Cocaine, like catecholamines or angiotensin II, may induce lethal cardiac or cerebral damage. Restrained rats were fitted with a caudal arterial catheter for on-line cardiovascular monitoring and antidote administration. They were given 60 mg/kg of cocaine i.p., a dose which produces behavioral and cardiovascular effects, convulsions and death in an average time of 10 min. Selected antidotes were administered 5 min after the lethal dose of cocaine. Incidence of lethality was not changed by propranolol, prazosin, labetalol, diazepam or enalaprilat, a converting enzyme inhibitor. Animals treated with any one of the following agents, alpha- or beta-blockers, diazepam or competitive inhibitors of angiotensin II [Sar-1-ile-8] and [Sar-1-thr-8] angiotensin II, presented myocardial infarction. All animals treated with calcium channel antagonists or enalaprilat, whether they survived or not, did not present myocardial infarction. Treatment with nitrendipine, flunarizine or diltiazem, resulted in survival of the animals with no observable aftereffects. Similar results were observed when enalaprilat was administered, with diazepam as an antidote, to a lethal dose of cocaine. Antagonists to the sympatho-adrenal system and to the renin angiotensin system appear to be effective antidotes to cocaine toxicity in the present experimental model.