Accelerated reversal of carbon tetrachloride-induced cirrhosis in rats by the endothelin receptor antagonist TAK-044.
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 ETA/ETB 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 ETA receptor density declined to normal values in both groups. In contrast, increased ETB 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.
Anselmi
Kristin
K
Department of Surgery, Thomas E Starzl, Transplantation Institute, University of Pittsburgh, PA 15213, USA.
Subbotin
Vladimir M
VM
Nemoto
Edwin
E
Gandhi
Chandrashekhar R
CR
D000818:Animals; D001158:Arteries / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002251:Carbon Tetrachloride; D003094:Collagen / Q000235:genetics; D017364:Collagenases / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011169:Portal Vein / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C088196:TAK 044; D003094:Collagen; D002251:Carbon Tetrachloride; D017364:Collagenases; D006909:Hydroxyproline