title: The effects of vesamicol on trains of endplate currents and on focally recorded nerve terminal currents at mammalian neuromuscular junctions.
abstract: 1. The effects of vesamicol, an inhibitor of vesicular acetylcholine (ACh) storage, were studied on trains of endplate currents (e.p.cs) in the cut rat hemidiaphragm nerve-muscle preparation and on trains of focally recorded nerve terminal current waveforms in the mouse triangularis sterni nerve-muscle preparation. 2. In the rat, 0.1 and 1 microM (-)-vesamicol produced an enhancement of the rundown of e.p.c. amplitudes during trains of high frequency (50 Hz) nerve stimulation. However, 1 microM (+)-vesamicol had no effect on the rundown of e.p.c. amplitudes. 3. In the mouse, high concentrations of (-)-vesamicol (10-100 microM) produced a concentration- and stimulation-dependent decrease in the amplitude of the second negative-going deflection of focally recorded nerve terminal current waveforms. 4. At 1 mM, (-)-vesamicol produced a stimulation-independent decrease in the amplitude of the first negative-going deflection of the nerve terminal current waveforms, an increase in signal delay and evidence of nerve conduction failure. These all indicate a local anaesthetic-like block of nodal Na(+)-channels. 5. In contrast to its effects on trains of e.p.cs, the effects of vesamicol on the nerve terminal current waveforms were not stereoselective, the (+)-isomer being equipotent with the (-)-isomer. 6. Low concentrations of the Na(+)-channel blocking toxin, tetrodotoxin (15-60 nM), produced similar changes in the focally recorded nerve terminal current waveforms to those seen with vesamicol. 7. It is concluded that the stereoselective rundown of e.p.c. amplitudes produced by (-)-vesamicol is due to an effect, either direct or indirect, on ACh mobilization within motor nerve terminals. Furthermore, in mammalian species, the inhibitory effects of vesamicol on nodal Na+-channels which are seen at high concentrations do not contribute to the principal neuromuscular effects of the compound.
authors.affiliation: Department of Physiology and Pharmacology, University of Strathclyde, Glasgow.
authors.forename: K E
authors.initials: KE
authors.lastname: Pemberton
authors.forename: C
authors.initials: C
authors.lastname: Prior
authors.forename: I G
authors.initials: IG
authors.lastname: Marshall
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D009045:Motor Endplate / Q000187:drug effects*; D009411:Nerve Endings / Q000187:drug effects*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; C006189:vesamicol; D013779:Tetrodotoxin