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)

We studied the effect of endotoxin on bradykinin-induced inositol 1,4,5-triphosphate (IP3) production and the relationship between IP3 and phospholipase A2 or thromboxane A2. When exposed with 0.1, 1.0, and 10 microg ml(-1) lipopolysaccharide (LPS) for short-term (60 min), 100 nmol L(-1) bradykinin-induced IP3 production was stimulated in a dose-dependent manner from 569.2+/-42.4 in absence of LPS to 714.3+/-52.8, 804.5+/-42.6, and 894.1+/-62.6 pmol mg protein(-1). Treatment of 100 micromol L(-1) ACA (a phospholipase A2 inhibitor) and 10 micromol L(-1) BM13.177 (a thromboxane A2 inhibitor) significantly decreased bradykinin-induced IP3 production and LPS (1.0 microg mL(-1)) modulation of bradykinin-induced IP3 formation from 804.5+/-42.6 to 217.4+/-12.7 and 208.6+/-17.1 pmol mg protein(-1), respectively. LPS modulation of bradykinin-induced IP3 production was significantly blocked by 1 micromol L(-1) TMB-8 (an intracellular Ca2+ antagonist) from 804.5+/-42.6 to 507.8+/-33.4 pmol mg protein(-1). LPS modulation of bradykinin-induced IP3 production was significantly inhibited from 804.5+/-42.6 to 397.4+/-30.3 pmol mg protein(-1) by treatment of 10 micromol L(-1) indomethacin. In conclusion, short-term administration of LPS stimulates bradykinin-induced IP3 formation through activation of phospholipase A2 and thromboxane A2 and the stimulation is associated with an elevation of intracellular Ca2+.
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PMID:Bradykinin-induced inositol 1,4,5-triphosphate in neonatal rat cardiomyocytes is activated by endotoxin. 1113 14

The 4-amino analogue of tetrahydrobiopterin (4-ABH(4)) is a potent pterin-site inhibitor of nitric oxide synthases (NOS). Although 4-ABH(4) does not exhibit selectivity between purified NOS isoforms, a pronounced selectivity of the drug towards inducible NOS (iNOS) is apparent in intact cells. This work was carried out to investigate the potential iNOS selectivity of 4-ABH(4) in isolated pig pulmonary and coronary arteries. Endothelium-dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore A23187 were inhibited by 4-ABH(4) in a concentration-dependent manner. Half-maximal inhibition was observed at 60 - 65 microM (pulmonary artery) and 200 - 250 microM 4-ABH(4) (coronary artery). Pig coronary artery strips precontracted with 0.1 microM 9, 11-dideoxy-9, 11-methanoepoxy-prosta-glandin F(2alpha) (U46619) showed a time-dependent relaxation (monitored for up to 18 h) upon incubation with 1 microg ml(-1) lipopolysaccharide (LPS). Addition of 10 microM 4-ABH(4) 1 h after LPS led to a pronounced inhibition of the LPS-triggered relaxation, whereas the pterin antagonist had no effect when given> or =4 h after LPS. Incubation of pulmonary and coronary artery strips with 1 microg ml(-1) LPS attenuated contractile responses to norepinephrine (1 microM) and U46619 (0.1 microM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4-ABH(4) in a concentration-dependent manner [IC(50)=17.5+/-5.9 microM (pulmonary artery) and 20.7+/-3 microM (coronary artery)]. The effect of 0.1 mM 4-ABH(4) was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH(4) via a salvage pathway. These results demonstrate that 4-ABH(4) is a fairly selective inhibitor of iNOS in an in vitro model of endotoxaemia, suggesting that this drug and/or related pterin-site NOS inhibitors may be useful to increase blood pressure in severe infections associated with a loss of vascular responsiveness to constrictor agents caused by endotoxin-triggered iNOS induction in the vasculature.
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PMID:Inhibition of endotoxin-induced vascular hyporeactivity by 4-amino-tetrahydrobiopterin. 1113 56

1. Although endotoxaemia induces kinin B(1) receptors in several animal models, this condition is not documented in primates. This study examined the up-regulation of haemodynamic and pro-inflammatory responses to the B(1) agonist des-Arg(10)-kallidin (dKD) in a non-human primate model. 2. Green monkeys (Cercopithecus aethiops St Kitts) received lipopolysaccharide (LPS; 90 microg kg(-1)) or saline intravenously. After 4 h, anaesthetized monkeys were cannulated via the carotid artery to monitor blood pressure changes following intra-arterial injections of dKD or the B(2) agonist bradykinin (BK). Oedema induced by subcutaneous kinin administration was evaluated as the increase in ventral skin folds in anaesthetized monkeys injected with captopril at 4 h to 56 days post-LPS. 3. LPS increased rectal temperature but did not affect blood pressure after 4 h. dKD reduced blood pressure (E(max): 27+/-4 mmHg; EC(50): 130 pmol kg(-1)) and increased heart rate (E(max): 33 b.p.m.) only after LPS. In contrast, the dose-dependent fall in blood pressure with BK was comparable in all groups. The selective B(1) antagonist [Leu(9)]dKD (75 ng kg(-1) min(-1), intravenously) abolished responses to dKD but not BK. 4. dKD injection induced oedema dose-dependently (2.4+/-0.1 mm at 150 nmol) only following LPS (at 4 h to 12 days but not 56 days). In contrast, BK-induced oedema was present and stable in all monkeys. Co-administration of [Leu(9)]dKD (150 nmol) significantly reduced oedema induced by dKD (50 nmol). 5. These results suggest LPS up-regulation of B(1) receptor effects in green monkeys. This non-human primate model may be suitable for testing new, selective B(1) antagonists with therapeutic potential as anti-inflammatory agents.
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PMID:Endotoxin sensitization to kinin B(1) receptor agonist in a non-human primate model: haemodynamic and pro-inflammatory effects. 1115 93

