Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NG-monomethyl-L-arginine (L-NMMA) is an inhibitor of the enzyme nitric-oxide-synthetase. Nitric oxide (NO), produced by endothelial and vascular cells regulates physiological vascular tone, blood pressure and tissue perfusion via guanylate-cyclase and cGMP. In an advanced stage of therapy resistant septic shock in response to inflammatory mediators, NO is overproduced. This leads to vasodilatation, a fall in systemic blood pressure and an attenuated vasoconstriction-response to sympathetic-stimuli. Two episodes of severe and prolonged hypotension in a patient with sepsis were successfully treated twice by bolus therapy of L-NMMA within 4 weeks. On both occasions blood pressure was reversed to normal and the continuous use of high doses of catecholamines were stopped. In contrast to the immediate response of blood pressure, heart rate and central venous pressure remained stable. Cardiac output dropped to 68% and PaO2 increased. These findings indicate that NO-synthetase-inhibitors may be of value in the therapy of human septic shock.
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PMID:A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase. 769 53

Impaired vascular contractility is a hallmark of sepsis and endotoxemia. The purpose of the present investigation was to determine mechanisms responsible for the abnormal contractility in sepsis using the rat cecal ligation and perforation (CLP) model. 24 h after CLP or sham surgery, rats were anesthetized with halothane and a segment of the thoracic aorta removed. Aortic rings measuring 1.6-2.0 mm in length were mounted in a water bath and stretched to optimal diameter. Aortic rings from control rats demonstrated a 57% increase in maximum contraction to phenylephrine and a 68% increase to KCl compared to aortic rings from rats with sepsis (p < .01). There was no difference in the concentrations of phenylephrine or KCl which elicited a half-maximal contraction (EC50) in control versus septic aortic rings. Removal of the endothelium increased the sensitivity of aortas to both phenylephrine and KCl in septic and control aortic rings but did not reverse the defects in contraction in sepsis. Treatment of the aortic rings with N gamma-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased contraction in aortic rings from both septic and control rats but also failed to correct the contractile defect in sepsis. The frequency and amplitude of the oscillations in wall tension which occurred with phenylephrine were slower, i.e., .07 +/- .10 vs. .17 +/- .02 Hz, for septic and control rings, respectively (p < .05), and had a greater amplitude .65 +/- .01 vs. .41 +/- .09 mN/mm, for septic and control rings, respectively (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sepsis decreases phenylephrine- and KCl-induced aortic ring contraction and decreases the frequency of oscillations in active wall tension. 772 82

The gastrointestinal tract is a major immunologic organ that must be maximally supported during critical illness. Gastrointestinal tissues require direct contact with nutrients to support their own rapid cellular turnover rate and carry out the multitude of metabolic and immunologic functions needed for successful adaptation to stress. Disruption in the ecologic equilibrium of the gastrointestinal tract often occurs during critical illness and the therapies provided. Problems encountered include stress ulcers, intestinal ischemia, bacterial overgrowth, aspiration pneumonia, bacterial translocation, sepsis, and the systemic inflammatory response syndrome. Early enteral nutrition has been shown to be a viable, economic, and physiologically beneficial way to support the gastrointestinal tract during critical illness. The fortification of enteral formulas with glutamine, arginine, or fiber is being studied to determine each one's unique role in the gut and immunologic changes that occur with severe stress.
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PMID:The role of the gut in critical illness. 774 36

The effects of endotoxin on the activities of the major Na(+)-independent amino acid transporters in rat liver (Systems n, asc, L, bo,+, and y+) were studied using using hepatic plasma membrane vesicles (HPMVs). Rats were treated with a single dose of Escherichia coli endotoxin (E. coli lipopolysaccharide 0127:B8 (LPS), 7.5, 15, or 30 mg/kg BW) and HPMVs were prepared by Percoll density gradient centrifugation at various timepoints after LPS administration. Vesicle purity and integrity was established by assay of enzyme markers and identical equilibrium uptakes. The activities of the Na(+)-independent amino acid transport systems y+ and bo,+ (arginine), asc (alanine and cysteine), L (leucine), and n (glutamine) were evaluated by measuring the uptake of radiolabeled amino acids using a rapid mixing/filtration technique. Amino acid uptake by HPMVs consisted of saturable and nonsaturable components. Prior treatment with endotoxin did not alter the activities of Systems n, asc, or L but resulted in a time- and dose-dependent stimulation of saturable arginine transport. Arginine transport increased within 2 h of LPS administration and exhibited a return towards basal levels by 24 h. Nonsaturable uptake (diffusion) in HPMVs was unaltered by LPS treatment. Kinetic analysis of arginine transport demonstrated the presence of both a high affinity and a low affinity carrier. Treatment with LPS resulted in a 73% increase in the Vmax of the high affinity carrier (System y+) and a 25% increase in the Vmax of the low affinity transporter (System bo,+). The data indicate selective stimulation of Na(+)-independent arginine transport in the liver during endotoxemia which may serve to support important arginine-dependent pathways during sepsis.
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PMID:Hepatic Na(+)-independent amino acid transport in endotoxemic rats: evidence for selective stimulation of arginine transport. 774 45

