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1 Department of Internal Medicine and 2 Department of Biochemistry, University of Iowa; 3 Veterans Administration Medical Center, Iowa City, Iowa 52242; and 4 Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
Noncyclooxygenase metabolites of
arachidonic acid (AA) have been proposed to mediate
endothelium-dependent vasodilation in the coronary microcirculation.
Therefore, we examined the formation and bioactivity of AA metabolites
in porcine coronary (PC) microvascular endothelial cells and
microvessels, respectively. The major noncyclooxygenase metabolite
produced by microvascular endothelial cells was
12(S)-hydroxyeicosatetraenoic acid (HETE), a lipoxygenase
product. 12(S)-HETE release was markedly increased by
pretreatment with 13(S)-hydroperoxyoctadecadienoic acid but
not by the reduced congener 13(S)-hydroxyoctadecadienoic acid, suggesting oxidative upregulation of 12(S)-HETE
output. 12(S)-HETE produced potent relaxation and
hyperpolarization of PC microvessels (EC50, expressed as
log[M] = 13.5 ± 0.5). Moreover, 12(S)-HETE
potently activated large-conductance Ca2+-activated
K+ currents in PC microvascular smooth muscle cells. In
contrast, 12(S)-HETE was not a major product of conduit PC
endothelial AA metabolism and did not exhibit potent bioactivity in
conduit PC arteries. We suggest that, in the coronary microcirculation,
12(S)-HETE can function as a potent hyperpolarizing
vasodilator that may contribute to endothelium-dependent relaxation,
particularly in the setting of oxidative stress.
arachidonic acid; 12(S)-hydroxyeicosatetraenoic acid; vasodilation; hyperpolarization; oxidative stress
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