(Bayliss, 1902; Folkow, 1949). The reaction, according to its strength and the

Transcription

1 614 J. Physiol. (1959), 149, pp ) With 4 text-figure8 Printed in Great Britain THE INCREASE IN TONE IN FOREARM RESISTANCE BLOOD VESSELS EXPOSED TO INCREASED TRANSMURAL PRESSURE BY D. A. BLAIR, W. E. GLOVER, A. D. M. GREENFIELD AND I. C. RODDIE From the Department of Physiology, The Queen's University of Belfast (Received 31 July 1959) The response of resistance blood vessels to an increase in the distending or transmural pressure remains a controversial matter. There are two views. The first is that the walls of the vessels behave passively, the vessels becoming distended and the resistance to the flow of blood through them reduced. The second view is that the muscle in the walls of the vessels reacts actively (Bayliss, 192; Folkow, 1949). The reaction, according to its strength and the pressure to which it is opposed, may limit distension, enable the vessel to maintain its calibre unchanged, or even cause the vessel to narrow. An active response implies the existence of a pressure detector or baroreceptor. This detector would presumably be sensitive to stretch. The detector could be sited in the wall of the resistance vessels. If it were sensitive to circumferential stretching of the vessel wall, the response would presumably tend to restore the calibre of the vessel, but would not cause the vessel to narrow. If the detector were sensitive to longitudinal stretching of the vessel wall, the response might sometimes lead to a narrowing of the lumen of the vessel. The nature of the detector has not been determined; it has been assumed to be in the muscle cells of the vessel wall, and the mechanism has been called myogenic (Bayliss, 192). Alternatively, the detector may not be in the wall of the responding resistance vessel, but in a nearby vessel. Such separation demands a nervous or humoral connexion. The veni-vasomotor reflex (Gaskell & Burton, 1953) by which a rise in pressure in the veins or venules is claimed to cause constriction of the resistance vessels would be an example of this mechanism. Since an active response may fail to prevent some distension, it cannot be excluded without the use of poisons to provide a perfectly inert vessel for comparison. On the other hand, a narrowing of resistance vessels, or an increase in the resistance to the flow of blood through them, is a clear indication of an active response.

2 VASCULAR REACTIONS TO TRANSMURAL PRESSURE 615 Some previous work has indicated that, in animals, an increase in transmural pressure causes distension and a decrease of resistance. This was seen in the limb of the dog when the arterial pressure alone was varied (Green, Lewis Nickerson & Heller, 1944; Levy, 1958) and in the dog's limb and rabbit's ear when the arterial and venous pressures were simultaneously raised by equal increments (Phillips, Brind & Levy, 1955; Levy, 1956; Burton & Rosenburg, 1956). Others have reported an increase in resistance. Haddy & Gilbert (1956) found that in the dog's paw, perfused by pump at a constant rate, venous congestion raised the pressure in all the vessels, and increased the resistance between the small arteries and small veins. Haddy (1956) found the resistance of the innervated kidney to be raised when pressures were raised by venous congestion, but to be unaltered when the arterial pressure was progressively increased. In the human subject various responses have been reported. Observations by venous occlusion plethysmography immediately after a period of raised transmural pressure indicate an increased resistance to flow, suggesting the persistence of an increased activity of the muscular elements in the walls of the resistance vessels. Such a reaction was seen in the forearm after venous congestion (Patterson & Shepherd, 1954), and in the forearm and calf after local exposure to subatmospheric pressures (Greenfield & Patterson, 1954 a; Coles, Kidd & Patterson, 1956). Similarly, if during arrest of the circulation to a limb the intravascular pressure is maintained at a higher value than normal, on release of the circulation the reactive hyperaemia is smaller than normal (Wood, Litter & Wilkins, 1955; Patterson, 1956). All this evidence may be held to support an active response of the resistance vessels to increases in transmural pressure. Since Patterson & Shepherd (1954) found that the sympathectomized and chronically denervated forearm behaves like the innervated forearm, the response is independent of those nervous pathways which degenerate after sympathectomy or major nerve lesions. How successfully the response opposes the increase in transmural pressure probably depends on the conditions of observation. A modest degree of venous congestion, of about 15 mm Hg, sufficient to impound about 1-2 % of blood in the forearm or calf, causes no change in blood flow, and therefore a small reduction in resistance to flow; and by inference a slight dilatation of the resistance blood vessels (Greenfield & Patterson, 1954 b; Coles & Kidd, 1957). With greater degrees of initial venous filling the method of venous occlusion plethysmography is of uncertain reliability; some experiments have indicated a reduction (Edholm, Moreira & Werner, 1954) and some an increase (Gaskell & Burton, 1953; Yamada & Burton, 1954; Beaconsfield & Ginsburg, 1955; Formel & Doyle, 1957) in resistance; transmural pressure was increased

3 616 D. A. BLAIR AND OTHERS by venous congestion, appropriate change of posture or local subatmospheric pressures. Calorimetric observations indicate that, in the digits, venous congestion either reduces resistance (Roddie & Shepherd, 1957) or leaves it almost unchanged (Shanks, 1955; England & Johnston, 1956). Lowering the limb to the passive dependent position, thereby increasing the arterial and venous pressures about equally, diminishes resistance in the digits (R. A. Roddie, 1955; England & Johnston, 1956), but greater increases in transmural pressure. brought about by local exposure to pressures 5-15 mm Hg below atmospheric, increase the resistance in the hand and toes (Coles & Greenfield, 1956: Coles, 1957). The calorimetric method provides information about the skin of the extremities. The modest increase in venous oxygen saturation in a limb lowered to the passively dependent position (Wilkins, Halperin & Litter, 195: Rosensweig, 1955) indicates a generally reduced resistance, and therefore a dilatation of the resistance vessels. To summarize, there is evidence for an active response of the human resistance vessels to an increase in transmural pressure. With a modest rise in pressure, particularly at the venous end of the circulation, the response if present fails to prevent passive dilatation of the resistance vessels. With a greater rise in pressure, the response may increase the resistance to blood flow through the skin of the digits. The present paper presents observations on the response of the resistance vessels of the muscles of the human forearm during exposure to increased transmural pressure, about which there is at present little satisfactory information. Some of the experiments have already been briefly described (Blair & Roddie, 1958). METHODS The subjects were ten healthy young adults wearing normal indoor clothing, and the experiments were carried out in a laboratory maintained at a temperature of C. This temperature was chosen to ensure that the oxygen saturation of the skin venous blood would be relatively low, but the subjects were not uncomfortably cold and did not shiver. Throughout each experiment the subject lay on a couch. Two nylon catheters, 9 mm in external diameter, were inserted into the veins at the antecubital fossas of one arm through thin-walled needles, which were then withdrawn. One catheter was inserted into a superficial vein, the other into a deep vein (Roddie, Shepherd & Whelan, 1956). Usually they were inserted for about 5 cm, but sometimes for a smaller distance if their passage was obstructed by valves. Their positions were determined by palpation. This arm was then inserted through a closely, but not tightly, fitting rubber sleeve into a tank (Greenfield & Patterson, 1956), the catheters passing under the sleeve and their free ends remaining outside. Care was taken to have the point of entry of the catheters into the arm inside the tank, and clear of the sleeve. In an early experiment in which the point of entry was under the cuff, a considerable volume of air was drawn into the tissues of the arm. In this case, through leakage between the sleeve and the arm, the pressure at the point of entry was evidently greater than that in the tank. When the pressure in the tank was first reduced, care was always taken to prevent air being drawn down the catheters into the veins. There was, in fact, little tendency for this to

4 VASCULAR REACTIONS TO TRANSMURAL PRESSURE 617 happen, and within a few seconds the flow in the catheter was outwards rather than inwards while the syringes were being changed. The temperature of a thermo-electric junction in contact with the skin of the forearm was measured every few minutes. The pressure in the tank could be lowered by a motor-driven pump, controlled by a variable leak, and measured by a mercury manometer. The subject rested for half an hour before any samples were withdrawn. The circulation was then arrested at the wrist by inflating a pneumatic cuff to a pressure of 22 mm Hg. Blood samples of 1 ml. were withdrawn slowly over 2-4 sec and the percentage saturation with oxygen was determined immediately by a rapid spectrophotometric method (Roddie, Shepherd & Whelan, 1957). After three or four resting samples had been found to be in good agreement the pressure in the box was lowered within 5-1 sec to 5 mm Hg below atmospheric. Further samples were withdrawn at short intervals and the suction was continued until the oxygen saturation reached a steady level, usually after 5-1 min. The pressure in the box was then returned to atmospheric, and further samples were taken until the oxygen saturation had returned to the previous resting level. In one similar experiment three superficial veins were catheterized and blood samples were withdrawn as nearly simultaneously as possible. RESULTS The typical changes in the oxygen saturation of blood samples from a deep forearm vein during exposure to subatmospheric pressure are shown in Fig. 1. When the pressure was reduced to 5 mm Hg below atmospheric the oxygen 8 a, 6 x c4 Minutes Fig. 1. The effect of increased transmural pressure on the oxygen saturation of blood samples obtained from a deep forearm vein. The forearm was exposed to a pressure 5 mm Hg below atmospheric for the period shown. saturation was at first increased. During the next 5 min it gradually fell to slightly below the resting level. This new level was then maintained until the end of the exposure. On returning the forearm to atmospheric pressure there was a further sharp fall in oxygen saturation and then a quick return to the resting level.

5 618 D. A. BLAIR AND OTHERS In eighteen experiments on nine subjects, the changes in oxygen saturation were followed in superficial and or deep venous blood, and the results are summarized in Table 1. In the deep forearm veins the changes in oxygen saturation followed a consistent pattern. There was an initial transient increase. This was followed by a slower fall towards, or in some experiments below, the resting level. In the superficial forearm veins the changes were less consistent, but in general they were of the type regularly seen in the deep veins. TABLE 1. The effect of exposure of the forearm to 5 mm Hg subatmospheric pressure on the oxygen saturation of blood sampled from deep and superficial forearm veins Deep vein Superficial vein Before During After Before During After Resting Initial Final Initial Resting Resting Initial Final Initial Resting level sample level sample level level sample sample sample level H H.McK W.E.G W*E.G. * jl D.A.B I C R I I.C.R. l A.D.M. G. f ~~~~ J.B E.W. C S.D.C S.D.C. l I B.G Average It is likely that the blood samples from superficial and deep forearm veins represented blood draining from skin and muscle, respectively. This was tested in five experiments, and the results of one of these are shown in Fig. 2. Initially the environmental temperature was relatively low and the oxygen saturation of the superficial blood was similar to that of the deep. When the subject was warmed with hot water bottles, blankets and radiant heat, there was a rise in the oxygen saturation of the superficial but not of the deep blood. As it has been shown that body heating increases the blood flow through the skin but not the muscle of the forearm (Barcroft, Bock, Hensel & Kitchin, 1955; Edholm, Fox & Macpherson, 1956; Roddie et al. 1956) the result indicated that the blood withdrawn from the deep vein did not include any appreciable amount of blood returning from skin. It has also been shown that, when a subject's legs are passively raised, there is a reflex increase in the blood flow

