Nifedipine increases cholesteryl ester hydrolytic activity in lipid-laden rabbit arterial smooth muscle cells. A possible mechanism for its antiatherogenic effect.

Etingin, Orli R.; Hajjar, David P.

doi:10.1172/jci111860

Cited by 108 publications

(24 citation statements)

References 31 publications

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“…Ninety-nine of the 217 patients were in the nicardipine group, and 118 patients were in the placebo group. With respect to the baseline clinical and angiographic characteristics listed in Table 6, the two groups were well (31) 16 (16) 39 (39) 42 (42) 2 (2) 6.88± (20) 3 (3) 19 (19) 3 (3) 15 (15) 31 (31) 36 (36) 17 (17) (31) 24 (20) 55 (47) 35 (30) 4 (3) 7.01 ± (14) 3 (3) 12 (10) 6 (5) 27 (23) 35 (30) 45 (38) 11 (9) (31) 40 (18) 94 (43) 77 (36) 6 (3) 6.95± (14) 9 (4) 42 (19) 60 (30) 81 (37) 28 (13) balanced. The placebo patients were slightly younger-49.6+8.0 versus 51.5+7.7 years (p =0.08) -and had a shorter duration of angina -27.6+33.1 versus 38.3±44.6 months (p=0.13).…”

Section: Progression Of Coronary Stenoses Of 20% or Lessmentioning

confidence: 99%

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

et al. 1990

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To determine whether calcium channel blockers influence the progression of coronary atherosclerosis, 383 patients age 65 years or less with 5-75% stenoses in at least four coronary artery segments were selected at random within 1 Ninety-two nicardipine patients (55%) and 95 placebo patients (57%) had progression at one or more sites (p=NS). Regression, that is, an improvement by l1o0 or more in diameter stenosis, was seen in 140 of 2,323 lesions (6.0%) overall, with no significant intergroup difference. Among the 217 patients with 411 stenoses of 20% or less in the first study, such minimal lesions progressed in only 15 of 99 nicardipine patients compared with 32 of 118 placebo patients (15% versus 27%, p =0.046). In this subgroup, 16 of 178 minimal lesions in nicardipine patients and 38 of 233 minimal lesions in placebo patients progressed (p=0.038). By stepwise logisticregression analysis, baseline systolic blood pressure (p=0.04) and the change in systolic blood pressure between baseline and 6 months (p=0.002) correlated with progression of minimal lesions. This suggested blood pressure reduction may account for the beneficial action of nicardipine. These results suggested nicardipine has no effect on advanced coronary atherosclerosis but may retard the progression of minimal lesions. (Circulation 1990;82:1940-1953 Several calcium channel blockers have been shown to retard the development of athero-1, sclerosis in rabbits fed cholesterol-rich diets.1-7 The mechanism through which these drugs exert their antiatherogenic effects is not known, but is being From the

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Section: Progression Of Coronary Stenoses Of 20% or Lessmentioning

confidence: 99%

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

et al. 1990

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“…1). This inhibition was observed in a concentration-dependent manner at 10-9 M to 10-' M, and higher inhibition was observed at 10-5 M. Nifedipine has been reported to inhibit cholesteryl ester accumulation in macrophages (19). Recently, we have reported that efonidipine suppressed cholesteryl ester accumulation in the arterial wall by 64010 (P <0.05) in the aortic arch at 100 mg/kg dosage in cholesterol fed rabbits, and the maximal plasma efonidipine concentration reached 82.1 ± 17.0 ng/ml (115 nM) under this condition (21).…”

Section: Resultsmentioning

confidence: 83%

“…There are several reports that calcium antagonists show antiatherogenic effects in animal models with inhibition of cholesterol ester accumulation (14)(15)(16)(17). These calcium antagonists suppress the cholesterol ester accumulation in macrophages by inhibiting acyl-CoA cholesterol acyl-transferase (ACAT) and enhancing cholesterol ester hydrolysis (18,19). ACAT activity was induced by modified lipoprotein receptors including the scavenger-receptor-mediated pathway.…”

mentioning

confidence: 99%

Effects of Efonidipine Hydrochloride on Cholesterol Estérification Mediated by Beta-Very Low Density Lipoprotein in J774 Macrophages

