Role of mitochondrial dysfunction in cardiac glycoside toxicity

Results and significance: ► The present study shows that the cardiac glycoside ouabain increases cytosolic Na+, blunts mitochondrial Ca2+ accumulation during increased work (β-adrenergic stimulation and electrical pacing), causes net oxidation of the NAD(P)H pool, increases reactive oxygen species accumulation, and causes triggered arrhythmias. ► The mitochondrial dysfunction caused by ouabain could be prevented by enhancing mitochondrial Ca2+ uptake with an inhibitor (CGP37157) of the mitochondrial Na+/Ca2+ exchanger (mNCE). ► CGP37157 effectively preserved mitochondrial function during ouabain administration, potentiating the positive inotropic actions of the glycoside (and β-adrenergic agonists) and mitigating the toxic effects in cells, perfused hearts, or intact animals. ► The results suggest that partial mNCE inhibition may represent a novel strategy for improving cardiac glycoside therapy in the context of heart failure.