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)

A variety of monovalent anions and cations were effective in stimulating both calcium ion/calmodulin (Ca2+/CaM)-independent NADPH-cytochrome c reductase activity of, and Ca2+/CaM-dependent nitric oxide (NO.) synthesis by, neuronal nitric oxide synthase (nNOS). The efficacy of the ions in stimulating both activities could be correlated, in general, with their efficacy in precipitating or stabilizing certain proteins, an order referred to as the Hofmeister ion series. In the hemoglobin capture assay, used for measurement of NO. production, apparent substrate inhibition by L-arginine was almost completely reversed by the addition of sodium perchlorate (NaClO4), one of the more effective protein-destabilizing agents tested. Examination of this phenomenon by the assay of L-arginine conversion to L-citrulline revealed that the stimulatory effect of NaClO4 on the reaction was observed only in the presence of oxyhemoglobin or superoxide anion (generated by xanthine and xanthine oxidase), both scavengers of NO. Spectrophotometric examination of nNOS revealed that the addition of NaClO4 and a superoxide-generating system, but neither alone, prevented the increase of heme absorption at 436 nm, which has been attributed to the nitrosyl complex. The data are consistent with the release of autoinhibitory NO. coordinated to the prosthetic group of nNOS, which, in conjunction with an NO. scavenger, causes stimulation of the reaction.
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PMID:The stimulatory effects of Hofmeister ions on the activities of neuronal nitric-oxide synthase. Apparent substrate inhibition by l-arginine is overcome in the presence of protein-destabilizing agents. 1002 50

Using a reversible chronic constriction injury (CCI) model of neuropathic pain, we previously demonstrated that changes in thermal hyperalgesia correlate with the changes in peripheral microvascular blood flow in the affected paw, and that recovery can be assessed by normalization of both behavioral and vascular responses. Using the same model, this study examined age-related changes in recovery after nerve injury and the involvement of free radicals and nitric oxide (NO) in these changes. Four loose, nonconstrictive ligatures were applied to the sciatic nerve in the right, mid-thigh region of young and old (3 and 24 months) Sprague Dawley rats. All rats were monitored weekly (for 8-10 weeks) for their thermal threshold using a 46 degrees C water bath and some groups were used to examine endothelial and smooth muscle-dependent microvascular responses to substance P (SP) and sodium nitroprusside (SNP), respectively. These substances were perfused over the base of blisters raised on the footpad innervated by the injured nerve. Free radical activity in the sciatic nerve was assessed by measuring the activity of xanthine oxidase (XO) and lipid hydroperoxides (LPO). Young rats showed signs of recovery (reduction in thermal hyperalgesia and improvement of peripheral microvascular blood flow) from the fifth week. No signs of recovery were observed in old rats for 8 weeks, with some reduction in thermal hyperalgesia observed by weeks 9 and 10. XO activity was significantly higher in young injured nerves compared to sham (400%) and was even significantly greater in old injured nerves (680%). Similarly, old injured nerves showed 300% increase in LPO levels compared to sham. The role of reactive oxygen species (ROS) in delayed recovery in old rats was examined using the antioxidant tirilazad mesylate. Tirilazad (20 mg/kg) was injected intramuscularly (im) in the mid-thigh region starting on day 1 post CCI, (early treatment) or day 7 (late treatment). Levels of LPO in the injured sciatic nerves were significantly reduced using either early or late treatment, however tirilazad had opposing effects on recovery, prolonging or alleviating thermal hyperalgesia, respectively. The role of neuronal nitric oxide (nNO) was then examined using the specific neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (3Br-7NI) (10 mg/kg). 3Br-7NI resulted in a significant alleviation of thermal hyperalgesia with improvement in the vascular responses from weeks 5 and 6 onwards. A combination of 3Br-7NI and tirilazad treatment was also used but did not show an additive effect. The results suggest that ROS and nNO contribute to delayed recovery of injured nerves in old rats and to the maintenance of thermal hyperalgesia and the reduction in microvascular blood flow in the area innervated by the injured nerve. The results also raise the notion that possible interaction of free radicals with NO to form peroxynitrite might be responsible for such delayed recovery. Ironically, this study also reveals a positive role for free radicals in tissue repair and raises the notion that early intervention with antioxidants could exert a negative effect on repair of injured nerves.
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PMID:A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. 1149 76

