ ater in

a COlorittU t> r.

After the hand or \<><>\ has been in I - a

few degrees below thai of the bodj

temperature of I he \\ ater will ■

which thi^ occurs, multiplied '

centimeters, will give in calories <;

application «>f a \n\ simple formu

how much !>1 1 must have passed thi

in order t<> give <>ut the observed am<

■ i by the diffi r< nee 11

Ulg l'l I -nit in ■

cubic centimeters, that has

equals \ olume multiplied 03 -I

explain the equation by w hich I

it i m on ti t of blood, H th<

the temperature ol I /

II*

\ enous 1)1 1, tlirn we I u

kr thr <>l ■

282 THE CIRCULATION OF THE BLOOD

by Stewart that T may be taken as the same as that of the mouth, or 0.5°
C. below that of the rectum, and 2" as the average temperature of the
water in the calorimeter during the observation. To allow for the specific

heat of blood, the result is multiplied by-^-, the reciprocal of the specific

heat of blood.

Theoretically, then, the method is very simple, and there are no un-
usual technical difficulties in applying it. The only special precaution
is that the air surrounding the calorimeter should be kept fairly con-
stant in temperature, so that we may be enabled to allow in our calcula-
tions for the loss of heat from the calorimeter itself, this value being
obtained by observing the change of temperature in the calorimeter for
a certain period of time after the hand has been removed from it.

The Normal Flow

The results are calculated on the basis of grams of blood flowing
through 100 c.c. of tissue in one minute. The volume of the hand or foot
is ascertained by placing it in water contained in a small-sized irrigation
can, the tube of which is connected with a burette. The height to which
the water rises in the burette is noted, and after withdrawing the hand,
water is added from a graduate to the irrigation can until the same
height is reached on the burette. The number of cubic centimeters re-
quired gives the volume of the hand. In a normal, healthy individual
the average flow in the hand is from 12 to 13 gm. for the right hand,
and about half a gram less for the left. This difference between the two
hands corresponds, of course, with their relative degree of development.
The average foot flow is much less, and varies according to whether the
patient is sitting up or lying down while the measurement is being made.
In a normal individual, while lying down, it was 5.11 gm. in the right
foot and 5.23 gm. in the left, per 100 c.c. of foot; but only 2.96 gm. for
the right and 4.1 gm. for the left foot, while sitting up. The results have
been found to undergo only a slight variation from month to month in a
given healthy individual, provided the air temperature during the dif-
ferent observations is the same and the person has been some time in the
room before the observations are begun.' This precaution is especially
important if he is a dispensary patient and has been in the open air with
bare hands. The flow varies in different individuals both with regard
to absolute amount and the ratio between the two hands or feet. When
the total flow in the hands is compared with that in the feet, a ratio of
about 3 to 1 is usually obtained.

'ilu Physiological Causes for Variations in Blood flow. — As above indicat-
ed, the most marked of these is probably the temperature of the room. The

•' ..

uxl

and for tin mparison o

room and calorimi
contractions, produced bj mo
marked in in flovi

that was at real A
f/»< ,/;•/» of sufficient «l
the constriction,
bet\* een the Byatolic and
through tli<- hand.

By immersing the opposite hand i
Muw through the observed hand «*aaeat

Tl e change may 1 1 a tempoi

out the whole period <>f imm<

b vascular r< ■'♦ x, and i
the Btudy of th< i
centers con ned in vascul

Clinical Conditions which AfTert the BloodtV
I ! en in cases where 1

Of flow, * t may b<

an alteration in the vascular r<

hands, for demonsl ra1 ing 1 1

acute inflammati

in flow on the affected - on

the other aide! This indicates tl

impanied by a
larly in 1 tricall) p

body. In caai s of nonbi
sign of vi
Th< i many clinical i

a altei in blo<

ordinary clinical n It ''*■'

thod i
follow

Anemia 1
in pernieious anemia

in ehloi Since the i l •"

in tl

in compelling
<\> fici( ■

284 THE CIRCULATION OF THE BLOOD

Fever. — Since changes in the cutaneous circulation probably con-
stitute the chief factor in the derangement of the temperature-regu-
lating mechanism in fever (cf. page 723), it is evidently of great ad-
vantage to be able to measure such changes quantitatively. This has
been done by Stewart in several cases of typhoid fever and in one case
of pneumonia. In general it was found that the flow in the feet never
exceeded the normal flow, and was usually much below it. This ten-
dency to vasoconstriction seems to be carried into convalescence. For
practical reasons the handflow has not been so extensively studied.
This hyperexcitability of the vasoconstrictor mechanism at the periph-
ery is most naturally interpreted as a defensive reaction of the or-
ganism by which an increased supply of blood is imported to those
internal organs "which bear the brunt of the infection. When we con-
sider that in spite of this constriction of the periphery the blood pres-
sure is low and the pulse dicrotic, we must conclude that there is con-
siderable dilatation of other vascular parts, especially the splanchnic
area. A very practical application of these facts presents itself in con-
sidering the rationale of the cold-bath treatment for fever. If, for
example, we conclude that the cutaneous constriction is in the inter-
ests of an increase in the bloodflow to the organ on which the stress
of the infection falls, it will evidently be more rational to lower the
temperature by methods which will not diminish, and may even in-
crease, the cutaneous constriction than to do so by causing the vessels
to dilate. In other words, the use of antipyretics seems to be contra-
indicated, since they diminish the body temperature by causing vaso-
dilatation at the periphery with a consequent withdrawal of blood
from the seat of infection.

Cardiovascular Diseases. — In cardiac cases the handflow is far more
apt to be markedly deficient where there is evidence of serious impair-
ment of the myocardium than in cases where a gross valvular lesion
exists but the heart action is strong and orderly. This indicates that
it is more serious for the force of the heart pump to be interfered
with than for its valves, particularly the mitral, to be leaky. Even
where there is considerable venous engorgement, the flow may be lit-
tle diminished. In untreated cases of auricular fibrillation the blood-
flow is subnormal. After the administration of digitalis the bloodflow
in such cases is often promptly and decidedly increased.

As would be expected, arteriosclerosis is associated with a small blood-
flow, and the vasomotor reflexes are weaker than in normal persons.

In aortic cmeurism, when the aneurism is of such a size as to cause
pressure on the subclavian artery or vein, there is a diminution in flow
of the corresponding hand, but aortic aneurism itself, although it may

Ml

cause greal

edly affecl the mam mo
clavian arterj . the bloodfl
than in the opposite hand,

ry obviously dimini
diastolic pr<

than on the normal • :• B
fore, fata esti ■ .

ilts are no doubl ow ing
pressure of the aneurism
lower resistance to I

In Raynaud's dis<
diminution being
dis< I contralateral

liarly inten

1 1 tie gangn m of I

the hi Mil the The \ asom< I

It is aometimea difficull to tell whel
ll<>\v is a nervous reflex

i are two v, a; w hich I

1 by obsen ing the ll"\\ from d
any alteration must be dep< on m<

the change in flow jM aboul

salorimeter and -■
Bins unci i or b(

uality in flow musl be d

Diseases of the Nervous System I
varies with the duration of the dis< i

unilateral neurit

en the two hands with I
neuritis of long standi
<ui the healthy sid< l
alterations in the lumen i
In

lie:

i a iii'l:

int. •. ith bloodflo

Hemiplegia \

d, and tl
tig thai

286 THE CIRCULATION OF THE BLOOD

In sonic eases an abnormal tendency to vasoconstriction is a conspicuous
feature.

Tabes Dorsalis. — The flow is distinctly diminished, especially in the
feet, although also in the hands, and the vasomotor reflexes are feeble.
Sometimes there is inequality in the flow of the two hands, which how-
over need not necessarily indicate a unilateral lesion of the cord in the
cervical region.

< HAPTER XWill

moi r

SI k may be dm

Bcribed as a condition in which I
sensory and motor portio
torbances in the circulal
and shallow respirati<

these symptoms may be C

aii importanl step in tl •
problem being to distinguish 1" I
ing to <1" this, hov • it will l"- pi

possible tli«" various
\ ari< shock is saki I ur.

The foUowing varietie

I Gravity Shock. This
splanchnic els and tl i
diasl • l' • tours, when tin- •
which the mechanism \\ hich

.vity td make the 1»1<>h<1 |]<.
Thus, when a domesticated rabbit with
held in tin- \ ertical tail-do^ o i"

dually passes into a shocked c
•J" I minutt 1 1

art. -rial 1>1 1 |

this bas been

p&i • be bod) . and t1

shock is entirely d nw

tur< it" a binder i

performed on a rabbil •

tion, gravity

iduced in a dog, h in

m.-. all in

*i«.M is aasumi d I
highly ■!•

-SS THE CIRCULATION OF THE BLOOD

2. Hemorrhagic Shock. -Woe hemorrhage produces a typical condi-
tion of shock, but the extent to which different individuals react to the
same degree of hemorrhage varies considerably. The essential factor in
the production of hemorrhagic shock is of course similar to that of grav-
ity shock— namely, a deficient diastolic filling of the heart with blood.
Details concerning the effect of hemorrhage Avill be found elsewhere
(page 135).

3. Anesthetic Shock. — So far as blood-pressure reflexes are concerned,
an animal can be kept in a perfect condition when ether is administered
in just sufficient amount to produce light anesthesia. When larger
quantities of other arc employed, a typical condition of shock is almost
certain to supervene after a time. In such instances the arterial blood
pressure remains low and can not be restored even after an hour or two
of artificial respiration. There is, however, a difference between ether
shock and the variety which we shall discuss later under the title of
surgical shock : in the former, removal of the anesthetic causes all reflexes to
return, whereas in surgical shock most of these are subnormal. The danger
of anesthetic shock has been considerably diminished in the clinic by
the more careful administration of ether or by the use of other anesthet-
ics, such as nitrous oxide gas. A condition closely simulating shock
may also bo induced in the earlier stages of the administration of anes-
thetics when these are badly given, but paralysis of the heart or of the
respiratory center is a usual contributory cause.

4. Spinal Shock. — Spinal shock is produced by section of the spinal
cord, but it is to be carefully distinguished from all other forms of shock
because of its local character, as it affects only those parts of the body
which lie below the level of the lesion in the cord. Above this level the
animal may be in a perfectly normal condition, except in cases where
the section has been at so high a level that it has severed the vasocon-
strictor pathway and thereby produced a fall in blood pressure from
vasodilatation. Even when this has happened the part of the animal
anterior to the spinal lesion is by no means in a condition of shock. Thus,
Sherrington observed in a monkey whose spinal cord had been cut far
forward that, although the posterior part of the body was in profound
spinal shock and the blood pressure very low, the animal amused him-
self by catching flies with his hands. A sufficient description of the con-
dition of spinal shock has been given elsewhere, but here it may be noted
that it consists essentially in a paralysis involving at first all of the re-
flex mechanisms, including the control of the sphincters, in the part of
the cord posterior to the section. In the course of a few days or weeks,
according to the position of the animal in the scale of development, the
reflexes gradually return, until ultimately in a couple of months — in a

dog, for example tl •

shuck is no doubt the sudden ii I
u liii-h reflex action ordinaril;

5. Nervous Shock; Shell Shock." I
paid t « » the oen ous shock that i
h;i\ e been subjected to tin- i

;in incurred in modern

suddenly at the front or i hej n
themselves in an apparently aormal n
w hen they pass into a condition d

n<lit icins may alfi

ma! individuals would not in I

■_r i i • .- 1 1 .shock. The characterisl

different from thus.- of other forma

Elliot Smith and T. II. Pear, th( i must !■

aeurologic or psychopathic point ■

»'». Surgical Shock. It is this variety thai is
speal shock. It may be produced <*al

injury to B healthy person or b

handling on the operating table [1 mmon in I

ing th( • an important variety -

be used only in a general Bense. B
BUrgical shock are very much the same. i
apathetic condition, caring little for what ii
answering questions only when rep<
His skiii. lips and gums are very pa

feels Cold and is moist w ith

and it is usually only after applying a
movement of defen icited

patient. The postural r<
lifted it falls back limp and I

rapid, thin and almost imperceptil

abnormally low. i
tal temperature is, 1 I

and •- ..■ t slowly to ligl W

tient 's voice is hoi

; lympl

Experimental In\ :10ns of Sho

Por indueing shock exi
employed: either rou

290 THE CIRC1 LATION OF THE BLOOD

peated stimulation of large afferent nerves. Since 1 lie experiments are
usually performed on anesthetized animals, the effect of 1 lie anesthetic
has to be discounted in experimental work on the causes of shock.

The first step in such an investigation is naturally to classify the
symptoms into primary and secondary, for on the success of the classi-
fication must depend the outcome of further investigation into the
problem.

The earlier investigators were naturally attracted to the pronounced
fall in blood pressure as the primary cause of shock. It is true that a
pronounced lowering will ultimately produce symptoms that are not
unlike those of shock, bul^ on the other hand it can readily be shown that
this is a result only — a symptom and not a cause of the condition. It
Avas believed by Crile that the fall in blood pressure depended on a
universal dilatation of the blood vessels caused by exhaustion of the tone
of the vasoconstrictor center. It has been clearly shown, however, that
the tone of this center is practically normal in shock, and that the arte-
rioles are maintained not in a dilated but in a contracted state, indicat-
ing clearly therefore that the low blood pressure must be dependent
upon inadequate output of blood from the heart. The evidence for this
conclusion is as follows: (1) W. T. Porter26 and his collaborators have
shown that both pressor and depressor reflexes are perfectly normal
in a rabbit that is in a condition of extreme shock. It is particularly im-
portant that depressor effects were still obtained, since this indicates
that tonic activity of the center must still have been present. (2) The
blood vessels in a shocked animal are in a contracted state. On opening
a vessel and observing the outflow of blood, an increase occurs when the
nerve to the blood vessel is cut. (3) This same fact has been shown by
Seelig and Joseph,27 who cut the vasomotor nerve proceeding to the
vessels of one ear of a white rabbit and thus caused a local paralytic
dilatation of the vessels. Intense shock was then produced in the animal
in the usual way, after which the blood pressure in the anterior part of
the animal was suddenly raised by applying a clamp to the abdominal
aorta just below the diaphragm. This increased blood pressure caused
the vessels of the denervated ear to become engorged with blood, but
not those of the opposite normal ear, which retained their tone (Fig.
106). (4) The volume of blood expelled by the ventricles has been
shown by Henderson28 to be distinctly diminished in the early stages of
shock, the lack of pronounced fall in blood pressure indicating that there
must be a compensatory constriction of the arterioles. Lastly (5), it

has been found by Morrison and Hooker29 that 1he outflow of bl 1

from the perfused organs of a shocked animal is less than that from the

*

name organs under i I

n. m such an organ i

To th< i"Us pi( f at

t certain
dence furnished by the pallor of I
thai the sympathetic

in an •

Furthermore, we kn

on tli<- resuscitat
w ith the circulation t<> the brain,
alii; "ant to anemia. [1

- reflex activity bett< r tl

Those \\li" have maintained thai a d<
constrictor and

their evidence parti) <»n histological exam
animals, ii being imed thai il •
indicates an exhausted condition. T
unwarranted, and no I is '_':

similar histological changes may be produced b;

lertain] conclude thj

are the result and nol I
condition.

Since the fall in arterial 1>1 1

oles, it must be dependenl

\rt. I nterferei with I

the blood carried to t i

t rides iIid'hil' <li.iv'

illar) ; the possible i

isibility thai th.
paral) Bis of the \ agus m<
lias been ^}\<>w u to be unt<

entral
reflt -is mechanist

rial blood ]»:

K idently, ti
ficienl <li-

f'tllii \ I • •

blood supph

292 THE CIRCULATION OF THE RLOOD

cient return of venous blood to the heart. In the first place, let us see
-whether shock can be produced experimentally in animals by mechanical
interference with the bloodflow in the vena cava. That such is the case
was shown by H. H. Janeway and Jackson,31 who found that mechanical ob-
struction of the inferior vena cava for a short time was followed by the usual
signs of shock. Such interference with the venous return to the heart
may also be produced by excessive movements of the thorax as a re-
sult of artificial respiration. That this in itself may cause shock is known
to all experimental investigators on the subject, although the interpre-
tation has not always been that which is given above. Yandell Hen-
derson32 thought that the excessive ventilation caused a blowing off
of carbon dioxide from the blood .(see page 293), thus producing a
low tension of this gas in the blood (acapnia), which he believed to be
the responsible factor.

As in gravity shock, so in surgical shock, stagnation of blood in the
splanchnic area is common; the animal bleeds into his own (splanchnic)
blood vessels (capillaries and venules), because these have lost their tone.
As we have noted above, one of the most certain ways of producing
shock is by exposure and rough handling of the abdominal viscera. It
is therefore of importance to study the effects that can be noted on
the blood vessels of this area under such conditions. When the viscera
are first exposed to air, there may be a short period during which vaso-
constriction is evident. This is soon followed by a dilatation of the
arterioles in the exposed area, causing the capillaries and veins to be-
come markedly distended as during the first stage of inflammation. This
accumulation of blood in the mesenteric veins has been shown by Mor-
rison and Hooker to cause an increase in the weight of an isolated loop
of intestine as an animal passes into a state of shock.

Splanchnic engorgement alone does not, however, suffice to explain all
the loss of blood, and 'we are driven to conclude that the capillaries of
the tissues outside the abdomen must entrap much of it. As a matter of
fact, Cannon, and others, have found that concentration of the blood
occurs in these capillaries as indicated by comparisons of the corpuscles
and hemoglobin in blood drawn from veins and from capillaries. Nor-
mally the values are equal; in shock the capillary blood is much con-
centrated.

In so far as the circulatory disturbances are concerned, wre may there-
fore sum up the conditions occurring in shock as follows: The blood
accumulates in the veins and capillaries — that is, in a part of the vas-
cular system that is beyond vasomotor control. The consequent with-
drawal of this blood from the circulation produces a diminution of the
bloodflow in the vena cava and consequently an inadequate filling of the

heart. The consequent curtailment

ho* at first eausi

••ails-- of a reciprocal

body. Meanwhile, however, *

progressively inereasi]

for th- temic eircnlation. «'"t

the arterial constriction, the bl<

level, and the secondary symptoms of fall ii I
refli ipervene. Ii

its flow.

Fundamental question in th<
fore tki cauti of tl • itagnation

uenulet. Two hypotheses have 1 n offered, i

of afferent nerve fibers to tin lar

ventilation with a consequent washii

blood acapnia . which causes a '- •■•

thai a bombardment of th<

by afferent impulses brings tl

tion, which is the essential caua

• may be at once dismissed, since, on I
shown tlmt in typical Bhoch there is
the venous blood Short d on t;

• often produced withoul

Nor is there any «•'• idei ce
fatigue of the cardinal cent<
latinii. In the first place, i1
dling of the abdominal \ isce
spinal COl much less mark". I thai '

tral enda wry n<

limbs an<l joints, althougl - much 11

mer procedure Tl t method empl
• at imp

which

and the cum tion whicl

pulses registered ;
simple and direct in prii

•ar«- in practice
of the head end «»f the animal t

I the furtl, " tliis

ones

observed *"

294 THE CIRCULATION OF THE BLOOD

the theory that shock is dependent upon an impairment of a higher
nerve mechanism as a result of overstimulation by afferent impulses.

Cannon35 has recently suggested that the engorgement of the splanch-
nic blood vessels may be the result of a constriction of the portal rad-
icles in the liver, which dams back the blood in 1he portal circulation.
He points out that these radicles have vasoconstrictor nerve libers, as
evidenced by the fact that the rate of flow of fluid through the per-
fused liver decreases during asphyxia, as well as when the hepatic
nerve plexus is stimulated electrically or when epinephrine is injected
into the portal vein. He argues that, since the blood vessels in other
areas of the body are constricted in shock, so also will be those of the
liver, with the result that the blood of the portal vein, in which ordinarily
there is a very low blood pressure (10 mm.Hg), will become dammed
back in these veins and therefore removed from the systemic circulation.
It does not seem to the writer, however, that this explanation is likely
to be the correct one, for, although it is true that vasoconstrictor in-
fluences have been shown to exist in the hepatic radicles of the portal vein,
yet, since it is only under special experimental conditions that this can
he done, they must' be very feeble in nature. As we have seen else-
where, portal vasoconstriction can not be demonstrated by stimulation
of the hepatic plexus with stimuli which are sufficient to produce marked
constriction of the hepatic artery radicles (see page 255).

The engorgement of the splanchnic capillaries and venules is much
more likely to be dependent upon local influences acting on the vessels
Ihnnselves. When shock is produced by manipulation of the abdominal
viscera, it is easy to see how this local disturbance might be set up.
When shock is caused in other ways, as by violent stimulation of sen-
sory nerves, the atony of the splanchnic vessels is not so easily accounted
for unless we assume that it is a type of abnormal reciprocal vascular
innervation. For example, when stimuli arc applied locally lo sensory
surfaces under ordinary conditions, a distribution of the blood of the
body takes place, more being sent to the irritated region and less to
oilier parts of the body (see page 238). During the sensory stimula-
tion preceding shock, it is conceivable that this reciprocal innervation
acts in a faulty manner, causing at first a dilatation of the splanchnic
arterioles and thus allowing more blood to enter the splanchnic capil-
laries and venules, which being possessed of little tone are incapable
of responding by increased tonicity, so that they become overdistended
and the blood in them stagnates.

In any case there is no doubl that the initial change is the stagnation
of blood in these vessels, and when once such stagnation has occurred,
the process goes on spontaneously probably on account of the accumula-

tion in tl nanl U-....I ,,

which rai

;i further relaxation "f tl

has guch an •

progi

privation

not exhibit their usual I

Ti :it

Whatever may be th<
venules in sh<><-k. t
hopeful line of treatn enl is I
[1 will be remembered thai in

•omplished l>y the app
or by placing the animal in a
• 1 in t : an ha

!>!>li«-.l i*-

the atonic Cannon has 1

thai a hopeful ] I in in

domen a lution i

tnembered direcl Ij on b ■• olui

I o other methods

nan or I>1 1 '

neither method lias pro> <-<\
do in<! rily raise th<

quenl condition of shock is |

the injection of bl I •

muc the M 1 pi

falls again. In this regard

hemorrhage, in w lii«-l
blood '

omplished l>.\ trans
in g i <

.il diflVrriuv
onlj trcatmi
•

■

I •
de> i

\

296 THE CIRCULATION OF THE BLOOD

ent upon the low arterial blood pressure, although some authors have
suggested that the loss of sensation may be dependent upon an increased
resistance or block at the synapses of the receptor neurons (page 803).
This suggestion depends on the fact, demonstrated by Sherrington, that
repeated stimulation of the receptors of a reflex arc produces fatigue
of that particular reflex, and that this fatigue must be resident in the
synapsis and not in the motor neuron, since the same motor neuron
that participated in the fatigue can still be called into activity by afferent
stimuli transmitted to its nerve cell through other sensory pathways
(see page 825). It is thought that in shock the frequent afferent stimula-
tion produces synaptic fatigue and therefore dulls the sensory responses
of the animal. The researches of Mann above referred to, in which he
shows that shock may occur without any demonstrable afferent stimuli
in the brain stem, would seem, however, to negative the above hypothesis.

The raised threshold of sensory stimulation is no doubt an effect of the
low blood pressure. It has been shown, for example, by E. L. Porter36
that when the arterial blood pressure is maintained at a uniform level,
the threshold stimulus for spinal cord reflexes remains practically uni-
form, but becomes promptly increased when the arterial blood pressure
is made to fall. Why a lower blood pressure should have this effect is,
however, difficult to understand in the light of the researches of Stewart
and his coworkers, who, as remarked above, found that the cells of the
central nervous system may endure total anemia for many minutes and
still recover their physiological condition. It may be, however, that the
low blood pressure affects the conductivity of the synapsis.

The muscular weakness is probably also dependent on low blood
pressure, for it has been found in animals that, when the arterial blood
pressure is lowered to about 90 mm. Hg, the muscles contract much less
efficiently than ordinarily. The fall in body temperature is dependent
upon the muscular inefficiency.

In conclusion, it should be pointed out that W. T. Porter, in the inves-
tigation of acute shock met with at the front, has found that, in many
cases at least, the circulatory disturbance is due to a condition of fat
embolism. The fat is derived from the marrow of long bones, such as
the femur, by injuries which smash the bones. Porter's observations
are at least very suggestive.

CIRCULATION REFERENCES

(Monographs)

Wiggers, C. J.: The Circulation in Health and Disease, Philadelphia, 1915.
Mackenzie, J.: Diseases of the Heart, Oxford Medical Publishers, ed. 2, 1910.
Lewis, Thomas: Mechanism of the Heart Heal, 1911, Shaw & Son, Fetter Lane,
London.

Hill, I aard: 'i

PI y, 11. 19

Oaakell, \v. n.: The

nd.
Flack, M. : Purthi
London.
W. T. : ajneriean

1 Original I'ajx

>M:i. William, J. \ . ■ ./.: H(

Journal, Nov., 19] I; VII h
1 1. Phyaiolo
•Hill, Leonard, r. B. B P B

lww i. - ad 516.
J.: km. Jour. Phj
(Downs, \. W .: Am. Jour. Phj

1.--. W . M.: ]■•■■■ . I.

■ Knowlton, r. P.: Jour. Physiol., 1911, rli
rlOlroy, T. II.: Jour. PI jrsiol., 1917, 1

• and Meek: Heart, 191 1, v, 1 19; 11
nczi V,
•Porter, w. T.: \r. on I lr< la I on in
' I
ro li< . T. 0.: PrO( PI
"Strwart. (i. N.: II. art. 191 I, iii,

srrey, W.: Am. Jour. Physiol., I l.

M i; : Jour. Physiol., 1913, xlvi, I

i*Cohn, A. 1 tfed., 1912,

w ii, 129 j Cohn and I

r. Phj -
rter, u . T.: in . J . PI iiol., 191
irtin, 1.. • ;., and co m \m. .

1915, \\m iii, 98; 1916, i
ij lias, W. M.:
■•Hill, I • onard The Phj
\ Churchill, I -
111, i. . and hfaeleod, J. J.
n.Ms

r, W. T.:

i .1 Barnard, H

and Pi sr, i' I

' i

II. lerson, Yai M»«a: Km

l •! :. drl

R. A ., a i 1 1

..•. r. H

■ii
ii ii .

1918, xh.

2!><S THE CIRCULATION OF THE BLOOD

^Henderson, Y., and Eaggard, W. H.: Jour. Biol. Chem., 191S, xxxiii, 3::::, 345-355

365 (gives older references). See also Macleod, J. J. l;.: .lour. Lab. and Clin.

Med., (editorial), 1918, iii.
ssShort, Eendel: Lancet, London, 1914, p. 131.
s*Mann: .Jour. Am. Med. Assn., 1918, Ixx, ('ill. Also Boston Med. and Surg. Jour.,

1917.
ssCannon, W. B.: Papers by Cannon and Collaborators in Jour. Am. Med. Assn., 1918.

Ixx, 520, 526, 531, 611, 618.
' Porter, E. L.: Proc. Am.'pliysiol. Sue, Am. Jour. Physiol., 1916, xlii, 606.
• Wiggers, C. J., and Dean, A. L.: Am. Jour. Physiol., 1916, xlii, 17<'>; Am. Jour.

Med. Sc., li»17, elii, 666.

PARI l\

THE RESPIRATION

CHAP1 ER XXXIV

RESPIRATIi

For convenience, the phj Biol
der its mi ch

THE MECHANICS OF RESPIRATION

1 ''" tin- many factors concen ed in maintaii
•In- animal body, the respiral
< >n this accounl .mil also l
movements, tin- physiolof

earliest times Much of il arlier work Dal

\\ itli tlit> stu<ly of tli«' air thai tut.

ration the ventilation of the ' I

properties of the respired air are: l

The Pressure of the Air in the Respiratory P.issages-

or Intrapulmonh- Press-

This i> readih measured In ins<
necting the tube \\\\\\ a n
manometer regis!
expiration, a i" '
normally of small magnitud

t when anj ob*
air. The

ply Mow big i 1 1 1 « » a m<
which all the in •*•*•

ing the longs. In

I L- Similarly, th<

may be n

« ith a manoi I

300 THE RESPIRATION

of the thorax and abdomen can open up the thoracic cage, and may
equal -70 mm. Hg. These measurements in themselves are not of much
importance, except as a measure of muscular development.

Intrapulmonic pressures that are intermediate between the two ex-
tremes Avill be acquired in the loAver air passages in cases in which there
is partial obstruction of the upper respiratory passages, as in bronchitis,
spasm of the glottis, diphtheria, etc. During coughing also, the intra-
pulmonic pressure may become very high. In this act the thorax is first
filled with air by a deep inspiration ; the glottis is then closed, and a
forced expiration is made. "When a sufficiently high intrapulmonic pres-
sure is attained, the glottis opens and the sudden change in pressure
causes so forcible a blast of air that the offending foreign substance is
frequently carried with it out of the air passages. It is often assumed
that during coughing the sudden increase in pressure in the alveoli will
tend to cause their Avails to rupture. This, however, is not the case.
The alveoli do not alone support the increase of pressure ; they merely
act as the inner layer of a practically homogeneous structure com-
posed of lung, pleura and thoracic cage. "When the tissues of the lung
are partially degenerated or atrophied, as in old people, then it is pos-
sible that a rupture may take place, but under ordinary conditions it
is not likely to occur.

Amount of Air in the Lungs

Measurements of the amount of respired air have recently assumed a
considerable interest on account of the various applications which can
be made of them in the study of lung conditions. The tidal air is that
which enters and leaves the lungs with each respiration (about 500 c.c.) ;
the complemented air is that which we can take in over and above an
ordinary tidal respiration (about 1500 c.c.) ; and the supplemental air,
is that which we can give out after an ordinary tidal expiration (about
1500 c.c). Taking these three together, we have what is known as the
vital capacity. It is usually about 3500 c.c, and is represented by the
amount of air which we can expel from the lungs after as deep an inspi-
ration as possible. The vital capacity is diminished in certain pulmo-
nary diseases (see page 314). After all the supplemental air has been
expelled, there still remains in the lungs a large volume of air which
can not be voluntarily expelled. This is known as the residual air. To
measure it in a dead animal it is necessary to clamp the trachea, open
the thorax, remove the lungs to a vessel of water, and then allow the air
to collect from the opened trachea in an inverted graduated cylinder.
One part of the residual air is sometimes called Ihe minimal air; it is

i:

represented l>> thai which ^

animal when the thorax is In

produced, the alveoli

imei i keted within them and

compressed under water.

Tin- volume of the residual sir i
by causing a person, after a forced
breaths in and oul of a rubber bag
an indifferenl gas such as hyd
the start 4000 e c. of hydrogen, and

this gas and l • e.c of otl

expired air in the bag l»«-in<_r still •

Uaxlmua.

lomplrmm'

TIQAL A R

>mrnlal t

n

2000

cub in

or JO aib.

in

1500 100

or L

■

'

UMl o<

c . for it i> i\ idenl 1 I
: » i t«-< 1 air in the bag will be
calculation i^ based upon tl

the blood during th< i i m «-u •

amount absorbed is,
make it pei missible to
ing a t't-u bi
ertaining the proportion of n
quantity of residual air i v'

Lsuremenl of tl ■
tance in connection « ith ll c n •
lunj

:i()l2 THE RESPIRATION

Alveolar and Dead Space Air

In addition to these moieties of respired air, we have to consider the
division of the air in the lungs into what is called alveolar air and
dead -apace air. The former is the air which comes in contact with the
epithelium through which gas diffusion between the blood and the air
occurs, the latter being the air which fills the respiratory passages. The
dead space can not be defined anatomically with exactitude; it is func-
tional rather than morphologic.

Measurement of the volume of the alveolar and dead-space air can be
made in an animal breathing under normal conditions by taking ad-
vantage of the fact that, while it is in the lungs, the air has added to
it C02 gas, which is present in the inspired air only in negligible traces.
The necessary data are: (1) the volume of the tidal respiration; (2) the
percentage of C02 in alveolar air; (3) the percentage of C02 in the tidal
air. Suppose the values to he 500 c.c, G per cent and 4 per cent, re-

4

spectively; then the volume of alveolar air must be 500x^ = 333 c.c,

and the dead space 167 c.c. The measurement so made is accurate only
when certain precautions are taken. Because of the practical impor-
tance of this part of our subject we shall, however, defer its further
consideration until we have become familiar with the general features
of pulmonary physiology. Since the first air to move into the alveoli
at the beginning of inspiration is that present in the dead space,— the
last air expelled from the alveoli on the previous expiration, — it is of
no value in purifying the air already present in the alveoli. If we take
a tidal inspiration as amounting to 500 c.c. and the functional dead space
as 150 c.c, it is plain that only 350 c.c. of the outside air gains the
alveoli, and that the subsequent expiration is composed of 150 c.c of
outside air that had lodged in the dead space plus 350 c.c. of alveolar air.

These facts deserve a certain amount of emphasis because of their
practical importance in many phenomena connected with respiration.
One seldom thinks, for example, that out of the 500 c.c of air inspired
with each breath, 'only 350 c.c. reaches the alveoli, where it comes in
contact with the 2500-3000 c.c of air already present in this part of the
lungs.

There must therefore be a sort of interface somewhere in the alveoli
between the fresh outside air that comes in with each breath through
the bronchioles and the air which is more or less stagnant in the alveoli.
This interface must move backward and forward somewhat with each
breath, and a rapid diffusion of oxygen and of C02 must take place

The abo> <• dew
he maintenai

• he .lit ii'-' - '

lions in the ami
such variation
importi

in sini|>!>- s..hiti<in in

in g

Respiratory Tr

T1

• made by tl

■

■

- *

This \

en l>\ attae]

; \ pe is >li«»w n !
■
desired merely I
Riieh ;i ti.

ol.t

\ith t
knoM '

mi.

• I in fi

must

::<)4

TTIK KKSI '[RATION

ber of c.c. of water from a graduate into a bottle with which the record-
ing instrument is connected by tubing. The displacement of the "writing
point gives us the necessary data for standardization.

The Intrapleural Pressure

The air -which we have just been considering depends for its move-
ment in and out of the air passages upon changes occurring on the outer
aspect of the lungs in the space between them and the thoracic wall.
This is called the intrapleural space. It does not really exist as an
actual space in the living animal, for the visceral pleura which covers
the lungs is in accurate and intimate apposition with the parietal pleura
on the inner aspect of the thorax.

Fig. 109. — Body plethysmograph for recording respiration. (From J. S. Haldane and J. G.

Priestley.)

If the thoracic walls are punctured in a living animal or in one which
has recently died, the air will rush into the thorax, the two layers
of pleura separate, and the lungs collapse, causing temporarily a space
to be formed between the two layers of pleura and indicating that a
certain subatmospheric or negative pressure must exist in the intact
thorax to prevent the lungs from collapsing. The degree of this nega-
tive pressure may be measured by connecting a tube and a manometer
with the thoracic cavity. While the thorax is at rest, as in expiration
or immediately after death, this pressure amounts to about -5 milli-
meters.* On inspiration it increases to -10 millimeters. There are there-
fore two problems to be considered: (1) the cause of the negative pres-
sure in the quiescent thorax, and (2) the cause of the increase of the
negative pressure during inspiration.

*The minus sign indicates that t lie pressure is negative or subatmospheric. It is a suction pressure.

The Permanent Negative Pressure I
thai occur in the thorax \\ hen
una! is still in uter o, the In
first breath ii dram n the tl
1 u 1 1 <_r ^ . to thai ili<- latter become
the air thai i> introduced into them
chea and bronchial tub
increased spj i ted in tl.. thorax

thoracic <■■ This in itself, 1 ,f a

subatmospheric pressure in the inti
come into play namely, the elsstic I
expansion will !>»■<•< mp I and, tl
lax t" its previous condition and
tu ten it and the thoracic wall. II •
measure when we conned a manomel ith tl
Throughoul life the lungs remain of small." all.

and therefore to till the thoracic cavit;
l.->s distended and the elastic tisc
are, however, no1 the only Btructu
panded; all thin-walled ■ and viscera, Ii
gua, the aurich . must also b m<

When the thoracic wall is punctured and the out
entry t<> the intrapleural diffei

on the inner and outer :\^\>< the In

ih.' postmortem <-'>u<liti<»!i on accounl
in the thoracic wall of a li\i: i» in

luiiirs W ill ••\|>a iii. be<

intrapleural space and n
the lungs. This absorption •
rapid; bul if the /"" umothoraxt

■ f..r any length of tim< . the 1'
panded again.

The Greater Negative Pressure on Inspiration
rax becomes increased in ;i!:
suit thai i g] in the

thin-walled structures in the I

artieipi
entrance of outside air

ter pull, or negate
[nstead "t" being •"> nun 1 1
now comes t.. be atxn e 10

When anv obstru r*"

306 THE RESPIRATION

thoracic pressure produced by the movements of respiration become
more pronounced than under normal conditions. When the thorax ex-
pands with the trachea blocked, the lungs are not able to open up suffi-
ciently to fill all the space so that there is excessive dilatation of the
veins, auricles and esophagus, as well as drawing in of the intercostal
spaces and bulging upwards of the diaphragm. If a manometer is con-
nected with the pleural space under these conditions, a very large
negative or suction pressure will be observed, amounting often to -70
or -80 mm. Hg. It is possible that under such conditions some space
might temporarily exist between the parietal and visceral layers of the
pleura, but it could not remain long, for it would very soon be filled
by fluid exuding from the blood vessels. In the opposite condition, in
which the respiratory passages are blocked and a forced expiration is
made, as for example in the first stage of coughing or during such acts
as defecation and parturition, the thoracic cage is compressed upon the
viscera, with the result that the air in the lungs assumes a positive
pressure, amounting often to nearly 100 mm. Hg. If a puncture wound
is made in the thorax under these conditions, the lungs instead of col-
lapsing will bulge out of the wound, for what is .really occurring is
that the thorax is forcibly contracting on occluded sacs of air.

It is the alternating changes in intrapleural pressure that are respon-
sible for the changes in intrapulmonic pressure and these for the move-
ment of air in and out of the lungs with each respiration. In other
words, the thorax does not expand on inspiration because air rushes
in, as the uninitiated imagine, but air rushes in because the thorax
expands.

The Influence of Intrapleural Pressure on the Blood Pressure. — The
movements of respiration produce effects on the vascular system that
are of considerable importance in maintaining the circulation of the
blood. If an arterial blood-pressure tracing is examined, it will be
observed that aside from the cardiac pulsations large waves exist on it that
are approximately synchronous with the respiratory movements, the
upstroke of each of these waves corresponding in general with inspira-
tion, and the downstroke with expiration (Fig. 22). These respiratory
variations in blood pressure might be due either to changes in heart
rhythm or to a purely mechanical cause. Regarding 1 lie first possi-
bility, it is indeed the case in most animals that the pulse is quicker on
inspiration than on expiration, but that this alone is not an adequate
explanation of the rise is shown by the fact that it still persists after
the vagus control of the heart has been eliminated, either by cutting
the nerve or by the action of atropine.

The eause must therefore be a mechanical one. Bearing in mind the

u hich
out of the lu]
piration, turallj me thai

be <lu>' to thi 'ii ins!'

bj Btemic veins into tl.

polled bj the heaii into I

<*n expiration the opp

the thorax on u ion do

blood ia traveling I

ments of 1»I ltl<>\\ .

This explanation, h<

changes of 1>1 1 ; rhich

\ ery accurate i racings lood pi

ments ride bj Bide, w e Bhall fi
presau] ith inspiratii

erably delayed; thai is, immedial

inspiratory act the arterial l»l 1 pn

fall, and al the beginninj

rise ■ Pig. 22 .Mo it ill I"- found,

nt animals are com]
piration ia to cause mor< than

than rise. It w ill be found thai tl
on the type of respiration, w hi

Lei as consider firsl ial

breathing entirely by the tl
the inspiration i ause tl

themselves and the blood \ i
ded More l»l I

■ this blood will, l

it w ill be until ii

■
in arterial blond pi V\

has boon filled with bl<
tii-all;. .1 th<

side of th'

the ■
Ihc thi
Bqueeze the I
the bul

will be tl
then

r '

308

TITE RESPIRATION

phragm descends and crowds the viscera against the vena cava, with
the result that at first more blood is squeezed into the thorax and the
blood pressure tends slightly to rise. After this initial effect, how-
ever, the compression of the vena cava causes less blood to reach the
thorax, and the arterial blood pressure falls. The conditions will be
exactly reversed on expiration. The initial effect of thoracic inspira-
tion is, therefore, to make the arterial blood pressure fall, and the in-
itial effect of abdominal inspiration, to make it rise. The net effect

A. ABDOMEN.

JUX/LU

B. CHEST.

C. ABDOMEN.

Fig. 110. — Effect of abdominal and chest breathing on the pulse and blood pressure of man.
Abdominal inspiration raises the pressure and diminishes the amplitude of the pulse curve. Thoracic
inspiration less clearly lowers the pressure. Expiration has the opposite effects. (From Lewis.)

produced will be the algebraic sum of these two opposing influences
(see Fig. 110).

Another factor that comes into play in determining the effect of the
respiratory movements on the cardiac output acts through the changes
in the pericardial pressure. When this is lowered, as early in inspira-
tion, it encourages diastole, thus causing better filling and therefore
better discharge from the heart.

These considerations taken together make it easy to understand the
changes in blood pressure, particularly in the veins, which occur when
a forced inspiratory or expiratory movement is made with the glottis
closed. A forced expiration of this nature occurs during the acts of

defecation and partui it

also produ 1 by blowinj

( in account of tin- poaith •• p

aa thej enter the thorax, *

down the flow «>i" blood through t:

the veins and, if the •

si<l<- iif the vascular

squeezing oul into the left Bide of 1 1 •

lariea of the lungs, then a mo

the fact thai leaa blood la noi

side of thf heart After some time i

partly on account of the back pr< .e»s*l*

and partly bee of va vial

conditio] -

In the opposite condition, during
the glottis cloaed or with tli<- mouth atl
which the attempt is made to suck sir, ti
without the lunge l > < • i 1 1 «_r able t<»
The dilatation "f the veins her thin-v

rax ilius cauaea an immediate fall in both I
preasure in tin- venous, bee i the bl<
in tho thorax :m<l lungs, and in *
now delayed in its j > ; i *- ^ .- 1 lt • • from tl art

[f this condition is maintained, tl
what, but that in the veins is permanently

CHAPTER XXXV

• THE MECHANICS OF RESPIRATION (Cont'd)

VARIATIONS IN THE DEAD SPACE, THE RESIDUAL AIR AND
MID-CAPACITY, AND THE VITAL CAPACITY IN VARI-
OUS PHYSIOLOGICAL AND PATHOLOGICAL
CONDITIONS

By R. G. Pearce, B.A., M.D.

Dead Space

Under ordinary conditions of breathing the dead space is fairly con-
stant in volume. Haldane5 and Henderson6 believe that it may be in-
creased by 400 per cent in maximal deep breathing, and that the in-
crease is due to the passive stretching of the lower air sacs. Although
such large variations in the capacity of the dead space has not been ob-
served by Krogh and Lindhard7 or by R. G. Pearce,8 it is undoubted
that moderate rhythmic variations may occur. Even in deeper breath-
ing (1500 c.c. or over), a slight increase, which with maximum breaths
may amount to 100 c.c, can be demonstrated. This is not surprising
when Ave remember that the walls of the bronchi and bronchioles are
made up largely of readily expansible tissue (elastic and smooth-muscle
fibers). As the respirations become deeper and the expanding force of
the inspiratory movements of the thorax becomes more pronounced, the
diameter of the bronchi and bronchioles will enlarge proportionately —
that is, the diameter or circumference will increase in direct proportion
to this force; but the area of the cross section of the bronchi (i. e., the
capacity) will increase as the square of the diameter. This depends on
the fact that the area of a circle is increased by 125 per cent when the
diameter is increased by 50 per cent, and by about 300 per cent when
the diameter is increased by 100 per cent.

The capacity of the dead space has a certain clinical significance.
Siebeck8 has estimated that the dead space may increase by 100 c.c. in
asthma, but others believe that the increase may be greater. One rea-
son for the discordant results lies in the fact that the percentage of
C02 found in the alveolar air obtained by the Haldane-Priestley method
has been used as one of the basic figures in the determination of the

310

I li

capacity of the air ;
longation ration

method gives figures that

and it is plain that til

expiration is tlj pr< \\

dead space must !"■ accompai ied I

ume if the alveoli a

by Borne clinicians thi

diac decompensation ma;

< lareful esl imal h-ns of 1 1 •

t'ail to demonstrat< any g

An explanation of the

patients lias l q found I

Baldane-Prieetley method :

teal phenomena accompanying t!

emphysema the \\ alls of il •

lower borders "t' tin- lunu's. have !• i fail •

<>r relax properly <lurin>_r th<

tli. vs.- alveoli remains relatively ni

tions air made. When a samp

dead air i-- pushed oul of tin- .1

jpi ration required in the .1
Since the air in these ah eoli 1
in<_r the lungs, it has a h I •

with the uniformly 1 nd in

large ti'_'i the d<

is not increased, the l.l ! i>

ventilated in or<

entering the left hea H

en! blood l'M\ in-

cam can

Compensate for the lo
■ ■A alveoli, tl

hlix.il lr,r, il

emphysema P< \

alveoli in t'

The Residual Air Ukd M of U *■

Dur • muacul
I the * ital i

312 THE RESPIRATION

sunie a more inflated condition between breaths or, as it has been clum-
sily styled, a greater mid-capacity. These changes may serve as a
physiologic method for increasing the efficiency of alveolar ventilation
so as to meet the greater needs of the body. This is partly because the
pulmonary vessels become dilated and the bloodflow through the lungs
is favored, and partly because of the influence of the reserve and sup-
plemental airs on the tension of the arterial blood gases during the res-
piratory cycle. For example, if the lungs were completely depleted
of air during expiration, the blood leaving them at the end of this act
would be entirely venous. On the other hand, if the amount of air left
in the lungs at the end of expiration were above the normal amount,
each increment of C02 given off from the blood, or of 02 absorbed by
it would produce less change in the pressure of the C02 or 02.

The importance of these influences will be seen from the following
figures. If the residual and supplemental air amounts to 2000 c.c, and
the percentage of C02 in the alveolar air at the end of expiration is
5 per cent, then 100 c.c. of C02 must be present in the lungs. In a con-
dition of bodily rest about 20 c.c. of this gas is excreted during a res-
piratory cycle, so that if the breath were held during this period, the
percentage of C02 would rise from 5 to 6 per cent, and an inspiration of
400 c.c. would be required to bring the air in the lungs back to 5 per
cent of C02. On the other hand, if the residual and supplemental air
amounted to 3000 c.c. with 5 per cent of C02 in the alveolar air at the
end of the expiration, there would be 150 c.c. of C02 in the lungs at
the end of the expiration, so that holding the breath for the time of the
respiratory cycle would raise the percentage of CO, only to 5.66 (pro-
vided the production of C02 was the same as in the first case), and an
inspiration of 600 c.c. Avould be necessary to reduce it to the normal
expiratory figure. Or. putting it another way, the production of CO.,
can be increased 50 per cent in the time of a respiratory cycle without
affecting the tension of gases in the lungs, provided the residual and
supplemental air and the volume of the respiration are increased 50
per cent. If only one of the factors is changed, however, then the bal-
ance of the respiration must be disturbed, and the greater variation
in the tension of the gases in the arterial blood must occur at the dif-
ferent phases of the respiratory cycle. -Bohr and Siebeck have shown
that the residual air is invariably increased in emphysema and that the
mid-capacity of the lungs is likewise increased; and it Avould appear
from Siebeck's data that a similar condition must bo present in cases of
decompensated heart.

Patients suffering from dyspnea, particularly those suffering from

Ill

cardiac dyspnea, can not bi
Bitting. Thia condition ii ki

ting over the lying p
plained Th< • ter \ ital eap
ing of ti

gravity; the increa
enlarged thoracic ca\ ity
air of the lungs are all

The Vitui Capacity, i\
of the lungs to their

the determination of I ; lue in :

t.iiit. Recently Peabod
Eac1 that : ■ itli heaii <\

do healthy subjects, ai •! thai I
on their inability to inci he depth

manner. They find thai this Inability
a diminished vital capacity of th(
by the volume of th< possil

spiration. They believe thai any condition which !
of increasing the minute volui

tor in the production of >h

In normal adults the follow ; I

;i large bi rii clinical c I

clas ich group being subdivided

.

Mm i

)IT I*

Lowrmt

•

I
11

III

44

$* B

*)

SO

S'|

I

n

in

It would •'!!'!"

!it. and aln i I
adopted for each group

darda may !

314 THE RESPIRATION

Table II

The Relation of the Vital Capacity of the Lungs to the Clinical Condition in

Patients with Heart Disease*

group

VITAL

NUM-

MOR-

SYMPTOMS

WORK-

REMARKS

CAPACITY

BER OF

TALITY

OF DECOM-

ING

7o

CASES

%

PENSATION

%

%

I

90 -

25

0

0

92

Few symptoms ref-
erable to heart.

II

70 to 90

41

5

2

54

History of dyspnea
with exertion, yet
able to do moder-
ate work.

III

40 to 70

67

. 17

89

7

Dyspnea with mod-
e r a t e exercise.
Few able to work.

IV

Under 40

23

61

100

0

Bedridden, with
marked signs of
cardiac insuf-
ficiency.

(Peabody and Went/worth.)

'Certain cases were tested several times and, owing to changes in the vital capacity they appear
in more than one group. In the "mortality" column they are included only in the lowest group into
which they fell. "Symptoms of decompensation" indicate dyspnea while at rest in bed or on very
slight exertion. Under "working" are included only those actually at work, and able to continue.
Many other patients in Group II were able to work, but they are not included as they were still in
the hospital.

Table II shows that there is a remarkably close relationship between
the clinical condition of cardiac patients, particularly as regards the
tendency to dyspnea, and the vital capacity of the lungs. Peabody and
Wentworth believe that the determination of the vital capacity affords
a clinical test as to the functional condition of the heart, since compen-
sated patients who do not complain of dyspnea on exertion have a nor-
mal vital capacity. Patients with more serious disease in whom dyspnea
is a prominent symptom, have a low vital capacity; and the decrease in
vital capacity runs parallel with the clinical condition. As a patient
improves, his vital capacity tends to rise ; as he becomes worse, it tends
to fall. In other diseases in which mechanical conditions interfere with
the movements of the lungs, the tendency to dyspnea corresponds closely
to the decrease in the vital capacity. The cause of the decrease in the
vital capacity of the lung in cardiac decompensation is difficult to ex-
plain satisfactorily. It may be the limitation in the movements of the
lungs produced by engorgement of the pulmonary vessels, by the weak-
ness of the intercostal muscles, the rigidity of the bony thorax,
emphysema, or accumulation of fluid in the pleural cavities.

In cardiac disease the air in the lungs at the end of a normal expiration
is usually increased. This is similar to the condition which attends exer-
cise, and is probably ;i physiological adaptation 1<> give optimum aeration
to the blood, as explained above.

CUAPTEK .1
THE MECHANK B OF RE8PJB

THE MECHANISM BY WHICH THE CHANGES I PACITY OF
THE THORAX AND LUNGS ARE BROUGHT ABO

Bi k. i. . r i-. a MH

that take place in tl
thorax daring respiratioD are b
diaphragm, sternum, and vertebra
considered separately.

The Movements ol the R:

attached directly to t aum b;

the twelfth pairs pro
truth thej are indirectly atta
the ' I The el< ■ I h and t h elfti

may be considered a pi
the thoracic

Bach pair of r jether w it h r

ms a riii^r, the plane of •■ I
Th- J articnlatioi

uii- [n the form*

which (it int

, whil<
ribs arc flat Eacl I
little more backwai
ribs t to thi

rtifiilatit.ii of the lipp<

in thr spii
movement in thi

:" the rih *
hich ti

thr
oflV.-f

316

THE RESPIRATION

converted into an upward movement, which is greatest in that part of the
shaft lying parallel to the axis of rotation of the neck (Fig. 111).

The upper ribs from the first to the fifth form a cone-shaped top to the
thorax, whereas the lower ones form a vertical series, each being situated
almost directly above its neighbor. The upper set is arranged for the
expansion of the conical upper lobe of the lungs, the lower for the ex-
pansion of the more or less cylindrical lower lobes. During inspiration
the anteroposterior diameter of the conical portion of the thorax in-
creases, because the ribs, together with the sternal connections, move
through progressively increasing arches, and each lower rib tends to over-
ride the rib just above. The maximal rise of the ribs from the first to the

A.

Fig. 111. — A, first dorsal vertebra; Bt sixth dorsal vertebra and rib. Axis of rotation shown in

each case.

tenth during inspiration shifts more and more from the anterior to the
lateral aspects of the thorax, because the angle formed by the shaft near
the neck of the rib approaches nearer to the articulating joints on the
vertebrae.

An examination of the shape of the first rib, its relationship to adjacent
structures and its movements, shows that it differs from the others in
its respiratory function. The first pair of ribs and the manubrium sterni
are bound closely together by short, wide costal cartilages, and form a
structural unit which Keith1 calls the thoracic operculum. This lid is
articulated behind with the first thoracic vertebra by a joint, which is
more nearly transverse than that of the rest of the costal series; and in
front with the manubrium, which is also articulated with the clavicles

I II M l :

above and with tin- bod) of
men! at the angle which 1 1 * « - main.
joint is related to the 1
sternum la el I during inspiral

• . luit w hen the sternum
amount to 16 . Lack "t' m<

I ii considered by some physician

pulmonary tuberculosis. During
attachments are raised b) tl •
the second, third, Fourth and fifth rib
they are depressed toward the lower ril
fixed baa

The combined effecl of these influe
upper ribs which is described by the clii
movement is more apparent in the npp<
here the relative difference in tl
attributes a certain <1 i.i ltd « >-t i <• sif
movement, diminution in the i ibilit)

it t<> become less or to disapp< I

the tip of the ring finger on the Becond rib in tl
iip of the middle finger on the third iil> mi<l
lar and anteroaxillary line, and the tip of t;

rib in the midaxillary line. The patienl is tl (» a

moderately rapid and deep inspiration.

observed to move Farther than that 01 tl
mi the Fourth rib will move Farther thai tl
mint of «'a«-li rib From above downv
the rib just ;i1m>\ .•.

When there is a mod
the upper lobe, the three ribs move in m
tanee, so thai the undulator) m<
may exhibit a considerabh i
impaired by any di w hich i

interstitial tissue of the lung, <>r <l I *n

enlarged heart or ad

in this jih. ;..n is that an)

nt tissue w ill product

ami thus limit the exp
. is i.f m..\ cm

• MM:. Is \\ itll t!

•■ tli.- mils
their im»\

• t-l,

318

THE KKSIMRATION

sixth to the tenth are joined to the sternum by the cartilages which unite
the sixth, seventh, eighth, ninth, and tenth, so that any movement in
which the ribs are raised is accompanied by an anterior movement of the
sternum (Fig. 112). The ribs are so articulated to the spinal column that
the inspiratory act canses the lateral and anterior part of each rib arch
to move forward and outward more than the one above it.

In natural breathing in the standing or sitting posture there is a
slight extension of the spine during inspiration. This serves to increase
all diameters of the thorax and its absence is undoubtedly an important

Fig. 112. — Lower half of the thorax from the 6th dorsal to the 4th vertebra, seen from the
front, c, ensiform process; d, d', aorta; e, esophagus; /, aperture in tendon of diaphragm for
passage of vena cava inferior; /, 2, .?, trilobate expansions of tendinous center of diaphragm; 4, 5,
costal portions, right and left, of diaphragm muscle; 6, right crus of diaphragm; 8, 9, internal
intercostal muscles, which are absent near the vertebral column, where it joins p and 9, the ex-
ternal intercostals; 10, 10, subcostal muscles of left side. (From Luschka.)

contributory factor in reducing the vital capacity of an individual when
lying on the back. Figures given by Hutchinson for the effect which
posture has on the vital capacity are of interest because of their bearing
on the cause of orthopnea. In the same individual he found the following
vital capacities:

Standing 4300 c.c.

Sitting 4200 c.c.

Supine 3800 c.c.

Prone 3620 c.c.

The Action oi the M

In a

a broad ••■■
the riba aa

'

lir.st rili so thai h
int. I muscles in •

three paii bs along

■

.

'

32(1

THE RESPIRATION

debate, and can not be said to be definitely settled. The direction of the
fibers in the internal intercostals indicates that they are expiratory in
function, since they can not shorten in the inspiratory position; while,
on the other hand, the fibers of the external intercostals can not shorten"
in the expiratory position, and hence must be considered inspiratory in
character (Fig. 113). In 1751 Hamberger showed that mechanically this
is the case, and gave the schema shown in Fig. 114.

The function of the intercartilaginous muscles, however, must be
inspiratory, as is shown in Fig. 115.

Fig. 115. — Schema to demonstrate that the function of the internal intercartilaginous intercos-
tals is identical with that of the external interosseous intercostals.

The ribs and costal cartilage may be regarded as rods bent at the angles acd and bef, in
which the articular points c and e represent the symphysis between the bony and the cartilaginous
parts on which traction is made. During inspiration the fibers of the intercartilaginous muscles,
which have the direction gh, move the sternum df away from the vertebral column ab, like the
ribers of the external intercostals, which run in the direction kl. During this double action the
angles c and e must be decreased, because the muscles of the upper intercostal spaces work simul-
taneously, and the entire thorax is slightly elevated during inspiration. From this scheme it is
apparent that the external intercostals and the intercartilaginous muscles must be the same. (From
I.uciani's Human Physiology.)

The Action of the Diaphragm

It is possible, however, that the main function of both the intercostal
muscles is to regulate the tone of the intercostal spaces and so prevent
their suction inwards when the negative pressure in the thorax increases
(i. e., suction becomes greater). The ascent of the ribs, while producing an
increase in the anteroposterior and transverse diameters of the thorax,
would decrease the vertical diameter if this was not counteracted by the
fixation of the lower ribs and the descent of the diaphragm. The periph-
eral edges of the diaphragm are attached behind to the lumbar vertebrae,
laterally to the lower edges of the six lower ribs and their cartilages,
and in front to the tip of the ensiform cartilage. The fibers converge to

enter the

the intraabdomina

they form a dome shaped

mach and the spleen ii

Duri »ira1 ion the I

with the parietal pleui

• he pleura] sinuses 1 1
Bhorten; this Btraig
lateral edges of tin- diapl
ing up the pleural Binusi
opening up of the
external cheat v\ all, « hich is

l the diaphragm

L5 linn, nn each Bide, which
the volume of air exchange !•;
diaphragm does not ' much in

its jii<>\ ement may ;
Because of its attach]
diaphi ■ pull the margii

l»ut under normal conditions tl
the externa] into Is in raisi tal

<li;i Of the tin. i,

the position of the l"\\ er ril
/ relativi p
t play in th*

inn 1 1

thai tl).- contraction <•!' the dia|

• of the thorax, I"
\ iscera a

It tliis iiiiL'lit occui

w ii by experimental a

•,il ni.i
calls attention I
the ril.s .- 1 1 1 < 1 in<
This w idei

nuin is very p
■
the median !
the diaphragm must I

tral tend< v' ■€■

well defin< .1 arcl .

H22

TTIE RESPIRATION

Fig. 116. — Diagram to show the effect of high and low positions of the diaphragm on the
costal angle.

Line 1. Normal position of diaphragm Costal margins move out during inspiration.

Line 2. High position of diaphragm. Normal outward movement of costal margins accentuated.

Line 3. l,ow position of diaphragm. Costal margins move in during inspiration.

Line 4. Very low position of diaphragm. Costal margins move out during inspiration.

Line 5. Actual line of traction of diaphragm. (From T. Wingate Todd.)

I I!

IL'I Till: RESPIRATION

t filial intercostals have the mastery and cause the costal borders to
spread. When the arch of the diaphragm is depressed, as in pleurisy
with effusion, emphysema, and empyema, the line of traction and the
line of the muscular fibers of the diaphragm correspond more closely,
so that the diaphragm is able to use its full force against the intercostal
muscles, with the result that the costal border moves towards the median
line. The curves of the different fibers of the diaphragm vary greatly;
the arch is much less marked in the portion attached to the costal margin
near the median line than in that attached in the axillary line. For this
reason the anterolateral part of the diaphragm requires less depression
to give it a horizontal position than is required for parts occupying a
more lateral position. A small pericardial effusion or an increase in the
size of 'the heart may therefore depress the diaphragm sufficiently to give
it mastery over the intercostals in the front portion, so that the costal
border may here move towards the midline, while the lower borders
move in a perfectly normal manner (see Figs. 116 and 117).

During forced breatliing several muscles are brought into play, among
the most important of which are the scaleni, sternomastoid, trapezius,
pectorals, rhomboids, and serratus magnus.

There has been considerable debate as to whether expiration is normally
an active or a passive process. Undoubtedly the expiratory phase under
normal conditions does not require the same muscular effort as does that
of inspiration, but there are many observations which indicate that ex-
piration is partly under muscular control. The abdominal musculature,
for example, increases in tone during expiration, so as to bring about a
rise in the abdominal pressure, with the result that the relaxed diaphragm
is pushed up into the thoracic cavity. To this extent at least, expiration
is accompanied by increased muscular activity.

Before leaving the subject of the diaphragmatic movements, reference
must be made to the recent observations of Lee, Guenther and Meleney "'
bearing on the general physiologic properties of the diaphragmatic
muscle. They point out that most skeletal muscles in the living body
contract with varying degrees of intensity and at irregular intervals,
between which relatively long periods of rest occur, but the diaphragm
from birth to death performs a continuous succession of brief contrac-
tions of fairly regular rhythm and uniform extent, alternating with brief
periods of rest. Its muscle fibers, together with those of the other
respiratory muscles, therefore hold a unique position among skeletal
muscles, which suggests a crude analogv with that of the heart. They
have compared the physiological properties of the diaphragm with those
of the extensor longus digitorum, the sartorius, and the soleus, and found

tint the diaphragm
than thai of th<

The Effects of the Re. Uontl

produced in the >\\
the tip

turea are nol equally

lungs 1 1 1 ; i \ !»<• <li\ ided int" thre< i

the bronchu8,

■
any expandii . 2 l

and bronchia] ramificatio
with pulmonary tissue impl
lungs has varying deg
tin-

perhaps 25 I nun. in depth,

equall; throup I

accomplished by a mo> in-_r apa
as to permit th<
tween them. Keith com]
• i p an.

B the lui lands in I

th«' inflated dead

■ ut by ili«' thoracic moven
limited in some regions than ii
distinguished on the Burfi •

■ |y immovable parts of
panded directlj 'I

• limn ami the Btructun
with the Bpinal column and I

•
brium expand
of tin' In
apex i •
ond ril

Ml

ami the

diaphragm Kron
is |(

M

326 THE RESPIRATION

by the fact that, in the region immediately surrounding a localized con-
solidation, a fluid has increased resonance, which would not be the case
if the relaxation produced was equally distributed throughout the lung.
The root of the lung, which has generally been regarded as more or
less fixed, undergoes in normal breathing a definite forward, downward
and outward movement, and the heart shares in this movement (Keith).
The movements of the lower ribs and diaphragm are responsible for the
expansion of the lower lobes and dorsal portion of the upper lobes of the
lungs, whereas the movement of the upper five ribs expands the anterior
portion of the upper lobes. The relative infrequency of pleuritic fric-
tion-sounds and pain over the upper lobes as compared with their fre-
quency over the lower lobes is explained by the fact that the expansion
of the upper lobes is accomplished with little displacement of the pleural
surfaces, whereas in the lower lobes expansion is accompanied by a glid-
ing of the lungs across the ribs.

I MAM I , ,||

I HE CON! ROL OF THE KESPI RATIO

The participation of Buch wid
tor) acl demands that

trol With i ,1..

nasi |

dud ad the intei

diaphragm are contracting « h

relaxing; and all tl

bring about the mi I

dently there musl ome mechanism I

is effected through the i m.

THE RESPIRATORY NERVE CENTERS

I nt fibers to • : ■

tive motor neur» hich in d

matter <>f the Bpinal cord. I
i-ons. or subsidiary

impulses from a highi
longata, the pathway of trai
subsidiary centers being in I

evidence thai
nished By obsen ii
by scri.il destruction
1 1 this method the ap
location being thru del

of tin- supposed loc *»■»

before backw ard, p
produced on tli-
mcdulla, w hen imra

[f W •' ll'iW

tricle in i
located about the tip

resides in I
Bolitariu [1

::i>s

THE RESPIRATION

The subsidiary centers are entirely dependent upon the master center
for their harmonious action, as is shown by the fact that if the phrenic
motor neuron — which is situated in the cervical spinal cord between the
fourth and sixth spinal segments — is isolated from the medulla by a
Lateral hemisection of the cord just above the fourth segment and by
mesial section of the cord opposite the center, the corresponding half of
the diaphragm no longer participates in the inspiratory act (see Fig. 118).

The chief center on cither side of the midline of the medulla is con-
nected with the motor neurons of botli sides of the spinal cord, as is
proved by the following experiment. When the central end of the vagus
nerve is stimulated, the respiratory center becomes excited and the respi-
rations more pronounced, the participation of the muscles on both sides
of the body being equal in extent. If now we bisect the medulla down the

Medulla

Spinal cord

Fig. 118. — Diagram to show cuts required for isolation of the phrenic center.

midline and repeat the stimulation of one vagus, the muscles on both sides
will still participate in the increased respiration, which they will likewise do
if the cervical cord is bisected or hemisected but the medulla left intact
(Fig. 119). The simplest interpretation of these results is that commis-
sural fibers connect both halves of the respiratory center in the medulla
and that each half is also connected with the motor neurons of both sides
of the spinal cord. Often, especially in young animals, a hemisection of
the cord causes cessation of the movements of the diaphragm on the same
side; bid this paralyzed side at once begins to contract again when the
phrenic of the opposite side is cut, probably because the respiratory
impulse descending from the chief center, on finding its way along the
motor center of the same side of the cord blocked, is forced to follow the
crossed path. The crossing in the cord is believed to take place at the
same level as thai at which the subsidiary center is located (W. T.
Porter12).

I III

The tiucstion w
purely reflex in I

IIMIlMli

in the 3( use i hal
tomaticitj of the hearl i
which ■

hi inli-
matic respirator} eei t<

suit of chi
the facl that il
nervous impulses. I
of ihf center as beinj
dependent u\ aff< Its

Medulla

t roofj

y

be merelj a facto i
ordinarily controlli

11 \\ hich .
'•'■lit .-r iua\ or ii

undertaken I
isolation "f

Tin- iiillu-
the pedum
puis

the spina
the i><>-'

330

THE RESPIRATION

by them to the respiratory center. By such an operation the only lower
respiratory neurons left intact are those of the phrenic nerve, so that the
respiratory movements that alone are possible are those in which the
diaphragm participates and the muscles of the alae nasi and larynx. It
was found that the animal after the operation went on respiring, though
imperfectly, and that the respirations soon became more marked and
asphyxia] in character, indicating that the blood was not becoming

Vagus.X.

Disphracjm.

Fig. 120. — Diagram to show where cuts arc made to isolate the chief respiratory center from

afferent impulses.

properly aerated and that the chemical changes occurring in it were
acting directly on the center, stimulating it to greater activity. The
conclusion seems warranted that the respiratory center can act auto-
matically, for the only possible afferent nerves left in the above prepara-
tion were those carried to the center by the tit'tli nerve (Fig. 120).

That the respiratory center is extraordinarily sensitive to changes in
the composition of the blood flowing through it is a, fact that has been
knoAvn for a long time, but it is only within recent years that the exact

in

nature of this conl ■

it }\a\ e been tl

Mil M>

which the cent

THE REFLEX CONTROL OF THE RESPIRATORY

I afferent n<
iently be <li\ ided i-
and i i hich a< I

The Occasionally Acting Impulse!

I the first group 1-
the body. .That impr<
is w.'ll kiinu 11 by tin- inci
water. The influei
an-i quently taken a«I\ .

take t; th. Stimu

in tin- mucous membrani
immediately inhibits pesp
impulses ma) 1>«- added the imp

ter from the higher i
are largely voluntary in natun

ebral impulsi
ence being seen b) "I
aft- ioning the po

!"■< te distinctly affected, bul

art' cm' Othei
at<n\ ■ is furnished

stimulation »»t' 1 1
respirator} mo^ i m<

l; • 'h\ thn

in order that the respii

than tl •

the form of .1 up p<
respiration ma} !"•
ble alteration in tl
■
tion. We must
from the

ntlv inhibit

332 THE RESPIRATION

Stimulation of the endings of the glossopharyngeal nerve inhibits res-
piration, which explains the holding of the breath that occurs in swal-
lowing.

The Continuously Acting Afferent Impulses

The continuously acting afferent impulses are transmitted to the chief
respiratory center by the vagi and their branches, the superior laryngeal
nerves. If the vagus nerves are cut or their continuity severed by
freezing a portion of them, the respiratory movements become markedly
slower. Evidently, the vagus nerves in some way hurry up the respira-
tory movements. Again, if the central end of either vagus is stimu-
lated with the ordinary interrupted faradic current, a profound effect
on the respiratory movements is usually observed. This effect is how-
ever not strictly predictable. Usually there is a quickening of respira-
tion, and if the stimulus is a strong one, there may be a standstill of the
thorax in the inspiratory position. On the other hand, if the central
end of the nerve is stimulated with other types of stimuli, as by slow,
weak faradic shocks or by the stimulus produced by the closure of an
ascending voltaic current, the effect may be to stimulate expiration
rather than inspiration. Such results would seem to indicate that the
vagus contains two kinds of afferent fibers to the respiratory center, one
kind stimulating inspiration, the other, stimulating expiration.

Supposing that such fibers exist, the next question is, how do they
become stimulated at their terminations in the lungs? The most nat-
ural assumption is that the mechanical distention and collapse of the
alveoli which occurs with each respiratory act, serves as the stimulus —
an hypothesis to which support is offered by the observation that, when
air is blown into the lungs so as to distend the alveoli, the animal im-
mediately makes a forced expiratory movement, whereas when the air
is sucked out, the thorax assumes the inspiratory position.

Of the many methods that have been employed to produce disten-
tion of the alveoli, the best is undoubtedly that recently employed by
Ilaldane and Boothby.13 The person or animal is made to respire through
a tube in which is inserted a three-way stopcock, which communicates
either with the outside air or with a side-tube leading to a spirometer
or bag containing air under slight pressure, so that when the stopcock
is turned breathing takes place against a definite positive pressure.
Such a method is obviously much more physiological than one in which
the air-tube is suddenly clamped at the end of inspiration and the lungs
lefl in a distended condition.

The term used to designate the cessation of breathing is called apnea.
The extenl 1o which it occurs varies very considerably in different an-

Tli

imals and, in tl
man i^ made suddi
last about i

piration followed ;

mi with pro

any influences w hich i

of the bl 1

Bider the possibil
\ ague This Is an old
does nol lend Bupp 1 1

example, thai a similar e

!"■ produ I in <h-L'> in which

nerves had been
fore, nol a reflex of thi
«.ii> impulses passii
the nervous bj Btem, pei 1 i
mitted to the r<
spiratory must

Tl i
tomatically by alternate dis
through the afferent fi
in Buch a way as to brii
inspiration, must, thei •

\ agus plaj a a most imp*
the respiratory
follow the

ation oi \
i the
cun

ithing ; and wh<
appears during both
he\\e\ ing that tl
'i-.u w ith •

that in an in'

rlion diox
ami qu

i«l«

a bu1

I priii

■

334 THE RESPIRATION

excitability, and being active to ;i greater or less extent all the time;
while the other acts only occasionally on the "limed up" center. There
is, of course, no doubt that it is through the nerves that the occasional
alterations of respiration occur. They appear also to have a certain
influence on the rhythm, for Stewart, Pike and Guthrie17 observed that,
after resuscitation from acute brain anemia, the respirations when they
returned were of the same rhythm as that of the artificial respirations
i 'in ployed during the resuscitation.

The usually accepted hypothesis as to the mechanism by which the
nerve impulses hasten the respiratory movements is that an afferent
impulse is transmitted to the respiratory center towards the end of each
inspiration, which has the effect of inhibiting the inspiratory discharge
from the center and thus cutting short the act of inspiration so that ex-
piration automatically supervenes. This explanation is in agreement
with the fact that quiet inspiration involves activity on the part of the
respiratory muscles, whereas expiration is usually almost entirely pas-
sive, being due to the return to a resting position of the stretched and
displaced structures. On the other hand, in forced respiration and in
certain animals under normal conditions, expiration becomes active, in
which event a current of action becomes evident in the vagus nerve dur-
ing the expiratory phase.

The superior laryngeal branch of the vagus should really be classified
as one of those nerves that have an occasional influence on the respiratory
center, its particular function being in connection with the act of cough-
ing. When a foreign body irritates the mucous membrane of the larynx,
the nerve fibers transmit impulses to the respiratory center which ex-
cite a violent expiration and at the same time cause the glottis to close.
The closure of the glottis lasts, however, only during the first part of
the expiration; it then opens, with the result that the sudden release of
intrapulmonic pressure causes the expulsion of the foreign substance
in the air passages.

CIIAITKK XXXVIII

THE I I »vi i:< 'I. I >F RKSP1R \ l [<

THE HORMONE CONTROL OF THE RESPIRATORY R KR

Jusl rhythmii

changes in the composition i
the respiratory In I

cium, potassium and sodium
whereas in the case of the i espii
centration of hydrogen and

C of the lil I. This influi

injecting acid or alkaline Roluti<
artery of an anesthetized animal,
decei ebrati d Acid injei
line injectioi i to depr<

are injected intravenously in ol
come thoroughly mixed with t;
reached, the effi cl
flucnce of the blood has

Prom the resull i> injection ■

not draw th( slusion thai

the respirator} center is affected
blood, for, as u e hai •• •
able properl ■ imal fluid i

piratorj cent*
beha\ ior of & i ily m<

tl)<> Id 1 thai und<

alteration in Ci l
Riihstance may 1"-, it w ill b<
concerned in maintaining I
dependenl upon the 1

■ •li it

mounl
nously, l

duced dm
demands

U5

:,).°)(! THE RESPIRATION

the amino groups— split off from the amino bodies— become converted
into ammonia instead of into the neutral substance, urea. Rnt the chief
variations seem to concern acids rather than the basic substances. These
acids may be divided into three "roups: fixed inorganic acids, represented
by phosphoric; fixed organic acids, represented by lactic; and volatile
acids, represented by carbon dioxide. Of these three groups, the first
shows the least tendency to change, and the third, the greatest. Changes
in Hie second group I fixed organic acids) are effected partly by excretion
through the urine and partly by oxidation into volatile acid. The sud-
den and rapid changes in the third group are brought about by the dif-
fusion of the CO, of the blood into the alveolar air. Gross changes in
the acid content of the blood are therefore mainly effected through al-
teration in the excretion of the fixed acids, Avhereas sudden changes art'
effected by excretion of the volatile acid. It is important to note here
that the fixed organic acids do not participate to any great extent in
the makeup of the acid content of normal blood: they appear only under
unusual conditions, as in dyspnea. The variations in CH that ordinarily
affect the activity of the respiratory center are therefore dependent
upon changes in the volatile acid, a direct measure of which is found
in the tension of CO2 in the blood. The correlation between CH of the
blood and respiratory activity must be a very close one if CH is to be
maintained.

The Laws of Gases. — In order to understand the principles upon which
alterations in CO, tension are dependent, it will be necessary for us to
review briefly some of the gas laws. Among these laws the first in im-
portance is the law of pressure, which states that, other things being
equal, the pressure of a gas is inversely proportional to its volume ; if
a gas occupying a certain volume is compressed by a pump so that it oc-
cupies one-half of its previous volume, its pressure will become doubled.
The second is the law of partial pressure, which states that the partial
pressure of a gas in a mixture of gases, having no action on one another,
is equal to that which this particular gas would exert did it alone oc-
cupy the space occupied by the mixture. Thus, atmospheric air consists
roughly of 79 volumes per cent of nitrogen and 21 of oxygen; the par-

21
tial pressure of the oxygen is therefore equal ^^X 760 mm. Hg,

this last figure being the barometric pressure of air at sea level. The
third is the law of solution of gasi s, which is to the effect that the amount
of gas which goes into solution in a liquid having no chemical attraction
for the gas, is proportional to the partial pressure of gas. If water is
exposed to air, the amount of oxygen which it dissolves will be the same
as if the water had been exposed to oxygen at a pressure equal to that

of the partial pi
the case w itli the n

ionics dissoh cil in ili-- fluid, p
depends partly on |
fluid. For examph
differenl From that ii
•_r,.|| and CO

i-y. il •
will dissolve in a particu
of solubility i
volume of fluid tidard

•h. efficiei •

0 02 '■'' meai - that, at this tern]
Bure, l ill diss

a pure atmosphere of this

. 9 per cent of an atm

w mild li tne dissoh •••! in pad ■

In solul ions containing i
enter inin combination
proportional to the amount •
from the fluid. < Mi th<
tin- combined lm^ p ill
this will I..- indep<

will ha

if pun

amoui

pressure I Pal

the CO w ill 1"
larger quantity I ' I will bi

mineral acid 1
the atmosph<

tii »ns |

The Tension of CO and 0 in the A: Blood

s hi

confim

iriit that the p(

th

the blood
other hand.

fus

338

THE RESPIRATION

atmosphere in the space would show thai the C02 percentage had been
raised. If the blood contained a lower tension than that corresponding
to the percentage of C02 in the space, some of the CO, would diffuse
into the blood, and its percentage in the atmosphere would be lowered.
By successively exposing blood to gas mixtures that contain slightly
different percentages of C02, we should ultimately find one with which
the free C02 in the blood was in perfect equilibrium, and we should be
able to state that 1 lie tension of this gas in the blood was equal to a
certain percentage in the atmosphere surrounding the blood (see Fig.
121).

Many forms of apparatus based on the above principle have been in-
vented for the examination of the tension of the gases in the blood.
The most accurate is that devised by Krogh,ls the principle of which

,* S.t%a\eni

sfaf",- , \ ssY^^^JBtovtS*y>s>^*r:^< -^^-<^, ,

S. 5 at itavT
C0X s.1 ».Te.Yid

SSS'SySSSs ^X^/X/Jl<*<>^/^^/^^^^>^^

CO, s.-\s »T £**
5.-13 i'd>a

IT

Fig. 121. — Diagram to show principle for measurement of the tension of C02 in blood. The

C02 tension of blood is supposed to be 5.75.

differs slightly from that just described in that a bubble of air is
exposed to a relatively large quantity of blood, so that after a time
actual equilibrium of gas tension becomes established between the bub-
ble and the gases of the blood. This apparatus is shown in Figs. 122
and 123. It consists of a graduated tube of narrow bore sur-
rounded by a water jacket. To the upper end of the graduated tube
a small syringe is attached. The loAver end of the graduated tube ex-
pands into a thistle-shaped bulb, closed below by a cork, through which
is inserted a tube (inflow tube) ending near the top of the bulb in a
fine opening and connected outside with an artery. An outflow tube is
also connected with the thistle-shaped bulb.

At the beginning of the experiment the thistle-shaped bulb and the
graduated tube arc filled with physiological saline. By means of the
syringe a small bubble of air is then introduced, so that it lies at the

junction ol the thistle i l>ull>

is allow ed to enter thr<
around the bubble "i air, •••• hicl
displaces the salim
ble has been subjected to t;
the gases in it come into p<
The percentage of 0 CO

tu the tension "i' ;
draw ing th«' bubble int..

cz

•■

asuring its eapacil
which absorbs the CO

.in measuring i
i bubbl •
tion, \\ hei e the 0 l *

The Tension of CO lad 0 in A * Air

may determine tin

340 Till' RESPIRATION

the method by which the tensions of these gases in alveolar air can be
determined. The simplest and until recently the most accurate method
is that of Haldane and Priestley.10 This consists in having an individual,
v\ith his nostrils clamped, breathe quietly through a piece of hose pipe
about a meter long, which has at the mouth end a short side-tube lead-
ing to an evacuated gas-sampling bulb of about 50 c.c. capacity.* After
the subject has become accustomed to breathing through the tube, he
is asked to make a forced expiration and at the end of it to close the
mouthpiece with his tongue. At this moment the operator opens the
tap of the sampling tube, allowing the air from the tubing through
which the individual has made the forced expiration to rush in and fill
it. This sample represents the air from the alveoli (see page 302), and
is analyzed for percentages of C02* and 02. Since each normal inspira-
tion dilutes the alveolar air someAvhat, it is necessary, for constant re-

Fig. 12-t. — Apparatus for collection of a sample of alveolar air by Ilaldane's method. It is

better to use a mouthpiece than a mask.

suits, to make two analyses of alveolar air from each subject, one taken
at the end of a normal inspiration and the other at the end of normal
expiration. The average of the two results is taken as the composition
of the alveolar air.

On account of the difficulty in securing intelligent cooperation in the
application of this method, particularly with children, others have been
devised. One of the simplest is that of Fridericia, which is a modifica-
tion of the Ilaldane-Priestley method, the apparatus for which is shown
in the figure (Fig. 125), and the manipulation of -which is outlined in
the legend. Another is to take a mixed sample of the very last portion
of several normal expirations. On account of the extended use which is
being made of measurements of alveolar air composition, both in lab-

*In place of the gas-sampling tube it is much more convenient ami equally accurate to employ one
of the modern ground glass piston syringes (l.r.er). The piston should, of course, be well smeared
with a good mineral grease.

\ N

X j

•

/

I

IE

3tt

■

?

if

■:■'

■■■:

•

■

ft

1

a

1

•

Ml

—

i,

"" - _

M •

342

THE RESPIRATION

oratory and in clinical work, a special chapter lias been devoted to the
subject, giving in detail the more recent methods devised by R. G. Pearce.

Lastly, it should be noted that several observers believe that a more
reliable estimate of the alveolar tension of C02 (and of 02) can be made
by analyzing a sample of ordinary expired air and calculating the per-
centages of CO, and 02 in the alveolar air by allowing a constant dead-
space capacity of 140 c.c. (Krogh, etc.).

If Ave compare the C02 tension of arterial blood, as measured by the
Krogh method, with that of alveolar air, we shall find that there is a
remarkable correspondence, indicating, therefore, that, when the arterial

H % Co 2 in itrxpirretair

220

30 tO

Fig. 127. — Same as Fig. 126, except that in this case the tension of C02 in the alveolar air was
experimentally altered. (From A. and M. Krogh.)

blood leaves the alveoli, its partial pressure or tension of C02 is exactly
equal to that in the alveolar air. This is shown in the accompanying
curves of experiments performed by Krogh. The dotted line in these
curves represents the tension of C02 or 02 in alveolar air, and the con-
tinuous line, these tensions in arterial blood. Close correspondence
will be observed between the C02 curves even when sudden changes in
alveolar C02 were induced by artificial means. In the case of the 02
tensions, however, that of the blood is always lower than that of the
alveolar air, the differences being especially marked when the 02 ten-
sion in the alveoli is raised (Figs. 126 and 127).

Tension of CO., in Venous Blood. — If we examine the C02 tension of
the venous blood coming to the lungs, we shall find that it is distinctly

1 li

higher than that in th<
it consisted in passing ..
blocking the ■
rubber collar <»r ampulla, i

pro fiit.-. I. ;iikI a sample of tl

In BUCh B

round the body, and w ttfa onlj
thai mor< CO ia being di
responds to t h<- tensioi

Much more practical mcl I '•

sun and R G P< ■ 1 1 i « - 1 1

method, the person Bret
gaseous mixture w iili ;il""it 10 CO

ing the lungs, li<- maki
with a \ alve lia\ i r i >_r four opt i u
complete circuit durii
pired air <':tn lie coll( in rubber !■•

opening opp< ;i»' four o]

contain ■ little less than l<
while the fourth will contain tl
librium between the CO
attained. This '
blood of the lunge I l1
formed int

Tl then indicate tl

I in the lungs \s

diffuses from a plai f hif

s.i until equilibrium is

CHAPTER XXXIX

THE CONTROL OF RESPIRATION (Cont'd)

THE ESTIMATION OF ALVEOLAR GASES

By R. G. Pearce, B.A., M.D.

Methods such as that of Haldane and Priestley, which calculate the
mean percentage composition of the alveolar air by analysis of a sample
taken from the end of a prolonged forced expiration, give values which
are too high for C02 and too low for 02. There are several reasons
for this: (1) In the time taken for the prolonged deep expiration an
appreciable amount of CO, will be given off by the blood to the alveolar
air, and oxygen will be absorbed — that is, the sample will not contain
the same percentages of C02 and 02 at different stages of expiration.
(2) The portion of the tidal air which reaches the alveoli dilutes the
alveolar air and thus causes the amount of C02 given off by the blood to
vary during the different phases of respiration. If we bear in mind that
the tensions of CO, in the alveolar air and in the blood leaving the lungs
are always the same (page 343), and that the entire fall in C02 tension
in the alveolar air occurs during inspiration, then it is clear that the
blood in the pulmonary capillaries must have a maximum tension and
load of C02 at the end of expiration, and a minimum tension and load
of CO, at the end of inspiration. Accordingly, the average of the per-
centage of CO, and 0, at the end of inspiration and expiration, as de-
termined by the Haldane-Priestley method or by any of its modifications,
nn ist fail to give the correct mean tension of these gases in the alveolar
air during expiration. The error which makes the CO, higher than it
should be, makes the percentage of 0, less than it should be. These in-
fluences taken along with the fact, which will be shown later, that the
evolution of CO, from the blood is relatively more rapid at low than at
high tension of CO,, indicates that the blood in the pulmonary capil-
laries during inspiration must contribute a greater part of the CO,
excreted during a respiratory cycle than that in the pulmonary capil-
laries during expiration, and moreover that a greater part of the CO,
excreted must be evolved at a tension which is below the mean tension
of the CO, present in the entire time of the expiration. We conclude,
therefore, that the average tension of CO, in the alveolar air, determined

344

by thi

l"'ss than tl.
b respirati

In the c
••iT-

gh en off « 1 1 1 1- i » » i_r 1 1
influence on the an
diti'.nv Thia is e> idenl
globii

hemoglobin is pi
in the alveolar air und<

i
during il •
pha it.

While th( >lii|» o

at differenl
periods includh
more or tant, b(

and mathematicall;
The average relative pei

must therefore be 1 In

I by the Haldane i

pirator} <|u",i,'|i, *
These points ha> e been .

■ ■

I] as tl

the Haldane Priest 1;
shall <i'> in subsequent i
limitations of 1 1

■
now , the i>i«'u, ,
\\ hicli w ill enable

An Accurate Standard Mi' N ; ibj<

r 1 1 <• t hod, and oi

rent

ins: | | !

346

THE RESPIRATION

Gad-Krogh typo, one being capable of holding ten liters, and the other one and a half.
The exact time during which air enters is recorded by the small spirometer by means of
a grooved dial on the axis of the lid, on which a thread works over a system of pulleys,
and any movement is accurately recorded by a writing point on the smoked paper of a
drum. The spirometers are connected so that the air current may be directed in the
three following ways: (1) through Cocks 1 and 2 outside; (2) directly through both
rocks into the large spirometer for the purpose of collecting a series of expirations;
and (3) through Cock 1 directly into the small spirometer for catching a single expira-
tion. In all experiments the first filling of the spirometer is rejected, so that the dead
space of the spirometers is filled with air of approximately the same composition as in
the succeeding expirations. The time is marked in seconds by a time clock. The respira-
tory movements are recorded by a pneumograph. (Fig. 128.)

The subject is brought into respiratory equilibrium by having him breathe through
the valves for a period of time lief ore the observation. The respiratory movements
during this time are recorded while the cocks are in Position 1. When the observation
is started, the cocks are turned into Position 2 during the time an inspiration is being

Fig. 128. — Arrangement of meters and connections of Pearce's method for measurement of CO-

of alveolar air in normal subjects.

made, so that the expirations which follow may be collected in the large spirometer.
After about ten respirations (a counted number) have been collected, the cocks are
turned to Position 3 during an inspiration, and a single deep expiration is collected
in the small spirometer. In order that the time of this may be the same as the normal
expiration, it is necessary to quicken it. This is more or less a chance procedure, but
with a little training, the operator can close the stopcock with sufficient accuracy to
interrupt the deep expiration at the end of the normal expiratory time. Should
there be any gross variation from the normal expiratory time, the sample must be col-
lected again. Not infrequently the inspiration immediately preceding the expiration
into the small spirometer is varied involuntarily by the subject on account of his being
aware that the following expiration has to be deepened and quickened; this can be
partially overcome by giving him the signal to breathe out deeply after he has actually
begun to expire.

Determinations are made of the average volume of the tidal air (c.c. air in large
spirometer divided by number of breaths), of the volume collected from the deep ex-
piration, and of the percentage composition of the tidal air and that of the deep
expiration. A criterion for determining whether or not the procedure has been carried

II!

which :

I 111 thi

tmri will .lilT.-r from tl

ration,
give cither
alveolar air.
I • \

■
l: the ;
: the
x

the i 0, in I

\ B \ I Ai X B

■

\ \: ! ■ '

x = 1 ^ : —

\ I : \ ■

■

Clinical Method. The u an'

other complicating fad
practicable for clinical | . but I

with the follow ing modi!
clinical purp<

Imrt tiini . w hich tl

small Bph ■• 1>\ turn im

pie «'i* this i

of sue
done by directing
into tho Bpiron

■• .1 I- eacl

.\ hen the
coll

amounts but all o<
expirations
the

CO
■
h\ perbolic
curve indie

348

THE RESPIRATION

this observation should be discarded. The different observations are
then combined in the formula given on page 347. The determination
of the CO, percentage of expired air is so simple that a number of speci-
mens of varying depths of expiration can be taken and thus many points
on the curve determined. For the most accurate results it is in general
best to compare only those expirations which differ from one another
by at least 0.3 per cent in C02 and b}r at least 200 c.c. in volume. This
depends on the fact that the diluting effect of the dead space in reduc-
ing the percentage of CO, in the expired air from that in the alveolar
air is greater in relatively small expirations. If more exact work is de-
sired, the 0, content can be determined on each specimen, the respiratory
quotient calculated, and only those expirations which show the same
respiratory quotient combined.

In the table each observation is compared with each of the others in
all possible combinations.

NO. OF
OBSERVA-
TION

TOTAL

EXPIRED
AIR

PER CENT
CO., IX

EXPIRED
AIR

ALVEOLAR CO.,

DEAD SPACE

1

2

o

1

o

3

1

2
3
4
5

6

450

637

750

960

1120

1440

3.10

3.66
4.00
4.28
4.30
4.40

4.99
5.34
5.30
5.11
5.16

5.48
5.1.5
4.98

5.27
4.92

4.82

170

189
189
161
171

183
140
127

214
184
171

General average for CO2 in alveolar air, 5.13.

General average for dead space, 172. Dead space in valves in this experiment was
about 30 c.c.

Another method which has been suggested for clinical purposes is
that of Plesch; this consists in having the subject breathe several times
in and out of a small bag. It is assumed that after such respiration
the composition of the air in the bag will become the same as that in the
alveoli. Although this is no doubt true, it has been shown that the
method is fallacious, because the CO, tension determined in this way
is not that of the arterial blood alone, but is the average between it and
that of the venous blood.

• MAPI KH \l.
THE l l <\\\;< 'I. I -I RKSI'IR \ I

THE NATURE OF THE RESPIRATORY HORMO'

practical importai
chapters in the ii
blood spiratory actn ii

to consider the phj siolog

the first place, lei us consid< r the behavior of the urn

during conditions of abnormal breathing — hyperpnea
A - CO accumulates and < •
athing becomes inti ; I •

effect, w •■ musl first of ;ill ;i-

defi or to th< CO

ments bearing on these prob
man than on laboratory a
iln> Bubjecth •• s\ mptoms

tat ion of the resull j. If an
ehambi ! 00 liters' cap

sen •••! as 'I imu1at<

the chaml

CO ;iir ;

• r, the hyperpm
n hen the CO

fallen to 1 I 5, it becomes in ;
ling obsen at ion n

it.iti-.n of tl

the in< CO If 1

thai the CO

u ill develop even w h<

\Y. in i. conclodi

\ i«l

• !

350 THE RESPIRATION

velops more rapidly than in the large cabinet, and a higher percentage
(10 per cent) of C02 can be tolerated. That in this case also deficiency of
02 is not responsible for the hyperpnea can be shown by repetition of the
experiment either with an excess of 02 in the bag or with absorption of the
CO, by soda lime. In the former case hyperpnea will develop as usual,
while in the latter it will not supervene until the percentage of 02 has
fallen below 10, when cyanosis becomes marked. In fact, some people
become cyanosed and unconscious, and collapse under these conditions
I )<■ fore there is any respiratory disturbance. A peculiarity of the effect
of 02 deficiency is that the person may be unaware of the seriousness
of his condition; indeed he may be somewhat stimulated. The conclusion
may be drawn that deficiency of 02 per se can serve as a respiratory
stimulus only when it is so extreme as to cause other serious symptoms.
This conclusion does not rule out an important influence of 02 deficiency
in increasing the excitability of the center towards C02. Under ordi-
nary conditions, however, the center is far more sensitive towards slight
changes in the C02 percentage.

There is an obvious reason why the adjustment of pulmonic ventila-
tion should not depend upon changes in 02 supply to the respiratory cen-
ter. If it were so, many other tissue activities and other nerve centers
would suffer from the 0, deficiency before there was time for the breath-
ing to become stimulated sufficiently to make good the loss of 02. As a
matter of fact, headache, dizziness, nausea and even fainting are almost
certain to be caused whenever any muscular exercise is attempted in an
atmosphere containing a deficiency of 02 but no excess of C02 (cf. moun-
tain sickness). An adequate 02 supply of the body is, therefore, insured
by changes in C02 tension of the blood.

Quantitative Relationship between CO. of Inspired Air and Pulmonary
Ventilation. — These results suggest, as the next step in the investigation
of our problem, the determination of the quantitative relationship be-
tween the C02 percentage of the respired air and the amount of air
breathed (pulmonic ventilation).* That there is such a relationship has
been most successfully demonstrated by R. W. Scott, who used for his
purpose decerebrate cats.f The trachea was connected, through a T-tube
provided with valves, with tubing leading to a large bottle and a Gad-Krogh
spirometer, so that the animal breathed out of the bottle into the
spirometer, these two being also connected together. The spirom-

*A distinction is somewhere drawn between pulmonic ventilation and alveolar ventilation, the
former being the total amount of air that enters and leaves the lungs, and the latter, that which en-
ters and leaves the alveoli. This distinction is based on the assumption that the capacity of the dead
space may vary considerably from time to time, which, as pointed out elsewhere, is erroneous. For
practical purposes pulmonic ventilation is the safer value to give.

"(■Decerebrate animals must be used in 'these experiments, since anesthetics markedly depress the
activity of the respiratory center.

I I!

made to n cord

»ord of the depth and frequc

plea of air w ere remoi ed f i om t J i • - i

quenl inten als during tin
the tubing

i

sot

1

\m

F

1

i" ■ ■

/ • • •

* '

: : : : i . : :

:-■

3

r-

T

: \

iftrt

jWU 'x

4

-s

* •

•j

_2

r

.

J

/

," i'i H

/

*Qg "pi

t

U

•c

a

/

i r

X

/

r Ft.«i cxt- .

1 t«v

j» uUftflXi .

i

1 1 1 1 lit

i 3

-

• •
1

♦- - # *
5

«

I

.

The rasull m in the accom

that there ia ■ p
air of the bottle and I
bottle I "i'li 1 1

wrei ined, riion ii

tho h> perpn< e I

352 THE RESPIRATION

system after hyperpnea had become extreme, was far above that at which
direct excitation of the center from 02 deficiency is possible.

Experiments of a similar type had previously been performed by Por-
ter and his pupils,23 but their objed was not so much to show the close
parallelism between the < '< >L. content of the respired air and the pulmonic
ventilation as to demonstrate the changes produced in the sensitivity of
the respiratory center in pneumonia.

Possibility that COL. Specifically Stimulates Center. — After showing
that CO, ads as an excitant of the respiratory center, the question arises
whether we are justified in the assumption thai lias been made tentatively
that the action depends on the raising of the CH of the blood, or whether
it may be a specific action of the HC03 anion itself. Many attempts have
been made to decide this question experimentally, the general principle
of the experiments being to determine whether CH of the blood runs
parallel with the CO, content of the respired air and with the hyperpnea.
Using the gas-chain method (page 31), Hasselbalch and Lundsgaard22
found that the hyperpnea produced in rabbits by breathing in CO,-rich
air runs approximately parallel with the increase in the CH of the blood,
but on account of the experimental difficulties encountered they could not
decide whether changes in CH are alone responsible for the effect. These
authors had previously demonstrated that changes in CH can be induced
in blood removed from the body by alterations in the CO, tension within
the physiological limits. An increase of one millimeter in C02 tension
was found to cause an increase in CH of 0.0065 x 10 7 (see page 27).

R. W. Scott's experiments, above referred to, have, however, yielded
more definite results. By using the colorimetric method for determining
Ch of the blood (see page 32), it could be readily shown, as is evident
from the table (col. 8 in table), that a marked rise in CH became evident
when the inspired air contained 5 per cent or more of C02. That this
rise was due to increase in the C02 tension was shown not only by finding
a greater percentage of CO, (col. 15) in the blood, but also by being able
to demonstrate that when CO,-free air was bubbled through the blood
removed during the dyspnea, CH immediately returned to the normal.
which it also did when the blood removed after the animal had breathed
for a few minutes in outside air (col. 16). The CO, content likewise re-
turned (col. 17). Had the increase in acidity been caused by nonvolatile
acids — lactic, for example — these results, particularly the latter, could
not have been obtained.

Although there is therefore no doubt that the CH of the blood may
be raised because of an increase in CO, in solution in the blood plasma —
a C02 acidosis, as we may call it (see page 354)— this does not prove that
the stimulation of the respiratory center is brought about solely by CH.

I II

The increase in 1 1 tu Imi CO

stimulus. Thai such in
finding that, if the < of the blood w

alkali intra\ enously, hj i" ' •

accumulated in the inspired ai
h) perpnea w as ai its hij
other factor than ' 'n musl obi iouslj ;
must l-«- the 1 1< '< ' anion.

Tin I CT OF B BRl tVTHINO Cab ON D
II

Blood

I'M I IMIV \H\ ft MOD*

M

ft.

3 j:

s

— b

3 ^

Tmir

w

h

la

_ „

»-

'3

a

r

o a-

-

a

-

- -

33

30

32

31

31

2.0
2.0

• a in

1 ."in pjn.

10.30 p.m.

1 1.00 cm.

11.15 .i in

616

7.40

* i' '

7 in

.1 1

• I'ii is I he

Further corroboration of the claim that the II'
stimulating effect on the respii
has been furnished by Hooker. "^
rocceeded in keeping the

deflbrinated bl 1 thi

that, although the respii

pressed with a d< e in Cm of 1

fused fluid, I

tained a high tension of CO, 1

but with a l"\v tension CO,. W

important r> *d*

it stint ultttii

354 THE RESPIRATION

Relationship Among Acidosis Conditions, Alveolar CO., and Respir-
atory Activity. — It will be plain that variations in the respiratory hor-
mone, whatever this may he, are associated with changes in the C02
content of the alveolar air. Closer examination has shown, however,
that this relationship is by no means always so simple as in the instances
just described, where increased respiration was found to he associated
with an increase in alveolar C02. There are many cases where the re-
verse relationship obtains — namely, decreased alveolar C02 and hy-
perpnea. The whole question is very closely linked with that of the con-
trol of the reaction of the body fluids and with the etiological factors in
acidosis. When it is fully answered, many obscure clinical conditions in
which respiratory disturbances occur will be much better understood than
they are at present. On account of its great importance, considerable
attention will be devoted in the next few pages to some of the researches
which have been made bearing on the relationship between the C02 of
the alveolar air and the various modified types of breathing that can be
produced experimentally or become developed under altered physiologic
conditions.

We shall consider these conditions in the following order: (1) Con-
stancy of the alveolar C02 under normal conditions and during moderate
variations in barometric pressure. (2) The quantitative relationship
between an artificially induced increase in alveolar CO, tension (as by
breathing C02-rich air) and the increased respiration. (3) The results
of these observations will demonstrate a very precise relationship to exist
between alveolar C02 tension and respiration, but if we proceed to repeat
the latter observations under conditions where the accumulation of C02
in the inspired air is accompanied by oxygen deficiency (as by breathing
in a confined space), we shall see that the relationship no longer holds,
indicating that the oxygen deficiency has caused something to happen
which disturbs it.

We shall find that the disturbing factor is accumulation of unoxidized
acids in the blood, and this will naturally lead us to study the conditions
in which such acids might develop; namely, (4) Breathing in rarefied
air (mountain -sickness). (5) Apnea. (6) Muscular exercise.

In succeeding chapters, Ave intend to review- the work in these fields in
considerable detail, partly because of its very important bearing on the
genera] question of the control of the respiratory center and partly be-
cause of the light the observations throw on the nature of the mechanism
involved in the adjustment of the CH of the blood and tissues.

As we have seen, much work concerning the physicochemical principles
involved in the control of the reaction of the blood has been contributed
during recenl years by physical and biological chemists, but much of this

i our j uri p
complicated coi d I
larl;

that hi
Hiding the I"
■
w hich tin B < i i ■ 1 1 i 1 1 1 1 *

duced by the dischi
it fails t..

It is the molecular ratio I ;

L N 1 1 ' ' ■

Whi CO is added to 1 1

natural!}
which th(

dencj of the equation t«> cl

•••■I partly 1»\ Btimulat
CO,, and partly by an in.-
center is £ ^ 1 i *_r 1 1 1 •

before a sufficient incn ET,CO

ratio I • When

L NaHCOs.J

inator of the i quation, v I ;

and in< I respiration II3CO

ratio.

CHAPTER XLI
THE CONTROL OF RESPIRATION (Cont'd)

THE CONSTANCY OF THE ALVEOLAR C02 TENSION
UNDER NORMAL CONDITIONS

Since a close relationship exists between the alveolar C02 tension and
the respiratory activity, it is to be expected that the two would bear a
strict proportionality to each other, and since the breathing under normal
conditions does not vary much, the C02 tension should also be constant.
Many observations show this to be the case. The tension is remarkably
constant from day to day and even from month to month in the same
individual, provided the physiological conditions are the same. A slight
seasonal variation is said to exist, a rise in the temperature of the en-
vironment of the individual causing a slight depression in the C02 ten-
sion, while a fall in temperature causes a slight rise (Haldane). These
changes are independent of any demonstrable change in rectal temper-
ature and, therefore, are probably due to the influence of the temperature
on the skin.

Since it is the number of molecules of C02 in a given volume of alve-
olar air (i. e., the partial pressure or tension) that is of importance, it
is only when the barometric pressure is the same that the percentage of
C02 in the sample of alveolar air can be constant. To allow for this,
all results are reduced to standard barometric pressure (760 mm. Hg).
If the barometric pressure is lowered, there will have to be a higher
percentage of CO, in the sample in order that there may be the same
tension of this gas in the air of the alveoli ; and vice versa when the bar-
ometric pressure is raised. The equation by which this tension, ex-
pressed in millimeters of mercury, is determined is: 100:760::a:p, where
a is the percentage actually found in the air of the sampling tube and p
the tension. A correction must also be introduced in this equation to
allow for the vapor tension of the air in the alveoli, for of course H20
molecules will behave like C02 molecules in causing a partial pressure.

When reduced to this standard, it has been found that the tension of
C02 in the alveolar air remains constant under the different barometric
conditions that obtain at the top of a mountain or at the foot of a deep
mine. This is shown in the following table:

356

I II

• r.l

I

it iliflrrcnt t' •

Changes in th<

limits li;i .

exactly the same time is I -i in ;
during which the samp

The Degree of Sensitivity of the Respiratory Center to Changes in the

CO Tension of the Alveolur Air

This can : ined ;

volume «»f air thai actually •
ing breathing in atmosphen
In man an incn

Bufficienl to double approximately I
ly. an increa ten liters in I

oli per minute is caused i

' I mm II- D

THE ALVEOLAR CO TENSION DURING BREATHING IN A

CONFINED SPACE

We (-;•■. ,• already emp
1 I ' 'cumulation •
duced under th< W

mi elo
correct, t ! •

This is
alvt
pnh v.

■:n- rtT. Ct II"

that tl • 0

thi I

i'.oS THE RESPIRATION

02 the excitability of the center is raised (i.e., its "threshold" lowered),
so that LI becomes stimulated by Ch, to which ordinarily it does not re-
spond. We shall now proceed to examine the experimental evidence
bearing on these possibilities.

V>y examination of the alveolar air of an individual confined in a pneu-
matic cabinet in which the barometric pressure is gradually lowered,
it has been found that although the C02 tension remains constant for
a considerable range (cf. page 356), it begins to fall when the barometric
pressure has reached about 550 mm. Hg. At this pressure the tension
of Oo in the alveolar air will be 62 mm. instead of its normal of about
105 at atmospheric pressure. Below it the alveolar C02 tension quickly
falls, and at the same time hyperpnea becomes evident, although the
person himself may be unaware that he is breathing more deeply. If
this experiment is repeated with the difference that, as the pressure is
lowered, an excess of 02 is introduced into the chamber, the hyperpnea
dues not supervene until a barometric pressure has been reached that is
distinctly lower than when no excess of 02 is present, and at the same
time the C02 tension in the alveolar air remains unchanged. The ex-
planation of this result is that by lowering the 02 tension in the alveolar
air and. therefore, in the blood and tissues, oxidative processes become
depressed so that unoxidized acids, such as lactic, accumulate in the
blood and by adding their effect to that of the C02 serve to raise the CH
of the blood. As a result, the respiratory center becomes excited, hy-
perpnea supervenes, and the volatile CO, is removed from the blood into
the alveolar air. On supplying 02 artificially, this failure of proper
oxidation does not set in and breathing goes on normally.

In the above experiment there must be a period during which the
I '< >._. tension of the alveolar air tends to become increased — namely, when
the fixed acids first appear and decompose the carbonates of the blood.
This increase is prevented by the more thorough alveolar ventilation.
When a person is kept in such a chamber for some time at a pressure
which causes a diminution in the alveolar C02 tension, the tension does
not immediately return to its oormal Level when atmospheric air is again
breathed, indicating thai the fixed acids are only slowly got rid of.

The second hypothesis — namely, that the 02 deficiency directly raises
the excitability of the respiratory center — has many advocates, among
them Lindhard,25 who found that, when the percentage of 02 in the alve-
olar air Avas raised, a higher percentage of C02 was necessary to cause
an increase in the ventilation of the lungs, and conversely, that a distinct
increase in the excitability of the center occurred when the inspired air
contained less than the normal percentage of ( )L.. Although it is ad-
mitted by Haldane and his school that such alteration in the excitability

I li

of t 1 1 • - respii

tinued exposuri
deny that sii<-ii all
workers Pound that, in i
per cent, the inci
the Bame
1 1 a hen it contj

In the \V

has secured
contention. 1 1- I ound thai

l 1 1
latter contained a lov 13 1 1

possibility thai th<
directly by the ' » tension
portanl problems av ail i i
it ultimately de
that respiration be
the final Btag< asph>

for thi

M uch light has been t Im.u □
activity 1»\ obsen ing 1 1
rubber bags through soda
pernor e t he CO We 1

bservatioi
a respirators Btimulanl
M ore particular in

nut the« nclu

under w hicl

With a verj small h

ising t\ pe bt
alveolar air contai

still -

ratio 1'ft w .in th<
tory quol
indicating tl

explain*
quantil

the blood more qui '

tliis expli

• llou ii

I •
lit.-

360 THE RESPIRATION

a much longer period without any evident symptoms of hyperpnea, even
though the 02 percentage in the alveolar air may fall as low as in the
previous experiment, and there are marked symptoms of 0, want, such
as cyanosis, twitching of the muscles of the hands, lips, etc. The re-
spiratory quotient does not become abnormal in this experiment indicat-
ing that no excessive expulsion of CO, from the blood can have occurred as
in the previous experiment. The cause for the virtual abscence of hyper-
pnea in this experiment is no doubt that the more gradual reduction in
02 of the alveolar air and therefore of the blood did not bring about the
accumulation of lactic acid at a rate that was greater than that at which
the CO, was got rid of into the alveolar air.

BREATHING IN RAREFIED AIR; MOUNTAIN SICKNESS

In considering the part played by fixed organic acid in the control
of the CH of the blood, the most important results have been secured
by observations on the condition of individuals living at high altitudes.
As is well known, under these conditions certain symptoms are likely
to develop, the condition being known as mountain sickness. The great
interest which physiologists have taken in this subject has been owing,
not so much to the importance of the observations in connection with
the condition itself, as to the light which they throw on the mechanism
of respiratory control and on the cause for abnormal types of breathing.

More or less hyperpnea, especially on exertion, soon appears in a
rarefied atmosphere, and the alveolar C02 tension assumes a value con-
siderably below the normal. For example, at sea level the minute vol-
ume of air breathed in one individual was 10.4 liters, and the alveolar
C02 tension 39.6 mm. Hg. After being some time on Pike's Peak, where
the barometer registers only 459 mm. Hg, Douglas26 found the minute
volume of air to be 14.9 liters, and the alveolar C02 tension 27.1 mm. Hg.
At first sight the above statement may seem to contradict one pre-
viously made, to the effect that the alveolar CO, tension remains constant
at different barometric pressures. This applies, however, to the imme-
diate effects, Avhereas we are now considering the later effects. The im-
portant point is: How are we to reconcile with the above hypothesis the
fact that a diminution in the alveolar CO, tension should be accompanied
by hyperpnea? A solution of the seeming contradiction will not only
be of importance in connection with our present problem, but will assist
us in the investigation of the clinical conditions of hyperpnea, in. which
likewise a diminished CO, alveolar tension is often observed. Mountain
sickness may indeed be considered as an intermediate condition between
the physiological and tin pathological.

From what we have learned Ave should expect the above result to be

dependent upon an ii

That such ia reallj ti

tion met! ad by obscn in

which, .is will I xplained

. t

ii index >>i 1 1 • 1 1
nature "i the noin o

kiniw ii Tu .. t

362 THE RESPIRATION

acids, of which lactic acid may be taken as the representative, or inor-
ganic substances, like the acid phosphates. That it is not lactic acid is
shown by both direct and indirect evidence. The direct evidence has
been furnished by Ryffel, who was unable to find any increased per-
centage of this substance either in the mine or in the blood of persons
who had been living for some time in the famous Regina Margherita
hut on Monte Rosa.27 The indirect evidence has been furnished by ob-
serving the time that it takes after the individual has started breathing
the rarefied air for the alveolar C02 tension to fall, as well as that re-
quired to bring about the recovery to the normal when he descends to
sea level. The following curve, which is self-explanatory, will illustrate
these points.

Thus, on Pike's Peak, where the barometric pressure is 459 mm. Hg,
the C02 tension after an initial fall took about seven days before it
came to its permanent level for that barometric pressure, and fourteen
days elapsed after descending from the mountain before the sea-level
tension had been regained. The slow nature of these changes, when com-
pared with the rapid changes observed in the experiment with the bags
already alluded to (page 358), shows clearly tliat lactic acid can not be
responsible for the increase in H-ion concentration in mountain sickness.
By exclusion it would appear that the increase in CH is the result of an
excess of fixed inorganic acid (H3P04) in the blood dependent on a dis-
proportionate excretion of bases by the kidneys during the period of
acclimatization to the rarefied air.

Other observers aver that the acidosis does not really exist, but that
the excitability of the respiratory center itself becomes raised (its
threshold lowered), so that it responds more readily to the normal CH
of the blood. It has been stated that the increase in excitability of the
center is dep'endent upon the action of the intense light rays at high
altitudes — the erythema of the skin, etc., being evidence of this excit-
ing action of light. The constant irritation of the skin, these authors
say. serves by stimulation of afferent nerves to maintain a hyperexcit-
ability of the respiratory center. Others believe that the hyperexcit-
ability of the center is a direct result of the maintained 02 deficiency.
The balance of evidence, however, stands in favor of the view that the
phenomena of mountain sickness depend on changes occurring in the in-
organic nonvolatile acids of the blood. The other phenomena of this
interesting condition will be discussed elsewhere (page 399).

APNEA

If a man breathes forcibly and quickly for about two minutes, he
will experience no desire to breathe for a further period of about the

Ill

me duration \\

turns, the breathii •
marked, until at la
alveolar air
it will be found >■
tome tit

thai if < » defici< :ould Btim

much earlier than it ., i .| \

an experiment b; II

show s\ it, I I

breathe returns, which t
a Btimulus I
center to act must
upon the pernor al of CO
preceded I CO

really occurred can readily l
tenl of a sample of alveolar

pi ration early ill ;:■ I » a

[>iratory quotiei I 1 3

during tl
'nit, tlif quotienl is o n tim<

\> would 1"' expected, I ar

air tnu :ir<! the end of th(

• though it iii.i\ I
Tlii
>ir-

the normal, indie

in 1 1

Inn er tei CO

s|»l I

' if tl •• List t .

are made in

\\ ith < > . the a]

ami u I

alvc

■
it p

lt\ el requ
during \\ I

364

THE RESPIRATION

Fig. 131. — Curves showing variations in alveolar gas tensions after forced breathing for two
minutes. Thin line = O* tension; thick line = COo tension. Double line = normal alveolar
C02 tension. Dotted line shows the alveolar COa tension at which breathing would recommence
at the end of apnea with the alveolar 02 pressures shown by the thin line. The actual breathing
is indicated at the lower part of the figure. It is periodic to start with. (From Douglas and
Haldane.)

phenomena] ; in out- indi> id
a few minutes and
minutes ;ni<l

The Bnppo ed N at in Apnea

[| to po

in. •thuds for the inv<
physiologists inter]

ilt of a Borl of inhibition
its repeated stimulation
along the vagus nerves I
lapse and distention of th<
oerve. In justification of the
claimed by the earlier ol
in animals after - ering bol
sliuwn that this is nol an
the vagi implished not by cutting but

readily produced as in an i

That chemical and
demon I hy th<- w ell knov n

ligating t ; tebral and 01

tomosed I itral 1

peripheral end of the carotid of t

i circulation. He tin
respiration t<> t! animal. I

other animal ami DOl that 1

actually been applied. \
api • furnished by tl •

formed in an atmosphere coi

sin.' as in tl •

times wit I
CO, in th< • ach time, '1

in." CO

\ • igh in tl
thai

only w hen it

\ S i

live pr
experii

\\ ■
■ 1 on this n

CHAPTER XL1I

THE CONTROL OF RESPIRATION (Cont'd)

THE EFFECT OF MUSCULAR EXERCISE ON THE

RESPIRATION

During muscular exercise the pulmonic ventilation increases to an
extraordinary extent. At rest an average man respires 6 to 8 liters of
air per minute, but during walking on the level at the rate of 5 kilometers
an hour, this figure may increase to about 20 liters.

The first investigations as to the cause of the relationship between
muscular activity and pulmonic ventilation were made by animal ex-
periments in which tetanus of the muscles of the hind limbs was pro-
duced by electric stimulation of the spinal cord. The problem was to
find out Avhat serves as the means of correlation (nerve reflex or hormone
control) between the muscular activity and the respiratory activity.
By cutting the spinal cord above the point of stimulation, it wras found
that the tetanus was still accompanied by as marked a hyperpnea as
before. On the other hand, when the spinal cord w'as left intact but the
blood vessels of the limb were ligated, no hyperpnea followed the teta-
nus. Evidently therefore the pathway of communication is the blood.

The next step was to seek in the blood for the substance or hormone that
acted as the respiratory excitant, and naturally the first possibility con-
sidered was a change in the gases of the blood, either a deficiency
of 02 or an increase in C02. Direct examination of the blood for the
quantity of these gases, however, yielded results which were quite con-
trary to such an hypothesis. It was found that the percentage of Oo,
if anything, was slightly increased, and that of the CO,, if anything,
diminished. Moreover, when the expired air was analyzed during the
hyperpnea, the percentage of C02 contained in it was distinctly below
the normal average, and the percentage of Oo above it. Evidently, there-
fore, the amount of gases in the blood has nothing to do with the excita-
tion of the respiratory center, and the conclusion drawn by the earlier
investigators was to the effect that the exciting substance carried from
the active muscles to the respiratory center must be some unusual meta-
bolic product, possibly the lactic acid produced by contraction.

It was further found, by examination of the respiratory quotient, that

36G

.-in • CO

after it, bul thai tl

t it-ii t . indicating thai ' i i

in conformity with t]

into the blood, on the

pag

alterations in th<

it lactic acid is actually :
howei er, !"• BhoM ii l»\ all ii
later thai I etcher and Hopki
under \\ 1 1 i * - 1 1 it maj app<
found that lactic acid is p
muscular coi I in a d<

adequate supply ■ • 1 1 . CO

Taking these fi
the conditions under which th(
which presumably cans.- a chanj
late the hypothesis tl
is due to a Blighl increase in tl • I

partly to an actual i CO

w ould .-t.it i! i in why 1

mighl be belo^ the normal duri
be "washed oul " ■■ on -; • ;

• I

The obvious met!
amine the alveolar I

• tnusculai I I

in the accompai

i.i'

■

.368 thi: respiration

In the first column is given the 02 used in c.c. per minute. Among other
things these figures indicate the actual amount of work done. In the
second column is given the C02 production in c.c. per minute. By divid-
ing the figures of the second column by those of the first, we obtain the
figures of the third column, representing the respiratory quotient. The
fourth column gives the CO, content of the alveolar air, and the last
column the total alveolar ventilation in liters per minute.

Taking for the present the figures in the first and fourth columns and
postponing a consideration of the respiratory quotient, it will be noted
that, as the muscular work increases up to a total consumption of about
1600 c.c. of 02 per minute, the CO, percentage in the alveolar air
steadily increases. The question arises, does the alveolar ventilation
increase in proportion to the increase in C02 tension? If it does so,
increase in C02 tension in the blood can be held solely responsible for
the hyperpnea (i. e., a pure C02 acidosis) ; whereas if the hyperpnea is
greater than can be accounted for by the increase in C02 tension, other
acids must be partly responsible for the acidosis. By making this same
individual breathe atmospheres containing different percentages of C02
it was found that to produce a doubling of the alveolar ventilation it
required an increase amounting to 0.33 per cent of an atmosphere of C02
in the alveolar air (see also page 357). When we examine the above
figures during muscular exercise, however, we find that a rise in alveolar
CO, from 5.70 to 6.36 (i. e., 0.66 per cent) multiplied the normal alveolar
ventilation by considerably more than four times, whereas had it been
entirely due to an increase in CO,, it should not have been more than
three times as much. Evidently therefore, some other factor than C02 ten-
must have been responsible for the increased respiratory activity. This
conclusion is further confirmed by examination of the alveolar CO,
during very strenuous muscular effort, when a relative decrease in the
CO, percentage becomes apparent.

If it is true that the exciting agency has been dependent partly on an
increase in the C02 tension of the blood, and partly on the production of
nonvolatile organic acids (lactic acid), we should expect that imme-
diately after discontinuing the muscular exercise the CO, tension of the
alveolar air would fall to a level distinctly below normal, that it would
only slowly recover thereafter, and that further exercise before the re-
covery had occurred would produce only a slight increase in alveolar
CO,. These results we should expect because of the much slower rate at
which the nonvolatile organic acid is got rid of from the organism, com-
pared with the volatile CO,. By actual experiment these suppositions
have been found to be correct, as is shown in the following table.

Ill ;,;.,

Pi rio,1

■ 1 L\

In this table the figures of Period 1
tension in mm. Bg immediately foll<
The figures in Period 2
the same amounl of work n ith, ho
tervening, and the figures of the third
conditions. It w ill be obsei * ed tl al I
the alveolar tension of CO from 1 1
thai in three minutes aft<
was considerably below the normal. l>urii
t-nlar exercise the CO,
••iTnrt did not increase al
tin' increase \\.i- Mill 1- ilts whirl

\ ifw that sonsequen

vulatih Die a<-i<ls had

the requi spirai •> a

mnch less increase i: i i
We ' .; gum it i > the conclu
- that during muscular
increased because of the
the
the slightest inc I

h\[ t, w ith tl

blood thai

I slll.v1 |l\ t ll.

able is the ' I

370 THE RESPIRATION

The readiness with which ('()., can be go1 rid of prevents the hormone
which excites the respiratory activity from continuing to act after it is
no longer required. Provision for the removal of a hormone after its
activity has been displayed is of course essential to efficient correlation
of function, and is seen in the case of other hormones, such as epinephrine
and secretin, whose discontinuance of action is effected by their de-
struction in the blood (see page 7-L.r)).

Direct evidence that lactic acid is formed during strenuous muscular
exercise in man has been furnished by Kyffel.30 Blood removed from a
person immediatey after running at full speed for about three minutes
contained 70.8 milligrams of lactic acid per 100 c.c. of blood, the normal
amount being 12.5 milligrams. Much of the lactic acid accumulating in
the blood is no doubt got rid of by oxidation, but a large part of it is
also excreted by the urine, in which it was found by Ryffel in consider-
able amount after strenuous muscular exertion.

Finally, let us consider for a moment the behavior of the respiratory
quotient. This ratio rises early in the muscle work (Table on page 367),
indicating that more C02 is being excreted than 02 absorbed. After the
work is discontinued, it usually falls below the normal because of retention
of C02 to take the place of the lactic acid that is being gradually used up
or excreted. A similar fall may sometimes occur in the respiratory
quotient during muscular exercise, if this is continued for a long time.
It probably indicates that a balance has been struck between the produc-
tion of lactic acid in the muscles and the loss of this substance by oxida-
tion. In any case it is a significant occurrence, for it coincides with the
great improvement in the subjective sensations accompanying muscular
exercise. It occurs, for example, at the same time as the appearance of
the "second wind," when the circulatory and respiratory distress expe-
rienced during the earlier stages of strenuous muscular exertion disap-
pear. The stages prior to the second wind correspond to the period when
considerable quantities of free C02 are being got rid of from the blood
and are probably creating a temporary maladjustment of the CH which
acts on the various medullary centers. If by forced breathing much of
this CO. is discharged before the muscular exercise is undertaken, the
initial hyperpnea is not nearly so marked.

< Haiti in

THE « I >NTR< 'I. OF RESI'M \ I H
PERIODIC BREATH IN

Ty] ; Pert

In the besl kn<>\\ n of thes< I

of hyperpnea Bup< upon

\ ;m a ]

faintl; iually becon

d, and thru fad< a
apneic period is immediate!} folio
being i idual ii •• in tl i

two tj pea all variel

ttditions in w hich !
physiological and pathological gi
follow ing may be taken
taining a deficit i

in 1 in persons li

luw ing an apnea induced b}
apneic periodicity . Ihe apneic p
breathing retui

adually li
13] Br< thing tin.

ing soda lime inserted
of till I a ixl

in pi

brej through tl

The /-nth
oped ■

ln-1 I

mental t \ pea l
influei

\- •
tions is

372

Tirr: RESPIRATION

periodic breathing is nearly always aggravated during sleep. Many of
these cases are greatly benefited by administration of caffeine.

In both the physiological and the pathological groups, the breathing may
develop a periodic character only when the person is asleep, and even
normal people, particularly infants or very old people, may exhibit it to
:i certain degree.

\ifrm\(r^w^yN^

vAaaa/TAA/WWTv^

Fig. 132. — Various types of periodic breathing. (From Mosso's "Life of Man in the High Alps.")

Causes of Periodic Breathing

Great interest attaches to an investigation of the causes of periodic
breathing, but it can not be claimed that any perfectly satisfactory ex-
planation has as yet been offered. Pembrey31 attributes it to a diminished
excitability (a raised threshold) of the respiratory center due to faulty
blood supply, the supposition being that, when thus suppressed, the
normal CH of the blood is unable to excite the center, so that breathing
stops. During the resulting apnea, C02 again accumulates until it has

I I!

raised the < \i sufficient!; H

folli ing a v. .i-l.ii

the «■!"!"■ itimui

apnea stipen •

to I"' furnished by the feci that, n I

ing are made to breathe

C0S, the periodicity "f i i

ing; a result which i

ithe in atmosph* i h in o

raised to meet the dep

Stability of the r is h

.s<> that it is enabled I
granted that the excitability of tl •

why this- should occasion a period
Bume thai it is- only v I imulus

stability of th nter are ad

smooth and continuous action can

Said ami his school a\ . r |

th^ excitability of th inter, hut

which do not a!v. a;, b operate 1
conditions in which such |
• •t conditions existing in tl

I experimentally in man
• simp'. k is the ]

['ro.luc.-,l in a person -
ami b< a total 1 lit

I such a <•.•!- !■!.• si

dead space The
quickly falls, until at '
is directly stimulated 1

when this falls |
• < <hyp

and the in dis

now, in .

hen a low ering

the apnea th( I '

cent

want becom<

That

:!T4 THE RESPIRATION

merely show a steadily increasing hyperpnea is probably due to the un-
equal rates at which the 02 and C02 tensions change in the blood. Be-
cause of a "buffer action" the latter fluctuates much loss than the for-
mer. Another cause for the periodicity is no doubt the delay between
the gas exchange in the Lungs and the arrival of the blood in the brain.
When the 02 tension of the blood supplying the respiratory center falls
to so low a level that excitation of the center occurs, the resulting in-
creased breathing aspirates outside 02 into the alveoli. After a moment
or so, the 02 is carried by the blood to the center, so that its stimula-
tion by 02 deficiency is removed, and it is left in a condition in which
it fails to discharge any impulses, since there is a subnormal CH of the
blood as a consequence of the lowering of the C02 tension produced by
the hyperpnea. A little time must now elapse before the C02 again
rises or the 02 falls sufficiently to excite the center.

l'ig. 133. — Quantitative record of breathing air through a tube 260 cm. long and 2 cm. in diameter.

(From Douglas and Haldane.)

A similar although less marked degree of periodic breathing can
sometimes be obtained by merely respiring through a long tube without
any provision for the absorption of C02. In this ease it is more difficult
to explain the cause of the periodic breathing, but that the main factor
concerned is one of 02 deprivation is evidenced by the fact that in this
as in the previous experiment, the periodic nature of the respiration is
immediately changed to the regular breathing if 02 is introduced into
the tube. The interest of the experiment lies in the fact that a similar
relative elongation of the dead space is probably accountable for the
periodic breathing seen in the winter sleep of hibernating animals. Dur-
ing ihis condition, on account of the depression of metabolism less 02
i^ required and less ('<>_. is produced, so that the exchange of gases
through the pulmonary endothelium is greatly diminished. The dead
space, however, remains of the same capacity, which amounts to the
same thing as if the latter had been prolonged under unchanged con-
ditions of pulmonary gas exchange.

Ill

anation •
much less satisfactor I
the tensions of 0, and CO
arterial blood of the i espii

ithing has been
a period of apnea product
of Buch obsen ations

The thin line repi

1 I » tension. I
sents the average CO i

respiratory mo> emenl
the eun e along the al 1 1

falls very rapidly during tl

ing recommei a it may

mal of aboul 95. Meanwhil< CO

level of 12 mm., at fii
when breathing recommences, it ;
! a result of the first periods of ;
shunts up, but 1 1 ■ CO falls o
the 0| quickly comes « i< «\\ n again,
tain normal tension before bi catl
ibsequently become less ;
stand almost at its normal lei el,
< ' tension continue
Several interesting
first place, it is plain thi
which it can p
blood, w hereas Iom ard I ■
further be ol I thai the CO

rapidly during the t1, -* :
uallj . the explanation

it first migl

• hat operating durii

rlli'
that t:

slighl

376 THE RESPIRATION

quickly oxidize the lactic acid, so that the still slightly subnormal CH
of the blood is unable to excite the center. Apnea therefore supervenes
and lasts until lactic acid has again accumulated in the center. To ex-
plain why local accumulation of lactic acid in the center should produce
a periodic type of breathing, we must further assume that there is con-
siderable delay between the moment at which equilibrium of the gases
in the blood and alveolar air becomes established and that at which
the blood arrives at the respiratory center. This delay is caused by
the slowing of the bloodflow on account of the absence of respiratory
movements.

Emphasis is placed on the fact that it is in the center itself and not
in the blood that the lactic acid becomes oxidized by the excess of 02,
because lactic acid is known to disappear slowly under these conditions
from isolated blood, but to do so very quickly from tissues such as muscle,
and presumably therefore also from nervous tissue.

In support of the above explanation it has been found that, if toward
the end of the forced breathing the lungs are filled with sufficient (X
so that the tension of this gas in the alveoli is not loAver than 120 mm.
Hg, breathing is regular in type when it returns, and the C02 tension
of the alveolar air is several millimeters above instead of below the nor-
mal stimulating level.

To sum up, the periodic character of the breathing supervening on
a period of apnea may be explained as follows: Under ordinary condi-
tions of breathing and barometric pressure the. 02 tension of the blood
is sufficient between normal respirations to prevent any accumulation of
Tactic acid in the respiratory center, so that the stimulus afforded by the
CH of the blood produces a constant effect. During the apnea which
supervenes upon forced breathing, lactic acid accumulates in the center,
causing this to respond to the gradually rising CH of the blood before the
latter has reached its physiological level. The hyperpnea thus excited
does not, however, bring about a prompt oxidation of the lactic acid
in the center or a lowering of the CH of the blood circulating through it,
because more time than usual is taken for the blood to get from the
lungs to the brain on account of the absence of respiratory movements.
When the aerated blood does reach the respiratory center, the excess of
Oo which it contains oxidizes the lactic acid so that apnea supervenes,
and the lactic acid again accumulates, although not now so much as
before because of the gradually rising CH of the blood itself. The essen-
tial factor in the causation of periodic breathing is therefore a delayed
mass movement of the blood from Ihe pulmonary capillaries to the re-
spiratory center. The delay may be caused by cessation of the respira-

I li

t..r\ n i - . \ ement, a> is postap eic
aulatorj disturbam

I ' riodio breathing
rarefied air than at Bea l< \ cl II
ing forcibly for one mil
returned shou ed 8 t'- 10 diff(
repetition ol the experimei I
sin . 10 mm . 25 Buch \>>

responding to 520 mm., I
breathing maj 1"- broughl abo il

piration ; <-\ en taking a di
periodicity in the racceedii
at high altitudes periodic breathii -
A-> in pathological cases exhib • ■

odie breathii g at high altitu
ing 0x3 gen.

We li.-i\ -• devoted considerabl<
difficult problems in the hope that din
quaint. -,1 with the juir.-l
conducl moi ching in>

and other pathological forms of periodic I

CHAPTER XLIV
RESPIRATION BEYOND THE LUNGS

Up to the present our studies in respiration have concerned the various
mechanisms involved in bringing about a constant change in the com-
position of the alveolar air. We must now consider the nature of the
means by which the oxygen is conveyed to the tissues and the C02 re-
moved from them.

In the first place, it is important to note that it is not for purposes

*

of oxidation in the blood itself that the 02 is required. In its respiratory
function this fluid serves as a transporting agency between the lungs
and the tissues, in which reside the furnaces of the body that con-
sume the Oo and produce the C02. This does not imply that there is no
oxidation in the blood itself; indeed, we should expect a certain degree
of oxidation because of the fact that the blood contains some living
cells — the leucocytes. It is scarcely necessary nowadays to offer evi-
dence for the foregoing conclusion. One Avell-known experimental proof
consists in replacing the blood in a frog with physiological saline solution
and then subjecting the frog with the saline in its blood vessels to an
atmosphere of pure Oo, when it will be found that the animal continues
to absorb the normal amount of 02 and exhale the normal amount of
C02. It respires normally without any blood in the blood vessels.

In order that this transportation of gases between the lungs and the
tissues may be efficiently performed, the blood must be provided with
means for carrying adequate amounts of gases to supply the requirements
of the tissues, both during rest and during their varying degrees of
activity. Not only, therefore, must the 02 and C02 capacity of the
blood be very considerable; but it must be capable of very rapid adjust-
ment from lime to time.

Our problem naturally resolves itself into three parts: (1) the call
of Hie tissues for oxygen (Barcroft) : of. ;is it is style'd, tissue or infernal
respiration; (2) the mechanism by which the blood transports 1he proper
amounts of gases to meet the requirements of the tissues; and (3) the
mechanism by which the blood gases are exchanged in the lungs — ex-
ternal respiration. For convenience, however, we shall change this nat-
ural order and consider the transportation of the gases first.

378

THE TRANSPORTATION OF BE BLOOD

The Transp.

It is plainly • I
itii. n •
isting in the ah •

.1.1 be dissoh ed
is actually found t< i

5, it would P<
more it order to
t.> •
tw much

The substance that cat r
may be described as .1 1

■ he put
animal

of them is to be 1 pared in it

merel) 1 r imitatioi

Regarding the condit
delivers up 0„ th<

tli. • it 1 1 1 i n I

must be capabli

•
tioiislnj. direct I

ambling the bin

the
is I
amount

• in tin- 1 •

w itli a" tit lin
of 1

In

mical lav

w hich
ii\ crcd u:
in •• 1 1 1 . and

\\ fll know 11

380 THE RESPIRATION

In other words, we must recognize that, although it is essentially a
chemical reaction, the combination of 02 with hemoglobin is greatly in-
fluenced by other factors, and that it is these that are likely to be of
physiological importance.

In order to understand the conditions under which hemoglobin will
hike up and give off 02 in the animal body, we must study the combining
power of hemoglobin when it is exposed to different partial pressures
of Oo (for laws governing this, see page 33G). In the blood, the ex-
tremes of the partial pressure of 02 are represented, at the one end, by
that in the alveolar air, which we have seen to be about 100 mm. Hg,
and at the other, by that existing in the tissues, such as muscle, which
has been shown to be not more than 19 or 20 mm. Hg. We must further
bear in mind that the 02 in its passage from the alveolar air to the hemo-
globin and from the hemoglobin to the tissues, is transmitted in solution
through the plasma; that is, so far as the supply of 02 to the tissue cells
is concerned, the plasma serves as the immediate source. Since the tis-
sues are using up 02 at a very great speed, especially when active, and
are thus tending to lower the tension of 02 in the plasma, favorable con-
ditions have to be created whereby the hemoglobin liberates 02 at the
same rate as that at which it is leaving the plasma. In brief, it is the
02 tension of the plasma in the tissue capillaries that is the important
factor, the hemoglobin merely serving as a storehouse, which delivers
its 02 at just such a rate as to maintain the plasma-oxygen tension at
a constant level. It is obviously of the greatest importance that we
should understand how this mechanism of an adequate plasma-oxygen
tension is maintained.

Methods of Investigation. — We must remember that the combination
of 02 and hemoglobin, being a definite chemical reaction, will be re-
versible, and must, therefore, obey the laws of mass action (see page
23) according to the equation: Hb + 02<=±Hb02. In order to ascertain
the position of the balance of this equation at different partial pressures
of 02, — that is, the relative quantities of oxy- and reduced hemoglobin
formed in a solution of hemoglobin when this is shaken with 02 at differ-
ent pressures, — we may proceed as follows: A few c.c. of the hemoglobin
solution are placed in each of a scries of vessels called tonometers, like
those shown in Fig. 134. In addition to the hemoglobin solution, each
tonometer contains a mixture of nitrogen and 02 in different propor-
tions. Suppose we use six vessels and in No. 1 have pure nitrogen; in
No. 2, nitrogen containing 5 mm. partial pressure of 02; in No. 3, 10
mm. ; in No. 4, 20 ; in No. 5, 50 ; and in No. 6, 100. We now rotate the
tonometers in a water-bath at body temperature for about twenty min-
utes, so that, by the formation of a thin film of hemoglobin solution over

the walla of tin

tin* Muni in.t\ be atta i
jlobin solution 0.1 (

-

and pla I. together w i1 •

in one ol the small bottl<

• This man. in

tube nf narrow bore, containii

being coi I w itli

two fluids can !"•

ln.ttlt- is \ iol< nl I »*ll

:!sii

TIIK RKXP1KATI0N'

bottles and the manometer serves to permil communication of the
manometer with the outside air.

An equal quantity of hemoglobin solution that lias been saturated
with' oxygen — i. e., oxyhemoglobin — is placed in the bottle on the other
end of the manometer tube from that containing the bottle with the un-
saturated hemoglobin solution. The bottles having been attached to
the manometer with th'e stopcocks open to the outside, the apparatus
is placed in a water-bath until the temperature conditions are constant.
The manometers are then closed to the outside air and the bottles are
shaken in order that the hemoglobin solution that is unsaturated with
Oo may take up 02 from the atmosphere in the bottle until it becomes

rv--'

...'-'

Fig. 136. — Barcroft blood gas manometer. This form can be used either as a differential
manometer (page 390) or for direct measurement of pressure. For the latter purpose one bottle
is removed and the pressure of gas generated in the other bottle is measured by the height to
which it raises the clove oil in the distal tube of the manometer, the meniscus in the proximal
limb being readjusted to its original level by compression with the brass screw of the rubber tube
shown in the center.

saturated. The resulting shrinkage in the volume of the atmosphere
on the side of the unknown hemoglobin solution causes the clove oil
meniscus to move towards that side, the degree of movement being pro-
portional to the initial unsaturation of the hemoglobin. The manometer
tubes are then again brought into communication with the atmosphere
so that the meniscus of clove oil may move back to its old level, and the
bottle with saturated hemoglobin is removed from the manometer and a
drop or two of a saturated solution of potassium ferricyanide placed
in the separate compartment of the bottle without allowing it. to mix
with the hemoglobin. The bottle is then reattached, the temperature

?

1

1

I

^

1

V

| 1

-

*

-

?

i

(

k

«

*

01

c

7

-

•

3
I

i

*

■•■

1
1

■

»

o

'

*

*

O

io ao

*

Ptrctntag* Maturation
ti oxugtn

1 >S I.'

-

» - '

■•

• litii.hs readjust)
;ni<l the appai atus np i
hemoglobin Bolutioi I
solution, and, then
bottle so thai tl

. tin- degree of <li>i>

. hemoglobin.
We h.i\ •• n. >\'. all '

of redu 1 hemoglobin in tl •

tonom<

tells us lniw much moglol

hemoglobin been Baturati d i
taken tip by the original 1 •

The Dissociation Curve I
From the various 1 •

known ;is ti It

relath • • duced

tions along tl rd

cury to w hich they w •
thus thaw n i-* exad !;. of tl •■ Ban

duced it' w e w ere to plac<

another corn

tained, then to mark on each I

reduced and oxyhemoglobin found in tl

line joining tlir^.- mai

N|l..|nl

clear Prom the accompany] '

In su<-li a chart '1
tin- percent*
reduced hemoglobin blue in • ;

I I n lii«-li

mospl

•i;il pressure

sul\ I.I

Difference betWMO Curv. s of Bloou H noulol

curve obtained from

Up tl

ilis, liai

all the more difficult,

globin in

partial

384

THE RERPTRATION

stead of readily yielding up its load of 02, would greedily retain prac
tically the whole of it. The curve, in other words, would satisfactorily
explain why hemoglobin should readily absorb 02 from the alveolar air,
but would fall far short of explaining how this 0, is readily released
when it is required in the tissues. Obviously there is some artificial con-
dition present in the above experiment which can not obtain in the nat-
ural environment of the blood.

WO
<<0

do

70
GO
50
HO
30
2.0

10
0

z/

a/

fa/

d/

10 ZO 30 HO 50 bO 10 80 10 100

Fig. 138. — Average dissociation curves.

Ordinates — Percentage saturation of hemoglobin with oxygen.

Abscissae — Tension of oxygen in mm. of mercury.

Curve A — Degree of saturation of pure hemoglobin solutions at varying pressures.

Curve B — Disregard this curve.

Curve C — Effect of 20 mm. CO2 pressure on above solution.

Curve D — The saturation curve in normal blood at 40 mm. carbon dioxide pressure.

Since hemoglobin takes up 02 in proportion to its iron, it can not be
because of changes in the 02 combining part of the hemoglobin itself
that blood and pure hemoglobin solutions have dissimilar dissociation
curves, but rather because of differences in the environment in which the
hemoglobin acts. That this is so can be readily shown by plotting the
dissociation curve, not for a hemoglobin solution, but for blood itself

/> il :-

of < I of about 60 mm II
long alveoli 100
wh<

then y com

i i question ii

the hemoglobin in the bli

"00

J-

•

^*~

■

w ith 1.

int.. j)l.t.\ I

CO
hemoglobin i
in t

386

'1 III. RESPIRATION

Since the plasmas of different animals contain different proportions oi
salts, the artificial plasma required to secure the result is not always the
same. It differs, for example, for the dog- and man. Potassium salts
are particularly efficient in causing hemoglobin to absorb 02. The in-
fluence of varying hydrogen-ion concentrations of the solution may
be conveniently studied by adding varying percentages of C02 to the
gas mixture in the tonometers, when it will be found that the curve be-
comes lowered in proportion to the amount of CO, present. This is shown
in Fig. 140.

The effect of temperature on the dissociation curve is twofold: (1) on
the rate with which equilibrium is established at the given partial pres-

100
90
80
70
60
50
40
30
20
10

°/

/ /

If

<¥

/ /

■ III

•

■

■ j 1/ /

0

10 20 30 40 50 GO 70

80

100

Fig. 140 — Dissociation curves of human blood, exposed to 0, 3, 20, 40 and 90 mm. C02. Ordinate,
percentage saturation. Abscissa, oxygen pressure. (From Joseph Barcroft.)

sure of 02, and (2) on the position of the curve; the lower the tempera-
ture, the higher the curve.

The Rate of Dissociation. — Though it is now clear that the three con-
ditions— namely, saline content, CH, and temperature — are capable of
altering the dissociation curve of a pure hemoglobin solution so as to
make it correspond with that of blood, -this does not entirely solve our
problem, for we have yet to show how the cooperation of these forces
renders it possible for the rate at which hemoglobin takes up 02 in
the lungs to correspond exactly with that at which it gives up its 02
to the tissues. To study this problem a somewhat different kind of
experiment must be undertaken. The hemoglobin solution is placed in
a tube and the gas mixture slowly bubbled through it, samples of the
solution being removed at intervals for analysis in the differential blood-

u.i> appai atu I

and 1 1 bubbled through I

•
mm Hgj an<l to obtain •
bled through.

I luctioi

plotted in ••ui" •

I

a

i

3

'. ■

60

A

t.V

B

-'.

V

s~

\*~~ "

\

/

\

r

.

c

'

'

I

I i

388 THE RESPIRATION

hemoglobin on the ordinates and the time in minutes along the abscissa'
(Fig. 141). Even if we use blood in lliis experiment and therefore make
certain that the hemoglobin is acting in the presence of the proper pro-
portion of salts, we shall find, as Fig. A shows, that at room temperature
the rate of oxidation is very much greater than the rate of reduction.
If now we repeat the observation at a temperature of 37° C, the two
curves come more nearly to correspond, but still the rate of reduction is
slower than that of oxidation. If in a third experiment, besides having
proper temperature and chemical conditions, we produce the oxidation
and reduction in the presence of a partial pressure of CO, of 40 mm.,
which corresponds to that of the arterial blood, we shall find that oxida-
tion becomes a little slower, whereas reduction is further quickened.
Indeed the two curves, as seen in C in the figure, come practically to
correspond, indicating that the environmental conditions under which
hemoglobin combines and gives off 02 in the blood are exactly adjusted.
One word more with regard to the influence of CH. Its effect in flat-
tening out the curve, especially at the lower partial pressures of 02,
indicates that when a high CH is present, the blood will very readily part
with its 02 supply. Now, the most significant application of this fact
is that high concentrations of II ion will occur just exactly where it
will be of benefit — namely, in the capillaries (because of the C02 and
lactic acid produced by the tissues). Some doubt has, however, recently
been thrown on the importance of this factor.

Since, as we have seen, hemoglobin absorbs 02 according to chemical
laws, it will naturally be asked not only why the dissociation curve flat-
tens out Avhile yet maintaining the shape of a right-angled hyperbola,
as by the action of acids or an increase in temperature, but also why it
should change its shape when salts are also present. The explanation
offered by Barcroft and his pupils is that the changes depend on the
fact that hemoglobin being a colloidal substance, its molecules undergo
processes of aggregation under the conditions referred to above, and
therefore cause the reaction to become of a different type from that
represented by the equation Hb02^±Hb + 02. As has been pointed out
by Bayliss, although such an explanation might suffice to explain the
flattening out of the curve, it fails to explain the change in its shape;
for, according to the laws of mass action, such a change could occur
only if molecules of a different type came to take part in the reaction.

