Interdigestive Migrating Contractions Research Articles

Thyroid hormone activated upper gastrointestinal motility without mediating gastrointestinal hormones in conscious dogs

This study was conducted to clarify the relationship between thyroid function and gastrointestinal motility. We established an experimental configuration in which the feedback of thyroid function was completely removed using conscious dogs. With hypothyroidism, time of phase I of interdigestive migrating contractions (IMC) was longer, time of phase II and phase III was significantly shortened, and both the continuous time of strong tetanic contraction at antrum and 10-h frequency of phase III counted from the first IMC after meal significantly decreased. Whereas, hyperthyroidism caused the opposite events to those with hypothyroidism. Furthermore, We found giant migrating contractions (GMC) occurred from the upper gastrointestinal tract when we administrated high dose of thyroid hormone. One GMC occurred from anal sides propagated to cardiac, and this propagation was similar to the emesis-like interdigestive motor activity, the other GMC occurred from oral sides propagated to anal sides and this was similar to the diarrhea-like interdigestive motor activity. We examined the relationship between thyroid function and gastrointestinal hormones including of ghrelin, GLP-1, and cholecystokinin (CCK). However, we could not find significant differences under different thyroid hormone status. This is the first report that thyroid hormone activated upper gastrointestinal motility without mediating gastrointestinal hormones.

Interdigestive migrating contractions are coregulated by ghrelin and motilin in conscious dogs

During fasting, gastrointestinal (GI) motility is characterized by cyclical motor contractions. These contractions have been referred to as interdigestive migrating contractions (IMCs). In dogs and humans, IMCs are known to be regulated by motilin. However, in rats and mice, IMCs are regulated by ghrelin. It is not clear how these peptides influence each other in vivo. The aim of the present study was to investigate the relationship between ghrelin and motilin in conscious dogs. Twenty healthy beagles were used in this study. Force transducers were implanted in the stomach, duodenum, and jejunum to monitor GI motility. Subsequent GI motility was recorded and quantified by calculating the motility index. In examination 1, blood samples were collected in the interdigestive state, and levels of plasma ghrelin and motilin were measured. Plasma motilin peaks were observed during every gastric phase III, and plasma ghrelin peaks occurred in nearly every early phase I. Plasma motilin and ghrelin levels increased and decreased cyclically with the interdigestive states. In examination 2, saline or canine ghrelin was administered intravenously during phase II and phase III. After injection of ghrelin, plasma motilin levels were measured. Ghrelin injection during phases II and III inhibited phase III contractions and decreased plasma motilin levels. In examination 3, ghrelin was infused in the presence of the growth hormone secretagogue receptors antagonist [D-Lys3]-GHRP-6. Continuous ghrelin infusion suppressed motilin release, an effect abrogated by the infusion of [D-Lys3]-GHRP-6. Examination 4 was performed to evaluate the plasma ghrelin response to motilin administration. Motilin infusion immediately decreased ghrelin levels. In this study, we demonstrated that motilin and ghrelin cooperatively control the function of gastric IMCs in conscious dogs. Our findings suggest that ghrelin regulates the function and release of motilin and that motilin may also regulate ghrelin.

Nonsteroidal anti‐inflammatory drugs induce hypermotilinemia and disturbance of interdigestive migrating contractions in instrumented dogs

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastric ulcers due to inhibition of prostaglandin production. Prostaglandins have an influence on physiological gastrointestinal motility, but the relationships between NSAID-induced gastric ulcer, gastrointestinal motility and motilin are unknown. Fifteen dogs were allocated randomly to three groups in which either gelatin, meloxicam or indomethacin was administered. Fecal occult blood and gastrointestinal motility were monitored continuously for 6 days. In addition, analyses of the plasma motilin concentration, gastrointestinal endoscopy and gastric emptying, and detection of motilin cells were performed. Gastrointestinal motility was disturbed in the indomethacin group, presenting as disappearance of interdigestive migrating contractions (IMCs) 3 days before gastric ulcers were detected. Delayed gastric emptying and hypermotilinemia were observed significantly more often in the indomethacin group compared with the other groups. Motilin cell-crypt/villi ratio in the indomethacin group significantly decreased in the duodenum and jejunum, compared with the other groups. No significant changes in any tests were observed in the meloxicam group, when compared with the gelatin group. These findings suggest that the disturbance of IMCs caused by hypermotilinemia, with changes in motilin cell distribution, and delayed gastric emptying induced by indomethacin may contribute to the development of gastric ulcers.

POSTOPERATIVE GASTROPYLORODUODENAL MOTILITY AND GASTRIC EMPTYING AFTER PYLORUS-PRESERVING GASTRECTOMY IN DOGS

Pylorus preserving gastrectomy (PPG) has been thought as a beneficial reconstruction procedure to reduce the incidence of postgastrectomy syndrome, and then, to ameliorate quality of life of the gastrectomized patients.In the early postoperative period after PPG, however, dyspeptic symptoms such as bloating or early satiety were commonly observed. This may be caused by altered motility after PPG. To investigate this problem, we studied fasted and fed motility in control (η=4) and PPG dogs (η=4) by using strain gauge transducer method in conscious state. Gastric emptying of the liquid meal was also assessed by paracetamol method.In fasted state, the contractions were rarely seen, and interdigestive migrating contractions (IMCs) had not appeared in the gastroduodenum at early postoperative period. In contrast, the incidence of pyloric contractions had greatly increased. These motility changes had seen in both group of dogs, however, was more evident in PPG dogs. IMCs began to appear in the gastroduodenum at one week in control dogs and at two weeks in PPG dogs, respectively. Although the IMCs appeared in PPG dogs were rather atypical. During IMCs, when the antrum was contracted, the pylorus was synchronously relaxed in control dogs, though the pylorus was not relaxed with the contraction of the remnant stomach in PPG dogs.In fed state, there was no remarkable motility change between control and PPG dogs. Gastric emptying of the liquid meal was delayed in PPG dogs both in fasted and fed state. These motility changes in PPG dogs may, in part, explain the occurrence of dyspeptic symptoms in the PPG patients at early postoperative period.

ROUX-EN Y RECONSTRUCTED INTESTINAL MOTILITY AND GUT HORMONE SECRETION AFTER TOTAL GASTRECTOMY, AN EXPERIMENTAL STUDY

Motility of the reconstructed intestine and the secretion profile of gut hormones (gastrin and motilin) were experimentally examined in dogs receiving total gastrectomy with Rouxen Y reconstruction in the postprandial and fasting periods. The following results were obtained.(1) After total gastrectomy, motor activities of the reconstructed intestine increased immediately after feeding. A new interdigestive migrating contractions (IMC) appeared in the fasting periods in the ascending portion of the reconstructed jejunum. Abnormal migrations of IMC were frequently seen early after operation.(2) In the interdigestive pattern of the blind-loop duodenum, a reduction in phase I and III and, a prolongation in phase II and in the cycle of phase III appearance were observed compared with the control dog.(3) Motilin secretion has not decreased after feeding and, in the fasting periods, increased to coincide with IMC of the blind-loop duodenum. The newly appearing IMC of the ascending jejunum, however, were not accompanied by an increase in motilin secretion. In contrast, gastrin secretion was low with little fluctuation both in the postprandial and fasting periods.Based on these findings, it is considered that the motor disorders of the reconstructed intestine, the blind-loop duodenum and changes in gut hormone secretion are, at least partially, the causes of postoperative complaints after total gastrectomy.

Involvement of cholinergic motor neurons in pharmacological regulation of gastrointestinal motility by glucagon in conscious dogs.

To clarify the exact mechanisms of the pharmacological effects of glucagon on gastrointestinal motility, the following experiments were performed on the conscious and anesthetized dogs. 1) During phase I of interdigestive migrating contractions (IMC), glucagon (5 approximately 50 microg/kg, drip infusion for 5 minutes) induced phasic contractions in the duodenum, jejunum and ileum, but not in the antrum. These excitatory responses were also observed in the truncal vagotomized dogs. These contractions were abolished by atropine or hexamethonium in the conscious dogs, and also by tetrodotoxin in the anesthetized dogs. 2) Glucagon inhibited cisapride-induced contractions only in the antrum in the conscious dogs. After pre treatment with hexamethonium, glucagon inhibited these contractions in the duodenum, jejunum and ileum as well as in the antrum. After pre treatment with tetrodotoxin in the anesthetized dogs, glucagon did not affect acetylcholine induced contractions in any region. 3) Glucagon inhibited spontaneous phase III contractions and erythromycin induced phase III like contractions in the antrum, but did not inhibit either contractions in the other regions in the conscious dogs. These paradoxical effects of glucagon between the antrum and intestine were similar to those involved in the blockade of 5-hydroxytryptamine 3 receptors. After pre-treatment with hexamethonium, glucagon inhibited these contractions in the duodenum, jejunum and ileum as well as in the antrum. 1) Glucagon latently inhibits cholinergic motor activities in the antrum and intestine not directly, by binding to either receptor on the smooth muscle cells, but through postganglionic cholinergic neurons and possibly through 5-hydroxytryptamine neurons. 2) On the other hand, in the intestine the reverse effects through preganglionic cholinergic neurons involving nicotinic and muscarinic receptors are more potent. 3) As a result, glucagon inhibits antral contractions and does not affect intestinal contractions in a conscious state.

