Abstract

Interactions of O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonothioate (VX), an irreversible, organophosphorus, anticholinesterase (anti-ChE) agent, with the nicotinic acetylcholine receptor-ion channel complex (AChR) of the frog Rana pipiens were investigated using electrophysiological techniques. At low concentrations (0.1-0.5 microM) of VX, typical effects due to cholinesterase (ChE) inhibition, such as potentiation of indirect muscle twitches as well as increases in the peak amplitude and decay time constant (tau EPC) of end-plate currents (EPC), were observed. At concentrations greater than or equal to 1.0 microM, VX produced opposite effects. The indirectly elicited muscle twitches and EPC peak amplitude were depressed with an IC50 of about 33 microM. tau EPC was reduced, and at a higher concentration of 100 microM, VX split the decays into faster and slower components. Similar results were also obtained with the amplitude and decays of miniature end-plate currents (MEPC). However, although the MEPC peak amplitude and tau MEPC were not decreased to levels below control values, EPC peak amplitude (but not its tau EPC) was markedly depressed beyond the control values, in a concentration-dependent manner. The fact that nerve action potential-evoked events were more affected than the spontaneous MEPCs suggested an interference with the depolarization-evoked release process. Indeed, VX caused a reduction of the quantal content and, in addition, induced a significant increase in the frequency of MEPCs. All these effects, except the anti-ChE activity, were reversible upon wash. The results from both EPC fluctuation analysis and single channel recordings disclosed a concentration-dependent shortening of the channel open times without change in single channel conductance.(ABSTRACT TRUNCATED AT 250 WORDS)