Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes
| Autor: | A J, Workman, G E, Marshall, A C, Rankin, G L, Smith, J, Dempster |
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| Rok vydání: | 2012 |
| Předmět: |
Ion Transport
Patch-Clamp Techniques Potassium Channels Isoproterenol Models Cardiovascular Action Potentials Arrhythmias Cardiac Adrenergic beta-Agonists Cardiovascular digestive system Adrenergic beta-1 Receptor Antagonists Electric Stimulation Electrophysiological Phenomena Atenolol cardiovascular system Potassium Animals Humans Myocytes Cardiac Heart Atria Rabbits |
| Zdroj: | The Journal of physiology. 590(17) |
| ISSN: | 1469-7793 |
| Popis: | 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% (P0.05 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% (P0.05). 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. |
| Databáze: | OpenAIRE |
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