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)

A new model of acute reduction in renal function induced by a 2-h infusion of endotoxin (Escherichia coli 026:B6 lipopolysaccharide, 5 mg X kg-1 X h-1) was developed in the anesthetized male rat. In the absence of significant glomerular fibrin deposition, inulin clearance (glomerular filtration rate, GFR) was reduced from 8.50 +/- 0.34 to 4.01 +/- 0.45 ml X kg-1 X min-1 (P less than 0.0005), and p-aminohippuric acid clearance was reduced from 23.7 +/- 0.8 to 15.0 +/- 1.8 ml X kg-1 X min-1 (P less than 0.0005), indicating a hemodynamic basis for the reduction in GFR. The lack of morphological tubular injury and a decreased fractional Na excretion (from 2.63 +/- 0.27 to 0.54 +/- 0.09%, P less than 0.00005) exclude a significant contribution of tubular mechanisms to the reduction in GFR. Administration of theophylline, a competitive adenosine receptor antagonist, concurrently with or immediately after the endotoxin infusion, restored inulin and PAH clearances and fractional Na excretion toward normal. Moreover, the renal effects of endotoxin were mimicked by intravenous administration of N6-(L-phenylisopropyl)-adenosine (L-PIA), an adenosine receptor agonist, and the effects of L-PIA in turn were also antagonized by theophylline. These data suggest that adenosine plays a significant role in mediating the hemodynamic derangements of this model.
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PMID:Renal effects of endotoxin in the male rat. 330 73

The effects of adenosine receptor agonists on plasma NOx- (NO2- and NO3-) production in mice treated with lipopolysaccharide (LPS) were investigated. NOx- is the stable decomposition product of nitric oxide (NO), which can be measured as a marker of NO production. Injection of the mice with LPS resulted in increased plasma NOx- concentration, reaching a peak after 8 hr (38 times basal level) and then declining slowly. Pretreatment with the adenosine agonists R-phenylisopropyladenosine (R-PIA), 5'-N-ethylcarboxamidoadenosine (NECA), 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA) and N6-cyclohexyladenosine (CHA) 1 hr before LPS administration caused a dose-dependent reduction of plasma NOx- concentration. The rank order of inhibitory potency was NECA > or = R-PIA > CPCA > CHA, which is characteristic of neither A1 nor A2 receptors.
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PMID:Effects of adenosine receptor agonists on nitric oxide release in mouse during endotoxemia. 754 26

The effects of exogenous ATP and physical stimulation on ciliary beat depressed by lipopolysaccharide from Pseudomonas aeruginosa were studied in cell culture. Both the ciliary beat frequency (CBF) and the amplitude (CBA) of human respiratory cells in monolayer cell cultures were studied by using a differential interference microscope equipped with a high speed video. Both the ATP and the physiol stimulation stimulated temporarily the depressed CBF and CBA. In both groups the CBF and CBA increased in 1 min to the initial level and then gradually decreased to the level before the stimulation. The duration of the ATP stimulation on the CBF (10.1 +/- 1.8 min) and CBA (10.1 +/- 2.3 min) were significantly better than the duration of physical stimulation on CBF (8.0 +/- 1.8 min) and CBA (6.8 +/- 1.6 min). However, the areas under the CBF/CBA curves (from the beginning of stimulation until the initial level of CBF or CBA was reached again) did not differ significantly. After the removal of the bacterial toxin the CBF was restored to the initial level. In the present study the adenosine receptor antagonist could not prevent the ciliostimulative effect of exogenous ATP combined with the physical stimulation. Both exogenous ATP and physical stimulation have a clear but temporary stimulative effect on the ciliary beat depressed by bacterial toxin, ATP being slightly more effective. It seems that the effects of ATP are not mediated by adenosine receptors.
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PMID:Effect of exogenous ATP and physical stimulation on ciliary function impaired by bacterial endotoxin. 807 67

We hypothesized that adenosine, known to be release from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of infection. We investigated the effect of adenosine on PMN primed with cell-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in TNF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alpha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medium increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium contained adenosine (approximately 30 nM). Converting the adenosine in the LPS-MNL-conditioned medium to inosine with adenosine deaminase (ADA) or blocking adenosine binding to PMN with the adenosine receptor antagonist 1,3-dipropyl-8-(phenyl-p-acrylate)-xanthine (BW A1433U) resulted in a near doubling of chemiluminescence. The LPS-MNL-conditioned medium contained TNF alpha (836 pg/mL; approximately 1 U/mL). Recombinant human TNF alpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Added adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 approximately 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP-stimulated PMN. The activity of adenosine was counteracted by ADA and BW A1433U, and the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosine reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by damping the TNF alpha-primed PMN oxidative response.
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PMID:Adenosine modulation of tumor necrosis factor-alpha-induced neutrophil activation. 861 64

Murine macrophage-derived tumor necrosis factor alpha (TNF-alpha) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-kappa B (NF-kappa B) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominantly express the adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A3 receptor, blocked the endotoxin induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A3 receptor antagonist BW-1433 dose-dependently reversed this adenosine inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A3 receptor interrupts the endotoxin CD14 receptor signal transduction pathway and blocks induction of cytokine TNF-alpha, revealing a novel cross-talk between the murine adenosine A3 receptor and the endotoxin CD14 receptor in J774.1 macrophages.
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PMID:Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-alpha. 888 19

Inhibition of inducible nitric oxide (NO) synthase during endotoxaemia may be of therapeutic value. We have previously shown that pretreatment of mice with adenosine receptor agonists 1 h before lipopolysaccharide administration results in a dose-dependent reduction of plasma nitrite and nitrate (NOx-) levels. This report examines the effects of adenosine receptor agonists, 5'-N-ethylcarboxamidoadenosine (NECA), N6-cyclohexyladenosine (CHA), R-phenylisopropyl-adenosine (R-PIA) and 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA), on the level of inducible NO synthase expression in a model of liver inflammation induced by lipopolysaccharide. Following lipopolysaccharide administration (10 mg/kg, i.p.), liver mRNA expression peaked at 3 h and declined to 35% of maximal level after 24 h. Pretreatment with adenosine receptor agonists (0.001 mg/kg to 5 mg/kg, i.p.) depressed inducible NO synthase mRNA expression significantly. Down-regulation of inducible NO synthase mRNA expression corresponded with changes in plasma NOx- level as well as activity of NO synthase in the liver. Administration of R-PIA (5 mg/kg, i.p.) increased the survival of animals injected with a lethal dose of lipopolysaccharide. Thus adenosine receptor agonists may useful as anti-inflammatory agents in the treatment of endotoxaemia.
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PMID:Expression of inducible nitric oxide synthase in mice: pharmacological evaluation of adenosine receptor agonists. 898

The A(3) adenosine receptor (A3AR) is one of four receptor subtypes for adenosine and is expressed in a broad spectrum of tissues. In order to study the function of A3AR, a mouse line carrying a mutant A(3) allele was generated. Mice homozygous for targeted disruption of the A3AR gene, A3AR(-/-), are fertile and visually and histologically indistinguishable from wild type mice. The lack of a functional receptor in the A3AR(-/-) mice was confirmed by molecular and pharmacological analyses. The absence of A3AR protein expression in the A3AR(-/-) mice was demonstrated by lack of N(6)-(4-amino-3-[(125)I]iodobenzyl)adenosine binding to bone marrow-derived mast cell membranes that were found to express high levels of A3AR in wild type mice. In A3AR(-/-) mice, the density of A(1) and A(2A) adenosine receptor subtypes was the same as in A3AR(+/+) mice as determined by radioligand binding to brain membranes. Additionally, A(2B) receptor transcript expression was not affected by ablation of the A3AR gene. A3AR(-/-) mice have basal heart rates and arterial blood pressures indistinguishable from A3AR(+/+) mice. Functionally, in contrast to wild type mice, adenosine and the A3AR-specific agonist, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-carboxamide (2-Cl-IB-MECA), elicit no potentiation of antigen-dependent degranulation of bone marrow-derived mast cells from A3AR(-/-) mice as measured by hexosaminidase release. Also, the ability of 2Cl-IB-MECA to inhibit lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo was decreased in A3AR(-/-) mice in comparison to A3AR(+/+) mice. The A(2A) adenosine receptor agonist, 2-p-(2-carboxyethyl)phenylamino)-5'-N-ethylcarboxamidoadenosine, produced inhibition of lipopolysaccharide-stimulated tumor necrosis factor-alpha production in both A3AR(-/-) and A3AR(+/+) mice. These results show that the inhibition in vivo can be mediated by multiple subtypes, specifically the A(3) and A(2A) adenosine receptors, and A3AR activation plays an important role in both pro- and anti-inflammatory responses.
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PMID:Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. 1066 Jun 15

Adenosine and its receptor agonists enhanced the production of nitric oxide (NO) in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The enhancement of LPS-induced NO production by adenosine, as represented by the amount of its oxidation products, nitrite and nitrate, was inhibited by adenosine uptake inhibitors, such as dipyridamole, S(4-nitrobenzyl)-6-thioinosine (NBTI) and S(4-nitrobenzyl)-6-thioguanosine (NBTG). These indicate that the uptake of adenosine by macrophages is a prerequisite for the enhancement effects observed. A downstream metabolite of adenosine, inosine, also potentiated the LPS-induced NO production in a dose-dependent manner while its enhancement effect was also inhibited by dipyridamole. However, the degree of enhancement by inosine on NO production and nitric oxide synthase (NOS) activity in LPS-treated RAW 264.7 was weaker than the effect of adenosine. Furthermore, adenosine agonists also enhanced the NO production in a dose-dependent manner, but were not specific for A1, A2 nor A3 adenosine receptor. Adenosine uptake inhibitors had no effects on the enhancement activity of the adenosine receptor agonists. Thus, extracellular receptor/s may also play an important role in the observed enhancement responses. The results of this study indicate that the enhancement effects of adenosine on NO production in macrophages could be mediated by the extracellular adenosine receptors as well as the downstream metabolites of adenosine.
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PMID:Adenosine and its receptor agonists regulate nitric oxide production and RAW 264.7 macrophages via both receptor binding and its downstream metabolites-inosine. 1080 76

The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure during endotoxemia. CGS 21680 completely inhibited endotoxin-induced release of TNFalpha, augmented sympathetic activity and PRA, and increased +dP/dtmax and +dP/dtmax/VPSP in the absence and presence of endotoxin. The present study provides strong evidence that inhibition of adenosine deaminase reduces cytokine release in vivo without producing significant hemodynamic and cardiac effects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cytokine release induced by endotoxin. Further studies are warranted to determine the impact of these effects on cardiac function and hemodynamics in the late phase of endotoxemia.
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PMID:Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats. 1153 Oct 21

Dendritic cells (DCs) are specialized antigen-presenting cells characterized by their ability to migrate into target sites, process antigens, and activate naive T cells. In this study, we analyzed the biological activity and intracellular signaling of adenosine by using reverse transcriptase-polymerase chain reaction assays to investigate mRNA expression of A(1), A(2a) and A(3) adenosine receptors in immature and mature human DCs. Functional experiments on adenosine stimulation showed chemotaxis, intracellular calcium transients, and actin polymerization, but no activation of adenylate cyclase in immature DCs. Experiments with receptor isotype-selective agonists and antagonists as well as pertussis toxin revealed that chemotaxis, calcium transients, and actin polymerization were mediated via G(i-) or G(0-)protein-coupled A(1) and A(3) receptors. Maturation of DCs induced by lipopolysaccharide (LPS) resulted in down-regulation of A(1) and A(3) receptor mRNAs, although A(2a) receptor mRNA was still expressed. However, in LPS-differentiated DCs, adenosine and an A(2a) receptor agonist stimulated adenylate cyclase activity, enhanced intracellular cAMP levels, and inhibited interleukin 12 (IL-12) production. These effects could be completely prevented by pretreatment with A(2) receptor antagonist. These findings strongly suggest that adenosine has important but distinct biological effects in DCs activity as a chemotaxin for immature DCs and as a modulator of IL-12 production in mature DCs. These effects can be explained by differential expression of adenosine receptor subtypes.
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PMID:Expression and function of adenosine receptors in human dendritic cells. 1153 76


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