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 utility of a new nitric oxide (NO) donor, NOC-18, and the contribution of the neurotransmitter NO to nociception in response to tissue injury in rats, were examined following the subcutaneous injection of formalin into the hindpaw. This model induces biphasic responses in pain-related behavior, such that C-fiber activation during the first phase triggers a state of central sensitization characterized by the second phase. Formalin-induced nociceptive behavior was facilitated by intracerebroventricular administration of NOC-18 in the second phase, but not the first phase. This enhancement was completely abolished by the soluble guanylate cyclase inhibitor, methylene blue. These findings indicate that NO causes nociception via the NO-cGMP pathway in the central nervous system and NOC-18 proved to be a convenient and useful tool for the investigation of nociception-related NO.
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PMID:A new nitric oxide donor, NOC-18, exhibits a nociceptive effect in the rat formalin model. 888 Jun 84

We used hippocampal synaptosomes to study the effect of NO originating from NO donors and from the activation of the NO synthase on the Ca2+-dependent release of glutamate due to 4-aminopyridine (4-AP) depolarization. We distinguished between the effects of NO on the exocytotic and on the carrier-mediated release of glutamate, which we found to be related to an increase in cGMP content and to a reduction of the ATP/ADP ratio, respectively. The NO donor hydroxylamine, at concentrations < or = 0.3 mM, inhibited the Ca2+-dependent glutamate release evoked by 4-AP, and addition of the NO donor, NOC-7, had a similar effect, which was reversed by the NO scavenger, carboxy-PTIO. Increasing the activity of NO synthase by addition of L-arginine also led to a decrease in the Ca2+-dependent release of glutamate induced by 4-AP, and this effect was reversed by inhibiting NO synthase with NG-nitro-L-arginine. This depression of the exocytotic release of glutamate was accompanied by an increase in cGMP levels due to the stimulation of soluble guanylyl cyclase by NO, produced either by the NO donors (hydroxylamine <0.3 mM) or by the endogenous NO synthase, but no significant decrease in ATP/ADP ratio was observed. However, at concentrations > or = 0.3 mM, hydroxylamine drastically increased the basal release and completely inhibited the Ca2+-dependent release of glutamate (IC50 = 168 microM). At these higher levels of NO, cGMP levels dropped to about 40% of the maximal values obtained at lower concentrations, and the ATP/ADP ratio decreased to about 50% (at 0.3 mM hydroxylamine). The large increase in the basal release could be partially inhibited by L-trans-2,4-PDC, previously loaded into the synaptosomes, suggesting that the nonexocytotic basal release occurred by reversal of the glutamate carrier. Therefore, the increase in cGMP induced by NO stimulation of the guanylyl cyclase decreases the exocytotic release of glutamate, but higher NO levels reduce the ATP/ADP ratio by inhibiting mitochondrial function, which therefore causes the massive release of cytosolic glutamate through the glutamate carrier.
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PMID:Modulation of glutamate release from rat hippocampal synaptosomes by nitric oxide. 944 4

A nitric oxide releasing compound, NOC-18, was injected intrathecally in order to determine the role of NO in spinal nociceptive mechanisms in rats. The nociceptive threshold was evaluated by the radiant heat tail-flick test. The effects of intrathecal injection of N-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor; methylene blue (MB), a soluble guanylate cyclase inhibitor and hemoglobin (Hb), an NO scavenger, on the nociceptive threshold were measured in the presence and absence of 0.1, 1 and 10 microg of NOC-18. The results were compared with a control group of rats which were injected with the same volume of normal saline. NOC-18 caused a dose-dependent curtailment of the tail-flick latency during the period from 15 to 150 min. L-NAME, MB and Hb all produced prolongation of the tail-flick latency during the same time period. The hyperalgesia induced by this concentration range of NOC-18 was completely blocked by Hb, but was not affected by either L-NAME or MB. These findings indicate that NO plays a direct role in thermal hyperalgesia in the spinal cord, and that an another pathway in addition to the NO-cGMP pathway may be involved.
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PMID:Intrathecal administration of a new nitric oxide donor, NOC-18, produces acute thermal hyperalgesia in the rat. 945 70

