Reduction in hepatic endothelin-1 clearance in cirrhosis

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ET^B receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49±0.04 fmol/ml (mean±S.E.M.) to 1.0±0.18 fmol/ml (P<0.01). Liver ET-1 extraction was reduced from 81±1% (mean±S.E.M.) in controls to 50±6% in cirrhosis (P<0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ET^B receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ET^A antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure (r=-0.457; P<0.001) and the increase in ET-1 levels (r=-0.462; P=0.002). Immunohistofluorescence with specific anti-(ET^B receptor) antibodies revealed a preponderant distribution of ET^B receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET^B receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.