6 VASCULAR REACTIONS TO TRANSMURAL PRESSURE 619 through the muscles, but not the skin, of the forearm (Roddie & Shepherd, 1956). In the present experiment, when the subject's legs were raised the oxygen saturation of the deep blood increased, whereas that of the superficial was not affected. This showed that the sample from the superficial vein did not contain any appreciable amount of blood returning from muscle Ao 2 o 12 C~~~~~~~~~iue 1 2 Minutes Fig. 2. Oxygen saturation of blood samples obtained from a superficial () and a deep () forearm vein, in the left panel before, and in the right panel after general body heating. During the time represented by the black rectangle the subject's legs were passively raiwd, and during the period between the vertical lines in the right-hand panel the part was exposed to a pressure 5 mm Hg below atmospheric. It was, therefore, clear that in this case under resting conditions the samples of blood withdrawn from the superficial and deep forearm veins were derived from skin and muscle, respectively. It was, nevertheless, possible that during exposure to subatmospheric pressure the changed pressure relationships in the veins might cause some of the venous blood from the skin to enter the veins normally draining muscle, as has been shown to happen during venous congestion (Roddie et at. 1956; Coles, Cooper, Mottram & Occleshaw, 1958). Alternatively, muscle blood might enter the veins normally draining the skin. In this experiment the rise in oxygen saturation of the deep blood during exposure to -5 mm Hg might, therefore, be accounted for by diversion of blood from skin veins with a relatively high resting oxygen saturation to muscle veins where the resting saturation is lower. In the experiment illustrated by Fig. 3, panel A, however, the oxygenl saturation of the blood from the deep vein rose to a much higher level than 4 PHYSIO. CXLIX

7 62 D. A. BLAIR AND OTHERS that of the blood from a superficial vein. It seems unlikely that other superficial veins contained blood appreciably more highly oxygenated than the one that was sampled, for in panel B is shown another experiment in which the oxygen saturation in three different superficial veins of an arm was similar before, during and after exposure to subatmospheric pressure. Wemay conclude that, in the experiment in panel A, the rise in oxygen saturation in the deep venous blood was certainly not due to contamination with blood from the superficial vein sampled, and most probably not due to contamination with blood from any other superficial vein. AB 8 8 ~6 6 GA.~' Minutes Fig. 3. Results of experiments on a cool (panel A) and on a warm (panel B) subject. Oxygen saturation of blood samples from deep () and superficial (O [] A) veins. During the periods -4 and -3 min the part was exposed to a pressure 5 mm Hg below atmospheric. There remains the possibility that highly oxygenated blood from deep veins might enter the superficial veins during exposure to subatmospheric pressure, and be responsible for the raised oxygenation of superficial samples. There are two reasons for rejecting this explanation as the sole cause of the observed rise. First, in the experiment of Fig. 3 panel B it would be necessary to assume substantial and almost equal contamination with very highly saturated blood in each of three superficial veins. Secondly, in this same experiment, which was done with the subject much warmer than in the main series of experiments, the oxygen saturation in each of the superficial veins reached a higher level than was ever observed in the deep veins of either cold (Table 1) or warm (Fig. 2) subjects; it is doubtful if the oxygen saturation in the deep veins is ever high enough to account for the result even if liberal mixing occurs.

8 VASCULAR REACTIONS TO TRANSMURAL PRESSURE 621 We therefore conclude that intermixing cannot account for the observed changes in oxygen saturation either in the superficial or the deep veins, and that there are similar and independent changes in the oxygenation of blood draining the skin and muscle of the forearm. On the assumption that exposure to subatmospheric pressure did not alter the metabolic requirements of the tissues of the forearm, the changes in oxygen saturation represented changes in skin and muscle blood flow. It is also clear from Figs. 1-4 that changes in blood flow are reflected by changes in oxygen saturation with very little delay, certainly not more than a fraction of a minute. The mechanism of these changes was next considered x A B 3 3 Minutes Fig. 4. Oxygen saturation of blood samples obtained from a deep forearm vein. During the period A the forearm was exposed to a pressure 5 mm Hg below atmospheric, and during B the subject tensed the forearm muscles voluntarily. When subatmospheric pressure was applied to an arm, the arm tended to be drawn into the box. Though a support was provided to prevent movement of the arm it was thought that the subject might involuntarily tense his forearm muscles, and that this muscular activity might, in part, explain the change in oxygen saturation when subatmospheric pressure was applied. However, no increase in electrical activity was detected in either the flexor or extensor groups of muscles of the forearm during exposure to subatmospheric pressure, although the recording system was sensitive to slight voluntary contraction. As a further check the experiment illustrated in Fig. 4 was carried out. Blood was sampled from a deep forearm vein, and exposure to subatmospheric pressure produced the usual response. The subject was then asked to tense his forearm muscles for a similar length of time. The change in oxygen saturation during this mild muscular activity did not resemble the change seen during suction. 4-2

