title: Sivelestat attenuates myocardial reperfusion injury during brief low flow postischemic infusion.
abstract: The neutrophil elastase inhibitor sivelestat (ONO-5046) possesses unknown mechanisms of cardioprotection when infused following global ischemia, even in the absence of neutrophils. Since myocardial ischemia-reperfusion injury is strongly associated with endothelial dysfunction and reactive oxygen species (ROS) generation during reperfusion, we have tested the hypothesis that infusion of sivelestat during postischemic low flow would preserve endothelial and contractile function and reduce infarct size through an ROS-mediated mechanism. Isolated male rat hearts, subjected to global ischemia of 25 minutes, were reperfused with low flow with or without sivelestat followed by a full flow reperfusion. Hearts treated with sivelestat showed a significant improvement of LV contractile function and a reduction in infarct size. Infusion of L-NAME (nonspecific blocker of endothelial nitric oxide synthase (eNOS)) along with sivelestat during reperfusion reversed the preservation of contractile function and infarct size. In vitro EPR spin trapping experiments showed that sivelestat treatment decreased superoxide adduct formation in bovine aortic endothelial cells (BAECs) subjected to hypoxia-reoxygenation. Similarly, dihydroethidine (DHE) staining showed decreased superoxide production in LV sections from sivelestat-treated hearts. Taken together, these results indicate that sivelestat infusion during postischemic low flow reduces infarct size and preserves vasoreactivity in association with decreased ROS formation and the preservation of nitric oxide.
authors.affiliation: Department of Emergency Medicine, The Davis Heart Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Sverre E
authors.initials: SE
authors.lastname: Aune
authors.forename: Steve T
authors.initials: ST
authors.lastname: Yeh
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.forename: M Lakshmi
authors.initials: ML
authors.lastname: Kuppusamy
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Mark G
authors.initials: MG
authors.lastname: Angelos
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002417:Cattle; D003326:Coronary Circulation / Q000187:drug effects*; D003402:Creatine Kinase / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013481:Superoxides; C069195:sivelestat; D052250:Nitric Oxide Synthase Type III; D003402:Creatine Kinase; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester