Aberdeen University
Studies : No. 102
Physiological Studies
(Second Series)
University of Aberdeen.
UNIVERSITY STUDIES.
General Editor : The University Librarian.
1900-1913. Nos. 1-63.
1914. No. 64. — Zoological Studies. Professor Thomson and others. Ser. VIII.
„ No. 65— Highland Host 0/ 1678. J. R. Elder, D.Litt.
„ No. 66. — Concise Bibliography 0/ Aberdeen, Banff, and Kincardine. J. F. Kellas Johnstone.
„ No. 67. — Bishop Burnet as Educationist. John Clarke, M.A.
1915. No. 68. — Territorial Soldiering in N.E. Scotland. J. M. Bulloch, M.A.
„ No. 69. — Proceedings of the Anatomical and Anthropological Society, 1908-14.
„ No. 70. — Zoological Studies, Professor Thomson and others. Ser. IX.
,, No. 71. — Aberdeen University Library Bulletin. Vol.11.
-1916. No. 72. — Physiological Studies. Professor MacWilliam, F.R.S., and others. Ser. I.
1917. No. 73. — Concise Bibliography of Inverness-shire. P.J.Anderson.
„ No. 74. — The Idea of God. Professor Pringle-Pattison. (Gifford Lectures, 1912-13.)
„ No. 75. — Interamna Borealis. W. Keith Leask, M.A.
„ No. 76. — Roll of Medical Service of British Army. Col. W. Johnston, C.B., LL.D.
191 8. No. 77. — A bercleen University Library Bulletin. Vol.111.
„ No. 78. — Moral Values and the Idea of God. W. R. Sorley, Litt.D. (Gifford Lect., 191415.)
1919. No. 79. — God and Personality. C. C. J. Webb, M.A. (Gifford Lect., 1918.)
1920. No. 80. — Divine Personality and Human Life. C. C. J. Webb. (Gifford Lect., 1919.)
No. 8i. — Bulletins of College of A gricidture. Nos. 15-27.
1921. No. 82. — Suitject Catalogue of Cruickshank Science Library.
„ No. 83. — Physical Geology of the Don Basin. Alexander Bremner, D.Sc.
„ No. 84. — Roll of Service, ign-ig. M. D. AUardyce.
„ No. 85. — Catalogue of Taylor Collection.
1922. No. 80. — Aberdeen University Library Bulletin. Vol. IV.
„ No. 87. — Records of Banffshire. James Grant, LL.B.
1923. No. 88. — Viri Illustres Universitatum Abredonensium. W. E. McCulIoch, M.B.
„ No. 89. — Domain of Natural Scietice. E. W. Hobson, F.R.S. (Gifford Lect., 1921-22.)
,, No. 90. — Studies in Parasitology, John Rennie, D.Sc, and others.
, No. gi.— James W. H. Trail — a Memorial Volume.
J924. No. 92. — Agricultural Studies. Professor Hendrick and others.
„ No. g^.—Bpistolare inusum Eccl. Cath. Aberd. Bruce M'Ewen, D.Phil.
„ No. 94. — Bibliography of the Gordons. J. M. Bulloch, LL.D.
,, No. 95. — Alba Amxcorum. J. F. Kellas Johnstone, LL.D.
1925. No. 96. — Botanical Studies. Macgregor Skene, D.Sc, and others,
,, No. 97. — Aberdeen University Library Btdletin. Vol. V.
,, No. 98. — List of Incunabula in Library.
„ No. 99. — Records of Inverness. Vol. II. W. Mackay. LL.D., and G. S. Laing.
„ No. 100. — Traditional Ballads. Gavin Greig, M.A., and Alexander Keith, M.A.
1926. No. loi. — Reconstructioft of Texts of the Gospels used by Saint Augustine. C. H. Milne, M.A.
„ No. 102.— Physiological Studies. Professor MacWilliam, F.R.S. , and others. Ser. II.
Physiological Studies
(Second Series)
By
J. A. MacWilliam, M.D., F.R.S.
Professor of Physiology
Edward S. Edie, M.A., B.Sc.
Robert H. A. Plimmer, D.Sc.
John L. Rosedale, M.A., Ph.D.
Charles Reid, M.A., B.Sc, M.B., Ch.B.
W. J. Webster, M.B.
G. Matthew Fyfe, M.B., Ch.B.
Printed for the University of Aberdeen
1926
<
CONTENTS.
PAQBS
The Mechanism and Control of Fibrillation in the Mammalian Heart. By
Professor MacWilliam 1-22
The Effect of Alcohol on the Digestion of Fibrin and Caseinogen by
Trypsin. By Mr. Bdie 23-29
Further Observations on the Digestion op Fibrin and Caseinogen by
Trypsin. By Mr. Edie 32-40
A Note on the Question of the Identity op Gastric Eennin and Pepsin.
By Mr. Edie 41-43
Distribution of Enzymes in the Alimentary Canal of the Chicken. By Dr.
Plimmer and Dr. Rosedale 36 [46J-38 [48]
The Animo-acids op Flesh. By Dr. Rosedale 39 [49J-42 [52]
Abnormal Left Coronary Artery op Ox Heart. By Mr. Reid - - - 54-69
Some Applications of Physiology to Medicine — I. By Professor MacWilliam
and Mr. Webster 61-66
A Method of Estimation of Diastase in Blood. By Mr. Fyfe ... 67-71
Some Applications of Physiology to Medicine — II. By Professor MacWilliam 73-97
Some Applications of Physiology to Medicine — III. By Professor MacWilliam 99-109
Blood Pressures in Man under Normal and Pathological Conditions. By
Professor MacWilliam - - - 303 [111]- 335 [143]
DiASTATic Activity in Blood and Urine. By Mr. Reid 145-157
The Effect on Renal Efficiency of Lowering the Blood-pressure in Cases
op High Blood-pressure. By Mr. Reid 159-178
N
-^
[Frmn the Proceedings op the Royal Society, B. Vol. 90] '
The Mechanism and Control of Fibrillation in the Mammalian
Heart.
By Professor J. A. MaoWiluam, F.E.S.
(Received June 6, 1918.)
The results of the present investigation are founded on a very extended
study of the subject, carried on from time to time during the past 30 years,
in the course of very numerous experiments (hundreds) on the mammalian
heart.
These results establish the conclusion that in fibrillation there is an
essential change in the manner of conduction of the excitation process in the
cardiac musculature; the relation of this change to the excitability of the
muscle determines the appearance and characters of the different forms of
" fibrillar " action that may be observed. The conduction of the excitation is
essentially altered, inasmuch as it is propagated along the muscular fibre
systems or fasciculi, instead of travelling directly through the muscular
substance, without obvious regard to the arrangement of the fibres, as in the
normal beat of the heart.* Fascicular dissociation is an essential feature of
fibrillation, which is, strictly speaking, a condition of " fasciculation " rather
than " fibrillation." The essential change in conduction may be induced in
very different ways. The state of fibrillation is rendered persistent by a
disturbance in the normal relations of conduction time and refractory period
in the cardiac musculature, resulting in the establishment of a mechanism of
circulating excitations.
The cat's heart was the one most largely investigated, but those of rabbits,
guinea-pigs, rats, etc., were also employed. The heart action was usually
examined and recorded with the thorax open, while artificial respiration, by
means of a pump or by continuous insufflation of the lungs with oxygen, was
maintained. A myocardiograph of the type described by Cushnyf was
employed, arterial blood pressure or pulse being often registered at the same
time. Intra-cardiac pressure records were often made from the auricles and
the ventricles on the principles described by Frank. Anaesthesia was main-
tained by chloroform, ether, urethane, morphia, chloretone, paraldehyde, or
combinations of these. In a number of experiments the method of decapita-
tion was used. The perfused heart was frequently utilised, records being
* See the electrocardiographic evidence advanced by Lewis and Kothschild, 'Phil.
Trans.,' vol. 206, p. 181 (1915).
t 'Heart,' vol. 2, p. 1 (1910-11). ^^
( 302r ) *
2 Professor J. A. Mac William.
made by {a) the myocardiograph, used in the same way as with the heart
in situ, and (h) by a rubber bag placed in the left ventricle and connected
with a Hiirthle manometer, the system being filled with liquid. All the
tracings are to be read from left to right ; they are all ventricular (L.V.
of cat) records except where otherwise noted.* The time is shown in seconds.
For the more accurate use of faradic currents, a Kronecker's inductorium
was employed, with two volts in the primary circuit ; the values of the
units stated are to be taken as obtained with this E.M.F. in each case. For
obtaining series of shocks at different rates, a Brodie cut-out arrangement
was used, giving either make or break shocks at regular intervals ; these
shocks were recorded on the tracings by an electrical signal. The shocks
were often applied through the myocardiograph, so that they traversed a
considerable amount of the cardiac substance ; at other times they were sent
through electrodes about 1 mm. apart, etc.
The Conduction of the Excitation in Fibrillation.
Instead of travelling uniformly right through the mass of muscle without
evident regard to the direction of the fasciculi or bands of muscle, as under
normal conditions, the excitation wave in fibrillation travels most easily
along the complexly-arranged fasciculi, there being an impairment or
failure of propagation at most of the inter-fascicular connections. Such
a mode of propagation of the rapidly-recurring contraction waves may be
clearly perceived on direct inspection of the heart, and on palpation of the
ventricles the apical portion being held between the finger and thumb with
varying degrees of light pressure. In the latter case, instead of the normal
uniform hardening of the muscular wall at systole, there is a striking want of
synchronism in the hardening of the constituent fasciculi, short contraction
waves in rapid succession hardening different sets of fibres, while others are
relaxed and soft, the contracted ones momentarily standing out and giving a
characteristic " wiry " feeling among the quiescent fasciculi ; the impression of
an incessant turmoil of dissociated or in-coordinated activity is a vivid one.
The myocardiograph record shows a series of rapid irregular oscillations,
varying to some extent from place to place in rate and in range of excursion.
Similar records are obtained from the perfused heart.
The failure of normal conduction may be induced in two ways : (1) by
depressing agencies acting directly on conductivity, and causing more or less
extensive blocking in the most susceptible parts, the inter-fascicular
junctions, while the intra-fascicular connections remain functional. This
effect may be produced even with a moderate or slow succession of
* Upward movement of the ventricular lever = systole.
( 303 ) 1
Fibrillation in the Mammalian Heart. 8
contractions, but is greatly favoured by rapidity of sequence of the contractions.
Such depressing agencies are of various kinds — cooling, intra- vascular
injection of potassium salts, bile, over-doses of many drugs, etc., including
some substances that are in suitable doses useful as remedial agents
promoting recovery from fibrillation ; (2) by excessive rapidity of excita-
tion, e.g., by electrical stimulation. This (2) may be the sole cause of the
alteration in conduction, or it may co-operate with a depressing influence
acting directly on conduction, i.e. a combination of (1) and (2) is specially
effective.
Change in Mode of Conduction due to Direct Depression.
Fibrillar Beats. — That depression of conductivity is of fundamental
importance is evidenced by the fact that individual beats may be " fibrillar "
in character (fig. 1). This is strikingly realised on palpation ; instead of the
AAAAAiVvAAA-'^
A. B.
Fig. 1. — The systolic movement of the lever is upward. A = normal beats.
B = fibrillar beats, which are strikingly wiry on palpation.
usual sensation of uniform hardening at each systole, the contraction is felt
to be passing in asynchronous fashion along the different systems of fasciculi
or bands of fibres, some feeling firm and contracted, with the characteristic
wiry feeling, while others are soft and relaxed. On the surface of the
ventricles the contraction wave is visibly slowed, and in the auricles this
may be very strikingly evident in its progress over the muscle.* In this
condition the nature of the ventricular beat is similar, whether it occurs in.
response to an impulse travelling down the A-V. conducting system, or is
excited by a direct stimulus applied to the outer surface of the ventricles.
The fascicular dissociation is evident even when the impulse is distributed
through the endings of the Purkinje system of fibres (fig. 2).
Fibrillar beats are often able to give considerable excursions of the
recording lever, and they are often able to pump out a very appreciable
amount of blood into the aorta. The contraction and relaxation phases are
* In the ventricles waves can often be plainly seen entering at or emerging from the
vortex.
( 304 ) J 3
4 Professor J. A. MacWilliam.
both prolonged ; the systolic power is relatively small. The individual beats
are quite discrete ; there is a very definite interval, varying in duration, of
A. B.
Fig. 2. — ^A shows normal curves, the upper one ventricular (systolic movement upward)
and the lower auricular (systolic movement downward). B shows two fibrillar beats
at a later phase of the experiment. Simultaneous points are marked by short
vertical lines at the first beat. The Au. and V. contract together ; the excitation
apparently originates in the A-V. junctional tissues.
complete quiescence between them (fig. 2). The excitability of the cardiac
muscle is low when such separate beats are present ; the refractory period is
long. The occurrence of these fibrillar beats shows that the " fibrillar "
mode of contraction is not essentially dependent on or necessarily associated
with rapidity of succession at all, though the latter is a very striking
feature of typical " fibrillation," giving complexity of movement, complete
in-coordination, and mechanical ineffectiveness as regards expulsive power.
Continuous Series of Mbrillar Beats as seen in a More Excitable Heart.
When the excitability is at a higher level, or when stimulation is applied
to make the fibrillar beats follow one another more quickly, a continuous
succession of contraction waves appears ; one fibrillar beat excites another,
and they are thus strung in a series, constituting a slow coarse fibrillation
(fig. 3). The rate depends on the excitability of the muscle, the degree of
Fig. 3. — Continuous irregular series of fibrillar beats, each beat exciting a subsequent
one through the mechanism of circulating excitation. An overdose (intra- vascular)
of sodium carbonate induced this condition.
( 305 )
Fibrillation in the Mammalian Heart. '6
dissociation varies with the rate of succession — the faster the rate the
higher the grade of dissociation. In some cases the depression of conduction
may be of such a degree that a beat coming after a long interval may show
no distinct sign of dissociation by inspection or palpation, whereas, when a
quick series occurs, each beat is markedly dissociated, giving the charac-
teristic " wiry " feeling on palpation (fig. 4). When the excitability of such a
Fig. 4, — The quick series of beats are fibrillar in character. The larger beats coming
after long intervals do not show evidence (on palpation) of that character.
heart gradually rises, e.g., under the influence of massage, improved nutrition,
certain remedial drugs, removal of depressing influences, etc., the rate of
continuous movement may increase, with an accompanying increase in the
.grade of dissociation.
There is a very definite gradation from {a) the phase of discrete fibrillar
beats, through (&) slow and then quicker series of successive contraction waves,
up to (c) the rapid and mechanically ineffective oscillations of typical fibrilla-
tion. The increase in rate depends on the augmented responsiveness of the
more excitable muscle. The degree of asynchronism or dissociation increases
with the rise in the rate of succession, the partial blocking between the larger
fasciculi or bands and layers of fibres giving the lower grade of dissociation
seen in slow coarse fibrillation, while the higher grades of dissociation
between fasciculi are present in the condition of rapid fine fibrillation.
Similarly with diminishing excitability and conductivity, a downward
gradation may be observed from typical fibrillation, through grades of slower
and coarser fibrillation, to the phase of individual fibrillar beats.
ChaTige in Mode of Conduction Due to Excessive Rapidity of Excitation.
When the rate of beat is excessively accelerated by a series of induction
shocks of increasing rapidity, a gradation of changes is observable as the rate
of succession rises. The individual contractions become briefer and gradually
give smaller and smaller excursions of the recording lever. Inspection shows
evidence of dissociation becoming very pronounced at the higher rates, so as
to bear a close resemblance to the familiar appearance of the ventricular
surface in typical fibrillation. Palpation at the same time reveals increasing
degrees of asynchronism as the rate rises, until the characteristic wiry
( 306 )
6 I*rofessor J. A. Mac William.
wriggling feeling, practically indistinguishable from that of true fibrillation,
becomes very marked, instead of the solid push normally given to the
palpating finger. These phenomena are obviously due to the rapid series of
short contraction waves traversing, at relatively slowed rates, the various
layers, bands or fasciculi of the ventricular musculature according to the lower
or higher grades of inter-fascicular blocking and dissociation that are present,
thus giving asynchronous contractions at different parts of the thickness of
the muscular walls. These changes in their various grades are attended by
related degrees of lowering of the arterial pressure, and by auricular accelera-
tion and irregularity. At high rates the force and range of the contractions
become small, the output from the ventricles is cut down and a great fall of
arterial pressure results.
When the rapidly stimulated ventricles have been brought into the condition
above described — presenting many features of resemblance to true fibrillation
but not identical in n^chanism as will be explained later — diminishing rates
of excitation are attended by graded changes of converse order — slower
succession of contractions, less dissociation, quicker conduction, apparent
coarsening of the oscillations and a gradual return, as the rate falls, to the
characters of normal beats.
Pseudo-fihrillation and Fibrillation.
The above-described condition into which the ventricles may be brought by
rapidity of excitation (graduated series of shocks or faradic currents of suitable
strength) short of the rate necessary to induce true fibrillation, may for
convenience be termed pseudo-fibrillation (figs. 5 and 6). As regards the
evidence afforded by inspection, palpation, tracings of the oscillations, fall of
blood-pressure, etc., the two conditions may be difficult or impossible of
distinction, but they differ strikingly as regards persistence ; pseudo-fibrilla-
tion ceases immediately or at varying short periods after the cessation of the
stimulation, while true fibrillation in ordinary circumstances, in the absence of
remedial measures, goes on as a rule to the death of the heart. (The duration of '
pseudo-fibrillation after cessation of the stimulation varies according to the
excitability of the stimulated area, the strength and duration of the stimulating
current, etc.) The difference depends on the fact that in true fibrillation a
mechanism of circulating excitation has been established, whereas in pseudo-
fibrillation this is not so. The latter condition depends on the emanation of
an excessively rapid series of excitation waves from the area of stimulation ;«
these short waves travelling at reduced speed over the interlaced fasciculi give
rise to the condition described. But as soon as the issue of excitations from the
stimulated area ceases, the disturbance ceases 'and the conditions revert to the
( 307 )
Pihrillation in the Mammalian tteart, 7
normal. The pseudo-fibrillation at once ceases when the stimulated area is
disconnected from the rest of the muscle, e.g., by forcible clamping, etc., or
Fig. 5. — Rabbit's heart (R.V.). Faradisation with 800 units induced first a rapid
tachycardia, then pseudo-fibrillation which promptly stops at the end of the
faradisation. A blood-pressure record taken at the same time showed a great fall,
with minute oscillations showing on the tracing.
Fig. 6. — Pseudo-fibrillation induced almost immediately in fully developed form by
faradisation ; it ends with a larger oscillation when the stimulation ceases.
when it is cut off — as may be done in the perfused heart — or when it is
rapidly cooled. In pseudo-fibrillation there has not been established in the
mass of the muscle outside the stimulated region a mechanism which ensures
the continuance of the movement after the impulses emanating from the
excited area have ceased or have been excluded — in striking contrast to what
holds good in the case of true fibrillation. This method of differentiating
between pseudo-fibrillation and fibrillation may be more easily applied in the
case of the auricles, by isolation of the appendix after the stimulation has
been applied to the tip.
Mode of Becovery from Fibrillation.
When the ventricles are recovering from the state of typical fibrillation,
with the aid of massage and of drugs, as stated later, the oscillations visible
( 308 )
8 Professor J. A. MacWiiliam.
on the surface become more vigorous and clearly much coarser, the dissociation
becoming much less fine and larger groups of fasciculi contracting together ;
there is evidently an extension of conduction through inter-fascicular junctions
that were formerly blocked. On palpation the muscular substance feels of
good tone, and the gradation from fineness to coarseness of fibrillation is very
clearly realised — the sensation of universal turmoil due to the fine rapid
dissociated twitchings throughout the ventricular walls grading into more
vigorous contraction waves of coarser type, and these again into beats giving
the normal feeling of uniform hardening of the muscle (figs. 7 and 8).
A.
B.
Fio. 7. — Spontaneous recovery from fibrillation in:30 seconds, preceded by coarsening of
the fibrillar movement. Urethane, 2'5 grm., had been given hypodermically, in
addition to chloroform. In A, the fibrillation was caused by shocks sent into the
ventricle at the rate of 480 per minute. A brief tachycardia precedes the fibrilla-
tion. In B, recovery is seen, preceded by slower and coarser oscillations.
( 309 )
Pihritlation in the Mammalian Heart, 9
In the case of a heart which is showing individual fibrillar beats of the
nature already described the process of recovery under the influence of
A.
B.
Fia, 8. — K.V. recorded. Fibrillation from application of faradic current (200 units).
A is taken 7 seconds after beginning of fibrillation. B shows recovery occurring
after fibrillation had lasted 75 seconds, massage being done at intervals. Adrenaline,
0'27 mgrm., had been injected previously, and this i probably favoured recovery.
Marked coarsening of the movement (followed by a long pause) is seen prior to
recovery. •
massage, removal of depressing influences, etc., is usually a more elaborate one.
The phase of slow coarse fibrillation has to be passed through, with a gradual
increase in the rate and the grade of dissociation as excitability is restored ;
this leads up to the condition of rapid fine fibrillation — from which recovery
occurs in the fashion stated above. But treatment with certain doses of
adrenaline, etc., may sometimes change the fibrillar beats into co-ordinated
ones without a transition through the various phases just enumerated (fig. 9).
A. B.
Fig. 9. — A shows slow coarse fibrillation — a series of irregular fibrillar beats. B is
taken shortly after the injection of 0*2 mgrm. adrfenalin into the L.V. (1 in 5000
solution used). The fibrillar beats are changed into normal ones.
( 310 ) .
10 Professor J. A. MacWilliam.
The coarsening of the rapid oscillation in the process of recovery is quite
different from a coarse slow movement that is not on the way to recovery at
all and where the muscle is lax and feeble. It is also different from the
apparent coarsening with slowing of the oscillations in the graphic record due,
as direct inspection of the heart shows, to irregular summation of fine feeble
twitchings which are present with a high degree of dissociation and which
may gradually become weakened to extinction. It is important to correlate
the information derived from {a) inspection, {h) palpation, and (c) graphic
records.
Bates of Stimulation Necessary to Establish the Mechanism of Circulating
Excitations.
"With excitable ventricles in good condition high rates of excitation by
induction shocks of moderate strength are necessary to overpass the phase of
pseudo-fibrillation and induce true fibrillation, e.g., single induction shocks at
rates of 450-500 per minute are commonly effective, but the duration of the
application of the series of shocks has an influence in this respect ; with longer
application lower rates may suffice. When faradic currents are employed the
current has to be of such a strength and duration as to raise the rate of
responsive contractions to about the above rates. Beyond such rates the
state of pseudo-fibrillation is not as a rule maintained, but gives place to true
fibrillation as soon as the mechanism of circulating excitation has been
established, this point being often recognisable on the tracing by a change
from the rapid and more or less irregular curves of small excursion that are
present during rapid tachycardia or pseudo-fibrillation to the much smaller
and entirely irregular oscillations of true fibrillation (fig. 11).
The conductivity of the muscle plays an essential part in regard to the
rate of stimulation needed to cause fibrillation ; the necessary rate is not a
constant or absolute one, but varies much in relation to the state of the
conductivity at the time. The lower the conducting power, the lower is the
rate of stimulation required to establish the circulating mechanism, since
under these conditions the normal relations between conduction time and
refractory period are more readily upset, a relatively low grade of acceleration
sufficing to cause slowed excitation waves to reach different parts of the
fascicular systems after the refractory period is over in these situations.
Agents that depress conduction, e.g., potassium salts, bile, cooling, etc., can be
used in such a way and to such a degree as not to induce fibrillation by
themselves, but to render the muscle prone to fibrillate with unusually low
rates of excitation. Thus the minimal rate of stimulation which induces
true fibrillation affords an indication of the state of conductivity. In
( 311 )
Fibrillation in the Mammalian Heart. 11
conditions of greatly depressed conduction power stimuli not faster than
rates commonly seen when the heart is beating in co-ordinated fashion may
cause fibrillation. The rate of oscillation when fibrillation is established in
such hearts is naturally a slow one, as the excitability is commonly reduced
as well as the conductivity.
In such conditions of depressed ventricular conductivity, it is sometimes,
though rarely, possible to excite ventricular fibrillation by faradisation of the
auricles or of the sino-auricular junction in the region of the S.A. node.
Such a result has been quite definitely obtained in a very few cases. The
A-V. conducting mechanism was apparently able to transmit a series of
impulses to the ventricles sufiicient to excite in the latter the relatively low
degree of acceleration necessary, in presence of their lowered conductivity, to
establish the circulating mechanism.
Rates of Oscillatwi in Fibrillation.
As has been stated, the rates of oscillation are usually high when fibrillation
is induced, and they remain high for some time ; if massage is employed,
quick oscillation may be maintained for an hour or more. But when, in the
absence of massage, etc., the excitability of the muscle becomes lowered, as
happens even with massage after a variable time under the usual experi-
mental conditions — the rate of oscillation falls markedly, the less excitable
muscle being unable to give such rapid responses to the circulating excita-
tions. And in conditions where the excitability is depressed when fibrillation
is induced, the rate of oscillation is, from the beginning, very much slower
than usual; such rates as about 280, 250, 240, 140, etc., being seen, i.e.
rates sometimes below the rhythm of a normally-beating heart when acting
rapidly. It must be noted that the graphic records of the oscillations have
to be interpreted with caution. For the oscillations caused by contractipn
waves coursing along the interlaced fasciculi are very complex and irregular
and do not denote the succession of contractions in any one fasciculus.
Still, the rates observed are, within certain limits, quite definite anH
significant, though on account of the irregularity precise figures may not be
obtainable. Such records must be controlled by the methods of inspection
and palpation, and, as a rule, yield results that are in accordance with the
evidence afforded by the latter methods.
Influence of Duration of Stimulation.
When electrical stimulation, e.g., faradisation, is used to excite fibrillation,
its efficiency shows a marked relation to the duration of its application, as
well as to the strength of the current ; a longer application, e.g., 10 seconds,
( 312 )
l2 t*rofessor J. A, Mac William.
may elicit persistent fibrillation when a shorter one, e.g., 3 seconds, only
causes a rapid tachycardia or pseudo-fibrillation. The greater effect of the
more prolonged application may be ascribed to at least two factors : —
1. The time needed for the current to produce its full effect in the way of
acceleration of the succession of contractions. With suitable strengths of
current, the tracings clearly show an increasing acceleration for some little
time after the beginning of the application, the excursions become more
rapid and smaller until, when the circulating mechanism is established,
fibrillation supervenes with its very irregular oscillations. With strong
currents the characters of fibrillation may become manifest in the tracing
immediately or almost immediately. It is evident that, with relatively
weak currents, some time is needed to get up the full rate, with its
influence in promoting fibrillation by shortening the refractory period and
slowing and impairing the propagation of the excitations.
2. A continuance for some time of the rapid succession of contractions may
be assumed to promote fatigue in the more vulnerable parts of the inter-
fascicular connections (in analogy to what is known of fatigue of the
A-V. conducting mechanism) by an unduly early repetition of an impulse to
be conducted. Continuance of the stimulating current after the circulating
mechanism has been established seems to be of no importance.
Parallelism between Auricles and Ventricles.
There are close analogies between the behaviour of the auricular and the
ventricular muscular systems as regards (1) the occurrence of single con-
traction waves passing slowly through the muscle, constituting fibrillar beats
in the ventricles, and (2) the development of (a) regular tachycardias,
(b) irregular tachycardias, (c) pseudo-fibrillation, and (d) fibrillation, as
results of graduated artificial stimulation.
The persistence or non-persistence of fibrillar movements is clearly
explicable on the same principles in both auricles and ventricles — by the
altered relation between conduction and refractory period — and the mode of
conduction in fibrillation is, as in the ventricles, a fascicular one, depending
on the presence of more or less extensive blocking in the inter-fascicular
connections. Slow coarse fibrillation may be seen in the auricles as in the
ventricles, and separate waves of contraction sweeping over the auricles in
irregular fashion, more or less resembling what have been described as
fibrillar beats in the ventricles, are often very striking in conditions of
depressed conductivity; the progress of the greatly slowed wave can be
followed by the eye with the greatest ease. And, with some increase of
excitability, the wave of excitation may excite another, just as in the
( 313 )
Fibrillation in the Mammalian Heart. 13
ventricles, and so set up a continuous slow series — slow here also because of
obviously depressed excitability, as shown by diminished readiness to respond
to stimuli of definite strengths.
Pseudo-Fibrillation and Fibrillation in the Auricles.
Under gradually increasing electrical stimulation, the auricles, like the
ventricles, show higher and higher grades of disturbance : (1) extra-systoles,
(2) regular tachycardia, (3) irregular tachycardia, (4) pseudo-fibrillation, and,
at least in certain conditions of the auricular muscle, (5) fibrillation. The
gradually increasing rate of auricular response rises through the grades of
tachycardia or flutter, with diminishing range of lever excursions, up to a
condition of rapid tremulous movement (pseudo-fibrillation), with irregular
succession and range of oscillations more or less closely approximating to
the characters of true fibrillation and often hard to distinguish with
certainty from the latter, either by inspection of the auricles or in the
tracings, though in pseudo-fibrillation the oscillations are commonly larger
and of a less high grade of irregularity than in fibrillation. The movement
may last for variable periods after the stimulation has been discontinued.
A ready method of discriminating between the two conditions is afforded
by the experiment of isolating the stimulated area (by clamping, etc.).
Tachycardia or pseudo-fibrillation is at once arrested, while true fibrillation is
not affected.
In the majority of the animals examined special conditions are necessary
in the auricular muscle for the production of true fibrillation with its essential
mechanism by faradisation, etc., the stimulation per se is not, as a rule,
sufficient in the easier conditions of quick conduction normally present in the
auricles. Contractions in very rapid sequence, e.g., 500-600 or more per
minute, may be excited without establishing the mechanism of persistent
fibrillation. Certain conditions involving an alteration of conductivity
without a great lowering of excitability, are often effective in determining the
occurrence of fibrillation, e.g., vagus influence, defective blood supply, certain
phases in the action of some drugs, such as chloroform, paraldehyde,
pilocarpine, etc.
" Spontaneous " fibrillation, i.e. when the precise exciting cause cannot be
defined, depends no doubt on the presence of irritation plus an altered state
of conductivity. The latter is sometimes supplied, under experimental
conditions, by the tonic influence of the vagus centre exercised through either
the right or the left vagus, as can be seen when only one nerve is intact ;
section of the nerve in such cases is speedily followed by recovery from
fibrillation which may have persisted during the whole preceding part of the
( 314 ,)
14 Professor J. A. Mac William.
experiment, or at least since the heart was exposed. Such vagus control has
not appeared as a common cause of auricular fibrillation in these experiments,
but in some instances its influence has been unmistakable.
The simplest and most easily available method of producing true auricular
fibrillation for a time is by a combination of electrical stimulation and vagus
stimulation. Eapid tachycardia set up by electrical stimulation is converted
by vagus influence into true fibrillation which persists as long as the vacuus
influence is maintained in sufficient strength to provide the condition in the
auricular musculature necessary for the keeping up of circulating excitation ;
the fibrillation so excited goes on under vagus influence long after the
electrical stimulation has been discontinued ; the latter may indeed have been
applied only for a second or two. Under vagus influence the fibrillation
oscillations, though very rapid, become greatly weakened, the irregular
movements of the recording lever becoming minute. With pretty strong
vagus control this weakening may go on to invisibility, so that the auricles
look entirely quiescent, even when their surface is scrutinised with a lens.
As the vagus influence wears off during prolonged stimulation of the nerve,
very fine fibrillation oscillations again begin to become perceptible, and these
gradually gaiiT in vigour and range until after a variable time the normal
type of beat replaces the fibrillation movement.
A similar sequence of events, more quickly passed through, is evident when
vagus stimulation is diminished or discontinued instead of the influence of
the nerve being allowed to wear off during continued stimulation. What
evidently occurs in these cases when the auricles become motionless under
vagus influence, is that the mechanism of circulating excitation goes on
working in spite of the inhibitory influence which cuts down the mechanical
response to invisibility ; there is no true inhibition of the essential mechanism
of fibrillation.
The experiment may be done in another way. Instead of first exciting the
tachycardia and then stimulating the vagus, the latter may be brought into
action first so as to reduce the auricles to complete quiescence ; during this
period an electrical current is applied briefly {e.g., for one or two seconds) to
the auricle ; a fine tremulous (fibrillation) movement of small range may at once
appear and continue until the vagus influence wanes or is discontinued.
Mechanism of Circulating JSxcitations without Contractions.
But if the vagus is strongly inhibiting the muscle when the electrical
current is briefly applied, there may be no visible effect at all ; the auricles
remain perfectly motionless until the vagus control has become weakened,
when the fine tremulous movement usually appears and gradually gains in
( 315 )
Fibrillation in the Mammalian Heart. 15
vigour as in the former experiment, after a time giving place to normal
action. What has happened in this case is that the electrical stimulation,
falling within the period of vagus influence, is effective in setting up the
mechanism of circular excitation, while the latter finds no expression in con-
tractile movement on account of the mechanical response to excitation being
kept in abeyance by the vagus inhibitory power. "When the latter wanes
and the mechanical response again becomes manifest, the circulating excita-
tationS are attended by the circulating contractions of visible fibrillation.
When the electrical stimulation is applied in the foregoing way without
apparent effect on the inhibited auricles, the subsequent appearance and
development of fibrillation as described above is not affected by the stimulated
area (e.g., auricular appendix) being isolated from the rest of the auricle
shortly after the brief application of the stimulating current and while the
auricles are still kept in complete quiescence by the vagus ; the subsequent
fibrillation involves the whole of the auricular muscle, apart from the isolated
area. It is plain that the mechanism of excitation necessary for fibrillation
has been established in the mass of the auricular muscle, and that it is
independent of a continued emission . of impulses from the stimulated area —
now isolated. In these experiments the isolation was effected {a) by
clamping off or (6) by section, after a weak clip or a ligature not too tightly
drawn had been applied along the base of the appendix to prevent haemor-
rhage. In some cases rapid cooling of the stimulated area was employed
instead of isolation. Control experiments were made to determine that the
methods used do not themselves cause fibrillation in the conditions present,
under vagus influence, etc.* The vagus evidently can act more strongly on
auricular contraction force, if not also on conductivity, than on excitability,
for the latter property must remain functional (though depressed) in auricles
that respond by subsequently manifested fibrillation movements to an
electrical stimulus applied during the period of mechanical quiescence of the
muscle.
As ia rule, as stated above, the auricular muscle is not sufficiently depressed
by vagus influence to prevent excitation occurring in response to adequate
stimulation, or to stop the circulation of excitations once this mechanism has
been established, though the normally-associated mechanical response may
be cut down to the point of invisibility. But in some instances the vagus
seems to be able to act so strongly on excitability that after electrical stimu-
lation during the vagus period, fibrillation does not gradually appear in the
usual way as the vagus control is passing off, but visible action recommences
* Under certain conditions it is clear that mechanical stimulation may sometimes
excite auricular fibrillation.
( 316 )
16 Professor J. A. Mac William.
in the form of slowed auricular heats. This is to be ascribed to the vagus
acting more strongly than usual on excitability, in addition to the usual
effects on contraction force and conductivity.
"When the influence of the vagus in converting a rapid tachycardia or
flutter into fibrillation was first studied, the question naturally arose as to
whether the changes visible on inspection and in the graphic records might
not be due simply to the cutting down of the force of the rapidly-recurring
contractions, the mechanical limitation of the range of movement associated
with distension of the auricular chambers, etc. But the clamping-off experi-
ment brings out there is an essential difference in the mechanisms in the two
cases.
The vagus alters or depresses conductivity in the auricles in such a way
that the inter-fascicular connections are unable to functionate normally when
the succession of excitations is much accelerated. (Distinct from this is the
question of the power of the vagus to slow the conduction along the main
transmitting paths in the auricles.) Certain other depressant agencies have
an influence on the inter-fascicular connections in the ventricles (already
described), which resembles that of the vagus in the auricles, and these
agencies, when acting in great intensity, may have the further result of
causing obvious and striking retardation in the passage of the contraction
wave both in the ventricles and the auricles, even when the sequence is not
a rapid one, but may indeed be slower than the normal.
Some Biferences in the Behaviour of Auricles and Ventricles.
While the analogies between the various phenomena are very close in the
auricles and ventricles, certain points of difference may be noted.
1. Electrical stimulation of strength adequate to give a sufficiently excessive
rate of beat is, by itself, a ready means of exciting ventricular fibrillation,
though, as has been stated, the addition of some influence depressing con-
ductivity causes fibrillation to develop when the rate of beat is not nearly so
rapid as would otherwise be required. Auricular fibrillation, on the ' other
hand, is not, in most cases when the heart is in good condition, excited by
electrical stimulation per se, but requires an alteration of conductivity (in the
sense already defined) by some other agency, e.g., vagus influence, defective
nutrition, toxic substances, etc. The reason of this difference is probably to
be found in conduction being less easily upset in the auricles with their
simpler structure and easier conditions of rapid conduction, as compared with
the highly elaborate ventricular architecture with the much slower rate of
conduction in the ventricular muscle proper — apart from the Purkinje
system.
( 317 )
Fibrillation in the Mammalian Heart. 17
2. The relation of the vagus to fibrillation is quite different in auricles and
ventricles ; in the auricles the vagus favours fibrillation in the presence of
some irritation, e.g., electrical stimulation ; in the ventricles vagus influence
can often be clearly shown to retard or prevent fibrillation, while not able to
remove the latter once it has been established. The difference is due to the
stronger action of the vagus on conductivity than on excitability, as a rule,
in the auricles ; this naturally promotes fibrillation. In the ventricles, on
the other hand, in regard to these two properties, the main, if not the sole,
incidence of the vagus influence is on excitability ; this, of course, tends to
repress the development of fibrillation. Pilocarpine, in suitable doses, acts
similarly to the vagus, and its relation to fibrillation in auricles and ventricles
is to be explained on the same lines.
3. Some drugs and toxic substances, etc., have a different incidence on the
auricles and ventricles respectively both in regard to promoting and retarding
fibrillation.
Confirmation of Former Views.
So long ago as 1887 the writer* put forward the view that the essential
mechanism of typical fibrillation is explicable not simply as an excessive
acceleration of rate per se or on the assumption of a mechanism of a different
nature, in the sense of muscular v. nervous, from that concerned in the normal
beat, but in a disturbance in the relation between the refractory period and
the conduction time in the cardiac musculature ; that when this relation is
upset by shortening of the refractory period or lengthening of the conduction
time or a combination of such changes, the excitation wave, in spreading over
the muscular systems, reaches fibres in which the refractory period has already
ended and further excitation occurs ; the co-ordinated beat is thus abolished
and replaced by a rapid and continued series of in-coordinated fibrillar con-
tractions. The alteration in conduction — the'passage of the slowed contraction
waves in peristaltic fashion along the various complexly-arranged bundles of
the ventricular wall at different points of time was described — and also the
important fact that single beats may in certain circumstances be fibrillar in
character.
Control of Ventricular Fibrillation.
The various actions of different agencies, in promoting or retarding the
development of fibrillation and of removing it after it has been established,
are to be explained by their incidence on the functions of conduction and
excitability and the effects which they bring about in the relations of these
functions in different conditions of the cardiac muscle (as a whole) and in the
different conditions that may obtain in the auricles and ventricles respectively.
* ' Journal of Physiology,' vol. 8, p. 296 (1887).
( 318 ) c
18
Professor J. A. MacWilliam.
Any influence which depresses excitability without depressing — at least
proportionately — the function of conduction naturally tends to be in some
measure protective against the occurrence of fibrillation and favourable to
recovery from that condition when once it has been estabhshed. A diminution
of excitability opposes the attainment of acceleration sufficient to determine
fibrillation ; it also diminishes the responsiveness of the muscular fasciculi to
circulating excitations. (The control of auricular fibrillation which differs in
some respects from that of ventricular fibrillation will be dealt with elsewhere.)
Similarly any agency which improves conductivity without unduly exalting
excitability is inimical to the mechanism of circulating excitation. Obviously
a combination of a depressing influence on excitability with the maintenance
of a high level of conductivity would afford the most favourable condition for
protection or recovery. Concurrent depressions or elevations of excitability
and conductivity in proportionate degree naturally have no specific influence
on the question of fibrillation. The agencies which operate successfully in
opposing the development of fibrillation — either spontaneous {i.e. from
unknown causes) or excited artificially by drugs, electrical stimulation, etc. —
are often effective in restoring the normal action after fibrillation has been
established. Eemedies for fibrillation have commonly, in these experiments,
been injected into the cavity of the left ventricle through the apex by means
of a slender needle ; sometimes intravenous injection (external jugular, etc.)
was used, massage of the heart being done in both cases, while the artificial
respiration is of course maintained. Smaller doses were sufficient by the
intra-ventricular mode of injection. Approximately isotonic solutions were
used, warmed to body temperature. The doses stated are for cats, usually
weighing 2-3 kilos, but sometimes more.
Urethane. — Doses varying between 0'025 and 0*25 grm. injected into the
left ventricle were found effective in removing fibrillation in very numerous
experiments (fig. 10); 3 per cent, solutions were commonly used for
Fia. 10. — The middle portion of the tracing shows fibrillation caused by strong
faradisation (5000 units). After it had lasted for 2 minutes (with occasional
massage) 0'05 grm. urethane was injected into the L.V. The restored action is seen
in the right-hand portion.
( 319 )
Fibrillation in the Mammalian Heart.
19
intra-cardiac or intra-vascular injections. Hypodermic doses of 0'5 grm. per
kilogramme and upwards (given in 25-per-cent. solution, etc.) have a
pronounced influence in protecting against fibrillation in light chloroform
anaesthesia and in diminishing, though not always obviating, the danger of
adrenaline fibrillation in the same grade of anaesthesia. Sufficient time has to
be allowed for absorption before the effects are tested. Smaller doses suffice
for this purpose when given by intra-vascular (e.g., saphenous vein) injection.
Strontium Chloride was given in doses of 0*01 — 0-06 grm., a 1-per-cent.
solution in dilute Ringer's fluid being usually employed.* Especially when
applied at an early phase of the fibrillation this remedy often succeeded very
well, and the condition of the heart and circulation were excellent afterwards
(fig. 11). In other cases after fibrillation had lasted for a long time and other
A. B.
Fig. 11. — A, fibrillation, preceded by period of tachycardia and pseudo-fibrillation, from
faradising with 500 units. Injection of 0*06 grm. strontium chloride was followed
in 30 seconds by restoration of the normal action, shown in B, taken shortly after
recovery. Soon afterwards faradisation with 1000 units again caused fibrillation ;
recovery followed injection of 0'03 grm., with the usual massage.
measures had been unsuccessful, this salt sometimes speedily induced
recovery. Fibrillation, in its various phases, caused by potassium salts is, as
might be expected, specially amenable to treatment with strontium in doses
varying according to the toxic dose of potassium.
Adrenalin. — Solutions of 1 in 10,000 or 1 in 5,000 were commonly used ;
sometimes as strong as 1 in 1,000 ; in Einger's fluid in each case. The dose
varied from O'l to 1 mgrm. Successful results were very frequent in fibrilla-
tion which had been induced in various ways — by electrical stimulation,
chloroform, adrenalin injection during light chloroform anaesthesia (the
* The amounts here stated are of strontium chloride crystals (SrClg+eHgO). The
doses of the anhydrous salt would be represented by about 60 per cent of the above
amounts.
( 330 )
20
Professor J. A. Mac William.
chloroform-adrenalin reaction described by Levy and abundantly illustrated
in this investigation), intravenous injection of potassium salts, etc. In many
instances fibrillation has been induced by a small dose {e.g., 0"1 mgrm.) of
adrenalin and remedied by the intraventricular injection of a very large dose
(up to 1 mgrm.), the state of the heart and circulation remaining good after-
wards (fig. 12). The excitability and conductivity of the muscle are
B.
C.
Fig. 12. — The upper tracing is from the left ventricle, the lower indicates the blood-
pressure. In A, fibrillation caused by faradisation with 1500 units lasted 6 minutes,
recovery following injection of 05 mgrm. adrenalin in three doses, B is shortly
after recovery. C, taken 1 minute later, shows much increase in the range of the
lever excursions. Note that the blood-pressure is still elevated.
enhanced by a small injection and as early effects of a large injection ;
subsequently a pronounced depression of excitability occurs — shown in
many cases by a great diminution in responsiveness when tested by graduated
faradic currents; stimulation, that formerly induced fibrillation readily, now
fails to do so even when strengthened to many times its former intensity.
Diminished sensitiveness to faradic currents is often pronounced, while the
blood-pressure is still elevated and the heart is beating very strongly.
Adrenalin can thus act in two ways : (a) by reducing excitability, and (h) by
improving conduction.
Hirudin. — Injections* (into the saphenous vein) of about 8-10 mgrm. per
* Doses of 0*3-0'5 mgrm. were often effective in removing fibrillation injected into the
L.V. The solution of hirudin used generally contained 1 mgrm. in each cubic
centimetre of Ringer's fluid.
( 321 )
Fibrillation in the Mammalian Heart. 21
kilogramme of body-weight showed striking effects in opposing the develop-
ment of fibrillation, either " spontaneously " or in response to electrical
stimulation, etc. Even powerful faradisation (often several thousand units)
caused only a pseudo-fibrillation, ceasing almost immediately or lasting only
a short time (seconds) after the stoppage of the current, or a true fibrillation,
which is spontaneously recovered from — on account of the diminished
responsiveness of the muscle to the circulating excitations.
PilocarpiTie. — Intravenous injection (into jugular, etc.) of 0*0025 grm. (with
massage of the ventricles) was often effective in arresting ventricular
fibrillation. There was a good deal of variation in regard to this result ;
there seemed to be a parallelism between the efficiency of pilocarpine in
this respect and the activity of vagus inhibition in the particular heart in
question — as tested by stimulation of the vagus in the neck or, preferably,
the inhibitory area on the dorsal aspect of the auricles. Though vagus
stimulation has not been found to arrest fibrillation once it has been
established, it has shown notable effects in opposing the development of
fibrillation in certain circumstances. And pilocarpine is much more potent
than the vagus, though its influence is in the same direction and of the same
nature in many respects at least.
Similar remedies were found applicable to the perfused heart, also, a
little of the solution of urethane, adrenalin, etc., being injected into the
tube leading to the aorta ; very small doses usually sufficed.
