I-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium

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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 [Ca 2+]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 [Ca 2+]i-dependent augmentation of IK1 was largely attenuated after inhibition of CaMKII by 1 μM KN-93. Elevation of [Ca 2+]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 [Ca 2+]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.

Original languageEnglish
Pages (from-to)1621-1635
Number of pages15
JournalPflugers Archiv European Journal of Physiology
Volume465
Issue number11
DOIs
Publication statusPublished - Nov 1 2013

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Keywords

  • Action potential duration
  • Ba
  • Canine/human myocardium
  • Cytosolic Ca
  • Inward rectifier K current (I )
  • Ventricular repolarization

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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