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The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl-
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
2014 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 7, e102654- p.Article in journal (Refereed) Published
Abstract [en]

Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a similar to 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of Cr-51-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl- from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl- and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.

Place, publisher, year, edition, pages
2014. Vol. 9, no 7, e102654- p.
National Category
URN: urn:nbn:se:uu:diva-209667DOI: 10.1371/journal.pone.0102654ISI: 000339418300075PubMedID: 25033198OAI: diva2:658964
Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2014-09-08Bibliographically approved
In thesis
1. Regulation of Duodenal Mucosal Barrier Function and Motility: The Impact of Melatonin
Open this publication in new window or tab >>Regulation of Duodenal Mucosal Barrier Function and Motility: The Impact of Melatonin
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The duodenal mucosa is regularly exposed to acid, digestive enzymes and ingested noxious agents. It is thus critical to maintain a protective barrier to prevent the development of mucosal injury and inflammation, which are often observed in situations when barrier function is impaired. The rate of mucosal bicarbonate secretion, the regulation of epithelial paracellular permeability and motility are each key components of duodenal barrier function. The hormone melatonin is present in high levels in the gastrointestinal tract and it has been hypothesized that melatonin exerts protective properties. This thesis aims to investigate the impact of exogenous melatonin on the regulation of duodenal barrier function and motility in anesthetized rats in vivo. In addition, duodenal tissue was examined histologically and the expression levels of tight junction proteins and melatonin receptors were assessed with qRT-PCR.

It was found that melatonin stimulated mucosal bicarbonate secretion and decreased basal paracellular permeability. Exposing the duodenal mucosa to the well-characterized barrier breaker ethanol increased mucosal bicarbonate secretion, paracellular permeability and motility. Omission of luminal Clˉ abolished, while pretreatment with a nicotinic receptor antagonist reduced, the ethanol-induced bicarbonate secretion suggesting that the secretory response to ethanol is meditated via Clˉ/HCO3ˉexchangers and enteric neural pathways.

Melatonin reduced the ethanol-induced increases in paracellular permeability and motility either when injected intravenously or when administered in drinking water for two weeks. The actions of melatonin were abolished by the melatonin receptor antagonist luzindole and by nicotinic acetylcholine receptor inhibition.

Two weeks oral administration of melatonin up-regulated the expression levels of melatonin receptors, down-regulated the expression of ZO-3 while the expression of ZO-1, ZO-2, claudin 2-4, occludin and myosin light chain kinase were unaffected. Superficial epithelial changes in a few villi were seen in response to ethanol exposure, an effect that was histologically unchanged by melatonin pretreatment.

In conclusion, the results suggest that melatonin plays an important role in the neurohumoral regulation of gastrointestinal mucosal barrier function and motility via receptor- and enteric neural-dependent pathways in vivo in rats. Melatonin might be a candidate for treatment of barrier dysfunction in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 74 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 944
51Cr-EDTA, bicarbonate secretion, duodenum, enteric nervous system, enterochromaffin cell, ethanol, hexamethonium, in vivo, mecamylamine, motility, mucosal permeability, parecoxib, rat
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Research subject
urn:nbn:se:uu:diva-209669 (URN)978-91-554-8790-4 (ISBN)
Public defence
2013-12-06, B21, Biomedicinskt centrum, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2013-11-14 Created: 2013-10-23 Last updated: 2014-01-23

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