title: Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats.
abstract: In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia.
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., 2512-1 Numagami, Oshikiri, Kumagaya-shi, Saitama, Japan. masanao-kawachi@zeria.co.jp
authors.forename: Masanao
authors.initials: M
authors.lastname: Kawachi
authors.forename: Yugo
authors.initials: Y
authors.lastname: Matsunaga
authors.forename: Takao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hori
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagahama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozaki
authors.forename: Naonori
authors.initials: N
authors.lastname: Inoue
authors.forename: Ryoko
authors.initials: R
authors.lastname: Toda
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yoshii
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Mineo
authors.initials: M
authors.lastname: Takei
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D004558:Electric Stimulation; D005746:Gastric Emptying / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; C410959:Z 338; D000110:Acetylcholinesterase; D003000:Clonidine