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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway.
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PMID:Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. 788 56

Hypoxemia and anemia are associated with increased CBF, but the mechanisms that link the changes in PaO2 or arterial O2 content (CaO2) with CBF are unclear. These experiments were intended to examine the contribution of nitric oxide. CaO2 in pentobarbital-anesthetized rabbits was reduced to approximately 6.5 mL O2/dL by hypoxemia (PaO2 approximately 24 to 26 mm Hg) or hemodilution with hetastarch (hematocrit approximately 14% to 15%). Animals with normal CaO2 (approximately 17.5 to 18 mL O2/dL) served as controls. In part I, each animal was given 3, 10, and 30 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) intravenously (total 43 mg/kg) to inhibit production of nitric oxide. Forebrain CBF was measured with radioactive microspheres approximately 15 to 20 minutes after each dose. Baseline CBF was greater in hypoxemic rabbits (111 +/- 31 mL x 100 g-1 x min-1, mean +/- SD) than in hemodiluted (70 +/- 22 mL x 100 g-1 min-1) or control animals (39 +/- 12 mL x 100 g-1 min-1). L-NAME (which reduced brain tissue nitric oxide synthase activity by approximately 65%) reduced CBF in hypoxemic animals to 80 +/- 23 mL x 100 g-1 x min-1 (P < 0.0001), but had no significant effect on CBF in either anemic or control animals. In four additional rabbits, further hemodilution to a CaO2 of approximately 3.5 mL O2/dL increased baseline CBF to 126 +/- 21 mL x 100 g-1 min-1, but again there was no effect of L-NAME. In part II, animals were anesthetized as above, and a close cranial window was prepared. The cyclic GMP (cGMP) content of the artificial CSF superfusate was measured under baseline conditions, and then after the reduction of CaO2 to approximately 6.5 mL O2/dL by either hypoxemia or hemodilution. Concentrations of cGMP did not change during either control conditions or after hemodilution. However, cGMP increased significantly with the induction of hypoxemia. The cGMP increase in hypoxemic animals could be blocked with L-NAME. These results suggest that nitric oxide plays some role in hypoxemic vasodilation, but not during hemodilution.
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PMID:Cerebral blood flow during hypoxemia and hemodilution in rabbits: different roles for nitric oxide? 939 31

It has been shown that granulocyte/macrophage colony stimulating factor (GM-CSF) is able to support myeloma cell propagation in cooperation with interleukin (IL)-6, the major growth factor for malignant plasma cells, although the biological mechanisms involved remain unknown. Therefore we investigated (i) the expression levels of the GM-CSF receptor (GM-CSFR) constituents in three malignant plasma cell lines and in native malignant plasma cells, (ii) the ability of the receptor to mediate common signalling pathways regulating proliferation and cell survival in malignant plasma cell lines, and (iii) the effects of GM-CSF on tumour cell biology. The GM-CSFRalpha subunit was detected in the malignant plasma cell lines RPMI-8226, MC/CAR, IM-9 as well as 6/6 native myeloma cell samples derived from the bone marrow of patients with overt disease. Furthermore, GM-CSFR expression was also detected in the CD19+ fraction from 2/3 bone marrow samples and 5/8 peripheral blood samples derived from patients with malignant plasma cell disorders, but not in the CD19+ fraction of peripheral blood from healthy donors. The expressed cytokine receptor alpha-subunit was able to constitute a functional signalling complex with the ubiquitously expressed GM-CSFRbeta subunit, as demonstrated by the fact that GM-CSF induced the p21-ras/mitogen-activated protein kinase (MAPK) signalling cascade in malignant plasma cell lines. Since this signalling cascade plays an essential role in the mediation of both proliferation and cell survival, we investigated the impact of GM-CSF on these two events. Application of GM-CSF led to an increase of DNA-synthesis in MC/CAR, IM-9 and RPMI-8226 cells. Furthermore, it increased longevity of these malignant plasma cell lines by reducing the rates of spontaneous apoptosis. We conclude that (i) the functional GM-CSFR is commonly expressed on malignant plasma cells and that (ii) GM-CSF promotes the clonal expansion of myeloma cells by inhibiting spontaneous apoptosis and promoting DNA synthesis.
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PMID:Functional granulocyte/macrophage colony stimulating factor receptor is constitutively expressed on neoplastic plasma cells and mediates tumour cell longevity. 973 60

