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)

In a previous paper we showed that the nitric oxide (NO) donors azide and hydroxylamine inhibited eosinophil apoptosis. Azide and hydroxylamine generate a nitrosyl-heme complex - due to endogenous catalase activity - which activates soluble guanylate cyclase. In contrast, in the present paper, we show that NO donors (SNAP, SIN-1, S-nitroso-L-cysteine, NOC-18) which spontaneously release NO in physiological solutions did not support the survival of eosinophils and induced apoptosis or necrosis. However, the addition of hematin (the ferric form of heme) together with low doses of NO (SNAP 10 microM) promoted eosinophil survival. In conclusion, we propose that NO and heme (e.g. from heme-containing enzymes such as peroxidase or catalase), both released in inflammation sites, could form nitrosyl-heme and thus promote eosinophilic inflammation.
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PMID:Effects of nitric oxide on the eosinophil survival in vitro. A role for nitrosyl-heme. 992 48

The effects of possible activators of soluble guanylate cyclase were studied. Hydroxylamine and some oxime derivatives such as pyridinium aldoximes and bispyridinium dioxime (dipyroxime) were tested as possible guanylate cyclase activators. These compounds are known to be reactivators of choline esterase which has been preinhibited with phosphoorganic compounds. All the tested compounds were found to activate human platelet guanylate cyclase in the concentration range 10-6-10-3 M. The highest stimulatory affect was achieved at 10-4 M with hydroxylamine and dipyroxime: 210 +/- 10 and 320 +/- 15%, respectively. Potassium ferricyanide oxidation of these compounds under mild conditions formed nitroprusside ion, as registered by the electrochemical (polarographic) method; this is evidence that these compounds are NO donors. It is concluded that the activation of guanylate cyclase by the tested compounds is associated with their ability to generate NO during their biotransformation. The possible role of guanylate cyclase activation by oxime derivatives in the mechanism underlying the reactivation of inhibited choline esterase at the cell level is discussed.
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PMID:Role of soluble guanylate cyclase in reactivation of choline esterase inhibited by phosphoorganic compounds. 998 19

Involvement of nitric oxide (NO) in nociceptive transmission is well documented. However, there is controversy concerning the exact role of NO in mediation of nociception at different levels of the nervous system. Most studies agree that NO promotes hyperalgesia at the level of the spinal cord. Conversely, at supraspinal sites exogenously applied NO has been found to be both pro- and antinociceptive. In light of this discrepancy, the aim of the present study was to compare the effects of NO donors on nociceptive transmission at spinal and supraspinal sites of the central nervous system using mechanical (paw pressure; PP) and thermal (tail-flick; TF) noxious stimulation. Four NO donors which release NO through different mechanisms were used: S-nitrosoglutathione (SNOG; 3-600 nmol), S-nitroso-N-acetylpenicillamine (SNAP; 0.18-4.5 nmol), hydroxylamine (HYD; 60-1200 nmol) and 3-morpholino-sydnonimine (SIN-1; 490-970 nmol). They were injected intrathecally (i.t.) or intracerebroventricularly (i.c.v.) to male Wistar rats and nociceptive thresholds were evaluated in TF and PP tests. It was found that NO donors administered i.t. or i.c.v. produced a dose-dependent hyperalgesia in the PP test. The hyperalgesia induced by mechanical stimuli was stronger after i.t. than after i.c.v. administration of NO donors. The SIN-1-induced hyperalgesia, as evaluated by teh PP test, was reversed by i.t. pretreatment with haemoglobin (1.5-4 nmol) a NO scavenger, and methylene blue (267-1070 nmol) a guanylate cyclase and NO synthase inhibitor, suggesting that NO exerts its action by facilitating cyclic guanosine 3',5'-monophosphate (GMP) formation. Unlike in the PP test, SNAP and SNOG had no effect on the nociceptive threshold in the TF test, and only SIN-1 administered i.t. produced a weak hyperalgesia in that test, while HYD caused a mild but significant prolongation of the TF reflex. The above data show that NO produces hyperalgesia principally in response to noxious mechanical stimuli. This effect seems to be predominantly mediated in the spinal cord, however, it occurs at both levels of the central nervous system.
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PMID:Differential effects of intrathecally and intracerebroventricularly administered nitric oxide donors on noxious mechanical and thermal stimulation. 1038 23

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
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PMID:Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice. 1042 31

