Department of Neuroscience.
Department of Pediatrics.
J Physiol. 2019 Oct;597(20):5093-5108. doi: 10.1113/JP278279. Epub 2019 Oct 1.
We report that a sodium-activated potassium current, IK , has been inadvertently overlooked in both conduit and resistance arterial smooth muscle cells. IK is a major K resting conductance and is absent in cells of IK knockout (KO) mice. The phenotype of the IK KO is mild hypertension, although KO mice react more strongly than wild-type with raised blood pressure when challenged with vasoconstrictive agents. IK is negatively regulated by angiotensin II acting through Gαq protein-coupled receptors. In current clamp, KO arterial smooth muscle cells have easily evoked Ca -dependent action potentials.
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 , 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 is the largest contributor to ASM cell resting conductance. A genetic knockout (KO) mouse strain lacking K 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 , which increases the excitability of the ASMs. The complete genetic removal of IK 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 may represent a new therapeutic target for hypertension and stroke.
我们报告称，一种钠激活钾电流（IK）在导管和阻力动脉平滑肌细胞中被无意中忽略。IK 是主要的 K 静息电导，在 IK 敲除（KO）小鼠的细胞中不存在。IK KO 的表型是轻度高血压，尽管 KO 小鼠对血管收缩剂引起的血压升高的反应比野生型更强烈。IK 受血管紧张素 II 通过 Gαq 蛋白偶联受体的作用负调控。在电流钳中，KO 动脉平滑肌细胞的 Ca2+依赖性动作电位很容易被激发。
尽管已经报道了几种钾电流在动脉平滑肌（ASM）中发挥作用，但我们发现，在决定细胞固有兴奋性的关键生理电压范围内，对膜电导贡献最大的钾电流之一被无意中忽略了。在本研究中，我们表明，一种钠激活钾电流（IK），在决定细胞固有兴奋性的关键生理电压范围内，对宏观外向电流有很大贡献；IK 是 ASM 细胞静息电导的最大贡献者。一种缺乏钾通道（KCNT1 和 KCNT2）的基因敲除（KO）小鼠品系仅表现出温和的高血压表型。然而，急性给予血管收缩剂，如血管紧张素 II（Ang II）和苯肾上腺素，会导致 KO 动物的血压异常升高。在野生型动物中，Ang II 通过 Gαq 蛋白偶联受体下调 IK，从而增加 ASM 的兴奋性。在 KO 小鼠中完全遗传去除 IK 会使突变动物对血管收缩剂更敏感，从而产生阵发性高血压表型。这可能是由于细胞静息 K 电导降低，使细胞更容易向各种兴奋刺激去极化。因此，钠激活钾电流可能在应激升高时起到调节血压的作用。IK 可能成为高血压和中风的新治疗靶点。
