Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged

Background-Intracellular sodium concentration ([Na+](i)) modulates cardiac contractile and electrical activity through Na/Ca exchange (NCX). Upregulation of NCX in heart failure (HF) may magnify the functional impact of altered [Na+](i). Methods and Results-We measured [Na+](i) by using sodium binding benzofuran isophthalate in control and HF rabbit ventricular myocytes (HF induced by aortic insufficiency and constriction). Resting [Na+](i) was 9.7+/-0.7 versus 6.6+/-0.5 mmol/L in HF versus control. In both cases, [Na+](i) increased by approximate to2 mmol/L when myocytes were stimulated (0.5 to 3 Hz). To identify the mechanisms responsible for [Na+](i) elevation in HF, we measured the [Na+](i) dependence of Na/K pump-mediated Na+ extrusion. There was no difference in V-max (8.3+/-0.7 versus 8.0+/-0.8 mmol/L/min) or K-m (9.2+/-1.0 versus 9.9+/-0.8 mmol/L in HF and control, respectively). Therefore, at measured [Na+](i) levels, the Na/K pump rate is actually higher in HF. However, resting Na+ influx was twice as high in HF versus control (2.3+/-0.3 versus 1.1+/-0.2 mmol/L/min), primarily the result of a tetrodotoxin-sensitive pathway. Conclusions-Myocyte [Na+](i) is elevated in HF as a result of higher diastolic Na+ influx (with unaltered Na/K-ATPase characteristics). In HF, the combined increased [Na+](i), decreased Ca2+ transient, and prolonged action potential an profoundly affect cellular Ca2+ regulation, promoting greater Ca2+ influx through NCX during action potentials. Notably, the elevated [Na+](i) may be critical in limiting the contractile dysfunction observed in HF.