1995 Fiscal Year Final Research Report Summary
Analysis of motilin receptor in human gastric antrum for clinical application of motilide
| Project/Area Number |
06454256
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | Gunma University |
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Principal Investigator |
ITOH Susumu Institute for Molecular and Cellular Regulation, Gunma University, Biosignal Physiology Professor, 生体調節研究所, 教授 (00008294)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAI Takafumi Institute for Molecular and Cellular Regulation, Gunma University, Biosignal Phy, 生体調節研究所, 助手 (40235114)
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| Project Period (FY) |
1994 – 1995
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| Keywords | motilin. / motilin receptor. / erythromycin derivatives. / smooth muscle of the gastrointestinal tract. / autoradiography. / isolated smooth muscle cell. / receptor binding assay. / smooth muscle contraction |
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| Research Abstract |
1.Since motilides are not permitted to use in human, the biological activity of motilides was studied in conscious dogs with force transducers chronicanlly implanted in the gastrointestinal tract. As a result, EM523 induced strong contractions in the fed state in addition to the fasted state. EM523-induced contractions in the stomach is mediated through cholinergic neurons including 5-HT3 receptors in the stomach. Moreover, it was also found that EM523 induced contractions in the stomach through substance P neurons without cholinergic pathways.
2.It was found that EM523 stimulates pancreatic islet hormones through vagally cholinergic muscarinic receptors.
EM574 and motilin stimulated contractile activity in isolated smooth muscle of human gastric antrum. EM574 also stimulated contractile activity of smooth muscle strips of human gastric antrum in a dose-dependent manner, and these contractions were TTX-resistant.
In radioreceptor binding study, it was found that motilin receptors were present in the smooth muscle tissue of the human gastric antrum, and the specific binding was replaced by EM574 in a dose-dependent fashion.
In the study of autoradiography, it was found that specific bindings of motilin were found in the smooth muscle layr of the human gastric antrum, and these bindings were also inhibited by addition of EM574 in a dose-dependent manner.
Since the binding of motilin in the membrane fraction of the human stomach was very low, iodinated motilin was bound to the homogenate preparation of smooth muscle in the human stomach, and the bound was analyzed by means of a SDS gel electrophoresis. The three different bands in molecular weight were detected, and a single peak could be obtained from one of the bands, and now further be purifying.
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[Publications] Sakai, T., Satoh, M., Hayashi, H., Fujikura, K., Sano, I., Koyama, H., Tatemoto, K.and Itoh, Z.: "Biotinyl C-terminal extended motilin as a biologically active receptor probe." Peptides. 15. 257-262 (1994)
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[Publications] Satoh, M., Sakai, T., Sano, I., Fujikura, K., Koyama, H., Ohshima, K., Itoh, Z.and Omura, S.: "EM574, an erythromycin derivative, is a potent motilin receptor agonist in human gastric antrum." J.Pharmacol.Exp.Ther.271. 574-579 (1994)
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[Publications] Shiba, Y., Mizumoto, A., Inatomi, N., Haga, N,, Yamamoto, O., and Itoh, Z.: "Stimulatory mechanism of EM-523-induced contractions in postprandial stomach of conscious dogs." Gastroenterology. 109. 1513-1521 (1995)
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