UMLS:C0406810 - FACTA Search

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

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. 137 15

Previous findings indicate that nitric oxide (NO) may play a role in the regulation of sleep-wake activity. In rabbits, blocking the production of endogenous NO by a nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NAME) suppresses spontaneous sleep and interferes the somnogenic actions of interleukin 1. In the present experiments we extended our earlier work by studying the long-term effects of L-NAME treatment on sleep-wake activity including power spectra analyses of the electroencephalogram (EEG) in rats. Rats implanted with EEG electrodes, brain thermistor, and intracerebroventricular (i.c.v.) guide cannula were injected i.c.v. with vehicle or 0.2, 1, or 5 mg L-NAME at light onset. In separate experiments, rats were injected intraperitoneally (i.p.) with L-NAME three times (50, 50, 100 mg/kg), 12-12 h apart. Both i.c.v. and i.p. injections of L-NAME elicited decreases in time spent in NREMS and REMS. After i.c.v. injection of 5 mg L-NAME the sleep responses were long-lasting; NREMS did not return to baseline even 72 h after injection. EEG delta-wave activity during NREMS (slow wave activity) was also suppressed after 0.2 and 5 mg L-NAME. Brain temperature was slightly increased after the two lower doses of L-NAME, whereas there was a transient decrease in Tbr after 5 mg L-NAME. Acute i.p. injection of 50 mg/kg L-NAME elicited an immediate decrease in NREMS which lasted for approximately 2 h. The second injection of 50 mg/kg L-NAME and the following injection of 100 mg/kg L-NAME induced biphasic decreases in NREMS but not REMS.
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PMID:Inhibition of nitric oxide synthesis inhibits rat sleep. 753 1

Blockade of nitric oxide (NO) formation with the arginine derivative L-N omega nitro-L-arginine-methylester (L-NAME) produces a dramatic increase in ACTH released by the iv injection of interleukin-1 beta (IL-1 beta). The present work investigated the potential role of three mechanisms in this effect: the activation of adrenergic receptors and/or the release of vasopressin (VP) or prostaglandins (PG). As previously observed, blockade of adrenergic receptors with prazosin and propranolol did not alter the stimulatory effect of IL-1 beta. We show here that this treatment did not significantly interfere with the potentiating influence of L-NAME 30 min after IL-1 injection, but blunted this effect at 60 min. Immunoneutralization of endogenous VP did not consistently decrease the ACTH response to IL-1 beta regardless of whether NO was present. Finally, as expected, blockade of PG synthesis with ibuprofen totally abolished IL-1 beta-induced ACTH secretion; in addition, it prevented the interaction between L-NAME and the pituitary response. In contrast to results obtained after the injection of IL-1 beta, neither the adrenergic antagonists nor ibuprofen significantly altered the ability of L-NAME to potentiate the stimulatory effect of VP. Collectively, these results indicate that the influence of NO on ACTH released by blood-borne IL-1 beta (an effect thought to be primarily exerted on nerve terminals in the median eminence) is not primarily mediated by endogenous VP. The inability of L-NAME to augment the stimulatory effect of the cytokine on ACTH secretion in the presence of ibuprofen suggests that PG play an obligatory role in the response of the hypothalamic-pituitary axis to systemic cytokine administration that cannot be compensated for by removing the restraining influence of NO. Finally, removal of the inhibitory effect of NO either unmasks the participation of adrenergic receptors in modulating the response of the hypothalamic-pituitary axis to IL-1 beta or stimulates catecholamine secretion, which, in turn, acts on CRF nerve terminals and/or synergizes with IL-1 beta-induced CRF release.
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PMID:Blockade of nitric oxide formation augments adrenocorticotropin released by blood-borne interleukin-1 beta: role of vasopressin, prostaglandins, and alpha 1-adrenergic receptors. 762 98