Experiments were carried out to explore the possible role played by the nitric oxide (NO) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation. Intracerebroventricular (ICV) or intra-OVLT administration of NO donors such as hydroxylamine, sodium nitro-prusside or s-nitro-acetylpenicillamine caused an up to 55 mmHg decrease in blood pressure (BP) but an increase in NO release (measured by porphyrin/nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV or intra-OVLT administration of N(G)-nitro-L-arginine methyl ester (L-NAME; a constitutive NO synthase inhibitor) caused an up to 45 mmHg increase in BP but a fall in NO release in the OVLT. Compared with the BP responses induced by ICV injection of NO donors or NO synthase inhibitors, the OVLT route of injection required a much lower dose of NO donors or NO synthase inhibitors to produce a similar BP effect. The depressor effects induced by ICV or intra-OVLT administration of NO donors were attenuated by pretreatment with intra-OVLT injection of methylene blue (an inhibitor of guanylate cyclase), haemoglobin (a NO scavenger), L-NAME or spinal transection. On the other hand, the L-NAME-induced pressor effects were attenuated by pretreatment with intra-OVLT injection of L-arginine or spinal transection. The data suggest that activation of cyclic GMP-dependent NO synthase in the OVLT of rat brain causes cyclic GMP-dependent decreases in arterial pressure via inhibiting the sympathetic efferent activity.
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PMID:Central control of blood pressure by nitrergic mechanisms in organum vasculosum laminae terminalis of rat brain. 1045 3

1. Certain heterocyclic N-oxides are vasodilators and inhibitors of platelet aggregation. The pharmacological activity of the furoxan derivative condensed with pyridazine di-N-oxide 4,7-dimethyl-1,2, 5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (FPTO) and the corresponding furazan (FPDO) was studied. 2. FPTO reacted with thiols generating nitrite (NO), S-nitrosoglutathione and hydroxylamine (nitroxyl) and converted oxyHb to metHb. FPDO did not generate detectable amounts of NO-like species but reacted with thiols and oxyHb. 3. FPTO and FPDO haem-dependently stimulated the activity of soluble guanylate cyclase (sGC) and this stimulation was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and by 0.1 mM dithiothreitol. 4. FPTO relaxed noradrenaline-precontracted aortic rings and its concentration-response curve was biphasic (pIC(50)=9. 03+/-0.13 and 5.85+/-0.06). FPDO was significantly less potent vasodilator (pIC(50)=5.19+/-0.14). The vasorelaxant activity of FPTO and FPDO was inhibited by ODQ. oxyHb significantly inhibited only FPTO-dependent relaxation. 5. FPTO and FPDO were equipotent inhibitors of ADP-induced platelet aggregation (IC(50)=0.63+/-0.15 and 0.49+/-0. 05 microM, respectively). The antiplatelet activity of FPTO (but not FPDO) was partially suppressed by oxyHb. The antiaggregatory effects of FPTO and FPDO were only partially blocked by sGC inhibitors. 6. FPTO and FPDO (10 - 20 microM) significantly increased cyclic GMP levels in aortic rings and platelets and this increase was blocked by ODQ. 7. Thus, FPTO can generate NO and, like FPDO, reacts with thiols and haem. The vasorelaxant activity of FPTO and FPDO is sGC-dependent and a predominant role is played by NO at FPTO concentrations below 1 microM. On the contrary, inhibition of platelet aggregation is only partially related to sGC activation.
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PMID:Vasorelaxant and antiplatelet activity of 4,7-dimethyl-1,2, 5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide: role of soluble guanylate cyclase, nitric oxide and thiols. 1072 65

Nitric oxide (NO) modulates processes of synaptic transmission at pre- and postsynaptic levels. In the present work we studied the mechanisms of action of NO on [gamma-14C]amino-n-butyric acid ([14C]GABA) release in rat cortical synaptosomes. NO donors--S-nitroso-L-cysteine and hydroxylamine (but not sodium nitroprusside)--inhibited the neurotransmitter efflux in a concentration range from 10 microM to 1 mM. Nitrosocysteine completely and selectively suppressed the Ca2+-dependent (vesicular) [14C]GABA release, while not affecting the Ca2+-independent component of the [14C]GABA transport. The influence of NO donors was not related to activation of guanylyl cyclase, since the membrane-permeable cGMP analog dibutyryl-cGMP did not mimic and the guanylyl cyclase inhibitor methylene blue did not change the NO effects. In contrast, the membrane-permeable SH-reagent N-ethylmaleimide (NEM) resembled the effects of NO donors on the Ca2+-dependent [14C]GABA release. The degree of inhibition of the release by nitrosocysteine, hydroxylamine, and NEM correlated with their ability to oxidize intra-synaptosomal SH-groups. These data suggest that synaptosomal sulfhydryl groups are the target for NO action at the presynaptic level. The NO-induced oxidation of thiols may be involved in physiological and, especially, pathological effects of nitric oxide in the central nervous system.
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PMID:Effects of nitric oxide donors on Ca2+-dependent [14C]GABA release from brain synaptosomes: the role of SH-groups. 1104 94

Yawning is a phylogenetically old, stereotyped event that occurs alone or associated with stretching and/or penile erection in humans, in animals from reptiles to birds and mammals, under different conditions. Several neurotransmitters and neuropeptides are involved in its control at the central level. One of these at the level of the paraventricular hypothalamic nucleus (PVHN) is nitric oxide (NO). First, NO synthase inhibitors injected into this hypothalamic nucleus prevent yawning induced by dopamine agonists, oxytocin or N-methyl-D-aspartic acid (NMDA), which induce yawning by activating PVHN oxytocinergic neurons projecting to extra-hypothalamic brain areas. The inhibitory effect of NO synthase inhibitors was not observed when these compounds were given concomitantly with L-arginine, the precursor of NO. Second, dopamine agonists, NMDA and oxytocin given at doses that induce yawning, increase NO production in the PVHN, as determined by in vivo microdialysis. Conversely, the opiate morphine, which prevents yawning induced by dopamine agonists, oxytocin and NMDA, also prevents the increase in the paraventricular NO production induced by these compounds. Third, NO donors, such as nitroglycerin, sodium nitroprusside and hydroxylamine, induce yawning when injected into the PVHN apparently by activating oxytocinergic transmission. Since guanylate cyclase inhibitors and NO scavengers (hemoglobin) injected into the PVHN do not prevent drug-induced yawning, nor 8-Br-cGMP injected into the PVHN induces this behavioral response, it is likely that NO acts as an intracellular rather than an intercellular modulator inside the PVHN oxytocinergic neurons in which NO is formed to facilitate the expression of this phylogenetically old event by guanylate cyclase-independent mechanisms.
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PMID:Yawning: role of hypothalamic paraventricular nitric oxide. 1124 84

Nitric oxide (NO), a radical gas, acts as a multifunctional intra- and intercellular messenger. In the present study we investigated the effects of NO on muscle membrane potassium currents of isolated single muscle fibers from the marine isopods, Idotea baltica, using two-electrode voltage clamp recording techniques. Voltage-activated potassium currents consist of an outward current with fast activation and inactivation kinetics and a delayed, persistent outward current. Both currents were blocked by extracellular 4-aminopyridine and tetraethylammonium; the currents were not blocked by charybdotoxin or apamin. Application of the NO donors S-nitroso-N-acetylpenicillamine (SNAP) or hydroxylamine increased both the early and the delayed outward current in a dose- and time-dependent manner. PTIO, a NO scavenger, suppressed the effect of SNAP. N-Acetyl-dl-penicillamine, a related control compound which does not liberate NO, had no significant effect on outward currents. Methylene blue, a guanylyl cyclase inhibitor, prevented the increase of the outward current while 8-bromo-cGMP increased the current. Our experiments show that potassium currents of Idotea muscle are increased by NO donors. They suggest that NO by stimulating cGMP production mediates the effects on membrane currents involved in regulation of invertebrate muscle excitability.
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PMID:Nitric oxide activates voltage-dependent potassium currents of crustacean skeletal muscle. 1148 74

The present study describes the role of endothelium in the vascular response to purified acteoside from Ligustrum purpurascens in rat mesenteric arteries. In endothelium-intact rings, acteoside (3-50 micromol/L) enhanced phenylephrine-induced contraction without affecting the maximum response. This enhancement was absent in endothelium-denuded rings. Pretreatment with nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine (L-NNA, 100 micromol/L) and N(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/L), or a selective guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ, 10 micromol/L), increased both the sensitivity of vasoconstriction to phenylephrine and the maximal response. The enhancing effect of acteoside (30 micromol/L) was abolished in the presence of L-NAME, L-NNA, or ODQ. Tetraethylammonium (TEA(+), 3 mmol/L), a putative K(+) channel blocker, also abolished the effect of acteoside. CaCl2 (0.01-10 mmol/L) induced contractions in 50 mmol/L K(+)-containing Krebs solution. Neither acteoside nor TEA(+) affected CaCl2-induced contraction in elevated K(+) solution. Acteoside (30 micromol/L) attenuated acetylcholine-induced endothelium-dependent relaxation. Acteoside did not influence relaxation induced by exogenous NO donors, hydroxylamine or sodium nitroprusside, in endothelium-denuded rings. Acteoside did not alter endothelium-independent relaxation induced by forskolin or NS 1619. The present results indicate that acteoside enhanced the evoked vasoconstriction, mainly through inhibition of endothelial NO production/release and inhibition of NO-mediated TEA(+)-sensitive activation of K(+) channels.
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PMID:Enhancement of contraction of rat mesenteric artery by acteoside: role of endothelial nitric oxide. 1214 58


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