PROBUCOL IMPROVES ENDOTHELIAL-DEPENDENT RELAXATION AND DECREASES VASCULAR SUPEROXIDE PRODUCTION IN CHOLESTEROL-FED RABBITS

Recent data indicate that hypercholesterolemia increases endothelial s uperoxide anion (. O-2(-)) production, and that this diminishes the bi oactivity of nitric oxide produced in the endothelium. Probucol, a dru g commonly employed for treatment of hypercholesterolemia, has antioxi dant properties and inhibits oxidation of low density lipoproteins in vitro. We tested the hypothesis that probucol would decrease vascular . O-2(-) production and improve endothelium-dependent relaxations in c holesterol-fed rabbits. Rabbits were divided into four groups: 1) a co ntrol group fed a standard diet; 2) a probucol group fed a standard di et containing 0.3% probucol; 3) a hypercholesterolemic group fed a die t containing 0.5% cholesterol; 4) a hypercholesterolemia-probucol grou p fed a diet containing 0.5% cholesterol and 0.3% probucol. The choles terol-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 lo wer plasma cholesterol, but markedly reduced TBARS in the plasma of ch olesterol-fed rabbits. Aortic segments from cholesterol-fed rabbits pr oduced 1.8-fold more . O-2(-) (assessed by lucigenin-enhanced chemilum inescence) and decreased endothelium-dependent vascular relaxations to acetylcholine compared to vessels from normal rabbits. In cholesterol -fed rabbits, probucol treatment normalized both . O-2(-) production a nd endothelium-dependent relaxations to acetylcholine. In control rabb its, probucol had no effect on either of these parameters. We conclude that probucol treatment may prevent . O-2(-)-induced inactivation of endothelium-derived nitric oxide and reduce vascular oxidant stress vi a reducing the level of . O-2(-).