Sodium-activated potassium channels moderate excitability in vascular smooth muscle

Abstract

Key points: We report that a sodium-activated potassium current, IK_Na , has been inadvertently overlooked in both conduit and resistance arterial smooth muscle cells. IK_Na is a major K⁺ resting conductance and is absent in cells of IK_Na knockout (KO) mice. The phenotype of the IK_Na KO is mild hypertension, although KO mice react more strongly than wild-type with raised blood pressure when challenged with vasoconstrictive agents. IK_Na is negatively regulated by angiotensin II acting through Gαq protein-coupled receptors. In current clamp, KO arterial smooth muscle cells have easily evoked Ca²⁺ -dependent action potentials.

Abstract: Although several potassium currents have been reported to play a role in arterial smooth muscle (ASM), we find that one of the largest contributors to membrane conductance in both conduit and resistance ASMs has been inadvertently overlooked. In the present study, we show that IK_Na , a sodium-activated potassium current, contributes a major portion of macroscopic outward current in a critical physiological voltage range that determines intrinsic cell excitability; IK_Na is the largest contributor to ASM cell resting conductance. A genetic knockout (KO) mouse strain lacking K_Na channels (KCNT1 and KCNT2) shows only a modest hypertensive phenotype. However, acute administration of vasoconstrictive agents such as angiotensin II (Ang II) and phenylephrine results in an abnormally large increase in blood pressure in the KO animals. In wild-type animals Ang II acting through Gαq protein-coupled receptors down-regulates IK_Na , which increases the excitability of the ASMs. The complete genetic removal of IK_Na in KO mice makes the mutant animal more vulnerable to vasoconstrictive agents, thus producing a paroxysmal-hypertensive phenotype. This may result from the lowering of cell resting K⁺ conductance allowing the cells to depolarize more readily to a variety of excitable stimuli. Thus, the sodium-activated potassium current may serve to moderate blood pressure in instances of heightened stress. IK_Na may represent a new therapeutic target for hypertension and stroke.

Keywords: KNa1.1; KNa1.2; Slo1; Slo2.1; angiotensin II; persistent sodium current; potassium channel; vascular smooth muscle.