RT Journal Article SR Electronic T1 Role of Muscarinic Receptor Subtypes in the Constriction of Peripheral Airways: Studies on Receptor-Deficient Mice JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1444 OP 1451 DO 10.1124/mol.64.6.1444 VO 64 IS 6 A1 Nicole Struckmann A1 Sandra Schwering A1 Silke Wiegand A1 Anja Gschnell A1 Masahisa Yamada A1 Wolfgang Kummer A1 Jürgen Wess A1 Rainer V. Haberberger YR 2003 UL http://molpharm.aspetjournals.org/content/64/6/1444.abstract AB In the airways, increases in cholinergic nerve activity and cholinergic hypersensitivity are associated with chronic obstructive pulmonary disease and asthma. However, the contribution of individual muscarinic acetylcholine receptor subtypes to the constriction of smaller intrapulmonary airways that are primarily responsible for airway resistance has not been analyzed. To address this issue, we used videomicroscopy and digital imaging of precision-cut lung slices derived from wild-type mice and mice deficient in either the M1 (mAChR1-/- mice), M2 (mAChR2-/- mice), or M3 receptor subtype (mAChR3-/- mice) or lacking both the M2 and M3 receptor subtypes (mAChR2/3-/- double-knockout mice). In peripheral airways from wild-type mice (mAChR+/+ mice), muscarine induced a triphasic concentration-dependent response, characterized by an initial constriction, a transient relaxation, and a sustained constriction. The bronchoconstriction was diminished by up to 60% in mAChR3-/- lungs and was completely abolished in mAChR2/3-/- lungs. The sustained bronchoconstriction was reduced in mAChR2-/- bronchi, and, interestingly, the transient relaxation was absent; the bronchoconstriction in response to 10-8 M muscarine was increased by 158% in mAChR1-/- mice. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the disruption of specific mAChR genes had no significant effect on the expression levels of the remaining mAChR subtypes. These results demonstrate that cholinergic constriction of murine peripheral airways is mediated by the concerted action of the M2 and M3 receptor subtypes and suggest the existence of pulmonary M1 receptor activation, which counteracts cholinergic bronchoconstriction. Given the important role of muscarinic cholinergic mechanisms in pulmonary disease, these findings should be of considerable therapeutic relevance.