Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (.NO) is a signal transducing free radical which can modify oxidant stress by limiting superoxide (O2.-)-mediated injury. However, the product of .NO reaction with O2.-, peroxynitrite (ONOO-), is a potent oxidizing and nitrating agent. Exposure of a mixture containing phosphatidylcholine liposomes and surfactant apoprotein A (SP-A; 10% by weight) to increasing concentrations of .NO, generated by spermine NONOate, and constant O2.- levels, produced by the action of xanthine oxidase on lumazine, suppressed O2.(-)-induced lipid peroxidation in the presence of Fe3(+)- EDTA. On the other hand, an increase in the .NO/O2.- value resulted in nitration of SP-A tyrosine residues, located in the carbohydrate recognition domain (CRD), and decreased the ability of SP-A to aggregate lipids and bind mannose, two functions that require an intact CRD. SP-A was also nitrated to a large extent following exposure to 3-morpholinosydnonimine (SIN-1) or tetranitromethane at pH 8. In each case, increased nitrotyrosine content correlated in a monotonic fashion with inhibition of lipid aggregation and mannose binding, correlated with the extent of functional inhibition. Superoxide dismutase (2400 U/ml) and urate (100 microM; nonspecific scavenger of both ONOO- and hydroxyl radical), but not mannitol (50 mM; hydroxyl radical scavenger), prevented the SIN-1-induced injury to SP-A. In contrast, spermine NON-Oate or xanthine oxidase plus lumazine alone neither inhibited SP-A function nor nitrated the protein. These results indicate that at high concentrations, .NO inhibit O2.-induced lipid peroxidation. However, ONOO., formed by the reaction of .NO and O2.-, nitrates SP-A leading to decreased ability to aggregate lipids and bind mannose.
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PMID:Nitration of surfactant protein A (SP-A) tyrosine residues results in decreased mannose binding ability. 880 82

Inhaled nitric oxide (NO) may modify surfactant either by interacting with the surfactant complex or by changing the capacity of the proteins of the epithelial lining fluid to inhibit the surface activity. Natural surfactant was exposed to NO (80 parts/million) in air in vitro while the gas-liquid surface was cycled. In the presence or absence of oxidants (Fe2+, xanthine, xanthine oxidase), surfactant exposed to NO retained the high surface activity significantly better than control surfactants exposed to air. Two surfactant inhibitors, hemoglobin (Hb) and albumin, were separately exposed to NO. In contrast to albumin, NO-exposed Hb and methemoglobin (MetHb; 16-125 micrograms/ml) decreased the surface activity at low surfactant concentrations, whereas native Hb had no effect. Surfactant recovered by sedimentation after exposure to MetHb had decreased surface activity and contained MetHb, whereas Hb did not bind to surfactant. Acidic phospholipid phosphatidylglycerol increased the binding of MetHb to surfactant. The MetHb-induced decrease in surface activity was elicited in the presence of surfactant proteins, including a peptide mimicking surfactant protein B. MetHb (but not Hb) added to a low dose of exogenous surfactant decreased the efficacy of surfactant to improve the lung compliance of premature rabbits. We propose that inhaled NO promotes the surface activity of surfactant during tidal ventilation and that, in high-permeability lung edema and surfactant deficiency, inhaled NO increases the inhibition of surface activity by converting Hb to MetHb in the alveolar space.
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PMID:A mechanism of nitric oxide-induced surfactant dysfunction. 880 11

This study was designed to test the hypothesis that nitric oxide (NO) is the relaxant metabolite produced by metabolic activation of glyceryl trinitrate (GTN) in rabbit aortic strip (RAS). Superoxide anion, an inactivator of NO, was included in a two-tissue bioassay in which rabbit Taenia coli strip (RTCS) relaxed to GTN in the presence of RAS. Superoxide as generated by xanthine (10 microM)/ xanthine oxidase (20 mU/ml) failed to attenuate relaxations of RTCS to GTN (0.1 nM-10 microM) and RAS, compared with the untreated control. In contrast, superoxide attenuated the relaxation of RTCS to both authentic NO gas and to SIN-1 (0.1 nM-10 microM), a known spontaneous releaser of NO; the attenuation of RTCS relaxation to NO gas was reversed by superoxide dismutase (100 units/ml). In addition, another drug that has been reported to scavenge NO, hydroquinone, did not attenuate the RTCS relaxation to GTN. These results suggest that biotransformation of GTN in vascular smooth muscle that leads to relaxation is caused by a NO-containing species (i.e. a S-nitrosothiol). Such a molecule would be less susceptible to inactivation by superoxide anion and hydroquinone.
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PMID:Superoxide does not inhibit glyceryl trinitrate-rabbit aortic strip-mediated relaxation of rabbit Taenia coli. Evidence against a role for nitric oxide itself as the smooth muscle active drug metabolite? 881 76

