Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo

Background/Aims: Endothelin-1 has been suggested to play a key role in cirr hotic portal hypertension, but a role of its receptors in vivo is not fully elucidated. Methods: Biliary cirrhosis was induced by bile duct ligation. Expressions o f endothelin-l and its receptors were evaluated by radioimmunoassay and/or reverse-transcription polymerase chain reaction, Hemodynamics were studied using endothelin receptor agonist or antagonist. Results: Portal pressure and hepatic endothelin-1 concentrations progressiv ely increased in parallel after bile duct ligation, Gene expression of hepa tic prepro-endothelin-1 and endothelin B receptor enhanced after bile duct ligation, while that of endothelin A receptor was unchanged. Intraportal ad ministration of endothelin-1 or endothelin B receptor agonist sarafotoxin 6 c (0.5 nmol/kg, respectively) progressively raised portal pressure in both sham and cirrhotic rats. Portal hypertensive effect of sarafotoxin 6c was m ore intense in cirrhotic rats than sham animals, Neither endothelin A recep tor antagonist FR139317 (1 mg/kg) nor endothelin B receptor antagonist BQ78 8 (1 mg/kg) alone ameliorated cirrhotic portal hypertension. Only the combi ned endothelin A and B blockade was associated with a decrease in portal pr essure in cirrhotic rats. Conclusions: These results indicate that endothelin-1 plays a major role in cirrhotic portal hypertension through endothelin receptor subtype B togeth er with subtype A in vivo. (C) 2001 European Association for the Study of t he Liver. Published by Elsevier Science B.V, All rights reserved.