| 6636179 |
Schwab BW, Costa LG, Murphy SD: Muscarinic receptor alterations as a mechanism of anticholinesterase tolerance. Toxicol Appl Pharmacol. 1983 Oct;71(1):14-23.
Tolerance to the toxic signs of the organophosphorus ester acetylcholinesterase inhibitor, O,O-diethyl S-[2-(ethylthio) ethyl] phosphorodithioate (disulfoton), was induced in rats by giving 10 doses of 2.0 mg/kg/day. Concurrent with the induction of tolerance, decreased sensitivity to the cholinergic agonists carbachol and oxotremorine could be demonstrated in studies of heart rate in vivo and in isolated preparations of ileum and atria. A significant decrease in the binding of the muscarinic antagonist [3H] quinuclidinyl benzilate could be demonstrated in ileum from disulfoton-tolerant animals. However, no alterations in the binding of [3H] quinuclidinyl benzilate, [3H] oxotremorine-M, or oxotremorine were evident in atria from tolerant animals. The results suggest that, in addition to receptor loss, other mechanisms distal to ligand recognition sites or removed from the receptor complex may contribute to the subsensitivity of tissues to muscarinic cholinergic agonists. |
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