Intrathecal injection of a nitric oxide releasing compound, NOC-18, was used to define the role of nitric oxide (NO) in the spinal mechanism of neuropathic pain caused by unilateral chronic constriction injury to rat sciatic nerves. Paw withdrawal latency was used to evaluate nociception induced by thermal stimuli before surgery and afterwards at 1, 3, and 6 h, and on days 1, 2, 3, 4, 5, 8, and 12 after the nerve ligature. In the sham-surgery control groups, intrathecal injection of 10 or 100 microg of NOC-18 did not produce any change in withdrawal latencies. In rats with unilateral nerve ligation, however, administration of 1 or 10 microg, but not 0.1 microg, of NOC-18 significantly shortened the time in which thermal hyperalgesia developed after nerve injury. Injection of 1 microg of NOC-18 decreased the onset time of thermal hyperalgesia from 2 days to 3 h and with 10 microg hyperalgesia developed within 1 h after the nerve injury. The effects of intrathecal injection of MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist, N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, methylene blue (MB), a soluble guanylate cyclase inhibitor, and hemoglobin (Hb), a NO scavenger, on the development of thermal hyperalgesia after the sciatic nerve ligature were examined in the presence and absence of 1 and 10 microg of NOC-18. Acceleration of the development of thermal hyperalgesia induced by 1 and 10 microg NOC-18 was completely inhibited by Hb, but was not affected by either MK-801, L-NAME or MB. These findings indicate that NO plays an important role in the rapid development of thermal hyperalgesia after the nerve injury, but that facilitation of nociceptive processing in the spinal cord may entail an alternate to the NO-cyclic guanosine 3',5'-monophosphate (cGMP) pathway.
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PMID:Rapid development of nitric oxide-induced hyperalgesia depends on an alternate to the cGMP-mediated pathway in the rat neuropathic pain model. 959 28

The effects of various spontaneous nitric oxide (NO) donors and NO synthase inhibitors on endothelin- production were examined using porcine cultured aortic endothelial cells. NO donors such as (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 2), (+/-)-(E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 3) and (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridine carboxamide (NOR 4) suppressed effectively the release of endothelin-1 from the cells. Endothelin-1 mRNA expression was also attenuated by these compounds. Other NO donors such as 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamin e (NOC 5), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC 18), s-nitroso-n-acetyl-DL-penicillamine, N-morpholino sydnonimine (SIN-1) had no effects on endothelin-1 production. Endothelial intracellular cyclic guanosine monophosphate (cGMP) levels were significantly increased by all NO donors. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective soluble guanylyl cyclase inhibitor, had no effect on the NOR 3-induced decrease in endothelin-1 secretion, although cGMP production was abolished by ODQ. NOR 3 also inhibited endothelin-1 secretion even in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetrametylimidazole-1-oxyl 3-oxide (carboxy-PTIO), a NO scavenger. NOR 3-induced inhibitory effects on endothelin-1 secretion were abolished by preincubation of the compound in phosphate-buffered saline (37 degrees C, 4 h), a procedure by which about 98% of the parent compound's ability to release NO was lost. NO synthase inhibitors such as N(G)-nitro-L-arginine, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced prepro endothelin-1 mRNA expression and significantly increased endothelin-1 release from endothelial cells. Endothelin-1 secretion was also increased effectively by carboxy-PTIO or ODQ. When the cells were exposed to L-NAME with carboxy-PTIO or ODQ, no significant further increase in endothelin-1 release was observed. These results suggest that endogenous NO inhibits endothelin-1 production through guanylyl cyclase/cGMP-dependent mechanisms. In contrast, it seems unlikely that exogenous NO has an inhibitory effect on endothelin-1 production in endothelial cells. NOR compounds inhibit endothelin-1 production perhaps through NO/cGMP-independent mechanisms, i.e., through an unknown effect of the parent compound itself.
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PMID:Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. 992 Jan 86

