Tolerance Following Organophosphate Poisoning of Tracheal Muscle.

Chronic reduction in acetylcholinesterase activity leads to accumulation of acetylcholine at synapses. The continual presence of acetylcholine induces changes in sensitivity of tissues to acetylcholine, in part due to down-regulation (decreased number) of muscarinic receptors. The following report describes experiments designed to determine whether tracheal muscle muscarinic receptors and the tissue response to activation of these receptors change with subacute exposure to diisopropylfluorophosphaonate (DFP). Muscarinic receptor binding characteristics on control and DFP-treated animals, and isometric tension developed in response to various agents (acetylcholine, DFP, Bethanechol, K+) and membrane potential of muscle cells were determined in control and subacutely animals treated with DFP. Displacement of Tritium quinuclidinyl benzilate Tritium QNB binding by agonists and antagonists suggests that the tracheal muscle receptors are of the M2 subtype. Agonists induce a state change in the receptor to a lower affinity form. Subacute treatment with DFP results in a decrease in receptor number of 70% after 7 days and 95% decrease in acetylcholinesterase activity. The dose-response relationships for contraction induced by acetylcholine or bethanechol show several shifts in animals treated for up to 14 days with DFP. In vitro treatment with DFP in control tissue causes a spontaneous development of tension which can be clocked by atropine and pirenzepine and marginally by mecamylamine, but is unaffected by tetrodotoxin (TTX).