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

D Estrella, K L Green, C Prior, J Dempster, R F Halliwell, R S Jacobs, S M Parsons, R L Parsons, I G Marshall

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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. 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. (-)-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. 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. 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. 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.
LanguageEnglish
Pages759-768
Number of pages10
JournalBritish Journal of Pharmacology
Volume93
Issue number4
Publication statusPublished - Apr 1988

Fingerprint

Neuromuscular Agents
Anura
Acetylcholine
Neuromuscular Blockade
Muscles
Aminopyridines
vesamicol
Neostigmine
Lanthanum
4-Aminopyridine
Synaptic Vesicles
Neuromuscular Junction
Neural Conduction
Choline
Diaphragm
Action Potentials

Keywords

  • local anesthetics
  • animals
  • electrophysiology
  • male
  • motor endplate
  • muscle contraction
  • muscles
  • neuromuscular depolarizing Agents
  • neurons
  • phencyclidine
  • phrenic nerve
  • piperidines
  • rana pipiens
  • rats
  • stereoisomerism

Cite this

Estrella, D., Green, K. L., Prior, C., Dempster, J., Halliwell, R. F., Jacobs, R. S., ... Marshall, I. G. (1988). A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity. British Journal of Pharmacology, 93(4), 759-768.
Estrella, D ; Green, K L ; Prior, C ; Dempster, J ; Halliwell, R F ; Jacobs, R S ; Parsons, S M ; Parsons, R L ; Marshall, I G. / A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity. In: British Journal of Pharmacology. 1988 ; Vol. 93, No. 4. pp. 759-768.
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Estrella, D, Green, KL, Prior, C, Dempster, J, Halliwell, RF, Jacobs, RS, Parsons, SM, Parsons, RL & Marshall, IG 1988, 'A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity' British Journal of Pharmacology, vol. 93, no. 4, pp. 759-768.

A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity. / Estrella, D; Green, K L; Prior, C; Dempster, J; Halliwell, R F; Jacobs, R S; Parsons, S M; Parsons, R L; Marshall, I G.

In: British Journal of Pharmacology, Vol. 93, No. 4, 04.1988, p. 759-768.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A further study of the neuromuscular effects of vesamicol (AH5183) and of its enantiomer specificity

AU - Estrella, D

AU - Green, K L

AU - Prior, C

AU - Dempster, J

AU - Halliwell, R F

AU - Jacobs, R S

AU - Parsons, S M

AU - Parsons, R L

AU - Marshall, I G

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N2 - 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. 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. (-)-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. 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. 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. 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.

AB - 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. 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. (-)-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. 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. 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. 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.

KW - local anesthetics

KW - animals

KW - electrophysiology

KW - male

KW - motor endplate

KW - muscle contraction

KW - muscles

KW - neuromuscular depolarizing Agents

KW - neurons

KW - phencyclidine

KW - phrenic nerve

KW - piperidines

KW - rana pipiens

KW - rats

KW - stereoisomerism

M3 - Article

VL - 93

SP - 759

EP - 768

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 4

ER -