UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the study was to investigate the effect of iNOS expression on eNOS and nNOS functional activity in porcine cerebral arteries. iNOS was induced in pig basilar arteries using lipopolysaccharide (LPS). Arteries expressing iNOS generated NO and relaxed when challenged with L-arginine (30 microM), an effect that was reduced by treatment with dexamethasone (coincubated with LPS) and prevented by the iNOS inhibitor 1400 W (administered 10 min prior to precontraction). eNOS was activated by A23187 and was found to be impaired in arteries that had iNOS induced (A23187 1 microM relaxation: control 110+/-8%, LPS-treated 50+/-16% ; p<0.05, N=5-6). This was due mainly to reduced formation of NO by A23187 (NO concentration in response to A23187 1 microM: control 25+/-6 nM, LPS-treated 0.8+/-1.2 nM; p<0.001, N=5-6), in addition to a small reduction in the vasodilator response to the NO-donors NOC-22 and SIN-1. Cerebral vasodilation produced by stimulation of intramural nitrergic nerves was impaired in arteries that had iNOS induced, and this was reversed by 1400 W (control 23+/-4% relaxation, LPS-treated 11+/-1% relaxation, LPS plus 1400 W 10 microM treated 25+/-2% relaxation; p<0.01 for control versus LPS, N=6). It is concluded that the induction of iNOS in cerebral arteries reduces NO-mediated vasodilation initiated by eNOS and by nNOS, primarily by modulation of NO formation.
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PMID:Induction of iNOS restricts functional activity of both eNOS and nNOS in pig cerebral artery. 1560 45

We have previously observed an increase in nitric oxide (NO) content in rat brain cortex following halothane, sevoflurane or isoflurane anaesthesia. This study was undertaken in order to determine whether isoform-specific nitric oxide synthase (NOS) inhibitors and inducers could modify these increases in NO contents. Rats were subjected to isoflurane and sevoflurane anaesthesia with concomitant administration of neuronal nitric oxide synthase (nNOS) inhibitor 7-Nitro-indazole (7-NI), inducible nitric oxide synthase (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) or lipopolysaccharide. NO concentration in different organs was measured by electron paramagnetic resonance (EPR) spectroscopy. 7-NI significantly decreased NO concentration in cerebellum but not in brain cortex, whereas AMT decreased NO in all the organs studied. Anaesthesia significantly increased NO concentration in brain cortex and decreased that in cerebellum. AMT abolished the NO increase in brain cortex. Anaesthesia enhanced the drastic increase in NO concentration in brain cortex after intraventricular lipopolysaccharide administration. Isoflurane was found to inhibit recombinant nNOS and iNOS activities at high concentrations (EC50=20 mM). Our data suggest a putative role for iNOS in the increase in NO levels produced by isoflurane and sevoflurane, whereas nNOS activity is probably inhibited during anaesthesia.
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PMID:Putative role of nitric oxide synthase isoforms in the changes of nitric oxide concentration in rat brain cortex and cerebellum following sevoflurane and isoflurane anaesthesia. 1586 1

Fish are known to express the three isoforms of nitric oxide synthase (NOS), the constitutive forms endothelial or eNOS, neuronal or nNOS and the inducible form iNOS. Most studies in fish have focussed on possible roles for NO in cardiovascular physiology although there has been recent attention on the role of nNOS in embryonic development. However compared to mammalian studies there have been relatively few studies on effects of nitric oxide (NO) on fish. Studies on heart and blood vessel preparations from various fish species appear to show results specific to the species or to the particular preparation. Possible roles of NO in the in vivo biology of adult fish or larval fish have received little attention. This article reviews effects of nitric oxide on cardiovascular physiology in fish with special emphasis on larval fish. It introduces some experimental work on possible signaling pathways in larval fish and introduces the possibility that NO could be an important environmental influence for some aquatic organisms. In higher vertebrates LPS (lipopolysaccharide) is known to activate the cytokine signaling system and stimulate increased expression of iNOS and increased production of NO, but this remains less investigated in fish. The effects of LPS on cardiovascular and osmoregulatory physiology of larval and juvenile salmonids are discussed and a possible role of NO in stress-induced drinking is suggested.
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PMID:Role of nitric oxide in larval and juvenile fish. 1597 64

The role of prostaglandins and nitric oxide (NO), generated after peripheral lipopolysaccharide (LPS) administration, in the adaptation of hypothalamic-pituitary-adrenal (HPA) axis under stressful circumstances remains to be elucidated. The aim of the present study was to assess the effect of chronic repetitive restraint or social crowding stress on the involvement of nitric oxide and prostaglandins in the LPS-induced pituitary-adrenocortical response. Male Wistar rats were restrained in metal tubes 2 x 10 min/day or crowded in cages for 7 days prior to treatment. All compounds were injected i.p., cyclooxygenase (COX) and nitric oxide synthase (NOS) inhibitors 15 min before LPS. Two hrs after injection LPS induced a significant increase in ACTH and corticosterone secretion. Repeated restraint impaired more potently than crowding stress the LPS-induced HPA-response. Indomethacin, a non-selective COX inhibitor, considerably reduced the LPS-induced HPA response in non-stressed rats and to a lesser extent diminished this response in repeatedly restrained or crowded rats. Neuronal NOS inhibitor, Nomega-nitro-L-arginine decreased the LPS-induced HPA response, more potently in control than crowded rats. Aminoguanidine, an iNOS inhibitor, diminished the LPS-elicited ACTH response in crowded rats. These results indicate that prostaglandins and NO generated by neuronal and inducible NOS are involved in the LPS-induced HPA axis response under basal conditions and during its adaptation to chronic social stress circumstances.
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PMID:Psychosocial stress affects the involvement of prostaglandins and nitric oxide in the lipopolysaccharide-induced hypothalamic-pituitary-adrenal response. 1598 9

Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult.
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PMID:Sepsis inhibits recycling and glutamate-stimulated export of ascorbate by astrocytes. 1619 26

We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NO synthases at 86 nM, 17 microM, and 162 microM, respectively. Inhibition of inducible NO synthase was competitive with l-arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. In radioligand and surface plasmon resonance experiments, BYK191023 exhibited an affinity for iNOS, nNOS, and eNOS of 450 nM, 30 microM, and >500 microM, respectively. Inhibition of cellular nitrate/nitrite synthesis in RAW, rat mesangium, and human embryonic kidney 293 cells after iNOS induction showed 40- to 100-fold higher IC(50) values than at the isolated enzyme, in agreement with the much higher l-arginine concentrations in cell culture media and inside intact cells. BYK191023 did not show any toxicity in various rodent and human cell lines up to high micromolar concentrations. The inhibitory potency of BYK191023 was tested in isolated organ models of iNOS (lipopolysaccharide-treated and phenylephrine-precontracted rat aorta; IC(50) = 7 microM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC(50) > 100 microM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC(50) > 100 microM). These data confirm the high selectivity of BYK191023 for iNOS over eNOS and nNOS found at isolated enzymes. In summary, we have identified a new highly selective iNOS inhibitor structurally unrelated to known compounds and l-arginine. BYK191023 is a valuable tool for the investigation of iNOS-mediated effects in vitro and in vivo.
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PMID:The novel imidazopyridine 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) is a highly selective inhibitor of the inducible nitric-oxide synthase. 1622 57

Endothelins exert pathological effects in the eye and much interest centres on their role in causing retinal neuronal death in ischemic diseases like glaucoma. In the present study the influence of the non-selective endothelin antagonist, sulfisoxazole on raised intraocular pressure-induced ischemia to the rat retina was investigated. Moreover, in vitro studies on primary rat retinal cultures were undertaken to see whether sulfisoxazole is able to blunt the toxic effect of lipopolysaccharide (LPS) to retinal neurones. In order to determine whether sulfisoxazole provides protection to the retina the a- and b-wave amplitudes of the electroretinogram (ERG), the localisation of retinal choline acetyltransferase (ChAT), nitric oxide synthase (nNOS) and Thy-1 and the retinal mRNA levels of Thy-1 and FGF-2 were deduced in retinas subjected to ischemia in the absence or presence of sulfisoxazole. The results showed that the ischemia-induced changes to the a- and b-wave amplitudes of the ERG and changes associated with the localisation of ChAT, nNOS and Thy-1 to be significantly blunted by sulfisoxazole. However, while the ischemia-induced changes to Thy-1 and FGF-2 mRNAs were reduced by sulfisoxazole, the reduction was non-significant. The in vitro studies provided support for the protective effect of sulfisoxazole. Here, it was clearly shown that sulfisoxazole attenuated the elevation of nitric oxide (deduced by measuring nitrite) and the reduction in numbers of GABA-containing neurones caused by LPS. The present study provides evidence for the first time that endothelin antagonist can protect the retina from ischemic-like insults as occurs in glaucoma.
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PMID:Sulfisoxazole, an endothelin receptor antagonist, protects retinal neurones from insults of ischemia/reperfusion or lipopolysaccharide. 1646 16

