Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to examine mechanisms underlying nitroglycerin (NTG) tolerance and "cross-tolerance" to other nitrovasodilators. Rabbits were treated for 3 d with NTG patches (0.4 mg/h) and their aortic segments studied in organ chambers. Relaxations were examined after preconstriction with phenylephrine. In NTG tolerant rabbit aorta, relaxations to cGMP-dependent vasodilators such as NTG (45 +/- 6%), SIN-1 (69 +/- 7%), and acetylcholine (ACh, 64 +/- 5%) were attenuated vs. controls, (90 +/- 2, 94 +/- 3, and 89 +/- 2% respectively, P < 0.05 for all), while responses to the cAMP-dependent vasodilator forskolin remained unchanged. In tolerant aorta, endothelial removal markedly enhanced relaxations to NTG and SIN-1 (82 +/- 4 and 95 +/- 3%, respectively). Other studies were performed to determine how the endothelium enhances tolerance. Vascular steady state .-O2 levels (assessed by lucigenin chemiluminescence) was increased twofold in tolerant vs. control vessels with endothelium (0.31 +/- 0.01 vs. 0.61 +/- 0.01 nmol/mg per minute). This difference was less in vessels after denudation of the endothelium. Diphenylene iodonium, an inhibitor of flavoprotein containing oxidases, and Tiron a direct .-O2 scavenger normalized .-O2 levels. In contrast, oxypurinol (1 mM) an inhibitor of xanthine oxidase, rotenone (50 microM) an inhibitor of mitochondrial electron transport and NG-nitro-L-arginine (100 microM) an inhibitor of nitric oxide synthase did not affect the chemiluminescence signals from NTG-tolerant aortas. Pretreatment of tolerant aorta with liposome-entrapped, pH sensitive superoxide dismutase (600 U/ml) significantly enhanced maximal relaxation in response to NTG, SIN-1, and ACh, and effectively reduced chemiluminescence signals. These studies show that continuous NTG treatment is associated with increased vascular .-O2-production and consequent inhibition of NO. mediated vasorelaxation produced by both exogenous and endogenous nitrovasodilators.
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PMID:Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. 781 13

Chondrocytes stimulated with IL-1 produce high levels of nitric oxide (NO), which inhibits proliferation induced by transforming growth factor-beta or serum. This study analyzes the role of NO and IL-1 in the induction of chondrocyte cell death. NO generated from sodium nitroprusside induced apoptosis in cultured chondrocytes as demonstrated by electron microscopy, 4',6-dianidino-2-phenylindole dihydrochloride staining, FACS analysis, and histochemical detection of DNA fragmentation. Similar results were obtained with two other NO donors, 3-morpholinosynonimide-hydrochloride and s-nitroso-N-acetyl-D-L-penicillamine. In contrast, oxygen radicals generated by hypoxanthine/xanthine oxidase caused necrosis but did not induce chondrocyte apoptosis. To analyze whether endogenously generated NO induces apoptosis, chondrocytes were stimulated with IL-1, but there was no evidence for apoptotic changes. Combinations of NO inducers such as IL-1, lipopolysaccharide, tumor necrosis factor, and interferon-gamma also failed to trigger apoptosis. IL-1-stimulated chondrocytes are known to produce oxygen radicals that react with NO to form products that can induce cell death in other systems. We thus tested IL-1 in combination with the oxygen radical scavengers N-acetyl cysteine, dimethyl sulfoxide, or 5,5'-dimetylpyrroline 1-oxide. Under these conditions IL-1 was able to induce apoptosis, which was inhibited in a dose-dependent manner by the NO synthase inhibitor N-monomethyl L-arginine. Conversely, endogenous oxygen radicals induced by inflammatory mediators caused necrosis under conditions in which the simultaneous production of NO was reduced. These results suggest that NO, but not oxygen radicals, is the primary inducer of apoptosis in human articular chondrocytes.
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PMID:Chondrocyte apoptosis induced by nitric oxide. 785 40

