The alpha 2-adrenergic receptor antagonist yohimbine is often used as a neuroendocrine probe in human studies, in which it is assumed to increase plasma norepinephrine (NE) by increasing sympathetic outflow. In this study we have tested that assumption by using a radioisotope dilution technique to measure norepinephrine (NE) kinetics in arterialized plasma after administration of oral yohimbine (20 or 40 mg) or placebo to normal young men. In agreement with previous studies, we found that yohimbine causes dose-dependent increases in blood pressure, heart rate, and plasma NE. We further found that the increase in plasma NE is, in fact, due to an increase in the rate of appearance of NE into plasma and not to reduced NE clearance from plasma. In addition, we found that yohimbine causes a dose-dependent increase in plasma epinephrine, which had not been found in studies measuring catecholamines in venous plasma. We conclude that yohimbine increases plasma NE levels by increasing the rate of NE release from sympathetic nerves, and probably increases epinephrine release from the adrenals.