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)

Altered release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) has been proposed as a final common pathway underlying the abnormal vasodilator responses to gram-negative lipopolysaccharide (endotoxin). However, mechanisms responsible for lipopolysaccharide-induced changes in EDRF/NO release from endothelial cells have not been clarified. We evaluated direct effects of Escherichia coli endotoxin on agonist-stimulated cytosolic Ca2+ mobilization and NO biosynthesis in cultured bovine and porcine aortic endothelial cells (ECs). Two methods were used to assay for NO: (1) analysis of NO-induced endothelial levels of cGMP as a biological indicator of NO generation and (2) direct quantitative measurement of NO release (chemiluminescence method). Cytosolic free Ca2+ ([Ca2+]i) was evaluated using fura 2 fluorescence methodology (340/380-nm ratio excitation and 500-nm emission). Incubation of ECs with endotoxin (0.5 microgram/mL, 1 hour plus 1-hour wash) significantly inhibited bradykinin (100 nmol/L)- and ADP (10 mumol/L)-mediated increases in endothelial cell cGMP to 37% and 22% of control responses, respectively. In contrast, endotoxin failed to inhibit the increase in cGMP produced by the non-receptor-dependent Ca2+ ionophore A23187 (1 mumol/L) or sodium nitroprusside (1 mmol/L). Similarly, incubation with endotoxin inhibited ADP-stimulated increases in NO release and EDRF bioactivity to 55% and 56% of control values, respectively, but did not affect A23187-stimulated increases in NO release or EDRF bioactivity. Endotoxin produced significant decreases in both transient and sustained [Ca2+]i responses of ECs to bradykinin and ADP. For example, the initial rapid increase in bovine EC [Ca2+]i in response to bradykinin was reduced to 31% of the initial increases in control cells, and the secondary plateau phase was reduced to only 3% of respective control responses. Concentration-response relation to endotoxin (10(-3)) to 10(0) micrograms/mL) indicated high correlation and similar IC50 values (0.025 and 0.021 micrograms/mL, respectively) for inhibitory effects on cGMP and [Ca2+]i. Endotoxin had no effect on inositol trisphosphate formation ([3H]myo-inositol incorporation) and intracellular Ca2+ release ([Ca2+]i responses in Ca(2+)-free medium) induced by bradykinin. However, agonist-stimulated Mn2+ quenching (index of Ca2+ influx) was significantly attenuated by endotoxin treatment. These studies demonstrate that endotoxin directly decreases agonist (bradykinin and ADP)-mediated biosynthesis and release of EDRF/NO from ECs. These effects can be explained by altered [Ca2+]i mobilization mechanisms, which in turn produce subsequent decreases in activity of the Ca(2+)-calmodulin-dependent constitutive isoform of NO synthase and, ultimately, impairment of agonist-mediated NO release and endothelium-dependent vasodilation.
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PMID:Escherichia coli endotoxin inhibits agonist-mediated cytosolic Ca2+ mobilization and nitric oxide biosynthesis in cultured endothelial cells. 792 12