Pretreatment of porcine aortic endothelial cells with high D-glucose results in enhanced endothelium-derived relaxing factor (EDRF) formation (39%) due to increased endothelial Ca2+ release (57%) and Ca2+ entry (97%) to bradykinin. This study was designed to investigate the intracellular mechanisms by which high D-glucose affects endothelial Ca2+/EDRF response. The aldose-reductase inhibitors, sorbinil and zopolrestat, failed to diminish high D-glucose-mediated alterations in Ca2+/EDRF response, suggesting that aldose-reductase does not contribute to high D-glucose-initiated changes in Ca2+/EDRF signaling. Pretreatment of cells with the nonmetabolizing D-glucose analog, 3-O-methylglucopyranose (3-OMG), mimicked the effect of high D-glucose on Ca2+ release (41%) and Ca2+ entry (114%) to bradykinin, associated with elevated EDRF formation (26%). High D-glucose and 3-OMG increased superoxide anion (O2-) formation (133 and 293%, respectively), which was insensitive to inhibitors of cyclooxygenase (5,8,11,14-eicosatetraynoic acid [ETYA], indomethacin), lipoxygenase (ETYA, gossypol, nordihydroguaiaretic acid [NDGA]), cytochrome P450 (NDGA, econazole, miconazole), and nitric oxide (NO) synthase (L-omega N-nitroarginine), while it was diminished by desferal, a metal chelator. The gamma-glutamyl-cysteine-synthase inhibitor, buthioninesulfoximine (BSO), also increased formation of O2- by 365% and mimicked the effect of high D-glucose on Ca2+/EDRF signaling. The effects of high D-glucose, 3-OMG, and BSO were abolished by co-incubation with superoxide dismutase. Like high D-glucose, pretreatment with the O2(-)-generating system, xanthine oxidase/hypoxanthine, elevated bradykinin-stimulated Ca2+ release (+10%), Ca2+ entry (+75%), and EDRF (+73%). We suggest that prolonged exposure to pathologically high D-glucose concentration results in enhanced formation of O2-, possibly due to metal-mediated oxidation of D-glucose within the cells. This overshoot of O2- enhances agonist-stimulated Ca2+/EDRF signaling via a yet unknown mechanism.
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PMID:High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. 882 76

In the present study we demonstrated that synaptosomes isolated from rabbit brain cortex contain NO synthase and xanthine oxidase that can be activated by ultraviolet B radiation and Ca2+ accumulation to produce nitric oxide and superoxide which react together to form peroxynitrite. Irradiation of synaptosomes with ultraviolet B (up to 100 mJ/cm2), or increase the intrasynaptosomal calcium concentration using various doses (up to 100 mu M) of the calcium ionophore A 23187, a gradual increase in both nitric oxide and peroxynitrite release that was inhibited by N-monomethyl-L-arginine (100 mu M) was observed. The rate of nitric oxide release and cyclic GMP production by NO synthase and soluble guanylate cyclase, both located in the soluble fraction of synaptosomes (synaptosol), were increased approximately eight fold after treatment of synaptosomes with Ultraviolet B radiation (100 mJ/cm2). In reconstitution experiments, when purified NO synthase isolated from synaptosol was added to xanthine oxidase, in the presence of the appropriate cofactors and substrates, a ten fold increase in peroxynitrite production at various doses (up to 20 mJ/cm2) of UVB radiation was observed. Ultraviolet B irradiated synaptosomes promptly increased malondialdehyde production with subsequent decrease of synaptosomal plasma membrane fluidity estimated by fluorescence anisotropy of 1-4-(trimethyl-amino-phenyl)-6-phenyl-hexa-1 ,3,5-triene. Desferrioxamine (100 mu M) tested in Ultraviolet B-irradiated synaptosomes showed a decrease (approximately 80%) in malondialdehyde production with subsequent restoration of the membrane fluidity to that of non-irradiated (control) synaptosomes. Ca(2+)-stimulated ATPase activity was decreased after Ultraviolet B (100 mJ/cm2) radiation of synaptosomes indicating that the subsequent increase of intrasynaptosomal calcium promoted peroxynitrite production by a calmodulin-dependent increase of NO synthase and xanthine oxidase activities. Furthermore, it was shown that UVB-irradiated synaptosomes were subjected to higher oxidative stress by exogenous peroxynitrite (100 mu M) compared to non-irradiated (control) synaptosomes. In summary, the present results indicate that activation of NO synthase and xanthine oxidase of brain cells lead to the formation of peroxynitrite providing important clues in the role of peroxynitrite as a causative factor in neurotoxicity.
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PMID:NO synthase and xanthine oxidase activities of rabbit brain synaptosomes: peroxynitrite formation as a causative factor of neurotoxicity. 883 24

Susceptibility of islet cells to damage by hydrogen peroxide, superoxide, and nitric oxide was determined on islets isolated from humans, pigs, and rats. Islets were incubated for 20 hr at 37 degrees C with different concentrations of hydrogen peroxide, hypoxanthine/xanthine oxidase, or nitroprusside sodium, respectively. Islet cell damage was then measured as trypan blue-uptake. Rat islets showed a higher sensitivity than human or pig islets to damage by reactive oxygen species or nitric oxide. These results indicate that pig islets may be a more suitable model than rat islets to study inflammatory islet cell damage in diabetes and clinical islet transplantation.
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PMID:Different toxic effects of hydrogen peroxide, nitric oxide, and superoxide on human, pig, and rat islets of Langerhans. 883 70

High levels of glycosylated human hemoglobin impair nitric oxide-mediated responses. However, the percentage of glycosylation for which this effect is observed and the mechanisms involved are unknown. We tested endothelium-dependent relaxations caused by acetylcholine in rat aortic segments either in control conditions or after preincubation with increasing percentages of glycosylated human hemoglobin. Human hemoglobin (1 and 10 nmol/L) inhibited endothelium-dependent relaxations only when glycosylated at 9% or higher. We evaluated the effect of 14% glycosylated human hemoglobin on acetylcholine-evoked responses in vessels preincubated with scavengers of superoxide anions, hydroxyl radical, or hydrogen peroxide (superoxide dismutase, deferoxamine, and catalase, respectively); with inhibitors of xanthine oxidase, cyclooxygenase, or thromboxane synthase (allopurinol, indomethacin, and dazoxiben, respectively); with blockers of thromboxane A2/prostaglandin H2 or endothelin receptors (SQ 30741 and BQ-123); and with the precursor of nitric oxide synthesis L-arginine. Superoxide dismutase abolished the effect of glycosylated hemoglobin, and the other substances did not have any effect. Glycosylated hemoglobin at 14% did not modify either the vasoconstrictions induced by the blocker of nitric oxide synthase NG-nitro-L-arginine methyl ester or the relaxations evoked in deendothelialized vessels by sodium nitroprusside and 8-bromo-cGMP. However, it inhibited the vasodilations evoked by exogenous nitric oxide. Superoxide dismutase abolished this latter effect. We conclude that the threshold for glycosylated human hemoglobin (Hb A1) to inhibit endothelium-dependent relaxation is 9%. This effect is due to interference with endothelial nitric oxide by means of superoxide anion production.
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PMID:Impairment of endothelium-dependent relaxation by increasing percentages of glycosylated human hemoglobin. Possible mechanisms involved. 884 82

Sources of reactive O2 species in the vessel wall that potentially contribute to the control of vascular tone include NADPH oxidases, arachidonic acid metabolizing enzymes, xanthine oxidase, nitric oxide synthase and mitochondria. Specific physiological stimuli (such as changes in PO2) as well as pathophysiological stimuli control the production of reactive O2 species by many of these sources. Certain key reactive O2 species activate specific signalling mechanisms that control vascular tone, often through processes involving the metabolism of these species. The production of prostaglandins and cyclic GMP are some of the most sensitive systems regulated by hydrogen peroxide; whereas the conversion of nitric oxide (NO) to peroxynitrite (ONOO-) and inhibition of the stimulation of the cytosolic form of guanylate cyclase are processes that are very sensitive to superoxide anion (O2.-). High levels of NO production readily result in the formation of significant amounts of ONOO-, because NO competes with superoxide dismutase for the metabolism of cellular O2.- and thereby activates additional signalling mechanisms such as regulation through thiol nitrosation. As the levels of individual reactive O2 species increase, other signalling mechanisms likely to participate in vascular responses to oxidant injury seem to become activated. Thus, evidence is developing to support the concept that reactive O2 species are important contributors to the control of vascular tone.
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PMID:Reactive oxygen species and vascular signal transduction mechanisms. 884 67

