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)

Peroxynitrite (1-100 microM) induced a concentration-dependent relaxation of rat aortic rings; the logEC50 and maximum relaxation on endothelium-denuded rings were -5.31 +/- 0.03 and 105 +/- 5%, n = 6, respectively. The presence of the endothelium significantly impaired this relaxation (logEC50, -4.41 +/- 0.04; maximum relaxation, 71 +/- 4%; n = 6); an effect which was reversed by the inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM). Incubation with a high concentration of peroxynitrite (1 mM, 10 min followed by washout) had no effect on subsequent relaxation to acetylcholine (0.01-1 microM). It did, however, significantly depress subsequent contraction to phenylephrine (1-300 nM). This depression was dependent upon the presence of D-glucose in the Krebs solution, could be reversed by the inhibitor of soluble guanylate cyclase, methylene blue (10 microM) and reversed spontaneously after 2 h. When peroxynitrite (1 mM) was mixed with D-glucose (11 mM) and subsequently neutralised to remove unreacted peroxynitrite, a new more potent relaxant was formed. Despite this, the ability of peroxynitrite (1-100 microM) to produce relaxation of endothelium-denuded rings was similar in normal and glucose-free Krebs. Glycerol (22 mM), which like D-glucose is membrane permeant, also reacted with peroxynitrite (1 mM) to form a new more potent relaxant. L-cysteine (1 mM) had no effect by itself on the tone of aortic rings and when present in the tissue bath had no effect on the ability of peroxynitrite or neutralised peroxynitrite (1-100 microM) to produce relaxation. It did, however, potentiate the relaxant actions of the products formed from the reaction of peroxynitrite with D-glucose or glycerol. The membrane impermeant sugars, mannitol and sorbitol (each 11 mM) also reacted with peroxynitrite (1 mM), but expression of the vasorelaxant properties of their respective derivatives was seen only in the presence of L-cysteine (1 mM). Membrane permeance cannot, however, explain why peroxynitrite reacts with D-glucose and glycerol, but not mannitol or sorbitol to form products with intrinsic relaxant activity, as the product formed from the impermeant sugar, L-glucose (11 mM), also has intrinsic activity. The relaxant potency of this product was equipotent to that formed from D-glucose and was also potentiated by L-cysteine (1 mM). These result confirm that peroxynitrite can react with glucose and other compounds with alcohol functional groups to form vasorelaxant species. The relaxation induced when peroxynitrite is added to rat aortic rings is not, however, dependent upon this reaction since it occurs in glucose-free Krebs.
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PMID:The effects of peroxynitrite on rat aorta: interaction with glucose and related substances. 940 2

Neurohypophyseal secretion of arginine vasopressin is stimulated by decreased systemic glucose availability. Nitric oxide is produced by paraventricular and supraoptic magnocellular neurons, and is implicated in central mechanisms controlling plasma sasopressin and glucose levels. The current studies investigated the role of this neurotransmitter in glucoprivic induction of AP-1 transcriptional activity in hypothalamic vasopressinergic neurons by examining whether pharmacological manipulation of central nitric oxide/guanylate cyclase/cGMP signaling alters nuclear accumulation of Fos immunoreactivity in these cells. Adult male rats pretreated by intraventricular administration of saline exhibited extensive colabeling of vasopressinergic neurons in both brain sites for Fos following systemic injection of the glucose antimetabolite, 2-deoxy-D-glucose. Pretreatment with the nitric oxide donor. SIN1, resulted in decreased numbers of paraventricular and supraoptic Fos-positive vasopressinergic neurons during glucoprivation. In other animals. coadministration of SIN1 and the nitric-oxide sensitive guanylate cyclase inhibitor, ODQ, prior to the antimetabolite reversed these inhibitory effects of SIN1 on Fos expression by these cells. Intracerebral administration of ODQ alone did not significantly enhance expression of Fos by vasopressinergic neurons in either site. The present studies demonstrate that exogenous activation of the nitric oxide/guanylate cyclase/cGMP pathway in the brain inhibits nuclear accumulation of the AP-1 transcription factor, Fos, in vasopressinergic neurons during cellular glucopenia, and suggest that this neurotransmitter is critical for transactivational effects of glucoprivation on these neuropeptidergic neurons.
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PMID:Pharmacological manipulation of central nitric oxide/guanylate cyclase activity alters Fos expression by rat hypothalamic vasopressinergic neurons during acute glucose deprivation. 1056 36

Organic nitrates, such as glyceryl trinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20-h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20-h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.
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PMID:Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryl trinitrate-tolerant rat femoral arteries. 1096 51

