Ozone-induced loss of neuronal M₂ muscarinic receptor function is prevented by cyclophosphamide

We tested the hypothesis that inflammatory cells mediate the loss of neuronal M₂ muscarinic receptors in the lung after ozone exposure. Pathogen- free guinea pigs treated with cyclophosphamide (30 mg · kg^-1 · day^-1 ip for 7 days) before exposure to ozone were compared with untreated ozone- exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 μg/kg iv) and potentiated by the selective M₂ antagonist gallamine (0.1-10 mg/kg iv), indicating that the neuronal M₂ muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M₂ muscarinic receptor function. However, in those animals treated with cyclophosphamide, M₂ muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone- induced hyperresponsiveness and inflammation may be the neuronal M₂ muscarinic receptor.