Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia

Vasc Med. 2015 Feb;20(1):14-22. doi: 10.1177/1358863X14565374. Epub 2015 Feb 3.


The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166:

Keywords: endothelial function; endothelium-derived hyperpolarizing factor; exercise; hypercholesterolemia; nitric oxide; vasodilation.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Biological Factors / metabolism*
  • Blood Flow Velocity
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Enzyme Inhibitors / administration & dosage
  • Exercise*
  • Female
  • Forearm / blood supply*
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / physiopathology*
  • Infusions, Intra-Arterial
  • Male
  • Middle Aged
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Potassium Channel Blockers / administration & dosage
  • Potassium Channels, Calcium-Activated / antagonists & inhibitors
  • Potassium Channels, Calcium-Activated / metabolism
  • Regional Blood Flow
  • Signal Transduction
  • Time Factors
  • Vasodilation* / drug effects
  • Vasodilator Agents / administration & dosage
  • Young Adult


  • Biological Factors
  • Enzyme Inhibitors
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated
  • Vasodilator Agents
  • endothelium-dependent hyperpolarization factor
  • Nitric Oxide Synthase

Associated data