title: Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation.
abstract: Inward rectifier potassium currents I(K1) and acetylcholine activated I(K,ACh) are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I(K,ACh) develops a receptor-independent, constitutively active component that together with increased I(K1) is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I(K1) and I(K,ACh) in patients with and without cAF. I(K1) and I(K,ACh) were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2 microM) was employed to activate I(K,ACh). In SR, basal current was not affected by either drug indicating no effect of these compounds on I(K1). In contrast, all tested drugs inhibited CCh-activated I(K,ACh) in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at -80 mV, -15.2 +/- 1.2 pA/pF, n = 88/35 vs. -6.5 +/- 0.4 pA/pF, n = 194/58 [myocytes/patients]; P < 0.05), whereas CCh-activated I(K,ACh) was smaller (-4.1 +/- 0.5 pA/pF vs. -9.5 +/- 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive I(K,ACh) contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I(K,ACh) channels. In cAF, all tested drugs reduced CCh-activated I(K,ACh). We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I(K,ACh), suggesting that they may block I(K,ACh) channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I(K,ACh).
authors.affiliation: Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Nadiia
authors.initials: N
authors.lastname: Rozmaritsa
authors.forename: Anne
authors.initials: A
authors.lastname: Trausch
authors.forename: Thomasz
authors.initials: T
authors.lastname: Zimniak
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D013616:Tachycardia, Sinus / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D002217:Carbachol; D000109:Acetylcholine