Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that the systemically administered nitric oxide synthase (NOS) inhibitor Nw-nitro-L-arginine methyl ester, L-NAME, administered before, during and after the angiogenic treatment stimulated angiogenesis induced by basic fibroblast growth factor, bFGF, in the rat. This suggests that suppression of constitutively expressed NOS, cNOS, plus inducible NOS, iNOS, and thus reduced production of nitric oxide, NO, was the stimulating factor. In those studies, the rat mesenteric-window angiogenesis assay was used. Moreover, the systemic administration of a NO releaser inhibited bFGF-mediated angiogenesis. Using the same experimental system, we have now studied whether the inhibition of cNOS alone in adult animals under physiological conditions, i.e. prior to the administration of the angiogenic stimulation with bFGF, affected the subsequent angiogenic response. cNOS constitute endothelial cell NOS (ecNOS) and neuronal NOS (nNOS). L-NAME or its inactive enantiomer Nw-nitro-D-arginine methyl ester, D-NAME, were given continuously in the drinking water (1.0 g/L) during 14 days prior to the start of the treatment with bFGF. The treatment with L-NAME significantly enhanced the subsequent angiogenic response. NO synthesized under physiological conditions by ecNOS in endothelial cells and platelets or nNOS in platelets may thus act as a first constitutional angiostatic factor in bFGF-mediated mammalian angiogenesis.
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PMID:Constitutively synthesized nitric oxide is a physiological negative regulator of mammalian angiogenesis mediated by basic fibroblast growth factor. 1129 89

In this study, the role of nitric oxide (NO) on neutrophil migration induced by staphylococcal enterotoxin B (SEB) in the mouse peritoneal cavity was investigated. The NO synthase inhibitors L-NAME and aminoguanidine, as well as dexamethasone, markedly reduced SEB-induced neutrophil influx. In mice with an increased population of peritoneal macrophages, the inhibition of SEB-induced neutrophil influx by these agents was significantly lower. The in vivo treatment with aminoguanidine inhibited only the iNOS activity, whereas L-NAME inhibited both the cNOS and iNOS activities. In conclusion, NO modulates the neutrophil migration in response to SEB through the activity of an iNOS isoform.
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PMID:Involvement of nitric oxide on the peritoneal neutrophil influx induced by staphylococcal enterotoxin B in mouse. 1138 27

Gastric ulceration was induced in rats by i.p. injection of the non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) (30 mg kg(-1)). Pyloric ligation was carried out in each animal before injection to enable collection of the gastric juice. Three hours later, the animals were killed and their stomachs were removed. In the gastric juice, the amounts of mucin, pepsin and HCl were assessed. Gastric mucosa were scrapped for the determination of nitric oxide (NO) (as nitrite) after evaluation of the gastric ulcer index. The influence of arginine (ARG) (300 mg kg(-1)), a NO precursor, N(G)-nitro- l -arginine methyl ester (l -NAME) (50 mg kg(-1)), a non-selective constitutive nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS) inhibitor, and the selective iNOS inhibitor aminoguanidine (AMG) (50 mg kg(-1)) were studied. Each NO modulator was injected i.p. 30 min before IND administration. Results indicated that IND elevated gastric acidity by 80% of the normal group, decreased non-significantly mucosal nitrite by 22% and exhibited a remarkably high ulcer index (chi = 17). Neither mucin nor pepsin levels were significantly altered. In comparison with the IND group, pretreatment with l -NAME caused a significant decrease in gastric HCl, further decrease in mucosal nitrite (50% of normal) and a two-fold increase in the ulcer index score (chi = 34), despite the decrease in HCl. AMG did not alter gastric acidity, decreased mucosal nitrite by 38% of the normal value and failed to alter significantly the ulcer index of IND. On the other hand, pretreatment with ARG did not alter the gastric acidity and raised mucosal nitrite by 10% above normal. Surprisingly, ARG improved the gastric ulcer score (chi = 1) almost similar to the normal score (chi = zero). Therefore, this study creates a new pathway for the potential treatment of NSAID gastric ulceration through modulation of NO synthesis, regardless of the effect on gastric acidity.
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PMID:Protective role of nitric oxide in indomethacin-induced gastric ulceration by a mechanism independent of gastric acid secretion. 1139 38

