Miotic tolerance to sarin vapor exposure: role of the sympathetic and parasympathetic nervous systems.
O-isopropyl methylphosphonofluoridate, also known as sarin or GB, is a highly toxic organophosphorous compound that exerts its effect by inhibiting the enzyme acetylcholinesterase. While the effects of a single exposure to GB vapor are well characterized, the effects of multiple exposures to GB vapor are less clear. Previous studies in the rat and guinea pig have demonstrated that multiple exposures result in tolerance to the miotic effect of nerve agents. The aim of the present study was to examine potential mechanisms responsible for tolerance to the miotic effect of GB vapor that has been observed in the rat after multiple exposures. Multiple whole-body inhalation exposures to GB vapor were conducted in a dynamic airflow chamber. Exposures lasted 60 min and each of the three exposures occurred at 24-h intervals. The results of the present study demonstrate that the alpha-adrenergic antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol did not affect the development of tolerance to the miotic effect of GB vapor, suggesting that enhanced sympathetic tone to the eye is not responsible for the observed tolerance. Administration of atropine before the first exposure prevented the tolerance to the miotic effect of GB vapor after the third exposure, suggesting that the tolerance is the result of muscarinic receptor desensitization secondary to receptor stimulation. The present study extends the findings of previous studies to strengthen the hypothesis that the miotic tolerance observed in the rat upon repeated exposure to nerve agents is due to desensitization of muscarinic acetylcholine receptors located on the pupillary sphincter.
Dabisch
Paul A
PA
National Academy of Sciences-National Research Council, Washington, DC, USA. paul.dabisch@us.army.mil
Miller
Dennis B
DB
Reutter
Sharon A
SA
Mioduszewski
Robert J
RJ
Thomson
Sandra A
SA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D005740:Gases; D007259:Infrared Rays; D008297:Male; D015877:Miosis / Q000139:chemically induced* / Q000473:pathology; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects; D012524:Sarin / Q000633:toxicity*; D013564:Sympathetic Nervous System / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D002800:Cholinesterase Inhibitors; D005740:Gases; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D001285:Atropine; D012524:Sarin; D010646:Phentolamine