Endothelium-dependent relaxation counteracting the contractile action of endothelin-1 is partly due to ET(B) receptor activation

The vasomotor effects of the endothelins (ETs) are mediated by activation of receptor subtypes termed ET(A) and ET(B). The present study aimed to char acterize the interaction of ET(A) and ET(B) 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 F-2 alpha. In some segments, the endothelium was removed mechanically. In precontracted arteries, ET-1 elicited contraction only. In the presence of the ET(A) receptor antagonist, BQ-123 (10(-5) M), however, ET-1 induced a concentration-related relaxation with a pD(2) value of 8.93+/-0.16 (mean +/- SEM, n = 15). The relaxant action was abolished following preincubation with an ET(B) receptor antagonist, IRL-1038 (3x10(-6) M), or with a nitric oxide synthase inhibitor, N-G-nitro-L-arginine (10(-5) M). These results indicate that the relaxation was mediated by ET(B) receptor activation coupled to the release of nitric oxide. Under resting tension, ET-1 elicited concentration-related contraction (pD(2): 8.03+/-0.04, n = 37). In arteries ies devoid of a functional endothelium, the concentration-effect curve was shifted to the left yielding a pD(2) 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 ET(B) receptor blockade with 3x10(-6) M BQ-788 (pD(2): 8.94+/-0.18, n = 19). The results suggested that, in the isolated rat basilar artery, ET-1 induced coactivation of the contraction-mediating ET(A) receptor and the relaxation-mediating ET(B) 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.