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)

We have investigated the expression of neuronal-type NO synthase I (NOS I) and inducible-type NOS II in guinea pig skeletal muscle (diaphragm). Expression of NOS I mRNA and protein was highest in muscle of specific pathogen-free animals, lower in normally bred animals, and lowest in lipopolysaccharide (LPS)-treated animals. NOS II mRNA and protein levels were highest in muscle of LPS-treated animals. Elevated NOS activity in muscle from LPS-treated animals was less susceptible to the NOS I-selective inhibitor N(G)-nitro-L-arginine. Expressional downregulation of NOS I in sepsis may have implications for contractile function of skeletal muscle.
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PMID:Expressional downregulation of neuronal-type NO synthase I in guinea pig skeletal muscle in response to bacterial lipopolysaccharide. 923 54

Endothelial nitric oxide exerts local vasodilatory actions in the gastrointestinal (GI) microvasculature and is proposed to play a role in enteric vasomotor regulation. The aims of this study were to characterize the tissue distribution of mRNA for endothelial nitric oxide synthase (NOS-III) and to examine its response to endotoxin challenge in vivo. We demonstrate the expression of NOS-III mRNA and protein in mucosa throughout the gastrointestinal tract and show for the first time that NOS-III mRNA expression in the GI mucosa was down-regulated in the rats treated with endotoxin. The ubiquitous expression of NOS-III mRNA in digestive tissues is consistent with the proposed role of NOS-III in the physiology of the gastrointestinal tract. The decreased NOS-III mRNA, in parallel to induction of inducible NOS (NOS-II) mRNA, may contribute to the impaired endothelium-dependent relaxation and damaged mucosal integrity during sepsis.
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PMID:Expression of endothelial constitutive nitric oxide synthase mRNA in gastrointestinal mucosa and its downregulation by endotoxin. 932 74

We studied the effect of PPM-18, a chemically synthesized naphthoquinone derivative and also an anti-inflammatory agent, on the lipopolysaccharide (LPS)-activated inducible NO synthase (iNOS) expression in rat alveolar macrophages. Pretreatment of macrophages with PPM-18 (0.1-10 microM) significantly inhibited nitrite production, iNOS protein expression and iNOS mRNA accumulation. PPM-18 did not directly affect the enzymic activities of iNOS and other constitutive NOS forms. The LPS-induced increase in nuclear transcription factor kappaB (NF-kappaB) p65 and p50 in nucleus was suppressed by PPM-18 (10 microM). Moreover electrophoretic mobility-shift assays demonstrated that PPM-18 inhibited DNA binding to NF-kappaB induced by LPS in whole cells but not when added in the nuclear extract, suggesting that PPM-18 did not interfere directly with the binding of NF-kappaB to DNA and that some events had to be processed before NF-kappaB could bind DNA. Examination of NF-kappaB showed that PPM-18 stabilized the NF-kappaB inhibitor, IkappaBalpha, by preventing its degradation from NF-kappaB. Therefore the stabilization of IkappaBalpha might have contributed to the inhibition of NF-kappaB activation. These results also indicate strongly that NF-kappaB is involved in the production of NO on stimulation by LPS. PPM-18 significantly decreased the production of tumour necrosis factor alpha in response to LPS. PPM-18 protects mice against LPS-induced lethal toxicity. These results also indicate that PPM-18 is a potent inhibitor of iNOS expression by blocking the binding of NF-kappaB to promoter and exerts a beneficial effect in the mouse model of sepsis.
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PMID:Inhibition of nitric oxide synthase expression by PPM-18, a novel anti-inflammatory agent, in vitro and in vivo. 937 89

It is now just 10 years since it was first appreciated that NO is endogenously synthesized in mammals. In this period, two constitutive and one inducible isoform of NOS have been isolated, sequenced, and characterized with respect to their protein chemistry and catalytic mechanism. A wide variety of NOS inhibitors, most targeted to the arginine binding site in the oxygenase domain, have been synthesized and used to elucidate the physiological and pathophysiological roles of NO. It is now clear that NO is involved in signal transduction (e.g., in neurotransmission and blood pressure homeostasis), and that these roles are mediated by low concentrations of NO synthesized by nNOS or eNOS. The NO receptor is the heme cofactor of soluble isoform of guanylyl cyclase. Higher amounts of NO, typically but not always synthesized by iNOS, are often cytotoxic. At a minimum, high concentrations of NO derange the signal transduction pathways normally served by nNOS or eNOS. In addition, NO or its nitrosative products (RSNO, N2O3, or ONOO-) inhibit or damage cellular constituents, interfering with DNA synthesis, energy metabolism, and the structural integrity of the cell. Such cytotoxicity can be beneficial to the host if pathogens or tumor cells are destroyed, but is detrimental to the host if it results in inappropriate inflammation, hypotension, or immunosuppression. Therapeutic utility of NOS inhibitors has been demonstrated in sepsis and cytokine-induced hypotension; additional applications are being identified in a treatment of inflammatory and autoimmune disorders.
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PMID:Design of nitric oxide synthase inhibitors and their use to reverse hypotension associated with cancer immunotherapy. 938 71

