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)

B1 receptors for kinins are selectively stimulated by bradykinin (BK) or Lys-BK (kallidin) fragments without the C terminal arginine residue. The present study was performed using an established in vivo model of B1 receptor-mediated cardiovascular action. Rabbits pretreated with bacterial lipopolysaccharide (LPS) (25 micrograms/kg) and anesthetized 5 h later exhibit acute and transient hypotension in response to intra-arterial boluses of B1 receptor agonists. The naturally occurring B1 agonist Lys-des-Arg9-BK was more potent than des-Arg9-BK in the in vivo model, but the effect of either natural sequence was brief. Evidence derived from previous in vitro experiments suggests these peptides may be substrates for angiotensin I converting enzyme (ACE). In addition, Lys-des-Arg9-BK is hydrolyzed in vitro by aminopeptidase M. Therefore, we tested the hypotensive effects of Lys-des-Arg9-BK analogs selectively protected against ACE activity (Lys-[D-Phe8]des-Arg9-BK) or against both ACE and aminopeptidase M (Sar-[D-Phe8]des-Arg9-BK). Both analogs were found to elicit a biphasic response consisting of a brief hypotensive effect followed by a prolonged hypotensive state. Indomethacin prevented only the second, prolonged phase of the hypotension induced by the metabolically protected analogs. The duration of hypotensive episodes induced by Lys-des-Arg9-BK was increased in rabbits pretreated with either captopril, an ACE inhibitor, or the aminopeptidase M inhibitor amastatin, consistent with the prolonged effect of metabolically protected analogs. An infusion of the B1 agonist Sar-[D-Phe8]des-Arg9-BK (1 microgram/min) in lipopolysaccharide-pretreated rabbits led to a very important and persistent hypotensive state that was not prevented by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Hypotensive effects of Lys-des-Arg9-bradykinin and metabolically protected agonists of B1 receptors for kinins. 166 80

1. The aim of this investigation was to study the relationship between contractile responsiveness, activation of the L-arginine pathway and tissue levels of guanosine 3':5'cyclic monophosphate (cylic GMP) in aortic rings removed from rats 4 h after intraperitoneal administration of bacterial endotoxin (E. coli. lipopolysaccharide, LPS, 20 mg kg-1). 2. LPS-treatment resulted in a reduction of the sensitivity and maximal contractile response to noradrenaline (NA). 3. Depression of the maximal contractile response was restored to control by 6-anilo-5,8-quinolinedione (LY 83583, 10 microM), which prevents activation of soluble guanylate cyclase. 4. Cyclic GMP levels in tissue from LPS-treated rats were 2 fold greater than cyclic GMP levels detected in tissue from control (saline-treated) rats. The LPS-induced increase in cyclic GMP content was observed both in the presence and absence of functional endothelium. 5. Addition of L-arginine 1 mM) to maximally contracted aortic rings produced significantly relaxation of rings from LPS-treated rats but not rings from control animals. In the LPS-treated group, addition of L-arginine was also associated with a significant increase in cyclic GMP content. L-Arginine had no effect on the cyclic GMP content of control rings. D-Arginine (1 mM) was without effect. 6. In rings from LPS-treated rats, NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), an inhibitor of nitric oxide (NO) production, increased the contractile response to NA and prevented the LPS-induced increase in cyclic GMP content. In control rings, L-NAME increased the NA sensitivity only when the endothelium remained intact and reduced the cyclic GMP content of these rings to that of control endothelium-denuded rings. 7. These results demonstrate that LPS-induced hyporeactivity to NA occurs secondarily to activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase in vascular tissue. In addition they suggest that LPS induces the production of an NO-like relaxing factor in non-endothelial cells.
 ...
PMID:Evidence that an L-arginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin. 167 81

Bleomycin (BLM) is a useful anticancer agent sometimes associated with a diffuse pulmonary inflammation and fibrosis. Using an intratracheal model of BLM-induced pulmonary damage, we have further investigated alveolar macrophage (AM) activation following intratracheal BLM. From rats that had been treated with either a single, fibrogenic, intratracheal dose of BLM (BLM-AM) or a comparable volume of saline (C-AM), bronchoalveolar lavage fluid was collected, and AM were isolated using Percoll gradient centrifugation. Using a spectrophotometric assay, production of nitrites by AM was measured. C-AM released low levels of nitrites, whereas BLM-AM as well as C-AM activated in vitro with lipopolysaccharide released significant amounts of nitrites. The addition of N6-monomethylarginine, a substrate-specific inhibitor of the L-arginine-dependent effector mechanism in activated macrophages, reduced the amount of measurable nitrites released from both BLM-AM and activated C-AM. Similar results were observed when 12 x 10(6) RBC were added to the cocultures. In the presence of N6-monomethylarginine, BLM-AM had no effect on two consequences of BLM-AM-induced cytostatic activity, DNA synthesis inhibition and aconitase activity reduction in the L1210 target cell. These results suggest that reactive nitrogen intermediates measured as nitrites are important moieties in our in vivo model of macrophage activation. Further, the identification of this effector molecule presents possibilities for therapeutic and biochemical manipulations.
 ...
PMID:Role of reactive nitrogen intermediate production in alveolar macrophage-mediated cytostatic activity induced by bleomycin lung damage in rats. 170 56

