Nitric oxide- and EDHF-mediated arteriolar tone in uremia is unaffected by selective inhibition of vascular cytochrome P450 2C9.
BACKGROUND
Uremia is a state of endothelial dysfunction as demonstrated by a reduced agonist-induced endothelium-dependent vasodilatation. Recent studies suggest that an endothelial cytochrome P450 (CYP) epoxygenase (CYP 2C9) can modulate endothelium-dependent vasodilatation in two different ways: (1) by the production of epoxyeicosatrienoic acids (EETs), which elicit hyperpolarization and relaxation; and (2) by the release of oxygen-derived free radicals, which compromise the bioavailability of nitric oxide. We therefore determined whether one of these pathways is involved in endothelial dysfunction of uremia.


METHODS
Using venous occlusion plethysmography, we measured forearm blood flow (FBF) in response to the intrabrachial infusion of acetylcholine (ACh; endothelium-dependent vasodilator; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium nitroprusside (SNP; endothelium-independent vasodilator; 2.5, 5 and 10 microg/min) in 10 stable patients on hemodialysis (HD) and 9 healthy control subjects. In HD patients, ACh infusions were repeated together with sulfaphenazole (SPZ, 6 mg/min), a highly selective inhibitor of CYP 2C9 with and without concomitant blockade of the nitric oxide synthase (NOS) by N(omega)monomethyl L-arginine (L-NMMA, 16 microumol/min).


RESULTS
Endothelium-dependent vasodilatation to ACh was reduced in HD compared to control subjects (P= 0.002), indicating endothelial dysfunction in the patients examined. Endothelium-independent vascular responses to SNP were attenuated in HD, but not significantly different to control. SPZ failed to modulate both baseline FBF and Ach-induced vasodilatation in HD. Furthermore, SPZ had no effect on baseline FBF and ACh-mediated vasodilatation in the presence of L-NMMA in HD.


CONCLUSIONS
Our results do not support a major role for CYP 2C9-derived products in the regulation of arteriolar tone in early endothelial dysfunction of uremic subjects.
Passauer
Jens
J
Division of Nephrology, Department of Medicine, University Hospital Carl Gustav Carus, Dresden, Germany. passauer@rcs.urz.tu-dresden.de
Pistrosch
Frank
F
Lässig
Grit
G
Herbrig
Kay
K
Büssemaker
Eckhart
E
Gross
Peter
P
Fleming
Ingrid
I
D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001685:Biological Factors / Q000502:physiology*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000008:administration & dosage; D013426:Sulfaphenazole / Q000494:pharmacology; D014511:Uremia / Q000201:enzymology / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D001685:Biological Factors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013426:Sulfaphenazole; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019001:Nitric Oxide Synthase; D001189:Aryl Hydrocarbon Hydroxylases; D000109:Acetylcholine