Effect of losartan, an angiotensin II antagonist, on hepatic fibrosis induced by CCl4 in rats.
In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system (RAS) is also involved in hepatic fibrogenesis. We aimed to investigate the effect of losartan, an angiotensin II (Ang II) antagonist, on CCl4-induced hepatic fibrosis in rats. Hepatic fibrosis was induced by a subcutaneous injection with 50% CCl4 in Sprague-Dawley rats. The amount of CCl4 administered was 1 mg/kg. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma and hydroxyproline (Hyp) contents in liver tissue were assayed by spectrophotometry. Hyaluronic acid (HA) and procollagen III (PC III) were assessed by radioimmunoassay. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) levels in culture supernatants of Kupffer cells (KCs) stimulated with Ang II was determined by ELISA. Liver samples collected after 12 weeks of CCl4 treatment were stained with hematoxylin and eosin, then scored. Losartan (2.5, 5, and 10 mg x kg(-1), ig) and captopril (100 mg x kg(-1), ig) significantly decreased liver and spleen indexes, serum transaminase (AST, ALT) activities, HA and PC III levels, and Hyp contents in liver tissue in rats of hepatic fibrosis. Histopathological scores showed that losartan had an inhibitory effect on the progression of hepatic fibrosis. In in vitro experiments, losartan (1 x 10(-9) - 1 x 10(-5) M) significantly reduced TNF-alpha and TGF-beta1 levels in culture supernatants of KCs, but captopril (1 x 10(-5) M) did not. The results showed that losartan significantly inhibited the progression of hepatic fibrosis induced by CCl4, and the inhibitory effect of losartan on hepatic fibrosis might be associated with its ability to inhibit the production of TNF-alpha and TGF-beta1 by activated KCs.
Wei
Yao Hong
YH
Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310031, China. yhgwei@hotmail.com
Jun
Li
L
Qiang
Chen Ji
CJ
D000410:Alanine Transaminase / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D047228:Angiotensin II Type 1 Receptor Blockers; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019808:Losartan