Substance P-induced airway hyperreactivity is mediated by neuronal M(2) receptor dysfunction

Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L477-86. doi: 10.1152/ajplung.2000.279.3.L477.


Neuronal muscarinic (M(2)) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M(2) 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 M(2) receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar(9),Met(O(2))(11)]- substance P, guinea pigs were hyperreactive to vagal stimulation and M(2) receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK(1)) receptor antagonist (SR-140333) all prevented substance P-induced M(2) dysfunction and hyperreactivity. Intravenous heparin acutely reversed M(2) receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK(1) receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M(2) receptors by MBP, resulting in increased release of acetylcholine.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Blood Proteins / immunology
  • Blood Proteins / physiology
  • Bronchial Hyperreactivity / chemically induced*
  • Bronchial Hyperreactivity / physiopathology
  • Cyclophosphamide / pharmacology
  • Electric Stimulation
  • Eosinophil Granule Proteins
  • Female
  • Guinea Pigs
  • Heparin / pharmacology
  • Neurokinin-1 Receptor Antagonists
  • Neurons / metabolism*
  • Piperidines / pharmacology
  • Quinuclidines / pharmacology
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / physiology*
  • Ribonucleases*
  • Substance P* / analogs & derivatives*
  • Vagus Nerve / physiopathology


  • Antibodies
  • Blood Proteins
  • Eosinophil Granule Proteins
  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Quinuclidines
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • substance P, Sar(9)-Met(O2)(11)-
  • SR 140333
  • Substance P
  • Cyclophosphamide
  • Heparin
  • Ribonucleases