Kitahara

Toyoda

Yamashita

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-The effects of efonidipine hydrochloride (efonidipine), a dihydropyridine calcium antagonist, on the cholesterol ester metabolism induced by beta-migrating very low density lipoprotein (;3-VLDL) in J774 macrophages were studied. The cholesteryl ester content in the macrophages was increased by incubation with 3-VLDL, and the increase was inhibited by efonidipine. Oleic acid incorporation into cellular cholesteryl ester was increased by r3-VLDL in J774 macrophages. The incorporation at an early phase of ~-VLDL induction (0-3 hr) was inhibited by efonidipine. This inhibitory effect of efonidipine was greater at an early phase of ~-VLDL induction (0-3 hr) than at a late phase of the induction (8-11 hr). Pretreatment of the cells with efonidipine enhanced the inhibitory effect. Efonidipine also inhibited 13-VLDL degradation but not the binding and association in macrophages without pretreatment. p-VLDL binding and association to macrophages were decreased by pretreatment of the cells with efonidipine. 13-VLDL metabolism was also decreased by dibutyryl cyclic AMP pretreatment. The decrease of 13-VLDL metabolism by efonidipine was prevented by co-treatment with efonidipine and HA1004, a protein kinase A inhibitor. Furthermore, efonidipine increased the intracellular cyclic AMP content in J774 macrophages. These findings suggest that efonidipine suppresses cholesterol ester deposition in atherosclerotic foam cells by inhibiting the modified lipoprotein metabolism and cholesterol esterification mainly through elevation of the cellular cyclic AMP level.Keywords: Efonidipine, Macrophage, Cholesteryl ester, p-Very low density lipoprotein, Cyclic AMP Cholesterol ester deposition in atherosclerotic intimal thickening is mainly due to the accumulation of lipid laden foam cells derived from monocyte/macrophages and intimal smooth muscle cells (1, 2). Cholesterol ester accumulation in the foam cells is caused by incorporation of beta-migrating very low density lipoprotein (~-VLDL) or modified lipoproteins such as acetylation or oxidation of low density lipoprotein (LDL) (3 -7) and due to subsequent induction of cholesterol esterification in the cells (4,(8)(9)(10)(11). These p-VLDL or modified lipoproteins are recognized by a scavenger receptor or LDL receptor related receptor family on the cell surface and internalized into the cells (10, 11). On the contrary, high density lipoproteins (HDL) diminish the intracellular cholesterol ester content by stimulating cholesterol ester hydrolysis activity and cholesterol translocation to the cell membrane and by enhancing the efflux of cholesterol from the cell membrane (12, 13).Calcium cation mobilization into cells and intracellular calcium cation contents affect the cholesterol ester metabolism in macrophages. There are several reports that calcium antagonists show antiatherogenic effects in animal models with inhibition of cholesterol ester accumulation (14-17). These calcium antagonists suppress the cholesterol ester accumulation in macrophages by inhibiting acyl-CoA chole...

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“…For example, some have shown that the stimulation of acid cholesterol hydrolase leads to increased hydrolytic breakdown of cholesterol ester in VSM cells following exposure to Ca2+-channel blockers [9]. Thus, an over-accumulation of cholesterol ester in VSM cells can be prevented by the use of these agents, thereby economizing cellular cholesterol metabolism.…”

Section: Reviewmentioning

confidence: 99%

A new perspective on the antiatherosclerotic activity of Ca²⁺‐channel blockers

Block

Emmons

1990

Eur J Clin Investigation

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Nifedipine increases cholesteryl ester hydrolytic activity in lipid-laden rabbit arterial smooth muscle cells. A possible mechanism for its antiatherogenic effect.

Abstract: Calcium and cholesterol (CHOL) accumulation are characteristic features of human atherosclerotic plaques. Calcium

Cited by 108 publications

References 31 publications

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

Effects of Efonidipine Hydrochloride on Cholesterol Estérification Mediated by Beta-Very Low Density Lipoprotein in J774 Macrophages

A new perspective on the antiatherosclerotic activity of Ca²⁺‐channel blockers

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Nifedipine increases cholesteryl ester hydrolytic activity in lipid-laden rabbit arterial smooth muscle cells. A possible mechanism for its antiatherogenic effect.

Abstract: Calcium and cholesterol (CHOL) accumulation are characteristic features of human atherosclerotic plaques. Calcium

Cited by 108 publications

References 31 publications

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis.

Effects of Efonidipine Hydrochloride on Cholesterol Estérification Mediated by Beta-Very Low Density Lipoprotein in J774 Macrophages

A new perspective on the antiatherosclerotic activity of Ca2+‐channel blockers

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A new perspective on the antiatherosclerotic activity of Ca²⁺‐channel blockers