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)

Diabetic rats manifest abnormal renal hemodynamic responses, with persistent renal vasodilation at reduced renal perfusion pressures. We hypothesized that in diabetes, renal hemodynamics are modulated by increased activity of the endogenous vasodilator, NO. In anesthetized Munich-Wistar rats, after 6 wk of streptozotocin-induced, insulin-treated diabetes, and in age-matched, nondiabetic littermates (n = 7-8), basal renal hemodynamics and responses to graded reductions in renal perfusion pressure were determined before and after intrarenal arterial infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). An identical protocol was followed in a second cohort of rats pretreated with indomethacin (4 mg/kg iv). Diabetic rats demonstrated hyperglycemia, renal enlargement, hyperfiltration, and increased urinary excretion of the stable NO metabolites, NO2 and NO3. L-NAME eliminated basal hyperfiltration in diabetic rats, and L-NAME, but not indomethacin, also eliminated persistent renal vasodilation at reduced renal perfusion pressure. We conclude that in a rat model of diabetes, increased endogenous NO activity may play a role in basal hyperfiltration and in the persistent renal vasodilatation manifested at reduced renal perfusion pressures.
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PMID:Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO. 750 73

We previously reported that increased endogenous nitrosation in human subjects infected with the liver fluke Opisthorchis viverrini in north-east Thailand could be a risk factor for the development of cholangiocarcinoma. In the present study we examined our hypothesis that this increased endogenous nitrosation is mediated by nitric oxide (NO) synthase induced by O. viverrini infestation. Syrian golden hamsters experimentally infected with O. viverrini liver fluke excreted in the urine significantly greater amounts of nitrate, a stable oxidization product of NO, than untreated hamsters (3.64 +/- 0.86 versus 2.64 +/- 0.60 mumol/hamster/day, P < 0.001). When the rapidly nitrosatable thiazolidine 4-carboxylic acid was administered orally, the infected hamsters also excreted significantly elevated levels of N-nitrosothiazolidine 4-carboxylic acid than untreated hamsters (4.27 +/- 2.20 versus 2.33 +/- 1.13 nmol/hamster/day, P < 0.01), indicating that endogenous nitrosation is elevated in the animals with liver fluke. NO synthase activity measured in liver cytosol was about twice as high in the infected hamsters as in untreated animals. The enzyme, whose biochemical characteristics were similar to that induced in activated murine macrophages, was immunohistochemically localized in the cytoplasm of macrophages and eosinophils in the inflammation zone surrounding the parasite-containing bile ducts. These results support our hypothesis that, in fluke-infected subjects, NO synthase induction leads to excess production of NO and the observed elevated endogenous nitrosation. Since high concentrations of NO exert cytotoxic and mutagenic effects per se, excess NO produced in chronically infected/inflamed tissues may also play a role in initiation and subsequent modulation stages of cholangiocarcinoma development.
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PMID:Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini). 750 24

Nitric oxide (NO) has been shown to be important for intracellular microbiostasis in vitro. To determine the role of NO in immune function in vivo, groups of C57BL/6 mice were given a sublethal intravenous inoculum of Listeria monocytogenes EGD, and their urine was monitored daily for nitrate, the mammalian end product of NO metabolism. Urinary nitrate levels peaked at 5 to 10 times the basal level on days 5 to 6, when spleen and liver Listeria counts declined most steeply, and decreased thereafter, when spleens and livers were nearly sterile. Peritoneal macrophages explanted from Listeria-infected mice produced nitrite spontaneously, whereas macrophages from uninfected mice did not. The inducible NO synthase mRNA was detectable in the spleens of infected mice on days 1 to 4 of infection. When Listeria-infected mice were treated orally throughout the infection with NG-monomethyl-L-arginine (NMMA), a specific NO synthase inhibitor they showed no detectable rise in urinary nitrate excretion. Mean Listeria counts in the livers and spleens NMMA-treated mice were 1 to 3 orders of magnitude greater than counts in control mice on days 4 through 8 of infection. Compared with control mice, NMMA-treated mice also showed worse clinical signs of infection, namely, weight loss, hypothermia, decreased food and water intake, and decreased urine output. Histologically NMMA-treated mice had many more inflammatory foci in their livers and spleens than control mice. The histologic observation that mononuclear cells are present at sites of infection suggests that inhibiting NO production did not block the flux of macrophages into infected viscera. As controls for possible drug toxicity, a group of uninfected mice given NMMA orally showed no detrimental effects on weight, temperature, and food and water intake. These experiments demonstrate that inhibition of NO production in Listeria-infected mice results in an exacerbated infection and thus that NO synthesis is important for immune defense against Listeria infection in mice.
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PMID:Nitric oxide produced during murine listeriosis is protective. 750 15

