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)

In the present work, an experimental system was designed to study superoxide anion radical, implicated as the cause of vascular dilatation. To circumvent its direct effect, we employed a two-bath system. When the endothelial cells (EC) were exposed to electrical field stimulation (EFS) or to a hypoxanthine-xanthine oxidase system in bath A plus its physiological buffer solution suffused on a helical strip of cat basilar artery in bath B, the contraction to 5-hydroxytryptamine (5-HT) was depressed to approximately 40-50% of the control value. The reduction was not elicited on EFS in a state of calcium deficiency or in the absence of EC. The depression could be prevented by pretreatment with superoxide dismutase (SOD), but not with an effective dose of catalase, dimethyl sulfoxide (DMSO), mannitol, or indomethacin. The percent depression of contraction was paralleled by an increase in SOD-inhibitable cytochrome c reduction, which was not associated with cyclic guanosine 3',5'-monophosphate formation. These results suggest that superoxide-dependent relaxing factor is released from EC differently than the endothelium-derived relaxing factor mediated by acetylcholine.
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PMID:Release of superoxide-dependent relaxing factor(s) from endothelial cells. 255 45

A yellow substance was isolated by Sephadex LH-20 gel chromatography, silica gel TLC, and reversed-phase HPLC after incubation of 5-hydroxytryptamine (5-HT) with the superoxide anion (O2-)-generating system, i.e., the xanthine-xanthine oxidase system, in the presence of the Fe-EDTA complex and glycine in alkaline medium. The product gave a blue color with Ehrlich's reagent very slowly but no color with xanthydrol and Gibbs' reagent. Its reduced form, however, gave an immediate blue-violet color with all three reagents. No color was developed with ninhydrin, but the reduced form was orange-red. The chemical structure of the yellow substance was identified by 1H-nuclear magnetic resonance and field desorption-mass spectrometry as 4,9-dihydro-3H-pyrido[3,4-b]indol-6-ol (6-hydroxy-3,4-dihydro-beta-carboline, 5-hydroxy-2,3-dihydrotryptoline). The one carbon unit inserted into 5-HT came from glycine, with its 14C-2 being incorporated into C-1 of the yellow substance. The mechanism for the formation of the yellow substance from 5-HT is discussed. This compound inhibited 5-HT uptake into rat brain cortical synaptosomes with an IC50 of 1.5 X 10(-4) M and a Ki value of 1.2 X 10(-5) M.
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PMID:Isolation, structure, and properties of the beta-carboline formed from 5-hydroxytryptamine by the superoxide anion-generating system. 284 54

We were interested in determining the effect of lung injury initiated by superoxide anions and hydroxyl radicals on removal of 5-hydroxytryptamine (5-HT) and phenylethylamine by the isolated perfused lung. The rate of removal and percentage of removal of these bioamines was determined before and after lung injury initiated by perfusion of the lung with hypoxanthine (HX) and xanthine oxidase (XO) or xanthine oxidase alone for 10 or 30 minutes; free radicals are generated by such treatment. Because of variation in removal of bioamines among lungs of different animals, the effects of lung injury on bioamine removal were determined by calculating the percentage of inhibition of removal using data from the control and test period for each lung. Perfusion of the lung with HX/XO or XO for 10 or 30 minutes significantly inhibited 5-HT removal by 39.5% and 63.3%, respectively. In contrast, only perfusion of the lung for 30 minutes with HX/XO produced inhibition of phenylethylamine uptake (by 54.8%). As uptake of 5-HT is the rate-limiting step in 5-HT removal, these data demonstrate dose (time)-related depression of active 5-HT uptake by free radicals generated in vitro. The rate-limiting step of phenylethylamine uptake, metabolism by monoamine oxidase, is inhibited only by severe lung injury.
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PMID:Xanthine oxidase-induced lung injury inhibits removal of 5-hydroxytryptamine from the pulmonary circulation. 628 49

Oxygen-derived free radicals have been shown to damage endothelial cells in tissue culture. We have extended these observations to demonstrate a direct toxic action of oxy radicals on endothelial cell function in the isolated perfused rat lung model. Using an enzymatic system of hypoxanthine and xanthine oxidase, we generated a superoxide flux of 5-7 nmol/min within the pulmonary circulation. This resulted in alteration of endothelial cell function, including a progressive fall in the cellular transport of (14C) 5-hydroxytryptamine, edema formation manifested by a falling dry weight ratio and increasing mean transit times appearance of thiobarbituric acid reactive material in the perfusate indicating lipid peroxidation, and histologic evidence of edema formation with disruption of the endothelial cell plasma membrane. Inhibitor studies confirmed that the observed effects were due to superoxide radical generation. Oxygen derived free radicals may play a role in the pulmonary endothelial cell damages seen in inflammatory disorders and oxidant lung injury.
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PMID:The effect of oxygen-derived free radicals on pulmonary endothelial cell function in the isolated perfused rat lung. 628 99

The protective effect of N-acetylcysteine (NAC) against oxidant lung injury was investigated in a model of acute immunological alveolitis in the rat. Intrapulmonary immune complex deposition into rat lungs, induced by intratracheal infusion of immunoglobulin G (IgG) anti-bovine serum albumin (BSA) antibodies and intravenous injection of the antigen, caused lung damage associated with a marked decrease in [14C]5-hydroxytryptamine ([14C]5HT) uptake capacity, taken as a biochemical marker of endothelial cell function. The oral administration of a single dose of NAC (2 mmol.kg-1) 60 min before antigen/antibody (Ag/Ab) treatment was effective in preventing pulmonary endothelial cell [14C]5HT uptake loss induced by immune complex deposition. The mechanisms involved in this lung protective action of NAC were investigated by studying the antioxidant activity of NAC on hypoxanthine/xanthine oxidase-induced lung damage in vitro, and the effectiveness of the drug as lung glutathione (reduced form) (GSH) precursor in diethylmaleate-depleted rats. The results obtained provide further evidence on the ability of NAC to reduce the susceptibility of lung tissue to free radical-induced damage, by potentiating the antioxidant defence systems.
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PMID:Protection by N-acetylcysteine against pulmonary endothelial cell damage induced by oxidant injury. 847 21

Levels of uric acid, xanthine, hypoxanthine, ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum and/or in the brain stem of 3-month-old male Wistar rats given allopurinol (300 mg/kg day by gavage) for 3 days before a single MPTP 35 mg/kg dose IP. Allopurinol alone decreased uric acid and increased xanthine levels both in the striatum and in the brain stem; moreover, allopurinol decreased striatal DOPAC + HVA/DA ratio and increased 5-HIAA/5HT ratio in the brainstem. Allopurinol affected neither regional MPTP nor MPP+ disposition. Allopurinol potentiated the MPTP-induced decrease in the DOPAC+HVA/DA ratio and increase in striatal AA oxidation; in addition, allopurinol antagonised the MPTP-induced: (i) increase in uric acid levels; (ii) decrease in NA levels in both regions, in DA levels, and in the 5-HIAA/5-HT ratio in the brain stem: (iii) increase in AA oxidation in the brain stem. In conclusion, the MPP(+)-induced oxidative stress mediated by xanthine oxidase seems to be involved in DA depletion in the brainstem and in NA depletion in both regions; moreover, striatal uric acid may have an active role in the neuronal antioxidant pool.
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PMID:Further investigation of allopurinol effects on MPTP-induced oxidative stress in the striatum and brain stem of the rat. 874 98

Previous studies from our laboratory have shown that nitric oxide (NO) can reduce the release of free radicals from activated leukocytes. The aim of this study was to assess the role of endothelium-derived nitric oxide and leukocyte-derived free radicals in the contractile response to non-preactivated leukocytes. Vessel tension studies were performed in rabbit endothelium-intact aortic vessel rings precontracted with 5-hydroxytryptamine (1 microM). Addition of leukocytes isolated from rabbit blood were added to the rings in increasing concentrations (10(3)-10(6) cell ml(-1)) under control conditions and in the presence of L-nitroarginine methyl ester (L-NAME 1 mM), D-NAME (1 mM), or superoxide dismutase (100 U ml(-1)). The responses to superoxide radical (generated by xanthine plus xanthine oxidase, X/XO), hydrogen peroxide, hypochlorite and peroxynitrite were also assessed. The nature of the free radicals released from non-activated isolated leukocytes, zymosan-stimulated leukocytes (in whole blood) and isolated vessel rings was assessed using luminol-enhanced chemiluminescence. Cumulative addition of leukocyte suspensions to aortic rings caused a concentration-dependent contractile response which was abolished by preincubation of the vessel ring with L-NAME. D-NAME and superoxide dismutase were without effect. All the free radicals tested produced a relaxation of the precontracted aortic ring. The response to X/XO was not affected by superoxide dismutase, but abolished by catalase. The responses to hydrogen peroxide and hypochlorite were both found to be dependent upon the presence of endothelium and NO. The response to peroxynitrite was endothelium-independent and was blocked by methylene blue. While the main free radical released from unstimulated leukocytes and vessel rings was superoxide, the main radical released from activated leukocytes was found to be hypochlorite. These results suggest that the vascular contraction seen in response to non-preactivated leukocytes is due to inhibition, by NO, of the release of free radicals from the leukocytes when activated by contact with the vascular endothelium, thus allowing co-released vasoconstrictor substances to exert their effect.
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PMID:Role of nitric oxide and free radicals in the contractile response to non-preactivated leukocytes. 959 26

