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)

Treatment of mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to increase cGMP formation, most probably due to induction of nitric oxide synthase. Here we report that maximum stimulation of cGMP formation over a 24-h period required the presence of IL-1 beta or TNF alpha during the first 18 h of induction. N4-monomethyl-L-arginine (L-NMMA) was a potent inhibitor of cytokine-induced cGMP formation while N4-nitro-L-arginine (L-NNA) was less active. Formation of nitric oxide was detected in the cytosol of cytokine-treated mesangial cells by activation of purified soluble guanylate cyclase and was stimulated by tetrahydrobiopterin, but not by calcium calmodulin. Treatment of cells with IL-1 beta or TNF alpha markedly attenuated the contractile response to a subsequent challenge with angiotensin II. Furthermore, conditioned medium from IL-1 beta-treated cells increased cGMP in untreated control cells.
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PMID:Interleukin 1 beta and tumour necrosis factor alpha induce a macrophage-type of nitric oxide synthase in rat renal mesangial cells. 137 Apr 9

In primary cultures of astrocytes and granule cells from neonatal rat cerebellum, the activity and function of nitric oxide (NO) synthase were measured by the conversion of [3H]arginine to [3H]citrulline and the accumulation of cyclic guanosine monophosphate (cGMP), respectively. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) and the Ca2+ ionophore A23187 stimulated NO synthase activity in cerebellar granule cells but not in astrocytes. In granule cells, NMDA, A23187, and sodium nitroprusside (SNP) elicited an accumulation of cGMP, whereas only SNP was active in astrocytes. However, in astrocytes that were incubated together with granule cells, NMDA induced a more than 3-fold increase in the concentration of cGMP; this increase was blocked by both the NO synthase inhibitor NG-monomethyl-L-arginine (MeArg) and the allosteric NMDA receptor antagonist (+)5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801). Thus, cerebellar astrocytes do not appear to express NO synthase but do contain guanylate cyclase, which can be activated by an NO-like factor produced by cerebellar granule cells after stimulation by NMDA.
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PMID:In vitro interaction between cerebellar astrocytes and granule cells: a putative role for nitric oxide. 137 59

Toxic shock syndrome toxin 1 (TSST-1) is a Mr 22,000 protein produced by Staphylococcus aureus. It is thought to be the cause of toxic shock syndrome. We investigated the hypothesis that TSST-1 induces nitric oxide (NO) synthase and that the NO formed may be involved in the pathogenesis of toxic shock syndrome. We used the murine monocyte-macrophage cell line J744.2 that responds to TSST-1 and also expresses NO synthase activity upon immunological stimulation. J774.2 macrophages stimulated with TSST-1 (10-100 nM) generated nitrite, a breakdown product of NO, and induced concentration-dependent elevations of cGMP in the pig kidney epithelial cell line (LLC-PK1). This latter effect was due to the generation of L-arginine-derived NO for it was (i) abolished by oxyhemoglobin (10 microM), a scavenger of NO, or by methylene blue (10 microM), an inhibitor of NO-activated guanylate cyclase; (ii) potentiated by superoxide dismutase (100 units/ml), which prolongs the life of NO; (iii) inhibited by NG-monomethyl-L-arginine (0.3 mM), an inhibitor of NO synthase; (iv) significantly decreased when L-arginine (0.4 mM) in the medium was replaced by D-arginine (0.4 mM). Moreover, TSST-1 (100 nM) enhanced the activity of cytosolic NO synthase in J774.2 cells. Hydrocortisone (1 microM) but not indomethacin (5 micrograms/ml) or salicylic acid (5 micrograms/ml) prevented the generation of NO2- and the increases in cGMP levels in LLC-PK1 cells induced by J774.2 cells stimulated with TSST-1. The effects of hydrocortisone were partially reversed by coincubation with RU 486 (1 microM), an antagonist of glucocorticoid receptors. Thus, TSST-1 and perhaps other exotoxins produced by Gram-positive bacteria induce NO synthase and the increased NO formation may contribute to toxic shock syndrome and possibly to changes in the immune responses that accompany infection.
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PMID:Induction of nitric oxide synthase activity by toxic shock syndrome toxin 1 in a macrophage-monocyte cell line. 137 33

