Endothelium-independent vascular relaxation mediating ETB receptor in rabbit mesenteric arteries

Discovery Research Laboratories II, Shionogi & Company Limited, Osaka 561-0825, Japan Vascular response mediating endothelin (ET) B receptor was studied using isolated rabbit mesenteric arteries. ET-1 (0.1-30 nM) caused a concentration-dependent contraction, whereas ET-3 >100 nM caused only weak contraction. Up to 1 µM of sarafotoxin S6c showed no contraction. In arteries precontracted with phenylephrine, ET-3 (0.03-1 nM) caused a concentration-dependent relaxation, which was not affected by endothelium denudation. The ET-3-induced relaxation was antagonized by BQ-788 and PD-142893 but not by BQ-123 in the endothelium-denuded arteries. Treatment with indomethacin but not with N G -nitro- L -arginine methyl ester completely inhibited the relaxation. ET-3 stimulated the release of 6-keto-PGF 1 and PGE 2 from the endothelium-denuded arteries. ET-3 also significantly increased cAMP content but not cGMP content in the arteries. Radioligand-binding studies using serial sections of the artery revealed the expression of not only ET A but also ET B receptors in the smooth muscle layer of the arteries. These results suggest that ET-3 activates ET B receptor in smooth muscle cells of rabbit mesenteric artery, producing vasodilator prostaglandins from arachidonic acid probably via a catalysis of cyclooxygenase, which accumulates cAMP in subendothelial tissues and produces relaxations. endothelin; prostaglandin I 2 ; adenosine 3',5'-cyclic monophosphate