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)

Oxytocin, bradykinin, melittin and A23187 increased cyclic GMP levels through activation of soluble guanylate cyclase in cultured porcine kidney epithelial cells, LLC-PK1. NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide formation, decreased both basal and stimulated levels of cyclic GMP in a concentration-dependent manner. L-Arginine, but not D-arginine, augmented basal as well as stimulated levels of cyclic GMP and prevented the inhibition induced by NG-monomethyl-L-arginine. Similar effects of L-arginine were also observed with L-argininamide, L-arginine ethyl ester, L-arginine methyl ester and the dipeptide L-arginyl-L-aspartic acid. NG-monomethyl-L-arginine did not affect cyclic GMP accumulation induced by sodium nitroprusside, an activator of soluble guanylate cyclase, and atrial natriuretic factor, an activator of particulate guanylate cyclase. Stimulatory effects of oxytocin, glyceryl trinitrate, sodium nitroprusside, bradykinin, melittin and A23187 on cyclic GMP accumulation were enhanced with superoxide dismutase and diminished with oxyhemoglobin. However, atrial natriuretic factor-induced cyclic GMP accumulation was not affected. Furthermore, endothelium derived relaxing factor-like activity was detected in the conditioned medium from LLC-PK1 cells stimulated with oxytocin. Based on these data, we conclude that endothelium-derived relaxing factor is produced in this cell type and participates in the regulatory mechanism of cyclic GMP formation as an intra- and intercellular messenger for activation of soluble guanylate cyclase.
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PMID:Formation of endothelium-derived relaxing factor in porcine kidney epithelial LLC-PK1 cells: an intra- and intercellular messenger for activation of soluble guanylate cyclase. 167 Oct 98

General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
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PMID:Inhibitory effects of anesthetics on cyclic guanosine monophosphate (cGMP) accumulation in rat cerebellar slices. 752 47

The effect of NG-nitro-L-arginine methylester (NAME) and N-mono-methyl-L-arginine (NMMA), inhibitors of nitric oxide (NO) synthase on penile erection and yawning induced by N-methyl-D-aspartic acid (NMDA) injected in the paraventricular nucleus of the hypothalamus (PVN) was studied in male rats. NAME (75-150 micrograms) and NMMA (250-500 micrograms), but not N-monomethyl-D-arginine (D-NMMA)(250-500 micrograms) prevented both responses in a dose-dependent manner when given intracerebroventricularly (i.c.v.) 15 min before NMDA (50 ng). NMDA-induced penile erection and yawning was also prevented by the guanylate cyclase inhibitor methylene blue (200-400 micrograms i.c.v.), but not by the NO scavenger methemoglobin (50-100 micrograms i.c.v.). NAME (10-20 micrograms), but not Methylene blue or methemoglobin (10-20 micrograms), prevented NMDA-induced responses also when injected in the PVN 15 min before NMDA. The present results suggest that NMDA-induced penile erection and yawning is mediated by an increased NO synthesis in the PVN.
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PMID:Nitric oxide synthase inhibitors prevent N-methyl-D-aspartic acid-induced penile erection and yawning in male rats. 753 16

Whilst the depolarization of postsynaptic N-methyl-D-aspartic acid (NMDA) receptors leads to an influx of Ca2+ and subsequent synthesis of nitric oxide (NO), we examined roles for NO at striatal NMDA receptors regulating transmitter release. In superfused rat striatal slices, NMDA-evoked release of gamma-[3H]aminobutyric acid ([3H]GABA) was investigated in the presence of nitrergic drugs. NMDA-induced release of [3H]GABA was attenuated by D-2-aminophosphonopentanoate, tetrodotoxin and omission of Ca2+. L-Arginine enhanced NMDA-evoked release of [3H]GABA, but exogenous NO donors were ineffective. Inhibitors of NO synthase (NG-nitro- and NG-amino-L-arginine) and guanylate cyclase (LY83583) elevated release. Since NMDA-evoked release of [3H]GABA was partially tetrodotoxin-sensitive, nitrergic-linked NMDA receptors regulating the release are both pre- and extrasynaptic. Thus not only does NO arise from multiple sites, and involve NMDA receptors with their redox site insensitive to exogenous NO donors, but the NMDA receptors are under the influence of nitrergic and cGMP-linked negative feedback mechanisms.
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PMID:Complex involvement of nitric oxide and cGMP at N-methyl-D-aspartic acid receptors regulating gamma-[3H]aminobutyric acid release from striatal slices. 763 91

