BACKGROUND There is increasing evidence that neuropeptide Y (NPY) contributes to the autonomic control of the circulation. NPY coexists with noradrenaline in perivascular nerve terminals, may be released during sympathetic stimulation, and is a potent constrictor of the human coronary circulation and other vascular beds. In vitro studies show that NPY can act either directly on vascular smooth muscle or indirectly by modulation of the presynaptic release or the postsynaptic actions of noradrenaline. It is unclear to what extent these mechanisms operate in vivo. RESULTS The effect on forearm blood flow of intra-arterial NPY was studied in six volunteers during coinfusion of noradrenaline and during reflex sympathetic stimulation induced by lower-body negative pressure. NPY alone induced a dose-dependent reduction of forearm blood flow in all subjects studied, to a maximum of 49 +/- 6.1%. The reduction of flow during infusion of noradrenaline alone was 42 +/- 8%. The response to noradrenaline was unaffected by coinfusion of a threshold constrictor dose of NPY (50 pmol/min). Furthermore, the reflex sympathetic vasoconstrictor response to 20 cm H2O of lower-body negative pressure was similar in both the infused and control arms during the infusion of 50 pmol/min NPY. The response to noradrenaline was abolished by alpha-blockade with phentolamine, but the flow reduction induced by NPY was unaffected by alpha-blockade. CONCLUSIONS NPY is a potent constrictor of human forearm resistance vessels and has a direct effect independent of alpha-receptors. NPY has no detectable modulating effect in vivo on the action of endogenous or infused noradrenaline.