We have previously reported that melatonin modifies carbohydrate and lipid utilization in exercised rats, maintaining glycemia and reducing plasma and liver lactate and plasma beta-hydroxybutyrate. This study was undertaken to determine whether effects on fuel metabolism were related to changes in nitric oxide (NO) production or growth hormone (GH) secretion. Male Wistar rats received melatonin i.p. at a dose of 0.5 mg/kg body weight 30 min before being exercised to exhaustion on a treadmill at a speed of 24 m/min and a 12% slope. Melatonin ameliorated the decrease in plasma glucose and the increase in plasma urea, free fatty acid, beta-hydroxybutyrate, and nitrite induced by exercise. Melatonin-treated exercised rats had significantly elevated liver glycogen content and hepatic tissue showed a lowered expression of both inducible and constitutive NO synthase (iNOS and cNOS). Administration of the NO inhibitor NG-nitro-L-arginine (L-NAME) to exercised rats caused a significant reduction in plasma nitrite, but liver glycogen and biochemical parameters in blood did not significantly differ from untreated exercised animals, indicating the absence of a direct association between melatonin effects on fuel metabolism and NO levels. Although results of treatment with pyridostigmine, a cholinergic agonist drug that stimulates GH release, partially differed from that of melatonin, modulation of GH secretion could play a role in the metabolic actions of the hormone because effects of melatonin on exercised rats were almost completely blocked by simultaneous administration of L-NAME.
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PMID:Effects of melatonin on fuel utilization in exercised rats: role of nitric oxide and growth hormone. 1155 72

1. This study analyses the neural pathway involved in the modulation of gastric motor function by stress. 2. Systemic administration of low doses of endotoxin (40 microg kg(-1), i.v.) prevents the increase in gastric tone induced by 2-deoxy-D-glucose (200 mg kg(-1), i.v., 2-DG) in urethane-anaesthetized rats. 3. Functional inhibition of afferent neurones by systemic administration of capsaicin (20+30+50 mg kg(-1), i.m.) in adult rats prevented the inhibitory effects of endotoxin. 4. Pre-treatment with the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), both i.v. (10 mg kg(-1)) and i.c. (200 microg rat(-1)), prevented the inhibitory effects of endotoxin on gastric tone induced by 2-DG. 5. Immunohistochemical studies show Fos expression in the dorsal vagal complex (DVC) of the brainstem of 2-DG-treated animals. Peripheral administration of endotoxin (40 microg kg(-1), i.p.) increased the number of Fos-immunoreactive cells induced by 2-DG, both in the nucleus tractus solitarii (NTS) and in the dorsal motor nucleus (DMN) of the DVC. Pre-treatment with L-NAME prevented the increase in Fos expression induced by endotoxin in both nuclei. 6. Endotoxin (40 microg kg(-1), i.p.) increased Ca(2+)-dependent nitric oxide synthase (cNOS) activity in the brainstem. Addition of 7-nitroindazole (600 microM, 7-NI) to the assay significantly inhibited the increase in cNOS activity caused by endotoxin. No change in NOS activity of any isoform was observed in the stomach of animals treated with endotoxin. 7. The present study suggests that inhibition of gastric motor function by low doses of endotoxin involves activation of capsaicin-sensitive afferent neurones and neuronal NOS in the brainstem.
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PMID:A cerebral nitrergic pathway modulates endotoxin-induced changes in gastric motility. 1156 50

HIV transgenic mice bearing multiple copies of a noninfectious (Deltagag/pol) proviral DNA were tested for the systemic production of nitric oxide (NO). Serum levels of NO metabolites were reduced about 50% in HIV transgenic mice compared with nontransgenic sibling mice. This difference persisted when NO production was induced with peritoneal injections of bacterial endotoxin (LPS). Peritoneal inflammatory macrophages, but not resident peritoneal macrophages, derived from HIV-1 transgenic mice and activated in vitro with LPS and IFN-gamma (or tumor necrosis factor alpha and IFN-gamma) also produced about 50% less NO than did macrophages harvested from nontransgenic littermates. Isogenic, transgenic mice bearing mutated nef or vpr genes had normal serum levels of NO metabolites and their macrophages produced normal levels of NO when stimulated. An explanation for the reduced NO response of HIV[Vpr+Nef+] macrophages was not apparent from measured levels of iNOS expression, viral gene expression, or arginase activity in activated macrophages. Inhibition of nitric oxide synthase (NOS) isoforms with L-NAME or aminoguanidine blocked time-dependent increases in HIV gene expression in activated macrophages cultured ex vivo. Inhibition with L-NAME occurred despite high levels of NO generated by iNOS, and exogenously supplied NO induced HIV gene expression only weakly, suggesting that cNOS had the greater influence on proviral gene induction. This system is presented as a model of HIV-1 proviral gene expression and dysfunction in macrophages.
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PMID:A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production. 1159 Jan 96

Lipopolysaccharides (LPS) are major components of the outer membrane of gram-negative bacteria playing a central role as potent endotoxins in the pathogenesis of endotoxic shock. Although large amounts of endotoxin may produce hemorrhagic lesions in the stomach, the possible gastroprotective effect of central or peripheral LPS against the acute gastric lesions has not been extensively studied. The aim of the present study was to compare the effect of intracerebroventricular (i.c.v.) and parenteral (i.p.) injection of LPS against gastric lesions induced by 100% ethanol. Male Wistar rats were treated either with a) vehicle (control); b) E-coli-LPS in various concentrations (1-10 microg/kg i.c.v or 0.1-40 mg/kg i.p.) followed 30 min later by 100% ethanol. The effects of pretreatment with nonselective inhibitor of nitric oxide synthase (L-NAME, 20 mg/kg i.g.) or selective inhibitor of inducible nitric oxide synthase, L-NIL (30 mg/kg i.g.) on the gastroprotection induced by LPS was investigated. One hour after ethanol application, the gastric blood flow (GBF) and the area of gastric lesions were determined. In addition, the mucosal expression of iNOS, cNOS and leptin was assessed using RT-PCR. LPS applied i.c.v. or i.p. dose dependently reduced gastric lesions induced by ethanol and this effect was similar to that observed after the administration of NO donor (SNAP). LPS-induced protection was significantly abolished by L-NAME and significantly attenuated by the selective inhibitor of iNOS (L-NIL). The expression of cNOS was detected in vehicle treated gastric mucosa and did not change after LPS administration. iNOS was not detectable in intact mucosa but its expression dose-dependently increased after the LPS administration. The i.c.v. administration of LPS did not upregulate further the iNOS expression, and dose-dependently inhibited the leptin mRNA expression in gastric mucosa. We conclude that LPS applied centrally or peripherally protects gastric mucosa against ethanol-induced damage through an increase in gastric microcirculation mediated by NO due to overexpression of iNOS. Transcriptional downregulation of leptin in gastric mucosa is probably due to the increased leptin release induced by the intracerebroventricular application lipopolysaccharide.
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PMID:Central and peripheral neural aspects of gastroprotective and ulcer healing effects of lipopolysaccharides. 1178 62

Inhibiting platelet and endothelial nitric oxide production favours platelet adhesion and aggregation, and arterial vasoconstriction. This study investigated the effect of NG-nitro-l-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, on P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates, and on soluble P-selectin levels. Twelve healthy male volunteers were infused intravenously with L-NAME and then with a 10% solution of either l- or d-arginine. Blood pressure responses were recorded and whole blood and serum collected at baseline and after each infusion. P-selectin expression was analysed in all samples by flow cytometry. Serum levels of soluble P-selectin were batch analysed using an enzyme-linked immunosorbent assay at the end of the study. P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates did not vary significantly from baseline levels following the infusion of L-NAME or l- or d-arginine. However, endothelial nitric oxide synthase inhibition caused a marked elevation of arterial blood pressure (P < 0.01) that was restored to pretreatment values by l- but not d-arginine. Serum levels of the soluble form decreased significantly (P = 0.001) following the infusion of l- and d-arginine compared with samples taken at baseline and following L-NAME infusion. In conclusion, inhibition of constitutive nitric oxide synthase in the endothelium and platelets produced significant increases in blood pressure but did not alter platelet membrane expression of P-selectin.
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PMID:Effect of nitric oxide modulation on systemic haemodynamics and platelet activation determined by P-selectin expression. 1271 82

