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Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.