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CARDIOVASCULAR

Formation of Hydrogen Peroxide and Reduction of Peroxynitrite via Dismutation of Superoxide at Reperfusion Enhances Myocardial Blood Flow and Oxygen Consumption in Postischemic Mouse Heart

The Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio (Y.X., B.L., J.L.Z, G.H.); and Key Laboratory of Organ Transplantation, Ministry of Education Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.X.)

Reactive oxygen/nitrogen species suppress myocardial oxygen consumption. In this study, we determined that endogenous hydrogen peroxide through dismutation of superoxide enhances postischemic myocardial blood perfusion and oxygen consumption. Electron paramagnetic resonance oximetry was applied to monitor in vivo tissue Po₂ in mouse heart subjected to regional ischemia reperfusion. Heart rate, arterial blood pressure, blood flow, infarction, and activities of mitochondrial NADH dehydrogenase and cytochrome c oxidase were measured in six groups of wild-type (WT) and endothelial nitricoxide synthase knock-out (eNOS^-/-) mice treated with phosphate-buffered saline (PBS), superoxide dismutase mimetic (SOD_m) M40403 [a manganese(II)-bis(cyclohexylpyridine)-substituted macrocyclic superoxide dismutase mimetic, C₂₁H₃₅Cl₂MnN₅], 10006329 EUK 134 [EUK134, manganese 3-methoxy N,N¹-bis(salicyclidene)ethylenediamine chloride], and SOD_m plus glibenclamide to study the protective effect of hydrogen peroxide via dismutation of superoxide on the activation of sarcolemmal potassium channels. In the PBS group, there was an overshoot of tissue Po₂ after reperfusion. Treatment with SOD_m, EUK134, and SOD_m + glibenclamide protected mitochondrial enzyme activities, reduced infarct size, and suppressed the postischemic hyperoxygenation. In particular, in the SOD_m-treated group, there was a transient peak of tissue Po₂ at 9 min after reperfusion, which was dependent on endogenous hydrogen peroxide but not nitric oxide formation as it appeared in both WT and eNOS^-/- mice. Blood flow and rate pressure product were higher in the SOD_m group than in other groups, which contributed to the transient oxygen peak. Thus, SOD mimetics protected mouse heart from superoxide-induced reperfusion injury. With treatment of different SOD mimetics, it is concluded that endogenous hydrogen peroxide via dismutation of superoxide at reperfusion enhances postischemic myocardial blood perfusion and mitochondrial oxygen consumption, possibly through activation of sarcolemmal ATP-sensitive potassium channels.

Address correspondence to: Dr. Guanglong He, 460 West 12th Avenue, 0388/BRT, Columbus, OH 43210. E-mail: guanglong.he{at}osumc.edu