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The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats
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.
2012 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 205, no 3, 433-451 p.Article in journal (Refereed) Published
Abstract [en]

AIM:

To examine whether the prevention of post-operative duodenal ileus by treatment with parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, affects the ability of the duodenum to respond to luminal hypertonicity.

METHODS:

The proximal duodenums of anaesthetized rats were perfused with hypertonic NaCl solutions with osmolalities of 400, 500, 600 or 700 mOsm kg−1, and the effects on mucosal permeability, motility, transepithelial net fluid flux and effluent osmolality were assessed in the absence (control) and presence of parecoxib.

RESULTS:

Parecoxib-treated, but not control animals, exhibited duodenal contractions, which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg−1. All animals responded to luminal hypertonicity with induction of net fluid secretion, which peaked at an osmolality of 500 mOsm kg−1. The hypertonicity-induced increases in fluid secretion were twofold greater in parecoxib-treated than in control rats and attenuated by nicotinic receptor blockade. The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib-treated animals but the osmolality-adjusting capability was markedly better in the latter group. Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats. Perfusion with 700 mOsm kg−1 increased mucosal permeability in parecoxib-treated animals only, an effect abolished by nicotinic receptor blockade.

CONCLUSION:

Parecoxib markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of COX-2 and stimulation of nicotinic acetylcholine receptors.

Place, publisher, year, edition, pages
2012. Vol. 205, no 3, 433-451 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-168964DOI: 10.1111/j.1748-1716.2012.02411.xISI: 000305823700013PubMedID: 22251854OAI: oai:DiVA.org:uu-168964DiVA: diva2:504410
Available from: 2012-02-20 Created: 2012-02-20 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Prevention of Postoperative Duodenal Ileus by COX-2 Inhibition Improves Duodenal Function in Anaesthetised Rats
Open this publication in new window or tab >>Prevention of Postoperative Duodenal Ileus by COX-2 Inhibition Improves Duodenal Function in Anaesthetised Rats
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abdominal surgery inhibits gastrointestinal motility, a phenomenon referred to as postoperative ileus. Since the postoperative ileus disturbs duodenal physiology it is important to minimize the side effects of this condition. Recent experiments in our laboratory show that treatment of anaesthetised rats with parecoxib, a selective cyclooxygenase-2 inhibitor, prevents duodenal postoperative ileus, increases duodenal mucosal bicarbonate secretion and improves other functions as well. One aim of the thesis was to investigate whether removal of luminal chloride affect the parecoxib- and the vasoactive intestinal peptide (VIP)-induced stimulation of duodenal mucosal bicarbonate secretion. The proximal duodenum of anaesthetised Dark Agouti rats was perfused with isotonic solutions containing zero or low Cl- and the effect on luminal alkalinisation determined. The basal as well as the parecoxib-induced increase in alkalinisation, but not that stimulated by VIP, were markedly reduced in the absence of luminal Cl-.

One important function of the duodenum is to adjust luminal osmolality towards that in the blood. It is believed that the adjustment of osmolality in the duodenum is achieved by osmosis and diffusion of electrolytes along their concentration gradients and that these processes occur predominately paracellularly. Another aim of the thesis was to examine whether prevention of postoperative ileus affects the duodenal response to luminal hypertonicity. The proximal duodenum of anaesthetised Dark Agouti and Sprague-Dawley rats were perfused with hypertonic solutions of different composition and osmolality and the effects on duodenal motility, alkaline secretion, transepithelial fluid flux, mucosal permeability and the adjustment of luminal osmolality were determined in absence and presence of parecoxib.

It is concluded that COX-2 inhibition increases duodenal mucosal bicarbonate secretion by stimulating apical Cl-/HCO3- exchange in duodenocytes. Furthermore, pretreatment of anaesthetised rats with parecoxib improves a number of duodenal functions in both rat strains that contribute to improve the ability to adjust luminal osmolality. The choice of rat strain is another important feature to consider when interpreting the results because the DA strain was more responsive to luminal hypertonicity than the SD strain. Finally, several evidences are provided to suggest that the adjustment of luminal osmolality in the rat duodenum is a regulated process. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 895
Keyword
duodenum, motility, enteric nervous system, luminal alkalinisation, CFTR, VIP, luminal Cl-, fluid secretion, solute absorption, mucosal permeability, 51Cr-EDTA, luminal osmolality, luminal hypertonicity, glucose, mannitol, orange juice, parecoxib, hexamethonium, mecamylamine
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-198049 (URN)978-91-554-8650-1 (ISBN)
Public defence
2013-05-24, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-02 Created: 2013-04-08 Last updated: 2017-06-19

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Sedin, JohnSjöblom, Markus

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