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)

It is known that renal ischemia enhances the production of adenosine, which is further metabolized by xanthine oxidase, and that the inhibition of this metabolizing enzyme by allopurinol ameliorates the consequences of renal ischemia. This study was undertaken to define the effect of allopurinol on the renal responses to adenosine. It was found that 5 minutes of intrarenal infusion of adenosine in control dogs produced a typical biphasic response characterized by an initial vasoconstriction, decreasing renal blood flow by 46.3% +/- 6.0%, followed by vasodilation, increasing renal blood flow by 8.5% +/- 3.6% above the control levels. Adenosine infusion was also accompanied by a significant reduction of plasma renin activity, from 8.4 +/- 0.6 ng/ml/hour to 3.8 +/- 0.4 ng/ml/hour. The administration of an intravenous infusion of 50 mg allopurinol did not alter the vasoconstrictor phase of adenosine--the average decrease was 41.1% +/- 3.3%; however, it prevented much of the vasodilation because renal blood flow over the 5 minutes remained 17.9% +/- 5.0% less than the levels recorded before adenosine infusion. Allopurinol also prevented the decrease of plasma renin activity, for which the average values recorded before and after adenosine were 9.6 +/- 0.6 ng/ml/hour and 8.2 +/- 0.6 ng/ml/hour, respectively. The results of this study indicate that allopurinol exerts specific effects on the vasodilatory component of adenosine and prevents the adenosine-suppressive effect on the renin-angiotensin system.
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PMID:Effect of allopurinol on the renovascular responses to adenosine. 351 11

A new spectrophotometric method for the determination of adenosine deaminase is described. Adenosine is deaminated to inosine, the latter is cleaved by an inosine-guanosine specific nucleoside phosphorylase to hypoxanthine and ribose-1-phosphate. Hypoxanthine can be oxidized further to uric acid by xanthine oxidase or to allantoin by xanthine oxidase and uricase. The hydrogen peroxide formed in these reactions is reduced by catalase to water. In the presence of high concentrations of ethanol, equivalent amounts of acetaldehyde are produced. The acetaldehyde is oxidized NAD(P) dependent and the production rate of NAD(P)H is recorded at 334 nm. The new method is suitable for the detection of adenosine deaminase in whole blood, lymphocytes, sera and tissues.
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PMID:A new spectrophotometric assay for enzymes of purine metabolism. IV. Determination of adenosine deaminase. 736 76

The present study investigated the effect of the administration of oxypurinol (40 mg/kg), an inhibitor of xanthine oxidase, on adenosine and adenine nucleotide levels in the rat brain during ischemia and reperfusion. The brains of the animals were microwaved before, at the end of a 20-min period of cerebral ischemia, and after 5, 10, 45, and 90 min of reperfusion. Cerebral ischemia was elicited by four-vessel occlusion with arterial hypotension to 45-50 mm Hg. Adenosine and adenine nucleotide levels in the oxypurinol-pretreated (administered intravenously 20 min before ischemia) rats were compared with those in nontreated animals exposed to the same periods of ischemia and reperfusion. Oxypurinol administration resulted in significantly elevated ATP levels at the end of ischemia and 5 min after ischemia, but not at 10 min after ischemia. ADP levels were also elevated, in comparison with those in the control rats, at the end of the ischemic period. Conversely, AMP levels were significantly reduced at the end of ischemia and during the initial (5 min) period of reperfusion. Adenosine levels were lower in oxypurinol-treated rats, during ischemia, and in the initial reperfusion phase. Oxypurinol administration resulted in a significant increase in the energy charge both during ischemia and after 5 min of reperfusion. Physiological indices, namely, time to recovery of mean arterial blood pressure and time to onset of respiration, were also shortened in the oxypurinol-treated animals. These beneficial effects of oxypurinol may have been a result of its purine-sparing (salvage) effects and of its ability to inhibit free radical formation by the enzyme xanthine oxidase. Preservation of high-energy phosphates during ischemia likely contributes to the cerebroprotective potency of oxypurinol.
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PMID:Oxypurinol-enhanced postischemic recovery of the rat brain involves preservation of adenine nucleotides. 772 3

Adenosine is now widely accepted as the major inhibitory neuromodulator in the central nervous system besides GABA. It has been suggested to be an endogenous neuroprotective metabolite. In situations of metabolic stress, e.g. ischemia adenosine decreases energy demand and increases energy supply. Of particular relevance in this context is its modulation of glutamate release. A shift of this adenosine-glutamate balance in favor of adenosine helps to restore function at the cellular, organ and organism level. Adenosine A1 receptor agonists and metabolic inhibitors, e.g. of transport, deaminase and xanthine oxidase have been demonstrated to be effective in different animal models of ischemia. Nimodipine, a L-type channel calcium antagonist currently in clinical trials for stroke and dementia syndromes, has now been shown to be a potent adenosine transport inhibitor in clinically relevant concentrations. Increase of adenosinergic neuromodulation may well be one of several future therapeutic strategies in neuroprotection.
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PMID:Adenosine--an endogenous neuroprotective metabolite and neuromodulator. 788 4

1. The absorption and metabolism of purine nucleosides and their constituent bases has been investigated by perfusion through the lumen of isolated loops of rat jejunum. In control perfusions and those with luminal purines or purine nucleosides, high-performance liquid chromatography (HPLC) revealed uric acid as the only detectable purine in the mucosal epithelial layer and the serosal secretions unless the xanthine oxidase inhibitor allopurinol was present. 2. Adenosine (0.5 mM) was quantitatively deaminated to inosine in the lumen after perfusion for 30 min. 3. Luminal inosine and hypoxanthine (0.15-1.0 mM) increased the serosal uric acid concentration significantly (P < 0.001); at 0.5 and 1.0 mM the nucleoside gave a significantly greater (P < 0.01) rate of serosal uric acid appearance than the base. 4. Luminal guanosine (0.05-0.50 mM) and guanine (0.05-0.15 mM) increased the serosal uric acid concentration significantly (P < 0.001); with 0.15 mM nucleoside the serosal uric acid appeared significantly faster (P < 0.01) than it did from the base. 5. Luminal allopurinol (0.3 mM) inhibited xanthine oxidase by 80% and reduced serosal purine appearance significantly (P < 0.01) from luminal guanine, hypoxanthine and inosine. With allopurinol, guanosine (0.1 and 0.15 mM) and inosine (0.1-1.0 mM) gave significantly higher (P < 0.01) total serosal purine concentrations than their respective bases. 6. Inosine and guanosine were cleaved to their respective bases plus ribose phosphate by the action of a cytoplasmic nucleoside phosphorylase, which was found to have widely different Michaelis constants (Km; 318 +/- 45 and 41.4 +/- 3.6 microM for inosine and guanosine, respectively) and maximum velocities (Vmax; 79.3 +/- 4.0 and 20.5 +/- 0.05 mumol min-1 (mg protein)-1 for inosine and guanosine, respectively). 7. We conclude that hypoxanthine and guanine absorbed by rat small intestine are oxidized to uric acid which is released in the serosa. The corresponding nucleosides are split by phosphorolysis after absorption and the resulting purine bases are converted to uric acid which appears on the serosal side with similar quantities of ribose phosphate.
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PMID:Purine nucleoside transport and metabolism in isolated rat jejunum. 825 12

Adenosine is a potent autocoid that acts as a vasodilator and modulator of inflammatory responses. Endothelial cells possess several mechanisms for altering circulating levels of adenosine and are capable of release of adenosine metabolites. We used cultured bovine aortic and main pulmonary arterial endothelial cells to determine whether endotoxin can alter adenosine uptake or release of adenosine metabolites. We found that 24 hours, but not 6 hours, of incubation with endotoxin caused endothelial cell injury, as assessed by cell detachment and chromium 51 release. Despite this injury the extent of [3H]adenosine uptake was unchanged. Using thin-layer chromatography to identify adenosine and its metabolites, we found that [3H]adenosine was primarily metabolized into intracellular hypoxanthine and adenine nucleotides. After 1, 6, and 24 hours of incubation with endotoxin there was an increase in extracellular adenosine metabolites, which was accompanied by decreases in the level of intracellular adenosine 5'-triphosphate. The appearance of adenosine metabolites in culture supernatants was a more sensitive measure of endothelial cell injury than 51Cr release or adherent cell number. The extracellular purine metabolite observed in response to endotoxin injury was mainly hypoxanthine. Our findings suggest that hypoxanthine release is an early event in endotoxin-induced endothelial cell injury. Because hypoxanthine may act as a substrate for xanthine oxidase, resulting in toxic oxidant production, its release has the potential of exacerbating vascular injury caused by endotoxin.
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PMID:Effects of endotoxin injury on endothelial cell adenosine metabolism. 830 Dec 8

