Lidocaine and Mexiletine Inhibit Mitochondrial Oxidation in Rat Ventricular Myocytes


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Abstract

BackgroundAccumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate–sensitive K+ (KATP) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial KATP channel activities.MethodsMale Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 μm), a selective mitochondrial KATP channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential.ResultsDiazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial KATP channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial KATP channels. Lidocaine (103 to 10 mm) and mexiletine (103 to 10 mm) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98 ± 63 μm for lidocaine and 107 ± 89 μm for mexiletine.ConclusionsBoth lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial KATP channels.

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