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12‐ and 15‐Hydroxyeicosatetraenoic Acids (HETEs) Function as Endothelium‐Derived Hyperpolarizing Factors (EDHFs) in Human Coronary Arterioles
Author(s) -
Larsen Brandon T,
Miura Hiroto,
Campbell William B,
Gutterman David D
Publication year - 2009
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.23.1_supplement.952.17
Subject(s) - iberiotoxin , apamin , charybdotoxin , hyperpolarization (physics) , chemistry , medicine , endocrinology , vasodilation , endothelium , hydroxyeicosatetraenoic acid , potassium channel , arachidonic acid , biology , biochemistry , stereochemistry , enzyme , nuclear magnetic resonance spectroscopy
12‐ and 15‐HETEs are lipoxygenase (LO)‐derived arachidonic acid metabolites that are produced abundantly by human coronary arterioles (HCAs); however, their biological role is unknown. We hypothesized that 12‐ and 15‐HETEs function as EDHFs. HCAs were isolated from atrial appendages and studied by immunohistochemistry (IHC), membrane potential (E m ) recording, and videomicroscopy. IHC revealed endothelial expression of 12‐ and 15‐LO. In endothelium‐denuded vessels, 1 μM 12‐HETE induced smooth muscle hyperpolarization (E m ‐54±2 vs ‐43±1 mV at baseline, n=4, p<0.05) that was attenuated by charybdotoxin + apamin (K + channel inhibitors that block EDHFs; ‐43±1 vs ‐37±1 with inhibitors alone, n=4, p<0.05 vs. 12‐HETE alone). 12‐ or 15‐HETE elicited concentration‐dependent vasodilation (68±5% and 67±6% at 10 μM, respectively, n=11 each) that was inhibited by 40 mM KCl (3±6% and 1±4%, respectively, n=5, p<0.05) but not by endothelial denudation (65±17% and 64±6%, respectively, n=3). 12‐ and 15‐HETE‐induced dilations were reduced by charybdotoxin + apamin (16±6% and 6±5%, respectively, n=4, p<0.05), but not by iberiotoxin (a specific inhibitor of large‐conductance Ca 2+ ‐activated K + channels; 92±8% and 87±2%, respectively, n=2). We conclude that 12‐ and 15‐HETEs elicit endothelium‐independent dilation and hyperpolarization of HCAs by a mechanism requiring K + channels. These findings support a role for LO‐derived eicosanoids as EDHFs and suggest that these HETEs modulate vasomotor tone in the human heart.