TY - JOUR
T1 - Mechanisms underlying the effects of the pyrethroid tefluthrin on action potential duration in isolated rat ventricular myocytes
AU - Spencer, C. Ian
AU - Sham, James S.K.
PY - 2005/10
Y1 - 2005/10
N2 - 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 INa, 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 (IEAD) that triggered secondary sarcoplasmic reticulum (SR) Ca2+ release. The notion that EADs could stimulate Ca2+ current was strengthened by the persistence of IEAD in myocytes exposed to extracellular Li+ and Sr2+ ions, used to minimize Na+-Ca2+ exchange and SR Ca2+ release, respectively. Tefluthrin inhibited IEAD 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 Ca 2+ 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 INa.
AB - 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 INa, 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 (IEAD) that triggered secondary sarcoplasmic reticulum (SR) Ca2+ release. The notion that EADs could stimulate Ca2+ current was strengthened by the persistence of IEAD in myocytes exposed to extracellular Li+ and Sr2+ ions, used to minimize Na+-Ca2+ exchange and SR Ca2+ release, respectively. Tefluthrin inhibited IEAD 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 Ca 2+ 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 INa.
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U2 - 10.1124/jpet.105.084822
DO - 10.1124/jpet.105.084822
M3 - Article
C2 - 15980056
AN - SCOPUS:25644457582
SN - 0022-3565
VL - 315
SP - 16
EP - 23
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -