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)

Little is known of the action of nitric oxide (NO) at the synaptic level on identified interneurones in local circuits that process mechanosensory signals. Here, we examine the action of NO in the terminal abdominal ganglion of the crayfish Pacifastacus leniusculus, where it has modulatory effects on the synaptic inputs of 17 identified ascending interneurones mediated by electrical stimulation of a sensory nerve. To analyse the role of NO in the processing of sensory signals, we bath-applied the NO donor SNAP, the NO scavenger PTIO, the nitric oxide synthase (NOS) inhibitor l-NAME, the NOS substrate l-arginine, a cyclic GMP (cGMP) analogue, 8-Br-cGMP, and the soluble guanylate cyclase (sGC) inhibitor ODQ. The effects of these chemicals on the synaptic inputs of the interneurones could be divided into two distinct classes. The NO donor SNAP enhanced the inputs to one class of interneurone (class 1) and depressed those to another (class 2). Neither the inactive isomer NAP nor degassed SNAP had any effect on the inputs to these same classes of interneurone. The NO scavenger PTIO caused the opposite effects to those of the NO donor SNAP, indicating that endogenous NO may have an action in local circuits. Preventing the synthesis of NO using l-NAME had the opposite effect to that of SNAP on each response class of interneurone. Increasing the synthesis of endogenous NO by applying l-arginine led to effects on both response classes of interneurone similar to those of SNAP. Taken together, these results suggested that NO was the active component in mediating the changes in amplitude of the excitatory postsynaptic potentials. Finally, the effects of 8-Br-cGMP were similar to those of the NO donor, indicating the possible involvement of a NO-sensitive guanylate cyclase. This was confirmed by preventing the synthesis of cGMP by sGC using ODQ, which caused the opposite effects to those of 8-Br-cGMP on the two response classes of interneurone. The results indicate that a NO--cGMP signal transduction pathway, in which NO regulates transmitter release from mechanosensory afferents onto intersegmental ascending interneurones, is probably present in the local circuits of the crayfish.
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PMID:Opposing actions of nitric oxide on synaptic inputs of identified interneurones in the central nervous system of the crayfish. 1124 41

We examined the effect of NO on acid secretion in vitro using isolated preparations of Bullfrog stomach. The bullfrog fundic mucosa was bathed in unbuffered Ringer solution gassed with 100% O2 on the mucosal side and HCO3- Ringer's solution gassed with 95% O2/5% CO2 on the serosal side, and the acid secretion was measured at pH 5.0 using the pH-stat method and by adding 5 mM NaOH. Serosal addition of a NO donor NOR-3 (10(-5) approximately 10(-3) M: (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexnamine) caused an increase of acid secretion in a dose-dependent manner, the effect lasting about 1 hr and reaching a maximal level of 2-fold the basal values. The acid stimulatory effect of NOR-3 was mimicked by another NO donor SNAP (10(-3) mol/L: S-nitroso-O-N-acetyl-penicillamine) and markedly and markedly inhibited by prior administration of cimetidine (10(-5) mol/L) as well as compound 48/80 (the mast cell degranulator). Likewise, the increased acid response to NOR-3 was significantly mitigatd by pretreatment with carboxy-PTIO (a NO scavenger) or superoxide dismutase (SOD), but not by indomethacin or methylene blue (a guanylyl cyclase inhibitor). Neoither L-NAME, L-arginine nor dibutyryl guanosine-3',5'-cyclic monophosphate (dbcGMP) has any effect on the basal acid secretion. Serosal addition of NOR-3 caused a significant increase in the luminal release of histamine, and this response was inhibited by pretreatment with either compound 48/80, carboxy-PTIO or SOD. These results suggest that the NO donor increases gastric acid secretion in the isolated frog stomach in vitro, and this action is mediated by endogenous histamine released from mast cells, the process being cGMP-independent but requiring the presence of superoxide radicals. In addition, it was speculated that the histamine releasing action of NO may be due to peroxynitrite produced by NO and superoxide radicals.
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PMID:Stimulation by nitric oxide of gastric acid secretion in bullfrog fundic mucosa in vitro. 1132 16

