AIM: To assess the effect of ACE inhibitor and AngII type 1 (AT1) receptor antagonist in preventing hepatic fibrosis caused by CCl 4 administration in rats; to investigate whether or not there are expression of AT1 receptors on hepatic stellate cells; and to observe the effect of AngII on proliferation and ECM synthesis of cultured HSCs.

METHODS: Studies were conducted in male Sprague-Dawley rats. Except for the hepatofibrotic model group and the control group, in three treated groups, either enalapril (5 mg/kg), or losartan (10 mg/kg), or enalapril+ losartan were given to the fibrotic rats by daily gavage, and saline vehicle was given to model and normal control rats. After 6 wk, liver fibrosis was assessed directly by hepatic morphometric analysis, which has been considered the gold standard for the quantification of fibrosis. The expressions of AT1 receptors and (α-mooth muscle actin, α-SMA) in liver tissue or isolated hepatic stellate cells (HSCs) were detected by immunohistochemical techniques. The effect of AngII on HSC proliferation was determined by MTT method. Effect of AngII on collagen synthesis of HSCs was de termined by 3 H-proline incorporation.

RESULTS: Contrasted to the fibrosis in rats of the model group, groups of rats treated with either enalapril or losartan, or a combination of two drugs showed a limited expansion of the interstitium (4.23±3.70 vs 11.22±4.79, P< 0.05), but no difference was observed among three treated groups (5.38±3.43, 4. 96±2.96, 4.23±2.70, P> 0.05). Expression of AT1 receptors was found in fibrotic interstitium of fibrotic rats, whereas in normal control rats they were limited to vasculature only to a very slight degree. AT1 receptors were also expressed on activated HSCs in the culture. At concentrations from 10-9 to 10-5 mol/L, AngII stimulated HSC proliferation in culture in a dose-dependent manner. Increasing AngII concentrations produced corresponding increases in 3 H-proline incorporation. Differences among groups were significant.

CONCLUSION: Angiotensin-converting enzyme inhibitors and AT 1 blocker may slow the progression of hepatic fibrosis; activated HSCs express AT1 receptors, and AngII can stimulate the proliferation and collagen synthesis of HSCs in a dose-dependent manner; and activation of RAS may be related to hepatic fibrogenesis induced by CCl 4.