increasing the pressure within the vessels of the human forearm, and if so, Bayliss in 1902 and Folkow in 1949 found that increasing or decreasing the

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1 501 J. Physiol. (I954) I25, 50I-507 THE BLOOD FLOW IN THE HUMAN FOREARM FOLLOWING VENOUS CONGESTION By G. C. PATTERSON AND J. T. SHEPHERD From the Department of Physiology, The Queen's University of Belfast (Received 20 March 1954) Bayliss in 1902 and Folkow in 1949 found that increasing or decreasing the internal pressure in blood vessels in the cat's hindleg caused the tone of the vessel wall to increase or decrease respectively. As this response still occurred after complete denervation of the vessels Folkow concluded that it was a property of the vessel wall and was not neurogenic in origin. Hilton (1953) noted an absence of reactive hyperaemia following venous occlusion in the hindlimbs of the cat and attributed this to the fact that the intravascular pressure did not decrease during this procedure. The experiments to be described were devised to see if such an increase in tone could be obtained by increasing the pressure within the vessels of the human forearm, and if so, whether it was an inherent property of the vessel wall, or was mediated through nervous pathways. METHODS The subjects were healthy young men from 18 to 30 years of age, and the experiments were carried out at laboratory temperatures of C. The blood flow through a segment of the forearm was measured by venous occlusion plethysmography as described by Barcroft & Swan (1953). The plethysmographs were filled with water at 350 C. All measurements were made with the subjects in the recumbent position and the forearm was raised 2-5 cm above the sternal angle to facilitate rapid emptying of the forearm veins. In each experiment preliminary observations were made of the apparent rate of arterial inflow when the collecting cuff was inflated to various pressures. The lowest pressure which interfered with arterial inflow was thus determined. A pressure mm Hg lower than this, usually mm Hg, was used during the remainder of the experiment both for the recording of the blood flow and for the production of venous congestion in the forearms. Base-line records of forearm flow were made over a period of 1-2 min. The wrist cuff was then released and the collecting cuff was inflated for 5 min to produce venous congestion. One min before the end of this 5 min period the cuff around the wrist was re-inflated (Kerslake, 1949). The collecting cuff was then deflated and the vessels allowed to empty. Recordings of blood flow were made, beginning 3-5 sec after release of the congesting cuff. The recordings were continued at intervals of sec for 3-4 min or until the blood flow had returned to the level present before the venous congestion.

2 502 G. C. PATTERSON AND J. T. SHEPHERD RESULTS Experiments on normal subjects. Fig. 1 shows a typical plethysmographic record; the venous congestion was produced by a cuff inflated to 110 mm Hg for 5 min. The resting flow (A) was steady. The blood flow immediately after deflation of the congesting cuff was greatly increased (B), then rapidly fell within about 15 sec to a level (C) well below the resting value, and finally gradually returned to the resting level (E), which was reached in about 1 min. This return could often be seen to take place during a single record of flow as in (D). 5 sec Fig. 1. A typical plethysmographic record from a normal subject (J.T.S.). Between records A and B the arm cuff was inflated to 110 mm Hg for 5 min to produce venous congestion in the forearm. The forearm flows in ml./l0o ml./min were as follows: A, 3 0 ml.; B, 15-5 ml.; C, 0.8 ml.; D, 1st slope 1-2 ml., 2nd slope 2-8 ml.; and E, 2-5 ml. Fig. 3A shows a typical result. The blood flow in ml./100 ml./min has been plotted against the time in min from the release of the congesting cuff. The results of twenty-two experiments on twelve normal subjects are shown in Fig. 2. Each estimation of blood flow has been expressed as a percentage of the average resting flow during a period of 1-2 min before the congesting pressure was applied. In every case the flow 3-5 sec after deflation of the congesting cuff was much above the resting level; these flows are omitted from the figure. The second flow (first in the figure) was usually, and the third invariably, below the resting level, which was not attained until about 1 min after deflation of the congesting cuff. In two experiments, each on a different subject, the congesting pressure was maintained for 20 and 30 min respectively. On release, the decrease in flow was no more and no less marked than after a 5 min period of congestion. There was therefore no evidence of adaptation for periods of at least half an hour. A similar response to that seen in the forearm was also obtained in two experiments on one subject in whom the blood flow through the calf was measured after congestion for 5 min. In three subjects (three, two and one experiments respectively), the blood flow through both forearms was measured simultaneously using the same collecting pressure but only one arm was subjected to venous congestion. The responses just described were obtained in the congested forearm and not in the control forearm. This shows that these responses are local ones in the previously congested vessels, and not a part of a general disturbance of the circulation.

