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 arid 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^-.