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(Circulation. 2006;113:1730-1737.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Kir3-Based Inward Rectifier Potassium Current

Potential Role in Atrial Tachycardia Remodeling Effects on Atrial Repolarization and Arrhythmias

Tae-Joon Cha, MD^*; Joachim R. Ehrlich, MD^*; Denis Chartier, BSc; Xiao-Yan Qi, PhD; Ling Xiao, BSc; Stanley Nattel, MD

From Kosin University College of Medicine, Busan, South Korea (T.C.); J.W. Goethe University, Frankfurt, Germany (J.R.E.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (L.X., S.N.); and Department of Medicine and Research Center, Montréal Heart Institute and University of Montréal, Montréal, Québec, Canada (T.C., J.R.E., D.C., X.Q., L.X., S.N.).

Correspondence to Dr Stanley Nattel, 5000 Belanger St E, Montréal, Québec, H1T 1C8, Canada. E-mail stanley.nattel{at}icm-mhi.org

Received May 12, 2005; revision received December 19, 2005; accepted February 10, 2006.

Background— We previously characterized a novel K⁺ current (I_KH) with properties of constitutively active acetylcholine-related current in dog atrium. I_KH is sensitive to tertiapin-Q (IC₅₀ 10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of I_KH in atrial tachycardia (AT)–remodeled canine left atrium (LA) with the use of tertiapin-Q as a probe.

Methods and Results— Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation. I_KH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (I_KH) at –110 mV from –1.8±0.3 (control) to –3.4±0.5 pA/pF (AT) and the 100-nmol/L tertiapin-sensitive component from –1.5±0.4 (control) to –3.3±0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation–promoting effects of AT remodeling. In AT-remodeled preparations, tachyarrhythmia duration averaged 11.0±5.2 seconds, with a cycle length of 108±6 ms. Tertiapin-Q decreased tachyarrhythmia duration (to 0.6±0.1 second; P<0.001) and increased tachyarrhythmia cycle length (to 175±10 ms; P<0.001). Atrial action potential duration (APD) was increased 65±6% by tertiapin in AT-remodeled hearts versus 19±2% (P<0.001) in control. In 2 AT-remodeled preparations, tachyarrhythmia lasted uninterrupted for >20 minutes; tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD.

Conclusions— AT remodeling increases I_KH, and a highly selective Kir3 current antagonist, tertiapin-Q, increases APD and suppresses atrial tachyarrhythmias in AT-remodeled preparations without affecting ventricular electrophysiology. Constitutive acetylcholine-related K⁺ current contributes to AT-remodeling effects in dogs and is a potentially interesting antiarrhythmic target.

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