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 majority of the data on nitric oxide (NO) in the central nervous system (CNS) relies on histochemical and immunohistochemical evidence concerning the distribution of the nitric oxide synthase (NOS), its inhibition by specific antagonists and its co-localization with the receptor enzyme guanylate cyclase (GC) in the same functional region. All three isoforms, endothelial (eNOS), neural (nNOS) and macrophage type inducible (iNOS), are of importance to the normal and pathological function of the CNS. In nNOS gene deleted mice eNOS seems to contribute to the maintenance of neuronal function. NO may contribute to synaptic plasticity as a retrograde mediator that is released by postsynaptic NMDA-receptor activation. Microglia contains membrane-bound inducible iNOS that may be important in host defence function. Glia and pericytes surrounding the blood vessels contain GC that is stimulated by NO released from endothelium and nerve endings. Excessive production of highly reactive NO may be responsible for the neurotoxicity mediated by NMDA receptors that contributes to the symptomatology of strokes and neurodegenerative diseases. Moreover, after initial stimulation by cytokines, large amounts of NO produced by iNOS in the microglia (brain-based macrophages) may cause cellular damage.
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PMID:Nitric oxide in the central nervous system. 754 27

We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice. 765 39

In addition to mediating several physiological functions, nitric oxide (NO) has been implicated in the cytotoxicities observed following activation of macrophages or excess stimulation of neurons by glutamate. We extend our previous observations of glutamate-stimulated, NO-mediated neurotoxicity in primary cultures of rat fetal cortical, striatal, and hippocampal neurons. Neurotoxicity elicited by either NMDA or sodium nitroprusside (SNP) exhibits a similar concentration-effect relationship and time course. The concentration-effect curve of NMDA-induced neurotoxicity is shifted to the right in the presence of nitro-L-arginine and farther to the right in arginine-free media. The rank order of potency of several NO synthase (NOS) inhibitors in preventing neurotoxicity is the same as the rank order of these compounds in inhibiting NOS, and this inhibition is stereospecific. NMDA neurotoxicity is also prevented by flavoprotein inhibitors and calmodulin inhibitors, fitting with the roles of flavoproteins and calmodulin as NOS regulators. 8-Bromo-cGMP and guanylyl cyclase inhibitors do not affect neurotoxicity, while superoxide dismutase attenuates neurotoxicity. NOS neurons appear to be the source of neurotoxic NO in culture, as lesions of these neurons with 20 microM quisqualate diminish subsequent NMDA neurotoxicity. Moreover, NMDA neurotoxicity develops over time in culture coincident with the expression of NOS. Immunohistochemical localization of NOS in cultures and intact brain demonstrates widespread distribution of the cell processes suggesting that NOS neurons contact the majority of cortical neurons and so could mediate widespread neurotoxicity.
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PMID:Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. 768 76

The aim of this study was to investigate the role of NO-cGMP pathway in NMDA-induced NGF mRNA expression by T67 astrocytoma cells. Levels of nitrite, a breakdown product of NO, in supernatants of NMDA-treated astrocytoma cells were significantly higher compared with control cells, this effect being reversed by the specific NO synthase inhibitor L-NAME. Furthermore, NGF mRNA expression was induced by NMDA treatment, this effect being inhibited by pretreating cells with L-NAME. Moreover, methylene blue, an inhibitor of NO biological activity at guanylate cyclase level, inhibited NMDA-induced NGF mRNA expression and this effect was reversed by dbt2-cGMP. These findings suggest that NO-cGMP pathway mediates the synthesis of NGF mRNA.
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PMID:NMDA-dependent NGF mRNA expression by human astrocytoma cells is mediated by nitric oxide. 769 84

Involvement of endogenous nitric oxide (NO) on glutamate receptor-mediated response was investigated in neuronal cells cultured from embryonic rat hippocampus. L-NG-Nitroarginine (NOARG), a NO synthase inhibitor, augmented NMDA- and kainate-induced increase in intracellular Ca2+ concentration ([Ca2+]i) measured by fura-2 fluorometry. However, quisqualate-induced response was not affected. The potentiating effect of NOARG was blocked by L-arginine, a substrate for NO synthase. NOARG was also effective when added after glutamate-induced response had reached a steady-state. Hemoglobin itself increased the basal level of [Ca2+]i at concentrations higher than 10 mM, and treatment of the cells with 1.0 mM hemoglobin had no effect on NMDA response. 8-Bromo-cyclic GMP was not effective on NMDA response. These results suggest that endogenous NO inhibits NMDA- and kainate-induced increase in [Ca2+]i as a negative feedback system independent of guanylate cyclase activation.
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PMID:Endogenous nitric oxide inhibits NMDA- and kainate- responses by a negative feedback system in rat hippocampal neurons. 790 57

N-Methyl-D-aspartate (NMDA) microinjection (1 mM, 0.2 microliter) into the hypothalamic supraoptic nucleus (SON) stimulated heart rate in urethane-anaesthetized rats. This effect was inhibited by coinjection of a competitive blocker of NMDA receptors, CPP (20 nmol) or by pretreatment with a sympathetic ganglionic blocker, chlorisondamine chloride (5 mg/kg i.p.), but not by prior hypophysectomy. Furthermore, the cardioexcitatory effect of intra-SON NMDA was inhibited by prior intra-SON injection of a competitive blocker of nitric oxide (NO) synthesis, NG-nitro-L-arginine methyl ester (40 nmol) or a blocker of the soluble guanylate cyclase, Methylene blue (20 nmol), and was mimicked by intra-SON injection of a calcium ionophore, A23187 (10 nmol), which stimulates NO production by raising intracellular free calcium levels. Finally, intra-SON microinjection of a membrane-permeating cGMP analog, 8-bromo-cGMP (20 nmol) stimulated heart rate in urethane-anaesthetized rats. The results point to a functional link between a sympathetically mediated cardiophysiological effect of NMDA receptor stimulation in the SON and activation of the NO/cGMP signal transduction pathway.
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PMID:N-Methyl-D-aspartate receptor-mediated signaling in the supraoptic nucleus involves activation of a nitric oxide-dependent pathway. 806 94

Microinjection of N-methyl-D-aspartate (NMDA; 1 and 2.5 nmol) or kainate (KA; 50 pmol) into the deep prepiriform cortex elicited behavioral signs of seizure activity. No epileptiform activity was observed after deep prepiriform cortex microinjection of either L-arginine (L-Arg, 5 and 10 nmol) or its D-enantiomer, D-arginine (D-Arg, 2.5-10 nmol). However, both the seizure score and the incidence of electroencephalographic (EEG) epileptic discharges elicited by NMDA (1 and 2.5 nmol) and KA (50 pmol) were significantly increased by L- but not D-Arg. The facilitatory effects of L-Arg on seizure activity elicited by both NMDA and KA were dose-dependent and could be prevented by co-administration of L-Arg (10 nmol) and the nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 20 nmol). Motor and electrocortical seizures were observed after microinjection of the NO donor sodium nitroprusside (SNP; 5 to 20 nmol) into the deep prepiriform cortex. Infusion of methylene blue (20 nmol), a soluble guanylate cyclase inhibitor, protected against SNP-induced seizures. Furthermore, prior infusion of a subconvulsant dose of SNP into the deep prepiriform cortex significantly potentiated the seizure activity elicited by either NMDA (1 and 2.5 nmol) or KA (50 pmol). These results support the proposal that NO is formed from L-Arg upon excitatory amino acid receptor activation within the deep prepiriform cortex, thereby contributing to the genesis of seizure activity.
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PMID:L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. 842 97

