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 pathogenesis of airway hyperresponsiveness was investigated by using two congenitally related strains of guinea pigs, bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR). CCh-induced airway responses in vivo and in vitro were investigated by comparing the effects of muscarinic receptor subtype antagonists, and the relative amounts of M-2 and M-3 muscarinic receptor mRNA in tracheal smooth muscle and lung tissue were investigated. After treatment with muscarinic receptor subtype antagonists, the ventilatory mechanics (V-T R-aw, and C-dyn) of response to CCh aerosol inhalation were measured by the bodyplethysmograph method. The effects of these antagonists on CCh-induced tracheal smooth muscle contraction were also investigated. The 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-induced tracheal contractions in BHS were significantly greater than those in BHR. In tracheal smooth muscle from BHS, the relative amount of M-2 muscarinic receptors mRNA was less but that of M-3 muscarinic receptor mRNA was more than those in BHR, These results suggest that the high ACh level as a consequence of dysfunction of M-2 muscarinic autoreceptors and the excessive effect of M-3 muscarinic receptors on the airway smooth muscle may play an important role in the pathogenesis of airway hyperresponsiveness.