title: Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits.
abstract: Recent data indicate that hypercholesterolemia increases endothelial superoxide anion (.O2-) production, and that this diminishes the bioactivity of nitric oxide produced in the endothelium. Probucol, a drug commonly employed for treatment of hypercholesterolemia, has antioxidant properties and inhibits oxidation of low density lipoproteins in vitro. We tested the hypothesis that probucol would decrease vascular .O2- production and improve endothelium-dependent relaxations in cholesterol-fed rabbits. Rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol group fed a standard diet containing 0.3% probucol; 3) a hypercholesterolemic group fed a diet containing 0.5% cholesterol; 4) a hypercholesterolemia-probucol group fed a diet containing 0.5% cholesterol and 0.3% probucol. The cholesterol-rich diet markedly increased plasma total cholesterol level and lipid peroxidation in the plasma, as reflected by thiobarbituric acid-reactive substances (TBARS). This concentration of probucol did not lower plasma cholesterol, but markedly reduced TBARS in the plasma of cholesterol-fed rabbits. Aortic segments from cholesterol-fed rabbits produced 1.8-fold more .O2- (assessed by lucigenin-enhanced chemiluminescence) and decreased endothelium-dependent vascular relaxations to acetylcholine compared to vessels from normal rabbits. In cholesterol-fed rabbits, probucol treatment normalized both .O2- production and endothelium-dependent relaxations to acetylcholine. In control rabbits, probucol had no effect on either of these parameters. We conclude that probucol treatment may prevent .O2(-)-induced inactivation of endothelium-derived nitric oxide and reduce vascular oxidant stress via reducing the level of .O2-.
authors.affiliation: Cardiology Division, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: N
authors.initials: N
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Ohara
authors.forename: T
authors.initials: T
authors.lastname: Fukai
authors.forename: D G
authors.initials: DG
authors.lastname: Harrison
authors.forename: K
authors.initials: K
authors.lastname: Nishida
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000097:blood; D011341:Probucol / Q000494:pharmacology*; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D008055:Lipids; D013481:Superoxides; D011341:Probucol