Kir3-Based Inward Rectifier Potassium Current

Abstract

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 (IC 50 ≈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.