Hypercholesterolemia increases endothelial superoxide anion (O₂⁻) production, as shown by increased O₂⁻ generation in hypercholesterolemic (HV) rabbit aortas compared to normal (NV) vessels. This increase was not due to smooth muscle but rather the endothelium itself or associated cells. Oxypurinol, a xanthine oxidase inhibitor, reduced O₂⁻ production in HV to levels similar to NV, suggesting xanthine oxidase activation is a key source of O₂⁻ in hypercholesterolemia. This excess O₂⁻ may inactivate endothelium-derived nitric oxide (NO), contributing to early atherosclerosis. In HV, oxypurinol improved acetylcholine-induced relaxations, indicating that O₂⁻ impairs endothelium-dependent relaxation. The study used lucigenin-based chemiluminescence to measure O₂⁻, showing that O₂⁻ production in HV was threefold higher than in NV. Endothelial removal increased O₂⁻ in NV but decreased it in HV, suggesting that the endothelium normally suppresses O₂⁻ production. The findings suggest that hypercholesterolemia leads to increased O₂⁻ production, which may contribute to atherosclerosis by inactivating NO and generating other oxygen radicals. The study also highlights the role of xanthine oxidase in O₂⁻ generation and the potential therapeutic benefit of oxypurinol in reducing O₂⁻ and improving vascular function in hypercholesterolemic conditions.Hypercholesterolemia increases endothelial superoxide anion (O₂⁻) production, as shown by increased O₂⁻ generation in hypercholesterolemic (HV) rabbit aortas compared to normal (NV) vessels. This increase was not due to smooth muscle but rather the endothelium itself or associated cells. Oxypurinol, a xanthine oxidase inhibitor, reduced O₂⁻ production in HV to levels similar to NV, suggesting xanthine oxidase activation is a key source of O₂⁻ in hypercholesterolemia. This excess O₂⁻ may inactivate endothelium-derived nitric oxide (NO), contributing to early atherosclerosis. In HV, oxypurinol improved acetylcholine-induced relaxations, indicating that O₂⁻ impairs endothelium-dependent relaxation. The study used lucigenin-based chemiluminescence to measure O₂⁻, showing that O₂⁻ production in HV was threefold higher than in NV. Endothelial removal increased O₂⁻ in NV but decreased it in HV, suggesting that the endothelium normally suppresses O₂⁻ production. The findings suggest that hypercholesterolemia leads to increased O₂⁻ production, which may contribute to atherosclerosis by inactivating NO and generating other oxygen radicals. The study also highlights the role of xanthine oxidase in O₂⁻ generation and the potential therapeutic benefit of oxypurinol in reducing O₂⁻ and improving vascular function in hypercholesterolemic conditions.