Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Involvement of the nitric oxide (NO) system in complications following human orthotopic liver transplants (OLT) has been reported, but the contribution of the graft to the modulation of the NO system during reperfusion in normal OLT has not been characterized. We have studied the contribution of the graft efflux to the modulation of the NO system in 20 consecutive OLT. We evaluated its effects on isolated vascular reactivity of the rabbit and on rat cultured macrophages stimulated with lipopolysaccharide (LPS). In none of the donor liver biopsies was expression of inducible NO synthase (iNOS) activity by Northern or Western blot analysis found. Graft efflux after the onset of liver reperfusion, but not pre-transplant patient plasma, reversibly inhibited the acetylcholine-induced relaxation of norepinephrine-contracted rabbit aortic rings. Moreover, graft efflux reversibly inhibited NO production in rat macrophages treated with LPS, as evidenced by both a decrease in nitrite plus nitrate formation and a decrease in the production of [14C]citrulline from [14C]arginine. Addition of a 10% dilution of graft efflux to cultured rat macrophages incubated with LPS increased iNOS mRNA levels, suggesting direct inhibition of the enzyme but not of its expression. These results cannot be ascribed to the depletion of arginine the iNOS substrate since they can be reproduced even in the presence of an excess (10 mM) of exogenously added arginine. No correlation was found between the iNOS inhibitory activity in each sample and the corresponding clinical parameters related to either the graft function after the OLT or the existence of post-reperfusion syndrome. Our results indicate the existence of a soluble factor in the graft efflux from human OLT that reversibly and unspecifically inhibits NOS activity. Its involvement in the physiology and/or pathology of human liver diseases deserves further study.
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PMID:Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation. 1038 2

Nitric oxide (NO) is a well-documented effector molecule in rodent phagocytes but its synthesis in human neutrophils has been controversial. In this study, NO production in human neutrophils activated by chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) was measured in the presence of L-arginine (L-Arg) and N(G)-hydroxy-L-arginine (OH-L-Arg), the precursor and intermediate amino acids in NO synthesis, respectively. Incubation of fMLP-activated neutrophils with OH-L-Arg resulted in a production of nitrite, nitrate, and citrulline that was greater than with unstimulated neutrophils but was not inhibited by the NOS inhibitors L-NMMA and L-NIO or the cytochrome P450 inhibitor troleandomycin and was not seen when OH-L-Arg was replaced with L-Arg. This nitrite, nitrate, and citrulline production was not associated with any detectable NO synthesis because no increases in cyclic GMP were observed in the presence of phosphodiesterase inhibitors and in the presence or absence of superoxide dismutase. Moreover, no increases in the formation of the reaction product of NO with superoxide, peroxynitrite, were observed on addition of either OH-L-Arg or L-Arg to activated neutrophils, as assessed either by dihydrorhodamine oxidation or protein nitration. This suggests that, in spite of the production of nitrite, nitrate, and citrulline, commonly used indicators of NO formation, normal human blood neutrophils, are not producing detectable amounts of either NO or peroxynitrite when stimulated with fMLP in the presence of OH-L-Arg.
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PMID:No detectable NO synthesis from L-arginine or N(G)-hydroxy-L-arginine in fMLP-stimulated human blood neutrophils despite production of nitrite, nitrate, and citrulline from N(G)-hydroxy-L-arginine. 1041 Oct

Recent studies implicate iNOS as the mediator of the late phase of ischemic preconditioning (PC). However, it is unknown whether induction of iNOS activity is mediated by transcriptional, post-transcriptional, translational, or post-translational mechanisms. To address this issue, we isolated and sequenced a partial iNOS cDNA expressed in preconditioned rabbit myocardium. Using a rabbit-specific probe generated from this sequence, we measured the steady state levels of the iNOS transcript after ischemic PC [six cycles of 4-min occlusion/4-min reperfusion (O/R)]. Three hours after ischemic PC, the iNOS mRNA levels in the ischemic/reperfused region were increased approximately three-fold relative to samples from the non-ischemic region and from control rabbits. This increase in mRNA levels was completely abolished by pretreatment with the NOS inhibitor Nomega -nitro- L-arginine. Conversely, administration of the NO donor nitroglycerin induced an increase in iNOS mRNA levels similar to that induced by ischemic PC. We conclude that in the conscious rabbit, ischemic PC induces an increase in iNOS mRNA levels, and that this induction is triggered by increased generation of NO during the PC stimulus. These results provide direct evidence that upregulation of iNOS is a natural response of the heart to a brief ischemic stress and that NO itself, in the absence of ischemia, upregulates myocardial iNOS transcript levels, a finding that may have implications for nitrate therapy. This previously unrecognized NO-dependent upregulation of iNOS mRNA is likely to play an important role in the development of late PC as well as in many other pathophysiological conditions in which NO is implicated.
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PMID:Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism. 1042 45

