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Luminal hypotonicity increases duodenal mucosal permeability by a mechanism involving 5-hydroxytryptamine
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.
2006 (English)In: Acta Physiologica, ISSN 1748-1708, Vol. 186, no 1, 45-58 p.Article in journal (Refereed) Published
Abstract [en]

Aim: To investigate whether 5-HT participates in the mediation of the hypotonicity-induced increase in duodenal mucosal permeability.

Methods: Proximal duodenum in anesthetized rats was perfused in situ with a hypotonic NaCl solution and effects on duodenal motility, net fluid flux, mucosal permeability (blood-to-lumen clearance of 51Cr-EDTA) and the release of 5-HT into the luminal solution studied in the presence of the cyclooxygenase inhibitor indomethacin.

Results: Perfusion of the duodenum with 50 mM NaCl increased mucosal permeability eightfold, increased the luminal output of 5-HT twofold and induced net fluid absorption. This rise in permeability was enhanced 25% by 5-HT (3 · 10-3 M), reduced by the 5-HT3-receptor antagonists granisetron (10-4 - 3 · 10-4 M) or ondansetron (10-5 - 10-4 M) or by the 5-HT4 receptor antagonist SB 203186 (10-4 M). The 5-HT3/4 receptor antagonist tropisetron, at 10-4 M, did not affect while 3 · 10-4 and 3 · 10-3 M augmented the hypotonicity-induced increase in mucosal permeability. Lidocaine (1.1 · 10-3 M) similarly potentiated while tetrodotoxin (5 · 10-5 M) inhibited the hypotonicity-induced increase in mucosal permeability. Compared to animals treated with indomethacin alone ondansetron and granisetron augmented (by 30-40%) while tropisetron and lidocaine reduced (by 60-70%) the hypotonicity-induced net fluid absorption. TTX and all 5-HT receptor antagonists, except tropisetron, depressed duodenal motility.

Conclusions: Luminal hypotonicity increases duodenal mucosal permeability by a neural mechanism involving 5-HT acting on 5-HT3 and 5-HT4 receptors. 5-HT also appears to participate in the regulation of the hypotonicity-induced fluid flux.

Place, publisher, year, edition, pages
2006. Vol. 186, no 1, 45-58 p.
Keyword [en]
Anesthetics; Local/pharmacology, Animals, Cyclooxygenase Inhibitors/pharmacology, Duodenum/drug effects/*physiology, Granisetron/pharmacology, Indoles/pharmacology, Indomethacin/pharmacology, Intestinal Mucosa/drug effects/*physiology, Lidocaine/pharmacology, Male, Ondansetron/pharmacology, Osmotic Pressure, Piperidines/pharmacology, Rats, Rats; Inbred Strains, Receptors; Serotonin; 5-HT3/antagonists & inhibitors, Receptors; Serotonin; 5-HT4/antagonists & inhibitors, Serotonin/*metabolism, Serotonin Agents/metabolism, Serotonin Antagonists/pharmacology, Tetrodotoxin/pharmacology
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-95372DOI: 10.1111/j.1748-1716.2005.01507.xPubMedID: 16497179OAI: oai:DiVA.org:uu-95372DiVA: diva2:169555
Available from: 2007-01-12 Created: 2007-01-12 Last updated: 2009-10-15Bibliographically approved
In thesis
1. Luminal Hypotonicity and Duodenal Functions: An Experimental Study in the Rat
Open this publication in new window or tab >>Luminal Hypotonicity and Duodenal Functions: An Experimental Study in the Rat
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

After drinking water, the fluid quickly leaves the stomach thereby creating a hypotonic luminal environment in the duodenum. This in turn constitutes a potential threat to the integrity of the duodenal epithelium. It therefore seems highly likely that luminal hypotonicity activates physiological mechanisms that aim to increase luminal osmolality. One such physiological mechanism may be to increase mucosal permeability thereby facilitating the transport of osmolytes into the lumen.

A draw-back of performing experiments in anesthetized animals is that surgery per se depresses gut functions, such as peristalsis, by mechanisms involving endogenous prostaglandins. In this thesis it is shown that inhibition of cyclooxygenase-2 (COX-2), in animals subjected to an abdominal operation, restore and/or improve duodenal functions such as motility, mucosal bicarbonate secretion, hypotonicity-induced increase in mucosal permeability and the osmolality-adjusting capability.

Experiments revealed that the stomach is resistant to hypotonic challenge while the jejunum is more sensitive to hypotonicity-induced increase in mucosal permeability than the duodenum. The hypotonicity-induced increase in duodenal mucosal permeability is not due to injury but possibly reflects physiological dilatation of paracellular shunts.

Luminal perfusion of the duodenum with an isotonic solution lacking Cl- decreased bicarbonate secretion while the lack of luminal Na+ increased mucosal permeability. Stimulation of bicarbonate secretion by COX-2 inhibition is to a large extent dependent on luminal Cl- while that induced by vasoactive intestinal peptide is not.

The hypotonicity-induced increase in mucosal permeability involves the release and action of serotonin (5-HT) on 5-HT3 and 5-HT4 receptors and stimulation of enteric nerves strongly implicating physiological regulation of this process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 217
Keyword
Physiology, luminal alkalinization, mucosal permeability, osmolality, cyclooxygenase-2, rat, duodenum, jejunum, motility, enteric nervous system, Fysiologi
Identifiers
urn:nbn:se:uu:diva-7444 (URN)978-91-554-6778-4 (ISBN)
Public defence
2007-02-02, B21, BMC, Norra vägen, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-01-12 Created: 2007-01-12Bibliographically approved

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