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)

Tissue damage as a consequence of ischemia is a major medical problem in an industrialized society. Whereas the conventional view has attributed this injury process to ischemia itself, recent studies have found that a variable, but often substantial proportion of the injury is caused by toxic oxygen metabolites that are generated from xanthine oxidase at the time of reperfusion. This mechanism was first identified and characterized in a model of moderately mild partial vascular occlusion in the feline small intestine. Strikingly similar mechanisms have been subsequently confirmed as the basis for ischemia/reperfusion injury in the stomach, pancreas, liver, skin, skeletal muscle, heart, lung, kidney and central nervous system. The potential for clinical application of this concept is related primarily to that proportion of the total post-ischemic injury that is due to this reperfusion mechanism, set against the proportion due to ischemia itself. Ironically, in clinical cases of intestinal ischemia the reperfusion component appears to be proportionately small, and the potential for treatment of ischemic bowel disease is correspondingly limited. On the other hand, there is reason to expect that the ablation of free radical-mediated reperfusion injury, something that can be readily achieved through non-toxic means, may provide substantial benefit for the treatment of ischemic renal disease, myocardial infarction, stroke, cardiac arrest, and of organs preserved for transplantation.
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PMID:Free radical-mediated reperfusion injury: a selective review. 330 76

Allopurinol reduces formation of cytotoxic free radicals during myocardial ischemia/reperfusion in animals. To evaluate the effect of allopurinol on cardiac performance and metabolism after coronary bypass in humans, we divided 33 patients into two groups: 15 patients (controls) received no allopurinol and 18 patients received 200 mg allopurinol intravenously (i.v.) 1 h preoperatively. Hemodynamic measurements were made with a triple-lumen thermodilution pulmonary artery catheter before cardiopulmonary bypass (CPB), 30 min after completion of CPB and 6 h later in the intensive care unit (ICU). A catheter placed into the coronary sinus was used for blood sampling for measurement of lactate and creatine phosphokinase MB. Peripheral blood was obtained for measurement of xanthine oxidase activity (XO), uric acid, and thiol groups. A myocardial biopsy was taken for measurement of thiol group content and XO before CPB and after heparin neutralization with protamin (a few minutes after CPB). Treated patients had better recovery of cardiac output (CO) and left ventricular stroke work (LVSW) 30 min and 6 h after completion of CPB than did controls. Allopurinol significantly reduced plasma XO. Plasma concentrations of uric acid increased significantly in both groups 30 min after completion of CPB, but the increase in controls was greater (p < 0.02) than with allopurinol. Thiol group levels increased (p < 0.05) only in controls. Our results demonstrate improvement of cardiac function in coronary artery bypass surgery with allopurinol that is related to its metabolic effects consistent with protection against XO catalyzed free radical-mediated injury.
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PMID:Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. 772 40

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

Oxygen free radicals are cytotoxic and generated in excessive quantities during reoxygenation of ischemic organs. It has been demonstrated that oxygen free radicals impair cardiac contractile mechanisms in in vitro studies as well as depress myocardial contractility in in vivo experiments. The objectives of the present studies are to evaluate alterations in cardiac contractility and hemodynamics in two canine models of shock, namely, Wigger's model of hemorrhage and splanchnic artery occlusion (SAO) model. The data obtained in these models are comparatively evaluated with that caused by oxygen free radicals. Pentobarbital anesthetized dogs were instrumented to record blood pressure, heart rate, left ventricular pressure, (LVP & LVEDP) and LVdp/dt. Contractility index was evaluated as max dp/dt.p. In the Wigger's model, during the period of hemorrhage or after reinfusion of the shed blood despite marked variations in preload and afterload, index of contractility was not altered. Similarly, in the SAO model also, during the period of occlusion or after release, contractility index was not depressed. However, in both the models, after reinfusion of the blood (Wigger's) or after release of splanchnic arteries, there were gradual deteriorations of stroke volume, cardiac output, and arterial blood pressure. In contrast, after generation of free radicals by exogenous administration of xanthine plus xanthine oxidase, cardiac contractility was significantly depressed leading to decreases in stroke volume, cardiac output, and blood pressure. Using identical procedures to evaluate contractility, we have demonstrated that the initial depression of myocardial contractility was not the causative factor for circulatory failure in the two models of shock.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative evaluation of the acute effects of oxygen free radicals on myocardial contractility in anesthetized dogs with those occurring in the early stages of splanchnic artery occlusion and hemorrhagic shock. 795 76

Shichimotsu-koka-to, a Chinese herb, is a medicine prescribed to treat patients with hypertension. We investigated the effects of Shichimotsu-koka-to on the lesions of stroke-prone spontaneously hypertensive rats (SHRSP). The SHRSP were given 1% or 2% Shichimotsu-koka-to solution (1 g/kg/day or 2 g/kg/day) instead of drinking water from 8 to 42 weeks of age. When the 2 g/kg/day Shichimotsu-koka-to was chronically administered to the SHRSP, their life span was significantly prolonged by prevention of stroke, but there was no effect on blood pressure. The Shichimotsu-koka-to treatment decreased superoxide dismutase (SOD) activities in the cytosol of the cerebral cortex and increased SOD activities in the cytosol of the brain stem. The treatment with 2 g/kg/day Shichimotsu-koka-to decreased xanthine oxidase (XOD) activities in the cytosol of the cerebral cortex, and Shichimotsu-koka-to quenched superoxide anion (O2-) as determined by electron spin resonance analysis in vitro. In addition, SOD activities in the cytosol of the cerebral cortex of SHRSP not administered Shichimotsu-koka-to were increased by the drug in vitro. XOD activities in the cytosol of the cerebral cortex of SHRSP not administered Shichimotsu-koka-to were inhibited by this herb in vitro. These results suggest that these preventive effects of Shichimotsu-koka-to on the stroke in SHRSP are due its ability to scavenge O2- and to inhibit O2- production by the hypoxanthine-XOD system in the cytosol of the cerebral cortex.
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PMID:[Shichimotsu-koka-to prevents stroke and changes free-radical-related enzymes in stroke-prone spontaneously hypertensive rats (SHRSP)]. 881 Apr 92

It is well-known that, in ischemic cerebral injury, a free radical and its byproducts are generated by xanthine-xanthine oxidase system and eliminated by scavengers such as superoxide dismutase (SOD), catalase, uric acid and ascorbic acid. To investigate the possible involvement of the xanthine-xanthine oxidase system in hypertensive cerebral injury, we examined chronological changes in uric acid level in the cerebral cortex and the effects of the inhibition of xanthine oxidase or catalase using stroke-prone spontaneously hypertensive rats (SHRSP). In young SHRSP, uric acid content was lower than age-matched Wistar-Kyoto rats (WKY), but in mature SHRSP strongly exposed to oxidative stress uric acid content had risen dramatically. Administration of allopurinol, an inhibitor of xanthine oxidase, caused a marked decrease in uric acid content. In these SHRSP, cerebral injury was much more intense compared to the control group. On the other hand, administration of aminotriazole, an inhibitor of catalase, did not affect the brain pathology of SHRSP, in spite of a mild reduction in tissue uric acid content. These results suggest that the xanthine-xanthine oxidase system is not the major source of free radical generation in hypertensive cerebral injury. Moreover, the results also suggest that tissue uric acid may have a key role for the incidence of hypertensive cerebral injury in SHRSP.
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PMID:Acceleration of hypertensive cerebral injury by the inhibition of xanthine-xanthine oxidase system in stroke-prone spontaneously hypertensive rats. 914 Jul 8

Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.
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PMID:Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases. 946 46

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.
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PMID:Preventive effects of Shichimotsu-koka-to on renal lesions in stroke-prone spontaneously hypertensive rats. 978 38

It has been reported that the production of oxygen radicals mediated by xanthine oxidase (XO) is stimulated in hypertensive cardiovascular endothelium, suggesting involvement of oxidative stress in pathogenesis of hypertension. In this study we estimated the effect of nicardipine, a calcium blocker, on the oxidative stress and antioxidant activities in left ventricles from spontaneously hypertensive rat (SHR) and stroke-prone SHR (SHRSP). The activity of XO increased 3.5-fold in SHR and 6.2-fold in SHRSP compared to that in normal controls (WKY). Interestingly, the levels of glutathione (GSH) and the activity of its synthesizing enzyme (gamma-glutamylcysteine synthetase, gamma-GCS) elevated concomitantly in SHR and SHRSP: the level of GSH increased 1.2-fold in SHR and 1.3-fold in SHRSP. The activity of gamma-GCS was elevated 1.5-fold in SHR and 2.4-fold in SHRSP, accompanying an increase in the expression of its mRNA. Treatment of these rats with nicardipine, for 4 weeks improved blood pressure, from 176 +/- 10 to 140 +/- 8 mmHg in SHR, and from 201 +/- 11 to 167 +/- 5 mmHg in SHRSP, respectively, and decreased wet weight of heart, levels of GSH, and the activities of XO and gamma-GCS. Nicardipine reduced the expression of gamma-GCS mRNA. Collectively, these results suggest that reactive oxygen species produced by XO in hypertensive rat heart cause induction of the expression of gamma-GCS and nicardipine plays a role in reducing the oxidative stress in hypertensive heart.
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PMID:Nicardipine normalizes elevated levels of antioxidant activity in response to xanthine oxidase-induced oxidative stress in hypertensive rat heart. 979 May 16

Cerebral ischemia followed by oxygen reperfusion induces apoptosis in hippocampal neurons in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar Kyoto rats (WKY). The overproduction of oxygen-free radicals that occurs in the tissues of SHRSP is implicated in reoxygenation injury after hypoxia. Antioxidants inhibit reoxygenation injury in hippocampal slices, and temporal cortices in Alzheimer's disease increase sensitivity to oxygen-free radicals. Because this sensitivity may contribute to the development of the disease, we have studied hypoxia and oxygen reperfusion using cortical neurons isolated from WKY and SHRSP (at 15 days of gestation). We have tried to determine whether cortical neurons are damaged under these conditions, and whether neurons from SHRSP are more vulnerable than those from WKY. We have tried also to verify whether neuronal damage is minimized by vitamin E using the following techniques: (a) Trypan blue staining, (b) in situ staining of apoptosis, (c) ultrastructural examination, and (d) measurement of lactic dehydrogenase (LDH) activity in the bathing medium. Furthermore, we have examined the mechanisms involved in the development of neuronal damage and have studied ways of minimizing it. We demonstrated that 36 hours of hypoxia significantly increased the rate of cell death in SHRSP (p < 0.01), although 12 to 24 hours of hypoxia did not increase cell death in either WKY or SHRSP. In addition, 6 to 36 hours of hypoxia and 1.5 to 5 hours of oxygen reperfusion heavily damaged cells of both WKY and SHRSP, and most became apoptotic or necrotic. In contrast, cells incubated with 50 to 300 microg/ml of vitamin E remained intact, although 10 to 20 microg/ml of vitamin E did not totally preserve the cells. Moreover, vitamin E protected the neurons from high concentrations of sodium nitroprusside (nitric oxide donor) in a dose-dependent manner. Vitamin E, when added to the cells, increased in concentration in a time-dependent manner over a 24-hour period and in a dose-dependent manner below 200 microg/ml, and it was detected mostly in the mitochondria. We also demonstrated that serial treatments with allopurinol (a xanthine oxidase inhibitor) or superoxide dismutase preserved neurons during hypoxia and oxygen reperfusion. These data indicate that SHRSP neurons are weaker than WKY neurons in long-term hypoxia; oxygen radical generation occurs in the early minutes after reperfusion, and then the oxygen-free radicals cause heavy damage to the cells; and antioxidants including vitamin E react with the radicals, thereby preventing apoptosis and necrosis. Therefore, antioxidants appear to be the most important agents in lowering oxygen-free radical damage in cortical neurons.
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PMID:Vitamin E prevents apoptosis in cortical neurons during hypoxia and oxygen reperfusion. 984 Jun 16


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