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

The possible role of nitric oxide (NO) in the regulation of airway tone remains to be fully explored. In the present study we examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on airway responsiveness in rats. The effect of L-NAME on endotoxin (lipopolysaccharide; LPS)-induced changes in airway responsiveness was also evaluated. L-NAME (1 mg/kg given intravenously) caused a 33.3 +/- 6.9% increase in blood pressure, but did not influence baseline airway tone or the provocative dose of carbachol causing a 50% increase in pulmonary resistance (RL)(PD50RL). Exposure of F344 rats to LPS induced a transient increase in airway responsiveness at 90 min after exposure, followed by a significant hyporesponsiveness between 9 and 12 h after exposure. L-NAME (1 mg/kg intravenously) did not influence the increase in responsiveness but inhibited the LPS-induced hyporesponsiveness; in LPS-exposed, L-NAME-treated animals, the PD50RL for carbachol was 3.0 +/- 0.1, versus 4.8 +/- 0.3 micrograms/kg in the LPS-exposed, placebo-pretreated group (p < 0.05). The effect of L-NAME was abolished by pretreatment with L-arginine but not with D-arginine. L-NAME did not influence the LPS-induced increase of neutrophils in bronchoalveolar lavage fluid (BALF). These results suggest that in rats, consitutive NO synthesis does not contribute either to basal airway tone or to the basal degree of airway responsiveness, but that inducible NO synthesis mediates endotoxin-induced hyporesponsiveness.
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PMID:The effect of a nitric oxide synthase inhibitor on the modulation of airway responsiveness in rats. 769 47

The importance of gastrointestinal injury in endotoxin-induced shock and multiple organ failure is of great interest. In this paper we describe a method to assess the degree of intravascular congestion and bleeding into the wall of the intestine by determining the hemoglobin content of the tissue. After validating this method, we used it to study the mechanism of jejunal injury induced by intravenous injection of Escherichia coli lipopolysaccharide (LPS, 50 mg/kg bw), the role of nitric oxide release in maintaining the integrity of endothelial cells, and the participation of H2O2 production in the LPS-induced intestinal damage in rats. Our results show that after the administration of LPS at the dose of 50 mg/kg intravenously, the hemoglobin content of the jejunum (17.8 mg/100 mg tissue) increased 7.7-fold over that of control animals (2.3 mg/100 mg), reflecting a serious degree of congestion, bleeding, and damage in the gastrointestinal tract. Administration of nitro-L-arginine methyl ester (L-NAME) not only enhanced this injury, but also markedly decreased the dose of LPS necessary to induce intestinal damage. Infusion of L-arginine (300 mg/kg bolus plus infusion 600 mg/kg.h intravenously) protected the intestine against LPS or LPS plus L-NAME. Inhibition of basal nitric oxide release by L-NAME produced significant changes in cardiovascular variables, but failed to induce a significant bleeding damage. However, when inhibition of NO release was combined with enhanced H2O2 production by a small dose of LPS, a serious bleeding damage was observed. This was accompanied by a marked decrease in mesenteric blood flow and cardiac output. High dose of LPS induced the above effects, and thus could be responsible for the bleeding damage, while low dose of LPS that fails to inhibit nitric oxide, did not induce any intestinal bleeding. It seems that inhibition of NO release and stimulation of H2O2 production are both involved in the LPS-induced bleeding damage.
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PMID:The roles of nitric oxide and hydrogen peroxide production in lipopolysaccharide-induced intestinal damage. 774 48

