BACKGROUND: In several animal species, nitric oxide (NO) buffers central neural sympathetic outflow, but data concerning humans are sparse and conflicting. We hypothesized that these conflicting results could be related to large differences in the dose of N(G)-monomethyl-L-arginine, a stereospecific inhibitor of NO synthase, infused in these human studies. OBJECTIVE: To investigate the haemodynamic and sympathetic effects of systemic inhibition of NO synthase by intravenous infusion of two different doses of N(G)-monomethyl-L-arginine into healthy humans and compare these effects with those of an equipressor dose of the non-endothelium-dependent vasoconstrictor phenylephrine. METHODS: Muscle sympathetic nerve activity was measured by microneurography and blood flow by venous occlusion plethysmography. N(G)-monomethyl-L-arginine was infused over 15 min at a rate of 50 microg/kg per min into members of one group (n = 8) and at a rate of 450 microg/kg per min into members of another group (n = 7). An equipressor dose of phenylephrine was infused into four subjects from each group. RESULTS: Infusions of N(G)-monomethyl-L-arginine and of phenylephrine at the higher dose similarly suppressed sympathetic activity. In contrast, infusions of N(G)-monomethyl-L-arginine and of an equipressor dose of phenylephrine at the lower dose had different sympathetic effects. Burst frequency of muscle sympathetic nerve activity remained unchanged during infusion of N(G)-monomethyl-L-arginine but decreased by roughly 50% during infusion of phenylephrine. Infusion of N(G)-monomethyl-L-arginine at both doses did not alter forearm blood flow. Only infusion of N(G)-monomethyl-L-arginine at the higher dose increased forearm vascular resistance. CONCLUSIONS: Haemodynamic and sympathetic effects of inhibition of NO synthase by infusion of N(G)-monomethyl-L-arginine into humans are dose dependent. At higher doses, N(G)-monomethyl-L-arginine exerts sympathoinhibitory effects that are comparable to those evoked by a non-specific vasoconstrictor drug, whereas at lower doses, it exerts sympatho-excitatory effects.