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  • 1.
    Al-Saffar, Anas K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Baghdad Univ, Coll Vet Medicine, Dept Surg & Obstet, Baghdad, Iraq..
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hall, G.
    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.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Small intestinal lactulose and sucralose hyper-permeability in inflammatory bowel disease2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, p. S124-S124Article in journal (Other academic)
  • 2.
    Al-Saffar, Anas Kh.
    et al.
    Baghdad University/ College of Veterinary Medicine.
    Halim, Abdul
    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.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Concurrent small and large intestinal permeability in inflammatory bowel disease: Hyper-permeability in IBDManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Hyper-permeability in inflammatory bowel disease (IBD) has mostly been explored in the colon, where symptomatic inflammation is prevalent. Relationships between small and large intestine barrier function were examined. Fasted (4h) IBD (19 ulcerative colitis, 11 Crohn's disease) and 25 healthy control subjects’ were investigated. Lactulose (10g), mannitol (5g), riboflavin (0.05g) and sucralose (5g) were ingested with 500 mL water. Urine lactulose and mannitol were measured by enzyme assays, riboflavin by intrinsic fluorescence and sucralose by HPLC. CRP was measured by nephelometry. In IBD, small intestine lactulose and sucralose % recoveries were 1.77 and 2.73 fold higher than controls; combined data revealed the two probes were correlated (R2=0.6). In IBD, large intestine sucralose % recovery was 2.6 fold higher than controls and correlated with small intestine sucralose % recovery (R2=0.6). Conclusions: Sucralose yields similar result as lactulose for small intestine permeability, while having higher S:N, implying sucralose is more sensitive. No evidence was found for riboflavin malabsorption in IBD. There is concurrent small and large intestine hyper-permeability in IBD. Small intestine hyper-permeability is presumably related to inflammation in the large intestine, but without obvious deficiency in transporter mediated micronutrient absorption (i.e., riboflavin) in the small intestine.

  • 3.
    Diaz Tartera, Hetzel O.
    et al.
    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.
    Al-Saffar, Anas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lindberg, G
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Gastroenterol & Hepatol Unit, Huddinge, Sweden.
    Sangfelt, Per
    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.
    Validation of SmartPill® wireless motility capsule for gastrointestinaltransit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy2017In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no 10, article id e13107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is interest in ultimately combining endoscopy and motility assessments. Gastric emptying (GET), small bowel (SBTT), colon (CTT) and whole gut transit (WGTT) times are conveniently obtained by SmartPill® wireless motility capsule (WMC) that records luminal pH, temperature and pressure. Reproducibility within same subjects and accuracy of software derived times (MotiliGI® ) were investigated for diagnostic application. GET and SBTT were separately measured using video capsule endoscopy (VCE). The aim of this investigation was to assess same subject reproducibility of WMC, accuracy of software derived transit times and relate to Pillcam® SB (small bowel) VCE motility data.

    METHODS: Seventy three healthy adults ingested a 260 kcal mixed meal followed by WMC tests. Food intake was permitted after 6 hours. Regional transit data was obtained for GET, SBTT and CTT, the sum yielding WGTT. Nineteen subjects repeated WMC tests 2 or 4 weeks later; a separate 70 underwent VCE while fasted.

    KEY RESULTS: Visually derived data from WMC yielded GET 3.46±0.27, SBTT 5.15±0.21, CTT 20.76±1.19 and WGTT 29.53±1.28 hours (mean±SEM). Pearson's correlation coefficients (r) against software derived results were: GET 0.78 (P<.0001), SBTT 0.28 (P<.05), CTT 0.96 (P<.0001), WGTT 0.99 (P<.0001). VCE yielded lower GET (0.71±0.08 hours) and SBTT (4.15±0.13 hours).

    CONCLUSIONS AND INFERENCES: GET, SBTT, CTT and WGTT obtained by WMC are commensurate with literature values, including by other methods. Visually and software derived transit times have strongest correlations for CTT and WGTT. WMC yields longer GET and SBTT than VCE, perhaps due to meal related effects on motility.

  • 4.
    Halim, Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Degerblad, Marie
    Karolinska Institutet.
    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, Upper Abdominal Surgery.
    Juul Holst, Jens
    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.
    Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 2, p. 575-585Article in journal (Refereed)
    Abstract [en]

    Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.

    Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.

    Design: Single-blind parallel study.

    Setting: University research laboratory.

    Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.

    Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).

    Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.

    Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.

    Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.

  • 5.
    Halim, M. Abdul
    et al.
    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.
    Boghus, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 6.
    Halim, Md. Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Gut peptides in gastrointestinal motility and mucosal permeability2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.

    This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.

    A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.

    NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.

    Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.

    Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.

    In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

     

    List of papers
    1. Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens
    Open this publication in new window or tab >>Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens
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    2015 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 439, p. 115-121Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Although organoboronic acids are efficient high-throughput sugar sensors, they have not been pursued for gut permeability studies. A modification of the lactulose/mannitol assay is described by which small intestinal permeability is assessed at the time of urine collection using a lactulose/riboflavin ratio.

    METHODS: Volunteers ingested 50mg riboflavin and either 5g mannitol or 10g lactulose. Urine was collected for 6hrs. Riboflavin was assayed by autofluorescence. Riboflavin was removed by C18 solid phase extraction. Lactulose and mannitol were then assayed using 1,1'-bis(2-boronobenzyl)-4,4'-bipyridinium (4,4'oBBV) coupled to the fluorophore HPTS.

    RESULTS: The temporal profile over 6hrs for riboflavin paralleled mannitol. Riboflavin recovery in urine was 11.1±1.9 % (mean±SEM, n=7), similar to mannitol. There was selective binding of 4,4'oBBV to lactulose, likely involving cooperativity between the fructose and galactose moieties. Lower limits of detection and quantification were 90 and 364μM. The lactulose assay was insensitive to other permeability probes (e.g., sucrose, sucralose) while tolerating glucose or lactose. This assay can be adapted to automated systems. Stability of 4,4'oBBV exceeds 4years.

    CONCLUSIONS: Riboflavin measured by autofluorescence combined with lactulose measured with 4,4'oBBV represents a useful new chemistry for rapid measurement of intestinal permeability with excellent stability, cost and throughput benefits.

    Keywords
    Intestinal permeability, Organoborane, Gastroenterology, Lactulose, Mannitol, Riboflavin
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:uu:diva-236349 (URN)10.1016/j.cca.2014.09.031 (DOI)000347499700021 ()25300228 (PubMedID)
    Note

    De två första författarna delar första författarskapet.

    Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2017-12-05Bibliographically approved
    2. Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
    Open this publication in new window or tab >>Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
    Show others...
    2015 (English)In: 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) Published
    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.

    Keywords
    inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-264766 (URN)10.1152/ajpgi.00104.2015 (DOI)000364068300002 ()26206857 (PubMedID)
    Funder
    The Swedish Medical Association, SLS-176671Swedish Research Council, 7916Swedish Society of Medicine, SLS-176671Swedish National Board of Health and Welfare, SLS-176671
    Note

    Shared first name: Wan Salman Wan Saudi and Md. Abdul Halim.

    Shared last name: Dominic-Luc Webb, Markus Sjöblom and Per M. Hellström.

    Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2018-01-11Bibliographically approved
    3. Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
    Open this publication in new window or tab >>Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
    Show others...
    2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed) Published
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

    Keywords
    motility, myenteric plexus, NG-monomethyl-l-arginine, nitric oxide, nitric oxide synthase
    National Category
    Gastroenterology and Hepatology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-259469 (URN)DOI:10.1111/apha.12554 (DOI)
    Funder
    Swedish Research Council, 7916
    Note

    De 2 första författarna delar förstaförfattarskapet.

    The study was supported by Swedish Research Council (7916), Uppsala University (540113) and the Erik, Karin och Gösta Selander Fund (14-03-07)

    Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2017-12-04Bibliographically approved
    4. GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motility
    Open this publication in new window or tab >>GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motility
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. Receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.

    Keywords
    Antroduodenojejunal motility, Glucagon-like peptides, Peptide hormones, ROSE-010, exendin(9-39) amide
    National Category
    Medical and Health Sciences
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-294388 (URN)
    Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2016-05-25
  • 7.
    Halim, Md Abdul
    et al.
    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.
    Boghus, Sandy
    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.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    M. Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 8.
    Halim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Marie, Degerblad
    Karolinska Institutet.
    Magnus, Sundbom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Per, Hellström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motilityManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. Receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.

  • 9.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    D-erythro-Sphingosine and Pregnenolonesulphate activate TRPM3 channels synergistically in INS-1E cells2017In: Bangladesh Journal of Medical Science, ISSN 2223-4721, E-ISSN 2076-0299, Vol. 16, no 1, p. 98-106Article in journal (Refereed)
    Abstract [en]

    Background: A group of ion channels have recently been studied to understand the pathogenesis of diabetes. The transient receptor potential (TRP) channels are thought to be involved in many cellular functions. TRPM3, a member of the melastatin-like transient receptor is mainly expressed in human kidney and brain. It is also expressed in human pancreas. Therefore, it is desirable to find compounds able to induce an increase of intracellular calcium([Ca2+](i)) in pancreatic beta cells thereby trigger insulin secretion. Aims: The aim of the study was to confirm whether D-erythroSphingosine and Pregnenolonesulphate activates TRPM3. Another aim was to investigate whether pancreatic beta cells express TRPM3-channels. INS-1E cells were used as a model of beta-cells for [Ca2+](i) measurement. Results: Application of endogenous neurosteroidpregnenolonesulphate (35 mu M) led to a rapid Ca2+ influx in INS-1E cells and pancreatic beta cells. When PS was applied in the absence of extracellular Ca2+ the [Ca2+](i) response to PS was completely lost. The increase in [Ca2+](i) induced by PS was inhibited by cholesterol. Western blot data identified a protein reacting specifically with polyclonal antibodies for TRPM3. Conclusion: Our results demonstrate that both pancreatic beta-cells and INS-1E cells express functional TRPM3-channels and both SPH and PS are TRPM3 agonists.

  • 10.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Tryggve, Ljung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Holst, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Institutet.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Luminal Nitric Oxide and Plasma Nitrite/Nitrate As Predictors of Colectomy in Corticosteroid-Treated Acute Colitis2015In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 148, no 4, suppl. 1, article id Sul 231Article in journal (Refereed)
    Abstract [en]

    Background: Nitric oxide (NO) is known to be up-regulated by the induction of induciblenitric oxide synthase (iNOS) in inflammatory conditions. NO gas can be used as a markerof inflammatory activity in hollow organs. In parallel, plasma nitrite + nitrate (NOx) canreflect the ongoing inflammatory activity. We analyzed rectal NO before and after threedays, as well as plasma NOx in patients on glucocorticosteroid (GC) therapy in hospitalizedpatients. The aim of the study was to evaluate the relationship of rectal luminal NO andcirculating plasma NOx in acute fulminant colitis to the outcome as therapeutic responseor colectomy.

    Methods: 50 patients with median age 41 (range 20-78) years were hospitalizeddue to acute fulminant colitis and received treatment with high-dose GCs. Luminal nitricoxide was analyzed with chemiluminescence before therapy onset of therapy with GC andon day 3 of treatment. NOx was measured by nitrite/nitrate colorimetric assay. NO levelsand plasma NOx were compared to clinical disease activity index and C-reactive protein(CRP).

    Results: 32 responded to GC treatment and 18 did not, resulting in colectomy.The responders had higher luminal NO than non-responders (day 1: 12525±2600, day 3:15590±4157 ppb) vs non-responders (day 1: 2874±1283, day 3: 1137±297 ppb) (p<0.0114).Using an optimal cut-off NO level of 2250 ppb, sensitivity and specificity was 86% and81% for colectomy (p<0.0001). The area under the curve was 0.88 and likelihood ratio4.8. Similarly, plasma NOx was higher in responders vs non-responders (day 1: 6.2±0.3 vs3.9±0.4 umol/L) (p<0.0001). Using plasma NOx, we found a corresponding cut-off at 5umol/L with sensitivity 87% and specificity 87%. The area under the curve was 0.88 andlikelihood ratio 6.7. Luminal NO was also correlated to plasma NOx (r=0.33, p=0.0205).In the responder group, CRP levels decreased (day 1: 22.31±2.95, day 3: 15.69±3.57mg/L), whereas among non-responders CRP levels increased (day 1: 45.83±11.10, day 3:76.35±16.96 mg/L) (p<0.0167). Kaplan-Meier analysis showed that patients with baselineNO levels lower than 2250 ppb were at a significantly higher risk of colectomy within onemonth from onset of GCS treatment (p<0.0001). Twelve out of 18 (67%) in patients withday 1 NO <2250 ppb were colectomized, the corresponding number of patients with NO>2250 ppb was 3 out of 32 (9%). In a similar manner, using plasma NOx <5 uml/L foranalysis, we found 13 (72%) to be colectomized, and with >5 umol/L only two (6%).

    Conclusion: NO and its oxidation product NOx are markers of inflammatory activity in thegut. However, with more intense inflammation and mucosal damage, the less NO is produced.Luminal NO as well as plasma NOx can be used as a sensitive biomarker to predict colectomyin the outcome of acute fulminant colitis

  • 11. Resendez, Angel
    et al.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Landhage, Caroline M
    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.
    Singaram, Bakthan
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens2015In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 439, p. 115-121Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although organoboronic acids are efficient high-throughput sugar sensors, they have not been pursued for gut permeability studies. A modification of the lactulose/mannitol assay is described by which small intestinal permeability is assessed at the time of urine collection using a lactulose/riboflavin ratio.

    METHODS: Volunteers ingested 50mg riboflavin and either 5g mannitol or 10g lactulose. Urine was collected for 6hrs. Riboflavin was assayed by autofluorescence. Riboflavin was removed by C18 solid phase extraction. Lactulose and mannitol were then assayed using 1,1'-bis(2-boronobenzyl)-4,4'-bipyridinium (4,4'oBBV) coupled to the fluorophore HPTS.

    RESULTS: The temporal profile over 6hrs for riboflavin paralleled mannitol. Riboflavin recovery in urine was 11.1±1.9 % (mean±SEM, n=7), similar to mannitol. There was selective binding of 4,4'oBBV to lactulose, likely involving cooperativity between the fructose and galactose moieties. Lower limits of detection and quantification were 90 and 364μM. The lactulose assay was insensitive to other permeability probes (e.g., sucrose, sucralose) while tolerating glucose or lactose. This assay can be adapted to automated systems. Stability of 4,4'oBBV exceeds 4years.

    CONCLUSIONS: Riboflavin measured by autofluorescence combined with lactulose measured with 4,4'oBBV represents a useful new chemistry for rapid measurement of intestinal permeability with excellent stability, cost and throughput benefits.

  • 12. Resendez, Angel
    et al.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Singh, Jasmeet
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Singaram, Bakthan
    Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose.2017In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 45, p. 9727-9733Article in journal (Refereed)
    Abstract [en]

    To address carbohydrates that are commonly used in biomedical applications with low binding affinities for boronic acid based detection systems, two chemical modification methods were utilized to increase sensitivity. Modified carbohydrates were analyzed using a two component fluorescent probe based on boronic acid-appended viologen-HPTS (4,4'-o-BBV). Carbohydrates normally giving poor signals (fucose, l-rhamnose, xylose) were subjected to sodium borohydride (NaBH4) reduction in ambient conditions for 1 h yielding the corresponding sugar alcohols from fucose, l-rhamnose and xylose in essentially quantitative yields. Compared to original aldoses, apparent binding affinities were increased 4-25-fold. The chlorinated sweetener and colon permeability marker sucralose (Splenda), otherwise undetectable by boronic acids, was dechlorinated to a detectable derivative by reactive oxygen and hydroxide intermediates by the Fenton reaction or by H2O2 and UV light. This method is specific to sucralose as other common sugars, such as sucrose, do not contain any carbon-chlorine bonds. Significant fluorescence response was obtained for chemically modified sucralose with the 4,4'-o-BBV-HPTS probe system. This proof of principle can be applied to biomedical applications, such as gut permeability, malabsorption, etc.

  • 13.
    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)
  • 14.
    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)
  • 15.
    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.

  • 16.
    Webb, Dominic-Luc
    et al.
    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.
    Gillberg, Linda
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Theodorsson, Elvar
    Sanger, Gareth J.
    Campbell, Colin A.
    Boyce, Malcolm
    Näslund, Erik
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression2013In: 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.

1 - 16 of 16
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