Pyrethroids: involvement of sodium channels in effects on inositol phosphate formation in guinea pig synaptoneurosomes.
The effects of pyrethroids were studied on phosphoinositide breakdown in guinea pig synaptoneurosomes. Similar to other agents that activate voltage-dependent sodium channels, type I and type II pyrethroids stimulated phosphoinositide breakdown. Type II pyrethroids, like deltamethrin and fenvalerate, were more potent and, at least for deltamethrin, more efficacious than type I pyrethroids, like allethrin, resmethrin and permethrin. The effects of type II pyrethroids could be partially inhibited by the sodium channel blocker tetrodotoxin. The effects of allethrin and resmethrin were not affected by 5 microM tetrodotoxin. Stimulation of phosphoinositide breakdown by fenvalerate was additive to the stimulation elicited by the receptor agonists carbamylcholine and norepinephrine, but not to the stimulation elicited by sodium channel agents (batrachotoxin, scorpion venom and pumiliotoxin B). Stimulation by allethrin was not additive to the stimulation elicited either by receptor agonists or sodium channel agents. A submaximal concentration of allethrin, a type I pyrethroid, did not greatly affect the dose-dependent stimulation elicited by a type II pyrethroid, deltamethrin, while a higher concentration of allethrin prevented further stimulation by type II pyrethroids. A local anesthetic, dibucaine, which inhibits sodium channel activation, inhibited phosphoinositide breakdown induced by type II, but not by type I pyrethroids, except at higher concentrations. Thus, type II pyrethroids appear to stimulate phosphoinositide breakdown in synaptoneurosomes in a manner analogous to other sodium channel agents, while type I pyrethroids elicit phosphoinositide breakdown by a different mechanism, probably not involving sodium channels.
Gusovsky
F
F
Laboratory of Bioorganic Chemistry, NIDDK, Bethesda, MD 20892.
Secunda
S I
SI
Daly
J W
JW
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D007295:Inositol Phosphates / Q000378:metabolism*; D007306:Insecticides / Q000494:pharmacology; D009570:Nitriles; D011722:Pyrethrins / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013403:Sugar Phosphates / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D007295:Inositol Phosphates; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; D015222:Sodium Channels; D013403:Sugar Phosphates; C017180:decamethrin; C017690:fenvalerate