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

This study investigates some of the mechanisms involved in the up-regulation of the B1 receptor in the rabbit aorta. Pre-treatment of rabbit aorta with cyclooxygenase (COX) inhibitors 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsuphonyl) phenyl-2 (5H)-furanone (DFU), N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide (NS-398) or with indomethacin, but not with piroxicam, for 6 h, resulted in a significant inhibition of time-dependent contraction to the B1 selective agonist des-Arg9-Bradykinin (des-Arg9-BK), without affecting noradrenaline (NA) response. The kinase inhibitors bisindoylmaleimidine IX (RO 318220), staurosporine, genistein or tyrphostin B42 and the nuclear factor-kappaB (NF-kappaB) inhibitors pyrrolidinedithiocarbamate (PDTC), N(alpha)-p-tosyl-L-lysine chloro-methyl ketone (TLCK) or sulfasalazine, incubated for 6 h each, resulted in similar inhibition of des-Arg9-BK-induced contraction. When these inhibitors were pre-incubated for only 30 min, 6 h after setting up the preparations, sulfasalazine was the only drug tested that inhibited des-Arg9-BK-induced contraction, an effect which was reverted after the washing-out of the preparations. In preparations obtained from animals treated with lipopolysaccharide i.v. (LPS) 12 h prior, the up-regulation of B1 receptor in the aorta was markedly increased. The treatment of rabbits with PDTC, dexamethasone (Dexa), genistein or an association of subliminal doses of Dexa or with PDTC 12 h prior, which alone had no effect, all caused significant inhibition of des-Arg9-BK-induced contraction in the rabbit aorta. These results indicate that the time-dependent up-regulation of des-Arg9-BK-mediated contraction in the rabbit aorta involves the activation of protein kinase C, tyrosine kinase, through participation of COX-2 and the NF-kappaB transcription factor pathways.
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PMID:The "in vivo" and "ex vivo" roles of cylcooxygenase-2, nuclear factor-kappaB and protein kinases pathways in the up-regulation of B1 receptor-mediated contraction of the rabbit aorta. 1116 47

In the present study, contractile responses and [3H]-noradrenaline overflow evoked by electrical field stimulation were assessed, respectively, in the small mesenteric artery and in tail artery removed from rats pre-treated with either saline or lipopolysaccharide (LPS). In small mesenteric arteries, LPS treatment did not significantly modify the contractile responses elicited by electrical stimulation, in the absence or in the presence of L-arginine. However, in arteries removed from rats treated with LPS, L-arginine addition produced relaxation of vessels pre-contracted with noradrenaline. The amplification of neurogenic contraction by the nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) was similar in arteries removed from saline and LPS-infused rats. In mesenteric arteries, LPS treatment suppressed the potentiation of the neurogenic responses by the alpha2-adrenoceptor antagonist, yohimbine and by the inhibitor of neuronal uptake of noradrenaline, cocaine. In rat tail artery exposed to L-arginine, LPS treatment produced an increase in [3H]-noradrenaline overflow evoked by electrical stimulation. Altogether, these data suggest that an enhanced noradrenaline release from sympathetic nerves, probably resulting from inhibition of the modulatory effect of both prejunctional alpha2-adrenoceptors and neuronal uptake mechanism, may play a role in the preservation of neurogenic response after LPS treatment despite evidence of the induction of NO synthase.
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PMID:Effect of lipopolysaccharide treatment on neurogenic contraction and noradrenaline release in rat arteries. 1120 10

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.
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PMID:Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. 1127 Sep 17

