The effect of adenosine on the forearm vasoconstrictor response to a-adrenergic and sympathetic stimulation was studied in healthy volunteers. During a predilated state achieved by infusion of sodium nitroprusside into the brachial artery, subsequent infusion of norepinephrine induced a mean increase in forearm vascular resistance of 571%, whereas this response was only 270% when an equipotent vasodilator dose of adenosine was used instead of sodium nitroprusside (nitroprusside versus adenosine,p<0.05, n=6). A comparable difference was found when the endogenous release of norepinephrine was stimulated by the local infusion of tyramine, with tyramine-induced increments in forearm vascular resistance of 438% during nitroprusside versus 93% during adenosine (n=6, p<0.05). During these tyramine infusions a similar increase in the calculated forearm norepinephrine overflow occurred in the adenosine and the nitroprusside tests. In a third experiment, we demonstrated that adenosine also reduced the vasoconstrictor response to lower body negative pressure, an endogenous stimulus, of the sympathetic nervous system. During nitroprusside, lower body negative pressure induced an increase in forearm vascular resistance of 135%, whereas this was 39% during adenosine (n=6, p<0.05). We conclude that adenosine attenuates the response to sympathetic nervous system-mediated vasoconstriction in humans, and that this effect may at least partly be explained by a postsynaptic inhibition of or-adrenergic vasoconstriction. Therefore, we think that adenosine may be an important endogenous modulator of sympathetic nervous system activity in humans.