Effect of gastrectomy on gallbladder motility: an experimental study

Gallstone formation is frequently seen following gastric surgery. Since dysmotility and bile stasis of the gallbladder is considered as an important factor in the pathogenesis of gallstone formation, altered gallbladder motility due to gastric surgery may have a role in the development of post-gastrectomy gallstone formation. To test this hypothesis, the effect of distal partial gastrectomy on gallbladder motility were studied. Gastroduodenal and gallbladder contractions were recorded by chronically implanted strain gauge transducers under conscious state. Gallbladder volume changes were monitored using chronically indwelling gallbladder catheter. Fasted and fed motility were studied in control (n = 5) and gastrectomized (n = 3) dogs. Plasma concentration of putative hormone CCK was measured. Effect of CCK-OP and motilin on gallbladder emptying were also studied. In fasted state, gallbladder volume was periodically decreased synchronous with phase 3 of interdigestive migrating contractions (IMC) in the gastroduodenum in both group of dogs. The correlation between gastric and gallbladder contractions was preserved even following distal partial gastrectomy, though the frequency of phasic contractions during phase 3 of IMC was decreased in the gastrectomized dogs. Postprandial gallbladder emptying tend to decreased in the gastrectomized dogs, while there were no difference in the postprandial plasma CCK concentrations and CCK-OP induced gallbladder emptying between groups. Digestive period was shortened in the gastrectomized dogs, which resulted in early gallbladder refilling and prolonged interdigestive period. Decreased frequency of gallbladder phasic contractions during IMC and prolonged interdigestive period could cause bile stasis in the gallbladder, which may, in part, explain post-gastrectomy gallbladder formation.

CHANGES IN GASTRIC ACID SECRETORY ACTIVITY DURING THE INTERDIGESTIVE STATE IN THE DOG

The relationship between acid secretion, interdigestive migrating contractions (IMC) in the stomach, and gastrointestinal hormones in the dog was investigated. Heidenhain pouches and Pavlov pouches were perfused with saline (1.3 ml/min) and pH changes in the perfusate were recorded continuously by means of an indwelling pH sensor. Force transducers were used to detect contractions. The pH value started to increase 3.2min after a bolus injection of cimetidine, and decreased 3.1min after the administration of betazole hydrochloride. Seventy percent of all registered IMC cycles obtained from Pavlov pouch dogs showed a decrease in pH values from 4.2±0.1 to 1.7±0.1 (mean±S.E.) corresponding to phase II contractile activity. The other 30% of the cycles did not demonstrate any changes in pH value. Acid outputs during 10min, including the minimum pH value, were 29.9±4.6% of those observed 30-40min after feeding. The decrease in pH values during phase II was also recognized in Heidenhain pouch dogs. The serum gastrin concentration during the pH-decreasing phase (40.8±4.5pg/ml) was significantly higher (p<0.05) than that in the pH-increasing phase (23.0±3.4), and significantly lower (p<0.01) than that (141 8±10.6) obtained at 30min after feeding. The serum concentration of motilin during the pH-decreasing period (265.3±49.3pg/ml) was significantly lower (p<0. 05) than that during the increasing phase (430.8±34.3). Administration of exogenous motilin induced phase III-like contractile activity and significantly elevated the pH value from 3.9±0. 1 to 4.6 ± 0.3. Cimetidine increased pH values significantly from 4.0 ± 0.3 to 5.5 ± 0.1 (p<0. 01), and the duration of an IMC cycle (101.8±4.5min) was not significantly different from that of the control (103.5±6.5). These data indicate that a simple device used in these experiments detects changes in acid secretory activity in the canine gastric pouch within 3 min. Acid secretion during fasting is activated in association with phase II contractile activity in 70% of IMC cycles in the stomach. Gastrin and motilin are likely to be involved in controlling the activity. The H2 receptor blocker (cimetidine) suppresses acid secretion during phase II, but does not affect the IMC cycle.