In some instances, where ventricular fibrillation does not yield so readily
as usual to a single remedy, combinations such as urethane and adrenalin,
or these followed by strontium chloride, prove very effective. After such
treatment the ventricles commonly show a remarkably great resistance
to electrical stimulation as far as the induction of fibrillation is concerned,
very powerful currents up to 7,000-10,000 units, etc., often causing only
pseudo-fibrillation, and, if true fibrillation, with its special mechanism, is
induced, it very frequently shows spontaneous recovery after variable
periods, frequently without any massage or with massage for some seconds.
The difficulty in exciting fibrillation, and its notable tendency to recover,
are often very striking, and are to be accounted for, in the main at least, by
the diminished responsiveness of the muscle induced by the drugs.
Some relations of different remedial agents to special conditions of the
heart may be noted. In very excitable hearts that have fibrillated,
depression of excitability is the primary requirement. On the other hand,
when direct depression of conductivity {e.g., by potassium salts, bile, cooling,
etc.) is the predominant factor in any particular heart, remedies calculated to
enhance this function are obviously indicated, whether they act {a) by
( 322 )
22 Fibrillation in the MaTumalian Heart.
direct improvement of conductivity or (h) secondarily through the slowing
of the rate of succession which they may induce, i.e. by lowering excitability,
provided that this effect is not attended by a proportionate lowering of
conductivity. Adrenalin is notably useful in this respect, as indicated by
the remarkable improvement in conduction often seen under its influence,
especially evident in the auricles, where a strikingly slow contraction wave,
present during gravely depressed conduction, may be replaced by an
approximation or a return to the normal type. Hence the special utility of
adrenalin in dealing with forms of slow coarse fibrillation, already described,
and also with fibrillar beats — unless the damage in the latter case has been
carried to an irreparable stage (fig. 9).
The success of the above-mentioned methods of obtaining recovery from
typical fibrillation, induced by means that did not permanently damage the
heart, has been such that in recent years of experimentation there has not
been failure in any instance.
For valued assistance in some of the experiments of this investigation, I
have to record my thanks to Drs. Gr. Spencer Melvin and J. R. Murray.
A portion of the costs was defrayed by a grant from the Carnegie Trust.
Harbison and Sons, Printers in Ordinary to His Majesty, St. Martin's Lane.
( 323 )
2a
[From THE BIOCHEMICAL JOURNAL, Vol. XIII, No. 2, July, 1919]
THE EFFECT OF ALCOHOL ON THE DIGESTION
OF FIBRIN AND CASEINOGEN BY TRYPSIN.
By EDWAKD STAFFORD EDIE.
From the Physiological Department,
{Received May 19th, 1919.)
The behaviour of extracts of pancreas or pure pancreatic juice under different
conditions has led various observers to conclude that the pancreas contains a
number of proteolytic enzymes. It was shown by Fermi [1890] that after treat-
ment with mercuric chloride, salicylic acid and various other substances,
trypsin lost its power of digesting fibrin but would still digest gelatin, Vernon
[1901] arguing from the varying sensitiveness of pancreatic extracts towards
sodium carbonate, concluded that "trypsin" was really a mixture of enzymes
of different degrees of stability, the more sensitive enzymes being destroyed
first. Vernon only tested the digestive power of trypsin on raw fibrin in this
connection however. In a later paper Vernon [1903, 2] states that pancreatic
extracts contain an erepsin as well as trypsin. Pollak [1905] using different
preparations of enzymes found that the relative amounts of serum and gelatin
digested varied enormously in different cases. He also found that after treat-
ment with hydrochloric acid trypsin lost its power of acting on serum, but
was still about as active as ever on gelatin. Pollak concluded that extracts of
pancreas contained in addition to trypsin (to which the action on serum was
due) a special enzyme which acted only on gelatin. To this enzyme Pollak
gave the name of glutinase.
According to Ascoli and Neppi [1908], however, this assumption of a
special enzyme acting on gelatin is unjustified, as they find that slight varia-
tions in the reaction of the medium affect the digestion of different proteins
to different degrees. Mays [1906] after a long series of experiments remarks
that the presence of two proteolytic enzymes in pancreatic extracts can only
be proved when it is possible to make a separation of the enzymes. It had
been previously shown by Bayfiss and Starling [1903] that pancreatic juice as
secreted contains no trypsin (as tested on coagulated egg white), but contains
a weak enzyme hke erepsin. This has some action on caseinogen, but very
slight. The erepsin has a slight action on fresh fibrin but practically none on
fibrin which has been heated to 70°. It may here be mentioned that Long and
Barton [1914] state that raw fibrin even when very carefully purified may
soon become liquid owing to autolysis.
(219)
24 E. S. EDIE
In later papers Fermi [1913, 1914] contests the theory that some proteo-
lytic enzymes have a specific action, and maintains that all proteolytic
enzymes have a general action on all proteins.
Slight differences of behaviour of trypsin towards different proteins
under the same conditions have also been noted by Berg and Gies [1906],
Porter [1910], Long and Hull [1917], but not much importance seems to have
been attached to the facts. Others such as Glaessner and Stauber [1910] and
Auerbach and Pick [1912] find differences between the proteolytic and pepto-
lytic actions of trypsin, but in these cases possibly some of the action was due
to the pancreatic erepsin also.
It seems to have been assumed, however, by all the authors quoted and
by others such as Hedin [1905] that try])sin is the enzyme responsible for the
digestion of fibrin and caseinogen, especially in experiments lasting only a
few hours.
The action of alcohol on trypsin has been variously stated. Fermi and
Pernossi [1894] using Mett's tubes filled with gelatin found that in presence
of alcohol trypsin had more digestive action than in presence of water only.
The percentage of alcohol used is not stated. Chittenden and Mendel [1896]
found that the action of trypsin on fibrin was markedly inhibited by alcohol,
but did not test the action on any other substrate. Dastre [1896] found that
trypsin still digested fibrin and boiled albumin in presence of 15 to 20
per cent, of alcohol, while Gizelt [1906, 1, 2] states that 20% alcohol totally
inhibits trypsin. According to Bayliss [1915] trypsin will digest gliadin even
in presence of 80 % alcohol, the action in this case being due to the trypsin
in suspension. Vernon [1903, 1] noted that dilute alcohol had a considerable
inhibitory effect on the digestion of raw fibrin by trypsin.
As dilute alcohol is frequently used in making extracts of various digestive
organs, it is important to know how the digestive action is affected thereby.
1:;
Experimental Details.
The experiments were carried out as described previously [Edie, 1914].
Ox fibrin after being finely minced and thoroughly washed was suspended in
water and gradually heated to 85°. The fibrin was then pressed dry and pre-
served in glycerol and a little chloroform until required. The caseinogen was
a 3 % solution in 1 % sodium carbonate. The pancreatic extracts were pre-
pared by finely mincing sheep's pancreas and extracting with chloroform
water for about a fortnight. The extract was then filtered and a little chloro-
form added as a preservative.
The digestion was carried on at 37° in small flasks, a small measured
quantity of chloroform being added to exclude baeterial action in every case.
When fibrin was used, the amount of digestion was estimated by filtering off
the undissolved fibrin and determining the nitrogen in the filtrate by a
Kjeldahl determination. When caseinogen was the substrate, the amount of
(220)
EFFECT OF ALCOHOL ON TRYPSIN DIGESTION
25
digestion was found by precipitation with tannic acid and subsequent esti-
mation of the nitrogen in the filtrate. Controls showed that the sodium car-
bonate alone had no digestive action whatever either on fibrin or caseinogen.
The following are typical results showing the effect of dilute alcohol on the
digestion of fibrin and caseinogen by trypsin.
c.c. trypsin, 20 c.c. 10 % alcohol, 20 c.c. 1 % NajCOs
c.c. trypsin, 20 c.c. water, 20 c.c. 1 % NajCOg
4 g. fibrin added. Digestion 3 hours,
c.c. trypsin, 20 c.c. 10 % alcohol, 20 c.c. caseinogen
c.c. trypsin, 20 c.c. water, 20 c.c. caseinogen
Digestion 1 hour.
c.c. trypsin, 20 c.c. 12 % alcohol,
c.c. trypsin, 20 c.c. water,
g. fibrin. Digestion 2*75 hours,
c.c. trypsin, 20 c.c. 12 % alcohol,
c.c. trypsin, 20 c.c. water.
Digestion 1-25 hours.
c.c. trypsin, 20 c.c. 10 % alcohol,
c.c. trypsin, 20 c.c. water,
3 g. fibrin. Digestion 2 hours,
c.c. trypsin, 20 c.c. 10 % alcohol,
c.c. trypsin, 20 c.c. water.
Digestion 1-25 hours.
c.c. trypsin, 20 c.c. 10 % alcohol,
c.c. trypsin, 20 c.c. water,
5 g. fibrin. Digestion 2-25 hours,
c.c. trypsin, 20 c.c. 10 % alcohol,
c.c. trypsin, 20 c.c. water.
Digestion 1 hour.
c.c. trypsin, 20 c.c. 8 % alcohol,
c.c. trypsin, 20 c.c. water,
g. fibrin. Digestion 3 hours,
c.c. trypsin, 20 c.c. 8 % alcohol,
c.c. trypsin, 20 c.c. water.
Digestion 1'25 hours.
c.c. trypsin, 20 c.c. 8 % alcohol,
c.c. trypsin, 20 c.c. water,
g. fibrin. Digestion 3 hours,
c.c. trypsin, 20 c.c. 8 % alcohol,
c.c. trypsin, 20 c.c. water.
Digestion 1 hour.
20 c.c. 1 % Na^COg
20 c.c. 1 % NaaCO;.
20 c.c. caseinogen
20 c.c. caseinogen
20 c.c. 1 % Na^COa
20 c.c. 1 % NajCOa
20 c.c. caseinogen
20 c.c. caseinogen
20 c.c. 1 % NaaCOg
20 c.c. 1 % Na.^C03
20 c.c. caseinogen
20 c.c. caseinogen
20 c.c. 1 % NajCOg
20 c.c. 1 % NagCOg
20 c.c. caseinogen
20 c.c. caseinogen
20 c.c. 1 % NaaCOg
20 c.c. 1 % Na^COs
20 c.c. caseinogen
20 c.c. caseinogen
c.c. trypsin, 20 c.c. 6 % alcohol, 20 c.c. 1 % NagCOa
c.c. trypsin, 20 c.c. water, 20 c.c. 1 % NajCOs
g. fibrin. Digestion 3 hours.
c.c. trypsin, 20 c.c. 6 % alcohol, 20 c.c. caseinogen
c.c. trypsin, 20 c.c. water, 20 c.c. caseinogen
Digestion 1 hour.
(221)
Digestion in cc.
of N/IO nitrogen
4-6
171
23-8
23-6
4-6
13-8
241
24-3
3-8
141
27-9
27-0
8-1
23-6
300
29-3
51
121
30-6
30-6
4-9
121
27-7
28-0
11-0
20-3
22-2
220
26
E. S. EDIE
8.
(a)
(b)
(a)
(b)
9
ia)
(b)
(a)
(b)
10.
(a)
(b)
(a)
(b)
11.
(a)
(b)
(a)
(6)
12.
{«)
(b)
(«)
(b)
Digestion in cc.
of NIIO nitrogen
20 C.C. 1 % Na^COs ...
20 C.C. 1 % NaaCOa ...
12-5
22-2
20 c.c. caseinogen
20 c.c. caseinogen
250
24-6
20 c.c. 1 % NajjCOg ...
20 c.c. 1 % Na^COs ...
71
18-2
20 c.c. caseinogen
20 c.c. caseinogen
... - 31-6
31-9
20 C.C. 1 % NagCOg ...
20 c.c. 1 % NajCOg ...
140
25-2 •
20 c.c. caseinogen
20 c.c. caseinogen
34-5
34-6
20 c.c. 1 % Na^COg ...
20 c.c. 1 % Na^COg ...
13-7
26-8
20 c.c. caseinogen
20 c.c. caseinogen
32-5
32-5
20 c.c. 1 % NagCOg ...
20 c.c. 1 % Na^COg ...
10-8
24-6
20 c.c. caseinogen
20 c.c. caseinogen
300
301
1 c.c. trypsin, 20 c.c. 6 % alcohol,
1 c.c. trypsin, 20 c.c. water,
1 g. fibrin. Digestion 3 hours.
1 c.c. trypsin, 20 c.c. 6 % alcohol,
1 c.c. trypsin, 20 c.c. water.
Digestion 1 hour.
5 c.c. trypsin, 20 c.c. 16 % alc«hol,
6 c.c. trypsin, 20 c.c. water,
1 g. fibrin. Digestion 2 hours.
5 c.c. trypsin, 20 c.c. 16 % alcohol,
5 c.c. trypsin, 20 c.c. water.
Digestion 1 hour.
5 c.c. trypsin, 20 c.c. 13 % alcohol,
5 c.c. trypsin, 20 c.c. water,
1-3 g. fibrin. Digestion 3 hours.
5 c.c. trypsin, 20 c.c. 13 % alcohol,
6 c.c. trypsin, 20 c.c. water,
Digestion 1-25 hours.
5 c.c. trypsin, 20 c.c. 14 % alcohol,
5 c.c. trypsin, 20 c.c. water,
1-2 g. fibrin. Digestion 2-5 hours.
5 c.c. trypsin, 20 c.c. 14 % alcohol,
6 c.c. trypsin, 20 c.c. water,
Digestion 1 hour.
5 c.c. trypsin, 20 c.c. 14 % alcohol,
5 c.c. trypsin, 20 c.c. water,
1 g. fibrin. Digestion 2 hours.
5 c.c. trypsin, 20 c.c. 14 % alcohol,
5 c.c. trypsin, 20 c.c. water.
Digestion 1 hour.
These experiments are sufficient to show that alcohol, when present in
percentages varying from 3 to 7, has a very marked inhibitory effect
on the digestion of fibrin by trypsin but no such effect on the digestion
of caseinogen. The amount of fibrin digested under these conditions varied
from about 25 to 50 % of the amount digested in absence of alcohol, the
proportion varying somewhat with different trypsin solutions and with vary-
ing percentages of alcohol. In no case was there any appreciable difference in
the amount of caseinogen digested, beyond the limits of experimental error.
With higher percentages of alcohol the digestion of fibrin was in some
cases entirely stopped, a fair amount of caseinogen still being digested, how-
ever.
Digestion in c.c.
of N/10 nitrogen
13. (o) 1 c.c. trypsin, 20 c.c. 25 % alcohol, 20 c.c. 1 % NajCOg
(6) 1 c.c. trypsin, 20 c.c. water, 20 c.c. 1 % NagCOg
1 g. fibrin. Digestion 3 hours,
(o) 1 c.c. trypsin, 20 c.c. 25 % alcohol, 20 c.c. caseinogen
(6) 1 c.c. trypsin, 20 c.c. water, 20 c.c. caseinogen
Digestion 1 hour.
(222)
1-3
27-2
200
23-7
EFFECT OF ALCOHOL ON TRYPSIN DIGESTION 27
* Digestion in cc.
of 2^/10 nitrogen
14. (a) 1 CO. trypsin, 20 cc. 25 % alcohol, 20 c.c. 1 % NejCOs 4-8
(6) 1 cc. trypsin, 20 cc water, 20 cc 1 % NajCOs 25-2
0-8 g. fibrin. Digestion 3 hours.
(«) 1 cc. trypsin, 20 cc 25 % alcohol, 20 cc caseinogen 32-8
(6) 1 cc. trypsin, 20 cc water, 20 cc caseinogen ... ... 37-9
Digestion 1*75 hours.
16. (a) 1 cc trypsin, 20 cc 50 % alcohol, 20 cc 1 % NajjCOg 0-0
(6) 1 cc trypsin, 20 cc water, 20 cc 1 % NajCOa 23-6
1 g. fibrin. Digestion 3 hours.
(a) 1 cc trypsin, 20 cc. 50 % alcohol, 20 cc caseinogen 5-3
(6) 1 cc trypsin, 20 cc. water, 20 cc. caseinogen 25-2
Digestion 1 hour.
16. (a) Ic.c trypsin, 20 cc 50 % alcohol, 20 cc. 1% NajCOs 0-0
(6) 1 cc trypsin, 20 cc water, 20 cc 1 % NaoCOg 23-4
1 -2 g. fibrin. Digestion 3 hours.
(a) 1 cc. trypsin, 20 cc 50 % alcohol, 20 cc caseinogen ... ... 4-6
(6) 1 cc trypsin, 20 cc. water, 20 cc caseinogen ... ... 28-2
Digestion 1 hour.
Thes« experiments show that in presence of 25 % of alcohol the digestion
of fibrin by trypsin is entirely inhibited, while digestion of caseinogen still
proceeds to a limited extent. In presence of 12 % alcohol the amount of
fibrin digested is from 10 to 20 % of the control, while the caseinogen digested
amounts to about 85 % of the control.
Trypsin is well known to be very unstable under some circumstances, and
it was considered possible that contact with dilute alcohol for some time
might lead to an actual destruction of that part of the enzyme molecule
which digests fibrin. The following experiments were carried out to test such
a theory.
Digestion in cc
of N/IO nitrogen
17. (a) 20 cc. trypsin, 15 cc. 15% alcohol! , , , „„„ „ , „ ,
/I^ «-. . ■ ,. / } kept at 37° C. for 3 hours
(o) 20 cc. trypsin, 15 cc water )
2 cc of (a), 40 cc 0-5 % NagCOa 31-2
2 cc of (6), 40 cc 0-5 o/o NagCOs 31-0
1 '3 g. fibrin. Digestion 3 hours.
18. la) 20 cc trypsin, 5 cc 30 % alcohol I , „„„ ^ r
,' „ .. • ^ 1 [ kept at 37° C. for 3 hours
(o) 20 cc trypsin, 5 cc water ) ^
2 cc of (a), 40 cc 0-5 % NaaCOg 18-2
2 cc of (6), 40 cc 0-5 % NagCOg 18-3
1-2 g. fibrin. Digestion 2 hours.
lit. (a) 40 cc. trypsin, 10 cc 30 % alcohol I , ^ . .,.,0 n r ou
/\x AC. 4- • in / \ kept at 37° C. for 3 hours
(0) 40 cc trypsin, 10 cc water )
1 cc of (a), 40 cc 0-5 % NaaCOa ... 14-0
1 cc of (6), 40 cc 0-5 % NaaCOg 14-2
1 g. fibrin. Digestion 3 hours.
;0. (a) 15 cc. trypsin, 10 cc. 15 % alcohol 1 , , , .,_o ^ , „ .
,,,,„..,- / > kept at 37° C. for 3 hours
(0) lo cc trypsin, 10 cc. water ) '■
2 cc of (o), 40 cc 0-5 % NagCOg 17-4
2 cc of (6), 40 cc 0-5 % NagCOs 17-0
1 g. fibrin. Digestion 2-75 hours.
(223)
28 E. S. EDIE
Digestion in cc.
of Njl^i nitrogen
21. (a) 15 cc. trypsin, 10 cc. 15 % alcohol I , ^ ^ .,„. „ , „ ,
a( IK ^ • lA / [ kept at 37° C. for 3 hours
(0) 15 cc. trypsin, 10 cc water )
2 cc of (a), 40 cc 0-5 % Na^COa 16-3
2 cc of (6), 40 cc 0-6 % NajCOa 16-2
1 g. fibrin. Digestion 2-75 hours.
No destruction whatever of the trypsin is caused by the action of 6 %
alcohol, although the digestive action of the enzyme is reduced to 30 % or
less of the normal amount by the presence of this proportion of alcohol.
A solid substrarte such as fibrin might be rendered less digestible by pro-
longed treatment with concentrated alcohol, owing to the hardening thus
brought about. Alcohol of under 30 %, however, could hardly be supposed
to have such an effect, and a few experiments showed that after treatment
with dilute alcohol fibrin was no less digestible by trypsin than previously.
Digestion in cc.
of NIIQ nitrogen
22. (1) Fibrin + 10% alcohol) , , , .,^, ^ , ., .
/ > T?-u • / \ kept at 37° C. for 3 hours
(2) Fibnn + water |
1 cc trypsin, 40 cc 0-5 % NaaCOg, 1 g. fibrin (1) ... 19-3
1 cc trypsin, 40 cc 0-5 % NaaCOg, 1 g. fibrin (2) 18-1
Digestion 2*5 hours.
23. (1) Fibrin + 10 %alcohon , ..nont ^a^.
(2) Fibrin + 10 % alcohol [ ^'^' ^' ^^ ^- ^""^ ^^ ^""'^
1 cc trypsin, 40 cc 0-5 % NajCOg, 1 g. fibrin (1) 22-9
1 c.tj. trypsin, 40 cc. 0-5 % NaaCOs, 1 g. fibrin (2) 20-2
Digestion 3 hours.
The fibrin which was to be treated with alcohol in these experiments was
first washed with alcohol in order to remove any adherent moisture. It will
be seen that after treatment with 10 % alcohol fibrin is apparently slightly
more readily attacked by trypsin than previously.
The action of trypsin on fibrin and on caseinogen is affected by dilute
alcohol to such different degrees that it is reasonable to suppose either that
there are two enzymes concerned in the digestion of these proteins or that
different groups of the same enzyme molecule take part in the hydrolysis of the
different proteins. In the latter case the groups which digest fibrin are very
much more easily inhibited by alcohol than the groups which digest casein-
ogen.
The theory that different side chains in the molecule of an enzyme are
responsible for different functions is used to explain the zymoid modification
of enzymes. Some observers also, for example, Nencki and Sieber [1901],
hold that the behaviour of pepsin and rennin under varying conditions can
best be explained on the theory that only one enzyme is concerned here,
with different side chains responsible for the proteolytic and milk coagulating
functions. Vernon [1903, 1] also considers this probable in the case of the
milk coagulating and proteolytic actions of trypsin.
Hitherto it has apparently been assumed that one enzyme "trypsin" is
responsible for the digestion of fibrin and caseinogen by pancreatic extracts.
(224)
EFFECT OF ALCOHOL ON TRYPSIN DIGESTION 29
In this case the function is the same (hydrolysis of a protein to. form simpler
products), but it would seem that different side chains may be necessary for
the hydrolysis of different proteins.
Summary.
Alcohol when present to the extent of 3 % and upwards markedly inhibits
the action of trypsin on fibrin. The digestion of caseinogen by trypsin is not
affected until the concentration reaches 10 %. The action of alcohol is not
due to the destruction of the trypsin, since on suitable dilution of the mixture
of trypsin and alcohol the digestion of fibrin is as great as in the control.
Fibrin is not rendered less digestible by contact with dilute alcohol, but
seems to be slightly more readily dissolved by trypsin than previously.
If "trypsin" is a single enzyme the digestion of fibrin and caseinogen is
probably carried on by different side chains, those digesting fibrin being
much more readily affected by alcohol than the others.
REFERENCES.
Ascoli and Neppi (1908). Zeitsch. physiol. Chem., 56, 135.
Auerbach and Pick (1912). Quoted from Biochem. Centralbl., 14, 1668.
Bayliss (1915). J. Physiol., 50, 90.
Bay'liss and Starling (1903). J. Physiol., 30, 61.
Berg and Gies (1906). J . Biol. Chem,., 2, '^m.
Chittenden and Mendel (1896). Amer. J. Med. Sci., Ill, 181.
Dastre (1896). Arch. Physiol. (Ser. 5), 8, 120.
Edie (1914). Biochem. J., 8, 193.
Fermi (1890). Arch. Hygiene, 10, 1.
(1913). Centralbl. Bakt. Par., I Orig., 68, 433.
(1914). Centralbl. Bakt. Par., I Orig. 72, 401.
Fermi and Pernpssi (1894). Zeitsch. Hygiene, 18, 83.
Gizelt (1906, 1). Centralbl. Physiol., 19, 769.
(1906, 2). Pfluger's Arch., Ill, 620.
Glaessner and Stauber (1910). Biochem. Zeitsch., 25, 204.
Hedin(1905). J. Physiol, 32, 468.
Long and Barton (1914). J. Amer. Chem. Soc, 36, 2151.
Long and Hull (1917). J. Amer. Chem. Soc, 39, 1051.
Mays (1906). Zeitsch. physiol. Chem., 49, 124.
Nencki and Sieber (1901). Zeitsch. physiol. Chem,., 32, 291.
PoUak (1905). Beitrdge, 6, 95.
Porter (1910). Quart. J. Exper. Physiol, 3, 375.
Vernon (1901). J. P^sio?., 26, 405.
(1903, 1). J. Physiol, 29, 302.
(1903, 2). J. Physiol, 30, 330.
(225)
From THE BIOCHEMICAL JOURNAL, Vol. XV, No. 4, 1921]
[All Bights reserved]
FURTHER OBSERVATIONS ON THE DIGESTION
OF FIBRIN AND CASEINOGEN BY TRYPSIN
By EDWARD STAFFORD EDIE.
From the Physiology Department, Aberdeen University.
{Received June 18th, 1921.)
In a previous paper [Edie, 1919] it was shown that the activity of trypsin as
measured by its digestive action on fibrin and on caseinogen is affected to
such a different degree by alcohol as to make it seem either that two enzymes
are concerned, or, if only one enzyme, that the two substrates are acted on
by different groups or side chains, one group being much more sensitive than
the other. The effect of heat on the digestion of fibrin and caseinogen by
trypsin was next studied. It had been found previously [Edie, 1914] that
trypsin when boiled in acid solution still retains much or in some cases all
of its power of hydrolysing caseinogen, but in only one case was its action
on fibrin tested after heating in this way. Digestion of the fibrin was still
noticed, but the amount even in the case of the unheated trypsin was so small
that a fresh series of experiments was undertaken.
The trypsin solutions were generally prepared by extracting finely minced
sheep's pancreas with water and a little chloroform for 10 to 14 days and
filtering. A httle chloroform was then added as a preservative. The experi-
ments were carried out as previously detailed.
In the experiments described in the previous paper it had been found
that in presence of iV/25 to iV/50 HCl the trypsin solutions used retained
60 to 100 % of their original digestive power, as tested on caseinogen, after
being heated to 100° for three minutes. The same treatment was appUed to
the trypsin solutions in this series of experiments and the results are shown
in the table.
In making these extracts, one part of pancreas was extracted with two
parts of water in each case.
In each experiment 1 cc. trypsin + 40 cc. 0-5 % NagCOg + 1 g. fibrin were
used on the one hand, digestion being for three hours, and 1 cc. trypsin + 40 cc.
1-5 % caseinogen in 0-5 % NagCOg on the other hand, digestion being for one
hour.
The amount of digestion was estimated by precipitating unchanged
caseinogen with tannic acid, or by filtering off the undissolved fibrin in the
different sets of experiments respectively, and determining the nitrogen in
(498)
TRYPTIC DIGESTION
33
the filtrate by Kjeldahl's method. Control experiments were always carried
out at the same time.
Fibrin digested
Reaction
(in cc. of Nl\0
Caseinogen
No.
(HCl)
Treatment
nitrogen)
digested
1
NI55
3 min. at 100°
00
1-2
Control
201
28-6
2
NI20
1-5 min. at 60°
0-0
31
Control
21-9
34-7
3
NI20
1-5 min. at 60°
00
61
Control
221
30-9
4
NjSO
I min. at 85°
00
1-9
Control
71
22-4
5
Nj30
1 min. at 65°
00
3-2
Control
8-6
22-9
6
NI20
0-75 min. at 100°
00
3-2
Control
21-2
34-6
7
N/20
0-75 min, at 66°
2-2
19-6
Control
16-6
34-3
8
iV/20
1-5 min. at 66°
11
8-3
Control
16-2
31-8
9
NI40
1-5 min. at 75°
3-4
170
Control
17-4
37-4
In the above experiments it will be seen that even in acid solution the
pancreatic extracts used generally lost practically all their power to digest
fibrin even when heated only to 60° for a minute and a half. The power to
digest caseinogen was not so completely lost, especially in the last three
experiments, but it was so markedly reduced, compared with what had been
previously found, that the matter merited further investigation.
The extracts used above were aqueous, so a few experiments were carried
out to compare the effect of heat on aqueous and alcohohc (20 %) extracts
of the same pancreas. The experiments were carried out in the same way
as those previously noted.
Reaction
Fibrin
Caseinogen
No.
(HCl)
Extract
Treatment
digested
cc.
digested
cc.
10
iyr/40
Aqueous
1-5 min. at 75°
3-4
170
„
Control
17-4
37-4
Alcohol
1-5 min. at 75°
17-3
29-3
j>
Control
310
47-2
11
iV/50
Alcohol
1 min. at 100°
23-4
34-4
jj
Control
27-9
42-8
12
NI40
Aqueous
1 min. at 100°
00
—
tf
Control
11-8
—
Alcohol
1 min. at 100°
211
—
99
Control
231
—
13
Nj'LO
Aqueous
1 min. at 100°
0-4
—
„
Control
11-7
—
Alcohol
1 min. at 100°
140
—
>»
Control
21-5
—
It will be seen that the alcohohc extracts retain very much more of their
power to digest fibrin after being heated than do the corresponding aqueous
extracts. The amount of protein and other nitrogenous substances was
practically the same in the two sets of extracts. It might be supposed that
the alcohol itself in some way protected the trypsin from destruction when
(499)
Reaction
Fibrin
(HCl)
Extract
Treatment
digest«d
cc.
xV/40
Alcoholic
1 min. at 100"
211
,^
Control
231
Aqueous,
1 min. at lOO*-
0-0
alcohol added
afterwards
,,
Control
18-9
iV/40
Alcoholic
1 min. at 100°
140
jj
Control
21-5
Aqueous,
I min. at 100'
00
alcohol added
afterwards
34 E. S. EDIE
heated, the lower boihng point of alcohol preventing the alcoholic extract
from reaching such a high temperature in the water-bath as the corresponding
aqueous extract would reach. No such protection was found to be afforded
by alcohol, however. Corresponding aqueous and alcoholic extracts were
diluted with alcohol and water respectively so that the percentage of alcohol
was the same in both. They were then heated to the same extent and tested
on fibrin.
No.
14
15
Control 7-9
These experiments show that the addition of alcohol to an aqueous extract
of pancreas does not afford any protection against heat to the trypsin as
measured by its action on fibrin.
In the original experiments on the resistance of trypsin solutions to heat,
the solutions, when heated, contained only a very small amount of nitrogen,
not more, in some cases, than 0-02 %. The pancreatic extracts used in the
experiments now described were very much richer in nitrogen and generally
contained 15 to 20 times as much as the older extracts. This corresponds to
a considerable amount of protein in the solution and as protein is known to
form a loose compound with hydrochloric acid it was decided to try the effect
of considerably higher amounts of acid in the solutions to be heated.
It was now found that the protection afforded to trypsin solutions when
heated depends on the amount of acid present, and the more protein there
is in solution, the more hydrochloric acid must be added to prevent the trypsin
being destroyed by heat.
The following experiments show this increasing protection with increase
of acid:
Reaction
Fibrin
Caseinogen
No.
(HCl)
Treatment
digested
cc.
digested
cc.
16
i^/50
1 min. at 100°
5-6
211
Control
16-9
391
17
NI23
1 min. at 100°
Control
z
251
35-7
18
Nin
1-5 min. at 100°
7-4
26-8
Control
7-6
26-7
19
NJ15
.3 min. at 100°
10-9
26-2
Control
10-9
26-4
20
NI15
2 min. at 100°
. 3-5
19-2
Control
11-6
28-7
21
NjU
2 min. at 100°
8-4
14-8
Control
12-2
15-6
(500)
TRYPTIC DIGESTION 35
Experiments 16 to 19 show the effect of using increasing amounts of-
hydrochloric acid with the same trypsin preparation, and experiments 20
and 21 show this again with another sample of trypsin.
Similar results have been obtained with many aqueous extracts of pancreas
prepared in the laboratory, and it may be stated generally that the higher
the proportion of nitrogen contained in such an extract the larger the amount
of hydrochloric acid which must be added in order to prevent destruction of
the trypsin by heat.
In a few cases, as for example experiments 18 and 19, it was found that
the protection against heat afforded by a certain amount of acid was the same
as regards digestion both of fibrin and of caseinogen. Usually, however, the
destruction of the fibrin digesting power was considerably greater than that
of the caseinogen digesting power.
It has been pointed out by Mellanby and Woolley [1913] that in acid of
the strength of 0-05 N (HCl) trypsin is slowly destroyed at 16° and more
rapidly at 35°. Apparently at room temperature about half the trypsin is
destroyed in four hours, and two-thirds is destroyed in a day. The activity
of the trypsin in their experiments was measured by its power of coagulating
calcified milk. Other references to the effect of hydrochloric acid on trypsin
at moderate temperatures have been mentioned in a previous paper [Edie,
1914]. It was also found by Lenard [1914] that if trypsin is rendered inactive
by addition of acid, only a trace of its activity is restored by neutralising and
then adding alkali. These observers appear only to have tested the activity
of the trypsin on one substrate, but in the following experiments the action
of hydrochloric acid on trypsin at room or body temperature has been tested
as regards the power to digest both fibrin and caseinogen. In these experi-
ments alcohohc (15 %) extracts of pig's pancreas were used. These were
practically neutral. In every case 1 cc. of the original trypsin was compared
with that quantity of the trypsin + acid which would contain 1 cc. of trypsin
originally, and the solutions so adjusted as to contain the same amount of
sodium chloride. Digestion both of fibrin and of caseinogen was carried on in
presence of 0-5 % sodium carbonate, 1 g. fibrin or 0-6 g. caseinogen being
used, in about 40 cc. of fluid. The amount of digestion is expressed, as usual,
in cc. of iV/10 nitrogen.
22. 10 cc. trypsin + 20 cc. N HCl. Kept at 36° for 12 min. 20 cc. N NaOH then added.
Digestion by control 21-6 cc. fibrin, 38'2 cc. caseinogen.
„ treated trypsin 0-0 cc. „ 8-8 cc. „
23. 20 cc. trypsin + 10 cc. N HCl. Room temperature for 4 days. 10 cc. N NaOH added.
Digestion by control 12-1 cc. fibrin, 31-6 cc. caseinogen.
„ treated trypsin 0-0 cc. ,, 5-4 cc. „
24. 40 cc. trypsin + 20 cc. N HCl. Room temperature for 11 days. 20 cc. N NaOH added.
Digestion by control 11-7 cc. fibrin, 38-7 cc. caseinogen.
„ treated trypsin 0-0 cc. „ 5-6 cc. „
It will be seen from these experiments that the power of trypsin to digest
fibrin is destroyed considerably more readily in acid solution at moderate
(501)
36 E. B. EDIE
temperatures than is the power to digest caseinogen. It is also seen that the
power to digest caseinogen withstands a considerably higher percentage of
hydrochloric acid than has generally been supposed, the strength of acid
being N/3 in these experiments and several others with similar results. Tn
one experiment, after 24 hours at room temperature in N/3 hydrochloric acid,
the trypsin still retained about 10 % of its original fibrin digesting power,
but otherwise no fibrin was digested at all after treatment of the trypsin
with acid of this strength for a day or upwards.
On the whole, then, treatment of trypsin solutions with hydrochloric acid
either at high or low temperatures shows that the power to digest fibrin is
more readily destroyed than the power to digest caseinogen. This bears out
the theory discussed previously [Edie, 1919] that in some respects the fibrin
digesting poAver is the more subject to outside influences and again points
to the hydrolysis of fibrin and of caseinogen being carried out by different
side chains, those digesting caseinogen being the more stable.
In my previous paper [1919], the work of Fermi was referred to as showing
that after treatment with various reagents trypsin would no longer digest
fibrin but w^ould still digest gelatin. Pollak was also mentioned as finding
that with different enzyme preparations the relative amounts of serum and
gelatin digested varied enormously. I have also found that the relative
amounts of fibrin and caseinogen digested by different trypsin solutions vary
very much, and this without subjecting the enzyme to treatment of any kind.
Thus, three enzyme solutions were prepared in exactly the same way, by
extracting minced sheep's pancreas with three times its weight of water for
14 days and filtering. These were compared at the same time. 1 cc. of each
trypsin was taken, with 40 cc. 0-5 % NagCOg and 1 g. fibrin on the one hand,
and 1 cc. trypsin with 40 cc. 1-5 % caseinogen in 0-5 % Na2C03 on the other
hand. The amounts of digestion in the three cases were as follows:
Enzyme
Fibrin digested
in 2 hours, cc.
Caseinogen digested
in 1 hour. cc.
1
12-4
33-7
2
161
32-9
3
3-3
17-6
The differences in the relative amounts of fibrin and caseinogen digested
by these enzymes, especially Nos. 2 and 3, are very marked. Similar results
were frequently noticed in other cases, the general rule being that considerable
amounts of caseinogen were digested even though a particular enzyme solution
had httle or almost no action on fibrin.
When enzyme solutions were kept for some time it was found that the
fibrin digesting power as a rule diminished to a very much greater extent than
the caseinogen digesting power. For example, a freshly prepared trypsin,
under the usual conditions, digested 16-1 cc. fibrin and 32-9 cc. caseinogen.
In 15 months, under the same conditions, this trypsin digested 4-8 cc. fibrin
and 18-5 cc. caseinogen.
(502)
TRYPTIC DIGESTION 37
In one extreme case I examined a solution of trypsin which had been in
the laboratory for over ten years. It had no digestive action on fibrin at all,
but still digested caseinogen to the extent of 26-6 cc. under the usual condi-
tions.
These facts afford further evidence that the digestion of fibrin and of
caseinogen by pancreatic extracts is either due to different enzymes or at
least to different side chains if only one enzyme is involved. In my previous
paper [1914] I mentioned that the power to digest caseinogen seemed to be
less affected by heat than the power to coagulate milk, which was taken as
the measure of activity of trypsin by Mellanby and Woolley. I further sug-
gested that different sets of side chains might be responsible for these different
functions.
In a later paper [1914] Mellanby and Woolley take exception to my sug-
gestion and say "Pancreatic rennin and trypsin are identical. In fact the
coagulation of milk by trypsin is an expression of a general law that all
proteolytic ferments coagulate milk provided sufficient calcium be contained
in it." These authors further say "The unique fact that the ferment or fer-
ments in pancreatic juice which digest protein and coagulate milk should
withstand boihng in acid solution is practically conclusive piX)of that the two
actions are produced by one and the same substance." If this assumption
of Mellanby and Woolley is correct, however, then the milk coagulating power
and the power to hydrolyse both fibrin and caseinogen should presumably
be quite parallel in their behaviour. The experiments detailed in the present
paper, and those described previously [Edie, 1919], however, tend to show
that the digestion of j&brin and of caseinogen, if carried out by one enzyme,
involves at least two sets of groups of the enzyme molecule, and therefore
cannot be said really to be produced by the same substance in the sense
evidently meant by Mellanby and Woolley.
I have also carried out some experiments comparing the milk coagulating
power of pancreatic extracts with their proteolytic power, and shall now deal
with these.
25. To 20 cc. of pancreatic extract (alcoholic) was added 0-5 cc. N HCl. Half of this was
then heated to 100° for 1 minute and filtered.
1 g. fibrin. Digestion 2-75 hours at 37°.
(a) 1 cc. trypsin, 40 cc. 0-5 % NagCOj. Digestion 21-0 cc. NjlO nitrogen.
(6) 1 cc. trypsin (heated), 40 cc. 0-5 % NagCOg. Digestion 10-2 cc. iV/10 nitrogen.
To 20 CO. milk was added 1 cc. of trypsin (1) fresh trypsin.
„ „ „ „ „ (2) heated trypsin.
(1) Complete coagulation in 6 minutes at 37°.
(2) No coagulation in 3 hours.
26. (Similar to last experiment.
1 g. fibrin. Digestion 2-5 hours.
(a) 1 cc. trypsin, 40 cc. 0-5 % NagCOg. Digestion 26-2 cc.
(6) 1 cc. trypsin (heated), 40 cc. 0-5 % NajCOg. Digestion 8-1 cc.
( 1 ) 20 cc. milk, 1 cc. fresh trypsin. Complete coagulation in 5 minutes,
' (2) 20 cc. milk, 1 cc. heated trypsin. No coagulation in 2 hours.
(503)
38 E. S. EDIE
From these two experiments it will be seen that though the heated trypsin
is still able to digest a considerable amount of fibrin, its milk coagulating
power, if any, is now quite negligible.
27, 20 cc. trypsin + 0-5 cc. N HCl. Half kept at 100° for 1 minute and filtered.
(a) 1 cc. trypsin, 20 cc. milk. Digestion 39*3 cc.
(6) 1 cc. trypsin (heated), 20 cc. milk. Digestion 4-6 cc.
Digestion 1 hour. Tannic acid added and digestion estimated as in the usual caseinogen
experiments.
(1) 20 cc. milk, 1 cc. fresh trypsin. Complete coagulation in 5 minutes.
(2) 20 cc. milk, 1 cc. heated trypsin. No coagulation in 2 hours.
28. Similar to last experiment.
(a) 1 cc. trypsin, 20 cc. milk. Digestion 38-4 cc. -
(b) 1 cc. trypsin (heated), 20 cc. milk. Digestion 3-9 cc.
(1) 20 cc. milk, 1 cc. fresh trypsin. Complete coagulation in 5 minutes.
(2) 20 cc. milk, 1 cc. heated trypsin. No coagulation in 2 hours.
These two experiments confirm Nos. 25 and 26 in showing that the milk
coagulating power of pancreatic extracts is more readily destroyed by heat
than the proteolytic power.
It was noticed that the coagulated casein gradually dissolved under the
influence of the fresh trypsin, digestion of this protein taking place rapidly
even in neutral solution.
More striking differences are found between the milk coagulating power
and the proteolytic action of pancreatic extracts under certain conditions
without subjecting these to any such drastic treatment as heating to 100°
involves. Edkins [1891] found that fresh, active pancreatic extracts were not
so active in altering milk so as to produce Roberts' "metacasein" reaction
as were older extracts, but that the proteolytic action was greater in the fresh
extracts. Edkins suggested that the production of the metacasein reaction
might be an aspect of the proteolytic enzyme of the pancreas. Halliburton
and Brodie [1896] confirmed what had been pointed out by Benger, that
freshly prepared extract of pig's pancreas had very Httle curdhng action on
milk, but acquired this property on being kept a considerable time. They
accounted for this fact by supposing that the trypsin at first masks or hinders
the milk curdhng enzyme, but that the former enzyme deteriorates more
quickly and so finally allows the rennin to reveal its presence. Vernon [1901]
obtained similar results and found that the ratio of rennin value to tryptic
value varied largely in different extracts of pancreas and also in the same
extracts at different times. In alcohohc extracts the ratio usually became
higher as the extract became older, the tryptic value deteriorating more
rapidly than the rennin. In glycerol extracts, however, the ratio diminished
after say nine weeks, owing to the trypsin being liberated more slowly from
its zymogen than the rennin. Some glycerol extracts which were very rich
in trypsin gave practically no clot at all, as though the clot were dissolved
nearly as fast as it was formed. In a later paper, Vernon [1903] found that
rennin and trypsin were precipitated from pancreatic extracts to practically
(504)
TRYPTIC DIGESTION 39
the same extent when excess of alcohol was added. He considered that in
the case of trypsin some groups have the property of coagulating milk and
others have the proteolytic power.
I have tested a number of pancreatic extracts at different stages apd
record some of the principal results below.
In each case sheep's pancreas was used. It was finely minced and ex-
tracted with two and a half times its weight of water and a Uttle chloroform.
The experiments were similar to Nos. 25 to 28 in technique.
29. Pancreas extracted for two days and extract then tested.
1 cc. trypsin, 40 cc. 0-5 % NaaCOo, 1 g. fibrin. 14-9 cc. digested in 3 hours.
1 cc. trypsin, 40 cc. caseinogen (1-5 % in 0-5 % NaaCOg). 44-6 cc. digested in 1 hour.
1 cc. trypsin, 40 cc. milk. 23-3 cc. digested in 0-5 hour.
1 cc. trypsin +20 cc. milk. No coagulation in 0-5 hour. No coagulation on now adding
an active coagulating extract, as the caseinogen had been changed (as can be seen
above) into products which no longer give a coagulum with rennin.
30. Pancreas extracted for l-S hours and extract then tested.
26-4 cc. fibrin digested in 3 hours.
41-8 cc. caseinogen digested in 1 hour.
No coagulation of milk, but much digestion (tannic acid).
31. Pancreas extracted for 3 days and extract then tested.
26'7 cc. caseinogen (milk used) digested in 0-5 hour.
No coagulation of milk.
32. Pancreas extracted for 3 days and extract then tested.
31-0 cc. caseinogen digested in 0-5 hour.
No coagulation of milk, but much digestion.
These four experinients show that freshly prepared aqueous extracts of
pancreas generally do not coagulate milk, but are very active proteolytic
agents, both on fibrin and on caseinogen.
In a few cases I have found that the filtrate after three hours' extraction
coagulated milk rapidly, but this was exceptional.
It has already been mentioned that Halhburton and Brodie accounted
for the fact that fresh extracts have very Uttle curdhng action on milk by
supposing that trypsin deteriorates more quickly and in a few days or weeks
allows the rennin to reveal its presence. Vernon seems to suggest that a clot
IS formed but is dissolved almost at once. In the extracts which I used, the
coagulating power seemed to be fully developed within 15 days, but I never
found the proteolytic power to diminish as rapidly as would have to be the
case if the above suggestion accounted for all the facts.
The extract used in experiment 30 was tested again for proteolytic power
when five weeks old. Complete coagulation of milk now took place within
four minutes, and the amount of caseinogen digested was now 44-7 cc, this
being actually shghtly more than it digested at first. If in the first case a
clot were formed but almost immediately redissolved, this should have been
still more the case when the proteolytic power had increased, instead of which
complete coagulation rapidly took place. In other cases the milk coagulating
power seemed to have developed completely within four days, the proteolytic
(505)
40 E. S. EDIE
power being practically the same as at first and there was no evidence whatever
in support of the view that with extracts a few hours old coagulation really
takes place but the clot is redissolved almost instantly. These last experiments
once more show that pancreatic extracts differ greatly in their milk coagulating
and proteolytic powers. This again points to there being either two or more
separate enzymes present, which develop at very different rates from their
zymogens, or at least the groups which are responsible for the different
functions develop their properties quite independently.
Summary.
