title: Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure.
abstract: BACKGROUND
  Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans.
  
  
  RESULTS
  FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery.
  
  
  CONCLUSIONS
  FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.
authors.affiliation: Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Fischer
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Stephan
authors.initials: S
authors.lastname: Spiekermann
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Marian
authors.initials: M
authors.lastname: Hospely
authors.forename: Maja
authors.initials: M
authors.lastname: Müller
authors.forename: Rudi
authors.initials: R
authors.lastname: Busse
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
mesh_terms: D000368:Aged; D000890:Anti-Infective Agents / Q000494:pharmacology; D001158:Arteries / Q000502:physiology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D002908:Chronic Disease; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D018056:Hemorheology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D012039:Regional Blood Flow / Q000502:physiology; D013426:Sulfaphenazole / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000890:Anti-Infective Agents; D013426:Sulfaphenazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases