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)

Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.
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PMID:Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits. 811 16

We have studied the influences of atherosclerosis, age and sex on arterial responsiveness to vasoactive agents using male and female Watanabe heritable hyperlipidaemic (WHHL) rabbits (4-12 months, n = 36) as a model for atherosclerosis and sex- and age-matched New Zealand White (NZW) rabbits (n = 36) as controls. The responses of isolated rings of basilar arteries mounted in organ baths to vasoactive substances were studied. KCl-induced contractions in female atherosclerotic rabbits were greater than controls but those of male atherosclerotic rabbits were equivalent to the respective controls. Age did not influence KCl-induced contractions of rabbits of either strain or sex. Histamine-induced contractions increased with age in female atherosclerotic rabbits only. Acetylcholine (ACh)-induced relaxations of 6-month-old male and female atherosclerotic rabbits were greater than their respective controls. ACh-induced relaxations of female but not male NZW rabbits decreased with age. Calcitonin gene-related peptide- and vasoactive intestinal polypeptide-induced relaxations in atherosclerotic male and female rabbits were not affected by age. However, relaxations of female but not male control rabbits decreased with age. These findings suggest that there are subtle changes in the control of vascular tone which develop with the onset and progression of atherosclerosis. Of particular significance is the increase in endothelium-dependent relaxation in WHHL rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Responses of rabbit basilar arteries to vasoconstrictor and vasodilator agents: the effects of atherosclerosis, age and sex. 811 59

We examined whether coronary risk factors and atherosclerotic lesions in the study artery were associated with impaired endothelium-dependent dilation of coronary resistance arteries. Acetylcholine (ACH) at graded doses (1, 3, 10 and 30 micrograms/min) and papaverine (10 mg) were selectively infused into the left anterior descending coronary artery of 28 patients, in whom the study artery was angiographically normal (n = 16) or with mild stenosis < or = 40% (n = 12). Coronary blood flow (CBF) was estimated from the product of mean CBF velocity measured by an intracoronary Doppler catheter and the arterial cross-sectional area of the study artery determined by quantitative arteriography. ACH increased CBF in a dose-dependent manner. However, the maximum CBF response to ACH varied widely among patients (from 50% to 660%). By multivariate analysis, the presence of atherosclerotic lesions in the study artery was an independent predictor for impaired CBF response to ACH (P < 0.01). Hypertension (P < 0.001), hypercholesterolemia (r = -0.52, P < 0.005), age > or = 50 yr (P < 0.01) and total number of coronary risk factors (r = -0.62, P < 0.001) were associated with the impaired increase in CBF with ACH by univariate analysis. The percent increase in CBF evoked with papaverine did not correlate with these risk factors. The results suggest that mild atherosclerotic lesions in the study artery and coronary risk factors are accompanied by impaired endothelium-dependent dilation of coronary resistance arteries evoked with ACH. Endothelial dysfunction of coronary resistance arteries may result in altered regulation of myocardial perfusion in patients with mild coronary atherosclerosis and coronary risk factors.
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PMID:Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. 842 26

1. The function of endogenous nitric oxide (NO) at the level of vascular smooth muscle, was assessed in a popular experimental model of accelerated atherosclerosis, the cholesterol-fed rabbit. 2. Endothelium-dependent vasorelaxation in response to acetylcholine (ACh, 1 microM) was significantly impaired in the carotid artery from rabbits maintained on a 1% (W/W) cholesterol diet for 8-10 weeks. Furthermore, the ability of an inhibitor of nitric oxide synthase (NOS), NG-nitro-L-arginine methyl ester (L-NAME, 1-300 microM), to enhance the contractile reactivity to a submaximal concentration of noradrenaline (NA, 3 microM), was significantly attenuated in hypercholesterolaemia. 3. A significant linear correlation between the maximal contractile effect of L-NAME (300 microM) and maximal vasorelaxation to ACh (1 microM) was determined in the carotid artery from control rabbits. In contrast, no such linear correlation was found in the carotid artery from hypercholesterolaemic rabbits. 4. We conclude that there are lesions both in agonist-stimulated, endogenous NO-dependent vasorelaxation and in the regulation of vasoconstrictor reactivity by endogenous NO in the hypercholesterolaemic rabbit carotid artery. Furthermore, the normal linear relationship between the contractile effect of L-NAME and vasorelaxation to ACh is lost after cholesterol-feeding.
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PMID:Investigation of endogenous nitric oxide vascular function in the carotid artery of cholesterol-fed rabbits. 873 Jul 41

Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with L-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary L-arginine supplementation prevents this. The effects of L-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2 x 2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial L-arginine levels were measured by chromatography. Chronic L-arginine supplementation increased serum (P < .001) and endothelial (P = .003) L-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and L-arginine blocked this adverse effect (P = .04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (P = .06). Neither environmental tobacco smoke nor L-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as L-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.
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PMID:Chronic dietary L-arginine prevents endothelial dysfunction secondary to environmental tobacco smoke in normocholesterolemic rabbits. 914 85

