Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites

Background Evidence suggests that small airways contribute to clinically significant processes in asthma. Cysteinyl leukotrienes (CysLTs) are considered to be pivotal mediators in the pathogenesis of asthma. Montelukast (MK), a specific CysLT(1) receptor antagonist, is metabolized in two main hydroxylated metabolites (termed M5 and M6, respectively). Objectives The aims of this study were to compare the responsiveness of small and large human bronchi to the three CysLTs, to evaluate the antagonist activity of MK, M5 and M6 in these preparations of human bronchi, and to characterize the CysLT receptors involved in the contractile response. Methods and results In isolated small bronchus (i.d. 0.5-2 mm), the potencies (-log molar EC50 ) of LTC4 , LTD4 and LTE4 were 9.3 (n = 11), 9.1 (n = 30) and 8.4 (n = 14), respectively. The three CysLTs were about 30-fold more potent in small bronchi than in larger bronchi (i.d. 4-6 mm). In small bronchi, MK significantly shifted to the right the CysLT concentration-effect curves with pA(2) values against LTC4 , LTD4 and LTE4 of 9.1 (n = 3), 9.0 (n = 11) and 8.7 (n = 5), respectively. The antagonist potencies of M6 and M5 were similar to MK and fivefold lower, respectively. A similar activity of MK against the three CysLTs suggested that CysLT(1) receptors are involved in the contraction of human bronchus. Analysis by RT-PCR also indicated that human bronchus mainly expressed CysLT(1) receptors. Conclusion MK exerts a potent antagonist activity against the particularly potent constricting effects of CysLTs in isolated human small bronchi, which only expressed the CysLT(1) receptor subtype. The metabolites of MK are also potent in vitro antagonists, but may not participate in the therapeutic activity of MK due to their low plasma concentrations in patients treated with the recommended dose of MK.