VASCULAR RESPONSES TO INTRAVENOUS CATECHOLAMINES IN HANDS AND FOREARMS WITH NORMAL AND WITH INCREASED SKIN BLOOD

FLOW

J. A. Allen, Y. Kawai* and I. C. Roddle

The Department of Physiology, The Queen's University of Belfast.

Summary I~LOOD flow responses to intravenous I .# adrenaline and noradrenaline infus- ions were compared in hands and forearms with normal resting blood flow ( plethysmograph temperature. 35 ~ C) and in hands and forearms where skin blood f low had been raised by local heating (42~ body heating or local application of rubefacient. The vasodilator response to adrenaline (10 #g.min -1) seen in fore.- arms with normal resting blood flow was not significantly affected by raising skin blood flow 2-3 fold by any of the three methods. In the hands, intravenous adrenaline caused pronounced vasocon- striction in both the control hands and in those, with augmented skin circulation, and there was little difference between the magnitude of the vasoconstrictor responses in the. normal and vasodilated hands. There was little, difference bet- ween the vasoconstrictor responses to intravenous noradrenaline (5 #g.min -1) in hands and forearms with control blood flow levels and in those with skin blood flow raised by any of the three methods. So the results show that the skin vessels dilated by local heat, body heating and application of rubefacient are little affec- ted by circulating o~ receptor agonists and that adrenaline will still produce a net vasodilator response, in the forearm at high levels of skin blood flow.

Introduction Intravenous infusion of adrenaline in

man causes a marked but transient vaso-

* Present address : Department of Physiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumo~o 39'0, Japan.

dilation in the forearm followed by a more moderate but sustained increase in f low (Allen, Barcroft and Edholm, 1946). This is thought to be the net result of vasoconstriction in skin and vasodilation in muscle (Skinner and Whelan, 1962). Normally, forearm skin blood flow is quite low, about 1 -2 ml.100 ml-l.min -1 (Cooper, Edholm and Mottram, 1955; Detry, Brengelmann, Rowell and Wyss, 1972). Cutaneous vasoconstriction could therefore contribute relatively little to the total forearm response to intravenous adrenaline, at normal resting levels and might be, masked by the relatively large vasodilation in muscle.

It seemed possible, however, that if skin blood flow in the forearm was in- creased, vasoconstriction in the augmen- ted skin circulation might be. great enough to mask the muscle, vasodilation and the net response of forearm blood flow to intravenous adrenaline would be converted from vasodilation to vaso- constriction.

Accordingly, in the present experi- ments, the. responses of forearm blood flow to intravenous infusions of adren- aline and noradrenaline, have been compared at normal and at high levels of skin blood flow. Three methods were used to increase, skin blood flow in the forearm - - applying local heat to the forearm (Barcroft and Edholm, 1943), indirect body heating (Gibbon and Landis, 1932), and application of a rubefacient cream (Crockford, Hellon and Heyman, 1962). For purposes of comparison, similar experiments were carried out on the hand.

178

Volume 154 Vascular blood flow responses 179 Number 5

Methods All experiments were carried out on

four healthy male subjects aged 20-25 years who gave their informeU consent. The subjects lay supine on a couch in a laboratory maintained at 23-24~ Fore- arm or hand blood flow was measured by venous occlusion plethysmography using water - filled plethysmographs (Greenfield, 1954). Instantaneous heart rate was recorded using a Devices rate- meter (Type 2750) triggered by the QRS complex of the electrocardiogram. Core temperature was monitored continuously by a zero-gradient aural thermometer (Addison Process Control Limited (Type 8151.1)) as originally described by Keatinge and Sloan, 1973. Adrenaline (adrenaline tartrate, Evans Medical Limited) and noradrenaline (Levophed, Bayer Products) were diluted in a mix- ture of 0.9% (w/v) saline and 0.003% (w/v) ascorbic acid and infused intra- venously through a catheter in an ante- cubital vein at a rate of 1 ml.min-L During control and recovery periods, the saline-ascorbic acid mixture, alone was infused at the same rate.