NO synthase (NOS; EC 1.14.23) catalyzes the conversion of L-arginine into L-citrulline and a guanylyl cyclase-activating factor (GAF) that is chemically identical with nitric oxide or a nitric oxide-releasing compound (NO). Similar to the other isozymes of NOS that have been characterized to date, the soluble and Ca2+/calmodulin-regulated type I from rat cerebellum (homodimer of 160-kDa subunits) is dependent on NADPH for catalytic activity. The enzyme also possesses NADPH diaphorase activity in the presence of the electron acceptor nitroblue tetrazolium (NBT). We investigated the requirements of NOS and its content of the proposed additional cofactors tetrahydrobiopterin (H4biopterin) and flavins, further characterized the NADPH diaphorase activity, and quantified the NADPH binding site(s). Purified NOS type I Ca2+/calmodulin-independently bound the [32P]2',3'-dialdehyde analogue of NADPH (dNADPH), which, at near Km concentrations during 3-min incubations was utilized as a substrate and at higher concentrations or after prolonged incubations and cross-linking inhibited NOS activity. The NADPH diaphorase activity was Ca2+/calmodulin-independent, required higher NADPH concentrations than NOS activity, and was affected by dNADPH to a lesser degree. Divalent cations interfered with the diaphorase assay. Per dimer, native NOS contained about 1 mol each of H4biopterin, FAD, and FMN, classifying it as a biopteroflavoprotein, and incorporated 1 mol of dNADPH. No dihydrobiopterin (H2biopterin), biopterin, or riboflavin was detected. These findings suggest that NOS may share cofactors between two identical subunits via high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+/calmodulin-dependent NO synthase type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities. 137 27

The metabolism of glyceryl trinitrate (GTN) to nitric oxide (NO) was studied in the mouse macrophage cell line J774 and in the human monocytic cell line U937 in the absence or presence of Escherichia coli lipopolysaccharide (LPS). Two bioassay systems were used: inhibition of platelet aggregation and measurement of cGMP after stimulation by NO of guanylate cyclase in J774 cells. In addition, NO produced from GTN by cells or by cellular fractions was measured as nitrite (NO2-) one of its breakdown products. J774 cells (1.25 x 10(5) cells) treated with indomethacin (10 microM) enhanced the platelet inhibitory activity of GTN (22-352 microM) but not that of sodium nitroprusside (4 microM). This effect was abrogated by co-incubation with oxyhaemoglobin (oxyHb, 10 microM) indicating release of NO from GTN. U937 cells (up to 60 x 10(5)) did not metabolize GTN to NO. LPS (0.5 micrograms/mL for 18 hr) enhanced at least 2-fold the capacity of J774 cells but not that of U937 cells to form NO from GTN and this enhancement was attenuated when cycloheximide (10 micrograms/mL) was incubated together with LPS. In the absence of LPS stimulation, cycloheximide had no effect. Furthermore, when incubated with GTN (200 microM), J774 cells treated with LPS released more NO from GTN as indicated by a 3-fold greater increase in their level of cGMP which was prevented by oxyHb (10 microM). Incubation of J774 cells with GTN (75-600 microM) for 30 min led to a concentration-dependent increase in NO2- which was substantially reduced when the cells were boiled. The microsomal fraction was more potent than the cytosol in producing NO2- from GTN (1.2-2.4 mM). Release of NO2- from GTN by J774 cells was not affected by treating the cells with the NO synthase inhibitor, NG-monomethyl-L-arginine (MeArg, 300 microM). In J774 cells made tolerant to GTN, potentiation of the anti-platelet effects of GTN (11-352 microM) and release of NO2- from GTN was reduced. Thus, J774 cells but not U937 cells convert GTN to NO. This enzymic pathway (present mainly in the microsomal fraction of the J774 cells) is induced by LPS and is not regulated by endogenous NO released from L-Arg by the enzyme NO synthase. Furthermore, when compared to normal cells, tolerant J774 cells metabolize GTN to NO less effectively as assessed by a reduced capacity to potentiate the anti-platelet effect of GTN and to release NO2-.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The metabolism of glyceryl trinitrate to nitric oxide in the macrophage cell line J774 and its induction by Escherichia coli lipopolysaccharide. 137 39

Nitric oxide, which accounts for the biological activity of endothelium-derived relaxing factor (EDRF), is synthesized in endothelial cells from L-arginine by nitric oxide synthase (NOS). We report here the cloning and functional expression of a cDNA encoding human endothelial NOS. Oligonucleotides corresponding to amino acid sequences shared by cytochrome P450 reductase and the recently identified brain NOS were synthesized to amplify a partial cDNA encoding a bovine endothelial cell NOS-related protein. This partial cDNA was used to isolate a cDNA encoding a human vascular endothelial NOS. The translated human protein is 1294 amino acids long and shares 52% of its amino acid sequence with brain NOS. Using RNA blot hybridization, abundant endothelial NOS mRNA was detected in unstimulated human umbilical vein endothelial cells. To determine the functional activity of the endothelial protein, we ligated the cDNA into an expression vector and transfected it into NIH3T3 cells. Cells expressing this cDNA contained abundant NADPH diaphorase activity, a histochemical marker for NOS. In co-culture assays, nitric oxide production by transfected cells increased guanylate cyclase activity in reporter rat fetal lung fibroblasts. In addition, NOS-catalyzed conversion of arginine to citrulline in transfected cells was significantly increased by A23187, a calcium ionophore. Isolation of a cDNA encoding a calcium-regulated, constitutively expressed human endothelial NOS, capable of producing EDRF in blood vessels, will accelerate the characterization of the role of this enzyme in normal and abnormal endothelial regulation of vascular tone.
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PMID:Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. 138 4

Guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in single and cocultures of calf pulmonary arterial endothelial (CPAE) and rabbit pulmonary arterial smooth muscle cells (RPASM) was investigated to discover whether endothelial cGMP is involved in the feedback regulation of basally released endothelium-derived relaxing factor (EDRF). Endothelial cell-induced increases in smooth muscle cGMP levels were inhibited by competitive inhibitors of endothelial nitric oxide synthesis, NG-monomethyl-L-arginine and N omega-nitro-L-arginine, in both long-term cocultures and short-term bioassay. Such treatment had no effect on endothelial content of cGMP. Coculture cGMP accumulation was stimulated (twofold increases) by endothelium-dependent vasodilators, bradykinin and acetylcholine. Bradykinin and acetylcholine did not elicit cGMP accumulation in single cultures of either smooth muscle or endothelial cells. To investigate the underlying mechanism(s) of dissociation in cGMP accumulation between cocultures and single endothelial cell cultures, the distribution profile of guanylate cyclase isoforms was determined by stimulating CPAE and RPASM cells with vasodilators activating selectively the soluble or particulate isoenzymes. Both nitrovasodilators, sodium nitroprusside and a putative EDRF, S-nitroso-L-cysteine, produced a 20-fold increase in cGMP content of RPASM cells only, having no effect on endothelial cells. Conversely, atriopeptin II caused 80-fold increases in endothelial cells. Exposure of the short-term bioassay system to 100 nM atriopeptin II, which caused 60-fold increases in CPAE cGMP levels, did not affect basal EDRF-induced smooth muscle cell cGMP accumulation, suggesting that a cGMP-mediated negative feedback mechanism does not appear to be involved in the regulation of basally released EDRF in culture.
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PMID:Endothelial cGMP does not regulate basal release of endothelium-derived relaxing factor in culture. 137 1

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.
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PMID:Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. 137 15

Nitric oxide is a newly recognized cell messenger for the activation of soluble guanylate cyclase and is produced from L-arginine by the enzyme nitric oxide synthase in a wide variety of tissues, including vascular endothelium and brain. Inhalational anesthetics inhibit nitric oxide production from vascular endothelium and also decrease resting cyclic guanosine monophosphate content in multiple brain regions. Halothane has been shown to depress neurotransmission by L-glutamate and N-methyl-D-aspartate. These amino acid neurotransmitters are known to increase neuronal cyclic guanosine monophosphate content by stimulation of nitric oxide production. To investigate the possible involvement of the L-arginine-to-nitric oxide pathway in the anesthetic state, the effect of a specific nitric oxide synthase inhibitor, nitroG-L-arginine methyl ester, on the minimum alveolar concentration (MAC) for halothane anesthesia was determined in Sprague-Dawley rats. Bolus injection of nitroG-L-arginine methyl ester at 0, 1, 5, 10, 20, and 30 mg/kg resulted in a dose-dependent reduction in MAC for halothane of 0 +/- 0, 2.3 +/- 0.4, 21.5 +/- 3.9, 30.5 +/- 2.4, 51.0 +/- 7.8, and 26.0 +/- 2.8%, respectively. NitroG-L-arginine methyl ester had no effect on MAC for halothane. Bolus infusion of L-arginine 300 mg/kg after MAC reduction by nitroG-L-arginine methyl ester 10 mg/kg resulted in an immediate and complete reversal of the MAC reduction. No reversal was observed after infusion of D-arginine 300 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide synthase inhibitor dose-dependently and reversibly reduces the threshold for halothane anesthesia. A role for nitric oxide in mediating consciousness? 138 99

Retinal stimulation with a brief pulse of light (200 lx, 3 min) stimulated heart rate in dark-adapted urethane-anaesthetized rats. This effect was inhibited by prior infusion of a competitive blocker of N-methyl-D-aspartate (NMDA) receptors, (+-)-3-(2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP, 20 nmol) into the hypothalamic suprachiasmatic nucleus (SCN) region. Furthermore, this inhibition of the stimulatory effect of light on heart rate was mimicked by prior infusion in the SCN region of a competitive blocker of nitric oxide (NO) production from L-arginine, NG-nitro-L-arginine methyl ester (40 nmol), or a blocker of the soluble guanylate cyclase. Methylene blue (20 nmol). None of these effects was seen when infusions were made in a region located 2 mm dorsal to the SCN or when a non-visual stimulus (tail pinch) was used to stimulate heart rate. These results point to a functional link between activation of an NMDA receptor coupled NO/cGMP signalling pathway and light transmission to the SCN.
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PMID:Blocking NMDA receptors or nitric oxide production disrupts light transmission to the suprachiasmatic nucleus. 138 31


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