T Peeters

Motilin and the interdigestive migrating motor complex in man.

In order to assess the possible role of the new candidate gut hormone, motilin, in cantrolling the interdigestive migrating motor complex (MMC) in man, 14 normal subjects were studied after an overnight fast by means of three pressure-recording catheters with orifices 25 cm apart in the upper small intestine. The typical aboral progressing bursts of pressure waves occurred at a mean interval of 137 minutes and were preceded by a peak motilin level 25 pmol/liter higher than the lowest level in the postactivity-front quiescent period. To study the effect of exogenous motilin, an infusion of pure porcine motilin at various dose levels was given to 16 normal volunteers shortly after the onset of the phase I quiescent period. Motilin infusion induced an activity front in 12 of the 16 subjects. The mean activity front interval was reduced to 46 min (P<0.001). This effect could be obtained tained even at the low dose level of 0.4 pmol/kg/min, which produced an increase in plasma motilin level of only 57 pmol/liter. These data suggest that a cyclic rise in plasma motilin levels is one of the factors involved in the production of the activity front of the migrating motor complex in man.

Influence of ghrelin on interdigestive gastrointestinal motility in humans

Background: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. Materials and methods: Nine healthy volunteers (four males; aged 22–35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 μg was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15–30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and χ2 testing. Results: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. Conclusions: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach.

The Secretory Component of the Interdigestive Migrating Motor Complex in Man

Intraduodenal pH, bicarbonate and amylase secretion, and gastric acid and pepsin output were studied in relation to the migrating motor complex in man. The occurrence of a motor complex in the duodenum was preceded by an increase in gastric acid and pepsin output and followed by a peak in bicarbonate and amylase secretion. It is concluded that the interdigestive phase in man is characterized by periodic activity complexes comprising both motor and secretory components. These observations may have important implications for the interpretation of currently used functional tests of gastrointestinal secretion.

Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

Background and aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. Methods: In vivo, the dose dependent effects (1–150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (l-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 µM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. Results: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. Conclusion: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.

Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice

Abstract  Ghrelin is an orexigenic peptide with prokinetic effects in the rat. We investigated the effect of ghrelin and growth hormone‐releasing hormone 6 (GHRP‐6) on gastric emptying and transit in control and septic mice. Mice were injected i.p. with lipopolysaccharides (LPS) or saline (control). After 16–17 h mice were pretreated with saline, ghrelin or GHRP‐6 1 h before intragastric administration of Evans blue. Fifteen minutes later, after assessment of the behaviour scale, mice were killed and gastric emptying, transit and rectal temperature were measured. In control mice, ghrelin (100 μg kg−1) and GHRP‐6 (20–100 μg kg−1) accelerated gastric emptying, whereas ghrelin and GHRP‐6 failed to increase transit significantly. Septic mice developed a delay in gastric emptying and transit, hypothermia and a deterioration of the behaviour scale. In septic mice, ghrelin (20 μg kg−1) accelerated gastric emptying without effect on transit while GHRP‐6 significantly accelerated gastric emptying dose‐dependently and failed to increase transit significantly. Ghrelin and GHRP‐6 had no effect on the endotoxin‐induced hypothermia or deterioration of behaviour scale. Therefore, the beneficial prokinetic effect of ghrelin but mainly of GHRP‐6 offers potential therapeutic options in the treatment of septic gastric ileus.

The activity front of the migrating motor complex of the human stomach but not of the small intestine is motilin-dependent

Abstract The role of motilin in the generation of the gastric component of phase 3 of the migrating myoelectric complex (MMC) was studied in human volunteers. Interdigestive motor activity was recorded manometrically in five normal subjects after a fast of at least 15 h. Intraluminal pressures were measured in the gastric antrum at 4 levels 3 cm apart and in the upper small bowel at 3 levels 25 cm apart. Blood samples were drawn every 10 min for radioimmunoassay of motilin and PP. After 2 spontaneously occurring activity fronts (AF) had been recorded, bovine PP was infused intravenously at a rate of 50 μg/h. Following the third AF a combination of PP (50 μg/h) and 13-norleucine-motilin (30 μg/h) was infused until after the next AF. It was found that 90% of the spontaneous AFs originated in the stomach. They were preceded by a motilin peak. During the PP infusion, plasma PP levels increased from 29 to 256 pmol/l, motilin decreased from 42 to 15 pmol/l, and all AFs originated in the small bowel. During the combined PP and motilin infusion, plasma motilin increased to 330 pmol/l, and all AFs again originated in the stomach. It is concluded that motilin has an important role in the regulation of the MMC activity front in the stomach, but not in the small intestine. Postprandial rises in plasma PP might be involved in lowering motilin levels after a meal, and indirectly, in the disruption of gastric MMCs during digestion.