Nitric oxide (NO) synthase (NOS), the enzyme responsible for NO formation, is found in hypothalamic neurons containing oxytocin (OT), vasopressin (VP), and to a lesser extent corticotropin-releasing factor (CRF). Because NO is reported to modulate endocrine activity, we have investigated the hypothesis that endogenous NO participates in ACTH released by various secretagogues in the rat. In the adult male rat, the intravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 micrograms/kg), VP (0.3-0.9 micrograms/kg), and OT (30 micrograms/kg) significantly increased plasma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N omega nitro-L-arginine-methylester (L-NAME; a specific inhibitor of NOS) markedly augmented the effects of these secretagogues whether it was injected acutely or over a 4 d period. Blockade of NOS activity also caused significant (P < 0.01) extensions of the duration of action of IL-1 beta, VP, and OT. In contrast, L-NAME did not significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginine, but not D-arginine (100 mg/kg), used as a substrate for basal NO synthesis and which did not by itself alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion, and reversed the interaction between L-NAME and IL-1 beta. The stimulatory action of endotoxin, a lipopolysaccharide that releases endogenous cytokines, was also augmented by inhibition of NO formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocin. 815 53

Release of inflammatory mediators by mast cells can be modulated by certain cytokines and by nitric oxide. An in vitro platelet aggregation bioassay was used to assess the effects of interleukin-1 beta (IL-1 beta) on the release of platelet-activating factor and nitric oxide from resting or ionophore-activated peritoneal mast cells (PMC) from rat. PMC spontaneously released a substance that inhibits thrombin-stimulated platelet aggregation. The activity of this substance is abolished by addition of hemoglobin to the platelet suspension and augmented by preincubation of the PMC with L-arginine, suggesting that it is nitric oxide. Within minutes, IL-1 beta concentration-dependently (1 pg/ml-100 ng/ml) enhanced the release from activated PMC of nitric oxide, as measured by its ability to inhibit thrombin-induced platelet aggregation, and as confirmed with a biochemical assay for nitrite. This action of IL-1 beta was inhibited by pretreatment of PMC with a calmodulin antagonist (calmidazolium), an IL-1 receptor antagonist, or either of two nitric oxide synthase inhibitors (L-NAME and LY-83583). IL-1 beta also inhibited the release of platelet-activating factor from PMC through a nitric-oxide-dependent mechanism. These results demonstrate that IL-1 beta is a potent and rapid-acting modulator of mast cell reactivity, stimulating nitric oxide release while inhibiting the production of platelet-activating factor.
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PMID:Modulation of rat mast cell reactivity by IL-1 beta. Divergent effects on nitric oxide and platelet-activating factor release. 839 60

We examined the effects of exogenous nitric oxide (NO) on prostaglandin production in fetal ovine astroglia. Astroglia in secondary culture grown in 12 well plates were exposed to medium alone or medium containing 10 ng/ml interleukin 1 alpha (IL1 alpha), in the presence or absence of 10 and 100 microM sodium nitroprusside (SNP). Sodium nitroprusside is a NO donor. Prostaglandin F2 alpha (PGF2 alpha) levels were determined by enzyme immunoassay after 4 h of medium and/or drug application. Application of 100 microM SNP reduced basal levels of PGF2 alpha from 530 +/- 48 pg/ml (mean +/- SEM) (n = 9) to 248 +/- 60 pg/ml (n = 8) (P < 0.05). In IL1 alpha treated cells, PGF2 alpha levels were 846 +/- 109 pg/ml (n = 9) (P < 0.05, compared to basal levels) in the absence and 567 +/- 122 pg/ml (n = 9) in the presence of 100 microM SNP (P < 0.05, compared to IL1 alpha alone). We tested whether effects of exogenous NO on PGF2 alpha levels would be influenced by elimination of endogenously produced NO. Inhibition of NO synthase with 100 microM NG-nitro-L-arginine-methyl ester (L-NAME) did not affect PGF2 alpha levels during basal conditions, or affect reductions in PGF2 alpha levels during application of 100 microM SNP. In addition, L-NAME application did not affect IL1 alpha-induced increase in PGF2 alpha levels or reductions in PGF2 alpha levels with coapplication of 100 microM SNP. In contrast to the higher dose, application of 10 microM did not significantly affect PGF2 alpha levels. In summary, application of 100 microM SNP reduces basal production of PGF2 alpha and attenuates increases in PGF2 alpha levels with IL1 alpha application.
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PMID:Modulation of prostaglandin production by nitric oxide in astroglia. 917 71

