Contribution of direct actions of the oxime HI-6 in reversing soman-induced muscle weakness in the rat diaphragm.
The actions of the bispyridinium oxime HI-6 ([[[(4-aminocarbonyl)pyridino]-methoxy]methyl]-2- [(hydroxyimino)methyl]-pyridinium dichloride) were investigated in vitro on rat phrenic nerve-hemidiaphragm preparations. Isometric twitch and tetanic tensions were elicited at 37 degrees C with supramaximal nerve stimulation at frequencies of 20 and 50 Hz. To approximate normal respiration patterns, trials consisting of 30 successive 0.55 s trains were alternated with 1.25 s rest periods. Under control conditions, the above stimulation pattern generated tensions that were well maintained at both frequencies. In contrast, a marked depression of muscle tension was observed in diaphragms removed from rats administered 339 micrograms/kg soman (3 LD50) and tested in vitro. Addition of HI-6, 4 h after soman exposure, led to a nearly complete recovery of muscle tension at 20 Hz. At 50 Hz, muscle tensions still declined especially when trains were elicited at 1.25 and 3 s intervals. The recovery by HI-6 observed in this study appears to be mediated by mechanisms unrelated to acetylcholinesterase reactivation since no increase of enzymatic activity was detected and the effect was reversed by a brief washout in oxime-free physiological solution. The results suggest that the direct action of HI-6 may play a role in restoring soman-induced diaphragmatic failure but this effect would be significant primarily under low use conditions.
Adler
M
M
Neurotoxicology and Biochemical Pharmacology Branches, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010.
Maxwell
D M
DM
Filbert
M G
MG
Deshpande
S S
SS
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010091:Oximes; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000494:pharmacology*
D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride