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)

This review addresses current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion. The mechanism for radical production remains speculative in large part because of the difficulty of measuring radical species in vivo. Breakdown of lipid membranes during ischemia leads to accumulation of free fatty acids. Decreased energy stores during ischemia result in the accumulation of adenine nucleotides. During reperfusion, metabolism of free fatty acids via the cyclooxygenase pathway and metabolism of adenine nucleotides via the xanthine oxidase pathway are the most likely sources of oxygen radicals. Although leukocytes have been found to accumulate in some models of ischemia and reperfusion, their mechanistic role remains in question. Therapeutic strategies aimed at decreasing brain injury have included administration of radical scavengers at the time of reperfusion. Efficacy of traditional oxygen radical scavengers such as superoxide dismutase and catalase may be limited by their inability to cross the blood-brain barrier. Lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and because of their presence in membrane structures where peroxidative reactions can be halted.
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PMID:Oxygen radical mechanisms of brain injury following ischemia and reperfusion. 175 40

We used mouse soleus in vitro (n = 30) and canine gastrocnemius-plantaris preparations (n = 20) pump-perfused at the animal's blood pressure to establish if free radicals contribute to fatigue in oxidative skeletal muscle. The soleus from each leg contracted for 200 ms (70 Hz) once every minute for 60 min in Hepes buffer gassed with 100% oxygen at 27 degrees C. When contracting in Hepes alone, both muscles fatigued at 0.9 mN/mm2.min over the 60 min. The addition of purines to the bath increased the rate to 1.4 mN/mm2.min and the addition of xanthine oxidase to generate free radicals increased the rate again to 1.9 mN/mm2.min. Thus free radicals appeared to attenuate oxidative skeletal muscle function. Each canine muscle contracted isometrically at 4 Hz for 30 min and then rested for 45 min before contracting for a second 30 min at 4 Hz. In each experiment, we infused saline at 0.76 mL/min into resting muscle and at 1.91 mL/min during the first contraction period. During the remainder of the experiment, we infused, at the same rates, saline (n = 4), 10 microM dimethyl sulfoxide (DMSO) (n = 4) to identify the effect of scavenging hydroxyl radicals, 1 mM allopurinol to establish the effect of blocking xanthine oxidase (n = 4), or 200 microM desferoxamine to determine the effect of chelating iron (n = 4). With saline, the fatigue rate over the 30 min of contractions increased from 5.0 +/- 0.2 to 6.3 +/- 0.5 N/kg.min from the first to the second stimulation period. The fatigue rate was slower in the second period with each of the three experimental substances (DMSO, 5.9 +/- 0.8 to 3.2 +/- 0.3; allopurinol, 7.3 +/- 1.1 to 4.6 +/- 0.6; desferoxamine, 6.8 +/- 0.8 to 4.4 +/- 0.8 N/kg.min). The fatigue rate was the same as control when DMSO was infused only during the second contraction period. Therefore, free radicals appeared to contribute to fatigue in oxidative skeletal muscle.
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PMID:Free radicals may contribute to oxidative skeletal muscle fatigue. 205 45

Cold injury is a tissue trauma produced by exposure to freezing temperatures and even brief exposure to a severely cold and windy environment. Rewarming of frozen tissue is associated with blood reperfusion and the simultaneous generation of free oxygen radicals. In this review is discussed the current understanding of the mechanism of action of free oxygen radicals as related to cold injury during rewarming. Decreased energy stores during ischaemia lead to the accumulation of adenine nucleotides and liberation of free fatty acids due to the breakdown of lipid membranes. On rewarming, free fatty acids are metabolized via cyclo-oxygenase and adenine nucleotides are metabolized via the xanthine oxidase pathway. These may be the source of free oxygen radicals. Leukocytes may also play a major role in the pathogenesis of cold injury. Oxygen radical scavengers, such as superoxide dismutase and catalase, may help to reduce the cold induced injury but their action is limited due to the inability readily to cross the plasma membrane. Lipid soluble antioxidants are likely to be more effective scavengers because of their presence in membranes where peroxidative reactions can be arrested.
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PMID:The role of free radicals in cold injuries. 760 50

Uric acid is the end product of purine metabolism in human. Then, the enzymatic abnormalities, concerning purine metabolism, cause disorders of uric acid metabolism including hyperuricemia and hypouricemia. The superactivity of 5-phosphoribosyl-pyrophosphate (PRPP) synthetase and deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) caused hyperuricemia. In glycogen storage diseases of type I, III, V, and VII, decreased energy supply induces hyperuricemia by accelerating ATP degradation. Deficiencies of xanthine oxidase (XO), purine nucleoside phosphorylase (PNP), and PRPP were reported causing hypouricemia. Many methods for DNA-diagnosis were developed including Southern blot, Northern blot, PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism), PCR-RFLP (restriction fragment length polymorphism), and allele specific oligonucleotide hybridization etc.
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PMID:[Inherited disorders of uric acid metabolism--classification, enzymatic- and DNA-diagnosis]. 897 10

