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Accelerated reversal of carbon tetrachloride‐induced cirrhosis in rats by the endothelin receptor antagonist TAK‐044
Author(s) -
ANSELMI KRISTIN,
SUBBOTIN VLADIMIR M,
NEMOTO EDWIN,
GANDHI CHANDRASHEKHAR R
Publication year - 2002
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1046/j.1440-1746.2002.02705.x
Subject(s) - cirrhosis , carbon tetrachloride , medicine , endothelin receptor , endocrinology , receptor antagonist , endothelin receptor antagonist , pathophysiology , receptor , antagonism , saline , antagonist , collagenase , endothelin 1 , chemistry , biochemistry , enzyme , organic chemistry
Background: A multifunctional mediator, endothelin (ET)‐1 is implicated in the pathophysiology of liver cirrhosis. Carbon tetrachloride (CCl 4 )‐induced cirrhosis in rats resolves upon termination of CCl 4 treatment. We determined the hepatic ET‐1 system during such reversal and assessed whether ET‐1 receptor antagonism enhances this process.Methods: Cirrhosis was induced in rats by CCl 4 treatment for 8 weeks. Treatment with an ET A /ET B antagonist TAK‐044 (10 mg/kg per day) was then started and determinations were made at 1, 2 and 4 weeks.Results: After termination of CCl 4 treatment, accelerated normalization of liver architecture and portal hypertension occurred in TAK‐044‐treated rats compared with saline‐treated rats. The increased hepatic hydroxyproline concentration and collagen I mRNA expression also declined to greater extents in the TAK‐044‐treated group. Higher collagenase activity in cirrhosis decreased in saline‐treated rats, but did not reach basal values. In TAK‐044‐treated rats, collagenase activity tended to increase at weeks 2 and 4. Increased ET‐1 concentration and ET A receptor density declined to normal values in both groups. In contrast, increased ET B receptor density did not change in saline‐treated rats, but decreased to control values in TAK‐044‐treated rats.Conclusions: Our results emphasize the role of ET‐1 in chronic liver disease and strongly indicate the potential for ET‐1 receptor antagonists in its treatment. © 2002 Blackwell Publishing Asia Pty Ltd