title: Characterization of cysteinyl leukotriene receptors on human saphenous veins: antagonist activity of montelukast and its metabolites.
abstract: The aims of this study were to determine the cysteinyl leukotriene (CysLT) receptors expressed in the human saphenous vein, to examine contractile response to LTC4 and LTD4, to evaluate antagonist activity of montelukast, a specific CysLT1 receptor antagonist used in asthma, and to characterize the CysLT receptors involved in the contractile response. The analysis by reverse-transcriptase polymerase chain reaction indicated that CysLT1 and CysLT2 receptors are expressed by saphenous veins. In varicose vein rings, the potencies (pD2) of LTC4 and LTD4 were similar: 7.4 +/- 0.2 and 7.4 +/- 0.1, respectively. Pretreatment with acivicin, a gamma-glutamyl transpeptidase (gamma-GT) inhibitor, to prevent potential metabolism of LTC4 to LTD4, did not alter the response to LTC4. In nondistended vein rings from patients undergoing arterial bypass, the LTC4 pD2 was 7.8 +/- 0.1, and pretreatment with S-hexyl-GSH, a potent gamma-GT inhibitor, caused a fourfold rightward shift of the LTC4 concentration-response curve. In varicose and nondistended saphenous vein rings, montelukast (10(-8) and 10(-7) M) exerted a potent activity against LTD4 and LTC4, in the presence or absence of gamma-GT inhibitors. In varicose vein rings, the two active metabolites of montelukast also exerted antagonist activities with potencies similar to montelukast. BAY u9773 (CysLT2 agonist/dual CysLT1/CysLT2 antagonist) did not cause contraction and inhibited the LTC4- and LTD4-induced contractions. In conclusion, human saphenous veins express CysLT1 and CysLT2 receptors, but only CysLT1 receptors are implicated in the contraction.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University Hospital, Reims, France.
authors.forename: Hakima
authors.initials: H
authors.lastname: Mechiche
authors.forename: Luz
authors.initials: L
authors.lastname: Candenas
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Pinto
authors.forename: Pierre
authors.initials: P
authors.lastname: Nazeyrollas
authors.forename: Claude
authors.initials: C
authors.lastname: Clément
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000494:pharmacology*; D000328:Adult; D003521:Cyclopropanes; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D018077:Receptors, Leukotriene; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein; D013440:Sulfides; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C083169:leukotriene D4 receptor; C093875:montelukast