title: Impact of a combination of a calcium antagonist and a beta-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and efflux of cholesterol in human macrophages and murine J774 cells.
abstract: Calcium antagonists and beta-blockers may retard or inhibit atherogenesis. In the absence of data pertaining to the potential cardioprotective action of an association of such agents, we have investigated the impact of nifedipine and atenolol, alone or in combination, on the capacity of monocyte-macrophages (ex vivo) and copper ions (in vitro) to oxidize LDL and on intracellular metabolism and efflux of free and esterified forms of cholesterol in human macrophages and foam cells. At concentrations up to 100 micromol/L, atenolol had no effect on the oxidative resistance of LDL; on the contrary, nifedipine displayed a significant dose-dependent capacity to protect LDL during copper-mediated oxidation (100 micromol/L; P<.001). Using a DPPH radical generating system, nifedipine was shown to exert free radical-trapping activity (molar ratio of scavenging activity, nifedipine:alpha-tocopherol, 1:114). The addition of atenolol to nifedipine was without effect on the antioxidant activity of the calcium antagonist. In experiments in which oxidative modification was mediated by monocyte-macrophages, nifedipine but not atenolol conserved its antioxidant capacity. Furthermore, we demonstrated that association of atenolol with nifedipine did not modify the antioxidant properties of nifedipine itself. Using a human monocyte-derived macrophage culture system, nifedipine, atenolol, or a combination of the two drugs was ineffective in inhibiting foam cell formation induced by acetylated LDL or oxidized LDL. However, atenolol (100 micromol/L) increased cellular accumulation of cholesteryl ester (+17%; P<.05), whereas nifedipine (100 micromol/L) decreased total cholesterol (-37.4%; P<.05) accumulation induced by acetylated LDL in the mouse macrophage cell line J774. A combination of the two drugs neutralized these antagonistic effects. None of these results were reproduced during the oxidized LDL-induced transformation of murine J774 cells into foam cells. Furthermore, cholesterol efflux from preloaded human macrophages was equally unaffected by the addition of the drugs alone or in combination. It therefore seems unlikely that the beneficial effect of atenolol on coronary heart disease is mediated by changes in either LDL oxidizability or cholesterol metabolism in human macrophages and foam cells. Our findings with nifedipine suggest, however, that this calcium antagonist may potentially exert antiatherosclerotic properties via a reduction of the oxidative modification of LDL, thereby affecting a reduction in foam cell formation and in the pathophysiological cellular activities of oxidized lipids, rather than by inducing a direct reduction in cholesterol accumulation in human foam cells of macrophage origin.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherches sur Les Lipoproteines et l'Athérogénèse, Hôpital de la Pitié, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Lesnik
authors.forename: C
authors.initials: C
authors.lastname: Dachet
authors.forename: L
authors.initials: L
authors.lastname: Petit
authors.forename: M
authors.initials: M
authors.lastname: Moreau
authors.forename: S
authors.initials: S
authors.lastname: Griglio
authors.forename: P
authors.initials: P
authors.lastname: Brudi
authors.forename: M J
authors.initials: MJ
authors.lastname: Chapman
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants; D001262:Atenolol / Q000008:administration & dosage / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction
chemical_list: D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002121:Calcium Channel Blockers; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D001262:Atenolol; D003300:Copper; D002784:Cholesterol; D009543:Nifedipine