Blood flow was measured in the hands and forearms of recumbent subjects by venous occlusion plethysmography during leg exer cise on a bicycle ergometer. In three highly practiced subjects, exercise resulted in a small fall in forearm flow and a moderate rise in arterial pressure. Resistance to blood flow was therefore considerably increased. Blocking the vasomotor fibers to forearm skin did not affect this, but blocking the deep nerves to the muscle vessels prevented the increase in vascular resistance during exer cise. Treating the forearm with bretyliurn tosylate had the same effect as deep nerve block. It was concluded that vasoconstrictor tone in muscle is increased during exercise. Since treating the forearm with atropine did not affect the normal response, it was concluded that activation of vasodilator fibers to muscle is not an integral part of the gen eral vasomotor response to exercise. Evidence was also found that the vasodilator outflow to a specific muscle group is not specifically activated when the muscle group in question is exercised. During fairly heavy exercise, vasodilatation occurred in both hand and forearm skin. In the hand this was preceded by vasoconstric tion. Evidence was found that the vasodila tation in the hand was due to release of vaso constrictor tone, whereas that in the forearm was mediated through vasodilator fibers. It is likely that the increase in heat production during exercise was responsible for the reflex vasodilatation in skin.

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After intra-arterial infusion of bretylium tosylate (12.5 mg.), the reflex changes in vasoconstrictor tone which normally occur in the forearm with body cooling, positive pressure breathing, the Valsalva mancouvre and postural change were greatly reduced or abolished. Reflex vasodilatation mediated by cholinergic fibres in response to body heating or to emotional stress was little affected. It was concluded that bretylium can selectively block the activity of sympathetic noradrenergic fibres without causing a similar block of sympathetic cholinergic fibres. As the responses to intravenous or intra-arterial infusions of adrenaline or noradrenaline were not reduced after bretylium, it was concluded that bretylium interferes with the activity of noradrenergic fibres rather than with the activity of the noradrenaline released at the nerve ending. After bretylium infusion, forearm and hand blood flow did not often rise to levels characteristic of full release of vasoconstrictor tone. As infusion of bretylium into a nerve-blocked forearm resulted in a pronounced reduction in flow, it is concluded that bretylium also has a constrictor effect on blood vessels. The state of the vessels following an infusion of bretylium appears to depend on the balance between this constrictor action and the longer-acting sympathetic blocking effect.Bretylium tosylate (" Darenthin," Burroughs Wellcome) is one of a series of benzyl quaternary ammonium compounds described by Boura and Green (1959). Experiments in cats suggested that it blocks the peripheral sympathetic (adrenergic) nervous system selectively, without antagonizing the effects of released or injected adrenaline or noradrenaline, and without depression of the parasympathetic or central nervous systems. A preliminary trial in hypertensive patients by Boura, Green, McCoubrey, Laurence, Moulton and Rosenheim (1959) has shown that it lowers the supine blood pressure slightly and causes postural hypotension; and measurements of the circulatory response to the Valsalva manceuvre in a healthy volunteer by Dornhorst (1959) confirmed that the drug produces effects characteristic of block of the sympathetic system.In the present experiments we have studied the effect of bretylium tosylate on certain vascular reflexes in the human hand and forearm. A brief account of this work has previously been published (Blair, Glover, Kidd and Roddie, 1959). METHODS The experiments were carried out on male normotensive subjects, who lay supine on a couch in a laboratory maintained at a temperature of 20 to 210. The subjects were lightly clad but covered with a blanket. Blood flow in the hands or forearms was measured by venous occlusion plethysmography. A needle was inserted in the left brachial artery in the antecubital fossa, and through it 0.9%

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Simultaneous measurements of skin temperature of various skin areas of the body were made during indirect cooling and heating of the body. Cooling the body caused a much larger fall in the nose and finger temperature than in mouth temperature, indicating active vasoconstriction in these areas. In the ear, cheek, chest and forehead there was no evidence for vasoconstriction. Evidence of vasodilatation in all the skin areas studied was obtained when the body was indirectly heated. Blocking the vasomotor nerves to the ear resulted in a large increase in skin temperature and, during body heating, the skin temperature of the normal ear did not exceed that of the nerve-blocked ear. It was concluded that the changes in ear blood flow subserving temperature regulation are mainly due to alterations in vasoconstrictor tone. In the chest and cheek, cutaneous nerve block did not alter skin temperature, yet it reduced the rise in skin temperature normally seen during body heating. It was concluded that the vasodilatation normally seen in these areas is not due to release of vasoconstrictor tone, but rather to an active vasodilator mechanism, mediated through fibers running with the cutaneous nerves. Submitted on May 27, 1960