Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a complex and multifactorial disease, the endpoint of which is the formation of a calcified plaque. Intermediate events include intimal injury, smooth muscle cell proliferation and migration, macrophage infiltration, lipid accumulation and excess formation of ground substance. To determine whether the newly developed, long-acting calcium antagonist, amlodipine, slows the development of atherosclerotic lesions under experimental conditions, young New Zealand white rabbits were fed on a diet of 2% cholesterol plus 1% peanut oil for up to 12 weeks. Half the rabbits received 1 or 5 mg amlodipine/kg body weight/day. Amlodipine caused a significant and dose-dependent reduction in lesion formation in the thoracic aorta. At the same time thoracic aorta Ca2+ and cholesterol content were maintained at near normal levels, despite the raised plasma cholesterol levels. The protective effect of amlodipine persisted throughout a treatment period of 12 weeks, indicating the absence of tachyphylaxis.
 ...
PMID:The antiatherogenic effects of amlodipine: promise of preclinical data. 128 82

Although calcium antagonists were originally developed for use in the management of patients with angina pectoris, they are now used in the management of other cardiovascular disorders, including hypertension. More recently, the calcium antagonists have been under investigation for their potential protective role in atherosclerosis. Coupled with these new possibilities for therapeutic use are the development of new, long-acting, tissue-specific calcium antagonists. Amlodipine belongs to this group, and although it is a dihydropyridine-based calcium antagonist, its pharmacologic profile differs from that of other dihydropyridine-based calcium antagonists. Differences include: different pH optimum for receptor binding, different rates of association and dissociation, and differences in allosteric interaction with the diltiazem and verapamil binding sites. Amlodipine, when given orally to rabbits receiving a high-cholesterol diet, reduces atheroma formation. Evidence of its ability to protect the vasculature is provided by its ability to significantly increase (p less than 0.001) survival in stroke-prone hypertensive rats.
 ...
PMID:Protecting the vasculature: an eye toward the future. 214 59

Treatment of atherosclerosis has mainly focused on decreasing low-density lipoprotein cholesterol (LDL-C). However, recent coronary angiographic trials revealed that aggressive lowering of LDL-C below 100 mg/dl arrests atherosclerosis progression in only 50-60% of patients. Furthermore, quantitative coronary angiography in these trials showed significant regression only in advanced fibrous-fatty plaques (> or = 50% stenosis) and not in the younger, more cell-proliferative lesions (< 50% stenosis). It is clear that lipid-lowering therapy has limited efficacy and there is therefore a need for other drugs, especially anti-proliferative agents, for secondary and primary prevention. To test this hypothesis, a new calcium antagonist, amlodipine, was studied for its anti-atherogenicity in non-human primates because of its known in vitro anti-cell proliferant, cell membrane stabilising and anti-oxidant properties. Amlodipine was found to normalise elevated plasma levels of oxidised LDL without reducing elevated total LDL-C levels in monkeys fed an atherogenic diet which, however, significantly suppressed atherosclerosis progression. These data suggest that amlodipine may be an excellent candidate, in combination with lipid-lowering drugs, for dual therapy of atherosclerotic vascular disease and may also be effective as monotherapy even when LDL-C is not lowered satisfactorily.
 ...
PMID:Limits of lipid-lowering therapy: the benefits of amlodipine as an anti-atherosclerotic agent. 778 12

Migration of monocytes into the subendothelial space of the aorta has been considered to be an important event in the development of atherosclerosis. Because hypertension is commonly associated with atherosclerosis, we studied the effect of applied pressure on the migration of monocytes. Direct applied pressure increased the migration (P < .001) of monocytes across a filter when compared with normal atmospheric pressure. The migration of monocytes was found to be directly related to the amount of the applied pressure. Amlodipine, a calcium channel blocker, attenuated the migration of monocytes under normal as well as increased pressure conditions in a dose-dependent manner. These studies provide a basis to speculate on the role of direct pressure in the migration of monocytes into the subendothelial space and the possibility that vasoactive agents may modulate the migration of monocytes independent of their pressure-lowering effect.
 ...
PMID:Pressure modulates monocyte migration. 939 50

Vascular smooth muscle cells (VSMC) are involved in the pathogenesis of hypertension and coronary artery disease. Amlodipine, a calcium channel blocker of the dihydropyridine type, is widely used in the therapy of these diseases, and has been shown to reduce the progression of the underlying pathophysiological mechanisms, such as atherosclerosis and restenosis. Research on the impact of calcium channel blockers on cell behavior has revealed an antiproliferative effect on VSMC. Cell proliferation is tightly controlled by permanent interaction of cells with their surrounding microenvironment, the extracellular matrix (ECM). The ECM is subjected to a continuous turnover and implicated in (i) stabilization and compartmentalization of tissue architecture and (ii) local binding and preservation of growth factors and cytokines. These growth factors and cytokines can be released during degradation of the ECM, and can function as local inflammatory factors without de novo synthesis. In this context, we assessed the effects of amlodipine on the composition of the ECM and related factors. We investigated the effects of amlodipine on (i) the regulation of cellular cholesterol metabolism, (ii) the activation of genes encoding for inflammatory factors, (iii) gene expression and turnover of ECM compounds, and (iv) the activity of matrix-degrading enzymes. Most of these effects of calcium channel blockers require direct induction of gene expression. In this respect, we demonstrate that amlodipine increases expression of the cytokine interleukin-6 by directly activating the respective gene promoter in human VSMC.
 ...
PMID:Effects of amlodipine on gene expression and extracellular matrix formation in human vascular smooth muscle cells and fibroblasts: implications for vascular protection. 948 93

It is well known that the atherogenic dyslipidemias of either elevated serum LDL or reduced HDL levels correlate with the degree and severity of atherosclerosis. However, how this leads to atherogenesis is poorly understood. A role for cellular oxidative stress mediated by oxidized LDL has gained widespread acceptance, but this pathway is unlikely to be the sole atherogenic signal. Recent evidence obtained from arterial smooth muscle cells (SMC) and endothelial cells (EC) is consistent with another pathway that may explain, in part, the early alterations contributing to the initiation of cellular atherogenic modifications. This pathway involves enrichment of the cell plasma membrane with cholesterol. In SMC, in vitro (cell culture) and in vivo (cholesterol feeding) experiments demonstrate that cholesterol enrichment of the SMC membrane occurs rapidly and is associated with an increase in membrane bilayer width, calcium permeability, and cell proliferation. Removal of excess membrane cholesterol with human HDL restores these alterations, suggesting that this membrane structural 'defect' mediates these changes in cell function. In vitro, the increased calcium permeability is inhibitable by calcium channel blockers (CCBs), but in vivo, a calcium 'leak' pathway develops that is virtually uninhibitable. It is not surprising that the literature on the application of CCBs for atheroprotection is not wholly convincing. However, with the advent of the new third generation of CCBs, new hope arises. One of the first CCBs of this generation is amlodipine (Norvasc), a charged dihydropyridine that has a remarkable pharmacologic profile. First, it is markedly lipophilic allowing it to partition readily into cell membranes. Second, in the membrane it has the ability to re-order, or restore, the 'swollen' membrane bilayer back to normal in atherosclerotic SMC. Third, it has potent antioxidant properties. Fourth, it appears to inhibit the expression of a variety of genes implicated in atherogenesis. Fifth, it is a CCB. Amlodipine has demonstrated atheroprotection in both rabbit and subhuman primate models of this disease. We propose that cellular alterations induced by enrichment of the cell membrane with cholesterol, which appears to modulate SMC to the atherosclerotic phenotype, are inhibitable by amlodipine through a combination of its varied pharmacologic properties. The potential for atheroprotection with amlodipine is currently being investigated in a human trial (PREVENT trial) and the results of this trial will determine the relevance of the preclinical findings to humans.
 ...
PMID:Cholesterol, calcium and atherosclerosis: is there a role for calcium channel blockers in atheroprotection? 948 96

In both atherosclerosis and arterial hypertension, structural and functional abnormalities result in vascular hypertrophy that is associated with an increased ratio of vascular media thickness to lumen diameter and hyperreactivity of vascular smooth muscle cells (VSMCs), resulting in uncontrolled cell migration and growth in vivo. In culture, VSMCs isolated from the spontaneously hypertensive rat (SHR) also display exaggerated growth and/or proliferation compared to VSMCs isolated from normotensive control Wistar Kyoto (WKY) rats. In vitro studies of cultured VSMCs can therefore be used as a model to investigate the mechanisms whereby a drug such as amlodipine can exert its antihypertensive and antiatherogenic effects. The present in vitro investigations examine the mechanisms whereby amlodipine reduces VSMC growth/proliferation promoted by basic fibroblast growth factor (bFGF), a peptide growth factor likely to participate in the vascular smooth muscle hypertrophy of the SHR. VSMCs from SHR and/or WKY rat aortae were isolated, passaged, and cultured. The influence of amlodipine on VSMC growth/proliferation was studied by measuring DNA synthesis and cell number under experimental conditions, which allowed us to determine the cell cycle phase in which amlodipine exerts its effects. Amlodipine was found to inhibit growth and bFGF-induced DNA synthesis in a concentration-dependent manner. Delayed addition of amlodipine showed that the drug exerts its effect early in the G1 phase, a result that was confirmed by the finding that amlodipine could not inhibit bFGF-induced DNA synthesis in VSMCs arrested at the G1/S boundary. In comparative experiments, the inhibitory effect of amlodipine on both cell growth and DNA synthesis was found to be of similar magnitude in SHR- and WKY-derived VSMCs. It is therefore likely that by modulating cell growth/proliferation induced by bFGF, amlodipine may reduce the vascular hypertrophy of the SHR. Since amlodipine also has been found to inhibit VSMC migration, one may reasonably envisage that these characteristics are important components of the antiatherogenic properties of the drug.
 ...
PMID:Amlodipine and vascular hypertrophy. 948 98

Myocardial ischaemia and reperfusion cause dysfunction of the coronary vasculature leading to a sustained reduction in coronary blood flow and an impairment of responses to both endothelium-dependent and endothelium-independent vasodilators. In contrast, when previously ischaemic arteries are removed from the myocardium and vascular function is examined in vitro, it is evident that while endothelial function is impaired, smooth muscle reactivity remains intact. Therefore, other changes must be responsible for the general reduction in vasodilator reserve. Examination of the vasculature in the ischaemic myocardium by electron microscopy reveals adhesion of leukocytes and plugging of capillaries. There also is evidence that polymorphonuclear leukocytes (PMNs) release a factor that constricts coronary arterioles, and that release of this factor is increased by atherosclerosis. The identity of this factor remains uncertain, but the calcium antagonist amlodipine prevents the coronary vasoconstriction. Amlodipine is also able to prevent the impaired perfusion and the reduction in vasodilator reserve that occurs after myocardial ischaemia and reperfusion in the dog. In addition, amlodipine prevents the endothelial dysfunction observed in isolated arteries after ischaemia and reperfusion. The interaction between the endothelium and activated PMNs may be a suitable target for pharmacological intervention to improve postischaemic vascular function.
 ...
PMID:Prevention of ischaemia-induced coronary vascular dysfunction. 948

Treatment of atherosclerosis has focused mainly on decreasing low-density lipoprotein cholesterol (LDL-C). However, recent coronary angiography trials have revealed that aggressive lowering of LDL-C below 100 mg/dl arrests atherosclerosis progression in only 50% to 60% of patients. Furthermore, with quantitative coronary angiography, significant regression occurred only in advanced fibrous-fatty plaques (> or = 50% stenosis) and not in the younger, more cell-proliferative lesions (< 50% stenosis). It is clear that lipid-lowering therapy has limited efficacy; therefore, other drugs, especially antiproliferative agents, may be useful for secondary and primary prevention. To test this hypothesis a new calcium antagonist, amlodipine, which has in vitro antiproliferative, cell membrane stabilizing, and antioxidative properties, was studied to determine whether it has antiatherogenic effects in nonhuman primates. Amlodipine normalized elevated levels of oxidized arterial cholesterol without reducing elevated total plasma cholesterol levels and significantly suppressed atherosclerosis progression in monkeys who had been fed an atherogenic diet. These data suggest that amlodipine may be an excellent candidate, in combination with lipid-lowering drugs, for dual therapy of atherosclerotic vascular disease, and also may be effective monotherapy, even when LDL-C is not lowered satisfactorily.
 ...
PMID:Limits of lipid-lowering therapy: the potential benefits of amlodipine as an antiatherosclerotic agent. 948 3

The major factor limiting the long-term success of cardiac transplantation is the development of accelerated arteriosclerosis that occurs in the coronary arteries of the cardiac allograft. Transplant arteriosclerosis is characterized by diffuse, uniform, concentric narrowing of the artery by a proliferative, fibrocellular intima. The etiology of transplant arteriosclerosis is thought to be immune-mediated, and endothelial cells, smooth muscle cells, and inflammatory cells participate in the progression. Based on data derived from studies of conventional atherosclerosis, in which calcium channel blockers (CCBs) have demonstrated beneficial effects, preliminary studies designed to determine if CCBs might affect transplant arteriosclerosis similarly have been performed in animal models as well as in a limited number of cardiac transplant patients. Amlodipine suppressed transplant arteriosclerosis in one animal study, while diltiazem preserved vasodilatory responses in another animal study. Small prospective trials and retrospective studies in humans have shown that CCBs have a favorable effect on the development of transplant arteriosclerosis. While no work has been directed specifically at determining the mechanisms by which CCBs might prevent transplant arteriosclerosis, there are several likely candidates. These include preservation of endothelial function, suppression of smooth muscle cell migration and proliferation, production of extracellular matrix, and regulation of lipid metabolism and certain components of the immune system.
 ...
PMID:Accelerated arteriosclerosis after transplantation: the possible role of calcium channel blockers. 948 4


1 2 3 4 Next >>