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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. (Gastroenterology & Hepatology)ORCID iD: 0000-0001-6220-3936
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. (Gastroenterology & Hepatology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
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2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed) Published
Abstract [en]

Aim

The 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.

Methods

Twenty-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.

Results

l-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.

Conclusion

Nitric 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.

Place, publisher, year, edition, pages
2015. Vol. 215, no 2, 105-118 p.
Keyword [en]
motility, myenteric plexus, NG-monomethyl-l-arginine, nitric oxide, nitric oxide synthase
National Category
Gastroenterology and Hepatology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-259469DOI: DOI:10.1111/apha.12554OAI: oai:DiVA.org:uu-259469DiVA: diva2:844288
Funder
Swedish Research Council, 7916
Note

De 2 första författarna delar förstaförfattarskapet.

The study was supported by Swedish Research Council (7916), Uppsala University (540113) and the Erik, Karin och Gösta Selander Fund (14-03-07)

Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Gut peptides in gastrointestinal motility and mucosal permeability
Open this publication in new window or tab >>Gut peptides in gastrointestinal motility and mucosal permeability
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.

This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.

A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.

NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.

Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. 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. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.

Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.

In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1233
Keyword
Gut regulatory peptides, Neuropeptides, Gastrointestinal mucosal permeability, Gastrointestinal motility, GLP-1, NPS, ROSE-010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294390 (URN)978-91-554-9607-4 (ISBN)
Public defence
2016-06-14, Enghoffsalen, Entrance 50, Uppsala University Hospital, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-24 Created: 2016-05-19 Last updated: 2016-06-15

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Publisher's full texthttp://onlinelibrary.wiley.com/doi/10.1111/apha.12554/epdf

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Halim, Md AbdulSundbom, MagnusKarlbom, UrbanDominic-Luc, WebbM. Hellström, Per

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