Using the shear stress laser diffractometer (Rheodyn) we have studied the role of nitric oxide on erythrocyte deformability during the initial 10 min after the i.v. administration of LPS at a dose of 5 mg/kg. At the stress shear force of 30 Pa the control erythrocytes elongation index (Ei) of untreated animals was 38% +/- 1.5 (mean +/- SD, n = 6) while in LPS treated animals it was decreased to 33% +/- 1.8 (n = 6) indicating significant (p < 0.01) loos of red blood cell deformability. The loss of deformability was accompanied by increased fragility of erythrocyte membranes as measured by enhanced release of free hemoglobin (E lambda 420 = 0.43 +/- 0.05 in control vs. E lambda 420 = 0.65 +/- 0.07 in LPS group) from isolated erythrocytes exposed to centrifuging at a speed of 3000 rpm for 10 min. Inhibitor of NO-synthase, NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg i.v.), significantly decreased deformability (Ei = 33.5- +/- 4.6, n = 6, p < 0.01) but did not influence fragility (E lambda 420 = 0.36 +/- 0.14, n = 6) of erythrocytes. However, when L-NAME was administered 10 min. prior to LPS it significantly improved the LPS-impaired fragility (E lambda 420 = 0.38 +/- 0.1, n = 6, p < 0.01) as compared to rats treated with LPS-alone (E lambda 420 = 0.65 +/- 0.07, n = 6). A similar protective effect of L-NAME was observed for LPS-induced impairment of erythrocyte deformability. It is concluded that NO seems to influence deformability and fragility of erythrocytes at the first stage of sepsis. During an acute phase of LPS action, possibly reflected by stimulation of endothelial constitutive (ecNOS) but not inducible NO-synthase (iNOS), the excessive amount of NO leads to a damage of erythrocyte plasticity and then the pretreatment with L-NAME exerts a protective action of LPS-impaired deformability and fragility of erythrocytes. On the other hand, basal release of NO maintains erythrocyte deformability at the physiological range and lowering of the basal level of NO by NOS-inhibitors leads to impairment or erythrocyte deformability.
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PMID:The role of nitric oxide in regulation of deformability of red blood cells in acute phase of endotoxaemia in rats. 944 20

Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems. The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense. Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections. It has a high mortality rate of 40 to 60%. Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients. In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS). Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. It may be a key factor leading to pronounced vasodilation and myocardial toxicity. Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals. Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients. However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery. Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available. This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock.
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PMID:Nitric oxide in sepsis-syndrome: potential treatment of septic shock by nitric oxide synthase antagonists. 947 85

Nitric oxide (NO) is an important vasodilator that is produced by constitutive (cNOS) as well as inducible (iNOS) isoforms of nitric oxide synthase. The pore-forming hemolysin of Escherichia coli (HlyA), an important virulence factor in extraintestinal E. coli infections, was found to be a potent stimulator of NO liberation in isolated endothelial cells, and that it also causes thromboxane generation and related vasoconstriction in rabbit lungs. We investigated the effect of different concentrations of HlyA on pulmonary NO synthesis in buffer-perfused rabbit lungs. NO release into the alveolar as well as the intravascular compartment was monitored on-line by chemiluminescence detection of expired NO and by measurement of (peroxy-)nitrite/nitrate release into the perfusate. HlyA induced a pressor response and an immediate dose-dependent increase of exhalative and intravascular NO liberation, further enhanced by the addition of the NOS substrate L-arginine. The nonspecific NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), but not the iNOS selective inhibitors aminoguanidine and 2-(2-aminoethyl)-2-thiopseudourea-dihydrobromide, blocked the HlyA-evoked NO liberation into both the alveolar and the intravascular compartments. Enhancement of NO formation (L-arginine) slightly reduced, and inhibition of NO synthesis (L-NMMA) amplified greatly, the HlyA-elicited vasoconstrictor response. Inhibition of the pressor response by a thromboxane receptor antagonist did not interfere with the exotoxin-elicited NO formation. We conclude (1) that marked NO biosynthesis occurs in this model of the septic lung, (2) that the signal transduction in response to HlyA proceeds via activation of cNOS directly related to exotoxin activity and not to secondary changes in shear stress, and (3) that this vasodilator release mitigates the HlyA-induced pulmonary vasoconstriction. These findings may have important implications for therapeutic approaches using NOS inhibitors in sepsis.
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PMID:Nitric oxide biosynthesis in an exotoxin-induced septic lung model: role of cNOS and impact on pulmonary hemodynamics. 947 64

Systemic bacterial lipopolysaccharides (LPS) induce inflammatory responses characteristic of sepsis. Instillation of LPS into rat bladder produces a localized inflammatory response similar to that seen in urinary tract infections (UTIs). Four hours after intravesical instillation of LPS, neutrophils infiltrate into the bladder, and mRNA for inducible nitric oxide synthase (iNOS) and the cytokines, interleukin (IL)-6 and IL-10, is detected in rat bladder but not in the kidney. Induction of iNOS protein is inferred because urinary nitrate and cGMP levels are increased 4 hr after LPS intravesical instillation and remain elevated for at least 24 hr. When LPS is injected intraperitoneally, iNOS and IL-6 mRNA are induced both in the bladder and in the kidney. These data are consistent with the effects of intravesical instillation of LPS remaining localized, iNOS activity increases in both particulate and soluble bladder fractions when measured 4 hr after intravesical instillation of LPS. The magnitude of these increases in iNOS activity in the bladder is not as great as when LPS is injected intraperitoneally. Intravesical instillation of LPS induces no increase in lung or kidney NOS activity. The localized inflammatory response produced by intravesical instillation of LPS demonstrates the importance of LPS as a mediator of the host response in UTIs and supports the use of urinary measurements of nitrate and cGMP in humans as indicative of the localized induction of iNOS in UTIs.
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PMID:Bladder instillation and intraperitoneal injection of Escherichia coli lipopolysaccharide up-regulate cytokines and iNOS in rat urinary bladder. 949 84

Nitric oxide (NO) is one of many vasoactive substances released, from a variety of cells, under conditions of endotoxaemia and sepsis. Under physiological conditions it is produced by two constitutive calcium-dependent enzymes (nitric oxide synthase; NOS) in neurones (nNOS) and endothelial cells (eNOS) and has functions ranging from neurotransmission and vasodilatation to inhibition of platelet adhesion and aggregation. Following bacterial infection, especially with Gram-negative organisms, its formation from L-arginine is enhanced due to the cytokine-mediated induction of a NOS enzyme (iNOS) in cells (e.g. cardiac myocytes, vascular smooth muscle) that do not normally have the ability to synthesize NO. The result of this excessive NO production is enhanced bacterial lysis by activated macrophages, vasoplegia and myocardial depression. These cardiovascular effects can be alleviated by inhibitors of the L-arginine NO pathway, which results in elevated perfusion pressure, restored responsiveness to sympathetic nerve stimulation and to exogenous catecholamines, and to enhanced (endothelin-dependent) myocardial contractility. In patients in shock this approach also leads to detrimental effects (increased systemic vascular resistance, elevated pulmonary artery pressure, reduced cardiac output and oxygen delivery, increased platelet accumulation) and survival is not improved. Because some of these detrimental effects are due to inhibition of eNOS, attempts have been made to examine the effects of substances with a higher selectivity for the induced form of the enzyme. In experimental animals, one of these (L-canavanine) protects endothelial cells from damage, increases survival time and restores vascular responsiveness without increasing blood pressure or peripheral vascular resistance. However, whether even this approach will be of benefit to patients with sepsis remains in doubt since studies in iNOS knock-out mice do not support the concept that eliminating this particular source of NO improves ultimate survival.
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PMID:Nitric oxide in sepsis and endotoxaemia. 951 Oct 84

The vasodilator nitric oxide (NO) is involved in the regulation of systemic blood pressure and local organ blood flow. Inhibitors of the constitutively expressed nitric oxide synthase in endothelial cells (eNOS), e.g., Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), aggravated liver injury in a variety of models. On the other hand, inhibitors of the inducible NOS (iNOS), e.g., 2-aminoethyl-isothiourea (AET), were found to be beneficial during endotoxemia. The aim of this investigation was to study the effect of AET compared with L-NAME on liver microvascular blood flow and injury in more complex models with multiple insults, i.e., ischemia (20 min)-reperfusion (8 h) in combination with .5 mg/kg endotoxin (IRE). Male Fisher rats were treated with 10 mg/kg AET or L-NAME and subjected to IRE. At 8 h, liver injury (plasma ALT: 1320+/-164 U/L) was significantly increased in AET-treated (5,018+/-1,379 U/L) and L-NAME-treated groups (2,429+/-228 U/L). Each inhibitor attenuated microvascular blood flow (assessed by laser Doppler flowmetry) to a similar degree. In striking contrast, AET completely reversed the endotoxin-induced impairment of the microvascular blood flow and significantly protected against an endotoxin-induced liver injury (plasma ALT: 3,007+/-268 U/L (ET); 460+/-39 U/L (ET+AET)). Infusion of endothelin-1 reduced microvascular blood flow by 50-60% and caused liver injury. Our data demonstrated that an inhibitor of eNOS (L-NAME) has a consistent detrimental effect on liver injury during ischemia-reperfusion and endotoxemia mainly because it can cause additional ischemia by reducing the microvascular blood flow. However, selective inhibitors of iNOS (AET) can impair hepatic blood flow and aggravate the injury or improve blood flow and attenuate organ injury depending on the experimental model. These results suggest that iNOS inhibitors may not be universally beneficial and should be tested in a variety of experimental models of sepsis/endotoxemia before used in clinical settings.
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PMID:Differential effect of 2-aminoethyl-isothiourea, an inhibitor of the inducible nitric oxide synthase, on microvascular blood flow and organ injury in models of hepatic ischemia-reperfusion and endotoxemia. 968 86


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