Using microdialysis in the hippocampus of anaesthetised rats, the concentration of extracellular adenosine was estimated to be 0.8 microM. Kainic acid (0.1-25 mM) in the perfusate evoked a concentration-dependent release of adenosine with an EC50 of 940 microM. Two 5-min pulses of 1 mM kainic acid in the perfusate increased the dialysate levels with an S2/S1 ratio of 0.52 +/- 0.03. Kainate-evoked release of adenosine was reduced significantly by 10 microM tetrodotoxin and by a kappa-receptor agonist, U50, 488H (100 microM). The S2/S1 ratio was reduced by 4.5 microM 6-cyano-7-nitroquinoxaline-2,3-dione, a non-NMDA receptor antagonist, but not by the NMDA receptor blockers (+)-MK-801 (dizocilpine; 100 microM) or (+/-)-2-amino-5-phosphonopentanoic acid (1 mM), indicating a non-NMDA receptor-mediated process. The S2/S1 ratio was also reduced significantly by 10 mM ascorbic acid, 10 mM glutathione (a scavenger of hydroperoxides), and 1 mM oxypurinol (a xanthine oxidase inhibitor), indicating the possible involvement of free radicals. Neither the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (100 microM) nor the A1 adenosine receptor agonist R(-)-N6-(2-phenylisopropyl)adenosine (100 microM) affected release. Adenosine release evoked by kainic acid is therefore mediated by activation of non-NMDA receptors and may involve the propagation of action potentials and the production of free radicals.
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PMID:Kainate-evoked release of adenosine from the hippocampus of the anaesthetised rat: possible involvement of free radicals. 897 31

Adenosine is thought to prevent or reduce the increase in permeability, which is a hallmark of oxidant injury to endothelium. However, the effect of adenosine on endothelial cells directly exposed to oxidant species has not been demonstrated in vitro. By measuring the passage of Evan's blue dye-labeled albumin across confluent monolayers, we demonstrated the ability of adenosine (0.1-100 microM) to lower basal permeability of human umbilical vein endothelial cells in a concentration-dependent fashion and prevent the permeability increase induced by exposure of the cells to xanthine plus xanthine oxidase (X/XO). Whereas pretreatment of monolayers for 10 min with adenosine (10 and 100 microM) prevented the X/XO-induced permeability increase, these same concentrations of adenosine failed to increase intracellular adenosine 3',5'-cyclic monophosphate in X/XO-exposed cells. The protective effect of adenosine on endothelial monolayers was mimicked by adenosine amine congener and 5'-(N-ethylcarboxamido)adenosine but not by other agonists examined. Hence, the protective effect of adenosine against oxidant injury may include an adenosine 3',5'-cyclic monophosphate-independent mechanism by direct action of adenosine at A1 receptors on endothelial cells.
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PMID:Adenosine prevents permeability increase in oxidant-injured endothelial monolayers. 945 49

This study investigates whether ozone could confer protection from hepatic ischemia reperfusion by modifying the accumulation of adenosine and xanthine during ischemia. A significant increase in both adenosine and xanthine accumulation was observed as a consequence of ATP degradation during hepatic ischemia. Adenosine exerts a protective effect on hepatic ischemia reperfusion injury since the elimination of endogenous adenosine accumulation with adenosine deaminase increased the hepatic injury associated with this process. On the other hand, the high xanthine levels observed after ischemia could exert deleterious effects during reperfusion due to reactive oxygen species generation from xanthine oxidase. The administration of allopurinol, an inhibitor of xanthine oxidase, attenuated the increase in reactive oxygen species and transaminase levels observed after hepatic reperfusion. Ozone treatment in liver maintained adenosine levels similar to those found after ischemia but led to a marked reduction in xanthine accumulation. In order to evaluate the role of both adenosine and xanthine, we tried to modify the protection confered by ozone, by modifying the concentrations of adenosine and xanthine. The metabolization of endogenous adenosine after ischemia abolished the protective effect conferred by ozone. When xanthine was administered previous to ozone treatment, the protection conferred by adenosine disappeared, showing both postischemic reactive oxygen species and transaminase levels similar to those found after hepatic ischemia reperfusion. Ozone would confer protection against the hepatic ischemia reperfusion injury by the accumulation of adenosine that in turns benefits the liver and by blocking the xanthine/xanthine oxidase pathway for reactive oxygen species generation.
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PMID:Effect of ozone treatment on reactive oxygen species and adenosine production during hepatic ischemia-reperfusion. 1120 91

Reactive oxygen species (ROS) are believed to be involved in the pathogenesis of several neurological disorders. We now tested whether the endogenous neuroprotective substance, adenosine, attenuates the cell damage induced by ROS. In rat hippocampal slices, the xanthine oxidase (40 mU/ml) plus xanthine (1 mM) (X/XO) system produced a 27.8+/-7.3% (n=3) increase in ROS, measured by fluorimetry with 2',7'-dichlorodihydrofluorescein, a 246.9+/-18.4% (n=6) increase in the release of tritiated adenosine, and a decrease in synaptic transmission that fully recovered after washout. In the presence of the adenosine A(1) receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (100 nM), X/XO induced a similar inhibition, however synaptic transmission only recovered to 70.7+/-5.8% of control (n=5). The blockade of A(2A) receptors was devoid of effect (n=4). Adenosine is released by ROS-generating systems, and attenuates the deleterious cellular consequences of ROS through A(1) receptor activation.
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PMID:Adenosine promotes neuronal recovery from reactive oxygen species induced lesion in rat hippocampal slices. 1261 11


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