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CARDIOVASCULAR

Mechanisms Underlying the Effects of the Pyrethroid Tefluthrin on Action Potential Duration in Isolated Rat Ventricular Myocytes

Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland

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.

Address correspondence to: Dr. C. Ian Spencer, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: ian.spencer{at}cvt.com