Endothelium-dependent relaxation counteracting the contractile action of endothelin-1 is partly due to ETB receptor activation.

Abstract

The vasomotor effects of the endothelins (ETs) are mediated by activation of receptor subtypes termed ETA and ETB. The present study aimed to characterize the interaction of ETA and ETB receptor activation in the cerebral circulation. Ring segments obtained from rat basilar artery were used for measurement of isometric force under resting tension or following precontraction with prostaglandin F2 alpha. In some segments, the endothelium was removed mechanically. In precontracted arteries, ET-1 elicited contraction only. In the presence of the ETA receptor antagonist, BQ-123 (10(-5) M), however, ET-1 induced a concentration-related relaxation with a pD2 value of 8.93 +/- 0.16 (mean +/- SEM, n = 15). The relaxant action was abolished following preincubation with an ETB receptor antagonist, IRL-1038 (3 x 10(-6) M), or with a nitric oxide synthase inhibitor, NG-nitro-L-arginine (10(-5) M). These results indicate that the relaxation was mediated by ETB receptor activation coupled to the release of nitric oxide. Under resting tension, ET-1 elicited concentration-related contraction (pD2: 8.03 +/- 0.04, n = 37). In arteries devoid of a functional endothelium, the concentration-effect curve was shifted to the left yielding a pD2 value of 8.88 +/- 0.11 (n = 31). Similarly, in endothelium-intact arteries contraction to ET-1 was augmented following nitric oxide synthase inhibition or ETB receptor blockade with 3 x 10(-6) M BQ-788 (pD2: 8.94 +/- 0.18, n = 19). The results suggested that, in the isolated rat basilar artery, ET-1 induced coactivation of the contraction-mediating ETA receptor and the relaxation-mediating ETB receptor. The coactivation resulted in opposing vasomotor effects, but the contraction covered relaxation under normal conditions. However, force development by ET-1 was suppressed by its endothelium-dependent relaxant action.