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:1.14.13.39 (NO synthase)
15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. 794 48

NO is produced during cardiac allograft rejection by expression of inducible NO synthase (iNOS) in the rejecting heart. Recent evidence indicates that NO modulates vascular permeability under both physiological and pathophysiological conditions. The present study explored the effects of early acute cardiac allograft rejection, and specifically the effects of NO, on myocardial and systemic vascular barrier function using a quantitative double-tracer permeation method in a rat cardiac transplant model. Early allograft rejection increased albumin permeation twofold to fivefold in the allograft heart and systemic vasculature (brain, lung, sciatic nerve, diaphragm, retina, muscle, kidney, and uvea) compared with isografts and controls. There were no detectable differences in regional blood flow or hemodynamics, suggesting that increased albumin permeation resulted from increased vascular permeability. iNOS mRNA was expressed in the allograft heart and native lung and was associated with increased serum nitrite/nitrate levels. iNOS inhibition with aminoguanidine prevented or attenuated allograft heart and systemic vascular barrier dysfunction and reduced allograft serum nitrite/nitrate levels to isograft values. Aminoguanidine did not affect the mild histological changes of rejection present in allografts. These data demonstrate the novel observations that (1) endothelial barrier function is compromised in the systemic vasculature, particularly in the brain, remote from the site of allograft rejection; (2) allograft vascular barrier dysfunction is associated with increased NO production and iNOS mRNA expression in the affected tissues (eg, native lung and grafted heart); and (3) inhibition of NO production by iNOS prevents vascular barrier dysfunction in the allograft heart and systemic vasculature.
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PMID:Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. 862 May 96

Exhaled nitric oxide (NO) may be derived from constitutive NO synthase (NOS) in normal airways, but the increased concentration in asthma is likely to be derived from inducible NOS expressed in inflamed airways. To investigate this, we administered a nonselective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor of inducible NOS, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in both normal subjects and subjects with asthma. L-NAME resulted in a significant reduction in exhaled NO compared with saline control in eight normal subjects (maximum fall from baseline, 53 +/- 7.6% versus 8.9 +/- 6.5%; P < 0.05) and in seven patients with asthma (maximum fall, 67 +/- 7.4% versus 10 +/- 7.4% versus 10 +/- 9.3%; p < 0.05). Aminoguanidine at the same molar concentration decreased exhaled NO in subjects with asthma (maximum fall, 53 +/- 7.2% versus 7.1 +/- 10.4%; p < 0.05), but caused no significant change in normal volunteers (maximum fall, 28 +/- 9.3 versus 15 +/- 11). No rise in blood pressure, fall in FEV1, or adverse effects were observed in either subject group. We have demonstrated that NOS inhibitors can safely be given by inhalation in a single does in normal subjects and subjects with asthma. The raised exhaled NO concentration in patients with asthma may be attributable to induction of NOS, with that in normal subjects reflecting basal constitutive NOS activity.
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PMID:Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. 868 Jun 89

This study compares the effects of aminoguanidine, a relatively selective inhibitor of inducible nitric oxide (NO) synthase, and N omega-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of endothelial NO synthase, on hypotension and multiple organ dysfunction caused by endotoxaemia in the anaesthetised rat. In the sham-operated rats, L-NAME, but not aminoguanidine, caused a dose-dependent increase in blood pressure. Endotoxin caused hypotension, increased in plasma nitrite (an indicator of inducible NO synthase activity), and dysfunction of kidney, liver and pancreas. Treatment of endotoxic rats with aminoguanidine or L-NAME caused significant and sustained rises in blood pressure. The increase in plasma nitrite caused by endotoxin was inhibited by aminoguanidine, but not by L-NAME. Aminoguanidine, but not L-NAME, attenuated the renal, liver and pancreatic dysfunction caused by endotoxaemia. Thus, selective inhibition of inducible (aminoguanidine), but not endothelial NO synthase (L-NAME) attenuates the circulatory failure and the multiple organ failure caused by endotoxaemia.
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PMID:Comparison of the effects of aminoguanidine and N omega-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat. 874 Nov 72

