The class III effect of azimilide is not associated with reverse use-dependence in open-chest dogs.
Certain class III antiarrhythmic agents manifest loss of effect at short cycle lengths (CLs). This effect may limit their efficacy in the presence of tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a new class III agent, on the right ventricular monophasic action potential (APD90) in 12 open-chest dogs. The monophasic action-potential duration at different pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL (VFCL) from left epicardial electrograms were recorded before and after increasing doses of intravenous azimilide. At pacing CL of 400 ms, APD90 was significantly prolonged after 7, 17, and 30 mg/kg of azimilide by 5.4, 7.7, and 10.7%, respectively. The extent of APD90 prolongation was independent of rate. Azimilide increased the APD90 by similar amounts at CL of 400 ms and at the fastest possible stimulation rate maintaining 1:1 capture (mean, 171 +/- 23 ms): by 2.6 +/- 8.6% and 5.6 +/- 5.9% at 2 mg/kg, 5.4 +/- 4.8% and 4.8 +/- 4.7% at 7 mg/kg, 7.7 +/- 5.6% and 9.9 +/-4.5% at 17 mg/kg, and 10.7 +/- 2.6% and 19.3 +/- 11.9% at 30 mg/kg, respectively. Azimilide caused no changes in arterial blood pressure or heart rate. Azimilide prolongs APD90 even at very short CLs. The absence of reverse use-dependence of effect on APD90 may have clinical importance.
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Department of Medicine, St. Michael's Hospital and University of Toronto, Ontario, Canada.
Newman
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Dorian
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D051668:Delayed Rectifier Potassium Channels; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C086123:azimilide