Endothelin receptor subtype antagonist activity of S-0139 in various isolated rabbit and canine arteries.

Vascular responses to endothelin peptides have been proposed to be mainly mediated via subtypes of the endothelin receptor, endothelin ET(A1), endothelin ET(B1), and endothelin ET(B2). The antagonist activity of 27-O-3-[2-(3-carboxy-acryloylamino)-5-hydroxyphenyl]acryloyloxy myricerone, sodium salt (S-0139) at these endothelin receptor subtypes was evaluated using isolated rabbit femoral, pulmonary, and mesenteric arteries. S-0139 competitively antagonized the endothelin-1-induced contraction mediated by the endothelin ET(A1) receptor in endothelium-denuded rabbit femoral arteries with a pA(2) value of 8.6+/-0.1. Endothelin ET(B2) receptor-mediated contraction induced by sarafotoxin S6c in endothelium-denuded rabbit pulmonary arteries was also inhibited by S-0139 with a pA(2) value of 5.6+/-0. 1. The pA(2) value of S-0139 for the endothelin ET(B1) receptor, evaluated from the endothelin-3-induced relaxant response in endothelium-intact rabbit mesenteric arteries, was 6.2+/-0.2. In isolated canine basilar, coronary, mesenteric and renal arteries, endothelin-1 caused concentration-dependent contractions with EC(50) values of 0.49+/-0.07, 0.61+/-0.25, 0.92+/-0.21 and 1.18+/-0.24 nM, respectively. S-0139 antagonized the endothelin-1-induced contraction in these arteries with pA(2) values of 8.0+/-0.1, 7. 6+/-0.2, 7.6+/-0.2 and 7.6+/-0.1, respectively. These results suggest that S-0139 is a potent and selective endothelin ET(A1) receptor antagonist, and that the contractions induced by endothelin-1 in canine basilar, coronary, mesenteric and renal arteries are mediated mainly via the endothelin ET(A1) receptor subtype.