Endothelium-derived hyperpolarizing factor: Identification and mechanisms of action in human subcutaneous resistance arteries

• Published in: Circulation (New York, N.Y.) N.Y.), 2001-03, Vol.103 (12), p.1702-1708
• Main Authors: COATS, Paul, JOHNSTON, Fiona, MACDONALD, John, MCMURRAY, John J. V, HILLIER, Chris
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Acetylcholine - pharmacology; Adipose Tissue - blood supply; Aged; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arachidonic Acid - metabolism; Arteries - drug effects; Arteries - metabolism; Barium - pharmacology; Biological and medical sciences; Biological Factors - chemistry; Biological Factors - metabolism; Biological Factors - pharmacology; Blood vessels and receptors; Cyclic GMP - metabolism; Cyclooxygenase Inhibitors - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Epoprostenol - metabolism; Epoprostenol - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Ouabain - pharmacology; Phospholipases A - pharmacology; Potassium - metabolism; Potassium - pharmacology; Vasodilation - drug effects; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.103.12.1702

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. 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. 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.