Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility.

OBJECTIVE

This study analyzed the ability of montelukast, a cysteinyl-leukotrienes receptor antagonist and anti-inflammatory agent, to produce a consistent tocolytic effect alone or in combination with nifedipine, a calcium (Ca(2+)) channel blocker currently used in clinical practice.

STUDY

DESIGN

Uterine biopsies were obtained from consenting women undergoing elective cesarean sections at term (n=20). Myometrial microsomal fractions were analyzed by immunoblotting to quantify relative cysteinyl leukotrienes receptor 1 (CysLTR1) levels. Isometric tension measurements were performed in vitro on human myometrial strips (n=120) in isolated organ baths in order to establish concentration-response curves to montelukast and to quantify changes in Ca(2+) sensitivity on β-escin permeabilized tissues.

RESULTS

Immunodetection analysis revealed the presence of CysLTR1 receptor in uterine tissues, fetal membranes and placenta. A significant increase in area under the curve (AUC) was quantified following the addition of leukotriene D4 (LTD4) (0.01-0.3 μM), an end-product of the lipoxygenase pathway. Conversely, addition of montelukast produced a significant tocolytic effect by decreasing the frequency and AUC (IC₅₀=1 μM). Moreover, addition of montelukast also resulted in a reduced Ca(2+) sensitivity as compared to control tissues (EC₅₀ values of 654 and 403 nM; p=0.02 at pCa 6), while an additive effect was observed in combination with 0.1 nM nifedipine (p=0.004).

CONCLUSION

This original study demonstrates the potency of montelukast as a tocolytic agent in an in vitro human uterine model. Montelukast, in combination with nifedipine, could represent a therapeutic approach to reduce inflammation associated with prematurity while facilitating the inhibition of preterm labor.