ACTIONS OF ANTI-CHOLINESTERASES ON ENDPLATE POTENTIAL OF FROG MUSCLE

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Abstract
A systematic study has been made of the effects produced on the endplate potential (e.p.p.) of the curarized frog''s sartorius by 7 anti-cholinesterases. All slow the time course of the e.p.p. set up by single or repetitive nerve volleys and increase the relative size (voltage) of the slowly decaying component. Four criteria have been adopted in order to express graphically the concn.-action relationship for these 7 substances in respect both of the time course of the e.p.p. and of the relative size of the slowly decaying component. Each of the 4 criteria increases along a sigmoid curve when plotted against the negative logarithm of the prostigmine concn., and this relationship also appears to hold with the other anti-cholinesterases. For any one criterion there are wide divergences in the activities of the substances, prostigmine being the most effective and DFP usually the least. However, the relative activities assessed by the 4 criteria are in good agreement, a finding which is inherently probable, for all 4 criteria have been chosen because they are likely to assess anti-cholinesterase activity. In contrast, the curare-like depressant action of all 7 substances diverges widely from these assumed anti-cholinesterase activities. By the above 4 criteria for testing anti-cholinesterase activity in vivo, the concn. for half effectiveness has to be much higher than with in vitro testing, but less so with prostigmine than with others. Presumably this discrepancy is attributable to the special type of cholinesterase at the frog''s endplate. The ACh hypothesis of neuro-muscular transmission is fully in accord with all the observations, which themselves throw light on the detailed mechanisms involved in this transmission[long dash]in particular the removal of ACh from the site of its action and the generation of the slow component of the endplate potential. The concn.-action curves of prostigmine as detd. in vivo are discussed in relationship to the concn.-inhibition curves for in vitro inhibition of ChE, and are shown to correspond to a mono-molecular inhibitory action on an enzyme of low concn.

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