The Effect of Anticholinesterase Action on Mammalian Skeletal Neuromuscular Transmission

  • P.F. Burd

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

A brief outline of skeletal neuromuscular transmission as
a sequence of events leading to muscular contraction and the
actions of anticholinesterases is presented in the Introduction.

The work has been largely concerned with the irreversible
inhibition of cholinesterase by ecothiopate (phospholine) at the
neuromuscular junction, thereby altering the time course of
transmitter action, and the subsequent effect on the contractile
response of isolated mammalian diaphragm preparations.

Ecothiopate (5 x 10-7M) evokes a complex and, apparently,
time —- dependent series of changes in the contractile response,
one of which, the prolonged endplate- localised contraction, was
believed to be a new observation and was to be the main subject
of further study.

Electrophysiological, radioisotopic and histological methods
have been employed to determine the cause of these prolonged
contractions. They have been found to be associated with prolonged
currents and with an accumulation of calcium,both at the endplates,
It has not been possible to exclude a direct effect of membrane
depolarisation or an effect of post ~ junctional calcium entry as
the cause of the prolonged localised contraction, It has been
concluded that ecothiopate (5 x 10-7M) is unlikely to have a
significant direct effect on the changes in contraction and endplate
calcium accumulation.

A biochemical method to determine cholinesterase activity has
been devised which is believed to give results which represent
endplate cholinesterase activity. An attempt has been made to
correlate the ecothiopate-meaditated changes in contractile response with the degree of cholinesterase inhibition. It has been concluded that the time-dependent changes in the contractile response after ecothiopate are mainly due to a time-dependent inhibition of
cholinesterase in non~ perfused muscles.

Finally, the waning of the ecothiopate~ mediated changes in
contraction have been suggested to be due to a reduction in
transmitter action, perhaps, by receptor desensitisation. The
association between desensitisation and endplate calcium accumulation
has been discussed,


Date of AwardSept 1980
Original languageEnglish
Awarding Institution
  • Aston University

Keywords

  • anticholinesterase
  • calcium
  • diaphragm
  • prolonged contraction

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