Antiarrhythmic effect of a new class 1 antiarrhythmic drug, AN-132, on ventricular arrhythmias in beagles

Abstract

Using two-stage coronary-ligation-, digitalis- and adrenaline-induced ventricular arrhythmias in beagles, antiarrhythmic effects of AN-132 were examined, and the minimum effective plasma concentration for each arrhythmia model was determined. AN-132 suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-hour coronary ligation, 48-hour coronary ligation, digitalis, and adrenaline were 3.4-4.6, 1.5-2.3, 0.83, and 9.3 micrograms/ml, respectively. The concentration for adrenaline-induced arrhythmia was significantly higher than that of 24-hour coronary ligation arrhythmia, and it was also higher than that of digitalis arrhythmia. This pharmacologic profile is similar to those of pirmenol and mexiletine. Since AN-132 had no deleterious effects on the hemodynamics and the central nervous system, it may become a clinically useful antiarrhythmic drug.

Utilization of an Isolated, Blood-Perfused Canine Papillary Muscle Preparation as a Model to Assess Efficacy and Adversity of Class I Antiarrhythmic Drugs

“…Although these arrhythmias most likely are caused by triggered activity from delayed after depolarizations, ab normal automaticity and/or re-entrant excitation in very depolarized tissues (11,39,40), a good correlation was found only between EDSO(IVCT) in this current study and IC50 of two different types of arrhythmia models. The results may indicate that the antiarrhythmic mechanism of class I drugs in the canine arrhythmia models is closely related to the suppression of the normal intraventricular conduction.…”

“…Other drugs were tested at 500-msec driving interval. An tiarrhythmic plasma concentrations were calculated from our earlier reports (11,39,40). P: procainamide, D: disopyramide, L4: lido caine at 400-msec driving interval, L3: lidocaine at 300-msec driving interval, M4: mexiletine at 400-msec driving interval, M3: mexiletine at 300-msec driving interval, F: flecainide, ME: ME3202, AN: AN 132.…”

“…Correlation between cardiac direct effects and antiar rhythmic activity: We examined the correlation between the intraarterial ED50 doses in this study and the antiar rhythmic IC50 plasma concentrations obtained in our previous canine arrhythmia model studies, namely digi talis and coronary ligation-induced arrhythmias (11,39,40). Although these arrhythmias most likely are caused by triggered activity from delayed after depolarizations, ab normal automaticity and/or re-entrant excitation in very depolarized tissues (11,39,40), a good correlation was found only between EDSO(IVCT) in this current study and IC50 of two different types of arrhythmia models.…”

Effects of antiarrhythmic drugs on canine ventricular arrhythmia models: Which electrophysiological characteristics of drugs are related to their effectiveness?

“…As reported earlier [1,2,[5][6][7][8][9][11][12][13][14][15][16][17][18]20,21,[23][24][25][26][27][28][29][30][31][32], mongrel and beagle dogs of either sex, as well as female beagle dogs, weighing about 7-15 kg, were anesthetized initially with thiopental sodium. After intubation, 1.0% halothane, vaporized with 100% oxygen, was administered with a volume-limited ventilator (20 ml/kg, 15 strokes/min).…”

“…For intravenous infusion studies, a constant-rate infusion was performed for 10 minutes using a syringe pump, and arterial blood samples were drawn from one lumen of the arterial double-lumen cannula at 0, 1, 3,5,7,9,13,15,30, and 60 minutes after the start of the infusion. [6][7][8]12,14,17,18,[20][21][22][23][24][25][26][27][28][29][30][31][32], female beagle dogs, weighing about 7-12 kg, were anesthetized initially with intravenous thiopental sodium, 30 mg/kg, and intubated. The chest was opened and a two-stage coronary ligation of the left anterior descending artery (LAD) was performed under halothane anesthesia.…”