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The Duodenal Mucosal Bicarbonate Secretion: Role of Melatonin in Neurohumoral Control and Cellular Signaling
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Physiology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The duodenal lumen is exposed to aggressive factors with a high potential to cause damage to the mucosa. Bicarbonate secretion by the duodenal mucosa is accepted as the primary important defense mechanism against the hydrochloric acid intermittently expelled from the stomach.

The present thesis concerns the influence of the central nervous system and the effects of the hormone melatonin on bicarbonate secretion in anesthetized rats in vivo. Effects of melatonin on intracellular calcium signaling by duodenal enterocyte in vitro were examined in tissues of both human and rat origin. The main findings were as follows:

Melatonin is a potent stimulant of duodenal mucosal bicarbonate secretion and also seems to be involved in the acid-induced stimulation of the secretion. Stimulation elicited in the central nervous system by the α1-adrenoceptor agonist phenylephrine induced release of melatonin from the intestinal mucosa and a four-fold increase in alkaline secretion. The melatonin antagonist luzindole abolished the duodenal secretory response to administered melatonin and to central nervous phenylephrine but did not influence the release of intestinal melatonin. Central nervous stimulation was also abolished by synchronous ligation of the vagal trunks and the sympathetic chains at the sub-laryngeal level.

Melatonin induced release of calcium from intracellular stores and also influx of extracellular calcium in isolated duodenal enterocytes. Enterocytes in clusters functioned as a syncytium.

Overnight fasting rapidly and profoundly down-regulated the responses to the duodenal secretagogues orexin-A and bethanechol but not those to melatonin or vasoactive intestinal polypeptide.

In conclusion, the results strongly suggest that intestinal melatonin plays an important role in central nervous elicited stimulation of duodenal mucosal bicarbonate secretion. Sensitivity of this alkaline secretion to some peripheral stimulators markedly depends on the feeding status.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 71
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1277
Keyword [en]
Physiology, alkaline secretion, central nervous system, duodenal enterocyte, duodenal ulcer, duodenum, enterochromaffin cell, human, intraarterial, intracellular calcium, intracerebroventricular, melatonin, rat, vagal nerve
Keyword [sv]
Fysiologi
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-3521ISBN: 91-554-5688-X (print)OAI: oai:DiVA.org:uu-3521DiVA, id: diva2:163101
Public defence
2003-10-03, B42, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Peripheral melatonin mediates neural stimulation of duodenal mucosal bicarbonate secretion
Open this publication in new window or tab >>Peripheral melatonin mediates neural stimulation of duodenal mucosal bicarbonate secretion
2001 In: Journal of Clinical Investigation, ISSN 0021-9738, Vol. 108, no 4, p. 625-633Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90655 (URN)
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2014-04-07Bibliographically approved
2. Central nervous α1-adrenoceptor stimulation induces duodenal luminal release of melatonin
Open this publication in new window or tab >>Central nervous α1-adrenoceptor stimulation induces duodenal luminal release of melatonin
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90656 (URN)
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2010-01-13Bibliographically approved
3. Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion
Open this publication in new window or tab >>Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion
2003 (English)In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 34, no 4, p. 288-293Article in journal (Refereed) Published
Abstract [en]

Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin(R)) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ . Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 mu m increased (P < 0.05) the secretion from 7.20 +/- 1.35 to 13.20 +/- 1.51 mu Eq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 +/- 0.82 to 12.35 +/- 1.51 mu Eq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-90657 (URN)000181835000009 ()
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2018-01-13Bibliographically approved
4. Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes
Open this publication in new window or tab >>Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes
2003 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 284, no 6, p. G1034-G1044Article in journal (Refereed) Published
Abstract [en]

The amount of melatonin present in enterochromaffin cells in the alimentary tract is much higher than that in the central nervous system, and melatonin acting at MT2 receptors mediates neural stimulation of mucosal HCO3- secretion in duodenum in vivo. We have examined effects of melatonin and receptor ligands on intracellular free calcium concentration ([Ca2+](i)) signaling in human and rat duodenal enterocytes. Clusters of interconnecting enterocytes (10-50 cells) were isolated by mild digestion ( collagenase/dispase) of human duodenal biopsies or rat duodenal mucosa loaded with fura-2 AM and attached to the bottom of a temperature-controlled perfusion chamber. Clusters provided viable preparations and respond to stimuli as a syncytium. Melatonin and melatonin receptor agonists2-iodo-N-butanoyl-5-methoxytryptamine and 2-iodomelatonin (1.0-100 nM) increased enterocyte [Ca2+](i), EC50 of melatonin being 17.0 +/- 2.6 nM. The MT2 receptor antagonists luzindole and N-pentanoyl-2-benzyltryptamine abolished the [Ca2+](i) responses. The muscarinic antagonist atropine ( 1.0 muM) was without effect on basal [Ca2+](i) and did not affect the response to melatonin. In the main type of response, [Ca2+](i) spiked rapidly and returned to basal values within 4-6 min. In another type, the initial rise in [Ca2+](i) was followed by rhythmic oscillations of high amplitude. Melatonin-induced enterocyte [Ca2+](i) signaling as well as mucosal cell-to-cell communication may be involved in stimulation of duodenal mucosal HCO3- secretion.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-90658 (URN)10.1152/ajpgi.00500.2002 (DOI)000182699700021 ()
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2018-01-13Bibliographically approved
5. Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin
Open this publication in new window or tab >>Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin
2003 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 285, no 6, p. G1091-G1096Article in journal (Refereed) Published
Abstract [en]

Orexins are involved in the central nervous control of appetite and behavior, and in addition, they are present in endocrine cells and/or neurons in the intestine. The role of these peptides in peripheral regulation of intestinal secretion has not been investigated. We thus compared the effects of orexin A and some established secretagogues on duodenal HCO3- secretion in fed rats with effects in rats exposed to short (overnight) food deprivation. Rats were anesthetized with thiobarbiturate, a 12-mm segment of proximal duodenum with intact blood supply was cannulated in situ, and the alkaline secretion was titrated by pH stat. Secretagogues were supplied specifically to the duodenum by close intra-arterial infusion. Orexin A (60-600 pmol·kg-1·h-1) caused marked and dose-dependent stimulation of the duodenal secretion in fed animals but did not affect secretion in overnight food-deprived animals. Similarly, short fasting caused a 100-fold increase in the amount of the muscarinic agonist bethanechol (from 50 to 5,000 nmol·kg-1·h-1) required for stimulation of the secretion. In contrast, the secretory responses to VIP (50-1,000 pmol·kg-1·h-1) and melatonin (20-200 nmol·kg-1·h-1) were not affected. The appetite-regulating peptide orexin A is thus a stimulant of intestinal secretion, but the response to this peptide as well as the muscarinic agonist bethanechol is markedly dependent on previous intake of food. Overnight fasting is a standard experimental procedure in studies of gastrointestinal function and pathophysiology in humans and animals. Studies made on neuroendocrine control of intestinal secretion may require reevaluation with respect to feeding status.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-90659 (URN)10.1152/ajpgi.00193.2003 (DOI)
Available from: 2003-09-09 Created: 2003-09-09 Last updated: 2018-01-13Bibliographically approved

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