OZONE-INDUCED LOSS OF NEURONAL M(2) MUSCARINIC RECEPTOR FUNCTION IS PREVENTED BY CYCLOPHOSPHAMIDE

We tested the hypothesis that inflammatory cells mediate the loss of neuronal M(2) 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 mu g/kg iv) and potentiated by the selective M(2) antagonist gallamine (0.1-10 mg/kg iv), indicating that the neuronal M(2) muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M(2) muscarinic receptor function. However, in those animals treated with cyclophosphamide, M(2) 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 M(2) muscarinic receptor.