In order to evaluate a possible role of brain nitric oxide (NO) on the control of penile erection, the effect of nitroglycerin, that is thought to act by producing NO, was studied on spontaneous penile erection in male rats. In addition the effect of drugs that prevent NO formation and/or activity such as NG-nitro-L-arginine methyl ester (NAME) and methylene blue, on N-methyl-D-aspartic acid (NMDA)-, apomorphine- and oxytocin-induced penile erection was also studied. Nitroglycerin induced penile erection in a dose-dependent manner when given intracerebroventricularly (i.c.v.) (33-99 micrograms) or in the paraventricular nucleus of the hypothalamus (0.8-3.3 micrograms). Nitroglycerin-induced penile erection was prevented by the guanylate cyclase inhibitor methylene blue injected i.c.v. (200-400 micrograms) but not in the paraventricular nucleus of the hypothalamus (10-20 micrograms). Conversely, NMDA-, apomorphine- and oxytocin-induced penile erection was prevented by NAME (150 micrograms) or methylene blue (400 micrograms) given i.c.v. NAME (20 micrograms), but not methylene blue (20 micrograms), was effective in preventing the behavioral response also when injected in the paraventricular nucleus. The present results suggest that NO is a common mediator of several neurotransmitters involved in the control of this primary male sexual function.
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PMID:Nitric oxide is a central mediator of penile erection. 787 Feb 89

Mastoparan activated membrane-bound guanylate cyclase and potentiated the effect of atrial natriuretic factor (ANF) and ATP on guanylate cyclase activity in rat lung membranes. Mastoparan is a cationic, amphiphilic tetradecapeptide with an amidated carboxyl terminus. It takes the alpha-helical conformation upon interacting with the membrane. Several analogs were synthesized to study the role of the positive charges, the carboxyl amino group and the alpha-helical conformation of mastoparan in the activation of guanylate cyclase. The results showed that substitution of the C-terminal amide group of mastoparan with a carboxyl group significantly reduced its potency on the activation of guanylate cyclase. Replacement of three lysine residues of mastoparan with aspartic acid or serine residues completely abolished the stimulatory effect of mastoparan. When the alanine at position 10 of mastoparan was substituted by a proline, the resulting analog had no effect on guanylate cyclase activity. These results demonstrate that the positive charges and the helical structure of mastoparan are critical determinants for the activation of guanylate cyclase.
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PMID:Structural requirements of mastoparan for activation of membrane-bound guanylate cyclase. 790 30

The key roles of the excitatory neurotransmitter glutamate and its second messengers, nitric oxide (NO) and cGMP, in long-term potentiation and neural plasticity are well documented. However, complex functions such as memory are likely to require long term changes in synaptic efficacy which require gene expression and protein synthesis. Here we demonstrate that the glutamate receptor agonist, N-methyl-D-aspartic acid (NMDA), nitric oxide (NO) and cGMP each repress expression of the gonadotropin-releasing hormone (GnRH) gene in the hypothalamic cell line, GT1. This repression is dependent upon signals from NMDA receptors activating NO synthase to synthesize NO. In turn NO induces guanylyl cyclase to synthesize cGMP, activating cGMP- dependent protein kinase. Repression requires elevation of calcium because it only occurs in the presence of calcium ionophore or with release of intracellular calcium. Repression also requires protein synthesis. Activation of this pathway specifically represses expression of a reporter gene containing the regulatory region of the GnRH gene in transfected GT1 cells, indicating that repression occurs at the transcriptional level. Furthermore the target for transcriptional repression is a 300 bp neuron-specific enhancer found 1.5 kb upstream of the GnRH gene which is sufficient to confer repression to a heterologous promoter. Thus the NMDA/NO/cGMP neurotransmitter signal transduction pathway controls not only synaptic function but also neuron-specific gene expression.
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PMID:NMDA and nitric oxide act through the cGMP signal transduction pathway to repress hypothalamic gonadotropin-releasing hormone gene expression. 859 37

