HYPERCHOLESTEROLEMIA INCREASES ENDOTHELIAL SUPEROXIDE ANION PRODUCTION

Indirect evidence suggests accelerated degradation of endothelium-deri ved nitric oxide (EDNO) by superoxide anion (O2-) in hypercholesterole mic vessels (HV). To directly measure O2- production by normal vessels (NV) and IIV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced thr eefold more O2- than NV (1.47+/-0.20 nM / mg tissue / min, n = 7 vs. 0 .52+/-0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2 production in NV (0.73+/-0.08, n = 6, P < 0.05), while de creasing it in HV (0.76+/-0.15, n = 5, P < 0.05). There was no differe nce between denuded HV and denuded NV. Oxypurinol, a noncompetitive in hibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while hav ing no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2 - in hypercholesterolemia probably via xanthine oxidase activation. In creased endothelial O2- production in HV may inactivate endothelium-de rived nitric oxide and provide a source for other oxygen radicals, con tributing to the early atherosclerotic process.