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)

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.
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PMID:Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat. 747 83

Involvement of endogenous nitric oxide (NO) on glutamate receptor-mediated response was investigated in neuronal cells cultured from embryonic rat hippocampus. L-NG-Nitroarginine (NOARG), a NO synthase inhibitor, augmented NMDA- and kainate-induced increase in intracellular Ca2+ concentration ([Ca2+]i) measured by fura-2 fluorometry. However, quisqualate-induced response was not affected. The potentiating effect of NOARG was blocked by L-arginine, a substrate for NO synthase. NOARG was also effective when added after glutamate-induced response had reached a steady-state. Hemoglobin itself increased the basal level of [Ca2+]i at concentrations higher than 10 mM, and treatment of the cells with 1.0 mM hemoglobin had no effect on NMDA response. 8-Bromo-cyclic GMP was not effective on NMDA response. These results suggest that endogenous NO inhibits NMDA- and kainate-induced increase in [Ca2+]i as a negative feedback system independent of guanylate cyclase activation.
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PMID:Endogenous nitric oxide inhibits NMDA- and kainate- responses by a negative feedback system in rat hippocampal neurons. 790 57

Nitric oxide (NO) is shown to be synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation in the central nervous system remains unclear. The present study examines whether NO plays a role in the regulation of neuronal activity in the nucleus tractus solitarius (NTS). Single-unit extracellular recordings were obtained from NTS neurons in slices (400 microns) of the rat brainstem, which had spontaneous discharges at a frequency of 0.5 to 3 spikes per second. Eighty-one neurons were tested for sensitivity to L-arginine, which is the physiological precursor of NO. L-Arginine (10(-7) to 10(-4) mol/L) increased neuronal activity dose dependently in 33 (40.7%) of 81 neurons tested, but D-arginine (10(-5) mol/L) did not. The neurons that responded to L-arginine responded to glutamate as well. NG-Monomethyl-L-arginine (10(-5) to 3 x 10(-5) mol/L), an inhibitor of the formation of NO, dose-dependently blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Hemoglobin (1.5 mg/L), a trapper of NO, and methylene blue (10(-5) mol/L), an inhibitor of guanylate cyclase, also blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Sodium nitroprusside (SNP, 10(-5) to 10(-4) mol/L), which spontaneously produces NO, increased the neuronal activity in the neurons that responded to L-arginine. SNP did not alter the neuronal activity of the neurons that did not respond to L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide influences neuronal activity in the nucleus tractus solitarius of rat brainstem slices. 801 84

Hydroxylamine (0.01-30 mM), a nitric oxide (NO) generator, produced a concentration-dependent release of [3H]dopamine ([3H]DA) from rat striatal slices. Hemoglobin (10 microM), a NO scavenger, reduced basal [3H]DA release and blocked hydroxylamine (100 microM)-stimulated [3H]DA efflux. Tetrodotoxin (0.5 microM) had no significant effect. Sodium cyanide was used as a model compound to test the possibility that NO acted through blockade of mitochondrial electron transport. Calcium-free experimental buffer (1 mM EGTA) reduced basal release and the hydroxylamine response, while sodium cyanide-induced release did not change under these experimental conditions. Cadmium (200 microM), a non-selective inhibitor of voltage-dependent calcium channels, reduced the hydroxylamine response by 69%. Methylene blue (10 microM), an inhibitor of guanylate cyclase, produced a 3-fold increase in the basal release but had no significant effect on the hydroxylamine response. These data suggest that NO induces calcium-dependent [3H]DA release from the striatum via a mechanism which is independent of blockade of electron transport or activation of guanylate cyclase.
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PMID:Nitric oxide induces calcium-dependent [3H]dopamine release from striatal slices. 810 May 88

Endothelium derived relaxing factor (nitric oxide, or NO) activates cytoplasmic guanylate cyclase in vascular smooth muscle and decreases vascular tone through cGMP-dependent mechanisms that are not yet understood fully. In cultured vascular smooth muscle cells (A7r5 cell line) sodium nitroprusside (NP), a vasodilator that decomposes into nitric oxide, lowered [Ca2+]i in cells in which [Ca2+]i was elevated after depolarization. NP decreased current through voltage-gated calcium channels, but did not affect release of calcium from intracellular stores. Hemoglobin, a scavenger of NO, reversed the effect of NP on [Ca2+]i and 8-Br-cGMP, a membrane permeant form of cGMP, mimicked the effect of NP on [Ca2+]i and on calcium currents. Thus, the signal transduction mechanism of endothelium dependent relaxation of vascular smooth muscle involves a decrease in [Ca2+]i by inhibition of Ca2+ entry. Relaxation or vasodilation would then result from decreased activity of myosin light chain kinase, in addition to myosin light chain dephosphorylation.
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PMID:Nitric oxide decreases [Ca2+]i in vascular smooth muscle by inhibition of the calcium current. 814 12

