Bellien Jeremy, Iacob Michele, Gutierrez Laurence, Isabelle Marc, Lahary Agnes, Thuillez Christian, Joannides Robinson
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.
Hypertension. 2006 Dec;48(6):1088-94. doi: 10.1161/01.HYP.0000246672.72188.bd. Epub 2006 Oct 30.
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.
一氧化氮（NO）是否参与人体中持续的导管动脉血流介导的扩张尚不清楚。此外，由细胞色素环氧化酶合成并通过钙激活钾通道起作用的内皮衍生超极化因子（EDHF）的作用，及其在血流介导的扩张过程中与NO的关系，此前从未被研究过。在12名健康受试者中，我们测量了在逐渐进行远端手部皮肤加热（34至44摄氏度）诱导的血流介导的扩张过程中、局部输注生理盐水以及一氧化氮合酶抑制剂（N(G)-单甲基-L-精氨酸[l-NMMA]：8至20微摩尔/分钟/升）、钙激活钾通道抑制剂（氯化四乙铵：9微摩尔/分钟/升）和细胞色素环氧化酶抑制剂（氟康唑：0.4至1.6微摩尔/分钟/升）单独及联合使用时的桡动脉直径（回声跟踪）和血流量（多普勒）。在每个血流水平计算平均壁面切应力，即血流介导的扩张刺激，并构建直径-壁面切应力关系。在加热过程中，与生理盐水相比，l-NMMA、氯化四乙铵、氟康唑使直径-切应力关系向下移动，而l-NMMA与氯化四乙铵或氟康唑联合使用时这种移动更为明显。因此，与生理盐水（0.62±0.03毫米）相比，在我们的实验条件下，l-NMMA（-39±4%）、氯化四乙铵（-14±4%）、氟康唑（-18±6%）使最大桡动脉血流介导的扩张降低，而l-NMMA与氯化四乙铵（-64±4%）或氟康唑（-71±3%）联合使用时降低程度更大。这项研究表明，在持续血流条件下，NO和一种细胞色素相关的EDHF参与人体外周导管动脉血流介导的扩张。此外，抑制剂的协同作用强烈提示NO和EDHF途径之间存在功能相互作用。
