Effect of isradipine on the formation and regression of fatty streaks in cholesterol fed rabbits

Kunjara-Na-Ayudhya, Rapeephon; Thomson, Abr; Kappagoda, C. T.

doi:10.1093/cvr/28.7.1089

Cited by 5 publications

(3 citation statements)

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“…Although Ca2+ channel blockers have long been known to slow down the progression of lesion development in animal models of atherosclerosis, the molecular mechanisms of these effects are not yet completely understood (14)(15)(16). Under physiological conditions, the composition of the ECM is subjected to a permanent turnover that results from balanced synthesis and degradation (5,25).…”

Section: Effect Of Ca2+mentioning

confidence: 99%

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Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

Roth

Eickelberg

Köhler

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

149

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The Cell biological changes during the development of sclerotic lesions are characterized by an increased deposition of extracellular matrix (ECM) proteins such as laminin, fibronectin, and collagens (1-3). The latter represent a family of proteins with at least 14 different members, which form the major structural part of the ECM (4). The ECM has been previously considered to be a relatively inert mass of proteins. However, recent reports have shown that it is subjected to a continuous turnover that accounts for a remodeling of -5-15% of total ECM per day (5). The ECM influences cell functions and is essentially involved in tissue-typespecific gene expression and proliferation (6-8). It is able to affect the differentiation state of a cell, and, consequently, alterations of the composition of the ECM modulate the responsiveness of cells to physiological stimuli such as growth factors, hormones, and cytokines (7). In addition, changes in the relative proportions of components of the ECM are apparently of crucial relevance for the pathogenesis of various diseases such as atherosclerosis (6, 9, 10). Here, the prominence of collagen as a major element of atherosclerotic plaques is well established, taking into account that 90% of the total collagen found in these lesions is formed by collagens type I and III (1). Furthermore, an increased expression of collagens IV, V, and VI was reported in human atherosclerotic plaques (1, 2).ECM metabolism is tightly regulated by a complex network of interactions, including (i) the de novo synthesis of compounds by interstitial cells; (ii) the degradation of existing ECM molecules by the action of various proteases, including members of the matrix metalloprotease (MMP) family; and (iii) the inhibition of protease activities by specific endogenous antagonists such as the tissue inhibitors of metalloproteinases (TIMPs) (11)(12)(13) (17,18). Fibroblasts were cultivated in RPMI 1640 medium supplemented with 10% fetal calf serum and 8 mM stabilized L-glutamine; VSMCs were cultivated in DMEM supplemented with 5% colostrum, 20 mM Hepes, and 8 mM L-glutamine. Subconfluent cultures (80% confluence) were used between passages two and six. Cells were synchronized by starvation for 48 hr in low-serum medium (0.1% fetal calf serum), replacing the medium every 24 hr. Quiescent cells were challenged with human recombinant PDGF BB (10 ng/ml; GIBCO/BRL) in the presence or absence of the drugs.

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Section: Effect Of Ca2+mentioning

confidence: 99%

“…The latter represent a family of proteins with at least 14 different members, which form the major structural part of the ECM (4). The ECM has been previously considered to be a relatively inert mass of proteins.…”

mentioning

confidence: 99%

Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

Roth

Eickelberg

Köhler

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

149

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“…endothelial injury, and experimental calcinosis [8][9][10][11][12][13]. The in vitro effects of these drugs on pro-cesses which play a role in the development of athero-…”

Section: Introductionmentioning

confidence: 99%

Direct Antiatherogenic Activity of Isradipine and Lacidipine on Neointimal Lesions Induced by Perivascular Manipulation in Rabbits

Donetti

Fumagalli

Paoletti

et al. 1997

Pharmacological Research

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The in vivo antiatherogenic activity of two calcium antagonists of the dihydropyridine class (isradipine and lacidipine) was investigated in a new experimental model. The proliferative lesion induced in the rabbit carotid artery was obtained by positioning a hollow silastic collar around the vessel. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries obtained 14 days after collar placement. The effectiveness in inhibiting neointimal formation was assessed for isradipine (0.5, 1 and 4 mg kg-1 day-1) in normocholesterolemic (NC) animals and for lacidipine (1, 3, and 10 mg kg-1 day-1) in hypercholesterolemic (HC) rabbits. In NC control animals a neointimal formation was clearly detectable (I/M 0.53 +/- 0.18, n = 5). In isradipine-treated groups I/M ratios were significantly decreased (0.15 +/- 0.03, 0.12 +/- 0.02, 0.1 +/- 0.02 for the 0.5, 1 and 4 mg kg-1 day-1 doses respectively). In HC rabbits the administration of cholesterol 1% mixed with food and drug treatment started either 60 days before collar insertion (pretreated group, HC60) or on the same day (non pretreated group, HC15) of the collar placement. Only the pharmacological pretreatment was effective in reducing neointimal formation (0.47 +/- 0.02, 0.4 +/- 0.09, and 0.32 +/- 0.02 for dose 1, 3 and 10 mg kg-1 day-1 vs 1.1 +/- 0.14 in control animals). The inhibition of neointimal hyperplasia was much less evident in nonpretreated animals (0.7 +/- 0.15, 0.6 +/- 0.18 and 0.43 +/- 0.08 for dose 1, 3, and 10 mg kg-1 day-1 vs 0.72 +/- 0.2 in control animals). These results suggest a direct antiatherosclerotic effect of isradipine and lacidipine on neointimal hyperplasia induced in NC and HC pretreated rabbits independently of modulation of risk factors such as hypercholesterolemia and/or hypertension.

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The effect of isradipine administration on existing fatty streaks in the cholesterol-fed rabbit: A morphometric study

Skepper

Kappagoda

1996

Atherosclerosis

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Effect of isradipine on the formation and regression of fatty streaks in cholesterol fed rabbits

Abstract: Isradipine protects against the development of fatty streaks in rabbits fed a diet supplemented with 2.5% cholesterol. Administration of this drug after fatty streaks are formed also promotes their resolution.

Cited by 5 publications

References 0 publications

Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

Direct Antiatherogenic Activity of Isradipine and Lacidipine on Neointimal Lesions Induced by Perivascular Manipulation in Rabbits

The effect of isradipine administration on existing fatty streaks in the cholesterol-fed rabbit: A morphometric study

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