Published Online
on April 3, 2006

A more recent version of this article appeared on April 11, 2006

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Submitted on May 12, 2005
Revised on December 19, 2005
Accepted on February 10, 2006

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, and 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.).

^* To whom correspondence should be addressed. E-mail: stanley.nattel{at}icm-mhi.org.

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.

Key words: antiarrhythmia agents • arrhythmia • electrophysiology • ion channels • remodeling

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