Evaluation of changes in gastrointestinal motility caused by altered thyroid function 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-hours 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.

The Roles of Motilin and Ghrelin in Gastrointestinal Motility

In structure, ghrelin resembles motilin. The two peptides are considered to be members of the motilin-ghrelin peptide family. Motilin is considered to be an endocrine regulator of the interdigestive migrating contractions, the fasted motor pattern in the gastrointestinal (GI) tract. It has been reported that ghrelin stimulates GI motility. The gastrokinetic capacity of ghrelin has been well documented in the rodent. However, there have been few positive reports of the gastrokinetic capacity of ghrelin in dogs. Some reports with human subjects have shown that an i.v. ghrelin injection accelerated gastric emptying of a meal and improved meal-related symptoms. These results suggest that ghrelin has potential as a prokinetic. However, it seems unlikely that plasma ghrelin would play a physiological role in these digestive physiological events and stimulate gastric emptying, as these outcomes would appear to be in contradiction with the suppression of the endogenous release of ghrelin after eating. The physiological roles of ghrelin need to be clarified.

Motilin controls cyclic release of insulin through vagal cholinergic muscarinic pathways in fasted dogs

The effect of motilin on insulin release has not been studied in the interdigestive state. Adult mongrel dogs were chronically implanted with force transducers in the stomach and duodenum to monitor contractile activity, and the plasma motilin and insulin concentrations were measured by a specific radioimmunoassay and enzyme immunoassay, respectively. The concentration of insulin in plasma was found to fluctuate in close association with that of motilin and phase III of the interdigestive migrating contractions in the stomach. This spontaneous release of insulin was mimicked by intravenous infusion of motilin at a dose of 0.3 μg ⋅ kg−1⋅ h−1. Exogenous motilin (0.01–0.3 μg/kg) dose dependently stimulated insulin release, which was abolished by atropine, hexamethonium, ondansetron, and truncal vagotomy. Phentolamine significantly enhanced, whereas propranolol inhibited, motilin-induced insulin release. In a perifusion system using islet cells from the canine pancreas, motilin did not affect insulin release. In conclusion, motilin stimulates insulin release through vagal cholinergic, muscarinic receptors on pancreatic β-cells, and the effect appears to be modulated by adrenergic nerves.

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.

Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog

The gastrointestinal motor stimulating activity of erythromycin (EM) was studied in conscious dogs. It was found that a 20-min intravenous infusion of EM lactobionate at a dose of 50–100 micrograms (potency) X kg-1 X h-1 induced a group of strong contractions in the stomach and the duodenum, and the contractions migrated along the small intestine to the terminal ileum. The EM-induced contractions were quite similar to the naturally occurring interdigestive migrating contractions (IMC) in the gastrointestinal tract in frequency, contractile force, and duration of the contractions, migrating velocity, and accompanying peaks of plasma motilin concentration. The EM-induced contractions in the stomach were inhibited by feeding and intravenous infusion of pentagastrin (1.5 micrograms X kg-1 X h-1) but were not affected by secretin; these findings are identical to those found with the naturally occurring and motilin-induced contractions. Like motilin, EM stimulated motor activity only during the interdigestive state. We conclude that EM induces IMC associated with the release of endogenous motilin in the dog.