title: A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats.
abstract: Statins present many beneficial effects in chronic liver disease, but concerns about safety exist. We evaluated the hepatic effects of a nitric oxide-releasing atorvastatin (NCX 6560) compared to conventional statins. Simvastatin, atorvastatin and NCX 6560 were evaluated in four-week bile duct-ligated rats (BDL) simulating decompensated cirrhosis and in thirteen-week carbon tetrachloride (CCl4) intoxicated rats, a model of early cirrhosis. In the BDL model, simvastatin treated rats showed high mortality and the remaining animals presented muscular and hepatic toxicity. At equivalent doses, NCX 6560 eliminated hepatic toxicity and reduced muscular toxicity (60-74%) caused by atorvastatin in the more advanced BDL model; toxicity was minimal in the CCl4model. Atorvastatin and NCX 6560 similarly reduced portal pressure without changing systemic hemodynamics in both models. Atorvastatin and NCX 6560 caused a mild decrease in liver fibrosis and inflammation and a significant increase in intrahepatic cyclic guanosine monophosphate. NCX 6560 induced a higher intrahepatic vasoprotective profile (activated endothelial nitric oxide synthase and decreased platelet/endothelial cell adhesion molecule-1), especially in the CCl4model, suggesting a higher benefit in early cirrhosis. In conclusion, NCX 6560 improves the liver profile and portal hypertension of cirrhotic rats similarly to conventional statins, but with a much better safety profile.
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Rodríguez
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.
authors.forename: Imma
authors.initials: I
authors.lastname: Raurell
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres-Arauz
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: García-Lezana
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Genescà
authors.affiliation: Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martell
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology*; D020030:Nitric Oxide Donors / Q000009:adverse effects* / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP