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: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the plant product magnolol on neutrophil superoxide anion (O2-*) generation has been investigated in the rat. Intraperitoneal injection of magnolol (30mg kg(-1)) significantly inhibited the formylmethionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat whole blood ex-vivo. Magnolol also inhibited the 02-* generation with an IC50 (concentration resulting in 50% inhibition) of 15.4+/-1.6 microM and O2 consumption in rat neutrophils in-vitro. Magnolol weakly inhibited the O2-* generation in the xanthine-xanthine oxidase system, decreased cellular cyclic AMP level and had no effect on cyclic GMP levels. It weakly inhibited neutrophil cytosolic protein kinase C activity but did not alter porcine heart protein kinase A activity. Magnolol attenuated fMLP-induced protein tyrosine phosphorylation with an IC50 of 24.0+/-1.9 microM and the phosphorylation of mitogen-activated protein kinase p42/44 with an IC50 of 28.5+/-4.5 microM. However, magnolol alone activated neutrophil phospholipase D activity as determined by the formation of phosphatidic acid and phosphatidyl-ethanol in the presence of ethanol. In the presence of NADPH, the arachidonate-activated NADPH oxidase activity in a cell-free system was weakly suppressed by magnolol. These results suggest that the inhibition of respiratory burst in fMLP-activated neutrophils by magnolol is probably attributable mainly to the attenuation of protein tyrosine phosphorylation and p42/44 mitogen-activated protein kinase activation, and partly to the suppression of protein kinase C and NADPH oxidase activities.
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PMID:Inhibition by magnolol of formylmethionyl-leucyl-phenyl alanine-induced respiratory burst in rat neutrophils. 1034 29

1. The effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) on tension, levels of cyclic GMP and cyclic AMP were investigated in guinea-pig trachea. We especially studied the combined effect of YC-1 with exogenous or endogenous nitric oxide on these parameters. 2. YC-1 at the concentration 3 or 10 microM, which caused only minor effect by itself, elicited concentration-dependent potentiation of sodium nitroprusside (SNP)-induced tracheal relaxation. This relaxation of YC-1 with SNP was reversed by ODQ. 3. Relaxant responses to electric field stimulation (EFS) in the presence of indomethacin, atropine, guanethidine, alpha-chymotrypsin and histamine were also markedly increased by YC-1 (10 microM). In the presence of L-NAME or ODQ, the relaxant effects to EFS were attenuated and the following addition of YC-1 did not further enhance relaxation. 4. YC-1 (10 microM) or SNP (0.3 microM) alone did not induce significant elevation of cyclic GMP levels in the presence of IBMX, whereas simultaneous application of both compounds markedly elevated the cyclic GMP accumulation. In contrast, the cyclic AMP levels were not altered even at the combination of YC-1 and SNP. Additionally, YC-1 also affected cyclic GMP metabolism, since it inhibited the activity of phosphodiesterase type V in human platelets. 5. YC-1 (30 microM) did not scavenge superoxide anion and had no effect on the removal of superoxide anion by superoxide dismutase in a xanthine/xanthine oxidase system. 6. In conclusion, these results indicate that although YC-1 elicits negligible relaxation of guinea-pig trachea by itself, it can potentiate the relaxant responses of exogenous or endogenous NO. This synergistic response of YC-1 is via the elevation of cyclic GMP contents.
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PMID:YC-1 potentiates nitric oxide-induced relaxation in guinea-pig trachea. 1051 35

1 In order to understand mechanisms that limit the safe ischaemic time of donor hearts, this study evaluated NO/cyclic GMP biosignalling in the recovery of function after cardioplegia and hypothermic storage. 2 Hearts removed from anaesthetized rats were either perfused in working mode (Fresh) or arrested (St. Thomas' II cardioplegia) and stored at 3 degrees C for 8 h (CPL) prior to working mode perfusion. LV work and indices of the production of NO (Ca2+-dependent and Ca2+-independent NOS), cyclic GMP (soluble guanylyl cyclase (sGC) and GTP) and superoxide (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)) were measured. 3 Relative to Fresh hearts, CPL hearts were deficient in cyclic GMP and had poor function. Correction of cyclic GMP deficiency (SNP, 200 microM) improved LV work and LV compliance. SNP effects were prevented by inhibition of sGC (ODQ, 3 microM), and potentiated by inhibition of cyclic GMP-dependent phosphodiesterase (zaprinast, 20 microM). SNP (200 microM) had no effect on function of Fresh hearts. 4 NOS activities (pH = 7.2) were similar in CPL and Fresh hearts, but at end-ischaemic pH (6.3), Ca2+-dependent NOS activity was reduced. The sensitivity of sGC to SNP was greater, and activities of XO and XDH were higher, in CPL than in Fresh hearts. 5 The deficiency in NO biosignalling in CPL hearts may arise due to acidosis-induced inhibition of NOS activity, reduced availability of GTP and/or enhanced inactivation of NO by superoxide. These findings provide rationales for novel strategies to prevent the deficiency in NO biosignalling and so improve the function of the transplanted heart.
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PMID:Deficiency in myocardial NO biosignalling after cardioplegic arrest: mechanisms and contribution to post-storage mechanical dysfunction. 1055 23

The effects of hypoxanthine and xanthine oxidase-induced superoxide anion were evaluated on various signal transduction pathways in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Superoxide increased inositol 1,4,5-tris-phosphate (IP(3)) formation in a concentration- and time-dependent manner in both strains but more markedly in SMCs from SHR. Various antioxidants significantly decreased the superoxide-induced IP(3) formation in both strains. In addition, tyrosine kinase inhibitors, genistein and tyrphostin A25, inhibited the superoxide-induced IP(3) formation more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced by S-nitroso-N-acetylpenicillamine. In addition, the superoxide-induced increase in IP(3) formation was significantly inhibited by guanylyl cyclase stimulator S-nitroso-N-acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) and KT5823 (a cGMP-dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the superoxide-enhanced IP(3) formation was not accompanied by simultaneous changes in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the superoxide-induced IP(3) formation. Our results thus demonstrate a stimulatory effect of superoxide on IP(3) formation, mediated by the tyrosine kinase-coupled phospholipase C(gamma) activity, and an inhibitory effect of superoxide on cGMP formation in vascular SMCs. The increased reactivity of the phospholipase C pathway and the decreased cross inhibition of the IP(3) pathway by cGMP in the presence of superoxide may underlie the altered functions of vascular SMCs in SHR.
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PMID:Effects of superoxide on signaling pathways in smooth muscle cells from rats. 1060 Nov 26

The present study examined some possible mechanisms underlying the previously demonstrated release of adenosine by nitric oxide (NO) donors. Perfusion with the NO-donor S-nitroso-N-acetyl penicillamine (SNAP; 300 microM) led to a significant increase in the release of [3H]purines from both unstimulated and electrically stimulated hippocampal slices prelabeled with [3H]adenine. The NO-donor also evoked the release of endogenous ATP and ADP from unstimulated slices and, when combined with electrical stimulation, the release of ATP, AMP and adenosine. The SNAP-induced [3H]purine release was calcium-dependent, but not affected by the glutamate receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]-cyclohepten-5,10-imine;100 nM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 10 microM). Zaprinast (5 microM), an inhibitor of the cyclic GMP-dependent phosphodiesterase and 8-Br-cyclic GMP (0.01-1 mM) failed to evoke the release of purines, whereas generation of oxygen free radicals by xanthine plus xanthine oxidase did evoke purine release. Coperfusion of SNAP with the free radical scavengers superoxide dismutase (SOD; 60 microg/ml) and catalase (50 microg/ml) reduced or eliminated the ability of the NO-donor to enhance [3H]purine release, but the poly (ADP-ribosyl) synthetase (PARS) inhibitor benzamide (500 microM) did not affect it. These data indicate that NO interacts with superoxide, likely forming peroxynitrite, which subsequently acts to release adenosine and adenine nucleotides from hippocampal tissue.
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PMID:Nitric oxide interacts with oxygen free radicals to evoke the release of adenosine and adenine nucleotides from rat hippocampal slices. 1086 5

