Prevention of diisopropylphosphorofluoridate-induced myopathy by botulinum toxin type A blockage of quantal release of acetylcholine.
Botulinum toxin type A (BTx), which blocks quantal and partially reduces spontaneous nonquantal acetylcholine (ACh) release at neuromuscular junctions, was tested for its possible attenuating effect on diisopropylphosphorofluoridate (DFP)-induced muscle lesions. The extent of muscle lesion in extensor digitorum longus and soleus muscle of DFP injected rats with and without BTx pretreatment was evaluated using light and electron microscopic procedures. In parallel experiments, acetylcholinesterase (AChE) activity was measured and the functional state of muscles in experimental groups was determined by electrophysiological methods. The results show that pretreatment with BTx almost completely protects the muscles from DFP-induced spontaneous activity and lesions in spite of critically inhibited synaptic AChE. These results are consistent with the conclusion that the effect is not mediated by direct action of organophosphate on muscle, but by the accumulation of ACh resulting in muscle hyperactivity. Therefore, it is concluded that in conditions of acutely inhibited synaptic AChE, the quantal release of ACh is essential for lesion induction, whereas the spontaneous nonquantal ACh release, which is only partially affected in BTx-blocked nerve endings, seems not to be involved.
Sket
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Institute of Pathophysiology, School of Medicine, Ljubljana, Yugoslavia.
Dettbarn
W D
WD
Clinton
M E
ME
Misulis
K E
KE
Sketelj
J
J
Cucek
D
D
Brzin
M
M
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D004576:Electromyography / Q000187:drug effects; D007531:Isoflurophate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D008854:Microscopy, Electron; D009132:Muscles / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009336:Necrosis; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D010276:Parasympatholytics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*
D010276:Parasympatholytics; D007531:Isoflurophate; D000110:Acetylcholinesterase; D001905:Botulinum Toxins; D000109:Acetylcholine