UMLS:C0243026 - FACTA Search

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)

The role of nitric oxide during neonatal sepsis is complex. We tested the hypothesis that nonselective inhibition of nitric oxide synthase with N(omega) -nitro-L-arginine methyl ester (L-NAME) is detrimental during the early phase of experimental sepsis in the newborn piglet. Newborn piglets were divided into four groups: 6 in the control group, 6 in the L-NAME control group, 12 in the sepsis group (SG), and 11 in the sepsis with L-NAME group (NS). Sepsis was induced by intravenous injection of 10(8) colony forming units of Escherichia coli. L-NAME 10 mg/kg was given intravenously 60 min before the induction of sepsis. The survival rate of piglets after 4 hr was 27% in NS, while it was 100% in other groups. Systemic hypotension, observed in both SG and NS, were more profound in NS. Leukopenia was observed in both SG and NS. Thrombocytopenia, prolongation of prothrombin time and activated partial thromboplastin time, and increase in thrombin-antithrombin complexes were observed only in NS. Decreased PaO2 /FiO2 ratio, arterial pH and base excess, and increased blood lactate levels observed in both SG and NS, but were more profound in NS. These findings suggest that nonselective inhibition of nitric oxide synthase with L-NAME is detrimental during the early phase of experimental neonatal sepsis.
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PMID:Detrimental effects of N(omega) nitro-L-arginine methyl ester (L-NAME)in experimental Escherichia coli sepsis in the newborn piglet. 1455 13

Much effort has been made in recent years to clarify metabolic and renal function changes in sepsis. A number of studies performed in different models of sepsis have been described. One such model that is frequently used is cecal ligation and puncture (CLP) in rats. This model resembles human sepsis in several important aspects, such as an early phase of hyperdynamic, hypermetabolic sepsis followed by a late hypodynamic, hypometabolic phase. The present study evaluated the blood pressure (n = 5) and renal function changes during development of CLP renal failure and to determine the effects of NOS inhibition (L-NAME) and 0.15 M NaCl administration on tail blood pressure and renal function in randomly assigned five groups (n = 10 each): (1) Sham-operated, (2) Sham-operated L-NAME-treated, (3) CLP rats, (4) CLP L-NAME-treated, and (5) CLP 0.15 M NaCl-treated rats. The basal tail blood pressure was not significantly different among the four groups. One week later, arterial pressure was significantly increased in sham-operated L-NAME-treated rats (159 +/- 12 mmHg) compare with the other groups (118 +/- 9.0 mmHg in nontreated rats, p < 0.05). Blood pressure shows a slightly and not significant decrease up to 12h in L-NAME and 0.15 M NaCl treated rats, which in turn was followed by a significant reduced arterial pressure 18h after CLP in both groups (L-NAME: 96.0 +/- 3.6 mmHg, p < 0.05) and NaCl: 82.3 +/- 2.4 mmHg, p < 0.05) compared to sham-operated groups. The glomerular filtration rate estimated by CCr decreases significantly in the CLP untreated group (p < 0.001) and did not significantly differ from the sham-operated and L-NAME-treated groups (p = 0.4) during the studies of renal tubule sodium handling. On the other hand, subcutaneous 0.15 M NaCl administration prevented CCr decreases in CLP rats (p = 0.25). CLP increased the FENa in the sham-operated from: 857.2 +/- 85.1 delta%min(-1) to CLP: 1197.8 +/- 119.0 delta%min(-1). The high FENa to CLP was blunted and significantly reduced by previous systemic treatment of animals with L-NAME from sham-operated+L-NAME: 1368.0 +/- 72.0 delta%min(-1) to CLP+L-NAME: 1148.0 +/- 60.4 delta%min(-1) (p < 0.01). The enhanced FENa in the CLP group were accompanied by a significant increase in proximal sodium reabsorption rejection. The salient findings of the present study suggest that a decrease in the blood pressure and creatinine clearance caused by CLP may benefit from L-NAM and fluid resuscitation during initial bacteremia (first 12 h) by promoting an additional increase of tubule sodium reabsorption in the post-proximal segments of nephrons, but these therapies could not prevent acute renal failure after established endotoxemia.
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PMID:Effect of nitric oxide synthase inhibition and saline administration on blood pressure and renal sodium handling during experimental sepsis in rats. 1466 49

Although sepsis-induced release of nitric oxide (NO) is known to have an antithrombotic effect, it is unknown if NO exerts this same effect under physiological conditions. We have there-fore attempted to determine whether or not NO protects against thrombus formation in normal Wistar rats injected with various amounts (0.8, 4.0, 20.0 and 100 mg/kg/4 hr) of L-NAME (N (omega)-nitro-l-arginine methyl ester), an NO synthase inhibitor, via the tail vein. Plasma levels of D-dimer fragments of fibrin were significantly increased in rats receiving L-NAME (0.21+/-0.04, 0.22+/-0.05, 0.26+/-0.07, 0.59+/-0.17 micro g/mL, means+/-SE; p<0.05, 0.05, 0.05, 0.01: L-NAME 0.8, 4, 20, 100, respectively, compared with control levels: <0.06 micro g/mL), and thrombin-anti-thrombin complex (TAT) levels were significantly increased in rats receiving 20mg/kg/4 hr or greater doses of L-NAME (4.5+/-1.1, 4.7+/-1.4, 18.7+/-4.9, 42.5+/-4.0 ng/mL, NS, NS, p<0.05, 0.01, respectively, compared with control levels: 3.8+/-1.2 ng/mL). Glomerular fibrin deposition was increased in a dose-dependent manner in rats receiving L-NAME (6.8+/-1.5, 13.9+/-1.6, 32.4+/-2.6, 49.2+/-5.2%, p<0.05, 0.05, 0.01, 0.01, respectively, com-pared with control levels: 0.0+/-0.0%). Renal dysfunction and hepatic dysfunction were observed in rats receiving 20mg/kg/4 hr or greater, or 100mg/kg/4 hr, doses of L-NAME, respectively. Mean blood pressure was also elevated in rats receiving L-NAME in a dose-dependent manner. These findings suggest that NO, in addition to regulating blood pressure, is involved in prevention of thrombus formation under physiological circumstances.
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PMID:Antithrombotic role of nitric oxide in rats under physiological conditions. 1469 70

Sepsis has been associated with a lipopolysaccharide (LPS) induced bacterial infection and causes biochemical, hemodynamic and physiological alterations in a system. Erythrocyte deformability is very critical for a microcirculatory system to function effectively. Hence, we were interested in examining the effects of a potent antioxidant, melatonin (Mel), on lipid peroxidation and deformability of eythrocytes in LPS-induced experimental sepsis. Male Swiss Albino rats were used in 6 groups, each group comprising of 10 animals. The first group was the control, and the other groups were administered LPS (10 mg/kg, i.p.), Mel (10 mg/kg, i.p.), LPS + L-NAME (5 mM, i.p.), Mel + LPS and Mel + LPS + L-NAME, respectively. Deformability of the RBCs decreased significantly (p < 0.05) in the LPS group in comparison to all other groups. This reduction was prevented with both L-NAME and Mel, but was not as significant as when administering L-NAME or Mel alone. This result was adversely seen in nitric oxide levels, i.e. RBCD was reduced when the NO levels were higher. Therefore in the Mel group the NO levels were reduced while the RBCD enhanced. In addition to these, as an index of lipid peroxidation, the Malondialdehyde levels were elevated in LPS groups whereas the deformability was reduced. This lipid peroxidation was suppressed by Mel and/or L-NAME significantly, where the RBCD was enhanced. These results show that, Melatonin can elevate the RBCD in experimental sepsis due to its nitric oxide scavenging activity and antioxidant effect as revealed by lipid peroxidation.
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PMID:Lipid peroxidation and deformability of red blood cells in experimental sepsis in rats: The protective effects of melatonin. 1500 32

The methanol extract of Anacardium occidentale stem bark was evaluated for activities against the lipopolysaccharide (LPS)-induced septic shock, as well as LPS-induced microvascular permeability in mice. Pre-treatment with Anacardium occidentale extract (25-200 mg/kg) caused a dose-dependent and significant (p < 0.05) reduction in the elevated levels of alanine and aspartate aminotransferases in the sera of D-galactosamine-primed mice injected with LPS. The highest dose of the extract studied (200 mg/kg) produced a 100% protection against death from sepsis. Pentoxifylline (100 mg/kg) and L-NAME (5 mg/kg) offered 100% protection against LPS-induced septic shock, and produced marked reduction in elevated levels of transferases. A dose-related inhibition of LPS-induced microvascular permability in mice was also produced by pentoxifylline, L-NAME and the extract.
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PMID:Effects of Anacardium occidentale stem bark extract on in vivo inflammatory models. 1550 26

