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)

Nitric oxide has been determined to be a potential mediator of the haemodynamic changes associated with sepsis. The haemodynamic eects of nitric oxide can be partially antagonised by methylene blue, through inhibition of the enzyme, guanylate cyclase. The case report presented here demonstrates a beneficial haemodynamic eect of continuous infusion of methylene blue during sepsis. These findings could be extrapolated to other patients or prompt additional research.
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PMID:Continuous infusion of methylene blue for septic shock. 897 44

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in patients with the adult respiratory distress syndrome (ARDS). Approximately 30% of ARDS patients fail to respond to iNO. Because sepsis syndrome often accompanies a decreased response to iNO, we investigated NO responsiveness in isolated, perfused lungs from rats exposed to lipopolysaccharide (LPS). Eighteen hours after intraperitoneal injection of 0.5 mg/kg LPS, rat lungs were isolated, perfused, and preconstricted with U-46619. Ventilation with 0.4, 4, and 40 parts per million by volume NO vasodilated LPS-pretreated lungs 75, 47, and 42% less than control lungs (P < 0.01 value differs at each concentration). The diminished vasodilatory response to iNO was associated with decreased NO-stimulated guanosine 3',5'-cyclic monophosphate (cGMP) release into the perfusate. Soluble guanylate cyclase activity did not differ in lung extracts from LPS-pretreated and control rats. LPS increased pulmonary cGMP-phosphodiesterase (PDE) activity by 40%. The PDE-sensitive cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate vasodilated lungs from LPS-pretreated rats less than lungs from control rats. In contrast, the PDE-insensitive 8-para-chlorophenylthioguanosine 3',5'-cyclic monophosphate vasodilated lungs equally from both groups. After LPS challenge, the rat pulmonary vasculature becomes hyporesponsive to iNO. Hyporesponsiveness to iNO appears partly attributable to increased pulmonary cGMP-PDE activity.
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PMID:Hyporesponsiveness to inhaled nitric oxide in isolated, perfused lungs from endotoxin-challenged rats. 899 69

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.
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PMID:Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. 921 22

The hemodynamic effects of sepsis have been attributed in part to increased nitric oxide (NO) production and activation of guanylate cyclase, resulting in increased cGMP and relaxation of vascular smooth muscle. Heme oxygenase-1 (HO-1), a heat shock protein, has been shown to increase intracellular cGMP levels by formation of carbon monoxide (CO). We hypothesized that HO may be an important mediator of the hepatic response to infection. Male Swiss Webster mice underwent standard cecal ligation and puncture (CLP, 18 gauge 2X) or sham operation, and received either normal saline (NS) or Zn protoporphyrin IX (ZN PP IX), a competitive HO inhibitor (n = 6-8/group). Hepatic tissue samples were collected at 3, 6, 12, and 24 hr from separate mice. Serum was collected at 3 and 24 hr. A semiquantitative reverse transcriptase polymerase chain reaction method was used to measure HO-1 mRNA levels. Hepatic cGMP levels were measured by ELISA. Groups were repeated (n = 10/group) to assess mortality. Serum was collected at 3 and 24 hr to measure serum aspartate aminotransferase (AST) levels. HO-1 mRNA expression increased significantly by 3 hr after CLP and with HO inhibition alone (P < 0.05 vs sham + NS). HO-1 mRNA remained elevated through 24 hr. CLP animals with HO inhibition showed a significant reduction of hepatic cGMP following CLP compared with CLP + saline at 24 hr (P < 0.05). Mortality was significantly increased in the CLP + ZN PP group at 24 hr (P < 0.05 CLP NS vs CLP ZN PP). CLP caused a marked increase in AST activity, which was increased further with HO inhibition. HO-1 mRNA expression was induced by CLP. AST levels following CLP were markedly increased with HO inhibition. HO-1 function appeared to contribute to elevation of hepatic cGMP during peritonitis and may be an important hepatic adaptive response to infection.
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PMID:Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. 927 Dec 71

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

The mechanism underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide is still not completely understood. The present study was designed to determine the role of soluble guanylate cyclase in the relaxations to a nitric oxide/nucleophile complex, diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate). Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) were measured by radioimmunoassay technique. During contractions to uridine 5'-triphosphate (UTP), DEA-NONOate (10(-10) to 10(-5) M) caused concentration-dependent relaxations. Measurements of cyclic GMP levels in cerebral arterial wall demonstrated that DEA-NONOate is a potent stimulator of guanylate cyclase and subsequent formation of cyclic GMP. Increasing concentrations of a selective soluble guanylate cyclase inhibitor, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), caused concentration-dependent reduction of both cyclic GMP production and relaxations to DEA-NONOate. Interestingly, in the presence of the highest concentration (3 x 10(-6) M) of ODQ, production of cyclic GMP in response to 10(-6) M of DEA-NONOate was abolished, whereas the same concentration of DEA-NONOate caused almost complete relaxation, suggesting that mechanisms independent of cyclic GMP production may mediate relaxing effect of high concentration of a nitric oxide donor. A selective Ca2+-activated potassium channel blocker charybdotoxin (CTX) significantly reduced relaxations to DEA-NONOate resistant to ODQ, supporting the idea that in cerebral arteries nitric oxide may activate potassium channels independently of cyclic GMP. The results of our study suggest that under physiological conditions, guanylate cyclase is a key mediator of cerebral arterial relaxations to nitric oxide. However, under pathological conditions associated with induction of nitric oxide synthase and increased biosynthesis of nitric oxide (e.g., cerebral ischemia, inflammation, sepsis), mechanisms other than formation of cyclic GMP may be activated.
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PMID:The effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and charybdotoxin (CTX) on relaxations of isolated cerebral arteries to nitric oxide. 952 59

To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] to 70 [65-100] mmHg, median [25-75th percentiles]; P<0.05), systemic vascular resistance index (649 [479-1084] to 1066 [585-1356] dyne s-1 cm-5 m-2; P<0.05) and the left ventricular stroke work index (35 [27-47] to 38 [32-56] g m-1 m-2; P<0.05) from baseline to 60 min. The pulmonary vascular resistance index increased from 150 [83-207] to 186 [121-367] dyne s-1 cm-5 m-2 after 20 min (P<0.05). Mixed venous saturation decreased from 65 [56-76] to 63 [55-69]% (P<0.05) after 60 min. The PaO2/FiO2 ratio decreased from 168 [131-215] to 132 [109-156] mmHg (P<0.05) after 40 min. Arterial lactate concentration decreased from 5.1 +/- 2.9 to 4.5 +/- 2.1 mmol/l, mean +/- SD (P<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.
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PMID:Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue. 1058 32

To evaluate the effect of exogenous nitric oxide (NO) and endogenous NO on the production of prostacyclin (PGI(2)) by cultured human pulmonary artery smooth muscle cells (HPASMC) treated with lipopolysaccharide (LPS), interleukin-1(beta)(IL-1(beta)), tumor necrosis factor alpha (TNF(alpha)) or interferon gamma (IFN(gamma)), HPASMC were treated with LPS and cytokines together with or without sodium nitroprusside (SNP), NO donor, N(G)-monomethyl-L-arginine (L-NMMA), NO synthetase inhibitor, and methylene blue (MeB), an inhibitor of the soluble guanylate cyclase. After incubation for 24 h, the postculture media were collected for the assay of nitrite by chemiluminescence method and the assay of PGI(2)by radioimmunoassay. The incubation of HPASMC with various concentrations of LPS, IL-1(beta)or TNF(alpha)for 24 h caused a significant increase in nitrite release and PGI(2)production. However, IFN(gamma)slightly increased the release of nitrite and had little effect on PGI(2)production. Although the incubation of these cells for 24 h with SNP did not cause a significant increase in PGI(2)production, the incubation of HPASMC with SNP and 10 microg/ml LPS, or with SNP and 100 U/ml IL-1(beta)further increase PGI(2)production and this enhancement was closely related to the concentration of SNP. However, stimulatory effect of SNP on PGI(2)production was not found in TNF(alpha)- and IFN(gamma)- treated HPASMC. Addition of L-NMMA to a medium containing LPS or IL-1(beta)reduced nitrite release and attenuated the stimulatory effect of those agents on PGI(2)production. MeB significantly suppressed the production of PGI(2)by HPASMC treated with or without LPS or IL-1(beta). The addition of SNP partly reversed the inhibitory effect of MeB on PGI(2)production by HPASMC. These experimental results suggest that NO might stimulate PGI(2)production by HPASMC. Exogenous NO together with endogenous NO induced by LPS or cytokines from smooth muscle cells might synergetically enhance PGI(2)production by these cells, possibly in clinical disorders such as sepsis and acute respiratory distress syndrome.
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PMID:Nitric oxide enhances PGI(2)production by human pulmonary artery smooth muscle cells. 1091 30

The molecular mechanism of the participation of carnosine in the functioning of soluble guanylate cyclase is discussed. It is shown that carnosine inhibits the activation of soluble guanylate cyclase by sodium nitroprusside and a derivative of furoxan--1,2,5-oxadiazolo-trioxide (an NO donor). However, carnosine has no effect on stimulation of the enzyme by a structural analog of the latter compound, a furazan derivative (1,2,5-oxadiazolo-dioxide) that is not an NO donor; nor was carnosine involved in the enzyme activation by protoporphyrin IX, whose stimulatory effect is not associated with the guanylate cyclase heme. The inhibition by carnosine of guanylate cyclase activation by an NO donor is due to the interaction of carnosine with heme iron with subsequent formation of a chelate complex. It was first demonstrated that carnosine is a selective inhibitor of NO-dependent activation of guanylate cyclase and may be used for suppression of activity of the intracellular signaling system NO-soluble guanylate cyclase-cGMP, whose sharp increase is observed in malignant tumors, sepsis, septic shock, asthma, and migraine.
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PMID:Carnosine as a regulator of soluble guanylate cyclase. 1095 Oct 96

Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms.
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PMID:Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase. 1098 65


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