USE OF SELECTIVE ANTAGONISTS FOR FURTHER CHARACTERIZATION OF TACHYKININ NK-2, NK-1 AND POSSIBLE SEPTIDE-SELECTIVE RECEPTORS IN GUINEA-PIG BRONCHUS

NK-1 and NK-2 tachykinin receptors in guinea pig airways appear to hav e some unusual characteristics. The analog [pGlu(6),Pro(9)] SP(6-11) ( septide) may also act on atypical NK-1 receptors in guinea pig ileum. In this study, we used new tachykinin antagonists to investigate furth er the receptors in the guinea pig bronchus. In the presence of 1 mu M indomethacin and phosphoramidon, the selective agonists [Sar(9),Met(O -2)(11)]-SP and [Pro(9)]-SP (both NK-1), [Lys(5),MeLeu(9),Nle(10)]-NKA (4-10) (NK-2) and septide were full agonists, with pD(2) values of 8.0 0, 7.78, 9.11 and 8.52, respectively on epithelium-intact preparations . Contractions to septide were unaffected by atropine (5 mu M) and tet rodotoxin (1 mu M). Denudation of epithelium significantly enhanced th e potency of [Sar(9),Met(O-2)(11)]-SP and [Pro(9)]-SP but not of septi de and [Lys(5),MeLeu(9),Nle(10)]-NKA(4-10). The potency order for NK-2 -selective antagonists against [Lys(5),MeLeu(9),Nle(11)]-NKA(4-10) was GR 94800 > SR 48968 MDL 29913 > MEN 10207 (pA(2) values 8.97, 8.73, 7 .11 and 6.49, respectively). The NK-1 selective antagonists, OP 96345, GR 82334 and RP 67580 were weak or ineffective against [Sar(9),Met(O- 2)(11)]-SP and [Pro(9)]-SP (pA(2) 6.69 or less), whereas they were mor e than one order of magnitude more potent against septide (pA(2), 7.78 , 7.48 and 6.58, respectively). In epithelium-denuded bronchi, the ant agonist potency of GR 82334 was unchanged. These data indicate that se ptide interacts with tachykinin receptors in guinea pig bronchial smoo th muscle in a manner different from that of [Sar(9),Met(O-2)(11)]-SP and [Pro(9)]-SP, and provide some evidence for heterogeneity of NK-1 r eceptors in the guinea pig airways.