Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension.
OBJECTIVE
To assess the effects of the early and chronic administration of losartan--a specific angiotensin II receptor antagonist--in the prevention of hepatic fibrosis and portal hypertension.


RESULTS
(1) In CCl(4) rats, losartan at 5 and 10 mg/kg per day significantly decreased portal pressure (-11, -18%, respectively), splenorenal shunt blood flow (-60, -80%) and liver fibrosis (liver hydroxyproline and area of fibrosis) without significant changes in mortality and mean arterial pressure (MAP). (2) In bile duct ligated (BDL) rats, losartan at 5 mg/kg per day significantly decreased portal pressure (-14%), splenorenal shunt blood flow (-70%) and liver fibrosis. Losartan at 10 mg/kg per day significantly worsened liver and renal functions, mortality and liver fibrosis, without significant changes in portal pressure and splenorenal shunt blood flow. Losartan at 5 and 10 mg/kg per day significantly decreased MAP (-24, -30%). (3) In portal vein ligated (PVL) rats, losartan significantly decreased MAP (-12%) but did not change portal pressure or splenorenal shunt blood flow.


CONCLUSIONS
In BDL and CCl(4) rats, losartan has beneficial effects on splanchnic hemodynamics and liver fibrosis. Losartan might decrease hepatic resistances in fibrotic liver. Losartan decreased MAP except in CCl(4) rats. Higher dosage of losartan had deleterious effects in BDL rats.
Croquet
Vincent
V
Laboratoire HIFIH, UPRES EA 2170, Université d'Angers, 49033 Angers Cedex 01, France.
Moal
Frédéric
F
Veal
Nary
N
Wang
Jianhua
J
Oberti
Frédéric
F
Roux
Jérôme
J
Vuillemin
Eric
E
Gallois
Yves
Y
Douay
Olivier
O
Chappard
Daniel
D
Calès
Paul
P
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001652:Bile Ducts; D001663:Bilirubin / Q000097:blood; D002251:Carbon Tetrachloride; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008026:Ligation; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D019808:Losartan / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D019808:Losartan; D001663:Bilirubin