Anti-cholinesterase activity of dopamine D2 receptor antagonist: its clinical significance

Anti-cholinesterase activity of dopamine D2 receptor antagonist, domperidone was studied by means of chronically implanted force transducers in the gastrointestinal (GI) tract in five conscious dogs. Cisapride was used as a drug to stimulate endogenous release of acetylcholine. In the digestive state, cisapride (0.25 mg/kg) stimulated 18.6 +/- 5.6% increase in the motor index of the gastric antrum alone, however, combined administration with domperidone (1.0 mg/kg-hr) significantly enhanced the motor index in the gastric antrum and duodenum. In the gastric antrum, the increase was 68.1 +/- 7.2%. During the interdigestive state, cisapride did not always induce the interdigestive migrating contractions (IMC)-like contractions in the GI tract, but the background infusion of domperidone significantly increased the incidence of the occurrence of IMC-like contractions by cisapride. In in vitro study, weak but significant anti-cholinesterase activity was found in domperidone, the activity being about 1/1,000 of that of neostigmine. In dog experiment, similar enhancement of motor stimulating activity of cisapride was observed when neostigmine was given at 1.0 micrograms/kg-hr. In conclusion, domperidone has anti-cholinesterase activity and acts to enhance motor stimulating activity of cisapride through inhibition of cholinesterase activity in the upper digestive tract.

Effect of cisapride on the cholinergic control mechanisms of gastrointestinal motility in dogs.

The action of cisapride on physiological and disturbed gastrointestinal motor function was investigated in conscious and anesthetized dogs and the mechanism of action involved. Regardless of the presence or absence of vagal innervation, administration of cisapride (0.2 mg approximately 1.0 mg/kg body weight, i.v.) during the quiescent period of interdigestive migrating contractions (IMC), induced non-migrating IMC-like motility in the entire gastrointestinal tract from gastric body to distal colon. Administration of cisapride in the digestive state resulted in the excitatory response of increased amplitude of digestive peristalsis and strong IMC-like motility was not observed. All of these excitatory responses in gastrointestinal motility disappeared by the administration of atropine (0.5 mg approximately 0.1 mg/kg body weight, i.v.). Furthermore, the excitatory response in gastrointestinal motility induced by cisapride in anesthetized dogs disappeared by the administration of TTX (10 micrograms/kg of body weight, i.v.). These results suggest that the excitatory action of cisapride on the gastrointestinal motility is based on its mechanism in which cisapride acts on the cholinergic neurones in the gastrointestinal wall to stimulate ACh release, resulting in the increase in gastrointestinal motility. Cisapride caused powerful IMC-like motility in the ileum of animal with pseudo-obstruction-like motor disturbance which had been seen after preparation of Thiry loop (ileum). This motility migrated from the proximal ileum to the Thiry loop and then to the distal ileum. Trimebutine maleate also demonstrated this effect, but metoclopramide and domperidone were ineffective. Administration of cisapride at the doses (0.2 mg approximately 1.0 mg/kg body weight, i.v.) causing stimulated motor response in the gastrointestinal tract did not induce significant secretion of gastric acid, pancreatic juice and bile.

Effect of proglumide on gastrointestinal motility and gastric secretion in the conscious state.

Proglumide suppressed neither phase III activity nor propagation of interdigestive migrating contractions (IMC) in the gastrointestinal tract. Furthermore, proglumide did not inhibit the gastric motor activity stimulated by pentagastrin, however, it suppressed the pH in Pavlov pouch stimulated by pentagastrin in the interdigestive state. On the contrary, in the digestive state, proglumide did not suppress the pH. That might be due to not only various gut hormones including gastrin, but also neural stimulation, mechanical stimulation and so on. In conclusion, antigastrin effect of proglumide is rather remarkable on the acid secretion not on the gastrointestinal motor activity. Proglumide may be an antacid without suppression of motor activity.

Does motilin control interdigestive pepsin secretion in the dog?

Pepsin output in the Heidenhain pouch, plasma motilin concentration, and contractile activity in the pouch and the main stomach were investigated in five dogs. During the interdigestive state, the pepsin output was significantly increased with a cyclic increase in contractile activity in both the pouch and main stomach at approximately 100-min intervals. The plasma immunoreactive motilin (IRM) concentration fluctuated during the interdigestive state, and, peaks of IRM concentration coincided with the maximum pepsin secretory activity. Exogenous administration of motilin (0.5 μg/kg-hr) increased contractile activity in the main stomach and pouch quite similar to the natural interdigestive migrating contractions (IMC), and increased pepsin output significantly. Atropine pre-treatment suppressed the naturally-occuring and motilin-induced pepsin output and contractions in the pouch. It is concluded that pepsin output and contractions in the Heidenhain pouch increase in close association with the IMC in the main stomach during the interdigestive state and these cyclic motor and secretory events in the vagally denervated fundic pouch are most likely regulated by motilin through the intramural cholinergic pathway.

