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)

The importance of nitric oxide (NO) in mediating macrophage functions has been demonstrated, but production of this potent gas has not been examined in Langerhans cells (LC). Using murine LC purified from epidermal cell suspensions and the recently established LC-like cell line derived from newborn BALB/c epidermis (XS-52), it was shown with reverse transcriptase (RT)-PCR that inducible nitric oxide synthase (iNOS) message is present in these cells. Murine keratinocytes did not contain iNOS message. iNOS mRNA was increased in a concentration-dependent manner by lipopolysaccharide (LPS) in purified murine LC and XS-52 cells, and immunofluorescence using an antibody to iNOS revealed bright cytoplasmic staining in LPS-treated XS-52 cells. Anti-iNOS antibody brightly stained LC on human neonatal foreskin cryosections. An increase in NO production by LPS-treated XS-52 cells over 16 h, as measured by the determination of nitrite levels in culture supernatants using the Griess Reaction, was observed. Interferon-gamma (IFNgamma) did not affect NO production on its own. In the presence of LPS and IFNgamma, NO production was 3 times more than observed with LPS alone. NO production was inhibited by the NOS inhibitor L-NAME. Western blots with anti-iNOS antibody demonstrated an increase in iNOS expression in LPS-treated XS-52 cells that was suppressed by IL-10. NO produced in LC may affect LC functions such as microbicidal activity, antigen presentation, and cytotoxicity and may affect adjacent keratinocytes and melanocytes.
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PMID:Langerhans cells express inducible nitric oxide synthase and produce nitric oxide. 894 67

Gentamicin-induced decreases in glomerular filtration rate have been associated with a marked decline in the glomerular capillary ultrafiltration coefficient which could be mediated by mesangial cell contraction. We have assessed a possible role of endogenous nitric oxide (NO) as a modulator of the proliferative and contractile effects of gentamicin on mesangial cells. NO synthesis and release, measured as nitrite production, were increased in the presence of gentamicin; this increase was blocked by coincubation with L-NAME. Mesangial cells treated with gentamicin, but not cells under control conditions, expressed mac-iNOS mRNA and presented positive immunoreactivity for mac-iNOS. Gentamicin induced a reduction of the planar surface area of cultured rat mesangial cells; cell treatment with gentamicin plus L-arginine significantly decreased the contractile effect of gentamicin. Gentamicin increased both [3H]thymidine incorporation into DNA and viable cell number; when L-arginine was added together with gentamicin, this abolished the effect of gentamicin on mesangial cell proliferation. The present studies demonstrate that gentamicin induces the expression of mac-iNOS and produces contraction and proliferation in mesangial cells. These actions seem to be modulated by mesangial NO synthesis and release.
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PMID:Gentamicin treatment increases mesangial cell nitric oxide production. 905 45

Using an in vitro primary cell culture model in which cortical neurons undergo a gradual and delayed neuronal death after a brief (5 min) challenge with glutamate receptor agonist N-methyl-D-aspartate (NMDA, 300 microM), the neuroprotective effects of various nitric oxide synthases (NOS) inhibitors were compared with that of the NMDA receptor antagonist dizocilpine maleate (MK-801). Our rat cortical cultures consisted of approximately 80-96% neurons and 5-20% astroglia as determined by immunocytochemical staining with antibodies against glial fibrillary acidic protein (GFAP) or neuron specific enolase (NSE). The delayed type of NMDA-induced neurotoxicity was examined by the morphological estimate of cell injury and was further confirmed by the activity of lactate dehydrogenase (LDH) in the extracellular fluid measured 24 hrs after the 5-min NMDA exposure. The accumulation of nitrite, the stable metabolite of nitric oxide (NO), was also measured 24 hrs after the 5-min NMDA exposure. The brief NMDA exposure caused about 60% neuronal death, as compared with persist (24 hr) NMDA exposure at 24 hr after NMDA exposure. Effects of drugs were studied by pretreating the cultures for 10 mins prior to the induction of NMDA neurotoxicity. Both the nonselective NOS inhibitor N alpha-nitro-L-arginine methyl ester (L-NAME, 100 microM) and the selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindozale (7-NI, 100 microM) suppressed nitrite accumulation and attenuated neuronal damage induced by NMDA. However, the selective inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (AG, 100 microM) exhibited no neuroprotective effects and no reduction in the nitrite production. The NMDA-induced neurotoxicity and nitrite production was abolished by pretreatment with the NMDA receptor antagonist MK-801 (100 microM). Thus the results indicate that a brief NMDA exposure leads to delayed neuronal damage with concomitant increase in NO production in cortical neuronal cultures. We suggest that the NO may originate primarily from nNOS. The neuroprotective effects of NOS inhibitors are weaker than that of MK-801.
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PMID:Effects of various nitric oxide synthase inhibitors on NMDA-induced neuronal injury in rat cortical neurons. 905 7

In this study, we investigated the expression of genes for inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) of Kupffer cells in the presence of lipopolysaccharide (LPS), and the tissue expression of iNOS in a rat liver after LPS injection at various time intervals. The effects of L-NG-nitroarginine-methyl-esther HCI (L-NAME), a NO inhibitor, also were examined. The mRNA transcripts of TNF-alpha, IL-1 beta, and IL-6 were rapidly detected no more than at 1 h after LPS stimulation, whereas the iNOS transcript was detectable from 3 h after LPS stimulation and maximally increased at 12 h. This fact suggested that these early induced cytokines were related to expression of iNOS. Using an anti-iNOS antiserum raised against recombinant iNOS protein, immunohistochemical analysis was made to reveal kinetics of NO producing cells. The cells immunoreactive for iNOS appeared at 6 h post-LPS injection in the sinusoids of the liver. By structural and immunohistochemical studies, almost all iNOS positive cells were identified as Kupffer cells and endothelial cells. The number of cells immunoreactive for iNOS increased until 12 h post-LPS injection. At 24 h after LPS injection, iNOS positive cells were restricted to the foci of spotty necrosis. Hepatic injury measured by released enzymes was increased by pretreatment of L-NAME before LPS injection.
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PMID:In vitro and in vivo expression of inducible nitric oxide synthase during experimental endotoxemia: involvement of other cytokines. 913 91

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
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PMID:Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset. 918 19

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.
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PMID:Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. 921 22

The principal goal of the present study was to test the hypothesis that cytokines modulate glucose transport in skeletal muscle by increasing nitric oxide production. Cultured L6 skeletal muscle cells were incubated in the presence of tumour necrosis factor-alpha, interferon-gamma or lipopolysaccharide (LPS) alone or in combination for 24 h. Neither cytokines nor LPS alone induced NO production, as measured by nitrite concentrations in the medium. However, when used in combination, the two cytokines significantly stimulated NO production, and this effect was synergistically enhanced by the presence of LPS. Reverse transcriptase-PCR (RT-PCR) analysis revealed that NO release was associated with the induction of inducible (macrophage-type) NO synthase (iNOS). The increase in iNOS expression was confirmed at the protein level by Western-blot analysis and NADPH/diaphorase histochemical staining. Cytokines and LPS markedly increased basal glucose transport in L6 myocytes. Insulin also stimulated basal glucose transport, but significantly less in cells chronically exposed to cytokines/LPS. The sensitivity of L6 muscle cells to insulin-stimulated glucose transport was also significantly decreased by cytokines/LPS treatment. The NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) inhibited nitrite production in cytokine/LPS-treated cells, and this prevented the increase in basal glucose transport and restored muscle cell responsiveness to insulin. Cytokines/LPS exposure significantly increased GLUT1 transporter protein levels but decreased GLUT4 expression in L6 cells. l-NAME treatment prevented the increase in GLUT1 protein content but failed to restore GLUT4 transporter levels. These results demonstrate that cytokines and LPS affect glucose transport and insulin action by inducing iNOS expression and NO production in skeletal muscle cells. The data further indicate that cytokines and LPS increase the expression of the GLUT1 transporter protein by an NO-dependent mechanism.
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PMID:Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase. 923 Jan 32

1. In airway epithelium, nitric oxide (NO) is synthesized in the setting of inflammation by inducible nitric oxide synthase (iNOS). Although the role of epithelial derived NO in the regulation of human airways is unknown, prostaglandin E2 (PGE2) is recognised as an important inhibitory mediator in human airways. Cyclo-oxygenase (COX) is the rate limiting enzyme in the production of prostanoids and since inflammatory pathways enhance the expression of an inducible COX (COX-2), both COX-2 and iNOS may be co-expressed in response to an inflammatory stimulus. Although regulation of the COX-2 pathway by NO has been demonstrated in animal models, its potential importance in human airway epithelium has not been investigated. 2. The effect of endogenous and exogenous NO on the COX-2 pathway was investigated in the A549 human airway epithelial cell culture model. Activity of the COX-2 pathway was assessed by PGE2 EIA, and iNOS pathway activity by nitrite assay. A combination cytokine stimulus of interferon gamma (IFNgamma) 100 u ml(-1), interleukin-1beta (IL-1beta) 1 u ml(-1) and lipopolysaccharide (LPS) 10 microg ml(-1) induced nitrite formation which could be inhibited by the competitive NOS inhibitor N(G)-nitro-L-arginine-methyl-ester (L-NAME). IL-1beta alone (1-50 u ml(-1) induced PGE2 formation without significant nitrite formation, a response which was inhibited by the COX-2 specific inhibitor nimesulide. Submaximal stimuli used for further experiments were IFNgamma 100 u ml(-1), IL-1beta 1 u ml(-1) and LPS 10 microg ml(-1) to induce both the iNOS and COX-2 pathways, and IL-1beta 3 u ml(-1) to induce COX-2 without iNOS activity. 3. Cells treated with IFNgamma 100 u ml(-1), IL-1beta I u ml(-1) and LPS 10 microg ml(-1) for 48 h either alone, or with the addition of L-NAME (0 to 10(-2) M), demonstrated inhibition by L-NAME of PGE2 (3.61 +/- 0.55 to 0.51 +/- 0.04 pg/l0(4) cells; P<0.001) and nitrite (34.33 +/- 8.07 to 0 pmol/10(4) cells; P<0.001) production. Restoration of the PGE2 response (0.187 +/- 0.053 to 15.46 +/- 2.59 pg/10(4) cells; P<0.001) was observed after treating cells with the same cytokine stimulus and L-NAME 10(-6) M, but with the addition of the NOS substrate L-arginine (0 to 10(-5) M). 4. Cells incubated with IL-1beta 3 u ml(-1) for 6 h, either alone or with addition of the NO donor S-nitroso-acetyl-penicillamine (SNAP) (0 to 10(-4) M), demonstrated increased PGE2 formation (1.23 +/- 0.03 to 2.92 +/- 0.19 pg/10(4) cells; P< 0.05). No increase in PGE2 formation was seen when the experiment was repeated in the presence of the guanylate cyclase inhibitor methylene blue (50 microM). Cells treated with SNAP alone did not demonstrate an increased PGE2 formation. Cells incubated with IL-1beta 3 u ml(-1) for 6 h in the presence of dibutyryl cyclic guanylate monophosphate (0 to 10(-3) M) also demonstrated an increased PGE2 response (2.56 +/- 0.21 to 4.53 +/- 0.64 pg/10(4) cells; P<0.05). 5. These data demonstrate that in a human airway epithelial cell culture system, both exogenous and endogenous NO increase the activity of the COX-2 pathway in the setting of inflammatory cytokine stimulation, and that this effect is likely to be mediated by guanylate cyclase. This suggests a role for NO in the regulation of human airway inflammation.
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PMID:Regulation of the inducible cyclo-oxygenase pathway in human cultured airway epithelial (A549) cells by nitric oxide. 925 31

