title: 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.affiliation: The Johns Hopkins University, Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, 720 Rutland Ave., 1060 Ross Bldg, Baltimore, MD 21205-2195, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002301:Cardiac Glycosides / Q000633:toxicity*; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009243:NAD / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D002301:Cardiac Glycosides; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D009243:NAD; D010042:Ouabain; D002998:Clonazepam; C079032:CGP 37157; D012964:Sodium; D007545:Isoproterenol; D002118:Calcium