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

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 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 K-o reduced Na+,K+-ATPase (NKA) currents, increased cytosolic Na+ concentration and increased the Na+ level sensed by the Na+, Ca2+ 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 Ca2+ transient amplitude by reducing NKA activity despite hyperpolarization of the RMP. Selective inhibition of the NKA (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 Ca2+ transient amplitude. We conclude that low K-o, within the range of moderate hypokalaemia, increases Ca2+ levels in ventricular myocytes by reducing the pumping rate of the NKA (2) isoform with subsequent Na+ accumulation sensed by the NCX. These data highlight reduced NKA (2)-mediated control of NCX activity as a possible mechanism underlying triggered ventricular arrhythmias in patients with hypokalaemia.