The mechanism by which exogenous tetrahydrobiopterin (BH(4)) impairs the action of endothelial nitric oxide (NO) in the presence of platelets was investigated. The endothelial NO generated by shear stress was determined by the anti-aggregating activity of indomethacin-treated endothelial cells and the cyclic GMP concentration in platelets. The inhibitory effect of exogenous BH(4) was suppressed by superoxide dismutase (SOD), or diclofenac sodium at concentrations inhibiting O(2)(-) generation, but not by allopurinol, a xanthine oxidase inhibitor. BH(4) similarly inhibited the anti-aggregatory effect of sodium nitroprusside (SNP), a NO donor. The inhibitory effect was suppressed by diphenyleneiodonium, a specific inhibitor of NADPH oxidase. Six(S)-BH(4), an inactive diastereoisomer of 6(R)-BH(4), and the 5,6,7,8-tetrahydropterin compounds inhibited the endothelial NO action, whereas sepiapterin and 7,8-dihydrobiopterin (BH(2)), 5,6-double bond pterins, were inactive. These tetrahydropterins, but not sepiapterin and BH(2), scavenged superoxide (O(2)(-)) generated by the hypoxanthine-xanthine oxidase reaction, possibly due to electron transfer during oxidation to its quinonoid-form. BH(4) markedly stimulated the O(2)(-) generation from platelets, in the presence of NADH, rather than that of NADPH. These findings suggest that BH(4) stimulates platelet NAD(P)H oxidase to generate O(2)(-), and inhibits the anti-aggregating effect of NO. SOD activity in the local environment may modify the effect of BH(4) on the endothelial NO activity.
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PMID:Tetrahydrobiopterin impairs the action of endothelial nitric oxide via superoxide derived from platelets. 1105 17

Chrysin relaxed the contractions induced by noradrenaline in isolated endothelium-intact rat aortic rings (IC(50) = 16 +/- 4 microM). Endothelium removal and N(G)-nitro-L-arginine methyl ester inhibited this relaxant effect. Chrysin potentiated the relaxation to acetylcholine under control conditions or after incubation with the superoxide anion generator hypoxanthine/xanthine oxidase. It also potentiated the relaxation induced by 3-morpholino-sydnonimine, sodium nitroprusside, and 8-bromoguanosine-3':5'-cyclic-monophosphate. Therefore, vasorelaxation induced by chrysin in the rat aorta is endothelium- and NO-dependent. This effect is mediated by the prevention of O(2)(-)-induced inactivation of endothelial derived NO and also by the potentiation of cGMP-induced vasodilatation.
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PMID:Vasorelaxant effects of the bioflavonoid chrysin in isolated rat aorta. 1150 85

We have recently found evidence for impairment of nitric oxide (NO) formation and induction of oxidative stress in residents of an endemic area of chronic arsenic poisoning in Inner Mongolia, China. To investigate the underlying mechanisms responsible for these phenomena, a subchronic animal experiment was conducted using male New Zealand White rabbits. After 18 weeks of continuous exposure of rabbits to 5 mg/l of arsenate in drinking water, a significant decrease in systemic NO production occurred, as shown by significantly reduced plasma NO metabolites levels (76% of control) and a tendency towards decreased serum cGMP levels (81.4% of control). On the other hand, increased oxidative stress, as shown by significantly increased urinary hydrogen peroxide (H(2)O(2)) (120% of control), was observed in arsenate-exposed rabbits. In additional experiments measuring aortic tension, the addition of either the calcium ionophore A23187 or acethylcholine (ACh) induced a transient vasoconstriction of aortic rings prepared from arsenate-exposed rabbits, but not in those prepared from control animals. This calcium-dependent contractility action observed in aorta rings from arsenate-exposed rabbits was markedly attenuated by the superoxide (O2(.-)) scavenging enzyme Cu, Zn-SOD, as well as diphenyleneiodonium (DPI) or N(G)-nitro-L-arginine methyl ester (L-NAME), which are inhibitors for nitric oxide synthase (NOS). However, the cyclooxygenase inhibitor indomethacin or the xanthine oxidase blocker allopurinol had no effect on this vasoconstriction. These results suggest that arsenate-mediated reduction of systemic NO may be associated with the enzymatic uncoupling reaction of NOS with a subsequent enhancement of reactive oxygen species such as O2(.-), an endothelium-derived vasoconstricting factor. Furthermore, hepatic levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)), a cofactor for NOS, were markedly reduced in arsenate-exposed rabbits to 62% of control, while no significant change occurred in cardiac L-arginine levels. These results suggest that prolonged exposure of rabbits to oral arsenate may impair the bioavailability of BH(4) in endothelial cells and, as a consequence, disrupt the balance between NO and O2(.-) produced from endothelial NOS, such that enhanced free radicals are produced at the expense of NO.
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PMID:A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits. 1282 60

Vaso-occlusive events are the major source of morbidity and mortality in sickle cell disease (SCD); however, the pathogenic mechanisms driving these events remain unclear. Using hypoxia to induce pulmonary injury, we investigated mechanisms by which sickle hemoglobin increases susceptibility to lung injury in a murine model of SCD, where mice either exclusively express the human alpha/sickle beta-globin (halphabetaS) transgene (SCD mice) or are heterozygous for the normal murine beta-globin gene and express the halphabetaS transgene (mbeta+/-, halphabetaS+/-; heterozygote SCD mice). Under normoxia, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine, and cGMP than controls (C57BL/6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in lungs with a greater content of XO and nitrotyrosine. Under normoxia, the association of heat shock protein 90 (HSP90) with endothelial nitric oxide synthase (eNOS) in lungs of SCD and heterozygote SCD mice was decreased compared with the levels of association in lungs of controls. Hypoxia further decreased association of HSP90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the control lungs. Pretreatment of rat pulmonary microvascular endothelial cells in vitro with xanthine/XO decreased A-23187-stimulated nitrite + nitrate production and HSP90 interactions with eNOS. These data support the hypotheses that hypoxia increases XO release from ischemic tissues and that the local increase in XO-induced oxidative stress can then inhibit HSP90 interactions with eNOS, decreasing *NO generation and predisposing the lung to vaso-occlusion.
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PMID:Hypoxia-induced acute lung injury in murine models of sickle cell disease. 1500 34

Several experimental and clinical studies have demonstrated the antiatherogenic profile of the long-acting calcium antagonist amlodipine. Given the pivotal role of endothelial (dys)function during atherogenesis, we investigated the influence of amlodipine on endothelial nitric oxide (NO) bioavailability. Acute addition of amlodipine to segments of porcine coronary arteries resulted in a significant increase in NO release which could be blocked by the NO synthase inhibitor L-NMMA (N-monomethylarginine). This effect was mirrored by a rise in intracellular cGMP levels in porcine endothelial cell cultures. Long-term (24 h) treatment of porcine endothelial cell cultures with amlodipine (0.1-10 micromol/l) significantly enhanced the basal NO formation in a concentration-dependent manner which was abrogated in the presence of L-NMMA (0.1 mmol/l). In EA.hy 926 endothelial cells, amlodipine treatment for 24 h significantly increased the endothelial NO synthase protein expression. To evaluate whether the observed increase in NO was additionally due to an antioxidative protection of NO, we examined the influence of amlodipine in different in vitro models. In a cell-free system, amlodipine quenched superoxide anions (hypoxanthine/xanthine oxidase assay) at high concentrations (150 micromol/l). Addition of artificial membrane preparations (dimyristoylphosphatidylcholine) to mimic a physiological environment significantly enhanced this antioxidative effect. In a more physiological model of hyperglycemia (30 mmol/l, 20 min) induced formation of reactive oxygen species from native endothelial cells of porcine coronary arteries, amlodipine concentration dependently attenuated the reactive oxygen species release (>60%; 10 micromol/l). We conclude, that amlodipine increases the endothelial NO bioavailability, firstly via enhanced NO formation and secondly by prolonging the half-life of NO through antioxidative properties. This may result in an improved endothelial function.
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PMID:Amlodipine increases endothelial nitric oxide by dual mechanisms. 1464 55


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