The role of voltage-gated chloride channels in type II pyrethroid insecticide poisoning.
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 </= 0.01 and p </= 0.02, respectively), whereas phenobarbitone, 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 </= 0.05) and also (in anesthetized rats) in repetitive electromyogram discharge and muscle twitch (p </= 0.01 and p </= 0.05, respectively). Pentobarbitone significantly reduced the motor signs score due to deltamethrin (p </= 0.01). 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 </= 0.05), although it partially reversed the block of salivation (p </= 0.05). These results support the hypothesis that the voltage-dependent 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.
Forshaw
P J
PJ
MRC Toxicology Unit, Lancaster Road, Leicester, LEI 9HN, United Kingdom.
Lister
T
T
Ray
D E
DE
D000818:Animals; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000502:physiology*; D007306:Insecticides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D007559:Ivermectin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D009570:Nitriles; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011722:Pyrethrins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D065101:Chloride Channel Agonists; D018118:Chloride Channels; D007306:Insecticides; D007546:Isoquinolines; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; C017498:cismethrin; D007559:Ivermectin; D010424:Pentobarbital; C037850:PK 11195; D010634:Phenobarbital