The antiarrhythmic effects of amitriptyline (1), its secondary amine metabolite nortriptyline (2), as well as cyclobenzaprine (3) and cyproheptadine (4), tertiary amine analogues of 1, were studied in conscious dogs 24 h after myocardial infarction. Since the sedative side effect of 4 presents a potential problem for its clinical use, a quarternary derivative of 4, cyproheptadine methiodide (5), was prepared and its effects also studied in this model. Complete conversion to a normal sinus rhythm occurred in all animals studied after cumulative doses of 1700 micrograms/kg (6.17 mumol/kg) of 3, 1300 micrograms/kg (4.69 mumol/kg) of 1, 300 micrograms/kg (1.04 mumol/kg) of 4, and 25 micrograms/kg (0.058 mumol/kg) of 5. While 2 significantly decreased ventricular ectopic activity, it did not convert any of the animals studied to a sinus rhythm at doses up to 3000 micrograms/kg. Thus, the order of potency for conversion to a normal sinus rhythm appears to be 5 >> 4 > 1 > 3 >> 2. These data suggest that 5 is very potent in converting ventricular arrhythmias associated wtih myocardial infarction.