Z-338 facilitates acetylcholine release from enteric neurons due to blockade of muscarinic autoreceptors in guinea pig stomach.
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 microM) enhanced electrically stimulated contractions and the release of acetylcholine (ACh) that was tetrodotoxin sensitive and extracellular Ca(2+) dependent, in gastric strips. Membrane-binding assay revealed that Z-338 possessed binding affinity for muscarinic M(1) and M(2), but not M(3) receptors. In Xenopus oocytes expressing M(1) and M(2) muscarinic receptors, Z-338 did not produce any response, but inhibited ACh-induced outward currents, thereby indicating that Z-338 acts on the M(1) and M(2) muscarinic receptors as an antagonist. The M(1) receptor antagonist pirenzepine (0.5 microM) and M(2) receptor antagonist AF-DX 116 (1 microM) also enhanced electrically stimulated release of ACh. These results indicate that Z-338 facilitates ACh release from cholinergic nerve terminals by blocking muscarinic M(1) and M(2) autoreceptors, which regulate the release of ACh.
Ogishima
M
M
Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan.
Kaibara
M
M
Ueki
S
S
Kurimoto
T
T
Taniyama
K
K
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000494:pharmacology*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000032:analysis; D013270:Stomach / Q000187:drug effects* / Q000294:innervation; D013844:Thiazoles / Q000494:pharmacology*; D014981:Xenopus
D017660:Autoreceptors; D001549:Benzamides; D005765:Gastrointestinal Agents; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013844:Thiazoles; C410959:Z 338; D000109:Acetylcholine