Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation due to decreased nitric oxide activity. The present study aimed to determine whether this form of endothelial dysfunction is related to enhanced extracellular breakdown of nitric oxide by superoxide anions. To this end, the vascular responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct smooth muscle dilator) were studied before and after combined administration of copper-zinc superoxide dismutase (a scavenger of superoxide anions with poor intracellular penetrance; 6,000 U/min) in 20 normal controls (11 men and 9 women, age 50 +/- 6 years) and in 20 hypercholesterolemic patients (10 men and 10 women, age 49 +/- 9 years). Drugs were infused into the brachial artery and the response of the forearm vasculature was measured by plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypercholesterolemic patients compared with normal controls (maximal flow 8.8 +/- 2 vs 12.7 +/- 3 ml/min/100 ml, respectively; p < 0.03); however, no difference was observed in the response to sodium nitroprusside (9.7 +/- 2 and 9.5 +/- 3 ml/min/100 ml). In normal controls, the infusion of superoxide dismutase did not significantly modify the response to acetylcholine (maximal flow 12.7 +/- 3 vs 12.1 +/- 3 ml/min/100 ml before and after superoxide dismutase, respectively). Similarly, in hypercholesterolemic patients, the infusion of superoxide dismutase did not alter the response to acetylcholine (maximal flow 8.8 +/- 2 and 8.9 +/- 2 ml/min/100 ml). A subset of 19 subjects (8 normal and 11 patients) received a 60-minute infusion of superoxide dismutase at 24,000 U/min without alteration in their response to acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)