Evidence for heterogeneous subsarcolemmal Na⁺ levels in rat ventricular myocytes

The intracellular Na⁺ concentration ([Na⁺]) regulates cardiac contractility. Previous studies have suggested that subsarcolemmal [Na⁺] is higher than cytosolic [Na⁺] in cardiac myocytes, but this concept remains controversial. Here, we used electrophysiological experiments and mathematical modeling to test whether there are subsarcolemmal pools with different [Na⁺] and dynamics compared with the bulk cytosol in rat ventricular myocytes. A Na⁺ dependency curve for Na⁺-K⁺-ATPase (NKA) current was recorded with symmetrical Na⁺ solutions, i.e., the same [Na⁺] in the superfusate and internal solution. This curve was used to estimate [Na⁺] sensed by NKA in other experiments. Three experimental observations suggested that [Na⁺] is higher near NKA than in the bulk cytosol: 1) when extracellular [Na⁺] was high, [Na⁺] sensed by NKA was ~6 mM higher than the internal solution in quiescent cells; 2) long trains of Na⁺ channel activation almost doubled this gradient; compared with an even intracellular distribution of Na⁺, the increase of [Na⁺] sensed by NKA was 10 times higher than expected, suggesting a local Na⁺ domain; and 3) accumulation of Na⁺ near NKA after trains of Na⁺ channel activation dissipated very slowly. Finally, mathematical models assuming heterogeneity of [Na⁺] between NKA and the Na⁺ channel better reproduced experimental data than the homogeneous model. In conclusion, our data suggest that NKA-sensed [Na⁺] is higher than [Na⁺] in the bulk cytosol and that there are differential Na⁺ pools in the subsarcolemmal space, which could be important for cardiac contractility and arrhythmogenesis. NEW & NOTEWORTHY Our data suggest that the Na⁺-K⁺-ATPase-sensed Na⁺ concentration is higher than the Na⁺ concentration in the bulk cytosol and that there are differential Na⁺ pools in the subsarcolemmal space, which could be important for cardiac contractility and arrhythmogenesis. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/heterogeneous-sodium-in-ventricular-myocytes/ .