Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ETB 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 ETB receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ETA 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-(ETB receptor) antibodies revealed a preponderant distribution of ETB 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 ETB receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.

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