Vol. 294, Issue 1, 33-37, July 2000

Z-338 Facilitates Acetylcholine Release from Enteric Neurons Due to Blockade of Muscarinic Autoreceptors in Guinea Pig Stomach¹

Masayuki Ogishima , Muneshige Kaibara, Shigeru Ueki, Tadashi Kurimoto and Kohtaro Taniyama

Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan (M.O., M.K., K.T.); and Department of Applied Research, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan (M.O., S.U., T.K.)

The mechanism by which Z-338, a novel gastroprokinetic agent, stimulates gastric motility was studied in relation to muscarinic receptors in the guinea pig. Z-338 (3-30 µM) enhanced electrically stimulated contractions and the release of acetylcholine (ACh) that was tetrodotoxin sensitive and extracellular Ca²⁺ dependent, in gastric strips. Membrane-binding assay revealed that Z-338 possessed binding affinity for muscarinic M₁ and M₂, but not M₃ receptors. In Xenopus oocytes expressing M₁ and M₂ muscarinic receptors, Z-338 did not produce any response, but inhibited ACh-induced outward currents, thereby indicating that Z-338 acts on the M₁ and M₂ muscarinic receptors as an antagonist. The M₁ receptor antagonist pirenzepine (0.5 µM) and M₂ receptor antagonist AF-DX 116 (1 µM) also enhanced electrically stimulated release of ACh. These results indicate that Z-338 facilitates ACh release from cholinergic nerve terminals by blocking muscarinic M₁ and M₂ autoreceptors, which regulate the release of ACh.