Although controversial, growing evidence indicates that reactive oxygen species (ROS) alter contractions of skeletal muscle, including the diaphragm. However, the impact of ROS on contractility of the aging diaphragm is unknown. The xanthine oxidase (0.01 U/ml) system was used as an ROS generator, imposing an oxidant challenge. Contractile function [twitch tension; twitch time to peak tension; twitch one-half relaxation time; tension at 10 and 20 Hz; maximal tetanic tension (Po) at 100 Hz] of costal diaphragm fiber bundles from young (4 mo) and old (25 mo) Fischer 344 rats was examined in vitro before and after treatment with control Krebs solution [young control (YC) and old control (OC)], or with xanthine oxidase (XO; 0.01 U/ml) plus hypoxanthine (0.29 mg/ml) substrate [young XO treated (YXO) and old XO treated (OXO)]. Contractile function of fiber bundles was reassessed after oxidant challenge in an unfatigued state (Post-u) or 10 min after a fatiguing stimulation protocol (Post-f). Oxidant challenge in the unfatigued fiber bundles increased twitch tension and tension at 10 and 20 Hz in YXO, but not OXO, without increasing Po. Conversely, XO significantly depressed fatigued diaphragm twitch and low-frequency tension in both OXO and YXO, compared with controls. Po was depressed Post-f in OXO but not YXO. Oxidant challenge also increased twitch one-half relaxation time of the fatigued diaphragm in both age groups. Furthermore, fiber bundles from old rats suffered greater fatigue during the stimulation protocol. We conclude that the response to oxidant challenge and increased contractile demand is impaired in the aging diaphragm.
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PMID:Effect of oxidant challenge on contractile function of the aging rat diaphragm. 912 23

Acidosis during exercise has long been associated with skeletal muscle fatigue. Recent evidence also has linked reactive oxygen species (ROS) with fatigue in skeletal muscle, including the diaphragm. We hypothesized that acidosis (designed to mimic blood pH during maximal exercise) would worsen ROS-induced depression of diaphragm contractility. The xanthine oxidase (XO) reaction in solution (0.01 U/ml) allows direct assessment of the effects of oxidant stress by ROS. Costal diaphragm fiber bundles from 24 Sprague-Dawley rats (200-250 g) were divided into four treatment groups: 1) pH 7.4, no XO (H); 2) pH 7.4 + XO (HXO); 3) pH 7.0, no XO (L); and 4) pH 7.0 + XO (LXO). Baseline twitch mechanics and force-frequency relationships (Pre) were determined in control Krebs solution (pH 7.4, no XO) before treatment. Treatment solutions were introduced, and the diaphragm underwent 2 min of contractions at 25 Hz (250 ms) at a rate of 1/s. After 10 min of recovery, the control solution was reintroduced into the bath and postcontractile function (Post) was measured. Significant reductions in twitch tension and low-frequency tetanic tension were greater in HXO and LXO compared with H, without an effect on maximal tetanic tension. One-half relaxation time was prolonged only by the combination of acidosis and oxidative stress. Addition of superoxide dismutase (50 U/ml) worsened and catalase (1,800 U/ml) attenuated XO-induced depression of diaphragm contractility. We concluded that XO induced a reduction of low-frequency tension in the fatigued diaphragm, which was mediated directly or indirectly through hydrogen peroxide and was exacerbated to a modest extent with acidosis.
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PMID:Effect of oxidative stress and acidosis on diaphragm contractile function. 927 48

The purpose of the present study was to determine whether it is possible to alter the development of fatigue and ablate free radical-mediated lipid peroxidation of the diaphragm during loaded breathing by administering oxypurinol, a xanthine oxidase inhibitor. We studied 1) room-air-breathing decerebrate, unanesthetized rats given either saline or oxypurinol (50 mg/kg) and loaded with a large inspiratory resistance until airway pressure had fallen by 50% and 2) unloaded saline- and oxypurinol-treated room-air-breathing control animals. Additional sets of studies were performed with animals breathing 100% oxygen. Animals were killed at the conclusion of loading, and diaphragmatic samples were obtained for determination of thiobarbituric acid-reactive substances and assessment of in vitro force generation. We found that loading of saline-treated animals resulted in significant diaphragmatic fatigue and thiobarbituric acid-reactive substances formation (P < 0.01). Oxypurinol administration, however, failed to increase load trial time, reduce fatigue development, or prevent lipid peroxidation in either room-air-breathing or oxygen-breathing animals. These data suggest that xanthine oxidase-dependent pathways do not generate physiologically significant levels of free radicals during the type of inspiratory resistive loading examined in this study.
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PMID:Oxypurinol administration fails to prevent free radical-mediated lipid peroxidation during loaded breathing. 1048 86

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

Reactive oxygen species contribute to diaphragm dysfunction in certain pathophysiological conditions (i.e., sepsis and fatigue). However, the precise alterations induced by reactive oxygen species or the specific species that are responsible for the derangements in skeletal muscle function are incompletely understood. In this study, we evaluated the effect of the superoxide anion radical (O(2)(-).), hydroxyl radical (.OH), and hydrogen peroxide (H(2)O(2)) on maximum calcium-activated force (F(max)) and calcium sensitivity of the contractile apparatus in chemically skinned (Triton X-100) single rat diaphragm fibers. O(2)(-). was generated using the xanthine/xanthine oxidase system;.OH was generated using 1 mM FeCl(2), 1 mM ascorbate, and 1 mM H(2)O(2); and H(2)O(2) was added directly to the bathing medium. Exposure to O(2)(-). or.OH significantly decreased F(max) by 14.5% (P < 0.05) and 43.9% (P < 0. 005), respectively.OH had no effect on Ca(2+) sensitivity. Neither 10 nor 1,000 microM H(2)O(2) significantly altered F(max) or Ca(2+) sensitivity. We conclude that the diaphragm is susceptible to alterations induced by a direct effect of.OH and O(2)(-)., but not H(2)O(2), on the contractile proteins, which could, in part, be responsible for prolonged depression in contractility associated with respiratory muscle dysfunction in certain pathophysiological conditions.
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PMID:Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. 1113 92

Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 microM) were studied on isometric and isotonic force generation during hypoxia (PO(2) approximately 7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (PO(2) approximately 85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.
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PMID:Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase. 1170 36


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