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

1. L-2-Chloropropionic acid (L-CPA) produces selective neuronal cell necrosis in rat cerebellum when administered orally at 750 mg kg-1 that is mediated in part through activation of N-methyl-D-aspartate (NMDA) receptors. Cerebellar granule cell death occurs between 30 and 36 h following L-CPA administration exhibiting a number of features in common with excitatory amino acid-induced cell death. We have used this in vivo model to examine the neurochemical processes following L-CPA-induced activation of NMDA receptors leading to neuronal cell death in the rat cerebellum. 2. The effects of a number of compounds which potently block nitric oxide synthase in vitro were examined on L-CPA-induced neurotoxicity 48 h following L-CPA dosing, to discover whether the neuronal cell death is mediated in part by excessive nitric oxide generation. Four inhibitors were studied, NG-nitro-L-arginine (L-NOARG), NG-nitro-L-arginine methyl ester (L-NAME), NG-iminoethyl-L-ornithine (L-NIO) and 3-bromo-7-nitroindazole (BrNI). 3. L-NAME (50 mg kg-1, i.p. twice daily) and BrIN (50 mg kg-1, i.p. twice daily) administration prevented the L-CPA-induced loss of granule cells which can reach up to 80-90% of the total cell number in rats treated with L-CPA alone. L-NOARG (50 mg kg-1, i.p. twice daily) and L-NIO administered at either 25 or 100 mg kg-1, twice daily did not produce any significant protection against L-CPA-induced neurotoxicity. 4. Both L-NAME and BrIN also prevented the L-CPA-induced increase in cerebellar water content and sodium concentrations. L-NIO when administered at the highest doses prevented the increase in cerebellar sodium concentration but not water content. L-NIO and L-NOARG were ineffective in preventing the L-CPA-induced increases in cerebellar water and sodium concentrations. 5. L-CPA-induced reductions in cerebellar aspartate and glutamate concentrations and increases in glutamine and GABA concentrations were prevented by L-NAME and BrIn, but not by L-NIO or L-NOARG. Also reductions in L-[3H]-glutamate binding to glutamate ionotrophic and metabotrophic receptors in the granule cell layer of rat cerebellum was prevented by L-NAME and BrIN, but not L-NIO or L-NOARG. 6. In conclusion, the neuroprotection offered by L-NAME and BrIN suggests that L-CPA-induced cerebellar granule cell necrosis is possibly mediated by or associated with excessive generation of nitric oxide. The inability of nitric oxide synthase inhibitors, L-NOARG and L-NIO to afford protection may result from their limited penetration into the brain (L-NIO) or rapid dissociation from the enzyme.
 ...
PMID:Possible role of nitric oxide in the development of L-2-chloropropionic acid-induced cerebellar granule cell necrosis. 873 88

The effect of altering hippocampal nitric oxide (NO) levels on basal and N-methyl-D-aspartate receptor-evoked release of GABA has been studied in freely moving rats. N-Methyl-D-aspartate (NMDA) increased extracellular GABA in a concentration-dependent manner. The nitric oxide synthase inhibitor L-nitro-arginine-methyl ester (L-NAME; 100 microM) increased basal GABA release, and also enhanced release of GABA evoked by NMDA (100 microM) compared with the same concentration of NMDA infused alone. 200 microM L-NAME increased basal dialysate GABA, but to a lesser extent than the 100 microM concentration of the drug, and the NMDA-induced release of GABA was decreased. 1.0 mM L-NAME significantly decreased basal extracellular GABA, while abolishing the NMDA-evoked release of the amino acid. The actions of L-NAME were not mimicked by its much less active isomer D-nitro-arginine-methyl ester. The NO donor S-nitroso-N-acetylpenicillamine decreased dialysate GABA at a 500 microM concentration but increased the extracellular level of the transmitter when infused at 1.0 and 2.0 mM concentrations. These data suggest that NO may mediate both excitatory and inhibitory functions in vivo.
 ...
PMID:Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo. 873 73

Nitric oxide (NO) is synthesized in the neurons by constitutive NO synthase (NOS). Within given neuronal sets, this enzyme is colocalized with different other neurotransmitters such as, for example, GABA, acethylcholine or serotonin. Our attention has been focused on the fact that serotoninergic neurons, well known for their involvement in sleep triggering and maintenance, synthesize also NO. In order to evaluate the modalities of release of this compound throughout the rat sleep-waking cycle, we prepared a sensor allowing its specific detection in freely moving animals. The active part of this sensor is a carbon fiber (phi = 30 microns) successively coated with porphyrin nickel and nafion. In vitro, together with differential normal pulse voltammetric measurements, it allows the detection of a 650 mV signal varying linearly in NO solutions ranging from 5.10(-7) to 10(-4) M. At physiological concentrations, L-arginine, L-citrulline, nitrites and nitrates do not yield a signal at 650 mV. Similarly, the compounds administered to the animals, hydroxylamine, L-arginine p-nitroanilide (L-ANA) and L-N omega-nitro arginine methyl ester (L-NAME) are not electroactive at 650 mV. L-ANA and L-NAME, also appear to be trapping agents for NO while leaving the electrochemical properties of the sensor untouched. In vivo, in the frontal cortex of the anesthetized rat, a signal is measured at 650 mV. The administration of hydroxylamine (40 mg/kg, i.p.) induces a 100% increase in its height. The administration of L-ANA (100 mg/kg, i.p.) produces its complete disappearance within 50 min. Finally, the administration of L-NAME (100 mg/kg, i.p.) is without effect. This last aspect might be dependent upon the inability of L-NAME to cross the blood brain barrier. On the contrary, the increase in the signal height obtained with hydroxylamine and its disappearance with L-ANA support that it might depend upon NO. In vivo, and in animals also equipped with polygraphic electrodes, the signal measured in the same area of the cortex exhibits the highest height during the waking state and decreases during either slow-wave sleep (-6%) or paradoxical sleep (-9%). These mild variations might represent the mean of several NO sources (cortical GABAergic interneurons, cholinergic and serotoninergic axonal nerve endings), each of them varying differently throughout the sleep-waking cycle.
 ...
PMID:[Voltametric detection of cerebral NO in rats. Variations of the signal throughout the sleep-wakefulness cycle]. 876 65

1. GABA (3 x 10(-4) M) and electrical stimulation (60 mV, 1 ms, 0.1 Hz) produced a non-adrenergic non-cholinergic (NANC) relaxation response in the rat isolated duodenum. 2. Tetrodotoxin (10(-6) M) incubation abolished GABA and electrical stimulation responses but not ATP (10(-3) M)-induced relaxation. 3. Desensitization to ATP (10(-3) M) or alpha, beta-methylene ATP (10(-5) M) and incubation with the P1 receptor antagonist 8-phenyltheophylline (10(-5) M) failed to affect relaxation induced by GABA and low frequency electrical stimulation. 4. The inhibitor of L-arginine-NO synthase N omega-Nitro-L-arginine methyl ester (L-NAME) (10(-4)-3 x 10(-4) M) reduced the NANC relaxations elicited by GABA and low frequency electrical stimulation in a dose-dependent manner. These effects were partially reversed by the addition of L-arginine (10(-3)-3 x 10(-3) M). ATP (10(-3) M)-induced relaxations were not modified by L-NAME (3 x 10(-4) M) incubation. 5. These results suggest that nitric oxide is involved in inhibitory NANC transmission in the rat duodenum. We provided original evidence that nitric oxide is involved in neurally mediated relaxations induced by GABA in rat isolated duodenum.
 ...
PMID:Evidence that nitric oxide mediates non-adrenergic non-cholinergic relaxation induced by GABA and electrical stimulation in the rat isolated duodenum. 895 71

1. Whole-cell recordings were obtained from type I paraventricular nucleus (PVN) neurones in coronal slices of rat hypothalamus to study the involvement of nitric oxide (NO) in the modulation of inhibitory transmission resulting from the activation of N-methyl-D-aspartate (NMDA) receptors by the high affinity receptor agonist D,L-tetrazol-5-ylglycine. 2. A brief pulse of NMDA agonist (0.1-10 microM) faithfully elicited increases in action potential firing frequency in all type I cells tested (n = 55). In cells with membrane potentials positive to -75 mV, this excitation was accompanied by an underlying depolarization (> 2 mV) in the majority of cases (n = 45). At membrane potentials negative to -75 mV, NMDA agonist application elicited an initial monotonie depolarization, which was auxiliary to profound, rhythmic oscillations of the membrane potential, resulting in the emergence of burst-like activity in these cells (n = 8). 3. In addition to depolarizing the neurones, the NMDA agonist also elicited inhibitory postsynaptic potentials (IPSPs) in 40% (n = 22) of the cells tested. The IPSPs were inhibited by the GABAA receptor antagonist bicuculline methiodide (BMI). 4. Microdialysis of NO into the PVN has been shown to increase local levels of inhibitory neurotransmitters, including GABA. The possibility that NO-induced increases in GABA lead to an increase in inhibitory synaptic activity in PVN was investigated by administering NO by three different methods. Bath application of the donor compound, S-nitroso-N-acetyl-penicillamine (SNAP; n = 7), bubbled NO solution (n = 5), or the NO precursor L-arginine (n = 6) all elicited increases in IPSP frequency. 5. Production of NO in other brain centres has been linked to the activation of the NMDA receptor. In order to determine whether the increase in IPSPs following NMDA was the result of activation of NO, the production of NO was blocked with the NO synthase inhibitor N omega-nitro-L-arginine methylester (L-NAME). Subsequent NMDA receptor activation elicited more pronounced depolarizations, but there was no accompanying increase in IPSP frequency (n = 5). 6. This study demonstrates that GABAergic inhibition resulting from NMDA receptor activation can be regulated profoundly by NO. By increasing inhibitory transmission within a nucleus, NO may serve as an important intermediary in the regulation of neuronal excitability in the central nervous system.
 ...
PMID:Nitric oxide regulates NMDA-driven GABAergic inputs to type I neurones of the rat paraventricular nucleus. 913 Jan 69

Both nitric oxide (NO) and GABA are known to provide inhibitory inputs to the paraventricular nucleus (PVN) of the hypothalamus and are involved in the control of sympathetic outflow. The purpose of the present study was to examine the interaction of NO and GABA in the regulation of renal sympathetic nerve activity in rats. The responses of renal nerve activity, blood pressure, and heart rate to microinjection of sodium nitroprusside (SNP), an NO donor, into the PVN were measured in the presence and absence of blockade of the GABA system (bicuculline; 2 nmol). Microinjection of SNP (50, 100, and 200 nmol) into the PVN elicited significant decreases in renal nerve discharge, arterial blood pressure, and heart rate, reaching -36.4 +/- 9.7%, -11 +/- 5 mmHg, and -34 +/- 14 beats/min, respectively, at the highest dose. These responses were eliminated by blockade of the GABA system. Conversely, microinjection of Nomega-nitro-L-arginine methyl ester (L-NAME; 50, 100, and 200 nmol) elicited significant increases in the renal sympathetic nerve discharge, arterial blood pressure, and heart rate, reaching 88.9 +/- 16.6%, 9 +/- 1 mmHg, and 29 +/- 9 beats/min, respectively, at the highest dose. These sympathoexcitatory responses were masked by prior blockade of the GABA system with bicuculline. The sympathoexcitatory effect of L-NAME was also eliminated by activation of the GABA system with muscimol. In conclusion, our data indicate that the inhibitory effect of endogenous NO within the PVN on the renal sympathetic nerve activity is mediated by GABA.
 ...
PMID:Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. 972 69

1. The effects of streptozotocin (STZ)-induced experimental diabetes on nitrergic-mediated responses to GABA and electrical field stimulation (EFS) have been evaluated in rat isolated duodenum. 2. In the presence of noradrenergic and cholinergic blockade, EFS (60 V, 1 ms, 0.1-32 Hz) induced frequency dependent relaxations of the preparation. GABA also caused submaximal relaxation of the rat duodenum. The relaxations induced by GABA and EFS were reduced in duodenal tissues from diabetic rats compared with control rats. 3. Neither ATP- nor sodium nitroprusside-induced relaxations were altered in diabetic duodenal tissues. GABA- and EFS-induced relaxations were inhibited by NG-nitro-L-arginine methyl ester (L-NAME; 300 mmol/L) in both diabetic and control rats. Although the inhibition caused by L-NAME of GABA- and EFS-induced relaxation was partially reversed by L-arginine (1 mmol/L), L-arginine alone had no effect on GABA- and EFS-induced relaxation in diabetic rats. 4. These results suggest that STZ-induced diabetes impairs non-adrenergic, non-cholinergic relaxation induced by EFS and GABA. Impairment of nitrergic innervation of the rat duodenum may contribute to the abnormalities of intestinal motility abnormalities associated with diabetes.
 ...
PMID:Effects of diabetes on non-adrenergic, non-cholinergic relaxation induced by GABA and electrical stimulation in the rat isolated duodenum. 1049 62

Relaxation induced by NANC-nerve stimulation is reduced by nitric oxide synthase (NOS) inhibitors but not by superoxide generators or NO scavengers, casting doubts on the precise nature of the neurotransmitter being released by these nerves. The lack of effect of superoxide anion generators to inhibit nitrergic nerve-mediated relaxations has been attributed to the protective action of high tissue levels of superoxide dismutase (SOD). The effects of hydroquinone, hydroxocobalamin and carboxy-PTIO, three NO inactivators which do not depend on superoxide anion generation, upon nitrergic nerve-mediated relaxations of the rat proximal duodenum were determined in order to elucidate whether they are mediated by free NO. GABA and nicotine caused relaxations of isolated segments of the rat proximal duodenum in a concentration-dependent manner that were abolished by tetrodotoxin (TTX). Similarly, transmural electrical stimulation (TES) caused frequency-dependent relaxations that were also abolished by TTX. The NOS inhibitors L-NAME and L-NOARG reduced in a concentration-dependent manner nerve-mediated relaxations elicited by TES, nicotine and GABA. The effect of NOS inhibitors was prevented by L-arginine but not D-arginine. NO caused concentration-dependent relaxations that were not affected by TTX or L-NOARG but were abolished by hydroquinone, hydroxocobalamin and carboxy-PTIO. In contrast, these compounds failed to affect TES-, nicotine- and GABA-induced relaxations. The lack of effect of hydroquinone, hydroxocobalamin and carboxy-PTIO upon nerve-mediated relaxations was unaltered by pretreatment with the SOD irreversible inhibitor DETCA. The present findings show that nitrergic nerve-mediated relaxations of the rat duodenum are unaffected by NO inactivators that do not generate superoxide anion. It is suggested that either a NO-containing molecule that is unreactive with the inactivators tested is the inhibitory neurotransmitter released by nitrergic nerves or that NOS activity fulfills another role in nitrergic nerves which could be related to the release of an still unidentified transmitter.
 ...
PMID:Effect of hydroquinone, hydroxocobalamin and carboxy-PTIO on non-adrenergic non-cholinergic nerve mediated relaxations of the rat duodenum. 1058 74

GABA(B) receptors influencing vagal pathways to the lower oesophageal sphincter and heart were investigated. In urethane-anaesthetized ferrets, the GABA(B) agonist baclofen (7 micromol kg(-1) i.v.) increased basal lower oesophageal sphincter (LOS) pressure. This was reversed by antagonism with CGP35348 (100 micromol kg(-1) i.v.). Baclofen's effect was abolished by vagotomy, suggesting a central action, yet it was ineffective when given centrally (3 - 6 nmol i.c.v.). Peripheral vagal stimulation (10 Hz, 5 s duration) caused LOS inhibition, followed by excitation, then prolonged inhibition. Bradycardia was also evoked during stimulation. Bradycardia and LOS responses were abolished after chronic supranodose vagotomy, indicating that they were due to stimulation of vagal pre-ganglionic neurones, not antidromic stimulation of afferents. Baclofen (1 - 10 micromol kg(-1)) reduced bradycardia and enhanced LOS excitation, which was also seen in animals pretreated with atropine (400 microgram kg(-1) i.v.) and guanethidine (5 mg kg(-1) i.v.), but not in those pretreated with L-NAME (100 mg kg(-1) i.v.). Effects of baclofen (7 micromol kg(-1) i.v.) on vagal stimulation-induced LOS and cardiac responses were unchanged by the GABA(B) antagonists CGP35348 or CGP36742 (up to 112 micromol kg(-1) i.v.), but were reversed by CGP62349 (ED(50) 37 nmol kg(-1) i.v.) or CGP54626 (ED(50) 100 nmol kg(-1) i.v.). Responses of isolated LOS strips to electrical stimulation, capsaicin, NK-1, NK-2 and nicotinic receptor agonists were all unaffected by baclofen (</=200 microM). We conclude that baclofen reduces vagal output at two peripheral sites: one presynaptically on pre-ganglionic neurones (CGP35348-insensitive), and another (CGP35348-sensitive) that could not be identified. This demonstrates heterogeneity of GABA(B) receptors through differential sensitivity to antagonists.
 ...
PMID:GABA(B) receptor-mediated effects on vagal pathways to the lower oesophageal sphincter and heart. 1080 64

The effects of bath applications of the nitric oxide (NO) donors sodium nitroprusside (SNP), diethylamine sodium (DEA), 3-morpholinosydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine (SNAP) on the resting activity (RA) of afferent crista fibers were studied in isolated statocysts of the cuttlefish Sepia officinalis. The NO donors had three different effects: inhibition, excitation, and excitation followed by an inhibition. The SNAP analog N-acetyl-DL-penicillamine (xSNAP; with no NO moiety) had no effect. When the preparation was pre-treated with the NO synthase inhibitor N(G)-nitric-L-arginine methyl ester HCl (L-NAME), the NO donors were still effective. When the preparation was pre-treated with the guanylate cyclase inhibitors methylene blue (M-BLU) or cystamine (CYS), NO donors had only excitatory effects, whereas their effects were inhibitory only when pre-treatment was with the adenylate cyclase inhibitors nicotinic acid (NIC-A), 2',3'-dideoxyadenosine (DDA), or MDL-12330A. When pre-treatment was with a guanylate and an adenylate cyclase inhibitor combined, NO donors had no effect; in that situation, the RA of the afferent fibers remained and the preparation still responded to bath applications of GABA. Selective experiments with statocysts from the squid Sepioteuthis lessoniana and the octopod Octopus vulgaris gave comparable results. These data indicate that in cephalopod statocysts an inhibitory NO-cGMP and an excitatory NO-cAMP signal transduction pathway exist, that these two pathways are the key pathways for the action of NO, and that they have only modulatory effects on, and are not essential for the generation of, the RA.
 ...
PMID:Effects of nitric oxide donors on the afferent resting activity in the cephalopod statocyst. 1082 23


1 2 3 4 5 6 Next >>