Overexpression of the Na⁺/Ca²⁺ exchanger influences ouabain‐mediated spontaneous Ca²⁺ activity but not positive inotropy

Administration of digitalis in heart failure ( HF ) increases quality of life but does not carry a prognostic benefit. Digitalis is an indirect inhibitor of the Na + /Ca 2+ exchanger ( NCX ), which is overexpressed in HF . We therefore used the cardiac glycoside ouabain in Ca 2+ imaging experiments and patch‐clamp experiments in isolated ventricular myocytes from nonfailing transgenic NCX overexpressor mice ( OE ). In field‐stimulated myocytes, ouabain (1–100 μ m ) increased the amplitude of the Ca 2+ transient in OE and wild‐type ( WT ) similarly. Ouabain‐mediated spontaneous Ca 2+ ‐activity was significantly more pronounced in OE compared to WT myocytes at higher concentrations (100 μm). Also, at very high concentrations (1000 μ m ) of ouabain, the number of cells with hypercontraction leading to cell death was higher in OE . Ouabain (10 μ m ) shortened the action potential duration in both genotypes. Our findings suggest that the proarrhythmic but not the inotropic effects of cardiac glycosides are enhanced by increased NCX expression. This may offer an explanation for the observed lack of prognostic benefit but increased quality of life in HF , which is accompanied by NCX upregulation.