sr-142801 and Cough

The purpose of this work was to investigate the role of tachykinins in cough induced by citric acid (0.8 M) in pigs. With this object, we have studied the effect of citric acid on substance P content in the tracheo-bronchial tree and the effects of substance P and of tachykinin receptor antagonists on citric acid-induced cough. Citric acid exposure significantly increased substance P concentration in both broncho-alveolar and tracheal lavage fluids, while it decreased significantly the substance P content in tracheal mucosa. Substance P did not elicit cough, but significantly potentiated the citric acid-induced cough frequency. Tachykinin NK(1), NK(2) or NK(3) receptor antagonists, SR 140333 (nolpitantium), SR 48968 (saredutant) and SR 142801 (osanetant), respectively, significantly inhibited citric acid-induced cough. The same inhibitory effect of tachykinin receptor antagonists was observed, when substance P was nebulised before citric acid challenge. We conclude that citric acid induces in pigs a release of substance P in the tracheo-bronchial tree, which plays a sensitising role on the cough reflex. The involvement of tachykinin NK(1), NK(2), NK(3) receptors are also demonstrated in this reflex.

Topics: Animals; Benzamides; Citric Acid; Cough; Female; Lung; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Reflex; Substance P; Swine, Miniature

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 . kg-1 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 . kg-1), 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 . kg-1 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.

Topics: Animals; Benzamides; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Citric Acid; Cough; Female; Guinea Pigs; Male; Piperidines; Receptors, Neurokinin-2; Receptors, Neurokinin-3