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

Workman, A.J. , Marshall, G.E., Rankin, A.C., Smith, G.L. and Dempster, J. (2012) Transient outward K+ current (ITO) reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes. Journal of Physiology, 590(17), pp. 4289-4305. (doi:10.1113/jphysiol.2012.235986)

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Abstract

Background and aim: Human atrial transient outward K+ current (ITO) is decreased in a variety of cardiac pathologies, but how ITO reduction alters action potentials (AP) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of ITO blockers.<p></p> Aim: to investigate effects of selective ITO changes on AP shape and duration (APD), and on afterdepolarisations or abnormal automaticity with beta-adrenergic-stimulation, using the dynamic-clamp technique in atrial cells.<p></p> Methods and Results: Human and rabbit atrial cells were isolated by enzymatic dissociation, and electrical activity recorded by whole-cell-patch clamp (35-37oC). 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-61mV (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 beta-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 beta1-antagonism with atenolol at therapeutic concentration (1 μM).<p></p> Conclusion. 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Workman, Dr Antony and Smith, Professor Godfrey and Rankin, Professor Andrew
Authors: Workman, A.J., Marshall, G.E., Rankin, A.C., Smith, G.L., and Dempster, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
Journal Name:Journal of Physiology
ISSN:0022-3751
ISSN (Online):1469-7793
Published Online:25 June 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in Journal of Physiology 17 4389-4305
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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