THE NATURE OF THE INTERACTIONS OF PYRIDOSTIGMINE WITH THE NICOTINIC ACETYLCHOLINE-RECEPTOR IONIC CHANNEL COMPLEX .1. AGONIST, DESENSITIZING, AND BINDING-PROPERTIES

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 25  (1) , 92-101
Abstract
The actions of pyridostigmine (Pyr), an anticholinesterase agent, were studied on the acetylcholine (ACh) receptor-ion channel complex and on the electrically excitable membrane of the frog cutaneous pectoris and sartorius muscles, and the chronically denervated soleus muscle of the rat. Pyr at concentrations of 0.2-0.4 mM potentiated the indirect evoked muscle twitch and at concentrations .gtoreq. 0.8 mM depressed the indirect twitch with an IC50 [median inhibitory concentration] of .apprx. 2 mM. Twitch depression produced by Pyr was reversed slowly, and after a 60 min wash only 59% of the control muscle twitch had returned. Pyr did not affect either the membrane potential or the muscle action potential. Pyr had several effects at the neuromuscular junction of the frog and rat. It decreased the peak amplitude of the end-plate current (EPC) in a voltage- and concentration-dependent manner. In contrast to diisopropylfluorophosphate, which depresses the EPC amplitude and induces a double exponential decay of the EPC and miniature end-plate current (MEPC). Pyr produced a marked prolongation of the time constants of EPC and MEPC decay while maintaining a single exponential decay. The decrease caused by Pyr of indirect twitch tension, EPC amplitude and ACh sensitivity indicated mechanisms which limit the number and/or properties of conducting channels. The drug decreased channel conductance and prolonged channel lifetime as revealed by Fourier analysis of ACh-induced end-plate current fluctuations. An altered form of the conducting species induced by Pyr appeared to be responsible for either the apparent agonist-induced depolarization or its ability to increase the affinity of ACh for its recognition site. Pyr inhibited the binding of ACh and .alpha.-bungarotoxin to receptor-rich membrane from the electric organ of Torpedo nobiliana, and had a higher affinity for the receptor than for the ion channel binding sites. These actions are distinct from acetylcholinesterase inhibition caused by the agent. The direct influences of the agent on neuromuscular transmission evidently involve at least 3 distinct, although possibly interacting, mechanisms: a weak agonist action, the formation of desensitized receptor-complex intermediates, and the alteration of the conductance properties of active channels.

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