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SUMMARY. We studied postsynaptic a-adrenoceptors in human blood vessels by measuring the influence on forearm blood flow induced by intra-arterial infusions of selective a t -and a 2 -adrenoceptor agonists (methoxamine, B-HT 933, clonidine and guanfacine) and antagonists (doxazosin and yohimbine). The studies were done in healthy volunteers, and forearm blood flow was measured by plethysmography. All agonists produced a significant and dose-dependent vasoconstriction. The effect of B-HT 933 was completely abolished by the concomitant infusion of yohimbine, whereas it was hardly influenced by doxazosin. The effect of methoxamine was prevented by doxazosin and little influenced by yohimbine. The vasoconstriction by clonidine and guanfacine was partially prevented by both doxazosin and yohimbine. The single intraarterial infusion of yohimbine, as well as doxazosin, resulted in vasodilation. These findings provide strong evidence for the existence of postsynaptic ai-as well as a 2 -adrenoceptors, both mediating vasoconstriction and contributing to basal vascular tone. The (patho-)physiological significance of this subdivision of a-adrenoceptors remains to be elucidated. (Circ Res 54: 447-452, 1984)

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The role of muscarinic (M)-receptor subtypes in the regulation of vascular tone has not yet been defined in humans. To analyze the role of M-receptor subtypes in the forearm resistance vasculature of normotensive volunteers (n = 20), we infused acetylcholine (ACh) and methacholine (MCh) in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1 selective), and AF-DX 116 (M2 selective), using automated R-wave-triggered venous occlusion plethysmography. Schild analysis was applied by calculating plasma concentrations of the infused compounds and determining EC50 values. ACh and MCh both caused dose-dependent vasodilation, with EC50 values of 537 and 52 nmol/L, respectively. The apparent 10-fold higher potency of MCh compared with ACh may be explained by rapid degradation of ACh in plasma. The concentration-response curve of MCh was shifted to the right by atropine, pirenzepine, and AF-DX 116, with apparent pA2 values of 8.03 +/- 0.03, 6.71 +/- 0.08, and 5.32 +/- 0.05, respectively, and slopes not different from unity. The present technique enabled us to perform M-receptor characterization by Schild analysis in humans. The affinity constants and rank order of potency--atropine > pirenzepine > AF-DX 116-suggest that cholinergic vasodilation in this vascular bed is predominantly mediated by the M3-receptor subtype. The EC50 value of MCh and the pA2 values of pirenzepine and AF-DX 116 are comparable to values reported for in vitro experiments.