Presynaptic and postsynaptic neuromuscular effects of a specific inhibitor of acetylcholinesterase

Previous studies have shown indirectly that the neuromuscular effects of nonselective cholinesterase inhibitors are mediated through the inhibition of acetylcholinesterase (AChE). To test this hypothesis more directly we studied the effects of the specific inhibitor of AChE, BW 284c51, at the neuromuscular junction of rat diaphragms. BW 284c51 inhibits AChE in a dose-dependent partially reversible manner at all concentrations tested (10(-9) to 10(-4) M). Maximum inhibition was never greater than 92%. The drug increased miniature end-plate potential (MEPP) amplitude and prolonged half-decay time at 10(-7) and 10(-6) M. However, BE 284c51 had no effect on the resting membrane potential at any concentration. BW 284c51 at 10(-7) M reversibly increased MEPP frequency by almost 4-fold. There was a 2-fold increase in the occurrence of giant MEPPs in the presence of BW 284c51. The quantum content (m) of the end-plate potential was increased in 10(-7) M BW 284c51 as were end-plate potential amplitude and quantum size (q). Animals injected subcutaneously with 10 mg/kg of BW 284c51 displayed typical signs of AChE inhibition including salivation, whole body tremor and prostration. Spontaneous muscle fasciculation was more noticeable after in vivo injection of BW 284c51 than after in vitro administration. Furthermore, MEPP frequencies were considerably faster when the drug was injected in vivo than when applied in vitro. The data are discussed with respect to the hypothesis that inhibition of AChE causes presynaptic as well as postsynaptic effects.