Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generation of toxic concentrations of nitric oxide by the inducible nitric oxide synthase expressed in microglia and other brain cell types is frequently invoked as a causative factor in neurodegeneration. Experiments were carried out on slice cultures of rat hippocampus to test this hypothesis. Exposure of the slices to bacterial lipopolysaccharide plus interferon-gamma led to a time-dependent expression of functional inducible nitric oxide synthase that was found only in microglia. Microglial activation by other means, such as physical damage, was not associated with inducible nitric oxide synthase expression. Damage and cell death in slices expressing inducible nitric oxide synthase was evaluated over a period of 6 days, but none was found. Consistent with this result, cGMP measurements indicated that the average local nitric oxide concentration remained in the low nanomolar range. When the microglial population was expanded to a density three-fold above normal by applying granulocyte-macrophage colony stimulating factor, however, lipopolysaccharide plus interferon-gamma provoked neurodegeneration that could be blocked by an inducible nitric oxide synthase inhibitor. The associated nitric oxide concentration in the slices was saturating for guanylyl cyclase-coupled nitric oxide receptors, signifying at least 10 nM. It is concluded that inducible nitric oxide synthase is expressed in microglia only in response to specific stimuli involving the innate immune system, and that the resulting level of nitric oxide in intact brain tissue is normally too low to inflict damage directly. Quantities of nitric oxide sufficient to contribute directly or indirectly to pathology could be produced should the density of microglia become high enough, although caution must be exercised in extrapolating this finding to the human brain in vivo.
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PMID:Pathological consequences of inducible nitric oxide synthase expression in hippocampal slice cultures. 1616 95

We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 micromol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier. Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.
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PMID:Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity. 1632 31

Nitric oxide (NO), applied by inhalation or released from NO donors, has been used to reduce the expression of cell adhesion molecules (CAM) and ameliorate other consequences of ischemia/reperfusion (I/R) injury. In this study, we have assessed the time frames of pretreatment and of the duration of the preconditioned state using human umbilical vein endothelial cells (HUVECs) and the NO donor, SNAP, in combination with cysteine. The induction of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and E-selectin by the cytokines TNFalpha and IL-1beta, and by bacterial lipopolysaccharide (LPS) was reduced by SNAP/Cys preincubation (30 min, 1mM) to less than 10% of controls. This refractory state in respect to cytokine-induced CAM expression persisted for 6h after washout of the NO donor in the combination TNFalpha/VCAM, and a partial block was still observed after 8h. The effect was not mediated by the cGMP pathway, as was demonstrated by using the inhibitor of guanylyl cyclase, ODQ, and the cGMP analogue, 8-Br-cGMP. The TNFalpha-induced expression of CAM was exclusively dependent on the transcription factor NFkappaB since the inhibitor of NFkappaB activation, BAY 11-7082, completely blocked the induction. The TNFalpha-induced phosphorylation and degradation of the inhibitor of kappaB (IkappaBalpha) was suppressed for up to 8h after SNAP/Cys pretreatment. The inhibitory S-nitrosation of IkappaB kinase (IKKbeta), as assessed by the biotin-switch-procedure and immunoprecipitation, was only detectable immediately after SNAP/Cys incubation but not at later time points. In summary, a short preincubation of HUVEC with SNAP/Cys results in a persistent suppression of NFkappaB-dependent expression of CAM. The stabilization of IkappaBalpha over the same time span may be causally related to this effect.
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PMID:Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and NFkappaB activation in endothelial cells. 1650 56

Increased expression of CD11b, the beta-integrin marker of microglia, represents microglial activation during neurodegenerative inflammation. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of nitric oxide (NO) in the expression of CD11b in microglial cells. Bacterial lipopolysaccharide (LPS) induced the production of NO and increased the expression of CD11b in mouse BV-2 microglial cells and primary microglia. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric-oxide synthase (L-NIL) blocked this increase in microglial CD11b expression. Furthermore, co-microinjection of PTIO with LPS was also able to suppress LPS-mediated expression of CD11b and loss of dopaminergic neuronal fibers and neurotransmitters in striatum in vivo. Similarly, other inducers of NO production such as interferon-gamma, interleukin-1beta, human immunodeficiency virus type-1 gp120, and double-stranded RNA (poly(IC)) also increased the expression of CD11b in microglia through NO. The role of NO in the expression of CD11b was corroborated further by the expression of microglial CD11b by GSNO, an NO donor. Because NO transduces many intracellular signals via guanylate cyclase (GC), we investigated the role of GC, cyclic GMP (cGMP), and cGMP-activated protein kinase (PKG) in microglial expression of CD11b. Inhibition of LPS- and GSNO-mediated up-regulation of CD11b either by NS2028 (a specific inhibitor of GC) or by KT5823 and Rp-8-bromo-cGMP (specific inhibitors of PKG), and increase in CD11b expression either by 8-bromo-cGMP or by MY-5445 (a specific inhibitor of cGMP phosphodiesterase) alone suggest that NO increases microglial expression of CD11b via GC-cGMP-PKG. In addition, GSNO induced the activation of cAMP response element-binding protein (CREB) via PKG that was involved in the up-regulation of CD11b. This study illustrates a novel biological role of NO in regulating the expression of CD11b in microglia through GC-cGMP-PKG-CREB pathway that may participate in the pathogenesis of devastating neurodegenerative disorders.
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PMID:Up-regulation of microglial CD11b expression by nitric oxide. 1655 37

Pfaffia glomerata is used in southern American countries against inflammatory diseases. We have explored the ability of a crude hydroalcoholic extract of P. glomerata root (HEPG) to prevent the oedematogenic action of several inflammatory agents in mice. We have examined also the duration of its effects and the mechanisms involved. The oral or intraperitoneal treatment of mice with HEPG (1, 10, 30, 100 or 300 mg kg(-1)) reduced, in a dose-dependent manner, carrageenan-induced paw oedema in the early (1-4 h) and late (48 h) periods. In the early period, the ID50 value (the median dose that caused 50% inhibition) of HEPG was 60.5 (28.5-128.71) and 20.4 (14.8-28.3) mg kg(-1) after oral and intraperitoneal administration, respectively. This effect was still evident when HEPG was administered up to 6 h before carrageenan. HEPG inhibited also paw oedema induced by histamine, serotonin, bradykinin, substance P and bacterial lipopolysaccharide. In addition, oral administration of HEPG increased the levels of nitrate and nitrite in the blood of mice. Further, its anti-oedematogenic action against carrageenan was prevented fully by N(G) nitro-L-arginine-methyl-ester (10 mg kg(-1), s.c.), as well as by methylene blue (20 mg kg(-1), s.c.) or 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (2 mg kg(-1), s.c.). The results indicated that stimulation of endogenous production of nitric oxide, followed by soluble guanylate cyclase activation, was implicated in the anti-oedematogenic action of HEPG.
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PMID:Involvement of the nitric oxide/soluble guanylate cyclase pathway in the anti-oedematogenic action of Pfaffia glomerata (Spreng) Pedersen in mice. 1664 Aug 36

Recently, heme oxygenase-carbon monoxide (HO-CO) pathway has been reported to be involved in the development of lipopolysaccharide (LPS) fever. However, no information exists about its participation in LPS tolerance, which is defined by an attenuation of the febrile response to repeated administrations of LPS. Thus, we tested the hypothesis that HO-CO pathway plays a role in endotoxin tolerance, which was induced by means of three consecutive LPS intraperitoneal injections (i.p.) at 24-h intervals. Body temperature (Tb) was measured by biotelemetry. Induction of the HO pathway using intracerebroventricular (i.c.v.) heme lysinate reversed tolerance, and this effect could be prevented by pretreatment with ODQ [a soluble guanylate cyclase (sGC) inhibitor; i.c.v.]. These results indicate that HO-CO pathway seems to be down-regulated during LPS tolerance, and that CO is the HO product that can prevent LPS tolerance, acting via cGMP. In further support, either biliverdine or iron (the others HO products; i.c.v.) had no effect in LPS-induced tolerance.
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PMID:Central heme oxygenase-carbon monoxide pathway participates in the lipopolysaccharide-induced tolerance in rats. 1690 72

Carbon monoxide (CO) has been identified as a diffusible signaling messenger in the brain, capable of altering body temperature by stimulating soluble guanylate cyclase (sGC). However, its site of action remains unclear. Locus coeruleus (LC) is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the lipopolysaccharide (LPS)-induced fever regulation by LC neurones was investigated. Induction of the HO pathway using heme-lysinate (7.6 nmol, intra-LC) attenuated the febrile response, and this effect could be prevented by pretreatment with ODQ (an sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Moreover, ZnDPBG (an HO inhibitor; 5 nmol, intra-LC) augmented the febrile response. Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP plays an antipyretic role during LPS-fever in rats.
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PMID:Role of the locus coeruleus carbon monoxide pathway in endotoxin fever in rats. 1694 Nov 38

