Role of mitochondrial dysfunction in cardiac glycoside toxicity

Cardiac glycosides, which inhibit the plasma membrane Na+ pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects. Elevated cytoplasmic Na+ ([Na+](i)) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca-2 ([Ca2+](m)) accumulation, and this impairment can be prevented by enhancing [Ca2+](m). Here, we investigate whether this effect underlies the toxicity and arrhythmogenic effects of cardiac glycosides and if these effects can be prevented by suppressing mitochondrial Ca2+ efflux, via inhibition of the mitochondrial Na+/Ca2+ exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na+] in a dose-dependent way, blunted [Ca2+](m) accumulation, decreased the NADH/NAD+redox potential, and increased reactive oxygen species (ROS). Concomitant treatment with the mNCE inhibitor CGP-37157 ameliorated these effects. CGP-37157 also attenuated ouabain-induced cellular Ca2+ overload and prevented delayed afterdepolarizations (DADs). In isolated perfused hearts, ouabain's positive effects on contractility and respiration were markedly potentiated by CGP-37157, as were those mediated by beta-adrenergic stimulation. Furthermore, CGP-37157 inhibited the arrhythmogenic effects of ouabain in both isolated perfused hearts and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca2+ retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca2+-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure. (C) 2010 Elsevier Ltd. All rights reserved.