Contractile mechanism of GM-611 on gastrointestinal motility in conscious dogs

• Published in: Japanese Journal of Pharmacology Vol. 82; no. suppl.2; p. 256
• Main Authors: Sudo, Hirokazu, Ozaki, Ken-ichi, Onoma, Mitsu, Kamei, Kenshi, Dan, Takashi, Takanashi, Hisanori, Itoh, Zen, Omura, Satoshi
• Format: Journal Article
• Language: English; Japanese
• Published: The Japanese Pharmacological Society 2000
• ISSN: 0021-5198
• DOI: 10.1016/S0021-5198(19)48485-0

GM-611, an acid-resistant erythromycin A derivative, is currently under clinical trials as a gastroprokinetic agent. It has been demonstrated that GM-611 stimulates gastrointestinal (GI) motility in conscious dogs, but the detail of the contractile mechanism of GM-611 remains unclear. In the present study, the contractile mechanism of GM-611 was examined using GM-109, motilin antagonist, and various receptor agonists and antagonists in conscious dogs and compared with that of porcine motilin (pMTL). The GI contraction was measured by means of chronically implanted force transducers. GM-611 (0.1-10 μg/kg, i.v.) induced strong gastric contractions in the fasting state and the contractions migrated along the small intestine caudally. This pattern of the contractions was similar to that of pMTL. The GI contractions induced by GM-611 or pMTL were suppressed by i.v. infusion of GM-109 in a dose-dependent manner. Atropine, hexamethonium, dopamine and ondansetron significantly inhibited the GM-611-induced contraction by 81.7±6.7%, 69.0±10.5%, 87.5±3.6% and 87.4±2.5%, respectively. On the other hand, neither naloxone, phentolamine, propranolol nor ketanserin inhibited GM-611-induced contraction significantly. This profile of GM-611 was the same as that of pMTL reported preciously. These results suggest that GM-611, like pMTL, acts on motilin receptor and induces GI contraction, this contraction is partially mediated through the cholinergic pathway.