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)

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.
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PMID:Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats. 898 10

The mechanism by which bradykinin induces catecholamine release from neural tissues was investigated in two experimental models of rat origin. The rat phaeochromocytoma cell line PC12 was used to identify the subtype of bradykinin receptors involved in the stimulation of noradrenaline secretion and to compare the effects of three different B2-antagonists. An increase of catecholamine release induced by bradykinin in vivo could be confirmed by measuring plasma levels in pithed spontaneously hypertensive rats (SHR) during electric preganglionic stimulation of the spinal cord. In this whole animal model, the effects of inhibition of both uptake and alpha 2-adrenoceptors on plasma levels of noradrenaline and adrenaline were studied as well as the potentiation of exogenous bradykinin by inhibition of angiotensin I-converting enzyme and neutral endopeptidase. The receptor subtypes involved (i.e. B1 or B2) were characterized by application either of HOE 140 or desArg9-[Leu8]-bradykinin respectively. In PC12 cells bradykinin provoked a prominent increase of noradrenaline release at low concentrations (concentration required for 50% of the maximum response 1 nM), whereas the B1-agonist desArg9-bradykinin was only effective at concentrations higher than 30 microM. The effects of both kinins could be blocked by the B2-specific antagonist HOE 890307 which, like HOE 140, exerted no agonistic effect of its own. As has been shown in other neural cells, the B2-specific antagonist [Thi5,8, D-Phe7]-bradykinin only acted as a low-affinity agonist without any antagonistic effects. In experiments where the intention was to induce B1-receptor expression either by angiotensin I-converting enzyme inhibition or lipopolysaccharide application, no alteration of the secretory response of PC12 cells to bradykinin or desArg9-bradykinin could be shown. In pithed SHR, infusion of bradykinin (up to 1200 ng/min/kg) did not enhance stimulation-dependent release of noradrenaline or adrenaline. After pretreatment of the rats with ramipril bradykinin became effective and its effects were further potentiated by the concomitant application of phosphoramidon. B2-antagonism by HOE 140 abolished the bradykinin-induced release of noradrenaline and reduced the effect on plasma adrenaline. The B1-specific antagonist desArg9-[Leu8]-bradykinin was unable to diminish the stimulatory effects of bradykinin and instead brought about an increase of plasma adrenaline levels. In conclusion, bradykinin stimulates release of catecholamines from PC12 cells, peripheral sympathetic neurons and chromaffine cells by activation of ganglionic or presynaptic B2-receptors. The adrenal medulla and PC12 cells appear to be highly susceptible not only to stimulation by bradykinin, but also to non-specific stimulatory effects of certain kinin-antagonists.
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PMID:Bradykinin increases catecholamine release via B2 receptors. 899 50

We investigated the mechanism of the hypotensive effect of Sar-[D-Phe8]des-Arg9-bradykinin (BK) in lipopolysaccharide-treated anesthetized rabbits. The study involved pharmacokinetic and hemodynamic measurements and tests of antagonism with various drugs. The rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma was slower than that of Lys-BK, a naturally occurring B1 agonist. The amplitude of the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK was not affected by pretreatment with indomethacin, diclofenac, dazmegrel, NG-nitro-L-arginine, glibenclamide, MK-886, BN-50739, atropine or propranolol, but its duration was shortened by indomethacin and diclofenac. Sar-[D-Phe8]des-Arg9-BK-induced hypotension was associated with decreases of total peripheral resistance, cardiac output, carotid, mesenteric and femoral blood flow, transient reductions followed by secondary increases of vascular resistance in the carotid and femoral beds, reductions of central venous pressure, but no change of hematocrit. Animal pretreatment with diclofenac or hexamethonium abolished the secondary increases of carotid bed vascular resistance caused by the B1 agonist. These and other results suggest that peripheral vasodilation leading to a decrease of total peripheral resistance and a decrease of cardiac output may both contribute consecutively to the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK in this animal model. Inappropriate compensatory responses to arterial hypotension, prostaglandin release, and slow rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma, may all be at the basis of the prolonged duration of the hypotension caused by the B1 agonist.
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PMID:Cardiovascular effects of Sar-[D-Phe8]des-Arg9-bradykinin, a metabolically protected agonist of B1 receptor for kinins, in the anesthetized rabbit pretreated with a sublethal dose of bacterial lipopolysaccharide. 899 75

