title: Enhancement by KW-5092, a novel gastroprokinetic agent, of the release of acetylcholine from enteric neurons in the guinea pig ileum.
abstract: KW-5092 ((1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]ethyl]-2- imidazolidinylidene) propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity. The present study examined the effects of KW-5092 on intestinal contraction and on acetylcholine (ACh) release in the isolated longitudinal muscle-myenteric plexus preparation of guinea pig ileum. In the electrically stimulated preparation, KW-5092 enhanced the contraction at 10(-9) M to 3 x 10(-6) M and potentiated the ACh release at 10(-8) M to 3 x 10(-6) M. In the unstimulated preparation, KW-5092 at 10(-8) M to 10(-4) M evoked the contraction and ACh release. Both the contraction and the ACh release by KW-5092 were abolished by tetrodotoxin (10(-7) M) or removal of external Ca2+, and the evoked contraction was abolished by atropine (10(-7) M). The ACh release by KW-5092 was not affected by hexamethonium (3 x 10(-5) M), suggesting that the nicotinic receptor is not involved in the ACh release. Neostigmine, whose AChE inhibitory activity is equipotent to that of KW-5092, did not evoke ACh release even at 3 x 10(-6) M, indicating that the ACh release by KW-5092 is not due to its AChE inhibitory activity. The present results suggest that KW-5092 evokes ACh release by stimulating a cholinergic pathway and that the ACh release by KW-5092 may contribute to its gastroprokinetic effects.
authors.affiliation: Department of Pharmacology, Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000294:innervation*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D009570:Nitriles; C081341:KW 5092; D000109:Acetylcholine