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 . Low K , corresponding to moderate hypokalaemia, increased Ca transient amplitude, sarcoplasmic reticulum (SR) Ca load, SR Ca leak and Ca wave probability in field stimulated rat ventricular myocytes. The mechanisms leading to Ca overload were examined. Low K reduced Na ,K -ATPase (NKA) currents, increased cytosolic Na concentration and increased the Na level sensed by the Na , Ca exchanger (NCX). Low K 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 increases the Ca transient amplitude by reducing NKA activity despite hyperpolarization of the RMP. Selective inhibition of the NKA α isoform by low dose ouabain abolished the ability of low K to reduce NKA currents, to increase Na levels sensed by NCX and to increase the Ca transient amplitude. We conclude that low K , within the range of moderate hypokalaemia, increases Ca levels in ventricular myocytes by reducing the pumping rate of the NKA α isoform with subsequent Na accumulation sensed by the NCX. These data highlight reduced NKA α -mediated control of NCX activity as a possible mechanism underlying triggered ventricular arrhythmias in patients with hypokalaemia.