Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.