Endothelium-derived hyperpolarizing factor : identification and mechanisms of action in human subcutaneous resistance arteries.
BACKGROUND
Both a vascular endothelial cytochrome P450 (CYP450) product of arachidonic acid metabolism and the potassium ion (K(+)) have been identified as endothelium-derived hyperpolarizing factors (EDHFs) in animal vascular tissues. We studied the relative importance of EDHF, nitric oxide (NO), and prostacyclin (PGI(2)) as vasodilators in human subcutaneous arteries. We also examined the mechanisms underlying the vasodilator action of EDHF to elucidate its identity.


RESULTS
Subcutaneous resistance arteries were obtained from 41 healthy volunteers. The contribution of EDHF to the vasodilation induced by acetylcholine was assessed by inhibiting production of NO, PGI(2), and membrane hyperpolarization. The mechanisms underlying the relaxation evoked by K(+) and EDHF were elucidated. EDHF was found to account for approximately 80% of acetylcholine-mediated vasorelaxation. Its action was insensitive to the combination of barium and ouabain, whereas barium and ouabain reversed K(+)-mediated vasorelaxation. EDHF-mediated vasorelaxation, however, was sensitive to the phospholipase A(2) inhibitor oleyloxyethyl phosphorylcholine and the CYP450 inhibitor ketoconazole.


CONCLUSIONS
EDHF is the major contributor to endothelium-dependent vasorelaxation in human subcutaneous resistance arteries. A product of phospholipase A(2)/CYP450-dependent metabolism of arachidonic acid and not K(+) is the likely identity of EDHF in human subcutaneous resistance arteries.
Coats
P
P
Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, Scotland. p.coats@gcal.ac.uk
Johnston
F
F
MacDonald
J
J
McMurray
J J
JJ
Hillier
C
C
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000273:Adipose Tissue / Q000098:blood supply; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D001464:Barium / Q000494:pharmacology; D001685:Biological Factors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010741:Phospholipases A / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D001464:Barium; D016718:Arachidonic Acid; D009569:Nitric Oxide; D010042:Ouabain; D011464:Epoprostenol; D010741:Phospholipases A; D006152:Cyclic GMP; D000109:Acetylcholine; D011188:Potassium