1. The aim of the study was to assess the regional haemodynamic responsiveness to vasoconstrictor and vasodilator challenges during continuous 24 h infusion of lipopolysaccharide (LPS) in conscious Long Evans rats. 2. Rats were chronically instrumented for the measurement of regional haemodynamics (either internal and common carotid or renal, superior mesenteric and hindquarters) and received 3 min of infusions of acetylcholine (22 nmol min-1), methoxamine (120 nmol min-1), salbutamol (0.83 nmol min-1) and bradykinin (14.4 nmol min-1) at 2, 6 and 24 h after the start of saline or LPS (150 micrograms kg-1 h-1) infusion (rats with carotid probes received only acetylcholine and methoxamine). 3. During infusion of LPS there was a changing haemodynamic profile. After 2 h, there was a modest hypotension and vasodilatation in the internal carotid, renal and hindquarters vascular beds. After 6 h, arterial blood pressure had returned to baseline, there was still vasodilatation in the renal vascular bed but vasoconstriction in the internal and common carotids and the hindquarters. After 24 h, there was hypotension, tachycardia and generalized vasodilatation. 4. Acetylcholine caused a fall in blood pressure, tachycardia and hyperaemic vasodilatation in the carotid and renal vascular beds. Throughout the infusion of LPS, the carotid vasodilator response was enhanced after 2 h, reduced after 6 h and enhanced again after 24 h, whereas the renal vasodilator response to acetylcholine was either reduced (6 h) or absent (2 and 24 h); at this juncture the hypotensive response to acetylcholine was also enhanced and the tachycardia was reduced. 5. Methoxamine caused a rise in blood pressure, a fall in heart rate, and vasoconstriction in all the vascular beds monitored. During infusion of LPS, the pressor response to methoxamine was consistently reduced as were the vasoconstrictor responses in the carotid and mesenteric vascular beds, whereas the renal and hindquarters vasoconstrictor responses to methoxamine were only significantly reduced at some time points (renal 6 h, hindquarters 2 and 6 h).6. Salbutamol caused hypotension, tachycardia and hyperaemic vasodilatation, particularly in the hindquarters vascular bed. Throughout the infusion of LPS, the cardiovascular responses to salbutamol were substantially attenuated.7. Bradykinin caused hypotension, tachycardia and hyperaemic vasodilatation in the renal, mesenteric and hindquarters vascular beds. During the infusion of LPS, the hypotensive response to bradykinin was consistently augmented, and the tachycardia was consistently reduced, but the regional haemodynamic profile changed with time. Thus, after 2 h, the mesenteric vasodilator response was augmented and the hindquarters vasodilator response was reduced; after 6 h, the mesenteric vasodilator response appeared normal, but the renal and hindquarters vasodilator responses were reduced; after 24 h, the hindquarters vasodilator response was markedly augmented and the renal response had changed to a vasoconstriction.8. The present findings indicate marked regional variations in response to acetylcholine, methoxamine,salbutamol and bradykinin with time during LPS infusion. The changes observed are likely to reflect the interplay of a number of endogenous vasodilator and vasoconstrictor systems; further investigations will be required to clarify the mechanisms involved.
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PMID:Regional haemodynamic responses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats. 795 64

1. In guinea-pigs previously sensitized with ovalbumin, the intra-plantar administration of the antigen induced dose-dependent and sustained oedema. An intense infiltrate of neutrophils and eosinophils was observed at the peak of the oedema (4 h). 2. Oedema induced by ovalbumin at the doses of 50 or 200 micrograms/paw was not inhibited by antihistamines (meclizine and cetirizine), a PAF antagonist (BN 50730), a cyclo-oxygenase inhibitor (indomethacin), a lipoxygenase inhibitor (MK-886), a dual type lipo- and cyclo-oxygenase inhibitor (NDGA), a bradykinin antagonist (Hoe 140) or the combination of cetirizine, MK-886, indomethacin and BN 50730. These drugs did inhibit paw oedema induced by their specific agonists or by carrageenin. These results suggest that histamine, PAF, prostaglandins, leukotrienes or bradykinin are not important in the development of immune paw oedema in guinea-pigs. 3. Dexamethasone (10 mg kg-1) inhibited oedema induced by ovalbumin (50 or 200 micrograms/paw, P < 0.05). This effect apparently does not result from inhibition of arachidonate metabolism, since indomethacin, MK-886 and NDGA were without effect. 4. Oedema induced by ovalbumin (50 or 200 micrograms/paw) was also inhibited by azelastine. This effect was not due to the anti-histaminic property of azelastine since two other potent-antihistamines, meclizine and cetirizine, were ineffective. 5. Intravenous injection of lipopolysaccharide (LPS) dose-dependently inhibited the oedema induced by ovalbumin (200 micrograms/paw). This effect could not be attributed to hypotension or leucopenia since the maximal dose applied (81 micrograms kg-1) did not induce significant changes in the blood pressure or in the white blood cell levels of the animals. It is suggested that the effect of LPS is mediated by the endogenous release of cytokines, including tumour necrosis factor (TNF alpha). Murine TNF alpha dose dependently(9-81 microg kg-1) inhibited the paw oedema induced by ovalbumin.7. The anti-oedematogenic effects of LPS and/or TNF alpha are possibly associated with their capacity to inhibit leucocyte emigration. Accordingly, guinea-pigs rendered leucopenic with vinblastine exhibited less intense oedema after ovalbumin. Vinblastine did not affect oedema induced by PAF or bradykinin,indicating that vascular responsiveness was not involved.
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PMID:Drug modulation of antigen-induced paw oedema in guinea-pigs: effects of lipopolysaccharide, tumour necrosis factor and leucocyte depletion. 803 30

Recent work suggests that thromboxanes may play a major pathogenic role in inflammatory bowel disease. Thromboxanes are produced in excess not only in inflamed mucosa but also in Crohn's disease, by uninflamed bowel and by isolated intestinal and peripheral blood mononuclear cells. Their cellular source is likely to include platelets, neutrophils, endothelial and epithelial cells as well as mononuclear cells, possible stimuli to their overproduction being chemotactic peptides, lipopolysaccharide, leukotrienes, platelet activating factor, interleukin-1, bradykinin and angiotensin II. The pro-inflammatory effects of thromboxanes are both direct (diapedesis and activation of neutrophils, mucosal ulceration, reduction of suppressor T-cell activity) and indirect (vasoconstriction, platelet activation). Although corticosteroids and aminosalicylates inhibit thromboxane synthesis, this action does not necessarily explain their therapeutic effect in inflammatory bowel disease. Selective thromboxane synthesis inhibitors and receptor antagonists, however, ameliorate experimental colitis in animals. Picotamide and ridogrel are dual thromboxane pathway blockers already used in man. Drugs of this type could prove useful not only for the prevention of systemic thrombo-embolism but also for suppressing intestinal mucosal inflammation in patients with inflammatory bowel disease.
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PMID:Review article: thromboxanes in inflammatory bowel disease--pathogenic and therapeutic implications. 821 51

1. The hyperalgesic activities in rats of bradykinin, carrageenin and lipopolysaccharide (LPS) were investigated in a model of mechanical hyperalgesia. 2. Bradykinin and carrageenin evoked dose-dependent hyperalgesia with maximum responses of similar magnitude to responses to LPS (1 and 5 micrograms). 3. Hoe 140, an antagonist of BK2 receptors, inhibited in a dose-dependent manner hyperalgesic responses to bradykinin, carrageenin and LPS (1 microgram) but not responses to LPS (5 micrograms), prostaglandin E2, dopamine, tumour necrosis factor alpha (TNF alpha), IL-1, IL-6 and IL-8. 4. Responses to bradykinin and LPS (1 and 5 micrograms) were inhibited by the cyclo-oxygenase inhibitor, indomethacin and by the beta-adrenoceptor antagonist, atenolol. The effects of indomethacin and atenolol were additive: their combination abolished responses to bradykinin and LPS (1 microgram) and markedly attenuated the response to LPS (5 micrograms). 5. Antiserum neutralizing endogenous TNF alpha abolished the response to bradykinin whereas antisera neutralizing endogenous IL-1 beta, IL-6 and IL-8 each partially inhibited the response. The combination of antisera neutralizing endogenous IL-1 beta+IL-8 or IL-6+IL-8 abolished the response to bradykinin. 6. Antisera neutralizing endogenous TNF alpha, IL-1 beta, IL-6 and IL-8 each partially inhibited responses to LPS (1 and 5 micrograms). Increasing the dose of antiserum to TNF alpha or giving a combination of antisera to IL-1 beta+IL-8 or IL-6+IL-8 further inhibited responses to LPS (1 and 5 micrograms). 7. These data show that bradykinin can initiate the cascade of cytokine release that mediates hyperalgesic responses to carrageenin and endotoxin (1 microgram). The lack of effect of Hoe 140 on hyperalgesic responses to LPS (5 microgram) suggests that the release of hyperalgesic cytokines can be initiated independently of bradykinin BK2 receptors.
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PMID:Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. 829 13