Aminoguanidine treatment prevents the development of nerve conduction velocity (NCV) deficits and some renal and retinal complications in diabetic rats. Pharmacological actions include inhibition of the formation of advanced glycosylation end products (AGEs) and nitric oxide (NO) synthase. The aims of the study were to determine the extent to which diabetic NCV and nerve blood flow deficits could be corrected by aminoguanidine in an intervention study, to assess the time course of drug action, and to examine the effects of cotreatment with the NO synthase inhibitor, NG-nitro-L-arginine (NOLA). A 19.3% +/- 0.9% reduction in sciatic motor NCV after 4 weeks of untreated diabetes was corrected 86.6% +/- 3.7% by aminoguanidine treatment for a further 4 weeks. Time-course studies showed that 50% of the maximal effect was attained within 6 days. Sciatic endoneurial capillary blood flow, reduced approximately 45% by diabetes, was corrected 85.6% +/- 12.1% by aminoguanidine treatment. The NCV and blood flow effects of aminoguanidine were completely blocked by cotreatment with NOLA. Thus, the data support a neurovascular mechanism for aminoguanidine involving improved NO action. The rapidity of aminoguanide's effect is consistent with inhibition of free radical production by autoxidative glycosylation or glycoxidation.
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PMID:Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition. 878 3

We tested the hypothesis that selective inhibition of the inducible form of nitric oxide (NO) synthase with aminoguanidine would prevent the loss of vascular contractility after exposure to endotoxin [lipopolysaccharide (LPS)]. Aortic rings were dissected from Sprague-Dawley rats, suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Vessels incubated with LPS (1 microgram/ml) for 5 h exhibited a significant decrease in the maximal contractile response to phenylephrine. Aminoguanidine (100 microM) restored the maximal contractile response of LPS-treated vessels to the level of the control vessels. Aminoguanidine was approximately 250-fold less potent than NG-nitro-L-arginine methyl ester in inhibiting the constitutive NO synthase in vascular tissue as determined by its ability to further increase tone of submaximally contracted aortic rings. NO synthase activity was determined in vascular tissue incubated with and without LPS. Vessels incubated with LPS exhibited a marked increase in the levels of inducible NO synthase activity compared with control vessels. This increase was restored to control levels when tissue homogenates were incubated with aminoguanidine. We conclude that aminoguanidine is a selective concentration-dependent inhibitor of the inducible form of NO synthase and may be a useful probe to evaluate the role of inducible NO synthase in the abnormal vascular contractility characteristic of endotoxemia and sepsis.
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PMID:Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine. 884 14

Excessive NO produced by an inducible NO synthase (iNOS) has been implicated in many types of immune-associated disorders of the cardiovascular system, but it remains to be determined whether NO plays a role in myocarditis. Thus, the significance of iNOS expression in the development of experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, was investigated. Lewis rats were immunized with cardiac myosin and were killed 7, 14, 21, 28, and 49 days after immunization. The development of severe myocarditis was observed on days 14, 21, and 28 in association with significant deterioration of hemodynamics determined by cardiac catheterization, which peaked on day 21. In parallel with histological severity of myocarditis and deterioration of cardiac performance, iNOS activity in the heart measured by [14C]L-citrulline formation was markedly increased on days 14, 21, and 28. The expression of iNOS was confirmed by immunoblotting and was localized to the infiltrating inflammatory cells found in the vicinity of necrotic myocytes by immunohistochemical analysis. Aminoguanidine, a selective inhibitor of iNOS, significantly decreased the iNOS activity (1.04 +/- 0.37 compared with 29.1 +/- 8.62 pmol.min-1.mg protein-1 in untreated myosin-immunized rats, P < .01) and effectively attenuated histopathological changes of EAM on day 21. Hemodynamic parameters were also improved from 64 +/- 3 to 89 +/- 3 mm Hg for mean blood pressure, from 80 +/- 2 to 113 +/- 4 mm Hg for left ventricular systolic pressure, from 7.8 +/- 0.3 to 3.2 +/- 0.3 mm Hg for left ventricular end-diastolic pressure, from 2867 +/- 137 to 4180 +/- 102 mm Hg/s for +dP/dt, and from 2717 +/- 132 to 4180 +/- 184 mm Hg/s for -dP/dt (P < .01). The values after aminoguanidine treatment were not significantly different from the control values. These results suggest an important role for NO in mediating pathophysiological changes in myocarditis of autoimmune origin.
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PMID:Expression of inducible nitric oxide synthase in rat experimental autoimmune myocarditis with special reference to changes in cardiac hemodynamics. 897 17

