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)

The effects of aminoethylisothiuronium bromide known as a radioprotector on the activity of human platelet soluble guanylate cyclase and on ADP-induced aggregation of human platelets have been studied. It has been shown that in Tris-buffer and at definite pH values aminoethylisothiuronium bromide is converted into mercaptoethylguanidine as a result of a transguanidine rearrangement. The latter contains in its molecule both guanidine and SH-groups which appear to be the donor and acceptor of nitric oxide, respectively. It was found that after its rearrangement into mercaptoethylguanidine, aminoethylisothiuronium bromide activates human platelet soluble guanylate cyclase, inhibits ADP-induced aggregation of human platelets and accelerates their spontaneous disaggregation. The stimulating effect of aminoethylisothiuronium bromide depends on the effectiveness of its transguanidine rearrangement into mercaptoethylguanidine. A molecular mechanism of the hypotensive side effect of aminoethylisothiuronium bromide is proposed.
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PMID:[A new activator of soluble guanylate cyclase generated by nitric oxide and having antihypertensive and anti-aggregation properties]. 856 54

1. The effects of the nitric oxide (NO) donors, 3-morpholino-sydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside on basal and electrically evoked release of [3H]-acetylcholine were studied in myenteric plexus longitudinal muscle preparations of the guinea-pig small intestine preincubated with [3H]-choline. 2. The NO donors concentration-dependently increased basal release of [3H]-acetylcholine. The increase in release was calcium-dependent and was prevented in the presence of tetrodotoxin. Superoxide dismutase (150 u ml-1) potentiated the effect of SIN-1. The selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 0.01-1 microM), antagonized the facilitatory effect of SNAP. 8-Bromo cyclic GMP and the cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (both 0.1-1 mM), also enhanced basal [3H]-acetylcholine release. The effect of 10 microM SNAP was significantly enhanced in the presence of zaprinast. 3. The NO donors concentration-dependently inhibited the electrically evoked release of [3H]-acetylcholine, whereas 8-bromo cyclic GMP and zaprinast enhanced the evoked release. The inhibition of acetylcholine release by SNAP was not affected by ODQ (0.01-1 microM). 4. It is concluded that NO stimulates basal acetylcholine release from myenteric neurones through activation of guanylyl cyclase. In addition, NO inhibits the depolarization evoked release of acetylcholine by a presynaptic mechanism unrelated to cyclic GMP. The data imply that NO is not only an inhibitory transmitter to intestinal smooth muscles but also a modulator of cholinergic neurotransmission in the myenteric plexus.
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PMID:Differential effects of nitric oxide donors on basal and electrically evoked release of acetylcholine from guinea-pig myenteric neurones. 886 45

Cells of the ciliate Tetrahymena thermophila produce compounds that act as autocrine (paracrine) survival and/or growth factors. 8-Bromo cyclic GMP, sodium nitroprusside, hemin, protoporphyrin IX, human recombinant and bovine insulin were tested for their ability to substitute for the cell-produced factors and stimulate cell survival and proliferation. The cells were inoculated into conical flasks in a nutritionally complete, chemically defined medium at known cell densities from 5 to 5000 cells/ml. In unsupplemented medium cells at 5 to 500 cells/ml ('low initial cell density cultures') died within 8 h, whereas cells at 1000 and 5000 cells/ml ('high initial cell density cultures') proliferated with lag phases lasting for up to 4 h. In the presence of insulin compounds, hemin, protoporphyrin IX, or 8-bromo cyclic GMP, cells also proliferated at all low initial cell densities. Sodium nitroprusside was effective over two separate concentration ranges: at the nanomolar levels as well at low pico- to femtomolar levels. At initial population densities of up to 50 cells/ml the cells at both concentrations of sodium nitroprusside survived about 4-fold longer than the controls. At 500 initial cells/ml, cells at the high concentrations of sodium nitroprusside survived about 4-fold longer than those of the control cultures; they proliferated in the low concentrations of sodium nitroprusside. Concentrations of hemin, too low to have any effects on their own, had synergistic effects with sodium nitroprusside. NG-methyl-L-arginine inhibited proliferation at high initial cell densities. This inhibitory action was reduced by high concentrations of L-arginine, protoporphyrin IX, sodium nitroprusside, or 8-bromo cGMP, but not by insulin. Methylene blue inhibited cell proliferation at high initial cell densities. This inhibition was circumvented by addition of 8-bromo cGMP. The findings that insulin-related material may be released from Tetrahymena and that insulin and sodium nitroprusside increase intracellular cGMP in these cells are discussed in relation to the presented results. Together these observations suggest that cGMP is responsible for supporting cell survival in Tetrahymena and switching the cells into their proliferative mode, and that cell-produced signal molecules and insulin stimulate an NO-dependent guanylate cyclase into producing cGMP.
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PMID:Cell death, survival and proliferation in Tetrahymena thermophila. Effects of insulin, sodium nitroprusside, 8-Bromo cyclic GMP, NG-methyl-L-arginine and methylene blue. 896 58