In a previous paper we showed that the nitric oxide (NO) donors azide and hydroxylamine inhibited eosinophil apoptosis. Azide and hydroxylamine generate a nitrosyl-heme complex - due to endogenous catalase activity - which activates soluble guanylate cyclase. In contrast, in the present paper, we show that NO donors (SNAP, SIN-1, S-nitroso-L-cysteine, NOC-18) which spontaneously release NO in physiological solutions did not support the survival of eosinophils and induced apoptosis or necrosis. However, the addition of hematin (the ferric form of heme) together with low doses of NO (SNAP 10 microM) promoted eosinophil survival. In conclusion, we propose that NO and heme (e.g. from heme-containing enzymes such as peroxidase or catalase), both released in inflammation sites, could form nitrosyl-heme and thus promote eosinophilic inflammation.
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PMID:Effects of nitric oxide on the eosinophil survival in vitro. A role for nitrosyl-heme. 992 48

The present study was designed to examine the mechanisms of inhibitory effect of barbiturates on endothelial function by determining whether thiopentone and phenobarbitone reduce relaxations to acetylcholine mediated by endothelial Ca2+-dependent K+ channels in rat aortas. Cumulative applications (10(-9) to 10(-5) M) of acetylcholine induced endothelium-dependent relaxations, which are abolished by inhibitors of nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 10(-4) M) and of soluble guanylate cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; ODQ, 5 x 10(-6) M). Selective inhibitors of large-conductance Ca2+-dependent K+ channels (iberiotoxin, 5 x 10(-8) M), but not of those with small-conductance (apamin, 5 x 10(-8) M), significantly reduced the acetylcholine-induced vasorelaxation. ODQ, but neither iberiotoxin nor apamin, blocked the relaxations of arteries without endothelium induced by nitric oxide donors, sodium nitroprusside (10(-9) to 10(-5) M) and 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-10) to 10(-5) M). Thiopentone (10(-4) and 3 x 10(-4) M) but not phenobarbitone (3 x 10(-4) M) significantly impaired relaxations to acetylcholine, whereas thiopentone did not alter relaxations to sodium nitroprusside. Thiopentone (3 x 10(-4) M) did not affect relaxations to acetylcholine in arteries treated with iberiotoxin (5 x 10(-8) M), whereas it reduced these relaxations in arteries treated with apamin (5 x 10(-8) M). These results suggest that in rat aortas, large-conductance, but not small-conductance, Ca2+-dependent K+ channels in endothelial cells, play a role in endothelium-dependent relaxations to acetylcholine, and that thiopentone, but not phenobarbitone, impairs relaxations to acetylcholine mediated by these channels.
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PMID:Thiopentone inhibits endothelium-dependent relaxations of rat aortas regulated by endothelial Ca2+-dependent K+ channels. 1035 55

The inhibition of nitric oxide synthase by N-nitro-L-arginine methyl ester (0.03-3 mM) dose-dependently reduced nitric oxide (NO(*)) levels and enhanced the outward currents carried by human ether-a-gogo-related gene-1 (hERG1) K(+) channels expressed in Xenopus laevis oocytes, whereas the increase in NO(*) levels achieved by exposure to L-arginine (0.03-10 mM) inhibited these currents. Furthermore, four NO(*) donors belonging to such different chemical classes as sodium nitroprusside (1-1000 microM), 3-morpholino-sydnonimine (100-1000 microM), (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate (NOC-18; 1-300 microM), and S-nitroso N-acetylpenicillamine (1-300 microM) dose-dependently inhibited hERG1 outward K(+) currents. By contrast, the NO(*) donor NOC-18 (0.3 mM) did not affect other cloned K(+) channels such as rat neuroblastoma-glioma K(+) channel 2, rat delayed rectifier K(+) channel 1, bovine ether-a-gogo gene, rat ether-a-gogo-related gene-2, and rat ether-a-gogo-related gene-3. The inhibitory effect of NO(*) donors on hERG1 K(+) channels was prevented by the NO(*) scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide and hemoglobin. The membrane permeable analog of cGMP, 8-bromo-cGMP (1 mM), failed to reproduce the inhibitory action of NO(*) donors on hERG1 outward currents; furthermore, the specific inhibitor of the NO(*)-dependent guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (50 microM), neither interfered with outward hERG1 K(+) currents nor prevented their inhibition by 0.3 mM NOC-18. Both L-arginine (10 mM) and NOC-18 (0.3 mM) counteracted the stimulatory effect on hERG1 outward currents induced by the radical oxygen species-generating system FeSO(4) (25 microM)/ascorbic acid (50 microM; Fe/Asc). Finally, L-arginine (10 mM) and NOC-18 (0.3 mM) inhibited both basal and Fe/Asc (0.1 mM/0.2 mM)-stimulated lipid peroxidation in X. laevis oocytes. Collectively, the present results suggest that NO(*), both endogenously produced and pharmacologically delivered, may exert in a cGMP-independent way an inhibitory effect on hERG1 outward K(+) currents via an interaction with radical oxygen species either generated under resting conditions or triggered by Fe/Asc.
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PMID:Modulation of the K(+) channels encoded by the human ether-a-gogo-related gene-1 (hERG1) by nitric oxide. 1057 58

