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/ .