1. The role of nitric oxide (NO) in leukocyte (polymorphonuclear cells, monocytes and lymphocytes) emigration was studied in a model of carrageenin-sponge implants in rats. 2. The subcutaneous implantation of 1% (w/v) of lambda-carrageenin-soaked sponges elicited an inflammatory response that was characterized by a time-related increase in leukocyte infiltration in the sponges and increased levels of nitrite in the exudate. Total leukocyte infiltration and nitrite production were maximal at 24 h and decreased after 48 and 96 h. The mononuclear cell influx was maximal at 48 h (21% of the total leukocytes). Therefore, this time point was used in the successive experiments. 3. Polymorphonuclear cell (PMN) and lymphocyte infiltration in the sponges significantly increased when rats were treated with the non-specific NO-synthase (NOS) inhibitor, NG-nitro-L-arginine methylester (L-NAME) (1 mg ml-1) in drinking water ad libitum). Monocyte emigration was not affected by L-NAME treatment. The nitrite levels in the exudate of L-NAME-treated rats were significantly reduced. The concomitant ingestion of L-arginine (30 mg ml-1) resulted in a reversion of the L-NAME effect, while D-arginine (30 mg ml-1) had no effect, indicating the involvement of the L-arginine: NO pathway. 4. Administration of L-NAME resulted also in an increased release of tumour necrosis factor-alpha (TNF-alpha) and prostacyclin (measured as the stable metabolite, 6-keto-PGF 1 alpha). L-NAME had no effect on monocyte chemoattractant protein-1 (MCP-1) release in the exudate. 5. Since L-NAME may have effects on the local blood flow, phenylephrine (0.034 mg ml-2) in drinking water) was used as it has an effect on the local blood flow similar to L-NAME. Phenylephrine had no effect on either leukocyte emigration, or on nitrite, TNF-alpha, prostacyclin or MCP-1 accumulation in the exudate. 6. In contrast, the more selective iNOS inhibitor S-methyl-isothiourea (SMT) (10 micrograms ml-1) in drinking water) significantly reduced PMNs and lymphocyte influx in the sponge having no effect on monocyte influx. Moreover, SMT decreased nitrite production in the exudate to a comparable extent as L-NAME. 7. Administration of SMT significantly reduced MCP-1 release in the exudate, without an effect on TNF-alpha or prostacyclin production. Moreover SMT did not produce any changes in local blood flow. 8. Our results show that a different outcome of the inflammatory process can be obtained depending on the types of NOS inhibitor used.
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PMID:Differential effect of L-NAME and S-methyl-isothiourea on leukocyte emigration in carrageenin-soaked sponge implants in rat. 928 97

Nitric oxide (NO) plays a crucial role in the regulation of kidney function and metabolism. Our previous study showed that dexamethasone, one of several known selective inhibitors of inducible nitric oxide synthase (NOS), had a stimulatory effect on soluble guanylyl cyclase in the glomeruli of rat kidney. However, in the presence of dexamethasone, the atrial natriuretic factor (ANF)-dependent system remained suppressed. The aim of the present study was to investigate whether inhibition of synthesis of endogenous NO modulates the activity of the guanylyl cyclase system(s) in glomeruli. In these studies, rats were injected with a non-selective NOS inhibitor, N-omega-nitro-L-arginine methyl ester (NAME; NAME-group), or saline solution (controls; C-group). Creatinine clearance (C(Cr)), and plasma and urinary nitrate/nitrite (NOx-) levels decreased in the NAME-group, but plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) contents were unchanged. In the presence of 0.1 microM ANF, synthesis of cGMP in the NAME-group exceeded threefold the cGMP production in the C-group. In addition, the pre-contracted glomeruli of the NAME-group were fully relaxed at 0.1 microM ANF, but glomeruli obtained from the C-group were relaxed in the presence of a 10 times higher dose of ANF. The increased sensitivity of glomeruli to ANF was possibly due to the more than doubled activity of particulate guanylyl cyclase (pGC) in the NAME-group in comparison with the C-group. In the presence of 100 microM sodium nitroprusside (SNP), soluble guanylyl cyclase (sGC) generated significantly lower cGMP production in the NAME-group than in the C-group (1.61 +/- 0.33 vs. 2.91 +/- 0.69 nmol/mg protein/10 min, respectively). These results demonstrate that inhibition of the synthesis of endogenous NO may also have an inhibitory effect on the activity of sGC. In addition, increased activity of the pGC and ANF-dependent system appears to be compensatory to the altered activity of soluble guanylyl cyclase.
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PMID:Inhibition of endogenous nitric oxide synthesis activates particulate guanylyl cyclase in the rat renal glomeruli. 929 Nov 84


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