Abstract
Neuronal muscarinic (M2) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M2 autoreceptors by eosinophil major basic protein (MBP) increasing the release of acetylcholine. In vivo, substance P-induced hyperactivity is vagally mediated. Because substance P induces eosinophil degranulation, we tested whether substance P-induced hyperreactivity is mediated by release of MBP and neuronal M2 receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar9,Met(O2)11]-substance P, guinea pigs were hyperreactive to vagal stimulation and M2 receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK1) receptor antagonist (SR-140333) all prevented substance P-induced M2 dysfunction and hyperreactivity. Intravenous heparin acutely reversed M2 receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK1 receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M2 receptors by MBP, resulting in increased release of acetylcholine.
Original language | English (US) |
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Pages (from-to) | L477-L486 |
Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
Volume | 279 |
Issue number | 3 23-3 |
DOIs | |
State | Published - 2000 |
Externally published | Yes |
Keywords
- Antigen challenge
- Eosinophil major basic protein
- Muscarinic receptors
ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Physiology (medical)
- Cell Biology