Role of mitochondrial dysfunction in cardiac glycoside toxicity.

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 Ca(2+) ([Ca(2+)](m)) accumulation, and this impairment can be prevented by enhancing [Ca(2+)](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 Ca(2+) efflux, via inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na(+)](i) in a dose-dependent way, blunted [Ca(2+)](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 Ca(2+) 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 Ca(2+) retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca(2+)-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.

• Authors: Ting Liu, David A Brown, Brian O'Rourke
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 49 Issue 5 Pg. 728-36 (Nov 2010) ISSN: 1095-8584 [Electronic] England
• PMID: 20620145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Cardiac Glycosides
• Sodium-Calcium Exchanger
• Thiazepines
• NAD
• Ouabain
• Clonazepam
• CGP 37157
• Sodium
• Isoproterenol
• Calcium

Topics

• Action Potentials (drug effects)
• Animals
• Arrhythmias, Cardiac (physiopathology)
• Calcium (metabolism)
• Cardiac Glycosides (toxicity)
• Clonazepam (analogs & derivatives, pharmacology)
• Guinea Pigs
• Heart (drug effects, physiopathology)
• In Vitro Techniques
• Isoproterenol (pharmacology)
• Mitochondria (drug effects, metabolism, pathology)
• NAD (metabolism)
• Ouabain (pharmacology)
• Oxygen Consumption (drug effects)
• Perfusion
• Sodium (metabolism)
• Sodium-Calcium Exchanger (antagonists & inhibitors, metabolism)
• Thiazepines (pharmacology)