Upregulation of the sodium-leak channel NALCN contributes to arterial hyperexcitability and excessive vasoconstriction in mineralocorticoid-induced hypertension

Introduction: Voltage-gated potassium (Kv) channels regulate vascular smooth muscle membrane potential. Consequently, they are considered the primary regulators of both resting vascular tone and agonist-evoked excitability in physiological and pathological conditions, including hypertension. Recently, we reported that the NALCN (sodium Na + -leak channel, non-selective) protein is also upregulated in the mesenteric arteries under the mineralocorticoid-induced hypertension. The roles of NALCN in regulating the resting membrane potential (RMP) in neurons are widely reported. However, it remains unclear whether this channel plays similar or distinct roles in vascular smooth muscle cells and how it contributes to elevated basal arterial tone and stronger agonist-induced vasoconstriction under hypertension. Hypothesis: Upregulation of NALCN increases background and agonist-stimulated Na + conductance, leading to exaggerated excitability in arterial smooth muscle. Methods: Mesenteric arterial smooth muscle cells were isolated from sham rats (subjected to uninephrectomy alone) and DOCA-hypertensive rats (receiving DOCA treatment combined with uninephrectomy and a high-salt diet). Perforated-patch clamp was employed to measure L-type Ca 2+ currents, macroscopic Kv currents, RMP, and membrane conductance under both basal and serotonin (5-HT)–stimulated conditions. Na + dependence was assessed using an external solution with low Na + concentration ([Na + ]). Results: The arterial smooth muscle cells from DOCA-treated rats exhibited a markedly depolarized RMP that was largely restored toward normal values when extracellular [Na + ] was reduced, indicating increased Na + -dependent conductance. Membrane conductance near the RMP was significantly higher in DOCA cells and decreased more prominently than in sham cells under low-[Na + ]. During 5-HT stimulation, DOCA arterial smooth muscle cells showed greatly increased depolarization accompanied by a pronounced Na + -dependent rise in conductance, whereas sham cells displayed the expected Kv inhibition–driven responses. These results indicate that the enhanced depolarization in DOCA-hypertensive arterial smooth muscle cells is primarily driven by activation of inward Na + currents, whereas the depolarization in sham cells results mainly from inhibition of outward Kv currents. Lastly, L-type Ca 2+ currents and Kv currents did not differ between smooth muscle cells from sham rats and those from DOCA-hypertensive rats, indicating that increased excitability by DOCA-induced hypertension was not attributable to changes in these channels. Conclusion Increased NALCN expression in arterial smooth muscle cells modulates membrane excitability by enhancing Na + influx, depolarizing the RMP, and amplifying receptor-evoked response, which contributes to arterial hyperexcitability and excessive vasoconstriction in mineralocorticoid hypertension. Funding: Supported by AHA 25IVPHA1471033 (J.O.-U. and Y.M.B.) and by the National Research Foundation of Korea (NRF) RS-2023-00278350 (H.L., S.P., and Y.M.B) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.