title: 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.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.forename: Anne
authors.initials: A
authors.lastname: Trausch
authors.forename: Elisa
authors.initials: E
authors.lastname: Mintert-Jancke
authors.forename: Lutz
authors.initials: L
authors.lastname: Pott
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials; D000368:Aged; D001146:Arrhythmia, Sinus / Q000378:metabolism / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018721:Muscarinic Agonists; D021122:Protein Subunits; D002217:Carbachol; D012964:Sodium; D000109:Acetylcholine
keywords: AF; AP; AP duration; APD; Action potential; Atrial fibrillation; CCh; I(Ca,L); I(K,ACh); I(K1); I(NaK); Inward-rectifier K(+) current; L-type Ca(2+) current; Na(+); Na(+)-K(+) ATPase current; PIP(2); SR; [Na(+)](i); action potential; atrial fibrillation; basal inward-rectifier K(+) current; cAF; carbachol; chronic AF; intracellular Na(+); muscarinic-receptor-activated K(+) current; phosphatidylinositol-4,5-bisphosphate; sinus rhythm