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

Authors

  • Chandrashekhar R. Gandhi Ph.D.,

    Corresponding author
    1. Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    2. Departments of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
      Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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  • Edwin M. Nemoto,

    1. Departments of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Simon C. Watkins,

    1. Cell Biology University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Vladimir M. Subbotin

    1. Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    2. Departments of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA

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; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62±8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 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 also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<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.

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