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

Neuronal muscarinic (M-2) receptors inhibit release of acetylcholine from t he vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due t o blockade of these M-2 autoreceptors by eosinophil major basic protein (MB P) increasing the release of acetylcholine. In vivo, substance P-induced hy peractivity is vagally mediated. Because substance P induces eosinophil deg ranulation, we tested whether substance P-induced hyperreactivity is mediat ed by release of MBP and neuronal M-2 receptor dysfunction. Pathogen-free g uinea pigs were anesthetized and ventilated. Thirty minutes after intraveno us administration of [Sar(9),Met(O-2)(11)]-substance P, guinea pigs were hy perreactive 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 (NK1) receptor antagonist (SR-140333) all prevented substance P-induced M-2 dysfunction and hyperreactivity. Int ravenous heparin acutely reversed M-2 receptor dysfunction and hyperreactiv ity. Thus substance P releases MBP from eosinophils resident in the lungs b y stimulating NK1 receptors. Substance P-induced hyperreactivity is mediate d by blockade of inhibitory neuronal M-2 receptors by MBP, resulting in inc reased release of acetylcholine.