title: Preventative and therapeutic effects of perindopril on hepatic fibrosis induced by bile duct ligation in rats.
abstract: The aim of this study was to examine the preventative and therapeutic effects of an angiotensin-converting enzyme inhibitor, perindopril, on cholestasis-induced liver fibrosis. Perindopril was administered orally for 21 days immediately after bile duct ligation at a dose of 2 mg/kg in order to evaluate the preventative effects, and for 21 days starting 3 weeks after bile duct ligation at doses of 2 and 8 mg/kg in order to evaluate the therapeutic effects. With regard to the preventative effects, perindopril reduced the hepatic hydroxyproline content by 33%, collagen-I mRNA by 38%, α-smooth muscle actin (α-SMA)-positive cells by 46%, α-SMA mRNA by 40%, transforming growth factor-β1 (TGF-β1) mRNA by 21% and connective tissue growth factor (CTGF) mRNA by 27%. With regard to the therapeutic effects, at 2 mg/kg perindopril had no inhibitory effects on the progression of liver fibrosis, but at 8 mg/kg, it reduced hepatic hydroxyproline contents by 63%, collagen-I mRNA by 94%, TGF-β1 mRNA by 79%, CTGF mRNA by 97% and tissue inhibitor of metalloproteinase-1 mRNA by 87%. Significant decreases in the oxidative stress markers hepatic 4-hydroxy-2-nonenal and 8-hydroxy-2-deoxyguanosine were noted for perindopril administration at 8 mg/kg, but not at 2 mg/kg. In conclusion, perindopril had preventative and therapeutic effects on cholestasis-induced liver fibrosis through the inhibition of oxidative stress and/or the activation of hepatic stellate cells, thus suggesting the possible application of perindopril as an antifibrotic drug.
authors.affiliation: Second Department of Internal Medicine, Tottori University, Faculty of Medicine, Yonago 683-8504, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yeki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Matono
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sugihara
authors.forename: Kazunori
authors.initials: K
authors.lastname: Maeda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki