The interaction of anticholinesterase agents with the acetylcholine receptor-ionic channel complex.

The actions of pyridostigmine (Pyr), a quaternary carbamate compound, and physostigmine ( Phy ), a tertiary carbamate, both known for their reversible inhibition of acetylcholinesterase (AChE), were studied on the electrically excitable membrane and acetylcholine (ACh) receptor of the frog cutaneous pectoris, sartorius, and interosseal muscles, as well as the chronically denervated soleus muscle of the rat and myoballs from neonatal rats. Both Pyr and Phy first potentiated, then depressed and finally blocked the indirectly evoked muscle twitch. Pyr and Phy had negligible effects upon either membrane potential or muscle action potential. But at the synaptic junction, they decreased the peak amplitude of the endplate current (EPC) in a voltage- and concentration-dependent manner. Pyridostigmine produced a marked prolongation of the decay time constants of both the EPC and the miniature endplate current ( MEPC ), while maintaining a single exponential decay, and Phy decreased peak amplitude, while having little effect on its voltage dependence. Physostigmine also decreased the decay time constant, suggesting a channel block, presumably in open state. Single channel recordings using patch clamp techniques disclosed that Pyr interacts with the ACh receptor as a weak agonist capable of inducing desensitization, alone, and when combined with ACh. Physostigmine interacts directly with the ACh-ionic channel complex, blocking it in open conformation.