Analysis of anticholinesterase‐induced neuromuscular transmission failure

Abstract

To define the underlying mechanism of neuromuscular transmission failure induced by anticholinesterases, we simultaneously performed surface recordings of compound muscle action potentials (CMAPs) and intracellular recordings of miniature end-plate potentials (MEPPs), miniature end-plate current (MEPCs), and end-plate potential (EPPs) in rat diaphragms exposed in vitro to 1 x 10(-4) to 2 x 10(-2) mmol/L neostigmine methylsulfate. At low concentrations of neostigmine, repetitive stimulation of the phrenic nerve resulted in decrement followed by complete recuperation of CMAP amplitudes. This bimodal pattern was associated with maximal end-plate depolarization at the beginning of the stimulation period, increased MEPP amplitudes, and prolonged time constants of MEPC decays. Higher concentrations of neostigmine resulted in a unimodal decline of amplitudes of CMAPs and EPPS, reduced MEPP amplitudes, and a double exponential time course of MEPC decays. These results indicate that low concentrations of anticholinesterases impaired neuromuscular transmission by producing transient depolarization of the end-plate region. Higher concentrations induced desensitization and direct blockade of the end-plate receptor channel, probably in its open conformation.

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

“…However, in that case one would expect an accompanying MEPP and EPP broadening (due to a prolonged action of ACh, as shown in many electrophysiological experiments using cholinesterase inhibitors, see e.g. (Fiekers, 1985;Maselli and Leung, 1993)), but this was not found here. Instead, we observed faster MEPPs and EPPs.…”

Phrenic nerve conduction studies in acute organophosphate poisoning

“…22 The basis of reduced amplitudes of the diaphragmatic CMAPs in acute OP poisoning is probably transmission failure in the motor endplates. 4,12 The amplitude of the diaphragmatic CMAP is dependent on the number of muscle fibers activated by a nerve impulse. As indicated earlier, patients requiring mechanical ventilation had more severe intoxication.…”

Red Blood Cell Acetylcholinesterase and Plasma Butyrylcholinesterase Status: Important Indicators for the Treatment of Patients Poisoned by Organophosphorus Compounds

“…At RBC-AChE activity of about 15 % to 20 % mainly decrement-increment-phenomena occurred (23). This type of response is typically found in moderate to severe poisoning (37,38), presumably also indicating the need for artificial ventilation. At RBC-AChE activity above 30 %, little disturbance of neuromuscular transmission could be detected (23).…”

“…A series of experiments on phrenic nerve-diaphragmpreparations of mice circumfused with paraoxon showed that obidoxime restored muscle force, and this was clearly accompanied by an increase in muscle AChE activity (36). Comparably, in patients with insecticide OP-poisoning, it was reported that low RBC-AChE activity (<10 %) was associated with marked decrement-phenomena (23) (stimulation of a nerve with frequencies of 30 Hz to 50 Hz and recording of compound action potentials), indicating severe disturbance of neuromuscular transmission and urgent requirement of artificial ventilation (37,38). At RBC-AChE activity of about 15 % to 20 % mainly decrement-increment-phenomena occurred (23).…”