I have previously documented an inhibitory effect of atrial natriuretic factor (ANF) on postganglionic muscle sympathetic nerve activity (MSNA) in normal subjects that was consistent with either a central or ganglionic sympathoinhibitory action. To test the latter hypothesis, I examined, in seven young normotensive men, the effect of saline (as vehicle) and ANF (50 micrograms, then 50 ng.kg-1.min-1), given on 2 separate days according to a random double-blind study design, on blood pressure, heart rate, and MSNA before and after ganglionic neurotransmission was stimulated with edrophonium (ED; 12 mg iv), a rapidly reversible acetylcholinesterase inhibitor without central nervous system effects, and during subsequent augmentation of central sympathetic outflow by a cold pressor test (CPT). In five of these subjects, the protocol was replicated during nitroprusside infusion (0.4 micrograms.kg-1.min-1). ED increased MSNA during vehicle (P < 0.005) and nitroprusside (P < 0.003) but not during ANF infusion. The sympathoneural response to the combined stimuli of ED and CPT was also attenuated by ANF compared with either saline or nitroprusside infusions. Conclusions were that 1) postganglionic MSNA is increased by ED, 2) this facilitative effect of ED is attenuated by ANF, and 3) modulation of ganglionic neurotransmission is one mechanism for the relative sympatho-inhibition observed when ANF is infused at this dose.