The vascular effects of endothelin-1 (ET-1; ET(A)/ET(B) agonist), sarafotoxin 6b (S6b; ET(A) agonist), and IRL 1620 (ET(B) agonist) were investigated in the isolated canine liver arterial circuit before and alter infusions of indomethacin (cyclo-oxygenase inhibitor) and N(ω)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 and the liver was perfused via the hepatic artery and portal vein with oxygenated (95% O2/5% CO2) Krebs solution at 37°C. Intra-arterial bolus injections of either ET-1 (0.4-400 pmol) or S6b (0,4-400 pmol) induced dose-dependent and long-lasting vasoconstriction accompanied by significant prostacyclin release. The vasoconstrictor responses to these peptides were slightly increased during infusion of indomethacin. Subsequent infusion of L-NAME potentiated both ET-1- and S6b-induced vasoconstriction (p < 0.05). IRL 1620 (up to 1.2 nmol) had no effect on the hepatic arterial vascular resistance even during indomethacin and L-NAME infusions. Infusion of the ET(A) receptor antagonist FR-139317 (0.3 μM) markedly reduced both ET-1- and S6b-induced vasoconstriction without affecting that evoked by NE. Our results indicate that pressor responses to ET-1 and S6b in the isolated canine liver are modulated by concomitant release of vasodilator mediators, including prostacyclin and nitric oxide. These effects appear to depend primarily on the activation of ET(A) receptor subtypes. IRL 1620 (but not ET-1) induced a significant release of hemoglobin into the venous effluent, suggesting that ET(B) receptors are located in the venous side of the intrahepatic circulation Ver menos