Similar mode of action of pyrethroids and DDT on sodium channel gating in myelinated nerves

Abstract

Synthetic pyrethroids are a new class of highly active insecticides with great potential for practical application¹. They are generally recognized as neurotoxicants that act directly on excitable membranes^2,3. Previous studies have shown that the effect of the pyrethroid allethrin closely resembles that of the classical insecticide dichlorodiphenyl trichloroethane (DDT) in the peripheral nervous system of Xenopus laevis^4,5. Both compounds induce intense repetitive activity in sense organs and in myelinated nerve fibres. In the lateral-line sense organ this repetitive activity increases with cooling, a phenomenon that may be related to the negative temperature coefficient of toxicity of DDT⁶ and pyrethroids⁷ in insects. In frog node of Ranvier, DDT slows the closing of sodium channels that open during depolarization^8,9 so that a prolonged sodium tail current persists after the membrane has been repolarized. We have recently found that the pyrethroid allethrin¹⁰ causes a similar sodium tail current in the nodal membrane of Xenopus. Pyrethroids^11,12 and DDT^13,14 are also known to cause prolongation of the sodium current together with repetitive activity in nerve fibres of invertebrates. The prolonged sodium current is thought to be directly responsible for this repetitive activity^3,15, and it has been suggested that the sodium channel in the nerve membrane is the major target site of pyrethroids and DDT-like compounds^10,12. We have now investigated the mechanism by which pyrethroids and DDT prolong the sodium current in Xenopus nodal membrane. Our results show that these compounds—despite marked differences in chemical structure—modify sodium channel gating in a strikingly similar way and reduce selectively the rate of closing of the activation gate.