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Transient outward K + current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic‐clamp study in human and rabbit cardiac atrial myocytes
Author(s) -
Workman A. J.,
Marshall G. E.,
Rankin A. C.,
Smith G. L.,
Dempster J.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.235986
Subject(s) - atrial action potential , atrial fibrillation , medicine , cardiology , electrophysiology , voltage clamp , membrane potential , stimulation , myocyte , patch clamp , atrium (architecture) , atrial myocytes , cardiac transient outward potassium current , chemistry , biophysics , repolarization , biology
Key pointsThe shape of the cardiac atrial action potential is influenced by the flow of a transient outward K + current ( I TO ) across atrial muscle cell membranes. Whether changes in I TO could alter atrial cell action potentials in ways that could affect mechanisms of abnormal heart rhythms (arrhythmias) is unclear, because currently available I TO 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 I TO during action potential recording. We found that I TO decrease prolonged atrial cell action potential duration and, under β‐adrenergic‐stimulation, provoked abnormal membrane potential oscillations (afterdepolarisations) that were preventable by I TO increase or a β‐blocker. These results help us better understand the contribution of I TO 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 ( 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 μ m ; 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 μ m ). 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.