Abstract
Pyrethroid insecticides are known to modify neuronal sodium channels, inducing persistent, steady-state sodium current at depolarized membrane potentials. Cardiac myocytes are also rich in sodium channels but comparatively little is known about the effect of pyrethroids on the heart, or on the cardiac sodium channel isoform. In the present study therefore, we determined the actions of type I and type II pyrethroids against rat and guinea pig ventricular myocytes under current and voltage clamp, and on isolated perfused rat hearts. In myocytes, tefluthrin (type I) and fenpropathrin and α-cypermethrin (type II) prolonged action potentials and evoked afterdepolarizations. The time course of sodium current (INa) was also prolonged by these compounds. Pyrethroids delayed INa inactivation, when measured under selective conditions as current sensitive to 30 μM tetrodotoxin, by increasing the proportion of slowly inactivating current at the expense of fast inactivating current. Further experiments, focusing on fenpropathrin, revealed that its effects on INa inactivation time course were dose-dependent, and the Na+ “window-current” was increased in its presence. In unstimulated, isolated hearts perfused with the same pyrethroids, the variability in contraction amplitude increased due to variations in the intervals between heartbeats. These potentially arrhythmogenic changes are consistent with the effects observed at the cellular level. The type I pyrethroid tetramethrin had little effect in any of the preparations. These findings suggest that some pyrethroids possess considerable mammalian cardiac arrhythmogenic potential, the manifestation of which in vivo may depend on the route of exposure.
Footnotes
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↵1 Present address: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.
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C.I.S. and J.J.B. were kindly supported by Oxford Molecular PLC and the Medical Research Council of Great Britain. K.Y. and J.C.H. acknowledge the support of the Wellcome Trust.
- Abbreviations:
- INa
- sodium current
- BAPTA
- 1,2-bis(2-aminophenoxy)ethaneN,N,N′N′-tetraacetic acid
- TTX
- tetrodotoxin
- AP
- action potential
- APD90
- action potential duration at 90% repolarization
- TTX-S
- tetrodotoxin-sensitive
- I-V
- current-voltage
- FOC
- force of contraction
- COV
- coefficient of variation
- Received February 26, 2001.
- Accepted May 29, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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