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(Circulation. 2001;103:1702.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Endothelium-Derived Hyperpolarizing Factor

Identification and Mechanisms of Action in Human Subcutaneous Resistance Arteries

Paul Coats, PhD, BSc; Fiona Johnston, BSc; John MacDonald, MD, MRCP, BSc; John J. V. McMurray, MD, FRCP, FESC, BSc; Chris Hillier, PhD, BSc

From the Department of Biological and Biomedical Sciences, Glasgow Caledonian University (P.C., F.J., C.H.), and the Department of Medicine and Therapeutics, Western Infirmary (J.M., J.J.V.M), Glasgow, Scotland.

Correspondence to Dr Paul Coats, School of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow, Scotland, UK. E-mail p.coats{at}gcal.ac.uk

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 (PGI₂) as vasodilators in human subcutaneous arteries. We also examined the mechanisms underlying the vasodilator action of EDHF to elucidate its identity.

Methods and 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, PGI₂, and membrane hyperpolarization. The mechanisms underlying the relaxation evoked by K⁺ and EDHF were elucidated. EDHF was found to account for 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 A₂ 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 A₂/CYP450–dependent metabolism of arachidonic acid and not K⁺ is the likely identity of EDHF in human subcutaneous resistance arteries.

Key Words: endothelium-derived factors • nitric oxide

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