Isolated, perfused rat liver preparations (IPRL), obtained from rats with carbon tetrachloride-induced cirrhosis and normal controls, were used to investigate responses to the vasoactive peptide endothelin-1 (ET-1). The mean perfusion resistance (R) of cirrhotic IPRL was significantly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mmHg/mL per min per g; P < 0.01). Both control and cirrhotic IPRL demonstrated a concentration-related increase in resistance (delta R) in response to ET-1, with a minimum effective concentration of approximately 3 x 10(-11) mol/L. The EC50 (-log of the 50% effective concentration) was not significantly different between cirrhotic and control IPRL (8.48 +/- 0.19 and 8.79 +/- 0.11, respectively); however, the maximum response to ET-1 was significantly greater in cirrhotic preparations (R: 10.4 +/- 2.2 vs 4.4 +/- 0.5 mmHg/mL per min per g, P < 0.01; DR, 7.8 +/- 2.1 vs 2.8 +/- 0.4 mmHg/mL per min per g, P < 0.01). Following maximal stimulation by ET-1, the mean portal-hepatic venous pressure gradient at a physiological flow rate of 1 mL/min per g was approximately 90% greater across cirrhotic IPRL than that across normal IPRL (11.2 +/- 2.0 vs 5.9 +/- 0.9 mmHg, respectively; P < 0.05). These results support the hypothesis that endogenously released ET-1 has a significant influence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.