Nitric oxide (NO), a diffusible and unstable gas, has been implicated in inter- and intra-cellular communication in the nervous system. NO also plays a role in neural development, plasticity and alterations of synaptic function such as long-term potentiation and long-term depression (Gally et al.: Proc NY Acad Sci, 87: 354-355, 1990; Zhuo et al.: Science 260:1946-1950, 1993; Schuman and Madison.: Science 254:1503-1506, 1991; Bruhwyler et al.: Neurosci Biobehav Rev 17:373-384, 1993) some of which likely involve growth and remodelling of neurites. Some actions of NO are mediated directly by protein modification (e.g., nitrosylation) and others by activation of soluble guanylyl cyclase (soluble GC), which increases intracellular levels of guanosine 3',5'-cyclic monophosphate (cGMP). NO is synthesized by the enzyme nitric oxide synthase (NOS), which is induced by treatment of CNS neurons (Holtzman et al.: Neurobiol Disease 1:51-60, 1994) or pheochromocytoma PC12 cells (Hirsch et al.: Curr Biol 3:749-754, 1993) with NGF. NO has been proposed to mediate some of the effects of NGF on PC12 cells by inhibiting cell division (Peunova and Enikolopov: Nature 374:68-73, 1995). In addition, NO can substitute for NGF by delaying the death of trophic factor-deprived PC12 cells through a mechanism that does not involve a cytostatic action (Farinelli et al.: J Neurosci 16:2325-2334, 1996). We investigated whether NO stimulated neurite outgrowth from hippocampal neurons and PC12 cells. Primary cultures of E17 mouse hippocampal neurons co-cultured with neopallial astrocytes were exposed to the NO donors sodium nitrite (100 microM) or sodium nitroprusside (100 nM). After 48 hr, NO donor-treated cultures contained a greater proportion of cells bearing neurites and neurites that were much longer than those found in control cultures. In cultures of PC12 cells, NO donors also enhanced the neuritogenic effects of NGF. The proportion of PC12 cells with neurites 48 hr after exposure to NO donors sodium nitrite (100 microM-10mM) or sodium nitroprusside (100 nM-1 micro M) plus 2.5S nerve growth factor (NGF) was approximately twice the proportion of cells with neurites in sister cultures grown in NGF alone. Neither of the NO donors elicited neurites from the PC12 cells in the absence of NGF. The effects of the NO donors were likely mediated by release of NO since their effects were antagonized by addition of hemoglobin, which avidly binds NO, to the culture medium. The enhancement by NO of NGF-mediated neurite outgrowth in PC12 cells appeared to occur through a cGMP-dependent mechanism. The NO donors stimulated a prompt increase in intracellular cGMP in PC12 cells. Moreover their action was mimicked by addition of the membrane-permeant cGMP analogs 8-Bromo-cGMP (8-Br-cGMP) and para (chlorophenylthio)-cGMP (pCPT-cGMP) to the culture medium and by atrial natriuretic factor which stimulates particulate guanylyl cyclase. The neuritogenic activity of the NO donors was inhibited by LY83583 and methylene blue, inhibitors of guanylyl cyclase. These data imply that NO may act alone or with other growth factors to regulate synapse formation and maintenance by stimulating neurite outgrowth.
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PMID:Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. 905 36