The growing evidence that glutamate may be an important agent mediating ischemic damage to neurons, led us to investigate the possible protective effects of pharmacological agents against glutamate in a model system of cortical neurons. In this study we examined, in particular, the cytoprotective effect of prostaglandins. Experiments were carried out in vitro by using rat cortical neurons in culture for 10 days. They were incubated for 3h with glutamate (10 microM) in the presence or absence of various pharmacological agents including prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-Keto-PGF1 alpha, carba-TXA2, carba-PGI2 and PGF2 alpha-methylester). Increase in lacticodehydrogenase (LDH) release into the culture medium has been measured as an index of cell injury. When neurons were incubated with glutamate they released LDH due to NMDA-receptor activation since D-L-2-amino-5-phosphonovaleric acid, a specific receptor antagonist, protected the cells. The protective activity of oxypurinol, amflutizole, superoxide dismutase, NG nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitrix oxide, as well as phospholipase A2 stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF2 alpha-methylester, afforded significant protection at concentrations between 0.1 and 10 microM. The order of potency of the prostanoids was: PGF2 alpha = PGE2 > Carba-TXA2 > PGE1 > PGD2 > PGI2 = Carba-PGI2 > 6-Keto-PGF1 alpha. Additional experiments showed that prostaglandins did not compete for the NMDA binding site and that they did not inhibit free radical-related membrane damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection by prostaglandins from glutamate toxicity in cortical neurons. 791 88

Inhaled nitric oxide (NO) decreases pulmonary arterial pressure (Ppa) and improves oxygenation in the adult respiratory distress syndrome. Endogenous NO can modulate the development of acute tissue injury. We investigated the effects of inhaled NO and of inhibition of endogenous NO synthase in oxidant-induced acute lung injury in the isolated buffer-perfused rabbit lung. A rapid (45 min) and a more gradual (3 h) model of oxidant-induced acute lung injury were developed using the production of superoxide free radicals from the reaction of purine with low and high doses of xanthine oxidase, respectively. The effects of rapid injury included increases in Ppa, precapillary pulmonary vascular resistance, capillary filtration coefficient (Kfc), and lung weight. In the gradual-injury model, only lung weight and Kfc increased. Pretreatment with inhaled NO (90-120 ppm) prevented the rise in Ppa and precapillary pulmonary vascular resistance in the rapid-injury model and prevented elevation of Kfc in the gradual-injury model. Pretreatment with an inhibitor of endogenous NO synthase (NG-nitro-L-arginine methyl ester) resulted in increased pulmonary capillary pressure and postcapillary pulmonary vascular resistance in the rapid-injury model and increased peak Ppa, pulmonary capillary pressure, and pulmonary vascular resistance in the gradual-injury model. These data suggest that in oxidant-induced acute lung injury 1) inhaled NO may attenuate increases in capillary permeability and 2) endogenous NO may function as a modulator of pulmonary vascular tone without affecting capillary permeability.
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PMID:Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. 800 78

Recent findings have suggested that nitric oxide (NO) reacts with superoxide anion (O2-) to form a potential oxidant, peroxynitrite anion, which then decays to hydroxyl radical and nitrogen dioxide. In order to ascertain this hypothesis in human polymorphonuclear leukocytes (PMNs) which release both NO and O2-, we studied oxidation of L-cysteine (CYS) and bovine serum albumin (BSA) by PMNs and cell-free O2(-)-generating system of hypoxanthine (HX)-xanthine oxidase (XO) reaction. Oxidation of CYS by HX-XO was equally inhibited by superoxide dismutase (SOD) and catalase (CAT), and that of BSA by HX-XO was inhibited weakly by SOD and strongly by CAT. PMNs stimulated with phorbol 12-myristate 13-acetate increased the oxidation rates of CYS and BSA, and they were inhibited by SOD and CAT almost in a similar way to those by HX-XO. The NO synthase inhibitor, NG-monomethyl-L-arginine (NMMA), was confirmed to have an inhibitory effect on the inhibition of platelet aggregation by PMNs, and L-arginine (ARG) reversed this effect. However, pretreatment of PMNs with either of NMMA, or ARG, or both did not change the oxidation rates of CYS and BSA. We could not confirm the hypothesis at least in human PMNs that interaction of NO with O2- forms powerful oxidants to sulfhydryls of CYS and BSA. These results suggest that oxidation of sulfhydryls of CYS and BSA by PMNs is primarily dependent on reactive oxygen species, and is not modified by NO production.
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PMID:Nitric oxide does not contribute to superoxide-mediated sulfhydryl oxidation in human polymorphonuclear leukocytes. 803 64

