Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and Tempol.
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.
Kutala
Vijay Kumar
VK
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, and Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.
Khan
Mahmood
M
Mandal
Rajarsi
R
Potaraju
Vandana
V
Colantuono
Giuseppe
G
Kumbala
Damodar
D
Kuppusamy
Periannan
P
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
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