Protein tyrosine nitration may be relevant for the pathogenesis of hepatic encephalopathy (HE). Infections, sepsis, and trauma precipitate HE episodes. Recently, serum levels of tumor necrosis factor (TNF)-alpha were shown to correlate with severity of HE in chronic liver failure. Here the effects of inflammatory cytokines on protein tyrosine nitration in cultured rat astrocytes and rat brain in vivo were studied. In cultured rat astrocytes TNF-alpha (50 pg/ml-10 ng/ml) within 6h increased protein tyrosine nitration. TNF-alpha-induced tyrosine nitration was related to an increased formation of reactive oxygen and nitrogen intermediates, which was downstream from a NMDA-receptor-dependent increase of intracellular [Ca(2+)](i) and nNOS-catalyzed NO production. Astroglial tyrosine nitration was also elevated in brains of rats receiving a non-lethal injection of lipopolysaccharide, as indicated by colocalization of nitrotyrosine immunoreactivity with glial fibrillary acidic protein and glutamine synthetase, and by identification of the glutamine synthetase among the tyrosine-nitrated proteins. It is concluded that reactive oxygen and nitrogen intermediates as well as protein tyrosine nitration by inflammatory cytokines may alter astrocyte function in an NMDA-receptor-, Ca(2+)-, and NOS-dependent fashion. This may be relevant for the pathogenesis of HE and other conditions involving cytokine exposure the brain.
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PMID:Inflammatory cytokines induce protein tyrosine nitration in rat astrocytes. 1657 53

The cysteinyl leukotrienes (CysLTs) LTC(4), LTD(4) and LTE(4) are potent proinflammatory lipid mediators that play a central role in inflammation, contraction and remodelling of airways observed in asthmatics. Montelukast, a competitive inhibitor of the cysteinyl leukotriene-1 (CysLT(1)) receptor attenuates asthmatic airway inflammation, contraction and remodelling. As a number of studies have shown that montelukast reduced exhaled nitric oxide (NO) levels, a marker of inflammation that correlates with the severity of asthma, we investigated whether or not a direct inhibition of NO synthase (NOS) by montelukast takes place. In an ex vivo rat lung perfusion and ventilation model the NOS-dependent vasodilation effect after lipopolysaccharide (LPS) infusion was assessed with and without montelukast. Functional organ bath studies using isolated aortic rings from the same species aimed to assess effects of montelukast on the inducible and endothelial NOS isoenzymes (i- and eNOS) as well as on iNOS expression. Neuronal NOS (nNOS) was assessed by field stimulated rabbit corpus cavernosum, and isolated human iNOS enzyme activity was assessed for potential inhibition. Montelukast failed to cause vasoconstriction in LPS challenged rat lung, or to inhibit i- and eNOS activity as well as iNOS expression in aortic rings from the same species. Also the assays for nNOS in rabbit corpus cavernosum and on isolated human iNOS enzyme gave no evidence for a direct inhibition by montelukast in physiological and supraphysiological concentrations up to 10(-4)M. We therefore conclude that montelukast has no acute NOS inhibitor action. Its effect on exhaled NO is therefore probably indirectly mediated by a modulation of the asthmatic airway inflammation.
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PMID:Montelukast exerts no acute direct effect on NO synthases. 1681 57

Although the inducible isoform of nitric oxide synthase (iNOS) is a well-established source of nitric oxide (NO*) during inflammation of the central nervous system (CNS), little is known about the involvement of constitutive isoforms of NOS (cNOS) in the inflammatory process. The aim of this study was to compare the responses of the expression and activity of iNOS and the two cNOS isoforms, neuronal and endothelial (nNOS and eNOS, respectively), in the brain to systemic inflammation and their roles in the cascade of events leading to degeneration and apoptosis. A systemic inflammatory response in C57BL/6 mice was induced by intraperitoneal injection of lipopolysaccharide [LPS; 1 mg/kg body weight (b.w.)]. The relative roles of the NOS isoforms were evaluated after injection of NG-nitro-L-arginine (NNLA; 30 mg/kg b.w.), which preferentially inhibits cNOS, or 1400W (5 mg/kg b.w.), an inhibitor of iNOS. Biochemical and morphological alterations were analyzed up to 48 hr after administration of LPS. Systemic LPS administration evoked significant ultrastructural alterations in brain capillary vessels, neuropils, and intracellular organelles of neurons, astrocytes, and microglia. Apoptotic/autophagic processes occurred in many neurons of the substantia nigra (SN), which coincided with exclusive enhancement of iNOS expression and activity in this brain region. Moreover, inhibitors of both iNOS and cNOS prevented LPS-evoked release of apoptosis-inducing factor (AIF) from SN mitochondria. Collectively, the results indicate that synthesis of NO* by both the inducible and constitutive NOS isoforms contribute to the activation of apoptotic pathways in the brain during systemic inflammation.
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PMID:Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation. 1746 18

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