The eosinophilic (EOS) leukocyte has been implicated as a primary effector cell in inflammatory and allergic diseases. Cytokines are among the mediators of inflammatory and allergic diseases which modulate the effector functions of EOS. Certain cytokines, elevated in patients with various allergies, are thought to modulate EOS reactive oxygen species superoxide anion and nitric oxide (NO) responses. Though EOS transcribe and translate mRNA for inducible NO synthase, the effects of cytokines on NO generation remain largely unknown. Thus, we have investigated effects of IL-3, IL-5, GM-CSF, IL-8, RANTES and the proinflammatory cytokines TNF-alpha and IFN-gamma, on superoxide anion and NO generation by clone 15 HL-60 human eosinophilic cells. Cytokine treatments (3 and 18 h) resulted in production of small amounts of superoxide anion which were enhanced by the NO inhibitor L-NAME. In the presence of L-NAME, PMA (1 nM) stimulation significantly increased superoxide anion generation following 3 h treatments with IL-3, TNF-alpha or IFN-gamma. Eighteen hour cytokine treatments with GM-CSF, IL-8, RANTES, IFN-gamma or TNF-alpha primed the cells for enhanced reactive oxygen species following exposure to an EOS stimulant. Inhibition of NO synthesis resulted in increased levels of superoxide anion. Collectively, these results suggest that an environment of proinflammatory cytokines may potentiate the generation of reactive oxygen species by EOS. These results further suggest that at an inflammatory site or during an allergic response, EOS may concomitantly synthesize NO and generate superoxide anion, fractions of which may rapidly react to form the potent oxidant peroxynitrite.
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PMID:Cytokines potentiate human eosinophil superoxide generation in the presence of N(omega)-nitro-L-arginine methyl ester. 1068 1

The role of oxygen free radical generation during reversible focal cerebral ischemia and its relationship to nitric oxide mediated mechanisms were examined. In this study, a left frontal cortex microdialysis probe was placed into the previously defined ischemic penumbra region and perfused with a salicylate/CSF solution in the presence or absence of the nitric oxide synthase (NOS) inhibitor L-NAME. Rats were then subjected to transient left hemisphere focal cerebral ischemia. Dialysate was collected at baseline and during the ischemic/reperfusion phase, and the hydroxylation products of salicylate were measured by HPLC with electrochemical detection. A significant elevation of free radical adduct formation was observed in the penumbra region during ischemia/reperfusion. This elevation was significantly attenuated by L-NAME during the reperfusion phase. Elevation of free radical adduct formation within the penumbra region during cerebral ischemia/reperfusion may be mediated in part by NOS-dependent mechanisms.
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PMID:Attenuation of free radical generation during reversible focal cerebral ischemia with the nitric oxide inhibitor, L-NAME (L-N(G)-nitro-L-arginine methyl ester). 1079 96

Intracellular Ca(2+) mobilization and release into mammal CSF plays a fundamental role in the etiogenesis of fever induced by the proinflammatory cytokine interleukin-1beta (IL-1beta) and other pyrogens. The source and mechanism of IL-1beta-induced intracellular Ca(2+) mobilization was investigated using two experimental models. IL-1beta (10 ng/ml) treatment of rat striatal slices preloaded with (45)Ca(2+) elicited a delayed (30 min) and sustained increase (125-150%) in spontaneous (45)Ca(2+) release that was potentiated by l-arginine (300 microm) and counteracted by N-omega-nitro-l-arginine methyl ester (l-NAME) (1 and 3 mm). The nitric oxide (NO) donors diethylamine/NO complex (sodium salt) (0.3 and 1 mm) and spermine/NO (0.1 and 0.3 mm) mimicked the effect of IL-1beta on Ca(2+) release. IL-1beta stimulated tissue cGMP concentration, and dibutyryl cGMP enhanced Ca(2+) release. The guanyl cyclase inhibitors 1H-[1,2, 4]oxadiazole[4,3-a] quinoxalin-1-one (100 microm) and 6-[phenylamino]-5,8 quinolinedione (50 microm) counteracted Ca(2+) release induced by 2.5 but not 10 ng/ml IL-1beta. Ruthenium red (50 microm) and, to a lesser extent, heparin (3 mg/ml) antagonized IL-1beta-induced Ca(2+) release, and both compounds administered together completely abolished this response. Similar results were obtained in human astrocytoma cells in which IL-1beta elicited a delayed (30 min) increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) (402 +/- 71.2% of baseline), which was abolished by 1 mm l-NAME. These data indicate that the NO/cGMP-signaling pathway is part of the intracellular mechanism transducing IL-1beta-evoked Ca(2+) mobilization in glial and striatal cells and that the ryanodine and the inositol-(1,4,5)-trisphosphate-sensitive Ca(2+) stores are involved.
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PMID:Nitric oxide modulation of interleukin-1[beta]-evoked intracellular Ca2+ release in human astrocytoma U-373 MG cells and brain striatal slices. 1112 73

We examined the role of the central nervous system, and particularly the renin-angiotensin (RA) system, in the development of hypertension produced by chronic inhibition of NO synthesis. In experiment 1, Wistar rats drank either nitro-L-arginine-methyl ester (L-NAME) or tap water. Before L-NAME treatment rats were divided into 6 groups. Four of them were administered either losartan or artificial cerebroventricular fluid (a-CSF) intracerebroventricularly (i.c.v.) for 1 week using an osmotic mini pump. The other two groups were administered the same amount of losartan intravenously (i.v.). In experiment 2, cardiovascular responses to acute i.c.v. losartan and muscimol, a GABA(A) agonist, were examined in conscious L-NAME-treated rats. Finally, in experiment 3, effects of ablation of the AV3V (anteroventral third ventricle) area, known to be one of the centers of cardiovascular control, were tested in the development of L-NAME hypertension. The development of hypertension by L-NAME treatment was attenuated with chronic i.c.v. losartan in a dose-dependent manner, while i.v. losartan had no effect. One week after cessation of i.c.v. losartan, blood pressure was elevated to the same level as in a-CSF-infused, L-NAME-treated rats. Acute i.c.v. losartan produced no cardiovascular changes in either L-NAME-treated or control rats. On the other hand, although i.c.v. muscimol elicited depressor effects in both groups, these responses were significantly larger in L-NAME-treated rats. Cardiovascular responses to i.v. hexamethonium were similar in both groups. The existence of prior lesions in the AV3V area significantly attenuated the development of L-NAME-induced hypertension. These results indicate that the central RA system plays an important role in the development of hypertension produced by chronic inhibition of NO synthase. Moreover, disorder of the central GABA system, rather than that of the RA system, might be important in the maintenance of hypertension in this model.
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PMID:Role of the central nervous system in the development of hypertension produced by chronic nitric oxide blockade in rats. 1121 29

TNF-related apoptosis-inducing ligand (TRAIL) shares significant homology with CD95 (Fas) ligand and has the ability to induce apoptosis in sensitive cells through a caspase-mediated pathway. We have evaluated the activity of purified human recombinant soluble TRAIL (S-TRAIL, comprising residues 114-281; Biomol, Plymouth Meeting, PA, USA) and a leucine zipper construct of TRAIL (LZ-TRAIL; Immunex, Seattle WA, USA) against myeloma cell lines NCI H929, U266, RPMI 8226, the FasL-sensitive Jurkat T cell ALL line, the lymphoblastoid cell line MC/CAR and primary tumour cells from 16 myeloma patients. Furthermore, we examined the relationship between TRAIL-induced apoptosis and TRAIL receptor expression utilising RT-PCR and flow cytometry. Two of three myeloma cell lines and Jurkat were TRAIL sensitive whereas MC/CAR was relatively resistant. Five of 16 (31%) primary tumours demonstrated > or =20% reduction in myeloma cells following TRAIL incubation (20-59%). This did not correlate with prior therapy. Four cell lines (two sensitive) and five primary tumours (two sensitive) demonstrated mRNA expression of the intra-cellular death domain containing TRAIL-R1. Variable expression of the two decoy (TRAIL-R3 and R4) and soluble (osteoprotegerin) receptors was seen and this did not correlate with TRAIL resistance. We conclude that myeloma cell expression of death effector receptors for TRAIL is insufficient to confer sensitivity to TRAIL-induced apoptosis but that in a significant minority of patients, irrespective of prior therapy, tumour cells are sensitive to TRAIL. The further investigation of TRAIL as an adjunct to presently available therapies for myeloma is justified.
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PMID:TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy. 1158 25

Angiotensin II (50 ng/5 microl) and L-NAME (250 microg/5 microl), an inhibitor of NO synthase (NOS), were administered intracerebroventricularly alone or in combination to conscious rats. Mean arterial blood pressure (MABP) increased reaching a peak within 5 min in all groups compared to controls treated with the vehicle, artificial CSF (5 microl). MABP returned to basal levels at 30 min after angiotensin II and remained stable for the following 90 min. In animals treated with L-NAME alone, after the initial pressor response, MABP declined but began to increase progressively from 30 min until the end of the experiment at 120 min. When administered with angiotensin II, however, the initial pressor response was prolonged. Angiotensin II-induced drinking was significantly attenuated by L-NAME. In control rats, inhibiting NOS elevated plasma levels of oxytocin and vasopressin but in angiotensin II-stimulated animals, only oxytocin was further elevated after L-NAME. Thus, NO formed centrally inhibits basal secretion of oxytocin and vasopressin as well as the resting blood pressure. During stimulation with angiotensin II, NO facilitates drinking, limits the pressor response and selectively inhibits oxytocin release.
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PMID:NO and angiotensin II effects on blood pressure and fluid homeostasis. 1530 73

It has been clearly established that osteoclasts, which play a crucial role in bone resorption, differentiate from hematopoietic cells belonging to the monocyte/macrophage lineage in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). We have here investigated the M-CSF- and RANKL-induced osteoclastic differentiation of two distinct clones of the murine monocytic/macrophagic RAW 264.7 cell line, known as TIB-71 and CRL-2278, the latter cell clone being defective for the expression of the inducible nitric oxide synthase isoform in response to interferon-gamma or lipopolysaccharide. CRL-2278 cells demonstrated a more rapid osteoclastic differentiation than TIB-71 cells, as documented by morphology, tartrate-resistant acid phosphatase positivity, and bone resorption activity. The enhanced osteoclastic differentiation of CRL-2278 was accompanied by a higher rate of cells in the S/G2-M phases of cell cycle as compared to TIB-71. The analysis of nitric oxide synthase (NOS) isoforms clearly demonstrated that only neuronal NOS was detectable at high levels in CRL-2278 but not in TIB cells under all tested conditions. Moreover, the broad inhibitor of NOS activity L-NAME significantly inhibited osteoclastic differentiation of CRL-2278 cells. Altogether, these results demonstrate that a basal constitutive neuronal NOS activity positively affects the RANKL/M-CSF-related osteoclastic differentiation.
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PMID:Different levels of the neuronal nitric oxide synthase isoform modulate the rate of osteoclastic differentiation of TIB-71 and CRL-2278 RAW 264.7 murine cell clones. 1614 87


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