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: Niels Voigt, Nadiia Rozmaritsa, Anne Trausch, Thomasz Zimniak, Torsten Christ, Erich Wettwer, Klaus Matschke, Dobromir Dobrev, Ursula Ravens
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 381 Issue 3 Pg. 251-9 (Mar 2010) ISSN: 1432-1912 [Electronic] Germany
• PMID: 19760273 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Potassium Channel Blockers
• Potassium Channels, Inwardly Rectifying
• Carbachol
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Aged
• Anti-Arrhythmia Agents (administration & dosage, pharmacology, therapeutic use)
• Atrial Fibrillation (drug therapy, metabolism)
• Carbachol (pharmacology)
• Cells, Cultured
• Female
• Heart Atria (drug effects, metabolism)
• Humans
• Ion Channel Gating (drug effects)
• Male
• Membrane Potentials (drug effects)
• Myocytes, Cardiac (drug effects, metabolism)
• Patch-Clamp Techniques
• Potassium Channel Blockers (administration & dosage, pharmacology, therapeutic use)
• Potassium Channels, Inwardly Rectifying (antagonists & inhibitors)
• Tachycardia, Sinus (drug therapy, metabolism)
• Treatment Outcome