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: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects on rat aorta of EUK-8, a salen-manganese complex with high superoxide dismutase and catalase activities, were investigated. EUK-8 protected the acetylcholine-induced relaxation of rat aortic rings from inhibition by superoxide anions and reduced H2O2-induced relaxation. Moreover, EUK-8 dose-dependently relaxed rat aorta precontracted with phenylephrine (10(-6) M) and decreased the vascular tone of noncontracted aortic rings. The relaxant effect of EUK-8 was significantly potentiated by endothelium abrasion and/or preincubation with N-nitro-L-arginine methyl ester (10(-5) M and 5 x 10(-4) M), an inhibitor of nitric oxide synthase. Indomethacin (10(-5) M) had no effect on the action of EUK-8, showing that it was not dependent on prostacyclin synthesis. Methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, partly abolished relaxation induced by EUK-8. Incubation of rat aorta with EUK-8 (10(-4) M) induced an increase in vascular cyclic AMP content. The lack of inhibition by dl-propranolol showed that adenylate cyclase activation by EUK-8 was not mediated through beta-adrenergic receptors. The inhibition of the effects of EUK-8 by tetraethylammonium (10(-2) M) and glibenclamide (10(-5) and 2 x 10(-5) M) showed the implication of potassium channels in the intracellular cascade triggered by EUK-8. The vasorelaxant activity of EUK-8 was neither affected by xanthine oxidase inhibition (incubation with oxypurinol 25 microM) nor by superoxide anion scavenging (incubation with oxypurinol 125 microM). Finally, the ligand for EUK-8 (EUK-8 without manganese), which has the same aromatic structure as EUK-8 without its antioxidant activities because of the absence of manganese, conversely potentiated phenylephrine-induced contraction of aortic rings. We conclude that the vasorelaxant effect of EUK-8 observed under our experimental conditions is essentially mediated through an activation of adenylate cyclase and soluble guanylate cyclase of smooth muscle cells and is different from a classical antioxidant effect of protection of nitric oxide.
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PMID:Vasodilatory effects of a salen-manganese complex with potent oxyradical scavenger activities. 907 25

The effects of nitrosothiol depleting compounds (p-hydroxymercuribenzoate, iodacetamide and ethacrynic acid), a guanylyl cyclase inhibitor (1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and nitric oxide (NO) scavenger agents (xanthine/xanthine oxidase and 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; carboxy-PTIO) on light-induced photorelaxation in rat thoracic aorta were investigated. Photorelaxation responses were decreased in the presence of nitrosothiol depleting compounds suggesting S-nitrosothiols as the tissue source of the NO, whereas reduction in photorelaxation by the guanylyl cyclase inhibitor and NO scavenger agents indicates involvement of both NO and cGMP in photorelaxation. In addition the sensitivity of photorelaxation to the voltage-gated potassium channel (KV) inhibitor, 4-aminopyridine, indicates that photorelaxation is mediated via a NO/cGMP-dependent, and, perhaps, direct light, activation of KV channels.
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PMID:Involvement of nitrosothiols, nitric oxide and voltage-gated K+ channels in photorelaxation of vascular smooth muscle. 965 85

Soluble guanylate cyclase (sGC), which is found in many cells and tissues, represents the receptor for the intra- and intercellular messenger molecule NO. Superoxide dismutase (SOD), an enzyme involved in the degradation of toxic superoxide radicals, has been proposed as a non-NO activator of sGC. Here we show that SOD stimulated sGC purified from bovine lung up to 10-fold. Activation by SOD was not influenced by the hydroxyl radical scavengers mannitol and DMSO. In contrast, the presence of the NO scavengers oxyhaemoglobin and 2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1-oxyl-3-oxide, as well as the O2(-)-generating system xanthine oxidase/hypoxanthine, led to inhibition of SOD-stimulated cGMP production. NO-insensitive sGC mutants were not influenced either by SOD or by xanthine oxidase. We have previously shown that sGC was stimulated by NO present in the normal atmosphere. Here we show that the SOD effect depended on the NO concentration from the atmosphere, as the stimulation of sGC by defined NO gases (0, 120, 330 and 1000 parts per billion NO) was potentiated by SOD. NO stimulation of sGC and its potentiation by SOD were inhibited by oxyhaemoglobin to identical levels. We conclude that the SOD-mediated stimulation of sGC is due to the elimination of superoxide, thereby preventing its reaction with NO to form peroxynitrite.
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PMID:Stimulation of soluble guanylate cyclase by superoxide dismutase is mediated by NO. 979 91

