A Reduction in Some Vasodilator Responses

Transcription

1 Cardiovasc. Res., 1969, 3, A Reduction in Some Vasodilator Responses in Free-standing Man J. G. MOSLEY" From the Department of Physiology, The Queen's University of Belfast, Northern Ireland AUTHOR'S SYNOPSIS. Experiments were carried out to stucjy the effect of a change in posture on some rasodilator responses. Reactire hyperaemia, post-exercise hyperaemia, and local heat hyperaemia in the forearm were investigated with the subject lying and standing. In each case the hyperaemia was reduced on standing, though this reduction could be abolished by the intra-arterial infusion of a sympathetic adrenergic antagonist. The intravenous infusion of adrenaline into the recumbent subject causes a vasodilatation of the forearm blood vessels (Allen, Barcroft, and Edholm, 1946). If the infusion is given to the standing subject, the sustained vasodilatation does not occur (Brick, Glover, Hutchison, and Roddie, 1967). Brick et al. (1967) suggested that the increase in vasomotor tone which occurs on standing, is responsible for the alteration in the response to adrenaline. The present experiments were designed to see if vasodilatation in the forearm caused by some other stimuli was affected by a similar change in posture. Vasodilatation was produced by occluding the forearm circulation for 5 min (reactive hyperaemia), by rhythmic contractions of the forearm muscles (exercise hyperaemia), or by the local application of heat. Methods Two series of experiments were carried out. In the first series, observations were made on seven healthy young adults. They rested, normally clothed, for at least 30 min before any measurements were taken. Room temperature was between 21 C and 25"C, but varied by only f 1 C in any experiment. Both forearms were inserted into venous occlusion plethysmographs (Greenfield, Whitney, and Mowbray, 1963) maintained at 35'C+ 1 C. Throughout the experiment flows were recorded at 15 sec intervals. In all the experiments the stimulus was applied to the left forearm. Five of the subjects were able to attend for all three experiments. The order of hyperaemic stimuli had been previously decided up011 in a random fashion. Some subjects stood first, others lay first; this order was also varied at random. Reactive Hyperaemia Resting flows were recorded for 3 min, the collecting cuff was then inflated to 200 mm Hg for 5 min. On release of the occlusion, flows were recorded for a further 7 min; for the first 45 sec of this period a lower pressure (30-40 mm Hg) was used in the collecting cuff (Patterson and Whelan, 1955). Two runs were carried out in each position. Post-exercise Hyperaemia A similar set of experiments was carried out using a standard rhythmic exercise in place of the 5 min occlusion. The exercise was performed for 45 sec by squeezing a mercury-filled rubber bulb, connected to a vertical glass tube (13 mm internal diameter). Each contraction raised the mercury column 15 cm. The rate of exercise was 36 contractions/rnin, timed with a metronone. Local Heat Resting flows were recorded for 5 min. The temperature in the left plethysmograph was raised to 42"+ 1 C within 5 min, and was then maintained for a further 20 min before blood flows were measured for 10 min. The subject was then removed from the plethysmographs and rested for at least I hr before the experiment being repeated in a different position. Sympathetic Blockade In the second series, nine experiments were carried out, each on a different subject; no subject had taken Received April 17, * Supported by a grant from the Medical Research Council. part in the first series of experiments. 14

2 Reduction in Vasodilator Responses on Standing 15 Bretylium tosylate (Darenthin, Burroughs Wellcome), 12.5 mg, a known sympathetic adrenergic blocking agent (Blair, Glover, Kidd, and Roddie, 1960), dissolved in 40 ml. 0.9% w/v saline was infused through an in-dwelling needle into the left forearm over a period of 10 min. Results Reactive Hyperaemia Figure 1 illustrates part of a typical experiment. Blood flow was measured in both forearms before and after the circulation to the left forearm had been arrested for 5 min. The left panel shows the response of the left forearm to the occlusion when the subject was lying recumbent on a couch. The right panel shows the response of the same forearm when the subject was standing with his forearms raised slightly above heart level. There was a reduction in the size of the reactive hyperaemia on standing; thus the highest flow immediately after the release of the occlusion was smaller and blood flow returned to the resting level more quickly. In six experiments each on a different subject, two runs were carried out with the subject lying and two runs with the subject standing. Resting forearm blood flow when the subject was lying ranged from 2.1 to 6.2 m1./100 ml./min with a mean value of 3.7 m1./100 ml./min. In each case there was a fall on standing; in this position the resting blood flow ranged from 0.9 to 4.2 m1./100 ml./min, mean value was 1-9 m1./100 ml./min. In the top panel of Fig. 2 the rectangles represent the average size of the various parameters measured in the two positions. n LYING 301 The peak blood flow was the size of the highest blood flow recorded after the release of the occlusion, less the calculated resting value. The resting value was taken as the average level in the same forearm during the 3 rnin period preceding the occlusion, corrected for general changes in vasomotor tone by reference to the blood flow on the control side (Duff, 1952). When lying, the peak flow varied between 13.6 and 27.2 m1./100 ml./min, mean 21.6 m1./100 ml./min. In all but one run the peak flow was reduced on standing, ranging from 11-9 to 21.2 m1./100 ml./min, mean 15.4 m1./100 ml./min. The duration was measured as the time (to the nearest 0.25 min) from the end of occlusion, until the blood flow was down to 0.5 m1./100 ml./min of the expected resting blood flow. When lying, the duration varied from 1.25 to 6.25 rnin (mean 3-25 min), and while standing the duration was reduced in all but two runs and varied from 0.75 to 4-25 (mean 1.25 rnin). The excess blood flow was calculated as the blood flow in excess of the expected resting level during the 7 min period after release of occlusion. When lying, the excess flow ranged from 10.5 to 30.1 m1./100 ml. (mean 18.9 m1./100 ml.). When standing the excess blood flow ranged from 6.3 to 12.6 m1./100 ml. (mean 10.5 m1./100 ml.). This represents an average reduction in the excess flow of 8.4 m1./100 ml. The final column shows the average effect of standing on the size of the excess flow when this was expressed as a percentage of the expected flow. STANDING O M +eu e-4 mmu,., mmut.. Fig. 1. A typical effect of change of posture on reactive hyperaemia in the forearm. The circulation to the left forearm (0) was occluded during the 5 min period indicated by the vertical lines. Right (control) forearm (0). Observations shown in the left panel were made with the subject lying; right panel subject standing.

3 16 J. G. Mosley REACTIVE HYPERAEMIA PEAK DURATION EXCESS EXCESS,1/0i BLOOD FLL)W m u BLOOD m FLOW i,o,pcrcm BLOOD FLDW LOCAL HEAT F'K)orm'nin I Fig. 2. Comparison of the average values for excess blood flow and percentage excess blood flow of reactive hyperaemia, post-exercise hyperaemia, and local heat in the forearm; average values for peak blood flow and duration of reactive and post-exercise hyperaemia. The rectangles represent the average size of the various parameters measured when the subjects were lying ). ( and standing (0). LYING STAND1 NG minutes Fig. 3. The effect of change of posture on exercise hyperaemia in the forearm. Average of 12 runs on six subjects. Forty-five seconds of rhythmic contractions of the left forearm (0) muscles occurred during the period indicated by the vertical lines. Right (control) forearm (0).

4 Reduction in Vasodilator Responses on Standing 17 When lying, the excess flow was 28% to 121% greater than the expected (mean 73%). When standing the percentage increase was greater in four runs and varied between 43% and 10Syo (mean 75%). Post-exercise Hyperaemia Figure 3 illustrates the average result of six experiments of this type. The left panel shows the response of the left forearm after 45 sec rhythmic exercise while the subject was lying. The right panel shows the course of the hyperaemia while the subject was standing. Standing produced a decrease in the peak flow, duration, and excess blood flow of the post-exercise hyperaemia. When lying, resting forearm blood flow varied between 1.7 and 6.5 m1./100 ml./min; the average value was 3.9 m1./100 ml./min. In each experiment the resting forearm blood flow fell on standing. In this position the resting blood flow ranged from 0.5 to 4.3 m1./100 ml./min with a mean value of 1.8 ml./ 100 ml./niin. The average results of the experiments of this type are shown in the middle row of Fig. 2. The difference between the average peak blood flow when lying and standing is shown in the first column. When the subjects were lying, the peak blood flow varied between 7.0 and 24,O m1./100 ml./min (mean 17-1 m1./100 ml./min.) In every case the peak blood flow was reduced when the subject was standing; the flows ranged from 6.8 to 17.5 m1./100 ml./min. As with reactive hyperaemia, the duration of the hyperaemia was reduced on standing. The average duration of the hyperaemia when lying was 6.75 min. When the subject was standing the average duration was 5.75 min. While lying, the excess flow following exercise ranged from 14.0 to 39.2 m1./100 ml. (mean 23.8 m1./100 ml.). In all but one run, the hyperaeniia was reduced on standing and ranged from 7.7 to 32.9 m1./100 ml. (mean 16.1 m1./100 ml.). The average size of the hyperaemia when lying was reduced by 7.7 m1./100 ml. on standing. When the excess flow was expressed as a percentage of the calculated flow, flow varied between 47% and 124% (mean 85%), greater than the expected flow when lying. The percentage increase in flow when standing varied between 62% and 157% with a mean of 115%. Local Heat Hyperaemia Figure 4 illustrates the average result of six local heat experiments. The upper panel shows the LYING 25 ml"yic, STANDING LOCAL HEAT LOCAL HEAT Fig. 4. The effect of change of posture on the hyperaemia produced in the forearm by local heat. Average of six runs on six subjects. The temperature of the water in the left plethysmograph was raised ftom 35C to 42 C after 5 min. Symbols as for Fig. 3. response to local heating of the left forearm when the subject was lying. The lower panel shows the response of the left forearm to local heat when the subject was standing. Resting forearm blood flow when lying varied between 2.1 and 5-0 m1./100 ml./min (mean 2.9 m1./100 ml./min). As before, resting blood flow was reduced on standing and varied between 0-9 and 3.0 m1./100 ml./min (mean 1.6 m1./100 ml./min). The bottom panel of Fig. 2 compares the level of forearm blood flow in the different positions. When the subject was lying, the excess blood flow above that calculated ranged from 2.9 to 10.4 m1./100 ml./min. The average excess blood flow was 6.2 m1./100 ml./min. In two experiments the blood flow was greater when standing. The flow ranged from 1.5 to 6.3 m1./100 ml./min (mean 3.9 m1./100 ml./ min). The increase in blood flow was expressed as a percentage of the calculated resting level. The

5 18 percentage increase when lying varied between 94% and 237% (mean 168%). The percentage increase when standing was greater in four experiments and varied between 88% and 246% (mean 163%). The Effect of Sympathetic Adrenergic Blockade In nine experiments, sympathetic adrenergic nerves to one forearm were blocked by the intraarterial infusion of bretylium tosylate before the following procedures were carried out. Reactive Hyperaemia Occlusion was applied simultaneously to both forearms for 5 min, and after one run the subject changed position. Three such experiments were carried out and Fig. 5 illustrates a typical experiment. When lying, the reactive hyperaemia was similar in the forearm which had been infused with bretylium and in the control forearm. When the subject was standing, the hyperaemia in the blocked side 'was greater than that in the control side. The average results of the three experiments of this type are shown in the first column of Fig. 6. The rectangles represent the absolute size of the hyperaemia. The hyperaemia has been calculated as the amount of blood flowing during the 7 min period following the release of the circulation in excess of the previous resting level. J. G. Mosley On the blocked side the hyperaemia while lying varied from 17.5 to 35 ml./100 ml. (mean 26.6 m1./100 ml.). When the subject was standing, the absolute size of the hyperaemia was less in two cases and greater in one. The absolute size of the hyperaemia varied from 16.8 to 30.8 m1./100 ml. (mean 25.9 m1./100 ml.). The reduction in the hyperaemia was very much greater on the control side. Here the absolute size of the hyperaemia while lying varied from 17.5 to 25.2 m1./100 ml. (mean 21.0 m1./100 ml.). When the subject was standing, the absolute size of the hyperaemia on the control side varied between 7.7 and 18.2 m1./100 ml. (mean 13.3 m1./100 ml.). Hence, in the sympathetic blocked forearm, the size of the reactive hyperaemia was reduced on average by 0.7 m1./100 ml. when standing, compared with an average decrease of 7.7 m1./100 ml. on the control side. Post-exercise Hyperaemia In three experiments, rhythmic exercise was performed by both forearms in place of the occlusion. It was found that the post-exercise hyperaemia on the blocked side was similar in the two positions. However, there was the usual reduction in post-exercise hyperaemia on the control side when the subject was standing. The average result is shown in the second column of Fig. 6. When lying, the size of the hyperaemia on the blocked side varied between 3. LYING -1 STANDING Fig. 5. A typical effect of change of posture on reactive hyperaemia in the normal forearm (c) and in the forearm (e), which had received an intra-arterial infusion of bretylium tosylate (12.5 mg). minutes occlusion applied to both forearms between the vertical lines. Five

