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)

The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.
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PMID:Inhibition of GABA-gated chloride channel function by arachidonic acid. 132 73

Human interferon-alpha A/D (Bg/II) (IFN-alpha A/D) and mouse interferon-gamma (IFN-gamma) are shown to induce xanthine dehydrogenase (XD) mRNA in L929 fibroblastic cells. XD mRNA accumulation after IFN-alpha A/D treatment is relatively fast, being already evident after 4 h and reaching its maximum after 24 h. IFN-alpha A/D is active in inducing XD mRNA at 0.1 unit/ml and it is maximally active at 10(3) units/ml. The half-life of the XD message is unaffected by IFN-alpha A/D treatment, whereas the transcriptional activity of the XD gene and the concentrations of XD heterogeneous nuclear RNA are increased by 2- and 6-fold respectively. The effect of IFN-alpha A/D on XD mRNA is insensitive to cycloheximide, suggesting that protein synthesis de novo is not required. Experiments conducted with specific inhibitors suggest that protein kinase C, cyclic AMP and arachidonic acid metabolites derived from lipoxygenase or cyclooxygenase do not act as second-messenger molecules in the induction of XD mRNA by IFN-alpha A/D. XD mRNA is also induced in NIH3T3 fibroblastic cells, but not in F9 teratocarcinoma or B16 melanoma cells after treatment with IFN-alpha A/D. NIH3T3 are the only cells so far tested that have detectable XD and xanthine oxidase activities under basal conditions and after IFN-alpha A/D treatment, although their responsiveness to the cytokine is much less than that observed in L929 cells.
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PMID:Interferons induce xanthine dehydrogenase gene expression in L929 cells. 137 96

Impaired endothelium-dependent relaxation occurs in diabetic rabbit aorta and normal aorta exposed to elevated concentrations of glucose and is prevented by cyclooxygenase inhibitors. The role of free radicals in the endothelial cell impairment was examined with free radical scavengers and in aortas from rabbits fed with probucol (1% wt/wt, a lipid-soluble antioxidant). Rings of aorta suspended for measurement of isometric tension were incubated for 6 h in control (5.5 mM) or elevated (44 mM) glucose. Impairment of endothelium-dependent relaxation to acetylcholine caused by exposure to elevated glucose was prevented by superoxide dismutase, catalase, deferoxamine, or allopurinol and did not occur in aortas from probucol-fed rabbits. Similarly, impairment of acetylcholine relaxations in aortas from alloxan-induced diabetic rabbits was restored to normal by superoxide dismutase. Oxygen-derived free radicals generated by xanthine oxidase also caused impaired acetylcholine relaxations. Exposure of aortic segments to elevated glucose or to xanthine oxidase caused a significant increase in release of immunoreactive prostanoids. These data indicate that the endothelial cell dysfunction caused by elevated glucose is mediated by free radicals that are likely generated through the increased cyclooxygenase catalysis occurring in the endothelium. Treatment with antioxidants protects against impaired endothelium-dependent relaxations caused by elevated glucose.
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PMID:Free radicals mediate endothelial cell dysfunction caused by elevated glucose. 151 Jan 28

The purpose of this study was to determine if the bronchoconstriction and airway hyperresponsiveness (AHR) resulting from aerosolized xanthine (x; 0.1%)-xanthine oxidase (xo; 4.1 U) and the subsequent production of oxygen radicals is mediated by the secondary generation of lipid mediators. In seven conscious sheep, specific lung resistance (SRL) was measured before and after x-xo challenge; approximately 30 min later when SRL had returned to baseline, airway responsiveness to carbachol was determined from dose-response curves by calculating the cumulative provocating dose of carbachol in breath units (BU, defined as one breath of a 1% wt/vol carbachol solution) that increased SRL 400% over baseline (PD400). Inhaled x-xo caused in immediate increase in SRL of 162 +/- 36% (mean +/- SE; p less than 0.05) over baseline and decreased PD400 from a baseline value of 32.5 +/- 5.0 to 16.6 +/- 1.7 BU (p less than 0.05). Pretreatment with the H2O2 scavenger, catalase (CAT,; 38 mg aerosol), methylprednisolone succinate (MS; 1 mg/kg given intravenously), the cyclooxygenase inhibitor, indomethacin (IND; 2 mg/kg given intravenously), and the PAF antagonist, WEB-2086 (3 mg/kg given intravenously) all attenuated the x-xo-induced increase in SRL (p less than 0.05); the leukotriene D4 antagonist, MK-571 (5 mg by aerosol) had no effect. All agents inhibited the x-xo-induced decrease in PD400: mean BUs were 27 after CAT, 32 after WEB-2086, 34 after IND, 31 after MS, and 25 after MK-571 (all p less than 0.05 versus x-xo alone).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid mediators contribute to oxygen-radical-induced airway responses in sheep. 174 41

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

Four pharmacological mechanisms for antagonizing free radical generation or reactions were compared in terms of their efficacy in attenuating hemorrhagic shock in rats. These included opposing superoxide generation by xanthine oxidase (e.g., oxypurinol), inhibiting arachidonic acid oxidation by cyclooxygenase (e.g., ibuprofen), chelating iron (e.g., desferal), and inhibiting lipid peroxidation (e.g., tirilazad mesylate [U-74006F] and U-78517G). Animals were hemorrhaged to a mean arterial pressure (MAP) of 43-45 mmHg where they were held for 2 hr. Five minutes prior to the end of the hemorrhage period, either vehicle, U-74006F (10 mg/kg), U-78517G (10 mg/kg), oxypurinol (10 or 25 mg/kg), desferal (10 or 25 mg/kg), or ibuprofen (10 mg/kg) was administered i.v., followed by the reinfusion of shed blood. In vehicle-treated animals, MAP declined progressively over the 2 hr post-reinfusion. Ibuprofen, desferal, and oxypurinol treatments each failed to attenuate this decline. In contrast, both U-74006F and U-78517G resulted in a significantly improved maintenance of MAP. Evidence of shock-induced lipid peroxidation was observed in terms of a 73.8% depletion in liver vitamin E content at 2 hr post-reinfusion in vehicle-treated rats. This decrease was prevented by both U-74006F and U-78517G. Inhibition of free radical-induced lipid peroxidation appears more effective for attenuating free radical pathophysiology in hemorrhagic shock that attempting to inhibit specific pathways of oxygen radical generation.
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PMID:Comparison of the efficacy of mechanistically different antioxidants in the rat hemorrhagic shock model. 177 58

Exposure of human lymphocyte cultures to superoxide generated by the xanthine-xanthine oxidase (X-XO) system, resulted in formation of a clastogenic factor (CF), as expected from previous work. We speculated that arachidonic acid (AA), the major polyunsaturated fatty acid of biological membranes, was oxidized via the cyclooxygenase-lipoxygenase pathways or nonenzymatically by oxygen free radicals in the culture medium to products with clastogenic properties. In the present study, we analyzed CF for AA-derived products and tested corresponding commercial standards for their clastogenic properties. The results show that prostaglandins, thromboxane, and H(P)ETEs were not increased in supernatants from X-XO treated cultures compared to untreated cultures. Synthetic H(P)ETEs added to the medium of lymphocyte cultures were only slightly or not clastogenic. In contrast hereto, the degradation product 4-hydroxynonenal was found in 50% of CF samples, while it was absent in all 43 control samples. The kinetics of detectability in the culture medium was similar to that of CF. Also, the clastogenic effect of synthetic 4-hydroxynonenal at concentrations as low as 0.1 microM suggested that this aldehyde, known for its genotoxic effects, was a clastogenic component of CF. The indirect action mechanisms of 4-hydroxynonenal via inactivation of functional SH groups in DNA polymerases, may explain why chromatid-type damage is predominant in lymphocytes exposed to CF in the Go-G1 phase of the cell cycle. This particularly was already stressed 20 years ago in the first observations of radiation-induced CF. However, 4-hydroxynonenal is not the only clastogenic component of CF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydroxynonenal, a component of clastogenic factors? 190 88

Inhibitors of the arachidonic acid metabolism (AA) as well as scavengers of oxygen free radicals (OFR) have been shown to reduce myocardial infarct size. We investigated the effects of two inhibitors of AA metabolism on the cardiac effects of OFR. Isolated rat hearts were retrogradely perfused for 10 min with buffer containing hypoxanthine (HX, 1 mmol l-1) and xanthine oxidase (XOD: 24 U l-1) alone (n = 11), or with the addition of ibuprofen (IBU) (n = 6) (a cyclooxygenase inhibitor) or BW 755C (n = 6) (a dual inhibitor of cyclo-oxygenase and lipoxygenase). The hearts were observed for 30 min thereafter (total observation time 40 min). Left-ventricular pressures were measured by a balloon in the left ventricle. HX + XOD significantly reduced left-ventricular developed pressure (LVDP) and coronary flow (CF), but not heart rate. The reduction of LVDP and CF was not significantly ameliorated by the addition of IBU (7.6 x 10(-4) mol l-1) or BW 755C (2 x 10(-3) mmol l-1). OFR increased left-ventricular end-diastolic pressure (LVEDP) from (mean +/- SEM) 0 to 22 +/- 4 mmHg (10 min) and 30 +/- 5 mmHg (40 min). Upon addition of IBU, LVEDP increased from 0 to 24 +/- 8 mmHg and 17 +/- 6 mmHg at 10 and 40 min respectively. The addition of BW 755C almost completely inhibited the increase in LVEDP (1 +/- 1 mmHg and 3 +/- 3 mmHg at 10 min and 40 min). In conclusion, except for inhibition of OFR-induced diastolic dysfunction by BW 755C, neither BW 755C nor IBU appear to inhibit cardiac injury induced by OFR.
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PMID:Oxygen free radical-induced injury in isolated rat hearts: effects of ibuprofen and BW 755c. 194 22

We investigated the interaction between activated cat polymorphonuclear neutrophils (PMNs) and coronary vascular endothelial cells in vitro. It was shown that 1) 90 minutes of low-flow perfusion without reperfusion had no deleterious effects on endothelium-dependent vasodilation, whereas 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free solution induced a 20-25% endothelial dysfunction; 2) activated PMNs produced endothelium-dependent vasoconstriction in coronary artery rings isolated from cat hearts undergoing 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free Krebs-Henseleit solution; 3) addition of the superoxide free radical scavenger, superoxide dismutase (150 micrograms/ml), or an antibody directed against CD18 of PMN adherence glycoprotein complex (MAbR15.7, 20 micrograms/ml) attenuated PMN-induced vasoconstriction significantly, but addition of a hydroxyl radical scavenger [N-(2-mercaptopropionyl)-glycine, 150 micrograms/ml], a cyclooxygenase inhibitor, or a lipoxygenase inhibitor had no protective effect; 4) exposure of rings to a superoxide radical-generating system (i.e., xanthine and xanthine oxidase) produced significant vasoconstriction that was similar to that observed with activated PMNs and was inhibited by superoxide dismutase; and 5) activated PMNs produced a marked coronary endothelial dysfunction characterized by a decreased response to the endothelium-dependent vasodilators acetylcholine and A23187. Addition of either superoxide dismutase or MAbR15.7 protected against endothelial dysfunction. These results indicate that activated PMNs produce significant vasoconstriction and endothelial dysfunction in coronary arteries isolated from low-flow perfusion-reperfused hearts. These effects appear to be mediated primarily by superoxide radicals generated by activated PMNs that either inactivate or inhibit the synthesis and release of endothelium-derived relaxing factor. We conclude that activated PMNs are able to induce endothelial dysfunction by releasing free radicals and possibly other substances.
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PMID:Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion-reperfused cat coronary artery. 205 45

Reactive oxygen species alter pulmonary arterial vascular tone and cause changes in pulmonary vascular resistance. The objective of this investigation was to determine direct effects of oxygen radicals on the contractile properties of pulmonary arterial smooth muscle. Isolated pulmonary arterial rings from Sprague-Dawley rats were placed in tissue baths containing Earle's balanced salt solution (gassed with 95% O2 - 5% CO2, 37 degrees C, pH 7.4). Vessels were contracted with 80 mM KCl to establish maximum active force production (Po). All other responses were normalized as percentages of Po for comparative purposes. Reactive oxygen metabolites were generated enzymatically with either the xanthine oxidase (XO) reaction or the glucose oxidase (GO) reaction, or hydrogen peroxide (H2O2) was added directly to the muscle bath. Exposure to XO, GO, or to H2O2 resulted in a contractile response that was sustained during the 30-min exposure period. The muscle fully relaxed following removal of the reactive oxygen species. Resting tension remained unchanged throughout the experimental period, suggesting no functional change in membrane potential. The contractile response was dose dependent and was not prevented by either cyclooxygenase or lipoxygenase inhibition, or by removal of the endothelium. Pretreatment of vessels with superoxide dismutase (SOD) partially blocked the XO-induced contraction, while mannitol or deferoxamine had no effect on the response to XO. However, pretreatment with catalase (CAT) completely blocked the XO-induced contraction. These data suggest that superoxide ions and hydrogen peroxide are the major causative agents. Following O2-radical exposure, vessels showed a decrease in contractile responsiveness to 80 mM KCl (recovery response), suggesting damage to the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle. 208 2


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