Mechanisms underlying the effects of the pyrethroid tefluthrin on action potential duration in isolated rat ventricular myocytes.

Due to increased global use, acute exposures to pyrethroid insecticides in humans are of clinical concern. Pyrethroids have a primary mode of action that involves interference with the inactivation of Na+ currents (I(Na)) in excitable cells, which may include cardiac myocytes. To investigate the possible cardiac toxicity of these agents, we have examined the effects of a type-1 pyrethroid, tefluthrin, on isolated rat ventricular myocytes. Under whole-cell current-clamp, tefluthrin prolonged the mean action potential duration at 90% repolarization (APD90) by 216 +/- 34% in 19 myocytes isolated from 14 hearts. About one-third of this prolongation was apparently due to persistent I(Na), with the balance associated with spontaneous cytosolic Ca2+ waves, and Na+-Ca2+ exchange. In some action potentials, tefluthrin also activated early after-depolarizations (EADs). Using a selected EAD-containing action potential clamp, we observed that EADs could evoke a Cd2+-sensitive membrane current (I(EAD)) that triggered secondary sarcoplasmic reticulum (SR) Ca2+ release. The notion that EADs could stimulate Ca2+ current was strengthened by the persistence of I(EAD) in myocytes exposed to extracellular Li+ and Sr2+ ions, used to minimize Na+-Ca2+ exchange and SR Ca2+ release, respectively. Tefluthrin inhibited I(EAD) by approximately 10%. Together, our results support an arrhythmogenic model whereby tefluthrin exposure stimulated Na+ influx, provoking cellular Ca2+ overload by reverse Na+-Ca2+ exchange. During Ca2+ waves, forward Na+-Ca2+ exchange prolonged the action potential markedly and kindled EADs by permitting the reactivation of Ca2+ current. Similar mechanisms may be involved in pyrethroid toxicity in vivo, and also in type 3 long QT syndrome, wherein Na+ channel mutations prolong I(Na).