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PO3-5-21

Human motilin transgenic mice are useful for evaluation of motilin receptor agonists as gastric prokinetic drugs

[Speaker] Shinichi Kato:1
[Co-author] Aoi Takahashi:1, Mai Shindo:1, Kenjiro Matsumoto:1, Kikuko Amagase:1, Bunzo Matsuura:2
1:Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Japan, 2:Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Japan

Background & Aim: Motilin, 22-amino acid peptide, was firstly identified in 1977 as a gastrointestinal hormone for stimulation of motor activates. This hormone is synthetized and secreted by endocrine M cells in duodenum and jejunum, and is predominantly released in the fasted state for association with phase III of migrating motor complex. Motilin receptors (MR) belong to a family of Class I G protein-coupled receptor and high sequence homology with ghrelin receptors in humans. The actions of motilin are highly species-dependent and remains poorly understood. Because a functional motilin system is the absent in rodents including rats and mice that are used for basic studies. In the present study, we examined the usefulness of human MR transgenic (hMR-Tg) mice for evaluation of MR agonists in experimental animals for gastric prokinetic drugs.
Methods: Male hMR-Tg mice and wild-type (WT) mice were used. Strips of muscle from the gastric fundus and corpus were prepared and placed on organ bath including physiological salt solution. The tension of smooth muscle strips was measured isometrically. The gastric emptying was determined using phenol red methods. The distribution of hMR was examined immunohistochemically in WT and hMR-Tg mice.
Results: Motilin and erythromycin had no influence on the tension in WT mice but produced concentration-dependent contraction of gastric smooth muscle in hMR-Tg mice. The contractile response to motilin and erythromycin in hMR-Tg mice was affected by neither atropine nor tetrodotoxin. In contrast, motilin-induced contractile response in hMR-Tg mice was totally disappeared in Ca2+-free solution. Intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMR-Tg mice but not WT mice. Immunohistochemical study revealed that hMR were abunduntly expressed in smooth muscle layer and partly in myenteric plexus in the stomach of hMR-Tg mice but not WT mice. The expression of hMR in myenteric plexus was not co-localized with vesicular acetylcholine transporter (VAChT), a maker of cholinergic neurons.
Conclusion: Motilin and erythromycin stimulate gastric motor response in hMR-Tg mice. This action is mediated by direct contraction of smooth muscles via influx of extracellular Ca2+. Thus, hMR-Tg mice are useful for evaluation of MR agonists as gastric prokinetic drugs.
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