EFFECTS OF CALCIUM-ANTAGONISTS ON CHOLESTEROL-METABOLISM IN HUMAN AORTIC INTIMAL CELLS AND IN MOUSE P388D1 MACROPHAGES

Effects of verapamil and nifedipine on total cholesterol concentration in and accumulation by human aortic intimal smooth muscle cell and P388D1 macrophages were investigated The synthesis and hydrolysis of cholesterol esters in these cells were also studied Both calcium antagonists reduced the content of total cholesterol in the cells derived from the sites of atherosclerotic lesions of human aortic intima by 25-40% but did not affect the cholesterol content in normal aortic intimal cells or P388D1 cells. Verapamil and nifedipine (2.10(-5) M) abolished the accumulation of cholesterol induced in both cell types by atherogenic sera or atherogenic low-density lipoproteins. Both calcium antagonists produced 2- to 3-fold inhibitions in the synthesis of cholesterol esters by aortic intimal cells (at concentrations above 10(-5) M) and in P388D1 macrophages (at concentrations above 10(-6) M). At 2.10(-5) M, both antagonists activated hydrolysis of cholesterol esters by both cell types. Bay K8644, a calcium channel agonist, did not affect the syntheses of cholesterol esters, nor did it abolish the inhibitory action of the calcium antagonists. Propranolol, a beta-blocker which promotes the accumulation of cholesterol in intimal cell, inhibited both the synthesis and the hydrolysis of cholesterol esters in the aortic intimal cells. Our results suggest that the antiatherogenic properties of calcium antagonists observed in experimental and clinical tests are due to their ability to reduce cellular levels of cholesterol, an action primarily mediated by activation of the cellular hydrolysis of cholesterol esters.