This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Coats, P. Articles by Hillier, C. Search for Related Content PubMed PubMed Citation Articles by Coats, P. Articles by Hillier, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB BARIUM COMPOUNDS BARIUM, ELEMENTAL NITRIC OXIDE OUABAIN POTASSIUM Related Collections Ion channels/membrane transport Endothelium/vascular type/nitric oxide

(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

This article has been cited by other articles:

				L. Luksha, H. Nisell, N. Luksha, M. Kublickas, K. Hultenby, and K. Kublickiene Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous contribution, mechanisms, and morphological prerequisites Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R510 - R519. [Abstract] [Full Text] [PDF]

				J. C. Gillham, J. E. Myers, P. N. Baker, and M. J. Taggart Regulation of Endothelial-Dependent Relaxation in Human Systemic Arteries by SKCa and IKCa Channels Reproductive Sciences, January 1, 2007; 14(1): 43 - 50. [Abstract] [PDF]

				S. Taddei, D. Versari, A. Cipriano, L. Ghiadoni, F. Galetta, F. Franzoni, A. Magagna, A. Virdis, and A. Salvetti Identification of a Cytochrome P450 2C9-Derived Endothelium-Derived Hyperpolarizing Factor in Essential Hypertensive Patients J. Am. Coll. Cardiol., August 1, 2006; 48(3): 508 - 515. [Abstract] [Full Text] [PDF]

				M. A. James, J. Tullett, A. G. Hemsley, and A. C. Shore Effects of Aging and Hypertension on the Microcirculation Hypertension, May 1, 2006; 47(5): 968 - 974. [Abstract] [Full Text] [PDF]

				F. J. Haddy, P. M. Vanhoutte, and M. Feletou Role of potassium in regulating blood flow and blood pressure Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R546 - R552. [Abstract] [Full Text] [PDF]

				F. Khan, J. J.F. Belch, M. MacLeod, and G. Mires Changes in Endothelial Function Precede the Clinical Disease in Women in Whom Preeclampsia Develops Hypertension, November 1, 2005; 46(5): 1123 - 1128. [Abstract] [Full Text] [PDF]

				W. G. Schrage, N. M. Dietz, J. H. Eisenach, and M. J. Joyner Agonist-dependent variablity of contributions of nitric oxide and prostaglandins in human skeletal muscle J Appl Physiol, April 1, 2005; 98(4): 1251 - 1257. [Abstract] [Full Text] [PDF]

				C Cleary, C H Buckley, E Henry, P McLoughlin, C O'Brien, and P W F Hadoke Enhanced endothelium derived hyperpolarising factor activity in resistance arteries from normal pressure glaucoma patients: implications for vascular function in the eye Br J Ophthalmol, February 1, 2005; 89(2): 223 - 228. [Abstract] [Full Text] [PDF]

				L. Luksha, H. Nisell, and K. Kublickiene The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1102 - R1109. [Abstract] [Full Text] [PDF]

				W. W. Batenburg, I. M. Garrelds, J. P. van Kats, P. R. Saxena, and A. H. J. Danser Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries Hypertension, February 1, 2004; 43(2): 488 - 492. [Abstract] [Full Text] [PDF]

				M. Tanaka, H. Kanatsuka, B.-H. Ong, T. Tanikawa, A. Uruno, T. Komaru, R. Koshida, and K. Shirato Cytochrome P-450 metabolites but not NO, PGI2, and H2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1939 - H1948. [Abstract] [Full Text] [PDF]

				P. Koobi, J. Kalliovalkama, P. Jolma, J. Rysa, H. Ruskoaho, O. Vuolteenaho, M. Kahonen, I. Tikkanen, M. Fan, P. Ylitalo, et al. AT1 Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure Hypertension, June 1, 2003; 41(6): 1364 - 1371. [Abstract] [Full Text] [PDF]

				R. Ceravolo, R. Maio, A. Pujia, A. Sciacqua, G. Ventura, M. C. Costa, G. Sesti, and F. Perticone Pulse pressure and endothelial dysfunction in never-treated hypertensive patients J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1753 - 1758. [Abstract] [Full Text] [PDF]

				S. Kashiwagi, M. Kajimura, Y. Yoshimura, and M. Suematsu Nonendothelial Source of Nitric Oxide in Arterioles But Not in Venules: Alternative Source Revealed In Vivo by Diaminofluorescein Microfluorography Circ. Res., December 13, 2002; 91 (12): e55 - e64. [Abstract] [Full Text] [PDF]

				Z. Lacza, M. Puskar, B. Kis, J. V. Perciaccante, A. W. Miller, and D. W. Busija Hydrogen peroxide acts as an EDHF in the piglet pial vasculature in response to bradykinin Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H406 - H411. [Abstract] [Full Text] [PDF]

				V. L. Clifton, R. Crompton, R. Smith, and I. M. R. Wright Microvascular Effects of CRH in Human Skin Vary in Relation to Gender J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 267 - 270. [Abstract] [Full Text] [PDF]

				R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]