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)

Estradiol is known to exert a protective effect against the development of atherosclerosis, but the mechanism by which this protection is mediated is unclear. Since animal studies strongly suggest that production of endothelium-derived relaxing factor is enhanced by estradiol, we have examined the effect of estrogens on nitric oxide (NO) synthase (NOS) activity, protein, and mRNA in cultured bovine aortic endothelial cells. In reporter cells rich in guanylate cyclase, it has been observed that long-term treatment (> or = 24 hr) with ethinylestradiol (EE2) dose-dependently increased guanylate cyclase-activating factor activity in the conditioned medium of endothelial cells. However, conversion of L-[14C]arginine to L-[14C]citrulline by endothelial cell homogenate or quantification of nitrite and nitrate released by intact cells in the conditioned medium did not reveal any change in NOS activity induced by EE2 treatment. Similarly, Western and Northern blot analyses did not reveal any change in the endothelial NOS protein and mRNA content in response to EE2. However, EE2 dose- and time-dependently decreased superoxide anion production in the conditioned medium of endothelial cells with an EC50 value (0.1 nM) close to that which increased guanylate cyclase-activating factor activity (0.5 nM). Both of these effects were completely prevented by the antiestrogens tamoxifen and RU54876. Thus, endothelium exposure to estrogens appears to induce a receptor-mediated antioxidant effect that enhances the biological activity of endothelium-derived NO. These effects could account at least in part for the vascular protective properties of these hormones.
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PMID:Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting superoxide anion production. 863 24

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

1. Inhibitory junction potentials (IJPs) and relaxations evoked in response to field stimulation (supramaximal voltage, 0.1 ms, single stimulus and 5 stimuli at 5-40 Hz) of non-adrenergic non-cholinergic (NANC) nerves with atropine and phentolamine (each 1 microM) were measured in the guinea-pig internal anal sphincter (gpIAS). The mean resting membrane potential was -44.2 +/- 0.2 mV (n = 1119 cells from 260 preparations). 2. NANC nerve stimulation evoked frequency-dependent IJPs (19.7 +/- 1.1 mV, n = 165, 33 tissues to a single stimulus) and relaxations. IJPs consisted of two tetrodotoxin (1 microM)-sensitive components: one was abolished by apamin (0.3 microM) and the P2-purinoceptor antagonist suramin (100 microM); the other, smaller in amplitude, was sensitive to inhibitors of nitric oxide synthase (NOS, e.g. L-NAME, 100 microM) and the nitric oxide (NO) scavenger oxyhaemoglobin (HbO, 10 microM). 3. ATP (1 mM), vasoactive intestinal polypeptide (VIP, 0.01-0.25 microM) and pituitary adenylate cyclase-activating peptide (PACAP(1-27), 0.84 microM) each hyperpolarized and relaxed the gpIAS; only ATP responses resembled the evoked IJPs in time course. 4. The guanylyl cyclase inhibitor LY83583 (10 microM) abolished apamin-insensitive IJPs and relaxations. The cGMP phosphodiesterase inhibitor M&B 22948 (30 microM) and 8-Br-cGMP (100 microM) each hyperpolarized the gpIAS. 5. Two components comprise the IJP and relaxation evoked in response to NANC nerve stimulation in the gpIAS. One, sensitive to apamin, resembles the response to ATP and is modulated by purinoceptor antagonists; the other, apamin and suramin insensitive, is inhibited by NO antagonists.
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PMID:Neuronal mediators of inhibitory junction potentials and relaxation in the guinea-pig internal anal sphincter. 878 13

Nitric oxide (NO) acts as an autocrine- and paracrine-acting signaling autacoid that, among other functions, has been shown to regulate cardiac contractile responsiveness to beta-adrenergic and muscarinic cholinergic agonists. Nitric oxide (NO) is formed by the oxidation of one of two equivalent guanidino nitrogens in L-arginine by O2 to form NO and L-citrulline. This reaction is catalyzed by a family of enzymes termed NO synthases. Three distinct isoforms of NOS have been identified, each the product of a separate gene. Cellular constituents of cardiac muscle, including ventricular myocytes as well as microvascular endothelial cells, have been shown to express the "endothelial constitutive" isoform of NO synthase (ecNOS or NOS3) in vivo, and both cell types also express the NO synthase isoform induced by specific inflammatory cytokines (iNOS or NOS2) in vivo and in vitro. While NO-dependent intracellular signalling in cardiac myocytes clearly involves the activation of guanylate cyclase and downstream signalling by cGMP, there is accumulating evidence that non-cGMP-dependent regulatory signalling events are also initiated by NO. In addition, decreased contractile responsiveness of cardiac myocytes to beta-adrenergic agonists, following induction of NOS2 by inflammatory cytokines, requires the presence of insulin and the co-induction of enzymes responsible for production of tetrahydrobiopterin, a NOS co-factor. Inappropriate or excessive production of NO by cardiac myocytes and by microvascular endothelial cells likely contributes to the cardiac contractile dysfunction characteristic of the systemic inflammatory response syndrome and cardiac allograft rejection.
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PMID:The role of the NO pathway in the control of cardiac function. 895 72

Although endogenous nitric oxide (NO) modulates basal tone in the fetal pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal lambs demonstrated strong staining for endothelial NO synthase (eNOS) in DA endothelium. To study the physiological role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) system in the DA in vivo, we measured the hemodynamic effects of NG-nitro-L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxygenase inhibitor, in 10 chronically prepared late-gestation fetal lambs. L-NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0.05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a slight rise in resistance across the DA. Methylene blue increased both MPA pressure and the pressure gradient between the MPA and the aorta from 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.05) after 40 min. Indomethacin decreased DA flow and increased DA resistance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cyclooxygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We speculate that, although the NO and cGMP system modulates DA tone, prostaglandins may play a greater role.
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PMID:Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus. 899 26

Using immunohistochemistry and in situ hybridization, it has been previously shown that gonadotropes and folliculo-stellate cells in the rat anterior pituitary gland express nitric oxide (NO) synthase (NOS), and that NOS expression is increased by gonadectomy. Using the indirect immunofluorescence technique in conjunction with antibodies raised to conjugated cGMP, we have attempted to establish the target cells for NO in the anterior pituitary and to define the mediator of NO regulation. After incubation of pituitary slices with several NO donors, numerous endocrine cells, but no folliculo-stellate cells, expressed cGMP. Most of these cells stained for LH, that is they were gonadotropes. However, there were apparently cGMP-positive, LH-negative and LH-positive, cGMP-negative endocrine cells. The increase in cGMP could be virtually completely blocked by a guanylyl cyclase inhibitor. cGMP was not expressed in corticotropes, but cGMP-positive cells often contained NOS-like immunostaining. Incubation with GnRH did not result in detectable levels of cGMP. However, when castrated rats were pretreated with a potent longlasting GnRH antagonist, antide, the castration-induced increase in NOS was completely blocked. This suggests that GnRH is involved in the in vivo upregulation of NOS after castration, but that GnRH cannot induce cGMP accumulation in normal pituitary slices in vitro. Taken together, the present results give further evidence for a role of NO in the control of, in particular, LH secretion from the anterior pituitary gland in the rat.
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PMID:Nitric oxide synthase and cGMP in the anterior pituitary gland: effect of a GnRH antagonist and nitric oxide donors. 906 93

The stimulation of NMDA receptor activates NO dependent cGMP biosynthesis with dynamic and extent different for hippocampus and brain cortex. The significantly higher NO mediated cGMP level was observed in hippocampus than in brain cortex. NMDA receptor stimulation increases NO mediated cGMP formation about 8 fold in hippocampus and 2.5 fold in brain cortex as compared to basal value (2 mM CaCl2). The activity of NO synthase and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus then in brain cortex. The CA2+ calmodulin dependent NO synthase was found in brain membrane and cytosol fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in a dose of 40 mg/kg b.w. Brain ischemia induced by ligation of both common carotid arteries in gerbils increases significantly NOS activities as well as the level of cGMP and putrescine but decreases mono-ADP-ribosylation of brain proteins during reperfusion period. The ischemia evoked changes of NOS/cGMP were eliminated by specific inhibitor of neuronal form of NOS, 7-Nitrodazole (7NI) administered in a dose of 25 mg/kg b.w. 5 min. before ischemia. This inhibitor has no effect on the level of putrescine enhanced during ischemia and also biphasically during reperfusion. The inhibitor of guanylate cyclase, LY 83583 administered in a dose of 6 mg/kg b.w. 5 min before ischemia diminishes not only the enhanced level of cGMP but also NOS activity stimulated by ischemia. These results indicate that activation of NMDA receptor stimulates more significantly NO/cGMP production in hippocampus than in brain cortex suggesting the role of NO in neuronal form of NOS and inhibitor of guanylate cyclase protect the brain against excessive production of nitric oxide and cGMP during ischemia-reperfusion. These compounds may offer a new strategy in the therapy of brain ischemia.
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PMID:NMDA receptor mediated nitric oxide dependent cGMP synthesis in brain cortex and hippocampus. Effect of ischemia on NO related biochemical processes during reperfusion. 910 Feb 45

