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 effect of the second generation dihydropyridine calcium antagonist lacidipine on cholesterol metabolism in vivo in the aortic arch of cholesterol 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 +/- 12, 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 (approximately 20%); no effect was observed at the lowest dose used (1 mg kg-1 day-1). These results suggest that the action of lacidipine on cholesterol esterification in the arterial wall involves, at least in part, a direct effect on cellular cholesterol metabolism. Inhibition of cholesterol 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 cholesterol metabolism we performed in vitro experiments with murine macrophages, the main cell type that accumulates cholesterol in the arterial wall. 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 rate of cholesteryl ester hydrolysis in the cell. All together these results indicate an inhibitory effect of lacidipine on cholesterol esterification catalyzed by the enzyme ACAT in murine macrophages. 4. We concluded that lacidipine influences cellular cholesterol metabolism. This effect may contribute to the potential antiatherosclerotic activity of this drug.
Bernini
F
F
Institute of Pharmacology and Pharmacognosy, University of Parma, Italy.
Canavesi
M
M
Bernardini
E
E
Scurati
N
N
Bellosta
S
S
Fumagalli
R
R
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004951:Esterification; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D002121:Calcium Channel Blockers; D002788:Cholesterol Esters; D004095:Dihydropyridines; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; C060285:lacidipine; D002784:Cholesterol; D002785:Sterol O-Acyltransferase