Our laboratory recently isolated free PQQ (2,7,9-tricarboxy-pyrroloquinoline quinone, methoxatin), a bacterial redox cofactor, from red cells, neutrophils, serum and milk and found free PQQ in CSF, synovial fluid and bile. The metabolism and functions of PQQ and ascorbate may be coupled. Physiologically, free PQQ catalyzes dioxygen-superoxide interconversion, and participates in both superoxide generation (respiratory burst) and scavenging (cell protection). Using a labeled aromatic o-diamine, superoxide formation by activated neutrophils was inhibited and the labeled phenazine adduct of PQQ could be isolated from the inhibited cells (Karnovsky et al., 1992). PQQ may convert xanthine oxidase to xanthine dehydrogenase (XD) and could be the physiological coenzyme of XD. PQQ plus copper, form a potent amine-oxidizing system. Shah et al., 1992 found that PQQ-Cu2+ catalyzes the oxidation of epsilon-amino groups in collagen and elastin. Rucker's lab (Smidt et al., 1991) has found that PQQ may be a vitamin for mouse pups. Watanabe et al., 1988 and Nishigori et al., 1989, showed that injected PQQ protects animals against oxidative stress injury. PQQ's in vivo antioxidant action, spares reduced glutathione. PQQ, as an actively transported organic anion, concentrates in cells. In other experiments (Aizenman et al., 1992), PQQ protected neurons against the neurotoxin action of the glutamate-receptor against NMDA. We shall consider possible roles for PQQ in the biosynthesis of nitric oxide (NO, endothelium-derived relaxing factor, EDRF) from L-arginine and in NO removal by superoxide. NO has now been linked to the inhibition of osteoclastic bone resorption.
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PMID:Is the antioxidant, anti-inflammatory putative new vitamin, PQQ, involved with nitric oxide in bone metabolism? 840 96

Much evidence has suggested that the superoxide generated by xanthine oxidase (XOD) within the endothelial cell triggers characteristic free-radical-mediated tissue injuries. Although it has been reported that XOD exists not only in the cytoplasm, but also on the outside surface of the endothelial cell membrane, it is not clear how XOD localizes on the outside of the plasma membrane. Purified human xanthine oxidase (h-XOD) had an affinity for heparin-Sepharose. The binding was largely independent of the pH over the physiological range, whereas it tended to increase at lower pH and to decrease at higher pH. Exposure of h-XOD to the lysine-specific reagent trinitrobenzenesulphonic acid or the arginine-specific reagent phenylglyoxal caused it to lose its affinity for heparin-Sepharose. The binding of h-XOD to heparin is apparently of electrostatic nature, and both lysine and arginine residues are involved in the binding. h-XOD was found to bind to cultured porcine aortic endothelial cells, and this binding was inhibited by the addition of heparin or pretreatment of the cells with heparinase and/or heparitinase. Intravenous injection of heparin into two healthy persons led to a prompt increase in plasma h-XOD concentration. These results suggest that XOD localizes on the outside surface of endothelial cells by association with polysaccharide chains of heparin-like proteoglycans on the endothelial-cell membranes. Superoxide extracellularly generated by XOD may injure the source-endothelial-cell membrane and also attract and activate closely appositional neutrophils, which themselves actually cause progressive oxidative damage.
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PMID:Binding of human xanthine oxidase to sulphated glycosaminoglycans on the endothelial-cell surface. 842 93