Arginine deficiency and/or increased levels of circulating nitric oxide (NO) synthesis (NOS) inhibitors can cause reduced NOS, which may contribute to hypertension in patients with end-stage renal disease (ESRD). To test these hypotheses, NO oxidation products (NO(2) + NO(3) = NO(x)) and cyclic guanosine monophosphate (cGMP), the vasodilatory second messenger of NO, were measured in the blood, urine, and dialysate effluent of hemodialysis (HD) patients and compared with the blood and urine of healthy subjects. The subjects ate a controlled low-nitrate diet (approximately 330 micromol/d) for 48 hours before and during blood, dialysis effluent, and 24-hour urine collection. NO(x) output was significantly reduced in HD patients versus controls (552 +/- 51 v 824 +/- 96 micromol/24 h; P < 0.001), whereas cGMP output was not low versus controls. Plasma arginine level was normal and plasma levels of citrulline and the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA), were markedly elevated in patients with ESRD versus controls. Systolic blood pressure was greater in HD patients compared with controls despite concurrent antihypertensive therapy in most patients with ESRD. These studies suggest NO production is low in patients with ESRD undergoing HD, possibly because of the increased ratio of plasma ADMA to arginine.
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PMID:Indices of activity of the nitric oxide system in hemodialysis patients. 1043 Sep 67

Effects of excessive nitric oxide (NO) produced in vivo by an i.p. injection of bacterial lipopolysaccharide (LPS) on hepatic microsomal drug oxidation catalyzed by flavin-containing monooxygenase (FMO) were determined. At 6 and 24 h after the LPS injection, liver microsomes were isolated and FMO activities were determined by using FMO substrates like thiobenzamide, trimethylamine, N,N-dimethylaniline, and imipramine. Liver microsomal FMO activities of LPS-treated rats were decreased significantly for all these substrates. Microsomal content of FMO1 (the major form in rat liver) in LPS-treated rats as determined by immunoblotting, was severely decreased as well. In support of this, hepatic content of FMO1 mRNA was decreased by 43.6 to 67.3%. However, the hepatic content of inducible NO synthase (iNOS) mRNA was increased by 2.6- to 5.4-fold and the plasma nitrite/nitrate concentration was increased by about 30-fold in the LPS-treated rats. When this overproduction of NO in the LPS-treated rats was inhibited in vivo by a single or repeat doses of either a general NOS inhibitor N(G)-nitro-L-arginine or a specific iNOS inhibitor aminoguanidine, the FMO1 mRNA levels were not severely depressed (70-85% of the control level). Attendant with the reduction of plasma nitrite/nitrate concentration by single and repeated doses of NOS inhibitors, activity and content of FMO1 in liver microsomes isolated from these NOS inhibitor cotreated rats were restored partially (in single-dose inhibitors) or completely (in repeat doses). In contrast to these NO-mediated in vivo suppressive effects on the mRNA and enzyme contents of FMO1 as well as the FMO activity, the NO generated in vitro from sodium nitroprusside did not inhibit the FMO activities present in microsomes of rat and rabbit liver as well as those present in rabbit kidney and lung. Combined, the excessive NO produced in vivo (caused by the LPS-dependent induction of iNOS) suppresses the FMO1 mRNA and enzyme contents as well as the FMO activities without any direct in vitro effect on the activities of premade FMO enzyme. These findings suggest that NO is an important mediator involved in the suppression of FMO1 activity in vivo. Thus, together with the previously reported suppression on the cytochrome P-450 activities, the overproduced NO in the liver caused by induction of iNOS under conditions of endotoxemia or sepsis suppresses FMO and appears to be responsible for the decreased drug oxidation function observed generally under conditions of systemic bacterial or viral infections.
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PMID:Suppression of flavin-containing monooxygenase by overproduced nitric oxide in rat liver. 1046 38

We hypothesized that abnormal ventilation-perfusion matching in chronically infected lungs was in part due to excess nitric oxide (NO) production after upregulation of inducible NO synthase (iNOS) expression. Rats were anesthetized and inoculated intratracheally with Pseudomonas aeruginosa incorporated into agar beads (chronically infected) or with sterile agar beads (placebo inoculated) and killed 10-15 days later. Immunohistochemistry demonstrated increased expression of iNOS and reduced expression of endothelial NOS (eNOS) in chronically infected compared with placebo-inoculated or noninoculated lungs. In isolated lungs from chronically infected rats, NOS inhibition with N(omega)-nitro-L-arginine methyl ester increased the mean perfusion pressure (14.4 +/- 2.7 mmHg) significantly more than in the placebo-inoculated (4.8 +/- 1.0 mmHg) or noninoculated (5.3 +/- 0.8 mmHg) lungs (P < 0.01). Although the chronically infected lungs were more sensitive to NOS inhibition, further evidence suggested that the increased iNOS expression was not associated with enhanced iNOS activity. Selective inhibitors of iNOS did not produce an increase in vascular resistance similar to that produced by nonselective inhibitors. Accumulation of nitrate/nitrite in the perfusate of isolated lungs was unchanged by chronic infection. Thus although iNOS expression was increased in chronic pulmonary infection, iNOS activity in the intact lung was not. Nonetheless, endogenous NO production was essential to maintain normal vascular resistance in these lungs.
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PMID:Enhanced expression of inducible nitric oxide synthase without vasodilator effect in chronically infected lungs. 1048 70

The goal of this study was to interrogate the role of inducible NO synthase (iNOS) in the late phase of ischemic preconditioning (PC) in vivo. A total of 321 mice were used. Wild-type mice preconditioned 24 h earlier with six cycles of 4-min coronary occlusion/4-min reperfusion exhibited a significant (P < 0.05) increase in myocardial iNOS protein content, iNOS activity (assessed as calcium-independent L-citrulline formation), and nitrite + nitrate tissue levels. In contrast, endothelial NOS protein content and calcium-dependent NOS activity remained unchanged. No immunoreactive neuronal NOS was detected. When wild-type mice were preconditioned 24 h earlier with six 4-min occlusion/4-min reperfusion cycles, the size of the infarcts produced by a 30-min coronary occlusion followed by 24 h of reperfusion was reduced markedly (by 67%; P < 0.05) compared with sham-preconditioned controls, indicating a late PC effect. In contrast, when mice homozygous for a null iNOS allele were preconditioned 24 h earlier with the same protocol, infarct size was not reduced. Disruption of the iNOS gene had no effect on early PC or on infarct size in the absence of PC. These results demonstrate that (i) the late phase of ischemic PC is associated with selective up-regulation of iNOS, and (ii) targeted disruption of the iNOS gene completely abrogates the infarct-sparing effect of late PC (but not of early PC), providing unequivocal molecular genetic evidence for an obligatory role of iNOS in the cardioprotection afforded by the late phase of ischemic PC. Thus, this study identifies a specific protein that mediates late PC in vivo.
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PMID:The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. 1050 Jan 5

1. The inducible isoform of nitric oxide synthase (iNOS) may be involved in the pathogenesis of inflammatory bowel disease. Using the human intestinal epithelial cell line, Caco-2, iNOS expression, regulation and sensitivity to the glucocorticoid, dexamethasone after cytokine exposure and its relationship to the degree of differentiation has been studied. 2. NOS activity, assessed by NO2- and NO3- release, was time-dependently increased after exposure to interferon gamma alone or in combination with interleukin-1beta and tumour necrosis factor alpha. 3. Cytokine-induced iNOS activity was increased with days in culture over 20 days and number of passages, suggesting iNOS up-regulation during enterocyte-like differentiation. This activity was inhibited by the selective iNOS inhibitor 1400 W (0.1 - 100 microM). In addition, iNOS protein induction was confirmed by Western blot. 4. Actinomycin D (5 microg ml(-1) inhibited cytokine-induced iNOS activity, protein expression and mRNA level. Pyrrolidine dithiocarbamate (PDTC: 10 - 200 microM) and 3,4 dichloroisocoumarin (0.1 - 100 microM) reduced cytokine-induced iNOS activity and protein expression at both day 10 and 15 after confluence. PDTC also decreased iNOS mRNA levels, suggesting NF-kappaB involvement in its transcription at these times. 5. The tyrphostins A25 and B42 reduced cytokine-induced iNOS activity at both day 10 and 15 after confluence, indicating the JAK-2 kinase is also involved at these times. The tyrphostins also reduced the iNOS protein expression. 6. Dexamethasone (0.1 - 10 microM, for 24 h) reduced cytokine-induced iNOS activity at day 15 and 20 after cell confluence, but not at day 5 or 10. 7. Dexamethasone (5 microM) decreased cytokine-induced iNOS protein expression at day 10 as well as at day 15 after confluence. 8. These findings indicate that iNOS induction and its inhibition by dexamethasone in this human intestinal epithelial cell line is dependent on the degree of differentiation.
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PMID:Regulation of induction of nitric oxide synthase and the inhibitory actions of dexamethasone in the human intestinal epithelial cell line, Caco-2: influence of cell differentiation. 1051 52

Injection of lipopolysaccharide (LPS) (Salmonella W. Typhosa i.v. bolus) into conscious rats, induced a rapid drop of circulating platelets analogous to that induced by ADP. The animals showed a small fall in mean arterial blood pressure (MABP), an increase in heart rate and a significant increase in plasma nitrite and nitrate level. This result is consistent with the stimulation of an inducible NO synthase (i-NOS). The administration of the stable prostacyclin analogue, iloprost plus ADP or LPS, significantly protected against the decrease in free platelet number induced by ADP or LPS. The plasma nitrite and nitrate level stimulated by LPS was significantly reduced by iloprost and also by prostacyclin. These results are consistent with an inhibition of i-NOS by agents that increase the intracellular level of cAMP. The administration of the NO donor S-Nitroso-N-acyl-D-penicillamine (SNAP) plus ADP or LPS, significantly prevented thrombocytopenia induced by ADP and by LPS. SNAP did not decrease the plasma nitrite and nitrate level stimulated by LPS; furthermore it induced a significant increase of heart rate, without affecting MABP, suggesting a direct accelerating effect of NO on the sino-atrial node. The administration of S-nitroso-glutathione (GSNO), a stable nitrosothiol, plus ADP or LPS, significantly prevented thrombocytopenia induced by ADP but not by LPS. GSNO significantly reduced the plasma nitrite and nitrate level stimulated by LPS. These data demonstrate that the L-Arginine: NO pathway in vivo may be modulated by prostanoids and that compounds which increase cAMP, such as iloprost, are able to protect against LPS-induced early thrombocytopenia.
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PMID:Platelet activation and modulation of the induction of nitric oxide synthase in the conscious rat. 1053 Jul 98

Four-day-old BALB/c mice were infected by the oral administration of 50,000 Cryptosporidium parvum oocysts, and the resulting infection was scored histologically and by counting colonic oocysts. Infection occurred in the ileum and proximal colon (but not duodenum and jejunum), peaked on days 14 to 18, and was cleared between days 24 and 30. Nitric oxide (NO) appeared to play a protective role in this model as evidenced by the facts that plasma nitrite and nitrate levels increased during the period of peak parasitosis; immunohistochemically detected inducible nitric oxide synthase (iNOS) was increased in the ileum and colon enterocytes of infected animals; the NOS inhibitor L-N-iminoethyl lysine or N-nitro-L-arginine methyl ester (L-NAME) decreased the elevated plasma nitrite and nitrate levels while exacerbating the infection and increasing oocyst shedding; administration of a NO donor, S-nitroso-N-penicillamine, reduced oocyst and infection scores; and neonatal iNOS knockout mice exhibited a slightly longer infection than control animals. The oral administration of oocysts to L-NAME-treated BALB/c mice, but not control animals, between 24 and 40 days old resulted in the fecal excretion of oocysts 1 week later. Administration of the antioxidant ascorbic acid also exacerbated the C. parvum infection, suggesting a protective role for reactive nitrogen and/or reactive oxygen compounds, while administration of the superoxide scavenger superoxide dismutase exacerbated the infection. Taken together these data suggest that both reactive nitrogen and reactive oxygen species play protective roles in experimental cryptosporidiosis.
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PMID:Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model. 1053 Dec 44


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