1 . The amount of acid required in order to protect trypsin from destruc-
tion by heat depends on the amount of protein present. The more protein
in solution, the more acid required. If not enough acid is present to afford
complete protection to the trypsin, the fibrin digesting power is usually
destroyed by heat to a considerably greater extent than the power to digest
caseinogen.
2. Hydrochloric acid at moderate temperatures also destroys the fibrin
digesting power considerably more rapidly than the caseinogen digesting
power.
3. The relative amounts of fibrin and caseinogen digested vary very
much in different pancreatic extracts.
4. The milk coagulating power of pancreatic extracts is more easily
destroyed by heat than the proteolytic power.
5. Generally, but not always, freshly prepared pancreatic extracts have
no milk coagulating power. These extracts are always actively proteolytic, but
the proteolytic power does not fall off so rapidly as to justify the assumption
that the non-appearance of a coagulum with milk is due to the coagulum
being really formed but instantly redissolved. All these facts point to the
proteolytic and milk coagulating powers of pancreatic extracts being due to
a number of distinct enzymes, or, if only one enzyme is concerned, to the
different functions being due to different groups of the molecule.
REFERENCES.
Edie (1914). Biochem. J. 8, 84.
(1919). Biochem. J. 13, 219.
Edkins (1891). J. Physiol. 12, 193.
Halliburton and Brodie (1896). J. Physiol. 20, 101.
Lcnard (1914). Biochem. Zeitsch. 60, 43.
MeUanby and WooUey (1913). J. Physiol. 47, 339,
(1914). J. Physiol. 48, 287.
Vernon (1901). J. Physiol. 27, 174.
(1903). J. Physiol. 29, 302.
(506)
A NOTE ON THE QUESTION OF THE IDENTITY
OF GASTRIC RENNIN AND PEPSIN.
By EDWARD STAFFORD EDIE.
Frofn the Physiology Department, Aberdeen University.
{Received June 18th, 1921.)
Much has been written on the question of the identity of gastric rennin and
pepsin, and two theories have been brought forward. One, first associated
with Pavlov [Pavlov and Parastschuk, 1904], is that pepsin and rennin are
identical, Savjalov [1905] and Gewin [1907] holding that coagulation is the
first stage in the digestion of milk by pepsin. The identity theory is based
on the parallelism between the behaviour of the proteolytic and milk coagu-
lating actions of gastric extracts under different conditions. The other theory
is that the enzymes are different. There are twt) possibihties here, one, put
forward by Nencki and Sieber [1901] and others, being that "pepsin" consists
of a large molecule with different side chains, one set of which digests protein
in acid solution, while another set is responsible for the coagulation of milk
in neutral solution. A second possibihty is that there are two distinct enzymes
involved in the two functions. This is the theory which has been mainly
developed by Hammarsten [1908]. It is difficult to distinguish experimentally
between these two possibihties, and indeed the present state of our knowledge
of the constitution of enzymes renders a distinction hardly practicable. Both
depend on the fact that by suitable treatment the two actions can be separated
from one another, so that a solution may be obtained which coagulates milk
but has no proteolytic action, and on the other hand it is also possible to
obtain an active proteolytic solution which has no milk coagulating pro-
perties.
Porter [1911] in support of Hammarsten's theory found that various com-
mercial preparations, while coagulating milk, were actually anti-peptic. A
full discussion of the subject is given by Oppenheimer [1913].
When investigating the development of enzymes from foetal hfe onwards
I tested the properties of extracts of stomachs of young rabbits and compared
these with similar extracts from adult animals. The differences found are
recorded in this note.
According to Oppenheimer, pepsin is already present in the stomach of
rabbits before birth, while according to Gmelin [1902] rennin is absent from
the stomach of new-born animals. Other observers find that rennin develops
(507)
42
E, S. EDIE
very rapidly after birth. Rakoczy [1910, 1911] and Van Hasselt [1910] found
that in the case of calves the rennin disappeared rapidly during the first
month after birth, while the pepsin increased greatly. The youngest animal
employed by Rakoczy was apparently nine days old, but Van Hasselt does
not state the exact age of the animals he used. In my experiments the stomachs
of rabbits were taken as soon as possible after birth, washed out thoroughly
and ground up with twice their weight of water. A little chloroform was added
and after three days the liquid was filtered ofE and the filtrate tested. The
stomachs of adult rabbits were tested in exactly the same way. The extracts
were subjected to no further treatment with acid, sodium chloride or other
substances such as were used by Hammarsten and others with a view to
destroying the proteolytic or milk coagulating action as the case might be.
In the coagulating experiments 1 cc. of extract together with 5 cc. of milk
was kept in a water-bath at 37° and examined every five minutes. Coagulation
was considered complete when the test tube could be inverted without dis-
turbance of the contents. Experiments were always repeated three times at
least.
The proteolytic experiments were carried out on fibrin which had been
finely minced, thoroughly washed and heated to 85°. 1 cc. extract + 40 cc.
iV/20 HCl + 1 g. fibrin were kept at 37° for a certain time and then filtered,
the nitrogen being determined in the filtrate by Kjeldahl's method. Controls
(HCl + fibrin) were also done and allowance was made for the amount of
nitrogen originally present in the extracts.
The results are expressed as the number of cc. of decinormal nitrogen
obtained from the fibrin digested.
Results of experiments:
A. New-born rabbits (each represents a different litter) :
Coagulation
time
12 minutes
18
30
12
13
22 „
B. Adult rabbits :
No.
Fibrin digested
in 2 hours
1
0-0 cc.
2
3
4
„
5
6
bits:
No.
Fibrin digested
in 1 hour
1
4-6 cc.
2
8-0
3
9-3
4
23-8
5
8-4
Coagulation
time
No coagulation in 2 hours
1 hour
2 hours
2 „
These results show the very wide differences which exist between the
gastric extracts prepared from young and adult rabbits respectively with
regard to their content of rennin and pepsin.
(508)
RENNIN AND PEPSIN 43
In some cases the extract from young rabbits' stomachs was incubated
with acid and fibrin for 18 hours without any appreciable amount of digestion
taking place.
At the end of every coagulation experiment, in the case of the adult
extracts, a few drops of active rennin were added to the mixture of extract +
milk. Coagulation now always took place, proving, if need be, that the absence
of coagulation at first was not due to lack of calcium or other deficiency in
the milk, but to lack of rennin in the extract. These facts, so far as they go,
seem to argue against pepsin and rennin being identical. The extracts were
exactly similar in mode of preparation and it is unlikely that one set would
contain any inhibitory substance (for example removable by dialysis) which
would be absent from the other. No stomach, either of young or adult rabbit,
was an exception to the rule that in young animals we get rennin but no
pepsin, and as the animal reaches adult life the rennin entirely disappears
but pepsin is now found in the stomach.
REFERENCES.
Gewin (1907). Zeitsch. physiol. Chem. 54, 32.
Gmelin (1902). Pflvger\s Arch. 90, .591.
Hammarsten (1908). Zeitsch. physiol. Ghem. 56, 18.
Nencki and Sieber (1901). Zeitsch. physiol. Chem. 32, 291.
Oppenheimer (1913). Die Fermente und ihre Wirkungen, 4te Auflage.
Pavlov and Parastschuk (1904). Zeitsch. physiol. Chem. 42, 415.
Porter (1911). J. Physiol. 42, 389.
Rakoczy (1910). Zeitsch. physiol. Chem. 68, 421.
(1911). Zeitsch. physiol. Chem. 73, 453.
Savjalov (1905). Zeitsch. physiol. Chem. 46, 307.
Van Hasselt (1910). Zeitsch. physiol. Chem. 70, 171.
(509)
>v
[PnoM THE BIOCHEMICAL JOURNAL, Vol. XVI, No. 1, pp. 23—26, 1922] i
[All Riiilits reserved]
V. DISTRIBUTION OF ENZYMES IN THE ALI-
MENTARY CANAL OF THE CHICKEN.
By ROBERT HENRY ADERS PLIMMER
AND JOHN LEWIS ROSEDALE.
From the Biochemical Department, Rowett Research Institute for Animal
Nutrition, University of Aberdeen and North of Scotland College of Agri-
culture.
{Received December 20th, 1921.)
The presence of lactase in the intestines of animals and the non-adaptation
of the pancreas and intestine to lactase by feeding with lactose was investi-
gated by Plimmer [1906]. Lactase was always found to be absent from the
intestine of chickens, A diet containing lactose had been used by us [1921]
in feeding chickens from birth for a period of over three months. Examination
of the birds' excreta showed that reducing sugar was absent therefrom, a
fact which indicated that the sugar was assimilated. Assimilation of disac-
charides is usually preceded by hydrolysis to monosaccharides, which would
imply the presence of lactase in the alimentary canal, either in the intestine
by adaptation or in some other part. The intestines of the cockerels in this
group of birds were therefore examined, after they were killed, for the presence
of lactase : it was not found to be present, and the non-adaptation of this organ
was verified. If hydrolysis of lactose previous to assimilation occur, it must
take place in some other part of the gut. The crop, pancreas and proventri-
culus were tested and lactase in small amount was detected in the crop. The
investigation was then extended to the presence of other enzymes, as no
information could be found in the literature about their occurrence in the
alimentary canal of birds. The enquiry did not extend to the detection of all
known enzymes, but was limited to those concerned in the digestion of the
common foodstuffs.
Experimental.
The methods of preparing the enzyme solutions and detecting the presence
of enzymes were in general in accordance with those usually adopted ; in many
cases a longer time of action (up to seven or ten days) was allowed, and in the
case of the sucroclastic enzymes, proteins etc. were removed before testing
for the reducing sugar formed by their action.
The various parts of the alimentary canal were always taken from chickens
killed the same day, or not later than the day previously; on account of the
)f6 R. H. A. PLIMMER AND J. L. ROSEDALE
small size of the crop, proventriculus and pancreas, the organs from four to
eight birds were collected and examined together. A single small intestine
provided sufficient material, but in most experiments several were combined
as the whole series of sucro- or proteo-clastic enzymes were tested for simul-
taneously. Separate tests were made for lactase. At least two experiments
were made with each part, except the caeca.
Preparation of enzyme solutions.
The pancreas, on removal, was cut up into small pieces and ground with
sand in a mortar; the ground mass was put into glycerol in which it was kept
for several days in the presence of a few cc. of toluene. The solution was then
prepared by diluting with rather more than an equal volume of water and
filtering from sand, etc.
The other parts of the alimentary canal were cut open and washed with
running water to remove the contents. The mucous membrane was scraped
off, ground up with sand and water and extracted for 24-48 hours with water
in the presence of a little toluene to prevent putrefaction. The aqueous
portion was strained off through cloth to remove sand and larger pieces and
used for testing for enzymes.
It was not possible to scrape off mucous membrane from the inside of the
proventriculus. The organ is glandular, covered with numerous small teats,
which, on pressing with a scalpel, emit a yellowish, viscous, distinctly acid
secretion. This secretion was the material actually used after grinding with
sand and mixing with water. Nothing could be scraped off the gizzard, the
interior surface of which resembled parchment.
Detection of enzymes.
(a) Diastase and invertase. As substrates 100 cc. of 1 % starch solution
and 50 cc. of 3 % cane sugar solution were used. Two portions were measured
out with a pipette in separate flasks; a know!Q volume of enzyme solution was
added to one, and the same volume of boiled enzyme solution, after cooling,
to the other; 2 or 3 cc. of toluene were added to each, the flasks corked and
put into an incubator at 37° for one or more days. A test for starch by the
:odine reaction was made from time to time with a drop removed from the
mixture. At the end of the reaction time, the mixtures were washed into a
250 cc. measuring flask, a slight excess of colloidal ferric hydroxide added,
any excess of the latter removed by a few crystals of magnesium sulphate,
the volumes made up to the mark, the solutions filtered and reducing sugar
tested for by the complete reduction of 10 cc. of Fehling's solution. The
control solutions containing boiled enzyme did not reduce, or only gave a
slight reduction due to sugar present in the extract.
(6) Lactase. The detection of lactase was carried out in a similar way to
that of diastase and invertase, using 50 cc. of 4 % lactose solution as substrate.
The enzyme and control mixtures were put directly into 250 cc. measuring flasks
DIGESTIVE ENZYMES OF THE CHICKEN j|7
and made up to volume after clearing with colloidal ferric hydroxide and
magnesium sulphate. The reducing sugar was estimated by the reduction of
10 cc. of Fehling's solution. The observed difference in reading indicated
whether hydrolysis had or had not occurred. No difference in reading was
observed in the case of the intestine or proventriculus, but a small though
distinct difference was always noticed in the case of the crop extract; it varied
from 0-2 to 0-5 cc. in a total of 10 or 10-1 cc. This slight difference indicated
an hydrolysis of 10-20 % of the lactose.
(c) Lipase. This enzyme was not looked for except in the case of the
pancreas. Two exactly equal portions of oil in separate test tubes were made
just alkaline to phenolphthalein with 0-1 iV caustic soda. Enzyme and boiled
enzyme solution were added. On keeping at 37° and occasionally shaking,
the pink colour of the tube containing enzyme solution disappeared and it
was restored by adding a few drops of the soda. This could be repeated several
times and altogether from 1-2 cc. of alkali were added; the control tube did
not change colour.
{d) Proteoclastic enzymes. Proteoclastic enzymes were detected by their
action on Congo-red fibrin in neutral, acid and alkaline media. In the first
case, a definite volume of enzyme solution and the same volume of boiled
enzyme solution were put into separate flasks; in the other cases the same
volumes of enzyme and boiled enzyme solutions were mixed with an equal
volume of 0-2 iV hydrochloric acid or 0-2 N sodium carbonate solution in
separate flasks; 1 g. of Congo-red fibrin and 2 cc. of toluene were added to
each and the several flasks were put in an incubator at 37° for one to seven
days. Solution of Congo-red fibrin, which, in the case of hydrolysis, generally
occurred in one or two days, was taken as indication of the presence of proteo-
clastic enzyme; solution did not occur in those flasks with boiled enzyme
solution. No investigation was made of the products of the hydrolytic action.
Results.
The presence or absence of enzymes in the various parts of the alimentary
canal is most easily seen from the following table:
Proven-
Intestine
Duo-
Crop
triculus
Pancreas
whole
denum
Ileum
Caeca
Invertase
0
0
+
0
Diastase
+
0
+
+
,
.
-f
Lactase
+
0
0
.
.
^
Lipase
.
+
,
.
Proteoclastic
in neutral
0
6
+ slight
6
0
6
0
„
acid
+ slight
+
+ less rapid
-1-
+
+
0
„
alkaline
0
0
+ rapid
+ slight
+
+ slight
0
media
The distribution of the sucroclastic enzymes corresponds in most parti-
culars with that in the animal ; most animals have invertase in the intestine,
lactase is present in some, absent in others : diastase and lipase are generally
J|8 R. H. A. PLIMMER AND J. L. ROSEDALE
present in the pancreas of animals. The proteoclastic enzymes show a differ-
ence: the animal has trypsin acting in alkaline media; the chicken in both
alkaline and acid media. The intestine of the chicken has an enzyme acting most
rapidly in acid medium, less rapidly in alkali. The proteoclastic enzyme of
the proventriculus acts only in acid medium; the organ corresponds to the
stomach of animals. The caeca, as expected, had no enzyme of this group,
but contained diastase.
We wish to thank Prof. J. A. MacWilliam, F.R.S., for kindly allowing us
to carry out these experiments in his laboratory.
REFERENCES.
Plimmer (1906). J. Physid. 34, 93; 35, 20.
Plimmer and Rosedale (1921). J. Agric. Sci
[From THE BIOCHEMICAL JOURNAL Vol. XVI, No. 1, pp. 27— .30, 1922J (\
[Ail Rights reserved]
VI. THE AMINO-ACIDS OF FLESH.
THE DI-AMINO-ACID CONTENT OF RABBIT, CHICKEN,
OX, HORSE, SHEEP AND PIG MUSCLE.
By JOHN LEWIS ROSEDALE.
From the Biochemical Department, Rowett Research Institute for Animal
Nutrition, University of Aberdeen and North of Scotland College of Agri-
culture.
{Received December 20th, 19'£1.)
A LONG series of food analyses has recently been made by Plimmer [1921, 1],
who points out that by the ordinary routine method of analysis, in which
the amount of protein is estimated by multiplying the nitrogen content by
6-25, no discrimination is made between the flesh of different animals. The
protein of one animal is regarded as being the same as that of another. The
work of Emil Fischer and Kossel and their pupils has definitely proved that
the various proteins differ very widely in their composition as regards the
amino-acids, and this difference is emphasised by the experiments on the food
value of the individual amino-acids by Hopkins in conjunction with Willcock
and Ackroyd, by Osborne and Mendel and other American investigators^.
These chemical and biological differences are sufficient evidence that quality
of protein in nutrition must be taken into consideration.
Complete analyses of the protein of the muscle of the ox, chicken, halibut
and scallop have been made by Osborne and Heyl [1908] and Osborne and
Jones [1909], and Drummond [1916] has made some analyses of muscular
tissue by Van Slyke's method. Both the more complete analyses by Osborne
and co-workers and those by Drummond do not show any marked difference
in the amino-acid content of the various muscle proteins. The flesh of various
animals shows such distinct appearances, different both to the eye and palate,
that it seems probable that greater differences may exist, and that there may
be smaller differences in the flesh from various parts of the same animal's
carcase, such as back and leg. Some further amino-acid analyses have there-
fore been made.
The methods of protein analysis are far from perfect: Fischer's ester
method for the mono-amino-acids, as he pointed out, is not quantitative:
Kossel and Patten's method for the di-amino-acids, in spite of the numerous
manipulations, is generally considered to be fairly accurate, but it has been
largely superseded by Van Slyke's method which gives higher values for these
amino-acids. Van Slyke's method also possesses the advantage of requiring
only small amounts of protein and is more rapidly carried out. This method
of protein analysis has been used in these experiments, since it was chiefly
^ See summary by Plimmer [1921, 2],
go J. L. ROSEDALE
desired to compare the muscle protein of several animals with a view to more
complete data at a later time. A comparison of these results with those by
Kossel's method has been made in a few cases. The results indicate that
differences exist in the amino-acid content of the various muscle proteins.
Duplicate analyses were always carried out; frequently these analyses were
not so concordant as was expected. This inconsistency of the results was
under investigation by Plimmer [1916] who tested the arginine determination;
other details of the method are now being studied.
Experimental.
In the case of the smaller animals (rabbit, chicken) opportunity was taken
of comparing the flesh of different parts of the body of the same animal. In
other cases the flesh was taken from the thigh. The mode of operation was
the same throughout. The flesh (about 350 g.) was freed from inside fat,
minced and put into about 2 litres of boiling water containing 0-1 % acetic
acid and heated for about ten minutes so as to coagulate the protein and
remove the extractives. The liquid was poured off and the coagulated protein
squeezed dry in a cloth. This procedure was repeated twice. The coagulated
protein (about 200 g.) was then digested with 1 g. pepsin in 2 litres of
0-liV HCl, so as to separate nucleins, indigestible matter, etc. After digestion,
which usually occupied about ten days at 37° the liquid was filtered off and
the total nitrogen estimated. A portion containing about 6 g. of protein was
then hydrolysed by boiling with hydrochloric acid added to the liquid so as
to make a concentration of 20 %. The hydrolysis was carried on for 36 hours.
The hydrolysed solution was evaporated to dryness in vacuo, made up to
250 cc. and two samples of 100 cc. were analysed by Van Slyke's method.
This was performed as described except for the arginine estimation which
was effected by Plimmer's modification [1916]. In the earlier experiments it
was impossible to make determinations of amide N owing to the facilities for
vacuum distillation not being adequate. The analyses were made in duplicate
and the percentage has been calculated from the average.
Table I. Nitrogen percentages.
Di-amino-aci«1g
Mono-amino- acids
Total N
^
Non-
Argi-
Histi-
"^
Non-
of hydro-
Humin
Total
Amino
amino
nine
dine
Lysine
Total
Amino
amino
lysed
solution
Amide
K
N
N
• N
N
N
N
N
N
N
Rabbit, back
—
—
45-7
21-5
240
15
19
11-5
49
—
—
94-7
„ fore limb
—
—
441
17-9
27-7
8-8
30-9
6-5
50-7
—
—
94-8
„ hind limb
—
—
44-8
18-4
26-6
13
26
5-8
56-3
—
—
1011
Chicken, breast
6-9
3
27
9
18
10
13
2
611
49-7
11-4
980
legs
5-5
1-3
25-6
15
10-5
8
7
11
68-5
66-6
1-9
100-8
Beef
6-3
0-5
28-5
15
13-5
13-3
5
11-2
55
26-8
28-2
90-3
Horse
2-9
0-9
371
18-8
18-3
14-9
10-5
11-6
70
58
11-9
110-9
Mutton
6-5
0-5
38-3
22-3
15-6
15
18
4-3
54
52
2
99-3
Pork
6-4
1-2
28-2
13-3
16
14
7
7
67
53
4
92-8
Relatively little difference can be observed from the figures for the different
meats. The amide N is almost similar, in each case averaging about 6-0 %
of the total N.
AMINO-ACIDS OF FLESH J\
Table II. Percentages of amino-acids. Giving the amount of
amino-acids in 100 g. of protein.
Arginine
Histidine
Lysine
Total di-amino N
Rabbit, back
8
10
13
31
„ fore limb
5
19
5
29
„ hind limb
7
15
5
27
Chicken, breast
6
8
1
15
legs
4
4
10
18
Beef
7
3
10
20
Horse
7
6
9
22
Mutton
7
11
4
22
Pork
7
4
6
17
Humin N shows a difference. It is, if anything, higher in the white meats,
e.g. breast of chicken 3 %, legs 1'3 %, pork 1-2 %, than in the red meats,
where the average is 0-5 %, except in the horse, where 0-9 % was found. The
explanation of this slightly higher value may be that the animal was nut
properly bled on slaughter.
Lysine figures are, with the exception of mutton, higher for the red meats,
averaging about 11 %, while, of the white meats, rabbit limbs show only 5*5 %,
chicken breast 2 % and pork 7 %.
Gortner and Holm [1920, 1], working with mixtures of pure amino-acids,
have shown that tryptophan, and in the presence of aldehyde also tyrosine,
and their analogues are the only known amino-acids which go to form humin.
There is therefore no connection between the humin content and the lysine
content of the meats; this is exemplified especially in the chicken, where the
humin is high, and the lysine is low in the breast; and humin is low and
lysine high in the legs. It may perhaps be mentioned that in the preparation
of the di-amino-acids by the method of Kossel and Patten a distinct yellowish
colouring adheres to the lysine portion.
At the same time too much reliance must not be placed on the humin
as an estimation of tryptophan and tyrosine. Gortner and Holm [1920, 2]
and Thomas [1921] have shown that tyrosine and tryptophan which go to
form humin are not necessarily the only substances giving a reaction with the
phenol reagent of Folin and Denis. Estimations of substances giving the blue
colour with this reagent were made during the progress of this work, both
before the removal of the humin and afterwards. In the case of chicken
breast, a white meat, the readings before removal of the humin represented
4% "tyrosine" whereas after its removal the readings represented 3-5%.
In the case of beef however^a red meat — the difference was greater, the
former reading being 3-5 % and the latter 2-1 %, yet the humin N was much
lower in the case of beef.
The arginine figures are more constant at about 14 or 15 % except in
rabbit fore limb and chicken legs where the average is 8 %.
The histidine figures are less satisfactory, and exhibit perhaps a weak
point in the method. In this connection it is of interest to point out that in
the cases of abnormally high histidine the figures for the non-amino N are
lower than normal and vice versa, e.g. beef 5 % histidine, 28 % non-amino N,
i2 J. L. ROSEDALE
mutton 18 % histidine, 2 % non-amino N, while in other cases this observa-
tion cannot be made. This may be due, either to incomplete precipitation of
the hiistidine by the phosphotungstic acid, or to washing. Work in this con-
nection is in progress.
It is not possible to draw any conclusions from the figures of the mono-
amino fraction, which account for about 55 to 60 % of the total N.
The average percentage of the di-amino N is 35.
Comparison with former work on the hydrolysis of meat is difficult, because,
with the exception of Drummond [1916] on chicken meat, the other figures
relate to the method of Kossel, which generally gives lower results than the
Van Slyke method.
The above figures for chicken breast agree in the main with those of
Drummond, his total hexone bases N 27-26 being the same as that above.
The arginine figures are within 1 % and he records having used the same
modification of that process as mentioned above. The figures for histidine
and lysine are discordant, Drummond finding 8*45 and 9-81 respectively,
while the total N of the mono-amino fraction is 4 % higher than that found
by Drummond.
In order to compare the figures of Osborne and co-workers with the above
it is necessary to refer to the percentages not of total N but of actual arginine,
histidine and lysine. The figures for arginine are generally constant within
1 %, those for histidine are higher than Osborne's, while the lysine figures,
owing to the calculation in Van Slyke's method, are dependent on the histidine
values. Apart from the arginine values, only the beef of the present sets has
given results comparable with those of Osborne, who found 7-5 % arginine,
1-8 % histidine and 7-6 % lysine against 6-8 % arginine, 2-6 % histidine and
9*6 % lysine in this experiment.
Summary.
1. Determinations have been made of the di-amino-acids of the protein of
the flesh muscle of rabbit, chicken, ox, horse, sheep, pig by Van Slyke's method.
2. The red meats show a higher lysine content than the white meats.
I wish to take this opportunity of expressing my gratitude to Dr Plimmer,
who suggested this work, for his kindness and guidance throughout the time
I was under him, and also to Professor J. A. Mac William, F.R.S., for so kindly
placing his laboratory at my disposal.
REFERENCES.
Drummond (1916). Biochem. J. 10, 473.
Gortner-Holm (1920, 1). J. Amer. Chem. Soc. 42, 821.
Gortner-Holm (1920, 2). J. Amer. Chem. Soc. 42, 1682.
Osborne and Heyl (1908). J. Biol. Chem. 22, 433; 23, 81.
Osborne and Jones (1909). J. Biol. Chem. 24, 161, 437.
Plimmer (1916). Biochem. J. 10, 115.
Plimmer (1921, 1). Analyses and Energy Values of Foods (Stationery Oflfice).
Plimmer (1921, 2). Proc. Roy. Inst.; Nature, 107, 664; J. Soc. Chem. Ind. 40, 227.
Thomas (1921). Bui. Soc. Chim. Biol. 3, 197.
o
^
[Reprinted from the JOURNAL OF ANATOMY,
Vol. LVII, Part I, October, 1922]
AU Bights reserved
ABNORMAL LEFT CORONARY ARTERY OF OX HEART
COMMUNICATING DIRECTLY WITH THE CAVITY OF
THE LEFT VENTRICLE NEAR THE APEX
By CHARLES REID, M.A., B.Sc, M.B., Ch.B.
From the Physiological Laboratory, University of Aberdeen
A HITHERTO undescribed abnormality was observed in an ox heart received
by the above department about the end of October, 1921. Externally, the
heart showed at the apex of the left ventricle a circular cyst-like structure.
The heart was then held, with the cut end of the aorta pointing upwards,
under a tap of running water. The water was allowed to run gently into the
aorta, and the cyst-like structure was observed to bulge with fluid. On closer
examination, a tubular vessel of arterial type about the calibre of one's middle
finger was observed in the interventricular groove between the aorta and this
structure at the apex of the left ventricle. This vessel appeared to follow the
usual course of the descending branch of the left coronary artery towards the
apex of the heart. It should be noted that, anteriorly, over the cyst-like
dilatation, the ventricular muscle was quite deficient, and seemed to have been
displaced by this abnormal structure.
Heart : weight with attachments of great vessels and fat, 95 ounces.
[Weight of another normal ox heart, 89 ounces.]
Length of heart, 24 cm.) , .
Width of heart, 19 cm.] ^"""^ "^^^-
The auricles looked normal. The thickness of the walls of the left ventricle
during rigor was about 5 cm. and did not differ materially from that of the
normal ox heart.
With regard to the previous history and health of the animal, the following
facts were obtained:
Age, rising 3 years old. Never off feed; very good feeder; always active;
walked to sale from the farm (f mile). Proportion of beef to live weight, fair
average.
The calibre and thickness of the walls of the following vessels are given for
the purpose of comparison :
Thickness
Vessel Calibre of wall
Aorta (about 8 cm. beyond the valves) ... 3*0 cm. 8 mm.
Innominate artery (at its origin) 1-75 „ 5 „
Abnormal artery (at its origin above the cusp) 1-5 „ 1-5 „
It will be observed that, while the calibres of the innominate artery and
abnormal artery are approximately equal, the wall of the latter is much
thinner than that of the former.
Abnormal Left Coronary Artery of Ox Heart 55
Further dissection showed that this abnormal vessel arose about 1-25 cm.
above the middle of the left posterior cusp of the aortic valve. The tip of the
middle finger could be inserted into the vessel at its origin. A coronary artery,
smaller in size, arose above the anterior cusp, but no artery arose above the
right posterior cusp. In the normal ox heart the calibres of the two coronaries
differ considerably, the left being the larger, but the normal left coronary
artery did not admit the tip of the middle finger.
No other abnormal opening was noted at the base of the aorta. The aortic wall
was healthy and the aortic valves appeared healthy, and, when tested by means
of a stream of water directed into the cut end of the aorta, proved competent.
The abnormal vessel passed forward between the left auricular appendix
and the pulmonary artery. The first branch came off the main vessel about
3*5 cm. from the cusp, and ran transversely outwards in the left auriculo-
ventricular groove. Its calibre appeared similar to that of the normal right
coronary artery. This branch was evidently the transverse branch of the left
coronary artery and was of normal size.
The abnormal vessel passed along the interventricular septum giving off
numerous small branches to the septum without any marked diminution in
calibre until it reached just above the apex of the left ventricle anteriorly
where it dilated into a cyst-like structure roughly conical in shape with its
base anterior and its apex on a level with the inner surface of the left ventricle.
With regard to the dimensions of the above structure, the diameter of the
base of the cone was about 7 cm. while the height of the cone was about
6 cm. It will be noted that the height of this structure is practically equal to
the thickness of the wall of the left ventricle.
The wall of the cone-shaped structure appeared similar in structure to the
wall of the abnormal vessel but slightly thinner. It was lined by smooth
endothelium, and its base was quite uncovered by cardiac muscular fibres,
being apparently in direct relationship with the pericardium. The rest of the
wall of the cone-shaped structure was attached firmly to the muscle of the
left ventricle throughout its entire thickness.
The walls of the abnormal vessel and the dilated portion were apparently
continuous. Anteriorly, where the wall of the dilated portion was not attached
to the wall of the ventricle, the epicardium passed directly on to the wall of
the dilated portion. At first, the union was not firm, the two being held to-
gether by loose tissue, but at a distance of about 2 cm. from the place where
the ventricular muscle became deficient the wall of the dilated portion and
the epicardium became fused apparently into one.
The cavity communicated directly with the left ventricle near its apex by
a circular aperture, which was sufficiently large to admit the middle finger,
and was guarded by a valve-like structure. Examination showed that the
latter consisted of :
(1) an inner fibrous ring, diameter 1'5 cm., forming the circumference of
the aperture,
56
Charles Reid
(2) an outer fibrous ring, 3*5 cm. in diameter,
(3) thin fibrous material covered by smooth endothehum, stretching
between the two rings and thickened by six or seven fibrous bands running
radially between the two circular fibrous rings.
No other abnormality, developmental or acquired, was noted in the right
or left chambers of the heart. The interventricular septum did not appear to
be in any way abnormal, and the coronary veins both right and left were small.
They did not appear to be enlarged on either side of the heart.
Lateral view of valve-Iike structure between cavity of left
ventricle above and cyst-like dilatation below.
From its origin and course, this abnormal vessel was taken to be a left
coronary artery — the abnormality affecting more particularly the descending
branch of the left coronary artery. The dilatation of the terminal portion of
the vessel at the apex was difficult to explain. This dilatation might have been
due wholly to the developmental abnormality, or it might have been acquired
mainly. If the latter supposition was correct, the dilatation would have been
of the nature of an aneurismal dilatation. Support might be lent to this view
by the fact that, when the dilated portion was distended with water, it was
noted that at two or three places the wall was much thinned. The distension
might have been brought about by the escape of blood from the left ventricle
throughout the greater part of systole before the opening between the cavities
of the left ventricle and the dilated part was closed by the contraction of the
left ventricle towards the end of systole.
Developmentally, no explanation of the abnormal coronary and com-
munication with the left ventricle has been suggested.
Journal of Anatomy, Vol. L VII, Part 1
Plate I
6"-
Fig. A. a, a, a, track of abnormal descending branch of the left coronary artery; h, cyst-like dilatation
at apex.
Fig. B. Wall of dilated part at apex has been opened and held back.
Appearance presented by the pseudo-valvular structure on looking at the apex of the heart:
(a) external fibrous ring; (h) internal fibrous ring; (c) radial fibrous l)and; {d) communication
between the left ventricle and the abnormal coronary.
EEID — Abnormal Left Cokonaky Artkry of Ox Heart
f
Abnormal Left Coronary Artery of Ox Heart 57
The only related case on record was described by Mr H. Blakeway in
the Journal of Anatomy, vol. lii, p. 354. The heart in this case — a child which
lived 36 hours — had amongst other abnormalities no direct communication
betAveen the left ventricle and the aorta, but an indirect one by means of the
anterior interventricular branch of the left coronary artery. Mr Blakeway
considered the question of the possibility of the origin of the abnormal com-
munication between the aorta and the left ventricle as being due to some
developmental peculiarity of the bulbus cordis. He, however, rejected this
consideration.
The actual course taken by the blood in the abnormal ox heart forms an
interesting speculation. Before the heart went into rigor, the left ventricle
was artificially compressed above the apex to imitate systole, and at the same
time a stream of fluid under pressure was directed against the pseudo-valvular
opening by means of a tube introduced through the aorta past the aortic
valves. Practically no fluid escaped into the dilated part. Again, fluid was
allowed to run into the aorta. The aortic valve being competent, most of the
fluid passed along the abnormal channel. The fluid entered the cavity of the
left ventricle (the left ventricle being empty) through the pseudo-valvular
opening, if the left ventricle was not compressed.
It would appear that during the greater part of systole leakage took place
directly from the left ventricle to the dilatation at the apex. In all probability,
the opening between the left ventricle and the dilated portion would not be
closed by ventricular contraction except towards the end of systole. During
diastole, unless the pseudo-valvular structvire acted as an efficient valve, there
must have been free communication between the aorta and the interior of
the left ventricle, and the diastolic pressure in the abnormal vessel and in the
interior of the left ventricle must have been equal to the pressure in the aorta.
After the wall of the distended part at the apex of the left ventricle was laid
open, a strong stream of fluid was directed against the valve-like structure.
It appeared to act as an efficient valve except when the left ventricle was
distended or relaxed.
As bearing on the accepted relation between increased diastolic intraven-
tricular pressure and dilatation and the striking development of dilatation and
hypertrophy in aortic regurgitation in man, it is noteworthy that in this ox
regurgitation into the left ventricle with its concomitant high diastolic
pressure was not associated with appreciable dilatation or hypertrophy.
The following notes give a brief account of the microscopical appearance
of the parts of which sections were made :
(1) Ventricle {MVj.
Muscle, healthy. Nothing abnormal noted.
(2) Innominate artery.
Intima, healthy.
Media, towards inner part of media regularly arranged bundles of plain
58 Charles Reid
muscle circularly disposed and elastic fibres; towards outer part of media,
amongst the circularly disposed plain muscle and elastic fibres irregularly
arranged groups of plain muscle, many running longitudinally.
(3) Wall of abnormal coronary artery.
Endothelium, healthy.
Subendothelial elastic layer, quite well marked. Wall varies in thickness,
the thinner parts being at most one-half the thickness of the thicker portions.
Thicker portions : large amount of plain muscle arranged in bundles; rather
granular looking elastic tissue between the bundles — apparently split longi-
tudinally in places.
Thinner portions : much less plain muscle than the preceding; towards the
centre of one portion of the media, small oval-shaped area which does not
stain well : nuclei stain fairly well but are variable in shape. The elastic tissue
apparently shows large coarse granules and it appears to become fragmented
transversely into more or less elliptical portions.
Externa, well marked.
(4) Wall of dilated portion of abnormal coronary artery.
Two layers: (1) External, epicardium;
(2) Internal, part corresponding to wall of the abnormal
coronary artery; practically no plain muscle or elastic fibres; rather de-
generate-looking connective tissue showing nuclei which stain fairly well,
fibrils, and perhaps "ghost-like" elastic fibres.
Interior to the above is a fairly thick endothelial and subendothelial layer
showing connective tissue and elastic tissue arranged parallel to the inner
surface; nuclei stain well.
Endothelium appears to show proliferation of its cells, the deeper layers of
which show signs of organisation.
(5) Lining of cavity and subjacent myocardium,
(a) Endothelium, normal; no proliferation.
(6) Subendothelial elastic layer, fairly well marked.
(c) Layer of more or less homogeneous tissue taking up eosin stain, no
sign of elastic or muscle fibres.
(d) More or less continuous layer of about ^th thickness of (c), consisting
of heart muscle fibres and white fibrous connective tissue.
(e) Vascular layer, thinner than (d).
( /') Heart muscle proper.
(6) Junction of dilated end of abnormal coronary artery with ventricle.
Epicardium and wall of distended portion can be seen separated by heart
muscle; the heart muscle ceases and the epicardium and the wall fuse loosely
at first, but firmly within a distance of 2 cm. from the point where the heart
muscle ceases ; epicardium at the point where the heart muscle ceases becomes
much thinned quite abruptly, and continues thin for about a distance of
Abnormal Left Coronary Artery of Ox Heart 69
1*5 cm. as it lies in direct relationship with the wall of the dilated portion; it
then becomes thicker, approximating to its original size.
(7) Branch of abnormal coronary artery.
Healthy arterial wall.
(8) Branch of right coronary artery.
Nothing abnormal to be noted.
(9) and (10) Coronary arteries from normal ox heart.
Left: the larger vessel; wall of left varies in thickness considerably.
Conclusions in regard to:
I. Course taken by blood during life in the abnormal vessel.
(1) During systole. Probably regurgitation occiu'red from the left ventricle
throughout the greater part of systole through the abnormal communication
at the apex. This would give rise to a pulse wave apart from the question of
the quantity of blood regurgitated. Another pulse wave would be sent along
the abnormal vessel from the aorta. In this way the abnormal vessel would
be subjected to strain, and the cyst-like part would be subjected probably to
the greatest strain. The movement of blood in the abnormal vessel would
perhaps be from the apex of the left ventricle towards the aorta.
(2) During diastole. The blood-flow in the abnormal vessel would in all
likelihood be from the aorta to the left ventricle. The diastolic pressure in
the left ventricle and in the abnormal coronary would be high, viz. aortic
pressure. Hence conditions would be favourable for increased strain on the
abnormal vessel and dilated part during diastole and on the dilated part more
particularly during diastole. On the whole, there would be a relative stagnation
of blood in the abnormal vessel.
II. Respective proportions of the abnormality, congenital and acquired.
It would appear clear that the communication between the left ventricle
and the coronary was developmental wholly. The pseudo-valvular structure
must have been present before birth as a congenital peculiarity.
That the abnormal coronary and dilated portion were subjected to abnormal
pressures and in consequence became expanded is concluded from the
following :
( 1 ) Varying thickness of the wall of the abnormal coronary and dilated part.
(2) The wall does not show the typical structure of a normal artery.
(3) Irregular arrangement of bundles of unstriped muscle etc. in wall.
(4) Evidence of impaired nutrition of portions of the wall of the abnormal
vessel.
(5) High diastolic pressure.
In all probability, had the animal not been killed, it would have died at
some period of rupture into the pericardial sac through one of the thinned
portions of the wall of the dilated portion at the apex.
I am indebted to Professor J. A. MacWilliam for his help and permission
to publish the above, and to Mr George C. Kelly for the sketches.
[From British Medical Journal, 13th January, 1923.]
SOME APPLICATIONS OF PHYSIOLOGY
TO MEDICINE.
I.— SENSORY PHENOMENA ASSOCIATED WITH DEFEC-
TIVE BLOOD SUPPLY TO WORKING MUSCLES.
BY
J. A. Mac WILLIAM, M.D., F.R,S.,
PROFESSOB OF PHYSIOLOGY,
AND
W. J. WEBSTER, M.B.,
ASSISTANT IK PHYSIOLOGY, IN THE UNIVERSITY OF ABEBDEEN.
(From the Physiological Laboratory.)
Accurate knowledge of the effects of defective blood supply
to the various tissues and organs is obviously of great
importance in view of the innumerable conditions of stress,
derangement, and disease in which this factor comes into
play, with manifold results in the way of disturbed or im-
paired functions in the different systems of the body.
" Defective supply " naturally covers different conditions-
quantitative deficiency in normal constituents, or the presence
of abnormal and injurious constituents, or inadequacy as
regards the volume, pressure, and rapidity of flow of normal
blood. This communication deals with the last-named —
certain effects of deficiency in the supply of normal blood to
normal muscles.
Many impairments of functional activity from more or
less extensive interference with blood supply have long been
known, such as the weakening of the heart muscle from
deficient coronary supply and the common occurrence of
fibrillation after sudden coronary obstruction ; the effects
on the brain in the form of giddiness, faintness, or loss of
consciousness; and the primarily exciting and secondarily
depressing influences exercised powerfully on the medulla
(respiratory, vasomotor, and cardio-inhibitory centres, etc.)
and on the spinal centres from sufficiently extensive or sudden
acute lack of blood supply ; also the derangement or stoppage
of kidney function from similar interference.
Various observations are on record dealing with the func-
tional behaviour of excised organs and muscles artificially
perfused with blood or in the exsanguine condition, and also
observations on the effects of artificial interference with the
blood supply of organs and muscles in situ in animal experi-
ments. Under such conditions there is of course no informa-
tion obtainable as to sensory phenomena attendant on altered
blood supply in the conditions of rest and activity.
The present inquiry deals with the behaviour of human
muscles temporarily deprived of their blood supply while their
normal innervation remains intact ; the sensory phenomena
[562/22]
62 J. A. MacWILLIAM AND W. J. WEBSTER.
recognizable in the states of rest and activity are examined
and brought into relation with other functional conditions,
such as changes in contractile power, etc.
MetJiods of Experiment.
The forearm was investigated (a) while the normal circula-
tion was going on, and (6) when the blood supply was stopped,
the limb either retaining its blood in a stationary condition or
being rendered exsanguine before the circulation was arrested
— that is, the " congested arm " and the " ischaemic " arm
were examined with arrested cii'culation. The circulation
was stopped by a blood pressure armlet applied to the upper
arm, which was rapidly pumped up to a constricting pressure
much above what was necessary to produce arterial oblitera-
tion in the particular individual examined — that is, an armlet
pressure largely exceeding the systolic pressure. When this
was done in the usual way, as for the measurement of systolic
blood pressure, a " congested arm " was obtained containing
a large amount of stationary blood shut off from the general
circulation, the veins becoming prominent and tense. To
obtain the bloodless or ischaemic arm an elastic bandage was
first applied to the hand and arm, and removed after the
armlet had been pumped up as described.
In the congested arm the sensory phenomena are naturally
complex, being partly attributable to conditions attendant on
the arrest of the circulation as influencing the muscles, etc.,
and partly to the discomfort caused by the venous turgescence.
To avoid the latter complication the metliod of the ischaem'c
arm is employed; the sensations induced by muscular
activity in presence of acute want of blood can then be
examined.
Under these conditions muscular action was tested in
various ways. Graphic records of the flexor muscle of the
middle finger were made by means of a Mosso's ergograpb,
the voluntary flexion movements being made in regular
series — one in one second or in two seconds, etc. — timed by
a metronome, while the weight lifted at each contraction
varied in different experiments from 1 to 3 kg. The be-
haviour of the muscle in different conditions, the amounts of
mechanical work done as measured in kilogram- metres, the
development of fatigue, etc., were graphically recorded, while
the sensations associated with different phases were noted.
The results as regards fatigue, etc., will be described else-
where, the present communication having to do with the
sensory phenomena.
Another method is to use a series of grasping movements
with the hand, bringing them to bear on a dynamometer or a
dynamograph; this method is in some respects less precise
than the preceding.
Another mode of experiment was to use the abductor
indicis muscle, working against the resistance of a strong
elastic band embracing the fingers ; successive abduction
movements of the fingers were then made in regular series ;
only the hand was rendered ischaemic in this case, the armlet
being applied to the forearm. The hand was supported on a
APPLICATIONS OF PHYSIOLOGY TO MEDICINE. 63
table with the palmar surface downwards. Graphic records
can be obtained by making the movements of the finger
inscribe on a moving smoked paper.
Iscliaemia of the Besting Arm.
In observations made by these methods it was found that
simple deprivation of blood in the ischaemic limb for periods
up to twenty minutes caused no great sensory effects, only
coldness in the bloodless part, with an inclination to shift the
position of the limb, and a certain amount of discomfort from
the continued constriction by the obliterating armlet; the
absence of pain is to be noted.
Muscular Action in the Ischaemic Arm,,
Muscular action in the ischaemic limb soon becomes pain-
ful, and when carried to the point of " fatigue " is acutely
painful. "Fatigue" is indicated by inability to go on
executing contraction movements even of greatly reduced
range. This index of " fatigue " is convenient for comparing
the state of matters in normal and ischaemic muscles, though
it does not represent inability of the muscle to do more
mechanical work in more favourable circumstances — for
example, with less resistance opposing the contraction, a
lighter weight to lift, etc. It is a useful index of the stage
of enfeeblement of the voluntary contractile power with
which the sensory manifestations in muscles under different
conditions can be correlated. The actual time necessary to
induce fatigue and the number of movements that can be
executed prior to this point are of course largely influenced
by the weight used; with a sufficiently light weight the
movements can be kept up for hours without the occurrence
of fatigue in the normal arm while the circulation is intact.
Under normal conditions the phenomena of fatigue as shown
by ergograph records are well known. The associated
sensations as the fatigue point is approached take the form
of a sense of increased effort being necessary to raise the
weight even for a short distance, an increasing disinclination
to go on making the successive efforts, aching or dull pain in
the central part of the forearm, etc. We have often found
a certain amount of local tenderness to pressure in the
fatigued muscles, lasting for some little time after action has
been discontinued.
