Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors

被引:27
|
作者
Fisher, JT [1 ]
Vincent, SG
Gomeza, J
Yamada, M
Wess, J
机构
[1] Queens Univ, Dept Physiol, Kingston, ON K7L 3N6, Canada
[2] Queens Univ, Dept Med, Kingston, ON K7L 3N6, Canada
[3] Queens Univ, Dept Pediat, Kingston, ON K7L 3N6, Canada
[4] NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA
来源
FASEB JOURNAL | 2004年 / 18卷 / 02期
关键词
heart rate; airway smooth muscle; asthma; COPD; vagus nerve; parasympathetic nervous system;
D O I
10.1096/fj.03-0648fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The presence of multiple muscarinic acetylcholine receptor (mAChR) subtypes in the heart and lung, combined with the lack of mAChR subtype-selective ligands, have complicated the task of identifying the mAChR subtypes mediating cardiac slowing (bradycardia) and airway narrowing (bronchoconstriction) due to vagal innervation. To determine which of the five mAChRs are responsible for the cholinergic control of heart rate and airway caliber in vivo, we performed experiments on mutant mice lacking the two prime candidates for such control, the M-2 or M-3 mAChR. Here, we report that in vivo, bradycardia caused by vagal stimulation or administration of the muscarinic agonist methacholine (MCh) was abolished in mice lacking functional M-2 mAChRs (M2(-/-) mice). In contrast, heart rate responses remained unchanged in M-3 receptor-deficient mice (M3(-/-) mice). The reduced hypotensive response of M3-/- mice to MCh suggests M-3 mAChRs contribute to peripheral vasodilation. The M2-/- mice showed significantly enhanced in vivo bronchoconstrictor responses to vagal stimulation or MCh administration. In contrast, bronchoconstrictor responses were totally abolished in M3-/- mice. Because altered cardiac or pulmonary vagal tone is involved in a number of pathophysiological conditions, including cardiac arrhythmias, chronic obstructive pulmonary disease and asthma, these results should be of considerable therapeutic relevance.
引用
收藏
页码:711 / +
页数:18
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