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 regulatory signals required to induce the production of IL-8, an important neutrophil chemoattractant and activator, have yet to be clearly defined. We examined the role of nitric oxide (NO) in IL-8 regulation. The NO synthase inhibitor, (L)-NG-nitroarginine methyl ester (L-NAME), inhibited the TNF-stimulated IL-8 production in the human endothelial cell line, ECV304, in a dose-dependent manner without affecting cellular viability (TNF alone, 5.5 +/- 0.9 ng/ml; TNF + 5 mM L-NAME, 2.4 +/- 0.5 ng/ml). Moreover, exogenously added NO produced by the spontaneous NO generating compounds, S-Nitroso-N-acetyl-D,L-pennicillamine (SNAP) and Ethanamine, 2,2'-(hydroxynitrosohydrazono)bis- (DETA NONOate), induced a dose-dependent release of IL-8 from these cells. Maximal stimulation of IL-8 was found to be 1.2 +/- 0.1 ng/ml with the 1 mM concentration of SNAP and 1.6 +/- 0.1 ng/ml with the 2 mM concentration of DETA NONOate. These results provide key evidence substantiating a regulatory role of NO in IL-8 expression.
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PMID:Nitric oxide regulation of IL-8 expression in human endothelial cells. 779 82

Adhesion of circulating tumor cells to microvascular endothelium plays an important role in tumor metastasis to distant organs. The purpose of this study was to determine whether nitric oxide (NO) would attenuate tumor cell adhesion (TCA) to naive or lipopolysaccharide (LPS)-treated postcapillary venules. A melanoma cell line, RPMI 1846, was shown to be much more adhesive to postcapillary venules isolated from rat mesentery than to corresponding precapillary arterioles. Although venules exposed to LPS for 4 h demonstrated an increased adhesivity for the melanoma cells, TCA to LPS-treated arterioles was not altered. Isolated venules exposed to DETA/NO (1 mM), an NO donor, for 30 min prior to tumor cell perfusion prevented the increment in adhesion induced by LPS and attenuated TCA to naive postcapillary venules. While L-arginine (100 microM), an NO precursor, failed to decrease TCA to naive postcapillary venules, this treatment abolished LPS-stimulated TCA to postcapillary venules. The effect of L-arginine was reversed by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), an NO synthase (NOS) inhibitor. These observations indicate that both exogenous and endogenous NO modulate TCA to postcapillary venules. To assess the role of NO-induced activation of cGMP in the reduction in TCA produced by DETA/NO, two additional series of experiments were conducted. In the first series, LY-83583 (10 microM), a guanylyl cyclase inhibitor, was shown to completely reverse the effect of DETA/NO on TCA to both naive and LPS-activated postcapillary venules. On the other hand, administration of 8-bromoguanosine 3',5'-cyclic monophosphate (8-B-cGMP) (1 mM), a cell permeant cGMP analog, mimicked the effect of DETA/NO and reduced TCA to LPS-stimulated postcapillary venules. These data suggest that (a) tumor cells are more likely to adhere to postcapillary venules than to corresponding precapillary arterioles, (b) LPS enhances TCA to postcapillary venules, (c) both exogenously applied (DETA/NO) and endogenously generated (L-arginine) NO attenuate the enhanced adhesion induced by LPS, but only DETA/NO reduced TCA to naive postcapillary venules, and (d) the NO-induced reduction in TCA to LPS-activated postcapillary venules occurs by a cGMP-dependent mechanism.
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PMID:Nitric oxide reduces tumor cell adhesion to isolated rat postcapillary venules. 887 7

While the regulation of nitric oxide (NO) by inflammatory cytokines or lipopolysaccharide (LPS) has received considerable attention, NO modulation of cytokine expression has yet to be fully explored. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited interleukin (IL)-8 and IL-6 production in LPS-stimulated human whole blood in a dose-dependent manner. In the presence of 1 microgram/mL LPS, L-NAME blocked IL-8 release (72 +/- 4% inhibition at 20 mM (mean +/- SEM, p < .05)) 24 h post-LPS without affecting cellular viability. IL-6 production was significantly inhibited only with the highest dose of L-NAME used. L-NAME inhibition of IL-8 production was also observed at the mRNA level. Conversely, direct exposure of whole blood to NO with the spontaneous NO liberator DETA NONOate caused a dose-dependent stimulation of IL-8, but had no effect on IL-6 release. IL-8 concentrations rose from 8.3 +/- 1.9 ng/mL at 24 h to 31.7 +/- 7.6 ng/mL at 72 h with a single stimulation of 10 mM DETA NONOate. The hydroxyl radical scavenger dimethyl sulfoxide (DMSO) prevented the DETA NONOate induction of IL-8, suggesting the participation of the hydroxyl radical in the NO-induced IL-8 production. These results provide important evidence substantiating a role for NO as a regulator of cytokine expression.
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PMID:Nitric oxide regulation of interleukin-8 gene expression. 898 33

The beneficial effects of angiotensin-converting enzyme inhibitors on ameliorating cardiac fibrosis have been partially attributed to their ability to prevent the degradation of kinins. The potential role of bradykinin and the related signaling molecule nitric oxide (NO) in modulating extracellular matrix (ECM) production was examined in primary cultures of adult rat cardiac fibroblasts. Treatment of fibroblasts with 5 nM bradykinin for 24 h led to a reduction in steady-state mRNA levels for fibronectin (34 +/- 7%) and collagens type I (19 +/- 8%) and type III (48 +/- 4%), as determined by Northern blot analysis. The NO synthase inhibitor L-NAME attenuated the reduction observed in fibronectin and collagen mRNA levels in response to bradykinin. The NO donor DETA NONOate (100 microM) mimicked the effects of bradykinin on ECM mRNA levels. Protein levels of soluble fibronectin, assessed in conditioned medium by ELISA, were decreased by 14 +/- 4% and 21 +/- 4% after 48 h treatment with 1 microM bradykinin and 100 microM DETA NONOate, respectively. Bradykinin stimulated intracellular cGMP accumulation 73.7 +/- 10.3% after 10 min of treatment. Cell proliferation rates at 48 h were unaffected by bradykinin, but were reduced by 26 +/- 12% by 100 microM DETA NONOate. These data indicate that bradykinin downregulates ECM protein production in cardiac fibroblasts and suggest that NO and the related signaling molecule cGMP may play an important role in mediating this response.
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PMID:Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. 1009 57

The present study investigated the effect of nitric oxide (NO) on the lifespan of the corpus luteum (CL). Using a competitive nitric oxide synthase (NOS) inhibitor, L-nitro arginine methyl ester (L-NAME, 600 micromol/l), and a long-life NO donor, diethyl-aminetriamine (DETA-NONOate, 10(-8), 10(-6) or 10(-4) mol/l), we found that in ovaries from rats at the mid stage of CL development, endogenous NO increased both glutathione (GSH) and progesterone production. However, during prostaglandin F(2 alpha) (PGF(2 alpha))-induced luteolysis NO acted as an intermediary molecule in the inhibitory effect of PGF(2 alpha), on GSH content. This was supported by the fact that in-vivo PGF(2 alpha) treatment enhanced nitric oxide synthase (NOS) activity. These results indicate that the NO could act with a dual action (protective or pro-oxidant) in CL development.
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PMID:Dual effects of nitric oxide in functional and regressing rat corpus luteum. 1113 59

Nitric oxide (NO) affects cyclooxygenase (COX) and lipooxygenase (LOX) activities in several tissues. The aim of this study was to investigate the effect of NO on the AA metabolism in the anterior pituitary. LOX and COX products from anterior pituitaries of Wistar male rats were determined by [14C]-AA radioconversion method. Sodium nitroprusside (NP, 0.5 mM) and DETA NONOate (1 mM), NO donors, decreased 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) synthesis (P<0.05), effects that were reversed by hemoglobin. L-arginine also inhibited LOX activity. To the contrary, the inhibition of NO synthase by L-NAME (0.5 mM) or aminoguanidine (0.5 mM) increased 5-HETE production (P<0.05). COX activity was slightly stimulated by NP and L-arginine. However, DETA NONOate induced a stimulation of the synthesis of all prostanoids (P<0.05), this effect being reversed by hemoglobin. Neither NOS inhibitors nor hemoglobin modified basal prostanoids synthesis. These results indicate that NO inhibits LOX activity and stimulates COX activity in the anterior pituitary gland. The inhibition of LOX by NO may be another mechanism involved in the effects of NO on hormone release in the anterior pituitary.
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PMID:Role of nitric oxide in the metabolism of arachidonic acid in the rat anterior pituitary gland. 1116 34

The present study investigated the effect of nitric oxide (NO) on megakaryocyte (Mk) proliferation induced by thrombopoietin (TPO). Low-density mononuclear cells (MNCs) and CD34+ cells from human bone marrow (BM) were cultured in liquid medium in the presence of sodium nitroprusside (SNP) or (Z)-1-[2-(aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate (DETA/NO) and then stimulated with TPO. Mk number decreased in both NO donors, as identified by flow cytometry 11 to 13 days after TPO stimulation. Nitrite, cyanide, or the carrier molecule DETA failed to reproduce the inhibition caused by NO donors. When CD34+ cells were treated with DETA/NO, the inhibition of Mk growth was even more pronounced than that in MNCs. Failure of the guanosine 3',5'-cyclic monophosphate (cGMP) analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) to inhibit Mk proliferation suggests that cGMP is not involved in Mk suppression mediated by NO. On the other hand, DNA analysis by flow cytometry showed that apoptosis of CD34+ cells and Mks seemed to be at least one of the mechanisms associated with the cytotoxic DETA/NO effect. Stimulation of MNCs or CD34+ cells with tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) increased endogenous NO levels and suppressed Mk growth. Treatment with NO synthesis inhibitors such as L -N(G)-monomethyl arginine (L -NMMA) or L -N(G)-nitroarginine methyl ester hydrochloride (L -NAME) partially reversed Mk growth inhibition induced by TNF-alpha and IFN-gamma, although increased NO levels returned to normal values. The results presented here strongly indicate that NO regulates the growth of Mks induced by TPO by a direct effect on both progenitors and mature Mks.
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PMID:Effect of nitric oxide on megakaryocyte growth induced by thrombopoietin. 1128 20

Leukocyte accumulation has been shown to be increased in sepsis. Moreover, in inducible nitric oxide synthase (iNOS) knockout mice, a further increase in leukocyte accumulation has been observed during sepsis, suggesting that nitric oxide (NO) may affect leukocyte/endothelial interaction. Accelerated peroxynitrite formation also occurs during sepsis. In the present study, the effect of peroxynitrite or NO on leukocyte adhesion to nitric oxide synthase (NOS)-inhibited or endotoxin-treated endothelium was examined. Bovine aortic endothelial cells were treated with either L-NAME or lipopolysaccharide (LPS) and interferon-gamma for 4 hr and subsequent leukocyte adhesion was measured. Both L-NAME and LPS treatment resulted in increased leukocyte adhesion compared with control. Neither a peroxynitrite donor, SIN-1, nor a direct NO donor, DETA-NO, had any effect on leukocyte adhesion to untreated endothelium. However, when the L-NAME or LPS-treated endothelial cells were treated simultaneously with either SIN-1 or DETA-NO, there was a significant reduction in leukocyte adhesion. Moreover, at the concentrations used in the present study, neither peroxynitrite nor NO showed harmful effects on normal cultured endothelial cells. These data demonstrating inhibition of leukocyte adhesion to endotoxin-treated endothelium suggest that peroxynitrite or NO may exert a beneficial effect during sepsis.
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PMID:Effects of nitric oxide and peroxynitrite on endotoxin-induced leukocyte adhesion to endothelium. 1147 60

Communication of agonist-induced membrane potential changes along blood vessels has been proposed to contribute to the coordination of microvascular function. Factors mediating septic shock may compromise this coordination. Using electrophysiology in a simplified in vitro model of endothelial cells grown as capillary-like structures, we aimed to determine (i) the effect of lipopolysaccharide (LPS) on endothelial cell membrane potential responses to ATP and KCl and (ii) the effect of LPS and nitric oxide (NO) on cell-to-cell communication. Treatment of 'capillaries' with LPS (10 microg/ml for 1 h) did not affect local responsiveness to ATP or KCl, but reduced cell communication by a tyrosine-kinase-dependent mechanism. Treatment of 'capillaries' with the NO donor DETA (100 microM) or the NO synthase inhibitor L-NAME (100 microM) had no effect on cell communication or the response to LPS. Endogenous NO production, stimulated by LPS + interferon-gamma (100 U/ml) treatment, also had no effect on cell communication beyond that of LPS alone. We conclude that LPS, but not NO, can modulate conduction of agonist-induced electrical responses along endothelial capillary-like structures in vitro.
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PMID:Communication of agonist-induced electrical responses along 'capillaries' in vitro can be modulated by lipopolysaccharide, but not nitric oxide. 1229 3

The purpose of this study was to investigate the role of endothelial nitric-oxide synthase (eNOS), cAMP, and p38 MAPK in tumor necrosis factor-alpha (TNF-alpha) expression induced by lipopolysaccharide (LPS). LPS dose- and time-dependently induced phosphorylation of p38 MAPK and TNF-alpha expression in neonatal mouse cardiomyocytes. TNF-alpha expression was preceded by p38 MAPK phosphorylation, and selective inhibition of p38 MAPK abrogated LPS-induced TNF-alpha expression. Deficiency in eNOS decreased basal and LPS-stimulated TNF-alpha expression in cardiomyocytes. NOS inhibitor l-NAME attenuated LPS-induced p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes, whereas NO donor 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (DETA-NO) (2 microm) or overexpression of eNOS by adenoviral gene transfer restored the response of eNOS(-/-) cardiomyocytes to LPS. These effects of NO were mediated through cAMP-dependent pathway based on the following facts. First, deficiency in eNOS decreased basal levels of intracellular cAMP, and DETA-NO elevated intracellular cAMP levels in eNOS(-/-) cardiomyocytes. Second, a cAMP analogue 8-Br-cAMP mimicked the effect of NO in eNOS(-/-) cardiomyocytes. Third, either inhibition of cAMP or cAMP-dependent protein kinase attenuated LPS-stimulated p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes. In conclusion, eNOS enhances LPS-stimulated TNF-alpha expression in cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-alpha expression. Moreover, the effects of NO on LPS-stimulated TNF-alpha expression are mediated through cAMP/cAMP-dependent protein kinase-dependent p38 MAPK pathway in neonatal cardiomyocytes.
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PMID:Endothelial nitric-oxide synthase enhances lipopolysaccharide-stimulated tumor necrosis factor-alpha expression via cAMP-mediated p38 MAPK pathway in cardiomyocytes. 1250 17


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