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Food-induced expression of orexin receptors in rat duodenal mucosa regulates the bicarbonate secretory response to orexin-A
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
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2007 (Engelska)Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 293, nr 2, s. G501-G509Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Presence of appetite-regulating peptides orexin-A and orexin-B in mucosal endocrine cells suggests a role in physiological control of the intestine. Our aim was to characterize orexin-induced stimulation of duodenal bicarbonate secretion and modulation of secretory responses and mucosal orexin receptors by overnight food deprivation. Lewis x Dark Agouti rats were anesthetized and proximal duodenum cannulated in situ. Mucosal bicarbonate secretion (pH stat) and mean arterial blood pressure were continuously recorded. Orexin-A was administered intra-arterially close to the duodenum, intraluminally, or into the brain ventricles. Total RNA was extracted from mucosal specimens, reverse transcribed to cDNA and expression of orexin receptors 1 and 2 (OX1 and OX2) measured by quantitative real-time PCR. OX1 protein was measured by Western blot. Intra-arterial orexin-A (60–600 nmol·h–1·kg–1) increased (P < 0.01) the duodenal secretion in fed but not in fasted animals. The OX1 receptor antagonist SB-334867, which was also found to have a partial agonist action, abolished the orexin-induced secretory response but did not affect secretion induced by the muscarinic agonist bethanechol. Atropine, in contrast, inhibited bethanechol but not orexin-induced secretion. Orexin-A infused into the brain ventricles (2–20 nmol·kg–1·h–1) or added to luminal perfusate (1.0–100 nM) did not affect secretion, indicating that orexin-A acts peripherally and at basolateral receptors. Overnight fasting decreased mucosal OX1 and OX2 mRNA expression (P < 0.01) as well as OX1 protein expression (P < 0.05). We conclude that stimulation of secretion by orexin-A may involve both receptor types and is independent of cholinergic pathways. Intestinal OX receptors and secretory responses are markedly related to food intake.

Ort, förlag, år, upplaga, sidor
2007. Vol. 293, nr 2, s. G501-G509
Nyckelord [en]
bicarbonate secretion, enteroendocrine cells, fed and fasting state, perfused duodenum in situ, TRH
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-97103DOI: 10.1152/ajpgi.00514.2006ISI: 000248487800012OAI: oai:DiVA.org:uu-97103DiVA, id: diva2:171898
Tillgänglig från: 2008-04-23 Skapad: 2008-04-23 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
Öppna denna publikation i ny flik eller fönster >>Effects of Orexins, Guanylins and Feeding on Duodenal Bicarbonate Secretion and Enterocyte Intracellular Signaling
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2008. s. 70
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 337
Nyckelord
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
Identifikatorer
urn:nbn:se:uu:diva-8664 (URN)978-91-554-7173-6 (ISBN)
Disputation
2008-05-15, B21, Uppsala Biomedicinska Centrum (BMC), Norra vägen, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2008-04-23 Skapad: 2008-04-23Bibliografiskt granskad

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