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

Growing evidence indicates that oxidized low-density lipoprotein (LDL) may promote atherogenesis. Therefore, inhibition of LDL oxidation may impede this process. Carvedilol is a vasodilating, beta-adrenoceptor blocking agent. As a new antihypertensive drug, carvedilol is unique by virtue of its potent antioxidant activity. Therefore, we tested the ability of carvedilol to inhibit the oxidation of LDL by either macrophages or Cu2+. Carvedilol inhibited LDL oxidation by macrophages in a dose-dependent manner, with an IC50 value of 3.8 microM, as assessed by a thiobarbituric acid reactive substance (TBARS) assay. Under the same conditions, propranolol showed only a mild inhibitory effect (IC50 > 100 microM), while pindolol, atenolol and labetalol had almost no effect. Carvedilol, at 10 microM, almost completely inhibited the macrophage-induced increase in electrophoretic mobility of LDL, while other beta-blockers at 50-300 microM had no significant effect. Carvedilol inhibited superoxide release from mouse macrophages, which correlated well with its inhibition of LDL oxidation. Carvedilol also inhibited Cu(2+)-induced LDL oxidation with an IC50 value of 17 microM, while all other beta-blockers were inactive up to 300 microM. These observations suggest that carvedilol might not only be an effective antihypertensive drug, but might also be effective in prevention of atherosclerosis.
Atherosclerosis 1992 Dec
PMID:Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper. 136 24

The effects of a beta-blocker, carvedilol, on peripheral hemodynamics and hemorheologic parameters were evaluated in 11 geriatric patients with essential hypertension [3 men and 8 women aged 62-79 years (mean, 68.6 years)]. Carvedilol was given orally after breakfast at a dose of 10 or 20 mg daily for 8 weeks. Peripheral hemodynamics, the common carotid arterial flow, and hemorheologic parameters were determined twice prior to administration and after 4 and 8 weeks of carvedilol treatment. The common carotid arterial flow was determined using the pulsed Doppler method. Peripheral hemodynamics were assessed by venous occlusion plethysmography. The hemorheologic parameters assessed include erythrocyte aggregation, erythrocyte deformability, plasma viscosity, whole-blood hematocrit, and platelet function tests. Erythrocyte aggregation was measured using an Erythrocyte Aggregometer MA-1 (Myrenne, USA), taking a high shear rate of 600 s-1 and a low shear rate of 3 s-1 as the indices. Statistical comparisons of values before and after carvedilol administration were made using the paired Student's t-test. Systolic and diastolic blood pressure were decreased by carvedilol. The common carotid arterial flow was increased, and peripheral hemodynamics were improved by carvedilol. Erythrocyte aggregation (measured at both a high and a low shear rate) and plasma viscosity were decreased, erythrocyte deformability was increased, and levels of circulating platelet aggregates were also improved by carvedilol. This improvement of hemorheologic variables may contribute to prevention of the initiation and progression of thrombosis and atherosclerosis in geriatric patients with essential hypertension.
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PMID:Effects of carvedilol on common carotid arterial flow, peripheral hemodynamics, and hemorheologic variables in hypertension. 197

We examined the antiproliferative effect of the novel multiple-action antihypertensive agent carvedilol on human vascular smooth muscle cells (VSMC). Carvedilol inhibited the increase in cell number induced by foetal calf serum (FCS) in 86% (18 of 21) of human VSMC grown both from saphenous vein (17.6 +/- 3.5% inhibition, mean +/- SEM, n = 15) and restenotic lesions (31.4 +/- 5.5% inhibition, mean +/- SEM, n = 5). Carvedilol had a greater antiproliferative effect than other beta-adrenoceptor antagonists. In comparison with calcium channel blockers, carvedilol (10 microM) elicited a degree of growth inhibition similar to that of verapamil, but was less effective than the dihydropyridine amlodipine at equimolar concentrations. Although carvedilol had a greater antiproliferative effect on cells derived from restenotic lesions cells than on control saphenous vein cells, the difference was not statistically significant. In the present study, the antiproliferative effect of carvedilol on human VSMC in vitro occurred at concentrations higher than those in plasma. Although this may represent a limitation to the clinical efficacy of carvedilol against proliferation of VSMC associated with hypertension and atherosclerosis, the apparent relative selectivity of carvedilol for restenosis-derived cells is a promising line of investigation.
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PMID:Inhibition of human vascular smooth muscle cell proliferation by the novel multiple-action antihypertensive agent carvedilol. 759 35

Carvedilol is a cardiovascular drug currently used for the treatment of hypertension. Clinical studies have recently demonstrated efficacy in angina and congestive heart failure. Recently, carvedilol has been shown to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis induced by a wide variety of growth factors. These findings are of interest since smooth muscle proliferation and abnormal lipid metabolism are proposed to play an important role in the pathogenesis of atherosclerotic plaque formation and in development of stenotic lesions following vascular injury by balloon angioplasty and coronary artery bypass grafting. On the basis of these observations, the antiproliferative actions of carvedilol have been explored in detail. In human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 microM) produced a concentration-dependent inhibition of the mitogenesis stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum, with IC50 values ranging from 0.3 to 2.0 microM. Carvedilol also produced a concentration-dependent inhibition of vascular smooth muscle cell migration induced by platelet-derived growth factor, with an IC50 value of 3 microM. The extensive neointimal formation that occurs following balloon angioplasty of rat carotid arteries was markedly attenuated by carvedilol (1 mg/kg, i.p.; twice daily starting 3 days before angioplasty and continuing until 14 days after angioplasty). Quantitative image analysis demonstrated that carvedilol reduced the neointimal growth following angioplasty by 84% without altering either medial or adventitial cross-sectional areas. These observations indicate that carvedilol may also be effective in the treatment of pathological disorders principally associated with abnormal vascular smooth muscle growth, such as atherosclerosis and acute vascular wall injury induced by angioplasty or coronary artery bypass grafting.
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PMID:Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. 832 99

Carvedilol is a vasodilating, beta-adrenoceptor antagonist currently marketed for the treatment of mild to moderate hypertension. Carvedilol acts to reduce total peripheral resistance by blocking peripheral vascular alpha 1-adrenoceptors, thereby producing systemic arterial vasodilation, while at the same time inhibiting reflex tachycardia through the blockade of myocardial beta-adrenoceptors. In addition to its established efficacy and safety as an antihypertensive agent, carvedilol has been shown to produce significant cardioprotection in experimental animal models of acute myocardial infarction, with the most dramatic effect being observed in the pig model of myocardial ischaemia and reperfusion, where the reduction in infarct size reached 91%. Recent pharmacological studies have revealed additional novel properties of carvedilol which may account for the marked protection produced by the drug in the ischaemic myocardium and which may also result in protection against other chronic pathological processes, such as atherosclerosis and acute vascular injuries. The latter arise from surgical procedures, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Specifically, carvedilol, as well as some of its hydroxylated metabolites, are potent antioxidants. In physicochemical, biochemical and cellular assays, carvedilol and several of its metabolites prevent lipid peroxidation and the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol and its metabolites prevent the oxidation of LDL to oxidized LDL, the latter being directly cytotoxic and known to activate monocytes/macrophages and to stimulate foam cell formation. In addition, carvedilol was found to inhibit both rat and human vascular smooth muscle cell proliferation and migration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. 852 83

Carvedilol is a vasodilating beta-blocker currently marketed for the treatment of mild to moderate hypertension and application is being filed to the FDA for treatment of congestive heart failure. Carvedilol reduces peripheral vascular resistance by blocking arterial alpha 1-adrenoceptors, thereby producing vasodilation, while preventing reflex tachycardia by blocking cardiac beta 1- and beta 2-adrenoceptors. In addition to the safety and efficacy of carvedilol as an antihypertensive agent, experimental studies indicate that carvedilol also provides significant cardioprotection in animal models of acute myocardial infarction as well as protection against the vascular remodelling that occurs following injury of the vasculature. Recent pharmacological studies have uncovered several novel properties of carvedilol which may function to protect the heart and vasculature from chronic pathological processes, such as ischaemia, atherosclerosis and the remodelling that occurs in the heart and blood vessels as a consequence of pressure overload, injury or shear stress. Specifically, carvedilol, likely as a result of the carbazol moiety, is a potent anti-oxidant. In physicochemical, biochemical and cellular assays carvedilol and several of its metabolites inhibit lipid peroxidation, scavenge oxygen free radicals, inhibit the formation of reactive oxygen radicals and prevent the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol blocks the oxidation of low-density lipoproteins (LDL), and thereby prevents the formation of oxidized-LDL which is believed to stimulate foam cell formation and augment the development of atherosclerotic plaque. The ability of carvedilol to prevent the formation of oxidized LDL, in addition to the general anti-oxidant properties of the compound, results in the protection of the endothelium from oxygen free radical injury, and thereby prevents the subsequent events triggered by endothelial damage. Recently, carvedilol has also been shown to inhibit vascular smooth muscle cell proliferation and migration. Because carvedilol can inhibit vascular smooth muscle cell proliferation induced by a wide variety of mitogens (e.g. growth factors, angiotensin II, endothelin, thrombin), it is likely that the site of inhibition occurs at some point beyond the specific mitogen receptors, possibly at a distal common pathway that affects the smooth muscle cell cycle. These unique activities of carvedilol have also been confirmed in vivo in a rat model of neointimal formation following vascular injury by balloon angioplasty, where vascular smooth muscle cell migration and proliferation are the key processes involved in the formation of neointima leading to vascular stenosis. In this model, carvedilol suppressed neointimal growth to a remarkable extent ( > 85% inhibition of neointimal formation) at a dose that is similar to the antihypertensive dose used clinically in hypertensive patients. Taken together, these unique multiple actions of carvedilol provide not only for adequate control of elevated blood pressure, but may also provide for protection of the heart and vasculature from secondary damage due to hypertension itself, as well as from other causes, such as ischaemia, pressure overload, shear stress, vascular injury and atherosclerosis.
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PMID:Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection. 873 68

Low density lipoprotein (LDL) oxidation plays a crucial role in the development and progression of atherosclerosis and is enhanced in patients with essential hypertension. This finding has stimulated a search for antihypertensive drugs with high intrinsic antioxidant properties. We investigated the antihypertensive and antioxidant effects of carvedilol, a new vasodilating beta-adrenoceptor blocking agent in a group of patients with mild to moderate essential hypertension after 4-month treatment. Carvedilol administration markedly increased the resistance to oxidation of LDL isolated from treated patients to values comparable to those of control, nonhypertensive subjects. This effect was achieved despite a significant loss in LDL-associated vitamin E. The increased resistance of LDL to oxidation promoted by carvedilol was not related to the normalization of previously increased blood pressure (BP). Indeed, the administration of other conventional antihypertensive drugs, capable of decreasing arterial BP but without high intrinsic antioxidant properties, to a control group of matched hypertensive patients failed to ameliorate LDL oxidation parameters. Carvedilol treatment also reduced the extent of in vivo LDL oxidation, as reflected by the decrease in antioxidized LDL autoantibody titer. This effect as well was detected only in the group of carvedilol-treated hypertensive patients and not after the simple reduction in BP obtained with antihypertensive drugs different from carvedilol.
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PMID:Protective effects of carvedilol, a vasodilating beta-adrenoceptor blocker, against in vivo low density lipoprotein oxidation in essential hypertension. 884 70

A stable HL60 subline having the potential for monocytic differentiation was established by use of GM-CSF. HL60, a human promyelocytic cell line, has frequently been employed for research in the fields of monocytic differentiation and atherosclerosis because of its potential to differentiate into either granulocytes or monocytes. However, HL60 are frequently seen to change their phenotype during long-term culture. To date, many sublines or variants of HL60 cells have been established. However, most of them display diminished or complete loss of activities that characterize parental cells. The present study was conducted to establish a stable HL60 subline with the potential for monocytic differentiation. Firstly, a single HL60 cell was isolated by limiting dilution, and was successfully proliferated by incubation with GM-CSF. Secondly, from this population, cells were selected that had the ability to generate superoxide after VD-induced monocytic differentiation. Cells obtained in this manner (designated HL60/DU-1) exhibited expression of CD14 and CD11b and suppression of CD3 expression after monocytic differentiation. NBT positivity showed a consistent level of over 971% after a 6-day challenge with VD throughout the experimental period of 12 months. HL60/DU-1 cells, which were cryopreserved in liquid nitrogen for 6 months, thawed and re-cultured, exhibited over 97% NBT positivity. Carvedilol and probucol, which exhibit antioxidative activity, inhibited superoxide release from the differentiated HL60/DU-1 cells. HL60/DU-1 cell line is a promising model for the study of monocytic differentiation and the effects of oxygen radicals.
Atherosclerosis 1998 Aug
PMID:Establishment of a stable HL60 subline having the potential for monocytic differentiation using granulocyte-macrophage colony-stimulating factor: possible use for the study of monocytic differentiation and oxidative stress. 971 36

Carvedilol is an antihypertensive drug with properties that may be potentially beneficial for kidney graft recipients. The purpose of the study was to investigate if progression of an established chronic rejection may be attenuated or reversed by carvedilol. An open, single-centre, phase II, pilot study, with a 2-yr follow-up, was performed in 25 kidney graft recipients with chronic rejection or accelerated transplant atherosclerosis. Seventeen patients had stable graft function assessed by serum creatinine levels. Eight patients withdrew from the study due to lack of efficacy (increase in serum creatinine 174-477 micromol/L (46-191%) from the initial levels). However. these patients had higher serum creatinine levels and proteinuria already at the start of the study. Both systolic and diastolic blood pressure, as well as heart rate, were stable in all study patients. Low density lipoprotein (LDL)/high density lipoprotein (HDL) cholesterol ratio decreased from 4.7 +/- 1.9 at 1 month to 3.5 +/- 1.2 at 18 months (p < 0.05), and MDA plasma levels decreased from 0.714 +/- 0.119 to 0.493 +/- 0.073 micromol/L after 3 months of carvedilol treatment (p < 0.05). No attenuation of progression of chronic graft rejection by carvedilol treatment was observed in the study. It is suggested that the process of chronic rejection could not be reversed by carvedilol because the patients included in the study already had severe morphological and functional changes of the graft. In conclusion, our study demonstrated that carvedilol provides a good control of blood pressure in renal transplanted patients. Carvedilol treatment had a beneficial effect on lipid pattern and reduced lipid oxidation, but there was no obvious effect on progression of chronic rejection.
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PMID:Carvedilol treatment of kidney graft recipients with chronic rejection. 1061 38

The cellular mechanisms by which hypertension enhances atherosclerosis are still not known in detail. Recently, evidence has been obtained that oxidative stress plays a role in the pathogenesis of pressure-induced atherosclerosis. We examined the effects of pressure on oxidative stress in cultured human coronary smooth muscle cells (SMCs). Application of increased pressure (+100 mmHg) with He gas for 48 h increased oxidative stress of measured by flow cytometry by 71% and F2-isopretane by 77%. Increased pressure also increased the activities of phospholipase D (PLD), and particulate protein kinase C (PKC). The PLD inhibitor suramin 100 micromol/l, 1-butanol 40 mmol/l, and the PKC inhibitors chelerythrine 1 micromol/l and calphostin C 100 nmol/l and completely blocked the increase in oxidative stress induced by pressure. Carvedilol 1 micromol/l but not propranolol 1 micromol/l blocked pressure-induced increases in oxidative stress in cultured SMCs. These findings suggest that pressure increases oxidative stress and that carvedilol significantly inhibits pressure-induced increase in oxidative stress in cultured human coronary smooth muscle cells.
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PMID:Carvedilol inhibits pressure-induced increase in oxidative stress in coronary smooth muscle cells. 1213 21


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