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 investigated the involvement of nitric oxide in transmural jejunal alterations induced by Trichinella spiralis (T. spiralis) infection in rats. Rats were gavaged with either saline or T.spiralis larvae, and, 1 h later, rats were treated orally with water, NG-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg), or NG-nitro-D-arginine methyl ester (D-NAME; 30 mg/kg) on a daily basis. Although not observed in jejunum from uninfected rats, inducible nitric oxide synthase (iNOS) mRNA was present in the mucosa and neuromuscular layers of jejunum from T. spiralis-infected rats. On day 6, T. spiralis-infected rats had a 6-fold decrease in transmural nitric oxide synthase activity, an 11-fold increase in plasma nitrite, and a 7-fold elevation in transmural myeloperoxidase (MPO) activity compared with uninfected controls. Intestinal smooth muscle cell hyperplasia and hypertrophy were only detected in the infected rats. L-NAME, but not D-NAME, treatment of infected rats for 6 days caused a pronounced increase in transmural iNOS mRNA expression, coinciding with significantly increased mucosal nitric oxide synthase activity. T. spiralis numbers in L-NAME-treated rats were significantly lower compared with the other two infected groups although L-NAME had no direct effect on T. spiralis viability in vitro. Furthermore, L-NAME treatment significantly reduced plasma nitrite and jejunal MPO but not intestinal smooth muscle cell hyperplasia or hypertrophy. In contrast, D-NAME treatment of infected rats significantly enhanced intestinal smooth muscle hyperplasia and hypertrophy. Taken together, these results suggest that alterations in the T. spiralis-infected jejunum are mediated, in part, by a suppression of nitric oxide synthase activity in the inflamed jejunum.
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PMID:Effects of oral L-NAME during Trichinella spiralis infection in rats. 877 50

Drugs with high selectivity for iNOS inhibition may be useful for treatment of neurodegenerative disorders, chronic inflammatory diseases, and septic shock. Therefore, U-19451A (2-benzyl-2-thio-pseudourea hydrochloride), a potential NOS inhibitor, has been investigated for its selectivity for iNOS using tissues, primary cerebellar granule cell cultures and glial cell cultures. Lungs isolated from rats treated with intravenous injection of E coli lipopolysaccharide and glial cell cultures treated with the same bacterial toxin plus gamma-interferon were used for iNOS activity. Rat cerebellum and primary cerebellar granule cell cultures were utilized for neuronal NOS (nNOS) activity. S-methylthiourea (SMT) and L-nitroarginine methyl ester (L-NAME), selective iNOS and nNOS inhibitors, respectively, were chosen as standards. Both U-19451A and SMT were 4-times more selective for iNOS as compared to nNOS in tissues. U-19451A was more selective than SMT for iNOS inhibition using cultures. L-NAME was 16-31 times more selective for inhibiting nNOS activity. Based on the selectivity of U-19451A for iNOS inhibition, this drug would be expected to be effective in the treatment of diseases with inflammatory pathology without producing side effects associated with nNOS inhibition.
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PMID:U-19451A: a selective inducible nitric oxide synthase inhibitor. 879 6

1 The role of nitric oxide (NO) derived from constitutive and inducible nitric oxide synthase (cNOS and iNOS) and its relationship to oxygen-derived free radicals and prostaglandins (PG) was investigated in a carrageenan-induced model of acute hindpaw inflammation. 2 The intraplantar injection of carrageenan elicited an inflammatory response that was characterized by a time-dependent increase in paw oedema, neutrophil infiltration, and increased levels of nitrite/nitrate (NO2-/NO3-) and prostaglandin E2(PGE2) in the paw exudate. 3 Paw oedema was maximal by 6 h and remained elevated for 10 h following carrageenan administration. The non-selective cNOS/iNOS inhibitors, NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME) given intravenously (30-300 mg kg-1) 1 h before or after carrageenan administration, inhibited paw oedema at all time points. 4 The selective iNOS inhibitors, N-iminoethyl-L-lysine (L-NIL) or aminoguanidine (AG), failed to inhibit carrageenan-induced paw oedema during the first 4 h following carrageenan administration, but inhibited paw oedema at subsequent time points (from 5-10 h). iNOS mRNA was detected between 3 to 10 h following carrageenan administration using ribonuclease protection assays. iNOS protein was first detected 6 h and was maximal 10 h following carrageenan administration as shown by Western blot analysis. Administration of the iNOS inhibitors 5 h after carrageenan (a time point where iNOS was expressed) inhibited paw oedema at all subsequent time points. Infiltrating neutrophils were not the source of iNOS since pretreatment with colchicine (2 mg kg-1) suppressed neutrophil infiltration, but did not inhibit the iNOS mRNA expression or the elevated NO2-/NO3- levels in the paw exudate. 5 Inhibition of paw oedema by the NOS inhibitors was associated with attenuation of both the NO2-/NO3- and PGE2 levels in the paw exudate. These inhibitors also reduced the neutrophil infiltration at the site of inflammation. 6 Recombinant human Cu/Zn superoxide dismutase coupled to polyethyleneglycol (PEGrhSOD; 12 x 10(3) u kg-1), administered intravenously either 30 min prior to or 1 h after carrageenan injection, inhibited paw oedema and neutrophil infiltration, but had no effect on NO2-/NO3- or PGE2 production in the paw exudate. The administration of catalase (40 x 10(3) u kg-1), given intraperitoneally 30 min before carrageenan administration, had no effect on paw oedema. Treatment with desferrioxamine (300 mg kg-1), given subcutaneously 1 h before carrageenan, inhibited paw oedema during the first 2 h after carrageenan administration, but not at later times. 7 These results suggest that the NO produced by cNOS is involved in the development of inflammation at early time points following carrageenan administration and that NO produced by iNOS is involved in the maintenance of the inflammatory response at later time points. The potential interactions of NO with superoxide anion and PG is discussed.
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PMID:Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. 879 51

Systemically administered 3-nitropropionic acid (3-NPA) that inhibits the mitochondrial oxidative phosphorylation induces selective lesions in the striatum. To investigate the nature of these selective lesions, we administered 3-NPA (20 mg/kg, s.c. daily for 2 or 3 days) to Wistar rats and investigated the behavioral disturbance, striatal lesions and their variations after modulating the activity of nitric oxide synthase (NOS). On the second or third day of 3-NPA administration, half the animals manifested behavioral disturbances (paddling, rolling, tremor, abnormal gait, and recumbence). A strong extravasation of immunoglobulin G (IgG) and a decrease in immunoreaction for glial fibrillary acidic protein (GFAP) were detected, and iNOS-like (iNOS-L) immunoreactive small cells appeared in the lateral and central striatum especially around the vessels. A week later, lesions lacking GFAP-immunoreaction were detected in the striatum in survived animals. Pretreatment with N-nitro-L-arginine methyl ester (L-NAME) along with each injection of 3-NPA did not improve the behavioral disturbances nor the survival rate, but attenuated the extravasation of IgG and iNOS-L immunoreaction. Pretreatment with aminoguanidine or FK506 improved the behavioral symptoms and survival rate. Extravasation of IgG and expression of iNOS-L immunoreactivity were attenuated, and the striatal lesion was reduced. Data indicate the involvement of NO in the high vulnerability of the striatum, and that iNOS, one of inflammatory markers, is induced following exposure to 3-NPA.
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PMID:3-Nitropropionic acid produces striatum selective lesions accompanied by iNOS expression. 881 25

We addressed the hypothesis that administration of nitric oxide synthase inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) does not result in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS). L-NAME was administered in the drinking water (0.1-1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [1] ex vivo formation of nitrite in blood vessels and intestine [2] tissue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diaphorase staining [5] direct assessment of NO release in tissue explants using a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p < 0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pigs and novel sites of NADPH diaphorase staining in the intestine. We conclude that iNOS expression is responsible for a compensatory increase or normalization of NO synthesis during sustained administration of L-NAME.
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PMID:Failure of L-NAME to cause inhibition of nitric oxide synthesis: role of inducible nitric oxide synthase. 881 57

Gram-positive bacteria are recognized pathogens in urinary tract infections. Lipoteichoic acids, major components of the cell wall of gram-positive bacteria, are important virulence attributes, but their mechanism of action is not well understood. We have postulated that infection-induced altered function of progenitors of urothelial cells (UT) residing in the basal layer is likely to have long-lasting effects on the architecture and function of the urothelium. Our earlier in vitro studies in UT of basal type, grown under growth restricting conditions, have shown that 1) treatment with lipoteichoic acid from Streptococcus faecalis (LT-2) stimulates a subpopulation of progenitors of urothelial cells to proliferate, and 2) resulting large colonies differentiated at an increased rate under conditions simulating those in the basal layer of the urothelium. The hypothesis underlying the present studies was that nitric oxide (NO) mediated LT-2 action on these functions of UT. Immunocytochemical studies using an antibody against inducible nitric oxide synthase (iNOS) confirmed expression of iNOS in LT-2-treated UT. Our hypothesis was tested by treating UT grown under growth restricting conditions (0.005% bovine pituitary extract) with LT-2 (25 micrograms/ml), in the presence or absence of inhibitors of NOS (1 mM NG-nitro-L-arginine methyl ester [L-NAME]; 1 microM dexamethasone [DEXA]) or 25 microM hemoglobin, a potent inactivator of NO. Treatment with LT-2 in the presence of these agents prevented the following effects of LT-2 alone: 1) the stimulatory effect on proliferation of single cells, as well as within the resulting large colonies; 2) the subsequent differentiation of large colonies resulting from this proliferative activity, as indicated by distribution of beta 1 subunit-containing integrins to cell-cell contacts; 3) the inhibitory effect on the subsequent ability of LT-2-treated UT to attach to extracellular matrix proteins. These studies suggest that induction of NOS by LT-2, initially aimed at restricting the replication of infectious agents, may have potential cost of damage to the host bladder by interfering with urothelial differentiation.
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PMID:Nitric oxide mediates the action of lipoteichoic acid on the function of human urothelial cells. 884 23

The inducible nitric oxide synthase (iNOS) present in vascular smooth muscle cells (VSMC) may play a role in the generation of nitric oxide (NO) in the vascular wall, regulating blood vessel tone in normotension and hypertension. In this study the effect of interleukin (IL)-1 beta, a cytokine that induces iNOS, on NO generation (measured as nitrite), cyclic guanosine monophosphate (cGMP) generation, and steady-state abundance of iNOS mRNA were examined in VSMC from 3 week old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, during the period preceding the elevation of blood pressure. With cell density dependent variations in nitrite production eliminated, VSMC from SHR and WKY did not differ in NO generation except after prolonged incubation (30 h), when SHR cells produced less NO. However, cGMP concentrations associated with IL-1 beta stimulation were significantly smaller in SHR VSMC than in cells from WKY. IL-1 beta stimulation resulted in increased abundance of iNOS mRNA to the same extent in both WKY and SHR VSMC. Inhibitors of NOS, NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine methyl ester (L-NAME), did not block the induction of iNOS mRNA, although nitrite production and cGMP generation were inhibited. The protein synthesis inhibitor cycloheximide and the RNA synthesis inhibitor actinomycin-D almost completely blocked the production of nitrite in cells from both strains of rats. Actinomycin-D completely blocked the induction of iNOS mRNA by IL-1 beta in cells from both strains of rats, whereas cycloheximide partially blocked its synthesis in WKY, but had no significant effect on IL-1 beta induced expression of iNOS mRNA in SHR VSMC. Thus, IL-1 beta controls iNOS gene expression at the transcriptional level, and an intermediate labile protein, whose synthesis is inhibited by cycloheximide, is required for IL-1 beta stimulated induction of iNOS mRNA transcription in WKY cells but not in SHR. We conclude that although iNOS is expressed to similar extent in VSMC of prehypertensive SHR and WKY and similar amounts of NO are initially generated, there are differences between the VSMC of SHR and WKY in the regulation of the transcription of iNOS mRNA, there is a lower sustained production of NO, and there is a reduced generation of cGMP in response to IL-1 beta stimulated NO production. These differences between VSMC from prehypertensive SHR and WKY may indicate a pathophysiological role of iNOS in early blood pressure elevation in SHR.
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PMID:Inducible nitric oxide synthase in vascular smooth muscle cells from prehypertensive spontaneously hypertensive rats. 887 43

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.
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PMID:Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats. 888 85

Administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) results in fetal growth retardation. This study was designed to further examine the influence of NO on fetal growth, specifically, the potential role of inducible NOS and to evaluate the possibility that apoptosis contributed to uteroplacental dysfunction. L-NAME administration caused a paradoxical increase in NO synthesis determined by direct detection of NO by electrochemistry, nitrite accumulation, and cGMP levels, indicating that a lack of NO was not the cause of the fetal growth retardation. Additionally, supplemental L-arginine or NO donors failed to reverse the effects of L-NAME on fetal and placental size. Administration of low dose endotoxin (30 micrograms/kg IP daily for 6 d) also caused significant reductions in fetal and placental size and increased NO synthesis comparable to that seen with L-NAME. Inducible NOS was constitutively expressed in the pregnant uterus (smooth muscle and epithelia) and placenta (sinusoids and macrophages) but was absent in the nonpregnant state as determined by RT-PCR and immunohistochemistry. Neither L-NAME nor endotoxin modified the expression of iNOS. In situ evidence for apoptosis (DNA fragmentation) was minimal to absent in control pregnant rats, but markedly evident in the placenta (decidua) and uterus of rats treated with L-NAME or endotoxin. Immunohistochemical evidence for nitrotyrosine, a marker for peroxynitrite formation, was absent in control rats but colocalized with apoptosis in the L-NAME and LPS groups. We conclude that L-NAME-induced fetal growth retardation is not due to a lack of NO, but as for endotoxin, results from a net reduction in cellular proliferation due to the induction of apoptosis, possibly in response to peroxynitrite formation.
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PMID:Fetal growth retardation in rats may result from apoptosis: role of peroxynitrite. 889 65

The aim of this study was to determine if nitric oxide (NO) production and nitric oxide synthase (NOS) isoforms change within the uterus and cervix during pregnancy and labour either at term or preterm. NO production was compared in the rat uterus and cervix of non-pregnant and pregnant rats on days 18-22 prior to labour, day 22 during delivery, 1 day post-partum and after treatment with either 10 mg onapristone or progesterone. Uterine NO synthesis, reflected in nitrite production, increased during gestation (194.2 +/- 22.6 nmol/g on day 19) compared with the non-pregnant state (76.2 +/- 18.4 nmol/g, P < 0.05) and decreased during term labour and post-partum. Furthermore, injection of lipopolysaccharide (LPS) (100 micrograms/rat i.p.) on day 20 of gestation resulted in a significant increase in NO synthesis after 6 h. Conversely, cervical NO synthesis and nitrite production was low in the non-pregnant (65.1 +/- 9.2 nmol/g) and pregnant animals on days 18-22 of gestation (53.2 +/- 9.0 nmol/g on day 22, P > 0.05), but markedly increased during term labour (139 +/- 28.6 nmol/g, P < 0.05). Treatment with the antiprogestin onapristone suppressed uterine NO production and increased cervical production while continuous administration of progesterone from day 19 had the opposite effect. LPS produced a significant increase in cervical NO production in both the pregnant (8-fold) and non-pregnant (4-fold) states. All three known NOS isoforms (i.e., iNOS, nNOS and eNOS) were detected in the cervical samples but only two were present in the uterus (iNOs and eNOS). An increase in the presence of iNOS occurred during labour at term compared with cervices collected from day 19. This was contrary to the measurements of the isoform in the uterus. Also, there was a similar increase of nNOS in the cervix during labour. This isoform seemed absent in the uterus during gestation. No significant changes occurred in the abundance of eNOS in the cervix during labour at term compared with day 19. During preterm labour after onapristone, iNOS concentrations increased significantly in the cervix. In order to examine whether the NO pathway plays a role in cervical ripening, the effects of the nitric oxide synthesis inhibitor L-nitro-arginine methylester (L-NAME) on the duration of delivery and on cervical extensibility were also investigated. The duration of delivery was significantly prolonged in L-NAME-treated rats compared with the control group (2.4-fold). Moreover, cervical extensibility decreased significantly (1.7-fold) after in-vitro incubation with L-NAME (P < 0.005). We conclude that the NO system may have an active role in the cascade of processes involved in preparing the uterus and cervix for parturition.
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PMID:Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. 892 Nov 28


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