a Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Sweden b Obesity Unit, Karolinska University Hospital-Huddinge, Sweden c Department of Clinical Chemistry, Karolinska University Hospital-Solna, Karolinska Institutet, Stockholm, Sweden d Department of Gastroenterology and Hepatology, Karolinska University Hospital-Solna, Karolinska Institutet, Stockholm, Sweden e Department of Medical Physiology, University of Copenhagen, Copenhagen Denmark f Biopsychology Group, Institute of Psychological Sciences, University of Leeds, LS2 9JT, United Kingdom g Human Movement Queensland University of Technology, Brisbane, Australia

CONTEXT:Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis.MAIN OBJECTIVE:The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers.DESIGN:This was a randomized, double-blind, crossover study.SUBJECTS:Subjects included normal human volunteers and patients with GH deficiency.INTERVENTION:Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients.MAIN OUTCOME MEASURES:Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin.RESULTS:The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution.CONCLUSION:Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

Orexin A (OXA) increases food intake and inhibits fasting small bowel motility in rats. The aim of this study was to examine the effect of exogenous OXA and endogenous OXA on gastric emptying, acid secretion, glucose metabolism and distribution of orexin immunoreactivity in the stomach. Rats equipped with a gastric fistula were subjected to intravenous (IV) infusion of OXA or the selective orexin-1 receptor (OX1R) antagonist SB-334867-A during saline or pentagastrin infusion. Gastric emptying was studied with a liquid non-nutrient or nutrient, using 51Cr as radioactive marker. Gastric retention was measured after a 20-min infusion of OXA or SB-334867-A. Plasma concentrations of OXA, insulin, glucagon, glucose and gastrin were studied. Immunohistochemistry against OXA, OX1R and gastrin in gastric tissue was performed. OXA alone had no effect on either acid secretion or gastric emptying. SB-334867-A inhibited both basal and pentagastrin-induced gastric acid secretion and increased gastric retention of the liquid nutrient, but not PEG 4000. Plasma gastrin levels were unchanged by IV OXA or SB-334867-A. Plasma OXA levels decreased after intake of the nutrient meal and infusion of the OX1R antagonist. Only weak effects were seen on plasma glucose and insulin by OXA. Immunoreactivity to OXA and OX1R were found in the mucosa, myenteric cells bodies and varicose nerve fibers in ganglia and circular muscle of the stomach. In conclusion, endogenous OXA influences gastric emptying of a nutrient liquid and gastric acid secretion independent of gastrin. This indicates a role for endogenous OXA, not only in metabolic homeostasis, but also in the pre-absorptive processing of nutrients in the gut.

Ghrelin is a gut peptide that is secreted from the stomach and stimulates food intake. There are ghrelin receptors throughout the gut and intracerebroventricular ghrelin has been shown to increase gastric acid secretion. The aim of the present study was to examine the effects of peripherally administered ghrelin on gastric emptying of a non-nutrient and nutrient liquid, as well as, basal and pentagastrin-stimulated gastric acid secretion in awake rats. In addition, gastric contractility was studied in vitro. Rats equipped with a gastric fistula were subjected to an intravenous infusion of ghrelin (10–500 pmol kg− 1 min− 1) during saline or pentagastrin (90 pmol kg− 1 min− 1) infusion. After administration of polyethylene glycol (PEG) 4000 with 51Cr as radioactive marker, or a liquid nutrient with 51Cr, gastric retention was measured after a 20-min infusion of ghrelin (500 pmol kg− 1 min− 1). In vitro isometric contractions of segments of rat gastric fundus were studied (10− 9 to 10− 6 M). Ghrelin had no effect on basal acid secretion, but at 500 pmol kg− 1 min− 1 ghrelin significantly decreased pentagastrin-stimulated acid secretion. Ghrelin had no effect on gastric emptying of the nutrient liquid, but significantly increased gastric emptying of the non-nutrient liquid. Ghrelin contracted fundus muscle strips dose-dependently (pD2 of 6.93 ± 0.7). Ghrelin IV decreased plasma orexin A concentrations and increased plasma somatostatin concentrations. Plasma gastrin concentrations were unchanged during ghrelin infusion. Thus, ghrelin seems to not only effect food intake but also gastric motor and secretory function indicating a multifunctional role for ghrelin in energy homeostasis.

Orexin A (OXA) is found in the central nervous system (CNS) and in the gut. Peripheral administration of OXA to rats results in an inhibition of fasting motility. Plasma OXA increases during fasting and central administration of OXA increases food intake. The aim of the present study was to assess the pharmacokinetic profile of OXA and the effect of intravenously (IV) administered OXA on plasma concentrations of insulin and glucagon concentrations. Rats were given OXA IV (100 pmol kg−1 min−1) for time periods of 0, 10, 20, 30 min and for 10, 20, 30 min after ceasing a 30-min infusion. After each time period, rats were then sacrificed and blood obtained. OXA was also administered at increasing doses (0, 100, 300 and 500 pmol kg−1 min−1) for 30 min and blood was obtained. Plasma OXA, insulin and glucagon levels were measured using commercially available radioimmunoassay (RIA) kits. The plasma half-life of OXA was 27.1±9.5 min. Stepwise increasing infusion rates of OXA confirmed a linear concentration–time curve and thus first-order kinetics. Its volume of distribution indicated no binding to peripheral tissues. Plasma glucagon decreased during infusion of OXA, while insulin was unaffected. Plasma OXA was raised fourfold after food intake. Thus, OXA has a longer plasma half-life than many other peptides found in the gut. This needs to be taken into account when assessing effects of OXA on biological parameters after peripheral administration.

Background and purpose: Ghrelin is a peptide discovered in endocrine cells of the stomach. Since ghrelin mRNA expression and plasma levels are elevated in the fasting state, we investigated the effects of ghrelin on the interdigestive migrating myoelectric complex (MMC) in the small intestine in vivo and compared with motor effects of ghrelin in vitro. Methods: Sprague–Dawley rats were supplied with a venous catheter and bipolar electrodes in the duodenum and jejunum for electromyography of small intestine in awake rats. In organ baths, isometric contractions of segments of rat jejunum were studied. Results: Ghrelin dose-dependently shortened the MMC cycle length at all three recording points. At the duodenal site, the interval shortened from 17.2±2.0 to 9.9±0.8 min during infusion of ghrelin (1000 pmol kg−1 min−1) and at the jejunal site from 17.5±2.2 to 10.5±0.8 min. Ghrelin contracted the muscle strips with a pD2 of 7.97±0.47. Atropine (10−6 M) in vitro and (1 mg kg−1) in vivo blocked the effect of ghrelin. Conclusion: Ghrelin stimulates interdigestive motility through cholinergic neurons. Ghrelin also stimulates motility, in vitro, suggesting that ghrelin receptors are present in the intestinal neuromuscular tissue and mediate its effects via cholinergic mechanisms.

reactive for NOS or VIP, whereas colocalization with calbindin was not observed.In functional experiments, galanin 1-16, the GAL-R1 preferring fragment, inhibited in a concentrationdependent manner (300 nM -3 I~M) the ascending excitatory reflex recorded in the oral compartment in response to gut wall distension (evoked by balloon inflation in the caudal compartment).The inhibitory effect of galanin 1-16 (max.60%) was antagonized by 1 p.M RWJ-54708, a selective GAL-R1 antagonist.Galanin 1-16 was ineffective when added in the imermediate or the caudal compartment up to 3 p,M.Conclusions: ChAT immunoreactive neurons labeling inhibitory GAL-R1 are cholinergic motor neurons responsible for the ascending excitatory reflex.GAL-R1 does not appear to be present on ascending interneurons and intrinsic primary afferent neurons.