Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats.
OBJECTIVE
Sinusoidal endothelial dysfunction with decreased nitric oxide (NO) production contributes to increased hepatic resistance in cirrhosis. Statins improve endothelial dysfunction in peripheral vasculature. This study was designed to characterize the hemodynamic and molecular effects of statins in cirrhotic rats.


METHODS
Systemic and splanchnic hemodynamics were evaluated in CCl(4) ascitic cirrhotic rats treated with placebo or simvastatin (25 mg/kg/day, for 3 days), at baseline and after volume expansion. Vascular responses of liver vasculature were evaluated after isolation and perfusion of the liver.


RESULTS
There were no differences in baseline hemodynamics in rats treated with simvastatin or placebo. However, in rats treated with simvastatin the increase in portal pressure induced by volume expansion was significantly attenuated. In isolated and perfused cirrhotic livers simvastatin pre-treatment significantly attenuated the pressure response to methoxamine, and significantly improved paradoxical vasoconstriction induced by acetylcholine. These effects were not observed in the presence of a nitric oxide synthase inhibitor. Simvastatin increased eNOS expression, Akt-dependent eNOS phosphorylation and cGMP liver content.


CONCLUSIONS
The administration of simvastatin might constitute a new way to selectively increase NO availability in the cirrhotic liver circulation and, therefore improve the vascular disturbances that contribute to portal hypertension.
Abraldes
Juan G
JG
Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Ciberehd, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
Rodríguez-Vilarrupla
Aina
A
Graupera
Mariona
M
Zafra
Carmen
C
García-Calderó
Héctor
H
García-Pagán
Juan Carlos
JC
Bosch
Jaime
J
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D006152:Cyclic GMP / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D009569:Nitric Oxide; D019821:Simvastatin; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP