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 Ca²⁺ transient, and prolonged action potential all 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.