title: Relationship between bradykinin-induced relaxation and endogenous epoxyeicosanoid synthesis in human bronchi.
abstract: Epoxyeicosanoids (EETs) are produced by cytochrome P-450 epoxygenase; however, it is not yet known what triggers their endogenous production in epithelial cells. The relaxing effects of bradykinin are known to be related to endogenous production of epithelial-derived hyperpolarizing factors (EpDHF). Because of their effects on membrane potential, EETs have been reported to be EpDHF candidates (Benoit C, Renaudon B, Salvail D, Rousseau E. Am J Physiol Lung Cell Mol Physiol 280: L965-L973, 2001.). Thus, we hypothesized that bradykinin (BK) may stimulate endogenous EET production in human bronchi. To test this hypothesis, the relaxing and hyperpolarizing effects of BK and 14,15-EET were quantified on human bronchi, as well as the effects of various enzymatic inhibitors on these actions. One micromolar BK or 1 μM 14,15-EET induced a 45% relaxation on the tension induced by 30 nM U-46619 [a thromboxane-prostanoid (TP)-receptor agonist]. These BK-relaxing effects were reduced by 42% upon addition of 10 nM iberiotoxin [a large-conductance Ca(2+)-sensitive K(+) (BK(Ca)) channel blocker], by 27% following addition of 3 μM 14,15-epoxyeicosa-5(Z)-enoic acid (an EET antagonist), and by 32% with 3 μM N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH, an epoxygenase inhibitor). Hence, BK and 14,15-EET display net hyperpolarizing effects on airway smooth muscle cells that are related to the activation of BK(Ca) channels and ultimately yielding to relaxation. Data also indicate that 3 μM MS-PPOH reduced the hyperpolarizing effects of BK by 43%. Together, the present data support the current hypothesis suggesting a direct relationship between BK and the production of EET regioisomers. Because of its potent anti-inflammatory and relaxing properties, epoxyeicosanoid signaling may represent a promising target in asthma and chronic obstructive pulmonary disease.
authors: Le Bilarium, Department of Physiology and Biophysics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Yacine
authors: Y
authors: Tabet
authors: Marco
authors: M
authors: Sirois
authors: Chantal
authors: C
authors: Sirois
authors: Edmond
authors: E
authors: Rizcallah
authors: Éric
authors: É
authors: Rousseau
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D012132:Respiratory Muscles / Q000187:drug effects / Q000502:physiology
chemical_list: D000577:Amides; D015777:Eicosanoids; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D001920:Bradykinin