The cardiovascular effects of the selective serotonin uptake inhibitor, fluoxetine, and its N-desmethyl metabolite, norfluoxetine, were studied in anesthetized dogs during constant iv infusion of supratherapeutic doses (0.1 mg/kg/min for 50 min). Fluoxetine and norfluoxetine did not significantly affect mean blood pressure, pulmonary artery wedge pressure, or heart rate compared to a corresponding vehicle group. Cardiac output fell 15 to 20% during fluoxetine infusion due to nonsignificant decreases in both heart rate (10%) and stroke volume (5 to 10%). In contrast, the tricyclic antidepressant agent, amitriptyline, infused at the same dose, decreased both mean pressure and systemic vascular resistance (20%) and increased heart rate (20%). Pulmonary wedge pressure rose by 35%, and stroke volume fell by 20% suggesting impaired ventricular contractility. Both intramyocardial and infranodal conduction was slowed during amitriptyline infusion as indicated by increases in the QRS duration, and the PQ and HV interval. Fluoxetine and norfluoxetine had no influence on cardiac impulse conduction velocity as assessed by either surface or intracardiac conduction indices. Plasma concentrations of fluoxetine, norfluoxetine, and amitriptyline reached during infusion ranged from 1.0 to 2.5 micrograms/ml. Platelet [3H]serotonin uptake was inhibited by 95% during infusion of fluoxetine and about 75% during infusion of norfluoxetine or amitriptyline. These observations indicate that large iv doses of fluoxetine or norfluoxetine lack prominent cardiodepressant effects in dogs, suggesting a greater margin of safety for fluoxetine compared to tricyclic antidepressant drugs.