NEUROKININ SUBTYPE RECEPTORS MEDIATING SUBSTANCE-P CONTRACTION IN IMMATURE RABBIT AIRWAYS

Two-week-old rabbit tracheal smooth muscle (TSM) and bronchial smooth muscle (BSM) segments were placed in baths, and isometric contractions to substance P (SP) were obtained. In the presence of phosphoramidon (PHOS), a neutral endopeptidase inhibitor, BSM segments were significa ntly more reactive and sensitive to SP than TSM segments. Neither neos tigmine (NEO) nor atropine (ATR) eliminated these regional differences . Airway contractile responses to: I) Senktide (NK-3 agonist); 2) neur okinin A (NKA, a NK-2 agonist); and 3) Septide (a highly selective NK- 1 agonist) were separately obtained. In the presence of PHOS and NEO, Senktide was virtually inactive in both BSM and TSM. In the presence o f PHOS, NEO, and ATR, NKA was equipotent in all airway segments; in co ntrast, the Septide response was significantly more reactive in BSM th an in TSM segments. After inhibition of NK-1 activity with GR 82334, a competitive NK-1 receptor antagonist, the regional differences in SP reactivity were greatly diminished. This latter indication of a NK-1 c ontribution was confirmed using Septide-mediated inactivation of NK-I receptors whereby the regional differences in airway sensitivity to SP were eliminated. These findings indicate that both endogenous neutral endopeptidase a activity as well as NK-1 and NK-2 receptor influences map modulate the contractile responses to SP in immature rabbit airwa ys.