title: Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits.
abstract: Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: J F
authors.initials: JF
authors.lastname: Keaney
authors.forename: J M
authors.initials: JM
authors.lastname: Gaziano
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: B
authors.initials: B
authors.lastname: Frei
authors.forename: J
authors.initials: J
authors.lastname: Curran-Celentano
authors.forename: G T
authors.initials: GT
authors.lastname: Shwaery
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
authors.forename: J A
authors.initials: JA
authors.lastname: Vita
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects; D008297:Male; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D011817:Rabbits; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014680:Veins / Q000187:drug effects / Q000502:physiology; D014810:Vitamin E / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D002791:Cholesterol, Dietary; D008074:Lipoproteins; D014280:Triglycerides; D014810:Vitamin E; D009599:Nitroprusside; D009569:Nitric Oxide; D000001:Calcimycin; D002784:Cholesterol; D000109:Acetylcholine