9 622 D. A. BLAIR AND OTHERS It was concluded that the changes in the oxygen saturation of the muscle blood during exposure to subatmospheric pressure could not be explained by altered activity of the muscle fibres. Assuming that the changes in oxygen saturation in muscle and skin indicated changes in blood flow through these tissues, the next problem was to decide whether these changes were due to alterations in the calibre of the blood vessels, or due to changes in the perfusion pressure. Venous pressure in a deep vein was measured during exposure of the forearm to -5 mm Hg subatmospheric pressure (Fig. 5); the pressure was referred to atmospheric pressure. At first there was a rapid fall in venous pressure, but this returned to normal within 1 min. When the tank pressure was returned to atmospheric, X + 2 I E +1 E cv Seconds Fig. 5. Pressure relative to atmospheric pressure recorded from a needle in an antecubital vein. During the period represented by the rectangle the forearm was exposed to a pressure 5 mm Hg below atmospheric. the venous pressure increased only slightly, and for only a few seconds. Since under these conditions arterial pressure remains constant (Patterson, 1956). the initial fall in venous pressure would increase the perfusion pressure and would, while it lasted, contribute to the increase in the blood flow. However, the increase in blood flow during exposure to subatmospheric pressure usually persisted for about 5 min. The idcrease, therefore, could not wholly be attributed to an increase in perfusion pressure, but must have been due mainly to a fall in resistance to blood flow, presumably due to a widening of the resistance vessels. Similarly, the small transient decrease in perfusion pressure at the end of the exposure could not explain the more prolonged reduction in flow which occurred at this time, and was presumably due to an active narrowing of the resistance vessels. DISCUSSION When a distending force was applied to the blood vessels of the forearm, there was an immediate increase in the oxygen saturation of the venous blood, and by inference the blood flow through both skin and muscle. This increase could not be explained by an increase in the perfusion pressure, and must, therefore,

10 VASCULAR REACTIONS TO TRANSMURAL PRESSURE 623 have been mainly due to dilatation of resistance blood vessels. This would be the expected result for distensible vessels exposed to an increase in transmural pressure. However, the dilatation was only transient, for within several minutes the oxygen saturation of the venous blood returned to about the resting level. Measurements of intramuscular tissue pressure during exposure of the forearm or calf to subatmospheric pressure indicate that accumulation of oedema fluid only slightly diminishes the effect of the subatmospheric pressure at the wall of the blood vessel (Coles, 1956). Since the vessels were not compressed by oedema fluid the fall in venous oxygen saturation indicated an active constriction of their walls. Folkow (1949) has shown in animal experiments that the increase in tone in response to a distending force persists after sympathectomy and chronic denervation, and Patterson & Shepherd (1954) have shown that the vasoconstriction in the forearm which follows venous congestion persists after sympathectomy and chronic denervation. These workers suggested that the increase in tone represented a direct response of smooth muscle in the resistance vessel wall to the increased distending force. The present results are, on the whole, in keeping with this hypothesis. In these experiments there was an increase in transmural pressure in all the vessels while the arm was exposed to subatmospheric pressure. There is therefore no indication as to the site of the receptors responsible for the reactions in the resistance vessels. In some experiments there was an indication that the resistance vessels were narrowed while the transmural pressure was increased. There is some doubt as to whether this was really so, because the method is not sufficiently accurate to permit fine analysis, but if this effect is genuine it would indicate that the effective stimulus was some deformation of the resistance vessels other than circumferential stretch, or that it was a deformation in some other type of vessel. When the transmural pressure was returned to normal, the increase in tone in the resistance vessels persisted for a short time, causing an initial narrowing before the vessels reverted to their normal calibre. This is in keeping with the findings of Greenfield & Patterson (1954a), who measured the blood flow in the forearm immediately after it had been exposed to subatmnospheric pressure and found a similar transient narrowing. A similar result has also been reported for the human calf by Coles, Kidd & Moffat (1957). It is clear that the response is a slow one, for there is a considerable delay after the stimulus is either applied or removed before the subsequent vascular readjustments are completed. The time required would appear to be considerably longer than that of other vascular reflexes involving the sympathetic nervous system. This in itself supports the theory that it is an intrinsic response of the smooth muscle in the wall of the vessels concerned.

