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Endothelin, a recently discovered endothelium-derived peptide, has been reported to produce potent vasoconstriction in various vessels of experimental animals. To study the involvement of endothelin in the regulation of vascular tonus in humans, isolated human mesenteric arteries were investigated by both pharmacological and immunohistochemical methods. The vasoconstrictor action of endothelin-1 was examined on ring segments of human mesenteric arteries.Endothelin-1 induced a slowly developing and sustained contraction, with an EC50 value (half-maximal effective concentration) of 2.9x 10-9 M, two orders of magnitude smaller than that of norepinephrine (EC50 of 3.9xlO0`M), indicating that the vasoconstrictor action of endothelin-1 is about 100 times more potent than that of norepinephrine. The contractile effect of endothelin-1 was affected neither by adrenergic, cholinergic, histaminergic, nor serotonergic antagonists, nor by inhibitors of arachidonic acid metabolism. The vasoconstrictor response to endothelin-1 was effectively antagonized by nicardipine, a dihydropyridine Ca21 channel blocker. Endothelin-1 profoundly augmented contractile response to Ca21 in partially depolarized tissues. Immunohistochemical studies revealed for the first time that endothelin-like immunoreactivity was localized in endothelial cells of human mesenteric artery. The results of the present study indicate that endothelin-1 is one of the most potent vasoconstrictors in the human mesenteric artery and that it induces vasoconstriction via an ultimately accelerating Ca21 influx through voltage-dependent Ca21 channels. Since endothelin-1 can be located in human endothelial cells, it may play an important physiological or pathophysiological role. (Circulation 1990;81:1874-1880 Since the discovery of endothelium-dependent vasodilation by Furchgott and Zawadzki in 1980,1 it has become evident that the endothelial cells covering the luminal surface of blood vessels play a key role in the motor effects of certain vasoactive substances.2 In addition to mediating relaxations, endothelial cells can also facilitate conFrom the

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