RH-3421, AN INSECTICIDAL DIHYDROPYRAZOLE, INHIBITS SODIUM CHANNEL-DEPENDENT SODIUM UPTAKE IN MOUSE-BRAIN PREPARATIONS

Assays of radiosodium uptake into mouse brain vesicles were used to assess the actions of RH 3421, an insecticidal dihydropyrazole, on voltage-sensitive sodium channels. Survey experiments showed that RH 3421 acted as a general inhibitor of sodium channel-specific sodium uptake, blocking the uptake stimulated by veratridine, batrachotoxin, crude scorpion (Leiurus quinquestriatus) venom, and pumiliotoxin B. Reciprocal competitive interactions were found between RH 3421 and two activating neurotoxins, veratridine and batrachotoxin. The inhibition by RH 3421 of the sodium uptake stimulated by either veratridine or batrachotoxin was concentration-dependent, but the potency of RH 3421 in these assays depended on the concentration of the activator used to stimulate uptake. RH 3421 also decreased the potency of veratridine as a sodium channel activator. We conclude from our findings that RH 3421 blocks sodium channels by binding to a domain of the sodium channel that is allosterically coupled to the recognition site for veratridine and batrachotoxin. The recognition site for RH 3421 is distinct from the binding domains involved in the actions of N-alkylamides and of pyrethroids and DDT analogs, two other classes of sodium channel-directed insecticides, and therefore defines a new binding site on the sodium channel that is involved in insecticide action. © 1991.