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)

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society.
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PMID:Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice. 980 22

Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction of NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucidated. The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic features of asthmatic airway inflammation. Guinea-pigs were exposed to lipopolysaccharide (LPS) (1 mg x mL(-1)) by inhalation in order to induce iNOS in the airways, and the histochemical staining of reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was determined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 microg x kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animals using Evans blue dye and Monastral blue dye. In the LPS-exposed animals, increased NADPH-diaphorase activity was observed in the airway microvasculature compared with the control animals. Substance P caused significant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS-exposed animals but not in the control group. This was also confirmed by Monastral blue dye extravasation. Aminoguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing the systemic blood pressure. These results may suggest that inducible nitric oxide synthase-derived nitric oxide is capable of potentiating neurogenic plasma leakage in airways.
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PMID:Induction of nitric oxide synthase by lipopolysaccharide inhalation enhances substance P-induced microvascular leakage in guinea-pigs. 981 54

Mice given lipopolysaccharide (LPS) intravenously developed lung edema, which was maximum after 6 h. Tumor necrosis factor, interleukin 12 (IL-12), IL-6, and interferon-gamma (IFN-gamma) appeared in the serum, and levels of nitrogen oxide (NO) derivatives were increased in serum and bronchoalveolar fluid. Mice pretreated with neutralizing anti-IFN-gamma antibodies had lower serum levels of IFN-gamma, and fewer died. However, levels of other cytokines and NO derivatives as well as lung edema were unchanged. If IFN-gamma and LPS were given together, pulmonary edema was less, but levels of cytokines and NO derivatives in serum were raised, and the mortality was greater. IFN-gamma receptor knockout mice had more edema after LPS, but were less sensitive to the lethal effects. Treatment with anti-IL-12 antibody inhibited IFN-gamma induction and reduced mortality, but had no effect on the lung edema; exogenous IL-12 also failed to affect edema, but boosted serum cytokine levels and increased the mortality. Aminoguanidine, an inhibitor of NO synthase, protected against pulmonary edema, but did not modify the lethal effects of LPS. Clearly, in this model, early pulmonary edema and lethality are not directly related, and induced IFN-gamma has no role in causing early lung edema, but augments other events that result in death.
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PMID:Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide. 1061 6

We have previously reported that leukotoxin, 9,10-epoxy-12-octadecenoate (Lx) dilates rat pulmonary arteries by means of nitric oxide synthase (NOS) activation. In this study, we investigated if Lx stimulates constitutive and/or inducible NOS. We studied the effect of the NOS inhibitors, N(G)-monomethyl-L-arginine and aminoguanidine, as well as endothelium denudation on Lx-induced rat pulmonary arterial dilation and that of aminoguanidine on Lx-induced endothelium denuded lipopolysaccharide (LPS)-treated rat pulmonary arterial dilation and tissue cGMP content. Furthermore, we assessed the effect of aminoguanidine, an inducible NOS (iNOS) inhibitor, on the cGMP content increase induced by Lx in LPS-treated human pulmonary artery smooth muscle cells (HPASMC). The NOS inhibitors and endothelium denudation significantly attenuated Lx-induced vasodilation. Aminoguanidine also significantly attenuated Lx-induced vasodilation in LPS-treated rat denuded pulmonary arteries, and attenuated Lx-induced cGMP content increase in denuded pulmonary arterial rings from LPS-treated rats and in LPS-treated HPASMC. These results suggest that Lx causes pulmonary vasodilation by stimulation of vascular endothelial NOS (eNOS) and iNOS.
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PMID:Leukotoxin, 9,10-epoxy-12-octadecenoate, causes pulmonary vasodilation by stimulation of vascular eNOS and iNOS. 1087 32

Overproduction of nitric oxide has been implicated in the pathogenesis of the vascular hyporesponsiveness of endotoxic shock. In this study, we investigated the effects of aminoguanidine, an inducible nitric oxide synthase inhibitor, on the decreased vascular responsiveness in endotoxic shock. Male albino rats were administered intraperitoneally aminoguanidine (25, 50 or 75 mg kg(-1)) 1 h after they received saline or lipolysaccharide (Escherichia coli serotype 055:B5). The thoracic aortas were removed 18 h after lipopolysaccharide administration and suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Contractile responses to phenylephrine and potassium chloride, and relaxant responses to acetylcholine were reduced in endotoxaemic animals. Aminoguanidine was ineffective in improving the vascular hypocontractility at 25 and 75 mg kg(-1) doses; but at 50 mg kg(-1) dose, it restored the decreased contractile responses toward normal values. Diminished relaxant responses to acetylcholine were restored by aminoguanidine at all three different doses. There were no significant differences in sodium nitroprusside induced relaxant responses between all groups. Administration of aminoguanidine in control animals did not change vascular responses to any agent. These data suggest that aminoguanidine treatment improves the vascular hyporesponsiveness to contractile- and endothelium-dependent relaxant agents observed in endotoxic shock.
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PMID:Effects of aminoguanidine administration on vascular hyporeactivity in thoracic aorta from endotoxaemic rats. 1108 May 24

The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca(2+)handling within the rat thoracic aorta and further to examine whether in vitro inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine would account for this effect or not. Endothelium denuded aortic rings from rats injected with lipopolysaccharide (LPS) (5 mg kg(-1), i.p. 18 h prior to functional studies) or saline were mounted in isolated organ baths. Various experimental conditions were studied on paired rings of the same animal which were incubated in the presence or absence of aminoguanidine (100 microM). Phenylephrine contractility in Ca(2+)-containing buffer or in Ca(2+)-free buffer, contractions induced by K(+)depolarization and CaCl(2)in depolarized muscle and by caffeine exposure were significantly decreased in LPS-treated rings and were reversed by aminoguanidine exposure. Aminoguanidine also improved the contractions recorded while switching the Ca(2+)-free buffer to Ca(2+)-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca(2+)and release of Ca(2+)from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.
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PMID:Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine. 1142 6

The molecular mechanisms underlying endotoxin-induced insulin resistance remain unclear. Endotoxin or lipopolysaccharide (LPS) injection is a potent stimulator of inducible nitric oxide synthase (iNOS). This study in rats, using the specific iNOS inhibitor aminoguanidine, investigated the role of iNOS in endotoxin-induced hyperglycemia and insulin resistance. LPS injection led to hyperglycemia, insulin resistance, and increased iNOS protein expression and activity. Aminoguanidine prevented LPS-induced hyperglycemia without affecting insulin levels or iNOS expression. Aminoguanidine attenuated the LPS-induced insulin resistance, reflected by the requirement for a higher glucose infusion rate to maintain euglycemia during a hyperinsulinemic clamp study. Aminoguanidine completely blocked the LPS-elevated hepatic glucose output and also inhibited LPS-induced increases in hepatic glycogen phosphorylase activities and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression, key enzymes for glycogenolysis and gluconeogenesis, respectively. Thus, these data demonstrate an important role for iNOS in LPS-induced insulin resistance, evidenced by the attenuation of LPS-induced hyperglycemia and reversal of increased hepatic glucose output by aminoguanidine. The protective effect of aminoguanidine on insulin resistance is probably by attenuation of hepatic glucose output via its inhibition of key enzymes for glycogenolysis and gluconeogenesis, including glycogen phosphorylase and PEPCK.
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PMID:Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance. 1178 71

Some of the effects of bacterial toxins are mediated through the local production of nitric oxide (NO) or its products. This study examined if NO inhibition in the intestinal mucosa had effects on the responses to intravenous lipopolysaccharide (LPS) in anesthetized rats. Aminoguanidine (AMGU, 500 microM), a relatively selective inducible NO synthase (iNOS) inhibitor, or N(G)-nitro-L-arginine (NOLARG, 50 or 500 microM), a nonselective inhibitor of iNOS and constitutive NOS (cNOS), were perfused through the ileal lumen during intravenous LPS (17 mg/kg) or saline administration. Intestinal H20 transport, NO3- + NO2- (NOx) secretion, absorptive site mucosal blood flow (ASBF), blood pressure, plasma [NOx], tissue damage, and blood leukocytes were measured for 4 hr. LPS increased luminal NOx secretion. At 50 microM, luminal NOLARG attenuated the LPS-induced NOx secretion and increased blood pressure. There were no significant changes in lethality, plasma [NOx] or other parameters. At 500 microM, luminal NOLARG converted a nonlethal dose of LPS into a lethal dose, but AMGU did not increase lethality. The LPS-induced luminal NOx secretion was blocked by 500 microM intraluminal AMGU and NOLARG. Luminal NOx secretion also increased in control animals. This increase was blocked by 500 microM NOLARG but not AMGU. Luminal 500 microM NOLARG increased blood pressure, but AMGU did not. Luminal 500 microM NOLARG prevented the LPS-induced increase in plasma [NOx] and the decrease in leukocytes, but AMGU did not. Tissue damage occurred with intravenous LPS plus intraluminal 500 microM NOLARG. It was concluded that luminal AMGU inhibited mucosal iNOS. Luminal NOLARG inhibited mucosal cNOS and iNOS, and cNOS inhibition primed a lethal LPS effect. NOLARG, but not AMGU, was absorbed from the intestine and had systemic effects.
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PMID:Ileal luminal nitric oxide synthase inhibitors and E. coli lipopolysaccharide effects in the anesthetized rat. 1183 23

Mild hypothermia is neuroprotective, but the reasons are not well known. Inflammation contributes to ischemic damage; therefore, we examined whether the protection by hypothermia may be attributable to alterations in the inflammation. We examined whether hypothermia might alter the inflammatory cell-associated inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) and peroxynitrite generation in experimental stroke and inflammation. Rats underwent 2 hr of middle cerebral artery occlusion (MCAO). Brain inflammation was modeled by intravenous lipopolysaccharide (LPS) (2 mg/kg) injection. Temperature was maintained at 33 degrees C for 2 hr immediately after MCAO and LPS injection, delayed 2 hr after MCAO or maintained at 38 degrees C. Cultured microglia were activated with LPS and then incubated at 33 or 37 degrees C. Both intraischemic and delayed mild hypothermia attenuated infarct size by 40% (p < 0.05). Immunohistochemistry was performed to identify cell type, iNOS, and peroxynitrite. The majority of iNOS- and peroxynitrite-positive cells were activated microglia-macrophages, and mild hypothermia significantly decreased the numbers of immunoreactive cells at 72 hr by >50% (p < 0.05). After ischemia, mild hypothermia decreased NO production by 40%. Similarly, hypothermia attenuated NO and iNOS in LPS-injected rats, as well as in cultured microglia. Aminoguanidine, an iNOS inhibitor, also attenuated infarct size and NO in ischemic and inflammation models. We conclude that mild hypothermia significantly inhibits the inflammatory response by affecting microglial iNOS-NO generation. Therapies directed against microglia or their activation may be useful in treating stroke.
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PMID:Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. 1201 11

Nitric oxide (NO) fulfils important functions during pregnancy and has a role in implantation, decidualization, vasodilatation and myometrial relaxation. However, at high concentrations, such as those that are produced in sepsis, NO has toxic effects as it is a free radical. The aim of this study was to characterize uterine and decidual NO production in lipopolysaccharide (LPS)-induced embryonic resorption in mice and to determine which isoforms of nitric oxide synthase (NOS) take part. LPS produced 100% embryonic resorption at 24 h, with complete fetus expulsions at 48 h. Decidual and uterine NO production were increased by LPS, with maximum production at 6 h. This increase was due to the induction of expression of inducible nitric oxide synthase (iNOS) isoform in the decidua and uterus, and neuronal nitric oxide synthase (nNOS) isoform in the decidua, as detected by western blot analysis and immunohistochemistry. LPS increased iNOS expression in decidual and myometrial cells and increased nNOS expression in decidual cells. In addition, LPS caused fibrinolysis and infiltration of mesometrial decidua by macrophages positive for iNOS and CD14 (LPS receptor). Endothelial nitric oxide synthase (eNOS) was found in decidual and uterine arteries but LPS did not modify its expression. LPS induced CD14 expression in endometrial glands, and this could have amplified the inflammatory response. Aminoguanidine, an inhibitor of iNOS activity, totally reversed the LPS-induced embryonic resorption. This result could be explained by an inhibition of the increase in NO production but also by an inhibition of the cellular infiltration and fibrinolysis. These results show that NO fulfils a fundamental role in LPS-induced embryonic resorption.
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PMID:The fundamental role of increased production of nitric oxide in lipopolysaccharide-induced embryonic resorption in mice. 1262


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