Hypercholesterolemic and hypertensive patients have impaired endothelium-dependent vasorelaxation because of decreased nitric oxide activity, but the mechanism underlying this abnormality is unknown. This study sought to determine whether an increased breakdown of nitric oxide by xanthine oxidase-generated superoxide anions could participate in these forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vasodilator, 7.5 to 30 micro gram/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 micro gram/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 micro gram/min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patients, 20 essential hypertensive patients, and 20 normal subjects. The vasodilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2 +/- 8 mL [center dot] min-1[center dot] dL-1) and hypertensive (8.5 +/- 4 mL [center dot] min (-1) [center dot] dL-1) patients compared with control subjects (13.8 +/- 6.6 mL [center dot] min-1[center dot] dL-1) (both P < .001); however, no differences were observed in the response to sodium nitroprusside. Oxypurinol did not change the response to acetylcholine in control subjects (P = .26) and improved, but did not normalize, its vasodilator effect in hypercholesterolemic patients (P < .01). Oxypurinol did not affect the response to acetylcholine in hypertensive patients (P = .34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanthine oxidase-generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic patients. In contrast, this mechanism does not appear to play a significant role in essential hypertension. (Hypertension. 1997;30[part 1]:57-63.)