title: Methoctramine induces nonspecific airway hyperresponsiveness in vivo.
abstract: We investigated the effects of subtype-selective muscarinic receptor antagonists upon aerosol antigen-induced bronchoconstriction in anesthetized guinea pigs. Neither pirenzepine (muscarinic M1 receptor-selective), 4-methylpiperidine methiodide (4-DAMP, muscarinic M3 receptor-selective), [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCl (DAC-5945, muscarinic M3 receptor-selective), ipratropium or atropine inhibited bronchoconstriction, but methoctramine (muscarinic M2 receptor-selective) produced a dose-dependent increase in bronchoconstriction (up to 46%). Methoctramine also produced increases in bronchoconstriction induced by aerosols of histamine (up to 45%) and platelet activating factor (up to 118%), demonstrating nonspecific airway hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsiveness, suggesting that this effect resulted from the reported ganglionic blocking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchoconstriction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarinic receptors in airway inflammatory responses in vivo.
authors.affiliation: Nova Pharmaceutical Corporation, Baltimore, MD 21224.
authors.forename: R E
authors.initials: RE
authors.lastname: Howell
authors.forename: M P
authors.initials: MP
authors.lastname: Kovalsky
authors.forename: K D
authors.initials: KD
authors.lastname: Laemont
mesh_terms: D000336:Aerosols; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001285:Atropine / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D016084:Bronchoconstriction / Q000187:drug effects*; D003959:Diamines / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000633:toxicity; D008297:Male; D018727:Muscarinic Antagonists; D010047:Ovalbumin / Q000633:toxicity; D010276:Parasympatholytics / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000633:toxicity; D011433:Propranolol / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism
chemical_list: D000336:Aerosols; D003959:Diamines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010879:Piperazines; D010880:Piperidines; D010972:Platelet Activating Factor; D011976:Receptors, Muscarinic; C070672:DAC 5945; D016718:Arachidonic Acid; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D006632:Histamine; D010047:Ovalbumin; D011433:Propranolol; C054938:methoctramine; D005703:Gallamine Triethiodide; D000420:Albuterol