title: Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension.
abstract: BACKGROUND
  We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension.
  
  
  RESULTS
  Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (N(G)-monomethyl-l-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter-shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients.
  
  
  CONCLUSIONS
  These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension.
  
  
  BACKGROUND
  https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.
authors.affiliation: Department of Pharmacology, Rouen University Hospital, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Michele
authors.initials: M
authors.lastname: Iacob
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.forename: Daniele
authors.initials: D
authors.lastname: Lucas
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
authors.forename: Laurence
authors.initials: L
authors.lastname: Gutierrez
authors.forename: Cathy
authors.initials: C
authors.lastname: Vendeville
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dreano
authors.forename: Alain
authors.initials: A
authors.lastname: Mercier
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannides
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000008:administration & dosage; D000328:Adult; D015777:Eicosanoids / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage; D006358:Hot Temperature; D006801:Humans; D006940:Hyperemia / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D011673:Pulsatile Flow / Q000187:drug effects / Q000502:physiology; D017534:Radial Artery / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D013314:Stress, Mechanical; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D058888:14-alpha Demethylase Inhibitors; D015777:Eicosanoids; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D015725:Fluconazole