Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation.
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.
Oberti
F
F
Laboratoire d'Hémodynamique Splanchnique, UFR de Médecine, Université d'Angers, France.
Pilette
C
C
Rifflet
H
H
Maïga
M Y
MY
Moreau
A
A
Gallois
Y
Y
Girault
A
A
le Bouil
A
A
Le Jeune
J J
JJ
Saumet
J L
JL
Feldmann
G
G
Calès
P
P
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
D000960:Hypolipidemic Agents; D013148:Spironolactone; D008148:Lovastatin; D019821:Simvastatin; D010431:Pentoxifylline