11 624 D. A. BLAIR AND OTHERS SUMMARY 1. The transmural pressure of all the blood vessels in the forearm has been increased by local exposure of the part to a pressure 5 mm Hg below atmospheric. The behaviour of the resistance blood vessels of the skin and the muscle has been inferred from measurements of the oxygen saturation of venous blood. 2. At the onset the resistance vessels of both skin and muscle are widened. They then, over the next few minutes, contract; the final diameter is sometimes less than the initial. 3. This contraction is evidently an active response. 4. On removing the extra distending pressure there is a further narrowing; the diameter at this time is probably always less than it was before exposure. This narrowing is probably due to the removal of opposition to the enhanced contractile force of the muscle in the vessel walls. 5. The present observations indicate that the resistance blood vessels of both the skin and muscle of the forearm more or less successfully oppose a distending force by an active response in the walls. REFERENCES BARCROFT, H., BOCK, K. D., HENSEL, H. & KITCHN, A. H. (1955). Die Muskeldurchblutung des Menschen bei indirekter Erwarmung und Abkuhlung. P:ifg. Arch. ges. Phy8iol. 261, BAYLISS, W. M. (192). On the local reactions of the arterial wall to changes of internal pressure. J. Phy8iol. 28, BEACONSFIELD, P. & GINSBURG, J. (1955). Effect of changes in limb posture on peripheral blood flow. Circulation Res. 3, BLAR, D. A. & RODDIE, I. C. (1958). The changes in tone in forearm resistance blood vessels during local exposure to subatmospheric pressures. J. Physiol. 143, 67-68P. BURTON, A. C. & ROSENBURG, E. (1956). Effects of raised venous pressure in the circulation of the isolated perfused rabbit ear. Amer. J. Physiol. 185, COLES, D. R. (1956). Observations on the Respon8es of Human Blood Vessels to Local Alterations in Transmural Pressure. M.D. Thesis, University of Bristol, pp COLES, D. R. (1957). Heat elimination from the toes during exposure of the foot to subatmospheric pressures. J. Physiol. 135, COLES, D. R., COOPER, K. E., MOTTRAM, R. F. & OcCLEsHAw, J. V. (1958). The source of blood samples withdrawn from deep forearm veins via catheters passed upstream from the median cubital vein. J. Physiol. 142, COLES, D. R. & GREENFIELD, A. D. M. (1956). The reactions of the blood vessels of the hand during increases in transmural pressure. J. Physiol. 131, COLES, D. R. & KIDD, B. S. L. (1957). Effect of small degrees of venous distension on the apparent inflow rate of blood to the human calf. Circulation Res. 5, COLES, D. R., KIDD, B. S. L. & MOFFAT, W. (1957). Distensibility of blood vessels of the human calf determined by local application of subatmospheric pressures. J. appl. Physiol. 1, COLES, D. R., KIDD, B. S. L. & PATTERSON, G. C. (1956). The reactions of the blood vessels of the human calf to increases in transmural pressure. J. Physiol. 134, EDHOLM,. G., Fox, R. H. & MACPHERSON, R. K. (1956). The effect of body heating on the circulation in skin and muscle. J. Physiol. 134, EDHOLM,. G., MOREIRA, M. F. & WERNER, A. Y. (1954). The measurement of forearm blood flow during a raised venous pressure. J. Physiol. 125, 41-42P.

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