In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 304, No. 3 ( 2013-02-01), p. H382-H392
Kurzfassung:
Arachidonic acid (AA) metabolites mediate endothelium-dependent relaxation in many vascular beds. Previously, we identified the major AA 12/15-lipoxygenase (12/15-LO) metabolite of mouse arteries as 12-hydroxyeicosatetraenoic acid (12-HETE). The goal was to determine the stereospecific configuration of mouse vascular 12-HETE and characterize the role of 12-HETE stereoisomers in the regulation of vascular tone. Using normal, reverse phase, and chiral HPLC, the stereospecific configuration was identified as 12( S)-HETE. 12( S)-HETE relaxed U46619-, carbocyclic thromboxane A 2 -, PGF 2α -, and 8-iso PGF 2α -preconstricted mesenteric arteries, but not phenylephrine-preconstricted arteries. 12( R)-HETE was more potent than 12( S)-HETE in relaxing U46619-preconstricted mouse arteries (maximum relaxations = 91.4 ± 2.7% and 71.8 ± 5.9%, respectively). Neither 12-HETE isomer caused constriction. Pretreatment with 12( S)- or 12( R)-HETE (1 μM) inhibited constrictions to U46619 but not phenylephrine. To investigate the role of thromboxane A 2 (TP) receptors in 12-HETE vascular actions, [ 3 H]SQ29548 radioligand binding studies were performed in mouse platelets. U46619, 12( R)-HETE, and 12( S)-HETE displaced [ 3 H]SQ29548 binding with IC 50 s of 0.07, 0.32, and 1.73 μM, respectively. Both 12( S)- and 12( R)-HETE inhibited intracellular calcium increases induced by U46619 (10 nM) in HEK293 cells overexpressing TP α receptor (65.5% and 45.1%, respectively) and coexpressing prostacyclin (IP) and TP α receptors (58.0% and 27.1%, respectively). The LO inhibitor NDGA (10 μM) reduced AA relaxations in arteries preconstricted with U46619 but not phenylephrine. These results indicate that exogenous and endogenous 12( S)-HETE relax mouse mesenteric arteries that are preconstricted with thromboxane agonists. These 12( S)-HETE relaxations are mediated by TP receptor competitive inhibition and inhibition of TP agonist-induced increases in intracellular calcium.
Materialart:
Online-Ressource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00690.2012
Sprache:
Englisch
Verlag:
American Physiological Society
Publikationsdatum:
2013
ZDB Id:
1477308-9
SSG:
12
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