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Successful oxime therapy one hour after soman intoxication in the rat

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Author: Wolthuis, O.L. · Kepner, L.A.
Type:article
Date:1978
Institution: Medisch Biologisch Laboratorium TNO
Source:European Journal of Pharmacology, 4, 49, 415-425
Identifier: 228428
Keywords: Biology · 1 (3 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether · 1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether · Atropine · Cholinesterase · Oxime · Radioisotope · Soman · Acetylcholine h 3 · Aging · Animal experiment · Breathing · Cytology · Diaphragm · Drug comparison · Drug intoxication · In vitro study · Intoxication · Muscle · Neuromuscular transmission · Peripheral nervous system · Phrenic nerve · Rat · Respiratory failure · Respiratory system · Animal · Atropine · Cholinesterases · Diaphragm · Male · Muscle Contraction · Organophosphorus Compounds · Oximes · Phrenic Nerve · Rats · Soman · Time Factors

Abstract

The bisquarternary mono-oxime HI-6, and to a lesser extent HS-6, caused functional recovery of neuromuscular transmission in vivo and in vitro when given 60 min after soman, i.e. when the soman-cholinesterase (AChE) complex is said to be fully 'aged'. Atropinised rats, with the tracheas intubated, received 4 x LD50 soman i.v. and were kept alive by artificial respiration. 60 min later HI-6 was administered and after an additional 15 min the tracheal tube was removed. Nearly all animals survived for 24 h. After 6 x LD50 soman followed by HI-6, respiratory failure was delayed for hours but almost all animals died within 24 h. Against equal doses of soman, HS-6 was less effective. In experiments with isolated rat phrenic nerve-diaphragm preparations, HI-6 given 60 min after soman produced functional recovery which could be abolished by a second dose of soman, suggesting that HI-6 had reactivated the AChE and that this enzyme was then reinhibited by the second dose of soman. HI-6 reactivates purified bovine erythrocyte AChE when added immediately after inhibition by soman, but does not reactivate tabun-inhibited AChE. Accordingly, no functional recovery of neuromuscular transmission was found in rat diaphragm when HI-6 was administered 60 min after tabun. Furthermore, functional recovery was not obtained with HI-6 after exposure of diaphragms to S 27, which carries a hydroxyl group instead of an alkoxy group - i.e. it is 'pre-aged' - and instantaneously forms an inhibitor-enzyme complex identical to the 'aged' soman-enzyme complex. These results exclude the possibility that the functional recovery was caused by a direct pharmacological effect of the oxime. The functional recovery of diaphragms treated with HI-6 60 min after exposure to soman was not accompanied by a return of histochemically detectable AChE activity. The capacity of the isolated diaphragm to hydrolyze (3H)-acetylcholine, however, seemed to be reactivated to a very small (1-2%) extent by HI-6, 60 min after exposure to soman. It is concluded that soman-inhibited cholinesterase in intact rat tissue 'ages' much more slowly than does soman-inhibited purified cholinesterase, so that even after 60 min enough 'non-aged' inhibited AChE is still susceptible to reactivation to be lifesaving. Chemicals/CAS: 1 (3 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 22625-23-6; 1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether, 34433-31-3; atropine, 51-55-8, 55-48-1; cholinesterase, 9001-08-5; soman, 96-64-0; Atropine, 51-55-8; Cholinesterases, EC 3.1.1.8; Organophosphorus Compounds; Oximes; Soman, 96-64-0