The Toxic Effects of Enzyme Inhibitors on Muscle and Nerve

Abstract

Previous attempts have been made to determine the relationship between the reduction in activity of acetylcholinesterase (AChE) and the prolongation of extracellularly recorded miniature endplate potentials (MEPPs)o. These attempts however have not been entirely successful and it was thought that this may be due to the biochemistry and the electrophysiology measuring different populations of AChE. In an attempt to avoid this the method of Younkin e¢ al (1982) was used, by Mrs A. Rowbotham, to extract the different molecular isoforms of AChE and new correlations calculated. Using this technique a better correlation was arrived at and it has been suggested that it is the non extractable enzymes found specifically in the endplates which constitutes the functional enzyme, i.e. that responsible for the termination of transmitter action. Increases in the variability of action potentials, "jitter", are seen with neuromuscular disease and also after intoxication with an anticholinesterase (anti-ChE), although the mechanism by which this jitter is caused are not entirely clear. An attempt has been made to clarify the origin of jitter by recording trains of action potentials at 1 and 30 Hz.. The data obtained suggests that jitter is a functional disorder caused by a postsynaptic mechanism. The effect of multiple doses of the carbamates pyridostigmine and physostigmine, by implantated osmotic pump, on jitter, prolongation of the timecourse of (MEPPs)o and the deformation of the endplates have been measured. These results have then been compared with the activity of functional AChE. Pyridostigmine and physostigmine caused similar reductions in the activity of functional AChE resulting in similar prolongation of (MEPPs)o and deformation of the endplate. Both carbamates also caused an increase in jitter although the onset of this occurred sooner with physostigmine. Single doses of carbamates have been shown to protect against poisoning with organophosphorus anti-ChEs. Here, the protective abilities of continuous administration of low doses of pyridostigmine and physostigmine against a dose of ecothiopate were tested. Complete protection from all of the effects of ecothiopate were not found with either pyridostigmine or physostigmine, although the protection found with, physostigmine was considerably greater