DIFFERENTIAL ACTIVATION OF THE EPITHELIAL AND SMOOTH-MUSCLE NK1 RECEPTORS BY SYNTHETIC TACHYKININ AGONISTS IN GUINEA-PIG TRACHEA

1 The presence of tachykinin NK1 receptors have been shown in the epit helium and smooth muscle of guinea-pig airways. Previous data showed t hat substance P (SP), and the NK1 receptor agonist, [Sar(9), Met (O-2) (11)]-SP, relax guinea-pig tracheal tube preparations by stimulation o f epithelial NK1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK1 receptor agonist, septide, was unable to produce this effect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK1 receptors of guinea-pig airway epithelium. 2 Isometric tension was recorded in isol ated tracheal tube preparations in which compounds were administered i ntraluminally in the presence of phosphoramidon, indomethacin (both 1 mu M) and the tachykinin NK, receptor antagonist, SR 48,968 ((S)-N-met hyl piperidino)-2-(3,4-dichlorophenyl)butyl)benzamide) (0.1 mu M). Cum ulative concentration-response curves were obtained in preparations un der resting tone or in preparations precontracted with acetylcholine ( ACh, 10 mu M). 3 Contractile responses to low concentrations (0.1-10 n M) of substance P (SP) and the selective agonist of NK1 receptors, [Pr o(9)]-SP, in non precontracted tracheae were higher in preparations pr etreated with the NO-synthase inhibitor, N-G-monomethyl L-arginine (L- NMMA, 100 mu M) than in preparations pretreated with its inactive enan tiomer D-NMMA (100 mu M). Tracheal tube preparations precontracted wit h ACh and pretreated with D-NMMA were relaxed by low concentrations of SP and [Pro(9)]-SP (0.1-10 nM). In contrast, after pretreatment with L-NMMA, SP and [Pro(9)]-SP contracted tracheae at all the concentratio ns tested. 4 Concentration-response curves to the NK1 receptor agonist s, SP methyl ester, [Apa(9-10)]-SP and [pGlu(6)] SP (6-11) obtained in non-precontracted tracheae were similar in the presence of either D-N MMA or L-NMMA. SP methyl ester, [Apa(9-10)]-SP and [pGlu(6)] SP (6-11) did not produce any relaxation, but instead, cause contractions in tr acheal tube preparations precontracted with ACh and pretreated with D- NMMA. Concentration-response curves produced by all these agonists wer e similar in preparations precontracted with ACh and pretreated with L -NMMA or D-NMMA. 5 In guinea-pig tracheal tube preparations two groups of NK1 receptor agonists can be distinguished: one group, including [ Pro(9)]-SP, stimulator epithelial NK1 receptors, the other group, incl uding SP methyl ester, [Apa(9-10)]-Sp and [pGlu(6)] SP (6-11), does no t. One possible explanation for these findings and for the existence o f compounds with a peculiar 'septide-like' pharmacological profile in the guinea-pig trachea could be the recently proposed phenomenon refer red to as 'agonist-directed receptor traacking'.