Enhancement by KW-5092, a Novel Gastroprokinetic Agent, of the Release of Acetylcholine from Enteric Neurons in the Guinea Pig Ileum.

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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 × 10-6 M and potentiated the ACh release at 10-8 M to 3 × 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 × 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 × 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.
公益社団法人日本薬理学会の論文