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)

Lodoxamide tromethamine, an orphan antiallergy drug, inhibits degranulation of mast cells that reside in the myocardium and inhibits xanthine oxidase located in myocytes and predominantly in the vascular endothelium. The hypothesis evaluated was that lodoxamide tromethamine would attenuate oxygen free radical damage. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing 0, 1, 10, 100, or 1,000 mumol/L lodoxamide tromethamine at 37 degrees and 24 degrees C with ischemic times of 22 and 93 minutes, respectively. These ischemic intervals yielded 50% survival and 50% return of function in untreated hearts. Lodoxamide treatment alone at the onset of reperfusion was also studied. Performance end points were aortic flow, pressure, and coronary flow. Biochemical analyses included serotonin collected from coronary effluent as a marker of mast cell degranulation, uric acid for xanthine oxidase inhibition, myocardial adenosine triphosphate, and carbonyl group concentrations. Performance data demonstrated that lodoxamide was beneficial in a log-linear dose response when given continuously at both temperatures. Percent of preischemic values for untreated and maximal responses at 1,000 mumol/L of lodoxamide were as follows: a mortality of 50% in nontreated hearts versus 0%; aortic flow, 47% to 94% (37 degrees C), 46% to 86% (24 degrees C); cardiac output, 60% to 98% (37 degrees C), 58% to 97% (24 degrees C); adenosine triphosphate, 59% to 90% (37 degrees C), 48% to 65% (24 degrees C). Serotonin was undetectable from any hearts. Uric acid concentrations and carbonyl group content did not change with increasing dose. Lodoxamide demonstrated no benefit when given only during reperfusion, suggesting injury occurred at times other than reperfusion.
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PMID:Prevention of ischemia-reperfusion injury by the allergy drug lodoxamide tromethamine. 192 38

The effect of H2O2 on the active transport of serotonin (5-HT) by human platelets was investigated. Platelets were exposed to either a single dose of H2O2 or to H2O2 generated by the glucose/glucose oxidase or xanthine/xanthine oxidase enzyme systems. H2O2 (12.5 to 100 microM) produced a rapid, concentration-dependent and time-dependent increase in 5-HT transport which was maximal after a 2-min incubation and decreased with continued incubation. Catalase (1000 units) completely prevented H2O2-induced stimulation, and fluoxetine (1 microM) totally blocked 5-HT uptake into stimulated platelets. The glucose/glucose oxidase (3.12 to 100 milliunits) and the xanthine/xanthine oxidase system, superoxide dismutase (250 units) failed to alter the stimulation, whereas catalase (1000 units) effectively prevented the response. The kinetics of 5-HT transport indicated that H2O2 treatment did not alter the Km of 5-HT transport (Km control = 1.0 +/- 0.2 x 10(-6) M vs Km H2O2 = 1.1 +/- 0.1 x 10(-6) M) but markedly increased the maximal rate of 5-HT transport (Vmax control = 131.4 +/- 4.6 pmol/10(8) platelets/4 min vs Vmax H2O2 = 206.7 +/- 9.1 pmol/10(8) platelets/4 min). These data demonstrated that exposure of human platelets to H2O2 resulted in a stimulation of the active transport of 5-HT and suggested that H2O2 may function to regulate this process.
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PMID:Stimulation of the active transport of serotonin into human platelets by hydrogen peroxide. 216 92

The effect of oxidant stress on the active transport of serotonin (5-HT) into mouse platelets was examined. Oxidant stress was produced using either H2O2 or the xanthine-xanthine oxidase generating system that yields both superoxide anion and H2O2. H2O2 (6.25-100 microM) caused a rapid (2-4 min) stimulation of platelet 5-HT transport that returned to control levels after 15 min of incubation. Catalase (1500 U/ml) completely prevented the stimulation, and the hydroxyl radical trapping agents mannitol (1 nM) and thiourea (1 mM) failed to alter the stimulation. Fluoxetine (1 microM) totally blocked all 5-HT uptake into stimulated platelets. The xanthine-xanthine oxidase (3.12-25 mU/ml) generating system produced a response similar to that of H2O2. In this system, superoxide dismutase (250 U/ml) did not alter the stimulatory response, whereas catalase (1500 U/ml) totally prevented the stimulation. The kinetics of 5-HT transport showed that oxidant stress did not alter the Km of 5-HT transport (Km control = 8.0 +/- 1.0 x 10(-7) M versus Km H2O2 = 9.5 +/- 1.1 x 10(-7) M) but markedly increased the maximal rate of transport (Vmax control = 36.1 +/- 4.8 pmol/10(8) platelets/4 min versus Vmax H2O2 = 79.9 +/- 9.1 pmol/10(8) platelets/4 min). Washed platelets failed to be stimulated by H2O2; however, the addition of small amounts of plasma to the buffer medium fully restored the stimulating response to H2O2. These data suggest that a plasma factor regulates the active transport of 5-HT by platelets that are oxidatively stressed.
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PMID:Oxidant stress stimulates active transport of serotonin by platelets. 253 34

The purpose of this study was to evaluate in freely moving animals the effect of morphine on the 5-hydroxyindole oxidation current recorded in the nucleus raphe magnus (NRM) which is the origin of serotonergic control systems modulating the transmission of noxious inputs at the spinal level. A current recorded at 270-290 mV (peak 3), characteristic of 5-hydroxyindoleacetic acid (5-HIAA), was measured with treated multi-fiber carbon electrodes, using differential pulse (DPV) or differential normal pulse (DNPV) voltammetry. In control rats the amplitude of the peak remains constant for many hours. Morphine (10 mg/kg i.p.) caused a very significant increase which plateaued between 60 and 80 min (mean increase: 142 +/- 7% of control values); recovery was complete by about 3 h. Simultaneous injection of naloxone (1 mg/kg i.p.) completely abolished the effect of morphine. The peak 3 augmentation was still observed (151 +/- 5%) in rats pretreated with the xanthine oxidase inhibitor, allopurinol (12 mg/kg i.p.), but did not occur when animals were given an anaesthetic dose (450 mg/kg i.p.) of chloral hydrate. It is concluded that morphine clearly increases the metabolism of serotonin (5-HT) in the NRM, and one could speculate that the increase in 5-HIAA results from 5-HT release. Such a release could be due either to 5-HT terminals originating in the periaqueductal gray, or to somato-dendritic mechanisms. Thus the question remains as to the relationship between the activation of 5-HT metabolism in the NRM and previous neurochemical evidence for morphine-induced augmentation of 5-HT metabolism within the terminal area of serotonergic raphe-spinal pathways.
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PMID:Morphine increases 5-HT metabolism in the nucleus raphe magnus: an in vivo study in freely moving rats using 5-hydroxyindole electrochemical detection. 337 Apr 93

Adult Respiratory Distress Syndrome (ARDS) is a feared complication of trauma or sepsis, characterized by an interstitial and alveolar edema due to increased pulmonary microvascular permeability. In ARDS polymorphonuclear granulocytes (PMN) aggregate and accumulate in the pulmonary microvessels and activation of the complement system, especially C5a, is suggested to be of importance supporting this aggregation. Such complement activated PMN can increase vascular permeability, probably by initiating endothelial cell (EC) damage. Addition of PMN and C5a to cultured EC monolayers in vitro produced both morphological and functional EC damage. A similar EC damage could be reproduced in the absence of white cells by exposing EC monolayers to oxygen free radicals induced by xanthine and xanthine oxidase or hydrogen peroxide. High dose corticosteroid (HDC) administration has been advocated in shock and ARDS and it has been experimentally demonstrated that methylprednisolone or hydrocortisone at a concentration corresponding approximately to a dose of 30 mg/kg i.v. inhibited both PMN aggregation and adhesion to the endothelium. On the other hand, no effect of HDC on PMN thromboxane synthesis or cell membrane morphology alterations was found. It has been suggested that HDC increases PMN hydrophobicity and thus reduces the tendency of the white cells to adhere to the endothelium of the microvasculature. Furthermore, it has been demonstrated that HDC can inhibit PMN production of oxygen free radicals. Platelets seem to play a role in ARDS. Serotonin released from platelets increased the cytotoxic effect of PMN on EC more than 100% in vitro, and activated PMN seemed to recruit platelets and release vasoactive substances. On the other hand, platelet serotonin enhanced the adhesion of complement stimulated PMN to EC, thus creating a vicious circle. To conclude, complement activated PMN aggregate and adhere to the pulmonary microvascular EC which are injured by e.g. PMN-generated oxygen free radicals. Platelet aggregation and release of serotonin augments this injury and activated PMN probably stimulate platelet aggregation and release. Agents capable of diminishing PMN activation and aggregation, e.g. HDC, might be of value in attenuating these cell-cell interactions in ARDS.
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PMID:High dose corticosteroids and cell-cell interactions. 391 7

