| Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists. | |
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MedLine Citation:
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PMID: 22537158 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH: Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS: EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1-300 nM and the selective motilin agonist GSK962040 0.1-30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (E(max) ≈ 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS: Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. |
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Authors:
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J Broad; S Mukherjee; M Samadi; J E Martin; G E Dukes; G J Sanger |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 167 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-09-25 Completed Date: 2013-02-12 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 763-74 Citation Subset: IM |
Copyright Information:
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© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
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Neurogastroenterology group, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Electric Stimulation Female Gastrointestinal Motility Humans Intestines / drug effects*, physiology Male Middle Aged Motilin / pharmacology* Piperazines / pharmacology* Piperidines / pharmacology* Receptors, Gastrointestinal Hormone / agonists*, physiology Receptors, Neuropeptide / agonists*, physiology Stomach / drug effects*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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//Biotechnology and Biological Sciences Research Council |
| Chemical | |
Reg. No./Substance:
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0/N-(3-fluorophenyl)-1-((4-(((3S)-3-methyl-1-piperazinyl)methyl)phenyl)acetyl)-4-piperidinamine; 0/Piperazines; 0/Piperidines; 0/Receptors, Gastrointestinal Hormone; 0/Receptors, Neuropeptide; 0/motilin receptor; 52906-92-0/Motilin |
| Comments/Corrections | |
Comment In:
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Br J Pharmacol. 2012 Oct;167(4):760-2
[PMID:
22616752
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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