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)

1. In this study we investigated the role of catalase in relaxation induced by hydroxylamine, sodium azide, glyceryl trinitrate and hydrogen peroxide in isolated rings of rat aorta. 2. Hydrogen peroxide (1 microM-1 mM)-induced concentration-dependent relaxation of phenylephrine (PE)-induced tone in endothelium-containing rings. In endothelium-denuded rings, however, higher concentrations (30 microM-1 mM) of hydrogen peroxide were required to produce relaxation. The endothelium-dependent component of hydrogen peroxide-induced relaxation was abolished following pretreatment with N(O)-nitro-L-arginine methyl ester (L-NAME, 30 microM). L-NAME (30 microM) had no effect, however, on hydrogen peroxide-induced relaxation in endothelium-denuded rings. 3. Pretreatment of endothelium-denuded rings with catalase (1000 u ml-1) blocked relaxation induced by hydrogen peroxide (10 microM-1 mM). The ability of catalase to inhibit hydrogen peroxide-induced relaxation was partially blocked following incubation with 3-amino-1,2, 4-triazole (AT, 50 mM) for 30 min and completely blocked at 90 min. 4. Pretreatment of endothelium-denuded rings with methylene blue (MeB, 30 microM) inhibited relaxation induced by hydrogen peroxide (10 microM-1 mM), sodium azide (1-300 nM), hydroxylamine (1-300 nM) and glyceryl trinitrate (1-100 nM) suggesting that each acted by stimulation of soluble guanylate cyclase. 5. Pretreatment of endothelium-denuded rings with AT (1-50 mM, 90 min) to inhibit endogenous catalase blocked relaxation induced by sodium azide (1-300 nM) and hydroxylamine (1-300 nM) but had no effect on relaxation induced by hydrogen peroxide (10 microM-1 mM) or glyceryl trinitrate (1-100 nM). 6. In a cell-free system, incubation of sodium azide (10 microM-3 mM) and hydroxylamine (10 microM-30 mM) but not glyceryl trinitrate (10 microM-1 mM) with catalase (1000 u ml-1) in the presence of hydrogen peroxide (1 mM) led to production of nitrite, a major breakdown product of nitric oxide. AT (1-100 mM) inhibited, in a concentration-dependent manner, the formation of nitrite from azide in the presence of hydrogen peroxide. 7. These data suggest that metabolism by catalase plays an important role in the relaxation induced by hydroxylamine and sodium azide in isolated rings of rat aorta. Relaxation appears to be due to formation of nitric oxide and activation of soluble guanylate cyclase. In contrast, metabolism by catalase does not appear to be involved in the relaxant actions of hydrogen peroxide or glyceryl trinitrate.
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PMID:The inhibitory effect of 3-amino-1,2,4-triazole on relaxation induced by hydroxylamine and sodium azide but not hydrogen peroxide or glyceryl trinitrate in rat aorta. 871 11

1. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001-10 micrograms) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. 2. The LPS-induced febrile response was mimicked by intra-OVLT injection of the nitric oxide (NO) donors, S-nitroso-acetylpenicillamine (SNAP, 1-10 micrograms), sodium nitroprusside (SNP, 50 micrograms), or hydroxylamine (10 micrograms), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10-100 micrograms), or prostaglandin E2 (PGE2, 0.2 micrograms). 3. Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 micrograms), anisomycin (a protein synthesis inhibitor, 100 micrograms), L-N5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10-200 micrograms), aminoguanidine (a specific iNOS inhibitor, 1000 micrograms), or NG-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 micrograms of NG-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. 4. Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1-10 micrograms), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 micrograms), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 micrograms) attenuated the fever induced by intra-OVLT injection of SNAP. 5. The PGE2-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 micrograms), L-NMMA (100 micrograms) or L-NIO (200 micrograms). 6. These results suggest that iNOS-COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.
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PMID:Nitric oxide synthase-cyclo-oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits. 873 93

In order to provide further support for a role of central nitric oxide as a mediator of penile erection and yawning, the nitric oxide donors sodium nitroprusside, hydroxylamine, isoamyl nitrite and S-nitroso-N-acetyl-penicillamine were injected into the lateral ventricles (i.c.v.) or into the paraventricular nucleus of the hypothalamus of male rats. Of the above compounds injected i.c.v., only isoamyl nitrite (10-100 micrograms) induced penile erection and yawning, while the others induced dramatic behavioral changes, such as motor hyperactivity and convulsions, that masked the above responses. Nevertheless, nitric oxide donors in doses ranging from 10 to 50 micrograms, for except S-nitroso-N-acetyl-penicillamine that was injected only at the dose of 10 micrograms and isoamyl nitrite that was not injected at all because of poor solubility, induced penile erection and yawning when injected in the paraventricular nucleus. Nitric oxide donor-induced responses were prevented by methylene blue and LY 83583, inhibitors of guanylate cyclase, the best known target of nitric oxide, given i.c.v. but not in the paraventricular nucleus. However, 8-bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a stable cGMP analog, and hemoglobin, a nitric oxide scavenger, were ineffective in inducing and preventing, respectively, penile erection and yawning when injected either i.c.v. or in the paraventricular nucleus. Nitric oxide donor-induced responses were also prevented by the nonapeptide oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin given i.c.v. but not in the paraventricular nucleus. The present results suggest that nitric oxide donors induce penile erection and yawning by activating central oxytocinergic transmission in the paraventricular nucleus of the hypothalamus via a cGMP-independent mechanism.
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PMID:Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. 878 10

Ultraviolet B (UVB)-irradiated human keratinocytes and human endothelial cells release nitrogen oxides, i.e. nitric oxide (NO). S-nitrosothiols, hydroxylamine (H2NOH) as well as ammonia (NH3) formed from L-arginine. Generation of these compounds was time and concentration-dependent and decreased by both N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine (L-NA). UVB radiation of the cells resulted in a concomitant increase of soluble guanylate cyclase (sGC) activity which was inhibited by L-NMMA and L-NA. S-nitrosothiols formed during the irradiation of the cells directly increased purified sGC activity by a mechanism characteristic of release of NO from a carried molecule. UVB-irradiated cells promptly increased thiobarbituric acid reacting substance (TBARS) (estimated as malondialdehyde. MDA) production which were inhibited by desferrioxamine. In in vivo experiments using guinea pigs subjected to UVB radiation, a Protection Factor (PF) of 2.25 +/- 0.75 was calculated when an emulsified cream formulation containing L-NMMA (1% w/w) and L-NA (1% w/w) was applied to their skin. In human volunteers subjected to UVB radiation, a dose-dependent increase of PF was observed. When an emulsified cream formulation containing L-NMMA (1% w/w) and L-NA (1% w/w) was applied to their skin the PF was 2.15 +/- 0.80: by increasing the concentration of L-NMMA (1% w/w) and L-NA (2% w/w) the PF was 4.25 +/- 1.25. The present results indicate that UVB radiation acts as a potent stimulator of human keratinocytes and endothelial cells to release nitrogen oxides that may diffuse out of the keratinocytes and endothelial cells, activating sGC in neighboring smooth muscle cells. This may be a major part of the integrated response of the skin leading to vasodilation and erythema.
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PMID:Inhibition of ultraviolet B-induced skin erythema by N-nitro-L-arginine and N-monomethyl-L-arginine. 918 9

Nitric oxide (NO) is produced by the enzyme nitric oxide synthase (NOS) and has been implicated in inter- and intracellular communication in the nervous system. The present study was undertaken to assess the effects of sodium nitroprusside (SNP) and hydroxylamine (HOA), NO donors, on a dopamine (DA)-induced K+ current in identified Aplysia neurons using voltage-clamp and pressure ejection techniques. Bath-applied SNP (10-25 microM) reduced the DA-induced K+ current without affecting the resting membrane conductance and holding current. The DA-induced K+ current also was inhibited by the focal application of 200 microM HOA to the neuron somata. The DA-induced K+ current suppressing effects of SNP and HOA are completely reversible. Pretreatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microM), a specific inhibitor of NO-stimulated guanylate cyclase, and hemoglobin (50 microM), a nitric oxide scavenger, decreased the SNP-induced inhibition of the DA-induced current. In contrast, intracellular injection of 1 mM guanosine 3',5'-cyclic monophosphate (cGMP) or bath-applied 3-isobutyl-1-methylxanthine (IBMX; 50 microM), a non-specific phosphodiesterase inhibitor, inhibited the DA-induced current, mimicking the effect of the NO donors. These results demonstrate that SNP and HOA inhibit the DA-induced K+ current and that the mechanism of NO inhibition of the DA-induced current involves cGMP-dependent protein kinase.
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PMID:Nitric oxide inhibits the dopamine-induced K+ current via guanylate cyclase in Aplysia neurons. 936 30

Calcium-dependent guanylate cyclase activator protein (CD-GCAP) is a low-molecular-weight retinal calcium-binding protein which activates rod outer segment guanylate cyclase (ROS-GC) in a calcium-dependent manner. This investigation was undertaken to determine the protein's structure and identity. Partial amino acid sequencing (72% of the protein), mass spectral analysis, cloning, and immunological studies revealed that CD-GCAP is identical to S100beta, another low-molecular-weight calcium-binding protein whose structure was known. We had shown earlier that the latter protein, which is usually called S100b (S100betabeta or dimer of S100beta), also activates ROS-GC but that the Vmax of activated cyclase was about 50% lower than when stimulated by CD-GCAP. S100b also required about 15 times more calcium (3.2 x 10(-)5 vs 1.5 x 10(-)6 M) for half-maximal stimulation of cyclase. To investigate the possibility that CD-GCAP is a post-translationally modified form of S100b, both proteins were treated with 1 M hydroxylamine which is known to deacylate proteins. After the treatment, CD-GCAP did not activate cyclase while S100b activation remained unaffected suggesting that CD-GCAP could not be a modified form of S100b. Hydroxylamine also broke down CD-GCAP into smaller fragments while leaving S100b intact. It therefore appeared that in spite of identical primary structures, the conformations of the two proteins were different. We then investigated the possibility that the purification procedures of the two proteins, which were quite different, could have contributed to such conformational differences: CD-GCAP purification included a step of heating at 75 degrees C in 5 mM Ca, while S100b purification included zinc affinity chromatography. To test the influence of these treatments on the properties of the proteins, CD-GCAP was subjected to zinc affinity chromatography and purified as S100b (CD-GCAP-->S100b) and S100b was heated in Ca and purified as CD-GCAP (S100b-->CD-GCAP). Cyclase activation, calcium-sensitivity, and hydroxylamine-lability measurements revealed that CD-GCAP-->S100b is identical to S100b and that S100b-->CD-GCAP is identical to CD-GCAP. Taken together the results demonstrate that CD-GCAP and S100b are one and the same protein and that their functional differences are due to different interconvertible conformational states.
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PMID:Structural and functional characterization of retinal calcium-dependent guanylate cyclase activator protein (CD-GCAP): identity with S100beta protein. 936 88

1. Recent experimental evidence has shown that nitric oxide (NO) plays an important role in the expression of penile erection and yawning and that this molecule has to be added to the list of the best known neurotransmitters and neuropeptides involved in this symptomatology. 2. This was first suggested by the ability of NO synthase inhibitors injected in the lateral ventricles (i.c.v.) or in the paraventricular nucleus of the hypothalamus (PVN) to prevent these behavioral responses induced by dopamine agonists, oxytocin and NMDA. The inhibitory effect of NO synthase inhibitors was not observed when these compounds were injected concomitantly with L-arginine, the precursor of NO. Most important, this hypothalamic nucleus is one of the richest brain areas of NO synthase and also the brain site where dopamine, NMDA and oxytocin act to induce penile erection and yawning by activating central NO synthase containing oxytocinergic neurons. 3. NO synthase inhibitors given i.c.v. but not in the PVN prevent also penile erection and yawning induced by ACTH and serotonin1c agonists, which induce these responses by acting with mechanisms unrelated to oxytocinergic transmission. 4. Dopamine agonists, NMDA and oxytocin increase NO production in the PVN at doses that induce penile erection and yawning, as determined by measuring the concentration of NO2- and NO3- in the dialyzate obtained with a vertical probe implanted in the PVN by in vivo microdialysis. 5. NO donors, such as nitroglycerin, sodium nitroprusside and hydroxylamine, induce penile erection and yawning indistinguishable from those induced by oxytocin, dopamine agonists or NMDA when injected in the PVN. The NO donor response was prevented by the i.c.v. injection of the oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin, indicating that these compounds also induce penile erection and yawning by activating oxytocinergic transmission. 6. Finally, guanylate cyclase inhibitors (i.e. methylene blue and LY 83583) and hemoglobin injected in the PVN do not prevent drug-induced penile erection and yawning, nor 8-Br-cGMP injected in the PVN induces these behavioral responses suggesting that the mechanism by means of which endogenous or NO donor-derived NO facilitates oxytocinergic transmission to induce penile erection and yawning is not related to the activation of guanylate cyclase. Furthermore, since hemoglobin, in spite of its ability to prevent drug-induced NO production in the PVN, does not prevent penile erection and yawning, it is likely that NO acts as an intracellular rather than an intercellular modulator in the PVN neurons in which is formed to facilitate the expression of these behavioral responses.
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PMID:Role of central nitric oxide in the control of penile erection and yawning. 938 Jul 88

