Dihydropyridine calcium antagonist modulates cholesterol metabolism and eicosanoid biosynthesis in vascular cells.
Recent clinical studies have shown that calcium channel blockers can retard and possibly reduce the angiographic progression of coronary artery disease. Calcium channel blockers also inhibit dietary-induced atherosclerosis in animal models of this disease. In this study, we delineate potential cellular and molecular mechanisms by which nicardipine, a dihydropyridine calcium antagonist, may alter lipoprotein and cholesterol trafficking, affect the regulatory signal transduction pathways involved in accelerating cholesteryl ester (CE) catabolism in vascular smooth muscle cells, and modulate cell-cell interactions of vascular and inflammatory cells. We demonstrate in arterial smooth muscle cells that nicardipine increases 1) LDL binding, uptake, and degradation, 2) RNA transcript levels for the LDL receptor, 3) CE catabolic activity, 4) PGI2 release, and 5) RNA transcript levels for cyclooxygenase. Furthermore, nicardipine blocked cytokine-induced monocyte adhesion to endothelial cells and smooth muscle cells. Taken together, these findings support the hypothesis that nicardipine may function as an anti-atherosclerotic agent by promoting CE catabolism and cholesterol clearance and by reducing monocyte adhesion to the activated endothelium.
Nicholson
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Department of Biochemistry, Cornell University Medical College, New York, New York.
Etingin
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Pomerantz
K B
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Summers
B D
BD
Friday
K
K
Wolff
A A
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Hajjar
D P
DP
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D000242:Cyclic AMP / Q000032:analysis; D015777:Eicosanoids / Q000096:biosynthesis*; D011464:Epoprostenol / Q000032:analysis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats
D002121:Calcium Channel Blockers; D015777:Eicosanoids; D012333:RNA, Messenger; D002784:Cholesterol; D009529:Nicardipine; D011464:Epoprostenol; D000242:Cyclic AMP