title: Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach.
abstract: Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 μM) and itopride (1 and 3 μM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 μM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 μM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach.
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kawachi
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nagahama
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawabata
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takei
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004415:Dyspepsia / Q000188:drug therapy; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D009388:Neostigmine / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D001593:Benzyl Compounds; D002800:Cholinesterase Inhibitors; D009025:Morpholines; D013844:Thiazoles; D009388:Neostigmine; C102254:itopride; D002217:Carbachol; C410959:Z 338; D000110:Acetylcholinesterase; C062720:mosapride; D000109:Acetylcholine