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  • 1.
    Bassil, A K
    et al.
    Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK.
    Häglund, Y
    Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet.
    Brown, J
    Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK.
    Rudholm, Tobias
    Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet.
    Hellström, P M
    Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet.
    Näslund, E
    Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet.
    Lee, K
    Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK.
    Sanger, G J
    Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK.
    Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract.2007In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 150, no 1, p. 58-64Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated.

    EXPERIMENTAL APPROACH: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPgammaS assay and transfected cells.

    KEY RESULTS: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01-1000 nM, respectively (P>0.05 each; n=4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 microM to facilitate EFS-evoked contractions of the stomach (increases were 42.7+/-7.8% and 21.2+/-5.0 % in the absence and presence of obestatin 1 nM; P<0.05; n=12); higher concentrations (10-1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT(4) receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3+/-14.0% and 42.6+/-8.7% in the absence and presence of 1000 nM obestatin; n=10). Obestatin (up to 10 microM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg(-1) min(-1)) had no effects. Obestatin (2500 pmol kg(-1) min(-1), starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg(-1) min(-1)) to shorten MMC cycle time.

    CONCLUSIONS AND IMPLICATIONS: Obestatin has little ability to modulate rat GI motility.

  • 2. Hellström, Per M.
    et al.
    Rudholm, Tobias
    Gillberg, Linda
    Theodorsson, Elvar
    Webb, Dominic
    Sanger, Gareth J.
    Näslund, Erik
    Gastrin Receptor Antagonist YF476: Effects on Gastric Acid Secretion, Regulatory Peptides and Receptor Gene Expression in Rats2011In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 140, no 5, p. S730-S730Article in journal (Other academic)
  • 3.
    Rudholm Feldreich, Tobias
    Karolinska Institutet.
    Gastric acid secretion and gut peptides: mechanisms involved in inflammatory response2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The regulation of gastric acid secretion is complex and involves endocrine, paracrine, and neurocrine mechanisms. Among these, the interconnecting cross-talk between different gut peptides is an important part in the control of acid secretion. The aims of this thesis were (1) to develop a new method of measuring intragastric pH for prolonged periods of time, and (2) apply developed and in-use methods using different substances and their impact on gastric acid secretion in vivo experiments on rats. (3) To study the changes in acid output and the migrating motor complex (MMC) when subjected to different substances, and (4) to further study the alterations in expression of different gut peptides in tissue samples in vitro, and the impact of inflammation in the gut. The novel Bravo model developed gave reliable recordings compared to the chronic fistula model. The pH rose during treatment with esomeprazole and the acid output in the fistula model decreased accordingly. Gut peptides ghrelin and somatostatin increased in plasma when subjected to esomeprazole treatment, while gastrin remained unchanged. Ghrelin administered in bolus doses increased the intragastric pH in accordance with previous experiments. The gut peptides somatostatin, neurotensin, and vasoactive intestinal peptide increased during pentagastrin-stimulated infusion and challenge with hydrochloric acid and polyethylene glycol both in plasma and intestinal perfusate, though the most pronounced elevation was seen in perfusate and with somatostatin. Gastrazole gave the most extensive inhibitory effect on acid secretion compared to ranitidine and esomeprazole. The CCK2-receptor antagonist YF476 inhibited acid secretion long-term and increased concentrations of ghrelin and somatostatin in plasma, but gastrin remained low. Tissue mRNA content of the peptides and their receptors were unchanged except for the ghrelin receptor. When subdued to NSAID gastrin, CCK2-receptor and iNOS increased in mRNA expression while other peptides and receptors were unchanged. Administration of NPS evoked a response in the MMC pattern with irregular spiking and prolonged cycle length of the activity fronts, and the mRNA expression of iNOS, TNF, and IL-1ß increased in the tissue. In conclusion, The Bravo model can be used as a complement to the chronic fistula model for measurements of pH. The regulation of gastric acid secretion is not only limited to the stomach, but also present in the smaller intestine where release of somatostatin seems to be most important. Different mechanisms are involved in the blockage of acid secretion when subjected to YF476, but under NSAID treatment the expression of gastrin and its receptor CCK2 increase and COX- 2 is activated which demonstrates a novel pathway for the study of gastric ulcerations. NPS, a novel neuropeptide influences the gastric motility and could have a role in inflammatory responses seen in the changes in the migrating motor complex and inflammatory markers iNOS, TNF, and IL-1ß.

  • 4. Rudholm, Tobias
    et al.
    Campbell, Colin A.
    Mclean, Peter G.
    Hellström, Per M.
    Näslund, Erik
    A novel method for studying intra-gastric pH over prolonged periods of time in freely moving rats2007In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 132, no 4, p. A606-A606Article in journal (Other academic)
  • 5. Rudholm, Tobias
    et al.
    Campbell, Colin A.
    McLean, Peter G.
    Hellström, Per M.
    Näslund, Erik
    A novel technique for prolonged studies of gastric acid secretion in free roaming conscious rats2006In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 130, no 4, p. A386-A386Article in journal (Other academic)
  • 6.
    Rudholm, Tobias
    et al.
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Gillberg, L
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Theodorsson, E
    Clinical Chemistry, Linköping University.
    Sanger, G
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK.
    Campbell, C A
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK.
    Boyce, M
    Hammersmith Medicines Research, London, UK.
    Näslund, E
    Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Medical Sciences, Gastro unit, Uppsala University.
    CCK2-receptor antagonist YF476 prevents NSAID-induced gastric ulceration through acid inhibition mediated by regulatory peptidesManuscript (preprint) (Other academic)
  • 7.
    Rudholm, Tobias
    et al.
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Gillberg, L
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Webb, D L
    Department of Medical Sciences, Uppsala University.
    Näslund, E
    Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Medical Sciences, Gastro unit, Uppsala University.
    Neuropeptide S in the gastrointestinal tract: effects on motility and inflammatory markers TNF, IL-1β, and iNOS in the ratManuscript (preprint) (Other academic)
  • 8.
    Rudholm, Tobias
    et al.
    Department of Medicine Solna, Karolinska Institutet.
    Hellstrom, Per Mikael
    Department of Medicine Solna, Karolinska Institutet.
    Theodorsson, Elvar
    Department of Neurochemistry, Linköping University Hospital.
    Campbell, Colin Allan
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK, Essex CM19 5AW, United Kingdom.
    McLean, Peter Geoffrey
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK, Essex CM19 5AW, United Kingdom.
    Näslund, Erik
    Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet.
    Bravo capsule system optimizes intragastric pH monitoring over prolonged time: effects of ghrelin on gastric acid and hormone secretion in the rat.2008In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 14, no 40, p. 6180-6187Article in journal (Refereed)
    Abstract [en]

    AIM: To evaluate measurements of intragastric pH with the Bravo capsule system over a prolonged time.

    METHODS: A Bravo capsule was placed inside the rat gastric body and pH was studied for periods up to five consecutive days. For comparison, a gastric fistula model was used. Effects of ghrelin and esomeprazole, with or without pentagastrin, on gastric pH were studied. In addition, effects of esomeprazole on plasma ghrelin, gastrin and somatostatin were analyzed.

    RESULTS: All rats recovered after surgery. The average 24-h pH during free feeding was 2.3 +/- 0.1 (n = 20) with a variation of 18% +/- 6% over 5 d. Ghrelin, 2400 pmol/kg, t.i.d. increased pH from 1.7 +/- 0.1 to 3.1 +/- 0.3 (P < 0.01) as recorded with the Bravo system. After esomeprazole (1 mg/kg, 3 mg/kg and 5 mg/kg) there was a dose-dependent pH increase of maximally 3.4 +/- 0.1, with day-to-day variation over the entire period of 8% +/- 3%. The fistula and pH studies generated similar results. Acid inhibition with esomeprazole increased plasma ghrelin from 10 +/- 2 pmol/L to 65 +/- 26 pmol/L (P < 0.001), and somatostatin from 10 +/- 2 pmol/L to 67 +/- 18 pmol/L (P < 0.001).

