Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.39 (NO synthase)
 15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute ingestion of alcohol [ethanol (ETOH)] adversely affects the immunocompetence of both naive individuals as well as chronic alcohol abusers. An increased incidence and severity of tuberculosis is found in chronic alcohol abusers. Nitric oxide (NO) produced by alveolar macrophages (AMs) may play a role in the in vitro killing of Mycobacterium avium and Mycobacterium tuberculosis (MTB). Moreover, tumor necrosis factor-alpha (TNF-alpha) is believed to be a primary cytokine mediator of NO production by AMs. Recent studies from our laboratory demonstrated that ETOH suppressed endotoxin-induced increases in both TNF-alpha and NO in AMs, in vivo. We tested the postulate that acute ingestion of ETOH can interfere with mycobacteria-induced upregulation of the NO system in AMs, in vivo. We show that heat-killed M. avium complex (MAC) and human virulent MTB instilled into rat lungs rapidly increased mRNA for inducible NO synthase II (iNOS) of AMs in fluid obtained by bronchoalveolar lavage (BAL fluid). This was associated with production of reactive nitrogen intermediates [(RNIs); NO2- and NO3-] in BAL fluid, lung homogenate, and AMs in the absence of a significant increase in BAL fluid TNF-alpha. A single dose of ETOH (5.5 g/kg, ip) administered 30 min before intratracheal administration of MAC or MTB attenuated both MAC and MTB-induced increases in RNI in BAL fluid, lung, and AMs, and the increase in mRNA for iNOS. Thus, mycobacteria upregulate iNOS mRNA and enhance RNI production by AMs without any increase in the production of TNF-alpha. Moreover, ETOH attenuates mycobacteria-induced upregulation of mRNA for iNOS and RNI production in the absence of ETOH-mediated suppression of TNF. Speculatively, ETOH-mediated inhibition of the AM NO system may offer an explanation for the increased severity of mycobacterial infections in alcoholics.
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PMID:Ethanol suppresses Mycobacteria tuberculosis-induced mRNA for nitric oxide synthase in alveolar macrophages, in vivo. 754 49

Nitric oxide (NO), a highly diffusible cellular mediator involved in a wide range of biological effects, has been indicated as one of the cytotoxic agents released by leukocytes to counteract malaria infection. On the other hand, NO has been implicated as a mediator of the neuropathological symptoms of cerebral malaria. In such circumstances NO production has been thought to be induced in host tissues by host-derived cytokines. Here we provide evidence for the first time that human red blood cells infected by Plasmodium falciparum (IRBC) synthesize NO. The synthesis of NO (measured as citrulline and nitrate production) appeared to be very high in comparison with human endothelial cells; no citrulline and nitrate production was detectable in noninfected red blood cells. The NO synthase (NOS) activity was very high in the lysate of IRBC (while not measurable in that of normal red blood cells) and was inhibited in a dose-dependent way by three different NOS inhibitors (L-canavanine, NG-amino-L-arginine, and NG-nitro-L-arginine). NOS activity in P. falciparum IRBC is Ca++ independent, and the enzyme shows an apparent molecular mass < 100 kD, suggesting that the parasite expresses an isoform different from those found in mammalian cells. IRBC release a soluble factor able to induce NOS in human endothelial cells. Such NOS-inducing activity is not tissue specific, is time and dose dependent, requires de novo protein synthesis, and is probably associated with a thermolabile protein having a molecular mass > 100 kD. Our data suggest that an increased NO synthesis in P. falciparum malaria can be directly elicited by soluble factor(s) by the blood stages of the parasite, without necessarily requiring the intervention of host cytokines.
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PMID:Erythrocyte stages of Plasmodium falciparum exhibit a high nitric oxide synthase (NOS) activity and release an NOS-inducing soluble factor. 754 94