Protocol for the local heating experiments

There were two experiments on each of the four subjects; on one occasion his forearm blood flow was measured and on the other his hand flow. The protocol was identical for all experiments. There were six periods of drug infusion each with a 3 min control period, a 5 min period of drug infusion and a 5 min recovery period with continuous meas- urement of blood flow and heart rate throughout.

During the first three runs, both hands or forearms were. in plethysmographs at 35~ so that the. responses of the two sides were measured under identical conditions. There was no significant difference between the responses on the two sides. The temperature, of the water in one plethysmograph was then raised

to 42~ and 20 min later the three runs were repeated. The order of drug infus- ion was as follows :

Run 1 Adrenaline 5/~g.min -1 2 Adrenaline 10/~g.min -1 3 Ncradrenaline 5/~g.min -1

Temperature. of one side raised to 42~

4 Adrenaline 5/~g.min -1 5 Adrenaline 10/~g.min -1 6 Noradrenaline 5/~g.min -~

Protocol for body heating experiments Forearm blood flow in a plethysmo-

graph at 35~ was measured in the same four subjects and core temperature was monitored continuously. Runs 1-3 were carried out as previously with the subject under normal laboratory conditions. Indirect body heating was then applied by immersing the subject's feet and legs up to the knees in a stirred water bath at 44~ and wrapping him in blankets (Gibbon and Landis, 1932). 30 min later the three drug infusions were repeated, the plethysmograph still being main- tained at 35~

Protocol for local rubefacient experiments

There were two experiments on each of three of the. same four subjects. On one occasion forearm blood flow was measured and on the other hand blood flow. The water in the plethysmograph was kept at 35~ throughout. Runs 2 and 3 were carried out as before. Then one forearm or hand was removed from its plethysmograph and Trafuril cream (5% tetra-hydro-furfuryl nicotinic acid ester, Ciba Laboratories Limited) was applied rapidly to the area of skin which had been enclosed in the plethysmo- graph. The forearm or hand was re- inserted into the. plethysmograph and when blood flow was seen to be elevated and fairly constant (20 min later in the forearm and between 20 and 30 min

180 Allen et at. I .J.M.S. May, 1985

later in the hand), runs 5 and 6 were carried out.

The significance of the responses and the differe.nces between responses was determined by analysis of variance, and paired t tests.

Results Skin vasodilation by local heating

Fig. 1 shows a comparison of the responses, in unheated (35~ and locally heated (42~ forearms to intra- venous infusions of adrenaline (10 #g. men-') and noradrenaline (5 /~g.min-1). The results are the means -+ 1 SEM for the four subjects.

A 8

o 6 ; ; ;, ; ;2 MINS

Fig. 1 - - T h e effects of intravenous infusion of adrenaline (A) and no radrenal ine (B) on blood flow in a forearm at 35~ (O) and 42~ ( l ) . Heart rate is also shown ( [~ ) . The results are

the mean + 1 SEM for 4 subjects.

In the adrenaline experiments (Fig. 1A), drug infusion caused forearm vase- dilation and a tachycardia. Blood flow in the control forearm (35~ was 5.8 -+ 1.6 ml.100 mI-Lmin -~ before the infusion. During infusion it rose rapidly to a peak (13.5 -+ 3.5) and then declined to a plateau value (8.5+_1.5 ml.100 ml-l.min -1) during the last 2 men of the infusion. When the infusion stopped, flow fell again to the resting level within about 1.5 men. In the locally heated forearm the vasodilator response, to adrenaline infusion was similar to that in the un- heated forearm but from a higher resting

level. The mean resting flow rate in the heated forearm was almost three times greater than that in the unheated side. During adrenaline infusion, flow in- creased from a resting level of 13.7+2.3 to a peak of 19.5-+1.8 and then plateaued at a value of 16.2_+1.5 ml.100 ml-l.min -1 during the last 2 men of the infusion. The increase in flow in the plateau phase of the. adrenaline response in the heated forearm was not significantly different from that in the unheated arm but the increase in flow at the peak in the heated arm was significantly smaller (p<0.01) than in the unheated arm. Qualitatively similar responses were obtained in the experiments where lower doses of adren- aline (5/~g.min-') were used.

