We examined the role of nitric oxide (NO) in the regulation of neuronal uptake of norepinephrine (uptake-1) in rats under anesthesia. The effect on systolic blood pressure of two pressor drugs that work by different mechanisms, norepinephrine and angiotensin II, was explored in anesthetized rats under control conditions and after prevention of NO synthesis with Nw-nitro-l-arginine (L-NNA). The results showed that whereas the pressor effects of increasing doses of norepinephrine were potentiated by L-NNA, those of angiotensin II were not affected, which implied that NO was selectively involved in modulating the pressor effect of norepinephrine. To explore the mechanisms involved in this potentiation, we examined the effect of L-NNA on the pressor effect of tyramine, a purely-indirectly-acting sympathomimetic amine which enters nerve terminals thorough uptake 1 and liberates norepinephrine from storage vesicles. Increasing doses of tyramine produced pressor effects which, in contrast to those of norepinephrine, were significantly attenuated by pre-treatment with L-NNA. Similarly, pretreatment with cocaine, the classical inhibitor of uptake 1, significantly decreased the pressor effect of tyramine; however, the response to tyramine was then restored when L-NNA was administered, thus reversing the effect of cocaine. We conclude that NO plays a major role in the adrenergic system by enhancing the activity of uptake 1 in sympathetic nerve terminals. Blockade of uptake 1 by cocaine is also partly dependent on NO. The stimulus for the mobilization of the NO synthase pathway in adrenergic neurons and the subsequent steps involved in modulating uptake 1 deserve further exploration.