    CONCLUSION: pH measurements with the Bravo capsule are reliable, and comparable to those of the gastric fistula model. The Bravo system optimizes accurate intragastric pH monitoring over prolonged periods and allows both short- and long-term evaluation of effects of drugs and hormones.

  • 9.
    Rudholm, Tobias
    et al.
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Wallin, B
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Theodorsson, E
    Department of Clinical Chemistry, Linköping University.
    Näslund, E
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Department of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 152, no 1-3, p. 8-12Article in journal (Refereed)
    Abstract [en]

    The impact of exposure of the intestinal mucosa to acid and hyperosmolal solutions on the release of the inhibitory gut peptides somatostatin (SOM), neurotensin (NT) and vasoactive intestinal peptide (VIP) was studied in conscious rats during pentagastrin-stimulated gastric acid secretion. The animals were equipped with a chronic gastric fistula to measure acid secretion and a jejunal Thiry-Vella loop for intestinal challenge with saline, hydrochloric acid (HCl, 200 mmol L(-1)) or hyperosmolal polyethylene glycol (PEG, 1200 mOsm kg(-1)). Gut peptide concentrations were measured in intestinal perfusates, and in plasma samples collected during stimulated acid secretion, and at the end of experiments with luminal challenge of the loops. After pentagastrin-stimulation acid secretion was dose-dependently inhibited by intravenous administration of the gastrin receptor antagonist gastrazole, as well as ranitidine and esomeprazole by maximally 73+/-10%; 95+/-3%; 90+/-10%, respectively. Acid perfusion of the Thiry-Vella loop caused a prominent release of SOM both to the lumen (from 7.2+/-5.0 to 1279+/-580 pmol L(-1)) and to the circulation (from 18+/-5.2 to 51+/-9.0 pmol L(-1)) simultaneously with an inhibition of gastric acid secretion. The release of NT and VIP was not affected to the same extent. PEG perfusion of the loop caused a release of SOM as well as NT and VIP, but less. Simultaneously acid secretion was slightly decreased. In conclusion, intestinal perfusion with acid or hyperosmolal solutions mainly releases SOM, which seems to exert a major inhibitory action in the gut, as shown by inhibition of acid secretion. The other peptides NT and VIP also participate in this action but to a much lesser degree. The operative pathways of these gut peptides hence involve both endocrine (SOM) and paracrine actions (SOM, NT, VIP) in order to exert inhibitory functions on the stomach. The inhibitory action of gastrazole, was in a similar range as that of SOM implying that physiological acid-induced inhibition of gastric acid may primarily be exerted through inhibition of gastrin endocrine secretion.

  • 10.
    Webb, Dominic-Luc
    et al.
    Department of Medical Sciences, Gastroenterology & Hepatology unit, Uppsala University.
    Rudholm-Feldreich, Tobias
    Department of Medical Sciences, Gastroenterology & Hepatology unit, Uppsala University.
    Gillberg, Linda
    Department of Medicine and Gastroenterology & Hepatology Unit, Karolinska Institutet, Karolinska University Hospital.
    Halim, Md Abdul
    Department of Medical Sciences, Gastroenterology & Hepatology unit, Uppsala University.
    Theodorsson, Elvar
    Clinical Chemistry, Linköping University.
    Sanger, Gareth J
    lizard Institute, Neurogastroenterology group, Queen Mary, University of London, Harlow, UK.
    Campbell, Colin A
    Neurology & GI CEDD, GlaxoSmithKline, Harlow, UK.
    Boyce, Malcolm
    Hammersmith Medicines Research, London, UK.
    Näslund, Erik
    Hellström, Per M
    Department of Medical Sciences, Gastroenterology & Hepatology unit, Uppsala University.
    The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression.2013In: Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN 0028-1298, E-ISSN 1432-1912, Vol. 386, no 1, p. 41-49Article in journal (Refereed)
    Abstract [en]

    YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (±0.06). YF476 raised pH to 3.67 (±0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.

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