In Man, Only Activity Fronts That Originate in the Stomach Correlate with Motilin Peaks

We have tested the hypothesis that the imperfect correlation between the occurrence of plasma motilin peaks and the migrating motor complex (MMC) is related to the site of origin of the MMC. Gastric and small-intestinal motor activity was recorded manometrically in 16 normal subjects after an overnight fast. Blood samples were taken every 10 min and assayed for motilin. Fifty MMCs were recorded: 29 (58%) originated in the antrum and 21 (42%) in the small intestine. For gastric MMCs a motilin peak (45 +/- 5 pM) was found 10 min before the occurrence of the MMC in the duodenum. For intestinal MMCs no peak could be demonstrated. On an individual basis 27 of the 29 gastric activity fronts were associated with a motilin peak, versus 5 out of 21 intestinal MMCs. It is concluded that in man only gastric activity fronts are associated with plasma motilin peaks. Apparently, motilin is only involved in the regulation of the MMCs originating from the stomach.

Stress-Induced Changes in Gastric Emptying, Postprandial Motility, and Plasma Gut Hormone Levels in Dogs

The influence of acoustic stress on postprandial gastrointestinal motility, gastric emptying, and plasma gastrin, pancreatic polypeptide, motilin, and somatostatin was evaluated in conscious dogs. Six dogs were equipped with strain-gauge transducers and were exposed from 1-3 h after the meal to prerecorded music (80-90 dB broad frequency noise), which produced a significant (p less than or equal to 0.05) lengthening of the gastric (31.2%) and jejunal (37.0%) postprandial pattern. In 4 other dogs with gastric cannula, a 2-h session of acoustic stress beginning just after eating a radiolabeled standard meal induced a slowing of gastric emptying of both liquid (45.7%) and solid (47.1%) phases of the test meal when measured 0.5 h after feeding. In contrast, when measured 2 h after feeding, similar values of gastric emptying of liquids and solids were observed in stressed and control animals. Compared with controls, the postprandial increases of plasma gastrin and pancreatic polypeptide levels were significantly enhanced in stressed animals and occurred early (15 min after the meal). Although postprandial decrease in plasma motilin was unchanged by acoustic stress, the rise in plasma somatostatin level was significantly (p less than or equal to 0.05) prolonged in stressed dogs. These results indicate that acoustic stress affects gastric and intestinal postprandial motility in dogs, delaying the recovery of the migrating motor complex pattern, inducing a transient slowing of gastric emptying, and enhancing the feeding-induced release of gastrin, pancreatic polypeptide, and somatostatin. Such hormonal changes might be due to a direct effect of stress rather than being the consequence of acoustic stress-induced slowing of gastric emptying.

Effect of different prokinetic agents and a novel enterokinetic agent on postoperative ileus in rats

BACKGROUND/AIM The effects of different prokinetic agents, the motilide erythromycin and the substituted benzamides metoclopramide and cisapride, were investigated in a rat model of postoperative ileus. These effects were compared with that of granisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist, and a novel enterokinetic agent, prucalopride, a 5-HT4 receptor agonist. METHODS Different degrees of inhibition of gastrointestinal transit, measured by the migration of Evans blue, were achieved by skin incision, laparotomy, or laparotomy plus mechanical stimulation of the gut. RESULTS Metoclopramide decreased the transit after laparotomy with or without mechanical stimulation, whereas cisapride increased it after all three operations. Granisetron had no effect on the transit after the three operations when given alone. Prucalopride tended to increase the transit after laparotomy with or without mechanical stimulation when given alone. However, statistical significance was only reached when prucalopride was combined with granisetron. Erythromycin, a motilin receptor agonist, did not improve postoperative ileus in the rat. CONCLUSIONS Cisapride, but not metoclopramide or erythromycin, is able to improve postoperative ileus in the rat. The results suggest that a combination of 5-HT3 receptor antagonist and 5-HT4 receptor agonist properties may be required to obtain a beneficial effect on surgery induced ileus in the rat. Furthermore, they indirectly indicate that stimulation of the excitatory mechanisms is not able to overcome the inhibitory influence of the neural reflex pathways activated during abdominal surgery.

Motilin induces gall bladder emptying and antral contractions in the fasted state in humans

Background—Animal studies have shown that motilin affects gall bladder motility. In humans, no effect has been shown, but erythromycin, a motilin receptor agonist, induces gall bladder emptying. Aims—To explore the effect of increasing doses of exogenous motilin on gall bladder volume and antral contractility in the fasted state in humans. Methods—After an overnight fast, eight healthy men received increasing intravenous doses of Leu13-motilin (KW-5139) or 0.9% NaCl in a double blind, randomised fashion. Gall bladder volume and antral contraction frequency were determined by ultrasonography. Results—Infusion of motilin increased plasma motilin levels. Motilin induced a reduction in gall bladder volume of 8.0 (5.0)%, 17.1 (5.0)%, 18.5 (4.7)%, and 16.1 (4.9)% of baseline volume at the end of infusion of 2, 4, ,8 and 16 pmol/kg/min respectively, compared with mean stable gall bladder volumes during placebo infusion (p<0.05). Antral contraction frequency increased during motilin infusion, but not during placebo infusion (p<0.05). Conclusions—Exogenous motilin reducted fasting gall bladder volume and increased antral contractions. After reaching maximal reduction, the gall bladder volume did not decrease further during continuous motilin infusion at higher doses and stayed at the same reduced volume. The degree of gall bladder volume reduction during motilin infusion mimicked gall bladder emptying preceding antral phase III activity of the migrating motor complex in humans. This study indicates that motilin may play a physiological role in the regulation of gall bladder emptying in the fasted state.