Activation of the estrogen receptor-alpha (ERalpha) mediates the vasculoprotective effects of estrogen, in part, through modulating nitric oxide (NO) production and vasodilation. Whereas inflammation is accompanied by altered vascular reactivity and underlies the pathogenesis of vascular disease, the role of the ERalpha in the vascular responses associated with acute systemic inflammation remains poorly characterized. Contractile and relaxation responses of isolated aortic segments were investigated 12 h after ip injection of saline or lipopolysaccharide (LPS, 10 mg/kg) in male wild-type (ERalpha(+/+)) and ERalpha-deficient (ERalpha(-/-)) mice. As previously observed, LPS-injected ERalpha(+/+) mice displayed reduced contractile responses to phenylephrine and enhanced vasodilation in response to acetylcholine. In contrast, aortic tissues from LPS-injected ERalpha(-/-) mice displayed enhanced contractile responses and reduced sensitivity to acetylcholine- and sodium nitroprusside-induced vasodilation. LPS treatment in ERalpha(+/+) and ERalpha(-/-) mice resulted in similar increased levels of systemic NO production and inducible NO synthase expression in the vascular wall. However, expression of mRNA and protein for endothelial NOS and soluble guanylate cyclase (alpha- and beta-subunits) were significantly reduced in aortic tissues from LPS-treated ERalpha(-/-) animals, possibly accounting for reduced endothelial NO production and reduced smooth muscle responses to NO. These findings represent new evidence of the functional role of ERalpha in the male vasculature and suggest that during acute LPS-induced inflammatory responses, the ERalpha mediates the sustained expression of the molecular machinery essential for endothelial NO synthesis (i.e. endothelial NOS) and the vascular responses to NO (i.e. soluble guanylate cyclase).
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PMID:Compromised aortic vasoreactivity in male estrogen receptor-alpha-deficient mice during acute lipopolysaccharide-induced inflammation. 1715 9

Nitric oxide ((*)NO) plays an important role in a number of physiologic processes. Evidence exists that (*)NO, which stimulates soluble guanylate cyclase and enhances cyclic guanosine monophosphate (cGMP) levels, may inhibit platelet activation. In contrast, during platelet activation induced by different agonists, synthesis of (*)NO in platelets occurs. In these studies, production of the stable end-products of (*)NO-nitrite and nitrate (NO(x)) in human platelets, stimulated by different doses of lipopolysaccharide from Proteus mirabilis (LPS; endotoxin), has been evaluated. LPS is a weak platelet agonist that may activate various steps of platelet activation with the generation of reactive oxygen species. The mechanism of platelet activation induced by the endotoxin is not known. The aim of the present study was to measure the level of nitrite and NO(x) in blood platelets treated with LPS and to examine the level of nitrotyrosine in platelet proteins caused by LPS. Our results show that LPS at a low concentration (6.8 ng/ml) caused a decrease (approximately 80%) in the NO(x) level, whereas at higher concentrations (13.6 and 25 ng/ml) it induced an increase in the NO(x) level (approximately 210% and 260%, respectively). Our results indicate that LPS, like other agonists (thrombin, platelet-activating factor), can stimulate (*)NO production in platelets. After incubating platelets with LPS, we also observed a distinct increase in platelet protein nitration (3-nitrotyrosine).
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PMID:The effect of lipopolysaccharide from Proteus mirabilis on the level of the stable end metabolic products of nitric oxide in blood platelets. 1716 Mar 61

The development of carbon monoxide-releasing molecules (CO-RMs) in recent years helped to shed more light on the diverse range of anti-inflammatory and cytoprotective activities of CO gas. In this study, we examined the effect of a ruthenium-based water-soluble CO carrier (CORM-3) on lipopolysaccharide (LPS)- and interferon-gamma (INF-gamma)-induced inflammatory responses in BV-2 microglial cells and explored the possible mechanisms of action. BV-2 microglial cells were stimulated with either LPS or INF-gamma in the presence of CORM-3 and the inflammatory response evaluated by assessing the effect on nitric oxide production (nitrite levels) and tumor necrosis factor-alpha (TNF-alpha) release. Similar experiments were also performed in the presence of inhibitors of guanylate cyclase (ODQ), NO synthase (L-NAME), heme oxygenase activity (tin protoporphyrin IX) or various mitogen-activated protein kinase (MAPK) inhibitors. CORM-3 significantly attenuated the inflammatory response to LPS and INF-gamma as evidenced by a significant reduction (p < 0.001) in nitrite levels and TNF-alpha production (P < 0.05). Such effect was maintained in the presence of ODQ, L-NAME or tin protoporphyrin without showing any cytotoxicity. The use of an inactive form of CORM-3 that does not contain carbonyl groups (Ru(DMSO)(4)Cl(2) failed to inhibit the increase in inflammatory markers suggesting that liberated CO mediates the observed effects. In addition, inhibition of phosphatidylinositol-3-phosphate kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways seemed to amplify the anti-inflammatory effect of CORM-3, particularly in cells stimulated with INF-gamma. These results suggest that the anti-inflammatory action of CORM-3 could be exploited to mitigate microglia activation in neuro-inflammatory diseases.
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PMID:A carbon monoxide-releasing molecule (CORM-3) attenuates lipopolysaccharide- and interferon-gamma-induced inflammation in microglia. 1733 83


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