X.: The reversible cholinesterase inhibitor physostigmine has channel-blocking and agonist effects on the acetylcholine receptor-ion channel complex

The actions of the carbamate cholinesterase inhibitors, physostigmine (Phy) and phy-sostigmine methiodide (MetPhy), were studied on the acetylcholine receptor-ion channel complex (AChR) of skeletal muscles. Low concentrations of these agents produced cholinesterase inhibition which resulted in potentiation of nerve-elicited muscle twitches and an increased peak amplitude and prolongation of the decay time constant (TEPC) of endplate currents (EPCs) elicited in frog (Rana pipiens) sartorius muscles. However, increasing concentrations of Phy depressed the peak amplitude and shortened the decay phase of the EPC with an apparent loss in the voltage dependence of TEPC. At higher concentrations and depolarized potentials, EPC decays were double exponential. The effects of both Phy and MetPhy on the postsynaptic AChR complex were also evident in preparations pretreated with diisopropylfluorophosphate. Under these conditions, a linear relationship between the reciprocal of TEPC and the concentration of these agents was observed. Single channel studies revealed that Phy (20-600 M) shortened channel lifetime and decreased channel conductance at very high concentrations. In addition, Phy (0.5 tM) induced the appearance of channel openings with conductance similar to that of acetyicholine. High concentrations (>50 jIM) of this agent activated channel openings with decreased conductance. Similar results were obtained with MetPhy. Thus, the reversible cholinesterase inhibitors Phy and MetPhy altered the properties of the AChR by interacting as agonists capable of inducing desensitization and blockade