Protective effect of verapamil on multiple hepatotoxic factors-induced liver fibrosis in rats

ArticleinPharmacological Research 55(4):280-6 · May 2007with15 Reads
DOI: 10.1016/j.phrs.2006.12.003 · Source: PubMed
Abstract
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.
    • "Thus, the exact role of L-type voltageoperated calcium channels in HSCs stimulated by TGF-b1 remains to be elucidated. Verapamil was reported to suppress liver fibrosis induced by multiple hepatotoxic factors, including CCl 4, ethanol and high cholesterol, in rats (Xu et al., 2007). However, doses of 20, 40 and 80 mg·kg -1 ·day -1 were suggested to be inappropriately high doses for the following reasons. "
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  • [Show abstract] [Hide abstract] ABSTRACT: AIM: To investigate the distribution and significance of kupffer cells (KCs) and hepatic stellate cells (HSCs) during spontaneous reversible carbon tetrachloride (CCl 4)-induced liver fibrosis in rats. METHODS: Rat liver fibrosis was induced by peritoneal injection of CCl 4 (500 mL/L) for 8 weeks. Serum activity of alanine transaminase (ALT) and aspartate transaminase (AST), total protein (TP) content, ratio of liver/body weight, and area density of collagenous fiber were examined 8 and 12 weeks after injection. Meanwhile, the pathological changes in the liver were observed by light microscopy after Hematoxylin and eosin (HE) staining. The expression of ED1 and α-smooth muscle actin (α-SMA) was detected by immunohistochemical streptavdin-peroxidase-biotin (SP) method. RESULTS: Compared with the control group, the levels of ALT (2568.18 ± 630.46 nkat/L vs 472.26 ± 167.37 nkat/L, P < 0.05) and AST (5845.84 ± 1353.27 nkat/L vs 1698.51 ± 663.30 nkat/L, P < 0.01), ratio of liver/body weight (3.900 ± 0.850 vs 2.560 ± 0.240, P < 0.001), and area of collagenous fiber (5.867 ± 1.127 vs 0.518 ± 0.2995, P < 0.001) were significantly increased 8 wk after injection of CCl 4. Diffuse cirrhosis was observed in most rats, and ED1- and α-SMA-positive cells were prominently aggregated in the fibrotic tissue and septa. Compared with that at 8 wk, ALT (1020.70 ± 306.73 nkat/L vs 376.74 ± 304.06 nkat/L, P < 0.05) level was still higher 12 wk after injection, but the area of collagenous fiber had decreased, fibrous septa became thinner, discontinuous and understained, the number of ED1-positive cells was reduced, and α-SMA-positive cells had disappeared. CONCLUSION: CCl 4 induced obvious liver dysfunction and diffuse cirrhosis in rats, and KCs are closely associated with the activation of HSCs. Rat liver fibrosis is reversible 4 wk after stopping CCl 4 injection.
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