title: Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility.
abstract: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Obstetrics and Gynecology, CHUS, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Corriveau
authors.affiliation: Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Rousseau
authors.affiliation: Obstetrics and Gynecology, CHUS, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Blouin
authors.affiliation: Obstetrics and Gynecology, CHUS, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: Jean-Charles.Pasquier@usherbrooke.ca.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Pasquier
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D002118:Calcium / Q000494:pharmacology; D003521:Cyclopropanes; D005321:Extraembryonic Membranes / Q000737:chemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009215:Myometrium / Q000737:chemistry / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010920:Placenta / Q000737:chemistry; D011247:Pregnancy; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000032:analysis*; D013440:Sulfides; D046509:Tissue Culture Techniques; D015149:Tocolytic Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D015149:Tocolytic Agents; D017998:Leukotriene D4; D009543:Nifedipine; C083169:leukotriene D4 receptor; C093875:montelukast; D002118:Calcium
keywords: 5-LO; Leukotrienes; Montelukast; Tocolytic; Uterine contractile activity