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 (I TO) is decreased in a variety of cardiac pathologies, but how I TO reduction alters action potentials (APs) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of I TO blockers. The aim of this study was to investigate effects of selective I TO 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 I TO reduction or block slowed AP phase 1 and elevated the plateau, significantly prolonging APD, in both species. In human atrial cells, I TO block (100%I TO subtraction) increased APD 50 by 31%, APD 90 by 17%, and APD -61 mV (reflecting cellular effective refractory period) by 22% (P 0.05 for each). Interrupting I TO block at various time points during repolarisation revealed that the APD 90 increase resulted mainly from plateau-elevation, rather than from phase 1-slowing or any residual I TO. In rabbit atrial cells, partial I TO block (～40%I TO 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 I TO (～40%I TO addition). ISO+I TO decrease-induced CADs were abolished by β 1-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.