title: Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.
abstract: 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.
  
  
  CONCLUSIONS
  LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Mura
authors.forename: Marcos
authors.initials: M
authors.lastname: Pasarín
authors.forename: Cintia Z
authors.initials: CZ
authors.lastname: Meireles
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Diana
authors.initials: D
authors.lastname: Hide
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D019821:Simvastatin