The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I-2) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI(2) synthesis, measured as immunoreactive 6-keto-PGF(1 alpha) was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ET(A) and ET(B) receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ET(B) receptor agonist, enhanced 6-keto-PGF(1 alpha) synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF(1 alpha) synthesis. Moreover, the selective ET(B) receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF(1 alpha) synthesis. Furthermore, ET-1-induced 6-keto-PGF(1 alpha) synthesis was attenuated by an ET(A) receptor antagonist, BQ-123, in a dose-dependent manner but not by an ET(B) receptor antagonist, BQ-788. Depletion of extracellular Ca2+ or addition of Ca2+ channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1-mediated 6-kelo-PGF(1 alpha) synthesis, while a Ca2+ channel aqonist, S(-)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1-induced 6-keto-PGF(1 alpha) synthesis. These data suggest that PGI(2) synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca2+ via activation of an ET(A) receptor and is independent of protein kinase C.