Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

Abstract

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

• Authors: Niels Voigt, Jordi Heijman, Anne Trausch, Elisa Mintert-Jancke, Lutz Pott, Ursula Ravens, Dobromir Dobrev
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 61 Pg. 142-52 (Aug 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 23531443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Muscarinic Agonists
• Protein Subunits
• Carbachol
• Sodium
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Action Potentials
• Aged
• Arrhythmia, Sinus (metabolism, physiopathology)
• Atrial Fibrillation (metabolism, physiopathology)
• Carbachol (pharmacology)
• Female
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (metabolism)
• Humans
• In Vitro Techniques
• Male
• Muscarinic Agonists (pharmacology)
• Patch-Clamp Techniques
• Protein Subunits (metabolism)
• Sodium (metabolism)