Many individuals with cardiac diseases undergo periodic physical conditioning with or without medication. Therefore, this study investigated the interaction of physical training and chronic nitric oxide synthase (NOS) inhibitor (nitro-L-arginine methyl ester, L-NAME) treatment on blood pressure (BP), heart rate (HR) and cardiac oxidant/antioxidant systems in rats. Fisher 344 rats were divided into four groups and treated as follows: (1) sedentary control (SC), (2) exercise training (ET) for 8 weeks, (3) L-NAME (10 mg/kg, s.c. for 8 weeks) and (4) ET+L-NAME. BP and HR were monitored with tail-cuff method. The animals were sacrificed 24 h after last treatments and hearts were isolated and analyzed. Physical conditioning significantly increased respiratory exchange ratio (RER), cardiac nitric oxide (NO) levels, NOS activity and endothelial (eNOS) and inducible (iNOS) protein expression. Training significantly enhanced cardiac glutathione (GSH) levels, GSH/GSSG ratio and up-regulation of cardiac copper/zinc-superoxide dismutase (CuZn-SOD), manganese (Mn)-SOD, catalase (CAT), glutathione peroxidase (GSH-Px) activity and protein expression. Training also caused depletion of cardiac malondialdehyde (MDA) and protein carbonyls. Chronic L-NAME administration resulted in depletion of cardiac NO level, NOS activity, eNOS, nNOS and iNOS protein expression, GSH/GSSG ratio and down-regulation of cardiac CuZn-SOD, Mn-SOD, CAT, GSH-PX, glutathione-S-transferase (GST) activity and protein expression. Chronic L-NAME administration enhanced cardiac xanthine oxidase (XO) activity, MDA levels and protein carbonyls. These biochemical changes were accompanied by increases in BP and HR after L-NAME administration. Interaction of training and NOS inhibitor treatment resulted in normalization of BP, HR and up-regulation of cardiac antioxidant defense system. The data suggest that physical conditioning attenuated the oxidative injury caused by chronic NOS inhibition by up-regulating the cardiac antioxidant defense system and lowering the BP and HR in rats.
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PMID:Oxidative injury due to chronic nitric oxide synthase inhibition in rat: effect of regular exercise on the heart. 1200 27

We have investigated the action of melatonin against lipid peroxidation in membranes including brain homogenates (BH), brain and liver microsomes (MIC), and phosphatidylcholine (PC) liposomes, as well as its effect on the activity of pro-oxidant enzymes such as constitutive neuronal nitric oxide synthase (cnNOS), xanthine oxidase (XO) and myeloperoxidase (MPO). The liposomes were reconstituted by a dialysis method, lipid peroxidation was monitored using the thiobarbituric reactive substances (TBARS) method and enzyme activities were measured spectrophotometrically. The ascorbyl and hydroxyl free radicals were generated by the reaction of ascorbic acid + FeSO4 and H2O2 + FeCl2, respectively, and peroxynitrite using a mixture of NaNO2 in an alkaline medium. Melatonin protected against lipid peroxidation induced by distinct reactive oxygen species (ROS) in all membranes tested although with different potency, in the following order BH < MIC < PC. The K0.5 for enzyme inhibition by melatonin was determined for nNOS (2.0 +/- 0.1 mm), for XO (0.8 +/- 0.1 mm) and for MPO (0.063 +/- 0.003 mm), the latter one with high affinity. Melatonin showed a weak effect as a nitrogen monoxide (NO) scavenger in the presence of sodium nitroprusside (NO donor) and low reactivity with 1,1-diphenyl-2-picryl hydrazyl (DPPH). These results demonstrate the antioxidant action of melatonin, principally that related to the activity of pro-oxidant enzymes such as XO and MPO.
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PMID:Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite. 1452 32

The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.
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PMID:Investigations on the pharmacology of the cardioprotective guanidine ME10092. 1524 98

Although interactions between superoxide (O(2)(.-)) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O(2)(.-) -producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated O(2)(.-) production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O(2)(.-) -generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.
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PMID:Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. 1554 89

