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

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.