title: Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide.
abstract: 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 100-4,000 pmol·kg(-1)·min(-1) 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 precontracted by bethanechol, NPS 1-1,000 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 upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.
authors.affiliation: Department of Neuroscience, Division of Gastrointestinal Physiology, Uppsala University, Uppsala, Sweden;
authors.forename: Wan Salman
authors.initials: WS
authors.lastname: Wan Saudi
authors.affiliation: Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden;
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Halim
authors.affiliation: Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden;
authors.forename: Tobias
authors.initials: T
authors.lastname: Rudholm-Feldreich
authors.affiliation: Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden;
authors.forename: Linda
authors.initials: L
authors.lastname: Gillberg
authors.affiliation: Department of Neuroscience, Division of Gastrointestinal Physiology, Uppsala University, Uppsala, Sweden;
authors.forename: Evelina
authors.initials: E
authors.lastname: Rosenqvist
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden;
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; and.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sundbom
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; and.
authors.forename: Urban
authors.initials: U
authors.lastname: Karlbom
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden;
authors.forename: Dominic-Luc
authors.initials: DL
authors.lastname: Webb
authors.affiliation: Department of Neuroscience, Division of Gastrointestinal Physiology, Uppsala University, Uppsala, Sweden;
authors.forename: Markus
authors.initials: M
authors.lastname: Sjöblom
authors.affiliation: Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden; per.hellstrom@medsci.uu.se.
authors.forename: Per M
authors.identifier: http://orcid.org/0000-0001-8428-0772
authors.initials: PM
authors.lastname: Hellström
mesh_terms: D000328:Adult; D000818:Animals; D018723:Bethanechol; D015415:Biomarkers; D005769:Gastrointestinal Motility / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009479:Neuropeptides / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C568280:neuropeptide S receptor, rat; C506531:neuropeptide S, human; C534458:neuropeptide S, rat; D018723:Bethanechol; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I
keywords: NO; inflammation; inflammatory bowel disease; migrating motor complex; peristalsis