Probucol attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits.
1. Probucol was administered to rabbits fed a cholesterol-enriched (2% wt/wt) diet to determine potential anti-atherogenic effects in a preparation in which the disease process is due to elevated plasma concentrations of cholesterol ester-rich very low density lipoproteins (CER-VLDL). 2. Probucol was supplemented to the diet at 1% wt/wt which resulted in plasma concentrations rising steadily to 53 +/- 8 micrograms ml-1 after 14 days, with no significant changes during continued administration. Dietary consumption and body weight gains were comparable in the drug-treated and control groups during the observation period. 3. Probucol treatment did not significantly affect plasma concentrations of total cholesterol, unesterified cholesterol, triglycerides or phospholipids. 4. The concentration of CER-VLDL in plasma and its physicochemical characteristics were not significantly changed during administration of probucol. CER-VLDL from both control and probucol-treated animals was a potent stimulant of the augmentation of the intracellular incorporation of [3H]-oleate into cholesteryl-[3H]-oleate in cultured macrophages. 5. Despite the lack of effect of probucol on concentrations of plasma lipids and the cell interaction characteristics of CER-VLDL, administration of the drug markedly decreased the extent of intimal aortic surface area covered by grossly discernible atherosclerotic lesions from 55.6 +/- 11.8% to 11.6 +/- 1.9% in thoracic sections, and from 49.1 +/- 10.2% to 7.2 +/- 0.4% in abdominal sections. Furthermore, probucol treatment significantly reduced the deposition of total cholesterol in vascular tissue. 6. Probucol reduced the extent of aortic atherosclerosis produced by diet-induced hypercholesterolemia in rabbits. This reduction occurred in the absence of any significant change in the characteristics of plasma lipoproteins that were determined. These results indicate that either there is a role of oxidation in the disease process of this animal model of atherosclerosis or that probucol is acting via a presently undefined mechanism.
Daugherty
A
A
Cardiovascular Division, Washington University School of Medicine, St Louis, MO 63110.
Zweifel
B S
BS
Schonfeld
G
G
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001018:Aortic Diseases / Q000517:prevention & control*; D001161:Arteriosclerosis / Q000517:prevention & control*; D002788:Cholesterol Esters / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004032:Diet; D008079:Lipoproteins, VLDL / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D010636:Phenols / Q000627:therapeutic use*; D011341:Probucol / Q000627:therapeutic use*; D011817:Rabbits
D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D008079:Lipoproteins, VLDL; D010636:Phenols; D011341:Probucol