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

• Published in: Journal of molecular and cellular cardiology Vol. 61; pp. 142 - 152
• Main Authors: Voigt, Niels, Heijman, Jordi, Trausch, Anne, Mintert-Jancke, Elisa, Pott, Lutz, Ravens, Ursula, Dobrev, Dobromir
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2013
• Subjects: Acetylcholine - pharmacology; Action potential; Action Potentials; Aged; Arrhythmia, Sinus - metabolism; Arrhythmia, Sinus - physiopathology; Atrial fibrillation; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Carbachol - pharmacology; Cardiovascular; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Humans; In Vitro Techniques; Inward-rectifier K+ current; Male; Muscarinic Agonists - pharmacology; Na+; Patch-Clamp Techniques; Protein Subunits - metabolism; Sodium - metabolism; ICa,L; AF; Atrial fibrillation; cAF; CCh; [Na+]i; Action potential; INaK; Inward-rectifier K+ current; IK1; AP; APD; Na+; IK,ACh; PIP2; SR; PIP 2; [Na +] i; L-type Ca 2 + current; basal inward-rectifier K + current; atrial fibrillation; Na; I NaK; sinus rhythm; Inward-rectifier K + current; carbachol; I K1; muscarinic-receptor-activated K + current; I Ca,L; phosphatidylinositol-4,5-bisphosphate; chronic AF; action potential; Na +-K + ATPase current; intracellular Na; AP duration; I K,ACh; Inward-rectifier K(+) current; I(K,ACh); basal inward-rectifier K(+) current; intracellular Na(+); I(K1); Na(+)-K(+) ATPase current; Na(+); I(Ca,L); L-type Ca(2+) current; [Na(+)](i); PIP; I(NaK); muscarinic-receptor-activated K(+) current
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2013.03.011

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”. •Increased intracellular Na+ inhibits basal IK1 in human atrial myocytes•Carbachol-activated IK,ACh is augmented by [Na+]i in SR but not cAF myocytes•Na+-dependent inhibition of IK1 at fast rates blunts AP adaptation in SR and cAF•A Na+-dependent IK,ACh increase enhances AP adaptation in SR but is impaired in cAF•Our computer model with updated IK1 and IK,ACh facilitates studies of AF mechanisms