Although the incidence of many vascular diseases differs in men and women, sex differences in vascular physiology have not been extensively examined in human in vivo studies. The present study compared finger blood flow responses of normal men and women with brachial artery infusions of adrenergic agonists and with other neurally and nonneurally mediated procedures. In response to phenylephrine and clonidine, men showed significant dose-related vasoconstriction while women did not. In response to isoproterenol, men showed significant dose-related vasodilation while women did not. There were no sex differences in response to intra-arterial nitroglycerin or digoxin or to reactive hyperemia, procedures that do not act through adrenergic receptors. These data show that the sensitivity and/or density of peripheral vascular adrenergic receptors is lower in women than in men. There were no sex differences in response to reflex vasoconstriction or to intra-arterial tyramine, suggesting that neurally released norepinephrine acts at alpha-adrenergic receptors that are spatially removed from those that respond to circulating catecholamines.

Previous work in the canine saphenous vein has shown that cooling augments alpha 2- but not alpha 1-mediated contractile responses and that warming produces the opposite effects. Here we sought to determine whether these results occur in the human finger, a cutaneous vascular bed. Healthy men received brachial artery infusions of phenylephrine and clonidine with and without yohimbine while sympathetic tone was reduced by hearing the legs. Finger blood flow was recorded by venous occlusion plethysmography from two fingers, one cooled and one uncooled, on each hand. Cooling augmented alpha 2-adrenergic vasoconstriction produced by clonidine; this effect was reduced by yohimbine, an alpha 2-adrenergic antagonist. In contrast, cooling abolished alpha 1-adrenergic vasoconstriction produced by phenylephrine, which was not affected by yohimbine. Further studies were conducted in which fingers were warmed rather than cooled. Warming augmented alpha 1- but reduced alpha 2-adrenergic vasoconstriction. Thus, in human fingers, cooling augments alpha 2- and suppresses alpha 1-adrenergic vasoconstriction, whereas warming produces the opposite effects.

Although finger temperature feedback has been used to produce digital vasodilation in normal persons and those with Raynaud's disease, the mechanism and site of this effect have not been studied. In the present investigation, feedback-induced vasodilation was attenuated by brachial artery infusions of propranolol in infused, but not contralateral, hands and was not affected by digital nerve blockade. Quantitative measurements of finger blood flow demonstrated that this vasodilation occurred in arteriovenous shunts in normal persons and in the finger capillary bed in those with Raynaud's disease. Raynaud's disease patients who received finger temperature feedback reported 80 fewer percent symptoms 1 and 2 years after treatment and retained the ability to increase finger temperature and capillary blood flow at these times. These effects were not shown by patients given autogenic training, a relaxation procedure.

In our study of 28 patients with idiopathic Raynaud's disease, the patients had significantly greater digital blood flow responses to intraarterial phenylephrine and clonidine than did normal control subjects. There were no group differences in finger blood flow responses to body heating, reflex cooling, digital ischemia, or to intraarterial tyramine or isoproterenol. There were also no group differences in blood pressure or heart rate during any procedure. These results suggest that patients with idiopathic Raynaud's disease have increased peripheral vascular a-adrenergic receptor sensitivity and/or density compared with normal persons.Idiopathic Raynaud's disease is characterized by episodic vasospasms in the fingers and toes, triggered by cold or emotional stress (1,2). Although the etiology of Raynaud's divease is not known, 2 major theories have been put forth to explain it. Raynaud (3) From thought that hyperactivity of the sympathetic nervous system caused an increased vasoconstrictor response to cold, while Lewis (4) hypothesized a "local fault" in which precapillary resistance vessels were hypersensitive to local cooling, Thus far, neither theory has been proven. Blood flow in the fingers and toes of humans is controlled through sympathetic nerves and through the interactions of circulating cateeholamines with a-adrenergic and p-adrenergic receptors. Vasoconstriction in Raynaud's disease could be caused by increased a or decreased p receptor sensitivity and/or density. This hypothesis has been proposed (3, but it has not been tested. We therefore compared finger blood flow (FBF) responses to brachial artery infusions of a range of doses of phenylephrine, an a , agonist; clonidine, an a2 agonist; isoproterenol, a nonselective p agonist; and tyramine, which causes vasoconstriction by releasing norepinephrine from sympathetic nerve endings, in Raynaud's disease patients versus normal subjects. We also examined FBF responses during rapid cooling of the neck, which produces digital vasoconstriction through a reflex sympathetic nervous pathway (6).Some, but not all, Raynaud's disease patients have lower levels of FBF than do normal persons (7). Since differences in blood flow levels could affect the concentrations of drugs given by intraarterial infusion (8), we matched the patients and controls according to their baseline levels of FBF prior to the infusion of each compound. Then, on a separate day, all patients and controls had FBF measured during total body heating and reactive hyperemia, to detect possible structural vascular changes (9, lo). The former procedure causes vasodilation through the release of sym-

Using a combination of environmental and local cooling, we induced vasospastic attacks of Raynaud's phenomenon in nine of 11 patients with idiopathic Raynaud's disease and in eight of 10 patients with scleroderma. Attacks were defined as occurring if two of the possible three color changes (pallor, cyanosis, and rubor) occurred, and serial photographs were scored by three independent raters. Two fingers on one hand were anesthetized by local injection of lidocaine, and the effectiveness of nerve blocks was verified by plethysmography. The frequency of vasospastic attacks in nerve-blocked fingers was not significantly different from that in the corresponding intact fingers on the contralateral hand. These findings show that the vasospastic attacks of Raynaud's disease and phenomenon can occur without the involvement of efferent digital nerves and argue against the etiologic role of sympathetic hyperactivity.