Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes

Abstract

AimsCardiac glycosides induce cardiomyocyte hypertrophy via yet to be defined mechanisms. These hypertrophic effects are likely related to changes in intracellular signalling secondary to Na+-K+ ATPase (NKA) inhibition which would produce elevations in intracellular sodium concentrations. Sodium-hydrogen exchanger isoform 1 (NHE-1) also contributes to intracellular sodium regulation. Accordingly, we determined the contribution of NHE-1 to cardiac glycoside-induced hypertrophy.Methods and resultsThe majority of the experiments were performed on cultured neonatal rat ventricular myocytes exposed to either ouabain (100 M) or digoxin (40 M) for 24 h, although additional experiments were also done using adult left ventricular myocytes with 30 M of either glycoside. Both glycosides increased cell surface area by 30 and atrial natriuretic peptide gene expression by two-to three-fold (P < 0.05 for both). These effects were associated with a significant reduction in the expression of two NKA isoforms, α2 and α3, whereas the α1 isoform was unaffected. Conversely, both glycosides increased NHE-1 expression in cardiomyocytes by approximately two-fold and significantly increased intracellular sodium concentrations by more than 60 (P < 0.05). Both ouabain and digoxin were also found to significantly increase phosphorylation of mitogen-activated protein kinases. All these effect were prevented when identical experiments were carried out in the presence of the NHE-1 inhibitors EMD 87580 or AVE 4890. Identical results were obtained using adult myocytes, although this was associated with downregulation of all three NKA isoforms. Glycoside-induced increase in cell shortening or intracellular Ca2+ transients was not significantly affected by NHE-1 inhibition.ConclusionWhen taken together, these studies show that NHE-1 inhibition attenuates the hypertrophic effect of cardiac glycosides without affecting inotropic parameters and suggest a possible approach to limiting glycoside-induced hypertrophic responses while preserving therapeutic, i.e. inotropic, actions.