12-lipoxygenase in porcine coronary microcirculation: implications for coronary vasoregulation.
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 (EC(50), expressed as -log[M] = 13.5 +/- 0.5). Moreover, 12(S)-HETE potently activated large-conductance Ca(2+)-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.
Zink
M H
MH
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Oltman
C L
CL
Lu
T
T
Katakam
P V
PV
Kaduce
T L
TL
Lee
H
H
Dellsperger
K C
KC
Spector
A A
AA
Myers
P R
PR
Weintraub
N L
NL
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000493:pharmacokinetics; D002109:Caffeic Acids / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007476:Ionophores / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015289:Leukotrienes / Q000494:pharmacology; D008041:Linoleic Acids / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008833:Microcirculation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D013552:Swine; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D002109:Caffeic Acids; D007476:Ionophores; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015289:Leukotrienes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D014662:Vasoconstrictor Agents; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; D014316:Tritium; C038649:13-hydroperoxy-9,11-octadecadienoic acid; D016718:Arachidonic Acid; D000001:Calcimycin; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C021201:12-HPETE; D001092:Arachidonate 12-Lipoxygenase