(Received 25 July 1938)

Transcription

1 244 J. Physiol. (I939) 95, I82 THE EFFECT OF PERIPHERAL VASOMOTOR ACTIVITY ON SYSTOLIC ARTERIAL PRESSURE IN THE EXTREMITIES OF MAN BY J. DOUPE (Winnipeg), H. W. NEWMAN (San Francisco) AND R. W. WILKINS (Baltimore) From the Research Unit, National Hospital, Queen Square, London (Received 25 July 1938) THE purpose of this communication is to demonstrate that systolic arterial pressure in the extremities may show considerable variations as the result of local vasomotor changes, and that such variations in peripheral pressure are independent of and at times opposite to alterations in systemic pressure as measured in more central arteries. It will be shown that alterations in the blood flow in the extremities are responsible for these phenomena. METHODS The blood pressure has been determined by several methods. Intermittent measurements of arterial pressure were taken in the upper arm and occasionally in the forearm by the ordinary auscultatory method, using a mercury manometer. Intermittent measurements of systolic arterial pressure in the fingers were made by Gaertner's method. This consists of slowly lowering the pressure in a cuff placed around a digit previously rendered bloodless by an elastic band. The pressure in the cuff when the first flush of the returning blood is seen is reckoned as the systolic pressure at the site of the cuff. In several experiments more exact intermittent measurements of systolic arterial pressure were obtained and recorded by a plethysmographic method as follows: A plethysmograph was fitted to a digit and a blood-pressure cuff applied above at the point where it was desired to estimate systolic pressure. Air at greater than systolic pressure was suddenly introduced from a pressure tank into the cuff, occluding the circulation and stopping all pulsations below it. The pressure in mm. Hg within the cuff and the digital volumetric changes were continuously recorded on moving bromide paper by means of an optical system. Pressure was allowed to

2 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 245 leak gradually from the cuff until an increase in volume of the digit commenced. The pressure within the cuff at this instant was taken as the systolic arterial pressure at the point of application of the cuff (Fig. 9). This method will be referred to as the "plethysmographic method". Continuous measurements of systolic arterial pressure were made by the method of Doupe, Newman & Wilkins [1939], which allowed the detection of rapid changes. Measurements of arterial pressure by whatever method were always made with the part at heart level. Temperature of the fingers was taken by means of constantancopper thermojunctions placed on the finger tips. Records of the changes in finger volume were obtained and optically recorded by the method of Bolton, Carmichael & Stiirup [1936]. Blood flow in the finger was measured by a modification of the method of Hewlett & Van Zwaluwenburg [1909]. Blood flow in the forearm or calf muscles was taken by a similar method, while the circulation in the hand or foot was excluded by a cuff at the wrist or ankle inflated to 200 mm. Hg. The subjects on whom this study was made included nine normal young males and one patient with a cervical stellate ganglionectomy performed for other than vascular disease. The subjects sat or lay lightly covered in a draught-free room which was maintained at a constant temperature (+ 10 C.). Reflex dilatation of the blood vessels in the hands and feet was produced by immersing indifferent limbs in water at 450 C. Constriction of the peripheral blood vessels was produced by leaving the subject uncovered, or by immersing the indifferent arm or leg in water at C. When a subject was warm and the digital vessels dilated, brief reflex digital vasoconstrictions were induced by the application of ice or pin-pricks to an indifferent area, the solving of a mental problem or the taking of a deep breath. It had previously been shown that these stimuli were effective and that the vasoconstriction was the result of impulses in the sympathetic nerves [Sturup, Bolton, Williams & Carmichael, 1935]. Dilatation of the blood vessels in the muscles was induced by exercise of the muscles under observation. The forearm muscles were exercised by repeatedly squeezing a sphygmomanometer bulb, those of the whole arm by flexing and extending the arm while holding a heavy sand-bag, and those of the legs by a bicycling exercise while lying supine. RESULTS Effect of vasodilatation on digital systolic pressure. The following experiments were carried out to determine first the pressures in the brachial and digital arteries during the state of vasoconstriction and

3 246 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS then after vasodilatation of the peripheral vessels had been obtained by immersion of the indifferent limbs in water at 450 C. This procedure of immersion is known to result in widespread peripheral vasodilatation. This was done on seven occasions in three individuals, using the three different methods to obtain the systolic pressure. It was found that the systolic arterial pressure measured in the arm and in the finger was approximately the same at the start of each experiment, at which time the peripheral vessels were constricted. Following the vasodilatation the digital systolic pressure was found to fall by mm. Hg, while brachial arterial pressure remained fairly constant. The results are shown in Table I. TABLE I. Systolic arterial pressure in mm. Hg Subject cold Subject warmed Exp. no. Upper arm Digital Difference Upper arm Digital Difference To determine the time relationship of these changes in digital arterial pressure to the peripheral vasodilatation the following experiment was carried out. With the subject in a cold state and the peripheral vessels constricted measurements of systolic arterial pressure in one upper arm and in a finger of the opposite hand were taken. The skin temperature of an adjacent finger was recorded and from a third alterations in blood flow observed. At the beginning of the experiment the fingers were cold and the blood flow was at a minimum, and at this time systolic arterial pressures in the finger and in the upper arm were essentially the same. The legs were then immersed in tanks of water at 450 C., which 12 min. later caused vasodilatation of the digital vessels. This was shown by a marked increase in finger temperature and blood flow. With the dilatation, digital systolic pressure fell progressively below the brachial, and when the maximum dilatation had been reached was some 20 mm. Hg below the brachial. The legs were then transferred to tanks of cold water, which caused body cooling. Digital vasoconstriction followed immediately, as shown by the fall in finger temperature and finger blood flow. Further, with the peripheral vasoconstriction the digital pressure became nearer to the brachial. These pressures were estimated by the plethysmographic method. Fig. 1 illustrates graphically the sequence of events.

4 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 247 bo 0 O 0 rc CB Go be 0 C; : ' 6( Minutes Fig. 1. Graphic record of systolic pressures in right upper arm (solid line) and in right middle finger (interrupted line), of temperature of right ring finger, and of blood flow in right forefinger (calculated in c.c./min./10 c.c. of finger volume). At zero time, subject's legs were placed in water at 450 C. Arrow indicates when legs were taken out of hot water and subject was uncovered.

5 248 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS Effect of transient vasoconstriction on systolic pressure in the digits and upper arm. In the experiment recorded in Fig. 1 it has been shown that when the peripheral vessels, already in a dilated state, are constricted over a prolonged period by immersion of the legs in cold water, the digital systolic pressure rises to that in the upper arm vessels. It therefore seemed advisable to determine the effect of a transient vasoconstriction of vessels in a dilated state upon the systolic pressure in the digit and upper arm. Accordingly the peripheral vessels were dilated by the immersion of the indifferent limb in tanks of water at 450 C., and during this period a variety of stimuli known to produce transient vasoconstriction of the digital vessels, such as the application of ice or Sec. & signal ' t,,a It-a S1e atie, Pulse R.F.4 Resp R.F.2 t B.P. R.F.4 Base-line -- MM Hg Fig. 2. Record of systolic pressure in right ring finger (B.P.R.F. 4) and of volume of right forefinger (R.F. 2). Arrows indicate direction of increase of volume: in respiratory record downward stroke is inspiratory phase: appended scale gives calibration in mm. Hg of arterial pressure tracing: these are the same for all records. Subject warmed and peripheral vessels dilated. Ice to right thigh at signal. pin-prick to the skin of the trunk, were given. The effects of such stimuli during the early constricted state and during the dilated state were also compared. When cold there was already marked digital vasoconstriction, as shown by minimal pulsations in the plethysmographic tracing from a finger. As a result of the stimulus no further vasoconstriction occurred, and there was hardly any change in systolic pressure in the finger or arm. The subject was then warmed and the digital vessels became dilated, as shown by the marked increase in the size of pulsations. During the warming and digital vasodilatation the systolic pressure in the finger fell some 20 mm. Hg. When the vasoconstricting stimulus was now given there was a marked decrease in the size of pulsation and volume of the finger, and simultaneously a rise in digital systolic pressure. As the transient constriction following the stimulus passed off the digital arterial pressure fell to its previous level (Fig. 2). Fig. 3 is a record of the -90

