DIETARY PROBUCOL PRESERVES ENDOTHELIAL FUNCTION IN CHOLESTEROL-FED RABBITS BY LIMITING VASCULAR OXIDATIVE STRESS AND SUPEROXIDE GENERATION

Excess vascular oxidative stress and the local formation of oxidized L DL (ox-LDL) have been implicated in the development of impaired endoth elium-dependent arterial relaxation in hypercholesterolemia and athero sclerosis, Dietary antioxidants limit LDL oxidation in vitro and treat ment of cholesterol-fed rabbits with dietary antioxidants preserves en dothelium-derived relaxing factor (EDRF) action, To investigate the me chanism(s) responsible for these observations, we examined EDRF action , vascular oxidative stress, and antioxidant protection in male New Ze aland White rabbits using four dietary treatments, Animals consumed st andard chow (chow group) or chow supplemented with: (a) 0.5% cholester ol(0.5% cholesterol group); (b) 1% cholesterol(1% cholesterol group); or (c)1% cholesterol and 1% probucol (probucol group), After 28 d of d ietary treatment, segments of thoracic aorta from the 0.5 and 1% chole sterol groups demonstrated impairment of acetylcholine-mediated endoth elium-dependent arterial relaxation compared to chow-fed animals (57+/ -11% and 45+/-9% vs 78+/-3%, respectively; P < 0.05), In contrast, ves sels from the probucol group demonstrated normal relaxation to acetylc holine (83+/-5%), Plasma cholesterol levels and the extent of atherosc lerosis were similar among all cholesterol-fed groups, Probucol treatm ent was associated a threefold increase in LDL resistance to copper-in duced oxidative modification (P < 0.05) and a reduction in tissue lipi d peroxidation (as assessed by thiobarbituric acid-reactive substances ; P < 0.05) compared to animals fed cholesterol alone, Most importantl y, both of these changes were strongly correlated with preserved EDRF action, Moreover, cholesterol feeding was associated with a dose-depen dent increase in vascular superoxide generation and lysophosphatidylch oline content, both of which were prevented by probucol treatment, Fro m these findings, we conclude that probucol, a lipid-soluble antioxida nt, preserves EDRF action in cholesterol-fed rabbits in association wi th limiting vascular oxidative stress and superoxide generation.