A comparison of cholinergic effects of HI-6 and pralidoxime-2-chloride (2-PAM) in soman poisoning.
The effects of HI-6 and pralidoxime chloride (2-PAM) on soman-induced lethality, time to death and several cholinergic parameters in rats were compared to understand the beneficial action of HI-6. Treatment with atropine sulfate (ATS) or HI-6 alone protected against 1.2 and 2.5 LD50s of soman respectively, whereas 2-PAM or methylated atropine (AMN) alone afforded no protection. Addition of ATS, but not AMN, to HI-6-treated rats enhanced the protection from 2.5 to 5.5 LD50s. HI-6 increased the time-to-death, while 2-PAM had no effect; a combination of HI-6 and ATS provided the most significant increase in time-to-death. Cholinesterase (ChE) activity was not altered in any tissue by ATS, HI-6 or 2-PAM treatment individually, but was markedly inhibited in all tissues by 100 micrograms/kg of soman. In soman-poisoned rats, the HI-6, but not the 2-PAM, group had significantly higher levels of ChE in blood and other peripheral tissues than did the group given soman alone. Neither HI-6 nor 2-PAM affected soman-inhibited ChE in the brain. Additional ATS treatment had no effect on ChE activity. HI-6 and 2-PAM neither modified baseline brain acetylcholine (ACh) or choline (Ch) levels nor protected against soman-induced ACh or Ch elevation. 2-PAM exhibited a 4-fold more potent in vitro inhibition of 3H-quinuclidinyl benzilate (3H-QNB) binding and sodium-dependent high-affinity Ch uptake (HACU) than did HI-6 in brain tissues. The findings that 2-PAM is a more potent in vitro inhibitor of muscarinic receptor binding and HACU than HI-6, and yet neither elevates ChE activity in the periphery nor protects rats against soman poisoning, indicate the importance of higher ChE activity in the periphery of HI-6-treated rats. Maintenance by HI-6 of a certain amount of active ChE in the periphery appears to be important for survival after soman exposure.
Shih
T
T
U.S. Army Medical Research Institute of Chemical Defense Center, Aberdeen Proving Ground, MD.
Whalley
C E
CE
Valdes
J J
JJ
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism*; D004347:Drug Interactions; D007928:Lethal Dose 50; D008297:Male; D010091:Oximes; D011220:Pralidoxime Compounds / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D012999:Soman / Q000037:antagonists & inhibitors / Q000506:poisoning*
D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; D002802:Cholinesterases; C022870:asoxime chloride; C028797:pralidoxime