We used hippocampal synaptosomes to study the effect of NO originating from NO donors and from the activation of the NO synthase on the Ca2+-dependent release of glutamate due to 4-aminopyridine (4-AP) depolarization. We distinguished between the effects of NO on the exocytotic and on the carrier-mediated release of glutamate, which we found to be related to an increase in cGMP content and to a reduction of the ATP/ADP ratio, respectively. The NO donor hydroxylamine, at concentrations < or = 0.3 mM, inhibited the Ca2+-dependent glutamate release evoked by 4-AP, and addition of the NO donor, NOC-7, had a similar effect, which was reversed by the NO scavenger, carboxy-PTIO. Increasing the activity of NO synthase by addition of L-arginine also led to a decrease in the Ca2+-dependent release of glutamate induced by 4-AP, and this effect was reversed by inhibiting NO synthase with NG-nitro-L-arginine. This depression of the exocytotic release of glutamate was accompanied by an increase in cGMP levels due to the stimulation of soluble guanylyl cyclase by NO, produced either by the NO donors (hydroxylamine <0.3 mM) or by the endogenous NO synthase, but no significant decrease in ATP/ADP ratio was observed. However, at concentrations > or = 0.3 mM, hydroxylamine drastically increased the basal release and completely inhibited the Ca2+-dependent release of glutamate (IC50 = 168 microM). At these higher levels of NO, cGMP levels dropped to about 40% of the maximal values obtained at lower concentrations, and the ATP/ADP ratio decreased to about 50% (at 0.3 mM hydroxylamine). The large increase in the basal release could be partially inhibited by L-trans-2,4-PDC, previously loaded into the synaptosomes, suggesting that the nonexocytotic basal release occurred by reversal of the glutamate carrier. Therefore, the increase in cGMP induced by NO stimulation of the guanylyl cyclase decreases the exocytotic release of glutamate, but higher NO levels reduce the ATP/ADP ratio by inhibiting mitochondrial function, which therefore causes the massive release of cytosolic glutamate through the glutamate carrier.
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PMID:Modulation of glutamate release from rat hippocampal synaptosomes by nitric oxide. 944 4

Incubation of striatal slices with sodium nitroprusside (SNP) or hydroxylamine (HA) for 60 min caused a dose-dependent increase in dopamine (DA) release. This effect was inhibited completely by tetrodotoxin (TTX) (1 microM) if low concentrations of SNP (1 microM) or HA (10 and 100 microM) were tested. Although-higher concentration of SNP (10 and 100 microM) and HA (500 microM) were still effective in stimulating DA release, increases observed under these conditions were less than the values found in the absence of TTX. Verapamil (10 microM), but not omega-conotoxin (100 nM), significantly reduced DA release stimulated by high concentrations of SNP or HA. When verapamil was combined with TTX, moreover, SNP and HA failed to stimulate DA release. If striatal slices were incubated in the presence of nomifensine (10 microM), SNP and HA did not enhance DA release. SNP and HA-induced depletions in tissue DA levels were also protected by nomifensine. Inhibition of guanylate cyclase with 10 microM of methylene blue could not reduce the effects of NO-donors. SNP and HA also failed to alter endogenous glutamate release from striatal slices. Similarly, SNP and HA-induced increases in DA release were not affected by kynurenic acid and MK-801. These results indicate that NO-donors SNP and HA stimulate DA release by facilitating reverse DA transport. This effect seems to be dependent on the activation of both voltage dependent sodium channels and L-type of calcium channels. Results presented here also indicate that neither endogenous glutamate nor guanylate cyclase activation plays an intermediary role in stimulatory effects of NO-donors on DA release from rat striatal slices.
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PMID:Effect of nitric oxide donors on endogenous dopamine release from rat striatal slices. II: The role of voltage-dependent sodium channels, calcium channel activation, reverse transport mechanism, guanylate cyclase and endogenous glutamate. 944 20

Nitric oxide (NO) is known to potentiate neurotransmitter release in several types of neuronal cells. In the present study, the influence of NO on the membrane potential of isolated nerve endings (synaptosomes) from rat brain was studied. NO donors--sodium nitroprusside (SNP), S-nitroso-L-cysteine (CysNO), and hydroxylamine (HA)--induced synaptosome depolarization monitored by decreasing accumulation of 86Rb+ and the lipophilic potential-sensitive probe [3H]tetraphenylphosphonium. SNP reduced plasma membrane potential by 3-5 mV with half-maximal effect at approximately 10 microM. More potent NO donors, CysNO and HA, led to significant depolarization of the plasma membrane at 10-100 microM concentrations and also induced depolarization of mitochondria at concentrations above 1 mM. At 10 microM-10 mM concentrations, NO donors inhibited potassium channels; CysNO and HA also suppressed the activity of the sodium pump. NO-induced depolarization was not blocked by guanylate cyclase inhibitor methylene blue and the permeable cGMP analog dibutyryl-cGMP did not affect the membrane potential. The effects of NO donors were mimicked by SH-modifying reagents including 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) and N-ethylmaleimide (NEM). Non-permeable SH-reagent DTNB caused small depolarization resembling SNP action in its magnitude and kinetics. Significant decrease of potential in the presence of NEM, which permeates through the plasma membrane, was similar to that of CysNO and HA. The data suggest that in the presynaptic nerve endings, NO-induced depolarization of the plasma and mitochondrial membranes involves modification of protein SH-groups. The plasma membrane depolarization is due to the decreased potassium permeability and inhibition of the sodium pump.
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PMID:Depolarization of isolated brain nerve endings by nitric oxide donors: membrane mechanisms. 966 6


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