Experiments were designed to determine the effect of oxygen-derived free radicals in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution bubbled with 95% O2-5% CO2 (temperature = 37 degrees C; pH = 7.4). A radioimmunoassay technique was used to measure production of prostaglandins and thromboxane B2. Xanthine oxidase (1-9 mU/ml, in the presence of 10(-4) M xanthine) and hydrogen peroxide (10(-6) to 10(-4) M) caused concentration-dependent contractions. The removal of endothelium reversed these contractions into relaxations. Contractions to xanthine oxidase and hydrogen peroxide were inhibited in the presence of superoxide dismutase (150 U/ml), catalase (1,200 U/ml), indomethacin (10(-5) M), and SQ 29548 (10(-6) M) but not in the presence of deferoxamine (10(-4) to 10(-3) M) and dimethyl sulfoxide (10(-4) M). NG-monomethyl-L-arginine (3 x 10(-5) M) augmented the contractions to hydrogen peroxide. Xanthine oxidase stimulated production of 6-ketoprostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and thromboxane B2. The stimulatory effect was prevented by the removal of endothelial cells. These studies suggest that xanthine oxidase causes endothelium-dependent contractions mediated by: 1) hydrogen peroxide-induced stimulation of the endothelial metabolism of arachidonic acid via the cyclooxygenase pathway, leading to activation of prostaglandin H2-thromboxane A2 receptors, and 2) inactivation of basal production of nitric oxide by superoxide anions.
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PMID:Endothelium-dependent contractions to oxygen-derived free radicals in the canine basilar artery. 845 88

1. Endothelial barrier function was assessed by use of an in vitro model in which transfer of trypan blue-labelled albumin was measured across monolayers of bovine aortic endothelial cells grown on polycarbonate membranes. 2. Addition of either hypoxanthine (0.2 mM) or xanthine oxidase (20 mu ml-1) alone during a 90 min incubation did not affect albumin transfer across endothelial cell monolayers, but a combination of both increased transfer. 3. The increase in albumin transfer induced by hypoxanthine and xanthine oxidase was abolished by catalase (3 u ml-1), reduced by allopurinol (4 mM), but unaffected by superoxide dismutase (6000 u ml-1), the hydroxyl radical scavengers, mannitol (15 mM), dimethylthiourea (10 mM) and N-(2-mercaptopropionyl)-glycine (1 mM), the iron chelator, deferoxamine (0.5 mM), ferric chloride (50 microM), an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (30 microM), or the antioxidant, dithiothreitol (3 mM). 4. Hydrogen peroxide (0.1-30 mM) itself increased albumin transfer across endothelial cell monolayers, exhibiting a biphasic concentration-response curve. The increase induced by 0.1 mM hydrogen peroxide was abolished in the presence of 0.3 u ml-1 catalase whilst that induced by 10 mM hydrogen peroxide was abolished by 3000 u ml-1 catalase. 5. Homocysteine (0.5-1.5 mM) did not affect albumin transfer across endothelial monolayers when added alone, but when added in combination with copper sulphate (50 microM), which catalyses its oxidation, a significant increase in albumin transfer was observed. 6. The increase in albumin transfer induced by the combination of homocysteine (1.5 mM) and copper sulphate was abolished by catalase (1 u ml-1), but was unaffected by superoxide dismutase (6000 u ml-1), mannitol (15 mM), dimethylthiourea (1 mM) or deferoxamine (0.5 mM).7. The data suggest that the endothelial barrier dysfunction induced by the combination of hypoxanthine and xanthine oxidase is mediated solely by the action of hydrogen peroxide and not by superoxide anion, hydroxyl radical, peroxynitrite anion or hypochlorous acid. The copper-catalysed oxidation of homocysteine also induces endothelial barrier dysfunction through the generation of hydrogen peroxide.These findings may have relevance to the endothelial barrier dysfunction associated with ischaemia reperfusion injury and the atherogenic actions of homocysteine.
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PMID:Arterial endothelial barrier dysfunction: actions of homocysteine and the hypoxanthine-xanthine oxidase free radical generating system. 848 31

Cultured rat retinal neurons exposed to kainate produced free radicals, as demonstrated by electron spin resonance (ESR) spin trapping using the nitrone 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and the generation of DMPO hydroxyl adduct (DMPO-OH). This DMPO-OH production was abolished by EGTA, nitro-arginine and oxypurinol, suggesting that it was dependent on Ca2+ influx and subsequent activation of nitric oxide synthase and xanthine oxidase. Moreover, kainate induced a receptor-mediated Ca2+ influx and neuronal injury assessed by lactate dehydrogenase release. Neuroprotection afforded by nitro-arginine and oxypurinol shows that calcium-dependent free radical production plays a major role in kainate retinal toxicity.
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PMID:Calcium-dependent free radical generation in cultured retinal neurons injured by kainate. 857 85


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