TY - JOUR
T1 - Oxime reactivators and their in vivo and in vitro effects on nicotinic receptors
AU - Soukup, O.
AU - Krůšek, J.
AU - Kaniaková, M.
AU - Kumar, U. K.
AU - Oz, M.
AU - Jun, D.
AU - Fusek, J.
AU - Kuča, K.
AU - Tobin, G.
PY - 2011
Y1 - 2011
N2 - Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators Indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
AB - Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators Indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
KW - Isometric muscle contraction
KW - Nicotinic receptors
KW - Organophosphates
KW - Patch-clamp
KW - Reactivator
KW - TE671 cells
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U2 - 10.33549/physiolres.932105
DO - 10.33549/physiolres.932105
M3 - Article
C2 - 21574759
AN - SCOPUS:80053634057
SN - 0862-8408
VL - 60
SP - 679
EP - 686
JO - Physiological Research
JF - Physiological Research
IS - 4
ER -