The endothelium modulates vascular tone by producing vasodilator vasoconstrictor substances. Of these, the most well characterized and potentially important are .NO and .02-. These small molecules exhibit opposing effects on vascular tone, and chemically react with each other in a fashion which negates their individual effects and leads to the production of potentially toxic substances. These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. .NO is produced in endothelial cells by an enzyme termed nitric oxide synthase. The endothelial .NO-synthase is activated when the intracellular level of calcium is increased. This occurs in response to neurohormonal stimuli and in response to shear stress. Acetylcholine and substance P are examples of neurohumoral substances that are able to stimulate the release of nitric oxide and to assess endothelial regulation of vasomotor tone. Importantly, the vasodilator potency of nitric oxide released by the endothelium is abnormal in a variety of diseased states such as hypercholesterolemia, atherosclerosis and diabetes mellitus. This may be secondary to decreased synthesis of nitric oxide or increased degradation of nitric oxide due to superoxide anions. More recent experimental observations demonstrate increased production of superoxide in atherosclerosis, diabetes mellitus and high renin hypertension suggesting that endothelial dysfunction in these states is rather secondary to increased .NO metabolism rather than due to decreased synthesis of .NO. Superoxide rapidly reacts with nitric oxide to form the highly reactive intermediate peroxynitrite (ONOO-). Peroxynitrite can be protonated to form peroxynitrous acid which in turn can yield the hydroxyl radical (OH.). These reactive species can oxidize lipids, damage cell membranes, and oxidize thiol groups. .NO given locally, exerts potent antiatherosclerotic effects such as inhibition of platelet aggregation, inhibition of adhesion of leukocytes and the expression of leukocyte adhesion molecules. It is important to note, however, that in-vivo treatment with .NO (via organic nitrates) increases rather than decreases oxidant load within endothelial cells. It remains therefore questionable whether systemic treatment with .NO may have antiatherosclerotic properties or whether .NO may initiate or even accelerate the atherosclerotic process.
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PMID:The physiology and pathophysiology of the nitric oxide/superoxide system. 923 65

1. Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that is implicated in the pathogenesis of ischaemic states and atherosclerosis. We tested the hypothesis that the vasoprotective effects of the oestrogens may be mediated in vivo by inhibition of the formation of TNF-alpha. 2. Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state resulting in a fatal outcome within 75-90 min after the release of occlusion. Sham-operated animals were used as controls. 3. Splanchnic artery occlusion (SAO) shocked rats had a marked hypotension, enhanced levels of TNF-alpha in serum and macrophages, leukopenia and increased ileal leukocyte accumulation, studied by means of myeloperoxidase activity (MPO). Furthermore, aortae from SAO rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM-10 microM), reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) and an increased staining for intercellular adhesion molecule-1 (ICAM-1). 4. In vivo administration of 17 beta oestradiol (500 micrograms kg-1, i.m., three hours before the induction of SAO) increased survival rate (100%, 4 h after SAO), enhanced mean arterial blood pressure; reduced serum TNF-alpha (25 +/- 5 u ml-1 vs 379 +/- 16 u ml-1), ameliorated leukopaenia and reduced ileal MPO (0.7 +/- 0.02 u 10(-3) g-1 tissue vs 4.2 +/- 0.4 u 10(-3) g-1 tissue). Furthermore aortae from SAO rats treated with 17 beta oestradiol exhibited a greater contractile response to phenylephrine, improved responsiveness to ACh and a blunted staining of ICAM-1. Finally 17 beta oestradiol, added in vitro to peritoneal macrophages collected from untreated SAO rats, significantly reduced TNF-alpha production. 5. Our results suggest that inhibition of TNF-alpha in vivo may explain, at least in part, the vasoprotective effects of oestrogens.
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PMID:The involvement of tumour necrosis factor-alpha in the protective effects of 17 beta oestradiol in splanchnic ischaemia-reperfusion injury. 928 18

Vascular remodeling has been demonstrated in advanced and early coronary artery disease. Whereas the endothelium may play a role in the adaptive process of vascular remodeling, it is not known if this process occurs in association with changes in coronary blood flow reserve. Early coronary atherosclerosis is characterized by endothelial dysfunction which is manifested by an abnormal coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine. This study was designed to test the hypothesis that coronary vascular remodeling occurs in association with coronary endothelial dysfunction early in the development of coronary atherosclerosis. Thirty-six patients found to have normal coronary angiograms or mild coronary artery disease were studied. Acetylcholine was infused into the left anterior descending artery. Patients were divided into 2 groups based on their coronary blood flow response to acetylcholine. Intravascular ultrasound measurements of the proximal left anterior descending diameter and area were obtained. Vessel diameter and area were measured at the external elastic membrane and indexed to body surface area. Vessel diameter and area were greater in patients with abnormal than normal responses to acetylcholine (5.2 +/- 0.3 mm and 19.5 +/- 0.9 mm2 vs 3.9 +/- 0.3 mm and 12.3 +/- 1.0 mm2; p <0.02, respectively). This difference persisted when measurements were indexed to body surface area. The current study suggests in vivo in humans that coronary vascular remodeling characterized by enlargement of the proximal coronary arteries occurs in association with endothelial dysfunction early in the course of coronary artery disease.
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PMID:Coronary vascular remodeling in association with endothelial dysfunction. 960 50

