Overexpression of the Na+ /Ca2+ exchanger (NCX) influences ouabain mediated spontaneous Ca2+ activity but not positive inotropy.
Fundam Clin Pharmacol. 2018 Aug 09;:
Authors: Bögeholz N, Pauls P, Bauer KB, Schulte JS, Frommeyer G, Dechering DG, Boknik P, Kirchhefer U, Müller FU, Pott C, Eckardt L
BACKGROUND/METHODS: 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 non-failing transgenic NCX-overexpressor-mice (OE).
RESULTS: 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.
CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.
PMID: 30092622 [PubMed – as supplied by publisher]