Neural regulation of interdigestive motor activity in canine jejunum

The hypothesis that extrinsic innervation of the small bowel provides pathways for initiation and coordinated propagation of the interdigestive migrating contractions (IMC) was reinvestigated in dogs. Motor activity was measured by chronically implanted force transducers. After a control study, 40-cm segments of the jejunum were extrinsically denervated. All IMC migrated distally through the extrinsically denervated segments. Thiry loops were then constructed from the extrinsically denervated segments, and continuity of the intestine was restored by end-to-end anastomosis. IMC proximal to the anastomosis did not migrate through the extrinsically denervated loop but migrated to sites across the anastomosis. In the extrinsically denervated loop, bands of strong contractions, quite similar to the IMC, occurred at the orad end of the loop independent of the IMC and propagated distally to the caudad end of the loop. The duration, frequency, and migrating velocity of these bands of contraction were different from those of IMC. These results suggest that extrinsic innervation is not essential for the initiation and orad sequential propagation of periodic motor activity like IMC, even when intrinsic innervation is discontinued.

Periodic contractions of the canine gallbladder during the interdigestive state

Interdigestive contractile activity of the gallbladder, the stomach, and the duodenum was measured by means of chronically implanted force transducers in five conscious dogs. During the interdigestive state, contractions of the gallbladder were identified to be closely associated with the initial period of phase II of the interdigestive migrating contractions (IMC) in the duodenum. The mean contractile force of the gallbladder during this phase was 6.5 +/- 0.77 g, which corresponded to approximately 80% of the force of the postprandial contractions. When the duodenum exhibited phase II contractions, the gallbladder had already returned to the resting level. Intravenous infusion of synthetic motilin induced IMC in the stomach and duodenum and during the initial period of motor response of the duodenum reproduced contractions in the gallbladder that were identical to the natural contractions as to their period and pattern. We cannot yet ascribe the interdigestive contractions observed in the gallbladder to the direct action of motilin, but the present study clearly indicates that the gallbladder contracts even in the interdigestive state, and the contractions are associated with the phase II contractions in the duodenum.

Neurohormonal control of gastrointestinal motor activity in conscious dogs

Interdigestive migrating contractions (IMC) were analyzed for their occurrence interval, duration, migrating velocity, and frequency in long term records obtained by means of chronically implanted force transducers in the main stomach and the extrinsically denervated fundic pouches or in the intact jejunum and the extrinsically denervated Thiry loop in 10 conscious dogs. Plasma immunoreactive motilin (IRM) was measured simultaneously. It was found that concomitant occurrence of IMC in the main stomach and pouch was closely associated with increase in plasma IRM concentration. On the other hand, in the extrinsically denervated jejunal loop, IMC-like contractions occurred independently of and more frequently than those in the intact jejunum and did not correlate with an increase in IRM concentration. It is concluded that gastric motor activity is under humoral control but in the jejunum, autoregulation by the intrinsic nerve plexus is more predominant than humoral factor(s).

Interdigestive migrating contraction in short bowel dogs.

Extraluminal force transducers were chronically implanted onto the serosal surface of the gastrointestinal tract in dogs and the interdigestive migrating contractions (IMC) were studied in conscious dogs. When the IMC occurring periodically in the stomach reaches the distal ileum, the next IMC develops in the stomach. We therefore studied the effect of isolation or resection of the lower third of the small bowel on the periodic occurrence of IMC in the stomach. Transducers were sutured onto the antrum, the upper jejunum, the mid intestine and the terminal ileum. After control records on gastrointestinal motility were made for these dogs, the abdominal cavity was again opened to prepare a Thiry loop in the lower third of the small bowel. (isolation group) Next, the loop was removed (resection group) and gastrointestinal motility was recorded. In these groups, we 1) measured the time from the feeding to the initiation of the first IMC. 2) measured the time from the termination of one IMC to the termination of the next IMC. 3) measured the migrating time of the IMC. 4) and measured the duration of the IMC in the stomach. As a result, it was found that the time interval between the termination of one IMC in the stomach and the termination of the next was almost constant throughout all experiments. The migrating time of the IMC from the stomach to the terminal ileum in isolation and resection groups was slightly shortened. These findings indicate that the existence of the lower gut has no significant influence upon the regular periodic occurrence of the IMC in the stomach and the migrating time.