Substance P-induced airway hyperreactivity is mediated by neuronal M(2) receptor dysfunction.
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.
Evans
C M
CM
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Belmonte
K E
KE
Costello
R W
RW
Jacoby
D B
DB
Gleich
G J
GJ
Fryer
A D
AD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001798:Blood Proteins / Q000276:immunology / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004558:Electric Stimulation; D047091:Eosinophil Granule Proteins; D005260:Female; D006168:Guinea Pigs; D006493:Heparin / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D012260:Ribonucleases; D013373:Substance P / Q000031:analogs & derivatives*; D014630:Vagus Nerve / Q000503:physiopathology
D000906:Antibodies; D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C062618:substance P, Sar(9)-Met(O2)(11)-; C085215:SR 140333; D013373:Substance P; D003520:Cyclophosphamide; D006493:Heparin; D012260:Ribonucleases