Biosensors sensitive for in vivo monitoring of serotonin (5-HT) in the CNS by differential normal pulse voltammetry were constructed by coating treated multicarbon fiber electrodes (mCFEs) with Nafion (N-mCFE). In vitro sensitivities of mCFE and N-mCFE were compared in solutions ranging from 5 nM to 20 microM of uric acid (UA), 5-hydroxyindoleacetic acid (5-HIAA), and 5-HT. The mCFEs were three to seven times less sensitive for 5-HIAA or UA than for 5-HT. Nafion treatment dramatically decreased sensitivity for 5-HIAA and UA of N-mCFEs (approximately 10(3) times), whereas it remained in the nanomolar range for 5-HT. In vivo, in the dorsal horn of the lumbar spinal cord of anesthetized rats, the monoamine oxidase inhibitor clorgyline (10 mg/kg i.p.) produced a reduction (55 +/- 3% at 180 min) of peak 3 of oxidation current (characteristic of 5-hydroxyindoles) monitored with mCFEs, but with N-mCFEs (in this latter case the peak was termed 3N) peak 3N increased to 135 +/- 5% at 180 min. The 5-HT release-inducer p-chloroamphetamine (PCA; 6 mg/kg i.p.) induced a slight (12 +/- 3% at 150 min) decrease in peak 3 measured with mCFEs, whereas with N-mCFEs PCA induced a rapid increase of peak 3N (137 +/- 6% at 90 min). The xanthine oxidase inhibitor allopurinol (10 mg/kg i.p.) produced a decrease (30 +/- 3% at 180 min) in peak 3 (mCFEs), but peak 3N (N-mCFEs) was not affected (106% at 180 min). After pretreatment with allopurinol, PCA also produced an increase (135 +/- 6% at 90 min) in peak 3N.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo electrochemical monitoring of serotonin in spinal dorsal horn with Nafion-coated multi-carbon fiber electrodes. 754 31

Exposure of serotonin (5-HT) to oxygen-derived free-radical-generating system, xanthine oxidase-hypoxanthine or to a Fenton reaction results in the formation of the neurotoxin, tryptamine-4,5-dione. In cultured embryonic chick brain neurons, incubation of tryptamine-4,5-dione or its ethyl carbonate derivative resulted in a dose-dependent neurotoxicity (1-100 microM). The addition of sulfhydryl compound, glutathione at 2 or 10 microM significantly enhanced the toxicity induced by 10 microM tryptamine-4,5-dione. On the contrary, glutathione at 10 microM decreased the neurotoxic effect caused by 10 microM 5,6- and 5,7-dihydroxytryptamine in the cultured neurons. The toxicity resulted from 5,6- and 5,7-dihydroxytryptamine could be fully prevented by a 5-HT uptake inhibitor, fluoxetine. However, the toxicity caused by tryptamine-4,5-dione and glutathione conjugate could not be blocked by fluoxetine (10 or 100 microM) or by a glutathione transferase inhibitor, boric acid/serine. The results indicate a different molecular mechanism among 5-HT derived neurotoxins and suggest that tryptamine-4,5-dione and/or its glutathione conjugate would cause neuronal damage, if they are formed in vivo.
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PMID:Neurotoxicity of free-radical-mediated serotonin neurotoxin in cultured embryonic chick brain neurons. 880 18

The effect of serotonin (5-HT) on the metabolism of infused 1-methylxanthine (1-MX), a putative substrate of capillary endothelial xanthine oxidase (XO), and on the distribution of infused fluorescent microspheres (15 microns) by the artificially constant-flow perfused rat hindlimb preparation was investigated. 1-MX (5-100 microM) caused a slight inhibition of oxygen uptake (Vo2) but was not vasoactive, either alone or with 5-HT. 1-MX was converted to 1-methylurate (1-MU) and this conversion was inhibited by allopurinol and xanthine. 5-HT (0.35 microM), which caused vasoconstriction and decreased Vo2, also inhibited the conversion of 1-MX, indicated by a lowered venous perfusate steady-state 1-MU:1-MX ratio from 1.14 +/- 0.02 to 0.71 +/- 0.02 (P < 0.001), which is equivalent to the rate of conversion decreasing from 0.83 +/- 0.03 to 0.63 +/- 0.05 nmol min-1 g-1. This change closely followed the time course for changes in Vo2 and perfusion pressure and all three changes reversed in parallel when 5-HT was removed. Recoveries of 1-MU plus 1-MX at all times were high (100 +/- 5%). 5-HT did not act to inhibit XO. When compared with vehicle alone, 5-HT had either no effect (plantairs, gastrocnemius white, tibialis, extensor digitorum longus, vastus and thigh), or increased microsphere content (soleus and gastrocnemius red, P < 0.05) of muscles with only bone showing a significant decrease (P < 0.05). Since 5-HT did not inhibit XO or alter the net flow to individual muscles in this constant-flow model, the inhibition of conversion of 1-MX to 1-MU is concluded to be the result of a 5-HT-mediated decrease in the access of 1-MX to capillary XO within individual muscles. Possibilities include the redirection of flow to capillaries either in muscle or in connective tissue closely associated with muscle, where resistance is low and effective surface area is less. 1-MX has potential as a marker for muscle nutritive flow.
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PMID:Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb. 936 58

We investigated the role of nitric oxide (NO) in the development of gastric mucosal lesions induced by serotonine (5-HT) in rats. Repeated subcutaneous administration of 5-HT (20 mg kg-1) produced damage in the stomach with severe edema in the submucosa. Gastric lesions induced by 5-HT were prevented by simultaneous administration of aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, as well as by methysergide, a 5-HT antagonist. In addition, the lesions were inhibited by pretreatment with the antioxidative drugs, such as allopurinol (a xanthine oxidase inhibitor) and hydroxyurea (a neutrophil reducing agent). Following 5-HT treatment, the Ca(2+)-independent NOS activity in the gastric mucosa was significantly increased within 6 h and remained elevated for 2 days thereafter. The serum NOx levels increased 12 h after the administration of 5-HT, reaching a peak 24 h later. Gastric mucosal thiobarbituric acid (TBA) reactants and myeloperoxidase (MPO) activity were also significantly increased after 2 days treatment with 5-HT. Our results suggest that: (1) the repeated administration of 5-HT induced inflammatory gastric lesions in the rat stomach; (2) iNOS is upreguated during 5-HT treatment, and NO produced by iNOS contributes to development of gastric lesions in response to 5-HT, in addition to the oxyradical formation, and (3) the deleterious role of NO in this model may be accounted for by a cytotoxic action of peroxynitrite that is formed in the presence of NO and superoxide radicals.
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PMID:Role of nitric oxide in pathogenesis of serotonine-induced gastric lesions in rats. 942 24

Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4, 4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo-1H,3H, 7H-purine (7) as the major products. These products differ from those formed in the HO*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine-4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4, 5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.
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PMID:Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders. 962 32


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