Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure.
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.
Fischer
Dieter
D
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Landmesser
Ulf
U
Spiekermann
Stephan
S
Hilfiker-Kleiner
Denise
D
Hospely
Marian
M
Müller
Maja
M
Busse
Rudi
R
Fleming
Ingrid
I
Drexler
Helmut
H
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*
D000890:Anti-Infective Agents; D013426:Sulfaphenazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases