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- Halim, Abdul, 1983-, et al.
(författare)
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Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans
- 2018
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:2, s. 575-585
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Tidskriftsartikel (refereegranskat)abstract
- Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.Design: Single-blind parallel study.Setting: University research laboratory.Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.
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| 2. |
- Halim, Md Abdul, 1983-, et al.
(författare)
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Nitric oxide regulation of migrating motor complex : randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
- 2015
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 215:2, s. 105-118
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Tidskriftsartikel (refereegranskat)abstract
- AimThe migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.MethodsTwenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.Resultsl-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.ConclusionNitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.
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| 3. |
- Wan Saudi, Wan Salman, et al.
(författare)
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Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
- 2015
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 309:8, s. G625-G634
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.
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