In primary cocultures of neurons and glial cells prepared from the neonatal rat brain, lipopolysaccharide (LPS) reduced the numbers of neuronal cells but the effects were markedly inhibited by NG-monomethyl-L-arginine, indicating the involvement of NO and LPS-induced NO synthase in neuronal death. LPS stimulated the expression of inducible NOS (iNOS) in preparations of primary cultured microglias/astrocytes, but not in primary cultured neurons. In addition, LPS caused DNA fragmentation only in NG108-15 cells but not in primary cultured astrocytes as well as astrocytes in cocultures of the two cell types, suggesting that NOS induces the apoptosis of neurons but not glial cells. We then examined the NO-induced neuronal death in NG108-15 cells using NO donors. SNP, and NO donor, caused NO-2 accumulation in the reaction medium and lactate dehydrogenase (LDH) leakage from NG108-15 cells. Although SNP stimulated guanylyl cyclase and accumulated cGMP, cGMP analogs did not affect LDH leakage. In addition, SNP induced chromosomal condensation and fragmentation of nuclei in NG108-15 cells. Gel electrophoretic analysis of cellular DNA extracted from SNP-treated cells, confirmed the internucleosomal DNA fragmentation typical of apoptosis in this culture. SNP increased the amount of radioisotopic labeled glyceraldehyde-3 phosphate dehydrogenase (GAPDH) in the presence of [32P]NAD and inhibited the enzyme activity. The results suggested that SNP-induced cell death is partly due to the NO-induced inhibition of GAPDH, perhaps by stimulating the binding of NAD to GAPDH.
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PMID:Neuronal apoptosis by glial NO: involvement of inhibition of glyceraldehyde-3-phosphate dehydrogenase. 918 51

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.
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PMID:Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. 921 22

1. In airway epithelium, nitric oxide (NO) is synthesized in the setting of inflammation by inducible nitric oxide synthase (iNOS). Although the role of epithelial derived NO in the regulation of human airways is unknown, prostaglandin E2 (PGE2) is recognised as an important inhibitory mediator in human airways. Cyclo-oxygenase (COX) is the rate limiting enzyme in the production of prostanoids and since inflammatory pathways enhance the expression of an inducible COX (COX-2), both COX-2 and iNOS may be co-expressed in response to an inflammatory stimulus. Although regulation of the COX-2 pathway by NO has been demonstrated in animal models, its potential importance in human airway epithelium has not been investigated. 2. The effect of endogenous and exogenous NO on the COX-2 pathway was investigated in the A549 human airway epithelial cell culture model. Activity of the COX-2 pathway was assessed by PGE2 EIA, and iNOS pathway activity by nitrite assay. A combination cytokine stimulus of interferon gamma (IFNgamma) 100 u ml(-1), interleukin-1beta (IL-1beta) 1 u ml(-1) and lipopolysaccharide (LPS) 10 microg ml(-1) induced nitrite formation which could be inhibited by the competitive NOS inhibitor N(G)-nitro-L-arginine-methyl-ester (L-NAME). IL-1beta alone (1-50 u ml(-1) induced PGE2 formation without significant nitrite formation, a response which was inhibited by the COX-2 specific inhibitor nimesulide. Submaximal stimuli used for further experiments were IFNgamma 100 u ml(-1), IL-1beta 1 u ml(-1) and LPS 10 microg ml(-1) to induce both the iNOS and COX-2 pathways, and IL-1beta 3 u ml(-1) to induce COX-2 without iNOS activity. 3. Cells treated with IFNgamma 100 u ml(-1), IL-1beta I u ml(-1) and LPS 10 microg ml(-1) for 48 h either alone, or with the addition of L-NAME (0 to 10(-2) M), demonstrated inhibition by L-NAME of PGE2 (3.61 +/- 0.55 to 0.51 +/- 0.04 pg/l0(4) cells; P<0.001) and nitrite (34.33 +/- 8.07 to 0 pmol/10(4) cells; P<0.001) production. Restoration of the PGE2 response (0.187 +/- 0.053 to 15.46 +/- 2.59 pg/10(4) cells; P<0.001) was observed after treating cells with the same cytokine stimulus and L-NAME 10(-6) M, but with the addition of the NOS substrate L-arginine (0 to 10(-5) M). 4. Cells incubated with IL-1beta 3 u ml(-1) for 6 h, either alone or with addition of the NO donor S-nitroso-acetyl-penicillamine (SNAP) (0 to 10(-4) M), demonstrated increased PGE2 formation (1.23 +/- 0.03 to 2.92 +/- 0.19 pg/10(4) cells; P< 0.05). No increase in PGE2 formation was seen when the experiment was repeated in the presence of the guanylate cyclase inhibitor methylene blue (50 microM). Cells treated with SNAP alone did not demonstrate an increased PGE2 formation. Cells incubated with IL-1beta 3 u ml(-1) for 6 h in the presence of dibutyryl cyclic guanylate monophosphate (0 to 10(-3) M) also demonstrated an increased PGE2 response (2.56 +/- 0.21 to 4.53 +/- 0.64 pg/10(4) cells; P<0.05). 5. These data demonstrate that in a human airway epithelial cell culture system, both exogenous and endogenous NO increase the activity of the COX-2 pathway in the setting of inflammatory cytokine stimulation, and that this effect is likely to be mediated by guanylate cyclase. This suggests a role for NO in the regulation of human airway inflammation.
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PMID:Regulation of the inducible cyclo-oxygenase pathway in human cultured airway epithelial (A549) cells by nitric oxide. 925 31


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