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)

Challenge of guinea pig mast cells with antigen under aerobic conditions induced the expected release of histamine and led to a significant increase in intracellular calcium ([Ca2+]i) and cyclic adenosine monophosphate (cAMP) levels. Prior exposure to CO decreased the immunological histamine release. This effect was accompanied by a decrease in the levels of [Ca2+]i and by an increase in the cyclic guanosine monophosphate (cGMP) levels. The exposure of mast cells to nitrogen (N2) did not modify the release of histamine. The CO-mediated inhibition of the immunological release of histamine was reversed by the soluble guanylate cyclase inhibitor (1 H-[1.2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and by oxyhaemoglobin (HbO2). Incubation of mast cells for 4 h with hemin, a heme oxygenase (HO) inducer, resulted in an increase in HO activity, measured as bilirubin production. Hemin abated the immunological release of histamine, in similar fashion to exogenous CO, and increased the cGMP levels. These effects were reversed by ODQ and HbO2. It is proposed that CO from an exogenous or endogenous source stimulates guanylyl cyclase and causes cGMP formation which then induces calcium to be sequestrated so that the [Ca2+]i concentration falls and histamine release is inhibited.
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PMID:Modulation of the immunological response of guinea pig mast cells by carbon monoxide. 1043 58

1. Nitric oxide (NO) has been shown to modulate neuropeptide secretion from the posterior pituitary. Here we show that NO activates large-conductance Ca2+-activated K+ (BK) channels in posterior pituitary nerve terminals. 2. NO, generated either by the photolysis of caged-NO or with chemical donors, irreversibly enhanced the component of whole-terminal K+ current due to BK channels and increased the activity of BK channels in excised patches. NO also inhibited the transient A-current. The time courses of these effects on K+ current were very different; activation of BK channels developed slowly over several minutes whereas inhibition of A-current immediately followed NO uncaging. 3. Activation of BK channels by NO occurred in the presence of guanylyl cyclase inhibitors and after removal of ATP or GTP from the pipette solution, suggesting a cGMP-independent signalling pathway. 4. The sulfhydryl alkylating agent N-ethyl maleimide (NEM) increased BK channel activity. Pretreatment with NEM occluded NO activation. 5. NO activation of BK channels occurred independently of voltage and cytoplasmic Ca2+ concentration. In addition, NO removed the strict Ca2+ requirement for channel activation, rendering channels highly active even at nanomolar Ca2+ levels. 6. These results suggest that NO, or a reactive nitrogen byproduct, chemically modifies nerve terminal BK channels or a closely associated protein and thereby produces an increase in channel activity. Such activation is likely to inhibit impulse activity in posterior pituitary nerve terminals and this may explain the inhibitory action of NO on secretion.
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PMID:Direct actions of nitric oxide on rat neurohypophysial K+ channels. 1051 9

