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

Authors

  • Vincenzo La Mura,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Marcos Pasarín,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Cintia Z. Meireles,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Rosa Miquel,

    1. Servei d'Anatomia Patològica, Centre de Diagnòstic Biomèdic, Hospital Clinic, Barcelona, Spain
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  • Aina Rodríguez-Vilarrupla,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Diana Hide,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Jorge Gracia-Sancho,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Juan Carlos García-Pagán,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Jaime Bosch,

    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Juan G. Abraldes

    Corresponding author
    1. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    • Hepatic Hemodynamic Laboratory, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain
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  • Potential conflict of interest: Nothing to report.

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. 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)

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