Modulatory role of tachykinin NK1 receptor in cholinergic contraction of mouse trachea.

The role of the NK1 receptor in airway contraction induced by electrical field stimulation (EFS) was evaluated by comparing the response in NK1 receptor knockout mice (NK1R-/-) with that of NK1 receptor wild-type controls (WT). A frequency/response curve on tracheas from NK1R-/- mice and NK1R WT littermates was constructed. After incubation with [3H]choline, [3H]acetylcholine release upon EFS was measured by high-performance liquid chromatography and liquid scintillation counting. The effects of atropine (1 x 10(-6) M), tetrodotoxin (1 x 10(-6) M) and a specific NK1R antagonist (SR140333, 1 x 10(-8) M) were studied, as well as the effects of substance P (1 x 10(-5) M) on precontracted tracheas. Upon EFS, NK1R-/- mice had a significant lower trachea contractility than the NK1R WT animals, accompanied with less [3H]acetylcholine release. Pretreatment with atropine or tetrodotoxin abolished the EFS-induced contraction in both strains. Pretreatment with the NK1R antagonist SR140333 significantly reduced the contractility in the NK1R WT but not in the NK1R-/- mice. Substance P caused a small contraction in both NK1R WT and NK1R-/- mice. Substance P induced a relaxation in precontracted tracheas in NK1R WT but not in NK1R-/- mice. The data presented here provide direct evidence that the NK1 receptor augments cholinergic neurotransmission in mouse trachea.

Airway inflammation and tachykinins: prospects for the development of tachykinin receptor antagonists.

The tachykinins substance P and neurokinin A are contained within sensory airway nerves. Immune cells form an additional source of tachykinins in inflamed airways. Elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease. Airway inflammation leads to an upregulation of tachykinin NK(1) and NK(2) receptors. Preclinical studies have indicated a role for the tachykinin NK(1), NK(2) and NK(3) receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. Compounds that are able to block two or three tachykinin receptors hold promise for the treatment of airways diseases such as asthma and/or chronic obstructive pulmonary disease.