Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K ϩ channels. Am J Physiol Heart Circ Physiol 279: H2620-H2626, 2000.-Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that

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... ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10 Ϫ12 -10 Ϫ7 M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N -nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), 1 H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation ϭ 69 Ϯ 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation ϭ 66 Ϯ 7 vs. 41 Ϯ 13%, P Ͻ 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither 1 H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K ϩ channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase. coronary disease; calcitonin gene-related peptide; hypertension; congestive heart failure ADRENOMEDULLIN (ADM) is a novel vasodilator and natriuretic peptide consisting of 52 amino acids (17). It is a member of the calcitonin gene-related peptide (CGRP) family (17). Plasma ADM levels are increased in patients with hypertension