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)

We evaluated regional blood flows in a hyperdynamic sepsis model and the reversal of increased flows by blockade of nitric oxide (NO) synthase. Seven awake sheep were continuously infused with Escherichia coli endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1] for 48 h. The NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg) was injected after 24 h. Blood flows to systemic organs were determined with the radioactive microsphere technique. LPS induced elevation of cardiac index by 36% (P < 0.05) and a fall in systemic vascular resistance index by 37% (P < 0.05) at 0 h [time of L-NAME administration, 24 h after infusion of LPS had begun] L-NAME administration normalized cardiac index [6.1 +/- 0.5 at 4 h posttreatment, 6.1 +/- 0.5 l.min-1.m-2 at -24 h (baseline)] and systemic vascular resistance index (1,333 +/- 105 at 4 h posttreatment, 1,280 +/- 163 dyn.s.cm-5.m2 at -24 h) and reduced all regional blood flows to near-baseline levels for the remainder of the study period (24 h). O2 consumption was unaffected by treatment.
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PMID:Increased organ blood flow in chronic endotoxemia is reversed by nitric oxide synthase inhibition. 752 59

To evaluate the role of nitric oxide (NO) in the attenuated vascular reactivity observed in sepsis, we utilized the specific NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Male Sprague-Dawley rats (n = 16) were randomized to either sepsis induced by cecal ligation and perforation (CLP; n = 8) or sham procedure (Sham; n = 8). Vascular reactivity was assessed by measuring the pulmonary pressor response to hypoxia (HPV) (fractional inspired O2 concentration = 0.08) and the pulmonary and systemic pressor response to an intravenous infusion of phenylephrine (1.5-6.0 micrograms.kg-1.min-1). Twenty-four hours after surgery, CLP animals had significantly attenuated HPV compared with Sham animals. In response to hypoxia the change in total pulmonary vascular resistance during hypoxia was 0.008 +/- 0.004 and 0.021 +/- 0.006 mmHg.min-ml-1 in CLP and Sham animals, respectively (P < 0.05). The pulmonary and systemic blood pressure response to phenylephrine was also attenuated in CLP compared with Sham animals. After L-NAME infusion (15 mg/kg), there was a significant augmentation of the HPV response in Sham animals. In contrast, the HPV response in CLP animals was unchanged after L-NAME. The attenuated pressor response to phenylephrine in neither the pulmonary nor the systemic circulation was changed after the administration of L-NAME. These data suggest that in rats, excess NO is not an important mediator of the attenuated vascular reactivity observed in sepsis.
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PMID:Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis. 752 65

Treatment of rats with bacterial endotoxin resulted in a significant induction of hepatic nitric oxide synthase within 3 hours. The response was maximal at 12 hours and was maintained over 18 hours. The induction of nitric oxide synthase correlated well with the increase in plasma nitrate plus nitrite concentrations and also with the inhibition of glucose synthesis in subsequently isolated hepatocytes. The decline in the rate of gluconeogenesis also correlated with an inhibition of flux through phosphoenolpyruvate carboxykinase but not with alterations in flux through either pyruvate kinase or 6-phosphofructo-1-kinase, suggesting that a nitric oxide-induced inhibition of phosphoenolpyruvate carboxykinase may underlie the decreased glucose production in sepsis.
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PMID:Endotoxin causes reciprocal changes in hepatic nitric oxide synthesis, gluconeogenesis, and flux through phosphoenolpyruvate carboxykinase. 752 53

Nitric oxide (NO) has been reported to have a protective function in attenuating hepatic injury during endotoxemia or sepsis. As a result, the role of NO in attenuating the hepatic microcirculatory alterations associated with endotoxemia was investigated in mice by in vivo microscopy. The livers were examined 2 h after intravenous injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS) alone or in combination with inhibitors of the synthesis of NO, NG-nitro-L-arginine methyl ester or NG-monomethyl-L-arginine. In the animals treated with the combination of NO synthase inhibitors and LPS, leukocyte adherence was increased threefold above that in animals treated with LPS alone. This was accompanied by a 33% reduction in sinusoidal blood flow. Simultaneous administration of L-arginine, but not D-arginine, eliminated these microcirculatory disturbances. The results demonstrate that inhibition of LPS-stimulated NO production results in an early hepatic microvascular inflammatory response to a dose of endotoxin which by itself is scarcely inflammatory. This suggests that NO plays a significant role in stabilizing the hepatic microcirculation during endotoxemia, thereby helping to protect the liver from ischemia and leukocyte-induced oxidative injury.
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PMID:Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia. 752 79

Tumor necrosis factor-alpha (TNF-alpha) inhibits release of nitric oxide (NO) in vitro by stimulating the degradation of constitutive NO synthase (cNOS III) mRNA. However, TNF-alpha is believed to be the cytokine mediator of the hypotension and upregulation of inducible NO synthase (iNOS II) produced by gram-negative bacterial endotoxin (LPS). Some in vivo effects of TNF-alpha are opposite to those which occur in vitro. This study tested the hypothesis that in vivo administration of exogenous TNF-alpha and endogenously released TNF-alpha induce iNOS II activity and inhibit cNOS III activity, and thereby mediate the acute phase effects of LPS on blood pressure and the NO system in the rat. We show that LPS produces acute phase hypotension in ketamine anesthetized rats. The hypotension was associated with elevation of biologically active TNF-alpha in plasma, increased production of RNI (NO2- and NO3- anion) in rat neutrophils (PMN) and suppression of RNI production by A23187 (1 microM) stimulated thoracic aorta (RTA) ex vivo. TNA-alpha (10(6) U/ml, iv) did not produce acute phase hypotension but initially raised arterial blood pressure and heart rate (HR), did not increase RNI production by PMN, and inhibited RNI production by A23187 stimulated RTA ex vivo. Pretreatment of rats with the immunex monomeric soluble P75 receptor binding protein for TNF-alpha (TNFsr, 0.5 mg/kg, iv) 15 min prior to LPS administration decreased circulating TNF-alpha from 92,137 +/- 12,456 U/ml to undetectable levels as determined by the L929 bioassay. However, LPS-induced increases in RNI in PMN was enhanced and LPS-induced decreases in RNI production by RTA was inhibited by TNFsr. Thus, in vivo administration of TNF-alpha does not mimic the hemodynamic and NO-inducing effects of LPS. However, TNF-alpha mediates in part LPS-induced inhibition of RNI production by RTA. Thus, endogenous TNF-alpha is not required for LPS-induced acute phase hypotension or iNOS II activity. The importance of TNF-alpha in sepsis resides in systems other than iNOSII and blood pressure.
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PMID:In vivo administration of endotoxin and tumor necrosis factor-alpha produce different effects on constitutive and inducible nitric oxide synthase activity in rat neutrophils and aorta ex vivo. 753 Mar 65

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFN gamma and LPS and cardiac myocytes treated with TNF-alpha, IL-1 beta, and IFN gamma. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity. TGF-beta reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-beta or NO synthase antagonists to mute these lethal effects. These findings may help explain the cardiac response to sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of diverse etiologies.
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PMID:The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. 753 89

The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
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PMID:Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. 753 50

Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Arginine analogs, such as N omega-nitro-L-arginine methyl ester (L-NAME), are competitive antagonists of NO synthase and inhibit NO synthesis. Group B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lung vascular injury, and reduced cardiac output in both human newborns and neonatal piglets. Lung vascular injury associated with prolonged GBS infusion in piglets may attenuate NO production and thus promote severe pulmonary hypertension. We studied the effect of the NOS inhibitor, L-NAME and the precursor of NO, L-arginine, on pulmonary and systemic hemodynamics during late-phase GBS sepsis in the piglet model. Neonatal piglets were anesthetized, ventilated with room air, and randomized to receive a continuous infusion of saline (n = 5) or GBS (n = 5) for 4 h. After 3 h of infusion, both groups received a bolus of L-NAME (3 mg/kg). Hemodynamic and gas exchange indices were measured at baseline, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treatment. L-NAME treatment caused 1) significant increases in mean pulmonary arterial pressure, pulmonary vascular resistance, mean systemic arterial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for the two groups; 3) greater reduction in cardiac output and SV in the GBS compared with the control group; and 4) no significant alterations in arterial partial pressure of oxygen or the difference between alveolar and arterial partial pressure of oxygen for either group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of nitric oxide synthase inhibition during group B streptococcal sepsis in neonatal piglets. 753 3

Previous studies have yielded contradictory results about interrelations between endotoxin and endothelium-derived relaxing factor (EDRF). We tested the hypothesis that in vivo endotoxemia inhibits basal and/or agonist-mediated release of EDRF and nitric oxide (NO). EDRF bioactivity, NO production, and NO synthase (NOS) activity were measured in aorta from guinea pigs following 16 h of Escherichia coli endotoxemia (4 mg/kg endotoxin i.p.). Endothelium-dependent relaxation of aortic rings was studied under standard isometric conditions. Endotoxemia resulted in an 89% reduction in basal EDRF bioactivity and a 62% reduction in basal NO production in perfused aorta. EDRF bioactivity and NO production in response to the receptor-dependent agonists acetylcholine and ADP were significantly reduced in perfused aorta from endotoxemic animals. In contrast, endotoxin did not significantly inhibit EDRF bioactivity and NO production by the receptor-independent agonist A-23187. Aortic rings from endotoxemic animals likewise showed decreased vasodilator responses to acetylcholine and ADP but not to A-23187. Inducible (Ca2+ independent) NOS activity was not significantly different in control and endotoxin-treated animals. These findings indicate that prolonged endotoxemia resulted in diminution of release of EDRF, consistent with the interpretation that endotoxemia decreases basal and agonist-stimulated EDRF bioactivity and NO production with loss of endothelium-dependent vasodilator reserves during gram-negative sepsis.
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PMID:Release of EDRF and NO in ex vivo perfused aorta: inhibition by in vivo E. coli endotoxemia. 753 9

Sepsis, as a general inflammatory process, affects the whole organism, mainly because of the intense vasodilation and reduced perfusion pressures associated with it. The high mortality rates seen with sepsis are correlated with a reduction in mean arterial pressure. Therefore, the restoration of adequate arterial pressures is imperative. Nitric oxide (NO.) is at least partly responsible for the vasodilation. Inhibition of nitric oxide synthase (NOS) is, therefore, a logical approach for the treatment of sepsis. As with any other vasoconstrictive drug, NOS inhibitors are clinically indicated only in hyperdynamic sepsis. In animal models, their administration leads to an immediate restoration of blood pressure, accompanied by improved myocardial, pulmonary, and renal function. An increase in oxygen extraction prevents oxygen consumption from decreasing, despite a marked reduction in cardiac output to normal concentrations. In sepsis, virtually all regional blood flows are increased. In our experiments, no organ systems showed a reduction below preseptic baseline values when NOS inhibitors were administered. Furthermore, NOS inhibition did not cause an increase in lactate concentrations, indicating adequate nutritive organ blood flow. Consequently, NOS inhibitors seem to be beneficial and safe when administered under the right circumstances and in a controlled fashion.
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PMID:Use of nitric oxide synthase inhibitors in animal models of sepsis. 753 47


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