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)

Endotoxin injures bovine pulmonary endothelial cells in culture but the cytotoxicity is unaffected by a host of antiinflammatory drugs. We hypothesized that agents which could decrease intracellular concentrations of toxic metabolites of O2 would prevent endotoxin effects on cultured pulmonary artery endothelial cells. We measured endotoxin-induced release of lactate dehydrogenase (LDH) from and production of prostanoids by cultured bovine pulmonary endothelial cells in the presence and absence of dimethyl sulfoxide (DMSO) and the xanthine oxidase inhibitor allopurinol. Escherichia coli endotoxin (0.001-10 micrograms/ml) caused a dose-related release of LDH and stimulated production of both prostacyclin [measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] and prostaglandin E2 (PGE2). Both DMSO and allopurinol decreased endotoxin-induced LDH release; this effect was related to concentration of the drugs (0-2% for DMSO and 0-0.3 mg/ml for allopurinol). Both drugs also prevented endotoxin-induced changes in endothelial morphology. Endotoxin increased intracellular reduction of the redox dye nitro blue tetrazolium, caused intracellular oxidation of 2',7'-dichlorofluorescein diacetate and caused release of conjugated dienes from endothelial cells; both DMSO and allopurinol inhibited those responses. DMSO, but not allopurinol, prevented endotoxin-induced production of prostacyclin and PGE2 by endothelium. Direct injury of pulmonary endothelium by endotoxin is inhibited by two chemically dissimilar drugs which have a common potential for decreasing intracellular concentrations of toxic metabolites of O2; indirect evidence suggests that potential as a mechanism for the protective effects of the drugs.
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PMID:Antioxidants protect cultured bovine lung endothelial cells from injury by endotoxin. 365 44

The responses of pig aortic endothelial cells to sublethal doses of potentially toxic stimuli were investigated by monitoring K+ efflux, prostaglandin production, and the release of cytoplasmic purines. Xanthine plus xanthine oxidase reversibly stimulated these three parameters of endothelial cell function at doses that were not cytotoxic, as measured by chromium release, adenine uptake, and vital dye exclusion. The effects of xanthine plus xanthine oxidase were inhibited by catalase but not by superoxide dismutase, suggesting that H2O2 was responsible. Reagent H2O2 also reversibly stimulated K+ efflux, prostaglandin production, and the release of purines. The threshold concentration of H2O2 for these effects was approximately 10 microM, which was at least 30-fold lower than that which caused cytotoxicity. In addition to the direct effect of H2O2 in stimulating prostaglandin production (PGI2 and PGE2), prior exposure of endothelial cells to lower doses of H2O2 (less than 0.1 microM) at high oxygen tension inhibited the subsequent stimulation of prostaglandin production by ATP, A23187, and H2O2 itself. We conclude that H2O2 has substantial effects on endothelial physiology at doses up to 3,000-fold lower than those which induce cytotoxicity.
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PMID:Differential effects of hydrogen peroxide on indices of endothelial cell function. 636 99

Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive O2 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate O2-metabolite-induced pulmonary vasoconstriction. We found that O2 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27 +/- 4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels of thromboxane B2 (the stable metabolite of thromboxane A2) compared with only twofold increases in 6-keto-PGF1a (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4 +/- 1.5 mmHg). Furthermore, imidazole, a thromboxane synthetase inhibitor, also decreased O2-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in O2-metabolite-induced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree of vasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to O2 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.
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PMID:Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. 654 30

In addition to the hemodynamic components, the roles of various humoral factors have been emphasized in the progression of vascular and renal injury in hypertension. Radical scavenging properties have attracted much attention in this field. This article discusses the implication of antioxidant properties of the antihypertensive diuretic indapamide on renal injury in Dahl salt-sensitive (Dahl S) rats. Hydroxyl radicals, oxygen radicals toxic to cellular membranes, are eradicated by indapamide in different assay systems, e.g., reduction of alpha-alpha-diphenyl-beta-picrylhydrazyl, rat brain homogenate, or xanthine-xanthine oxidase systems. Such antioxidant effects of indapamide are primarily due to inhibition of lipid peroxidation induced by hydroxyl radicals, and this mechanism may stimulate prostacyclin generation through activation of prostacyclin synthase. In fact, the antioxidant properties of indapamide are well expressed in vivo as well; indapamide treatment reduced oxygen radicals in the kidney of Dahl S rats with hypertension. This was accompanied by a functional improvement of the kidney; decreases in urinary protein and n-acetylglucosaminidase excretion and an increase in glomerular filtration rate were observed. In addition, indapamide morphologically ameliorated the renal injury, and decreased glomerular sclerosis score, arterial injury, and renal tubular injury. Trichloromethiazide reduces blood pressure similar to that produced by indapamide. However, trichloromethiazide did not lead to reduction of oxygen radicals in the kidney, and did not improve the functional disturbance or morphological injury seen in Dahl S rats. These results indicate that indapamide has antioxidant properties, and in addition to blood pressure reduction, such radical scavenging effects may contribute to its beneficial effects on renal function in vivo.
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PMID:Oxygen radical scavengers and renal protection by indapamide diuretic in salt-induced hypertension of Dahl strain rats. 750 60

