Nitric oxide- and EDHF-mediated arteriolar tone in uremia is unaffected by selective inhibition of vascular cytochrome P450 2C9

Abstract

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 μg/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 ωmonomethyl L-arginine (L-NMMA, 16 μmol/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. Conclusion. 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. © 2005 by the International Society of Nephrology.