Inhibitory effect of a leukotriene receptor antagonist (montelukast) on neurokinin A-induced bronchoconstriction.
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 microg/mL (+SE, 407.1 microg/mL; -SE, 207.84 microg/mL). Montelukast pretreatment significantly increased (P <.01) the PC(15) NKA value (708.8 microg/mL; +SE, 890.47 microg/mL; -SE, 564.15 microg/mL) in comparison with placebo (394.4 microg/mL; +SE, 491.88 microg/mL; -SE, 248.16 microg/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.


CONCLUSIONS
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.
Crimi
Nunzio
N
Department of Internal and Specialistic Medicine, Section of Respiratory Diseases and Infectious Diseases, University of Catania, Catania.
Pagano
Corrado
C
Palermo
Filippo
F
Mastruzzo
Claudio
C
Prosperini
Gaetano
G
Pistorio
Maria P
MP
Vancheri
Carlo
C
D000085:Acetates / Q000494:pharmacology*; D000328:Adult; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D003545:Cysteine / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D015289:Leukotrienes / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D015288:Neurokinin A / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C112381:cysteinyl-leukotriene; D016210:Methacholine Chloride; D017998:Leukotriene D4; D015288:Neurokinin A; D003545:Cysteine; C093875:montelukast