Linda Gillberg

Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide

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.

Nitric oxide regulation of migrating motor complex: randomized trial of NG‐monomethyl‐l‐arginine effects in relation to muscarinic and serotonergic receptor blockade

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.

Su1911 Neuropeptide S: Effects on Motility, Contractility and Inflammation in the Rat and Human Gastrointestinal Tract

Background: Neuropeptide S (NPS) is expressed by gastrointestinal (GI) enteroendocrine cells and macrophages in rat and man. Polymorphisms of the NPS receptor are linked to increased risk of inflammatory bowel disease as well as motor and sensory disturbances of the gut, suggesting a role for NPS in GI disorders. Further knowledge of NPS effects on motility and inflammation is needed. Methods: Studies of motility were carried out in rats with electrodes implanted in the small bowel. NPS was infused IV for 60 min and effects on myoelectrical activity were recorded. Motility effects of NPS were further studied as luminal pressure changes in anaesthetized rats where the proximal small intestine with intact blood supply was perfused with saline for motility recordings. Tissue samples were obtained from rats for evaluation of gene expression and protein elaboration of inflammatory biomarkers. Muscle strips of the human stomach, small intestine and colon were used for pharmacological analysis in organ baths of motility responses to NPS. Localization of the NPS receptor was done with fluorescent-protein tagging using Cy3-NPS. Plasma levels of NPS were measured using ELISA in 5 healthy and 14 IBD patients before and after meal. Results: In conscious rats, NPS 1 nmol kg-1min-1 increased irregular spiking, 4 nmol kg-1min-1 reduced spiking and increased the MMC cycle length (P=0.005). In anesthetized rats, NPS 0.01-1 nmol kg-1min-1 dose-dependently reduced small bowel motility (P<0.001). In rats, NPS also increased the mRNA expression of iNOS, and CXCL1 and IL-1β at the protein level. In human, fluorescent protein-tagging showed the NPS receptor primarily to be present in enolase-positive nerve fibers, but some scattered also in muscle tissue. In organ baths, NPS 1-100 nM caused TTX-dependent relaxations of the smooth muscle. We found no detectable levels of NPS in plasma of neither healthy subjects nor IBD patients. Conclusion: NPS has a smooth muscle-relaxing effect in the GI tract and dampens myoelectrical and contractile motor activity of the small bowel. This is achieved primarily through an inhibition of nerve-mediated relaxation of smooth muscle cells. Circulating NPS levels in humans are undetectable in healthy subjects and in active IBD. This implies that NPS exerts its inhibitory function by a paracrine or neurocrine mechanism in the gut. NPS seems also capable of intervening with inflammation by increasing gut cytokines and iNOS expression.

Gastrin Receptor Antagonist YF476 : Effects on Gastric Acid Secretion, Regulatory Peptides and Receptor Gene Expression in Rats

Gastrin Receptor Antagonist YF476 : Effects on Gastric Acid Secretion, Regulatory Peptides and Receptor Gene Expression in Rats