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 i.p. 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 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), 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.
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
L M
LM
Gambone
C L
CL
Elbon
A D
AD
Fryer
D000758:Anesthesia; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003520:Cyclophosphamide / Q000494:pharmacology*; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006168:Guinea Pigs; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010126:Ozone / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010862:Pilocarpine / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011976:Receptors, Muscarinic / Q000187:drug effects*; D015656:Respiratory Mechanics / Q000187:drug effects
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D010126:Ozone; D003520:Cyclophosphamide; D005703:Gallamine Triethiodide