In this study the local vasoactive effects of adenosine were explored in the human forearm. Adenosine (15 micrograms/100 ml forearm/min) infused into the brachial artery (n = 6) increased forearm blood flow by 572% +/- 140%, versus - 0.5% +/- 5.8% during placebo infusion (p less than 0.01). Lower adenosine infusion rates (5 micrograms/100 ml forearm/min, three times) induced forearm blood flow increments to 330% +/- 94%, 339% +/- 67% and 330% +/- 79%, respectively (n = 8). These forearm blood flow responses were reduced (p = 0.02) during concomitant intra-arterial infusion of two doses of caffeine (30 and 90 micrograms/100 ml forearm/min) to 150% +/- 45% and 98% +/- 28%, respectively. Theophylline (30 micrograms/100 ml forearm/min; n = 6) also significantly attenuated the adenosine-induced increase in forearm blood flow. Enprofylline (30 micrograms/100 ml forearm/min), a related xanthine with a low affinity to adenosine receptors in vitro, did not change the response to adenosine. Nonspecific vasodilation by sodium nitroprusside infusion (50 ng/100 ml forearm/min) was not inhibited by caffeine compared with placebo (forearm blood flow responses were 202% +/- 21% versus 216% +/- 40%; n = 6). This study demonstrated that caffeine and theophylline specifically reduce adenosine-induced vasodilation in humans, supporting the existence of functional human vascular adenosine receptors.