EVIDENCE THAT ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH HYPERCHOLESTEROLEMIA IS NOT DUE TO INCREASED EXTRACELLULAR NITRIC-OXIDE BREAKDOWN BYSUPEROXIDE ANIONS

Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation due to decreased nitric oxide activity. The present stud y aimed to determine whether this form of endothelial dysfunction is r elated to enhanced extracellular breakdown of nitric oxide by superoxi de onions. To this end, the vascular responses to acetylcholine (an en dothelium-dependent vasodilator) and sodium nitroprusside (a direct sm ooth muscle dilator) were studied before and after combined administra tion of copper-zinc superoxide dismutase (a scavenger of superoxide an ions with poor intracellular penetrance; 6,000 U/min) in 20 normal con trols (11 men and 9 women, age 50 +/- 6 years) and in 20 hypercholeste rolemic patients (10 men and 10 women, age 49 +/- 9 years). Drugs were infused into the brachial artery and the response of the forearm vasc ulature was measured by plethysmography. The vasodilator response to a cetylcholine was significantly blunted in hypercholesterolemic patient s compared with normal controls (maximal flow 8.8 +/- 2 vs 12.7 +/- 3 ml/min/100 mi, respectively; p<0.03); however, no difference was obser ved in the response to sodium nitroprusside (9.7 +/- 2 and 9.5 +/- 3 m l/min/100 mi). In normal controls, the infusion;of superoxide dismutas e did not significantly modify the response to acetylcholine (maximal flow 12.7 +/- 3 vs 12.1 +/- 3 ml/min/100 mi before and after superoxid e dismutase, respectively). Similarly, in hypercholesterolemic patient s, the infusion of superoxide dismutase did not alter the response to acetylcholine (maximal flow 8.8 +/- 2 and 8.9 +/- 2 ml/min/100 mi). 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. Superoxide dismutase did not modify the response to sodium nitroprusside in either group. These findings c onfirm previous observations of impaired endothelium-dependent vasodil ation in hypercholesterolemic patients, but do not support the concept of increased extracellular destruction of nitric oxide by superoxide onions as the mechanism responsible for this abnormality.