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

Abstract

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⁺ /Ca²⁺ exchanger (NCX), which is overexpressed in HF. We therefore used the cardiac glycoside ouabain in Ca²⁺ imaging experiments and patch-clamp experiments in isolated ventricular myocytes from nonfailing transgenic NCX overexpressor mice (OE). In field-stimulated myocytes, ouabain (1-100 μm) increased the amplitude of the Ca²⁺ transient in OE and wild-type (WT) similarly. Ouabain-mediated spontaneous Ca²⁺ -activity was significantly more pronounced in OE compared to WT myocytes at higher concentrations (100 μm). Also, at very high concentrations (1000 μm) of ouabain, the number of cells with hypercontraction leading to cell death was higher in OE. Ouabain (10 μm) 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.

Keywords: Na+/Ca2+ exchanger; arrhythmia mechanisms; digitalis; heart failure; sudden cardiac death; translational research.