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Duodenal bicarbonate secretion in rats: Stimulation by intra-arterial and luminal guanylin and uroguanylin
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2007 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 191, no 4, 309-317 p.Article in journal (Refereed) Published
Abstract [en]

Aim: Uroguanylin and guanylin are endogenous ligands for guanylate cyclase C, an upstream regulator of the cystic fibrosis transmembrane resistance (CFTR) anion channel, and both peptides increase intestinal anion export in vitro. We have compared the effects of close intra-arterial and luminal administration of uroguanylin and guanylin on duodenal bicarbonate secretion in vivo and studied the interactions with melatonin and cholinergic stimulation.

Methods: Lewis × Dark Agouti rats were anaesthetized and a segment of the proximal duodenum with intact blood supply was cannulated in situ. Mucosal bicarbonate secretion (pH stat) was continuously recorded and peptides were infused intra-arterially or added to the luminal perfusate.

Results: Intra-arterial (50–1000 pmol kg−1 h−1) as well as luminal administration (50–500 nmol L−1) of guanylin or uroguanylin caused dose-dependent increases in the duodenal secretion. Luminal administration induced more rapidly appearing rises in secretion and the two peptides induced secretory responses of similar shape and magnitude. The melatonin MT2-selective antagonist luzindole (600 nmol kg−1) significantly depressed the response to intra-arterial guanylins but did not affect secretion induced by luminal guanylins. Similarly, the muscarinic antagonist atropine (0.75 μmol kg−1 followed by 0.15 μmol kg−1 h−1) abolished the response to intra-arterial uroguanylin but caused only slight suppression of the response to luminal uroguanylin.

Conclusions: Intra-arterial as well as luminal uroguanylin and guanylin are potent stimuli of duodenal mucosal bicarbonate secretion in vivo. The response to luminal guanylins reflects an action at apical receptors. Stimulation by parenteral guanylins, in contrast, is under cholinergic influence and interacts with melatonin produced by mucosal enteroendocrine cells.

Place, publisher, year, edition, pages
2007. Vol. 191, no 4, 309-317 p.
Keyword [en]
bicarbonate secretion, cholinergic stimulation, duodenum in situ, enteroendocrine cells, guanylyl cyclase C, luzindole, melatonin
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97106DOI: 10.1111/j.1748-1716.2007.01759.xISI: 000250795300006PubMedID: 17995576OAI: oai:DiVA.org:uu-97106DiVA: diva2:171901
Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2011-01-19Bibliographically approved
In thesis
1. Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
Open this publication in new window or tab >>Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells.

The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats in situ and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied in vitro.

Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX1-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX1-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming.

The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally.

In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 70 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 337
Physiology, alkaline secretion, carbohydrates, central nervous system, cholinergic stimulation, duodenum, enteric nervous system, enterochromaffin cell, fasting, feeding, glucose, guanylyl cyclase C, humans, hypocretin, intra-arterial, in situ, intracerebroventricular, luminal acid, luzindole, orexin-B, SB-334867, Fysiologi
urn:nbn:se:uu:diva-8664 (URN)978-91-554-7173-6 (ISBN)
Public defence
2008-05-15, B21, Uppsala Biomedicinska Centrum (BMC), Norra vägen, Uppsala, 13:15
Available from: 2008-04-23 Created: 2008-04-23Bibliographically approved

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