Motilin Release Research Articles

Relationship between interdigestive gallbladder emptying, plasma motilin and migrating motor complex in man

The aim of this study was to elucidate the importance of biliary output for the regulation of migrating motor complex and the release of plasma motilin. Gallbladder emptying was monitored by hepatobiliary scintigraphy, plasma motilin concentration by radioimmunoassay and gastrointestinal motility by a perfused catheter system. During a total recording time of 46 h and 20 min in 16 volunteers, we observed 29 episodes of gallbladder emptying, 27 plasma motilin peaks and 23 activity fronts (phase 3 activity) of the migrating motor complex (MMC). Twelve episodes of gallbladder emptying started in phase 1 and continued into phase 2 of the MMC. The remaining 17 episodes of gallbladder emptying started in phase 2, and three of these continued into phase 3 of the MMC. Biliary output was associated with a significant rise in plasma motilin concentration, whereas plasma motilin significantly decreased after the activity fronts. These observations may explain the well-known fluctuations of plasma motilin concentration in the fasted state. Motilin is released into the circulation as a result of biliary output, while the ensuing activity front of the MMC removes this stimulant from the proximal small bowel, resulting in a fall in plasma motilin. In conclusion, we have confirmed a temporal relationship between biliary output into the duodenum and the release of plasma motilin. The observed transition from phase 1 to phase 2 and from phase 2 to phase 3 of the MMC during gallbladder emptying episodes suggests that biliary output stimulates gastrointestinal motility in the fasted state.

Plasma Gastrointestinal Hormones during Spontaneous and Induced Menstrual Cycles*

Plasma levels of secretin, vasoactive intestinal polypeptide (VIP), somatostatin (SRIH), motilin, and/or pancreatic polypeptide, as well as serum estradiol, progesterone, PRL, LH, FSH, and/or GH were measured during the follicular phase, midcycle, and luteal phase of a spontaneous menstrual cycle in eight women and during ovarian stimulation with clomiphene citrate/human menopausal gonadotropin and hCG for in vitro fertilization in nine women. Plasma SRIH concentrations were significantly (P less than 0.02) higher in the luteal phase of spontaneous menstrual cycles than in follicular phase and midcycle. Serum GH levels, however, did not change. Plasma motilin concentrations also were higher in the luteal phase than at mid-cycle (P less than 0.04). Plasma secretin, VIP, and pancreatic polypeptide concentrations did not change during the cycle. Throughout the spontaneous menstrual cycle we found significant positive correlations between plasma SRIH and serum progesterone (P less than 0.007; r = 0.5869), plasma motilin and serum progesterone (P less than 0.02; r = 0.5331), plasma secretin and serum estradiol (P less than 0.04; r = 0.4711), and plasma secretin and serum PRL (P less than 0.02; r = 0.5507). During ovarian stimulation both plasma secretin and VIP gradually increased to a peak on cycle days 0 and 1, respectively (day 0 = the day of hCG injection), whereas plasma SRIH did not change. Serum estradiol and PRL increased significantly, and both peaked on cycle day 1. During ovarian stimulation plasma secretin correlated significantly with serum estradiol (P less than 0.00001; r = 0.9333), serum PRL (P less than 0.03; r = 0.6521), and plasma VIP (P less than 0.03; r = 0.6534). In addition, plasma VIP and serum PRL both correlated significantly with serum estradiol (P less than 0.05; r = 0.6024 and P less than 0.04; r = 0.6384, respectively). These results indicate 1) a possible effect of progesterone on the release of SRIH and motilin during the spontaneous menstrual cycle; 2) the unaltered serum GH concentrations in the luteal phase of the spontaneous menstrual cycle despite elevated plasma SRIH levels are probably due to a stimulatory effect of both progesterone and motilin on GH release; and 3) the increase in plasma secretin and VIP concentrations during ovarian stimulation is probably secondary to the concomitant increase in serum estradiol and/or PRL. We suggest that estradiol and/or PRL beyond a certain threshold level stimulate the release of secretin, and possibly also VIP, into plasma.

Dual effect of bombesin and gastrin releasing peptide on gastric emptying in conscious cats

The effect of bombesin (BBS) and gastrin releasing peptide (GRP) on gastric emptying was studied in conscious cats. This effect was measured simultaneously with antral motility. Acid and pepsin secretions as well as blood hormonal peptide release were additionally measured. A dual effect was observed. First, BBS and GRP slowed gastric emptying of liquids, while antral motility was decreased, then after 60 minutes of continuous intravenous infusion, antral motility returned to basal values and gastric emptying effect reversed. The mechanism of this peculiar action is independent of gastrin, pancreatic polypeptide, somatostatin and motilin release and most probably connected with a cholinergic stimulation induced by the peptides, the late predominance of which counterbalances the inhibitory effect of bombesin-like peptides on antral motility.

Role of the duodenum in the control of canine gastrointestinal motility

This study was designed to determine the role of the duodenum in controlling the interdigestive migrating motor complex of the canine stomach and small intestine. The motility patterns of 4 dogs were studied before and after resection of the entire duodenum with reimplantation of bile and pancreatic ducts. Before duodenectomy, plasma concentrations of motilin and pancreatic polypeptide varied cyclically with the migrating motor complex. After duodenectomy, the migrating motor complex was abolished in the stomach in 3 of the 4 dogs during fasting. The other dog demonstrated what appeared to be an intermittent cyclic increase in gastric contractile activity, but with markedly abnormal characteristics and at irregular intervals. The jejunal migrating motor complex continued to cycle after duodenectomy in all 4 dogs, but the mean period was shorter than before duodenectomy (83 min vs. 147 min, p < 0.01). Duodenectomy abolished the cyclic variations of plasma motilin and pancreatic polypeptide and lowered the concentration of both peptides during all phases. This study suggests that the duodenum plays an important role in the initiation of the gastric migrating motor complex and in the coordination of interdigestive gastrointestinal motor activity, possibly by the release of motilin.

An experimental study on the remnant gastric motilities and gastrointestinal hormones after various types of gastrectomies

Using adult mongrel dogs, remnant gastric motility in relation to the changes of gastrointestinal hormone (gastrin and motilin) levels were measured under conscious states before and after distal partial gastrectomy in the Billroth I (BI) or II (BII) reconstruction and proximal partial gastrectomy with or without pyloroplasty. Remnant gastric motility was studied during the digestive and interdigestive states by chronically implanted strain gage transducer (S.G.T.) along the gastrointestinal tract. Gastrointestinal hormone levels were determined by radioimmunoassay. Results were summarized as follows: 1. Remnant gastric motility after BI was different from BII, that is, digestive patterns after BII were more shorter than BI, as a result, gastric emptying times were shortened. 2. Gastrin release by the meal intake in the dogs with BI was greater than that in BII. On the other hand, motilin release in the dogs with BII was higher level than that in BI during the digestive and interdigestive states. Gastrointestinal hormone levels after BI were approximately as same responses as controls. These findings suggested that BI reconstruction for distal partial gastrectomy was more physiological surgical procedure than BII reconstruction. 3. Remnant gastric motility during the digestive state after proximal gastrectomy showed the excitatory pattern and gastric emptying time was remarkably shortened than in controls. 4. In gastrin and motilin levels stimulated by the meal in the dogs with proximal gastrectomy, the peak of gastrin and the depression of motilin were observed more early in relation to remnant gastric emptying time. These findings suggested that the pyloroplasty for the proximal gastrectomy was necessary to prevent an increased motility of the remnant stomach during the digestive states.

Interdigestive intestinal motility in dogs with chronic exclusion of bile from the digestive tract.

To elucidate the role of bile delivery into the duodenum on the regulation of plasma motilin and on the interdigestive migrating complex, three dogs were operated upon to ligate the main bile duct and divert the biliary flow into the urinary bladder via a Foley catheter. After the operation, despite the chronic diversion of bile from the digestive tract, all animals maintained an excellent health status and exhibited recurrent periods of phase III motor activity migrating from the duodenum to the ileum, which were associated with cyclic increases in plasma motilin. Following the infusion of pooled dog bile (1 mL/min for 10 min) into the duodenum, a premature phase III and a concomitant rise in plasma motilin were observed. These results suggest, that although bile delivery into the duodenum can induce motilin increase in plasma and period of phase III activity in the gut, this phenomenon does not constitute an essential stimulus for the release of motilin and for the induction of the phase III of the interdigestive migrating complex.

Increased plasma motilin concentrations in small cell carcinoma of the lung.

Plasma samples from 21 patients with small cell carcinoma of the lung were screened for pancreatic polypeptide, somatostatin, motilin, and vasoactive intestinal polypeptide. One patient had severe impairment of both renal and liver function. In the 20 remaining subjects vasoactive intestinal polypeptide concentrations were normal, and only two patients had increased concentrations of somatostatin. Increases in pancreatic polypeptide were detected more commonly (7/20), but these may have been non-specific age related increases. The major finding was high concentrations of motilin (greater than 496 pg/ml) in 17 of 20 patients. Plasma motilin was subsequently assayed in 16 more patients with lung cancer, including 10 patients with non-small cell carcinoma of the lung. At concentrations over 900 pg/ml plasma motilin appears to be a tumour marker for small cell carcinoma of the lung with acceptable sensitivity (59%) and specificity (78%). The origin of increased plasma motilin in small cell carcinoma of the lung was investigated. Bombesin (gastrin releasing peptide), a peptide known to stimulate the release of motilin in man, was, as in previous studies, detected in tumour but not in plasma, except in one patient out of 21. Immunohistochemical studies failed to detect motilin antigen in biopsy samples. Motilin tumour content was found to be low in tumour tissue from three patients with small cell carcinoma of the lung who had appreciable hypermotilinaemia and from three patients with non-small cell carcinoma of the lung who had either normal or slightly raised plasma motilin concentrations. The stimulus to motilin secretion in patients with small cell carcinoma of the lung remains unclear.

Effect of central administration of motilin on migrating complexes in the dog.

The effects of intravenous, intrathecal, and intracerebroventricular injection of motilin on the interdigestive myoelectric (MMC) activity of the stomach and small intestine were examined in conscious dogs. To monitor electrical activity, electrodes were implanted on the stomach and small bowel. To inject motilin into the central nervous system, catheters were chronically positioned in the intrathecal space at the lumbar level and in one of the lateral cerebral ventricles. In all dogs, intravenous injection of motilin caused a transient increase in the plasma concentration of motilin and initiated gastric MMCs, which propagated aborally to the ileum. Intrathecal and intracerebroventricular injections of motilin did not affect plasma motilin levels and did not induce MMCs. These data suggest that initiation of MMCs after intravenous injections of motilin occurs through receptors for motilin possibly located outside the central nervous system. These data also suggest the hypothesis that initiation of naturally occurring MMCs in the dog may not be dependent on endogenous release of motilin from the central nervous system.

Effect of insulin on motilin release in man.

The effect of insulin on motilin release was investigated by use of the euglycemic glucose clamp technique. By use of this technique plasma glucose concentration was maintained constant at 80-90 mg/100 ml, and plasma insulin immunoreactivity (IRI) was increased from 15 +/- 6 microU/ml to 171 +/- 22 microU/ml in 10 min, and remained at this level for 2 hr. Plasma motilin like immunoreactivity (MLI) concentration decreased within 10 min from 199 +/- 36 pg/ml to 120 +/- 28 pg/ml and remained low during the course of study. A significant negative correlation between MLI and IRI concentrations (r = -0.72, p less than 0.01) was observed. The present results indicate that the suppressive effect of insulin on motilin release is a direct action of insulin and is not mediated by glucose.

Gastro-oesophageal reflux and alcoholic cirrhosis: A reappraisal

The oesophageal pH was recorded for 3 h after a test-meal in 27 healthy control subjects (group I), 40 patients with alcoholic cirrhosis (group II), and 22 patients with a normal liver and symptoms of gastro-oesophageal reflux (control refluxers). Gastro-oesophageal reflux was observed in 10 of the cirrhotic patients. Marked reflux episodes lasted longer in cirrhotic refluxers than in control refluxers (P less than 0.05). The frequency of ascites, bleeding from ruptured oesophageal varices, peripheral neuropathy and hepatic encephalopathy were not significantly different according to presence or absence of reflux. Plasma concentrations of gastrin, somatostatin, motilin and vasoactive intestinal peptide (VIP) were measured in groups I and II. Fasting plasma motilin levels, and the release of motilin and of VIP after the meal were higher in group II than in group I. Basal levels and post-prandial profiles of the four peptides tested did not differ between cirrhotics with or without gastro-oesophageal reflux. We conclude that in patients with alcoholic cirrhosis: gastro-oesophageal reflux is frequent (25%) and characterized by prolonged reflux episodes; reflux is not correlated with the degree of liver failure and plays no significant role in the rupture of oesophageal varices; and raised plasma motilin and VIP levels cannot account for the high incidence of reflux in cirrhotics.

Effects of corticotropin-releasing factor on plasma motilin and somatostatin levels and gastrointestinal motility in dogs

The effects of intracerebroventricular and intravenous administration of corticotropin-releasing factor (CRF) on gastrointestinal motility, motilin-induced gastric motor response, and plasma motilin and somatostatin levels were investigated in fasted dogs chronically prepared with strain gauge transducers on the antrum and proximal jejunum. Administered intracerebroventricularly at doses of 20 and 100 ng/kg in fasted dogs, CRF suppressed for 4–5 h the gastric cyclic migrating motor complex. A similar dose (100 ng/kg) administered intravenously was inactive. Corticotropin-releasing factor administration by the intravenous route at 100 ng/kg did not alter the cyclic plasma motilin and somatostatin variations associated with the cyclic gastric motor events. During the blockade of antral migrating motor complex induced by intracerebroventricular administration of CRF, cyclic peaks of plasma motilin were absent whereas those of somatostatin persisted. The gastrointestinal migrating motor complex induced by the intravenous administration of porcine motilin (0.25 μg/kg) was abolished when motilin was injected 2 h after the intravenous administration of CRF (100 ng/kg), whereas a similar dose of CRF administered intracerebroventricularly did not abolish the antral and jejunal motor responses to motilin. It is concluded that in fasted dogs, CRF administered centrally affects the interdigestive gastric motility and the release of motilin but not that of somatostatin. These results also suggest that (a) the intracerebroventricular CRF-induced blockade of motilin release is responsible for the inhibition of gastric migrating motor complex and (b) circulating CRF is able to affect the gastric motor response to porcine motilin through a peripheral mechanism that does not involve somatostatin and motilin secretion.

Motilin in chronic idiopathic constipation.

The plasma motilin levels were studied in seven patients with severe long-standing idiopathic constipation before and after a fat-rich test meal. The results were compared with those of a control group consisting of 10 apparently healthy persons with normal bowel function. The constipated patients had reduced basal motilin levels and a reduced motilin release after the test meal. Motilin is known to stimulate intestinal motility by inducing interdigestive descending contractions in the stomach and small intestine. A defective motilin release may therefore play a part in the pathogenesis of idiopathic constipation.

Interdigestive gastroduodenal motility and serum motilin levels in patients with idiopathic delay in gastric emptying

The interdigestive gastroduodenal motor activity and serum motilin levels were studied in 22 dyspeptic patients with markedly delayed gastric emptying not due to diseases known to impair gastroduodenal motility and in 7 control subjects with normal gastric emptying. Motor activity was recorded using a manometric probe positioned in the gastric antrum and in the proximal duodenum, and blood samples for radioimmunoassay of motilin were taken every 15 min during the recording period. The control subjects showed gastroduodenal activity fronts of the migrating motor complex associated with motilin peaks. Almost all patients with delayed gastric emptying showed no activity fronts in the stomach, and only half of them showed activity fronts starting in the duodenum. In these patients a significant reduction in the number of motilin peaks and in the integrated motilin output during the identified peaks was also observed. The results of this study indicate that most dyspeptic patients with idiopathic delay in gastric emptying may also have an alteration in interdigestive gastroduodenal motility, mainly characterized by a lack of gastric activity fronts, associated with an impaired motilin release.

Variations in plasma motilin, somatostatin, and pancreatic polypeptide concentrations and the interdigestive myoelectric complex in dog.

We have looked at the plasma concentrations of motilin, pancreatic polypeptide (PP), and somatostatin (STS) during the various phases of the interdigestive motor complex (IDMC) in dogs. As expected, motilin cyclical increase was always associated with the phase III of the IDMC. Statistical analysis of PP variations revealed a significant rise 10 min before duodenal phase III; however, in individual animals, this relationship was inconsistent. Although a dose-related increase in PP blood levels was induced by administration of synthetic canine motilin (0-200 ng kg-1 iv), fasting plasma levels of PP were not correlated with the concentrations of circulating endogenous motilin. After truncal vagotomy, while motilin release and the intestinal motility pattern remained unaltered, the phase III associated cyclical increases of PP disappeared. Infusion of physiological amounts of PP (1 microgram kg-1 h-1 for 3 h) mimicking the postprandial release failed to reproduce a fed pattern type of intestinal motility and of motilin secretion. No statistical correlation could be established between STS plasma levels and the motor activity of the intestine. STS plasma levels were not correlated with circulating concentrations of motilin and the exogenous administration of physiological doses of synthetic canine motilin failed to modify STS plasma levels. Morphine (200 micrograms kg-1 iv) stimulated only the release of motilin. These data suggest that the role played by circulating concentrations of PP and STS in the control of the IDMC in dog is at most minimal.

Effect of vagal blockade on food- and hormone-stimulated release of pancreatic polypeptide and motilin in dogs.

Vagal control of food- and hormone-stimulated release of pancreatic polypeptide (PP) and motilin was investigated in four conscious dogs by examining the effect of cryogenic vagosympathetic blockade. The postprandial PP response of 189 +/- 7 pM was totally, although reversibly, inhibited to 58 +/- 11 pM with the vagi blocked. Similarly, bombesin-, CCK-OP-, or neurotensin-stimulated PP release was abolished. Although the PP response to intraduodenal perfusion of an elemental diet was also reduced by blockade, the 52 +/- 15% inhibition was less than observed with the meal. In contrast to PP, plasma motilin fell after the meal from a fasting level of 128 +/- 16 pM to a nadir of 52 +/- 7 pM. Vagal blockade reversed this decline as plasma motilin rose to a peak of 121 +/- 18 pM with a pattern resembling the motilin response in the interdigestive state. This motilin increment during blockade was inhibited by atropine and by infusion of porcine PP. Plasma motilin also fell with the elemental diet, but this response was not affected by blockade. During infusion of bombesin, plasma motilin rose by 60 +/- 9 pM; vagal blockade augmented this increment twofold. Thus, the PP response to a meal and to hormonal stimulation is controlled by a vagal cholinergic excitatory pathway. However, intestinal release of PP is mediated in part by the vagus and in part by a vagally independent mechanism which may be neural or hormonal. Alternatively, vagal noncholinergic inhibition is a major mechanism modulating the motilin response after oral food but motilin release exclusively from intestinal nutriments is mediated by nonvagal, noncholinergic mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive correlation between symptoms and circulating motilin, pancreatic polypeptide and gastrin concentrations in functional bowel disorders.

Motilin, pancreatic polypeptide and gastrin blood concentrations in response to drinking water have been studied in 40 patients with functional bowel disease and compared with results in two groups of healthy control subjects. Patients with slow transit constipation and idiopathic megacolon showed impaired motilin release. Pancreatic polypeptide release was reduced in patients with slow transit constipation, but increased in those with functional diarrhoea. Gastrin release was impaired in all groups complaining of chronic constipation. Circulating motilin, pancreatic polypeptide and gastrin concentrations appear to bear some relationship to intestinal transit time in patients with functional bowel disorders.

The failure of truncal vagotomy to affect motilin release in dogs

To elucidate the relationship between vagus nerve and motilin release, we have studied the influence of truncal vagotomy with pyloroplasty (TV) on motilin release in the fasting state and for 120 min following an intraduodenal administration of 10 g glucose in a 50-ml water solution or 5 g soybean oil. TV did not influence the intermittent fluctuation or concentration of plasma motilin in the fasting state. Intraduodenal glucose administration inhibited motilin release, but this was not affected by TV. Intraduodenal fat administration accelerated motilin release, but this effect also was not affected by TV. These results suggest that motilin secretion in the fasting state and after nutrient ingestion is not influenced by TV.

Structure-activity relation among macrolide antibiotics in initiation of interdigestive migrating contractions in the canine gastrointestinal tract.

The relation between the chemical structure of commercially available macrolide antibiotics and their activity in inducing interdigestive migrating contractions (IMC) was studied in conscious dogs. It was found that the 14-membered macrolides erythromycin and oleandomycin are active in inducing IMC in the stomach in association with the endogenous release of motilin. These erythromycin- and oleandomycin-induced contractions in the stomach migrated through the small intestine in a caudad direction. Conversely, 16-membered macrolide antibiotics such as leucomycin, acetylspiramycin, and tylosin do not induce any contractions in the stomach or stimulate endogenous release of motilin. These findings suggest that the IMC-inducing activity in macrolides seems to be closely related to their chemical configuration, i.e., the structure of 14-membered macrolides with dimethylaminosugar (desosamine) bound at C-5 and neutralsugar at C-3 in glycosidic linkage in parallel is likely to be necessary for IMC-inducing activity. The mechanisms by which erythromycin and oleandomycin stimulate endogenous motilin release are not known.

The effects of vagal nerve stimulation on endoluminal release of serotonin and substance P into the feline small intestine.

Endoluminal release of serotonin (5-HT), substance P (SP), and motilin was quantitated after thoracic vagal nerve stimulation in the cat. In duodenum and jejunum, simultaneous release of these compounds was observed. In contrast, vagal stimulation did not augment the rate of luminal secretion of either 5-HT or SP in the distal ileum. Immunohistochemical studies demonstrated 5-HT in both enterochromaffin (EC) cells and nerves throughout the small bowel. However, we were unable to visualize any SP-containing EC cells in the cat, which suggests that the source of luminal SP in this species must be intramural nerves.

Motilin and the vagus in dogs.

The aim of this work was to determine the influence of the vagus on the circulating levels of immunoreactive (IR) motilin. Five mongrel dogs were equipped with chronically implanted electrodes in the small intestine to record the myoelectrical activity. The release of IR motilin during fasting, after a meal, and during an infusion of insulin was studied before and after truncal vagotomy at the diaphragmatic level. When tested at least two weeks after the operation, the motility pattern of the small intestine and the secretion of IR motilin remained unaltered by vagal section. Cyclic increases in IR motilin associated with phase III's of the interdigestive myoelectric complexes were still observed after vagotomy (maximum levels of IR motilin: 250 +/- 37 versus 239 +/- 19 fmol X mL-1, not significant), and they were still abolished by feeding or by insulin. However, an inhibitory influence can probably be mediated by the vagus since, in normal animals, vagal stimulation by a "modified sham feeding" (tease feeding or presentation of food) at the beginning of a period of phase III activity promptly interrupted this part of the complex and decreased significantly the release of IR motilin by about 20%. The release of motilin is not chronically altered by distal vagotomy in dogs.