Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1988 Apr;93(4):759–768. doi: 10.1111/j.1476-5381.1988.tb11460.x

A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity.

D Estrella 1, K L Green 1, C Prior 1, J Dempster 1, R F Halliwell 1, R S Jacobs 1, S M Parsons 1, R L Parsons 1, I G Marshall 1
PMCID: PMC1853909  PMID: 3260527

Abstract

1. The effects of vesamicol (2-(4-phenylpiperidino) cyclohexanol), an inhibitor of acetylcholine storage, and its two optical isomers have been studied on neuromuscular transmission in rat and frog muscle, and on nerve conduction in frog nerve. 2. Racemic vesamicol produced a pre-block augmentation of twitch tension that also occurred in directly-stimulated muscle. This effect is thus at least partially due to an increase in muscle contractility. 3. (-)-Vesamicol was approximately 20 times more potent than (+)-vesamicol in blocking twitches elicited at 1 Hz. This degree of stereoselectivity is similar to that measured for inhibition of acetylcholine uptake by isolated synaptic vesicles. Both enantiomers were equally weak in reducing nerve action potential amplitude in frog nerve. 4. Further studies with the active isomer, (-)-vesamicol, showed that, like that produced by racemic vesamicol, the neuromuscular block was highly frequency-dependent. The block was not reversed by choline or neostigmine, but was partially reversed by 4- or 3,4-aminopyridine. 5. Preliminary electrophysiological studies showed that vesamicol reduced miniature endplate potential amplitude in rapidly-stimulated frog nerve-muscle preparations. Addition of lanthanum ions increased the frequency of miniature endplate potentials and led to the appearance of apparently normal-sized potentials amongst those of reduced amplitude. 6. The results show the close agreement between pharmacological and biochemical observations indicating the suitability of the rat diaphragm as a test model for substances of this nature. The degree of reversibility of the vesamicol-induced neuromuscular block by aminopyridines was unexpected, and it is suggested that in the presence of a drug which greatly increases release, a pool of acetylcholine is capable of being released which is not normally releasable after block of storage by vesamicol. It is also considered possible that the results from the intracellular recording studies may be explained in these terms.

Full text

PDF
763

Images in this article

761Figure 2
on p.761

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson D. C., King S. C., Parsons S. M. Pharmacological characterization of the acetylcholine transport system in purified Torpedo electric organ synaptic vesicles. Mol Pharmacol. 1983 Jul;24(1):48–54. [PubMed] [Google Scholar]
  2. Bahr B. A., Parsons S. M. Demonstration of a receptor in Torpedo synaptic vesicles for the acetylcholine storage blocker L-trans-2-(4-phenyl[3,4-3H]-piperidino) cyclohexanol. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2267–2270. doi: 10.1073/pnas.83.7.2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blioch Z. L., Glagoleva I. M., Liberman E. A., Nenashev V. A. A study of the mechanism of quantal transmitter release at a chemical synapse. J Physiol. 1968 Nov;199(1):11–35. doi: 10.1113/jphysiol.1968.sp008637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brittain R. T., Levy G. P., Tyers M. B. The neuromuscular blocking action of 2-(4-phenylpiperidino) cyclohexanol (AH 5183). Eur J Pharmacol. 1969 Oct;8(1):93–99. doi: 10.1016/0014-2999(69)90133-2. [DOI] [PubMed] [Google Scholar]
  5. Collier B., Welner S. A., Rícný J., Araujo D. M. Acetylcholine synthesis and release by a sympathetic ganglion in the presence of 2-(4-phenylpiperidino) cyclohexanol (AH5183). J Neurochem. 1986 Mar;46(3):822–830. doi: 10.1111/j.1471-4159.1986.tb13046.x. [DOI] [PubMed] [Google Scholar]
  6. DeBassio W. A., Schnitzler R. M., Parsons R. L. Influence of lanthanum on transmitter release at the neuromuscular junction. J Neurobiol. 1971;2(3):263–278. doi: 10.1002/neu.480020307. [DOI] [PubMed] [Google Scholar]
  7. Durant N. N., Marshall I. G. The effects of 3,4-diaminopyridine on acetylcholine release at the frog neuromuscular junction. Eur J Pharmacol. 1980 Oct 17;67(2-3):201–208. doi: 10.1016/0014-2999(80)90499-9. [DOI] [PubMed] [Google Scholar]
  8. Heuser J., Miledi R. Effects of lanthanum ions on function and structure of frog neuromuscular junctions. Proc R Soc Lond B Biol Sci. 1971 Dec 14;179(1056):247–260. doi: 10.1098/rspb.1971.0096. [DOI] [PubMed] [Google Scholar]
  9. Johnson E. W., Parsons R. L. Characteristics of postjunctional carbamylcholine receptor activation and inhibition. Am J Physiol. 1972 Mar;222(3):793–799. doi: 10.1152/ajplegacy.1972.222.3.793. [DOI] [PubMed] [Google Scholar]
  10. Katz B., Miledi R. Estimates of quantal content during 'chemical potentiation' of transmitter release. Proc R Soc Lond B Biol Sci. 1979 Aug 31;205(1160):369–378. doi: 10.1098/rspb.1979.0070. [DOI] [PubMed] [Google Scholar]
  11. Kirsch G. E., Narahashi T. 3,4-diaminopyridine. A potent new potassium channel blocker. Biophys J. 1978 Jun;22(3):507–512. doi: 10.1016/S0006-3495(78)85503-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lundh H. Effects of 4-aminopyridine on neuromuscular transmission. Brain Res. 1978 Sep 22;153(2):307–318. doi: 10.1016/0006-8993(78)90409-2. [DOI] [PubMed] [Google Scholar]
  13. Manthey A. A. The effect of calcium on the desensitization of membrane receptors at the neuromuscular junction. J Gen Physiol. 1966 May;49(5):963–976. doi: 10.1085/jgp.49.5.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marshall I. G. Studies on the blocking action of 2-(4-phenyl piperidino) cyclohexanol (AH5183). Br J Pharmacol. 1970 May;38(3):503–516. doi: 10.1111/j.1476-5381.1970.tb10592.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Molgo J., Lemeignan M., Lechat P. Modifications de la libération du transmetteur à la jonction neuromusculaire de grenouille sous l'action de l'amino-4 pyridine. C R Acad Sci Hebd Seances Acad Sci D. 1975 Nov 24;281(21):1637–1639. [PubMed] [Google Scholar]
  16. Molgó J., Lundh H., Thesleff S. Potency of 3,4-diaminopyridine and 4-aminopyridine on mammalian neuromuscular transmission and the effect of pH changes. Eur J Pharmacol. 1980 Jan 11;61(1):25–34. doi: 10.1016/0014-2999(80)90378-7. [DOI] [PubMed] [Google Scholar]
  17. Van der Kloot W. 2-(4-phenylpiperidino) cyclohexanol (AH5183) decreases quantal size at the frog neuromuscular junction. Pflugers Arch. 1986 Jan;406(1):83–85. doi: 10.1007/BF00582958. [DOI] [PubMed] [Google Scholar]
  18. Whitton P. S., Marshall I. G., Parsons S. M. Reduction of quantal size by vesamicol (AH5183), an inhibitor of vesicular acetylcholine storage. Brain Res. 1986 Oct 15;385(1):189–192. doi: 10.1016/0006-8993(86)91565-9. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES