[Ca2+]i-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium.

Nagy, Norbert and Acsai, Károly and Kormos, Anita and Sebők, Zsuzsanna and Farkas, Attila S. and Jost, Norbert and Nánási, Péter P. and Papp, Gyula and Varró, András and Tóth, András (2013) [Ca2+]i-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium. PFLÜGERS ARCHIV - EUROPEAN JOURNAL OF PHYSIOLOGY. ISSN 0031-6768

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Abstract

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 Ba2+-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.

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