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 have recently shown that cultured endothelial cells produce kinins that can stimulate endothelial nitric oxide (NO) production in an autocrine manner. Because both the kallikrein-kinin system and the L-arginine/NO pathway have been implicated in the pathogenesis of septic shock, we investigated the possible involvement of endothelium-derived kinins in the response of cultured endothelial cells to bacterial lipopolysaccharide (LPS). In primary cultures of human umbilical vein and porcine aortic endothelial cells, LPS (0.3 to 3 micrograms/ml) induced significant concentration-dependent increases in cyclic GMP and 6-keto-PGF1 alpha, both of which were abolished in the presence of the selective bradykinin B2-receptor antagonist HOE 140 (0.1 microM). These LPS-induced increases in cyclic GMP and 6-keto-PGF1 alpha were short lived, being maximal after 5 min but were not apparent after 60 min. In parallel with these effects, LPS (30 micrograms/ml) induced a distinct, HOE 140-sensitive increase in the intracellular calcium concentration of human endothelial cells loaded with indo-1. In summary, these data suggest that the release of endothelium-derived kinin and subsequent stimulation of endothelial cells, followed by the enhanced production of NO and prostacyclin (PGI2), are implicated in the immediate hypotension induced by LPS in vivo.
J Cardiovasc Pharmacol 1992
PMID:Endothelium-derived kinins account for the immediate response of endothelial cells to bacterial lipopolysaccharide. 128 49

The nitric oxide (NO) synthase activity present in murine J774.2 monocyte/macrophages was characterized in terms of its intracellular localization, substrate specificity, and Ca2+ dependency. Traces of constitutive NO synthase activity were found in the microsomal fraction from noninduced J774.2 cells, whereas no NO synthase activity was detected in the cytosol. After 24 h in the presence of bacterial lipopolysaccharide and mouse interferon, NO synthase activity was substantially increased in both fractions with 51-60% of the total activity present in the cytosol. These activities, however, were clearly different, for the microsomal enzyme was Ca2+ dependent, whereas the cytosolic NO synthase was not. Moreover, NG-hydroxy-L-arginine (L-HOArg), L-homo-arginine, and several L-arginine (L-Arg)-containing dipeptides could replace L-Arg as substrates for the Ca(2+)-independent NO synthase, whereas the Ca(2+)-dependent enzyme accepted only L-Arg, L-HOArg, or L-Arg-L-Arg as substrates. Thus, a microsomal Ca(2+)-dependent NO synthase is induced in J774.2 monocyte/macrophages with a substrate specificity different from the inducible Ca(2+)-independent NO synthase as well as the constitutive NO synthase in, for example, endothelial cells. Irrespective of their intracellular localization, therefore, at least three isoforms of NO synthase exist, all of which can accommodate substrates different from L-Arg in size, charge, and hydrophobicity.
J Cardiovasc Pharmacol 1992
PMID:Characterization of a microsomal calcium-dependent nitric oxide synthase in activated J774.2 monocyte/macrophages. 128 50

Bovine endothelial cells (ECs, P1) and lipopolysaccharide/gamma-interferon-induced mouse macrophages (MMs) were incubated in the presence of SIN-1 and C 3754 (1 microM to 1 mM), sydnonimine metabolites of the antianginal predrugs molsidomine and pirsidomine, respectively up to 48 h. No change of the endogenous nitric oxide output from MMs and A23187- or adenosine triphosphate-stimulated ECs was found by means of the methemoglobin method. Data indicate that downregulation of the nitric oxide (NO) synthase is not obvious within the intact cells under exogenous NO stress supplied by high concentrations of the spontaneous NO donors. Cytosolic MM NO synthase extracts, however, revealed reduction in the enzymic [3H]arginine turnover to [3H]citrulline by SIN-1, but not by C 3786, the pharmacologically active metabolite of pirsidomine.
J Cardiovasc Pharmacol 1992
PMID:Exogenous nitric oxide stress on endothelial cells and macrophages. 128 53

Interleukin-1 receptor antagonist (IRA) is a secretory product of human monocytes or related cell lines that acts as a pure interleukin-1 (IL-1) antagonist in several bioassays. IRA administration was reportedly a life-saving intervention in rabbits injected with lethal doses of bacterial lipopolysaccharide (LPS). We report the inhibitory effect of IRA on three distinct types of vascular responses to IL-1 in rabbit isolated blood vessels. The rabbit isolated superior mesenteric artery, when precontracted with phenylephrine, relaxed in a sustained manner in less than 30 min following application of recombinant interleukin-1 beta (12-290 pM), and this was a prostaglandin (PG)-dependent and endothelium-independent process. IRA (human recombinant sequence; 0.9-15 nM) behaved as an antagonist of IL-1 alpha or IL-1 beta, based on the surmountability and the concentration dependence, but could only prevent the effect of IL-1, not reverse it. IRA had no direct effect on the preparation and did not influence the acute relaxing effect elicited by substance P or iloprost, a PGI2 mimetic. Exposure to IL-1 beta depressed the response to noradrenaline (NA) in several hours in rabbit aorta rings. The inhibitory effect of IL-1 beta was endothelium and prostaglandin independent, but was prevented by a treatment with NG-nitro-L-arginine (a nitric oxide synthesis inhibitor), cycloheximide, dexamethasone, or IRA. Using the residual NA-induced contraction as a quantification of the IL-1 agonist effect, IRA was a very potent antagonist of IL-1 beta but was not totally surmountable.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1992 May
PMID:Effects of interleukin-1 receptor antagonist on three types of responses to interleukin-1 in rabbit isolated blood vessels. 138 81

Plasma endotoxin concentrations and oxidative burst response of peripheral blood polymorphonuclear leukocytes were examined in 12 patients undergoing coronary artery bypass. The measurements were made just before the operation, 5 minutes after removal of the aortic crossclamp, and 24 hours after the operation. Endotoxin was quantitated by a combination of a sensitive Limulus amebocyte lysate assay and rocket immunoelectrophoresis measuring picogram amounts of endotoxin. Peripheral blood neutrophils were purified by a two-step dextran sedimentation and metrizoate sodium Ficoll (Lymphoprep., Nyegaard, Oslo, Norway) centrifugation. The oxidative burst response of these cells was measured for their ability to generate superoxide anion and was determined by a cytochrome c reduction assay. Preoperatively, all the plasma samples except one were free of endotoxin. The endotoxin levels reached 100 pg/ml 5 minutes after removal of the aortic crossclamp, and except in one sample they had decreased 24 hours after the operation. Studies on the generation of superoxide by neutrophils showed a decline in the response 5 minutes after removal of the aortic crossclamp and an enhancement of the response to f-Met-Leu-Phe by cells obtained from 11 of 12 patients 24 hours postoperatively. In vitro addition of bacterial lipopolysaccharide to blood from healthy individuals also enhanced the superoxide response of the neutrophils. We conclude that during cardiopulmonary bypass the circulating blood is contaminated by endotoxin and the neutrophils are primed for enhanced generation of oxygen radicals. The released oxygen radicals may be involved in the tissue damage observed in these patients.
J Thorac Cardiovasc Surg 1989 Sep
PMID:Endotoxemia and enhanced generation of oxygen radicals by neutrophils from patients undergoing cardiopulmonary bypass. 254 7

Endotoxin (lipopolysaccharide) concentrations were determined in the systemic venous blood in nine patients undergoing cardiopulmonary bypass. Lipopolysaccharide concentrations were low and stable until institution of cardiopulmonary bypass (preanesthetic concentration 0.128 +/- 0.032 ng/ml [mean +/- standard error of the mean]; prebypass level 0.136 +/- 0.03 ng/ml). After the start of bypass, the plasma concentration of lipopolysaccharide rose progressively with time to a mean value of 0.347 +/- 0.044 ng/ml (p less than 0.01), which was 0.227 ng/ml above baseline. Upon release of the aortic clamp, an additional rise in lipopolysaccharide concentration occurred after to 5 to 15 minutes to a mean value of 0.428 +/- 0.06 ng/ml (p less than 0.001) above baseline. The concentration then decayed to the baseline level 45 to 75 minutes after termination of bypass. The peak lipopolysaccharide concentration above the baseline positively correlated with both the length of bypass (r = 0.839, p less than 0.005) and the duration of aortic cross-clamping (y = 0.0030X + 0.173 r = 0.85, p less than 0.001) when flow was nonpulsatile. The peak occurred during the period of myocardial and pulmonary reperfusion. This rise in endotoxin concentration may be one of the factors responsible for the prolonged postoperative recovery seen in some patients.
J Thorac Cardiovasc Surg 1987 Jun
PMID:Endotoxemia associated with cardiopulmonary bypass. 357 96

We characterized the contractile effect of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) in endothelium-denuded rat aortic rings. Incubation with L-NNA (4 x 10(-6)-6.4 x 10(-5) M) for 5 h dose-dependently contracted endothelium-denuded aortic rings. In contrast, incubation with NG-nitro-D-arginine (D-NNA 6 x 10(-6)-4 x 10(-4) M), diphenyleneiodonium (DPI, NO synthase inhibitor, 3.2 x 10(-6) M) or dexamethasone (10(-7) M, inhibitor of expression of inducible NO synthase) did not contract the denuded rings. The L-NNA-induced contraction was not significantly altered by the presence of the endothelium or by pretreatment with L-arginine (L-Arg 2 x 10(-3) M) or lipopolysaccharide (100 ng/ml). These results suggest that L-NNA causes slow contraction of endothelium-denuded vascular smooth muscle (VSM) by a mechanism independent of the inhibition of constitutive or inducible NO biosynthesis.
J Cardiovasc Pharmacol 1994 Jul
PMID:NG-nitro-L-arginine contracts vascular smooth muscle by an endothelium-independent mechanism. 752 91

The effects of methylene blue, an inhibitor of the activation of the soluble guanylyl cyclase by nitric oxide (NO), were studied on blood pressure (BP) and on hyporesponsiveness to norepinephrine (NE) induced by Escherichia coli lipopolysaccharide (LPS) in pentobarbital-anesthetized rats. Methylene blue intravenous (i.v.) injection (3 mg/kg) produced a transient increase in BP which, in LPS-treated rats, was followed by a more sustained increase in BP. Methylene blue restored the reactivity to NE in LPS-treated rats but did not change either BP or reactivity to NE in saline-infused control rats. Cyclic GMP level was significantly increased in small femoral resistance arteries removed from LPS-treated rats as compared with controls (125.2 +/- 19.5 and 83.5 +/- 18.8 fmol/mg DNA, respectively, n = 8). In rats receiving methylene blue, there was no significant difference in cyclic GMP content of the arteries of LPS-treated rats as compared with controls (59.4 +/- 8.1 and 78.5 +/- 6.1 fmol/mg DNA, respectively, n = 8). These results support the involvement of increased stimulation of arterial guanylyl cyclase in hyporeactivity to NE elicited by LPS. They show that in vivo administration of methylene blue is able to restore both vascular cyclic GMP level and pressor responses to NE to control levels in LPS-treated rats.
J Cardiovasc Pharmacol 1993 Jun
PMID:Effects of methylene blue on blood pressure and reactivity to norepinephrine in endotoxemic rats. 768 18

Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 10(6)/ml) were incubated at 30 degrees or 37 degrees C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30 degrees C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28 degrees to 30 degrees C, n = 15) or warm (37 degrees C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor alpha and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1 beta (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this "tepid" heart surgery (32 degrees to 34 degrees C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.
J Thorac Cardiovasc Surg 1994 Jan
PMID:A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines. 828

Previous studies have suggested the presence of nitric oxide synthase (NOS) enzyme in human platelets. We herein provide definitive evidence for the presence of both endothelial constitutive NOS (ecNOS) and inducible NOS (iNOS) isoforms and their mRNA in human platelets. Total RNA was isolated from human platelets, and reverse-transcription polymerase chain reaction (RT-PCR) demonstrated the expression of the ecNOS and iNOS isoforms in platelets. High-stringency Southern analysis confirmed the molecular authenticity of the RT-PCR products for each NOS isoform. Western analysis with mouse monoclonal antibody against human ecNOS consistently demonstrated a band with a molecular weight of 140-150 kDa. Western analysis with mouse monoclonal antibody against rat macrophage iNOS showed a single 200-kDa band in both resting and lipopolysaccharide (LPS)-plus interferon-gamma (IFN-gamma)-stimulated platelets. Immunoprecipitation further confirmed the presence of the 200-kDa iNOS band. Expression of iNOS protein, measured with densitometry, was increased in LPS- and IFN-gamma-stimulated platelets (p < 0.01 vs. resting platelets). Thus, human platelets possess both ecNOS and iNOS isoforms and their mRNA, and iNOS exhibits molecular weight and kinetic characteristics distinct from those of ecNOS.
J Cardiovasc Pharmacol 1996 Jan
PMID:Further evidence of the presence of constitutive and inducible nitric oxide synthase isoforms in human platelets. 865 50


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