1. By using the selective, potent and long acting platelet-activating factor (PAF) antagonist, UK-74,505, we investigated the role of PAF in a local Shwartzman reaction (LSR) and a reversed passive Arthus (RPA) reaction in rabbit skin. For comparison, we also studied the effect of the PAF antagonist on neutrophil aggregation in vitro and on acute inflammatory responses induced by intradermally (i.d.) injected lipopolysaccharide (LPS), PAF, bradykinin and zymosan-activated plasma. 2. Neutrophil aggregation was assessed photometrically. Haemorrhage, oedema formation, platelet deposition and neutrophil accumulation were quantified in rabbit skin by measuring the accumulation of i.v. injected 51Cr-labelled red blood cells (RBC), 125I-labelled human serum albumin, 111In-labelled platelets and 111In-labelled neutrophils respectively. 3. UK-74,505 inhibited in vitro neutrophil aggregation induced by PAF but not by leukotriene B4. When injected i.v. into rabbits UK-74,505 suppressed oedema formation in response to i.d. PAF for up to 4 h but had no effect on oedema induced by bradykinin or zymosan-activated plasma. 4. Oedema formation, but not neutrophil accumulation, produced during the RPA reaction was significantly inhibited by i.v. UK-74,505. The PAF antagonist also suppressed 111In-platelet but not 111In-neutrophil accumulation in response to i.d. LPS. UK-74,505 did not affect haemorrhage or oedema formation produced during the LPS-mediated LSR. 5. The results demonstrate that PAF is an important mediator of oedema formation, but not neutrophil accumulation, in the immune-complex mediated RPA reaction in rabbit skin. PAF also appears to be required for platelet, but not neutrophil, accumulation in response to locally injected LPS. Our studies do not suggest a role for PAF in the LPS-mediated LSR.
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PMID:Comparison of the reversed passive Arthus and local Shwartzman reactions of rabbit skin: effects of the long-acting PAF antagonist UK-74,505. 910 4

1. The effect of central injection of selective kinin B1 and B2 receptor antagonists on the febrile response induced by endotoxin (E. coli lipopolysaccharide, LPS) in rats was investigated. 2. Intracerebroventricular (i.c.v.) injection of a selective B2 receptor antagonist (Hoe-140, 8 nmol) reduced the early (0-2 h), but increased the late phase (4-6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 microgram kg-1). 3. Co-administration of Hoe-140 (8 nmol, i.c.v.) with LPS (0.5 microgram kg-1, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B1 receptor antagonist [des-Arg9-Leu8]-bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period. 4. Intravenous injection of Hoe-140 (1 mg kg-1) significantly reduced the febrile response induced by LPS (0.5 microgram kg-1, i.p.). 5. Pretreatment (24 h) with LPS (0.5 microgram kg-1, i.v.) reduced the febrile response induced by BK or [Tyr8]-BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des-Arg9]-BK (5 nmol, i.c.v.). The response induced by [des-Arg9]-BK in LPS-pretreated rats was significantly inhibited by co-injection of [des-Arg9-Leu8]-BK (15 nmol, i.c.v.). 6. The results suggest that kinins are involved in the induction of LPS-induced fever and that central B2 and B1 receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B2 receptors and induction and/or upregulation of B1 receptors in LPS-pretreated animals may have a significant pathophysiological role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des-Arg9]-BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B1 receptors that occurs in such states.
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PMID:Central involvement of kinin B1 and B2 receptors in the febrile response induced by endotoxin in rats. 915 40

