XANTHINE-OXIDASE INHIBITION WITH OXYPURINOL IMPROVES ENDOTHELIAL VASODILATOR FUNCTION IN HYPERCHOLESTEROLEMIC BUT NOT IN HYPERTENSIVE PATIENTS

Hypercholesterolemic and hypertensive patients have impaired endotheli um-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 the se forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vaso dilator, 7.5 to 30 mu g/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 mu g/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 mu g/ min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patient s, 20 essential hypertensive patients, and 20 normal subjects. The vas odilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2+/-8 mL.min(-1).dL(-1)) and hypertensive (8.5+/-4 m L.min(-1).dL(-1)) patients compared with control subjects (13.8+/-6.6 mL.min(-1).dL(-1)) (both P<.001); however, no differences were observe d in the response to sodium nitroprusside. Oxypurinol did not change t he 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 acetylcho line in hypertensive patients (P=.34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanth ine oxidase-generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic pat ients. In contrast, this mechanism does not appear to play a significa nt role in essential hypertension.