title: Improved bioavailability of epoxyeicosatrienoic acids reduces TP-receptor agonist-induced tension in human bronchi.
abstract: Epoxyeicosatrienoic acid (EET) and thromboxane A(2) are arachidonic acid derivatives. The former has initially been defined as an epithelium-derived hyperpolarizing factor displaying broncho-relaxing and anti-inflammatory properties, as recently demonstrated, whereas thromboxane A(2) induces vaso- and bronchoconstriction upon binding to thromboxane-prostanoid (TP)-receptor. EETs, however, are quickly degraded by the soluble epoxide hydrolase (sEH) into inactive diol compounds. The aim of this study was to investigate the effects of 14,15-EET on TP-receptor activation in human bronchi. Tension measurements performed on native bronchi from various species, acutely treated with increasing 14,15-EET concentrations, revealed specific and concentration-dependent relationships as well as a decrease in the tension induced by 30 nM U-46619, used as a synthetic TP-receptor agonist. Interestingly, acute treatments with 3 μM N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, an epoxygenase inhibitor, which minimizes endogenous production of EET, resulted in an increased reactivity to U-46619. Furthermore, we demonstrated that chronic treatments with trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a sEH inhibitor, reduced human bronchi reactivity to U-46619. During our tension measurements, we also observed that human bronchi generated small-amplitude contractions; these spontaneous activities were reduced upon acute 14,15-EET treatments in the presence of t-AUCB. Altogether, these data demonstrate that endogenous and exogenous 14,15-EET could interfere with the activation of TP-receptors as well as with spontaneous oscillations in human airway smooth muscle tissues.
authors.affiliation: Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Farid Yannick
authors.initials: FY
authors.lastname: Senouvo
authors.forename: Yacine
authors.initials: Y
authors.lastname: Tabet
authors.forename: Caroline
authors.initials: C
authors.lastname: Morin
authors.forename: Roula
authors.initials: R
authors.lastname: Albadine
authors.forename: Chantal
authors.initials: C
authors.lastname: Sirois
authors.forename: Eric
authors.initials: E
authors.lastname: Rousseau
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004852:Epoxy Compounds; D005455:Fluorescent Antibody Technique; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D009129:Muscle Tonus / Q000187:drug effects*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D004852:Epoxy Compounds; D018078:Receptors, Prostaglandin E; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D014508:Urea; D015118:Eicosapentaenoic Acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid