EFFECT OF LACIDIPINE ON CHOLESTEROL ESTERIFICATION - IN-VIVO AND IN-VITRO STUDIES

1 Cholesterol esterification and accumulation in the arterial wall is a hallmark of atherogenesis. Several preclinical studies suggest that calcium antagonists may exert antiatherosclerotic activity by directly affecting atherogenesis in the arterial wall. We investigated the eff ect of the second generation dihydropyridine calcium antagonist lacidi pine on cholesterol metabolism in vivo in the aortic arch of cholester ol fed rabbits, and in vitro in mouse cultured peritoneal macrophages. 2 Treatment of cholesterol-fed rabbits with 1, 3 and 10 mg kg(-1) day (-1) of lacidipine for two months reduced, in a dose-dependent manner, cholesterol esterification in the aortic arch: 24+/-6, 30+/-2, and 41 +/-8% inhibition, respectively (P<0.001 vs HC control). Concomitantly, drug treatment reduced total cholesterol content of the vessel wall. Lacidipine 3 and 10 mg kg(-1) day(-1) reduced cholesterolaemia (simila r to 20%); no effect was observed at the lowest dose used (1 rag kg(-1 ) day(-1)). These results suggest that the action of lacidipine on cho lesterol esterification in the arterial wall involves, at least in par t, a direct effect on cellular cholesterol metabolism. Inhibition of c holesterol esterification in the arterial wall was observed also in a reference group of animals treated with the specific ACAT inhibitor CI -976. 3 To evaluate the action of lacidipine on intracellular choleste rol metabolism we performed in vitro experiments with murine macrophag es, the main cell type that accumulates cholesterol in The arterial wa ll. Lacidipine almost completely inhibited cholesterol esterification in cholesterol loaded macrophages in culture. The effect was observed independently of esterification stimuli and in cell free homogenates. The drug modified intracellular cholesterol distribution, doubling the free-to esterified sterol ratio, but did not influence the cellular r ate of cholesteryl ester hydrolysis in the cell. All together these re sults indicate an inhibitory effect of lacidipine on cholesterol ester ification catalyzed by the enzyme ACAT in murine macrophages. 4 We con cluded that lacidipine influences cellular cholesterol metabolism This effect may contribute to the potential antiatherosclerotic activity o f this drug.