Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes

摘要

Human atrial transient outward K⁺ current (ITO) is decreased in a variety of cardiac pathologies, but how ITO reduction alters action potentials (APs) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of ITO blockers. The aim of this study was to investigate effects of selective ITO changes on AP shape and duration (APD), and on afterdepolarisations or abnormal automaticity with β-adrenergic-stimulation, using the dynamic-clamp technique in atrial cells. Human and rabbit atrial cells were isolated by enzymatic dissociation, and electrical activity recorded by whole-cell-patch clamp (35–37°C). Dynamic-clamp-simulated ITO reduction or block slowed AP phase 1 and elevated the plateau, significantly prolonging APD, in both species. In human atrial cells, ITO block (100%ITO subtraction) increased APD50 by 31%, APD90 by 17%, and APD−61 mV (reflecting cellular effective refractory period) by 22% (P < 0.05 for each). Interrupting ITO block at various time points during repolarisation revealed that the APD90 increase resulted mainly from plateau-elevation, rather than from phase 1-slowing or any residual ITO. In rabbit atrial cells, partial ITO block (∼40%ITO subtraction) reversibly increased the incidence of cellular arrhythmic depolarisations (CADs; afterdepolarisations and/or abnormal automaticity) in the presence of the β-agonist isoproterenol (0.1 μm; ISO), from 0% to 64% (P < 0.05). ISO-induced CADs were significantly suppressed by dynamic-clamp increase in ITO (∼40%I_TO addition). ISO+I_TO decrease-induced CADs were abolished by β₁-antagonism with atenolol at therapeutic concentration (1 μm). Atrial cell action potential changes from selective I_TO modulation, shown for the first time using dynamic-clamp, have the potential to influence reentrant and non-reentrant arrhythmia mechanisms, with implications for both the development and treatment of atrial fibrillation.