Endothelins (ETs) cause initial and transient vasodilation via an endothelium-dependent mechanism. We studied the cellular mechanism by which ETs stimulate synthesis and release of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) in cultured bovine endothelial cells (EC). ET-1 and ET-3 rapidly (within 1 min) and dose-dependently (10(-10) to 10(-7) M) stimulated production of nitrate/nitrite (NOx) in bovine EC; ET-3 was more potent than ET-1 at generating endothelial NOx. The ET-3-stimulated NOx production was completely abolished by a NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), the effect of which was reversed by coadministration of excess L-arginine. NOx production stimulated by ET-3 was blocked by an intracellular Ca2+ chelator but not by an extracellular Ca2+ chelator. A selective calmodulin inhibitor W-7 dose-dependently inhibited the ET-3-stimulated NOx production, whereas a nonselective calmodulin inhibitor W-5 failed to affect NOx production. These data suggest that ETs stimulate receptor-mediated EDRF/NO synthesis via a Ca2+/calmodulin-dependent pathway in vascular endothelial cells.
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PMID:Cellular mechanism of endothelin-induced nitric oxide synthesis by cultured bovine endothelial cells. 750 51

Nitric oxide (NO), among several other functions, may play a role in hypoxia and reoxygenation injury due to its free radical nature and high reactivity with the superoxide radical to yield peroxynitrite, an oxidant molecule. The present study was undertaken to evaluate a potential role for NO, either endogenous or exogenous, in a model of hypoxia/reoxygenation (H/R) in freshly isolated rat proximal tubules. NO synthase activity, as assessed by conversion of L-[3H]arginine to L-[3H]citrulline, was detected in normoxic tubules. This activity could be inhibited by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and was stimulated by 15 min of hypoxia. The injury in proximal tubules caused by 15 min of hypoxia followed by 35 min of reoxygenation was completely prevented by L-NAME as assessed by release of lactate dehydrogenase, whereas D-NAME, which does not inhibit NO synthase, had no effect. In contrast, L-arginine (NO substrate) enhanced the H/R injury. These effects were paralleled by nitrite/nitrate production. In separate experiments, the addition of sodium nitroprusside, a NO donor, to proximal tubules enhanced the H/R injury; this effect could be blocked by hemoglobin, a NO scavenger. Also, addition of nitroprusside reversed L-NAME protection against H/R injury. These results demonstrate that NO is synthesized in rat proximal tubules and participates as one of the mediators in rat tubular H/R injury.
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PMID:Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. 751 Apr 5

BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS) developed lethal septic shock. This was accompanied by significantly elevated concentrations of nitrite and nitrate in the plasma and expression of high levels of nitric oxide (NO) synthase activity in the lungs, heart, spleen and peritoneal macrophages. Mice pretreated with anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody or anti-interleukin-1 beta (IL-1 beta) polyclonal antibody were protected, in a dose-dependent manner, from endotoxin-induced mortality. This effect was accompanied by a significant reduction in plasma levels of nitrite and nitrate. Antibody treatment also reduced the level of NO synthase activity in peritoneal macrophages, spleen and heart but had no effect on enzyme expression in the lung. These results demonstrate that TNF-alpha and IL-1 beta play an important role in the induction of NO following administration of LPS and in the development of endotoxin-induced shock. In addition, NO synthase activity is differentially expressed in various organs and this may not always require TNF-alpha and IL-1 beta.
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PMID:Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. 751 27

The purpose of this investigation was to determine whether mouse lung fibroblast subsets have the ability to produce nitric oxide (NO), and if so, to characterize the induction and effects of its synthesis. Previously, we isolated Thy1+ and Thy1- subpopulations of mouse lung fibroblasts, which differ in terms of cytokine production, morphology, response to cytokines and radiation, and ability to present antigen to T lymphocytes. When treated with the proinflammatory cytokines IFN-gamma, TNF-alpha, and IL-1 alpha, these fibroblast lines produce micromolar quantities of NO2- and NO3-, two stable end products of the NO pathway. A combination of all three cytokines provided the greatest induction, and there was no measurable production of NO in unstimulated cells. Thy1+ fibroblasts have fewer requirements for induction of NO production than the Thy1- line, in that NO production could be induced by only two of the above cytokines, where the Thy1- fibroblasts required all three. Inducible NO synthase (iNOS) mRNA was shown to be present by the reverse transcriptase-polymerase chain reaction as early as 2 hr after cytokine treatment in both cell lines. Addition of the NO synthase inhibitors NG-monomethyl-L-arginine and aminoguanidine inhibited production of NO2- and NO3-, but not iNOS mRNA. This inhibition was partially reversed by the addition of an excess of L-arginine. Interestingly, inhibition of NO synthesis was shown to decrease IL-6 production by more than 50% in cytokine-treated Thy1+ fibroblasts. These results indicate for the first time that Thy1+ and Thy1- mouse lung fibroblast subsets have the capability to produce NO to differing extents in response to cytokines and may therefore play an important role in the inflammatory response in the lung as well as in the progression of lung disease.
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PMID:Induction of nitric oxide synthase in subsets of murine pulmonary fibroblasts: effect on fibroblast interleukin-6 production. 751 14

Nerve-induced release of the nitric oxide (NO) breakdown products nitrite (NO2-) and nitrate (NO3-) and the histochemical localization of NO synthase in the human penile corpus cavernosum and urethra were studied. Relaxations induced by nerve stimulation were inhibited by N omega-nitro-L-arginine methyl ester (L-NAME), an effect which was reversed by L-arginine. Relaxations elicited either by nerve stimulation or exogenous NO were accompanied by the appearance of equivalent amounts of NO2- and NO3- over a very similar time course. Nerve-induced release of NO2- and NO3- was inhibited by L-NAME. Histochemical studies showed NADPH diaphorase and NO-positive nerve fibres surrounding the arteries and smooth muscle bundles in the corpus cavernosum and the urethra. The results suggest that NO is a mediator for non-adrenergic non-cholinergic relaxation in the human urogenital tract.
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PMID:Release of nitric oxide by nerve stimulation in the human urogenital tract. 751 92

Endotoxinaemia stimulates the generation of cysteinyl leukotrienes (LT), potent mediators of inflammation which are preferentially eliminated into the bile. Nitric oxide (NO) is a mediator molecule that has a possible protective role in liver injury. As sepsis and shock often lead to the development of hypoxic regions in the liver, the influence of hypoxia on the metabolism of cysteinyl leukotrienes and the hepatic production of NO were investigated in the isolated perfused rat liver. Livers were perfused in a non-recirculating haemoglobin-free system from the portal to the caval vein. Perfusion medium was equilibrated with 95% O2/5% CO2. In hypoxia experiments, gassing was changed to 95% N2/5% CO2 for 20 min. Tritiated leukotrienes were infused to the portal vein and metabolites in effluent and bile were measured by HPLC. Hypoxia did not influence the uptake of 3H-LTC4 and 3H-LTE4 but biliary elimination was reduced by 50-60% compared to normoxic control experiments. In hypoxia, the metabolite pattern in bile was also significantly changed with a decrease of omega-oxidation products. Following reoxygenation larger amounts of leukotrienes were excreted from the liver into the bile. To induce NO synthase in the liver, rats were injected intraperitoneally with endotoxin 6 hours before livers were isolated for perfusion. In contrast to nontreated livers, nitrite and nitrate, the oxidation products of NO, were detectable in the effluent perfusate. Basal NO2(-)+NO3- release was 5.3 (1.2) nmol/g liver/min. NO2(-)+NO3- release was stimulated by L-arginine infusion, whereas hypoxia resulted in an almost complete inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effect of hypoxia on nitric oxide formation and leukotriene metabolism in the perfused rat liver]. 751 4

The sensitivity of animals to endotoxin differs significantly between species. Thus, factors that determine the susceptibility to endotoxin may play important roles in the pathogenesis of septic shock. In order to determine the mechanism responsible for susceptibility to endotoxin, the effect of lipopolysaccharide (LPS) on the circulatory status of Propionibacterium acnes (PA)-sensitized rats was studied. Following the intravenous administration of a low dose of LPS, the arterial blood pressure of PA-treated rats, but not of normal animals, progressively decreased; the PA-sensitized animals died of circulatory shock within 7 h of LPS administration. N omega-nitro-L-arginine (NA) reduced the depressor effect of LPS by an L-arginine-inhibitable mechanism. Administration of LPS markedly increased the level of the inducible type of nitric oxide (NO) synthase in various tissues, including the aorta, of PA-treated rats but not of control animals. LPS also increased plasma levels of nitrate plus nitrite and aortic levels of cGMP. Dexamethasone inhibited the de novo synthesis of NO synthase in the aorta and other tissues and reduced the depressor effect of LPS. These and other findings suggest that induction of nitric oxide synthase in resistant arteries might underlie the pathogenesis of LPS-induced hypotension in PA-sensitized animals and the mechanism responsible for the susceptibility to endotoxin.
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PMID:Role of vascular nitric oxide synthase in endotoxin shock of Propionibacterium acnes-sensitized rats. 751 20


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