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...

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Published in:Clinical science (1979) Vol. 105; no. 2; p. 227
Main Authors: Tran Duc, Anh Thu, Schwab, Andreas J, Simard, André, Villeneuve, Louis, Dupuis, Jocelyn
Format: Journal Article
Language:English
Published: England 01.08.2003
Subjects:
Animals
Blood Pressure
Carbon Tetrachloride
Endothelin-1 - blood
Endothelin-1 - metabolism
Liver - metabolism
Liver Cirrhosis, Experimental - blood
Liver Cirrhosis, Experimental - metabolism
Liver Cirrhosis, Experimental - pathology
Male
Portal Vein - physiopathology
Rats
Rats, Sprague-Dawley
Receptor, Endothelin B
Receptors, Endothelin - metabolism
ISSN:0143-5221
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Summary: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.
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ISSN:0143-5221
DOI:10.1042/cs20030026