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

N. Nagy, K. Acsai, Anita Kormos, Zsuzsanna Sebok, Attila S. Farkas, N. Jost, P. Nánási, J. Papp, A. Varró, A. Tóth

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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 2013

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Action Potentials
Canidae
Myocardium
Potassium
Egtazic Acid
Stabilization
Membrane Potentials
Muscle Cells
Cardiac Arrhythmias
Dogs
HMR 1556
dofetilide
KN 93

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)
  • Medicine(all)

Cite this

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title = "I-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium",
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.",
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author = "N. Nagy and K. Acsai and Anita Kormos and Zsuzsanna Sebok and Farkas, {Attila S.} and N. Jost and P. N{\'a}n{\'a}si and J. Papp and A. Varr{\'o} and A. T{\'o}th",
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T1 - I-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium

AU - Nagy, N.

AU - Acsai, K.

AU - Kormos, Anita

AU - Sebok, Zsuzsanna

AU - Farkas, Attila S.

AU - Jost, N.

AU - Nánási, P.

AU - Papp, J.

AU - Varró, A.

AU - Tóth, A.

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

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KW - Canine/human myocardium

KW - Cytosolic Ca

KW - Inward rectifier K current (I )

KW - Ventricular repolarization

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