Inhibitory effect of a leukotriene receptor antagonist (montelukast) on neurokinin a-induced bronchoconstriction

• Published in: Journal of allergy and clinical immunology 2003-04, Vol.111 (4), p.833-839
• Main Authors: Crimi, Nunzio, Pagano, Corrado, Palermo, Filippo, Mastruzzo, Claudio, Prosperini, Gaetano, Pistorio, Maria P., Vancheri, Carlo
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Adult; Aqueous solutions; Asthma; Biological and medical sciences; Bronchoconstriction - drug effects; Cross-Over Studies; Cysteine - pharmacology; Double-Blind Method; Female; Forced Expiratory Volume - drug effects; Histamine and antagonists. Allergy; Humans; Laboratories; Leukotriene Antagonists - pharmacology; Leukotriene D4 - antagonists & inhibitors; Leukotrienes - pharmacology; Male; Medical sciences; Methacholine Chloride - pharmacology; Muscular system; Neurokinin A - antagonists & inhibitors; Neuropeptides; Patients; Permeability; Pharmacology. Drug treatments; Quinolines - pharmacology; Smooth muscle; Studies
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1067/mai.2003.161

Background: Tachykinins are potent contractors of human airways producing a dose-related bronchoconstriction when administered by means of inhalation to asthmatic subjects. Objective: The aim of this study was to examine the effective role played by leukotrienes (LTs) in neurokinin A (NKA)-induced bronchoconstriction in asthmatic patients. Methods: To address this question, we investigated the protective effect of a selective cysteinyl LT receptor antagonist, montelukast, against inhaled NKA and determined LTE 4 excretion in the urine. Results: Inhaled NKA in the absence of any drug treatment produced a concentration-related bronchospasm with a geometric mean provocative concentration required to produce a 15% decrease in FEV 1 from the postsaline baseline value (PC 15) value of 290.9 μg/mL (+SE, 407.1 μg/mL; −SE, 207.84 μg/mL). Montelukast pretreatment significantly increased ( P < .01) the PC 15 NKA value (708.8 μg/mL; +SE, 890.47 μg/mL; −SE, 564.15 μg/mL) in comparison with placebo (394.4 μg/mL; +SE, 491.88 μg/mL; −SE, 248.16 μg/mL) and produced a shift of the NKA concentration-response curve to the right in all the subjects studied. When compared with placebo, montelukast did not have a significant protective effect against methacholine challenge; the geometric mean PC 15 values obtained were 0.87 and 0.96 mg/mL with placebo and montelukast, respectively. Although we have not observed any increase in urinary LTE 4 excretion after NKA inhalation, we have shown that pretreatment of asthmatic subjects with montelukast elicits a significant protection against NKA-induced bronchoconstriction. Conclusion: In asthmatic subjects NKA-induced bronchoconstriction is indirectly caused by the release of LTs, and this mechanism could explain some of the antiasthmatic and anti-inflammatory effects of LT antagonists. (J Allergy Clin Immunol 2003;111:833-9.)