Intracerebroventricular (ICV) injection of propranolol in the dog, cat and rabbit produces a significant fall in arterial pressure. In the following experiments, regional brain propranolol concentrations and changes in mean arterial pressure (MAP) have been measured in the rabbit after central and peripheral administration of the drug and the results compared to human brain/plasma levels. In the conscious rabbit, ICV injection of l-propranolol (500 mug) produced a prolonged fall in MAP, maximal at 105 minutes (16.8 plus or minus 5.9 mm Hg below base line). The regional brain propranolol concentrations after ICV injection of 14C-dl-propranolol (530 mug) were determined and the levels compared to those achieved following i.v. infusion of the unlabeled drug (1.0 and 2.0 mg/kg/hr). The propranolol concentrations in the hypothalamus, medulla pons and midbrain after i.v. infusion were similar to the propranolol content in these areas at 60 and 120 minutes after ICV injection. Intravenous infusion of propranolol also resulted in significant falls in MAP between 60 and 120 minutes. In control studies, infusions of d-propranolol (1.0, 2.0 and 4.0 mg/kg/hr), which is virtually devoid of beta adrenoceptor blocking activity, produced only slight reductions in MAP. Postmortem studies in patients treated with prolonged i.v. infusions of d-propranolol as part of the treatment of paraquat poisoning indicate that the brain/plasma concentration of propranolol in man is similar to that observed in the rabbit. Propranolol is therefore highly concentrated in human brain tissue and comparable brain levels in the rabbit result in a hypotensive response.