AN ENDOTHELIN RECEPTOR ANTAGONIST TAK-044 AMELIORATES CARBON-TETRACHLORIDE INDUCED ACUTE LIVER-INJURY AND PORTAL-HYPERTENSION IN RATS

Hepatic levels of a powerful vasoconstrictor endothelin-l (ET-1) and i ts receptors increase in human and carbon tetrachloride (CCl4)-induced liver cirrhosis. The aim of this study was to determine whether antag onism of hepatic ET-1 receptors ameliorates CCl4-induced hepatic injur y and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl4 (0.3 ml/kg), whereas cirrhos is 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 it s receptors occurred within 24 h of CCl4 administration, and progressi vely thereafter during the development of cirrhosis. The acute CCl4-in duced hepatic injury was characterized by significant increases in por tal pressure (from 8.7+/-1.8 to 17.6+/-3.3 mmHg; p<0.01) and serum lev els of liver enzymes, as well as massive hepatocellular necrosis (62+/ -8%). Intravenous administration of an ET-1 receptor antagonist TAK-04 4 reduced portal pressure to 13.6+/-2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment als o produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hyper tension by about 40% (p<0.05). In conclusion, these results indicate i nvolvement of ET-1 in acute liver injury as well as portal hypertensio n associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.