ANALYSIS OF ANTICHOLINESTERASE-INDUCED NEUROMUSCULAR-TRANSMISSION FAILURE

To define the underlying mechanism of neuromuscular transmission failu re induced by anticholinesterases, we simultaneously performed surface recordings of compound muscle action potentials (CMAPs) and intracell ular recordings of miniature end-plate potentials (MEPPs), miniature e nd-plate current (MEPCs), and end-plate potential (EPPs) in rat diaphr agms exposed in vitro to 1 x 10(-4) to 2 x 10(-2) mmol/L neostigmine m ethylsulfate. At low concentrations of neostigmine, repetitive stimula tion of the phrenic nerve resulted in decrement followed by complete r ecuperation of CMAP amplitudes. This bimodal pattern was associated wi th maximal end-plate depolarization at the beginning of the stimulatio n period, increased MEPP amplitudes, and prolonged time constants of M EPC decays. Higher concentrations of neostigmine resulted in a unimoda l decline of amplitudes of CMAPs and EPPS, reduced MEPP amplitudes, an d a double exponential time course of MEPC decays. These results indic ate that low concentrations of anticholinesterases impaired neuromuscu lar transmission by producing transient depolarization of the end-plat e region. Higher concentrations induced desensitization and direct blo ckade of the end-plate receptor channel, probably in its open conforma tion.