In the ischaemic arm the fatigue point is reached much
more rapidly, often in one-half or one-third the time needed
in the normal arm, with a proportionate diminution in the
number of contractions executed, the more rapid development
of extensive weakening at a relatively early stage, etc. Pain
develops and by the time the fatigue point is reached becomes
severe ; further efforts at contraction movements lead to
distressingly acute pain and the desire for relief becomes
urgent, while there is a strong disinclination to attempt
further efforts.
Distribution and Characters of the Pain,
The pain is felt over the flexor aspect of the forearm and
is most intense in the central part of the forearm; it is
64 J. A. MacWILLIAM and W. J. WEBSTER.
specially marked from wrist to elbow along the line of the
flexor digitorum sublimis. It seems to be centred in the
belly of the working muscle with a good deal of spreading,
but there is, as a rule, no referred pain in more distant parts ;
in one subject pain in the palm of the hand was complained
of. The pain goes on increasing progressively while con-
tractile activity is kept up ; there is no remission, as may
sometimes occur markedly in the normal arm, where, work-
ing with a suitable load, decided aching may develop at a
comparative early stage, to pass off more or less completely
at a later stage.
It is to be noted that the pain, increasing to almost
intolerable severity in some of these experiments, arises from
exercise of a comparatively small amount of muscular tissue
— the limited portion of the flexor muscle engaged in moving
a single finger — in presence of an acute lack of blood supply,
involving urgent want of oxygen (anoxaemia) and its con-
sequences, with excessive accumulation of metabolic products,
acids, and other bodies. The pain is no doubt protective in
character, tending to limitation of effort and shielding the
muscle from being spurred on to further and injurious
activity. Discontinuance of further effort for short periods
does not remove the pain, but it is almost immediately
relieved — in a few seconds — by readmission of b'ood into the
limb by removal of the obliterating pressure of the armlet.
Contractile energy, on the other hand, recovers gradually and
slowly; it takes some time to be fully re-estabhshed, and
even then is apt to fail more readily than before on repetition
of the experiment. It is evident that the pain and the
depression of contraction force do not run parallel in the
ischaemic arm.
Relation of Pain to WeaTiening of Contraction Force.
The conclusion just stated is supported by the fact that in
the ischaemic arm the development of pain in the course of a
successive series of contractions is much greater in proportion
to the weakening of contraction force than in the arm with
intact circulation ; with an equally extensive cutting down
of the energy of movement in the two types of arm, as
shown by the ergograph tracings, there was sharp pain in
the ischaemic arm at a stage when there was only a tired
feeling with some aching in the normal arm ; pain and
weakening of contractile force were differently related to one
another in the two cases.
It may be noted that in the normal arm slight aching or
local tenderness may last for some little time after the
exercise of the flexor muscle (as recorded by the ergograph)
has been discontinued, while in the ischaemic arm the sharp
pain disappears quickly on re-establishment of the circula-
tion. There is reason to believe that in fatigue following
severe muscular exertion under normal conditions (for
example, football, etc.) the muscular aching and tenderness,
felt for a considerable length of time afterwards, especially
in individuals out of training, are dependent on a mechanism
of production that is not identical with that of the pain
caused by working an ischaemic muscle.
APPLICATIONS OF PHYSIOLOGY TO MEDICINE. 65
The production of severe pain from a small amount of
skeletal muscle working with its blood supply cut off recalls
the agonizing pain excited by excessive contraction of a
small amount of unstriped muscle in a bit of bile duct in
gall-stone colic, or of ureter in renal colic, etc. Of course
it does not follow that the mechanism of pain production
is similar in the two kinds of muscle — the unstriated and
the striated.
Observations on the Abductor Indicis Muscle.
Experiments with the abductor indicis muscle gave results
essentially similar to those described above. For example, in
an experiment when a certain strength of elastic band was
used to resist the abduction movement, a series of about
240 movements could be carried out in the normal state at
the rate of one per second before the " fatigue " point was
reached — that is, the point where any abduction movement
failed to occur against the resistance of the band; this was
attended by only slight discomfort and aching — where the
latter was present at all. In the ischaemic hand the fatigue
point was reached at about one hundred contractions — that
is, in less than two minutes, as compared with four minutes
in the normal state ; this was attended by pain, which spread
more or less over the dorsum of the hand, though most sharply
felt in the working muscle. Stoppage of the efforts at abduc-
tion for a minute did not lead to removal of the pain, but the
latter was promptly relieved by re-establishment of the circu-
lation; contractile power recovered much more slowly, and
was more easily fatigued subsequently. Some minutes later
the hand was again rendered ischaemic, and kept in that
condition with quiescent muscles for ten minutes ; the hand
became cold, but there was no pain, simple ischaemia having,
as described above, no appreciable effect in this respect.
Abduction movements of the index finger were then per-
formed as before ; there was painful fatigue after about
sixty- five movements; the pain was removed as before by
readmission of the blood. The usual well-known flushing
occurred after the period of ischaemia ; sensations of tingling
gradually developed somewhat later.
Effects of Continuous Muscular Tension.
Experiments were also performed with the middle finger
flexor muscle kept voluntarily contracted to sustain the ergo-
graph weight at a certain level instead of making a series of
consecutive lifting efforts as already described ; graphic
records of the behaviour of the muscle were made. Con-
tinuous motor effect failed to preserve the initial level
beyond a certain time, which varied according to the weight
employed, etc. ; then came a general progressive decline,
varied by minor irregularities in the slope of the tracing, until
alter a time the weight sank back to the resting position.
This " fatigue " is attended by comparatively little subjective
disturbance, even in the ischaemic arm. There was disincli-
nation to keep up the tension of the muscle, which seems to
need more and more voluntary effort, with some discomfort
and aching — the latter felt chiefly in the upper arm and the
finger — probably attributable not to the muscle itself but to
(56 J. A. MacWILLIAM and W. J. WEBSTER.
the mechanical conditions connected with the fixed position
of the hmb and pressure on the skin of the finger by the loop
at the end of the cord which supports the weight. There is
evideutly a notable difference as regards pain production
between an alternately contracting and relaxing muscle doing
mechanical work and the condition of sustained tension neces-
sary to maintain tlie weight at certain levels. Similar results
were obtained with the abductor indicis.
Relation to Pains of Angina Pectoris, Intermittent
Claudication, etc.
It need hardly be pointed out that the foregoing observa-
tions have a close bearing on the problems associated with
the production of the pain of angina pectoris, showing as
they do how readily acute pain can be excited in skeletal
muscle working with lack of blood supply, the pain develop-
ing while the contractile power, though to some extent
weakened, is still sufficient to execute movements of con-
siderable range and energy — that is, long before complete
fatigue.
There is every reason to believe that processes of the same
nature, with a similar production of pain of varying grades
of severity, up to the agonizing suffering of fully developed
angina, occur in cardiac muscle compelled to work with a blood
supply that is inadequate — absolutely or relatively to the
amount of work which the arm has to perform. Sir James
Mackenzie has emphasized the conception of anginal pain
as an expression of exhaustion of the cardiac muscle,
commonly associated with a defective coronary blood supply
and a susceptible nervous system. He has laid stress on
the production of the symptoms of heart failure— pain, breath-
lessness, giddiness, faintness — as expressions of impaired
functions of organs which fail to receive a blood supply
adequate to the needs of their normal activities in con-
sequence of a defective output of blood from the heart,
the latter itself suffering from insufficient blood supply
to its muscular walls; heart failure is thus recognized,
not by direct examination of the organ itself, but by the
functional effects of diminished blood supply to various
organs.
It may be added that the results of the present experi-
ments have an obvious application to the phenomena of
the condition called " intermittent claudication," as seen
in the legs of men and horses, in which muscular exertion
is interrupted by attacks of pain, loss of power, coldness
of the limbs, etc. These symptoms can be definitely ex-
plaiued : in consequence of blocking of the main artery, or
disease or spasm of the vascular walls, the blood stream
has been reduced to such an extent tliat, while it may
suffice to supply the muscles in the resting state, it is
quite inadequate for their greater requirements during
activity — the results (pain, etc.) of the defective blood
supply are of the same nature and mechanism of produc-
tion as those demonstrable in the ischaemic arm of the
healthy subject.
[From British Journal of Experimental Pathology,
1923, Vol. IV.]
67
A METHOD OF ESTIMATION OF DIASTASE IN
BLOOD.^
a. MATTHEW FYFE, M.B., Ch.B.
From the Physiological Laboratory, University of Aberdeen.
Received for publication March 22nd, 1923.
There is a general acceptance of the view that estimation of blood diastase
is of distinct diagnostic value, and it is unfortunate that certain features of
recent methods render them not entirely satisfactory. Stocks (1916), and later
Harrison and Lawrence (1923), adopting Wohlgemuth's method, incubate a
series of dilutions of blood serum, or blood plasma, with starch and obtain their
results from the colour reaction which occurs on the addition of iodine. In the
first place it is very difficult to obtain in general practice a sufficiency of serum
for the purpose of the test (from 1 c.c. to 3 c.c.) without veni-puncture, and, in
the second place, sera do occur occasionally of which the tint definitely masks
the delicacy of the colour reaction. Myers and Killian (1917), using the Lewis
and Benedict method of blood sugar estimation, determine the amount of sugar
formed from a known quantity of starch by 2 c.c. blood after incubation for a
definite period, calculating their results in terms of the percentage of starch
reduced. Here again the question of veni-puncture arises, and in addition that
of the inaccuracies which the picric acid methods of sugar estimation present
as compared with more recent means of blood-sugar determination.
In view of these difficulties the problem of the estimation of blood diastase
was approached, and, by an adaptation of MacLean's (1919) method of blood-
sugar estimation, a means has been evolved which has the advantage of
simplicity and accuracy, while it necessitates the minimum of discomfort to the
patient. It also permits of an almost concurrent reading of the blood-sugar
and the blood-diastase figures, dispensing with the need for two different
techniques. For the method proposed 0'2 c.c. blood only is required — an
amount which can easily be obtained by pricking the ear or the finger. The
final result depends upon a determination of the patient's blood sugar by
MacLean's method, and upon a second determination after 0"2 c.c. of the
patient's blood has been incubated for half an hour at 37° C. with 1 c.c. of a
0"1 per cent, solution of starch.
The Effect on Blood Sugar of Incuhation at 87° G.
In view of the fact that the literature of the subject gives most discordant
views on the problem of glycolysis in blood, it was thought best to make an
investigation of the question. It was found that under the experimental
conditions described below no glycolysis was in evidence. Freshly drawn blood
to the amount of 0'2 c.c. was pipetted into a small Erlenmeyer flask containing
2'8 c.c. normal saline solution. The suspension was incubated for half an hour
in a water-bath at an accurately maintained temperature of 37° C. During
this period a direct control estimation of the sugar in another sample of 0*2 c.c.
was done. When the incubation time was completed the amount of sugar
* Work carried out in the tenure of a Carnegie Research Assistantship.
68
G. MATTHEW FYFE.
present in the specimen was estimated,
taken from some forty.
Table I shows the results in six cases
Table I. — The Effect of Incuhation on the Sugar in 0'2 ex. Blood.
Control Percentage after
percentage.
Case.
•081
•097
•102
•13
•097
131
incubation.
•082
•097
•106
•13
•097
•134
No appreciable change in the sugar content occurs on incubation of 0'2 c.c.
blood in 2^8 c.c. saline solution at 37° C. for half an hour. It should be stated
here that throughout the experiment and also throughout the entire diastase
investigation, strict aseptic precautions were observed to exclude the possibility
of bacterial action during incubation.
THE PROPOSED METHOD DESCRIBED.
Into one of two 100 c.c. Erlenmeyer flasks 1'8 c.c. of 0^9 per cent, saline
solution and 1 c.c. of 0^1 per cent, starch solution {i. e., 1 mg. starch) is accu-
rately pipetted, while into the other (control flask) exactly 2'8 c.c. of 0*9 per cent,
sahne solution is introduced. 0"2 c.c. blood is withdrawn from the finger into
a special MacLean pipette* and carefully ejected into the fluid of the first
flask, the point of the pipette being held beneath the surface of the solution,
while the flask is held at an angle. The pipette is rendered free from blood
by repeated washing with the clear fluid into which the blood has just been
delivered. The flask is then gently shaken with a circular movement so as to
mix thoroughly the blood and the solution. A second sample of 0^2 c.c. blood
is similarly delivered and washed into the control flask. Both flasks, provided
with rubber stoppers, fitted with capillary points, are placed in a water-bath,
the temperature of which is accurately maintained at 37° C. Incubation is
allowed to proceed for exactly half an hour, at the end of which time the flasks
are removed and 21 c.c. of MacLean's acid sodium sulphate solution is added.
In the case of the first flask the addition should be made immediately on
removal from the water-bath so as to stop the action of the diastase. The
subsequent steps in the estimation are precisely as described by MacLean.
Briefly the treatment is as follows : The flasks are heated till the boiling-
point is just reached. 1 c.c. dialysed iron is added to each and after cooling
under the water tap the contents are filtered. To 20 c.c. of each filtrate is
added 2 c.c. alkaline copper solution. The resulting solutions are then boiled
for six minutes over a flame suitably adjusted to effect distinct boiling in one
minute forty seconds. At the end of that period the flasks are immediately
plunged into cold water and cooled thoroughly. 2 c.c. of 75 per cent. HCl
(or H2SO4) are added, and after effervescence has finished and after standing for
one minute with occasional agitation, the iodine content of the solutions is
found by titration with N/400 sodium thiosulphate. During titration, in the
case of the first flask, a variation of colour is seen ranging from dark amber to
* To be obtained from Hawksley & Son, Wigmore St., London.
ESTIMATION OF DIASTASE IN BLOOD. 69
leaden and to pale blue, the final disappearance of which marks the completion of
titration ; in some cases when the blue colour is very faint the end-point may
be rendered more distinct by the addition of a drop of 3 per cent, starch
solution. The amount of sodium thiosulphate used is noted and its exact
glucose equivalent ascertained from the glucose-thiosulphate table, or very
much better, from a plotted graph. The second flask is treated in exactly the
same manner except that starch must be added to complete the titration.
Calculation.
The result is calculated as the percentage of soluble starch transformed to
sugar (calculated as glucose) by the 0"2 c.c. blood employed. The amount of
starch used is 1 mg., and the difference between the sugar contents, measured
in fractions of a milligramme, of the two samples of 0'2 c.c. blood will be
equivalent to the amount of starch reduced to sugar.
Suppose that, reading from the glucose-thiosulphate graph, the sugar con-
tent of the control preparation is 0'164 mg., while for the starch preparation it
is 0"259 mg. Since the amount of filtrate used corresponds to -f of 0*2 c.c. blood,
that amount of blood would contain 0'205mg. sugar in the one case and 0"323 mg.
sugar in the other. The difference, 0'118, is equivalent to the amount of starch
transformed to sugar by incubation with 0"2 c.c. blood, so that the diastatic
index in this case is 11'8. Allowance should, of course, be made for any slight
reducing action of the soluble starch. During the course of this investigation
the starch solutions were repeatedly tested for any such action, and in no case
was it found necessary to make correction.
In view of the fact that glycolysis does not occur on incubation of 0"2 c.c.
blood under the conditions of the experiment, there appears to be no good
reason for running a control. The half hour during which the starch prepara-
tion is incubating may be very conveniently occupied in making a direct
estimation of freshly-drawn blood.
DETAILS OF METHOD AND EESULTS.
Accuracy. — It may seem superfluous to call attention to the need for
accuracy in this estimation, but in view of the fact that determinations are
made in milligrammes and fractions of milligrammes, perhaps a few points
which lend themselves to precision are worthy of note. Cleanliness and
attention to aseptic precautions should be maintained throughout. Burettes,
flasks and pipettes should be thoroughly cleaned. Antiformin or a solution of
potassium bichromate in sulphuric acid is a very useful help. Standardised
burettes and pipettes should be used. During the process of the boiling of the
blood filtrate and the copper solution, the manometer should be carefully
watched for any change in gas pressure and any necessary adjustment made.
Preparation of the starch solution. — Lintner's soluble starch was used
throughout this investigation. The solvent was physiological salt solution
prepared with water, double (glass) distilled and practically neutral to rosolic
acid. The presence of the salt solution prevents haemolysis, and tends to
accelerate the action of diastase. A litre of 0"9 per cent. NaCl is prepared
with re-distilled water, and 0"2 grm. of soluble starch weighed out and
suspended in about 5 c.c. of the saline solution. Sufficient saline to make
200 c.c. is measured out and heated in a large flask almost to boiling-point.
70
G. MATTHEW FYFE.
when the starch suspension is carefully added drop by drop, the contents of the
flask being shaken after each addition. A reflux condenser is then attached,
and the solution allowed to boil for about ten minutes. The resulting starch
solution is homogeneous and transparent, and allows of an intimate association
of the enzyme and substrate. It is not advisable to submit the small quantity
of starch to prolonged boiling, as is recommended by certain authors (Sherman,
Kendal and Clark, 1910), who, however, use a larger quantity of starch.
Table II shows how the diastatic index tends to be lowered when starch which
has been boiled for some time is used in the test.
Table II. — Showing Variations in Diastatic Activity when 0"2 ex. Blood is
treated with Starch Solutions boiled for Different Lengths of Time.
starch sokition boiled for —
Case.
1
2
3
4
5
The starch solution should be made with great care, and should be freshly
prepared every second or third day. No advantage seems to be gained in the
use of glycogen instead of starch (Table III).
Table III. — Showing Comparative Activity of Diastase on Starch
and Glycogen.
Sugar formed.
i hour.
1 hour.
2 hours.
I
J
Reducing svxgar formed
'251 mg.
•230 mg.
•200 mg
•180 „
•145 „
•127 „
•230 „
•165 „
•16 „
•108 „
•098 „
•08 „
•143 „ *
•035 „
Case.
0. B—
Blood sugar,
per cent.
•13
0-1 per cent.
starch.
mg.
•200
O'l per cent.
glycogen.
mg.
•130
H
M—
•10
•087
•08
E.
A—
•11
•141
•14
A.
T—
•09
•093
•083
A.
I—
•195
•315
•320
The diastatic figures of six normal subjects are given in Table IV. The
figure seems to vary in different individuals, the average being about 8 to 10 —
a figure somewhat lower than that of Myers and Killian (1917), and similar to
that of Stocks (1916). From data obtained it would seem that the normal
index should not exceed 15.
Table IV.
Case.
K.
E.
A.
A.
C.
K—
A—
T—
G—
R—
W. S-
-Showing the Diastatic Activity of Blood in Normal Cases.
Age.
30
22
33
34
30
30
Sex.
Diastase.
Blood sugar.
M.
8^5
*102 per cent
M.
90
•097
M.
118
•134
M.
8^8
•102
M.
71
•131
M.
65
106
ESTIMATION OP DIASTASE IN BLOOD. 71
Table V gives the diastatic activity of three cases of diabetes. In the
case D. G — , cardiac complications and pulmonary JSbrosis were present.
Table V. — The Diastatic Activity of the Blood in three Abnormal Cases.
Bir^r.^ Blood TT,.;„<» Urine
Case. A.e. Sex. Date. ^fj-^, peTc^^.^. dia^. ^^S, ^^^et. Remarks.
A. I— . 39 . M. . 13/12/22 . 245 . 19 . — . 5 . Restricted . —
D. G-. 28 . M. . 16/2/23 . 145 . -111. 66 . -25. Not . No albumin in
restricted urine.
A.C- . 30 . M. . 8/3/23 { |f ^5 . ;122 . 10 . 66 J R^.^ricted { ^^ "^^^i^^" ^"
In the course of this investigation certain points have arisen which seem
to suggest that the hourly diastatic activity of the blood should not be repre-
sented by a constant figure as has been suggested by some. An investigation
of the matter has already been commenced and certain observations have been
made.
ADVANTAGES OF THE PROPOSED METHOD.
Sugar estimations with picric acid very frequently give results which are
decidedly too high. This may be due to —
{a) The disturbing effect of creatinine, which varies in amount patho-
logically and physiologically. In certain renal conditions creatinine is found
in excess. On ingestion of food it may be increased, as has been confirmed by
many observers, in particular Kose and Dimmitt (1916), who showed that the
excess may continue for some days after ingestion. On muscular exercise an
increase may be found if measured at a short interval after exercise
(Schulz, 1912). No doubt other metabolic influences may have an effect on
the creatinine content.
(6) The presence of an unknown substance or substances in the red blood -
cells, as demonstrated by De Wesselow (1919), who found marked variation in
the sugar concentrations depending on the number of red blood-corpuscles, and
obviously not due to creatinine.
The present method has the advantage of avoiding these sources of
inaccuracy. In addition, its simplicity, rapidity and cheapness are notable
considerations ; the avoidance of the necessity of using such expensive apparatus
as a colorimeter, as in Benedict's and Folin's methods, is important.*
I am indebted to Prof. J. A. MacWilliam and to Prof. Hugh MacLean for
much kindly help and criticism.
EEFEKENCES.
De Wesselow, 0. L. V.-(1919) Biochem. J., 13, 148.
Harrison, G. A., and Lawrence, E. D. — (1923) Lancet, 1, 169.
MacLean, Hugh.— (1919) Biochem. J., 13, 135.
Myers, V. C, and Killian, J. A.— (1917) /. Biol. Chem., 29, 179.
Rose, W. C, and Dimmitt, P. W.-(1916) /. Biol. Chem., 26, 345.
Schulz, W.— (1912) Arch.f. d. ges. Physiol, 186, 726.
Sherman, H. C., Kendal, E. C, and Clark, E. D. — (1910) /. Amer. Chem. Soc, 32,
1073.
Stocks, P.— (1916) Quart. J. Med., 9, 216.
* The necessary equipment for the present method can be obtained from Hawksley & Sons,
Wigmore Street, London, for about three pounds.
ADLABD AND SON AND WEST NEWMAN, LTD., IMPR., LONDON AND DOBKlNa.
73
Reprinted from the British Medical Journal, August lllh,
and 18th, 1923.
SOME APPLICATIONS OF PHYSIOLOGY
TO MEDICINE.
II.— VENTRICULAR FIBRILLATION AND SUDDEN
DEATH.*
BY
J. A. MacWILLIAM, M.D., F.R.S.,
PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF ABERDEEN.
(From the Physiological Laboratory.)
It may be permissible to recall that in the pages of this
JouiiNAL^ thirty-four years ago I brought forward a new
view as to the causation of sudden death by a previously
unrecognized formi of failure of the heart's action in man — a
view fundamentally different from those entertained up to
that time. In the course of a long series of experiments on
the mammalian heart, sudden deaths, occurring under
varied experimental conditions, were found to be invariably
associated with a very definite mechanism of failure entirely
different in character from what had hitherto been believed
to be present in cases of sudden dissolution in man depending
on cardiac failure. Little attention was given to the new
view for many years. At that time the current conception
of the relations of the experimental physiology of the heart
to practical medicine was widely removed from what it now
is, thanks very largely to the work of Sir James Mackenzie
and his associates and followers; it was not then recognized
that most of the disturbances that have been experimentally
induced in the mammalian heart (for example, fibrillation,
flutter, heart-block, extra-systoles of various types, rhythms
of abnormal origin, alternation of the heart beat, etc.) have
their clinical counterparts in the manifold derangements of
function in diseased conditions in man.
•Part I was publisbed in the British Mediqil Journal of January 13th,
J923 (p. 51).
[292'23]
74
In more recent times the view that ventricular fibrillation
is a cause of sudden death in man has been accepted by-
numerous observers. Sir James Mackenzie^ writes of sudden
death in auricular fibrillation: "It has appeared to me
probable that in these cases the ventricle has passed into
fibrillation as MacWilliam suggested." Again, referring to
sudden death from heart failure: " The cause of sudden
death is almost certainly due to the onset of an abnormal
rhythm, probably ventricular fibrillation." Sir Thomas
Lewis* states that " We have now the strongest a priori
reasons for believing that sudden and unexpected death
comes to many patients in a manner suggested by
MacWilliam in 1889." The causation of death in this way
has also been recognized by Hering* and many other
observers.
Direct electrocardiographic curves indicative of ven-
tricular fibrillation at the moment of death have been
recorded, notably by an American observer, Halsey.* Oppor-
tunities for the gaining of such direct evidence are naturally
scanty, but the indirect evidence that has accumulated is
sufficient to show that this is, in all probability, not only a
common cause but the usual cause of sudden and unexpected
death of cardiac origin.
Relation of Death from Fibrillation to Ordinary
Myocardial Failure.
The mode of death described in this article is a failure
of the heart's action essentially different from cardiac (or
myocardial) failure in the sense of exhaustion of the con-
tractile power of the cardiac muscle ; a verdict in the latter
sense would usually be, in cases of sudden death, fallacious.
While such exhaustion of contractility is, of course, of
common occurrence in disease, it is a gradual process,
leading to more and more marked impairment of the
pumping power necessary to maintain a good circulation and
to respond to the increased demands of muscular exercise,
etc. There is no ground for the assumption that a sudden
loss of power can occur — that is, that muscular fibres
endowed with contractility adequate for a tolerably good
blood pressure and blood flow should abruptly become
enfeebled or paralysed, apart, of course, from the sudden
action of violent poisons or such gross causes as asphyxia,
obstruction of coronary supply, haemorrhage, etc. What
really happens in the supervention of ventricular fibrillation
is a misapplication of contractile energy thrown away in a
turmoil of fruitless activity, a disastrous change occurring
in muscle that may be already more or less limited in power,
or that may, on the other hand, be possessed of vigour more
than siifficient for the ordinary needs of the circulation.
This often occurs in a heart showing no failure of
rhythmicity, excitability, or contractility.
The inadequacy of former explanations of sudden death
by failure of the heart to contract and expel its contents,
75
asystole, etc., need hardly be emphasized; such explanations
assumed a failure of rhythm or a sudden loss of muscular
power for which there is no warrant. Before the experi-
mental investigation of the mammalian heart had shown
the actual mode of abrupt and complete failure of the ven-
tricular pump by the occurrence of fibrillation, the observed
phenomena of sudden death by syncope — the sudden
abolition of pulsation and all other manifestations of the
beating of the heart — naturally led to the belief that the end
had come through a simple failure of contractility. It was
not realized how extraordinarily resistant and enduring the
contractile power of the heart is, even under experimental
conditions of exposure, manipulation, and severe strain of
various kinds.
Sudden Death and the Pathological Changes found
post Mortem.
It is well known that in many cases where death is believed
to have resulted from cardiac failure the heart has been found
post mortem to present structural charactei-s apparently little
if at all removed from the normal. An elaborate study of
sudden death and the pathological conditions associated
with it was made by Brouardel and Benham.* In this book,
extending to more than ?00 pages, a great deal is to be found
as to numerous and varied morbid conditions and structural
changes in various organs, etc., in cases where death has
occurred suddenly, while it is stated that in some cases no
lesion is found. Elaborate details of dead-house anatomy
are presented, but no explanation is given, or indeed
attempted, as to how vital function has suddenly broken
down, when up to that point in many cases, in spite of
pathological conditions that have often been present, the
individual has been able to go about his affairs with fair
or good actiyity of body and mind. It is obvious that such
structural alterations (coronary lesions, myocardial de-
generative changes, etc.) as were found after death were,
up to the sudden catastrophe, quite compatible with tolerable
efficiency of the functions necessary for the maintenance of
a more or less active life; to determine death an abrupt
change must have occurred — a process fundamentally
different from such slow impairment or limitation of
function as may have been present up to the final disaster.
Some Characters of Ventricular Fibrillation.
The inception of ventricular fibrillation is a sudden event,
though very often preceded by more or less complex dis-
turbances in the normal action. There is an abrupt replace-
ment of tiie effective systole by a continuous turmoil of
inco-ordinated activity in the muscular bundles, excessively
rapid small contractions, each of short duration, coursing
over the intercommunicating muscular fasciculi, so that,
while some portions are contracted, others are relaxed; the
76
result is mere oscillation or inco-ordinated quivering of the
ventricular wall.?, with complete loss of the expulsive power
normally brought to bear on the contained blood by the
strong and simultaneous state of mechanical tension present
in all the muscular fibres during the normal systole. The
effect on the circulation resembles that of absolute stoppage
of the ventricular beat with complete cessation of its mus-
cular activity, such as may be caused by the introduction of
certain poisonous agents", etc. While fibrillation is of
universal occurrence, under certain conditions, in all warm-
blooded animals — both mammals and birds — its tendency to
persist when once established varies greatly, being much
greater in the higher mammalian types. In some animals
among the lower mammals (rat, rabbit, etc.), as well as in
some birds, spontaneous recovery from fibrillation frequently
occurs, but in the higher mammals, and probably in man,
the condition of true fibrillation seems to be invariably fatal
— in the absence of the remedial measure of cardiac
" massage," which may, in animals at least, be supple-
mented by the administration of certain drugs, while arti-
ficial respiration is maintained. Some instances of assumed
spontaneous recovery in the higher mammals and in man are
probably not cases where true fibrillation had been fully
established, but a related though essentially different con-
dition, which may easily be mistaken for true fibrillation.
The essential feature of fibrillation is the establishment of
a mechanism of circulating excitation in the musculature,
depending on a derangement of the normal relations of
(1) the time taken for conduction of the excitation wave
over the ventricular muscle, and (2) the refractory period
of the individual fibres. If the conduction time is unduly
prolonged, or the refractory period is relatively too short,
re-excitation is apt to occur when the excitation wave
reaches fibres that have already recovered sufficiently after
the previous excitation to respond again ; the excitation
wave can then circulate through the complexly arranged
intercommunicating fasciculi ; after a time it becomes
feebler and slower as exhaustion develops, until in a few
minutes all visible movement becomes extinguished. If
rhythmical compression (massage) of the ventricles is
employed (while artificial respiration is kept up) the fibrilla-
tion may be maintained for prolonged periods (an hour or
longer), with ultimate recovery under favourable conditions ;
and such a heart may show regular and vigorous action for
the remainder of a long experiment extending over hours.
So long ago as 1887' I described this mechanism as a peri-
staltic contraction wave along the complexly arranged and
intercommunicating muscular bundles, in contradistinction
to the normal beat.
" The peristaltic contraction travelling along such a structure as
the ventricular wall must reach adjacent muscle bundles at different
points of time, and since these bundles are connected with one
another by anastomosing branches, the contraction would naturally
be propagated from one contracting fibre to another over which the
77
contraction wave had already passed. Hence, if the fibres are
sufficiently excitable and ready to respond to contraction waves
reaching them, there would evidently be a more or less rapid series
of contractions in each muscular bundle in consequence of the
successive contraction waves reaching that bundle from different
directions along its fibres of anastomosis with other bundles. Hence
the movement would tend to go on until the excitability of the
muscular tissue had been lowered so that it failed to respond with a
rapid series of contractions. Then there might be some isolated
peristaltic contractions, such as I have often seen after the cessation
of the fibrillar movement."
Those conclusions were confirmed and extended in a paper
in 1918,* while in the interval similar views had been
advanced and supported by experimental evidence — by
Mines' (1913) in the case of the frog heart and by Garrey^"
(1914) in the mammalian heart. Suggestive experiments
had been made by Mayer^^ (1908) on medusa, etc.
lielations of Refractory Period and Conduction Time.
If the fundamental importance of the relation between the
duration of the refractory period and the conduction time
of the muscle is kept in view it is easy to understand how the
mechanism of circulating excitation may come into operation
under very diverse conditions affecting the ventricles. Any
influence cutting down the refractory period or lengthening
the conduction time disproportionately must naturally tend
to favour the process of re-excitation ; a combination of such
changes is, of course, still more effective. Hence the develop-
ment of fibrillation is witnessed at one time as an apparently
" spontaneous " event in a vigorous heart manifesting signs
of extreme irritability (for example, from chloroform,
digitalis, etc.) or in a normal heart subjected to stimulation
— excessive rapidity of excitation playing an essential part
by shortening the refractory period and slowing the con-
duction time. At another time fibrillation appears in a
heart that presents features of grave depression, diminished
contraction force, loss of tone, lessened excitability, and —
what is the determining factor in this case — pronounced
slowing of the propagation of the excitatory wave, relatively
to the duration of the refractory period; such may be seen
in poisoning by potassium salts, extreme cooling, etc. ; thus
it is often a terminal, or approximately terminal, phase in
the dying heart. In some depressed hearts there is a decided
liability to fibrillation from mechanical disturbance, external
pressure on the ventricles, incising the pericardium so as to
remove its support from a relaxed ventricular wall, etc. In
either case, whether fibrillation is a manifestation of per-
verted irritability or of abnormal depression, the same
explanation of disturbed relationship between the processes
named holds good.
In accordance with this conception it is readily intelligible
that the absolute values of refractory period and conduction
time may undergo extensive variation without fibrillation
being set up; if both of these factors vary proportionately
78
the conditions of circulating excitation do not arise. Thus
artificial cooling of the heart, stopping short of a certain
extreme point (about 23° C. in the perfused cat's heart),
does not induce fibrillation, there being a concurrent
lengthening of refractory period and conduction time as the
cooling goes on — within the limit stated.
Conversely there may be, as results of a rise of tempera-
ture, etc., a marked shortening of the refractory period
without fibrillation occurring, the rate of conduction of the
excitatory impulse being also accelerated. The essential
dependence of the mechanism of fibrillation on the factors
named makes it clear why there should be no constant or
necessaiy relation between the incidence of fibrillation, and
even great alterations in contractile force, tone, etc. Dila-
tation of the ventricles is credited by Levy with a protective
influence ; this view is negatived by various observed facts—
among others the proneness to fibrillation seen in ventricles
weakened, relaxed, and distended as a result of potassium
poisoning; and conversely, the marked resistance or insus-
ceptibility to fibrillation in ventricles that are of small
volume, acting strongly and rapidly and well emptied at
each beat, in sequence to a large dose of adrenaline, etc.
So long as the essential relationship, described above, is not
upset a heart may be profoundly influenced in many ways
without fibrillating : it may beat very rapidly or very slowly,
regularly or very irregularly, powerfully or feebly ; it may
be well emptied or imperfectly emptied at each beat — with
consequent distension in the latter case ; it may be very sensi-
tive or very dull to direct stimulation, and its muscle may
be lax or firm, etc.
Pseudo-Fihrillation.
Apart from the disastrous event of true fibrillation there
is also to be observed under certain experimental conditions
(for example, rapid artificial excitation by a series of elec-
trical shocks, mechanical stimulation, etc.) a temporary
condition in the ventricles presenting many points of
resemblance to true fibrillation — a degree of inco-ordination
or asynchronous contraction of the musculature, recognizable
on inspection and on palpation of the ventricular substance,
attended by great reduction in the range of contraction
movement and very little expulsion of blood at each beat, a
great fall in arterial pressure, and a failure of recognizable
pulsation in the peripheral arteries, etc. It is impossible
to distinguish this condition from true fibrillation by
examination of the arterial pulse.
Usually this condition is soon recovered from when the
artificial stimulation is discontinued, though it may persist
for variable periods. It apparently differs essentially from
true fibrillation in its dependence on a rapid series of
excitatory impulses emanating from a stimulated area or
" spontaneously " from one or more irritable foci, these
impulses forcing a succession of ventricular beats at a rate
79
incompatible with their normal characters; cessation of
these excitatory impulses is speedily followed by a reversion
to the more moderate rates that are compatible with the
normal type of beat. The non-persistence of the abnormal
condition is due to the fact that the mechanism of circu-
lating excitation, characteristic of true fibrillation, has
not been fully established. To this condition 1 have applied
the term " pseudo-fibrillation." It is probable that most, if
not all, the alleged instances of transient fibrillation in man
where recovery occurred — apart from the application of
cardiac massage — were examples of pseudo-fibrillation as
recognized experimentally; this would account for the
features observed in man during the brief attack, and for
the subsequent recovery.
Such is probably the explanation of such a case as that
described by llobinson and Bredeck^^ in which there were
repeated syncopal attacks simulating those of the Adams-
Stokes syndrome; in one of these attacks an electro-
cardiographic record was obtained and showed characters
apparently resembling in some measure those of ventricular
fibrillation — followed by recovery. In another case F. M.
Smith'^ obtained an electrical record suggestive of fibrilla-
tion, the attack being recovered from within a minute.
Hoft'mann^* has also published an electrical curve of a
temporary condition evidently approximating to, but not
reaching, the fully developed condition of fibrillation. There
is also a case reported by Kerr and Bender^ ^ of temporary
fibrillation or a closely allied condition (under quinidine
therapy) where records were obtained.
The Question of Becovery from True Fibrillation.
As has been already stated, spontaneous recovery from
ventricular fibrillation is very frequently seen in the hearts
of the lower mammals — for example, rat — but recovery is
increasingly difficult and rare in the higher forms. In the
cat and rabbit, after true fibrillation has lasted for periods
of considerable duration (minutes), the ventricles may,
without treatment, sometimes show cessation of the fibrilla-
tion movement and " spontaneous " recovery of the power
to execute weak co-ordinated beats, with more or less definite
pumping out of blood from their chambers into the arteries.
This recovery occurs too late as a rule, if not invariably, to
provide for continuance of the life of the animal, for the
collapse of the circulation has lasted too long for restoration
of the vital functions. Most instances of true fibrillation do
not show this sort of ventricular " recovery "; the fibrilla-
tion movement usually becomes slower and feebler and
gradually flickers out in the dying muscular fibres.
In the human subject it is probable that true fibrillation
is (apart from treatment by cardiac massage, etc.) usually
if not invariably fatal, though it seems possible that such
recovery of separate though feeble ventricular beats too late
80
for the survival of the individual may occur — if one may
put this interpretation on the phenomena of some cases that
have been recorded by Sir William Osler/« cases presenting
in striking fashion the external features associated with the
occurrence of fibrillation. Referring to sudden death in
some anginal subjects, he writes :
" Possibly in some act combining intense emotion with muscular
effort there is a rapid change, a sudden unconsciousness, a stony
stare, a slight change in the facial expression, and then with two
or three gasps all is over ; no pulse is felt at the wrist ; the respira-
tion stops; but even when the patient is apparently dead a feeble
heart impulse may be felt or faint heart sounds heard."
In one of these cases where slowly recurring respiratory
gasps occurred over some minutes, cardio-puncture with a
long thin aspirator needle showed movements indicating
heart beats at gradually diminishing rates — 52, 44, 32 per
minute — ceasing fifty minutes after collapse and forty-live
minutes after the last inspiratory gasp. (It may be
remarked that the phenomena here described by Osier were
not such as to be suggestive of reflex vagus inhibition.)
Osier's description of such deaths may be compared with
what Sir Thomas Lewis' '^ says of deaths from ventricular
fibrillation, occurring in subjects of auricular fibrillation :
" From time to time a sudden and unexpected catastrophe
happens; regarded as convalescent, the patient is sitting in bed,
chatting or feeding maybe. A nurse in charge, or perhaps a neigh-
bouring patient, hears a cry or choking sound ; the patient falls
back on the pillows intensely pale, there are a few gasping respira-
tions, a little convulsive movement, and the pulseless patient,
rapidly becoming livid, is still."
Melation of the A-V Junctional Tissues to Ventricular
Fibrillation.
Unlike auricular fibrillation, which, as is well known, may
go on over a long term of years, ventricular fibrillation is
promptly fatal, involving as it does an abrupt and complete
abolition of the pumping action of the ventricles and a
speedy cessation of the circulation. The effect of auricular
fibrillation is to impose a more or less extensive limitation
to the efficiency of the heart in two ways — by the absence of
the normal action of auricular systole in completing the
filling of the ventricular force-pump, and still more by the
rapid and disorderly lead given to the ventricles by the
rapid and irregular excitations transmitted from the
fibrillating auricles to the ventricles; the latter involves a
wasteful and exhausting expenditure of the energy of the
ventricular muscle, attended by relatively poor results in the
way of maintaining the circulation.
Fortunately the structure and properties of the junctional
tissues between auricles and ventricles are such as to afford
a most important protection against transmission of the
fibrillation from the auricles to the ventricles. In default
of such protection the onset of auricular fibrillation would
necessarily be fatal by extension to the ventricles. It is
81
known from experiment that in the auricular and ventri-
cular muscle, with their complexly arranged bundles of fibres,
fibrillation can be propagated across an artificial isthmus,
made by incision, connecting portions of the musculature,
only as long as the isthmus is of sufficient breadth; in the
junctional mechanism, comprising the a-v node with its
special properties, and the narrow a-v bundle with its
longitudinally arranged fibres terminating in the Purkinje
network on the inner surface of the ventricles, the fibrilla-
tion process fails to be transmitted (as such) either from
auricles to ventricles or from ventricles to auricles. The
junctional mechanism, while able to conduct impulses
sufficiently fast to give ventricular beats at rates much above
those of the normal heart under resting conditions or in
moderate exercise, is not able to transmit the vastly more
rapid and characteristic series of excitations of fibrillation.
It is only under certain very special conditions, where the
susceptibility of the ventricles to fibrillation (at relatively
slow rates of excitation) is extraordinarily great, that the
writer has in rare instances seen any experimental evidence
of the possibility of ventricular fibrillation being excited
from the auricles by impulses passing through the a-v
bundle. The possibility of such occurring under pathological
conditions in man is worthy of consideration.
The Purkinje network formed in the interior of the
ventricular walls by the arborizations of the fibres of the
A-v bundle form a sort of distributing board over which
the normal impulses descending the bundle spread swiftly
so as to be delivered almost simultaneously to the myo-
cardium at the various parts of the ventricular cavities,
bringing about the normal co-ordinated contraction of the
ventricular fibres at each beat. Such mode of excitation is
obviously unfavourable to the development of the fibrillation
mechanism, but the latter might under certain conditions
be promoted by an abnormal delivery of irregular and
aberrant exciting impulses, dependent on defects in the
branches of the bundle or its terminal arborizations, such
partially interrupted or distorted impulses impinging upon
the myocardium at different points in abnormal fashion —
alterations in timing or direction of the impulses as might
readily be determined by morbid conditions in some parts of
the conducting network. An exaggeration of these func-
tional aberrations may easily be favoured by circumstances
making an extra call on the heart, such as emotion or mus-
cular effort, or by the succeeding phase of reaction with its
increase of vagus control and other changes.
There is some clinical and pathological evidence that
points to the operation of such causes, resulting in ven-
tricular fibrillation and sudden death in the human subject,
though the particular mode of causation indicated above
does not seem to have been suggested. Thus Nuzum'*
described a case of sudden death in a man, aged 38, who
had shown no definite signs of ill health and where there
82
were no adequate microscopic post-mortem findings to
account for the fatal issue, apart from marked alterations
present in the branches of the a-v bundle in the shape of
fatty infiltration or replacement, the Purkinje fibres being
beset with fatty droplets, etc.
Sapegno,^* from a study of seventy-two cases, inferred
that rapid unexpected death may be due to acute or chronic
lesion of the bundle fibres, the acute changes being pre-
dominant in these fibres when both they and the ventricular
myocardium were affected. He cites an instance of sudden
death in a girl twelve days after recovery from typhoid
fever, not associated with the acute changes sometimes seen
in the myocardium after typhoid, but with lipomatosis in
the bundle fibres — the cell substance being largely replaced
by fat — from the point of division of the main stem to the
point where the two main divisions decrease rapidly in size.
Monckeberg^" described two cases of sudden death associated
with lesions of the Purkinje fibres. One was a diphtheria
case, where no gross changes were found in the myocardium,
but fatty changes were shown by staining with Scharlach B
in the main stem, branches, and subdivisions; the myocar-
dium was fat-free. In the other case (trephining of skull,
etc.) there were more pronounced fatty changes in the bundle
fibres than in the myocardium, though some of the Purkinje
fibres seemed to have remained normal.
It need hardly be recalled that several observers have
described certain abnormal features in electrical records
from the heart as being indicative of defective conduction in
the main branches, bundle block (Lewis and others), or in
the intraventricular Purkinje network (arborization block) —
bizarre ventricular complexes with notching or splintering
of the deflections, prolongation of the duration of the Q R S
group oscillations, inversion of the T wave, etc., in addition
to a remarkably low altitude of the curves in arborization
block. (Oppenheimer and Rothschild,'^^ Carter,'*^ Willius,"
and others.)
Exciting Causes of Ventricular Fibrillation.
In the many observed cases where all the facts point to
ventricular fibrillation as the immediate cause of sudden
death the common association of muscular exertion or
emotional excitement is notable. The ever-recurring reports
of sudden deaths during or shortly after exertion, in persons
who up to the fatal issue had been able to pursue their usual
avocations, emphasize the importance of the conditions
attendant on muscular effort — those involving an increased
demand on the powers of the heart and more or less stress
on the organ. This is brought about in various ways : by
the augmentation of rate and force and irritability through
the agency of the cardiac nerves (diminution or suspension of
vagus control and excitation of the cardiac sympathetic aug-
mentor fibres), increased arterial pressure presenting greater
resistance to the pumping out of the ventricular contents,
83
increased diastolic filling due to more rapid inflow from the
venae oavae, etc. Similar changes attend emotional excite-
ment, with the exception of the greatly increased venous
return to the heart depending on the pumping action of the
working muscles during exertion driving on the blood in
the veins.
While the normal heart is not injured by such changes,
and in virtue of its great reserve power easily responds to
increased demands on it, a heart that is temporarily or per-
manently in an abnormal condition of excessive susceptibility
is apt to be thrown into fibrillation.
Susceptibility to Ventricular Fihrillation.
Both in healthy and diseased animals notable differences
in the ease with which fibrillation may be induced were seen
under experimental conditions that were apparently similar.
And a heart may sometimes be seen, under altered con-
ditions, to pass from the susceptible condition to a stable
one, which may be exceedingly resistant to the induction of
fibrillation by various forms of stimulation that are usually
very effective. Or a change in the opposite sense may take
place ; or there may be variation from one phase to another
more than once in the course of a single experiment in the
case of a healthy heart subjected to certain abnormal
influences. On the other hand, there are many cases where
the abnormal susceptibility is a persistent one associated
with altered nutritive conditions, toxic agencies, etc., in the
muscle.
In healthy animals, cats particularly, a great susceptibility
to fibrillation may be established by the administration of
chloroform; the relation of this condition to the phase of
light chloroform anaesthesia has been specially worked out
by Levy, most (though not the whole) of whose results are
in agreement with those obtained by the present writer over
a long series of years. It is after a deeper phase of chloro-
form anaesthesia that the lighter phase is apt to be attended
by the marked susceptibility referred to.
In the latter condition fibrillation is often readily induced
by stimulation of afferent nerves in various ways — resulting
in reflex contraction of skeletal muscles, disturbance of
respiration, rise of blood pressure, increased rate and force
of the heart with increased return of blood through the
great veins, etc. — in short, the same group of changes that
occur in muscular effort, and brought about in similar
fashion through the instrumentality of the vagus and cardiac
augmentor nerves, excitation of the respiratory and vaso-
motor centres, and the mechanical action of the skeletal
muscles in propelling blood more rapidly back to the heart
by the veins — increasing the rate of its diastolic filling and
its output and work per minute very largely.
It is plain that it is through these changes that the sudden
fibrillation of the ventricles is determined in a susceptible
heart under chloroform, and there is a strong a priori case
84
for the presence of a similar mechanism in the occurrence
of fibrillation and sudden death (apart from chloroform)
during or shortly after muscular effort — granted a condition
of abnormal susceptibility in the ventricular muscle.
In addition to chloroform there are various other toxic
agencies capable of establishing the hypersensitive state.
Referring to drugs, it is well known from experimental
evidence (adduced by Cushny and others) that bodies of the
digitalis series have a powerful influence in this direction —
as also have barium salts, etc. — and when pushed to
extremity kill by causing fibrillation. A whole series of
chemical substances might be cited as having well defined
effects in this direction. And some abnormal metabolic
products may well exercise a similar influence in this respect
on the cardiac muscle. The development of the hypersensi-
tive condition is not necessarily attended by any recognizable
structural alteration. A prominent part in the setting up
of abnormal susceptibility to fibrillation must be assigned to
defective coronary blood supply.
Some Effects of Experimental Coronary Obstruction.
It is unnecessary to recall in detail the long series of
experimental investigations at the hands of many workers
which have demonstrated the frequent occurrence of fibrilla-
tion as a result of ligation of a coronary artery or one of
its larger branches. The evidence available leaves little, if
any, room for doubt that death from sudden coronary
obstruction in man is due to fibrillation ; the clinical features
of many recorded cases are very significant, taken in con-
junction with the very definite facts established by experi-
ment in animals. The reason of the difference between non-
fatal and suddenly fatal coronary obstruction is usually to
be found in the non-occurrence or occurrence of ventricular
fibrillation in the different cases.
It has been found experimentally that coronary occlusion,
if suflBicient to prove fatal, may do so in more than one way :
(1) it may kill rapidly (minutes) from acute ischaemia
causing ventricular fibrillation, or (2) failing this, it leads
to damaged nutrition with degenerative changes (anaemic
necrosis, fibrosis, etc.) ; these changes, apart from leading
in rare instances to rupture of the heart, naturally diminish
the contractile efl&ciency in degrees varying according to
the severity of the anaemia and its distribution. iRecovery
may occur and life be prolonged indefinitely; or death may
be suddenly caused by the supervention of fibrillation. It is
easy to understand how altered functional relations in the
tissues of the damaged area may lend themselves under
certain conditions to the decisive upset of the normal rela-
tions of refractory period and conduction time in the ven-
tricular walls. It remains to be seen whether the tendency
to fibrillation after coronary ligation is dependent mainly
on the conditions induced in the Purkinje system or in the
ordinary myocardium or in both of these.
85
The significance of some of these results of experimental
physiology does not seem to have been fully realized in
relation to their bearing on the human subject. In this con-
nexion the conrincing researches of W. T. Porter^* (1896),
Baumgarten=^« (1899), Miller and Matthews^"* (1909), and
F. M. Smith*^ (1918) are specially relevant. Numerous
observations show that in presence of the defective blood
supply following ligation the abnormal conditions that
develop in the anaemic areas can not only predispose and
lead up — often after months — ^to fibrillation, either during
muscular exertion or during rest, but that the abrupt onset
of fatal fibrillation may come without preceding signs of
cardiac failure, as tested by exercise, or without immediately
premonitory evidences of cardiac disturbance in the shape of
extra-systolic irregularities, tachycardia, etc. Thus fibrilla-
tion can occur without apparent exciting cause and quite
apart from the sequence commonly observed — extra-systoles,
tachycardia, and fibrillation — when death suddenly comes as
an early event after coronary ligation. In other cases, at a
much later time, disturbances of rhythm and evidences of
heart failure present themselves, increasing in intensity and
eventuating in fibrillation. Or temporary irregularities
may have developed at varying periods after ligation — to
give place later to regular I'hythm, and then after weeks or
months to fibrillation and sudden death.
Sudden and Unexpected Death during Best.
The difficulty of explanation of such deaths has long been
felt, in the absence of recognized conditions (effort and
excitement) tending to make an extra call on the heart and
of such powerful afferent excitation as might be assumed
to be provocative of reflex inhibition of intensity and dura-
tion sufficient to be fatal. Recourse has constantly been had
to the verdict of " failure of the heart's action," though the
sudden collapse in cardiac efficiency remains unaccounted
for, post-mortem examination often affording no explana-
tion of the abrupt ending of life. Sir Clifford Allbutt,^^
while suggesting vagus inhibition as a mode of death during
anginal attacks, writes with regard to the class of deaths
now under consideration — during conditions of rest, apart
from anginal attacks, and where no exciting cause is
apparent :
" But the riddle, which I have done so little to read, is the
frequent suddenness of death in one who, having scarcely known
illness, expires under no extraordinary effort; or in the peace of
his own bed or chair passes silently away. The reading of this
riddle is not yet."
In this relationship the facts that have been stated with
regard to the more or less remote effects of experimental
interference with the coronary blood supply by ligation of
a branch are obviously of profound significance, showing
as they do that ordinary life can go on for prolonged periods
(months), either with or without signs of cardiac distur-
bance, until a sudden ending comes by fibrillation, sometimes
86
during muscular effort, but often apart from this, in the
absence of recognizable exciting cause or in presence of
causes too trivial to have any effect under ordinary con-
ditions. And, apart from sudden obstruction, there is no
reason to doubt that a gradual interference with the blood
supply as a result of coronary disease can, by damaging
the nutrition and altering the properties of the muscle,
lead to an abnormal susceptibility to fibrillation.
The applicability to man of these results is naturally easy
in view of the widespread tendency to serious impoverish-
ment of the blood supply (local or general) of the cardiac
muscle in the later half of life, the period when deaths of
the class under consideration usually occur. In the light
of these facts we have a rational basis for many unexplained
disasters — fatal events that otherwise remain shrouded in
mystery.
While the effects of limitation of the blood supply are
proved by abundant and convincing evidence, other
agencies, such as perverted nutrition, toxic influences,
generative changes, etc., can be effective causes. Inter-
ference with normal functioning of the Purkinje fibres on
the inside of the ventricles comes into question as well as
alterations in the ordinary myocardium. Fibrillation may be
determined at a certain point of time by a sudden aggrava-
tion or cumulation of the toxic condition, etc., aided, it
may be, by the incidence of some disturbance of the vas-
cular system too slight to produce any serious effects except
in the specially predisposed condition.
It is to be borne in mind that the conditions disposing
to and leading up to fibrillation need not pervade the whole
of the ventricular musculature, but may be limited to a
certain amount of that tissue, as after obstruction of a
coronary branch and in other conditions; changes in
restricted areas can set up fibrillation, which involves the
rest of the muscle, healthy as the great bulk of it may be.
It is readily intelligible that such limited changes may
naturally be associated with little or no recognizable altera-
tion in the force of the ventricular beat or its general
efficiency. Thus there may be little or no warning of the
impending catastrophe, even at a time when the mine has
been laid and only a spark is needed to precipitate the
explosion.
Ahnormal Cardio-vascular Variations of Obscure Origin.
Under certain conditions of cardio-vascular instability —
usually occurring in association with morbid states of the
arterial system — irregular tides of circulatory change, often
obscure as regards their exciting causes, are sometimes recog-
nizable; one manifestation of these is found in the exten-
sive variations of arterial pressure as measured under
similar conditions from day to day or at shorter intervals.
These variations are sometimes, but not necessarily,
associated with discrepancies in the sphygmomanometer
87
readings from diflFerent limbs, depending on local causes —
the presence or absence of strong contraction in the large
arteries of the respective limbs. Actual rises of general
arterial pressure involve cardiac changes in addition to
vascular constriction, etc. It is evident that disturbances
of this kind may be influential with regard to the onset of
anginal attacks or of sudden death in subjects where a
special predisposition exists.
The Question of Coronary Sjxism.
With regard to sudden interference with coronary blood
supply, apart from the rare accident of embolism and the
less rare occurrence of thrombosis, there arises the question
of spasmodic contraction — an old hypothesis as applied to
the explanation of anginal attacks. The obscure cardio-
vascular disturbances already referred to might be invoked
to account for the onset of some anginal attacks during
rest ; the attack might be determined by antecedent unrecog-
nized changes in blood pressure and heart action. But
there are on record cases in which such attacks during a
period of rest are found to be unattended by elevation of
the blood pressure or recognizable changes in the heart's
action. Again, there are instances among anginal subjects
who have varying periods of relatively low and high
pressures, where no greater tendency to angina has been
found in the phases of high pressure; a notable example of
this has been recorded by Sir James Mackenzie. In such
cases the idea of coronary spasm has commended itself to
many observers, supported by such analogies as the extreme
arterial constriction of Raynaud's disease, the thickening
and narrowing of the temporal artery on the same side as
the pain in migraine and the occasional association of Ray-
naud's disease and migraine, the occurrence (sometimes in
relatively youthful subjects) of transitory aphasias, hemi-
plegias, etc., attributed to an acute temporary anaemia or
ischaemia from extreme constriction of a cerebral artery,
and sometimes associated with migraine. Again, there is
the so-called " abdominal angina," which has been cor-
related with spasmodic contraction of sclerosed mesenteric
arteries. Sir William Osler,^* referring to arteries in
general, states that in a certain stage of sclerosis arteries
are very prone to spasm — a view repeatedly urged by Pro-
fessor W. RusselP' and supported by PaP" and many others.
It is evident that a temporarily excessive contraction of
some part of the coronary system (especially in cases where
the blood supply is already reduced or minimal) would
induce an ischaemic condition which might be responsible
for the onset of fibrillation or of an anginal attack; in this
way an apparently unprovoked paroxysm of pain during
rest might be accounted for and also its equally unexplained
passing off after variable periods. It might also be sur-
mised that amyl nitrite may relax a constricted coronary
as part of its general vascular effect, with relief of pain
88
which may last after the general blood pressure has again
risen to its former level. The spasm hypothesis has been
subjected to searching criticism by Sir Clifford AUbutt, who
among many other considerations states that amyl nitrite
gives no relief in transitory hemiplegias and aphasias.
There is also the occurrence of dyspnoea in coronary
obstruction from sudden thrombosis or embolism (as estab-
lished post mortem) and its absence as a necessary feature
of typical angina; but a possible explanation of this
difference can be suggested.
Evidence of the occasional presence of strong contraction
of large arteries (brachial, etc.) in diseased conditions in
man was obtained by the present writer, in conjunction with
Professor G. Spencer Melvin^* and Dr. J. E. Kesson,^^ in
an investigation of blood pressure a number of years ago,
and surviving sclerosed arteries from the legs of old horses
were found to show extraordinarily intense contraction,
causing complete obliteration of their lumen and an
enormous resistance to attempts to force blood through
them.
In relation to the question of arterial spasm, doubt as to
the existence, at least in effective degree, of vasomotor
innervation of the coronary arteries is not a consideration
of decisive moment. For there is no proof that the forms
of excessive contraction now under discussion — for example,
in the brachial artery or the horse's leg, etc. — are vaso-
motor phenomena ; it is more probable that they are directly
dependent on morbid conditions present in the arterial
muscle at the time.
It may be argued that the foregoing considerations point
to the feasibility of the hypothesis of coronary spasm, in
view of there being no sufficient reason to assume that the
coronary vessels — specially prone as they are to sclerotic
changes — should in diseased states be immune from such
functional disturbances as seem to occur in other arteries.
But the question is far from being closed.
Fatal and Non-Fatal Angina.
It is necessary to discriminate clearly between the separate
questions of (1) the mechanism of pain production in anginal
attacks, and (2) the mechanism of death occurring during
or between attacks, sometimes without warning.
The striking tendency of the graver forms of angina to
terminate in sudden death need not be emphasized. There
is every reason to believe that, in many cases at least, the
end comes by ventricular fibrillation, and that the different
issue in fatal and non-fatal cases hangs on the supervention
of fibrillation in the former and its absence in the latter.
The development of fibrillation as a frequent and charac-
teristic result of defective coronary blood supply, as demon-
strated experimentally, has already been described; and
89
we know, from abundant pathological evidence in man,
the association of coronary and myocardial impairment
with fatal angina. Further, the clinical features of many
recorded anginal cases, where sudden death took place
either in an attack of pain or apart from such, are very
noteworthy in their similarity to those attendant on death
by ventricular fibrillation. The significance of these facts
taken together need not be enlarged upon.
If we accept the view, which has commended itself to
many observers, that an important factor in the production
of pain in angina is to be found in the heart muscle working
with a defective blood supply, it becomes plain how increased
demands on the oi'gan by muscular ejffoi't or emotional stress
may excite an attack by leading to a relative anaemia, the
blood supply, which was sufficient during rest to ensure the
absence of pain, now becoming inadequate for the muscle.
Such a conception might be brought into relation with the
results obtained in an ischaemic limb where, on working a
muscle, acute pain is caused long before the fatigue point
(as indicated by inability to raise the weight in ergograph
experiments) is reached — a mechanism of pain production
apparently different from that present in a muscle
working to fatigue while its normal circulation is going on
(MacWilliam and Webster'^).
It may be conceived that in the close and striking asso-
ciation of angina and sudden death we see the working of
distinct but related mechanisms, based in part at least
on a common underlying process, essentially similar in
character but differing in intensity and in the fatal or
non-fatal issues, these issues being no doubt also influenced
by other conditions which affect the results of the funda-
mental process. A conception of this kind would include
two categories of dangerous anginal conditions — one with
more or less transient attacks of pain of varying grades of
severity, the other with the process, common to the two
categories, going further in some directions, attaining
greater intensity, and culminating in ventricular fibrilla-
tion. But the pros and cons of the vexed question of pain
production in angina are beyond the scope of this paper.
In connexion with the well known fact that pronounced
coronary sclerosis very frequently exists without angina, it
has to be borne in mind that an essential point is, not the
structural change in the arterial wall, but the amount of
actual defect of blood supply through the sclerosed vessels
from greater or less narrowing of their channels, the
presence or absence of contraction in their muscular coats,
the state of the capillary field, etc. Much depends no doubt
on the more or less gradual development of obstructive
change, the establishment of more or less efficient collateral
circulation, etc. It is known that life may go on after the
gradual development of complete occlusion of one coronary
while the other may be found to be very greatly reduced in
calibre; also after complete blocking of a large branch.
90
Collateral circulation obviously plays an important part; it
is now well known that the coronary branches are not end
arteries, as was at one time believed, but have numerous
anastomotic connexions. Further, as described by Gross,^*
the blood vessels (arteriae telae adiposae) of the subepi-
cardial fat, which increases in amount as life advances, can
in some measure exercise a compensating influence, supply-
ing a considerable amount of blood to the subjacent muscle.
Belonging to this system are delicate parallel vessels accom-
panying (at some distance) the main coronary branches, as
well as a feltwork of vessels in the fat of the auriculo-
ventricular groove. Gross emphasizes the importance of a
relative anaemia of the muscular walls of the right heart in
old age, as bearing on failure in pneumonia, etc. ; he
suggests a variation of the adage that a man is "as old as
his arteries " to "as old as his right coronary artery."
It is noteworthy that when the main trunks and large
branches of the coronaries are the seat of pronounced
sclerotic changes the intramuscular twigs and finer ramifica-
tions may remain practically unaffected. The extent and
efl&ciency of the capillary system are obviously of prime
importance.
Syncope from Ventricular Standstill due to Seart-hlocJc.
In cases of heart-block, Adams-Stokes syndrome, etc.,
Avhere death occurs suddenly, it is uncertain whether simple
stoppage of the ventricular beat in the state of diastolic
relaxation alwaj's lasts long enough to kill by paralysis of
the nerve centres, following the phases of unconsciousness
and convulsive phenomena. The time needed in man for
irretrievable damage of these centres by acute anaemia is
not known ; in the ordinary experimental animals it is rela-
tively long — a number of minutes. Of course, there may
sometimes be morbid conditions present in man which would
shorten the time that circulatory arrest can be survived.
But in view of the associated structural damage present
in the Adams-Stokes syndrome, the possibility of the ven-
tricular standstill terminating in fibrillation in some
instances must not be overlooked, though there seems to be
at present no actual evidence of this happening in man. On
the other hand, it is true that a fall of blood pressure, such
as accompanies ventricular standstill, exercises a restrain-
ing influence on the development of fibrillation under cer-
tain conditions; but this does not always hold good under
other conditions — for example, fibrillation sometimes develops
in the gravely depressed or dying heart, notwithstanding the
fact of excessively low blood pressure. In any case it must
be concluded that only a fraction of cases of sudden death
can possibly be attributed to ventricular standstill depending
on the relatively rare condition of heart-block.
Syncope during Tachycardia.
There is strong reason to believe that the fibrillation
mechanism is operative in many cases of sudden death
91
associated with ventricular tachycardia. The myocardial
conditions underlying tachycardia are closely related to
those on which fibrillation is dependent, and there is abun-
dant evidence that the former may develop into the latter.
The excessive rate of beat — whatever be the origin of the
tachycardia — is in itself favourable to this development,
since it involves shortening of the refractory period and
lengthening of the conduction time. The rapidity of
succession of contractions — whether arising in the ventricles
themselves or transmitted with abnormal frequency from the
auricles as in auricular flutter — that the ventricles can stand
without fibrillating varies much in different conditions;
when the conductivity is already depressed and the con-
duction time long, a much lower grade of acceleration
natiirally suffices to establish fibrillation, as can be demon-
strated experimentally.
From the work of many observers we know that in certain
hearts (for instance, after coronary ligation, etc.) there is
often a characteristic sequence of events illustrative of the
close relations of tachycardia and fibrillation — extra-systoles,
first singly, then in irregular runs, more or less continuous
tachycardia, and finally fibrillation. Apart from the super-
vention of fibrillation it is known that the fall of blood
pressure attendant on tachycardia is compatible with life
for very considerable periods ; there have been recoveries
after periods of excessively low blood pressure attended by
unconsciousness, etc., for hours. It remains to be seen
whether the fall of blood pressure is often or ever sufficient
per se to kill, or whether the fatal issue is always deter-
mined by the occurrence of fibrillation. There are no
grounds for accepting vagus inhibition as a mode of sudden
death during tachycardia. The vagus is known to lose
effectiveness in this condition. Auricular flutter, etc., may
induce unconsciousness lasting for hours without causing
death; a very small blood supply can suffice to keep the
nerve centres alive, as Leonard Hill showed many years ago.
The absence of fibrillation is an essential feature in the
recovery from ordinary cases of fainting due to temporary
vascular relaxation due to vasomotor failure or to vagal
inhibition, etc.
Status Lymphaticus, Electrical Shock, Digitalis.
A possible development of the mechanism of fibrillation is
worthy of consideration in connexion with the sudden and
unexplained deaths of the status lymphaticus, occurring, as
they often do, in the absence of any recognized causation.
The features of some recorded examples would fit in with
the known phenomena of fibrillation — for example, such
cases as have shown an abrupt abolition of the signs of
heart action while the respiratory movements persisted for
some little time, in marked contrast to the order of events
in death by asphyxia.
Fibrillation is one of the modes of death in electrical
92
shock, and according to Jex-Blake^* it is operative in death
from lightning. There is convincing evidence — experi-
mental and clinical — that the same mechanism is respon-
sible for sudden death during overdosing with bodies of the
digitalis series.
Sudden Death in Aortic Regurgitation.
The frequency of absolutely sudden death in this con-
dition has long been recognized. In view of the usual
coronary and myocardial involvements, the causation of the
fatal issue — sometimes occurring without antecedent signs
of cardiac failure — may naturally be ascribed to ventricular
fibrillation. There seem to be no good grounds for the
assumptioii of protracted vagus inhibition as an effective
cause.
Tteflex Cardiac Inhibition.
Reflex vagus inhibition has in the past been freely invoked
to account for sudden death in many diseased conditions
and even in healthy persons — for example, from a violent
blow on the epigastrium, etc. On the experimental side
extended investigations on a great number of healthy
animals and a considerable number of diseased ones have
failed to lend support to the hypothesis ; it has usually been
found impossible to stop the heart long enough to kill by
reflex inhibition or even by strong direct stimulation of the
vagus, escape of the heart or the ventricles usually occurring
much too soon for death to be caused by circulatory arrest.
The conclusion has been reached by different observers that
the possibilities of a fatal issue in this way have, to say
the least, been greatly exaggerated, and that there is no
sufl&cient ground for assuming reflex inhibition per se to be
a frequent or important mode of death.* In some instances
where the vagal hypothesis had met with a large measure of
acceptance — for example, in cases of sudden death during an
early phase of ordinary chloroform anaesthesia — the view has
not proved to be tenable, since such deaths have been shown
to be essentially due to an altogether different mechanism —
ventricular fibrillation.
On the other hand, the possibility of increased sus-
ceptibility to vagus inhibition under certain abnormal con-
ditions must be borne in mind. In Embley's^* work on
chloroform it was found that under special conditions, in
dogs after a large dose of morphine, the inhalation of strong
chloroform vapour may cause great slowing of the heart,
fall of blood pressure, and stoppage of respiration — conse-
quences evidently depending on excessive vagus action, and
obviated or removed by exclusion of such action by section
of the vagi or by atropine. But the conditions present in
* Sudden death during operative procedures in the thoracic cavity
(thoracocentesis, etc.) seems, in the light of the work of Capps and D. D.
Lewis, to depend on fall of hlood pressure due to vasomotor changes rather
than to reflex cardiac inhibition (,Arch. of Int. Afedicme, 1907, cxxxiv, 868).
93
these experiments differ widely from those of simple chloro-
form anaesthesia as ordinarily conducted in man. It is well
known that in dogs morphine tends to exaggerate the con-
trolling influence exercised by the vagus centre over the
heart.
In Laslett's^'^ well known case it was clear that vagus
inhibition induced repeated syncopic attacks, causing car-
diac standstill of the whole heart, sometimes lasting for
periods of six to eight seconds, but not long enough to cause
death ; atropine was found to be effective as a counteracting
agent.
In this connexion certain observations by Sir Hugh
Anderson, cited by Sir Clifford Allbutt,** are very note-
worthy. These were on cats in which the cardiac augmentor
nerves were cut, by the stellate ganglia being excised some
time previously. It was found that swinging the animal in
the air caused pronounced slowing of the heart — for
example, from 120 down to 40 in the case of old cats.* (It
may be remarked that such degrees of slowing were not at
all dangerous, and probably did not even cause much
lowering of the systolic blood pressure.) But a remarkable
tendency to sudden death was observed in these animals. No
evidence is stated to show whether such deaths were actually
due to extraordinarily prolonged cardiac standstill, or to
the supervention of some other change — for example, ven-
tricular fibrillation, to which cats are known to be specially
prone under various conditions. So far as the available
evidence goes, there is nothing to indicate that the observed
slowing was more threatening to life than similar slowing
as seen often in common cases of non-fatal syncope in man.
With reference to possible applications of indications
afforded by such experiments to the human subject it has
to be remarked that we know of no clinical condition in
man where there is reason to believe that conditions at all
resembling those stated above are ever present — conse-
quences of an interruption of the various paths that traverse
the stellate ganglia, loss of the nerve cells contained in them,
etcf Experimental investigation shows that the cardiac
augmentor nerves are very persistent in their action,
extremely resistant against drugs and various abnormal
conditions, and demonstrably capable of strikingly effective
action in many gravely depressed states of the cardiac
muscle — in contrast to the vagus functions, which are well
* Sir Clifford Allbutt predicated an increased potency of the vagus in
old and damaged hearts. Gilbert (Arch, of Int. Med., 1923, xxxi, 423) has
recently found in old people a more ready response of the vagus to
digital compression — an age effect, apart from pathological cause. The
mechanism of digital pressure is undecided — whether it acts directly by
stimulation of efferent (inhibitory) fibres or reflexly by excitation of
afferent fibres. There seems to be no proof of actual danger to life in
this way.
t Jonnesca's operation for angina pectoris is an example, resection of
the lower cervical and the first thoracic sympathetic ganglion being done
with the object of interrupting afferent paths from the heart. Jonnesco
recommends the bilateral operation, regarding it as harmless: hA does not
seem to have recognized any such dangers as were noted in Anderson's
experiments. (Jonnesco, Bull, de I'Acad. de Med., Paris, 1920, Ixxx, 93 ;
Presse MM., 1921, xxix, 193; Ibid., 1922, xxx, 353.)
94
known to be readily diminished or cut out altogether by
various chemical agencies, etc.
In many cases of common syncope vagus slowing of the
heart down to 50, 40, etc., a minute is a feature, but such
slowing is wholly insufficient to account for the fall of blood
pressure and the loss of consciousness ; there are other
factors concerned. Such cases do not have a fatal issue.
Some instances of this condition were described by Lewis'*
a few years ago in subjects of " iritable heart." Pretty
extensive cardiac slowing is quite compatible with a fairly
good blood pressure — vastly higher than what is necessary
for the continuance of life. Pronounced slowing (without
danger to life as a rule) is, of course, familiar in some forms
of violent pain — for example, in biliary and renal colic, etc.
The conditions under which sudden death most commonly
occurs — namely, muscular exertion — are not favourable to
prolonged vagus inhibition, but on the contrary are asso-
ciated with reduction of the normal vagus control over the
heart and concomitant activity of the augmentor nerves,
leading to acceleration with increased force of the beats,
etc. — conditions favouring the development of fibrillation in
predisposed subjects. The same holds good generally in
emotional excitement, apart from the very brief standstill
(or prolongation of diastole) which may be caused by sudden
fright.
Vagus Inhibition succeeded hy Fibrillation.
There is another possibility with reference to the effects
of vagal inhibition. Experiment has shown that attacks of
auricular fibrillation of varying duration sometimes develop
after a period of inhibition, sometimes after one or more
recommencing auricular beats have occurred. The develop-
ment of fibrillation in these instances is definitely related to
the occurrence of the preceding phase of inhibition induced
by vagus stimulation.
Fibrillation of the ventricles has also been seen following
vagus standstill, but this is a rare phenomenon as compared
with the development of auricular fibrillation in similar
circumstances. In the course of researches over a great
many years I have obtained records of only a very few
examples. Still these are enough to indicate that, in
presence of undue ventricular susceptibility, fibrillation may
sometimes be determined in this way in some of the manifold
varieties of abnormal conditions that can occur in man.
Thus vagus inhibition, much too brief to be dangerous
through the standstill induced, may possibly involve a
mortal issue through a succeeding fibrillation.
Fibrillation or Beflex Inhibition in Sudden Death in
Anginal Subjects.
The following considerations may be cited in favour of
the fibrillation view of death in angina.
1. The presence of coronary and myocardial conditions
95
which are known in certain circumstances to predispose to
fibrillation. The invariable or almost invariable occurrence
of coronary lesions in cases of fatal angina is a matter of
general agreement. Sir Clifford Allbutt has adduced a
wealth of facts and considerations marshalled with his usual
skill, in favour of his view of the aortic origin — as con-
trasted with coronary and myocardial origin — of anginal
pain. But this veteran clinician at the same time recog-
nizes that the question of a fatal issue to an anginal
attack is essentially associated with the condition of the
myocardium.
2. The recognition by numerous observers, in some anginal
attacks, of acceleration of the heart's action with irregu-
larities, extra-systoles, etc. ; such are known in many con-
ditions to herald the onset of fibrillation. Among others,
Windle recorded a fatal attack of angina in which the
heart rate rose from 75 to 150 and became very irregular.
3. Though some slight slowing of the heart may occur in
an anginal attack, there seems to be no direct evidence of
the occurrence of pronounced inhibition, such as might, if
somewhat intensified, threaten a suddenly fatal issue; the
degrees of inhibitory slowing observed have been far removed
from determining circulatory failure or even causing any
considerable fall of blood pressure. There seems to be no
relation between the severity and duration of the pain and
the tendency to die in the paroxysm.
4. Death often occurring at the beginning of an anginal
attack or in one that is relatively slight as regards pain,
etc., is probably of the same mechanism as absolutely sudden
death occurring between attacks or in persons y^ho are not
subjects of angina; the considerations bearing on such
deaths are probably applicable to deaths during anginal
attacks.
5. In the case of death between attacks or during rela-
tively slight pain there is no evidence of such powerful
aflFerent excitation as might be supposed to produce cardiac
inhibition of such intensity and duration as to be fatal.
Of course it would be rash to dogmatize at the present
time on an exclusive application of one mechanism as being
the only one operative in all instances of anginal death ; it
may be that one or other form is present under different
conditions. But there is a strong case for fibrillation as a
common mode of death in anginal subjects, whatever the
precise mechanism of pain production in angina may be.
Conclusions as to Sudden and Unexpected Death of
Cardiac Origin.
Rupture of the heart is a very rare accident. Simple
standstill of the ventricles in complete heart-block can only
be a rare cause — assuming thai; such standstill may some-
times kill without fibrillation as the terminal event. As
has been stated, it is open to grave doubt whether reflex
vagal inhibition per se — that is, without the supervention of
fibrillation — is responsible for many deaths. Blocking of
the mitral orifice by a thrombus and embolism of the pul-
monary artery are known to be of very rare occurrence.
(Thrombosis and embolism of the coronary arteries kill, as
has been already stated, by fibrillation.)
The old idea of a heart that is working with fair efiiciency
abruptly " failing to contract " against excessive resistance
may be set aside as untenable, in the absence of the sudden
action of violent poisons, etc.
There remains the conclusion that the great majority of
absolutely sudden deaths are to be ascribed to ventricular
fibrillation.
Symptoms of Ventricular Fibrillation in Man and
Animals.
The similarity between the group of symptoms associated
with many cases of sudden death in man and those attendant
on ventricular fibrillation experimentally induced in animals
is indeed striking. The abrupt abolition of pulse, cardiac
impulse, and heart sounds, the sudden fall of blood pressure,
unconsciousness, muscular relaxation often preceded by a
brief phase of rigidity or convulsive movement, dilatation of
the pupils, and the continuance of slow deep respiratory
movements, are identical in animals and in the human
subject, while in the latter the speedy replacement of the
initial intense pallor by lividity or marked cyanosis is a
notable feature. The amount of colour in the face, together
with the occurrence of several respirations after the collapse,
have sometimes made onlookers somewhat incredulous that
death has taken place. The occurrence in some cases of
premonitory features such as extra-systolic irregularities,
bouts of tachycardia, etc., is significant. It is important
that, in the collection of evidence as to unexpected and
unexplained death, special attention should be devoted to
ascertaining the occurrence of the group of associated
features just stated; these have been very definitely recog-
nized in many cases of sudden death where accurate observa
tions have been made. Some such cases have come under
the direct observation of the writer.
No doubt some of these phenomena are common to certain
other forms of sudden circulatory failure — for example, from
heart-block, collapse induced by violent afferent impulses
(blow on epigastrium, etc.), or in certain cases of auricular
flutter, etc. But there are special features in some of
these — for instance, as regards the behaviour of the
respiratory centre, etc.
Protective and Bemedial Agencies.
In animal experimentation — on cats, which are remark-
ably liable to ventricular fibrillation — the use of certain
drugs has been found by the present writer*' (working in
97
conjunction with Professor Spencer Melvin and Dr. J. R,
Murray) to have decidedly beneficial effects, both in the
way of pi'otection against the onset of persistent fibrillation
(for example, against faradic currents one hundred times a3
strong as are usually effective) and — in combination with
cardiac massage — as regards recovery from the actual
attack. These methods are at present only applicable undei
experimental conditions. But they give some ground for
hope that, with fuller knowledge of the conditions that influ-
ence the inception and persistence of fibrillation, much may
be possible in the future as regards the warding off of such
catastrophic happenings as often bring life to an unexpected
and sudden close from failure of cardiac function, occurring
often in persons whose hearts are far from being worn out,
but on the contrary are endowed with myocardial power
amply sufficient not only for quiet existence but not infre-
quently for the demands of considerable bodily and mental
activity.
There is reason to believe that in man, as in animals, an
undue susceptibility to fibrillation is sometimes a temporary
phenomenon depending on circumstances that may be more
or less markedly transitory, though no doubt it is very
often a persistent condition depending on abnormal changes
in the ventricular musculature; in the latter case immunity
from sudden death must in large measure depend on avoid-
ance of the directly provocative causes of fibrillation in
a predisposed heart, such as sudden muscular exertion,
especially when accompanied by emotional stress, etc.
References.
' MacWilliam : British Medical Journal, 1889, i, 6. ' Mackenzie : The
Future of Medicine, London, 1919, 178. 'Lewis: The Mechanism and
Graphic Registration of the Heart Be^t, London, 1920, 318. * Hering :
MUnch. med. Woch., 1912, lix, 750 and 818. 'Halsey: Heart, 1915, vi, 67.
•Brouardel and Benham : Death and Sudden Death, London, 1902, 2nd
edition. ' MacWilliam : Journ. of Physiology, 1887, viii, 296. ' MacWilliam :
Proceedings of the Royal Society, 1918, B, xl, 302. 'Mines: Journ. of
Physiology, 1913, xlvi, 349. '» Garrey : Amer. Journ. of Physiology, 1914,
xxxiii, 397. " Mayer : Popular Science Monthly, 1908, 471. " Robinson and
Bredeck : Arch. Int. Med., 1917, xx, 725. "Smith, F. M. : Arch. Int. Med.,
1918, xxii, 8. "Hoffmann: Heart, 1911-12, iii, 213. '^^ Heart, 1922, ix, 269.
>* Osier: Lancet, 1910, i, 699. i' Lewis: Lectures on the Heart, London,
1915, iii. "Nuzum: Arch. Int. Med., 1914, i, 640. "Sapegno: Arch, per
le sc. med., 1910, xxxiv, 143. ^° Monckeberg : Untersuch.uber das au.-ventr.
Bundle bet Mann, Jena, 1906, 318. " Oppenheimer and Rothschild : Proc.
Soc. Exp. Biol, and Med., 1916, xiv, 57. "Carter: Arch. Int. Med., 1918,
xxil, 331. "Willius: Arch. Int. Med., 1919, xxiii-xxiv, 431. "Porter:
Journ. Exper. Med., 1896, i, 46. ^'Baumgarten : Amer. Journ. of Physiology,
1899, ii, 243. "Miller and Matthews: Arch. Int. Med., 1909, iii, 476.
" Smith : Arch. Int. Med., 1918, xxii, 8.
='Allbutt: Diseases of the Arteries, etc., London, 1915, ii, 58. ^» Osier:
Allbutt and Rolleston's System of Medicine, London, 1909, vi, 144.
=» Russell : Arterial Hypertonus, Sclerosis and Blood Pressure, Edinburgh
and London, 1907. "Pal: Gefasskrisen, Leipzig, 1905. »» MacWilliam and
Melvin : British Medical Journal, 1914, ii, 777. " MacWilliam and
Kesson : Heart, 1913, iv, 279. " MacWilliam and Webster : British
Medical Journal, 1923, i, 51. " Gross : The Blood Supply of the Heart,
London, 1921. " Jex-Blake : British Medical Journal, 1913, i, 548 and 601.
'•Embley: British Medical Journal, 1902, i, 817, 885, 991. ''Laslett:
Quart. Journ. of Medicine, 1908-9, ii. 347. »» Allbutt: Loc. cit., p. 475.
"Lewis: Heart, 1920, vii, 175. *» MacWilliam : Proc. Roy. Soc, 1918, B,
xl, 302.
a"^
lieprmtedfrom the British Medical Journal, December 22nd, 1923
SOME APPLICATIONS OF PHYSIOLOGY
TO MEDICINE.
III.— BLOOD PRESSURE AND HEART ACTION
IN SLEEP AND DREAMS:
Their Relation to Haemorrhages, Angina, and
Sudden Death.*
BY
J. A. MacWILLIAM, M.D., F.R.S.,
PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF ABERDEEN.
(From the Physiological Laboratory.)
This is an important, and in some of its aspects an almost
unexplored, field of study, with an obvious bearing on many
questions. Precise data on the subject are naturally some-
what diflBcult to obtain. The present paper contains some
results of slowly accumulating observations carried on by
the writer as opportunities presented themselves over a long
series of years.
Changes in Normal Sleep.
The slowing of the pulse rate (noted by Galen) and the
respiration during sleep has long been known to be accom-
panied by a lowering of bodily temperature, a great reduc-
tion in metabolic activity and heat production, depression
of reflexes, diminished secretion, etc. There is general
agreement as to a definite lowering of the systolic blood
pressure, varying in different conditions and as recorded
by different observers, but often amounting to 15 to
30 mm. Hg at the end of two hours' sleep ; the pressure
gradually rises in the later portion of the night's sleep.
Greater reductions have been noted in persons with high
pressures in the daytime. Thus some years ago Brooks
*A communication on this subject was made to the International
Physiological Congress at Edinburgh on July 26th, 1923. Part I of this
series was published on January l3th, 1923 (p. 51), Part II on August
11th, 1923 (p. 215).
[476/23]
100
and Carroll in 39 " hypertonic " subjects with an average
systolic pressure of 204 mm. found a fall of 44 mm. after
two hours' sleep; at the moment of waking it rose 22 mm.
from the level present in sleep. More recently, in the last
year or two, C. Miiller in normal persons found the systolic
pressure to be down to 94 mm. in men and 88 mm. in women
during sleep, after a small dose of veronal. Blume, in
men and women with moderate day pressures, recorded
falls of 15 mm. and 21 mm. respectively, while in those
with high day pressures the falls averaged 31 mm. and
39 mm. Much importance has been attached by some
writers to this reduction of pressure; it has even been
regarded, though on very insufficient groimds, as the deter-
mining cause of sleep.
It must be borne in mind that in the recumbent position
a fall of aortic pressure would be necessary to prevent the
pressure in the cerebral arteries from being higher in the
horizontal than in the erect position — from the influence
of gravity, the hydrostatic factor of the weight of the
column of blood between the levels of the heart and the brain.
Allowance for this factor in the recumbent posture cuts
down the observed lowering of arterial pressure to a com-
paratively small amount, probably much too small to play
the potent role that has been ascribed to it in the pro-
duction of sleep. Further, the crude analogy of uncon-
sciousness caused by an arrest or sudden great diminution
in the blood supply to the brain cannot be regarded as
valid when applied to the induction of the normal process
of sleep.
Diminished vascularity of the brain substance during
sleep has been described by various writers (Durham and
others) on the ground of direct observations on exposed
portions of the brain surface. A similar change has been
inferred from the plethysmographic records obtained by
Mosso and his followers, who found evidence of an increased
volume of blood in the limbs (arm, etc.) during sleep, and
assumed this to be attended by lessened vascularity of the
brain, the converse conditions being present after awaking.
But this hypothesis has to be revised in view of Leonard
Hill's work establishing the practical accuracy of the old
Monro-Kellie doctrine that the amount of blood within the
skull is a constant quantity, whilst its distribution in
arteries, capillaries, and veins respectively varies in
different conditions. Weber's more recent work indicates
that when there is less blood in the limbs there is more in
the abdomen, not in the brain.
Plethysmographic observations have clearly shown respon-
siveness to stimuli during sleep, inducing alterations in the
volume of a limb and showing certain changes in the dis-
tribution of the blood in the vascular system. But such
observations give no information as to the state of the
aortic blood pressure, upon .which the pressure in the
cerebral arteries depends.
101
Eelations of the Period of Sleep to Some Diseased
Conditions.
In accordance with the accepted view that the vital
activities, as indicated by heart action, respiration, blood
pressure, temperature, and general metabolism, reach their
low-water mark in the early hoiiis of the morning, it is
easily intelligible that death from illnesses involving pro-
gressive exhaustion and a gradual running down of the
machinery of life should often take place in that period.
Statistics are available which bear this out. Thus
Schneider (Berlin), in a total of nearly 58,000 deaths, found
that deaths were most common between 4 and 7 a.m.
Watson and Finlayson (Glasgow), dealing with records of
nearly 14,000 deaths, fixed the highest mortality between
5 and 6 a.m.
Many phenomena of disease, aggravation of morbid con-
ditions and symptoms in the night, can be brought into
relation with the general lowering of vital activities during
sleep — for example, some respirator}^ troubles which may
in some cases be associated with the depression in respira-
tion naturally occurring in that period, the reduced sensi-
tiveness of the respiratory centre to the normal excitation
by CO^ with the consequent modification in the state of the
blood, heightening of the grade of acidosis which may be
present, development of Cheyne-Stokes respiration, etc.,
often associated with attacks of severe dyspnoea, etc.
Incidence of Haemorrhages, Anginal Attacks, and
Sudden Death in the Night.
In contrast with the associations of depressed functions
during sleep as affecting some of the manifestations of
disease there is another class of phenomena for which a
different interpretation is required, for they obviously do
not lend themselves to ex])lanation by the lowered vital
activities of nightly rest and sleep.
In connexion with the subject of haemorrhages of various
kinds and their times of occurrence and mechanism, ques-
tions arise. The time incidence of many vascular ruptures
is naturally accounted for by the conditions prevailing at
the moment of their occurrence — rise of blood pressure and
increased stress on the walls of the vessels determining rup-
ture at the weakest part — for example, muscular effort,
the influence of gravity in cei'tain postures, abdominal
straining, etc.
But why should a weakened vessel give way during the
period of nocturnal rest and sleep, since a lowered blood
pressure is naturally protective against rupture? Why
cerebral haemorrhage should frequently occur in the night
and in sleep is a question that was asked long ago by Sir
Samuel Wilks and apparently never answered. In view of
the lowering of blood pressure and a diminished blood flow
through the brain in sleep, why should a cerebral vessel
102
burst at that time? A similar question has to be dealt
with in the case of pulmonary haemorrhage, which, as is
well known, is frequently nocturnal in its incidence. The
same applies to gastro-intestinal haemorrhages.
It is, of course, a matter of familiar knowledge that true
anginal pain occurring in the daytime is commonly asso-
ciated with exertion or excitement involving raised blood
pressure and an increased call upon the heart, the pain
diminishing or passing off with cessation of the muscular
effort or emotional disturbance, reduction of the blood
pressure by amyl nitrite, etc. But it is also well known
that anginal pain sometimes seizes the patient in the quiet
of the night, awakening him from sleep. What is to be put
down as determining the onset in these cases?
Again, we know that sudden death in the night is not
rare, sometimes coming thus to persons who have shown
little or no evidence of serious departure from the level of
their ordinary health, or at least nothing to warrant the
expectation of so sudden a termination. In a former paper
considerations were advanced in support of the view that
the usual mechanism of such deaths is to be found in
fibrillation of the ventricles, occurring in a heart which
has become specially susceptible as a result of defective
coronary blood supply, degenerative changes, toxic
influences, etc. , But, granted such predisposition, what
is the exciting cause that precipitates the sudden and
unforeseen disaster in the night-time?
Becognition of Two Different Conditions in Sleep.
The results obtained in the present investigation lead
to the conclusion that m considering the subject of
sleep we have to deal with two distinct conditions, which
have strikingly different associations as far as nervous,
circulatory, respiratory, and other functions are concei'ned :
(1) undisturbed or sound sleep, attended by lowering of
blood pressure, heart and respiratory rates, etc., and (2)
disturbed sleep, modified by reflex excitations, dreams,
nightmare, etc., sometimes accompanied by extensive rises
of blood pressure (hitherto not recognized), increased heart
action, changes in respiration, and various reflex effects.
The circulatory changes in disturbed sleep are sometimes
so very pronounced that it is somewhat remarkable that
they should so long have escaped observation. So far as
the present writer knows, the occurrence of marked rises
in blood pressure during sleep has not even been suggested
— apart from the fact that no actual measurements have
been recorded. No doubt paucity of opportunities and
diflBculties in observation have stood in the way. But the
considerations as regards the occurrence of haemorrhages,
etc., in the night (stated in the earlier part of this paper)
give distinct indications of the probability of important
blood pressure changes being present in some instances.
103
Disturbed Sleep.
In connexion with the circulatory and the other
plienomena of disturbed sleep there are various categories
with regard to the degree in which the subject is able to
recall his dreams or is conscious of the disturbances after
awaking.
1. There is no recollection of the disturbed sleep or
dreaming condition, though the presence of such was
clearly shown by observations on the sleeper — occurrence
of muttering, talking, groaning, movements of the face,
fingers, etc. ; reflex disturbances were evidently active in
pronounced degree.
2. On awaking there is a sense of the sleep having been
uncomfortable and troubled, but there is no recollection of
dreaming having occurred.
3. The fact of dreaming is remembered, but not the
definite sequence of the dream.
4. Vivid dreams remembered in great detail.
In all the above categories cardio-vascular disturbances,
etc., have been recognized in more or less marked degree.
These disturbances disappear at various periods after
awaking — often in a variable number of minutes.
Distribution of the Changes in Disturbed Sleep.
The incidence of the recorded disturbances upon the
various systems varies widely in different instances.
The heart's action may be specially affected by the
impinging of nervous impulses on the cardiac regulating
centres in the medulla, etc. There may be much accelera-
tion of the pulse with comparatively little elevation of
arterial pressure; there may be a strong cardiac impulse,
with or without sensations of palpitation.* On the other
hand, the arterial tone may be mainly influenced, vaso-
constriction being chiefly instrumental in causing a large
rise of jiressure, attended in some instances by moderate
or slow heart rates; in accordance with Marey's law the
high blood pressure acts by increasing the controlling
influence of the vagus centre over the rate of beat.
A strong cardiac impulse and a large pulse wave may be
prominently in evidence. Again, both heart and arteries
may be markedly influenced, giving a high blood pressure
with strong and rapid cardiac beats, powerful cardiac
impulse, etc.
