title: Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin.
abstract: The pyrethroid insecticides are known to slow the kinetics of the activation and inactivation gates of sodium channels. This results in prolonged openings of individual sodium channels and prolonged flow of whole-cell sodium current, which in turn cause hyperexcitation in animals. The aim of the present study was to solve three important remaining questions. First, the percentages of the sodium channels modified by the pyrethroid tetramethrin were measured and compared with the threshold concentration to initiate repetitive discharges in rat cerebellar Purkinje neurons. Tetramethrin at 0.1 microM modified only 0.6% of the sodium channels and generated repetitive afterdischarges. Thus, the pyrethroid toxicity is greatly amplified from the sodium channel to the whole animal. The pyrethroid sensitivity of Purkinje neuron sodium channels was lower than that of invertebrate sodium channels by a factor of > or = 10. Chloramine-T at 200 microM removed the sodium channel inactivation and increased the percentage of sodium channel modification by tetramethrin through open channel modification. Second, temperature had a profound effect on the ability of tetramethrin to cause repetitive afterdischarges; at 0.1 to 0.3 microM tetramethrin, repetitive discharges were induced at l5 degrees C and 20 degrees C, but this effect subsided at 25 degrees C to 35 degrees C. This negative temperature dependence could be explained by an increase in charge movement during slow tail current as temperature was lowered. The Q10 value for the charge movement during tail current was 0.22 between 20 degrees C and 30 degrees C. Third, the selective toxicity of pyrethroids between mammals and insects could be explained quantitatively on the basis of sodium channel factors that include temperature dependence, intrinsic sensitivity and recovery rate and detoxication factors.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois.
authors.forename: J H
authors.initials: JH
authors.lastname: Song
authors.forename: T
authors.initials: T
authors.lastname: Narahashi
mesh_terms: D000818:Animals; D002700:Chloramines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D013696:Temperature; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D002700:Chloramines; D007306:Insecticides; D011722:Pyrethrins; D015222:Sodium Channels; D014105:Tosyl Compounds; C016300:chloramine-T; C009424:tetramethrin