Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation.
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).
Voigt
Niels
N
Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany.
Rozmaritsa
Nadiia
N
Trausch
Anne
A
Zimniak
Thomasz
T
Christ
Torsten
T
Wettwer
Erich
E
Matschke
Klaus
K
Dobrev
Dobromir
D
Ravens
Ursula
U
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
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D002217:Carbachol; D000109:Acetylcholine