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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) has been proposed as a neuronal messenger molecule in hypoxic/ischemic cell injury (Nowicki et al., 1991; Trifiletti, 1992). We conducted studies in a model of combined glucose-oxygen deprivation using cultured rat cerebellar granule cells. Experiments were designed to test the hypothesis that sustained elevation of cytosolic calcium ([Ca2+]i) and NO generation act in concert to trigger neuronal injury after anoxic insult. A hypoxic state was achieved by perfusing the cells with medium pre-equilibrated with argon gas. [Ca2+]i was monitored using digital-imaging fluorescence microscopy in cells loaded with fura-2 AM. Under short-term hypoxic conditions, cells displayed a progressive and sustained, moderate increase of [Ca2+]i, which returned to near basal levels on restoration of O2-containing medium. Prolonged hypoxic conditions (> 60 min) caused irreversible elevation of [Ca2+]i followed by disruption of cell membrane integrity, as indicated by severe swelling, loss of regular cell shape and processes, leakage of dye fura-2, and propidium iodide uptake ("point of no return"). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a specific NO synthase inhibitor, markedly delayed the onset of intensity of the rise of [Ca2+]i. The hypoxia-induced elevation of [Ca2+]i was also greatly attenuated if L-NAME (100 microM) was added to the argon-perfused medium before the cells demonstrated signs of irreversible injury. Prolonged or repeated hypoxic conditions, however, caused a rapid and intense increase of [Ca2+]i, which could not be blocked by inhibition of NO synthase (NOS). In addition, reoxygenation after the "point of no return," as characterized above, greatly potentiated [Ca2+]i overload and facilitated the process of cell injury. The potentiation and facilitation of cell damage, as demonstrated by rapid massive increase of [Ca2+]i and subsequent cell death, was not blocked by NOS inhibitor, L-NAME.
Mol Chem Neuropathol 1996 Feb
PMID:Involvement of nitric oxide in the deregulation of cytosolic calcium in cerebellar neurons during combined glucose-oxygen deprivation. 896

Recombinant human interferon-gamma (r-hu-IFN-gamma) has been found to exert an antitumor action in vivo in early stages of human malignant mesothelioma, and an antiproliferative effect in vitro. In order to study the mechanisms of cytostasis in mesothelioma cells, we examined two IFN-gamma-controlled metabolic pathways known to mediate growth arrest in various cell types, measuring production of the antiproliferative compound nitric oxide (NO) and degradation of tryptophan in nine human mesothelioma cell lines (HMCLs) displaying different sensitivities to the antiproliferative effect of r-hu-IFN-gamma. Two rat mesothelioma cell lines were also studied. IFN-gamma receptor was present and functional in HMCLs, regardless of their sensitivity to the growth-inhibitory effect of r-hu-IFN-gamma. However, no NO synthase activity or the resulting antiproliferative molecule NO were induced in HMCLs treated either with r-hu-IFN-gamma alone or with a combination of r-hu-IFN-gamma and other cytokines, and/or with lipopolysaccharide (LPS). In responsive HMCLs, r-hu-IFN-gamma induced strong indoleamine-2,3-dioxygenase (IDO) activity, which causes rapid degradation of tryptophan; however, the correlation between r-hu-IFN-gamma-mediated growth arrest and IDO induction was not absolute. In rat mesothelioma cells, NO synthase was induced in response to murine IFN-gamma + interleukin-1beta (IL-1beta) treatment, and played a role in the cytokine-mediated antiproliferative activity. However, NO production did not seem to be the unique antiproliferative mechanism induced by cytokines in these cells. Our results indicate that two classical pathways accounting for some of the cytostatic effects of IFN-gamma in rodent cells are not efficient in human mesothelioma cells, and suggest that cytokine-induced growth inhibition is mediated by a different pathway in HMCLs.
Am J Respir Cell Mol Biol 1997 Feb
PMID:Differential responsiveness of human and rat mesothelioma cell lines to recombinant interferon-gamma. 903 25

