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-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.
Gandhi
C R
CR
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
Nemoto
E M
EM
Watkins
S C
SC
Subbotin
V M
VM
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006975:Hypertension, Portal / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C088196:TAK 044; D002251:Carbon Tetrachloride