Previous studies in our laboratory have shown that nitric oxide (NO) gas enhances NMDA-stimulated release of preloaded tritiated norepinephrine ([3H]NA) from rat brain slices in a dose-dependent, oxygen-sensitive, and cyclic GMP-independent manner. In this study we have attempted to determine the mechanism for the enhancement of neurotransmitter release seen with NO. No-enhanced transmitter release was not due to buffer acidification or generation of NO degradation products, since reducing buffer pH below 7.3 inhibited NMDA-stimulated [3H]NA release and nitrite or nitrate ions (3-100 microM) had no significant effect on release. Carbon monoxide (CO, 10-300 microM), another diatomic gas with properties similar to NO including heme binding and guanylate cyclase activation, had no significant effect on depolarization-induced [3H]NA release. The NO effect was probably not due to mono-ADP-ribosylation of cellular proteins, since the ADP-ribosyltransferase (ADPRT) inhibitors nicotinamide (10 microM-10 microM) and luminol (1 microM-1mM) did not diminish the enhancement of transmitter release seen with NO. The NA reuptake inhibitor desmethylimipramine (DMI, 10 nM-10 microM) neither mimicked nor blocked the effect of NO, suggesting that NO was not acting via inhibition or reversal of the NA transporter. Similar to NO, the metabolic inhibitors sodium azide (NaN3, 0.1-3 mM), potassium cyanide (KCN, 0.1-3 mM), and 2,4-dinitrophenol (2,4-DNP, 10-300 microM) also dose-dependently enhanced NMDA-stimulated [3H]NA release. These results suggest that NO may enhance neurotransmitter release by inhibiting cellular respiration and perhaps ultimately via altering calcium homeostasis.
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PMID:Mechanism for nitric oxide's enhancement of NMDA-stimulated [3H]norepinephrine release from rat hippocampal slices. 853 39

Opioid tolerance can be modulated by the N-methyl-D-aspartate/nitric oxide (NMDA/NO) cascade. Evidence exploring a daily injection paradigm indicates that agents antagonizing NMDA receptors can prevent tolerance to morphine and delta drugs, but not kappa agents. Drugs work regardless of whether they act as competitive or noncompetitive antagonists. Even an agent acting as an antagonist on the glycine site of the NMDA receptor is effective. Blockade of nitric oxide synthase has similar effects on opioid tolerance, preventing morphine and delta tolerance but not that of kappa drugs. Even methylene blue, which can inhibit guanylyl cyclase activity, is effective, presumably by blocking cGMP formation resulting from NO release. These results demonstrate the importance of an intact NMDA/NO cascade in the production of opioid tolerance and open new possibilities in the design of agents acting on opioid tolerance.
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PMID:Perspectives on the N-methyl-D-aspartate/nitric oxide cascade and opioid tolerance. 874 55

The activation of nitric oxide synthase (NOS) has been linked to excitatory input via NMDA receptors. We hypothesized that NOS-positive neurons that have NMDA receptors on their surface would have high levels of cytochrome oxidase (C.O.) as energy generator for membrane repolarization. In order to compare the distribution of these markers on the same section, we reacted rat brain sections for C.O. histochemistry followed by NOS immunogold silver staining (IGSS). Adjacent sections were reacted for NOS IGSS followed by indirect immunoperoxidase for NMDA receptor subunit R1 (NMDAR1). We found that the staining pattern varied among regions but were consistent within each region examined. There are three types of NOS immunoreactive (NOS-ir) cells: (1) NOS-ir neurons that had moderate to high levels of both NMDAR1 and C.O. staining, such as the pontine reticular nuclei, motor and mesencephalic nuclei of the trigeminal nerve, and some motor neurons in the spinal cord. (2) NOS-ir neurons that were immunoreactive for NMDAR1 (NMDAR1-ir) but had low levels of C.O. activity in thei- somata. Their dendrites, however, were both NMDAR1-ir and rich in C.O. Examples of this type include neurons in the caudate and putamen, and periglomerular cells in the olfactory bulb. (3) We also found that some NOS-ir neurons were not NMDAR1-ir and had low C.O. activity. In addition to postsynaptic neurons, C.O. and NOS levels were both high in the inner segments of retinal photoreceptor cells where energy-demanding active ion transport maintains the dark current and where NO presumably activates guanylate cyclase for the production of cGMP, which keeps the Na+ channels open in the dark. Our findings suggest that NMDA receptors are available for the majority of NOS-ir neurons, which comprise a heterogenous population with varying energy demands.
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PMID:Do nitric oxide synthase, NMDA receptor subunit R1 and cytochrome oxidase co-localize in the rat central nervous system? 887 89


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