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 have some unusual characteristics. The analog [pGlu6,Pro9] 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 further the receptors in the guinea pig bronchus. In the presence of 1 microM indomethacin and phosphoramidon, the selective agonists [Sar9,Met(O2)11]-SP and [Pro9]-SP (both NK-1), [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK-2) and septide were full agonists, with pD2 values of 8.00, 7.78, 9.11 and 8.52, respectively on epithelium-intact preparations. Contractions to septide were unaffected by atropine (5 microM) and tetrodotoxin (1 microM). Denudation of epithelium significantly enhanced the potency of [Sar9,Met(O2)11]-SP and [Pro9]-SP but not of septide and [Lys5,MeLeu9,Nle10]-NKA(4-10). The potency order for NK-2-selective antagonists against [Lys5,MeLeu9,Nle10]-NKA(4-10) was GR 94800 > SR 48968 MDL 29913 > MEN 10207 (pA2 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 [Sar9,Met(O2)11]-SP and [Pro9]-SP (pA2 6.69 or less), whereas they were more than one order of magnitude more potent against septide (pA2, 7.78, 7.48 and 6.58, respectively). In epithelium-denuded bronchi, the antagonist potency of GR 82334 was unchanged. These data indicate that septide interacts with tachykinin receptors in guinea pig bronchial smooth muscle in a manner different from that of [Sar9,Met(O2)11]-SP and [Pro9]-SP, and provide some evidence for heterogeneity of NK-1 receptors in the guinea pig airways.