We investigated whether blockade of the smooth muscle cell (SMC) inducible nitric oxide synthase (iNOS)-soluble guanylyl cyclase (sGC) vasodilator pathway would restore the fall in vasoreactivity produced by sepsis following cecal ligation and perforation (CLP) in rats. Contraction of adjacent aortic rings paired for the presence or absence of endothelial cells (EC) was recorded following high [K(+)](e) (40 mm) or norepinephrine (NE, 10(-8) to 10(-5) m) in the presence of the nitric oxide synthase inhibitor (NOS), N(G)-nitro-l-arginine methyl ester (l-NAME, 0.3 mm) or the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 5 mum). In EC-denuded rings, sepsis halved SMC contraction induced by high [K(+)](e) or NE; neither l-NAME nor ODQ produced an increase in NE E(max) or high [K(+)](e)-evoked contraction. In conclusion, SMC contractility is globally reduced in CLP; this reduction does not appear to be explained by induction of SMC NOS in this CLP model.
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PMID:Decreased aortic smooth muscle contraction in a rat model of multibacterial sepsis. 1554 39

Septic shock is characterized by hypotension and decreased systemic vascular resistance and impaired vascular reactivity. Renal vasoconstriction markedly contrasts with sepsis-induced generalized systemic vasodilation, which is strongly dependent on nitric oxide. Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice. LPS-injected mice displayed lower MAP, RBF, and GFR than controls (P < 0.001). Despite a lower MAP, basal renal vascular resistance (RVR) was higher during endotoxemia (P < 0.02). Angiotensin II infusion produced a weaker MAP response in septic mice (24 versus 37%; P < 0.005), suggesting impaired vasoconstriction and hyporeactivity. A similar MAP increase was observed between groups during norepinephrine (NE) infusion. The MAP increase to nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) was much greater in LPS-treated mice (41 versus 15%, P = 0.01), indicating a strong influence of nitric oxide in sepsis. In contrast, the RBF and RVR responses to angiotensin II, NE, or L-NAME were similar in both groups. Moreover, vasopressin produced greater changes in MAP, RBF, and RVR in septic mice than in controls. Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection. The in vivo results demonstrate that the renal microvasculature displays a normal or enhanced reactivity to constrictor agents as compared with nonrenal circulatory beds. Such responsiveness may contribute to reduced RBF and GFR during endotoxemia.
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PMID:Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock. 1556 66

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.
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PMID:Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice. 1577 87

We have previously shown that repeated administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to mice treated with beta-glucan, a biological response modifier, induced severe lethality. The lethality would be strongly related to the translocation of enterobacterial flora to the peritoneal cavity and disruption of the cytokine network. Reports suggest that nitric oxide (NO) can have an effective or detrimental role in septic shock. In the present study, we examined the effect of NO, an inflammatory mediator, on beta-glucan/indomethacin (IND)- induced septic shock by inhibiting its synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NO synthase (NOS) inhibitor. Nitrite concentration was used as an indicator of NO generation. Mortality in beta-glucan/IND-treated mice was increased by administering L-NAME. Numbers of bacteria in various organs of mice treated with beta-glucan/IND rose significantly within a couple of days of the administration of L-NAME. Additionally, TNF-alpha, IL-1beta, and IL-6 concentrations were enhanced in peritoneal exuded cells in culture. These results suggest a significant loss of the bactericidal activity of macrophages on the administration of a NOS inhibitor which enhanced the rate of enterobacterial invasion to the peritoneal cavity, resulting in systemic inflammatory response syndrome. The production of NO, therefore, provides a protective effect in beta-glucan/IND-induced sepsis.
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PMID:Effect of nitric oxide on beta-glucan/indomethacin-induced septic shock. 1599 9

Nitric oxide (NO) plays an important role in the pathophysiology of sepsis and septic shock but the mechanism is not well understood. The aim of this study was to investigate the role of NO in the cytochrome P450 (CYP) isozyme activity and the expression of its gene during polymicrobial sepsis. The rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Aminoguanidine (AG, 100 mg/kg body weight) or N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg body weight) was injected intraperitoneally at 0, 3, 6, 10, and 20 h after CLP. The plasma nitrite/nitrate concentration increased 24 h after CLP, and this increase was almost completely abolished by AG and L-NAME. Sepsis increased the serum aminotransferase and lipid peroxidation levels, which were attenuated by AG but augmented by L-NAME. The hepatic concentration of the reduced gluthathione decreased in the CLP rats, which was inhibited by AG but augmented by L-NAME. The total CYP content decreased after CLP, which was restored by AG and L-NAME. The CYP1A1, 1A2, and 2E1 activities, along with their protein levels, decreased 24 h after CLP but these decreases were reversed by AG and L-NAME. The CYP1A1, 1A2, 2B1, and 2E1 mRNA expression levels decreased 24 h after CLP, and L-NAME inhibited this decrease. NO plays a key role in the sepsis-mediated decrease in CYP via the interplay of two different mechanisms: NO-dependent suppression of protein via the enhanced inducible NO synthase, and NO-dependent transcriptional suppression via endothelial NO synthase.
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PMID:Role of nitric oxide in the inhibition of liver cytochrome P450 during sepsis. 1688 34

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