The functional importance of Ca++ activated K+ (K(Ca)) channels in cGMP mediated relaxation of pressurized septal arteries (internal basal diameter 213 +/- 4 microm) was investigated. Vascular tone was increased by the thromboxane A2 analogue, U-46619 and internal pressure was maintained at 60 mmHg. Vessels were tested with an endothelium independent agonist (nitroprusside) and endothelium dependent agonist (acetylcholine) of nitric oxide which activates soluble guanylate cyclase. Receptor activation of particulate guanylate cyclase was tested by atrial natriuretic peptide. Direct changes in intracellular cGMP concentration were done with the cell permeable analog, 8-Bromo-cGMP. Tetraethylammonium ion (TEA+), 1 mM, significantly inhibited relaxation to nitroprusside from 10(-7) to 10(-3) M with a maximal inhibition of 53 +/- 8% at 10(-3) M. Relaxation to acetylcholine from 10(-9) M to 10(-5) M was significantly inhibited by TEA+ with a maximal inhibition of 52 +/- 13% at 10(-7) M. TEA+ significantly inhibited relaxation to 8-Bromo-cGMP from 10(-6) M to 10(-3) M with a maximal inhibition of 59 +/- 14% at 10(-4) M. The relaxation response to atrial natriuretic peptide from 10(-12) M to 10(-7) M was significantly inhibited by TEA+ with a maximal inhibition of 84 +/- 5% at 10(-11) M. The large conductance K(Ca) channel blocker, iberiotoxin, eliminated the relaxation response to 8-Bromo-cGMP (10(-3) M). The results suggest that a large portion of the dilator action of cGMP is mediated by effects on K+ membrane channels.
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PMID:Inhibition of cGMP mediated relaxation in small rat coronary arteries by block of CA++ activated K+ channels. 931 9

Atrial natriuretic peptide (ANP) interacts with high-affinity, guanylyl cyclase-linked receptors in the inner medullary collecting duct (IMCD), where it exerts important regulatory control over sodium handling. We sought to determine whether receptor activity in these cells would be modulated (downregulated) by prolonged exposure to ligand. A number of natriuretic peptides (ANP, brain natriuretic peptide, and urodilatin) were found to decrease ligand-dependent natriuretic peptide receptor A (NPR-A) activity in IMCD cells. This inhibition was in direct proportion to their capacity to increase basal cGMP levels in this cell population. The reduction in receptor activity was accompanied by a dose- and time-dependent reduction in NPR-A mRNA levels in these cells. The decrease in transcript levels arose, in part, from a reduction in NPR-A gene transcription. ANP reduced NPR-A gene promoter activity in a transiently transfected IMCD cell population. 8-Bromo-cGMP was also effective in inhibiting NPR-A mRNA levels and NPR-A promoter activity, suggesting that the second messenger (i.e., cGMP) rather than ANP, itself, is responsible for downregulation of NPR-A gene expression.
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PMID:Ligand-dependent regulation of NPR-A gene expression in inner medullary collecting duct cells. 968 13

Intracellular recordings were made from neurones E-8, E-16 and E-13a in the visceral ganglion of Helix aspersa. GSPYFVamide inhibits the activity of these neurones and the role of a second messenger system in this inhibition was investigated. 8-Bromo-cGMP, 100 microM was found to potentiate this inhibition while ODQ, 100 microM, an inhibitor of guanylyl cyclase, almost completely blocked GSPYFVamide-induced inhibition. Four NO donors sodium nitroprusside, 100 microM, sodium nitrite, 1 mM, SNOG, 50 microM, and SNAP, 10-50 microM, all potentiated the GSPYFVamide-induced inhibition. L-NAME, 100-1000 microM, a competitive inhibitor of NOS, blocked the GSPYFVamide-induced inhibition. In some cases recovery was only partial. The possible role of NO in modulating the inhibitory response to GSPYFVamide is discussed.
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PMID:Evidence for the involvement of nitric oxide in the inhibitory effect of GSPYFVamide on Helix aspersa central neurones. 971 72