The role of nitric oxide (NO) in the gastric mucosal blood flow response and the healing of HCl-induced gastric lesions was investigated in rats. After 18 h fasting rats were given 0.6 N HCl p.o. for the induction of gastric lesions, and 1 h later they were fed normally. After induction of gastric lesions, they were repeatedly administered the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 5-20 mg/kg p.o. twice daily) or aminoguanidine (20 mg/kg s.c. once daily) for 7 days. Gastric lesions caused by HCl healed almost completely within 5 days with granulation and to an extent with re-epithelialization. Repeated administration of L-NAME but not aminoguanidine significantly delayed the healing of gastric lesions in a dose-dependent manner. The damaged mucosa secreted less acid, but showed a marked rise in H+ permeability, resulting in luminal acid loss accompanied by an increase of mucosal blood flow. Aminoguanidine did not significantly affect any of these functional changes observed in the stomach after damage by HCl, whereas L-NAME treatment slightly reversed the decreased acid response, increased the luminal H+ loss, and totally inhibited the mucosal hyperemic response associated with luminal acid loss in the damaged mucosa. In addition, the deleterious influences of L-NAME on the mucosal blood flow response and the healing of gastric lesions were significantly antagonized by co-administration of L-arginine but not of D-arginine (500 mg/kg x 2, i.p.). Luminal output of NO2-/NO3- was significantly increased in pylorus-ligated stomachs in control rats on days 3 and 5 after damage, and such increases in gastric NO output were completely attenuated by L-NAME treatment. These results suggest that endogenous NO may contribute to the healing of acute gastric injury by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the damaged mucosa. NO mediating such responses and participating in the healing aspect of gastric lesions may be produced by the constitutive type of NO synthase.
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PMID:Role of nitric oxide in mucosal blood flow response and the healing of HCl-induced lesions in the rat stomach. 901 6

Nitric oxide (NO) produced by the inducible nitric-oxide synthase (iNOS) is responsible for some of the pathophysiological alterations during inflammation. Part of NO-related cytotoxicity is mediated by peroxynitrite, an oxidant species produced from NO and superoxide. Aminoguanidine and mercaptoethylguanidine (MEG) are inhibitors of iNOS and have anti-inflammatory properties. Here we demonstrate that MEG and related compounds are scavengers of peroxynitrite. MEG caused a dose-dependent inhibition of the peroxynitrite-induced oxidation of cytochrome c2+, hydroxylation of benzoate, and nitration of 4-hydroxyphenylacetic acid. MEG reacts with peroxynitrite with a second-order rate constant of 1900 +/- 64 M-1 s-1 at 37 degrees C. In cultured macrophages, MEG reduced the suppression of mitochondrial respiration and DNA single strand breakage in response to peroxynitrite. MEG also reduced the degree of vascular hyporeactivity in rat thoracic aortic rings exposed to peroxynitrite. The free thiol plays an important role in the scavenging effect of MEG. Aminoguanidine neither affected the oxidation of cytochrome c2+ nor reacted with ground state peroxynitrite, but inhibited the peroxynitrite-induced benzoate hydroxylation and 4-hydroxyphenylacetic acid nitration, indicating that it reacts with activated peroxynitrous acid or nitrogen dioxide. Compounds that act both as iNOS inhibitors and peroxynitrite scavengers may be useful anti-inflammatory agents.
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PMID:Mercaptoethylguanidine and guanidine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage. 908 27

We investigated the effects of aminoguanidine, a relatively selective inhibitor of inducible nitric oxide (NO) synthase, on the systemic inflammatory response syndrome induced by platelet activating factor (PAF) and by lipopolysaccharide in rats, with emphasis on NO production in vivo. Aminoguanidine treatment improved survival rates after lipopolysaccharide challenge, whereas it aggravated the lethality caused by PAF. Lipopolysaccharide induced a marked increase in the concentrations of nitrate and nitrite in plasma compared with vehicle administration, and the increase was prevented by aminoguanidine. In contrast, PAF challenge with or without aminoguanidine did not affect the concentrations of nitrate and nitrite in plasma compared with vehicle administration. These results suggest that NO derived from inducible NO synthase is not a major participant in the systemic inflammatory response syndrome induced by PAF. Aminoguanidine is not likely to provide beneficial effects in conditions where PAF is produced and the concentrations of nitrate and nitrite in plasma are not significantly increased.
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PMID:Effects of aminoguanidine on systemic inflammatory response syndrome induced by platelet activating factor and by lipopolysaccharide in rats. 910 85


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