Basal vasomotor tone in coronary vessels is, in part, maintained by nitric oxide (NO) production by endothelial constitutive NO synthase (ecNOS). Alteration of coronary circulation observed in left ventricular hypertrophy secondary to hypertension could be associated with a decrease in NO production. The aim of this study was to measure: (1) coronary flow in the Langendorff-perfused heart model at baseline, after maximum vasodilation in response to adenosine (10(-5) M), after endothelium-dependent vasodilation in response to bradykinin (10(-8) M) and after ecNOS inhibition by nitro-L-arginine methyl ester (L-NAME) (10(-4) M); (2) medial thickening of coronary microvessels and perivascular collagen on histological heart sections; and (3) ecNOS expression by immunohistochemical staining in these vessels using 20-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto control rats (WKY). These measurements were determined by computer-directed color analysis. When SHR were compared with WKY rats, we found: (1) a decrease in basal flow (10.1+/-0.6 v 15.3+/-1.2 ml/min/g, n=10, P<0.0001), in maximum flow (15.4+/-0.7 v 24.3+/-1.3 ml/min/g, n=10, P<0.001), in bradykinin-induced flow increment (1.5+/-0.3 v 2.6+/-0.3 ml/min/g, n=5, P<0.05) and in L-NAME-sensitive flow (3.3+/-0.6 v 6.3+/-0.9 ml/min/g, n=7, P<0.05); (2) an increase in medial thickness (9.4+/-0.6 v 5.4+/-0.3 microm, n=8, P<0.001) and in perivascular collagen area (1509+/-311 v 462+/-120 microm2, n=8, P<0.01) of coronary arterioles; and (3) a decrease in ecNOS expression in the endothelium (ecNOS-stained cross-sectional area in arterioles: 40.0+/-9.1 v 84.6+/-9.0 microm2, n=7, P<O.005). These results suggest that in SHR the decrease in basal coronary flow can be related to a structural alteration of the microvessels with an increase of perivascular collagen but also to a decrease in ecNOS expression which might be associated with reduced NO production.
J Mol Cell Cardiol 1997 Jan
PMID:Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats. 904 21

The effects of prolonged (20 day) hyperbaric exposure (HBO) to oxygen on non adrenergic non cholinergic (NANC) contractile and relaxant responses of rat trachea were examined. The electrical field stimulation (EFS) of rat tracheal rings was performed at 30 Hz and contractile and relaxant responses were assessed in the absence or in the presence of pretreatment with L-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase, and L-Arginine (L-ARG), a precursor of NO synthesis, plus L-NAME. Our data demonstrated that L-NAME significantly (p < 0.05) enhanced the contractile responses induced by EFS (controls 30.6 +/- 0.99%; L-NAME 76.07 +/- 2.00%) and statistically (p < 0.05) reduced the relaxant component of EFS (controls 31.10 +/- 0.46; L-NAME 15.00 +/- 0.12); these effects were reversed when tissues were pretreated with L-ARG plus L-NAME, suggesting that NO plays a modulatory role in cholinergic neurotransmission and participates in EFS relaxant responses. Moreover, prolonged HBO exposure (20 days) at 202.6 and 303.9 kPa did not modify the contractile or relaxant responses induced by EFS, nor modify the L-NAME or L-ARG effects on EFS responses.
Res Commun Mol Pathol Pharmacol 1997 Jan
PMID:Effects of hyperbaric oxygen exposure on non-adrenergic non-cholinergic responses of rat trachea. 905 53

