Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease.
BACKGROUND
Nitric oxide (NO)- and prostacyclin-independent vasodilatation in several vascular beds has been linked to the activation of cytochrome P450 (CYP) epoxygenases expressed in endothelial cells. However, these enzymes, which generate vasodilator epoxyeicosatrienoic acids, may also produce oxygen-derived free radicals, which attenuate the bioavailability of NO. Here, we studied the involvement of CYP 2C9 in modulating endothelium-dependent and -independent changes in forearm blood flow (FBF) in healthy volunteers and in patients with manifest coronary artery disease.


RESULTS
The effects of sulfaphenazole, a selective inhibitor of CYP 2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside, SNP) FBF responses were measured by venous occlusion plethysmography in 5 healthy subjects and in 16 patients with angiographically documented stable coronary artery disease. Sulfaphenazole did not modify FBF responses to acetylcholine or SNP in healthy subjects. In contrast, sulfaphenazole markedly and dose-dependently enhanced the FBF response to acetylcholine without affecting the response to SNP. Vitamin C also increased the FBF response to acetylcholine, but this effect was further potentiated by sulfaphenazole. In the presence of N(omega)-monomethyl-l-arginine, sulfaphenazole failed to significantly improve acetylcholine-induced vasodilatation. The oxidation of serum proteins was enhanced in patients with coronary artery disease, and this effect was significantly attenuated by sulfaphenazole.


CONCLUSIONS
The CYP 2C9 inhibitor sulfaphenazole enhances endothelium-dependent vasodilator responses in patients with manifest coronary artery disease. This effect seems to be related to an increase in the bioavailability of NO, probably as a consequence of an attenuated generation of reactive oxygen species by CYP 2C9 in endothelial cells.
Fichtlscherer
Stephan
S
Departments of Internal Medicine IV, Division of Cardiology, Johann W. Goethe-University, Frankfurt am Main, Germany.
Dimmeler
Stefanie
S
Breuer
Susanne
S
Busse
Rudi
R
Zeiher
Andreas M
AM
Fleming
Ingrid
I
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001205:Ascorbic Acid / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000503:physiopathology*; D065729:Cytochrome P-450 CYP2C9; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D013426:Sulfaphenazole / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D013426:Sulfaphenazole; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000109:Acetylcholine; D001205:Ascorbic Acid