Document Detail


Atrial effects of the novel K(+)-channel-blocker AVE0118 in anesthetized pigs.
MedLine Citation:
PMID:  14613859     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: AVE0118 is a novel blocker of the K(+) channels K(v)1.5 and K(v)4.3 which are the molecular basis for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)) and the transient outward current (I(to)). The objective of this study was to investigate the effect of AVE0118 on atrial refractoriness (ERP), left atrial vulnerability (LAV) and on left atrial monophasic action potentials (MAP) in pentobarbital anesthetized pigs in comparison to the selective I(Kr) blocker dofetilide in order to assess the therapeutic potential of the novel K(+) channel blocker for atrial fibrillation. METHODS: Atrial ERP was determined with the S1-S2-stimulus method in the free walls of left and right atrium at 240, 300 and 400 ms basic cycle length (BCL). The inducibility of mostly nonsustained atrial tachyarrhythmias by the premature S2 extrastimulus, which is very high in the left pig atrium and referred to as LAV, was evaluated before and after drugs. Left atrial epicardial MAP was recorded to study the influence of the potassium channel blockers on the time course of repolarization. Left ventricular epicardial MAP, ERP and QT interval were measured to investigate a possible effect of AVE0118 on ventricular repolarization. RESULTS: ERPs determined at 240, 300 and 400 ms BCL were significantly shorter in the left vs. right atrium (99+/-3, 106+/-4 and 113+/-3 ms vs. 133+/-4 ms, 142+/-4 and 149+/-5, respectively; p<0.001; n=21). AVE0118 administered i.v. dose-dependently prolonged the atrial ERP independent from rate and inhibited LAV (100% at 0.5 and 1 mg/kg) while having no effect at all on the corrected QT (QTc) interval. At 1 mg/kg (n=5) AVE0118 prolonged left vs. right atrial ERP by 49.6+/-4.1 ms vs. 37.7+/-9.7 ms (means+/-SEM of changes at 240, 300, and 400 ms BCL), respectively, corresponding to a relative increase of 53.2+/-6.2% vs. 27.6+/-6.8% (p<0.05 for percent increase of left vs. right atrial ERP). In a separate group of pigs (n=5) AVE0118 had no effect on left ventricular ERP at 333, 400 and 500 ms BCL and no effect on MAP duration and QT at 600 ms BCL. After 1 mg/kg of AVE0118 the atrial MAP was significantly prolonged already at 10% repolarization (P<0.05; n=7) reaching the maximum at 40% repolarization. In contrast to AVE0118 the effect of dofetilide (10 microg/kg) on atrial MAP started to become significant only at 60% repolarization (n=6) with a maximum increase at 90%. Dofetilide, which prolonged the QTc interval by 16.9% (P<0.001), had a significantly stronger effect on right (34.7+/-5 ms) vs. left atrial ERP (23.5+/-7 ms) at 300 ms BCL, respectively, but did not significantly inhibit LAV (14%; n=6). CONCLUSION: The novel K(+) channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.
Authors:
Klaus J Wirth; Tobias Paehler; Bjoern Rosenstein; Karsten Knobloch; Thomas Maier; Jennifer Frenzel; Joachim Brendel; Andreas E Busch; Markus Bleich
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Cardiovascular research     Volume:  60     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-11-17     Completed Date:  2004-02-13     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  298-306     Citation Subset:  IM    
Affiliation:
Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Industriepark Höchst, Building H826, 65926, Frankfurt am Main, Germany. klaus.wirth@aventis.com
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects*
Animals
Atrial Fibrillation / drug therapy*,  metabolism
Cardiac Pacing, Artificial
Heart Atria / drug effects
Kv1.5 Potassium Channel
Male
Myocardial Contraction / drug effects*
Myocardium / metabolism
Phenethylamines / pharmacology
Potassium Channel Blockers / therapeutic use*
Potassium Channels / drug effects
Potassium Channels, Voltage-Gated / drug effects
Shal Potassium Channels
Sulfonamides / pharmacology
Swine
Chemical
Reg. No./Substance:
0/Kv1.5 Potassium Channel; 0/Phenethylamines; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/Potassium Channels, Voltage-Gated; 0/Shal Potassium Channels; 0/Sulfonamides; 115256-11-6/dofetilide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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