Epoxyeicosatrienoic Acids Function as Selective, Endogenous Antagonists of Native Thromboxane Receptors: Identification of a Novel Mechanism of Vasodilation
| العنوان: | Epoxyeicosatrienoic Acids Function as Selective, Endogenous Antagonists of Native Thromboxane Receptors: Identification of a Novel Mechanism of Vasodilation |
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| المؤلفون: | Stephen A. Douglas, Charlene Wu, Andrea Ogbonna, David J. Behm, Cynthia L. Burns-Kurtis |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 328:231-239 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Male, Agonist, medicine.drug_class, Thromboxane, Guinea Pigs, Receptors, Thromboxane, TRPV Cation Channels, Aorta, Thoracic, Vasodilation, Arachidonic Acids, Pharmacology, Rats, Sprague-Dawley, Thromboxane receptor, Mice, chemistry.chemical_compound, 8,11,14-Eicosatrienoic Acid, Hydroxyeicosatetraenoic Acids, medicine, Animals, Splanchnic Circulation, Receptor, Mice, Knockout, Leukotriene, Chemistry, Prostanoid, Rats, Trachea, Biochemistry, Vasoconstriction, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, cardiovascular system, Molecular Medicine, Vascular Resistance, lipids (amino acids, peptides, and proteins), Arachidonic acid |
| الوصف: | Epoxy- and dihydroxy-eicosatrienoic acids (EETs and DHETs) are vasoactive cytochrome P450 metabolites of arachidonic acid. Interestingly, however, the mechanism(s) by which EETs/DHETs mediate smooth muscle relaxation remains unclear. In contrast to previous reports, where dilation was purportedly large-conductance Ca(2+)-activated K(+) (BK(Ca)) and/or transient receptor potential cation channel, subfamily V, member 4 (TRPV4) channel-mediated, 14,15-EET-induced vasodilation [reversal of contractile tone established with the thromboxane receptor (TP) agonist 15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic acid (U-46619)] was unaltered in BK(Ca) and TRPV4 knockout mouse isolated aortae compared with wild-type controls, indicating a significant BK(Ca)/TRPV4-resistant mechanism. Whereas all EET and DHET regioisomers reversed U-46619 contraction in rat aortae and mouse mesenteric resistance arteries, these eicosanoids failed to alter phenylephrine-induced contraction, suggesting that they mediated dilation via a "TP-selective" mechanism. Competitive TP antagonism was also observed in nonvascular tissue, including rat fundus and tertiary bronchus, indicating that the effect is not specific to blood vessels. Such effects were TP-selective because 14,15-EET failed to inhibit "non-TP" prostanoid receptor-mediated function in multiple cell/tissue-based assays (K(b) > 10 microM). In accordance, 14,15-EET inhibited specific [(3)H]7-(3-((2-((phenylamino)carbonyl)hydrazino)-methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ-29548) binding to human recombinant TP receptor, with a K(i) value of 3.2 microM, and it showed weaker affinity for non-TP prostanoid receptors, including DP, FP, EP(1-4), and IP receptors (K(i) values of 6.1, 5.3, 42.6, 19.7, 13.2, 20.2, and >25 microM, respectively) and no appreciable affinity (K(i) values >10 microM) for a diverse array of pharmacologically distinct receptors, including the leukotriene receptors Cys-LT(1/2) and BLT(1). As such, EETs/DHETs represent a unique class of "endogenous" G protein-coupled receptor competitive antagonists, inducing vasodilation via direct TP inhibition. Thus, EETs/DHETs represent novel autoregulatory agents, directly modulating the actions of cyclooxygenase-derived eicosanoids following arachidonic acid mobilization. |
| تدمد: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.108.145102 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2a613ffe06355ad3580511c2bd8cff5 https://doi.org/10.1124/jpet.108.145102 |
| رقم الانضمام: | edsair.doi.dedup.....d2a613ffe06355ad3580511c2bd8cff5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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| DOI: | 10.1124/jpet.108.145102 |