The recent discovery of a NOS1 gene product (i.e. a neuronal-like isoform of nitric oxide synthase or nNOS) in the mammalian left ventricular (LV) myocardium has provided a new key for the interpretation of the complex experimental evidence supporting a role for myocardial constitutive nitric oxide (NO) production in the regulation of basal and beta-badrenergic cardiac function. Importantly, nNOS gene deletion has been associated with more severe LV remodelling and functional deterioration in murine models of myocardial infarction, suggesting that nNOS-derived NO may also be involved in the myocardial response to injury. To date, the mechanisms by which nNOS influences myocardial pathophysiology remain incompletely understood. In particular, it seems over simplistic to assume that all aspects of the myocardial phenotype of nNOS knockout (nNOS(-/-)) mice are a direct consequence of lack of NO production from this source. Emerging data showing co-localisation of xanthine oxidoreductase (XOR) and nNOS in the sarcoplasmic reticulum of rodents, and increased XOR activity in the nNOS(-/-) myocardium, suggest that nNOS gene deletion may have wider implications on the myocardial redox state. Similarly, the mechanisms regulating the targeting of myocardial nNOS to different subcellular compartments and the functional consequences of intracellular nNOS trafficking have not been fully established. Whether this information could be translated into a better understanding and management of human heart failure remains the most important challenge for future investigations.
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PMID:The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function. 1699 Mar 66

Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (oblob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2- to 6-month-old oblob (n=26) and C57Bl/6 controls (n=27). Cardiac NOS1 protein abundance (P<0.01) and mRNA expression (P=0.03) were reduced in oblob (n=10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in oblob mice after leptin treatment (n=3; P<0.05 vs leptin untreated oblob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in oblob mice (n=5; P=0.02). Furthermore, oxidative stress was increased in oblob mice as GSH/GSSG ratio was decreased (n=4; P=0.02). Whereas XOR activity measured by Amplex Red fluorescence was increased (n=8; P=0.04), XOR and NADPH oxidase subunits protein abundance were not changed in oblob mice (n=6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.
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PMID:Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice. 1730 68

Transgenic and knockout mice can be used to study the genes and basic mechanisms involved in heart disease, and have therefore assumed a central role in modern cardiac research. MRI and MRS techniques have recently been developed for mice that enable the quantitative or semi-quantitative in vivo assessment of cardiac anatomy, function, perfusion, infarction, Ca(2+) influx, and metabolism. With these techniques, the normal mouse heart has been shown to be well suited as a model of human cardiac disease. The roles of individual genes in normal cardiac physiology have recently been studied by MR, including the role of neuronal nitric oxide synthase in beta-adrenergic stimulation, the roles of the inducible nitric oxide synthase and myoglobin in function, dilation, and energetics, and the role of cardiac troponin I in contractility. Furthermore, with a mouse model of myocardial infarction, the roles of the angiotensin II type 2 receptor, xanthine oxidase inhibitors, blood coagulation factor XIII, and inducible nitric oxide synthase in post-infarct function and remodeling have been further elucidated. Non-invasive in vivo MRI and MRS in mice provide a unique and powerful means for phenotyping genetically engineered mice and can improve our understanding of the roles of specific genes and proteins in cardiac physiology and pathophysiology.
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PMID:MR in mouse models of cardiac disease. 1745 Nov 82

We report here the detection and characterization of spin adducts formed from the trapping of reactive oxygen species (superoxide and hydroxyl radicals) and glutathiyl and carbon-centered radicals by a newly synthesized nitrone, Mito-DEPMPO. This is a cationic nitrone spin trap with a triphenyl phosphonium cation conjugated to the DEPMPO analogue. The Mito-DEPMPO-OOH adduct, formed from the trapping of superoxide by Mito-DEPMPO, was enzymatically generated using xanthine/xanthine oxidase and neuronal nitric oxide synthase, and chemically generated by KO2 in 18-crown-6. The Mito-DEPMPO-OOH adduct exhibits an eight-line EPR spectrum with partial asymmetry arising from the alternate line-width effect. The half-life of the Mito-DEPMPO-OOH adduct is 2-2.5-times greater than that of the DEPMPO-OOH. The Mito-DEPMPO-SG adduct, formed from the trapping of glutathiyl radicals by Mito-DEPMPO, is 3-times more persistent than the analogue DEPMPO-SG adduct. In this study, we describe the EPR characterization of spin adducts formed from Mito-DEPMPO. The EPR parameters of Mito-DEPMPO adducts are distinctly different and highly characteristic. The detection of superoxide from an intact mitochondrion was feasible with Mito-DEPMPO but not with DEPMPO. We conclude that Mito-DEPMPO nitrone and its analogues are more effective than most nitrone spin traps for trapping superoxide, hydroxyl, and thiyl radicals formed in biological systems, including mitochondria.
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PMID:Detection, characterization, and decay kinetics of ROS and thiyl adducts of mito-DEPMPO spin trap. 1755 35


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