EVIDENCE THAT TACHYKININS RELAX THE GUINEA-PIG TRACHEA VIA NITRIC-OXIDE RELEASE AND BY STIMULATION OF A SEPTIDE-INSENSITIVE NK1 RECEPTOR

1 This study investigated the possibility that tachykinins relax the g uinea-pig isolated trachea by releasing nitric oxide (NO) from the epi thelium. The types of tachykinin receptor mediating both relaxation an d contraction of the trachea were also studied. Isometric tension was recorded in isolated tracheal tube preparations precontracted with ace tylcholine (10 mu M) in which compounds were administered intraluminal ly in the presence of phosphoramidon and indomethacin (both 1 mu M) an d the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl-N[4- (4-acetyl iperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), 0.1 mu M) . 2 In the presence of the inactive enantiomer of an NO-synthase inhib itor, N-G-monomethyl-D-arginine (D-NMMA, 100 mu M), substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and the selective NK1 receptor agonist, [Sar(9), Met(O-2)(11)]-SP, (0.1-10 nM) relaxed tracheal tube preparations. This relaxation was changed into a contraction by pretre atment with the NO-synthase inhibitor, N-G-monomethyl-L-arginine (L-NM MA, 100 mu M). The effect of L-NMMA on SP- and [Sar(9), Met(O-2)(11)]- SP-induced responses was reversed by L-arginine (L-Arg, 1 mM), but not by D-Arg (1 mM). After removal of the epithelium SP, NKA and NKB and [Sar(9), Met(O-2)(11)]-SP (0.1-10 nM) evoked contractile responses in the presence of either L-NMMA (100 mu M) or D-NMMA (100 mu M). The eff ects of SP and [Sar(9), Met(O-2)(11)]-SP obtained in the presence of a nother NO-synthase inhibitor, N-G-nitro-L-arginine methyl ester (L-NAM E, 100 mu M) or its inactive enantiomer, N-G-nitro-D-arginine methyl e ster (D-NAME, 100 mu M) were similar to those observed with L-NMMA or D-NMMA, respectively. 3 The selective NK1 receptor agonist, [pGlu(6), Pro(9)]-SP(6-11) (septide, 0.1-10 nM) evoked contractile responses of tracheal tube preparations in the presence of either D-NMMA (100 mu M) or L-NMMA (100 mu M). The log concentration-response curve to septide obtained in the presence of L-NMMA was similar to that obtained in th e presence of D-NMMA. [Sar(9), Met(O-2)(11)]-SP (0.1-10 nM) relaxed tr acheal tube preparations precontracted with septide (1 mu M), whereas septide (0.1 nM-1 mu M) further contracted tracheal tube preparations precontracted with [Sar(9), Met(O-2)(11)]-SP (1 mu M). 4 Relaxant and contractile responses evoked by SP, NKA, NKB and by [Sar(9), Met(O-2)( 11)]-SP (0.1-10 nM) were not affected by a combination of the histamin e H-1 (pyrilamine, 1 mu M) and H-2 (cimetidine, 1 mu M) receptor antag onists, but were abolished by the tachykinin NK1 receptor antagonist, CP-99,994 2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine 1 mu M), though not by its inactive enantiomer CP-100,263 (1 mu M). Contractile responses evoked by septide (10 nM and 1 mu M) were also abolished by CP-99,994 (1 mu M) but not by CP-100,263 (1 mu M). 5 These results de monstrate that tachykinins relax guinea-pig tracheal tube preparations by releasing NO via the stimulation of epithelial NK1 receptors by a mechanism independent of histamine release. The NK1 receptor type invo lved is sensitive to SP, NKA, NKB and [Sar(9), Met(O-2)(11)]-SP but no t to septide, and is pharmacologically distinct from the NK1 receptor that mediates contraction, which is stimulated by all the agonists, in cluding septide.