1. The involvement of endogenous platelet activating factor (PAF) and thromboxane A2 in the acute microvascular damage in the ileum and colon induced by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) following endotoxin administration was investigated in the rat over a 1 h period. 2. Administration of L-NAME (1-10 mg kg-1, s.c.) concurrently with E. coli lipopolysaccharide (LPS; 3 mg kg-1, i.v.) dose-dependently increased vascular permeability in the ileum and colon, as determined by the leakage of radiolabelled albumin, and caused macroscopic mucosal damage in the ileum determined 1 h later. Neither LPS administration nor L-NAME (5 mg kg-1) alone affected resting vascular permeability. 3. Infusion of phenylephrine (10 micrograms kg-1 min-1, i.v. for 1 h) caused an elevation in blood pressure similar to that found following L-NAME administration (5 mg kg-1, i.v. or s.c.), but did not increase intestinal vascular permeability, when administered with LPS (3 mg kg-1, i.v.). 4. The increased vascular permeability in the ileum and colon and macroscopic damage in the ileum, induced by L-NAME (5 mg kg-1, s.c.) and LPS (3 mg kg-1, i.v.) was dose-dependently inhibited following s.c. pretreatment (15 min before challenge) with the thromboxane synthase inhibitors, OKY 1581 (5-25 mg kg-1) or 1-benzyl-imidazole (1-50 mg kg-1), or with the thromboxane receptor antagonist, BM 13177 (0.2-2 mg kg-1). 5. Pretreatment with the cyclo-oxygenase inhibitor, indomethacin (2-5 mg kg-', s.c., 15 min before challenge) reduced the microvascular injury in the ileum and colon and macroscopic lesions in the ileum,observed after the concurrent administration of L-NAME and LPS.6. Pretreatment (15 min) with the PAF-receptor antagonists, WEB 2086 (0.5-1 mg kg-', s.c.) or BN52021 (2.5-10 mg kg-', s.c.) likewise attenuated this intestinal vascular injury.7. Combined administration of low doses of l-benzyl-imidazole (1 mg kg-') with WEB 2086(0.5 mg kg-')15 min before L-NAME and LPS challenge, abolished this vascular damage and macroscopic injury.8. These results suggest that PAF and thromboxane A2 are released acutely following challenge with a low dose of endotoxin. However, these mediators do not appear to injure the intestinal micro vascular bed unless NO synthase is concurrently inhibited. Such findings support the protective role of constitutively-formed NO, counteracting the injurious vascular actions of cytotoxic mediators released under pathological conditions.
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PMID:Interactions of constitutive nitric oxide with PAF and thromboxane on rat intestinal vascular integrity in acute endotoxaemia. 788 65

We have examined the role of soluble guanylyl cyclase and possible mediators of its activation in the vascular hyporeactivity caused by bacterial endotoxin (lipopolysaccharide, LPS) ex vivo. Treatment of rats with E. coli LPS (10 mg/kg, i.v. for 3h) resulted in a significant reduction in the contractions elicited by norepinephrine (NE; 10(-9)-10(-6) M) in endothelium-denuded aortic rings ex vivo. Methylene blue or LY-83583, inhibitors of soluble guanylyl cyclase, completely restored contractions to NE, whereas the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), caused only a partial restoration. Zinc protoporphyrin-IX, an inhibitor of heme oxygenase, did not enhance NE-induced contraction in rings from LPS-treated rats, indicating that the production of carbon monoxide (CO) does not contribute to this vascular hyporeactivity. Indomethacin, an inhibitor of cyclooxygenase, further suppressed the contractions in rings from LPS-treated rats. These results suggest that hyporesponsiveness to NE caused by LPS is due to the activation of soluble guanylyl cyclase, which is partially mediated by N(O), but not by CO. Moreover, LPS may induce the production of another mediator(s) that activate soluble guanylyl cyclase in the vascular smooth muscle.
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PMID:Activation of soluble guanylyl cyclase by a factor other than nitric oxide or carbon monoxide contributes to the vascular hyporeactivity to vasoconstrictor agents in the aorta of rats treated with endotoxin. 791 Oct 15

In an analysis of nitric oxide (.NO) production and toxicity, chicken macrophage-generated .NO inhibited mitochondrial activity in both .NO-producing macrophages themselves and lymphoid tumor targets. However, differences in targeting of mitochondrial toxicity were observed among these cells. Two chicken macrophage cell lines, HD11 and MQ-NCSU, produced .NO (measured as nitrite) dependent upon concentrations of L-arginine and bacterial endotoxin (lipopolysaccharide). Mitochondrial activity was negatively correlated with the amount of .NO produced. Using a modified MTT assay, .NO induced suppression in two mitochondrial complexes. Mitochondrial activity was significantly suppressed among HD11 cells receiving LPS alone (complex I, 63.0 +/- 5.5% suppression; complex II, 27.9 +/- 5.2%). In contrast, mitochondrial activities in samples receiving LPS plus inhibitor, NG-nitro-L-arginine methyl ester (NAME; 5 mM) or 2,4-diamino-6-hydroxypyrimidine (DAHP; 5 mM), were not significantly different from control values. When HD11 macrophages were cocultured with lymphoblastoid tumor targets, RECC-CU60 (T cell) or LSCC-RP9 (B cell), adding LPS (1 microgram/ml), tumor cell mitochondrial activity was significantly suppressed. In the generator macrophages, complex I was more suppressed than complex II, whereas in lymphoid targets no such difference was observed. These results indicate that .NO inhibits complex I and II mitochondrial activity but that differential targeting can occur among chicken leukocyte populations.
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PMID:Nitric oxide (.NO)-induced mitochondrial injury among chicken .NO-generating and target leukocytes. 802 70

