Kir3-based inward rectifier potassium current - Potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias

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 approximate to 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.