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

Abstract

BACKGROUND:

We previously characterized a novel K+ current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium. I(KH) is sensitive to tertiapin-Q (IC50 approximately 10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of IKH 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. IKH was 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; 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 IKH, 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.

• Authors: Tae-Joon Cha, Joachim R Ehrlich, Denis Chartier, Xiao-Yan Qi, Ling Xiao, Stanley Nattel
• Journal: Circulation (Circulation) Vol. 113 Issue 14 Pg. 1730-7 (Apr 11 2006) ISSN: 1524-4539 [Electronic] United States
• PMID: 16585394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels

Topics

• Animals
• Arrhythmias, Cardiac (physiopathology)
• Atrial Fibrillation (physiopathology)
• Disease Models, Animal
• Dogs
• Electrophysiology
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (physiology)
• Heart Atria (physiopathology)
• Tachycardia (physiopathology)
• Ventricular Remodeling