SIGNAL-TRANSDUCTION MECHANISMS IN SUBSTANCE P-MEDIATED CILIOSTIMULATION

Substance P is a neuropeptide released by afferent neurons in the respiratory tract during inflammatory reactions. It produces effects on blood vessels, bronchial smooth muscle, nasal glands, and respiratory cilia, We studied the in vitro effect of substance P on the ciliary beat frequency of human adenoid explants and its mechanism of action, Substance P was added to cultured adenoid at concentrations of 10(-10), 10(-8), 10(-6), and 10(-4) mol/L, Ciliary beat frequency was determined with phase-contrast microscopy and microphotometry, Substance P increased ciliary beat frequency a maximum of 11.9% +/- 3.8% (p < 0.01). Diclofenac (10(-6) mol/L) significantly blocked the ciliostimulatory effects of SP (p < 0.022), indicating that prostaglandin synthesis is an intermediate step in the action of substance P on ciliary beat frequency, The L-arginine analogs, N-G-nitro-L-arginine methyl ester and N-G-monomethyl-L-arginine, inhibit nitric oxide synthesis from L-arginine. L-Arginine analogs (10(-4) to 10(-2) mol/L) Inhibited the effect of substance P (p < 0.02 at the higher concentration), This inhibition was reversed by adding L-arginine, demonstrating that nitric oxide production is a required step in substance P-induced ciliostimulation, Substance P stimulates ciliary activity in human nasal mucosa as a result of secondary production and release of endogenous prostaglandins and nitric oxide, It is likely that inflammatory disease processes that stimulate release of substance P and subsequent prostaglandin and nitric oxide production modify mucociliary transport, Pharmacologic modification of substance P and its second messengers may eventually permit regulation of this important defense mechanism and control of neurogenic inflammation.