The purpose of this study was to determine whether a subthreshold dose of cocaine (one that is well-tolerated in a resting state with no significant hemodynamic changes) causes cardiotoxic responses when superimposed upon a subthreshold infusion of norepinephrine. Adult mongrel dogs were anesthetized, instrumented and assigned to one of five treatment groups: saline control, norepinephrine infusion (0.75 microgram/kg/min, i.v. for 60 min); cocaine (5.0 mg/kg, i.v. bolus); combination of cocaine (0.5 mg/kg) or (5.0 mg/kg) with the last 45 min of norepinephrine infusion. The combination groups exhibited increased blood pressure and contractility (dP/dt), and a greater variety and frequency of arrhythmias. Cocaine did not increase plasma catecholamine levels beyond norepinephrine alone. There were significantly more contraction band lesions/mm2 with cocaine in combination with norepinephrine than in any of the individual treatment groups. These data indicate that, even in anesthetized animals, a well-tolerated dose of cocaine may become toxic when superimposed on an excited or hyperadrenergic state with elevated levels of norepinephrine.