Atrial natriuretic peptide (ANP) is a hormone involved in cardiovascular homeostasis through its natriuretic and vasodilator actions. The ANP receptor that mediates these actions is a glycosylated transmembrane protein coupled to guanylate cyclase. The role of glycosylation in receptor signaling remains unresolved. In this study, we determined, by a combination of HPLC/MS and Edman sequencing, the glycosylation sites in the extracellular domain of ANP receptor (NPR-ECD) from rat expressed in COS-1 cells. HPLC/MS analysis of a tryptic digest of NPR-ECD identified five glycosylated peptide fragments, which were then sequenced by Edman degradation to determine the glycosylation sites. The data revealed Asn-linked glycosylation at five of six potential sites. The type of oligosaccharide structure attached at each site was deduced from the observed masses of the glycosylated peptides as follows: Asn13 (high-mannose), Asn180 (complex), Asn306 (complex), Asn347 (complex), and Asn395 (high-mannose and hybrid types). Glycosylation at Asn180 and Asn347 was partial. The role of glycosyl moieties in ANP binding was examined by enzymatic deglycosylation of NPR-ECD followed by binding assay. NPR-ECD deglycosylated with endoglycosidase F2 and endoglycosidase H retained ANP-binding activity and showed an affinity for ANP similar to that of untreated NPR-ECD. Endoglycosidase treatment of the full-length ANP receptor expressed in COS-1 cells also had no detectable effect on ANP binding. These results suggest that, although glycosylation may be required for folding and transport of the newly synthesized ANP receptor to the cell surface, the oligosaccharide moieties themselves are not involved in hormone binding.
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PMID:Glycosylation sites in the atrial natriuretic peptide receptor: oligosaccharide structures are not required for hormone binding. 2698 Jul 29

Organic nitrates, such as glyceryltrinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20 h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20 h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.
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PMID:Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryltrinitrate-tolerant rat femoral arteries. 1109 Jun 52

We investigated the effects of endothelin 3 (ET-3) on electrolyte transport in rat small intestine using a voltage clamp technique in Ussing's chamber. ET-3 diminished potential difference (PD) and short circuit current (Isc). ET-3 did not affect PD or Isc in low Na(+) and/or D-glucose-free medium. Phloridzine (an inhibitor of sodium-glucose cotransporter [SGLT1]) pretreatment abolished the effect of ET-3 on Isc. Methylene blue (a soluble guanylate cyclase inhibitor) or N-nitro-L-arginine methyl ester (a NOS inhibitor) pretreatment delayed the effect of ET-3 on PD and Isc. ET-3 enhanced NOS activity on enterocytes and systemic NO production. Then, ET-3 could inhibit SGLT1 with the participation of NO.
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PMID:Effects of endothelin-3 on intestinal ion transport. 1178 92

ATP/dithiothreitol (DTT)-stimulated guanylate cyclase (GC) in lung membrane was stimulated 18-fold by ATP and DTT, and both its activity and atrial natriuretic peptide (ANP)-stimulated GC activity were observed to be additive. ATP/DTT-stimulated GC was solubilized by octyl glucoside (OG) to examine the mechanism of ATP/DTT-stimulation. GC in OG-extracts was stimulated maximally 2.5-fold by both ATP, ATPgammaS or AMPPNP, and DTT. Preincubation of OG-extracts at 10 degrees C with AMPPNP and DTT (1st-preincubation) converted GC to an insensitive state to stimulation by both ATP and DTT, and this conversion was partly inhibited by a protein phosphatase-1 inhibitor (10-1,000 nM okadaic acid). On the other hand, ANP-stimulated GC was not converted to an insensitive state to ANP/ATP-stimulation by the 1st-preincubation. Subsequent preincubation of OG-extracts at 10 degrees C with both DTT and, ATP or ATPgammaS but not AMPPNP converted GC to a state sensitive to ATP/DTT-stimulation, and this conversion was partly inhibited by inhibitors of Ca2+/calmodulin-dependent protein kinase II (KN-62 and KN-93). In contrast, the preincubation with KN-62 and KN-93 had no effect on ANP-stimulated GC activity. The results suggested that phosphorylation was involved in the regulation of ATP/DTT-stimulated GC sensitivity to ATP/DTT-stimulation and that ATP/DTT-stimulated GC activity was likely to be a different type from ANP-stimulated GC activity.
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PMID:Regulation of guanylate cyclase by ATP and dithiothreitol in rat lung membrane: involvement of an insensitive and a sensitive state to ATP/dithiothreitol-stimulation. 1208 46

The influence of streptonigrin on the activity of human platelet guanylyl cyclase was investigated. Streptonigrin (0.1-5 microM) had no effect on the basal activity of the enzyme, but inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet soluble guanylyl cyclase with an IC(50) value of 4.16 microM. Streptonigrin (10 microM) also inhibited (by 28%) the activation of the enzyme by the direct nitric oxide (NO) donor-spermine-NONO (100 microM), but had no influence on the stimulation of soluble guanylyl cyclase by protoporphyrin IX. The absence of a correlation between the inhibition of NO-stimulated guanylyl cyclase activity by streptonigrin (I) and its derivatives (streptonigrone (IV), streptonigrone-2'-imine (V), amide of 1 and 2'-deoxy-2'-amino-D-glucose (VI), amide of 1 and 2'-deoxy-2'-amino-2'-D-galactose (VII), amide of 1 and 1-O-methyl-6-deoxy-6-amino-D-glucose (VIII), diphenylmethyl ester of I (IX), conjugate of I and daunorubicin (X)), and the level of cytotoxic effects of these compounds excludes the involvement of guanylyl cyclase in the mechanism of antitumor action of streptonigrin. Inhibition of guanylyl cyclase activation by NO donors but not by protoporphyrin IX represents a new biochemical effect of streptonigrin, which should be taken into account in addition to its antitumor action.
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PMID:Antitumor antibiotic streptonigrin and its derivatives as inhibitors of nitric oxide-dependent activation of soluble guanylyl cyclase. 1472 99

GC-C (guanylate cyclase C) is the receptor for heat-stable enterotoxins, guanylin and uroguanylin peptides. Ligand binding to the extracellular domain of GC-C activates the guanylate cyclase domain leading to accumulation of cGMP. GC-C is expressed as differentially glycosylated forms in HEK-293 cells (human embryonic kidney-293 cells). In the present study, we show that the 145 kDa form of GC-C contains sialic acid and galactose residues and is present on the PM (plasma membrane) of cells, whereas the 130 kDa form is a high mannose form that is resident in the endoplasmic reticulum and serves as the precursor for the PM-associated form. Ligand-binding affinities of the differentially glycosylated forms are similar, indicating that glycosylation of GC-C does not play a role in direct ligand interaction. However, ligand-stimulated guanylate cyclase activity was observed only for the fully mature form of the receptor present on the PM, suggesting that glycosylation had a role to play in imparting a conformation to the receptor that allows ligand stimulation. Treatment of cells at 20 degrees C led to intracellular accumulation of a mature glycosylated form of GC-C that now showed ligand-stimulated guanylate cyclase activity, indicating that localization of GC-C was not critical for its catalytic activity. To determine if complex glycosylation was required for ligand-stimulated activation of GC-C, the receptor was expressed in HEK-293 cells that were deficient in N -acetylglucosaminyltransferase 1. This minimally glycosylated form of the receptor was expressed on the cell surface and could bind a ligand with an affinity comparable with the 145 kDa form of the receptor. However, this form of the receptor was poorly activated by the ligand. Therefore our studies indicate a novel role for glycosidic modification of GC-C during its biosynthesis, in imparting subtle conformational changes in the receptor that allow for ligand-mediated activation and perhaps regulation of basal activity.
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PMID:Glycosylation of the receptor guanylate cyclase C: role in ligand binding and catalytic activity. 1474 40

The aim was to evaluate whether high glucose influences the nitric oxide (NO)/cyclic nucleotide pathway in human platelets via osmotic stress and to clarify the role of protein kinase C (PKC) in this phenomenon. The study was carried out on 33 healthy lean male volunteers, aged 28.3+/-1.3 years. NO synthesis was detected as L-citrulline production after L-arginine incubation in platelets incubated for 6 min with 22.0 mM D-glucose and iso-osmolar concentrations of mannitol, L-glucose and fructose. To evaluate the influence of PKC, experiments with D-glucose and mannitol were repeated in the presence of the PKC-beta selective inhibitor LY379196, and NO synthesis was detected after a 6-min incubation with phorbol 12-myristate 13-acetate (PMA), a non-selective PKC activator. Platelet content of guanosine-3',5'-cyclic monophosphate (cGMP) and adenosine-3',5'-cyclic monophosphate (cAMP) was measured by radioimmunoassay in platelets incubated with iso-osmolar concentrations of D-glucose, mannitol, L-glucose and fructose. NO-dependence of cyclic nucleotide enhancements was evaluated by inhibiting NO synthase and guanylate cyclase. Platelet aggregation to ADP and collagen was evaluated in Platelet-Rich Plasma (PRP) in the presence of a 6-min incubation with D-glucose and mannitol, both without and with LY379196 and the guanylate cyclase inhibitor (H-[1,2,4]Oxadiazolo [4,3-a]quinoxaline-1-one)(ODQ). Iso-osmolar concentrations of D-glucose, mannitol, L-glucose and fructose, and PMA increased NO production (p=0.0001). Effects of D-glucose and mannitol were blunted by LY379196. D-glucose and mannitol enhanced platelet cGMP and cAMP (p=0.0001) with a mechanism blunted by NO synthase and guanylate-cyclase inhibition, but did not modify platelet aggregation. In conclusion, glucose activates the NO/cyclic nucleotide pathway in human platelets with an osmotic mechanism mediated by PKC-beta.
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PMID:High glucose rapidly activates the nitric oxide/cyclic nucleotide pathway in human platelets via an osmotic mechanism. 1573 85


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