Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-Melanocyte stimulating hormone has been shown to prevent endotoxin shock. A heptapeptide analog (HP-228) has recently been synthesized and shown to be an even more potent protective agent. Because the hypotensive and toxic actions of lipopolysaccharide (LPS) appear to involve the induction of type II nitric oxide synthase (iNOS), we have examined the actions of HP-228 on nitric oxide production using an endotoxemia model in conscious rats given E. coli LPS (5 mg/kg i.v.) and monitored for 6 h. A group of rats received HP-228 (30 micrograms/kg) 30 min before LPS. Using nitro L-arginine methyl ester-sensitive cGMP production as an estimate of nitric oxide synthase activity in aortic segments, ex vivo, we determined that LPS increases iNOS activity and that HP-228 pretreatment markedly reduces this response. Additionally, the rate of conversion of 3[H]-arginine to 3[H]-citrulline was significantly reduced in lung homogenates from HP-228-treated rats. HP-228 did not alter the activity of the constitutive nitric oxide synthase in aortic rings or in cerebella. In isolated rat aortic smooth muscle cells, LPS or interleukin-1 beta caused prominent rises in nitric oxide generated by iNOS. HP-228 did not antagonize the effect of these inducing agents. However, in these cells, plasma obtained from rats 1 h after administration of HP-228 prevented the induction of iNOS by both LPS and interleukin-1 beta. In conclusion, HP-228 prevents the in vivo induction of nitric oxide synthase by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. 747 42

Nitric oxide (NO), a free radical gas, has been suggested to mediate both synaptic plasticity and neuronal death. NO is generated by constitutive and inducible types of NO synthase (cNOS and iNOS, respectively). The neuronal cNOS was recently cloned, sequenced and characterized. In contrast, properties of iNOS in the brain are not fully understood. It is noted that glial cells can form NO and that microglial and reactive astroglial cells are accumulated around neurodegenerative sites in the brain, suggesting a relationship between neuronal injury and NO originated from glial cells. We found that several stimuli such as endotoxin (lipopolysaccharide) and cytokines induced iNOS in glial cells of rat brain. This article reviews recent findings on characteristics and the induction mechanism of iNOS in the glial cells, and discusses the possible pathophysiological functions of iNOS in the brain.
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PMID:Inducible nitric oxide synthase in glial cells. 751 Mar 74

To detect mRNA expression of nitric oxide synthase (NOS) isoforms in human monocytes/macrophages reverse transcription polymerase chain reaction (RT-PCR) was used. mRNA was isolated from stimulated or unstimulated monocytes/macrophages and RT-PCR was performed using oligonucleotide primers derived from mRNA sequences of either human endothelial constitutive (c) or human hepatocyte inducible (i) NOS. RT-PCR of mRNA isolated from resting monocytes and macrophages resulted in the amplification of a cNOS specific mRNA fragment. When the cells were stimulated with lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma) prior to mRNA extraction, RT-PCR yielded an iNOS-specific amplification product. Whereas the activation of both cell types was accompanied by expression of iNOS mRNA, the cNOS signal seemed to be diminished upon immunostimulation. Not only in purified human monocytes but also in the human monocytoid cell lines MonoMac 6, THP-1, and U937 cNOS mRNA was detected. The data clearly demonstrate the presence of iNOS and cNOS mRNA in human monocytes/macrophages and provide the necessary tools to investigate the regulation of NO synthesis in these cell populations.
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PMID:Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. 752 3

Treatment of rat cerebellar astrocyte-enriched primary cultures with dexamethasone enhances the nitric oxide-dependent cyclic GMP formation induced by noradrenaline in a time-(> 6 h) and concentration-dependent manner (half-maximal effect at 1 nM). Stimulation of cyclic GMP formation by the calcium ionophore A23187 is similarly enhanced. In contrast, cyclic GMP accumulation in cells treated with lipopolysaccharide is inhibited by dexamethasone. The potentiating effect of dexamethasone is prevented by the protein synthesis inhibitor cycloheximide and is not due to increased soluble guanylate cyclase activity. Agonist stimulation of [3H]arginine to [3H]citrulline conversion is enhanced by dexamethasone in astrocytes but not in cerebellar granule cells. These results indicate that glucocorticoids may up-regulate astroglial calcium-dependent nitric oxide synthase while preventing expression of inducible nitric oxide synthase and are the first report of a differential long-term regulation of the expression of neuronal and astroglial constitutive nitric oxide synthase activities.
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PMID:Dexamethasone up-regulates a constitutive nitric oxide synthase in cerebellar astrocytes but not in granule cells in culture. 752 66

1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 +/- 4 mmHg (time 0, control) to 79 +/- 9 mmHg at 180 min (P < 0.05, n = 10). The pressor effect of noradrenaline (NA, 1 microgram kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 +/- 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the pressor response to NA: indeed, at 180 min, the pressor response returned to normal in aminoguanidine pretreated LPS-rats. 3. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractile responses elicited by NA (10-9- 10-6 M). Pretreatment with aminoguanidine (15 mg kg- 1, i.v.,at 20 min prior to LPS) significantly prevented this LPS-induced hyporeactivity to NA ex vivo.4. Endotoxaemia for 180 min resulted in a significant increase in iNOS activity in the lung from 0.6 +/- 0.2 pmol mg-1 min-1 (control, n = 4) to 4.8 +/- 0.3 pmol mg-1 min-1 (P<0.05, n = 6). In LPS-rats treated with aminoguanidine, iNOS activity in the lung was attenuated by 44+/- 5% (n = 6, P <0.05).Moreover, when added in vitro to lung homogenates obtained from LPS-rats, aminoguanidine and N omega-nitro-L-arginine methyl ester (L-NAME; 10-8 to 10-3 M) caused a concentration-dependent inhibition of iNOS activity (n = 3-6, IC50: 30 +/- 12 and 11 +/- 6pEM, respectively P>0.05). In contrast,aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 +/- 10 and 0.6 +/- 0.1 I1M, respectively, P<0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME(maximal inhibition at 90 min and 30 min, respectively).5. Treatment of conscious Swiss albino (T/O) mice with a high dose of endotoxin (60 mg kg-1, i.p.)resulted in a survival rate of only 8% at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75%(n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate(11%, n=9).6 Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine,or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock.
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PMID:Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. 754 Dec 82

A common basis to genetic regulation of leishmanial and mycobacterial infections is provided by the action of the murine Lsh/Ity/Bcg gene in controlling the priming/activation of macrophages for antimicrobial activity. This relies on the TNF-alpha-dependent sustained expression of the inducible nitric oxide synthase (iNOS) gene responsible for the generation of large amounts of toxic nitric oxide (NO). The Lsh/Ity/Bcg gene has many pleiotropic effects, including differential expression of the early response gene KC following stimulation of macrophages with bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM). The major signal transduction pathway involved in KC induction requires the generation of low levels of NO via constitutive nitric oxide synthase (cNOS) activity, leading to activation of guanylate cyclase and the cGMP-dependent kinase pathway. NO therefore appears to provide a common link between the early influence of Lsh in regulating the expression of genes which mediate many pleiotropic effects, and the later production of NO as the final effector mechanism for kill. The recently cloned candidate for Lsh/Ity/Bcg, designated Nramp for Natural resistance associated macrophage protein, encodes a polytopic integral membrane protein that has structural features common to prokaryotic and eukaryotic transporters and includes a conserved binding-protein-dependent transport motif which may be involved in interaction with peripheral ATP-binding subunits. The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues. 773 96

1. We have compared the effect of aminoguanidine with that of N omega-nitro-L-arginine methyl ester on isolated thoracic aortic rings obtained either from endotoxin (lipopolysaccharide, 10 mg/kg, i.v. for 3 h) or vehicle (saline) treated rats. 2. Administration of endotoxin for 3 h resulted in a hypotension and a significant reduction of pressor responses to norepinephrine (1 micrograms/kg, i.v.) in the anaesthetized rat. 3. In intact rings obtained from vehicle treated rats, aminoguanidine (0.3 and 1 mmol/L) had no significant effect on acetylcholine-induced relaxation (10(-9)-10(-5) mol/L), whereas N omega-nitro-L-arginine methyl ester (0.3 mmol/L and 1 mmol/L) abolished that response, suggesting that aminoguanidine does not inhibit the activity of constitutive nitric oxide synthase. 4. Relaxation induced by L-arginine (10(-6)-10(-2) mol/L) was competitively inhibited by both aminoguanidine (0.3 mmol/L) and N omega-nitro-L-arginine methyl ester (0.3 mmol/L) in endothelium-denuded aortic rings obtained from endotoxin treated rats. 5. Three hours of endotoxaemia was associated with an impairment of contraction to norepinephrine (10(-9)-10(-6) mol/L) in the endothelium-denuded aorta ex vivo. This hyporeactivity to norepinephrine was partially restored by treatment of the vessels either with aminoguanidine (0.3 mmol/L) or with N omega-nitro-L-arginine methyl ester (0.3 mmol/L) in vitro. 6. These results in isolated thoracic aortae of the rat reinforce that aminoguanidine is a selective inhibitor of the inducible nitric oxide synthase, whereas N omega-nitro-L-arginine methyl ester is a non-selective inhibitor of both the inducible and constitutive nitric oxide synthase.
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PMID:Comparison of responses to aminoguanidine and N omega-nitro-L-arginine methyl ester in the rat aorta. 854 78

1. The cardiovascular failure in sepsis may result from increased nitric oxide biosynthesis, through the diffuse expression of an inducible nitric oxide synthase. In such conditions, nitric oxide synthase inhibitors might be of therapeutic value, but detrimental side effects have been reported with their use, possibly related to the blockade of constitutive nitric oxide synthase. Therefore, the use of selective inhibitors of inducible nitric oxide synthase might be more suitable. The aim of this study was to evaluate the effects of L-canavanine, a potentially selective inhibitor of inducible nitric oxide synthase, in an animal model of septic shock. 2. Anaesthetized rats were challenged with 10 mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a 5 h infusion of either L-canavanine (20 mg h-1 kg-1, n = 15), nitro-L-arginine methyl ester (5 mg h-1 kg-1, n = 13) or 0.9% NaCl (2 ml h-1 kg-1, n = 21). Lipopolysaccharide induced a progressive fall in blood pressure and cardiac index, accompanied by a significant lactic acidosis and a marked rise in plasma nitrate. All these changes were significantly attenuated by L-canavanine, which also improved the tolerance of endotoxaemic animals to acute episodes of hypovolaemia. In addition, L-canavanine significantly increased survival of mice challenged with a lethal dose of lipopolysaccharide. In contrast to L-canavanine, nitro-L-arginine methyl ester increased blood pressure at the expense of a severe fall in cardiac index, while largely enhancing lactic acidosis. This agent did not improve survival of endotoxaemic mice. In additional experiments, we found that the pressor effect of L-canavanine in advanced endotoxaemia (4 h) was reversed by L-arginine, confirming that it was related to nitric oxide synthase inhibition. In contrast, L-canavanine did not exert any influence on blood pressure in the very early stage (first hour) of endotoxaemia or in the absence of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide synthase inhibition by this agent. 3. In conclusion, L-canavanine produced beneficial haemodynamic and metabolic effects and improved survival in rodent endotoxic shock. The actions of L-canavanine were associated with a selective inhibition of inducible nitric oxide synthase and were in marked contrast to the deleterious consequences of nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, in similar conditions.
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PMID:Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, during rodent endotoxaemia. 866 74

The enzyme responsible for nitric oxide (NO) formation, NO synthase (NOS), is found in hypothalamic neurons that control ACTH secretion. This led to the hypothesis that brain NO may modulate the response of the hypothalamic-pituitary (HP) axis to various stimuli. We tested this hypothesis by measuring changes in constitutive (c) NOS mRNA levels in the hypothalamus of rats systemically injected with endotoxin, a lipopolysaccharide (LPS) that releases endogenous cytokines, and analyzed these results in the context of the appearance of ACTH-releasing secretagogues such as corticotropin-releasing factor (CRF) and vasopressin (VP), as well as CRF receptors type A (CRF-RA). We purposefully chose doses of LPS thought to only minimally disrupt the blood-brain barrier and not be accompanied by an endotoxin shock, so that the results we obtained did not primarily stem from abnormal passage of compounds into the brain, or non-specific stress. Three to four hours following LPS injection (100 micrograms/kg, i.v.), cNOS mRNA levels increased in the paraventricular nucleus (PVN) of the hypothalamus. LPS treatment also upregulated PVN CRF gene transcription (measured by CRF heteronuclear RNA) and increased steady-state gene expression of the immediate early genes (IEG) c-fos and NGFI-B, with the first changes noted 1-2 h after treatment. Transcripts of CRF receptors type A were present in the hypothalamus 6 h after endotoxin treatment. On the other hand, no alterations in cytoplasmic VP mRNA levels were noted in rats injected with LPS. Because the dose of LPS we used stimulates ACTH secretion within 30 min, our results suggest that systemic LPS acts first within the median eminence, where it stimulates peptidic nerve terminals. Neuronal activation of hypothalamic cell bodies takes place later, and whether this phenomenon is due to the production of brain neurotransmitters and/or cytokines, or whether it primarily results from increased demand on the synthetic machinery, remains to be established. These studies extend prior work showing that systemic LPS increases the neuronal activity of hypothalamic regions known for their involvement in the responses of the HP axis, and bring forth two important additional points. First, increases in CRF primary nuclear transcripts are delayed with regard to the temporal release of ACTH. This suggests, though it does not demonstrate, that under the experimental conditions we used, the first site of action of LPS is the median eminence. Second, the observation of increased cNOS gene expression following LPS treatment, and the presence of this enzyme in neurons that regulate ACTH secretion, bring support to the hypothesis that this gas plays an important function in mediating the HP axis response to an immune challenge.
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PMID:Systemic endotoxin increases steady-state gene expression of hypothalamic nitric oxide synthase: comparison with corticotropin-releasing factor and vasopressin gene transcripts. 882 44

HF-2035, 2-[N-(2-aminoethyl)-N-(2,4,5-trichlorobenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, was synthesized and its effects on calmodulin-dependent enzymes were investigated. HF-2035 inhibited calmodulin kinase I, calmodulin kinase II and myosin light-chain kinase with IC50 values of 1.3 microM, 1.6 microM and 68 microM, respectively. HF-2035 also inhibited the activity of recombinant rat neuronal nitric oxide synthase, one of the calmodulin-dependent enzymes, with a Ki of 0.78 microM. Partially purified nitric oxide synthase of rat brain was also inhibited by HF-2035 with an IC50 of 3.2 microM. Kinetic analysis indicated that this inhibitory effect of HF-2035 was competitive with respect to calmodulin. We examined the effects of HF-2035 on constitutive nitric oxide synthase in a bioassay using vascular strips of rabbit carotid artery with and without endothelium. HF-2035 inhibited acetylcholine- and calcium ionophore, A23187 (6S-[6 alpha (2S*,3S*),8 beta (R*),9 beta, 11 alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)- ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazol ecarboxylic acid)-induced relaxation of endothelium-intact strips with an ED50 of 1.5 +/- 0.5 microM and 2.8 +/- 1 microM, respectively. This compound, however, did not inhibit N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A), an exogenous nitric oxide donor, -induced relaxation of endothelium-denuded strips. W-7 (N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide) inhibited acetylcholine-induced relaxation with an ED50 of 46 +/- 7 microM, which was 30-fold less potent than HF-2035. HF-2035 was unable to inhibit the activity of the inducible form of nitric oxide synthase in isolated thoracic aorta of rat treated with Escherichia coli lipopolysaccharide. These findings suggest that HF-2035 is a new and potent calmodulin antagonist, and may be used as a mother compound to develop more selective inhibitors of constitutive nitric oxide synthase.
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PMID:A new and potent calmodulin antagonist, HF-2035, which inhibits vascular relaxation induced by nitric oxide synthase. 890 Oct 14


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