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Sodium‐activated potassium channels moderate excitability in vascular smooth muscle
Author(s) -
Li Ping,
Halabi Carmen M.,
Stewart Richard,
Butler Alice,
Brown Bobbie,
Xia Xiaoming,
Santi Celia,
England Sarah,
Ferreira Juan,
Mecham Robert P.,
Salkoff Lawrence
Publication year - 2019
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp278279
Subject(s) - endocrinology , medicine , chemistry , angiotensin ii , phenylephrine , potassium channel , potassium , vascular smooth muscle , sodium , receptor , patch clamp , membrane potential , biophysics , blood pressure , biology , biochemistry , smooth muscle , organic chemistry
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 Ca 2+ ‐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.