Successful oxime therapy one hour after soman intoxication in the rat.
The bisquaternary 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, 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 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 "age" 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 II-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.
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002802:Cholinesterases / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D062025:Organophosphate Poisoning; D010091:Oximes / Q000627:therapeutic use*; D010791:Phrenic Nerve / Q000187:drug effects; D051381:Rats; D012999:Soman / Q000506:poisoning*; D013997:Time Factors
D010091:Oximes; D001285:Atropine; D012999:Soman; D002802:Cholinesterases