Presynaptic effects of neuromuscular cholinesterase inhibition.
Paraoxon, an irreversible organophosphorus inhibitor of cholinesterase, produces a myopathy beginning at the neuromuscular junction in rat diaphragm muscles. Thirty minutes after paraoxon was injected i.p. (0.5 mg/kg), neuromuscular cholinesterase activity was reduced to 36% of control. The frequency of miniature end-plate potentials (MEPPs) in diaphragms from paraoxon-treated rats was 109/sec compared with 2.9/sec in saline-injected controls. The faster frequency was seen after paraoxon gradually declined to control rates within 6 hours after injection. The quantum content of end-plate potentials was reduced to 66% of that seen in saline controls. Spontaneous and impulse-related antidromic activity was observed along the phrenic nerve after paraoxon which also gradually diminished with time. When the phosphorylated acetylcholinesterase was reactivated with 10(-3) pyridine-2-aldoxime methiodide, MEPP frequency was reduced significantly and antidromic activity was abolished. Block of axonal excitability with 10(-6) M tetrodotoxin reduces the effects of paraoxon on MEPP frequency and antidromic activity, while acetylcholinesterase remains inhibited. In vitro perfusion with 6 times 10(-8) M paraoxon increases MEPP frequency and initiates antidromic activity. It is concluded that inhibition of neuromuscular cholinesterase by paraoxon leads to an alteration of transmitter release, and this may be associated with ultrastructural abnormalities observed at the motor endplate.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases / Q000032:analysis; D003964:Diaphragm / Q000201:enzymology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000187:drug effects / Q000201:enzymology; D009119:Muscle Contraction / Q000187:drug effects; D009469:Neuromuscular Junction / Q000201:enzymology*; D010261:Paraoxon / Q000494:pharmacology*; D010791:Phrenic Nerve / Q000502:physiology; D011220:Pralidoxime Compounds / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D011220:Pralidoxime Compounds; D002802:Cholinesterases; D010261:Paraoxon