Non‐bronchodilating mechanisms of tiotropium prevent airway hyperreactivity in a guinea‐pig model of allergic asthma

BACKGROUND AND PURPOSE Asthma is characterized by reversible bronchoconstriction and airway hyperreactivity. Although M3 muscarinic receptors mediate bronchoconstriction, non‐selective muscarinic receptor antagonists are not currently recommended for chronic control of asthma. We tested whether selective blockade of M3 receptors, at the time of antigen challenge, blocks subsequent development of airway hyperreactivity in antigen‐challenged guinea‐pigs. EXPERIMENTAL APPROACH Ovalbumin‐sensitized guinea‐pigs were pretreated with 1 µg·kg−1 of a kinetically selective M3 receptor antagonist, tiotropium, or 1 mg·kg−1 of a non‐selective muscarinic receptor antagonist, atropine, and challenged with inhaled ovalbumin. Animals were anaesthetized, paralyzed, ventilated and vagotomized 24 h later. We measured vagally mediated bronchoconstriction and i.v. ACh‐induced bronchoconstriction. KEY RESULTS Electrical stimulation of both vagus nerves induced frequency‐dependent bronchoconstriction in sensitized animals that was significantly increased after antigen challenge. Antigen‐induced hyperreactivity was completely blocked by tiotropium pretreatment but only partially blocked by atropine pretreatment. Surprisingly, although tiotropium blocked bronchoconstriction induced by i.v. ACh, it did not inhibit vagally‐induced bronchoconstriction in sensitized controls, suggesting that tiotropium does not block hyperreactivity by blocking receptors for vagally released ACh. Rather, tiotropium may have worked through an anti‐inflammatory mechanism, since it inhibited eosinophil accumulation in the lungs and around nerves. CONCLUSIONS AND IMPLICATIONS These data confirm that testing M3 receptor blockade with exogenous ACh does not predict vagal blockade. Our data also suggest that selective blockade of M3 receptors may be effective in asthma via mechanisms that are separate from inhibition of bronchoconstriction.