Nitric oxide (NO) is produced in diseased joints and may be a key mediator of IL-1 effects on cartilage. Therefore, we compared the potency of new [aminoguanidine (AG), S-methylisothiourea (SMT), S-aminoethylisothiourea (AETU)] and classical [Nomega-monomethyl-L-arginine (L-NMMA), Nomega-nitro-L-arginine methyl ester (L-NAME)] NO synthase (NOS) inhibitors on the inhibitory effect of recombinant human interleukin-1beta (rhIL-1beta) on rat cartilage anabolism. Three different culture systems were used: (1) isolated chondrocytes encapsulated in alginate beads; (2) patellae and (3) femoral head caps. Chondrocyte beads and cartilage entities were incubated in vitro for 48 h in the presence of rhIL-1beta with a daily change of incubation medium to obtain optimal responses on proteoglycan synthesis and NO production. Proteoglycan synthesis was assessed by incorporation of radiolabelled sodium sulphate [Na2(35)SO4] and NO production by cumulated nitrite release during the period of study. Chondrocytes and patellae, as well as femoral head caps, responded concentration-dependently to IL-1beta challenge (0 to 250 U ml(-1) and 0 to 15 U ml(-1) respectively) by a large increase in nitrite level and a marked suppression of proteoglycan synthesis. Above these concentrations of IL-1beta (2500 U ml(-1) and 30 U ml(-1) respectively), proteoglycan synthesis plateaued whereas nitrite release still increased thus suggesting different concentration-response curves. When studying the effect of NOS inhibitors (1 to 1000 microM) on NO production by cartilage cells stimulated with IL-1beta (25 U ml(-1) or 5 U ml(-1)), we observed that: (i) their ability to reduce nitrite level decreased from chondrocytes to cartilage samples, except for L-NMMA and AETU; (ii) they could be roughly classified in the following rank order of potency: AETU > L-NMMA > or = SMT > or = AG > or = L-NAME and (iii) AETU was cytotoxic when used in the millimolar range. When studying the effect of NOS inhibitors on proteoglycan synthesis by cartilage cells treated with IL-1beta, we observed that: (i) they had more marked effects on proteoglycan synthesis in chondrocytes than in cartilage samples; (ii) they could be roughly classified in the following rank order of potency: L-NAME > or = L-NMMA > > AG > SMT > > AETU and (iii) potentiation of the IL-1 effect by AETU was consistent with cytotoxicity in the millimolar range. D-isomers of L-arginine analog inhibitors (1000 microM) were unable to correct nitrite levels or proteoglycan synthesis in IL-1beta treated cells. L-arginine (5000 microM) tended to reverse the correcting effect of L-NMMA (1000 microM) on proteoglycan synthesis, thus suggesting a NO-related chondroprotective effect. However, data with L-NAME and SMT argued against a general inverse relationship between nitrite level and proteoglycan synthesis. Dexamethasone (0.1 to 100 microM) (i) failed to inhibit NO production in femoral head caps and chondrocytes beads whilst reducing it in patellae (50%) and (ii) did not affect or worsened the inhibitory effect of IL-1beta on proteoglycan synthesis. Such results suggested a corticosteroid-resistance of rat chondrocyte iNOS. Data from patellae supported a possible contribution of subchondral bone in NO production. In conclusion, our results suggest that (i) NO may account only partially for the suppressive effects of IL-1beta on proteoglycan synthesis, particularly in cartilage samples; (ii) the chondroprotective potency of NOS inhibitors can not be extrapolated from their effects on NO production by joint-derived cells and (iii) L-arginine analog inhibitors are more promising than S-substituted isothioureas for putative therapeutical uses.
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PMID:Modulation of IL-1-induced cartilage injury by NO synthase inhibitors: a comparative study with rat chondrocytes and cartilage entities. 975 89

Neuroendocrine and neurochemical responses were studied following administration of recombinant mouse IL-6 (mIL-6) to mice. Intravenous (iv) or intraperitoneal (ip) injection of mIL-6 caused a rapid and short-lived activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, as indicated by increases in plasma ACTH and corticosterone, with peak responses around 30-60 min. These responses contrast with those to ip mIL-1beta which is substantially more potent and induces a greater response which does not peak until about 2 h following ip administration. Unlike IL-1 and lipopolysaccharide (LPS), IL-6 had no detectable effect on norepinephrine metabolism. However, tryptophan concentrations were elevated in most brain regions studied 1-2 h following iv mIL-6, and 2 h following ip mIL-6, significantly later than the peak HPA response. 5-hydroxyindoleacetic acid (5-HIAA) and the ratio of 5-HIAA to serotonin (5-HT) were elevated at around the same time in the brain stem, and occasionally in other brain regions. These responses were observed at doses of mIL-6 as low as 0.25 microg, and near maximal effects were achieved by 0.5 microg. Recombinant human IL-6 elicited similar responses, but was significantly less potent. Heat-treated mIL-6 elicited none of the responses. Serum amyloid A protein (SAA) concentrations were not elevated until 4 h after iv or ip mIL-6 administration, suggesting that the neuroendocrine and neurochemical changes were not secondary to an acute phase protein response. Intracerebroventricular injection of mIL-6 also elevated tryptophan and 5-HIAA in the hypothalamus and brain stem. Pretreatment of mice with the cyclooxygenase inhibitor, indomethacin, or the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) did not attenuate the mIL-6 induced neuroendocrine or neurochemical responses. However, the ganglionic blocking drug, chlorisondamine, prevented the increases in tryptophan and 5-HIAA:5-HT ratios. IL-6 may contribute to the HPA and indoleaminergic responses to LPS and IL-1. It is possible that the increases of tryptophan and serotonin metabolism may contribute to some of the biological effects of IL-6.
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PMID:Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism. 976 58

We have proposed that endothelin-1 (ET-1), formed through the activation of a cytochrome P450 (CYP450)-based monooxygenase reaction, is important for generation of contractile tone in the ductus arteriosus and, consequently, for closure of the vessel at birth. The present investigation was undertaken to ascertain, using an isolated ductus preparation from near-term fetal lambs, whether carbon monoxide (CO) and nitric oxide (NO) qualify as regulators of the CYP450/ET-1 system. Preparations released ET-1 at rest and its amount showed no significant reduction following removal of the endothelium. Basal release was not changed by the NO synthesis inhibitor, N(G)-nitro-L-arginine methylester (L-NAME, 100 microM), nor by agents altering cyclic GMP content (i.e. increase; ONO-1505, 1 microM) and action (i.e. decrease; LY-83583, 10 microM). These findings extend previous work showing no effect of the CO synthesis inhibitor zinc protoporphyrin IX (ZnPP, 10 microM) under the same conditions (10). Conversely, both CO (65 microM) and the NO donor, sodium nitroprusside (SNP, 10 microM), curtailed ET-1 release. ET-1 release was increased by oxygen and reduced by pyrogens (endotoxin and IL-1, both at 100 ng mL(-1)). The endotoxin effect tended to be reversed by L-NAME and ZnPP, used singly or in combination. We conclude that ET-1 is formed naturally in the ductus and that its formation may change in response to physiological (oxygen) and pathophysiological (pyrogens) stimuli. Endogenous CO and NO, however, appear to have little or no role as ET-1 regulators.
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PMID:Endothelin-1 release from the lamb ductus arteriosus: are carbon monoxide and nitric oxide regulatory agents? 1088 39

Interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) markedly stimulate glucose utilization in primary cultures of mouse cortical astrocytes. The mechanism that gives rise to this effect, which takes place several hours after application of cytokine, has remained unclear. Experiments were conducted to identify the major signaling cascades involved in the metabolic action of cytokine. First, the selective IL-1 receptor antagonist (IL-1ra) prevents the effect of IL-1alpha on glucose utilization in a concentration-dependent manner, whereas it has no effect on the action of TNF-alpha. Then, using inhibitors of three classical signaling cascades known to be activated by cytokines, it appears that the PI3 kinase is essential for the effect of both IL-1alpha and TNF-alpha, whereas the action of IL-1alpha also requires activation of the MAP kinase pathway. Participation of a phospholipase C-dependent pathway does not appear critical for both IL-1alpha and TNF-alpha. Inhibition of NO synthase by L-NAME did not prevent the metabolic response to both IL-1alpha and TNF-alpha, indicating that nitric oxide is probably not involved. In contrast, the Na(+)/K(+) ATPase inhibitor ouabain prevents the IL-1alpha- and TNF-alpha-stimulated 2-deoxyglucose (2DG) uptake. When treatment of astrocytes with a cytokine was followed 24 h later by an acute application of glutamate, a synergistic enhancement in glucose utilization was observed. This effect was greatly reduced by ouabain. These data suggest that Na(+) pump activity is a common target for both the long-term metabolic action of cytokines promoted by the activation of distinct signaling pathways and the enhanced metabolic response to glutamate.
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PMID:Long-term modulation of glucose utilization by IL-1 alpha and TNF-alpha in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms. 1211 71

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