INVOLVEMENT OF CYCLO-OXYGENASE-GENERATED VASODILATING EICOSANOID(S) IN ADDITION TO NITRIC-OXIDE IN ENDOTHELIN-1-INDUCED ENDOTHELIUM-DEPENDENT VASORELAXATION IN GUINEA-PIG AORTA

This study investigates the vasodilatory effects of endothelin-1 (ET-1 ) in isolated guinea pig aortic rings in vitro. Cumulative dose-respon se curves to ET-1 were constructed and ET-1 actions on prostaglandin F 2alpha (PGF2alpha)-precontraction were studied in both endothelium-int act and endothelium-denuded preparations, in the presence or absence o f a cyclo-oxygenase inhibitor (indomethacin) and/or nitric oxide inhib itors (N(G)-nitro-L-arginine methyl ester and hemoglobin). In endothel ium-intact preparations, pretreatment with indomethacin (10(-5) M, 30 min), alone or in combination with N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), significantly augmented the constrictive responses to ET-1, whereas indomethacin, L-NAME, and hemoglobin (10(-5) M) had no significant effects in the endothelium-denuded preparations. Furthe rmore, in PGF2alpha-precontracted, endothelium-intact preparations, ET -1. at a dose of 10(-9) M, induced initial relaxation followed by subs equent contraction, while it only contracted the endothelium-denuded p reparations. The initial relaxation was abolished by indomethacin, but not by L-NAME or hemoglobin. In addition, this relaxation was not inh ibited by a specific ET(A) receptor antagonist, BQ-123 (6 x 10(-6) M). In addition to the involvement of nitric oxide, these results show th e involvement of cyclo-oxygenase-generated vasodilating eicosanoid(s) derived from endothelium in ET-1-induced vasorelaxation in guinea pig aorta in vitro. The results also indicate that this vasorelaxation is mediated by ET(B) receptor activation.