The cytosol fraction of J774-1 murine macrophages activated with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) was found to nitrosate a wide range of secondary and tertiary amines. The reaction was dependent on L-arginine and NADPH. The optimal pH for nitrosation was 7.2-7.3. Nitrosation was inhibited by arginine derivatives such as NG-monomethyl-L-arginine and NG-nitro-L-arginine, well-known inhibitors of nitric oxide (NO) synthase. These results indicate that nitrosation is mediated by NO synthase, which catalyzes formation of NO and L-citrulline from L-arginine. Nitrosamine formation also required oxygen and was inversely correlated with the basicity of nitrosatable amines. The nitrosation was inhibited by oxyhemoglobin, an NO trapping agent, and enhanced by superoxide dismutase, which stabilizes NO. LPS + IFN-gamma induced approximately 500-600 times greater nitrosation activity than that of non-activated macrophages. Macrophages treated with LPS alone exhibited 3-4 times greater nitrosation activity than untreated macrophages, whereas macrophages treated with IFN-gamma alone did not show enhanced nitrosation activity. A combination of the cytosols from macrophages treated with LPS alone and IFN-gamma alone did not nitrosate morpholine as rapidly as the cytosol of macrophages treated with both compounds together. The activity for forming L-citrulline and nitrite/nitrate from L-arginine was markedly induced by treatment with either LPS alone or LPS + IFN-gamma but not with IFN-gamma. Those results suggest that some other factor(s) in addition to NO synthase is involved for efficient nitrosation by the macrophage cytosol. This factor(s) was not induced in macrophages by either LPS- or IFN-gamma alone, but was induced only in the presence of the two compounds.
 ...
PMID:L-arginine-dependent formation of N-nitrosamines by the cytosol of macrophages activated with lipopolysaccharide and interferon-gamma. 171 76

A soluble nitric oxide (NO) synthase activity was purified 426-fold from a mouse macrophage cell line activated with interferon gamma and bacterial lipopolysaccharide by sequential anion-exchange, affinity, and gel filtration chromatography. SDS/PAGE of the purified NO synthase gave three closely spaced silver-staining protein bands between 125 and 135 kDa. When assayed in the presence of L-arginine, NADPH, tetrahydrobiopterin, FAD, and reduced thiol, purified NO synthase had a specific activity of 1313 nmol of NO2- plus NO3- per min per mg. The apparent Km of the enzyme for L-arginine and NADPH was 2.8 and 0.3 microM, respectively. Addition of calcium ions with or without calmodulin did not increase the activity of the purified enzyme, and NO synthesis was not altered by calmodulin inhibitors. Gel filtration chromatography indicated that the induced NO synthase was catalytically competent as a dimer of approximately 250 kDa but could be dissociated into inactive monomers of approximately 130 kDa in the absence of L-arginine, FAD, and tetrahydrobiopterin. Upon heat denaturation, NO synthase released 1.1 mol of FAD and 0.55 mol of FMN per mol of 130-kDa subunit. Thus, inducible macrophage NO synthase differs in several respects from constitutive NO synthases and is one of very few eukaryotic enzymes containing both FAD and FMN.
 ...
PMID:Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. 171 79

Rat serosal mast cells were evaluated for their capacity to generate a nitric oxide-like factor by two bioassays: inhibition of platelet aggregation and stimulation of mast cell guanylate cyclase. Incubation of mast cells with human washed platelets, both treated with indomethacin, inhibited thrombin-induced platelet aggregation which was potentiated by superoxide dismutase and reversed by oxyhaemoglobin. When mast cells alone were stirred at 1000 rpm, a time dependent increase in the levels of their cGMP but not cAMP was observed. Preincubation of mast cells with NG-monomethyl-L-arginine significantly enhanced E. coli lipopolysaccharide-evoked histamine release. Our results show that mast cell histamine release can be modulated by an intrinsically generated nitric oxide-like factor.
 ...
PMID:Rat mast cells synthesize a nitric oxide like-factor which modulates the release of histamine. 171 38

