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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by nilvadipine of ischemic and carrageenan paw edema as well as of superoxide radical production from neutrophils and xanthine oxidase. 165 7

There is evidence to suggest that the deposition of lipid within the arterial wall, which is characteristic of atherosclerosis, involves a break in the integrity of the endothelial barrier. Oxidative modification of low density lipoproteins by reactive oxygen species may enhance this process. In this study, an aortic endothelial (EC) smooth muscle cell (SMC) bilayer was briefly exposed to a free-radical generating system to determine the effect of superoxides on lipid permeability and uptake. 125I-LDL (10 micrograms/ml) was added to the EC medium at various time intervals (3, 24, and 48 hr and 9 days). The amount of lipid reaching the subendothelial space was measured. Measurements of EC and SMC binding and uptake of LDL were also obtained and compared with those of untreated cells. The results demonstrate a significant increase in the permeability of the treated EC layer to LDL (P less than 10(-6)), which was sustained over time. Superoxide exposure led to a limited initial increase in EC binding and uptake of LDL, which later returned to control values. In contrast, SMC uptake of LDL was significantly (P less than 10(-3)) and persistently increased over control values and disproportionately increased over cellular binding. Such results suggest that superoxides can increase LDL permeability of the EC barrier. Because this was not associated with a comparable increase in EC binding and uptake, it is unlikely to be due to changes in receptor-mediated, transcellular transport.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen radicals alter LDL permeability and uptake by an endothelial-smooth muscle cell bilayer. 175 68

In 116 patients with atherosclerosis of the arteries of the lower extremities in stages I-IV of the impairment in circulation and 35 healthy subjects, the immune status was studied. With aggravation of the disease, the number of leukocytes, B-cells, concentration of the IgM, IgG and circulating immune complexes, the number of immature lymphocytes and T-cells sensitizised to antigens of the arterial intima increase. At the same time, the total activity of the complement and phagocytic activity of neutrophilic granulocytes decrease, the relative number of neutrophilic granulocytes, which spontaneously generate a superoxide radical, increases. The likeness of atherosclerosis of the lower extremities to atherosclerosis of the heart vessels was noted.
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PMID:[Immunological status of patients with atherosclerotic lesions of the vessels of the lower limbs]. 279 31

Superoxide production by macrophages and leukocytes may have an important role in atherogenesis. Whether lipoproteins modulate the superoxide production of these cells is not clear. Therefore, the effect of lipoproteins on the production of superoxide by rat peritoneal macrophages was tested. VLDL and LDL inhibited digitonin-stimulated superoxide production in a dose-dependent manner. Maximum inhibition was observed at 10 micrograms ml-1 of VLDL protein and 50 micrograms ml-1 of LDL protein respectively. In contrast, HDL (40 micrograms protein ml-1) enhanced digitonin-stimulated superoxide production (by 47 per cent). Macrophage superoxide production induced by arachidonic acid was enhanced by both VLDL (130 per cent) and HDL (84 per cent), whereas LDL had no effect. The lipoproteins had no effect on macrophage superoxide stimulated by other agonists such as phorbol myristate 13-acetate, sodium fluoride or the calcium ionophore, A23187. The effect of lipoproteins was also tested on human polymorphonuclear leukocyte superoxide generation, stimulated by digitonin and PMA. Ten micrograms of VLDL, 50 micrograms of LDL and 50 micrograms of HDL proteins ml-1, inhibited digitonin-induced superoxide production by 50, 100 and 33 per cent respectively. Lipoproteins had no effect on PMA stimulated superoxide generation by human polymorphonuclear leukocytes. The stimulatory and inhibitory effects of lipoproteins on macrophage and neutrophil superoxide generation could be important in the understanding of oxidation-mediated development of atherosclerosis.
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PMID:Effect of lipoproteins on macrophage superoxide generation. 775 48

Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury.
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PMID:Agonist-induced peroxynitrite production from endothelial cells. 817 19

Low-density lipoprotein (LDL) oxidation induced by superoxide radicals generated in a cell-free system could not stimulate the subsequent development of high-uptake LDL during incubation in a medium normally permissive for cell-mediated oxidation. Similarly, LDL oxidative modification by macrophages was not accelerated when extracellular superoxide generation was increased 5-10-fold by stimulation of NADPH oxidase. The NADPH oxidase inhibitor, diphenylene iodonium, did inhibit macrophage-mediated modification of LDL, but its effects do not appear to involve superoxide generation. Superoxide dismutase (SOD) was shown to be inappropriate as a test for the involvement of superoxide radicals in cell-mediated oxidation due to its metal-chelating properties and to the development of a pro-oxidant activity by heat inactivation. We conclude that there is presently no secure evidence for the involvement of superoxide radical in macrophage-mediated oxidative modification of LDL.
Atherosclerosis 1993 Feb
PMID:Does superoxide radical have a role in macrophage-mediated oxidative modification of LDL? 838 55

Fifty-one pigs were fed a low-cholesterol basal diet, to which either 10% (by weight) of lard fat (group INORM, n = 7), 2% cholesterol plus 8% lard fat (group II, n = 33), or 2% cholesterol plus 4% lard fat plus 4% fish oil (group IIIPREV, n = 11) was added. In all pigs, the left anterior descending coronary artery and the abdominal aorta were denuded at 1 month. In the first 24 hours thereafter, three animals in group II and two in group IIIPREV died suddenly. After 3 months, 0.5% bile acids was added to the diet in groups II and IIIPREV. After 8 months the degree of atherosclerosis was evaluated in groups INORM and IIIPREV and in 14 animals from group II (IIIND). At 4 months, one animal from Group II died of pneumonia. For the next 4 months (postinduction period), the remaining 15 animals from group II received the basal diet, to which either 10% lard fat (group IILF, n = 6) or 5% lard fat plus 5% fish oil (group IIFO, n = 9) was added. The hypercholesterolemic diet increased plasma cholesterol from 2 to 9-12 mM after 8 months. Fish oil had no major effects on plasma lipids during both induction and postinduction. Superoxide production by granulocytes in response to the membrane receptor-dependent N-formyl-methionyl-leucyl-phenylalanine (fMLP) gave a higher response in group IIIND than in group INORM. In group IIIPREV, the response to phorbol myristate acetate (PMA) and fMLP was lowered, while in groups IIFO and IILF the responses to PMA and fMLP were not affected. The response to serum-treated zymosan was similar in all groups. Abrasion caused increases in free cholesterol (40%) and phospholipids (46%) in the abdominal aortas of group INORM animals. Hypercholesterolemia increased both free and esterified cholesterol in the entire aorta. Fish oil prevented accumulation of free cholesterol in the nonabraded ascending aorta during induction and further accumulation of free cholesterol and phospholipids in the abdominal aorta during postinduction. In the nonabraded ascending aorta, triglycerides were significantly (almost five times) lower in group IIFO than in group IILF. During both induction and postinduction, a large incorporation of n-3 polyunsaturated fatty acids (up to 20%) occurred in plasma and aortic cholesterol esters and phospholipids of groups IIFO and IIIPREV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development and regression of atherosclerosis in pigs. Effects of n-3 fatty acids, their incorporation into plasma and aortic plaque lipids, and granulocyte function. 838 31