Intravenous infusion of noradrenaline (Fig. 1B) caused bradycardia and a decrease in flow in the forearm. The responses of the. heated and unheated forearms to intravenous noradrenaline (5 /~g.min -1) were quite similar. In the unheated forearm, flow fell from a resting level of 5.7-+1.6 to 4.9+_1.6 ml.100 m1-1. men -1 in the last 2 men of noradrenaline infusion. In the heated forearm the, fall was slightly greater, from 13.0-+1.8 to 11.0-+1.9 ml.100 mI-Lmin -~ in the last 2 men of the infusion. Though this fall was significant (P<0.01) there was no sig- nificant difference between the vasocon- strictor responses to noradrenaline in the heated and unheated forearms in the last 2 men of noradrenaline infusion.

These experiments showed that raising skin blood flow in the. forearm by the application of local heat had little effect on vasodilator and vasoconstrictor re- sponses in the forearm to adrenaline and noradrenaline respectively.

Fig. 2 shows a comparison of the responses of unheated (35~ and heated (42 ~ ) hands to intravenous infus- ions of adrenaline (10 /~g.min -~) and noradrenaline (5/~g.min-'). Each obser- vation is the mean + 1 SEM for the. four subjects. Though hand blood flow was

Votume 154 Vascular bloo(~ flow responses 181 Number 5

SO

A

, I ; ,~, MIX$

~ 42"C

Fig. 2 - - T h e effects of intravenous infusion of adrena l ine (A) and noradrena l ine (B) on blood, f low in, a hand, at 3 5 ~ (O') and 4 2 ~ (O). Heart rate is also shown (1"-]). The results are

the mean + 1 SEM for 4 subjects.

more variable than forearm blood flow, both adrenaline, and noradrenaline in- fusions caused pronounced falls in blood flow in both the unheated and heated hands. Adrenaline (Fig. 2A) reduced blood flow in the unheated hand from about 22 in the pre-infusion period to about 9 ml.100 mI-Lmin -~ in the last 2 min of the infusion, a reduction in absolute terms of about 13 ml.100 mI-Lmin -~ and in percentage, terms of about 59%. In the heated hand, the reduction was from about 31 to about 14 ml.100 mI-Lmin -], a fall in absolute terms of about 17 ml. 100 mi-Lmin -~ and in percentage terms of about 55%.

Noradrenaline (Fig. 2B) reduced blood flow in the unheated hand from about 25 ml in the pre-infusion period to about 16 ml.100 mI-Lmin -~ in the last 2 min of the infusion, a fall in absolute terms of about 9 ml.100 ml-l.min -] and in percentage terms of about 36%. In the heated hand the corresponding reduction was from about 35 to about 22 ml.100 mI-Lmin -], a fall in absolute terms of 13 ml.100 mI-L min -~ and in percentage terms of about 37%.

These results show that both adrenal- ine and noradrenaline infusions cause marked vasoconstriction in both heated and unheated hands.

Skin vasodifation by body heatir~g Fig. 3 compares the effect of intra-

venous adrenaline infusion 10 (/~g.min -1) on forearm blood flow before and during body heating. Each observation is the mean _+ SEM of the 4 measurements on each of the 4 subjects. Before body heating (Fig. 3A) intravenous adrenaline

A

IS

,,_o%,~.~ ,o

0 , , , 0 6 9 12 0 6 9 12

Fig. 3 - - T h e effects of intravenous infusion of adrena l ine on b lood ~ f low in a forearm at 35~ (O) before (A) and during (B) body heating. Heart rate (I--1) and~ core temperature (A) are also shown. The results are the mean + 1 SEM' for

4 subjects.

produced its characteristic vasodilator response, an initial, peak followed by a smaller but more. sustained vasodilation. After 45 min of body heating (Fig. 3B) resting forearm blood flow had risen from about 5 to about 12.5 ml.100 m1-1. min -~ and core temperature had risen from 36.6 +- 0.06 to 37.3 +- 0.04~ Under these conditions, adrenaline infusion still caused a significant increase (P<0.01) in forearm blood flow though it was not as great in either absolute or percentage terms as that in the unheated subjects. However, there was no significant differ- ence between the magnitude of the peak or plateau vasodtlations in the heated and unheated subjects.

Fig. 4 compares the responses to in- travenous noradrenaline in unheated and heated subjects. Before body heating (Fig. 4A), when mean core temperature

182 Al len et al. I . J . M . S . M a y , 1 9 8 5

A B

2

' I o ' I , , ,

Fig. 4--The effects of intravenous infusion, of nor- adrenaline on blood, flow in a forearm at 35~ (O) before (A) and during (B) body heating. Heart rate ( [~) and! core temperature (/k) are also shown. The results are the mean +_ 1 SEM for

4 subjects.

was 36.6 + 0.06~ noradrenaline (5/~g. min -J) caused a slight decrease in flow from 5.6_+0.5 to 5.2_+0.4 ml.100 ml-'.min-L Though this decrease was not significant, there was a significant ( P < 0 . 0 1 ) de- crease in heart rate from 64_+2 to 52_+4 beat.min-L

After 60 min of body heating (Fig. 4B) forearm blood flow had risen to about 16.5 ml.100 mI-Lmin -~ and core tempera- ture to 37.7-+0.09~ Under these con- ditions, noradrenaline infusion had no significant effect on flow though it still caused a significant decrease in heart rate (P<0.01).

Skin vasodilation by rubefacient Fig. 5 compares the responses in

control and rubefacient-treated forearms to intravenous adrenaline (10/~g.min -~) and noradrenaline (5/~g.min-1). Applica- tion of rubefacient to the skin of one forearm increased flow on that side to about three times that seen in the control forearm. When adrenaline was infused (Fig. 5A), a vasodilator response occur- red in both the control and treated fore~ arms and there was little difference between the responses on the two sides.

A

AOR ~ m - ' ~V

m ioo mP I t~l~-I

' ' ~ 1'2

B

kilNS

Fig. 5 - - T h e effects of intravenous infusion of adrenaline (A) and noradrenaline (B) on blood flow in a control forearm (O) and a forearm treated with Trafuril (e ) . Heart rate is also shown ( D ) " The results are the mean + 1 SEM for 3

subjects.

Intravenous noradrenaline (5 /~g.min-') caused a slight decrease in flow in both the control and treated forearms (Fig. 5B) but again there was little difference between the responses on the two sides.

Fig. 6 compares the responses of con- trol and rubefacient-treated hands to intravenous infusions of adrenaline (10 /.~g.min -1) and noradrenaline (5/~g.min-~).

A

,~,,~ f I~ ~, ,,

o ~6 i ; ; ,;

MIN$

B

I

Fig. 6 - - T h e effects of intravenous infusion of adrenaline (A) and noradrenaline (B) on blood flow in a control hand, (O) and a hand~ treated with Trafuril ( I ) . Heart rate is also shown ([--I). The results are the mean + 1 SEM for 3 subjects.

Adrenaline, infusion (Fig. 6A) caused pronounced vasoconstrictions in both the treated and untreated hands. In the untreated hand, blood flow fell from about 12 ml.100 ml-l.min -1 in the pre-

Vo'ume 154 Number 5

infusion period to about 4 ml.100 m1-1. min -1 in the last 2 min of the infusion, a reduction in absolute terms of about 8 ml and in percentage, terms of about 66%. In the hand treated with rubefac- lent, blood flow fell from about 19 ml in the, pre-infusion period to about 8 ml. 100 ml-l.min -1 in the last 2 min of the infusion. This was a reduction in absolute. terms of about 11 ml.100 mI-Lmin -1 and in percentage terms of about 58%. With noradrenaline infusion (Fig. 6B), blood flow fell in the control hand from about 11 ml in the pre-infusion period to about 6 ml in the last 2 min of the infusion, a fall in absolute terms of about 5 ml.100 ml-l.min -1, and in percentage terms of about 45%. The corresponding fall in the rubefacient-treated hands was from about 18 to about 15 ml.100 mI-Lmin-', a reduction in absolute terms of about 3 ml.100 mI-Lmin -~ and about 17 in per- centage terms. There were no significant differences between the vasoconstrictor responses of the control and rubefacient- treated hands to adrenaline or noradren- aline.

Discussion Cutaneous vasoconstrictor responses

are difficult to detect in the forearm by non-invasive methods since under normal conditions blood flow to muscle com- prises more than half of the total forearm flow. It seemed possible that increasing the skin component of total forearm flow by direct or indirect heating or by rube- facient might render cutaneous vasocon- strictor responses more obvious. In order to test this hypothesis, the present ex- periments were carried out to compare the effects of intravenous infusion of catecholamines on blood flow in normal forearms or hands with their effects when the skin blood flow had been increased by heat or rubefacient. Catecholamines are known to cause, vasoconstriction in cutaneous blood vessels in man (Skinner and Whelan, 1962).

The response of the forearm circula- tion to adrenaline is complicated because

Vascular blood flow responses 183

it affects the skin and muscle circulations differently. When adrenaline is adminis- tered subcutaneously or by iontophor- e sis, it causes blanching and suppres- sion of the skin circulation (Barcroft, Bonnar, Edholm and Effron, 1943; Cooper e t al, 1955; Detry et al, 1972). Skin so treated will not bleed when cut. This action is thought to be due. to an effect on c~ adrencceptors and has been ob- served in the skin vessels of all animals studied whether the adrenaline is admin- istered intravenously, intra-arterially or topically (Green and Kepchar, 1959).

In muscle, however, adrenaline causes vasodilation. It is thought that adrenal- ine has an action on both e and /~ adrenoceptors in' muscle vessels but that /~ activity predominates, e receptor blockade, potentiates the vasodilator response to adrenaline in forearm mus- cle (de la Lande and Whelan, 1959). Bock, Hensel and Ruef (1955) and Gol- enhofen (1962), using heated thermo- couple, devices mounted in needles implanted in forearm muscle, found that adrenaline, whether given intravenously or intra-arterially, caused a sustained vasodilation in muscle. Using changes in oxygen saturation of blood from deep and superficial veins in the forearm as indices of muscle and skin blood flow respectively, Skinner and Whelan (1962) found that skin blood flow fell whereas muscle blood flow rose with intra-arterial adrenaline in doses of 0.05-0.1 /~g.min -1. They concluded that changes in total blood flow in the muscular segments of the forearm must be the, resultant of the simultaneous changes in the skin and muscle circulations.

These facts led the authors to assume that the response of forearm blood flow to intravenous adrenaline would vary as the magnitude of the skin component of forearm blood flow varied, a decrease in the skin component making the muscle vasodilation more conspicuous and vice versa. Evidence that this is so has been found using intra-arterial infusions of

184 Allen et al.

adrenaline during body cooling and heating (Whelan and de la Lande, 1963). However, it was found in the present experiments that increasing the. level of skin blood flow by a variety of methods did not greatly change the response, of forearm blood flow to intravenous adren- aline or noradrenaline. In no instance was the vasodilator response to adren- aline made vasoconstrictor. In addition the, vasoconstrictor responses to norad- renaline infusion were not significantly greater in forearms with augmented skin circulation than in control forearms.

This would suggest that the vessels in the forearm skin dilated by local heating, indirect heating or application of rube- facient were little affected by circulating noradrenaline or adrenaline. It has been suggested that when the perfusate tem- perature, is raised to 42~ cutaneous vessels, become less responsive to sym- pathetic nerve stimulation and circulating catecholamines (Webb-Peploe and Shep- herd, 1968). This could not explain the present results since adrenaline and nor- adrenaline both caused pronounced vasoconstriction in blood vesels of hands heated to 42~ In addition, the response

I.J.M.S. May. 1985

to circulating adrenaline was vasodilator whether the skin blood flow was in- creased by local heating or by indirect heating when the forearm skin tempera- ture was maintained at 35~

Barcroft and Edholm (1943) found that raising the. plethysmograph tempera- ture to 42~ raised the deep temperature of the. forearm to about 39~ and it is likely that this temperature could cause some. dilation of muscle vessels. In experiments carried out in these labora- tories, changes in the oxygen saturation of the, effluent blood from deep and superficial forearm veins were used as an index of muscle and skin blood flow respectively, Raising theplethysmograph temperature to 42~ caused an increase in deep oxygen saturation (Table I) which would be, equivalent to about an 80% increase in muscle blood flow, a small fraction (20%) of the total increase in forearm blood flow with local heating.

