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  • 1.
    Allen, Adrian
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Flemström, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.2005In: Am. J. Physiol. Cell Physiol., Vol. 288, no Jan, p. C1-C19Article in journal (Refereed)
    Abstract [en]

    Secretion of bicarbonate into the adherent layer of mucus gel creates a pH gradient with a near neutral pH at the epithelial surfaces in stomach and duodenum, providing the first line of mucosal protection against luminal acid. The continuous adherent mucus layer is also a barrier to luminal pepsin thereby protecting the underlying mucosa from proteolytic digestion. Here we review the current state of the gastroduodenal mucus bicarbonate barrier two decades later from when the first supporting experimental evidence appeared. The primary function of the adherent mucus gel layer is a structural one to create a stable unstirred layer to support surface neutralisation of acid and act as a protective physical barrier against luminal pepsin. The emphasis therefore on mucus in this review is on the form and role of the adherent mucus gel layer. The primary function of the mucosal bicarbonate secretion is to neutralise acid diffusing into the mucus gel layer and for there quantitatively to be sufficient secretion to maintain a near neutral pH at the mucus-mucosal surface interface. The emphasis on mucosal bicarbonate in this review is on the mechanisms and control of its secretion and the establishment of a surface pH gradient. Evidence suggests that under normal physiological conditions the mucus bicarbonate barrier is sufficient for protection of the gastric mucosa against acid and pepsin and, even more so, in the duodenum

  • 2.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Duodenal defence mechanisms:: Role of mucosal bicarbonate secretion2002In: InflammoPharmacology, ISSN 0925-4692, E-ISSN 1568-5608, Vol. 10, no 4-6, p. 327-332Article in journal (Refereed)
    Abstract [en]

    The duodenal epithelium secretes bicarbonate at higher rates than does the stomach (or more distal small intestine) and the duodenal secretion is currently accepted as the most important defence mechanism against acid discharged from the stomach. HCO3 - entering the continuous layer of visco-elastic mucus gel on top of the epithelial surface maintains pH in its cell-facing portion at neutrality at acidities encountered in the healthy duodenum. The secretion is decreased in patients with acute and chronic duodenal ulcer disease and is inhibited by non-steroidal anti-inflammatory agents. Studies of the neurohumoral control of the duodenal alkaline secretion and of acid/base transport processes and intracellular signaling in duodenal enterocytes are currently of great research interest.

  • 3.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Fysiologi.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Fysiologi.
    Epithelial Cells and Their Neighbors: II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells2005In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 289, no 3, p. G377-G380Article in journal (Refereed)
    Abstract [en]

    Surface sensory enteroendocrine cells are established mucosal taste cells that monitor luminal contents and provide an important link in transfer of information from gut epithelium to the central nervous system. Recent studies now show that these cells can also mediate efferent signaling from the brain to the gut. Centrally elicited stimulation of vagal and sympathetic pathways induces release of melatonin, which acts at MT(2) receptors to increase mucosal electrolyte secretion. Psychological factors as well mucosal endocrine cell hyperplasia are implicated in functional intestinal disorders. Central nervous influence on the release of transmitters from gut endocrine cells offers an exciting area of future gastrointestinal research with a clinical relevance.

  • 4.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Åkerman, Karl EO
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin2003In: 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)
    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.

  • 5.
    Sjöblom, Markus
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Flemström, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Central nervous alpha1-adrenoceptor stimulation induces duodenal luminal release of melatonin.2004In: J Pineal Res, ISSN 0742-3098, Vol. 36, no 2, p. 103-8Article in journal (Refereed)
  • 6.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion2003In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 34, no 4, p. 288-293Article in journal (Refereed)
    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.

  • 7.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lindqvist, Ramin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bengtsson, Magnus W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Cholecystokinin but not ghrelin stimulates mucosal bicarbonate secretion in rat duodenum: Independence of feeding status and cholinergic stimuli2013In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 183, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Cholecystokinin (CCK) is an important regulator of food digestion but its influence on small intestinal secretion has received little attention. We characterized effects of CCK-8, ghrelin and some related peptides on duodenal HCO3- secretion in vivo and demonstrated CCK-induced calcium signaling in acutely isolated enterocytes. A segment of proximal duodenum with intact blood supply was cannulated in situ in anaesthetized rats. Mucosal HCO3- secretion was continuously recorded (pH-stat). Peptides were administrated to the duodenum by close intra-arterial infusion. Clusters of duodenal enterocytes were attached to the bottom of a perfusion chamber. The intracellular calcium concentration ([Ca2+](i)) was examined by dual-wavelength imaging. CCK-8 (3.0, 15 and 60 pmol/kg,h) caused dose-dependent increases (p < 0.01) in duodenal alkaline secretion in both overnight fasted and continuously fed animals. The CCK1R-antagonist devazepide but neither the CCK2R-antagonist YMM022 nor the melatonin MT2-selective antagonist luzindole inhibited the rise in secretion. Atropine decreased sensitivity to CCK-8. The appetite-related peptide ghrelin was without effect on the duodenal secretion in fasted as well as fed animals. Superfusion with CCK-8 (1.0-50 nM) induced [Ca2+](i) signaling in acutely isolated duodenal enterocytes. After an initial peak response, [Ca2+](i) returned to near basal values within 3-5 min. Devazepide but not YMM022 inhibited this [Ca2+](i) response. Low doses of CCK-8 stimulate duodenal alkaline secretion and induce enterocyte [Ca2+](i) signaling by an action at CCK1 receptors. The results point to importance of CCK in the rapid postprandial rise in mucosa-protective duodenal secretion.

  • 8.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Säfsten, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes2003In: 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)
    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.

1 - 8 of 8
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