We have examined the bradykinin (BK)-stimulated production of prostacyclin (PGI2) by cultured human pulmonary artery smooth muscle cells (HPASMC) pretreated with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) or interferon gamma (IFN gamma). BK from 0.01 to 1 microM induced a dose-dependent increase in PGI2 production by HPASMC. A striking increase in PGI2 production in response to BK was observed in HPASMC which had been incubated with 1 microgram/ml LPS, 20 U/ml IL-1 beta, 50 U/ml TNF alpha or 100 U/ml IFN gamma. After incubation with various concentrations of LPS or cytokines, the production of PGI2 by BK-stimulated HPASMC showed significant, dose-dependent increases beginning at 0.1 microgram/ml of LPS, 2 U/ml of IL-1 beta and 5 U/ml of TNF alpha, while higher concentrations of IFN gamma failed to cause any further increase in PGI2 production. Our results indicate that BK is a potent agonist to stimulate HPASMC to produce PGI2. LPS, IL-1 beta and TNF alpha effectively enhanced BK-stimulated production of PGI2 by HPASMC, while IFN gamma had only a weak effect on BK-stimulated PGI2 production. Bradykinin-induced enhancement of PGI2 production by LPS, IL-1 beta and TNF alpha might be involved in the regulation of pulmonary vascular tension and prevent a paradoxical thrombogenic effect in endotoxin- or cytokine-mediated inflammation and acute lung injury. These experimental results suggest that vascular smooth muscle cells might actively control the vascular tension and blood supply by producing PGI2 in response to an agonist such as BK.
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PMID:Lipopolysaccharide and cytokines enhance bradykinin-stimulated production of PGI2 by cultured human pulmonary artery smooth muscle cells. 924 8

Neurogenic inflammation implies stimulation of nerves with resultant inflammation in tissue surrounding the nerve terminals. We hypothesized that neurogenic inflammation has a role in cholecystitis. Capsaicin (stimulant of afferent, nociceptive neurons), 6-hydroxydopamine (stimulates release of peptides from sympathetic nerve terminals), bradykinin, lipopolysaccharide, and saline were instilled into guinea pig gallbladders for 24 hr (N = 5 in each group). In parallel, test agents were instilled with 1% Iidocaine. Water transport across gallbladder mucosa, myeloperoxidase and interluekin-1 release from gallbladder tissue, and prostaglandin E2 in luminal fluid were measured. Capsaicin caused water secretion and significant release of myeloperoxidase, interleukin-1, and prostaglandin-E2, effects that were blocked by Iidocaine. 6-Hydroxydopamine did not affect water transport or prostaglandin E2, but did cause myeloperoxidase and interleukin-1 release. Bradykinin- and lipopolysaccharide-induced inflammation were partially inhibited by lidocaine. Taken together, these results suggest that neurogenic inflammation has a role in the pathophysiology of cholecystitis.
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PMID:Neurogenic inflammation in cholecystitis. 924 52

We have reported that bradykinin induces graded contraction in guinea-pig gallbladder in vitro through activation of bradykinin B2 receptors and prostanoid release, while des-Arg9-bradykinin, a selective bradykinin B1 receptor agonist, causes only a weak contraction, suggesting the presence of badykinin B1 receptors in this tissue. In the present study, we attempted to characterise the receptor subtype and the possible mechanism by which des-Arg9-bradykinin induces contraction in this preparation. Contractions induced by des-Arg9-bradykinin in guinea-pig gallbladder (1 pM to 1 microM) increased significantly as a function of time elapsed after setting up of the preparation, reaching the maximum after 6 h of equilibration (EC50 16.4 pM and Emax 0.6 +/- 0.08 g). Des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder was totally prevented by cycloheximide (70 microM, an inhibitor of protein synthesis), indomethacin (3 microM), ibuprofen (30 microM), phenidone (30 microM) or Ca2+-free medium plus EGTA, and was partially antagonised by MK 571 ((3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3-oxo-propyl) thio) methyl) propanoic acid, 0.1 microM) or by nicardipine (1 microM), but was not affected by dazoxiben (30 microM), staurosporine (100 nM) or L 655,240 (240 (3-[1-(4-clorobenzil)-5-fluoro-3-metilhyindol-2il] 2,2-dimetilpropanoic acid, 1 microM). Unexpectedly, des-Arg9-bradykinin-induced contraction was unaffected by the selective bradykinin B1 receptor antagonists, des-Arg9-[Leu8]-bradykinin and des-Arg9-NPC 17761 (des-Arg0-D-Arg [Hip3, D-HipE (transtiofenil)7, Oic8]-des-Arg9-bradykinin). However, the selective bradykinin B2 receptor antagonists, HOE 140 (D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) and NPC 17731 (D-Arg0 [Hyp3, DHypE (transpropyl)7, Oic8]-bradykinin), completely blocked des-Arg9-bradykinin-mediated contraction. Pre-treatment of the animals with Escherichia coli endotoxin (lipopolysaccharide, 30 microg/animal, i.v., 24 h) did not significantly change the response to des-Arg9-bradykinin induction. It is concluded that des-Arg9-bradykinin-induced contractions in guinea-pig gallbladder are mediated primarily by the release of proinflammatory eicosanoid(s) derived from the cyclo-oxygenase pathway. These effects are unrelated to thromboxane A2 and do not seem to be coupled to activation of a protein kinase C-dependent mechanism. Response to des-Arg9-bradykinin increases as a function of the equilibration period of the preparation by a mechanism dependent on protein synthesis and seems to be mediated by activation of bradykinin B2 (but not B1) receptors. Finally, in contrast to that observed for bradykinin, the contraction induced by des-Arg9-bradykinin in guinea-pig gallbladder is fully dependent on the influx of extracellular Ca2+, partially through L-type Ca2+ channels.
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PMID:Characterization of des-Arg9-bradykinin-induced contraction in guinea-pig gallbladder in vitro. 927 27

Cultures of myenteric ganglia from adult guinea-pigs were used to study the influence of neuroactive substances on glial cells by monitoring changes in their morphology. The following substances had no effect on glial morphology: adenosine, ATP, carbachol, glutamate, bradykinin, isoprenaline, prostaglandin E2, sodium nitroprusside and lipopolysaccharide. The only substances found to affect glial morphology were phorbol esters, and in particular phorbol 12-myrisate 13-acetate (PMA), which acted at the nM range. Glial cells, which were normally polygonal, assumed a stellate shape within 30-60 min after the addition of PMA. Protein kinase C (PKC) inhibitors did not block this effect, and PKC activators did not mimic it. The effect of PMA was also not mediated by changes in the intracellular concentrations of either Ca2+, H+ or cyclic AMP. Dye coupling among glial cells was blocked by PMA. The phorbol ester-mediated effect on glial structure may have profound influence on neuronal organization and function.
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PMID:Phorbol esters alter the morphology of cultured guinea-pig myenteric glia via a protein kinase C-independent mechanism. 935 Aug 32

1. In this study, the abilities of PC12 cells to synthesize and degrade kinins were investigated. Kinin formation was assessed as kinin and kininogen content of cells and supernatants in serum-free incubations by use of a bradykinin-specific radioimmunoassay. Expression of kininogen mRNA was demonstrated by reverse-transcriptase PCR. Kinin degradation pathways of intact PC12 cells were characterized by identification of the kinin fragments generated from tritiated bradykinin either in the absence or presence of the angiotensin I-converting enzyme inhibitor ramiprilat. 2. Kinin immunoreactivity in the supernatant of PC12 cell cultures accumulated in a time-dependent fashion during incubations in serum-free media. This effect was solely due to de novo synthesis and release of kininogen (35 pg bradykinin h-1 mg-1 protein) since it could be suppressed by cycloheximide. Continuous synthesis of kininogen was a specific property of PC12 cells, as it was not observed in cultured macro- or microvascular endothelial cells. PC12 cells contained only minor amounts of stored kininogen. The rate of kininogen synthesis was not affected by ramiprilat, bacterial lipopolysaccharide, nerve growth factor or dexamethasone, but was stimulated 1.4 fold when cells were pretreated for 1 day with 1 microM desoxycorticosterone. 3. By use of cDNA probes specific for kininogen subtype mRNAs, expression of low-molecular-weight kininogen and T-kininogen in PC12 cells was confirmed. Expression of high molecular weight kininogen mRNA was also shown, though only at the lowest limit of detection of the assay. 4. Degradation of tritiated bradykinin by PC12 cells occurred with a half-life of 48 min resulting in the main fragments [1-7]- and [1-5]-bradykinin. The degradation rate of bradykinin decreased to 15% in the presence of ramiprilat (250 nM). Apart from angiotensin I-converting enzyme direct cleavage of bradykinin to [1-7]- and [1-5]-bradykinin still occurred under this condition as a result of additional kininase activities. 5. Along with previous findings of B2-receptor-mediated catecholamine release, these results now confirm the hypothesis that a cellular kinin system is expressed in PC12 cells. The presence of such a system may reflect a role of kinins as local neuromodulatory mediators in the peripheral sympathetic system.
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PMID:Synthesis of kininogen and degradation of bradykinin by PC12 cells. 942 2


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