Differential activation of the epithelial and smooth muscle NK 1 receptors by synthetic tachykinin agonists in guinea‐pig trachea

The presence of tachykinin NK 1 receptors have been shown in the epithelium and smooth muscle of guinea‐pig airways. Previous data showed that substance P (SP), and the NK 1 receptor agonist, [Sar 9 , Met (O 2 ) 11 ]‐SP, relax guinea‐pig tracheal tube preparations by stimulation of epithelial NK 1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK 1 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 NK 1 receptors of guinea‐pig airway epithelium. Isometric tension was recorded in isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 μ M ) and the tachykinin NK 2 receptor antagonist, SR 48,968 (( S )‐N‐methyl N‐(4‐acetyl‐amino‐4‐phenylpiperidino)‐2‐(3,4‐dichlorophenyl)butyl)benzamide) (0.1 μ M ). Cumulative concentration‐response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 μ M ). Contractile responses to low concentrations (0.1–10 n M ) of substance P (SP) and the selective agonist of NK 1 receptors, [Pro 9 ]‐SP, in non precontracted tracheae were higher in preparations pretreated with the NO‐synthase inhibitor, N G ‐monomethyl L ‐arginine ( L ‐NMMA, 100 μ M ) than in preparations pretreated with its inactive enantiomer D ‐NMMA (100 μ M ). Tracheal tube preparations precontracted with ACh and pretreated with D ‐NMMA were relaxed by low concentrations of SP and [Pro 9 ]‐SP (0.1–10 n M ). In contrast, after pretreatment with L ‐NMMA, SP and [Pro 9 ]‐SP contracted tracheae at all the concentrations tested. Concentration‐response curves to the NK 1 receptor agonists, 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 ‐NMMA 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 tracheal tube preparations precontracted with ACh and pretreated with D ‐NMMA. Concentration‐response curves produced by all these agonists were similar in preparations precontracted with ACh and pretreated with L ‐NMMA or D ‐NMMA. In guinea‐pig tracheal tube preparations two groups of NK 1 receptor agonists can be distinguished: one group, including [Pro 9 ]‐SP, stimulator epithelial NK 1 receptors, the other group, including SP methyl ester, [Apa 9–10 ]‐SP and [pGlu 6 ] SP (6–11), does not. One possible explanation for these findings and for the existence of compounds with a peculiar ‘septide‐like’ pharmacological profile in the guinea‐pig trachea could be the recently proposed phenomenon referred to as ‘agonist‐directed receptor trafficking’.British Journal of Pharmacology (1997) 121 , 773–781; doi: 10.1038/sj.bjp.0701188