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Role of Muscarinic Receptor Subtypes in the Constriction of Peripheral Airways: Studies on Receptor-Deficient Mice

Institute for Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany (N.S., S.S., S.W., A.G., W.K., R.V.H.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive Kidney Diseases, Department of Health and Human Services, Bethesda, Maryland (M.Y., J.W.)

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.

Address correspondence to: Dr. R.V. Haberberger, Institut fur Anatomie and Zellbiologie, Autweg 123, D-35385 Gliessen, Germany. E-mail: rainer.v.haberberger{at}anatomie.med.uni-giessen.de

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