The protective effects of a new, selective, plant-derived platelet-activating factor (PAF) antagonist, yangambin, on the cardiovascular alterations and mortality due to endotoxic shock were investigated in anaesthetized rats. We also studied the involvement of PAF in the induction of the vascular and cardiac hyporesponsiveness to adrenergic stimulation observed during endotoxaemia. The animals were sensitized to the lethal effects of Escherichia coli lipopolysaccharide (LPS) with D(+)-galactosamine (50 mg/kg, i.v.) 15 min before LPS injection. LPS (3 mg/kg, i.v.) induced a progressive and marked decrease in mean arterial blood pressure from 85+/-4 to 30+/-3 mmHg and a reduction of cardiac output (CO) from 180+/-7 to 37+/-3 ml/min (120 min) accompanied by a maintenance of systemic vascular resistance, suggesting that cardiovascular collapse resulted mainly from myocardial depression. The maximum pressor responses to noradrenaline (0.3-3.0 microg/kg, i.v.) fell from 72+/-9 (control) to 5+/-1 mmHg (LPS) while the CO responses decreased from 81+/-5 to 8+/-3 ml/min. Pre-treatment with yangambin (30 mg/kg, i.v.) or with WEB 2086 (5 mg/kg, i.v.), a reference PAF receptor antagonist, completely prevented the LPS-induced cardiovascular collapse and abolished the sharp reductions of the arterial blood pressure and CO responses to noradrenaline observed during endotoxaemia. Post-treatment with yangambin 90 min after LPS administration did not reverse the arterial hypotension, cardiac failure or cardiovascular hyporesponsiveness to catecholamines. Finally, the acute (150 min) survival rates of endotoxic shock increased from 0% (LPS group) to 100% in the groups pretreated with either yangambin or WEB 2086. The long-term (7-day) survival also increased from 0% (LPS group) to 85% (yangambin pre-treatment group). In conclusion, these data suggest a role for PAF in the pathogenesis of endotoxin-induced vascular and cardiac hyporesponsiveness to catecholamines and confirm its involvement in the complex cascade of multiple mediators released during endotoxic/septic shock. Yangambin proved to be an effective pharmacological agent against cardiovascular collapse and mortality in endotoxin shock.
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PMID:Protective effects of yangambin on cardiovascular hyporeactivity to catecholamines in rats with endotoxin-induced shock. 1128 40

Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N(G)-monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (P<0.0005) and heart rate (P<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by approximately 50% (P<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.
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PMID:Adrenoceptor hyporeactivity is responsible for Escherichia coli endotoxin-induced acute vascular dysfunction in humans. 1178 67

We investigated whether organ-specific differences exist in the role of inducible nitric oxide synthase (iNOS) in hyporeactivity to vasoconstrictors following 20 h in vitro exposure of isolated superior mesenteric, renal, hepatic and coronary arteries from the rat to bacterial lipopolysaccharide (LPS). LPS attenuated contraction in response to depolarizing KCl in all arteries. Maximum contractile responses to noradrenaline were attenuated in superior mesenteric and hepatic arteries, and those to the thromboxane A(2) analogue U46619 were attenuated in coronary arteries. LPS shifted the concentration-response curve to noradrenaline in renal arteries to the right. Removal of extracellular L-arginine improved the response to noradrenaline in superior mesenteric and renal arteries only. Addition of the iNOS inhibitor aminoguanidine resulted in full recovery of the responses to noradrenaline in superior mesenteric, renal and hepatic arteries. Contractile responses in coronary arteries did not improve after inhibition of iNOS activity. Therefore the pattern of the LPS-induced changes in vascular reactivity, as well as the contribution of iNOS to impaired vascular constriction, differed among vascular beds. These differences are likely to represent a contributory factor in the sepsis-associated redistribution of cardiac output.
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PMID:The role of inducible nitric oxide synthase in lipopolysaccharide-mediated hyporeactivity to vasoconstrictors differs among isolated rat arteries. 1186 70

The effects of repeated local immune challenges with lipopolysaccharide (LPS) over 24 h on basal and noradrenaline-stimulated lipolysis and the development of sensitivity to interleukin-4 and tumour necrosis factor-alpha in adipocytes associated with lymph nodes were studied in adult guinea-pigs. Properties characteristic of perinodal adipocytes appeared in adipocytes at least 10 mm from the locally stimulated popliteal lymph node within 12 h, and in other node-containing depots over 24 h. All effects appeared first in perinodal adipocytes and spread as though in response to signals emanating from the enclosed lymph node. The popliteal depot was more completely activated than the mesenteric, but its maximum rate of lipolysis/100 adipocytes was lower. None of the pre-treatments in vivo, nor incubation with cytokines in vitro modulated lipolysis in adipocytes from the nodeless perirenal depot. The sensitivity of the perinodal adipocytes to cytokines changed within 3 h of immune stimulation, preceding detectable increases in lipolysis. Cytokine-stimulated and noradrenaline-stimulated lipolysis sum, suggesting separate pathways. We conclude that sustained local activation of a single popliteal lymph node recruits additional adipocytes in node-containing depots only. Signals spread from lymph nodes to surrounding adipocytes, but the time courses of activation of adipocytes and their maximum responses differ between the mesenteric and popliteal depots.
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PMID:The activation of the adipose tissue associated with lymph nodes during the early stages of an immune response. 1189 31

