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.
Zeng
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XP
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
Burcher
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D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D015320:Tachykinins / Q000819:agonists
D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; D013373:Substance P; C054725:septide; D011761:Pyrrolidonecarboxylic Acid