1. Drinking was induced in rats by 24 h of water deprivation. Water intake (ml) was evaluated for a 1 h period. 2. NG-nitro-L-arginine methyl ester (L-NAME, 5-10 micrograms, i.c.v., 50-100 ng into the preoptic area (POA)), an inhibitor of nitric oxide (NO) synthase, and methylene blue (50-100 ng into POA), an inhibitor of guanylate cyclase activation, antagonized the inhibition of drinking induced by E. coli endotoxin (LPS, 640 micrograms kg-1, i.v.) and tumour necrosis factor (TNF alpha, 40 ng, i.c.v.) in 24 h water-deprived rats. 3. L-Arginine (25, 50 and 100 ng), the precursor amino acid of NO, but not the stereoisomer D-arginine (100 ng), inhibited drinking induced by water deprivation when injected into the POA 30 min before water presentation (74.4% of inhibition with the highest dose). A dose of 12.5 ng L-arginine into the POA did not exhibit antidipsogenic effects. 4. TNF alpha (20 and 40 ng, i.c.v.; 1.25, 2.5 and 5 ng into the POA) showed a dose-dependent and powerful inhibition of drinking behaviour in water-deprived rats (70.4% and 80.8%, i.c.v. and into POA, with the highest doses, respectively). A dose of 10 ng of TNF alpha given i.c.v. had no effect on the intake of water. 5. LPS and TNF alpha, given at doses (160 micrograms kg-1, i.v. and 10 ng, i.c.v., respectively) that did not influence drinking in water-deprived rats, exhibited a strong antidipsogenic effect in water-deprived rats treated with a dose of L-arginine (12.5 ng, into the POA) which did not modify drinking by itself. (LPS + L-arginine:53.6% of inhibition; TNFalpha + L-arginine: 52.0% of inhibition).6. These results suggest that NO into the POA: (1) acts as an inhibitory mechanism on thirst and (2)plays a role in the antidipsogenic effect of LPS and TNFalpha.
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PMID:Mediation by nitric oxide formation in the preoptic area of endotoxin and tumour necrosis factor-induced inhibition of water intake in the rat. 803 19

1. The effects of bacterial lipopolysaccharide (Escherichia coli 0111-B4; LPS) on coronary vascular tone were examined in the isolated perfused heart of the rat. The role of nitric oxide and/or prostaglandin products of the cyclo-oxygenase pathway in mediating the actions of LPS were also investigated. 2. Coronary vascular tone was raised and maintained by a continuous perfusion of the thromboxane-mimetic U46619 (5 nM). LPS perfusion (0.1-100 micrograms ml-1) caused a concentration-dependent fall in coronary tone without any significant change in the force of cardiac contractility. 3. At 5 micrograms ml-1, LPS reduced perfusion pressure by 38 +/- 9 mmHg. This effect was rapid in onset, maximal within the first 5 min and sustained for 90 +/- 10 min (n = 6). 4. The vasodilatation induced by LPS was dependent on the presence of an intact endothelium and abolished following endothelial damage caused by air embolism. 5. NG-nitro-L-arginine methylester (L-NAME; 50 microM) or NG-nitro-L-arginine (L-NOARG; 50 microM) blocked the vasodilatation induced by LPS (5 micrograms ml-1). The inhibition caused by these arginine analogues was partially reversed by 1 mM L- but not D-arginine. 6. The vasodilator action of LPS was also completely blocked by the glucocorticoid, dexamethasone (10 microM) but unaffected by indomethacin (10 microM). 7. These results suggest that LPS evokes rapid release of nitric oxide (NO) in the microvasculature of the rat isolated heart presumably via activation of the constitutive L-arginine-NO pathway in the endothelium. Furthermore, the lack of effect of indomethacin suggests that prostaglandins released via the cyclo-oxygenase pathway are not involved in mediating this action of LPS.
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PMID:Bacterial endotoxin rapidly stimulates prolonged endothelium-dependent vasodilatation in the rat isolated perfused heart. 840 52