6 Reduction in Vasodilator Responses on Standing 19 EXCESS BLOOD FLOW CONTROL I REACT IV E ml/k)oml POST EX ERC ISE LOCAL HEAT ml/k)oml/mm BRETY LI U M :I Fig. 6. The top panel compares the average excess flow in the normal forearm during reactive hyperaemia, TOSY LATE post-exercise hyperaemia, and during local heat when the subjects were lying (w) and standing (z). In the bottom panel similar comparisons are made in the forearm which had received an intra-arterial infusion of bretylium tosylate (12.5 mg),, - I LY I NG +.STANDING I P. t I- LOCAL HEAT is' ' ' ' ' 35 ' 45 '.. '. 5P ' '. ' ' 55 ' rnl"",., Fig. 7. Effect of change of posture on the hyperaemia produced by local heat in normal forearm (L) and forearm (0) that had received an intra-arterial infusion of bretylium tosylate (12.5 mg). Subject was lying until 35th min and thereafter standing. Temperature of both plethysmographs raised from 35'C to 42 C at 5th min.

7 20 J. G. Mosley 25.2 and 37.8 m1./100 ml. (mean 32.9 m1./100 ml,). In each experiment, standing produced a decrease in the post-exercise hyperaemia, the sizes of which varied between 24.5 and 35.0 m1./100 ml. (mean 29.4 m1./100 ml.). When lying, the size of the post-exercise hyperaemia in the control side varied between 28.0 and 51.8 m1./100 ml. (mean 41.3 m1./100 ml.). The size of the hyperaemia when standing varied from 12.6 to 21.0 m1./100 ml. (mean 17.5 m1./100 ml.). On standing, the average reduction in the size of the hyperaemia in the sympathetic blocked forearm was 3.5 m1./100 ml., whereas the average reduction on the control side was 23.8 m1./100 ml. Local Heat Figure 7 illustrates a typical experiment. In three experiments, resting blood flows in each forearm were measured for 5 min. The temperature in both plethysmographs was then raised to 42 k 1 C and maintained at this temperature. After 20 min blood flows were recorded for 10 min. The subject then stood, the temperature in the plethysmographs being maintained at 42"Cf 1"C, and blood flows were recorded for a further 10 min. The average results are shown in the final column of Fig. 6. When lying the blood flow to the sympathetic blocked side during local heat varied from 3.4 to 11.5 m1./100 ml./min (mean 7.3 m1./100 ml./min). In each experiment the average blood flow fell slightly when the subject stood, the blood flows varying between 2.5 and 11.4 m1./100 ml./min (mean 6.9 m1./100 ml./min). When lying, the blood flow on the control side during local heat varied between 6.6 and 11.8 ml./ 100 ml./min (mean 9.2 m1./100 ml./min). In each experiment there was the usual reduction in the heat hyperaemia on standing. In this position the blood flow varied between 1.9 and 8.5 m1./100 ml./min (mean 4.8 m1./100 ml./min). The average blood flow on the side which had been infused with bretylium was reduced 0-4 m1./100 ml./min by standing. This reduction was considerably less than on the control side, where standing reduced the average blood flow due to local heat by 4.4 m1./100 ml./min. Discussion These experiments show that the vasodilatation in the forearm after occlusion, exercise, or during the application of local heat is reduced on standing. This reduction does not occur after the local administration of the adrenergic antagonist, bretylium tosylate, which would indicate that it is due to an increase in vasoconstrictor tone. Fewings, Roberts, Stepanas, and Whelan (1965) have shown that post-exercise hyperaemia is reduced by the increase in sympathetic vasoconstrictor tone, which occurs during passive tilting. Reactive hyperaemia is also reduced by simulated postural stress, such as exposure of the lower parts of the body to sub-atmospheric pressure (Ardill, Bhatnagar, and Fentem, 1967), or by passive tilting (Paterson, 1967). The present experiments show that similar mechanisms operate during the more physiological stimulus of free standing. The results indicate that at least some of the vessels affected by local heat also take part in postural reflexes. There is some evidence that muscle, but not skin, vessels participate in postural reflexes (Roddie and Shepherd, 1956). However, Crossley, Greenfield, Plassaras, and Stephens:( 1966) have shown that vessels involved in thermoregulatory reflexes-presumably mainly in the skin-may participate in postural reflexes. The present experiments favour the latter hypothesis, since it is likely that local heat causes a vasodilatation confined mainly to the skin vessels (Hellon, 1963). Finally, it has been found that the reduction in reactive and post-exercise hyperaemia is proportional to the increase in vasoconstrictor tone, as judged by the fall in the resting level of blood flow. If it is maintained that the size of these hyperaemiae is related to the metabolic disturbance, one must postulate that an increase in vasoconstrictor tone causes a proportional fall in metabolism. An increase in vasoconstrictor tone can cause a decrease in metabolism (Renkin and Rosell, 1962), but it seems unlikely that the 50% fall in forearm blood flow, which occurs on standing, could be associated with as much as a 50% fall in metabolism. Hence, these results support the conclusion of Blair, Glover, and Roddie (1959) that the size of the hyperaemia following occlusion or exercise is not strictly related to the size of the metabolic disturbance. I should like to thank Dr. W. E. Glover for his help in some of the experiments and for his criticism of the manuscript. References Allen, W. J., Barcroft, H., and Edholrn, 0. G. (1946). On the action of adrenaline on the blood vessels in human skeletal muscle. J. Physiol. (Lond.), 105, Ardill, B. L., Bhatnagdr, V. M., and Fentern, P. H. (1967). Reduction in the vasoconstriction produced by sym-

