Pathology-specific effects of the I Kur/I to/I K,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation

T. Christ, E. Wettwer, N. Voigt, O. Hála, S. Radicke, K. Matschke, A. Várro, D. Dobrev, U. Ravens

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Abstract

Background and purpose: This study was designed to establish the pathology-specific inhibitory effects of the I Kur/I to/I K,ACh blocker AVE0118 on atrium-selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF). Experimental approachOutward K ±-currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole-cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting. Key results: Four components of outward K ±-currents and AF-specific alterations in their properties were identified. I to was smaller in cAF than in SR, and AVE0118 (10 μM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of I Kur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non-inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF-related constitutively active I K,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF. Conclusions and implications: In atrial myocytes of cAF patients, we detected reduced function of distinct I Kur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active I K,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.

Original languageEnglish
Pages (from-to)1619-1630
Number of pages12
JournalBritish journal of pharmacology
Volume154
Issue number8
DOIs
Publication statusPublished - Aug 26 2008

Keywords

  • AVE0118
  • Action potentials
  • Atrial fibrillation
  • Human atrium
  • IKur/Ito/IK,ACh

ASJC Scopus subject areas

  • Pharmacology

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