(Received 24 August 1962)

Transcription

1 J. Phy8iol. (1963), 167, pp With 2 text-ftgures Printed in Great Britain TH MCHANISM OF TH RSPONS OF TH CHRONICALLY SYMPATHCTOMIZD FORARM TO INTRAVNOUS ADRNALIN BY W.. GLOVR AND R. G. SHANKS From the Department of Physiology, The Queen's University of Belfast (Received 24 August 1962) When adrenaline is administered intravenously in man there is an initial transient increase in forearm blood flow, followed by a smaller but sustained increase (Allen, Barcroft & dholm, 1946; Duff & Swan, 1951; Whelan, 1952). This response is still seen after the deep nerves to one forearm are blocked with local anaesthetic or within the first few days of a cervical sympathectomy, so the sustained increase is not mediated by sympathetic nerves (Whelan, 1952). However, this dilator effect becomes diminished and may disappear with the development of the chronic state after sympathectomy (Duff & Swan, 1951). Whelan (1952) has suggested that this latter phenomenon may be related to the gradual return of tone in the vessels of the upper limb, demonstrated by Barcroft & Walker (1949). Recent work has suggested that the action of adrenaline on smooth muscle in man can be explained by its effect on two types of receptors, a or excitatory, and,b or inhibitory (Ginsburg & Cobbold, 196; Glover, Shanks & Stanford, 1962). The present experiments provide evidence that the altered response to adrenaline following chronic sympathectomy is largely due to increased sensitivity of the oc (constrictor) receptors to this drug. MTHODS The experiments were carried out on three patients. M. R. female aged 52 yr; right cervical sympathectomy for Raynaud's disease 1 days before observations. D.L. male aged 54 yr; left cervical sympathectomy for Raynaud's disease 6 days before observations. M.M. female aged 21 yr; left cervical sympathectomy for M6niere's disease 1 yr before observations. In each case the operation consisted of removal of the inferior cervical and first two thoracic ganglia of the sympathetic trunk. The subject, wearing normal indoor clothing, lay on a couch in a laboratory maintained at a temperature of 2-22' C. Forearm blood flow was measured by venous occlusion plethysmography. A needle was inserted into the brachial artery of the sympathectomized

2 264 W.. GLOVR AND R. G. SHANKS Ad Ad I.v F iol S Ih Il 1-1.C - 2 * 15 1 _ - S _ o*%4 b 4n C C >_ -o 1- m 2 F- 15F- 1 F- 5 ' r linutes 3 35 Fig. 1. ffect of intravenous adrenaline (1 jag/min) on the blood flow to a chronically sympathectomized forearm in three subjects before and after the intra-arterial administration of dibenyline (-5 mg/min for 6 min). *-* sympathectomized forearm; - control forearm. Upper panel, subject D. L. Middle panel, subject M.R. Lower panel, subject M. M.

3 SYMPATHCTOMY AND INTRAVNOUS ADRNALIN 265 side, and a polyethylene catheter was inserted into an antecubital vein. Saline (NaCi.9 g/ 1 ml.) was infused continuously into both vessels at the rate of 4 ml./min. Adrenaline (1,ug/min) was added to the intravenous infusion and dibenyline (.5 mg/min for 6 min) to the intra-arterial infusion, so that the minute dose was contained in 4 ml. In two experiments isopropylnoradrenaline *5 Aug/min was given intra-arterially. Ascorbic acid (43 %) was added to the saline to delay the oxidation of adrenaline (Gaddum, Peart & Vogt, 1949). RSULTS Response to intravenous adrenaline In each experiment the response to adrenaline 1,g/min intravenously was recorded before and after the intra-arterial administration of 3 mg dibenyline to the sympathectomized forearm. The results of these experiments are shown in Fig. 1. In each case the blood flow to the sympathectomized forearm was initially higher than that to the normal forearm. The typical response to intravenous adrenaline was seen on the normal side. The sympathectomized side showed a large initial increase in flow. In two experiments the flow fell on this side to or below the resting level and did not subsequently rise above it. In the remaining experiment (bottom panel) there was a rise in flow, but this was small compared with the rise observed on the control side. The intra-arterial infusion of dibenyline did not change the blood flow, but greatly altered the pattern of response to intravenous adrenaline. In each case a sustained vasodilatation was seen on the sympathectomized side, which was qualitatively the same as but quantitatively larger than that observed on the control side. Response to intra-arterial isopropylnoradrenaline In two experiments in two subjects isopropylnoradrenaline was infused into the brachial artery of the sympathectomized forearm at the rate of -5 pug/min before and after the infusion of dibenyline. The results of one of these experiments is illustrated in Fig. 2. The response in both experiments consisted of a large transient vasodilatation followed by a smaller sustained vasodilatation, and was not affected by the infusion of dibenyline. DISCUSSION The present experiments show that the vessels of a sympathectomized forearm dilate normallyin response to intra-arterial isopropylnoradrenaline, which is believed to act by stimulating the fi receptors (Ginsburg & Cobbold, 196). After dibenyline, which blocks the a receptors, these vessels dilate in response to intravenous adrenaline, presumably also by,b receptor stimulation. It therefore appears that the,8 receptor response is normal, and the lack of a sustained vasodilatation in the chronically sympathectomized forearm results from an enhanced response to stimulation of

