Accelerated reversal of carbon tetrachloride‐induced cirrhosis in rats by the endothelin receptor antagonist TAK‐044

Abstract

Background : A multifunctional mediator, endothelin (ET)‐1 is implicated in the pathophysiology of liver cirrhosis. Carbon tetrachloride (CCl₄)‐induced cirrhosis in rats resolves upon termination of CCl₄ 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 CCl₄ 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 CCl₄ 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