Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic‐clamp study in human and rabbit cardiac atrial myocytes
Authors: Workman A. J. , Marshall G. E. , Rankin A. C. , Smith G. L. , Dempster J. 
Published: June 2012

Key points
The shape of the cardiac atrial action potential is influenced by the flow of a transient outward K+ current (ITO) across atrial muscle cell membranes.
Whether changes in ITO could alter atrial cell action potentials in ways that could affect mechanisms of abnormal heart rhythms (arrhythmias) is unclear, because currently available ITO blocking drugs are non‐selective.
We used the ‘dynamic‐clamp’ technique, for the first time in atrial cells isolated from patients, and from rabbits, to electrically simulate selective changes in ITO during action potential recording.
We found that ITO decrease prolonged atrial cell action potential duration and, under β‐adrenergic‐stimulation, provoked abnormal membrane potential oscillations (afterdepolarisations) that were preventable by ITO increase or a β‐blocker.
These results help us better understand the contribution of ITO to atrial cell action potential shape and mechanisms of arrhythmia, with potential implications for both the development and treatment of atrial fibrillation.
Abstract  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%ITO addition). ISO+ITO decrease‐induced CADs were abolished by β1‐antagonism with atenolol at therapeutic concentration (1 μm). Atrial cell action potential changes from selective ITO 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.