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)

Nitric oxide (NO) is a potent vasodilator that is synthesized by constitutive and inducible isoforms of the enzyme NO synthase (eNOS and iNOS, respectively). The half-life of NO averages only 3 to 4 s in biological fluids, where it is rapidly converted to the stable oxidation products nitrite (NO2-) and nitrate (NO3-). Our objectives were to use 2 commercial kits to measure total plasma NO, as NO2- + NO3-, and to assess plasma NO values during experimental protocols designed to influence NO accumulation in the plasma. One kit employed copper-coated cadmium as a catalyst for reducing NO3- to NO2-; the second kit employed the enzyme NO3- reductase for the same purpose. Both then employed Griess reagent for the colorimetric determination of NO2- as a measure of total plasma NO. Broilers in Experiment 1 were infused i.v. with solutions containing increasing concentrations of sodium NO2-. Broilers in Experiment 2 were injected with 1 mg of lipopolysaccharide (LPS), which is known to stimulate iNOS activity. Both commercial kits successfully detected increases in total plasma NO attributable to ongoing i.v. NO2- infusion or to increased iNOS expression at 5 h after the LPS injection. In Experiment 3, we compared the total plasma NO responses to LPS in the presence and absence of aminoguanidine (AG), a selective inhibitor of iNOS. The AG significantly attenuated the LPS-mediated increase in total plasma NO at 5 h post-injection. In Experiment 4, broilers were infused with sodium nitroprusside (SNP), an exogenous NO donor molecule that previously had been shown to lower the pulmonary arterial pressure in broilers. The SNP infusion did substantially reduce the pulmonary arterial pressure, but an increase in total plasma NO was not detected during the SNP infusion. Overall, NO accumulation in the plasma was successfully detected after sustained infusion of NaNO2 and administration of LPS for 5 h, but biologically effective levels of NO released from SNP were not detected. Therefore, total plasma NO concentrations (assayed as NO2- + NO3-) qualitatively reflect whole-body NO synthesis, but biologically relevant quantities of NO may be produced at levels that cannot be detected by colorimetric assays.
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PMID:Evaluation of total plasma nitric oxide concentrations in broilers infused intravenously with sodium nitrite, lipopolysaccharide, aminoguanidine, and sodium nitroprusside. 1652 32

The pulmonary hypertensive response to pulmonary vascular obstruction caused by intravenously injected microparticles is amplified by pretreatment with N(omega)nitro-L-arginine methyl ester (L-NAME). The L-NAME prevents the synthesis of the potent vasodilator nitric oxide (NO) by inhibiting both the constitutive [endothelial NO synthase (eNOS or NOS-3)] and inducible [inducible NO synthase (iNOS or NOS-2)] forms of NO synthase. In the present study we used the selective iNOS inhibitor aminoguanidine (AG) to evaluate the role of iNOS in modulating the pulmonary hypertension (PH) triggered by microparticle injections. Experiment 1 was conducted to confirm the ability of AG to inhibit NO synthesis by iNOS in broiler peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide (LPS, endotoxin). Mononuclear leukocytes treated with LPS produced 10-fold more NO than untreated (control) cells. The LPS-stimulated production of NO was partially inhibited by L-NAME and was fully inhibited by AG, thereby confirming that AG inhibits LPS-mediated iNOS activation in broilers. In Experiment 2 we evaluated the responses of male progeny from a base population (MP Base) and from a derivative line selected for one generation from the survivors of an LD50 microparticle injection (MP Select). The pulmonary arterial pressure (PAP) was lower in MP Select than in MP Base broilers. Both lines exhibited similar percentage increases in PAP after microparticles were injected, and AG modestly amplified the PH triggered by microparticles in both lines. In Experiment 3 we evaluated the responses of male progeny from a second base population (PAC Base) and from a derivative line selected for 3 generations using the unilateral pulmonary artery clamp technique (PAC Select). The PAP was lower in PAC Select than in PAC Base broilers, and both lines exhibited similar percentage increases in PAP in response to the microparticles. The PH triggered by microparticles was not amplified by AG but was doubled by L-NAME. These experiments demonstrate that during the 30 min following pulmonary vascular entrapment of microparticles, iNOS modulated the PH elicited in broilers derived from the MP pedigree line, but not in broilers from the PAC pedigree line. Different NOS-mediated responses among broiler populations may affect pulmonary hemodynamic characteristics of broiler lines selected using i.v. microparticle injections.
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PMID:Influence of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on the pulmonary hypertensive response to microparticle injections in broilers. 1655 84

Nitric oxide (NO) is a potent pulmonary vasodilator that modulates the pulmonary vasoconstriction and pulmonary hypertension (PH) triggered by bacterial lipopolysaccharide (LPS) in broilers. The amplitude and duration of the LPS-induced PH are markedly enhanced following pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits NO synthesis by both the constitutive (endothelial) and inducible (inflammatory) forms of nitric oxide synthase (eNOS and iNOS, respectively). In the present study L-NAME and the selective iNOS inhibitor aminoguanidine (AG) were administered to differentiate between iNOS and eNOS as the primary source of NO that attenuates the pulmonary vascular response to LPS. Clinically healthy male progeny from ascites-susceptible and ascites-resistant lines were anesthetized, and their pulmonary artery was cannulated. The initial pulmonary arterial pressure (PAP) was recorded, then the broilers either remained untreated (control group) or were injected i.v. with AG. Ten minutes later all birds received an i.v. injection of LPS, followed 40 min later by an i.v. injection of L-NAME. When compared with untreated controls, AG neither increased the baseline PAP nor did it increase or prolong the PH response to LPS. The ascites-susceptible broilers maintained a higher PAP than the ascites-resistant broilers throughout the experiment, and the ascites-resistant broilers exhibited greater relative increases in PAP in response to LPS than did the ascites-susceptible broilers. Within 40 min after the LPS injection, PAP subsided to a level that did not differ from the respective preinjection value for each line. Injecting L-NAME reversed the decline in PAP, and within 5 min PAP returned to hypertensive levels approaching the maximum peak PH response to LPS. The absence of any impact of AG coupled with the profound response to L-NAME indicates that NO synthesized by eNOS rather than iNOS likely modulated the acute (within 1 h) PH elicited by LPS. Evidently eNOS is activated by the increased shear stress exerted on the endothelium during the PH response to LPS, whereas LPS-mediated up-regulation of iNOS expression may take longer than 1 h before biologically effective quantities of NO are produced.
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PMID:Pulmonary hypertension triggered by lipopolysaccharide in ascites-susceptible and -resistant broilers is not amplified by aminoguanidine, a specific inhibitor of inducible nitric oxide synthase. 1655 85

To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.
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PMID:Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat. 1672 27

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

The aim of the present study was to assess the relative contributions of peroxynitrite formation following induction of nitric-oxide synthase (iNOS) in the pathophysiology of endotoxin-induced shock in the rat. To this end, we used a selective inhibitor of iNOS, N-(3-(aminomethyl)benzyl)acetamidine (1400W), and a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTTPs). Intravenous (i.v.) administration of Escherichia coli lipopolysaccharide (LPS; 4 mg/kg) elicited a time-dependent fall in mean arterial pressure as well as liver, renal, and pancreatic tissue damage. 1400W (3-10 mg/kg i.v.) administered 30 min before LPS delayed the development of hypotension but did not improve survival. On the other hand, FeTTPs administered (10-100 mg/kg i.v.) inhibited in a dose-dependent manner LPS-induced hypotension, tissue injury, and improved mortality rate. In separate experiments, rats were treated with LPS (4 mg/kg) or saline for control, and their aortas were isolated and placed in organ baths 2 h later. Tissues from LPS-treated rats had significant inhibition of contractile activity to phenylephrine as well as a significantly impaired relaxation response to acetylcholine. FeTPPs, when administered (100 mg/kg i.v.) 1 h before LPS, prevented the LPS-induced aortic contractile and endothelial dysfunction. These results demonstrate that nitric oxide-derived peroxynitrite formation plays an important role in this model of endotoxemia. Our results also suggest that use of an iNOS inhibitor in this setting has little beneficial effect in part because, in the presence of a failing eNOS system, some NO is needed to maintain adequate organ function.
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PMID:A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock. 1681 67

Nitric oxide (NO) is produced in almost all tissues and organs, exerting multiple biological actions under both physiological and pathological conditions. NO is synthesized by three different isoforms of NO synthase (NOS): neuronal, inducible, and endothelial NOSs. Due to the substantial compensatory interactions among the NOS isoforms, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. To address this point, we have successfully developed mice in which all three NOS genes are completely disrupted. NOS expression and activities were totally absent in the triply n/i/eNOS(-/-) mice before and after treatment with lipopolysaccharide. While the triply n/i/eNOS(-/-) mice were viable, their survival and fertility rates were markedly reduced as compared with wild-type mice. The phenotypes of those mice that we first noticed were polyuria, polydipsia, and renal unresponsiveness to vasopressin, characteristics consistent with nephrogenic diabetes insipidus. We subsequently observed that in those mice, arteriosclerosis is spontaneously developed with a clustering of cardiovascular risk factors. These results provide the first evidence that the systemic deletion of all three NOSs causes a variety of cardiovascular diseases in mice, demonstrating a critical role of the endogenous NOSs system in maintaining cardiovascular homeostasis.
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PMID:Development of genetically engineered mice lacking all three nitric oxide synthases. 1703 Oct 76

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

We compared the lipid-lowering, vasodilating, anti-thrombotic and anti-inflammatory properties of NCX 6560, a novel NO-releasing derivative of atorvastatin, with those of atorvastatin. NCX 6560 and atorvastatin induced similar inhibition of cholesterol biosynthesis in rat smooth muscle cells (IC(50)=1.9+/-0.4 and 3.9+/-1.0 microM, respectively). However, in hyperlipidemic mice, a 5-week oral treatment with NCX 6560 (46.8 mg/kg/day, p.o.) was more effective than equivalent atorvastatin (40 mg/kg/day, p.o.) at lowering serum cholesterol (NCX 6560: -21% vs controls, P<0.05; atorvastatin: -14% vs control, P=NS). In norepinephrine-precontracted rabbit aortic rings, NCX 6560-induced vasodilation (EC(50)=53.5+/-8.3 microM) and in PC12 cells it stimulated cGMP formation (EC(50)=1.8+/-0.7 microM), while atorvastatin was inactive. In lipopolysaccharide from Escherichia coli (LPS)-treated RAW 264.7 macrophages, NCX 6560 reduced iNOS expression and dimer assembly more efficiently than atorvastatin and inhibited nitrite accumulation (IC(50)=6.7+/-1.6 microM) and TNFalpha release. U46619- or collagen plus epinephrine-induced platelet pulmonary thromboembolism in mice was reduced by NCX 6560 at 46.8 mg/kg p.o. (mortality: -44% and -56% vs vehicle, respectively; P<0.05), but not by atorvastatin 40 mg/kg, p.o. In the U46619-induced mortality model, isosorbide mononitrate (ISMN) (20 mg/kg, p.o.), a pure NO-donor, was also active (mortality: -40%, P<0.05). NCX 6560 significantly reduced ex vivo platelet adhesion to collagen at high shear (-31+/-1.3% vs vehicle), and so did ISMN (-33.3+/-1.7% vs vehicle). Atorvastatin was ineffective. NCX 6560, but not atorvastatin, reduced blood pressure in eNOS knockout mice (-16%, P<0.001 vs vehicle), an effect not observed in wild type mice. On the contrary, ISMN provoked a significant drop of blood pressure both in wild type (-20%, P<0.05 vs vehicle) and in eNOS-/- mice (-21%, P<0.05 vs vehicle). In conclusion, NCX 6560 exerts greater lipid-lowering, anti-thrombotic and anti-inflammatory effects than atorvastatin, due to a large extent to NO release.
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PMID:NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. 1763 98

Toll-like receptor 4 (TLR4) is a pattern recognition receptor for lipopolysaccharide from Gram negative bacteria and thus is integral to the innate immune response in mammals. In addition, TLR4 is associated with atherosclerosis in murine models. The current study shows that blood vessels from TLR4(-/-) mice have an intact endothelial layer and comparable expression of nitric oxide synthase 3 protein. However, endothelium-dependent dilation in response to acetylcholine in vessels from TLR4(-/-) mice is greatly reduced. By contrast, endothelium-independent smooth muscle dilation in response to sodium nitroprusside in vessels from TLR4(-/-) mice remains intact. Furthermore, this study shows that hearts from TLR4(-/-) mice display signs of left ventricular dilation. In contrast to results in vessels from TLR4(-/-) mice, endothelium-dependent responses to acetylcholine in vessels from TLR2(-/-) mice remain intact. These observations illustrate a novel role for TLR4 in the homeostatic control of a functional endothelium and, thereby, cardiovascular health.
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PMID:Homeostatic role of Toll-like receptor 4 in the endothelium and heart. 1817 27


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