Endothelin-1 induces vasoconstriction and nitric oxide release via endothelin ET B receptors in isolated perfused rat liver

Abstract

Endothelin-1 (0.1, 1 and 10 nM) induced a significant increase in portal pressure and nitric oxide (NO) release in the isolated rat liver. The endothelin ET B receptor agonist, IRL 1620 (Suc-[Glu 9,Ala 11,15]endothelin-1-(8–21)) (0.1, 1 and 10 nM) also elicited a marked increase in portal pressure and NO release. The potency of endothelin-1 was higher than that of IRL 1620. The endothelin ET A receptor antagonist, BQ-123 ( cyclo(- d-Trp- d-Asp-Pro- d-Val-Leu)) (1 and 10 μM), had no effect on the endothelin-1-induced change in portal pressure and NO current. In contrast, the endothelin ET B receptor antagonist, BQ-788 ( N- cis-2,6-dimethylpiperidinocarbonyl- l-γ-methylleucyl- d-1-methoxycarbonyltryptophanyl- d-norleucine) (1 and 10 nM), attenuated the endothelin-1-induced change in portal pressure and NO current. Administration of N G-monomethyl- l-arginine ( l-NMMA), a NO synthase inhibitor, completely abolished the endothelin-1- or IRL 1620-induced NO release. l-NMMA enhanced the increase in portal pressure and decrease in O 2 consumption caused by endothelin-1. These results indicated that endothelin ET B receptors mediate both vasoconstriction and NO release and that NO plays a significant role in stabilizing microcirculation in isolated perfused rat liver.