METHOCTRAMINE INDUCES NONSPECIFIC AIRWAY HYPERRESPONSIVENESS IN-VIVO

We investigated the effects of subtype-selective muscarinic receptor a ntagonists upon aerosol antigen-induced bronchoconstriction in anesthe tized guinea pigs. Neither pirenzepine (muscarinic M(1) receptor-selec tive), 4-methylpiperidine methiodide (4-DAMP, muscarinic M(3) receptor -selective), thyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl)] pipera zine HCl (DAC-5945, muscarinic M(3) receptor-selective), ipratropium o r atropine inhibited bronchoconstriction, but methoctramine (muscarini c M(2) receptor-selective) produced a dose-dependent increase in bronc hoconstriction (up to 46%). Methoctramine also produced increases in b ronchoconstriction induced by aerosols of histamine (up to 45%) and pl atelet activating factor (up to 118%), demonstrating nonspecific airwa y hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to alter ed arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsivenes s, suggesting that this effect resulted from the reported ganglionic b locking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchocon striction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarin ic receptors in airway inflammatory responses in vivo.