This short review deals with the role of a recently found signalling molecule, nitric oxide (NO), in inflammatory and immune responses. NO regulates inflammatory erythema and oedema and has cytotoxic action against micro-organisms. In some instances (such as reperfusion injury) NO has cytoprotective properties. Production of large amounts of NO by activated macrophages accounts for their ability to suppress lymphocyte proliferation. NO synthesis in lymphocytes is questionable but cytokines secreted by activated lymphocytes regulate NO synthesis by macrophages. Constitutive NO synthase is activated in neutrophils in response to inflammatory stimuli and NO has diverse, often biphasic effects on neutrophil functions. Increased concentrations of nitrite and nitrate (metabolites of NO) are present in arthritic joints. NO is synthesized not only by migrated inflammatory cells but also by articular chondrocytes and inflamed synovial membrane. In the inflamed joint, NO regulates the synthesis of several inflammatory mediators and functions of inflammatory cells. In addition, NO seems to mediate some destructive effects of proinflammatory cytokines such as interleukin-1. In conclusion, NO regulates several humoral and cellular responses in inflammation, having both anti-inflammatory and proinflammatory properties depending on the type and phase of the inflammatory reaction.
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PMID:Nitric oxide in inflammation and immune response. 754 26

We have investigated the possible role of nitric oxide (NO) in the pathophysiology of bacterial meningitis (BM) by using the rat model of experimental BM. The nitrite concentration in cerebrospinal fluid (CSF) was used as a measure of NO production in vivo since NO rapidly degrades to nitrite and nitrate. Rats were inoculated intracisternally with live bacteria (5 x 10(6) CFU of Haemophilus influenzae type b strain DL42 or Rd-/b+/O2), with bacterial endotoxin (20 ng of DL42 lipooligosaccharide [LOS] or 200 ng of Escherichia coli lipopolysaccharide), or with a saline control vehicle. CSF samples were collected preinoculation and at the time of maximal alteration in blood-brain barrier permeability (BBBP). CSF [nitrite] was quantified by measuring A550 after addition of the Greiss reagent and comparison to a standard curve of sodium nitrite. Rats inoculated with either DL42, Rd-/b+/O2, LOS, or lipopolysaccharide demonstrated a significantly elevated mean peak CSF [nitrite] (8.34, 15.62, 10.75, and 10.44 mM, respectively) versus the concentration prior to treatment and/or those in saline-treated animals (5.29 and 5.33 mM, respectively; P < 0.05 for each comparison). We then determined if there was a correlation between CSF [nitrite] and percent BBBP (%BBBP) at various time points postinoculation with Rd-/b+/O2. %BBBP was defined as the concentration of systemically administered 125I-labeled bovine serum albumin in the CSF divided by the level of 125I-labeled bovine serum albumin in serum multiplied by 100. The mean %BBBP increased in tandem with the mean CSF [nitrite] (R = 0.84, P = 0.018), which peaked at 18 h in the absence of a change in the serum [nitrite]. Systemic administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester demonstrated a significant reduction of mean CSF nitrite production (0.95 versus 6.0 mM in controls; P = 0.02) when administered intravenously to animals which had been inoculated intracisternally with 20 ng of LOS. Suppression of mean leukocyte pleocytosis (3,117 versus 11,590 leukocytes per mm3 in control LOS-challenged rats; P = 0.03) and mean alterations of BBBP (2.11 versus 6.49% in control LOS-challenged rats; P = 0.009) was observed concomitantly with decreased CSF [nitrite]. These results support the hypothesis that NO contributes to increased %BBBP in experimental BM.
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PMID:Potential role of nitric oxide in the pathophysiology of experimental bacterial meningitis in rats. 755 88

The murine model of Lyme disease was used to determine the role of inflammatory induced nitric oxide (NO) during infection by the spirochete Borrelia burgdorferi. The outer surface lipoproteins of B. burgdorferi are potent stimulators of inflammatory cytokines and NO production by cultured macrophages in vitro. The addition of NO to cultures of B. burgdorferi prevents growth, suggesting a protective role of NO for the infected host. NO is also a crucial effector in some models of arthritis. Therefore, the involvement of NO in controlling B. burgdorferi infection and its participation in pathological development of arthritis were investigated. Both mildly arthritic (BALB/c) and severely arthritic (C3H/HeJ) strains of mice systemically produced high levels of NO 1 week after infection with B. burgdorferi, as determined by urinary nitrate. NO production remained high throughout the infection in BALB/c mice, while in C3H/HeJ mice NO production returned rapidly to uninfected levels. The in vivo inhibitor of the NO synthase enzyme NG-L-monomethyl arginine (LMMA) was given to mice to investigate whether decreasing NO production would alter the course of disease. LMMA effectively blocked NO production in infected mice; however, there was no significant difference in arthritis development, spirochete infection of tissues, or production of specific antibody in LMMA-treated mice. These results indicate that B. burgdorferi is able to persist in the host even in the presence of high levels of NO. Furthermore, NO is not involved in the control of spirochete infection of tissues, nor is it involved in the development of arthritis. The potent activity of NO against intracellular pathogens and the in vivo resistance of B. burgdorferi to NO suggest that this organism is not located in an intracellular compartment during an essential portion of its infection of the mammalian host.
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PMID:Nitric oxide production during murine Lyme disease: lack of involvement in host resistance or pathology. 755 96

Adenosine per se is a potent vasodilator of vascular smooth muscle. Endothelial cells modulate vascular tone via the release of nitric oxide (NO), which also elicits vasodilation. This study was undertaken to determine whether adenosine could directly stimulate endothelial cells to enhance NO production, which could subsequently reduce vascular tone. NO production was evaluated in porcine carotid artery endothelial cells (PCAEC) and human saphenous vein endothelial cells (HSVEC) seeded on multiwell plates, grown to confluence, and treated with adenosine for 1 h. The bathing medium was collected, and the NO production was determined as reflected by the formation of NO2- and NO3-. NO production by PCAEC was significantly increased by adenosine in a dose-dependent manner, whereas there was only an insignificant tendency for an increase by HSVEC. The addition of the NO synthase competitive inhibitor, NG-monomethyl-L-arginine (NMMA), or the adenosine receptor antagonist, theophylline, prevented the increase in NO production by adenosine. The results suggest that adenosine stimulates, by a receptor-mediated mechanism, the production of NO by arterial, but not by venous, endothelial cells.
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PMID:Adenosine enhances nitric oxide production by vascular endothelial cells. 765 35

In rats treated i.v. with heat-killed Propionibacterium acnes (100 mg/kg body wt), followed 5 days later by an i.v. dose of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt), acute hepatic cell necrosis was accompanied by significant induction of nitric oxide (NO) synthase activity in the liver. Endogenous nitrosation of thiazolidine 4-carboxylic acid (TCA, 50 mumol/rat) administered by three different routes (i.v., i.p. and p.o.) 5 h after LPS injection to the P. acnes-treated rats was assessed by analysing its nitrosated product (NTCA) excreted in 24 h urine. The amounts of NTCA formed in vivo after i.v., i.p. and p.o. administration of TCA were 4.07 +/- 1.00, 5.79 +/- 2.15 and 58.3 +/- 20.7 nmol/rat (n = 5-10) respectively, which were about 5-, 10- and 8-fold greater than those excreted by rats which had not been treated with P.acnes and LPS but received TCA by the same route. Nitrate concentration in plasma and NO synthase activity in the liver started to increase within 2.5 h after LPS injection, reached a maximum at 7.5 h and remained at high levels for several further hours. Levels of nitrite and nitrate in gastric contents were also increased significantly after LPS administration. The co-administration of N omega-nitro-L-arginine (an inhibitor of NO synthase) and LPS resulted in a marked reduction of urinary levels of nitrate and NTCA, indicating that nitrosation is mediated by NO synthase. These results together suggest that induction of NO synthase by infection with bacteria, parasite and viruses could result in increased endogenous nitrosation not only in the infected tissues but also in the stomach, where nitrosamines would be formed more rapidly under acidic conditions.
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PMID:Increased endogenous N-nitrosamine and nitrate formation by induction of nitric oxide synthase in rats with acute hepatic injury caused by Propionibacterium acnes and lipopolysaccharide administration. 767 86

Nitric oxide (NO) has been implicated as a mediator of hemodynamic and metabolic changes associated with endotoxemia and inflammation. In vitro studies suggest that NO inhibits hepatocyte protein synthesis but the role of NO in the regulation of hepatic protein synthesis in vivo is not known. In this study, rats were given endotoxin or saline after pretreatment with the NO synthase inhibitor NG-nitro-L-arginine or solvent, and plasma levels of nitrite (NO2), nitrate (NO3), and aspartate aminotransferase and hepatic protein synthesis rate in vivo were measured after 4 and 10 hours. The NG-nitro-L-arginine effectively blocked the increase in serum NO2/NO3 seen in endotoxemia and also inhibited the increase in hepatic protein synthesis in endotoxemic rats. The aspartate aminotransferase levels were elevated in endotoxemic rats pretreated with NG-nitro-L-arginine. Results support previous reports of a protective effect of NO on the liver in endotoxemia and suggest that NO may upregulate hepatic protein synthesis in vivo. Further study is needed to clarify the reason for the apparent difference between the effect of NO on hepatic protein synthesis in vivo and in vitro.
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PMID:Nitric oxide may upregulate in vivo hepatic protein synthesis during endotoxemia. 767 68

Previous studies have suggested that nitric oxide (NO) plays a role in regulation of renal vascular tone and sodium handling. We questioned whether the effects of NO synthase inhibition on renal function are direct or due to increased renal perfusion pressure (RPP) and whether stimulation of endogenous NO activity plays a role in adaptation to increased dietary salt intake. Intrarenal arterial infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in control rats resulted in decreased glomerular filtration rate, renal vasoconstriction, natriuresis, and proteinuria. When RPP was held at basal levels with suprarenal aortic snare, L-NMMA had similar hemodynamic effects but decreased sodium excretion and did not induce proteinuria. Exposure of rats to high salt intake (1% NaCl drinking water) for 2 wk induced increased serum concentration and urinary excretion of the NO decomposition products, NO2 + NO3. Urinary NO2 + NO3 and sodium excretion were significantly correlated. Compared with controls, chronically salt-loaded rats also demonstrated enhanced renal hemodynamic responses to NO synthase inhibition. We conclude that the endogenous NO system directly modulates renal hemodynamics and sodium handling and participates in the renal adaptation to increased dietary salt intake. Enhanced NO synthesis in response to increased salt intake may facilitate sodium excretion and allow maintenance of normal blood pressure.
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PMID:Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide. 767 14

We reported previously that plasma levels, urinary excretion, and metabolic production of cyclic guanosine 3',5'-monophosphate (cGMP) are increased in gravid rats, and postulated that endogenous nitric oxide (NO), a potent vasodilator and immune modulator, may mediate this change. Four lines of evidence are now presented demonstrating increased biosynthesis of NO during pregnancy in rats: 1) Urinary excretion and plasma levels of the stable NO metabolite, nitrate, are elevated in pregnant rats; urinary excretion of nitrate is increased in pseudopregnant rats. 2) The urinary excretion of cGMP also increases during pregnancy and pseudopregnancy, paralleling the rise in urinary nitrate excretion. 3) Chronic treatment with the NO synthase inhibitor, NG-nitroarginine methyl ester (NAME), inhibits the increase in urinary nitrate excretion. 4) Nitric oxide hemoglobin is detected by electron paramagnetic resonance spectroscopy in the blood of pregnant, but not in nonpregnant, rats. The results show endogenous NO production is increased in gravid rats. This finding raises the possibility that NO may contribute to maternal vasodilation and uterine immune suppression of normal pregnancy.
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PMID:Identification of increased nitric oxide biosynthesis during pregnancy in rats. 768 24


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