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CARDIOVASCULAR

Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties

Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, Ohio (V.K.K., M.K., R.M., L.P.G., S.T., P.K.); and Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary (T.K., K.H.)

Trimetazidine (TMZ), an anti-ischemic metabolic drug, is used to treat chest pain (angina pectoris). We hypothesized that derivatives of TMZ with antioxidant functions may improve the cardiac dysfunction caused by ischemia-reperfusion (I/R) above that observed with TMZ alone. Isolated rat hearts perfused with Krebs-Henseleit buffer according to the Langendorff method were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Trimetazidine, TMZ-NH (TMZ modified with a pyrroline moiety), or TMZ-NH (TMZ-NH with a phenyl substitute) were infused (50 µM) for 1 min before the onset of ischemia. Untreated (control) hearts at the end of 45 min of reperfusion showed a significant decrease in the recovery of coronary flow (42%), left ventricular-developed pressure (22%), and rate-pressure product (25%) compared with preischemic baseline values. The I/R hearts also showed markedly increased lactate dehydrogenase and creatine kinase activities in the coronary effluent, significant myocardial infarction (46% of risk area), and activation of Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. Pretreatment of hearts with TMZ-NH or TMZ-NH significantly enhanced the recovery of heart function and decreased infarct size. The I/R-induced activation of Akt was further enhanced by TMZ-NH. The present study demonstrated that TMZ-NH and TMZ-NH significantly protected hearts against I/R-mediated cardiac dysfunction and injury. The protective effect of the TMZ derivatives could be due to the combined effects of antioxidant and anti-ischemic activities as well as enhanced pro-survival Akt activity.

Address correspondence to: Dr. Periannan Kuppusamy, Davis Heart and Lung Research Institute, The Ohio State University, 420 W. 12th Ave., Room 114, Columbus, OH 43210. E-mail: kuppusamy.1{at}osu.edu

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