SIGNAL-TRANSDUCTION MECHANISMS IN SUBSTANCE P-MEDIATED CILIOSTIMULATION

Substance P is a neuropeptide released by afferent neurons in the resp iratory tract during inflammatory reactions. It produces effects on bl ood vessels, bronchial smooth muscle, nasal glands, and respiratory ci lia, We studied the in vitro effect of substance P on the ciliary beat frequency of human adenoid explants and its mechanism of action, Subs tance 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 increa sed ciliary beat frequency a maximum of 11.9% +/- 3.8% (p < 0.01). Dic lofenac (10(-6) mol/L) significantly blocked the ciliostimulatory effe cts of SP (p < 0.022), indicating that prostaglandin synthesis is an i ntermediate step in the action of substance P on ciliary beat frequenc y, The L-arginine analogs, N-G-nitro-L-arginine methyl ester and N-G-m onomethyl-L-arginine, inhibit nitric oxide synthesis from L-arginine. L-Arginine analogs (10(-4) to 10(-2) mol/L) Inhibited the effect of su bstance P (p < 0.02 at the higher concentration), This inhibition was reversed by adding L-arginine, demonstrating that nitric oxide product ion is a required step in substance P-induced ciliostimulation, Substa nce P stimulates ciliary activity in human nasal mucosa as a result of secondary production and release of endogenous prostaglandins and nit ric oxide, It is likely that inflammatory disease processes that stimu late release of substance P and subsequent prostaglandin and nitric ox ide production modify mucociliary transport, Pharmacologic modificatio n of substance P and its second messengers may eventually permit regul ation of this important defense mechanism and control of neurogenic in flammation.