Neurocardiology emphasizes the role of the higher cerebral mechanisms in cardiovascular disorders. Several large clinical trials (BHAT, MIAMI, and ISIS) have consistently shown that treatment with a beta-receptor blocker (propranolol, metoprolol, or atenolol) will produce a 26% to 29% reduction in mortality in high-risk survivors of acute myocardial infarction. Because all beta-blockers cross the blood-brain barrier, it is not clear whether the salutary action is on the central or peripheral receptors. Therefore the effects of intracerebral versus intravenous propranolol were observed in 30 conscious pigs following complete occlusion of the left anterior descending coronary artery. Controls showed the propranolol to remain confined throughout the experiment to the central or peripheral compartment into which it was injected. To assure the occurrence of ventricular fibrillation (VF), each pig was psychologically stressed by being unconditioned to the laboratory. Intracerebral propranolol (0.05 mg/kg) prevented VF within a 20 min period of reversible ischemia in 6 of 9 pigs, whereas VF was prevented in 0 of 11 controls injected intravenously with either dextro-propranolol (2 pigs) or vehicle (9 pigs) (P less than .0006, binomial probability ratio). In some pigs in which VF was not manifested by 20 min, the ischemia was reversed and additional control observations were achieved; a total of 10 counter-balanced within-subjects experiments confirmed the between-subjects result (P less than .01, paired-t test). In contrast intravenous propranolol (0.2 to 2.0 mg/kg) in 7 pigs had no effect on VF latency compared to 7 vehicle controls. It is concluded that beta-receptor antagonists prevent VF in the ischemic myocardium by their effect on the brain and not the heart.