The effects of 5-hydroxytryptamine (5-HT) on ethanol-induced gastric mucosal damage and on epithelial and vascular integrity were investigated. Male Sprague-Dawley rats were administered with 5-HT (5 or 10 mg/kg, IP) 30 min prior to the challenge with ethanol (40% v/v, 10 ml/kg, PO). 5-HT dose dependently aggravated ethanol-induced injury in the gastric mucosa. Both xanthine oxidase (XO) and myeloperoxidase (MPO) activities in the mucosa were significantly increased with the high dose of 5-HT, which also potentiated the elevation of these enzyme activities by ethanol. However, the mucosal superoxide dismutase activity was left unaltered. In neutropenic (antineutrophil serum-treated) animals, the ethanol-induced gastric mucosal injury was significantly ameliorated, with or without the pretreatment of 5-HT (10 mg/kg). In addition, the effect of 5-HT on the activity of MPO, but not of XO, was also attenuated in these animals. In the ex vivo gastric chamber study on pentobarbital-anesthetized animals, volume of gastric secretion was significantly decreased in the 5-HT-treated groups, with further reduction after ethanol incubation. Transmucosal potential difference (PD) was significantly reduced in 5-HT-treated rats, which also potentiated the ethanol-induced drop in PD. Nevertheless, 5-HT dose dependently increased mucosal vascular permeability and further enhanced during ethanol incubation. These findings suggest that 5-HT adversely affects the defense mechanisms of the gastric mucosa by reducing the secretory function of the mucosal cells and to weaken the epithelial and vascular integrity. Neutrophil activation appears to be responsible for the detrimental effects of 5-HT partly through the elevation in MPO activity. The increase in mucosal XO activity by 5-HT may induce free radical production and possibly modulate the ulcerogenic processes.
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PMID:The correlation of the weakening effect on gastric mucosal integrity by 5-HT with neutrophil activation. 960 12

Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4, 4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo-1H,3H, 7H-purine (7) as the major products. These products differ from those formed in the HO*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine-4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4, 5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.
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PMID:Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders. 962 32

The present study investigated the mechanisms involved in the increased 5-hydroxytryptamine (5-HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 microg x ml-1) for 1-5 h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed. LPS exposure increased 5-HT (10 microm) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 microm), the COX-2 inhibitor NS 398 (10 microm), the TXA2/PGH2 receptor antagonist SQ 29548 (1 microm) and the TXA2 synthase inhibitor furegrelate (1 microm) reduced 5-HT contraction of LPS-treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mm) increased 5-HT contraction from hour three of LPS incubation. The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml-1) and the H2O2 scavenger catalase (1000 U ml-1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mm) and allopurinol (0.3 mm), reduced 5-HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG-SOD. Subthreshold concentrations of the TXA2 analogue U 46619, xanthine/xanthine oxidase and H2O2 potentiated, whereas those of sodium nitroprusside inhibited, the 5-HT contraction. COX-2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn-SOD and Mn-SOD was only increased after 5 h. All the three vascular layers expressed COX-2 and Cu/Zn-SOD. iNOS expression was detected in the endothelium and adventitia after LPS. In conclusion, increased production of TXA2 from COX-2, superoxide anion and H2O2 enhanced vasoconstriction to 5-HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock.
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PMID:Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteries. 1453 51


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