Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

Abstract

Aims/Methods: Our aim was to the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg·kg⁻¹·J⁻¹, PTX (50 mg·kg⁻¹·J⁻¹) and SPN (100 mg·kg⁻¹·J⁻¹). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres).

Results: Portal venous pressure (PL: 15.5±1.5, SMV: 15.8±2.5, PTX: 15.9±1.8, SPN: 13.5±2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30±31, SMV: 18±27, PTX: 25±24, SPN: 5±4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between porto-systemic shunts and portal pressure (r_s=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7±3.9, SMV: 7.1±3.6, PTX: 7.8±2.7, SPN: 6.6±3.3%) but was higher than in sham rats (1.5±0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374±162 to 420±131 μg/l, among the four groups) than in sham rats (52±16 μg/l, p<0.0001).

Conclusions: In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effect in patients with early portal hypertension.