Hypokalaemia induces Ca 2+ overload and Ca 2+ waves in ventricular myocytes by reducing Na + ,K + ‐ATPase α 2 activity

Key points Hypokalaemia is a risk factor for development of ventricular arrhythmias. In rat ventricular myocytes, low extracellular K + (corresponding to clinical moderate hypokalaemia) increased Ca 2+ wave probability, Ca 2+ transient amplitude, sarcoplasmic reticulum (SR) Ca 2+ load and induced SR Ca 2+ leak. Low extracellular K + reduced Na + ,K + ‐ATPase (NKA) activity and hyperpolarized the resting membrane potential in ventricular myocytes. Both experimental data and modelling indicate that reduced NKA activity and subsequent Na + accumulation sensed by the Na + , Ca 2+ exchanger (NCX) lead to increased Ca 2+ transient amplitude despite concomitant hyperpolarization of the resting membrane potential. Low extracellular K + induced Ca 2+ overload by lowering NKA α 2 activity. Triggered ventricular arrhythmias in patients with hypokalaemia may therefore be attributed to reduced NCX forward mode activity linked to an effect on the NKA α 2 isoform.Abstract 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 K o . Low K o , corresponding to moderate hypokalaemia, increased Ca 2+ transient amplitude, sarcoplasmic reticulum (SR) Ca 2+ load, SR Ca 2+ leak and Ca 2+ wave probability in field stimulated rat ventricular myocytes. The mechanisms leading to Ca 2+ overload were examined. Low K o reduced Na + ,K + ‐ATPase (NKA) currents, increased cytosolic Na + concentration and increased the Na + level sensed by the Na + , Ca 2+ exchanger (NCX). Low K o 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 K o increases the Ca 2+ transient amplitude by reducing NKA activity despite hyperpolarization of the RMP. Selective inhibition of the NKA α 2 isoform by low dose ouabain abolished the ability of low K o to reduce NKA currents, to increase Na + levels sensed by NCX and to increase the Ca 2+ transient amplitude. We conclude that low K o , within the range of moderate hypokalaemia, increases Ca 2+ levels in ventricular myocytes by reducing the pumping rate of the NKA α 2 isoform with subsequent Na + accumulation sensed by the NCX. These data highlight reduced NKA α 2 ‐mediated control of NCX activity as a possible mechanism underlying triggered ventricular arrhythmias in patients with hypokalaemia.