Abstract
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 M1and M2, but not M3 receptors. InXenopus 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 M2muscarinic 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.
Footnotes
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Send reprint requests to: Kohtaro Taniyama, M.D., Ph.D., Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan. E-mail: taniyama{at}net.nagasaki-u.ac.jp
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↵1 This study was supported by grants from the Ministry of Education, Science, Sports and Culture, Japan.
- Abbreviations:
- Z-338
- N-(N′,N′-diisopropylaminoethyl)-[2-(2-hydroxy-4,5-dimethoxy-benzoylamino)-1,3-thiazole-4-yl] carboxyamide monohydrochloride trihydrate
- 5-HT
- 5-hydroxytryptamine
- ACh
- acetylcholine
- NMS
- N-methyl scopolamine
- GIRK1
- G protein-gated inward rectifying K+ channel
- AF-DX 116
- 11,2-(diethylamino)methyl-1-piperidinyl-acetyl-5,11-dihydro-6H-pyrido-2,3b-1,4-benzodiazepine-6-one
- TTX
- tetrodotoxin
- Received September 20, 1999.
- Accepted March 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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