Kir3-Based Inward Rectifier Potassium Current

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Abstract
Background—We previously characterized a novel K+current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium.IKHis sensitive to tertiapin-Q (IC50≈10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role ofIKHin 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.IKHwas recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (IKH) 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;PPP20 minutes; tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD.Conclusions—AT remodeling increasesIKH, 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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