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Prevention of Postoperative Duodenal Ileus by COX-2 Inhibition Improves Duodenal Function in Anaesthetised Rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
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 [en]
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: urn:nbn:se:uu:diva-198049ISBN: 978-91-554-8650-1 (print)OAI: oai:DiVA.org:uu-198049DiVA: diva2:615209
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
List of papers
1. Motility-induced but not vasoactive intestinal peptide-induced increase in luminal alkalinization in rat duodenum is dependent on luminal Cl-
Open this publication in new window or tab >>Motility-induced but not vasoactive intestinal peptide-induced increase in luminal alkalinization in rat duodenum is dependent on luminal Cl-
Show others...
2010 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 200, no 2, 181-191 p.Article in journal (Refereed) Published
Abstract [en]

Aim: To investigate whether the motility- and the vasoactive intestinal peptide (VIP)-induced increase in luminal alkalinization in the duodenum is dependent on luminal Cl-. Methods: Experiments were performed in anaesthetized rats in vivo. The proximal duodenum was perfused luminally with an isotonic solution, containing zero or low Cl- and the effects on luminal alkalinization, motility, fluid flux and epithelial permeability were determined. Parecoxib, a COX-2 inhibitor, was used to induce duodenal contractions. Results: Control rats lacked duodenal wall contractions while parecoxib-treated ones exhibited contractions throughout the experiment. Most animals had a net fluid absorption during the perfusion with isotonic NaCl. Luminal alkalinization was about 100% higher in parecoxib-treated rats than in controls. Cl--free solutions did not affect epithelial permeability or motility but decreased luminal alkalinization by >= 50% and decreased net fluid absorption in both control and parecoxib-treated animals. Reduction in luminal Cl- decreased alkalinization in a concentration-dependent manner. The parecoxib-induced increase in alkalinization was markedly reduced in the absence of luminal Cl-. VIP increased luminal alkalinization and induced fluid secretion. The lack of luminal Cl- did not affect the VIP-induced increase in alkalinization but reduced fluid secretion. Conclusions: The parecoxib-induced increase in luminal alkalinization is highly dependent on luminal Cl- and it is proposed that COX-2 inhibition, via induction of duodenal motility, enhances HCO3- efflux through stimulation of apical Cl-/HCO3- exchange in duodenal epithelial cells. Although the VIP-induced stimulation of fluid secretion is partly dependent on luminal Cl-, the VIP-induced increase in luminal alkalinization is not.

Keyword
bicarbonate transport, fluid secretion, jejunum, motility, mucosal permeability, parecoxib
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-134905 (URN)10.1111/j.1748-1716.2010.02112.x (DOI)000281557700007 ()
Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2017-12-12Bibliographically approved
2. The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats
Open this publication in new window or tab >>The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats
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.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-168964 (URN)10.1111/j.1748-1716.2012.02411.x (DOI)000305823700013 ()22251854 (PubMedID)
Available from: 2012-02-20 Created: 2012-02-20 Last updated: 2017-12-07Bibliographically approved
3. Prevention of duodenal ileus reveals functional differences in the duodenal response to luminal hypertonicity in Sprague-Dawley and Dark Agouti rats
Open this publication in new window or tab >>Prevention of duodenal ileus reveals functional differences in the duodenal response to luminal hypertonicity in Sprague-Dawley and Dark Agouti rats
2014 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 3, 573-589 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The mechanism by which the duodenum adjusts the luminal osmolality remains unclear. The aim was to compare the duodenal osmoregulation in response to different hyperosmolar solutions in Sprague-Dawley and Dark Agouti rats and to elucidate whether cyclooxygenase-2 inhibition affects these responses.

Methods: The duodenum was perfused in situ with a 700-milliosmolar solution (NaCl alone, D-glucoseNaCl, D-mannitolNaCl or orange juice), and the effects on the duodenal motility, mucosal permeability, luminal alkalinization, fluid flux and osmoregulation were assessed in anaesthetized rats.

Results: The change in net fluid flux and luminal osmolality, in response to a given hyperosmolar solution, was almost identical in control rats of both strains. In control rats, hypertonic D-glucose-NaCl induced fluid secretion only in the presence of phlorizin, an inhibitor of SGLT1. Cyclooxygenase-2 inhibition potentiated the hypertonicity-induced fluid secretion and increased the osmolality-adjusting capability in both strains, but the responses were greater in Dark Agouti rats. While cyclooxygenase-2-inhibited Dark Agouti rats responded to the hyperosmolar solutions with depression of motility and increased mucosal permeability, these effects were absent or smaller in the Sprague-Dawley strain. In contrast, orange juice induced the same duodenal responses in cyclooxygenase-2-inhibited Dark Agouti and Sprague-Dawley rats.

Conclusion: The duodenum possesses the ability to absorb fluid despite a very high luminal osmolality. Inhibition of cyclooxygenase-2 markedly enhanced the capability of the duodenum to secrete fluid and to decrease luminal osmolality, irrespective of the hyperosmolar solution or the rat strain used, and revealed notable differences between the two strains with regard to their osmolality-adjusting capability.

Keyword
Absorption, secretion, bicarbonate, mucosal permeability, motility, COX-2, postoperative ileus
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-198039 (URN)10.1111/apha.12201 (DOI)000330676200015 ()
Available from: 2013-04-08 Created: 2013-04-08 Last updated: 2017-12-06Bibliographically approved

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