3 VENOUS CONGESTION AND BLOOD FLOW 503 Several findings suggest that the apparent decrease in the rate of blood flow is the result of a genuine vasoconstriction and not due to a fault in technique. It might be suggested that after release of the congesting pressure the reinflation of the cuff for collection of blood failed to occlude the veins completely, thus giving a deceptively low result. This is unlikely for the following reasons: (a) the collecting pressure used was identical with the congesting pressure; (b) if measurements of flow were withheld until the volume of the forearm segment, as indicated by the base line in the tracing, was steady, the flow was observed to be below the resting level. There is no evidence, from observations 150-0~~~~~~~~~~~ 0~~~~~~~~~~~~~~ *% * E: : E_3 0 ~~~ ~ ~~~~~ 0~~~~~~~~~~~~~~ O. ' ~ ~ ~~~~. l Minutes After 5min congestion 81*0mm at Hg Fig. 2. The results of twenty-two experiments on twelve normal subjects, showing forearm blood flow following 5 min venous congestion as a percentage of the average resting flow before congestion. The first flow in each experiment has been omitted. Resting levels of flow varied between 1-4 ml. and 4-5 ml./100 ml./min. On the limb volume, that the vessels were still distended, and therefore liable to resist further inflow of blood, at the time the reduced inflow was observed. The vessels were disteided immediately after the release of the congestion, but at this stage the flow was high. Further, the inflow tracings were straight for several seconds, usually 10 sec or more, and the slope often increased during a single record of flow (Fig. 1 D). It is concluded that the decrease in blood flow is due to constriction of vessels in the region previously congested. Experiments on subjects with sy tmpathectomrzed limbs. Two subjects were used; one had had a unilateral sympathectomy 12 months previously, and the other a bilateral sympathectomy 3 months previously, for Raynaud's disease. They were otherwise free from vascular abnormality. Both subjects were indirectly heated for 1 hr with their feet in a water bath at 440 C to release sympathetic

4 504 G. C. PATTERSON AND J. T. SHEPHERD tone (Lewis & Pickering, 1931). The first subject showed no increase in blood flow through the sympathectomized forearm and a normal vasodilatation in the other arm. The second subject showed no increase in flow through either forearm. There was thus no evidence of sympathetic activity in the vessels of the sympathectomized limbs. Fig. 3B shows a typical result on one of these subjects; it differs in no way from that obtained in the normal subjects. A i B. G. 5I E - E 5 B R.W. -0 E, 0 p 0 D_ C 5 0 0~~~~ C'1 A.R.S. S0 D \ /0 0_O Minutes Fig. 3. Forearm blood flow recorded in B.G.: a normal subject; R.W.: a patient who had had a cervical sympathectomy for Raynaud's disease 3 months previously; and A.R.S.: a patient who had sustained a traumatic rupture of the brachial plexus 1 yr previously. The dotted lines indicate a 5 min period during which the collecting cuff was kept inflated to produce venous congestion in the forearm. Experiments on subjects with completely denervated limbs. Two subjects A.R.S. and G.McC. (Duff & Shepherd, 1953) were examined, one 1 yr, and one 3 yr, after brachial plexus injuries. Both had initially suffered complete anaesthesia and paralysis below the elbow. There was no evidence of return of nervous activity in A.R.S., while in G.McC. there was a slight return of sensation in the upper half of the forearm. The former subject showed no alteration in forearm blood flow in response to indirect heating. In both subjects the arterial pulsations in the denervated limbs were normal. Five experiments were performed

