Because of difficulties in separating the systemic from local effect, the role of presynaptic beta 2-adrenergic receptors in facilitating the neural release of norepinephrine has not been defined previously in humans in vivo. To determine whether stimulation of presynaptic beta-receptors alters local release of norepinephrine, we examined the effects on norepinephrine kinetics of 60 and 400 ng/min intra-arterial isoproterenol in seven healthy male volunteers. Isoproterenol, 60 ng/min, increased forearm norepinephrine spill-over sixfold from a baseline spillover of 0.45 +/- 0.08 to 2.89 +/- 0.69 ng/min (p < 0.01), whereas 400 ng/min isoproterenol increased forearm norepinephrine spillover to 13.25 +/- 2.49 ng/min (p < 0.005), a 29-fold increase above baseline. Coinfusion of 20 to 40 micrograms/min propranolol with 400 ng/min isoproterenol in four subjects significantly attenuated the isoproterenol-induced increase in local norepinephrine spillover to 2.09 +/- 0.92 ng/min (p < 0.05 versus 400 ng/min isoproterenol). This study shows that presynaptic beta-adrenergic receptors facilitate local release of norepinephrine in vivo in humans.