Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits.
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-.
Inoue
N
N
Cardiology Division, Emory University School of Medicine, Atlanta, Georgia, USA.
Ohara
Y
Y
Fukai
T
T
Harrison
D G
DG
Nishida
K
K
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*
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D008055:Lipids; D013481:Superoxides; D011341:Probucol