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Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+,K+-ATPase α2 activity

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J. M. Aronsen, J. Skogestad, A. Lewalle, W. E. Louch, K. Hougen, M. K. Stokke, F. Swift, S. Niederer, N. P. Smith, O. M. Sejersted, I. Sjaastad

Original languageEnglish
Pages (from-to)1509-1521
Number of pages13
JournalThe Journal of Physiology
Issue number6
Publication statusPublished - 15 Mar 2015

King's Authors


 Hypokalaemia is a risk factor for development of ventricular arrhythmias. The aim of this study was to determine the cellular mechanisms leading to triggering of arrhythmias in ventricular myocytes exposed to low Ko. Low Ko, corresponding to moderate hypokalaemia, increased Ca2+ transient amplitude, sarcoplasmic reticulum (SR) Ca2+ load, SR Ca2+ leak and Ca2+ wave probability in field stimulated rat ventricular myocytes. The mechanisms leading to Ca2+ overload were examined. Low Ko reduced Na+,K+-ATPase (NKA) currents, increased cytosolic Na+ concentration and increased the Na+ level sensed by the Na+, Ca2+ exchanger (NCX). Low Ko also hyperpolarized the resting membrane potential (RMP) without significant alterations in action potential duration. Experiments in voltage clamped and field stimulated ventricular myocytes, along with mathematical modelling, suggested that low Ko increases the Ca2+ transient amplitude by reducing NKA activity despite hyperpolarization of the RMP. Selective inhibition of the NKA α2 isoform by low dose ouabain abolished the ability of low Ko to reduce NKA currents, to increase Na+ levels sensed by NCX and to increase the Ca2+ transient amplitude. We conclude that low Ko, within the range of moderate hypokalaemia, increases Ca2+ levels in ventricular myocytes by reducing the pumping rate of the NKA α2 isoform with subsequent Na+ accumulation sensed by the NCX. These data highlight reduced NKA α2-mediated control of NCX activity as a possible mechanism underlying triggered ventricular arrhythmias in patients with hypokalaemia.

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