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12‐ and 15‐hydroxyeicosatetraenoic acids may function as endothelium‐derived hyperpolarizing factors in the human coronary microcirculation
Author(s) -
Larsen Brandon T,
Campbell William B,
Gutterman David D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.914.8
Subject(s) - hydroxyeicosatetraenoic acid , chemistry , arachidonic acid , vasodilation , endothelium , microcirculation , metabolism , biochemistry , medicine , endocrinology , enzyme , biology
12‐ and 15‐hydroxyeicosatetraenoic acids (12‐ and 15‐HETEs) are 12/15‐lipoxygenase metabolites of arachidonic acid (AA) that exhibit vasodilator activity characteristic of endothelium‐derived hyperpolarizing factors (EDHFs) in some animals. EDHFs predominate in microvessels, particularly in cardiovascular disease; however, a role for HETEs in human coronary arterioles (HCAs) has not been explored. We hypothesized that HCAs produce HETEs and that these lipids elicit vasodilation. HCAs (diameter 100–200 ìm) were isolated from right atrial appendages (n=13) and 14 C‐AA metabolism was assayed by HPLC. HETE formation was quantified by mass spectrometry. Diameter changes of pressurized HCAs were measured by videomicroscopy. As observed by HPLC, HCAs metabolized 14 C‐AA primarily to two products that coeluted with authentic 12‐ and 15‐HETE. Mass spectrometry confirmed the structures and revealed endogenous release of these lipids into perfusate (4.9±2.2 and 8.7±5.2 pg/min, respectively, n=6). Furthermore, 12‐ and 15‐HETE each induced a concentration‐dependent dilation (81±5% and 72±6% at 10 −5 M, respectively, n=5 each) that was abolished by 40 mM KCl (6±5% and −2±3%, respectively, n=3 each, p<0.05). We conclude that 12‐ and 15‐HETE are endogenously produced in HCAs and that they elicit dilation by a mechanism requiring K + channels. These findings support a role for these lipids as EDHFs in the human heart.