Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes.
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 μm; 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 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.
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. antony.workman@glasgow.ac.uk
A J
AJ
Workman
G E
GE
Marshall
A C
AC
Rankin
G L
GL
Smith
J
J
Dempster
D000200:Action Potentials / Q000187:drug effects; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism; D001262:Atenolol / Q000494:pharmacology; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011817:Rabbits
D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D015221:Potassium Channels; D001262:Atenolol; D007545:Isoproterenol; D011188:Potassium