Nitric oxide (NO) and carbon monoxide (CO) have been identified as two diffusible signaling messengers in the brain, capable of stimulating soluble guanylate cyclase. Locus coeruleus (LC) is rich in the alpha 1 and beta 1 subunits of soluble guanylate cyclase. Therefore, the possible role of the cGMP pathway in the regulation of LC neurons was investigated with electrophysiological techniques in rat brain slices. Bath application of various NO donors or CO-containing solutions increased the firing rate of most LC neurons. This activation was reversed by the NO scavenger hemoglobin, but not by methemoglobin. Bath or intracellular application of selective activators of cGMP-dependent protein kinase also caused increases in LC cell firing rate. The actions of NO donors and kinase activators were mutually occlusive and reversed by H8, an inhibitor of the cGMP-dependent protein kinase. Hemoglobin and H8 reduced the firing rate of LC neurons, but no change was found with inhibitors or activators of the NO synthase. In intracellular and whole-cell recordings, NO effect was associated with an inward current and an increase in the input conductance (mean reversal potential = -27 mV); these effects were abolished using a low-sodium buffer. Spontaneous EPSCs of LC cells were not modified with the NO donor administration. Taken together, these data suggest that NO and CO activate noradrenergic neurons of LC via a cGMP-dependent protein kinase and a nonselective cationic channel. It also is proposed that these effects occur at the postsynaptic level and that there may be a tonic regulation of LC neuronal firing by the cGMP pathway.
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PMID:Nitric oxide and carbon monoxide activate locus coeruleus neurons through a cGMP-dependent protein kinase: involvement of a nonselective cationic channel. 877 90

Both prostaglandins (PGs) and nitric oxide (NO) have cytoprotective and hyperemic effects in the stomach. However, the effect of NO on PG synthesis in gastric mucosal cells is unclear. We examined whether sodium nitroprusside (SNP), a releaser of NO, stimulates PG synthesis in cultured rabbit gastric mucus-producing cells. These cells did not release NO themselves. Co-incubation with SNP (2 x 10(-4), 5 x 10(-4), 10(-3) M) increased PGE2 synthesis, and SNP (10(-3) M) increased PGI2 synthesis in these cells. Hemoglobin, a scavenger of NO, (10(-5) M) eliminated the increase in PGE2 synthesis by SNP, but methylene blue, an inhibitor of soluble guanylate cyclase, (5 x 10(-5) M) did not affect the increase in PGE2 synthesis by SNP. 8-bromo guanosine 3':5'-cyclic monophosphate (8-bromo cGMP), a cGMP analogue, (10(-6), 10(-5), 10(-4), 10(-3) M) did not affect PGE2 synthesis. These findings suggest that NO increased PGE2 and PGI2 synthesis via a cGMP-independent pathway in cultured rabbit gastric cells.
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PMID:Nitric oxide stimulates prostaglandin synthesis in cultured rabbit gastric cells. 913 30

Recent data support a role for nitric oxide (NO) in pain processing at the level of the spinal cord, possibly via regulation of neuropeptide release. The goal of this study was to determine whether capsaicin, which selectively activates primary afferent neurons and evokes neuropeptide release, acts in an NO-dependent manner. Our results indicate that capsaicin (1 microM)-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) is significantly reduced in the presence of the NO synthase inhibitor, L-NAME (10-400 nM; F(3,45)=68.38; P<0.001) and, the selective nNOS inhibitor, 3-bromo-7-nitroindazole (170-680 nM; F(5,48)=56.2; P<0. 01). D-NAME (200 nM) had no effect on capsaicin-evoked iCGRP release. Hemoglobin (an extracellular scavenger of NO; 3 mg/ml) significantly reduced the effect of capsaicin on the release of iCGRP (F(1,8)=9.12; P<0.05). The NOS substrate, L-arginine, effectively reversed the inhibitory effect of 3-bromo-7-nitroindazole on capsaicin-evoked iCGRP release. To determine whether the NO-mediated release was NMDA-driven, we superfused spinal cord slices with competitive and non-competitive NMDA antagonists in the presence and absence of capsaicin. MK-801 (0. 1-10 microM; F(4,33)=8.49; P<0.0001) and AP-5 (0.01-10 microM; F(4, 38)=3.34; P<0.05) reduced capsaicin-evoked iCGRP release. CNQX, an AMPA/kainate antagonist (10 nM-10 microM), significantly decreased capsaicin-evoked release of iCGRP (F(6,42)=8.76; P<0.01) in a dose-dependent fashion. Additionally, our results demonstrate that while capsaicin-evoked release is significantly reduced in the presence of LY-83583 (10 microM; F(2,18)=3.46; P<0.01; a cyclic GMP lowering agent), there is no effect of ODQ (a potent and selective inhibitor of guanylate cyclase). Moreover, the application of a cell permeable analog of cyclic GMP (8-bromo-cGMP; 0.01-1000 microM) is without effect on both basal and evoked iCGRP release. Finally, we observed no colocalization of immunoreactive neuronal NOS (nNOS) with CGRP in the dorsal horn. In summary, these data indicate that capsaicin evokes the release of iCGRP, in part, via the production of NO which enters the extracellular space prior to having an effect. Moreover, iCGRP and nNOS are produced in distinct populations of neurons within the dorsal horn. We conclude that capsaicin-evoked release involves the activation of the NMDA receptor but is also modified by the activation of AMPA or kainate receptors. Finally, these data suggest that while capsaicin-evoked iCGRP release is modified by NO, this release does not require the activation of guanylate cyclase and subsequent production of cyclic GMP.
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PMID:Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP. 1076 Apr 83

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 microg/10 microl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 microg/10 microl; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain.
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PMID:The dual effect of a nitric oxide donor in nociception. 1128 53

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


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