Effect of M-2 and M-3 muscarinic receptors on airway responsiveness to carbachol in bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs

The expression balance of M-2 and M-3 muscarinic receptor subtypes on the p athogenesis of airway hyperresponsiveness was investigated by using two con genitally related strains of guinea pigs, bronchial-hypersensitive (BHS) an d bronchial-hyposensitive (BHR). CCh-induced airway responses in vivo and i n vitro were investigated by comparing the effects of muscarinic receptor s ubtype antagonists, and the relative amounts of M-2 and M-3 muscarinic rece ptor mRNA in tracheal smooth muscle and lung tissue were investigated. Afte r treatment with muscarinic receptor subtype antagonists, the ventilatory m echanics (V-T R-aw, and C-dyn) of response to CCh aerosol inhalation were m easured by the bodyplethysmograph method. The effects of these antagonists on CCh-induced tracheal smooth muscle contraction were also investigated. T he effects of M-2 muscarinic receptor blockade were less but the effects of M-3 muscarinic receptors blockade on the airway contractile responses were greater in BHS than in BHR. in M-3 muscarinic receptor blockades, CCh-indu ced tracheal contractions in BHS were significantly greater than those in B HR. In tracheal smooth muscle from BHS, the relative amount of M-2 muscarin ic receptors mRNA was less but that of M-3 muscarinic receptor mRNA was mor e than those in BHR, These results suggest that the high ACh level as a con sequence of dysfunction of M-2 muscarinic autoreceptors and the excessive e ffect of M-3 muscarinic receptors on the airway smooth muscle may play an i mportant role in the pathogenesis of airway hyperresponsiveness.