Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary.
Pflugers Arch. 2013 Nov;465(11):1621-35. doi: 10.1007/s00424-013-1309-x. Epub 2013 Jun 27.
The inward rectifier K⁺ current (IK1) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although IK1 was shown to be sensitive to changes in intracellular Ca²⁺ concentration ([Ca²⁺]i), the nature of this Ca²⁺ sensitivity-in spite of its deep influence on action potential morphology-is controversial. Therefore, we aimed to investigate the effects of a nonadrenergic rise in [Ca²⁺]i on the amplitude of IK1 in canine and human ventricular myocardium and its consequences on cardiac repolarization. IK1, defined as the current inhibited by 10 μM Ba²⁺, was significantly increased in isolated canine myocytes following a steady rise in [Ca²⁺]i. Enhanced IK1 was also observed when [Ca²⁺]i was not buffered by ethylene glycol tetraacetic acid, and [Ca²⁺]I transients were generated. This [Ca²⁺]i-dependent augmentation of IK1 was largely attenuated after inhibition of CaMKII by 1 μM KN-93. Elevation of [Ca²⁺]o in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca²⁺]o enhanced the action potential lengthening effect of the Ba(2+)-induced IK1 blockade and attenuated the prolongation of action potentials following a 0.3-μM dofetilide-induced IKr blockade. Blockade of IKs by 0.5 μM HMR-1556 had no significant effect on APD90 in either 2 mM or 4 mM [Ca²⁺]o. It is concluded that high [Ca²⁺]i leads to augmentation of the Ba²⁺-sensitive current in dogs and humans, regardless of the mechanism of the increase. This effect seems to be at least partially mediated by a CaMKII-dependent pathway and may provide an effective endogenous defense against cardiac arrhythmias induced by Ca²⁺ overload.
内向整流钾电流 (IK1) 在心脏细胞的终末复极化和静息电位稳定中发挥重要作用。尽管已经表明 IK1 对细胞内 Ca²⁺浓度 ([Ca²⁺]i) 的变化敏感，但这种 Ca²⁺敏感性——尽管对动作电位形态有深远影响——仍存在争议。因此，我们旨在研究非肾上腺素能的 [Ca²⁺]i 升高对犬和人心室心肌 IK1 幅度的影响及其对心脏复极的影响。IK1 定义为 10 μM Ba²⁺抑制的电流，在 [Ca²⁺]i 稳定升高后，在分离的犬心肌细胞中显著增加。当 [Ca²⁺]i 未被乙二胺四乙酸缓冲时，也观察到增强的 IK1，并且产生 [Ca²⁺]I 瞬变。这种 [Ca²⁺]i 依赖性的 IK1 增强在 CaMKII 被 1 μM KN-93 抑制后大部分减弱。在多细胞犬和人心室标本中升高 [Ca²⁺]o 导致动作电位缩短和终末复极化加速。高 [Ca²⁺]o 增强了 Ba(2+)-诱导的 IK1 阻断引起的动作电位延长作用，并减轻了 0.3 μM 多非利特诱导的 IKr 阻断后动作电位的延长。0.5 μM HMR-1556 对 IKs 的阻断对 2 mM 或 4 mM [Ca²⁺]o 中的 APD90 均无显著影响。结论是，高 [Ca²⁺]i 导致犬和人中 Ba²⁺敏感电流的增强，而不管增加的机制如何。这种作用似乎至少部分由 CaMKII 依赖性途径介导，并且可能为 Ca²⁺ 过载引起的心脏心律失常提供有效的内源性防御。
