Evaluation of antidotes against the acute cardiovascular toxicity of propranolol

Rats anesthetized with pentobarbital and ventilated artificially were intoxicated with 1 mg/kg X min propranolol i.v. After 30 min heart rate, mean arterial blood pressure and peripheral resistance had dropped by about 50% and cardiac output by about 25% and were stable for up to 120 min. Isoprenaline proved to be the best antidote for the treatment of propranolol intoxication antagonizing the bradycardia by 76% and the hypotension completely. The antagonistic activities of orciprenaline and prenalterol were lower than those of isoprenaline. Dopamine, adrenaline and noradrenaline antagonized propranolol-induced hypotension but did not considerably influence the bradycardia whereas dobutamine was nearly ineffective in both respects. Glucagon and aminophylline displayed some chronotropic activity without influencing propranolol-induced hypotension. Calcium chloride, on the other hand, produced a moderate elevation of blood pressure but only a small chronotropic activity, and atropine was inactive in both respects. Isoprenaline also restored the cardiac function of propranolol-poisoned rats if administered by infusion and, furthermore, increased the lethal dose of propranolol from 77 to 165 mg/kg. The strong antagonistic activity of isoprenaline against propranolol-induced cardiovascular depression was also confirmed by experiments in pigs. In conclusion, isoprenaline is the most active antidote for the treatment of propranolol intoxication in the rat though the administration of massive doses are required. The vasodilatory effect of isoprenaline can be overcome by the additional administration of a vasoconstricting agent like dopamine.