Role of mitochondrial dysfunction in cardiac glycoside toxicity

Ting Liu, David A. Brown, Brian O'Rourke

Research output: Contribution to journalArticle

Abstract

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 Ca2+ ([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+]i 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 β-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.

Original languageEnglish (US)
Pages (from-to)728-736
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number5
DOIs
StatePublished - Nov 1 2010

Keywords

  • Arrhythmias
  • Cardiac glycosides
  • Energy metabolism
  • Heart failure
  • Ion transport
  • Na/Ca exchanger

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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