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

• Published in: British journal of pharmacology 1997-06, Vol.121 (4), p.773-781
• Main Authors: Figini, Michela, Emanueli, Costanza, Bertrand, Claude, Sicuteri, Riccardo, Regoli, Domenico, Geppetti, Pierangelo
• Format: Article
• Language: English
• Subjects: airway; Animals; Biological and medical sciences; Cell receptors; Cell structures and functions; Dose-Response Relationship, Drug; epithelium; Epithelium - drug effects; Epithelium - metabolism; Fundamental and applied biological sciences. Psychology; Guinea Pigs; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Male; Molecular and cellular biology; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Neurokinin-1 Receptor Antagonists; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; NK1 receptors; omega-N-Methylarginine - pharmacology; Peptide Fragments - pharmacology; Physalaemin - analogs & derivatives; Physalaemin - pharmacology; Piperidines - pharmacology; Pyrrolidonecarboxylic Acid - analogs & derivatives; Quinuclidines - pharmacology; Receptors, Neurokinin-1 - drug effects; Receptors, Neurokinin-1 - metabolism; septide; Substance P; Substance P - analogs & derivatives; Substance P - pharmacology; tachykinins; Tachykinins - antagonists & inhibitors; Trachea - drug effects; Trachea - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701188

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. 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). 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, NG‐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. Concentration‐response curves to the NK1 receptor agonists, SP methyl ester, [Apa9–10]‐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, [Apa9–10]‐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. 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, [Apa9–10]‐SP and [pGlu6] SP (6–11), does no