Rat peritoneal macrophages stimulated with lipopolysaccharide (LPS) and Phorbol myristate acetate (PMA) generated increased levels of superoxide anions (O2.-) by 122% as compared to those stimulated with PMA alone. However, Nitric oxide (NO) synthase inhibitors-n-monomethyl arginine (nMMA) or spermine-HCI lowered the enhanced levels of O2.- released by LPS treated macrophages. The Superoxide dismutase (SOD) activity in LPS treated macrophages was 51% lower than that observed in resident cells. NO synthase inhibitors prevented the loss of SOD activity in LPS treated cells. Exogenously added SOD during sensitization of cells with LPS also inactivated the enzyme. This inactivation of SOD is inhibited by Nitric oxide synthase inhibitors. PMA alone did not affect SOD activity. NO synthase inhibitors also did not affect PMA activated superoxide anion generation in macrophages. These studies indicate that nitric oxide generated by LPS treated macrophages can inactivate SOD activity.
Mol Cell Biochem 1997 Mar
PMID:Studies on the inactivation of superoxide dismutase activity by nitric oxide from rat peritoneal macrophages. 906 97

Lesion-induced induction of neuronal nitric oxide synthase (nNOS) was examined in the rat cerebellum. The stab-lesioned cerebellar cortex was examined with NADPH-diaphorase (NADPH-d) histochemistry and in situ hybridization using nNOS cRNA probe at 1, 3, 7, 14, 35 days post-lesion. NADPH-d- and nNOS mRNA-positive Purkinje cells appeared adjacent to the lesion by 3 days after the lesion. The area of distribution expanded and the number of positive cells increased at 7 days after the lesion, and at 14 days post-lesion, shrunken NADPH-d-positive Purkinje cells with irregular surface appeared. NADPH-d activity and nNOS mRNA signal could not be detected in Purkinje cells after 35 days post-lesion. Combined NADPH-d histochemistry and in situ hybridization using glutamic acid decarboxylase (GAD) cRNA probe revealed that nNOS-expressing Purkinje cells showed fewer GAD mRNA signals than those in normal Purkinje cells. The atrophic contour and the lower expression of GAD mRNA signals in NADPH-d positive Purkinje cells suggest that nNOS is expressed under a degenerating process.
Brain Res Mol Brain Res 1997 Mar
PMID:Lesion-induced neuronal nitric oxide synthase in Purkinje cells of the rat cerebellar cortex: histochemical and in situ hybridization study. 907 64

The levels of nitric oxide (NO) and NO synthase (NOS) activities in the brain of young-adult (3 months old), aged (11 months old) and nimodipine-administered (11 months old) senescence-accelerated mouse (SAM), of which SAMP8 sub-strain is inferior in acquisition of learning and has a lower content in testosterone, were compared. Nimodipine, which is L-type calcium ion channel blocker and has memory-enhancing effects, was administered orally for 5 months. In the cerebral cortex of aged SAMP8, NOS activity was increased compared with that of young-adult SAMP8. Though nimodipine did not alter the contents of NO in any brain regions compared with those in aged SAMP8, nimodipine increased NOS activity in the aged cerebellum. Our data suggest that nimodipine may increase NOS activity through elevation of testosterone level, as testosterone increases NOS only in the cerebellum, although further work is clearly needed to ascertain effects of nimodipine on testosterone metabolism and maintenance in the acquisition of learning.
Biochem Mol Biol Int 1997 Apr
PMID:The effects of chronic administration of nimodipine on age-related changes in nitric oxide and its synthase in senescence-accelerated mouse brain. 911 36

