Inhibition of cholesteryl ester deposition in macrophages by calcium entry blockers: an effect dissociable from calcium entry blockade

Abstract

1 The effects of calcium entry blockers on stimulated cholesteryl [³H]-oleate deposition in cultured macrophages were characterized in order to elucidate mechanisms underlying possible antiatheros-clerotic effects. Stimulation of intracellular cholesteryl [³H]-oleate deposition was initiated by incubation of macrophages with β-very low density lipoproteins (β-VLDL). 2 Nifedipine (Class I) markedly reduced cholesteryl [³H]-oleate deposition at all concentrations tested. However, Bay K 8644, a dihydropyridine which is known to stimulate calcium entry, also reduced cholesteryl [³H]-oleate deposition with a similar potency to nifedipine. 3 The effects of three Class II calcium entry blockers were evaluated: verapamil, methoxyverapamil, and diltiazem. Verapamil inhibited cholesteryl [³H]-oleate deposition in a concentration-dependent manner. Similarly, methoxyverapamil reduced cholesteryl [³H]-oleate deposition in a concentration-dependent manner although the reduction was not as great as that produced by verapamil. In contrast, diltiazem at any concentration tested did not inhibit cholesteryl [³H]-oleate deposition. 4 Flunarizine (a Class III calcium entry blocker) produced a modest stimulation of cholesteryl [³H]-oleate deposition at the lowest concentration used (10⁻⁷ m) but marked depression at the highest concentration (10⁻⁵ m). 5 The results indicate calcium entry blockers may exert protective effects on the development of atherosclerosis in animal models of diet-induced hyperlipidaemia by inhibiting intracellular cholesteryl ester deposition, but this effect may not be related to their calcium entry-blocking effects.