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Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H941-H957. doi: 10.1152/ajpheart.00637.2018. Epub 2019 Jan 18.

Evidence for heterogeneous subsarcolemmal Na+ levels in rat ventricular myocytes.

Author information

1
Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo , Oslo , Norway.
2
Simula Research Laboratory, Center for Cardiological Innovation , Oslo , Norway.
3
K. G. Jebsen Center for Cardiac Research, University of Oslo , Oslo , Norway.
4
Bjørknes College , Oslo , Norway.

Abstract

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/ .

KEYWORDS:

NKA; Na channels; Na homeostasis; fuzzy space; subsarcolemmal space

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