Differential activation of the epithelial and smooth muscle NK₁ receptors by synthetic tachykinin agonists in guinea-pig trachea

Abstract

1. The presence of tachykinin NK₁ receptors have been shown in the epithelium and smooth muscle of guinea-pig airways. Previous data showed that substance P (SP), and the NK₁ receptor agonist, [Sar⁹, Met (O₂)¹¹]-SP, relax guinea-pig tracheal tube preparations by stimulation of 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 isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 μM) and the tachykinin NK₂ receptor antagonist, SR 48,968 ((S)-N-methyl N-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzamide) (0.1 μM). Cumulative concentration-response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 μM).

3. Contractile responses to low concentrations (0.1–10 nM) of substance P (SP) and the selective agonist of NK₁ receptors, [Pro⁹]-SP, in non precontracted tracheae were higher in preparations pretreated with the NO-synthase inhibitor, N^G-monomethyl L-arginine (L-NMMA, 100 μM) than in preparations pretreated with its inactive enantiomer D-NMMA (100 μM). Tracheal tube preparations precontracted with ACh and pretreated with D-NMMA were relaxed by low concentrations of SP and [Pro⁹]-SP (0.1–10 nM). In contrast, after pretreatment with L-NMMA, SP and [Pro⁹]-SP contracted tracheae at all the concentrations tested.

4. Concentration-response curves to the NK₁ receptor agonists, SP methyl ester, [Apa^9–10]-SP and [pGlu⁶] 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 [pGlu⁶] 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.

5. In guinea-pig tracheal tube preparations two groups of NK₁ receptor agonists can be distinguished: one group, including [Pro⁹]-SP, stimulator epithelial NK₁ receptors, the other group, including SP methyl ester, [Apa^9–10]-SP and [pGlu⁶] 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'.

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