Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation.
OBJECTIVE
This study was designed to establish the pathology-specific inhibitory effects of the IKur/Ito/IK,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).


METHODS
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.


RESULTS
Four components of outward K+-currents and AF-specific alterations in their properties were identified. Ito was smaller in cAF than in SR, and AVE0118 (10 microM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of IKur 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 IK,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF.


CONCLUSIONS
In atrial myocytes of cAF patients, we detected reduced function of distinct IKur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active IK,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.
Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
T
T
Christ
E
E
Wettwer
N
N
Voigt
O
O
Hála
S
S
Radicke
K
K
Matschke
A
A
Várro
D
D
Dobrev
U
U
Ravens
D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002908:Chronic Disease; D004594:Electrophysiology; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism
C501729:AVE 0118; D001713:Biphenyl Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels