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

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 microM 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 NG-nitro-L-arginine methyl ester completely inhibited the relaxation. ET-3 stimulated the release of 6-keto-PGF1alpha 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 ETA but also ETB receptors in the smooth muscle layer of the arteries. These results suggest that ET-3 activates ETB 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.