Substance P-induced airway hyperreactivity is mediated by neuronal M2 receptor dysfunction

Christopher M. Evans, Kristen E. Belmonte, Richard W. Costello, David Jacoby, Gerald J. Gleich, Allison Fryer

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume279
Issue number3 23-3
StatePublished - 2000
Externally publishedYes

Fingerprint

Substance P
Eosinophil Major Basic Protein
Acetylcholine
Guinea Pigs
Neurokinin-1 Receptor Antagonists
Muscarinic M2 Receptors
Neurokinin-1 Receptors
Autoreceptors
Proteins
Vagus Nerve
Eosinophils
Intravenous Administration
Cyclophosphamide
Heparin
Antigens
Lung
Antibodies

Keywords

  • Antigen challenge
  • Eosinophil major basic protein
  • Muscarinic receptors

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Substance P-induced airway hyperreactivity is mediated by neuronal M2 receptor dysfunction. / Evans, Christopher M.; Belmonte, Kristen E.; Costello, Richard W.; Jacoby, David; Gleich, Gerald J.; Fryer, Allison.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 279, No. 3 23-3, 2000.

Research output: Contribution to journalArticle

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