Macrophages and certain tumor cell lines can be induced to synthesize nitric oxide (NO) from L-arginine after stimulation with lipopolysaccharide (LPS) or cytokines. In the present study, we have found that culture medium collected after 24 h from unstimulated rat mesangial cells (MC) contains 6.3 +/- 1.2 microM of NO3-/NO2- (the degradation products of NO). These levels were significantly increased when MC were incubated with LPS (10 micrograms/ml) for 24 h (23.9 +/- 4.1, P less than 0.05). The specific inhibitor of NO synthesis, NG-monomethyl-L-arginine (L-NMMA) completely inhibited LPS-stimulated production of NO3-/NO2-, confirming that the NO3-/NO2- was derived from NO within the MC. Recent studies suggest that endothelium-derived relaxing factor (EDRF) produced by vascular endothelium is also NO, and we have previously shown that both EDRF and NO stimulate increases in MC guanosine 3',5'-cyclic monophosphate (cGMP). Thus we sought to determine whether NO synthesized by the MC could affect cGMP levels within the same cells. After 24-h incubation with LPS (10 micrograms/ml), intracellular cGMP level within the MC was 706.3 +/- 197 (SE) compared with 40.5 +/- 7 fmol/micrograms protein in control MC incubated in media alone (P less than 0.01). The changes in cGMP in response to LPS were inhibited by greater than 90% by L-NMMA. Similar to LPS, incubation of MC with the cytokine gamma-interferon also increased NO3-/NO2- in the culture media and increased cGMP levels within MC. The induction of NO synthesis within MC and the concomitant stimulation of MC cGMP may be important in the modulation of the effects of endotoxemia, as well as inflammation, within the glomerulus.
 ...
PMID:Synthesis and action of nitric oxide in rat glomerular mesangial cells. 171 66

Phorbol 12-myristate 13-acetate-induced luminol chemiluminescence in rat Kupffer cells was doubled by the addition of L-arginine and significantly (up to 70%) inhibited by NG-nitro-L-arginine and NG-monomethyl-L-arginine, competitive inhibitors of L-arginine-dependent nitric oxide (NO) formation. The release of superoxide anion (O2-) by NADPH oxidase was neither affected by L-arginine nor by the inhibitors. Only very slight luminol chemiluminescence was detectable in lipopolysaccharide-pretreated Kupffer cells, a condition in which significant amounts of NO were formed but no O2-. In a cell-free system, significant luminol chemiluminescence only occurred when both authentic NO and the O2-/H2O2- generating system xanthine/xanthine oxidase were present. The results indicate that luminol chemiluminescence in phorbol-ester-activated Kupffer cells largely depends on L-arginine metabolism by NO synthase, requiring the concurrent formation of NO and O2-/H2O2.
 ...
PMID:Contribution of nitric oxide synthase to luminol-dependent chemiluminescence generated by phorbol-ester-activated Kupffer cells. 171 62

Nitric oxide (.NO) synthase (NOS) activity in subcellular fractions from cultured endothelial cells (EC) and lipopolysaccharide-activated J774.2 monocyte/macrophages was investigated by monitoring the .NO-mediated increase in intracellular cyclic GMP in LLC-PK1 pig kidney epithelial cells. The constitutive NOS in EC (NOSc) was largely membrane-bound, whereas the inducible NOS in J774.2 cells (NOSi) was equally distributed among cytosol and membrane(s). Both the cytosolic NOSc in EC and the membrane-bound NOSi in J774.2 cells were strictly Ca(2+)-dependent, whereas the membrane-bound NOSc in EC and the cytosolic NOSi in J774.2 cells were not. L-Homoarginine and L-arginine-containing small peptides, such as L-arginyl-L-phenylalanine, replaced L-arginine as a substrate for the NOSc in EC and the Ca(2+)-independent NOSi in J774.2 cells, but not the Ca(2+)-dependent NOSi. Thus, irrespective of their intracellular localisation, at least three isoforms of NOS exist, which can be differentiated by their substrate specificity and Ca(2+)-dependency.
 ...
PMID:On the substrate specificity of nitric oxide synthase. 172 80

The coronary vasoconstriction induced by the thromboxane mimetic U46619 (9, 11 dideoxy methanoepoxy 9 alpha, 11 alpha prostaglandin F2 alpha, 3-30 nM) was significantly attenuated in hearts obtained from rabbits treated with endotoxin (lipopolysaccharide, LPS, 200 micrograms kg-1, i.v.) 4 h before isolation of the heart. Under these conditions the vasoconstriction induced by two inhibitors of nitric oxide (NO) synthase, NG-monomethyl-L-arginine (L-NMMA) and N-iminoethyl-L-ornithine (L-NIO) (1-100 microM for each) was significantly enhanced when compared to that induced in hearts from control animals. Both the decreased response to U46619 and the increased response to inhibitors of NO synthase were significantly attenuated by administration of dexamethasone (4 mg kg-1, i.v.) 90 min before treatment with LPS. These data are consistent with the induction, by LPS, of an NO synthase, and the inhibition of this induction by dexamethasone. The enhanced NO synthesis contributes to the haemodynamic changes known to occur in endotoxin shock.
 ...
PMID:Coronary vasodilatation induced by endotoxin in the rabbit isolated perfused heart is nitric oxide-dependent and inhibited by dexamethasone. 172 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>