Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Release of nitric oxide occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme nitric oxide synthase. Since nitric oxide may serve as an intracellular messenger for NMDA glutamatergic neurons, it could be hypothesized that blockade of its synthesis may produce pharmacological effects similar to those of NMDA receptor antagonists. The purpose of the present study was to compare the effects of nitric oxide synthase inhibitors to those of the high affinity NMDA open channel blocker phencyclidine in drug discrimination, a pharmacologically selective procedure in which phencyclidine produces distinctive effects. Rats were trained to discriminate 2 mg/kg phencyclidine from saline in a standard two-lever discrimination task with food reward. Whereas phencyclidine dose-dependently substituted for itself, 7-nitroindazole, L-NAME (N(G)-nitro-L-arginine methyl ester), and L-NOARG (N(G)-nitro-L-arginine) failed to substitute for phencyclidine when administered intraperitoneally. L-NAME and 7-nitroindazole were tested up to doses that disrupted responding, providing evidence that a behaviorally-relevant dosage range was evaluated. Although these results conflict with those of a previous study which found that nitric oxide synthase inhibitors substituted for phencyclidine and produced phencyclidine-like catalepsy in pigeons, they are consistent with research showing that these drugs did not produce phencyclidine-like pharmacological effects in behavioral procedures in rats.
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PMID:Nitric oxide synthase inhibitors do not substitute in rats trained to discriminate phencyclidine from saline. 1008 58

Both the rise in extracellular glutamate concentration and anoxic depolarization in the rat striatum during 15 min of global ischemia and reperfusion were monitored using glutamate biosensor and direct current potential electrodes, respectively. Cerebral blood flow (CBF) was simultaneously monitored with a glutamate biosensor or a direct current potential electrode. Before the onset of ischemia, treatment with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) decreased CBF, while L-arginine increased CBF. However, neither L-NAME nor L-arginine significantly changed CBF during ischemia and reperfusion compared with vehicle-treated animals. The time-course and extracellular glutamate concentration increase during ischemia and reperfusion among L-NAME-, L-arginine- and vehicle-treated animals were very similar. These results were strengthened by the time-course and amplitude of anoxic depolarization. The study suggests that NO is not an important mediator of glutamate release during ischemia and reperfusion.
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PMID:Neither L-NAME nor L-arginine changes extracellular glutamate elevation and anoxic depolarization during global ischemia and reperfusion in rat. 1020 28

Lentiviruses such as Maedi Visna virus (MVV) in sheep, and human immunodeficiency virus (HIV) in man often cause a variety of neurological syndromes in later stages of infection. Neuropathological investigations reveal damage to myelin and astrocytosis in both white and grey matter. MVV infection induces axonal damage with some areas of necrosis while neuronal loss, and synaptic damage have been reported in HIV-1 infection. It is not clear, at present, how this neurodegeneration is mediated but, as these viruses do not directly infect neurons, an indirect neurotoxic action of the viruses is indicated. Previous experiments have shown that the intra-striatal injection in rats of a synthetic peptide derived from the basic region of the MVV transactivating protein Tat causes considerable neurotoxicity 1 week post-operatively. By in vivo stereotaxic injections of the same synthetic peptide, and subsequent immunocytochemical detection of neurons, astrocytes and microglia, we show that this neurotoxicity displays a distinctive and unusual lesion profile and is evident as rapidly as 0.5 h post-operatively. Furthermore, neuroprotection studies suggest that the early effects of the MVV tat peptide may involve glutamate neurotoxicity via the N-methyl-D-aspartate (NMDA) receptors since the application of dizolcipine (MK801) reduces the volume of the lesion seen at 1 h after the injection of neurotoxic peptide, while L-NAME is ineffective. The mechanism of this early neurotoxicity is thus different from the longer term actions already described.
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PMID:Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat. 1036 85

The intrathecal (i.t.) administration of glutamate (10-100 nmol) caused dose-related hyperalgesia (mean ED50 of 35 nmol) when assessed in the thermal behaviour model of nociception, the hot-plate test maintained at 50 degrees C. The i.p., i.t. or intracerebroventricular (i.c.v.) injection of the nitric oxide synthase inhibitors, L-NOARG and L-NAME, did not induce any detectable effect per se, but instead, produced dose-related inhibition of glutamate-induced hyperalgesia. D-NAME, the inactive enantiomer of L-NAME, had no effect. The i.c.v. or i.t. administration of L-NIO caused graded attenuation of glutamate-induced hyperalgesia. L-arginine (3.4 mmol kg(-1), i.p.), but not D-arginine (3.4 mmol kg(-1), i.p.) significantly potentiated glutamate (10 nmol)-induced hyperalgesia, an action that was prevented by L-NOARG (137 nmol kg(-1)). The co-injection of S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (0.22 micromol) or 8-bromo-cGMP (22.5 nmol) with glutamate (10 nmol), via either i.t. or i.c.v. routes, also significantly enhanced glutamate-induced hyperalgesia. The guanylate cyclase inhibitors LY 83583 (0.1-1.0 nmol) or ODQ (30-300 pmol) co-administered with glutamate, dose-dependently antagonised the glutamate-induced hyperalgesia. Collectively, these results demonstrate that the i.t. injection of glutamate into the spinal cord of mice produces dose-related hyperalgesia an effect that was largely mediated by the L-arginine-nitric oxide-cGMP pathway from both spinal and supraspinal sites.
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PMID:The role of systemic, spinal and supraspinal L-arginine-nitric oxide-cGMP pathway in thermal hyperalgesia caused by intrathecal injection of glutamate in mice. 1046 87

The significant increase of free calcium concentration ([Ca2+]i) was found in rat cerebral cortex synaptosomes and hippocampal crude synaptosomal fraction after their exposure to glutamate. But no change of [Ca2+]i was revealed in cerebellar synaptosomes, the slight increase of [Ca2+]i in striatal synaptosomes was not significant. The presence of Ng-nitro-L-arginine methyl ester (L-NAME) in the incubation medium practically prevented the increase of [Ca2+]i initiated by glutamate in cerebral cortex synaptosomes, but not in hippocampal ones. The significant diminution of [Ca2+]i in the presence of this inhibitor was shown in striatal synaptosomes exposed to glutamate. Na+,K+-ATPase activity is significantly lower in cerebral cortex, striatal and hippocampal synaptosomes exposed to glutamate. L-NAME prevented the inactivation of this enzyme by glutamate. In cerebellar synaptosomes the tendency to the decrease of enzymatic activity in the presence of L-NAME was on the contrary noticed. Thus, the data obtained provide evidence of the protective effect of NO synthase inhibitor in brain cortex and striatal synaptosomes, but not in cerebellar synaptosomes. Synaptosomes appear to be an adequate model to study the regional differences in the mechanism of toxic effect of excitatory amino acids.
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PMID:The difference in the effect of glutamate and NO synthase inhibitor on free calcium concentration and Na+, K+-ATPase activity in synaptosomes from various brain regions. 1048 80

The major aim of the present study was to evaluate the role of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats subjected to long-term treatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (70 mg/kg orally for 1 week). We inhibited or stimulated RVLM neurons with the use of drugs such as glycine, L-glutamate, or kynurenic acid in urethane-anesthetized rats (1.2 to 1.4 g/kg IV). Bilateral microinjection of glycine (50 nmol, 100 nL) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 158+/-4 to 71+/-4 mm Hg (P<0.05), which was similar to the decrease produced by intravenous administration of hexamethonium. In normotensive rats, glycine microinjection reduced MAP from 106+/-4 to 60+/-3 mm Hg (P<0.05). Glutamate microinjection into the RVLM produced a significant increase in MAP in both hypertensive rats (from 157+/-3 to 201+/-6 mm Hg) and normotensive rats (from 105+/-5 to 148+/-9 mm Hg). No change in MAP was observed in response to kynurenic acid microinjection into the RVLM in either group. These results suggest that hypertension in response to long-term L-NAME treatment is dependent on an increase in central sympathetic drive, mediated by RVLM neurons. However, glutamatergic synapses within RVLM are probably not involved in this response.
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PMID:Rostral ventrolateral medulla : A source of sympathetic activation in rats subjected to long-term treatment with L-NAME. 1052 53

1. Glutamate neurotoxicity has been attributed to cellular Ca2+ overload. As mitochondrial depolarisation may represent a pivotal step in the progression to cell death, we have used digital imaging techniques to examine the relationship between cytosolic Ca2+ concentration ([Ca2+]c) and mitochondrial potential (DeltaPsim) during glutamate toxicity, and to define the mechanisms underlying mitochondrial dysfunction. 2. In cells of > 11 days in vitro (DIV), exposure to 50 mM potassium or 100 microM glutamate had different consequences for DeltaPsim. KCl caused a small transient loss of DeltaPsim but in response to glutamate there was a profound loss of DeltaPsim. In cells of 7-10 DIV, glutamate caused only a modest and reversible drop in DeltaPsim. 3. Using fura-2 to measure [Ca2+]c, responses to KCl and glutamate did not appear significantly different. However, use of the low affinity indicator fura-2FF revealed a difference in the [Ca2+]c responses to KCl and glutamate, which clearly correlated with the loss of DeltaPsim. Neurons exhibiting a profound mitochondrial depolarisation also showed a large secondary increase in the fura-2FF ratio. 4. The glutamate-induced loss of DeltaPsim was dependent on Ca2+ influx. However, inhibition of nitric oxide synthase (NOS) by L-NAME significantly attenuated the loss of DeltaPsim. Furthermore, photolysis of caged NO at levels that had no effect alone promoted a profound mitochondrial depolarisation when combined with high [Ca2+]c, either in response to KCl or to glutamate in cultures at 7-10 DIV. 5. In cells that showed only modest mitochondrial responses to glutamate, induction of a mitochondrial depolarisation by the addition of NO was followed by a secondary rise in [Ca2+]c. These data suggest that [Ca2+]c and nitric oxide act synergistically to cause mitochondrial dysfunction and impaired [Ca2+]c homeostasis during glutamate toxicity.
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PMID:Excitotoxic mitochondrial depolarisation requires both calcium and nitric oxide in rat hippocampal neurons. 1054 45

The nucleus isthmi (NI) is a mesencephalic structure of the amphibian brain. It has been reported that NI plays an important role in integration of CO2 chemoreceptor information and glutamate is probably involved in this function. However, very little is known about the mechanisms involved. Recently, it has been shown that nitric oxide synthase (NOS) is expressed in the brain of the frog. Thus the gas nitric oxide (NO) may be involved in different functions in the brain of amphibians and may act as a neurotransmitter or neuromodulator. We tested the hypothesis that NO plays a role in CO2-drive to breathing, specifically in the NI comparing pulmonary ventilation, breathing frequency and tidal volume, after microinjecting 100 nmol/0.5 microl of L-NAME (a nonselective NO synthase inhibitor) into the NI of toads (Bufo paracnemis) exposed to normocapnia and hypercapnia. Control animals received microinjections of vehicle of the same volume. Under normocapnia no significant changes were observed between control and L-NAME-treated toads. Hypercapnia caused a significant (P<0.01) increase in ventilation only after intracerebral microinjection of L-NAME. Exposure to hypercapnia caused a significant increase in breathing frequency both in control and L-NAME-treated toads (P<0.01 for the control group and P<0.001 for the L-NAME group). The tidal volume of the L-NAME group tended to be higher than in the control group under hypercapnia, but the increase was not statistically significant. The data indicate that NO in the NI has an inhibitory effect only when the respiratory drive is high (hypercapnia), probably acting on tidal volume. The observations reported in the present investigation, together with other studies on the presence of NOS in amphibians, indicate a considerable degree of phylogenetic conservation of the NO pathway amongst vertebrates.
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PMID:Participation of nitric oxide in the nucleus isthmi in CO2-drive to breathing in toads. 1055 41

Nitric oxide (NO) is a free-radical gas with a role in various signal transduction processes. In the CNS, NO acts as an important central nervous messenger, but in excess it may be neurotoxic. Chronic or high dose administration of D-amphetamine (AMPH) has been shown to induce striatal neurotoxicity in rodents and primates. In this study, we studied whether AMPH given systemically elicits NO formation in the striatum of rats and determined the relationship between NO formation and striatal DAergic terminal damage. Our results demonstrated that a single large dose administration of AMPH with desipramine elicited a delayed production of NO and concomitant long-term DA loss in the striatum. These phenomena were blocked by treatment with either the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or the glutamate N-methyl-D-aspartate antagonist MK-801. It appears that AMPH-induced NO formation is critical for development of long-lasting DAergic terminal toxicity in the striatum of rats.
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PMID:Systemic administration of D-amphetamine induced a delayed production of nitric oxide in the striatum of rats. 1061 25

The present study has been aimed to investigate the effect of nitric oxide (NO) on the concentration of gamma-aminobutyric acid (GABA) in rat brain. The concentrations of GABA and glutamate and the activities of glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) were determined in groups of animals 5 and 30 min after intraperitoneal injection of a NO-increasing dose (1,000 mg/kg) of its precursor, L-arginine and a dose (50 mg/kg) of N-nitro-L-arginine methyl ester (L-NAME) that inhibits NO synthesis from L-arginine. L-arginine-induced elevation of NO concentration was accompanied by an increased concentration of GABA in the brain. GABA-T activity was inhibited in these animals. NO-decreasing action of L-NAME coincided with a reduction in the concentration of GABA and an enhancement of GABA-T activity. Both L-arginine and L-NAME did not alter the activity of GAD and the concentration of glutamate. An interpretation of these data suggests that NO has a GABA-T-inhibiting role in the brain.
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PMID:A role of nitric oxide as an inhibitor of gamma-aminobutyric acid transaminase in rat brain. 1065 79


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