The effects of feeding beef suet (mostly saturated and monoenoic fatty acids), sunflower oil (rich in n-6 fatty acids) and fish oil (rich in n-3 fatty acids) on the response of mesenteric, omental, popliteal and perirenal adipocytes to experimentally-induced local inflammation were studied in adult guinea pigs. After 6 weeks on the experimental diets, the animals were fed standard chow, and lipopolysaccharide was injected unilaterally daily for 4 d to induce swelling of one popliteal lymph node. Basal lipolysis in the perinodal adipocytes of all depots studied was higher in the sunflower oil-fed animals than in the controls fed on standard chow, and lower in those fed on suet or fish oil. Dietary lipids altered rates of lipolysis during incubation with l0(-5) M noradrenaline in all samples studied from the locally-activated popliteal depot, but only in adipocytes within 5 mm of a large lymph node in the other depots. The fish-oil diet attenuated the spread of increased lipolysis within the locally-activated popliteal adipose tissue, and from this depot to other node-containing depots. These experiments show that n-6 polyunsaturated fatty acids promote and n-3 fatty acids suppress the spread of immune activation to adipocytes within and between depots, and alter the sensitivity of perinodal adipocytes to noradrenaline. Dietary effects are reduced or absent in adipocytes in sites remote from lymph nodes, and thus such samples do not adequately represent processes in perinodal adipose tissue. These results are consistent with the hypothesis that perinodal adipocytes interact with adjacent lymphoid cells during immune responses.
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PMID:The effects of dietary lipids on adrenergically-stimulated lipolysis in perinodal adipose tissue following prolonged activation of a single lymph node. 1206 47

The involvement of cyclooxygenase-2 (COX-2)-derived products and superoxide anion in the effect of lipopolysaccharide in noradrenaline (NA)-induced contraction was investigated in small mesenteric arteries (SMA) from normotensive, Wistar Kyoto (WKY), and spontaneously hypertensive (SHR) rats. In WKY, lipopolysaccharide (10 microg/ml, 1 and 5 h) only inhibited the NA response (0.1-30 microM) in the presence of dexamethasone (1 microM), indomethacin (10 microM), the selective COX-2 inhibitor, NS 398 (10 microM), and the TXA(2)/PGH(2) receptor antagonist, SQ 29,548 (10 microM) but not of superoxide dismutase (SOD, 100 U/ml). In SHR, lipopolysaccharide inhibited the NA response by itself; this inhibition was potentiated by dexamethasone, indomethacin, NS 398, SQ 29,548 and SOD. The effect of lipopolysaccharide plus indomethacin, NS 398 or SQ 29,548 was higher in SMA from WKY than SHR only after 1 h lipopolysaccharide incubation. N(G)-nitro-L-arginine methyl ester (100 microM) and endothelium removal abolished the indomethacin-induced potentiatory effect of lipopolysaccharide in both strains. Endothelium removal also abolished the SOD potentiatory effect in SMA from SHR. Lipopolysaccharide increases COX-2 expression to a similar level in both strains and iNOS expression in a greater extent in SHR; these increases were reduced by dexamethasone. These results indicate: 1) lipopolysaccharide induces the endothelial production of contractile prostanoids from COX-2 in SMA, probably to compensate the increase in NO from iNOS; 2) the production of prostanoids in the presence of lipopolysaccharide seems to be greater in normotensive than hypertensive rats only after lipopolysaccharide short incubation times; 3) endothelial production of O(2)(.-) contributes to counteract depression of NA contraction caused by lipopolysaccharide only in SHR.
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PMID:Hypertension alters the participation of contractile prostanoids and superoxide anions in lipopolysaccharide effects on small mesenteric arteries. 1217 94

Norepinephrine turnover rate in the murine locus coeruleus (LC) is known to be enhanced by the intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Approximately 40% of LC neurons are also known to project to the olfactory bulb (OB) and the anterior olfactory nucleus (AON). Therefore, we investigated whether an i.p. injection of 500 microg LPS could modulate the catecholamine biosynthesis in these sites in 8-week-old C3H/HeN male mice. Unexpectedly, the content of norepinephrine was not elevated in both sites during 6-h-observation after LPS injection. The contents of dopamine and its metabolites in the AON were highly increased at 4 h after LPS injection, whereas those in the OB were not elevated during 6-h-observation. Although the AON has been considered not to belong to the dopaminergic neuron system, our report is the first to show an elevated dopamine content in the AON under a stressful condition such as endotoxemia.
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PMID:Effect of peripheral lipopolysaccharide injection on dopamine content in murine anterior olfactory nucleus. 1254 Oct 11


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