Using specific antisera for IL-1 beta and IL-8, as well as cyclooxygenase inhibitors and propranolol, we have demonstrated that these cytokines are responsible for the prostaglandin and sympathetic components of carrageenin-induced hyperalgesia in the rat paw test. The release of IL-1 beta and IL-8 is preceded by the liberation of TNF-alpha. We have also tested in a nociceptive model the effects of bradykinin and a specific bradykinin antagonist, HOE 140, on the hyperalgesia induced by carrageenin and lipopolysaccharide (LPS). Bradykinin-induced hyperalgesia was abolished by HOE 140 and by treatment of the paws with anti-TNF-alpha antisera. HOE 140 significantly inhibited the hyperalgesia induced by carrageenin and LPS. It is suggested that in these two models bradykinin is associated with the release of hyperalgesic cytokines.
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PMID:Bradykinin release of TNF-alpha plays a key role in the development of inflammatory hyperalgesia. 831 26

The B1 receptors for kinins are selectively stimulated by bradykinin (BK) and Lys-BK metabolites that do not have the C-terminal arginine, des-Arg9-BK and Lys-des-Arg9-BK, respectively. B1 receptors mediate a definite subset of the cardiovascular effects of kinins in normal and septic animals. We have studied the metabolism of the best selective B1 antagonist, Lys[Leu8]des-Arg9-BK, in order to support the rational design of new antagonists that have increased metabolic stability. The affinity of the new compounds was evaluated using the pA2 scale and was based on the antagonism of the contractile effect of kinins in the rabbit isolated aortic preparation. Acetylation of the alpha-amino group of the N-terminal Lys residue provided an excellent protection from the degradation by rabbit blood plasma. This and the inhibitory effect of amastatin on the metabolism of Lys[Leu8]des-Arg9-BK indicated that aminopeptidase M (AmM) is the major route of inactivation for this class of peptides in plasma. Various other modifications afforded a more or less complete resistance to purified angiotensin I converting enzyme (ACE). One analog, Ac-Lys[MeAla6, Leu8]des-Arg9-BK, was found resistant to the above-mentioned enzymes and to neutral endopeptidase-24.11 extracted from rabbit kidney. This antagonist, although 100 times less potent than the parent peptide Lys[Leu8]des-Arg9-BK on the rabbit aortic preparation, was equipotent in vivo against the hypotensive effect of a B1 agonist in lipopolysaccharide-treated rabbits, and unlike the original compound, its effect was persistent after the end of the infusion. Ac-Lys[MeAla6, Leu8]des-Arg9-BK does not antagonize B2 receptors either in vitro or in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development and in vivo evaluation of metabolically resistant antagonists of B1 receptors for kinins. 839 50

The nitric oxide (NO) production by porcine aortic valve endothelial cells was estimated in cusps incubated at 37 degrees C by measuring their cyclic GMP content and the nitrite levels of the incubation medium. After a stabilization period, incubation for 5 min with acetylcholine, bradykinin, ADP and bovine thrombin resulted in a receptor-mediated increase in cyclic GMP which could be blocked by EGTA, N-omega-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA). Incubation with lipopolysaccharide (endotoxin) from E. coli O111:B4 or bovine for 5 h, dose-dependently increased nitrite production as well as cyclic GMP content. The elevated nitrite production was completely abolished in the presence of the protein synthesis inhibitor cycloheximide, was reduced by more than 50% by dexamethasone but was not affected by EGTA. L-NMMA dose-dependently reduced the increased nitrite production and cyclic GMP content. These results suggest that besides the presence of a constitutive NO synthase in porcine aortic valve endothelial cells thrombin, like lipopolysaccharide, triggers the de novo expression of an inducible Ca(2+)-independent NO synthase.
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PMID:Thrombin triggers the de novo expression of an inducible NO synthase in porcine aortic valve endothelial cells. 856 77

