In favour of the vesicular hypothesis: neurochemical evidence that vesamicol (AH5183) inhibits stimulation-evoked release of acetylcholine from neuromuscular junction.
1. The effects of optical isomers of vesamicol (2-(4-phenylpiperidino) cyclohexanol), an inhibitor of acetylcholine (ACh) storage, on stimulation-evoked release of [3H]-acetylcholine [( 3H]-ACh) from the neuromuscular junction have been studied in the region of the mouse hemidiaphragm which contains the motor endplates, and which can easily be loaded with [3H]-choline. This method made it possible to detect exclusively the Cao-dependent release of [3H]-ACh in response to stimulation, and therefore to test the vesicular hypothesis. 2. (-)-Vesamicol was approximately 20 times more potent than (+)-vesamicol in reducing stimulation-evoked release of [3H]-ACh. 3. 4-Aminopyridine, a potassium channel blocker, enhanced the release of ACh in response to stimulation, but failed to increase release from hemidiaphragm which had been pretreated with (-)-vesamicol. 4. The fact that (-)-vesamicol inhibited the release of [3H]-ACh in response to electrical stimulation only when it was administered prior to the loading of the tissue with [3H]-choline, and had no effect when the stores had already been filled with labelled [3H]-ACh indicates that the stimulation-evoked release of [3H]-ACh is of vesicular origin and (-)-vesamicol has no effect on the release process. This is the first neurochemical evidence for the vesicular origin of stimulation-evoked release of ACh from the neuromuscular junction.
Vizi
E S
ES
Dept. of Pharmacology, Hungarian Academy of Sciences, Budapest.
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002794:Choline / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines
D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; C006189:vesamicol; D010622:Phencyclidine; D002794:Choline; D000109:Acetylcholine; D002118:Calcium