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Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation

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Abstract

Inward rectifier potassium currents IK1 and acetylcholine activated IK,ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), IK,ACh develops a receptor-independent, constitutively active component that together with increased IK1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial IK1 and IK,ACh in patients with and without cAF. IK1 and IK,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 µM) was employed to activate IK,ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on IK1. In contrast, all tested drugs inhibited CCh-activated IK,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 IK,ACh was smaller (−4.1 ± 0.5 pA/pF vs. −9.5 ± 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive IK,ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active IK,ACh channels. In cAF, all tested drugs reduced CCh-activated IK,ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active IK,ACh, suggesting that they may block IK,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of IK,ACh.

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Acknowledgments

The authors thank Trautlinde Thurm, Ulrike Heinrich and Annegret Häntzschel for excellent technical assistance.

Sources of funding

These studies were supported by the Deutsche Forschungsgemeinschaft (Do 769/1-1-3), the German Federal Ministry of Education and Research through the Atrial Fibrillation Competence Network (01Gi0204), the European Union (“NORMACOR”, grant LSHM-CT-2006-018676), and a grant of Fondation Leducq (07 CVD 03).

Disclosures

Ursula Ravens is a consultant to MEDA Pharma GmbH & Co. KG, Bad Homburg (flecainide).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Germany

    Niels Voigt, Nadiia Rozmaritsa, Anne Trausch, Thomasz Zimniak, Torsten Christ, Erich Wettwer, Dobromir Dobrev & Ursula Ravens

  2. Department of Cardiosurgery, Dresden University of Technology, Fetscherstr. 76, 01307, Dresden, Germany

    Klaus Matschke

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  1. Niels Voigt
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Correspondence to Dobromir Dobrev.

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Voigt, N., Rozmaritsa, N., Trausch, A. et al. Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation. Naunyn-Schmied Arch Pharmacol 381, 251–259 (2010). https://doi.org/10.1007/s00210-009-0452-6

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