The aim of this work was to characterize the effect of experimental diabetes on neurotransmission in rat vagina. Female Sprague-Dawley rats were divided into two groups: non-diabetic controls (NDM, n=38) and diabetics (DM, n=38). DM was produced by intraperitoneal injection of streptozotocin. Eight weeks later the animals were killed, the distal part of the vagina was removed, and smooth muscle strips were prepared for functional organ bath experiments and for measurement of nitric oxide synthase (NOS) activity. In DM preparations, the EC(50) value for noradrenaline (NA) was significantly increased (P<0.05) and the maximal contractile response decreased (P=0.001). In preparations precontracted with NA, the NO donor SNAP and calcitonin gene-related peptide (CGRP) caused concentration-dependent relaxations, which were significantly decreased (P<0.001) in the DM group. Electrical stimulation of nerves (EFS) caused frequency-dependent contractions, which were significantly lower in DM than in NDM strips (P<0.001). SNAP and CGRP concentration-dependently inhibited EFS evoked contractions in both NDM and DM preparations. The inhibition was significantly lower (P<0.05) in the DM group. In NDM preparations precontracted with NA, EFS evoked frequency-dependent relaxations; such relaxations were inhibited or reduced in DM. Treatment with the NOS inhibitor, L-NOARG 0.1 mM, abolished relaxations in all preparations or produced contraction in DM preparations. Calcium-dependent NOS activity was not significantly different in the DM and NDM groups. However, the DM animals showed a small but significant increase in calcium-independent NOS-activity (P<0.05). Diabetes interferes with adrenergic-, cholinergic- and NANC-neurotransmitter mechanisms in the smooth muscle of the rat vagina. The changes in the nitrergic neurotransmission are not due to reduction in NOS-activity, but seem to be due to interference with later steps in the L-arginine/NO/guanylate cyclase/cGMP system.
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PMID:Effects of diabetes on neurotransmission in rat vaginal smooth muscle. 1142 40

1. The regulation of L-type Ca(2+) current (I(Ca)) by the two nitric oxide (NO) donors sodium nitroprusside (SNP, 1 microM to 1 mM) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 3 or 10 microM) was investigated in frog ventricular myocytes using double voltage clamp and double-barrelled microperfusion techniques. 2. SNP and SNAP depressed the isoprenaline (ISO, 10-100 nM)- or forskolin (FSK, 1 microM)-mediated stimulation of I(Ca) via cGMP activation of the cGMP-stimulated phosphodiesterase (PDE2). Complete inhibition of the ISO (100 nM) response was observed at 1 mM SNP. 3. When SNP was applied locally, i.e. to one-half of the cell, and ISO to the whole cell, the response of I(Ca) to ISO was strongly antagonized in the cell half exposed to SNP (up to 100 % inhibition at 1 mM SNP) but a relatively small depression was observed in the other half of the cell (only 20 % inhibition at 1 mM SNP). 4. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO, 1 mM) reversed the local effect of SNAP (3 microM) on FSK-stimulated I(Ca) when applied to the same side as the NO donor, but had no effect when applied to the other side of the cell. 5. A local application of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 30 microM), a selective inhibitor of PDE2, fully reversed the local effect of SNP (100 microM) or SNAP (10 microM) on I(Ca) but had no effect on the distant response. 6. When EHNA was applied on the distant side, with SNP (1 mM) and ISO (100 nM) applied locally, the distant effect of SNP was fully reversed. 7. Our results demonstrate that in frog ventricular myocytes stimulation of guanylyl cyclase by NO leads to a strong local depletion of cAMP near the L-type Ca(2+) channels due to activation of PDE2, but only to a modest reduction of cAMP in the rest of the cell. This may be explained by the existence of a tight microdomain between L-type Ca(2+) channels and PDE2.
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PMID:Local response of L-type Ca(2+) current to nitric oxide in frog ventricular myocytes. 1143 96

The present study was performed to explore two of the possible signalling mechanisms through which nitric oxide (NO) inhibits steroidogenesis in bovine granulosa cells. Because cGMP is generally known to play a pivotal role in NO signal transduction, the first aim of the present study was to verify the presence of a functional NO-cGMP signalling pathway. Because non-cGMP-dependent pathways could be involved in the inhibition of steroidogenesis by NO, we examined the formation of lipid hydroperoxides (LPOs), possibly induced by NO. Using bovine granulosa cells collected from small (< 5 mm) and large (> 8 mm) follicles, the effectiveness of the NO donor s-nitroso-N-acetylpenicillamine (SNAP; 10(-3), 10(-4) and 10(-5) M) in stimulating cGMP production and the formation of LPOs was examined. The second aim of the present study was to determine whether the effects of NO on steroidogenesis could be mimicked by treatment of cells with a cGMP analogue (8-bromo-cGMP (8-Br-cGMP); 10(-3), 10(-4) and 10(-5) M) and whether these effects could be reversed by [1H]-[1,2,3]oxadiaziolo[4,3a]quinoxaline-1-one (ODQ; 10(-5) and 10(-4) M) an inhibitor of NO-sensitive soluble guanylate cyclase. The highest dose of SNAP used induced a significant (P<0.01) increase in cGMP levels, while other concentrations tested were ineffective. Neither concentration of ODQ used significantly inhibited basal cGMP output, while both concentrations counteracted the stimulatory effect of SNAP. Treatment of cells with 8-Br-cGMP and ODQ was ineffective in modifying steroidogenesis. Treatment with SNAP, at the three concentrations tested, had no significant effect on the level of LPOs. The present results suggest that NO inhibits steroidogenesis in bovine granulosa cells without involving cGMP and LPOs.
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PMID:Lipid hydroperoxide and cGMP are not involved in nitric oxide inhibition of steroidogenesis in bovine granulosa cells. 1145 Oct 20

1. The subcellular mechanisms involved in the effect of nitric oxide (NO) on the release of vasoactive intestinal polypeptide (VIP) were examined in synaptosomes isolated from rat small intestine. 2. VIP release was stimulated by the NO donor SNAP (10(-7)-10(-4) M) in an oxyhaemoglobin-sensitive manner. The presence of the guanylate cyclase inhibitor ODQ (10(-5) M), or inhibition of protein kinase G (PKG) by KT 5823 (3 x 10(-6) M) or Rp-8Br-PET-cGMPS (5 x 10(-7) M), antagonized the SNAP-induced VIP release, suggesting a regulatory role of PKG, confirming previously published data from enteric ganglia. This finding was further supported by the fact that direct PKG activation by the stable cGMP analogue 8-pCPT-cGMP stimulated VIP secretion to the same extent as SNAP. 3. Basal VIP secretion was enhanced in the presence of zaprinast, an inhibitor of cGMP-dependent phosphodiesterase 5 (PDE 5), suggesting a functional role of PDE 5 in NO-cGMP signalling. Supportive evidence for this finding was obtained by demonstration of the presence of PDE 5 using RT-PCR. 4. Stimulation of endogenous NO production by L-arginine was also effective in releasing VIP. The effect was abolished in the presence of KT 5823, but was insensitive to oxyhaemoglobin (10(-3) M), suggesting that an interaction between NO and VIP is likely to occur within the same nerve terminal rather than between terminals. 5. NO synthesis was not affected by VIP (10(-8)-10(-5) M), suggesting that there is no feedback regulation between the NO and the VIP pathways. 6. These findings support the notion that an anatomical and functional interrelationship exists between NO and VIP in enteric nerve terminals and that complex signalling mechanisms involving PKG and PDE 5 contribute to NO-induced VIP release.
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PMID:Functional coupling between nitric oxide synthesis and VIP release within enteric nerve terminals of the rat: involvement of protein kinase G and phosphodiesterase 5. 1148 12

The present investigation was undertaken to verify if the two nitric oxide synthase isoforms, eNOS and iNOS, are present in swine granulosa cells and whether the enzyme soluble guanylate cyclase is functionally active in the same cells and can account for NO effects. Using western blotting, the presence of endothelial NO synthase was demonstrated in freshly collected cells; on the contrary, iNOS expression was not observed in the same cells either before or after culture with the inflammatory cytokine hTNF-alpha. The treatment with a strong NO donor (S-Nitroso-L-acetyl penicillamine, SNAP) determined an increase of cGMP levels in culture media, which was attenuated by the combined treatment with an inhibitor of NO-sensitive soluble guanylate cyclase, 1H-[1,2,3]oxadiaziolo [4,3a]quinoxaline -1-one (ODQ). The cGMP analog, 8 bromo-cGMP, mimicked the strong inhibitory effect exerted by SNAP on estradiol 17 beta and progesterone production, while ODQ did not modify steroids concentrations in culture media. These observations demonstrate the presence of a follicular NO-generating system, which in swine granulosa cells seems to include only the endothelial NOS isoform. Furthermore, the nitric oxide/cyclic GMP system seems to be functionally active in these cells, since cGMP appears to mediate NO action, even if it cannot account completely for NO inhibitory effect on steroidogenesis.
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PMID:Nitric oxide synthase expression and nitric oxide/cyclic GMP pathway in swine granulosa cells. 1151 18

We used authentic NO or NO from NO donors to show that the physiological levels of NO (<1 microM) induce a positive inotropic effect and demonstrated that the effect is evoked through a cGMP-dependent pathway. In isolated rat ventricular myocytes, authentic NO at 588 nM increased both cell shortening and the intracellular Ca(2+) ([Ca(2+)]i) transient (133 and 117%, respectively; p < 0.05 vs. baseline), and 0.16-1.7 microM NO elicited reproducible dose-dependent increases in cell shortening. NOC18 (0.1 mM: actual NO concentration 673 nM) or SNAP (0.1 mM: actual NO concentration 285 nM) showed similar effects (shortening 215% and [Ca(2+)]i transient 160% increases, and shortening 148% and [Ca(2+)]i transient 117% increases, respectively). The NO-induced increases in cell shortening and the [Ca(2+)]i transient were inhibited by an inhibitor of soluble guanylate cyclase (ODQ, 30 microM) or by an inhibitor of cAMP-dependent protein kinase (KT5720, 0.1 microM). In the presence of an inhibitor of cGMP-inhibited cAMP-phosphodiesterase (milrinone, 10 microM), NO failed to increase both cell shortening and the [Ca(2+)]i transient. These results suggest that physiological levels of NO induce positive inotropy through a cGMP-dependent pathway.
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PMID:Physiological concentration of nitric oxide induces positive inotropic effects through cGMP pathway in isolated rat ventricular myocytes. 1156 82

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.
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PMID:Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock. 1157 81

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
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PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80


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