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CCK2-receptor antagonist YF476 prevents NSAID-induced gastric ulceration through acid inhibition mediated by regulatory peptides
Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
Clinical Chemistry, Linköping University.
Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK.
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(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:rkh:diva-1435OAI: oai:DiVA.org:rkh-1435DiVA: diva2:787483
Note

As manuscript in doctoral thesis

Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2015-02-10Bibliographically approved
In thesis
1. Gastric acid secretion and gut peptides: mechanisms involved in inflammatory response
Open this publication in new window or tab >>Gastric acid secretion and gut peptides: mechanisms involved in inflammatory response
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The regulation of gastric acid secretion is complex and involves endocrine, paracrine, and neurocrine mechanisms. Among these, the interconnecting cross-talk between different gut peptides is an important part in the control of acid secretion. The aims of this thesis were (1) to develop a new method of measuring intragastric pH for prolonged periods of time, and (2) apply developed and in-use methods using different substances and their impact on gastric acid secretion in vivo experiments on rats. (3) To study the changes in acid output and the migrating motor complex (MMC) when subjected to different substances, and (4) to further study the alterations in expression of different gut peptides in tissue samples in vitro, and the impact of inflammation in the gut. The novel Bravo model developed gave reliable recordings compared to the chronic fistula model. The pH rose during treatment with esomeprazole and the acid output in the fistula model decreased accordingly. Gut peptides ghrelin and somatostatin increased in plasma when subjected to esomeprazole treatment, while gastrin remained unchanged. Ghrelin administered in bolus doses increased the intragastric pH in accordance with previous experiments. The gut peptides somatostatin, neurotensin, and vasoactive intestinal peptide increased during pentagastrin-stimulated infusion and challenge with hydrochloric acid and polyethylene glycol both in plasma and intestinal perfusate, though the most pronounced elevation was seen in perfusate and with somatostatin. Gastrazole gave the most extensive inhibitory effect on acid secretion compared to ranitidine and esomeprazole. The CCK2-receptor antagonist YF476 inhibited acid secretion long-term and increased concentrations of ghrelin and somatostatin in plasma, but gastrin remained low. Tissue mRNA content of the peptides and their receptors were unchanged except for the ghrelin receptor. When subdued to NSAID gastrin, CCK2-receptor and iNOS increased in mRNA expression while other peptides and receptors were unchanged. Administration of NPS evoked a response in the MMC pattern with irregular spiking and prolonged cycle length of the activity fronts, and the mRNA expression of iNOS, TNF, and IL-1ß increased in the tissue. In conclusion, The Bravo model can be used as a complement to the chronic fistula model for measurements of pH. The regulation of gastric acid secretion is not only limited to the stomach, but also present in the smaller intestine where release of somatostatin seems to be most important. Different mechanisms are involved in the blockage of acid secretion when subjected to YF476, but under NSAID treatment the expression of gastrin and its receptor CCK2 increase and COX- 2 is activated which demonstrates a novel pathway for the study of gastric ulcerations. NPS, a novel neuropeptide influences the gastric motility and could have a role in inflammatory responses seen in the changes in the migrating motor complex and inflammatory markers iNOS, TNF, and IL-1ß.

Place, publisher, year, edition, pages
Stockholm: Department of Medicine, Karolinska Institutet, 2010. 97 p.
National Category
Basic Medicine
Identifiers
urn:nbn:se:rkh:diva-1434 (URN)978-91-7457-063-2 (ISBN)
Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2015-02-10Bibliographically approved

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