ToxSci Advance Access published online on July 20, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi263
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1 Department of Pharmacology, Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, Israel
* To whom correspondence should be addressed. Epinephrine-induced arrhythmias (EPIA) are known to be associated with local cardiac cholinergic activation. The present study examined the development of QT prolongation and the effect of whole body exposure of animals to a potent acetylcholine esterase inhibitor, on EPIA. Freely moving rats were exposed to sarin vapor (34.2±0.8 µg/liter) for 10 min. The ECG of exposed and control animals were monitored every 2 weeks for 6 months. One and six months post exposure rats were challenged with epinephrine under anesthesia and the threshold for arrhythmias was determined. Approximately 35% of the intoxicated rats died within 24 h after sarin exposure. Additional occasional deaths were recorded for up to 6 month (final mortality rate of 48%). Surviving rats showed, agitation, aggression and weight loss compared to non-exposed rats and about 20% of them even sporadic convulsions. Sarin challenged rats with severe symptoms demonstrated QT segment prolongation during the first 2-3 weeks after exposure. The EPIA that appeared at a significantly lower blood pressure in the treated group in the first month after intoxication, continued for up to 6 months. This decrease in EPIA threshold was blocked by atropine and methyl-atropine. Three months post exposure no significant changes were detected in either kD or Bmax values of [3H]N-methyl scopolamine binding to heart homogenates, or in the affinity of carbamylcholine to cardiac muscarinic receptors. The increase in the vulnerability to develop arrhythmias long after accidental or terror-related organophosphate (OP) intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.
Received May 5, 2005
Accepted July 12, 2005
Environmental Toxicology
Acute and Long Lasting Cardiac Changes Following a Single Whole Body Exposure to Sarin Vapor in Rats
N. Allon, E-mail: nahum{at}iibr.gov.il
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