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Author Notes:

Corresponding Author: Arshed A. Quyyumi, MD, FRCP, Professor of Medicine, Emory University, 1364 Clifton Rd. NE, Suite 403C, Atlanta, GA 30322, Tel: (404) 727-3655, Fax: (404) 712-8785, aquyyum@emory.edu

Disclosures: none


Research Funding:

Funding sources: National Institutes of Health Research Grant RO1 HL79115, and in part by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award Program, and PHS Grant M01 RR00039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources, British Cardiovascular Society Research Fellowship, and the National Blood Foundation.


  • endothelium-derived factors
  • vasodilation
  • endothelial function
  • endothelium-derived hyperpolarizing factor
  • nitric oxide

Endothelium-Derived Hyperpolarizing Factor Determines Resting and Stimulated Forearm Vasodilator Tone in Health and in Disease


Journal Title:



Volume 123, Number 20


, Pages 2244-2253

Type of Work:

Article | Post-print: After Peer Review


Background We assessed the contribution of endothelium-derived hyperpolarizing factors (EDHFs) to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was employed to inhibit K+Ca channel activation and fluconazole to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that 1) EDHFs contribute to resting vascular tone by K+Ca channel activation and epoxyeicosatrienoic acid release, and 2) EDHFs compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and Results In 103 healthy subjects and 71 non-hypertensive subjects with multiple risk factors, resting forearm blood flow (FBF) was measured using venous occlusion plethysmography before and after intra-arterial infusions of NG-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF, and on bradykinin- and acetylcholine-mediated vasodilation was studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001), however, the vasoconstrictor response to L-NMMA was greater (p=0.04) and to TEA lower (p=0.04) in healthy subjects compared to those with risk factors. Fluconazole decreased resting FBF in all subjects and addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K+Ca channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects, but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions Firstly, EDHFs by activating TEA inhibitable K+Ca channels together with NO contribute to resting microvascular dilator tone. The contribution of K+Ca channel activation compared to NO is greater in those with multiple risk factors compared to healthy subjects. Second, activation of K+Ca channels is only partly through epoxyeicosatrienoic acid release, indicating presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine stimulates K+Ca channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K+Ca channel-mediated vasodilation compensates for the reduced NO activity. Thus, enhanced EDHF activity in conditions of NO deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration Information: http://clinicaltrials.gov/, Identifier: NCT00166166

Copyright information:

© 2011 American Heart Association, Inc.

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