The growing evidence that glutamate may be an important agent mediating ischemic damage to neurons, led us to investigate the possible protective effects of pharmacological agents against glutamate in a model system of cortical neurons. In this study we examined, in particular, the cytoprotective effect of prostaglandins. Experiments were carried out in vitro by using rat cortical neurons in culture for 10 days. They were incubated for 3h with glutamate (10 microM) in the presence or absence of various pharmacological agents including prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-Keto-PGF1 alpha, carba-TXA2, carba-PGI2 and PGF2 alpha-methylester). Increase in lacticodehydrogenase (LDH) release into the culture medium has been measured as an index of cell injury. When neurons were incubated with glutamate they released LDH due to NMDA-receptor activation since D-L-2-amino-5-phosphonovaleric acid, a specific receptor antagonist, protected the cells. The protective activity of oxypurinol, amflutizole, superoxide dismutase, NG nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitrix oxide, as well as phospholipase A2 stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF2 alpha-methylester, afforded significant protection at concentrations between 0.1 and 10 microM. The order of potency of the prostanoids was: PGF2 alpha = PGE2 > Carba-TXA2 > PGE1 > PGD2 > PGI2 = Carba-PGI2 > 6-Keto-PGF1 alpha. Additional experiments showed that prostaglandins did not compete for the NMDA binding site and that they did not inhibit free radical-related membrane damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection by prostaglandins from glutamate toxicity in cortical neurons. 791 88

Reactive oxygen species have earlier been shown to induce vasoactive changes. In the present investigation we hypothesized that active oxygen intermediates would stimulate arachidonic acid metabolism and thereby influence the pulmonary circulation. Four groups of 8-week old pigs were studied after infusion of an oxygen radical generator. Haemodynamic changes were recorded, and thromboxane (TX)B2 (the stable metabolite of TXA2) and 6-keto-prostaglandin (PG)F1 alpha (the stable metabolite of prostacyclin, PGI2) measured by a radioimmunoassay technique after infusion of xanthine oxidase (XO) alone or in combination with pharmacological inhibitors. In the XO group pulmonary vascular resistance increased rapidly compared to baseline levels. Maximum resistance increase was 118.4 +/- 27.5%, 25 min after the XO infusion (p < 0.05 compared to baseline). The vasoconstriction was significantly attenuated after pretreatment with the cyclo-oxygenase inhibitor indomethacin. In this group the pulmonary resistance increase was 21.2 +/- 24.3% at 25 min (p < 0.01 vs. XO group). In a group given allopurinol (xanthine oxidase inhibitor), the resistance increased by 44.3 +/- 28.8% (p < 0.02 vs. XO group), and during catalase infusion (hydrogen peroxide scavenger), the increase was 52.9 +/- 24.2% (p < 0.01 vs. XO group). Along with the pulmonary vascular pressure augmentation, we measured 1.9 fold TXB2 and 2.2 fold 6-keto-PGF1 alpha concentration increases in the XO group. However, both TXB2 and 6-keto-PGF1 alpha formation was significantly inhibited by indomethacin (p < 0.01 respectively vs. XO group), allopurinol (p < 0.01 and p < 0.05 respectively vs. XO group) and catalase (p < 0.01 and p < 0.02 respectively vs. XO group).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen radicals stimulate thromboxane and prostacyclin synthesis and induce vasoconstriction in pig lungs. 821 Sep 66

