Effects of an antiarrhythmic drug A-2545 on canine ventricular arrhythmia models; comparison with mexiletine and flecainide

We investigated effects of a new Na+ channel blocking antiarrhythmic drug, .A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthali mide-hydrochloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compa red them with those of mexiletine. A-2545 showed antiarrhythmic effects, si gnificantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligat ion-, digitalis- and adrenaline-induced automaticity arrhythmias. The antia rrhythmic plasma concentrations (IC50) of A-2545, 2 mg kg(-1) 10 min(-1), i .v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induce d arrhythmias were 1.8, 1.3, 5.8 and 3.7 mu g ml(-1), respectively, and tha t calculated for oral A-2545 (25 mg kg(-1)) in 24-h coronary ligation-induc ed arrhythmia was 1.8 mu g ml(-1). A-2545 is specifically potent in suppres sing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously g iven experiments A-2545 was effective at lower concentrations than other ar rhythmia models, A-2545, 2 mg kg(-1) 10 min(-1), was equipotent to 5 mg kg( -1) 10 min(-1) mexiletine in suppressing 24-h coronary ligation-induced arr hythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed el ectrical stimulation (PES)-induced reentry arrhythmias in dogs with old myo cardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg(-1) 10 min(-1),significantly suppressed the PES-induced arrhyt hmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg(-1) 10 min(-1); moreover even in one out of six dogs aggravation of arrhythmia was noted af ter 1 mg kg(-1) 10 min(-1). In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effe cts compared to flecainide.