Endothelin receptor antagonist TAK-044 arrests and reverses the development of carbon tetrachloride induced cirrhosis in rats.
OBJECTIVE
Hepatic concentrations of the powerful vasoconstrictor and fibrogen endothelin 1 (ET-1) and its receptors increase in human and experimental cirrhosis, suggesting a major role for ET-1 in the pathology of chronic liver disease. We investigated whether ET-1 receptor antagonism, after the development of fibrosis and cirrhosis, arrests/reverses the progression of chronic liver disease.


METHODS
Chronic liver injury was induced in rats by carbon tetrachloride (CCl(4)) treatment (0.15 ml/kg intraperitoneally twice a week) in conjunction with phenobarbital in drinking water (0.4 g/l) for four (group 1: fibrosis) and eight (group 2: cirrhosis) weeks. Rat were then treated concurrently with the ET-1 receptor antagonist TAK-044 (10 mg/kg/day) and CCl(4)/phenobarbital for a further four weeks.


RESULTS
Histopathological examination revealed significant arrest of progression to cirrhosis in group 1 and reversal of cirrhosis in group 2 rats. TAK-044 treatment caused significant amelioration of portal hypertension, systemic hypotension, and liver injury (reduced activities of serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), and improved hepatic synthetic capacity (increased serum albumin concentration) in both groups of rats relative to vehicle treated rats. TAK-044 treatment reduced collagen synthesis, as evidenced by decreased hepatic hydroxyproline content, mRNA expression of collagen-alpha type I, and tissue inhibitors of matrix metalloproteinases 1 and 2, and mRNA and protein expression of a potent fibrogenic cytokine, transforming growth factor beta1.


CONCLUSIONS
The results emphasise the role of ET-1 in the development of cirrhosis and strongly suggest that blockade of its actions can be a rational therapy for chronic liver disease and its complications.
Thirunavukkarasu
C
C
Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Yang
Y
Y
Subbotin
V M
VM
Harvey
S A K
SA
Fung
J
J
Gandhi
C R
CR
D000818:Animals; D002251:Carbon Tetrachloride; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology; D006975:Hypertension, Portal / Q000188:drug therapy; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010456:Peptides, Cyclic / Q000627:therapeutic use*; 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