Intracellular Na + Concentration Is Elevated in Heart Failure But Na/K Pump Function Is Unchanged

Abstract

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 ≈2 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 Ca 2+ transient, and prolonged action potential all profoundly affect cellular Ca 2+ regulation, promoting greater Ca 2+ influx through NCX during action potentials. Notably, the elevated [Na + ] i may be critical in limiting the contractile dysfunction observed in HF.