Chronic hypoxia enhances 15-lipoxygenase-mediated vasorelaxation in rabbit arteries.
15-Lipoxygenase (15-LO-1) metabolizes arachidonic acid (AA) to 11,12,15-trihydroxyeicosatrienoic acids (THETAs) and 15-hydroxy-11,12-epoxyeicosatrienoic acids (HEETA) that dilate rabbit arteries. Increased endothelial 15-LO-1 expression enhances arterial relaxations to agonists. We tested the effect of hypoxia on 15-LO-1 expression, THETA and HEETA synthesis, and relaxations in rabbit arteries. The incubation of rabbit aortic endothelial cells and isolated aortas in 0.7% O(2) increased 15-LO-1 expression. Rabbits were housed in a hypoxic atmosphere of 12% O(2) for 5 days. 15-LO-1 expression increased in the endothelium of the arteries of rabbits in 12% O(2) compared with room air. THETA and HEETA synthesis was also enhanced in aortas and mesenteric arteries. AA hyperpolarized the smooth muscle cells in indomethacin- and phenylephrine-treated mesenteric arteries of hypoxic rabbits from -29.4 +/- 1 to -50.1 +/- 3 mV. The hyperpolarization to AA was less in arteries of normoxic rabbits (from -26.0 +/- 2 to -37 +/- 2 mV). This AA-induced hyperpolarization was inhibited by the 15-LO inhibitor BW-755C. Nitric oxide and prostaglandin-independent maximum relaxations to acetylcholine (79.7 +/- 2%) and AA (38.3 +/- 4%) were enhanced in mesenteric arteries from hypoxic rabbits compared with the normoxic rabbits (49.7 +/- 6% and 19.9 +/- 2%, respectively). These relaxations were inhibited by BW-755C and nordihydroguaiaretic acid. Therefore, hypoxia increased the relaxations to agonists in the rabbit mesenteric arteries by enhancing endothelial 15-LO-1 expression and synthesis of the hyperpolarizing factors THETA and HEETA.
Aggarwal
Nitin T
NT
Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Pfister
Sandra L
SL
Gauthier
Kathryn M
KM
Chawengsub
Yuttana
Y
Baker
John E
JE
Campbell
William B
WB
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D001685:Biological Factors / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
C528813:15-hydroxy-11,12-epoxyeicosatrienoic acid; D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid; D009569:Nitric Oxide; C066049:11,12,15-trihydroxyeicosatrienoic acid; D001093:Arachidonate 15-Lipoxygenase; D015126:8,11,14-Eicosatrienoic Acid