This study was undertaken to investigate the influence of exogenous NO on intracellular calcium levels of porcine aortic endothelial cell culture monolayers. Spontaneous NO liberating substances with different half-life periods (NOC-9 [10 micromol/L] approximately 1 min, SNAP [10 micromol/L] approximately 4 h), and an aqueous NO gas solution [130 nmol/L] were added onto the monolayers. All three solutions induced a rapid and similar calcium rise in the endothelial cells. NOC-9 as a rapidly NO releasing compound was selected to be investigated more thoroughly. The NOC-9 calcium rise is not dependent on the activation of the guanylate cyclase since preincubation with a specific guanylate cyclase inhibitor [ODQ, 10 micromol/L] did not alter the effect and a cGMP analogue [8-bromo-cGMP 10 micromol/L] did not significantly elevate calcium levels. The NOC-9 induced calcium rise could be completely blocked by removal of extracellular calcium and partly blocked by SKF 96365 [10 micromol/L], an unspecific inhibitor of the receptor operated calcium channels. Incubation with N-nitroarginine [100 micromol/L] slightly but significantly reduced basal calcium levels in the cell cultures. Therefore, we conclude that exogenous NO elevates [Ca(2+)](i) in cultured porcine aortic endothelial cells. This effect is not dependent on cGMP, and a calcium influx is involved. Moreover, constitutively formed endogenous NO seems to be necessary to maintain basal calcium levels.
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PMID:Nitric oxide causes a cGMP-independent intracellular calcium rise in porcine endothelial cells-a paradox? 1062 69

The present study was designed to examine the role of basally released nitric oxide in relaxations to an ATP-sensitive K+ channel opener. Whether relaxations to levcromakalim are modulated by endothelial removal or the inhibitors of vasodilator effects of endothelium-derived nitric oxide, were investigated in the rat aorta. During contractions to phenylephrine (3 x 10(-7) to 10(-6) M), levcromakalim (10(-8) to 10(-5) M) or a nitric oxide donor, 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7, 10(-9) to 10(-5) M), was added in a cumulative fashion. Relaxations to levcromakalim (10(-8) to 10(-5) M) were significantly reduced by the endothelium-removal. In aortas with endothelium, relaxations in response to levcromakalim were decreased by selective inhibitors of nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 10(-4) M) and soluble guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; ODQ, 10(-5) M) and a scavenger of nitric oxide (carboxy-PTIO, 10(-3) M). Relaxations to levcromakalim in aortas treated with these inhibitors are comparable to those seen in aortas without endothelium. KCl (30 mM) and an ATP-sensitive K+ channel inhibitor, glibenclamide (10(-5) M), abolished relaxations to levcromakalim in aortas with or without endothelium, whereas glibenclamide did not alter relaxations to NOC-7 (10(-9) to 10(-5) M) in aortas without endothelium. These results suggest that in rat aortas, inhibition of vasodilator effects of basally released nitric oxide can reduce relaxations via ATP-sensitive K+ channels, although these channels do not mediate relaxations to exogenously applied nitric oxide.
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PMID:The role of endothelium-derived nitric oxide in relaxations to levcromakalim in the rat aorta. 1066 41


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