The discoveries of physiological roles of nitric oxide (.NO) as the mediator of endothelium-derived relaxing factor (EDRF) action and the activator of guanylyl cyclase to increase cyclic guanosine monophosphate (cGMP), which lead to vasorelaxation in the cardiovascular system, have been awarded with the 1998 Nobel Prize of Medicine. The present review discusses putative beneficial effects of .NO in the central nervous system (CNS). In addition to its prominent roles of the regulation of cerebral blood flow and the modulation of cell to cell communication in the brain, recent in vitro and in vivo results indicated that .NO is a potent antioxidative agent. .NO terminates oxidant stress in the brain by (i) suppressing iron-induced generation of hydroxyl radicals (.OH) via the Fenton reaction, (ii) interrupting the chain reaction of lipid peroxidation, (iii) augmenting the antioxidative potency of reduced glutathione (GSH) and (iv) inhibiting cysteine proteases. It is apparent that .NO--a relative long half-life nitrogen-centered weak radical--scavenges those short-lived, highly reactive free radicals such as superoxide anion (O2.-), .OH, peroxyl lipid radicals (LOO.) and thiyl radicals (i.e., GS.), yielding reactive nitrogen species including nitrites, nitrates, S-nitrosoglutathione (GSNO) and peroxynitrite (ONOO-). GSNO is 100-fold more potent than GSH; it completely inhibits the weak peroxidative effect of ONOO-. Moreover, CO2 and .NO neutralize prooxidative effects of ONOO-. CO2 prevents protein oxidation but not 3-nitrotyrosine formation caused by ONOO-. Finally, neuroprotective effects of GSNO and .NO have been demonstrated in brain preparations in vivo. These novel neuroprotective properties of .NO and GSNO may have their physiological significance, since oxidative stress depletes GSH while increasing GS. and .NO formation in astroglial and endothelial cells, resulting in the generation of a more potent antioxidant GSNO and providing additional neuro-protection at microM concentrations. This putative GSNO pathway (GSH-->GS.-->GSNO-->.NO + GSSG-->GSH) may be an important part of endogenous antioxidative defense system, which could protect neurons and other brain cells against oxidative stress caused by oxidants, iron complexes, proteases and cytokines. In conclusion, .NO is a potent antioxidant against oxidative damage caused by reactive oxygen species, which are generated by Fenton reaction or other mechanisms in the brain via redox cycling of iron complexes.
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PMID:Neuroprotective properties of nitric oxide. 1066 35

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cGMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague-Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline (ip) or MB (ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NO(x)) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NO(x) and striatal cGMP. Furthermore, NO(x) and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NO(x) or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NO(x)-cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development.
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PMID:Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. 1084 Jan 45

Dopamine-beta-hydroxylase (DbetaH) is a copper-containing enzyme that uses molecular oxygen and ascorbate to catalyze the addition of a hydroxyl group on the beta-carbon of dopamine to form norepinephrine. While norepinephrine causes vasoconstriction following reflex sympathetic stimulation, nitric oxide (NO) formation results in vasodilatation via a guanylyl cyclase-dependent mechanism. In this report, we investigated the relationship between NO and DbetaH enzymatic activity. In the initial in vitro experiments, the activity of purified DbetaH was inhibited by the NO donor, diethylamine/NO (DEA/NO), with an IC(50) of 1 mm. The inclusion of either azide or GSH partially restored DbetaH activity, suggesting the involvement of the reactive nitrogen oxide species, N(2)O(3). Treatment of human neuroblastoma cells (SK-N-MC) with diethylamine/NO decreased cellular DbetaH activity without affecting their growth rate and was augmented by the depletion of intracellular GSH. Co-culture of the SK-N-MC cells with interferon-gamma and lipopolysaccharide-activated macrophages, which release NO, also reduced the DbetaH activity in the neuroblastoma cells. Our results are consistent with the hypothesis that nitrosative stress, mediated by N(2)O(3), can result in the inhibition of norepinephrine biosynthesis and may contribute to the regulation of neurotransmission and vasodilatation.
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PMID:Inhibitory effects of nitric oxide and nitrosative stress on dopamine-beta-hydroxylase. 1088 4

Acute endotoxemic renal failure involves renal vasoconstriction, which presumably occurs despite increased nitric oxide (NO) generation by inducible NO synthase in the kidney. The present study examined the hypothesis that the renal vasoconstriction during endotoxemia occurs in part because of desensitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shock and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manner, reaching the highest levels at 24 h, in parallel with induction of inducible NO synthase protein in the renal cortex. In renal cortical slices obtained from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 24 h after injection of lipopolysaccharide. Incubation of renal cortical slices in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cGMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. However, in slices from 24-h endotoxemic mice, accumulation of cGMP in response to sodium nitroprusside was significantly lower. This lower stimulability of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the associated renal vasoconstriction.
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PMID:Desensitization of soluble guanylate cyclase in renal cortex during endotoxemia in mice. 1105 91

Nitric oxide (NO) is a natural and stable free radical produced in soil and water by the bacteriological reduction of nitrites and nitrates and in animals by the enzyme oxidation of L-arginine. NO is biosynthesised by finely regulated enzymatic systems called NO-synthases and readily diffuses through tissues. It reacts rapidly with hemoproteins and iron-sulphur centers to form nitrosylated compounds. It oxidises more slowly to form nitrogen oxides that nitrosate thiols into thionitrite. NO is transported in these various forms and released spontaneously or through yet unclear mechanisms into most cells; it also regulates oxygen consumption at the mitochondrial respiratory chain level through interaction with cytochrome oxidase. In the cardiovascular system, NO lowers blood pressure by activating a hemoprotein, the guanylate cyclase present in muscle cells; through such interaction it acts also as a neuromediator and neuromodulator in the nervous system. However, many of NO's roles result from rapid coupling to other radicals; for example, it reacts with the superoxide anion (O2-) to form oxoperoxinitrate (ONOO-, also known as peroxynitrite). This strong oxidant of metallic centers, thiols, and antioxidants is also able to convert tyrosine to 3-nitrotyrosine and to act upon tyrosine residues contained in proteins. The biological aspects of the roles of NO are presented with particular respect to the rapid interactions of NO with hemoproteins' iron and other radicals. Concurrently, NO oxidation enables nitrosation reactions primarily of thiols but ultimately of nucleic bases. The thionitrite function (R-S-NO) thus formed and the dimerisation and nitration of tyrosine residues are protein post-translational modifications that are being investigated in animals.
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PMID:[Intervention by nitric oxide, NO, and its oxide derivatives particularly in mammals]. 1123 75

We have shown that endogenous nitrogen oxides (NOx) modulate excitation-contraction coupling in diaphragm. Because cyclic GMP (cGMP) is a second messenger for nitric oxide (NO) inhibition of smooth muscle contraction, we rested the hypothesis that NO acts via cGMP in diaphragm. Fiber bundles from rat diaphragm were studied in vitro. Immunohistochemical analysis using a cGMP-specific monoclonal antibody confirmed the presence of cGMP in the subsarcolemmal region, near nitric oxide synthase (NOS). cGMP measured by ELISA in control muscle (0.27 pmol/mg +/- 0.01 SE) was significantly increased by the NO donor S-nitroso-N-acetylcysteine 1 mM (0.55+/-0.05; N = 6; P < 0.001). Contractile studies showed that the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) 10 mM increased submaximal (40 Hz) tetanic force (P < 0.0001). L-NNA effects were exaggerated by the guanylate cyclase inhibitor LY83583 5-10 microM; force at 40 Hz was increased (P < 0.001). L-NNA effects were partially reversed by 8-bromo-cGMP 1 mM (8-Br-GMP; a cell-permeable cGMP analogue; P < 0.0001) or dipyridamole 10 microM (DPM; a phosphodiesterase inhibitor; P < 0.0001). 8-Br-GMP and DPM produced more-complete L-NNA reversal in combination (P < 0.0001). We conclude that cGMP functions as a second messenger by which NO inhibits diaphragm contraction.
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PMID:Cyclic GMP is a second messenger by which nitric oxide inhibits diaphragm contraction. 1125 83

Nitric oxide (NO), a simple free radical gas, elicits a surprisingly wide range of physiological and pathophysiological effects. NO interacts with soluble guanylate cyclase to evoke many of these effects. However, NO can also interact with molecular oxygen and superoxide radicals to produce reactive nitrogen species that can modify a number of macromolecules including proteins, lipids, and nucleic acids. NO can also interact directly with transition metals. Here, we have reviewed the non--3',5'-cyclic-guanosine-monophosphate-mediated effects of NO including modifications of proteins, lipids, and nucleic acids.
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PMID:Novel effects of nitric oxide. 1126 56

Haloperidol persists in brain tissue long after discontinuation while haloperidol-induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol-associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol-induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol-associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/guanylate cyclase inhibitor, methylene blue (5 mg/kg/d i.p.), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol-associated motor dysfunction.
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PMID:Early suppression of striatal cyclic GMP may predetermine the induction and severity of chronic haloperidol-induced vacous chewing movements. 1138 52


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