Angiotensin II is a powerful vasoconstrictor and proatherogenic factor. It was recently suggested that the endothelium may influence the actions of angiotensin II by production of, for example, nitric oxide and superoxide. By using venous occlusion plethysmography, forearm blood flow was measured in 26 healthy subjects during intraarterial cumulative infusion of angiotensin II. In 14 subjects, the interaction between angiotensin II and NO was studied by infusion of angiotensin II before and after clamping NO availability at a fixed basal level by using N(G)-monomethyl-L-arginine (L-NMMA) and nitroprusside. During a "free" NO system, blood flow decreased on angiotensin II infusion from 2.70+/-0.30 ml/100 ml forearm/min to 1.38+/-0.15 ml/100 ml forearm/min, whereas during NO-clamp vasoconstriction was significantly enhanced (blood flow from 2.56+/-0.25 to 1.19+/-0.13; p<0.05 saline vs. NO clamp). In 12 other subjects, the interaction between angiotensin II and superoxide was evaluated by comparison of the effects of angiotensin II before and after coinfusion of vitamin C. Angiotensin II-induced vasoconstriction was significantly attenuated by vitamin C at higher dosages of angiotensin (saline, blood flow from 3.08+/-0.33 to 1.12+/-0.09; vitamin C, blood flow from 3.01+/-0.23 to 1.61+/-0.13; p<0.05 saline vs. vitamin C). Vitamin C had no effect on baseline forearm blood flow. In conclusion, this study demonstrates that the constrictor actions of angiotensin II are enhanced during NO clamp and attenuated during vitamin C, suggesting direct angiotensin II-associated stimulation of endothelial NO and of oxygen radicals, respectively, in humans in vivo.