title: Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and Tempol.
abstract: Nitric oxide (NO) plays a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the concomitant production of superoxide and other reactive oxygen species (ROS) during I/R may diminish the bioavailability of NO and hence compromise the beneficial effects. The objective of this study was to investigate the protective effect of the coadministration of NCX-4016 [2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester] (an NO donor) with antioxidants Tempol, superoxide dismutase (SOD), or urate on I/R injury. Isolated rat hearts, perfused with Krebs-Henseleit buffer, were subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. Before the induction of ischemia, the hearts were infused for 1 minute with NCX-4016 (100 microM) either alone or in combination with Tempol (100 microM), SOD (200 U/mL), or urate (100 microM). Hearts pretreated with NCX-4016 showed a significantly enhanced recovery of function and decreased infarct size and LDH/CK release compared with the controls. However, treatment of hearts with NCX-4016 + Tempol, SOD, or urate showed a significantly enhanced recovery of heart function compared with NCX-4016 alone. The treatment of hearts with NCX-4016 + Tempol showed significantly enhanced NO generation and decreased ROS and dityrosine (a marker of peroxynitrite) formation. In conclusion, NCX-4016 in combination with Tempol demonstrated significant cardioprotection and, thus, may offer a novel therapeutic strategy to prevent I/R-mediated myocardial injury.
authors.affiliation: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, and Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Rajarsi
authors.initials: R
authors.lastname: Mandal
authors.forename: Vandana
authors.initials: V
authors.lastname: Potaraju
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Colantuono
authors.forename: Damodar
authors.initials: D
authors.lastname: Kumbala
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D003497:Cyclic N-Oxides; D013113:Spin Labels; D013481:Superoxides; D030421:Peroxynitrous Acid; D014527:Uric Acid; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003402:Creatine Kinase; C102148:nitroaspirin; D001241:Aspirin; C001803:tempol