Crucial role of NO and endothelium-derived hyperpolarizing factor in human sustained conduit artery flow-mediated dilatation.
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 degrees C), during the local infusion of saline and inhibitors of NO synthase (N(G)-monomethyl-l-arginine [l-NMMA]: 8 to 20 micromol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 micromol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 micromol/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.
Bellien
Jeremy
J
Department of Pharmacology, 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.
Iacob
Michele
M
Gutierrez
Laurence
L
Isabelle
Marc
M
Lahary
Agnes
A
Thuillez
Christian
C
Joannides
Robinson
R
D000328:Adult; D001685:Biological Factors / Q000502:physiology*; D001783:Blood Flow Velocity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017534:Radial Artery / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology*; D033081:Shear Strength; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001685:Biological Factors; D004791:Enzyme Inhibitors; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase