Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates

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Abstract
1 The effects of a range of organophosphorus anticholinesterases on the nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. Diisopropylfluorophosphate (DFP), sarin and soman had no effect on open times at concentrations of up to 100 μm, but ecothiopate (Eco) and O-ethyl S-[2-(diisopropylamino)ethyl]methyl phosphonothiolate (VX) were found to have voltage- and concentration-dependent open channel-blocking actions at concentrations of 1–50 μm. In addition to its channel-blocking action, Eco (50 μm) had a weak agonist effect: it is suggested that this may be attributable to thiocholine produced by hydrolysis of Eco. 2 Rate constants for blockade by Eco and VX were determined according to a sequential model. The greater voltage-dependence of the block by Eco was due to a greater voltage sensitivity of the blocking rate constant compared to VX: the voltage-dependence of the unblocking rate constant was similar for both compounds. 3 In control recordings, the frequency of channel opening declined exponentially with time after formation of the gigaseal. Sarin and soman both increased the rate of this decline, indicating that they accelerated the rate of desensitization of the receptors. Eco and VX reduced the initial frequency of opening, which may have been due to enhancement of a fast phase of desensitization during gigaseal formation, or to blockade of closed channels. 4 It is concluded that the direct actions of organophosphates on nicotinic receptor ion channels are of little importance for their toxicity under normal conditions, since they occur only at much higher concentrations than those which cause inhibition of acetylcholinesterase. Such actions may become apparent, however, when therapies against the anticholinesterase effects of organophosphates increase their lethal dose sufficiently. These direct actions should also be taken into account when the effects of organophosphates on cholinergic transmission are studied.