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

C. Ian Spencer, James S.K. Sham

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)16-23
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number1
DOIs
StatePublished - Oct 1 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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