Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Br J Pharmacol. 2012 Mar;165(5):1501-14. doi: 10.1111/j.1476-5381.2011.01632.x.
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.
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.
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.
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.
哮喘的特征是支气管收缩和气道高反应性的可逆性。虽然 M(3)毒蕈碱受体介导支气管收缩，但目前不推荐非选择性毒蕈碱受体拮抗剂用于哮喘的慢性控制。我们测试了在抗原挑战时选择性阻断 M(3)受体是否能阻止抗原攻击后的豚鼠气道高反应性的发展。
卵清蛋白致敏的豚鼠用动力学选择性 M(3)受体拮抗剂噻托溴铵 1 µg·kg(-1)或非选择性毒蕈碱受体拮抗剂阿托品 1 mg·kg(-1)预处理，然后用吸入的卵清蛋白进行挑战。动物在 24 小时后被麻醉、麻痹、通气和迷走神经切断。我们测量了迷走神经介导的支气管收缩和静脉内 ACh 诱导的支气管收缩。
在致敏动物中，双侧迷走神经电刺激诱导出频率依赖性的支气管收缩，在抗原攻击后显著增加。噻托溴铵预处理完全阻断了抗原诱导的高反应性，但阿托品预处理仅部分阻断。令人惊讶的是，尽管噻托溴铵阻断了静脉内 ACh 诱导的支气管收缩，但它并没有抑制致敏对照动物中迷走神经诱导的支气管收缩，这表明噻托溴铵通过阻断迷走神经释放的 ACh 的受体来阻断高反应性。相反，噻托溴铵可能通过抗炎机制发挥作用，因为它抑制了嗜酸性粒细胞在肺和神经周围的聚集。
这些数据证实了用外源性 ACh 测试 M(3)受体阻断并不能预测迷走神经阻断。我们的数据还表明，选择性阻断 M(3)受体可能通过与抑制支气管收缩无关的机制在哮喘中有效。
