Published Online
on October 30, 2006

A more recent version of this article appeared on December 1, 2006

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Submitted on June 19, 2006
Revised on July 8, 2006

Crucial Role of NO and Endothelium-Derived Hyperpolarizing Factor in Human Sustained Conduit Artery Flow-Mediated Dilatation

Jeremy Bellien; Michele Iacob; Laurence Gutierrez; Marc Isabelle; Agnes Lahary; Christian Thuillez; and Robinson Joannides^*

From the Departments of Pharmacology (J.B., M. Iacob, M. Isabelle, C.T., R.J.) and Hematology (A.L.) and Centre d’Investigation Clinique (L.G.), Institut National de la Santé et de la Recherche Médicale U644, Institut Fédératif de Recherche Multidisciplinaire sur les Peptides 23, Centre Hospitalier Universitaire-Hopitaux de Rouen, Rouen, France.

^* To whom correspondence should be addressed. E-mail: robinson.joannides{at}chu-rouen.fr.

Abstract--Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear. Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44°C), during the local infusion of saline and inhibitors of NO synthase (N^G-monomethyl-L-arginine [L-NMMA]: 8 to 20 µmol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 µmol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 µmol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter-wall shear stress relationship was constructed. During heating, compared with saline, the diameter-shear stress relationship was shifted downward by L-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of L-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62±0.03 mm), was decreased under our experimental conditions by L-NMMA (-39±4%), tetraethylammonium chloride (-14±4%), fluconazole (-18±6%), and to a greater extent, by the combinations of L-NMMA with tetraethylammonium (-64±4%) or with fluconazole (-71±3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways.

Key words: conduit arteries • endothelium • flow-mediated dilatation • nitric oxide • endothelium-derived hyperpolarizing factor • cytochrome P450

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