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

The kinin B1 receptors (B1Rs), stimulated by des-Arg9-kinins, are completely inducible, notably following treatment of animals with bacterial lipopolysaccharide. Several studies based on cultured cells have suggested a form of autoregulation of kinin receptors, because B2 receptor (B2R) or B1R stimulation could transcriptionally upregulate B1R expression. The B2R may rather be downregulated in inflammatory conditions. A rabbit B2R-green fluorescent protein (GFP) conjugate stably expressed in HEK 293 cells was rapidly internalized in response to the agonist bradykinin. Ligand-induced receptor cycling was documented applying confocal microscopy. The results confirm agonist-induced B2R endocytosis, but extensive recycling to the cell membrane does not support agonist-induced downregulation.
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PMID:Ligand-mediated regulation of kinin receptors in the rabbit. 1125 63

1. In the present study, we used a microphysiometer to measure bradykinin-induced acidification responses in IMR-90, a human lung fibroblast cell line, and INT-407, a human colonic epithelial cell line. Furthermore, we investigated the effect of 24 h exposure of transforming growth factor (TGF)-alpha on the bradykinin response in INT-407 cells. 2. Bradykinin (0.1-100 nmol/L) was potent in producing acidification responses in IMR-90 cells (pEC50 8.79+/-0.13; Hill slope 0.96+/-0.04) and INT-407 cells (pEC50 8.90+/-0.04; Hill slope 1.00+/-0.07). These responses were competitively antagonized by the bradykinin B2 receptor antagonist icatibant in both IMR-90 cells (apparent pKB = 8.54+/-0.15; Hill slope = 1.09+/-0.13 and 1.66+/-0.26 in the absence and presence of 10 nmol/L icatibant, respectively) and INT-407 cells (pKB = 8.12+/-0.07 (3, 10 and 30 nmol/L icatibant); Hill slope = 1.06+/-0.04). However, the bradykinin B1 receptor antagonist des-Arg9Leu8-bradykinin (3 micromol/L) had no effect on the bradykinin responses. 3. The non-peptide bradykinin B2 receptor antagonist FR173657 selectively antagonized bradykinin-induced acidification responses in INT-407 cells in a competitive manner (pKB = 8.76+/-0.10; Hill slope = 0.92+/-0.05) at lower concentrations (1 and 3 nmol/L) but in an insurmountable manner at higher concentrations (10 nmol/L; Hill slope = 1.04+/-0.09). This compound, at concentrations of 10 and 100 nmol/L (Hill slope = 1.38+/-0.15), also proved to be an insurmountable antagonist in IMR-90 cells. 4. The bradykinin B1 receptor selective agonist Lys0des-Arg10-bradykinin (0.1 nmol/L to 0.1 micromol/L) failed to produce acidification responses in IMR-90 cells, even after 24 h pre-incubation with bacterial lipopolysaccharide (0.1 microg/mL). 5. A 24 h pre-incubation of INT-407 cells with TGF-alpha (1, 10 and 100 ng/mL) caused a significant concentration-dependent decrease in maximal bradykinin response without affecting the pEC50. 6. In addition to this study being the first to use a microphysiometer to characterize bradykinin B2 receptors in cultured IMR-90 human lung fibroblast cells and INT-407 human colonic epithelial cells, we also showed that pre-incubation of INT-407 cells with TGF-alpha caused a significant decrease in maximal acidification response mediated by bradykinin B2 receptors.
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PMID:Pharmacological characterization of bradykinin B1 and B2 receptors in IMR-90 and INT-407 human cell lines using a microphysiometer. 1138 May 14

The induction of B(1) receptors (B(1)Rs) and desensitization or down-regulation of B(2) receptors (B(2)Rs) as a consequence of the production of endogenous kinins has been termed the autoregulation hypothesis. The latter was investigated using two models based on the rabbit: kinin stimulation of cultured vascular smooth muscle cells (SMCs) and in vivo contact system activation (dextran sulphate intravenous injection, 2 mg kg(-1), 5 h). Rabbit aortic SMCs express a baseline population of B(1)Rs that was up-regulated upon interleukin-1beta treatment ([(3)H]-Lys-des-Arg(9)-BK binding or mRNA concentration evaluated by RT - PCR; 4 or 3 h, respectively). Treatment with B(1)R or B(2)R agonists failed to alter B(1)R expression under the same conditions. Despite consuming endogenous kininogen (assessed using the kinetics of immunoreactive kinin formation in the plasma exposed to glass beads ex vivo) and producing hypotension mediated by B(2)Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B(1)Rs in conscious animals (RT - PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 microg kg(-1), 5 h) was an effective B(1)R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve. We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B(1)Rs. Kinin receptor antagonists (icatibant combined to B-9858, 50 microg kg(-1) of each) failed to prevent or reduce the effect of LPS on B(1)R expression. Dextran sulphate or LPS treatments did not persistently down-regulate vascular B(2)Rs (jugular vein contractility assessed ex vivo). The kinin receptor autoregulation hypothesis is not applicable to primary cell cultures derived from a tissue known to express B(1)Rs in a regulated manner (aorta). The activation of the endogenous kallikrein-kinin system is ineffective to induce B(1)Rs in vivo in an experimental time frame sufficient for B(1)R induction by LPS.
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PMID:Absence of ligand-induced regulation of kinin receptor expression in the rabbit. 1148 27

The present study was performed to: (a) evaluate the effects of kinin B1 (Sar[D-Phe8]-des-Arg9-BK; 10 nmol/kg) and B2 (bradykinin (BK); 10 nmol/kg) receptor agonists on plasma extravasation in selected rat tissues; (b) determine the contribution of a lipopolysaccharide (LPS) (100 microg/kg) to the effects triggered by B1 and B2 agonists; and (c) characterize the selectivity of B1 ([Leu8]desArg9-BK; 10 nmol/kg) and B2 (HOE 140; 10 nmol/kg) antagonists as inhibitors of this kinin-induced phenomenon. B1 and B2 agonists were shown to increase plasma extravasation in the duodenum, ileum and also in the urinary bladder of the rat. LPS pretreatment enhanced the plasma extravasation mediated only by the B1 agonist in the duodenum, ileum, trachea, main and segmentar bronchi. These effects were prevented by the B1. but not the B2 antagonist. In normal rats, the B2 antagonist inhibited the effect of B2 agonist in all the tissues analyzed. However, in LPS-treated rats, the B2 antagonist was ineffective in the urinary bladder. These results indicate that kinins induce plasma extravasation in selected rat tissues through activation of B1 and B2 receptors, and that LPS selectively enhances the kinin effect on the B1 receptor in the duodenum, ileum, trachea and main and segmentar bronchi, and may increase B1 receptor expression in these tissues.
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PMID:Plasma extravasation mediated by lipopolysaccharide-induction of kinin B1 receptors in rat tissues. 1154 53

When the defence response of the body to infectious bacteria fails, septic shock ensues with hypotension and death. RPPGF,(1-5)-bradykinin, was until recently considered to be an active metabolite of bradykinin. In an animal model of septicaemia (lipopolysaccharide administration to rats), RPPGF is protective, and can even prolong life. RPPGF, or stable mimetics, have potential in the treatment of septic shock.
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PMID:A daughter of bradykinin that protects against septicaemia. 1178 56

Hypertension-associated alterations of the nitric oxide (NO) pathway were analyzed in middle cerebral arteries (MCA) from normotensive (WKY) and hypertensive (SHR) rats. The vasoconstrictor response to prostaglandin F2alpha (PGF(2 alpha), 30 and 100 microM) was smaller in MCA from SHR than from WKY. Endothelium-dependent relaxations to bradykinin (1 nM-10 microM) or acetylcholine (10 microM) were similar in MCA from both strains, whereas the endothelium-independent response to sodium nitroprusside (1 nM-0.1 mM) was smaller in MCA from SHR. L-arginine (L-Arg, 10 microM) similarly inhibited the vasoconstrictor responses in both strains; however, the inhibitory effect of 100 microM of L-Arg was greater in MCA from SHR. N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), but not aminoguanidine (100 microM) or 7-nitroindazole (10 microM), increased basal tone, potentiated the PGF(2 alpha)-induced vasoconstrictor responses and reduced the bradykinin-elicited relaxation in a similar way in MCA from WKY and SHR. N(omega)-nitro-L-arginine methyl ester also antagonized the inhibitory effect of 10 microM of L-Arg. Incubation for 5 h with lipopolysaccharide (10 microg/ml) similarly reduced the response to PGF(2 alpha) in MCA from WKY and SHR; this reduction was antagonized by dexamethasone (1 microM). Cerebral arteries expressed endothelial (eNOS) and neuronal (nNOS) NO synthase similarly in both strains, but inducible NOS (iNOS) expression was more evident in SHR. Lipopolysaccharide increased iNOS expression in both strains to a similar level. The basal constitutive NOS (cNOS) and iNOS activities were similar in arteries from WKY and SHR. Lipopolysaccharide increased iNOS activity only in arteries from SHR. These results indicate that hypertension did not impair endothelial NO production by NOS activation but induced an up-regulation of basal iNOS expression.
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PMID:Alterations of the nitric oxide pathway in cerebral arteries from spontaneously hypertensive rats. 1186 17


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