Regulation of the hepatic endothelin system in advanced biliary fibrosis in rats

The aim of the present study was to analyze the hepatic endothelin system and its regulation in liver cirrhosis due to bile duct obstruction. Wistar rats were subjected for 6 weeks to: 1) sham operation; 2) bile duct obstruction; 3) bile duct obstruction and the selective oral endothelin A receptor antagonist LU 135252; 4) bile duct obstruction and oral silymarin, a hepatoprotective and antifibrotic compound. We determined tissue concentrations of endothelin-1 and big-endothelin-1 by ELISA and the density of both endothelin receptor subtypes in plasma membrane fractions by Scatchard analysis. The hepatic endothelin system in liver cirrhosis due to chronic bile duct obstruction is characterized by a simultaneous up-regulation of both endothelin-1 tissue concentration (7.2 fold compared to sham operation; p<0.001) as well as the density of both endothelin receptor subtypes (ET(A) 7.4-fold, ET(B) 4.9-fold, p<0.001, respectively) suggesting a synergistic activation of the hepatic endothelin system in this rat model of non-inflammatory cirrhosis. Treatment with proven antifibrotic agents such as silymarin or a selective endothelin-A-receptor blocker (LU 135252) did not reduce the activity of the hepatic endothelin system, suggesting that the hepatic endothelin system is not activated by the fibrotic process itself.