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.
The ability of neuromuscular junctions in old animals to maintain tetanic output was tested in phasic and tonic limb muscles and the physiologic mechanism of maintenance was elucidated by analysis of the turnover of a false transmitter during prolonged tetani. Transmitter release during and after tetani was compared in limb muscles of young (8-9 month) and old (28-30 month) male CBF-1 mice. Amplitudes of end-plate potentials (epp's) in curarized preparations and of spontaneous miniature end-plate potentials (mepp's) were measured in vitro at 30 degrees C in soleus and extensor digitorum longus (edl) muscles. In both young and old soleus muscles, epp amplitude was maintained at about 45% of resting level during the latter part of trains of 1,200 stimuli at 10 Hz but recovered to about 90% control within a few seconds after stimulation ceased. In edl muscles of young mice, epp amplitudes during a 20 Hz train of 1,200 impulses steadily declined to about 20% of control and gradually recovered over 2 min after the tetanus. In old edl muscles, tetanic decay of the epp's was greater and recovery slower than in young muscles, but absolute epp amplitudes were invariably greater. During trains of 6,000 impulses at 10 Hz, plateau epp amplitude decayed to 40-50% in young soleus muscle and 30-40% control in old muscle, but recovery was similar and absolute epp amplitudes were greater in old soleus muscle. A false transmitter precursor, homocholine (HoCh), was used to investigate the mechanism of this prolonged output, and, therefore, the use of HoCh in this system was first validated.(ABSTRACT TRUNCATED AT 250 WORDS)
1 Multiple low doses of the direct acting organopho sphates, ecothiopate, paraoxon and mipafox produced persistent and additive inhibition of diaphragm acetylcholinesterase. Paraoxon and mipafox had similar effects on brain acetylcholinesterase. There was greater recovery from inhibition between doses for paraoxon and ecothiopate than for mipafox. 2 Ecothiopate did not inhibit brain acetylcholinesterase but there was a small increase in activity. 3 Mipafox also had a cumulative inhibitory effect on brain neuropathy target esterase. 4 These results have particular implication for the use of multiple low doses of organophosphates occupation- ally by man.
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