Title
Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation
Author
van Helden, H.P.M.
de Lange, J.
Busker, R.W.
Melchers, B.P.C.
Medisch Biologisch Laboratorium TNO
Publication year
1991
Abstract
Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 (see Compounds) showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals followed HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6. Chemicals/CAS: Antidotes; Cholinesterase Reactivators; HGG 12, 83972-73-0; HI 6, 34433-31-3; Obidoxime Chloride, 114-90-9; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; pralidoxime, 6735-59-7; Pyridinium Compounds
Subject
Biology
Acetylcholinesterase
Direct effect
HGG-12
HI-6
Obidoxime
Organophosphate poisoning
P2S
1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether
[(3 benzoyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether
Obidoxime
Organophosphate
Oxime
Soman
Animal experiment
Animal tissue
Diaphragm
Enzyme inhibition
Enzyme reactivation
Intravenous drug administration
Male
Nonhuman
Priority journal
Rat
Animal
Antidotes
Blood-Brain Barrier
Cholinesterase Reactivators
Diaphragm
In Vitro
Male
Neuromuscular Junction
Obidoxime Chloride
Organophosphorus Compounds
Oximes
Pralidoxime Compounds
Pyridinium Compounds
Rats
Respiratory Insufficiency
Synaptic Transmission
Animalia
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TNO identifier
231594
ISSN
0340-5761
Source
Archives of Toxicology, 65 (7), 586-593
Document type
article