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/ .