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) because denuded vessel wall exposed to blood following thrombolysis is a favourable surface for platelet and leucocyte deposition. We have applied a chemiluminescence technique to detect superoxide radical (0(-2)) produced by leucocytes adherent to the femoral artery 24 h after photochemically induced thrombogenesis in the guinea pig in vivo and subsequent thrombolysis by rt-PA. Intravenous administration of MCLA, a specific chemiluminescence reagent for detecting O(-2), markedly increased photon emission. the photon emission was markedly potentiated by phorbol myristate acetate and was suppressed by superoxide dismutase. Reocclusion 24 h after rt-PA induced thrombolysis was observed in 10 of 16 animals. Histological observations revealed extensive polymorphonuclear leucocytes adherent to the vessel wall at the site of thrombogenesis and thrombolysis. A higher level of 0(-2) could be detected from the arteries in which thrombolysis was induced compared with those without thrombolysis. Further, the level 0(-2) detected was greater in reoccluded arteries compared with those in which reflow was established. These observations suggest that 0(-2) is produced by adherent leucocytes at the site of thrombolysis and that leucocytes are involved in reocclusion after thrombolysis.
Atherosclerosis 1996 May
PMID:A chemiluminescent detection of superoxide radical produced by adherent leucocytes to the subendothelium following thrombolysis: studies with a photochemically induced thrombosis model in the guinea pig femoral artery. 876 84

Calcium antagonists are well accepted in the prevention of ischaemia in patients with chronic stable angina, unstable angina, variant angina, and silent ischaemia, and in the treatment of hypertension. Although all of these compounds increase myocardial oxygen supply by reducing coronary tone and decrease myocardial oxygen demand by reducing systolic pressure and myocardial contractility, the magnitude of these effects may differ from one agent to another. Some calcium antagonists, such as verapamil and diltiazem, reduce heart rate and attenuate heart rate increases in response to stress, while in contrast, dihydropyridine calcium antagonists such as nifedipine may cause reflex increases in heart rate. These differences may be of importance in light of epidemiologic evidence that lower heart rates are associated with a reduced long-term risk of cardiovascular mortality, and experimental data showing that a lower heart rate may protect against the development of atherosclerosis. Calcium antagonists also inhibit platelet aggregation and thrombus formation which may contribute to their anti-ischaemic effects. Clinical trial data suggest that calcium antagonists may stay the progression of atherosclerosis. Mechanisms underlying an anti-atherosclerotic effect may include attenuation of endothelial dysfunction, prevention of LDL, peroxidation, stimulation of LDL receptor activity, inhibition of superoxide radical generation, and inhibition of vascular smooth muscle cell growth. Heart-rate-controlling calcium antagonists, such as verapamil and diltiazem, may reduce reinfarction rates following acute myocardial infarction and thus may have a role in post-infarction patients who do not show evidence of heart failure. Their use in heart failure patients receiving an angiotension-converting enzyme inhibitor (ACE-I) is under investigation in several large trials. Because calcium antagonists have a mechanism of action different from ACE-I, the pairing of a heart-rate-controlling calcium antagonist with an ACE-I might be expected to offer additive cardioprotective and vascular protective effects.
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PMID:The role of calcium antagonists in ischaemic heart disease. 884 1

We have recently shown that ex vivo gene therapy of rabbit autologous vein grafts with antisense oligodeoxynucleotides (AS ODN) blocking cell cycle regulatory gene expression inhibits not only neointimal hyperplasia, but also diet-induced, accelerated graft atherosclerosis. We observed that these grafts remained free of macrophage invasion and foam cell deposition. Since endothelial dysfunction plays an important role in vascular disease, the current study examined the effect of this genetic engineering strategy on graft endothelial function and its potential relationship to the engineered vessels' resistance to atherosclerosis. Rabbit vein grafts transfected with AS ODN against proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (cdc2) kinase elaborated significantly more nitric oxide and exhibited greater vasorelaxation to both calcium ionophore and acetylcholine than did untreated or control ODN-treated grafts. This preservation of endothelial function was associated with a reduction in superoxide radical generation, vascular cell adhesion molecule-1 (VCAM-1) expression, and monocyte binding activity in grafts in both normal and hypercholesterolemic rabbits. Our data demonstrate that AS ODN arrest of vascular cell cycle progression results in the preservation of normal endothelial phenotype and function, thereby influencing the biology of the vessel wall towards a reduction of its susceptibility to occlusive disease.
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PMID:Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts. 907 39


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