4 266 W.. GLOVR AND R. G. SHANKS the a receptors. Such an increase in the sensitivity of hand blood vessels to the constrictor action of adrenaline and noradrenaline after sympathectomy has been reported by Duff (1955) and by Parks, Skinner & Whelan (1961). 2 opn I.A. IPN IA. - 1 LL Minutes Fig. 2. ffect of intra-arterial isopropylnoradrenaline (.5 /ig/min) on the blood flow to a chronically sympathectomized forearm before and after the intra-arterial administration of dibenyline (.5 mg/min for 6 min). Subject, M.R. *- sympathectomized forearm; - control forearm. It is not possible to say whether these changes after sympathectomy are due to altered receptor sensitivity or to normal receptor sensitivity but with an altered response to stimulation of the receptors. SUMMARY 1. Adrenaline (1pg/min) was given intravenously to three subjects after unilateral cervical sympathectomy. An initial transient increase in flow occurred in both forearms; this was followed by a smaller sustained increase in blood flow to the control forearm only. 2. Following the administration of dibenyline (.5 mg/min for 6 min) into the brachial artery of the sympathectomized side, a sustained vasodilatation was seen during the intravenous infusion of adrenaline. 3. It is suggested that the change in response to intravenous adrenaline following sympathectomy is due to an increased sensitivity to the constrictor but not the dilator action of adrenaline. We should like to express our grateful thanks to Professor A. D. M. Greenfield for his advice and encouragement.

5 SYMPATHCTOMY AND INTRAVNOUS ADRNALIN 267 RFRNCS ALLN, W. J., BARCROFT, H. & DHOLM,. G. (1946). On the action of adrenaline on the blood vessels in human skeletal muscle. J. Physiol. 15, BARCRoFT, H. & WALKR, A. J. (1949). Return of tone in blood vessels of upper limb after sympathectomy. Lancet, 256, 135. Du1F, R. S. (1955). ffect of adrenaline and noradrenaline on blood vessels of the hand before and after sympathectomy. J. Phy8iol. 129, DUFF, R. S. & SwAN, H. J. C. (1951). Further observations on the effect of adrenaline on the blood flow through human skeletal muscle. J. Phy8iol. 114, GADDUM, J. H., PART, W. S. & VOGT, M. (1949). The estimation of adrenaline and allied substances in blood. J. Phy8iol. 18, GINSBIURG, J. & COBBOLD, A. F. (196). ffects of adrenaline, noradrenaline and isopropylnoradrenaline in man. Ciba Foundation Symposium on Adrenergic Mechanism8, 196. d. WOLSTNHOLM, G.. W. and O'CoNNoR, M. London: Churchill. GLOVR, W.., SHA.s, R. G. & STANFORD, C. F. (1962). Peripheral vascular effects of mixtures of isopropylnoradrenaline and noradrenaline in man. Nature, Lond. 196, 999. PARxs, V. J., SKNR, S. L. & WHLAN, R. F. (1961). Mechanisms in the return of vascular tone following sympathectomy in man. Circuktion Res. 9, WHLAN, R. F. (1952). Vasodilatation in human skeletal muscle during adrenaline infusions. J. Phy8iol. 118,