State-dependent block of rat Nav1.4 sodium channels expressed in Xenopus oocytes by pyrazoline-type insecticides

Insecticidal pyrazolines inhibit voltage-sensitive sodium channels of both insect and mammalian neurons ill a voltage-dependent manner: Studies on the effects of pyrazoline insecticides oil mammalian sodium channels have been limited to experimentation oil the tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channel populations of I-at dorsal root ganglion (DRG) neurons. In this study, we examined the effects of the insecticidal pyrazolines indoxacarb, the N-decarbomethoxyllated metabolite of indoxacarb (DCJW), and RH 3421 oil rat Na(v)1.4sodium channels expressed ill Xenopus laevis oocytes using the two-electrode voltage clamp technique. Both DCJW and RH 3421 were ineffective inhibitors of rat Na(v)1.4 sodium channels at a membrane potential of - 120 in V but depolarization to -60 mV or -30 ill V during insecticide exposure resulted ill substantial block. Inhibition by pyrazoline insecticides was nearly irreversible with washout, but repolarization of the membrane relieved block. DCJW and RH 3421 also caused hyperpolarizing shifts ill the voltage dependence of slow, inactivation without affecting the voltage dependence of activation or fast inactivation. These results suggest that DCJW and RH 3421 interact specifically with the slow inactivated state of the sodium channel. Indoxacarb did not cause block at any potential, yet it interfered with the ability of DCJW, but not RH 3421, to inhibit sodium current. Phenytoin, all anticonvulsant, reduced the efficacy of both DCJW and RH 3421. These data imply that the bindin -, site for pyrazoline insecticides overlaps with that for therapeutic sodium channel blockers. (c) 2005 Elsevier Inc. All rights reserved.