The coagulation abnormality in patients with Lesch-Nyhan syndrome (LNS) prompted us to examine 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), a stable metabolite of prostacyclin (PGI2). Plasma levels of 6-keto PGF1 alpha were significantly low in 4 patients with LNS, but they were elevated after discontinuation of allopurinol. Other indicators of coagulation and fibrinolysis systems did not change after the discontinuation of allopurinol. PGI2 prevents the production of superoxide which is formed after cerebral ischemia. The potential source of superoxide is xanthine oxidase which is inhibited by allopurinol. It is assumed that plasma PGI2 increased in response to formed superoxide because xanthine oxidase inhibition was abolished after discontinuation of allopurinol.
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PMID:Decreased 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) in patients with Lesch-Nyhan syndrome. 827 55

Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.
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PMID:Possible radical scavenging properties of cicletanine and renal protection in Dahl salt sensitive rats. 834 28

It has been reported that vasodilatory prostaglandins have cytoprotective effects against various types of liver damage. We investigated the effects OP 2507, a stable analogue of prostaglandin I2, on carbon tetrachloride-induced liver damage in starved rats. Intraperitoneal administration of OP 2507 at 1,500 micrograms/kg lessened both an increase in serum alanine aminotransferase activity and an inhibition of starvation ketosis, both of which were induced by carbon tetrachloride. At lower doses, however, OP 2507 not only failed to ameliorate the carbon tetrachloride-induced changes, but it actually exaggerated them. Although the deterioration of carbon tetrachloride-induced liver damage by lower doses of OP 2507 was not statistically significant, it seems possible that OP 2507 has dual effects on carbon tetrachloride-induced liver damage. While none of the three agents cimetidine, reduced glutathione and deferoxamine, prevented increase in serum alanine aminotransferase activity induced with lower dose OP 2507, allopurinol had a tendency to prevent the increase, indicating that lower doses of OP 2507 may promote a reaction catalyzed by xanthine oxidase. We propose that both the co-administration of prostaglandins and other potentially hepatotoxic drugs, and the administration of prostaglandins to patients with drug-induced liver damage should be done carefully.
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PMID:Effects of OP 2507, a stable analogue of prostaglandin I2, on carbon tetrachloride-induced liver damage in starved rats. 872 10

The goal of the present study was to determine whether oxygen-derived free radicals contribute to baroreceptor dysfunction in atherosclerosis. Baroreceptor activity was measured from the carotid sinus nerve during pressure ramps in isolated carotid sinuses of anesthetized rabbits. Rabbits fed a 0.5% to 1.0% cholesterol diet for 7.9 +/- 0.4 months (mean +/- SE; range, 5.5 to 10) developed atherosclerotic lesions in the carotid sinuses. Maximum baroreceptor activity measured at 140 mm Hg and the slope of the pressure-activity curve were reduced in atherosclerotic (n = 15) compared with normal (n = 13) rabbits (425 +/- 34 versus 721 +/- 30 spikes per second and 6.2 +/- 0.6 versus 10.8 +/- 0.8 spikes per second per mm Hg, respectively, P < .05). The level of activity was inversely related to plasma cholesterol concentration (r = .86, P < .001) and total cholesterol load (plasma concentration x duration of diet, r = .92). Mean arterial pressure was normal in both groups. Exposure of the carotid sinus to the free-radical scavengers superoxide dismutase (SOD) and catalase significantly increased maximum baroreceptor activity by 25 +/- 4% in atherosclerotic rabbits (n = 6) but caused only small and irreversible changes in activity in normal rabbits (n = 8). Catalase alone but not SOD also increased baroreceptor activity in atherosclerotic rabbits (n = 7). Exposure of the carotid sinus of normal rabbits to exogenous free radicals generated from the reaction between xanthine and xanthine oxidase inhibited baroreceptor activity in a dose-dependent and reversible manner (n = 8, P < .05). The inhibition of activity was attenuated by SOD and catalase but was not attenuated by the inhibitor of hydroxyl radical formation, deferoxamine. Neither restoration of baroreceptor activity in atherosclerotic rabbits by catalase nor inhibition of activity by xanthine/xanthine oxidase could be explained by changes in the carotid pressure-diameter relation or prostacyclin formation. These results indicate that oxidant stress inhibits baroreceptor activity and that endogenous oxyradicals produced in atherosclerotic carotid sinuses contribute to baroreceptor dysfunction.
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PMID:Oxygen-derived free radicals contribute to baroreceptor dysfunction in atherosclerotic rabbits. 883 4


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