The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles

Abstract

1 The purpose of this investigation was to determine the long-term effects of a single dose of persistent anticholinesterases on muscle action potentials evoked by nerve stimulation. 2 Action potentials (APs), elicited by stimulation of the phrenic nerve, were recorded intracellularly in muscle fibres of mouse diaphragm. The time between stimulus and AP was measured and the variability of this latency was calculated during trains of APs. At the beginning of trains of APs there was an increase in latency, and this delay was also measured. 3 Within 3h of subcutaneous injection, a single dose (500nmolkg-1) of the anticholinesterase, ecothiopate produced about 90% reduction in the acetylcholinesterase activity of homogenates of mouse diaphragm muscle, but five days after injection, this activity was not different from values in untreated animals. The initial delay of APs and the variability of latencies were increased four fold and two fold respectively, remained at these maxima from the 1st to the 5th day after ecothiopate, and returned to the values in untreated animals between 15 and 27 days after ecothiopate. 4 These effects of ecothiopate on AP latency were dose-dependent and were also seen in extensor digitorum longus and soleus muscles. 5 Other anticholinesterases used were BOS (pinacolyl S-(2-trimethylaminoethyl)methylphosphonothioate), a quaternary compound, and diisopropyl fluorophosphate, a tertiary compound, which had effects similar to those of ecothiopate; the greater duration of the effects of this compound may be related to the greater duration of reduction in cholinesterase activity. 6 Ecothiopate had no effect on the delay or variability of latencies of endplate potentials which were recorded in cut-fibre preparations 5 days later. 7 It is concluded that the effects of ecothiopate on the latencies of indirectly-evoked muscle APs are postjunctional, may not be related to the degree of reduction in cholinesterase activity at the time of recording, and are not directly linked to necrosis.

Protection against the effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles

“…The acetylcholinesterase activity of diaphragm homogenates was inhibited rapidly after the injection of ECO and its recovery was evident 1 day later (Townsend, 1988;Bamforth, 1989) and was complete by 5 days (Kelly et al, 1990 (Dirnhuber & Green, 1978;French et al, 1979;Leadbeater et al, 1985). In our experiments, protection by PYR of some of the AChE against inhibition of ECO or the early reactivation of some of the ECO-inhibited enzyme with 2PAM, was associated with prevention of increased MCD or delay.…”

“…Considering these results in isolation, it might seem that initiation of increased jitter requires inhibition of more than 75% of the AChE. However, Kelly et al (1990) showed that ECO 0.3 mol kg-' caused 87% inhibition at 3 h, but only an increase in delay at 5 days, and 1 mol kg-' BOS increased MCD but caused only 37% inhibition of acetylcholinesterase. Thus there appears to be no simple relationship between increased jitter and the maximum inhibition of the AChE of diaphragm homogenates at 3 h after injection of organophosphate.…”

“…However, neither vitamin E nor NAC, alone or in combination, in dosage regimes which ameliorated the myopathy, had any effect on the increase in MCD and delay produced by ECO, even after prolonging the daily dosing with Vitamin E to cover the period after ECO exposure until the day when the jitter was measured. The failure of treatment with antioxidants to prevent the increased jitter together with the observation that non-necrotizing doses of ECO can produce increased MCD and delay (Kelly et al, 1990), is evidence that increased jitter is not a consequence of necrosis. Thus the common steps in the aetiology of necrosis and jitter after ECO precede the generation and action of free radicals.…”

“…It has been reported (Kelly et al, 1990) that the organophosphate (OP) anticholinesterases, ecothiopate (ECO), pinacolyl S-(2-trimethylaminoethyl) methylphosphonothioate (BOS), and diisopropylfluorophosphate (DFP) affected the latencies of indirectly-evoked muscle action potentials (APs). A single dose of any of these OPs increased the variability of the latencies of a train of indirectly-evoked muscle APs, i.e.…”

The origin of the effects of an anticholinesterase on the latencies of action potentials in mouse skeletal muscles

“…Experiments reported by Kelly et al (1990) showed that the 'jitter' i.e. the variability of latencies of indirectly-elicited diaphragm muscle action potentials was increased 5 days after administration of a single dose (0.5 jmol kg-') of ecothiopate, a quaternary organophosphate.…”