6 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 249 effects of such a stimulus, showing in addition a simultaneous tracing of brachial systolic pressure measured in the opposite upper arm. Again, contemporaneously with the vasoconstriction, digital systolic pressure rose towards the brachial pressure, which remained essentially unchanged. In seventy instances on five subjects it was never possible to produce a good digital vasoconstriction by these stimuli without a rise in digital systolic pressure. It thus appears that a transient constriction of the digital vessels produced by a sensory stimulus may result in a rise in digital systolic pressure without a corresponding rise in the brachial pressure. Sec. & et signal * MI$ II$ a I I 9 I I... Pulse L.F Resp. & R.F.2t 120 B.P. Lt. arm Hg B.P. R.F.4 80 Pulse R.F.4, 60 Base-line Fig 3. Record of systolic pressures in right ring finger (B.P.R.F. 4) and left upper arm (B.P.L. arm), and of volume of right forefinger (R.F. 2). Subject warmed and peri. pheral vessels dilated. Pulse tracing in left middle finger (pulse L.F. 3) shows pulse waves which actuated mechanism for recording arterial pressure in left upper arm. Ice to thigh at signal. In occasional instances with the subject warm and the peripheral vessels in a dilated state a stimulus such as ice or pin-prick may cause not only a rise in digital systolic pressure but also a rise in brachial systolic pressure. The rise in the brachial arterial pressure, however, was never of the same magnitude as found in the digital pressure. Further, it was observed by adjustment of the severity of the stimulus that marked digital vasoconstrictions could easily be produced without a rise of brachial systolic pressure. The relationship of the rise in digital arterial pressure to the decrease in digital blood flow following a stimulus is shown in Fig. 4. In this experiment the actual blood flow was determined simultaneously with digital systolic and brachial systolic pressures. The steepness with which the blood-flow curves rise from the horizontal is a measure of the rate of flow to the finger. After the stimulus, which produced transient

7 250 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS vasoconstriction, there was a marked decrease in flow, and simultaneously a rise in the digital arterial pressure toward the brachial pressure. From these observations it is apparent that the transient vasoconstriction with which is associated a rise in digital systolic pressure is accompanied by a marked diminution in blood flow to the finger. Sec. & signal Resp. Pulse R.F B.P. Rt. arm H g B.P. L.F. 3 Blood flow L.F.2 Pulse L.F.3 60 Signal-- Calculated flow c.c./min./10 c.c. finger Fig. 4. Record of systolic pressures in left middle finger (B.P.L.F. 3) and right upper arm (B.P.R. arm) and of blood flow determinations in left forefinger (blood flow L.F. 2). Subject warmed and peripheral vessels dilated. Lower signal indicates time during which venous outflow of blood from left forefinger was obstructed by cuff inflated at less than diastolic pressure. Rate of blood flow indicated by steepness of rise from horizontal. ]Figures below give blood flows calculated in c.c./min./10 c.c. finger volume. Ice to right thigh at upper signal. Effect of deep breath on digital and brachial systolic pressures. It has previously been shown [Bolton et al. 1936] that a reflex digital vasoconstriction occurs following a deep thoracic inspiration. The decrease in digital volume and in the size of pulsation follows about 3 sec. after the rapid inspiratory phase. It is not dependent upon the direct effects of the respiratory movements, but is a true autonomic reflex, for it fails to appear in the sympathectomized limb, while it appears in the normally innervated digits. It is also known that with a thoracic deep breath there may be a fall in brachial systolic pressure. It was therefore of interest to determine the direction of the changes in digital pressure following upon a deep breath. Experiments demonstrated that the effect of such a deep breath on the digital systolic pressure was to produce a rise coincident with the vasoconstriction. In other experiments it was found that the effect of a deep breath on the brachial systolic pressure was to produce a fall coincident with the vasoconstriction in the digital vessels. Similarly it was possible to show that a rise in digital pressure with digital vasoconstriction occurred in the toes after a deep breath, and that simul-

