Acute and long-lasting cardiac changes following a single whole-body exposure to sarin vapor in rats.
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 on EPIA of whole-body exposure of animals to a potent acetylcholine esterase inhibitor. Freely moving rats were exposed to sarin vapor (34.2 +/- 0.8 microg/liter) for 10 min. The electrocardiograms (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 of sarin exposure. Additional occasional deaths were recorded for up to 6 months (final mortality rate of 48%). Surviving rats showed, agitation, aggression, and weight loss compared to non-exposed rats, and about 20% of them experienced 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 lasted 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 k(D) or B(max) values of (3)H-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.
Allon
N
N
Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona. nahum@iibr.gov.il
Rabinovitz
I
I
Manistersky
E
E
Weissman
B A
BA
Grauer
E
E
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001285:Atropine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine; D006321:Heart / Q000187:drug effects*; D019570:Inhalation Exposure; D007928:Lethal Dose 50; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*; D012601:Scopolamine / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D014662:Vasoconstrictor Agents
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D014662:Vasoconstrictor Agents; D001285:Atropine; D012524:Sarin; D012601:Scopolamine; D004837:Epinephrine