Dissociation Constant. — Notwithstanding these criticisms, it is of con-
siderable practical importance to know that an equation exists from
which the entire dissociation curve can be plotted by making only one
determination of the relative amounts of oxy- and reduced hemoglobin
at a particular tension or partial pressure of oxygen. This equation is as

f"11' I K

hemoglobin \\ iili 0 tl

being I uilibrium

hemoglobin sup]
• •II this equation
unchai

to find the \ all K

of A by measuring I
sun- of this gas, then ;
0, pressui
blood

\m importanl

I
curve I" ci I in p

ion-. I lidity >'

parison of its dissociatioi
K, with thai of normal bio

n added. When tl
name amount

I
it indi thai il

uf ii il »1 «• load of 0

than normal H

must be lo

In determining K For I '
thai it should be subji

This condition \\ ould !»•• in

■
taining the aam<
Since this valu<

rtaiiH'<l in <

lifications, K

0.1 212 Bi •! 0

in the I'l"
■ufferii

death to I nl

in ;
i;ii

*» r, i

CHAPTER XLV
RESPIRATION BEYOND THE LUNGS— Cont'd

THE MEANS BY WHICH THE BLOOD CARRIES THE GASES

In the foregoing account of the physiology of the blood gases, empha-
sis is placed on the tension under which the gases exist rather than on
the total amount of each gas present in the blood. This has been done
because the exchange of gases between alveolar air and blood and be-
tween blood and tissues proceeds according to the laws of gas diffusion,
which are of course dependent upon differences in gas pressure or
tension.

Something must now be said regarding the amount of the gases. This
may be measured either by physical or by chemical methods. In the
former, a measured quantity of blood is received into an evacuated glass
vessel, which is then attached to a mercury pump, by which the gases
are sucked out of the blood and transferred, by suitable manipulations
of stopcocks, to a graduated tube, in which they are then analyzed by
chemical means. The principle of the chemical method has already been
described in connection with the measurement of oxygen in hemoglobin
solutions (see page 382). A measured quantity of blood, kept free from
contact with the air, is transferred under some weak ammonia solution
to one of the blood-gas bottles of the blood-gas differential manometer,
and a few drops of a saturated solution of potassium ferricyanide is
placed in the pocket of the bottle. After the blood has been laked and
temperature conditions adjusted, the ferricyanide is mixed with the
blood solution, thus causing the 02 to be quantitatively displaced. From
the increased pressure produced in the manometer the amount of 02 can
readily be computed. To determine the CO. of the blood, the bottle is
now removed from the manometer and a few drops of a saturated solu-
tion of tartaric acid placed in the pocket. When this is mixed with the
deoxygenated blood mixture, after the usual adjustment for tempera-
ture, the pressure caused by the evolved CO, is recorded and the amount
present calculated.

The results of the analysis are expressed as the number of cubic centi-
meters of gas present in 100 c.c. of blood — the volume percentage, as it
is called. The following are approximate percentage values:

390

■

timatii

in c ith the pi

supply ii . ■/ informal

•.ins and I

an animal by measurii
-■xpiri'-l air, bo Hi. i
change bj analysis of tl

•: of the ' I

not the percentage but t:

sid. ■!•••.!. and that it is th-
flnv

of the results of such ii

At • i with

■i''«l in tli.' blood,
globin, being also in a si I

1 1 1 . which it will l.r noted is
Biderably r amounl th. the 0

form bicarbonati Ikali a

time to time according to thi
Since th<
amounl
ing about, as v .

raising

What particularly i:
hi v. I < I

phen CO,, it will take up
is, between t\\i> and tl"

It has therefoi ■ \

tii.ti of tl CO
•

will ii I Wl en 1

other hand, all the CO
plasma

red thai blood c
that hemoglobin or
from aolu1

shows that this
caused h\

that tl

392

TI1E RESPIRATION

them into the plasma of acid radicles. At least it has been found that
the alkalinity of the plasma increases when C02 is bubbled through
blood, this increase in alkalinity being interpreted as the result of the
migration of acid radicles into the corpuscles. This would lead us to
expect that under the opposite conditions (i. e., in vacuo) acids would
leave the corpuscles.

Proteins are amphoteric substances — that is, they combine with acids
or alkalies — which would lead us to expect that they would be capable
of absorbing some C02. That this is the case, particularly for hemo-

•
75

70

"ff*

65

o 60

bb

50

45

40

: /^

S

Jf_ J^

r / S

A ' *"

•
•

_1

/k

/ ,

-

//

*

/ .

'

//-

f

30

40

50

60

70

80

90

vjVe*>uAX oi COj vrv rrvm. 3£a.

Fig. 142. — Curve of C02 tension in blood. For description, see text. (From Christiansen, Doug-
las and Haldane.)

globin, has been shown by comparing the CO,-combining powers of water
and a solution of pure hemoglobin.

Attempts have been made to determine the relative amounts of CO.,
carried by these various agencies in the blood. The following is an ex-
ample of such a table:

In simple solution in plasma and corpuscles

a in corpuscles 6.S

As sodium bicarbonate j ^ ^ ^.^^

In combination with hemoglobin

In combination with proteins of plasma

12.0

7.5 1

L1.8 |

1.9 c.c.

18.8

40.0

(Locwy.)

I : e power «>r blood to a
determined in the

saturation of the hemoglobin w ith 1 1
earrj ing power of the blood I

The various tensions
volume per cenl l 1 1 taken up
upper curve is dra* n from
with CO, in the i

of a'n- The dol
drain ii beta een the t \

!>1 1 within th<- bodj it a

alveolar sir see pi ads in

per cent ; and si s pressure mm.

/.' stands in venous 1>1< •< •«! at about I •

would be 7 per cenl ]"•■■■
with < > at the latter pressure. Tl

therefore, helps to <1H\ <• out the CO

in the tissues enhat power of absorbii : I

are of fundamental imports]

I la\ in'_r show 11 how the blood t
lunj tissu< may i

the tissues, and in this connection
of < K which they require under
and *_' the mechai isms bj which I

THE OXYGEN REQUIREMENT OF THE TISSUES

In ordei ' tain th<

nu.-s of the bodj , it is n. ••
the smounl of 0
tain it w e must know l
under investigation; 2 the bloodflow t
in <• e. per minute ; and
I venous blood of the I

I k t.. r.-\ i.-w in an\ del

have been undertaken in t;

: important results
burtoi /''

In tl
Hon, as it is called, the l
muscul unectn

stand ab<

msumpl

394

THE RESPIRATION

ORGAN

CONDITION OF REST

OXYGEN USED

PER MINUTE

PER GRAM

OF ORGAN

OXYGEN
USED PER
CONDITION OF ACTIVITY MINUTE

PER GRAM
OF ORGAN

Voluntary
muscle

Nerves cut. .Tone
absent

0.003 c.c.

Tone existing in rest
Gentle contraction
Active contraction

0.006 c.c.
0.020 c.c.
0.080 c.c.

Uustriped
muscle

Resting

0.004 c.c.

Contracting

0.007 c.c.

Heart

Very slow and
feeble contractions

0.007 c.c.

Normal contractions
Very active

0.05 c.c.
0.08 c.c.

Submaxillary
gland

Nerves cut

0.03 c.c.

Chorda stimulations

0.10 c.c.

Pancreas

Not secreting

0.03 c.c.

Secretion after injec-
tion of secretin

0.10 c.c

Kidney

Scanty secretion

0.03 c.c.

After injection of
diuretic

0.10 c.c.

Intestines

Not absorbing

0.02 c.c.

Absorbing peptone

0.03 c.c.

Liver

In fasting animal

0.01 to
0.02 c.c.

In fed animals

0.03 to
0.05 c.c.

Suprarenal
gland

Normal

0.045 c.c.

Nabarro). It is of course necessary in making these comparisons to
secure the coefficient of oxidation both when the tissue is at rest and
when it is thrown into varying degrees of activity. Special attention
has been devoted to the requirements of skeletal muscle, heart muscle
and the salivary glands.

Skeletal Muscle. — In observations on skeletal muscle, Verzar (cf. 27)
isolated the gastrocnemius muscle of the cat, and without disturbing its
blood supply collected samples of blood by introducing a 1 c.c. pipette
into a branch of the saphenous vein. Activity was produced by throw-
ing the muscle into tetanus by the application of an electrical stimulus
to the sciatic nerve. During its contraction the muscle lifted a weight,
so that it did about 70 gram-centimeters of work at the beginning of
each period of tetanus. The velocity of bloodflow was determined by
the rate at which the blood flowed along the pipette, and the 02 consump-
tion, by the difference in percentage of 02 in the venous and the arterial
blood. These measurements were made: (1) before contraction, (2) dur-
ing contraction, and (3) after contraction. It was found that during the
tetanus the 02 consumption in some cases was greater than during rest,
while in others it was actually less, but in every instance a great increase
in 02 consumption followed the tetanus — that is, the call for 02 continues
for some time after the actual work has been performed. This result

shows that th Dtracl i<

in muscular

which energy in lib< • ated in

The mechanism mu

ind daring the muscular

[nteresting results
cured by ob I-

was found thai heal production
mut ol only dui

er it. |iin\ ided 0 In tl

eithei tly delayed

the view I I 1 1 - used lai pj<
"like an engine charging an i
taining a considerable amoui
accumulator, it discha hen appi

V. Bill, cf. 27). 0 immediately tl
with these interesting r< rail
ami Fletcher ' have sho* n thai th -
1 1 • i i frog mu bul « I

d or, if so, quickly disap]

Heart Muscle. Another m
in thi- action is thai of th< <*n

studied both on is
change in the Inn— a coml
mosl important in tions I

:~ . wh>' i
1 1 taken in by the hearl d
sion se1 up in the hearl 1»\ I
by placing a rubber bag in I *'

!i«.w n pressui e. By all
pull • as found thai I

prod'; the pu

produ*

q

— — itanl quantil

NT

inc

[t should b<
the ah

amour t of 0

I ho t'-

396 THE RESPIRATION

the heart is becoming overtaxed — that it is losing its efficiency. The
same result occurs when the heart is dying, and when depressing drugs
are used, such as chloral hydrate, potassium cyanide, veratrine, etc.
Some other drugs, however, such as epinephrine, do not cause altera-
tion in the ratio, nor does vagus stimulation. Of course when the vagus
is stimulated, the 02 consumption in a given period decreases because
the heartbeats are slowed ; but the absorption of 02 is not increased rela-
tively to the slowing of the heart.

Glands. — Most work has naturally been done on the most accessible
gland — the submaxillary. By stimulating the secretory nerve of this
gland (the chorda tympani) in the dog, it has been found that, whereas
the more abundant secretion lasts only so long as the stimulus is ap-
plied to the nerve, the 02 consumption is increased to several times that
of rest, and remains increased for a considerable period after the stimulus
has been removed. Accompanying the increased functional activity in
such structures as muscles, there is a very marked increase in bloodflow
due to vasodilatation, which, in part at least, is dependent upon the
secretion into the blood of some substances resulting from the glandular
activities, and is not entirely due to the action of vasodilator nerve fibers.

Similar results have been obtained in the case of the pancreas when
excited to secrete by the injection of secretin (see page 425). Under
such conditions, the oxygen consumption has been observed to increase
about fourfold and to be accompanied by a dilatation of the gland.

The work on the kidney has been especially interesting, because it
has been found that increased activity, which of course is measured by
the rate of urine excretion, is not always accompanied by increased
consumption of oxygen. When diuresis is produced by injecting Ring-
er's solution into the circulation, a great increase in urine outflow may
occur without any change in oxygen consumption ; whereas, on the other
hand, when a diuretic such as sodium sulphate or caffeine is used, the
oxygen consumption increases enormously.

Regarding the other tissues and organs, the 02 consumption of the
lungs and brain appears to be small. It is a very significant fact, how-
ever, that the higher cerebral centers are extremely sensitive to depri-
vation of Oo.

The Blood. — In the blood itself, a certain amount of oxidation goes
on because of the presence of leucocytes. This oxidation becomes con-
siderable in the blood of animals rendered anemic by the injection of
phenyl hydrazin. A thorough investigation of the cause of this greater
oxidation has shown it to be owing, not to an increase in nucleated
corpuscles, bu1 to the presence of 1hc young unnucleated w(\ blood

corpuscles, « hich appear in
ditions. A similar inci i
rhagic anemia, the rat elation

regeneral ion of the red corp

The Mechanism by Which the Demands oi the Tissues for

Oxygen Are Met

There are two possible methods bj w i
I i... a chai -•• in the <
the plasma, bo thai the hemoglobin m<
of < >_ : and 2 by an inc

the 3 of tin' act i'

Regarding the firsl of these possibility
are produced during metabolism of acting tis
when muscles contracl in tl
produced in large amounts, and when the
Barcolactic acid. In the submaxilL -i j...s-

show that the Ch of the venous bl 1. as m<

the dissociation curve of hemoglobin, becon

ing glandular activity. Thai this increase in I

aln-ady seen As to the

in temperature and in saline constitui i at

presenl be said.

Regarding the second possibility,

either upon the action <>n the hi I

along vasomotor nerves, or upon tl
vasodilating or depressor subst

has 1 ii accumulal ing in recenl ;

depressor substances are produced, and I
2 organic bases of a similar
mine . This latter subst;
cause of its close relationship t<>
protein molecule namely, histidii
ducing \ asodilatation is exl rao
drug injected intravenously inti
pressure bj fifty i"

Bui bi such an h> p<

show that, independently •

hi may dilate Tl
effe< • stimulating w itl
the submaxillan

398 THE RESPIRATION

and dilatation of the artery occurs, although on blood vessels alone
epinephrine in similar dosage produces constriction. Of course in show-
ing that local chemical products of activity serve as the excitant of local
dilatation, we do not mean to imply that the vasodilator fibers going to
the blood vessels are of no use. Indeed we know that such fibers do be-
come active in the case of a salivary gland whose cells have been para-
lyzed by atropine, but it is a significant fact that this dilatation is of rela-
tively short duration, whereas that produced by glandular activity lasts
for some time. The suggestion seems therefore not out of place that un-
der normal conditions the initial dilatation of an acting gland may be
brought about through nervous stimuli, but the later dilatation is main-
tained by metabolic products.

I IIAI'l EH XI. \ 1

Tin: i-in SlOIXXn OF BREA1 nr i OH

l\ RAREFIED UR

In the application i
thf in\ estigation of di

■ rable interf< \ itli pi

• . but <>i" changes in tl
tic ii of the functions of r« lion depends

the physical and chemical prop*

■ 1 thai similar cha

iull on the respiratory acti\ itj

the animal.
The moe1 thoroughly in

p in rarefied and compressed air. I.
dnced experimentally in the lal
(pneumatic cabinets and suitable pumps, all
portanl work on tl
altitudes, w here the baromi

MOUNTAIN SICKNESS

dition de]
unction, and it

oing the oatu
disease itself, t! I much
tion durii
at:

disappear, indicating
the compensator} n

trol bi V\

cabinets from which i
diate B) mpt< -
impracticabh
time to allnu the compel

r.
hormone, many <>f tl

-

B88

400 THE RESPIRATION

sickness have been given elsewhere in this volume (page 360), where the
general symptoms are also described. In this place we shall consider
very briefly some of the more general aspects of the condition, and, more
particularly, the nature of the adaptation that occurs. All of the symp-
toms are essentialy dependent upon lack of oxygen. Cyanosis is com-
mon and the symptoms are much the same as those of coal-gas poisoning.
Not only does this deficiency of oxygen cause acid substances to appear
in the blood, thus raising the CH and stimulating the respiratory center,
but it allows other poisonous materials to accumulate. These act on the
various nerve centers, producing symptoms which vary in different in-
dividuals according to their relative susceptibilities. In some, the diges-
tive centers are affected and nausea and vomiting occur; in others, the
higher cerebral centers are affected, causing depression and general men-
tal apathy, great drowsiness, muscular weakness, or it may be mental
excitement and loss of self-control.

The susceptibility of different individuals also varies according to the
amount of previous experience in mountaineering and the type of breath-
ing. Much of the value of previous experience and training depends on
the ability to perform muscular effort economically; to adjust the effort
to the available oxygen supply without permitting unoxidized harmful
products to accumulate in the body. It often happens that no symptoms
appear so long as the person is at rest, but immediately do so whenever
any muscular effort demands a much more abundant oxygen supply.

The type of breathing that best withstands the rarefied air is sIoav and
deep, rather than rapid and shallow. The reason for this is of course
that much more of the outside oxygen gets into the alveoli in the former
case than in the latter, the dead space being practically constant. The
following figures taken from observations on three different individuals
will illustrate the importance of this factor.

Subject 1

< <

C.C. PER

NO. OP RES-

HEIGHT IN METERS

RESPIRATION

PIRATIONS

AT WHICH SYMP-

PER MINUTE

TOMS OCCURRED

270

20

3300

440

14

6000

700

8

6500

(From Halliburton.)

After living for some time in the rarefied air and quite independently
of training in the efficient performance of muscular work, adaptation
occurs, so thai the symptoms pass off. The essential feature of this adap-
tation is increased absorption of 02 into the blood. Three mechanisms
have been described as responsible for this effect: (1) increase in the ten-
sion of 0., in the alveolar air; (2) assumption by the pulmonary epithelium

BR] \llli\

i.i' the i'"

and hemoglobin

the more rapid
blood. I

mm. and at 15,<

The evidei •
epithelium depend!

mnd thai bio
a liiu'h mountain is brig
shaken in a flask with .

taken, it w ill 1 me d

believed thai the pulmons
to the la diffusio

\ !: ■

"•' ( >• and « '< » that bl 1 would take up l

body and 2 ' bile in t!

at avidity for hemoglobi
air containing 0.07 p<

v an equal mixtui
monoxide is destroyed \\ ith <

causing a man t" bre
sample "t' drawn blood,

med as in vitro. If >•>. tl
tlit- alveoli ; i

suit which H I

ample, when blood

the amoui

hemoglobin. When th(

the

(•nit. w hi.-li would c

n not

corp

due

nail > t
in t

blood

402 THE RESPIRATION

Cliristiania

Zurich

Davos

Arosa

Cordilleras

height above sea
(meters)

RED CORPUSCLES
(PER C. MM. BLOOD)

0

412
1560
1800
4392

4,970,000
5,752,000
6,551,000
7,000,000
8,000,000

(From Starling.)

COMPRESSED-AIR SICKNESS; CAISSON DISEASE;

DIVER'S PALSY

Divers and caisson workers are susceptible to peculiar symptoms.
These are frequently of sufficient severity to cause death, but may be so
mild as almost to escape notice. They first appear, not when the worker
is subjected to the high pressure, but after he has come back to atmos-
pheric pressure.*

While in the compressed air the worker as a rule suffers no discom-
fort. A stuffiness may be felt in the ears and temporary giddiness ; the
respiration and pulse rate may become slow and frequency of micturition
may be noticed, but none of the symptoms of disease appear until after
the caissonier or diver has been decompressed (after he has returned to
atmospheric pressure), the exact time of their onset being either imme-
diately after decompression or at the end of several hours. The worker
may have returned home and spent the evening feeling perfectly well
until he went to bed, when symptoms supervened which may include mus-
cular and joint pains, vertigo, embarrassed breathing, subcutaneous em-
physema and hemorrhages, pains in the ears and deafness, vomiting,
perhaps hemoptysis and epigastric pain. These symptoms usually pass
off after some hours but the arthralgia and myalgia sometimes persist
for a considerable time.

In the more severe cases the first symptom is severe pain in the mus-
cles and joints, quickly followed by motor paralysis, so that the patient
falls and is likely to become unconscious. The pulse is almost imper-
ceptible, the respiration is labored, sometimes even asphyxial, the face
cyanosed, and the surface of the body cold. Many of the cases are fatal ;
indeed, death may be almost instantaneous. Such cases are common in
careless diving when the divers, to return the more quickly, screw up the
outlet valve in their helmets so as to fill their suits with air, which car-

*A caisson is a steel or wooden chamber sunk in water and prevented from filling by means of
compressed air. For the passage of the workmen and of material, into and out of the caisson, the
latter is connected with a second smaller chamber fitted with air-locks and decompressing cocks. A
diver works in a waterproof suit, the head being enclosed in a copper helmet connected by hose with
air pumps. Every 10 meters or 33 feet of water corresponds to one atmosphere pressure (IS pounds
to the square inch), so that at this depth the total air pressure in a caisson, or in a diver's helmet,
would amount to 30 pounds to the square inch, that is, + 1 atmosphere.

BRI 4TH1NI

them to tin
the valve.

intense congestion
brain, and ecch} nrn
interlobar emphj sema
brain ha I

The Cause of the BymptOmi

The cause for I tnptom

the pr< the blood fi

nt' the body, including tl •

I ause the fluids of the bodj and all

of fluid are incompn

will In- immediately distribut

imt si-, lift- would 1"' 1 1 1 1 ; • •

sure. It is now clearrj establ ished that a

are due to cU compr< . and not, in th<

ical the pressure its< If (Paul Bert, 1 . 1 1

W m animal is under pi i

amounl of '-'as. They ab«

fluid, w hi<'li Btatea that tl i
directly proportional to the partial |
phere ; at two atmospl
solution as at sero pr<
lution, it doe
the blood and t luida I

dis8oh -''l gas will be so qui<

it B I

lillaries or blocking up
large and
bubble lu 1 in I ,**u^

if in the an*'

:.-^ the action of th<
The folio* u

. small
1 air and |

••-1 througl •
on ■ wire and •'
ing a mici
the circul of the :

404 THE RESPIRATION

tive pressure, amounting in some experiments to + 50 atmospheres, was
introduced but no effect could be noted on the circulating blood. By
opening a tap in the chamber, decompression to zero pressure was quickly
effected and, immediately, large bubbles were seen to develop in the
blood, blocking the vessels and producing stasis. The bubbles Avere de-
rived from the gas that had gone into solution under pressure. On re-
applying the pressure the bubbles of gas again went into solution and
the blood circulated normally. "When the pressure was subsequently very
gradually lowered to zero, the circulation went on undisturbed, and the
frog was removed from the chamber in normal conditioh.

The process involved in causing caisson disease is evidently the same as
that which can be observed in a bottle of aerated water; if the cork in
such a bottle is drawn, the dissolved gas escapes as bubbles and effer-
vescence results; if the bottle is recorked, the gas reenters solution and
the fluid becomes quiet. If a pin hole is made in the cork, the gas will
gradually escape and no effervescence will result.

Confirmatory results have been secured by observations on mammals.
The arterial blood pressure of rabbits was not found to become altered
by exposure to compressed air, and various animals placed in a large,
strong steel chamber at pressures far in excess of those to which man
ever subjects himself did not show any symptoms like those of caisson
sickness, unless the pressure was suddenly lowered. Many times also, if
symptoms had appeared they could be removed by again subjecting the
animals to the compressed air.

Investigations "were also carried out to determine exactly how much
gas the blood of an animal subjected to high pressures contains, and how
long it takes to absorb the maximal amount of gas and to release it. It
was found that the gases that increased in amount were nitrogen and
oxygen, and that these become dissolved in the blood according to Dal-
lon's law.

The Prevention of the Symptoms

The most important practical application of these observations con-
cerns the length of time required for the saturation and desaturation to
occur, for the results serve as a basis upon which the safe regulation of
work in compressed air by man can be conducted. The most significant
outcome of the above experiments from this standpoint is that it takes
considerable time for the blood to absorb its full quota of gas at a given
atmospheric pressure and to liberate it again when the animal is decom-
pressed. The cause of delay is that the tissue fluids other than the blood
take much longer than would be expected to reach equilibrium with the
partial pressure of gas in the blood plasma.

BR] vi iir.

understand wl

only '_m-> c ed is nil

eapillai the lungs m

siiri- nt* tli m the ;il

t iss , ,!lt il tl

them ;iii«I the l»l I Tl c i

nitrogen, returns to the lungs ami a^ain I
on until blood ;in<l tissue hai
pressu i •• tissues arc I

to 20 p< lit ol

nitrogen than water (Verno

volume of tissue than of M 1 to bee<

i be l»l<»u.| in man constitutes
thai if the tic e all li<i"i'l I

nitrogen as the blood < i nl of the

tissues take up more than th
man aboul 35 times more than t; d. All th<

aboul one minuti
time, after being suddenly subj<
that the blood circulates equally I
thirty fifth saturated ; in tl
thirty-four thirty-fifths v» ill
the body w ill be aboul 22 per
saturated; but it will tafo
These calculations assume that th<
oul the body ; but this is nol I
considerably in different
and in the glands than it
eular | \ ill tl ■

n.l tl
saturation of the bodj

\\
and acth will '

will contain up -

Tl

the l"»l\ ap]
nal i>-
hit
reu
and return

406 THE RESPIRATION

same number of minutes to desaturate that it took to saturate, and the
parts of the body that will lag behind the others, in being desaturated,
are those with a sluggish circulation.

"When the mass movement of the blood is increased by muscular exer-
cise, the rate of saturation and desaturation with nitrogen is increased
in proportion. During active work the increase in movement of the
blood may be four or five times over the normal, so that the tissues of
the caisson worker become much more quickly desaturated during decom-
pression than the above figures would lead one to expect.

Application of Foregoing- Laws in Practice

With regard to the application of these principles in the decompression
of caisson workers, it is impracticable to occupy as much time as it takes
to saturate the body even at comparatively low pressures. If the great
dangers attending work in compressed air are to be avoided, we must
either insist on very gradual decompression or we must show how the
dissolved gases may be got rid of by some modification in the decom-
pression procedure. With this object in view, we must determine what
difference of pressure may be allowed between the external air and the
body without the formation of bubbles. Actual experience shows that
there is no risk of bubble-formation, however quick the decompression,
after exposure to + 15 pounds pressure ( i.e., 2 atmospheres absolute).
"Now, the volume of gas capable of being liberated on decompression
to any given pressure is the same, if the relative diminution of pressure
is the same" — (Haldane35). On reduction from 4 to 2 atmospheres,
the same volume of gas will tend to be liberated as on reduction from 2
to 1 atmospheres — that is to say, no bubbles will form. The practical
conclusion is "that the absolute air pressure can always be reduced to
half the absolute pressure at which the tissues are saturated without
risk." Thus, after saturation at 00 pounds absolute pressure (+ 5 atmos-
pheres), a man can be immediately decompressed to 45 pounds (+ 2
atmospheres) in a few minutes without risk, but from this point on the
decompression must be conducted slowly, so as to insure that the nitrogen
pressure in the tissues is never more than twice the air pressure. The
great advantage of this method is that it makes the greatest possible use
of difference of pressure between tissues and blood in order to get rid of
the gas that these contain.

When the decompression from the start is gradual, the desaturation
of the tissues will progressively lag behind that of the blood, and the
tendency to the liberation of free gas will become greater. In such a
case the decompression is far too slow at first and far too rapid later.

I1ICI \ I I

I

later.
Bi

■ »ii in c ! i

mm the incidi
animals. Th< thai tl

uniform method, tl
< >n the other hai I I • Hill i

tage metl od i
actual ■ k al I

atmosphei \ "■

Btagi red w itli the ui

method Bhould :
will absolutely

•
it possible to persuade tl it

There an

tur.-itiuii

an indiffercn ' ■
I •
tin- fi-

of the blood, and it if
in the decon

the sir

I man al
and tl

TV Up

joints. fa1 this infl

[1 tly in tl

cur

i
■

l • ring d<

kne

But < en in tl

mav la

408 THE RESPIRATION

sion has been properly controlled. This lias boon shown by Leonard
Hill in the case of the kidney. The "tissue" gas in this case can be
taken as the gas dissolved in the urine, by analyzing which, therefore,
at different stages of decompression, the excess of nitrogen over what
it should he at the external pressure, can be ascertained. On decom-
pression from +30 pounds by two stages to zero, a considerable super-
saturation was found to exist. The excess of nitrogen can, however, be
cleared out of the kidneys rapidly and completely by breathing oxygen,
which should therefore be administered during decompression in cases
where great care has to be exercised (Leonard Hill).

When symptoms do appear, they can, in most cases, be relieved by
recompression, and all modern caisson works are provided with a special
chamber for this purpose. We need scarcely say anything about this
treatment here, as its value is so well known. Suffice it to say that,
although it is most likely to afford relief when applied as soon as pos-
sible after the appearance of the symptoms, yet it is often efficacious
when applied several days after their onset.

Quite apart from the dangers of decompression, it must of course be
remembered that the working conditions in a caisson are somewhat dif-
ferent from those at atmospheric pressure, as the air, oAving to its com-
pression, is warmer and is loaded to saturation point with moisture.
This hot, wet air interferes with the heat-regulating mechanism of the
body, making hard muscular work very uncomfortable because of the
tendency of the body temperature to rise. The reaction of the body
against this tendency to hyperthermia consists in dilatation of the su-
perficial capillaries and increased heart action.

When such working conditions are repeated day by day, the appetite
is likely to fail, partly because of the tendency of the body to suppress
the activity of the metabolic processes, so as to keep down heat produc-
tion, and partly, no doubt, because the digestive processes are working
below par on account of there being less blood circulating through the
visceral blood vessels, it having been sent to the surface of the body to
be cooled off. The worker therefore tends to take less food, his metabo-
lism becomes depressed, and his factors of safety against bacterial
infections become lessened.

The risk of the appearance of symptoms on decompression is also
greater when the air in the caisson has been moist and hot, for the heart
has been overworking to maintain the bloodfloAY in the dilated vessels;
it gets fatigued and is consequently unable to maintain, during decom-
pression, a rate of bloodflow that is adequate for carrying the gas-
saturated blood to the lungs, where the excess of gas becomes dissi-
pated.

BRJ ITBINl

The criterion
e the wet-bulb ten i

maintain this condition it
rralilv w itli a if 1 1 ; .

case, tin- ventilation should
temperature

would soon 1"' balan 1

nt circulation of the air in

also in ini | > t - 1 > \ iii!_r the

heal from th>' hoch

CHAPTER XL VII

THE CIRCULATORY AND RESPIRATORY CHANGES ACCOM-
PANYING MUSCULAR EXERCISE*

During activity the muscles require many times more blood than dur-
ing rest. When the activity is widespread the greater blood supply is
provided by increased heart action accompanied by dilatation of the
muscular arterioles and constriction of those of the splanchnic area, so
that the entire available blood supply of the body is made to circulate
more rapidly. When, on the other hand, the activity is confined to a
limited group of muscles, the increased blood supply is mainly provided
by a local dilatation of the blood vessels of the active muscles accom-
panied by a reciprocal constriction of those of inactive parts. Under
these conditions there may therefore be no quickening of the bloodflow
as a "whole. In order that this accurate adjustment of blood supply to
tissue demands may be promptly and adequately brought about, all
available types of coordinating mechanism are called into play; that is
to say, mechanical, nervous and hormone factors cooperate to an extent
which is dependent upon the type of work being performed.

Besides the changes in pulse rate and blood pressure which are evi-
dently designed to supply more blood to the acting muscles, changes
dependent upon a secondary effect of the muscular movements have also
to be considered. Although the various factors work together and are
more or less interdependent, the final effect can be understood only after
we have studied the relative influence of each separately.

The Mechanical Factor. — It is particularly with regard to this factor
that the circulatory changes may be an unavoidable consequence of,
rather than a useful adjustment to, the muscular effort. The effects vary
with the type of exercise performed. In repeatedly lifting and lowering
dumbbells from the floor to above the head, the contracting muscles of
the back and extremities and of the abdomen compress the veins and
cause the blood to flow more rapidly into the heart, so that the arterial
pressure suddenly rises. So long as this compression exists, the veins
remain relatively empty and the arteries overfilled, but whenever it
ceases and the muscles relax, the veins fill up again and the arterial pres-

*This chapter is placed here rather than following circulation because of the interdependence of
the circulatory and respiratory adjustments.

410

< 1 1 \ '

mre markedly fall*, until tl
by blood It is for to
Pound tn be little, if ai
after such i II

responsible for the increased

ire still in operal ion at 1
blood. The purely mechanical infl
paratively Bhort time, w i

tinue acting. This int< -hat

the fall of blood pi

••li amounl of dumbbell i
with his elbo iting on liis

sure mi the abdominal

causes more M I ' Llect in the lar ■

I Being purely mechanical ii

follow ing dnmbbel]

tions are made at close enough inl

The mechanical response of I
through tl filling rt \\ it)

in a healthy condition, it will
ingly increased discharge Liki i
heart \\ orka \\ ith a 1. i
the rate of venous filling thi

called npon to maintain 1 1
arations Starling and his
close depend* f cardiac output u]

•incus range through which ti
vary by altering this • \

p..'. the heart is

is longer in attaining
; longer tim<
furnishes a m< ful fin

Oth< - mechanical fa
the it

■

walled
thoracic •■

so thai the bl I finds it

\ Itl ngh tliis dilal •
in tho intrathi

•
exl

412 THE RESPIRATION

arteries. It is obvious that increased depth and frequency of the respira-
tory movements will accelerate the bloodtlow and tend to raise the arte-
rial blood pressure.

The above factors will come into play during most kinds of muscular
exercise such as walking, running, or swinging dumbbells, etc. There
are certain types of muscular effort, however, in which, the mechanical
factors produce decidedly disturbing effects on the circulation. During
a sustained effort as, for example, in pulling against a resistance or in
attempting to lift a heavy load, the respirations are suspended, often after
a deep inspiration, and the contracted abdominal muscles press the dia-
phragm up into the thoracic cavity. After a preliminary squeezing out
of blood first of all from the veins of the abdomen into the thorax and
then from those of the latter into the systemic arteries, with a consequent
rise in arterial pressure, there comes to be a damming back of blood into
the peripheral veins, causing them to swell and, if continued, marked
cyanosis may develop. When such efforts are maintained for long, the
arterial pressure begins to fall, and this fall is very pronounced indeed
at the end of the effort, because, the compression being removed from the
abdominal and thoracic veins, these open up and form a large unfilled
blood reservoir.

A similar mechanism comes into play during expulsive acts such as
defecation, parturition, etc. In these the glottis is closed, usually after
a preliminary inspiration, and a powerful expiratory movement is per-
formed, with the consequence that the intrathoracic and intraabdominal
pressures rise considerably, greatly augmenting the systolic discharge
and causing the blood pressure to rise. Because of the obstruction to
the bloodflow in the large veins of the abdomen and thorax, however,
the later effect of the effort is to diminish the systolic discharge, but the
fall in blood pressure which this would be expected to occasion is masked.
The pressure remains high because other factors increasing the peripheral
resistance come into play. The fall in blood pressure following these acts
may be very marked indeed. Similar mechanical effects are produced
in the acts of coughing, sneezing, etc.

The capacity of the veins varies considerably with the position of the
body, and it is in order that we may cause alterations in this capacity
and therefore encourage a more rapid bloodflow that Ave stretch the body
after sitting for some time in a cramped position.

The Nervous Factor. — The vagus, vasoconstrictor and respiratory cen-
ters are all excited during muscular effort. In the earlier stages the
excitation depends entirely on nervous impulses transmitted to the cen-
ters, but later il depends on changes in the composition and temperature
of the blood flowing through them — the hormone factor. The initial

« II •

stimulation of I
ently t ranKm
and respirations maj be
(Mint ractions.

The Hormone Factor W
hormo

7 / the li

bonic acid, bul \\ hen thi
the eerj Btarl i

than the blood i ipply it '
I ! idenee for 1 1
--is i pired air

acid before and during musculj
is belies ed to be an • H

is, lie
■tualh
tion of the arterial bli

would I r no significance d<

be dependenl upon acid produetion •

iwn buffer action
siderable quantities

in II ion cone
must be the B i

demonstrating a change in H
finding the dissociation eonstanl
-. n thai acidosis d<
B So

direct me

well 1
much

can

■ •ill ar * • '

inert n Ihe

Isr

k, t 1 . i —

1 1 v \\ 1

\ ||( , ,

addi

IICO I"
liveh

414 THE RESPIRATION

state. That the C02 tension of the alveolar air should be found to be
lowered by prolonged muscular exercise in no way detracts from this
explanation, for it is dependent upon the greatly increased rate of
movement of air into and out of the alveoli (see also page 366).

One serious difficulty in accepting the HC03 ion as the exciting hor-
mone of the nerve centers during muscular exercise depends on the ob-
servation that the alveolar C02 after some time is lower than normal.
If we accept Ilaldane's teaching that there is accurate correspondence
between the tensions of C02 in arterial blood and alveolar air not only
during rest but also during muscular activity, then obviously we must
discard the HC03 hypothesis. Leonard Hill and Flack,37 however, have
shown quite clearly both in experimental animals and in man that equi-
librium between the blood and alveolar tensions of C02 may fail to
occur. When blood with excess of C02 is injected into the jugular vein
of dogs, the respiratory center is stimulated, as shown by the increased
breathing, which indicates that the C02-rich blood must have passed
through the lungs without the excess of C02 being removed from it.
Hill believes that the diffusion of C02 out of the blood into the alveolar
air may be depressed in muscular exercise, and that this rather than the
appearance of lactic acid in the blood is responsible for the low C02 ten-
sions usually found present (see page 369). He points out in support
of this view that a person after exercise can hold his breath for a much
shorter time than is usual, and the C02 meanwhile mounts in the alveolar
air very rapidly.

The only way by which progress may be made in a problem like that
under discussion is, however, to adopt some hypothesis and then to
gather evidence for or against it. At the present stage of our knowl-
edge, the hypothesis usually adopted is that a slight change in H-ion
concentration of the blood is the effectual hormone. It is an hypothe-
sis which is supported by the parallelism between the effects observed
during muscular exercise and those produced by experimental increase
in H-ion concentration.

The Effects of the Hormone. — These may be classified as follows: (1)
strictly local effects on the muscles themselves; (2) effects on the heart;
and (3) effects on the nerve centers. The local production of acids in
the muscles will cause dilatation of the arterioles, for it has been shown
by various observers that acids cause relaxation of vascular muscle.
Even the capillaries themselves are said to be dilated by carbonic acid
(Severini). The effects produced on the heart by changes in H-ion con-
centration of the blood have been particularly studied by Starling and
Patterson,38 who, working on isolated heart-lung preparations, have
shown that the heart relaxes more and more and discharges less blood

- I!

aa the II ion

' I ' t«. the air \ entilatinj

influence of cl in II

-is and vasomol
There is no doubl that an in

-, not onl;
of the spinal cord But it i-> a qu<

tolio pressure during m
for the enormously
makes it problematical
it does bo, it must be eonfi]
have the • of brii

blood bj wing il from the vise*

inn

The effect of inc IB

be insignificant II mmonly I

is actually ol i. a quickening, bul

Hut even this is doubtful i
asphyxia, for example, is in pi

nial pressure, for w hen the

eury valve bo thai the hi 1 i

normal level, no b1<
I i mard Bill and Flai

(feet the l

tone, \\ hich is
lieved to have The acth it;
cited by inci ease in H-ioi
cause important ehai
which follow
Along w ith hormoi i
p< raft ■ I •

well ki but that it

icular adjust

hen 1
% part

leasl of tl

it is

thn' ou* n

culai '

IKi THE RESPIRATION

very deiinitc changes occur at the time the relief is experienced — namely,
a sloAviiiii and steadying of the previously much quickened and irregu-
lar pulse, sweating, and a marked fall in the respiratory quotient. T he-
last mentioned change possibly gives a clue to the cause of the others.
In the early stages /.'. Q. is raised, which indicates that relatively more
C02 is being expelled from the blood into the alveolar air than oxygen
is being absorbed, perhaps because of inadequate movement of blood
through the lungs. At the time of the adjustment it is possible that a
pronounced vasodilatation occurs in the muscles and coronary arteries.
The former change by lowering the arterial blood pressure Avill relieve
the pumping action of the heart, and the latter will improve its power of
contraction by supplying it with more oxygen.

RESPIRATION REFERENCES

(Monographs)

Barcroft, J.: The Respiratory Function of the Blood, University Press, Cambridge,
1914.

"Borrutau, H.: Nagel's Handbuch der Physiologie, 1905, i, 29.

Douglas, C. G.: Die Regulation der Atmung beim Menschen, Ergebnisse der Physiol-
ogie, 1914, p. 338.

Hill, Leonard: Caisson Sickness, International Medical Monographs, E. Arnold,
London, 1912.

Keith, Arthur: The Mechanism of Respiration in Man, Further Advances in Physi-
ology, E. Arnold, London, 1909.

Schenck, F.: Innervation der Atmung, Ergebnisse der Physiologie, 1908, p. 65.

(Original Articles)

iKeith, Arthur: Cf. Further Advances.

-'Hoover, C. F.: Arch. Int. Med., 1913, xii, 214; ibid., 1917, xx, 701.
3Lee. F. S., Guenther, A. E., and Meleney, H. F.: Am. Jour. Physiol., 1916, xl, 446.
•»Meltzer, S. J.: Jour. Physiol., 1892, xiii,*218.

•'■Haldane, J. S., and Priestley, J. G.: Jour. Physiol., 1905, xxxii, 225.
Haldane and Douglas: Ibid., 1913, xlv, 235.
^Henderson, Y., Chillingworth and "Whitney: Am. Jour. Physiol., 1915, xxxviii, 1.

Henderson and Morriss: Jour. Biol. Chem., 1917, xxx, 217.
TKrogh, A., and Lindhard: Jour. Physiol., 1913, xlvii, 30; ibid., 1917, li, 59.
sPearce, R. G.: Am. Jour. Physiol., 1917, xliii, 73; ibid., 1917, xliv, 369.
'-'Siebeck, R.: Skand. Arch. f. Physiol., 1911, xxv, S7; Carter, E. P.: Jour. Exper.

Med., 1914, xx, 21.
Peabody, P. W., and Went worth, J. A.: Arch. Int. Med., 1917, xx, 443.
"Lewis, T.: Jour. Physiol., 1908, xxxiv, 213, 233.
' -Porter. W. T.: Jour. Physiol., 1895, xvii, 455.
^Christiansen and Haldane, J.: Jour. Physiol., 1914, xlviii, 272.
"Boothbv, W. M., and Berry, F. B.: Am. Jour. Physiol., 1915, xxxvii, 433; also

Boothby, W. M., and Shamoff, V. N.: Ibid., p. 418.
i^Alcock, N. H., ami Seemann, J.: Jour. Physiol., 1905, xxxii, 30.

Scott, F. H.: Jour. Phvsiol., 1908, xxxvii, 301.
"Stewart, G. N., and Pike, F. H.: Jour. Physiol.. 1907, xx. 61.
"aCoombs, H. C, and Pike, F. H.: Proc. Soc. Exper. Biol. Med., 1918, xv, 55.
isRrogh, A.: Skand. Arch. f. Physio]., 1910, xxiii, 248; and A. Krogh with Marie
Krogh, ibid., 179.

CHANG] S \< I OMl'AN ^ INO M i S( i L \\: 1 1 1

LOHaldane, J. S., and Priestley, f. G.: Jour. Physiol., 19

Scott, B. W.: Am. Jour. Physiol., 1917, xliv, I
siNewburg, .Means, and Porter, W. T. : Jour. Exper. Med., 19K
s Easselbalch, K. A., and Lundsgaard, Chr.: Biochci , Zl chr., 191J

Skand. Arch, f. Physiol., 1912, xxvii, 13.
Hooker, D. B., Wilson, D. \\ ., and Connett, II.: Am. Jour. Physiol., 1917, xliii,
^Campbell, J. -M. II.. Douglas, C. G., and Eobson, I'. G.: Jour. PI 1914, xl

303.
- •!. milliard, J.: Jour. Physiol., 1911, rxxviii, 337; Ealdane, J. >.. and

[bid., 1913, xhi.
-'•Douulas, C. (J.: Art, Ergebnisse dor Physiologie, set Monoj

!7Barcroft, J.: sei Bespiratory Function of Bl 1.

28Milroy, T. II.: Quart. Jour. Physiol., 1913, vi, 373.

eoFletcher, W. M.. and Hopkins, F. <;.: .lour. Physiol., 1907, xxxv, ^17: a

W. M.: Jour. I'1i\mo1., l'.U:i, xlvii, 361.
snRyffel, J. H.: Proc. Physiol. Soc. in Jour. Physiol., 1909, xxxix, 29.
BiPembrey, M. S., and Allen, B. W.: .lour. Physiol., 1909, xxxii, 18.
B2Buckmaster, G. A.: -lour. Physiol., 1917, li, 105.
ssDouglas, C. G., Haldane, J. S., Henderson, Y.. and Schneider, E. C: Phil

Boy. Soc, 1913, 203, B, 185.
■ Hill. Leonard, Macleod, J. J. K.: Jour. PhysioL, 1903, mx, 507; Hill, Leonard,

Greenwood, M., Flack, M.. etc.: se< Hill's ' Sicknet

3'Haldane, J. 8.: Deep Water Diving, Committee of the Admiralty iBriti-

Hill 's Caisson Sickni
seCotton, T. F.. Bapport, and Lewis, T.: Heart, 1918.
•"•.■Hill, Leonard, and Macleod, J. J.K.: Jour. Physiol., 1908, xxxvii, 77.
sspatterson, S. W., Piper, H., and Starling, F.. II.: Jour. Physiol., 1914, xlviii.

PART V

DIGESTION

CHAPTER XLVIII
GENERAL PHYSIOLOGY OF THE DIGESTIVE GLANDS

The function of digestion is to bring the food into such a condition
that it can be absorbed through the intestinal epithelium into the blood
and lymph. Carbohydrates are broken down as far as monosaccharides ;
neutral fats are split into fatty acids and glycerine; and proteins are
broken down into the amino acids. The agencies which effect these
decompositions are the digestive enzymes, or ferments, contained in the
various digestive fluids or juices. The digestive juices are produced by
glands, which are most numerous in the upper levels of the gastro-
intestinal tract, the lower levels having as their main function that of
absorption of the digested products. In order that the masses of food
may be kept in a state of proper consistency, and that they may move
readily along the digestive canal, numerous mucous glands are also
scattered along the whole extent of the canal. Some of the digestive
glands, such as the main salivary glands, the pancreas, and the liver,
discharge their secretions into the digestive canal by special ducts,
whereas others, such as the isolated salivary gland follicles in the mouth,
the gastric glands and the crypts of Lieberkuhn in the intestine, do not
have an anatomically distinct duct, but discharge their secretions directly
into the digestive tube.

It will be convenienl to consider, first of all, certain properties that are
common to the digestive glands, and then, the conditions under which
each gland functionates during digestion.

MICROSCOPIC CHANGES DURING ACTIVITY

Structurally the active part of the glands, represented by the acinus
or tubule, is composed of a basement membrane lined internally with the
secreting epithelium. Outside the basal membrane are the lymph spaces
and blood capillaries. Alter the gland has been ;i1 rest, the cells become

418

I'llYRJOLOOY <»l Till hi... - i i\ i .,i v

H9

filled with granules or small globules, which are often •-<> numerous

••lliiHist entirely to obliterate the nucleus. When the gland I mea acl

on the other hand, the granules or globules leave the cells, »r :•

few which remain inward the lumen border. Pigs. 143 and 14}

B.

Fig. 143.— Cells of parotid gland showing z

moderate secretion; C, after prolonged secretion. (From I

These observations indicate thai the granular or globular material m
represent part at least of the secretion of the glands. Sometimes, even
before they are extruded, the granules become changed me difl

ciii material, as is indicated by the fact thai they stain differently from

A.

:'r

-f

Fig. 144. — Parotid glaud ol
upper left-hand acini are The upper right-ha

activity by injecting pilocarpine, and I
pathetic nerve. (After tangle;

those of the resting gland. It musl not be thought, 1 thai an

extrusion of granules necessarily accompanies * \ity.
under certain conditions a copious secretio

as well as a certain amounl of organic material, d ! with-

420 DIGESTION

out any change in the arrangement of the granules. In such cases it has
been observed, as in the pancreas, that fine channels develop in the
protoplasm of the cell (see page 429).

From this histological evidence it would appear that the gland cell
during rest is endowed with the property of building up out of the pro-
toplasm, as granules or globules, the material which is to serve as one of
the main organic constituents of the secretion. It is commonly believed
that this is the precursor of the active ferment of the secretion ; hence its
name, zymogen. It has been shown that the process of separation of the
zymogen granules starts around the nucleus with the production of a
basophile substance, which in hardened specimens sometimes takes the
form of filaments. From this basophilic ergastoplasm, as it is called, the
granules are gradually formed, and then for some time continue to
undergo slight further changes, as is evidenced by the fact that the
staining reaction of those near the base of the cells differs from that of
those at the free margin. "When the gland cell is excited to secrete,
the granules before being extruded, as noted above, often undergo a
definite change, becoming swollen and more globular in shape.

MECHANISM OF SECRETION

These microscopic studies merely tell us that active changes, associated
with the production and liberation of certain of the constituents of its
secretion, are occurring in the gland cell, but they throw no light on the
mechanism whereby the gland cells secrete water and inorganic salts.
This may be dependent, to a certain extent at least, on differences in
osmotic pressure (see page 11). A possible explanation of the flow of
water is as follows: If a watery solution of some osmotically active sub-
stance is put in a tube, which is closed at one end by a membrane
impermeable to this substance and at the other by one permeable to it.
and the tube immersed in water, a continuous current will be
found to issue from the permeable end so long as there remains any
osmotically active substance in the tube. If we assume, then, that the
membranes at the two ends of the secreting cell are of such a nature that
the one next the basement membrane is impermeable to some osmotically
active substance manufactured by the cell, and the other toward the
lumen is permeable, it will be clear that, so long as this substance
exists in the cell, it will attract water from the blood, and the water
together with the osmotically active substance will be discharged into
the lumen.

It is possible that when anything excites the cell to secretory activity,
such as a nerve impulse or hormone, it does so by causing a change in

PHT8I0L001 OP THE DIGE8TTV1 OLANDE ll!l

the permeability of the lumen border of the eelL Thia change in permea-
bility may be dependent upon alterations in surface tension brought
about by the migration of electrolytes to the border. That such a migra-
tion of electrolytes docs actually occur has been den by A B
Macallum8 who developed a microchemical tesl for potassium, by the use
of which he was able to show thai this electrolyte accumulates at the lumen

border of il II during secretory activity, that is. al the border of the

cell through which the secretion takes place. Potassium may be taken
as a prototype of electrolytes in general. In the epithelium of the -mall
intestine, where the currenl goes in the opposite direction to thai in
gland cells, the accumulation of potassium occurs al the portion of the
cell next the basement membrane.

Other observers believe that, when the gland becomes more active, the
molecules present in the cell become broken down into smaller mole.-
and so raise the osmotic pressure of the cell content, with the result that
water is attracted from the blond and is then transferred to the lumen.
When the gland is excited so that the zymogen granules, aa well as
water and salts, are secreted, the primary change appears to involve the
granules only. Those near the lumen swell up by absorbing \ and

become converted into spheres in which salts are dissolved in smaller
proportions than exist in the lymph bathing the cells. These swollen
structures are then ruptured a1 the periphery of the cell and discharged
into the lumen. This discharge of a fluid containing fewer saline con-
stituents than the cell or surrounding blood plasma brings about in-
creased concentration in the remaining parts of the cell, a p which
possibly is assisted by a breaking up of molecules In the protoplasm itself,
and which causes an increase in osmotic pressure with a conseqn
How of water from the lymph to the cells and therefore from the bl
to the lymph.

OTHER CHANGES DURING ACTIVITY

Whatever may be the nature of the physiological changes thai
are responsible for the secretory activity of the cell, the fact star
prominently that a considerable expenditure of energy is entailed T
is indicated by the fad thai considerably larger quantity
are taken up by the gland when it is in an active state than whei
rest. Thus, the oxygen consumption of the resting submaxillary gland
of the cat may be increased five times during active tion.

account of this increased oxygen consumption it is i rprising that

it should be found that the Becretory activity of tin 11 ;~ im-

paired by a deficiency in oxygen.

422 DIGESTION

These active processes occurring in the gland when i1 is excited to
secrete are associated with changes in electric reaction and in the
volume of the gland. The electric changes have been most extensively
studied in connection with the salivary gland. Cannon and Cattel,6 by
connecting a galvanometer with nonpolarizable electrodes, one placed
on the gland and the other on neighboring connective tissue, were able
to show that with each period of active secretion a current of action was
set up. This was first discovered by Rose Bradford and Bayliss, and
has been carefully studied by Gesell.68 That the electric current is
definitely associated with the secretion of saliva and is not caused by
the vascular changes which usually accompany this act was shown by
its occurrence when the blood supply was shut off from the gland,
and by its absence when there was no secretion even though the vascular
changes were brought about; neither is the electric change due to the
movement of fluid along the duct, as evidenced by its persistence after
ligation of the duct.

With regard to change in volume, it might be expected, on account of
the greater vascularity of the gland accompanying activity, that this
would increase. On the contrary, however, it has been shown to de-
crease, because of the large quantity of fluid secreted from the gland cells.

The action of two drugs on the gland cells is of considerable physio-
logic importance: that of atropine, which paralyzes the secretion, and
that of pilocarpine, which stimulates it. We shall see later how this
information may be used in working out the exact mechanism of the
different glands.

Important observations concerning the relationship of glandular activ-
ity to the Wood supply have been made by experiments in which glands
were artificially perfused outside the body. "When the submaxillary
gland of the dog is perfused with oxygenated Ringer's solution, stimula-
tion of its nerve supply does not produce the usual secretion, but if the
Ringer's solution is mixed with blood plasma, the nerve stimulation has its
usual effect for a short time. Although no secretion occurs when
oxygenated Ringer's solution is perfused alone, the usual vascular
changes still occur in the gland. The results seem to indicate that the
presence of some constituent of the blood plasma is essential for the
change in the permeability of the cell wall necessary for the process of
secretion. Similar results have been obtained during artificial perfusion
of the pancreas when secretin was used as. the stimulus.

CONTROL OF GLANDULAR ACTIVITY

Having outlined the general nature of the changes occurring in gland
cells during their activity, we may now proceed to study the nature of

Center for \

crdnial secretory fibers

Facial nerveJti.VII).
Cerebellum
GlossopharynqeaCnerve^
(N.IX) "&£

Medulla oblongata^

Parotid gland

Center for
vasodilator nerves

Otic ganglion

Jemilunar{Gasserian)ganglion
'Chorda tympani nerve
Small superficial
petrosal nerve
Pon^j^^ni^lnf. max. div. N. V *

Electrodes'
^Small amount of thick saliva
vasoconstriction )

Vaso constrictor fibers
sympathetic secretory fibers

ut going sympathetic
rami communicantes

Parotid duct
(Stensc

/Submaxillary
J duct(Whartons,

h/Sublingual
duct

[Bartholin's)
ingual nerve

Chordo-lingual

triangle

Electrodes
[Large amount of thm
saliva,
vasodilatation

Sublingual gland

Post ganglionic fibers are
dotted thus —

Fig. 145. Diagrammatic representation

J a. ksi •

PHYSI0L001 OP Till. DIGESTIVE QLA1 123

the process by which this glandular activity is controlled. Two mechan-
isms of control arc known: I by the nervous Bystem, and (2) by means
of hormones.

Nervous Control. Control through the tier a system is mosl marked

— indeed if may be the only means of control in glands which hav<
produce their secretion promptly, whereas hormone control pre-
dominates in those in which prompl changes in tory activity are not
required. Thus, nervous control alone is present in the salivary glands,
whereas hormone control is predominanl in the pancreas, intestinal
glands and liver. The gastric glands are partly under nervou trol,

and partly under hormone control. It should be pointed out here that

the glands of the body other than the digestive glands are also Bubjecl to
nervous or hormone control according to the promptness with which they
arc required to secrete. The lachrymal and sweat glands, and the venom
glands of reptiles, for example, are practically entirely under nerv<
control, whereas most of the ductless glands, with the exception of the
adrenals, are mainly under the influence of hormoi

The exact nature of the nervous control of glandular function fa
therefore, been mosl extensively studied iii the salivary glands, and that
of the hormonic in the pancreas. With regard to the salivary glands,
the following points are of importance: Their nerve supply comes from
two sources: the cerebral autonomic, and the sympathetic autonomic
see page s77 . These two nerve supplies have usually an opposite intlu
ence on the secretory activity of the glands, and very frequently also on
the vascular changes that accompany secretory activity.

On account of its ready accessibility, the submaxillary gland in the
dog and cat has been most thoroughly investigated. Th< bral auto-

nomic nerve in this case is represented by the chorda tympani, and the

sympathetic autonomic by postganglionic fibers that run from the

superior cervical ganglion to the gland along its hi 1 vessels Fig, 1 :

After tying a cannula into the duct of the gland, it will be found in
dog that stimulation of the chorda tympani produces an immedial
abundant secretion of thin watery saliva a mpanied by a mar'

dilatation of the hi I \essels of the gland.

That this Becretion is not dependent on the vasodilatation is easily
shown by repeating the experiment after administering a sufficient d
id' atropine to paralyze the secreting cells, stimulation of the nerve then
produces a vasodilatation bul no secretion. The sane elusion

arrived at by an experiment of an entirely different nature: namely, by

observing the pressure produced in the duct when the chorda tympani is
stimulated. This pressure rises considerably above that in the art
so that no Buch physical process as mere diffusion can be held accountal

424 DIGESTION

for the secretion, and therefore vasodilatation alone can not be respon-
sible for it. If the sympathetic nerve supply is stimulated, a very scanty,
thick secretion takes place accompanied by vasoconstriction.

Repetition of these experiments in the cat yields different results,
particularly with regard to the influence of the sympathetic, a copious
secretion being produced by stimulation of this nerve. The histological
changes produced in the gland cells are marked after sympathetic stimula-
tion, but very slight, if present at all, after chorda stimulation.

The outstanding conclusion which may be drawn from these results
is that two kinds of secretory activity are mediated through the nerves;
one causing a thin watery secretion, containing only a small percentage
of organic matter, and the other, a thick viscid secretion with a large
amount of organic material. To explain these differences the hypothe-
sis has been advanced that, there are really two kinds of secretory
fibers, called secretory and trophic, the former having to do with the
secretion of water and inorganic salts, and the latter with the secretion
of organic matter ; i. e., with the extrusion of the zymogen granules.
Certain authors (Langley) believe that such an hypothesis is unneces-
sary, and that the different results are dependent upon the concomitant
changes in the blood supply produced by stimulating one or other nerve.

That there are really different kinds of true secretory fibers is, however,
evident from the following experiment. If the duct of the gland is
made to open on the surface of the cheek, secretion of saliva through
the fistula can be induced by placing various substances in the mouth, such
as meat powder or weak solutions of acid. When the experiment is per-
formed in such a way that the bloodflow through the gland can be observed,
it has been found that the saliva produced by the stimulation with the meat
powder contains a very much higher percentage of organic material than
that produced when hydrochloric acid is the stimulant, whereas the vascular
changes in the gland and the inorganic constituents of the saliva are the
same in both cases. Since stimulation of the chorda tympani causes the
secretion of a watery saliva, while that caused by stimulation of the
sympathetic is thick, it might be thought that the secretory fibers are
contained in the former and the trophic fibers in the latter nerve; that
this is not the case can be shown by a repetition of the above experiment
in animals from which the superior cervical ganglion has been removed.
The same results are obtained, indicating that the chorda tympani con-
tains both secretory and trophic fibers.

CHAPTER XI. IX
PHYSIOLOGY Oh THE DIGESTIVE GLANDS Cont'd

THE HORMONE CONTROL

This is exhibited besl in the case of the pancn The crucial experi-
111**1 1 1 demonstrating tli;it this yhnid is nol primarily dependenl U]
nervous impulses for the control of its activity was performed bj B
liss and Starling.- Starting with the well-known fad that the application
of weak acid to the duodenal mucous membrane exciti iretion '-i' pan-
creatic juice, these workers carefully severed all the 1 i
a portion of the duodenum, and found on again applying arid to the muc
membrane thai the secretion persisted. To explain this result they postu-
lated thai the acid must cause some substance to be liberated Into the
blood stream, which carries it to the pancreas, the cells of which it then
excites to activity. To tesl this hypothesis they scraped off the mucous
membrane of the duodenum and ground it in a mortar with weak hydro-
chloric acid i <Mi per cent . and. after boiling the solution so as to coagulate
the protein, nearly neutralizing and filtering, they obtained a fluid which.
immediately caused a copious secretion of pancreatic juice when injected
intravenously.

Accompanying the secretion, however, a marked fall in arterial hi 1

pressure was observed, making it possible thai the secretion mighl h
been due to a vasodilatation occurring in the pancreatic blood v< 'I o

eliminate this possibility they prepared an extract that wa the

depressor substances by extracting intestinal epithelium without any of the
submucous tissue. The resulting extract had merely the
and produced no fall in blood pressure. This secretagoguary sul
they named si <-r< tin.

Further evidence thai the action of secretin is independent i
depressor substances has been obtained by taking advai I
that the depressor substance is more soluble in alcohol than tl
If an acid decoction of duodenal mucous membrane is poured inti
lute alcohol, a precipitate is formed, [f this precipitati
in water and reprecipitated several times by absolute alcohol, thei
drying a white powder is obtained, which is easily soluble in wi I

resulting solution injected intravenously lias ;i :

luit produces no eff< cl on hi I prea Tl i

Il'ti DIGESTION

liquor, on the other hand, when similarly injected produces a marked fall
in blood pressure. It is believed that this effect is due to the action of
/?-imidazolylethylamine. A very strong preparation of secretin can also
be prepared by the method of Dale and Laidlaw,7 which depends on pre-
cipitation by mercuric chloride.

Secretin does not exist preformed in the epithelial cells, as is shown by
the fact that an extract, made with neutral saline solution, does not as a
rule, have any secretory action when injected intravenously. Sometimes
a slight secretion may be produced, but this is probably to be explained
by the fact that some secretin remains behind in the cells as a result of a
preceding phase of activity. If, on the other hand, the above neutral or
slightly alkaline opalescent solution of the mucous membrane is boiled
with acid, secretin may become developed in it. The interpretation put
upon these results is that a substance, called prosecretin, exists in the
epithelial cells, and that this becomes converted into secretin by the action
of acid on the cells. The secretin thus produced is then taken up by the
blood, none of it passing into the intestinal canal, because the free borders
of the cells are impervious to secretin. That this is actually the case has
been shown by finding that the introduction of neutralized secretin solu-
tion into the duodenum, or other parts of the small intestine, does not
cause a secretion of pancreatic juice.

We know practically nothing concerning the cl>< mical nature of secretin.
Being soluble in about 90 per cent alcohol and in fairly weak acids, it can
not belong to any of the better known groups of proteins. As it is
readily diffusible through parchment membrane, it can not be of very
complex structure, and as it withstands heat, it can not be an enzyme.
It rapidly deteriorates in strength in the presence of alkalies.

Any acid when applied to the mucous membrane is capable of producing
secretin, and so are certain other substances, such as mustard oil. Watery
solutions of saccharose or urea, when rubbed up with the duodenal mucosa
in a mortar, produce secretin solutions of varying activity, but they do
not in the living animal excite pancreatic secretion when applied to the
duodenum. Secretin is very susceptible to destruction by such digestive
enzymes as those present in the pancreatic, gastric, and intestinal juices.
That secretin is present in the blood when acid is in contact with the
duodenal mucosa has been shown by the fact that injection into a normal
dog of blood from one in which secretin formation is going on (as a
result of acid in the duodenum I, excites pancreatic secretion.

The pancreatic juice produced by the injection of secretin, like that
which is produced under normal conditions, does tiol contain any active
trypsin, but instead contains its precursor, trypsinogen. This becomes
converted into trypsin in the intestine, being activated by contact with

PHI - KH OF Till. l»h. i - I i\ i Ul \-

;jt

enterokinase, an enzj me presenl in the intestinal juic< Bj such a mechan-
ism the mucosa of the pancreatic dud is protected again I ■ ition
by trypsin.

NERVOUS CONTROL OF PANCREAS

Prior to the discovery of secretin, Pavlov1 and his pupils had publial
numerous experiments purporting to show thai the secretion of pai

Fig, ! • I'.. creal d with

the figure arc from a
for over three ho .1 in t!"

the vagus nerve supply of which bad
the rymogen granules an i trudi ! onlj afl
Ralikin, Rubaschkin and Ssawit

■

juice is controlled through the vagus nerve. The smounl
produced bj nervous stimulation was, howi
as thai produced b) secretin, and For several

428

DIGESTION

the latter hormone, much doubt existed as to the correctness of Pavlov's
claim. As in many other fields of physiological science, investigators at-
tempted to show that one or the other mechanism obtained, and they were
not inclined to consider the possibility that both mechanisms might exist
side by side. That such is the case, however, is clear from the most recent
work, in which it has been found that if proper precautions are taken,
repeated stimulation of the vagus nerve does call forth a secretion of
pancreatic juice which, besides being less copious than that following

h

0

M

[i.

in.

Fig. 147. —Three preparations of pancreatic acini stained by eosin orange toluidin blue. The
acini of Fig. I were from a gland after vagus stimulation, and it is noted that besides free ex-
trusion of the granules, globules staining with orange (and appearing in deep black in the photo-
graph) have formed and may be present in the ductules. Some of the globules, however, change
in their staining properties, becoming light red (dark gray in photograph). The acini in II and III
were from glands excited by secretin. Xo globules appear; the granules remain, and fine canaliculi
appear in the clear protoplasm. (From- Rabkin, Rubaschkin and Ssawitsch.)

secretin injection, differs from it in the important fact that it contains
not trypsinogen but active trypsin. Since the normal pancreatic juice
contains trypsinogen, this last mentioned fact would appear to indicate
that vagus control of the normal secretion can not be an important affair.
The vagus secretion of pancreatic juice is, moreover, paralyzed by atro-
pine, which has no action mi the secretin mechanism (cf. Bayliss).

I'llS S10L0QY i »F l in I'hil fc I 129

Tlie copious secretion of pancreatic juice produced I tretin, on I

une band, and the Bcanty, thick secretion produced by vag tnula-

tion, on the other, calls to mind .similar differences observed in tin
tion of saliva as the resull of chorda-tympani or sympathetic stimulation
It will be remembered thai from these latt< nils it was conclu

thai there must be secretory and trophic fibers concerned in tl trol

of the activities of gland cells. Interesting corroboration of this conclusion

lias recently 1 n obtained by histological examination o) tin pancn

lowing secretin or vagus activity. After the repeated injection oi
tin. it is difficult to observe any signs of fatigue in Us; the zymo(

granules remain practically as numerous as in a resting gland, but in the
clear protoplasm of the outer third of the cell, it is said thai fine channels
of fluid can be seen. Through these channels water is beli
from the blood towards the Lumen and in its course to carry with it some
of the zymogen granules, without, however, changing them. Thus, when
the gland cells are stained with eosin and orange, afti tretin activity
some of the zymogen granules can occasionally 1"- seen in the Lumen of
the acini stained with eosin Like those in the cell itself. Aftei
stimulation the appearances are different ; no1 only are the granules m

freely extruded from the cells, but they undergo a preliminary cha;
they lose the property of staining with eosin and become stained with
orange, at the same time increasing in size so as to form vacm
These vacuoles may wander into the ductules, and when they are |
here they are stained by orange Figs. 14ii and 147 l I Babkin, etc.Ta).

Why there should be both a nervous and a hormone control of the pan-
creatic secretion is not clear. This gland, unlike t: trie and salivary
glands, is not called upon to become active all of a sudden, and it is dif-
ficult to see what could serve as the normal stimulus operating thro
the nervous pathway. Taking it all in all, it is probably safe I
elude that the nervous mechanism is relatively unimportant, and that
under normal conditions it seldom if ever is called into operation I
roboration for this view is afforded by the Eaet, above menti
the pancreatic juice produced by vagus Btimulatio tryp-
sin, which is not the case with normal pancreatic juid

CHAPTER L

PHYSIOLOGY OF THE DIGESTIVE GLANDS (Cont'd)

Up to the present we have been concerned with the physiological activi-
ties of digestive glands in general, but now we must study each of them
separately in order to find out the conditions under which they become
stimulated to activity in the normal process of digestion. The secretion
of each gland has a definite role assigned to it in the complex and lengthy
process of digestion. It takes up its work where the preceding secre-
tion left off; e.g., the pepsin of gastric juice digests protein so far as
proteoses and peptone ; the trypsin of pancreatic juice then attacks the
proteoses and peptone, and the resulting loAver degradation products
are finally attacked by the erepsin of the intestinal juice. The secre-
tions of the various glands are, therefore, required in a certain definite
order — they are correlated; and we must now give some attention to the
precise conditions upon which the activity and correlation depend.

THE NORMAL CONDITIONS UNDER WHICH THE GLANDS
BECOME STIMULATED TO INCREASED ACTIVITY

To make possible such observations on the normal activities of the
glands, a preliminary operation has to be performed so as to bring the
duct of the gland to the surface of the body and permit of the observa-
tion of its secretory activity after the animal has recovered from the
immediate effects of the operation. We owe to Pavlov1 the surgical
technic by which these conditions can be fulfilled. The general principle
of the operation, in the case of glands provided with ducts, consists in
making a circular cut through the mucous membrane surrounding the
opening of the duct and then, after dissecting the duct free, stitching
the edges of the cut to the skin wound. Healing then takes place without
the formation in the duct of any stricture .due to cicatricial tissue. After
the wound has healed, the secretion can readily be collected in a receiver
attached over the duct fistula, the animal being in every other way in a
perfectly normal condition. In the case of glands not provided with a
duct, other methods must be adopted to collect the secretions. These
Avill be described elsewhere.

430

rin RIOLOm OF i ii 111

THE NORMAL SECRETION OF SALIVA

The duel fistula can in this case he made either for tin- submaxillary
gland, representing a mucous gland, <>r for the parotid, representing
serous gland. Under ordinary conditions their i tion

from either duet. When secretion occurs, 'u is, of course, caused by
influences acting mi a nerve center or centers in the medulla oblo
the exact location of which for the different glands has been worked nut
in recent years by Miller.'' The impulses acting on ii nay be

transmitted along afferent nerves coming from the mucous membrane

'he mouth, nares, etc., or by impulses which we may call psychic, trans-
mitted from tlie higher nerve centers. The refle: caused by
impulses traveling by the afferenl nerve from the moutl have b<
called unconditioned, and those from the higher nerve centei
Honed. With regard to the former, there is considerable discriminal
in the type of stimulus that will he effective. Thus, if the dog for i
of the experiments have been performed on this animal given m
a secretion of thick, mucous saliva will lie observed I ur submaxil-
lary gland . <>n the other hand, if the meat is dried and pulverized,
the secretion which it calls forth will he very copious and watery par-
otid gland). There is, then, an obvious association between the nature
of the secretion and the function it will he called upon to perform when
it becomes mixed with the food. The muc< sretion called forth by
meal will serve to Lubricate the bolus of food and thus facilil
swallowing, whereas the thin watery secretion produced by the dry
powder will have the effed of washing the powder from the mouth.

It is evident that the mechanical condition of tl 1 partly •

mines its exciting quality. .Mechanical stimulation of the mucosa in it-
self is. however, not an adequate stimulus, for if pebbh i in
the mouth, little secretion occurs, whereas with sand 'ion imm<
ately becomes copious. The nerve endings also respond t.. chemical stimuli.
Thus, weak acid causes a copious secretion, while alkali h

disagreeable, nauseous substanc< 'tion. The above dif-

ferences in the response of the glands according to the mechanii idi-

tion of the food lias been observed in the .-.is,- of the parotid gland,
increase in tin- submaxillary secretion being obtained only win

f lstulTs are placed in the mouth.

The investigations that have been made on the condil hie

secretion ..I' saliva are still more inten s and im] ir im-
portance depends not so much on the information tin • rn-
ing the secretion of saliva as such, as on the m

investigating the various conditions thai

432 DIGESTION

associated with the taking of food. Jt is from the psychic rather than
from the physiologic standpoint, therefore, that these observations are
of importance, for they permit us, by objective methods, to study on
dumb animals problems that would otherwise be beyond our powers of
investigation. Many of the results, with their bearing on the functions
of the higher nerve centers, have been discussed elsewhere (Chapt. XCVII).
Meanwhile, however, even at the risk of repetition it may not be out of
place to cite a few of the most interesting experiments.

If we tease a hungry animal with food for which he has a great appe-
tite, a copious secretion of saliva immediately occurs. If we go on teas-
ing him without giving him food, and repeat this procedure on several
succeeding days, it will be found that gradually he no longer responds
to the teasing by increased salivation. Evidently, therefore, the reflex
is conditioned upon the animal's afterward receiving the food.

The experiment may be performed in another way. If, for example,
we offer the animal some food for which he has no appetite, no secre-
tion of saliva will occur; but, if at the end of the process we give him
appetizing food, it will be found after repeating this procedure on
several successive days that the presentation of the unappetizing food
calls forth a secretion. He has learned to associate the presentation of
unappetizing food with the subsequent gratification of his appetite. The
experiment can even be performed so that a definite interval of time
elapses between the application of the stimulus and the salivation: if
the animal is teased on successive days with food for which he has an
appetite but is not given the food until after ten or twenty minutes,
presentation of this food will come to be followed by salivation — not
immediately, but after the exact interval of time that had been allowed
to intervene in the training process. During this interval there must be
an inhibition of psychic stimulation of the salivary centers by other nerve
centers. It is of great interest that this inhibition may itself be inhib-
ited by various forms of stimulation of the nervous system (see page 858).

THE SECRETION OF GASTRIC JUICE

Methods of Investigation

There being no common duct, the secretion of the gastric glands is a
much more difficult problem to investigate than is that of glands which,
like the salivary, are supplied with ducts. One of the most interesting
chapters in the history of physiology concerns the methods which from
time to time have been evolved for the collection of this juice and for
studying the digestive processes in the stomach. Prominent among the
problems confronting the earlier investigators was the question whether

PHYSIOLOGY "i i 111 DIG] 3TTV1 01

the main function of the stomach is to crush or triturate t. :■ to

act on it chemically. Ti t French sciential Reaumur and a little

later the Italian Abbe* Spallanzani L729-179 icked this problem by

methods that anticipate those of Rehfuss and Einhorn. Spallanzani ulti-
mately devised the method of swallowing small perforated wooden tu
containing foodstuffs and covered by small linen bags. After the i
were passed per rectum, he found that considerab iion or digestion

of the food had occurred, bul that the wooden tubes, h< r thin-

walled they might be, were qo1 crushed. In order to secure sam]
the gastric juice free from fund, the only method available to the older
investigators consisted in swallowing sponges attached to threads, which
after being for some time in the Stomach were withdrawn and
dry of juice.

The next great contribution came from this country, where, In 18
\)v. Beaumont, while a surgeon in the service of the American troops
located at Mackinaw, made observations on a Canadian voyageur by the

name of Alexis St. Martin, who by the premature disci gun

had wounded himself in the stomach, the wound never healing but le
ing a permanent gastric fistula. Beaumont arranged to keep Alexis Si
Martin in his service for several years, during which time he made
numerous observations on the process of digestion in tl h —

observations many of which are of great value oven at the pr< lay.

By none of these methods, however, could a sample of pUT trie

juice be secured while the digestive process was actually in pi
To make the collection of such a sample possible, Eeidenhain devised a
method of isolating portions of the stomach wall as pouc pening

through fistula on the abdominal wall. The results of Heidenhain'a
experiments are, however open to the objection that the I ion in

the isolated pouches may not really correspond to thi irring in

main stomach, s'n the connections of the pouches with tl

nervous system must have been Si In order that tl

tions might remain as nearly intact as possible, the Russian ph;
Pavlov,1 devised an ingenious operation in which the pouch, or "minia-
ture stomach," remains coi n< cted with the main stomach tl

siderable width of mUCOUS and submucous tissue and in which tl

connections arc not severed. Th< ntial nature <<( tl

will be evident from the accompanying diagram. Fig 148

The most leeent i u \ est i ga 1 ions have been made DJ I
Carlson.'' The former fed animals food impregnated with bismuth sub-
nitrate. and then exposed the animal to the JC-rays \ -

produced by the food mass in tl •lach, and from I in the

outline «.f this shadow facts have been collect - the

4:J4

DIGESTION

movements of the viseus, but also concerning the rate of discharge of
food into the intestine and therefore the duration of the gastric digestive
process. Carlson's contribution has been rendered possible by his good
fortune in having in his service a second Alexis St. Martin, a man with
complete closure of the esophagus and a gastric fistula large enough to
permit of direct inspection of the interior of the stomach. Seizing the
opportunity thus presented, Carlson during the last four or five years
has devoted his attention exclusively to a thorough investigation, not
only of the movements of the stomach, but also of the rate of secretion
of the gastric juice under different conditions. He has also, with praise-
worthy enthusiasm and keen scientific spirit, extended his observations
both on laboratory animals and on himself and his coworkers, so as not

A**

Fig. 148. — Diagram of stomach showing miniature stomach (5) separated from the main stomach
(V) by a double layer of mucous membrane. A. A., is the opening of the pouch on the abdominal
wall. (Pavlov.)

to incur the error, which is all too frequently made, of confining the
observations to one species of animal.

The Nervous Element in Gastric Secretion

The first stimulus to the secretion of gastric juice is nervous in origin,
and is dependent on the gratification of the appetite and the pleasure of
taking food. This fact, after having been suggested by observations
made in the clinic, was first thoroughly investigated by Pavlov, who for
1li is purpose observed the gastric secretion flowing either from a fistula
of the stomach itself, or from a "miniature stomach," in dogs in which
also an esophageal fistula had been established. AYhen food was given
by month to these animals, it was chewed and swallowed in the usual
manner, but before reaching the stomach, it escaped through the esopha-

PHI 8101 OOS OF Till DIG! BTH I '.l \

I fistula. This experimenl ia known as thai

Within a £ev» minutes after <_ri\in«_: food the gastric juia ind t..
be secreted actively, and if the Eeedii • was kepi ap, which ••• >ul< 1

be done almost indefinitely since 1 1 1 * - animal never became ed, the

secretion continued to flow. Thus, in one instance l'a\ 1 in

collecting about 700 c.c. of gastric juice after Bham feeding an animal
for five or six hours in the manner abovi

After the stomach has emptied itself of thi en with tin- p

vious meal, it is said by Pavlov to contain only a little alkali
The more recenl \\ ork of < larlson, how ever, shov» s that this i
the case, there being more or less of a continuous secretioi

in the entire absence of E 1. The amount varies Erom

60 c.c. per hour, more secretion being produced when it is collei
five or icn minutes than it' it is collected every thirty thus

indicating that, ordinarily, some escapes through the pylorus ii I
duodenum. The secretion contains both pepsin and hydrochli
As to the cause of this continuous secretion, little is known [1 i
an example of the periodic activities of the digestive glai
Boldyreff, or it may in part be due to a psychic stimulation dep<
upon the thought of food. That the latter is probably not the cans.-. is
indicated by the fact that, at least in Carlson's patient, the psychic
could not be made to flow short of giving £ 1.

The sham feeding causes stimulation of the gastric tion tl

impulses transmitted to the stomach along the vagus nervt

n found, in animals in which the vagus nerve has I.. •. that the

sham feeding no longer induces a Becretion rtric juice l

tion therefore arises as to how the nerve cent stimulated. I

possible causes may be considered: 1 mechanical stimulation
sensory nerves of the mouth; 2 chemical stimulation of these nen
(3) the agreeable stimulation of the taste buds and

concerned in the tasting of f 1. In investigating th<

mechanical stimulation was readily ruled oul by Bhowing thai
taking of solid matter in the mouth did nol excite anj
it might cause a flov» of saliva. .Mere chemical stimulation could
the cause, for no secretion was induced by placing sub

acetic acid or mustard oil in the mouth. B tlusion, then, it would

appeal- that the adequate stimulus mui sist in th.

tion of the taste buds, etc. thai is to Bay, in thi

Further justification for this conclusion was readily
that foodstuffs for which the animal had no p
tite failed to excite the Becretion Mosl dogs, althot

they ma\ lake it, are nol particularly fond I d. and w

4."»(i DIGESTION

it, these annuals did not produce any appetite juice, in one animal that
showed considerable liking for bread, active secretion occurred when he
was fed with this foodstuff.

Pavlov further noted that usually it was not necessary actually to
alloAv the animal to take the food into his mouth, but that mere teasing
with savory food was sufficient to cause the secretion, and that in
highly sensitive animals even the noises and other events usually asso-
ciated with feeding time were sufficient to excite the secretion. In the
case of a hungry animal, the mere approach of the attendant with food,
or some other noise or action definitely associated with feeding time,
was a sufficient excitant. The appetite juice when started was found
to persist for some time after the stimulus causing it had been removed.

Carlson has succeeded in confirming in man most of these observa-
tions. He noted, however, that the secretion produced by seeing or
smelling or thinking of food is much less than would be expected from
Pavlov's observations on dogs. Even when his subject was hungry,
Carlson did not observe that the bringing of a tray of savory food into
the room caused any secretion- of gastric juice. It is, of course, to be
expected that the quantity of the psychic secretion will not be the same
in different individuals. It has been observed by Pavlov, for example,
to vary considerably in the case of dogs, and it is very likely that it will
vary still more in man, with his more highly complicated nervous system.
In no case could Carlson observe any secretion of gastric juice to be pro-
duced by having his patient chew on indifferent substances, or by stim-
ulating the nerve endings in the mouth by substances other than those
directly related to food.

In man the rate of secretion is proportional to the palatability of the
food, the smallest amount, during twenty minutes' mastication of pal-
atable food, being 30 c.c. and the largest 150 c.c, in a series of 156 obser-
vations. A typical curve showing the amount of the secretion is given
in Fig. 149. To construct this curve the gastric juice was collected dur-
ing five-minute intervals while the man was chewing a meal of average
composition and of his own choice. An interesting feature depicted on
this curve is that the secretion rate was highest in the last five-minute
period, this being the time during which the dessert was being taken,
for which this man had a great relish. Quite clearly there was a direct
relation between the rate of the secretion of the appetite juice and the
palatability of the food. It will further be observed that it took only
from fifteen to twenty minutes after discontinuing the chewing before
the juice returned to its original level.

The practical application of these facts in connection with the hygiene

PHYSIOLOGY 01 in.

Hi' diet and the feeding <ji patients during convi

very great. Bowever perfect in othi it will

probably fail to be digested at the propi a with

relish. Frequenl feeding with favorite n

Lowed by thorough digestion and assimilation thi

with larger amounts. \\ too in th<

of the well-established praeti f starting a meal with mu'

savory. A hors d'oeuvn is nothing more than a pi

to appetite. It is also interesting from a practical standpoint I

that with those who have a keen relish for - eel m< a1 s * '

sert has a real physiologic significance, for, as in Carle t, it

stimulates toward the end of a meal a furl

:

■ •

JO

DO

)^

«

«S

»3

Chewing food

Fig. 149. — -Typical cur\<
tication of palatable food for 20 minutes. The rise in »ecrel

mastication is doe t" chewing

Carlson.)

juice, and thus insures a more rapid digestion of the f 1 i ■•

it should be remembered, is really the t' and h

the only stage over which we can exercise voluntarj >1,

The Hormone Element in Gastric Secretion

Although gastric digestion is initiated by the a]
clear that this alone can not accounl

during the time the f 1 is in the stomach. \

occupies usually about four hours, whereas w< rly

from Carlson's observations, that the ap]

fifteen or twenty minutes after the exciting stimu

The appetite juice, in oth<

retion, and the quest ion ariw b, u
the resi t Tl

438 DIGESTION

observed animals in which not only a miniature stomach had been made,
but a fistula into the main stomach as well. The .behavior of the secre-
tion of gastric juice as a whole could be followed by collecting that
which was secreted in the miniature stomach, for it was shown, in con-
trol experiments, that this secretion runs strictly parallel with that in
the main stomach, being quantitatively a definite fraction of it — accord-
ing to the relative size of the miniature stomach — and qualitatively
identical. The miniature stomach, in other words, mirrors the events
of secretion in the main stomach.

It was observed that when the animal was allowed to take the food
into the main stomach by the mouth and esophagus, the secretion from
the miniature stomach continued to flow until the process of gastric
digestion had been completed, a result which was quite different from
that obtained after sham feeding. The only possible explanation for this
result is that the food in the stomach sets up secretion as a result of
local stimulation. To investigate the nature of this local stimulation,
Avhether mechanical or chemical, food and other substances were placed
in the main stomach through the gastric fistula without the animal's
knowledge so as to avoid possible psychic stimulation, and the secretion
observed from the miniature stomach. When the mucous membrane of
the main stomach was stimulated mechanically, as by placing inert
objects such as a piece of sponge or sand in the stomach, no secretion
occurred. Evidently, therefore, the stimulus is dependent upon some
chemical quality of the food.

By introducing various foods it was found that there is considerable
difference in the degree to which they can excite the secretion. "Water,
egg white, bread and starch, were all found to have very little if any
effect. On the other hand, when protein thai had been partly digested
by means of pepsin and hydrochloric acid was introduced into the
stomach, it immediately called forth a secretion. The conclusion is that
the partly digested products, even of insipid food, are capable of directly
exciting the secretion. These include proteoses and peptones, and it
was, therefore, of great interest to find that a solution of commercial
peptone is also an effective stimulus. This is a result of deep significance,
for it indicates that the food which has been partially digested by the
appetite juice will serve as a stimulus to continued secretion.

The psychic juice has been aptly called the "ignition juice," because
by producing partial digestion it serves to ignite the process of gastric
secretion. Experimental evidenee of its great importance in gastric
digestion was secured by Pavlov in experiments in which he placed
weighed quantities of meat attached to threads in the stomaeh through
;i gastric fistula, and after some time removed them and determined by

PHYSIOLOGY OF Till. DIG] BTn I '.I

the difference in weights the extenl to which they had become digested.
It was found thai when tin- appetite juice .ham feeding

;|i the same time that £ 1 was placed directly in the Btomach, its di|

tion was much more rapid than in discs in which it was placed in the

stomach without the animal's knowing, ;is when In- was • p.

Other foods having a direct stimulating effecl on th<
tion are meal extracts an. I, to a certain extent, milk. This effecl of d
extract is Interesting in connection with the practice of taking sou;,
a first or early stage in dining. It not only excites the appetite j>.
hut also serves as a dired stimulus to the gastric Becretion.

As to the nature of the mechanism /"/ which this </<>
place, it was shown hy Popielski"" that the secretion still occurs r all
the nerves proceeding to the stomach are cut. Evidently, th< e, it

is independent of the extrinsic nerve supply of th< is. A suit

of his experiments Popielski concluded that the Becretion must dep<
on a local reflex mediated through the ner icturea present in tin-

walls of the stomach itself. Another explanation of the result ;
however, in recent years been given more credence by the experimi
Bayliss ami starling on the influence of hormones on the
pancreatic juice (cf. page 425). Bdkins10 suggested that a similar
process in the stomach might account for the continued
gastric juice. To test the possibility this investigator, after ligating the
cardiac sphincter in anesthetized animals, i' I a tube into the

pyloric end of the stomach, through which he placed in the stomach
about 50 c.c. of physiological saline. After this had been in the stomach

for an hour, he found that no water was absorbed, ami that it conl
neither hydrochloric acid nor pepsin, (in the other hand, if during the

time the saline was in the stomach a decoction of the mucous membrane

the pyloric end. made cither with peptone solution or with a BOlul

dextrine, was injected intravenously in small quantil min-

utes, the saline contained distinct quantities of hydrochloric acid and n
sin. Furthermore, it was found that, if the peptone solution or the dextrine
solution alone was injected intravenously, there was no such
of gastric secretion. The conclusion which Bdkins drew from 1
ments is to the effecl that the half-digested products of the earlier
of gastric digestion act on the mucous membrane of the Bton

produce a hormone, which is then carried by the bl(

the LMstric <_dands, upon which, like -in. it directly

exciting effect. This hormone has l.een T

tions of Edkins have been confirmed, and they explain \ nply fa

gastric secretion is maintained after the cessation of the the

440

DIGESTION

appetite juice.10 By such a mechanism gastric juice would continue to be
secreted so long as any half-digested food remains in the stomach.

The action of gastrin is the first instance of a hormone control of the
digestive glands. In the earlier stages of digestion, the secretion of saliva
and appetite juice is mediated through the nervous system, because these
juices must be produced promptly. In the later stages of gastric diges-
tion, such promptitude in response on the part of the gland is no longer
necessary, so that the slower, more continuous process of hormone con-
trol is sufficient.

Quantity of Gastric Juice Secreted

According to Carlson, the total amount of gastric juice secreted in
man on an average meal composed of meat, bread, vegetables, coffee or

Hours
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Flesh. 200 gm.

Bread, 200 gm.

Milk, 600 c.c.

Fig. 150. — Cubic centimeters of gastric juice secreted after diets of meat, bread, and milk. (From

Pavlov.)

milk, and dessert, amounts to about 700 c.c, being divided into 200 c.c.
in the first hour, 150 in the second, and 350 c.c. during the third, fourth
and fifth hours. These figures were estimated partly on the basis of
observations made on the man with the gastric fistula, and partly from
the data supplied by Pavlov's observations on dogs. Carlson believes
that Pavlov overestimated the relative importance of the appetite juice
in gastric digestion. He found, for example, that after division of both
vagus nerves in dogs normal gastric digestion might be regained a few
days after the operation, although, of course, under such circumstances no
appetite juice could have been secreted. Moreover, he observed that cats
when forcibly fed with unpalatable food may digest that food as rapidly
as when they eat voluntarily. In support of his contention, Carlson
states that he has frequently removed all of the appetite juice from his
patient's stomach before the masticated meal was put into it without
any evident interference with the digestive process.

Fat has a distinct inhibiting influence on the direct secretion of gas-

PHYSIOLOGY OP 1 BE DIi

HI

trie juice; cream takes considerably long* be be than milk.

and the presence of oil in the stomach delays the

out on a subsequent meal of otherwise readily digestible t I B

lectin- all of the gastric juice from the miniature Btomach i

by mouth with quantities <>!' differenl protein-rich Eoodi

same quantities of nitrogen, interesting observations have be< p

<•« > 1 1 .-( ii i i 11 *j: the amounl of juice Becreted ami its proteolytic power. '1 I

results of some of the experiments are Bhown in the accompanying

curves (Figs. 150 and 151).

It will bo seen that the mosl abundai etion occurs with meat. t;

mi' milk being not only smaller but also slower in starting Tl •
power is greatesl in the ease of bread.

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Flesh, 200 gm.

. !, 200 gm.

Milk. 600 c.c.

Fig, 151. — Digestive power of the juice, as measured by the length of the rrotei-

in Mett's tubes, with diets of flesh, bread, and milk. (From Pavb .

THE INTESTINAL SECRETIONS

Pancreatic Juice

Regarding the natural secretion of pancreatic juice, litth
to what has already been said see page 125 Tl tion begins when the

chyme enters the duodenum, and attains its maximum when the outfl
of this is greatest. By collecting the juice from a permanent fistula of the
pancreatic duct, it has been found thai the amount varies witl

\ Is. When quantities of food containing equivalei I

gen are fed, the greatest secretion is said t cur with bread and the '

with milk. Such difference 8 are probably d< t opo unt of

acid Becreted in the Btomach and passed on into the duodenum,
thoughl at one time that, besides variation in qi

enzymes in the pancreatic juice mighl \a>- • kind of

food. This, however, has been shown

442

DIGESTION

Bile

The secretion of bile runs practically parallel with that of pancreatic
juice. The liver is producing bile more or less continuously, since besides
being a digestive fluid it is also an excretory product. The bile produced
between the periods of digestion is mainly stored in the gall bladder.
When the acid chyme comes in contact with the duodenal mucous mem-
brane, it excites afferent nerve endings that cause a reflex contraction of
the gall bladder, and this expresses some of the bile into the duodenum.
The secretin, which the acid at the same time produces, besides affecting
the pancreas, acts on the liver cells, stimulating them to the increased
secretion of bile. Thus, by a nervous reflex operating on the gall bladder
and later by a hormone mechanism operating on the liver cell, the increased
secretion of bile is insured throughout digestion. Of the bile discharged
into the intestine, a certain proportion of the bile salts is reabsorbed into
the portal blood. When these arrive at the liver they also excite secre-
tion of bile, thus assisting secretin in maintaining the secretion through-
out the process of intestinal digestion.

Fig. 152. — Loop of intestine after tying off the portions, cutting the nerves running to the middle
portion, and returning the loop to the abdomen for some lime. (From Jackson.)

Intestinal Juice

The secretion of intestinal juice, or succus entericus, can obviously be
studied only after isolating portions of the intestine and connecting them
with fistula? of the abdominal walls. It appears here again that both a
nervous and a hormone mechanism exist. Mechanical stimulation of the
intestinal mucous membrane causes an immediate outflow of intestinal
juice, the purpose of Avhich under normal conditions is evidently to assist
in moving forward the bowel contents. This mechanically excited juice
• lues not contain any enterokinase and only small amounts of the other
enzymes. Further evidence for nervous control of the secretion of intes-
tinal juice has been obtained by isolating three pouches of intestine be-

PHI 3101 '».'i 01 i in DIG] STIVE GLAV 1 13

tween Ligatures, and then denervating the central pouch illy

cutting all the nerves withoul wounding the blood turning

the pouches to the abdomen and Leaving them j, it ha

found thai the middle pouch becomes distended with secretion, v
the two end pouches remain emptj Pig. 152 . if the pouc
several days in the abdomen, however, il i i tion from the d< ted

portion disappears again. The explanation of the resull is possibly that
the nerves under ordinary conditions convey impulse tinal

glands, which tonically inhibit their activity.

The existence of hormone control is evidenced bj tl
enterokinase is presenl in the intestinal juice unless pancreatic juic<
placed in contact with the mucous membrane, [njection "i' pan
juice into the blood, however, does qo1 cause any Becretion of intestinal
juice; whereas the injection of secretin 1ms such an eff<

CHAPTER LI
THE MECHANISMS OF DIGESTION

MASTICATION. DEGLUTITION, VOMITING

Mastication

By the movements of the lower jaw on the upper, the two rows of
teeth come together so as to serve for biting or crushing the food. The
resulting comminution of the food forms the first step in digestion. The
up and down motion of the lower jaw results in biting by the incisors,
and after the mouthful has been taken, the side to side movements enable
the grinding teeth to crush and break it up into fragments of the proper
size for swallowing. The most suitable size of the mouthful is about
5 c.c, but this varies greatly with habit. After mastication, the mass
weighs from 3.2 to 6.5 gm., about one-fourth of this weight being due to
saliva. The food is now a semifluid mush containing particles which
are usually less than 2 mm. in diameter. Some, however, may measure
7 or even 12 mm.

Determination of the proper degree of fineness of the food is a func-
tion of the tongue, gums, and cheeks, for which purpose the mucous
membrane covering them is supplied with very sensitive touch nerve
endings (see page 794). The sensitiveness of the tongue, etc., in this
regard explains why an object which can scarcely be felt by the fingers
seems to be quite large in the mouth. If some particles of food that are
too large for swallowing happen to be carried backward in the mouth,
the tongue returns them for further mastication.

The saliva assists in mastication in several ways: (1) by dissolving
some of the food constituents; (2) by partly digesting some of the
starch; (3) by softening the mass of food so that it is more readily
erushed; (4) by covering the bolus with mucus so as to make it more
readily transferable from place to place. The secretion of saliva is
therefore stimulated by the chewing movements, and its composition
varies according to the nature of the food (page 431). In some animals,
such as the cat and dog, mastication is unimportant, coating of the food with
saliva being the only change which it undergoes in the mouth. In man
the ability thus to bolt the food can readily be acquired, not, however,
without some detriment to 1 lie efficiency of digestion as a whole. Soft

444

THE Ml 'H INISMS 01 DIQ1 SI [( 1 1".

starchy food is little chewed, the Length of time required for the mastica-
tion of other foods depending mainly on their nature, but also to a
certain degree on the appetite and on the size of the mouthful.

It can not be too strongly insisted upon thai the mastication is

of far more importance than merely t<> break up and pi
for swallowing. It causes the food to I"' moved about in the moutl
to develop its full effed on the last.' buds; the crushing
odors which stimulate the olfactory epithelium, On tl timuli dep<

the satisfaction and pleasure of eating, which in turn initiate
of gastric digestion see page 135 .

The benefit to digestion as a whole of a large secretion of saliva, brought
about by persistenl chewing, has been assumed by some to be much
greater than it really is, and there has existed, and indeed may still
exist, a school of faddists who, by deliberately chewing far beyond
the necessary time, imagine themselves to thrive better on 1< '1 than

those who occupy their time with more profitable pursuits.

Deglutition or Swallowing
After being masticated tho fond is polled up into a bolus by the action

of the tongue againsl the palate, and after being lubricated by saliva is

moved, by elevation of the front of the tongue, towards the back of the
mouth. This constitutes the first stag< of swallowing, and far, a

voluntary act. About this time a slight inspiratory contraction of the
diaphragm occurs — the so-called respiration of swallowing a
mylohyoid quickly contracts, with the consequence that the bolus pat
between the pillars of the fauces. This marks the beginning of the
second stage, the first event of which is that the bolus, by stimulating
sensory nerve endings, acts on nerve centers situated in the medulla

oblongata bo as to cause a i rdinated seri< movemei I

muscles of the pharynx and larynx and an inhibition for a moment
the respiratory center paj
The movements alter the shape of the pharynx and of the varii
nings into ii in such a manner i the bolus

into the esophagus Fig. 153 thus, I) th< palate b<

elevated and the posterior wall of the pharynx bulges forr
shut off the posterior nares, 2 the posterior pillars
proximate so as to shut on* the mouth cavit:

a second after the mylohyoid ; ted, the laryi : up-

wards and forwards under the root of the toi nrhich

drawn backwards becomes bai ked up 'he la- Phis

pulling up <>f the larynx brings the opening int.
half of the dorsal side of the i piglottis, but the U] tl - -•rue-

in;

DIGESTION

lure projects beyond and serves as a ledge to guide the bolus safely past
this critical part of its course. (4) As a further safeguard against any
entry of food into the air passages, the laryngeal opening is narrowed by
approximation of the true and the false vocal cords.

So far the force which propels the bolus is mainly the contraction of
the mylohyoid, assisted by llie movements of the root of the tongue.
When it has readied the lower end of the pharynx, however, the bolus
readily falls into the esophagus, which has become dilated on account
of a reflex inhibition of the constrictor muscles of its upper end. This so-
called second stage of swallowing is, therefore, a complex coordinated
movement initiated by afferent stimuli and involving reciprocal action
of various groups of muscles: inhibition of the respiratory muscles and

Fig. 153.- — The changes which take place in the position of the root of the tongue, the soft
palate, the epiglottis and the larynx during the second stage of swallowing. The thick dotted line
indicates the position during swallowing.

of those that constrict the esophagus, and stimulation of those that
elevate the palate, the root of the tongue, and the larynx. It is purely
an involuntary process.

The third stage of deglutition consists in the passage of the swallowed
food along the esophagus. The mechanism by which this is done de-
pends very much on the physical consistence of the food. A solid bolus
that more or less fills the esophagus excites a typical peristaltic wave,
which is characterized by a dilatation of the esophagus immediately in
front of and a constriction over and behind the bolus. This wave travels
down the esophagus in man at such a rate that it reaches the cardiac
sphincter in about five or six seconds. On arriving here the cardiac

THE MM ll \\ .|.,i - i i } }7

sphincter, ordinarily contracted, relaxes for a momei hat th<

passes into the stomach. In many animals, including man and tl
the peristaltic wave travels much more rapidly in the upper part of the
esophagus than lower down because of differences in the nature of the
muscular coat, this being of the striated variety above, and of th<
striated below. The purpose of more rapid movement in the upp<
is no doubl thai the bolus may be hurried past the rej . by

distending the esophagus, it mighl interfere with the function of
boring structures, such as the heart. In other animi the dog, th<

muscular fiber is striated all along the esophagus, and the boh
correspondingly travels at a uniform, quick rate all the way. [1 I
only about four seconds for the bolus to reach tl Lach in the dog.

The peristaltic wave of the upper part of the esophagus in the cat a
presumably in man. unlike thai of the intestines see ■•■■-
mittcd by the esophageal branches of the vagus I •

severed, but the muscular coats left intact, the esophagus becomes dih
above -the level of the section and contracted below, and no peristaltic
wave can pass along it; on the other hand, the muscular

ered (by crushing, etc.) but t he peristaltic wave will conth
travel, provided no damage lias Pen done to the nerv<

Tn the lower part of the esophagus, however, the wave of peristals
like that of the intestines, travels independently of extrinsic -
This has been observed in animals in which all of the extrinsic
have been cu1 some time previously. This differei en the up]

and the lower portions is ated with the difference in the na1

the muscular fibers above noted i Meltzer)."

The propagation of ihe wave by the nerves in the upper part of

esophagus indicates thai the se id stage and the first part of the third

stage of deglutition must be r< sed, as it were, in the medullary
centers from which arise the nerve li: the pharynx and the np

levels of the esophagus. It is thoughl that the dischai "om t;

local centers are controlled by a higher swallowing tuated in

medulla just above that of respiration, the afferent stimuli ■ Inch

pr ied from the pharynx by the fifth, superior lar;

nerves. The exad location of thi ory areas wl timulation is

most effective in initiating the swallowing reflex \

in different animals. in man it is probably at tl

pharynx; in the dog it is on the posterior wall. A t body

directly in the upper portion of the esophagus ••

to remain stationary until the individual made llowing

The afferent fibers in th< -■••'d ii' ful

inhibitory influence on the deglutition •

448 DIGESTION

tion. Thus, if swallowing movements are excited by stimulating the cen-
tral end of the superior laryngeal nerve, they can be instantly, inhibited
by simultaneously stimulating, the glossopharyngeal, and the respiratory
movements stop in whatever position they may have been at the time.
When the glossopharyngeal nerves are cut, the esophagus enters into a
condition of tonic contraction, which may last a day or so. This shows
that the inhibitory impulses are tonic in nature.

This inhibition of the esophagus is indeed a most important part of
the process when liquid or scmiliquid food is swallowed. By the contrac-
tion of the mylohyoid muscle, fluids are quickly shot down the distended
esophagus, at the lower end of which, on account of the closure of the
cardiac sphincter, they accumulate until the arrival of the peristaltic
Avave which has meanwhile been set up by stimulation of the pharynx.
If the swallowing is immediately repeated, as is usually the case in
drinking, the esophagus remains dilated because peristalsis is inhibited,
and the fluid lies outside the cardiac orifice until the last mouthful has
been taken.

The Cardiac Sphincter

The passage between the esophagus and the stomach is guarded by
the cardiac sphincter or cardia. This exists in a permanently con-
tracted state, or tonus, superimposed on which from time to time are
rhythmic alternations of contraction and relaxation. This tonus is never
very pronounced. In man it is said that a water pressure of from 2 to 7
cm. applied to the esophageal side of the sphincter will drive air or
"water into the stomach, this pressure being less than that of a column
of fluid filling the thoracic esophagus in the erect position. During
repeated deglutition the tonus becomes less and less marked, and after
a number of swallows the sphincter may become completely relaxed.
When this relaxation disappears, however, the sphincter becomes more
contracted than usual and remains so for a longer time.

The tonic condition of the sphincter is controlled by the vagus nerve,
stimulation of which causes relaxation with an after-effect of strong
contraction. Mechanical or chemical stimulation of the lower end of the
esophagus increases the tonus of the sphincter. Forcing of the sphincter
from the stomach side requires a higher pressure than from the esopha-
geal. Eructation of gas, for example, does not take place until intra-
gastric pressure has risen to about 25 cm. of water. In deep anesthesia,
however, intragastric pressure may rise considerably higher without
forcing the sphincter.

In animals fed with starch paste impregnated with subnitrate of bis-
muth and then examined by means of the x-rays, the variation in degree

THE Ml .1 II \\'l-\l- i.i :>i'.

of tone of the sphincter has been observed to be responsible I nal

regurgitation of sonu of tl" gastric contents into the esopl
level of the hearl or even to the base of the neck Tl e pr<
gastric contents in the esophagus starts a peristaltic \ vhich ;

the material back again into the stomach. This p

in the absei if any other phases of the deglutition pro

thai ii has been excited by the presence of the material in tl
itself, and belongs, therefore, to the lower order of peristaltic
seen in the intestines bul nol in the upper half of the esophag R gur-
gitation iif food into the esophagus occurs only when the ii ' trie
pressure is fairly high. It maj last for a period of from twenty to th
minutes after the meal is taken, and disappears when the tonus
sphincter becomes increased as a resull of the presence in tl trie
contents of free hydrochloric acid.

Much information lias been secured by listening with a stethi i to
the sun mis caused by swallowing and by observing with the x-n
shadows produced along the course of the esophagus when food imp
nated with bismuth subnitrate is taken. When a solid bolus al-

lowed only one sound is usually heard, hut with liquid food th<
two, one al the upper end, due to the rush of the fluid and air, and
the other at the lower end (heard over the epigastrium . four or six
seconds later, due to the arrival lure of the peristaltic wave with the
accompanying opening of the cardiac sphincter and tl •
fluid and air into the stomach. Sometimes, when the person is in
horizontal position, this second sound may be broken up inti eral,
indicating that, unassisted by gravity, the fluid does no1 so readily p
through the sphincter. The x-ray shadows yield results in conformity
with the above. After Bwallowing milk and bismuth, i mple, the

shadow falls quickly to the lower end of the esophagus and then pas
slowly into the stomach. When the passage of a solid bolus is
by the x-ray method, its rate of descent will he found to depend

whether "i- not it is well lubricated with saliva: if not so, it in.

long as fifteen minutes to reach the stomach; if moist, bul
to eighteen seconds.

Vomitiin;

Vomiting is usually preceded by a feeling of sickni
is initialed h> a very active secretion of saliva. The . mixed with

air. accumulates to a considerable extent at the I"

gUS, which it distends. A forced inspiration is now made, during the

tirst stage of which the glottis is op. thai tl i

bul later the glottis closes so thai the inspired aii the

450 DIGESTION

esophagus, which, already somewhat distended by saliva, now becomes
markedly so. The abdominal muscles then contract so as to compress
the stomach against the diaphragm and, simultaneously, the cardiac
sphincter relaxes, the head is held forward and the contents of the
stomach are ejected through the previously distended esophagus. The
compression of the stomach by the contracting abdominal muscles is
assisted by an actual contraction of the stomach itself, as has been clearly
demonstrated by the x-ray method. After the contents of the stomach
itself have been evacuated, the pyloric sphincter may also relax and
permit the contents (bile, etc.) of the duodenum to be vomited.

The act of vomiting is controlled by a center located in the medulla,
and the afferent fibers to this center may come from many different
regions of the body. Perhaps the most potent of them come from the
sensory nerve endings of the fauces and pharynx. This explains the
tendency to vomit when the mucosa of this region is mechanically stimu-
lated. Other afferent impulses come from the mucosa of the stomach
itself, and these are stimulated by emetics, important among which are
strong salt solution, mustard water and zinc sulphate. Certain other
emetics, particularly tartar emetic and apomorphine, act on the vomit-
ing center itself, and can therefore operate when given subcutaneously.
Afferent vomiting impulses also arise from the abdominal viscera, thus
explaining the vomiting which occurs in strangulated hernia, and in
other irritative lesions involving this region. X-ray observations have
been made on the movements of the stomach of cats after the admin-
istration of apomorphine (Cannon). The first change observed is an
inhibition of the cardiac end of the stomach, which becomes a perfectly
flaccid bag. About the midregion of the organ, deeper contractions then
start up, which sweep towards the pylorus, each contraction stopping as a
deep ring at the beginning of the vestibule, while a slighter wave con-
tinues. A very strong contraction at the incisura angularis finally
develops and completely divides the gastric cavity into two parts. On
the left of this constriction the stomach remains completely relaxed, but
at the right of it waves continue running over the vestibule. It is while
the stomach is in this condition that the sudden contraction of the dia-
phragm and abdominal muscles shoots the cardiac contents into the
relaxed esophagus. As these jerky contractions are continued, the gastric
walls seem to reacquire their tone.

CHAPTER I. II
THE MECHANISMS OF BSTION Cont'd)

THE MOVEMENTS OF THE STOMACH

The Character of the Movements

Even from the earliest days it has been recognized that the stomach
performs two important functions: (1) receiving the swallowed fi
and then discharging it slowly into the intestine, and -J initiating the
chemical processes of digestion. In order to understand the mechanism

by which the stomach collects and then discharges the food, it is n»-
sary first of all to recall certain anatomic facts concerning tin- org
and for this purpose it is most convenient to accept the description
given by Cannon, which is illustrated in the accompanying figure. The
oriran is divided into a cardiac and a pyloric portion by a deep notch in
the Lesser curvature, called the incisura angularis. The cardial- porl
is further subdivided into two by the cardiac orifice. The part which
lies, in man. above a line drawn horizontally through the cardia is I
fundus. The part lying between the fundus and the incisura angularis
is known as the body of the stomach, which, when full, has a ta]
shape. The pyloric portion Lying on the right of the incisura angul
is further divided into two parts: the pyloric vestibule and the pyl<
• •anal, the latter of which lies next the pyloric sphincter and in man
measures about 3 em. in Length see Pig. 154 .
The filled stomach of a person standing erect is so disposed that I
atest curvature forms its lowest point, which may be Lerably

below the umbilicus. An digestion proceeds and the stomach empl

the greater curvature becomes gradually raised, so that ultimately the
pylorus comes to be the most dependent part of ti mach. From

these and many other observations it is certain that the emptying
Stomach does not at all depend on the operation of the ■ ity.

Indeed, that this can not be the case IS perfectly clear when Wt

sider the disposition of the stomach in quadrupeds.
Exact observation on the movements which the Btomacl

the time it is tilled with food till it empties, ha

x-ray method, firsl introduced by Cannon." The metl

i.v-

DIGESTION

ing the animal with food thai has been impregnated with bismuth sub-
nitrate, then exposing him to the x-ray and either taking instantaneous
photographs of the shadows or observing them by means of a fluorescent
screen. The descriptions of the original observations made by Cannon

Fig. 154. — Schematic outline of tin stomach. At C is the cardia; /■'. fundus; IA, incisura an-
nularis; U. body; PC, pyloric canal; P, pylorus. (From Cannon.)

on the stomach of the cat have been so little modified by observations
on man that we may take them as a convenient type. In the accompany-
ing figure (Fig. 156) the outline of the shadow cast by the stomach is
shown at intervals of an hour each during digestion. Soon after the

A U

Fig. 155. — Diagrams of outline and position of stomach as indicated by skiagrams taken on

man in the erect position al intervals after swallowing food impregnated with bismuth subnitrate.

A, moderately full; B, practically empty. The clear space at the upper end of the stomach is due

to gas, and it will he noticed that this " tomach bladder" lies close to tin heart. (From '1'. Win-

Todd.)

Till. All CIIAN1SM.S <i| Dli

stomach has become filled, peristaltic t.. lake tl

origin aboul the middle of the bod) of the stomach, and I
towards the pylorus. Above the region al which thesi
thai is, the cardiac half of the bod) of the stomach and all
fundus- there are no waves, bul as digestion proc iwly

and steadily contrad on the mass of food. Thi lied cardiac pouch

does not, however, diminish in size bo rapidly a> the : the bod)

the stomach over which the peristaltic wav< passing ilar

fibers of the walls of this pari of the stomach sometimes called the
gastric tube contrad tonically, bo thai it becomes tubular in form,
with the full cardiac pouch al the lefl and abi loric p

of the 'l

it with i I in

tion al the right. The latter portion meanwhile does not diminish much
in size, although the peristaltic waves travelii
nounced. As will be clear from the figure, thi n outl

on until the cardiac pouch has become practically empty and th<
has been all moved along the now tubular portion of the bod)
pyloric vestibu

Prom this description it is evidenl thai the (u-
end is to serve as a reservoir for the food, which,
of the walls, is gradually delivered into the gastric t
peristalsis it is carried towards the pyloi

The time required for the peristaltic v
of origin to the pylorus is considerably h

454 DIGESTION

the waves, so that several of these are always seen on the stomach at
the same time. They sometimes become so pronounced in the pyloric
region, especially in a half-empty stomach, that they appear almost to
obliterate the cavity. They always stop at the pylorus, never going on
to the duodenum. The rate of recurrence of the waves varies somewhat
in different animals, being about six per minute in the cat and about
three in man. Their initiation does not seem to depend on the presence
of acid in the gastric contents, for, when food is introduced into the
stomach, they do not wait for the gastric contents to become acid in
reaction (see page 482). Nevertheless, acid does seem somewhat to stim-
ulate the depth and frequency of the waves, and they recur oftener with
carbohydrate than with fatty food.

The pressure in the stomach contents — the intragastric pressure — is
low and constant at the cardiac end and fairly high and variable in the
pyloric end (in the former from 6 to 8 cm. of water, and in the latter
from 20 to 30). Constancy of pressure in the cardiac end indicates
that the stomach wall must adapt itself very promptly to the amount of
food in the organ. The higher and more variable pressure in the pyloric
end is, of course, due to the peristaltic waves, and it is interesting to note
that it is sufficient to propel the gastric contents through the pylorus for
several centimeters into the duodenum.

The Effect of the Stomach Movements on the Food

This has been studied: (1) by dividing the food into portions that
are differently colored and, after some time, killing the animal, freezing
the stomach and making sections of it (see Fig. 157) ; (2) by mak-
ing little pellets of bismuth subnitrate with starch and observing their
behavior under the x-rays; or (3) by removing samples of the stomach
contents by means of a stomach tube (Rehfuss tube) inserted so that
its free end lies in either the cardiac or the pyloric region. By the
first of the above methods it has been found that the first mouthfuls
of food lie along the greater curvature, where they form a layer over
which that subsequently swallowed accumulates, with the last por-
tions next the cardia. The pepsin and hydrochloric acid of the car-
diac end. therefore, act soonest on the first swallowed portion of a
meal, and the more recently swallowed central masses are not affected
by the secretions for some time, so that opportunity is given for the
saliva mixed with the food to develop its digestive action.

As has been shown by removing the stomach contents with a tube at
various periods after feeding with starchy food, considerable amylolysis
may occur for some time. "When separate samples are removed in this
way from the eardiae and pyloric parts, it has been found that after

THE ICECHANI8HE OP DIG! 455

half an hour the contents of both have about the Bame percentage of
sugar, but thai for Borne time after this interval the cardiac conto
contain considerably more BUgar than the pyloric. Later the percentfl

of sugar again become aboul equal, qo doubl on a ant of diffusion.

The diastatic action in the fundus is finally brought to an «ii«l when
the contents become completely permeated by the hydrochL "id.

In this connection it is worthy of note that the addition of hydrochloric
acid up to the point of neutrality greatly accelerates the rate of diasti
digestion.

As the outer layers of food in the stomach become partly digested

account of the action of the pepsin and hydrochloric acid, the f 1 is

slowly pressed into the active right half of the stomach, \
action of the peristaltic waves it is moved on to the pyloric vestibule.
By observing the x-ray shadows east by two pellets of bismuth subni-
trate it has been noted by Cannon that, as the peristaltic wave appr

Fig. 157. — Section of the frozen stomach (rat) some time after* feeding wit:. . ven in three

differently colored portions. (From Howell's Physiology.)

a pellet, it causes it to move forward more rapidly tor a Bhort distal
but soon overtakes it and in doing bo causes the pellet to move back ji

little towards the fundus. This backward movement is less than the
forward movement, so that after the wave has passed, the position

the pellet is a little forward of that which it would ha. ipied bad

there been llo wave. The behavior of the pellet, and. the:'' ' the

stomach contents, is very like that of a cork floating at the edge of the
sea; as each wave approaches, it hurries the cork on a little, but aft

its passage the cork re les again until the Becond wave carries it still

a little farther forward. As the peristaltic wave approaches the pyl
vestibule and becomes more powerful its effect on the pellets becomes

more marked. They are carried rapidly along this part of tin eh.

Until the pylorus is reached. If this remain^ dosed, thej

into the vestibule. From nine to twelve minutes may elapse tx they

are transferred to the pylorus from the place where tl •

by the peristaltic wa1

l.")i; DIGESTION

These observations made on cats and other laboratory animals no
doubt also apply in the case of man. Removal of the contents of the
cardiac and pyloric regions separately with a stomach tube after feeding
with a tesl meal pari of which was colored with carmine or charcoal,
has shown thai none of Ihc coloring material was present in the contents
of the pyloric end np to twenty minutes or so after the food had been
taken. It then appeared but at firsl only in 1 races. Another important
distinction between Hie food in the two portions of the stomach relates
to its consistency. In the pyloric end it is semifluid and homogeneous
in character; in the cardiac end, on the oilier hand, it is a lumpy, rather
Incoherent mass.

The gastric movements must greatly facilitate the digestive processes
in the stomach. In the cardiac part the undisturbed condition of the
food will, as we have seen, facilitate the digestive action of ptyalin,
whereas in the body of the stomach the peristaltic waves, besides mov-
ing the food onward, will tend to bring fresh portions of mucous mem-
brane and food in contact, so that the latter becomes more thoroughly
mixed with the pepsin and hydrochloric acid. In the pyloric part, where
no hydrochloric acid is secreted, the contents, already sufficiently acid
in reaction, become more thoroughly churned up with the local pepsin
secretion, so that proteolytic action progresses very rapidly.

The peristaltic waves also facilitate absorption from the stomach of such
substances as glucose in concentrated solution and, probably, of hydro-
lyzed protein; water, however, is not absorbed. One effect of such
adsorption is the production of gastrin, which we have seen is the hor-
mone concerned in maintaining the gastric secretion after the psychic
flow. The fact that the mucosa of the vestibule has. relatively to the
cardiac end, few secreting glands is in harmony with the view that
absorption is an important function of this part of the stomach.

THE EMPTYING OF THE STOMACH

The Control of the Pyloric Sphincter

When digestion has proceeded far enough in the stomach to bring the
food into a homogeneous, souplike fluid (chyme), portions of this, as they
are driven againsl the pyloric sphincter by the peristaltic waves, instead of
being returned as an axial stream into the stomach, are ejected into the
duodenum.

We niiisl now consider the mechanism by which the pyloric sphincter
opens to permit ihe passage of the chyme. Bombardment by Ihc peri-
staltic waves is evidently no1 the cause of its opening, for, as we have

THE MECHANISMS l }"»7

scrii, many such waves may arrive al it without tl

evidently in order thai the intestine may not Buddenl

whelmed with large masses of food thai the pylo ally

opens, it mighl be thoughl thai its opening dep<

tion of the upper pari of the intestine. It is true tl

tion of the upper pari of the intestine does liol.l the pyloric sphinc

closed, lmt this can not be the physiological stimulus, I

quantities of chyme are never found here.

The first clue to the real nature of the mechanism i by

observing the behavior of the sphincter when solutions are intn
into the duodenum through a fistula. Acid solutio
cause a e plete inhibition of gastric evacuation, wh< alkaline solu-

tions ha<l no effect. This difference indie :ids in cl with

the duodenal mucous membrane reflexly excite contraction of the Bphi
ter, and thai it relaxes only after the acid has b
by mixing with the pancreatic juice and bile.

On account of the greal importance of the pyloric mechanism in insur-
ing thai the chyme shall enter the intestine only in such quantities thai
it can be properly acted upon by the intestinal digesting juic< will

be of interest to consider briefly some of the experimental observati
by which this mechanism has been studied. W< ma the

evidence thai acid on tht stomach sid( of thi pylorus causes a
of tin sphincter: 1 When carbohydrate food is fed, it ordinarily
the stomach fairly rapidly, bul it' its acid-absorbing po
l>y mixing it with sodium bicarbonate, exit from the stomach atly

delayed. 2 Proteins ordinarily leave the stomach m< than

carbohydrates, bu1 it' acid proteins are fed, their • - much m

rapid. (3 If a fistula is made into the pyloric vestibule through wl
some of the tents can be removed, ii will be found that

the opening of the pyloric sphincter, a distinctly acid r<

in the f 1: and furthermore if acid solutio

fistula, they cau^e the pyloric sphincter to open, -

its opening. 1 A similar effect of acid in 0]

be demonstrated bj applying it to the pyloric mucosa o
stomach kept alive in oxygenated R

Tl vidence thai acid on 0

sphincter is as follows: 1 When acid is placed in I
a fistula, the sphincter will not open ; 2 V
ducts are ligated, the stomach empties much m<
and !n' discharge of protein is considcrabl

is sutured to the intestine belov the cl lenum. N

tion it was obsen cd that i he protein

458 DIGESTION

the pyloric sphincter about the same time as normally, but the subse-
quent evacuation was very much accelerated, because no acid came in
contact with the duodenal mucosa. Water and egg white may leave
the stomach independently of any acid reflex control of the pylorus. By
observations made through a duodenal fistula it has been found that,
after a quantity of water has been swallowed, most if not all of it very
soon enters the duodenum in a more or less continuous stream. It is no
doubt on this account that drinking contaminated water is especially
dangerous on an empty stomach.

The nervous pathway through which these acid reflexes take place has
been shown to be the myenteric plexus. Indeed, the whole mechanism
is quite analogous with that which Ave shall see occurs in the intestine
during peristalsis : the stimulus, that is, the acid, causes a contraction
of the gastric tube behind it and a dilatation in front.

Fig. 158. — Outlines of shadows in abdomen obtained by exposure to x-rays 2 hours after
feeding with food containing bismuth subnitrate. The food in A was lean beef, and in B boiled
rice. The smaller size of the stomach shadow and the much greater total area of the intestinal
shadows in B than in A show that carbohydrate leaves the stomach earlier than protein. (From
Cannon.)

Rate of Emptying- of Stomach

The relationship of these facts to the rate at which different foodstuffs
leave the stomach is very readily explained. The method for investigat-
ing this problem, which again we owe to Cannon, consists in feeding ani-
mals with a strictly uniform amount of different foods made up, as
nearly as possible, of equal consistency and containing bismuth subni-
trate in the proportion of 5 gm. to each 25 c.c. By feeding such mix-
tures to cats previously starved for twenty-four hours, and examining
the abdomen by the x-ray at regular intervals, the shadows cast by the food
after passage into the intestine can be outlined on tracing paper, and
the total length* measured (Fig. 158). In taking this as an estimate of
the amount of food in the intestine, several errors are no doubt incurred

'This is permissible since the shadows are practically all of the same width.

THE Ml I 11 \\l- \l- OF l»I(il sTION

on account of the crossing and foreshortening of the loops, etc., I \
their constancy testifies, there is no doubt thai the resnll atly

close for the purpose of finding oul how quickly
small intestine; and the method lias a greal advant •

in thai digestion is allowed to pr sed practically without interruption.

The points we have to determine are: 1 I when the food ti
stomach; (2) the rate a1 which differenl foods are dischar
time required for the passage through the small intestii

Let us consider firsl of all the results obtained I oith pr

tically pure fat or carbohydraU or protein. By plotting
the shailows in centimeters along the ordinates, with I ■ the

abscissa?, curves such as those shown in Pig. 159 have been
When fats were fed (dash line in charl . the discharge begai
slowly, and continued at a slow rate. Even aft en hour-

still remained in the stomach, and a1 no time was any large quanl I

40

30

8

u
&

<D

.§20

9

a

to

O

10

i

Ss-

* ~ ~

"—■ •

s

f
/

/

*^

m ■*<

^5

4

/>

1

h 1

3 4

Hours

Fig. 159. — Curves to show the average aggregate length of the

intestine at the designated intervals . The I

dash line, f"r protein foods in the heavy li:
I Prom Cannon.)

present iii the intestine, indicating thai almosl as quickly as it is •

charged into this pari of the gastrointestinal tract h

and absorbed. The discharge of carbohydrates was quite differenl

line in charl ) ; it began often in ten minut

reaching a maximum, as a rule, at the end of two hours

fell off, the stomach being empty in aboul three hour- P

rate intermediate between that for fats and tl I

heavy line . Little lefl before the firsl half hour; the
slowly rose, attaining a maximum in about tour 1
ally declining at aboul the Bame rat II is

that at the end of half an hour aboul eighl tin much c

had left the stomach as protein; at tl i ei d o!

These results are clearl) dependent up lif-

t'ereiit foodstuffs assume an acid reaction in the stomach I irbohyd

4G0 DIGESTION

has no combining power For acids, so that the acid secreted with the
psychic juice remains uncombined and on gaining t he pyloric vestibule
excites the opening of the sphincter. Protein, on the other hand, as is
■well known, absorbs considerable quantities of free hydrochloric acid,
so that for some considerable time after it is taken, none of the acid exists
in a free state. Fats owe their slow discharge partly to inhibition of
gastric secret ion, and partly to the Longer time it lakes for Ihem to become
neutralized in the duodenum, because of the fatty acid split off by the
action of lipase.

Interesting observations have also been made on the rate of discharge
when various combinations of foodstuffs were fed. This has been done
by feeding one foodstuff before the other, or by mixing the foodstuffs.
When carbohydrates were fed first and then protein, the discharge be-
gan much earlier than with protein alone, because the carbohydrate food
first reached the pyloric vestibule (see page 454). However, at the end
of two hours, when the carbohydrate curve should begin to come down,
it remained high, indicating that the protein had by this time reached
the pylorus and Avas being discharged at its own rate. When the meat
was fed before the carbohydrate, the curve to start with was exactly
like that for protein, becoming, however, considerably heightened later
when the carbohydrate reached the pyloric vestibule. The presence of
protein near the pylorus, therefore, distinctly retards the evacuation of
'carbohydrate from the stomach. These facts, it will be remarked, all
tit in admirably with the observations which we have already detailed
concerning the disposition of food in the stomach.

When mixtures of equal parts of different foods were fed, the results
indicated that the emptying of the stomach occurred at a rate which
was intermediate between those of the foods taken separately. Mixing
protein with carbohydrate, for example, accelerated the rate at which
protein left, and mixing fats with protein caused the protein to leave
the stomach considerably more slowly than if protein alone had

been U'(\.

Influence of Pathologic Conditions on the Emptying

An important surgieal application of these facts concerns the behavior
of food after gastroenterostomy. It has been thought that this operation
would cause the fund to be drained from the stomach into the intestine
and thus leave the region of the stomach between the fistula and 1he
pylorus inactive. This assumption is based on the idea, which avc have
seen to be erroneous, thai gravity assists in the emptying of the stomach.
As a matter of fact, it has been found thai, if the gastroenterostomy is
made when there is no obstruction at the pylorus, the chyme takes its

Tin \ir i ii wi- m.

normal passage through the sphincter and,

none leaves bj the fistula. When the pylo - parti

food sometimes passes in the usual way, and sometimes by I

The cause for this predilection for the pyloric pathv

pressure conditions in the gastric contents G

fore, is efficient only when gross mechanical obstruction i

pylorus. The operation should never be performed in

demonstrable organic pyloric disease.

Another objection to gastroenterostomy in the p
pyloric sphincter rests on the fad that the food, after pae
ter and moving along the intestine, may again enter the stomach through
the fistula. This is most likely to occur when the stomach is full
food, for under these conditions the stretching of its walls s<
edges of the opening, the intestine being drawn taut bel
so thai the opening between the stomach and the inti
form of two narrow slits, which act like valves permitting 11 I to

enter bu1 preventing its escape from the stomach. Only seldom un<
these circumstances can any food pass into the inl beyo

stomach opening. Repeated vomiting after gastroent ny has

observed in experimental animals only when obstructive kink- ther

demonstrable obstacles were present in the Lrut. the obstruction being h>-
cated in thai pari of the intestine beyond its attachment to the stomach.

When the pyloric obstruction is complete, food n
by the fistula, digestion by the pancreatic juice and I > i 1 « - being still c
ried on because of the fad that for a considerable distance down
intestine, secretin, which we have seen is ess< tial for the tion

of these fluids, is still produced by the contact of the acid chyme with
the intestinal mucosa. Further provision for adequate dig'
food in such cases is secured, as some of the food after leavii
fistula passes back for a certain distance into the duodenum, \\ i
it sim. n excites peristaltic waves, which again carry it i

insures thorough mixing with the digestive ju
menial experience Cannon and Bla ommend that, when the

fistula has to be made, it should be as l;ii\

pylorus, and that the stomach afterwards should i

become filled with f 1. To avoid kinkii >m>

mend thai several centinx »f the intestine should

stomach distal to the anastomo?

The elTeet of h fl }>< niciil "it \J of the route!'. the

Stomach has 1 n studied l>\ fei animals with I

varying percentages of hydrochloric acid. With

4ti2 DIGESTION

cent, the rate of discharge was increased, bu1 it became slower when the
acidity rose to 1 per cent. With an acidity of 0.5 per cent, the rate of
discharge was about the normal. Hyperacidity, therefore, causes a retar-
dation of the emptying of the stomach.

The consistency of the food appears to have little influence on its rate of
discharge from the stomach — at least in the case of potatoes. Dilution
of protein food, however, increases the rate. Distinctly hard particles
in the food retard the stomach evacuation.

There is usually a considerable amount of gas in the part of the stomach
above the entrance of the cardia, on account of which this part of the
stomach has sometimes been called the stomach bladder. In the upright
position this gas forms a bright area in the x-ray plate (Fig. 155), but
when the person reclines it spreads to a new location. Its presence may
influence gastric digestion by preventing the contact of the food with
the mucous membrane, and by interfering with the efficiency of the peri-
staltic waves in moving the food. Considerable gas therefore retards the
emptying of the stomach, as has been shown experimentally by x-ray
observations on animals fed with the standard amount of food followed
by the introduction of air. It was noted that the air did not diminish
the frequency or strength of the peristaltic waves, but that these could
not efficiently act on the food. When along with gas there is also atony
of the stomach walls, the retardation in the discharge will, of course, be
still more pronounced. The temperature of the swallowed food does
not appear to have much influence on the stomach movements or on the
the rate of discharge from the organ.

CHAPTER I. Ill
THE MECHANISMS OF DIGESTION Coi t'd

THE MOVEMENTS OF THE INTESTINES

The length of the small intestine and the size of the cecum •
large intestine vary considerably in differenl animal-. In r
such as the cat, the small intestine is relatively short; in tl
relatively long. Thus, it is three times the Length of the body in tl
and four to six times in the dog; whereas in the goal and -
be nearly thirty times the Length of the body. In the carnivora
cecum is either absent or rudimentary, whereas in those herbivora wh
do not have a divided stomach the cecum is very Large an
as is also the colon. The reason for the greal size in h< hat

practically the whole of the digestion of cellulose takes place in this
part of the gut. This digestion, as we shall see

on any secretion poured forth by the animal itself, but upon I ion

of bacteria and of certain enzymes (cytt 3ea thai are taken with the
vegetable food.

Movement of the Small Intestine

The movements of the small intestine have been studied 1 the

bismuth subnitrate and x-ray method, _ by observing them after
ing the abdomen of an animal subm< rged in a bath of physio'.. Jine

at body temperature, (3) by observing the changes in pr<
in a thin-walled rubber balloon i i in the lumen

connected with a recording tambour Pig. L60 . and 4 bj

portions of the intestine and keeping them alive in a bath of Balin(

tion at body temperature, through which oxygen is m.

The Si o mi nti no Mo1

When a suitably fed animal is placed OH the hold,
by the x-ray method, no movement in the intestinal b! illy

observed tor some time. The firsl movement to ap]

one of the columns of food into small BegUN

Each of these segments again quickly divid<

halves suddenly unite to Eorm oev - in, in ■ nuu

m

DIGESTION

which will be made clear by consulting Fig. 161. This rhythmic scg-
mentation, as Camion lias called it, continues without cessalion for more
than half an hour, and the food shadow does not meanwhile seem to change
it s position in the abdomen to any extent. The splitting up of the seg-
ment and the rushing together of the neighboring halves proceed as a
rule with great rapidity; thus, if we counl the number of different se.^-

Elasric rubber
band to attach
finqer cot to
'cdtfiekr

IfiO. — Apparatus fur recording contractions of the intestine. (From Jackson.)

meiits during a definite period, we may find the rate of division in the
eat to he as high as 28 or 30 a minute. In man the divisions occur at a
frequency of approximately 10 per minute, which corresponds to the fre-
quency with which sounds can lie heard when the abdomen is auscultated.
Although half an hour is the period which this process usually oc-
cupies, ii may last considerably Longer. In certain animals, such as the
rabbit, segmenting movements have not been observed, hul instead

Tin: mi - ii INISMS 01 DI(

• if them a rhythmic to-and Pro shifting of the ma* •«! along the

Lumen of the gut, rapidly repeated for man; minut

When the intestines are floated oul in a warm bath • solution,

it is Been thai the rhythmic segmentation i narrow ri

contraction. Under such conditions also it is often noted that
loops i>f intestine sway from side to Bide The balloon method a
veals the presence of slighl waves of contraction thai pass rapidly all
the gut, and follow each other al the rate of twel . |>'-r min

Both i>t' tlic muscular coats of the intestine are involved, and it i-> b<
thai the contractions are responsible nol only for the pendular m<
Hunts but for the rhythmic segmentation observed by tl • y method.

Aecording to this view these movements ai stantly p

the intestine, and become exaggerated by the mechanical Btimulus which
is offered by the masses of food to such an extenl thai they divide the
masses into portions. The evidence for this belief rests on the fad thai

;fdoc569b°bc

Fig. 161. — Diagrammatic representation of i in the inl An

unbroken shadow is shown in / and its segmentation in .'. The < 1> >t i c-. 1 I
slinw the position of division and in J is -
column together. U'roni Cannon.)

when tin1 contraction is studied by the balloon method, it becomes mar
over the middle of the balloon, where the greatest tension i \ sts
Several functions can be assigned to these movements. Ti

intimate mixture of the £ 1 with the digestive juices, and by bring

ever new portions of food in contacl with the m they

absorption. They also have an importanl massaging influen >n

blood and lymph in the vessels of the intestinal walls I
Bage of lymph from the lacteals into the m< c lymphat

depend very largely upon these movemei

Tli: I'l RI8TA1 TIC MOVI MEN1

Tl ther movemenl observed in the small intestine is thai

peristaltic wave. It occurs in two forms: I ely ad '>n-

traction I 1 to 2 cm. per minute , p d by an inhibiti dls.

and proceeding only through a short distance in a and

466

DIGESTION

(2) as a swift movement called the peristaltic rusli, which sweeps with-
out pause for much longer distances along the canal.

Further analysis of the peristaltic wave can readily be made by the
balloon method (Fig. 162). If the gut is pinched above the balloon, a
marked relaxation occurs over the latter, and this relation extends for about
two feet down the intestine. If, on the other hand, the gut is pinched
a little below the situation of the balloon, a long-continued contraction
occurs over the latter. The conclusion that we may draw from this result
is that the stimulation of the gut causes contraction above the point of
the stimulus and relaxation below, this being known as "the law of the
intestine" — (Bayliss and Starling). We have seen that it applies also in
the case of the cardiac and pyloric sphincters.

Fig. 162. — Intestinal contractions (balloon method) after excision of the abdominal ganglia and
section of both vagi. Mechanical stimulation above (/) and below (.?) the balloon causes relaxa-
tion and contraction respectively. (From Starling.)

The Physiologic Nature of the Rhythmic and Peristaltic Movements

Interesting information in this connection has been gained by obser-
vation of the behavior of the movements after the application of drugs
to the gut or after cutting the nerve supply. The rhythmic movements
are not affected by the application of nicotine or cocaine. Since these
drugs paralyze nervous structures it has been concluded that the rhythmic
movements are myogenic in origin. The question is not a settled one,
however, for it has been found by Magnus that, although strips of the
longitudinal muscle, isolated in oxygenated saline solution, will continue
to beat, they do not do so if the adherent Auerbach's plexus of nerves
is stripped off from them. The nature of the peristaltic contractions is
more definite ; they must clearly depend upon a local nervous struc-
ture, since they are paralyzed by the application to the gut of cocaine or
nicotine. This local nervous system no doubt also resides in Auerbach's
plexus, which must therefore be considered as complex enough to be (see

i III MECHANIC M OP DIG! 81 [I

page 7%; endowed with the power of directing nervous imp

bring about relaxation of the gul in front of the stimulus and conti

tion over it.

Nervous < Iontbol of Movemi -

The influence of the central aervous system on the intestinal movenu
has been studied by the usual methods of cutting ;in<l stimulating the
extrinsic nerve supply. Through the splanchnic nen
impulses are conveyed to the intestine i :cep1 the ileocolic Bphincfc
for after these nerves are Bevered the movements become more distil
[ndeed, in many animals after opening the abdomen no intestinal mo
inent can be observed until these nerves have been cut. stimulation of the
peripheral end of the nerve also inhibits any movement which n
while be in progress. The impulses through the vagus nei

Fig 1 3 Th of excitation of both splanchnic in

Starling.)

opposite character. Section of these nerves has little stimula-

tion causes contraction. | Pigs. 163 ami 164.

By observing the rhythmh ntractions of an isolated strip all

intestine suspended in a bath of oxygenated saline BOlutioD at body tem-
perature, it can readily- be shown that the presence of even a mimn

of epinephrine is sufficient to produce complete inhibition of tl
The parallelism between the effects of splanchnic stimulation and t;
epinephrine injection is very significant, for in this way the marked inhi-
bition of intestinal movemenl which occurs during fright may poasiblj
be explained I Bee page 7 :

The circular muscular coat of the last two Or tfw
the ileum before it joins the cecum is definitely thicker than the ■
this coat, indicating thai it has a sphincter-like action. This .
sphincter, as it is called, opens when food i» pressed against it from the
ileum, but remains closed w hen food is pressed against it from the cecum.

His

DIGESTION

It therefore obeys the law of the intestine. That it is physiologically
distinct from the musculature of the rest of the ileum is indicated by the
fact that the splanchnic and vagus nerves do not affect it in the same
way; thus, stimulation of the splanchnic causes a strong contraction of
the sphincter, whereas it is unaffected by stimulation of the vagus.

Peristalsis is much more rapid in the duodenum than in other parts of
the small intestine. During the first stages of digestion, the food ordi-
narily lies mainly in the right half of the abdomen, and later in the left
half. There is considerable variation in the time that elapses before it
enters the colon. In the cat, carbohydrates reach this part of the gut in
about four hours.

Fig. 164. — The effect of stimulation of right vagus nerve on the intestinal contractions. (From

Starling.)

Movements of the Large Intestine

On account of the great differences which we have already seen to
exist in the size and relative importance of the colon as a digestive organ
in different classes of animals, it is not surprising that the movements
observed are very different according to the dietetic habits of the animal.
Apparently the movements are much the same in the cat as in man. As
the food passes through the ileocolic sphincter into the cecum and
accumulates there, it gradually sets up, by its pressure, a contraction of
the muscular vails of the gut somewhere about the junction between
the ascending and transverse colon. This -wave of contraction then
begins 1»> travel slowly toward the cecum, -without, however, being pre-
ceded by any relaxation of the wall of the gut, as is the case with a true

I III MECHANISMS OF IHUI sTION

peristaltic wave. This first wave is bood followed by othi
result that the food ifl forced up into the cecum, againsl the blii
of which it is crowded, being meanwhile | from passing into

the ileum by the operation of the ileocolic Bphincter and l>y the obli
manner in which the ileum opens into the cecum.

As the result of the distention of tl scum Bet up by tl led

antiperistaltic waves, a true coordinated peristaltic wav< tonally

initiated, and passes along the ascending colon preceded by the usual
wave of inhibition. These waves, however, disappear 1" ach

the end of the colon, so that the food is again driven back by the

Fig. !i of time it taki

of tin- large intestine.

tailed antiperistaltic waves. The effeel of the movements i^ to ki •
and mix the intestinal contents, and thus encourage the absorption

water from them. The resulting more solid portions then collect toward

the splenic flexure, ami become separated from the remaining more fluid
portion by transverse waves of constriction, which develop into p
Btaltic waxes carrying the harder masses into the distal portic the

colon, where they colled chiefly in the sigmoid flexure. Tl liiig

colon itself is aever distended with contents and merelj
for transferring the masses from the trans toid

flexure. The time taken for a capsule of hismuth t.
parts of the large intestine is shown in Pig !>

After a certain mass has collected in the sigmoid I im,

the increasing distention causes an vacua"

470 DIGESTION

gut through centers located in the spinal cord. The impulses from these
centers, besides contracting the rectum, etc., also coordinate the contrac-
tion of the abdominal muscles and the relaxation of the sphincter ani
so as to bring about the act of defecation. By the skiagraphic method it
has been found that the pelvic colon gradually becomes filled with feces
from below upward, and that the rectum remains empty until just before
defecation.

Effect of Clinical Conditions on the Movements

Observations of practical value have been made on the behavior of the
peristaltic wave after various intestinal operations. After an end-to-end
anastomosis of the gut, no evidence can be obtained by the x-ray method
that any hesitation occurs in the movement of the shadows at the anas-
tomosis. On the other hand, when a lateral anastomosis is established,
stagnation of the food in the region of the junction may occur, this
having been found, on opening the gut, to be caused by the accumu-
lation of hair and undigested detritus at the opening between the op-
posed loops. Another objection to lateral anastomosis is the fact that
in performing the operation a considerable amount of the circular muscle
is cut, which interferes with peristaltic activity. Moreover, the end of
the proximal loop beyond the opening is in danger of becoming filled up
with hardened material, and the end of the distal loop may become
invaginated and induce obstruction in the region of the anastomosis.

Observations have also been made by the x-ray method on the be-
havior of the intestinal contents following intestinal obstruction. It has
been observed that, as the material collects in the gut just above the
obstruction, strong peristaltic waves are set up, which move the food
toward the obstruction so powerfully as to cause the walls of the canal
in front to become bulged, until at last the pressure causes the con-
tents to be squirted back through the advancing ring of peristaltic con-
traction. These waves were observed to succeed one another rapidly.
When a portion of gut is reversed in position, the peristaltic waves con-
tinue to travel in their old direction toward the duodenum. The effect of
this is to produce a partial obstruction at the upper end of the re-
versed gut.

The type of peristalsis known as the peristaltic rush can be induced
experimentally in animals by intravenous injection of ergot. It prob-
ably also occurs in conditions of abnormal irritation of the gut in man,
and is believed to be the characteristic activity of the gut after a
stroncr purge.

CHAPTER l. IV

EUNGEB AND APPETITE

Bunger and appetite are distincl and separate sensations, the former
being definitely correlated with contractions of the empty stomach, and I
latter, a complex of sensory impressions integrating in the nervous -
along with memory impressions of the Bight, taste, and smell of palatable
food. Appetite is therefore a highly complex nervous integration, .when
hunger is a much simpler process. It is particularly with hunger that
we shall concern ourselves at present.

When a thin-walled rubber balloon of proper size is placed in I
stomach and connected l»y a rubber tube with a water, bromoform or
chloroform manometer (made of vide irlass tubing 1.5 cm in diami
and provided with a suitable float on the free limb) a tracing may be
taken of the movements of the stomach. For use on man the caps
the balloon should be from 75 to 150 cubic criitini'*. iv | i . thus

obtained when the balloon is placid in the empty stomach rmal

person shows four types of wave. Two of these may be discount
being due to the arterial pulse and the respiratory movemi The

third is known as the tonus rhythm, and is caused by tonic contra
of the fundus of the stomach of varying amplitude. Tl,.- periods of tonus in-
crease during the powerful rhythmic contraction to be immedial
described. While these changes in tone are occurring, do Bubjectr
sation of hunger is experienced. See Pig. 167.

The fourth and most significant typ i - iU of powerful rkytkn

contractions, alternating with periods of quiesc Tl

tions occupy a period of aboul twenty seconds, and

upon the tonus rhythm. They gradually ii • in amplitude

quency; and, in the case of young and vigorou

pass into a condition of incomplete tetanus, aft.r which they nly

subside, leaving only a faint tonus rhythm. These rhythmic eontt

tions are definitely associated with the >f hue

more marked the more intense th< ition. When tetan - lurs

the hunger sensation is continuous, but it instantly
the tetanus gives place to relaxation Whei tl -tractions are com-
paratively feeble, the length of the period during which they occur i*

471

472

DIGESTION

about twelve minutes. When the contractions are powerful, the periods
are always initiated by weaker contractions with long intervening pauses;
finally the pauses disappear and the contractions become more and more
pronounced, often culminating in tetanus, lasting from two to five minutes
The duration of the entire hunger period varies from one-half to one and
a half hours, with an average of from thirty to forty-five minutes, and
the number of individual contractions in a period varies from twenty to
seventy. Between the hunger periods, intervals of from one-half to
two and one-half hours of quiescence may supervene. (See Fig. 168.)

Similar contractions, often passing into incomplete tetanus, have been
observed in the stomach of healthy infants, some of the observations hav-
ing been made before the first nursing. The intervals of motor quies-

Fig. 166. — Diagram of method for recording stomach movements. B, rubber balloon in stomach.
D, kymograph. F, cork float with recording flag. M, manometer. L, manometer fluid (bromo-
form, chloroform, or water). R, rubber tube connecting balloon with manometer. S, stomach.
T, side tube for inflation of stomach balloon. (From Carlson.)

cence between the hunger periods are shorter than in adults. In obser-
vations made during sleep, it was observed that, when the contractions
were very vigorous, the infant would show signs of restlessness and
might awake and cry. As in the adult, the contractions are evidently
associated with subjective sensations of hunger. Contractions of the
empty stomach have also been recorded on a large variety of animals,
including the dog, rabbit, cat, guinea pig, bird, frog and turtle. They
vary somewhat in type in different animals.

With regard to the time of onset of the tonus and hunger contractions,
it has been observed that the only period during which the fundus is
free of them is immediately after a large meal. After a moderate meal
the tonus rhythm begins to appear in about thirty minutes. It gradually

11' NGER \M> Al'1-I.'l :

increases in intensity, until bj the time I mach I

itself the tonus has become conspicuous, ;ni<l the ger hu con-

tractions usually begin to appear. Superimposed upon tho
tonus rhythm, hunger pangs may appear in mi

contains tract 8 of food.

Fig. Id/. — Tracing of the tonus rhythm of th<

Carlson.)

By Btudying the shadow of the outline of the stomach produced by
having a person or animal swallow two balloons, one inside the other
and with a paste of bismuth subnitrate between them, it lias been "1>-
served that the weaker type of hunger contraction begit ••"!!-

168. — Tracings from I

striction involving the cardiac end of the Btoniacl
the pyloric end ;is a rapid peristaltic wave. When tl
very vigorous, this wave spreads •*,. rapidly o\
difficull to determine whether it reall;
or as ;i contraction involving the fund i who

474 DIGESTION

resemble very closely the movements that have sometimes been observed
after a bismuth meal, and -which have been thought by clinical observers
to indicate ;i hyperperistalsis of the stomach. The fundus is therefore
not entirely passive during digestion; for, although early in this act
there may be no evidence of contraction, yet the contractions of the tonus
rhythm may appear and become pronounced before the stomach is en-
tirely empty. In other "words, the digestion contractions of the filled
stomach (see page 45] I pass gradually over into the hunger contractions
of the empty organ.

It appears that the stomach contractions produce the hunger sensa-
tions by causing stimulation of afferent nerve endings in the muscle
layers of the viscus. Mere pressure on the mucosa itself does not originate
such a sensation; thus, sudden distention of the balloon or rubbing the
mucosa with the closed end of a test tube, inserted through a gastric
fistula, was not found to cause any sensation of hunger, unless the stimulus
\v ;.s so strong as to excite a contraction of the musculature of the stomach.

It has been thought by some observers that, during hunger, contrac-
tions similar to those of the stomach also occur in the lower end of the
esophagus. It is believed by Carlson, however, that these contractions
are not at all responsible for the hunger sensation, although they may
give rise to a feeling that something has stuck in the esophagus. Con-
tractions of the intestine have also been observed in hunger, but it is doubt-
ful whether they have anything to do with the cause of the hunger
sensation.

REMOTE EFFECTS OF HUNGER CONTRACTIONS

It is well known that during hunger certain general subjective symp-
toms are likely to be experienced, such as a feeling of weakness and a
sense of emptiness, with a tendency to headache and sometimes even
nausea in persons who are prone to headache as a result of toxemic
conditions. Headache is likely to be more prounced or perhaps present
only in the morning before there is any food in the stomach. These
symptoms indicate that hunger contractions are associated with hyper-
excitability of the central nervous system, and it is of considerable
interest that objective signs of this association can be elicited. If the
knee-jerk be recorded along with a record of the gastric contractions, it
will be found that it is markedly exaggerated simultaneously with the
strong hunger contractions of the empty stomach, this augmentation
being greatest at the height of the stomach contractions, when the hun-
ger pan?s are most intense, and falling off again to normal when these
disappear (Fig. 160V Further changes occurring during the hunger

HUNG] l: AND APPET1T]

475

period include an increase in the pulse rate and vasodilatation B
comparing plethysmography tracings of the arm volume
and stomach contractions, it has been found thai the increase in volume
occurs pari passu with the increasing tonus of the stomach, but that it
begins to shrink before i he stomach contraction has reached its maximum.
Occasionally, however, as in acute hunger, a som< what different rela-
tionship obtains, vasoconstriction being more prominent. During i
hunger contraction there is also increased salivation, the deg
which varies with different individuals. This salivation is indepi

of the more copious "watering of the mouth" thai a mpanies the

thought or sight of appetizing food.

J_

1

\t*hn

itttttnttntmiiutittturtrrr

•xiiJt:ttstt:tttz:ttti:iirttmimtu:tuiiititumiittn

Fig. lo9. — Showing augmentation of the knee-jerk (upper tracing) during the marked hungci

tractions (lower tracing). (From Carlson.)

HUNGER DURING STARVATION

During enforced starvation for long periods of time, it is known
that healthy individuals at fust experience intense sensations of bin
and appetite, which last however only for a few days, then b< less

pronounced and finally almost disappear. It is of inten know the

relationship between these sensations and the hunger contractions in
the stomach. This has been investigated by Carlson and Luckhardt, who
voluntarily subjected themselves to complete starvation, excepl for the
taking of water, for four day- l> ;>; ■_. ;, greal part of this tin >rds

of the stomach contractions were taken by the balloon method, and il
was found that the tonus of the stomach and also the :" '• y and

intensity of the hunger contractions became progressively mon
- starvation proceeded. Towards the end of the period it was also noted
thai incomplete hunger tetanus made its appearance where ordinarily,
as in Carlson's case, this type of hunger contraction was infrequ
Sensations of hunger were present mi throughout tl iod,

being therefore probably due to the persistently ine tonus

onset of a period of hunger

476 DIGESTION

increase in the hunger sensation, and as these contractions became more
marked, the hunger sensations became more intense. On the last day of
starvation a burning sensation referred to the epigastrium was added to
that of hunger. The appetite ran practically parallel with the sensa-
tion of hunger, and both of these sensations became perceptibly dimin-
ished on the fourth or last day of starvation, this diminution being,
however, most marked in the sensation of appetite. Indeed, instead of an
eagerness for food, there developed on the last day a distinct repugnance
or indifference towards it. Accompanying these sensations of hunger
and appetite a distinct mental depression and a feeling of weakness were
experienced during the latter part of the starvation period.

On partaking of food again the hunger and appetite sensations very
rapidly disappeared, and also practically all of the mental depression
and a great part of the feeling of weakness. Complete recovery from
the latter, however, did not take place until the second or third day
after breaking the fast. From this time on both men felt unusually
Avell ; indeed they state that their sense of well-being and clearness of
mind and their sense of good health and vigor were as greatly improved
as they would have been by a month's vacation in the mountains. They
further point out that, since others who have starved for longer periods
of time unanimously attest the fact that, after the first few days, the
sensations of hunger become less pronounced and finally almost dis-
appear, they must have experienced the most distressing period during
their four days of starvation. Although the hunger sensation was
strong enough to cause some discomfort, it could by no means be called
marked pain or suffering, and was at no time of sufficient intensity to
interfere seriously with work. Mere starvation can not therefore be
designated as acute suffering. It is of further interest to note that dur-
ing the starvation period a continuous flow of secretion of acid gastric
juice was found to be occurring in the stomach, to the presence of which
acid or burning sensation experienced iii the epigastrium on the last days
is probably to be attributed.

CONTROL OF THE HUNGER MECHANISM

The control of the hunger mechanism, like that of any other mechan-
ism in the animal body, may be effected through the nervous system or
it may depend on the presence of chemical substances or hormones in
the blood. As a matter of fact, it can readily be shown that both those
methods of control are employed, and we will now consider briefly some
of the facts upon which this conclusion depends.

Although many facts are now known with regard to the nervous con-

Ill V«,l U \\l> MM'I.TITI 177

tro] of the hunger mechanism, il is difficull to piece these together in
such a way as to formulate a simple theory which fits in with all the

observed facts. We know that the stomach p in itself a local

nervous mechanism by which, like the hearl or intestine, ii can auto-
matically perform many of the movements which arc exhibited in the
intact animal. These local movements may, however, he considerably
influenced by impulses transmitted to the stomach along the vagus and

splanchnic nerves. We have therefore to seek for evidence indicating

the relative importance of the local nervous mechanism in the stomach
itself and of the impulses transmitted to this organ by the extrL
nerves. We musl then seek the position of the center which p<
the sensation of hunger.

It will he simplest to consider first the effect of section of the extrii
nerves in observations made on lower animals. Section <>i th< splancl
nerves increases gastric tonus and augments the gastric hunger contrac-
tions. Section of both vagus nerves, performed of course below the L<
of the heart, leaves the stomach in a more or less hypotonic condition.
The tonus is not entirely abolished; it varies somewhal from day 1" day.
and may become quite pronounced even though the vagi are cut. In
this hypotonic state the hunger contractions are diminished in
and regularity. Section of both the splanchnic and vagus nerves throws
the stomach into a permanent hypotonus, except in prolonged starva-
tion, when hunger contractions develop that are usually of great ampli-
tude and with particularly long intervals between the contractii
The genera] conclusion to hi' drawn from these experiments is that,
although completely isolated from the central nervous m, the

stomach still exhibits typical hunger contractions, which must there!
1m- essentially dependent upon an automatic mechanism in the stomach
wall itself. Over this mechanism, extrinsic nerve impulses have merely a
regulatory conl rol.

Variations and Inhibitions of the Hunger Contractions

The afferent stimuli that may set up impulses traveling by the extrin-
sic nerves to the stomach are conveyed by the nei
psychic origin. Stimulation of the gustatory end organs in the mouth,
as by chewing palatable food, always causes an inhibition of the tonus
ami a diminution or disappearance of tin1 hunger contractioi - the

chewing of indifferent substances, Buch as paraffin,

distinct inhibition, unless in a case in winch tl

into a tetanus. It is of interesl that swallowing movements, in the ab-
sence of any food substance in the month, are sufficient to
transitory inhibition of the gastric tonus a receptivi

478 DIGESTION

stomach, as it has been aptly called. The diminution in tonus and
hunger contractions in these various ways is accompanied by a diminu-
tion in the hunger pains.

Afferent nerve stimulation affecting the hunger contractions may also
originate in the stomach mucosa itself, as has been shown in the case of Carl-
son's patient by introducing the various substances to be tested through
a tube into the stomach. A glassful of cold water introduced in this
way inhibits the tonus and the hunger contractions for from three to five
minutes unless these are severe, this inhibition being followed by no
augmentation either of the tonus or of contractions. Ice-cold water has
a greater effect than water at body temperature. This result is some-
what different from that which most men experience as the result of
drinking a glass of cold water.

Weak acids of strengths varying up to that found present in the
gastric juice itself — 0.5 per cent — cause a marked inhibition of the
hunger movements, but this inhibition does not persist until all the acid
has escaped from the stomach or been neutralized, which explains why
hunger contractions should still occur when an acid secretion is present
in the stomach, as in starvation. Normal gastric juice itself produces
an inhibition. which is no doubt dependent upon the acid which it con-
tains, and it is probable that, at the same time that it leads to inhibition
of the hunger contractions, the acid initiates peristalsis of the pyloric
region (see page 453). Weak alkaline solutions have no greater effect on
the hunger contractions than an equal volume of .water. Weak solu-
tions of local anesthetics, such as phenol or chloretone, are without effect.

With regard to alcoholic beverages interesting results were obtained.
AVine, beer, brandy, and diluted pure alcohol inhibit both the tonus and
the contractions. The duration of this inhibition varies directly with the
quantity of the beverage introduced into the stomach and with its alco-
hol percentage. These observations are apparently not in harmony with
the experience of most men that the taking of alcoholic beverages serves
to awaken or increase the appetite, the difference being no doubt due to
the fact that appetite and hunger contractions of the stomach are not
dependent on each other, appetite being, as Ave have seen, a complex
psychic affair, whereas the hunger contractions depend upon a local
mechanism in the stomach Avail itself.

As the inhibition produced in one or other of these Avays passes off,
the hunger contractions are resumed at their previous intensity and not
in an augmented form. From the promptness of the inhibition, it would
appear that the stomach contractions are affected, not reflexly through
the central nervous system or by changes in the chemical composition
of the blood, but by a direct action on the neuromuscular mechanism

BUNGER \\i. x I - * - 1 Tin 479

in the stomach walls, ami it is important to bear in mind that
inhibitory effects on the stomach contractions of tin- fundus may p
quite independently of the changes in the pyloric region that an- c
cerned with the mechanical processes of digestion. After one <>r I
of the extrinsic nerves of the stomach were Bevered in dogs, a certain
degree of inhibition could still he induced by tin- above methods, indie
i » i i_r that, although section of the extrinsic nerves depresses the inhibitory
reflex, it docs not abolish it.

Various mitigations of the hunger contractions have been di
Smoking has this effect, and compression of tin- abdomen by tightening
the belt also inhibits the contractions provided they are not of mar

intensity. Considerable muscular exercise, such as brisk walking or
running, causes inhibition, which usually persists until after the ex
cise is discontinued. When the tonus and contractions return, in this
case, they seem to be somewhat more pronounced. Application of cold
to the surface of the body — as by placing an ice pack on the abdor
or taking ;i cold douche, procedures which are well-known to ind
increased neuromuscular tonus, in general — causes an inhibition of the
gastric tonus and hunger contractions, the degree of which is roughly
proportional to the intensity of the stimulation. There is certainly n<
an increase in the gastric tonus or hunger contractions. I E such stimula-
tion is maintained, the inhibitory effects on the stomach gradually
diminish, even though the individual be shivering intensely.

With regard to fin nervi centers cona nu </ in thest phenomena, little

that is definite is known. The sensory nuclei of the vagus nerve in the
medulla must be considered as the primary hunger center, and through

Ihis center, not only influences affecting the stomach contractions, but
also those associated with the hunger sensations, must be mediated. It
would appear from observations on the hunger behavior of decerebi

animals that there can be UO hunger Center located on the e,:-. lira'

itself, for such animals exhibit practically the same hunger eff<
normal animals. It is interesting to QOte that, at least in tl
decerebrate pigeons, this hunger behavior entirely disapp< in removal

of the optic thalami, where important nerve centers having '<< do with

the bodily responses of the animal to hunger impulses would th<
appear to be located. These observations support the suggestion that

has been made by several QeUTOloglStS that the sense of pain ited

somewhere in the thalamic region.

Concerning the influence of psychic I that in his

own case the hunger contractions became weaker and the inter
between them greater when he was suddenly aw. I during his

fast ami saw two of his friends partaking at his I

480 DIGESTION

porterhouse steak with onions, potatoes, and a tomato salad." These
results are no doubl due to local inhibition dependent upon the psychic
secretion of appetite gastric juice. When no such juice is produced,
the sight and smell of good food does not appear to affect materially
the hunger contractions of the stomach. No doubt it stimulates the
appetite, but that, as we have seen, is a psychic affair.

CHAPTEH l.\
THE BIOCHEMICAL PRO) ESSES OF DIGESTION

In a book designed primarily for clinical workers, it would be ou1
place to enter into details concerning the biochemical proc< taking

place during the digestive process. There is, however, a certain amount
of fundamental knowledge which it is essential thai we should consider.
In the firs1 place it should be borne in mind that in the digestion
carbohydrates and proteins, various intermediate stages are pas
through before the final absorption products are formed. Tin- highly
complex molecule of which protein, fur example, is composed, is I
of all broken down into several smaller bu1 still highly complex mole-
cules, each of which thou undergoes further disruption, until ultimately
the amino a<-ids are se1 free. Certain enzymes, such as trypsin, '-an
carry this process from the beginning through the - of its

course without the assistan f other enzymes, hut in the natural proc-
ess «'f digestion, as it occurs in the gastrointestinal tract, the different
stages of the. disruption arc controlled by different enzymes. One enzj

prepares the f 1 for action by the next. This interdepei the

actions of the enzymes demands that some provision should be made
whereby each enzyme is secreted :;t the proper lime; that is, when the
foodstuff has already been prepared for its action by that of 'in prede-

jor. Thus, it would he useless after food is taken for thi ic and

pancreatic juices t<» he secreted at the same time. Instead, the gastric
juice is secreted first, and the pancreatic only after the food has 1
prepared \'^r its action. This correlation in function we have already
seen to he dependent largely on the action of hormi i

DIGESTION IN THE STOMACH

The gastric juice contains two important digestive agencies 1
enzyme, pepsin, and 2 hydrochloric acid. It is particularly in ju
secreted in the cardiac rw<\ of the stomach that these two subst
found present; towards the pyloric end the hydrochloi
disappears, and the pepsin content 1" distinctly less

181

482 DIGESTION

The Functions of Hydrochloric Acid

The functions of hydrochloric acid may be conveniently divided into
physiological and biochemical. The former functions have to do with
the control of the movements of the stomach, including- the opening
of the pyloric sphincter, and, after the chyme has entered the duodenum,
with the secretion of pancreatic juice and bile. The biochemical functions
are concerned: (1) in assisting the pepsin in the digestion of proteins,
(2) in bringing about a certain amount of inversion of disaceharides,
and (3) in having an antiseptic action on the stomach contents. Re-
garding the last mentioned of these functions, it may be said that the
chyme, as it is ejected from the stomach, is usually sterile, although it
may contain spores and certain bacteria that are protected against the
digestive agencies of the stomach. This protection is afforded by an
outer covering of a chitinous nature (spores), or, as in the case of the
tubercle bacillus, by a covering of waxlike material. It is believed that
persons with strictly normal digestion are much less liable to infection
by such bacteria, as those of typhoid and cholera, than persons with less
active gastric secretion. When the acid of the gastric juice falls below
the level at which it develops an antiseptic action, various bacteria and
yeasts grow in the stomach contents, producing by the resulting fermen-
tation irritating organic acids and gases. It is under these conditions
that yeasts, sarcinag, and lactic and butyric acid bacilli find in the gastric
contents a suitable nidus on which to grow.

The Amount of Acid

It has long been known that considerable variations in the amount of
hydrochloric acid in the gastric juice are associated with symptoms of
indigestion. On this account a more or less elaborate technic has been
developed for the purpose of determining the amount of hydrochloric
acid in the gastric contents.* There are three things in connection with
this activity that Ave may measure: (1) the total titrable hydrochloric
acid; (2) the free hydrochloric acid; and (3) the actual hydrogen-ion
concentration. The determination of the total available acids is made
by titrating a measured quantity of gastric juice against a standard
alkali, using phenolphthalein as an indicator. By this method about
75 c.c. of decinormal alkali solution are required to neutralize 100 c.c.
of normal gastric juice. The determination of the free hydrochloric acid
is made by using special indicators, such as those of Giinzberg and
Topfer, which change color at a hydrogen-ion concentration of about
In (see page 27). To produce this hydrogen-ion concentration, a con-

"The methods can be found in any volume on clinical diagnosis.

Till r. II MICAL PBO( OP DIG1 STION

siderable quantity 0.05 per cenl or more of an organic acid is nee
sary, whereas it requires only a trace of hydrochloric acid. Normal
human gastric juice, when titrated with one of these indicators, gi
a figure which corresponds to aboul 0.03 N hydrochloric acid (see pi

22 . For the accurate determination of the hydrogen-i ioncentration,

it is necessary to use the gas-chain method (see page 29 .

When gastric juice is collected through a fistula from an empty
stomach, very little difference will be found between the free hydro-
chloric acid and the total acid; thai is, between the results obtained by
the sec. .ml and the firsl of the methods described above. This is- because
in such juice there is no organic matter capable of combining with the
hydrochloric acid, and there are no other acids, such as lactic or butyric,
which might l>e produced by fermentative processes The differei
between the two titrations, however, becomes quite marked when pro-
tein food is undergoing digestion in the stomach, because at its different
stages of digestion protein combines with increasing quantities of the
hydrochloric acid. The pathologic condition in which there is most
definitely a diminution of the hydrochloric acid is cancer, either of the
stomach itself or occasionally of some other part of the body. An in-
crease is particularly marked in ulcer of the stomach. A considerable
variation in hydrochloric acid may however be the resull merely of func-
tional (neurotic) conditions.

The Soubce of the Acid

A question that lias puzzled physiologists for many years concerns thr
mechanism l>n which hydrochloric acid is secreted. The percentage of
hydrochloric acid in the gastric juice is considerably above that at which
any animal cells can live, and ye1 this acid is secrete. I by the lining
membrane of the stomach, its source being, of course, the Bodium
chloride of the blood plasma. Bow then do the cells of the gastric
glands bring aboul the separation of this powerful acid from tl

fectly neutral bl 1 plasmal In the first place, it is significant thai the

mucous membrane of the Btomach contains a higher p< of

chlorine than the average of other organs and tissues, indicating that it
has the power "t' abstracting chlorine from the blood. The ei
chlorine in the mucosa must, moreover, he hut a very small fraction of
that actually secreted into the the gastric juice. The chlorine content

of the mucosa of the cardiac end is considerably greater than that of the
pyloric. These facta indicate that chlorine is attracted by the gastric
cells, bui they throw no light on the question as to where the hydro-
chloric acid is really forme, I. Is it in the cells, or only in the hum ■
the gland tubes.' That is to say, is it formed b< after the gastric

[84 DIGESTION

juice lias been secreted Prom the ('('lis0 After intravenous injection of
solutions of potassium Eerrocyanide and some inert salt of iron, such as
one of the scale preparations, examination of the gastric glands has
shown that the prussian blue reaction, which requires the presence of
free mineral acid, is most pronounced in certain of the parietal cells. A
considerable amount of the precipitate is, however, also visible in the
lumen of the glands and in the stomach itself. Certain observers affirm
that, although some of the parietal cells may take the stain, the vast
majority of them do not do so ; and, moreover, that cells incapable of
forming hydrochloric acid (e. g., of the liver) may also become stained,
and that the precipitation may occur in the blood and lymph.

The confusion in the results by these methods prompted A. B. Macal-
lum14 and Miss M. P. Fitzgerald to investigate the distribution of the
chlorine in the cells by a microchemical method, in which the chlorides
were precipitated with silver nitrate and the silver chloride then reduced
by exposing the section to light. It was found that both kinds of gas-
tric-gland cell, chief and parietal, but particularly the parietal, gave the
chloride reaction. Using as a stain a substance (cyaninine) which reacts
blue with acid and red with alkali, Harvey and Bensley,1"' however, aver
that the secretion of the glands is practically neutral until the foveola is
reached, where the stain becomes blue, indicating an acid reaction.
This seems to show that the acid is not really secreted by the cells of
the gastric gland, but is formed after secretion.

According to the latter investigators, the chlorine is secreted by the
cells into the fovea as some weak chloride, such as ammonium chloride,
or it may be as an ester. Shortly after its secretion this weak chloride
undergoes a hydrolytic or other dissociation, during which free hydro-
chloric acid is liberated and ammonia or some other weak base set free.
Of these two products of the reaction the Aveak base is reabsorbed by
the gland cells, but the hydrochloric acid is left behind because the
cells are impervious to it. Indirect evidence in support of this view is
afforded by certain other instances in which hydrochloric acid is pro-
duced by the action of cells; thus, the mold Penicillium glaucum when it
is grown in a medium containing ammonium chloride absorbs the am-
monia but leaves the hydrochloric acid. The high penetrating power
of the ammonia ion in practically all cells, and the fact that the mucosa
of the stomach contains a higher percentage of ammonia than any other
tissue in the body, must also be considered as circumstantial evidence
in favor of this view.

Whatever be the mechanism by which hydrochloric acid is produced,
there is no doubt that the epithelium is impenetrable to it. When the
vitality of the epithelium becomes lowered, as in anemia or after partial

Till BIOCHEMICAL PRO< 185

occlusion of the arteries, the acid may penetrate the • and ca

digestion of the stomach walls. Hyperacidity may <»n this account
become dangerous, as it lowers the resistance of the cell.

Tin digestiiH action of hydrochloric acid is closely linked with thai
pepsin, with which it will, therefore, be considered.

The Action of Pepsin

It is commonlj believed thai before it- tion pepsin twists in the

cells of the gastric glands as zymogen granules. The chief evidei
this belief appears to be thai after considerable activity the amounl
zymogen granules in the gland cells is found to be decidedly dimin-
ished. By such an hypothesis it is easy to explain certain interesting
results concerning the effed of weak alkali on the activities of extri

of the tin us membrane of the stomach. When the mucous membrane

stracted with weak acids, the extract is very acti olytically.

[f this so-called pepsin solution be made faintly alkali) n only

neutralized, and again made acid, it will be found to have lost much,
if not all, of its activity. On the other hand, an aqueous extract ma;
rendered slightly alkaline for a short time and still display its digestive
activity on subsequent acidification. The extract made with water is
therefore much more resistanl toward alkali than that made with weak
acid, and the difference is explained on the supposition that the wal
extract contains pepsinogen, whereas the acid extract contains pepsin.

It is believed that there are several varieties of pepsin, because the
optimum concentration of acid in which pepsin derived from the stomachs

of different animals acts is not always the same. Pepsin of tin' d<
example, acts besl in a hydrogen-ion concentration corresponding to
that .if a 0.05 \. hydrochloric acid solution, whereas thai of the human
stomach works besl at a concentration of 0.03 N D nt pepsin

solutions also show a difference with regard I optimum temp

ture at which the/ act, and with regard to the nature of tl tein

which they most readily attack. Thus, the pepsin of a calf's sti.n.
digests casein very rapidly, hut coagulated e'_"_r white only slowly,
ereas the pepsin of the pig's stomach acts on both these p

ahoiit the same pate.

It is well known that the activity of pepsin can p ly in the

i i ce of acids, hut this action of acids docs not appear to dep<
the hydrogen-ion concentration alo qual quantil the

same pepsin are mixed with quantities of different acids so that the
hydrogen-ion concentration of the mixtures is uniform, it is found that
digestion proceeds mosl rapidly with hydrochloric acid and leasl rapidly
with sulphuric acid. Th( SO 'ems. the unfavorable

486 DIGESTION

for peptic activities. The acid seems to combine with the protein before
the pepsin attacks the latter; for, if we first combine the protein with
acid ami then -wash away all traces of free acid, the protein can be
digested in a neutral pepsin solution without the liberation of any free
acid.

There is evidence to show that pepsin itself also becomes combined
with the protein during the digestive process. If a piece of protein such
as fibrin be immersed in a solution of pepsin and then taken out and
washed thoroughly to get rid of all adherent pepsin, it will be found, on
placing it in ;i hydrochloric acid solution of the proper strength, that
peptic digestion proceeds. Advantage may be taken of this fact to
separate pepsin from a solution, but the best protein to use for this pur-
pose is not fibrin but elastin. By such a method it has, for example,
been shown that there is some pepsin in the intestinal contents, which in-
dicates that when the chyme passes into the intestine, the pepsin is not, as
used to be thought, immediately killed by the proteolytic enzyme.

Products of Peptic Digestion

With regard to the products of gastric digestion, little can be said
here. The first product is a metaprotein known as acid albumin or
syntonin. It is precipitated from the digestion mixture by neutraliza-
tion. The next product is known as primary proteose, being precipi-
tated by half saturation with ammonium sulphate. The third product
is secondary proteose, produced by complete saturation with the above
reagent ; and after all these bodies have been separated out, there re-
mains in solution the fourth product — peptone — which among other
things is characterized by the fact that with the biuret test it gives not
n violet but a rose-pink color.

It has often been claimed that along with these products a certain
amount of free amino acids may also appear in a peptic digestive mix-
ture. This, however, may be due to the action of erepsin, which is
usually present in pepsin preparations. It is important to note that the
term proteose is a general one, and that there are probably many varieties
of this substance, differing from one another according to the protein
from which they are derived.

The change produced by pepsin and hydrochloric acid is of the nature
of an hydrolysis, for it has been found thai the amount of hydrogen and
oxygen in the digestive products is greater than that in the original
protein. It is by a similar process of hydrolysis that the other proteolytic
enzymes, such ;is pancreatin and erepsin, operate, but this does not
imply that the exact grouping thai is splil aparl by the hydrolytic proc-

THE BIOl III. MH \1. PROI OP DIGEE HON

ess is the same for each of these enzymes, [ndeed, there is considerable
evidence thai pepsin does not, like the other enzymes, break up the
chain of amino acids thai are linked together to compose the polypep-
tides, bul thai it only splits the big molecule of albumin or globulin
into several large groups, each of which is composed of long ami
chains. Its action appears to be analogous with thai of amy',
starch, by which, it will be remembered, the l>iur polysaccharide m
cule is split inio smaller polysaccharide molecules, which then become
attacked by the dextrinase and split into disaccharide moleculi
page 656). The evidence in support of this view is: l thai pepsin is
unable to dip-si polypeptides, and (2 thai it is able to digec tain

proteins upon which erepsin (see page 490) lias no action.

The hydrolytic splitting <>f large into smaller protein molecules, like
thai by which the chains of amino acids in the polypeptides bse-

quently broken up, consists in a breaking of amino-carboxyl linkings
(NHCO see page ">!,v . with the consequenl liberation of a large num-
ber of unattached amino groups. The number of these free amino groups
••an be determined quantitatively by the formaldehyde titration method
(if Sorensen.* By this method it can be shown that from the very start
of peptic digestion the number of free annuo groups increases, and |
passu the power of the digestive products t< mbine with free hydro-
chloric acid. Indeed, when the experiments are done quantitatively and
the digestion allowed to proceed for a considerable time, the increase in
the formol titration is practically equal to the decrease in the ids

as determined by the Giinsberg reagent.

The rate of peptic digestion is usually estimated by the law of Schutz
and Borissow, according to which the amounl of coagulated albumin
thai is digested in a .Melt's tube is proportional to the square n the

amounl of pepsin. J

The pepsin which leaves the stomach in the chyme is nol all destroyed
in the intestine, as was at one time believed to be the we

have seen above, some pepsin can be d< I in tin- gastrointestinal con-

tents. A pari of the pepsin may he absorbed into the blood and carried
back to the gastric glands to he used again. This would account for the

presence of antipepsin in the blood, and also for the pr< pepsin

in the urine. It is probable, however, that most of the pepsin

Stroved after it enters the intestine.

'In l!;
lli.il a hi|
titration with .1"

tThe amounl

, P. W.: /

4SS DIGESTION

Clotting- of Milk in the Stomach

Besides its power of digesting protein, the gastric juice is also endowed
with the property of clotting milk. This action is commonly attributed
to the presence of another enzyme besides pepsin, namely, rennin; but
in recent years considerable controversy has raged around the question
as to whether pepsin and rennin are not. the same thing. One strong
argument in favor of this view is that all digestive juices that are capable
of digesting protein can also clot milk. In any case, when gastric juice
acts on milk, it splits the casein* of the milk into two portions, one of
which, called paracasein, immediately combines with calcium to form an
insoluble colloidal compound, which is precipitated and, by entangling
the fat of the milk, forms the clot; the other protein remains in solution
and is known as whey albumose. From studies on molecular weight it
is believed that the paracasein is produced from casein by the splitting
of the molecule of the latter into two, from which it would appear that
the action of this enzyme is nothing more than the first stage in the
hydrolysis of the casein molecule. The whey albumose, according to this
view, is a by-product.

There are many investigators, however, who believe that rennin and
pepsin are not identical, since an infusion of the stomach of a calf has a
powerful clotting action on milk but a very weak digestive one on egg
white, whereas a similar infusion from the stomach of a pig shows exactly
the reverse properties. This question is one of so controversial a na-
ture that it would be out of place to go into it further here. It
should be pointed out, however, that, when the gastric contents are acid
in reaction, milk will become clotted by the action of the acid itself
quite independently of any pepsin or rennin the juice may contain.
This acid clotting of milk is probably of a different chemical nature
from that produced by the enzymes.

On other foodstuffs than proteins the action of the gastric juice is
relatively unimportant, although polysaccharides may be considerably
broken down in the cardiac end of the stomach on account of the action
of swallowed saliva (see page 454), and disaccharides. as we have seen,
may become split by the hydrolyzing effect of 1he hydrogen ion. Fat
digestion also lakes place in the stomach when the fat is taken in an
emulsified condition, as in milk and vix<z yolk, but not when in masses,
as in meat or butter. This action is due to the presence of a fat-splitting
enzyme, or lipase, in the gastric juice.

*Tn the above nomenclature casein is the same as caseinogen, and paracasein the same as casein,
nf the Knglish physiologists.

CHAPTER LV1
THE BIOCHEMICAL PROCESSES OF DIGESTION Cont'd

DIGESTION IN THE INTESTINES

The further changes which the half-digested foodstuffs in the chyme
undergo in the intestinal canal depend on the enzymes present in
secretion of the various glands and on the pn of bacteria, 'i

must importanl of the digestive juices are the pancreatic juice and Idle
The latter, however, does not contain any enzyme, its influence on * 1 i _
tion being entirely adjuvant.

Pancreatic Digestion

When we were considering the mechanism of secretion of the pon-
tic juice, we saw thai the juice produced by the action o eth
the gland cells does no1 contain any active proteolytic enzyme, although
it contains one capable of acting on polysaccharides and another, on fat.

The Action of Trypsin

When pancreatic juice is mixed with the secretion of the duodenum or
the upper pari of the small intestine, it immediately develops powerful
proteolytic power. The same resull may also be obtained by mixing it
with an extract of the mucous membrane of the duodenum made with
dilute bicarbonate solution. A very small amounl of ti tract is

capable of increasing the digestive activity of a very considerable quan-
tity of pancreatic juice, showing thai the action depends on the presence

of an enzyme which has been called enterol This inline:

intestinal secretion is readily destroyed by heating.
Large quantities of alkali are contained in the pancreatic juice and

bile, so that in the upper reaches of the intestine the acidity of the

chyme is practically neutralized. A little lower down, however, an acid
reaction may again devel< On account of these fact*

has been concluded that the activity of trypsin is most rapid in the p
ence of a slighl e\crss of hydroxy] ions; i.e.. in a weakly alkaline solu-
tion. It is interesting to note that, as a resull of th<
alkali by the pancreas, extracts of tl jan af- iw a v<

1 1 i >_r 1 1 degree of acidity in comparison with extract m oth(

490 DIGESTION

and tissues. It has also recently been shown that the activity of trypsin
does nut depend on the presence of free hydroxy! ions, but that it may
proceed in the presence of free acid, even up to a strength of CH = 1.5.
It' pepsin is present together with trypsin in a distinctly acid solution,
the pepsin seems to destroy the trypsin, unless the mixture contains a
considerable quantity of protein, when the tryptic activity may persist
even for several hours. A practical conclusion that we may draw from
these results is to the effect that preparations of trypsin — the so-called
pancreatin, for example — if given with the food, may pass in an active
condition into the duodenum, where, in the more favorable environment
created by the neutralization of the excess of acid, it will develop its
proteolytic power. The therapeutic administration of pancreatin is,
therefore, justified (Long10).

The activated trypsin acts on proteins in very much the same way as
pepsin, except that the decomposition of the peptone and proteoses into
polypeptides is the chief feature of the process. Thus, after tryptic
digestion has proceeded for some time, only a trace of primary proteoses
but considerable quantities of leucine, tyrosine and other amino acids
will be found present. Some investigators believe that the thorough
nature of the digestive action of activated pancreatic juice may depend
on its also containing erepsin, an enzyme which Ave shall see to be pres-
ent in considerable amount in the mucous membrane of the intestine and
other tissues, and whose particular function is to split polypeptides into
the amino acids. From the autolytic digestion which takes place in
organs kept in a sterile condition after death, tryptic digestion differs
in that it produces only small quantities of ammonia. The large quanti-
ties of ammonia produced in autolytic digestion no doubt have a rela-
tionship to the acids simultaneously set free during this process.

In the products of tryptic digestion it is usually found that, although
there has been considerable splitting of the protein into amino acids,
there are still a good many amino-carboxyl (NHCO) linkages left un-
broken, indicating that certain polypeptides are left intact in the mix-
ture. To split the polypeptides requires the aid of the erepsin, which is
presenl in the mucous membrane of the intestine. Interesting inves-
tigations have been made on the exact degree to which trypsin-entero-
kinase can split up the various known polypeptides. This seems to
depend on the structure of the polypeptide molecule and on the number
of amino acids presenl in the chain. For example, analylglycine, but
not glycylalanine is hydrolyzed, although both contain the same amino
acids but linked together in a different way; and tetraglycylglycine,
which contains five glycine radicles, is hydrolyzed, whereas diglycyl gly-
cine, which contains only three, is not.

Till BIOI BEMICAL PROl - ■ : ION 19]

The importance of the presence of erepsin in the mucous membri
of the intestine is thai it serves as a barrier to the pat ny unsplil

amino acids from the intestinal contents into the blood. It insures the
breaking up of the protein molecule into its ultimate units I
lion. The further fate of the absorbed amino acids will he considi
under the subject of protein metabolism.

'I'm \> tion op Lipase

Neutral t';it is decomposed into fatty acids and glycerine by tin1 lij>
presenl in the pancreatic juice. This enzyme may also 1"' extracted from
the glands by means of 'i'l per cent alcohol. Its action is remarkably
accelerated by the presence of I>il<'. and considerably depressed by i'
ganic suits. It is ;iisn very dependenl on the degree of alkalinity, the
optimum being a hydrogen-ion concentration of II x 1"". The favoring
action nt' bile is undoubtedly owing to the bile salts (see pj ; . and

it is probable that tins action is dependenl upon the influence which
those have in lowering surface tension ami therefore brinLriiiLr about a
more intimate contad between fat and water.

Tin: Action of A.mtlopsin

The action of pancreatic juice mi carbohydrates depends on the
amylolytic enzyme called <nniihii>sin. In animals having no active ptyalin
in the saliva, amylopsin serves as the only diastatic enzynn ncerned

in the digestive process. In any case, at least for the first Btag the

disruption of the starch molecule that is, its conversion into dextrines
amylopsin is a more powerful enzyme than ptyalin. It does not appear
to he so efficienl ;is ptyalin in the final stages of the hydrolj r it

does not produce so much reducing sugar as ptyalin does. Indeed
tracts of pancreas will sometimes convert starch into soluble starch and
dextrine with greal speed, bul produce scarcely any reducing sugar.
On this account it is believed by many investigators thai there are al l<

two distinct and separate enzymes in amylopsin and also perhaps in
ptyalin, one a tine amylase, which converts starch into dextrine, and

the other a dextrin ase, which converts dextrine into maltose. In

case of both ptyalin and amylopsin digestion proceeds besl i1:
weak acid reaction. Amylopsin, as it d in the p

is fully activated: bile, apart from the alkali which
no influence on its digestive power.

Besides amylopsin the pancreatic juice also eontai in

the case of young animals or of those that take milk with their f
throughoul their lives, lactase also. \\\, rkling animal 1

492 DIGESTION

continued taking milk, the lactase disappears from the pancreatic juice.
Ai tempts have been made to bring it back by feeding the adult upon
milk, but without success. Occasionally the pancreatic juice also con-
tains invcrtase.

The Bile

Associated with the pancreatic juice in all its functions is the bile.
When this fluid is prevented from entering the intestine, the digestive
process becomes very imperfect, the absorption of fat being particularly
interfered with (see page 691). Bile is also an excretory product, and
its composition therefore is much more complex than that of the other
digestive fluids. This varies very much, however, according to the
method of collection. Bile from the gall bladder after death contains
much more solid material, particularly bile salts and mucin, than that
collected from a fistula of the bile duct or gall bladder during life.
These differences will be evident from the accompanying table.

Bile from
Gall bladder Fistula

100 parts contain —

Water , 86 97

Solids 14 3

Organic salts (bile salts) 9 0.9-1-8

Mucin and bile pigment 3 0.5

Cholesterol 0.2 0.06-0.16

Lecithin and fat 0.5-1.0 0.02-0.00

Inorganic salts 0.8 0.7-0.8

-

In general it may be said that bile obtained from a fistula in man
contains only about 3 per cent of total solids, of which from one-fourth
to one-half are inorganic, whereas bile from the gall bladder contains
10 to 20 per cent of total solids, of which only about one-twentieth are
inorganic. The chief cause for this difference appears to be that when
the bile goes to the intestine, a considerable proportion of its bile salts
is reabsorbed into the portal blood and reexcreted by the liver. Some
of the difference may also be caused by the fact that absorption of
water takes place from the gall bladder, and that mucin and possibly
cholesterol are secreted by this organ. These striking differences be-
tween fistula and gall-bladder bile are observed only when the com-
mon bile duct is occluded. If the bladder fistula is made with the com-
mon duct left open, some of the bile gains entry to the duodenum and
therefore becomes reexcreted. It is well known that a fistula of the gall
bladder in man after a time closes up and the bile again takes its usual
oourso along tho bilo duct into the duodenum.

Till BIOCHEMICAL PROl

[nteresting observations have been collected on the amount of the
tion from a fistula both in man and in the lower animals. In man it
commonly stated that aboul 500 c.c. of bile ai ted daily, the

amount varying considerably during the different hours ■ day.

secretion of bile is greatly reduced by hemorrhage. It _ eater on a
meat diet than on one of carbohydrates. It is reduced durh rva-

tion, but continues to be secreted up to the momenl of death.

I-'i \< tione op Bile

One of the main functions of the bile salts is that they greatly
not only in the digestion, 1 nit also in the absorption i When bile

is excluded from the intestine, the \'<r,-^ are Loaded with fatty ac
which have been split <>ff partly by the now less i •• Lipase and

partly by the action of bacteria. The fatty acid thus Lib< in the

absence of bile salts is qoI absorbed, because the bile salts the

carriers of fatty acids into the epithelial cells and lacteals. They com-
bine with the fatty acids, probably by forming some chemical compoui
in which they cany them into the endothelial cells where the compounds
become disrupted, the fatty acid combining with glycerine to again form
neutral fat and the bile salts being carried to the liver and n
The influence of bile salts in assisting the action of Lipase is probably
due to a lowering of the surface tension, thus bringing water and fat

into closer union. This accelerating influence has also 1 o demons!

when synthetic bile salts have Keen used, showing clearly that it is really
these and no1 any other constituent of the bile that are responsible
its i derating influence.

Bile also functionates as a regulator of intestinal putrefaction. This
it does apparently because of its slight laxative properties, by which
the intestinal contents are expelled before the bacteria ha
any greal extent in them. Bile itself is a favorable culture medium
certain bacteria, bo that it can have no antiseptic action.
in the action of trypsin and amylopsin depends very largely up
alkali which it contains.

\ o excr icU bile is important, because it p the

power of dissolving cholesterol. Toxins and metallic po

kinds are also excreted in it.

Although not directly concerned with the digestive function, it will
convenient to say something here concerning thi chemical nature and
derivation of the various biliar stituei

494 DIGESTION

THE CHEMISTRY OF BILE

The Bile Salts

In most animals the bile salts consist of the sodium salts of glycocholic
and taurocholie acids. Each of these acids is composed of a part called
cholic acid which is more or less related to cholesterol, and of glycine
(CH2NH2COOH amino-acetic acid) or taurine (C,H7NS03), a derivative
of cysteine, which is a-amino-£-thiopropionic acid (CH,IIS.CHNH2.
COON i. The exact form of cholic acid varies in different animals, that
of the pig, for example, being different from that of man. Bile salts are
an exclusive product of liver metabolism; i.e., they are not formed in
any other part of the animal body. They give a very sensitive color
reaction known as Pettenkof er 's, which however is not specific of bile acids,
since it is also given by oleic acid and by many aromatic substances and
alcohols. It must be remembered that the part of the bile salts that is
characteristic of the liver is the cholic acid, the taurine and glycine
being present in other tissues and organs.

When cholic acid is given to animals mixed with the food, the amount
of taurocholie acid excreted with the bile is increased, indicating that
there must be a store of taurine available in the organism. This store
can not, however, be large, for if the feeding with cholic acid is repeated
several times, it will be found that the taurocholie acid diminishes and
glycocholic acid takes its place; and this increased excretion of glyco-
cholic acid goes on just as long as cholic acid is fed. The reserve of
taurine in the animal body appears therefore to be limited, although it is
used in preference to glycine when there is an excess of cholic acid to be
neutralized. On the other hand, the store of glycine seems to be inexhaust-
ible. That there is no reserve of cholic acid itself in the body is indicated by
the fact that no increase in taurocholie acid excretion by the bile results
when cystine, .the mother substance of taurine, is given with the food.
If both taurine and cholic acid be fed, however, the excretion of tauro-
cholie acid increases.

The relative amounts of taurocholie and glycocholic acids in the bile of
different animals differ considerably. Human bile contains relatively
a small amount of taurocholie acid; on the other hand, the bile of the dog
contains a large excess of it.

Cholesterol

In human bile the percentage of this important substance is not high
(l.G parts per 1000), but it is of great clinical importance because of the
fact that it may separate out as a precipitate forming gallstones. The

'I III BI0CH1 Mil \l. I'I;im i SSI g OF DIG! 81

percentage of cholesterol in these varies from 20 to 90; the remainder
being organic material such ;is epithelial cells, inorganic salts, pigm
etc. The origin of cholesterol is partly endogenous and partly
nous. In the former case it comes from the envelope of red blood cor
puscles and from the nervous tissues, where it is presenl in considerable
amount. The latter source is, of course, the food. The ii c in

cholesterol esters in the blood after feeding with \>»><\ rich in this Bub-
stance has been shown, particularly in rabbits.

That the bile should be the pathway through which cholesterol is
excreted depends oo doubl on the fact thai it contains bile salts, which
along with their other properties have a remarkable solvent action on
cholesterol. This solvenl property depends on the cholic acid pari
the bile salts, which, as already remarked, is chemically very closely

• «...

related to cholesterol; indeed, the relationship is -., close that some have
suggested thai cholic acid is derived from cholesterol. This would mean

that the cholesterol of blood is excreted in two ways, as cholesterol and

as cholic acid. Other observers, however maintain thai the cholesti
is excreted mainly by the lining membrane of the lmII bladder, and
that this explains why gall-bladder bile contains more of it than fis-
tula bile. This evidence is, however, nol very strong, for tl _ iter
excretion of cholesterol under conditions where the circulation <>f bile
is going on may be explained as due to the ]"■ of bile salts, which

serve to carry the cholesterol ou1 of the blood.

Many problems remain to be elucidated in connection with the metabolic

history of cholesterol. That son f it is absorbed when cholesterol is

contained in the food mighl seem to indicate that its source is entirely
exogenous. Againsl this view, however, stand two facts: (1) that the

cholesterol in the feces of herbivorous animals is of the same vai

that presenl in those of carnivorous animals and not the phytosterol
which is presenl in plants; and 'J thai the universal pr< of

cholesterol in cells indicates thai it must he manufactured tin

The Bile Pigments

The pigments of bile are bilirubin ami biliverdin. The latter is pi
duced from tin- former by oxidation. If the oxidation he carried a
stage further, a blue pigmenl called bilicyanin is formed. This p
of oxidation can he observed in the ring tesl for bile pigment with
fuming nitric acid. When bilirubin is reduced, urobilin, 01 the

pigments in urine, is formed. Bilirubin must therefore b<
as the mother substance of all those pigments, and it is ><{ 1 • in

connection with its derivation to know that it lias the sami lla

t96 DIGESTION

as iron-free hematiu or hematoporphyrin, which is produced by treating
hemoglobin with concentrated sulphuric acid.

Chemical investigation has shown that bilirubin is built up from sub-
stituted pyrrols, probably four such being contained in the molecule.
The pyrrol group is also present in indole and tryptophane, and con-
sists of four carbon atoms and an XII group linked together as a ring
see page 604). Similar pyrrol derivatives can lie produced by decom-
posing chlorophyl, the green coloring matter of plants. It is important
to remember that bilirubin is acid in nature, and, therefore, can cora-
lline with alkalies to form salts. The relative amounts of bilirubin and
biliverdin vary in the bile of different animals.

When these pigments enter the intestine they are reduced to urobilin,
part of which passes out with the feces, another part being absorbed into
the blood and excreted in the urine. Part of that excreted in the urine
exists, however, as a so-called chromogen named urobilinogen. The
urobilinogen is converted into urobilin by the action of oxygen.

The metliod by which urobilin is produced from blood pigment has
been studied by histological examination of the liver particularly of birds
and amphibia, in which destruction of blood pigment goes on rapidly.
Increased destruction of blood pigment can be induced by poisoning
with certain substances such as arseniureted hydrogen. From such
studies it is usually believed that the bile pigments are a peculiar product
of hepatic activity, being produced from blood pigments that are de-
rived from erythrocytes which have been broken down either in the liver
itself or in some other viscus (e. g., the spleen). Whipple and Hooper20
have brought forward seemingly incontrovertible evidence against such
a view. They have found, for example, that the bile pigments are
formed just as readily in animals in which the circulation of the liver
was greatly curtailed by anastomosing the portal vein with the vena
cava (Eck fistula) as in normal animals. Even when the circulation
was limited to the anterior end of the animal (head and thorax) bile
pigment appeared in the blood when hemolyzed erythrocytes were in-
jected, and it was also formed when hemoglobin was placed in the pleural
and peritoneal cavities. The endothelial cells of the blood vessels and
elsewhere can evidently form the pigments, at least when the liver is
absent. When such a process occurs under normal conditions, it is quite
probable that the liver acts merely as an excretory organ for the pig-
ments in the same way as the kidney dues for urea. Possessed of endo-
thelial cells, the liver mighl itself also produce some of the pigments,
1ml no more than other organs with a similar number of those cells.

Even the derivation of bile pigments from hemoglobin is called in
question, for the same workers have observed that, whereas the excre-

Till BIOCHEMIC \l. PRO( ESS DIG! 81 4!»7

tion of pigment from a biliary fistula is remarkably constanl in a dog
fed on a fixed mixed diet, it became increased, sometimes by l"1) per
cent, when the diel was changed to one of carbohydrates, and de]
on a diel of meal. The question arises as to whether, after all, the bile
pigments are really derived from broken-down hemoglobin. May I
not be manufactured d!< novo ou1 of other materials

Whipple and Hooper have also shown that bile is a most important

secretion, for dogs rarely survive on an ordinary diet it' bile is perma-
nently prevented from entering the intestine. Intestinal symptoms
soon supervene, and become progressively more severe until the death
of the animal. Feeding with bile does not relieve th< lition, hut

feeding with cooked liver seems to have a beneficial

After extravasation of blood in the subcutaneous tissues, as in a brui
for example, a decomposition of hemoglobin proceeds quite like that
oe. •ni-riii": in the liver, and Leads to the production of blue and In-own
and green pigments like those of the bile. When hemolysis is produc
as by inhalation of arseniureted hydrogen or the injection of inorganic
or biological hemolysins, there is an immediate increase in the amount
of bile pigment in the hile. Even the injection of hemoglobin solutions
has this effect. Under these conditions of hemolysis, besides an incr<
in urobilin, there may be considerable quantities of hemoglobin s<
in the urine.

Bile salts and pigments usually accompany each other when any-
thing occurs to interfere with the free secretion of bile. For exam]
after ligation of the bile duct both bile pigments and Idle salts accumu-
late in the blood, in the serum of which they may be recognized by
ordinary chemical tests in from four to six hours after the operation.
If the accumulation be allowed to proceed further, the bile pigments
become deposited in the tissues, giving them the peculiar yellowish ap-
pearance known as jaundice. Under these conditions the bile salts and
pigments also appear in the urine. The accumulation of bile salts ill
the body affects certain physiological process s; for one thing, it cs
a greal Lengthening in the clotting time of the blood.

If the blood supply to the liver is interrupted by ligation of the portal
vein and hepatic artery at the same time thai the bile ducts . 'tided,

not a trace either of bile salts or of bile pigmenl appears in the bli
during the six to eighteen hours thai the animals survive the i tion.

The amount of obstruction of the bile duct necessary to produce th<
Bymptoms is very Blight, since bile is secreted at a very low pr<
Even a clot ..t inn. -us or a swollen condition of the mucous membrt
of the duel is sufficienl to produce obstruction. In tl bile

from the gall bladder into the duodenum it is claimed by Mi I 'hat a

498 DIGESTION

reciprocal relationship exists between the contraction of the bladder
musculature and the relaxation of the muscular fibers surrounding the
duct in the duodenum. If this reciprocal innervation fails to operate
properly, discharge of bile into the duodenum may become obstructed
so that a certain amount passes back into the blood, as in cases of bile-
duct obstruction.

Bile also contains a certain amount of lecithin and oilier phospholipins.
The amount varies considerably in the bile of different animals, even in
animals of the same species. It is probably derived, as already men-
tioned, like the cholesterol, from the breaking-down of red blood cor-
puscles that goes on in the liver. It is no doubt digested by the ferments
of the intestinal tract, the liberated cholin, since it is toxic if absorbed,
being further attacked by bacteria so as to become converted into cer-
tain substances of a nontoxic nature.

CHAPTER I. VII
BACTERIAL DIGESTION IV THE [NTESTINE

On an average diet, in twenty-four hours the feces of man weigh
about 100 grams, or niter drying, aboul 20 grams. Aboul one-fourth of
t ho dry matter consists of the bodies of bacteria, h' plated out by I
ordinary bacteriologic methods, however, it will be found that only a
small proportion of these bacteria are Living. The greater Dumber have
been destroyed, probably by the action of the mucin in the large inl
tine. The nitrogen contenl of the feces amounts to aboul 1 5 gran
day, of which aboul one-half is bacterial nitrogen. It" the did ains

large quantities of cellulose material, as in green vegetable food and
fruit, the mass of feces as well as the bacterial contenl may be
erably greater.

The foregoing fads indicate that very extensive bacteriologic pr
esses must be going on all the time in the intestinal contents, and the
question arises as to whether such action is beneficial or otherwise to the
animal economy. To answer this question interesting observations have
been made on the growth and well-being of animals excised from the
uterus under strictly sterile conditions and maintained then
sterile food. Such observations made on guinea pigs have shown that
the animals thrive and grow perfectly for a considerable time. Experi-
ments carried out on chicks have not, however, yielded similar results,
('hicks hatched oul from the egg under strictly sterile conditions and
then fed on sterile grain, do not thrive, but do so if with the '-'rain is
mixed a certain amounl of fowl excrement. These experiments, appar-
ently contradictory in their results, show that \'<<v certain groups of
animals bacteria are required, bul QOl for Oth(

The difference Is probably dependenl on the nature of the foods. It
will be remembered thai the size of the large intestine varies consider-
ably according to the nature of the diet a page 163 Ai i als taking
great quantities of cellulose foodstuffs have very large ceca and v<
long large intestines; whereas those which, like tl I ally

entirely on cellulose-free food, have a rudimentary large intestine. The
of the lower intestine is obviously dependenl on the p'

absence of cellulose in the food. It will be remembered also that the

forward movement of the contents of the large intestine is very slow :

ind 1. special provision is made, by the present I tl ftnti-

500 i)i(ii:sTiox

peristaltic wave, to delay its movement. This suggests thai an important
digestive process must be proceeding in this part of the gut. In these
ways conditions become established in the cecum for the active opera-
tion of bacteria. They attack the cellulose, and liberate the more diges-
tible foodstuffs contained in the vegetable cells, also producing out of
the cellulose itself materials of nutritive value. The acids that are also
produced by this process arc neutralized by the carbonates secreted
by the mucosa.

In certain herbivorous animals — the ruminants — this process in the
cecum is not relatively of such importance, because it takes place in the
paunch. The animals swallow the food and it mixes in this part of the
stomach with the saliva, so that bacteria and ferments contained in it,
called cytases, attack the cellulose, liberating the more easily digested
foodstuffs inclosed within the cell walls. As this process goes on acids
accumulate in the digestive mixture. The food is then returned to the
mouth, chewed over again, and swallowed again into the main stomach,
where it is digested. The aid which bacteria render to digestion depends
therefore on the nature of the diet. Man, being omnivorous, stands mid-
way between the two groups of animals discussed above. Although the
cellulose contained in his food is not itself sufficiently digested to furnish
nutriment, yet it is so far acted upon as to permit the rupture of the
cell, the contents of which are then digested. The cellulose is, however,
of value in furnishing bulk to the intestinal contents — "intestinal bal-
last," it is sometimes called.

In the small intestine in man there are bacteria capable of acting on
carbohydrates and producing from them organic acids, such as lactic,
acetic, etc. So long as a sufficiency of carbohydrate exists to encourage
the action of these bacteria, others having an action on* protein do not
seem to thrive. It may be that this is to be accounted for partly by the
production of acid substances by the carbohydrate fermentation, and
partly by the fact that, as soon as the protein molecule is broken
down by the digestive enzymes, its building-stone amino acids are ab-
sorbed. There are probably also bacteria in the small intestine capable
of splitting fat into fatty acid and glycerine, but practically nothing is
known of their action. In the large intestine of man, along with the
cellulose-digesting bacteria already mentioned, protein-digesting bac-
teria are also present. These bacteria belong to the class, Bacillus coli
communis, the various members of which are known as facultative anae-
robes because they can grow in the presence or absence of oxygen.

If bacterial growth is excessive or there is an insufficiency of carbohy-
drates in the small intestine, the bacteria attack the amino acids pro-
duced by the digestive enzymes and decompose them into products
that may be toxic if absorbed into the blond.

BACTERIAL DIGESTION IN THE INTESTIK 503

Bacterial Digestion of Protein

From a pathological standpoint, the most importanl action of bacteria
is thai which takes place on protein. Under anaerobic conditions the
intestinal bacteria have in general the power of splitting off the amino
group whereas under aerobic conditions they split off the carboxyl
group. This splitting off of the carboxyl group as carbon dioxide is |
formed by the so-called carboxj lase bacteria, and it may tak< either

before or after deamidization se< pi 615 . It' it happens after this

process, the products are no1 highly toxic and include phenol, cresol,
indole and skatole, which are partly absorbed into the blood ami partly
excreted with the feci -

The fractions of those substances thai are absorbed into the blood
have their toxicity removed by conjugation mainly with sulphuric acid
to form tho so-called ethereal sulphates. A pari is also combined with
glycuronic acid (see page 632). In the case of phenol and cresol this
conjugation occurs immediately after absorption, but in the <• n
indole and skatole it is preceded by an oxidative pro converting

these substances into indoxy] and skatoxyl respectively. The detoxica-

tion pr iss occurs in the liver, as has been shewn by experiments in

which this organ was artificially perfused outside the body. Thi

then removed from the M 1 by the kidneys and excreted in the urine.

The proportion of ethereal sulphates in this fluid is therefore an indica-
tion of the extent of intestinal putrefaction of protein e I 12
The indican, being readily detectable by the well-known color reaction
of Jaffe", sen an indicator of the extent of intestinal putrefaction.
The indole ami skat«»le which are not thus absorbed ami detoxicated are
excreted with the feces, i<> which they give the characteristic ndor.

The source of the phenol is tyrosine and that of the indole is try;'

phane. The chein ica 1 pi - involved are shown in the following

equations, in which the by-products of the rei - arc in brackets

i ih COB I "II • "II >H

//\ //

Ih • ii in en in- <-n in- .11 in • CH

lie ill lie CH HC « II IK' 'II HC

. || CH "II ;l"

Ml
"IIMI ('II """II

I
OH "II

oxyphenyl enyl

propionic a.

502

DIGESTION

Putrefaction of tryptophane is probably preceded by dcamidization

en

//\
nc c-

-C'—L'il .('11X11 ,('()( )H

IIC c-

I I! li

BC C CH

\/\/

CH Ml

(tryptophane)

<'ll

//\
lie C C— CH...COOH

(NHa)

lie < ' CH

VH NH

(indole-acetic acid)

(C02 + HX>)

C— CH2CH2.COOB

HC C CH (CO. + Hp)

CH NH

(indole-propionic acid )
CH CH

//\ //\
IK' C CH IK' C C— CH3

I II II I II II

HC C CH IK' C C

\/\/ \/\/

CH NH (+CH3) CH NH

. (indole) (skatole)

If, however, the carboxylase bacteria remove the carboxyl group he-
fore the amino group has been removed, highly toxic substances called
amines are produced. They are the so-called ptomaines. From alanine,
ethylamine is formed; from tyrosine, phenolethylamine; from histidine,
which it will be remembered is an important protein building-stone,
imidazylethylamine, and so on. The process of formation is illustrated
in the accompanying formula?:

1. CH3.CH(NH2).COOH = C02 + CH3.CH2(NH2)

Alanine Ethylamine

2. C6H,(OH).CH2.CH(NH2).COOH = C02 + C6H4(OH).CH,.CH2.NH2

Tyrosine Phenvlethvl amine

3. C,X2H,.CH2.CH(NH,).COOH = C02 + C3H3N;i. CH2'.CH2.NH2

Histidine. Imidazyletliylamine.

Similar substances are very common in the metabolic products of
plants; for example, they constitute the active principle of ergot. They
are also no doubt produced in the tissues of mammals, imidazylethyla-
mine, commonly called histamine, being thus produced, as well as the
closely related epinephrine, which is the active principle of the supra-
renal gland (see page 737), and may be described as a methylated ethyla-
mine derivative of tyrosine.

Phenylaeetic acid produced by a similar process from tyrosine may
be excreted in the urine, where it forms the mother substance of homo-
gentisic acid, to which the dark brown color of the urine in alkaptonuria
is due.

The great importance attached to these decomposition products of

proteins depends on the fact that they have powerful pharmacological
actions. These actions arc developed very largely upon the vascular
system ; histamine, for example, produces marked vasodilatation and
lowers the coagulability of the blood, whereas other substances of the

MM Ti Kl \l. DIGESTION IN THE lvi I - I IM.

same class, like epinephrine, have the property of raising the blood p
sure. In larger doses, Berious aervons symptoms and a condition of pro-
found collapse are produced. These observations have led several in
tigators to believe thai the persistenl occurrence of bacterial f<
tation and the absorption of the resulting decomposition products of
protein into the blood ultimately cause arteriosclerosis and the other symp-
toms that accompany senescence. It is difficull at the presenl time to
know how much of lliis one oughl to believe, although it can not be
doubted thai putrefaction lias an unfavorable action «>n the arter
and that an excessive degree of it causes the Bymptoms of ptomaine
poisoning.

If the ptomaines have formed in the food before it is eaten, the symp-
toms develop in from one to five hours after the meal, but if the decomposi-
tion occurs in the intesl ine on account of bacteria that are taken at the same
time as the food, the ptomaines may not have developed sufficiently to
cause symptoms until from twelve to forty-eight hours; sometimes, 1 ■
ever, they develop in an hour or so. Prominent among the symptoms is
usually diarrhea, which develops for the purpose of getting rid of the
offending bacteria and ptomaines.

Actual infection of food with bacteria of the paratyphoid-enteritidis
type is much more common than poisoning by substanc( s [ptomaines) that
have been generated in food before it is taken {Jordan17). Meat, milk
and other protein foods are usually the carriers of the bacilli, and in mosl
of the accurately recorded cases the meat or milk was found to 1"'
derived from animals suffering from enteritis or some other infection.
Sometimes, however, perfectly good food may become infected by
handling. Although the Bymptoms are usually acute, they may
simulate those of typhoid irvw. and the effects of the attack may linger
for weeks or montl

Bon i. ism

The commonest type of poisoning by substances actually present in the
food is that known as botulism. In this the gastrointestinal Bymptoms
are nnt pronounced, indeed, paralysis of the intestinal tract with con-
stipation is the rule, bu1 those affecting the nervous system, du ness,

diplopia and other visual (list nrliances, with difficulty in BWallowing,
arc very prominent. The temperature and pulse are usually normal.

In practically all of the reported cases of botulism, the Bource of infection
has been food which after having been subjected to some preliminary ti
ment, Buch as smoking, pickling, or canning, had been allowed to stand
for Borne time and then eaten withoul cooking. The Bacillus botulinus,
which is responsible for the production of the p

504 DIGESTION

strict anaerobe and is readily destroyed by cooking, as are also the
poisons. Antitoxins are formed by sublethal injections. Another but
now very rare example of poisoning by products formed in food is
that caused by "ergotoxin."

The treatment in such cases is to encourage diarrhea by giving pur-
gatives. If the intoxication is of a more chronic character, the symptoms
are vague, consisting of drowsiness, lassitude, headache, and general de-
pression. The treatment here also is to clear out the intestines by a
good purge. There can be little doubt that many of the unhealthy condi-
tions of the skin leading to the formation of pimples, acnes, and boils,
are also caused by chronic intoxication with protein decomposition prod-
ucts. Again, purgation is the proper treatment.

It is unnecessary in a work of this character to go further into these
highly important questions. It is probable, however, that the importance
of the relationship of excessive protein putrefaction in the intestine to
many of the so-called minor diseases can not be overemphasized. On the
other hand, we must be careful not to attribute every sort of chronic
condition to this putrefaction. Toxemia is often a shibboleth of the
profession. When a chronic disease can not be diagnosed, it is put down
as a toxemia. This, however, is not medical science — it is medical shirk-
ing. It is certainly unsafe at the present time to conclude that the
ordinary symptoms of senescence, such as hard arteries or increased blood
pressure, are invariably to be attributed to this cause. It will be re-
membered that Metchnikoff is largely responsible for such a view, and
also that he suggested, as the surest way to ward off the chance of such
intoxication, the taking of buttermilk, which would supply bacteria
through whose growth in the intestine the protein-destroying bacteria
Avould not be able to thrive. It is probable that the same result could be
attained in patients showing undoubted signs of suffering from intestinal
putrefaction by a change in diet in the direction of giving more carbo-
hydrate, for, as we have seen, if there is a plentiful supply of this food-
stuff in the small intestine, the bacteria do not tend to attack the protein.

Before leaving this subject it is interesting to consider for a moment
the cause of the severe symptoms that follow intestinal obstruction.
This rpiestion has recently been diligently investigated by Whipple,18
who found that the nonprotein nitrogen of blood (page 606) becomes greatly
increased in intestinal obstruction. The cause for this increase in non-
protein nitrogen is found to be an excessive breakdown of tissue protein
caused by the absorption into the blood of a proteose. When this pro-
teose isolated from obstructed loops of intestine was injected into fast-
ing dogs, profound symptoms of depression were produced, followed, in
eases in which the dose was sublethal, by recovery in from twenty-four

BA( il Kl \l. i 3TI0N IN PHI -MM 505

to forty-eighl hours. Along with the iptoms the uitr< imina-

tioD by the urine increased by LOO per cent. A very interesting fact is
thai animals can.be rendered immune to this : .- by proj ely

increasing periodic administration. When they are thus immunized,
the toxic symptoms <h> not follow upon its injection, nor are the Bymp-
toms produced by artificially creating an intestinal obstruction. C
tersely, when a chronic toxic condition is kepi up by a partial obstruc-
tion, such as that produced by making a gastrojejunal fistula and occlud-
ing the duodenum, the animals are less susceptible than normal o
proteose injection.

We have here and there incidentally referred to tht reaction of voric
parts of fl" gastrointestinal contents, but we would call attention one
again to this important subject, especially since many points of un
tainty have recently been cleared up by the accurate observations
Long and Fenger," who used the electrometric method for measuring
the hydrogen-ion concentration. The contents of the duodenum removed
by means of the Rehfuss tube in man showed a reaction varying from dis-
tinctly acid to slightly acid, depending upon the proximity of the tube
to the pylorus or papilla, this position being determined by x-ray exam-
ination. The slighl degree of alkalinity is surprising. Lower down in
the duodenum the reaction was as frequently acid as alkaline, the de-
gree of acidity, however, being so slighl as to favor rather than retard
the digestive powers of the pancreatic juic

To determine the reaction lower down, the observations weir made on
recently slaughtered animals pigs, calves, and lambs . the small u
tine being tied off in loops of the upper, middle, and lower thirds. Tl
contents of the last loop were often alkaline, hut might be more acid even

than those of the first, which were usually faintly of this reaction. C
siderable variations were, however, the rule. The mixed intestinal con-
tents of a recently \'r<\ dog, removed immediately after death, gave

P,, = fi.70 ; i. e., very faintly acid.

DIGESTION REFERENC1 -
Monographs

iPavlov, J. P.: The Woi re Glands. Trans, bj sir W. II. I

Bon, London, Griffin, ed. 2, 1910.
81 Ling, E. H.: Ldvai s in the Phyaioli n, \v. 'I'. !

Co., Chicago, 1907.
anon, vv. B.: The Mechanical F stion, !•

Londoi ' mold, 191 1.

'Carlson, A. J.: The Control <>f Bunger in Health and D
Press, 1917.
Id) T. Wingate: The Clinical Anatoim •. Bdancl

tor, t"ni\ . Press, 1915.

506 DIGESTION

(Original Papers)

innon, W. B., and Cattell, McKeen: Am. Jour. Physiol., 1916, xli, 39.
' Gesell, B.: Proe. Am. Physiol, Soc, Am. .Tour. Physiol., 1918, xlv, 559.
~Da\o, H. H., and P. P. Laidlaw: Proc. Phys. Soc, Jour. Phvsiol., 1912. xliv, pp.
12, 13. 3 ' ' ' "

Babkin, I*. P., Bubaschkin, W. J., and Ssawitsch, W. W.: Arch. f. mikr. Anatomic,
1909, lxxiv, 68.
sMacallum, A. B. : Ergcb. dcr Phvsiol., xi, 59S-657.
Miller, F. R.: Quart. Jour. Exper. Phvsiol., 1913, vi, 57.
Edkins, J. S.: Jour. Physiol., 1906, xxxiv, 133144.

Eeeton, B. W., and Koch, F. C: Am. Jour. Physiol., 1915, xxxvii, 4S1; also
Popielski, L.: Arch. f. d. ges. Phvsiol.. 1901, lxxxvi, 215.
uMeltzer, S. J.: Am. Jour. Physiol., 1899, ii, 266.
i -Cannon, W. B.: Am. Jour. Phvsiol., 1898, i, 359.

I annon, W. B., and Blake, J. B.: Am. Surg., 1905, xli, 686. Cf. Xo. 3.
n.Uacallum, A. B.: See Fitzgerald, M. P., Proc. Roy. Soc, lxxxiii, B, 56.
isHarvey, B. C. H., and Bensley, R. R.: Biol. Bull.', Wood's Hole, 1912, xxiii, 225.
'• Long, J. H., et al.: Jour. Am. Chem. Soc, 1917, xxxix, 162 and 1493; also ibid.,

1916, xxxviii, 38.

I'Jordan, E. V.: Food Poisoning, Univ. of Chicago Press, 1917.

iv Whipple, G. H., Cooke, J. V., and Stearns, T.: Jour. Exper. Med., 1917, xxv, 479.

Also Whipple, G. H., Stone and Bernheim: Ibid., 1913, xvii. 286 and 307.
"Long, J. H., and Fenger, F.: Jour. Am. Chem. Soc, 1917, xxxix, 127^.
^Whipple, C. H., and Hooper, C. W.: Am. Jour. Physiol., 1916, xl, 332 and 349; ibid.,

1917, xlii, 257 and 264; Hoope: Ibid., p. 2S0.
ziMeltzer, S. J.: Am. Jour. Med. Sc, 1917, cliii, 469.

PART VI

THE EXCRETION OF URINE

CHAPTER I. VIII

THE EXCRETION OF URINE

By R. <;. Pear< i. B.A., M.D.

It will be advisable to introduce the aubjecl by a brief review of the
essentia] structural features of the kidney, in so far us they apply to
the excretory function of the organ.

STRUCTURE OF THE KIDNEY

The ki.lncy is mainly derived from the surface of the celom, and is
mesodermal structure. In this respecl it differs from ordinary ting

glands, which are endodermal in origin. Jusl as it is more or
unique in its developmenl as a gland, it is also unique in its method
of functioning. The physiological theories of the mechanism of urinary
secretion are closely related to the highly characteristic structure of
kidney. For this reason a brief Burvey "t' the structure of the different
parts of the ariniferous tubules ami the epithelial cells with which ti
are lined, is advisable.

The ariniferous tubule, which is the secreting unit of the kidn<
takes its origin in the capsule of Bowman, which may l>e likened '■
hollow sphere of very delicate epithelium, one side of which is
invaginated by a very much convoluted capillary mass, the glomerulus.

The capsule opens up l'.\ a narrow twisted neek into a luhule. which is

rather tortuous in the cortex the proximal convoluted tubule), hut soon
takes a sharp descending course iii the medulla towards the pelvis of the
kidney, and doubles back (loop of Henle) in a straight again '

the cortex, where it again makes a twisted course the distal convoluted

tubule), ami terminates in a collecting tubule, which, uniting with other

tubules, collects the urine and Conducts it to the pelvis of the kidney.
The capsule is lined with very thin epithelial eel the

capillaries coniprisiii'_r the glomerulus. The proximal and distal tubll

:,os

THE EXCRETION OF TRIM

contain epithelium showing a prominent striation. These striations are
rows of granules, which run towards the lumen of the cell, becoming
less distinct as they approach it and apparently standing in close rela-
tionship to the rather prominent internal (lumen) striated border of
the cell. Some histologists believe that the striations at the border are

Fig. 170. — Diagram of the uriniferous tubules (C) the arteries (A), and the veins (B) of the

kidney.

really cilia, which are described as being immobile. The cilia are shown
in Fig. 171. The descending limb of Henle's loop is lined with a thin
pavement epithelium with large bulging nuclei. The distal convoluted
tubule is lined with cells not unlike those found in the proximal tubules,
except that the inner border is not striated. The diameter of the lumen

THE I \' Ki I l"\ "I i l.i

of the capsule varies with the activity <>i' the kidm is shown in

the following figures given by Brodie and Mackenzie

Mean diameter of capsule

• • glomerulus

< i

Bpace of capsule
Lumen of proximal convoluted tubule
•• distal "

Kin-.

DIURESIS

12

10!

17.'-.

7.2

20.6

The urinary tubule has a remarkable l>l<><></ supply. The renal arteries
arise directly from the abdominal aorta and are short. They run

through the medulla to the cortex, and join with neighboring arterie

•«

./. B,

during maxima] - i

form arches from which proceed branches, thai radiate into the corl
and give off smaller branches each of which very shortly breaks up in-
small capillary tuft, the glomerulus, which lies in the invaginated spl
of Bowman's capsule. The capillaries collect into an efferent vessel, which
appears to be smaller than the afferent artery, and tlii- sg ging

from the capsule again breaks up to form ;i capillary network about tl
voluted tubules, forming their sole blood supply. These capillaries
coalesce to form the renal \ «-in. The blood of the kidney must
ingly, pass through two sets of capillars

Tin* kidney is richly supplied with nerves, which are for t;
derived from the celiac ganglion and are in connection with the Bplanch-

510 THE EXCRETION OF TRINE

nie and the vagus. Other branches from plexuses in the region of the
suprarenal body and the aorta join with those coming from the celiac
ganglion to form what is known as the renal plexus, which is arranged
in a network along the blood vessels and on the Avails of the pelvis of
the kidney. These fibers are distributed to the very smallest blood ves-
sels, and nerve fibers have been observed among the cells of the tubules.

THE MECHANISM OF THE EXCRETION OF THE URINE

The great number as well as the variety of substances which are pres-
ent in both the blood and the urine makes it appear improbable that
urine excretion is dependent upon chemical combinations within the
renal cells, and leads us to seek a physieochemical mechanism to explain
the phenomenon. Can we discover the processes by which the kidney
fabricates a highly concentrated solution of salts from a very dilute
solution of the same salts in the blood plasma? The problem is compli-
cated by the fact that the ratios existing between the concentration of
each urinary salt in the urine and the concentration of the same salt
in the blood are different. In other words, the urine is not merely
concentrated blood plasma freed from protein.

The passage of water and salts through the capillary wall and through
the basement membrane surrounding the renal cell probably takes place
by "simple diffusion. If it were otherwise, an expenditure of energy
would be required, and it is difficult to understand how a basement
membrane could bring about energy changes. Any substance to which
the cell membrane is permeable will diffuse into the cell until an equi-
librium is established between its concentration within the cell and
that of the lymph or blood plasma, A nondiffusible substance will not
enter the cell because it can not pass through the cell membrane, and
if it exerts an osmotic pressure, it will also tend to keep the water in
which it is dissolved from entering. If water does pass into the cell
under these conditions, it is due to the expenditure of energy opposed
to and greater than that which is offered by the osmotic pressure of the
nondiffusible substances. Possible sources for such energy are the pres-
sure of the blood in the renal capillaries, which would exert a force. op-
posite to that of its osmotic pressure, and the presence within the cell of
a concentration of salts greater than is present in the blood, and able to
exercise a sufficient osmotic force to draw fluid into the cell against the
osmotic force of the nondiffusible salts. The passage of the urinary
constituents through the cell might also be due to simple diffusion, the
substances passing through the cell to bo extruded on the other side in

THE l XCR1 TION OF ' RIN1 51 1

the same concentration as in the blood. In this the renal cells

would acl merely ;is a filter, the urine having the Bame concentration
of each urinary Ball as is presenl in the M I.

A comparison of the concentrations of the urinary Baits in the mine
and the blood shows, however, thai the urine is nol merely a deprotein-
ized blood plasma, bo that other factors must be sought to explain the
excretion. Since the concentration of the urine requires the expenditure
of much more energy than is provided by the known physical facto
it is generally accepted thai the renal cell in sum,' manner supplies this
energy by its metabolic activity. Ii is impossible at presenl even to
surmise the nature of the process. Two possibilities may be considered.
One is that the urine is a filtrate of the blood which lias passed through
a portion of the renal epithelium into the tubules as a very dilute fluid,
resembling the blood plasma minus its eolloidal substances, and that
this dilute fluid is concentrated by the reabsorption of fluid and of --alts
by other cells of the kidney, and again replaced in the blood stream. Tin-1
other is that the salts and fluid are each actively and individually
creted by the kidney. Whichever condition is the true one, the fact
remains that the change in the concentration entails the expenditure
of a greal amount of energy on the pari of the renal cells.

The energy which the kidney must use in the actual work of concen-
trating the urine from the fluid of the blood plasma <-;m not be cum
puted from a comparison of the concentration of the urinary sail
whole in both the blood ami the urine. Bach constituent must be con-
sidered apart. We can not, for example, determine the molecular c
eentration of the blood plasma and the urine (by measuring a page
10) and estimate the work which is expended in producing the con-
centration from the observed difference. On the basis of such comparisons,
however, it is said that the excretion of ln" c.c. of urine requires I the
minimum 500 Irilogrammeters of work (Cushny2). Even this conserva-
tive estimate may be wrong, for it does nol take int rideration the
possibility thai the excretion of water by the kidney requires energy
expenditure on the part of the renal cells.

Theories of Renal Function
For many years two rival hypotheses have dominated the teaching

• • i

the mechanism of renal function. Bowman and Eeidenhain postuli
thai the constituents of the urine are Becreted by the vital activity
the epithelium of the capsule and the tubules. The glomerular caps

secretes the water and the easily diffusible salts in a dilute solution, and

the uriniferous tubules add to this fluid the various organic and inor-
ganic salts to bring the urine to the necessary lentration. This

512 THE EXCRETION OP URINE

theory has been termed the vital theory. Luchvig, on the other hand,
advanced what is termed the physical theory, which holds that the
glomerulus and capsule act simply as a filter, which allows the fluid
of the blood plasma to pass through in a very dilute solution and in
large amounts. This fluid is concentrated by physicochemical processes
on its passage along the urinary tubules to the pelvis of the kidney.

Both of these theories are inadequate and fail to explain the phenom-
ena which research has shown to occur in the kidney, but they have
served to develop what Cushny terms a modern theory of urinary
excretion.

The Modern Theory of Urine Formation. — This theory accepts the
general scheme of filtration and rcabsorplion of Ludwig, but pays due
respect to the fact that the known physical forces are not adequate
to explain the reabsorption which must occur in the tubules. It therefore
supplements Ludwig 's theory by assuming a vital activity on the part
of the epithelium of the tubules in reabsorbing fluids and salts from
the dilute filtrate coming from the glomerulus and capsule. A large
amount of plasma fluid is filtered through the walls of the glomerular
vessels. This fluid has the same concentration of the salts to which the
capsule is permeable as does the blood plasma, but it is free of the col-
loidal substances normally present in the plasma. The blood leaving the
glomerulus is therefore a somewhat concentrated solution of plasma col-
loids, and must have returned to it the proper amount of water and
salts to make it an optimum fluid for the body cells. This is accomplished
by active absorption from the glomerular filtrate. The salts that are of
no use to the body are not reabsorbed and therefore appear in highly
concentrated form in the urine. These salts are termed nonthreshold sub-
stances, and sinec their presence in the plasma is unnecessary, they con-
tinue to be excreted as long as they are present in any concentration in
the blood. The salts that are necessary for the plasma are termed
threshold svhstances, and are reabsorbed until they are again present in
the plasma in optimal strength. For example, urea continues to be ex-
creted as long as any is present in the blood, while glucose is completely
reabsorbed so long as its concentration remains under a more or less
fixed level.

It is impossible to give a summary of the arguments which have been
advanced in support of any of the theories. However, since the modern
theory appears to offer a better explanation of the established facts, it
may be wise to recount some of the best experimental evidence in support
of it.

First, we must inquire as to the amount of deproteinized blood plasma
which the capsule must filter off from the blood in order to furnish the

i in i X( l;i TION <t i i;i\i: 513

amounl of the various salts excreted each day and the .- 1 1 1 1 < • 1 1 1 1 1 of water
absorbed by the epithelium of the tubules to accounl for the concentra-
tion in which the salts are found in the urine. In order i'> produce '-h|
grams of urea in 1200 c.c. of urine, 60 liters of blood-plasma fluid con-
taining 0.03 per cent of urea w.mld have to 1"' filtered through the cap-

20
suit' — =6000), and 5.9 liters of water returned to the blood from
0.03

tlir uriniferous tubules. Sine' the 1»1 Iflow through the kidneys is v<

great, a1 leasl 500 liters per day, only aboul 1". per cenl of the fluid con-
tained in the blood passing through the glomerulus would pass by
filtration through the capsule of Bowman.

The fact thai such a Large amounl of fluid would have to be reab-
sorbed from tlif uriniferous tubules 59 liters) is a possible a priori
criticism of the theory, bul Cushny points out that the amount each
tubule would have to absorb per hour would be very small in his
perimenl on a cal amounting to less than 0.014 c.c. per hour).

The filtration of the protein-free blood fluid through the renal capsule,
like that through any other membrane, depends on several factors. 1
There must be a difference in the pressure between the blood and the
urinary filtrate In the laboratory the pressure used in filtering is
usually supplied by gravity, bu1 in the ease of the filtration of the urine
through the capsule the force is furnished by the pressure of blood in
the glomerular 2 The character of the filter determines what
substances shall pass. The renal capsule is a membrane normally im-
pervious to the proteins of the blood, but pervious to the other constitu-
ents, ruder certain conditions it loses this character. (3) The char-
acter of the fluid determines how readily it will filter through the mem-
brane. If the fluid contains a substance which can nol pass through the
filter and which exerts an osmotic pressure in opposition to the filtering
force, the rate of filtration as well as the amount filtered, will be redu 1

If the capsule acts as a filter it should be possible to alter the n t<
urine excretion by varying any of these factors, and experimentally this

is true. The factors can be varied iii several ways. If the hi 1 pressure

is raised by tying off several of the branch* rta, the urine

appreciably increased, or if the blood pressure is d< :m be

done by compressing the renal artery by means of a screw clamp, the
amount of urine is decreased. In the artificially perfused kidney, the
fluid exuding from the ureter increases as the pressui the perfusion

fluid is increased, and decreases as the pressure is d< d Whetl

changes in the pressure in the Mood are directly responsible for variati
in the rate of uriu. tion. or whether the\ act indirectlv bv varvi

the rate of the bloodfiow in the kidneys, has been the subject of much

T)1 I Til I EXCRETION OP CJRINE

debate. Probably both factors are involved, as is shown by the follow-
ing observations. It' the blood pressure is increased by vasoconstriction
in the splanchnic area produced by stimulation of the splanchnic nerves,
the flow of blood through the kidney is decreased and the excretion of
urine falls. Apparently, secretion can continue only as long as the col-
loids of the plasma are oo1 notably increased, for, as the osmotic pressure
due to the indiffusible colloids rises, the pressure in the capillaries is no
longer able to oppose it. The same point has been beautifully shown by
Starling and his pupils, who found that the secretion of urine ceases
when the capillary pressure in the glomerulus fell below that exerted by
the osmotic pressure of the blood proteins, the critical pressure being
from 30 to 40 mm. Ilg. They also found that dilution of the blood with
saline solution by reducing the osmotic pressure of the proteins in the
plasma, was accompanied by an increase in the rate of excretion; excre-
tion in such eases being maintained at a blood pressure below the normal
critical pressure. If the dilution of the blood was made with saline con-
taining gelatin or gum arabic, on the other hand, the diuretic effect was
greatly decreased, and any fall in the blood pressure was followed by a
suppression in the urine (Knowlton9). These experiments evidently
indicate that the saline produces its diuresis by diluting the plasma
proteins and lowering their osmotic pressure, since Avhen the osmotic
pressure of the blood is maintained by the addition of colloids in which
this is present, no diuresis occurs. The significance of these facts, in
connection with the raising of lowered blood pressure after hemorrhage,
has already been alluded to (page 139).

This view is confirmed by the experiments of Barcroft and Straub,10
who showed that the oxygen consumption is often not appreciably
raised during the diuresis produced by the injection of saline. If the
diuresis produced by this means was due to an actual increase in the
work of the kidney, the oxygen consumption would have been increased.

In the frog, the glomerulus and the tubules are supplied with blood
by the renal artery, as is the case in the mammal, but the tubules cu-
riously enough are also supplied with some of the blood coming from the
lower extremities and the trunk through a vessel which has no counter-
part in the mammal — the renal portal vein. The blood, therefore, which
is supplied to the tubule is a mixture from the glomerulus and the renal
portal system. By ligating the renal vessels it is possible to cut off the
blood supply of the glomerulus while leaving the tubules supplied by the
renal portal vein. Normally the pressure in the renal portal system is
not sufficient to force blood hack through the glomerular vessels. Liga-
ture of the renal vessels at once results in a suppression of the urine.

If the glomerular vessels are perfused with Ringer's solution at a

'mi i \« l;i TION OP i i:l\T ;i \-<

pressure equal to thai found in the aorta, a considerable flovi <.r fluid
maj I"' secured from the ureters, bul no fluid is obtained when tin- renal
portal vein is perfused ;ii a pressure equal to thai normally | J in

this vein. Rowntree and Geraghty11 found thai phenolsulphonephthalein
added to the perfusion fluid passed through the renal portal vein, «li«l nol
cause secretion, bul when urea was added to the perfusate, fluid con-
taining the dye was obtained from the ureter. Unfortunately tin- pi
sine employed in these experiments may have allowed some fluid to be
forced backward into the glomerulus, so thai the results may be due to
filtration through the capsule.

Renal
artery

■Malpighian
corpuscle

Renal-portal vein

Fig, \7.'. Diagram of blood suppl) I \l Ipighian corpuscle

kidney. ( Redraw n I Cus

It is generally accepted thai the proof thai the capsule acts as a fill

is fairly < iplete. Unfortunately such decisive experimental facts can

nol 1 ffered to prove the assumption thai the epithelium of the tubules

reabsorbs the excess of water and salts which are filtered of? through
the capsule. It* the modern theory of urine excretion is i ells

of the tubules musl nol only absorb large amounts of water, but they
must also allow for the reentrance into the blood, either complel
partially, of certain salts, while thej must reject others entirely.

We have called attention above to the fad thai the glomerular filtrate is
very differenl from the urine thai is finally passed. The urine cont&ii
very high percentage of small molecules, and the proportion in which they

516

THE EXCRETION OF URINE

are present is entirely differenl Erom thai in 1 bo blood plasma or in the
glomerular filtrate. This is shown in the following figures, which give an
average normal value for the urea, uric acid, chlorine, and glucose in 100
c.c. of protein-free blood plasma and 100 c.c. of urine. In the third col-
umn is given the change in concentration which has occurred in the
kidney.

100 C.C. PROTEIN-

100

C.C. URINE

CHANGE IN

FREE BLOOD

CONTAINS

CONCENTRATION

PLASMA CONTAINS

IN THE KIDNEY

Urea

.n:::i

2.

60

Uric Acid

.0022

.05

22.7

Chlorine

.41

.6

1.5

Glucose

.1

—

—

Here the blood plasma fluid contained but 0.033 per cent of urea, and
the urine 2 per cent. Accordingly, 6 liters of glomerular filtrate would

be required to furnish 100 c.c. of urine,

0.33

6000). Six liters of

glomerular filtrate would contain 6.6 grams of sugar, 0.132 grams of
uric acid, and 24.6 grams of chlorine. But 100 c.c. of urine contains no
glucose, 0.05 grams of uric acid and 0.6 grams of chlorine. According
to the modern theory, these figures indicate that during the passage of the
urine through the tubules 5900 c.c. of water, 6.6 grams of sugar, 24 grams
of chlorine and 0.067 grams of uric acid would have to be absorbed by
the renal epithelium in the production of 100 c.c. of urine containing
the concentration given above.

Among the most convincing experiments that can be offered in sup-
port of the absorption of fluid and salts by the tubules, are those in
Avhich the pressure of the urine in the tubules is slightly increased by
partial closure of the ureter (Cushny). In these experiments the ureter
of one kidney is partly closed with a clamp and the excretion obtained
from this kidney is compared with that of the opposite normal kidney.
In general, obstruction of the ureter results in a decrease in the amounts
of water, chloride and urea excreted. But, curiously, the urea content is
decreased relatively less than is the chloride and water content. These
results can be explained on the basis that any pressure acting to oppose
the head of pressure producing filtration in the glomerulus will reduce
the amount of the glomerular filtration, and accordingly the time allowed
for the passage of this filtrate along the tubules is increased and absorp-
tion becomes more complete. Since urea is probably not absorbed at all
and chloride is, the discrepancy in the effects on the excretion of urea
and Chlorine in the partially obstructed kidney can be explained.

"When very large amounts of water are taken by mouth, it often hap-

TH1 i \« i;i i [ON ->i i i;i\i .".IT

pens thai the urine excreted has a concentration of salts less than thai
presenl in the fluid of the blood. Some investigators believe thai Buch a
condition is possible only on the assumption thai water is activ<
creted, but a more plausible explanation based on the modern th<
is that the water thai is absorbed from the alimentary trad the

kidney as a dilute saline solution, and is rapidly filtered off in a form
somewhal more dilute than the optima] solution which blood plasma musl
have for the well-being of the tissues. The tubules reabsorb the amounts
of water and <»t' those Baits, such as chlorides, uric acid, and sugar, nec-
essary to restore the plasma to the optimal concentration, bul <lo not
absorb the nonthreshold substances, such ;i^ un

It is impossible to analyze the forces 'hat are responsible for such a
degree of absorption by the epithelium of the tubules. For the :
we must classify them, for want of a better term, as vital forces. Tim
questions that await immediate investigation are whether absorpl

actually takes place, and, if il does BO, what factors cause it to vary.

Many attempts have been made, by destroying the capsules or •
tubules by menus of poisons or by operation, to determine directly
indirectly the question of the function of the tubule

In such experiments, however, the number of factors involved con-
fuse the issue and make the results practically valueless so far as de-
termining the normal functi f the tubules. Other experimenl

have attempted to show absorption in the tubules by injecting diffusible

substai s, such as chemicals and dyes, into the ureter under what they

deemed sufficienl pressure to force the solution into the tubules, and by
an examination of the 1 » 1 < »< »< 1 or the tissues to determine whether or
the injected substances had hen absorbed. The results obtained by
this method are not convincing, probably chiefly because of the difficulty
in reaching the tubules, [ndeed, it is very questionable whether it is
possible to inject a substance into the tubules from the ureter.

Fears ago ETeidenhain, tie exponent of the vital theory of excretion.
believed that he had demonstrated the ability of the renal cells to
crete dye Bubstances injected intravenously, since he failed to find
evidence of dye excretion in the capsule, bul found mass< [ye in the

tubules ami stained granules in the cells of the tubules, he concluded
that the cells of the tubules had the power to excrete 'he dye, ami from

analogy he believed that the tubules must likewise excrete the w.'.-
and the various nrinary salts. Subsequenl work, hi failed

t infirm his belief thai the capsule is no1 concerned in the ion

of the dye, and it is as reasonable to explain the result* i speri

ments with tin- dyes l>} assuming that the n

found in the tubules and in the cells are du< rption

518

Till: KXCKKTION OF TRINE

water and perhaps of sonic of the dye from the dilute glomerular filtrate,
;is to accept Heidenhain's hypothesis.

In the following table taken from Cushny the movements of the con-
stituents of the plasma may be followed through the kidney. The ulti-
mate destination of each is indicated in the enclosures.

67 LITERS PLASMA
CONTAIN

62 LITERS

FILTRATE

CONTAIN

IN ALL

61 LITERS

REABSORBED FLUID

CONTAIN

1 LITER URINE
CONTAINS

PER

CENT TOTAL

PER
CENT

TOTAL

PER
CENT

TOTAL

Water

92 62 1.

62 1.

—

61 1.

95

950 C.C.

Colloids

| 8 5360 gm.|

67 gm.

1.3 "

200 "
13.3 "

248 "

20 "

1.8 "

Dextrose

0.1 67 gm.

0.002 1.3 "
0.3 200 "
0.02 13.3 "
0.37 248 "
0.03 20 "
0.003 1.8 "

0.11

0.0013

0.32

0.019

0.40

67 gm.
0.8 "
196.5 "
11.8 "

242 "

Uric acid
Sodium
Potassium
Chloride

0.05

0.35

0.15

0.6

2.0

0.18

0.05 gm.
3.5 "
1.5 "
6.0 "
2.0 "
1.8 "

Urea
Sulphate

(From Cushny.-)

It will be noted that the dextrose alone is completely absorbed, and
that the urea and the sulphate are not absorbed at all from the glom-
erular filtrate. The other salts are partly absorbed.

As already mentioned, Barcroft and Straub have shown that the
diuresis which results from the injection of saline into the blood is not
accompanied by any increase in the oxygen consumption of the kidney.
This observation, coupled with the fact that the total amount of chloride,
urea, and sulphate which is excreted during saline diuresis, is greater than
under normal conditions indicates that the excretion of these salts is
not due to any vital secretory power of the kidney, but rather to factors
that are extrarenal in origin.

The diuresis produced by adding urea or sodium sulphate to the blood,
on the other hand, is accompanied by an increase in the oxygen con-
sumption of the kidney. This increase can not be due to active elimina-
tion of these salts by the tubules, the work of which requires oxygen,
for no increase in oxygen consumption accompanies the increased ex-
cretion of the same salts under saline diuresis. Sulphate and urea are
nonthreshold substances, and are not absorbed by the tubules. The
explanation of the oxygen consumption is probably thai the osmotic
pressure which these bodies in the glomerular filtrate exert makes it
necessary for the epithelium to oppose a greater absorbing force to con-
centrate the urine, and hence a greater expenditure of energy is requird.

Diuretics. The action of the xanthine compounds caffeine, theo-
bromine and theophylline in the production of diuresis is unexplained.

i in i \' ici riON 01 i kim. 519

It m;i\ be due in pari to vascular changes and in part in

the resistance to filtration broughl aboul by alteration in the pern
bility of the capsule.

According to the i lem theory the polyuria in < 1 iul >«• ■

by the excessive amounl of water taken and by tin- inabilM

Is i< 1 1 h-\ to concentrate tin- urine aLrain^t il smotic pressu

the concentrated sugar solution in the tubules The pres hy-

perglycemia in an amounl higher than is presenl in tin- optimal blood
plasma in this disease makes sugar a nonthreshold sub eak,

and none is absorbed. The diuresis following the injection oi - r is
therefore of the same type a- thai produced by sulphate and urei
diuretic action of the digitalis group U dependenl upon its infl
tlir circulatory system. IT the circulation is already sufficient, digitalis
does no1 cause diuresis. The cause of tin- diuresis produced by pituiti
extract is not known. It may !"• owing in pari to its action on *:
culation and in pari in a direct action on the kidney.

Albuminuria. — The plasma proteins ordinarily do not obtain entrai
into the tubules of the' kidney. In disease such as acul hritis and

cardiac failure, the plasma colloids are filtered off through thi jule,

probably because of some change that has i ccurred in the permeability
of its membrane due to inflammation or asphyxia. In th< • - the

urine is usually reduced in amount. Probably there i> no purely gl<
erular or tubular type of nephritis, both structures sharing in t:
ability. While it can uol he said that any of the SO-called renal t<

thai have been advanced in recent years are u-rr from criticism, tl
nevertheless have contributed very useful information. The fact that

the kidney of the ehronic nephritic excretes a urine of more or less t:
low specific gravity would suggesl that here there is an impairmenl
the resorbing mechanism, and the failure of a kidney to
proper a unl of dye, a- in the phenolsulphonephthalein I

an impairmenl in the filtering apparatus. Hard and fast rules can

■ applied, however, and probably the tests must at presenl be inl

preted for the kidney as a w hole.

The Influence of the Nervous System on the Secretion of Urine. I
spite of numerous and repeated attempts to demonstrate that
mechanism governs the excretion *<\ mine, no proofs which
criticism have l>ecn forthcoming. Stimulation of the splanchnic
results in a diminution in the excretion of urine, probably

diminution in the hi I SUpplj of the renal vess

striction. Stimulation of the vagus nerves below the

branches has been said to rcsull in the augra

excretion Ashcr and I' The results - doubl ful, 1

520

I'll I : EXCRETION OF URINE

there is no increase in the oxygen absorption under the above conditions
( Pearce and < !arter13). In the light of the modern theory this vagal diure-
sis would be interpreted as due to an inhibition of the absorption in the
tubules rather than an augmentation in the actual excretion of urine.

There is no doubt that the renal nerves profoundly affect the excretion
of urine, but that they do so directly is very improbable, since perfectly

Fig. 173. — Nerve supply of the kidney. K, kidney; Si, 5L>, major and minor splanchnic nerves; V,
vagus; C.G., Celiac ganglion; A, aorta. (From Cushny.)

adequate renal function can be maintained in animals that have had the
kidneys entirely removed and then replaced. There are numerous re-
flexes that affect the rate of urine excretion by constriction of the renal
vessels. Injury to the bladder or ureter, abdominal injuries to the kid-
ney, or even cold applied to the skin, may result in incomplete suppres-
sion of the urine.

CHAPTER I. IX

THE AMOUNT, COMPOSITION, AND CHARACTER OF URINE

Bi R. G. l'i LE( i. B.A., Ml).

In the chapters on digestion and metabolism, we have followed I
course which food takes with especial reference to the nutrition of
body. The excretion of these elements of nutrition is taken up under a
number of ihe subdivisions of physiology, viz.. respiration, digestion,
kidney function and the skin. In the chapters on digestion attention was
called to the fact that the feces, besides containing the indigestible resi-
due of the aliment, contain several excretory products which at i
time or another have actually been within the body proper. These in-
clude normally the pigments of the body and many of the heavier mineral
salts, such as iron, magnesium, lime and phosphates; and under abnormal
conditions, as when the metals are given as medicine, bismuth and mer-
cury. The respiratory system excretes most of the oxygen and carbon.

Tn this chapter we shall take up the manner in which the body rid- il

of tin1 nitrogenous and some of the mineral waste materials. Even at
the risk of repetition, it will he advantageous 1" recapitulate certain fi
concerning the essential chemical structure of the urinary constituents,
so thai we may lie in a position to appreciate the kidney function in
health and disea

We now know that the kidney docs not form any of the specith n-

stitucnts of it- secretion (excepl hippuric acid". These substances are

formed in the various tissues of the body, and are brought to the kidneys

by the blood, where they are eliminated Bui while the constituents are
unchanged in chemical composition in the urine from that in which they
are found in ihe blood, they do occur in greatly changed proporti<
It is this variation in the concentration of the urinary constituents in

the Mood and the urine which presents the most important and at the

same time the mosl difficull question in the physiology of the kidney.
In the following table ihe percentag imposition of the blood plasma is

compared with ihat of an average sample of human urine i
column gives ihe change in concentration which eacl lituenl un

•joes in passiii'_r through the renal fill'

522 THE EXCRETION OF URINE

BLOOD PLASMA

URINE

CHANGE IN

PER CENT

PER CENT

CONCENTRATION

Water

90-9:i

95

Proteins, fats ami other colloids 7-9

—

Dextrose

0.1

—

—

Urea

0.0.1

0

60

Uric acid

0.002

0.05

25

Creatinine

Ammonia

0.001

0.04 ■

40

Sodium

0.32

0.35

1

Potassium

0.02

0.115

7

Calcium

0.008

0.015

2

Magnesium

0.0025

0.00(5

2

Chlorine

0.009

0.27

30

Phosphates (PO.)

0.003

0.1S

GO

Sulphates (S04)

Amino acids

The Amount of Urine

The amount of urine passed in twenty-four hours varies -with the
amount of fluid ingested and the proportion of fluid retained by the body
or excreted by other channels. Under ordinary conditions a twenty-four-
hour sample amounts to from 1000 to 1800 c.c-. of urine. On a constant
water intake the volume of urine is extremely variable for any single
day or part of the day (Addis and Watanabe3). The average volume of
urine excreted by twenty individuals on the third, fourth and fifth days
of a constant diet in which the fluid intake was 2.070 c.c, varied from
1,013 to 1,712 c.c. for a twenty-four-hour period, from 684 to 1,195 c.c.
for the first twelve hours of the day, and from 501 to 788 c.c. for the
first eight hours of the day. In normal subjects the amount of urine
excreted during the night is usually less than that during the day. This
is such a constant finding that in cases where more than 50 per cent of
the urine is excreted in the twelve hours of the night, suspicions of renal
disease should be aroused.

The Specific Gravity of Urine

In urine collected at different times of the day the specific gravity may
show a variation of ten points. Indeed, the specific gravity of the urine
has been taken as a functional test by clinicians. With a constant food
and water intake the variations found in the specific gravity of samples
of urine taken al two-hour periods in normal and pathological conditions
are very useful as criteria of the functional state of the kidney. Fixa-
tion of the specific gravity at cither a low or a high figure is not the
usual normal finding. The following figures will illustrate;

WI'H NT, COMPOSITION, Wl> CHARACTKK "F I'R

s In
A.M.

A.M.

j .. .1
P.M.

U t
P.M.

P.M.

X . . t r i l : 1 1 person

In Hypertensive Nephritis

In Myocardial I mpensation

1.016 I."!'.' 1.012 I. "11 l 1.010

I. Din L.009 1.010 l."i".. 1.010

L.018 l.i 'l'ii 1.019 1.018 0.020 L.021

'

The proportion of water to total solid- i- often very similar in plasma
.•mil urine, bul when water is taken in large quantities the urine sho
much greater changes than does the blood, and the solids may sink *
very low concentration. On the other hand, when little fluid i> taken or
when ili«' skin and bowel eliminate a large amounl of fluid, the urine
may become very concentrated withoul any change in the blood plasma.
The total solids in urine can 1m- determined with approximate accuri

by multiplying the last two figures of the -i it:-- gravity by ti

slant coefficienl 0.233 I Baeser).

The Depression of Freezing- Point

While the soli. Is <ii' tin- blood consist, for the mosl part, of proteins
and colloids, those "f tin- urine air made up of inorganic salts and small
organic molecules. The molecular concentration thai is, the total number
of molecules in a given quantity of riuid is under ordinary condil
much greater in the urine than in tin' hi 1. The molecular concentra-
tion may be determined by the depression of the freezing poinl of a fluid
below thai of distilled water (see page 1" . Blood freezes almosl
stantly at 0.56 C, while urine may freeze at variations of temperature
between 1 C. and 2.5 C; if very concentrated it maj at a

temperature as low as 5 <'.. or if dilute the freezing poinl may b<
high a- 0.075 «'.

The variability of the freezing poinl and tin- specific gravity of the
urine lead us to a consideration of the relationship of the urinary volume
to its concentration. In the first place, the volume of water ingested is
more frequently than otherwise in excess of the minimum absolutely
quired by the body, and is Bubjecl to greater variation than the Bub-

stance- excreted in the urine. The kidney i- able to eliminate
stituent of the plasma Which may he present ill eXCe88 without ilivo]'.

any changes in others. For example, when salt is a. hied to the and

excreted in tin- urine, the total chlorides are increased, hut the amount

of urine ami the other constituents may remain Unchanged;

may happen, excess i^\ sail leads to an increase in the volui

urine, hut the salt COI ntratioii remains .nt while that

other urinary bodies is d< fd. Similarly, although the ra1

524 Till: EXCRETION OP URINE

excretion is not demonstrably augmented by an increase in the volume
of the urine, an increase in the rate of urea excretion induced by the
ingestion of urea is accompanied by a larger volume of urine. That these
two factors may not stand in a causal relationship to each other is sug-
gested by recent work of Addis and Watanabe,8 avIio find no quantitative
relationship between the rate of increase in urea excretion and the
increase in urine volume, and who believe that the apparent relationship
is due to a common cause, such as alteration in the rate of circulation or
change in the activity of the kidney cells. Nevertheless, there appears to
be a limit set to the power of the kidney to take the urinary salts or water
from the plasma and to place them in the urine in quite different propor-
tions. The definite amount of water required to hold the urinary salts
has been termed the "volume obligative" (Ambard5). These limits of
concentration may be fixed by the energy which the kidney can bring to
act against the osmotic resistance.

The inconstancy in the behavior of the kidney toward ingested salts is
probably due to the fact that the salts reach the kidney in the concen-
tration in which they are held by the blood plasma, and not as they were
invested. If salt is absorbed rapidly enough to disturb the salt equilib-
rium of the tissues and plasma, then water will be abstracted from the
tissues, and the plasma on reaching the kidney will eliminate the salt
and water together. The difference in the reaction arises from the
varied activity in the tissues in general rather than in the kidney itself.

The Reaction of Urine

In man and the carnivora this reaction is generally acid to litmus or
phenolphthalein. The cause is found in the fact that the end products
of protein metabolism give rise to sulphuric and phosphoric acids the
acidity of which s'ives the urine an acid reaction. In the herbivorous
animals the alkaline reaction is due to the fact that vegetables and
fruits contain salts of dibasic or polybasic acids, such as acid potassium
nialate, citrate, acetate, and tartrate. Oxidation of these in the body
<i'ives rise to carbonates. Some of the carbonic acid is excreted through
the lungs, and hence the associated base, generally sodium or potassium.
In combined so as to form a weak basic salt.

The measurement of the acidity of the urine in terms of gram anions
or cations, like the same measurement in blood, requires the use of the
rather difficult electrical or indicator method, the principle of which has
been described in Chapter V. Expressed in terms of Ch, the acidity
varies between -1.7 \ 10 7 ami Unix |o '. The l<>l<il potential acidity —
that is. the number of II ions which wil] be Formed in the face i)\' a con-

AMOUNT, COMPOSITION, \\l> CHARACTER OP ITRINE

timial neutralization of those in solution may !><• obtained fairly accu-
rately by titrating the urine with \\ rmal alkali in the presence

neutral potassium oxalate, using phenolphthalein as an indicator (Folin .
Tin- results may be expressed in acidity per cent in terms N 10

\a()II required to neutralize LOO c.c. of urine [f the ammonia tion

is added to the titration results, the total potential acidity is very closely
measured.

The urine is more alkaline shortly after meals than ;it other tin.
since acid is being excreted by the gastric glands. It is more acid on ;t
meat than on a vegetable diet, and is acid during starvation because
protein is then the chief metabolite. In disease there is do character!
variation, save thai the urine is more generally acid, which may be •
plained by the Eacl thai in serious illness the diel is restricted. When
the acidity is increased, the excretion of ammonia is usually greal
since ammonium carbonate, the forerunner of urea, acts as an alkali and
neutralizes the acid radicles. This rise in ammonia, however, is
always proportional to the acid radicles present, since the fixed alkali
derived from fruits and vegetables may be sufficienl to neutralize the
acid formed.

THE SOLID CONSTITUENTS

For practical reasons we shall divide the constituents of the urine into
normal and abnormal. The former are presenl in the average urine in
amounts sufficienl to 1"' detected by ordinary means; the Latter only
rarely appeal' in detectable quantities. In a person eating an ordinary
diet the most import ant organic and inorganic constituents of the urine

are as follows:

Total Solids i 10 to 60 Grams) in Oni Liter oi Normal \'\

ORGANIC CONSTITUENTS, 25 H' <:M. INORUAK

Urea, 20-35 L,rm. - I ium chloride NnCl ,8-15

Creatinine, L.011.5 gin. Phosphoric aei i gm.

Dric acid, 0.5-1.25 gm. Sulphuric acid, SO ,2-2.5

Uippui ic acid, 0.1 l .7 gm. ra K ■ I . _

Other constituents (ethereal sulphat<

alic acid, ui inary pigmi ' Jalciui i i

1.5 2.3 gm. Magnesium Mg< i

Ammonia Ml
Iron (in

1 oropiled from Mosi

These urinary salts are presenl in the hi 1. and an I only by

the kidney. An investigation of the mechanism of r<
therefore include ;i stud} of the relationship existing 1
centration of the urinary salts in the Mood and in the urine.

52fi THE EXCRETION OF URINE

The Normal Organic Salts of the Urine

Nitrogenous Constituents. — The greater number of the organic salts of
the urine are made up of bodies which contain nitrogen, and which are
derived from the protein element of nutrition. The proteins, which form
the chief building material of the body, are broken up into their con-
stituent amino acids in the intestinal tract and absorbed as such by the
Mood. Portions of these acids are taken up by the tissues to repair and
to replace those proteins which have been discarded, and the remaining
protein, in excess of the body need for amino acids, is deamidized, the
major portion of the carbon, oxygen and hydrogen being oxidized to
form CO, and water, and the lesser portion of these elements being com-
bined with the nitrogen to form urea, ammonia, uric acid, etc. A similar
fate later awaits the nitrogen moiety which found a place in the tissues,
and which is replaced in turn by new nitrogenous bodies.*

Since all the ingested nitrogen, except a small and rather constant
amount which is lost by the feces and the sweat, is excreted in the urine,
the total nitrogen of the urine has been taken as a measure of the nitro-
gen or protein metabolism of the body. In normal conditions the protein
metabolism is adjusted in such a manner that the nitrogen intake is
equal to the nitrogen output, a condition known as nitrogenous equilib-
rium. If the nitrogen intake is reduced below the actual body needs,
the excretion of nitrogen is greater than the intake which indicates that
the body protein is replacing the protein usually furnished by the food.
The minimum amount of protein that the body must have to maintain
equilibrium varies in individuals, but is on the average between 5 and 6
grams of nitrogen a day, which corresponds to about 40 grams of pro-
tein. With the ordinary diet it is usually between 12 and 20 grams a
day, or represents from 75 to 125 grams of protein. Since protein is not
stored by the body except in periods of growth or after periods of under-
nutrition, an increase in the protein food is accompanied by an increase
in the nitrogen excreted in the urine. For this reason, unless the amount
of nitrogen ingested is known, the study of the total nitrogen of the urine
gives no information concerning the nature of the nitrogen metabolism
of the body. The total output bf nitrogen per day usually amounts to
10 to 15 grams — from 1 to 2 per cent of the urine by weight.

All the nitrogenous bodies of the urine are normally nonprotein, and
arise from similar bodies in the blood, where they exist in concentra-
tions of from 20 to 30 mg. per 100 c.c. In excreting the nitrogen of the
urine the kidney therefore takes it from a solution in which it is found
in a concentration of 0.03 per cent on the average and delivers it to a

For further details sec page 610.

AMOUNT, COMPOSITION, \\i> CnARACTEB OP URINE

solution containing an average of 1.00, or concentrates it at l<

times.

Urea. The chief of the nitrogenous bodies of the urine is urea, the
origin of which has been fully described in the chapters on metabolism.
No constituenl of the urine is Bubjecl to greater variation both in abso-
lute and in relative amounts. <>n an average diel containing 120 grains
of protein per day, the absolute urea excretion may amounl to aboul 30
grams; on a low protein diet it may be only a few grams. When the pro-
tein intake is high, the nitrogen eliminated as urea may be !,(» per cent
of the total nitrogen; but when the protein intake is low, this proportion
may fall to tin per cent. The difference is because on a low protein diet
the greater percentage of nitrogen eliminated is endogenous in origin,
and urea, which is the chief constituenl of the exogenous nitrogen mo
of the urine, is accordingly decreased on low diets.

In recent years the importance of the relationship between the con-
centration of the urinary constituents in the blood and the urine has
been much insisted upon, and since the estimation of the amounl

urea in the hi 1 and the mine is relatively simple, most of the work

has been done by using these values. Ambard and Weil believe that a
quantitative relationship exists between the fate ■ * t" mine excretion and
t lie concentration of urea in the blood and the urine, since the urea in
the blood acts as a stimulus to the renal cells. By comparing the rate
of una excretion and the concentration of urea in the blood and urine
in a mathematical formula, they have obtained a value which they he-
lieve is more or less fixed for the normal kidney. This expression is

known as Ambard's <■<>< l]ici< ni oml formula,* and has 1 n us^d as a

means ..f evaluating the functional capacity of the kidney.

Whatever tin- value of the formula may lie in expressing the relationship
existing between the rate of urea excretion and the concentration of this
sail in the blood, it is certain that, in diseased iditions where impair-
ment of tlie kidney is certain, the concentration of urea in the blood
mains permanently at an abnormally high average level, although I

ibard and \V< U'a formula i-:

IV

K , in which:

\V

D — x

P

K

D = output ol

P - weight of the patient.

' f urine.

itandard weight

the urine.

The average value for tl
Critical review - of the « u k I
w tanabe.'

528 THE EXCRETION OF UftlNE

amount of urea excreted during twenty-four hours may be exactly the
same as under aorma] conditions. Probably the increased concentration
uf area in the blood under these conditions is a compensatory measure
to provide sufficienl pressure to cause its excretion through a damaged
outlet. It is tins increase in urea of the blood which is indicated by the
term urea retention in nephritis.

It must not be lost sight of, however, that the approximate constancy
of the combined formula is due in laru:e part to the mathematical con-
struction, and also to the fact that any increase in the concentration of
urea in the blood is usually accompanied by an increased rate of urea
excretion. The factors which are most variable occur as the square or
the square roots of their values, and thus the disturbing effect they pro-
duce on the constancy of the resultant of the formula is greatly re-
duced, while the most constant factor, the concentration of urea in the
blood, is used with modification. In such a complex mechanism as the
renal function it is very probable that other factors are of great im-
portance in controlling the rate of urinary excretion. Many of these
factors can not admit of mathematical expression. The writer seriously
doubts the advisability of adopting an empirical formula as a means
of expressing unknown physiological laws. Such measures are apt to
give a sense of knowledge altogether false, and thus hinder research
progress.

The upper limit of blood urea-nitrogen is about 20 mg. per 100 c.c..
which would correspond to about 0.45 gm. of urea per liter of blood.
The average figure is half of this amount. The maximum concentration
of urea in the urine is seldom over 8 per cent. On this basis the kidney
can raise the concentration of the urea in the urine, at a conservative
estimate, from 100 to 200 times. Normally the daily output of urea
nitrogen may range from 8 to 12 gm., and the nitrogen which it contains
is roughly 80 per cent of the total excretion for the day.

Ammonia. — The chief source of ammonia in the body is from the ni-
trogenous portion of the deamidized amino acids. The ammonia found
in excess in the portal blood is derived from ingested ammonium salts
and from ammonia resulting from bacterial action on proteins in the
intestinal tract. The ammonia of the body is present chiefly in the form
of ammonium carbonate, and it is this salt that is the precursor of urea.
Because ammonium carbonate is so readily converted into urea by the
tissues of the body, little ammonia is normally present in the systemic
blood. The greater portion of the ammonia that finds its way into the
urine serves as a base to transfer acid radicles either ingested or formed
within the body. The amount of ammonia in the urine, therefore, is an
indirect measure of the extent of urea formation and of the acid bodies

Wlni \T. COMPOSITION, \M> CHARACTER "l ' RIN

of the blood. For the latter reason the determination of the ammonia
excretion in urine is of some clinical importanc The ingestion of
mineral acids increases the ammonia excretion, while alkalies tend to
reduce it. During Easting and in diseases such as diabetes, where t!
is an abnormal metabolism, the amounl of ammonia in tli" urine is in-

creased. Ordinarily the dailj outpul of ai nia nitrogen does uol

exceed 0.5-0.6 gm., constituting 3-5 per cenl of the total amounl of
nitrogen.

Creatinine. — On a meat-free diet the daily excretion o tinine is

remarkably constant, amounting to from 7 to 11 1 1 1 -_r . per kilogram of
bodj weight. For this reason iu determination is accepted as an in-
dispensable feature in metabolism investigations involving urine an-
al \ sis.

Any gross variation from the normal amounl indicates the certain
failure of the attendants to colled all of the twenty-four-hour specimen
of urine. Normally the blood contains from 1 to 2 mg. per LOO e

The creatinine is one of the last of the urinary constituents to accumu-
late in the blood during renal insufficiency, and for this >n affords
a reliable prognostic indication concerning the patients' condition. A

rise in the creatinine concentration of the l»l 1 is eviden E serious

renal disease, patients with concentrations of 5 mg. never i ring

(Chase and Meyers : The concentration of creatinine in tin- urine is
aboul H»» times greater than in the bl 1.

In adult man creatine does no1 appear in the urine save during starva-
tion or wasting diseases. In woman it is absenl save after postpartum

olution of the uterus. Children commonly excrete creatine al< -
with creatinine until the middle years of childl I.

The Purine Bodies and Uric Acid. The mosl important purine in
human urine is uric acid. Xanthine is the nexl in importance, and small
amounts of hypoxanthine, guanine, and adenine are found. Among the
mosl interesting of the salts of the urine to the clinician are the un
because an accumulation of uric acid in the body was believed to be
responsible for many obscure clinical conditions. It is quite true that
tlif salts of uric acid arc found iii higher than normal amounl in some
.lis. especially gout, leukemia, and chronic nephritis, but the many

vague theories associated with uric acid and disease ha^ ago '

exploded.

The human body has the almost unique distinction among mammals
of not being able to destroy anj of the uric acid it produces, and h<
all the uric acid formed during metabolism must b< I in the urine

Unfortunately the kidney appears to be less competi rid the body

of this wast.- than it is of the other urinan metabolites, a the

530 THE EXCRETION OP URINE

earliest signs of renal insufficiency is now held to be a failure of the
kidney to prevent the uric acid of 1 lie blood from increasing. Perhaps
the reason for tin1 inability of the kidney to excrete uric acid readily
lies in the ('act that its salts are among the least soluble of those in the
urine. It is on this account that when the urine cools, a red sediment of
urates containing certain pigments often separates out.

The uric acid of the urine is possibly derived entirely from the purine
metabolism of the body, in which the nucleins either of the body cells or
of the exogenous food take part. It is decreased during starvation and
increased by eating food rich in nucleins, such as liver and sweet-
breads.

Under ordinary conditions the excretion of uric acid amounts to from
0.3 to 1.2 gm. per day (0.02 to 0.10 per cent), the variation being de-
pendent upon the state of health, diet, or personal idiosyncrasy. The
blood of a normal individual contains on the average 1.8 mg. of uric
acid per 100 e.e. The kidneys are therefore able to concentrate the
uric acid in the urine from 30 to 60 times over its concentration in the
blood plasma.

The purines found in coffee and tea (caffeine, etc.) are excreted in
the urine as salts not of uric acid but of methylated xanthines.

Hippuric Acid. — This is a constant constituent of the urine of her-
bivorous animals, and is usually present in small amounts in human
urine. The amount rarely exceeds 0.7 gm. a day, but on a diet rich in
fruits and vegetables it may exceed 2 gm. It is interesting, since it is
the only urinary constituent that is synthesized by the renal cells.

Amino acids are always present in small amounts in the urine, con-
stituting, according to D. D. Van Slyke, about 1.5 per cent of the total
nitrogen. The estimation of the amino-acid nitrogen of the urine has
not been found to be of any clinical significance.8

The aromatic oxyacids are normally present in the urine in varying
amounts. These include phenol, indoxyl, skatoxyl, and phenylacetic,
paraoxyphenyl, propionic, oxymandelic and homogentisic acids. These
bodies are derived from phenylamino acids, such as tyrosine, tryptophane,
and phenylalanine. It is believed that the putrefactive decomposition
of proteins in the large intestine results in the production of these toxic
Indies. The body protects itself by oxidizing them and uniting them
f<> sulphuric acid to form the ethereal or conjugated sulphates, which
are found in the urine in the form of sodium or potassium salts: The
determination of the amounts of these bodies in the urine has therefore
been taken as an index of the putrefaction going on within the bowel.

The chief of these bodies is urinary indican, which is found usually as
a potassium salt. The test for indican in the urine consists in oxidiz-

\Miii vr. COMPOSITION, \\l> CHARACTER OP I'BIl 531

ing the indoxyl in an a<-i<l solution by means of ferric chloride to indigo
blue, and shaking ou1 the indigo blue with chloroform. The depth of
the eolor of the chloroform affords a rough means of determining
the amount of indican present. The fad thai the indican tesl is m
live must nut be taken t" mean that the intestinal pi ormal,

fin- if the intestine fails to contain phenylated amino acids, or tin- pr<
bacteria are uo1 present, no indican will be found. On the other hand,
the putrefactive process of the large bowel may no1 he very i jive,
yel the amount of indican in the urine 1m- increased, becaus - ater

absorption due to constipation.

skatolc, a fecal-smelling substance, is formed by certain kinds of bac-
teria. The greater proportion of this substance is excreted by the bowel,
hut it' tin- person i> constipated, some of it may find its way into the
blood to impart ;i fecal odor t<i the breath ami urine. I'- pi
therefore has some diagnostic importance.

A very interesting body which is sometimes found in tin- urine is
homogentisic . /-•'',/. It is thoughl t" be an intermediate step in the metab-
olism of tyrosine, am) is found in the urine of people suffering from
alkaptonuria. The disease is remarkable in that it appears to run in
families ami produces no ill effects. Homogentisic acid is a str
reducing agent, ami fur this reason may he confused with sugar in
Pehling's test.

Tin inorganic constituents of the urine include the acids: chlorides
sulphates ami phosphates; ami the bases: sodium, potassium, magnesium,
ami calcium.

The Acids of the Urine. The chlorides compose the hulk of the acid
radicles in the urine. Although they appear to he necessary constituents
of the living cell, they do nut. so far as known, enter into combinati
with the organic constituents. The tissues appear to require a rather
definite concentration of sodium chloride in order rry on their

work, for reduction in the sodium-chloride intake of the body results
in a reduction in the chloride excretion by the urine. In salt s\
the chlorides may disappear entirely from the urine, the amounl
chloride excreted appearing t«> he closely related t>> the amount

invested. When the intake is constant, the rat< n is like

more or less constant, hut a sudden reduction in the salt of the diet may
b impanied by a slight d< in the salt content <>f the bl<

with an attendant loss of water. On the other hand, when the salt is

again taken, there is a retention of salt ami of water, with a c
increase in body weight, until equilibrium is ■ 1 on the

level. While the above is the usual reaction, a tenl

salt without an increase in the wati >f the bodv may occui

532 tin; EXCRETION of iimm:

some apparently norma] cases. This is due probably to the deposition
of salt in the tissues.

Careful studies fail to confirm the idea that there is a fixed relation-
ship between the salt and the water of the body. As with the nitroge-
nous constituents, however, there appears to be a relationship between
the rate of excretion of chlorides and the amount of chloride in the blood.
Ambard believes that this relationship, like that of the excretion of urea
to the blood urea, is capable* of being expressed mathematically (see
page 527), if allowance is made for the fact that NaCl is not excreted
after it falls below a certain concentration in the blood equal to about
5.62 gm. per 1000 c.c. This level is more or less constant for normal
individuals, but is considerably increased in disease of the kidney. This
is known as the threshold of chloride excretion.

The amount of sodium chloride excreted in the urine in twenty-four
hours varies between 8 and 20 gm. a day, according to the intake. It
is therefore apparent that the kidney is able to concentrate the salts
of the plasma from ten to twenty times.

The Sulphates. — Since the inorganic sulphates do not form an im-
portant constituent of the food, the greater portion of the sulphates of
the urine are derived from the sulphur found in the protein molecule.
For this reason the sulphates of the urine, like the nitrogen, are a meas-
ure of protein metabolism. An increase in the nitrogen excretion is
accompanied by an increase in the sulphur excretion, the ratio being
about 5 to 1. The daily output of sulphur is between 1 and 3 gm. The
greatest output is in the form of the alkaline sulphates, about 10 per
cent in combination with aromatic bodies, and a small amount in com-
bination with amino acids and neutral organic salts.

The phosphates of the urine are derived from the food and from the
oxidation of phosphorus-containing bodies in the tissues such as
nuclein, lecithin, etc. The daily excretion varies between 1 and 5 gm.,
calculated as P205. When calcium or magnesium is present in the
food, they are excreted by the bowel as phosphate, and proportionately
less is found in the urine. The amount usually excreted in the feces
equals about 30 per cent of the total.

Since phosphates in the urine exist as a mixture of the mono- and di-
sodium hydrogen phosphates, they have an important bearing on the
reaction of the urine, the amount of each varying with the degree of
the acidity of the urine.

On a heavy protein diet the urine is acid on account of the sulphuric
and other acids formed from the meat, and in this case there is a greater
amount of phosphoric acid and the mono-sodium hydrogen phosphate.
When the urine is alkaline or less acid, as il is on a vegetable diet, there

Whii \ r. « OMPOSITION, AND ' BAR ■ OP i RIN

is a large amounl of the disodium hydrogen phosphal lalcium

and magnesium phosphates are mo i nble than the diphosphat

the same metals, deposits of tl arthj phosphati I i"

neutral or alkaline urines. When the urine is heated, the diphospl
of calcium breaks up into the mono-calcium and a fcri-calcium pi

phate, which at nuts Eor the fine turbidity often taken for albumin in

the flame test. Addition of arid will cause this to disappear. Th<

tals of triple phosphates which occur in alkaline urine are ammonium

magnesium phosphate, N 'I I Mg I'1 1

KIDNEY REFERENCE

Monographs

Beddard, A. P.: Recenl Advances in Physioloj

L906.
Cushny, A. B.: Secretion of Urine, Longmans, Green ..v I '17.

(Original Pape

iBrodie, T. G., and Mackenzie, J. J.: Proc. Ro - . L914, lxzxvii, I
-•'ushiiv, A. I;.: Secretion of Urine, 1917, |>. Is.
sAddia and Watanabe: Jour. Biol. Chem., 1916, x\i\, 2
Mosenthal, II. O.: Arch. [nt. Med., 1915, xvi, 733.

Lmbard and Weil: Physiologie normale el pathologique des reins, Par
.1. B. Bailliere el fils.
BMaclean, P. C.: Jour. Exper. Med., 1915, xxii, 212.
• ('Ii.-isc and Meyers: Jour. Am. Med. Assn., 1916, Ixvii, 931.
JVan Slyke, D. D., and Meyer, G. M.: Jour. Biol. Chem., 1912, ■: and I

xvi, 197, 213 and 231.
»Knowlton, I'. P.: Jour. Physiol., 1911, xliii, 219.
Baxcroft, J., and Straub, II.: Jour. Physiol., 1910, xli, '
uRowntree and Geraghty: Jour. Pharm. and Exper. Therap., 1910, i. 57
i2Asher and Pearce, R. G.: Zeitschr. f. Biol., 1913, Ixiii, -
ispearce. R. G., and Carter, E. P.: Am. Jour. Physiol., 1915, \\\

PART VII

METABOLISM

CHAPTER LX

METABOLISE

Introductory. — The object of digestion, as we have seen, is to render
the food capable of absorption into the circulatory fluids — the blood and
lymph. The absorbed food products are then transported to the various
organs and tissues of the body, where they may be either used at once
or stored away against future requirements. After being used, certain
substances are produced from the foods as waste products, and these pass
back into the blood to be carried to the organs of excretion, by which they
are expelled from the body. By comparison of the amount of these ex-
cretory products with that of the constituents of food, we can tell how
much of the latter has been retained in the body, or lost from it. This
constitutes the subject of general metabolism. On the other hand, we may
direct our attention, not to the balance between intake and output, but to
the chemical changes through which each of the foodstuffs must pass be-
tween absorption and excretion. This is the subject of special metabolism.
In the one case we content ourselves with a comparison of the raw ma-
terial acquired and the finished product produced by the animal factory;
in the other we seek to learn something of the particular changes to which
each crude product is subjected before it can be used for the purpose of
driving the machinery of life or of repairing the worn-out parts of the
body.

In drawing up a balance sheet of general metabolism, we must select
\'<>r comparison substances that are common to both intake and output. In
general the intake comprises, besides oxygen, the proteins, fats and car-
bohydrates; and the output, carbon dioxide, wafer and Ihe various nitrog-
enous constituents of urine. This dissimilarity in chemical structure be-
tween the substances ingested and those excreted limits as, in balancing the
one against the oilier, to a comparison of the smallest fragments into which
each can be broken by chemical agencies. These are the elements, and of
them carbon and nitrogen arc the only ones which it is possible to measure

534

Ml TAB0U8M

with accuracj in both intake and output. Prom balai
and output of carbon and nitrogen and from information obtain ob-

serving the ratio between the amounts of oxygen consumed by the animal
and of carbonic acid excreted, we can draw Ear-reaching conclusi*
garding the relative amounts of protein, fa1 and carbohydrate that 1
been involved in the metabolism.

As has already been stated, thi ntial nature of the metabolic pn

< 38 iii animals is one of oxidation thai is, one by which large unstable
molecules are broken down to those thai are simple and stable. Dur-
ing this process of catabolism, as it is called, the potential e

away in the Large molecules l omes liberated as actual or kinetic energy

thai is, as movemenl and heat. It therefore becomes of imports
compare the actual energy which an animal expends in a given timo with

the energy which has meanwhile 1 □ rendered available bj metabolism.

W'c shall first of iill consider this Bo-called energy balanci and then ■
i to examine somewhal more in detail the material balance of the body.

ENERGY BALANCE

The unit of energy is the large calorie I written C.)j which is the amount
of heal required 1" raise the temperature of one kilogram of water through
one degree (Centigrade) of temperature. We can determine the cal<
value by allowing a measured quantity of a substance to burn in c
pressed oxygen in a steel bomb placed in a known volume of water at a
certain temperature. Whenever combustion is completed, we find out
through how many degrees the temperature of the water has bea
raised and multiply tins by the volume of water in liters. Measured

in such a calorimeter, as this apparatus is called, it has 1 a found that

the number of calories Liberated by burning one gram of each of the proxi-
mate principles of t 1 is as follow - :

Carbohydral ~ rch |J

Protein

The same llUtnlier of Calories will he lilierated at whatever lad1 the com-

bustion proceeds, provided it results in the same end products, When
a substance, such as sugar or fat, is burned in the pri s i, it

yields carbon dioxide an. I water, which are also the end produ the

metabolism of these foodstuffs in the animal bodj ; therefore, when a gram
of sugar <>r fat is quickly burned in a calorimeter, it rele - - the same

■ p •■

formi

536

METABOLISM

amount of energy as when it is slowly oxidized in the animal body. But
the ease is differenl for proteins, because these yield less completely oxi-
dized end products in the animal body than they yield when burned in
oxygen; so that, to ascertain the physiological energy value of protein, we
must deduct from its physical heat value the physical heat value of the
incompletely oxidized end products of its metabolism. It is obvious that
we can compute the total available energy of our diet by multiplying the
quantity of each foodstuff by its calorie value.

Methods.- In order to measure the energv that is actually liberated

Fig. 174. — Respiration calorimeter of the Russell Sage Institute of Pathology, Bellevue Hospital,
New York. At the right is seen the table with the absorption tubes; and in the middle, at the
back, the electric control table for regulating the temperature of the double walls of the calorimeter.
At the extreme left is the oxygen cylinder. ( Lusk's Science of Nutrition.")

in the animal body, we must also use a calorimeter, but of somewhat dif-
ferent construction from that used by the chemist, for we have to provide
for long-continued observations and for an uninterrupted supply of oxy-
gen to the animal. Animal calorimeters are also usually provided with
means for the measurement of the amounts of carbon dioxide (and water)
discharged and of oxygen absorbed by the animal during the observation.
Such respiration calorimeters have been made for all sorts of animals, the
most prefect for use on man having been constructed in America (see Pig.
171 . As illustrating the extreme accuracy of even the largest of these,

METABOLISM

it is interesting to note thai the actual heal given ou1 when a definite

amounl of alcohol or ether is burned in 01 E them exactly corresponds

t(. the amounl as measured by the smaller bomb-calorimeter. All of the
energy liberated in the body does not, however, take the form of heat. A
variable amounl appears as mechanical work, so thai to m< • in calo
fill of the energy thai an animal expends, cne must add to the actual cal-
ories given out. the calorie equivalenl of the muscular work which has
been performed by the animal during the period of observation. This
be measured l>\ means of an ergometer, a calorie corresponding to
kilogram* meters of work. That it has been possible to Btrike an accui
balance between the intake and the outpul of energy of the animal body,
in one of the achievements of modern experimental biology. It call be
done in the case of the human animal ; thus, a man doing work on a bicycle

ergometer in the Benedict calorimeter gave ou1 - ctual heal 4,833 I
and did work equalling 602 C, giving a total of 5,435 C. By drawing up

a balance sheet of his intake and output of t 1 mat. -rial during this

period, it was found that the hail consumed an amounl capable of

yielding .~>.4.~>!) < '.. which may be considered as exactly balancing the actual

olltpUt.

It would he out of plaee to give a full description of the respiration
calorimeter here. The general construction will be seen from the accom-
panying figure of the form of apparatus iu use for patients in the Russell
Sage Institute. New York. <>ne of the most interesting details of ita
struction concerns the means taken to prevenl any l"ss of heat from the
calorimeter to the surrounding air. This is accomplished in the following
way: Tie innermosl layer of the wall is of copper; then, separated from

this by an air space, is another wall of copper, outside of which are two
wooden walls separated from each other and from the outer cupper walls

by aii- spaces. The tw >pper walls are inected through thermoelectric

couples, so that an electric current is set up whenever there is any dif

elice ill their temperatures. The current is ohseiwed by means of a gal-

vanometer placed outside the calorimeter, and from its movements the ob-
server either heats up or cools down the outer copper walls - - ■

reel the difference of temperature causing the current. This is done hy an
electric heating device or by cold water tubes placed between the oul
most copper and tin- innermost wooden wall- Since the temperatur<

the two copper walls is the same, there can he no exchange of heat het w

them, and consequently none of the heat that is absorbed by the inner i
per walls is allowed to he carried away. All the heat given out by the
animal is absorbed by the stream of cold water flowii >ugh the coils

Igh \\ lii< !

538 METABOLISM

of pipe in the chamber. The heat used to vaporize the moisture from
skin and lungs must of course also be measured. This is done by collect-
ing the water vapor in a sulphuric-acid bottle placed in the ventilat-
ing current. By multiplying the grams of water by the factor for the
latent heat of vaporization, we obtain the calories of heat so eliminated.

' * The calorimeter contains a comfortable bed and is provided with two
windows, a shelf, a telephone, a fan, a light, and a Bowles stethoscope for
counting the pulse. The ordinary experiment takes about as long as a trip
from New York to New London. Patients, as a rule, doze from time to
time or else try to work out some scheme by which they can amuse them-
selves without moving. After three or four hours they are rather bored
by the quiet, and the observations are not prolonged beyond this time.
They are allowed to turn over in bed once or twice an hour, but reading
and telephoning are discouraged, since these increase the metabolism.
The air in the box is fresh and pure, the patient suffers no discomfort, and
objections to the procedure are very infrequent. Most of the patients
are only too glad of the extra attention, and they insist that the calor-
imeter has a marked therapeutic value." (Du Bois.)

Normal Values. — Having thus satisfied ourselves as to the extreme
accuracy of the method for measuring energy output, we shall now con-
sider some of the conditions that control it. To study these we must first
of all determine the basal lieai production — that is, the smallest energy
output that is compatible with health. This is ascertained by allowing a
man to sleep in the calorimeter and then measuring his calorie output
while he is still resting in bed in the morning, fifteen hours after the last
meal. When the results thus obtained on a number of individuals are
calculated so as to represent the calorie output per kilogram of body weight-
in each case, it will be found that 1 C. per kilo per hour is discharged
—that is to say, the total energy expenditure in 24 hours in a man of 70
kilos, which is a good average weight, will be 70X24 = 1,680 C.

When food is taken the heat production rises, the increase over the
basal heat production amounting for an ordinary diet to about 10 per
cent. Besides being the ultimate source of all the body heat, food is there-
fore a direct stimulant of heat production. This specific dynamic action,
as it is called, is not, however, the same for all groups of foodstuffs, being
greatest for proteins and least for carbohydrates. Thus, if a starving
animal kept at 33° ( !. is given protein with a calorie value which is equal
to the calorie output during starvation, the calorie output will increase by
:;i) per cent, whereas with carbohydrates it will increase by only G per
cent. Evidently, then, protein liberates much free heat during its as-
similation in the animal body; it burns with a hotter flame than fats or
carbohydrates, although before it is completely burned it may not yield

IfETABOU

inch enerj is tin1 ease, for examph w i

peculiar prop< if proteins accou U beating qual-

ities. It explains why protein « -• ■ 1 1 1 1 I on of I

pies living in cold regions, and why it I down in 1 t of 1

who dwell near the tropics. Individuals maintained on a lo*
may suffer intensely from cold.

It' we add to the basal heat production • t 1 680 ' ther 1' ■- I

lo per '-'lit I "ii account of food, tl

short of that which \\»- know must be Liberated when we calculate tin-
available energy of the diet, which \\<' may tak< a 2 0 C. Wnal
comes of the extra fuel ! The answer is that it

Thus it has been found that if the observed ; - if lying d<

in the calorimeter, is madi I in a chair, the heat pro

S per cent, or if he performs such n te - would

ordinary work (writing at a desk) it may rise 29 per cent — that - |

90 C. per hour. There is, however, practically no diffi in the

rv^y output of a person lying Hat or lying: in a semi-reclining j
tion, as in a steamer chair. Allowing eight hours for Bleep and -
hours for work, we can account for about 2,168 < '.. the remaining
( '. that are required to bring the total to that which we know, from b1
tical tables of the dirts of such worfa - i be the actual daily expeni I
being due to the exercise of walking, [ft!

still more calories will be expended; thus, to - I a hill of 1,( * at

the rate of 2.7 miles an hour requires 407 extra calories. Field work 5
may expend, in 24 hours, almost twice as many calori - -

in sedentary occupatio

Standard for Comparison

When the energy outpul per kilo body weight is determined in anin
of varying size, the values are greater the lighter the animal. This s
evidenl from the following results obtained on

n //

i;

When, on the other hand, instead of body weight, t; nir-

fa \ the body is taken as tl ilculation, results

constant are obtained. Following arc tin

this bas

54(1

METABOLISM

Surfact in squart cm.

(1)

-

(5)

10,750
7,662
5,286

3,724

.> (.)■■

Ih ni production in calorit s

pi r square mt t< r of sur-
face i>i r ilny
io.n,r,

1097
1183
1153
1212

(Rubner)

Such results have prompted observers to ('(include that the determining
factor in the calorie output of warm-blooded animals is the relative sur-
face of the animal. This is greater the smaller the animal, with the con-
sequence that heat is more rapidly lost to the surrounding air from the
surface, thus requiring more active combustion. Until quite recently it has
been generally believed that such a relationship between body surface and
heat production did actually exist, but, thanks to the work of F. G. Bene-
dict7 and E. F. and 1). Du Bois6, it is now known that the calculations wrere

20

200

30

40

50

60

70

80

90

100

o->

ct:.

190

180

70
i —

SI60
5150

CD

G'30
120
110
100

^

17
\

>.

\

\2D

N

^1

v22

K

&

13

\

\

\

s

\

\

N8

\e

«.

— h

1 — ^
\

\

\

\

\

\

N

^

\

\

\

^

19

20

\

\

\

\

N

17

>

\

\

\

\

\

\

>

^

\

\

\

\

I

4

Lb

3^

N?

\

\

i.;

I

\

\

\

sfl

i.i

~t2

110
200

190
180
170
160
150
140
130
120
110

20 30 40 50 60 70 80 90 100

WEIGHT-KILOGRAMS

100
10

Fig. 175. — Chart for determining surface area of man in square meters from weight in kilo-
grams (Wt.) ancl height in centimeters (Ilt.i according to the formula: Area (Sq. Cm.) = Wt.
0.425 XHt. 0.725 X71.84. (From Dubois and Dubois, Arch. Int. Med., 1917, vol. 17.)

based upon incorrect computations of the body surface. In the older re-
searches the calculation was made by usiii^- a formula known as Meeh's, in
which weight was multiplied by a certain factor (viz., 12.312 x ^weight).
Du I'.ois, however, has shown that an average error of 16 per cent is in-
curred in using this formula. For accurate measurement the body was
covered with thin underwear, which was then impregnated with melted
paraffin and reinforced with paper strips to prevent it from changing in
area when removed. rJ 'his model of the surface was afterwards cut up
into flat pieces and photographed on paper of uniform thickness, the pat-

METABOM ">ll

terns being then cul out, and weighed. Prom I ults it wa to

calculate the acl ual surface area.

Where the heighl and weighl are known, a fairlj accurate computation
of tlif surface can be secured by using the following formulas: A W

II 71.84 j .1 being the surface area in Bquare centimel H

heighl in centimeters; and W} the \\ • • i lt 1 1 1 in kilograms. Based on this
formula, a charl has been plotted from which the surfi de-

termined ;ii a glance Fig. 175 . Another method recently emplo;
Benedicl Is based on measurements made from photographs of the subj
in various post s.

By the use of these more accurate measurements of body surface, it -
now known that, although the surface-area law gives us eonstanl results
for the energy outpul of differenl individuals of similar build, and off<
us a much more accurate basis for comparing th differenl laboratory

animals than body weight, yel it breaks down when applied to men in widely
differing states of body nutrition. Thus, in the case of a man wl ved

for a month, the calorie output per square meter of surface decreased I

wards tl nd of the fast by 28 per cent. Obviously, therefore, it would be

incorreel to draw conclusions regarding possible ili.i mr< ^ in energy output
of a series <>t' emaciated or corpulenl individuals by <->>ni pai-ist >n of their
calorie output per square meter of surfj with that of normal individuals.

Tlic determining factor of energy output is undoubtedly the ral

condition of bodily nutrition — the active mass of protoplasm of the body

Benedict). Thai there is a relationship between the body Burface and

metabolism is undoubted, bu1 the relationship is not a causal one. Al

aent, therefore, the onlj - ■ method to employ in comparing
metabolism of normal and diseased individuals is that called by Benedict
"the group method," in which the metabolism of groups of :
like height and weighl is compared, ii being assumed that such individuals
have the Bame general growth relations. For the application of this group
method, however, more extensive data will be required than exist at p
rut. and although some of the conclusions drawn from results comput
the Burface-area 1»a^is may have to he revised, ii is probable thai
are in general correct.

Influence of Age and Sex

The energy output is low in the newly born; it inc
the first year, reaching a maximum at about thr<
then rapidl} declining to aboul twenty, after which i* declines much n
slowly. The decline in the earlier years do lily. 1
ever, tor at the period jusl preceding the oi puberl i in-
crease In mes evident, indicating that at this

542 METABOLISM

the growing organism is being stimulated. Females have a lower energy

output than males, and the stimulating influence of puberty is less marked
in them.

In round numbers, 40 C. per square meter of surface per hour is the
energy output of normal men, a 15 per cent deviation being considered
as decidedly abnormal. The average metabolism of fat and thin subjects is
the same, but that of women is 6.8 per cent lower than that of men. The
basal metabolism of a group of men and women between the ages of forty
and fifty was 4.3 per cent below the average for the larger group between
the ages of twenty and fifty; and that of a group between fifty and sixty
years was 11.3 per cent lower.

Influence of Diseases

The measurements have been made by the direct method which has just
been described, but since the much simpler indirect method (page 554)
yields comparable results, it is being adopted for clinical purposes. These
results were obtained by making parallel determinations of energy out-
put by both methods, in disease as well as in health. Some of the ob-
servations that have been made on the energy output in various diseases
are as follows : In very severe cases of exoplitlialmic goiter, heat produc-
tion may be increased by 75 per cent over the normal; in severe cases, by
50 per cent. The warmth of the skin and the sweating, which are promi-
nent symptoms of this disease, are therefore accounted for by the in-
creased elimination of heat, and it is considered possible that the other
symptoms would be produced in any normal individual were his metabo-
lism maintained for months or years at the high level which it occupies in
goiter. In the opposite condition of myxedema, the energy output is
markedly reduced, but rises slowly during treatment with thyroid extract,
or much more rapidly with the very active thyroid hormone recently iso-
lated by Kendall. In diabetes it has often been thought that the rapid
emaciation and loss of strength were dependent upon an excited state of
metabolism, or a useless burning up of the energy material. The most
reeent work, however, clearly shows that this is not the case, the basal
metabolism as calculated per unit of body surface being within the limits
indicated above. During the starvation treatment the energy output may
be much below the normal. Tn uncompensated cases of cardiorenal dis-
ease, there is increased energy output. Tn pernicious anemia the metabo-
lism is normal, although in severe cases there may be an increased demand
for oxygen.

Even at the risk of repetition, it is important to point out that in all
these diseases the energy output, is the same whether measured directly or
by the indirect method about to be described.

Ml T\l:u|.i>\i

THE MATERIAL BALANCE OF THE EODY

We musl distinguish between the balai i tic and the in-

organic foodstuffs. Prom a studj of the former we Bhall gain informal

arding the Bources of the energy production whose behavior under
various conditions we have just studied. Prom a stud] nic

balance, although we Bhall learn nothing regarding ene (change —

for Buch substances can yield no energy we shall become acquainl

with Beveral facts of extreme importance in the maintenam f nutrition

and growth.

To draw up a balanct sheet of organic intafo and output requires an
accurate chemical analysis of the food and of the excreta urine and
pired air).

Methods for Measuring- Output

The principle by which the output is measured will be understood by
referring to Pig. lTii. from which if will be seen thai the calorimeter
is connected with a closed system of tubes provided with an air-tighl

<Q * - water to absorb heat/

d Chamber for animal
window

Fig. 17i Dia(
the to
amoui

1. lh<

tary blower or pump to maintain a constant cum ted by

the arrows. Following the air stream .-is it leaves the chamber, v.
a side tube connecting with a meter to indicate changes in volume

544 \ii.T\r.nus\j

air in the system. Beyond this and the pump is a specially constructed
bottle containing concentrated 1LSO,. then one containing soda lime, and
lastly another JLS04 bottle. The first II,!S04 bottle absorbs all the water
vapor contained in the air coming from the chamber; the soda lime bottle
absorbs the C02J and the second 1LS04 bottle absorbs water that is pro-
duced in the chemical reaction involved in the absorption of the C02 by
the soda lime (2NaOH+C02=H20+Na2C03). By weighing these ab-
sorption bottles before and after an animal has been for some time in the
chamber, the weight of H20 and of C02 given out can be determined. An-
other side tube leads to an oxygen cylinder, the valve of which is manip-
ulated so as to cause oxygen to be discharged into the system at such a
rate as to compensate exactly for that used up by the animal, as indicated
by the behavior of the meter. The amount of oxygen required is de-
termined cither by weighing the oxygen cylinder before and after the ob-
servation or by measuring the volume of oxygen used by passing it through
a carefully calibrated and very sensitive water meter inserted on the side
tube that connects the 02 cylinder with the main tubing of the system.
Since muscular activity causes pronounced changes in the rate of me-
tabolism, means are usually taken to secure graphic records of any move-
ments made during the observation.

The growing importance in clinical investigations of measurements of
the respiratory exchange and the necessity for having methods that are as
simple as is consistent with accuracy, have led to the introduction of
several other forms of apparatus, of which those of F. G. Benedict and of
Tissot* are the most important. In the former a tightly fitting mask,
applied over the nose and mouth is connected, by a short T-piece, with
the same tubing as that used in the respiration calorimeter. The patient
thus breathes in and out of the air stream that is passing along the tubing
without any of the obstruction experienced when the breathing has to be
performed through valves, as in the older (Zuntz) forms of portable
respiratory apparatus. It is particularly for studies on man that this
apparatus has been devised. The Tissot and Douglas methods are shown
in Figs. 17!) and 180.*

To complete the investigation, it is necessary that the urine and feces
be collected and the nitrogen excretion measured. When the respiratory
excreta are measured over a considerable period of time, as in the large
calorimeter, the urine is collected for the same period, but when shorter
respiratory measurements are made, the urine of the twenty-four hours
is usually taken.

Principles Involved in Calculating- the Results. — Provided with Ihe an-
alyses furnished by ihe above methods, we proceed to ascertain the total

"Tlic Tissot method will be found described in full elsewhere fpage 554).

Ml TABOLIKM

;unoiiiits of nitrogen and carbon excreted and to calculate m
known composition of protein how much protein must have undergone
metabolism. We then compute how much carbon this quantity of pro-
tein would accounl for, and we deduct this from tin- total carbon
tion. The remainder of carbon must have come from tin- metabolism of
fats and carbohydrates, and although we can nol t«-ll exactly which,
we can arrive at a close approximation by observing tin- respiratory quo-
tient i K. Q.), which is the ratio "!' the volume of carbon dioxide exhaled

i- that of oxygen retained by the body in a given time, i.e.- - . By ob-

serving this quotient, therefore, we can approximately determine the
source from which the nonprotein carbon-excretion is derived.

Having in the above manner computed how much of each of the proxi-
mate principles has undergone metabolism, we next pr ied to compare

intake and output with a view to finding whether there is an equilibrium
between the two, or whether retention or loss is occurring.

It may serve to make clear the methods by which these calculations i
made to study the following example:

Examplt of a Metabolism Investigation. — H is desired to know whether :i d I
taining L25 grams protein, 50 grams fatj and 500 grams carbohydrafo
man doing a moderate amount of work.

Intake

boa

Nitrogen

1 '.iri.-

Protein,

62

gm.

■20 g

512.5

( larbohydrate,

200

—

_

38

—

Total,

300

-in.

1 1 PUT

< ':ti In. n

- gm.

Nil

In urine,

1 1 gm. L6

5

16.5 gm.

I ii

'<

l.e

In the breath,

25 I

Total,

gm.

gm.

"Retained in Body. 30 gm. carbon and 2.5 gn . i.
sent 6.25: :15.6 gm. 75 gm, Now, this amoonl

nit for B.25 gm. '■••oi ; so thai

1.3 28 gm. fat. On this .Int. therefore, the nil
protein and U^.". gm. tut per diem.

Furnished with these data we may now proceed to compute how much

energy must have been Liberated in the body.

To express the above result in terms n{ energy lil I, we know that

3027.5 C. were supplied and that all I pi 15.1

l.l til retained as protein, and -- - •'•

toto 327.2 C. We find, therefore that 3027 5 — 327 2 2 :• i
required.

541) METABOLISM

This is called the method of indirect calorimetry, and it has boon clearly
established by numerous observations that the results agree exactly with
those secured by the method of direct calorimetry described above. For
most purposes the indirect method is quite satisfactory, and it is espe-
cially valuable in cases in which there are considerable and sudden
changes in body temperature. That the results by the two methods should
agree shows clearly that the law of the conservation of energy must apply
in the animal body, for it is evident that if any energy were derived from
outside the body other than that taken with the food, the results by the
direct method would be higher than those by the indirect.

CHAPTER I. XI
THE CARBl >\ BALANi E

Before proceeding to discuss the special metabolism of proteins
and carbohydrates, it will be advantageous to consider briefly -
era! facts concerning the excretion of carbon dioxide and the intake
oxygen. In the firsl place, it is important to note thai the i the

combustion process in the animal body is proportional to the amounl
oxygen absorbed and of carbon dioxide produced, whereas tl
the combustion is indicated by the ratio existing between the amount*
carbon dioxide expired and of oxygen retained in the body. An invi si
gation of the carbon balance, in other words, is partly quantitative and
partly qualitative — quantitative in the Bense that it indicates how in-
tensely the body furnaces are burning, and qualitative in the - that
it tells us what sort of material is being burned at the time.

THE RESPIRATORY QUOTIENT

Influence of Diet. The respiratory quotient is determined by com-
parison of the volume of carbon dioxide expired with the volume
gen meanwhile retained in the body or, as a formula,

Vol. CO i xpired

■

Vol. ' ' retained
Km- the sake of brevity the respiratory quotient is often written K. Q. That
it Berves as an indicator of tin- kind oi combustion occurring will 1"- ■
Jciil from the following equations:

1. Carbohydrah : 0^,0 0 6H 0

I »■

-2. ! S.CC.H.O

.-. B.G

0

I || i MI

| Knipii :

album

-. B.Q 9°

77

."i|S METABOLISM

I. Conversion <>f fat into ca/rbohydratt :

2C3lK((,„JI;130..)3 + C40.1 = l()C(iH1..0(i-l-18('() 8H20
(Olcin.)

.-. R.Q.= C°' =— =0.281

,">. Conversion <>f carbohydrate into a mixed fat:

1 "CcPi120,. = CraH104O0 + 23C02 + 2fiILO.
(Oleostearopalmitin.)

Taking carbohydrates first, the general formula may be written CILO,
from which it is plain that, to oxidize the molecule, oxygen will he re-
quired to combine witli the carbon alone, according to the equation,
( !H2( ) + 02 = C02 + H20. In other words, the volume of carbon dioxide pro-
duced by the combustion will be exactly equal to the volume of oxygen
used in this process, in obedience to the well-known gas law that equi-
molecular quantities of different gases occupy the same volume. The
respiratory quotient is therefore unity (Equation 1). With fats and pro-
teins, however, the general formula must be written CH,-|-0, indicating
therefore that for its complete oxidation the molecule must be supplied
with oxygen in sufficient amount to combine not only with all of the car-
bon, but also with some of the hydrogen, forming water; so that the vol-
ume of CO, produced will be less than the volume of oxygen retained,
and the respiratory quotient will be less than unity. As a matter of fact,
as the above equations show (2 and 3), the respiratory quotient for fats
and proteins lies somewhere between 0.7 and 0.8, being usually nearer
0.7 in the case of fats, and nearer to 0.8 in the case of proteins.

That the conditions hypothecated in the equations exist in the animal
body during the combustion of the foodstuffs can easily be shown by ob-
serving the respiratory quotient of animals on different diets. An her-
bivorous animal, such as a rabbit, when it is well fed gives invariably a
respiratory quotient of about 1, whereas a strictly carnivorous animal,
such as the cat, gives a respiratory quotient of about 0.7. Even more
striking perhaps is the comparison of the respiratory quotients in an
herbivorous animal while it is well fed and after it has been starved for a
day or two. In the latter case the respiratory quotient will fall to a low
level -because, by starvation, the animal has been compelled to change its
combustion material from the carbohydrate of its food to the protein and
fat of its own tissues.

As already explained (page 545), it is from the respiratory quotient
that we are enabled to tell what proportions of fat and carbohydrate,
respectively, are undergoing metabolism. A useful table showing the
percentage of calories produced by each of Uiese foodstuffs, after allow-
ing for protein, is given by Graham Lusk (see page 565).

Till. CARBON BALANi 549

Influence of Metabolism. Apart from diet, the respiratory quotii
may often be altered by changes in the metabolic habits of the animal.
These are mosl conspicuously exhibited in the ■ -. hibernating

animals. In the autumn months, when the animal is eating voraciously
of all kinds of carbohydrate food and depositing large quantil
adipose tissue in his body, the respiratory quotient may be ably

greater than unity, indicating therefore either that relatively m
carbon dioxide is 1 > < • i 1 1 <_r discharged or Less oxygen retained As i matter
of Pact, it can easily be shown thai it is the former of the causes thai
is responsible for the higher quotient, the explanation for the inc
production of COs being that, as the carbohydrate changes inl t, the
relative excess of carbon in the former is go1 rid of as CO,, as indici
in Equation 5. On the other hand, if the animal is examined while in
his winter sleep, it will be found thai the respiratory quotienl is now
extremely low, often qo1 more than 0.3 to 0.4, which may be interpr<
as indicating either an excessive absorption of oxygen or a markedly
decreased excretion of carbon dioxide. As a matter of fad
ureal diminution in both the excretion of carbon dioxide and the intake

of Oa, 1 ause the whole metabolic activity of the animal is • tely

depressed, but this diminution affects the oxygen to a much less deg
indicating therefore a relative increase in the oxygen tion. '1

explanation is thai the oxygen is being used in the chemical process in-
volved in the conversion of the fat back into carbohydr

Whatever may be the relationship between fat and carbohydrate in
the nonhibernating animal, there is no doubt thai during hiberna-
tion, before the fat stores are burned, fat is converted into something
closely related to carbohydrates, the equation for the process being •
resented as gn en above No. 4).

In man and the higher mammalia, the only condition apart from diet
which can affect the nature of the combustion process is disease; thus
in total diabetes (page 678) the organism loses the power of burning
carbohydrate, so thai whatever the diel may be, the respirai
is very low, never higher than thai representing combustion of fat and
protein. It has been claimed bj certain investigators that in diabi
the respiratory quotient may fall considerably below 0.7, indicati
in hibernating animals, that fat is being converted into carbohydr
The most recent and carefully controlled observations, h<

this claim, and for the present we must assume that in the bod
fat is not converted into enrbohydrat In numei

diseases investigated b) Du Bois ami others' no qualitative change in
the combustion processes in man has been brou jht.

550

METABOLISM

THE MAGNITUDE OF THE RESPIRATORY EXCHANGE

It is evident thai the amount of carbon dioxide expired and of oxy-
gen retained will be proportional to the energy liberation in the animal
body. Even at the risk of repetition it should be noted that the
energy exchange can be very accurately calculated from the result of
the materia] balance sheet — indirect calorimetry, as it is called (page
562). On account of the comparative simplicity of measuring the carbon
dioxide output and oxygen intake, it is natural that many of the obser-
vations that have been made on energy production in the animal body
depend on the use of this method, justification for which is found in the
complete agreement between the results of direct and indirect calorim-
etry in a great variety of diseases and conditions in man (Du Boisr').*

In the first place, it is interesting to compare the respiratory ex-
changes of different animals computed per kilo body weight. This is
shown in the following table.

OXYGEN AB-

CARBON DIOXIDE

WEIGHT

SORBED PER KILO

DISCHARGED

VOL. C02

TEMPERA-

ANIMAL

GM.

AND HOUR
GM.

PER KILO
AND HOUR

TURE OF
AIR

VOL. O,

GM.

Insecta

Field cricket
A mphibia

0.25

2.305

Edible frog

0.063

(44.2 c.c.)

0.060
(30.76 c.c.)

0.69

15°-19°

0.105

0.1134

0.7S

—

(73.4 c.c.)

(57.7 c.c.)

A ves

Common hen

12S0

1.058
(740 c.c.)

1.327
(675 c.c.)

0.91

19°

Pigeon

232-380

3.236

—

—

Sparrow

90

9.595

(6710 c.c.)

10.492
(5334.5 c.c.)

0.79

18°

Mammalia

Ox

638 000

0.3S9-0.485

660,000

>Sheep

66,000

0.490
(343 c.c.)

0.671
(341 c.c.)

0.99

16°

Dog

6213

1.303
(911 c.c.)

1.325

(674 c.c.)

0.74

15°

Cat

2464

1.356

1.397

0.75

3047

(947 C.C.)

f710 c.c.)

> >

0.64.',

f 150 c.c.)

0.766

(.".SO c.c.)

0.86

29.6°

Hal. Kit

1433

1.012

1 .354

0.97

lS°-20°

Guinea pig

444.!i

1.478

1.758

0.86

22°

Rat (white)

80.5

3.518

—

~7°

(1789 c.c.)

\\ ( iiiun ' *

0->

s.l
n.::27

17°

- * 1 ' ' Ho*7

Man

— •J

66,70

0.292

—

(Modified from Pembrey.)17

"For the convenience of those who may desire lo know more about the methods of analysis
that are suitable in the clinic, a chapter on the subject will be found beginning on page 554.

Till < LBBON B U 551

Several factors operate to explain these differences, and of the
following are of importance:

1. The Body Temperature, [ncrease in body temperature entails in-
creased combustion. This explains whj the metabolism of a bird is
greater than thai of ;i mammal of the same size, for, as is well known,
temperature of a bird is two or three degrees centigrade above thai
other animals. Rise in bodj temperature also explaii s, in pari at least,
the increased metabolism observed in fev<

2. The Temperature of the Environment. In considering this we m

distinguish between tl ffecl produced on warm-bl led and on <•■

blooded animals, since the body temperature of a cold-blooded animal

is only o] p two degrees Centigrade above thai of its environmenl

follows thai the metabolic activity will be directly proportional to the
temperature of the latter. In a warm-blooded animal, on the other hand,
the body temperature remains constanl whatever changes may occur
in thai of the environment, this constancy of body temperature being
dependenl on the fad thai the intensity of the combustion pi
inversely proportional to tho cooling eflfed of the atmosphere. Tl
suppose the external temperature should fall, then the loss of heat from
the body will tend to become greater, and to maintain the body tempe
ture at a constanl level, the body furnaces must burn more briskly, -with
the result thai an increased excretion of carbon dioxide and in t
oxygen will occur.

This influence of the surrounding atmosphere on the metabolic activ-
ity of warm-blooded animals has. as already pointed out, been used by
several investigators to explain the greater combustion per kilo body
weighl of small as compared with large animals. The argumenl is that,
since the sin face of small animals relatively to their mass is much •_
than in large animals, the cooling of the small animals will he |> inn-
ately greater. The relationship between surface ami ma-- is Bhown by tak-
ing t v ubes ami putting them together; tin- mass of the two cubes

equal t<> double that <>f either cube, wi irface than

double, since two aspects of the cuhes ha\e l.eeii broughl I T

prove the contention, the respiratory exchange has been comput
square meter of surface instead of per kilo body weight, with suit

thai a very elos rrespondence in the metabolism of .i aimals

has been observed; hut this question has already been disc ssed, and we

now know that the law of cooling can not he the oiil\
extent of the respiratory exchang< <\\

3. Muscular Exercise. This has a most important influ
change ami it is particularly in connection with it that studies in
dioxide output and oxygen intake have been

552

METABOLISM

ticularly when the investigations are undertaken on men doing ordinary
types of muscular exercise, such as walking or climbing. It is true
that the influence of muscular exercise on the energy metabolism may
also be studied by having a person in the calorimeter do exercises on an
ergometer, but the results thus obtained are in many ways not nearly so
valuable as those which can be secured by observing the respiratory
exchange of persons doing ordinary types of muscular exercise in the
open. The following table of observations on horses is of interest in this
connection.

CONDITION

AIR EXPIRED

CARBON DIOXIDE

OXYGEN ABSORBED

CO,

IN LITERS

DISCHARGED IN

IN LITERS PER

o,

•

PER MINUTE

LITERS PER
MINUTE

MINUTE

Rest

44

1.478

1.601

0.92

Walk

177

4.342

4.766

0.90

Trot

333

7.516

8.093

0.93

It will be observed that the metabolism increases extraordinarily for
even a moderate degree of work, but that at the same time the respiratory
quotient remains constant. From observations on the respiratory ex-
change of Avorking men and animals, extremely important facts concern-
ing the efficiency of muscular work have been secured. The form of
respiratory apparatus (Zuntz or Douglas) employed for this purpose
must be capable of being strapped on the man's back without causing
any embarrassment to his bodily movements. By a comparison of the
respiratory exchange with the amount of work done, the efficiency of the
work can readily be determined. It has been found, for example, that
the efficiency is much greater after the man or animal has got into the
swing of the work, his energy expenditure per unit of work being much
greater during the first half hour's work in the morning than it is
later on. This indicates that after a little practice the muscles can ex-
ecute a given movement and perform a given amount of work much
more smoothly than when they are not in training. Another interesting
outcome of the investigations has been to show that work done under ab-
normal conditions that tend to produce any kind of muscular strain is
done inefficiently. It has been found in marching soldiers, for example,
that the slightest abrasion of the foot greatly increases the energy
expenditure, for the man, in trying to avoid the pain produced by the
abrasion, brings into operation muscular groups that are really not
required for the efficient performance of the movement, but are used
instead to avoid pressure on the sore. Fatigue also causes inefficient
performance of work; that is to say, the fatigued person, on attempting

I lii CARBON BALANCE

the same amount of work as he performed bi becoming fatigu

will i|(> bo at a much greater expenditure of energy.

There is a diurnal variation in the respirato e, which is in

genera] parallel with the body temperature; it rises during the day, 1 1 1 « -
time of activity and work, and falls during the night, the time
and sleep. Food also affects respiratory exchange, but it will V- nni
essary to go into this further after wha1 lias been said <>n ; 17.

CHAPTER LXII*

A CLINICAL METHOD FOR DETERMINING THE RESPIRATORY

EXCHANGE IN MAN

By R. G. Pearce, B.A., M.D.

Principle. — Since the determination of the respiratory exchange in
man is of some importance in the study of certain diseases of the respira-
tion, circulation and metabolism, and also because directions for carry-
ing out the necessary procedures are not generally available, we have
thought it might be of assistance to include here brief directions for the
Tissot and the Douglas methods. These methods have been found to
compare favorably in accuracy with others in use at present,f and be-
cause of their adaptability and simplicity they are specially suited for
clinical work.

By these methods the energy metabolism of the body is calculated from
oxygen consumption or carbon dioxide excretion per minute (indirect
calorimetry) (page 546), the figures for which are determined from the
volume and percentile gaseous composition of the expired air.

The subject breathes through valves which automatically partition the
inspired and expired air. The expirations from a number of respirations
are collected in a spirometer or bag, and the volume of the respirations
per minute is determined. The gaseous composition of the expired air
is determined by gas analysis, and the oxygen consumption and energy
output of the body are calculated from the data obtained.

Description and Use of Parts of the Apparatus: 1. The Mouthpiix i:
and Valves. — The mouthpiece is made of soft pure gum rubber, and con-
sists of an elliptical rubber flange having a hole in the center 2 cm. in
diameter, to Avhich on one side a short rubber tube is attached. On the
opposite side of the hole, at right angles to the rubber flange, are at-
tached two rubber lugs. The rubber flange is placed between the lips,
and llie lugs are held by the teeth. The rubber tube of the mouthpiece is
connected to the tube carrying the valves. The nose must be tightly
closed if mouth breathing is used. This is accomplished by a nose clip,
which consists of a V-shaped metal spring, the ends of which are pro-
vided with felt pads. A toothed rachet is attached to the ends of the

"This chapter is added for the convenience of workers in this subject.

ter: Carnegie Institution of Washington Reports, No. 216, 1915.

55 1

Ml I HMD FOR l»l Tl ({MIXING RESI'IHATI

N|niii'_r. and serves to hold the ^i>iiir_' tightly clamped on tl
the proper position see Pig 177 .

Si. in.- individuals experience greal .i: made '■> breathe

through Hi'' mouth. For these it is b use a face mask, i fortu-

nately a1 the present time no mask is entirely satis v. Perhaps

besl is one sold by Siebe, Gorman & Co., which is pictured in the cu1

After being placed in position the face mask should be I
which can be done by putting soap around the i

'J. The Valves. The valves of Tissol are probabl;
purpose, l»ut thej are expensive and difficull to obtain. We have made
perfectly satisfactory valves from the prepared >1 in the

manufacture of bologna saus I in

salt, and they will keep indefinitely <>n ice When needed

1 1 J.. Monadi

556

METABOLISM

is taken, Mashed free from salt by allowing water from the tap to run
through it, and softened in a weak glycerine solution. The gut becomes
very soft and pliable, and does not dry quickly. A piece of the casing
about 10 em. long is threaded through a glass tube of about 15 mm. bore
and 4 to 6 cm. long. One end of the easing is brought around the outside
of the tubing and secured by means of a thread. The lower end of the
membrane is pinched off and the casing is then cut a little more than
half way across its middle, so that the opening will lie just Avithin the
free end of the tube when the casing is drawn back through it. The
loose end of the casing is slightly twisted — an essential procedure — and
is then secured by a thread on the outer side of the tube. If properly
made, the valve will work freely without vibration, and the opening be
sufficiently large to allow a good current of air to pass. It should col-
lapse instantly and be air-tight when the current of air is reversed. The
back lash, or lag of closure, of these valves is extremely small, and
they will open or close with a pressure of air not exceeding the pressure

Fig. 178. — Diagram of respiratory valves.

changes in normal respiration. When not in use, the valves should be
kept in glycerine water on ice. Valves prepared in this way have been
in use a month without loss of efficiency. They are, however, made with
so great ease that new valves are provided for each subject, and they are
therefore especially adapted to ward work (Fig. 178).

The valves are inserted in reverse order into a supporting metal
T-piecc, and the joints made air-tight by tape. The stem of the T is
connected with the mouthpiece. Through a rubber tube of about 3/4
inch bore, the expired air is collected in the spirometer, or Douglas Bag.

3. The Tissot Spirometer is pictured in Fig. 170. We have found the
100-liter size to be very serviceable in the clinic. This instrument is
mounted on a platform having rubber wheels, and can be moved about
the wards with ease. The bell of the spirometer is made of aluminum
and is suspended in a water-bath between the double walls of a hollow
cylinder made of galvanized iron. The height of the bell is 72 cm.
and the diameter 42 cm. An opening at the bottom of the
cylinder connects through a three-way stopcock- with the rubber tube
leading from the expiratory valve of the mouthpiece (see Fig. 177).

Ml 'I'll. in FOR in 'II IRMINING RESIMRATOR^ IMIIW'i.i. IN WW

The bell is counterpoised by means of a weight. In the original Ti
spirometer an automatic adjustmenl permitted water in aim. nut equal
to the water displaced by the bell to flow Erom the spiromi tinder

int. * a counterpoise cylinder as the bell ascended out of the wal

Pig. 179. TI

The bell, being heavier ou1 of water than when it is immersed,

ingly counterpoised in any position, although Car] hown that

this refill. 'in. 'nt is ann< y. An opening in I spiromi

permits the insertion n\' a rubl pper, through which are passed a

thermometer, a water manometer, and a si with t r drav

558

MKTAP.OUSM

the sample of air. A scale on the side of the instrument gives the vol-
ume of the air.

During an observation the subject sits in a reclining position or lies
upon a couch. When the bell of the spirometer is placed at zero, the
mouthpiece adjusted in the month, and the nose clamped, respiration is
started, the expirations being passed through the stopcock, which is
so turned as to allow them to pass to the outside air. After a few
minutes the stopcock is turned so that the expirations are passed into

Fig. 180. — The Douglas bag method for determining the respiratory exchange. The arrange-
ment of mouthpiece, valves, and connecting tubes shown here has been found to be more con-
venient than that recommended by Douglas.

the spirometer for a definite length of time. At the end of the period
the cock is again turned, and after the barometric pressure, temperature,
and volume of the air have been noted, the composition of the air is
determined in the Haldane gas analysis apparatus.

4. The Douglas Bag. — The Douglas bag is made of rubber-lined cloth,
and is capable of holding from 50 to 100 liters. It is especially useful
for investigations during exercise, since it is fitted with straps so that
the bag can be fastened to the shoulders (Fig. 180). It is then connected
with the valves, the mouthpiece of which is placed between 1 lie lips.

METHOD FOR DETERMINING RESPIRATORY RXPHANOl IN MAN

Respirations are commenced with the three-way valve turned so as I
allow the expirations to pass directly outside After respiral equi-
librium'is established, the three-way valve is turned during an inspira-
tory period so thai the bu< ling expirations may pass into the '•■

The time required to fill the bag comfortably is determined with a stop-
watch. The air which has been collected in the bag durii i"'i
is thoroughly mixed and passed through a meter, the temperature and
barometric pressure are noted, and a sample analyzed in the Ilal<i.

B. ■
Pig. 181 II ipling hi

gas-apparatus. The bag should be emptied completely by rolling it up
when nearly empty.

5 The Haldane Gas-analysis Apparatus. PRINCE*] i .—The Hal. Ian.'
method of analysis of expired air is simple ami easily learned. The ap-
paratus (Pig. lsl consists of a gas burette, a control buretl th"
same Bize (both surrounded with a water jackel . and bulbs containing
dilute caustic potash or soda solution for the absorption of the carbon di-
oxide and an alkaline pyrogallate solution for the absorption i

f)f)0 METABOLISM

oxygen. The gas burette is connected with the bulbs by a two-way
stopcock, which allows a sample of gas to pass into either bulb. A con-
trol tube (10) is put into connection with the burette through a manometer
tube, which is connected with the alkali bulb, and can be made to com-
pensate for any changes in temperature that may occur during the course
of the analysis. For an analysis the gas is transferred to the burette
from the sampling tube, saturated with water vapor over mercury, and
then measured, after which it is transferred into the caustic solution to
free it from C02, and returned to the burette to determine the loss of
volume due to CO, absorption. It is then transferred into the alkaline
pyrogallate solution, which frees it from oxygen, after which it is again
brought back to the burette to determine the loss in volume due to the
absorption of the oxygen.

The Apparatus. — The detail of the Haldane apparatus is shown in
the accompanying cut. The measuring burette (i) holds 21 c.c. The bulb
is of 15 c.c. capacity, and the graduated stem, which is about 4 mm. in
bore and 60 cm. in length, is graduated to 0.01 c.c. from 15 c.c. to 21
c.c. The stopcock at the top of the burette is double-bored, so that in
one position air can be drawn in from a gas sampler (2) and in another
sent into the absorption bulbs (3). The lower part of the burette ex-
tends through the rubber cork at the bottom of the water jacket (4).
A piece of rubber tubing is attached to the bottom of the burette and
is passed through a metal tube, furnished on its inside with a metal disc
which presses against the rubber tubing, the pressure being controlled by
means of a fine adjusting screw (6). Below this a glass stopcock (7) con-
nects with rubber tubing to the mercury leveling bulb (J). The absorption
bulb for CO,, containing 20 per cent NaOH or KOH (9), is put in con-
nection with the burette by suitably turning stopcocks (3 and 8).* The
control burette (10) is also in connection with this bulb through the
manometer tube (11). \ Any variation in temperature which may occur
during the analysis will cause the level of the alkaline solution in the
manometer to change.

When final leadings of the shrinkage of volume are made, the level of
the caustic solution is returned to the level of that in the manometer.
By so doing any error due to temperature changes is avoided, since
change in temperature must be equal in the two burettes.

The absorption bulb for oxygen (12) is filled with a solution made by
dissolving 10 grams of pyogallic acid in 100 c.c. of a nearly saturated
l\< >II solution. The specific gravity of the KOH should be 1.55, which is
obtained approximately by dissolving the sticks (pure by alcohol) in an

*The Stopcock (8) is double-bored, so that the tube leading' from the burette can be brought into
connection with cither 9 or 12.

fThis tube also has a .three-way stopcock (/p), so that it may be opened to the outside.

METHOD TOR DETERMINING RESPIRATORY EXCHANGE I N MAN

equal weight of water. The mark /■ on the Btem of the bulb indi-
cates the level a1 which the solutions should Btand. Enough pyrogallate
Bolution is introduced through tube 15 to fill bulbs 12 and U two-thirds
full. Then pyrogallate solution is poured into tube 16 until the differ-
ence in level of the llui<ls is sufficient to produt aough pi •• to

raise the level of the pyrogallate solution in 12 to the level IS on the

stem. Stopcock 6 must I pen during this procedure. It may be ne

Bary to add or take awaj a little pyrogallate solution through t5 to
tain the above level.

Care must be taken to allow for complete absorption of oxygen \v<<m
the air thai is entrapped between 14 and 16 before an analysis is made;
otherwise changes will be produced in the level of the pyrogallate solu-
tion. The air in the capillary tubing connecting the burettes with

absorption bulbs must also be freed of COa and 02. This can be a m-

plished by making a ilniiiiny analysis of atmospheric air before the real
analysis. Great care must be taken to have atmospheric pressure in all
the tubes at the start of the analysis. This is accomplished by opening
the stopcock in the burette first to atmospheric air and then to the ab-
sorption bulbs, until no further change in the level of the fluids in
stems of the absorption bulbs occurs. This level is then marked and
used as the standard. A small amount of water in the burette over tlm
mercury assures saturation of the air with water vapor. Time for drain-
age must be allowed before making readings.

A very serviceable sampling tubi for the transfer of air can be made
from a 30 c.c. ground-glass syringe, to which is attached a two-way
stopcock. A cut of this is shown in Fig. L81. The dead Bpace in tl
syringes is washed out by working the piston back and forth several
times, a thin coating of vaseline prevents leakage of the gas. We have
found that these sampling tidies will retain a sample of expire. 1 air with-
out change up to eighl hours.

Manipulation of Apparatus. The sampling syringe [20 is attached
to opening 2 of the burette, and its stopcock opened to spheric air.

The level of the mercury is raised to the level of the stopcock of the syr
and is then turned so that syringe and burette are in communication.
hulb of mercury is lowered so thai the mercury falls in the burette. This
draws the piston of the syringe with it. and tills the burette with air
from the Byringe. It is advisable to put a little positive pressure on the
piston of the Byringe in the maneuver to prevenl possible leakage. When
all of the air is in the burette a slight positive pressure is produced in
the burette by gently pressing on the piston, and immediately there-
after the stopcock on the syrii gain tun riginal
position. This allows the pr< of aii- in the b 'hat

562 METABOLISM

of the atmosphere. The heighl of the mercury is now adjusted to a con-
venient height in the burette by closing cock 7 and turning the milled
screw 6. The cock 18 is now made to communicate with the absorption
bulbs. If the air in the burette is at atmospheric pressure, no change
will occur in the level of 1he fluids. The reading is then taken on the
burette.

The next step in the analysis consists in turning stopcock 8 to com-
municate with the caustic soda solution in bulb 9, and the leveling tube
(5) is raised, forcing mercury into the burette and the air into bulb 9.
The gas is passed back and forth several times until absorption is com-
plete, as can be determined by the fact that the level of the mercury in
the burette remains constant when the fluid in the bulb is returned to
its original level (13) on the stem. In this adjustment it is convenient
to make the gross leveling by the mercury bulb and the fine leveling by
closing 7 and turning 6 until the fluid in 9 is at the original height.
The reading on the burette indicates the loss in volume due to the CO,
absorbed.

The oxygen is removed by a similar procedure, the gas being passed
into the alkaline pyrogallate solution by turning cock 8 to communicate
with bulb 12. The absorption of oxygen is slower than for CO,, and
more care must be taken to get complete absorption. The air in the
tubing between the fluid in 9 and stopcock 8 must be washed out sev-
eral times in order to get the oxygen which is left in it after the absorp-
tion of the C02. When this is complete, the final reading on the burette
is made and the loss in volume from the second reading represents the

oxygen.

THE CALCULATIONS

The calculation of the percentile composition of the air and of the re-
spiratory quotient is represented in the following example of an actual
analysis:

(The temperature and barometric pressure as taken at the time of the
experiment were 20° C. and 747 mm. Hg.)

CO„ analysis —

1st reading of burette 20.00

2nd reading of burette after absorption of CO, 19.20

C02 absorbed 0.80

0.80-^20 = 4.0 per cent C02 in expired air.

O, analysis —

2nd reading of burette 19.20

3rd reading of burette after absorption of (X 15.90

02 absorbed 3.30

3.30-^- 20 = 16.50 per cent of 02 in expired air.

Mi THOD FOR Mil RMINING Rl 5PIRATORY l K( ll M

l>> I I: Q. —

0 in :iiin aii

0 CO,ii pircd air Id

100 20.9-1 : 79.06%, \ in atmo
LOO 20.50 : l N in expired i

Since the nitrogen is not changed in volume, the last figure Bhov
more oxygen musl have been taken in durii a piration than 0 CO
has been given back in expiration. This obviously must be taken into
accounl in the calculations. The amounl of O actually inspired
LOO c c. of air expired is found as follov

20.94 (% 0, in atmospln-i i<- :
79M (% N2 in atmospheric :<i,
stant factor 7:'.:, • . \ foui d foi this observation 21.
would have been present in expired di I ml for N present. 1

21.07 L6.50 l.57< 1 1 actually absorbed.
'■' .03 C< i ii. inspirt d air 3.97<

3.97
:. -£-z== 0.87, the respiratory quotient,

Total Gas E change. The volume of air expired in 15 minutes
tli«« Tissol spirometer was found to be LOO Utera measured at 20 C. and
717 mm. Mir (brass-scale barometer). This volume of gas musl

rected so as to give the volun E dry air at o ami Ttio nun. Bg. '1*.. .1"

this two things must be taken into account. 1 since the expired air is
saturated with water, the pressure dm' t" water vapor musl be subtract
from the observed barometric pressure to obtain the true pressure. I
vapor tension of water for various temperatu given in Table 11

"ii page 564. (2) The barometer tube lengthens or contracts with i
or cold, and therefore the barometric readings must \x
The corrections for ordinary barometric reading found in Table IN.

page 565. The figure corresponding to the temperature* s subl
from the barometric reading in order to obtain correcl barometric p
sure.

In the above experiment, the correction for the b ;1 mm.

Table III. pag . and that for vapor tension al 20 I i 17.4

Bee Table II. p t

Actual Barometrii /' i 747 17.5 2 727.21 mm.

coefficient of expansion of is taken as 0

the volume of 0 equals the volume at 1 divided by 1
hence

" T I
tThis
{ponding t" the i ' •

564 METABOLISM

Vo = — , w lien Vo = Volume al 0' and V = Volume at t°.

273 + t 1 + 0.003665 t

VP

The volume of gas being inversely as the pressure, Vo = , where V = V01ume at

760
P pressure; or working both corrections together,

VPx273 VP

VO:

760 x (273 + t) — 760 (1 + 0.003665 t)

This formula applied to the present problem reads:

,r 100x727.2 DooT*

V o = . = 89.2 liters.

760 (1 + 0.003665x20)

The latter calculation can be considerably simplified by using standard
tables which give constants for corrections of gas volumes. These are
easily obtainable and are given in part in Table IV.

According to these tables for 20° C. and 727.21 mm. Hg B.P., the
factor is 0.89124; therefore:

0.89124 x 100 = 89.12-1 liters, 0°C. and 760 mm. Hg.
0.89124x4.57 = 40.7 liters of O, in 15 min., or 16.28 L. per hour.

The Caloric Value Calculated from the Gas Exchange. — By reference
to Table V giving the heat value of 1 liter of 02 at various respiratory
quotients, it is found that at a R.Q. of 0.87, 4.888 calories are expended;
16.28 liters of 02 is therefore equivalent to 18.4 x 4.888 = 79 calories.

The results must be calculated for surface area as well as body weight.
Suppose the subject weighed 85 kg. and was 170 cm. in height; by refer-
ence to the chart for determining the surface area of man (page 540),
this would be found to be 1.96 square meters. The caloric expenditure

79
per square meter in the above case is therefore an = 40.3 calories.

l.yb

Table I

The Percentage of Oxygex which is Equivalent to the Nitrogen Found in the

Expired Air

To obtain the nitrogen in the expired air, add the percentage of CO, and 02 found
and subtract the sum from 100. The table gives the percentage for 0, corresponding to
this figure:

%N.

78.7

78.8

78.9

79.0

79.1

79.2

7!'.::

79.4

79.5

79.6

79.7

79.8

%o.

20.86

20.88

20.90

20.93

20.96

20.98

21.01

21.04

21.07

21.10

21.12

21.14

79.9

80.0

80.1

80.2

S0.3

80.4

80.5

80.6

21.16

21.19

21.22

21.25

21.28

21.31

21.35

21.38

Table II
Tension of Aqueous Vapor in Millimeters of Mercury
To obtain the dry barometer pressure, subtract the mm. Hg corresponding to the
temperature of the air from the barometer pressure at the time of the experiment:

Temp. 15° 16° 17° 18° 19° 20° 21° 22° 23° 24° 25°
Mm. 12.7 13.5 11.4 1.1.1 16.3 17.4 L8.5 19.7 20.9 22.2 23.5

METHOD l'"l; DETERMINING RESPIRATOR? EXCHANGE IN M

I II!
Ti MP1 i:.\ i i 1:1. < lOR] 0 B I.'

B

tbtract tin' appropriate quantity :i^ found in table from tl
The table is for :t barometer with ;i br little I

:2 nun.) than for the glass Bcale. The corrections for inl a be

approximated.

Temp.

7(.,i
mm.

710

mm.

720

mm.

730

mm.

740

mm.

750

760

770

15°

20

25°

1.69
2.26
2.83

1.72
2.:87

1.71

.i go

2.91

1.77
2.36

1 79

2.no

1.81

1.84
2. 1".

3.1 1

Table iv

Table fof Reducing Gaseous Volumes to Normal Temperatui
The observed volume, when multiplied by the factor correspond 'ire

and pressure, will give the volun f the expired air reduced 1 7 m.

Mm.

15°

1(5°
.894

17c

18°

19°

L'u

21°

22°

23°

24°

25°

720

.891

.888

.885

.882

>M

.877

.873

-

-

730

.910

.'.Ml 7

.904

.901

.897

-

.891

---

382

57

71ii

,,.,.,

.919

.'.'!•;

.913

.910

.907

.904

-

750

.935

.932

.928

.925

.922

.919

.916

.913

.910

1

760

.947

.94 1

.94]

.938

.934

.931

•

.922

.916

770

.960

.957

.950

-

.945

.940

1

TAB! I V

K. Q. CALORIES FOB 1 LITER O, RELATIVE CALORIES C<

Number • larbohydn I

per ■

~~0~ 100

1.4

-
11.6
15.0
18.4
21.8
25.2

28.6 71.4

32.0
35. 1

12.2

l.O
52.4

-

76 2

10.

0.707

1.686

0.71

4.690

0.72 •

1.702

0.73

1.71 1

".71

1.727

0.75

4.739

0.76

1.752

0.77

4.764

0.78

i77>;

0.79

1.789

0.80

1.801

0.8]

1.813

0.82

1.825

0.83

I 838

0.84

1.850

0.85

1.863

ii.s«;

•

1.887

0.88

1.1

1.912

0.90

1.924

0.91

1.948

0.93

0.94

1.985

0.96

1.00

'

CHAPTER LXI1I

STARVATION

In order to furnish us with a standard with which we may compare
other conditions, we shall first of all study the metabolism during starva-
tion. A valuable chart compiled from observations made in the Carne-
gie Institution of Washington on a man who fasted for thirty-one days
is reproduced in Fig. 182.

The Excretion of Nitrogen. — When an animal is starved, it has to
live on its own tissues, but in doing so it saves its protein, so that the
excretion of nitrogen falls after a few days to a low level, the energy
requirements being meanwhile supplied, so far as possible, from stored
carbohydrate and fat. Although always small in comparison with fat,
the stores of carbohydrate vary considerably in different animals. They
are much larger in man and the herbivora than in the carnivora. Dur-
ing the first few days of starvation it is common, in the herbivora, to find
that the excretion of nitrogen is actually greater than it was before
starvation, because the custom has become established in the metabolism
of these animals of using carbohydrates as the main fuel material, so
that when carbohydrates are withheld, as in starvation, proteins are
used more than before and the nitrogen excretion becomes greater. We
may say that the herbivorous animal has become carnivorous. The same
thing may occur in man when the previous diet was largely carbohy-
drate; thus, almost invariably in man the nitrogen output is larger on
the third and fourth days of starvation than on the first and second.

Another factor influencing the nitrogen excretion during the early
days of the fast is the amount of previous intake of nitrogen; the greater
this has been, the greater the excretion. By the seventh day, however, a
uniform output- of nitrogen will usually be reached irrespective of the
individual's protein intake. During the greater part of starvation, most
of the energy required to maintain life is derived from fat, as little as
possible being derived from protein. This type of metabolism lasts until
all the available resources of fat have become exhausted, when a more
extensive metabolism of protein sets in, with the consequence that the
nitrogen excretion rises. This is really the harbinger of death — it is often
••ailed ithe premortal rise in nitrogen excretion. It indicates that all the
•ordinary fuel <>f the animal economy has been used up, and that it has

566

STARVATION

OxrtfN AM) CARSON
OIOXIOC. ce

AiVCOLAR CO, TENSION. Mb

KOOOCUSSUU.*.

(nutrition laboratory or tmc carnicje institution v v«as«xtoh. ioston. hassacwstttsj
METABOLISM CHART OF A MAN FASTING 31 DAYS

APRIL 14- MAY 15. 1912
I 2 3 4 S 6 7 6 9 IOII 12 1314 IS 16 i 7 i« i» 20 21 22 2 J 24 2S 26 27 2S 2« SO If

HEM Pa MMB.CMI

BODY TCMtWATURC. *C

MIAT*«AJ10.KJII«,CALJ.

RESPIRATORY OUOTICNT

RCSPIIATION RATE
PULSC RATC

CHLORINC (CI). CMS.

TOTAL NiTROCtN. CMS.

__IIN URJNC.CMS j
WXYBUTYReAClO.CMS.)

URiC AOD-N.GM,

TOTAL SULPHUR (SI CM

AMMONIA-N. CMS

PHOSPHORUS (P,0J. CMS.

"j 3 4 » e 7 > » io i.i 12 > i4 is n mi t ro i< it ti i* n mi r* t» * *

Fig. 182.— Cun

I'ln
dinati From P. G

568 METABOLISM

become accessary to burn the very tissues themselves in order to obtain
sufficient energy to maintain life. Working capital being all exhausted,
an attempt is made to keep things going for a little Longer time by liq-
uidation of permanent assets. But these assets, as represented by pro-
tein, are of little real value in yielding the desired energy because, as
Ave have seen, only 4.1 calories are available against 9.3, obtainable
from fats.

These facts explain why during starvation a fat man excretes daily
Less nitrogen than a lean man, and why the fat man can stand the starva-
tion for a longer time. The premortal rise is, however, not prevented by
feeding oil, which would seem to indicate that death may be due not so
much to the absence of fuel as to serious nutritional disturbance of es-
sential organs; e. g., there may be no available material to supply the
glands of internal secretion with the building stones they must have
(see page 580).

Not only is there this general saving of protein during starvation,
but there is also a discriminate utilization of what has to be used by the
different organs, according to their relative activities. This is very
clearly shown by comparison of the loss of weight ivhich each organ un-
dergoes during starvation. The heart and brain, which must be active if
life is to be maintained, lose .only about 3 per cent of their original
weight, whereas the voluntary muscles, the liver and the spleen lose
31, 54 and 67 per cent, respectively. No doubt some of this loss is to
be accounted for as due to the disappearance of fat, but a sufficient
remainder represents protein to make it plain that there must have been
a mobilization of this substance from tissues where it wras not absolutely
necessary, such as the liver and voluntary muscles, to organs, such as the
heart, in which energy transformation is sine qua non of life. The vital
organs live at the expense of those whose functions are accessory.

The energy output per square meter of body surface steadily declines.
In the man examined by Benedict, it was 958 C. per square meter of
surface at the end of the first twenty-four hours, but only 737 on the
thirty-first day of the starvation period. The oxygen intake and carbon-
dioxide output correspondingly diminish.

The behavior of the nitrogenous metabolites in the urine is of par-
ticular interest, the following facts being of significance: Urea nitrogen
relatively falls and NIT., N rises. For example, on the last day of feeding
the percentage output of NIL-N in relation to total nitrogen Avas 3.16;
on the eighth day of the fast it was 14.88 (Cathcart).2 Acidosis is the
cause. The total amount of creatinine and creatine shows only a slight
fall, but creatinine relatively decreases and creatine increases (Cathcart).
Since creatine is a substance peculiar to muscle tissue, it is possible by

3TABVA1 [I

comparing the creatine and creatinine output with that of aitrogen t"
determine whether all of the aitrogen liberated by the breakdown of
muscle has been excreted, or whether some has been retained eitl
resynthesis in the muscle itself or for use elsewhere, li' the mm
breakdown as calculated from the creatine-creatinine outpul
than thai calculated from the nitrogen, synthesis of the n< tine

remainder must be wrringj whereas if the breakdown calculated from

nitrogen is greater than thai calculated from en
sues than muscle musl be contributory. Stored nitrogen or. free nil
gen in transit from tissue to tissue for utilization is the most likely
source of such excess oil rogen.

That transference of nitrogenous substances from place to place in the
body in starvation is proved 1 I by the constanl presen >f amino ni-
trogen in the blood and tissues Van Slyke ; and '-! by th<
copious water drinking. The Latter causes a decided increase in t;
put of nitrogen, bu1 it does not appear that the extra nitrogen is d
increased protein breakdown. It is probable, however, thai in such <•■
there would also be an increase in endogenous protein metabolism,
the washed-ou1 fvc nitrogen would have to be replaced.

Excretion of Purines. Although at firsl they fall sum. -what, the total
amount increases as the fasl progresses. Perhaps the firsl decli
due to genera] using up of hypoxanthine of muscle and the lat<
to the breakdown of nuclei (page 638 .

Excretion of Sulphur. It is importanl to compare tl
sulphur and nitrogen. In the early days of starvation a ratio of 17 N: 1 S
has been found, bul later one of 14.5: 1, which is practically the same

as that in mnsele i i. e.. 11:1. indicating that late in fasting the main

source of protein supply is muscle.

Several of the changes observed during starvation can be attribul
to the condition of acidosis which Bupervei ids are derived

from incomplete combustion of fal Bee page 68 nd are repn

by |9-oxybutyric, the amount being sometimes considerable 10-15 grams
a daj . 'specially in obese individuals. The large ammonia tion

(sometimes 2 grams a day' is evidently for the purp< utraliri

the excess of acid. Another consequence of the acidosis is tl sline

in the alveolar tension of « 0 page 354 . and it - hie that si

the circulatory changes shown in the chart may also be dependenl on
it. The method of repeated fasting us.d for reducing obesity is q
safe if the acidosis is carefullj watched.

.Man;, secondary changes also occur in the starving organism. Thus.
the mobilization of fal is often responsible for a pronounced ii ■• in

the fat content of the blood see p '- and tl

570 M ETABOLISM

the presence of an amount of amino nitrogen not much below that of
normal animals (viz., 4 mg. per 100 c.c. of blood). Similarly with
carbohydrates, early in the condition the blood sugar becomes much
lower than normal, but then remains steady. This is significant when
Ave remember that after two or three days of starvation all of the avail-
able glycogen has been used up. It indicates that carbohydrate must
be essential for life, and that it is produced in starvation from proteins
i sec page 667).

Starvation ends in death in an adult man in somewhat over four
weeks but much sooner in children, because of their more active metab-
olism. At the time of death the body weight may be reduced by 50 per
cent. The body temperature does not change until within a few days
of death, when it begins to fall, and it is undoubtedly true that if means
are taken to prevent cooling of the animal at this stage, life will be
prolonged.

Death from starvation must be due either to a general failure of all
the cells or to injury of certain organs that are essential for life. Since
the loss of protein from the body as a whole may vary between 20 and
50 per cent at the time of death by starvation, it is unlikely that general
failure can be its cause. If it were so, death would always occur when
some fixed loss of protein had occurred. Certain organs evidently cease
to perform their function, either because they are deprived of raw mate-
rial for the elaboration of some substance (hormone) necessary for life,
or because the organs themselves wear out from want of nourishment.

NORMAL METABOLISM

Apart from the practical importance of knowing something about the
behavior of an animal during starvation, such knowledge is of great
value in furnishing a standard with which to compare the metabolism
of animals under normal conditions. Taking again the nitrogen balance
as indicating the extent of protein wear and tear in the body, let us
• •(insider first of all the conditions under which equilibrium may be re-
gained. It would be quite natural to suppose that, if an amount of pro-
tein containing llic same amount of nitrogen as is excreted during
starvation were given to a starving animal, the intake and output of
nitrogen would balance. We are led to make this assumption because we
know thai any business balance sheet showing an excess of expenditure
over income could be met by such an adjustment. But it is a very differ-
enl matter with the nitrogen balance sheet of the body; for, if we give
the starving animal just enough protein to cover the nitrogen loss, we
shall cause the excretion to rise to a total which is practically equal to

STABVATIl

the starvation amounl plus all thai we have given id; and although

by daily giving this amounl of protein there maj be a Blight decline
1 lie excretion, it will never come near to being the Bame as that of tin-
intake The only effed of Buch feeding will be t<> prolong [ife p,,. a

few days.

Nitrogenous Equilibrium. To attain equilibrium we must .
amounl of protein whose nitrogen eontenl is at Least two and one-half
times thai of the starvation level. For a few -lays following the estab-
lishment of this pure protein diet, the nitrogen excretion will be far in
excess of iIk' intake, bu1 it will gradually decline until tin- tun practically
correspond. Eaving once gained an equilibrium, we may raise In
level by gradually increasing the protein intake During this prog
sive raising of the ingested protein, it will be found, at least in the c
nivora cat and dog), thai a certain amounl of nitrogen is retained by
the body for a day or so immediately following each increase in p
t.-in intake. The excretion of nitrogen, in other words, does nol immedi-
ately follow the dietetic increase. 'I 'he amounl of nitrogen thus retaine*
too greal to be accounted as a retention of disintegration products
protein; it must therefore be due to an actual building up of new |
tein tissue — that is. growth of muscli

Nitrogenous equilibrium on a protein diet alone is readily attainable
in the <-at, ami less readily in the dog. Bu1 in man ami tin- herbivor
animals, it is impossible to give a sufficiency of protein alone to maintain
equilibrium; there will always he an excess of excretion over intake.
Indeed it scarcely requires any experiment to prove this, for it is sol f-

evident when we consider that there are less than 1 » <* in a pound of

uncooked lean meat, and thai there are few who could eat over tl
pounds a day, an amount, however, which would scarcely furnish all of
the required calorics. A person fed exclusively on flesh is the
being partly starved, even although he may think thai he is eating
abundantly and be quite comfortable and active. This fad
tical application in the so-called Banting i In.

Protein Sparer*. Very different results are obtained when (hy-

drates or fats are freely given with the protein to the starving anii
Nitrogen equilibrium can then be regained on very much
so thai we speak of fats and carbohydrates as being ".
Carbohydrates are much better protein sparers than
are so cfiicieiit in this regard that it is now common!) believed
bohydrates arc essential for life, ami that when I us no

trace of carbohydrates, a part of the carbon of p
verted into carbohydrate. This important truth is su|
dence derived from other fields of investignti

572 METABOLISM

diabetic patients, in whom the power to use carbohydrates is greatly
depressed). The marked protein-sparing action of carbohydrates is il-
lustrated in another way — namely, by the fact that we can greatly
diminish the protein breakdown during starvation by giving carbo-
hydrates, in this way we can indeed reduce the daily nitrogen excre-
tion to about one-third its amount in complete starvation. Carbohy-
drate starvation is said to entail a failure of the muscles to use again in
their metabolism certain of the products (e. g., creatine) which result
from their disintegration. At any rate it has been found that creatine
is excreted in the urine when no carbohydrates are available.

In the case of man living on an average diet, although the daily nitro-
gen excretion is about 1.5 grams, it can be lowered to about 6 grams
provided that in place of the protein that has been removed from the
diet enough carbohydrate is given to bring the total calories up to the
normal daily requirement. If an excess of carbohydrate over the energy
requirements is given, the protein may be still further reduced with-
out disturbing the equilibrium. It has been found that it is not the
amount of carbohydrate alone that determines the ease with which the
irreducible protein minimum can be reached; the kind of protein itself
makes a very great difference. This has been very clearly shown by
one investigator, who first of all determined his nitrogen excretion while
living exclusively on starch and sugar, and who then proceeded to see how
little of different kinds of protein he had to take in order to bring him-
self into nitrogenous equilibrium. He found that he had to take the
following amounts: 30 gm. meat protein, 31 gm. milk protein, 34 gm.
rice protein, 38 gm. potato protein, 54 gm. bean protein, 76 gm. bread
protein, and 102 gm. Indian-corn protein. The organism is evidently
able to satisfy its protein demands much more readily with meat than
with vegetable proteins.

This variability in the food value of different proteins depends on their
ultimate structure — that is, on the proportion and manner of linkage
of the various amino acids that go to build up the molecule. In no two
proteins are these building stones, as they are called, present in exactly
the same proportions, some proteins having a preponderance of one or
more and an absence of others, just as in a row of houses there may be
no two that are exactly alike, although for all of them the same build-
ing materials were available. Albumin and globulin are the most im-
portant proteins of blood and tissues, so that the food must contain the
necessary units for their construction. M' il fails in this regard, even to
the extent of lacking only one (if the units, the organism will either be
unable to construct that protein, and will therefore suffer from partial
starvation, or it will have to construct for itself this missing unit. It

is therefore apparenl thai the mosl valuable proteins will I thai

contain an array of units thai can be reunited t<> form all th<
of protein entering into the structure of the bodj pi turally,

the protein which mosl nearly meets the requirements is meal prot<
so thai we are no1 surprised to find thai let than of any other

protein has to 1"' taken to gain nitrogen equilibrium.

Tli'- mosl exacl information regarding the d valu<

proteins has been Becured b} observations on the rate of growth ing

animals. This method yields more reliable information than ran be
Becured by studies on the nitrogenous balance, because it is no1 usually
possible to keep up the latter observations for fficient period

time, or to secure an adequate number of data. Dui a rowth I
building-up processes are in excess of the breaking-down, so that the
effecl is an increase in bulk of the tissues, thus permitting us. by the sim-
ple expedienl of observing the body weight, to dra tlusions
the influence of various E Istuffs on tissue construction.

CHAPTER LXIV

NUTRITION AND GROWTH

In the growth of animal tissues two factors arc concerned, one being
the property of the cell to grow, the growth factor; and the other, the
availability of suitable material to grow upon, the food factor. Concern-
ing the growth factor little is known ; its variability in different species
of animal, its irregularity despite proper adjustment of the food factors,
its abnormality leading to tumor formation, etc., are all well-known but
apparently inexplicable facts (MendeP).

THE FOOD FACTOR OF GROWTH

Our knowledge is constantly increasing concerning the food factor of
growth, and many facts of extreme practical importance have been ac-
cumulated in recent years. In seeking for the relationship of food to
growth, we must first of all consider whether this process entails a
greater expenditure of energy than is necessary for mere maintenance
in adult life. Important results bearing on this question have been se-
cured by observations on the basal metabolism of young children. In
computing the energy supply of fasting adult animals of different sizes,
it will be remembered that the smaller the animal, the greater is the
energy exchange in relationship to the body weight, although when
computed in relationship to body surface tolerably constant values are
obtained. When the calorie output per square meter is determined in
growing children, there is, as we have already seen, clear evidence of
greater energy expenditure (see page 541), particularly marked in boys
just before puberty. An increased energy metabolism has also been de-
scribed in the case of infants, but the uncontrollable muscular activity,
the psychic disturbances, etc., may explain the result. Even after dis-
counting these factors, however, it is possible that there may be a cer-
tain influence, depending probably on the active mass of growing proto-
plasmic tissue, which stimulates the energy expenditure. The question
is not yet finally settled.

The Relationship of Proteins to Growth and Maintenance of Life. —
Since protein constitutes the fundamental chemical basis of the cell, it
is natural to devote attention in the first place to this food principle.

574

NUTRITION \M> GROW1 II

In the pioneer investigations, studies on the nitrogen balance in young
animals yielded results from which it was concluded thai tl ditions

for the disintegration <>!' protein are less developed in young animals

than in adults, s<> that the growing organs rapidly withdraw circulating
protein and build it into tissue protein.

In consideration of the accumulation of data extendii pal

decades, Rubner denied these conclusions, and showed that the diel
the growing infant is by no means relatively rich in protein. II" con-
cluded that "growth is no1 proportional to the quantity of protein in I
diet." Important though this pioneer work may have been in the de-
velopment of our present-day conception, the viewpoinl of the men who
carried it out was very much narrowed on accounl of the paucity
knowledge concerning the structure of the protein molecule. No all*
ance was made for the fact, which has recently been firmly established,
thai the protein molecule may vary extremely in regard to the d
of which it is composed, and that the growing tissues may demand,
so much an abundance of protein as such, but rather a prop
all the building stones which are required for growth Mendel .

Quantitative Comparison of Amino a. eds Obtained b'v H'

(Compile! by T. B. Osborne, 19]

OVAL-

CASEIN

BUMIN

GLIADIN

IV

( rlycocoll

0.00

0.00

0.00

0.00

:;.sn

«

Alanine

1.50

■

13. 1

•

•

Valine

7. L'n

2.50

3.3 I

1.88

20

T

Leucine

9.35

10.71

19

1 1.:>"

-

Proline

6.70

3.56

13.22

i.i"

-

Phenylalani

lie

3.20
15.55

5.07
9.10

2.35

43 l

26.17

is. 71

I3.fi

i rlutaminic

acid

Aspartic acid

1.39

2.20

0.58

1.71

t '

lie

0.50

f

0.13

T\ rosine

4.50

1.77

1.61

2.13

< '\ st'me

f

T

0.45

t

f

f

II ist i.line

8.50

1.71

1.84

-

Arginine

3.81

1.91

2.84

1.55

14-17

12

I. sine

Ti 5 ptophane, about l."'11

1.00

Ammonia

L.61

1.34

IV

-

88.87

-

• i bt te bi
chemists.

tThe fiRiircs for the

From the accompanying table giving the
amino acids, etc., present in certain proteins, it will be evident that tl
arc very marked variations in the units of which differ*
composed ft any one of these units should be essential owth and

576

METAI'.nLISM

the organism be unable to manufacture the missing unit for itself, it

is clear that growth could not proceed however much protein not contain-
ing the necessary unit we might feed to the animal. It is an application
of the law of the minimum, and is analogous with the failure of growth
which has long been known to ensue when certain inorganic substances
are withheld from the growing animal. A diet might be perfectly bal-
anced as judged by comparison of the nitrogen intake and output, and
yet if it should fail to contain even one of the essential units and the
organism should be incapable of supplying this unit, then would the
diet be inadequate for growth.

These important facts are the outcome of modern work, and they
have been established by observations on the growth of young animals
fed with a "basal ration" to which were added mixtures of amino acids

.v^

Each division = 20 days

Days

Each division = 2.0 days.

Tig. 183. — Curves of growth of rats on basal rations plus the various proteins indicated. The
normal curve may be taken as that with casein (I). (Adapted from Lafayette B. Mendel and
T. B. Osborne.)

or various proteins which differ considerably from one another in the
nature of the units entering into their make-up. In such experiments
the periods during which growth is observed must be prolonged, since
a transient increase in weight might depend merely on repair processes
occurring in tissues which had previously for some reason been brought
below par.

Among the most important observations have been those of Lafayette B.
Mendel and T. B. Osborne8 and of McCollum and his collaborators. The
animals chosen for Mendel and Osborne's experiments were young white
rats. Large batches of these animals were fed on a basal ration consisting of
protein-free milk (containing the inorganic salts, the sugars, traces of
protein, and unknown substances having an important influence on

M TUITION \M» likuW I II

.'. .

growth vitamines? . to which were added more carbohydrate, purified
fat, and the protein whose influence <>n growth it was desired to Btudy.
The same diel was fed a1 regular intervals to a given batch of rats, and
the weighl of each ra1 was periodically taken, the observation l"-in<_r pro

longed until the animals grew to maturity and prodi 1 young, and these

again <Mrw to maturity, reproduced, and so on. By plotting the re-
sults in curves, with the time periods along the abscissae and the averi
weight of the rats of each batch along the ordinates, the extenl of the
influence of a given diel on tin curvt of growth was obtained. A normal
curve of growth is shown in No. 1 of Pig. 183. It was obtained from re-
sults secured by adding liberal amounts of casein to 1 1 1 « - basal diet.

■500

IU

vo
lie
too

Mf
IfeO

I-

ito

too

te

10

1 1 —

; ®

— i 1 1 1 l l i — i r-

•

*?/

.

<r>/

*/

■$/

//

!»/

1

<?/

fif

o /

.

t> /

v/

A /

•V

J9i

*/

^^""^

Ay

■ ®

t T 1

- T T 1

/

-

■

■

-

-

•

/

1

J'-

1 *

if/

9/

■ /

V

X — ■*

1*

■

/ ^

7 4V

IM,1

lacri division -Jto dayi

Days

Cach divijion - ZOday*

Pig, 184. — Cun growth of rau ina indicated. In curve

III tk of the additii n to an inadi I protein, lactalbumin,

1 in 1\' the effect of the addition from
I. at Mendel and T, B. Osb

Similar curves were obtained with Lactalbumin of milk and ovalbumin
and ovovitellin of egg Perhaps the mosl interesting substances capable
of producing the normal curve of growth are certain of tin- proteins thai
T. B. Osborne has succeeded in separating in crystalline form from

jetable foodstuffs. These are edestin hempseed . globulin squ
seed . excelsin (Brazil nut , glutelin maize . globulin (cottonseed ,
glutein (wheal . glycinin soy bean), cannabin (hempseed

Thai growth p Is normally with any one of these proteins when
fed abundantly does not, however, n sssarily indicate that each con-
tains in adequate proportion all of the n ry units to meel the pro-
tein demands of growing tissues. In the case of casein, I ample,
one of tin1 units, namely, glycocoll, which is the simplesl of all the

."">,> METABOLISM

amino acids, is entirely missing, and another, cystine, which is a sul-
phur-containing amino acid, is present only in small amount. The ab-
sence of glycocoll, however, is not of importance, because the organism
can manufacture it £or itself (sec page 630). In the case of cystine,
which the tissues can not manufacture themselves, the deficiency has to
be made up for by feeding an excess of casein so as to cover the needs
of the tissues tor this amino acid. By so doing a superabundance of
most of the other units will be ingested, and this superabundance will
entail the destruction and excretion of the useless amino acids, a process,
however, which is conducted in such a way as to permit of the utilization,
by the organism, of a part of the energy which the cast-off amino acids
contain .see page 667). It is. therefore, not entirely a wasteful process.
When the supply of casein is limited, on the other hand, the curve
of groAvth becomes subnormal, because an insufficient supply of cystine
is thereby offered (Fig. 184). Similar results have been obtained in the
case of edestin, a protein from hempseed. This contains an insufficiency
of the diamino acid, lysine. Fed in abundance, edestin gave a normal
curve of growth, but when fed in insufficient amount the curve failed to
ascend properly, which, however, it could be made to do by adding some
lysine to the edestin.

There is a large group of proteins which fail to permit of any growth
no matter in what amounts they may be added to the basal ration. These
include: legumelin (soy bean), vignin (vetch), gliadin (wheat or rye),
legumin (pea), legumin (vetch), hordein (barley), conglutin (lupine),
gelatine (horn), zein (maize), phaseolin (kidney bean). The adequacy
to maintain growth of any of these pure proteins varies according to
the deficiency in their amino acids. In the case of gliadin of wheat or
rye, glycocoll is lacking, and lysine is present only in small amount (see
table). The absence of glycocoll can not, however, as we have already
seen in the case of casein, explain the inadequacy of gliadin as a foodstuff
for growt I] ( Curve II in Fig. 183) . It must be the lysine that is at fault. A
still more deficient protein is the zein of maize. With this as the only
protein added to the basal diet, the curve of growth actually descends
(Curve III of Fi«r. 183), thus indicating that the animal is starving and
must soon succumb. The missing units in this protein are glycocoll.
lysine and tryptophane (see table on page 575), and it is very signifi-
cant that if the latter two amino acids are supplied along with zein, an
almost normal curve of groAvth will result. Some improvement can
even be brought about by giving tryptophane alone; that is to say, the
curve assumes a horizontal line instead of descending, indicating that,
although inadequate for growth, the diet is now sufficient for the main-
tenance of life.

RITION \'-l' GROWTH

The important fad demonstrated by these experiments, is thai eer
tain iluts are adequati for thi maintenana o) lif< although (l<<<i an
inadequaU for growth. In conformity with this conclusion, it \ ind

when young white rats were fed with gliadin alone for periods ..t" time ex-

Pig. 185. — Photograph! of rat< of lame bi 1 on • picture); on a n

ince diet bnt inadequate for p tret; an.l on a diet th.it was inadequate both

Maintenance ami growth. il '■' ndel ami Osoonx

ding those in which they Bhould have become full grown, that
they remained in an ungrown Btunted condition. The capacity to l,m-<>\\
had nut. however, been lost, fur when the gliadin was replaced by milk.
the animals resumed growth at a very greal rat capacity to lto\\

580 METABOLISM

had only been inhibited by the inadequate diet, and there was nothing
really abnormal aboul the stunted animals. For example, the reproduc-
tive function developed normally, as was shown in the ease of a young
female rat which, after being fed with gliadin as the sole protein sup-
ply for 354 days, was mated and produced four young. Although the
mother was still maintained on the gliadin diet, the young rats pre-
sented normal growth, for they were living on the milk supplied by the
mother, and this milk, because it contained cither casein or some other
necessary accessory tad or (vide infra), was an adequate food.

After removal from the mother, three of these rats were fed on an arti-
ficial diet of casein, edestin and the basal ration, and continued the nor-
mal course of growth, but when one of them was placed on the gliadin
food mixture it immediately failed to grow properly. It would, appear
from these experiments that, of the two amino acids that are missing or
deficient in gliadin — namely, glycocoll and lysine — it must be the lysine
that is essential for growth. This very important conclusion was fully
corroborated by finding that, in young rats stunted by previous gliadin
feeding, growth immediately started when lysine was added to the diet
and ceased again when the lysine was removed, and so on, the experi-
ments being often repeated in various modifications. Mendel and Os-
borne call attention to the relatively high percentage of lysine in all
those proteins that are concerned in nature with the growth of young
animals; thus, it is present in large amounts in casein, lactalbumiri and
egg vitellin.

It is particularly in protein of vegetable origin that indispensable units
are likely to be missing, the best known of these units being the aromatic
amino acids, tyrosine and tryptophane; the diamino acid, lysine; and
the sulphur-containing acid, cystine. Some animal proteins, such as
gelatine, also fail to contain aromatic groups, and are therefore utterly
inadequate as protein foods.

That the absence of one or two units should render a protein utterly
incapable of maintaining life suggests that a specific role may he taken
by certain amino acids in the maintenance of nutritional rhythm; thus.
they may be necessary for the elaboration of some hormone or other in-
ternal secretion essential to life, such as epinephrine, the active principle
of the suprarenal gland. This is an aromatic substance not far removed
in its chemical structure from tyrosine (see page 734). It is
therefore natural to suppose that the absence of the tryptophane unit
in zein is the reason that this protein is incapable of maintaining the in-
itial body weight.

In attacking the problem from this viewpoint, Hopkins and Willcock10
made observations on the survival period of young mia : that is, the
period during which the animals survived when fed on a basal diet

NUTRITION \NI> OBOW1 II

mixed either with zein al ■ or with zein plus small quantith

tophane. It was found that, with zein alone, th<- m
maintain growth; they Losl in weighl and died in from abonl i
aboul a month. Other mice fed on the same amount of basal did
zein, bu1 to which was also .- 1 < 1 « 1 « ■ < I sunn- tryptophane, although they <li<i
qoI grow, were capable of maintaining their body v. eighl and lived in
Borne instances for nearly a month and a half. There w<
tions of t li»" differei ce in t he efficienc
on the zein alone were "very inactive, and remained
period of the time in a condition of torpor. The hair iffled,

half closed, and the ear . I and tail were cold. Th<

mals, however, gave evid< E having a g I appetite. ( >n the

hand, the mice to which tryptophane was a manifested a strik-

ingly differenl behavior, being active and more or rmal until

jusl before death. Thai both groups of animals failed to live more than
forty-four or forty-eight days is probably to 1"- accounted for by the
absence in the zein of the other unit, lysine. Had this been added along
with the tryptophane i1 is probable, in the lighl of Mendel and I i
observations, thai the animals would have survived much long

To supply the missing unit, besides using the pur.- amino acid,
may employ other proteins which contain tin required an I irve

[II of Fig. 184 . That mixtures of protein f Istuffs are desirabl

been apparent to those who have studied practical dietetics. We must com-
bine the unsuitable protein with others which, although in themselves
perhaps also unsuitable, ye1 furnish us with a mixture which contains all
the essential units both \'<>v maintenance and growth. As M ndel ints
out, these considerations suggesl thai we may be able to utili
of the low priced protein by-products of th< al, me i milk in-

dustries. The tesl of the adequacy of the corrected diel m
be determined by experiments of the type which we have jusl described
II is probably in stock-raising rather than in connection with human nu-
trition thai these facts will prove of practical value; for, not only
of man more varied, but it contains animal p - in which the d<

eies are no1 so common.

Itfosl important w <<vk of this • I by McC

lum and his collaboratoi It would take

this book to discuss the results in detail, bul il m
they have shown that, since the adequi
multiplicity of factors besides the amino-acid make-up
some of which we shall discuss immediatel;
tions with various food mixtures must bi
of time. The nutritive valu< imon •

ard did that hml brought the animals

582 METABOLISM

were found to be as follows: "With cornmeal there "was immediate recov-
ery and rapid growth, both of which were also secured in considerable
degree by wheat embryo and entire wheat kernel ; with rye and oats, on
the other hand, there was little if any improvement.

Much work is, of course, yet to be done before we can determine the
exact role which each unit plays in the physiological development of
young animals. To sum- up what we already know, it may be said that
glycocoll is not essential, since it can be manufactured by the animal
itself; that tryptophane is essential for maintenance, probably because
it is required for the production of certain essential hormones, for the
make-up of which in its absence other tissues must become disintegrated,
leading therefore to a diminution in body weight ; and that lysine ap-
pears to be essential for growth. Tissues can be maintained without
lysine, but they can not grow, for the slight trace which most food con-
tains of this important amino acid may be sufficient for maintenance
purposes, but utterly inadequate for growth. That the young rats in
the experiments of Mendel grew normally while living on milk supplied
by the stunted mother indicates that the requisite lysine must have been
produced in the mother's body.

In the application of the foregoing principles to human dietetics, it
is undoubtedly safe to folloAV Bayliss's advice to take care of the calo-
ries and allow the proteins to take care of themselves.11 For example,
in the case of milk the deficiency of cystine in its chief protein, casein,
is corrected by the presence of lactalbumin, which, though present in
only small amounts, contains sufficient quantities of this amino acid to
meet the demands of the growing tissue.

These observations on maintenance and growth suggest very interest-
ing applications in connection with the growth of tumors. Is it possible
that we might retard the growth of tumors by a diet that was" insufficient
for growth while sufficient for maintenance. In an experiment devised
to test this proposition mice were fed on a diet of starch, lard, lactose
and gluten on which they could merely maintain existence but failed
to grow. Some of these rats were inoculated with a rapidly growing:
tumor at the same time as another batch of mice kept on normal diet, and
it was found that the tumor grew much more slowly in the stunted mice
than in the others. One mouse, for example, on the restricted diet had
a scarcely visible tumor 52 days after the inoculation. "When this mouse,
however, was placed on a normal diet of bread, milk, etc.. the tumor
immediately began to grow at a very srreat rate.13 Too much importance
should not he placed on this experiment.

"We shall now pass on to consider some of the factors besides the pro-
tein content which have an important bearing on dietetic efficiency.

CHAPTER I. XV

M TUITION .WD GROWTB Cont'd

THE RELATIONSHIP OF OTHER FACTORS THAN PROTEINS

The Relationship of Carbohydrates. As we have seen elsewhere, car-
bohydrates are almosl certainly essential for normal metabolism. If they
are not given with the food, the} musl l"- mannfactured out of protein by
the organism itself. It is not surprising, therefore, thai their absence
from the diel of growing animals should lead to abnormality in the
rate of growth. Pediatrists have nol infrequently insisted that one
form of carbohydrate is more advantagi 'or growth than another.
Th is in. doubl in the main is true, but the whole question of adequney
probably depends on the digestibility of the carbohydrate and not upon
its essential chemical nature. It is likely that the only carbohydi
required by the tissues is glucose. The readiness with which the car-
bohydrate of the food 1" mes converted into this monosaccharide is

probably the only determinant of its efficiency as E 1 material

The Relationship of Fats. Although fats are an invariable constit-
uent of practically every diet, it is yel a debatable question as to

whether thej are essential to the maintenan E a healthy normal

organism. Difficulties standing in the way of a solution of this problem
are thai it is nol only technically very difficull to remove fal entirely

from the common f istuffs, bu1 also thai the simple fats are usually

associated with substances having similar solubilities and physical
properties: namely, the lipoids, phosphatides, cholesterol, i >i Lrm<i •
Since these substances are presenl in practically every cell, it is aha
certain thai they can be manufactured by living protoplasm. Indeed,
experimental evidence is nol wanting to show thai this is actually the
Although the cell can manufacture lipoids, a young animal i

apparently nol gro"w when these Bubsta s, as well as simp'

entirely absenl from the diet. This has hen shown by feedi a nng
mice "ii a diel from which .-ill traces of fat and lipoids had been remo
by extraction with alcohol and eth< 31 On such a diet tt

lived only a few weeks. Thej could be kepi alive much Ion
sum-- of the alcohol-ether extract was mixed with the diet, hut not
when neutral fal instead of the alcohol-eth< trad was added. The

-

58-4 METABOLISM

addition of the ash of the lipoid extract failed to maintain the mice, so
that the lacking substance could not be inorganic in nature.

More recent and extended observations, however, have shown that neutral
fat is also necessary for the adequate and continued growth of the
animal. For a period of two months or so an animal may, as we have
seen from Osborne and Mendel's experiments, grow in apparently nor-
mal fashion on an artificial fat- and lipoid-free diet composed of casein,
carbohydrate and inorganic salts, but sooner or later the great majority
of these animals begin to show failure of adequate growth. The in-
adequately growing animals often manifest indications of malnutrition
other than the failure to increase in weight ; for example, inflammation
of eyes, roughening of the fur, etc. "When certain fats are added to
the inadequate diet, normal growth is immediately resumed. Fats pro-
ducing this normal growth are such as butter fat, or the fat extracted
from egg yolk, or cod-liver oil, added to the extent of 5 per cent of the
ration. On the other hand, vegetable oils, such as olive oil or almond
oil, are inefficient in promoting growth. That all oils or fats do not
suffice to produce growth, and that one dose of an adequate oil or fat may
be sufficient to stimulate it, indicate that something other than the mere
presence of the comparatively simple fat molecule — that is, some acces-
sory material — must be the agency responsible for the growth.

This conclusion is further supported by the interesting observation of
McCollum and Davis that vegetable oils can be rendered efficient for
growth by shaking them with a solution of soap prepared by com-
pletely saponifying butter fat with potassium hydroxide in the absence
of water.

ACCESSORY FOOD FACTORS, VITAMINES

In searching for the nature of the accessory food factors, the im:
portant observations which have been made in recent years concerning
the so-called vitamines must be considered. These are substances essential
in the diet for the proper maintenance of nutrition in adult animals.

The existence of such substances was suggested by observations on
the disease beriberi, which is caused by exclusive feeding on polished
rice; that is, on rice from which the pericarp had been removed by the
process of polishintr. When patients suffering from this disease were
given unpolished rice, the symptoms immediately disappeared. Further
investigation of the exact nature of these substances was greatly facil-
itated by the discovery that a similar condition is readily induced by
feeding fowls on polished rice. The birds develop a polyneuritis, from
which, however, they very promptly recover if some rice polishings <>r.

NUTRITION AND GROW1] ll 585

better still, an extract of rice polishings, is added to the polished rice
• lict. The extracl i> made by means of Blightly acid 9] pei alcohol,

and from it Punk has succeeded in separating a substance in c
line form apparently related to the pyrimidines, which it will be
membered are a characteristic constituenl of the nucleins. I»
small as 0.02 to ii.<>4 '_rm. of this material '.riven by mouth were adequate
to cure the polyneuritis of fowls in from six to twelve hours; indeed, in
some cases the bird seemed qnite well after three hours. A similar Bub-
Btance lias also been extracted from yeast, milk, brain and lime ju i<-«-.
and it lias been called, for want of a better name, vitamine.

[1 is quite likely that other diseases, such as scurvy, may also be due
to the absence of some vitamine in the diel Borne substance, namely,

which in the case of this particular disease would m to be absent in

preserved food, the continued taking of which is so frequently

Fresh fruit and other f Is added even in small amounl rach a diet

would appear to supply the accessary vitamine.

It is nut the higher animals alone that suffer from the want of some
such substance as vitamine. It has been shown, for example, that, when
a normal artificial culture medium is inoculated with yeast in \
small amounts, it fails to grow, whereas the same quantity will grow
luxuriantly in a medium to which sterilized beer wort has I n added.

Vitamine is uo1 of the nature >>\ a ferment, since it withstands heating
to 120 C. for more than an hour. The addition of yeast to dietaries
thai are deficient in vitamines is an excellent corrective.

Returning now to the accessory substances that seem to he adherent
to certain forms of fat. we see ,-it once that they can not lie exactly
the same as the BO-called vitamine of Funk, for they contain no nitrogen
There are. therefore, probably two accessory factors concerned in ade-
quate growth. One of these must he present in the protein-free milk
which serves as a constituent of the basal diet used iii Osborne and
.Mendel's experiments, for we have seen that animals will grow on this
(>^v a certain period, provided the proper amino acids are p
Later, however, they pass into a state where there is no g
adequate maintenance, if now the other accessory factor i^ added,

for example, butter fat <>r a small amount of milk i' . in pi

n\' protein-free milk), then growth will he resumed at its normal rate.

"Either of the determinants may become curative Both are

for growth when the bod of them becomes depleted." MhcCollum

suggests that these accessory factors should at present he called the
"fat-soluble A" and "water-soluble B " The latter ie ent in

cells, in fat-free milk, and in many other animal f Is. - probably

the same as Innk's vitamine. The former is snluhle in the fat solve? Is

586 METABOLISM

being present in most animal fats, but not in all; for example, it is
absent from the fat surrounding the pig's heart. By using such a
nomenclature it is recognized that the subject is as yet only in an early
state of development.

We may sum up the main facts of this chapter by stating that growth
and maintenance are more than a mere problem of energy supply.
Granted that this is sufficient, we must also have a suitable admixture of
building units of protein and the presence of extremely small quantities'
of some unknown accessory substances. These are present in some natural
foods but not in others, and some are soluble in water and others in fats.
They are found, for example, in animal fats but not in those of vegetable
origin. Both fat- and water-soluble factors are present in large quanti-
ties in milk.

Both accessory food factors are necessary, as is illustrated in the fol-
lowing summary of experiments from Lusk's "Science of Nutrition,"
(third edition).

Purified protein + carbohydrate + vegetable fat + inorganic salts = no growth.
" " -f " -t- butter fat 4- " " =no growth.

" + " + vegetable f at + " " +vitamines (accessory

factor B) = no growth.
" " + " + butter fat + " " + vitamines = growth.

The Relationship of Inorganic Salts. — Inorganic salts are also an es-
sential ingredient of the diet. McCollum found that young animals soon
ceased to grow when fed on a diet of corn and purified casein, but that
rapid growth returned when a suitable salt mixture was added. Oats,
wheat, and beans have also been shown to require some adjustment of their
ash content to make them adequate for growth. Most of the animal foods
contain in themselves sufficient inorganic material, as is evidenced
among other things by the adequacy of milk alone as diet for growing
animals and the abhorrence of salt that is shown by strictly carnivorous
animals. In the usual mixed diet of man there is almost always enough
inorganic material, the salt which he adds being largely for seasoning
purposes. When a preponderance of vegetable food is taken, however,
the salt comes to have a real dietetic value.

The practical application of the results of these numerous and at
present somewhat bewildering observations to the nutrition of man,
and particularly to the dietetic treatment of disease, is undoubtedly
very great. This is especially so in infants and growing children, in
whom the correction of some slight inadequacy in the diet may have
the most pronounced results, not only on growth and nourishment, but
also on the power of resistance against disease and infection. The bene-
ficial influence of eod-liver oil, for example, may depend on some fat-

NUTRITION AND OBOW1 B

.soluble accessory food factors, while tin- miraculous benefit \*. li i<-li
scorbutic children derive from the addition of the juice of limes, Lemons
etc., to the food is undoubtedly due to Buch influences. The accumu-
lating mass of evidence as to the faulty nutrition in animals fed on
single kinds of food that fail to contain both kinds of food factors
emphasizes the necessity in the dietetic treatmenl of Buch diseases as
diabetes, nephritis, etc., of seeing to it i hat the diel is sound, not only
in calories, protein content, and palatability, bul also with regard to
the presence <>f accessory food factors.

CHAPTER LXVI

DIETETICS

THE CALORIE REQUIREMENT

In the application of the important facts that have been revieAved in
the preceding chapters to the science of dietetics, the. question arises as
to how we may determine with scientific accuracy just exactly how much
food should he taken under varying conditions of bodily activity. In a
general way, we know that the amount of food that we require to take
is proportional to the nature and amount of bodily exercise that is
being performed at the time ; and that, if the food supply is inadequate,
the work before long will fall off not only in quantity but in quality as
well. "Horses (also men) work best when they are well fed, and feed
best when they are well worked," is an old adage and one the truth of
which can not be overestimated in the consideration of all questions of
dietary requirements. An ill-fed beggar will rather suffer from the
pain and misery of starvation than attempt to perform a piece of work
that the well-meaning housewife bargains should be done before she
gives him a meal. The spirit may be willing but the flesh is weak. If he
could be trusted, he should be fed first and worked afterwards. Besides
the amount of work, two other factors are well known to influence the
demand for food — namely, growth and climate. A young, growing boy
will often demand as much if not more food than would appear to be
his proper share, from a comparison of his body weight with that of
his seniors; and, other things being equal, it is well known that Ave are
inclined to eat much more heartily of food during the cold days of
winter than during the sultry days of July and August.

That Ave knoAv these facts in a general way, indicates that the first
step to take in the exact determination of dietetic requirements is to
find out how much energy the body expends under varying conditions
of activity. This, as Ave have seen, may be done by having the person
live for some time in a respiration calorimeter, so that Ave may measure
the calorie output. To the conclusions drawn from results of observa-
tions made under such artificial and unusual conditions of living, the
objection might, hoAvever, quite justly be raised that they need not
apply to persons kroin£ about their ordinary routine of life. To meet

588

I. II 1 1 1 1. -

this objection another method, which we may call 1 1 1 « - statistical, is avail-
able. It consists in baking the average diel of a Large number of indi-
viduals and comparing the calorie value with the average amounl ;m<l
type of work that they are meanwhile called upon to perform, and can
besl be used where the <liet is accurately known, as in public institu-
tions, the army, the oavy, etc. The total food supplied is then divided
by thf number of individuals, this giving the per capita consumption.
Obviously Borne gel more than others, bu1 when a sufficient number of
individuals is included, such errors become eliminated by the [aw of
averages.

The reliability of this method is testified to by the remarkable cor

spondei in the calorie value of the )'<><><1 consumed by farmers in widely

differenl communities:

Farmers in Connecticut 3,410

" '• Vermont 3,635

" " New York 3,785

" •' Ctaly 3,565

" Finland 3,474

Average 3,551*

*I.usk: The Fundamental P.asis of Nutrition.

The average inhabitant of various citi

I. ■ don 2,1

Paris 2,903

ich 3,01 I

Konigsberg 2,394**

>*Rubn< r.

lividuals in differenl callii _

V-.n- families Q.8 \ 3.£

Mi ■ ■' : ni -- families | I'.s.A ::.■

Proi 1 men's families [J.S. \

Am; l B.A.) 3,851

\ U.B.A 1,9981

' -water.

In _ ■ . i' is usually computed that a man

weigh] in caloi

2,500 for a Bedentarv li'

t'iir light muscular work,

3,500 for medium muscular work,
I. ecu and upward ery liar.l toil.}

: McKillop.

These figures apply to the average man, hut in calculating the calorie
requirements of a family or ;i community we must make allowai
the lesser requirements of women and children. Several dietitians h.

compiled tables showing how many calories are expended a< rding I

age and Bex, and the German authorities hav< tlv taken these figu

and from them calculated a generalized mean, which shows in eomparis

590 METABOLISM

with men the percentage thai should be allowed for women and children.
The figures are as follows:

Man 100

Woman 83

Boy over 1 6 92

Bov 14-lfi 81

Girl 14-10 74

Child 10-13 G4

' Child 6-9 49

Child 2-5 36

Child under 2 23

In calculating the calorie requirement of the population as a whole,
the necessity of making allowance for the varying needs of men, women,
and children would obviously make the calculations far too complicated
for practical purposes. It is necessary to have a factor by which we
may multiply the total population in order to determine its "man value."
This factor is based on the relative proportion of men to women and
children, and it amounts very nearly to 0.75, i. e., three-quarters of the
total population gives "the man value." Knowing the total population,
say, of a city, we must therefore multiply this by 0.75 in order to ascer-
tain for how many men doing moderate muscular work (3000 C.) food
has to be provided.

THE PROTEIN REQUIREMENT

The facts considered in the previous twro chapters lead to the question:
To what extent may the proportion of protein in the diet be reduced
with safety? It is evident that there must be a minimum below which
every one of the necessary building materials of protein could not be
supplied in adequate amount to reconstruct the worn-out tissue protein.

The extent to which the protein content of the diet of man can be
lowered with safety depends on several factors, of which the most im-
portant are: first, the nature of the protein; second, the number of non-
protein calories ; and third, the extent of tissue activity. Where so many
factors must be taken into consideration, the only method by which the
actual minimum can be determined consists in what may be called "cut
and try experiments." Of the many investigations of such a nature,
probably the best one for us to consider, is that recently published from
the Nutrition Laboratory of Copenhagen. The subject, an intelligent
laboratory servant, lived a perfectly normal and active life for a period
of five months on a diet of potatoes cooked with margarine and a little
onion, and containing 4000 C, with a total protein content of 29 grams.
During another period he did outdoor work as a mason and laborer, and
took 5000 C. daily, and 35 grams of protein.

I. II II 1

It is important to contrasl these results with the following based on
municipal statistics of gross consumption.

Mink ir\i Po » 8

PROTEIN

FAT

CAI •

gm.

gm.

gm.

Konigsbei g

M

31

II i

_ M

Munich

96

192

014

Paris

64

165

291

London

98

60

416

2«-'

It is certain thai man can lead a normal existence and remain in good
health on very much less protein than the !<"• grams which statistical
studies show to be the amounl he actually takes. This discrepancy be-
tween the amounl which experimenl demonstrates to be adequate and
thai which habil and custom demand, raises the question as to whether,
after all, our instincts may nol have erred and bo made us dju rily

extravagant in our protein intake. It has been suggested that Buch pro-
tein extravagance will in various ways have a deleterious effect on the
organism; thus, thai the excretory organs, Buch as the kidneys, will be
overtaxed in eliminating the unused amino acids, that the constant p

ence of these bodies in excess in the bl I will cause degeneration and

sluggish metabolism, and thai the excess protein in the intestine will
lead to the production of ptomaines, whose subsequent absorption into
the blood will cause toxemic symptoms.

Important Bupport to such views appeared to be supplied some -1"
years ago by Chittenden, who was able tn show that he himself and many
other persons doing different kinds of work could be supported on daily
amounts of protein that were not more than from one-third to one-half
of the amounl usually taken. Not only so, but it was averred that dis-
tinct improvement was experienced in the general - of well-being
and of mental efficiency as a result of the lesser protein consumption.

Taking these results as a whole, it is quite dear that man can
along under ordinary conditions with much less protein than he usually
takes; but thai really proves nothing, for the question is not can he but
should lie, bo deprive himself) Are instinct and custom wrong and is
Chittenden right I That is the question. To answer it many studies have

keen made of the condition of peoples who for economic or other
sons are compelled to live on less protein than t ho averagt \ ■ • •'
people healthier, less prone to infections and degenerative dis< and

more efficient mentally than Others [] BUCh stud ■ care must be

exercised to see thai conditions other than diet, such as climate, -•■

etc., are properly allowed for. It would not be fair, for example, to

compare the mental ami bodily condition s living in the tropics

592 METABOLISM

and who take comparatively little protein, with those living in temperate
zones, Avho consume much more. After discounting all of these other
factors, it has been quite clearly shown that, when the protein allowance
is materially reduced, the people as a whole are less robust, mentally in-
ferior, and, instead of being less prone to the very diseases which are
usually supposed to be due to overloading of the organism with useless
excretory products, are more liable to suffer from them.

That a decided reduction in protein weakens the defense of the organ-
ism against infection is probably due to the fact that the fluids of the
body normally contain a great variety of so-called antibodies — that is,
of highly complex substances that are largely protein in nature. When
bacteria, or the poisons produced by them, enter the body, they are met
by one or more of these defense substances and destroyed or neutralized.
Now it is clear that there should always be a surplus of protein-building
materials from which the antibodies may be constructed. Such an excess
will constitute a "factor of safety" against disease. And there are fac-
tors of safety of another nature to be provided for, two of which we are
in a position to appreciate. In the first place, there must always be an
adecpiate supply of tryptophane, of lysine, and of cystine, not only to
meet the bare necessities of the protein constructive processes that go on
under normal conditions, but also to make good the larger amount of
protein wear and tear that greater degrees of tissue activity will entail.
Although moderate muscular exercise does not appear to cause any im-
mediate consumption of protein (carbohydrate and, later, fat being the
fuel material used to produce it"), yet it does throw a greater strain on
the tissues and causes a greater wear and tear of the machinery, and
hence a demand for more protein-building material. In the second place,
there are certain of the internal secretions of the body, such as epineph-
rine (adrenaline), that are essential for life, and as crude materials
for the manufacture of which certain amino acids are essential. Tyro-
sine is one of these, and since proteins, as we have seen, differ from one
another quite considerably in the amount of this amino acid which they
contain, it is advisable to provide an excess, so that an adequate supply
of tyrosine may always be available.

The answer to one of the most important practical questions in die-
tetics—namely, ''What proportion of protein should the diet contain?"
depends on these scientific principles. The source of the protein is the
important thing. With animal protein there is no doubt that Ave could
get along with perfect safely by taking daily not more than 50 or (>0
grams, which is about half of what we actually consume. If the protein
is of vegetable origin ami part of it of the first quality, as wheat and
Indian corn preparations, more should be taken so as to alloAv for the

I'll 'II I

deficiencj of certain amino acids. When vegetable proteins of the
ond quality, such as those of peas, beans, lentils, are alone available,

much larger amounts are accessary. Such proteins are inadequate in tin-
case of growing children at least, and even in adults it is undoubtedly
advisable thai other proteins should Bupplemenl them.

To insure safety, therefore, it is almosl imperative that the diet should
contain proteins of various sources. If for economic reasons tin- main
source must be proteins of vegetable origin, then Borne animal protein, such
as is contained in milk or meal or eggs, should be added to at least on<
the daily meals. When peas and beans are mainly depended on for the
protein supply, thej should be taken either with milk or one of its prep-
arations, or with a thick gravy or sauce made from meat and containing
the finelj minced meat. This must not be strained off, for if it is, the
sauce will contain only the meat extractives but not any of the protein,
which is coagulated by the boiling water. Meal extract, in other words,
contains no proteins; it is not a food but merely a condiment of no greater
dietetic value than tea or coffee.

ACCESSORY FOOD FACTORS

Little need he added to what has already been said regarding this
subject. The practical point to be remembered is that there are at l<
two accessory factors concerned, one of them soluble in fat and present
in adequate amount in butter and other animal fats but not in vegetable
oils, and the other soluble in water and present in wheat, vegetables.
fruits, etc. Milk contains both of these factors, so that its inclusion in
a diet is a safeguard not only against inadequacy in suitable protein, but
also against the absence of ac ry food factors. There is little dang
of the diet being inadequate with regard to food factors if it contains
some fruits or green vegetables or unheated fresh milk. T >d fac-

tors are destroyed by prolonged cooking.

DIGESTIBILITY AND PALATABILITY

We have Been that practical dietetics depends on Beveral facl >rs, I
exaei relative importance of which can no1 perhapc
ease, but preparation of the food so as to make it appetizing must un-
doubtedly rank high. The important f good cooking will now be ap-
parent. It is the act of making food appetizing and thei ble.

It is really the tirst Btage in digestion, the Btage that we can control, and
one therefore to which much attention musl be given, especially when it

becomes accessary to make attractive articles of diet ordinarily . red

common and cheap. Most people can k a lamb - to make it

594 METABOLISM

reasonably appetizing, but few can take the cheaper cuts of meat and con-
vert them into cooked dishes that are as popular and attractive. And there
are still fewer who can take the left-overs and trimmings and convert them
in the same way. This is the real art of cooking, and too much encourage-
ment can not be given to the effort which our cooking experts are making
to show people how these things can be done. The waste of good food in
a large city is truly appalling.

Cooking has other advantages than making the food appetizing. The
heat loosens the muscle fibers of the meat so that it is more readily
masticated ; it destroys microorganisms and parasites in the meat ; it de-
stroys antibodies which might interfere with the action of the digestive
ferments. Thus, untreated raw Avhite of egg is not digested in the stom-
ach because it contains one of the antibodies which prevent the pepsin
from acting on it; but boiled egg Avhite, if properly chewed, can be di-
gested, and whipping the e<x^ white into a foam partly destroys the in-
hibiting substance.

Before concluding, something should be said about the laxative quali-
fies of food, for it is often in this particular alone that one food is more
satisfactory than another. A diet of meat, milk, eggs, and white bread is
apt to be unphysiological because there is nothing in it to act as what has
been called intestinal ballast; that is, a material which will keep the
intestines sufficiently filled to stimulate their muscular movements. This
ballast is best furnished in the shape of cellulose, the most important
constituent of green food. Peas, beans, cabbage, salad, and many fruits,
especially apples, should always occupy a place in the daily menu. An-
other valuable food yielding this ballast is the outer grain of wheat, oats,
etc. So much must not be taken as to produce a constant intestinal
irritation, and each person must determine for himself where this limit
lies. The difference among various breads is almost entirely in the de-
gree to which they supply ballast.

The all-important subject of food economies can receive no attention
here, excepl to point out that it is one which must be most carefully con-
sidered in the solution of all problems of dietetics. An admirable ac-
count of the subject will be found in Graham Lusk's "Science of Nutri-
tion" (third edition) and in McKillop's "Food Values."1

M6

CHAPTER LXVH
THE METABOLISM OF PROTEIN

Introductory. The older physiologists believed thai the protein tah
with the food was brougb.1 unto a soluble condition by the digestive en-
zymes, and thai it was then absorbed into the blood and directly incor-
porated with the tissues. The discovery of the enzymes trypsin and
erepsin and of free amino acids in the gastrointestinal contents clearly
slu.wcd thai this simple theory of Liebig could uol be correct. It v
furthermore, found thai when an excess of proteins such ?g albumin
gains entry to the blood, pari of the protein appears in an unchang
condition in the urine ; and thai enzj mes capable of digesting this protein
luii not other varieties make their appearance in the blood.

After the injection of foreign proteins into the blood, symptoms
varying severity often develop, from the almosl instantaneous death
produced by snake venom to the slowly developing anaphylactic r<
tions which follow- the injection into the blood of many proteins chemi-
cally indistinguishable from those of the blood serum itself. When p
tein is taken in the usual amounts by month, these poisonous reacti
do not supervene, even snake venom is harmless when swallowed. — nor
is it possible during digestion of a protein meal i«> det< od protein in

the blood by means of the precipitin reaction. Finally it was disci
that the very slow intravenous injection of completely di did

not produce on the pari of the body any of the reactions that injec
protein itself produces, indicating thai perfecl assimilation had occurred
Prom these and similar observations it soon became dear that protein
can not be absorbed as such from the alimentary canal, but must fursi
nil be completely broken <l<in-n into tin amino acids, which are t) nilt

into tin protein of tin organism. The direcl evidence for this important

change in belief icerning protein metabolism has been gained by the

discoveries that: I oitrogen equilibrium can be maintained in animals
fed with completely digested protein mixtures; and _* amino acids can
he isolated from the bipod.

Tin' experiments of the firsl group consist, in principle, in breaking
down protein until there is no longer the characteristic biurel ind

then feeding this digestion mixture to animals and observing them from
day to day. using as criteria of their nutritional condition Hie body weighl

596 METABOLISM

and the nitrogen equilibrium, i Page 571.) It has been shown that suc-
cess in maintaining nutritional efficiency depends partly on the nature
of the process used for digesting the protein, and partly on the presence
or absence of carbohydrate in the digestion mixture. It was found
that acid hydrolytic products failed to maintain equilibrium, and it was
believed that this "was owing to the fact that the acid had more completely
disrupted the protein molecule, and had left no polypeptides, which, it
was imagined, remained intad during enzyme action and were essential
for proper protein metabolism. This view has now been considerably
altered, since it has been shown that the acid actually destroys certain
amino acids which the enzyme leaves intact. The amino acid particu-
larly concerned is tryptophane. Thus, when animals were fed with three
diets, consisting of (1) fully digested casein, (2) fully digested casein
from which the tryptophane had been removed, and (3) fully digested
casein from which the tryptophane had been removed and then the
proper amount of pure tryptophane added, it was found that nitrogen
equilibrium could not be maintained on the second diet, which contained
no tryptophane, whereas it was maintained on the first and third diets.
That this explanation is correct is further supported by the fact that,
if the protein is only partly digested by acid — that is, not digested
enough so as to break up all the tryptophane — it can efficiently maintain
nitrogen equilibrium.

Regarding the necessity for carbohydrates, it is possible that under
certain conditions these may be produced from the protein itself. At
least, it has been possible for Abderhalden, who has done a large share
of this work, to maintain an animal in nitrogen equilibrium with a diet
of digestion products and fat containing no carbohydrate.

These results obtained in different classes of animals have also been
confirmed for the human subject. A boy suffering from a stricture of the
esophagus, when fed by rectum for fifteen days with digestion products
resulting from the action of trypsin and erepsin on flesh, gave evidence
of nitrogen retention.

Concerning the second type of evidence, many investigators attempted
to separate the amino acids themselves from the blood, particularly dur-
ing the digestion of a large amount of protein, but the results were at
first entirely negative because of the lack of methods that were suffi-
ciently delicate to make it possible to detect the slight increase that
could be expected even when a maximum absorption of nitrogen had
occurred. The very large flow of blood through the portal vein causes
such extensive dilution of any substances added to it that the concentra-
tion of the substance in an isolated sample of the blood can be only
trivial.

Till. METAB0LI8W OF PRO!

To account for the indisputable disappears the amini

the intestine during protein « 1 i -_r < - -« t i • - 1 1 . coupled with the in.
detecting any of them in the blood, two many

years. One of these was thai the amino acids become deaminated Ml.
group split up as Ml by the intestinal epithelium, and the other, that
these cells are endowed with the power of reconstructing the amino acids
into protein, which then passes into the blood. Justification for the de-
amination h.\ pothesis seemed to be obtained by the observation thai there
is more free ammonia in the blood of the portal vein than in that of the
systemic circulation. The falsity of this evidenc
nitely established by Folin and Denis, >und by mi

quantitative methods for the estimation of ammonia and urea in the 1.]
tli.it the amount of neither of these substances became increased in the
portal blood during absorption of amino acids from the int< I

made the further important discovery that the ammonia in the portal
blood is really very Little in amount, and represents that ah*
such from the intestinal lumen, where it is produced chiefly by the action
of putret';icti\ e bacteria.

Nor could any evidence 1 btained in favor of the hypotl hat

the absorbed amino acids become built up in the intestinal epithelium
into proteins, which are then transformed or carried away by the Mood.
This hypothesis was based entirely on negative findings, and had there-
fore to be dropped when discovery was made of the actual presence

amino acid in the blood.

This brief historical survey of the sub j eel brings us to a position whe

we may pi-. ed to discuss the present-day teaching regarding protein

metabolism. Briefl; d, this teaching is to the effect that the \

molecule is broken down into Us ultimate building stom vino a<

by the digestivt ■ f tht gash ttinal tract, and that t)

acids are absorbed ;nt" tin blood, by which th y an

organs and tissues, which amino acids and ut ' W

which they r< for t)

Tin amino <>> ids not r< qu '■•'• d for il

Jn lib( rati d in the tissues

an tht n split info two portions, om \mmon

by i iaind( r of t) e I form'

urea and tin hitter is oxidized to p '/.

CHEMISTRY OF PROTEIN

Bi ' re pr ding to dif the evidenc upon whi in-
clusions den ,nd. it will be n-e, ssarj I insider some of the most importanl

facts concerning the chemistry of the protein molecule. W<

598

METABOLISM

this information not only to understand the history of protein in the
animal body, but also to follow intelligently the important work that
lias already been discussed concerning the relative value of different
proteins as food. A knowledge of protein chemistry has come to be
essential in practically all branches of medical science.

Proteins, like starches, are composed of numerous smaller molecules
In the case of starch these molecules are the various monosaccharides —
glucose (dextrose), levulose and galactose; in the case of proteins they
are the amino acids. The breaking apart of the links that hold the mole-
cules together is effected in both cases by the process of hydrolysis, so
called because of the fact that the reaction consists in the taking up of a
molecule of water at each of the places where the chain falls apart. This
hydrolysis may be effected either by the action of mineral acids or alka-
lies, or by enzymes, the only difference in the action of these reagents
being that in the former case the breaking apart takes place more or
less indiscriminately, whereas in the latter it proceeds according to a
definite plan, which varies somewhat with the type of enzyme employed.
Just as a chemical knowledge of the structure of sugar or monosac-
charides is the basis of carbohydrate chemistry, so is that of the amino
acids the basis of protein chemistry.

Amino Acids. — There are, so far as known, eighteen different amino
acids concerned in the constitution of protein, but they are all alike in
their characteristic structure. The most striking characteristic depends
on the presence in the molecule of: (1) an amino group with a basicity
comparable to that of ammonia, and (2) an acid group with an acidity
comparable to that of acetic acid. Let us take in illustration one of the
simplest fatty acids — namely, acetic. It has the formula CH3COOH.
The COOH group is called carboxyl, and on it depend the acid properties
of the compound. The CH3 group is known as methyl, and the amino
group (NH2) is attached to it in place of one of the hydrogen atoms, thus
giving the formula CH2NH,COOH, which is aminoacetic acid or gly-
cocoll. If we take the next higher acid of the fatty acid series, having
the name propionic and the formula CH3CH2COOH, its amino acid, called
alanine, has the formula CH3CHNH2COOH. Now let us place the formu-
las of these two acids side by side in the following manner:

H

I'll

NH2 - C - COOH

NH2-C

COOH

(amino group) H (acid group)
Aminoacrtic acid
(glycocoll)

(amino group) H (acid group)
Ainmopropionic acid
(alanine)

Till. METABOLISM OF PBOl I IN

It will be observed thai the only difference I ids is

dependenl upon a change in the group thai is attacl upper verti-

cal valency bond of the central carbon atom, which th<
considered as the center of the entire molecule. The various amino acids
produced from protein differ from one another Bolely with regard
chemical nature of the group that is attached to this vertical vi
bond. Evidently, then, //" reactions that amino acids pot
must depend on the terminal groups containing the carboxyl and amino
radicles, whereas tin characteristic reaction of each of thi eighteen am
acids must depend upon the diffen in the radicles attached

upper vertical bond. This may be represented thus:

Any radicle

I
XII ,-C-COOII

I

H
Any amino acid

The end groups endow the amino acids with the power to combine with
both acids and bases. With acids they behave like substituted ammoi
to form salts, which can ionize into the amino acid, as the cation, and I

acid group, as the anion. With bases tl arboxyl group reacts to form

salts, which yield amino acid as the anion. A most important reaction con-

- in th> condensation of aldehydes with thi amino group. This occ
particularly readily with formaldehyde, water. being eliminated in the
action, and the basic nature of the amino acid being thus destroy
Upon this reaction depends the method of Sorensen for determining the
amount of amino acid in a mixture see page 606 The titration g
formed by rendering the solution of amino acids neutral, then add
formaldehyde and titrating with standardized acid, using phenolphtha-
lein as the indicator, and thus finding to what degree the acidity of the
mixture has become increased as a result of adding the formaldelr
Since this in iii acidity must depend upon the mini' lino

groups, it furnishes us with an ind estimate of the concentration of

the amino acids. The reaction is illustrated by the equation:

radicle II radi

Ml C COOH M ' 0 CH N-C-< OOH B

II TI

(amino aci

Another reaction of amino acid of physiologic u wn

•he carbamino reaction, consisting in a union i I d with

calcium and carbonic acid. Finally, il is important to note that the annuo

600 METABOLISM

group is very firmly attached; it remains intact in acids and alkalies and
is removable only by a process of oxidation. This can be accomplished by
treating the amino acid with such reagents as hydrogen peroxide or per-
manganate, when the amino group is displaced and a so-called ketonic acid
formed. The reaction will be evident from the accompanying equation:

CH3 CHS

I !

O + NH.-C-COOH ?± 0 = C-COOH+ NH3

I

H
(alanine) (pyruvic acid)

To illustrate this reaction we have chosen aminopropionic acid or ala-
nine, because the substance formed by its oxidation and known as pyruvic
acid is of very great importance in intermediary metabolism. It serves
as the common substance from which proteins, carbohydrates or fats may
be formed, and therefore as the intermediary substance through which
one of them may pass on being transformed into another (page 666). The
use of two arrows pointing in opposite directions in the above equation
indicates that the reaction may proceed readily in either direction.

The ammonia set free from amino acids may be oxidized to free nitrogen
by using nitrous acid according to the general equation: NH3-f-HONO=
2H20-f-N2. Upon this reaction depends another extremely important
quantitative method for measuring the number of amino groups present in
protein (Van Slyke). To make the estimation, nitrous acid is allowed
to act on the amino acids, and the volume of nitrogen gas set free by the
reaction is measured, the principle being similar to that used for the de-
termination of urea by the hypobromite method.

The apparatus employed for decomposing the substance and collecting and measuring
the evolved nitrogen consists essentially of a mixing bulb, connected below through stop-
cocks with two small burettes, one containing a solution of sodium nitrite and glacial
acetic acid, and the other a solution of the substance to be investigated. The upper end
of the mixing bulb is connected through a three-way cock with a graduated gas burette
and with another bulb containing potassium permanganate solution. By allowing some
nitrite and acid solution to run into it and shaking, the mixing bulb is first of all filled
to a certain mark with nitrous oxide gas. A measured quantity of the amino solution
is then allowed to mix with the nitrite; the apparatus is shaken for five minutes at 15
to 20° C, and the evolved nitrogen and nitric oxide are driven over into the permanganate,
which absorbs the nitric oxide, leaving the nitrogen, which is then measured in the burette.

The apparatus has now been so perfected that numerous analyses may
be made with it in a very short time and with a degree of accuracy that
is scarcely surpassed in any other biochemical estimation.

From the point of view of protein chemistry, the most significant reac-
tion of the amino acids is their ability to link together to form compounds

TDK METABOLISM OF PROTEIN 603

called peptides. This linking occurs between the amino group of one
amino arid and the carboxy] group of the other. When alanine and gl;
coll, with which we are familiar, are thus linked together, thi stiou
takes place according to the equation:

II CB II

CB

/ Il+lin OC C Ml HooC-C-Ml 00 C Ml ■ J:
BOOC C N '-

,, \h 11 II II

(alanini (gly (.11 1 (alanyl - glycocoll)

In this manner, then, a Bo-called dipeptide is formed, in which it will
be observed there still remain free carboxyl and amino groups, thus per-
mitting the linking on of other aniino-acid groups to form tripeptides
tetrapeptides or ether polypeptides. Indeed, this process of condensa-
tion may go on practically indefinitely, a polypeptide containing eighl
amino-acid groups namely, three leucine and fifteen glycocoll groups — hav-
ing actually been synthesized. The resulting polypeptides have the proper-
ties of derived proteins like the proteoses; thus, they give the biuret
and other reactions characteristic of proteins and are precipitated by
such reagents as mercuric chloride and phosphotungstic acid. Some
also digested by trypsin and erepsin. They have the same optical activities
as proteins. < >ne of them has Keen prepared which produces a typical
anaphylactic reaction. So far a polypeptide thai can he coagulated by
heat or is in other ways identical with Ihe naturally occurring proteins,
has not been synthesized; but there is no doubt that it is only a matter
of time before this will he accomplished.

Eighteen distinctly different amino acids have been isolated from pro-
tein, and it may assist in the conception of our problem if we place tl
amino acids side by side and link them together in the manner described
above. This is done in the accompanying chart compiled by D. D. Van
Slyke, in which also various other important facts concerning the chem-
istry of the amino acids are incidentally .added.

At the lower pari of each formula will be seen the characteristic ear-
boxyl and amino groups of neighboring acids linking 'her tl •

minal carbon atoms. The upper vertical bond of this carbon atom is con-
nected with the characteristic group of the amino acid, which may be very
simple and represented only by hydrogen, as in glycocoll, or highly com-
plex and including a ring formation, as in tryptophane. It will further

observed thai there may 1>> other amino groups connected in vari
positions in this radicle. This is particularly the case in the first three

the amino acids in the table namely, the hash- amino acids. In lysine

the extra amino group reacts with nitrous acid, liberatii g fre< i il

602

METABOLISM

5 _ = •

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£2 il

c „- £ r

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EE

THi: MIT\l:n|.l-M OF PROT] IN 603

by the Van Slyke method; hut in other cases, as in arginine, it fails to
give this and the other characteristic reactions of the amino group. That
the extra amino group in lysine reacts directly with nitrons acid explains
why various proteins when examined for amino nitrogen yield an amounl
that is equal to half of the lysine nitrogen.

It will further be observed thai the amino acids are arranged in thi
main groups: one basic, another neutral, and the third acid. TJu adds
of Hi< basic group are three in number and have an alkalinity similar to
thai of ammonia. Thej have been called the hexom bases, because e
contains six carbon atoms. They are alone presenl in certain forms of |
triii called protamines. The neutral amino acids contain one amino group
and one carboxyl group, which exactly neutralize each other. This is
thf largest 'jroiip of amino acids, and is further subdivided into thi
one containing aromatic or benzene rings and including the very im-
portant amino acids, tyrosine and tryptophane; another containing
so-called pyrrolidine ring; ami the third, the largest of all, containing
the so-called aliphatic chains; that is. the chains characteristic of the

fatty acids and which may he cither straighl Or branched. When the chains

are branched, the substance is called an isosubstance, as in isoleucine.
The acid amino acids, including glutamic acid and aspartic acid, are
characterized by containing two carboxyl groups and only one amino
group. They therefore resemble acetic acid in acidity.

Tt may be of assistance to some if Ave restate those chemical facts
from a Blightly different standpoint as follows:

Glycine, or glycocoll, is amine:, 1. I Ml Nil <'< K)H.

Ml

/
Alanine is glycine plus a methyl group, i'll«'ll : it u therefore amino-

\

N 'II

/

propionic acid run! ia closely relate. l to lactic acid, which ia f'lH'H . Mem

\

booH

the Other amino acid* may f alanin

1. s, rinr is alanine with an "OH" (hydros tup in | the ••II*'

Nil

/

alums of the moth} 1 gi oup, < !H ( " ' CH

\
OOOB

_ ' <■ ia alanine with an "8H" tliio) group in thii

Nil

/

CH 8H <'ll

\

COoii

604

METABOLISM

Two cysteine molecules united at the "S" groups give cystine.

NIL 1

/

I 1 1 .,& — CII

\

coon

NH,

3. Phenylalanine has a C6Ri (phenyl) group, CH,C6H5-CH

/

\

4. Tyrosine has a C6H4OH (phenol) group, CH,C6H4OH - CH

COOH

NH.,
/

\

COOH
C

/ \

5. Tryptophane has a C6H4 CH (indole) group:

\ /
NH

C — CH, - CH - NH, - COOH.

/ \
CBH4 CH

\ /
NH

CH

/ \
N NH

I !

6. Histidine has a CH = C - (imidazole) group:

CH

/ \
N NH

I !

CH = C.CH_, . CH. NH,-COOH.

The last two are also called heterocyclic compounds, of which there
is another, viz.;

Proline (and oxyproline), which is a-pyrrolidine carboxylic acid:

CH, — CH,

Other amino acids are

(1) Valine
Leucine
Isoleucinc
thus:

CH,

\ /
NH

CH.COOH

CIL CH3

\ /

CH

CH, . CH3

\ /
CH

CH3 C2H5

\ /
CH

1

CH.NH2

CH=

1

CH.NH2

1

COOH

CH.NIL

1

COOH

(valine)

COOH

(leucine)

(isoleucine)

Till \ll T \l:i'i ISM OP PBOT1 in

2 The amino dibasic acids:

artic, w 1 1 i « - 1 1 is amine-succinic acid,

CH COOH

!
CHNH COOH ; and
Q itaminic, which is aminoglutaric acid,

«'ll

• ■II COOH

CHNH, COOH.

Lastl there are the diamine- :t<i'l--, in which two urmij

Lysine a e-diaminoeaproic acid,

Ml

/
MM'll ell CH CH CH CH

\

COOH.

■lininr a-amino S-guanidine-valeriacic acid,

Nil.

/

1 1 N = C MI

\ /

Nii.nr -rii, rn CH

\

COOH
The guanidine group in this acid is t>( interest because of i1 ship 1

Ml

/

area, which is O = C

\

NIL

CHAPTER LXVIII

THE METABOLISM OF PROTEIN (Cont'd)

AMINO ACIDS IN THE BLOOD AND TISSUES

In the Blood. — Furnished with the general facts concerning the chem-
istry of proteins, Ave may now proceed to consider the more precise
knowledge recently acquired concerning the history of this substance
in the animal economy. Although no one has succeeded in separating
amino acids in pure condition from drawn blood even during the height
of digestion, it has nevertheless been possible to do so from circulating
blood by a method of dialysis, known as vividiffusion, elaborated by
Abel33 and his pupils. The method consists in connecting a long tube
of collodion with, the two ends of a cut artery in an anesthetized animal.
The tube, coiled many times, is then immersed in a solution containing
approximately the same salt content as the blood plasma of the animal.
The diffusible constituents of the blood plasma dialyze into the saline
solution; or any one of them may be prevented from dialyzing by adding
that particular substance to the saline in such amounts as will make its
concentration in plasma and saline alike. In some ways, it will be seen,
the apparatus may be considered as an artificial kidney. Its possible
clinical application for the purpose of removing poisons from the blood
is under investigation. It has been possible in this way to isolate several
of the amino acids and other ammonia-yielding substances from blood.
Thus, alanine and valine have been obtained as crystalline salts, and
histidinc and creatine (see page 622) shown to be present by their reac-
tions. All of the amino substances, however, do not dialyze, and these
exceptions are further characterized by the fact that they do not readily
give up their ammonia on the addition of sodium carbonate, as do the
diffusible substances (Rohde). Although amino acids can thus be sepa-
rated in a pure state from circulating blood, their concentration in a
drawn specimen is too low to make direct quantitative estimation possible.
My the methods of Van Slyke and Sorensen, already described, however,
it has been shown among other things that the blood always contains a
certain concentration of amino acids ; thus, in that of fasting animals from
3 to 5 mg. per 100 c.c. of blood are usually found present. During the
absorption of a protein meal, the amino content of the blood undergoes

606

THE Ml TABOI I- M OF PROTI IN

a marked increase, becoming doubled or more; and a Bimilar resull
been obtained h\ placing pure amino acida in the small inte I
Hi grams of alanine, for example, the amino nitrogen «>f tl
blood rose from 3.7 to 6.3 mg. per cent.*

In the Tissues. After entering the circulation, the ;niiiii<> acid vt
quickly disappear from it again. This has I n demonstrated by ob-
serving the amounl of amino acids in the blood after intravenously
injecting a solution of amino - * « - 1 « I into an anesthetized animal. After
injecting 12 gm. of alanine into the vein of a <h"_r. no per cenl - in<l

to have disappeared from the circulation within five minutes, Th<
tion is, What becomes of the amino acids thai rapidly disappear

they decomposed in the blood, or <1<> they I ime absorbed by the

suesl This problem has been attacked by analysing portions of vari

organs and tissues removed before and some time

into an animal <>f amino acid solutions. In the cas< muscles it

been found thai the amino acid contenl incr< intil from

v<» in lt. per eenl of amino acid i stimulated. Beyond tliis point.

however, th(> muscles <1<> m to be able t.> take up any more am

acid. The capacity <'t' the intestinal organs, hov

*Thi-

I JOS

METABOLISM

for example, the amino nitrogen of the liver has been observed to become
increased to 125 or 150 mg. per cent of the original amount. Although
this absorption of amino acids by the tissues is extremely rapid, it never
proceeds to such a point that the blood becomes entirely free of them.
Even after many days' starvation the blood contains its normal quota
of from 3 to 10 mg. per 100 gm. of moist tissue (Fig. 188). This indicates
that a certain equilibrium must become established between the amino-acid
content of the blood and that of the tissues, the concentration in the tissues
being approximately from five to ten times greater than in the blood.

ibO

Injectio

100

/

//.

Muscl <=

NH

50

n

0>

o
o

u

o
c

BO

a

I

2

Hours

Fig. 187. — Curves showing the amount of amino nitrogen taken up by different tissues after
the cutaneous injection of amino acids. The lowermost curve shows the urea concentration of the
blood. (From D. D. Van Slyke.)

The absorbed amino acids are very loosely combined with the tissues,
for they can be extracted by such feeble reagents as water or dilute al-
cohol. Their presence can not, however, be merely due to diffusion;
for if it were, the concentration could not become greater in the tis-
sues than in the blood. The further fate of the amino acids is difficult
to follow. We know that they do not remain in the body for a long time,
because most of the protein nitrogen in the food is excreted as urea
within twenty-four hours after ingestion; and when single amino acids
are fed, they quickly reappear in the urine as urea.

Till: Ml.TU'.ol.ISM OP I'ROTKIN

The tissues can therefore be only a stopping-place for the amine
acids. When tin- latter are determined in blood collected from different
parts while absorption of protein from the intestine is in process, it
lias been found, as shown in Pig. ivv. thai during the passage of the
blood through the liver there is a greater fall in the concentration of
amino acids than during its pj through the entire remainder of

the body.

It will I"' seen thai the above conclusions are drawn from estima-
tions made on blood taken from the vena cava, portal vein, and hepatic

iwing tli. ten in the iring i..

m D. D. Van Sl> k

artery, the upper enrves in the eliart being from animals during digestion

and the lower from fasting animals. The results show that the liver must

be particularly greedy of amino acids, which, however, must rapidly be-
come transformed into other sub s, since no icuous varia-
tion has been Sound to occur in the amino-acid content of the tissues

a rding to whether the animal is fasting or is digesting protein fi

This result, it is to be noted, is quite different from that which is ob-
tained after the intravenous injection of amino acids, and I

610 METABOLISM

the two experiments taken together, indicate that the amino acids after
their absorption can not remain in the tissues in a free condition for a
long time. It means that the amino acids during natural digestion must
be disposed of at a rate which is practically the same as that at ivhich ab-
sorption is proceeding.

THE FATE OF THE AMINO ACIDS

To follow the metabolism of the amino acids further we must deter-
mine the end product into which they are converted. This is urea,
whose estimation can nowadays be made with considerable accuracy on
account of the discovery, by Marshall, of the action of urease in con-
verting its nitrogen into ammonia, which can then be estimated by com-
paratively simple methods (Folin).

When the viscera are compared before and at various periods after
the intravenous injection of amino acids, the immediate increase in
amino nitrogen remains undiminished in all of them except the liver, in
Avhich a very rapid reduction is observed to occur. At the same time
the percentage of urea in the blood steadily rises. These facts are illus-
trated in Fig. 187.

The simplest interpretation of these results is that the liver converts
the amino acids into urea and discharges this urea into the blood. This
conclusion, however, it must be observed, is not inevitable; for it is pos-
sible that the amino acids may be condensed into polypeptides in the
liver, just as sugar is condensed by this organ into glycogen, and that
the increase in urea is merely coincident (Fiske).

It must not be imagined that the conversion of the amino acids into
urea is exclusively a function of the liver. On the contrary, it is well
known that this process may occur in animals from which the liver ha?
been entirely removed. It is probably safe to conclude, however, that
the liver is the most active center for amino-acid transformation and
urea formation.

When urea is estimated in samples of blood removed at short inter
vals of time after the ingestion of a large amount of protein, it is found
that the increase becomes very early established. In one experiment,
before the food was taken the concentration of urea nitrogen in the blood
was a little over 10 mg. per cent; one hour after taking 500 grams of
meat, it had risen to about 18, and in two hours to nearly 25. Evidently
the increase had occurred about the same time as the passage of food
from the stomach into the duodenum. These facts indicate that urea
formation in the liver becomes stimulated long before the other tissues,
such as the muscles, have had time to take up their full quota of amino

THE Ml TABOLIS \l OP PROI 61 1

acids. During digestion of protein the liver does not .- : ] » j » • - -■ 1 1 - to wait
until the other tissues have become saturated with amino acids before it
ins to destroy the unnecessary & by conversion into urea; on

the contrary, this process Bets in with the very first installment of amino
acid thai reaches the liver by the portal blood. This conclusion is in
harmony with tin' well established fact that, when protein is given '
starving animal, the greater pari of its nitrogen is soon excreted
urea, Leaving only a small fraction to be used fur rebuilding tl rted

tissues i see page 6 13 ,

The amino acids thai are absorbed by the extrahepatic tissues become
very quickly converted into formed protein, as is evident from the

that the concentration of free amino acids in the tissues of an animal
during absorption of protein is not perceptibly greater than in tl
a fasting animal, and the question remains to be considered, What
comes of tin protein thus formed? The answer is. that it is gradually
used up in the metabolic processes, so as to liberate again the amino
acids, which add themselves to those absorbed from the intestine and be-
come used again or excreted, according to the demands of the tiss i< -
the time for amino acid.

This process of liberation of amino acid from the breakdown of body
protein goes on of course irrespective of absorption of amino acid from
the intestine. Ii goes on, for example, during starvation; indeed, in
this condition the percentage of free amino acids in the museles is. if
anything, somewhat higher than that observed in an ordinarily fed an-
imal. In starvation also the migration of amino acid Lg on am
the various o rga us of which those whose activity jsential to the
maintenance of life, such as the heart and the respiratory muscles, are
supplied with amino acids from tissues that are less vital, such as the
skeletal muscles sei page 568 . Thes :periments further show that
free amino acids can not serve to any significant extent as food r<

in the same v. ,-i\ as glycogen and fat. If amino acids were of valui

food reserves, we should expect the store of them to be d<
by starvation. As to how long a period of time elaps
incorporation of tl "bed amino acids into tissue protein and tl

subsequent liberation again by autolysis, we arc entirely ignorant.

Tl arches which we have just been considering do not throw any

light on the relativi valu< of different proteins in

They do not inform us as to which of the amino acids n

ready-made from the digested food, and which of them may be

with since the organism can manufacture them V\ mow '

the higher animals can synthe8l 'lie amino oil.

but not others, such as tryptophane; but winch amino acids be'

(1 1:2 METABOLISM

the glycocoll and which to the tryptophane groups, can not as yet

be definitely stated. The investigation of this problem has to be under-
taken by experiments of an entirely different type — namely, by observing
the welfare and growth of animals fed on proteins of varying amino-
acid composition. A full discussion of these experiments is given in
the chapters on Nutrition and Growth.

CHAPTER I. XIX
THE METABOLISM OF PROTEIN (Cont'd)

THE END PRODUCTS OF PROTEIN METABOLISM

Introductory. So far we have approached the problem of protein
metabolism by Btudying the behavior of the absorbed products of pro-
tein breakdown, and we have seen thai these 1 ome gradually assimilal

by the tissues and used by them in their metabolic processes. We have
□ unable, however, to offer any farts regarding the exact chemical
changes which each amino acid undergoes during this i 3 of tist

metabolism. At first sight it might appear an easy matter to collect
such information by direct examination of the tissues them- either

by searching in them for amino derivatives which might be derived from
absorbed amino acids, or by studying the changes which occur when
the amino acids are subjected to the action of the isolated tissue en-
zymes that must be responsible for the change. Such methods of in-
vestigation are, however, fraught with technical difficulties so great that
very little can be Learned from them, and for the present at leasi
must be content to piece our information together from facts derived
by less direct methods. Such a method is I by investigating

the behavior of the end products of protein metabolism.

The main end product is una along with traces of its pr<

monia, but these are not the only ones, for some amino acids after being
incorporated with the tissue proteins break down into products that
are no longer members of the amino-acid series, although they may be
closely related tn certain amino acids. Such substances are creatim and

anhydrid rn<itini>i> . A pari of the amino acids during their p
eiice in a \'vei< state in the blood may also be excreted unchanged by
the kidney. Our list s.> far therefore includes urea, ammonia, creatine,
creatinine, and amino nitrogen, of which the last is usually included in
metabolism investigations in tin- fraction designated indetermined
nitrogen.

Another group of closely related substances coming, not from •
genera] protein metabolism of the tissues, but from the metabolism
which is peculiar to the nuclei, consists of the s,, called pvr
Furthermore, so as to Berve as a check on results obtained by examining
these nitrogenous metabolites, it is important to observe the manner

G 1 ••

614

METABOLISM

excretion of the sulphur moiety of the protein molecule, for it will be

remembered that it is in protein alone that sulphur is usually taken into
the animal body. The excretion of sulphur therefore runs more or less
parallel with the intensity of protein metabolism.

After selecting the end products that are most likely to be of signif-
icance, the first question concerns the amount of each of them excreted
during twenty-four hours on diets that are either rich or poor in pro-
tein. The possibility of conducting such investigations obviously de-
pends on the use of quick and yet reliable methods for the estimation
of the nitrogenous metabolites. Such methods have been furnished by
the painstaking and careful work of Folin, an example of whose results
are given in the accompanying table.

NITROGEN-RICH DIET

NITROGEN-POOR DIET

Volume of urine

1170 C.C.

385 C.C.

Total nitrogen

16.8 grams

3.60 grams

Urea nitrogen

14.7 grams = 87.5%

2.20 grams =61.7%

Ammonia nitrogen

0.49 gram = 3.0%

0.42 gram =11.3%

Urie-acid nitrogen

0.18 gram — 1.1%

0.09 gram = 2.5%

Creatinine nitrogen

0.58 gram = 3.6%

0.60 gram =17.2%

Undetermined nitrogen

0.85 gram — 4.9%

0.27 gram = 7.3%

Total S03

3.64 grams

0.76 gram

Inorganic S03

3.27 grams =90.0%

0.46 gram =60.5%

Ethereal S03

0.19 gram = 5.2%

0.10 gram =13.2%

Neutral SO,

0.18 gram — 4.8%

0.20 gram =26.3%

(Folin.)

The general conclusions which may be drawn from these results are
as follows:

1. With a protein-rich diet much more urine is excreted in twenty-
four hours than with one that is protein-poor. Evidently the nitrogenous
metabolites act as diuretics.

2. The total or absolute amounts of nitrogen and of all the other
nitrogenous metabolites, save creatinine, become diminished during the
starvation period. The same is true of the sulphur derivatives, except
in the case of the neutral sulphur, which behaves like creatinine.

3. The decrease in the portion of nitrogen excreted as urea is relatively
greater than the decrease in total nitrogen, this fact being shown in the
table by the percentage figures, which were secured by calculating
the proportion of nitrogen in the various substances as a percentage
of the total nitrogen excreted during the periods. The inorganic sul-
phate behaves in a manner similar to the urea — that is, the percentage
of total sulphate excreted in the inorganic form becomes much less
during starvation.

4. The relative amount of all the other nitrogenous metabolites, as
well as that of the ethereal and neutral sulphates, becomes increased
• luring starvation.

THE METABOLISM OF PROTEIN 615

The most striking results of the above investigation are thai creatinine

remains unchanged during starvation, but thai urea l>» mes relatively

increased. The former must be derived from metabolic pro >ing

on in the tissues independently of the supply of foodstuff carried to
them, whereas the Latter must depend, it' nol entirely, ; ely.

on the protein content of the food. Creatinine may therefore be called
an cud product of endogenous metabolism, and urea an end producl
i xogenous metabolism.

Other metabolites uamely, ammonia, uric acid and the undetermined
nitrogen, as well as the ethereal sulphates- must represent procee
of metabolism that arc partly exogenous and partly endogenous.

Having made ourselves acquainted with the general natur< the

changes thai occur in the nitrogenous metabolites when protein metab-
olism is stimulated by the taking of food or depressed by starvation,
we may now proceed to take up cadi of the metabolites separately and
what other information can be obtained regarding their source and
origin in the animal body.

UREA AND AMMONIA

For various reasons it is important to consider these two metabolil
together. During the intermediary metabolism of the majority of I
amino acids, the amino group becomes broken off as ammonia, which
immediately combines with the available acids to form neutral ammonium
salts. The most available acid for this purpose is carbonic acid; there-
fore ammonium carbonate is formed in large amounts. A small prop
t i < >n of the ammonia may combine with other acid radicles, roch
chlorine, to form ammonium chloride. The fate of these two types
salt is very different. The ammonium carbonate becomes quickly trans-
formed into urea, whereas the ammonium chloride is excreted in the
urine. The proc •' urea formation may therefore bi ridered as

having the function of preventing the accumulation of ammonium c
bonate in the animal body. It is the means by which a harmful substance
is converted into an innocuous substance a detoxication pi - . in
other words.

Regarding the natun of tin chemical process involve. 1 in this trans

formation of ammonium carbonate into urea, referei rmulas

below will show that the ammonium carbonate thai - rmed by I
union of carbonic acid with ammonia, by losing one molecule of water
! noes ammonium carbamate, which by repetition ^>( the pi

comes transformed into un

METABOLISM

..II ONII,

/ /
>0 2NB ;=±C0 ll,0<^'

\ "\

OH "Ml

ONH,

/
DO

\

Ml.

(carbonic (ammo- monium
acid) nia) rbonate)

(ammonium
carbamate)

NIL,
/

n,o = co

\

NIT,

(uvea)

Some of the urea may come from metabolic processes of an entirely
different type. One of those at least is known; namely, the splitting-off
of urea from arginine, which it will be remembered is guanidine-amino-
valerianic arid (see page 605). An enzyme called arginase, having this
action, has been isolated from various organs and tissues. The diamino-
valerianic acid, or ornithine, which remains after the urea is split off,
may be further used in protein metabolism. The reaction is shown in
the following equation:

NH2 - C - Nil - CIL - OH, - CLL, - CHNH2 - C00H + H..0

II

MI (arginine)

— NIL, -CO

+ NIL - CIL, - CH, - CLI2 - CLINH, - COOH

NTT,
(urea) (ornithine)

On an ordinary diet, as we have seen, a man excretes somewhat more
than 90 per cent of his total nitrogen as urea and about 3 per cent as
ammonia, the remainder of the nitrogen appearing in the other nitrog-
enous metabolites.

Influence of Acidosis on Ammonia-Urea Ratio. — It sometimes happens
thai a large proportion of the ammonia is not converted into urea, but
is used for the purpose of neutralizing abnormal acids present in the
organism. When mineral acids arc given to an animal, or when acids
arc produced in the organism itself by some faulty type of metabolism,
the ammonia excretion by the urine immediately rises. In diabetes, for
example, where considerable quantities of /3-oxybutyric acid are pro-
duced (see page 683), a decided increase in the ammonia excretion by
the urine is observed. A milder type of acidosis may also be induced
in normal persons by withholding carbohydrates from the diet, and
here again the ammonia excretion is relatively increased.

In such cases it is quite evident that ammonia is used as an alkaline
reserve of the body; thai is, as a substance Avhich is capable of prevent-
ing acidosis by neutralizing the acids. It does not appear, however,
that, all types of acidosis entail the utilization of ammonia as reserve
alkali, and an increase in the relative amount of ammonia in the urine
does not necessarily indicate a condition of acidosis. In the pernicious

THE METABOLISM OF PBOI 617

vomiting of pregnancy, for example, a relatively high excretion of am-
monia lias been found associated with no greater a def if acidosis, as
determined by the power of the plasma to absorb carbonic acid, than in
normal cases of pregnancy.

Influence of Liver on Ammonia-Urea Ratio. — Experimental Observa-
tions: (1) Removal of Ltveb. — There are several facts which indicate that
other causes than acid-production may interfere with the conversion of am-
monia into urea. What are these causes) Su
the liver is the organ which mosl actively converts amino
into area, it would be natural to expect, that, when the functions of
this organ were interfered with, relatively more of the nitrogen
tion would occur as ammonia and relatively less - area. Tn order to
determine the exact significance of the liver as a area-forming organ,
two types of in tion have been used; namely, (1) observation of

the changes produced in the ammonia-urea ratio in the urine by partial
or total removal of tho liver: and (2) observation of the urea-forming
power of a liver perfused outside the body.

To remove the liver from the circulation the portal vein is brought
in apposition with the vena cava, the two are sewed together, and a
passage opened between them, after which the portal vein is ligated al
the anastomosis (forming the so-called Eck fistula). The portal hi
then passes directly into the vena cava, and the liver is now supplied
only by the hepatic artery. The animals live for a considerable time
after the operation, and the urini intly contains relatively

urea and more ammonia than normal. The results are. however, not
nearly iking as would be expected if the liver were the main -

of urea formation. The experiments have nevertheless brought to 1:_
a fact of considerable clinical interest- namely, although the animals
may thrive if kept on a diet nol containing an they im-

mediately begin to develop peculiar symptoms, not unlike those of
lampsia or uremia, when they are fed with large amounts of flea!
Mosl of the symptoms can ! erred to abnormal stimulation of the

central nervous system, and examination of the urine has shown a 1.
increase in the excretion of ammonia and a change from the norma!
acid reaction to an alkaline

At one time it was assumed thai the toxic symptoms were caused by
the presence in the blood of ammonium carbamate, since large quantities
of the calcium salt of this substance could he separati urine.

It is now known, however, that the ammonium carbamate t only

use of tl Mim carbonate, the two ^-.hs existing I

gether in solution according tn the lav tion. That the in'

ication is not due to ammonium carbamate d< seclude tl

618 METABOLISM

sibility that it may be due to ammonia itself, although it is more likely
that other nitrogenous metabolites, produced when excess of flesh food
is taken, are the responsible agents.

If the liver is entirely removed by ligating the hepatic arteries in an
animal with an Eck fistula, a more pronounced decrease in urea and
increase in ammonia occur during the short period of time that the
animal survives the operation.

The results observed after the removal or diminution of liver function
fail to occur -when other viscera are removed from the animal, which
would at least tend to indicate that the liver is very important in the
manufacture of urea out of ammonia. This does not, however, warrant
the conclusion that the liver is the only place in the animal body in which
such a process occurs.

In corroboration of these observations on mammals, it may be of in-
terest to note that when the liver is removed from oirds, which is a com-
paratively simple operation on account of a natural anastomosis between
the portal and renal veins, there is a marked decrease in the excretion
of uric acid and a corresponding increase in the excretion of ammonia
during the twelve hours or so that the birds survive. In birds and
reptiles urea is excreted as uric acid, being produced by a synthetic
process in the liver (see page 644). The changes in this experiment are
of considerable magnitude; thus, before the operation the amount of
ammonia nitrogen relative to total nitrogen has been found to vary be-
tween 10 and 18 per cent; after the operation it may be increased to
between 45 and 60 per cent. The uric-acid nitrogen normally varies be-
tween 60 and 70 per cent of the total nitrogen ; after the operation it may
fall to between 3 and 6 per cent.

In animals with an Eck fistula and with the hepatic artery ligated,
an increase in the urea output occurs when amino acids are injected under
the skin. This result corroborates the conclusion that the liver can not
alone be responsible for the conversion of ammonia into urea.

(2) Perfusion of Organs. — This method consists in removing the or-
gan into a warm chamber or bath and perfusing it, through cannula
inserted in its main artery and vein, with a solution of defibrinated blood
or of defibrinated blood mixed with saline solution. The perfusion
liquid is kept at body temperature and is saturated with oxygen. By
means of a pump it is made to circulate in a pulsatile flow, and the total
amount of urea or other metabolite in the circulating fluid is determined
before and after the fluid has been circulated several times through the
organ. \Vhen the liver is perfused, urea gradually accumulates in the
fluid, particularly after the addition of one of its known precursors—
for example, ammonium carbonate. "When other organs or viscera are

THE METABOLISM OF PBOI 619

perfused, no urea is formed. The evidence shows thai the liver is an
important seal of urea formation, bn1 qo1 q< rily that other organs

arc unable to form ii in the intacl animal, for there are many
of inaccuracy in perfusion experiments. Even though
greatesl care, we can not hope to maintain the organ in other than .1
slowly dying condition. It is certainly far removed from the normal
state, as [3 revealed no1 only by histological examination, bul by the fact
thai edema almosl Invariably sets in and the blood vessels become
tremely constricted, thus necessitating a gradual increase in tl ■
fusion pressure as the perfusion goes on. Furthermore, the organ being
isolated from the nervous system, there can be no control of the rela-
tive blood supply of different parts. In the intact animal the circula-
tion is more or less distributed according to the particular needs of the
different viscera, and such conditions obviously can not be simulated in
a perfusion experiment. Another objection depends on the fact that
the well-being of the organs in the intact animal is largely dependent on
hormones conveyed to them from other organs. Such hormones
frequently quite labile in nature, and soon disappear from the perfusi
fluid.

Notwithstanding these objections, there can be no doubt that many
of the functions of an organ are retained much longer than they would
be if the organ were not perfused; for example, the contractility of the
muscle or the power of forming urea in the liver. Perfusion experim<
are of value therefore when they yield positive results. Negative
sidts may indicate either that the organ does not perform the particular
function that is being investigated or that it has lost this function , -
resull of partial death. That a perfused muscle retains its power of
contraction does not necessarily indicate that it maintains all of its
metabolic functions; neither docs the fact that the liver forms urea
prove that it is capable of performing its other functions, it to

show thai the liver dies piecemeal; some functions, such . 3 _
formation, die early, while others, such as urea-formation, remain for a
long time intact. Th\ use of perfusion ments for t'< ■ settling

questions of metabolism should tfo always h< very carefully 1

trolled and never used as tfn soli line of evidence on which to h •
tani conclusions.

Before leaving this subject it may be well to point out thai the
method which at firsl sighl mighl appea such

questions namely, the examination of t)n inflowing <i>i<l outflowing l>'
of different parts or organs is not applicable in d si Tl

cause of the extremely small changes in concentration which maj

even although large amounts of the particular sul in qi

620 METABOLISM

are being absorbed or produced. As Ave shall see later, this criticism is
particularly applicable in the case of sugar. Even during the injection
of considerable quantities of sugar into the portal vein, no difference
in percentage can be demonstrated between the blood of the two sides
of the liver, although Ave know that sugar is being retained to form
glycogen. For the same reasons, differences in the percentage amounts
of amino acids or of urea are often difficult to demonstrate in the blood
entering and leaving the liver even when Ave know that large quantities
of them are being added to or remoA^ed from it.

Clinical. — Since the liver is an important seat of urea formation, the
question arises as to whether the relate percentage of urea and am-
monia in the urine Avill become altered by disease of the liver. Many
observations Avith this point in view have been undertaken, but it can
not be said that the results are very striking. In extreme destruction,
such as that produced by phosphorus poisoning, there may indeed be
a great increase in the relative amount of ammonia and a decrease in
that of urea. The same is true in acute yellow atrophy of the liver, in
which disease the nitrogen excreted as ammonia may amount to as much
as 70 per cent of that excreted as urea. In milder forms of liver dis-
turbance, hoAvever, such as cirrhosis, the figures are much less striking.
When an increased ammonia excretion is observed in such cases, Ave
must be cautious in drawing the conclusion that it is due primarily to
abolition of the hepatic function. It may just as Avell be caused by the
development of acids in the organism that require the ammonia for
their neutralization. It is significant, for example, that considerable
quantities of acids are produced in phosphorus poisoning.

Although the urea and ammonia excretions become altered by exten-
sive destruction of liver tissue, it is a remarkable fact that very little if
any change occurs in the amino nitrogen, either of the urine or of the
blood. In experimental necrosis of the liver produced by chloroform
or by phosphorus, it is only in the latest stages of the condition and
when it is of the very severest type that an amino-acid increase has been
found to occur in the blood and urine. The conditions seem to be some-
what different in man, abnormally high amounts of amino nitrogen hav-
ing boon observed in the blood in a considerable proportion of patients
with impaired liver function. In very severe cases of diabetes, for ox-
ample, figures that are distinctly higher than normal have been observed
(Van Slyke, etc.)- In eclampsia the marked pathological changes in the
liver might be expected to be associated with an upset in the metabo-
lism of amino acids. Losee and Van Slyke35 haAre, hoAvever, recently
shoAvn by the most accurate methods that neither in the blood nor in the
urine is any excess of amino acids to bo found in this condition, although

THE Ml TABOLISM OP PRd 62]

in cases of pernicious vomiting of pregnancy, there was a relative in-
crease in the ammonia excretion. We have already seen that I
increase did qoI bear any relationship to the acid-absorbing power of
the blood plasma (see page 617).

The importance of tin "kidneys in removing the urm from thi blood
is readily seen Erom the change in the percentage of urea in ihis Hui<l
after the partial or complete removal of the kidneys. Animals sur-
vive nephrectomy Eor aboul three days, and during this time urea rapidly
accumulates in the blood and begins to make its appearance in the
saliva and the intestinal secretions. In man also where the kidi.
are extensively diseased, a similar accumulation of urea occurs in tin-
blood, some of the excess being got rid of through the sweat and to a
certain extent through the intestine. The importance of encouraging
perspiration and a free movement of the bowels in eases of nephritis
thus indicated. It must not be concluded that the accumulation of
area in the organism is the direct cause of the symptoms. Urea its
is comparatively inert, and it is generally believed thai other metabolic
products with which the urea runs parallel in amount are the toxic
agents. Hewlett has found, however, that very large injections of o
do produce symptoms in animals. '

CHAPTER LXX
THE METABOLISM OF PROTEIN (Cont'd)

CREATINE AND CREATININE

Creatine and creatinine are very largely products of endogenous metab-
olism: they are mainly derived from chemical processes occurring in
the tissues although some of the creatine and creatinine present in the
food may appear as creatine in the urine.

Essential Chemical Facts

Before Ave proceed further with a discussion of the metabolism of
these important substances, it will be necessary to refer briefly to some
points in their chemistry. The simpler of the two bodies is creatine,
which is methyl-guanidine-acetic acid; creatinine is its anhydrid, being
formed from creatine by the removal of a molecule of water, so that the
ML groups become joined together in the same way as they do in the
formation of peptides from amino acids (page 599). The relationships
are illustrated in the following formulas:

(methyl)

CH3— N

/ \

/ CH..COOH

NH = C - H20 =

\ (acetic acid) '

\

(guanidine) NH,

(creatine)

CH„ - N - CH - CO

i 1
i i

1 !

NHr=C

\

\ !

\ !
NH

(creatinine)

It should be

noted that guanidine is closely related to urea

NH2

/
(O^C ),

and that when creatinine is formed from creatine a ring

\

NH,

622

Till Mi I IBOI i-M OF PROI

Formation occurs, giving what may be regarded as an imidazole deriva-
tive (see page 604). Creatine is also related to one of the import
diamino acids, arginine, since both contain goanidine radic

NIL

/
\H=C and to histidine and the purines see pi - »oth

\

XII

of which contain the imidazole ring. The close relationship which
creatine bears to urea is illustrated by the Eacl that urea is I

when creatine is subjected to the action of boiling barium hydrate. When
it is oxidized by moans of potassium permanganate, urea is also fi
the remainder of the molecule, more or less intact, being split off

XII-CH3

/
motlivl-amino-acetic acid (CH, ), also known osine.

\

COOH

The conversion of creatine to creatinine goes n slowly in aqueous
solutions, but is much accelerated by heating with acid. Heated in an
autoclave at a temperature of 117 C. for thirty minutes, with half nor-
mal hydrochloric acid, the creatine goes over almost quantitatively into

atinine. It will be noted that the creatinine ring is partly oxidi.
This renders it unstable, so that creatinine in the presence of alk;;

- the power of reducing metallic oxides. Like glucose it can
alkaline solutions of copper, silver and mercuric salts: it al>
picric acid in weakly alkaline solution to picramic acid, which, beii
furnishes us with a solution the si _•■ which can be estimal

colorimetrically.

Quantitative Estimation. — Although the presence of creatinine in the
urine has been known for many years, there being from 1 to 2 g : -
it in the twenty-four-hour urine, little prog] 38 - in the study

of its metabolism because of the absence of a reliable method
estimation. The elaboration by Folin of a colorimetric quantitati
method for creatinine, depending on the reduction of pici id, has

Furnished the starting poinl for the modern work which has been d<
To estimate the creatine by this method, it is usual to pr<
lows: The creatinine content is first of all ither ! '

of urine being then heated with acid in the autoclave until all
creatine 1; m converted into creatinine. A. £ terminal

creatinine is then made, and the dif ie between the two -

at inc.

(»24 • METABOLISM

It should be pointed out that, since the creatine is estimated by an
indirect method, there are considerable chances for inaccuracy. Indeed,
it has been shown that errors may have been incurred in some of the
recent "work on account of the fact that when acetoacetic acid is present
in the urine it prevents the creatinine from developing its full reducing
power on picric acid in the cold, so thai when subsequently the urine is
heated with acid for the purpose of converting the creatine into creati-
nine, the destruction of acetoacetic acid allows the reducing power of the
creatinine to develop to full intensity. It is obvious that this would make
it appear as if creatine had been converted into creatinine. It is par-
ticularly in the urine of diabetic patients, in which acetoacetic acid is
present that mistakes are likely to be made.

Metabolism

When we come to consider the metabolism of creatine and creatinine.
we find that there are remarkably few facts definitely known concerning
it. The average amount excreted daily, expressed as the number of milli-
grams of creatinine in twenty-four hours per kilogram body weight,
is known as the creatinine coefficient (Shaffer).36 For a lean person this
is about 25 mg. ; for a corpulent person, about 20 mg., the difference in-
dicating that muscle mass, and not body weight, is the important factor
determining the coefficient. Further evidence that this relationship ex-
ists is furnished by the fact that in the muscular atrophies creatine ex-
cretion is distinctly below normal. It must be the mass of the muscles
rather than their activities that is the determining factor, for the creatine
excretion does not become increased by muscular exercise.

Influence of Food, Age, and Sex. — Although creatine and creatinine are
endogenous metabolites, it must be remembered that, under ordinaiy
dietetic conditions, a part of each is derived from these substances pres-
ent in the food. It is important therefore to consider the conditions
under which the creatine and creatinine in the food appear in the urine.
Regarding creatinine, it is pretty well established that practically all
that is taken with the food reappears as creatinine in the urine. Shaffer
has, for example, succeeded in recovering 76 per cent of ingested creat-
inine in the urine excreted during twenty-one hours following the in-
gestion of 0.7 gm. creatinine.

The conditions for the excretion of creatine are more complex. It is
present in the urine of children in considerable amount, but in that of
adults only as traces. In the first years of life the creatine in boys'
urine may amount to one-half of the total creatine and creatinine, but
it becomes gradually less and practically disappears at about seven

THE METAB01 I- M OP PROTEIN

62J

years of age. Girls, on the other hand, continue to excrete creatine until
about puberty, after which, although ordinarily absent, it reappears in
the urine ,-it each monthly sexual cycle, and is present during pregnancy
and for some days after delivery. Feeding creatine to children causes
it to appear in the urine, accompanied usually by a Blight increase in
the creatinine. The same results can be observed in women during the
monthly periods, when as much as o.l gm. may l»e present, and during
pregnancy. Creatine is also present in the urine of most if not al!
tlic other mammalia. Some of these fads are shown in the following
table:

CREATININE-N

< KKATINK-N EXCRETED
IN 24-HB. UBINE

f 2

0.02.1

0.02.".

3

0.057

0.022

1 tl IJ v

5

0.112

O.i _

-

0.163

0.0

11

0.157

0.0

l.->

0.378

0.0

5

0.069

0.005

6

0.032

0.00?.

Girla

7

0.157

0.1

LQ

0.147

0.020

12

0.201

0.011

'■Mm Mathewi

When creatine is given to an animal that has been kept in a starved
condition, most of it seems to disappear. It can not be recovered in the
urine either as creatine or as any other nitrogenous metabolite. It seems
to functionate more as a food than as a useless substance. The possi-
bility that some of it can be destroyed by the intestinal bacteria being
admitted, there is nevertheless some justification for the view that the
creatine finds a useful function in the anabolic process of the muse

Influence of Complete and Partial Starvation. Although, as we have
Been, the creatinine excretion remains constant when the amount of 1
tein in the diet is greatly reduced, yet it does not remain constant during
complete fasting or when carbohydrates are entirely withheld from the
diet. In fasting it h;is been found that creatine appears in place of I
creatinine which has disappeared, so that it* both creatine and creatinine
are determined, very little it* any diminution will be found to have
curred. Fasting, therefore, causes the adult creatine and creatinine

metabolism to become like the juvenile metabolism. As pointed <>ut by

Mathews, it would be interesting in the light of this observation to
whether other BUbstances, passed in the urine of young animals but ab-
sent ill that of the adidt. would reappear in the urine when the animals
were made to fast. In tl < of man, for instance, allantoin would be

worth investigating in this regard page 641

626 METABOLISM

A similar replacement of some of the creatinine by creatine appears
when carbohydrate is entirely withheld from the diet, or in diabetic
animals, either in the disease diabetes mellitns in man or in the experi-
mental condition induced in animals by giving phlorhizin. Unfortu-
nately, in a considerable part of the work that has been done on this
phase of the subject a method of estimation was employed which did not
take sufficiently into account the influence of acetoacetic acid on the
creatine estimation; but even after allowing for this possible source of
error, there can be no doubt that creatine appears in the urine when
carbohydrates are improperly metabolized. If carbohydrates are given
to a starving animal, for example, the creatine is replaced in its urine by
creatinine, although this will not occur when either protein or fat is fed.
The general conclusion which may be drawn from these observations is
that carbohydrates in some way are required for the proper conversion
of creatine into creatinine in the animal body (Cathcart)37.

Origin of Creatine and Creatinine

Notwithstanding the amount, of excellent work that has recently been
done on the metabolism of creatine and creatinine, we know very little
indeed regarding the origin of these bodies in the animal organism. It
would be profitless to discuss this problem to any great extent, but a
few of the most important facts so far established may be of interest and
of value. The first step in attacking such a problem is to compare the
amounts present in the various organs and tissues, in the blood, and in
the excreta. Of the approximately 120 grams of creatine and creatinine
in the body of an average adult, a very large proportion is in the muscles,
the voluntary muscles containing the largest percentage, the heart con-
taining a medium percentage, and the involuntary (intestinal) muscles
containing relatively a small amount (Myers and Fine)38. Next to the
skeletal muscles, and containing more than the involuntary mus-
cles, come the testis and brain. The liver, pancreas, thyroid, kidneys,
spleen, etc., contain traces, the smallest amount of all being found in the
blood.

In all these places by far the greatest proportion of the total creatine-
creatinine exists as creatine, which is exactly the reverse of the condi-
tion obtaining in the urine of adults, where practically all is excreted as
creatinine. The close chemical relationship between creatine and creat-
inine, considered along with the above facts regarding their quantitative
distribution in the body, indicates that the creatinine of the urine is de-
rived from the creatine of the tissues. The question is, How does the
creatine come to he converted into creatinine? Such a transformation is

THE METABOLISM OF PRO!

probably effected bj many of the tissues of the body and certainly by
the blood, the active agency in all cases being no doubt an enzyme. That
the blood contains snch an enzyme is indicated by tin- fact that creatine
is transformed to creatinine by ]»!<»<" I Bernm more quickly than it is
when merely dissolved in water. Even heated blood serum po
some of this power. The liver also probably brings about the transfor-
mation, as lias been shown by perfusion experiments, ami by ti
that in cases of phosphorus or hydrazine poisoning creatine < 1 i -^ j » 1 .
creat inin< in t he urine.

The problem therefore narrows itself down to the question of the
origin of creatine. In the light of chemical knowledge then
precursors from which creatine might be formed. One, sample, is

arginine, which it will be remembered is guanidine-amino-valerianic acid
page 605 . By oxidation this might become changed into guani-
dine-amino-acetic acid, which by methylation would then be changed into
creatine. That, snch a process of methylation may actually occur in the
animal body is definitely known, for it happens when such substai
pyridine or naphthalene are given with the food. They appear in the
urine as methyl derivatives. The possibility of the derivation <■ tine

from arginine is not, however, borne ou1 by the result of the injection of
arginine, for such injection does not increase the creatinine in the urine.
The closely related substance, guanidine-acetic acid, when fed to animals
(rabbits does cause a slight increase in the excretion of creatine (Jafl
and also, it is said, an increase in the creatine content of the i
Even in this case, however, by far the largest proportion of the admin-
istered guanidine-acetic acid is excreted in the urine unchanged.

The Large percentage of creatine in muscle tissue leads one to exp
that some relationship must exist between muscular metabolism and the
amount of creatine present either as such in the muscles or itinine

in the urine. Regarding the latter point it is definitely established that
muscular exercise leads to no increase in the creatinine excretion, al-
though it is said that an increase occurs following a tonic contracl
of the musides. With regard to the creatinine in the muscles, no definite
results indicating thai muscular metabolism chang 3 amount are on
record. In the light of the fact already stated regarding' the pres
of creatine in other organs than the muscles, it seems probable that the
substance has really little to do with muscular contraction h. but

rather is concerned in some way in the formative metabolism of the cell,
with its general growth or maintenance. Indeed, it is a question whether
creatine is an actual constituent of the living tissue. It may rat
lias 1 n suggested by Polin, be a postmortem product, represented dur-
ing life by creatinine.

628 M I BTABOLISM

Creatine appears in the urine in phosphorus poisoning, in carcinoma of
the liver and during postpartum involution of the uterus. It is not de-
rived from the disappearing uterine muscle, however, for creatinuria also
occurs after cesarean section with removal of the uterus. Creatine
elimination is not an index of cellular destruction, for it has been found
large in a dug injected with phlorhizin and maintained in constant weight
by feeding with washed meat (S. R. Benedict). Muscular fatigue also
leaves the creatine content of muscle unchanged. In late stages of
nephritis, creatinine accumulates in the blood and serves as an index of
the gravity of the condition (page 651).

CHAPTER I- XXI

THE METABOLISM OF PROTEIN Cont'd)

UNDETERMINED NITROGEN AND DETOXICATION

COMPOUNDS

In the present chapter we shall refer briefly to the groups "f urinary
substances styled undetermined nitrogenous compounds and to the com-
pounds that are excreted in the urine as the result of the combination in
the body of certain toxic bodies with chemical substances that render
them harmless (detoxication compounds).

Undetermined Nitrogen

Included under undetermined nitrogen are amino acids, peptides and
basic substances. The amount of amino acids and peptides in normal
mine is very small but may become considerable in disease, especially
of the liver, when leucine and tyrosine may appear. The presence of
traces of amino acid and peptone in normal urine is to be expected,
for although the actual concentration of amino acids in the blood is
never very great, a certain leakage of amino acids must occur into the
urine.

The peptide i^ sometimes known as oxyproteic acid. It becomes d a
tinctly increased in phosphorus poisoning and in such conditions as
accompanied by excessive protein metabolism. The basic constituents
include such substances as taimethylamine, ethylamine, putrescine and
cadaverine fpafre r>0'_M. and there axe probably many more of 8 similar
nature. Many of these substances are similar to the so-called ptomaines
found in meat, etc., and they have been called the ptomai] urine,

from which they can be isolated by rendering the urine alkaline and
shaking out with ether. It is probably to the presence of these sub-
stances that urine mainly owes its toxic action.

The Detoxication Compounds

Certain nocuous BUbstances arc produced in the intestine during the
digestive process (see page 501 and others may result from the n
bolio proci in the tissues. To guard againsl the harmful action of
these substances on the organism, they become det< in various

630 M KTABOLISM

ways, mainly by forming inert compounds with other substances, par-
ticularly with glycocoll, sulphuric acid or giycuronic acid. The com-
ix mud thus formed is then excreted in the urine.

Hippuric Acid. — Glycocoll is used mainly to detoxicatc the benzoic
acid which results from the oxidation of the aromatic substances pres-
ent in large quantities in vegetable food and fruit (particularly in cran-
berries). Some benzoic acid may also be produced by the breakdown
of the aromatic group of the protein molecule; phenylalanine, for ex-
ample, gives rise to benzoic acid by bacterial decomposition. The com-
pound formed is hippuric acid, this name indicating that it is present in
large quantities in the urine of the horse, as it is also in the urine of
all herbivorous animals.

Hippuric acid is benzoyl-glycine (CGH5.CO.NH.CH2COOH), and it
can readily be produced in the laboratory by bringing together benzoyl
chloride with ij'lycoeoll. thus:

CGH, . CO ; CI + H i HN . CH,COOH = C,;H,CO . Nil . CHXOOH + IIC1 .
(benzoyl chloride) (glycocoll) (hippuric acid)

Under ordinary dietetic conditions only a trace of hippuric acid is
present in the urine of man, but much larger quantities, 2 grams a day
for example, may appear when the diet contains a large proportion of
fruit or vegetables. It is not known to undergo any characteristic varia-
tions in disease. The benzoic acid which is contained in certain canned
foods as preservative also combines in the body with glycocoll, so that
any toxic effect which it might produce is practically negligible. There
is certainly no very evident reason why canned foods containing benzoic
arid should be tabooed, for in so far as the benzoic acid is concerned, they
can be no more toxic than a diet composed largely of vegetables and
fruit.

This detoxication of benzoic acid requires the presence in the organ-
ism of a constant supply of glycocoll, which, it will be recalled,
is the lowest in the series of amino acids, being aminoacetic acid
(CH2NH2COOII). It is present in greatest amount in the protein of the
connective tissues. It is said, however, that not more than from 2 to
3.5 per cent of glycocoll is available in the proteins of the body. Al-
though this amount of glycocoll would amply suffice to detoxicate the
benzoic acid produced by the metabolism of the food in carnivora, il '
is quite inadequate for this purpose in the case of herbivora, and the
question mil orally presents itself as to where the glycocoll in these
animals comes from. It is said, for example, that of the total nitrogen
excretion in herbivora 50 per cent may appear as glycocoll under cer-
tain conditions. These facts indicate thai the organism is capable of

THE METABOLISM < >F PROTEIN

producing new glycocoll for itself, and it is interesting to eons i how
this glycocol] may be derived. A vvy probable source is by syntl
between ammonia and glyoxylic acid (CHO. I OOH . That glyoxylic acid
or its aldehyde, glyoxal, is readily produced during metabolism from e
bohydrates and thai ammonia is always available would seem to •
some support to this view (see page 665 . The synthesis of glycocoll
from glyoxal and ammonia occurs thus:

B.COCHO I NH, = CB NH,COOH.

('glyoxal)

The linking up of glycocoll with benzoic acid occurs in the kidney.
If the kidney is removed from the circulation in the majority of animals
that produce hippuric acid in large amount — the rabbil being an excep-
tion— no hippuric acid will accumulate in the blood. On the other hand.
an isolated perfused preparation of the kidney produces hippuric acid
provided benzoic acid is added to the perfusion fluid, and the latter i
contains an abundance of oxygen, which is best secured by using de-
fibrinated arterialized blood instead of artificial serum (Locke's solu-
tion). The necessity of a plentiful supply of oxygen is further shown
by the fact that, if the hemoglobin of the blood is rendered incapable
of carrying 02 by bubbling carbon monoxide tras through it. no synthe-
sis of hippuric acid will result from perfusing the blood through the
kidney. The actual chemical process by which the synthesis occurs de-
hydration) is similar to that by which polypeptides are formed by the
union of amino acids, or creatinine from creatine.

(C, H CO OH II IIWILCOOH).

Glycocoll may be used for detoxicatdng other substances than benzoic
acid, particularly cholic acid, forming the glyeocholic acid of the bile
page 494) and phenylacetic acid. In birds the benzoic acid be-
comes combined with diamine-valerianic acid or ornithine Nil CH,
CH CH CH NHj CX)OH) in place of glycocoll, so that in the urine

of these animals in pla f hippuric acid a compound called omithuric

add occurs.

It is of importance to point oul here that this pairing of aromatic toxic
Bubstances with certain of the metabolic products of the organism has
frequently been found an excellent experimental method for demon-
strating the presence of intermediary metabolic substances that other-
wise would not have appeared in the excreta. T1
thus diverted from their normal course in metabolism s.. as to form
neutralization or detoxication compounds Glycuronic acid is an exam]

632 METABOLISM

Ethereal Sulphates and Glycuronates. — The other substances used for
detoxieation purposes are sulphuric and glycuronic acids. Phenol, and
its derivative cresol, after being absorbed from the intestine, in the
contents of which they are produced by the bacterial decomposition of
protein . (see page 501) become combined in the body, probably in the
liver, with sulphuric acid or with glycuronic acid to form the sulphate
or glycuronate. The aromatic sulphate further combines with potassium
to form the so-called ethereal sulphates, as which the substance is excreted
in the urine. A small amount of phenol may however appear in the
urine unchanged. As we have already seen, the sources of the phenol
in the intestine are tyrosine and phenylalanine (see page 530), and
since these amino acids are also present in the tissues, it might be sup-
posed that some of the phenol sulphate of potassium present in the
urine could come from the tissues. It is usually assumed that, however,
derivation from the tissues does not occur.

Another ethereal sulphate is indoxyl sulphate of potassium, which re-
sults from the absorption into the blood of the indole and skatole pro-
duced by intestinal putrefaction from tryptophane (see page 502).
Immediately after absorption indole is oxidized to indoxyl, which then
combines with sulphuric acid and with potassium to form indoxyl sul-
phate of potassium, which is the well-known indican of the urine. As
in the case of phenol sulphate of potassium, none of the urinary indican
seems to come from the normal metabolism (of the tryptophane) of the
tissue proteins. It is a much more reliable indicator than phenol sul •
phate of potassium of the extent of intestinal putrefaction, but it also
becomes increased in amount during putrefaction in the body itself,
as for example in abscess formation.

The amount of indican in the urine may be roughly gauged by oxi-
dizing the urine by means of hypochlorite and then shaking out with
chloroform. If the resulting extract is more than light blue in color,
it indicates excessive putrefaction. A negative test does not neces-
sarily mean that intestinal putrefaction is absent, but a marked positive
test always indicates that it is occurring. Skatole, the methyl deriva-
tive of indole, may undergo similar processes and appear in the urine
during excessive intestinal putrefaction. Its presence in the blood some-
times confers on the breath a distinct fecal odor, for this body, as its
name indicates, is that to which the odor of the feces is due.

Glycuronic acid, the other substance used for detoxieation processes,
is of the nature of a dextrose molecule with the one end-group oxidized
to carboxyl (CHO - (CHOH)4- COOH). It is probably produced under
normal processes of metabolism in the animal body, but is destroyed
unless when such poisonous substances as camphor, chloral hydrate or

THE METABOLISM OF PROTEIN

certain aromatic alcohols are given, when it is 1 1 -.• •< 1 for tin: purp -
detoxicating them. The resulting glycuronates have reducing ]><>■
and may 1"" confused with glucose when present in Large amount. Gly-
curonates may be distinguished from glucose in the urine 1
they are levorotatory, and (2) because they do aol ferment. The free
arid itself, however, is dextrorotatory.

CHAPTER LXXII

URIC ACID AND THE PURINE BODIES

Introductory. — The participation by highly trained organic chemists
in the investigation of biochemical problems has brought our knowledge
of the history of the purine substances in the animal body from a state
of chaos and guesswork to one of system and scientific accuracy. The
peculiar solubility reactions of uric acid and its salts and the discovery
of urates in gouty deposits served to make uric acid metabolism one of
the earliest research problems in both the medical clinic and the bio-
chemical laboratory, but the earlier results were practically valueless,
partly because they were inaccurate and partly because their interpretation
was impossible in the absence of even the most elementary facts concerning
the chemistry of uric acid.

Before any real progress was possible, a clean sweep had to be made
of all the old speculations and hypotheses, such as that dignified by the
high-sounding name of "uric-acid diathesis," and a foundation of ac-
curate chemical knowledge established. This foundation is now wonder-
fully complete, and a superstructure of biochemical fact is already
beginning to grow upon it. In the present chapter we shall examine
some of the most important contributions that have made this progress
possible.

As in the study of any other problem of metabolism, we must, however,
make ourselves familiar with the main facts concerning the chemistry
of the purine bodies and of the tissue constituents into the composition
of which they enter, before proceeding to the more strictly biological
aspect of the subject.

The Chemical Nature of the Purines

By an examination of the empiric formulas of the purines of biochem-
ical interest, it will be observed that they are all derivatives of a sub-
stance purine, which although in itself of no importance is interesting,
since it serves as the basic substance from which the others are derived.
The list is as follows:

Purine . . CSH..N4

C,H4N40 Monoxypurine

'VII X.XH, Amino-purine

I ' I f 4N40;, Dioxypurine

0BH,N4O.NH2 Aniino-oxypnrini'

I (gH4N40, Trioxypurine

634

Hypoxanthine

Adenine
Xanthine
Guanine
Uric acid .

Purine
f bases.

I KM \«'ll> AM' THE PI KIM BOD]

The first oxidation produd of purine is hypoxanthine, which I
long been known as a constituent of meat extract. Adenine, the amino
derivative of hypoxanthine, occurs in combination with other subsl
in the nuclear material. The second oxidation product is xanthine and
its amino derivative, guanine. They occur in the same places .-is hypo-
santhine and adenine. The lii-jhest oxidation product of ;ill is the well-
known urinary constituent, uric acid, which may therefore 1"- chemically
designated ;is trioxypurine. In addition t<. the purines <<( animal origin.
there arc also certain outs of vegetable origin -the methyl purines, which
exist .-is tlic alkaloids of tea and coffee namely, caffeine, theobromine,
and theine.

To understand the chemical structure of this group of Bubstanci
it is perhaps simplest to start with that of uric acid. This consists
3sentially of two urea molecules linked together by a central chain of
three carbon atoms, as will he evident from the accompanying structural
formula:

HN-CO

i i

OC C xir

\

ii

/
N-C-NH

(urea) (in

(C(

1
■ntral chain)

This structure can he shown by methods both of decomposition and
of s\ nt he-is. When uric acid is decomposed by oxidizing it with nitric

acid, it yields urea and a residue called alloxan; or it can he synthesized
from urea and trichlorlactamide, a derivative of lactic acid, which it

will he remembered contains three carbon atoms. The changes invol
in this synthesis will he mad.' clear by examination of th< mpanying

structural formula, in which the manner of production of the by-
products of the reaction (NH8, HaO and HC1 are show q by dotted In • -

MI. II Ml C=rO

/ I

/

/ ; ii • ' «wr n mi

\

\ '''

\

\ G- GIB Ml irra^

\

Curca^ Ml | II < 'I

■

636

METABOLISM

By milder oxidation by means of potassium permanganate in the
cold, uric acid becomes quantitatively converted to allantoin:

C5H4N408 + H20 + 0 = C4H6N403 + C02.
(uric acid) (allantoin)

The importance of this transformation lies in the fact that in most
animals, man and the higher apes being exceptions, uric acid is thus
decomposed in the animal body. The structural formulas for the other
purine bodies in relationship with those of purine and uric acid are given
below.
Purine itself has the following structural formula:

iN Co H

H2-C

NH?

\

(

/

C8-II

sN - O - N9

(For convenience of description the atoms in purine are numbered as shown.)
HN-C=0 HN-C=0

H- C C-NH

O = C C - NH

l

C-H

. II I! /

N - C - N

(hypoxanthine) (6-oxypurine)

N = C - NH,

C-H

H- C C-NH

N-C- N

\

(

//

1 1 X - C - N
(xanthine)

HN-C=0

I I
H..N = C C-NH

/

(2-6-oxypurine)

C-H

C-H

N-C- N

/

(adenine) (6-amino-purine) (guanine)
HN-CO

(2-amino-6-oxypurine)

OC

C-NH

\

CO

/

I \- C -NH

Uric acid (2-6-8-trioxypurine)

The substances with which the purine bases are most closely related
are the pyrimidine bases. Three of these are known:

cytosine ( N = C-NH, and uracil (NH-CO

I II

CO CB CO rn

I II I II

NH-CH); NH-CH).

thymine (NH-CO
I
CO C.CIL

.\H-CH );

URIC kCID Wl> 'I'll I PDBIN] B0D1

From an examination of the structural formulas, it will be Been thai
they are more or less related to purine (having one of the urea radicles
omitted), although it can scarcely be doubted thai thi eparate

constituents of the oucleic acid group in the animal body, and are nol
derived from purine. They are primary products.

The Chemical Nature of the Substances in Which Purine and
Pyrimidine Bases Exist in the Animal Body.- Tn general it may be said
thai the amino purines adenine and guanine together with the
pyrimidine bases thymine and cytosine — occur combined with phos-
phoric acid and a carbohydrate in the various nucleic acids, each of which
is again combined with some simple protein to form nuclcin. t lie essen-
tial constituent of the chromatin of the nucleus. One of the oxypuri
hypoxanthine, may also exist eombined with phosphoric ; s < - i * 1 i rbo-

hydrate to form a substance presenl in muscle and known as inosinic
acid. The general scheme of construction of a nucleic acid of animal
origin is illustrated in the following formula suggested by Levene and
Jacobs:89

110

\

\

O = PO C ii .>

■■11. N <)

/ C1,

■■ii; ■

/

0

no

1

\

1

1

\

o - PO

'•ir,o2-c h,n,o

/

1 thymine

P)

/

HO

0

IK)

1

\

\

I

o |")

.•IK) ''.II. N«)

/

- cytosine

I''1

/

IK)

1
o

\

Phosphoric acid

\

groups

PO C II 0

C.B

/ < hi

•Up |

/

IK)

According to this formula nucleic acid may be considered i »m-

pound of polyphosphoric acid, containing carbohydrate groups, which
Berve to link the phosphoric acid molecules to tl purine or pyrimi-

dine. Tn nucleic acids of animal origin, such as the example
above, the carbohydrate is a hexos . contains 6 C-al . whei

t;;;> metabolism

in those of plants (e. g., yeast), it is a pentose (5 C-atoms). It has been
found necessary to introduce some terms to designate the different parts
of the nucleic acid molecule; thus, the whole molecule is called a tetra-
nucleotide, each mononucleotide molecule of which is composed of a
phosphoric acid molecule plus a nucleoside, which again is composed of
a purine or pyrimidine nucleus attached to pentose or hexose. The
nucleoside is so named because it is similar in structure to a glucoside.
Apart from differences in the carbohydrate group, it appears that
there is a close similarity in the structures of nucleic acids from dif-
ferent cells. This would indicate a common function for them all, which
may be either of a skeletal or of a physiological nature; that is, nucleic
acid may have to do with the sustentacular material that builds the
nucleus, or it may have to do with some physiological function common
to all cells, such as irritability, or growth, or respiration. If nucleic
acid is merely a sustentacular material, then the study of the behavior
of chromosomes and chromatine in cells can not have the significance
that it would have were nucleic acid concerned in the more vital activ-
ities of the nucleus. All the so-called nuclear stains owe their specific
staining properties to the fact that they are of a basic nature and com-
bine with nucleic acid. Until we know more definitely what the exact
function of nucleic acid may be, it is unwise to place too much weight
on the behavior of the chromosomes in cytologic researches.

The History of Nucleic Acid in the Animal Body. — We shall first
of all study the manner in which nucleic acid may be broken down. As
is to be expected from its complex structure, various types of enzymes
are concerned in this process. The first to act are known as the nucle-
ases. They split the tetranucleotide molecule into two dinucleotides.
which immediately afterward split further into mononucleotides. Four
nucleotides, two of purine and two of pyrimidine, are thus formed from
each molecule of nucleic acid. Each nucleotide molecule may now un-
dergo decomposition in one of two ways: (1) either by the splitting off
of phosphoric acid, leaving a nucleoside (guanosine or adenosine), or
(2) by the splitting off of both phosphoric acid and carbohydrate, leaving
free purine bases. Nucleases have been found which specifically effect
either of these decompositions, and they have been called phospho-
nucleases* (1), and purine-nucleases (2), respectively. In the decompo-
sition of nucleic acid all of the four purine compounds — guanine, guano-
sine, adenosine and adenine — may be formed. This is illustrated in the
accompanying schema, in which the nucleic acid is represented as a
purine nucleotide:

*The numbers refer to the enzymes indicated in the schema.

; RIC KCID AND 'illi PI ki\i B0D1

Nucleic Acid (without the pyrimidine group)

(1) (1) ^(2)

(Action of nucleases)

sL \

Guanine *-(7) Guanosine Adenosine (8)— > Adenine

(4) (5)

(Action of dcaminizing enzymes)

Xacthosine Inosine

(9) (Action of hydrolyzing enzymes) (10)

UricAeid<— (11) Xanthine < -(H)— »• Hypoxanthine

(Action of xanthine oxidase)

(Jones.)

The next step in the disintegration process is that the amino group
is removed and tin- corresponding oxypurine is produced. To bring this
about, there exists a specific deaminizing enzyrru for each of the above
amino compounds, and each enzyme is named according to the exact
amino purine upon which it acts; thus, guanase '■'< . guanosine-deamii
(4), adenosine-deaminase (5), and adenase (6) have all been identified.
The free base may then be split off from the nucleosides by -
lunlrnlj/zitiif , h: ames (7 - '• (10).

The joint action of these enzymes leads to the formation of oxypurii
xanthine and hypoxanthine, which are oxidized to uric acid by xant)
oxidase (11).

In man and the anthropoid apes mic acid is the end product of the
above changes, bul in other mammals most of the uric acid is further

oxidized into allantoine. It has also 1 u found, except in man and the

chimpanzee, thai extracts of organs such as the liver, are capable of
decomposing uric acid into allantoine. The identification of th< - - scific
enzymes is sought by a determination of the free amino-purine bi
and the phosphoric acid produced by allowing an aqueous extract
the tissue iii question to act on nucleic acid of yeasl * at body tempera-
ture. Another portion of the digested mixture is then hydrolyzed by
means of boiling sulphuric acid and the constituents again determined.
From the results it is often possible to draw conclusions as to th<
nature of the enzymes present.

The mosl remarkable outcome of this work has been to show that

distribution of tht enzyme* - not ta< sonn In vans

of different animals. Very briefly, some of the most important results

that have so far been obtained are as follows trie and pancreatic

juices do not contain a trace of any of the enzymes. Entestinal jui

•Yeast nucleic ai ill is uscil because it is Ir- n than thymic nucleic .

640 MKTABOLISM

on the other hand, contains a nuclease capable of splitting the poly-
nucleotides into mononucleotides. The two pyrimidine nucleotides split
off do not undergo further change, but the purine nucleotides are con-
verted into nucleosides (the enzyme being designated "nucleotidase").
Extract of the intestinal mucosa, besides having the same action as the
intestinal juice, can also decompose the purine, but not the pyrimidine
nucleosides, into carbohydrate and purine groups (specific action of
:' nucleosidase"). A similar action is produced by extracts of kidney,
heart muscle, and liver. Blood serum, hemolyzed blood, and extract of
pancreas, on the other hand,- are capable only of carrying the decompo-
sition as far as the mononucleotides.

Regarding the other enzymes mentioned in the above list, it is im-
portant to note that they appear at different stages in embryonic develop-
ment, and that their distribution varies considerably in different species
of adult animal, the spleen, liver, thymus, and pancreas containing them
most abundantly. The distribution of enzymes in the organs of the
monkey resembles that in the lower animals considerably more than it
does that in man. Some remarkable facts have come to light regarding
guanase and adenase, particularly that guanase is deficient in the organs
of the pig, in the urine of which animal it has also been found that the
purine bases are in excess of the uric acid. This absence of guanase
no doubt accounts for the fact that deposits of guanine may occur in the
muscles, and that these may be so large as to constitute the condition
known as guanine gout found in this animal. Adenase, on the other
hand, is absent from the organs of the rat, which again corresponds with
the fact that, when adenine is injected subcutaneously into these ani-
mals, it undergoes oxidation without the removal of its amino group.
In the human organism, adenase appears to be absent from all of the
organs, whereas guanase is present in the kidney, lung and liver, but
not in the pancreas or spleen. Xanthine-oxidase exists only in the liver.

The distribution of uricase is perhaps the most interesting. It is pres-
ent in most of the lower animals. On account of its presence extracts
of the liver, spleen, etc., in all breeds of dogs, with the exception of
Dalmatians, rapidly destroy uric acid ; and practically no uric acid
when injected subcutaneously can be recovered unchanged in the urine,
but appears as allantoine. Uricase, however, is absent in man. This has
been demonstrated by finding (1) that when uric acid is injected sub-
cutaneously, nearly all of it appears in the urine, and (2) that uric acid
is not destroyed when extracts of the organs are incubated at body
temperature with uric acid or its precursors. It must of course be kept
in mind that, although the uric acid is thus shown not to be destroyed
in vitro, it may nevertheless be destroyed in the living animal.

IKIC AUI> a\|> 'nil. PURINE BODIES

641

Tlio importance of the above described results rests in the fad that
from them we may hope to be able, ultimately, to stair exactly in what
organs and tissues the intermediary metabolic processes concerned in
nucleic acid metabolism occur. The work at the present time is of spe-
cial significance, since it represents one type of evidence which we must

have before we can trace exactly every step in the metabolism of any
other biochemical substance.

The absence of uricase from the tissues of man places him in a unique
position with regard to the metabolism of nucleic acid, and renders the
investigation of the problem particularly difficult, since animal experi-
mentation is useless. Recently, however, S. R. Benedict has discovered
that the Dalmatian breed of dog — also known as the carriage dog, and
having a spotted or mottled skin- — has a purine metabolism like that of
man.4 "When fed on food containing no purine substances, he excretes
Large quantities of uric acid, and when the latter substance is injected
subcutaneously, it is eliminated quantitatively as such in the urine. We
shall see later how experiments on this animal have been made use of
in the investigation of problems of purine metabolism as applied to man.
In all other animals most of the uric acid is oxidized to allantoine before
being excreted. The degree to which this occurs varies between 79
and 98 per cent of the uric acid in different species. This has been
called the uricolytic index (Hunter and Givens).

The Balance between Intake and Output of Purine Substances under
Various Physiological and Pathological Conditions. The main purine ex-
cretory product in man is uric acid, but there is also a certain amount
of purine bases. The presence of uric acid has attracted attention for
a great many decades in medical investigation, because of the relative
ease with which it can approximately be determined quantitatively, and
because of the well-known fact that it may be responsible for certain
diseases, such as gout, when it accumulates in the tissues in an insoluble
form. On a diet containing meat, or more particularly on one con-
taining glandular substances, the total daily excretion of uric acid is
Very considerably greater than when the diet contains no such food
stuffs. The conclusion which Burian and Si-hur' drew from this ob-
servation is that purine must be partly of exogenous and partly of
endogenous origin. In other words, some of it is derived more or
directly from performed purine substances in the food, and the remain-
der from the purine constituents of the animal's own tissues

Endogenous Purines.- It was thought that a definite proportion
each of the administered purines could be invariably recovered from
the urine. Although this has not been found to be exactly true, there
is nevertheless a certain constancy in the proportion of administ.

642

MKTAIiOUSM

purine that is excreted. Tims, Mendel and Lyman have found recently
that about GO per cent of injected hypoxanthine, 50 per cent of xan-
thine, 19-30 per cent of guanosine, and 30-37 per cent of adenine were
eliminated as uric acid. "When combined purines — i. e., nuclear mate-
rial— are given, only a small proportion of the purine reappears as uric
acid in the urine. There is, therefore, a general parallelism between
the purine content of the food and that of the urine, which indicates that
purine-rich food should be eliminated from the diet of patients who are
suffering from deposition of insoluble urate in the tissues, as in gout.
The fate of the purine thai disappears in the body is unknown; some of
it may be decomposed in the intestine, but why so much of the remainder,
after absorption by the blood, should disappear is a mystery, since no
uricase can be discovered in any of the organs or tissues. The destroyed
purines can not be shown to influence any of the other well-known
nitrogenous metabolites of the urine.

The following table of experiments by Taylor and Rose45 may serve
to illustrate these points. The subject was placed on a purine-free diet
consisting of milk, eggs, starch and sugar, for three days. After this
period a part of the total nitrogen (3 grams) was supplied as sweet-
breads— thymus gland, etc.— containing a high percentage (0.482) of
purine nitrogen; for another period of four days still more of the nitro-
gen (6 grams) was replaced by sweetbread nitrogen; and this was fol-
lowed by a final period in which the original diet of milk, etc., without
purine substances, was restored. The following table gives the results:

1st period

4th period

PURINE-FREE

2n

1) PERIOD

3rd period

PURINE-FREE

DIET

DIET

Total urinary N

8.9

8.7

9.1

8.8

Urea N and NH2

7.3

7.1

7.1

7.05

Creatinine

0.58

0.55

0.56

0.47

Purine N (total)

0.11

0.17

0.26

0.10

Uric acid N

0.09

0.14

0.24

0.07

Remainder N

0.91

0.88

1.18

1.18

The increase of uric acid accounted for less than half of the purine
nitrogen ingested. This appeared as uric acid, the- excretion of purine
bases being practically unchanged.

CHAPTEB I. XXIII
URIC ACID AND THE PURINE BODIES Cont'd

SOURCE OF ENDOGENOUS PURINES

Even after the entire eliminati t" all purine substances from the

food in the ease of man, purine continues to be excreted in the urine
as uric arid. This, as above remarked, is called endogenous • tion.
At first it was thoughl by Burian and Schur thai the total nitrogen of
the purine-free diel could be considerably varied without causing any
alteration in the amounl of the endogenous purine excretion, but a rep-
etition of tli«' work lias shown that, when these changes are of consider-
able magnitude, the endogenous moiety does do1 remain constant. This
has already been demonstrated in the initio <>n Folin's results see p
614), and is still better illustrated in the accompanying table, which
shows Iho excretion of uric acid and coincidently of urea from hour to
hour in the urine after taking food which is free from nuclein or purine
substances. After a fasl of six hours, a diel consisting of bread and

potatoes was taken at 1:30, and the urea and uric acid measured in the
urine each hour thereafter.*

TIME

UREA

URK

AMOUNT OF URINE

MO.

c.c.

10-11

1.07

175

ri-12

1.13

IT

11^

12-1 P.M.

1.07

24

164

1-2 (meal)

0.64

21

2 3

1.12

an

3 I

1.16

11

I 5

0.84

"

1.16

56

6 :

1.20

: -

-

1.47

9 10

24

1 55

10-11

23

1->

II ■■'•-.. - and II

.1 postprandial increasi of endogenous purim ■ is very dis-

tinct, and it indicates thai during the process of assimilation something
must be occurring in the organism which entails the production of pui

• riu-sc in\ tuld l"- i

i

044 METABOLISM

from the organism itself. As to \vha1 this may lie, it is impossible to

say. It may be associated with the work of the gastric and intestinal
glands, -which recalls the interesting suggestion, originally made by
Horbac/ewski. that ingested substances increase the excretion of uric
acid by causing a leukocytosis, the purine being derived from the nucleic
acid set free when the leucocytes become broken down. That this is
not the correct explanation, however, is indicated by the fact that in-
gested substances that give rise to an increased number of leucocytes
affect the excretion of uric acid during the period the leucocytes are
present in the blood, and not after they have disappeared, which would
have to be the case were the uric acid a product of purine substances
liberated by their breakdown. This would indicate that the purine sub-
stance is a metabolic product of the living leucocytes and not a break-
down product of those that are dead. It should be noted that the increase
in the postprandial uric-acid excretion occurs earlier than that of urea.

The most pressing question concerns the origin of the endogenous
purines. Uric acid is the purine with which we are most concerned in
the case of man, and chemistry shows us that it may be produced either
by the oxidation of the lower purines — namely, of those which are the
constituent parts of the nucleic-acid molecule — or by a synthesis of two
urea molecules with a carbon residue containing three carbon atoms.
There are consequently two sources from which the endogenous purine
excretion in man may be derived : (1) synthesis of two urea molecules,
and (2) oxidation of the lower purines.

"We will consider first the possibility of synthesis. In birds and
reptiles practically all the nitrogen is excreted in the form of uric acid,
and it is easy to show that this has been produced in the organism by
the synthesis of urea with carbon-rich residues, occurring mainly in the
liver. Minkowski found that by removing the liver from geese, which
is a comparatively simple operation on account of an anastomotic vein
between the portal and the renal veins, the uric acid in the urine became
very markedly decreased and ammonium lactate took its place (page
618). Since we know that ammonium in the animal body is ordinarily
converted into urea, we may conclude from this observation that some-
thing has occurred to prevent the synthesis of urea into uric acid. In
confirmation of this ('(inclusion it was subsequently found that, if am-
monium lactate was added to the blood perfused through the isolated
liver of the goose, uric acid was produced in the perfusion fluid.* Fur-
thermore, when birds and reptiles are fed with ammonium salts or
with the degradation products of protein, there is an increase in the ex-

*The reason for the formation of this relatively insoluble metabolite in place of the soluble urea
is connected in some way with the fart that birds and reptiles do not take such large quantities
of water with their food as other animals.

i BIC ACID AM' i 111. PI BINE BODIES 6 15

cretion of uric acid i n >>t <;i < ! of area. Everything which in a mammal
lends io cause an increase in urea excretion causes in birds and reptiles
a similar increase in the excretion of uric acid.

In the earh days of research in the uric-acid problem, not inconsid-
erable mistakes were made on a »un1 of failure to recognize the

lial difference in the metabolism of uric acid in birds and mammals.
and the tendency for some time after the exact state of affairs was
discovered was to consider thai in mammals none of this synthetic proc-
ess occurs. The Latter view, however, is surely incorrect, for a
linn amount not only of uric n< i<l itself but of th, lower purim boa
can I" produced by synthesis in th< mammalian body. Tims. Ascoli and
Izar17 discovered that uric acid could be made either to disappear or
to be formed when a min 1 preparation of liver was incubated, depend-
ing upon whether oxygen or carbon dioxide was bubbled through it.
With oxygen uric acid disappeared, whereas with carbon dioxide uric
a.-id accumulated, indicating thai in the presence of this gas the destroyed
uric acid became reformed from the disintegration products of the oxy-
genation process. As similar results were obtained from the livi
birds, it is clear thai no essential difference exists between the purine
metabolic processes occurring in the livers of birds and of mamn
The difference is a quantitative not a qualitative one.

Regarding the chemical nature of the product into which uric acid is
broken down and from which it may be resynthesized, it has been |
sible so far to identify but one substance — namely, dialuric acid. This

is a perplexing result, for from all other investigations it would app<
that in mammals, with the exception of man and the anthropoid apes,
uricase splits uric acid into allantoine (see page 640), which substance,
however, when added to liver extract did not cause any uric acid to be
formed: nor did any of the other known decomposition products of uric
acid have such a result. The chemical reaction involved in the produc-
tion of uric acid from dialuric acid and urea is indicated as follows:

s\i — c = o

/
/
/

<> C • =H.OH H XII

\ \

\ + c=o

\ /

Ml C 0 II Ml

i dialuric acid •

The synthesis of uric acid is b rough 1 aboul bj the combined action
of a thermolabile enzyme in the blood and a thermostable body in the
tissues. An aqueous extract of hi I free liver of the <\"~ can destroy

1)41) METABOLISM

uric acid only in the presence of oxygen; it can not reform it even in
the presence of carbon dioxide. On the other hand, blood serum can
not reform uric acid, whereas a mixture of the bloodless liver extract
and blood serum produces uric acid readily under suitable conditions.
Boiling of the liver extract docs not affect the result, but boiling of the
blood scrum renders it incapable of exerting its joint action with the
bloodless liver extract.

These experiments with dog's liver serve only as circumstantial evi-
dence that uric-acid synthesis occurs in mammals as well as in birds.
More direct proof thai purine synthesis occurs in mammals "is as follows:
(1) It was discovered long ago by Miescher that salmon, after leaving
the sea to ascend the rivers, have a well-developed muscular system, but
thai in the upper reaches of the stream the muscular system becomes
considerably atrophied and the testes enormously developed. As the
fish takes no food during the migration, there must be conversion of
the protein of the muscles into the cellular tissue of the sexual glands,
and nucleic acid must be produced. (2) A hen's egg before its incuba-
tion contains practically no nucleic acid, whereas after development has
well started nucleic acid increases by leaps and bounds. Similarly the
eggs of insects increase in purine content very markedly as development
proceeds. (3) Milk contains practically no purine derivative, and yet
when it is fed to young growing animals, the organs lay on purine sub-
stances abundantly. In general, indeed, it may be said that the combined
purine increase is in proportion to the increase in body weight on the
milk diet. (4) In Osborne and Mendel's experiments already alluded
to, it has been shown that adequate growth depends primarily on the
nature of the protein building stones, and not upon the purine content
of the food. (5) An objection might be raised to these results on the
score that they do not apply to the adult mammal. Investigation of
the problem has hitherto been seriously impeded by the fact that no or-
dinary laboratory animals were known in which uric acid is excreted in
the urine. The discovery that this occurs in the Dalmatian dog has,
however, made it possible for S. R. Benedict41 to show, not only that
after increasing the amount of nonpurine food there was a very distinct
increase in the uric-acid excretion, but also that when the animal was
kept for a year on such foods there was excreted a total amount of uric
acid at least ten times greater than could have come from the traces
unavoidably included in the food.

Regarding the chemical nature of the substance from which the purine
is synthesized, we know ;it present practically nothing. No doubt some
of the protein building stones functionate in this capacity, pyrimidine
being probably the produd thai is firsl formed. Thus, pyrimidine may.

i BIC ACID AND THE PI BINE BODIES 6 17

be produced as a result of the combination of amino-malonic acid with
area, the amino-malonic acid being produced by condensation of hydro-
cyanic-acid molecules:

:: HCN-» II X CH CN CO Ml — Ml CO

I
CO CNB

Ml CNH,
(hydrocyanic (amino malonic (urea) (oxy-diamino-pyrimid
acid) nitri

Another possible source of pyrimidine is the oxidation of arginine to
guanidine-propionic acid, which then condenses to form amino pyrimi-
dine.

Purine synthesis undoubtedly occurs in the mammalian body, but it
is difficult to recognize in metabolism investigations because it is a Blow,
continuous process. The probability of its occurrence, however, is indi-
cated by such results as those described on page 614, in which incr<
in purine excretion is observed after varying the intake of food, even
when this is itself entirely free from purine substances. Whether or not
changes in the activity of purine synthesis occur in conditions of dis<
is a question which awaits investigation.

The Influence of Various Physiological Conditions, of Drugs, and of
Disease on the Endogenous Uric-acid Excretion. Muscular exercisi was
though.1 by Burian to cause an increased excretion of uric acid, from
which he drew the conclusion thai the hypoxanthine present in compara-
tively large amount in muscular extract, or its precursor, inosinic acid,
must be an importanl source of endogenous uric acid, other obsen
(Leathes, etc.) have found thai strenuous exercise causes a distinct in-
crease in uric-acid excretion, which, however, is much less marked on
repetition of the same kind of exercise on the next day. If Borne new
kind i>f muscular work is performed, another increase in uric acid will
result. There are still other investigators who deny that muscular work
has any influence "ii uric-acid excretion.

It has been observed by several investigators that the endogenous
purine excretion is distinctly higher during tin- waking hours than during
sleep. This can nut he shown to depend on variations in the urinary
function, and since it is decidedly doubtful whether ordinary muscular
activity has any influence, the diurnal variation is most difficult
account for. The endogenous excretion in man is not the same for
diffen n? individuals, even when calculated for the same body weighl ; it
varies between 0.12 and 0.20 per cenl purine nitrogen in an adult man.
It remains remarkably constant for a given individual from time tn
time, being unaffected by moderate degrees of variation in the amount

648 METABOLISM

of food taken provided this be purine-free; when, however, the amounts
are extremely variable, changes are produced (see page 614).

In disease, f< r< r causes an increased excretion. This has been most
clearly shown by Leathes, Avho took a large enough dose of antityphoid
serum to produce a distinct degree of fever (103° F.), and found that
an increase in uric-acid excretion occurred. That increased combustion
processes occurring in the tissues were responsible for the uric acid,
was shoAvn bv the same author, who caused a similar increase bv sub-
jecting himself to cold baths for a considerable period of time. The in-
creased loss of heat thus induced stimulated the combustion processes in
the body so as to maintain the body temperature, and as a result there
was an increase in uric-acid excretion. It has long been known that an
excessive amount of uric acid is excreted in leucocythemia. The nuclein
of disintegrated leucocytes is commonly held responsible for the increase.
Naturally, much work has been done on the endogenous and exogenous
purine excretion in gout. No very striking anomalies of excretion have,
however, been brought to light, except perhaps that after the ingestion
of purine-rich foodstuffs it takes longer for the resulting exogenous ex-
cretion to develop and pass away.

Certain drugs affect the excretion of uric acid. Salicylic acid is said
to cause an increased excretion, and citrates certainly have this effect.
In both cases the increase is followed by a compensatory fall, which
indicates that these drugs act by facilitating the excretion rather than
by influencing the metabolic processes that are the source of the uric
acid. The effect of caffeine has been very carefully investigated. Given
to the Dalmatian dog, referred to above, S. R. Benedict found that a
small dose caused a slight decrease, but that a larger dose had practically
no effect, although there was a notable retention of nitrogen. On man,
however, different results Avere secured, for it was found that when 1
gram of caffeine was given daily for several days, a slight but definite
progressive increase in the endogenous uric-acid excretion occurred, and
it lasted for 10 days after the caffeine administration was discontinued.
Liberal allowance of this alkaloid may, therefore, not be quite so innocu-
ous as it is assumed to be.

Uric Acid of Blood. — Tn all of the investigations considered above,
the behavior of uric acid is judged from the amount of it excreted in
the urine. Valuable though such results must be, their interpretation is
always difficult, since two factors that are quite independent of each
other have to be kept in mind — namely, the production of the uric acid
in the organs and tissues and its excretion by the kidneys. In connection
with the latter factor, we must also consider the method of transporta-
tion of uric acid by the blood From its place of production for absorp-

! RIO A < 11 » AM' THE PI kim. BODIES 649

tion) i" tlie kidneys. These problems have recently been very isider-

ably simplified by the elaboration of an accurate method for the estima-
tion lit' tin uric-acid content of blood.

By observing changes in the amounl of uric acid in the blood rati
than in ilic urine, the i tory factor is partly controlled, and it can
be completely so it' urine and blood are both investigated. Thanks to
the work of Polin, it is now possible to determine with an extreme de

'_rr< E accuracy the uric a< id in as little as 1" c.c. of 1>1 1. The imp

tance of this achievemenl will be appreciated when we state thai prior
to Folin's work mi method existed by which uric acid could be approx-
imately measured even when large quantities of-blood were available

Much of the work thai has been done by the use of this new method

so far applied to the amounl of uric acid in the 1>1 1 of man in

various diseases. We shall refer to these results inn liately, but

meanwhile it is importanl to call attention to some very suggestive
observations concerning th( condition of uric acid in tht blood. For
many years there have been investigators who have thought that uric
acid can not be simply dissolved in the blood plasma, Like sugar or some
inorganic salt. It is believed by many that at least a portion of the uric
acid circulates in combination with nucleic (thymic) acid sec pagi
which would accounl for the fad thai some purines are catabolized in
the body when they are given in a combined state, as thymic acid, but
are excreted unchanged when ingested in a free state* When given freely,
certain purines adenine, for example— may moreover cause inflamma-
tion and calculus formation in the kidneys of dogs, a resull not obtained
when thymic acid is fed.

Other observers have concluded thai uric acid exists as two isomeric
varieties, lactam and lactim, the monosodium salts of which i un-

equal stability. The less stable o-sall is much more soluble in blood

serum than the stable (8-salt. It is the o-sal1 thai 1" mes inc - 1 in

the blood in gout, the deposition of urates in the 1 which is the

must characteristic Bymptom of this disease, being caused by conversion
lit' the o-salts into ff-salts. The structural formulas of the two ison
are as follov

II. X C :0 N COB

I I

0 :C C Mi HO.C <• Ml

\

/

C.OH

I I.N «• Ml \ '

[lactam modification forini (lactim^

unstable a urat< stal
. relal ively solul lativclj

650 M ETABOLISM

The most recent work of S. R. Benedict has shown that uric acid ex-
ists, chiefly in combination in the blood of most mammals but not in
that of the bird. It was found, for example, that fresh ox-blood exam-
ined by the Folin method contains only 0.0005 gm. free uric acid per 100
gm. of blood; after boiling the protein-free blood filtrate with hydro-
chloric acid, however, the uric acid increased by about ten times. This
larger amount was also found present in whole blood that had been
allowed to stand for some time, indicating that the uric-acid compound
can be split by means of an enzyme. The compound exists in the cor-
puscles and not in the plasma. It is of some significance that after thus
set tiny free the uric acid, there should be about 50 per cent more of it
present in the blood of the ox than in that of the bird, where most exists
in a free state in the serum, although the urine of the ox contains only
the smallest trace of uric acid, and that of the bird is loaded with it.
Investigation of the condition of uric acid in human blood is at present
in progress.

Uricemia in Gout and Nephritis

The practical application of these observations is particularly impor-
tant in connection with the etiology of gout. In typical cases of this dis-
ease, the uric acid of the blood increases from its normal value of 1 to
3 mg. per cent to nearly 10 mg., indicating a considerable degree of
renal insufficiency. This uricemia can not in itself, however, be the cause
of the deposition of urates in the joints, because it also occurs in other
diseases with renal retention, such as nephritis. Moreover, the blood
serum is capable of dissolving much larger quantities of uric acid than
are ever found present in it in gout. The real cause for the gouty deposits
must depend on some change affecting the blood so as to alter the form
in which uric acid exists therein, with the result that it is excreted into
the joints and deposited there.

Other diseases showing uricemia are lead 'poisoning and nephritis. In
the latter disease the damaged excretory function of the kidney is
manifested first of all by an increase in the uric-acid content of the
blood, accompanied later by a retention of urea and later still by one
of creatinine. The severity of the renal involvement may therefore be
gauged by determining the percentage of these three metabolites. On
account of the importance of these facts from a clinical standpoint, we
append a tabic containing results secured by Myers and Fine, in which
the behavior of the metabolites in the blood is shown in relationship
to the severity of the case as gauged by the blood pressure.

i BIC A.( II' AND Till, ri BINE BODIES

65]

Uri< \< i i \ N and i of Blood in < > Late K

DIAGNOSIS

rjEio

ACID

•

Ul.oOD

140. TO 100 1

HI.'

Typical Cases of Gout

9.5

13

1.1

8.4

12

.. .i

164

7.2

17

2.4

1 1

1.7

Typical Early Interstitial Nephritis

9.5

25

2.5

185

8.0

.".7

2.7

l.-ii

5.0

37

3.9

130

7.1

L6

•

6.6

24

3.3

185

6.3

18

2.1

' 8.7

20

7."

2.6

117

6.3

31

2.1

6.3

nq

2.4

150

Chronic Diffuse and Chronic Intel

8.0

go

4.8

Btitial Nephritis

L9

17

2.9

17"

B.3

72

3.2

5.3

21

1.9

1 15

9.5

II

3.5

210

2.5

19

1.9

120

7.7

• '.7

::.l

6.7

17

1.6

165

-

39

2.9

6.5

24

3.0

Typical Fatal Chronic Interstitial

22.4

l'i.7

Nephi it is

15.0

240

20.5

225

1 (.3

263

13.0

90

11.1

8.7

1 II

11.0

Myers and Fine: Arch. Int. Med., 1916.)

Lastly, regarding the influence of drugs on the blood uric acid in dis-
ease, it lias been found by Pine thai both atophan and salicylates cause
a pronounced decrease in the amount, bul thai it gradually rises to the
old level even while administration of the drugs is being continued.

Important contributions to the behavior of uric acid in blood are
constantly appearing al present, mainly from the laboratories of Polin
in Boston, of S. R. Benedict, and of Myers and Fine in New York.

CHAPTER LXXIV

THE METABOLISM OF THE CARBOHYDRATES

The healthy animal organism is capable of rapidly oxidizing large
quantities of carbohydrate, as is evident from the following facts: If
carbohydrate is given to a starving animal, (1) the energy output very
shortly afterward increases; (2) the respiratory quotient also increases,
indicating that, relatively to oxygen intake, more carbon dioxide is being
excreted (see page 647) ; and (3) none of the ingested carbohydrate
makes its appearance in the excreta. Indeed, of the three proximate
principles of food, carbohydrate is the most available for combustion
in the animal body. It may therefore be considered as the quickly
available fuel for the body furnaces.

CAPACITY OF THE BODY TO ASSIMILATE CARBOHYDRATES

Assimilation Limits. — When the limit to the amount of carbohydrate
that the organism can metabolize is overstepped, some of it appears in
the urine. The amount that can be tolerated without causing glycosuria
is commonly called the assimilation or saturation limit. The use of the
term "limit" is, however, very unfortunate, for it implies that beyond
this point the organism is capable of dealing with no more carbohy-
drate, which is far from being the case, for if a larger amount is taken,
only a small trace of the excess will appear in the urine. When the
urine is allowed to collect for twenty-four hours, the mixed specimen
shows no trace of glucose in the majority of healthy individuals after
the ingestion of 200 gm. ; after 300 gm. a somewhat higher percentage
of cases develop a mild glycosuria, but frequently none is evident even
after 500 gm. Beyond the last mentioned amounts the limit of ingestion
is reached, on account of nausea, etc., and it is improbable that, even
if larger amounts could be tolerated, any more of the. dextrose would
be absorbed than with 300 or 400 gm. The testing of the so-called
assimilation limit has been considered an important aid in the diagnosis
of earh/ cases of diabetes, the characteristic feature of such cases being
the inability of the organism to assimilate properly the usual quantity
of carbohydrate contained in the diet.

It has been found thai to make the results of any value, certain
conditions musl be fulfilled in applying the assimilation test. The most

652

THE Mi TABOLISM OF Tin: C UtBOHYDR \ ■

importanl of thes ncerns ili«' activities of the gastrointestinal appa-
ratus ai the time the sugar is given, Eor it 1ms been found thai if other
foodstuffs are being absorbed at the same time as the sugar, more of
the latter can be tolerated than when the sugar alone is being absorl
It has therefore been customary to give the sugar dissolved in water,
or in weak coffee, the firsl thing in the morning after the patient awal
i.e., at leasl twelve to sixteen hours after the lasl meal was taken. In
making these tests the urine voided before the sugar is estimated should
of course itself be thoroughly examined Eor reducing substances, and
tin1 urine should be collected every ninety minutes and examined by a
reliable test (Benedict's or Nylander's).*

Although a limit is set to the ability of the organism Eor retaining
sugar i mono- or di-saccharides), this does no1 seem to apply, in healthy
individuals at least, when starches (polysaccharides) are ingested. Thus,
it is a well-known fact that people can eat enormous quantities of pota-
toes or of bread without the appearance of any trace of reducing sub-
stances in the twenty-four-hour urine. On the other hand, urine collee
and examined at short intervals (every half hour > after taking large
quantities of polysaccharide-rich Eood will Erequently be found to contain
traces of reducing substances.

For practical purposes it has been considered that an individual who
develops glycosuria after taking 100 gm. of glucose must he considered
.■is ;,t leasl a potential diabetic. In the light of the above results and
for many other reasons, there is, however, considerable doubt as to the
value of the assimilation lest. Thus, when a solution of glucose is
given orally, its rate of absorption will depend very largely on the
motility of the stomach. If this is normal, the solution will very quickly
find its way past the pyloric sphincter into the intestine, where it will
be rapidly absorbed. If. on the other hand, the pyloric sphincter does

not open freely, the passage of the glucose into the intestine may he

s,, delayed that no more is presenl in this place at one time than would

be the case after an ordinary diet of polysaccharide. And even &i
the BUgar solution enters the small intestine, differences in the amount
of the intestinal contents with which it becomes mixed, in the extenl

bacterial growth, and in the absorption pr ss, may very materially

affeet the rate at which the glucose gains entry to the blood.

Although often of doubtful diagnostic value, determination of the
assimilation limit is of considerable aid in controlling tin treat nn

'Examination of normal individuals has shown that the assimilation limit for different
- -. >mewhat .
will be remembered, is the monosaccharide the coi 'he cane-

sugar molecule, tl
the figures -. i m •

tnd Uir sugai I in milk, the a

(i.")t METABOLISM

diabetes. For tliis purpose the patienl should first of all be instructed
to follow his usual diet, so that, by examination of the amount of sugar
excreted in the urine, an opinion may be formed of the severity of the
case. The diet should then be changed so as to consist of a part that
contains no carbohydrates and another composed entirely of starchy
food. The. former is made up of c«-gs, fish, green vegetables, fat, etc.,
and the latter, to start with, should consist of 100 grams of bread, dis-
tributed between the two main meals of the day, one of which is break-
fast. This diet should be continued until the glycosuria either disappears
or attains a constant level. If it disappears, the case is classified as a
mild one of diabetes, and the daily allowance of bread may be increased,
by 50 grams a day, until the sugar again makes its appearance in the
urine, indicating that the assimilation limit has been reached. For
therapeutic purposes, the patient should now be instructed to take about
three fourths of this amount of carbohydrate in his daily rations, and
lie should be supplied with explicit instructions in the shape of diet
tables as to what variety and quantities of the various carbohydrate
materials his food may contain. His urine should be examined at fre-
quent intervals — once a week — and he should be instructed as to the
nature of his disease and the importance of his remaining aglycosuric.
By further treatment such so-called latent cases of diabetes may be
kept in perfect health for many years.

When, on the other hand, the glycosuria exists with 100 grams of
bread in the daily ration, this must be reduced to 50 grams, and if after
some days the first reduction does not suffice to render the urine free
from sugar, carbohydrates must be withheld entirely from the diet.
If the glycosuria does not now disappear, the case is to be considered
severe, and it may be necessary to undertake the starvation treatment,
which has recently been developed in this country by Allen18 and Joslin19
with apparent success. By the reduction of carbohydrate, or by the
starvation treatment, it is usually possible to make even the severest
cases of diabetes aglycosuric, and when this has been attained, then
gradually to increase the amount of protein or carbohydrate food until
the assimilation limit has been reached.

Saturation Limits. — To avoid error caused by irregular absorption from
the intestines, some investigators have recommended the determination
of the assimilation limit after intravenous or subcutaneous injections
of sugar. But even this refinement in technic has not, as a rule, had the
effect of rendering the results of any very evident value as a criterion
of the utilization of glucose in the animal body. The reason for this
unreliability of the method is mainly that the period of injection of the
glucose solution usually occupies only a fewT minutes, so that it causes

I Hi mi I IB0LI8M OP Till CABBOHTDRAT] -

a sudden instead of a very gradual increase in thi r concentration

of the blood, the condition- being quite unlike those which exist during
the normal absorption of glucose Prom the intestine. The mechanism
by which the body ordinarily disp if excessive amounts of glue

absorbed into the portal blood, is nol adjusted to operate when the
temic blood is suddenly overcharged with this Bubstance. In the
case the glucose is a foodstuff; in the other, because of it- ■ jive
concentration in the blood, it is more or less of a poison. Such results, in
other words, merely show us how much glucose can be add< '1 al
time to the organism without any overflow into the urine, but I
furnish us with no information regarding the power of the org m to
utilize a constant though moderate excess of this substance. In the
case it is the "saturation limit," in the other the "utilization limit" of
the organism for glucose, that we are really considering.

Consideration of these principles has led Woodyatt, Sansum and Wil-
der20 to undertake a thorough reinvestigation of the whole problem of
the utilization or, as they prefer to call it. tin toleranct <>f thi h<>(]>i for
(jlucose. They emphasize the obvious fad that the ability of the organism
to utilize glucose "must depend on the rate at which the tissues are
able to abstracl it from the blood by their combined powers, to burn it.
to reduce it into fat or to polymerize it into glycogen." To form any
estimate of the combined effect of these processes, we must take into
account not only the amount of glucose per unit of body weighl grams
per kilogram), but also the rate of injection, for "toll must be

regarded as a velocity, not as a weight."

Briefly summarized, the conclusions which Woodyatt, etc., have bo far
drawn from their investigations are as follows: in a normal rabbit, dog,
or man. 0.8 0.9 gm. of glucose per kilogram body weight and per hour
be utilized by the organism for an indefinite time without causing gly-
cosuria. When between 0.8 and 2 gm. are injected, a part of the ex
appeals hi the urine, steadily increasing until a maximum is read
after which the excreted fraction remains constant at about one-ten'

If more than about 'J grams per kilogram an hour are injected, "a 1
percentage of all glucose in excess of the 2 gm. per kilogram an hour
appears in the urine when constant conditions are once established."

The fact that so much glucose injected intravenously can be Ufi
without the appearance of any of it in the urine, indicates a method by
which foodstuffs may be supplied to the tissues in cases where, on account

of gastrointestinal disturbances, it is impossible to have f 1 a!

by the usual pathways. The possible value of such a method of tr
ment in cases of extreme weakness lias ben tested on laboratory animals
by Allen, who states that such injection seems to ha\ luable nutri-

C)t)C) METABOLISM

live and strengthening effect. 1 1 o found, for example, that in cats
starved to extreme weakness the injection of a fraction of a gram per
kilogram of glucose had an unmistakable strengthening effect, and
sometimes appeared to save Life. Such results would seem to indicate that
in certain cases where blood transfusion is impracticable, glucose in-
fusions should be tried. Subcutaneous injection of sugar, either for the
purpose of determining the assimilation limit or with the object of sup-
plying foodstuffs parenterally, is impracticable because of the pain and
sometimes sloughing produced at the point of injection.

We have devoted no inconsiderable space to a discussion of assimila-
tion limits because of the great interest in diabetic therapy which this
procedure has aroused during recent years. We may now turn our
attention to a closer analysis of the changes that take place in carbohy-
drates during their passage through the animal body.

DIGESTION AND ABSORPTION

Digestion. — All digestible carbohydrate taken with the food is con-
verted by the digestive agencies into the monosaccharides, glucose and
levulose, as which it is absorbed into the blood of the portal system.
To bring about this resolution of carbohydrate into monosaccharides,
several enzymes are employed. The first of these is the ptyalin of saliva.
It is not a very powerful enzyme, being capable of acting only on starches
that are in a free state, i. e.. not surrounded by a cellulose envelope ;
but even on free starch, ptyalin displays little of its activity during the
time the food is in the mouth. After the food is swallowed and becomes
deposited in the fundus of the stomach, there is an interval of time —
lasting until hydrochloric acid has been secreted to such an extent as to
permit some of the acid to exist in a free state — during which the ptyalin
acts on the starch of the swallowed food. During this time the activity
of the ptyalin is actually assisted on account of the fact that a slight
increase in hydrogen-ion concentration of the digestive mixture accel-
erates the action of ptyalin.

The product of ptyalin digestion is maltose, a disaccharide composed
of two molecules of glucose. On entering the intestine, the carbohydrates
therefore exist partly as undigested starch, partly as glucose, and partly
as maltose. In the favorable environment of the duodenum a much
stronger diastatic enzyme called amylopsin very quickly hydrolyzes the
starch through dextrine into maltose. The maltose derived from the
starch and the unchanged sugars, such as cane sugar, maltose and lac-
tose, which have been taken with the food, unless Ihey are present in very
high concentration in the intestinal contents, are not immediately ab-

THE METABOLISM OP THE CARBOHYDRATES

sorbed into the blood, bul become Bubjecl to the action of other enzym< -
contributed by the intestinal juice namely, the inverting enzymes, one
of which exists for each of the disaccharides. By their action maltose
is converted into two molecules of glucose by the enzyme maltase; lac-
tose, into galactose and glucose by Lactase; and cane Bugar, into levu-
lose and glucose by invertase. Ii is interesting to note thai in animals
whose fund does not contain one or other of those disaccharides, the cor-
responding inverting enzyme is absent from the intestinal juice. The her-
bivorous animals, for example, do nol take any lactose in their food, and the
intestinal juice contains therefore no lactase, although it is present in
thai of the young animals while still suckling.

A certain amounl of carbohydrate becomes attacked by the intestinal
bacteria. These split the monosaccharides into lower fatty acids and
erases, such as methane and carbon dioxide. Besides this obviously de-
structive process, bacteria also perform a useful function in the digesl
of carbohydrates, in that certain strains of them are able to di. ellu-
lose, for which no Bpecial enzyme is provided. Bacterial digestion is con-
sequently essential in herbivorous animals: it takes place in the cecum,
which is enormously developed for this purpose I page 463 .

Absorption. The glucose and levulose produced by digestion arc
absorbed into the blood of the portal system. When a very large quan-
tity of a disaccharide, such as cane sugar, is present in the food, a certain
amounl of the sugar is absorbed unchanged- -that is to say, as cane sugar
— ami appears in the blood, from which, Bince it is an abnormal con-
stituent, it is excreted unchanged in the urine. This alimentary gl]
suria is particularly evidenl when the sugar is taken without any other
food; thus, after taking cane sugar in an amount corresponding to 5
grams per kilogram body weight, it was found in our and a half hours
afterward that the urine of ten OUl of seventeen healthy individuals con-
tained cane sugar. The urine of three of these men, however, also con-
tained invert sugar that is. dextrose and levulose. Cane sugar con-
tinued to he excrete.] for from six to Seven llollfS.

The Sugar Level in the Blood. While no absorption of sugar is going
on, the percentage of this substance in the blood of the portal vein is the
same as that in the Bystemic circulation. During absorption the former
becomes perceptibly raised to what extent we can no1 -ay and in the
latter a less marked increase of BUgar concentration is usually detectable.
Evidently, then, between the point at which the sugar is absorbed ami

the blood of the systemic circulation, some barrier exists which holds

hack some of the excess of absorbed sugar. We have verj inaccui
information as to how efficiently these harriers hold back the
absorbed glucose because of the technical difficulty in collecting hi 1

658 METABOLISM

from the portal vein without serious disturbance to the animal. Indeed,
the only way by which the problem has been accurately studied is by
comparing the blood of the portal circulation with that of the systemic
circulation during the injection of a solution of dextrose into one of the
smaller branches of the portal vein.21 In such experiments it has been
found that the percentage of sugar is a little less in the blood of the
abdominal vena cava than in that of the portal vein, and is still less in
the blood of the systemic veins, such as the femoral — results which justify
the conclusion that the barriers responsible for taking out some of the
absorbed sugar from the blood exist in the liver and in the muscles. The
curve in Fig. 18!) will illustrate to what extent the mechanism operates.

Q/oot/ & u G* rf .

•' .%/Ofo

£PSO B/t>70 Br SO

<*!•:

^^ .•* | /Occ & HC L f /flee ■# HCL.

-*<F*^ Consta_nfc ii/pct/on of /2%Oextrose Solution,
'•'/i J /<J /y 20 £ S~ 30 33~ to ¥o~ SO SS 60 (,S~ 70 7S 80 S 5" 90 ?S~ ZOO

Fig. 189. — Curves showing the percentage of glucose in blood after a constant injection of
an IS per cent solution into a mesenteric vein. V.C., vena cava, continuous line; P.O., pan-
creaticoduodenal vein, broken line; /. iliac, dotted line.

It will be observed that, so far as can be judged from changes in the
concentration of sugar in the blood, the sugar-retaining power of the
liver is about equal to that of the muscles. This result shows that the
commonly held view is untenable that the liver is capable of removing from
the portal blood all of the sugar that is in excess of that present in sys-
temic blood. The muscles must assist extensively in this process.

One objection which may properly be raised to these observations is
that the animals on which they 'were made were under anesthesia, and
thai the anesthetic may have had a paralyzing effect on the sugar-retainer
power of the liver. In view of this criticism it is important to examine the
results obtained on animals thai are not under the influence of anes-

I ill \li TABOLISld OF Mil C IRBOHYDRA1

thesia. Such observations have been made on rabbits, and a few on man
himself. By collecting blood from the ear veins of rabbits, it lias !•
found that, after giving from two to ten grams of glucose by Btomach,
the glucose concentration of the systemic Mood begins to rise in fit-'
minutes, attaining ;i maximum in about an hour and then returning
tin' normal level in aboul three hours.

Similar results have been obtained by examination of the venous blood
in man. After giving 100 grams of glucose by mouth, for « • x .■ 1 1 1 1 1 » 1 < • . t!
is commonly an increase in blood sugar amounting to from 30 to 34
cent of the aormal and lasting for from one to four hours. The existo
of lliis postprandial hyperglycemia, ;is we may call it. indicates that tin'
sugar-retaining powers of tin- liver and mus re not sufficiently de-

veloped to prevent the accumulation of some of the absorbed sn-_rar in the
systemic blood. Whenever this increase exceeds a certain limit, some
(lie sugar begins i<> escape through tin1 kidney into the urine, producing
glycosuria postprandial glycosuria. Tin' concentration to which bl<
sugar must rise before glycosuria occurs in the case of man is. probably
aboul 0.10 to 0.11 gm. percent. After damage to the kidney, ;is in nephritis,
or in long-standing cmm's of mild diabetes, tin- percentage may probably
lis.- considerably higher in the blood without evidence of glycosuria.

Value of Bloccl Examination in Diagnosis of Diabetes. — The determina-
tion of the amount of ingested carbohydrate required to bring about |
prandial glycosuria constitutes, ;^ we have already seen, the so-called
assimilation limit for sugar, which is often taken as an index of the sugar-
metabolizing power of the organism. It is evident, however, that the time
of onset, and the extent and duration of post prandial hyperglycemia must
serve as a more certain index of the sugar-retaining power of the liver
and muscles; and now that a simple and rapid clinical method exists
I Lew is Benedicl method i \,,v the accurate determination of sugar in small
quantities of Mood, there is no reason why this index should not 1
for the detection of failing powers to metabolize carbohydrat<

Tu no disease, probably not even in tuberculosis, is it more important
than iii diabetes thai an early diagnosis should he made. Thus, if we find
that the p.. si prandial hyperglycemia after a certain amount of carbo-
hydrate develops to an unusually high degree ami persists for an unusual
length of time, we are just died in curtailing the carbohydrate supply -

to hold that tiles,- values down to the level they attain in normal individ
It is almosl certain that the earliest Bign of diabetes is an unusual defj
and duration of postprandial hyperglycemia. At first th( sugar

leads to no damage and it is insufficient to cause any e\ idem -l\ cosuria, al-
though it is quite likely that if the urine in such individuals were coiled
at very frequent intervals after eating carbohydrate-rich food, glucose would

fif>0 METABOLISM

be found presenl in al leasl some of the specimens. In incipient diabetes,
however, the condition progresses, until the postprandial hyperglycemia
after one meal has not become entirely replaced before the next is taken,
so that the increase in sugar produced by the second meal becomes super-
added on that following the first meal. The curve of blood sugar rises
ever higher and higher, until at last permanent hyperglycemia is estab-
lished, or rather the normal level from which the postprandial rise occurs
has become permanently raised, so that in blood collected at any time a
higher percentage of sugar is found.

The Relationship Between the Sugar Concentration of the Blood and
the Occurrence of Glycosuria. — Claude Bernard first pointed out that the
percentage of sugar in the blood may rise considerably above its normal
level without the appearance of any of the sugar in the urine, or at least
without a sufficient amount to give the usual tests for sugar. Even when
this limit is reached, as Ave have seen, the sugar which appears is not all of
the excess but only a small part of it. This overflow hypothesis, as it is
called, has not been universally accepted because of the many results
which are not in conformity with it. Many of these exceptional results
have been explained as due to alterations in the permeability of the kidney
for sugar, and in general it is probably safe to accept Claude Bernard's
hypothesis with certain reservations.

Strong support has been lent to a modified form of the hypothesis by
the recent work of Woodyatt and his collaborators, who have shown by
continuous intravenous glucose injections that as much as 0.8 gm. of
glucose per kilo body weight can be injected during an hour into an
animal without any glycosuria, although under such conditions a very
distinct increase occurs in the percentage of sugar in the blood.

To explain the failure of glucose to pass into the urine under normal
conditions, it has been supposed by several investigators that the glucose
exists in some form of chemical combination in the blood. This compound
is believed to behave like a colloid. One of the recent supporters of this
view is Allen, who has observed that, when glucose is injected intrave-
nously, it causes diuresis as well as glycosuria; whereas glucose injected
subcutaneously or taken by mouth causes neither of these conditions to
become developed ; indeed it causes for some time after the administration
of the sugar a distinct anuria. To explain these differences in behavior
between glucose administered intravenously and that taken in other ways,
it is supposed that the glucose molecule in passing through the intervening
wall of the capillaries combines with some substance to form a compound
which becomes available for incorporation into and utilization by the
tissues, glucose in a free stale being incapable of utilization. This com-
pound is supposed to be of a colloidal nature, and the substance which

THE METABOLISM 01 THJ I IBBOHYDRATEfi 661

combines with glucose to form it is believed to be related to the internal
secretion of the pancreas (see page 676 .

The difficulty in explaining why the glucose of the blood does uol con-
stantly leak into the kidnej is, however, the only evidence upon which the
hypothesis of a blood-sugar compound rests. No chemical evidence can
be offered in supporl of such ;i view. On the contrary, all experimental
work indicates that the sugar exists in a free state; but unfortunately even
this evidence is uot convincing. Thus, it has been found that, when Bpeci
mens of perfectly fresh blood are placed in a series of dialyzei sus-
pended in isotonic saline solutions, each solution containing a slightly dif-
ferent percentage of glucose, diffusion of glucose, in oi r other direction,

occurs in all of them Bave one namely, that in which the percentage of
glucose in the fluid outside the dialyzer is exactly equal to t lie total sugar

content of the blood. Such a result can I splained only by assuming that

all of the sugar in the blood exists in a freely diffusible state. In its general
nature this experiment is analogous to that by which the tension or partial
pressure of COa is determined in blood (see page 338 .

It has been assumed by many clinicians thai glycosuria may sometimes
become developed because the kidney fails to hold hack the blood sugar
even when the percentage is not above the normal- so-called renal dia-
betes. For the diagnosis of this condition a comparison must be made be-
tween the sugar concentration of the blood and that of the urine. In order
to do this a1 least tWO samples of blond must be taken, one of them at the

beginning and the other at the end of a period during which urine is being
collected. Merely to tind thai one sample of blood collected before or after
or during the period of urine collection contains a normal percenl g
sugar, docs not necessarily indicate that at some other period while the
urine was being produced a temporary hyperglycemia may not have ex-
isted.

CHAPTER LXXV
THE METABOLISM OF THE CARBOHYDRATES (Cont'd)

FATE OF ABSORBED GLUCOSE. GLUCONEOGENESIS

We may now consider what becomes of the sugar that is retained by
the liver and muscles. Two things may happen to it: It may become
stored, or it may become oxidized or split up. Of these processes, storage
occurs in both the liver and muscles, whereas oxidation occurs mainly if
not entirely in the muscles, although a certain amount of splitting of the
glucose molecule may also occur in the liver.

Storage of Sugar. — For the present Ave shall consider the process of
storage of sugar and defer a consideration of its utilization until after we
have studied, not only the nature of the process by which the storage
occurs, but also the immediate destiny of the stored sugar. The storage
of sugar by the liver is brought about by its conversion into a polysac-
charide called glycogen. After an animal has been absorbing large quan-
tities of glucose, an acidified watery extract of a portion of liver made
immediately after death will be found to contain no more sugar than that
of a normal liver. On the other hand, it will be observed that the extract
is highly opalescent and yields on the addition of alcohol a copious precip-
itate, which on further purification can readily be shown to consist of a
polysaccharide — that is to say, of a starch-like substance which on hydrol-
ysis with mineral acid becomes entirely converted into sugar. If instead
of examining the liver immediately after death, it is allowed to stand for
some time, the yield of glycogen Avill greatly diminish, and in its place
will appear large quantities of glucose, indicating that some enzyme must
exist which attacks the glycogen after death and converts it into sugar,
This enzyme is called glycogenase. The existence of postmortem gh/co-
genolysis, as it is called, would seem to indicate that during life a con-
stant tendency for the glycogen in the liver to be attacked by glycogenase
is held in check by conditions which depend on the vital integrity of
the liver cell. It is evident that if anything should happen during life
to interfere with this inhibiting influence, the glycogen will become con-
verted into glucose, which on escaping into the blood will produce hyper-
glycemia and glycosuria.

Sources of Glycogen. — In studying the sources of sugar in the animal
body it is of great importance that we should first of all know exactly the

G62

•Mil. METABOLISM OF THE CARBOHYDRATES 663

conditions under which glycogen may be formed in the liver; thai is,
whether it is formed exclusively from absorbed sugar, or whether other
substances, such as protein and fa1 may also form it. The importance of
such knowledge rests in the fad thai in severe diabetes, sugar continues

to be added to the blood, although do sugar is being taken with the f I.

To check the hyperglycemia in such cases i1 becomes necessary, therefore,
to curtail the did uo1 only with regard to its carbohydrate content, bul
also with regard to whatever other foodstuff may be capable of causing
glycogen formation. The practical question therefore is. What arc these
foodstuffs? There are two methods by which the problem may be investi-
gated. The first, which we may call the direct method, consists iii rendering

the liver free of glycogen and then some time afterward £ ling the animal

with the foodstuff in question, afterward killing it and examining the liver
for glycogen. The other, which we may call the indirect method, con-
sists in first of all rendering the animal incapable of oxidizing glucose —
that is. making it diabetic — and then proceeding to see whether the in-
gestion of a given foodstuff causes an increase in the sugar exeretion in
the urine. The methods for rendering an animal experimentally diabetic
will he considered later; for the present it is important to note that, if
a diabetic animal excretes more glucose while fed on a given foodstuff.
we may infer that the normal animal would convert it into glycogen.

The results of the direct method are much less reliable than those of
the indirect for the reason that it is extremely difficult to remove all
traces of glycogen from the liver. The methods employed for this pur-
pose have consisted in: (1) starvation of the animal; (2) muscular ex-
ercise; (3) exercise and starvation combined; and (4) the production of
certain forms of experimental diabetes — for example, that produced by
phlorhizin. Starvation alone is unsatisfactory, for it has been found
that, although a1 certain stages of this condition the liver may become al-
most entirely free from any trace of glycogen, at a later stage glycog
may again make its appearance. It is therefore most difficult to decide
at what stage in starvation the animal should be considered as glycogen-

frec.

If the starving animal is made to perform muscular exercise, coin])1
removal of glycogen from the liver can be depended upon. The exer

may be produced by the administration of strychnine in such dosage as

just to produi nvulsions of the voluntary muscles without permanent

contraction of those of respiration. The most useful method, however.
consists in starving the animal for a few days and then placing it in a
cold, damp room, after giving it a cold hath. The evaporation of m
ture from the surface so cools the body down that the stores of glycogen
all become used up in the attempt to supply fuel for the production of

664 METABOLISM

sufficient heat to maintain the body temperature. This method can be
rendered still more certain in effecting a removal of all carbohydrate
from the body by giving the- animal phlorhizin every eight hours. Phlor-
hizin, as -we shall see, renders the animal diabetic.

After removing the glycogen, further deposition in the liver can be
readily shown to occur when any of the ordinary sugars or starches are
given as food. It does not occur, however, when chemical substances
closely related to ordinary sugar, such as the wood sugars (pentoses)
or the alcohols and acids corresponding to dextrose, are contained in the
diet. Nor does it occur with cellulose or with inulin, a polysaccharide
built up from pentose sugar. When proteins are fed the results are not
so definite, although many observers have claimed that glycogen is
formed. With fat, on the other hand, no glycogen formation can be
shown to occur, although we know that a trace of carbohydrate must be
formed out of the glycerine of the fat molecule.

The results of the direct method, even when the conditions are per-
fectly controlled, are very unreliable, especially when they are of a nega-
tive character, because any new sugar that may be produced by the in-
gested substance instead of being stored as glycogen is likely to be used
by the tissues as it is formed. Where only a slight degree of gluconeo-
genesis, as the process of sugar formation is called, is occurring, it is not
probable that any of the glucose will be retained in the body as glycogen.
The methods employed for producing experimental diabetes in investi-
gation of these problems by the indirect method are (1) the entire removal
of the pancreas, and (2) the continuous administration of the drug
phlorhizin. The animal rendered diabetic by either of these methods is
first of all observed for several days to determine the normal daily ex-
cretion of sugar. At the same time the nitrogen excretion for the day
is determined, the ratio between the total nitrogen and the glucose —
known as G to X ratio — being about 1 to 3.65 when complete diabetes
has become established. The foodstuff in question is then fed to the
animal, and the amount of extra glucose excreted thereby is taken to
represent that which has been derived from the ingested food. By this
method it has been possible to show that, not only the above mentioned
carbohydrates, but protein as well produce a xevy considerable quan-
tity of glucose in the animal body. Fats, however, yield only negative
results.

The indirect method has another great advantage over the direct in
that the results are much inure quantitative in character; for example,
Lusk and his pupils have been able to determine the amount of glucose
which can be produced by feeding certain of the building stones of the
protein molecule. The greal practical importance of such results in

THE METABOLIS Id OP 1 HE I &RBOHYDBATE8

the therapy of diabetes makes it advisable for us to go into the subject
a little more in detail here.

Dogs are rendered diabetic by phlorhizin after a cold bath and
exposure in a cold room. When all of the original glycogen in the
body lias been go1 rid of, as evidenced by the constancy of the l> to N
ratio in the daily quantities of urine excreted, the Bubstance under in-
vestigation is fed. It' this substance contains no nitrogen and causes no
change in the nitrogen excretion, any increase in thai of glucose must
obviously represenl the extenl to which the substance has become con-
verted into this sugar. On the other hand, it' the Bubstance itself con-
tains nitrogen, or if it causes a change in the excretion of nitrogen, it
becomes necessary to calculate how much of the excreted glucose may
have been derived from the body protein, assuming that this can form
glucose, and how much from the administered substance.*

Prom the results of this method it lias been an easy matter to show
that the following substances are converted in the animal body into
glucose: (1) Glycol aldehydi CH2OB CHO). By placing three mol-
ecules of this substance together, a hexose molecule results, a syntht
which can be accomplished in the chemical laboratory. The hexose formed
in the animal body is glucose. Glycol aldehyde may be formed in normal
metabolisi it of glycocoll <UI Nil COOB .

(2) Glycerol (CH20B CHOB < II "II may also readily he con-
verted into hexose in the laboratory, the -possible intermediary prod
being dioxyacetone (CH20B < '< » CH2OB and glyceric aldehyde
CHaOB CHOB CHO). Two molecules of either of these may be
polymerized to form a hexose molecule, and when this process occurs
in the animal body, the hexose formed is glucosi

3 Lactic acid (CB CHOB COOB is completely i verted to glu-
cose in the diabetic animal, and the pr ss must involve both a re-

arrangemenl of the molecule and subsequent polymerization. The relat
substance, propyl alcohol (CB CH, CH2OB is also converted
glucose in the phlorhizinized d< g. As to the exacl nature of the chemical
changes which occur as intermediary steps iii the conversion of t;
substances into glucose, we are nol as yel certain, hut a clue has
been afforded by the discover} that a sul>si;inee called methylglyoxal

• II COCHO can I btained from lactic acid ami also from glucose, ami

that this substance is converted into glucose when it is administered to phlor-
hizinizcd do>_rs. We shall find later an importanl role for this substance

riiis

dedu the nit: lie differ . ;i of the

body pro
which tin- sul

niitiK fi then he ascert.v

from the t>>- on.

666 METABOLISM

iii the case of fat metabolism. It can also readily be produced during
the intermediary breakdown of certain of the protein building-stones,
such for example as alanine (CH3dINH2COOH).

These chemical possibilities regarding the nature of the substances
that serve as stepping stones between the above sugar-forming sub-
stances and sugar itself may be considered as probabilities on account
of the discovery thai enzymes exisl in various tissues which are capable
of converting methylgloxal into lactic acid:

CH3 CH,

I I

CO + II., -» IICOH

0"<- |
CHO COOH

(methylglyoxal) (lactic acid)

These enzymes are called glyoxalases, and since the reactions which
they mediate are undoubtedly reversible in character, it is probable that
the conversion into sugar of lactic acid and alanine — to take those two
as among the commonest of the sugar precursors of the animal body —
occurs according to the following equation:

CH3CHNII.,COOH v

(alanine) CH..COCHO -» C6Hr,06

CH,CHOHCOOH /<

(lactic acid) (methylglyoxal) (hexose)

The unique position of methylglyoxal, besides explaining the known
resolutions of protein and fat and carbohydrate in intermediary metab-
olism, is also of importance in explaining the synthetic production of
glucose from fructose (or levulose). Fructose will first of all become
converted into methylglyoxal radicles, and these will then become syn-
thesized into glucose.

The hypothesis of 1 lie conversion of glucose into lactic acid as a stepping
stone in the metabolism of carbohydrate is difficult to test by direct ex-
periment because the lactic acid does not accumulate in the organism,
except in cases where there is oxygen deficiency or excess of alkali in the
tissue fluids.

Coming now to the amino acids, which, it will be remembered repre-
sent the building si ones of the protein molecule, it has been found that
trlycocoll, alanine, and aspartic and glutamic acids increase the glucose
excretion when t>iven to phlorhizinized dogs, whereas leucine and tyro-
sine have no such action. By the method described above, it is possible
to determine the exact proportion of the carbon of each of those amino
acids which becomes converted to glucose. This is shown in the accom-
panying table.

THE METABOLISM OF THE CABB0HYDBA1

T s Grams of the Various Amino Bodies Were Gives
Phlorhizin-diabetio Da

MOUNT

UAT

ACID AM' FORMl 1 A

■:. PRO-

< 1 1 A

DUCI D IN BODY

l>rn D B

Glycocoll

I'll Ml <'()(>l!

13.43
one

L5.77

All C converted

k..oo

i. alanine

(II CHNB rooii

18.77

i two dogs

« <

_ 22

Aspartic acid
COOH 'II. CHNHj

COOH

1J.1L'

( four di

Three of the f<nir
ted

•

13

Glutamic acid

1 ■ ")||

/

I'll
I

13.31

Tin-".- of the i;

12..'

r\\- CHNB
1

rooir

It is of further interest to point out that these four amino acids
constitute about 26 per cent of all the amino acids in flesh protein, and
that the total yield of glucose from them could be 26.3 grams; thus
accounting for uearly one half of the 66 grams which a diabetic animal
produces i'rom 100 grams of flesh.

Gluconeogenesis in Normal Animals.- Although it has been clearly

shown by the indirect method that uo1 only protein bul its d mp

tion products as well, can be readily converted into glucose, yet this does
not aecessarily indicate thai a similar conversion occurs in the nondia-
betic animal. That such is the case, however, can be shown in various
way- Thus, at the end of a period of long starvation a lerable
quantities of glycogen are quite commonly found in the body, and the
blood Bugar, although lower than normal, never entirely disap
Now, since no carbohydrate is being b - ;. and the body s "his

foodstuff become exhausted early during starvation (cf. pag . it

vident that the carbohydrate must be produced from the protein of
the animal's body. A still mor< avinci perimenl can be con-

ducted by producing strychnine convulsions in a starving animal. I
the animal is killed after the convulsions have Listed for a certain time,
the tissues will be found almost if not entirely fr< gen,

bul it' the convulsions arc made to disappear by giving chloral and the
animal allowed to sleep for some time before killing it. glycogen again
accumulates in the body. This glycogen musl l.a- n manufactu

out of noncarbohydrate material.

i orroborative evidence of :i somewhal different nature is furnished by

668 METABOLISM

an examination of the respiratory quotient, which, it will be remem-
bered (page 54.7), varies according to the nature of the foodstuff or body
constituent that is undergoing metabolism at the time, being about 1
with carbohydrate and about 0.7 with protein. If the quotient is
observed during starvation, it will often be found to fall below 0.7, a
figure which can be explained only by assuming that oxygen has been
in, lined in the body beyond the quantity which is necessary for imme-
diate purposes of oxidation (cf. equations on page 548).

Since it is known that this retained oxygen can not exist in the body
in a free state it must be concluded that it has become incorporated
into substances having a high oxygen content. Such would be the case
if protein or fat, which contains only from 12 to 20 per cent of oxygen,
were converted to carbohydrate, which contains about 53 per cent,
Utilization of inhaled oxygen for this purpose, as we have seen, becomes
very striking in the case of hibernating animals during the winter sleep.

CHAPTER I.X.WI

THE METABOLISM OF THE CARBOHYDRATES Cont'd

FATE OF GLYCOGEN

Having become familiar with the sources from which glycogen may
be derived, we may now proceed to study the fate of the glycogen found
in tlio liver cells and In the muscles. For the present we shall confine our
attention to the glycogen of the liver. If a portion of liver removed
from a well-fed animal is examined microscopically after staining either
with iodine or with carmine by Best's method, it will be found that the
cells of the lobules are filled with glycogen excepl for the nuclei, which
are free from this substance. If. on the other hand, the liver is from an
animal that has not been recently fed, the lobules will contain no glyco-
gen excepl in an area bordering on the central vein and perhaps a
narrow strip at the periphery of the lobule. When ii is present the rela-
tive amount of glycogen in different lobules, as determined chemically,

is 1 he same over tl ntire liver — thai is to say, no one lobe is richer in

this substance than another. Nothing definite is known as to how the
glycogen is held in the protoplasm of the cells, although some histolo-
gists suggesl that it is combined with a sustentacular material • ally

provided for this purpose.

The glycogen stored in the liver is gradually given up to the blood of
the hepatic vein at such a rate as to maintain in the blood of t;
temic circulation a more or less constant percentage of glucose. Under
ordinary conditions this process of glycogenolysis is relatively slow, but
when the requirements of the organism for fuel become increased, as
during muscular exercise, ii becomes very rapid. The glycogenic fu

tion of the liver appears therefore 1,. exist, in pari at l< - the

purpose of preventing the tl ling <>f the blood of tin mic circu-

lation with excess of siiLrar during absorption from the intestine and of
maintaining the normal percentage at other tin This function is

analogous to thai occurring in plants, in which the sugar produced in
the leaves, if not immediately required, is transported to various parts

of the plant and there converted in eh. which, when the plant

requires it. as during new growth, may again become transformed into
glucosi
The agency converting the glycogen into glucose is the diastatic

G70 METABOLISM

enzyme glycogenasc, which is present, not only in the liver cell, but
also in the blood and lymph. It is a difficult matter to explain why
glycogen should be able to exist at all in the liver cells in the presence
of this powerful enzyme. The following possibilities may be considered:
(1) That glycogenase does not really exist in the living liver cells, but
is a postmortem product; (2) that, although present, glycogenase is pre-
vented from acting on the glycogen in the living liver cell on account of
the latter being protected from ils influence by combination with a
sustentacular substance; or (3) that some chemical substance in the liver
cell prevents the glycogenase from acting on the glycogen — an anti-
glycogenase. Since the removal of any one of these inhibiting influ-
ences would cause glycogenolysis to become excessive, and so bring
about hyperglycemia, it is important, in searching for the possible
causes of this condition, to examine the evidence that has been brought
forward in support of each of these views.

Against the view that glycogenase is a postmortem product may be
cited the very rapid conversion into glucose that occurs when glycogen
is added to living blood, as by injecting some into a vein. On account of
the active glycogenolytic action of blood, it has been suggested that
during life glycogen does not become transformed into glucose until
after it has been discharged into the blood from the liver cell. When
increased sugar must be mobilized, glycogen passes unchanged, or per-
haps as some dextrine, into the blood and lymph of the liver capillaries
and lymphatics, the glycogenase of which converts it into glucose, the
conversion being so rapid that, by the time the blood has traveled from
the liver through the heart and pulmonary vessels to the arteries, all
the glycogen has already become transformed into glucose. Postmortem
ulycogenolysis, according to this viewr, is due to the opposite occur-
rence— the transference of glycogenase from the blood into the liver
cell. Some facts supporting this view are as follows: (1) It has been
found that the amount of free glucose in the blood of the vena cava
is sometimes less than in that collected simultaneously from the carotid
artery. (2) After giving certain substances, such as phosphorus or
peptone, there is distinct diminution in the amount of glycogen in the
Liver, accompanied, it is said, by no increase in the amount of glucose
in the blood. And (3) if the liver of an animal that has been rendered
diabetic by stimulation of the splanchnic nerve or by puncture of the
floor of the fourth ventricle is examined microscopically, after staining
by the carmine method, masses of stained glycogen can be found present
in the capillaries (sinusoids) that lie between the liver cells.

According to the second view, the glycogen is removed from the
influence of the intrahepatic glycogenase on account of its combination

Till METABOLISM OP Till CARBOHYDRATES <i71

with a sustentacular material. By <1 irrupt inv this combination and thus
exposing the glycogen to the action of glycogenase, glycogen \ ill

occur. We may call this the mechanical hypothesis and it d<
serious consideration, for it lias been shown thai very little postmortem
glycogenolysis occurs in tin- intact liver of Progs in winter, though

at this time the organ contains an excess of glycogen,- hut becomes
marked when the liver is broken down by mechanical means.

The third view depends on the well-known fad thai enzyme activities
become mosl markedly altered by slight changes in the <-li«-m i«-;il nal
of the environment in which they art. Diastatic enzymes are partic-
ularly susceptible i<> the reaction ■:<',,, of their environment, a very
slighl degree of acidity favoring and a trace of alkalinity markedly
depressing their activities. That a tendency to increasing acidity in
the liver cells may accelerate the breakdown of glycogen is suggested by
the depressing effect produced on the assimilation limit i sugars by
administering acids, and by the observation that postmortem crl ;
olysis becomes marked in proportion as the dying liver becomi 1 in

reaction. It mighl ho thought then that glycogenolysis in the 1 i \ •
could he set up by the local production of a certain amount of acid.
Such a liberation of free acid could he brought aboul by a curtailment
in the arterial blood supply of the hepatic cell, producing a local ac
mulation either of carbonic or of other less completely oxidize.] adds
g., lactic'. It may he that asphyxia causes hyperglycemia by such
a mechanism. Vasoconstriction and consequent curtailment of arterial

hi 1 supply occurs in the liver when the hepatic nerves are stimulated,

and it i^ possible that the glycogenolysis which is also s.-t up by such
stimulation is due to the appearance of acids. The accelerate [
of epinephrine on glycogenolysis mighl also he explained as due to
limitation of blood supply on account of vasoconstriction and local

asphyxia.

THE REGULATION OF THE BLOOD SUGAR LEVEL
Tin' level at which the concentration of BUgar in the dc blood

is maintained represents the balance between two opposing factoi>: 1

the consumption of glucose bv the tissues, and 2 the production
glucose by the liver, since this is the most readily oxidizable of all

the proximate principles (>f f l pi j . muscular activity

large quantities of it to he consumed hat its concentration in the

blood tends to fall below the physiological level, a tendency which is
immediately met by an increased discharge of glucose from the 1;
The question therefore arises as to how tin
transmit their requirements for glucosi i<> //<< liver. There are two

f>72 METABOLISM

possible ways by which this could be done: (1) by means of a nervous
reflex, or (-2) by changes in the composition of the blood, either with

regard to the percentage of sugar itself or because of the appearance in
it of decomposition products of glucose or of some special exciting
agent or hormone.

In order to ascertain the relative importance of these methods of
correlation between the places of supply and demand of glucose in the
normal animal, it is necessary to investigate the conditions under which
an excessive discharge of glucose occurs cither because of overstimulation
of the nervous control, or because of the presence of exciting substances
(hormones) in the blood. The glycogenic function can be excited through
the nervous system in a variety of ways so as to cause hyperglycemia
and glycosuria. This constitutes one form of experimental diabetes. In
laboratory animals mechanical irritation of the medulla oblongata and
stimulation of the great splanchnic nerves act in this way. Similar stimula-
tion may also occur under certain conditions in man. Excitation as a result
of changes in the composition of the blood can be produced experimen-
tally by certain drugs (phlorhiziri), or by the removal of certain of the
ductless glands or the injection of extracts prepared from them, such
as epinephrine.

Nerve Control and the Nervous Forms of Experimental Diabetes. —
The simplest experimental condition which illustrates the relationship
between the nervous system and the blood sugar is electrical stimulation
of the great splanchnic nerve in animals in which, by previous feeding
with carbohydrates, a large amount of glycogen has been deposited in
the liver. By examination of the blood as it is discharged into the vena
cava from the hepatic veins, the increase in blood sugar is very evident
in from five to ten minutes after the first application of the stimulus;
but it is not until later that a general hyperglycemia becomes estab-
lished. The conclusion which Ave may draw from these results is that
the splanchnic nerve contains efferent fibers controlling the rate at
which glycogen becomes converted to glucose in the liver. The center
from which these fibers originate is situated somewhere in the medulla
oblongata, for the irritation that is set up by puncturing this portion of
the nervous system with a needle yields results similar to those which
follow splanchnic stimulation. This "glycogenic" or diabetic center, as
it has been called, must be provided with afferent impulses. Such im-
pulses have indeed been described in the vagus nerves, but their dem-
onstration is by no means an easy matter on account of the disturbance
in the respiratory movements coincidently produced by the stimulation.
The changes that such disturbances bring aboul in the aeration of the

Tin mi TABOl [8M OF Tin: CAftBOfiYDBAtES

blood may in themselves be responsible for the hyperglycemia see pi
332). 1 1 can .-it leasl be said thai when the respiratory disturbances are
guarded against, as by intratracheal insufflation of oxygen, vagal hyp
glycemia is much less marked, if nol entirely absent. But ihis question
awaits more thorough investigation.

Tlio increased glycogenolysis which results from stimulation of the
efferent filters in the splanchnic oerves maj depend either on a direcl
control exercised over the glycogenic functions of the hepatic cells, or
on the discharge into the blood of some hormone which excites the
glycogenolytic process. It must furthermore ool be lost sight of thai

the glycogenolysis may be s Ldary to local asphyxia] conditions in

the liver cells resulting from vasoconstriction. Prom their anatomic
Position, the adrenals are to be thought of as the source of the hormo
and evidence that splanchnic hyperglycemia is due to hyp, tion

from these glands has seemed to be furnished by the fact that after they
are extirpated splanchnic stimulation no longer produces hyperglycemia,
neither, indeed, does puncture of the medulla. There is also no doubt
that the nervous system, acting by way of the splanchnic nerves, does
exercise a control over the discharge of the internal secretion of the
adrenal glands and that extracts of the eland, which we must BUppose
aet in the same May as the internal secretion, cause hyperglycemia when
injected intravenously (epinephine hyperglycemia and glycosuria .

Bu1 on theoretical grounds alone, certain difficulties immediately pre-
sent themselves in accepting this as the mechanism by which the nervous

system controls the BUgar output of the liver, for if increased BUgar

formation in the liver is dependent on a discharge of epinephrine, the

question may be asked why this Secretion should be caused to trav<

the entire circulation before reaching the liver.

There are, besides, certain experimental facts which do nut conform
with such a view. Thus, after complete severance of the hepatic plexus
of aerves, stimulation of the splanchnic nerve docs not cause the usual
degree of hyperglycemia, whereas electric stimulation of the peripheral

end of the cut plexus docs cause it. (Mi the one hand, therefore, t!

is evidence that stimulation of the efferent nerve path above the level of

the adrenals has no effect on the sugar production of the liver in the

absence of these glands; and on the other, we see that when they are
present, stimulation of the nerve supply of the liver is effective, even
though the point of stimulation is beyond them. There is but con-

clusion that we may draw namely, that the functional integrity of the

efferent nerve libers that control the glycogenolytic process of the liver

depends on the presence of the adrenals, very probably because of the
hormone which the glands secrete into the blood. This conclusion is

til 4 METABOLISM

corroborated by the Eacl that stimulation of tlie hepatic plexus, even
with a strong electric current, some time after complete removal of
both adrenals, is not followed by the usual degree of excitement of the
glycogenolytic process.

These experiments demonstrate an important relationship between
the nervous control, and at least one form of hormone control, of the
sugar output of the liver. They indicate that when a sudden increase
of blood sugar is required, the glycogenic center sends out impulses
which not only directly excite the breakdown of glycogen in the he-
patic cells, but also simultaneously influence the adrenals in such a man-
ner as to produce more epinephrine in the blood and so augment the ac-
tion of the nerve impulse.

AVe are as yet quite in the dark as to the mechanism by which the
nerve impulses or the hormone brings about increased glycogenolysis.
It must consist of a removal of the influence that prevents glycogenolysis
from occurring in the normal liver, for it has been shown by direct ob-
servation that there is no increase in the amount of glycogenase present
in extracts of the liver removed from diabetic animals over that present
in extracts of the liver of normal animals. The possible nature of this
influence has already been discussed (page 669). The change may con-
sist either in a loosening of the combination between the glycogen and
the protoplasm of the liver cell, or in a removal of the chemical influence
that ordinarily prevents the glycogenase from attacking the glycogen.
In the former case the glycogen liberated from its union with the sus-
tentacular substances would either become attacked by the glycogenase
present in the liver cell itself or it would first of all migrate, as glyco-
gen, into the blood capillaries and there be attacked by the blood
glycogenase. Evidence for the possibility of the occurrence of such a
process has already been given (page 670). The chemical change re-
ferred to under the second possibility might consist in an alteration in
the hydrogen-ion concentration of the liver cell, a change, however,
which for obvious reasons it is impossible to investigate.

Nervous Diabetes in Man. — The main interest attaching to the inves-
tigation of these nervous forms of experimental diabetes depends on the
insight which they afford us into the nature of the mechanism by which
a prompt mobilization of glucose may be brought about in the normal
animal. There is also some evidence that a relationship may exist be-
tween certain of the clinical varieties of the disease in man and repeated
excitation of glycogenolysis brought about by nerve stimulation. In-
creased glucose output from the liver as a result of nerve excitation
may be a normal process, but there is reason to believe that frequent
repetition of this process tends to induce a permanent rise in the glucose

THE Ml TABOLTSM OP I Hi CARBOHYDRAI

level of ili»' blood ;in<l therefore a tendency to diabetes. There have
recently been collected several facts which lend Bome Bupporl t<> 1 1 1 i -•
view. The frequenl occurrence of diabetes in those predisposed by
inheritance t<> neurotic conditions, or in those whose daily habits entail
much nerve strain, and the aggravation of the Bymptoms which is lil i
to follow when a diabetic patienl experiences some oervoua shock, all
point in this direction.

Diabetes is common in locomotive engineers ami in the captains

ocean liners thai is, in men who in the performan i' their daily duties

are frequently pu1 under a severe nerve strain. It is apparently in-
creasing in men engaged in occupations that demand mental concentra-
tion and strain. Buch as in professional and business work. Canno
found glycosuria in four ou1 of nine students after a severe examination,
bul only in one of them after an easier examination.* In the urines of
twenty-four members of a famous football squad, sugar was found p
-•lit in twelve immediately after a keenly contested game. Anxiety and

excitement must have been responsible for it-- appearai since five of

the twelve players were substitutes who did uot gel into the game.

Although these nervous conditions, by excitement of hepatic glyco-
genosis, produce at first uothing more than an excessive discharge of
sugar into the blood — a condition which is exactly duplicated in our
laboratory experiments by stimulation of the nerve supply of the liver —
their repetition may gradually lead to the development of a permat
form of hyperglycemia. To prevenl the repetition of these transient
hyperglycemias musl be one of our aims in the treatment of early •' _
of the disease.

Although there can be no doubl thai the glycogenic function of the
liver is subject tn nerve control, it is probable that its control by I
mones is of equal if no1 greater importance. This dual control of a
glandular mechanism is by no means unique for the glycogenic functi
for we have already sen it to exisl in the case of thi ric glands

and the pancreas, and i1 is probable thai ii also exists in tl
the thyroid. It may well be that the nerve control "t' the glycogenic
function 1ms to do only with those transitory cha gea juj luc-

ti.ui that would be demanded by sudden activities nt* muscle, and that
the hormone control has in do with the more permanent pr< ' build-

ing up ami breaking down nt" glycogen to meet the general olic

requirements of the tissn

' \\ . I unable i m Ihia

•H76 METABOLISM

HORMONE CONTROL AND PERMANENT DIABETES

Nervous excitation can explain only transitory increases in blood sugar,
the more permanent hyperglycemias being dependent upon some dis-
turbance in the hormone control of carbohydrate utilization. This dis-
turbance is a much more serious affair than that produced by nervous
excitation. In the latter case the hyperglycemia ceases -whenever all
of the glycogen stores of the liver have been exhausted; whereas a dis-
turbance in the hormone control, besides causing as its first step a
breakdown of all the available glycogen, goes on to cause a production
of sugar out of protein. A process of gluconeogenesis (new formation
of glucose) becomes superadded on one of glycogenolysis.

To ascertain the nature of this hormone and the mechanism of its
action has been the object of most of the researches on those forms of
diabetes that are produced by changes in certain of the ductless glands.
The following possibilities may be considered: (1) that the controlling
agency is the concentration of glucose in the blood; (2) that it is the
presence in the blood of decomposition products of glucose; (3) that it
is due to a special hormone produced from some ductless gland. Con-
cerning the first of these possibilities, it is supposed that the mechanism
involved is dependent on the law of mass action; namely, that glycogen be-
comes converted into glucose whenever the blood flowing to the liver con-
tains less than its normal concentration of glucose, and conversely, when this
blood contains an excess of glucose, as during absorption, that a glycogen-
building process occurs. Although there can be little doubt that the process
of glycogen formation or destruction will depend to a certain extent
upon the amount of glucose present in the blood flowing to the liver
cells, yet it is impossible that this can be an important means in the
control that exists between sugar production by the liver and sugar
consumption by the tissues, because the sugar that is added to the portal
blood during absorption would mask any depletion caused by sugar
consumption in the tissues.

The second possibility — that the hormone is some decomposition prod-
uct of glucose — would appear to have some support, if we consider this
hormone to be an acid product (carbon dioxide or lactic acid) produced by
sugar metabolism, for it is known that an increase in the hydrogen-ion
concentration of the blood flowing to the liver cells excites a glycogen-
olysis. As we have already seen, however, it is difficult to secure ex-
perimental evidence, in anesthetized animals at least, that glycogen-
olytic, activity is readily excited in this way.

The third possibility — that some specific hormone may exist in the
blood exciting the glycogenolytic process — is investigated by producing

I in METABOLISM OP THE C \KK«>m DRAT] -

*

disturbances involving various of the ductli ands, particularly the

pancreas, the adrenals, the parathyroids and the pituitary. The influ-
ence of certain of these glands may be closely bound up with thai
exercised through the nervous control, as we have seen to be the c
with the adrenal gland. Whether it is by the production of hormo
directly necessary for proper carbohydrate metabolism, or by I
moval fit »m the blood of Buch substances as interfere with this p
that the ductless glands functionate, is one of the main problems
have i" consider.

Utilization of Glucose in Tissues. Although the experimental diab<
induced by disturbances in the function of the ductless glands is dependent
in ilic first instance on an upset of the glj oogenic function and later on glu-
coneogenesis, the utilization of glucose in the tissues ultimately 1"
interfered with. It is therefore important thai we should dig »r a

momenl to consider briefly whal is known regarding ilic process by

which sugar becomes utilized in the organism. Tlmt glucose 1 mes

used it]) by active muscle there can be no doubt. Thus, if the muscles
of one leg in the frog are tetanized, the glycogen content, compared with
thai of the other leg, will be found to be diminished.

At first sight it mighl appear thai the easiest way to study the utiliza-
tion of glucose in the muscles would be to compare its concentrations
in the Mood flowing to and coming from the muscle. The muscle that
has been most successfully employed in studies of this kind has been the
heart. Some years ago Starling and Knowlton" examined the consump-
tion of sugar by the excised mammalian heart, and in their earlier
experiments seemed to be aide to show that the extent to which this
consumption occurred was I milligrams per gram heart muscle per
hour. A more thorough repetition of tli^s, ■ experiments later by Pat-
terson and Starling28 showed, however, that the results can furnish no

criterion of the actual consumption of glucose by the tissue ,,.j a unt

of the fad that the tissue itself may store away large quantil -
carbohydrate in an unused state i.e., as glycogen.

Other in\ estimators have thought to study the utilization of glue

by observing the pate at which it disappears from drawn blood kept i'i

a Sterile condition at bodj temperature for some hours after death.

This process is failed glycolysis, and it has been assumed that the :

iinilar to that which occurs in the tissues themselves an assumpl
however, for which there is no warranty. Indeed, it may readily be
shown that the glycolysis occurring in blood has very little if anything
to do with the utilization of sugar in the tissues, for it has b und

that glucose disappears from drawn blood very slowly indeed when

678 METABOLISM

compared with the rate at which it disappears from the blood of animals
in which the addition of glucose from the liver lias been prevented by-
removal of this viscus (Macleod).2G

A third method for studying the utilization of glucose consists in
observing the respiratory exchangi of animals. In normal animals the
injection of glucose causes an increase in the carbon-dioxide excretion
and a rise in the respiratory quotient, which it will he remembered is
a ratio expressing the relationship between the amount of carbon dioxide
excreted and of the oxygen retained in the organism. When carbohy-
drate is undergoing combustion, the quotient is nearly 1, whereas with
that of protein it is about 0.7 (sec page 547). By observing the quotient
under given conditions one can compute the proportions of carbohydrate
and of fat and protein that are undergoing metabolism. In the hands
of Murlin and others,27 this method has proved of some value in settling
certain questions concerning the utilization of glucose in normal and
diabetic animals; but the results must be interpreted with great care on
account of the fact that temporary changes in the blood may cause a
greater or a less expulsion of carbon dioxide from it. Thus, if acids
appear in the blood, they will dislodge carbon dioxide and apparently
cause the respiratory quotient to rise. Alkalies, on the other hand, Ap-
parently cause the quotient temporarily to fall, and unless the observa-
tions are done over a long period of time and with great care, fault?
conclusions are very apt to be drawn from the results.

Diabetes and the Ductless Glands

AVe are now in a position to consider the forms of experimental dia-
betes produced by disturbances in the ductless glands.

Relationship of the Pancreas to Sugar Metabolism. — In no other of
the many causes of diabetes has greater interest been shown than in
that due to disturbance in the pancreatic function. Many of the earlier
clinicians who followed cases of diabetes mellitus into the postmortem
room, noted that definite morbid changes in the pancreas were a fre-
quent accompaniment of the disease. Prompted by these observations,
several investigators attempted experimental extirpation of the gland,
but did not succeed in producing glycosuria in the few animals that
survived the operation. Their failure, no doubt, was due to incom-
plete extirpation. To reduce the severity of 1he operation, Claude Ber-
nard injected oil into the pancreatic duct, and tied it; but he succeeded
in keeping only two dogs alive for any length of time, and these did
not exhibit glycosuria. Neither were other investigators that adopted
similar methods any more successful. It looked us if the pancreas bad
very little to do with the cause of diabetes. In the year L889 Minkowski

i III METABOLISM OP 1 HE < ABBOHYDBA I

and von Mering in Germany, and de Dominicis in Etaly, by thorough
extirpation of the gland, succeeded in producing in dogs a marked and
persistent glycosuria, accompanied by many of the other symptoms of

diabetes. The first two authors attributed the idition to removal of

an internal secretion.

The course of the diabetes thus produced is. however, somewhat diffi
cut from thai usually observed in man. It is extremely acute from the
start, tlic (!: X ratio being 1 Mt'> (see page 664 . and it is unaccompanied
by any of the classical symptoms Been in tin- clinical « • < n i « 1 i t i < > n . Exp<
mental pancreatic diabetes can, however, be made to simulate very clos
tin- disease in man. This was first of all demonstrated by Sandeme

•

who found that it' the greater part of tic- pancreas was removed, tin1
animals I'm- some months, if at all. were only occasionally glycosuric,
lmt later became more and mure frequently so, until at last the conditi
t ypical of complete pancreatectomy supervened. Similar results 1
nnne recently been obtained by Thiroloix ami Jacob, in Prance, ai •! by
Allen in this country. These investigators poinl out that differenl
suits are to he expected according to whether the portion <»f panci
which is left does, >>v does not. remain in connection with the duodenal
duct. When this dud is Ligated, atrophy of any remnant of panel
that is left is bound to occur, ami this is associated with rapid emacia-
tion of the animal, diabetes ami death. When the remnant surrounds a
still patent duct, a condition much more closely simulating diabetes in
man is likely to become developed one. namely, in which there is.
some months following the operation, a more or h-sS mild diabel
which, however, usually passes later into the fatal type.

It is. of course, difficult to state accurately what proportion o
pancreas must he Left in or, in- that the above described condition may super-
vene. Leaving a remnant amounting to from one-fifth to one-eighth
of the entire gland is commonly followed by a mild diabetes, wher
if only one-ninth or less is left, a rapidly fatal typ - As in

clinical experience, the distinguishing feature between the mild ami the

ere types of experimental pancreatic diabetes is the tolerant
carbohydrates. In the mild form, no glycosuria develops unless rbo-

hydrate food is taken: in the severe form, it is pies. -lit when the diet is

composed entirely of flesh. It is thus shown that "by removal o
suitable proportion of the pancreas, it is possible to bring an animal
to the verge of diabetes, ye1 to know that the animal will n<
become diabetic. . . . Such animals, therefor valuable

objects tor jnd'_riiiLr the effects of various agencies with
diabetes" A.llcn It therefore becomes theoretically possible to in-

vestigate, on the one hand, other conditions whirl) will have an inHii-

680 METABOLISM

similar to removal of more of the gland, or, on the other, conditions
which might prevent the incidence of diabetes, even though this extra
portion of pancreas is removed.

From the work which lie has already done, Allen believes that he has
sufficient evidence to show that the continued feeding Avith excess of
carbohydrate food will surely convert a mild into a severe case, and in
one experiment he succeeded in bringing about the same transition by
performing puncture of the medulla — that is, by creating an irritative
nervous lesion. By none of the other means usually employed to produce
experimental glycosuria could the bordering case be made diabetic,
although one such animal became acutely diabetic after ligature of the
portal vein. To the clinical worker the value of these results lies in the
fact that they furnish experimental proof that a so-called latent case
of diabetes — thai is, one that has a low tolerance value for carbohy-
drates— may be prevented from developing into a severe case by proper
control of the diet. Attempts to show whether or not there are any
conditions which might bring about improvements in animals that were
just diabetic have not as yet been sufficiently made to warrant any con-
clusions that could help us in the treatment of human cases. The en-
couragement of the internal pancreatic secretion by diminution of the
secretion into the intestine may be of value.

The certainty with which diabetes results from pancreatectomy in dogs,
as well as the frequent occurrence of demonstrable lesions in the pan-
creas in diabetes in man, leaves no doubt that this gland must be in some
way essential in the physiologic breakdown of carbohydrates in the
normal animal, but how, Ave can not at present tell. All we know is
that the first change to occur after the gland is removed is a sweeping
out of all but a trace of the glycogen of the liver, although the muscles may
retain theirs; indeed, in the cardiac muscle there may be more than
the usual amount. 2S Nor can any glycogen be stored in the liver when
excess of carbohydrates is fed. After the glycogen has disappeared,
gluconeogenesis sets in, so that the tissues come to melt away into sugar,
and all the symptoms of acute starvation, associated with certain others
that are possibly due to a toxic action of the excess of sugar or other
abnormal products in the blood, make their appearance.

So far it might be permissible to consider an overproduction of glu-
cose as the sole cause of the hyperglycemia of pancreatic diabetes, just as
Ave have seen it to be of these forms of hyperglycemia that are due to
stimulation of the nervous system; but this can not be the case, for
another very definite abnormality in metabolism becomes evident —
namely, an inability of the 1 issues to burn sugar. This fact is ascer-
tained by observing the respiratory quotient. When glucose is added

THE METABOLISM OF THE CABBOHTDSA1 681

to the blood in the case of a completely diabetic animal, no chai
cms in the quotient.

There are, therefore, two essential disturbances of carbohydrate
metabolism in pancreatic diabetes -overproduction ol r and aboli-

tion of the ability of the tissues to ase it. It becomes important for us
to Bee whether the tissues exhibil this inability to us.- Bugar when t;
are isolated from the animal; for if they Bhould, a much mo rching

investigation of the essential cause of their inability would 1"' possible
than is the case when they are functioning along with the other organs
and tissues. The earlier experiments of L6pine and his pupils, which Beemed
to show thai diabetic blood did nol possess the glycolytic power of
normal blood; and those of Cohnheim, from which it was concluded that
mixtures of the expressed juices of muscle (liver) and pancreas, although
ordinarily destroying glucose, failed to do so when they were taken from
a diabetic animal, are now known to be erroneous.

The failure to show a depression of glycolytic power by these methods
prompted Knowlton and Starling24 to investigate the question whether
any difference is evident in the rate with which glucose disappears Prom

a mixture <>f hi 1 and saline solution used to perfuse a heaii outside

the body, according to whether the hear! was from a normal or a dia-
betic dog. In the first series of observations which these workers made.

it was thoughl that the normal heart used glucose at the pate of ahout
i m<_r. pei' gram of heart substance per hour: whereas that <<\ a dia-
betic (depancreatized) animal used less than 1 mg. If such Btriking
differences in the rate of sugar consumption could make themselves

manifest \\>v SO relatively small a mass of muscular tissue as that of the

heart, it is permissible to assume that a much more striking din*
could he demonstrated when the perfusion fluid is made to traverse all
oi- practically all of the skeletal muscles, as well ;is the heart. For this
purpose an eviscerated animal max- he employed that is, one in which
the abdominal viscera are removed after ligation of the celiac axis and
mesenteric arteries, and the liver is eliminated by mass ligation of its
lobes. rsim_r such preparations, R »> Pearce and Macleod ' found that

the rate at which glucose disappears from the blood, although \

irregular, is in no way differenl in completely diabetic

with normal ihejs. They were thus unable to confirm any of Knowlton

and Starling's earlier conclusions. Patterson and Starling subsequently

pointed out that a serious error was involved in the earlier perfus
experiments, partly on accounl of a remarkable but irregular dis
pearance ^( glucose from the lungs, and partly because the diabetic

heart may contain a considerable <\ f glycogen, from which its

HS12 METABOLISM

demands for sugar may be met without calling on that of the perfusion
fluid.

In spite of the failure to show that the isolated tissues of diabetic
animals have a lower glucose-consuming power than those of normal
animals, it is important from a practical standpoint that Ave should
know something regarding the possible nature of the disturbance which
a removal of the pancreas entails. Even if we could not tell exactly
how this disturbance operates, it would be of value to know whether
it depends on the removal from the organism of some hormone that is
essential to carbohydrate utilization, for, if this Avere proved to be the
case, encouragement Avould be offered to seek for the chemical nature
of this hormone so that Ave might administer it with the object of re-
moving the diabetic state. The hope of a fruitful outcome of such an
investigation is encouraged by the success of researches on diseases of
other ductless glands, particularly the thyroid.

The remoA'al of some hormone necessary for proper sugar metab-
olism is, however, by no means the only way by which the results can
be explained, for Ave can assume that the pancreas OAves its influence
over sugar metabolism to some change occurring in the composition of
the blood as this circulates through the gland — a change Avhich is de-
pendent on the integrity of the gland and not on any one enzyme or
hormone which it produces. It is obvious that the results of remoA^al
of the gland could be explained in terms of either A'ieAv, and indeed
there is but one experiment which would permit us to decide Avhich of
them is correct. This consists in seeing Avhether the symptoms which
folloAv pancreatectomy are removed, and a normal condition reestab-
lished, when means are taken to supply the supposed missing internal
secretion to the organism; if they should be, conclusive evidence would
be furnished that it is by "internal secretion" and not by "local in-
fluence" that the gland functionates.

The experiments have been of tAvo types: in the one, variously pre-
pared extracts of the glands have been employed, and in the other,
blood which is presumably rich in the internal secretion. The most
recent work with pancreatic extracts has sIioavu that injection of pan-
creatic extracts into a depancreatized animal produces no change in the
respiratory quotient, although injections of extracts of pancreas and
duodenum may cause a temporary fall in the dextrose excretion in
the urine on account of the alkalinity of the extract. Neither have
experiments with blood transfusions yielded results that are any more
satisfactory. In undertaking these experiments it is of course assumed
thai the internal secretion is present in the blood, and that if this blood
is supplied to an animal suffering Prom diabetes because of the loss of

I III Mi i UBOLIS M OP i III I ARBOHYDB \ I

its pancreas, it will restore it to a nondiabetic stale. The al con-

clusion thai may be drawn from the numerous researches of this nature
is thai tlinc is no evidence thai the blood of a normal animal, e
when it is from the pancreatic vein, contains an internal secretion that
can restore to a diabetic animal any of its losl power to utilize carbo-
hydrates. When the extent of glycosuria alone is used as the criterion
iif the state of carbohydrate metabolism, serious errors in judgmenl are

liable t<> be drawn. The condition of the blood mcmt ami the extent

ami character of the respiratory exchange arc the mosl reliable [nde:

DIABETIC ACIDOSIS OR KETOSIS

Nature and Cause. Much confusion lias existed in medical literature
over the correcl definition of acidosis, mainly because the term was firsl
used for the particular variety of the condition observed in th<
stages of diabetes mellitus. The acids which accumulate in the ti-
fluids in this disease arc acetoacetic ami /8-oxybutyric, which are re-
lated to acetone ami are derived from fatty acids by a faulty metabo-
lism i see pane 709). The essential cause of the acidosis is therefore
entirely different from that in nephritis; in diabetes foreign acids are
added to the blood, whereas iii nephritis the acids of a normal metabo-
lism accumulate because of faulty excretion through the kidneys. The
usual siLrns nt' acidosis exist in both cases, because the surplus of acid

depletes ihc store of 1 >ica rl 1011a I e and causes changes in the al-
ar < <> . in the C02-absorbing power of the blood, in the reserve al-
kalinity, and in the acid excretion by the kidney. It is important t.>
recognize the special nature of diabetic acidosis by a separate name —
l,i tosis.

The chemical processes by which the ketone bodies are produced is
discussed elsewhere (page T « ^ * . It remains for us to consider the
general nature of the metabolic disturbance responsible for their ap-
pearance in diabetes.

For the thorough combustion of fat in the animal body a certain
amounl of carbohydrate must be simultaneously burned. Fat evidently
is a hss readily oxidized foodstuff than sugar; it needs the tire of the
burning sugar to consume it. If the carbohydrate fires do not burn
briskly enough, the fal is incompletely consumed; it smo
and the smoke is represented in metabolism by the ketones and der
acids. Such a closing <lown of the carbohydrate furnaces may
brought aboul either by curtailment of the intake of carbohydral
in starvation (page 569), >t bj Home fault in the mechanism of the
furnace itself, as in diabetes Besides fat, protein may als tribute

684 METABOLISM

to the production of ketones when carbohydrate combustion is de-
pressed. Fundamentally, therefore ketosis in diabetes is due to the
same cause as in starvation — namely, an improper adjustment between
the metabolisms of fat and carbohydrate.

Bearing these principles in mind, it is easy to see how the intensity
of acidosis which develops during starvation will depend upon the re-
lative metabolism of carbohydrate, on the one hand, and of fat and
protein, on the other; it will therefore depend on the amounts of these
foodstuffs which have been stored in the organism, and this again will
depend on the nature of the diet previous to the starvation period. For
the first few days following entire abstinence from food in a healthy,
well-nourished individual, very few if any ketones will be excreted in
the urine, because the carbohydrate stored in the body as glycogen has
sufficed during this time to maintain the proper proportion between fat
and carbohydrate. Afterwards, however, their appearance is to be ex-
pected, because the glycogen stores become exhausted long before those
of fat. If starvation is still further prolonged, a stage will come when
the. fat. as well as the carbohydrate, is used up so that the organism has
now to subsist on protein alone. When this stage arrives, the ketones
will diminish, for, although they might be derived from certain of the
amino acids, yet this does not actually occur, because a large part of the
protein molecule (nearly half) also becomes changed into glucose, which
by burning, as above explained, prevents the formation of ketones from
the other part of the molecule. For the same reasons, marked acidosis
will not be expected to occur during any stage of starvation in lean
persons, who from the start must utilize mainly their stored protein to
supply the fuel upon which to live.

In diabetes exactly the same principles apply, but to an organism in
which the ability to metabolize carbohydrate has been depressed, so that
"the maximum rate at which dextrose can be oxidized is fixed at some
level which is absolutely lower than in health."30 Therefore, since a cer-
tain proportionality must exist between the rates of combustion of fat
and carbohydrate, the diabetic can thoroughly oxidize less fat; in other
vords, an amount of fat which could readily be burned in a healthy body
is improperly burned by the diabetic, and ketones and their acids ac-
cumulate.

Starvation Treatment. — "In order to check a diabetic acidosis, it is
necessary to restore the proper ratio of fatty acid to glucose oxidation,
which can best be done by starvation, rest in bed and warmth. But this
treatment may not at first suffice, because wc have to deal not only with
the acidosis bodies derived from fat. but with those which can be derived
from protein on account of the diabetic organism having lost the power

Till \li i UJ01 ISM OF Till I &BOHYD&A I

even of burning the glucose which is derived from this foodstuff. Bj
persistence in the starvation, however, the ability of the organism to
utilize carbohydrate usually becomes bo fai I thai enough bun •

prevenl acidosis. Every <*a>e of diabetes can not,

to read in the same waj i<> starvation, the determining condition I »• • i 1 1 lt
Hi.' relation between the quantities of glycogen ami f;n 1 in the b

at tin- outset of tin' fasting period. This relationship depends on the
nature of the previous diet

To sum up. "fasting \\\\\ lower acidosis either in health or in diabeti
if it has the effecl of ^ 1 < > j > i > i 1 1 <_r a one-sided metabolism ami throwing the
lissii.v on a more nearly balanced ration of fatty acids ami glucose" —
(Woodyatl , A practical poinl may he noted here— namely, that ti
is likely to he more danger of serious acidosis developing during starva-
tion in fat than in lean diabetics. The importai our appreciation of
these facts in tlm starvation treatmenl of diabetes will he self-evident.

CHAPTER LXXVII

FAT METABOLISM

Before considering the physiology of fats, a few of the most essential
points regarding their chemistry may be of assistance.

THE CHEMISTRY OF FATTY SUBSTANCES

It is usual to classify all substances that are soluble in ether as lipoids.
They include fatty acids, neutral fats, cholesterols, cholesterol esters, and
phospholipids.

The fit tt>i acids belong to two main homologous series, which differ from
each other with regard to whether they are saturated or unsaturated. A
saturated fatty acid is typified by palmitic, whose formula is CH3-CH0-CH0-
CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH, or" CH3-
(CH2)14-COOH; that is to say it is a higher member of the series to which
acetic acid (CH3-COOII) belongs, differing from the latter in having four-
teen extra methyl radicles, each joined to its neighbor by one bond or satu-
rated linking on either side. Another member of this series is stearic, in
which there are sixteen extra CH2 groups (CH3(CH2)lr,-COOH). An un-
saturated fatty acid is oleic (CH,(CH2)7— CH29 = CH-(CH2)7-COOH).
Its unsaturation is represented in the formula by the double bond or
unsaturated linking, which it will be seen occupies a position in the mid-
dle of the molecule, the other methyl radicles being linked together by
single bonds.

The fatty acids readily combine with alkali to form soaps; thus,
CH3(CH2)14-COOH + KOH=CIT3(CH2)]4-COOK + H20, the reaction being

(palmitic acid) (soap)

analogous to that by which acetic acid forms an acetate with alkalies.
In place of being combined with alkali, the COOH (carboxyl) group of
fatty acids may combine with alcohols to form substances called esters.
Thus, acetic acid and ethyl alcohol form ethyl acetate,
CH3COO JH + OHi C2H5=CH ;COO-C2H, + H20. When the alcohol thus
(acetic (ethyl (ethyl acetate)

aeid) alcohol)
united with fatty aeid is glycerol (glycerine), in which there are three

686

PAT Ml TAB01 l-\!

<»II (hydroxyl) groups, the resulting ester called triglyceride is neu
trnl ful. Tripalmitin has the formula:

CH OOCC II
CH OOCC ii
CH, OOC-C H

By boiling neutral fats with alkali the fatty acid radicles are split «»ff
as soaps, 1 « • ; i \ i 1 1 >_r the glycerol. This process is called saponification, and
it may be effected in man} other ways, as for example by heating with
steam or by the action of special enzymes called lipases, which are widely
distributed in plants and animals.

The natural fats are usually a mixture of triglycerides, ;m<l their dif-
ferences in properties are dependent upon the relative amounts of fatty
acids present. The three mbsl important in animal fats arc tripalmitin,
t ristearin and triolein. Tt is essential in the study of fa1 metabolism that
we should know the mosl important methods by which the proportion of
fatty acids present in a mixed fat is determined. These methods are as
follows :

1. The melting point. Olein is liquid at 0° C; palmitic acid melts at
fiL'.U C: and stearic at (>!».:! ('. The solidity of animal fats depends

the proportion of olein. palmitin and stearin present. Mutton fat, for ex-
ample, is much stiffer than pig fat because it contains less olein and mere
stearin. The melting points of fats from different parts of the body may
also vary.

2. Tin acid unmix r indicates the amount of free fatty acid mixed with

the fat, and is determined by titrating a solution of a weighed quantity
the fa1 in alcohol with a N L0 alcoholic solution of K«>1I. phenolphtha-
lein being used as indicator.

:!. '/'!■• saponification valm indicates the total amount of fatty acid
present, both that which is free and that combined with glycerol. It is

determined by heating a weighed amount of fat with an exactly known

amount of alcoholic K(»ll determined by titration with standard acid .
After saponification is complete, titration of the mixture shows how much
alkali has 1 n used to combine with the fatty acid. This is the saponi-
fication value.

I //. ester valm indicate- the amount of fatty acid combined with
glycerol, and is obtained by subtracting the acid value from the saponi-
fication value.

Besides these there are two values, known as the iodine and the Reichl

Bfeiasl values, that are of importance because they depend on certain ci
iwti rist ■/" fatty-acid radu

688 METABOLISM

5. Thi iodine value indicates the amount of unsaturated fatty acids pres-
ent, or the number of double bonds. It depends on the fact that iodine,
like many other substances, is capable of directly attaching itself to the
fatty-acid chain wherever double bonds exist.

6. The Jit irln rl-Meissl value indicates the amount of volatile soluble
acid present in the fat. It is determined by first of all saponifying the
fat, then decomposing the soap by mixing it with mineral acid and dis-
tilling the liberated fatty acid, the distillate being collected in a known
amount of standard alkali and titrated. It is a value that is not of very
meat use in physiological investigations, but il is so in connection with
food chemistry. Since volatile acids are present in butter, the Reichert-
Meissl value helps us to distinguish between butter and margarine.

Fat is insoluble in water but soap is soluble, forming a colloidal solu-
tion which presents the phenomenon of surface aggregation of molecules.
This consists in the concentration of the soap both at the free surface of
the liquid, where a skin may form, and at the interfaces between the
soap solution and any undissolved particles present in it. This pellicle-
formation around the particles prevents them from running together so
that they remain suspended, thus forming an emulsion. An emulsion
may therefore be formed either of neutral fat of any other physically
similar substance. When fat itself is used, there is usually enough free
fatty acid admixed with it to make it unnecessary in forming the emul-
sion to do more than shake the fat with weak sodium-carbonate solution.
With other substances not containing any free fatty acid, some soaps
should be added. To preserve the emulsion it is often useful to add some
mucilage. In the emulsified state, neutral fats are much more readily
attacked by lipases than when they are present in an unemulsified state.
Thus, emulsified fats are "digested" by the relatively small amounts of
lipase present in the stomach, whereas neutral fats themselves are not so.

Fatty acids also exist in nature in combination not with the triatomic
alcohol, glycerol, but with monatomic alcohols such as cholesterol. These
cholesterol fats differ from the glycerol fats in being very resistant to-
wards enzymes and microorganisms. They are therefore used for pro-
tective purposes in the animal economy; for example, they occur in the
sebum, the secretion of the sebaceous glands, where they serve to moisten
the hairs and skin. They are also present in cells, in which it is prob-
able they take an important part in forming the skeleton of the cell.
Cholesterol is absorbed from the intestine; it is always present in the blood
both in plasma and in corpuscles; and it is an important constituent of bile,
from which it may separate out in the bile passages and form calculi
(gallstones).

In the cells themselves the lipoids are represented mainly by compounds

PAT METABOLISM

689

of it Bomewhat more complex structure namely, the phospholipid. As
their name indicates, these consist chemically of phosphoric acid combined
with neutral Cat and with a nitrogenous base, cholin. The beat known of
the phospholipid is lecithin, which Is w idely distributed in the animal body
(presenl in blood and bile as well as in all cells . Other phospholipid
present in nervous tissue are cephalin, cuorin and sphingomyelin. Tl
are various lecithins distinguished from one another by the fatty-acid
radicles which they contain. Distearyl-lecithin, for example, has the

formula:

CHt-0-OC(CH1)l,-CH

C|[ -O-OC CH . CH
teai ic acid I
cir.-o o

\ /

(glycerol) P

/ \
OK OCH, CH, N CH

(phosphoi i>'

aci.l) OH

(cholini

This complex molecule can readily be split up by hydrolysis (warming
with baryta water) into:

glycero-phosphoric acid, ('IT. -oil

I "
('II - oil

oir -o o
\ /

P ; choline, N

/ \

on oh

C ll/'il
i mi w ethyl anunoninm

oil

hydroxide) ; and fatty acida.

With hydrochloric aci.l, choline tonus a salt which readily forms ;i

double salt with platinic chloride Since this double salt forms chai

teristic crystals, it is used to identify ami separate lecithins. For quan-
titative purposes, however, it is more suitable to determine lecithin in-
directly by the amount of phosphoric acid present in an ethereal
tract of the organ or tU^im.

Evidence is constantly accumulating to show that lecithin is an I
tremely important constituent of cells; indeed, it srcnis to he the h •
mediate staire in the utilization of neutral fats hy protoplasm. Its p]

phorus also probably Berves as the source of this element for the con-
struction of nucleic acid i sec pa-_r'- 637 In nervous t - t is oft
associated with carbohydrate molecules (galactose . forming the sul»-
stance known as cerebrin. It may therefore have some role to play in
carbohvdrate metabolism. Some workers also attribute to lecithin an

690 MI'TAUOTJSM

important timet ion in the transference of substances through cell mem-
branes. When mixed with water it swells up by imbibition, and if crys-
talloids or other substances art' dissolved in the water, a means is offered
for bringing water-soluble and fat-soluble substances into intimate con-
tact.

DIGESTION OF FATS

A certain amount of fat, especially when it is in an emulsified condi-
tion, can be digested in the stomach by the lipase contained in the gas-
tric juice. Most of it, however, is digested in the small intestine, into
which as we have seen, it is gradually discharged suspended in the chyme.
For this intestinal digestion of fat both pancreatic juice and bile are nec-
essary. This is easily shown in the rabbit, in which the pancreatic duct
enters the intestine at a considerable distance below the bile duct. If the
mesentery is inspected during the absorption of fatty food, no fat in-
jection of the lymphatics will be noted between the bile and the pan-
creatic ducts but only below the latter. In the dog, in which both the bile
and the main pancreatic ducts enter the intestine at about the same level,
fat injection of the lymphatics starts at this point, but if the bile duct
(or rather the gall bladder) is transplanted at some distance down the
intestine, it will be found that the injection of the lymphatics with fat
occurs only below the new point of insertion of the bile duct.

Removal of the pancreas interferes very materially with the absorption
of fat. In man, for example, absence of the pancreatic juice alone di-
minishes the absorption of fat by 50 or 60 per cent. If the bile is also
absent, the diminution amounts to 80 or 90 per cent, and in such cases,
as is well known, the administration of bile or pancreas powder greatly
improves fat absorption. In the dog, although ligation of the pancreatic
duct apparently only slightly influences fat absorption, removal of the
pancreas itself greatly interferes with the process; from which fact some
observers have concluded that the pancreas, in addition to its external
secretion into the intestine, must produce an internal secretion into the
blood which has something to do with the efficient absorption of the
fat (Pratt, McClure and Vincent ,v ). It is. however, improbable that such an
hypothesis is necessary, for it is very likely that the moribund condi-
tion into which an animal is brought by extirpation of the pancreas,
adequately accounts for the suppression of the fat-absorbing function.

As to the relative roles of pancreatic juice and bile in the digestion of
fat, we know of course that in the pancreatic juice there exists a lipolytic
enzyme, lipase, which, under suitable conditions has the power of split-
ling neutral fat into fatty acids and glycerine. If bile is examined, no
lipolytic enzyme will be found in it. It is entirely inactive on fat, but

PAT Ml TABOMSM 691

if vve mix 1 » i I * * with fresh pancreatic juice, which by itself only slowly
digests Eat, we shall find thai the bile very materially increases the lipo-
lytic activity of the pancreatic juice, li has been found that the salts
of cholalic acid, the so-called bile salts, are th< stituents of bile

thai are responsible for this activation of lipase, this fad having bi
demonstrated with bile salts prepared in such a way thai then ■ no
possible chance of any other biliary constituenl being present as an
impurity. It is importanl to remember, however, that lipase itself be-
comes slowly activated on standing, which explains why it should be

that bile added to pancreatic juice thai has si 1 for some time, ha

less evident activating influence than bile added to fresh juice. It is
probable that the activating influence of bile salts is due to some physico-
chemical change induced in the digestion mixture.

< >ne may ask how it happens that, when bile and pancreatic juic
both absenl from the intestine, the fat which appeals in the feces is not
neutral fal bu1 fatty acid. The reason is that the neutral fat that has
escaped digestion in the small intestine becomes acted on by the intestinal
bacteria, particularly in the large intestine. Under these conditio
however, the fatty acid that is split off is tiol absorbed, because the
epithelium of the lower parts on the intestinal tract can not perform this
function.

Besides assisting the action of lipase, bile facilitates fat digestion in
other ways. Thus, by its containing alkali and mucin-like substai
it assists in the emulsification of fat. Although emulsification is no
sential part of fa1 absorption, yet it greatly facilitates the process by
breaking up the fa1 into small globules on which the lipase can act
much more efficiently. The alkali also combines with the fatty acids,
as they are liberated by the digestive process, to form water-soluble
s.»aps. which are readily absorbed by the epithelial cells. The bile salts
further assist in the solution of the fatty acids, and they lower the sur-
face tension ><\' fluids in which they are contained and so bring the fat
and lipase into closer itact.

ABSORPTION OF FATS

After its digestion fat lies in contacl with the intestinal border of the
epithelial cells as fatty acid and glycerine. The fatty arid is combi

either wilh alkali to form a water soluhle soap, or with bill - to

form a compound, which is also soluble. The glycerine and the dissol

fatty acids are separately absorbed into the epithelial cells of the in-
testine, in the protoplasm of which after the fatly acid has b<
\'\e^ from the alkali or bile Ball they 1 ome united or resynt

to form neutral fat. which graduallv finds iis way by the central lac-

692 METABOLISM

teals into the villi, and then by way of the lymphatics to the thoracic

duct.

The chemical explanation of the absorption of fat is very different from
that formerly held by histologists who maintained that the fine particles of
emulsified fa1 in the intestine penetrate by a mechanical process through
the striated border of the epithelial cell into its protoplasm. The histologic
evidence for this view seemed very convincing, for fine fat globules can
readily be seen in the epithelial cells of the intestine after fatty food
has been taken, while they are absent during starvation. These par-
ticles seemed to have passed directly from the intestinal canal into the
epithelial cells because, when the fat was stained with characteristic fat
stains before1 feeding it to the animal, the globules in the epithelial cells
were found to be similarly stained. The supporters of this mechanistic
view of fat absorption maintained that the appearance of the stained fat
globules in the epithelial cells could not be explained in any other way
than by supposing that the fat globules had wandered unbroken into
the epithelial cells. Such a conclusion is, however, unwarranted, for the
stains that are soluble in fat are also soluble in soap, so that when the
fat splits up, the stain will remain attached to the soap and be carried
along with it into the intestinal epithelium.

Absolute proof that the chemical theory is the correct one has been
supplied by a large number of experiments. The following may be
cited: (1) When the lymph flowing from the thoracic duct is examined
after feeding with fatty acids instead of neutral fat, it is found to contain
only neutral fat, indicating that a synthesis must have occurred between
glycerine and fatty acid during the absorption. The glycerine for this
synthesis is furnished from sources which will be described later. (2)
When an emulsion made partly of neutral fats and partly of some hy-
drocarbon, such as albolene, is fed and the feces are examined for these
substances, it has been found that all the fat but none of the hydrocar-
bon is absorbed; the feces contain all of the albolene but none of the fat.
This experiment supplies very strong evidence against the mechanistic
theory, for microscopic examination of the above described emulsion
shows the particles of neutral fat and hydrocarbon to be of exactly the
same size. (3) By examining the properties of the fatly substances in
the thoracic lymph collected during the absorption of such an emulsion
as thai described above, nothing but neutral fat has been found present.
(4) Similar results are obtained when wool fat, which is an ester of
cholesterol and fatty acid, is fed.

We may conclude that fatty substances which an insoluble in water or
(■(in no/ be changed by digestion into substances (soap) that ore soluble
in water, nn not absorb* <l, however like fat they may be in other particulars.

FAT METABOLISM

The chemical theory of Pa1 absorption further explains why there should
be such large quantities of soapy substances in the intestinal contents,
and also why the globules of fat presenl in the epithelial cells of the
intestine are so very much Smaller than those which lie on the surfi
the epithelium.

It mighl be objected to the conclusions just stated that, although unde-
tectable, there is really some essential physical difference between emul-
sified fat and emulsified hydrocarbon. En order entirely to prove tl
for the chemical theory, ii is necessary to feed a neutral fal | sing
some characteristic thai depends on the manner of union existing between
fatty acid and glycerine, and then to see whether it appears in an un-
changed idition in the thoracic duct. It" it does so, the fat must hi

been absorbed through the intestinal epithelium in an unbroken, unsapon-
ified condition, for it is unlikely that, in the resynthesis which occurs in
the intestinal epithelium, the fatty-acid molecules would reeombine with
the glycerine molecules in exactly the same manner as before.

There are, however, bul very \'rw qualities of neutral fats, apart from
those of the fatty acids which compose them, by which they can be char-
acterized. The most likely one is that of optical activity. None of the
ordinary fats is optically active, although from chemical considerations

it is quite < ceivable that Borne should be so. in order to obtain such a

fal Bloor" conducted numerous experiments with the esters of stearic
acid.* In a series of experiments Bloor fed isomannid-dilaurate, a syn-
thetic fat of dextrorotatory power and as readily absorbed as natural fats,
and by examination of the neutral fal present in the chyle flowing from
the thoracic duct, found no evidence of the dextrorotatory fat. This
confirms previous work by Frank, who found thai the ethyl esters of
tany acids are nol absorbed unchanged. The results tl\' both workers
emphasize the probability thai readily Baponifiable fatty-acid i si s <1"
not escape saponification under the favorable conditions of the normal
intestine. In other words, had the fats been absorbed unchanged,
would be required by the mechanistic theory of fal absorption, they

would have appeared in the chyle in optically active conditions.
These m08l important conclusions lead us to inqliit. a to

for the changi in fat during its absorption. It can nol be for the pur]
of preventing the absorption of undesirable fatty substai es, s as the
petroleum hydrocarbons or the wool fats, because such substanc
so rarely presenl in our food. It is most probable that the breakdo

• 1 '. loot
inc point

■

they lose on -

004 M ETABOLISM

and resynthesis of neutral fat occurs for the same reason that similar
processes occur during the absorption and assimilation of protein. It
-will be remembered thai protein is entirely disintegrated in the intestine
into its so-called building stones. These are absorbed separately into
the blood, -which carries them to the tissues, in which they become re-
synthesized to form Ihe body protein. And so it appears to be in the
case of fals. The process, in other -words, permits of the rearrangement
of fatty-acid molecules, as a result of which the newly formed fat is more
adaptable for use in Ihe organism. It comes to be more like the char-
acteristic fat of the animal. There may be another reason for the proc-
ess. It will be remembered that lecithins, -which constitute the most
important of Ihe fatty substances of the cell itself, are mixed glycerides —
that is to say, are compounds containing a variety of fatty acids. The
rearrangement of the molecules of neutral fat which occurs during ab-
sorption may be the first step in the transformation of fat into lecithin.

In order to throw further light on the question, Bloor has performed
a number of interesting experiments in which the chemical properties
of fats before and after absorption were compared. The criteria which
he took were melting point, iodine value, and mean molecular weight ;
the melting point representing the solidity of the fat, and the iodine
value, its degree of unsaturation — that is, the number of double links in
the fatty-acid chain. It was found that during absorption very con-
siderable changes occur in these two characteristics ; for example, when
fat with high melting point and Ioav iodine value Avas fed, the fat in the
thoracic lymph was of distinctly lower melting point and higher iodine
value. "When fat with a Ioav melting point and a high iodine value was
fed, the reverse change occurred, for the melting point of the thoracic
lymph fat Avas higher and the iodine value loAver. These results could
be explained as due in the first case to the addition of oleic acid to the
fat during its synthesis in the intestinal epithelium, and in the second
case to the addition of some saturated fatty acid.

When ;i fat consisting mainly of glyceride and saturated fatty acid,
but with a Ioav melting point, Avas fed, the addition of oleic acid Avas still
found to occur, as judged from the iodine value. This indicates that the
change is, not merely in order that the melting point of the absorbed fat
may be lowered, but also for some chemical reason. In a fourth series
of experiments, a lowering of iodine value occurred after feeding with
cod-liver oil, which contains a high percentage of glycerides of highly
unsaturated fatty acid.

Evidently, then, the intestine possesses the power of modifying Ihe com-
position of fat during its absorption, and this modification is apparently
of such a nature that it causes a change toward the production of a

PAT Mil UBOLISW

uniform chyle Eat, presumably characteristic of the animal body. I
changes are probably greater than could be produced by admixture
the absorbed fa1 presenl in the normal Easting chyle, but the Bource
the oleic acid or of the saturated acid required for this synthesis U
present unknown.

CI 1 A ITER LXXV1LI
FAT METABOLISM (Cont'd)

THE FAT OF BLOOD

Methods of Determination. — Normally the blood contains only a small
percentage of fat, but after a fatty meal it may contain so large an
amount that the fat actually rises to the surface of the blood like a cream.
By means of the ultramicroscope, examination of the blood in the dark
field after a fat-rich meal reveals the presence of glancing particles,
the so-called "fat dust." These particles are most abundant about six
hours after the meal has been taken, and they gradually disappear by
the twelfth hour. They do not appear after a meal when the thoracic
duct is ligated. They disappear when oxygen is bubbled through the
blood.

Fat dust has also been found abundantly present in the blood of em-
bryo guinea pigs at full time, but not in the mother's blood. This would
indicate that the placenta must have the power of taking the constitu-
ents of fat from the mother's blood and building them into fat, which
then passes into the blood of the fetus. The placenta under these condi-
tions acts like the mammary gland. In this connection it is of interest
that there is also much fat present in the blood of pregnant women. The
fat content of the placenta is, however, greater in the early stages of
pregnancy than later.

Although these facts have been known for some time, it has been
impossible, either on account of the large quantities of blood required
for a chemical examination or because of the difficulty in estimating
the amount of fat from the density of the "fat dust," to follow with any
great degree of accuracy the exact chemical changes that take place in
the fat of the blood. Recently, hoAvever, Bloor has succeeded in elab-
orating methods by which the fat content of the blood can be determined
with satisfactory accuracy in small quantities of blood, so that a con-
tinuous series of observations can be made over a considerable period.

The fat is extracted from the blood by an alcohol-ether mixture with moderate heat.
An aliquot portion of the filtrate is evaporated in the presence of sodium ethylate, which
saponifies the fat. The residue, consisting of soap, is well washed and then treated
with hydrochloric acid so as to precipitate the fatty acid. The density of the precipitate

696

PAT METABOLISM

thus produced is compared in an optical apparatus, called a nephclometer, with a
standard Bolution of tun milligrams of < 'l<-i<- acid treated in 1 1 1 < ■ Bame way. I ; • tatty
acids in human blood arc mainly oleic and palmitic.

Thr lecithin ami cholesterol max also I" estimated in the Bame blood extract.
lecithin tin' above exl racl of blood, after the removal of tin' alcohol ami ether, is <li;_"
1 iy heating with concentrated BNO and H 804. Thia decomposes the lecithin, liben •
the phosphorus, a solution of the res ilting ash being rendered faintly alkaline to phenol-
phthalein and then bIowI) added to a Bilver nitrate Bolution. The density <.t" tin-
cipitate thus produced is compared in the nephelometer with thai of a precipitate pro-
■ In 1 iu the Bame an it of Bilver nitrate by adding to i1 a Btandard phosphoric

BOlul i n.

For cholesterol an aliquol portion of the above extract i- saponified with sodium

ethylate and then Baturated with chloroform; the chl form extract is mixed with a

anhydrid and II. so, (con.) until the bluish color is fully developed (Liebermann i
tion), the intensity of which is then compared in a colorimeter with that obtained by
similar treatment from a Btandard cholesterol Bolution.

Variations in Blood Fat. In the dog the percentage of fat in the
blood is remarkably constanl under normal conditions. After a fatty
meal the increase in fal begins in aboul an hour, and reaches its maxi-
mum in aboul six. The increase is qo1 found in animals in which the
thoracic duel lias been ligated. Although this result would Beem to
contradid the view held bj some thai part of the fat which can not 1"'
accounted for in t lie thoracic-dud lymph is absorbed by way of the
portal vein, it does no1 by itself disprove the hypothesis, for it has been
found that the fat contenl of tin- portal blood is always higher titan that
nf the jugular.

Very interesting results have been obtained following the intravenc
injection of emulsions of nil. either the so-called casein emulsion or col-
loidal suspensions. Up t<> a dose of 0.4 gram per kilogram of h<i<ly
weighl which by calculation would Buffice t<» raise the fal contenl of
the hi 1 by LOO per cent — there was no increase in fat content. In or-
der to explain this disappearance of fat, it mighl be imagined that thr
injected fal particles formed emboli in the smaller capillaries. Againsl
such a view", however, is thr tact that the particles of fat in these emul-
siuiis an' one-half to one-seventh the size of a red corpuscle. Although
this argumenl is no doubl of some weight, it should he remembt
that the physical condition of this,- fine fat globules is not the samt
that of the m\ blood corpuscle. Their Burface condition maj he such

that they readily agglutinate BO as in form small massrs, which may

stick at the branching of the smaller arterioh capillaries. Bit

himself suggests thai the injected fal maj be stored, possibly in the li

since the fat in this organ, as we shall see later, inert similar

conditions. When twice thr above quantity was fed in the form •

698 METABOLISM

yolk fat, some of it persisted in the blood for several hours. This in-
crease may have been owing to the flooding of the temporary storehouse
with fat, or, more probably, to a retarding influence that lecithin may
have on fa1 assimilation, for lecithin itself persists in the blood for a
long time after intravenous injection.

During faslin</, no increase in blood fat was found unless the animal,
by special feeding, had been stuffed with excess of fat prior to the fast-
ing period. The lipemia in this case indicates that fat is being trans-
ported from one place to another to serve as fuel for the starving tissues.
Narcotics were found to produce an increase in blood fat. Ether pro-
duced this increase during the narcosis, whereas morphine and chloro-
form did not do so until after recovery. The explanation given for the
ether effect is that a mixture of blood and ether has higher solvent power
for fat than blood alone. The explanation for the chloroform and mor-
phine effects is that a certain amount of breakdown of the tissue cells,
in which lipins are set free, supervenes upon the action of these narcotics.

The blood fat also becomes enormously increased in about forty hours
after the administration of phlorhizin, and on the second- or third day
after the administration of phosphorus. The special significance of
these facts we shall consider later in connection with the relationship of
the liver to fat metabolism.

By comparison of the fatty acid, lecithin, and cholesterol contents of
blood during fat absorption, it has been found that there is a steady but
very variable increase in fatty acid, accompanied by no variation in
cholesterol, but with an increase in lecithin, which varies from 10 to 35
per cent, but does not run strictly parallel with the fatty-acid increase.
It is probable that this increase in lecithin represents that part of the
absorbed fat which is intended for immediate use in the tissues (page
705). The more or less independent increase in lecithin is of significance
in connection with the fact that in many pathologic conditions of so-
called lipemia the increase does not affect the fats of the blood but rather
the lipoids (i.e., lecithin and cholesterol). Separate analyses of blood
plasma and whole blood show the increase of lecithin to be much more
marked in the corpuscles than in the plasma, whereas the fatty-acid
increase is confined to the plasma.

To illustrate some of these points the following table will be of value.
In it. is shown the average distribution of fatty acid, lecithin and choles-
terol in normal individuals and in cases of diabetes, in which disease,
as has been known for long, there is marked disturbance of fat metab-
olism.

I 'AT METABOLISM

od Lipoids • in Di

Fat by Bloor'a I
Method I

rotal Fatty AcidsJ

Lecithin

Cholesterol

< ;]\ cerides
Total Lipoids

Whole Bl 1

Plasma

Whole Blood
ma

puscles

Whole Bl l

Plasma
< 'in puscles

Whole Bl 1

Plasma
puscles

Plasma
Corpuscles

Plasma

m a r.
i-i i: '

0.62

0.37

0.34

0.42

0.22
0.23

0.20

0.10
0.

0.68

Mil. I)
DIAB1

0.83

'
0.64

0.32
0.24
0.42

0.24
0.21

g

0.18

DIAB1

L.06

i

0.46
1.16

l-I \!:i

1.41
L.80

1.0]
1.28

0.40

0.41
0.51

-

S

It will be observed thai there i- about <».7 per cent of total fatty bud-
stances in norma] blood. The fatly acids (palmitic and oleic) amount to
aboul 0.4 per cent, and arc equally distributed between plasma and
corpuscles; the lecithin, aboul <>.:! per cent, being twice ;i^ abundant in
corpuscles ;i> in plasma, and the cholesterol, 0.2 per cent, about equally
distributed. In diabetes ;ill of these substances arc seen to 1'" inc
in proportion to the severity of the disease, tin- increase l><'in<_r mostly
in the plasma. The increase in cholesterol (confined mainly to tin'
plasma) is particularly interesting, since the substance is unaffected in
amounl 1».\ excessive feeding with fat.

The Destination of the Fat of the Blood. In general, it may be said
that tlif blood fnt is transported to three places: 1 the depots for fat ; _'
tin' liver; and (3 the tissues. The fal present in each of these pli
differs from that in the others, as is revealed by chemical examination
by the methods described on page 687. The depot fat usually yields about
95 per cenl of its total weight as fattj acid. The I fat, nn the other
hand, yields only aboul 60 per cenl of its total weighl as fatty acid.
This difference indicates thai the fatty acid must 1 ombined in the

tissues with a much larger molecule than is the case in the fat of the

depots. This large molecule is probably that of lecithin or other pi

pholipin, and the smaller molecule in the depots, that of neutral

The liver fat takes an intermediate position between depot fat and ti-
fat in its yield of fatty acid. When no active metabolism of fat is
ing on. the liver fat is like that of the tissues-, luit when fat metabolism
is active, the liver fat occupies an intermediate position between 1

fat and depot fat.

700 METABOLISM

Another difference among the fats in these three places is ^\ itli regard
in the degree of saturation of the fatty-acid radicles. This, it Avill be
remembered, is indicated by the iodine value; the higher the iodine
value, the greater the desaturation of fatty acid. In depot fat this value
is relatively low — for example, about ;S0 in the goal and about 65 in man;
depending somewhat on the fat taken in the food, compared with which
it is usually a little higher! The fat in the tissues, on the other hand,
lias a high iodine value, possibly 110 to 130. The iodine value of the
fat of the liver is remarkably inconstant, being about Ihc same as that
of the tissues when fatty-acid metabolism is not particularly active, but
approximating that of the depots when fat mobilization is proceeding.
The significance of this fact we shall consider later.

The Depot Fat. — The places in the animal body where depot fat is
deposited in greatest amount are the subcutaneous and retroperitoneal
tissues. These fat depots may sometimes become of enormous size, as
in the ease of the famous dog of Pfliiger, of whose total body weight
40 per cent was due to fat. Bloor suggests that there may really be two
different types of fat storage: one of a purely temporary character,
which readily takes up and liberates the fat, but which is of limited
capacity and possibly under the control of some quickly acting regulat-
ing mechanism, like that of the glycogenic function of the liver; and
another of a more permanent nature, into which the fat is slowly taken
up, but the capacity of which is very much greater.

Two questions present themselves concerning this depot fat: (1) where
does it come from, and (2) what becomes of it? Regarding the source
of the depot fat, there is no doubt that it comes partly from the fat and
partly from the carbohydrate of the food; in other Avords, it is either
taken ready-made with the food or manufactured in the organism. That
some of it comes from the fat of food is now a Avell-established fact, the
evidence for Avhich need not detain us long. The best-knoAvn experiment
consists in first of all starving an animal until his stores of fat are
nearly exhausted and then feeding him with some "ear-marked" fat —
that is, with some fat having a characteristic property Avhich it will
not lose during absorption. It will be found that the depot fat thereby
deposited presents many of the qualities of the fed fat. The "ear-
marking" of the fal may be secured by using fats of different melting
points, such as mutton fat. which has a high M.P., or olive oil, which has
a low M.P. On feeding a previously starved dog with mutton fat, the
M.I', of the depot fat approaches that of mutton fat — he becomes a
dog in sheep's clothing; whereas when olive oil is fed, the subcutaneous
fat becomes oily. Or again we may "ear-mark" the fat by combining it
with bromine, when the deposited fat will likeAvise be brominized fat.

F\T Ml TABOLISM 70]

It must no1 be imagined, however, that no change takes place in the
fat during its absorption and before it becomes deposited in the tissues.
On the contrary, the Btamp of individuality is pu1 upon the fat, for,
we have already seen, its iodine value may become altered and its melt-
ing poinl changed during the process of absorption. In other woi
although the absorbed fal does no1 become entirely adapted to conform
with the ordinary qualities of the depot fat, ye1 it tends to change in
this direction.

That sun f the depol fa1 comes from carbohydrate is well known to

stock raisers. When, for example, an animal is fed on large quantities
of carbohydrate and kept without doing museular exercise, its tias
become loaded with fat. It' we desire strict scientific proof for this, we
do not need to go further than the old experiments of Lawes and (!il-
bert, who, it will he remembered, showed thai the fat deposited in the
tissues of a growing pig is greatly in excess of the fat that could have
been derived from the fa1 or protein which was meanwhile metabolized.
The experiment was performed on two young pigs from the same lii
and of approximately equal weighl ; one was killed and the exacl amounts
of fat and nitrogen in the body determined; the other was fed for several
months on a diet the fat and protein contents of which were accurately

ascertained. When after four months this p'n_r was killed ami tin- fat

determined, it was found that much more had 1m me deposited than

could he accounted for by the fat and protein of the food, even Buppos-
ing that all the available carbon of the protein had become converted

into fat. The only conclusion is thai the carbohydrate must have 1 n

an important source of the extra fat.

The Destination of the Depot Fat. The depol fat becomes mobilized
and transported by the blood to the active tissues whenever the energy
requirements of the body demand it. During starvation, as we have
seen, the depol fat is used to supply !,(> per cenl of the energy on which

the animal maintains its existence. Before the fat is transported, il

probably broken down into fatty acid ami glycerine, as which it pas
through the cell walls to he again reconstructed into neutral fat in I

hi 1. What agency effects this constanl breakdown and resynthesis

<>f fat it is difficull to say. Two ester-splitting enzymes are | -in

blood, one acting mainly on simple esters, the other on glycerides; hut

it has been impossible to demonstrate any evident relationship betw<

either of them and the extent ..f t'at mobilization.

The Fat in the Liver. The physiology of the liver fat has 1 n \>

diligently studied, particularly by Leathes and his pupils. " Tin* out-
come of this work has hceii to buow that the liver upies an extremely

important position in the melabolism of fat. being, as it were, the half-

702 METABOLISM

way house in the preparation of the fatty-acid molecule \'ov consumption
in the tissues. Fat is a material containing large quantities of poten-
tial energy. While in the depots this potential energy is so locked away
as to be unavailable for tissue use. To make it available the depot fat
is carried to the liver, where the energy becomes unlocked but not actu-
ally liberated. The fat is then transported to the tissues, and the libera-
tion of the energy occurs. Neutral fat is like wet gunpowder: it con-
tains much potential energy, but not in a suitable condition for explo-
sion. The liver, as it were, dries this gunpowder, whence it is sent to
the tissues to be exploded.

The great importance of the liver in fat metabolism is indicated by
comparison of the percentages of fat — or better of fatty acid — contained
in it under different conditions of nutrition. In the ordinary run of
slaughter-house animals the liver contains from 2 to 4 per cent of higher
fatty acid, hut in about one in every eight animals a much higher per-
centage will be found to occur. The same is true in laboratory animals.
In the case of the human liver as obtained from autopsies in certain
classes of patients, from 60 to 70 per cent of the dry weight of the
organ, or 23 per cent of the moist weight, may be fatty acid. There is
no other organ in the animal body that is ever loaded with fat to this
extent. As in the depots, this liver fat might be derived either from fat
carried to the organ from elsewhere in the body, or it might represent
a surplus of manufactured fat.

That transportation of fat to the liver occurs is very readily demon-
strable both in the laboratory and in the clinic. About forty hours
after giving phlorhizin to a dog, it has been found that enormous quan-
tities of fat appear in the liver; a few hours later, however, this excess
of fat may have entirely disappeared. Fatty infiltration of the liver
is ;il so observed in phosphorus poisoning, although in this case the fat
usually persists till the death of the animal. In man, in delayed chlo-
roform poisoning and in cyclical vomiting, enormous quantities of fat
may be present in the liver within a very short period of time after the
onset of the condition. There can therefore be no doubt that fat is
transported to the liver under abnormal conditions, but this can not
be taken as evidence that the liver has anything to do with fat metab-
olism in the normal animal. Such evidence has been supplied by Coope
and Mottram,51 who have been able to show that, at least in rabbits, a
similar invasion of the liver with fat occurs in late pregnancy and early
lactation. They also found that the fatty acid deposited in the liver
in late pregnancy gives an iodine value which lies nearer to that of the
mesenteric fatty acid than is the case in normal animals. Mottram con-
cludes that "wherever . . . there is abundant fat metabolism, the

PAT METABOLISM

liver is Pound to be infiltrated with fats, presumably to be handed on
elsewhere when worked up." It is interesting thai the fetus is greedy
of unsaturated fatty acids.

The most likely soura of tin fat transported to tl>< liver is the fat
cut in the depots, unless when digestion is in | is, when it may l>c

the fat from the intestine. That much of it comes from the depot
easily demonstrated. Thus, the more extensive the infiltration
liver -with fat, the inure closely will this fa1 1"' found to with the

depot fat in its chemical characteristics. This has been very clearly
shown by, firsl of all, starving an animal so as to clear the dep fat

as much as possible; then feeding it on some "ear-marked" fat (unusual
melting-point or a brominized fat); and after another day or bo of
starvation, so as to clear the liver itself of fat, poisoning the animal
with phosphorus or phlorhizin. The liver will be found shortly afl
wards to be invaded with fa1 which lias all the ear-marks of that on

which the animal had been fed.

Evidence <>f the same character has been furnished in a series of clin-
ical cases by observations on the amount of fat and 'he iodine value of
the fatty acid of the liver. This is shown in the ai mpanying table.

r rn \' ros of Liver

CAUSE OK r>F.\Tir

HIGHER KATTY

ACIDS PER CENT

IODINE VALUE

:V WITiMIT

KATTY A>

12.1

116 9

13.7

IK -

1 1.25

116

1 l.l

119.6

Normal

< '"inni.-li

fatty
change

cing

1 . Pernicious anemia

_'. Lobar pneumonia

.".. Pernicious anemia

I. Diab

5. Toxemic jaundice
i\. Accident

7. Empyema

8. Phthisis

r o.

ncho-pneura wia

-

-

10.

Appendicil is

14.0

91.1

Afarked

u.

Carcinoma of bladder

17.2

77.8

fatty J

\-i.

cho-pneumonia

54.6

change

13.

Dlcei ativc colitis

!

l l.

Accident

15.

1 >\ Bentery

1 .

This table clearly shows that the more fat there is in the liver, the

nearer this fat approaches in character that Btored in the depots
That some of the fat -in the liver may come directly from t)
cently absorbed tfn intestim is also very readily demonstrable.

Thus, when COCOanul oil was placed in the intestine Of anestl an-

imals, along with bile salts and glycerine, it was found by Raper*' that
::n per emit of the absorbed oil appeared in the livi

704 METABOLISM

The characteristic feature of cocoanut oil is that its fatty acids are volatile in steam
and are saturated. Some of the fatty acids of the liver are volatile in steam, but they
arc unsaturated. By distillation in steam of the fatty acids obtained by saponification
iif the liver, it is possible to determine how much of the cocoanut oil lias passed to the
liver.

Similar results have been obtained when unsaturated fatty acids, such
as those contained in cod-liver oil, are fed. In all these eases the rela-
tionship of the liver fat to that of the food is even more evident than
that between food fat and. depot fat, because in the liver the newly absorbed
fat is not diluted by that deposited it may be months previously, as is
the case in the connective tissues.

The question now arises: What happens to the fat during its stay in
the liver? An indication of the nature of the change is furnished by
observing the iodine value of the fat. This, it will be remembered, in-
dicates the degree to which the fatty acid is unsaturated. It does not
necessarily indicate the number of unsaturated bonds present in the fatty-
acid molecule, for the difference in iodine-absorbing power may depend
not on the number of such bonds but on the position in the chain at
which a given double bond is inserted. Even with this reservation, how-
ever, it is evident that the increase observed in the iodine values shows
that the liver has the power of desaturating fat. The advantage of
this change depends on the fact that the desaturated fatty acid will
be more liable to break up than the saturated fatty acid. In other words,
the double linkage will weaken the chain with the consequence that it is
liable to fall apart at this place; such at least is the natural interpreta-
tion which the chemist would put on the result. It may not, however,
be the correct interpretation, for it has been shown that, although un-
saturated fatty acids are more susceptible to chemical change in the
laboratory than saturated, yet when fed to animals they appear to be
more stable than many saturated acids. It may then be wrong to con-
clude that the introduction of a double linkage in fat necessarily means
the liability of the fatty-acid chain to break at that point. However
this may be, it seems likely that one function of the liver consists in
introducing double linkages at places in the fatty-acid chain, as a result
of which the chain breaks at these places, and the fragments then undergo
further oxidation.

Double linkages may be introduced not only in one place in a fatty-
acid chain, but in several. For example, it has been found in the liver
of the pig, after oxidizing the fatty acids with permanganate, that oxida-
tion products are obtained indicating the existence of unsaturated acid
with four double links. Permanganate (in alkaline solution) is used for
detecting the position of these double bonds, because, when it is allowed

PAT METABOLISM 705

to acl od unsaturated fatty acids in tl old, it causes hydroxy] groups

Ik- introduced in the position oi the double bonds. When the oxidation is

formed al a moderate temperature, the fatty acid falls apart at the
hydroxy] groups. A fatty acid with eighl hydroxy] groups lias been
obtained in this way from the liver of the pig. The presence of the hy-
droxy] groups has been confirmed by finding thai an octobromide is ob-
tained by treatment with bromine. An acid of the same formula is said t<>
be presenl in cod-liver oil. Te sum up, we may conclude thai there are
certain positions, in the chains of carbon atoms which constitute the fatty-
acid radicle, where the liver introduces double bonds, and thai tin- weak-
ened radicles then circulate to the tissues, where they break u]> at tl

itions.

Bui this is probably nol the only way in which the liver assists in
the metabolism of fat. It may also lake pari in the building of fatty-
acid radicles into the complex molecule of lecithin. The process of de-
saturation thai we have just considered is probably a preliminary step
to this incorporation of the fatty-acid molecule into lecithin, for it is
well known that lecithin contains highly unsaturated fatty-acid radi-
cles. In support of such a view it is interesting to note that in alcohol-
ether extracts from normal and pathological livers, the lecithins, which are
precipitated by acetone, have higher iodine values i. e., are more ui
urated than the neutra] fats extracted from the same liver, which also
have higher iodine values than the depol fal of the same animal. The
desaturation process must, therefore, involve the fatty acids before t;
become built into the lecithin molecule.

The liver is probably not the only place in the animal body where the
desaturation of fatty acids i> broughl about. The relative activity of

the different tissues in this regard has 1 ii studied by feeding cats

with fatty fish and then determining the iodine value of fa1 from various
places in the body. The absorbed fal was more obvious in the fiver than
hi the subcutaneous tissues, because it had not become diluted with fat

deposited it may have keen months previously, which would he the

le in the fat of the tat depots: and it was found that, although the

iodine value of the subcutaneous fat was slightly raised, that of the

liver was much more so, indicating that the desaturation process had

I n more active in this organ, hut had als !CUrr< a certain extent

in the depots.

Before leaving this subjed of fat in the liver, it is important I
call the old observation of Rosenthal, that a more or less recipi
relationship exists between glycogen and fat in the liver. When much
glycogen is presenl th< little or > and v 1' is ita]

70(1 METABOLISM

taut to note that the exacl local ions of I'al and carbohydrate in the he-
patic lobule «*ire somewhat different in t lie two cases.

A practical clinical application of the above work is found in the fact
that fats will be more readily utilized by the body when they contain a
high percentage of unsaturated fatty acids. It is probably for this
reason that Norwegian cod-liver oil is of such undoubted nutritive value.
It is much more so than Newfoundland cod-liver oil, because in the prep-
aration of this variety oxidation occurs, which makes it no longer unsat-
urated. Fish oils in general are more unsaturated than other animal
oils, and are for this reason more nutritious.

The fat in the tissues differs very materially from that of the liver or
the depots. Only 60 per cent of this fat consists of fatty acid, which is
present very largely as part of the lecithin molecule, thus accounting for
the high iodine value. Some is probably also present as simple glyceride,
in a highly unsaturated and therefore very fragile condition.

CHAPTEB LXXIX
PAT METABOLISM (Cont'd

Two very important questions of fatty-acid metabolism may now be
considered: namely, (1) how is fatty acid formed (rum carbohydrate?
and (2) what becomes of the fragments into which thi fatty-acid molecuh
is split as the result of thi desaturation process? Although these prob-
lems involve chemical details of a somewhal complex nature, we must
not on lliis account fail to consider them; for, as we shall Bee, much of
what is known has an importanl practical application depending on the
fact that certain of the intermediary substances may accumulate in the
organism and develop a toxic action.

The Production of Fatty Acid out of Carbohydrate. If we place the
formulas for glucose and palmitic acid side by side, thus:

CH,0H-(CH0H)4-CH0 (glucose), and
CH3- (CH,)M-OOOH (palmitic ari.l) ;

we shall sec that this transformation must involve: (1) a considerable
alteration in the structure of the molecule, (2) the removal of oxygen,

and (3) the fusion of several glucose molecules into our molecule of fatty
acid.

The conversion of carbohydrate to fa1 therefore involves a process of
reduction, and the resulting molecule must be capable of yielding more
energy when it is oxidized than the original one of carbohydrate, for
obviously the system 08- CH2 (which corresponds 1«> fat) will d
more energy than thai of 0, CHO I which corresponds to carbohydrate
just as a piece of wood when it is burned will develop more heat than ;i
piece of charcoal. This explains why one gram of fat yields 9.3 calories
of heat, and one gram of carbohydrate, only 4.1 (page Patty

acid therefore contains more potential energy than sugar, and in explain-
ing its synthesis from BUgar in the animal body We must indicate

sourci of tin extra energy. Tins is dependent on oxidation of Borne Bug
molecules which do not themselves become changed to fatty acid
proceeding side bj side with the reduction which affects the others and
represented in the outcome of the reaction by the combustion products

CO, and II. <>. thus:

M •• 13 0 20 CO C16H„0 20H,0

gll BC itty acid

707

708 METABOLISM

What evidence have we thai such a j>roccss actually occurs in the body?
If we compare the intake of oxygen with the output of carbon dioxide
in the respired air, we shall find that usually there is less of the latter;
that is to say, the respiratory quotient, as this ratio is called, is usually
less than unity. During the extensive conversion of carbohydrate into
fat, however, which occurs during the fall months in hibernating animals,
the 1\.Q. has been round to rise as high as 1.4. The great excess of
C02- output over 0„ - intake which such a quotient indicates conforms
with the above equation.

The entire dissimilarity in chemical structure between the molecules
of fat and carbohydrate suggests that the primary step in the conversion
must be a thorough breakdown of the carbohydrate chain into compara-
tively simple molecules, from which the fat molecules are then recon-
structed and the unnecessary oxygen set free. The problem is to ascer-
tain the chemical structure of these simpler molecules and the manner
of their union into fatty acid.

Of the several suggestions which have been made, that of Smedleysa seems the most
likely. As will be seen from the following equations, the first step is the conversion of
glucose to pyruvic acid (page 600, No. 1 in equations). By enzymic action pyruvic
arid is converted into acetaldehyde (No. 2), which then condenses with another pyruvic-
acid molecule to form a higher ketonic acid (No. 3), from which by the loss of CO.,
as in the case of the production of acetaldehyde from pyruvic acid, an aldehyde is pro-
duced (No. 4). This higher aldehyde behaves like acetaldehyde in again combining with
pyruvic acid, forming a still higher ketonic acid; and so on until at last a long fatty-
acid chain is built up, thus:

(1) GVEijA, + 02 = 2CH3COCOOH + 2H,0
(glucose) (pyruvic acid)

( 2 ) CH3COCOOH = CH3CHO + CO.

(acetaldehyde)

(3) CJLCIIO 4- CH3COCOOH = CH3CH: CHCOCOOH + H20

(unsaturated ketonic acid)

(4) CH3CH : CHCOCOOH = CHsCH:CHCHO-rC02; and so on.

(higher aldehyde)
(5) From the ketonic aldehyde formed at any stage, an unsaturated fatty acid (with
one less C-atom) is readily formed, and this by taking up H may become saturated:
CH3CH:CII CO COOH +0 — CH, CH:CH COOH + C02.

During the butyric-acid fermentation of sugar a slightly different process may occur —
namely, the lactic acid, which we know is readily produced from glucose, may break down
into acetaldehyde (and formic acid), and two such molecules condense to form /3-oxy-
butyric aldehyde; and this a-ain condense to form higher fatty acids, thus:

( 1 ) C0H12O0 = 2CH3CHOHCOOH.
(glucose) (lactic acid)

(2) 2CH3CHOHCOOH = 2CH3CHO + II.COOH

(acetaldehyde)
2CH,CHO --('II CHOHCH2CHO; and so on.
(jS-oxybutyric aldehyde)

PAT METABOLISM

Thai higher fatty acids, Buch as caproic 0,H 0, and caprylic C,H « >_ . bi
actually been isolated from the products of ti entation is a •■

and it is of interest to note thai L< and an

acids ■ sur during the aseptic ii d of liver pulp ' . the

increase of fatty acid could not be Bhown to be affected by addii _ the

liver which, according to the above equal id.

The Method by Which the Fatty Acid is Broken Down, [n tl mi-

ca! laboratory, ordinary oxidizing agents attack tl e fatty-acid chain ;it the
C-atom iir\t the carboxy] (COOH group (the alpha C-atom). B I
this can nol occur in the animal body, because it would leave behind a
smaller chain containing an uneven number of C-atoms, and such chains
are never found presenl in the animal fats. < >n the contrary, the com-
moner fats all contain an even number of < ' atoms thus : Butyric, C I ! 0
palmitic, C II 02; stearic, C II 02; oleic, C 1 1 0

The intermediary substances which are produced during the gradual
breakdown of the fatty-acid molecule in the normal animal are of a v<
transitory character so much so indeed that it is impossible for any one
of them to accumulate in sufficient amounl to permil of isolation, or even
detection, by chemical means How then are we to idi

mediary products? This has 1 o rendered possible by the discovery that,

when anything occurs to disturb tlie normal course of fat metabolism, as,
for example, when the tissues are deprived of carbohydr; as in star-

vation or in severe diabetes . the oxidation of the fatty-acid chain stops
short when ;i chain of four C-atoms still remains unbroken. Those
four ( '-atoms seem to form a residue thai is more resistant to oxidation
than the remainder of the fatty acid molecule. It is a residue, theref
which is quite readily further oxidized to COa and II <> under normal con-
ditions, but which, although incapable of becoming completely oxidi
when the metabolism is upset, docs undergo a partial oxidation, result-
ing in the production of various intermediary products. These accumu-
late in the body in sufficienl amounl to overflow into the urine,
which they can be isolated and identified.

The fatty acid with 4 C-atoma is butyric, CH CB 'II COOH, and I
firsl oxidation producl formed from it in the body seems to be I

d, CH CHOHCH COOH. This then 1 omes oxidized t< i a

body having the formula ''II COCH COOH, d, which,

further oxidation, readily yields CH COCH . or Tl ib-

Btanci f-oxybutyric acid, acetoacetic acid and acetone ■at- in the

urine during carbohydrate starvation, as in diabei

It mighl be objected, however, thai a chemical pr< ng undi

abnormal conditions n I not als.. occur in the uiimal. Thai it

probablv docs, however, is indicated h\ the result incuts

710 METABOLISM

of Knoop and of Embden and his coworkers. Knoop conceived the idea
of introducing' into the fatty-acid molecule some group which is resistant
to oxidation in the body. The phenyl group (CuH5),was found to have
this effect. By feeding an animal with the phenyl derivatives of acetic,
propionic, butyric, and valeric acids, it "was found that the urine con-
tained either hippuric (see page 030) or phenaceturic acid. Both of
these are compounds of aromatic acids with glycocoll or aminoacetic
acid (CII .XILCOOIJ), one of the protein building-stones and always
available in the organism to form such compounds, thus:

( 1 ) c,iiscooi-i + ch.nh.cooh = cgh5conhch2 coon.

(benzoic (glycocoll) (hippuric acid)

acid)
(2) CcH5CH.COOH + CHNH.COOH = CcHsCH2CONHCH2COOH.
(phenylacetie (glycocoll) (phenaceturic acid)

acid)

When either benzoic acid (C6H5COOH) or phenylacetie acid (C0H5CH2-
COOH) is formed in the body as a result of the oxidation of phenyl
derivatives of the higher fatty acids, the acid combines with glycocoll
according to the above equations. From this it follows that if oxidation
occurs so that two C-atoms are thrown off at a time (/^-oxidation), fatty
acids with an even C-atom chain should yield hippuric acid, and those
with an uneven chain, phenaceturic. This was found to be the case, as
the accompanying table shows.

ACID FED OXIDATION' . EXCEETED Ag
■ PRODUCT

Benzoic acid, CcH5.COOH Not oxidized Hippuric acid

Phenylacetie acid, C6H5 . CH2 . COOH Not oxidized Phenaceturic

acid
Phenylpropionic acid, CaHB.CH2.CH2.COOH CHH,.COOH Hippuric acid

Phenylbutyric acid, C,.H5.CH,.CH2.CH,.COOH C6H5.CH,. COOH Phenaceturic

acid
Phenylvaleric acid, C6H5.CH,.CH2.CH.CH..COOH 0(1H,i.COOH Hippuric acid

(From Dakin.)

Embden 's experiments are equally convincing. He studied the forma-
tion of acetone in defibrinated blood perfused through the freshly excised
liver. Normally only a trace of this substance is formed, but when fatty
acids with an even number of carbon atoms were added to the blood,
they gave rise to a marked increase in acetone, whereas those with an
uneven chain failed to cause any change. The acetone was found to be
derived immediately from acetoacetic acid. The following table shows
the results.

FAT METABOLISM 711

' \I. KATTY ACID PORM OP

AC rlCACID

Acetic acid CH .COOB

Propionic add CB ,CB ,.COOB

Butyric add «'ll .CH,.CHt.COOB +

Valeric add CB ,CH1.CH1.CB .COOB

Oaproic add CB .CHf.CB .CB .CB .COOB

Beptylic arid CB .CB .CB .CB .CB .CB .COOB

(Mtiie acid <'ll .CB .CB .CB .CB .CB .OB .COOB

Nbnoic add CB .CH,.Cfl .CB .CB .CB .CB .CB .COOB

Heroic arid CH, . CH,.riI,;. CH, . CH,. ( 'H,. .CB,. CU, .('H7. CH;.COOH +

(From Dakin.)

For a long time it was difficult for chemists to understand how such
a process of oxidation at the /8-C-atom could occur, since they *
unable to bring it aboul in the laboratory by the use of tin- ordinary
oxidizing agents, hut recently Dakin has removed the difficulty by show-
ing that hydrogen peroxide II 0 oxidizes fatty acids just exactly in
this way.

We may sum up the results of these experiments and observations by
stating that normal saturated fatty acids "ml their phenyl derivatives cai
undergo oxidation, not only in thr animal body, but also in vitro, in such
a manner that tht two {or some multipU thereof) termial C-atoms an
removed at each successivi step in their decomposition.

But we must not be too hasty in concluding from these experiments thai
the steps in the process are necessarily in the order of first, the produc-
tion of a )8-hydroxy acid, and second, the oxidation of this to a ketone
group. The mere presence, side by side, of (i hydroxyhutyric acid ami of
acetone in the above experiments docs not indicate which is the ante-
cedent of the other, and indeed there arc several experimental facts that
seem to show that the hydroxy acid may he derived from t ho ketone

For example, when acetoacetlC acid is added to minced liver and the

mixture incubated, £-hydroxybutyric acid is formed a reduction process .

although less usually the reverse action oxidation! may occur when

0-hydroxy acid is added. A reversible reaction must therefore he capable
of occurring between these two substances, thus:

reduct ion

CB .CHOH.CB .•'noil « CB .<'<». en .COOB.

oxidation
(/9-oxy butyric add) » ;,i •

W'e know practically nothing as to the conditions determining whether
oxidation or reduction shall predominate, hut there are two Bignificanl

facts that one should hear in mind: | 1 thai a plentiful supply of o\\

gen is n ssar\ for the oxidative process, and 2 that the presence

rcadil\ oxidi/.ahlc material in the liver (e.g., carbohydrates may del

mine the direction which llic reaction shall take. It is COmmonl] Said
that fats burn in the tire of carbohydrates, and it ma\ he that t ho tin-

712 METABOLISM

doubted diminution in acidosis which occurs in diabetes when carbo-
hydrate food is given is dependent upon the directive influence which its
combustion in the liver has on the above processes. But we must be
cautious not to transfer results obtained by experiments with minced
liver in judging of the reactions which occur during life. Provisionally,
then, we must assume either that ^-hydroxybutyric acid is a necessary
stage in the oxidation of butyric acid or that it is formed by reduction
of acetoacetic acid, which is really the first step in that process.

Of course there is no evidence in the above experiments that the higher
fatty acids are also broken down by the removal of two C-atoms at a
time, nor has it been possible to detect any ketonic or ^-hydroxy deriv-
atives of them in the animal body. We can only reason from analogy
that a similar process may occur, although some support is furnished
for such a view by the fact that ketonic fatty acids have been found in
vegetable organisms.

What, then, it may be asked, is the relation of the desaturation of fatty
acids which we have seen occurs in the liver (and probably elsewhere) to
the p oxidation? There can be no doubt that both processes can occur
in the animal body, indeed in the same organ, e.g., the liver; and it is
important to ascertain their relationship to each other. The conclusion
which would seem to conform best with the known facts is that the
desaturation process occurs (in the liver) so as to break up the long
fatty-acid chain into smaller chains, which are then capable of /? oxida-
tion (in the tissues) ; desaturation may be the process by which the mole-
cule is rough hewn, and (3 oxidation that by which the resulting pieces
are finally split to their smallest pieces — that is, to molecules of the size
of acetic acid, ivkick are finally completely burnt to carbonic acid and
water.

The increase of iodine value observed by Leatlies and his coworker? need not, as has
already been pointed out, necessarily indicate that new double linkages have been intro-
duced in the fatty-acid chain; it may merely indicate that structurally isomeric deriva-
tives which absorb iodine more readily have been formed. Direct evidence of desatura-
tion has, however, been offered by Hartley, who isolated the unsaturated fatty acids (by
dissolving the lead soaps in ether) from pig's liver and then proceeded to oxidize them
with alkaline permanganate. "When the olein of the depot fat is thus treated at a low
temperature, two hydroxy] groups become attached where the double linkage existed
(forming dioxystearic acid'), and when the mixture is now warmed, the molecule splits
into two at this place, forming two lower acids (pelargonic and azelaic) :

(1) CIL- (CH;).CH :CH(CH2) ,00011;

(oleic acid)

OH : on

/ /

(2) CH3-(CH,)T-CH- CH- - (CH2).COOII ;

(dioxystearic acid)

(?,) CH, (CH,).COOH + COOH- (CH^COOH.
(pelargonic acid | ("azelaic acid)

PAT Mil IBOLISM , 1',

We may conclude from this that the doable linkage in the oleic acid of tlr
exists between the ninth and tenth C-a1 I the un-

saturated acid from the liver

yielded caproic acid, which, since this acid has six < ...

double linkage existed betwi i

ight to light by th( Inch

fell apart in such a way as to indicate that the hydi
and seventh and between the ninth and tenth '
would 1" ictoi ily explained l

■i.l double bond i. <-.. between the sixth ai < • 1 in

the pig's liver may be a< unted for, in other words, by supposing tl ation

of Btearic acid and of the ordinary (depot) oleic acid

double link between the Bixth and seventh carb d i thes). E

other double links may. however, be introduced into the fatty-acid chain, ( tho

linolic acid series ar< at in l-liver oil. Finally, it is of interest 1

acid i< a product of the above oxidation p Dumber

ami therefore will form |8-oxybutyric acid.

To go into these chemical problems any further here would l>e <>nt
place. One other fact, should, however, 1"' borne in mind- namely, that
the unsaturated acids may lie formed from saturated acids throng
intermediate formation of /8-hydroxy and /S-ketonic acids. Their m
presence, in other words, should no1 be taken as evidence that the oxida-
tion of fatty acids is initialed by the introduction of an hydroxy] gTOup
a1 tin' ft position in the chain.

CHAPTER LXXX

CONTROL OF BODY TEMPERATURE AND FEVER

The classification of animals into two groups — warm-blooded and cold-
blooded— according to their ability to maintain the body temperature at
a constant level, is more or less arbitrary. Between the two groups an-
other exists, represented mainly by hibernating animals, in which at
certain times of the year the animal is warm-blooded and at other times
cold-blooded. The ability of the higher mammals to maintain a constant
body temperature may or may not be present at the time of birth. The
heat-regulating mechanism of the human infant for example remains ill
developed for some time, so that exposure to cold is liable to lower the
body temperature to a dangerous degree.

VARIATIONS IN BODY TEMPERATURE

In animals in which the heat-regulating mechanism is fully developed,
there is not, even during perfect health, entire constancy in temperature
in the different parts of the body or in the same part at different periods
of the day. The average rectal temperature of man is usually stated as
being 37° C. (98.6° F.), but the diurnal variation may amount to 1° C,
being highest in the late afternoon and loAvest during the night. There
are probably several causes for this variation, and they are in part at
least dependent upon the greater metabolic activities of the waking
hours and upon the taking of food. Apart from these influences, how-
ever, others which are less evident appear to operate ; for it has been
found that, when the daily program is reversed by night work, the usual
diurnal variation, although much less pronounced, still remains evident
even although this reversal in habit may have been kept up for years.
It is of interest to note in this connection that nocturnal birds have their
maximum temperature at night and their minimum during the day.

Regarding the temperature in different parts of the body, that of the
rectum is usually about 1° C. higher than that of the mouth, and this
again higher than that of the axilla. Of these three the mouth tempera-
ture is the most variable, for many conditions, such as mouth breathing,
talking, drinking cool liquids and even exposure to cold air, are sufficient
to lower markedly the temperature of this region. When the mouth

714

CONTROL OF BODY TEMPERATURE AND FEVER 715

temperature is carefully taken by leaving the bulb of the thermon*
under the tongue for a minute or more, it is practically the Bame as the
temperature of the arterial blood of the hand when this Lb exposed to the
ordinary conditions of outside temperature. Greater differences than
1° c. i,, the temperature of differenl regions of the body are often ob
served in feeble individuals and in those with some circulatorj disturb-
ance.

FACTORS IN MAINTAINING THE BODY TEMPERATURE

The body temperature represents the balance between heal production
and heal loss. The production is effected mainly in the muscles by the
oxidative processes which are constantly ensuing there. When the
activity of the muscles is abolished by paralyzing the terminations
tin- motor nerves with curare, the temperature <>t" warm-blooded animals
immediately falls or rises a rding to the temperature "t' the environ-
ment. A curarized warm-blooded animal is thus made to behave lil
cold-blooded one. Increased muscular activity, on the other hand,
promptly raises the body temperature by 1" <>r 2: (•'.. above which, how-
ever, a further rise does not occur, provided nothing has been done to
interfere with the mechanism by whieh the excess of heat is Lr<»t rid
from the body. The temperature in such cases adjusts itself at n higher

level, ;it which it remains fairly constant however strenuous th<

cise. It is possible that a certain amount of heat may also he generated
by the chemical processes occurring in the liver and other viscera, hut
when compared with the muscles this source of heat is undoubtedly in-
significant. Many of these chemical pr isses, as in the liver, instead

of producing actually absorb heat, so that the balance between 1
producing and heat-evolving mechanisms may or may not come out in
favor of the liberal ion of heat.

The production id' heat goes on all the time in muscles mi account
the condition of tonic contraction in which they are held see page SH .
and which is also necessary for keeping the joints in the proper deg
of flexion or extension. When more heat is required by the animal body,
the tone of the muscles increases independently of the function which
they may he performing in controlling the position of the joints. -This
increased tone may become bo pronounced that it causes visible conti
tions, which we recognize as shivering. Whenever the irfsensible hyp
tonicity and the shivering are inadequate to produce a sufficient amount

of heat, the animal inst inct i\ el\ moves about in order that tl iter

contractions may liberate more heat.

The heat is produced in the muscles hy oxidation of tin- foodstuffs that

have been assimilated from the blood. Even during the p

716 METABOLISM

similation itself a certain amount of heat is generated; this is known
as the specific dynamic action of the foodstuff, and is most pronounced
with protein and least so with carbohydrate (page 538). Advantage
may be taken of this heating power of protein to produce more heat
when the cooling conditions are excessive; in winter, for example, there
is an inclination to take more protein food than during summer, and the
per capita consumption of such food is much greater in peoples- living in
temperate zones than in those living in the tropics. The ultimate amount
of heat produced by oxidation is greatest with fat and least with carbo-
hydrate.

TFrat loss in man is effected partly through the lungs, hut mainly
through the skin. Through the latter pathway heat is lost by the physical
processes of heat conduction and radiation and by the evaporation of the
sweat. Through the lungs it is lost mainly in the vaporization of the
water contained in the expired air (latent heat of vapor). The amount
of heat lost from the skin by conduction and radiation depends on the
temperature of the skin, which again depends on the rate at which the
blood is circulating through the cutaneous vessels. Under ordinary con-
ditions of external temperature tAvo or three times as much heat is lost
by these methods as by evaporation. The losses by evaporation, under
conditions of rest and average external temperature, are about equally
divided between the lungs and the skin.

From all these facts, it is evident that licat loss occurs mainly l>]i the
skin and only to a small degree by the lungs. This means that under
average conditions in man the main regulation of heat loss is effected by
variations in the sl:in temperature brought about by peripheral vasocon-
striction and dilatation. The marked sensitivity of the cutaneous
blood supply to changes in the temperature of the environment has been
very clearly shown by observations made with the hand calorimeter of
Stewart described elsewhere (page 281). When the bloodflow through
the hand is examined in a person who has been exposed to the outside
aii-. it may be little more than half that which it attains after he has
been in a warm room for some time. In the outside air the vessels con-
strict to prevent heat loss by conduction and radiation; in the warm room
they dilate to facilitate this loss. The afferent impulses which retlexly
• •oiitrol the change in the cutaneous blood circulation may be set up by
local applications of heat or cold, as can be shown in the hand-calorim
eter experiments by applying a cold pad to the skin of Hie correspond-
ing forearm, when an immediate curtailment of bloodflow takes place.
Or the reflex may be excited from distant skin areas, as illustrated in
the curtailment in bloodflow observed when the opposite hand to that
<>n which the observation is being made is placed in cold water. The

I ONI ROL OP BOD1 l l MP] R \ [M BK AND PEVFJJ 717

magnitude of the change in cutaneous circulation i^ nevertheless depend-
enl ii])(ni the extenl of the area of the body thai is opposed to the change
in temperature, as seen in tin- dilatation of the skin vessels prior *
rise in body temperature wh6n a person is immersed in a warm bath.

Although afferenl impulses from the skin are then eat im

portance in adjusting the cutaneous blood supply according to the

amounl of surface < ling thai has to occur, s further e also ;

duced on them by the action on the nerve centers of temperatun
ferences in the blood itself. Thus, when the temperature of blood going
to the brain is raised by placing the carotid arteries on some heati -
vice or when the region of the corpora .striata is directly warmed, the

skin vessels 1 ome dilated as if the animal had I o exposed I - eral

warmth.

When the loss of heal by radiation and conduction is no longer ade
quate to prevenl a rise in body temperature, or when the process
not operate on account of a high temperature in the environment, th<
'"-v of heal from the skin is mainly dependent upon tJn evajn
sweat. Under ordinary conditions this evaporation takes place at such
a rate that there is no visible perspiration on the surface of the body —
the so-called insensible perspiration. When the heal loss by this channel
must become greater, the perspiration is produced in larger amount,
thai it collects on the surface of the body; and. provided the conditions
the environment are such that evaporation can readily take p low-

relative humidity . the amount of cooling of the body that can I
becomes very great. A man may exist without any marked rise in b<
temperature in a very hoi environment even when he is exposed to an
side temperature that is the same as thai of 1 y, or even greater. To

encourage evaporation, however, he should be naked or very lightly clad,
and the air should be kepi in constant motion so that the la\ ait-

next to the skin, which ordinarily very quickly become saturated \

vapor, are transferred and repla I by dryer air. Movement of the air

also increases the heat loss by conduction, provided the temperature
the air is nol too near that of the body.

The importance of the movemenl of air in the regulation I --

has been' clearly demonstrated by Leonard Hill. ' P. S Lee, and ol s who
have found that a greal part of the discomf ied by living

stagnant air can be obviated by putting the air in motion by electri
without doing anything to improve its chemical purity. In one fam
leriment a number <>f young men were placed in an air-tight cabi
at the ordinary temperature of the room. Afl

exhibit the symptoms usually attributed to polluted air; they became
drowsy and some of them developed headaches, \ small e

718 METABOLISM

Can was then started so as to set the air in motion. Immediately all of
the men recovered and remained in a perfectly comfortable condition
so long as the fan Avas kept going. The practical application of these
facts to the hygienic control of the working conditions in mine shafts,
in submarines, in workshops, etc., will be self-evident.

The stimulus to increased sweating seems to be dependent mainly on
changes in the temperalure of the blood; for sweating does not im-
mediately set in when the body is subjected to heat, as by a warm bath or a
hot pack. It usually takes from ten to twenty minutes after the person
has been placed in the bath or surrounded by the warm blankets of the
pact before sweating becomes pronounced. It can usually be shown that
before it sets in the body temperature has been raised from 0.1 to 0.8
degrees C. (0.2 to 1.4 degrees F.). In this regard, therefore, the response
of the sweat glands does not occur so promptly as does the dilatation of
the cutaneous vessels.

Loss of heat by evaporation of sweat occurs only in certain animals.
It is practically absent, for example, in the dog. The degree to which
it may occur also varies in different individuals of the same species. The
power of withstanding high temperatures is proportional in man to the
facility with which he perspires. Where sweating is interfered with by
skin diseases, — by ichthyosis, for example, — exposure to heat or in-
creased heat production, as by muscular activity, may raise the body
temperature to a dangerous degree.

Another factor upon which the efficiency of evaporation of sweat in
cooling the body depends is the relative humidity of the air. When this
is high, evaporation of water into it can not occur, and it is on this
account that an increase in body temperature is much more likely to
occur in warm, humid atmospheres than in those that are dry. At the
same temperature people can live in perfect comfort in the dry air of the
open plains, but suffer immediately from rise of temperature when they
go into the humid air of the river valleys. Similarly, work in hot fac-
tories or in mines is quite possible at very high temperatures if the air
is kept dry and in motion, but becomes impossible when the air is moist.
In judging of the adequacy of air from this point of view, it is there-
fore important to take not the ordinary dry-bulb thermometer reading
but that of the wet-bulb.*

In animals, like the dog-, that do not perspire over the surface of the
body, vaporization of the water in the expired air is the most important
method of regulation of heat loss. When such an animal is exposed to

*The wet-bulb thermometer registers a temperature that is lower than that of the dry-bulb in
proportion to the relative humidity of the air. When the air is completely saturated with moisture.
the temperature recorded by the two instruments will be the same; when it is perfectly dry, the
difference will be maximal.

I ONTROL OP BODV l I MP1 R \'i 'i Bl IND I i \n: 719

warmth or when the region of il orpora striata is artificially warmed,

the breathing immediately becomes much quicker and deeper, bo thai
pulmonic ventilation is greatly increased and much more water is carried
i. ut as vapor with the expired air. To vaporize the water large quanti-
ties of heal are required Been in the latenl heal of steam). In man this
method is. ordinarily, nol of greal importance, bul it may become
when sweating is interfered with, as in ichthyosis. The more rapid
breathing also facilitates cooling by increasing the conduction of heal
from the mucous membranes of the tongue, mouth, throat, etc. The im-
portance of this method of ling has been shown by finding thai after

the introduction of a tracheal cannula a dog can nol withstand an in-
crease of external temperature nearly so well as a normal animal.

There are many other questions concerning the control of heat 1
from the human body thai mighl be considered, but it is -
essary to do so here. It should ho added, however, that the relative
humidity of the air in the control of heal loss has a different significance
when the temperature is high from that when it is low. High relative
humidity at high temperatures, as we have seen, interferes with evapora-
tion of sweat, whereas high relative humidity at low temperatures in-
creases tlio heat-conducting power of the air and therefore tends to c
off the surface of the body by greater conduction. It is on this account
that it is much more comfortable to live at a low temperature when tho
air is dry than when it is moist. On the dry plains of the Wesl a tom-
perature of many degrees below zero causes less bi E cold to be

perienced than in the moist atmosphere at a considerably higher tem-
perature along the Greal Lakes and in the river valleya

THE CONTROL OF TEMPERATURE

In the case of man the body temperature is very largely under volun-
tary control, as by the choice of clothing and the artificial heating of the
room. Desirable as this voluntary control of heal loss may be, there can
be little doubl thai it is often managed to the detriment of good health.
Living in overheated rooms during the cooler months of the year -
diminishes the loss of heal from the body thai the tone and heat-produc-
ing powers of the muscular system are lowered \ • only does this
diminish the resistance to cold, hut it causes the food to be incompletely
metabolized bo that it is stored away as fat. The superficial capillaries

also l me constricted and the skin bloodless and ••pasty." I-

looks alone that suffer, however, hut health as well, for by having
little to do the heat-regulating mechanism g< - it wore, oul

720 METABOLISM

so thai when it is required to act, as when the person goes outside to
the cold air. it may not do so as promptly as it should, with the result

■

that the body temperature falls somewhat and catarrh, etc., are the
result. There can be little doubt that much of the benefit of open-air
sleeping is owing to the constant stimulation of the metabolic processes
which it causes.

As will be inferred from what has been said above, the control between
heat production and heat loss is effected through a nerve center located
in or near the corpora striata. In most animals, when the spinal cord
is cut in the cervical region, the body temperature quickly falls unless
artifieally maintained. In the case of man, on the other hand, it has
usually been observed, after accidental section of the spinal cord in the
cervical region, that a rise in temperature occurs. In twent3T-four un-
complicated cases of spinal-cord injury in man, collected from the rec-
ords of Guy's Hospital by Gardiner and Pembrey, it was found that
nineteen showed hyperthermia (sometimes amounting to 43.9° C.), and
• inly five, hypothermia (sometimes 27.6° C.). If the patient lived, the
ultimate effect of the section, as in the lower animals, would no doubt
be the loss of the power of maintaining a constant temperature.

The extent to which the animal comes to behave as if cold-blooded after
section of the spinal cord varies considerably according to the level of
the lesion; if the cord is cut in the upper thoracic region, for example,
the regulation against cold, although distinctly less efficient than normal,
is far better than when the section is made through the cervical cord.
This difference is dependent on the fact that after the loAver lesion much
larger muscular groups and skin areas are left intact, so as to make
regulation possible. Section of the dorsal cord in mice has been found
by Pembrey to abolish entirely the increased metabolism which occurs
in normal mice when they are exposed to cold.

In the light of these experiments it is probable that the difference in
the effects produced on body temperature by section of the cervical
spinal cord in man and the lower animals depends on the relative im-
portance of the heat-producing and heat-dissipating mechanisms. When
the control of heat loss is paralyzed in the smaller animals, the cooling
of the body becomes excessive in relation to the amount of heat produced
in the paralyzed muscles, because the body surface is extensive in com-
parison with tlic body weight (sec page 551). In the Larger animals such
as man, on the other hand, the cooling effect is much less marked, espe-
cially when, as is common after such an accident, the patient is kept
nnusuallv warm.

CONTROL OF BOD'S TEMPERATURE AND FEVER 721

FEVER

The clinical application of a knowled the mechanism of heal regu-

lation in the animal body concerns the causes of fever. In the i
familiar form fever is produced by infectious p but it may also

be owing to various other causes, among which may 1"- mentioned I
parenteral injection of foreign protein, excessive destruction of prot
substances in the body itself, the action of certain drugs, and lastly.
injury to the base of the brain or lesions of the upper levels of the spinal
cord. Various types of fever are recognized: when the temperature re-
mains constantly above the normal, it is known as continuous fever:
when oscillations occur bu1 the temperature never falls to the normal
level, it is known as remittent; when it attains the normal level at cer-
tain periods during the day, it is known as intermittent.

Causes of Fever

During a sudden risi in temperature there is, on the one hand, in-
creased heat production in t lie muscles, and on the other, dimin-
ished heat loss from the surface of the body. Tht fever is therefore
due to an exaggeration of the processes b]i which the body normally re-
acts to conditions which tend tolowerthi body temperature. Theincreat
muscular activity thus induced often causes visible contractions, familiar
as shivering; and the constriction of the cutaneous blood vessels pro-
duces t he subjective sensation of chills, and causes the skin to 1 me

pale and cold to t lie touch. The skin muscles also contract, producing
"goose skin." During this Btage, objective demonstration of the cur-
tailment of the skin circulation can be secured by observation of the
bloodnow through the hands and feel page 283). When the temperature
suddenly falls again, the crisis, as it is called, muscles become flac
and produce less heat, and the cutaneous blood vessels dilate, as has
been shown by measurements of the bloodflow of the hands and ;•
At the same time also, the sweal glands are stimulated and marked ;
Bpiral ion occurs.

Concerning tin causi oj continuous fever, it most be assumed that I

balance between heat production and heat loss has been adjusted at a
higher plane than normal. \Y- can m>t explain the fever on th<
either thai heat production is permanently increased or that heat
is permanently diminished, for in neither of these cases would the tem-
perature stand at a permanent level but would steadily rise or fall, ac-
cording to which mechanism was disturbed. While this higher
plane of fever, the thermogenic nerve'eenters are still capable of re-
sponding in the usual way to the influences which cause the body tern-

722 METABOLISM

perature to change in a normal person. For example, when a fever pa-
tient is subjected to a hot bath so that his body temperature rises about
0.2 to 0.5 degrees C, sweating occurs just as in a normal individual; or
if exercise is taken the increased amount of heat thereby produced in
the muscles is dissipated in the usual way. When, on the other hand,
the patient is exposed to cold, the vessels of the skin contract and he
shivers.

Although fever is not caused by an actual disturbance of balance be-
tween heat production and heat loss, neither of these processes is pro-
ceeding at its normal level. That there is a distinct increase in the total
heat production of the body in acute fevers in well-developed persons
has been shown by means of the respiration calorimeter. This increased
heat production is not observed in patients who have been brought into
a weakened condition and in whom the muscular tissues have become
atrophied by long-continued fever. The increased heat production in
continuous fever is mainly dependent upon the increase in body tem-
perature and is not one of its causes, as is evident from the fact that far
larger quantities of heat are frequently produced in normal individuals
as a result of muscular exercise or the taking of large quantities of
protein-rich food. The heat thus produced is, however, very quickly
dissipated, so that onty a temporary rise in temperature occurs, (cf.
Hewlett.57)

Similarly, it can be shown that in continuous fever there is a relative
inefficiency in the mechanism of heat dissipation. When the temperature
of a normal person is artificially raised through about 1° C, a marked
increase in cutaneous bloodflow and profuse perspiration are invariably
noted. In a patient with fever of the same degree, on the other hand,
there is practically no change in the skin circulation; indeed, it is usually
diminished, and there is no unusual perspiration. The heat-regulating
mechanism is now fixed on a plane that is higher than the normal, so
that although further increase in body temperature, as we have seen,
calls forth responses like those in a normal individual, yet at the fever
temperature itself there are none of the reactions which a normal individ-
ual would exhibit if his temperature were artificially raised to that level."

The adjustment of the temperature at the higher level is by no means
so perfect as it is at the normal level of health, so that a normal subject
is more resistant to the effects of cold than is a patient with fever. The
degree of response of the fever patient, however, varies considerably
from time to time; a cold bath in typhoid fever, for example, lowers the
body temperature much less effectively at an early stage in the disease,
when the fever is more or less continuous, than later when it is becoming
of the intermittent type. In the third week of the disease the cold bath

CONTROL OF BOD? TEMPEBATUB1 wi' rivu: 72-°.

more readily brings down the temperature :im<1 keeps ii down for a Longer
time than during the firsl or Becond week. The mechanism for heal
is also tic ranged in fever, which explains the rise in temperature thai
likely to follow the performance of even moderate muscular i • or

the taking of too hearty a meal in tuberculous and convalescent typhoid
patients.

Changes in the Body During Fever

In seeking Eor the fans.' of fever which is evidently of an obscure
nature, it is necessary to colled all the information we can regarding
iln- in. 'tain. lie changes thai are then occurring in the animal body. A
few of the most significan1 facts thai have so far been collected may
be mentioned here. Some of the most important concern the dis-
turbance in nitrogenous equilibrium cause.] by th< nsiderable loss of

nitrogen which takes place in fever patients when they are fed on
the usual hospital did prescribed for such cases. This loss of nitro-
gen is no doubt the result of the partial starvation in which the pa-
tienl is kept: for it has Keen shown by Shaffer and Coleman88 that
patients with typhoid fever may be maintained in nitrogenous equi-
librium by feeding them with relatively largo am. units of carbohy-
drate, which acts by protecting the protein of the body from disintegra-
tion (see page 571). Even with a diel excessively rich in carbohydi
that no more than covers the calorie requirements of the patient, nitrog-
enous equilibrium has also been attained. The protein minimum to
which fever patients .-an be reduced is nevertheless considerably higher
than the minimum in normal individuals.

From the above results as a whole, it is probably safe to conclude that
there is a specific destruction of proU in Lr«>in>_r on in the body during fever.

Further evident £ such a destruction is furnished by the presence in

the urine of excessive amounts of creatinin, of purine bases, and. it is
said, of incompletely hydrolyzed proteins, such as the albumoses pro-
teoses.) Moreover, when the fever suddenly terminates in crisis, there
Lb a marked increase in the excretion of urea (the epicritical area in-
Be), which indicates that an extensive deamination of protein build-
ing ston.s amino acids is occurring. The so-called "diazo react:
obtained in the urine during the fever is also believed to depend on the
present f abnormal protein-disintegration produ

As t.» the specific cause of the increased protein disintegration, little
is known. Several factors may operate: 1 the partial starvation
patient, entailing an b tkdown of protein 10 meet the caloric

requirements; 2 the high temperature, which in itself may stimul
increased protein metabolism, for it has been shown that, when normal

724 METABOLISM

animals are artificially warmed, protein metabolism becomes increased;
and (3) toxic protein-decomposition products specifically causing an ex-
cessive breakdown of protein.

Although there is increased protein breakdown during fever, it must
not be forgotten that only about 20 per cent of the total expenditure
of the body is derived from this foodstuff, 80 per cent coming from non-
nitrogenous material, which must be fat, because the available carbo-
hydrates are used up at an early stage.

Since the general metabolism is increased, the excessive breakdown of
the fatty substances, occurring as it does in the presence of a diminished
combustion of carbohydrates, interferes with the proper oxidation of the
fatty-acid molecules and leads to the appearance of so-called acidosis
products in the urine, and consequently to a relative increase in the
urinary ammonia (page G16). A tendency to acidosis therefore exists.
The acidosis may reach a considerable degree of severity and cause the
tension of carbon dioxide in the alveolar air to become diminished. Since
a similar degree of acidosis may be produced in partially starved ani-
mals by overheating them with moist air, but not so if the animals are
liberally fed with carbohydrates, it is probably safe to conclude that
abundance of carboh37djate is advisable in the food that is furnished to
fever patients.

Another interesting metabolic change in fever concerns the salt bal-
ance. This is studied by observing the amount of sodium chloride excreted
by the urine. As is well known, this becomes markedly diminished until
the crisis of the fever, when it suddenly increases. Salt retention is more
marked in certain types of fever than in others, and it is essentially dif-
ferent in nature from the salt retention that has been observed to occur
in nephritis. This difference has been brought to light by examination
of the chloride content of the blood. In nephritis, the concentration of
chlorides in the blood is considerably increased, whereas in fever it is
markedly diminished. The deficiency in salt elimination can not be at-
tributed to a deficiency of salt in the food, for it sets in before the did
has been curtailed and, when salt is given to a febrile patient, it is re-
tained in the body to a greater degree than is the case in the normal
individual. For some reason the tissues in fever have acquired the
property of retaining large quantities of salt.

Attempts to study the water balance during fever have frequently been
made, but the technical difficulties of such investigations make the re-
sults uncertain and of little value. That some retention of water occurs
• luring fever is, however, evidenced by the dilution of the blood. At the
crisis this hydremia quickly disappears at the same time as the increased

CONTROL OF BOD1 TEMPEBATUR1 \m« PEVEB >-■>

elimination of chlorides is going on. Chlorides and water would th<
fore seem to behave in a similar fashion during fever.

The Heat-regulating Center

In all discussions on the regulation of body temperature and the
causes of fever, it is assumed that a I igulating or thermogenic

center exists somewhere in the brain. It is believed to b<
about the optic thalami or corpora striata, for it lias been found in
rabbits that destruction of the brain anterior to this region does
cause any change in body temperature, whereas destruction behind it
is followed by an entire upset in the heat-regulating mechanism. Fur-
thermore, artificial puncture of this part of the brain causes marked
elevation in body temperature in rabbits (heat puncture). Most in-
teresting experiments have been recorded by Barbour,58 who - eded
in applying boat or cold locally in the region of the centers. By the
application of cold, increased muscular metabolism, on t lie one hand,
and diminished heat loss, on the other, were excited; and conversely,
when warmth was applied, an increased heat loss and a diminished I
production were observed. Irritation of this region of the brain in man.
as after cerebral hemorrhage, is also accompanied by remarkable dis-
turbances in heat regulation. Tt is believed by many that the essential
cause of infectious fever is an action on these centers by toxic substai
which develop in the blood.

The centers may also be acted on by various drugs, some of which
excite them to increase the body temperature, others, to lower the tem-
perature when this has already been elevated. When solutions of sodium
chloride are injected intravenously or subcutaneously or even sometu
particularly in children, when administered by month, more or

may result. This must be a s| itie action of the Na ion, for, if

of pun solutions o \ CI. solutions containing calcium and potassium
salts as well as tho sodium are injected, no fever is induced. This

fact, taken along with the close similarity between puncture dial ■
and heal puncture, lends support to the view thai in its initial
experimental fever of this type is the result of an excessive breakdown
of glycogen in the liver. It must not be imagined, ho . that |

cut fever can be attributed to such a cause, sin.- er remaii

the glycogen has all been removed. Other chemical substanci duc-

ing fever are caffeine, certain Other purines, and particularly tetra-hy

naphthylamin.

Belonging to this group of fevers musl he im-

portant ones produced by the intravenous injection D -

protein, as 1 rom th<

726 METABOLISM

teria or from the laked corpuscles of a foreign blood. The fever in
those cases is no doubt caused by a mechanism closely related to that
responsible for anaphylaxis (see page 89). Such injections do not pro-
duce fever in animals after division of the cervical spinal cord or ex-
cision of the midbrain. It is believed that many cases of so-called asep-
tic fever, occurring after severe contusions or other wounds, may be
the result of destruction of proteins within the body. Similarly the rise
in temperature during infections may be owing to the breakdown protein
of the microorganism in the cells.

Significance of Fever in the Organism

It is impossible at present to state definitely whether fever is a re-
action of the organism against some infection and therefore of benefit
in assisting the organism to combat it, or whether it is in itself an un-
favorable condition. The question can certainly not be answered by
observing the behavior of bacteria growing at different temperatures
in various media outside the body. That certain bacteria should be
found not to thrive at incubator temperatures equal to those found in
the body during fever, does not at all prove that this fever is of sig-
nificance as a means of combating the growth of the bacteria in the
body. It is undoubted that, where the body temperature becomes ex-
cessively high, the correct treatment is to keep it down as much as
possible. On the other hand, the reduced mortality that has followed
the introduction of the cold-bath treatment in typhoid fever may not
be due so much to the reduction in body temperature itself as to
the favorable effect produced on the nervous system and circulation.
We certainly know that in normal animals moderate degrees of hyper-
pyrexia produced by exposure to moist heat are well borne for consider-
able periods of time, thus indicating that it is the infection and not the
hyperthermia that causes the serious damage to the body in infectious
fevers.

METABOLISM REFERENCES

(Monographs and Original Papers)

iLusk, Graham: The Elements of the Science of Nutrition, W. B. Saunders Co., eil.
3, 1917.

-Cat heart, E. P.: The Physiology of Protein Metabolism, Monographs on Bio-
chemistry, Longmans, Green &. Co., 1912.

•''Taylor, A. E.: Digestion and Metabolism, Lea & Febiger, New York, 1912.

lUnderhill, F. P. : The Physiology of the Amino Acids, Yale Press, New Haven, 1915.

•'•Macleod, J. J. "R.: Diabetes, Its Pathological Physiology, E. Arnold. 1913.

saFiirth, von: The Problems of Physiological and Pathological Chemistry, etc., J. B.
Lippincott Co., 1916.

sbJones. AV.: Nucleic Acids, Monographs in Biochemistry, Longmans, Green & Co.,
1914.

ccMendel, Lafayette B. : Eigcbnisse dcr Physiologic, 1911.

CONTROL OF BOD'S TEMPEBATUBE AND FEVER 727

^Leathes, J. !'».: The Fats, Monographs in Biochemistry, Longmans, Green A I

. A. I1.: Physiological Chemistry, Win. W 1 A Co., 1917.

s'Dakin, If. K.: Oxidations and Redactions in the Animal Body, Monographs in I

chemistry, Longmans, Green & Co., 1912.
5gLeathes, J. I:.: Problems in Animal Metabolism, P."

flDu Bois, E. F., and collaborators: Clinical Chemistry, Papers I Lrch. Int. M

L915 1 7, xvi-.xix.
I'.onedict, F. G. : Am. Jour. PhysioL, 1916, xli, 275 and -92.
'Mendel, Lafayette B.: Harvey Lecture, J. B. Lippincotl Co., 1914-1915, p. 101.
'■'McColIum, E. V., ami collaborators: Numerous papers in Jour. Biol, f'hem., bc-

ginning 1913.
Hopkins, P. Gowland, and Willcock, E. G.: Jour. Physiol., 1906, xxxv, 88.
"Baylies, W. M.: The Physiology of Pood and Economy in Diet, Longman-.

& Co., 1917.
"McColIum, E. V.: Harvey Lecture, Jour. Am. Med. Assn., 1917.
i Bweet, J. E., Carson-White, E. P., and Baxon, G. J.: Jour. Biol. Chem., 1913, xv,

181: ibid., 1915, xxi, ..
i*Stepp, W.: Biochfin. Ztschr., 190!), xxii, 4 ."2.
'Punk, Casimir: Ergebnisse der I'hysiologie, 1915.

i«McKillop, M.: Food Values: What Tiny Are and How to Calculate Them.
Rutledge.
McCoy, D. Major: The Protein Element in Nutrition, E. Arnold, London, 1912.
"Pembrey, ML B.: Chemistry of Respiration, in Schafer's Text Book of Physiol |

1898, i.
isAllen, F. P.: Glycosuria and Diabetes, Boston, 1913.
•'•'Joslin: Diab'

-"Woodyatt, R. T., Sansum, W. D., and Wilder, EL M.: Jour. Am. Med. Assn., I
lxv, 2067. Also Taylor, A. E., and Hulton, F.: Jour. Biol. Chem.. 1916. v
173.
acleod, J. J. B., and Fulk, M. E.: Am. Jour. Physiol., 1917, xlii, 193.
"Hamman. L., and Hirachbaum: Arch. Int. Med., 1917, xx, 761-788.
-3Cannon, W. B.: Bodily Changes in Pain, Hunger, Fear and Rage, B. Appleton &
Co., 1915.
'Knowlton, F. I'., and Starling, E. II.: Jour. Physiol., 1912, xlv, 146.
Patterson, S. W., and Starling, E. II.: Jour. Physiol., 1913, xlvii, 135; also Cruiek-

shank and Patterson: Ibid., p. 113.
la.leod, J. J. R.: Glycolysis, Jour. Biol. Chem, 1913, xv, 497.
lurlin, J. P.: Jour. Biol. Chem., 1913, xvi, 79.
asCruiekshank: Jour. Phvsiol., 1913, xlvii, 1.
•Macleod, J. J. R., and Pearee, K. G.: ZentralbL f. Phvsiol., 1913, xx\i, 1311.
"Woodyatt, R. T.: Jour. Am. Mod. Assn., 1916, lxvi, 1
31 Van Slyke, D. D.: The Presenl Significance of the Amino Acids in Physiologv and
Pathology, Harvey L , J. B. Lippincott A Co., 1915-1916, p. 146. Also

papers in Jour. Biol. Chem., 1911, ix, 185; xii, 27.": ibid., 1912, xii, 301 and 399:
ibid., 1913, xiii, 121, 125 an I L87.
a^Folin, O., and Denis, \\\: Jour. Biol. Chem.. \i, ^7 :in,i \>y.\ ■ ibid., 1912, xii. 11 and
253.
Abel, J. J.: The Mellon Lecture, Science, 1915, xlii, 135.
'Hewlett, \. w., Gilbert, L. 0., Wickett, A. D.: Arch. in*. Med., 1916, xviii, 636.

1. . .L 1;.. and Van Slyke, D. D.: Jour. Med. \-n., 1917, cliii, 94.

■•Shaffer, P. A.: Am. Jour. Physiol., 1908, xxviii, 1.
"Catheart, L. P.: dour. Physiol., 1007. txxv, 500.
ttiyera and Pine: Jour. BioL Chem., 1913, xiv, 9.
>Lev< ne, P. L: Cf. W. Jon.
*oJones, w.: Nucleic A da, " 1 raphs on Biochemistry, Longmans Co..

1914.
'i:. aediot, s. p.: Harvey L. . ture, L91fi

"Hunter, L, and Givens, M, IL: Jour. Biol Chem,, 1914, xviii, I
MBurian, P.. and Schur, H.: Cf. Macleod in Becenl Advances In Phys

chemistry, ed. by Leonard Hill, K. Arnold, London.
"Mendel Lafayette B., and Lyman, J. P.: Jour. Biol. Chem., 1910, viii, lit

■It. \. 1 .'and BoSC, W. • ir. Pool. Chem .

Hopkins. P. G . and Hope, w. B.: Jour. Physiol., 1-

728 METABOLISM

wAscoli, M., and Izar, G.: Ztsclir. f. Phvsiol. Chem., 1909, lviii, 529; ibid., 1911, lxiii,

319.
isMcClure, C. W., Vincent, P.., and Pratt, .1. H.: Am. Jonr. Physiol., 1916, xlii, 596.
4oBloor, W. E.: Jour. Biol. Chem., 1912, xi, 429; ibid., 1913, xv, 105; ibid., 1914, xvi,

517; ibid., 1912, xi, 141; ibid., 1915, xxi, 421; ibid., 1914, xix, 1; ibid., 1915,

xxiii, 317; ibid., 1914, xvii, 317; ibid, 1915, xxii, 133. Also Bloor and Knudson:

Jour. Biol. Chem., 1916, xxvii, 107; ibid., 1916, xxiv, 447; Bloor, Joslin and

Horner: Ibid., 1916, xxvi, 417; ibid., 1916, xxv, 577.
•^Lcathes, J. B.: The Fats, Monographs on Biochemistry, Longmans, Green & Co.
siCoope, E., and Mottram, V. H.: Jour. Physiol., 1914, xlix, 23; ibid., 191."). xlix, 1 r, 7 .
52Eaper, H. S.: Jour. Biol. Chem., 1913, xiv, 117.
••Rmedley, I. D. : Proe. Phys. Soc, Jour. Physiol., 1912, xlv, 2").
•"•■*Hill, Leonard: Address to the Phys. Sec. Brit. Assn. for the Adv. of Sci., Section,

J, 1912.
"-■Shaffer, P. A., and Coleman, W.: Arch. Int. Med., 1909, iv, 538.
^Barbour, H. G.: Arch f. Exper.'Path. u. Pharmac, 1912, lxx, 1. Also Barbour and

Wing, S. S. : Jour. Pharmac. and Exper. Therap., 1913, v, 105.
-'^Hewlett, A. W.: Monographic Medicine, D. Appleton & Co., 1917, i.

PART VIII
THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

CHAPTEB I. XXXI
THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

In order that the various activities of the animal organism may act
efficiently as a whole, it is necessary that those of one part be correlated
with those of another. This correlation of function is mediated either
through the nervous system or through the action on one part of the
body of substances produced in another part and carried between them by
the blood. Control through the nervous system is especially developed for
those functions which have to be brought promptly into play, such as
muscular movemenl and the other physiological processes concerned in the
adjustment of the organism to quickly changing conditions of its environ-
ment. ( lontrol through the blood is the mechanism by which the metabolic
activities of different organs are mainly correlated. The chemical sub-
sf.ii s involved are often called internal secretions.

Some of these internal secretions are merely by-products of metabolism,
and are only incidentally used Eor the purpose of bringing about control
between different parts of the body. To this group belong carbon dioxide,
which may act on the respiratory and other nerve centers, and urea, which
may stimulate increased activity of the kidneys. Indeed, the list of sub-
Stances included under such a definition of internal secretions is air
illimitable, ami to designate by the special name of hormone every con-
stituent thai can affect physiological functions, as Borne have done, can
only to confusion. The internal 'ions with which we are mort

directly concerned are those that are specially produced for the purp
of controlling the metabolic functions. They ate given the general name

of ant; ids ES. A. Schafer).60 Autacoids may be either the - lucl

of some special gland or a secondary product of glands which have o*
functions. To the former class belong the autacoids produced by the para-
thyroid, thyroid, pituitary and adrenal glands, and to the latl

produced by the pancreas and generative glands;

Autacoids have further been subdivided by S r into two •

729

730 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

according to "whether they excite metabolic processes or depress them.
Examples of excitatory autacoids, also designated as hormones, are the
epinephrine produced by the adrenal glands, "which excites the termina-
tions of the sympathetic nervous system, and pituitrin produced by the
posterior lobe of the pituitary gland, which excites plain muscular fiber.
Inhibiting autacoids, also called chalones, are not so commonly known, but
are illustrated by the substance contained in extract of the placenta,
which tends to prevent the secretion of milk.

Autacoids may have either an immediate or a delayed action; the effect
which they produce may be like that with which we are familiar as the
result of stimulation of the nerve supply of a gland, being illustrated
again by the effect of epinephrine, or they may act so slowly that it is
only after a considerable period of time during which they have been
in the organism in excess, that any apparent effect is produced. The
slowly acting autacoids have been called morphogenetic, and they are
well illustrated in the internal secretions of the anterior lobe of the
pituitary and of the generative glands — secretions which affect growth.

Regarding the chemical nature of autacoids, certain facts stand out
prominently. Being very largely the products of glands, it might be
imagined that they would be enzymic in nature, for enzymes are now
known to be the most important active agents in bioplasm as well as the
active agents in many of the external secretions, like those of the sali-
vary, gastric and intestinal glands. Autacoids, however, are not enzymes.
They are far simpler in chemical structure, and are not destroyed by
heat in the presence of water. They are represented by a comparatively
small molecule, and are therefore dialyzable. This latter fact justifies
the hope that it may be possible to prepare them or their simpler salts
in crystalline form — a hope which has already been realized in the case
of at least one of them — epinephrine. Great progress has likewise been
made in isolating the active principles of the thyroid and of; the anterior
and posterior lobes of the pituitary glands. To sum up, then, we may
say that an autacoid is a specific organic substance, formed by the cells
of one organ and secreted into the circulating fluid, which carries it to
other organs, upon which it produces effects similar to those of drugs.

Methods of Investigation

To investigate the function of an autacoid, careful studies are made of
the effects produced (1) by excision of the gland which furnishes the
autacoid and (2) by administering intravenously or subcutaneously or
orally extracts prepared from the gland. Frequently, also light is thrown
on the function of the autacoid by observing the effect which fol-
lows prolonged feeding with the endocrine organ that manufactures it

Tin: ENDOCRINE ORGANS, OB DUCTLESS GLANDE

and by observing the pathological changes in tin- various endocrine orgj
In diseased conditions. Embryological and histological studies are i
the greatest importance. A difficulty in investigatit *ion of

an endocrine organ lies in the fad that the secretion of no one gland
acts independently of those from other glands. < »n the contrary, there is
undoubtedly a close association of function, v., that we can not tell
whether a change of function observed after removal of some gland
administration of some extract is a direct consequence of the experi-
mental procedure, or is induce. 1 by some secondary - eloped on
another endocrine organ. It will no doubt take many years hefore suf-
ficient data have been collected to enable us definitely tate what the
particular function of each endocrine organ may be. Since most pi
has been made in connection with the adrenal gland, it will be advan-
tageous to consider the functions of this gland first.

ADRENAL GLAND

In mammals the adrenal gland is composed of two parts, th< x and

the medulla. In other groups of animals however, these two are more or

3 separate, being completely so in fishes. This not infrequent separa-
tion of cortex and medulla suggests a different function for the I
structures. Experimental investigation supports this view.

The Cortex

The cortex on microscopic examination is Been to be composed of rows
of epithelial cells arranged more or less in columns except at the
periphery, where they form glomerular mass< 3, and next the medulla,
where they assume a reticular formation. The cells of the greater part
of the cortex, unlike those of the medulla, contain no granules with
special Btaining qualities, but they do contain particles which are be-
lieved t<> be composed of cholesterol esters and lecithin. In the cells
the reticular portion of the cortex, however, pigment part re not

infrequently observed. The blood supply of the cortex is not relative]-, a
rich as that of the medulla, being represented by fine arterioles which
run inwards from the capsule towards the medulla in the connective ' -

Nile that lies between tli Jumna of cortical cells. N es similarly

penetrate into the cortex, some supplying its blood, vessels and cell

columns, but most mi* them pro ling to the medulla. Th<\\ are der

from ,i network of nerve fibers in the capsule of the organ, and the ni
supply of this network comes partly from the suprarenal plexus, and
partly from the splanchnic nerve. Embryologically ihe cortex is
veloped from the cells of the genital ridge, thai is, from mesodermic

cells.

732 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

Very little is known concerning the function of the adrenal cortex,
although there is little doubt that it is elosely related with the develop-
ment of the sexual organs. The evidence for this is as follows: (1) in
cases of sexual precocity it is found that the adrenal cortex is much
hypertrophied ; (2) it becomes hypertrophied during pregnancy; (3) it
is ill developed in sexual deficiency; (4) changes occur in it during the
estrnal cycle in many animals; (5) after castration it is said to be hyper-
trophied; (6) the innermost portion of the cortex,- sometimes called the
boundary zone, is much hypertrophied in the human fetus, but this hyper-
trophy entirely disappears after the first year of extrauterine life.

The other functions of the cortex are not as yet known, but there is very
strong evidence that they are of great importance to the welfare of the
animal. It has been suggested that the passage of blood through the
cortex before reaching the medulla indicates that some change which
is preparatory to the main change occurring in the medulla takes place
in the blood while it is in the cortex. This view is partly substantiated
by the observation that when an excised portion of cortex is incubated
at body temperature, a substance develops in it which has an action
like that of the hormone of the medulla — epinephrine. It is possible,
however, that this action is due to the fact that certain of the decomposition
products of protein develop an epinephrine-like action (see page 502).

The Medulla

Histologically the medulla is composed of masses of polygonal cells
with blood sinuses between them. The blood supply is derived from ves-
sels that have proceeded to the medulla through the capsule, and it is
extremely rich, being indeed the richest blood supply to any organ in the
body, greater even than that to the thyroid gland. The nerves form a
dense plexus, extending into and between the secretory cells. The most
characteristic feature of the cells composing the medulla is the presence
in them of granules which stain readily Avith chromic acid, and are hence
often called chromaffin cells. There are also some cells containing coarser
grannies that are soluble in water and do not stain with chrome salts.

Embryologically the medulla is developed from the same neuroblastic
cells that give rise to the sympathetic nervous system. This evidence of
the close association between the medulla and the sympathetic nervous
system, we shall see to be substantiated by the results of experimental
investigation.

On account of the anatomic relationships, it is impossible to study the
effect of excision of the cortex and medulla separately, or, indeed, of the
action of pure extracts prepared from either of these portions of the

THE ENDOCRINE ORGANS, OB DU< rLESS OLAND

gland. Our investigations must concern the effecl of removal of the

whole gland or of the injection of extracts of it, and as we proc 1 to

examine the data, it will become evidenl that most of tl ob-

served to occui a-, a resnll of injection of extracts of the gland, can
be attributed to the medulla. The fatal effects of complete extirpation,
on thr other band, are prohably due to removal of the centi

Adrenalectomy

Excision of the adrenal gland in most animals is very quickly fatal,
the only well-known exception being in the case of the white rat, in which
excision of both adrenals may uo1 be incompatible with life. For some
time after recovery from the anesthetic the animal upon which double
adrenalectomy lias been performed usually behaves in a perfectly non
fashion, although it may be less lively and less inclined 1" feed than
usual. Very soon, however, generally within twenty-four or forty-
eight hours, definite symptoms of muscular weakness are apparent. This
weakness soon becomes extreme, and is accompanied by a feeble ]>i,
a depression of body temperature, and, later, by dyspnea. After an
interval which is never longer than a few days, death supervenes, being
sometimes preceded by convulsions.

When only one adrenal is removed, very few animals succumb: and

if BOme time is allowed to elapse so that the immediate shock of the

operation has disappeared, it will usually be found that removal of the

remaining adrenal, although ultimately fatal, is not so quickly so as
when Imih glands are removed at one operation. The reason for this
result is that opportunity is given \<>v a compensatory hypertrophy of

accessory adrenal bodies to occur. Such acc< ry adrenal bodies may

l.e composed of cortical or medullary tissue, and there is a growing belief

that th trtical tissue is the more important. Chromaffin tissue is found

in most animals along the front of the aorta, between th • renal arteries,
where it can usually be recognized by Btaining the tissue with chromic acid.

Sometimes accessory chromaffin tissue is located in distant parts,

as in the epididymis Of the rat. for example. It is Baid that life can
be maintained if one-eighth of the total amount of the adrenal subsl

present in the body. Attempts to prolong lib adrenalectomy

by adrenal transplantation have almost invariably met with negative

results, because the grafl under rapid process of necrosis and dis-

appears; although it is said that transplantation may sometiim
cessfiilly accomplished if the grafting is done into the kidney. Adminis-
tration of suprarenal extract is also without definit<
adrenalectomy.

734 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

Suprarenal Extracts — Preparation

Injection, particularly intravenous, of extract of the adrenal gland
has furnished us with most of the evidence upon which our knowledge
regarding the function of this organ depends. Such an extract is best
made by grinding the entire gland with fine sand in a mortar and then
extracting with a weak' (decinormal) solution of hydrochloric acid. The
extract may then he boiled, filtered through muslin and nearly neutral-
ized, preferably by means of sodium acetate. If kept in this acid reac-
tion, the active principle of the extract does not materially deteriorate
with time, but if it he neutralized or considerably diluted, destruction
due to oxidation occurs, as evidenced by a distinct browning of the
solution. The active principle of such extracts has keen isolated in a
crystalline form (Takamine and Abel). It has been given various names
(adrenalin, suprarenin, adrenin, etc.), but the tendency is definitely
towards the use of epinephrine. Chemically, epinephrine has been found
to be orthodioxyphenylethylolmethylamine.

HO

IIO<^ \ -*CH(OH) - CH2NHCH3.

It will be noted that it is closely related to tyrosine (see page 604). It
is also closely related to a group of substances (amines) occurring in
putrid meat and to which the active principles of ergot belong. It
contains an asymmetric carbon atom (asterisked in formula), which
indicates that there must be three varieties of epinephrine, differing
from one another in the effect which they produce on the plane of
polarized light (i.e., a dextro- and a levo-rotatory and a racemic form).

Epinephrine can be prepared by synthetic means, the first product of
this synthesis being the racemic salt, which can then be split by appro-
priate methods into dextro- and levo- varieties. The levo- variety ap-
pears to be identical in its pharmacological action with the natural product.
The dextro- variety on the other hand has only poorly developed physio-
logic activities (about seven per cent that of the levo- variety), while
the racemic variety comes in between the two in its action. A valuable
assay of the amount of epinephrine in tissue extracts can be made by
the method of Cannon, Folin and Denis,62 in which an acid extract of
the gland is treated with phosphotungstic acid, and the blue color thereby
developed compared colorimetrically with a standard blue.

Physiological Action

The physiological effects of the intravenous injection of epinephrine are
markedly excitatory and slightly inhibitory in nature. We will consider

THE ENDOCRINE ORGANS, OB DUCTLESS GLANDS

the excitatory action first, [mmediately after the intravenous injection

of as small an ;i mount as 0 noons milligrams per kilogram of body weight,

a distincl rise in arterial hi I pressure may I"- observed. When the

pise is distinct, it is accompanied by a Blowing of the pulse. This Blow-
ing is caused l>.\ stimulation of the vagus center, as is evidenced by the
Fad thai it* the vagus nerves are eut, or sufficienl atropine administered
to paralyze them, the Bame dose of epinephrine produces not a Blowing
hut a quickening of the pulse, and consequently a much greater rise in
blood pressure. The vagus action is developed not because of an effecl
of epinephrine <>n the \a'_rus center, bul secondarily because of the rise
in blood pressure.

These preliminary experiments indicate that the locus of action
epinephrine, so far as the circulatory system is concerned, is mainly on
the small blood vessels, constricting them and thus raising the peripheral
resistance. This conclusion can readily ho confirmed by applying the
epinephrine directly to the blood vessels of the exposed mesentery, or
by enclosing a vascular organ such as the kidney in a plethysmograph
during the injection of epinephrine, when a greal diminution in volume.

accompanying the rise of arterial hi 1 pressure, will be obs< i. Tim

vasoconstricting effect of epinephrine dees not become developed on the
Large blood vessels near the hear! on account of t ho deficiency in muscu-
lar tissue in their vails. Indeed, these vessels may hecome passively
dilated because of the increased hlood pressure. The arterioles of dif-
ferent parts <>f the circulation are not equally sensitive to epinephrine;
those of the splanchnic area are mosl sensitive, ,wh< those of the

heart the coronary vessels do not respond at all in most animals

page 257). The pulmonary and cerebral \essels have a variable reactivity
to epinephrine.

The effect on the vessels persists after complete destruction, not only
of the central nervous system, hut also of the vasomotor nerves; epi-
nephrine still ads, for example, on vessels the nerve fibers of which
have been allowed to degenerate by cutting them several days before the
epinephrine is applied. This would seem to indicate that the epinephrine

acts directly on the muscular tissue in the walls of the hlood \

hut this does not appear to he the for it has been found that epi-

nephrine is incapable of acting on t a bich are devoid of sympathi

nerve fibers, and is also inactive on those • u the embryo which 1.

not yet received any nerve supply. In brief, then, although epinephrine
acts only on blood vessels that an- supplied by the Bympatheti(
system, it is not on the nerve fibers that the epinephrine unfolds its
action. We shall see immediately that this conclusion is in conformity

736 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

with the results of observations made on structures other than t he blood
\cssels.

Other muscular structures excited by epinephrine are as follows:
(1) the dilator muscle of the pupils, especially after the nerve supply has
been destroyed by extirpation of the superior cervical ganglion; (2) the
sphincters of the pylorus and of the ileocecal valve; (3) the muscle fibers
of the spleen, the vagina, the uterus, the vas deferens, and the retractor
penis. Regarding the action on the uterus, however, it should be noted
that a different response may be obtained according to whether the
uterus is pregnant or not. The plain muscles of the orbit and globe of
the eye are sometimes excited by suprarenal extract, causing the eyes to
protrude, the palpebral fissure to become large and the third eyelid to
be retracted, changes which are very like those which develop as a
result of fright.

Inhibitory effects of epinephrine on muscle are exhibited by the follow-
ing: (1) the muscle of the intestine; (2) the stomach; (3) the esophagus;
(4) the gall and urinary bladders.

The effect of epinephrine in inhibiting the rhythmic contractions of
an isolated portion of the intestine in oxygenated Ringer's solution is a
very striking phenomenon, and one which, as we shall see, may be very
successfully employed for detecting small quantities of epinephrine.

The effects of epinephrine on glandular structures are the same as those
which would be produced by stimulation of the sympathetic nerve supply
of the gland. Thus, the secretions of the lachrymal gland, the salivary
gland (in the cat), the mucous glands of the mouth and pharynx, the
gastric but not the pancreatic glands, can readily be shown to be
excited.

From these results as a whole, it is evident that the effect of epineph-
rine on muscles and glands is exactly the same as that which would be
produced by stimulation of their sympathetic nerve supply. This paral-
lelism of action between epinephrine and the sympathetic nervous sys-
tem becomes still more evident when we consider certain of the changes
in metabolism that follow administration of epinephrine. Injection of
epinephrine excites glycogenolysis in the liver so that hyperglycemia
and glycosuria become established, results which are also obtained by
stimulating the great splanchnic nerve. Intravenous injection of epineph-
rine causes the clotting time of the blood discharged from the liver
to be very materially shortened, an effect also produced by stimulating
the splanchnic nen e

As in the case of the blood vessels, the above results are obtained even
after the sympathetic nerves to the part have been allowed to undergo
degeneration, from which it is concluded that the tissues elaborate some

THE ENDdCBINE ORGANS, OR DUCTLESS OLA 7-17

substance which reacts with epinephrine. This substance may be ;
duced either al the junction between the nerve and muscle the myo-

aeural junction, or perhaps throug] i the protoplasm itself. It is

failed the receptor substance of Langley, and is believed to read not
only with epinephrine, bul also with various drugs. The receptor bud-
stance seems to increase, it' no1 in amount, ;it leasl in sensitivity
the removal of t he nerve control.

Ergotoxin, which is an amine obtained from ergol and also from <■■
tain of the products of histidine, lias an action on the receptor substance
which is inhibitory and therefore antagonistic to thai of epinephrine.

The antagonistic action of ergotoxin affects the excitatory bul not
the inhibitory actions of epinephrine. By using this drug we are en-
abled to show that, although the main effect of epinephrine on tissue is
excitatory, a less marked inhibitory influence may be simultaneously
developed. The inhibitory effed may also sometimes be evoked by
doses of epinephrine very much smaller than ihose used to produce
excitatory effects. These facts are well illustrated in the case of tho
muscle fiber of the blood vessels. With an ordinary dose of epinephrine
constriction occurs; after ergotoxin the same dose of epinephri ises

dilatation. Or this latter result may also be obtained by administer-
ing to a normal animal quantities of epinephrine that are very much

smaller than the usual quantity. The coexistent E inhibitory and

citatory influence is also well noted in the case of the uterus. In some
animals the effect of epinephrine on this organ is to augment its rhythmic
contractions, in others lo inhibit them. In the former case, however, if
ergotoxin is first of all administered, epinephrine in its usual d< will

invariably produce an inhibitory effect. The ergotoxin no doubt acts on

the receptor substance, and similar effects have also been produced with

apocodeine.

Although ii is especially on plain muscular fiber having a sympathetic
nerve supply that epinephrine unfolds its action, yet, accordii Can-

non, it increases the contracting power of voluntary muscle and dimin-
ishes the tendency to fatigue.*

•For further details of th< s the pa

CHAPTER LXXXIl

THE ADRENAL GLANDS (Cont'd)

Variations in Physiological Activity

Since it is clearly established that the adrenal glands are indispensable
to life and that extracts of them have very pronounced physiological ac-
tions, it remains to consider whether the glands produce this internal secre-
tion within the body, and if so, whether it is essential for the well-being
of the animal or is required only under certain conditions. "We must also
endeavor to find out upon which of the bodily functions of the intact
animal the internal secretion acts. These problems have been attacked
by three methods of investigation: (1) by comparing the epinephrine
content of similarly prepared extracts of the resting gland and of one
removed after a period of supposed increased activity; (2) by collecting
the blood as it flows into the vena cava from the adrenal vein and ex-
amining it for epinephrine by physiological tests. These consist in observ-
ing the behavior of some tissue that is sensitive to the action of epineph-
rine, such as the intestine or uterus, after applying the blood or serum
to it, or by injecting the blood or serum intravenously into another ani-
mal and looking for epinephrine effects; and (3) by allowing the blood
of the adrenal vein to be discharged under certain conditions through
the vena cava into the blood vessels of the same animal, and observing
the effect produced on certain physiological processes which in one way
or another have been sensitized toward the influence of epinephrine.
This autoinjection method has recently been used successfully by Stew-
art and Rogoff,66 their favorite structure upon which to observe the
epinephrine effect being the denervated pupil.

Assaying the Epinephrine Content of the Gland

With regard to the first mentioned of the methods, either chemical or
physiological means may be employed to assay the strength of the ex-
tracts. The best chemical method is that of Cannon, Folin and Denis,0-
the , principle of which has already been described. The physiologic
method yielding most satisfactory results is that of Elliott,67 which con-
sists in injecting a portion of the extract intravenously into animals
from which the influence of the nerve centers on the heart and blood
vessels has been removed by decapitation. The rise in arterial blood

738

i ill \hi;i N \l. GLAN

pressure produced by the injection is then ;i very fair measure of the

amount of epinephrine contai ! in it. It lias been shown that the re-

suits obtained by the chemical method agree very closely with those obtau
by the physiological, bul it should be remarked thai it is difficult to Bee how
the physiological method could be accurate in all cases, sine- it has been
shown that with greal dilution of epinephrine a reversed effed a vj
dilatation- may be obtained. Attempts to assay the strength of an
epinephrine solution by investigating the effects which it produe
other preparations, Buch as isolated loops of intestine or uterus, or the
enucleated eyeball of the frog, arc not always successful, sim effects

are no1 alone dependenl on the concentration of epinephrine in the
extract. When such preparations are used for quantitative purpos

the strength of the extract may be judged by finding tl stent to which

it can be diluted and still remain active.

Quite apart from the foregoing possible sources of error, it musl be
remembered that the results merely give us an idea of how much epineph-
rine may have been contained in the gland at the limo of its excision.
They can not tell us how much epinephrine the gland was secreting. Prior
to excision as much of this hormone mighl have been undergoing a proc< ss
of manufacture in the gland as was being discharged from it, so thai the
yed amount would represenl merely the balance of production and loss
of hormone by the gland. We mighl quite well find that the amount of
epinephrine in the excised gland was normal under conditions wl
there had been an excessive discharge of it into the blood; that is to say.

- and production mighl have been equal. Where, however, a marl
deficiency is found to exist, it probably indicates that exhaustion of the
power of producing epinephrine was taking place.

The Epinephrine Content of the Blood. The second method, in which
blood from one animal is tested for its epinephrine effed by intravenous
injection into another animal or by applying it to some isolated prepara-
tion on which epinephrine ads. has yielded important results. Since
serum contains all the epinephrine of blood, it can be conveniently used
for the tests Stewart and Rogoff). The isolated physiological prepara-
tions that have been used in testing for epinephrine in the animal fluids

are as follow B:

1. .1 segment of the small intestim of a rabbit, suspended in oxj -•
ated Locke's solution at body temperatu

2. .1 segment of the uterus of a nonpregnant rabbit similarly prepaid
The apparatus used for observing the contractions of either prepara-
tion consists of a small glass chamber furnished below with a hook to
which one end of the segmenl is attached, the other end bej

740

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

to a muscle lever, so thai the regular rhythmic contractions can be regis-
tered on a drum (Fig. 190).

Epinephrine inhibits the contractions of the intosline but stimulates
those of the uterus of most animals, the intestine preparation being the
more sensitive (Pig. 191). Indeed, it is said that the inhibition in this
case may be obtained with a solution containing 1 part of epinephrine in
20.000,000 of solution. In using this method, however, great care and
judgment must be exercised in drawing conclusions, because other sub-
stances present in the blood are liable to affect the contractions; thus,

Air. vent

Fig. 190. — Arrangement of apparatus for recording contractions of a uterine strip, intestinal

strip, or ring, etc. The metal water-bath is made of a cheap metal water-pail with a heating rod

soldered through the side at the bottom. A short metal tube is soldered into a 1-inch opening in

the bottom to receive a perforated cork for connecting with the Harvard muscle-warmer inside.
(From Jackson.)

certain substances in blood serum which have been produced by the act
of blood clotting may cause augmentation of the beat in both the intes-
tinal and the uterine preparations. A certain amount of epinephrine in
Locke's solution is consequently more likely to cause inhibition of the
intestine than a similar amount added to blood serum, because in the lat-
ter case the pressor substance will neutralize the depressor effect of the
epinephrine. On the uterine preparation, both the blood serum and the
epinephrine have pressor effects. As has been pointed out by G. N
Stewart,68 if both preparations are employed for testing a solution sup-

Till \l>kl \ \l. QLANDS

741

posed i" contain epinephrine, little chance of error is likely to I"' in-
curred; thai is, if the solution produces inhibition of the intestine along
with augmentation of the uterus, it musl contain epinephri

3. The fresh carotid artery of thi sheep. A ring cut from the art
is suspended in oxygenated Locke's solution and attached below to a

Pig, l''i Tracing • nephrine on the intestinal '. on the

arterial blood i>n - preliminary addition of barium to the nutritive fluid may be

garded, > < Prom J

small hook and above to a loaded muscle lever, by which th>' contraction
of the muscle fibers can 1"' magnified. Epinephrine causes the muscle
contract, I >u t the tesl is no1 so sensitive as the foregoii ally in

the presence of blood serum, because the pressor substances therein con-
tained also causr contraction. Blood plasma does not contain the r
sor substances, so thai oxalated plasma should be used in pi um

742

THE 11XD0CRINE ORGANS, OR DUCTLESS GLANDS

in applying the test. To increase the sensitiveness of the muscle, the
artery ring should be slightly stretched by loading the lever.
4. The blood vessels of a frog. This method depends on the same prin-

192. — Arrangement of apparatus for perfusion of the vessels of a brainli j. (From

Jackson.)

ciple as in that just described. The fluid supposed to contain epinephrine
is added to Locke's solution, which is meanwhile being perfused under
constant pressure through the blood vessels and the rate of outflow

i BE vi -K I nai. QLAND8 - 13

noted (Fig. L92 . If 1 1 1 « - fluid added to the inflowing fluid contains epi-
nephrine, the outflow will become diminished. This is a \
method, although it is Bomewhal limited in Bcope unless Large frogs are
procurable, because of the difficulty <>t' «_r « • 1 1 i 1 1 «_r the necessary cannula?
into the vessels (aorta and abdominal vein).

5. The pupil of tl>> enucleated < >i< of thi frog. Extremely small trac
of epinephrine are observed to cause a dilatation.

6. 77/< denervated iris. Tfie fluid to be tested is placed in the conjunc-
tival s;ic of an animal from which the superior cervical ganglion <>f the
corresponding side has been removed sum.- days previously. Under such
conditions, if epinephrine is present in the fluid, dilatation of the pupil
occurs. I'.oth of the preceding reactions we owe to Meltzer.7 '

It should ho emphasized that, although each of these methods is in
itself vn-y sensitive for the detection of epinephrine without being al-
ways specific, yet the result should not be considered conclusive unl<
definite effects have been secured hy at least two methods that are '''s
far as possible independent of each other.

As an outcome of investigations by these methods it has been found
that, when blood from the adrenal vein is collected in a pocket of vena
cava made by applying clamps above and below the entrance of the
adrenal veins, the presence of epinephrine can be revealed, the rate
secretion being from 0.0003 to 0.001 mer. per kilogram of body weighl
per minute (Stewart and Bogoff). The absolute amount of epinephrine
liberated from the gland can be measured only by finding the concen-
tration in the adrenal vein blood and the rate of bloodflow. This amount
is approximately constant, so that the concentration in the blood which
collects in the cava pocket varies inversely with the rate of bloodflow.
In asphyxia the bloodflow is d< \ so thai the concentration

nephrine increases, bu1 there is no change in the absolute amount. N
ther anesthesia nor trauma affects the amount. The concentration is
likely to rise late in an experiment because of the slowing of bloodflow.
Adrenal activity may, however, be excited by massage of the trland'.
by stimulation of its nerve supply through the greal splanchnic nerve

The presence of epinephrine in hi 1 collected directly from the adrenal

veins does nol justify us in concluding that, when mixed with the
mainder of the hi I in the body, there would be a sufficient concentra-
tion of this substance to develop any of its activities. It has th<
been necessary to devise methods by which this possibility could be
tested.

The Autoinjection Method. Such a method was first of all
fully used by Asher, who employed an animal from which all the abdom-
inal viscera had 1 n removed. On stimulation of the g splanchnic

744 THE ENDOCRINE ORGANS, OR DI'CTLESS GLANDS

nerve a rise in arterial blood pressure occurred provided the adrenal
veins were open, but not so if the adrenal veins were clamped. By re-
moving the viscera, the effect of splanchnic stimulation on the abdom-
innl IiIikkI vessels themselves is eliminated, and any constriction which
occurs in the blood vessels of the rest of the body must obviously be due
to the action of epinephrine.

The most satisfactory of these methods is that more recently employed
by Stewart, Rogoff: and Gibson,69 which consists in observing the be-
havior of the pupil on the side from which the superior cervical ganglion
has been removed about one week previously. Of course the blood pres-
sure cl'fccl is also observed.

Among the most important results secured by this method it may be
mentioned that dilatation of the pupil occurs on stimulation of the great
splanchnic nerve, provided the vena cava and adrenal vein are unobstructed
so that the blood from the adrenal glands can get to the head. If the vena
cava is clamped and the splanchnic nerve stimulated, there is no pupil-
lary dilatation, but it immediately occurs after the clamp is removed.
Epinephrine continues to be discharged for a considerable period of time
after stimulating the splanchnic nerve, but the immediate increase which
follows the application of the stimulus does not last long, so that more
secretion can be obtained by intermittent than by continuous stimula-
tion. It does not seem to be' possible to exhaust the adrenal gland of its
supply of active material by stimulating the splanchnic — a fact which
would seem to throw considerable doubt on the reliability of the con-
clusions arrived at by the use of those methods in which extracts of the
uland nre assnyed (see page 739).*

Many interesting facts concerning the nature of the innervation of the
gland have been secured by one or other of the above methods. After
section of the sympathetic chain and the great splanchnic nerves on both
sides (in the thorax), no epinephrine is secreted into the blood of the
adrenal vein, and when one gland is extirpated and the nerve connec-
tions of the other entirely cut, the epinephrine content of the adrenal
vein blood sinks to not more than 1/1000 of the normal amount. The
animals survive this latter operation and behave in a perfectly normal
fashion, indicating that the internal secretion of the adrenals can not have
the physiological significance so often ascribed to it.

The splanchnic fibers concerned in the secretion of epinephrine seem
to come from a nerve center situated relatively low down in the spinal
cord. Section of the cord at the level of the last cervical segment does
not affect the spontaneous secretion, but this disappears when the section
is made below the third thoracic segment. (Stewart and Rogoff.)

"Another great advantage >>f the aul'oinjection method is that no 'confusion can be caused by
the development of pri bstances through clotting.

I ill IDRENAL GLAN 745

In connection with these observations it is of interest to note that dur-
ing stimulation of the Bplanchnic nerve in a normal animal, the eoi

quenl rise in hi I pressure shows two pea Pig 29, page 137 . The

first is no doubl due to dired stimulati >f the splanchnic vasoconstric-
tors, and the second to the outpouring of epinephrine into the blood, the
justification for this conclusion being thai the latter rise fails to app<
after removal of the adrenal glands.

Taking the results as a whole, it is indeed doubtful whether under nor-
mal conditions a sufficienl amounl of epinephrine is discharged into the
blood of the vena cava to affed appreciably the tone of the blood vessels.
and ihis conclusion seems all the more justified because of the fad thai
small quantities <>f epinephrine have a dilating rather than a constricting
influence, at leasl on certain vessels (Hartman**). It may be, however, that
the maintenam t' vascular tone under certain conditions is greatly as-
sisted by the presence of epinephrine in the hi I. similarly the sympa-
thetic control of other functions may be facilitated by the presence
small amounts. It has been found, for example, that, although stimula-
tion of the celiac plexus causes the glj cogen stored in the liver to be con-
verted into sugar, this result is qoI as a rule obtained <»u stimulating
the plexus shortly after removal of the adrenal glands. The presence
of epinephrine in the blood would, therefore, seem to be necessary to bring
aboul functional activity of the sympathetic nerve endings concerned in
the glycogenolytic process see page 637 ,

Adrenalemia. — In the lighl of these researches it is important to point
out that a greal pari of the work done by clinical observers purporting to

show thai in such conditions as nephritis and arteriosclerosis there is an

increase of epinephrine in the blood, has been found by Stewart and
others, using controlled methods, to be entirely unproven.7 Some ur
tigators, however, still hold that temporary conditions, such as transient
rises of arterial blood pressure or temporary glycosuria, may sometimes
due to increased adrenal discharge into the blood.

Ephinephrine has been thoughl to be a substance which is - id into

the blood in supernormal amount when certain emergencies arise, the most

important of these being fright, or some other extreme .'motion. This

belief has arisen partly from the similarity in the general behavior
of an animal following the intravenous injection "f epinephrine and dur-
ing stales of extreme excitement. Dilatation of the pupils, bristling of
the hair, salivation, rise in arterial blood pressure, inhibition of the ii
tmal movements, protrusion of the eyeballs are all symptoms of tear ju^-
they arc of epinephrine injection. Impressed by these resemblances Can-
non7' undertook an extended research to test the hypothesis thai the reac

lion of an animal to fear and other emotional stales is partly dependent on

746 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

hypersecretion of epinephrine into the blood. The results seemed to con-
firm the hypothesis. In the first place, it was found that, whereas the blood
drawn from the vena cava opposite the entry of the adrenal veins (by
passing a catheter up the femoral vein till its free end lay at this level) in
a normal male cat did not give evidence of the presence of epinephrine
when tested by means of the intestinal segment method, it did so in a
cat that had previously been frightened by allowing a dog to bark at it.
Such results were not obtained after removal of the adrenal gland, or in
a female cat, which is usually indifferent to such a method of frightening.
Cannon also thought that many of the other adaptations which take place
in an animal in this condition are in part dependent on the presence of an
excess of epinephrine in the blood. The three most important of these
are: (1) increased discharge of sugar from the liver into the blood; (2) in-
creased efficiency of muscular contraction; (3) diminished clotting time of
the blood — all of which are adaptations enabling the animal either to con-
quer the source of the fear or to be in a better position to recover from
any bodily injury involving a loss of blood should he suffer bodily dam-
age. Stewart and Rogoff have more recently thrown considerable doubt
on these conclusions by finding that cats in which both adrenal glands are
entirely removed from the influence of the nervous system, behave like
normal animals when frightened, and develop hyperglycemia when as-
phyxiated or etherized. It is scarcely necessary to point out that, until
it is definitely established by experimental investigation that epinephrine
may be discharged in excessive amounts under certain conditions, it is
irrational to assume that such may occur in disease. Tit c surgical removal
of flu adrenal gland is certainly not warranted under any circumstances.

The Association of the Adrenal with Other Endocrine Organs

We have at present very little accurate and reliable information on the
association of the adrenal with other endocrine organs. That epinephrine
has an influence on many diverse organs and glands is an undoubted
fact, bu1 this is more probably to be attributed to an activating influence
on sympathetic nerve endings than to any specific relationship between
the adrenal glands and the gland in question. The most important of the
results that have been obtained are the following:

1. With the Thyroid and Parathyroid. — Cannon and Cattell, after con-
firming Bradford's discovery that an electric current of action is set up in
the salivary gland when it is excited to activity, proceeded to investigate
the occurrence of such a current in the thyroid gland.73 By placing one
nonpolarizable electrode on the gland itself and the other on the neigh-
boring subcutaneous tissues or on the trachea, a current was found to be
set up by stimulation of the sympathetic nerve supply of the thyroid, by
intravenous injection of epinephrine, or by stimulation of the great

THE ADRENAL GL VNDS 71.

splanchnic nerve before it reaches the adrenal gland. This !. rait,

which is the most Important in the present connection, was, ho not

observed when the blood of the inferior vena cava was prevented by the
application of a clamp from '_r<-t t i 1 1 -_r to the heart, but immediately ap-
peared, after stimulation, when the clamp was removed This experim
taken alone docs not, however, justify the conclusion that th< i any
direct relationship between the adrenal glands and the thyroid, because
there are in the thyroid gland structures such as the muscle fibers in the
blood vessels, which a hypersecretion of epinephrine might affect Bet
any direct relationship between the two glands could be claimed to exist,
it would bo necessary to show that the thyroid action current is obtained
with a concentration of epinephrine in the blood lower than that affecting
the blood vessels.

2. With the Sexual Glands. As mentioned above, a very direct rela-
tionship exists between the development of the sexual glands and that of
the suprarenale, particularly the cortex of the glands. In addition to the
evidence above furnished, it may be mentioned that in hyperplasia of the
adrenals changes occur in the testicles, particularly in their interstitial
celK

3. With the Liver. — Of the many functions of this gland that which is
most directly associated with epinephrine is the production of glue

from glycogen— the glycogenolytic pr ss see page 669 . The injection

of epinephrine causes an immediate discharge of such an excess of irlncose
into the blood that hyperglycemia and glycosuria immediately follow.
This result is most striking when the injection is made in glycogen-rich
animals. In animals from which all the glycogen of the liver lias been
removed by starvation, the injection of large amounts of epinephrine
causes glycogen to accumulate in the liver cells a result which it is
difficult to interpret.

In the lighl of the facl that stimulation of the greal splanchnic nerve
causes a demonstrable increase of epinephrine in the blood, ;1 natural con-
clusion is that the glycosuria and hyperglycemia which are known to re-
sult from stimulation of the splanchnic nerve or of its center in the
medulla, must be dependent upon a hypersecretion of epinephrine.
Evidence supporting this hypothesis seemed to be furnished by the obs<
\ation that, after the removal of the adrenal glands, stimulation

splanchnic or of the BO-Called "diabetic" center in the fourth vent!

no longer produced glycosuria even in a glycogen-rich animal. Bui it is
difficult to sec how such an important physiological proci ss as that of the
nerve control of the production of sugar by the liver should be depend
on the hypersecretion of the adrenal gland, i illy si; pineph-

rine would have to be carried by the blood around a considerable part

748 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

the circulation before it arrived at the place on which it is to act. More-
over, it has been shown that stimulation of the previously cut hepatic
nerve plexus (around the hepatic pedicle) in a normal animal produces
hyperglyeogenolysis, in which ease there can be no question of a hypcr-
S( 'iet ion of epinephrine.

No doubt the adrenal glands have some important relationship to the
nerve control of the glycogenolytic process, for, in animals from which the
adrenal glands have been removed, stimulation of the hepatic plexus does
not produce hyperglycemia. From this result it would appear that the
presence of a certain amount of epinephrine in the blood is necessary for
the proper transmission of the nerve impulse from the sympathetic nerve
fibers to the liver cell. When the nervous system is stimulated in such
a way as to excite the glycogenolytic process, two effects both operat-
ing in the same direction with regard to the glycogenic function are
developed: the one. a hypersecretion of epinephrine, which activates
the sympathetic nerve endings, the other, the transmission of the nerve
impulse to the liver cell (Macleod and R. G. Pearce).74

4. With the Pancreas. — The function of the pancreas here concerned
is that of its supposed internal secretion from the Isles of Langerhans.
Since epinephrine readily produces glycosuria, and since excision of
the pancreas has the same effect, it has been natural to inquire whether
any relationship exists between the two glands, and some observers
have obtained results which they interpret as indicating that it does.
Certain observers even state that glycosuria does not occur after the
injection if at the same time extract of pancreas is injected. It is al-
most certain, however, that these results are not trustworthy. Thus,
removal of the adrenal glands in an animal suffering from pancreatic
diabetes does not restore any of the lost power of utilizing glucose
during the few hours that the animal remains alive.74 That some rela-
tionship may, however, exist is indicated by the fact that epinephrine
causes dilatation of the pupil Avhen it is dropped into the eye of a per-
son suffering from diabetes, whereas it has no such effect in the normal
individual.

CHAPTEB I. XXXI II
THE THYROID AND PARATHYROID GLAND

Structural Relationships

The thyroid and parathyroid glands are intimately associated, anatom-
ically, in most animals. The thyroid is present in all the vertebral
1'iit the parathyroids do nol occur below the amphibia. The thyi
exists as two- lateral Lobes joined over the trachea by the BO-called isthmus.
The parathyroids are very much smaller, being four in number and
located in pairs on the posterior aspecl of the thyroid lobes. The two upper
parathyroids are usually more or less embedded in the thyroid tissue,
whereas the lower ones are much more loosely attached to the thyroid;
indeed, in Borne animals they are quite separate from it and may be
Located at a distance, as in the mediastinum. Accessory thyroid and
parathyroid glands are sometimes present in the tissues of the neck, or
in the anterior mediastinum, accessory parathyroids being common in
the rabbil and pat, and parathyroid tissue being present in the thymus
in 5 per eenl of dogs (Marine : . Before these anatomical relationships
were thoroughly worked out, there was much confusion in the inter]
tation of the results following removal of one or the other gland.

In their histological structure and embryological derivation, the two
glands are very different. The parathyroids are developed as an out-
growth from t ho third and fourth branchial pouches, and they are com-
posed of masses of epithelial-like cells, sometimes more or less divided
up into Lobules or trabecular by hands of connective tissue. The cells
contain granules, some of which are of a fatty nature. Sometimes col-
loid-like material is found between the cells, or it may be enclosed in
small vesicles nol unlike those of the thyroid, although usually consid< '
ably smaller. The blood vessels are extremely numerous, and form
sinusdike capillaries, which come into close relationship with the epi-
thelial cells of the glands. Xerxes also ;ire ahiindant and pass both to

the vessels and to the Becreting cells. The blood vessels are derived from
the inferior thyroid artery.

The thyroid is developed by immediate outgrowth from the entoderm
lining the floor of the pharynx, at a Level between the first and second
branchial pouches. Represented at first by a solid column of cells,
there very soon occurs a division at the lower end into two lateral p

749

/."ill Till ENDOCRTNE ORGANS, OR DUCTLESS (il.ANDS

lions, and the original soli* I column becomes hollowed out. The two
lateral branches of the original column divide again and again so as to
form a system of hollow tubes lined with epithelium. These afterward
become cut up so as to form the closed vesicles characteristic of the
gland. Each vesicle is more or less spheroidal in shape, and has no
basement membrane, but its walls are formed by a layer of epithelial
cells, which may be columnar, cubical, or flattened in shape. Each vesicle
is filled with the so-called colloid material, which is peculiar in con-
taining iodine, and between the vesicles is a layer of connective tissue
often containing small cells, some of which are not unlike those of the
parathyroid. The connective tissue also contains the blood vessels,
Avhich are very numerous— indeed, the thyroid, in proportion to its size,
receives more than five times as much blood as the kidneys, the only
tissue that surpasses it in this regard being the medulla of the adrenal
gland fsee page 211). The nerves arise, from both the vagus and the
sympathetic systems and have been traced to the secreting epithelial
cells. The above description applies to a strictly normal gland.

THE THYROID GLAND

Condition of the Gland

In the crowded communities of the Great Lakes Basin of this conti-
nent, it has been found that in most. animals the thyroid gland is more or
Less abnormal. In Cleveland, for example, Marine has found this to be
the case in well over 90 per cent of the dogs brought to the laboratory.77
The condition usually goes under the name of simple goiter, which in-
cludes all thyroid enlargements except those of exophthalmic goiter.
Tn man the goiter originates usually about the age of adolescence and
more frequently in girls than in boys. It may sometimes pass over into
tin' exophthalmic type. The exact pathological changes in the goitrous
gland vary with the species of animal and with the duration of the dis-
ease. In man, besides the cystic or colloid goiter an adenomatous type
is very common although rare in other animals.

From the numerous observations that have been made on the glands of
domestic animals, it has been clearly established that the very earliest
sign of goiter is a diminution in the iodine content of the gland; fol-
lowed by an increase in the epithelial cells and in the blood supply and a
decrease in the colloid. Such hyperplasia may be induced in what re-
mains after removal of a large part of a normal gland (compensatory
hyperplasia), or if a similar operation be performed early in pregnancy,
the young when born will be found to have hyperplastic thyroids. A
certain degree of hyperplasia exists as an accompaniment of pregnancy,

in i i ii n emu \\i> r \i; \ i in ROID 0LA1

"".1

and ii can I'" produced in certain normal animals (particularly rats) by
placing them on an excessive meal diet. Importanl observations bearing on

this point have I M made by Marine on brook trout, in which it has i

found thai ili«' so-called carci aa thai develops when the fish kept in

hatcheries are fed with unsuitable food and overcrowded, is really a
typical hyperplasia. In its second stage this develops into what is known

•

>

.;

>,

S"

"T.- .

w

/•■•.

193 Mi • thyroid gland of dog, .1. normal; B lloid

From .V .1 L,enhai I

as colloid goiter which is produced by a deposition of colloid material
between the rows of cells so as to cause an opening oul again of the
vesicles (Fig. 193 . with a consequent tendency to a reversion to the
normal histological structure, so far ;is this is possible. The vesicles in
such a gland are of enormous Bize, and the lining epithelium, low cubical,
or almost flat in shape.
The outstanding characteristic feature of th Moid material is that

752 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

it contains iodine, which exists in combination with a nonprotein nitrog-
enous base, and is usually called iodothyrin. In the gland itself the
iodothyrin may be in combination with protein, forming iodothyro-
globulin. E. C. Kendall7'-' has recently succeeded in isolating a pure
crystalline substance of perfectly constant composition and containing
over (io per cent of iodine. It has been identified as an indole compound
and has been made synthetically. In extremely minute dosage it greatly af-
fects the energy metabolism, and is said to induce symptoms like exophthal-
mic goiter. Its therapeutic value in eases of thyroid deficiency is remark-
able. Kendall believes this substance to be the active constituent of the thy-
roid and to be associated with the metabolism of amino acids. For one thing,
when it is given alone no change occurs in pulse rate, whereas if amino
acids are given along with it, there is acceleration.

The importance of the relationship between the function of the thyroid
and the iodine-containing material is indicated by the changes- which
occur in the percentage of iodine in the glands under varying condi-
tions of activity. Marine observed that the amount of iodine is inversely
proportional to the degree of hyperplasia of the gland, and when the
hyperplastic condition becomes fully developed, scarcely a trace of
iodine is contained in the gland. Later, when the hyperplasia gives
place to colloid goiter, the iodine increases again, both absolutely and
relatively. Moreover, it has been found that if iodide is administered
to an animal suffering from hyperplasia, the hyperplastic condition very
quickly disappears (Fig. 192) and the animal becomes normal. Thus, in
brook trout, the poor nutritive condition of the fish when hyperplasia has
developed can be immediately remedied by placing them in larger quan-
tities of running water or by adding small traces of iodide to the water.
The administration of small amounts of iodine as in ordinary salt from
salt deposits also prevents goiter in farm stock, this having been first
noted in the State of Michigan, where prior to the discovery of salt
deposits sheep breeding was an entire failure. The importance of admin-
istering small doses of iodides to school children living in goitrous dis-
tricts has recently been emphasized by Marine and Kimball.78 As small
a dose as 0.001 gm. at weekly intervals prevents goiter in puppies sus-
ceptible to it.

Experimental Thyroidectomy

A- correct interpretation of the functional changes and symptoms which
follow upon partial or complete removal of the thyroid gland, or from
its disease, has proved a very difficult problem, partly because sufficient
care has not been taken to note how much parathyroid tissue was re-
moved along with the thyroid, and partly because the fact has been over-

Till THYROID \M» PARATHYROID GLAN 753

looked thai the effects produced by thyroidectomy and parathyroid-
ectomy are often verj differenl in animals of the same kind at dif-
fered ages. Speaking generally, i1 may be said thai the influence of the
parathyroid is focused mainly on the nerve centers and only to a second-
ary degree on the metabolic functions, whereas the reverse is th<
with the thyroid, its main effecl being on metabolism, although it prob-
ably also exercises a secondary effecl on the aerve centers. Mori
than in the case of any other endocrine organ, our knowledge concerning
the function of the thyroid has been gained by clinical experience, -• i n < 1

it is difficull to saj whether the clinical or the experimental t h « ►< 1 has

contributed the greater amounl of information.

The results of experimental extirpation of the thyroid vary accord-
ing to the age of the animal, and frequently they are by no means
marked, provided sufficienl parathyroid tissue has been undamaged.
The symptoms are in general thickening and drying of the skin, with ;i
tendency to adiposity and a loss of i • of the muscle. The body tem-
perature is low and the sexual functions I me subnormal. Nervous

symptoms in the direction of mental dullness and lethargy are also
usually present. Surgical removal of the thyroid in man produces the
condition known as cachexia strumipriva. The symptoms may first of
all become a]. parent a few days after the operation, or they may remain
latent for years, and then develop so as to produce the condition known
as myxedema. When nervous symptoms are prominent in cachexia
strumipriva, it is usually taken as evidence that an excessive amount

of parathyroid tissue has hen destroyed. ECocher states that after com-
plete h>ss of the thyroid, life is impossible for more than seven years,
and thai to prevent ultimate ill effects, at leasl one-fourth of the organ

should be left intact.

Disease of the Thyroid

The symptoms of diseased conditions of the thyroid may be inter-
preted as the consequence of increased or diminished Functioning of the
gland. Sometimes, however, the less active gland is really inc 1 in

hulk, this increase being caused by the accumulation in it of very large
quantities of colloid material accompanied by an attenuated condition
of the vesicular cells (see page 751 . When the gland is atrophied at
birth, the condition of cretin on becomes developed Fig. 194 . The

Characteristic features of cretinism are: 1 An arr. gTOWtl

cially of the skeleton, accompanied by incomplete ossification of the long

hones and failure of the fontanelles of the skull I •• properly.

Poor development of the muscular system. :: An unhealthy, dry. swollen
condition of the skin, s.. that it is yellowish in color, the face being pale

754

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

and puffy. (4) An abnormal development of the connective tissues
causing a shapeless condition of the surface; the abdomen is always
swollen, the hands and feet are shapeless, and the nose depressed. (5)
The nervous system also fails to develop properly, so that at the age of
puberty or over, the child remains like an infant in his mental behavior,
idiotism being common. Indeed, the whole clinical picture is so char-
acteristic that once having seen a case no one can fail afterward to

-

■111- \ In

!

. *■'_..

1 >V -r".

p

1 * 4

1

1

Fig. 194. — Cretin, nineteen years old. The treatment with thyroid extract started too late to be ot

benefit. (Patient of Dr. S. J. Webster.)

recognize the disease. Besides being due to congenital absence of the
thyroid (sporadic type), cretinism may also occur as a result of goitrous
degeneration of the gland. This forms the so-called endemic variety of
the disease, and is more commonly seen in goitrous districts, being not
infrequently associated with disease of the parathyroid, in which case
the nervous symptoms are very prominent.

Atrophy of the thyroid in adults causes the clinical condition known

i III tii vi;iiin \M> l-\l: \TH\ ROIP 01. •

I .,.,

as myxedema, and here again the Bymptoms are very characteristic I
195). The skin is drj and thick, with a deposition of connective
often containing fal in its deeper layers; the hands and feet become
unshapely; the lips thick and the tongue somewhal enlarged, bo thai
when the person attempts to speak, it appears as if the tongue w<
large for the mouth ; the hair falls out ; there is a low bodj temperature,
and it can be shown that the energy metabolism is greatly depressed, and
thai a deficiency of oxygen is being consumed. It is said the person can
take a larger quantity of sugar than an ordinary individual withoul the
development of glycosuria, bu1 the depression of the metabolic function
causes the patienl to take sparingly of food, in spite of which, however,
the body weiehl maj steadily increase. The sexual function becomes

./. B.

Pig. l myxedema; B, ■ n montl ' I ■

depressed, and there is involvemenl of thi ous system wn by

mental dullness and Lethargy.

Although the thyroid gland is much atrophied in myxedema, sympto
thai are very similar may also occur when the gland is aously en-

larged. As already explained, however, this enlargement is due merely
to an accumulation of colloidal material and is really an atrophic c<
dition. A patienl Buffering from endemic goiter may at fin ibit

symptoms which are usually attributed to a hyp< etion of thyroid

material into tin1 blood (the Bymptoms will be described imm
Imt later these give placi ms not unliki I myxedema.

It is concluded that the above conditions leficiei

thyroid function, or hypothyt . beca ise I is atrophied,

756 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

and (2) similar symptoms to those exhibited by the clinical conditions
can be produced experimentally by 1 lie removal of the gland in animals.
By observations on the effect of administration of thyroid extract to
cretinous or myxedematous patients, prompt amelioration of the symp-
toms occurs, which certainly suggests that the real cause is the absence
of an internal secretion. There is probably nothing more striking in
the whole domain of therapeutics than this effect from the administration
of thyroid extract or, more so still, of alpha-iodine.* If the treatment is
stalled early enough, the cretinous child from being an ill-developed
idiot quickly cat (dies up with children of his own age and becomes in
every respect normal. Even if this treatment is not undertaken until
the child is several years of age, it is remarkable how quickly the benefit
may show itself. In myxedema and cachexia strumipriva also, the
symptoms very quickly disappear and the person becomes perfectly nor-
mal by the treatment. In all these conditions, however, the thyroid
extract must be administered continuously in order to prevent the reap-
pearance of symptoms.

Quite distinct from the above described conditions of hypothyroidism
are those produced by an excess of thyroid autacoid in the blood, namely,
hyperthyroidism. Such a condition can be produced experimentally in
normal animals by the administration of thyroid extract or alpha-iodine
(Kendall). In man large doses are soon followed by great quickening
of the pulse with some irregularity, flushing of the skin, increased per-
spiration, tremor in the limbs, emaciation, and marked nervous excita-
bility. Along with these symptoms, metabolic investigations have shown
that the energy output per square meter of surface is greatly increased,
being sometimes nearly doubled; that the nitrogen excretion is exces-
sive; and that alimentary glycosuria is very commonly present. The
body temperature is not, however, as a rule increased, because although
metabolism is excited, yet heat loss is correspondingly increased. Ex-
ophthalmos is said to develop very occasionally after such administra-
tion, but this is doubtful. Lastly, there are usually digestive disturb-
ances, although the appetite is likely to be increased. The pulse is quick-
ened after administration of alpha-iodine only when protein food is also
taken. This is believed by Kendall to be due to the association between
the thyroid hormone and the metabolism of the amino acids.

The symptoms following the injection of the extract are very similar
to those of the disease known as exophthalmic goiter. Indeed, the symp-
toms are so much alike in the two conditions that it is scarcely neces-
sary to describe them specially for the disease except to mention that
the exophthalmos is much more likely to be present.

Like simple goiter this variety is from three to four times more fre-

* Alpha-iodine refers to the active principle isolated by Kendall.

THE TllYi;<ill> .WD PABATHYBOID QLAND8 757

quenl in women than in men, a fact of significance when we recall the
evidence of association between the thyroid gland and the generative
organs. It is said that the disease is usually coupled with persistence of
the thymus gland. The thyroid gland in exophthalmic goiter is enlarged,
sometimes in one Lobe; it is hard and pulpy, and on auscultation a mur-
mur is heard. Histologically the gland presents a picture very like
thai which has been described above as hyperplasia; thai is to say, the
vesicles have a deficiency of colloid material: their epithelium is colum-
nar and folded up into t he vesicles; and the interstitial tissue betw<
the vesicles is very markedly increased.

Exophthalmic goiter is almosl universally claimed to be due to hyp<
secretion of the thyroid, because: 1 the symptoms of the di ire not

unlike those produced by excessive administration of thyroid to a normal
individual: and (2) they are in general opposite in character to the symp-
toms found in rases where the thyroid gland is atrophied. The blood of
a person with exophthalmic goiter when inject* d into mice increases their
resistance to the toxic action of acetonitrile, which is also the Eter

thyroid extract has been injected. In many cases of exophthalmic goiter
partial removal of the gland is said to ameliorate the symptoms. Other
clinicians, however, state that if the patient is given proper medical
treatment, rest, and diet, equally beneficial results can be obtained.

Certain investigators, however, deny that it has yet been conclusively
demonstrated that exophthalmic goiter is due to hypersecretion of the thy-
roid .Marine . It is pointed out that, if hypersecretion were the cause of
the disease, one would expect thai the injection into animals of the hi I

of patients suffering from ii would produce symptoms similar to tl
following the injection of thyroid extract. The results of such experi-
ments, however, have been extremely confusing and very indecisive, since
it is difficult to recognize in laboratory animals many of the characteru
symptoms, especially those affecting the skin and eyes and the gen<
bodily nutrition. Another difficulty in accepting the hy] m hypoth-

esis is the fact that an extrad of a gland removed from an exophthalmic
patient has no differenl physiological action on a normal animal from an

extrad of a normal gland containing the same percentag ;odine.

The evidence is by no means conclusive one way or the other, and it may
well he that the observed changes in the thyroid gland are not tin
of the symptoms of exophthalmic goiter, hut merely, like th- symp-

toms of this disease, a resull of Borne condition loc re.

The Relationship of the Thyroid with Other Endocrine Organs

1. With the Generative Organs. Evidence of an association between
the female generative organs and the thyroid is very strong; thus, the

758 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

lliyroid becomes enlarged at puberty, during the menses, and during
pregnancy, and in thyroidectomized young animals the sexual glands
fail to develop properly.

2. With the Adrenal Glands.— (See page 746.)

3. With the Pituitary Body. After removal of the thyroid, the pitu-
itary becomes greatly altered and enlarged, particularly the pars an-
terior, in which it is not uncommon to find that a certain amount of
vesicles containing colloid, not unlike those of the thyroid, become devel-
oped. This colloid material, however, does not contain iodine. It is said
that this increase of the pituitary after thyroidectomy does not occur if
thyroid extract be administered. Increased activity of the pars inter-
media of the pituitary is also quite plain. These facts -would at first
sight seem to indicate that the pituitary and the thyroid can act vica-
riously, but this is very doubtful, for it has not been found that pitu-
itary extract has any beneficial effect in the treatment of goiter and myx-
edema. Nevertheless the association in function of the two glands must
be more or less close, not alone for the above reasons, but also because they
arc both associated to much the same degree with the sexual organs,
and both act on the higher functions of the nervous system in much the
same manner.

4. With the Thymus Gland. — The persistence of the thymus in ex-
ophthalmic goiter, as well as the anatomic and embryological relationship
between thymus and thyroid, is taken to indicate some close relationship.

THE PARATHYROIDS

Experimental Parathyroidectomy

Experimental parathyroidectomy yields results which vary in dif-
ferent groups of animals, undoubtedly because of the fact that in some,
such as the rat and rabbit, accessory parathyroids may exist. In gen-
eral, however, it has been found that if more than two of the four
parathyroids be removed, very definite and pronounced nervous symp-
toms soon supervene and if all four glands be removed, a quickly fatal
result is inevitable. The most acute symptoms are exhibited by the
carnivora. They may not be apparent for a day or two after the opera-
tion, although during the period the animal is in a depressed state, re-
fusing food and losing weight rapidly. The muscles are also more or less
stiff during this stage. When more definite symptoms appear, they con-
sist of a marked abnormality of muscular contraction, leading to the
occurrence of fibrillar contractions, or tremors and, later, to cramp-like
and clonic contractions. When spontaneous movements are made, a

Mil THYBOID \\l> PABATHTBOID GLANDS 759

peculiar shaking of the foot, like thai made by a normal animal to shake

water off its pa. Is, is a characteristic symptom. The - 1 1 «_r 1 1 1 . ■ -v t stimulation

of tin' peripheral nerves is sufficient to induce one of tins.- attacks, which

recur with ever increasing frequency, 1> >miu'_r at tin- same time more

pronounced and accompanied by other disturbances, such as diarrhea,
profuse salivation, rapid pulse, and dyspnea (in the dog but not in I

cat). In cases that arc not quickly fatal, the hair tends to be shed, and
the teeth to he improperly calcified ! in young animals). Where a certain
amount of parathyroid tissue has been left — for example, one of the four
lobes the symptoms may nol appear except under conditions of special

strain to the animal economy, such as pregnancy Or improper <i

Thus, in a hitch from which three of the four glands had been removed,
no symptoms of tetany occurred until she became pregnant. Tender the

saint ml it ions it has been found that a diet of flesh is much more apt

to bring about the condition than one of vegetables or milk.

Tetany, as the above condition is called, may also become developed
in man either as the result of surgical removal of the parathyroids or
because of their improper development. The symptoms in man are very
similar to those observed in laboratory animals, the only difference being

that the muscular contractions are more likely 1" be tonic in charati
Certain symptoms that may develop during pregnancy or in the course

of infections diseases or in newborn infants have also been found to be

associated with degeneration of or hemorrhage into ihe parathyroid
(idiopathic tetany), and certain obscure nervous diseases in adults,
such as paralysis agitans, may possibly also be associated with changes
in this gland. Chorea, epilepsy, and eclampsia have likewise been
thought to In- associated with it.

The parathyroid gland, besides influencing the nerve centers, has also
an influence on metabolism. The metabolic disturbances following parathy-
roidectomy are : <1 rapid emaciation and failure to grow ; 2 ;i tendency
to the production of glycosuria, often detected by finding that the assimila-
tion limit for carbohydrate is lowered page 652 ; and :; most definitely
of all, an interference with calcium metabolism, as illustrated by the failure
of the teeth and bones to calcifj properly. This interference with normal
metabolism led Kellogg and Voegtlin81 to study the effect produced
parathyroidectomized animals by the administration of calcium. It was

found that the symptoms were considerably ameliorated. These authors
Concluded from their results that the essential cause of tetany :
deficiency Of calcium in the blood. It is possible however that the h
flcial action of calcium salts in this condition is that it d jes the

excitability of the nervous system, an action which it is known to
possess.

760 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

"When the tetany is the result of a complete extirpation of all parathy-
roid tissue, the symptoms can be combated by a successful transplan-
tation or graft of parathyroid tissue made from an animal of the same
species. Indeed, it has been found that the success of a graft of parathy-
roid is assured only when the graft is derived from the same kind of
animal as that from which the parathyroid has been removed. Implan-
tation into the subcutaneous tissue of a tetany patient of parathyroid
tissue obtained fresh from the deadhouse has been performed with bene-
ficial outcome.

Noel Paton, Findlay and Watson80 have recently contributed greatly
to our knowledge of the physiological pathology of tetania thyreopriva,
as the above condition is called. The symptoms are not due to any con-
dition affecting the muscles themselves, since they disappear after sec-
tion of the nerves. Nor are they primarily dependent upon the cere-
brum or cerebellum, since ablation of neither abolishes them. This does
not imply that secondary involvement of the higher centers never oc-
curs; on the contrary, the epileptiform convulsions and disturbances of
equilibrium sometimes observed indicate cerebral or cerebellar involve-
ment, respectively. This leaves some part of the lower neuron reflex
arcs as the site of involvement, It is not the afferent neuron, since the
tremors and jerkings persist after section of the posterior roots, leaving
the efferent neuron as the affected structure.

The foregoing conclusion led Paton and his co-workers to compare the
response of muscle and nerve to electric, stimulation in normal and
parathyroidectomized animals. Although there are considerable varia-
tions in the responses of a normal animal, they are very definitely ex-
aggerated in tetany when either the motor neuron or the muscle itself
is stimulated, the exaggeration in the latter case being dependent upon
alterations in the neural structures (nerve endings) in the muscle. The
increased electric excitability can not, however, be taken as a measure
of the severity of the condition, for it may be no more marked in cases
in which there is involvement of the cerebral hemisphere (causing epilep-
tiform fits) than in milder cases.

As to the cause of the symptoms, many possibilities have to be con-
sidered. In the first place, no direct relationship exists between the
thyroid and parathyroid in this connection. One cause might be the
absence of some substance which normally checks the activity of the nerv-
ous system, some chalone in Schafer's sense. That such is not the case is
shown among other tilings by the fact that bleeding and then transfusing
normal saline immediately removes the symptoms for some time. Moreover,
the metabolic disturbances go on when the nervous symptoms are slight.
It had previously been thought by W. <■'. Macallum83 that, since symp-

nil THYBOID \Nl> PARATHYROID QLAN1 761

toms like those of tetany can be induced by deficiency of calcium in the
body and the Bymptoms of parathj roidectomy relieved by administration
of this cation, calcium deficiency is the cause of the Bymptoms. While
not denying thai these ions may have some relationship to the Bymptoms,
Noel Paton ascribes them to intoxication by guanidim pag The

evidence is as follows: 1 Guanidine and methyl guanidine admin-
istered to normal animals produce Bymptoms thai are identical with tl
following parathyroidectomy. (2) There is a marked increase in the
amount of these substances in the Mood and urine of parathyroidec-
tomized do'_rs and in the urine of children suffering from idiopathic
tetany. (3) In certain eases the serum of parathyroidectomized d
acts upon the muscles of the frog similarly to weak solutions of guani-
dine and methyl guanidine. (4) There is a striking similarity in the
relative amounts of the nitrogenous metabolites in the urine of parathy-
roidectomized dogs and of normal animals injected with guanidine.

It is concluded thai the parathyroids control the metabolism of guani-
dine "by preventing its development in undue amounts, in this way
they probably exercise a regulative action upon the tone of the skeletal
muscles." It is believed thai disease of the parathyroids is the cause

idiopathic tetany, since it is similar with regard to its characters and
metabolism to the condition following thyroidectomy.

The Relationship of the Parathyroid with Other Endocrine

Organs

We know very little of the relationship of the parathyroid with other
endocrine organs. Vincent and others have stated that after removal

of the thyroid itself enlargemenl of the parathyroid may ur with the

formation of colloid material between the rows of cells, hut the con-
clusion that this represents a vicarious function between the thyroid and
parathyroid glands is not generally accepted. The supposed relation-
ships among the parathyroid ami the pituitary and adrenal glands are
also based upon uncertain evidenci

CHAPTER LXXXIV

THE PITUITARY BODY

Structural Relationships

Situated at the base of the brain and lying in the sella turcica, the
pituitary body in man does not weigh much more than half a gram. It
is connected with the brain by a funnel-shaped stalk, the infundibulum.
On account of a natural cleft, which runs across the gland in an oblique
plane, it is an easy matter to split it into two portions, an anterior, or
pars glandularis, and a posterior, or pars nervosa. This cleft in the
case of man is usually found to be more or less broken up into isolated
cysts containing a colloid-like material, and it represents the remains of
the original tubular structure from which the pars glandularis is de-
veloped ; namely, a pouch growing out from the buccal ectoderm.

On microscopic examination it will be found that the pars glandularis
consists of masses of epithelial cells with large sinus-like blood capil-
laries lying between them. These blood vessels are very numerous, so
that in an injected gland this portion of the pituitary stands out very
prominently. The vessels are derived from about twenty small arterioles
that converge toward the pituitary from the circle of Willis, and enter
the gland by the infundibulum or stalk by which the gland is connected
with the base of the brain. Three types of cell can be differentiated:
nonstaining (chromaphobe) and granular (chromaphil), of which latter
there are cells with acid-staining and others with base-staining granules,
the former being by far the more numerous (Schafer).60 In some
animals such as the cat, the cells of the pars anterior are arranged around
the blood sinuses in rows as in a columnar epithelium. The cells with
acid-staining granules are said to become much increased in number in
pregnancy and also in the enlarged gland of acromegaly (see page 772).
After thyroidectomy it has been observed that colloid-like masses ac-
cumulate in the pars glandularis, the cells sometimes arranging them-
selves around these masses as in the thyroid gland. The colloid, how-
ever, contains no iodine.

The posterior part of the gland, or pars nervosa, is composed almost
entirely of neuroglia, cells, and fibers, usually with some hyaline or
granular material lying between them, particularly in the neighborhood

762

THE ITU [TAB? BODY

of the infundibulum, into which it may be traced. It is believed that
the active principle of the gland is represented by this material. <
blood supply of the pars nervosa is relatively Bcanty.

Between the pars nervosa and the intraglandnlar cleft ab<
to is a layer of cells differing from those of either the anterior or the
posterior Lobe. This layer of cells constitutes the Bo-called part ini
media. The cells are somewhal like those of the pars glandulai sepl

that they are distinctly granular, the granules being of the neutrophile
variety, thai is to say, they slain with neither hash- nor acid dyes. Well-
defined vesicles containing an oxyphile colloid material are often found

f

Fig, 196.- Drawing from a photogi i through th< . 'anu,

of ■ human fetus < 5th month): ii 1a; c, third ventricle; d, e, infun-

dibulum surround' ial cells; ;. para intermedia; g, intraglandular cleft; h. pars ne:
(Herring, from Howell's Physiology.)

ii them. The blood supplj is much less abundanl than thai of the
pars glandularis. Although well separated by the cleft from the |
glandularis, the pars intermedia is not well separated from th<
nervosa, because many of its cells extend for some disl the lat-

ter between the neuroglial fibers Certain of the cells in the pars i< I
media may lie seen in various stages of conversion into globular hyaline
bodies, or a granular mass of material may appear in them. In either
e, the cells ultimately break down. Betting Tree the hyaline or granular
material, which is believed to be the origin of the similar material al-
ready described as existing between the neuroglial fibers of tl •

nervosa ami therefore ultimately finding its w a\ by the infundibulum

764 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

into the third ventricle of the brain. These hyaline globules are greatly
increased after thyroidectomy. It should be mentioned, finally, that at
the margin of the intraglandular cleft the intermediary and anterior
portions of the pituitary come together, although the cells of each can
readily be distinguished on account of their staining properties. This
pars glandularis et intermedia also extends as a thin layer over part of
the pars nervosa and around the neck of the gland at the infnndibnlum.
These relationships are "well shown in the accompanying diagram (Fig.
196).

Functions

Concerning the functions of the pituitary, it maybe said in general that
the anterior lobe has an important relationship to the nutritive con-
dition of the body during growth, especially of the skeletal structures,
and that the posterior lobe produces a very active autacoid having to do
with the physiological activity of unstriped muscle fiber. The pars inter-
media seems to be associated with the posterior lobe in the production of
this autacoid. The function of these two parts will therefore be con-
sidered together.

Function of the Anterior Lobe. — The facts concerning the function
of the pars glandularis have been gleaned largely by observing the ef-
fects produced by partial or complete removal of the entire pituitary,
justification for ascribing to the removal of the anterior, rather than
the posterior, lobe the results that are obtained being furnished by control
experiments, in which by removal of the posterior lobe alone similar
effects are not observed.

Complete removal of the pituitary is almost invariably fatal, the Gon-
dii ion being called apitiiitarism. Two operative procedures have been
employed for the removal of the gland. One of these, elaborated by Cushing
and his pupils,82 consists in trephining the skull and elevating the temporal
lobe of the cerebrum so as to expose the gland. The other, elaborated
by Horsley,83 consists in approaching the gland through the orbital
cavity. Although there is some danger of injury to nervous tissues by
the intracranial method, its results arc more dependable since the gland
is actually exposed to view before being removed.

Most hypophysectomized animals die within two or three days, unless
they are very young. This longer survival of young animals is ascribed
to the presence of accessory pituitary material situated in the dura mater
lining the sella turcica. The most extensive observations have been made
on dogs. On the day following the operation the animal appears about
normal, but it gradually becomes less active, refusing food and respond-
ing slowly to stimulation. It gradually gets weaker and weaker; muscu-

THE PITUITARY BOD?

lap tremors may appear, the respiration ;ui<1 pulse becomi . the back
arched, the temperature subnormal; and, usually within about forty-
eight hours, < a develops and the animal dies in this condition. When

the symptoms are less acute ;iu<l death does not occur arly, it is

believed by Cushing either thai small portions of the gland have b<
l«i't behind or thai some vicarious activity of other organs has developed
to replace thai of the pituitary.

When only a pari of the pituitary is removed, the symptoms are not
marly so acute, and the condition is known as hypopii m. It is |
study of this condition thai mosl facts concerning the Function of the an-
terior lobe have been learned. When the operation is performed on young
animals, they fail to grow properly; the milk teeth ami the lanugo are re-
tained; the epiphyses d >1 ankylose; the thyroid and thymus glands are

enlarged; and the cortex of the suprarenal and the sexual organs fails
develop. The animal, though small, becomes very fat and may therefore in-
crease in weight. There is distind evidence of mental dullness. Prom tl

ilts it is concluded that tin anterior lobe of tin pituitary pn
autacoids having to do with tin development of tin skeletal and other
structures of the growing nun, mi. That this autacoid is no1 derived from
the posterior lobe is evidenced by the fad thai partial injury of this
lobe, or indeed its entire removal, is qoI followed by similar symptoms.

Closer examination of the metabolic function in hypophysectomized
animals has shown that there is a marked depression in th< iratory

exchange of oxygen and carbon dioxide, and thai the ability to metabo-
lize carbohydrate becomes heightened ; that is to say, the animal can tolerate
a larger quantity of sugar than the normal animal without develop-
ing glycosuria. This effect on carbohydrate metabolism may how-
ever be associated no1 so much with the function of the anterior
with thai of ih<> posterio . ter, Cushing and his

pupils have found that extracl of the posterior lobe has a marked influence
on the assimilation limit of carbohydrat<

Attempts have been made to grafl the pituitary, especially the ai I
lobe, into various parts of the body. It has been found, 1 r, that

within a few days the grafts atrophy ami disappear unless thei
i complete removal of the pituitary itself, in whicl

may remain for a month or so and the otherwise fatal outcome of hypophy-

sectomy he warded off. Sometimes, where the grafl lias remained for a

longer time, [\ is said that a temporary increase in tin the

animal has been noticed

Other observers have investigated the effects in normal anim: ds
continuous oral administration of pituitary substance

766 Till ENDOCRINE ORGANS, OB DUCTLESS GLANDS

injection of extract. The earlier results were indefinite and confusing,
but recently Brailsford Robertson8^ has succeeded in isolating from the
anterior lobe a substance called tethelin, which accelerates growth in
young animals and is thought to have a possible value in hastening the
healing process in wounds.

Tethelin is precipitated by dry ether from an alcoholic extract of the
carefully isolated anterior lobes. It contains 1.4 per cent of phosphorus
and nitrogen in the proportion of four atoms for every atom of phos-
phorus, two of the nitrogen atoms being present as amino groups and
one in an imino group. The effects on growth of mice are in every par-
ticular like those of the administration of anterior lobes, and consist in
retardation of the first portion of the third growth cycle,* followed by
acceleration of the latter portion of this cycle. When fully grown,
tethelin-fed mice also differ from normal animals in being smaller in
size but of greater weight, with a distinct difference in the condition of
the coat. Normal animals at fourteen months of age have "shaggy,
staring and discolored coats," whereas in tethelin-fed animals they have
the glossy and silky appearance of young animals. During growth, nor-
mal animals display a greater variability in weight than tethelin-fed
animals.

Extraordinary effects have been observed by Clark8"' to be produced
by feeding laying hens with pituitary gland. Thus, by giving to one-
year-old hens, in addition to their usual food, 20 milligrams of fresh
pituitary substance for four days, it was found that the average daily
number -of eggs laid by a batch of 655 hens was raised from 273 during
the four days preceding the pituitary feeding to 352 during the four
days of the administration, these results being obtained at a time of
year when the natural egg-production of the hens was diminishing. It
was further observed that not only is the output of eggs greatly increased
as a result of the pituitary feeding, but likewise their fertility, for in
another experiment in which 35 hens were kept along with two cockerels
of the same breed, not only was the output of eggs increased (from 18 up
to 33), but the fertility of the eggs was greatly enhanced.

Functions of the Posterior Lobe (and Pars Intermedia). — As already
mentioned, excision of this part of the pituitary can be tolerably well with-
stood by the animal, so much so indeed that from its behavior after the
operation we can conclude little as to the function of the lobe. On the
other hand, extracts of the posterior lobe injected into normal animals
produce effects that arc very striking, indicating that the main function

'Robertson has contributed valuable and very extensive data on the normal curve of growth of
wh.te mice kept under carefully controlled conditions. Three growth cycles are present: the first
attains its maximum velocity between seven and fourteen days alter birth; the second, between
twenty-one and twenty-eight days; and the third about six weeks, after which the velocity decreases
progressively, until further growth ceases between the fiftieth and sixtieth weeks succeeding birth.

THE PITUITABY BODY

of this lobe is production of an autocoid. The extracts have more or Leas an
epinephrine-like action. Such extracts, rendered proteii teril-

i/«.,|, are obtainable on the markel under the various names of pituitrin,
hypophysin, etc. From them a crystallizable material has been obtained,
I. ut this is probably a mixture of various Bubstances. In disci] the

functions of these various extracts, it must be remembered that the inter-
mediary part (pars intermedia) is included with the posterior lobe in
their preparation.

Although the effed of pituitary extracl on plain musch fiber and on
glandular tissue) appears, on first sight, to be very like that produc
by epinephrine, it lias been found on closer examination thai the two
substances really act in different ways. The rise in blood pressure p
duced by pituitary autacoid is likely to be more prolonged than thai
produced by epinephrine. It stimulates increased cardiac activity, but
after the vagi have been cut or sufficient atropine administered to para-
lyze tlirin, the pituitary autacoid continues to stimulate th< gth of
the heartbeat without producing the acceleration noted with epinephrine.
Whereas epinephrine has little or no action on the coronary - or
on those of the lungs, pituitary autacoid usually produces constriction of
both types of vessel; and on the renal arteries the actions of the two
autacoids are entirely different, for epinephrine has a marked constric-
ing effect, while the pituitary autacoid produces dilatation.

Another striking difference in the extracts from the two glands is
\ealed by repeating the injection after the effect of a previous one has
completely passed oft". With epinephrine the original effect is rep

duced; with pituitrin, on the other hand, the effect of the second ii
tion is very often the reverse of that of the first: that is to say, the bl
pressure, instead of rising, may fall, or the rise be very much less

marked. Whether this effed of the Second dose is caused by the action

of an autacoid having a chalonic rather than a hormonic influe

whether it is due t<> a reversed effect ^\' the same hormone, it is impos-
sible at present to say. The chalonic effect in any case is much more
evanescent than the liorinoiiic, and it is not cause,] by cholin. as som<

have suggested. The effect of epinephrine, it will be remembered,
abolished by ergotoxin and apocodeine. These drugs, on the other hand.
have no influence on the action of pituitrin. The difference in
between the two autacoids is usually explained by assuming that the

epinephrine acts on the receptor substance associated in some way with
terminations of the sympathetic nerve fibers in involuntary mus
whereas pituitrin nets directly mi th< involuntary muscle fibers I

Other types of involuntary liber are also acted on by pituitrin. The
uterine contractions for example are stimulated Fig I

7fi8

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

the intestine (in contrast to the inhibiting effect of epinephrine), and of the
bladder-ureter musculature. Dilatation of the pupil of the excised frog

J9±L&».= /-*£

i?^;- /ZM*~-(%^$£jUOvsutt^

uMaajlA. Usn- sAAAAA..

Fig. 197. — Tracing showing the action of pituitrin on the uterine contractions and blood pressure
in a dog. Made by Barbour's method. (From Jackson.)

eye is produced. The effect of pituitrin on the muscle of the bronchioles

is shown in Fig. 198 by the diminished excursions of the respiratory tracing.

The glands on which the pituitrin has the most pronounced action are

Till: I'lTIITARY I'.nl.Y

tli.- mammary glands and the kidne; d" I evi-

denced by the remarkable increase in the arinary flow following injection
of the pitnitrin. This diuresis mighl dne merely to the

vasodilatation that we hs such extracts produce dilatation

which is all the more marked because the \ in the b

undergo constriction. But pituitrin continues I l arinary

outflow iii the abseii t* any demonstrable vascular change; it ah

after the administration of atropine, ■><> that it I by n

observers to act on the excretory epithelium «»f the convo tubules

on n.)

in much the same way i tain diuretics, like diuretin. This renal

hormonic action of pituitrin would appear t<> he analogous with that

m on the epithelium of the pancreas Auothe
ing that tin secretory hormone is independent of that producing \
dilatation of the renal that a repeated d pituitrin.

although, . it usually has a d<

. -rill produces a stimulating effect on ti
The value of pituitrin as a diuretic in clinical pi v well

i ized.
The etTeet on milk - *t demonsl by placii .

770 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

in the mammary ducts so that the milk may freely flow out. By observ-
ing the rate of outflow during the injection of pituitrin, it will be found
that a remarkable increase occurs. After this increased secretion has
ceased, however, the injection of more pituitrin has no further effect,
indicating that the influence of the first injection must have been, not so
much to stimulate the secretion of milk, as to accelerate the outflow of
that, which previously had been secreted and had collected in the alveoli
and ducts. This effect explains why the pituitary galactagogue should
have very little if any effect on the total production of milk or on the
total amount of fat and other constituents contained in it. Histological
examination of sections of a resting mammary gland and of the same
gland after administration of the pituitrin, bears out the above interpre-
tation of the action. Alveoli in the resting state will be found largely
distended with milk and the epithelium flattened against the basal mem-
brane, whereas alveoli from the gland after pituitary activity show small
shriveled-up alveoli, containing little milk, and with epithelium that is
well marked and stands out prominently from the basal membrane.

These facts taken together indicate that pituitrin stimulates the mus-
cular fibers of the ducts of the mammary glands, thus squeezing out the
milk contained in them. Muscular fibers have been described as existing
between the basal membrane and epithelial cells, much in the same way
as they do in the case of the sweat glands. At least Schafer has suc-
ceeded in demonstrating in this position rod-shaped nuclei which prob-
ably belong to muscular fibers.60 By their contraction, the milk in the
alveoli is expelled into the ducts. It has also been found that pituitrin
stimulates the secretion of cerebrospinal fluid, and that this stimulation
is independent of a rise in blood pressure.

Pituitrin has a distinct effect on carbohydrate metabolism. After its
intravenous or subcutaneous injection, a marked lowering in the toler-
ance for sugar is observed (page 652), usually to such an extent that
glycosuria becomes established, dishing and his pupils have concluded
that the posterior lobe contributes an autacoid which stimulates the utili-
zation of sugar in the body. Confirmatory evidence for this view is fur-
nished by the observation that mechanical stimulation of the posterior
lobe, such as is produced by puncturing it with a needle, is followed by
a temporary glycosuria, which is said to be as pronounced as that fol-
lowing puncture of the diabetic center (page 672), provided glycogen is
present in the liver. The production of this carbohydrate autacoid would
appear to be under the control of the sympathetic nervous system, for it
has been found by Cushing and others that stimulation of the superior
cervical ganglion, which has been known for many years to be fre-
quently followed by glycosuria, has this effect only provided the posterior

[Ill PITUITARY BODY

771

lobo of the pituitary is intact. Even surgical manipulation of the pitui-
tary may excite a hyp etion of pituitrin, which would
the glycosuria often observed after experimental i partial
destruction <>t' the pituitary. A similar irritation may be Bel up in •
of tlir gland. ,

Tin' glycosuria which is usually observed after partial hypoph; my

Boon passes off, to be followed by a permanent '-"li.lii ■
tolerance for sugar, because now Less pituitrin is being produced. 'It is
sai.l thai during the stage of increased tolerance diab< n nol ;

duced even by excision of the pancreas. The glycosuria produced by

irritation of the posterior lobe is a< npanied by a marked polyuri

betes insipidus), which may outlast tin- glycosuria.

A.

B.

Fig. 199. — A, To show the ai>] carai<cc before the

its of thi I

Clinica.1 Characteristics

Because of their importance from a physiological standpoint, we ^1
now proceed to review briefly some of the more important farts that 1
s.i far been broughl to I i -_r 1 » t by clinical observations. The path- _
condition most frequently observed affecting the pituitar; adenom-

atous growth particularly Located in the anterior Li !'••

ducing general symptoms of pressure, such as diminution of the visual
field ami, perhaps, headache, a shadow can usually be the

patient is examined by means of the \-ra.\ ieral

i 1 1 < 1 1 1 1 \ ascribed to a h\ persecretion of the nutacoid
the pituitary hyperpituitarism begrin sooner

772

THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

selves. These symptoms are almost exactly opposite in character to those
observed in animals after removal of this portion of the gland. Thus,
the hones of the extremities become stimulated to increased growth,
so that if the patient is young, and the epiphyses therefore
mil ossified, remarkable elongation of the long bones occurs, pro-
ducing the condition known as gigantism. On the other hand, if the dis-
ease does not develop until after ossification is complete, its effects be-
come most marked in the bones of the face, the lower jaw becoming

Fig. 200. — TIand of a person affected with acromegaly.

enormously hypertrophied and the supraorbital ridges very prominent.
The long bones also become enlarged at their extremities, and there may
be some increase in length of the vertebral column, although the stature
does not increase because of kyphosis (curvature of the spine). The
condition is called acromegaly. Nutritive disturbances of the skin and
hairs also become marked, causing the skin to become dry and yellowish,
and the hairs to undergo abnormal increase over the body. An early
symptom of the condition is failure of the sexual power (Figs. 199
and 200.)

I ill. ITU [TAB1 BOOT

After a time the disease begins to affect the pars intermedia el nervoi
and disturbances in carbohydrate metabolism come to be observed, con-
sisting usually in a diminished tolerance a impanied by glycosuria, in

the early stages of the disease, followed by increased tolerance in the
later stages. The glycosuria is usually accompanied by marked polyuria.

It should be qbserved thai sometimes tumor of the pituitary lias been
found to exist postmortem though none of the above symptoms had been
recorded during life. In these cases it is probable that the dia rom

the start had been of such a nature as to produce a tendency to hypo-
pituitarism rather than hyperpituitarism, for the symptoms are very like
those observed in animals after partial or complete removal of the gland,
[f the condition commences before adolescence, the body fails to grow,
although the child may continue to increase in weight because of the
remarkable deposition of fai in the tissues. Sexual development is strik-
ingly interfered with, ami the secondary sexual characteristics fail to

show themselves. In hoys, for example, the pubic hairs fail to extend up

to the umbilicus; ami the hairs on the chin do mu develop, whereas tin-
hair of the seal]) grows profusely. The hones remain of the female t;

and a broad pelvis, rounded Limbs, small feet ami hands are often ob-
served. In these eases there is usually excessive tolerance for carbohy-
drates, which may explain the adiposity, sii'_rar being converted into fat.
In the lighl of the experimental results, the effect on carbohydi
metabolism may he explained as due to involvemenl of the posterior
lobe. .Mental development is retarded, ami psychic derangements are
somel imes obsen rt\.

Where the hypopituitarism does not develop until after adolescent

some of the above symptoms will of course he missed, hut many will he
observed, such as dryness of the skin, loss of hair, and the tendency in
the male to adopt certain of the female characteristics, particularly with

regard to the growth id' hair. Obesit) and increased tolerance he
are also evident, and pigmentation of the skin, something like thai
Addison's disease, is said often to he a prominent feature. Operative
interference in the early stages in many of these cases is of undoubted
benefit, as is shown bj the brillianl work of Harvey dishing, to which
the reader is referred for further information.

The Relationship of the Pituitary Gland with Other Endocrine

Organs

The relationship of the pituitary gland with other endocrine organs

nc ems to he an intimate one.

I. With the Thyroid and Parathyroid Glands. Thai enlargemenl
the pituitary occurs after thyroidectomy in man has been known for a

t, I Till: KNIHM'KIXK ORGANS, or ductless glands

considerable number of years. The enlargement affects more particu-
larly the pars anterior, although changes arc also described in the pars
Intermedia et nervosa. Accompanying the enlargement of the anterior
lobe, vesicles containing colloid-like material often become developed in
it. bid even after the hypertrophy has proceeded to a considerable de-
gree, this colloid does not contain iodine, nor does an extract have the
same physiological effed as one of the thyroid gland. It can not replace
thyroid extract in the treatment of patients with goiter or myxedema,
or ameliorate 1 lie symptoms produced in animals by the removal of the
thyroid gland. Deposition of colloid-like material in the pars anterior
also occurs in myxedema. Histological changes in the pars intermedia et
nervosa, although less pronounced than in the pars anterior, are never-
theless said to be perfectly distinct following thyroidectomy, and to con-
sist in an increase in the hyaline and granular masses which have already
been described as present to a certain extent in the normal gland.

Less direct evidence of an association in function between the pituitary
and the thyroid is furnished by the similarity of the effects produced on
the sexual functions and on the general development of young animals
by the removal of cither gland. In both cases the animals fail to grow
properly; the sexual organs remain undeveloped; and the mental func-
tions are infantile in type. In hypophysial deficiency, however, extreme
adiposity is Likely to be more marked than is the case in cretinism.

2. With the Sexual Organs. — That the pituitary gland has much to do
with the development of the sexual organs has already been shown. Fur-
ther evidence of a relationship between the sexual glands and the pitui-
tary is furnished by the following observations. After castration en-
largement occiii's in the pituitary, and on histological examination the
gland is found to contain a large number of oxyphile cells, particularly
in the pars anterior. This influence of the -sexual glands on the pituitary
is believed to depend on the interstitial cells present in them, for it has
been found that if the ovary or testis is transplanted into other parts of
the body after the castration, the changes in the pituitary do not occur,
although, as we shall see, the transplanted gland becomes entirely
atrophied except for the interstitial cells. The enlargement of the pitui-
tary during pregnancy an enlargement which often brings it to two or
three times its normal weight — is further evidence of its association
with the ovary.

3. With the Suprarenals. Association of function is suggested in this
case by the fact thai extracts of suprarenal and pituitary have very much
the same effects on involuntary muscular fiber and glandular structures,
and il is said that the two extracts mutually facilitate each other's
action in this regard. It should be remembered, however, that pituitrin

i in lil i n \i;y BOD? 775

and epinephrine do qo1 appear to acl on exactly the same peripheral
mechanism I Bee page 767

4. With the Isles of Langerhans. Since pituitrin affects carbohydri
metabolism, which is thoughl to be primarily controlled by til.' [sles of
Langerhans, it is claimed by Borne observers thai a relationship i
exists between«the pituitary and these structures, [njectii duodenal

extracts are also said to cause a hypersecretion of pituitrin into the
cerebrospinal fluid.

CHAPTER LXXXV

THE PINEAL C4LAND AND THE GONADS

THE PINEAL GLAND

This peculiar structure lies between the anterior corpora quadrigem-
ina, and weighs about two-tenths of a gram. It is largest in the early
years of life, and undergoes retrogressive changes after puberty. Micro-
scopically it consists of epithelial cells arranged loosely in trabecular,
with large sinus-like capillaries between them; -neuroglia and sometimes
muscle-fiber cells are also present. Curious globules of calcareous mat-
ter (brain-sand) are also found, especially in the pineal gland of man.
The gland is developed from an evagination of the third ventricle, and
il is homologous with the so-called median eye of reptiles.

The functions of the pineal gland are obscure. In cases where its
extirpation has been successfully accomplished (in the fowl), it has been
found that the body growth is stimulated and that the sexual characteris-
tics develop more quickly. This result would seem to indicate that the
clinical observation that tumors of the pineal gland are associated in
young boys with abnormal growth of the skeleton and with the early
development of the secondary sexual characteristics, depends on the
fact that a condition of hypopinealism is produced by the growth of a
tumor. The immediate effects of the injection of extract of pineal gland
are not characteristic, consisting merely of a fall in blood pressure, which
is, however, obtainable Avhen an extract of practically any cellular organ
is injected. Prolonged administration of an extract to growing animals
is said to accelerate the growth and to bring about a precocious develop-
ment of the sexual organs; but this result is somewhat difficult to inter-
pret, for, as we have just seen, similar changes occur after experimental
removal of the gland.

THE GONADS OR THE GENERATIVE ORGANS

The Generative Glands of the Male

The structures which arc responsible for the well-known influence of
the testicles on the development of the male sexual characteristics are
the so-called interstitial cells of Leydig, which consist of polygonal-
shiiped epithelial-like cells, with well-marked nuclei and nucleoli. Lipoid

776

Tin. PINEAL GLAND \M> Tin; 0ONAD6 777

granules, staining black with osmic acid, are also present in tin- cyto-
plasm. The degree of developmenl of the interstitial cells varies in dif-
ferent animals, being marked in the <'at ami man ami ill-marked in the
rat and rabbit. In animals which slmw seasonal changes in Bexnal activ-
ity, the cells are mosl prominenl between the periods of sexual activity,
when the semeniferous epithelium is less evident. They also become
prominenl in eases where the Bemeniferous epithelium is atrophied,
either as a result of disease or following I iur;it inn of the vas deferens done
iii such a way that the artery and nerves to the testicles are not included
in the Ligature. When the testicle or a portion of it is grafted into
another part of the body, the Bemeniferous epithelium degenerates, but
the interstitial cells remain alive and become quite prominent. It is
believed that the interstitial cells are responsible for the production of
an autacoid thai has to do with the development of accessory sexual
characteristics.

'/'Ik i ffii-ts of castration are not significant in animals below the verte-
brata. In all of those, how-over, they are very pronounced. The .
trated male frog fails to show development of the thumb pad, hut this
development immediately ensues if portions of testis from another frog
be placed in the dorsal lymph sac. Tn birds the results are more pro-
nounced; in the Castrated male chick the comb, spurs, wattles, etc., fail to
develop, hut will usually do so if some testis from another bird is trans-
planted into it s tissues. In mammals tho effects are most Striking in
animals that develop marked male characteristics, such as the growth
of antlers in stairs. These fail to develop properly and are prematurely

sheil after castration. In man also, ;is is welhknown from a study of
eunuchs, castration has a very profound effect. Hair fails to grow on tho
face; the larynx remains undeveloped; the epiphyses are a long time in
Ossifying, so that the stature may become great, hut at the same time
the limb hones may he more delicate than Usual ; the sutures of the skull

are slow in closing; and the whole architecture of a castrated male comes

to he very like that of the female. Confirmatory evident f tho infiu-

ence of the testicles on the developmenl of secondary sexual character-
istics is afforded by the observation that malignant tumors of the tee
in hoys are associated with the premature development of the secondary

sexual characteristics, and thai these may recede after the removal of
tho tumor.

As a result of castration, interesting changes have also been observed
in other ductless glands. Thus, the suprarenal cortex and tho thymus
become enlarged, whereas the thyroid ami pituitary become atrophied.
The metabolic fund ions also l>( me tardy, as is e> idenced by i ncy

to the deposition of fat.

778 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

When the castration is performed on an adult man, the above changes
in the sexual characteristics are of course not so evident, although the
prostate, etc., atrophy. The effect on the metabolic functions is, how-
ever, very marked, there being a striking tendency to increased forma-
tion of fat. It is interesting that accompanying this there should usually
occur a lowering of the assimilation limit for carbohydrate, so that glyco-
suria is very readily induced. We can not assume, therefore, as dish-
ing has done in the case of hypopituitarism, that the fat deposition is
attendant upon an improper combustion of carbohydrate.

These remarkable effects of castration have naturally prompted ob-
servers to study the influence of injection of testicular extract on the
development of sexual characteristics in different animals, but the re-
sults have in general been considered to be negative in character.

The Female Generative Organs

It is veil known that, besides their function in producing ova, the
ovaries also produce autacoids that have to do not only with the fixa-
tion of the embryo in utero, but also with the changes that occur during
pregnancy in the maternal organism. It is however at present uncertain
as to where these autacoids are produced in the ovary. The two most
likely sources are the stroma cells and the corpus luteum. In the stroma
of the ovary of certain animals, groups of cells have been described
having a different appearance from those of ordinary stroma cells.
They have been called the interstitial cells of" the ovary, and are believed
to be analogous with the similar structures found in the testicle. It is
possible, however, that these interstitial cells are nothing more than
cells derived from previous corpora lutea. The latter are formed by
proliferation of the follicular epithelium which remains after extrusion
of the ovum, and by the ingrowing into the follicle of the so-called theca
cells and blood vessels. The fully developed corpus luteum in most
animals consists of cells arranged in trabecular converging toward the
scar which formed at the place where the follicle had burst. The luteal
cells, as they are called, are characterized by containing considerable
quantities of lipoid material.

That the ovary produces some autacoid is evidenced by both clinical
and experimental observations. Thus, if both ovaries are removed in a
young animal (oophorectomy or spaying), it is well known that not
only does the uterus fail to develop properly, but the external changes
characteristic of puberty in the female fail to materialize, although act-
ually the general effects arc not so pronounced as they are in the male
after castration. Menstruation does not set in; the mammary glands fail
to develop; and there is ;i tendency for the hair 1o grow as in the male.

i hi: PINEAL GLAND \ni> THE G0NAD6 i 12

When the operation is performed in adull life, the changes are no1 v<
pronounced, excepl thai menstruation ceases and tli<' uterus and mam-
mary glands atrophy. Metabolism also becomes altered, causing a
tendency to the deposition of fat, and in the case of the human animal at
least, there is frequently eviden< E mental disturbance.

Attempts to acquire more definite information regarding the physio-
logical effects of the ovarian autacoid have r atly been made by Schafer

and [tagaki.80 Extracts were prepared from the corpus luteum or Graafian
follicles or from the hilum ovariae, and observations were made on the
effect produced on the behavior of the chief forms of unstriated mut
by adding the extracts to isolated preparations of uterus or intestine
or by injecting the extracts Into animals. Applied to the isolated prepa-
rations, cxtr.-ict of follicular tissue or of liquor folliculi was found to
increase the force and rate of the rhythmic contractions of the uterus as
well as its tone, whereas inhibition was produced when extract of the
hilum was used. Extract of corpus luteum, when injected into the
veins, was found to cause the uterus to increase its contraction or if
quiescent to begin contracting. Tt was further noted that extracts of
hilum caused a fall in arterial blood pressure, whereas those of corpus
luteum had little or no effect. Tt would appear from these observat:
that the extracts contain two different autacoids, one having a hormonic
and the other a chalonic action on plain muscular fiber.

Extract of corpus luteum when intravenously injected also stimulates
the outpouring of the milk from the mammary glands, although no1
markedly so as extract of pituitary gland. This pituitary-like action is
not obtained with extracts of ovary that do not contain corpora Lut
Besides being concerned in the outpouring of milk, corpus luteum has

also been shown to lie related in some way to the development of the

mammary gland during pregnancy. These glands b me developed in

young virgin rabbits after the continuous administration for a month
or so of extract of corpus luteum. and they also develop in unimp
nated animals when the corpus luteum is made to develop by artificial

means such as puncturing the Graafian follicle. Furthermore, destruc-
tion of the corpora Lutea in a pregnanl rabbit arrests development
the mammary glands. Th rpus luteum has also an important func-
tion in connection with the formation of the uterine decidua and the

fixation of the embryo. Thus, after destruction of the corpus luteum at

an early period in pregnancy, the embryo fails to become adherent to

the Uterus.

780 THE ENDOCRINE ORGANS, OR DUCTLESS GLANDS

DUCTLESS GLANDS REFERENCES*

(Monographs)

58"Vincent, Swale: Internal Secretions and the Ductless Glands, Ed. Arnold, London.
soBiedl: The Internal Secretory Organs, Wm. Wood & Co., 1913.

G0Schafer, Sir E. A.: The Endocrine Organs, Longmans, Green & Co., New York and
London, 1916.

(Original Papers)

eiFulk, M. E., and Macleod, J. J. R,: Am. Jour. Physiol., 1916, xl, 21.
e^Folin, O., Cannon, W. B., and Denis, W. : Jour. Biol.' Chem., 1913, xiii, 447.
«3Cannon, W. B., and Gray, H.: Am. Jour. Phvsiol., 1914, xxxiv, 232; also with Men-

denhall, W. L.: Ibid., 243 and 251.
eiHartman, T. H., and others: Am. Jour. Phvsiol., 1915, xxxviii, 433; ibid., 1917, xliii,

311; ibid., xliv, 353; ibid., 1918, xlv.
e^Hoskins, R. G. : Am. Jour. Physiol., 1912, xxix, 363 ; Jour. Pharm. and Exp. Therap.,

1911, iii, 93; Am. Jour. Phvsiol., 1915, xxxvii, 471 ; ibid., 1916, xli, 513.
^Stewart, G. N., and Rogoff, J. M.: Jour. Lab. and Clin. Med., 1918, iii, 209. See full

bibliography by Rogoff in this paper.
e^Elliott, T. R.: Jour. Physiol., 1912, xliv, 374.

esStewart, G. N.: Jour. Exp. Med., 1911, xiv, 377; ibid., 1912, xv, 547; ibid., xvi, 502.
GoStewart, G. N, Rogoff, J. M., and Gibson: Jour. Pharm. and Exper. Therap., 1916,

viii, 205.
"Meltzer, S. J.: Deutsch. mod. Wchnschr., 1909, xiii.
"Stewart, G. N. : Jour. Exper. Med., 1912, xv, 547.
"Cannon, W. B., et al.: Am. Jour. Physiol., 1911, xxviii, 64; ibid., 1914, xxxiii, .".56;

also Bodily Changes in Hunger, Fear, and Rage, Appleton, 1915.
"Cannon, W. B., and Cattell, McKeen : Am. Jour. Physiol., 1916, xli, 74.
"Macleod, J. J. R., and Pearce, R. G. : Am. Jour. Physiol., 1912, xxix, 419.
"Marine, D. : Personal communication.
"Marine, D. : Jour. Exper. Med., 1914, xix, 89.
"Marine, D., and Lenhart, C. H. : Jour. Exper. Med., 1910, xii, 311; ibid., 1911, xiii,

455; also Bull. Johns Hopkins Hosp., 1910, xxi, 95.
"Marine, D., and Kimball, O. P.: Jour. Lab. and Clin. Med., 1917, iii, 41.
"Kendall, E. C. : Boston Med. and Surg. Jour., 1916, 175, 557; also Proc. Am. Physiol.

Soc, Am. Jour. Physiol., 1918, xliv.
sopaton, Noel and Finlav: Quart. Jour. Exp. Physiol., 1917, x, 203. Paton, Noel.

Finlav and Watson, A.: Ibid., 233, 243, 315, and 377.
siMacCallum, W. G., etc.: Jour. Exper. Med., 1909, xi, 118; ibid., 1913, xviii, 646;

dour. Pharm. and Exper. Therap., 1911, ii, 421.
s^Cushing, Harvey: The Pituitary Body and Its Disorders, J. B. Lippincott Co., 1912.
ssHorsley, V.: Brit. Med. Jour., 1885, i, 111.
siRobertson, Brailsford, and Ray, L. A.: Jour. Biol. Chem., 1916, xxiv, 347, 363, 385,

397, 409.
s^Clark, L. N. : Jour. Biol. Chem., 1915, xxii, 485.

*The numbering is in continuation with that for metabolism.

PART IX
THE CENTRAL NERVOUS SYSTEM

CHAPTER I. WW VI
THE EVOLUTION OF THE NERVOUS SYSTEM

The nervous system of the higher animals consists of the nerve cen-
ters, and the nerves with their various interconnecting trad The
nerve trad and centers are located mainlj in the spinal cord and brain,
where, by their interlacement, they form an extremely complex struc-
ture. The exad position of the centers and the course and connections
of tlie tracts with the centers are problems which, under t lie title of
neurology, have during recenl years been contributed to more particu-
larly by the anatomisl and the pathologist. The information thus
gathered tells us the possible tract or tracts of nerve fibers through which
the various centers may communicate either with one another or with
the structures outside the central nervous system upon which they
act. Since each of thes,. .-enters may, however, be played upon by in-
fluences coming from differenl regions of the body, it is evident that tl
must remain, as an equally important aspect of the subject, the investi-
gation of the means by which the various available centers and tracts are
broughl into communication and action at the proper time. In other
words, we must investigate tin functional uses <>t tin avaUabU paths.

We may compare the central nervous Bystem with a telephone system,
the exchanges representing the nerve centers, and the wires the nerve
trunks. Any incoming wire may be connected by the rator with
any outgoing wire, but a knowledge of how each wire runs does aot I
us under what conditions the various wires will be connected for trans-
mission of messages. It is the same with the nervous system; the neun
gist can tell ns how the tracts and centers run, hut not the conditi
under which they may art together. This it is the duty ^'.' the physiolo(
to ascertain.

Since it is the degree of development of the central nen .- system
which determines an animal's position in the evolutionary scale, much
Information concerning the relative importance of the various parts of

781

782 THE CENTRAL NERVOUS SYSTEM

it can be gleaned from a survey of the conditions under which the
nervous system makes its appearance in the lowest forms of animal
life. In the case of unicellular organisms, such as the ameba, the ap-
plication of a stimulus to the surface causes a movement, because the
protoplasm of the organism possesses, among its other properties, those
of excitability, conductivity and contractility. In the case of multicel-
lular organisms, on the other hand, some colls are set aside and spe-
cialized for the assimilation of food, others for movement, others to
receive stimuli from the outside, and yet others to compose the tougher
tissues which protect the surface of the animal from injury. This loca-
tion of specific function in specialized groups of cells makes it necessary,
for the welfare of the organism as a whole, that some means of com-
munication should be provided between the distant parts of the animal,
for otherwise the cells which are occupied in absorbing food would be
unable to move away or be protected from harm when some destructive
agency approached them, and indeed the moving (muscle) cells could
never know when the welfare of the organism as a whole demanded that
they should become active.

It is probable that, in some of the lower organisms, the messages trans-
mitted from one group of cells to the others are carried by chemical
substances present in the circulating fluid — hormones, as they are called
(page 729). For the quick adaptation that is necessary in the struggle
for existence, however, such hormones are usually too slow in bringing
about the response, and very early in the evolutionary scale we find that cer-
tain cells become differentiated for this special purpose. The cells thus
specialized constitute the nervous system, their differentiation, as would
be expected, being, however, antedated by that of the cells that form the
muscular tissues. In the sponrjes, for example, muscle cells become
developed from ameboid epithelium and from a layer underneath the
external epithelium. These muscle cells contract slowly so as to cause
opening and closing of the small mouths, or oscula, on the surface of
the sponge in response to movements in the sea water. They are in-
dependent of any nervous structures.

In certain Ccelenterates the muscle cells respond a little more quickly
than in the sponges, and this greater efficiency is found to be dependent
upon the appearance of a localized, very primitive nervous system1.
This nervous system consists of specially modified epithelial cells, or
receptors, sending branches from their inner ends, which either come in con-

tael with the muse] lis. of effectors. In the region between the receptors

and the effectors the network at first serves merely as a structure whereby
the entire musculature of the animal can he brought into harmonious action
from a single point on the surface, as, for example, in the ease of the sea

THE I V0L1 TION OP Till. \l RVO

anemone No. 2 of Pig. 201 . In the jellyfish, which in contrasl to the
anemone is a free moving animal, we find thai the receptors are more highly
specialized and, therefore, much more sensitive, and thai tin- impulses which
they receive are -transmitted to a more definite nerve network, capable doI
only of conveying the excitatory process from one pari <>t' the animal to an-
other, Km also of imprinting on the impulse ;i characteristic rhythmic ac-

i.

5|)ent)c

5ea anemone

Simple form in
earthworm

i e Addition of

association neurons
in earthworm

l. Diagram to show gradual e> iti '•'»' cell

and in the »| '■ epithelu

■ .11 in tbf m u | in a Kank-

mi simple form miii in the earth.. M -

invertebr.

tivity which brings aboul the contraction <»t' the bell ami the sw imming mo
m. 'lit hi' the animal. 'I'll.' network now assumes the function «>t' an n
as well as a transmitter of imputa

So far the adjuster is an extremely simple structure, ami it is possible
that the effector ami receptor organs are directly com by fil

running through it. When we come t.> the segnu nted ini

784

THE CENTRAL NERVOUS SYSTEM

(such as the earthworm, crayfish, lobster, etc.,) much more definite spe-
cialization of the adjuster occurs, for now this intermediate nervous tis-
sue becomes collected into so-called ganglia, a pair existing for each
segment and the various pairs being connected by definite
nerve structures, constituting the ganglion chain. It is in
tli is group of animals that we have, for the first time, def-
inite evidence of the existence of the neuron, which may be
considered as the elementary unit of which the nervous sys-
tem of all the higher animals is built. A neuron may be
either sensory or motor, and in both cases it consists of
a cell with a nucleus, one long process, called the axon,
and several short branching processes, called the den-
drites. The axon in its course may give off a branch,
or more, at right angles, — these are sometimes called
collaterals, — and at its end it may break up into very fine
branches called a synapsis. In a sensory neuron the im-
pulse is transmitted from the end of the axon to the
nerve cell, whereas in a motor neuron it is transmitted
in the opposite direction from the cell to the end of the
axon (Fig. 203).

The simplest arrangement of sensory and motor neu-
rons to constitute the nervous system is seen in the
earthworm, in which it forms the simplest type of reflex
arc (Fig. 201, No. 3). The sensory neuron has its cell
body in the skin, and its axon proceeds to one of the
segmental ganglia, in which are large nerve cells whose
thick axons pass out from the ganglion as motor fibers
to the muscles of the body wall. The dendrites of the
motor neuron and the branching of the termination of
the sensory neuron cause a very fine interlacement of
nerve fibers in the ganglia, forming a network known
as the neuropile. The sensory impulse, on reaching the
ganglion, is transmitted by the synapsis to the den-
drites, probably without the fibers actually joining to-
gether; that is, the nerve impulses pass from the one
to the other set of branches by contact rather than by
transmission through continuous tissue.

By such an arrangement it is evident that the nervous
apparatus in each segment could cause a contraction of
the muscles of its own neighborhood, but that a stimulus applied to one re-
ceptor would be incapable of calling forth a contraction of the muscles of a
far distant segment, much less a coordinated contraction of the musculature

Fig. 202.— Dia-
gram of nervous
system of seg-
mented inverte-
brate; a, supra-
esophageal g a n-
glion; b, subeso-
phageal ganglion;
oe, esophagus or
gullet.

I III EV0L1 TION OF Till M RVO STEM

of the whole animal such as would be required for locomotion. To ren

this possible it is n< Bsary that some means of communication become

tabli&hed between* the differenl segmental ganglia. This is effected by

association neurons, each of which, as the name implies, consists of a nerve
cell with its dendrites Located in one ganglion and of an axon, which passee
to the next or oven to some more distanl ganglion, where it ends by
synapsis. The important point to note is that tin--.. ;i-»hm;iT ion neurons
do not leave the central nervous system; they merely conned various
ganglia.

So far the ganglia of each segment are of equal importance, but if
we examine further we shall find that at the head end* of the animal
several of the ganglia become fused together to form a larger ganglion,

-'03. — Schema of simple r< ; r, receptor in an epithelial memhrane; a, afferent fiber; s.

synapsis; c, nerve cell of center; r , •; m, effector on

which lies jusl above the gullet, and from which fibers pro< d around

the gullet to unite in front of it in another large ganglion, which usually
shows three lobes. These Larger ganglia receive afferent nerve fibers
from the closely adjacent primitive BCnse organs for sight, sound and
smell, from structures, thai is, that are really highly specialized recep-
tors. The cells of the retina and ear have been made capable of reacting
to impulses of lighl or sound instead of those of pain, touch or tempera-
ture, to which the receptors of the integument an eially sensitised
They are distana receptors projicienl receptors . and it is evident that
the nerve reflexes with which they are concerned are of a higher 0]
than those located in the segmental ganglia themsel1

Some of the neurons of the head ganglia are merely motor and act on
the muscles of the head cud of the animal, but otic purely assoeia-

786 THE CENTRAL NERVOUS SYSTEM

tion neurons and proceed down the ganglion chain to terminate by
synapses in one or other of the segmental ganglia. These association
neurons exercise a dominating influence over the activities of the seg-
mental ganglia, so that they may determine Hie response of the animal
when its safety is threatened by some approaching enemy. When, for
example, the stimulus produced by some sight or sound of an approach-
ing enemy is received by the head ganglia, these will transmit impulses
down the ganglion chain which so influence the various nerve cells of
this chain as to produce in all of them a coordinated action for the pur-
pose of removing the animal from danger. Even should some local
stimulant be acting on one or more of the segments, the response may be
inhibited on account of stimuli meanwhile transmitted by way of asso-
ciation neurons from the large head ganglia; in other words, the part
controlled by the segmental ganglia becomes subservient to the whole
through the dominating control of the head ganglia.

This illustrates the beginnings of the integration of the nervous system;
and as we pass to the study of the higher animals, we shall see that this
integration becomes more and more complicated, and that, as it does so;
the nerve centers acquire the power of storing away the impressions they
receive, which they may afterwards apply to regulate the reflex response.
Thus memory and volition come to find their place in the nervous inte-
gration of the animal. The afferent stimulus arriving, let us suppose,
at nerve cells controlling the movement of the leg, may fail to cause
a response of the corresponding muscles because of impulses meanwhile
transmitted by association neurons from higher memory centers, for
the animal may have learned by experience that such a movement as the
local stimulus would in itself call forth is opposed to its own best in-
terests. This experience will have been stored away in memory nerve
centers, so that, whenever the local stimulus is repeated, impulses are
discharged from the memory centers to the local nerve centers, and
the reflex response does not occur, or is much modified in nature. For
storing away these memories and for related psychological processes of
volition, etc., the anterior portions of the nervous system in higher ani-
mals become very highly developed so as to constitute the brain, and
the simple chain of ganglia of the invertebrates is replaced by the
spinal cord.

As we ascend the scale of the vertebrates, the brain becomes more
and more developed, until in the higher mammalia, such as man, very
few reflex actions can occur independently of the higher centers which
are located in it. The reflex arc now involves, not one nerve center,
but several, and of these the most important are located in the brain.

There is thus no essential difference in the general nature of integra-

THE I VOLUTION OF Till \i RVOl i.M

tion in the nervous Bystem of the lower as compared with the higher
animals, bu1 there is a very distinct morphological difference: in the lower
or invertehrate animals the ganglion nerve chain is ventral to the alimen-
tary canal, whereas in the higher or vertebrate, the spinal cord, which
lakes the place of the ganglia, is dorsal to the alimentary canal. In b
groups the head ganglia arc dorsal to the alimentary canal, but in
vertebrates these become much more definite in structure, and constitute
the brain. This morphological difference between vertebrates and inverte-
brates is probably no1 so fundamental as a1 first sighl it may appear to
bo, for, as Gaskell has shown, ii is possible thai the alimentary canal of

the invertebrates is really homologous with tl intra] canal of the

spinal curd and the ventricles of the brain of the vertebrates. Accord-
ing to this observer, what has really happened in the latter group of
animals is thai the ganglia have grown up so as to Burround the alimen-
tary canal and so constitute a continuous structure, a new alimentary
canal beinir meanwhile provided by the enclosure of a space as a result
of ventral downgrowth of the body walls. Although this view'has nol
Keen generally accepted by biologists, their is no inherent reason why it
should not lie accepted. It is no more to be wondered at than the well-
known fact thai a new respiratory system 1" mes developed in the

passage from aquatic to land amphibians.

The fibers of the sensory neurons in vertebrates are collected tog
to form the posterior roots of the spinal cord, and the eel] bodies of these
neurons are located not on the surface, as in invertebrates, l>ut in t In-
posterior root ganglia, the cells being connected to the filters by T-sha]
junctions. The olfactory nerve is the only one in the higher vertebrates
winch retains its primitive condition.

In the vertebrate animals the spinal member in the integration of the
central nervous Bystem is the motor neuron, the fibers being collected in
the anterior roots. Toward the cell of this neuron impulses are transmitted,
not only from the segmenl in which it is itself located, hut by way of
SOCiation neurons from other BCgmentS or from far distant parts of the

central nervous system. In other words, this motor neuron may transmit
impulses which cause the muscles to perform local independent mi

merits, which are coordinated with those of adjl nd which

may lie of widely varying types. The motor neuron has therefore ■
appropriately been called the final common /><»//'. ami it will be one of our
main objects later to show the conditions under which several diffei
competing influences may obtain possession of this path.

CHAPTER LXXXVII

THE PROPERTIES OF EACH PART OP THE REFLEX ARC

Having briefly traced the physiological development of the nervous sys-
tem, we are prepared to consider in greater detail the peculiar function
of each of the parts which enter into the formation of the reflex arc.

THE RECEPTOR

With the advance in animal organization is associated the development
of the ability to appreciate and discriminate between external phe-
nomena, special organs called receptors being evolved to receive the
stimuli which these occasion. Those receptors which are distributed
over the skin of the animal are called external or cxteroceptors, and are
especially adapted to react to such stimuli as temperature, pressure,
and pain, but at the fore end of the animal certain receptors become more
highly specialized so as to react to stimuli coming from a distance —
that is, to stimuli that are not produced by contact of external objects
with the surface of the animal. These specialized receptors — sometimes
called proficient — include the eye, the ear, and the olfactory epithelium.
Receptors are also provided in the interior of the organism for the pur-
pose of receiving stimuli dependent upon the activities of the organism
itself. They may be called internal receptors, and we may further dis-
tinguish two groups of them — namely, those which come from the sur-
faces of the mucous membranes and those which come from the sub-
stance of the various organs and tissues themselves, as, for example,
from the substance of muscle or tendon.

A receptor may be denned in a general way as a mechanism in which
some particular kind of stimulus produces changes that result in the
excitation of the nerve fiber with which the receptor is connected, al-
though the stimulus in itself is incapable of exciting the nerve fiber. In
other words, as Sherrington puts it, the receptor has the threshold of
its excitability raised to every kind of stimulus save one, toward which
it is lowered. A nerve fiber, for instance, responds to every kind of
stimulus approximately equally; a receptor will also respond to these
same stimuli, but with great inequality, since each receptor is specialized
to react to one kind of stimulus and to others only when these are very
strong.

788

THE PROPERTIES 01 l LOH PABT OF THE Hi HI \ ABO

Ii is often a difficull matter to determine .just exactly what it is in
ihe nature of the stimulus thai makes it capable of affecting on<
and not another; for example, it is often merely a question of tl
of vibration of the stimulus. Lighl and heat rays both duo to

vibration of the ether which fills Bpace When these vibrations are
slow, they stimulate receptors thai have been specialized for apprecia-
tion of temperature, bu1 when they are rapid and exist as rays of li^ht.
they no longer aftVrt the temperature r iptors bul only the highly spe-
cialized receptors of the retina. Similar vibrations of tin- air in pli
of tho ether cause sound and stimulate tho auditory receptors. Tt is
quite likely that tho receptors in different groups of animals are attui
to react tn different rates of vibration. For example, a cat can hoar
higher pitehod notes than man, and it is possible that the retinas of
some animals respond to rays vibrating with a different frequency from
those to which the retina of man is adaptod. Tn this connection it is of in-
terest to note that tho touoh roooptors of tho skin rospnnd so promptly
to stimulation that ono hundred vibrations of a tuning fork per seeond
can bo felt as separate stimuli, whereas to tho oar at this frequency th^
fork omits a eontinuous note. Tho roooptors of touoh are therefore moro
prompt in their response than tho roooptors of tho auditory nerve.

When onee tho roooptor has boon stimulated, tho impulse passes and
is transmitted to the nerve centers, where it is translated into a par-
ticular sensation. Tho conditions are really not unlike those whioh ob-
tain in tho ease of tho various physioal instruments used to reeeive and

convert into tl lectric current stimuli <>f heat, light, chemical ene

eto. Tho roooiver required to bring about this transformation must ho
especially constructed in eaoh ease, that for light boinir the aotinomoter.
that for motion the dynamo, that for heat the thermopile, and that for
chemical energy the oonoontration coll. Eaoh of these physioal instru-
ments may bo considered as a specialized receptor for tho purpose of
producing an electric current out of other forms of energy

Tn accepting the above analogy we must not fail to boar in mind
that very feeble stimuli are often able to set in operation nerve impti
that are as potent as those produced by much stronger stimuli. Here
again, we have a physical analogue in the case of relay currents, in
which a fooblo electric current may operate to complete the circuit from
ind( 'it soi. •' electric discharge and thus set in motion a much

larger amount of oner

These general considerations ,,f the natal ptor naturally

lead u< ti. the law of thr >- properties of > which is to the

effect that, however excited, each nerve of special sense gives riso to
its own peculiar sensation. Tims, in whatever way the chorda tympani

790 THE CENTRAL Minors SYSTEM

nerve is stimulated (chemically, mechanically or electrically) during its
passage across the tympanum, the sensation evoked is that of taste.
And so with llif receptor; whatever the means by which it is excited,
whether by the particular kind of stimulus for which it is adapted or by
excessive intensities of other stimuli, excitation always evokes the same
sensation, [f the optic nerve or retina is mechanically stimulated, as
by pressure againsl the outer eanthus of the eye or by an electric cur-
rent, the sensation is thai of light. Applying these facts to less well-
known receptors, such as those of heat and cold, it is interesting to note
that stimulation of a "cold spot' by extreme heat or by mechanical
or electrical stimuli brings out the sensation of cold.

Properties of Epicritic and Protopathic Receptors

A valuable grouping of receptors of the skin has been demonstrated by
Eead and his pupils by experiments on himself. Head found after sec-
1 itMi of the skin nerves — of the radial nerve, for example — that deep
pressure and pain were still present in the area supplied by the nerve,
indicating that these deep sensations are carried by the sensory fibers
present in the muscular nerves. In such a paralyzed sensory region the
power of general localization is fairly good, although light, touch, tem-
perature and superficial pain are entirely absent in the overlying skin.

In the case of the fingers the nerves of deep sensibility run in the ten-
dons of the finger muscles, so that after severance of the cutaneous
nerves and tendons of the hand, all sensibility is gone.

During the regeneration of the cut nerve the cutaneous sensations re-
appear at two periods: one group, called the protopathic, begins to ap-
pear in from seven to twenty-six weeks, whereas the other, called epicritic,
does not fully appear for one or two years.2 The protophatic sensations
are of a distinctly lower order than the epicritic. When they alone arc
present, there is the sensation of pain, but not that of fine touch; tem-
perature sensations are fell when extreme degrees of heat or cold — above
-38° C. or below 20° C— are applied to the skin, but not for slight de-
grees; the power of discriminating between two points is almost entirely
absent ; and the sense of Localization is very imperfect. For example, the
person will often vd'ov the point that lias actually been stimulated to a
neighboring normal portion of skin. Protopathic sensibility is more or
less distributed in spots, mid il is strongly "affective" in character, caus-
ing an intense subjective sensation. A stimulus that causes only moderate
pain under normal conditions produces in a ''protopathic area" a pain
thai may he intense.

The epicritic sensation, as will he inferred from the foregoing, responds

Till PROPERTIES OP I \' M PART OF Mil REFLEX \K<

791

to finer grades of stimulation. Bj it we can feel the 1 i *_r 1 1 1 ♦ • s. t touch and
can discriminate, tin- finesl grades of temperature between 26 and 37 I
The power of localization of the stimulus and the ability to discrimii
between two points also return with epicritic regeneration.

In the Bpinal cord the nerve fibers carrying one kind of Bensation
are grouped together, in the Bense thai pain sensations, whether deep or
protopathic, run in the Bame column in the cord. Likewise temperature
sensations, whether protopathic or epicritic, run together.

The Peculiarities of Each of the Separate Sensations

Temperature. The receptors for temperature are arranged in groups,
Borne being sensitized for heat, others for cold. These groups of receptors
are called heat and cold spots. They can be very easily detected on an

Fig. 204. Thermoesthesii
area of s U i n by means of a pointed hollow vessel, through which water ifl

made to flow at a temperature a Little below or a little above that of the
skin. The instrument is called a thermo-csthesiometer. On a part of the
skiii where their are mi heat and cold spots, the thermo-esthesiometer will

elicit no sensation either of heat or of COld. This is charted on an Outline

drawing of the part as a neutral spot. At other places it will call forth

a Bensation of heat, indicating the presence of heat spots, or at othei

sensation of cold, indicating the presence of cold spots. It will he n<
that certain of the spots are much m ictive titan others, and that t1

of cold are much the more numerous Bee Pig 205 Both heal and cold

spots are most fre.pient at the nipples; then, in Order, cine the idlest, the
nose, the anterior surface ,,!' the arm. and the abdomen They are
marked on the exposed BUrfaCC of the skin, guch .is tin1 face, and tl

792

THE CENTRAL NERVOUS SYSTEM

also very infrequent in the scalp. They are almost absent from the mucous
membranes, which explains why one is able to swallow a liquid that is too
hot for the hand.

The acuteness of the temperature sensation, as with all the other cu-
taneous sensations, depends very much on the condition of the skin,
being most sensitive when this is at the ordinary temperature, but very
imperfect when it is either very hot or very cold. There is also very
marked adaptation of the sense. This can be very well shown by the simple
experiment of taking three vessels of water, one at a moderate tempera-
ture, one very hot and one very cold. If a finger of one hand is placed
in the hot water and a finger of the other in the cold, and they are left
there for a short time, until the skin has assumed the same temperature
as the water, and then transferred to the lukewarm water, the finger

Fig. 205. — Cold spots (A) and heat spots (B) of an area of skin of the right hand. In each
case the most intense sensations were experienced in the hlack areas, less intense in the lined,
and least in the dotted. The blank areas represent parts where no special sensation of either
kind was experienced. (From Goldseheider.)

transferred from the cold water will feel hot, and that transferred from
the hot water will feel cold. Temperature sensation also produces a
marked positive after-effect. Thus, if a cold coin is placed on the fore-
head and then removed, the cold sensation will persist for some time in
the area of skin on which the coin was laid.

That the receptors for heat and cold respond only to one kind of
stimulus, or if to others, only when these are excessive, can be well il-
lustrated by the experiment of touching a cold spot with a very hot ob-
ject: the sensation will be that of cold. The hot object has so pronounced
a power of stimulation that it has overstepped the threshold for heat
of the cold-adapted receptors. The sensation of cold is elicited more
promptly than that of warmth. The distinction between a warm and a

THE PROPERTIES OF EA< II I'AKT OF THE KEFLEX ARC

hot bath may really depend on the fact that in the tatter the cold s]

are stimulated as well as those of heat. It is at least interesting to note
thai the physiological reflexes stimulated by either a cold or a very hoi
bath are the same; thus, a rise of blood pressure and a contraction of the

muscles of the skin occur in both eases.

The Touch Sense. — In order to investigate the tonch sense fcely,

von Fvcy has devised a method of asing hairs of differenl thickness each
mounted on a different handle. The hair which prodn * 1 « » 1 1

of touch when pressed on the skin so that it just 1m ads is then similarly
pressed on one scale pan of a balance, and the weight required in the
other scale pan to hold the heam horizontal -when the hair just hends, is
ascertained. From the diameter of the hair one can then calculate how
many grams per square millimeter are necessary to elicit the Bensation
of touch. The following quantitative results have been ohtained by ap-
plying von Prey's method to different parts of the body:

Gm. per sq. mm.

Tongue and nose 2

Lip 2..">

Finger tip and forehead ?•

Back of finger 5

Palm 7

Forearm

Back of hand 12

Calf, shoulder 16

Abdomen 2fl

Outside of thigh

Shin and sole 2*5

Back of forearm

L"in )v

That the sense of touch is located in spots — touch spots — can best 1"'
demonstrated on the calf of the leg. Tf this is shaved and then carefully
explored with a fairly stiff hair, it will he found that there are only
some twelve to fifteen spots in an area of a square centimeter at which
the hair can he felt. Between these spots there is no sensation of touch.
That these spots are composed of specialized receptors can he very clearly
shown by pressing a fine needle into one of them, when no pain will he
experienced hut only a peculiar shotty sense of pressure.

Careful examination of the position of the touch spots will further
show that they are grouped around hair follicles, particularly on t:
front which the hair extends the windward ride, v 6 may call it. This
fact explains 1he well-known experience that an object may he felt n
acutely on a hairy surface than after that surface has been shaved. The

hairs bend slightly when the objeel eomes in contact with them, thus

794 THE CENTRAL NERVOUS SYSTEM

causing pressure to be exerted on the hair follicles, so that the touch
corpuscles in the neighborhood of the follicles, or perhaps the fine nerve
plexus which surrounds them, hecomes excited. The influence of hairs
in increasing the touch sensation can be demonstrated by the von Frey
method; For example, in one experiment over an area of 9 square mil-
limeters of skin with hairs present, 2 milligrams were found to produce the
sensation, whereas after the hairs had been removed, it required 36 milli-
grams.

The frequency of touch corpuscles differs very much in different parts
of the body. They are most plentiful on the fingers, relatively infrequent
over the skin of the back, and very scarce in the skin directly over bony
surfaces. They are entirely absent from the cornea, the conjunctiva
of the upper lid, and the glans penis. The adequate stimulus for touch
is evidently deformation of the surface. Pressure exerted over all the
touch corpuscles of a portion of skin is not felt. This can be demon-
strated by dipping the finger into mercury. The pressure of the mercury
is felt on the surface but not in the submerged portion of the finger.
Touch is the most responsive of all the sensations. Thus, as has already
been noted, a tuning fork can be felt vibrating by the finger when to
the ear its note is a continuous one, and the stimuli produced by a re-
volving serrated wheel can be felt by the fingers as separate even up
to a rate of five or six hundred stimuli per second. Adaptation is also
a marked feature of the touch sense, as is the experience of every one
who has worn flannel underclothing or a plate of false teeth.

Closely related to the tactile sense is the power of discrimination oc-
tween two points. This is tested by finding at what distance the two
points of a pair of calipers stand in order to be distinguished as separate.
The result in any given part of the body varies a little according to
whether the points rest on touch corpuscles and according to the rela-
tionship of the calipers to the hair follicles. On an average, however,
we may take the following distances in millimeters as being those at
which the two points can be distinguished over different areas of the
body:

mm.

Tip of tongue 1.1

Volar surface of finger tip 2.3

Dorsal of lost phalanx 6.8

Palm dl' hand 11.3

Ba<Jk of hand 31.G

l tack nf neck 04.0

Middle of back, upper arm and side 07.1

It is clear from this list that the power of discrimination lends to
diminish in proportion to the lessening mobility of the part. It is greatest

THE PBOPEBTIES <>f EACB PART OP Till. Kl.H.l.x ARC

at the tip of the tongue and the tip of the fingers; it is least on the
relatively immobile skin (lf the back. These distances are much less v. hen
the points real on two touch corpuscles*. Under these conditions, for in-

stai the distance for the volar Bide of the finger tip or even for the

palm of the hand may be only one-tenth of a millimeter; and for the
arm and back it may become reduced to half a millimeter.

Localization of touch is a very accurate process, al leasl in the d
sensitive parts of the skin, hut nevertheless it is very probably a mat-
ter of education. An evidence of this is the fart thai in tin- much more
highly specialized retina the power of localization of objects' in the visual
field is a process of education and experience. For tins reason a pei
from whom a congenital cataract has been removed, can not locate the
objects which he sees until after he has learned by his experience of touch,
taste, etc., to associate the portion of the retina stimulated with a certain
part of the visual field. If this is true for the retina, it is also probably
true for touch. The famous experiment of Aristotle is explicable on the
same basis. If the fingers are crossed and a marble placed between the
crossed fingers, it will be felt as double, since now it touches two skin
surfaces which have not been accustomed to touch the same object, but
educated to feel different objects. Experience associates those two skin
areas with different objects, not with the same object.

The Pain Sense. — It was at one time thought that the sensation of pain
was due to overstimulation of any kind of receptor, but it is now known that
for this, as for other skin sensations, there exist special receptors. Tims,
it is found thai in certain parts of the body, such as the cornea, and to 8
certain extent in. the glans penis, pain receptors alone are present, and
in disease the sense of pain may be entirely abolished, whereas that of
touch remains, this condition being called analgesia. Overstimulation of
a touch spot does not, as we have seen, cause pain but only a sense of
pressure. Although pain is appreciated by special receptors, the charac-
ter of the pain is dependent on the other sense receptors simultaneously

excited: for example, a throbbing pain is due to the simultaneous pi
snre produced by dilated blood vessels, etc. A sensation of pain accom-
panies certain reflexes of a protective nature (nociceptive reflexes, page
825), and when the reflex is absenl the part is likei) to suffer damage. On

this account the pain nerves may be regarded as trophic nerves. The

sense of pain ma\ als lir in structures which are devoid of ordinary

sensibility, such as the intestine and the ureter

CHAPTER L XX XV III

THE PROPERTIES OF EACH PART OF THE REFLEX

ARC (Cont'd)

THE NERVE NETWORK

Tn all animals above the Celenterates, no direct protoplasmic continuity
exists bet-ween the various neurons, the transmission of the nerve impulse
depending on contiguity rather than continuity of the elements that con-
stitute the reflex arc. This transmission may be effected through a syn-
apsis coming in contact either with dendrites or with nerve cells. It is
extremely difficult to know whether there is really any anatomic con-
tinuity between the various fibers which form the network in the gray
matter of. the central nervous system. "We shall not attempt to discuss
this vexed question here, but in order that we may learn something of the
possible functions of a nerve network, we may consider that present in
the Avails of the intestine (plexus of Auerbach and Meissner.) This plexus
seems to have an important function to perform in connection with the
myenteric reflex (see page 466). At least it has been shown by Meek3 that
after transsection of the intestine the muscular and epithelial structures be-
come regenerated considerably earlier than the nervous plexus, but that
the myenteric reflex, which, it will be remembered, is characterized by a
wave of inhibition preceding one of contraction does not occur until after
the plexus has been regenerated.

NETWORK ON SKIN NERVES

A very important type of nerve network, from the medical viewpoint,
is that which is produced close to their receptor endings by the branch-
ing of the afferent fibers of the skin. Through these branches the vas-
cular reactions following the application of an irritant to the sensory
surface take place without the intervention of any nerve cells. It used
to be thought that such reflex vasodilatation depended upon the trans-
mission of an impulse along an afferent neuron to an efferent vaso-
dilator neuron, a view strictly in consonance with the neuron hypothesis.
That such is not the case, however, is shown by the fact observed by
Xinian Bruce4 that irritants such as mustard oil applied to the skin
or cornea continue to produce their usual reaction for some time after

796

THE PROPERTIES 01 I \< H I'AUT OP 'Mil. REFLEX ARC

section of the posterior roota of the spinal cord, but fail to <io so if
the nerve fibers are cul and allowed to degenerate, or if the stimuli are
blocked by applying cocaine to the skin. What actually happens is
evidently that the impulse Be1 up by the irritanl as it travels up the
afferenl fiber passes on to one of the branches above referred to, along
which it then proceeds to the blood vessels, which it causes to dilate
Thai such vasodilator impulses may l>e transmitted down the fibers
an afferent aerve has been confirmed by Bayliss, who found thai va
dilatation occurred in the hind limb when the posterior spinal roots
were stimulated I Bee page 23 I .

Post, root
gang.-

I -■ Diagram I n reflex of sensory nerve fiber of shin. A stimulus applied I

the skin is transmitted by tb< i.l.< r i \ I, part . mu to the spinal co: . an>i

part of it parsing by the collateral (C) to the arteriole i.-ii, which it causes to dilate.

In this peripheral branching of the afferenl fibers of the skin, we
have therefore a sort of neuropile which, like that of certain forma
Celenterates see page T^-j . is capable of s,.r\ in lt as a pathway for the
transmission of a Bensory impulse to an effector organ without the in-
tervention of aerve cells. Such a reflex is known as an axon reflex, and
it is evident that it may occur through any fiber which gives off brand
one traveling to a sensory surface, the other to some effector organ,
occurs in the hypogastric aerves to the bladder Bee paj ~~ ; .

THE SYNAPSIS

At tin* poinl of ita.-t between a branch of one neuron and a nerve

cell of the next, we have seen thai there exists structure known
the synapsis. Although this is described by hist . tuft-like

798

Till CENTRAL NKRVOnS RYSTKM

branching ft' the end of the axon (Fig. 207), it may really consist of a
sort of membrane- the synaptic membrane. It permits the nerve im-
pulse to pass in one direction only, from synapsis to cell. Of what this
membrane may be composed, we do not know, but there can be no
doubt as to ils greal functional importance in connection with the in-
tegration of the central nervous system; for example, failure of an im-
pulse to pass between two neurons may be due to retraction of the
synaptic membrane from the cell, or to alteration in its permeability to-
wards the nerve impulse, perhaps as a. consequence of changes in surface

Fig. 207.- — Arborization of collaterals from the posterior root fibers around the cells of the
posterior horn. A, ascending fiber in posterior columns; B, collaterals; C, cells of posterior horn;
napsis. ( Prom Ramon y Cajal.)

tension. Similar changes may also be brought about by the action of
electrolytes or by chloroform, strychnine, and other drugs. As we shall
see when we come to study the reflexes of the higher animals, there can
be little doubt that it is in the synaptic membrane that many of the
peculiarities reside which characterize conduction in a reflex arc as
compared with that in a nerve trunk. The phenomena of summation,
of reciprocal inhibition, of facilitation, etc., are undoubtedly depend-
ent upon such alterations. The synapsis is also almost certainly the
seat of fatigue in the central nervous system, and it is possibly the
strueture whose physiologic activity becomes upset in surgical shock.

Till. PR0PRRTI1 - OP I \« II PART OP Till Kl III X \l:<

THE NERVE CELL

Aside Prom being a meeting place of fibers coming from various
sources, the nervi II may have other functions, such as that of rein-
forcing impulses, jusl as a relay may reinforce an electric current It
is also responsible for maintaining the nutrition of the axon with which
it is connected. In the case of the posterior rool fibers of higher ani-

Pig, 208. Normal cell from the anterior horn, stained to show N

( Prom 1 1' ■» ell. >

mala, this function is probably the must importanl which the cell |
forma, for it has been found by separating the ganglia from their bli
supply in the frog that, although the cells degenerate in about two
weeks, Bensory impulses continue to be transmitted through the gan-
glia, similar observations have I »«•«■! 1 made in tl • of the crab, in
which the '•••11 bodies of the neurons lie <>n the surfa the ganglion

MHI

THE CENTRAL NERVOUS SYSTEM

mass, from which they can be separated, leaving merely the neuropile,
through which, however, the reflex continues to be conveyed. After a
time, of course in this case also the reflex disappears, because
an axon can not live indefinitely after it has been separated from its
nerve cell.

These fads regarding the general function of the nerve cell arouse
our curiosity as to its morphological structure. When nerve cells are
fixed and stained in various ways they show certain elements in the

Ax

'

'i&M

Fig. 209. — Part of an anterior cornual cell from the calf's spinal cord, stained to show neurofibrils.

ax, axon; a, b, c, dendrites. (From Bethe.)

cytoplasm — namely, (1) large granules or masses, which stain deeply
with basic dyes and are called Nissl bodies (Fig. 208), and (2) a fine
network of fibrils passing through the cell substance from one process or
dendrite to another — neurofibrils (Fig. 209). These appearances in fixed
and stained preparations are possibly, however, entirely artificial ; for when
nerve cells are preserved in a living state — by being suspended in some of
the animal's own lymph or blood serum — it is found, when they are ex-
amined by the aid of the ultramicroscope (see page •rJ2), thai the cytoplasm

THE PROPERTIES OF I \<H PART OP 'rill REFLEX LRC B01

is composed of a visoous fluid full <»r extremely minute granules, each of
which apparently consists of a colloidal solution surrounded by a lipoid
envelope (Pig. 210). When the temperature is raised, the granules dis-
appear, and when th lis are deprived of oxygen, the cytoplasm and

nucleus become swollen. A similar swelling of the cell and nucleus super-
venes upon snt imi of the axon; and in stained specimens the Nissl
granules disappear and the protoplasm stains diffusely chromatolys

In embryonic life the proc< of the nerv 'lis appear to be capa-
ble of undergoing a certain amount of ameboid movement, and fibers
grow out from them, indicating, therefore, that in the development
of the nervous system the nerve cells appear first, and the nerves sub-
sequently grow oul from them to their proper destination. Prolifera-
tion of isolated tissue cells m vitro lias been observed for many other

ring nerve cells (from the <!• ■ i -:il rool ganglia "t .-, dog three icamined

by tlir ultramicroscope. There arc no Kit - it new ' i"

protoplasm. (From Marinesco.)

i issues, such as cardiac muscle, renal epithelium and connective tis-
sue. Its occurrence indicates that the therapeutic principle that the
aim of treatment should be to give the diseased organ a rest so that by
cell regeneration i1 may r ver its lost function, is one which may ap-
ply tn the nerve tissues of young animals. Whether adult n< ells
may regenerate is as \«t no1 certain.

This growing out of nerve fibers from their cells is t; ential na-

ture ut' the development of the nervous system in the developing animal.
At birth, unlike the cells of other tissues, those of the central nen

system are already provided. No new ones arc added during postnfl

life. The axons gradually develop from this inherited stock nt* n<
rolls, and by connecting with other neurons about the

integration which is the important characteristic of the adult i

MIL' THE CENTRAL NERVOUS SYSTEM

system. The more complex tlio integration, the higher the intelligence
of the animal.

Besides performing these functions the nerve cells serve as store-
houses for memory impressions, certain types of them being especially
adapted for this function. The differences observed in the relative thick-
ness of the cell layers composing the cerebral cortex are more or less
associated with the function which it can be shown the different areas
of this possess. Nerve cells are extraordinarily sensitive to deficiency
in oxygen supply, and yet little evidence of oxygen consumption by
the brain can be revealed by the usual methods of investigation (page
396).

THE INTERMEDIATE OR INTERNUNCIAL NEURON

1 1 would be profitless at this stage to consider the possible influences
thai the intermediate neuron may have on the impulses passing along
the reflex arc. Before doing so we must see how the problem can be
approached, for it is plain that the neuron in the case of the simpler
reflexes is too short to make any investigation of its peculiar functions
a possibility. We must study the characteristics of some type of re-
flex in which this neuron is drawn out, such as the scratch reflex, in
which, as we shall see, it extends from the shoulder area of the cord
to the lumbar region.

I HAPTER LXXXD5
THE REFLEXES OF THE SPINAL ANIMAL AND

SPINAL SHOCE

Saving become familiar with the peculiar properties of each of 4
structures which go to make up the reflex arc, we may now proceed to
consider the function of the arc as a whole. It may be well f all

to consider briefly the experimental method by which such studies may
be made. The object aimed at is to simplify the conditions
much as possible, for it will be evident that, in the intact nervous -

tern, with the brain exercising a dominating influen ver the crreat

majority of all the reflexes, it would be impossible by applying a given
stimulus, to predict exactly what kind of reflex response it might rail
forth. The reflex will be conditioned upon the accompanying influei
which the brain exercises on the reflex involved.

In order to render the reflex unconditioned, we must remove the in-
fluence of higher centers. This can be done experimentally for the
ilexes of a great part of the body by cutting the spinal cord above the
level of the segment in which the reflex under investigation resi
Some of the reflexes elicitable from the cord isolated in this way in-
volve only one or two neighboring segments, whereas others spr<
over several. The reflexes which have been most extensively emplo;
are those which involve the musculature of the hind limbs. Since some
of the receptors concerned come Erom the skin of the flank and shoul-
der areas, the section is usually made at the upper end of the thoracic
region of the spinal cord.

Spinal Shock in Laboratory Animals

Immediately after the operation a profound condition of depn -

in, involving all the reflex area in the separated portion of cord. This
condition is known as s/iiiml shock. It supervenes in all class ani-

mals having a spin;il cord, but is much more profound in the hi_
than in the lower animals. Afl a result of this depression, the part of
the body below the section exists in a limp ami flaccid condition, and the
application of even very BtTOng stimuli to the skin will evoke 1
of reflex movement. In the case of the lower animals, such as the f

804 THE CENTRAL NERVOUS SYSTEM

the condition begins to pass off in from twenty minutes to half an hour,
after which a stimulus applied to the skin of the foot is followed by a
typical flexion movement at knee and hip, the so-called flexion reflex.
In the rabbit very little reflex response is elicitable for several hours
after the operation, but in a few days the reflexes return completely
below the level of the section. In the dog, on which a great deal of
work has been done, the involved regions of the body are profoundly
paralyzed. The skin is in a more or less unhealthy, unnatural condi-
tion, the surface cold, the hairs ruffled; and if care is not taken, the
slightest abrasion of the surface may result in a nasty ulceration. On
account of the paralysis of the centers of micturition and defecation,
there is also incontinence of urine and of feces.

The Reflexes in the Spinal Animal

With reasonable attention, however, the dog makes a wonderful re-
covery. After an interval of two weeks the hind limbs, although com-
pletely paralyzed so far as voluntary movement is concerned, begin to
show considerable signs of improvement. The first reflexes to return
are those concerned with the deeper structures, such as the vascular
reflexes, thus bringing the skin back to its normal temperature and
condition. The reflexes of micturition and defecation also soon return,
so that the animal no longer suffers from the continuous discharge of
urine and feces. About the same time the knee-jerk becomes elicitable.
This reflex is obtained by tapping the tendon which connects the patella
with the tibia, the response being a smart contraction of the extensor
muscles of the knee joint. The flexion reflex also begins to reappear.
This is elicited by applying a pinprick or other hurtful stimulus to
the skin of a lower extremity, and when fully developed consists in a
flexion of the knee and hip joints. The evident object of this move-
ment is that the stimulated parts may be removed from the source of
stimulation, and it is plain that all stimuli that produce the flexion
reflex are such as would cause in the intact animal a sensation of pain.
Such stimuli are thus classified as nocuous, and the reflex is styled a
nociceptive reflex. Accompanying flexion of the stimulated limb the op-
posite or contralateral limb usually undergoes a definite extension,
called the crossed exit nsion reflex. The occurrence of this together with
the flexion of the stimulated limb is an important thing to remember
in testing the reflexes in man. Malingerers who attempt to make it ap-
pear that they have some lesion of the spinal cord may know that if
such lesion exists no movement of the leg occurs when the skin is
stimulated, but they are unlikely to know that under these conditions
the opposite leg also t';iils to show a simultaneous extension.

BEFLBXEfi l\ Till SPINAL WI.MAI. WD BPLNAL SHOCK

That the nociceptive reflexes should be among the firsl to return after
spinal transection is of considerable interesl as indicating their im-
portance in the protection of the animal from injury. They are the
essentia] reflexes of defense, and it is considerably later in the recov
of the animal before reflexes dependent upon stimulation of other tac-
tile receptors begin to show themselves. The most importanl of this
latter group of more special reflex movements include the so-called
scratch reflex and the extensor thrust. The scratch - its name

implies, is the scratching movemenl of flexion and extension of the hind
limb at a rate of about four contractions per Becond that occurs when
a mechanical stimulus is applied to the flank and shoulder area of the
animal. For example, if we gently draw a pencil or the fingers back-
ward and forward among the hairs on this region of the spinal animal.
the corresponding hind limb will be broughl up so thai the claws are
approximately at the place stimulated, and the limb thus directed will
undergo a series of flexions and extensions, designed evidently for the
purpose of scratching the area of skin that has been stimulated, [f the
stimulus is a weak one, only the initial stages of the movement may
occur, such as the preliminary flexion of the leg. As we. have already
stated, the receptive stimulus calling forth this reflex is very specific
in nature. A pinprick or rough friction of the reflex area will not produce
it, nor will the application of heat or of a single electric shock. The
most adequate stimulus is one simulating as nearly as possible the con-
dition which would he produced by the movement on the Hank of the
animal of some insect. This more or less complicated scratch reflex can
of course also he elicited in animals whose spinal cord has not been cut,
but we can U01 predict in such cases whether the reflex will occur. Tin*
brain may inhibit the reflex arc and prevent the movement. In a spinal
animal, however, the reflex always occurs provided an adequate stimulus
is applied. The greal importance of the scratch reflex in the study
the physiology of the spinal cord tests in the Pad thai a large stretch
of cord is involved in the reflex path. The afferenl impulses must enter
at a much higher level than the efferent impulses leave, and b< '
these two points there must exisl a long intraspinal neuron ' sec p
813). This permits us in study many conditions influencing reflex action
which otherwise in a reflex located in one segment only it would he im-
possible to invest igate '

The extensor thrust is elicited by applying pressure to the pad of the

paw or the soh' of the foot. Tl consists of a quick extension movement

of the corresponding limb usually with a flexion of tin' opposite limb.

After complete recover*) iY"m shock, the paralyzed parts of the bod
are capable of performing even more complex movements than those al-

806 THE CENTRAL NERVOUS SYSTEM

ready mentioned. For example, if the animal is held up with the hind
legs hanging down, these will often exhibit rhythmic flexion and exten-
sion movements, with the two limhs acting alternately, as they would
in walking or running. This is sometimes called the mark-time reflex.
Another complicated movement may be produced by placing the animal
in water, when it may make the movements of swimming, but its swim-
ming will not be sufficient to keep it on the surface. These swimming
movements are more perfect in the spinal frog.

After complete recovery from spinal shock, the hind limbs are more
or less in a condition of extension contracture; the vascular and other
visceral reflexes are in perfect condition, and a marked rise in blood
pressure occurs when one of the sensory nerves of the hind limb is
stimulated— an experiment which can be performed in such animals
without the administration of any anesthetic, since the animal feels
no pain. In female spinal animals impregnation may occur and preg-
nancy proceed in normal fashion accompanied by the usual secretion
of milk. The significance of this fact will be dwelt upon later.

SPINAL SHOCK IN MAN

As we ascend the animal scale we find that recovery from spinal shock
lakes longer and longer to occur and becomes less and less perfect. In
the case of man, recovery is never complete, for a permanent condition,
which has been called "isolation dystrophy," supervenes before the
symptoms of shock have been recovered from. The tendon jerks are
permanently abolished in complete lesions of the cord in man, and even
when the lesion involves only one lateral half of the cord, this reflex
is either entirely absent or very feeble on the corresponding side, though
normal on the other (Holmes5). Severe lesions above the lower dorsal
region practically always leave the legs in a permanently flaccid con-
dition, with accompanying atrophy, but sometimes automatic movements
of flexion and extension, like those of the mark-time reflex, may set in.

"When the injury of the cord is less severe, the limb musculature is
flaccid and toneless for some tiine, the tendon jerk and the abdominal
and cremasteric skin reflexes being entirely absent. After some time,
however — it may be as early as ten days — the muscles begin to reac-
quire some lone, and a little later the tendon jerk becomes elicitable.
"Regarding the behavior of the flexion reflex after spinal injuries in
man, it has been found that the part of it known as the Bakinski reflex
is not elicitable after severe lesions, but in those that are less severe
a flexion of the great toe may occur on stimulation of the sole. Later
this movemenl may lie accompanied by contraction of the hamstrings,
and later still, in favorable cases, by flexion at knee and hip. In these

REFLEXES l\ THE SPINAL ANIMAL AND SPINAL BH(X 807

eases also the Babinski reflex changes From a flexion to an extension
of the great toe. It is important to note in connection with the above
association of movements, thai the sensory area of the sole is connected
with the same segment of the Bpinal cord that famishes the mi I
fibers to the flexors of the toes and the hamstrings (first sacraL) The
overy after shock therefore sets in earlier for onisegmental n-fiVx
areas than for those involving several segments.

The Cause of Spinal Shock

The relationship of the profundity of spinal shock to the phylogenetic

position of the animal indicates that the shock must be due to the
isolation of the lower spinal segments from the higher centers (Pike'V
Tt has been suggested that the spinal section in the hitrher but not in
the lower animals breaks a nervous pathway in which normally the
reflex impulses travel. According to this view, the afferent impulse,
when it enters the spinal cord in the lower animals, chooses the shortest
possible route to the effector neuron of the same or closely adjacent seg-
ments by the collateral branehes springing from the sensory neuron.
In the higher animals, however, it would appear that, although this local
spinal pathway is present and may be taken, yet it is usually passed
by and the impulse travels up to the higher centers, from which it is
then transmitted by the pyramidal tracts to the motor neurons con-
cerned. This would appear to he the pathway for nervous reflex im-
pulses in higher animals the beaten track. When the spinal cord is
severed, therefore, the condition of shock supervenes because impulses
have not yet learned that they may find a shorter road to the motor
neuron by the collateral than by the pathway which they usually travel.
They learn this only after some time, which explains the slow
COVery of the reflexes from shock.

It is obviously a difficult matter to supply direct proof in support of
the above hypothesis of the cause of spinal shock, but besides the in-
direct evidence furnished by observations on the degree to which this
condition supervenes in different groups of anmials, the hypothi
also conforms well with all the other facts which we know regarding
the condition. For example, it is well known that the portion of the
body above the transection of the spinal cord in no way suffers from
the shock. Sherrington has described s monkey the cord of which was
cut below the cervical region, and which immediately after the opera-
tion amused itself by catching flies with the ant rtremities, wher
the posterior extremities were in a condition of the profoundeai shook.
Such experiments further indicate that the shock can not be dependent

>!>> THE CENTRAL NERVOUS SYSTEM

upon the lowering of arterial blood pressure which a section of the
cord higher than the mid-dorsal region must entail. The poor nutritive
condition of the skin which Ave have seen to exist in the hind limbs
in shock, shows that the blood vessels in them are profoundly dilated,
but evidently the fall in blood pressure has nothing to do with the
faulty conduction through the spinal cord, for such a fall would affect
the centers for the fore limbs as well as those for the hind, and yet
the former show no symptoms of shock.

Exactly similar shock is obtained by any section of the spinal cord
as high up as the medulla. Of course as the section is made higher and
higher up, the resulting paralysis becomes more and more marked, and
may reach such a degree of severity that recovery of the animal be-
comes an impossiblity.

When we come to consider the functions of the various parts of the
brain, we shall have occasion to study the effects following section at
higher levels of the cerebrospinal axis. Meanwhile, however, it is im-
portant to note that when a section is made across the crura cerebri, so
that the cerebral hemispheres alone are isolated from the rest of the
nervous system, a condition of contracture of all of the extensor muscles
occurs. This condition is known as decerebrate rigidity.

CHAPTEB XC
PHYSIOLOGICAL PROPERTIES OP THE SDfPLK KKFLKX ARC

We may now proceed to study the properties of reflex actios occur-
ring through the isolated spinal renters of a spinal animal. There are
two aspects of tlic qnestion to be considered: 1) the properties of a
single reflex arc, and (2) the action or influence of one reflex arc on
another. The importance of llie Latter will be evident when it is re-
membered thai complicated muscular movements depend for their proper
coordination entirely on the interaction between the various reflex arcs
which compose the nervous system. This interaction, as already ex-
plained, has been called l>y Sherrington the integration of tht nervous
system.

Probably the simplest way to study the physiologic properties of
the simple reflex is to compare the mode of conduction of a
nerve impulse through it with conduction along a simple nerve trunk.
\)y comparing the two modes of conduit ion we shall be better able to
appreciate the modifications to -which the impulse is subjected by con-
duction through the reflex are. The important points are these:

1. The Latent Period. — The latent period, or period which intervenes be-
tween the moment of application of the stimulus and the response, is
very short in the ease of a nerve trunk, and under normal conditions
always the same, but is quite variable and sometimes very long in the
case of a reflex arc. Thus, in the ease of the conjunctival reflex, which
is produced by applying a stimulus to the corneal conjunctiva (causing
a closing of the eyelids), the reflex time is very short and invariable,
whereas in the case of the scratch reflex it may vary From two and a
half to three and a half seconds, according to the strength of the stimu-
lus. The seat of delay in the reflex arc is probably in the synapse, but
its cause is obscure.

2. Grading- of Intensity. In a nerve trunk the intensity of the im-
pulse is more or less proportional to the strength of the stimulus. This
can be judged by observing either the action current in the nerve by
means of a galvanometer or the response of the end organ; e. g., mus
attached to the nerve. In the case of a reflex arc, on the other hand,

there is hy mi means BO evident a parallelism between stimulus and

response. Reflexes, however, vary considerably in this regard The
conjunctiva] reflex and the extensor thrust behave according to tl ■ Med

"all or nothing principle;" i.e., the intensity of the response is more "r

independent of the strength of the stimulus, in other reflexes, Buch
as the flexion reflex and the scratch reflex, the intensity of the response

90S

810 THE CENTRAL NERVOUS SYSTEM

is much more nearly proportional to the strength of the stimulus. Thus,
a feeble stimulus applied to the flank calls forth only a slight flexion
of the hind limb of the same side, whereas a stronger stimulus sets
going a typical scratching movement.

3. After-effect. — When a stimulus is removed from a nerve, the effect
which it produces, as judged, for example, by the action current, im-
mediately disappears. There is no after-response. In reflex arcs, how-
ever, such a phenomenon is usually well marked. Particularly is this
the case in the flexion and scratch reflexes of the spinal dog. A mo-
mentary stimulus of optimal strength applied to the scratch skin-area
may produce no immediate response, but after its removal a violent
scratching movement may set in. This after-discharge, in cases in which
the. stimulus is strong, may indeed, as in the flexion reflex, be more
marked than the response during the time of application of the stimulus.
In this particular reflex, the after-discharge often takes the form of a
clonus, with a rate of contraction of from seven and a half to twelve
per second. The crossed extension reflex also has a very pronounced
after-discharge, which may outlast the stimulus for from ten to fifteen
seconds. Regarding the phenomenon of after-discharge, Sherrington
has stated that there is "no feature of the conduction of a reflex arc
which distinguishes its mechanism more universally from that of a
nerve fiber, tract or trunk than lengthy after-discharge."

4. Summation. — When a subliminal stimulus — that is, one that has
in itself no visible effect — is frequently repeated in the case of a nerve,
no response occurs. In the case of a reflex arc, however, such repeti-
tion of subliminal stimuli ultimately calls forth response. This sum-
mation is wry evident in the case of the scratch reflex; e. g., one or
two elect l'ieal stimuli applied to the scratch field-area call forth, as a
rule, no movement of the coi'responding hind leg, but if these same
stimuli are frequently repeated, the typical reflex scratching movement
will occur. Evidently, then, in a reflex arc there is a considerable
amount of resistance towards a single stimulus, which resistance is
overcome by a succession of stimuli. In other words, the threshold of
the excitability of the reflex mechanism becomes lowered as a result
of its previous stimulation. Each stimulus excites the sensory surface
so that it responds more easily to the succeeding stimulus.

5. Irreversibility of the Direction of Conduction. — This is well illus-
trated in the so-called Bell-Magendie law of conduction in the spinal
nerve roots. A motor impulse travels oul of the cord by the anterior
roots, while a sensory impulse travels in by the posterior. This direc-
tive influence can not depend on the nerve trunks or the nerve cells, for
nerve trunks conduct equally in both directions, and so also must the
nerve cell. The irreversibility must therefore depend on the synaptic

PHYSIOLOGICAL PROPERTIES OP THE SIMPLE KEFLEX .\\:> Ml

connections. It can be demonstrated by observing t he action eur-
renl produced in the spinal cord by stimulating the anterior or posterior
spinal roots, in the former case no action currenl is ob L, l>ut it is

very evidenl in the latter case.

6. The Refractory Period. This lias been well defined by Sherrington
as being "a state during which apart from fatigue the mechanism sh
less than its full excitability." We are already familiar with the re-
fractory period in the cases of the heari muscle and the musculature of
the esophagus and intestine. For example, the application of a stimu-
lus to the quiescenl frog heari while it is contracting in response to an im-
mediately pre ling stimulus fails to produce any further effect. The re-

fractory period is extremely brief Tone thousandth of a second') in a
nerve trunk, hut is much longer in a reflex are, being probably longest
in the ease of the scratch reflex, in which it is demonstrated by the
fact that, however frequently we apply suitable stimuli to the sensory
surface, the rhythm of response of the contracting limb is always the
same. After each stimulus, therefore, a refractory period must become
developed during which a repetition of the stimulus has no effeet. Tt
is evident that the existence of the refractory period is the factor
responsible for the rhythm of the movements.

Tt is interesting to consider the exact structure of the reflex arc that
is responsible for the existence of the refractory phase It obviously
can not be a function of the motor neuron, for through the same motor
neuron may be discharged, at one time, impulses which bring about the
scratching movement and, a1 another, those causing a tonic flexion of
the same muscles. Nor can the scat of the refractory period be in the
sensory area of the skin or the afferent neuron, for if a scratch mi
nient is elicited by stimulation at a point .1 in the proper skin area.
the rhythm of response which it calls forth will not in any
way be altered by the application of a second stimulus applied at />'
at some distance from .1 and having a different frequency I Fig. 'Jll .
There is evidently, therefore, some part <>f the reflex arc that is common to
impulses starting both at .1 and at /»'. for if in each of these spots a refrac-
tory phase occurred, then there would be interference before the two im-
pulses had reached the centers of the spinal cord. By exclusion, there-
fore, "the seat of the refractory phase seems to lie somewhere central
to the receptive neuron in the afferent arc" — (Sherrington1*).

Many other types of reflex activity illustrate rhythm due to the re-
fractory phase Two laboratory examples may be given: 1 When
the central end of an afferent root is stimulated in the lumbar region
of the spinal cord, the movement produced is distinctly rhythmic in
character. (2) Upon stimulating the central end of the sciatic nerve

in a frog whose spinal cord has been cu1 some days previously, 8 clonic

812

THE CENTRAL NERVOUS SYSTEM

action of the contralateral foot occurs, and the rate of the rhythm is
not affected by variation in the frequency of the stimulus.

In all the above cases the refractory period may be held responsible
for the rhythmic nature of the contraction. In other reflexes it exists
for another purpose. In the case of the extensor thrust, which it will
be remembered is elicited by pressure applied to the pads of the plantar
aspect of the foot, the momentary extension of the leg lasts only for a
little less than two-tenths of a second, but is followed by a refractory

Fig. 211. — Tracing from the hind limb of a spinal dog during the scratching movements pro-
duced by applying stimuli at two skin points {A and B), the application of the stimuli being in-
dicated by the signals. Not only were the stimuli applied at different points, but at B they
were of much greater frequency than at A. Although there is a slight change in "local sign," it
will be observed that there is no alteration in rhythm, indicating that this property can not be a
function of the final common path. (From Sherrington.)

period lasting nearly a whole second, during which a second stimulus
elicits no response. The object of this loni>' refractory period is no doubt
that opportunity may be given for the flexor muscles to perform the
contraction that would naturally ensue (hiring the normal occurrence
of the extensor thrust, as in the act of walking. When the animal
places liis fool on the ground, the sudden pressure exerted on the pad
of the foot immediately calls forth the extensor thrust, by means of

PHYSI0IXX3ICAL PROPERTIES OP Till. SIMPLE REFLEX IRC B13

which the weighl of the body is temporarily removed from the ground,
and the muscles perform the contractions accessary in produce flexion
of the liml). Although the refractory period is unaffected by the strength
of the stimulus it is very dependenl upon the internal condition of the
nerve reflex arc, Buch as thai caused by changes in blood supply or by
narcosis.

Reflex conduct inn is much less resistant than aerv adnction t<> various

conditions affecting the nutritive condition of the conducting pathway.
For example, deprivation of oxygen causes hut slight interference with
the conduction along ;i nerve trunk, hut very soon abolishes the spinal
reflexes. Even in the frog, reflex movements entirely disappear in thirty
to forty-five minutes after the centers have been rendered completely
anemic, and in mammals they disappear in a few minutes. In the C
of drugs such as chloroform, 0.3 \«v cent of the drug may be required to
abolish conduction in a nerve, whereas a much lower percentage is Miffi-
cient to abolish it in a reflex are.

Prom the above differences in conduction in a nerve trunk and a re-
flex are, we learn many facts concerning the importance of the latter.
and we further see that the differences ;ire due very largely to the
synaptic connection.

SUCCESSIVE DEGENERATION

Before concluding the subject, it may be of interest to consider briefly
fjir ))i(tlio<] of successivi degeneration, by which Sherrington succeeded
in demonstrating the exact tracts in the white matter of the spinal cord
along which the intraspinal neurons travel from oi gment to another.
This was worked out in the case of the scratch reflex in the following

nmnner: The spinal cord was first of all cut in the upper thoracic region,

so that degeneration occurred in all the descending tracts below the
level of the section. In about a year's time these degenerated tracts had
entirely disappeared, and the debris of the degenerated fibers had been
replaced by cicatricial tissue, bo that a section of the cord revealed noth-
ing but healthy nervous tissue with cicatrices where the degenerated

tracts had existed. When at this stage a second cut W as made across

tl >rd a little lower than the first one. further degeneration occurred

involving those fibers whose centers were located between the two cuts —

that is, the fibers coming from the intraspinal neurons, with the eellfi

which the afferent nerve fibers coming From the skin of the Bcratch re-

tlex area wer innected. A section of the cord, Btained appropriately

for degenerated fibers, ai this time demonstrated these fibers t.

in the lateral column of white matter, those that travel a short distance —

i. e., between neighboring segments being near the gray matter, and
those traveling greater distances, towards the outside.

CHAPTEE XCI

RECIPROCAL INNERVATION

Reciprocal Inhibition. — It might appear that to bend a joint or to
move the eyeball the only muscular action required would be contrac-
tion of the muscles which flex the joint or rotate the eyeball, and that
the antagonistic muscles would merely become passively elongated.
When Ave remember, however, that all the muscles of the body are or-
dinarily in a condition of slight contraction, or tone, and that this tends
to become increased when the muscles are passively stretched, then we
see that for efficient movement there must be inhibition of the tone of
the muscles which oppose those that are contracting. This reciprocal
inhibition, as it is called, is a very widespread function throughout the
animal body. Sometimes it is purely peripheral in origin, as in the claw
of the crayfish, where stimulation of the nerve causes an opening of the
claw due to the contraction of one set of muscles and the simultaneous
inhibition of their antagonists. Instances of peripheral reciprocal in-
hibition in the higher animals are not so common, but are illustrated in
the case of the myenteric reflex, where it will be remembered a contraction of
the intestine over a bolns of food is accompanied by inhibition in front of
the bolns. The reciprocal action in this case is probably dependent on
the myenteric plexus.

On the other hand, reciprocal inhibition of central origin is very com-
mon in the higher mammalia. Thus, in the case of the lateral movement
of the eyes, if we cut the third and fourth nerves to one eye, say, the
left, the external rectus of that eye will alone be under the control
of the nervous system, through the sixth nerve; nevertheless, if we after-
ward cause the animal to look toward the right, as by holding some ob-
ject in that direction, it will be found that the left eye as well as the
right follows the object. Obviously there must be an inhibition of the
external rectus muscle of the left eye, an inhibition which is pronounced
enough to bring about a movement of the eyeball, and which exactly cor-
responds in point of time with the contraction of the external rectus of
the right eye. This movement, due to the atonicity of the external rec-
tus, does not however succeed in causing the eye to rotate beyond the
midline of the field of vision. This is an instance of n willed reciprocal
inhibition ; i. e., a reciprocal inhibition brought about by stimuli coming

814

Kl < ll-icoc \l. INNERVATION

Mr.

from the volitional center in the cerebrum. The Bame result may be
obtained by electric stimulation of 1 1 1 • - center for eye movements <m the
cerebral cortex.

The most importanl details concerning the mechanism of reciprocal
innervation have been obtained by studying the flexion reflex in a spinal
animal which has completely recovered from shock. In rach an animal
the tonus of the extensor muscles of the knees is well marked. This
tonus is maintained by afferent impulses transmitted to the spinal cord
from receptors situated in the muscles, and its degree of intensity can
l)c estimated by the briskness of the knee-jerk, which, it will he remem-

Fig. 21 Recoi myogra| with the extensor muscle of the knee. During

the time marked by the lower signal, the skin of the opposite foot was Stimulated, thus ca
the crossed extension reflex. While still maintaining this stimulation, faradic shocks
plied to the skin of the foot of the same side ( a* indicated by the upper signal), with the result
that immediate inhibition of the contra •: occurred. (From Sherrington.)

bered, is elicited by tapping the patellar tendon, and consists of a sud-
den extension movemenl at the knee joint. By observing the brisk]
of the knec-jerk we are therefore enabled to form an estimate of the
tonicity of the extensor muscles; and if after doing so we throw the
flexors which are their antagonists into activity by eliciting the flexion
reflex, the knee-jerk will he found much less active. Tf we prevent the
flexors from acting on the knee joint and the leg is held in an extended
position, irritation of the skin of the leg will cause :1 • Oil of the

B16 . THE CENTRAL NERVOUS SYSTEM

disconnected hamstring muscles simultaneously with a visible relaxation
of the extensors I Pig. 212 I. If the Leg is held properly, this relaxation may
be marked enough to cause a slight flexion at the joint; and in any case,
if the knee-jerk is regularly elicited by equal taps applied to the patellar
tendon, it will be found that, while the flexion is being produced, the
knee-jerk is very much less than normal, if not entirely absent, thus in-
dicating that the tone of the extensor muscles is diminished. This ex-
periment is very striking when performed on a decerebrate animal, in
which ;1S Ave shall see, the extensor muscles of the limb are in a per-
manent state of hypertonicity (Fig. 213).

Before it is permissible to conclude that this reciprocal inhibition is a
necessary event in the movement of a joint, we must however show that
it occurs at exactly the same time as the flexion of the antagonist. Sher-
rington has succeeded in doing this in a considerable variety of experi-

,-Ant Crural N.
(Femoralis)

Sciatic N.
(Isch'tadicus)

lig. 213. — Diagram showing the muscles and nerves concerned in reciprocal innervation. (After

Sherrington.)

ments, one of which we may cite here. If, in a spinal dog, the tendons
of the flexor muscles of the knee joint of one hind limb and the ex-
tensor tendons of the opposite limb are cut, then the former limb will
be unable to flex properly, but will nevertheless exhibit reciprocal
inhibition of the intact extensor muscle, while the latter limb will flex,
but require passive extension to bring it back to its old position. If
suitable stimuli are simultaneously applied to the skin of both legs and
the movements of the isolated muscles recorded, the onset of inhibition
of the intact extensor of the one leg and the contraction of the flexors
of the opposite leg will be found to agree with regard to latent periods,
strength of required stimulus, summation and indeed all the other phys-
iological properties of reflex action.

Reciprocal innervation can also be demonstrated by stimulating the
central end of suitable afferent nerves — that is, certain afferent nerves

RECIPRO( \l INN! RV \TIm\

-17

i decerr
gnaJ I the bomolatei f the I

hibition ol tbi
i Kciting the i 'hunt rei

. with llir I
of t lie- flexoi il of the

lattei stimulus, t1

the accurate i if the r<

sis

THE CENTRAL NERVOUS SYSTEM

acting on the same groups of neurons will produce a flexion reflex, others
an extension reflex; llnis. stimulation of the homolateral peroneal nerve
produces a flexion reflex of the hind limb (excitatory for flexors, in-
hibitory for extensors), whereas stimulation of the contralateral peroneal
nerve produces an extension (inhibitory for flexors, excitatory for ex-
tensors). By taking advantage of these facts further proof may be
supplied that inhibition and contraction occur simultaneously, as shown
in Pig. 214.
It is impossible to demonstrate any trace of inhibition of the skeletal

Fig. 215. — Sherrington's diagram illustrating the mechanism of reciprocal innervation. The
afferent fibers (5) from the skin of the leg and (5') from the flexor muscles of the knee (in
hamstring nerve) pass to the spinal cord, where each gives off a branch which divides into two
others, o-f which one in each case goes to a motor neuron of the extensor muscles (E) and the
other to a motor neuron (5) of the flexor muscles (F). Branches also pass across the median
line to similar motor neurons on the opposite side of the cord. As indicated by the plus and
minus signs, the afferent stimuli either stimulate or inhibit the activities of the motor neurons,
the determination of the exact effect being a function of the synapsis. (From Sherrington.)

muscles by stimulation of their motor nerves, thus indicating that in-
hibition is dependent upon the nerve center. Furthermore, since inhibition
occurs along with flexion of the antagonistic muscle, we must assume
that the afferent impulse on entering the spinal cord divides into
two branches, one going to one motor neuron so as to excite it, the other
to another neuron so as to inhibit the tonic stimuli which it is con-
stantly sending to the muscles (Fig. 215).

Since the seat of the inhibition is in the nerve center, it is to be ex-
pected that impulses transmitted from other parts of the nervous system

l;l . DPBOCAL l\ \i lev \Tl< >\ Blfl

than the particular lev£l of thai reflex, will also be able to induce the
inhibition. In the case of the decerebrate ea1 this can 1"- demonstrated
by stimulation of the Lateral columns of the Bpinal cord; inhibition of
the extensor muscles of the elbow joint occurs, which is all the more
marked because in Buch a preparation these muscles are iri a Btate of
hypertonicity. We shall sec later also thai through the pyramidal ti
impulses may descend from the cerebrum which exercise a marked in-
hibitory influence over the reflex activities of the cord. Similarly the
inhibition itself may be terminated by impulses from other sources, and
the motor neuron thus thrown from a ^tate of inhibition into one of
citation. This fact can perhaps beBt be demonstrated by exciting the
central end of the contralateral peroneal nerve (which produces a reflex
extension of the 1<'<_:'S; while the leg is being held in a flexed position by
stimulation of the homolateral peroneal oerve. This will be clear from ;i
study of Pig. 214.

Such alternating excitation and inhibition of an active motor neuron

serve to make it possible for rhythmic discharges t »cur through the

neuron, as in the action of the muscles of the leg in walking or during
the scratching movement. Tn order to insure that the same final com-
mon path may he occupied at one time by bu1 one kind of stimulus, either
inhibitory or excitatory, it is further of importance that the after-dis-
charge (see page sl" of the firsl stimulus should 1"' capable of imme-
diate inhibition; otherwise, while one reflex was in progress, it would he
impossible to st art another of a different type employing the same motor
neuron without confusion of movement. That this occurs can be demon-
strated in the ease of the after-discharge of the flexion reflex by stimula-
tion of the proper afferent nerve.

Tn view of all these facts it is probable that the seat of the reciprocal
innervation is al or about the synapsis. Tn other words, the synapsis at
the termination of one collateral will allow a stimulating impulse to |
to the cells of one motor neuron, whereas that at the end of another col-
lateral of the same afferenl fiber will allow an inhibiting impulse to p
to an antagonistic motor neuron, these conditions being, however, readily
interchangeable and thus making even rapid rhythmic contraction and
relaxation a possibility.

The Action of Strychnine and Tetanus Toxin on Reciprocal Inhibition

Under certain conditions reciprocal action may fail to OCCUT, I
example, al certain st. •' sf nii-lni' Ing and during the action

of tetanus toxin. In order to demonstrate this failure of reciprocal
t ion. it is necessary to examine muscles which acl on one joint only, and

820 THE CENTRAL NERVOUS SYSTEM

to observe their behavior when an afferent nerve is stimulated which un-
do r ordinary conditions would throw them into inhibition. Such a
preparation can be obtained in the hind limb of a dog by cutting all the
muscles thai act on the knee joint except the vastus crureus, which in a
norma] animal invariably undergoes inhibition when the central end of
the internal saphenous nerve is stimulated. If a suitable dose of strych-
nine is injected, it will be found that stimulation of the internal saphenous
nerve, in place of inhibition, causes contraction of the vastus crureus
muscle. The same result is obtained by injection of tetanus toxin.

The failure of the reflex inhibition explains the symptoms produced
by these substances. It explains, for example, the well-known rigidly
extended condition of the limbs in strychnine poisoning, and the dis-
tressing symptom of lockjaw in tetanus infection. In this latter con-
dition the sufferer is subjected to extreme torture with every endeavor
that he makes to open the jaw for the purpose of taking food or drink.
Firmer closure is the result because the normal inhibition of the temporal
and masseter muscles does not occur, but instead they become excited
and the jaw all the more firmly closed. Not only does the inhibition fail
to occur, but the above muscles are usually in a state of constant hy-
perexcitability, which it is impossible for the patient to restrain ; indeed,
whenever he attempts to do so the opposite occurs and the excitation
becomes heightened. Chloroform acts on reciprocal innervation in an
opposite way from strychnine and tetanus; namely, it paralyzes the ex-
citation of the contracting muscles.

Finally, it must be pointed out that this mechanism of reciprocal in-
nervation is by no means confined to the voluntary muscles. We have
already seen that it occurs in the case of the myenteric reflex. It is also
a most important function in the innervation of the blood vessels, dilata-
tion in one vascular area being accompanied by constriction in another.
These facts have been already sufficiently dwelt upon elsewhere (page
243). Sometimes also Ave may have reciprocal action between differently
acting nervous mechanisms, as for example in the case of the submaxil-
lary glands, which respond to stimulation of the chorda tympani nerve
by dilatation of the blood vessels, an inhibition of their tone occurring
along with stimulation of the activity of the gland cells.

CHAPTER X « 1 1

[NTERACTION AMONG REFLEXES

A single reflex acting independently of the rest oi the central nervous
system does not really occur. An afferent impulse on entering the cord
spreads so as to involve a large variety of motor neurons, each of which
may, however, be excite.] through other afferenl fibers arriving either
from other receptors or from higher nerve centers. The motor neuron
itself may therefore be a pathway occupied at different times by v<
different typos of nerve impulse. Hence it is appropriately ealled the
final common path, and its activity at any moment must depend on the
nature of the various afferent impulses that are transmitted to it through
the synapses. Tn other words, an entering afferent fiber must communi-
cate in the cord with internuneial paths which are available in various
degrees to other afferent fibers. Since it is through internuneial paths
that the impulse is transmitted to the final eommon path, it is obvious
that, if afferent impulses in several of these paths were competing at
the same time for the possession of the final common path, confusion of
movement would result unless some provision were made whereby only
one kind of stimulus could be transmitted at one time. "One kind of
stimulus must be inhibited and the other facilitated in its icupancy of
the final common path."

To understand the nature of this integration of the central nervous
system, it is therefore neeess;iry for us to consider the factors which de-
termine which of tiro competing afferent impulse* shall obtain possession
of the final common path. Let us take the competition between the flexion
reflex and the scratch reflex of the spinal dog. If we elicit the scratch
reflex and, while it is in progress, apply some nocuous stimulus to the
skin of the hind leg and thus induce the flexion reflex, it will be found
that the scratching movement subsides and the flexion movement comes
on without any overlapping or confusion. If. ho- timulus

responsible for the scratching movement is a strong One, and that ap-
plied to the skin of the hind leg a feeble one, then the displacement may

Dot Mir | see Pig. 216).

In considering this integration of reflex* died, we must dis-

tinguish between those that arc allied and those that are antagon:
and we must further distinguish between reflexes that are simub

SL'12

THE CENTRAL NERVOUS SYSTEM

ously competing Eor the same final common path and those which occupy
it successively.

INTEGRATION OF ALLIED REFLEXES

Perhaps the simplest experiment to show this is performed by using
the scratch reflex. The skin area from which this reflex can be elicited
is very widespread (see Fig. 217), the type of reflex produced from any
given area being in general the same, although "the local sign" — that
is, the point at which the animal scratches — will vary according to the
point stimulated. If then we take point A in the reflex scratch area
and apply to it a stimulus which is just inadequate to produce any reflex
at all, and then, while this stimulus is still in progress, apply a similar
subliminal stimulus to point B a little removed from it, the two sub-

Fig. 216. — Diagram showing the reflex arcs involved in the scratch reflex. Ra and RQ represent
the afferent neurons connected with hairs on the skin of the back and flank. The afferent im-
pulses are transmitted by these fibers, and on entering the corresponding segments of the spinal
cord terminate by synapses on cells of the internuncial neurons, whose arrows Pa and PQ travel
down in the lateral columns to terminate similarly around the cells of the motor neurons that
innervate the muscles of the hind limb. Since afferent impulses coming from elsewhere, par-
ticularly from the skin of the leg (R and L), also terminate on these neurons and may excite
them to a different type of action, the motor neuron is called the final common path (F.C.).
< From Sherrington.)

liminal stimuli will become effective and produce a typical scratching
movement. In other words, the subliminal stimulus of point A be-
comes added on the final common path with the subliminal stimulus of
point B; the one has reinforced the other and produced, therefore, a
simultaneous integration of allied reflexes.

The receptors from which these mutually reinforcing impulses are re-
ceived need not, as in the above example, be of the same kind, similar
results being obtained by stimulation of receptors of widely different
kinds, such as exteroceptors and proprioceptors (sec page 788). For ex-
ample, if a stimulus inadequate to elicit a flexion reflex is applied to the
skin of the leg, and another stimulus, itself also inadequate, is ap-
plied to the central end of some deep afferent nerve in the same leg,
then the two subliminal stimuli will become effective in producing a

INTi.KA" TION AMONG BEFL1

~j:;

flexion movement. Nevertheless, the more closely allied the receptors
are to one another, the more easily does summation occur.

The mutual reinforcement of allied reflexes lasts for a short time after
the stimulation has been removed, the phenomenon being HOW known as
successive integration of allied reflexes. It can be illustrated also in the
case of the BCratch reflex. If point A on the skin area is excited with a
stimulus that in itself would be inadequate, immediately after an effec-
tive stimulus has been discontinued ;it point /-'. then the scratch m-
ment will be kept up smoothly although it will of course become mo' li-
fted in local sign. For the same reason, a moving stimulus applied
to the BCratch area is far more effective than a stationary stimulus ap-
plied over the same extenl of area. In Mieli a ease the stimulus thai
excites a reflex lends by its occupancy of the oervous pathway to Eacili-

5 / ,' ^^L_L^;

..'17. — Showing region of body of dog from which the scratch reflex can be elicited. (From

Sherrington.)

tate the spread along the same pathway of succeeding allied stimuli;
towards such it lowers the threshold of excitability of the reflex arc.

This phenomenon is also often called immediate induction, and it is
by no means confined to the spinal cord. It is well illustrated, for ex-
ample, in the ease of vision. If a thin line drawn on a white card be
looked at so that it falls "ii the edge of the receptive field of the retina.
it will not be seen so well as a dot of similar width which is DMT
through the same distance as the line.

From these facts we see. therefore, that, when two allied impulses are
being transmitted to the final common path, the one is likely to reinfi
the other, and that this tendency to reinforce the allied impulse is main-
tained for a brief period of time after the impulse has been removed. We

may now proceed i osider the factors which will become operative

in determining to which of two competing or antagonistic reflexes the
final common path will become available.

S'J4 THE CENTRAL NERVOUS SYSTEM

Integration of Antagonistic Reflexes. — Although the phenomenon of
immediate induction encourages integration of allied reflexes, yet it is
frequently succeeded by one of successive induction, in which just the
opposite conditions occur; the resistance in the reflex pathway becomes
lowered for a type of movement antagonistic to that which first occu-
pied the reflex. To understand clearly what relationship this bears to
immediate induction, it may be well to take the instances in which these
phenomena apply in the case of vision. When the eye, after darkness,
is suddenly directed to a light and then closed, there remains a bright
image (positive after-effect) of the light; but if the light is looked at
for some time, then on closing the eyes it will be seen as a dark pat-
tern (negative after-effect). In the former instance we have an exam-
ple of immediate induction, in the latter, one of successive induction.

In the spinal animal successive induction is demonstrated with equal
ease by using two reflexes that are of a more or less antagonistic charac-
ter— for example, the flexion reflex and the knee-jerk, or better still
the crossed extension reflex and the flexion reflex. If we elicit the knee-
jerk in a spinal dog at regular intervals, with stimuli of equal intensity,
the extension movements (the kicks) will be approximately equal. If
now Ave apply a nocuous stimulus to the skin of the foot and so throw
the leg into flexion, it v\ ill be found, after the flexion movement has dis-
appeared, that the knee-jerk is much more pronounced than previously.
Similarly, if we elicit the crossed extension reflex by nocuous stimuli
of equal intensity applied to the opposite limb, the extension movements
will be approximately equal. By now throwing the limb exhibiting them
into the flexion reflex, the extensor movements will of course disappear,
but after the flexion has been discontinued, they will reappear with
marked intensity.

These facts show us, then, that after the final common path has been
occupied by a reflex of one type, it becomes more available to a reflex
of an opposite type. In other words, it is evident that if the two op-
posite reflexes are constantly competing with each other for possession
of the final common path, they will tend alternately to occupy it, thus
bringing about a rhythmic movement. Such is the mechanism involved
in walking: the leg is lifted from the ground (flexion reflex) ; it is then
brought on the ground, and the mechanical push given to the plantar
surface of the foot brings out the extensor thrust, the appearance of
which is greatly facilitated by the fact that immediately before the flexion
reflex occupied the final common path.

Other Factors Which Determine the Occupancy of the Final Common
Path. — Besides immediate and successive induction, several other fac-
tors affect the relative availability of the reflexes to afferent stimulation.

INTl.KM PION AMONG KEFLEX] 825

Important among these is fatigue of tht reflex arc for a particular kind
of stimulus. Many characteristics differentiate reflex fatigue from fat:.
of a nerve as observed in an isolated nerve-muscle preparation, 'i

most important of these distinguishing features are as follows: (1)
The fatigue comes on intermittently; thus, when the flexion reflex is

persistently elicited, the first dgn of fatigue is an irregular decline in
the flexion movement followed by its entire disappearance for a short
time. These lapses become more and more frequent, until at last com-
plete fatigue sets in and no flexion occurs 2 Reflex fatigue soon
passes off. (3) It appears earlier for weak than for Btrong stimuli. 4
The movement produced by the reflex action may also change in charai
during reflex fatigue; thus, the beat of the scratch reflex may become
Blower and less steady and the foot be less accurately directed to the
spot stimulated. The Incus of the fatigue in the reflex arc can not
be the motor neuron itself, for, after this has been completely fat i lt
by stimulation of the scratch area, the same muscles may quite readily
be thrown into a perfectly normal flexion reflex by stimulation of the
shin of the hind leg.

It is evident that, when two reflexes are competing with each other
for possession of the same final common path, the <>ne that becomes fa-
tigued will be mastered by the other, especially since at the same tim^
successive induction will be well developed. Tims, ordinarily tl itch

reflex is much less readily elicited than the flexion reflex, and if both
are excited at the same time the latter will prevail; but if the flexion re-
flex is kept up until it shows signs of fatigue, then by simultaneous
excitation of both reflexes the scratch reflex will obtain the mastery.

Another important factor is the relative strength of tht competing
impulses. This depends partly on the nature of the reflex and partly on the
intensity of the stimulus. Regarding the nature of tJir refii X, it is important

to remember that crossed reflexes are usually less easily obtained than homo-
lateral ones, but of still greater importance is the species of refl-

that is, whether flexion, scratch, extension, etc. The reflex movements

produced by nocuous stimuli [nociceptive refl< xes always tal ence

of those produced by other hinds of stimuli; or, to put it in other
words, "nociceptive reflexes are prepotent in their occupancy
final common path" (Sherrington1*).

The best known example of a »• is the flexion reflex.

Its movement is one produced with the intention of removi] mu-

tated portion of the body from the source of the stimulus, all stimuli which

produce it being such as would elicit pain in an intacl animal, or if |
sisted in cause some damage to the skin it- Buch nociceptive

reflexes we may take those which an ncerned in maintaining the cen-

826 THE CENTRAL NERVOUS SYSTEM

ter of gravity of the body — postural reflexes, as they are called. The
best type of this reflex is the knee-jerk, another good example being the
extensor thrust. The scratch reflex contains a certain element of the
nociceptive in it, and of the simpler reflexes it comes second in its claim
on the final common path. In brief, then, in reflexes which in an intact
animal would cause the sensation of pain and probably some reflex ac-
tivity of the vocal organs, we gel in the spinal animal a reflex flexion
movement of the part stimulated with the evident object of removing
that part from the stimulating agency. This reflex flexion secures pos-
session of the final common path whatever other reflex may at the time
be occupying it. Thus, if the animal is scratching itself and something
occurs to hurt its foot, then immediately the scratching movement will
give place to one of flexion, and so on.

Some integration between distant reflex arcs in the nervous system
is to a certain extent an application of the principle of reciprocal in-
hibition of the muscles moving a joint. In this broader integration the
inhibition affects more removed fields of reflex activity so as to harmonize
the activities of one part of the animal -with those of every other part.

The manner in which the stimulation may spread along the various
available pathways also depends on the strength of the afferent im-
pulses. If a very feeble stimulus is applied to the skin of the leg in a
spinal animal, the reflex will be represented only by a slight contraction
of the inner ends of the hamstring muscles. As the stimulus is increased
in strength the reaction will spread, until at last it involves all the
flexors in contraction and the antagonistic extensors in inhibition. If it is
still further increased, the flexion movement will be accompanied by an
extension of the muscles of the opposite hind limb — the crossed exten-
sion reflex. Further increase of the stimulus will cause the reflex move-
ment to spread to the anterior extremities, involving, first of all, the
fore limb of the same side (extension at the elbow and contraction at
the shoulder), and then that of the opposite side (flexion at the elbow
and extension at the wrist). A very powerful stimulus applied to the
hind limb will even spread to other more distant muscular groups, such
as those of the neck, causing a turning of the head to the side stimu-
lated, opening the mouth, etc.

This spread or irradiation of the reflex in the spinal cord can not be
entirely explained on anatomic grounds, and must depend, therefore,
upon varying resistance to the flow of the afferent impulse to different
motor neurons, some of which it excites while others it inhibits.

The necessity for adjustable resistance to the transmission of different
afferent stimuli on to the final common path becomes evident when Ave
remember that, not only are there about five times as many fibers en-

1NTI l; \< TIOM AMiiM, l;l H.l XI ^-~

tering the cord as motor fibers leaving it, hut also that each afferent
fiber, after its entry tu t lie cord, gives ofl BeveraJ collaterals, each of
which runs to some nerve center in the cord -■ ■ I - 207

Certain conditions may break down the path along which the impul
passes; for example, at a certain stage in the actioi trychnine all

pathways become opened ap, so thai the reflexes which ordinarily do
occur together, ad simultaneously, with the result thai a I cal convul-
sive movement is produced. Strychnine, as we have already seen, also
interferes with the sorting out of the impulses into inhibitory and ex-
citatory, so that no reciprocal action occurs.

CHAPTER XCIII

THE TENDON JERKS; SENSORY PATHWAYS IN

SPINAL CORD

Certain responses are of importance largely because of their clinical
application. Of greatest interest in this connection are the tendon jerks.
The location of the sensory pathways in the spinal cord also demands at-
tention.

The Tendon Jerks.— One of the most important reflexes for diagnostic
purposes is that known as the knee-jerk, which is elicited in man by ap-
plying a smart tap to the patellar tendon of a person who is sitting on
a high stool or table so that the joint is passively flexed and the leg
hangs loosely from the knee joint. In this position the extensor muscles
are put slightly on the stretch, and when the patellar tendon is struck,
these muscles contract and cause the leg to become extended as in kick-
ing. This reflex, as we haAre seen, is also readily elicited in spinal
animals. Its importance from a clinical standpoint depends on the
fact that it may be altered not only in various general conditions of the
body, but also when any pathological condition disturbs the continuity of
the reflex arc concerned in maintaining the tonicity of the extensor mus-
cles of the thigh. The centers involved in this arc are situated about
the third or fourth lumbar segment, and the afferent impulses come
partly from the antagonistic flexor muscles and partly from the extensor
muscle itself. Abolition of the reflexes may therefore be produced either
by neuritis involving the afferent fibers or myelitis affecting the gray
matter of the cord. That certain of the afferent impulses come from the
hamstring muscles is shown by the fact that when the central end of the
cut motor nerve of the extensor muscles is stimulated electrically, the
knee-jerk becomes much less evident, a result which is also obtained by
massaging the muscles.

Although such facts show clearly that the knee-jerk is of reflex na-
ture, yet there are difficulties in explaining the exact mechanism by
which the tap to the tendon produces the muscular contraction. The
chief difficulty is in accounting for the promptness with which the contrac-
tion occurs, the latent period being very much shorter than that of such
reflexes as the flexion or even the conjunctival. The total latent period
of the knee-jerk, as judged by the time elapsing between applying a tap

828

TENDON JERKS; SENSORY PATHWAYS IN SPINAL OORD

to the tendon and the electrical response observed in tin- vastus internus
muscle by the string galvanometer, was found by Jolly in the spinal cat
to be 0.0055 of a second, whereas measured in the Bame way the latent
period of the flexion reflex was tumid to lie just twice a> long; i. <•.. 0.0101
a second. These differences were explained by Jolly as indicating thai
the knee-jerk is a simple reflex, involving bul two neurons, whereas the
flexion reflex involves three and therefore 1ms twice as long a hv
period. r>y subtracting from the total latent period the time occupied
in the transmission of the impulse along the nerves and the time lost at
the afferenl and efferenl nerve endings, we secure a figure -_r i \- i 1 1 «_r the time

lost in the synapses between the neurons. Tins synapse time, ris it is
called, was found by Jolly to be 0.002] of a second for the knee-jerk
and <).()()4:! of a second for the flexion reflex.' Snyder obtained somewhal
similar results in man by the same method.

Some authors, particularly (lowers, do not, however, believe that the
knee-jerk is of the nature of a simple reflex, bul explain it as being due
to a contraction of the extensor muscles brought about by direct
mechanical stimulation while the muscle is in a hyperexcitable condition
as a result of a reflex increase in its tonicity. Cowers believes that by

putting tl stensor muscles on the stretch and the hamstring mua

in the relaxed condition, afferent impulses are transmitted to the cord
which excite the efferenl neurons of the extensor muscles, so as to throw
them into a hypertonic condition, during which the tapping of the ten-
don directly excites a contraction. Of course this hypothesis would ac-
count once and for all (■)!■ the remarkably short latency of the knee-
jerk, hut on the other hand it leaves US many difficulties to explain:
such, for example, as the fact that, although tapping the tendon produces
the jerk, similar tapping of the muscle itself has no effect.

The effective stimulus of the jerk is a slight passive increase of the
tension to which the extensor muscle itself is subjected, and not a stimu-
lation of receptors in the tendon, for it still occurs after the tendon has
i denervated. The importance of die relationship of the hamstring
nerve to the knee-jerk becomes evidenl in connection with recipr<
action; thus, when the flexor is contracted, as in the flexion reflex, the

knee-jerk disappears (page Hl I , whereas when the hamstring nerves an-

cut, it is augmented.

Whatever its nature may he. the knee-jerk is of value because of the
ease with which it can he altered not only by conditions affecting the
reflex arc concerned, hut also by changes occurring here in the

central nervous mi. The hest known of these conditions is that

known as reinforctment. This is brought about by having the patient
make some voluntary muscular effort at the moment that the tap is ap-

830 THE CENTRAL NERVOUS SYSTEM

plied to the tendon. If this voluntary effort coincides in time with the
tapping of the tendon, the knee-jerk will be found much augmented; but
if the two events do not accurately coincide, we may find instead that
the knee-jerk is diminished; thai is to say, we may have positive fol-
lowed by negative reinforcement. The most usual way of having the
patient make this voluntary efforl is to ask him to lock the fingers of his
two hands together and then at a given signal try to pull the locked
arms apart.

Similar reinforcement may also he produced by the application of a
strong sensory stimulus in some distant part of the nervous system, as,
for example, by pulling the hair or pinching the ear. Accurate work
on the time relationship between the reinforcing act and the tap on the
tendon has shown that the knee-jerk is most marked when the tap ac-
curately corresponds with the voluntary effort or sensory stimulation.
It then quickly declines and an inhibitory influence appears in about
0.3 to 0.6 of a second, immediately after which it becomes pronounced
again, gradually fading off to be no longer evident in about 1.7 of a
second ; that is. no change from the normal will be found in the knee-jerk
in about 1.5 of a second after the reinforcing act (Lombard8).

Many explanations have been offered of the mechanism involved in
this reinforcement, The most commonly accepted is that it is due to
the overflow of impulses from other parts of the nervous system, par-
ticularly the cerebrum, upon the reflex arc concerned in the knee-jerk.
During voluntary effort the cerebral impulses discharged down the spinal
cord pass not only to the neuron for which they are intended, but ir-
radiate or spread to other, even far distant, neurons, thus adding their
effect to that of the afferent impulse entering the cord locally. The suc-
ceeding inhibition may be assumed to be due to successive induction (see
page 824). It is difficult to offer direct experimental proof in support of
the explanation, but indirect evidence is furnished, in so far at least as
the augmentation is concerned, by the results of the experiments which
we have already described concerning the integration of allied reflexes
(paije 822). To these might be added the well-known fact that the simul-
taneous application of two subliminal stimuli, one to the cerebral cortex
and the other to the skin of the corresponding body area, may call forth
a contraction of certain groups of muscles.

AFFERENT SPINAL PATHWAYS

The nature of the impulses transmitted by the various afferent path-
ways in the spinal cord. We have seen that the sensory impulses travel-
ing from the periphery to the spinal cord group themselves into three

TENDON JERKS; DRY PATHWAYS IN SPINAL CORD 831

classes: protopathic, epicritie, and deep or muscular. It is important
now for ns to consider what becomes of each of these impulses after
entering the spinal cord, for there is abnndanl evidence thai they tr.
up to the brain by differenl pathways. This evidence is furnished partly
by examination of the cord of patients who during life exhibited per-
versions of the skin sensations, and partly by producing experimental
lesions affecting differenl p;irts of the spinal cord ill animals. Tn the
disease syringomyelia, for example, enlargemenl of the central canal
of the spinal cord causes rupture of certain of the tracts and a conse-
quent disintegration of the skin sensations; that is, the sensations of pain
and temperature disappear, whereas those of touch and deep muscular
sensation remain. Or, from the experimental side, if we make a lat <
hemiseetion of the spinal eord, then after recovery, so far as we can
study it in a dumb animal, we shall he able to show that certain sen-
s;iti(ins have disappeared, whereas others remain. Tt is evident, how-
ever, that we must judcre by objective and not by subjective phenomena
in these experiments, and our results are only approximate and very
liable to misinterpretation. Importanl contributions to this subject have
recently been made, particularly by Holmes6 and by Pnllier.9 on sol-
diers wounded in the spinal cord.

Summing up the results obtained by the earlier investigators, Brown-
Sequard sumo sixty years ago stated that hemiseetion of the eord on one
side produced the following results: (l") paralysis of voluntary motion
of the same side: (2) paralysis of vasomotor control on the same side.
so that the limb is hotter than oormal ; (3) anesthesia for all kinds of sen-
sation, excepl muscular sense on the side opposite to that of the lesion;
<4) a condition of heightened skin sensitivity (Called hyperesthesia) on

the same side as the lesion, with the exception of a narrow strip of skin

corresponding to the segmenl at which th rd is cut, which is anesthetic.

These results indicate that in general the skin sensations "f pain, touch.

ami temperature cross i>\rv to tl ther side shortly after their entry

into the corcl. but thai the deep muscular sensations remain in la

pari uncrossed. More recent experimental and clinical investigations
do not support Brown-Sequard's conclusions.

Ransom has recently shown that the afferent toots of the spinal cord

contain both medullated and nonmedullated uerve fibers, and he be-
lieves that the former transmit the epicritic sensations, and the la-
the protopathic. !'•> tracing those different kinds of fibers into the

spinal COrd, he found thai the nonmedullated lie in Lissauer's tract
one or two segments and then pas> into the substantia gelatinOSS R
landi. which, therefore, appears to be the nucleus for the reception

the protopathic impulses

832 THE CENTRAL NERVOUS SYSTEM

Among the reflex activities which become excited by these nociceptive
impulses are those causing a rise in blood pressure — pressor impulses.
This correlation between nociceptive impulses and those affecting the
vascular reflexes has prompted 'Hanson and von Hess"1 to make a care-
ful study in cats of the vascular reflexes that could be elicited from
various lesions in the spinal cord. Two kinds of vascular reflexes were
studied, pressor and depressor, the former being elicited by strong
and the latter by very feeble stimulation of the central end of the
sciatic and brachial nerves. They found that the pathways for pres-
sor and depressor afferent impulses were quite different. Thus, after
lateral hemisection of the cord, the depressor reflex obtained by weak
stimulation of the sciatic on the same side as the lesion was normal,
whereas it was greatly reduced when the sciatic nerve on the opposite
side from the lesion was stimulated. On the other hand, the pressor
reactions that were most markedly diminished were those from the
sciatic on the same side as the lesion. The depressor fibers evidently
cross in the cord, whereas the pressor do so only to a limited degree.
Further it was found, after cutting across the posterior part of the
cord, that the pressor reflexes were interfered with but not the de-
pressor, thus indicating that the former are transmitted either by the
posterior columns of white matter or by the gray matter of the posterior
horns. To determine which, experiments were also performed in which
the posterior columns were alone destroyed and the results compared
with others in which the tip of the posterior horn was included. Since
it, was only in the latter experiment that any interference with pressor re-
flexes was found to occur, it was concluded that the posterior horn alone
is concerned in the transmission of pressor impulses.

Regarding conduction of the afferent impulses which in consciousness
produce pain and of those concerned in the reflex changes in respiration,
il was found that the posterior horn of gray matter is not concerned,
from which it is inferred that such impulses are conducted by the same
afferent path that is involved in the depressor reflex; that is to say, as
we have indicated above, the impulses cross in the cord to the opposite
side and ascend in the lateral funiculus. The pathway of the epicritic
and pressor sensations in the cord is not well known. It is believed,
however, that impulses of touch pass up the posterior column on the
s;ime side of the cord for four or five segments, and then gradually pass
to the anterior column of the opposite side.

But for obvious reasons it is mainly from clinical observations and
accurate postmortem location of the spinal damage that the problem
must finally be solved. By these methods it has been shown that sen-
sations of pain and temperature pass through I he opposite lateral col-

TENDON JERKS; SENSOR! PATHWAYS IN SPINAL CORD

minis, nvusch si a si through tin homolateral dorsal column, whil( tactih
sensations pass partly by thi uncrossed fibers of tin dorsal column and
partly lm tin oppositi lateral columns. It is interesting thai of tl
two paths for tactile impulses the crossed one is alone closely associated
with the trad thai carries pain (Holmes .

Head and Thompson11 have also found thai the sensations are grouped
to the extenl thai those of one kind travel together, whether they are
from deep or superficial, from protopathic or epicritic receptors. When
the appreciation of cutaneous pain is lost, bo also is thai produced by
deep pressure; light touch and heavy touch are also losl simultane-
ously. The appreciation of ;ill degrees of temperature is abolished al the

same ti The ability to discriminate between two points, the apprecia

tion of \\ri'_rlit, the recognition of the vibrations of ;i heavy tuning fort
applied to the skin- all depend on impulses conducted through the
homolateral dorsal columns.

Because the crossing in the cord of sensory fibers carrying certain sen-
sations occurs more promptly than thai of those carrying others, and for
other less clearly understood reasons, the clinical findings are "I'i-mi diflficnll
of interpretation, especially when the lesions are only partial. Tin-
senses of pain and temperature are undoubtedly lost much more readily
than those of cutaneous sensibility, though sometimes the reverse con-
ditions are found. If a partial lesion of one-half of the cord occurs
aboul the level of the twelfth dorsal segment, ;i very common symptom
is loss of i»;iin and temperature on the opposite side, bul n<>t of touch
even when strong stimuli are applied. This crossed relation does not,
however, occur when the lesion is below the twelfth dorsal.

Regarding the number of segments necessary for the decussation of
each kiml of sense fiber, observations on cases in which there is unilal
eral injury of the cord are being collected, so thai the npper limit of the
anesthetic area maj be compared with the segmental level of the injury,
n appears thai pain and thermal impulses cross quickly i. e., within b
uegmenl <ir two in the middorsal region, hut thai those of touch cross
somewhal nun-.' gradually. In the upper segments the obliquity
crossing of both kinds of fibers is greater, and in the cervical region
it may require five or six segments for the crossing of pain impulse -
With this increasing obliquity, ;i distinction appears in the crossing levels
of pain and temperature, for the latter cross a little more quickly.
This conforms with the clinical observation thai thermal appreciation
may be disturbed without thai of pain. Even the thermal impulses <h>
nut .-ill decussate al the same level, for anesthesia t.> heat may reach
higher up on the skin area than thai to cold.

When recoven occurs, the sensations gradually reappear caudalwards

834 THE CENTRAL NERVOUS SYSTEM

Sometimes in high lesions of the cord there is anesthesia at the cor-
responding level, but the area supplied by the lower spinal roots, espe-
cially the skin in the region of the anus, is sensitive to one or other
kind of stimulation. In recovery, too, there may be an early reap-
pearance of sensations in isolated caudal areas. The explanation given
for these results is that the fibers carrying different kinds of sensation
have a Lamellar arrangement in the cord, the longest libers being on the
outside (see page 813). When a partial lesion affects the mesial fibers
more than the lateral, there will accordingly be recovery of the caudal
skin areas before those higher up.

CHAPTER XCTV

EFFECTS OF EXPERIMENTAL LESIONS OF VARIOUS PARTS

OF THE NERVOUS SYSTEM

Saving Learned the main characteristics of reflex action, we shall now
proceed to study the peculiar function of each part of the cerebrospinal
system by noting tin- effects which follow destruction or stimulation of
its different parts.

THE ANTERIOR ROOT

Section of an anterior root produces a limited degree <>f paralysis in-
volving several muscles having no functional relationships to one an

other. If several anterior roots are cut, the paralysis b mes much

more extended, and is followed yery soon by an evident atrophy of the
muscles concerned. Reflex actions from these muscles are of course im-
possible, stimulation of the peripheral end of a cut motor root cai
partial contraction of several muscles, no definite joint movement, how-
ever, being the result, because the affected muscles are not functionally re-
lated and there is no reciprocal inhibition Flexor and extensor, adductor
and abductor may contract at the same time, thus causing the joint on which
they act to become muscle-bound. It is in the plexus that the nerve
fibers of the roots become suited out, according to function, into motor
and sensory nerve trunks. The distribution of the anterior root fibers
according to segments in man for the cervical and lumbosacral regions
is as follov 8:

id, biceps, brachialis, supinators, rhomboids. 0 ally

radial extensors. Rarely pronator radii
C6 Pronators, radial extensors, peetoralia major (clavicular fibers

Berratns antiens.
C7 Triceps, extensor carpi ulnaria • - lingers, peetoralia

major.
OS Pl( icora of "i i-' and I
Tl Intrinsic muscles of hand.

• ; ti.i ani, sphincter ani, perineal muscli
Glutei, biceps, Bemitendinosus and semimembranoa

SI Intrinsic muscles of foot, tibialis ; 9, ami :

LS Muscles of ventrolateral leg t tibialis anticu

l.t Extensor! g and tibialis anti.

336 Till CENTRAL NERVOUS SYSTEM

The knowledge of the segmental innervation of the limb muscles, as
furnished in the above table, is of value in 1 lie localization of spinal
lesions. Paralysis of the extension movements of the wrist and fingers,
along with the triceps, for example, usually indicates a lesion of the
seventh cervical. It is more particularly in the trunk, however, that
the segmental innervation of the muscles is evident. The innervation
of the intercostal muscles being unisegmental, one may diagnose the
level of ,i lesion of the upper thoracic region of the cord by observing their
behavior during deep inspiration. If the fingers are placed in the in-
tercostal spaces, the paralyzed muscles will feel limp and the fingers
sink into the space during the act.

Localization may also be shown by studying the parajyses of the
abdominal muscles when the lesion involves one of the lower six thoracic
segments. "When the patient with a lesion of the eleventh thoracic raises
his head from the bed or coughs, the rectus contracts, but the iliac re-
gions bulge owing to paralysis of the lower portions of the obliques. Under
the same conditions, when the ninth segment is involved the rectus contracts
from aboul one inch above the umbilicus, whereas below this level it remains
oncontracted, so that the umbilicus is pulled up.

Besides muscular movement, stimulation of the anterior roots in lightly
anesthetized animals sometimes causes evidence of general reflex re-
sponse and of pain. The explanation is that there are present in the an-
terior root certain sensory fibers which are derived from the posterior root
but recur in the anterior, so as to reach the membranes of the spinal
cord where they terminate. The stimulation of the peripheral end of the
motor root must produce, therefore, the same reflex responses as stimu-
lation of the central end of the sensory root. Stimulation of the cen-
tral end of a motor root has of course no effect.

THE POSTERIOR ROOT

The posterior root is the pathway by which impulses of the various
receptors enter the spinal cord. Section of any considerable number of
posterior roots causes therefore, anesthesia of the corresponding skin
and muscle areas, but such a result does not become evident when one
root alone is cut, because the sensory area supplied by each root over-
laps at least half of that supplied by the neighboring roots. Although
it is often difficult to distinguish the segmental distribution in the
ramification of the fibers of the motor roots by finding what muscles
they influence, this is more evident in the case of the sensory roots. On
the trunk" itself this segmental arrangement is very plain, but in the

I Tl'i - TS OP l XP1 i;i Ml \T\I. LESION'S

- 17

extremities it is nol al firsl sighl so clear, although it ••an !»<• accurately
worked out, as is indicated in the accompanying diagram Pig 218

In attempting to determine the level of a lesion from the sensory paraly-
sis, some confusion often arises mi account of the oblique course of the
decussation of the sensor} fibers in the spin,!] cord, fibers for the differenl
sensations qoI crossing al the same levels. For example, the appreciation
of moderate temperature is often lost Blightly higher than thai of pain.
The appreciation <>!* the vibrations caused by drawing the base of a

Pig 218 Diagram showing • I "t th

Stew

ln-a\\ tuning fork over the skin is often very useful in locating the
Lesion, particularly in the abdomen. When this method is used on the
thorax, however, the skin Bhould be pulled up in folds before the fork
is applied, since otherwise the thorax will act as ;i resonator and spread
the sensation. Section of two or more sensor} a very

definite area <>i" anesthesia, involving all the skin sensations as well
several of those of deep sensat ion.

If ■• ■ tevered roots includi all of thost going to
there is nol onlj an entire absence of sensation, Imt a marked int ace

838 THE CENTRAL NERVOUS SYSTEM

with the usefulness of the limb, the condition being called apesthesia.
The exact results depend somewhat on the type of animal. If all the
posterior roots of the anterior extremity are cut in a monkey, the
corresponding Limb will not be used in climbing or for other purposes.
It will appear to be completely paralyzed, unless when the opposite
normal limb is in vigorous activity, when the apesthetic arm may be
moved in association.

On careful examination, however, it will be found that marked dif-
ferences exist in the types of paralysis produced by the section of the
anterior and the posterior roots. When a motor root is cut no reflexes
are possible either from the skin or from the cerebral cortex, and the
muscles undergo atrophy. After section of the posterior root, on the
other hand, although reflexes from the skin area affected are impos-
sible, yet movements may be elicited by artificial stimulation of the
cerebral cortex, and the muscles do not atrophy to the same extent.

If only one sensory root of an extremity is left uncut — for example,
the last cervical — so that the skin of the hand is still supplied with
sensation but all the deep receptors are severed, then the limb may be
used to a modified degree.' It may be used by the monkey to pick up
nuts, but the movement will be distinctly clumsy and ataxic in nature.
Instead of neatly picking up the nuts, he will make wild movements
and often miss them.

The apesthesia is not so profound in lower animals. After section of
all the sensory roots to both hind limbs in the dog, there may be a
certain attempt at walking on the part of the affected limb; that is to
say, when the animal tries to progress, the hind limbs, although at first,
merely dragged along the ground, afterwards begin to execute walking
movements, which howrever are very jerky or ataxic in nature and con-
tribute little to the forward progression of the animal, although he
may succeed to a certain extent in supporting the body by the hind limbs.

The importance of the sensory root in controlling the contraction of
the muscles is further illustrated by comparing the contraction curve of
a muscle produced by stimulating its uncut motor nerve with that pro-
duced by stimulating the peripheral end of the cut nerve. In the former
case, the curve is more prolonged and shows a gradual relaxation,
whereas when the peripheral end of the cut nerve is stimulated, the con-
traction is brief and the relaxation is followed by a distinct rebound
or "inertia swing," as it is called. That this difference depends on
afferent impulses is indicated by the fact that, after section of the
posterior roots, stimulation of the uncut nerve in the limb will produce
the same effect as occurs when the cut nerve is stimulated. These re-
sults can be very clearly obtained in the case of the frog, in which

EFFECTS OF EXPERIMENTAL LESIO 839

also it will be noted thai after section of the posterior roots of or

the corresponding limb hangs lower than its fellow because its muscles

are tonel*

Stimulation of the central end of a cul afferenl root prod
already been indicated, a contraction of the muscles accompanied K
reciprocal inhibition <>i' their antagonists, bo thai Borne definite move-
ment of the joint takes place. This movemenl is. however, merely a
flexion or extension or rotation, bu1 with no very evidenl objecl in vii
Tn this regard it is quite different from the purposeful movement wl
results from stimulation of a Bkin area, indicating, therefore, that the
receptor apparatus itself must contribute to the nerve impulse some-
thing which causes it to bring about a more perfectly integrated move-
ment Hi* the musculature than is the case when the nerve trunk is di-
rectly stimulated.

Besides the movements of the musculature innervated from segments
which are beside those <>t" the stimulated afferent root, there is a gen<
reflex response through other centers, for example, the respiratory and
the vasomotor; and, in animals which are not deeply anesthetized, there
is also evidence of pain, stimulation of the peripheral end of the sen-
sory root lias of course no effecl

THE SPINAL CORD AND BRAIN STEM

The results of transsection of the cord have been already sufficiently de-
scribed. It remains to discuss the effed of total ablation or removal of
portions of the cord. As would be expected, there is a marked degree
of shod; for some weeks after ablation. During this shock the tone
of the sphincters and vessels is greatly depressed, so that congestion
and edema of the feet, diarrhea and retentio urince are marked, and

ulcerati f the skin is practically unavoidable. After a few week-.

however, recovery becomes evidenl u far as the blood vessels and

sphincters are concerned, hut the skeletal musculature atrophies very
extensively and comes to resemble connective tissue, [f the spinal
ablation involves the thoracic region, for example, the affected in-
tercostal muscles become stiff and parchment-like; the hones ah
brittle, and visible perspiration can not be produced. On the other

hand, after s time the sphincters functionate more or less normally,

the hair is shed and renewed ill normal fashion, and the application of
cold to the skin causes the usual vascular reaction, it is of inter
that in female animals whose lumbar spinal cord has been remoi
pregnancy maj take place normally, followed by lactation.

Section Just Above the Medulla. After such an operation, the aui-

S40 THE CENTRAL NKRYOIS SVSTKM

mal -bulbospinal, as it is called — shows a greater integration of re-
flexes llian is possible when the section is between the medulla and the
spinal cord. Its reflex responses arc more broadly integrated, but the
extremities are incapable of executing movements that are of any value
in progression. Movements like those of progression may occur, but they
are quite ineffective. Such animals show marked superiority over strictly
spinal ones on account of the fact that in the medulla are located so
many of the important centers which control circulation, respiration
and the anterior openings of the body; that is, the mechanisms which
accompany the first stages in the digestion of food.

Section Just Behind the Posterior Corpora Quadrigemina. — A very
distinct improvement becomes noticeable in the responses of the animal.
'I'll is condition has been studied most carefully in the case of the froij,
which after such a section can Avalk, spring and swim apparently like a
normal animal, and croaks when the side of the body is stroked. In
the mammal a similar increase in the complexity of movement is evident,
but there is not yet any power of progression.

Section in Front of the Anterior Corpora Quadrigemina. — When the
medulla, pons and mesencephalon are present, as well as the spinal cord,
the condition known as decerebrate rigidity supervenes. This is most
marked in mammals, but is also present to a certain extent in much
lower animals, as, for example, in frogs. It consists of a tonic condition
of the postural musculature of the body, mainly of the extensor mus-
cles; the elbows and knees are extended and they resist passive flexing;
the tail is stiff and straight; the neck and head are retracted. The con-
dition is undoubtedly due to overactivity of the reflex tonic function of
the spinal centers, for it disappears when the posterior spinal roots are
cut. The reflexes that depend on the tone of the musculature — for example,
the knee-jerk and extensor thrust — are very pronounced in such an ani-
mal, and, on account of the higher integration present, reflexes appear
that are absent in animals having the cerebrospinal axis cut lower down.
For example, although such an animal can not feel, yet when a stimulus
is applied that in a normal animal would cause. pain, the vocal apparatus
may be excited so that a sound or cry of pain is produced. The rigidity
'Iocs not affect the respiratory muscles. After such an operation, how-
ever, normal respiration is much more likely to be maintained if the
section is in front of the anterior corpora quadrigemina than behind it.

Removal of the Cerebral Hemispheres. — This furnishes us with what
is known as a decerebrate preparation— thai is, one in which the animal
retains everything from the basal ganglia downward. The operation
produces a condition which varies according to the habits of 1he animal.
Thus, in such fish as the Elasmobranchs, which depend for their impressions

I I'll I TS OP l M'l Rl MENTAL l.i 310 841

very largely dm tin- sense of smell, we find thai d rebration caus< ani-
mal i" become completely immobile. It can nut seek f 1 I" the

sense of smell, upon which it ordinarily solely depends, lias been de-
stroyed. In a bony fish, mi the other hand, decerebration '•,-.
little difference in the behavior of the animal, provided the thalami
and optic lobes have been left intact. It continually swims aboul and is
able l<> distinguish edible from nonedible material.

In the frog the resull depends very largely upon whether the optic
thalami have been simultaneously removed. Even when 3tructu

have been removed along with the cerebrum, tin- animal at first appears
very Little different from the uormal frog. It sprint away when toucl

it (-limits up an inclined plane, and when thrown in water it swims. It

is. however, quite incapable of producing any spontaneous movement,
and is in short nothing more than an extremely complex machine, re-
acting always in exactly the same May to the same kind of stimulus.
When the optic thalami ate also intact, spontaneous movements are said
to he occasionally observed. Such a frog is said indeed to read on the
approach of winter as normal frogs do by preparing itself for hiberna-
tion, and with spring, to resume its activity and feed itself by catching
insects.

In the bird, in which the operation of removing the cerebral hemi-
spheres is a very easy one. the movements after decerebration may he
quite complicated, particularly if the optic lobes are intact. Such a
bird is more active than usual during daylight, hut becomes perfectly

still in the dark. It is, however, unable to distinguish friends from ene-
mies, and it shows no fear.

As we ascend further in the animal scale, the operation of ,;
bration becomes \^vy difficult. Goltz, however, succeeded some >•
ago in removing practically all of the cerebrum from a dog by perform-
ing the operation in three stages separated by considerable intervals

time. The animal lived eighteen months after the last operation, and

during this time it behaved exactly like an automatic machine. All its
reilexes were perfectly normal. It could not distinguish objects, hut a
brigh.1 light caused it to close its eyes. During daytime it walked
tinuously up and down its whereas at night it would sleep and

remain perfectly quiet. When food was placed in the mouth, the dog
would masticate and swallow in a perfectly normal fashion, and would

reject unpalatable food. While asleep, a very loud sound might awaken it.
and when a harmful stimulus was applied to the skin, the animal would
snarl and growl and attempt to fight the offending object. Then
absolutely no signs ,,f pleasure or of recognition of the person that
it or of fear.

^IL1 THE CENTRAL NERVOUS SYSTEM

From these results it is in general clear that the brain stem is able
to adjust the motor and the visceral reactions of the animal to changes
in the immediate environment, but that no power of spontaneous move-
ment is possible. Although in the higher apes and in man removal of
any considerable part of the cerebral cortex is impossible, yet we may
infer, from the results which have just been considered, that in the
higher animals more and more of the action becomes shifted to the
motor centers of the cerebrum. Reflexes which in the lower animals
involve only a spinal or a bulbo-spinal tract, also involve in the higher
forms a cerebral patli which is laid down only as the result of experience
and education. The newly born infant is able to perform fewer move-
ments than is the case in the lower forms of animal life, but his power
of learning new movements is incomparably greater. He inherits less
in the way of stereotyped reflexes, but in place of these he possesses
innumerable nerve tracts leading through cerebral neurons, through
which new reflex responses may be laid down as a result of education.

In connection with these experiments it is interesting to note that
in lower animals it can readily be demonstrated that the general in-
fluence of the higher on the spinal centers is of an inhibitory nature.
Thus, the latent time of the flexion reflex in the decerebrate frog, as
judged by the Turck method,* is very much prolonged when a stimulus,
such as that produced by a crystal of common salt, is applied to the
optic lobes just posterior to the cerebrum. In general, the influence
Avhich the cerebrum exercises on the spinal centers is an inhibitory one,
whereas that of the cerebellum is augmentatory.

*Turck's method consists in measuring with a metronome the time that elapses between dipping
the foot into weak acid solution and the reflex flexion of the leg.

CHAPTER \< \
CEREBRAL LOCALIZATION

Of niucli greater practical importance than the experiments in which
the entire cerebrum is removed, as described in the lasl chapter, i
those in which various parts of it are destroyed or stimulated. Prom
the results conclusions may be drawn regarding the important subji
of cerebral localization. The effects produced by removal or stimulation
different parts of the cerebral cortex vary considerably, some parts of I
cortex being set apart for the control of the motor mechanism of the
body, others for the reception and interpretation of affer* I stimuli,
while others, and these by far the mos1 extensive, are concerned in the
correlation or association of the sensory and motor centers. It may
!"■ stated in general that: (1) Tim precentral region of the cerebrum
contains the centers of higher thought. (2) The ascending frontal con-
volution immediately in fronl of the precentral buIcus contains the
chief motor centers, a center being distinguishable for each muscular
grouping of the body. (3) The postcentral convolution has to do with
the centers for the immediate reception of sensory stimuli, the lied

sensory centers. (4) A large area occupying most of the parietal lobe
ami pari of the occipital is undoubtedly associational in its function,
since from it do response can be obtained by stimulation, etc. 5 !'•
himl this, in the occipital lobe, there is a center having to do with

reception of visual impulses. (6 In the upper ivolution of the tem-

poro-sphenoidal lobe, is a similar center for hearing.

These centers have been differentiated from one another by anatomical.
experimental and clinical research. At present we shall confine ourselves
to the ' tperimental results. These are obtained by ablation and stimula-
tion, and in considering the results it will be convenienl to divide the
centers into motor, Bensory, and nonreactr

ABLATION OF THE MOTOR CENTERS

Removal of >'»< cortex from the area which controls the movements
a definite part of the body say, the arm will l>e found to pi an

immediate and profound muscular paralysis Th< animal do.
the paralyzed extremity for any purpose whatsoever, and yei the mus-

843

844 THE CENTRAL NERVOUS SYSTEM

cles do not undergo any more atrophy than can be accounted for by
disuse. The extremity docs not suffer from any of the nutritional dis-
turbances which we saw supervene upon destruction of the motor cen-
ter in the cord; and likewise Local reflex ad ions elicited by stimulation
of the local receptors are perfectly normal. A pinprick, for instance,
causes the usual flexion reflex.

After some weeks the limb begins to recover and can be used in
volitional movement. Recovery rapidly progresses until, in the case of
the higher apes, it becomes almost complete in a little over four months.
It occurs earlier in the lower animals. When a center is destroyed on
the cerebral cortex in the case of man, only partial recovery takes place.
So that in general we may say that the higher the animal in the animal
scale, the less complete will be recovery from the paralysis produced by
cerebral ablation.

Regarding the nature of Ihe recover)/, several possibilities exist: either
the nerve centers become regenerated in the destroyed area, or the cor-
responding area of the opposite hemisphere or some other part of the same
hemisphere or the basal ganglia assume the function. Evidence has been
furnished by Sherrington and Graham Brown12 tending to show that
the last of these is the most likely cause for the recovery. Thus, it was
found, in working on the arm centers on the brain of the chimpanzee,
that after complete recovery of the paralysis produced by removal of
the center on one side, stimulation of the area that had been removed
caused no movements, indicating that no regeneration had occurred, and
that removal of the corresponding center of the opposite hemisphere,
although followed by paralysis of the arm to which it corresponded, still
did not cause any paralysis of the limb which had recovered from the
previous operation. To see whether some other part of the gray cortex
might have assumed the lost function, the postcentral convolution was
removed two months after the removal of the arm centers. Although
a temporary weakness of both arms resulted, the voluntary movements
were soon as good as before. These results are of course exactly what
we should expect from the experiment on the dog, already described
in which Ihe cerebral cortex had been entirely removed, and the conclusion
that we niiisl draw is thai the basal ganglia assume the function of the
lost cerebral cortex.

STIMULATION OF THE MOTOR CENTERS

To investigate ihe effects of stimulation, it is found that tin1 stimulus is
besl applied by tie' electrical method, one pointed electrode, called the stim-
ulating, being applied to the area under investigation, and the other,

CEREBR \l. I 01 ILIZATIO B 15

called the indifferenl electrode and consisting of a flal pi eing

placed on some other pari of the body, Buch as the Bkin of the back. Tliis
unipolar method gives much finer results than when the ordinary bipolar
electrodes are employed.

Before we describe the results which have been obtained by the u
nf this method, a question arises which if may be well to consider
briefly; namely, how do we know thai the electric currenl is really stimu-
lating the center presenl in the gray matter of tl . and not
the numerous nerve fibers thai constitute the white matter <>f the brain
and along which, between the two electrodes, it is plain some of the
electric currenl musl pass? The evidence thai we are really stimulating
miters is as follows: I The latenl period for a response produced by
stimulating the centers is much longer than that which follows upon di-
rect stimulation of the white matter. '_' Under deep narc that

produced by chloral or morphine, tl ffed >f stimulation of the gray

matter is greatly delayed and altered in type; whereas stimulation <»t' the
white matter gives the usual response. (3 A weaker current suffices to
stimulate the gray matter than thai required for the exposed white
matter.

Tn order to demonstrate the movements which follow stimulation
the cerebral <-<>)-i<>x, [\ is necessary, as will be inferred from the p
ceding remarks, thai the animal be nol too leeply anesthetized! Pur-
thermore, it is necessary to ho very careful in adjusting the strength

of stimulati mployed, for the results vary considerably accordingly.

Winn the stimulus is of the proper intensity, the movements are Iocj
in some particular group of muscles, for example, those of the thumb
or of the hand, whereas, if the stimulation is strong, the movements
spread over much larger areas. As a result of feeble or moderj mu-

lation, it is found thai the muscles which move are those of the oppos
side uf the body, and thai the localization is finer the higher the position
of the animal in the scale of development. The movements are perfectly
coordinate and purposeful in character, and reciprocal innervation is
evident.

There is. however, a marked difference in the reactions obtained by
stimulation of the motor cortex and those obtained by eliciting spinal
reflexes. For example, the movements produced bj Btimulatii
cortex are much m idily modified by slight variations in 1 1

dition of the animal, the blood supply, the degn

are those elicited by stimulation of r iptor neuroi s. A can idy

of this difference h.-is been made in recenl ; Bro

rington." They observed the behavior of h

acl ing on the elbow w hen thi 'tivc corl mil-

B46 THE CENTRAL NERVOUS SYSTEM

Lated, and found that the latent periods were very variable, the after-
effects indefinite, and inhibition more prominent than excitation. More-
over, the inhibition was more or less independent of the simultaneous
excitation of the antagonistic muscle, in which respect it therefore dif-
fered from the type exhibited in the reciprocal innervation of the spinal
reflexes (see page 814). Nor were the results obtained from a given
cortical center always the same; thus, if a point giving a certain re-
sponse was stimulated immediately after previous stimulation, the re-
sult was often reversed; if it was inhibition in the first instance, it
might be excitation immediately afterward. But if sufficient time was
allowed, then the response was always of the same kind.

By comparing the effect of simultaneous stimulation of an afferent
spinal root and of a flexion or extension point on the cortex, it was
found that the stimulation of the afferent root Avhen a flexion point
was being stimulated augmented the flexion, but when an extension
point was stimulated, stimulation of the afferent root might change the
response to flexion, the exact result depending considerably on the rel-
ative strength of the two stimuli. The general conclusion that may be
drawn from these results is that the special function of the cortex is to
reverse the centers of purely spinal reflexes when such reversal is de-
sirable or necessary. The cortex dominates the spinal reflexes, and in
general it may be said that its main effect is inhibitory in nature.

It is particularly by the use of the method of moderate electrical stimu-
lation that exact localization has been worked out on the cerebral cor-
tex. As would be expected, this localization is much less defined and
definite in the lower as compared with the higher animals. In the
higher apes, it has been found that the motor centers are limited to a
narrow strip of cortex immediately in front of the Eolandic fissure —
the precentral area, as it is called. (Fig. 219.)

From the accompanying figure, it will be noted that the centers are
arranged from below upward, in the reverse order to that in which the
muscular groups occur in the body; that is to say, the face, neck, etc.,
are located lowest on the cortex, and the leg highest up. It will further
be noted that the extent of the centers for the neck and tongue is very
much greater than for the body or leg, that for the arm being interme-
diate. Tt is not. therefore, the extent of the muscular tissue that de-
termines the size of the cortical area controlling its movements, but
the type or complexity of the movements that the muscles perform.
The complex movements of the tongue and the vocal cords evidently
require greater cortical representation than do the coarser movements
of the large mass of muscular tissue of the trunk. The centers extend
somewhat upon the mesial aspect of the brain, but occupy here only a

I i REBR \l. LOCALIZATION

847

very small part of 1 1 1 « - superficial gray matter. They extend also into
the fissure of liolando and the other fissures, and thi at of the

citable area which is thus buried away in the fissures may d that

on the free surface of the hemispheres.

It will be noted that there are two centers for tin movements of tht
eyes, one in the frontal lobe isolated from the motor area, and the
other at the tip of the occipital lobe. The former is the motor center
for the conjugated movements of the two eyeballs, wl • the latter

functionates in association with the so-called visual center, which re-
ceives the visual impressions and transmits them to other parts of the

Anui & Vagina Sulcus centralis
Toes i
Ankle
Knee.

Abdomen
cnest

Shoulder--,

Elbow
Wrist

YES

Fingers
& thumb.

Closure
of jaw

Opening
of jaw

Vocal cords

Sulcus centralis

Mastication

Pig 219. i 'Mi. r i;ii nf the chim; i enters,

trie stimulation ;it the parts indicated
cle groups. Sherrington.)

brain to be interpreted and cm-related. Excitation of the center for
eye movements in the frontal lobe, say. of the right Bide, causes con-
jugate deviation of both eyes tn the opposite side, that is, to the l<

and it can readily be shown that this movement of the eyeballs is the

result of reciprocal innervation of the extraocular muscles 314).

Even at the risk of repetition we will again describe the fundamental
experiment that demonstrates this. When the i a in the ah

experiment, move to the left, it means that the internal rectus <>f the
righl eye and the external rectus of the left ting, when

the external rectus of the former and the internal rectus

848 THE CENTRAL NERVOUS SYSTEM

arc becoming reciprocally inhibited, the other muscles participating
to a slight degree. If all the nerves to the extraocular muscles of the
right eye are cut except the sixth, which supplies the external rectus,
it will be found that this eye looks permanently toward the right side;
that is, an external strabismus is produced. If now the right cortex is
stimulated, both eyes will, as before, move to the left, although the
right eye will not move farther than the middle Line. Us movement as
far as this, however, niusi evidently be due to an active inhibition of Ihe
externa] red us muscle, for none of Ihe other muscles can act since the
nerves are cut.

The experiment of conjugate deviation brings out another point re-
garding cerebral localization — namely, that the muscles which ordinarily
acl along with muscles on opposite sides of the body, are innervated
from both sides of the cerebral cortex. This applies not only to the
movements of the eyes, but to the respiratory and other movements of
the neck and trunk. Destruction of the trunk center of the cerebral
cortex on one side does not produce any paralysis, while stimulation in
this region produces an equal movement on both sides. We may say
therefore that bilaterally acting muscles are innervated from both sides
of the cerebral cortex.

The movements produced by stronger stimulation of the cerebrum do
not remain localized, and they persist for some time after the stimulus
has been removed. Still further increase in the strength of the stimulus
may cause the contraction to spread until it affects all parts of the
body, giving rise to a convulsion. There are two types of contraction
during this convulsion, the first being a strong tonic contraction, which
outlasts the stimulus for some time and then gives way to a series of
clonic contractions, occurring at intervals of from six to ten per second,
and gradually getting slower as the fit dies away. The convulsion al-
ways starts in the muscle group represented by the cortical center that
is being stimulated. Thus, if the hand area is the seat of stimulation,
the convulsions begin in the muscles of the hand; then they spread to
the muscles of the forearm and shoulder on the same side, and then to
the face, the trunk, and the leg; and if the stimulus is strong enough,
they may spread to the opposite side and thus involve the whole body.
This "march" of the convulsion depends upon the overflow of the stimu-
lus on to the various centers of Ihe brain, and the pathways through which
it occurs seem to be located in the subcortical centers, for the spread
is not prevented by isolating the cortical centers from one another by
cuts encircling them, or by division of the corpus callosum. Never-
theless, 1he centers do in some way become involved in the spread, as
is indicated by 1hc fact that Ihe complete excision of one of them

CEREBRAL L0( ALIZAT10

will exclude the corresponding muscular area from participation in

the fit.

CLINICAL OBSERVATIONS

The foregoing results obtained bj experimental stimulation in anim;
are very similar to the symptoms observed in man when the cerebral
cortex is stimulated by the pressure on it of a meningeal tumor o
spicule of bone. Such stimulation causes contraction in the correspond-
ing muscular area; the contraction then spreads to aeighborii ups
of muscles, and may ultimately involve the whole musculatu
body in a convulsive lit, like thai produced in animals. This is known
as Jacksonian epilepsy, and it is to be distinguished from ordinary
epilepsy by the fad that the patient does uo1 become unconscious dur-
ing the fit. Like ordinary epilepsy, however, l! ksonian typ
usually preceded l>\ a peculiar sensation of numb] a ing in the

area thai is to show the first contraction. i of tl • achi<

ments <>( modern brain surgery is the cure of Jacksonian epilepsy, by
trephining the skull over tin- affected center and removing the mening
tumor or spicule of bone which is responsible for the stimulation. T
enable the surgeon to locate exactly the position of the irritating body,
it is necessary to examine the patienl very closely as I ilar

group which is initially affected during the convulsions, ami then
examine an outline map of the cerebral hemisphere indicating the po-
sition of the various motor and sensory areas as deduced mainly from
experiments on the higher monkeys ami verified by the expe
trained by previous operations. Topographic maps indicating the sur-

e markings corresponding to the various convolutio -ebrum

must also he used. In such operations the surgeon often has the op.
portunity of experimentally verifying the position of various cent.

CHAPTER XCVI
CEREBRAL LOCALIZATION (Cont'd)

SENSORY CENTERS

That the motor centers are located in the areas which, we have just
described does not indicate that the nerve cells of the centers normally
dominate the reflex movements which their stimulation elicits. The motor
centers, strictly speaking-, are the anterior horn cells of the spinal cord;
and the so-called motor centers of the cerebral cortex must really repre-
sent nothing more than internuncial neurons between the entering and
leaving paths concerned in reflex movements. They are only links in
the long cerebral chain — way-houses on the reflex cerebral pathway.
According to this view we should expect that these centers would be
the ultimate recipients of sensation, as well as the distributors of motor
impulses ; sensorimotor, they have been called. Such, however, is not
the case, for Sherrington has shown that the centers most directly con-
cerned in the reception of sensory impulses are not located in front of
the Rolandic fissure but immediately behind it in the ascending parietal
or postcentral convolution. Electrical stimulation in this region does
not evoke any immediate response, at least if the stimulus is not too
strong. A movement indirectly due to the receipt of a sensation may
1)0 elicited by a strong stimulus, just as is the case when the visual cen-
ter in the occipital lobe is strongly stimulated, producing secondary
movements of the eyes.

Histologic, experimental and clinical evidence has been furnished to
support this location of the chief sensory center. The clinical evidence
was furnished by Harvey dishing,14 who induced two patients in whom
this part in the brain was exposed to allow him to stimulate it while they
were in a conscious slate. As the result of the stimulation of the post-
central convolution definite sensory impressions were experienced, consist-
ing of a sensation of numbness or deadness to tactual impressions, but
no muscular groups underwent movement unless the precentral con-
volution was stimulated. During these movements, moreover, no sen-
sations were experienced by the patient except those which accompanied
the change in the position of the part that was moved. The sensations
which are thus represented on the cortex are those of touch discrimina-

S50

CEREBRAL L0< IUZATION 351

tion and those relating to the position and movements of the muscles.
Pain and temperature sensations ■ !<» no1 seem to have cortical rep

tation.

There is of course a close association between sensory and motor cen
ters, as is illustrated in the experiment described elsewhere under the
head of apesthesia (page 838), in which it will be remembered that the
complete section of all the posterior roots <>f an extremity renders the
pari as effectively paralyzed for volitional movement as it would 1;
been had the motor roots themselves been cut. Afferenl impulses are
therefore necessary for the efficient volitional control of the muscular
nio\ ements.

SENSE CENTERS

Attempts to locate exactly the position on the cerebral cortex win
impressions of the projicient sensations vision, hearing, etc. — are re-
ceived are of course more or less difficult because of the fact that the
experiments have to he performed on dumb animals. Nevertheless Borne
information can lie gleaned from the results of ablation and stimulation
of various parts of the cortex, ablation causing, for example, definite
evidence either of blindness or of deafness, and stimulation causing
movements of the eyes or cars similar to those ordinarily observed when
these organs are stimulated in the usual way.

The auditory center is located in the hack part of the superior temporal
convolution. Stimulati f this area in animals causes a pricking up

of the ear on the opposite side as if the animal heard a sound. Clinical

observation has confirmed this conclusion.

The visual Ci nti r is located in the occipital lobe. Tt is important •

peal again that there are two centers uu the cerebral cortex concerned in
vision: the frontal visual center, located as we have Been in the frontal
lobe, and the so-called visual center itself, located in the occipital I
stimulation of the frontal visual center produces a prompter movement

of the eyes than does stimulation of the occipital center, indicating that
the frontal center has the immediate control of the muscular movements,

whereas the occipital lobe IS probably concerned in the adjust mi
the muscular reactions which are necessary in controlling the eye mo

incuts, bo that the objects may he properly viewed and judgmi
formed, by the extent of the movements, of its distanc sition,

The actual response to stimulation of the occipital i hat

the lobe on one side is connected with the corresponding half o
retina, the fovea centralis being, however, connected with both

852

THE CENTRAL NERVOUS SYSTEM

ASSOCIATION AREAS

The brillianl outcome of the researches conducted by the experimental
mot In id in enabling us to locate the chief motor and sensory areas of

• i

r * X

k

A

Motor leer area

fj".

m

ti * i {

k

i

^

Yisr.osensory

/

/* A A 1 1 K>

*

,**f m'aV* ^

:K; *A

Yisuopsychic

220. — Three sections through different parts of the cerebral cortex. For description see

Rei awn from Starling, i

the cerebral cortex leaves ye1 uncharted those vast areas lying between
them which do nol respond in any definite way to artificial stimulation,
and the ablation of which results only in more or less indefinite symp-

I I'.i: \l. I 0( \l.l/ \i

turns. I n order to discos er t 'unci ion of i

oecessary to employ «• ntirely diflferenl method that of

and embryological examination. When the patterns of the

are compared with the habits of the animals

animals (phylogenetic study . or even in diff* individuals

^-r-TTT -^

A.

<? .

POSTC

same group ontogenetic study . much useful kn>

cerebral localization can ;iK<> be gained In the human animal much

progress is being made by comparing the structural patl

854 THE CENTRAL NERVOUS SYSTEM

lex in differenl parts of the normal brain with that found in the brain
of psychopathic individuals whose mental symptoms have been care-
fully studied before death.*

For the purpose of this work it is necessary to recognize several
laminae or layers of nerve cells and nerve fibers composing the cortex.
The most practical division is represented in Fig. 220, and is as follows:
(1) a narrow superficial layer of nerve fibers, with a few scattered cells —
the outer fiber Lamina or molecular layer; (2) a much wider "layer of small,
medium and large pyramidal cells — the outer or pyramidal cell lamina;
(3) a layer of granules — the middle cell lamina; (4) an inner layer
of nerve fibers, sometimes containing large solitary cells (Betz cells) —
the inner fiber lamina; (5) a layer of polymorphic cells — the inner cell
lamina. This five-layer type undergoes structural modifications in the
different regions of the cortex, and these modifications possess a dis-
tinct functional significance. The only part of the brain in which they
can not be recognized is the hippocampus and the pyriform lobe. Based
on the relative thickness of these layers maps of the cerebral cortex
have been produced. The most important are those of Brodmann and
Campbell, of -which the latter is reproduced in Fig. 221. Two re-
gions can be very definitely located; namely, the precentral or Betz-
cell area, and the visual or visuosensory area of Campbell. Surrounding
the visuosensory area is a definite visuopsychic area, and similarly,
bordering on the precentral is the so-called intermediate precentral
area. At the very front of the frontal lobe is the prefrontal area. Post-
central and intermediate postcentral areas are indicated, but the re-
mainder of the center is undefined.

Reasoning from phylogenetic and ontogenetic data, we can assign to
each of these lamina? a functional significance, which according to Bol-
ton is as follows: The outer cell lamina (pyramidal cell lamina) proba-
bly constitutes the "higher level" basis for the carrying on of the higher
or psychic cerebral functions. It is a prominent feature of the human
cortex, the last cell layer to be evolved, and the one which undergoes
retrogression most readily. During development it rapidly attains ma-
turity in the visuosensory area, next in the visuopsychic, and only later
in the prefrontal region. In the visuopsychic area it is practically of
the same depth as in the visuosensory, whereas in the prefrontal region it
develops according to the mental capacity of the animal. In patients ex-
hibiting symptoms of dementia this layer of cells is distinctly deficient.
These facts indicate that the outer or pyramidal cell lamina "subserves
the psychic or associational functions of the cerebrum" — (Bolton).

*An excellent account of the physiologic basis for such work is given by Bolton in Leonard Hill's
Further Advances in Physiology. We have made free use of this article in the present review and
wouid strongly recommend its perusal by any who may desire further information.19

CI R] BR \I. L0< \U/ iTIO

The middl ■!! lamina is much hypertrophied in tl ailed proj<

lion areas of tl srel mi m for example, 111 the visuosensory ar<

Pig. 220 . where il is so thick thai it is usually described as being divided
into two parts by a oarrow fiber band the line of Gennari Dimination
in the layer occurs in the visuosensory area in long-standing c
atrophy. '"It Beems therefore primarily to Bubserve the function of re
ceiving afferent impressions whether these arrive directly from the lower
sensory neurons or indirectly through other regiot a of I • brum."

The fifth or inner cell lamina is the firsl to I me differentiated, and

ii is of extremely constant depth in the adult. It is qo1 much affected in
amentia, unless when this is very severe, as in patients who are unable
to carry on the ordinary animal functions. In short, 'it suIi-.tv.-s the lower
voluntary and instinctive activities of the animal economy"- -(Bolton).

Taking the results as a whole, it appears thai the region of t;
behind the Rolandic fissure consists of sensory areas and association
anas wliieli may be immediately connected with them (visuopsychic and
Intermediate postcentral) or mure removed in parietal lobe . Thi
tion in front of the Rolandic fissure, on the other hand, contains the
efferent areas, of which the precentral may bi irded as of 1"'

grade. The motor discharges from it an nditioned upon impul

coming partly from the adjacent intermediate pr. central area, in "which

again are elaborated those received from the 3< ad partly

from those coming from the prefrontal region, which is the n om-

plex /one of association. This last is indeed the Bupreme dominating
area. It coordinates or integrates the activities of the other association
areas and may be considered as the seal of the i) idence

for this high evolution of the prefrontal area is v< 3 sti g H -
last portion of the cortex to be evolved and the first to tu tro-

gre8sion. In idiots and iml iles the thickness of the pyramidal cell

layer in this region is directly proportional to tl tal power, and

in dementia degrees of retrogression occur thai vary directly with the
existing grade of dementia. In normal brains this layer is thi
one which varies in depth in differenl individuals. Along with its high

development in the brain of man. as compared with that of other ani-
mals, goes hand in hand a greal increase iii the other association an

Thought is the product of integration between I various

tion areas, and articulate and written language the outward ma;

tion of the proci as. It is owing to the relatively great extent ami com-
plexity and constant development of the prefrontal lobe that man
excels even the highest apes in his intellectual activil

1o the relative functional development of this lobe that individuals dif-
fer from one another in their mental pOW(

CHAPTER XCVI]

CONDITIONED AND UNCONDITIONED KEFLEXES

In studying' the reflexes in the spinal animal, we have seen that the
effect of a given stimulus or of different stimuli is predictable with
absolute certainly. There is a fatality in the -responses. When the
higher centers are included in the reflex arc, the reflexes become modi-
fied or inhibited by events occurring in other parts of the central ner-
vous system and the results come to be more and more unpredictable.
The reflex comes to be a conditioned reflex (Pavlov). Studies of the
circumstances affecting these conditioned reflexes really constitute a
study of the function of the higher centers in the brain. Since such
experiments must be performed on the lower animals, Ave are limited in
the investigation to motor responses, for we have no way whatever of
studying the subjective sensations produced. The motor phenomena by
which the animal may express its sensations can be interpreted by us
only in terms of psychological ideas thai in large part are derived from
our own experiences. Obviously the conclusions that can be drawn
are subject to very great sources of error, and it must be considered as
one of the greatest advances of modern physiology that Pavlov and
others should have succeeded in evolving methods by which Ave may ar-
rive at conclusions regarding the nature of certain of the integrations
that occur in the higher centers of the neiwous system preceding the
motor manifestations by which the animal expresses its sensations.

The methods employed for the study of these higher integrations of
the central nervous system all depend on the reactions of the animal
that are associated with the taking of food. When the food is actu-
ally placed in the mouth, it excites a secretion of saliva, Avhatever the
circumstances may be. This is an unconditioned reflex. Suppose, how-
ever, that every time food is given a particular sound is made; after
some time it will be found that the occurrence of the sound alone is-
sufficient to cause a secretion of saliva. In other Avords, a conditioned
reflex lias been formed. Similarly, sight or smell or any other type of
sensation m<ay be «made the excitant for the conditioned reflex. The
secretion now becomes psychic instead of merely physiological. To quote
Bayliss: "Any phenomenon of the outer world for which the animal in
question possesses appropriate receptors can be drawn into temporary

856

CONDITIONED \M> UNCONDITIONED REFLEX

association with salivary secretion, so thai ii becomes an i

cretion if only it has been frequently presented al the time with

the unconditioned reflex stimulus, E 1 in the moutl

Work along lines similar to thai devised by Pavlov has more recently
been undertaken by students of animal behavior, who have utilized the
acquired habits of an animal in searching for its food in ordei
influence of conditioning circumstances on its procedure. I
iif this method depends mainly on the fad thai it can be applied to all
groups of animals. In carrying ou1 such an observation, ihe animal is
placed in one compartmenl of a <-ii '_r<-. from which it is then r< ! t<>

a s i H 1 compartment, the end of which is « 1 i \ i . 1 # • « l int.. two pi

ways, one leading to food, the other leading to some apartment in

which the animal is punished for its mistake as by receiving an electric
shock. Objects such as colored lights are placed in tin- different p
sageways, ami the animal by repeated trial comes ultimately to learn
which particular colored lighl -> i <_r 1 1 i I i « - ~s the passage along which he

will receive food. A reflex has therefore becoi istablished conditioned

<»n the particular colored light.

On accounl of the unavailability of his publications, it is impossible
at presenl to -rive any complete ace. nut of Pavlov's discoveries A few-
facts, however, arc of such importance that it is i ry for us I
state them here as far as we know them. See Bayl as, /' ,"/. Two
mechanisms scon t . . he concerned in the conditioned refl that
of temporary association, ami (2) that of analysis. Temporary associa-
tion is well illustrated in the above experiment in which the secretion of
saliva is induced by a Bound Temporary association of the Bound with
the secretion of the saliva may readily he inhibited by all kinds of

ternal phenomena; thus, if the dog's attention 1 omes diverted while

tin- conditioned reflex is being stimulated, the response does not i ur.

In a dog that had been trained 1.. Becrete saliva to the sound of a i

ticular metronome heat, inhibition occurred one day because, .in-1
t ho dot,' waa being presented with the food, the laboratory servant made
a m.isc outside of the building which diverted the animal's attention.
The conditioned reflex may also he ; red with by internal inhibi-

tion, which is illustrated by experiments in which, after a •

trained to respond to a given conditional r> vera! follow

when food is not given to the animal after the particular Bensation to which
it has been trained to respond. The condition for examph

its effect. 'Phis is internal inhibition, hut it is a temp
since the reflex returns of itself after a period of

These experiments illustrate what is meant by • matioi tem-

porary associations occurring in conditioned reflexes, hut in i -hat

858 Tin: central nervous system

there may be a fine discrimination between those stimuli which shall
and those which shall not serve to call forth the conditioned reflex, an-
other mechanism becomes involved — that of analysis. This is performed
by a sense organ the function of "which is to separate and distinguish
the complicated phenomena of the outer world. For example, it has
been proved that small differences in the pitch of a musical note may
determine whether or not a conditioned reflex will be excited or in-
hibited, as in the case of one animal that was trained to respond by
the secretion of saliva to a tuning fork vibrating at 100 per second. It
was found that no secretion was produced by a tuning fork vibrating
at 104 or at 96. Much work has also been done with the skin receptors.
Thus, when a given spot of skin is stimulated every time that food is
presented, this becomes an active spot for the conditioned reflex. At
the same time another spot may be stimulated so as to be associated by
the animal with the nonpresentation of food ; it is a conditioned reflex
for no food, and is associated with the absence of salivary secretion.

By comparing the responses from active and inactive spots when both
are stimulated either simultaneously or at close intervals, much can
be learned concerning the delicacy of appreciation for external stimuli
and the influence of the inhibitory on the excitatory process. Bayliss
cites the following experiment. Along a series of spots on the skin
of the leg five devices are arranged for producing equal mechanical
stimulations of the skin. The four uppermost of these are made active
spots for the salivary reflex, and the lowest one inactive — that is, when-
ever it is stimulated no food is presented. Let us suppose that upon
administering mechanical stimuli of equal intensity to each of the active
four spots, a certain amount of saliva is produced in a certain time; if
now the inactive spot is stimulated and then thirty seconds later one
of the uppermost spots, there will be no secretion. The previous stimu-
lation of the inactive spot must evidently have caused an inhibition to be
set up in the nerve centers concerned in the reflex. This inhibition only
gradually passes away, disappearing first in the spot farthest removed
from that made inactive, but it may take several minutes before all the
active spots have reacquired their original sensitivity.

The persistence of the inhibition produced by stimulating the inac-
tive spot in the above experiment indicates an Important factor in con-
nection with the produd ion of conditioned reflexes. For example, an
animal can be trained to know that in a certain number of minutes after
the sound of a given bell food will be presented to him; the condi-
tioned reflex will become established so that he salivates at exactly
the same time after the bell is sounded. Something must be going on
in the centers during this time— something inhibiting the reflex. If

< 0NDI1 IONED .WD i M 0NDITI0N1 D I:i l i

during this interval of inhibition some other sensory stimulus is applied,
it will be likely to cul shorl the inhibition; in other words, i1 produ
an inhibition of inhibition, so thai the secretion of Baliva occurs.

Another mosl curious combination of conditioned stimuli is illustrated
in the following experiment. Suppose, for example, that a given light

and sound are each separately made a stimulus for a c litioned reflex,

but thai when they occur together there is no reflex. Suppose now that
while one of these act iv«> stimuli is being presented, the other stimulus
is also presented; the result will be thai the secretion produced by the
one stimulus will stop. Evidently, although each is in itself a stimulus.
acting together they cause inhibition.

By studying the conditioned reflexes after a certain part of the ce
bra! cortex has been removed, it has been found that the power of estab-
lishing certain kinds of conditioned reflexes becomes abolished, while
that Eor others is retained.

CHAPTER XCVIII

THE HIGHER FUNCTIONS OF THE CEREBRUM IN MAX;

APHASIA

The study of the higher functions of the cerebrum leads us to the border-
land between physiology and psychology, but into this vast and relatively
unexplored field we can not venture here, unless just far enough to gain a
suitable vantage point from which to understand the pathology of the
condition known as aphasia* As we have seen from our studies on cerebral
localization, the cerebrum must be regarded as a great sensorimotor gan-
glion, whose functional activities are indicated by various movements.
These movements may. in general, be classified as objective indications
cither of feeling and emotion or of intelligence. Although both classes arc
evident in all animals, it is particularly in the case of man that the evi-
dences of intelligent activity are especially prominent, since they include
gesticulation and the muscular activities required in spoken and written
language. The movements that express emotional conditions are evolved
earlier and from lower planes than those of intellectual activity. Thus,
very young infants "make faces" when there is reason to believe they
feel pain, and, as they develop, their power of expressing emotion is
evolved long before they present evidence of intelligent motor activity,
and still longer before they can articulate words.

The phenomenon of human psychic activity which is of greatest im-
portance is that of language, and to understand the nature of the cerebral
integration required to produce it, we must briefly consider the cerebral
processes involved in the intellectual development of the infant. The
first step in this development is the storing away in projection centers of
memories of the sensations which these centers have received. For ex-
ample, when the child looks at a bell, there is stored in the visual center a
memory of the shape of the bell, and when the bell moves so as to produce
sound, this also is stored as a sound impression in the auditory center.
Likewise, when he touches the bell impressions of its hardness and smooth-
ness and temperature are stored in the centers for cutaneous sensations.
At first each of these memory impressions occupies an isolated position ;
but later, association tracts open up between them, so that the calling

use of Bolton's articli is rriade in this chapter.

860

HIGHER FUNCTIONS OF THE CEREBRUM IX MAN: APHASIA v'd

forth of one memorj impression is associated with others, and the child
comes to 1"' able to associate the appearance or image of the bell with a
certain sound ami with certain sensations of hardness, rotundity, etc. This
preliminary use of observation is known as p< /•- < pi ion. It involves the
fusion of direcl sensations as well as their correlation with memory im-
pressions of former sensations. The number and variety of the latter
called into activity by a particular sensation will obviously vary at dif-
fered times. On seeing a bell, for example, a child may associate it with
sound "ii one occasion, and <>n the next with the feeling <>f the bell. On
accounl of this difference in the detail of the method of association, it is
evident thai perception musl 1"' a producl of cerebral integration rather
than one depending on memory impressions stored in the isolated centi

It is a nplicated process with an infinite variety of possibil the

exacl way iii which it is integrated on each occasion.

The act of perception, however, becomes considerably simplified in the
higher animals by the laying down of short-cut paths of association.
These are formed firsl of all with the auditory center, in which the memory
impression of an articulated sound representing the object— for example,
the word "bell"- is stored away. The child comes to learn that this par-
ticular word is to be associated with the memory impressions it has stored
away n? the sound, the sight, and the feeling of tic hell. Similar short -cut
paths later become developed in connection with the visual centers, where
a certain symbol, like the word '"hell." is presented to the child as signi-
fy inir all the other attributes of hell. In its mosl highly developed form,
therefore, perception may he described as the act of calling up one <m-
more sensorimemorial images when a name is seen or heard.

Saving acquired the ability i<> integrate sensorimemorial impressions
in the above described manner, the child oexl learns to integrate the motor
centers concerned in the control of the articulatory apparatus so ;is to
produce a sound. This sound is the word indicating the objeel invoh

in the integrating pr ss. It is the integration necessary to produce the

sound which symbolizes the particular object.

When the power of understanding ami producing lan<_'iia'_re has been
acquired, the crowning process of intellectual development the forma-
tion of a concept, or general notion becomes evolved. Thus, the evolu-
tion of a genera] name will include a number of particular objeel
"This process of conception involves Hie revivification of numerous
sorimemorial images which present common points of similarity' Bol-
ton). It is relatively a simple process for such genera] object animal,
man, building, hut becomes very complex for such abstract
heaviness, beauty, etc. it is obviously a proci ss I which m> one cerebral

• -

; ; ;

■ - -
I

.r'1 • ;f

:i imi,"-.yj."

." v. :

r

:
-

.

- " ; >~: ".".".v. ■;.: :z
•- : kins; itegMmfaat

■ad. depend am the

. . . - . ._ - -^ -i.;^ - ■

-

_

I

■

:r - - .

-

■- ■

:;i.:--'' . ■ :-; ■

"j r!i tine
■ -.J ■ .-„ ••-■--•••• •

H

m0V< -

:- mi]

cation in unjusl
aphasia, and 1

dOCM llOt ; iJIJO/j -

impairment.

Marie pc ■ ■ out that flu
intellectual impairment ha rj mad*

the intellectual •••• of the pal "■

fering from aphasia . .

or raise the hand, ean do them ■ rmal individual, >

a]] are very in the ordir. rforms -ma]

individual. To test the intellectual pc t is neeessa:

patient to perform acts which entail a considerable amount of t
integration. We must ask him to perform some sequ-
as walking several times in one direction, then in ai
tain objects, etc., or hould observe 1

business transactions and everyday routine of life I
things exactly as he did them be '■

to show that in aphasia the mental ;
predated.

The portion of the cerebral cortex affected in aphasia -
neighborhood of the so-called area of Wernicke, which
the visual and auditory cent* tg In making this s . sion,

Marie admits that e ses : pure word-blindness but not of word-deafness
may exist: that is. a patient still retaining his ini
his ability to interpret correctly what !>' gees, all
accurately what he he, -

This conclusion conforms exactly with those of ti - hys gists

garding the difference in the langua_ nanisms of educated i.

educated persons. Langaag 3 h sd through the sens ring, anc

I - only by later education that mor- - .amed by -

that is To - - learns to read only after

stand spoken language. Word-blindness m.-.; I
symptom, and is less than w ss 1

normal hit . tions of the an. T" ss p de-

pends upon a lesion involving the auditory I ss means

disturbance ii ss ition fund - :11m. ;v

ied b> mount of me- ' .

Tn porrol
I de*f-mu1 - infer' that is eons

ss of - - - .loss of s

864 THE CENTRAL NERVOUS SYSTEM

To quote Boltou again, ' ' In such cases deafness is therefore a more serious
deprivation than blindness, as, for the evolution of the functional activity
of the cerebrum, an entirely new development of associational spheres to
replace those normally employed for auditory and spoken language has
to he acquired. In the case of congenital or early-acquired hlindness, on
the other hand, the complex sphere of language, with all its psychic com-
ponents, can he employed in a perfectly normal manner and almost ex-
actly as it is brought into use in the case of persons who neither read nor
write."

It would he beyond the scope of this work to go into the clinical and
pathological evidence upon which Marie bases his far-reaching conclusions.
Suffice it to say that it is definitely shown that the old contention of Broca,
that a special speech center exists, is entirely unjustified by the facts of
clinical and pathological experience. Broca, it will be remembered, con-
tended that motor aphasia is always due to destructive processes occurring
in the lower portion of the ascending frontal convolution on the left side,
and he concluded that this portion of the cerebrum represents the speech
center. Marie has shown, however, that a patient may show distinct evi-
dence of aphasia without any lesion involving this so-called Broca area,
and, on the other hand, that cases not infrequently occur in which this is
completely destroyed without any evidence of aphasia. Important though
tli is discovery of the inaccuracy of Broca 's conclusion is, by far the most
important conclusion which we may draw from Marie's work is that, since
language is a product of an extended integration of impressions and
memories stored in different parts of the cerebrum, it is not so likely to be
interfered with by destruction of any one of the centers as it is by destruc-
tion of the paths which connect the centers with one another. As a matter
of fact, Marie has shown that in cases of aphasia the lesion is nearly
always located in the course of the pathway connecting the visual and
auditory centers with the other centers of the cerebrum ; it lies around the
upper end of the fissure of Sylvius in the region which in previous years
had been considered particularly associated with the condition known as
sensory aphasia. Those interested in this subject should consult Bolton's
article.

CHAPTEB X( IX

FUNCTIONS <»!•' THE CEREBELLUM

In our discussion of reflex action we have so Ear considered only tl,
receptors coming from the exterior of the body, although we have r<
aized thai a considerable Dumber of the afferenl aerve roots contain fibers
coming from receptors situated in the muscles, the tendons and the joints,
and called proprioceptors because they respond not to changes in the
environmenl but to alterations in the body itself. We ha o that the

proprioceptors consisl structurally of muscle spindles and of the ne
endings in the tendons and ligaments and synovial membranes. They are
receptors that are attuned to respond to differences in tension caused either
by bulging of the muscles or by stretching of the fibers of tendons a
Ligaments.

The impulses are transmitted in the spinal cord, either by the posterior
columns <>r by the lateral cerebellar tracts. Those traveling by th>' pos-
terior columns are sent mainly to the cerebral cortex of the opposite side,
whereas those in the cerebellar tracts enter the cerebellum by the inferior
peduncles of the same side. The cerebral impulses conned with ne
which transmit the impulse back again to the cerebellum of the oppos I
side, so that ultimately the cerebellar cortex is connected with the spinal
cord "i' tin- same Bide either directly or indirectly through the cerebral
cortex. These anatomical facts indicate in ;i general way that we may

expect the function of the cerebellum tn he that of the chief nerv niter

concerned in the integration of the proprioceptive impulses originated by
the condition of contraction or relaxation of the different groups
muscles in the body, and by the amount of tension existing in the var
tendons, ligaments and other membranes surrounding t lie joints.

Experimental investigation has justified thes tions The re-

moval of the entire cerebellum— an operation which has usually been
performed <m birds, particularly pigeons, because of the ease with which
it can be done in these animals— leads immediately to a condition in which
muscular activity is entirely uncontrolled. A pigeon after this operation

flies aboul in an hit rdinate way. turning summersaults, dashing i1 -

against the walls of its chamber, and ultimately after constanl futile mo
ments, exhausting itself, [f one cerebellar lobe i^ removed, the body when
at re>t is curved toward the side of the lesion, and the movements

866

THE CENTRAL NERVOUS SYSTEM

animal cause it to fall in that direction. A similar experiment with
dogs yields like results, but the operation is of course considerably- more
difficult. In man, a destructive tumor of the cerebellum produces a con-
dition known as "cerebellar ataxy," in which the patient moves his
limbs in a very incoordinate fashion; he staggers, is uncertain in his
gait, and behaves in general very like a drunken man.

Although these immediate effects of cerebellar extirpation indicate

Fig. 222. — Footprints after destruction of the cerebellum in a dog: a, before the operation;
b, four days after; c, five days after; d, a month after; e, two months after. (From Luciani.)

clearly that this organ lias to do with the control of muscular movements,
yet the results are probably not primarily dependent on the ablation,
but rather on the conditions of irritation which are set up as a result of
the operation, and which probably affect the cerebellar peduncles. At
least, such is the view that Luciani, one of the greatest investigators in this
field, has adopted because of the fact that, if the animal is kept alive for
sufficient time so that the. symptoms of irritation disappear, they become

IP THE CEREBELLUM 867

replaced by those of an entirely different nature. The pigeon may r<
qnire the power of flying straight, or and this is particularly importanl
the dog may reacquire the power of apparently normal pr< ion, al-
though, it' its muscular movements are carefully examined by physiological
methods, it will be found that at leasl three changes hav<
late resull of the extirpation; namely, a weakness of co tion, a tremor
during the contraction, and a want of tone when at pest. Th< mdi-
tiona have been called asthenia; atonia and astasia, res] tively. <>n su-
perficial examination it may often be difficult to make out these three con-
ditions, but they can readily be observed in animals in which tli pebellar

extirpation has been performed on one side, so that the abnormal may be
compared with the normal Bide. In a dog that has had one Mar

hemisphere removed some time previously, the muscles "-, the correspond-
ing side are so much weaker than those on the opp side that the
animal, in order to retain his equilibrium, lias to prop himself up
by leaning against whatever objecl may he convenient, or by extending
his legs so as to increase his base of support. In other words, 1.-' constantly
lends to fall to the side of the lesion, but tries to prevent this either by
increased muscular effort or by taking advantage of artificial support.
The effect which this weakening has on his <_rait ran he very clearly demon-
strated by comparing the footprints produced by the normal with those of
the abnormal side, these footprints being obtained by making the animal
trut along a piece of glazed paper blackened with a carbon de] - in
taking tracings (Fig. 222).

Localization of Function in the Cerebellum

Although these facts in themselves would tend to indicate a certain de-
gree of localization of function in the cerebellum, or at least that certain
parts of the cerebellar cortex have to do with certain groups of muse
yet for many years it was considered that the cerebellum did not show in
any marked degree the same kind of localization that we find in the e
bral cortex. One cause for the backward state of our knowledgi jern-
ing cerebellar localization is that, unlike I rebrum, its cortex is

practically inexcitable. In recent years, however, on account partly of

anatomic and partly of experimental and clinical work a high d« _
localization has 1 n found to exist in th pcbellum. Prom the anatomical

point of view it has been found that in certain groups of animals, such as

the nngulata, the postero-medial lobule of the cerebellum is very la

whereas the lobuli ansiformes are small. In another grou] earnivi

the opposite obtains, the lobuli ansiformes being oped and
postero medial lobule quite small.

SliS

THE CENTRAL NERVOUS SYSTEM

By studying these developmental differences in relationship to the activi-
ties of the muscular system, Bolk suggested that movement of those regions
of the body which are affected by muscle groups on both sides — for example,'
the head, neck or trunk — would be represented on the cerebellar cortex by
an unpaired center — that is, a center occupying a middle position — and that
this would be capable of exercising an influence equally upon the muscles
of both sides. Movements of the limbs would require an entirely different
type of coordination, since they are not accustomed to act together, unless
Eor certain movements, as walking. Based on these theoretic considerations
Bolk found a definite correspondence to exist between the variations in the
development of certain cerebellar lobules and the functional importance of
certain muscle groups, and the general conclusions deducible from his and

Fig. 223. — Diagrams to represent respectively a ventral view of the left half ami a dorsal
view of the_ right half of the human cerehellum illustrating the scheme of subdivision according
to Bolk. (From photographs of specimens from the Anatomical Museum, Western Reserve Medical
School.) (From Davidson Black.)

correlated work may be summed up as follows (cf. Davidson Black10) : The
lobus anterior cerebelli (see Fig. 223) contains the centers for the coordi-
nation of the muscle groups of the head (eyes, tongue, muscles of mastica-
tion, muscles of expression), and of the larynx and pharynx. The lobus sim-
plex contains centers for the coordination of the muscles of the neck. The
lobulus medianus posterior contains the unpaired centers for the synergic
movements required by the right and left extremities for the purposes
of progression. On the other hand paired centers for the extremities —
those centers thai have to do with the independent movements of each limb
of the same side of the body — are located in the lobuli ansiformes et para-
median! (crus primum and crus secundum). The centers for the rest of

I'l \< TIONS OP i III • i l:l r.l.l.l.i'M

the trunk ;iik1 tail region are located in the remainder of the cerebellum.
These conclusions are the l>asis of the accompan} ing map of the cerebellum.
Basing his work on these anatomic conclusions, Van Rijnberk has studied
t he effed of circumscribed extirpation of certain Lobules of the cerebellum
on the muscular control of the differenl parts of the body, with the following
results. Total or partial extirpation of the lobulua simplex produces sid<
side oscillations of the head, indicating the removal <>t' the influei the

cerebellum thai control the movements of the muscles of the neck. Complete
extirpation of the crus primum of the lobuli ansiformes causes ^ an imme-
diate irritative effecl dynamic disturbai the fore limb of the same
side, replaced later by a condition of atonia, which make* imb hang
limp, and of asthenia, which makes it feeble in its movement when i1
is excited to contract. Extirpation of the crus secundum lias a similar

3 luina of th<
■ in Rijnl i Luiciani. Op. lit.i On the riijlit I the

differenl lobules to the functional develop! g to the

theory of Bolk noted in the t< .ck.)

influenc i the muscles of the hind limb of the corresponding > i < 1 > • . Extir-
pation of both crura of the lobulus ansiformis causes marked asthenia and
atonia in both fore and hind limb on the same side as the Lesion. A char-
acteristic disturbance in walking develops as a late effed of this extirpation.
It lias been termed the "hen's gait." Extirpation of the lobulus pai
medianus causes rotation on the longitudinal axis of the body, with pleuro-
thotonus tu the operated side. Fig 224

•lust as in the case of cerebral localization, bo in ■ ar we find that

within each of the largesl centers a more particular localization can <><■ mi
out; thus, in cadi of the centers for the upper and 1"
there is a definite arrangemenl of subsidiary cent< the dii of

the activities of antagonistic muscle groups erned in the movem<
particular joints. It must be remembered, hi that in all I

no real paralysis is produced bj extirpation, bu1 only a want irdina-

870 '1111' CENTRAL NERVOUS SYSTEM

lion on account of the fact that the sthenic, tonic and static impulses re-
quired for muscular harmony are not properly elaborated.

After some time, as in the case of complete cerebellar extirpation, the
s\ mptoms gradually disappear, but they can be obtained more or less char-
acteristically in practically all animals., at least in all those that have been
investigated, including dogs and monkeys.

It will be of interest to consider for a moment the possible causes for the
ultimate disappearance of the symptoms of cerebellar extirpation. These
are either: (1) an organic compensation by the uninjured parts of the cere-
bellum, or (2) a functional compensation by the voluntary centers of the
cerebrum. Although the former of these methods of compensation may
sometimes develop after partial destruction of the cerebellar cortex, it can
not of course explain the recovery which we have seen to occur after the
entire cerebellum has been removed. The most important compensation no
doubt is effected by the cerebrum, as the following observation clearly in-
dicates. If half of the cerebellum of a dog is destroyed, and the animal
kept alive until the symptoms of cerebellar extirpation have entirely dis-
appeared, it will then be found, if the cerebral center on the opposite side
is removed, that the symptoms return in their original severity. After this
second operation the powers of standing in the erect position and of
walking are permanently lost.

CLINICAL OBSERVATIONS

Application of these laboratory results has been recently made in the
clinic, the most important contribution having come from the clinic of
Barany, who for his work was awarded the Nobel prize. In cases of abscess,
cysts, or regional agenesia, it is now possible to determine the exact site of the
lesion in the cerebellum. To effect this localization, it has been necessary to
work out certain clinical tests. The most important of these is called the
index test. This is described by Davidson Black as follows: "The patient's
eyes being closed, he is asked to execute a simple movement in a given
direction with one of his extremities. For example, the forearm being
firmly supported, the patient's index finger is extended and brought into
contact with thai of the observer; the patient is then required to move his
finger vertically downward and then to return it to its previous position.
The test is repeated a number of times, both in the vertical and in the
horizontal direction, and if any tendency toward deviation from the plane of
movement be present, its direction is noted. By slight modification of the
foregoing procedure it is possible to test each of the limb segments in all
positions of rotation, pronation or supination."

The index test is applied (1) without previously producing nystagmus

I r\< TIONS QP Tin - I 1:1 Rl I. MM

-71

and - after producing artificial i nus. The artificial

produced by spinning the patienl two or three times, and

slant lateral movements of the eyeballs, quick in the direction in which the

artificial movemenl took place, and slow in the opposite direction.

In a normal subject, previous to spinning the inde I I devia-

tion, bu1 after the production of artificial nystagmus a deviation is noted
in the direction corres] ling to the slow jerk of the i tion

Figi

• Hum h
Andre-Thomas N. VII, N. 1\, '

•V XII, dossus.

Tli'
the muscuiai

hand;

N. VI, Xcrvus .1 VII, N

Ncrv

deviation). When a cerebellar lesion < , the in
a patient without nystagmus Bometimes caus< tion in

the segment of the body corresponding to the position the

cerebellar cortex, l>ut more frequently, if it is applii

872 THE CENTRAL NERVOUS SYSTEM

of artificial nystagmus, the reaction deviation in that segment will fail to
he obtained. The exact site of the cerebellar lesion is diagnosed partly
from the nature and direction of the deviation which is produced and
partly from the segment of the limb in which it occurs, the explanation
for the disturbances being that interference with the cerebellar control of
one muscle group causes the antagonistic muscular groups to perform their
movements in an exaggerated manner, so that the segment moves too much
in their direction.

Barany's conclusions so far may be summarized as follows:

(1) The centers for the extremities are located on the cortex of the
hemispheres in the semilunar (superior and inferior) and digastric lobules
(see Pig. 225). The representation is uncrossed or homolateral, thus con-
trasting with cerebral localization, in which it is crossed or heterolateral.

(2) "Within each of these chief centers there is a further localization,
which however does not refer to anatomical groups of muscles but rather to
the functional performances of the different segments of the limb. Thus,
within the arm centers there are subsidiary centers concerned in the
movements of the limb in the various planes in rotation, in pronation
;\\](\ in supination. It is a functional rather than an anatomical localization.

(3) When a center concerned in the movements of the limb in a certain
direction, e. g., to the right, is suddenly destroyed, a spontaneous devia-
tion is produced in the opposite direction (to the left).

CHAPTER l

THE CEREBELL1 M AND THE SEM* [R( i l..\i; CANALS

FUNCTIONAL TESTS

The cerebellum serves as the great aerve center to which are transmit-
ted, through the various proprioceptors, the impulses which, as it w<

inform it as to the exacl degri t muscular effort required to maintain

the animal in its various postures, h is, as Sherrington ;
ganglion of the proprioceptive system. Such impulses from the na
tendons, etc., could not, however, supply information regarding the
position of the body in space. For this purpt I receptors eon-

nected with the eighth nerve are provided in the semicircular
These, it will be remembered, are three in number on either side, each canal
consisting of a semicircular bone tube attached to the vestibu
interna] cat-: and they are arranged so thai they lie at right ang one

another in the three planes of space. The thr< anals on eithei

thus disposed so as to form an arrangemenl like a V-shaped armchair with
the back inwards. This arrangement causes the posterior vertical canal
of one side to be in the same plane as the superior vertical canal of I
opposite side, the external canals being in the horizontal plane on hoth
sides. The arangement will be plain from the diagram Fig. 227 .

Within the osseous canals are suspended membranous tubes, which do i
fill the canals. The canals, etc., contain fluid, but are not completely
filled. The osseous as well as the membranous canals are dilated at
end to form the ampulla, and it is here that the vestibular division
eighth nerve ends in a structure called the "crista acustica,"
hair ••ells supported by sustentacula cells. The q< irminates in fine

arborizations between the hair cells, [nt ad utricle an j1

t hits similar to the crista, called the macule acust l - st

r ptors specialized for the purpose of respond ii I in the

position of the head, and therefore of the body in general. When the
head moves in a certain plane of Bpace, the fluid in the membran

and in the utricle and saccule "ii a unit of inertia nn-i

movement, which acts on the hi lis and I

stimulus. According to the d< timulation in tl

ampulhe. which again will be ^i'} I upon tl

which the movement of the head I urred, impuls

S74

THE CENTRAL NERVOUS SYSTKM

through the vestihular nerve, and these impulses ultimately reach the
cerebellum.

The experimental evidence for these conclusions regarding the functions
of the semicircular canals is very strong. Thus, after destruction of all
the canals — an operation which is particularly easy in the pigeon — the
animal behaves very much the same as after cerebellar destruction. After
some months these disorders disappear, because the cerebellum learns to
control the movements of the body from other proprioceptive impulses,
particularly those of sight, If such a recovered animal is bandaged, the
symptoms return in all severity. This compensation is furthermore an
educative process, for it does not occur when the cerebral centers as well

Fig. 27. — The semicircular canals of the ear, showing their arrangement in the three planes of

space. (From Howell's Physiology.)

as the semicircular canals are removed, and it can be abolished in a re-
covered animal by removal of the cerebral cortex.

Many observations of great interest have been made concerning these
labyrinthine sensations by Pike and others, but we can not discuss them
further here. One point of interest, however, is that forced movements
in definite planes are induced by removal of a canal. Removal of the
horizontal canals, for example, causes continued nodding movements of
the head in the plane of the injured canals. An experiment of great sig-
nificance was performed by Ewald to show the effect of causing a move-
ment of the fluid in one of the canals. For this purpose a bony canal was
opened at two places by a dental drill. Through the hole farther from the
ampulla, amalgam was introduced so as to block the backward movement
of fluid, and into that nearer the ampulla a fine tube was inserted con-
nected with a rubber bulb. ]U' manipulating the bulb, the membranous

CI REB] ! Li M Wi« llli I Mil !!:• I I

canal could be compressed and currents Bel up in tl
Pound tli.it these currents alv. animal to mi

eyes in the plane v\' the canal thai was I timulated and in

of the currenl of endolj mph.

Finally, visual impressions supply much of the inform
linn requires, the close association of the movemi

cerebellar and labyrinthine disturbai a b<

tagmus already described in i nection with B

upon tliis association. The symptoms and sent I
produced by rotation <>!' the body, or by unusual m<
(if ,-i boat, are no <1< »i il >t due to tin' irregular and in
rinthine s^ns^ti^ns which they excite.

In ;i word, then, tin- function of the cerebellun
ceptive impulses from the body ; 1 1 < • 1 1 «_r with labyri
pressions and to integrate and develop from them imp
being transmitted to tin' cerebral and other nei
muscular movements, so coordinate the n<
when muscular movemenl occurs, it does bo in relationship to th<
position of tin' animal and in the mosl efficient way I
for which the movement \\;is made. 'I rebellum

of tli»> proprioceptive Bystem.

THE ASSOCIATION BETWEEN THE EYE MOVEMENTS AND THE

SEMICIRCULAR CANALS

The close association between the eye m

canals is indicated by tl ccurrence of nystagmus \\1

lated either electrically or by means "t' mod<

mi the membrana t\ mpani. The latter m< tl

Btyled the caloric, and is employed in the r\;m

the aviation sen ice. Its value over t;

the body and the index tesl aln

that it enables us to ti ibular appai

Water a1 68 P. i-^ all run throu

ternal auditor} canal, fi
aboul "• feel above the l ead, which inwhili

forward. In aboul 10 s<
the jerk to the side opp i ti"1 douch<

dizziness complained
mediately afterward the head is incl
from the perpendicular, when
posite to the douched ear should

876 THE CENTRAL NERVOUS SYSTEM

The procedure is repeated on the other ear. If it takes longer than 90
seconds for the nystagmus to appear, the vestibular apparatus of that
side is abnormal. Absence of the reaction deviation after the douching is
a certain sign of internal car disease.

It is undoubtedly essential that these tests should be most carefully
applied to all would-be aviators. They frequently reveal lesions of the
vestibular apparatus or the cerebellum in subjects who had thought
themselves perfectly normal, and who indeed may have boasted of their
powers of equilibrium because they imagined that freedom from seasick-
ness or failure to become dizzy in dancing indicated a high development
of this function. There can be no doubt that many aviators have gone to
their death because of impairment in the ear mechanism. When on "terra
firma" the muscular sense and cutaneous sensations often make the
vestibular weakness of no consequence, but when deprived of these con-
tributory sensations and dependent on the ear-balance mechanism alone;
as in flying, any weakness becomes a serious menace.

It is probable that the value of the turning and past pointing tests has
been overestimated in appraising the flying abilities of aviation can-
didates. Recent work of Gordon Holmes and others has emphasized the
necessity of considering many other tests along with those designed to
detect changes in the equilibration apparatus of the ear. It is most im-
portant also to remember that the tests vary from time to time according
to the general body condition. Many aviators with unusually good flying
records have failed to pass the turning tests and others who have passed
them without a slip have found themselves quite incapable of judging
their position in the air while flying.

CHAP1 ER CI

THE AUTONOMIC NERVOl - SYSTEM

In discussing the physiology of the central oervou I m, we hi

broken away from the traditional text! k treatment of the Bubject in

that we have lefl practically untouched any description of the

various nerve tracts or of the position of the nerv nters. Wi

pursued this policy in the belief thai the study of tl ture

belongs just as surely to the anatomisl as does the structui

of the body, notwithstanding that to trace the course of ,: ath-

ways he may have to call to his aid the physiologist and clinical ne

There is one part of the nervous Bystem, however -namely, the involuntary

or autonomics] the physiology of which it is impossible to discuss a]

from its anatomy, because this lias depended very largely on physiological

methods for its elucidation. Until such methods were emphasized and

while anatomy alone was depended upon, little could be learned

functions and connections of the sympathetic chain and of the varii

nerve plexus thai compose the involuntary nervous Bystem. v.

review briefly the general anatomical plan of this Bystem ;is described by

Ga shell.17

GENERAL PLAN OF CONSTRUCTION

The plan of the involuntary nervous m is much the Bam<

of the voluntary, the main points of difference being dependenl upon the
location of the neurons composing the reflt It u ill be remembered

that there ate three of these: the receptor, the internuncio!

lector neurons (page 782). The receptor neurons have the -

for both systems; Qamely, the posterior root ganglia F 3 Tic- it

nuneial neurons of the involuntary system, lik<

have their cella in the spinal cord, where the d. in

thoracic region, by the cella of the lateral horn ol

sacral region, bj a similarly pla 1 collection of cells; and in the bul

region, mainly by the dorsal nucleus of the rhe m

tlu^ difference between the two systems is dependenl o
fibers of the internuncial neurons, in tin- involunl
spinal cord befon connecting with the eff<
are contained in the various ganglii

s7>

THE CENTRAL NERVOUS SYSTEM

in the voluntary, they remain within the spinal cord, and terminate on
the effector neurons, which are the anterior horn cells.

The outflow from the spinal cord of involuntary internimcial fibers,
which Ave shall hereafter style connector fibers, occurs along the an-
terior spinal roots, but is somewhat irregular in distribution, because
it is interrupted in the cervical and lumbar regions, where the nerve
plexus for the extremities come in. There are, therefore, three main
regions of outflow for the connector fibers — a thoracicolumbar, a bulbar,
and a sacral : and the fibers (Pig. 229) do not behave in the same manner
in all of them. The fibers of the thoracicolumbar region form the so-
called sympathetic sgsicni, and run by the corresponding white rami
communicantes either immediately to the ganglia of the sympathetic

Post root
gang.

ramus

Fig. 228. — Diagram to illustrate the different arrangements of the internuncial neurons of the
voluntary and involuntary nervous systems. In both systems the afferent fiber terminates (by col-
laterals) around a cell of the gray matter of the cord. In the voluntary system this cell is sit-
uated in the posterior horn, and its axon travels to an anterior horn cell. In the involuntary
system, on the other hand, it is located in the lateral horn, and its axon leaves the cord by the
anterior root and travels by the white ramus into a sympathetic ganglion, where it connects with
a nerve cell, whose axon forms the postganglionic fiber. (From Gaskell.)

chain, or by the splanchnic nerves to the abdominal ganglia. In the gan-
glia are situated the cells of the effector neurons. The fibers of the sacral
region connect with effector neurons, forming the pelvic ganglionic group
(pelvic nerves, nervi erigentes) ; and those of the bulbar outflow7 with
effector neurons located either peripherally or in the ganglia of the
vagus and the seventh, ninth, and eleventh cranial nerves. In the mid-
brain there is a fourth ^roup of involuntary connector fibers running to
effector neurons found in the ciliary ganglia.

The anterior roots <>f many of the spinal nerves are therefore not

Pi j

arrow

II. i

*t t

<Spinal cord

: .Sympathetic chain

;--->Solar ganglion

Fig, 230.- Diagram (aftei l.anglcy) showing Ihc mannei
ing the great Bplanchnic nerve. The left-hand diagram r<
preganglionic fibers (black) passing through the n:i"is-h.i
ilieir cell - in the solar ganglion, from which thi . -

to run to their destii Jong th< blood .

ptional arranf

'Mil \i rONOMIC NERVi M B79

composed entirely of fibers belonging to voluntary
also of connector fibers of the involuntarj tem l distin-

guished from the voluntary fibers by being much smaller in diamel
indeed it was by this characteristic thai Gaskell succeeded in ti
course of I he involuntary fibers.

In brief, therefore, the fibers of the internuncial neuroi volun-

tary nervous system are confined within the central ner
where they are contained mainly in tin1 white columns of tin- Bpinal cord,
pyramidal tracts, for example, being composed of internuncial fi:
from the cerebral ueurons; the corresponding fibers of the involuni

nervous system (connector), on the other hand, run oul of ti rd with

the anterior roots to effector neurons situated either in the ganglia
the sympathetic chain or in peripheral localities. Jus1 ;i- the voluntary
internuncial fibers give off many collaterals, so do those <>t* 'he involun-
tary system, so thai an impulse transmitted by one internuncial neuron
may excite a broad field of effectors. We shall see later thai it is through
these collaterals that reflex responses can apparently often
by the stimulation of the central ends of nerves such as the hypogastric
tn the bladder after all connections with the central nervo
have been severed. Pig. 230.

To elucidate the further coursi of the involuntary fibers, and d
mine the location of the effector neuron nerve cells, it becon • 3ary

to supplement anatomical with physiological methods of investigation,
various functions of the innervated parts ascular changes, muscular
movements, glandular activity are observed by the usual methods
the physiologist, and the nerve mots or nerves believed to contain
involuntary fibers either cu1 or stimulated. It' a change is ol i in

the functions, it indicates that part at least of the involuntary net
supply is contained in the nerve structure that has been cul of stimu-
lated. Such a resull does not. however, inform us a- \>> whethei
fiber is that of the connector or effector neuron whether it is
ganglionic or postganglionic. This may he determined in man;.
by observing whether nerve degeneration occu
the fibers, hut the most useful method for answering th(

that discovered h\ Langlej by the use of nicotine, which ii

cent rat ions specifically paralyzes the synaptic

connector and the effector neurons. IT a weak I

this alkaloid is painted on a ganglion or peripheral • • in

which the connector neuron finds its effector tie ill hn

the nerve path, so thai physiological responses produced l»> stinm

the preganglionic fibers become no longer elicitabh w '"•

tary connector fibers run through Beveral

880 THE CENTRAL NERVOUS SYSTEM

chain, it becomes possible, by systematically painting the ganglia with
nicotine, to tell exactly in which of them the fiber finds its effector
nerve cell.

The course and functions of the effector neurons of the three outflows —
bulbar, thoracolumbar, and sacral — vary in many details and must be
considered separately.

THE THORACICOLUMBAR OUTFLOW, OR SYMPATHETIC

SYSTEM PROPER

The connector fibers arc sharply confined in their outflow from the
cord between the first thoracic and the fourth lumbar segments, and
they run by the white rami communicantes to the sympathetic chain,
where some of them connect with effector nerve cells in its ganglia, while
others run beyond the chain to find their effector cells in collateral gan-
glia represented by the semilunar, superior and inferior mesenteric and
the renal in the abdomen: The fibers of the effector cells, often called
postganglionic, are distinguished from the connector or preganglionic
fibers by being nonmedullated. Those derived from cells in the lateral
sympathetic ganglia proceed to their destination either by way of the
gray rami communicantes to the segmental nerves after the fusion of
the anterior and posterior spinal roots, or by the outer walls of the blood
vessels. (Fig. 231.)

The effector neurons supply the following structures:

1. The blood vessels and heart.

2. The musculature of the sweat glands.

3. The musculature of the hair follicles and other muscles lying under
the shin.

4. The musculature of the so-called segmental duet, which is repre-
sented in the adult by the uterus, Fallopian tubes, ureters, etc.

5. The sphincters of the intestine.

Regarding the innervation of the blood vessels, the exact situation of
the ganglia in which the effector neurons are situated and of the nerve
roots which contain the connector fibers, is shown in the accompanying
table (page 881).

It is clear that the innervation of the blood vessels is practically con-
tinuous, the effector neurons being situated both in the lateral and in the
collateral chain of ganglia. Those of the former run to the vessels of
structures innervated by the crania! and spinal segmental nerves, while
those of the latter supply the vessels of the abdominal and pelvic viscera.

The connector fibers to the sweat glands are also strictly confined to
the thoracicolumbar system, the cell station being found in the ganglion

Post. root-
Ant, root -

i preganglionic fiber

\ — Sympathetic ganglion

White rami

- Postganglionic fiber

Fig. 231. Diagram (after Langlcy) t" *li"v\ the manner i
emanating from the spinal nervt by the white ramus commui
sympatl hain with I), the axon of which th<

fiber ircili 1 •>■ way of thi mmunicans hack to

it .i\<-]~ to the periphery. It will be
svnaosia in tin- first eancli

( '

Mil \i l"\o.\ll< VERVO II. M

-1

stellatum for the fore limb, and 'Ii«' lower lumbar :in<l upper
ganglia for the hind limb. When they are stimulated, the muscular
fibers surrounding the Bweal glands contracl and Bqueeze out ,:

si ri Ail' >N OF BLOOD

VESSELS LB

1 and neck. - perior cervical ganglion.

Anterior extremity.

tellatum and in-
cervical ganglion.

Ganglion stellatum.

terior extremity. 6th lumbar, 7ih lumbar, and
Isl Bacral ganglion.

Kidney. R i lion.

Spli

Semilunar ganglion.

Abdominal viscera. Superior mesenteric ganglion

and semilunar ganglion.

I'. Ivic viscera. Inferior mesenteric ganglion.

1. 2, ■"•. t. 5, •'■
rimum effect.

1. 2, ."•. I. 5
maximum.

I. 5, 6, 7. B, '.'. •
Blightly.

II. 12, 13, •
and 3 slightly.

I. 5, 6, 7. - 11. 12,

thoracic : I, 2, 3, 1. luml

::. I. 5, 6, 7. B, 9, 1". n. 12, 13,
thoracic ; I, 2, 3, lun

6, 7. 8, 9, 1". 11, 13, '!. 1. 2,

3, lumbar.

1. 2, •"■. 1. lumbar.

ikell)

The ganglia for the pilomotor fibers are more widespread (extending
from the fourth thoracic to the coccygeal ganglia); hut the eonnec
fibers are again Btrictly confined to the thoracicolumbar region. Stimu-
lation i>t' these fibers causes movement of the hairs, or <>n hairless animals,
the condition called " goose Bsdn."

The Motor Nerves of tin Muscles Surrounding t) v \a\ Duct. —

h will 1 bserved thai the connector fibers to the abdominal and -

vie viscera are collected into two Bpecial nerve trunks, the great*

the lesser or Lumbar) Bplanchnics. The collateral ganglia semilunar

and Buperior and inferior mesenteries with which thes nnect, I

ning to <i" with the segmental nerves, but their nei send fil

(postganglionic) which Bupply the various viscer only "v\ i t li vi

motor fibers but also with the "s; mpathetic" fibers, which we hav<
exercise Buch an importanl control over their glandular a n«l muscular
functions.

AM of the fibers contained in the lumbar Bplanchnics <1" n
have their cell stations in the inferior mesenti
through it :ni«l proceed in the hypogastric
cells mi the musculature of the vari<
from the Miillcrian and Wolffian ducts

vsl' THE CENTRAL NERVOUS SYSTEM

lopian tubes and vas deferens. Many of the fibers of the hypogastric
nerves are therefore those of involuntary internuncial neurons.

The ileocolic and internal anal sphincter muscles of the intestines and
internal vesical sphincter receive their nerve supply from effector neurons
situated in the superior and inferior mesenteric ganglia, the internuncial
fibers arising from the thoracicolumbar region. It is possible that the
other sphincters of the intestinal canal — viz., the cardiac and pyloric
sphincters of the stomach — are similarly innervated. (Fig. 232.)

Great aid in working out these nerve connections is received by study-
ing the effect of epinephrine, which acts specifically on those tissues that
are supplied by the sympathetic nervous system.* Epinephrine has no
effect on tissues innervated by the bulbar or sacral outflows, and it
develops its action peripherally, being indeed more potent on a dener-
vated organ even after all its nerves have been allowed to degenerate.
Advantage of this action of epinephrine has been taken in the investi-
gation of doubtful cases of sympathetic innervation, such as in the cere-
bral, coronary, and pulmonary blood vessels. The outcome of these in-
vestigations has been discussed elsewhere.

THE BULBOSACRAL OUTFLOW OR THE PARASYMPATHETIC

SYSTEM

From the medulla oblongata arise involuntary connector neurons,
which are carried mainly by the vagus nerves but partly by the seventh,
ninth and eleventh cranial nerves to effector nerve cells situated periph-
erally on the structures to which the nerves run (Fig. 233). These include
in a general way the muscles and glands of the alimentary canal and
its derivatives as far as the end of the small intestine. In the small
intestine itself the cells of these motor neurons are those of Auerbach's
plexus found between the two muscular coats. In the diverticula, which
include the lungs and the gall bladder, the nerve cells to Avhich the
vagus fibers run are also situated peripherally.

The sacral outflow occurs through the second and third sacral nerves,
the fibers joining to form a single nerve (the pelvic nerve or nervus
crigens) on each side. This passes directly to the bladder, where it
connects with a plexus, often called the hypogastric, which extends over
the bladder and neighboring portion of the rectum. The branches run
to connect either with the nerve cells of the ganglia of the plexus itself,
or with nerve cells situated on the walls of the large intestine and blad-
der. The pelvic nerve makes its connections with the periphery in the

"Its action is always tin >am< as that which is produced by stimulation of tin- sympathetic nerve
supply, whether this effect is one ot stimulation or inhibition.

Head t Neck

tPojfqang )

Splanchnic
(Pcutgang.)

Medulla = Key

PreGanyiionic Sympathetic

Post Ganglionic Sum;

Pre Ganglionic Bulbo Sacral

( Paralympa-

Post Ganglionic Bulbo-Sacral
Arm

Head o
...Neck

(Pre gang )
5ymparr'-
Ganglia

Thorjcic
6planinnic
v nerve

Coeliac Piexuj &
5up.Me5.0ang.

Leg

Arm
(Preg ■

Lumtwr
Jpiancnnic nerte

Abdominal
Vucera

^Pre-

Inf Mes.Gang.
Leg
iPojr

•

A5p. int
ceral nerve

I arts of t h< ■ be

with i

auton ire omittcii. but the position of t!

■
of the

I ill \i rONOMIl ■■: i;.

same manner as the vagui l

musculature of the gastrointestinal tract, inclu

vagus as far as the end of the Bmall

from this poinl on. It must of remem

muscles namely, the Bphinctera of the Bmall

receive their nerve supply from the sympathel

structures innervated by the sympathel

the action of epinephrine, it lias been disco

by the bulbosacral system are verj susceptible to tl

choline, which is presenl in ergot. I

nor arc the structures upon which this arts .

AXON REFLEXES

At this place 11 is convenient to consider for a momenl tl
mm which has already been referred to as an axon [|

covered that when oi f the hypogastric nerv<

end stimulated there was a reflex contraction of tin- bladder ami I

ternal anal sphincter, along with vasoconstriction in tl

turn ami thai this occurred, even after disconni the in-

teric ganglion from the .spinal cord by cutting the Lumba

Injection of nicotine immediately abolished tl ■ [1

if reflex action was possible through the ganglion; which ■

the name "sympathetic" originally given i<> the involunti

tein in the belief thai the ganglia were centers for local i

Further investigation showed, however, that this refl<

those occurring in the voluntary system, hut is dependenl

presence of a collateral on internuncial fibers that run thn

ferior mesenteric ganglia to nerve cells Bituated peri'

walls of the bladder and rectum. Th( (laterals termii

around nerve cells in the ganglion, th( hich, i

lam to the bladder, the rectal hi 1 vess "1 the int

ani. The evidence for this explanation d<

the axon reflex is no longer possible after the iun

been cu1 and lime allowed for their fibers to ;

erated.

Similar reflexes depending on coll

chain, and there can he little doubl tl
throughout the whole involunl
w ithin the spinal cord, in the volunl I

and the fact that ner\e fil

that a st.imulus transmitted througl

884 THE CENTRAL NERVOUS SYSTEM

neurons may excite a broad field of effectors and cause a widespread
effect.

FUNCTIONS OF AUTONOMIC NERVES

The functions of the autonomic nerve fibers have been discussed in
connection with the structures which they supply, and we shall require in
this place only to review them in a general way.

Two opposed effects may be obtained: stimulatory (augmentory) and
inhibitory; and these may be produced through one nerve by its being
stimulatory for one set of muscle fibers and inhibitory for another set
in the same viscus. The branches running from the inferior mesenteric
ganglion to the colon, for example, are augmentory (constrictor) for the
blood vessels and inhibitory for the muscular walls of the colon.

The greatest interest centers on the inhibitory impulses. They are
best known in connection with the vagus nerve to the heart, the sympa-
thetic to the small intestine, and the hypogastric to the musculature of
the bladder. It is interesting to compare the nature of inhibition in the
involuntary and voluntary systems. In the latter, it will be remembered,
inhibition can occur only through the internuncial neurons and the ef-
fector nerve cell, stimulation of the effector nerve fiber never having
any other than an augmentor effect. It is quite otherwise in the involun-
tary nervous system, for stimulation of the effector nerve fiber, after
complete destruction of the effector nerve cell, is still followed by a typical
inhibition. This, it will be remembered, may be demonstrated on the frog
heart by applying electric stimulation to the white crescentic line after
paralyzing the effector nerve cells by nicotine. The same may also be
shown in the case of the chorda tympani, Avhere stimulation of the post-
ganglionic fibers in the hilus of the gland causes dilatation of the blood
vessels after paralysis of the ganglion by nicotine, vasodilatation being
of course a phenomenon of inhibition.

It is a difficult matter to designate precisely which fibers in any part
of the involuntary nervous system are inhibitory and "which augmentory.
Indeed, as mentioned above, one fiber may perform both functions. In
cases where the existence of inhibitory fibers is doubtful, great aid is
afforded by the use1 of ergotoxine, an alkaloid of ergot, which possesses
the remarkable property of specifically paralyzing the augmentor nerves
of the sympathetic system (but not of the parasympathetic); that is,
the siimc fibers as are stimulated by epinephrine. When a particular
structure is supplied with augmentory and inhibitory fibers by a com-
bined sympathetic nerve, electric stimulation or the application of epi-
nephrine usually giv.es only augmentory effects; after the injection of

\pilo motor n7u.sc/e

Lachr

Nasal mucosa

Sublingual
gland

Submaxillary gland

Submaxilldry(5ublinqual J
ganglion

Call bladder and
ducts

5mall intest.
Pancreas

KEY -
Cranial and 5acrai nerves

<T^~ [Thoracicolumbar nerves

Postganglionic fibers
are dotted, thus

N XI

Jup. cervical ganglion

- ^^ — Thyroid gland

Inf.cervical ganglion
j r Ansa subclavia

Stellate itt Tba n

ganglion
Sweat gland

Vasomotor
fibers

8 Pilo motor muscle

Celiac [Semilunar)
ganglioniS: j- .

Splanchnic nerves
Sympathetic chain

lliocecal
sphincter

Bladder
Vesical sphincter
Urethral sphincter

umbar splanchnics

Sup Mesenteric

ganglion

Inf Mesenteric

ganglion

hypogastric ne .

Pelvic(Hypoga5tricjnteriHdc)
plexus [Vesical a rectal portions) Pelvic nerves {Nervus engens^

f P Hdiieck

■

THE M rONOMIC NERVO M 385

ergotoxine, however, a reversed effecl is observed; namely, inhibition
instead of augmentation. By taking advantage of this fact, Dale

□ able to demonstrate in the hypogastric nerves inhibitory fibers to
the uterus, and Elliotl has demonstrated the inhibitory action i
nephrine on the muscles of the ureter in the 'l"'-r. Inhibitory fibers I
also been discovered by these methods in the great splanchnic nerves, in
the nerve roots supplying the kidney, and in the cervical sympathi
supplying the blood vessels of the mucous membrane of the mouth, i
thai is, in nerve trunks which previously were believed to contain only
augmentory tihers. The accompanying diagram from Jackson will give
an idea of the currently accepted views concerning the distribution of
augmentory and inhibitory fibers. * Fig. 233.

THE AFFERENT FIBERS OF THE AUTONOMIC SYSTEM

It has long been known that the exposed viscera are remarkably ins<
sitive. This experience is in accord with the observation that the supply
of afferent fibers to the viscera is relatively very small. In the hypo-
gastric and probably in the great splanchnic nerve, Langley computes
that only about one-tenth of the medullated fibers are afferent. At the
two ends of the alimentary canal, where cooperative i - betwi

the somatic musculature and the viscera are of import iter

number of afferent fibers are found in the autonomic ner
ample, in the pelvic nerve about one-third of the fibers are afferent, and.
as Ave have frequently seen, the vagi contain large numbers of them
coming from the lungs, stomach, and no doubt from other viscera.

The afferent visceral fibers, as above stated, arise like thos the

voluntary system, from the ganglion cells of the posterior roots. They
travel in company with the connector fibers through the white ramus
communicans, so that the stimulation of the central end of one of t;
may cause reflex rise in blood pressure and other movemenl

It is found that, after opening the abdominal cavity under local
anesthesia, cutting and suturing of the viscera may be continued without
causing any pain. When the viscera are inflamed, how. ind on

certain conditions of stimulation, such as the distention • bile du

with biliary calculi, or the violent contraction of the inti ici-

ating pain may be evoked. This pain is frequently not localized in the
viscera, but is referred to certain parts of the SU1 E the

it has been shown by Mackenzie and by Head that it • the

area of skin which is supplied witl >ry nerves by the same segment

as that to which the afferent autonomic til- ticular via

run. It lias further been shown that vascular

ssii THE CENTRAL NERVOUS SYSTEM

tivity of the corresponding cutaneous areas, so that clinical methods are
available for Localizing the site of the disease by studying the exact
position and extent of the referred pain or skin tenderness.

NERVOUS SYSTEM REFERENCES
(Monographs and Original Papers)

iParker, G. H.: Proc. Am. Philos. Soc, 1911, i, 217-225.
*Head, 11.. and Riv.Ms. \\\ n. R.: Brain, 1908, xxxi, 323-450.
sMeek, W. .1.: Am. Jour. Physiol., 1911, xxviii, 356-360.
*Bruce, A. Ninian: Arch. f. exper. Path. u. Pharmakol., 1910, lxiii, 426-433.
^Sherrington, C. S. : Numerous papers on reciprocal innervation of antagonistic
muscles, Proc. Hoy. Soc, Vol. 1'., 6(}; also in Jour. Physiol., xxii, xxxiv, xxxviii,
xliii, and Quart. Jour. Exper. Physiol., ii.
Holmes, Gordon: Brit. Med. Jour., 1915, ii, Nov. 27, Dee. 4 and 11.
Pike, F. II.: Am. Jour. Physiol., 1909, xxiv, 124-152.
"Jollv, W. A.: Quart. Jour. Exper. Physiol., 1910, iv, 67-87.
BLombard, W. P.: Jour. Physiol., 1889, x, 122-148.
aCollier, J.: Lancet, April 1, 1916, 711.
lORanson, 8. W., and von Hess, C. L. : Am. Jour. Physiol., 1915, xxxviii, 128.

Hi-ad, II., and Thompson: Brain, 1906, xxix, 537.
"Sherrington, C. S., and Brown, T. Graham: Jour. Physiol., 1913, xlvi, Proc. Physiol.

Soc, p. xxii.
"Brown, T. Graham, and Sherrington, C. S. : Proc. Roy. Soc, 1912, 85, B>, 250-277.
"Cushing, Harvey: Proc. Am. Physiol. Soc, Am. Jour. Physiol., 1909.
"Luciani, L.: Kleinhirn, Ergebnisse der Physiol., 1904, i.
lsBlack, Davidson: Cerebellar Localization in the Light of Recent Research, Jour. Lab.

am! Clin. Med., 1916, i, 467.
i"Gaskell, W. II. : The Involuntary Nervous System, Monographs on Physiology, ed. by
E. II. Starling, Longmans, Green & Co., 1916.

Other Monographs not Specifically Referred to in the Context

errington, C. S.: (1) The Integrative Action of the Nervous System, Silliman Lec-
tures, Yale University. Scribher's Sons, New York. (2) Shafer's Textbook of
Physiology, II. Young J. Pentland, London, 1899.
"Bolton, J. S.: Recent Researches en Cortical Localization and on The Function of
the Cerebrum in Further Advances in Fhysiology, ed. by Leonard Hill, London,
E. Arnold, 1909.

I M ) E X

Abdominal respirat ion,
Abnormal pulses, 276
Absorption, in general, 13

from Btomach, 456

of fats, 691
Acapnia, 292

Accessory food factors, 584
Acetaldehyde, 7 -
Acetoacetic acid, 68
Acetone, 683, 7"'.'
Acid :

buffer action, •".»'>

excretion of, by kidneys, l«*>

number <>t' fats, i;s7

total concentration of, •"■-'
Acidity, actual degree "t". 23
Acidosis:

ammonia-urea rutin during, 616

compensated, 39

in diabetes, • S

in nephril is, 68

in starvation, 569

relationship to alveolar COj, 35 t

relationship to breathing, 354

theory of, 3

uncompensated,
Acids, of urine, 524
Actual 'i ' acidity :ui<1 alkalinity,

Adenini . I
Adenosine, • 9
Adjusters, 78
Adrenal glands and diabel
Adrenaline i< i Epinephi
Adsorption, 65

compounds,

conditions influenced by,

effect "i" chemical I

effect "t" electric changes on,
ryday reactions d< pending

Afferent tit' tutonora

nal pathways, -

effect on creatinine

Albolene absorption, I

Albuminuria, 519

Alkali retention, determinat

Alkaline buffer,

Alkaline

measurement of, il

Allantoin,
Allied

of, ■

-
Alloxan,
Alveolar air :
clinical in-
• stimation of i \

lericia metl
Ealdane n
Pearce method, 3 15
tension of i

during breathing in

tension

Ambard 's equatio

in acid ex<
Anil"
Amino acid

and •■ ■ _ H

in 1>1 1. I

chemistry

determination

fat

in growth,

in •
in urii

Alii;:

Aminopropioi
Ammonia :
ammonia art ■
influent

in d
int!

■
■

Ammonium
Ammonium

in

—

INDEX

bloodflow in, ! -
Anesthesia, !
Aneurism, bloodflow in, 284

pulse in, l •
Angina pectoris, fibrillation in, 196
Animal calorimeter, 5
Anions, 16,
Antagonistic muscl
Antagonistic reflexes, B24
Anterior roots. 7-7
Anticoagulai

Antidromic impulses, 234
[ferments in blood, 89
Antithrombin, 104, 112

Antitoxins, 69

Antitrypsin, 90

Aortic regurgitation, pulse in. 131

l, 838, 851
Apex beat, tracing of, 275
Aphasia, motor, 860, 862
3
subcortical, 862
Apnea, nervous element in, 332, 362, 365
Apparatus for measuring respiratory ex-
change, 554
Appetite juice, nature of, 440
Are, reflex, 784
Arginase, Bl, 616
Axginine, 605, 616, 627
Aromatic sulphates, 632
Arrhythmia of sinus, 266, 277
Arterial pressure, 122
Arteries, bloodflow in, 198
Arteriosclerosis, diastolic pressure in, 143
Aspartic acid, 605, 666
Asphyxia, 311
Assimilation limit, 652
Association areas, cerebral, 8.12, 861

neurons, 783, 785
Astasia, cerebellar, 8C7
Asthenia, 867

Asthma, dead space in, 311
Ataxy, cerebellar, 866
Atonia, cerebellar, 867
Atophan, 651

Atropine, eff< - lands, 122

Auditory center, 851
Auricle, pressure in, 148

propagation of beat in, 191
Auricular eun . L53

Auricular fibrillation, L96, 269, 280
Auricular flutter, 196, 269, 279
Auriculoventricular orifice, 1
bundle, 183
le, 183
Ausculatorv method of blood pressure),

130
Autocatalysis, 77
Autonomic nerves, cerebral, 423

■apathetic, 423
Autonomic nervo ^77

afferent fibers of, v~

Autonomic nervous system — Cont'd

axon reflexes in, 883

bulbosacral outflow, 882

connector fibers of, 878

functions of, 884

general plan of construction, 878

parasympathetic, 882

thoracicolumbar outflow, 880
internal vesical sphincter, 882
Axon, 784

reflexes, 797, 883
Azelaic acid, 712

B

Bacillus coli communis, 500
Bacteria, in intestine, 499, 657

in stomach, 482
Bacterial digestion, 499
Balance, energy, 535
material, 543
sheet of body, 543
Banting cure, 571
Basal heat production, 538
Basal ration, 576
Basophile cells, 96
"Bends" in caisson workers, 402
Benzoic acid, 630, 710
Benzoyl chloride, 631
Beriberi, 584

Beta-hydroxy butyric acid, 709
Bile, 442

and fat digestion, 690
chemistry of, 494
constituents of, 492
from gall bladder, 492
functions of, 493
pigments of, 495
salts, 494
Bilirubin, 495
Biliverdin, 495
B-imidazolylethylamine, effect on blood

vessels, 397
Birds, removal of liver from, 618
Blood:

absorption into, 13
amino acids in, 606
amount in body, 135
antiferments of, 89
circulation of, 122
dissociation curve of, 383
fat of,

estimation, 696, 697
variations in, 697
ferments of, 89
gases of, transportation, 379
general properties of, 85
mass movement of, 281
means by which gases are carried, 390
oxidation in, 396
proteases of, 89
proteins of, 87
origin, 88

INDEX

Blood Cont'd
quantity of, in body, s~,
refractive index of, 88
specific gravity of, B6
sugar level of, 657

regulation, 671
transfusion of, 93, 1 35, 139
viscosity of, 1 10

volim f, 136

water content of, 86

' od cell, red, fate of, 93

origin of, 92

regeneration of, 93
b1 roma of, 93

white, 96
.od clotting, 98

in diseases, 1 1 1

in physiological conditions. I In

influence of calcium on, 103

influence of tissues on, 104

intravascular, L07

methods of retarding, in drawn blood,
99

negative phase of, 108

theories of, 106

time of, 100, 108

visible changes during, 08
Blood corpuscles in mountain Bickness, 401

tdflow :

inical conditions affecting anemia, 283

cardiovascular diseases, 284

fever, 284

diseases of nervous system, 28
mass movement of, -08
movement in veins, 2 1 I

variations in, 282

velocity of, 206

visceral, 212
Blood gas manometer, •"•si

I'.l 1 platelets, 97

ill I pressure, 122

diastolic, 127

effeel of hemorrhage 135

effect of pleural pressur

factors maintaining, 134

11 ion of Moo, I on, 237

mean arterial, 123

in shock, 290

Bystolie, 127

tracing, L25
Blood vessels, S80

elasticity of, 1 12

tone of, 236

Body Quids, reactions of, 35

Body weighl and energy production,

Botulism, 5<

Bowman, capsule of, 507

Bradycardia, 193

Brain:

circulation in, l* 1 7

vasomotor oerves, 252

volume of, 250

ithing, in com]

in rarefied air.

periodic,
Brownian movement, collo
Bruits, I -

Buffer action of blood,
Buffer substam
B tones ol

Bulbosacral outflow
Butyric acid, '

Cadaverine,

« laffeini . I

Caisson disease, 102

can 103

dec pression of t 106

prevention, 404

Bymptoms, 402

working conditions in, I -
( *:i l.iuiii ion, influence on clotl u

influence on heart, 166
Calcium rigor, 166
('alonni electrode,

< laloi ie,

< !alorimeter, 535

animal, 536

Benedict, 537

bomb,

hand, 281

respiration, ■"

Rn>~' I B i
Calorimetry, direct, 5 16

indirect, 546, 554
< 'anal-, semicircular, B

removal of, s«t
Cannabin,

i lapillary anal] olloids,

Carbamino reaction, 59

< larbohydrates, absorption

assimilation limits, 652

• n of, 656
ami growth, 58
metabolism of, 652
production from protein, i
turation limit, 13
Carbon balance,
i larbon dioxide, combining
effect on respirati
• imation in bloc
output .

volume pei in bio

i 'ai li.m dioxide li osion,

in alveolar air. afl

in mountaii
in periodic

in arterial bid

in venous blo<
Carbonic acid
Carboxyl grou]

line il«

[NDEX

< *.- 1 r . I i : i . ■ depressor nerve, 239

Cardiac muscle, physiological characteris

of, 176
( iardiac pouch I Btomach I, 153

< Iardiac sphincter, 1 18

diorenal disease, bloodflow in, 284
energy output in, 5 12
Cardiograms, 275

Cardiovascular disease, bloodflow in, 284
Casein, 488, 576
Caseinogen, is^
Catalase, 90
Cations, 16
Catalysts, 72
Catalytic power, 23
Celenterates, nervous 3ystem of, 782
Cellulose, digestion of, 500

I 'inters :

association, 852, 855

diabetic, 672

motor, 843
rise,

auditory, 851
visual, v~' l

sensory, 850

word centers, 862
Cephalin, 689
' lereals and growth, 581
| lerebellar ataxy, 866
( Cerebellum :

ablation of," 869

clinical observations, 870

extirpation of, 869

functions of, 865

lobes of, 868

localization of function of, 867
Cerebral circulation, 247
' !ei i bra] compression, 253
Cerebral cortex, stimulation of, 844

-nurture of, 852
Cerebral localization, 843

clinical observations, 849

hemispheres, removal of, 840
Cerebral vessels, ligation of, 247
Cerebrospinal fluid, 248

rebrum, higher functions of, 860

< 'ir, method of expressing, 27

i Iheyne Stokes breathing, 371, .".77
Chlorides, urine, 513
Cholesterol, 194, 688

estimation of, 697
Choline, 689

Chorda tympani, 231, 396, 123
Chromatolysis, 801
Chromatine, <i.'i8
( Ihromosom
Chyme, 156, IS
Circle of Willis, 247
Circulation of blood:

control of, 216

influence of gra^ ity on, 2 II

mass in. > v ■ in' ii t iif blood,

through the heart, 257

Circulation of Mood — Cont'd

through the liver, 255

through the lungs, 253

time of, 213
Circulation time, 206
Clinical application, circulation, 259
nervous system, 828, 849, 862
respiration, 310, 399
Clotting of blood (see Blood clotting)
Coagulative ferments, 82
Cod-liver oil, nutritive value, 706
Coefficient of oxidation, 393
Coefficient of solubility of gases, 337
Cold spots, 792
Collaterals, 784
Colloids:

Brownian movement, 57

capillary analysis, 56

characteristic properties of, 50

diffusibility of, 51

dispersion means, 54

dispersoid, 54

electric properties of, 55
osmotic pressure, 57

electrophoresis, 56

external phase, 54

gelatinization, 61

heterogeneous, 51

homogeneous, 51

imbibition, 62

internal phase, 54

isoelectric point, 64

lyophobe, 60

mutual precipitation of colloids, 56

osmotic pressure of, 141

size of colloid particles, 53

suspensions, 53

suspensoids and emulsoids, action of
electrolytes on, 63

Tyndall phenomenon, 51
Compensated acidoses, 39
Complemental air, 300
Compressed air sickness, 399

cause of symptoms, 403
prevention of, 404
treatment of, 406
Concentration cell, 30
Concentration point, auricles, 185
Conception, 861
Concept, 861

< londitioned reflexes, 481, 856
Conductivity, determination of, 17

equivalent, 19
molecular, 19
specific, 17

< lonductivity cell, 18
Conglutin, 538

Construction of autonomic nervous sys-
tem, 877
Contracture, extension, 806
Cooking, 593

Coronary circulation, 257
Coronary vessels, vasomotor nerves, 268

INI)

Corpora quadrigemina, vi"
ction behind, st"
tion in front •

< lorpuscles of blood, red, !»1

white, 96
Cortex, removal of,
Coughinj ilL'

< franial <;<\ ity, pressure in,
Creatine, 606, 613

chemistry of, 622
estimation of, 623

in < 1 i ^ . ■ : i ■> . ■ . 626

metabolism of, 62 I
origin of, 626

< Ireal inine, ,;l 3

chemistry of, 622
coefficient, 624
estimation, 623
in urine, 529
metabolism, 624
of blood in diseasi . 651
origin of, 626
Crista acustica, -

Critical concent latioii, S

Crossed extension reflex, B04
Cuorin, 689

< 'iiri.ut of action of heart, 1 ^7
Cyanosis, 360, 100

' ysti in< . ''■"::
Cystine, 577, 592, 604
itosine, •

1»

Dalmatian dog, purine metabolism of, 646

Dalton 'a law.

Dead space, ■:<>-. 310

Deafness, B64

Deamidization, deaminization, 501

minizing enzyi
Decerebrate rigidity, B -
I tocerebration, B 13
Decolorization of liquids by charcoal

cation,
blood pressure during, Ml'
I »( fibrinated blood, l"l

■
I teglul ition, 1 i".
Delayed conduction, 27

irium cordis, I
Dendriti
Depression of I point, 1"

..t' arii
Depressor m

I '■ •• ation compoum

Dextrii
Dexti

•
imitation limits in,

I'l I examii

blood ■

•

■

-
pani

IHI

pern

phlorhizin,
itprandial I

renal, 661

tr>

-
Dig

Diab

Dialuric acid, I

|li:,

Dialysis, U

method, ■ "'1

Diaphragm, i

phj
jtolic filling
Diastolic i . 127, 1

in.; !", in n,

Dicrj
wa

■
--
Differential mi
Diffusion, 12
stibilit)

-
in inti
in

hormoi

■

infl

INIH.K

Diuri
Diaretii s,
Diver's palsy, 402
Douglas method, 5 1 •. 558
Dropped beat, -71
Du Bois formula, 5 1 1
Ductless glands, 729
in diabetes, ,;7s

Dys] a, 314, 349

Dystrophy, isolation, ^||S

E

Earth worm, nervous system of, 783

Eck fistula, '''I ~

Eclampsia, 620

Edema, 62, 120

Edestiu and growth, 577

Effectors, 782

Elastin, digesi ion of, 486

Electric conductivity, 16

Electric currents, development of, 20

Electric properties of colloids, 55

Electrocardiograms, 158, 259
normal, 261
■ indardizal ion of, 260
ventricular complex, 262
waves of, 261

P-wave, 189, 261

T-wave, 220, 263
Electrocardiograph, 260
Electrocution, cause of death in, 19.5
Electrolytes, 16

action of, on colloids, 63
Electrolytic solution pressure, 29
Electrophoresis of colloids, 56
Electrostatic attraction, 29
Emboli, 107
Emetics, 450

Emotional glycosuria, 675
Emphysema, 311, 314, 324
Empyema, •"■24
Emulsions, 688
Emulsoids, colloids, 60
Endocrine organs, 729
Endoenzyme, 71
Endogenous metabolism, 615

of purines, 647
Energy balance, 535
! Energy output, and age, 541

and body weight, 549

and disease, 542

and muscular work, 549

and sex, 541

and surface area, 540
in starvation, 568
Bnterokinase, 443, 489
Enzymes, 71
action of temperature on, 7 I
amylases, Bl
and catalysis, 72
antienzymes, si
arginase, sl

Enzymes — Conl M

coagulative ferments, 82

conditions of activity, 82

endoenzymes, 71

glyoxylase, 82

iuvertases, 81

lipases, 81

nature of, 72

oxidases,. 82

peculiarities of, 80

peroxidases, 82

properties of, 73

proteases, 80

reversibility of action of, 25, 77

specific action of, 73

types of, 79

urease, 82

velocity constant, 74
Epicritie receptors, 790
Epilepsy, Jacksonian, 849
Epinephrine, 236, 502

and diabetes, 673
Equilibrium, nitrogen, 571
Equivalent, conductivity, 19
Erepsin, 490, 601
Ergastoplasm, 420
Ergot, 502
Ergotoxine, 209
Erythrocytes, 91

fate of, 94

regeneration of, 93
Escapement, 218
Esophagus, during swallowing, 446

inhibition of, 447

peristaltic wave in, 447
Esters, 686
Ester value, 687
Ethereal sulphates, 501, 632
Excelsin, 577

Exogenous metabolism, 615
Exophthalmic goiter, 756

energy output in, 542
Excretion of acid combined with ammonia,

46
Excretion of urine, 507
Extension contracture, 45, 806
Extensor thrust, 57 •

reflex, 805
Exteroceptors, 788, 822
Extrasystole, 266
Eyes, movements of, 847

Factor safety, in diet, 592
Fatigue of reflexes, 825
Fats:

absorption of, 691
chemical theory, 693
mechanistic theory, 692
and growth, 583
blood, 696, 697

destination of, 699

IM>I X

Fate, blood Conl M

determination, •

daring absorption, 6

daring fasting, fl

variations in, 697
chemistry of, 686
depot fat, 699, 700

destination of, 70]

saturation of, 705j 712
digestion of, 690
fat dust, 696
liver fat, 699, 701
metabolism of, ,;'";
tissue fat, 699, 706
transportation to liver, 702
Fatty acids, 686

acid cumber, 087

breakdown of, 709
rter value, ,;^~

formation from carbohydrates, 701,
707

in liver in disease, 703

iodine Value, tiss
meltiiif,' point, C>s7

Eeichert-Meissl value, oss
saponification value, (>S7
Feces, 199, 521
Ferments (see Enzymes)
Ferments in blood, 89

Fever, bl Iflow in. 284

cold hath treatment, 284
purine excretion during, 648

Fibers, anterior root, I'm

connector, l!»".

internuncial, 802
Fibrillation, auricular, 196, 269

ventricular, 195
Fibrin, 99

fibrin needles, 99

source of, l"l
Fibrin ferment I -< i Thrombin >, 102
Fibrinog . 87, 101, L03, 111
Filtration, L3

Final eommon path, 787, B21, 824
Fistula, biliary, 192
trie, Fit

salivary, 430
Flexion-reflex, 804, B21
Flutter, surieular, 1
id:

accessor] factors

cooking, importance of,

effect of, on circulation, 243

effeel on creatinine excrotiou, 624

bixative qualities, 594

palatability, ■

Food factors, a . 584

Foodstuffs, rate of leaving stomach, i S

For 1 breathing, 324

Formaldehyde titration, amino acids, 187
Formation of solid surface films,
Fre< sing point constant, '

g point, depression of,

Fridericia's method f<

■
Frm

Functions of autonomic d<
Fund tomach,

Q

Gallstones, 194

i lalvanomi ter,

aglia, ! !

imach, 162

(ias laws,

adsorption of, I
coefficient of solubility,
estimation of, •"• 1 *

partial pressure i

solution of, 3
tension

transportation in blood, •
( raakell 's clamp, 1 75

Gastric contents, regurgitati f, 149

Gastric digestion, 181

rate of, 187

trie fistula. 134
I .astric juice, quantity •!. 1 I"

Btrength of, 1 1 1
retion, 132

hormone control of, 437

local stimulation of, I -

nervous control of, 134
Gastric tube, 153
Gastrin, 139, 156
i last roenterostomy, 160
Gastrointestinal contents, etion of,
I •■ latin, 578
1 1( latinization, 61

Glands, changes during activity, 122
electric changes, 122
normal conditions of activity, I

oxygen consumption . 121

respiration of,
Globulin, 577

< rliadin,
Glomerulus,

Glueoneog 2, 677, I -

direct method, 6(

indirect method,

iii normal animal
Glucose, 7 8

absorl

glucose to nitrogen ral

in j< ctions, intravenou •
Bubeuta

parenteral assimil

utilisation of, in •
Glut
Glutaminic

< llutein,

•

-''!

INDEX

Glycocholic acid, 194, 63]
Glycini .
Glycinin, 577

ill, 601, :. 71"

Glycogen, 662
fal I 69

if, 662
Glj . 662

Glycogenolysis, 669
hormone, i;7»>
- . 672
ortem, 670
Glycolaldehyde, •
Glycolysis, ,;77

genesis e < Huco gem -

Glycosuria, alimentary, 659
emotional, 675
postprandial, 659

relation to sugar of bl I, 060

renal, 661
Glycuronates, 630
Glyeuronic acid, 630, 631, 632
Glyoxal, •'>:■, i
Glyoxylase, -

sylic acid, 631
. ratio, •
Goiter, exophthalmic, 542
Gout, 648, 650
etiology of, 650
guanine, 'it11

uric acid excretion in, 648
ling of intensity of reflex action, 809
Gram molecule, •"■, 5

■a molecular solution, 22
i rravity, on circulation, 2 1 1

compensation for, 245
Growth, 574
accessory factors, 585
basal ration,
carbohydrates and, 58
curves of, 576

■ - of inhibition, 579
fats and, 58

inorganic salts and, 586
lysine and,

proteins and,
trypanophane and, 578
vitamines,

622
■ 35

■ I

Gum

II

Haldane Barcrofl apparatus, 15
Haldane ej.-is apparatus, 559
Hald • ethod for alveolar nir, 340

til :

1 t I
a i curve, i

iii. :', 1 !•"

Heart — Gont 'd

isometric period in, 1 19

muscle, properties, 170

nutrition of, 161

opening ami closing of valves, 15 1

oxygen requirements of, 396

oxygen supply of, 164

perfusion of outside body, 101

postsphygmic period, 150

presphygmic period, 149

pressure in, l 16

pumping action of, 134, 144

resuscitation in situ, 164

rhythmic power in, 170, 1 7 1

sounds of, 157

-vstole of, 14.1

utilization of glucose, in, 681

vagus control of, cold blooded, 217

vagus control of, mammalian, 220

vagus terminations in, 225

ventricular curve, 140

work of, 212
Heart beat :

arrhythmia of, 266

myogenic hypothesis of, 171

neurogenic hypothesis of, 170, 172

origin of, in cold-blooded animals, 170

origin of, in mammalian, 182, 189

pace maker of, 174

propagation of, 224

sympathetic control of, 223, 227

ultimum moriens, 185

vagus control of, 217, 221 1
Heart block, 174, 270, 276

effect of vagus on, 219
Heart disease, vital capacity of lungs in,

314
Heart dung preparation, 158
Heat production and age and sex, 541
and body weight, 539
surface, 540
disease, 542
Heat spots, 792
Heat value of foods, r,:\r,
Hematocrit, 7
Hematoporphyrin, 49 0
Hemiplegia, 258
Hemodromograph, 200
Hemoglobin, 91

dissociation constant, >^

dissociation, curve of, 380, 382, 383

estimation of, 92

rate of dissociation, 386

relationship to bile pigments, 496

specific oxygen capacity of, 379

transportation of 02 by, 390
Hemolysis, 7, 95
Hemolytic jaundice, 93
Hemophilia, 112

Hemopoietic activities of hone marrow, '.'3
Hemorrhage, 59

immediate effects of, 1".7

recovery from, 138

IM'I X

Hemorrhagic di L12

Henle, loop of, 507
Hepatic artery, flow in, 255
Heterocyclic compounds, 604
II. 652

Hibernating animal, metabolism of, 549
Hibernation, breathing during, 374
Higher functions i
II ion or hydrogen Ion, 168
II ton concentration, ~-
after hemorrhage, I 12
catalytic power of,
determination <>t', -".1
of Intestinal contents, 505
law nt' mass action and, 26
method of expressing, 27
method of measurement :
electric method, -'.'
indicator method, 32
standard solutions for, 34
II ion concentration in blood :
effect mi dissociation cui v< . 386, 38 •
effecl mi respiratory center, .';;;-"i
Hippuric acid, 530, ''.':;". 710
Hirudin, I""
Histamine, ■■'.':, 5
Histidine, 606, 623
Homogentisic acid, 502, 531
Hordein, 578
Hormon 729

in control ut' circulation, 216
respiratory . 3 19
Howell theory i blood clotting i, 106
Hunger, 171
Hunger contractions :
alcoholic beverages and, 178
control of, 176
during starvation, \~~>
in esophagus, 17 I
inhibition nt', 177
in stomach, 171
nerve centers and, 17:'
remote effects of, 17 1
rhythmic, 171
Bplanchnic nerve and, 177
\.il'iis nerve and, 177
Hurthle manometer, . l -<>, 1 i«i
Hydrocephalus, 249,
Hydrochloric acid, amount of,

:iinl emptying of Btomach, 460
functions of, 182
source of,
Hydrogen i' ;i

Hyperacidity, 161
II \ I

nia, in pa

postprandial, I

Bplanchnic,
11% perpnea,
1 1 \ ("it hj roidism, 7
Hypertonic solutioi
Hypcrtonicity, I
H}'1

thyroid
Hypotonic Bolution, «»
Hypoxanthii

1

Ignition ju
J IcOCOlic II;

Ileocolic sphii
Imbibition, •'>_'
Imidazole and

lini'l.i/ii

[midazolylethylam

[mmediate induct i<

Impulses, natui

Index b

[ndican, 632

Indicator method, li*t of indi

Indole, 501, 604, •

[ndoxy] Bulphate of ; ti

Induction, immedial

-
Inhibition, reciprocal, -
[nhibitory effecl
IniiiTvatii.ii, reciprocal. sl t
Inorganic eonstit ~ ;i

Inorganic Baits and growth, " -

[nosinic acid, I
Inspiration, negatii

• gration of allied r<
Integration of nervous I I
Intercostal muscles,
Internal anal Bphincter nm*<!'
Internal vesical sphirn I
Internal respiration, ■ 1 •
Intestinal bacteria,
[ntestinal juice, control of, 142

•inal obstruction, 170,
[ntestinal secretions, ill

Int. -•
absorption from,

an

bacterial digestion in,
digest i"ii in.

law of,
movements

l;ir.

clinical condit

•ntr..| l

'

Inti

intrapleural pn
liitrapulnu

lilt:.
Intr..

I

I

INDEX

[nvoluntary fibers, c< ai -:;'

[odine value of fa1
Conization, 16

[rradiation in nervous Bystem, 826
[irreversibility in reflexes, si"
[soelectric point, 64
[soleucine, 604
[somaltose, 79
[8ometric period, 1 19
• inic solution, i;

J

.1:,, ksoniau epilepsy, 849
Jugular pulse tracing, 27 I
.1 uice, gasl rnj, 13 '
intestinal, -I '-

pancreatic, 1 1 1

K

Keith and Hack, conducting tissue in

heart, 185
Kent, bundle of, Is"1
Ketonic acid, 708
Ketosis, I -
Kidney, oxygen requirements of, 396

removal of, 621

structure of, 507
Knee-jerk, 804, 815, B28

reinforcement of, 8^9

Lactalbumin, 577

Lactam, 649

Lactase, 191, 657

Lactic acid, 397, 603, 676, §65, 708

effect mi respiratory center, 376

in in tain Bickness, 362

produced by exercise, 367, W'->
Lactim, 649
Language, 8<iu
Latent period, -
Laws of gases, 336

of mass action, 23

applied measurement of E-ion concen-
tration, 26
Lead poisoning, 650
Lecithin, 689

estimation of, 697

in bile, 198

in blood, 696, ''■'.':'
i.i ech extract, 100
Legumelin, 578
Legumin, •"78

I., jiona of nervoua bj stem, 835
Leucine, 60 1, 666
Leucocytes, '-";

sitizing of, 70

transitorial, 97
ocythemia, 6 18
Levulose, 656

and Bowntree method, 41

Limulus, heartbeat of, 172

Lipase, 25, 90, 491, G87

Lipemia, 699

Lipoids of blood, 699

Lissauer-tract, 831

List of indicators, 33

Litten's diaphragm phenomenon, 321

Liver:

circulation through, 255

disease of, 620

glycogen in, 662

metabolism of fats in, 701

perfusion of, 618

removal of, 617

urea formation in, 017
Loral irritants, 243
Localization, cerebral, 843
Locke solution, 168
Loven reflex, 244
Lungs, circulation through, 253

mode of expansion of, 32.1
Lymph :

absorption into, 13

electric conductivity, 16

filtration in, 118

formation and circulation, 115

formation of, 15
Lymph spaces, 115
Lymphagogues, 119
Lymphatics, 115
Lymphocytes, 96
Lyophobe colloids, 60
Lysine, 592, 605
Lysine and growth, 576

M

Maculae acusticse, 873
Maintenance, diets for, 57!)
Malingerers, 42
Maltase, 491, 657
Maltose, 491
Manometer:

blood-gas differential, 382
Hiirthle, 124, 146
mercury, 123
optical, 146
spring, 126
valved mercury, 152
Mark-time reflex, 800
Mass action, 23

Mass action and H-ion concentration, 2(3
Mass movements of blood, 281
Mastication, 444
Mechanics of respiration, 299
Medulla, section above, 839
Megacaryocytes, 103
Melting point, fats, 687
Membrane synaptic, 798
Memory, 786
Mercury manometer, 123

Metabolism :

calculations, 5 1 1

endogenous, til")
genous, 615

general, 534

in starvation, 566

normal, 570

of carbohydrates, 652

of fal

hi* proteins, 505

of purines, 637

Bpecial, 53 i
Methyl glyoxal, 61
Methyl group, 598
Methyl purines, 635
Methylation, 627
Methylglyoxal, 665, 666
Metl 's method, 187
Microcytes, t'l
M icrotonometer, 339
Mid-capacity <>f lungs, -".1 1
Milk, clotting of, 188
Miniature stomach, 133

Minimal air, 300

Mononuclear leucocytes, 96
Morawitz theory, blood clotting, 1"7
Motor arras, ablation of, 843

stiiiuilatii.ii of, 84 1, B46, 848
Motor nerves of segmental duct mus

--]
Mountain Bickneas, 360, 399

adaptation to, I"11

alveolar 00, in, 360

blood corpuscles in, 401
Movements, <'!' intestine, 463

of stomach, 152
Municipal food statistics, 591
Muscarine, action on heart, 226
Muscle, cardiac, properties of, 176

refractory period, 178

respiration in,

Btaircase phenomenon treppe), 177
skeletal, 177

respiration in, .'■■>i
Muscles, ant tic, sis

Muscular exercise, 2 13, 539

circulatory changes during, 110

effect on metabolism, 551

effect mi respiration, 366

11 ion during, i L3

purines during, "''7

redistribution of bl 1 during, <l~>

changes during, 410
mperature of blood during, 11".
Mutual precipitation of collo
Myenteric reflex, 796

genie hypotl 171

Myxedema, 3

output in,

and 1-1 1 t

■

Nephrecton
Nephril

'inn iii,
i

net

■
■
specific proper!
vasodilati
Nerve cells,
Nervi erigentes, 23]
• iitml :
■
ileocolic Sphind

of intestinal glands,
i't' intestinal movemei
of pancreas, i_7
hi' salivary glandi

of stomach cement

Nervous diabeti

in man, 67
Nervoi m :

autonomic, 877

bulbar fibers, 88

functions •

sacral fibei

thoradcolumbar fib - 88
effe • ection at various li

anterior root, '.':•. -

just behind medulla, -

just behind post. corp. •

just in front of ant. corp. quad., -

posterior root

spinal cord, 8

evolution of, 718
influence mi excretion •■;' m ;
integration of, 78
Network, nerve, 796
neurofibrils, B00
neuropil

nil' hypothesis, of
rons, 78
•
intermedial
internuneial, s
Neutrality, regulati

notion mi i

M :
in

undetermined, urii

I

-

INDEX

tceptive, B04

I itipitl -■

reflex, -
Noeud vital,
Nonelectrolytes, 16
Nonthreshold Bubstances, 512
Normal acid, 22
Normoblasts,
Nueleas ■ 9

eic acid, 637, 689
Nuclein ferments, 90
Nuclei] ■
Nucleoside, I 3
Nucleotide,
Nystagmus, 871, B75

0

Obesity, Banting cure Eor, 571
Oleic acid, -
Olein, - ■
Opsonins, 70

us, loss of weight during .starvation,

568
perfusion of, 618
Ornithine, 616, 631
Ornithuric acid, 631
Orthopnea, 313,

llatory method of blood pressure, 130
ometer, 5, 230
Osmosis, 4

otic pressure, 4, 10
ami formation of lymph, 13
and hemolysis, 7
and plasmolysis, 8

measurement by depression of freez-
ing point, 11
in physiological mechanisms, 13
in production of urine by kidneys, 14
of transfusates, 141
Ovalbumin, as food, 577
vitellin, as food, "77
Oxidases, 82

i (Nidation of blood, 387
Oxybutyric aeid, 616, 683, 709
Oxygen :

coefficient of oxidation. 393
termination of, 562
■ Lmation in blood, 390
uirements of tissue-.
sion in alveolar air, 340, 344
-ion in arterial blood, 337
asportation by blood. 379
volume percentage in blood, 390
Oxygen insufficiency, and periodic breath-
ing, 373
effect of. on respiration, 350, 359
supply of heart, i I
add, til"."

chionian body, 249
a:

tion of, 8

1'aiii, sensation of — Cont'd
transmission in cord, 830
sense, 795
Palatability, 593
Palmitic acid, 686, 707
Pancreas :

hormone control of, 4U"
histological ehanges of, 129
oxygen requirements, 396
nervous control of, 427
sugar metabolism and, 678
Pancreatic diabetes, 678
Pancreatic digestion, 489
Pancreatic juice, 441
and fat digestion, 690
secretion of, 420, 426
Pancreatin, 490
Parasympathetic system, 882
Paroxysmal tachycardia, 269, 278
Partial dissociation, 271
Partial pressure of gases, 336
Pathways, sensory, in spinal cord, 830
Pelvic ganglionic group, 878
Pentose, 664
Pepsin, action of, 485

products of, 486
Pepsinogen, 485
Peptides, 601
Peptone, 105, 486
Perception, 861
Perfusion, of kidney, 631

of liver, 618
Perfusion fluid, of heart, 165
Perfusion of heart, 161
Periodic breathing, causes of, 372

types of, 371
Peripheral resistance, 134, 229
Peristalsis :

in esophagus, 446
in large intestine, 468
in small intestine, 465
in stomach, 453, 456
Peristaltic rush, 466, 470
Peristaltic wave, 465

Pernicious anemia, energy output in, 542
Peroxidases, 82
Ph, 27

Phagocytes, 97
Phenaeeturic acid, 710
Phenol, 501
Phenolacetic acid. 502
Phenolphthalein, 482. 525
Phenylacetic acid, 631, 710
Phenylalanine, 604
Phenyl group, 604
Phlorhizin, 664, 665
Phosphates, excretion of, 47
1'hosphate solutions for H-ion, 34
Phosphates of urine, 532
Phospholipid, 689

in bile, 498
Phrenic center, 328
Phygicochemical basis, 1

[NDEX

Physiological processes depouding on ad

sorption, I I
Pigments, absorption of, 1 1 7
Pilocarpine, action on heart, 226
Pilomotor fibers, v-

"1
Plasma, 99
Plasmolysis, B
Platelets, of blood, '.'7. L06
Plethora, 86

Plethysmograph, 209, 230, 27 .
Pleurisy, 324

Plexus of A.uerbach and Meissncr, 166, 71"
I 'neumothorax, 305
Poikilocytes, 94
Polygraph, 273
Polyneuritis, 58 i
Polynuclear cells, 96
Polypeptides, 187, 601
Polyphosphoric acid, 637
Polysaccharides, t89
Polysphygmograms, -'■'•
Portal vein, bloodflow in. 255

tdicrotic wave, pulse, 203
Postprandial hyperglycemia, 659
Postcentral convolutions, B50, B5 I
Posterior roots, 787, 836
Postsphygmic period, 150
Postural reflexes, 826
Potassium, microchemical test for, ii'l
Potassium ions, on heart, L67
Potential acidity of urine, 524
Precentral convolutions, 843, B5 I
Precipitins, 595
Predicrotic wave, pulse, 203
Prefrontal region, 85 i
Premature beats, 277
Premortal rise, 566
Presphygmic period, 1 •'•
Pressor impulse-, 238, 239, 240
Pressu

intrapleural, 30 I
effecl of, in blood pressure, 306

intrapulmonic, 299

negative, 305

osmotic, l"
Pressure pulse, 127
Principle of Willard Gibbs,
Proline, 604
Proprioceptive impulsi
rioceptors, B22
• in. 126
Proteas

Protein sparera, 571
Proteins
Proteii

a- colloids

bacterial digest ii f, 501

chemistry bf, 597

metabolism ol I 1 3

end products, 613

minimum requirement
S8

relative value irth, 'ill

• ing oul of,

Protopathic im]
Protopathic

Protothrombin, 103, 106, 111
Psychopatholog
Ptomaines, 502, 6
Ptyalin, 191, 656
Pulmonary circulation, !
Pulmona ry v< ntilation,
1'nl-

abnormal, 276

alternans, 181

bigeminus, 1-1

contour of wave, 200

length of wave,

palpable, 201

pressure, 127

pulse curves, 202

pulse waves, 189, 200, 2

rate of transmission, 198

Velocity. 'J00

venous, central, 205, 27 I

venous, peripheral, 205
I'urkinje fibers, 1M
Purine bodii Purines

Purines :

chemistry of, 529, 613, 634

endogenous, 641, l

exogenous, ,; ! 1

metabolism

in starvation,

synthesis of, 646
Putrefaction, intestinal, 501, •"
Putrescine, 629
Pyloric canal. 452
Pyloric sphincter, control of,
Pyloric vestibule, 453
Pyramidal cell lamina. -
Pyrimidine basi
Pyruvic acid, 600, ' -

B

Rami communicant)
Raj naud 's . bloodflo« in, - -

•inn deviat

tion of urine,
tions depending
ody flui
=
distant ■
epicril

rnal, 7— -

internal, 7*-

pro
pr<

!"

[NDEX

procal inhibition, 81 I
on of Btrychnine on, B19

;,1 innerval I'l"1"' vessels,

241 , 8 14
Bed blood corpuscles, origin of, 92
Reduction of bio
rred pain, v^
\. conditioned, 131
unconditioned, 131
Reflex B
after - BIO

ding of intensity, 809

versibility of c luction, 810

latent period, 809
oxygen deprivation, 813
properties of, 13, 29, 19
refractory period, 81 1
summation, 810
Reflex conduction, resistance of, 813
Reflexes:
allied, simultaneous integration of, 823
antagonistic, 824
axon, 797
Ral-inski, Sh7
conditioned, 856
cremasteric, 856
crossed extension, 804
extensor thrust, 805
fatigue of, 825
flexion, 804, 821
integration of allied, 821
interaction between, 82]
irradiation of, 826
mark-time, 806
myenteric, 796
nature of, 825
nociceptive, B25
postural, 826
unconditioned, 431, 856
Refractive index, blood, 88
Refractory period, 811
Refractrometric methods, 88
Regeneration of erythrocytes, 93
!.'• gulation of neutrality, 36

irgitation of gastric contents, lilt
Reichari Meissl value of fats, 688
Reinforcement of knee jerk, 829

1 diabetes, 661
Renal function, theorii '11

Rennin, 488

erve alkalinity, measurements of, indi-
t methods, 12, 16
measurement of, titration methods, ll
Residual air, 300, 311
liration :
abdominal, 307
beyond the lunj
during muscular exercise, 11"
in compressed air, 402
in rarefied air,
mechanics of, 299
movements of diaphragm in, 32]
iii<>\ ■ ibs in, 319

Respiration calorimeter, 536
Respiratory center, 327

afferent impulses to, 331, 332

automat icity of, 329

hormone control of, 335, 349

rellex control of, 331

sensitivity to alveolar CO.,, 357

stimulation by CO,, 352

subsidiary, 328
Respiratory changes in muscular exercise,

410
Respiratory exchange:

according to body weight, 550

and body temperature, 551

clinical method for determining, 554

in diabetes, 678

and muscular exercise, 551

and temperature of environment, 551

in tissues, 393, 397
Respiratory hormone, nature of, 349
Respiratory movements, 315
Respiratory passages, pressure of air in,

299
Respiratory quotient, 545

in diabetes, 678

influence of diet on, 547

influence of metabolism on, 549

influence of muscular activity on, 370
Respiratory tracings, 303
Respiratory valves, Pearce's, 554
Reticulated erythroblasts, 93
Reversible action of enzymes, 25
Ribs, movements of, 315
musculature of, 319
undulatory movements of, 317
Right lateral connection, heart, 185
Rigidity, decerebrate, 808
Rolandic fissure, 855
Roots, 787

anterior, 787, 835
posterior, 787, 836
Rhythmic segmentation, 464

S

Sacral outflow, 882

Salicylates, 648, 657 .

Saline injection, effect on blood pressure,

139
Saliva, control of secretion, nervous, 423
psychic, 431, 856
normal secretion, 431
Salt, dietetic value, 586 .

Salted Mood, 100
Salting of proteins, 60
Saponification, 687
Saicosine, 623
Saturation limits, 652, 654
Scratch reflex, 805, 821
Scurvy, 585

Sea anemone, nervous system of, 783
Second wind, 415
Secretory fibers, varieties of, 421

INI)

'ii|

• ii, 125

chemical nature of, 126
mechanism of action i

under various glan
general considerations, lis
mental distribution of nen
mentation movements, 163
mented invertebrates, net i
-
Semicircular canal

eye movements and, -
removal of, *7 I
Semilunar valves, 150, L55
Semipermeable membrane, I
Sense, temperature, 791
touch, 783
pain, 795
Sensory centers, B50, v"i
Serine, I

Scrum albumin, 87
Serum globulin, 87
Sex, effect « ■ • j creatinine excretion, 624

effeel mi energy oul put, 5 1 1
sham feeding, 435
Shell shock. 287
shock. 287

anesthetic, 288

blood pressure in, 290

experimental investigations, 289

gravity, 287

hemorrhagic, 288

nervous, S -

recovery from, B05

secondary Bymptoms of, 295

m.mI. 288, B03
surgical, 2J

treatment of, 295

vasomotor control in,
Sinoauricular node, 185, 266
Sinus arrhythmia, 266, 277
sinus bradycardia, 266, 277
Skatole, 501, 632

in urine, ."..",1
skeletal muscle, respiration in, 394
skin, receptors

Sodium ions, 166
Solution of
Solution

- laws and, ■'•

gram molecular, 5, 2"

hypertonic, hypotonii

nature of,

usen method for
groups,
trdiac, 1
ording of,
Specific conductivity, 17
Specific dynamic actioi

ific grai ity of urine.
Sphingonn elin,
Sphygmic period, i
Spin iph, In:

and isotonii

amino

ial animal,

I :

ablation oi -

in 1.

in mai
hemisection

-

Spinal path.

Spinal -ho. I -
Spire

Splanchnic circulation in
Splanchnic I

Stalagmomi I

iar.l of neutrality.

31 ■ adard solutions
Stannius ' ligature,

Starvation,
acidosis <lurii g

of death, 57
effeel of creatinine
energy output during
excretion of nitrogen,
loss of weigl •
nitrogenous me(
purines during

' g ~tric jt;

sations dm

iphur ilurii i_
treatment of diabeti
31 ' istical method, in

iric acid, 687
31 -v' - \ I
macfa :
arrangemei I od in,
digestion in, >sl

effect Of

rate of, I -
iii. #62

miniature,

movemi

■
•■-,1 cell,
SI imuhr, i '
Strychnine,

-

Subcostal ai %

Subdural -
Submicn

S

INDKX

Sulphates, ethereal, 632
Sulphates, of urine, 532
Sulphur, excrel ion of, <>l I

in starvation, 569
Summation in reflexes, si"

i rior la rj ngeal uerve, Influence on
piration, 334
Supplemental air, 300
Surface area, and energy output, 540
Surface tension, measurement of, 64
Surgical shock, 289
Survival period, 580
Suspensions, 51

'his, colloids, 60
Swallow ing, i 15
center, 1 17

"l" li<|iii.l I' 1, I is

nervous control of, 1 17

inds produced by, I 19
\ ray < i 1 1 r i 1 1 ur . 1 19
■ glands, S80
Sympathetic control <<f heart, 227

afferent, 223
Sympathetic nerve, 124
Sympathetic system, 878, 880
Synapsis, 784, 7:'7, 819
Synaptic fatigue, 296
Synaptic membrane, 798
Syntonin, 186

ilic index, 128
tolic pr< 1l'7

measurement of, in man, 128

Tain- dorsalis, 286
Tachycardia, paroxysmal, l.'<;;i
Tactile impulses, B33

transmission in cord, 833
Taurine, 494

irocholic ai id, 19 I
Tem] eral lire:
after effect, 792
effect on metabolism, 551
-.it ion «,f, 792, 832
transmission in cord, 832
porary association,
'I', ii. Ion jei

of CO in venous blood, 342
of . n alveolar air, 16, 339

•-mar],, 171

inua toxin, action on reciprocal inhi-
bition, -in
Theine, 635
■ obromini

meter, 7!'l
Thoracic operculum, 316

racicolumbar outflow, -
Thrombin, 102
Thrombogen, I
Thrombokii

omboplastin, 106, 1 ! 1
Thrombosis, 107

Thrombus format ion, 1 1 ::
Tii \ in i.- acid, 6 1!<
Thymine, 637
Tidal air, 300
Tissot method, 54 1, 556
Tissue fluid, lit;
Tissue juice, 117
Tissues :

amino acids in, 607

influence of, on clotting, 104

oxygen requirements of, 39.'5, '.VM

utilization of glucose by, 681
Titrable acidity and alkalinity, 22
Tonometer, 338, 381
Tonus rhythm, of stomach, 471
Torcular herophili, 250
Touch, discrimination, 701

localization, 37, 795

sense, 793
Toxins, 69

Transfusion of blood, 135, 139
Trephining, 253
Treppe, 178
Trichlorlactamide, 635
Trimethylamine, 629
True colloidal solutions, 51
Trypsin, 426, 428, 601

action of, 489
Trypsinogen, 426, 428
Tryptophane, 592, 596, 604, 632

and growth, 576, 578
Tubules, uriniferous, function of, 517
Tumors and diet, 582
Turbidity of colloids, 51
Turck's method, 115, 842
Tv in la 11 phenomenon, colloids, 51
Tyrodes solution, 108
Tyrosine, 502, 604, 632, 666
Tryptic digestion, products of, 490

Ultramicroseope, 800
Uncompensated acidosis, 39
Unconditioned reflex, 431, 856
Undetermined nitrogen, 613, <;l!0
Undulatory movement of ribs, 317
Urea, 527, 608
in blood, 610

during disease, 651
excretion of, 615
Urease, 82, 610
Uric acid, 529, 531, 614, 618

amount of, 522

liases of, 531

chemical nature of, 63 1

endogenous excretion, 647

in disease, 651

metabolism of, 64,'{

of blood, 648

synthesis of, (I I I

under drugs, 648

Uric acid diathesis, 63 I

INI)

Uricaso, G40
Uricemia, ,:
Oncolytic i n«i.x, 641

l'i in.- :

acids of, 531

amino acid, 5

aromatic oxyacids of,

chlorides of, ■"> ■'■ l

composition, 521

creatinine "t", 529

depression of freezing poinl •

bippuric acid,

homogentisic acid, 531

inorganic constituents of, 531

nitrogenous constituents of,

normal organic suit- of, 523

phosphate

physical processes involved in produc-
tion of, I i

purine bodies of, 529

rate of excretion, 643
iction of, 524

sk.-ituli', 531

— * ► 1 1 « I consi i 1 1 1 . in - of, 525

specific gravity of, 522

Bulphates of, 532

total potenl i.-il acidity of, 52 t

urea of, 527
Uriniferous tubule,
Urobilinogen, 496
Utilization limit, 653

B78
control of heart, 21 7
impulses, afferent, 222
jus center, effecl of nicotine on, 226
location of, 222
tonicity of, 221

is nerve, influence on respiration, 332
Valine, 604, 606

Valves, cardiac, mechanism of, 154
auriculoT entricular, L5 i
semilunar, 155
\':in Blyke method for acidosis, 12, tt
Van Blyke method for amino groups,
Vascular reflex, 283
Varicose veins, -I t

Vasoi b1 i i « - 1 ion, --'.>

constrictor fibers, 229
methods of detecting, 229
of extremities,
of head, 2
>.t* viscera, 2

"ri^'in of,
dilator till.

methods for detecting, .
origin
Vasodilator nen
\ .- 1 ^ . > 1 1 1 < • t < > r center :
aff< renl impu
chief center, 2
effecl of II Ion of blood on,

bormo

Vasomotor I
■
impul

Velocity, mean lineal, i
puk

■
■
Ven<

•
Venous ^i n
Ventilation of lung
Ventricli ■•• in,

Ventricles :

induct ivity I
fibrillation, 195

i of l»:it in. 192, i
Vignin,
Viscera, blood Bupply <.t", •_' )7

nil 1.1 Iflow, 212

Visceral Bensil ii

Viscosity "t" blood, 1 10

Visual center, Bal

Visual psychic

Visual sensory ai i a, 85 l

Vital activity, 1 i

Vital capacity, 13

in • 314

Vital theory of urine
Vitamit

Vivi diffusion, 6
Volition, 78
Vomiting, tl'.»

W

Water content <•( blood, -
Water hammer,

in blood ;
Wheatstone bridge, Is
Whit entic lu

- manometer, '
Willard (iil.l.s, principli
\\'..r.l blindness -
\V..t .1 .cut.

! .!.•:! t*i

X

Xanthim
Xanthim
Xanl

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