Effect of verapamil and nifedipine on cholesteryl ester metabolism and low-density lipoprotein oxidation in macrophages.
Using mouse macrophage cultures, the effects of verapamil and nifedipine on cholesteryl ester and low-density lipoprotein (LDL) metabolism were studied with special reference to the following parameters: (a) incorporation of [14C]oleate into cholesteryl esters (ChE), (b) contents of total and free cholesterol (FCh), (c) liberation of [14C]oleate from ChE and incorporation of [3H]FCh into ChE, (d) excretion of [3H]Ch from the cells, and (e) LDL oxidation. Verapamil and nifedipine (10-100 microM) were shown to decrease in a dose-dependent manner the incorporation of [14C]oleate into ChE and to increase the concentration of FCh but had no appreciable effect on the concentration of total cholesterol in macrophages cultured in the presence of acetylated LDL. The drugs stimulated the liberation of [14C]oleate from cellular ChE. The pharmacological concentrations (25-75 microM) of verapamil and nifedipine increased the excretion of [3H]FCh from ChE of macrophages in the presence of serum and high-density lipoproteins. The same concentrations of the drugs inhibited both LDL-derived malonyldialdehyde-like products and nitroblue tetrazolium dye reduction in a dose-dependent fashion. The results obtained suggest that verapamil and nifedipine exert their macrophage-mediated antiatherosclerotic effect via reduction of LDL oxidative modification, reduction of intracellular ChE synthesis, stimulation of ChE hydrolysis and cholesterol excretion from the cells.
Department of Atherogenesis, Siberian Branch of Russian Academy of Medical Science, Novosibirsk.
M I
MI
Dushkin
Y S
YS
Schwartz
D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis; D002788:Cholesterol Esters / Q000378:metabolism*; D004951:Esterification / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology*; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D013778:Tetrazolium Salts; D014700:Verapamil / Q000494:pharmacology*
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D013778:Tetrazolium Salts; C042207:4-anisyltetrazolium blue; D019301:Oleic Acid; D002784:Cholesterol; D014700:Verapamil; D009543:Nifedipine