5 VENOUS CONGESTION AND BLOOD FLOW 505 on the denervated arms of these subjects, and the response was similar in all respects to that obtained in normal subjects. A typical result is shown in Fig. 3C. DISCUSSION Following the release of pressure in a cuff on the upper arm inflated to mm Hg for 5 min there is a large but brief vasodilatation, followed by a vasoconstriction. The cuff causes an increase in pressure in the veins, capillaries and presumably in the distal portion of the arterial tree. Lewis & Grant (1925) measured the blood flow through the human forearm following the release of a cuff which had been applied at pressures of up to 90 mm Hg for min. They recorded flow 5 sec after release of the cuff and thereafter at 1 min intervals for 5 min. The flows after release were higher than the resting level and never fell below this level; there were, however, no observations at the time at which we observed the smallest flows. In these experiments the circulation to the hand was not occluded by the wrist cuff later introduced by Grant & Pearson (1938), and under these conditions the apparent flow rates may be incorrect,, and they may not even be directly proportional to the true flow rates. The error may vary with the individual subject, and in the same subject may vary with the state of the peripheral circulation and the exact arrangement of the plethysmograph and cuffs. Lewis & Grant described apparent resting flows of ml./100 ml./min. An attempt was made to repeat their observations without inflation of the wrist cuff. It was difficult to obtain apparent resting flows at a steady level of ml./100 ml./min even by raising the temperature of the water in the plethysmograph to 430 C and heating the subject generally. In twelve experiments on five subjects a decrease of flow which persisted for about 1-1l min after release of the cuff was observed in every case except one. The discrepancy between these results and those of Lewis & Grant may be due to individual variation in the subjects, or more probably to the unsatisfactory nature of forearm blood-flow estimation in which no wrist cuff is employed. The initial high flow may be a reactive hyperaemia following venous congestion, as suggested by Lewis & Grant (1925). Another possibility, however, is that the vessel walls, which are stretched during the period of congestion, require about 15 sec to take up their new position when the congesting pressure is released. We have no definite evidence to offer on this point. The constriction following the initial vasodilatation may be a direct reaction of the muscle or it may be mediated through a nervous pathway. Gaskell & Burton (1953) have described a vasoconstriction in the human finger brought about by the increase in intravascular pressure when the finger is lowered to a dependent position. The reaction was unaltered in the chronically sympathectomized limb. Gaskell & Burton concluded that a non-sympathetic

6 506 G. C. PATTERSON AND J. T. SHEPHERD veni-vasomotor reflex was responsible. Our own observations on chronically denervated limbs, in which the vasoconstrictor response was normal, show that the response is not mediated by nervous pathways which degenerate after such lesions. Apart from the possibility of peripheral nerve networks surviving in apparently denervated limbs, our evidence suggests that the vasoconstriction does not depend on nervous pathways. If the vasoconstriction is myogenic, it may be a response either to a chemical or to a mechanical stimulus. Considering first the evidence relating to the chemical stimulus, it may be supposed that during the period of venous congestion the local concentration of vasodilator substances rises because of the reduced rate of flow (Friedland, Hunt & Wilkins, 1943; Edholm, Moreira & Werner, 1954). After release of congestion the brief high flow may wash away so much vasodilator substance that the concentration falls below the normal resting level, so explaining the vasoconstriction. This type of over response to a chemical vasodilator stimulus is not seen after the intra-arterial injection of vasodilator substances in a wide range of doses (Duff, Greenfield, Shepherd & Thompson, 1953; Duff, Patterson & Shepherd, 1954). Conditions for washing away vasodilator substances are presumably not less favourable when their blood concentration has been raised than when their tissue concentration has been raised. It is also doubtful whether the very brief high flow, lasting usually not more than 15 sec, could wash away the material accumulated during 5 min of reduced flow. There are therefore difficulties in the way of a purely chemical explanation of the vasoconstriction. It is simpler to assume that the constriction is a response on the part of the vessel wall to the mechanical stimulus of stretching. We therefore suggest that the explanation of the vasoconstriction is that proposed by Bayliss (1902) and Folkow (1949). The question arises as to whether the existence of this vasoconstriction following venous congestion may invalidate the measurement of blood flow through the forearm by venous occlusion plethysmography. When, as is usually the case, the initial rate of increase in limb volume is linear any disturbance must either occur instantaneously when collection begins or else it cannot operate during the period of linearity used in the estimation of blood flow. As the pressure in the vessels presumably cannot rise before blood begins to accumulate it is difficult to believe that the disturbance can begin instantaneously. We therefore do not feel that these observations throw doubt on the measurement of forearm blood flow by venous occlusion plethysmography. SUMMARY L A cuff around the arm has been inflated for 5 min to pressures varying from 80 to 110 mm Hg in order to produce venous congestion in the forearm. 2. Immediately after release of this cuff, there is a transient increase in forearm blood flow, followed by a rapid decrease to about one half the resting

7 VENOUS CONGESTION AND BLOOD FLOW 507 value; the flow then increases until the resting level is again reached in 1-1 min. 3. This decrease in flow is the result of a vasoconstriction of the forearm blood vessels. 4. The vasoconstriction still occurs after the limb has been sympathectomized and somatically denervated. It is improbable, therefore, that any nervous mechanism is involved. 5. The vasoconstriction may represent a direct response of the vessels to an increase in intravascular pressure. 6. The existence of this phenomenon is unlikely to affect the validity of blood flow measurement by venous occlusion plethysmography. We wish to thank Prof. A. D. M. Greenfield for suggestions and criticism and Dr R. F. Whelan for reading and contributing to the manuscript. Prof. H. Barcroft, F.R.S., kindly gave us facilities to examine one of the patients in his laboratory. REFERENCES BARCROFT, H. & SWAN, H. J. C. (1953). Arnold. The Sympathetic Control of Human Blood Ve8sel8. London: BAYLISS, W. M. (1902). On the local reactions of the arterial wall to changes of internal pressure. J. Physiol. 28, DUFF, F., GREENFIELD, A. D. M., SHEPHERD, J. T. & THOMPSON, I. D. (1953). A quantitative study of the response to acetylcholine and histamine of the blood vessels of the human hand and forearm. J. Phy8iol. 120, DUFF, F., PATTERSON, G. C. & SHEPHERD, J. T. (1954). A quantitive study of the response to adenosine triphosphate of the blood vessels of the human hand and forearm. J. Phy8iol. 125, DUFF, F. & SHEPHERD, J. T. (1953). The circulation in the chronically denervated forearm. Clin. Sci. 12, EDHOLM, 0. G., MOREIRA, M. F. & WERNER, A. Y. (1954). The measurement of forearm blood flow during a raised venous pressure. J. Phy8iol. 125, 41-42P. FOLKow, B. (1949). Intravascular pressure as a factor regulating the tone of the small vessels. Acta phy8iol. scand. 17, FRIEDLAND, C. K., HUNT, J. S. & WILKNs, R. W. (1943). Effect of changes in venous pressure on blood flow in the limbs. Amer. Heart J. 25, GASKELL, P. & BURTON, A. C. (1953). Local postural vasomotor reflexes arising from the limb veins. Circulation Re8. 1, GRANT, R. T. & PEARSON, R. S. B. (1938). The blood circulation in the human limb; observations on the differences between the proximal and distal parts and remarks on the regulation of body temperature. Clin. Sci. 3, HILTON, S. M. (1953). Experiments on the post-contraction hyperaemia of skeletal muscle. J. Phy8iol. 120, KERSLAKE, D. McK. (1949). The effect of the application of an arterial occlusion cuff to the wrist on the blood flow in the human forearm. J. Physiol. 108, LEWIS, T. & GRANT, R. (1925). Observations upon reactive hyperaemia in man. Heart, 12, LEWIS, T. & PICKERING, G. W. (1931). Vasodilatation in the limbs in response to warming the body; with evidence for sympathetic vasodilator nerves in man. Heart, 16,