Inhaled montelukast inhibits cysteinyl-leukotriene-induced bronchoconstriction in ovalbumin-sensitized guinea-pigs: the potential as a new asthma medication.
Oral cysteinyl-leukotriene (LT) receptor antagonists such as montelukast are used for reducing airway inflammation and exacerbations. However, inhaled therapy using LT receptor antagonists has not been studied. In the present study, the effect of inhaled montelukast was investigated on airway hyperresponsiveness measured by cysteinyl-LT induced bronchoconstriction in an animal model of asthma. Bronchoconstriction responses were induced by inhaled LTC4 and LTD4 (0.2 microg/ml each) or three doses of intravenous LTC4 and LTD4 (0.3, 1, 3 microg/kg) in ovalbumin (OVA)-sensitized Hartley male guinea-pigs. The response was measured by the change in peak pressure of airway opening (Pao). The effect of montelukast was evaluated by the comparison of bronchoconstriction responses between the groups of animals pre-treated with 15-min inhalation of 10mg/ml montelukast and saline. To evaluate the tissue injury which might be caused by montelukast inhalation, lung tissues were examined for the histology. The broncoconstriction responses induced by inhaled LTC4 and LTD4 were enhanced by OVA sensitization in the guinea-pigs. In sensitized animals, the significant increases in peak Pao were 18.5+/-2.1 cmH(2)O by LTC4 inhalation and 25.0+/-1.6 cmH(2)O by LTD4 inhalation on average. Prior treatment of inhaled montelukast potently suppressed the peak Pao increases induced by both inhaled and intravenous LTC4 and LTD4 (all P<0.01 vs. saline control). Moreover, the suppression of inhaled montelukast against LTD4-induced bronchoconstriction was observed for at least up to 24h. According to the histological examination, montelukast inhalation produced no injury to the lung tissue. Inhaled montelukast, a cysteinyl-LT receptor antagonist, was effective in inhibiting cysteinyl-LT-induced acute bronchoconstriction, and may have the potential for clinical use as a new asthma drug.
Muraki
Masato
M
Department of Respiratory Medicine and Allergology, Kinki University School of Medicine, Japan. muraki@ko-arena.med.kindai.ac.jp
Imbe
Shu
S
Sato
Ryuji
R
Ikeda
Yoko
Y
Yamagata
Shigeyoshi
S
Iwanaga
Takashi
T
Tohda
Yuji
Y
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000280:Administration, Inhalation; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy*; D016084:Bronchoconstriction / Q000187:drug effects*; D003521:Cyclopropanes; D003545:Cysteine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000008:administration & dosage*; D017997:Leukotriene C4 / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D007155:Immunologic Factors; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C112381:cysteinyl-leukotriene; D017997:Leukotriene C4; D017998:Leukotriene D4; D010047:Ovalbumin; D003545:Cysteine; C093875:montelukast