title: Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension.
abstract: In young healthy subjects, epoxyeicosatrienoic acids synthesized by endothelial cytochrome P450 epoxygenases maintain basal conduit artery diameter during altered NO availability. Whether this compensatory mechanism is effective during essential hypertension is unknown. Radial artery diameter, blood flow, and mean wall shear stress were determined in 14 nontreated essential hypertensive patients and 14 normotensive control subjects during 8 minutes of brachial infusion for inhibitors of cytochrome P450 epoxygenases (fluconazole, 0.4 µmol/min) and NO synthase (N(G)-monomethyl-L-arginine, 8 µmol/min) alone and in combination. In controls, the radial artery diameter was reduced by fluconazole (-0.034 ± 0.012 mm) and N(G)-monomethyl-L-arginine (-0.037 ± 0.010 mm) and to a larger extent by their combination (-0.137 ± 0.011 mm), demonstrating a synergic effect. In contrast, the radial diameter in hypertensive patients was not affected by fluconazole (0.010 ± 0.014 mm) but was reduced by N(G)-monomethyl-L-arginine (-0.091 ± 0.008 mm) to a larger extent than in controls. In parallel, N(G)-monomethyl-L-arginine decreased local plasma nitrite to a lesser extent in hypertensive patients (-14 ± 5 nmol/L) than in controls (-50 ± 10 nmol/L). Moreover, the addition of fluconazole to N(G)-monomethyl-L-arginine did not further decrease radial diameter in patients (-0.086 ± 0.011 mm). Accordingly, fluconazole significantly decreased local epoxyeicosatrienoic acid plasma level in controls (-2.0 ± 0.6 ng/mL) but not in patients (-0.9 ± 0.4 ng/mL). Inhibitors effects on blood flow and endothelium-independent dilatation to sodium nitroprusside were similar between groups. These results show that, in contrast to normotensive subjects, epoxyeicosatrienoic acids did not contribute to the regulation of basal conduit artery diameter and did not compensate for altered NO availability to maintain this diameter in essential hypertensive patients.
authors.affiliation: Departments of Pharmacology, Rouen University Hospital, Rouen, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.forename: Michele
authors.initials: M
authors.lastname: Iacob
authors.forename: Etienne
authors.initials: E
authors.lastname: Blot
authors.forename: Alain
authors.initials: A
authors.lastname: Mercier
authors.forename: Daniele
authors.initials: D
authors.lastname: Lucas
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dreano
authors.forename: Laurence
authors.initials: L
authors.lastname: Gutierrez
authors.forename: Nathalie
authors.initials: N
authors.lastname: Donnadieu
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannides
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D015777:Eicosanoids / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D000075222:Essential Hypertension; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D017534:Radial Artery / Q000187:drug effects* / Q000503:physiopathology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D019323:omega-N-Methylarginine; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2