Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The manifestations of the septic syndrome are thought to be mediated by cytokines through their role in the production of nitric oxide (NO). It is hypothesized that the inhibition of NO production with an inhibitor such as NG-monomethyl-L-arginine (L-NMMA) may be beneficial in the treatment of septic shock. Sepsis was induced by the intravenous administration of Escherichia coli endotoxin (60 micrograms/kg) in six conditioned mongrel dogs (20-24 kg). Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and pulmonary artery pressure (PAP) were continuously monitored. Cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and arterial and mixed venous blood gases were obtained every 10 min. When the MAP decreased below 60 mm Hg, NO inhibitor L-NMMA was given by intravenous injection (25 mg/kg). Physiologic parameters were then measured at 2 and 5 min after L-NMMA injection. Subsequently, L-arginine (400 mg/kg), the substrate for the NO synthase enzyme, was administered and measurements were repeated at similar intervals. L-NMMA in septic canines produced a significant increase in MAP and SVR with a significant decrease in CO and tissue oxygenation (DO2 and VO2). These changes were reversed with the administration of L-arginine. There were no significant differences in the PCWP, CVP, PAP, or HR throughout the entire study. These results suggest that the inhibition of NO production by L-NMMA in a septic model produces elevated MAP and SVR at the expense of tissue oxygenation. Thus, its use, as a principal means of therapy for the septic syndrome, may not be appropriate because of detrimental effects on tissue oxygenation.
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PMID:Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. 804 Nov 56

A recombinant (r) NH2-terminal fragment of bactericidal/permeability-increasing protein, rBPI23, was shown to inhibit murine macrophage nitric oxide (NO) production elicited by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). Normal mouse plasma amplified NO synthesis (measured as NO2- release) at LPS concentrations of 1-10 ng/mL, and antibody to the plasma LPS-binding protein (LBP) partially inhibited NO2- release in the presence of normal mouse plasma. rBPI23 (1 microgram/mL) effectively inhibited LPS-dependent NO2- release in the presence or absence of normal mouse plasma. Fifty percent inhibition of IFN-gamma/LPS-elicited NO2- production or of binding of fluoresceinated LPS was obtained with approximately 0.2 microgram/mL rBPI23. These results provide a basis for studies of rBPI23 effects on NO synthase activity in murine models of gram-negative sepsis.
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PMID:Bactericidal/permeability-increasing protein inhibits induction of macrophage nitric oxide production by lipopolysaccharide. 827 72

The aim of this study was to clarify the role of Gram-positive organisms in the genesis of sepsis. In the present study, we investigated the effect of lipoteichoic acid (LTA) from the cell wall of Staphylococcus aureus on contractions elicited by norepinephrine (NE) in rings cut from human gastroepiploic arteries. LTA diminished the contractile response to NE. This attenuation began after several hours of exposure, whether or not endothelium was present. The cyclic guanosine monophosphate content of LTA-treated rings was higher than that of control rings, whether there was a functional endothelium. These LTA-mediated responses were reduced significantly by inhibitors of nitric oxide (NO) synthase and guanylate cyclase. All of this indicates that the main underlying cause of the vascular hyporeactivity to NE was a massive generation of No. In addition, cycloheximide, an inhibitor of inducible NO synthase, prevented the attenuation of NE-induced contractions caused by LTA. Thus, our results offer strong supporting evidence that the important factor in the genesis by Gram-positive organisms of a diminished contractile response to pressor drugs is their induction of inducible NO synthase in smooth muscle.
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PMID:Lipoteichoic acid from Staphylococcus aureus depresses contractile function of human arteries in vitro due to the induction of nitric oxide synthase. 861 Sep 4

That L-arginine (L-Arg) augments the host response to acute bacterial sepsis suggests that this amino acid intervenes early in the immune response, perhaps via the nitric oxide synthetase (NOS) pathway. The effect of L-Arg supplementation on in vitro phagocytosis of fluorescein-labeled, heat-killed Staphylococcus aureus by peripheral blood neutrophils (PMNs) from 12 normal human volunteers was studied. Separated PMNs were incubated for 2 h with labeled bacteria, with and without supplemental L-Arg, D-arginine, glycine, and/or the NOS inhibitors L-canavanine, aminoguanidine, or L-NG-nitroarginine methyl ester. PMNs were fixed and extracellular fluorescence quenched with crystal violet. By flow cytometry and confocal microscopy, L-Arg supplementation was shown to result in a highly significant increase in PMN bacterial phagocytosis, the maximal effect being seen with L-Arg 380 microM and falling off with higher concentrations. This augmentation was completely abrogated by NOS inhibitors in molar excess, but inhibitors alone did not suppress phagocytosis below that of unsupplemented controls. Neither D-arginine nor glycine affected phagocytosis; the L-Arg effect was stereospecific and not related to utilization of L-Arg as an energy source. L-Arg supplementation significantly enhances bacterial phagocytosis in human neutrophils, perhaps by effects on cytoskeletal phenomena, and this appears to be mediated through NOS activity. Phagocytosis by nonspecific immune cells which intervene early in the response to sepsis is critically important, and beneficial effects of L-Arg on the clinical course of sepsis may be due at least in part to augmentation of phagocyte function.
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PMID:Supplemental L-arginine HCl augments bacterial phagocytosis in human polymorphonuclear leukocytes. 864 19

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism trigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) beta1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-beta1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF-beta1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-beta1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-beta1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF-beta1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-beta1. Thus these studies suggest that TGF-beta1 inhibits iNOS in vivo and that TGF-beta1 may be of future benefit in the therapy of septic shock.
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PMID:Arrest of endotoxin-induced hypotension by transforming growth factor beta1. 870 Aug 84

Nitric oxide (NO) production is increased in the intestine and may contribute to intestinal injury in sepsis. However, the tissue expression of inducible NO synthase (iNOS) mRNA throughout the digestive tract and its relation with the mucosal damage after endotoxin challenge remain unknown. We therefore measured tissue expression of mRNA encoding iNOS by Northern blot analysis and reverse transcription PCR. The iNOS mRNA was detectable at 1 h, peaked at 4 h, and remained faint at 24 h after endotoxin injection in esophagus, duodenum, jejunum, ileum, and colon, but not in the stomach. Pre-treatment with dexamethasone attenuated the rise of iNOS mRNA. Both dexamethasone and NOS inhibitor, L-NAME, ameliorated the endotoxin-induced increase in intestinal mucosal permeability. Our results indicate that there is tissue-specific expression of iNOS mRNA in the digestive tract. The manipulations that decrease NO production may have therapeutic potential in preserving intestinal mucosal integrity in sepsis.
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PMID:Expression of inducible nitric oxide synthase mRNA in rat digestive tissues after endotoxin and its role in intestinal mucosal injury. 871 10

Nitric oxide (NO) may be produced in the vascular wall by different NO synthases. One of the constitutive isoforms, the endothelial NO synthase, contributes to the regulation of vascular tone and may prevent unwanted platelet and leucocyte adhesion to the endothelial surface. The release of NO by the endothelial NO synthase is exquisitely regulated by increases of intracellular free calcium following endothelial receptors activation by shear stress, neuromediators, hormones or platelet products. The immediate and transient release of NO diffuses towards the underlying smooth muscle and contributes to the appropriate response to local changes in blood flow or composition. The endothelial release of NO depends also on the availability of NO synthase cofactors; in addition, several experimental evidences suggest a transcriptional and postranscriptional regulation of the endothelial NO synthase itself. Another isoform of NO synthase insensitive to changes in intracellular calcium may be induced following exposure to cytokines or under some pathological conditions such as sepsis, inflammation or after vessel wall injury. The massive and long-lasting release of NO caused by induction of NO synthase requires a latency period of several hours. The inducible NO synthase may compensate the dysfunction of the endothelial isoform after injury (angioplasty) or in atherosclerosis. However, uncontrolled regulation of inducible NO synthase expression may have deleterious consequences on the vascular wall.
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PMID:[Endothelial NO synthase]. 876 34

