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-phthalimide-hydro
chloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary
ligation, digitalis and
adrenaline, and compared them with those of
mexiletine.
A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary
ligation-, digitalis- and
adrenaline-induced automaticity arrhythmias. The antiarrhythmic 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-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 microg ml(-1), respectively, and that calculated for oral
A-2545 (25 mg kg(-1)) in 24-h coronary
ligation-induced
arrhythmia was 1.8 microg ml(-1).
A-2545 is specifically potent in suppressing coronary
ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by
oral administration, and among the intravenously given experiments
A-2545 was effective at lower concentrations than other
arrhythmia 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
arrhythmia, indicating that
A-2545 is more potent than
mexiletine. In order to determine whether
A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old
myocardial 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 arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by
flecainide either with 1 or 3 mg kg(-1) 1O min(-1); moreover even in one out of six dogs aggravation of
arrhythmia was noted after 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 effects compared to
flecainide.