Am. J. Respir. Crit. Care Med., Volume 158, Number 1, July 1998, 42-48

Involvement of Tachykinin NK₃ Receptors in Citric Acid-induced Cough and Bronchial Responses in Guinea Pigs

SAMIRA DAOUI, CÉCILE COGNON, EMMANUEL NALINE, XAVIER EMONDS-ALT, and CHARLES ADVENIER

Laboratoire de Pharmacologie, Faculté de Médecine Paris-Ouest, 15 rue de l'Ecole de Médecine, 75006 Paris; and Sanofi Recherche, 371 avenue du Pr Blayac, 34184 Montpellier Cedex, France

Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK₁ and NK₂ receptor antagonists, as well as chronic treatment with high doses of capsaicin, have suggested that these effects are mediated through the release of tachykinins from sensory nerve endings. In the present study, we have investigated the effects of a tachykinin NK₃ receptor antagonist, SR 142801 (osanetant), on cough, bronchoconstriction, and bronchial hyperresponsiveness induced by aerosolized citric acid (0.4 M) in guinea pigs. SR 142801, at 0.3 and 1 mg · kg¹ by intraperitoneal route, significantly inhibited cough in conscious guinea pigs by 57 ± 3 and 62 ± 10% (n = 8), respectively. In anaesthetized guinea pigs, it failed to inhibit the bronchoconstriction induced by citric acid when given alone but abolished it when combined with the tachykinin NK₂ receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg · kg¹), aerosolized citric acid (0.4 M, 1 h) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. When given once intraperitoneally at 1 mg · kg¹ 30 min before the citric acid exposure, SR 142801 inhibited both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. The results suggest that tachykinin NK₃ receptors are involved in citric acid-induced effects on airways.

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