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

Abstract

BACKGROUND AND PURPOSE Asthma is characterized by reversible bronchoconstriction and airway hyperreactivity. Although M 3 muscarinic receptors mediate bronchoconstriction, non-selective muscarinic receptor antagonists are not currently recommended for chronic control of asthma. We tested whether selective blockade of M 3 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 M 3 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 M 3 receptor blockade with exogenous ACh does not predict vagal blockade. Our data also suggest that selective blockade of M 3 receptors may be effective in asthma via mechanisms that are separate from inhibition of bronchoconstriction. © 2011 The Authors.