It has been found that the forearm vasodilation in response, to adrenaline infusion is increased when muscle, blood flow is increased by sympathectomy (Whelan, 1952). Since local heating may have increased muscle blood flow in the

TABLE I

The % 0'5 saturation of deep venous blood from the forearms o,f 5 subjects. The temperature of the water in the plethysmograph was raised from 35~ to 42~ at t ime 0 min.

Plethysmograph 35~ Plethysmograph 42~ ' Subject

- -10min --5 min + 2 0 min + 3 0 min + 4 0 m i n

1 59.8 55.0 83.3 75.4 80.0

2 46.4 51.4 61.6 65.3 70.4

3 44.0 34.8 52.9 45.9 52.3

4 38.4 - - 57.8 64.4 69.8

5 35.6 35.4 56.9 56.5 65.8

Mean 44.8 44.1 62.5 61.5 67.7

S.E.M. 4.2 5.3 5.4 4.9 4.5

Volume 154 Number 5 Vascular blood flow responses 185

present experiments, consideration was given as to whether intravenous adrenal- ine might cause greater vasodilation in muscle during local heating and so mask an increased vasoconstrictor response in skin. However, an increase in muscle blood flow during local heating could not explain all the results. In the body heating experiments where muscle blood flow is not increased (Barcroft, Bock, Hensel and Kitchin, 1955; Edholm, Fox and Macpherson, 1956; Roddie, Shepherd and Macpherson, 1956; Roddie, Shepherd and Wherlan, 1956) the results were simi- la~ to the local heating experiments, i.e. there was little difference between the. effect of adrenaline in the heated and unheated subjects.

The. mean profile of the vasodilator response to adrenaline in the forearm of heated subjects was not identical to that in unheated subjects. This may be explained by the fact that the general circulatory state is different in the two conditions. During body heating, cardiac output rises by several litres per minute, peripheral blood flow is increased and the circulation time is shortened. Thus the injected dose of catecholamine is diluted in a greater volume flow and the drug concentration arriving at the. test forearm will be lower. In addition, the drug will arrive earlier because of the shorter circulation time. On the other hand, a greater proportion of the cardiac output is being channeled to the skin during body heating which would tend to increase the dose arriving at the skin vessels. These factors may explain the slight differences in the overall contours of the forearm vasodilations seen in the heated and unheated subjects.

The skin vasoconstriction in forearm and hand during adrenaline or norad- re naline infusion did not appear to be significantly greater at high than at low levels of skin blood flow. This is hard to explain. In the. forearm, injection or iontophoresis of adrenaline or noradren- aline into the skin produces marked

blanching. This indicates that ~ adreno- ceptors are present in the cutaneous blood vessels of the forearm although normally their response is masked by vasodilation in the muscle circulation. l"he absence of a demonstrable vasocon- strictor response, even when the skin blood vessels were dilated by local or body heating or by rubefacient may indicate that the vessels which had been dilated by these procedures were little affected by circulating adrenaline or noradrenaline. In the hand where skin blood flow normally predominates in the overall response, adrenaline and norad- renaline reduced blood flow by a similar amount in control and vasodilated hands. This again suggests an inability of the actively dilated blood vessels to respond fully to catecholamines. Perhaps the vessels dilated by local heat, body heat- ing and rubefacient creams have few o~ adrenoceptors.

Though the results are. surprising, they show clearly that raising the level of blood flow in the skin of either the fore- arm or hand has little effect on the vasodilator or vasoconstrictor responses to adrenaline or noradrenaline in these tissues.

We would like to thank Mr. Sean McGrann for his invaluable assistance with all aspects of the work.

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