Organophosphorus Insecticides Induce Airway Hyperreactivity by Decreasing Neuronal M2 Muscarinic Receptor Function Independent of Acetylcholinesterase Inhibition

• Published in: Toxicological sciences Vol. 83; no. 1; pp. 166 - 176
• Main Authors: Lein, Pamela J., Fryer, Allison D.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.01.2005
• Subjects: Acetylcholinesterase - metabolism; airway hyperreactivity; Animals; asthma; Brain - drug effects; Brain - enzymology; Bronchi - drug effects; Bronchi - enzymology; Bronchi - innervation; Bronchi - metabolism; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - physiopathology; Bronchoconstriction - drug effects; Dose-Response Relationship, Drug; Guinea Pigs; Insecticides - toxicity; M2 muscarinic receptor; Male; Muscle, Smooth - drug effects; Muscle, Smooth - enzymology; Muscle, Smooth - innervation; Muscle, Smooth - metabolism; Neurons - drug effects; Neurons - metabolism; Organophosphorus Compounds - toxicity; organophosphorus pesticides; Pilocarpine - pharmacology; Receptor, Muscarinic M2 - metabolism; Vagotomy; Vagus Nerve - physiology
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfi001

We previously demonstrated that the organophosphorus (OP) insecticide chlorpyrifos potentiates vagally induced bronchoconstriction independent of acetylcholinesterase (AChE) inhibition by decreasing the function of neuronal M2 muscarinic receptors that normally inhibit acetylcholine release from parasympathetic nerves supplying airway smooth muscle. However, it has been reported that different OPs may not affect muscarinic receptors equally. To determine if the effects of chlorpyrifos on airway hyperreactivity can be generalized to other OPs, we tested whether parathion and diazinon also inhibit neuronal M2 receptor function resulting in airway hyperreactivity. In control animals, the M2 agonist pilocarpine inhibits vagally induced bronchoconstriction in a dose-related manner. Treatment of guinea pigs with either parathion (1–10 mg/kg, sc) or diazinon (0.75–75 mg/kg, sc) shifted pilocarpine dose-response curves significantly to the right, indicating loss of neuronal M2 receptor function. These OP treatments also significantly potentiated vagally induced bronchoconstriction. Treatments that did not decrease M2 receptor function (parathion at 0.1 mg/kg, sc, or the non-OP insecticide permethrin at 150 mg/kg, sc) also did not cause airway hyperreactivity. None of the OP treatments altered bronchoconstriction induced by iv acetylcholine or methacholine in vagotomized guinea pigs, suggesting that OP-induced airway hyperreactivity is not due to altered function of muscarinic receptors on airway smooth muscle or to AChE inhibition. AChE assays of lung, blood, and brain confirmed that parathion and diazinon decreased M2 function at concentrations that did not inhibit AChE. These data suggest that multiple diethyl phosphorothionate OPs cause airway hyperreactivity via a common mechanism of M2 receptor dysfunction independent of AChE inhibition.