The respiration is sometimes much altered in the way of
augmentation or irregularity, but there is no constant
association between these changes and the circulatory dis-
turbances ; there may be marked respiratory changes while
• In contrast with the slowed pulse rate which is normal in the small
hours of the morning, there is sometimes an acceleration at this period,
apart from the development of abnormal rhythms, true tachycardias,
etc., and without evidence of the mere extensive disturbances of blood
pressure, etc., described in this paper. Such acceleration is probably
ascribable to reflex influences which have become operative during the
preceding period of sleep in the earlier part of the night.
104
there is little or no evidence of circulatory alteration.
Long ago Hammond described notable respiratory dis-
turbances in dreams while describing the pulse as being
unaffected, except in regard to slight* irregularity ascrib-
ablo to the respiratory alterations. In addition to the
circulation and respiration the disturbances of troubled
sleep may extend, in varying degree, over other systems,
somatic and visceral, as evidenced by sweating, tremors,
vomiting after awaking, etc. It is obvious that such dis-
turbances acting on vaj ious functions in different ways
may be responsible for important effects in some conditions
of disease.
A notable feature (remarked long ago by Hughlings
Jackson) is the absence (apart from somnambulism) of large
movements of the limbs, etc., even during dreams of
vigorous exertion, while movements of fingers, lips, etc.,
may occur, contraction of distal muscles being practicable
while proximal ones fail. It would seem that impulses
from the cerebral cortex can sometimes reach the medullary
centres (cardiac, respiratory, vasomotor, sweat, etc.)
while failing to activate the large muscles of the limbs
even during dreams with sti'ong emotional content.
The Dreaming State in the Dog.
The phenomena observed in the human subject are
evidently paralleled by what is recognizable in the healthy
dog during dreams of hunting, etc., with the familiar move-
ments of toes and paws, tail and ears, biting action, series
of subdued barks, etc. The heart is often rapid and irregu-
lar with inhibitory pauses, bouts of acceleration, etc., while
a violent cardiac impulse may be perceived ; respiration is
frequently hurried and irregular, with gasps, etc. The
knee-jerk may be increased — as Lombard noted in man
during a dream of active movement. It has not been
found practicable to get actual measurements of blood
pressure that are satisfactory, for disappearance of the
changes present in the dreaming state is very quick
when the animal awakes. But the finger on an artery
has sometimes given unequivocal evidence of a rise of
blood pressure.
Some Characters of the Nervous Disturbances.
The extent and intensity of the functional disturbances
which may be set up during troubled sleep and the
dreaming state are remarkable, though quite intelligible
in view of the diminution or suspension of the control
normally exercised in the waking state by higher neural
mechanisms, which come to be more or less completelj' in
abeyance during sleep ; released from such control the lower
mechanisms are apt to give exaggerated responses to
stimuli which would have comparatively little effect in the
daytime. Thus afferent imj)ulses (somatic or visceral)
105
which would have only slight and quite different effects in
the waking state may call forth complex and pronounced
reflex responses. The influence of afferent impulses in
provoking and shaping the course of dreams need not be
emphasized. Potent in this respect are impulses from the
viscera which in the waking state would only be productive
of slight sensations of discomfort— headache, nausea, etc. ;
in sleep elaborate responses may be set up, especially when
unrestrained emotional processes are called into action
with their resultant effects on both cerebro-spinal and
autonomic innervation — excitation of • sympathetic, etc.
Such emotional excitation is apt to reach a high grade of
intensity from lack of the balance and restraint normally
exercised by the fully active mechanisms of ordinary con-
sciousness, especially by those subserving the higher levels
of mental function acquired through experience after the
infantile stage of life.
The suddenness of development of the functional distui'b-
ances in blood pressure, heart action, etc., in the dreaming
state is an important feature. As is well known, most
dreams are of very brief duration as regards the actual
time occupied, a number of seconds or a very few minuted
often sufficing for a dream which is subjectively a long and
complicated one — for example, an apparently long and
varied dream has been recorded as running its course
between the beginning and the ending of a clock striking
midnight. The associated functional disturbances may thus
be set up with unusual abruptness, as compared with the
waking state — as, for instance, in ordinary muscular exei'-
cise. It follows that there is little or no time for the
coming into play of the various adjustments and compensa-
tions in the circulatory and respiratory systems, etc., that
are operative in muscular exercise ; in the latter the rise of
arterial pressure is checked by gradual dilatation of the
vessels of the skin and the working muscles, while the
heart accommodates itself with the aid of increased
coronary blood supply, etc. Thus the blood pressure rise
in certain dreams may be both large and steep in ascent.
The call on the heart, through its nervous apparatus, etc.,
may also be a sudden one.
Influence of the Recumbent Posture.
So far as the rupture of a weakened cerebral artery is
in question the hydrostatic factor in the recumbent
position is an added consideration ; the weight of the
column of blood between the levels of the head and the
heart, which reduces the cerebral artery pressure in the
standing position, is now largely out of action ; with a
given aortic pressure the pressure in a cerebral artery is
naturally higher by a very appreciable amount (varying
according to the elevation of the head) in the recumbent
than in the erect posture, and the danger of a cerebral
106
haemorrhage during a rise of aortic pressure is necessarily
increased.
Observations on Blood Pressnre, etc.
The subjects examined were persons mostly between the
ages of 30 and 65, all, so far as was known, without
organic disease of the circulatory system. The observations
were made quickly after the awakening of the subject, the
apparatus having been kept in readiness for immediate
use. Systolic blood pressure was measured by the auditory
Hour of Observation.
Pulse
Kate.
Systolic
Pressure.
Diastolic
Pressure.
Pulse
Pressure
1.0 a.m. ...
75
7.0
62
8.0
65
110
75
35
8.20 breakfast (in bed)
8.50
75
9.15
68-70
125
75
50
9.30
70
125
75
50
9.45
70
125
75
50
11.30
70
125
80
45
12 noon. Subject got up
12.25 p.m. Sitting quietly ...
85
12.55
81
12 midnight. In bed after first
sleep (somewhat disturbed)
70
140
80
60
Next morning—
6.0 Subject awoke with feeling
of disturbed sleep but no
memory of definite dream.
Arterial sounds (auditory
method) very loud and the
62
182
105
77
murmurish phase very pro-
nounced.
Another reading two or three
minutes later
165
95
70
6.15
60
145
90
55
6.30
58-60
115
70
45
8.0
60
130
80
50
10.30
76
120
70
50
During the day the pulse rate was generally 76 to 80.
and tactile methods, diastolic pressure by the auditory
method. On occasions when no measurements could be
made convincing evidence of the occurrence of extensive
changes was obtained by ordinary digital examination of
arteries, palpation of the cardiac impulse, etc. The follow-
ing are some of the examples of the sort of observations
made and the nature of the results obtained.
107
Subject No. 1.
The effect of walking upstairs (twenty steps) was compared
in this person with the disturbances occurring in sleep. The
pulse rate was raised from 80 to 90-95, the systolic from 120 to
140, and the diastolic pressure from 80 to 90; the observations were
made while the ascent was being continued, not after its cessa-
tion. Ordinary walking exercise on a fairly level road caused
comparatively slight changes in the heart rate and the blood
pressure. In the same subject some days previously atropine
(1/50 grain hypodermically) raised the pulse rate from 81-82 to
130, with systolic and diastolic pressures of 135 and 75-80 respec-
tively, as compared with 115 and 70 before atropine. Abdominal
straining (expulsive efforts) raised the systolic blood pressure only
a few millimetres.
It is evident that in this individual the stress on the circula-
tory system was vastly greater during such disturbed sleep as is
described above, than under the conditions of ordinary easy life
with avoidance of sudden violent effort, emotional excitement,
etc. The actual height of pressure attained during the disturbed
sleep was, no doubt, decidedly higher than as measured after
awaking when it is declining with some rapidity.
Subject No. 2.
Subject in bed in afternoon. While asleep he had lain on the
right side with the right arm pressed on by the head so that
the right radial pulse was abolished. The left radial pulse
was found to be very fast and the artery large and strikingly
tense, immediately after awaking ; these unmistakable evidences
of an extensive rise of blood pressure speedily passed off. The
sleeper reported having been under the influence of a pronounced
nightmare, with the illusion of his lying prone near the door of
a house while he heard a visitor approaching along the drive ;
he had vivid and distressing sensations of ineffectual efforts to
rise. The nightmare was no doubt determined by the posture,
the pressure on the arm, and the ischaemia caused. After awaking
numbness and tingling were felt in the right !iand, while the
radial artery became very large and the skin flushed — evidently
after-effects of the ischaemia.
Subject No. 3.
A subject, who had some symptoms of gastro-intestinal dis-
turbance but was pursuing his usual avocations, had in the course
of a night of broken sleep a dream in which he felt lively resent-
ment at the irritating conduct of an official on a public occasion
— a vivid dream but not distinctly a nightmare ; there was no
sense of fear, oppression, ineffectual effort, etc. On his awaking
it was found that there was no sense of palpitation, no sweating,
and no subjective alteration in respiratory sensations; no marked
change in the respiratory movements was observed. But the
cardiac impulse was greatly increased in force and felt over a
larger area than usual in this person. The pulse was accelerated
from a normal rate of 70-80 to 90-95. But the most notable change
was a greatly raised blood pressure with an extensive pulse pres-
sure, as shown by digital examination of the radials; the arteries
were large and tense, obliteration difficult, and the range of the
pressure variations at each beat palpably large. When examined
fifteen minutes later these altered conditions were practically gone.
Some hours later another dream took place, the details of
which were not clearly remembered. Similar phenomena, in
108
somewhat less pronounced degree, were recognized ; these virtually
disappeared in a few minutes.
In one dream systolic pressure rose from 130 to over 200
Emotion, Motor Effort, and Gastro-intestinal
Disturbance.
While the most striking cardio-vascular effects are
naturally present in dreams with a strong emotional con-
tent, it is to be noted that a vivid dream of active move-
ment (cycling, for example) without sensations of night-
mare, etc., may cause a pronounced rise of blood pressure.
Thus in an instance of this kind the pulse tension was
greatly increased and the pulse pressure was extensive while
the heart rate remained at 72-75 ; the elevation of blood
pressure was evidently brought about mainly by vaso-
constriction.
It is noteworthy that the amount of disturbance (circula-
tory, respiratory, etc.) associated with vivid and alarming
dreams varies greatly in different individuals and even in
the same individual under different conditions ; the effects
are sometimes remarkably slight in the case of dreams that
are at other times attended by very pronounced effects of
the kinds described above. There is reason to believe that
the presence of some gastro-intestinal disturbance at the
time may sometimes play a part in facilitating the
development of the more marked effects on circulation,
respiration, etc.
Dangers of the Circulatory Disturhanres.
These cardio-vascular changes, involving sudden demands
on the heart's power with great alterations in its rate and
force and a steep and sometimes very extensive rise in
blood pressure, are quite harmless in the healthy individual.
Vivid dreams, involving hurrying to catch trains, etc., with
failure to do so, are common in many persons and sometimes
persistently recurrent — with no injurious consequences
apparently. But the case is obviously very much otherwise
with a damaged vascular system, life going on under con-
ditions which afford only a narrow margin of safety. There
may be a myocardium abnormal in certain functional
respects, whether or not these be attended by recognizable
structural alterations with or without obvious coronary
lesions, giving a susceptibility to ventricular fibrillation, or,
on the other hand, a defective arterial tree with localized
weakenings (by miliary aneurysms, etc.) in the brain vessels,
tuberculous damage in the lungs, ulcerative conditions in
the gastro-intestinal tract, etc., where haemorrhage may
readily be determined. In a heart susceptible to fibrillation
a sudden call on the heart during muscular exertion and
excitement in the waking state is often fatal ; in the dis-
turbed conditions of sleep and dreaming a similar mechanism
is sometimes brought suddenly and strongly into action —
diminution of vagus control and, especially under emotional
109
stress, stimulation of the cardiac sympathetic together with
a high blood pressure — conditions which favour ventricular
fibrillation.
A possible discharge of adrenaline into the circulation
under emotional excitation also comes into question, though
the importance of such discharge or its existence has been
denied by Stewart and Rogoff, in opposition to the well
known work of Cannon and de la Paz. The time incidence
of attacks of anginal pain may obviously be determined by
similar conditions.
Conclusions.
It is clear that the foregoing facts must be taken as pro-
foundly modifying the simple conception of night as the time
of r-est, and sleep as a condition in which quiescence prevails
and recuperative changes go on, restoring the bodily and
mental capacities which have become more or less reduced
at the end of the hours of work and wakefulness — a period
of repose also attended by sedative and beneficial effects on
many morbid conditions. This conception, while true as
regards undisturbed or sound sleep, has to be qualified by
the consideration that night and sleep are occasionally the
season of acute reflex and emotional disturbances which, in
the peculiar conditions present, induce very pronounced
effects on the circulatory system, throwing a formidable
strain upon its weak points, whether these be cardiac, with
susceptibility to fibrillation or anginal pain, etc., or arterial,
with risk of rupture.
In this way the individual may, during the nocturnal
period of assumed repose, be subjected to suddenly developed
stresses, as estimated by the rise of blood pressure (even as
measured after awaking when it is falling) and the evidences
of increased heart action, far beyond what is involved in
ordinary muscular exercise gradually initiated — for example,
walking, cycling, slow ascent of stairs, straining, or mental
excitement in certain degrees. Thus haemorrhages, the
onset of anginal attacks, and other disturbances in the night
can be readily accounted for; also sudden death, probably
due to ventricular fibrillation in most instances
In the light of these observations it is easy to understand
how in certain circumstances death may come like a thief
in the night to a susceptible person living with circulatory
conditions that approach the danger line, though these con-
ditions may, in favourable circumstances and barring fresh
developments, be compatible with many years of moderately
active life.
Literature.
Brooks and Carroll : Arch, of Int. Med., August 15th, 1912.
C. Muller : Acta Medico Scandinavica, Stockholm, 1921, Iv, 443.
Blume : Ugeskrift for Laeger, Copenhagen, 1922, Ixxxiv, 1126
Schneider : Virchow's Archiv, 1896, xvi, 95.
Watson and Finlayson : Glasgoiv Med. Jonrn., New Series, vi, 171.
MacWilliam : British Medical Journal, 1923, ii, 215.
Cannon and de la Paz : Amer. Jotirn. of Physiol., 1910, xxxii, 44.
Stewart and Rogoff : Jonrn. of Exper. Med., 1916, xxiv, 709.
Made in United States of America
Reprinted from Physiological Reviews
Vol. V, No. 3, July, 1925
111
BLOOD PRESSURES IN MAN UNDER NORMAL AND
PATHOLOGICAL CONDITIONS
J. A. MacWILLIAM
The Physiological Laboratory of the University of Aberdeen, Scotland
Long after accurate measurements of blood-pressure had been
practised on experimental animals, the study of blood-pressure in man
remained virtually a sealed book. Various early methods were tried
without reliable results; it was not until Riva Rocci (112) and somewhat
later L. Hill and Barnard (63) introduced the armlet method that
systolic pressure estimation became really practicable. Even after
this method had superseded the earlier attempts of Mosso, Gaertner,
Von Basch and others, many results were rendered more or less in-
accurate by imperfection in technique, too narrow armlets, etc., while
the reliance on systolic pressure alone gave very inadequate and often
misleading information as regards the state of the circulation. The
later development of diastolic pressure estimation, especially by the
auscultatory method, marked a great advance in the usefulness of the
study of blood pressure. The adoption of the standard breadth of
armlet or cuff as a result of Von Recklinghausen's (109) work was an
important step.
As regards oscillatory methods the technique and the principles
involved have lost much of their interest and relevancy, since their
practical application has receded in importance in view of the develop-
ment and general adoption of the auscultatory method. The superi-
ority of the latter has become widely recognised, on the grounds of
simplicity, quickness and accuracy, as compared with the more cum-
brous apparatus and the more difficult and variable interpretation of
the oscillatory records, different readings of pressure often being made
from the same records by different observers of considerable experience
or even by the same observers at different times — difficulties examined
by Melvin and Murray (97) and others. A good many workers using
oscillatory methods have found the Pachon oscillometer with its visual
indications preferable to the Erlanger apparatus with its graphic
records. The more recent Pachon apparatus has a Gallavardin armlet
903
112
304 J. A. MACWILLIAM
with two independent pressure bags applied to the upper arm instead
of the wrist; this is the best form of oscillatory apparatus at present
available.
Experience has emphasised the importance of combining the tactile
systolic index with the auscultatory systolic as a routine 'procedure,
recommended by MacWilliam and Melvin (90) in 1914; the latter index
should always show a higher value when the estimation is correctly
made. This of course necessitates the use of one of the various forms
of apparatus that provide for the retention of the auditory receiver
in position, leaving the hands free, e.g., the Baumanometer, the Tycos,
the Laubrey sphygmophone, the Oliver tambour, etc. The checking
of the auscultatory systolic by the tactile systolic is essential for more
than one purpose — as a guarantee of the proper functioning of the
auditory apparatus, and in guarding against error which may some-
times arise after prolonged or repeated armlet compression. Repeti-
tion may be needed to correct the disturbances in pressure due to
excitement, etc., at the first compression; as is well known, subsequent
readings are frequently decidedly lower — until a constant level is
reached, the residual pressure. Some persons under pathological con-
ditions are specially liable to show a decided rise of pressure from re-
peated or continued compression especially when the arm becomes
congested distally to the compressing armlet. Effects (reflex, etc.)
from repeated compression by the armlet come into question, described
by Gallavardin with Haour (53) and Tixier (54) as involving differ-
ent types of pressure changes, rises, falls, etc.
The present writer has found important disturbances of the auditory
indications in a certain number of subjects, as a result of compression
which involves marked turgescence of the hand and forearm — a cutting
down of the systolic index with a rise of the diastolic. Sometimes
at a later stage of prolonged compression there is enfeeblement or dis-
appearance (at variable points) of all the sounds below the upper
region of sound, in the neighbourhood of the systolic level. Such
disturbances may occur while the actual blood pressure is not changed
— as shown by the tactile systolic index remaining unaltered; thus
incorrect measurements including an unduly restricted pulse pressure
may be obtained in these cases by the use of the auscultatory method
alone — unchecked by the tactile method. Some subjects are excep-
tionally susceptible to the development of such disturbances; the
significance of these differences in behaviour has not been determined.
Another purpose for which repeated compression has been used is to
113
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 305
reduce strong tonic contraction which may sometimes be present in
thickened arteries, giving a certain resistance to obliteration and
leading to an over-estimation (to some extent) of the actual intra-
arterial pressure. But a better method is to close the brachial artery
for three minutes by digital pressure upon it, as reconmiended by
Mac William and Melvin, instead of constricting the whole limb by the
armlet and leading to venous turgescence and the associated tendency
to error described above — as especially applicable to a certain (limited)
number of subjects. Experiments (unpublished) in this Laboratory
show that in some instances at least the trouble is caused mainly by
congestion of the limb, not simply by pressure on the brachial artery.
Digital compression while removing the abnormal resistance to oblit-
eration of the pulse does not induce the auscultatory error referred
to above.
When the auscultatory method is rendered difficult by noisy sur-
roundings or by impaired hearing in the observer, the vibratory method
of Ehret (38) a modification of the tactile method, can be usefully
combined — a finger being applied to the artery on the distal side of the
auditory tambour, to detect the vibration associated with the sound
at the diastolic level. This method is strongly recommended by
Gallavardin (51). It is much simpler than checking by oscillatory
methods. But difficulties are present in fat subjects with deep bra-
chials, small calibre, and cases (especially aortic regurgitation) where the
change in the vibration constituting the diastolic index is less definite
than usual.
As regards the mechanism of the sounds, the subject of various
conflicting views (Gittings (55), Erlanger (39), Mac William and
Melvin, L. Hill and others) there have been interesting investigations by
Gallavardin and Barbier (52), (8) who describe two zones in the curve
of sound; 1, in the upper half of the curve with maximum near the
systolic index and murmurs caused by whorls in the blood current as
it passes through the compressed area of the artery and gets into a
region of lower pressure distally to the armlet; 2, in the lower half of
the curve with maximum near the diastolic index, the sounds here
originating in the vessel wall and related to sympathetic nerve influence
on the arterial wall. Attempts to interpret the meanings of the notable
variations in the character of the sounds in different subjects, the
duration of the phases and the changes induced by armlet compression
have been made by Gallavardin with Haour, Barbier (52) and Tixier,
and by Tixier (126), B. Smith (116) Sorapure (117) and others, following
114
306 J- A. MACWILLIAM
observations by Ettinger, Goodman and Howell (57), (130) Warfield
and others. The characters of the sounds in different conditions are
so varied and striking that useful information as to circulatory states
may very possibly be derived from them when they are better under-
stood.
It need hardly be emphasised that the Hg manometer is the reliable
means of measuring pressures; it is only when frequently checked
against this instrument that other forms (aneroids, etc.) can be taken
as giving valid evidence. In regard to diastolic pressure it may be
noted that the reading taken when the armlet pressure is being raised
is often appreciably lower (5 mm., etc.) than when taken during de-
flation; in some subjects the difference shows more than in others.
With reference to the systolic index the difference in the readings by
the auscultatory method and those by the tactile method have been
estimated at 5-14 mm. The experience of the present writer agrees
with the lower values, usually only a few millimeters.
Blood pressures in young adults. In 1914 Melvin and Murray (97)
established by accurate methods normal values of both systolic and
diastolic pressures in healthy young male adults (sitting posture),
59 medical students, average age 20-9. As regards systolic pressure
only three were up to 130 mm. (viz., 130, 134 and 135) while five were
slightly below 100 mm., the average came out at 112 mm. Of the
diastolic pressures 28 were at 60 to 70 mm., 19 at 70 to 80 mm. and 12
at 50 to 60 mm. The pulse pressures gave an average value of 46 mm.
Subsequent observations on very large numbers of subjects by various
observers in different parts of the world have given S, and D. values
higher as a rule and sometimes with wider ranges of variation. Bear-
ing on this difference the observations of Alvarez (4) and of Burlage
(23) (to be stated presently) as to a lowering of pressure in the early
years of adult life are suggestive, as they include the ages dealt with
by Melvin and Murray. Sorapure (117) examining 769 British soldiers
also found a systolic maximum at 19 to 22 years followed by a slight fall,
as Stocks and Karn (121) did after a systolic maximum at 19 to 20.
It may be remarked that while large numbers are of course necessary
for statistical purpose, classification, etc., reliance on pressure measure-
ment on a single occasion is apt to introduce sources of error, in view of
the universally recognised tendency of single examinations to give
results disturbed by temporary causes, nervous excitement, etc. More
precise results, as regards the real pressure levels in individuals are
obtainable by a more intensive study of smaller numbers, by repeated
examinations under carefully ascertained and controlled conditions.
115
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 307
Among more recent investigations Alvarez (4) and his associates
made observations on systolic pressure (tactile method) on a very-
large number of University students (6000 men and 8934 women).
In women the average was 11 mm. lower than in men. In men (re-
clining after tepid shower bath) the pressures grouped mainly about
127 mm. at age of 16 and 118 mm. at 30; in women (standing) 118 mm.
at 16, 111 mm. at 24, 117 at 40. There is thus a noteworthy lowering
of systolic pressure in the early years of adult life, the average dropping
from age 17 to 21 in men and remaining at about the same level till
after 50; in women falling from 17 to 25, rising after 25 and especially
after the age of 40. After 45 the average pressure is higher in women
than in men. A fall of pressure was also noticed by Burlage who made
observations on 1700 girls by the auscultatory method; he found a
systolic pressure of 104 mm. at 9 years, 124 at 14 and 15, falling to
114 mm. at 18, then constant to 26. Alvarez notes that relatively high
pressure is common in young men — 45 per cent over 130 mm., 22 per
cent over 140 mm.; in young women, 12 per cent over 130 mm. and
2 per cent over 140 mm. Evidence of the occurrence of comparatively
high pressures in some young men is also to be found in the results of
Barach and Marks (7), Lee (81) and others. Alvarez pronounces his
extended investigation as not entirely satisfactory in establishing
normal systolic pressure standards for young men on account of the
lack of homogeneity, without arriving at any definite explanation of
the results, the possible causes of which he discusses — low pressures in
1918, raised in 1919, gradual return in 1920-21. Further there is the
disturbing observation that the averages even in 1918 were considerably
above those of high school boys of the same age in the same year.
Conception and Bulatao (29), examining 717 subjects (average age
28) in the Phillipines, found in males S.115, D.79; in females S.116,
D.83. Pulse rate a little over 72. In Denmark, Faber (43) in 1000
healthy soldiers (ages 20 to 25) by the Riva Rocci method (recumbent)
found S. pressures of 110 to 130 mm. in 80 per cent, and higher or lower,
84 to 156 mm., in 20 per cent. Emphasis is laid on these great varia-
tions of systolic pressure in healthy men. Men of greater weight
showed higher pressures than others of the same height; with equal
weights blood pressure is lower, though the differences were slight,
in men of greater height. What are termed the "overfat" averaged 123
mm. as compared with 117 mm. for the "underfat." Diastolic pressures
are not recorded. The systolic pressures found by Faber agree with
those obtained by Tavaststjerna (124), whose average was 117 mm.
116
308 J. A. MACWILLIAM
Addis (1) examined nearly 400 subjects in two categories, the pres-
sures being taken in the recumbent posture^ — ^1, under basal conditions;
systolic average 99, diastolic 71. 2, Under other conditions, food taken,
walking, etc., systolic average 127, diastolic 78.
The relation of hlood 'pressures to age. There is general agreement as
to the presence of lower systolic and diastolic pressures in childhood,
the differences from the adult being more marked in the systolic levels
with a consequent diminution of the pulse pressures.
The work of Judson and Nicholson (71), Melvin and Murray, and
Faber and James (44) may be referred to, also the more recent obser-
vations of Stocks and Karn (120). In connection with the smaller
pulse pressures the quicker pulse rate of children has to be taken into
account, tending to make the product of P.R. X P.P. approximate to
what holds good in the adult.
The available evidence shows that from the very early phase of life
there is a progressive steady rise of pressure, apparently a function of
increasing age, up to the onset of puberty, then an acceleration of the
rise up to the ages of 17 to 20. It is to be noted that there are decided
differences between the results of Judson and Nicholson and of Faber
and James on American boys, and those of Stocks and Karn on British
boys, as regards the actual values of the pressures recorded and the
extent of the rise between the ages of 5 and 14 years. At the former
age the American observers found systolic averages of 92 mm. and 93
mm. respectively; at the latter age 106 mm. and 110 mm. On the
other hand Stocks and Karn report a lower average, 85 mm., at age
5 and a higher level, 115 mm. at age 14 — a rise of 30 mm. which is
nearly twice that found by the other observers. The accelerated rise
during puberty and adolescence between the ages of 13 and 17 has been
found by Stocks and Karn to amount to 16 mm.
Woley (134) dealing with systolic pressures in 1000 apparently
healthy subjects, found an average level in males of all ages of 127.5
mm., in females of 120 mm., and a rise from 122 mm. in the age group
15 to 30 years to 132 mm. in the 50 to 60 age group. He distinguished
a high pressure group with an average pressure of 141 mm. at the ages
15 to 30 to 149 mm. at 50 to 60, and a low pressure group rising from
an average of 103 mm. in the 15 to 30 group to 115 mm. in the 50 to
60 category. At the intermediate ages averages of intermediate value
were obtained, a gradual rise occurring with increasing age and a cor-
responding rise in high and low averages. He regarded a pressure of
144 mm. in the 50 to 60 age group as being definitely acceptable for
117
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 309
insurance. Women at all ages were 8 mm. below the male average,
with the same ratio of increase at similar ages.
In Symonds' (122) report of 150,419 men successive age groups are
presented from a 15 to 19 year group up to one of 60 years and over;
also build groups (Medico-Actuarial Investigation I, 1912, 120) based
on the average weight for each inch of height in men at the age of 37.
Systolic pressure alone is studied. Age, weight and pressure are shown
to increase together. Differences appear of 11 to 12 mm. between the
youngest and the oldest in each build group, and of 10 mm. between
the very light and the very heavy groups; even at the ages of 60 and over
the difference was much the same. In the whole series the pressure
averages range from 121.2 mm. in the youngest (15 to 19) group to
135.2 mm. in the oldest (60 and over) group. Mackenzie (87) reporting
on 18,637 men, gives a range from 119 mm. to 137 mm. in similar age
groups. Rogers and Hunter's (113) 62,000 rise from 120 mm. at 15
to 19 to 134 mm. at 55 to 59; the results of Fisher (46) and Goepp (56)
are very similar though the age grouping differs slightly. As regards
the pressures in women, Symonds' 12,000 with age grouping similar
to the men show values ranging from 119.2 to 135.5 — a much closer
approximation to male pressures than has been found by most observers
who have commonly reported pressures in women, at least in the
first half of life, as 8 to 10 mm. lower than in men.
In a recent valuable study Stocks and Karn (120) present continuous
evidence of the pressure behaviour through the ages of puberty and
adolescence, from the ages of 5 to 40 years. They submit curves and
tables for the correction of pressure readings for age, weight (affecting
systolic pressure) height (affecting diastolic pressure) and pulse rate.
They find that there is a positive correlation of systolic pressure with
muscular strength apart from physical development and age. By
their method of correlation with pulse rate they believe that an ap-
proximate correction of the well-known disturbing effects of psycho-
logical factors, such as nervousness, can be made. With regard to
this conclusion of Stocks and Karn it is to be remarked that excitement,
emotion, etc., influence blood pressure by acting on the vasomotor
centre as well as on the heart, and that the relation between the two
actions is by no means constant; hence the pulse rate cannot be relied
on to give accurate indications of the degree of pressure alteration
developed, though a correction for pulse rate no doubt diminishes the
amount of the error. The range of apparent variability of the blood
pressure in healthy persons is substantially diminished by such cor-
118
310 J. A. MACWILLIAM
rections as the preceding, though not removed, since other and more
obscure factors remain. Stocks and Karn's figures show a remarkably
small increase of pressure with advancing age — from an average of
131 mm. at 20 years to 134 mm. in the group of 40 years and over
(average age, 49).
It is warrantable to conclude from the concurrent evidence of the
extended statistical evidence now available that the idea of an extensive
progressive rise of systolic pressure in healthy persons as life goes on
is an erroneous one. It is clear that the rising pressure of childhood
undergoes accleration about puberty and attains what is approxi-
mately the adult level somewhere in the 17 to 20 period. There is
some evidence of a slight subsequent lowering — in the early years of
adult life. Apart from this, the pressure remains almost steady till
the age of about 40, after which a more definite rise progresses. But
the rise, though quite a definite one, is more limited in amount than is
commonly assumed; the total rise shown in the statistics, due to the
combined influences of age and increasing weight is on an average under
15 mm. The pulse pressure follows a course pretty similar to that
of systolic pressure under the influence of age. The available evidence
also bears weighty testimony to the relative constancy of systolic pres-
sures at different ages, when large numbers are dealt with and the
necessary allowances and corrections are made. It is clear, in view
of the foregoing averages, that the occurrence of exceptionally high
pressures in healthy persons must be relatively rare; otherwise the
averages would be much higher. The very moderate level of the
averages for middle and advanced life is all the more noteworthy in
view of the fact that the real ordinary pressures are likely to be over-
estimated rather than under-estimated, under the influence of nervous
excitement, etc. But while the averages for large numbers are rela-
tively constant, the fact of notable variation in healthy individuals
remains, the pressures in such persons being apparently set at levels
different from the ordinary — from causes that cannot at present be
adequately defined. The importance of hereditary influences has
been emphasised by numerous observers, e.g., Oliver (104), Dana (34),
Alvarez, Warfield (130) and others.
With regard to the very high systolic pressures, S.200 to 250, some-
times (though rarely) met with in apparently healthy vigorous men
at such ages as 50, 55, etc., the mechanism of such pressures is well
worthy of careful investigation — with respect to the peripheral resist-
ance, capillary and venous pressures, blood volume, cardiac output,
119
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 311
etc. ; such would probably yield valuable information as to circulatory
conditions. Various observers have noted that in a considerable
number of high pressure cases there are no definite symptoms and no
evidence of disability; Kulbs (77) found so high a proportion as 20 per
cent in this category in a series of 172 males and 116 females with
pressures at or above 170 mm. As regards diastolic pressures the
American life insurance data are open to criticism from the adoption
of the end of the 4th phase as the diastolic index, the latter having been
experimentally proved to coincide with the beginning of the 4th phase
— in the dog by Warfield (129) and in the sheep by Mac William, Mel-
vin and Murray (91). It is certain that serious error may occur in
this way especially in young subjects where the duration of the 4th
phase may in some cases be long. Thus Melvin and Murray, by care-
ful examination in quiet surroundings using a sensitive Oliver auditory
tambour, found in 14 young men out of a total of 59 a prolonged 4th
phase, ranging between 24 and 55 mm. and averaging 38 mm. The
lower limit of the sound was sometimes found to be as low as 10, 14, 20
or 22 mm. armlet pressure in healthy subjects with normal systolic
pressures and complete absence of any collapsing character in the
pulse, etc.; obviously these figures could not possibly represent the
actual diastolic pressures.
Of course such very low readings of the lower limit of the sound are
exceptional. Many observers have noted a 4th phase of shorter
duration, e.g. Warfield up to 20 mm., Weysse and Lutz (131) not above
25 mm., Tixier usually 20 to 30 mm. at ages of 20 to 30 years and in
some abnormal subjects 20 to 40 mm., etc. Others have reported
figures 5 to 8 mm. (Goodman and Howell, Barach and Marks, Macken-
zie, Smith and others). In middle-aged and elderly subjects the ex-
perience of the writer is that the sound rarely persists in any important
degree (not more than a few millimeters) and consequently the lower
limit of sound in these subjects approximately indicates the diastolic
pressure- — ^in contrast to the serious discrepancy which may occur in
young persons.
In the insurance statistics referred to the relatively large numbers
in the younger groups of subjects (19 to 25 and 25 to 30) would naturally
tend to give scope for possible errors in this direction. But such errors
would be in the direction of underestimating the actual diastolic pres-
sure; on the other hand, the diastolic readings given in the insurance
series referred to are by no means low.
There is sometimes a tendency to undervalue precision of blood-
PHTSIOLOOICAL REVIEWS, VOL. V, NO. 3
120
312 J. A. MACWILLIAM
pressure measurement and to regard differences of 10 to 20 mm. in
blood-pressure readings as being of small moment in view of the larger
variations that may occur from time to time with apparently little
significance. But the importance of such differences varies greatly
in relation to their position in the scale of pressures. When they
start near the "normal" lower limits of systolic and diastolic pressures,
differences of 10 to 20 nxm. may mean much, e.g., between 100 and 80
or 90 systolic, or between 60 and 40 or 50 diastolic, such are of much
significance as compared with similar amounts at higher levels.
Relations of systolic, diastolic and pulse pressures. The 3:2:1 ratio
commonly cited as applicable to these pressures is subject to very
considerable variations without coming into the category of the abnor-
mal. The validity of the ratio is mostly evident with certain normal
pressures, e.g., S. 120, D. 80, P. P. 40, the pulse pressure being one-half
of the diastolic and one-third of the systolic. It does not hold good in
such low pressures as may sometimes be found in healthy persons,
e.g., S. 105, D. 60; where the P. P. is three-fourths, instead of one-
half, of the diastolic and much nearer one-half than one-third of the
systolic. Again with such a high diastolic as 120 mm. (muscular
effort, etc.) a S. 180 and P. P. 60 are apt to be under what actually
occur, the high diastolic tending to give a relatively higher S. and P. P.
on account of the tense condition of the arterial walls; the discharge
from an efficient L. V. causes a disproportionately large rise of systolic
pressure — apart from the influence of an increased discharge per beat
occurring in a distended or enlarged heart. Such effects of diminished
distensibility of the arterial system at high diastolic pressures may also
be paralleled by loss of elasticity and stiffening of the arterial walls
from degenerative changes, apart from the presence of a high diastolic
pressure. These factors being operative at different ages, it is evident
that while the average (absolute) values of pulse pressure in large num-
bers of persons vary with age in the manner already stated, the actual
amounts in individuals may be greatly affected, apart from the in-
fluence of age, in the ways just stated. Pulse pressures of deficient
amounts associated with a high diastolic level are naturally of evil
significance as indicating cardiac inefficiency, provided the low P. P.
is not accounted for by acceleration of the pulse rate.
Blood pressure in muscular exercise. While a rise of blood pressure
has long been known to be associated with muscular exertion, the
great majority of the measurements have been made after the period
of exertion has ended and have for the most part dealt only with sys-
121
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 313
tolic pressure. The methods adopted by Bo wen (19) (systolic pres-
sures only) and by Lowsley (86) (systolic and diastolic by the Erlanger
sphygmomanometer) enabled the course of the pressure changes to be
followed throughout the period of exercise (stationary bicycle) . They
found a rapid rise at first, reaching a maximum in a number of minutes,
(Bowen, 5 to 10 minutes, Lowsley, 5 to 25 minutes) then slowly de-
clining and after the end of the exercise sinking to normal or subnor-
mal levels.
McCurdy (96) measured systolic pressure during brief maximal
effort (heavy lifts involving thoracic fixation, etc.) lasting about 5
seconds, and found an average rise from 111 mm. before the effort to
180 mm. during and 110 after.
Measurements made "immediately" or at certain periods after-
wards are not valid guides to the actual height of the pressure during
the exercise, though such have been used by some observers in com-
paring the blood-pressure response to effort in different types of sub-
jects. Thus some observers have taken estimations half a minute
after the termination of exercise as a standard. Cotton, Lewis and
Rapport (28) making repeated measurements found a fall to, or nearly
to, normal in 10 seconds then a rise reaching a maximum in 20 to 60
seconds, there is then a gradual fall, reaching the resting level in from
1 to 4^ minutes after the end of the exercise (20 pound dumb-bells).
Similarly Chailly-Bert and Langlois (27) recorded a fall in 5 seconds
after the cessation of exercise to about normal, followed by a subsequent
rise. Graupner (58) and Barringer (9) had previously described a
secondary rise after the end of the period of exertion with a Zuntz
ergometer and with dumb-bells respectively. These observations
mainly deal with systolic pressures. The interpretation put upon their
results by Cotton, Lewis and Rapport is that, assuming the veins to
be depleted during the period of exertion, these veins fill up with blood
when the muscular action ceases and so cut down the return of blood
to the heart and the arterial pressure, until the veins have refilled and
the inflow into the heart is restored, leading to the subsequent rise in
presence of the continuance of the factors, other than the pumping
action of the muscles, operative during the exercise.
This interpretation has been disputed by Bainbridge (6) who re-
gards the veins as being full during the period of exertion, and the fall
of arterial pressure to be due to the cessation of the pumping action
of the muscles inducing a momentary stasis of blood in the capillaries,
involving a temporary diminution of the venous return to the heart.
122
314 J. A. macwilliam
It may be remarked that in neither of these explanations is it definitely
stated whether the whole of the venous system is regarded as depleted
or full — according to one view or the other — or whether the state of
a, the large venous trunks in the thorax and abdomen, or h, the veins
among or near the muscles in the trunk and limbs are specially in
question. Rapport (108) noted variations in the duration of the sec-
ondary rise after moderate and great efforts respectively.
Observations by C. Reid (110) in this Laboratory show that the
rate, character and extent of the pressure changes after the end of the
exercise vary much in different individuals and in the same individual
under different conditions.
The maximum height attained by the subsequent rise of pressure,
when such occurs, varies much and bears no precise or constant rela-
tion to the maximum height during the period of exertion, though
under some conditions it approximates or corresponds to that maximum.
After a type of exercise where the raised pressure during the exercise
shows a simple decline afterwards, without a subsequent rise, the
rate of the decline varies considerably, and measurements taken at
some fixed point of time (e.g., | minute) are not to be relied on. Again,
in those forms of exercise where a subsequent rise does present itself,
occurring in varying degree after a preliminary fall, it is obvious that
much will depend on the exact point in the series of changes at which
the estimation is made. Measurements at half a minute after the
cessation of exertion will naturally give very different results according
as a subsequent rise develops or a simple progressive decline occurs;
even in the latter type the finding of equal readings at the half minute
interval in two different individuals or in the same individual at dif-
ferent times and under different conditions does not prove that the
maximum pressures attained during the exercise were equal in the two
instances. It is to be emphasised that measurements during the
period of exertion constitute the only valid evidence as to the actual
rise of pressure. It is not surprising that many discordant results
have been recorded by different observers dealing with exercises of
different types and duration or even with comparable exercises, when
the estimations are made after the end of the period of exertion. Quite
small rises (e.g., 16 mm.) have been reported after short spells of severe
exertion involving dyspnea with doubling of pulse rate, etc., when the
actual pressure during the exercise has really been greatly raised.
Whatever significance may be attached to such estimations for some
purposes, it is clear that they are not reliable for determining the
123
BLOOD PRESSURES IN MAN, NORMAL ANI> PATHOLOGICAL 315
height of the blood pressure response to exertion. The extent and
course of this response varies much in different types and degrees of
muscular activity — whether the latter be 1, strong or maximal effort
with fixation of the thoracic walls, etc., bringing in the factors concerned
in Valsalva's experiment; 2, exercises of endurance as in walking, long
distance running, cycling, etc.; 3, execution of difficult, though not neces-
sarily strong, movements involving much mental concentration; 4,
static contraction of muscles.
A direct relation of the blood pressure rise (associated with exertion)
to the amount of work, rather than to its rate, has been affirmed. This
is applicable in a general way to certain types of exercise where the
mental factor remains tolerably constant, but it is not applicable for
comparison between different types involving variable degrees of mental
concentration, emotional accompaniments, etc.; in these very different
amounts of blood pressure change may be associated with the per-
formance of equivalent amounts of muscular work.
Blood pressures in sleep. That there is a lowered blood pressure
during sleep has been found by various observers, often amounting to
15 to 30 mm. at the end of two hours' sleep, then gradually rising to-
ward the time of waking. Such falls of general arterial pressure
obviously mean only a relatively limited reduction in the brain vessels
— the hydrostatic factor being largely taken off the head vessels in the
recumbent posture. Greater reductions have been noted in persons
with high pressures in the daytime, e.g., 44 mm. by Brooks and Car-
roll (22) in hypertonic subjects.
Muller (100) found the systolic pressure to be down to 94 mm. in
men and 88 mm. in women during sleep, after a small dose of veronal.
In persons with moderate day pressures Blume (15) recorded falls of
15 mm. and 21 mm. in men and women respectively while in subjects
with high day pressures the lowering averaged 31 mm. and 39 mm.
These observers describe a remarkable constancy of pressures during
sleep (rarely more than 5 mm. variation in sleep), even in high
pressure cases, in contrast to the great variability seen in the waking
pressures. Katsch and Pansdorf (72) while confirming the fall of
systolic pressure in sleep — parallel to the depth of the sleep — found
that the diastolic pressure sinks little if at all, but on the contrary
often rises during the deepest sleep, so that the pulse pressure is di-
minished. In essential hypertension they observed an abnormal
range of systolic lowering; in other hypertensions little or no lowering.
The present writer (88) finds that there are two entirely different
124
316 J. A. macwilliam
conditions in question in sleep — 1, sound sleep with lowering of pres-
sure, 2, disturbed sleep, dreaming, etc., which may be attended by-
remarkable elevations of pressure, e.g., systolic pressure raised from
125 to 182 mm., or from 130 to 200, etc.; diastolic pressure raised from
75 to 105 mm., etc. These changes were much greater than were
induced in the same individuals by moderate exertion (cycling, walk-
ing, stair climbing, etc.) straining abdominal efforts, dose of atropin
to remove vagus control over the heart, mental excitement, etc. In
view of the rapid development of such changes in sleep, especially in
dreams of motor effort, nightmares, etc., it is evident that a formidable
strain — harmless in the young and healthy person — may thus be
thrown on the weak points of the circulatory system, whether these be
cardiac with susceptibility to anginal attacks or to ventricular fibril-
lation and sudden death, or arterial with risk of hemorrhages, cerebral
(especially in the recumbent posture), gastro-intestinal or pulmonary'-.
The conception of sleep as a period of quiescence and recuperation has
thus to be qualified by the contingency of disturbed sleep with active
calls on the nervous system, the heart and the blood-vessels. The
mechanism of the rise of pressure in disturbed sleep differs in some
respects from that present in ordinary muscular exertion, since in the
former the pumping action of working muscles, greatly augmenting
the venous return to the heart, is absent. The above-mentioned dis-
turbances may occur during disturbed sleep when there is after awaking
no recollection of definite dreaming.
High blood pressure. Notwithstanding the very large amount of
attention that the subject has received the causation and mechanism
of persistently elevated blood pressure, whether in the form of simple
or essential hypertension (the hyperpiesis of Clifford Allbutt (3)) or
in association with kidney lesions, remain unexplained. While there
is general agreement as to the existence of excessive pressures apart
from an3^ recognisable renal lesions and in the absence of any sign of
functional inadequacy as tested by the modern methods for estimating
renal efficiency, it is also clear from the evidence available that the
significance of hypertension is greatly influenced by the co-existence of
renal inadequacy, the latter giving a sinister aspect to the condition
and seriously altering the prognosis. While there has long been a
strong presumption from the clinical side that, 1, toxic substances,
probably protein derivatives, are at work, whether a, absorbed from
the alimentary canal (pressor amines, etc.), or h, products of microbic
infection, or c, abnormal metabolism; or 2, that endocrine derangements
125
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 317
may be concerned (e.g., in hypertension associated with the meno-
pause, etc.) the search for such pressor agents has failed to elucidate
the problem, proving almost barren of results. When kidney involve-
ment is also present there are the further undecided possibilities of
3, defective elimination, and 4, the genesis of pressor agents by ihe
damaged renal tissues.
Mosenthal (98) concluded that high or low protein diet does not
increase or lower high blood pressures; similarly Newburgh (102) and
Squier and Newburgh (118) found high protein feeding ineffective,
though acting as a kidney irritant. On the other hand the observa-
tions of H. J. Starling (119), bearing on tuberculous cases, indicate a
definite elevation of pressure under the continued influence of an
abundant meat diet. An important point is raised by the finding
of Foster (48) that a reduction of blood pressure under the influence of
a continued low protein diet may take two months to develop; this
suggests that some negative conclusions with high or low protein diets
may possibly be due to periods of insufficient duration being studied.
Orr and Innes (105) observed a decided lowering of pressure after the
drinking of large quantities of water; they suggested a washing out
of metabolites as a probable cause of this effect.
On the other hand Strouse and Kelman (121), examining cases of
raised pressure associated with various degrees of renal damage, found
that high protein diet caused no rise of blood pressure and that diminu-
tion of the protein intake in cases of definite nephritis, while lowering
the non-protein N of the blood, did not lower the pressure. Sudden
variations of systolic pressure sometimes amounting to 60 mm. were
often seen, attributed to emotional causes acting directly on the vaso-
motor centre; these variations were not affected by alterations in
protein intake.
Salt has been surmised to have some relation to high blood pressure
and this hypothesis has influenced treatment, as in Allen's regimen with
a salt intake cut down to 0.5 gram per diem. The recent work of
O'Hare and Walker (103) lends no support to such a view. No rela-
tion was found to hold between the blood pressure and the chlorides
of blood and plasma, and no effect on the systolic and diastolic levels
was seen during wide variations in the amounts (0.5 to 4 grams) of
salt taken in high pressure cases without nephritis. Further in sub-
acute nephritis with edema and maximum salt retention comparatively
low pressures were often recorded.
Cholesterin has also been suspected, especially by some French
126
318 J. A. MACWILLIAM
(Chaffard and his school) and Russian investigators. Cantieri's (25)
results oppose this idea; he found no relation, in acute or chronic
nephritis, between the blood pressure and the cholesterin content of
the blood, which in a series of arterio-sclerotic cases was rather below
the normal content; also administration of cholesterin does not raise
the blood pressure.
Dixon and Halliburton (37) ascertained that the pressor effect of
cholesterin given by intravascular injection is negligible.
As regards urea, though high blood percentages of this substance
and high blood pressure are often found together, the relation is very
variable and it is evident that it is not a causal one. The same state-
ment holds good with regard to the viscosity of the blood, though a
group of high pressure cases associated with polycythemia has been
recognised.
The search for pressor bodies of endocrine origin (though possibly
present in toxemia in pregnancy, etc.) as a cause of persistent high
blood pressure has so far proved futile, and the same is to be said with
regard to the conceivable possibility of a lack of depressor substances
as an operative influence. A similar remark applies to the question of
retained pressor bodies when a rise of pressure follows reduction of the
kidney tissue below a certain limit, e.g., to one-third, as studied by
Passler and Heincke (106), Janeway (70) (with Carrel) and others.
It is a remarkable fact that no adequate explanation is available as to
how suppression of kidney function kills.
In the presence of structural kidney damage the question of altered
function becomes added to that of diminution of functional area.
Extracts of kidney have been found by various observers to have
pressor effects — Tigerstedt and Bergman's (125) "renin" — and the
throwing off of some such pressor agent from disintegrating renal
tissue in diseased conditions has been suggested (for some cases of
hypertension) by Eatty Shaw (12) ; it has not been found practicable
to establish the presence of such agents in the circulation. On the
other hand there is the possibility that the whole condition (hyper-
piesia) in which persistent high blood pressure is present may be due
to toxic agents in the general circulation, secondarily affecting the
kidneys and thus leading to an aggravation of the morbid effects.
The latest pressor substance suggested is guanidine, studied by
Major and Stephenson (92). These observers observed powerful
effects, doubling or tripling of arterial pressure in a few minutes, from
intravenous or intramuscular injection of guanidine salts in dogs, —
127
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 319
effects opposed by CaCU, KCl or NH4CI given intravenously. In
experimental uranium nephritis (dogs) a marked and persistent diminu-
tion in the excretion of guanidine bases was found. In a number of
patients with high blood pressures — essential hypertension or with
chronic nephritis — a decreased output of guanidine was observed, as
compared with the normal daily average of 100 mgm. in normal per-
sons and in patients with normal blood pressure and temperature. It
is suggested that kidneys only slightly damaged, e.g., with small vessel
sclerosis, might have difficulty in excreting guanidine while other sub-
stances might pass and the renal defect fail to be rendered evident by
the usual tests till the change has progressed further. With regard to
this question evidence is desirable as to the blood pressure in the con-
dition of tetany (e.g., from parathyroid defect) where guanidine has
been detected in the blood by Noel Paton (107) and his fellow workers.
It would also be of interest to find whether any types of high blood
pressure cases are favourably influenced by administration of para-
thyroid and calcium salts.
The normal relation of blood pressure to the body weight in the
healthy state has been shown to be a definite one, as illustrated by the
insurance statistics of Symonds and others and by the series of obser-
vations of Faber and others, increments of about 10 mm,, etc., being
found by Symonds in individuals of heavier build at all ages, while
the young subjects of Faber showed differences of 6 mm. according
to their build. While this appreciable difference holds good in healthy
persons the effects of obesity are much more pronounced and have
been emphasised by various observers. Among recent investigations,
Aubertin's (2) 70 obese subjects (average age 60) showed high pres-
sures in the great majority, only 7 being at or under 150 mm. while
24 non-obese controls of similar age averaged 149 mm. While greater
degrees of obesity were associated with higher pressures, arterial
sclerosis and chronic nephritis were not found to be the effective con-
nection between obesity and high pressure. Apoplexy and sudden
death are evidently related to the high pressures rather than the as-
sociations or effects of obesity acting in other ways. It is note-
worthy however that Symonds states that fat elderly subjects in good
condition and acceptable for insurance commonly have systolic pres-
sures below 140 mm. on an average.
Relation of high pressures to the regulating mechanisms. Marey's
Law. Under the circulatory conditions of normal life this law is one
that is more honoured in the breach than in the observance. An in-
128
320 J. A. macwilliam
verse relation of heart rate and arterial pressure only occurs in certain
conditions, such as are not usually present. It does not occur in the
great majority of normal elevations of blood pressure, e.g., in muscular
exercise with its raised pressure and quickened heart, nor in the similar
conjunction seen in emotional excitement, nor in sleep where both
pressure and heart rate are -lowered, nor in some forms of circulatory
depression accompanied by a slowed heart and a reduced blood
pressure.
A more warrantable statement, much more limited in scope than the
so-called law of inverse relation, is that when the blood pressure in the
head is raised by an increase of the peripheral resistance in the circula-
tion or by local causes acting on the head (hydrostatic factor, etc.),
such pressure tends to increase the controlling power of the vagus
centre, provided no other influence plays upon that centre in the direc-
tion of reducing its activity — as occurs during motor effort, emotional
stress, etc. Conversely a lowered pressure in the head involves di-
minished activity of the vagus centre unless this is opposed, as may
happen, by some concomitant influence tending to stimulate the
centre.
It is evident that if persistent high blood pressure is due, as is com-
monly assumed, to excessive peripheral resistance there must be some
agency in action which counteracts the working of Marey's law —
since, as is well known, the heart is not slowed even in presence of
exceedingly high arterial pressures. Thus in Mannaberg's (93) ob-
servations on 241 cases of high pressure, 55 per cent had normal pulse
rates, while 43 per cent showed tachycardia and 3 per cent bradycardia;
the tachycardias were chiefly in women and probably related to endo-
crine disturbances (thyroid, etc.). The mechanism of this is unknown.
There is no evidence to show why the usual slowing influence of high
pressure is not exercised — through direct influence on the vagus centre;
and also reflexly through high pressure in the heart and distention of
the aortic walls, if such a mechanism exists — as affirmed by Eyster and
Hooker (41) for the normal animal, though this view is not supported
by the recent work of Anrep and Starling (5) with cross-circulation
experiments.
While it is known that high venous pressure acting on the right
heart reduces vagus control and accelerates the heart, as Bainbridge
found by increasing the volume of the blood, there is no ground for
regarding this as a means of abrogating the slowing effect of an ex-
cessively high arterial pressure due to abnormally great peripheral
129
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 321
resistance. For when the latter is excessive, e.g., during compression
of the aorta at the level of the diaphragm, the right heart (as well as
the left) becomes largely distended and the venous pressure very high.
But slowing of the cardiac rhythm, due to the arterial pressure, persists
in spite of the elevated venous pressure; the arterial pressure dominates
the situation, so far as the heart rate is concerned.
As regards the direct relation of blood pressure to the normal func-
tioning of the vasomotor centre, Anrep and Starling have obtained
important evidence by a method of cross-circulation. They caused
the head of an animal to receive its whole blood supply from a heart-
lung preparation while the body of the animal retained its normal
blood supply from its own heart; this enabled them to study the direct
effects of changes of blood pressure in the head on the medullary cen-
tres. They found that a rise of blood pressure in the head actively
and almost immediately (after a latency measured in fractions of a
second) depresses the activity of the vasomotor centre, causing a fall
of blood pressure in the body generally. Changes of pressure in the
head induce reverse changes in the body; these are not transitory but
last for a long time, generally till the pressure in the brain again changes.
Such reversed changes in head and body, first observed by Francois-
Franck (49), have been studied by Hedon (GO), Tournade, Chabrol
and Marchand (127), Foa (47) and others. They have usually been
attributed to changes in the heart action through the vagus centre,
but such a mode of action is excluded in Anrep and Starling's experi-
ments. It is obvious that a mechanism of this sort must militate
strongly against the maintenance of an excessive pressure in the intact
circulation.
In view of many facts it is clear that in persistent high pressure in
man the condition is not simply one of increased vascular constriction,
whether determined by undue activity of the vasomotor centre or by
chemical agents acting directly on the walls of the vessels. Simple
vascular constriction, raising the general pressure and the pressure in
the head would bring into operation various normal regulating mecha-
nisms such as — 1, increased control of the heart through direct action
of the pressure on the vagus centre together with 2, a direct synergetic
inhibiting influence on the vasomotor centre; 3, a reflex depressing
influence on the vasomotor centre through (vagus) depressor fibres
arising in the aorta and heart, and possibly 4, an alteration of a pressor
reflex influence ascending from the terminations of the vagi — a reflex
advocated long ago by Pavlov and recently by McDowall.
130
322 J. A. macwilliam
It is evident that, whatever chemical agencies may be operative in
other ways, in persistent high blood pressures there is a marked inter-
ference with regulating nervous mechanisms, rendering them ineffective
in keeping down the pressure to anything like the normal levels.
The question of a compensatory influence of raised blood pressure.
Allbutt regarded high pressure as an attempt of the organism to main-
tain the equilibrium of the circulation. May the rise of pressure be
in some sense compensatory to drive more blood through a vital organ
that needs it, e.g., heart muscle or brain or kidney? In the last named
the high pressure might conceivably be related to the efforts of the
kidneys to excrete concentrated urine, salts or waste products when
in excess or when the renal mechanism is inadequate. Possibilities in
this direction are suggested by the known existence of the sensitive
mechanism by which a defective blood supply to the head promptly
sets up a rise in aortic pressure through synergetic changes of increased
activity of the vasomotor centre and diminished activity of the vagus
centre. A compensatory reaction might conceivably develop in con-
nection with other important organs where the blood supply may be
defective from narrowing of arterial channels or diminution in the
number of capillaries, or where functioning of the tissue — relatively
defective from other causes — might be improved by a higher capillary
pressure. A compensatory relation was suggested by Bier with refer-
ence to the kidney and later by others. The existence of a com-
pensatory function may be investigated by artificially lowering the
pressures (by vaso-dilators, etc.) in order to find whether functional
impairment or disturbances, renal, cardiac, or respiratory result
from a reduction of the pressure from an elevated level, which, under
the conditions present in these cases, had been favourable to efficiency.
A recent investigation on such lines by C. Reid (111) does not lend
support to the idea of a compensatory relationship as regards renal
efficiency, tested by modern methods, blood urea and non-protein
nitrogen being estimated and MacLean's urea concentration test, etc.
being employed ; the raised pressures present, associated with a variety
of kidney conditions, were lowered by nitrites, venesection, etc.
As regards the effects of high pressures in causing elongation and
tortuosity of arteries, it is obvious that such may result from more than
one cause. 1. Impairment of the power of the arterial wall to resist
distention may do this, even in the absence of abnormally and per-
sistently high pressures, from the frequent or continued existence of
a relaxed condition of the arterial muscle, especialh^ in arteries with
131
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 323
poor support like the temporal, where elongation and tortuosity may
develop in an apparently healthy vessel. The present writer (89)
has shown that the elongation of an artery by internal pressure is
enormously great in a relaxed as compared with a tonically contracted;
further, as the process of elongation needs time to develop, the con-
tinuous (diastolic) pressure is more effective than the transient systolic
rises. Abnormal conditions of the arterial wall may of course diminish
its resistance to distention.
2. Apart from such impairment of resistance persistently high pres-
sures tend to elongate the artery and to loosen or pull it away from
its normal attachments along its normally straight course, as easily
recognised in the case of the brachial, especially in a thin arm, where
the vessel is felt as a tube running an elongated and devious course in
bold curves down the arm — especially prominent a little above the
elbow. The absence of such conditions in the presence of high arterial
pressure of unknown duration affords presumptive evidence that the
high pressure is not of long standing.
It may be taken as established that high blood pressure readings,
when carefully taken, represent approximately correct measurements
of the actual intra-arterial pressures as a rule. It is only in a small
minority of abnormal cases of thickened arteries with excessive tonic
contraction, etc., that serious discrepancy may occur, sclerotic condi-
tions without muscular contraction having no important influence.
Digital compression for 3 or 4 minutes or massage of the artery are
useful in removing abnormal resistance and have the advantage of not
causing congestion of the limb which may arise from repeated com-
pressions by the armlet — with very disturbing results, especially in
some susceptible cases, giving erroneous auscultatory indications or
actual changes of arterial pressure, etc.
The pronounced effects of mental stress, excitement and worry in
producing and maintaining high blood pressure emphasise the signifi-
cance of the nervous system whether exercised directly through cardio-
vascular innervation or more indirectly through endocrine or metabolic
alterations. The frequent variation of the pressure from day to day
or even at shorter periods opposes the idea of structural causation
involving increased peripheral resistance and tells against the presence
of permanent chemical agencies acting on the vessels directly. The
constancy of a lowered pressure during sleep reported in some high
pressure cases points in the same direction (MuUer, Blume, Katsch
and Pansdorf).
132
324 J. A. macwilliam
Again the strikingly exaggerated pressure changes which may rapidly
occur in response to nervous disturbances, emotional causes, etc., as
noted by numerous observers in many cases of high blood pressure,
bear testimony to the presence of disturbed innervation involving de-
fective regulation as an important factor in the condition. Thus
causes of slight elevations of pressure in the normal state may have
abnormally great effects in causing rapid and extensive variations in
many subjects of high pressure.
Low hlood pressure. The mechanism of the acute condition of
excessively low pressures seen in circulatory shock, etc. — due to the
altered capacity factor dependent on capillary relaxation and later on
diminished blood volume — has been elucidated by various investiga-
tions, especially by the work of Cannon (24) on traumatic shock and
that of Dale with Laidlaw (32) and Richards (33) on the action of the
histamine and histamine-like bodies. Similarly the pressure falls in
acute infections like cholera, etc., are rendered intelligible. But in
persistent low pressures attendant on exhausting diseases or occurring
without obvious cause (essential hypotension) the available data are,
as in the case of persistent high pressure, inadequate for a satisfactory
explanation of the mechanism involved — whether a defective periph-
eral resistance or defective cardiac output depending, apart from
cardiac enfeeblement, or lessened return of blood to the heart as a
result of undue expansion of the capacity of the vascular system from
capillary or venous relaxation, contraction of venules, diminished
volume of blood in circulation, etc. It is also unknown how far such
conditions are mediated through the nervous system and how far due
to the direct injQuence of chemical agents — depressor bodies, lack of
pressor substances, etc.
As to what constitutes "low pressure" the level below which a pres-
sure is to be regarded as low or abnormal is not sharply defined and
no doubt varies considerably, as in the case of high pressure, for the
individual and the conditions present. Roughly anything decidedly
below 100 systolic or 60 diastolic may be suspected of being "subnor-
mal." Some athletes in good training have such pressures as systolic
105 and diastolic 65.
Subnormal blood pressures naturally exercise a generally depressing
influence on the active tissues and tend to establish a vicious circle.
There is significance in the observation of Markwalder and Starling
(95) that for the mammalian heart (in the heart-lung preparation)
an average (innominate artery) pressure of at least 90 mm. Hg is neces-
133
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 325
sary for the due vigour of the cardiac muscle; otherwise the coronary
circulation is apt to be insufficient. Excessively low pressure injures
the nutrition of the heart, favouring enlargement, etc. Muhlberg (99)
is quoted by Friedlander to the effect that low pressure after the age
of 50, unassociated with any organic lesion to account for it, constitutes
the best criterion of life beyond the normal expectancy; it is also stated
by Friedlander (50) from Fisher's figures that of 3,389 persons (ages
16 to 60) with systolic pressures of 100 mm. or less there was only
35 per cent of the expected mortality. Symonds (122) considers low
pressures after the age of 40 desirable; he also reports that the lowest
mortality was found in those subjects who were 15 per cent below the
average weight. Pressures not too low seem to favour longevity.
The general relation of low blood pressure to tuberculosis has been
the subject of several inquiries in recent years. Marfan and Vannieu-
wenhuyse (94) (700 cases) while finding systolic pressure lowered —
more so as the disease was serious or getting worse — do not regard
low pressure as excluding improvement or recovery. Normal or raised
systolic pressure they regard as a good prognostic. Diastolic pressure
falls only in the last stage. These workers emphasise the importance
of repeated examinations. De Bloeme (36) in 500 cases by the auscul-
tatory method affirmed the existence of an important group at 100
to 110 mm. S. where the seriousness of the condition was more recog-
nisable by the blood pressure than by other methods, while cases at
80 to 100 mm. were recognisable by ordinary diagnostic means. There
seemed to be a general relation between the higher pressures and better
conditions of the patients. The most favourable cases of both sexes
were between 110 and 150 mm. There was apparently an association
between low pressures and the tendency to relapse or the occurrence of
relapse, even after the local and general symptoms had subsided;
blood pressure rose with improvement.
While regarding blood pressure as being below normal in 60 per cent
of early cases, Naucler (101) sometimes found normal or higher pres-
sures in early cases and concluded that low pressure is not a reliable
sign of early phthisis. The low pressures seemed to depend more on
the severity than on the extent of the disease.
R. J. Cyriac (31) recorded differences in the systolic pressure readings
in the two arms in a number of tuberculous cases as E. F. Cyriac (30)
did in association with some traumatic conditions.
That excessive smoking can lower blood pressure has long been
known and comes into question when systolic pressures at or below
100 mm. are observed.
134
326 J. A. MACWILLIAM
Pressures in aortic regurgitation. Since the remarkable arm-leg
systolic pressure difference was recognised in cases of aortic regurgita-
tion by Hill, Flack and Holtzman (64) in 1909, numerous observations
have been made and differences of varying degrees of magnitude have
been recorded, one of 200 mm. by Rolleston (114) — leg pressure 350,
arm 150 — while the differences have as a rule been much smaller.
Similar phenomena have been observed in some other conditions —
violent muscular exertion in healthy persons, some cases with arterial
sclerosis, and in exophthalmic goitre. In these conditions question
naturally arises as to which reading represents the "blood-pressure."
The mechanism involved has proved difficult of elucidation. L. Hill
suggested a different "conductance" in the leg arteries, transmitting
the large systolic wave more effectively than in the arm. As the
diastolic pressure is virtually if not absolutely similar in arm and leg
it is evident that the systolic difference is a phenomenon of wave motion.
There are indications that both a, cardiac and b, vascular conditions
are usually concerned in the mechanism of the arm-leg difference in
pressure. That a cardiac factor plays a part is suggested by the clinical
evidence to the effect that in man the differential pressure is slight or
absent in recent aortic lesions, and is chiefly found in cases of com-
pensated aortic regurgitation with their enlarged heart, large and
powerful systolic wave and unusually extensive pulse pressure— con-
ditions also present in greater or less degree in other instances where
the arm-leg difference has also been recorded, e.g., exophthalmic
goitre, some arterio-sclerotic cases, violent muscular exertion, etc.
In toxic exophthalmic goitre many of the circulatory conditions
resembling those associated with aortic regurgitation (large heart,
exaggerated pulse pressure, etc.) may be strikingly present. Taussig
(123) has observed an arm-leg difference of 37 mm. Hg; the condition
has also been described by Harris (59). In a case of arterio-venous
aneurysm Lewis and Drury (83) have found that many similar circu-
latory features were temporarily abolished during artificial closure of
the arterio-venous communication, but not the differential pressure,
which they attribute to vascular conditions which had become estab-
lished.
As regards experimental animals there is a conflict of evidence be-
tween the results of Bazett who described the immediate appearance
of a differential pressure after an aortic valve lesion, and those of
Leschke (84) who did not find a differential pressure at this stage.
The important investigation recently published by Bazett (13)
135
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 327
deals with schema results, animal experiments and clinical observations.
He concludes that the differential pressure is essentially due to the
transference of kinetic energy in a fluid in rapid motion into stress when
the flow meets resistance, the relative degrees of slowing thus induced
in different vessels and the relative masses of blood concerned being
important, while the condition of the arterial wall (suggested by L.
Hill) probably plays a part as may also the "breaker formation"
of Bramwell and A. V. Hill (20), though not essential. The higher
leg pressures are accounted for on these lines, local arterio-sclerotic
changes being capable of exaggerating the phenomenon. Larger dif-
ferences in arm-leg pressure were found with contracted arterioles —
involving greater slowing and greater transformation of kinetic energy.
It is suggested that the effects obtained by L. Hill and Rowland (65)
with warm baths (equalisation of pressures) are explicable in this way
as well as on the hypothesis of altered conditions in the arterial walls.
The aortic arm-leg difference is thus regarded as a great exaggeration
of the normal carotid-femoral difference described by various observers
— essentially the water hammer action of Corrigan's "rushing current"
in aortic regurgitation.
In animal experiments a reversed differential pressure was sometimes
seen, i.e., a pressure higher in the upper than in the lower limb, in
association with a forcible heart action with regurgitation present and
an apparently low peripheral resistance. No evidence seems to be
available of the existence of such a condition clinically.
Capillary pressure. In the attempts to gauge the capillary pressure
the various methods and the different criteria applied have produced
a discordant and somewhat bewildering assortment of results repre-
senting "capillary pressure" as anything between 25 to 50 mm. H2O
and 70 mm. Hg. There are at least four modes of observation that
have been used.
1. Blanching methods (skin of finger or hand). Following Von
Kries' (75) idea there have been applications by numerous observers,
using however different criteria, e.g., the first production of visible
paling, used by Easier (11) and by White (132) or complete blanching
(v. Basch (10)) or the pressure at which the skin again begins to flush
(Recklinghausen (109) and others); much confusion has resulted. Von
Basch's figures were 25 to 30 mm. in healthy subjects; he concluded
that capillary pressure can vary independently of arterial pressure;
Recklinghausen's value was 52,2 mm. Basler with his ochrometer
found normal capillary pressures at about 7 mm. Hg, but Landerer
136
328 J. A. Mac WILL I AM
(79) by the same method reported pressures of 17 to 25 mm.
Briscoe (21) using Hooker's capsule to cause paling estimated the
normal pressure at 23.5 cm. H2O. Hill and McQueen (66) taking the
returning flush as their criterion obtained values of about 10 mm. Hg.
The interpretations put upon the results of blanching experiments
naturally depend on the different views held as to the causation of the
colour of the skin. There is thus much diversity of opinion as to what
is really being measured. While v. Kries, v. Basch, v. Recklinghausen
and Basler took the paling of the skin to be due to compression of the
capillaries, Lombard (85) and Danzer and Hooker (35) regard the empty-
ing of one or more of the venous plexuses in the dermis as the main
cause ; they find that paling is not necessarily accompanied by cessation
of flow in the capillaries. White (testing the influence of heat, etc.)
also concludes that the paling of the skin from external pressure is
not an indication of capillary pressure. He obtained values of 4 to
19.5 cm. H2O. Hill interprets the 10 mm. value (obtained as stated)
as indicating arteriolar, not capillary, pressure, plus the resistance of
the epidermis which has to be deducted. When a capillary area is
compressed the internal pressure is regarded as banking up to arteriolar
pressure. Such an arteriolar pressure value as 10 mm. Hg is about half
the amount reported for capillary pressures by many other observers.
The real capillary pressure Hill (62) estimates at something like 20 to
50 mm. H2O. Observing transparent parts of mammals and frogs by
Roy and Graham Brown's (115) method he found such a compressing
pressure to cause momentary checking of the blood flow and took this
as the true index — as distinguished from a compression stopping the
flow, which might require 350 mm. H2O.
2. Pressure required to cause obliteration of capillaries under the
microscope. Lombard (85), who introduced the use of a drop of oil
on the skin to permit of direct examination of the capillaries, found
very different pressures necessary to obliterate the vessels of different
orders. Stated in millimeters H2O, the following values were obtained
— subcapillary venous plexus, 135 to 205; superficial venous branches
205 to 270, most compressible capillaries, 245 to 300, middle-size capil-
laries, 475 to 545, most resistant capillaries and arterioles, 815 to
950. Methods founded on Lombard's plan have been used by Krauss
(74), Basler (11) (capillary tonometer) and Kylin (78). The last
named recorded normal pressures of 8.5 to 14 mm. Hg and abnormal
ones up to 40 or 50 mm. in glomerulo-nephritis and scarlet fever.
Difficulty arises from the unequal compressibility of different capillaries
in the field of observation.
137
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 329
3. Pressure required to cause stasis of corpuscular flow under the
microscope — by Danzer and Hooker's (35) micro-capillary tonometer,
a different criterion from those used in the preceding methods. They
found values of 18 to 26.5 mm. Hg averaging 22 mm. Boas and
Frant (17) using the same method reported normal capillary pressures
at 18 to 22 mm. Hg, rarely above 30 mm. ; high pressure cases reading
usually between 30 to 60 mm. In essential hypertonus capillary pres-
sure was found to be normal, i.e., below 30 mm. Boas and Mufson
(18) found a much higher mortality in a high capillary pressure group
(5 deaths in 28). Their post-mortem findings (a small number of
cases) did not support Kylin's hypothesis of an association of high
capillary pressure with glomerular nephritis.
4. Piercing capillaries with a very fine capillary glass needle (con-
taining saline at a measured pressure) under the microscope to measure
the pressure in a capillary loop — by Carrier and Rehberg (26). The
values 45 to 75 mm. H2O in two subjects at 7 cm. below the clavicle —
reported by this method — unfortunately unsuited for clinical applica-
tion— are relatively low and lend support to L. Hill's repeatedly stated
view as to the lowness of capillary pressure. The venous pressure was
parallel to the capillary pressure.
Supposing that the pressure in the minute vessels of the skin can be
accurately measured, there remains the question of the application of
such results to the conditions of the general circulation. Pressures in
the finger and hand are naturally influenced profoundly by the local
conditions of arterial tone as affected by vasomotor influences, heat,
cold, exercise, sleep, etc., with the result that the digital pressure may
rise while the brachial pressure falls, or vice versa. It is hardly neces-
sary to recall the frequently opposed conditions in the skin and splanch-
nic areas, as with muscular exercise, asphyxia, adrenalin, etc., also
the different incidence of the vaso-dilator effects of acetyl-choline —
as described by Reid Hunt (69) — marked in the skin, slight in the liver
and intestine, very slight in the voluntary muscles. Again the strong
constriction of the renal vessels, which is presumably the cause of the
anuria known to occur during short spells of violent muscular exercise,
is associated with increased pressure in the skin. The habitually cold
or habitually warm hands of different persons, naturally involve wide
variations in the pressure relations of the minute cutaneous vessels.
There are thus no means of ascertaining the relations between pres-
sure measurements in the skin and the pressures existing in other
parts, internal organs, etc., and how they stand with regard to the
138
330 J. A. MACWILLIAM
average pressure in the capillary field as a whole, made up as it is of
a great and varying distribution of capillary pressure values in multi-
tudinous districts. It is obviously not permissible to speak of capillary
pressure in the same sense as arterial pressure, the latter being a defi-
nite measurement virtually the same in all the large arteries throughout
the body, while capillary pressures vary widely and in different senses
in numerous districts under physiological conditions. Still if there is
definite association of high readings of pressure in the minute skin
vessels in some category of high blood-pressure cases and not in others
this — even if not representative of the capillary system as a whole —
is obviously a matter of much interest calling for further investigation
as to its mechanism and significance. Boas and Mufson report close
correspondence in the capillary readings from the same individuals
taken many months apart — with some exceptions for which explana-
tions are offered. As to the relations of capillary and venous pressures
there is some conflicting evidence. While it has generally been accepted
that capillary pressures run much more nearly parallel with venous
than with arterial pressures. Boas and Doonieff (16) in a recent in-
vestigation (using a needle in a vein connected with a manometer)
find that a rise in venous pressure up to 39 cm. H2O may have no effect
on capillary pressure — evidence that the high capillary pressure which
may occur in hypertension is not accounted for by high venous pressure.
On the other hand, Danzer and Hooker found venous compression to
cause increased capillary pressure; Carrier and Rehberg observed a
parallelism between venous and capillary pressures. Von Basch and
Kraus had formerly emphasised the close relationship between these
pressures.
The peripheral resistance. Recent work on the capillary system and
the very varied conditions that may obtain in it have re-opened the
question as to what the peripheral resistance in the circulation is con-
stituted by. Is the arterial resistance largely supplemented by resistance
in the capillary field and possibly also, as suggested by Hooker's (68)
work, in the venules, and capable of being altered in an important
degree by variations in these as well as in the small arteries?
Favouring the commonly accepted view that the chief resistance is
in the small arteries is the greater internal friction depending on the
relatively rapid rate of flow in the arteries as compared with the slow
flow in the capillaries under ordinary conditions ; also such evidence as
is available to show that the loss of pressure in passing through the
capillaries is relatively small, the great fall from the arterial pressures
139
BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 331
ordinarily measured having occurred before the capillary region with
its apparently low pressures is reached.
On the other hand there is to be considered the active and strong
contractiUty of capillaries as shown by Krogh (76) and others; Lewis
(82) estimated their contractile power as being capable of expelling
fluid against a pressure of 50 to 60 mm. Hg, and when contracted, of
resisting the entry of fluid up to 90 to 100 mm. Hg. Excessive con-
striction or closing of an unusually large proportion of the capillary
tubes, with diminution of the sectional area of the available capillary
bed, must necessarily affect the resistance offered to the outflow from
the arterial tree, as well as influencing the capacity of the vascular
system, especially in view of the fact that in small capillaries the red
corpuscles actually rub against the walls of the tube; it is not simply
a matter of internal friction between the layers of the moving blood
as in the arteries.
Conditions that might reduce the disparity between the sectional
area of the arterial and capillary fields (e.g., closure of many capil-
laries, arterial dilatation etc.) would naturally tend to enhance in some
measure the resistance presented in the capillaries. Again, Lombard
estimated the fall of pressure between the small arteries and the veins
at 40 to 50 mm. Hg which would postulate a resistance in the capil-
laries nearly as great as that in the small arteries. But the recent evi-
dence favours low values of capillary pressure, involving a great fall
from the pressure in the larger arteries (e.g., 120 mm.) before the
capillary field is reached with pressures estimated at one-sixth or one-
tenth or even much less — indicating the situation of the main resistance
in the circulatory system as being in the small arteries and arterioles.
On the other hand if higher estimates of capillary pressure are cor-
rect, especially such as have been reported in some diseased conditions,
with a large decline from capillary to venous pressure it is evident
that a considerable part of the peripheral resistance must be located in
the region of the capillaries and venules. With regard to the possible
influence of constriction of the venules, such might obviously have im-
portant effects.
Venous pressure. Venous pressures, easily measured in the veins
of the arm or hand by the method of Hooker (67), have been found
by that observer to be usually between 10 and 20 mm. H2O, progres-
sively increasing with age from 8 cm. in early youth to 25 cm. in old
age. Eyster and Middleton (42) report pressures rarely above 11 cm.
normally; Briscoe about the same, 11.4 cm. White (132), using a
140
332 J. A. macwilliam
method of instantaneous instead of gradual application of external
pressure to the vein, recorded lower values, often 4 to 6 cm., sometimes
as high as 12.5 cm. Venous pressure has been noted as being raised
in nephritic hypertension, in contrast to simple arterio-sclerosis, by
Villaret (128) and his associates. But this conclusion is opposed by
the results of Leconte and Yacoel (80). Like the pressures in the
minute vessels of the skin the venous pressures in a limb are liable to
be much influenced by local conditions. And it gives no actual measure
of the venous pressure at which the filling of the right heart takes
place — the "effective pressure" of Yandell Henderson and Barringer
(61) — the difference between the intra-auricular and intra-thoracic
pressures. As the latter pressure is variable, this, as Wiggers (133)
points out, raises a serious difficulty as regards the application of limb
venous pressure measurements to the study of circulatory conditions.
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BLOOD PRESSURES IN MAN, NORMAL AND PATHOLOGICAL 335
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■i^
146
DIASTATIC ACTIVITY IN BLOOD AND URINE.
CHAELES KEID, M.A., B.Sc, M.B., Ch.B.,
From the Physiological Laboratory, University of Aberdeen.
Received for publication June 6th, 1925.
As views on the utility of the estimation of diastase in urine and blood are
divergent, an investigation into the diastase activity of equal quantities of
whole blood and urine was undertaken. The diastatic activity of a specimen
of urine is estimated in terms of the amount of starch which, incubated at
37° C. with a definite volume of the urine, will be changed in 30 minutes, the
disappearance of the starch being indicated by the failure of the mixture of
starch and urine to give a blue colour or a violet tint with iodine. For the
estimation of the diastatic activity of blood, it is necessary to estimate the
amount of sugar present in a given amount of blood, to incubate a given
amount of blood with a given amount of starch at 37° C. for 30 minutes, and
to estimate the amount of reducing sugar which has been formed by the
diastase in the blood. The diastatic activity of the blood is given in terms of
reducing sugar, and in this way a comparison can be made between the
diastatic activities of equal volumes of blood and urine, although the actual
concentration of the diastase by the kidneys would not be available.
Technique.
Urine. — In order to obtain the diastatic activity of equal volumes of blood
and urine, a slight modification of the method described by Dodds (1922) was
used.
A series of ten small test-tubes was employed usually, the length of the tube
being about 3 inches, and capacity 4 c.c. A quantity of buffered urine was
prepared by mixing 5 c.c. of the urine with 20 c.c. of a mixture of Sorensen's
solutions. The buffer solution was obtained by mixing 15 c.c. of a solution
containing 11876 grm. Na2HPO42H20 in 1000 c.c. distilled water, and 85 c.c.
of a solution containing 9*078 grm. of KH2PO4 in 1000 c.c. distilled water.
These solutions were kept in paraffin-coated glass-stoppered bottles. To each
of the small ten test-tubes was added 1 c.c. of the buffered urine, and to the
series of ten tubes (1-10) were added respectively 2 c.c, 1'8 c.c, 1'6 c.c,
1*4 c.c, 1*2 c.c, 1*0 c.c, 0*8 c.c, 0*6 c.c, 0*4 c.c, 0*2 c.c. of a 0*2 per cent,
solution of Lintner's soluble starch made up in 0*9 per cent. NaCl solution.
The total volume in each tube was made up to 3 c.c by the addition of
distilled water. The tubes were shaken immediately, and placed in a water-
bath in an incubator for 30 minutes at 37° C. The tubes were then removed
1
146 DIASTATIC ACTIVITY IN BLOOD AND URINE.
from the incubator, and their contents poured into a series of larger test-tubes
about three parts full of cold tap-water. One or two drops of a N/10 solution
of iodine were added to the series of tubes (1-10) until a tube was obtained
where the blue or violet tint was not perceptible. The amount of diastase in
this tube was sufficient to digest all the starch present. The diastatic activity
of the urine was found empirically by dividing the number of c.c. of the starch
solution digested by the amount of urine in c.c, the number obtained often
being called Wohlgemuth units. With the above technique the range of
diastatic activities would be 20, 18, 16, 14, 12, 10, 8, 6, 4, 2 — an even series
of numbers not given by simple pipettings in previous methods. The range of
diastatic activities could be easily increased by the use of stronger solutions
of starch. For example, the use of a 0*4 per cent, solution of starch would
give a range of diastatic activities from 40, 38, 36, . . . 24, 22, but the
necessity for this was not common when the specimen of urine for examina-
tion was passed in the second two-hourly interval after the first meal of the
day. This period was chosen because it appeared to be a convenient time to
examine both the blood and urine, and because most of the diuresis due to the
intake of fluid with the meal had ceased.
It was shown by Michaelis and Peckstein (1914) that the pH at which
diastase was most active varied with the salt content of the medium. Stafford
and Addis (1924) pointed out that in the technique of Dodds {loc. cit.) and
Sladden (1922) there seemed to be a danger of a disturbing variation in the
chloride and phosphate concentration respectively. This difficulty has been
got over by the above modification, in which there was always in each tube a
sufficiency of chloride and phosphate, and in which the urine with the enzyme
was diluted equally in all the tubes, although the concentration of the substrate
varied. This, however, would not prevent a reasonably accurate study of the
diastatic activity of different urines.
In the present investigation the above modification was adopted, and was
used before the publication of the second and third papers referred to in the
preceding paragraph. Sladden {loc. cit.) considered that the addition of
phosphate buffer solutions tended to obscure the final readings. But in the
present inquiry no difficulty in reading the end-point was observed if small
tubes (4 c.c.) were used for incubation, and if these were emptied into larger
tubes (20-30 c.c.) containing cold water before the addition of iodine.
Blood. — For the examination of the diastase in the blood, the method
described by G. Matthew Fyfe (1923) was employed with one or two small
modifications.
Into one of two 100 c.c. Erlenmeyer flasks, 1'8 c.c. of Sorensen's buffer
solutions and 1 c.c. of 0*1 per cent, solution of Lintner's soluble starch in 0*9
per cent. NaCl are pipetted, and into the other 23*8 c.c. of a 15 per cent, solution
of sodium sulphate acidified by the addition of glacial acetic acid to the extent
of 01 per cent. Into each flask is introduced 0*2 c.c. blood by means of two
special pipettes which are thoroughly rinsed out in the clear fluid. The flask
containing starch is placed in a water-bath in an incubator for 30 minutes at
37° C. At the end of this period 21 c.c. of the acid sodium sulphate solution
are added immediately. The amount of sugar is estimated in both flasks by
MacLean's method (1919).
C. REID. 147
The amount of sugar formed by 0'2 c.c. blood from 1 c.c. of a O'l per cent,
solution of starch expressed in milligrammes is taken as an index of the
diastatic activity of the blood. The number obtained multiplied by 100 to
displace the decimal point is used as the number indicating the diastatic
activity of the blood.
VAEIATIONS IN THE TWENTY-FOUE-HOURLY SPECIMENS OF URINE.
With regard to 24-hourly specimens of urine, considerable variations were
found from day to day under apparently constant conditions, the variations
tending to be greater in the case of those individuals whose urine had a high
diastatic activity.
Table I gives the variations (in Wohlgemuth units) obtained in a number
of healthy individuals, specimens of the total urine passed in the 24 hours
being examined.
J. R—
D. M—
C. G—
G. M—
F. M—
R—
Table I.
5-4, 4-5, 6, 6, 3, 3*5, 3-8.
9-1, 6, 10, 10, 10, 9.
7-5, 9-7, 11, 8.
20-8, 16-3, 16, 12-5, 15-4, 11-8, 13-2, 136, 10.
7-2, 8-8, 6-5, 5-2, 5-7, 7-2, 5-8, 7-0, 5'5.
19, 19, 20, 18-2, 15-4, 22-2, 22, 12-5, 22, 21, 16-7, 18, 12*5,
19, 20, 12-8.
The diastatic activity was not always directly related to the specific
gravity or inversely to the average hourly rate of the secretion of urine,
although it was found that the 24-hourly specimens with a higher specific
gravity tended to have a higher diastatic value, while specimens with a lower
rate of secretion tended to have a higher diastatic activity.
The total diastatic activity for the 24 hours was taken as the amount
of urine in c.c. multiplied by the diastatic index stated in Wohlgemuth's units.
This was found to give widely different numbers in different individuals. But
by taking a large number of observations on the same individual over a
considerable period, it was found that the total diastatic activity gave, in the
majority of cases, a number which was fairly constant. For example :
In 9 readings on one individual, 6 gave a total diastatic content between
26,000-30,000.
In 9 readings on a second individual, 6 gave a total diastatic content
between 12,000-16,000.
In 10 readings on a third individual, 8 gave a total diastatic content
between 17,000-19,500.
In 15 readings on a fourth individual, 12 gave a total diastatic content
between 13,000-16,000.
The remaining results of the individual cases were either above or below
the respective numbers, the highest number obtained being as much as
50 per cent, above the lowest in the same case.
With regard to the individual specimens passed throughout the 24 hours.
148
DIASTATIC ACTIVITY IN BLOOD AND URINE.
considerable variations in the diastatic activity stated in Wohlgemuth units
were met with. For example, variations 5-18, 9-22, 2-10, 2-6, 4-8, 12-24,
etc., were obtained in different individuals.
The fewer the specimens, the less were the variations of the diastatic
activity of the different specimens.
Conditions of polyuria induced by exitement, cold, drinking large quantities
of fluids gave more striking variations. In one case it was noted that during
excitement the diastatic activity of the urine fell from 20 to 1 in the course of
two or three hours.
Stocks (1915-16) stated that it appeared that the concentration of diastase
was at a maximum just after breakfast (8 a.m.), and then decreased gradually
with a secondary rise after dinner.
Table II gives some observations made by the present writer on hospital
patients who had breakfast at 7 a.m., dinner at 12 noon, tea at 4 p.m., supper
at 7 p.m.
11 a.m.
5
25
5
8
6
8.30 a.m
F. M—
8
G. M—
16-6
C. G— (1)
8
„ (2)
12-5
D. M—
8
Table
II.
1.30 p.m.
5 p.m.
8 p.m.
5 a.m.
5
14
5
12-5
10
25
20
16-6
8
12-5
12-6
12-5
10
10
12-5
14-3
—
10
10
14-3
The highest concentration of diastase in hospital patients who were not
suffering from renal disease, and who were confined to bed, was obtained in
the specimen of urine passed at 5 p.m. or in the overnight specimen passed
at 6 a.m.
The observations in Table III were made on healthy young adults whose
ordinary daily routine was not altered in any way.
Subject A.
Diatastic activity of urine.
(Wohlgemuth units.)
16-7
22-2
20
18-2
16-7
20
14-2
15-4
18-2
22-2
Meal.
Meal.
Table III. — Breakfast 8 a.m.
Time.
8.45 a.m.
10.5 „
11.40 „
1.10 p.m.
4.40 „
6.15 „
8.0 „
9.5 „
12 midnight
8.20 a.m.
Subject B.
Diastatic activity of urine.
(Wohlgemuth units.)
14-3
22-2
20
15-4
12-5
20
18-2
25
Meal.
Time.
8.45 a.m.
9.45 „
1.25 p.m.
3.45
4.30
5.40
Meal.
10.30
8.0
a.m.
C. REID,
149
In neither of the above observations did the urine which was passed
immediately after breakfast have the highest concentration of diastase. It
would appear that the urine, which is secreted overnight, and which in
healthy individuals is secreted at the slowest rate, has the highest diastatic
activity, provided that factors producing polyuria were excluded. Specimens
of urine were obtained before and immediately after breakfast, the first
specimen being passed about 8 a.m. and the second about 8.45 a.m. to
9 a.m. The fii;st specimen included the urine secreted overnight (Table IV).
Table IV.
Urine passed
at 8 a.m. before
Urine passed at 8.45 a.m. after
breakfast.
breakfast.
A
Diastatic
Urine per hour
Diastatic Urine per hour
activity.
in c.c.
activity. in c.c.
18-2
22
,
16-7 26
22-2
17
16-7 40
25
17
14-3 27
25
• 18
16-7 27
22-2
24
16-7 35
25
23
20 27
22-2
21
18-2 30
The lower diastatic activity of the second specimen evidently depends
largely on the increased rate of secretion as compared with the relatively slow
rate of secretion of night urine. On the other hand, it was found occasionally
that the overnight urine had not the highest diastatic activity of specimens
passed during the 24 hours' period. This can be seen on reference to Tables
II and III.
The diastatic activity of the individual specimens passed during the 24
hours varied inversely as a rule with the average hourly rate of secretion.
Exceptions, however, were rather frequent.
Table V gives the type of results obtained on a day during which no food
or fluid was taken from 8 a.m. until evening.
Table V.
Time after
Diastatic activity. Rate of
Average hourly
Time.
Amount in c.c.
food in
(Wohlgemuth
secretion per
total diastatic
hours.
units.)
hour in c.c.
activity.
7.30 a.m.
. 330
—
16
33
528
7.45 „
18
—
20
36
720
8.0 „
(breakfast)
10..30 „
. 160
2i
16
58
932
11.35 „
. 102
H
12
94
1132
1.5 p.m.
. 131
5
10
87
883
2.10 „
73
6i
10
67
674
4.40 „
83
81
16
33
532
5.20 „
18
9i
18
27
486
150 DIASTATIC ACTIVITY IN BLOOD AND URINE.
VAEIATIONS IN DIASTATIC ACTIVITY OF BLOOD.
Wohlgemuth's method for diastase in the urine would appear not to be
sufficiently delicate for serum, owing possibly to the concentration of diastase
in the urine being higher than in the serum. The tint of the sera masks the
delicacy of the colour reaction which occurs on the addition of iodine.
Variations were found in the diastatic activity of whole blood when examined
by Fyfe's method, and they would appear to be related to the ingestion of
food.
Table VI shows the the variations obtained in two normal cases selected
at random from a number of estimations made on several normal cases.
Table VI.
Case A.
Case B
Time.
Blood diastase. Time.
Blood diastase
7.30 a.m.
10-2 . 8 a.m.
6
Meal at 8 a.m.
Meal at 8.15 a.m.
10.15 a.m.
11-9 . 9.15 a.m.
5
11.30 „
6-8 . 10.45 „
2-9
1.30 p.m.
6'3 . 1.0 p.m.
6-5
4.30 „
9-9 . 3.0 „
5.0 „
6-4
5
Stafford and Addis (toe. ci^.) foresaw the possibilities of variations in the
diastatic activity of plasma, but they gave no details. Cammidge and Howard
(1923) noted variations in the diastase content of the blood of a rabbit.
DIASTATIC ACTIVITIES OF UEINE AND BLOOD, AND THE DIASTATIC
CONCENTRATION FACTOR.
The diastatic activity of a specimen of urine has been shown to be —
Number of c.c. of 0"2 per cent, solution of starch converted by 0'2 c.c. urine
02 c.c. urine
_ number of milligrammes of starch converted
0'2 c.c. urine
TT -rv number of milligrammes of starch
%. e. U.D. = ^ — ■ — —
0-2.
The diastatic activity of the blood (B.D.) has been taken as the number of
milligrammes of sugar X 100 formed by the diastase in 0'2 c.c. blood from
the substrate, viz. starch.
The diastatic concentration factor (D.C.F.) for the kidneys which are being
examined may be taken as the power of the kidneys to concentrate diastase
from the blood. If, for example, a specimen of urine is obtained for the
second two-hourly period after the first meal of the day, in order to get the
mean value of the blood diastase during this period, it would be necessary to
carry out blood-diastase estimations at the beginning and end of this period or
C. REID.
161
alternatively at the middle of this period. As it is impossible to estimate
actually the amount of diastase in the urine and blood, the ratio of the amount
of starch converted by 0*2 c.c. urine to the amount of sugar formed by 0'2 c.c.
blood has been taken as the diastatic concentration factor.
number of milligrammes of starch converted by 0'2 c.c. urine
number of milligrammes of sugar formed by 0'2 c.c. blood
U.D. X 0-2
D.C.F. =
U.D. X 0-2
B.D.
X 100.
The diastatic concentration factor was found to vary considerably through-
out the 24 hours. The results in Table VII from two subjects — typical of a
series of at least half-a-dozen — show the sort of variations obtained in a
number of individuals.
Case A
Case B
Time.
Table VII. — Breakfast 8 a.m.
B.D. U.D. D.C.F.
7.30 a.m.
10-2
16
30 +
10.15 „
11-9
16
29
11.30 „
6-8
12
25
1.30 p.m.
6-3
10
30
4.30 „
9-9
16
40
8.0 a.m.
6
6
20 ap
9.15 „
5
—
—
10.45 „
2-9
8
36
1.0 p.m.
6-5
6
25
3.0 „
6-4
8
25
5.0 „
5
8
28
From the point of view of convenience it was decided to carry out a
number of investigations on healthy adults, and to examine the diastatic
activity of the blood at two hours and four hours or alternatively at three
hours after the first meal of the day, and to examine the diastatic activity of
the urine secreted during the second two-hourly period after the same meal.
Table VIII gives the diastatic concentration figures obtained in young
adults and in children of fifteen and under by the above method.
A factor which must be considered in cases giving low urinary diastatic
figures, apart from those due to polyuria, is that of the blood-diastase figure.
Case 6 has a low U.D. and moderately low B.D., but the lowness of the
D.C.F. is due to the presence of a certain amount of diuresis due to excite-
ment. Case 14, on the other hand, shows low figures for the U.D. and B.D.,
but the D.C.F. in the absence of polyuria is within normal limits.
152
DIASTATIC ACTIVITY IN BLOOD AND URINE.
It will be noted that if due allowance is made for variations due to
polyuria, the figure obtained from these normal individuals examined for the
diastatic concentration factor lies between 15 and 40.
Table VIII.
1.
2.
3.
4.
5.
6.
7.
8.
9.
•10.
11.
12.
13.
14.
16.
16.
17.
18.
Sex.
Age.
U.D.
B.D.
D.C.P.
. M.
. 31
16
. 9-4
. 29 .
. M.
. 25
. 12
. 81
. 29 .
. M.
25
6
4-7
. 25 .
. M.
. 29
12
6-4
. 37 .
. M.
9
6
8
15 .
. M.
. 5
2
5
8 .
M.
9
6
8
15 .
. M.
11
8
7
23 .
. M.
10
2
8
5 .
. M.
10
2
5
8 .
. P.
11
8
8
20 .
. r.
n
8
8
. 20 .
. F.
6i
6
5
24 .
. M.
H
4
3
27 .
. M.
13
6
10 .
12 .
. M.
13
4
10
8 .
. M.
14
8
11
15 .
. M.
13
6
9
14 .
110
65
175
115
80
155
125
90
275
240
55
35
130
75
110
160
70
70
Amount of urine during two hours.
„ (usually passes large quantity).
„ sp.
gl
. 1020.
., ,
1010;
polyuria.
>• I
1014.
)> „
1021.
,, ,,
1010;
polyuria.
)t »I
1010;
"
J) »>
» !>
1018.
1022.
polyuria.
SUMMARY OF RESULTS.
Healthy Subjects.
I. Diurnal variations in the urine. — The urine secreted during the night has
generally a higher diastatic activity than that secreted during the day. The
diastatic activity of the urine secreted during the day varies inversely, as a
rule, with the rate of excretion, and directly to a certain extent with the
specific gravity. The total diastatic activity of the urine (amount in c.c. X
diastatic index) for the 24 hours gives numbers only approximately constant
in the same individual. The total diastatic activity of specimens of urine
examined hourly after a meal is highest in the period of the second to the
fifth hour. Thereafter the value tends to fall.
II. Variations in the blood. — The blood diastase when examined by Fyfe's
method exhibits well-marked variations apparently related to the ingestion of
food.
The level is lower in the period from the third or fourth hour to the
seventh or eighth hour after a meal than it is after fasting or shortly after
a meal.
III. Variations in the diastatic concentration factor. — In the same individual
this varies throughout the day, being highest, as a rule, in the urine secreted
overnight or in urine secreted during the fasting condition.
IV. The figures obtained for the period 2-4 hours after a meal in healthy
individuals : (1) Blood diastase. — In the majority the figure obtained lies
between 6 and 10, with outside limits of from 3 (exceptionally) to 11 or 12,
C. REID. 163
(2) Urine diastase. — In the absence of polyuria the diastatic index in the
majority of healthy individuals lies between 6 and 14.
(3) Diastatic concentration factor. — The normal figure obtained lies in the
majority of cases between 20 and 30 with outside limits of about 15 to 40.
Nephritic Subjects, etc.
Numerous cases of nephritis mostly, of diabetes, arteriosclerosis, prostatic
enlargement, etc., were examined in the same way as the preceding normal
cases with a view to seeing whether there was any variation from the normal
diastatic concentration factor in renal disease.
The results are shown in Table IX.
Blood diastase. — High levels were found in a number of kidney conditions
such as acute nephritis, uraemia, cardio-renal cases with failing heart. In
addition, high levels were also found in 2 out of 5 diabetic cases and in
2 out of 4 cases of prostatic enlargement with retention of urine.
Urine diastase. — High levels were found in acute nephritis and in cases of
cardio-renal disease showing failure of urinary secretion. Low levels were
found in many cases of chronic kidney disease and of prostatic enlargement
with retention.
Diastatic concentration factor. — While the figures obtained in acute
nephritis were high, low figures were obtained in cases of chronic renal
disease, enlarged prostate and diabetes.
Prostatic Cases.
Table X shows the results obtained in four cases of prostatic enlargement
with retention of urine.
Case. Age. Blood urea. Urine urea. B.D. U.D. D.C.F. Remarks.
38 . 65 . 90 . — . 11-4 . 2.3-5. General condition fair.
39 . 85 . 150 . r35% . 3 . <2 . Low . General condition poor; chronic
ursemic state.
40 . 79 . 60 . 1-2% . 7 . <2 . „ . Pus in urine ; clearing ; general
condition improving.
41 . 63 . 90 . 1"6% .16 . 6.7 . Stricture and enlarged prostate ;
blood and pus in urine ; tongue
dry ; general condition poor.
Wide variations were observed in the blood-diastase figure. The urine
diastase figures were low with one exception. All the cases, however, gave a
low diastatic concentration factor, as the above-mentioned exception (Case 41)
had a high blood-diastase figure.
Urea Concentration and Diastatic Concentration Factor.
In the cases shown in Table XI the urea concentration test was performed
and a comparison was made with the diastatic concentration factor.
154
DIASTATIC ACTIVITY IN BLOOD AND URINE.
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156
DIASTATIC ACTIVITY IN BLOOD AND URINE.
Table XI
Age.
Sex.
Urea concentration.
D.C.F.
Hemarks.
30
M.
2-4%
24
Healthy.
25
M.
2-5%
22
>>
46 .
M.
1-25%
5
Arterio-sclerosis with retinal
haemorrhages.
42
F.
2-4%
15
Hyperpiesis.
63 .
M.
3-0%
22
Auricular fibrillation.
47
F. .
0-75%
3 .
Chronic interstitial nephritis.
50
M.
2-0%
18
>> >>
47
F.
3%-3-5%
16
Hyperpiesis.
40
F.
4-3%
44
Acute nephritis.
85
M.
1-3%
5
Enlargement of prostate.
79
M.
1-2%
5
>> )>
63
M.
1-6%
7
>f >>
81
. M.
3-05%
. 25
» »»
The figure obtained in healthy individuals for the diastatic concentration
factor lies between 15 and 40. When the figures in the two columns for the
urea concentration and the diastatic concentration factor are compared they
are found to be in general agreement, normal values of one corresponding to
normal percentages of the other, and low values of one corresponding to low
percentages of the other.
Stafford and Addis {loc. cit.) compare the rate of excretion of diastase with
the power of the kidney to concentrate urea, and state as a remarkable fact
that emphasis has usually been laid on the concentration of diastase, and not
on the rate of excretion of diastase. They obtain the rate of excretion or the
total hourly diastatic activity by multiplying the amount of urine in c.c. by the
urinary diastatic activity (Wohlgemuth units) , and dividing by the time in hours
which the kidney took to secrete the specimen considered. In MacLean's
urea concentration test stress is laid on the power of the kidney to concentrate
urea. In the present investigation stress is laid on the power of the kidney
to concentrate diastase from the blood, and not on the rate of excretion as
shown by the total hourly diastatic activity.
It is possible to have (c/. Case 13, Table IX) a normal urinary diastatic
activity and total hourly diastatic activity along with a high blood diastatic
activity, thus producing a diastatic concentration factor lower than normal.
Further, the hourly rate of excretion is found to vary so widely in different
normal individuals that the application of the hourly rate of excretion of
diastase to abnormal cases would not appear to be justifiable.
In addition, in the present investigation the diastatic concentration factor
is compared in many cases with the urea concentration as obtained by
MacLean's test, and in this way conclusions are avoided that depend on a
comparison between the urea concentration and the hourly rate of excretion
of diastase, which is very variable even in normal subjects.
C. REID. 157
CONCLUSIONS.
It is advisable to estimate the blood diastatic activity in all cases where the
urine diastatic activity is being examined, and especially in those cases which
give a urinary diastase figure towards the lower limits of normality.
It would appear that the diastatic concentration factor would serve as an
additional confirmatory test to MacLean's urea concentration test, as the figures
obtained for both tests in healthy and pathological cases were in general
agreement.
I am indebted to Prof. J. A. MacWilliam and to Prof. H. MacLean for much
kindly help and suggestion, and to Dr. W. Brander, Medical Superintendent,
Hackney Infirmary, for permission to examine numerous cases.
REFERENCES.
Cammidge, p. J., AND Howard, H. A. H. — (1923) ' New Views on Diabetes Mellitus,'
London (Frowde and Hodder and Stoughton), p. 38.
DoDDS, E. C— (1922) Brit. J. Exper. Pathol, 3, 133.
Fyfe, G. M.— (1923) Ibid., 4, 127.
MacLeak, H.— (1919) Biochem. J., 13, 135.
MiCHAELis, L., AND Peckstbin, H. — (1914) Biochem. Ztichr., 59, 77.
Sladden, a. F.— (1922) Lancet, 2, 68.
Stafford, D. D., and Addis, T.— (1924) Quart. J. Med., 17, 152.
Stocks, Pi— (1915-16) Ibid., 9, 225.
ADLABD and son and west NEWMAN, LTD., IMPR., LONDON AND DOBKINO.
169
THE EFFECT ON RENAL EFFICIENCY OF LOWERING
THE BtOOD-PRESSURE IN CASES OF HIGH
BLOOD-PRESSURE^
By CHARLES REID
(From the Physiological Laboratory, University of Aberdeen)
The following investigation was undertaken to ascertain the effects, especially
as regards the efficiency of the kidneys, of lowering the hypertension present in
cases which did and others that did not show evidence of renal disease. The plan
adopted was to make the following examinations on each case before, during, and
after periods of administration of vasodilator drugs ; the amounts of urea and
non-protein nitrogen in the blood, the power of the kidney to concentrate urea
after a dose of 15 grm. urea (MacLean's test (9)), the total amount of urea and the
total volume of urine excreted, records of blood-pressure, pulse, respiration, and
general condition of the subject being made also.
A current conception of elevated blood-pressure is that, while attended
by drawbacks in the way of increased heart work and stress on the ai-terial walls,
it is in large measure a compensatory process in the organism. This view has
gained wide acceptance, and many observers have emphasized the inadvisability of
indiscriminate lowering of the pressure by such artificial means as the use of vaso-
dilating drugs. Cases have been cited of deterioration in general condition being
associated with lowering of high pressures, and, on the other hand, improvement
in health being attended, not by lowering, but by some further rise of an already
elevated pressure. The high-pressure levels in such cases are regarded as not being
excessive in the circumstances, but rather as optimal, or at least not markedly
superoptimal under the conditions present in the body at the time. When
no symptoms are in evidence artificial reduction of the pressure is held to
be inadmissible. Even when symptoms are present it is conceivable that a
necessary compensatory action may be exercised in some respects, though the
high pressure may involve disturbances in other respects.
In view of the separation of a new antipressor piinciple from hepatic
extracts in comparative purity by James, Laughton, and Macallum (7), and
of the prospect of this method of lowering the raised blood-pressure being given
' Received December 10, 1925.
Q.J.M.,July, I9a6.] F f
160 QUARTERLY JOURNAL OF MEDICINE
an extended clinical trial, the importance of data dealing with the efficiency
of the kidney under conditions of lowered blood-pressure is obvious — with
regard to the differentiation of cases in which reduction of high pressure may be
permissible or desirable or the reverse. Some results of the clinical use of the
hepatic extracts have been described by Macdonald (8), by Major (13), and
by Major and Stephenson (15). Major (14) reported that in two cases of hyper-
tension the excretion of guanidine was not diminished, but rather increased, during
a period (several days) of blood-pressure lowering by hepatic extracts. Gruber,
Shackelford, and Ecklund (4) found that, when high arterial pressure was lowered
by pheno-barbital, no harmful effect was produced on the excretion of phenol-
sulphonephthalein.
The latter, however, is a foreign substance, and might be thrown out by the
kidney independently of any but very extensive changes in blood-pressure, so
that, while the above investigation agrees, so far as phenolsulphonephthalein is
concerned, with the findings of the present investigation as regards urea, the
evidence obtained in the former inquiry is not necessarily valid as an argument
against the compensatory theory.
Possible Compensatory Mechanisms.
It is evident that elevated blood-pressure might be a compensatory adjust-
ment in the way of driving more blood through some vital organ, e. g. brain,
heart-muscle, or kidney : such might be needed where there is inadequacy of
blood-flow depending on alteration in its vascular channels, arterial or capillary,
or when, even apai*t from such alteration, a higher capillary pressure and more
rapid blood-flow would be beneficial in enhancing the functioning of an organ —
deficient from structural or other causes.
There is the familiar instance of the mechanism by which an interference
with the normal blood-supply to the head (e. g. cerebral compression, experimental
closure of the carotids) promptly calls forth a rise of aortic pressure with an
obviously compensatory significance through excitation of the vasomotor centre,
causing constriction in the splanchnic and other areas, and diminution of the
activity of the vagus centre leading to increased action of the cardiac pump.
The recent experimental work of Anrep and Starling (1) by cross-circulation
experiments shows the converse action of increased blood-pressure in the head in
depressing the vasomotor centre, in addition to the well-known influence of such
pressure in stimulating the vagus centre and slowing the heart.
L. Hill (6) wrote in 1900, ' The vasomotor centre is not only excited reflexly,
but responds to every change in the circulation through the spinal bulb. A rise
of pressure in the cerebral arteries provokes a fall of aortic tension ; conversely,
a fall of pressure in the cerebral arteries provokes a rise. In other words,
cerebral anaemia, however produced, excites the centre and increases vascular
tone, while cerebral hyperaemia decreases vascular tone.'
In cases of high blood-pressure Starling (17) attaches much importance
RENAL EFFICIENCY AND BLOOD-PRESSURE 161
to a stimulating influence on the vasomotor centre resulting from a defective
blood-supply to that centre. The remarkable variability of the pressure from
day to day or hour to hour in some high-pressure cases has to be kept in mind
in relation to such a view.
It is obviously possible that with regard to other vital organs, as in the case
of the brain, there may be vascular adjustments of a compensatory character
involving a rise of aortic pressure.
In the case of the kidney a rise of general blood-pressure might have
a compensatory value in aiding the excretion of concentrated urine, salts,
abnormal substances, or excess of acid or other waste products ; or, again,
when the materials to be excreted are not abnormal or excessive in amount, but
the functioning of the organ is defective from structural change or other causes.
The improvement might be associated with increase in the flow of water or
determined in other ways.
Bier (2) first suggested that hypertension with the arteriosclerotic or athero-
sclerotic kidney is best regarded as a compensatory efibrt of the organism, to be
interfered with only when danger threatens either of cardiac failure or of cerebral
haemorrhage. According to this view, by diminishing hypertension, a danger
more or less imminent would be replaced by the certain danger derived from an
upset of the kidney efficiency, maintained only at an efficient level by the raised
blood -pressure.
Relations of Blood-pressures and Renal Efficiency,
The existing data bearing on the frequent coexistence of high blood-pressures
and defective kidney efficiency do not afford grounds for determining the relations
between the former and the latter. Examination of the relations between the
heights of the blood-pressures and the existence and degree of ascertained defects
in urinary excretion (urea, &c.) as studied in different individuals is obviously
inadequate, since the degree of kidney damage which may be present in the
different subjects constitutes a factor of unknown value. This factor may
obviously determine various relations between the levels of blood-pressures
present and the degrees of defect in urinary excretion. If it is assumed for the
moment that high blood-pressure (as many believe) can favour kidney efficiency,
the fact remains that there might be very different degrees of defective excretion
in presence of equally high blood-pressures, and, on the other hand, that excretion
might be relatively good in association with comparatively low blood-pressures —
the existence of varying (unknown) amounts of kidney damage constituting the
deciding factor in the different subjects examined.
To test the relationship of high blood-pressures and renal efficiency it
is clearly necessary to make observations on the same individual in whom, with
given kidney conditions, lowering of the blood-pressure is purposely induced in
order to ascertain what alteration, if any, in renal efficiency occurs in associa-
tion with the alteration in the blood-pressure, the response of the kidneys
F f 2
162 QUARTERLY JOURNAL OF MEDICINE
to a definite test (urea concentration) being ascertained, while the blood urea and
the non-protein nitrogen are also examined.
As regards the known relation of blood-pressure to the excretion of water,
Herringham (5) states that, broadly speaking, blood-pressure and amount of urine
vary together, though not from day to day in individual cases ; in disease the
quantity of urinary water does not vary so directly with blood-pressure as might
be expected. The urine may diminish while the pressure is steady, or the urine
may remain steady while the pressure falls. Such variations are not accounted
for by fresh access of local inflammation in the kidney, &c. ; they are ascribed to
local vascular changes.
Deviations from the general relationship between height of general blood«
pressure and volume of urine are readily intelligible in view of what is known of
the occurrence of special alterations in the calibre of the renal vessels from
nervous or chemical influences, apart from or in addition to variations in aortic
pressure, as well as the effects of changes in the composition of the blood
(hydraemia, presence of diuretic constituents, &c.), such being capable of aflfecting
the water excretion without parallel change in aortic pressure. But in view of
the general relationship between blood-pressure and urinary volume it is, of
course, to be expected that the administration of nitrites should have decided
effects.
Mason (16) has recently found that sodium nitrite alters the urinary volume
suflEiciently and frequently enough to warrant its withdrawal during a water test
for renal efficiency ; the effects on blood and urinary nitrogen were not described.
There is no evidence of nitrites influencing kidney function otherwise than
through the vascular changes induced. It is evident that dilatation of the renal
vessels and the usual fall of general blood-pressure under nitrites act in different
directions on the flow of urine, the former tending to give increased transudation
or filtration, and the latter to diminish the excretion of water. Upon the relative
predominance of one or other of these two influences the urinary result will
naturally depend.
The Method employed in the Study of the Renal Effi/iiemy of Cases ivith High
Blood-iyressure and of the same Gases umder the Influence of Vasodilators.
On the first day of examination, breakfast was taken about 5 a.m. No food
or drink was allowed after this until after completion of the urea concentration
test on that day.
About 9.30 a.m. to 10 a.m. at least 6 c.c. of blood were removed by puncture
of one of the veins over the anterior aspect of the elbow, and received into
a sterile test-tube containing a small quantity of powdered neutral potassium
oxalate. The blood was used for the estimation of the urea and non-protein
nitrogen.
Immediately after the vein puncture, the bladder was emptied, and 15 gim.
of urea in 100 c.c. of water administered.
Specimens of urine were obtained, with the exception of one or two cases, at
RENAL EFFICIENCY AND BLOOD-PRESSURE 163
one hour, two hours, three hours after the administration of the 15 grm. urea. The
quantity, urea concentration, specific gravity, presence of albumin, examination
of the centrifugalized deposit, were noted. The patient was then allowed to resume
his normal diet, and in the course of the afternoon, between 2 p.m. and 3 p.m.,
the exhibition of liquor trinitrini Cl)ij three-hourly for the succeeding twenty-four
hours was commenced.
In one series of cases referred to in Table VI, erythrol tetranitrate was used
as a vasodilator ; the general effects are seen to be similar. On the second day
of examination, i. e. about eighteen hours after the administration of the first dose
of trinitrinum, the same examinations of the blood and urine were carried out at
approximately the same time and with the same routine.
After the completion of the second urea test no further trinitrinum was given.
On the third day, the blood and urine were examined again as before.
Blood-pressure readings, both systolic and diastolic, pulse-rates, and respira-
tion-rates were observed each day during the forenoon in practically every case.
Full clinical notes were also made. No difficulty was experienced in getting
blood from the same vein on successive days, so that the other arm was always
used for blood-pressure readings.
In Case 1 no liquor trinitrini was employed, as a venesection was decided
on by the medical officer in charge of the case. No untoward effects due
to the liquor trinitrini were observed except in one or two cases. One case
(No. 2) complained of flushes and palpitation, while another case (No. 7) did
not show a lowered blood-pressure until the liquor trinitrini had been
administered in two-minim doses three-hourly for forty-eight hours, and three-
minim doses four-hourly for the succeeding twenty-four hours. This caused
the patient to vomit and to suffer from headache, palpitation, &c., while his
blood-pressure fell considerably on the third day of the administration of the
liquor trinitrini.
One or two cases showed a slight increase in the urea and non-protein
nitrogen of the blood while under the influence of the vasodilator. In order to
make certain that this increase in the blood urea was not due to diminished
power of the kidney, while the blood-pressure was lowered, to excrete the
increased amount in the blood due to the giving of the initial dose of urea
on the preceding day, the above routine was slightly altered as follows in a series
of cases :
1st day : Routine examination of blood, urine, &c.
2nd day : Administration of the trinitrinum begun.
3rd day : Routine examination of blood, urine, &c. Trinitrinum stopped
after completion of the urea concentration test.
4th day : Nil.
5th day : Routine examination of blood, urine, &c.
In all cases patients were kept in bed throughout the three- or five-day periods
of examination to obviate as far as possible the influence of variations in external
temperature, &c., on diuresis.
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168 QUARTERLY JOURNAL OF MEDICINE
Methods : (1) Urea. The urease method of Van Slyke as modified by
MacLean (10) was employed.
(2) Non-protein nitrogen. For this estimation the adaptation of Folin's
method described by MacLean (11) was used.
(3) Percentage of urea in the urine. The hypobromite method was used, the
volume of nitrogen evolved being measured within one minute after shaking, and
the equivalent percentage of urea read off from tables compiled by means of
estimations carried out on various specimens of urine by the urease method.
(4) Systolic and diastolic blood-pressure. The auscultatory method was
used throughout. The patient was kept in the semi-recumbent position, and the
same upper arm was employed for the compression armlet in all observations, an
Oliver auditory tambour being used. The systolic blood-pressure index was
always checked by simultaneous- employment of the tactile method, recommended
as a routine method a number of years ago by Mac William and Melvin (12). The
diastolic pressure was taken as usual as the beginning of the fourth phase. In
no cases were first readings relied on ; the readings were repeated in each case
several times during the course of half an hour till a constant level was obtained
as shown by both auditory and tactile indices. During this time, variations in
the pulse and respiration were noted. Each reading was made quickly, so as to
avoid prolonged compression by the armlet, undue congestion of the arm, &c. The
pressure was estimated twice in each three-hourly period, once before the middle
of each period and another in its latter part. Such a distribution of the estima-
tions tends to reduce possible disturbance of values due to any variations of
pressure that may occur within the period, and give a nearer approach to the
average level of pressure. Substantial lowering of pressure shows a general
parallelism with the reduction in the volume of urine excreted during the
same period.
The chief results obtained are stated in Table I on pp. 416-19, dealing with
pathological cases of high blood-pressure, some with and others without kidney
lesions, cardiovascular changes of various kinds being usually present as noted in
the table. The patients were mostly in middle or advanced life — sixteen males
and five females. Their general condition varied much.
The dietetic conditions were similar in almost all cases — the usual infirmary
full diet. The urea test was completed and blood samples taken in the morning,
no food or drink having been taken for at least five to six hours previously.
Preliminary Conclusions from the Results obtained in the Pathological Cases in
Table I under the Influence of the Vasodilator Drug.
1. Effects on the blood urea and non-'protein nitrogen. The blood urea
figure and the non-protein nitrogen figure expressed in milligrams per 100 c.c.
blood were not affected to any extent except in Cases 4, 7, and 8, in which a decided
rise occurred. The reasons for the rise in Cases 4 and 8 are quite definite. In
RENAL EFFICIENCY AND BLOOD-PRESSURE 169
Case 4 the observation was vitiated by the urea being given some minutes before
the blood sample was taken, while Case 8 was a terminal one dying from aortic
heart disease. In Case 7 the vasodilator drug was pushed to the point of intoler-
ance (vomiting, &c., being induced) as the blood-pressure was affected with
difficulty. This case received liquor trinitrini CWij three-hourly for two days,
followed by CCf'ii] three-hourly for one day. It may be noted that in Case 8, during
the period of comparatively slight lowering of systolic pressure under the influence
of trinitrinum, the general condition was obviously improved, the patient much
more comfortable, the pulse slower, and the Cheyne-Stokes' respiration abolished
— to recur on the day following the discontinuance of the vasodilator drug when
the pressure had again risen.
2. Effect on the power of the kidney to concentrate urea. All the cases, with
one exception, showed no impairment of the power to concenti*ate urea. This
Case — 14 — showed a 66 per cent, rise in the first hour in the total amount of
urine excreted. With regard to the other cases, the power of the kidney to
concentrate urea was increased commonly 25 per cent, up to 75 per cent, above
the original value.
3. Effect on the total quantity of the urine excreted during the three hours
following the administration of 15 grm. urea. The majority of the cases showed
a decrease in the total amount of urine excreted in the three hours. The percen-
tage decrease amounted in many cases to 20-40 per cent., with one case showing
a reduction of over 50 per cent. Notable exceptions to the decrease were Cases 7,
11, and 12 — the last two being recent cases of acute nephritis. Cases 11 (acute
nephritis of five days' duration) and 7 showed a 40 per cent, increase in the
amount of urine. The increased amount was observed principally during the
first hour (Cases 11, 12, 14), and during the first and second hours (Case 7).
4. Effect on the total urea excreted during the three hours' urea test. The
majority of the cases showed little or no substantial change. No case showed
any marked cutting down of the total amount. On the other hand, Cases 7, 11,
12, 18 showed percentage increases of from 35 to 80. The increase in each case
was associated with an increase in the total amount of urin6. Two cases
(4, 20) showed an increased excretion of urea with a decrease in the total amount
of urine.
5. The relation of the increase in the urea concentration to the fall in blood-
pressure is brought out in the following table :
170 QUARTERLY JOURNAL OF MEDICINE
Table II.
Percentage Increase
in Urea Concentra-
-se No.
Fall in Systolic
Fall in Diastolic
Fall in Pulse-
Pressure.
Pressure.
pressure.
tion.
(ram. of mercury.)
1
60
20-30
40
65
2
32
20
12
27
3
86
12
24
28
4
14
6
8
75
5
24
15
9
35
6
20
10-15
5-10
15
7
50-70
15-20
35-50
38-83
8
12
+ 10
2
-6
9
34
8
26
23
10
70
15
55
153
11
30
15-20
10-15
7
12
20
5-10
10-15
33
13
40
15-25
15-25
29
15
80
5-10
20-25
0
16
25
0
25
4
20
30-40
5
25-35
27
21
40-50
5-10
35-40
48
Cases with a lai-ge systolic fall (Cases 1, 7, 10, 21, especially) showed
the biggest percentage increase in the urea concentration.
6. Relation of the height of the systolic blood-pressure to the blood urea content.
No definite relationship is observable between the amount of urea in the blood
and the height of the blood-pressure.
Table III.
Relation of Changes in Urine Volume to Pulse-pressure Changes.
Change in Vol. of Urine in c.c.
(3-hourly interval after 15 grm. urea.)
-230
-60
-98
-140
-160
+ 20
-140
-25
-5
-10
-355
+ 240
+ 45
-101
+ 10
+ 1
-23
+ 1
+ 36
-105
-147
Cases 7 and 18 showed apparently some increase in the urea concentration,
total urea, and volume of urine, while the blood-pressure was not lowered.
The cases showing the greatest decrease in pulse-pressure tended to exhibit
the greatest decrease in the volume of the urine.
ase.
Change in Pulse-pressure.
(mm. of mercury.)
1
-40
2
-12
3
-10-24
4
-8
5
-9
6
-5-10
7
Oto +20
-35
8
-2
9
-20
10
-55
11
-10-15
12
-10-15
13
- 15-25
14
-15
15
-5-10
16
-15-25
17
-20
18
Oto 5
20
-25-35
21
-35-40
RENAL EFFICIENCY AND BLOOD-PRESSURE 171
Two factors enter into the determination of the increase in the total urea
excreted in cases showing an increase : (a) increased concentration of urea ;
(6) increased volume of urine. These factors may operate singly or in com-
bination. The increase in the total urea is due to :
(1) Increased concentration of urea in the urine.
Cases 4, 9, 12, 20.
(2) Increased volume.
C^se 11 (acute nephritis).
(3) Both factors.
Cases 6, 7, 18.
The slight decrease in the total urea in Cases 3, 5, 10, 21, is associated with
a great diminution in the volume of urine excreted.
Two healthy young adults were examined under the same routine observed
in the preceding pathological cases. The results are contained in Table IV on
pp. 424-5.
Case 22 showed, under the influence of the vasodilator, increased excretion of
urine (33 per cent.), increased total urea (22 per cent.), and slight decrease in the
urea concentration percentage of the urine. The increased excretion of urea
would thus be accounted for by the increased excretion of urine. On the other hand,
Case 23 showed a slight diminution in the amount of urine excreted, no substantial
change in the total amount of urea, and no diminution in the urea concentration
percentage. The variation in the effects on urinary volume in these two cases is
in accordance with Cushny's statement (3) that occasionally a slight increase in
the urinary volume may be observed, at other times a decrease. These eflfects are
evidently due to the changes in the calibre of the renal vessels. A small quantity
may widen them when they are too contracted to allow of the maximal secretion,
while on the other hand, if the normal calibre is the optimal, a nitrite may
lessen the secretion by lowering the general blood-pressure. When large quantities
lower the pressure greatly, they inevitably lead to a lessened secretion or anuria.
In order to exclude the possibility of a retention of blood urea in the early
stages of the administration of the vasodilator drug (leading to the increased
percentage of urea in the urine), the blood urea was examined about four hours
after the drug had been given in the two normal subjects and in the following
group of pathological cases dealt with in Table VI.
Cases 22 and 28.
30.10.24. Liq. tnnitrini CX)ij 3-ltourly for 24 hours.
Case 22.
Blood Urea.
31.10.24 25
1.11.24 22
3.11.24 24 32 10 a.m. 15 grm. Urea after 10 a.m.
Liq. tnnitrini Q)ij at 3 p.m. and 6 p.m.
29 41 7 p.m.
Case 23.
Blood Urea.
Time.
31
34
32
10 a.m.
10 a.m.
10 a.m.
172
QUARTERLY JOURNAL OF MEDICINE
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RENAL EFFICIENCY AND BLOOD-PRESSURE 173
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174
QUARTERLY JOURNAL OF MEDICINE
As a urea concentration test had been carried out nine hours previously, the
small increases in the blood urea at 7 p.m. on 3.11.24 might have been due to the
excess of urea in the blood not having been completely excreted. Accordingly
the blood urea was estimated on days on which no- urea concentration test was
carried out and on which the vasodilator drug was administered :
Blood Urea in Tng.
Case 22.
11a.m. 7.30 p.m. Case 23.
11 a.m.
7.30 p.m.
5.11.24
26 25
25
30
6.11.24
Liq, trinitrini CX)ij at 8 a.m. 3-hoiitiy for 12 hours.
27 25
30
33
7.11.24
24 21-5
27
31
It would appear therefore possible to exclude as a cause of the increased
percentage of urea in the urine the possibility of a retention of blood urea in the
early stages of the administration of the vasodilator drug in healthy subjects.
The excess of urea in the blood resulting from a dose of 15 grm. urea does
not appear to be excreted completely in nine hours in the case of the healthy
subjects considered above, although the residual amount is small.
The above observations with regard to the blood urea content in the early
stages of the vasodilator administration were repeated on six subjects with raised
blood-pressure. There was no evidence of an early retention of blood urea, which
might conceivably have been a factor in the increased percentage of urea in the urine.
The total amount of urea excreted daily was examined in two healthy
cases and in two high blood-pressure cases before and during the administration
of vasodilator drug, no urea being given.
Table V.
Noi-mal Day. Day with Vasodilator Drug.
Total
Urinary
Urea in
grm.
(1) •
Amount
Urine in
C.C.
(2)
Blood
Urea in
mg.
(3)
Total
Urinary
Urea in
grm.
(1)
Amount
Urine in
c.c.
(2)
Blood
Urea in
mg.
(3)
Case 22
121
906
26-25
18-0
1173
27-25
(healthy)
Case 23
128
(12 hours)
453
25-30
12-6
400
30-33
(healthy)
Case 24
23-6
(12 hours)
1770
83
26-5
2169
85
(high pressure)
Case 25
8-7
379
38
20-4
680
33
(high pressure)
Day after.
Four Days after.
Total
Urinary
Urea in
grm.
(1)
Amount
Urine in
c.c.
(2)
Blood
Urea in
mg.
, (3)
" Total
Urinary
Urea in
Amount
Urine in
c.c.
(2)
Blood
Urea in
mg.
(3)
Case 22
15-2
1246
24-22
147
837
—
(healthy)
Case 23
139
700
27-31
13-7
720
(healthy)
Case 24
27-8
2745
82
(high pressure)
Case 25
19-2
727
33
(high pressure)
RENAL EFFICIENCY AND BLOOD-PRESSURE
175
The amount of urea in the blood was not substantially changed, and the
amount excreted in the urine was not diminished in any of the above cases.
The following table, in addition to giving the blood-urea, urinary volume,
urea concentration test result, range of the urea percentage, and total urea of the
individual specimens of urine in Cases 24 and 25, gives the results observed in
four additional high blood -pressure cases where the vasodilator erythrol tetra-
nitrate was given for longer periods up to seven days without any administration
of urea. The object of this is to show the effects of the vasodilator apart from any
disturbance caused by the artificial introduction of urea into the circulation
in the application of the urea test.
Table VI.
Blood-
pressures.
Amount
Urine
in c.c.
(24 Hours).
Total
Urea in
grm.
% Urea in
Individual
Specimens.
Blood
Urea in
mg.
Urea Con-
centration
Test %.
Case 24.
M.46
240-160
1770
23-6
1-06-1-63
83
1-25
220-150
2169
26-5
1-03-1-52
85
2475
27-8
0-92-1-42
82
Case 25.
F.46
220-110
379
8-7
1-3-2-8
38
2-7
210-105
680
20-4
2-9-3-2
33
727
19-2
2-51-2-7
33
Case 26.
M.63
180-60
760
(25 hours)
1234
1025
24-7
(25 hours)
32.5
29-7
2-9-3-3
2-1-3-4
2-7-3-1
83
30
1097
26-6
1-4^3-05
44
Case 27.
F.47
148-88
773
806
811
6-5
8-3
7-0
0-81-0-93
1-01-1-06
0-77-0-96
50
0-75
1200
7-8
0-6-0-85
50
Case 28.
M.50
203-130
1672
1192
1380
1625
2257
980
15-3
17-5
21-1
19-2
20-1
15-4
0-8-1-24
0.76-2-31
0-56-2-25
0-4-1-81
0-65-1-65
1-03-1-84
43
170-118
1180
181
0-94-206
43
Case 29.
F.47
205-105
300
(10 hours)
545
530
313
745
843
7-5
(10 hours)
16-2
13-0
6-5
10-4
13-4
2-5
2-56-3-11
2-0-2-7
1-9-2-15*
1-4-1-2
1-4-1-7
59
3-8-5
889
15-6
1-4-1-8
52
Remarks. — Case 24.
Case 25.
Case 26.
Case 27.
Case 28.
Case 29.
* E. N. stopped on account of headache.
Liq. trin. OCji] 3-hourly ; showed early intolerance to erythrol tetranitrate.
Liq. trin. Ct)ij 3-hourly.
Erythrol tetranitrate gr. i 4-hourly.
Erythrol tetranitrate gr. i 4-hourly.
Erythrol tetranitrate gr. i t.d.s.
Erythrol tetranitrate gr. i 4-hourly.
Cases 24 and 29 showed an early intolerance to the vasodilator drug, and
the latter in addition showed a very marked reduction in the amount of urine
and urea excreted.
[Q.J.M., July, igae.l G g
176 • QUARTERLY JOURNAL OF MEDICINE
With regard to the general effects of lowering blood-presaure, it was excep-
tional to get any evidence of disturbance in the condition of the patient, except
in the cases where the vasodilator drug was used in the larger doses over a longer
period. Occasionally slight palpitation and headache were complained of in
one or two cases. There was no complaint of giddiness or faintness, and no
noticeable change in the colour of the face was observed. The chief complaints
in the cases exhibiting intolerance to the drug were of pain and throbbing in the
head. Pulse and respiration generally were but little affected (as shown by the
recorded figures in Table I), being, as a rule, increased very slightly in frequency.
Oedema, which was present in two or three cases, was not increased by the use of
the vasodilator drug. One case (acute nephritis), which showed a slight amount
of oedema, exhibited a marked increase in the amount of urine and urea
excreted, and a fall in the blood urea and blood-pressure during the time that the
drug was being used ; there was disappearance of the oedema. Another case of
acute nephritis with a very large amount of oedema was not affected adversely.
The amount of urine increased to some extent, although the drug was employed
for a period extending over a week. This is suggestive with regard to the
question of salt retention, since the latter is readily indicated by evidences
of oedema.
Although the effects of a single dose of liquor trinitrini on the systemic*
blood-pressure are diminished in a hour or so and pass off according to different
observers in periods varying up to two and a half hours, the decrease in the
amount of urine secreted throughout the three hours after the administration of
15 grm. urea in cases which had been previously under the iufluence of repeated
doses of nitrite, compared with the amount obtained on days on which the test
was carried out without the administration of nitrite, suggests that the effects of
repeated doses of nitrites on the kidney outlast those of a single dose on
the systemic blood-pressure. Erythrol tetranitrate, used in a number of cases,
has a more prolonged action. As a result of the above-mentioned decrease in the
amount of urine leading to an artificial increase in the specific gravity and urea
percentage of the urine, vasodilator drugs should not be given during the applica-
tion of MacLean's test, although cases giving urea percentages much under 2
are unlikely to show specimens of urine above this percentage even during
the administration of the vasodilator drug. In connexion with this an interesting
point comes up. For example, in the application of MacLean's test to Cases 1, 7,
10, 17, 21, under normal conditions, the second hourly specimen of urine gives
urea percentages of 17, 1*2, 1-5, 0-9, 2-1, respectively. During the period of
lowered pressure the corresponding figures obtained were 2-8, 2-2, 3-8, 1*4, 3«1.
The question arises naturally whether the efficiency of the kidney is indicated by
the higher figures, or whether kidneys which under normal conditions give a low
urea percentage with MacLean's test can be differentiated further as regards their
response to the test under lowered pressure.
The percentage of urea obtained from the highest of the thi-ee-hourly
specimens of urine after the application of MacLean's test to an individual is
RENAL EFFICIENCY AND BLOOD-PRESSURE 177
not necessarily the maximum for the kidneys of that individual, since some of the
individual specimens of urine obtained (apart from administration of urea)
throughout the twenty-four hours contain in many cases as high percentages of
urea as those obtained in the test specimens, sometimes even higher, as shown in
Table VI, Cases 24, 26, 27. It would appear, therefore, that useful guidance
to the power of the kidney to concentrate urea can sometimes be obtained
by ascertaining the percentages of urea in individual specimens of urine passed at
different periods throughout the twenty-four hours.
Conclusions.
1. In the healthy subjects the diuresis which usually follows the administra-
tion of 15 grm. urea may or may not be cut down by drugs of the nitrite series
in the doses stated, and the power of the kidney under the above conditions to
concentrate urea is not impaired. The blood urea and non-protein nitrogen are
not increased.
2. In high-pressure cases the diuresis which usually follows the administra-
tion of 15 grm. urea is usually cut down by drugs of the nitrite series in the doses
stated.
3. The total excretion of urea following the administration of 15 grm. urea
is usually not diminished by the administration of nitrites in doses sufficient
to cause a considerable lowering of the high blood-pressures present (falls of
20-60 mm.).
4. The power of the kidney to concentrate urea after the exhibition of
15 grm. urea is not impaired, inasmuch as urine of higher urea concentration
is still excreted during the period of lowered pressure, e. g. 2-8, 3'0, 3-5, as
compared with 1'7, 2*2, 2-0 respectively, when the test is applied before the
lowering of the pressure. It remains to be seen whether (apart from the evidence
afforded by the unimpaired total urea excretion) high urea concentration values,
e.g. 3-5, 3-8, during the period of lowered pressure are significant with regard to
reduction of pressure being warrantable, so far as the kidney is concerned.
5. If vasodilator drugs are given in pharmacopoeial doses as distinguished
from the larger doses referred to above, the functions of the kidney as regards the
excretion of water, the excretion of urea, and the power to concentrate urea
are not diminished.
6. The urea and non-protein nitrogen content of the blood is not increased
by the administration of vasodilator drugs over periods ranging from twenty-four
hours to more than one week. The increased urea concentration in the urine is
evidently not dependent on an increased percentage in the blood.
7. If the larger doses are maintained over a longer period, symptoms of
intolerance to the drug supervene long before the stage of suppression of urine.
Symptoms of intolerance may arise in different cases where the power of the
kidney to concentrate urea is either (1) above 2 per cent., or (2) well below
2 per cent.
a g 2
178 QUARTERLY JOURNAL OF MEDICINE
8. The excretion of urea was not interfered with by a large fall of blood-
pressure in a high-pressure case by venesection.
9. The virtual maintenance of the total excretion of urea during the period
of lowered blood-pressure in cases of hyperpiesia indicates that the mechanism of
hyperpiesis is not to be regarded as compensatory, at least so far as the excretion
of urea and non-protein nitrogen is concerned — a conclusion in accord with the
results of some clinical observations as regards phenolsulphonephthalein excretion
reported by Gruber (4), and guanidine excretion by Major (7).
10. No definite relationship is observable between the amount of urea in the
blood and the height of the blood-pressure.
11. Nitrites should not be administered either prior to or during the
application of MacLean's test.
12. Apart from the application of the urea concentration test, useful evidence
as to the urea-concentrating power of the kidney may often be obtained from the
examination of individual specimens of urine over the twenty-four hours, since in
some of such specimens there may be a percentage of urea as high as, or even higher
than is shown by MacLean's test.
I am indebted to Professor J. A. MacWilliam for much kindly help and
criticism, and to Dr. W. Brander, Medical Superintendent, Hackney Infirmary,
Loudon, for facilities for examining cases and for carrying out part of the necessary
laboratory work.
My thanks are also due to the Medical Research Council for a grant in aid of
the expenses of the above investigation.
REFERENCES.
1. Anrep, G. V., and Starling, E. H., Proc. Roy.Soc, Lond., 1925, B., xcvii. 463.
2. Bier, A., Miinch. med. Woch., 1900, xlvii. 527.
3. Cushny, A. R., Pharmacology and Therapeutics, 8th edit., Lond., 1924, 403.
4. Gruber, C. M., &c., Arch. Int. Med., Chicago, 1925, xxxvi. 366.
5. Herringham, W. P., Kidney Diseases, Lond., 1912, 219.
6. Hill, L., Schafet^s Textbook of Physiol., Lond., 1900, ii. 136.
7. James, A. A., Laughton, N. B., and Macallum, A. B., Science, N. York, Ixii. 1 81.
8. Macdonald, W. J., Ptvc. Soc.Exper. Biol, and Med., N. York, 1925, xxii. 483.
9. MacLean, H., Renal Diseases, Lond., 1921, 53.
10. MacLean, H., ibid., Lond., 1921, 44.
11. MacLean, H., ibid., Lond., 1921, 48.
12. MacWilliam, J. A., and Melvin, G. 3., Heart, Lond., 1913-14, v. 153 ; Brit. Med.Joum.,
Lond., 1914, 1. 693.
13. Major, R. H. Joum. Amer. Med. Assoc, Chicago, 1925, Ixxxv. 251.
14. Major, R. H., Bull. Johns Hopkins Hasp., Baltimore, 1925, xxxvi. 357-60.
15. Major, R. H., and Stephenson, W., ibid., Baltimore, 1924, xxxv. 140 and 186.
16. Mason, E. C, Joum. Lab. and Clin. Med., St. Louis, 1923-4, ix. 529.
17. Starling, E. H., Brit. Med. Joum., Lond,, 1925, ii. 196.
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