Vascular Biology – Hemodynamics – Hypertension

Kidney International (2005) 67, 1907–1912; doi:10.1111/j.1523-1755.2005.00289.x

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

JENS PASSAUER, FRANK PISTROSCH, GRIT LÄSSIG, KAY HERBRIG, ECKHART BÜSSEMAKER, PETER GROSS and INGRID FLEMING

Division of Nephrology, Department of Medicine, University Hospital Carl Gustav Carus, Dresden, Germany; and Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Correspondence: Dr Jens Passauer, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Medizinische Klinik III/Nephrologie, Fetscherstr. 74, 01307 Dresden, Germany. E-mail:passauer@rcs.urz.tu-dresden.de

Received 1 July 2004; Revised 19 October 2004; Re-revised 10 November 2004; Accepted 24 November 2004.

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Abstract

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 mug/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 Nomegamonomethyl L-arginine (L-NMMA, 16 mumol/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.

Keywords:

nitric oxide, endothelium-derived hyperpolarizing factor, sulfaphenazole, plethysmography

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