Incubation of endothelium-denuded rings of rat aorta at 37 degrees C for 18 hours in Krebs solution led to a profound depression of the contractile actions of phenylephrine (1 nM-10 mu M). A major component of this depression of vasoconstriction was due to the relaxant actions of nitric oxide since it was reversed following inhibition of the synthesis of nitric oxide with N(G)-nitro-L-arginine methyl ester or its actions with haemoglobin (30 microM) or methylene blue (10 mu M). The depression was also reversed upon treatment with LY83583 (0.1-1 microM which generates superoxide anions, intracellularly and extracellularly, but was unaffected by hypoxanthine (100 microM)/ xanthine oxidase (16 mu/ml) which generates superoxide anion only extracellularly. The ability of polymixin B (30 microM) to inhibit the development of the depression of vasoconstriction suggests that it results from the expression of an inducible form of nitric oxide synthase, stimulated by bacterial lipopolysaccharide, contaminating the Krebs solution. In contrast to aortic rings, we found that lipopolysaccharide (10-10,000 ng/ml) alone from S. typhosa was unable to stimulate the expression of the inducible form of nitric oxide synthase in rat aortic smooth muscle cells grown in culture from explant, as assessed either by measuring the accumulation of nitrite into the culture medium during a 24 hour incubation period or by measuring the smooth muscle cyclic GMP content. Interferon-gamma (1-100 IU/ml) and interleukin-1 alpha (1-10 IU/ml) alone were, however, able to stimulate the accumulation of nitrite in a concentration-dependent manner. These inductions of nitrite accumulation were abolished following treatment with N(G)-nitro-(L)-arginine methyl ester (1 mM) and dexamethasone (1 microM). Further investigations are required to determine whether the ability of bacterial lipopolysaccharide to induce the inducible form of nitric oxide synthase in rat aortic rings, but not in rat aortic smooth muscle cells in culture, results from the presence of an endotoxin-sensitive, cytokine-secreting cell type in the vessel wall which is absent in culture, or from differences in smooth muscle phenotype in situ and in culture.
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PMID:Induction of nitric oxide synthase by endotoxin in rat isolated aorta but not in rat aortic smooth muscle cells grown in culture from explant. 886 13

1. The influence of diethyldithiocarbamate (DETCA), that irreversibly inhibits Cu/Zn-containing superoxide dismutase, on the inability of 6-anilino-5,8-quinolinedione (LY83583), hypoxanthine/xanthine oxidase, hydroquinone and hydroxocobalamin to reduce electrically-induced NANC relaxations in the rat gastric fundus was investigated. 2. Longitudinal muscle strips of the rat gastric fundus were mounted for auxotonic recording in the presence of atropine and guanethidine and tone was raised by administration of prostaglandin F2 alpha DETCA (3 x 10(-3) M) slightly reduced the short-lasting relaxations induced by 10(-5) M exogenous nitric oxide (NO) and transmural electrical stimulation for 10 s at 4 Hz but this effect was not influenced by 1000 u ml-1 superoxide dismutase (SOD). 3. DETCA (3 x 10(-5) -3 x 10(-3) M) concentration-dependently potentiated the inhibitory effect of LY83583 upon the electrically-induced relaxations, although this was less pronounced than the inhibition of the NO-induced relaxations. The inhibition of the electrically-induced non-adrenergic non-cholinergic (NANC) relaxations was not reversed by SOD while that of the NO-induced relaxations was partially reversed. 4. The inhibitory effect of hypoxanthine/xanthine oxidase, hydroquinone and hydroxocobalamin on the electrically-induced NANC relaxations in the presence of DETCA (3 x 10(-3) M) was not different from the inhibitory effect of DETCA alone. 5. It was concluded that the differentiating effect of LY83583 between exogenous NO and the endogenous nitrergic neurotransmitter is partially related to protection of the endogenous nitrergic neurotransmitter by high levels of intracellular superoxide dismutase. This mechanism does not hold for hydroquinone and hydroxocobalamin, as they still discriminate between exogenous NO and the endogenous nitrergic neurotransmitter in the presence of DETCA. The possibility that the endogenous nitrergic neurotransmitter is not free NO in the rat gastric fundus therefore remains open.
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PMID:Influence of superoxide dismutase inhibition on the discrimination between NO and the nitrergic neurotransmitter in the rat gastric fundus. 886 58


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