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Pathology‐specific effects of the I Kur / I to / I K,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation
Author(s) -
Christ T,
Wettwer E,
Voigt N,
Hála O,
Radicke S,
Matschke K,
Várro A,
Dobrev D,
Ravens U
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.209
Subject(s) - chemistry , refractory period , biophysics , medicine , myocyte , effective refractory period , inhibitory postsynaptic potential , electrophysiology , endocrinology , patch clamp , atrium (architecture) , atrial myocytes , atrial fibrillation , biology
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 approach Outward 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 μ M ) 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. British Journal of Pharmacology (2008) 154 , 1619–1630; doi: 10.1038/bjp.2008.209 ; published online 9 June 2008