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• W2384689539 abstract "Background: AVE0118 (2′-{[2-(4-Methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide) blocks atrial ultrarapid delayed rectifier currents (IKur) and prolongs the atrial action potential (AP) plateau without affecting ventricular repolarisation. In patients with atrial contractile dysfunction due to atrial tachyarrhythmias, this response might increase atrial contractility without risk of ventricular proarrhythmia. This study was designed to evaluate the inotropic mechanisms of AVE0118. Methods and results: In isometrically contracting atrial trabeculae, AVE0118 increased contractile force by 55.4% in sinus rhythm patients (n=9) and by 107.4% in patients with atrial fibrillation (n=8). In freshly isolated canine atrial myocytes studied under perforated patch current clamp (37 °C), AVE0118 increased myocyte fractional shortening from 3.8±0.6 to 9.6±0.8% and prolonged action potential duration at 30% repolarisation from 9±2 to 102±11 ms. Clamping cells to an AP waveform recorded during exposure to AVE0118 produced the same inotropic response as the drug itself. In action potential clamp, peak Ca 2+ inward current (ICaL) current declined from 5.5±1.3 pA/pF during control to 4.1±0.7 pA/pF when an AP recorded in the presence of AVE0118 was used as command waveform. However, ICaL was more sustained with AVE0118 and the time integral did not change (135±37 vs. 173±30 pA/pF⁎ms, p=ns). Importantly, blockade of reverse mode Na + /Ca 2+ -exchanger activity with 5 μM KBR7943 or using a Na + -free pipette solution abolished the positive inotropic effect of the AP recorded in the presence of AVE0118. In ventricular myocytes AVE0118 did not elicit a positive inotropic response. Conclusions: Block of IKur by AVE0118 enhances atrial contractility both in patients with sinus rhythm and atrial fibrillation. The positive inotropic effect is atrial-specific and due to the changes of the action potential configuration which enhances Ca 2+ entry via reverse mode Na + /Ca 2+ exchange." @default.
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• W2384689539 date "2007-01-01" @default.
• W2384689539 modified "2023-09-24" @default.
• W2384689539 title "Rapid communication Blockade of atrial-specific K + -currents increases atrial but not ventricular contractility by enhancing reverse mode Na + /Ca 2+ -exchange" @default.
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