1. The aims of the present study were to determine the profile of tumour necrosis factor (TNF) release, and the effect of monoclonal antibodies to TNF, on the changes in regional haemodynamics and the responses to vasodilator and vasoconstrictor challenges, during a continuous 24 h low dose infusion of lipopolysaccharide (LPS) in conscious rats. 2. Male Long Evans rats were chronically instrumented for measurement of regional haemodynamics (renal, superior mesenteric and hindquarters) and were challenged with 3 min infusions of acetylcholine (22 nmol min-1), methoxamine (120 nmol min-1), salbutamol (0.83 nmol min-1) and bradykinin (14.4 nmol min-1). The rats were given either saline, or the TNF antibodies, TN3g1 or TN3g2a, 1 h before the start of a continuous infusion of LPS (150 micrograms kg-1 h-1) and were subsequently re-tested with the vasodilator and vasoconstrictor challenges 2, 6 and 24 h after the start of the LPS infusion. 3. Prior to infusion of LPS, TNF was not detectable in the plasma. During continuous infusion of LPS there was a transient elevation in plasma TNF levels, reaching a maximum (approximately 2300 pg ml-1) after approximately 1 h, and returning to undetectable levels after approximately 3 h of LPS infusion. 4. In the saline pretreated group, after 1-2 h of LPS infusion, there was a small hypotension and a marked renal vasodilation; 6 h after the start of LPS infusion there was a minor elevation in MAP above control levels, renal vasodilatation was maintained and a hindquarters vasoconstriction occurred; after 24 h of LPS infusion, there was a hypotension and renal and hindquarters vasodilatation. There were significant reductions in the tachycardic and renal vasodilator responses and an enhanced depressor response to acetylcholine after 24 h of LPS infusion. LPS infusion also caused a generalized hyporesponsiveness to the cardiovascular effects of methoxamine and salbutamol. The major changes in response to bradykinin were reduced tachycardic and enhanced depressor responses throughout the LPS infusion, a biphasic decrease and increase in renal conductance and enhanced hindquarters vasodilatation at 24 h. 5. Pretreatment with either TN3g1 or TN3g2a antibodies had no major effects on the changes in resting haemodynamics, or on the changes in response to methoxamine, salbutamol or bradykinin challenges during LPS infusion. However, the tachycardic responses to acetylcholine were generally preserved, and its hypotensive effect after 24 h of LPS infusion was not enhanced after TN3g1 or TN3g2a pretreatment. Thus, despite substantial, but transient, elevation of plasma TNF levels during continuous LPS infusion, it appears that the majority of cardiovascular changes were dependent on factors other than plasma TNF.
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PMID:Lack of effect of TNF antibodies on the cardiovascular sequelae of lipopolysaccharide infusion in conscious rats. 858 Dec 89

1. E. coli lipopolysaccharide (LPS) produced a dose-dependent (dose range: 0.02-150 micrograms) increase in rat core temperature that was maximal 6 h after intracerebroventricular (i.c.v.) administration. LPS (200 ng) increased core temperature by 1.0 +/- 0.2 degrees C, 6 h following administration, as compared to vehicle-treated controls (-0.2 +/- 0.2 degrees C). 2. LPS-induced (200 ng) hyperthermia was prevented by co-administration of the bradykinin (BK) B2 receptor antagonist, Hoe 140 (10 and 30 pmol, i.c.v.) or by indomethacin (10 nmol, i.c.v.). 3. Systemic administration of Hoe 140 at doses up to 1 mumol kg-1, s.c., did not attenuate LPS-induced (200 ng, i.c.v.) hyperthermia. However, LPS hyperthermia was significantly reduced by systemic administration of indomethacin (1 mumol kg-1, i.v.). 4. Co-administration of the selective B1 receptor antagonists, [des-Arg9, Leu8]BK (0.1 - 1 nmol, i.c.v.) or [des-Arg10] Hoe 140 (0.1 - 1 nmol, i.c.v.), did not prevent LPS-induced hyperthermia. 5. It is concluded that the development of hyperthermia following central administration of endotoxin requires activation of central, but not peripheral bradykinin B2 receptors. The formation of kinins within the CNS may be an important initial component of CNS inflammation following infection.
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PMID:Development of hyperthermia following intracerebroventricular administration of endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists. 864 14


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