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)

An understanding of the neural control of lower oesophageal sphincter (LOS) relaxation is clinically relevant because transient LOS relaxations (TLOSRs) are a mechanism of acid reflux into the oesophagus. Preganglionic motor neurones innervating the LOS are localized in the dorsal motor nucleus of the vagus (DMV). Based on a single study in cats, it is now widely accepted that these neurones are functionally organized into two separate populations, such that stimulation of the caudal and rostral DMV evokes LOS relaxation and contraction, respectively. Our goal was to map the functional LOS responses to chemical stimulation in the DMV and nucleus tractus solitarius (NTS) of ferrets, an animal model commonly used for conscious studies on TLOSRs, and to test whether DMV-evoked LOS relaxation is mediated through hexamethonium-sensitive vagal-inhibitory pathways to the LOS. We used miniaturized manometry with Dentsleeve to monitor LOS and oesophageal pressures in decerebrate unanaesthetized ferrets. LOS relaxation was evoked readily in response to gastric insufflation, which shows that the vago-vagal reflex was intact in this preparation. Microinjections of l-glutamate (12.5 nmol L-1 in 25 nL) were made into the DMV from approximately - 1.5 to + 2.0 mm relative to the obex. Microinjections into the caudal (- 1.5 to + 0.0 mm behind obex) and intermediate (+ 0.1 to + 1.0 mm rostral to obex) DMV both significantly decreased LOS pressure, and complete LOS relaxation was noted in 28/32 and 11/18 cases, respectively. LOS relaxation responses to DMV microinjection were highly reproducible and abolished by bilateral vagotomy or hexamethonium (15 mg kg-1 intravenously). A nitric oxide synthase inhibitor (l-NAME 100 mg kg-1 intramuscularly) significantly increased the time taken to reach the maximal response. Increases in LOS pressure (24 +/- 4 mmHg; n = 3) were obtained only when stimulation sites were located equal to greater than 1.5 mm rostral to the obex. LOS relaxation (- 78 +/- 10%; n = 6) was evoked by stimulation of the NTS but not immediately outside of the NTS (11 +/- 27%; n = 5). We conclude that there is a very extensive population of 'inhibitory' motor neurones in the DMV that may account for the predominant vagal-inhibitory tone in ferrets. As NTS stimulation evokes LOS relaxation and the predominant response to DMV stimulation is also LOS relaxation, this vago-vagal reflex may involve an excitatory interneurone between the NTS and DMV vagal inhibitory output.
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PMID:Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferrets. 1206 15

Interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) markedly stimulate glucose utilization in primary cultures of mouse cortical astrocytes. The mechanism that gives rise to this effect, which takes place several hours after application of cytokine, has remained unclear. Experiments were conducted to identify the major signaling cascades involved in the metabolic action of cytokine. First, the selective IL-1 receptor antagonist (IL-1ra) prevents the effect of IL-1alpha on glucose utilization in a concentration-dependent manner, whereas it has no effect on the action of TNF-alpha. Then, using inhibitors of three classical signaling cascades known to be activated by cytokines, it appears that the PI3 kinase is essential for the effect of both IL-1alpha and TNF-alpha, whereas the action of IL-1alpha also requires activation of the MAP kinase pathway. Participation of a phospholipase C-dependent pathway does not appear critical for both IL-1alpha and TNF-alpha. Inhibition of NO synthase by L-NAME did not prevent the metabolic response to both IL-1alpha and TNF-alpha, indicating that nitric oxide is probably not involved. In contrast, the Na(+)/K(+) ATPase inhibitor ouabain prevents the IL-1alpha- and TNF-alpha-stimulated 2-deoxyglucose (2DG) uptake. When treatment of astrocytes with a cytokine was followed 24 h later by an acute application of glutamate, a synergistic enhancement in glucose utilization was observed. This effect was greatly reduced by ouabain. These data suggest that Na(+) pump activity is a common target for both the long-term metabolic action of cytokines promoted by the activation of distinct signaling pathways and the enhanced metabolic response to glutamate.
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PMID:Long-term modulation of glucose utilization by IL-1 alpha and TNF-alpha in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms. 1211 71

The present study was performed to examine the effect of fangchinoline, a bis- benzylisoquinoline alkaloid, which exhibits the characteristics of a Ca2+ channel blocker, on cyanide-induced neurotoxicity using cultured rat cerebellar granule neurons. NaCN produced a concentration-dependent reduction of cell viability, which was blocked by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, verapamil, L-type Ca2+ channel blocker, and L-NAME, a nitric oxide synthase inhibitor. Pretreatment with fangchinoline over a concentration range of 0.1 to 10 microM significantly decreased the NaCN-induced neuronal cell death, glutamate release into medium, and elevation of [Ca2+]i and oxidants generation. These results suggest that fangchinoline may mitigate the harmful effects of cyanide-induced neuronal cell death by interfering with [Ca2+]i influx, due to its function as a Ca2+ channel blocker, and then by inhibiting glutamate release and oxidants generation.
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PMID:Protective effect of fangchinoline on cyanide-induced neurotoxicity in cultured rat cerebellar granule cells. 1213 9

The subretrofacial nucleus (SRF) has been known to play a crucial role in the expression of the exercise pressor reflex. Previously, we have reported that the release of glutamate (Glu) in the SRF was increased during muscle contraction in anesthetized cats. In this study, static muscle contraction of the triceps surae for 4 min was induced by electrical stimulation of L7 and S1 ventral roots. Endogenous release of Glu and citrulline (Cit) from the SRF was recovered by microdialysis and measured by HPLC. The microdialysis probes were also used to deliver L-arginine and L-NAME to test the effect of nitric oxide (NO) on release of Glu in the SRF and on the cardiovascular responses during muscle contraction. During control, muscle contraction significantly increased mean arterial pressure (MAP) from 98+/-8 to 151+/-9 mmHg, and the extracellular concentration of Glu from 610+/-120 to 1280+/-290 nM. Dialyzing 2 mM L-arginine into the SRF increased basal Cit concentration from 260+/-50 to 760+/-210 nM (P<0.05). During contraction after L-arginine, the increases in MAP and Glu concentration were significantly attenuated (86+/-3-124+/-6 mmHg and 300+/-60-460+/-100 nM, respectively). Dialysis of 0.5 mM L-NAME into the SRF decreased Cit concentration from 340+/-40 to 180+/-20 nM (P<0.05). During contraction after dialyzing L-NAME, the increases in MAP and Glu concentration were significantly potentiated (93+/-6-154+/-9 mmHg and 520+/-80-1290+/-380 nM, respectively). These results suggest that endogenous NO modulates the cardiovascular responses to static muscle contraction by affecting the release of Glu in the SRF.
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PMID:Effect of nitric oxide on release of glutamate in the subretrofacial nucleus (SRF) during the exercise pressor reflex in cats. 1223 Dec 44

It is recognized that an imbalance of the autonomic nervous system is involved in the genesis of ventricular arrhythmia and sudden death during myocardial ischemia. In the present study we investigated the effects of clonidine and rilmenidine, two centrally acting sympathomodulatory drugs, on an experimental model of centrally induced sympathetic hyperactivity in pentobarbital-anesthetized New Zealand albino rabbits of either sex (2-3 kg, N = 89). We also compared the effects of clonidine and rilmenidine with those of propranolol, a beta-blocker, known to induce protective cardiovascular effects in patients with ischemic heart disease. Central sympathetic stimulation was achieved by intracerebroventricular injection of the excitatory amino acid L-glutamate (10 micro mol), associated with inhibition of nitric oxide synthesis with L-NAME (40 mg/kg, iv). Glutamate triggered ventricular arrhythmia and persistent ST-segment shifts in the ECG, indicating myocardial ischemia. The intracisternal administration of clonidine (1 microg/kg) and rilmenidine (30 microg/kg) or of a nonhypotensive dose of rilmenidine (3 microg/kg) decreased the incidence of myocardial ischemia (25, 14 and 25%, respectively, versus 60% in controls) and reduced the mortality rate from 40% to 0.0, 0.0 and 12%, respectively. The total number of ventricular premature beats per minute fell from 30 +/- 9 in the control group to 7 +/- 3, 6 +/- 3 and 2 +/- 2, respectively. Intravenous administration of clonidine (10 micro g/kg), rilmenidine (300 microg/kg) or propranolol (500 microg/kg) elicited similar protective effects. We conclude that clonidine and rilmenidine present cardioprotective effects of central origin, which can be reproduced by propranolol, a lipophilic beta-blocking agent.
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PMID:Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits. 1253 31

Nitric oxide (NO) is known to regulate the release of arginine-vasopressin (AVP) and oxytocin (OT) by the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). The aim of the current study was to identify in these nuclei the NO-producing neurons and the NO-receptive cells in mice. The determination of NO-synthesizing neurons was performed by double immunohistochemistry for the neuronal form of NO synthase (NOS), and AVP or OT. Besides, we visualized the NO-receptive cells by detecting cyclic GMP (cGMP), the major second messenger for NO, by immunohistochemistry on hypothalamus slices. Neuronal NOS was exclusively colocalized with OT in the PVN and the SON, suggesting that NO is mainly synthesized by oxytocinergic neurons in mice. By contrast, cGMP was not observed in magnocellular neurons, but in GABA-, tyrosine hydroxylase- and glutamate-positive fibers, as well as in GFAP-stained cells. The cGMP-immunostaining was abolished by incubating brain slices with a NOS inhibitor (L-NAME). Consequently, we provide the first evidence that NO could regulate the release of AVP and OT indirectly by modulating the activity of the main afferents to magnocellular neurons rather than by acting directly on magnocellular neurons. Moreover, both the NADPH-diaphorase activity and the mean intensity of cGMP-immunofluorescence were increased in monoamine oxidase A knock-out mice (Tg8) compared to control mice (C3H) in both nuclei. This suggests that monoamines could enhance the production of NO, contributing by this way to the fine regulation of AVP and OT release and synthesis.
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PMID:The effects of nitric oxide on magnocellular neurons could involve multiple indirect cyclic GMP-dependent pathways. 1258 Nov 64

The study was designed to investigate the role of the activation of class III metabotropic glutamate receptors (mGluRs) in the behavioral activity of angiotensin II (AngII). The experiments were performed on adult male Wistar rats. Stimulation of group III mGluRs was evoked by icv injection of agonist, L-2-amino-4-phosphonobutyric acid (L-AP4) (5 microl of 80 mM solution of L-AP4). Fifteen minutes later, the animals were given icv solution containing 1 nmol of AngII. Memory motivated affectively was evaluated by passive avoidance and active avoidance responses (CARs). Moreover, the speculative influence of the treatment on motor activity was tested in open field. We observed that both compounds did not have significant influence on motor activity of rats in open field test. L-AP4 given alone had no influence on acquisition, consolidation and recall of passive avoidance responses. Examination of influence of L-AP4 on the acquisition and extinction of CAR proved that this compound decreased acquisition of CARs, while it did not alter extinction of these responses. AngII, as repeatedly shown before, greatly increased passive avoidance latency, rate of acquisition of CARs and decreased they extinction. Pretreatment of rats with L-AP4 prevented all above behavioral effects of the AngII administration.
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PMID:L-AP4, a potent agonist of group III metabotropic glutamate receptor, decreases central action of angiotensin II. 1259 28

This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cGMP in the acute inhibitory effects of central interleukin 1beta on pentagastrin-stimulated acid production.The acid-inhibitory effect of central interleukin 1beta was prevented by intracisternal (i.c.) microinjections of interleukin 1beta together with the NMDA receptor antagonist, dizocilpine maleate (MK-801). Intracisternal co-administration of the nitric oxide synthase inhibitor, N(G)-nitro- L-arginine methyl esther ( L-NAME) or 1H-[1,2,4]oxazodiolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC) blocker, both reversed the hyposecretory effect of central interleukin 1beta. Peripheral administration of endotoxin significantly reduced pentagastrin-stimulated gastric acid secretion. I.c. pre-treatment with the interleukin 1 receptor antagonist, IL-1ra, failed to restore acid secretory responses in these rats. In addition, endotoxin did not modify the levels of endogenous mRNA for IL-1beta in the brainstem. We conclude that central glutamate receptors are involved in the acid inhibitory effect of centrally administered interleukin 1beta. This central pathway involves synthesis of NO, which acts on the enzyme sGC. However, endogenous interleukin 1beta does not seem to be involved in the inhibition of gastric acid secretion elicited by peripheral endotoxin.
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PMID:Interleukin 1 beta-induced inhibition of gastric acid secretion involves glutamate, NO and cGMP synthesis in the brain. 1261 37

It is now well established that nitric oxide (NO) acts as a neuromodulator in the central nervous system. To assess the role of NO in modulating striatal activity, single-unit recording was combined with iontophoresis to study presumed spiny projection neurons in urethane-anesthetized male rats. Striatal neurons recorded were essentially quiescent and were therefore activated to fire by the iontophoretic administration of glutamate, pulsed in cycles of 30 sec on and 40 sec off. In this study, iontophoresis of 3-morpholinosydnonimine hydrochloride (SIN 1), a nitric oxide donor, produced reproducible, current-dependent inhibition of glutamate-induced excitation in 12 of 15 striatal neurons, reaching its maximal inhibitory effect (76.2 +/- 5.6% below baseline) during the application of a 100 nA current. Conversely, microiontophoretic application of N-omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, produced clear and reproducible excitation of glutamate evoked firing in 7 of 10 cells (51.4 +/- 2.3%, at 100 nA). To evaluate the involvement of cyclic guanosine monophosphate (cGMP) in the electrophysiological effects produced by the NO donor, the effects of methylene blue, an inhibitor of guanylyl cyclase, on the responses of nine neurons to SIN 1 were tested. In six of nine neurons the effect of SIN 1 was significantly reduced during continuous iontophoretic administration (50 nA) of methylene blue. Taken together, these data show that NO modulates the striatal network and that inhibitory control of the output neurons is involved in this effect. These results also suggest that the effects of nitric oxide on striatal neurons are partially mediated via cGMP.
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PMID:Nitric oxide modulates striatal neuronal activity via soluble guanylyl cyclase: an in vivo microiontophoretic study in rats. 1261 44

Glutamate, previously demonstrated to participate in regulation of the resting membrane potential in skeletal muscles, also regulates non-quantal acetylcholine (ACh) secretion from rat motor nerve endings. Non-quantal ACh secretion was estimated by the amplitude of endplate hyperpolarization (H-effect) following blockade of skeletal muscle post-synaptic nicotinic receptors by (+)-tubocurarine and cholinesterase by armin (diethoxy-p-nitrophenyl phosphate). Glutamate was shown to inhibit non-quantal release but not spontaneous and evoked quantal secretion of ACh. Glutamate-induced decrease of the H-effect was enhanced by glycine. Glycine alone also lowered the H-effect, probably due to potentiation of the effect of endogenous glutamate present in the synaptic cleft. Inhibition of N-methyl-d-aspartate (NMDA) receptors with (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine (MK801), dl-2-amino-5-phosphopentanoic acid (AP5) and 7-chlorokynurenic acid or the elimination of Ca2+ from the bathing solution prevented the glutamate-induced decrease of the H-effect with or without glycine. Inhibition of muscle nitric oxide synthase by NG-nitro-l-arginine methyl ester (l-NAME), soluble guanylyl cyclase by 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and binding and inactivation of extracellular nitric oxide (NO) by haemoglobin removed the action of glutamate and glycine on the H-effect. The results suggest that glutamate, acting on post-synaptic NMDA receptors to induce sarcoplasmic synthesis and release of NO, selectively inhibits non-quantal secretion of ACh from motor nerve terminals. Non-quantal ACh is known to modulate the resting membrane potential of muscle membrane via control of activity of chloride transport and a decrease in secretion of non-quantal transmitter following muscle denervation triggers the early post-denervation depolarization of muscle fibres.
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PMID:Glutamate regulation of non-quantal release of acetylcholine in the rat neuromuscular junction. 1264 42


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