8 Reduction in Vasodilator Responses on Standing 21 pathetic adrenergic nerves during reactive hyperaemia. Cardiorasc. Res.. 1, Blair, D. A., Glover, W. E., Kidd. 9. S. L., and Roddie, I. C. (1960). Peripheral vascular effects of bretylium tosylate in man. Brit. J. Pharmacol., 15, , and Roddie, 1. C. (1959). The abolition of reactive and post-exercise hyperaemia in the forearm by temporary restriction of arterial inflow. J. Physiol. (Lond.), 148, Brick, I., Glover, W. E., Hutchison, K. J., and Roddie, 1. C. (1967). Differences in cardiovascular responses to adrenaline in recumbent and free standing man. J. Physiol. (Lond.), 191, P. Crossley, R. J., Greenfield, A. D. M., Plassaras, G. C., and Stephens, D., (1966). The interrelation of thermoregulatory and baroreceptor reflexes in the control of the blood vessels in the human forearm. J. Physiol. (Lond.), 183, Duff, R. S. (1952). Effect of sympathectomy on the response to adrenaline of the blood vessels of the skin in man. J. Physiol. (Lond.), 117, Fewings, J. D., Roberts, M. L., Stepanas, A. V. and Whelan, R. F. (1965). The effects of decreased muscle blood flow on post-exercise hyperaemia in the human forearm. Aust. J. exp. Biol. med. Sci., 43, Greenfield, A. D. M., Whitney, R. J., and Mowbray, J. F. (1963). Methods for the investigation of peripheral blood flow. Brit. med. Bull., 19, Hellon, R. F. (1963). Local effects of temperature. Brit. med. Bull., 19, Paterson, N. A. N. (1967). The effects of increased vasomotor tone on reactive hyperaemia in the human forearm. Aust. J. exp. Biol. med. Sci., 45, Patterson, G. C., and Whelan, R. F. (1955). Reactive hyperaemia in the human forearm. Clin. Sci., 14, Renkin, E. M., and Rosell, S. (1962). The influence of sympathetic adrenergic vasoconstrictor nerves on transport of diffusible solutes from blood to tissues in skeletal muscle. Aeta physiol. scand., 54, Roddie, I. C., and Shepherd, J. T. (1956). The reflex nervous control of human skeletal muscle blood vessels. Cliu. Sci., 15,