Suppression of inducible ventricular arrhythmias by intravenous azimilide in dogs with previous myocardial infarction.
The class III antiarrhythmics azimilide dihydrochloride and dl-sotalol were evaluated for ability to suppress induction of ventricular tachyarrhythmias (VT) in anesthetized, male mongrel dogs 4-6 days after surgical infarction of the left ventricle (LV) produced by ligation/reperfusion of the left anterior descending coronary artery. Postmortem infarcts averaged 28.2 +/- 3.3% and 27.5 +/- 3.9% of the LV for azimilide- and sotalol-treated dogs, respectively. Both agents (0.3-30 mg/kg i.v.) increased ventricular effective refractory period as a function of dose in LV normal and infarcted zones without increasing conduction time. Azimilide was well tolerated hemodynamically up to 30 mg/kg i.v., whereas sotalol produced a significant and dose-related decrease in both blood pressure and heart rate. Azimilide was effective in five (56%) of nine dogs in preventing induction of ventricular arrhythmias by programmed electrical stimulation (PES) at doses from 1 to 30 mg/kg. Efficacy was seen for nonsustained and sustained VT and for ventricular fibrillation. Although sotalol (0.3-10 mg/kg) was effective in all five VT dogs tested, one of two nonsustained ventricular tachyarrhythmia (NSVT) dogs and two of three sustained ventricular tachyarrhythmia (SVT) dogs were reinducible with the baseline arrhythmia at doses higher than the effective dose, and one dog died after 30 mg/kg of sotalol. Both agents increased the cycle length of VT. Thus azimilide simultaneously increased refractoriness and provided antiarrhythmic efficacy as suppression of PES-induced ventricular arrhythmias in infarcted dogs without the hemodynamic depression seen with sotalol.
Drexler
A P
AP
Procter & Gamble Pharmaceuticals, Norwich, NY 13815-0191, USA.
Micklas
J M
JM
Brooks
R R
RR
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004285:Dogs; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D007262:Infusions, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D010879:Piperazines / Q000627:therapeutic use*; D013015:Sotalol / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide; D013015:Sotalol