Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

Background & Aims: In cirrhosis, an insufficient release of nitric oxide contributes to increased hepatic resistance and portal pressure and enhances the postprandial increase in portal pressure. We hypothesized that simvastatin, which enhances Akt-dependent endothelial nitric oxide synthase phosphorylation, may increase hepatic nitric oxide release and decrease hepatic resistance in patients with cirrhosis and portal hypertension. Methods: In protocol 1, 13 patients had measurements of the hepatic venous pressure gradient, hepatic blood flow, mean arterial pressure, cardiac output, and nitric oxide products before and 30 and 60 minutes after 40 mg of simvastatin. In protocol 2, 17 patients were randomized to receive placebo or simvastatin (40 mg) 12 hours and 1 hour before the study. After baseline measurements of the hepatic venous pressure gradient, hepatic blood flow, and nitric oxide products, a standard liquid meal was given, and measurements were repeated at 15, 30, and 45 minutes. Results: In protocol 1, acute simvastatin did not modify the hepatic venous pressure gradient but increased the hepatic blood flow (21% ± 13% at 30 minutes; P = 0.01) and decreased hepatic sinusoidal resistance by 14% ± 11% (P = 0.04). Nitric oxide product levels significantly increased in hepatic venous blood (from 31.4 ± 12.3 nmol · mL−1 to 35.8 ± 10.7 nmol · mL−1; P = 0.04), but not in peripheral blood. Systemic hemodynamics were not modified. In protocol 2, simvastatin pretreatment significantly attenuated the postprandial increase in hepatic venous pressure gradient (mean peak increase, 10% ± 9% vs. 21% ± 6% in placebo; P = 0.01). Hepatic blood flow increased similarly in the 2 groups. Hepatic nitric oxide products increased in the simvastatin group but not in the placebo group. Conclusions: Simvastatin administration increases the hepatosplanchnic output of nitric oxide products and decreases hepatic resistance in patients with cirrhosis.