Calcium (Ca)-dependent factors, including cholesterol-induced changes in membrane Ca permeability and Ca deposition into lesions, may contribute to plaque formation and stability during the early and late stages of atherogenesis. Amlodipine can reduce atheroma formation in cholesterol-fed rabbits and may be cardioprotective. We therefore examined the effects of chronic amlodipine treatment (5 mg/kg daily for 10 weeks, p.o.) on infarct size after 30-min coronary occlusion/48-h reperfusion in rabbits fed a diet with or without 1% cholesterol. Infarct size was significantly larger in cholesterol-fed rabbits (72.0 +/- 3.5%, n = 9, mean +/- S.E.M.) than in normal-fed rabbits (47.1 +/- 4.9%, n = 9, P < 0.05). Amlodipine treatment effectively reversed the infarct size augmentation in cholesterol-fed rabbits (46.3 +/- 6.3%, n = 9, P < 0.05), but did not affect infarct size in normal-fed rabbits (51.0 +/- 4.7%, n = 8). In both cholesterol-fed and normal-fed rabbits, Ca content and leukocyte accumulation as assessed by myeloperoxidase activity were significantly higher in the ischemic myocardium than in the nonischemic myocardium. However, Ca content and leukocyte accumulation were markedly elevated in the ischemic myocardium of cholesterol-fed rabbits compared with normal-fed rabbits. Amlodipine treatment effectively reversed this elevation. Acetylcholine showed a marked reduction in endothelium-dependent relaxation in the aorta of cholesterol-fed rabbits, which also was reversed by amlodipine treatment. These results indicate that chronic amlodipine treatment reduces infarct size only in cholesterol-fed rabbits.
Atherosclerosis 1998 May
PMID:Reduction in infarct size by chronic amlodipine treatment in cholesterol-fed rabbits. 967 82

Acetylcholine (Ach)-induced vascular relaxation is mediated by nitric oxide released from the endothelium. Hence, impaired Ach-induced relaxation reflects endothelial dysfunction. The action of lipoprotein lipase on chylomicrons and very low density lipoproteins produces remnant lipoproteins (RLP) rich in triglycerides (TG), cholesterol (C) and apolipoprotein E (apo E). Apo E on RLP serves as a ligand for uptake of RLP by macrophages, endothelial cells and other cells expressing the LDL receptor or the remnant receptor; uptake of RLP by vascular wall cells can promote atherosclerosis. Serum C, TG, Lp(a), apo E, apo A-I, apo B, HDL-C and RLP-C were measured in 652 patients who underwent diagnostic coronary angiography. Of these, 48 (32 males and 16 females, age 59 +/- 10 years) were suspected of having ischaemic heart disease because they had chest pain, but without angiographic evidence of atherosclerotic coronary artery disease defined as a discrete stenosis or intimal irregularity, and without any other known underlying heart disease. These were selected for acetylcholine provocation test in the left coronary artery. Nineteen of 48 patients had high RLP-C ( > or = 5 mg/dl, mean 8.7 +/- 3.1 mg/dl), 29 had normal RLP-C ( < or = 5 mg/dl, mean 2.4 +/- 0.4 mg/dl, P < 0.0001). The percent change (-, constriction, or +, dilation) in coronary artery diameter after intracoronary injection of Ach was smaller in the high RLP-C group, compared with the normal RLP-C group thus, in the left anterior descending artery, -33 +/- 23 vs -8 +/- 25 in the proximal segment (P <0.01), -30 +/- 37 vs -3 +/- 29 in the mid segment (P < 0.01), -17 +/- 47 vs 16 +/- 43 in the distal segment (P < 0.001); in the left circumflex artery, -29 +/- 46 vs -9 +/- 28 in the proximal segment (P < 0.01), -29 +/- 43 vs -5 +/- 34 in the mid segment (P < 0.01), -26 +/- 43 vs 10 +/- 31 in the distal segment (P < 0.001). There were no significant differences in other lipid levels. These results suggest that there is an association between high serum RLP-C and coronary vascular endothelial cell dysfunction and that RLP-C may be taken as a marker of early stage coronary artery atherosclerosis not detectable by angiography.
Atherosclerosis 1998 Aug
PMID:Impaired endothelium-dependent acetylcholine-induced coronary artery relaxation in patients with high serum remnant lipoprotein particles. 971 43


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