Effects of simvastatin administration on rodents with lipopolysaccharide‐induced liver microvascular dysfunction

• Published in: Hepatology (Baltimore, Md.) Vol. 57; no. 3; pp. 1172 - 1181
• Main Authors: La Mura, Vincenzo, Pasarín, Marcos, Meireles, Cintia Z., Miquel, Rosa, Rodríguez‐Vilarrupla, Aina, Hide, Diana, Gracia‐Sancho, Jorge, García‐Pagán, Juan Carlos, Bosch, Jaime, Abraldes, Juan G.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2013; Wiley Subscription Services, Inc
• Subjects: Animals; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - physiopathology; Disease Models, Animal; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Endotoxemia - chemically induced; Endotoxemia - drug therapy; Endotoxemia - physiopathology; Hepatology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipopolysaccharides - toxicity; Liver; Liver - blood supply; Liver - drug effects; Liver - physiopathology; Liver Circulation - drug effects; Liver Circulation - physiology; Male; Microcirculation - drug effects; Microcirculation - physiology; Nitric oxide; Rats; Rats, Wistar; Rodents; Sepsis; Simvastatin - pharmacology; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.26127

Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS) / endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. Conclusion: LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. (HEPATOLOGY 2013)