An endothelin receptor antagonist TAK‐044 ameliorates carbon tetrachloride‐induced acute liver injury and portal hypertension in rats

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Abstract
ABSTRACT— Hepatic levels of a powerful vasoconstrictor endothelin‐1 (ET‐1) and its receptors increase in human and carbon tetrachloride (CCl4)‐induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET‐1 receptors ameliorates CCl4‐induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl4 (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl4 treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET‐1 and its receptors, and portal venous pressures were determined. Increases in ET‐1 and its receptors occurred within 24 h of CCl4 administration, and progressively thereafter during the development of cirrhosis. The acute CCl4‐induced hepatic injury was characterized by significant increases in portal pressure (from 8.7 ± 1.8 to 17.6 ± 3.3 mmHg; pppp<0.05). In conclusion, these results indicate involvement of ET‐1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET‐1 receptor antagonists in the treatment of these pathologic conditions.