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/ .