ROLE OF ENDOTHELIN ET(A) AND ET(B) RECEPTORS IN THE ARTERIAL VASCULATURE OF THE ISOLATED CANINE LIVER

The vascular effects of endothelin-1 (ET-1; ET(A)/ET(B) agonist), sara fotoxin 6b (S6b; ET(A) agonist), and IRL 1620 (ET(B) agonist) were inv estigated in the isolated canine liver arterial circuit before and aft er infusions of indomethacin (cyclo-oxygenase inhibitor) and N(omega)L -nitro arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor ). Norepinephrine (NE) was used as vasoconstrictor control agent. The portal vein, hepatic artery, and vena cava were cannulated in vitro an d the liver was perfused via the hepatic artery and portal vein with o xygenated (95% O-2/5% CO2) Krebs solution at 37 degrees C. Intra-arter ial bolus injections of either ET-1 (0.4-400 pmol) or S6b (0.4-400 pmo l) induced dose-dependent and long-lasting vasoconstriction accompanie d by significant prostacyclin release. The vasoconstrictor responses t o these peptides were slightly increased during infusion of indomethac in. Subsequent infusion of L-NAME potentiated both ET-1- and S6b-induc ed vasoconstriction (p < 0.05). IRL 1620 (up to 1.2 nmol) had no effec t on the hepatic arterial vascular resistance even during indomethacin and L-NAME infusions. Infusion of the ET(A) receptor antagonist FR-13 9317 (0.3 mu M) markedly reduced both ET-1- and S6b-induced vasoconstr iction without affecting that evoked by NE. Our results indicate that pressor responses to ET-1 and S6b in the isolated canine liver are mod ulated by concomitant release of vasodilator mediators, including pros tacyclin and nitric oxide. These effects appear to depend primarily on the activation of ET(A) receptor subtypes. IRL 1620 (but not ET-1) in duced a significant release of hemoglobin into the venous effluent, su ggesting that ET(B) receptors are located in the venous side of the in trahepatic circulation.