1. In the present work, we study the effect of NO on the proliferation and differentiation of brown fat cells in primary cultures. 2. Brown fat precursor cells isolated from rat brown adipose tissue were cultured for 8 days until confluence and treated daily with the NO donating agents, S-nitroso-acetyl penicillamine (SNAP) or S-nitroso-L-glutathione (GSNO). Both agents (300 microM) decreased cell proliferation approximately 8 fold on day 8. The inhibitory effect of NO was unlikely to be due to cytotoxicity since (i) cells never completely lost their proliferation capacity even after 8 days of exposure to repeated additions of SNAP or GSNO, and (ii) the inhibitory effect was reversible after removal of the media containing NO donors. 3. Daily treatment with nitric oxide synthase inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), led to the stimulation of cell proliferation by 44+/-5%, n=3, suggesting that NO, endogenously produced in brown adipocytes, may be involved in modulating cell growth. 4. Daily treatment with both SNAP or GSNO induced significant mitochondriogenesis, measured as the mitochondrial conversion of 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyl tetrazolium bromide (MTT) to formazan, whilst daily treatment with L-NAME was without effect. 5. The inhibition of cell proliferation by NO donors was accompanied by the expression of two genes coding for peroxisome proliferator activated receptor-gamma and uncoupling protein-1, which are upregulated during differentiation. 6. Increasing cyclic GMP in cells by 8-bromo-cyclic GMP (100-1000 microM) did not reproduce the observed NO effects on either cell number or gene expression. On the other hand, chronic treatment with the inhibitor of the NO-stimulated guanylyl cyclase, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), reduced the expression of peroxisome proliferator activated receptor-gamma and uncoupling protein-1.
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PMID:Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures. 983 29

Nitric oxide (NO.) is important in the regulation of mitochondrial function, cell signaling, and gene expression. To elucidate how endogenous NO. regulates the function of airway epithelial cells, we used carboxy-PTIO, a hydrophilic, negatively charged NO. trap, to scavenge NO. from rat lung epithelial (RLE) and rat pleural mesothelial (RPM) cells and to determine the elicitation of cell cycle alterations, apoptosis, and oxidative stress. The reaction of NO. with PTIO causes the formation of PTI, which is measured by electron spin resonance (ESR) and is a quantitative measure of NO. formation. ESR spectroscopy revealed the production of NO. in RLE or RPM cells over a period from 1 to 24 h of exposure, indicating scavenging of NO. by PTIO. Cycle analyses in confluent RLE or RPM cells revealed two- to threefold increases in S and G2/M phases after exposure to 100-200 microM PTIO as well as increases in the fraction of cells undergoing apoptosis. Direct addition of PTI to cells failed to elicit cell cycle perturbations or apoptosis. The guanylyl cyclase inhibitor ODQ mimicked the effects of PTIO. 8-Bromo-cGMP but not 8-bromo-cAMP ameliorated the PTIO- or ODQ-mediated cell cycle perturbations and apoptosis, suggesting that cGMP-dependent pathways are involved in these cell cycle perturbations. Treatment of log-phase cells with PTIO resulted in more dramatic cell cycle perturbations compared with cells treated at confluence. Assessment of 5-bromo-2'-deoxyuridine incorporation to measure DNA synthesis demonstrated decreases in PTIO-treated compared with sham cells in addition to a cell cycle arrest in late S or G2/M phase. Last, incubation with dichlorofluorescin diacetate revealed oxidative stress in PTIO- but not in PTI-exposed RLE or RPM cells. We conclude that the depletion of endogenous NO. induces oxidative stress, cell cycle perturbations, and apoptosis. Our findings illustrate the importance of endogenous NO. in the control of cell cycle progression and survival of pulmonary and pleural cells and that a critical balance between NO. and superoxide may be necessary for these physiological events.
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PMID:Depletion of nitric oxide causes cell cycle alterations, apoptosis, and oxidative stress in pulmonary cells. 984 47

The diffusible intercellular messenger nitric oxide may have a modulatory role in the thalamus and this action may be mediated via activation of soluble guanylate cyclase. In order to investigate this possibility, we applied the cyclic-GMP analogue 8-Bromo-cyclic-GMP (8-Br-cGMP) onto neurones in the ventrobasal and lateral geniculate nuclei of the thalamus in anaesthetised rats, and compared its effects with those of a nitric oxide donor. 8-Br-cGMP enhanced the responses of neurones to iontophoretically applied NMDA and AMPA. Furthermore, somatosensory and visual responses of ventrobasal and lateral geniculate neurones were enhanced to 274+/-76% and 217+/-69% of control values, respectively. These effects were similar to those seen with nitric oxide donors in this study and previous work from this laboratory. When applied to thalamic neurones in an in vitro slice preparation, 8-Br-cGMP caused a membrane depolarisation associated with a decrease in input resistance. These findings indicate that activation of guanylate cyclase can cause a membrane depolarisation of thalamic neurones in vitro, and that this effect is sufficient to enhance action responses to ionotropic glutamate receptor stimulation via either exogenous agonists or sensory stimulation.
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PMID:Actions of 8-bromo-cyclic-GMP on neurones in the rat thalamus in vivo and in vitro. 1037 3


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