8 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 251 taneously a fall in arterial pressure measured in the calf may occur. That the rise in digital pressure after the stimulus depended upon simultaneous vasoconstriction was shown in a case with a right cervical sympathectomy which abolished all reflex vasoconstrictions in the right arm and hand. A deep breath, which was followed by a typical vasoconstriction in the digits of the other limbs, failed to raise the digital arterial pressure in the right hand, but was followed by a fall in pressure of the same degree as occurred in the brachial artery. Sec. & signall.h a-140. Resp. & R.F.2t mm. MM. B.P. Lt. arm Hg B.P. R.F.4 ^^ -80 Pulse R.F.4-60 Base-line Fig. 5. Record of systolic pressures in right ring finger (B.P.R.F. 4) and left upper arm (B.P.L. arm), and of volume of right forefinger (R.F. 2). Subject warmed and peripheral vessels dilated. Deep breath at signal. To determine the relationship of these apparently paradoxical changes to each other, simultaneous records were taken of the changes in systolic pressure as recorded from the finger and upper arm (Fig. 5). With the digital vasoconstriction, digital systolic pressure already below the brachial rose to meet the level of the brachial pressure which was simultaneously falling. If the brachial arterial pressure was made to fall to an even lower level as after a deep held inspiration (Fig. 6), the digital pressure after first rising to meet the brachial also fell; but so long as the vasoconstriction was maintained, the digital systolic pressure approximated the brachial pressure. As the vasoconstriction resulting from the deep breath passed off, the brachial pressure resumed its higher level and the digital pressure its previous and relatively lower level. From these experiments it appeared therefore that the fall in brachial arterial pressure was independent of changes in the limb's peripheral vascular bed. This was further clearly shown in an experiment in which the circulation to three limbs was cut off entirely as near to the trunk as possible by means of cuffs blown up to a pressure of over 200 mm. Hg.

9 252 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS The fourth limb, an arm, was used to record the blood pressure from the upper arm. As the cuff on this arm was blown up to the region of systolic pressure and the circulation intermittently entirely cut off, it may be assumed that changes in the vascular bed distal to this cuff would be unlikely to affect the systolic pressure registered in the upper arm. With the subject so arranged the taking of a deep breath caused a fall in systolic pressure registered in the upper arm. This experiment indicates that the cause of the fall of brachial arterial pressure following a deep breath is independent of the peripheral vascular bed in the limbs. a Sec. & signal... Pulse L.F. 3- j 140 Resp. & R.F.2 t-120 B.P. Lt. arml H MM. B.P. R.F.4-80 Pulse R.F.4 6 Base-line Fig. 6. Record of systolic pressure in right ring finger (B.P.R.F. 4) and left upper arm (B.P.L. arm), and of volume of right forefinger (R.F. 2). Subject warmed and peripheral vessels dilated. Deep breath held throughout time of signal. Sec. & signal ,. _140 Pulse L.F. 3 Resp. & L.T. 1 t -120 B.P. Lt. arm Aoo B.P. R.F.4 HgV9 80 Pulse R.F.4.^ 60 Base-line Fig. 7. Record of systolic pressure in right ring finger (B.P.R.F. 4) and left upper arm (B.P.L. arm), and of volume of left great toe (L.T. 1). At signal circulation to other four fingers of right hand occluded by 200 mm. of air pressure applied to cuffs around the proximal phalanges. Effect of sudden occlusion of digital circulation on systolic pressure in the digits. In three individuals the following experiment was done to mimic the effects of peripheral vasoconstriction. Digital systolic pressure

10 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 253 was taken from one finger. The other four fingers of the same hand were encircled at their bases by Gaertner's cuffs, which could be instantly and simultaneously inflated to 200 mm. Hg. Fig. 7 shows the results of such an experiment. At the signal the four cuffs were inflated and the systolic pressure in the remaining finger immediately rose toward the pressure in the upper arm. That the inflation of the cuffs was not a stimulus to digital vasoconstriction was shown by the steady volume of the toes, which have been shown to be even more sensitive than the fingers to vasoconstrictor stimuli [Doupe, Robertson & Carmichael, 1937]. Effect of vasodilatation in muscle on systolic pressure in the limbs. Five experiments were carried out to determine if changes in blood flow in TABLE II. At rest Systolic arterial pressure in mm. Hg After exercise Proximal Distal Proximal Distal to muscles to muscles Difference to muscles to muscles Difference I Exp. no the limbs elsewhere than the digits could affect the peripheral blood pressures. Table II records the results of these experiments. Dilatation in a muscle group was produced by - exercise. During the control period 130 before exercise the systolic arterial pressures obtained distalto the muscles = were essentially equal to the pressures A in the same or another limb measured 110 Lt. arm proximally. After exercise, the arterial p: pressuresdistaltotheexercisedmuscles IOO! wrist became some mm. lower than the proximal pressures which rose or remained the same. Fig. 8 is a graphic 90 3o - record of such an experiment showing Minutes the effects of exercise of the arm Fig. 8. Graphic record of systolic pressure muscles on the systolic pressures at in left upper arm (solid line) and wrist (interrupted right line). At arrow right the wrist on the same side and at the forearm was vigorously exercised for upper arm on the opposite side. 1 min. Before the exercise the two pressures were practically identical.

11 254 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS Immediately after the exercise brachial arterial pressure as measured on the opposite side had risen, but the arterial pressure at the wrist below the dilated muscles remained nearly as before, and was now some 20 mm. Hg below the brachial pressure. Brachial pressure then gradually fell while pressure at the wrist rose, but more slowly, thus approaching closer and closer to the brachial pressure. In some experiments both measurements were made on the same side with the same results, whether done plethysmographically, as these were, or by the other methods. Determinations of the blood flow to the muscles of the forearm or of the calf showed after exercise an increase of from 15 to 20 times its resting level. Sec. g Isisess 5. Resp. 160 Pressure cuff mm. Rt.&Lt. ankle -140 Hg L.T.l t -120 R.T.l t t ~~~~~-100 Base-linee- Control After exercise Fig. 9. Record of pressure in cuffs around right and left ankles, and of volume of right and left great toes (R.T. 1 and L.T. 1), before and after vigorous exercise of right leg. Arrows on record show when volume of toes increased, indicating when systolic level was reached in respective cuffs. Fig. 9 demonstrates typical photographic records of the plethysmographic method obtained in the legs before and after exercise of one leg. In this case there was not so great a rise in systemic pressure, the principal change after exercise being the fall in the pressure distal to the exercised muscle. DIsCUSSION All the methods used in this investigation for estimating systolic pressure involve the occlusion of the arteries and the cessation of arterial flow distal to that point. So-called "flow pressures" with the peripheral circulation intact can be established by inserting into an artery a needle

12 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 255 of sufficiently small size so as not significantly to impede the flow. Whether this method affords enough additional information in large arteries to warrant its not inconsiderable risk is open to question. In small arteries it is practically impossible to use the method. The occlusion measurements reveal the potential arterial pressure available at the point of the occlusion. They must be at least slightly higher than flow pressure, since outflow distal and the gradient resulting from it have been eliminated. When there is a negligible outflow of blood from an arterial tree, flow pressures and occlusion pressures should be practically equal to each other and the same throughout the course of the artery and its branches. On the other hand, when outflow of blood is large at a certain point, due to diminished peripheral resistance, flow pressures in the branches through which the major portion of the blood is draining will be lower than occlusion pressures. Measurements of pressure taken by the occlusion method will show the decrease only if taken at sites below the point of outflow. These considerations explain the experimental observations discussed below. Grant & Pearson [1938] have shown, and we have confirmed their observations, that on simple body warming, the principal sites of vasodilatation and increased blood flow in the extremities are the hands and feet. The blood flow to the digits may increase by as much as 100 times its previous amount [Wilkins, Doupe & Newman, 1938]. If the hands and feet are excluded from the circulation by pressure cuffs at the wrists and ankles, the increase in blood flow to the arms and legs after body warming is negligible. However, during and for some minutes after muscular exercise there is a great increase in flow to these parts. It has been shown that while the flow is greatest the systolic arterial pressure measured by occlusion distal to the dilated muscles becomes considerably lower than the pressure measured above. On body warming alone, however, occlusion pressures in the limbs remain essentially equal at points as far down as the wrists and ankles. Only at the digits has it been possible to show a considerable drop in occlusion pressures. Since the circulation to the digits is by a series of branches from the palmar arches, the measurement of pressure in a single digit should approximate flow pressures in these arches. This is especially so as the circulation in one digit represents less than one-fifth of the total hand or foot circulation. A lower systolic pressure in the digital arteries than in the brachial has been reported by Cohn & Lundsgaard [1918], who also stated that Doleschal [1900] and Hayashi [1901] had made similar observations. These PH. XCV. 17

13 256 J. DOUPE, H. W. NEWMAN AND R. W. WILKINS papers have not been available to us. Cohn & Lundsgaard themselves found fluctuations in the digital arterial pressures which had no counterpart in the brachial pressure and they attributed this to changes in vasomotor tone. Wishart [1933], paying particular attention to the state of the peripheral vessels, found that when the digital vessels were dilated the difference in systolic pressure between the wrist and digital arteries was approximately 20 mm. Hg. This agrees with the results reported above. However, when the peripheral vessels were in the constricted state, Wishart found the difference to be 40 mm. Hg. This finding conflicts with the present observations and may be explained by the difficulty encountered by Wishart in determining the systolic pressure in the digits when the peripheral vessels were constricted, or by the fact that Wishart was measuring pressure in vessels distal to the arterioles. Oppenheimer & Prinzmetal [1937] using Gaertner's method found that in normal people digital pressures averaged 29 mm. lower than arm pressures. A rise in digital arterial pressure with vasoconstriction and decreased blood flow in the hand has been demonstrated with the brief reflex vasoconstrictions resulting from various stimuli given when the vessels of the digits were previously dilated. That these reflex vasoconstrictions are accompanied by temporary decreases in blood flow to the digits to as much as one-twentieth of the previous level has been pointed out elsewhere [Wilkins et al. 1938]. The association between the decrease in blood flow and the rise in digital pressure was shown in Fig. 4. That this rise in digital pressure is actually due to the change in blood flow is supported by three considerations. First, with the hand cold and blood flow already so small that any further vasoconstriction could not significantly change it, the stimulus failed to produce any alteration in digital pressure. Secondly, no rise in digital pressure occurred when digital vasoconstriction was abolished by sympathectomy; and thirdly, the digital pressure could be raised in the absence of a vasoconstriction by the occlusion of the circulation to the other four digits. These observations seem to bear pertinently on the subject of arterial pressure in peripheral organs where the blood flow may be considerable and variable. That changes in peripheral blood flow can alter significantly systolic arterial pressure locally has been demonstrated. The fallacy of attempting measurements of systemic arterial pressure in such peripheral arteries without regard to these local variations perhaps needs emphasis. The experiments indicate that in man, at least, systemic arterial pressure should be measured in large arteries as centrally as feasible.

14 VASOMOTOR ACTIVITY AND ARTERIAL PRESSURE 257 These experiment also throw light on the effects of local physiological or pathological narrowing of arteries in areas where previously there had been a large flow of blood. By raising the pressure in adjacent side branches, such a narrowing, might result in an increased flow in that direction or in furthering the development of collateral circulation. On the other hand, too sudden a change, as in an abrupt occlusion, might increase the strain in side branches incapable of bearing it, and result in rupture or haemorrhage. SUMMARY AND CONCLUSIONS Measurements of systolic arterial pressure made proximally and distally in a limb are essentially equal so long as the blood flow is small. Vasodilatation in a limb is followed by a lowering of systolic arterial pressure measured distal to the site of maximal outflow compared with the pressure measured proximally. Contrariwise, vasoconstriction in a previously dilated area is followed by a rise in systolic pressure measured distally towards the pressure measured proximally. A lowering of systemic pressure as measured proximally in a limb may occur coincidentally with a rise distally, provided that there is a simultaneous peripheral vasoconstriction, and that the systemic pressure is not lowered too greatly. Our sincere thanks are due to Dr E. Arnold Carmichael, under whose direction this work was performed. The work was carried out during the tenure of a Halley Stewart Research Fellowship by Dr Doupe, of a Rockefeller Foundation Fellowship by Dr Newman, and of a Fellowship from the American College of Physicians by Dr Wilkins. REFERENCES Bolton, B., Carmichael, E. A. & Sturup, G. [1936]. J. Phy8iot. 86, 83. Cohn, A. C. & Lundsgaard, C. [1918]. J. exp. Med. 27, 487. Doleschal, M. [1900]. Inaugural Diss., Basel. Quoted by Cohn & Lundsgaard. Doupe, J., Newman, H. W. & Wilkins, R. W. [1939]. J. Physiol. 95, 239. Doupe, J., Robertson, J. S. M. & Carmichael, E. A. [1937]. Brain, 60, 281. Grant, R. T. & Pearson, R. S. B. [1938]. Clin. Sci. 3, 119. Hayashi, T. [1901]. Inaugural Diss., Erlangen. Quoted by Cohn & Lundsgaard. Hewlett, A. W. & Van Zwaluwenburg, J. G. [1909]. Heart, 1, 87. Oppenheimer, E. T. & Prinzmetal, M. [1937]. Arch. intern. Med. 60, 772. Sturup, G., Bolton, B., Williams, D. J. & Carmichael, E. A. [1935]. Brain, 58, 456. Wilkins, R. W., Doupe, J. & Newman, H. W. [1938]. Clin. Sci. 3, 403. Wishart, M. [1933]. Clin. Sci. 1,