Journal
HYPERTENSION
Volume 48, Issue 6, Pages 1088-1094Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000246672.72188.bd
Keywords
conduit arteries; endothelium; flow-mediated dilatation; nitric oxide; endothelium-derived hyperpolarizing factor; cytochrome P450
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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 mu mol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 mu mol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 mu mol/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.
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