Xu Dan, Wu Yong, Liao Zhang-Xiu, Wang Hui
Department of Pharmacology, Basic Medical School, Wuhan University, Wuhan 430071, Hubei Province, China.
Pharmacol Res. 2007 Apr;55(4):280-6. doi: 10.1016/j.phrs.2006.12.003. Epub 2006 Dec 19.
The purpose of the present work was to investigate the effect of verapamil on liver fibrosis induced by multiple hepatotoxic factors in rats. Male Wistar rats were divided into a normal control group, a liver fibrosis model control group, and verapamil groups with different dosages. Multiple hepatotoxic factors including carbon tetrachloride (CCl(4)), ethanol and high cholesterol were used to make the animal model of liver fibrosis. The parameters of serum l-alanine aminotransferase (ALT), liver malondialdehyde and hydroxyproline contents were measured. Samples of the liver obtained by biopsy were subjected to histological and immunohistochemical studies for the expressions of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta(1) (TGF-beta(1)). Results showed that verapamil induced a dose-dependent decrease of serum ALT, liver malondialdehyde and hydroxyproline compared with liver fibrosis model control. Verapamil reduced hepatocyte degeneration and necrosis, and delayed the formation of liver fibrosis. The levels of expression of alpha-SMA and TGF-beta(1) in the hepatic tissue of three of the verapamil-treated groups were significantly less than those of the liver fibrosis model control group. The results showed that verapamil acts against the formation of liver fibrosis, the mechanism might be due to a protective effect for hepatocytes and through decreasing TGF-beta(1) to block the activation of hepatic stellate cells (HSCs) and collagen gene expression.
本研究旨在探讨维拉帕米对大鼠多种肝毒性因素所致肝纤维化的影响。将雄性Wistar大鼠分为正常对照组、肝纤维化模型对照组和不同剂量维拉帕米组。采用四氯化碳（CCl₄）、乙醇和高胆固醇等多种肝毒性因素制备肝纤维化动物模型。检测血清丙氨酸氨基转移酶（ALT）、肝脏丙二醛和羟脯氨酸含量等指标。对经活检获取的肝脏样本进行组织学和免疫组织化学研究，检测α-平滑肌肌动蛋白（α-SMA）和转化生长因子-β₁（TGF-β₁）的表达。结果显示，与肝纤维化模型对照组相比，维拉帕米可使血清ALT、肝脏丙二醛和羟脯氨酸呈剂量依赖性降低。维拉帕米减轻了肝细胞变性和坏死，延缓了肝纤维化的形成。维拉帕米治疗的三个组肝组织中α-SMA和TGF-β₁的表达水平明显低于肝纤维化模型对照组。结果表明，维拉帕米可对抗肝纤维化的形成，其机制可能是对肝细胞具有保护作用，并通过降低TGF-β₁来阻断肝星状细胞（HSCs）的激活和胶原基因表达。
