ENDOTHELIN-INDUCED VASOCONSTRICTION IN ISOLATED-PERFUSED LIVER PREPARATIONS FROM NORMAL AND CIRRHOTIC RATS

Isolated, perfused rat liver preparations (IPRL), obtained from rats w ith carbon tetrachloride-induced cirrhosis and normal controls, were u sed to investigate responses to the vasoactive peptide endothelin-1 (E T-1). The mean perfusion resistance (R) of cirrhotic IPRL was signific antly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mm Hg/mL per min per g; P< 0.O1). Both control and cirrhotic IPRL demonst rated a concentration-related increase in resistance (Delta R) in resp onse 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 res ponse 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 maxima l stimulation by ET-1, the mean portal-hepatic venous pressure gradien t 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 infl uence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.