A dose of N-methyl-D-aspartic acid (NMDA, 50 ng) that induces penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus, increased the concentration of NO2- from 1.10 +/- 0.28 microM to 7.32 +/- 1.12 microM and of NO3 from 4.96 +/- 0.69 microM to 10.5 +/- 1.61 microM in the paraventricular dialysate obtained from male rats by in vivo microdialysis. NO2- concentration was not increased by (+/-)-alpha-(amino)-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 100 ng) or by trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (100 ng), which were unable to induce these behavioral responses. N-Methyl-D-aspartic acid effect on NO2- concentration, penile erection and yawning was prevented by dizolcipine (MK-801) (10-100 ng) or by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (20 microg), but not by the oxytocin receptor antagonist [d(CH2)5,Tyr(Me)2,Orn8]vasotocin (100 ng), or by the guanylate cyclase inhibitor methylene blue (20 microg) given in the paraventricular nucleus 15 min before N-methyl-D-aspartic acid or by the dopamine receptor antagonist haloperidol (0.5 mg/kg) given intraperitoneally 30 min before N-methyl-D-aspartic acid. In contrast, the nitric oxide scavenger hemoglobin (20 microg) given in the paraventricular nucleus prevented N-methyl-D-aspartic acid-induced NO2- concentration increase, but was unable to prevent penile erection and yawning. The results suggest that N-methyl-D-aspartic acid induces penile erection and yawning by increasing nitric oxide synthase activity in the paraventricular nucleus of the hypothalamus, possibly in the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating these behavioral responses.
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PMID:N-methyl-D-aspartic acid-induced penile erection and yawning: role of hypothalamic paraventricular nitric oxide. 921 92

Afferent nerves carrying signals from mechanoreceptors in the aortic arch and carotid sinus terminate predominantly in the nucleus tractus solitarii (NTS). Signal transduction and neurotransmission in the NTS are critical for central cardiovascular reflect control, but little was known about either until the late 1970's. None of the numerous neuroactive chemicals found in the NTS had met strict criteria as a neurotransmitter in the baroreflex arc until data suggested that the excitatory amino acid L-glutamate (GLU) might be released from baroreceptor afferent terminals in the NTS. In anesthetized animals microinjection into the NTS of GLU, which can be demonstrated in terminals in the NTS, produces cardiovascular responses like those seen with activation of the baroreceptor reflex. Similar responses occur in awake animals if the chemoreceptor reflex is eliminated; otherwise, in conscious animals responses mimic those of chemoreceptor reflect activation. GLU released in the NTS upon selective activation of the baroreceptor, and possibly the chemoreceptor, reflex. Responses to selective agonists as well as baroreflex responses are eliminated by GLU antagonists microinjected into the NTS. Non-NMDA (N-methyl-D-aspartic acid) receptors seem to predominate at primary baroreceptor synapses in the NTS while NMDA receptors may be involved at later synapses. Although inhibition of soluble guanylate cyclase attenuates responses to ionotropic glutamate agonists in the NTS, nitric oxide does not seem to play a role in glutamate transmission in the NTS. GLU may also participate in transmission at cardiovascular neurons beyond the NTS. For example, a role has been suggested for GLU in the ventrolateral medulla and spinal cord. Work continues concerning GLU signal transduction and mechanisms that modulate that transduction both at the NTS and at other cardiovascular nuclei.
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PMID:Glutamatergic transmission in the nucleus tractus solitarii: from server to peripherals in the cardiovascular information superhighway. 922 96

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular messengers have been intensively investigated during the last decade. NO and cGMP both mediate physiological effects in the cardiovascular, endocrinological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of the N-methyl-D-aspartic acid (NMDA) type of glutamatergic receptor induces Ca(2+)-dependent NOS and NO release, which then activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation and long-term depression, and thus may play important roles in the mechanisms of learning and memory. Aging and the accumulation of amyloid beta (A beta) peptides are important risk factors for the impairment of memory and development of dementia. In these studies, the mechanism of basal- and NMDA receptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by assay of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and NMDA receptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo-old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor-stimulated enhancement of the cGMP level determined in the presence of cGMP-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor response was preserved in aged brain cerebral cortex. A significant enhancement of the basal activity of NOS by about 175 and 160% in hippocampus and cerebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of A beta, peptide 25-35, decreased significantly the NMDA receptor-mediated calcium, and calmodulim-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cerebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. A beta peptide accumulated during brain aging and in Alzheimer disease may be an important factor in decreasing the NO-dependent signal transduction mediated by NMDA receptors.
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PMID:Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide. 1034 72


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