Abstract
Interactions of the oximes pyridine-2-aldoxime (2-PAM) and 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino++ +)-2-oxapropane dichloride (HI-6), reactivators of phosphorylated acetylcholinesterase enzyme, with the nicotinic acetylcholine receptor-ion channel complex were studied using electrophysiological techniques. Single channel studies revealed that both oximes increased the opening probability of channels that were activated by acetylcholine. The oximes reduced mean channel open time and burst time in a concentration- and voltage-dependent manner. End-plate current amplitude was increased by 2-PAM (10-100 microM) and HI-6 (1 microM) but depressed at higher concentrations of these agents. The oximes decreased the time constant of end-plate current decay, particularly at hyperpolarized membrane potentials. HI-6 depressed indirect twitch response of the sartorius muscle, whereas 2-PAM caused a facilitation followed by depression. Both agents directly hydrolyzed acetylthiocholine, in addition to weakly inhibiting acetylcholinesterase. Our study demonstrates a direct molecular interaction of the oximes HI-6 and 2-PAM with the natural agonist molecule and with the acetylcholine receptor-ion channel complex. These effects can explain the excitatory and inhibitory actions of both agents, and may form the basis for their antidotal effectiveness against organophosphorus poisoning. The quantitative differences between the effects of 2-PAM and HI-6 on the above parameters are important in view of their differential antidotal efficacies.
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