Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro

Abstract

1 The actions of oximes and related compounds on the nicotinic acetylcholine receptor ion channel at the adult mouse muscle endplate were investigated by use of single-channel recording techniques. The aim of the study was to determine whether the channel-blocking properties of the compounds could contribute to their therapeutic effectiveness against soman poisoning in vitro. 2 Therapeutic effectiveness was assessed in guinea-pig phrenic nerve-hemidiaphragm preparations by measuring the degree of recovery of neuromuscular function produced by the compounds following poisoning by soman. A number of the compounds, including some which lacked the oxime group, produced a significant recovery of neuromuscular function which was unrelated to acetylcholinesterase (AChE) reactivation; this was reversed by washing off the compound, and was therefore attributed to a direct pharmacological action on the muscle. 3 Single channel recordings showed that some of the compounds blocked open nicotinic receptor ion channels in preparations of mouse muscle fibres. The compounds which showed the greatest direct pharmacological actions in diaphragms produce a very fast, flickering blockade of the channels. Several quantitative measures of channel-blocking activity correlated very well with the direct pharmacological action. Furthermore, for two compounds studied in greater detail, the direct action and channelblocking showed similar concentration-response relationships. 4 The results of this study indicate that the direct pharmacological action of oximes and their analogues against neuromuscular blockade by soman in vitro is due to their channel-blocking activity. The direct action does not correlate well with protection against soman poisoning in vivo, however, which suggests that additional non-reactivating properties of these compounds, at sites other than the neuromuscular junction, may also be important for their therapeutic effectiveness.

Nicotinic Antagonists in the Treatment of Nerve Agent Intoxication

“…[13][14][15] Effective compounds have been shown to block the open ion channel of the nAChR 15,16 and this blocking action correlates well with their ability to relieve tetanic block induced by soman. 14 Open channel block, which is a form of noncompetitive antagonism of the action of ACh at the muscle nAChR, is an attractive concept because the block is use-dependent: antagonism becomes greater as activation of the nAChR increases. This is the converse of what happens with a competitive antagonist and, at least in principle, appears to be an ideal way of mitigating the effects of OP-induced overstimulation of muscle nAChRs.…”

“…There is strong experimental evidence that certain bispyridinium compounds have a beneficial effect in OP poisoning through this type of action. [13][14][15] These compounds, which fortuitously include certain oxime reactivators of phosphorylated AChE such as HI-6 and toxogonin, can lead to recovery of function even in the absence of enzyme reactivation. [13][14][15] Effective compounds have been shown to block the open ion channel of the nAChR 15,16 and this blocking action correlates well with their ability to relieve tetanic block induced by soman.…”

“…[13][14][15] These compounds, which fortuitously include certain oxime reactivators of phosphorylated AChE such as HI-6 and toxogonin, can lead to recovery of function even in the absence of enzyme reactivation. [13][14][15] Effective compounds have been shown to block the open ion channel of the nAChR 15,16 and this blocking action correlates well with their ability to relieve tetanic block induced by soman. 14 Open channel block, which is a form of noncompetitive antagonism of the action of ACh at the muscle nAChR, is an attractive concept because the block is use-dependent: antagonism becomes greater as activation of the nAChR increases.…”

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…According to the obtained results, oxime K027 seems to be the best AChE reactivator at the concentration 10 −2 M. However, this concentration level could be toxic to humans [17]. Quite different results were obtained at the lower affinities for human relevant concentrations (10 −4 M and lower) of oximes.…”

“…Current development of prophylaxis and treatment of nerve agent toxicity is focused on scavenger cholinesterases [1,17,18]. Unfortunately, this approach only protects against a few LD 50 nerve agents [19].…”