Nitric oxide (NO) is a cellular mediator and regulator of multiple biologic functions. NO released by alveolar macrophages (AM) is suggested to play a role in mediating pulmonary injury. In murine and rat macrophages, the expression of inducible NO synthase (iNOS) and the release of NO are well established. However, the existence of such a pathway in other species remains controversial. In this study, we examined NO production and iNOS expression by AM from rats and hamsters, two laboratory animal species that are characterized by their disparate pulmonary responses to various inhaled irritants/toxicants. AM were treated with lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), or tumor necrosis factor-alpha (TNF-alpha) in vitro, and nitrite, the stable oxidation product of NO, was assayed by the Griess reaction. Rat AM produced NO in a dose- and time-dependent manner upon stimulation with LPS and/or IFN-gamma, but not with TNF-alpha. Surprisingly, hamster AM did not release detectable levels of NO after the same treatment. Although iNOS expression was demonstrated in rat AM by immunocytochemical and Western blot analyses, no induction of iNOS expression could be found in hamster AM. Using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, we found that rat and hamster AM could be induced to express iNOS mRNA after treatment with LPS and IFN-gamma. The results presented here indicate that hamster AM, in contrast to rat AM, lack the ability to express iNOS protein and to generate NO in response to LPS, IFN-gamma, or TNF-alpha in vitro. In conclusion, our data suggest striking differences in iNOS regulation and NO production by AM from rats and hamsters, two rodent species that are commonly used in biomedical research and well-known for their disparate responses to pulmonary irritants/toxicants.
Am J Respir Cell Mol Biol 1997 Apr
PMID:Species differences in NO formation by rat and hamster alveolar macrophages in vitro. 911 52

Neuritic pathology is a major neuroanatomical correlate of dementia in Alzheimer disease (AD). Nitric oxide (NO) is linked to neuritic growth and synaptic plasticity. Expression of one of the enzymes responsible for NO synthesis, the constitutive endothelial NO synthase (ceNOS), was investigated in brains of AD and Down syndrome patients using RNase protection assays, in situ hybridization, and immunocytochemistry. In end-stage AD, ceNOS expression was reduced in cortical neurons, and the enzyme was aberrantly translocated to membranes of proliferated swollen or collapsed neuritic processes. In addition, ceNOS expression was strikingly increased in glial cells characterized mainly as protoplasmic (Type 2) astrocytes, which are responsible for maintaining the structural and functional integrity of cell processes in the CNS. In Down syndrome, similar abnormalities emerged by the third decade, preceding the cognitive decline and establishment of CERAD criteria for AD, indicating that aberrant ceNOS expression occurs early in the course of neurodegeneration. The results suggest that aberrant ceNOS translocation and gene regulation may have important roles in the pathogenesis of AD neuritic pathology.
Mol Chem Neuropathol
PMID:Aberrant expression of the constitutive endothelial nitric oxide synthase gene in Alzheimer disease. 913 25

Ribonuclease protection assay was used to demonstrate mRNA expression of several cytokines as well as inducible NO synthase (iNOS), constitutive endothelial NO synthase (cNOS) and perforin in the myocardium during the course of experimental autoimmune myocarditis (EAM) in rats. Interleukin 2 (IL-2) appeared in the initial inflammatory phase (day 14), subsided in the maximum inflammatory phase (day 19) and disappeared by the recovery phase (day 25). mRNA of IL-3 beta, interferon gamma INF-gamma and tumor necrosis factor alpha (TNF-alpha) were detected only in the maximum inflammatory phase and iNOS also appeared for several days at this time. In contrast. IL-10 mRNA was detected after the maximum inflammatory stage and persisted into the recovery phase (days 25-36). Although transforming growth factor beta 1 (TGF-beta 1) could be detected in all phases, the expression was markedly enhanced in the maximum inflammatory phase and gradually diminished (around day 36) to basal levels. Perforin mRNA was not detected at any point in the disease. Besides macrophages and CD4 T cells, a number of neutrophils were found in the myocardium especially at peak inflammatory stage. We suggest that antigen (Ag) primed Ag presenting cells or macrophages interact with T cells (Th1) to produce IL-2 and subsequent IFN-gamma, which further activates macrophages in the myocardium. Consequently, TNF-alpha and iNOS may inflict tissue damage to myocardium. It is also suggested that TGF-beta) and one representative Th2 cytokine, IL-10, help inhibit inflammation. These findings suggest that Th1 and Th2 cytokines are produced at different stages of EAM and modulate the inflammation and the course of EAM.
J Mol Cell Cardiol 1997 Feb
PMID:Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats. 914 Aug 9


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