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  • 1.
    Bengtsson, Magnus W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Uotila, Sanna
    Åkerman, Karl E. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Herzig, Karl-Heinz
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Food-induced expression of orexin receptors in rat duodenal mucosa regulates the bicarbonate secretory response to orexin-A2007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 293, no 2, p. G501-G509Article in journal (Refereed)
    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.

  • 2.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, P
    Tannergren, C
    Lundqvist, A
    Langguth, P
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 547, no 1-2, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

  • 3.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed)
    Abstract [en]

    The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

  • 4.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A.
    Tannergren, C.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Time-dependent effects on small intestinal transport by absorption-modifying excipients2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 19-28Article in journal (Refereed)
    Abstract [en]

    The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

  • 5.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, Anders
    AstraZeneca R&D.
    Tannergren, Christer
    AstraZeneca R&D.
    Langguth, Peter
    School of Pharmacy, Johannes Gutenberg-University, 55122 Mainz, Germany.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4243-4251Article in journal (Refereed)
    Abstract [en]

    There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

  • 6.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peters, Karsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A.
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C.
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 31-37Article in journal (Refereed)
    Abstract [en]

    The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

  • 7.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 411-420Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

  • 8.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari
    University of Oulu, Oulu, Finland.
    Purhonen, Anna-Kaisa
    University of Oulu, Oulu, Finland.
    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.
    Walkowiak, Jan
    University of Medical Sciences, Poznan, Poland.
    Herzig, Karl-Heinz
    University of Oulu, Oulu, Finland.
    Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Aim: Apelin peptides is the endogenous ligand of the G protein-coupled receptor APJ. Proposed actions include involvement in control of cardiovascular functions, appetite and body metabolism. We have investigated effects of apelin peptides on duodenal bicarbonate secretion in vivo and the release of cholecystokinin (CCK) from acutely isolated mucosal cells and the neuroendocrine cell line STC-1. Methods: Lewis x Dark Agouti rats had free access to water and, unless fasted overnight, free access  to food. A segment of proximal duodenum was cannulated in situ in anesthetized animals. Mucosal bicarbonate secretion was titrated (pH stat) and apelin was administered to the duodenum by close intra-arterial infusion. Total RNA was extracted from mucosal specimens, reverse transcripted to cDNA and expression of the APJ receptor measured by quantitative real-time PCR. Apelin-induced release of CCK was measured using (i) cells prepared from proximal small intestine, and (ii) STC-1 cells. Results: Even the lowest dose of apelin-13 (6 pmol kg-1 h-1) caused a significant rise in bicarbonate secretion. Stimulation occurred only in continuously fed animals and even a 100-fold greater dose (600 pmol kg-1 h-1) of apelin was without effect in overnight food deprived animals. Fasting also induced a 8-fold decrease  in the expression of APJ receptor mRNA. Apelin induced significant release of CCK from both mucosal and STC-1 cells, and the CCKA receptor antagonist devazepide abolished bicarbonate secretory responses to apelin. Conclusions: Apelin-induced stimulation of duodenal electrolyte secretion is feeding dependent and mediated by local mucosal release of CCK

     

  • 9.
    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.

  • 10.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Duodenal Protection: Influence of melatonin and other intestinal transmitters on duodenal bicarbonate secretion and enterocyte signaling. In: Mechanisms and Consequences of Proton Transport. Eds T. Urushidani et al.In: Mechanisms and Consequences of Proton Transport. Eds T. Urushidani et al.2002Chapter in book (Other academic)
  • 11.
    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.

  • 12.
    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.

  • 13. Leppilampi, Mari
    et al.
    Parkkila, Seppo
    Karttunen, Tuomo
    Gut, Marta Ortova
    Gros, Gerolf
    Sjöblom, Markus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Carbonic anhydrase isozyme-II-deficient mice lack the duodenal bicarbonate secretory response to prostaglandin E2.2005In: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 102, no 42, p. 15247-52Article in journal (Refereed)
  • 14.
    Nylander, Olof
    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.
    Modulation of mucosal permeability by vasoactive intestinal peptide or lidocaine affects the adjustment of luminal hypotonicity in rat duodenum2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 4, p. 325-335Article in journal (Refereed)
    Abstract [en]

    Aims: To examine whether modulation of paracellular solute permeability affects the capability of the duodenum to adjust luminal osmolality.

    Methods: Proximal duodenum was perfused with a hypotonic NaCl solution and effects on paracellular permeability to 51Cr-EDTA, motility, anion secretion, net fluid flux and perfusate osmolality determined in anaesthetized rats in the absence and presence of the COX-2 inhibitor parecoxib. Vasoactive intestinal peptide (VIP) was used to reduce and lidocaine to augment the hypotonicity-induced increase in paracellular permeability.

    Results: Luminal hypotonicity slightly increased paracellular permeability in control animals. Parecoxib induced motility, increased electrolyte and fluid secretion, potentiated the hypotonicity-induced rise in paracellular permeability and enhanced the capability to adjust luminal osmolality. VIP, given to control animals stimulated electrolyte and fluid secretion and augmented the capability to adjust luminal osmolality. Administration of VIP to parecoxib-treated animals increased secretion further, markedly reduced the hypotonicity-induced increase in permeability but did not change the osmolality-adjusting capability. Luminal lidocaine potentiated the hypotonicity-induced increase in permeability, reduced the hypotonicity-induced net fluid absorption and the osmolality-adjusting capability was 50% greater than in controls. Lidocaine, given to parecoxib-treated animals potentiated the hypotonicity-induced increase in permeability, reduced the hypotonicity-induced net fluid absorption but did not change the osmolality-adjusting capability.

    Conclusions: Vasoactive intestinal peptide reduces the osmolality-adjusting capacity of the duodenum by inhibiting paracellular solute permeability but improves this capacity by stimulating active electrolyte and fluid secretion. In contrast, lidocaine improves the osmolality-adjusting capability by augmenting paracellular solute transport but depresses it by reducing the hypotonicity-induced net fluid absorption.

  • 15.
    Pihl, Liselotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjöblom, Markus
    Nylander, Olof
    Some duodenal functions and their dependence on luminal NaClManuscript (Other academic)
  • 16.
    Pihl, Liselotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Seidler, U.
    Sedin, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Motility-induced but not vasoactive intestinal peptide-induced increase in luminal alkalinization in rat duodenum is dependent on luminal Cl-2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 200, no 2, p. 181-191Article in journal (Refereed)
    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.

  • 17.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed)
    Abstract [en]

    Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

  • 18.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 222-230, article id S0939-6411(18)30760-4Article in journal (Refereed)
    Abstract [en]

    The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

  • 19.
    Saudi, Wan Salman Wan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, A. L.
    Feldreich, T. Rudholm
    Sundbom, M.
    Karlbom, U.
    Naslund, E.
    Sommansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neuropeptide S reduce small intestinal motility in rats and humans2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 94-94, article id P61Article in journal (Other academic)
  • 20.
    Saudi, Wan Salman Wan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neuropeptide S Reduces Gut Motility in Rats and Humans2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no S1Article in journal (Other academic)
  • 21.
    Sedin, John
    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.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Clonidine abolishes the hypotonicity-induced increase in duodenal mucosal permeability by an alpha 2-adrenoceptor-mediated mechanism in rats2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no S701, p. 4-4, article id 8Article in journal (Other academic)
  • 22.
    Sedin, John
    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.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Prevention of duodenal ileus reveals functional differences in the duodenal response to luminal hypertonicity in Sprague-Dawley and Dark Agouti rats2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 3, p. 573-589Article in journal (Refereed)
    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.

  • 23.
    Sedin, John
    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.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats2012In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 205, no 3, p. 433-451Article in journal (Refereed)
    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.

  • 24.
    Seidler, Ursula
    et al.
    Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Birnir: Molecular Physiology and Neuroscience.
    Herzig, Karl-Heinz
    Univ Oulu, Res Unit Biomed, MRC, Univ Hosp, Oulu, Finland;Univ Oulu, Bioctr Oulu, MRC, Univ Hosp, Oulu, Finland;Poznan Univ Med Sci, Dept Gastroenterol & Metab, Poznan, Poland.
    Gunnar Flemström's legacy in intestinal bicarbonate secretion: A homage to Gunnar Flemström and his work in intestinal bicarbonate secretion2019In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 227, no 4, article id e13321Article in journal (Other academic)
  • 25. Seidler, Ursula
    et al.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Gastroduodenal Bicarbonate Secretion2012In: Physiology of the Gastrointestinal Tract / [ed] Leonard R. Johnson, London: Academic , 2012, 5, p. 1311-1340Chapter in book (Refereed)
  • 26. Singh, A K
    et al.
    Sjöblom, Markus
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    Zheng, W
    Krabbenhöft, A
    Riederer, B
    Rausch, B
    Manns, M P
    Soleimani, M
    Seidler, U
    CFTR and its key role in in vivo resting and luminal acid-induced duodenal HCO3-secretion2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 193, no 4, p. 357-365Article in journal (Refereed)
    Abstract [en]

    Background and aims:  We investigated the role of the recently discovered, villous-expressed anion exchanger Slc26a6 (PAT1) and the predominantly crypt-expressed cystic fibrosis transmembrane regulator (CFTR) in basal and acid-stimulated murine duodenal HCO3 secretion in vivo, and the influence of blood HCO3 concentration on both.

    Methods:  The proximal duodenum of anaesthetized mice was perfused in situ, and HCO3 secretion was determined by back-titration. Duodenal mucosal permeability was assessed by determining 51Cr-EDTA leakage from blood to lumen.

    Results:  Compared with wild type (WT) littermates basal duodenal HCO3 secretory rates were slightly reduced in Slc26-deficient mice at low (∼21 mm), and markedly reduced at high blood HCO3 concentration (∼29 mm). In contrast, basal HCO3 secretion was markedly reduced in CFTR-deficient mice compared with WT littermates both at high and low blood HCO3 concentration. A short-term application of luminal acid increased duodenal HCO3 secretory rate in Slc26a6-deficient and WT mice to the same degree, but had no stimulatory effect in the absence of CFTR. Luminal acidification to pH 2.5 did not alter duodenal permeability.

    Conclusions:  The involvement of Slc26a6 in basal HCO3 secretion in murine duodenum in vivo is critically dependent on the systemic acid/base status, and this transporter is not involved in acid-stimulated HCO3 secretion. The presence of CFTR is essential for basal and acid-induced HCO3 secretion irrespective of acid/base status. This suggests a coupled action of Slc26a6 with CFTR for murine basal duodenal HCO3 secretion, but not acid-stimulated secretion, in vivo.

  • 27.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Duodenal epithelial sensing of luminal acid: role of carbonic anhydrases2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, p. 85-95Article, review/survey (Refereed)
    Abstract [en]

    Sensing the luminal contents is a prerequisite to activate appropriate gastrointestinal functions. A major task of the duodenal epithelium is to resist the repeated challenges of hydrochloric acid expelled from the stomach. Although extensive research in this field, the complete mechanisms providing this defence remain to be revealed. The duodenal epithelium exports bicarbonate into a submillimetre-thick mucus gel on top of the mucosal surface. Despite the very low pH of the luminal contents, the duodenal mucus–bicarbonate barrier provides a means of maintaining a virtually neutral pH at the epithelial surface. Instead of pH, CO2 generated by the mixing of acid and bicarbonate at levels not found elsewhere in the body serves as the mediator for sensing the luminal acid. Carbonic anhydrases (CAs) catalyse the reversible hydration of CO2 and are heavily expressed in the duodenal segment. Accumulating data support the key function of CAs in sensing luminal acid and CO2. Recent advances demonstrate that the presence of CA II in upper villus plays a crucial role in enterocyte intracellular acidification preceding the secretory increase in response to luminal acid. However, CAs only have a minor role in the bicarbonate supply destined for duodenal bicarbonate secretion into the lumen. The purpose of this review is to summarize the current knowledge of how intraluminal acid is sensed by the duodenal mucosa, with a focus on the role of CAs.

  • 28.
    Sjöblom, Markus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    The duodenal mucosal bicarbonate secretion.2005In: Ups J Med Sci, ISSN 0300-9734, Vol. 110, no 2, p. 115-49Article in journal (Refereed)
  • 29.
    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)
  • 30.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Central nervous stimuli increase duodenal bicarbonate secretion by release of mucosal melatonin2001In: J Physiology and Pharmacology, Vol. 52, p. 671-Article in journal (Refereed)
  • 31.
    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.

  • 32.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Flemström, Gunnar
    Peripheral melatonin mediates neural stimulation of duodenal mucosal bicarbonate secretion2001In: Journal of Clinical Investigation, ISSN 0021-9738, Vol. 108, no 4, p. 625-633Article in journal (Refereed)
  • 33.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Peripheral melatonin mediates stimulation of duodenal mucosal bicarbonate secretion2001In: J Clin Investigation, Vol. 108, p. 625-Article in journal (Refereed)
  • 34.
    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.

  • 35.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Isoflurane-induced acidosis depresses basal and PGE(2)-stimulated duodenal bicarbonate secretion in mice2007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 292, no 3, p. G899-G904Article in journal (Refereed)
    Abstract [en]

    When running in vivo experiments, it is imperative to keep arterial blood pressure and acid-base parameters within the normal physiological range. The aim of this investigation was to explore the consequences of anesthesia-induced acidosis on basal and PGE2-stimulated duodenal bicarbonate secretion. Mice (strain C57bl/6J) were kept anesthetized by a spontaneous inhalation of isoflurane. Mean arterial blood pressure (MAP), arterial acid-base balance, and duodenal mucosal bicarbonate secretion (DMBS) were studied. Two intra-arterial fluid support strategies were used: a standard Ringer solution and an isotonic Na2CO3 solution. Duodenal single perfusion was used, and DMBS was assessed by back titration of the effluent. PGE2 was used to stimulate DMBS. In Ringer solution-infused mice, isoflurane-induced acidosis became worse with time. The blood pH was 7.15–7.21 and the base excess was about –8 mM at the end of experiments. The continuous infusion of Na2CO3 solution completely compensated for the acidosis. The blood pH was 7.36–7.37 and base excess was about 1 mM at the end of the experiment. Basal and PGE2-stimulated DMBS were markedly greater in animals treated with Na2CO3 solution than in those treated with Ringer solution. MAP was slightly higher after Na2CO3 solution infusion than after Ringer solution infusion. We concluded that isoflurane-induced acidosis markedly depresses basal and PGE2-stimulated DMBS as well as the responsiveness to PGE2, effects prevented by a continuous infusion of Na2CO3. When performing in vivo experiments in isoflurane-anesthetized mice, it is recommended to supplement with a Na2CO3 infusion to maintain a normal acid-base balance.

  • 36.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Singh, Anurag Kumar
    Zheng, Wen
    Wang, Jian
    Tuo, Bi-guang
    Krabbenhöft, Anja
    Riederer, Brigitte
    Gros, Gerolf
    Seidler, Ursula
    Duodenal acidity "sensing" but not epithelial HCO3- supply is critically dependent on carbonic anhydrase II expression2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 31, p. 13094-13099Article in journal (Refereed)
    Abstract [en]

