ENDOTHELIUM-DEPENDENT RELAXATION COUNTERACTING THE CONTRACTILE ACTIONOF ENDOTHELIN-1 IS PARTLY DUE TO ET(B) RECEPTOR ACTIVATION

The vasomotor effects of the endothelins (ETs) are mediated by activat ion of receptor subtypes termed ET(A) and ET(B). The present study aim ed to char acterize the interaction of ET(A) and ET(B) receptor activa tion in the cerebral circulation. Ring segments obtained from rat basi lar artery were used for measurement of isometric force under resting tension or following precontraction with prostaglandin F-2 alpha. In s ome segments, the endothelium was removed mechanically. In precontract ed 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 co ncentration-related relaxation with a pD(2) value of 8.93+/-0.16 (mean +/- SEM, n = 15). The relaxant action was abolished following preincu bation with an ET(B) receptor antagonist, IRL-1038 (3x10(-6) M), or wi th a nitric oxide synthase inhibitor, N-G-nitro-L-arginine (10(-5) M). These results indicate that the relaxation was mediated by ET(B) rece ptor 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, t he concentration-effect curve was shifted to the left yielding a pD(2) value of 8.88+/-0.11 (n = 31). Similarly, in endothelium-intact arter ies 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 b asilar artery, ET-1 induced coactivation of the contraction-mediating ET(A) receptor and the relaxation-mediating ET(B) receptor. The coacti vation resulted in opposing vasomotor effects, but the contraction cov ered relaxation under normal conditions. However, force development by ET-1 was suppressed by its endothelium-dependent relaxant action.