Potent Vasoconstrictor Effect and Existence in Endothelial Cells

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)