title: Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation.
abstract: OBJECTIVE
  Our aim was to study 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 x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x 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 portosystemic 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 microg/l, among the four groups) than in sham rats (52+/-16 microg/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 effects in patients with early portal hypertension.
authors.affiliation: Laboratoire d'Hémodynamique Splanchnique, UFR de Médecine, Université d'Angers, France.
authors.forename: F
authors.initials: F
authors.lastname: Oberti
authors.forename: C
authors.initials: C
authors.lastname: Pilette
authors.forename: H
authors.initials: H
authors.lastname: Rifflet
authors.forename: M Y
authors.initials: MY
authors.lastname: Maïga
authors.forename: A
authors.initials: A
authors.lastname: Moreau
authors.forename: Y
authors.initials: Y
authors.lastname: Gallois
authors.forename: A
authors.initials: A
authors.lastname: Girault
authors.forename: A
authors.initials: A
authors.lastname: le Bouil
authors.forename: J J
authors.initials: JJ
authors.lastname: Le Jeune
authors.forename: J L
authors.initials: JL
authors.lastname: Saumet
authors.forename: G
authors.initials: G
authors.lastname: Feldmann
authors.forename: P
authors.initials: P
authors.lastname: Calès
mesh_terms: D000818:Animals; D001652:Bile Ducts; D001794:Blood Pressure; D004311:Double-Blind Method; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006975:Hypertension, Portal / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D011170:Portasystemic Shunt, Surgical; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012079:Renal Circulation; D019821:Simvastatin; D013148:Spironolactone / Q000494:pharmacology* / Q000627:therapeutic use; D014655:Vascular Resistance
chemical_list: D000960:Hypolipidemic Agents; D013148:Spironolactone; D008148:Lovastatin; D019821:Simvastatin; D010431:Pentoxifylline