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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Smith, Professor Godfrey and Rankin, Professor Andrew and Workman, Dr Antony |
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 > School of Cardiovascular & Metabolic Health 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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