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-PGF₁ and PGE₂ 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 I₂; adenosine 3',5'-cyclic monophosphate

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