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)

We hypothesized that direct pulmonary administration of supercritical fluid-aerosolized (SFA) vitamin E would decrease acute oxidative lung injury. We previously reported that rapid expansion of supercritical CO2 formed respirable particles of vitamin E and that administering SFA vitamin E to rats increased lung vitamin E levels and decreased neutrophil-mediated lung leak. In the present investigation, we found that pretreatment with SFA vitamin E protected isolated rat lungs against the oxidant-induced lung leak caused by perfusion with xanthine oxidase (XO) and purine, an enzyme system that generates superoxide union (O2-.) and hydrogen peroxide. SFA vitamin E droplets were 0.7-3 microns in diameter, and inhalation of the airborne droplets for 30 min deposited approximately 55 micrograms of vitamin E in rat lungs. Isolated rat lungs perfused with XO (0.02 U/ml) and purine (10 mM) gained more weight (1.75 +/- 0.12 g, n = 8), retained more Ficoll (11.5 +/- 1.2 mg/left lung, n = 7), and accumulated more Ficoll in their lung lavages (700 +/- 146 micrograms/ml, n = 8) than control lungs [0.25 +/- 0.06 g (n = 10), 6.2 +/- 1.2 mg/left lung (n = 9), and 141 +/- 31 micrograms/ml (n = 8), respectively, P < 0.05]. In contrast, isolated lungs from rats that were pretreated with SFA vitamin E had decreased (P < 0.05) weight gains (0.32 +/- 0.06 g, n = 7), Ficoll retentions (3.3 +/- 1.1 mg/left lung, n = 7), and lung lavage Ficoll concentrations (91 +/- 26 micrograms/ml, n = 6) after perfusion with XO and purine compared with isolated lungs from control rats perfused with XO and purine. This protective effect was not observed in rat lungs given sham treatments (CO2 alone or vitamin E acetate aerosolized with supercritical CO2). Our results suggest that direct pulmonary supplementation of vitamin E decreases susceptibility to vascular leakage caused by XO-derived oxidants.
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PMID:Supercritical fluid-aerosolized vitamin E pretreatment decreases leak in isolated oxidant-perfused rat lungs. 945 45

Reactive oxygen species (ROS) are postulated to alter low-frequency contractility of the unfatigued and fatigued diaphragm. It has been proposed that ROS affect contractility through changes in membrane excitability and excitation-contraction coupling. If this hypothesis is true, then ROS should alter depolarization-dependent K+ contractures. Xanthine oxidase (0.01 U/ml) + hypoxanthine (1 mM) were used as a source of superoxide anion eliciting oxidative stress on diaphragm fiber bundles in vitro. Diaphragm fiber bundles from 4-mo-old Fischer 344 rats were extracted and immediately placed in Krebs solution bubbled with 95% O2-5% CO2. After 10 min of equilibration, a K+ contracture (Pre; 135 mM KCl) was induced. Fiber bundles were assigned to the following treatment groups: normal Krebs-Ringer (KR; Con) and the xanthine oxidase system (XO) in KR solution. After 15 min of treatment exposure, a second (Post) K+ contracture was elicited. Mean time-to-peak tension for contractures was significantly decreased in Post vs. Pre (16.0 +/- 0.7 vs. 19.8 +/- 1.0 s) with XO; no change was noted with Con. Furthermore, peak contracture tension was significantly higher (31.5%) in the XO group Post compared with Pre; again, no significant change was found with KR. The relaxation phase was also altered with XO but not with KR. Additional experiments were conducted with application of 1 mM hypoxanthine, with results similar to the Con group. We conclude that the application of ROS altered the dynamics of K+ contractures in the rat diaphragm, indicating changes in voltage-dependent excitation-contraction coupling.
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PMID:Effect of reactive oxygen species on K+ contractures in the rat diaphragm. 948 Sep 56

Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.
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PMID:Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. 981 11

Guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) and guanabenz (1-(2,6-dichlorobenzylidene-amino)-3-guanidine) are both known as centrally active antihypertensive drugs. We have previously shown that enzymatic activity in the rat spleen can induce N-reduction of guanoxabenz, leading to high affinity alpha 2-adrenoceptor binding, due to the formation of the alpha 2-adrenoceptor active drug, guanabenz. The spleen activity appears to reside in xanthine oxidase as it is activated by xanthine and blocked by allopurinol. We report that high affinity guanoxabenz binding is also induced in rat brain membranes after addition of NADH or NADPH cofactors. However, the brain process was clearly different from that of the spleen, as the formation of high affinity binding in the brain was not blocked by allopurinol. Moreover the NADH/NADPH activated mechanism of the brain membranes was not blocked by carbon monoxide and SKF525A, thus the activity appears not to reside in cytochrome P450 enzymes. Instead the activity was blocked by menadione and dicumarol. We conclude that the rat cerebral cortex contains an enzymatic activity that may activate guanoxabenz leading to formation of a metabolite showing high affinity for alpha 2-adrenoceptors. We also conclude that the rat brain activity is clearly distinct from that of the rat spleen.
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PMID:Characterization of guanoxabenz reducing activity in rat brain. 982 Aug 76

The primary product of the interaction between nitric oxide (NO) and superoxide () is peroxynitrite (ONOO-), which is capable of either oxidizing or nitrating various biological substrates. However, it has been shown that excess NO or can further react with ONOO- to form species which mediate nitrosation. Subsequently, the controlled equilibrium between nitrosative and oxidative chemistry is critically dependent on the flux of NO and. Since ONOO- reacts not only with NO and but also with CO2, the effects of bicarbonate () on the biphasic oxidation profile of dihydrorhodamine-123 (DHR) and on the nitrosation of both 2,3-diaminonaphthalene and reduced glutathione were examined. Nitric oxide and were formed with DEA/NO [NaEt2NN(O)NO] and xanthine oxidase, respectively. The presence of did not alter either the oxidation profile of DHR with varying radical concentrations or the affinity of DHR for the oxidative species. This suggests that the presence of CO2 does not affect the scavenging of ONOO- by either NO or. However, an increase in the rate of DHR oxidation by ONOO- in the presence of suggests that a CO2-ONOO- adduct does play a role in the interaction of NO or with a product derived from ONOO-. Further examination of the chemistry revealed that the intermediate that reacts with NO is neither ONOO- nor cis-HOONO. It was concluded that NO reacts with both trans-HOONO and a CO2 adduct of ONOO- to form nitrosating species which have similar oxidation chemistry and reactivity with and NO.
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PMID:The oxidative and nitrosative chemistry of the nitric oxide/superoxide reaction in the presence of bicarbonate. 1022 43

Recent reports have demonstrated that superoxide is released by the contracting diaphragm. Moreover, extracellular scavengers of superoxide (i.e., exogenously administered superoxide dismutase) reduce diaphragm fatigue rate, arguing that superoxide released from contracting muscles may have functionally significant effects. The mechanism by which free radical formation and release occurs has not, however, been determined, and all past studies of this phenomenon have been conducted at a single muscle length (the length of maximum force generation, Lo) and at a single level of carbon dioxide. The purpose of the present study was twofold: (1) to examine the effect of blockade of two free radical-generating pathways (i.e., to block cyclooxygenase with indomethacin and xanthine oxidase with oxypurinol) on superoxide release by the contracting diaphragm, and (2) to examine the effect of altering muscle length, carbon dioxide levels, and stimulation frequency on superoxide release during contraction. Studies were performed using an isolated, arterially perfused, rat diaphragm preparation in which superoxide release was assessed in real time by measuring arteriovenous cytochrome c reduction gradients across this muscle. We found that superoxide release during contraction was: (1) not altered by indomethacin administration, (2) partially reduced by oxypurinol administration, (3) reduced by decreasing muscle length, (4) reduced by increasing carbon dioxide concentrations, and (5) reduced by decreasing stimulation frequency. The first two findings indicate that xanthine oxidase pathways contribute to free radical formation under these circumstances but cyclooxygenase does not. The last three findings suggest that these common physiologic alterations have significant effects on free radical release by contracting muscle.
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PMID:Modulation of release of reactive oxygen species by the contracting diaphragm. 1071 39

To determine the origin of free oxygen radicals in the culture medium of bovine embryos, the effect of allopurinol, an inhibitor of xanthine oxidase, on the development of embryos (>4 cell) in modified synthetic oviduct fluid (m-SOF) medium was examined. When embryos were cultured in the presence of 0.2 mM allopurinol under high oxygen tension (5% CO2 in air), the blastocyst rate significantly (P<0.05) increased compared with the absence of allopurinol (allopurinol (+) 42 vs. (-) 25%; Day 6, 63 vs. 51%; Day 7, 69 vs. 58%; Day 8). However, allopurinol had no effect on embryo development under low oxygen tension (5% CO2, 5% O2, 90% N2). Moreover, it was found that the developmental rate and the total cell number of blastocysts decreased (development rate: 60 vs. 28%, cell number: 132 vs. 74) when the embryos were cultured in medium containing 0.01 U/mL xanthine oxidase (XOD) and 0.1 mM hypoxanthine (HXT), and the damaging effect of XOD and HXT was removed by the addition of 0.2 mM allopurinol. The beneficial effect of allopurinol was also observed when the glucose concentration was increased to 4.5 mM from 1.5 mM (control: 22% vs. allopurinol: 34%; Day 8), but no beneficial effects were observed in the media without glucose (control: 55% vs. allopurinol: 59%). Taken together, these results suggested that a portion of the free oxygen radicals are generated from the XOD and HXT reactions under culture conditions, and this generation is enhanced by high oxygen tension in the gas atmosphere or by high glucose concentrations in the medium.
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PMID:Allopurinol, an inhibitor of xanthine oxidase, improves the development of IVM/IVF bovine embryos (>4 cell) in vitro under certain culture conditions. 1072 46

Growing evidence indicates that reactive oxygen species (ROS) as well as nitric oxide (NO) have a profound influence on contractile function of skeletal muscle possibly through modulation of excitation-contraction coupling. We hypothesized that if NO and xanthine oxidase (XO) interact at key sites in excitation-contraction coupling, the effects of XO with nitric oxide synthase (NOS) inhibitors and NO donors on contractile function of the unfatigued diaphragm would not be additive. Diaphragm fibre bundles were extracted from 4-month Fischer-344 rats and placed in Krebs solution bubbled with 95% O2, 5% CO2. Baseline twitch tension, tension at 20 Hz (low-frequency), and maximal tetanic tension (Po) at 120 Hz were then measured (PRE). In Experiment 1 diaphragm fibre bundles were exposed to Krebs with 200 microM hypoxanthine as a control (CON); 0.02 U mL-1 XO + 200 microM hypoxanthine; 1 mM of the NOS inhibitor N-nitro-L-arginine (L-NNA) or L-NNA + XO. Five minutes were allowed for equilibration, and a second set of contractile measures was taken (POST). In Experiment 2 we exposed diaphragm fibre bundles to one of the following four solutions: CON, XO, 100 microM of the NO donor sodium nitroprusside (SNP) and XO + SNP, and evaluated contractile function as described above. In Experiment 3 we tested to determine if peroxynitrite production from the reaction of superoxide anion and NO affected the above results for SNP using 30 microM ebselen as a peroxynitrite quencher. Xanthine oxidase resulted in a significant potentiation of diaphragm twitch tension and tension at 20 Hz (+29%) without affecting Po. L-NNA also significantly increased 20 Hz tension but did not alter Po. However, the combination of XO + L-NNA did not further increase low-frequency contractility. Sodium nitroprusside alone did not affect diaphragm contractility, but did attenuate XO-induced potentiation in the XO + SNP group. Ebselen did not alter the impact of SNP on XO in the diaphragm. These data support the hypothesis that XO and NO interact or compete at similar sites of action that modulate contractility of the unfatigued diaphragm.
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PMID:Interaction of nitric oxide and reactive oxygen species on rat diaphragm contractility. 1088 37

Tyrosine nitration is a widely used marker of peroxynitrite (ONOO(-)) produced from the reaction of nitric oxide with superoxide. Pfeiffer and Mayer (Pfeiffer, S., and Mayer, B. (1998) J. Biol. Chem. 273, 27280-27285) reported that superoxide produced from hypoxanthine plus xanthine oxidase in combination with nitric oxide produced from spermine NONOate did not nitrate tyrosine at neutral pH. They suggested that nitric oxide and superoxide at neutral pH form a less reactive intermediate distinct from preformed alkaline peroxynitrite that does not nitrate tyrosine. Using a stopped-flow spectrophotometer to rapidly mix potassium superoxide with nitric oxide at pH 7.4, we report that an intermediate spectrally and kinetically identical to preformed alkaline cis-peroxynitrite was formed in 100% yield. Furthermore, this intermediate nitrated tyrosine in the same yield and at the same rate as preformed peroxynitrite. Equivalent concentrations of nitric oxide under aerobic conditions in the absence of superoxide did not produce detectable concentrations of nitrotyrosine. Carbon dioxide increased the efficiency of nitration by nitric oxide plus superoxide to the same extent as peroxynitrite. In experiments using xanthine oxidase as a source of superoxide, tyrosine nitration was substantially inhibited by urate formed from hypoxanthine oxidation, which was sufficient to account for the lack of tyrosine nitration previously reported. We conclude that peroxynitrite formed from the reaction of nitric oxide with superoxide at physiological pH remains an important species responsible for tyrosine nitration in vivo.
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PMID:Superoxide reacts with nitric oxide to nitrate tyrosine at physiological pH via peroxynitrite. 1090 40

Electron spin resonance spectroscopy has been used to study free radical generation in rats with acute sodium formate poisoning. The in vivo spin-trapping technique was used with alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN), which reacts with free radical metabolites to form radical adducts, which were detected in the bile and urine samples from Fischer rats. The use of [(13)C]-sodium formate and computer simulations of the spectra identified the 12-line spectrum as arising from the POBN/carbon dioxide anion radical adduct. The identification of POBN/*CO(2)(-) radical adduct provides direct electron spin resonance spectroscopy evidence for the formation of *CO(2)(-) radicals during acute intoxication by sodium formate, suggesting a free radical metabolic pathway. To study the mechanism of free radical generation by formate, we tested several known inhibitors. Both allopurinol, an inhibitor of xanthine oxidase, and aminobenzotriazole, a cytochrome P450 inhibitor, decreased free radical formation from formate, which may imply a dependence on hydrogen peroxide. In accord with this hypothesis, the catalase inhibitor 3-aminotriazole caused a significant increase in free radical formation. The iron chelator Desferal decreased the formation of free radicals up to 2-fold. Presumably, iron plays a role in the mechanism of free radical generation by formate via the Fenton reaction. The detection of formate free radical metabolites generated in vivo and the key role of the Fenton reaction in this process may be important for understanding the pathogenesis of both formate and methanol intoxication.
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PMID:An in vivo ESR spin-trapping study: free radical generation in rats from formate intoxication--role of the Fenton reaction. 1171 23


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