    Carbonic anhydrase (CA) is strongly expressed in the duodenum and has been implicated in a variety of physiological functions including enterocyte HCO(3)(-) supply for secretion and the "sensing" of luminal acid and CO(2). Here, we report the physiological role of the intracellular CAII isoform involvement in acid-, PGE(2,) and forskolin-induced murine duodenal bicarbonate secretion (DBS) in vivo. CAII-deficient and WT littermates were studied in vivo during isoflurane anesthesia. An approximate 10-mm segment of the proximal duodenum with intact blood supply was perfused under different experimental conditions and DBS was titrated by pH immediately. Two-photon confocal microscopy using the pH-sensitive dye SNARF-1F was used to assess duodenocyte pH(i) in vivo. After correction of systemic acidosis by infusion of isotonic Na(2)CO(3), basal DBS was not significantly different in CAII-deficient mice and WT littermates. The duodenal bicarbonate secretory response to acid was almost abolished in CAII-deficient mice, but normal to forskolin- or 16,16-dimethyl PGE(2) stimulation. The complete inhibition of tissue CAs by luminal methazolamide and i.v. acetazolamide completely blocked the response to acid, but did not significantly alter the response to forskolin. While duodenocytes acidified upon luminal perfusion with acid, no significant pH(i) change occurred in CAII-deficient duodenum in vivo. The results suggest that CA II is important for duodenocyte acidification by low luminal pH and for eliciting the acid-mediated HCO(3)(-) secretory response, but is not important in the generation of the secreted HCO(3)(-) ions.

  • 37.
    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.

  • 38.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    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.
    Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo2013In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 54, no 3, p. 282-291Article in journal (Refereed)
    Abstract [en]

    Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of (51) Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier.

  • 39.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Saudi, Wan Salman Wan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    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.
    Effects of melatonin in ethanol-induced increases in duodenal mucosal permeability, motility and bicarbonate secretion in rats2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no S701, p. 2-3, article id 5Article in journal (Other academic)
  • 40.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Saudi, Wan Salman Wan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    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.
    Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo2013In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 305, no 1, p. G95-G105Article in journal (Refereed)
    Abstract [en]

    Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a similar to 30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of Cr-51-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol-and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol-and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions.

  • 41.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Saudi, Wan Salman Wan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    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.
    The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl-2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e102654-Article in journal (Refereed)
    Abstract [en]

    Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a similar to 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of Cr-51-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl- from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl- and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.

  • 42.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Yamskova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nylander, Olof
    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.
    Long-term oral melatonin administration reduces ethanol-induced increases in duodenal mucosal permeability and motility in rats2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 212, no 2, p. 152-165Article in journal (Refereed)
    Abstract [en]

    Aim: Increased intestinal epithelial permeability is associated with intestinal inflammation and dysfunction. The aim of the present study was to investigate the role of long-term oral melatonin administration on ethanol-induced increases in duodenal mucosal permeability and hypermotility. Methods: Male Sprague-Dawley rats were administered melatonin in their tap water (0.1 mg mL(-1) or 0.5 mg mL(-1)) for 2 or 4 weeks. After the treatment period, the rats were anaesthetized with Inactin (R), and a 30-mm duodenal segment was perfused in situ. The effects on duodenal mucosal paracellular permeability, bicarbonate secretion, fluid flux and motor activity were studied. The expression levels of the tight junction components, zona occludens (ZO)-1, ZO-2, and ZO-3, claudin-2, claudin-3, claudin-4, occludin, and myosin light chain kinase and of the melatonin receptors MT1 and MT2 were assessed using qRT-PCR. Results: Melatonin administration for 2 weeks significantly reduced the basal paracellular permeability, an effect that was absent after 4 weeks. Perfusing the duodenal segment with 15% ethanol induced marked increases in duodenal paracellular permeability, bicarbonate secretion and motor activity. Melatonin for 2 weeks dose-dependently reduced ethanol-induced increases in permeability and motor activity. Four weeks of melatonin administration reduced the ethanol-induced increases in duodenal motility and bicarbonate secretion but had no effect on the increases in permeability. Two weeks of melatonin administration upregulated the expression of MT1 and MT2, although both were downregulated after 4 weeks. Melatonin downregulated the expression of ZO-3 and upregulated the expression of claudin-2, even as all other mRNA-levels investigated were unaffected. Conclusion: Although further studies are needed, our data demonstrate that melatonin administration markedly improves duodenal barrier functions, suggesting its utility in clinical applications when intestinal barrier functions are compromised.

  • 43.
    Säfsten, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Serotonin increases protective duodenal bicarbonate secretion via enteric ganglia and a 5-HT4-dependent pathway2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 11, p. 1279-1289Article in journal (Refereed)
    Abstract [en]

    Objective. Serotonin (5-HT) is present in much larger amounts in the gut than in the central nervous system and is predominantly synthesized and stored in mucosal enterochromaffin cells. Bicarbonate secretion by the duodenal mucosa is the major mechanism in maintaining mucosal integrity, neutralizing invading protons within the surface mucus gel. In this study the role of local 5-HT in the control of the protective secretion was investigated. Material and methods. A segment of proximal duodenum was perfused in situ in anaesthetized rats and the alkaline secretion was continuously recorded by pH-stat. Intracellular calcium signalling was measured in clusters of human and rat duodenal enterocytes devoid of neural tissue. After loading with the fluorescent probe, fura-2, the clusters were attached to the bottom of a temperature-controlled perfusion chamber. Results. Close intra-arterial infusion to the duodenal segment of 5-HT (20 - 200 nmol kg(-1) h(-1)) dose-dependently increased duodenal mucosal HCO3 secretion. A higher dose (2000 nmol kg(-1) h(-1)) did not further increase secretion. Responses were inhibited by the ganglionic blocker and nicotinic receptor antagonist hexamethonium, and were abolished by the 5-HT4 receptor antagonist SB 204070. The 5-HT3 antagonist tropisetron, in contrast, caused only slight inhibition. Viable human and rat duodenal enterocytes responded to 5-HT (100 - 500 nM) with an increase in intracellular calcium concentration. Pretreatment with SB 204070 or removal of external calcium abolished the response. Conclusions. Stimulation of the duodenal protective secretion by 5-HT thus involves receptors of the 5-HT4 subtype as well as nicotinic transmission, the myenteric plexus being a likely location. In addition, serotonin acts on enterocyte membrane receptors, inducing intracellular calcium signalling.

  • 44.
    Wan Saudi, Wan Salman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rudholm-Feldreich, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rosenqvist, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Näslund, Erik
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide2015In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, p. G625-G634Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

  • 45.
    Wan Saudi, Wan Salman
    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.
    Neuropeptide S reduces duodenal bicarbonate secretion and ethanol-induced increases in duodenal motility in rats2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0175312Article in journal (Refereed)
    Abstract [en]

    Alcohol disrupts the intestinal mucosal barrier by inducing metabolic and functional changes in epithelial cells. Recently, we showed that neuropeptide S (NPS) decreases duodenal motility and increases mucosal paracellular permeability, suggesting a role of NPS in the pathogenesis of disorders and dysfunctions in the small intestine. The aim of the present study was to investigate the effects of NPS on ethanol- and HCl-induced changes of duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. The effects on duodenal bicarbonate secretion, the blood-to-lumen clearance of 51Cr-EDTA, motility and transepithelial net fluid flux were investigated.

    Intravenous (i.v.) administration of NPS significantly reduced duodenal mucosal bicarbonate secretion and stimulated mucosal transepithelial fluid absorption, mechanisms dependent on nitrergic signaling. NPS dose-dependently reduced ethanol-induced increases in duodenal motility. NPS (83 pmol·kg-1·min-1, i.v.) reduced the bicarbonate and fluid secretory response to luminal ethanol, whereas a 10-fold higher dose stimulated fluid secretion but did not influence bicarbonate secretion. In NPS-treated animals, duodenal perfusion of acid (pH 3) induced greater bicarbonate secretory rates than in controls. Pre-treating animals with Nω-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NPS on bicarbonate secretion. In response to luminal acid, NPS-treated animals had significantly higher paracellular permeability compared to controls, an effect that was abolished by L-NAME.

    Our findings demonstrate that NPS reduces basal and ethanol-induced increases in duodenal motility. In addition, NPS increases luminal alkalinization and mucosal permeability in response to luminal acid via mechanisms that are dependent on nitric oxide signaling. The data support a role for NPS in neurohumoral regulation of duodenal mucosal barrier function and motility.

  • 46.
    Wan Saudi, Wan Salman
    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.
    Short-chain fatty acids augment rat duodenal mucosal barrier function2017In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 102, no 7, p. 791-803Article in journal (Refereed)
    Abstract [en]

    Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the large intestine, particularly from diets containing fibres and carbohydrates. The small intestinal epithelium is exposed to SCFAs derived mainly from oral bacteria or food supplementation. Although luminal nutrients are important in regulation of intestinal functions, the role of SCFAs in regulation of small intestinal mucosal barrier function and motility has not been fully described. The aim of the present study was to elucidate the effects of acetate and propionate on duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30 mm segment of proximal duodenum with an intact blood supply was perfused. The effects on duodenal bicarbonate secretion, blood-to-lumen clearance of Cr-51-EDTA, motility and transepithelial net fluid flux were investigated. Perfusion of the duodenum with acetate or propionate significantly decreased mucosal paracellular permeability and transepithelial net fluid flux and significantly increased bicarbonate secretion. Acetate or propionate administered as an I.V. infusion decreased the mucosal paracellular permeability, but significantly decreased bicarbonate secretion. Luminal SCFAs changed the duodenal motility pattern from migrating motor complexes to fed patterns. Systemic administration of glucagon-like peptide-2 induced increases in both bicarbonate secretion and net fluid absorption, but did not change motility. Glucagon-like peptide-2 infusion during luminal perfusion of SCFAs significantly reduced the motility. In conclusion, SCFAs decreased duodenal paracellular permeability and net fluid flux. Short-chain fatty acids induced opposite effects on bicarbonate secretion after luminal and i.v. administration. Presence of SCFAs in the lumen induces fed motility patterns. Altered luminal chemosensing and aberrant signalling in response to SCFAs might contribute to symptoms observed in patients with suppressed barrier function.

  • 47. Zheng, Wen
    et al.
    Kuhlicke, Johannes
    Jäckel, Kristian
    Eltzschig, Holger K
    Singh, Anurag
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Riederer, Brigitte
    Weinhold, Cornelia
    Seidler, Ursula
    Colgan, Sean P
    Karhausen, Jörn
    Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium.2009In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, ISSN 1530-6860, Vol. 23, no 1, p. 204-213Article in journal (Refereed)
    Abstract [en]

    Diarrhea is widespread in intestinal diseases involving ischemia and/or hypoxia. Since hypoxia alters stimulated Cl(-) and water flux, we investigated the influence of such a physiologically and pathophysiologically important signal on expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Located on the apical membrane, this cAMP-activated Cl(-) channel determines salt and fluid transport across mucosal surfaces. Our studies revealed depression of CFTR mRNA, protein, and function in hypoxic epithelia. Chromatin immunoprecipitation identified a previously unappreciated binding site for the hypoxia inducible factor-1 (HIF-1), and promoter studies established its relevance by loss of repression following point mutation. Consequently, HIF-1 overexpressing cells exhibited significantly reduced transport capacity in colorimetric Cl(-) efflux studies, altered short circuit measurements, and changes in transepithelial fluid movement. Whole-body hypoxia in wild-type mice resulted in significantly reduced small intestinal fluid and HCO(3)(-) secretory responses to forskolin. Experiments performed in Cftr(-/-) and Nkcc1(-/-) mice underlined the role of altered CFTR expression for these functional changes, and work in conditional Hif1a mutant mice verified HIF-1-dependent CFTR regulation in vivo. In summary, our study clarifies CFTR regulation and introduces the concept of a HIF-1-orchestrated response designed to regulate ion and fluid movement across hypoxic intestinal epithelia.

1 - 47 of 47
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