Reactive oxygen species such as superoxides, hydrogen peroxide (H2O2) and hydroxyl radicals have been suggested to be involved in the catalytic action of nitric oxide synthase (NOS) to produce NO from L-arginine. An examination was conducted on the effects of oxygen radical scavengers and oxygen radical-generating systems on the activity of neuronal NOS and guanylate cyclase (GC) in rat brains and NOS from the activated murine macrophage cell line J774. Catalase and superoxide dismutase (SOD) showed no significant effects on NOS or GC activity. Nitroblue tetrazolium (NBT, known as a superoxide radical scavenger) and peroxidase (POD) inhibited NOS, but their inhibitory actions were removed by increasing the concentration of arginine or NADPH respectively, in the reaction mixture. NOS and NO-dependent GC were inactivated by ascorbate/FeSO4 (a metal-catalyzed oxidation system), 2'2'-azobis-amidinopropane (a peroxy radical producer), and xanthine/xanthine oxidase (a superoxide generating system). The effects of oxygen radicals or antioxidants on the two isoforms of NOS were almost similar. However, H2O2 activated GC in a dose-dependent manner from 100 microM to 1 mM without significant effects on NOS. H2O2-induced GC activation was blocked by catalase. These results suggested that oxygen radicals inhibited NOS and GC, but H2O2 could activate GC directly.
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PMID:The effects of oxygen radicals on the activity of nitric oxide synthase and guanylate cyclase. 989 52

Transforming growth factor (TGF)-beta1 is a growth factor involved in the mechanisms of lung repair and fibrosis that follow inflammatory processes. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) or reactive nitrogen intermediates (RNI) by inflammatory cells and the expression of TGF-beta1 by alveolar epithelial cells. Exposure of the A549 lung epithelial cell line to either an ROI generating system (xanthine and xanthine oxidase) or an RNI donor (S-nitroso-N-acetyl-penicillamine [SNAP]) promoted a time- and dose-dependent increase in TGF-beta1 release, as measured by a specific enzyme-linked immunosorbent assay. At the peak, the levels of TGF-beta1 were twice the control values. The induction of TGF-beta1 release by ROI was blunted by catalase and unaffected by superoxide dismutase, indicating the involvement of hydrogen peroxide. The response was also blunted by 5, 6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB), a specific RNA polymerase II inhibitor, and accompanied by a corresponding increase in TGF-beta1 messenger RNA, as measured by quantitative/competitive reverse transcription polymerase chain reaction, suggesting the involvement of transcriptional mechanisms and possibly other downstream mechanisms. In contrast, RNI-induced TGF-beta1 release was unaffected by DRB and blunted by the protein synthesis inhibitor cycloheximide, suggesting the involvement of translational and post-translational mechanisms. This response required cyclic guanosine monophosphate (cGMP)- mediated processes because (1) immunoreactive cGMP accumulated in the culture medium of SNAP-treated cells; (2) SNAP-induced TGF-beta1 release was blunted by KT 5823, an inhibitor of cGMP-dependent protein kinase; and (3) similar increase in TGF-beta1 release was obtained by cell exposure to membrane-permeable dibutyryl-cGMP or to atrial natriuretic factor, a known agonist of particulate guanylate cyclase. These data suggest that in vitro exposure of human alveolar epithelial cells to ROI and RNI enhances TGF-beta1 release through different mechanisms. In vivo, this control may constitute a molecular link between inflammatory and fibrotic processes.
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PMID:Reactive oxygen and nitrogen intermediates increase transforming growth factor-beta1 release from human epithelial alveolar cells through two different mechanisms. 1038 1

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 effects of superoxide anion generators, the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoine-1-oxyl 3-oxide (carboxy-PTIO), the specific guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ), and thiol modulating agents were investigated on relaxations induced by nitrergic stimulation and exogenous NO addition in the sheep urethra. Methylene blue (MB, 10 microM), pyrogallol (0.1 mM) and xanthine (X, 0.1 mM)/xanthine oxidase (XO, 0.1 u ml(-1)) inhibited NO-mediated relaxations, without affecting those induced by nitrergic stimulation. This resistance was not diminished following inhibition of endogenous Cu/Zn superoxide dismutase (Cu/Zn SOD) with diethyldithiocarbamic acid (DETCA, 3 mM), which almost abolished tissue SOD activity. Carboxy-PTIO (0.1 - 0.5 mM) inhibited NO-mediated relaxations but had no effect on responses to nitrergic stimulation, which were not changed by treatment with ascorbate oxidase (2 u ml(-1)). Relaxations to NO were reduced, but not abolished, by ODQ (10 microM), while nitrergic responses were completely blocked. The thiol modulators, ethacrynic acid (0.1 mM), diamide (1.5 mM), or 5,5'-dithio-bis (2-nitrobenzoic acid) (DTNB, 0. 5 mM), and subsequent treatment with dithiothreitol (DTT, 2 mM) had no effect on responses to nitrergic stimulation or NO. In contrast, N-ethylmaleimide (NEM, 0.2 mM) markedly inhibited both relaxations. L-cysteine (L-cys, 0.1 mM) had no effect on responses to NO, while it inhibited those to nitrergic stimulation, in a Cu/Zn SOD-independent manner. Our results do not support the view that the urethral nitrergic transmitter is free NO, and the possibility that another compound is acting as mediator still remains open. British Journal of Pharmacology (2000) 129, 53 - 62
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PMID:Effects of superoxide anion generators and thiol modulators on nitrergic transmission and relaxation to exogenous nitric oxide in the sheep urethra. 1069 2

Individual reactive oxygen species (ROS) and oxidation products of NO interact with vascular signaling mechanisms in ways that appear to have fundamental roles in the control of vascular physiological and pathophysiological function. The activities of ROS-producing systems (including various NADPH and NADH oxidases, xanthine oxidase, and NO synthase) in endothelium and/or vascular smooth muscle are controlled by receptor activation, oxygen tension, metabolic processes, and physiological forces associated with blood pressure and flow. This review focuses on how the chemical properties and metabolic sensing interactions of individual ROS (including superoxide anion, hydrogen peroxide, and peroxynitrite) interact with cellular regulatory systems to produce vascular responses. These species appear to often function through producing selective alterations in individual heme or thiol redox-regulated systems (including guanylate cyclase, cyclooxygenase, mitochondrial electron transport, and tyrosine phosphatases) to initiate physiological responses through signaling pathways that control phospholipases, protein kinases, ion channels, contractile proteins, and gene expression.
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PMID:Interactions of oxidants with vascular signaling systems. 1084 55

We have recently reported that the nitric oxide (NO) donor, sodium nitroprusside (SNP), induces seizures which are associated with an increase in the basal release of aspartate and glutamate from rat hippocampus (Kaku et al., 1998). In order to determine whether taurine release occurs with SNP-induced seizures, we examined the effects of NO-related compounds, i.e., the NO trapper, diethyldithiocarbamate (DETC), the superoxide radical scavenger, dithiothreitol (DTT), the xanthine oxidase inhibitor, oxypurinol and the guanylyl cyclase inhibitor, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ), on SNP-induced seizures and in vivo taurine release from rat hippocampus using microdialysis. Perfusion with 0.5mM SNP provoked seizures and significantly increased taurine release, with the increase in release occurring primarily during reperfusion with artificial cerebrospinal fluid lacking SNP. Perfusion with 5mM DETC significantly abolished the SNP-induced seizures and reduced taurine release during and after perfusion with the drugs. Perfusion with 1mM DTT significantly reduced both the frequency of the SNP-induced seizures and taurine release during and after perfusion with the drugs. Perfusion with 1 mM oxypurinol or 0.5 mM ODQ did not reduce the frequency of the SNP-induced seizures, but tended to decrease taurine release during and after perfusion with the drugs. These results demonstrate that SNP-induced seizures are triggered by an increase in both NO and peroxynitrite and are related to an increase in taurine release from rat hippocampus.
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PMID:Sodium nitroprusside-induced seizure and taurine release from rat hippocampus. 1114 Mar 58

Oxygen-derived free radicals have been implicated in the pathogenesis of myocardial injury. We therefore investigated the pathophysiology of myocardial injury induced in isolated rat hearts by perfusion with superoxide radical generated by reacting 2.5 mmol/l purine, 0.03 U/ml xanthine oxidase and 300 U/ml catalase. Perfusion with superoxide significantly (P<0.05) increased left ventricular end-diastolic pressure within 15 to 20 min. During the same time period, heart rate and left-ventricular developed pressure significantly declined to 44.6+/-8.2% and 31.0+/-4.9% of control, respectively. Superoxide perfusion also significantly increased production of prostaglandins, nitric oxide (detected as nitrites) and peroxynitrite (detected immunohistochemically as nitrotyrosine). N(G)-nitro-l-arginine (100 micromol/l), a nitric oxide synthase inhibitor, attenuated superoxide-induced generation of peroxynitrite, increased synthesis of prostacyclin, and partially blocked myocardial dysfunction, as did 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 micromol/l), a selective inhibitor of soluble guanylate cyclase, and ONO-3708 (10 micromol/l), a selective thromboxane A(2)receptor antagonist. In contrast, nitroglycerin (4 micromol/l) and sodium nitroprusside (1 micromol/l) each exacerbated the superoxide-induced myocardial dysfunction. These results suggest that nitric oxide and related reactive species contribute to myocardial injury induced by superoxide. Moreover, they suggest that oxidative stress can be delayed or inhibited by reducing levels of nitric oxide, by inhibiting soluble guanylate cyclase, and by blocking thromboxane/prostaglandin receptors.
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PMID:Prostaglandins and nitric oxide mediate superoxide-induced myocardial contractile dysfunction in isolated rat hearts. 1144 16


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