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)

In the present study, we examined the role of nitric oxide (NO) in early-response cytokine production by using a rat model of hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia, followed by 4 h of reperfusion. Group I and II rats were sham-operated controls that received saline (vehicle) or N(W)-nitro-L-arginine methylester (L-NAME) (10 mg/kg, iv); group III and IV rats were subjected to HI/R and received vehicle or L-NAME (10 mg/kg, iv, 10 min before reperfusion), respectively. Administration of L-NAME to rats subjected to I/R resulted in a fourfold decrease in plasma NO levels, accompanied by a marked increase of plasma alanine aminotransferase (ALT) activity relative to group III. These changes in group IV were associated with elevation of superoxide generation in ischemic liver lobes by 2.1-fold and circulating leukocyte number by 1.42-fold, compared with group III. Normalized for expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger ribonucleic acid (mRNA), expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in ischemic liver of group IV was augmented by 207% and 175% compared with Group III. The expression of (iNOS) mRNA was also increased (223%) relative to group III. Moreover, in group IV, plasma TNF-alpha levels at 4 h of reperfusion and IL-1beta levels at 90 min and 4 h of reperfusion were significantly increased compared with group III. No statistically significant changes were observed between groups I and II in plasma ALT activity, plasma NO levels, circulating leukocyte counts, superoxide generation in the ischemic lobes of liver, and plasma TNF-a and IL-1beta concentrations. The observed enhancement of I/R injury by L-NAME is consistent with the hypothesis that endogenous NO down-regulates TNF-alpha and IL1beta generation, thereby decreasing HI/R injury.
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PMID:Role of endogenous nitric oxide in TNF-alpha and IL-1beta generation in hepatic ischemia-repefusion. 1071 79

Endotoxin-treated cochleas of the guinea pig were examined electrophysiologically and immunohistochemically concerning the expression of inducible nitric oxide synthase (iNOS/NOS II). One mg of bacterial lipopolysaccharide (LPS, 5 mg/ml) or mixed solution of 1 mg of LPS plus 1 mg of N(G)-nitro-L-arginine methyl ester (L-NAME, 5 mg/ml) (L-NAME/LPS) was injected into the middle ear of guinea pigs transtympanically. The electrocochleograms were measured prior to, immediately and 48 h after the injection. Immunohistological studies for iNOS followed after fixation, embedding and sectioning of the temporal bones. The threshold and amplitude of the compound action potential (CAP) became significantly worse in the LPS treated group. In contrast, the changes of the threshold and amplitude of CAP were decreased in the L-NAME/LPS group. iNOS was expressed in the stria vascularis, the spiral ligament, the organ of Corti and the spiral ganglion in the LPS group. These immunoreactivities in the L-NAME/LPS group were less intense than that in the LPS group. These results indicate that LPS has an ototoxic effect on the cochlea and that this effect could be mediated by iNOS produced high nitric oxide under inflammatory conditions.
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PMID:Inhibition of inducible nitric oxide synthase lowers the cochlear damage by lipopolysaccharide in guinea pigs. 1074 57

Ultraviolet (UV) irradiation is known to induce serious oxidative damage in the skin via lipid peroxidation. Nitric oxide (NO) synthesized by keratinocytes, melanocytes and endothelial cells in response to proinflammatory cytokines and UV radiation, has been reported to prevent UV-induced apoptosis in the skin. We have examined the effects of NO on UVB-induced lipid peroxidation in murine skin in vivo. UVB induced a dose-dependent increase in lipid peroxidation of skin extracts in vitro; however, lipid peroxidation in the skin in vivo remained unaffected at irradiation doses of less than 1.0 J cm-2 and decreased significantly at doses over 1.5 J cm-2 (P < 0.01). Time-delayed inhibition of lipid peroxidation in the skin in vivo was observed after irradiation at 1.5 J cm-2. Administration of N G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, enhanced lipid peroxidation (P < 0.05), while it suppressed the ear-swelling response (ESR), a biological marker of inflammation. By contrast, administration of sodium nitroprusside, an NO enhancer, suppressed lipid peroxidation (P < 0. 01), while it enhanced the ESR. Expression of inducible nitric oxide synthase (iNOS) was observed from 12 to 48 h postirradiation at doses of 0.4-1.6 J cm-2. The UVB-induced iNOS expression was markedly inhibited by L-NAME, suggesting that iNOS is a major enzyme in the production of NO. These results suggest that NO acts as a mediator of the inflammatory response in UVB-irradiated skin, and that lipid peroxidation is inversely regulated with the NO-mediated inflammatory response in vivo.
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PMID:Protective role of nitric oxide-mediated inflammatory response against lipid peroxidation in ultraviolet B-irradiated skin. 1079 14

Human cervical epithelial cells express mRNA for the nitric oxide (NO) synthase (NOS) isoforms ecNOS, bNOS, and iNOS and release NO into the extracellular medium. N(G)-nitro-L-arginine methyl ester (L-NAME), an NOS inhibitor, and Hb, an NO scavenger, decreased paracellular permeability; in contrast, the NO donors sodium nitroprusside (SNP) and N-(ethoxycarbonyl)-3-(4-morpholinyl)sydnonimine increased paracellular permeability across cultured human cervical epithelia on filters, suggesting that NO increases cervical paracellular permeability. The objective of the study was to understand the mechanisms of NO action on cervical paracellular permeability. 8-Bromo-cGMP (8-BrcGMP) also increased permeability, and the effect was blocked by KT-5823 (a blocker of cGMP-dependent protein kinase), but not by LY-83583 (a blocker of guanylate cyclase). In contrast, LY-83583 and KT-5823 blocked the SNP-induced increase in permeability. Treatment with SNP increased cellular cGMP, and the effect was blocked by Hb and LY-83583, but not by KT-5823. Neither SNP nor 8-BrcGMP had modulated cervical cation selectivity. In contrast, both agents increased fluorescence from fura 2-loaded cells in the Ca(2+)-insensitive wavelengths, indicating that SNP and 8-BrcGMP stimulate a decrease in cell size and in the resistance of the lateral intercellular space. Neither SNP nor 8-BrcGMP had an effect on total cellular actin, but both agents increased the fraction of G-actin. Hb blocked the SNP-induced increase in G-actin, and KT-5823 blocked the 8-BrcGMP-induced increase in G-actin. On the basis of these results, it is suggested that NO acts on guanylate cyclase and stimulates an increase in cGMP; cGMP, acting via cGMP-dependent protein kinase, shifts actin steady-state toward G-actin; this fragments the cytoskeleton and renders cells more sensitive to decreases in cell size and resistance of the lateral intercellular space and, hence, to increases in permeability. These results may be important for understanding NO regulation of transcervical paracellular permeability and secretion of cervical mucus in the woman.
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PMID:NO increases permeability of cultured human cervical epithelia by cGMP-mediated increase in G-actin. 1079 68

Ammonia is a neurotoxin whose administration in large doses causes coma and death of the exposed animals, but whether and in what degree these whole body effects are related to the death of CNS cells is not known. Since the downstream effects of ammonia in cultured CNS cells appear to be partly mediated by overactivation of several putative signalling mechanisms characteristic for the apoptotic program, we speculated that ammonia neurotoxicity may be apoptogenic. In this study, C6 glioma cells grown in 2% serum were exposed to 5 mM or 10 mM NH(4)Cl (ammonia) for 96 h and tested for the appearance of apoptosis by (a) Hoechst staining, (b) TUNEL reaction and (c) DNA ladder, at different times of exposure. In cultures exposed to either 5 mM or 10 mM ammonia, about 10% of the cells were found to enter apoptosis at 48 h of exposure, and the number of apoptotic cells rose to 30% at 72 h, and to 50% at 96 h of exposure, respectively. The first transduction signal purportedly involved in apoptosis, activation of PKCalphabeta, was transient and appeared already after 3-6 h of treatment. Coincident with pronounced manifestation of apoptosis (at 72 h and even more at 96 h of exposure) was an increased transfer of the transcription factor NFkappaB from cytoplasmto nucleus as revealed by EMSA assay. The number of cells affected by ammonia-induced apoptosis was markedly reduced by incubation with a NOS inhibitor, L-NAME at 100 microM concentration. The results indicate that ammonia-induced apoptosis is a result of a complex interplay of at least three signalling molecules: NO, PKC and the transcription factor NFkappaB, with NFkappaB being possibly involved in the induction of iNOS and generation of toxic levels of NO in the cells.
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PMID:Delayed induction of apoptosis by ammonia in C6 glioma cells. 1081 14

This study investigated the effect of nitric oxide on lipid peroxide formation during endotoxaemia. Nitric oxide synthase inhibitors N(G)-monomethyl-L-arginine acetate (L-NMMA, 20 mg/kg, intravenously), N(G)-nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg, intravenously), and N(G)-nitro-L-arginine (L-NA, 10 mg/kg, intravenously), and a relatively selective inducible nitric oxide synthase inhibitor aminoguanidine (10 mg/kg, intravenously), did not protect against endotoxin-induced death of mice. Superoxide dismutase activity in liver 18 hr after administration of endotoxin (6 mg/kg, intraperitoneally) to L-arginine analogues (L-NMMA, L-NAME, L-NA)-treated mice was lower than in mice treated with endotoxin alone, whereas the administration of L-arginine analogues increased xanthine oxidase activity in the livers of endotoxin-injected mice compared with mice treated with endotoxin alone. In mice treated with L-arginine analogues and aminoguanidine, the levels of non-protein sulfhydryl and lipid peroxide in liver 18 hr after endotoxin injection did not show significant differences from mice treated with endotoxin alone. L-Arginine analogues and aminoguanidine had little effect on lipid peroxide formation in liver caused by endotoxin. Treatment with aminoguanidine (300 microM) significantly inhibited endotoxin-induced intracellular peroxide in J774A.1 cells, however, aminoguanidine did not affect endotoxin-induced cytotoxicity in J774A.1 cells. Our results clearly demonstrate that treatment with catalase (10 microg/ml), D-mannitol (10 mM), or superoxide dismutase (100 U/ml), has little or no effect on nitric oxide production by endotoxin (1 microg/ml)-activated J774A.1 cells. These findings suggest that nitric oxide is not crucial for lipid peroxide formation during endotoxaemia. Therefore, it is unlikely that nitric oxide plays a significant role in liver injury caused by free radical generation in endotoxaemia.
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PMID:Effect of nitric oxide synthase inhibitors on lipid peroxide formation in liver caused by endotoxin challenge. 1081 49

The in vivo role of nitric oxide in inflammatory cell migration, vascular permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24 h following ovalbumin (OVA) challenge. The NO synthase (NOS) inhibitors N(G)-mono-methyl-L-arginine (L-NMMA; nonselective), aminoguanidine (two-fold inducible NOS-selective), N(omega)-nitro-L-arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) or S-methyl-L-thiocitrulline (100-fold neuronal NOS-selective) were administered (100 mg x kg(-1) s.c.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 consecutive days during which they were challenged with allergen (1% OVA). Responses to inhaled MCh were measured in anaesthetized animals 24 h after OVA challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administration of Evans blue (50 mg x kg(-1) i.v.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inflammatory cell influx and increased leakage of Evans blue into the BAL fluid (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-induced cellular influx and microvascular leakage (n=9, p<0.001) without altering responses to MCh. This effect was reserved by L-arginine. L-NAME (n=5, p<0.01) and S-methyl-L-thiocitrulline (n=6, p<0.001) further potentiated the allergen-induced hyperresponsiveness without altering cellular inflammation. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsiveness to MCh (p<0.05). From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo rats, nitric oxide production by inducible nitric oxide synthase plays a role in the migration of inflammatory cells and increase in vascular permeability following allergen challenge, whereas nitric oxide produced by the constitutively expressed neuronal nitric oxide synthase limits hyperresponsiveness to methacholine.
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PMID:Differential effects of nitric oxide synthase inhibitors in an in vivo allergic rat model. 1085 51

The role of nitric oxide (NO) derived from constitutive (cNOS) and inducible (iNOS) nitric oxide synthases and its relationship to oxygen-derived free radicals and prostaglandins was investigated in two models of inflammation, namely, carrageenan granuloma air pouch (acute model) and Freund's adjuvant-induced arthritis (chronic model) in rats. Inflammation was assessed by measurement of NO and prostaglandin E2 (PGE2) levels and the lysosomal leakage of the enzyme N-acetyl-B-D-glucosaminidase (NAG) into the exudate of the granuloma pouch 4 h after carrageenan injection. Evaluation of paw volume and determination of serum NO, lipid peroxide (LP), and PGE2 levels were used for the assessment of adjuvant-induced arthritis after either 4 days (early phase) or 16 days (late phase) of adjuvant injection. Results of the study showed that the administration of either NG-nitro-L-arginine methyl ester (L-NAME, non-selective cNOS/iNOS inhibitor) or aminoguanidine (AG, selective iNOS inhibitor), prior to carrageenan injection or during development of adjuvant arthritis, caused a significant reduction in NO and PGE2 levels and in the NAG activity of the granuloma inflammatory exudate, whereas decreases in paw volume and in serum NO level were noticed in the adjuvant model as related to untreated rats. Similar treatment with L-arginine failed to elaborate a significant change in the parameters measured. Other observations included: no noticeable differences between the results of early and late phases of adjuvant arthritis; no clear correlation between NO, LP and PGE2 levels in the adjuvant arthritis inflammation and inability of the NOS inhibitors to modify the levels of serum LP that is increased during adjuvant-induced arthritis. The data give further evidence that NO is implicated in the development of both acute and chronic inflammation and that NOS inhibitors have potential antiinflammatory activity. Further studies are required to unravel the mechanisms by which NO interacts with other mediators of inflammation.
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PMID:Modulation of nitric oxide synthesis in inflammation. Relationship to oxygen-derived free radicals and prostaglandin synthesis. 1085 72

1. Endotoxin shock is accompanied by an increase in peripheral vascular permeability. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Here we examined the effect of lipid A analogue ONO-4007 in increasing vascular permeability and the possible mediators in mouse skin by a dye leakage method. 2. Subcutaneous injection of ONO-4007 (1 - 2 mg site(-1)) induced a dose-dependent increase in vascular permeability which was evident after 120 min. 3. ONO-4007-induced dye leakage was significantly attenuated by pretreatments with anti-tumour necrosis factor-alpha (TNF-alpha) and anti-interleukin-1alpha (IL-1alpha) antibodies, but not with indomethacin (5 mg kg(-1)) or diphenhydramine (10 mg kg(-1)). ONO-4007-induced dye leakage was significantly inhibited by a pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg kg(-1)) but not with aminoguanidine (50 mg kg(-1)). In inducible nitric oxide synthase (iNOS)-deficient mice, ONO-4007 significantly increased the dye leakage, while ONO-4007 dilated rat thoracic aortic rings pre-contracted with phenylephrine, and the L-NAME pretreatment inhibited the dilation. 4. Thus, TNF-alpha, IL-1alpha and constitutive NOSs-derived nitric oxide but not prostaglandins or histamine play a role in ONO-4007-induced increase in vascular permeability. Although ONO-4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO-4007 were not identical to those of LPS.
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PMID:Role of inflammatory mediators in lipid A analogue (ONO-4007)-induced vascular permeability change in mouse skin. 1090 60

Cisplatin is known to cause inner ear damage (ototoxicity). The role of inducible nitric oxide synthase (iNOS) in the cochlea of guinea pigs after injections of cisplatin or a combination of cisplatin and NOS inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) i.p. was examined electro-and immunohistochemically. The auditory brain stem responses (ABR) were measured prior to injection and 3 days after the injection. Three days after injection, the cochleas were examined immunohistochemically for iNOS. We found that iNOS was expressed in the cisplatin- and L-NAME/ cisplatin-treated cochlea. The threshold shift of ABR was significant in the cisplatin group, whereas it was decreased in the L-NAME/cisplatin group. iNOS catalyzed high NO levels lead to inner ear dysfunction. Our results indicate that iNOS mediates the ototoxicity of cisplatin.
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PMID:Nitric oxide synthase inhibitor suppresses the ototoxic side effect of cisplatin in guinea pigs. 1091 57


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