EFFECTS OF SIMVASTATIN, PENTOXIFYLLINE AND SPIRONOLACTONE ON HEPATIC-FIBROSIS AND PORTAL-HYPERTENSION IN RATS WITH BILE-DUCT LIGATION

Aims/Methods: Our aim was to study the antifibrotic and hemodynamic ef fects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (S PN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension in duced in rats by bile duct ligation. A blind study was performed in fi ve groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg.k g(-1).J(-1)), PTX (50 mg.kg(-1).J(-1)) and SPN (100 mg.kg(-1).J(-1)). Drugs mere administered by daily gavage over a 4-week period as soon a s bile duct ligation was performed. At day 28, the following parameter s mere evaluated: area of hepatic fibrosis by image analysis after sta ining collagen with picrosirius and plasma concentrations of hyalurona te, 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 co rrelation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among t he 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 sha m rats (1.5 +/- 0.5%, p<0.001). Hyaluronate was significantly higher i n bile duct ligated rats (from 374 +/- 162 to 420 +/- 131 mu g/l, amon g the four groups) than in sham rats (52 +/- 16 mu g/l, p<0.0001). Con clusions: In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and preve nted porto-systemic shunts. Therefore, this drug may have beneficial e ffects in patients with early portal hypertension.