The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.
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PMID:Effect of modifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model. 774 50

Nephrotoxicity caused by cyclosporin A (CSA) is the result of vasoconstriction of the renal microcirculation. The endothelium-derived relaxing factor nitric oxide (NO) regulates microvascular blood flow in various tissues, and mediates the microcirculatory response during hypertension and sepsis. This study investigated the role of NO in CSA-induced renal vasoconstriction. Hydronephrotic kidneys in rats were suspended in an environmentally controlled tissue bath, and interlobular, afferent and efferent arteriolar diameters and blood flow were measured by in vivo videomicroscopy. CSA was administered alone, with the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) or with exogenous NOS substrate L-arginine. CSA significantly constricted the whole of the renal microvasculature whereas L-NAME alone preferentially constricted the preglomerular vessels. L-Arginine reversed the vasoconstriction induced by CSA whereas L-NAME had no further effect. Preglomerular basal vascular tone is dependent on continuous production of NO and alterations in the L-arginine-NO pathway contribute to CSA-induced renal vasoconstriction.
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PMID:An experimental study of altered nitric oxide metabolism as a mechanism of cyclosporin-induced renal vasoconstriction. 774 87

Group B streptococci (GBS) are an important cause of sepsis and shock in the new-born. We have previously reported that GBS induce the production of tumour necrosis factor-alpha (TNF-alpha) by human monocytes and culture-derived macrophages. We have also shown that fibronectin (FN) promotes interaction between GBS and human phagocytes. In the present study, we investigated the effect of FN and GBS on the production of TNF-alpha by adult and neonatal culture-derived macrophages. We report that soluble FN alone was a strong stimulus for the production of TNF-alpha by culture-derived macrophages (FN 50 micrograms/ml = 623.33 +/- 47 pg/ml TNF, versus media alone 3 +/- 1.5 pg/ml; P < 0.0001). While GBS also induce the production of TNF-alpha by macrophages, the addition of FN to GBS had more than an additive effect on TNF-alpha levels. FN-mediated TNF-alpha production by macrophages was inhibited by both soluble arginine-glycine-aspartic acid (RGD) peptide (71%; P < 0.0001) and anti-beta 3-integrin monoclonal antibody 7G2 (54%; P < 0.0001). Neonatal culture-derived macrophages produced significantly more TNF-alpha in response to GBS (356.4 pg/ml +/- 27.7) than adult cells did (222.0 pg/ml +/- 21.0; P = 0.037), and dramatically more in response to FN alone (neonatal 1931.0 pg/ml +/- 23.0 versus adult 463.5 43.5 pg/ml; P < 0.0001). FN may contribute to the high levels of TNF-alpha production implicated in the pathophysiology of GBS sepsis and shock.
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PMID:Effects of fibronectin and group B streptococci on tumour necrosis factor-alpha production by human culture-derived macrophages. 775 Oct 28

In recent studies, production of interleukin-6 (IL-6) in cultured enterocytes was stimulated by lipolysaccharide (LPS). In other cell types, IL-6 production was inhibited by nitric oxide (NO). We tested the hypothesis that LPS-induced IL-6 production in the enterocyte is regulated, at least in part, by NO. IEC-6 cells (a rat intestinal epithelial cell line) were cultured for 3 days with different combinations of LPS (1-10 micrograms/ml), the NO synthase inhibitor N-omega-nitro-L-arginine (NNA, 3-300 microM), L-arginine (10 mM), the NO donor sodium nitroprusside (SNP, 0.5-1 microM), or medium alone as control. IL-6 levels in the culture medium were determined by the B9 murine hybridoma bioassay. Nitrite, a stable end product of NO metabolism, was measured by HPLC. PCR was performed to determine inducible NO synthase (iNOS) mRNA expression in the IEC-6 cells. Treatment of IEC-6 cells with LPS stimulated IL-6 production. LPS-induced IL-6 production was further increased by NNA in a dose-dependent fashion. This effect of NNA was abolished by the addition of L-arginine. SNP caused a dose-dependent decrease in IL-6 production. Nitrite production was increased in a dose-dependent fashion after LPS treatment. PCR revealed an increase in iNOS mRNA expression in IEC-6 cells after administration of 1 microgram/ml LPS. The results suggest that NO inhibits LPS-induced IL-6 production in the enterocyte. NO may be an important regulator of intestinal cytokine response during sepsis and endotoxemia.
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PMID:Nitric oxide inhibits LPS-induced IL-6 production in enterocytes. 779 30

Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man.
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PMID:Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia. 783 64

Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of enzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combination of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhibition of glucose output and to a 45.0 +/- 6.4% suppression of urea production. Inhibition of NO synthesis with NG-monomethyl-L-arginine was able to totally prevent these effects. High concentrations of L-arginine overcame the inhibition of urea production caused by endogenous NO synthesis. Exposure of HC to NO donors resulted in a concentration-dependent inhibition of glucose output, without having any effect on urea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contribute to the development of hepatic dysfunction in chronic sepsis.
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PMID:Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine. 784 Feb 3


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