title: Protection against programmed electrical stimulation-induced ventricular tachycardia and sudden cardiac death by NE-10064, a class III antiarrhythmic drug.
abstract: The electrophysiologic and antifibrillatory properties of NE-10064 were studied in vivo in a conscious canine model of sudden cardiac death. Purpose bred male mongrel dogs weighing 14.5-21.5 kg were anesthetized, and surgical anterior myocardial infarction (MI) was induced by a 2-h occlusion, with reperfusion, of the left anterior descending coronary artery (LAD). Three to 5 days after induction of anterior wall MI, animals were subjected to testing by programmed electrical stimulation (PES). As compared with predrug incidence (12 of 12), NE-10064 (10 mg/kg intravenously, i.v.) reduced (p < 0.05) the incidence (8 of 12) of PES-induced ventricular tachycardia (VT). All but 1 control animal remained inducible after vehicle (5% dextrose in water). The cycle length of induced VT was not prolonged by NE-10064 (0.245 +/- 0.046 s predrug vs. 0.301 +/- 0.060 s postdrug). NE-10064 increased ventricular effective refractory period (VERP 166 +/- 5 ms predrug vs. 194 +/- 13 ms postdrug, p = 0.013), prolonged QTc interval (310 +/- 12 ms predrug vs. 350 +/- 16 ms postdrug, p = 0.004) and prolonged the effective refractory period (ERP) of noninfarcted myocardium (p = 0.045). The drug did not affect ECG-indexes of conduction velocity: QRS and P-R intervals were not affected, nor were activation delay and conduction time of noninfarcted and infarcted myocardium. In the sudden cardiac death protocol, NE-10064 protected (p = 0.018) against ischemia-induced ventricular fibrillation (VF, 75% survival with drug vs. 25% survival without drug). NE-10064 afforded protection (p = 0.040) throughout 14 h posterolateral ischemia in the presence of the previous anterior infarct.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: University of Michigan Medical School, Department of Pharmacology, Ann Arbor 48109-0626.
authors.forename: S C
authors.initials: SC
authors.lastname: Black
authors.forename: J L
authors.initials: JL
authors.lastname: Butterfield
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006339:Heart Rate / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D048289:Imidazolidines; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology; D010879:Piperazines; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000517:prevention & control*; D014693:Ventricular Fibrillation / Q000517:prevention & control
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D010880:Piperidines; C086123:azimilide