Three different isoforms of the enzyme nitric oxide synthase (NOS) (EC 1.14.13.39) catalyze the formation of nitric oxide (NO) from l-arginine, which is then converted to l-citrulline. NO released by the constitutive isoforms is involved in a variety of physiologic functions, whereas larger amounts of NO released from the inducible isoform (iNOS) are mostly associated with inflammatory processes. Overproduction of NO in these processes including sepsis and autoimmune diseases can have deleterious consequences and pathophysiologic relevance. In this regard investigations of the regulation and function of iNOS to find specific iNOS inhibitors to block unwanted high levels of NO seem of great interest. The present article gives an overview of several methods and techniques employed to study the expression and regulation of the inducible nitric oxide synthase in in vivo and in vitro models of inflammation. The induction of iNOS was detected at different levels of expression and was compared to functional activity of NOS measured as enzyme activity and nitrite/nitrate production, two stable end products of the NO pathway. Differences in vivo and in vitro are compared and discussed.
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PMID:Expression and Detection of Inducible Nitric Oxide Synthase in Experimental Models of Inflammation 881 45

Nitric oxide (NO), a free radical that is negatively inotropic in the heart and skeletal muscle, is produced in large amounts during sepsis by an NO synthase inducible (iNOS) by LPS and/or cytokines. The aim of this study was to examine iNOS induction in the rat diaphragm after Escherichia Coli LPS inoculation (1.6 mg/kg i.p.), and its involvement in diaphragmatic contractile dysfunction. Inducible NOS protein and activity could be detected in the diaphragm as early as 6 h after LPS inoculation. 6 and 12 h after LPS, iNOS was expressed in inflammatory cells infiltrating the perivascular spaces of the diaphragm, whereas 12 and 24 h after LPS it was expressed in skeletal muscle fibers. Inducible NOS was also expressed in the left ventricular myocardium, whereas no expression was observed in the abdominal, intercostal, and peripheral skeletal muscles. Diaphragmatic force was significantly decreased 12 and 24 h after LPS. This decrease was prevented by inhibition of iNOS induction by dexamethasone or by inhibition of iNOS activity by N(G)-methyl-L-arginine. We conclude that iNOS was induced in the diaphragm after E. Coli LPS inoculation in rats, being involved in the decreased muscular force.
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PMID:Induction of diaphragmatic nitric oxide synthase after endotoxin administration in rats: role on diaphragmatic contractile dysfunction. 883 3

We tested the hypothesis that selective inhibition of the inducible form of nitric oxide (NO) synthase with aminoguanidine would prevent the loss of vascular contractility after exposure to endotoxin [lipopolysaccharide (LPS)]. Aortic rings were dissected from Sprague-Dawley rats, suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Vessels incubated with LPS (1 microgram/ml) for 5 h exhibited a significant decrease in the maximal contractile response to phenylephrine. Aminoguanidine (100 microM) restored the maximal contractile response of LPS-treated vessels to the level of the control vessels. Aminoguanidine was approximately 250-fold less potent than NG-nitro-L-arginine methyl ester in inhibiting the constitutive NO synthase in vascular tissue as determined by its ability to further increase tone of submaximally contracted aortic rings. NO synthase activity was determined in vascular tissue incubated with and without LPS. Vessels incubated with LPS exhibited a marked increase in the levels of inducible NO synthase activity compared with control vessels. This increase was restored to control levels when tissue homogenates were incubated with aminoguanidine. We conclude that aminoguanidine is a selective concentration-dependent inhibitor of the inducible form of NO synthase and may be a useful probe to evaluate the role of inducible NO synthase in the abnormal vascular contractility characteristic of endotoxemia and sepsis.
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PMID:Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine. 884 14


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