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Forshaw PJ, Lister T, Ray DE: The role of voltage-gated chloride channels in type II pyrethroid insecticide poisoning. Toxicol Appl Pharmacol. 2000 Feb 15;163(1):1-8.
Pyrethroids act on mammalian sodium channels, but we have previously shown that low concentrations of the type II pyrethroid deltamethrin also decrease the open channel probability (P (o)) of voltage-gated chloride channels. This effect would be expected to amplify the sodium channel-mediated signs of poisoning produced by pyrethroids. In the present study we evaluated potential chloride channel agonists in vitro, and then tested the most effective of these on pyrethroid-poisoned rats to determine the practical significance of chloride channel effects in vivo. Patch clamp experiments showed that, for voltage-gated maxi chloride channels in excised, inside-out patches from mouse N1E 115 neuroblastoma cells, ivermectin (10 (-7) M) and pentobarbitone (10 (-6) M) significantly increased open channel probability (p hexobarbitone, mephobarbitone, thiopentone, and barbituric acid did not. This suggested that, if chloride channels were important in vivo, ivermectin and pentobarbitone should antagonize type II pyrethroid poisoning and phenobarbitone should not. Male F344 rats were then pretreated with ivermectin (4 mg/kg iv), equisedative doses of either pentobarbitone (15 mg/kg ip) or phenobarbitone (45 mg/kg ip), or solvent controls. This was followed by deltamethrin (1.5 or 2 mg/kg iv) or the type I pyrethroid cismethrin (4 mg/kg iv). Ivermectin produced a marked fall in deltamethrin-induced salivation (p muscle twitch (p Pentobarbitone significantly reduced the motor signs score due to deltamethrin (p Ivermectin therefore protected against the peripheral signs of deltamethrin poisoning and pentobarbitone protected against the central signs. As expected phenobarbitone had no protective effects. The motor signs produced by the type I pyrethroid cismethrin (which does not act on chloride channels) were not diminished by either barbiturate. The peripheral benzodiazepine receptor blocker PK11195 did not diminish the protective action of ivermectin on the muscle twitch (p block of salivation (p chloride channel is a toxicologically significant additional site of action for deltamethrin and that the use of chloride channel agonists can provide a rationale for a novel and effective therapy against type II pyrethroid poisoning. |
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