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)

Nitric oxide synthase (NOS) inhibition has been used to increase blood pressure in humans with septic shock despite a lack of data regarding its effects on O2 delivery (QO2). We studied the effects of NG-nitro-L-arginine methyl ester (L-NAME) on systemic, gut, and hindlimb circulations of endotoxic dogs. Twelve dogs were infused with 2 mg/kg of LPS over 1 h followed by 60 mL/kg of 6% dextran over 2 h. Six dogs also received 20 mg/kg of L-NAME, LPS caused mean arterial pressure (MAP), flow and QO2 to whole body, hindlimb and gut to decrease, but O2 uptake (VO2) did not change. Dextran resuscitation alone produced a hyperdynamic state with increased blood flow to or above baseline. With L-NAME, systemic and regional resistances increased twofold and MAP returned to near baseline. Late in the study, these dogs had significantly lower blood flow and QO2 to the gut but maintained VO2 by increasing oxygen extraction to near critical levels. These data suggest that in acute endotoxicosis, L-NAME may significantly improve blood pressure but may markedly encroach on O2 transport reserves to the gut.
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PMID:Effects of nitric oxide synthase inhibition on regional hemodynamics and oxygen transport in endotoxic dogs. 860 98

The effect of capsaicin-induced stimulation of afferent neurons on peristalsis and the possible neural mediators involved in this action were examined in the guinea-pig isolated ileum. The intraluminal pressure threshold for eliciting peristaltic waves was used to quantify facilitation (decrease in threshold) or inhibition (increase in threshold) of peristalsis. Capsaicin (0.1-1 microM) caused an initial short-lasting stimulation of peristalsis followed by a prolonged inhibition of peristaltic activity. Capsaicin (1 microM) was ineffective when the gut segments had been pretreated with 3.3 microM capsaicin, which is indicative of an afferent neuron-dependent action of the drug. In contrast, the abolition of peristalsis caused by a high concentration of capsaicin (33 microM) was fully reversible on removal and reproducible on readministration of capsaicin, a feature characteristic of a nonspecific depression of smooth muscle excitability. Baseline peristalsis and the excitatory/inhibitory effect of capsaicin (1 microM) on peristalsis remained unaltered by a combination of the tachykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994; 0.3 microM) and the tachykinin NK2 receptor antagonist (L(-)-N-methyl-N[4-acetylamino-4-phenyl-piperidine-2-(3,4- -dichlorophenyl)butyl]-benzamide (SR-48,968; 0.1 microM). Further experiments, performed in the presence of a low concentration of atropine (10 nM) showed that the calcitonin gene-related peptide (CGRP) antagonist human alpha-calcitonin gene-related peptide (8-37) [hCGRP(8-37); 10 microM] attenuated the delayed inhibitory effect of capsaicin on peristalsis, but did not influence baseline peristaltic activity and the capsaicin-induced facilitation of peristalsis. Blockade of nitric oxide (NO) synthesis by NG-nitro-L-arginine methylester (L-NAME, 300 microM) facilitated baseline peristaltic activity and reduced the delayed inhibition of peristalsis caused by capsaicin (1 microM) without affecting the initial peristalsis-stimulating action of capsaicin. The effects of L-NAME were prevented by L-arginine (1 mM). The data of the current study indicate that capsaicin-sensitive afferent neurons do not participate in the neural pathways subserving peristalsis in the guinea-pig small intestine, but modulate peristaltic activity upon stimulation with capsaicin. The initial stimulant action of capsaicin on peristalsis is independent of tachykinins acting via NK1 or NK2 receptors, while the delayed capsaicin-induced depression of peristalsis involves CGRP and NO.
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PMID:The inhibitory modulation of guinea-pig intestinal peristalsis caused by capsaicin involves calcitonin gene-related peptide and nitric oxide. 875 Sep 23

The present study was undertaken to test the hypothesis that 5-HT stimulates nitric oxide (NO) generating neurons, and that these neurons participate in the mediation of 5-HT-induced fluid secretion. 5-HT induced electrogenic Cl- secretion in guinea-pig distal colon. This response was abolished by tetrodotoxin but not by atropine. The maximum response to 5-HT (10(-5) M) was inhibited by approximately 65% (P < 0.05, n = 6) by the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 10(-4) M). The substrate of NO synthase, L-Arg (10(-3) M) reversed the inhibition of 5-HT-induced secretions by L-NNA. 5-HT-induced diarrhea in fasted mice was reduced by atropine in vivo. NG-Nitro-L-Arg methyl ester (L-NAME, 1-32 mg/kg, i.p.) dose-dependently inhibited 5-HT (1 mg/kg)-induced diarrhea. The inhibitory effect of L-NAME was reversed by L-Arg, but not D-Arg (600 mg/kg, i.p., respectively). Taken together, these data suggest that 5-HT-induced fluid secretion in the gut is partly due to the activation of neurons that generate NO.
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PMID:Is nitric oxide involved in 5-HT-induced fluid secretion in the gut? 878 22

1. The effect of amylin on gastric ulcers induced by oral administration of indomethacin (Indo, 20 mg kg-1 at a dosing volume of 5 ml) or ethanol 50% (EtOH, 1 ml/rat) was investigated in conscious rats. 2. Amylin given intracerebroventricularly (0.22, 0.66 and 2.2 micrograms/rat, i.c.v.) demonstrated a dose-dependent cytoprotective effect against both Indo and EtOH-induced ulcers. In contrast, amylin, given subcutaneously at doses effective in inhibiting acid gastric secretion (2.5, 10 and 40 micrograms kg-1, s.c.), did not show any cytoprotective effect. 3. The interaction between amylin and endogenous nitric oxide (NO) in the maintenance of gastric mucosal integrity was investigated by pretreating the rats with a selective inhibitor of NO-synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 25 and 70 mg kg-1, s.c.). Administration of L-NAME to rats did not significantly increase the degree of the Indo-induced ulcer index and was not able to remove the protective effect of amylin on Indo-induced ulcers, thus excluding a role for endogenous NO in mediating the protective effect of this peptide. 4. To determine whether the cytoprotective effect of amylin was mediated by endogenous prostaglandins, we studied the effect of amylin (2.2 micrograms/rat, i.c.v.) on EtOH- induced ulcers in rats pretreated with Indo (10 mg kg-1, s.c.) to inhibit prostanoid biosynthesis; Indo was injected 30 min before amylin and EtOH after a further 30 min. Pretreatment with Indo did not significantly increase the ulcer index induced by EtOH but counteracted the ability of amylin to prevent the ulcer formation. 5. These findings suggest that amylin exerts a gastroprotective activity that is not strictly related to inhibition of acid gastric secretion and can be partly explained through a prostaglandin-dependent mechanism mediated by receptors for the peptide in the brain. Amylin might be considered as a new brain-gut peptide.
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PMID:Protection by amylin of gastric erosions induced by indomethacin or ethanol in rats. 905 Dec 94

Intussusception is a major cause for intestinal obstruction in children. Its etiology is unclear, but it is often associated with some kind of infection. We have developed a model for intussusception in mice using intraperitoneal (IP) injection of lipopolysaccharide (LPS). The objective of this study was to identify the putative mediators that participate in this LPS-induced intussusception. LPS (12 mg/kg) was injected into adult mice (N = 52) and 6 hr later, 25% of the animals demonstrated intussusception in the small or large intestine. We next tested whether nitric oxide (NO) or various inflammatory mediators contributed to this effect: Indomethacin (10 mg/kg) injected with LPS (12 mg/kg) completely prevented the effect of LPS (N = 20). The tumor necrosis factor (TNF) blocker pentoxifylline (200 mg/kg) significantly reduced the incidence of intussusception to 6.6% (N = 30). The platelet-activating factor (PAF) antagonist BN52021 (10 and 20 mg/kg) reduced the incidence of intussusception to 13.3% in both doses (N = 15 for each dose). Addition of 2% arginine (NO precursor) to the drinking water 36 hr before the injection of LPS increased the incidence of intussusception to 30.7% (N = 32). In mice injected with the NO synthase inhibitor L-NAME (20 mg/kg) only 3.8% developed intussusception (N = 26). Our results indicate that the induction of intussusception by LPS proceeds via parallel pathways involving cytokines, prostaglandins, and NO. Our previous pathological study showed that LPS did not cause any changes that may act as a lead point for the intussusception, suggesting that LPS induced intussusception by altering gut motility. We therefore propose that these mediators combine to induce disturbed gut motility that results in the formation of intussusception.
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PMID:The contribution of inflammatory mediators and nitric oxide to lipopolysaccharide-induced intussusception in mice. 920 71

The aim of the present study was to investigate whether nerve stimulation-induced nitric oxide (NO) release in the guinea-pig colon is affected by acetylcholine and to identify the muscarinic receptor subtype involved. Nerve-smooth muscle preparations were suspended in a superfusion chamber and NO/NO2- overflow in the superfusate was detected by chemiluminescence analysis. Transmural nerve stimulation evoked a significant increase in NO/NO2- release, which was inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) and abolished by tetrodotoxin. Exogenous acetylcholine concentration-dependently increased NO/NO2- release and atropine reduced nerve stimulation-evoked NO/NO2- release. The muscarinic M1 receptor selective antagonist telenzepine (10(-8) M) was as effective as atropine (10(-6) M) in inhibiting NO/NO2- release. The muscarinic M3 receptor antagonists 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and para-fluoro-hexahydrosila-difenidol (p-F-HHSiD) markedly inhibited cholinergic contractions at 3 x 10(-8) M and 3 x 10(-7) M respectively, but did not affect NO/NO2- release. In conclusion, nerve-induced NO/NO2- release in the guinea-pig colon is to a substantial part due to muscarinic M1 receptor activation. Thus acetylcholine, a major contractile neurotransmitter in the gut, can release NO which could act as a negative feedback mechanism on intestinal smooth muscle or neuronal activity.
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PMID:Nerve stimulation-induced nitric oxide release as a consequence of muscarinic M1 receptor activation. 927 82

This study has investigated the relative importance of central nervous and peripheral nitroxidergic mechanisms in the control of pyloric motility. In 10 urethane-anaesthetized ferrets, drugs were administered directly to the CNS via a 0.5-mm-diameter cannula inserted into the 4th ventricle, approximately at the obex. Drugs were also given directly to the upper GI tract by close intra-arterial (i.a.) injection at the coeliac axis. Antropyloroduodenal pressures were recorded with a five-channel sleeve/sidehole micromanometric assembly (1.35 x 1.75 mm o.d.), which was introduced via the duodenum. Pyloric motility was stimulated throughout the main part of each study with a continuous i.v. infusion of CCK-8 (30 pmol min-1). This infusion produced an immediate and sustained increase in tonic and phasic pyloric activity, and sustained abolition of antral pressure waves. CCK-8 also induced a duodenal motor response, but this was short-lived (11.4 +/- 7.9 min). Coeliac axis injection of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) decreased phasic pyloric activity (from 330 +/- 35 to 148 +/- 21 mmHg min-1 after SNAP 5 micrograms, P < 0.01). By comparison central SNAP administration over the same dose range had no effect on CCK-stimulated pyloric motlity. Inhibition of endogenous NO synthase with L-Nitro Arginine Methyl Ester (L-NAME, 100 mg kg-1 close i.a.) caused a marked increase of phase pyloric motor activity from 349 +/- 59 to 1044 +/- 140 mmHg min-1 (P < 0.01). In addition, SNAP caused marked stimulation of pyloric tone from 2.6 +/- 0.5 to 13.1 +/- 2.8 mmHg (P < 0.01). Central nervous administration of L-NAME caused modest enhancement of phasic pyloric activity (248 +/- 31 to 283 +/- 32 mmHg min-1 P < 0.05) and pyloric tone (2.6 +/- 0.5 to 3.7 +/- 0.7 mmHg, P < 0.05). Our data indicate that motor activity of the ferret pylorus is potently modulated by NO released within the upper gut. Additionally, there is potential for modulation of pyloric motility by central nervous system production of NO.
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PMID:Pyloric motor response to central and peripheral nitric oxide in the ferret. 934 72

Repeated oesophageal acidification is a definitive feature of gastro-oesophageal reflux disease, which in turn is caused by relaxation of the lower oesophageal sphincter (LOS). This study in anaesthetised ferrets investigates the reflex pathways involved in effects of oesophageal acidification on motor function of the LOS, with particular focus on the role of tachykinins. LOS pressure was monitored with a perfused micromanometric sleeve assembly. Oesophageal acidification reduced LOS pressure by 48 +/- 5% until washout with saline. This reduction became larger with repeated tests, and was unaffected in amplitude by acute bilateral vagotomy, although the response became slower in onset. Intra-oesophageal capsaicin (0.5% solution) caused a 68 +/- 17% decrease in LOS pressure which remained unchanged with repeated tests. The NK-1 receptor antagonist CP96,345 (1-5 mg/kg intravenous (i.v.) blocked the post-vagotomy LOS responses to both intra-luminal acid and capsaicin. Close intra-arterial (i.a.) injections of capsaicin (1-100 micrograms) gut induced LOS relaxation which was neither vagally nor NK-1 receptor-mediated. Substance P or the selective NK-1 receptor agonist [Sar9, Met(O2)11] substance P (25-500 ng close i.a.) caused a biphasic LOS response, consisting of initial brief contraction followed by prolonged, dose-dependent relaxation. Tetrodotoxin (10 micrograms/kg close i.a.) changed the biphasic response to substance P to excitation only. The neurokinin-1 (NK-1) receptor antagonist CP96,345 (0.3-10 mg/kg i.v.) dose-dependently reduced the inhibitory response to substance P. The excitatory phase of the response to substance P was larger and prolonged after guanethidine (5 mg/kg, i.v.), or propranolol (1 mg/kg, i.v.). L-NAME (100 mg/kg i.v.) reduced the inhibitory phase. The selective NK-2 receptor agonist [beta-Ala8] neurokinin A(4-10) caused LOS excitation only. These data indicate that intra-oesophageal acid causes substance P release from extrinsic afferent nerve endings which activates local inhibitory pathways to the LOS via NK-1 receptors.
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PMID:Lower oesophageal sphincter responses to noxious oesophageal chemical stimuli in the ferret: involvement of tachykinin receptors. 940 24

5-hydroxytryptamine (5-HT) stimulates electrogenic Cl- secretion in rat ileum stripped of its outer smooth musculature and myenteric plexus. The myenteric plexus, however, is a site of 5-HT synthesis in the gut, and the plexus mediates electrogenic ion secretion activated by luminal enterotoxin STa and taurocholate. Thus, we investigated the role of the myenteric plexus in 5-HT-induced electrogenic secretion in vitro by measuring short-circuit current (Isc, microamps) with voltage-clamp apparatus as an index of electrogenic Cl-secretion in rat ileum which was either stripped of the myenteric plexus or was left intact. Serosally added 5-HT stimulated electrogenic Cl- secretion in muscle-stripped and intact ileum in a concentration-dependent manner. Pre-treatment of stripped ileum with atropine (1 micron), hexamethonium (100 microns), tetrodotoxin (1.25 microns) and capsaicin (1 micron) for 15 min did not effect the maximum Isc induced by 5-HT which would implicate a direct action on the enterocyte. In intact ilea, however, tetrodotoxin (TTX) and capsaicin reduced significantly the maximum values of Isc stimulated by 5-HT, and the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) caused a significant decrease in the maximum response to 5-HT. These results suggest that electrogenic secretion induced by 5-HT in rat ileum in vitro occurs partly by activation of a non-neural pathway probably involving a direct interaction with the enterocyte, and partly via a nitrinergic-myenteric secretory reflex activated by sensory afferent fibres. These data highlight the danger of characterising intestinal secretory activity from in vitro experiments by using muscle-stripped tissue only.
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PMID:Neural and non-neural activation of electrogenic secretion by 5-hydroxytryptamine in the rat ileum in vitro. 959 13

The aim of the study was to evaluate both morphologically and functionally the distal large intestine from the aganglionic lethal spotted (ls/ls) mutant mouse and their healthy litter mates. Immunohistochemically, the aganglionic murine distal large intestine showed an absence of nerve cell bodies, and a reduction or absence of nerve fibers displaying immunoreactivity (IR) for protein gene product (PGP), nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), substance P (SP), galanin and calcitonin gene-related peptide (CGRP), while in the ganglionic large intestine these neuronal populations were abundantly present throughout the gut wall. Pathological nerve trunks within the afflicted intestinal segment were found to harbour PGP- and neuropeptide Y (NPY)-IR nerve fibers. Smooth muscle specimens from the distal part of the murine distal large intestine were mounted as ring preparations in vitro and subjected to electrical field stimulation (EFS). EFS (4-20 Hz) caused a contraction in both ganglionic and aganglionic intestine. After pretreatment with atropine EFS (20 Hz) evoked a biphasic motor response, a relaxation followed by a contraction in control specimens, while no motor response was seen in aganglionic intestine. Addition of the NOS-inhibitor N-nitro-L-arginine methyl ester (L-NAME) caused per se a weak and transient contraction and reduced the amplitude of the EFS-induced relaxation in control intestine.
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PMID:Functional and morphological examination of ganglionic and aganglionic distal gut from the lethal spotted mouse. 978 48


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