We have evaluated the role of nitric oxide (NO) on the cyclooxygenase pathway in mouse glial cells. Exposure of primary cultures of neonatal mouse cortical astrocytes to bacterial lipopolysaccharide (LPS; 1 microgram/ml, 18 h) caused an increase in the release of both nitrite (NO2-) and prostaglandin E2 (PGE2), products of NO synthase (NOS) and cyclooxygenase, respectively. Production of both, NO2- and PGE2 by astrocytes, was inhibited by the exposure of the NOS inhibitor Nw-nitro-L-arginine methyl ester (L-NAME: 1, 10, and 100 microM) in a dose related manner. Besides, other NOS inhibitors such as Nitro L-arginine (NNA: 10(-3) M) prevented the increase in PGE2 release from LPS-stimulated astrocytes. Sodium nitroprusside (SNP; 100-200 microM) used as a NO donor caused a dose-related enhancement in the accumulation of PGE2 induced by LPS and the presence of hemoglobin blocked the SNP effects. The exposure to SNP counteracted the decrease of PGE2 production in LPS-treated astrocytes in which NO synthesis was blocked by L-NAME. In addition, SNP also enhanced the synthesis of PGE2 following exogenous arachidonic acid astrocytes exposure. Interestingly, this effect was blocked by indomethacin. Treatment of astrocytes cultures with dexamethasone (0.1, 1 microM) blocked dose-relatedly the LPS-induced release of both NO2- and PGE2. As expected, the presence of indomethacin (1, 10, and 20 microM) prevented in a dose related fashion, PGE2 production by astrocytes following exposure to LPS. These results strongly indicate that in astroglial cells, NO is able to activate the cyclooxygenase pathway.
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PMID:Evidence for cyclooxygenase activation by nitric oxide in astrocytes. 856 68

Inflammatory mediators stimulate arginine-derived nitric oxide (NO) production in a variety of cells. The purpose of this study was to determine if the inflammatory mediators, endotoxin (LPS) and interferon gamma (IFN), stimulate arginine transport and nitric oxide production in a murine breast cancer cell line. We also investigated the effect of the nitric oxide synthase (NOS) inhibitors, omega-nitro-L-arginine methyl ester (LNAME) and aminoguanidine (AG), as well as the effect of varying the concentration of L-arginine in the cellular media, on arginine transport and NO production in these tumors cells. Confluent EMT-6 murine breast cancer cells were incubated with LPS (10 microgram/ml) and IFN (50 units/ml) in the presence or absence of the NOS inhibitors, L-NAME (2 mM) or AG (1 mM), and arginine transport (using L-[3H]arginine) and NO production (the stable end-product nitrite was assayed using the Greiss reagent) were measured at various time points. In addition, the effect of varying the concentration of L-arginine (0, 10, 100, 1000, 10,000 mM) in the cellular media on stimulated L-arginine transport and nitrite accumulation was assessed. Incubation of EMT-6 with LPS and IFN stimulated arginine transport approximately 70% over control levels at 12 hr and transport returned to basal levels at 24 hr. LPS/IFN-stimulated EMT-6 cells produced 25 microM nitrite at 24 hr and reached a plateau of 55 microM nitrite at 48 hr. The NO synthase inhibitors, L-NAME and AG, failed to inhibit basal and stimulated levels of arginine transport, but significantly inhibited nitrite accumulation, which was restored by 10 mM L-arginine. Finally, L-arginine was necessary in the media for nitrite accumulation by LPS/IFN-stimulated cells, with maximal accumulation at 1 mM L-arginine. In summary, LPS/IFN stimulate arginine transport and NO production in the EMT-6 breast cancer cell line. L-NAME and AG do not inhibit basal or stimulated arginine transport in this tumor cell line and extracellular L-arginine is required for NO synthesis in these cells. LPS/IFN stimulation of arginine transport may represent an adaptive response to provide increased substrate for enhanced tumor cell NO production.
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PMID:Inflammatory mediators stimulate arginine transport and arginine-derived nitric oxide production in a murine breast cancer cell line. 859 55

Nitric oxide synthase (NOS) inhibition has been used to increase blood pressure in humans with septic shock despite a lack of data regarding its effects on O2 delivery (QO2). We studied the effects of NG-nitro-L-arginine methyl ester (L-NAME) on systemic, gut, and hindlimb circulations of endotoxic dogs. Twelve dogs were infused with 2 mg/kg of LPS over 1 h followed by 60 mL/kg of 6% dextran over 2 h. Six dogs also received 20 mg/kg of L-NAME, LPS caused mean arterial pressure (MAP), flow and QO2 to whole body, hindlimb and gut to decrease, but O2 uptake (VO2) did not change. Dextran resuscitation alone produced a hyperdynamic state with increased blood flow to or above baseline. With L-NAME, systemic and regional resistances increased twofold and MAP returned to near baseline. Late in the study, these dogs had significantly lower blood flow and QO2 to the gut but maintained VO2 by increasing oxygen extraction to near critical levels. These data suggest that in acute endotoxicosis, L-NAME may significantly improve blood pressure but may markedly encroach on O2 transport reserves to the gut.
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PMID:Effects of nitric oxide synthase inhibition on regional hemodynamics and oxygen transport in endotoxic dogs. 860 98


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