Phosphatidylinositol 3-kinase (PI3-K) has been shown to mediate insulin and insulin-like growth factor-1 (IGF-1)-induced nitric oxide (NO) generation and, thus, vascular tone. A role for PI3-K in G-protein-coupled receptor signal transduction has also been reported. As beta2 -adrenergic vascular actions are partly dependent on NO, this study the role of PI3-K on in vitro isoproterenol (Iso)-induced endothelial cell (EC) nitric oxide synthase (NOS) activation and rat aortic vascular relaxation. Cell lysates of rat aortic EC (RAEC), exposed to Iso (10 micromol/L) for 5 minutes, were immunoprecipitated with an antiphosphotyrosine antibody prior to assay for Western blot for the p85-kd regulatory subunit of PI3-K. Endothelial NOS activity was determined by measuring nitrite production. Endothelium-intact aortic rings from male Wistar rats were preincubated with the PI3-K inhibitors, wortmannin (WT), or LY294002 (LY), precontracted with phenylepinephrine (PE), and relaxation to graded doses of Iso was measured. NO contribution to vascular relaxation was assessed by L-N(G)-nitroarginine methyl ester (L-NAME), a NOS inhibitor. Both Iso and IGF-1 induced an increase in p85 subunit phosphorylation as demonstrated by Western analysis, effects inhibited by preincubation with WT. Iso also enhanced association of p85 with the Triton X-100-insoluble fraction of RAEC, reflecting translocation of this enzyme to a cytoskeletal fraction. In addition, Iso as well as IGF-1 significantly increased eNOS activity measured by nitrite production. Both WT and LY markedly inhibited relaxation to Iso, while L-NAME nearly abolished this beta-adrenergic-mediated vasorelaxation. These data indicate that both Iso and IGF-1 activate the EC PI3-K pathway which mediates, in part, the release of NO and subsequent vasorelaxation in response to this beta-agonist Iso as well as to IGF-1.
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PMID:Phosphatidylinositol 3-kinase may mediate isoproterenol-induced vascular relaxation in part through nitric oxide production. 1188 78

1. A deficiency of constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO), due to reduced availability of L-arginine, importantly contributes to allergen-induced airway hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and arginase use L-arginine as a common substrate, we hypothesized that increased arginase activity is involved in the allergen-induced NO deficiency and AHR. 2. Using a guinea-pig model of allergic asthma, we addressed this hypothesis by examining the effects of the specific arginase inhibitor N(omega)-hydroxy-nor-L-arginine (nor-NOHA) on the responsiveness to methacholine of isolated perfused tracheae from unchallenged control animals and from animals 6 h after ovalbumin challenge. Arginase activity in these preparations was investigated by measuring the conversion of L-[14C]arginine to [14C]urea. 3. Airways from allergen-challenged animals showed a 2 fold (P<0.001) increase in responsiveness to intraluminal (IL) administration of methacholine compared to controls. A similar hyperresponsiveness (1.8 fold, P<0.01) was observed in control airways incubated with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 mM, IL), while L-NAME had no further effect on the airways from challenged animals. 4. Remarkably, 5 microM nor-NOHA (IL) normalized the hyperresponsiveness of challenged airways to basal control (P<0.001), and this effect was fully reversed again by 0.1 mM L-NAME (P<0.05). Moreover, arginase activity in homogenates of the hyperresponsive airways was 3.5 fold (P<0.001) enhanced compared to controls. 5. The results indicate that enhanced arginase activity contributes to allergen-induced deficiency of cNOS-derived NO and AHR after the EAR, presumably by competition with cNOS for the common substrate, L-arginine. This is the first demonstration that arginase is involved in the pathophysiology of asthma.
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PMID:Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. 1202 42


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