Role of nitric oxide-producing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease.
Role of nitric oxide-producing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease.
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DOI：
10.1681/asn.2006040367
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发表时间：
2007-03
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影响因子：
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通讯作者：
S. Tatematsu;S. Wakino;T. Kanda;K. Homma;K. Yoshioka;K. Hasegawa;N. Sugano;M. Kimoto;T. Saruta;K. Hayashi
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文献类型：
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作者：
S. Tatematsu;S. Wakino;T. Kanda;K. Homma;K. Yoshioka;K. Hasegawa;N. Sugano;M. Kimoto;T. Saruta;K. Hayashi
慢性肾脏病（CKD）患者的心血管事件加速。尽管紊乱的一氧化氮（NO）通路和不对称二甲基精氨酸（ADMA）可引起内皮功能障碍，但尚无CKD患者冠状动脉内皮功能障碍的直接证据。采用半肾切除术（1/2Nx）或六分之五肾切除术（5/6 Nx）建立慢性肾脏病模型。4周后，肾消融降低GFR（对照组76 [54 - 85]; 12 Nx 38 [29 - 47]; 5/6 Nx 15 [12 - 46] ml/min）和血浆ADMA升高（对照组1.88 [1.68 - 2.54]; 1/2Nx 2.51 [2.11 - 3.55]; 5/6 Nx 3.84 [2.16 - 3.95] μ mol/L）。对乙酰胆碱的冠状动脉循环反应显示，对照组的冠状动脉血流量显著增加（增加83 +/- 17%），但1/2Nx（增加34 +/- 8%）和5/6 Nx（增加20 +/- 4%）的反应迟钝。乙酰胆碱引起的心外膜小动脉直径的变化，使用针透镜探针电荷耦合器件视频显微镜，显示了类似的结果。对硝普钠的反应性在三组之间没有差异。1/2Nx和5/6 Nx组血浆亚硝酸盐/硝酸盐水平降低，冠状动脉中二甲基精氨酸二甲氨基水解酶-II（DDAH-II）、ADMA降解酶和内皮型一氧化氮合酶（eNOS）mRNA表达下调。最后，4周的治疗全反式维甲酸恢复受损的内皮依赖性血管舒张和逆转eNOS的表达，但不DDAH-II。CKD早期冠状动脉内皮功能受损。这种功能障碍归因于冠状动脉中eNOS和/或DDAH-II的下调。此外，NO通路的操作可能构成一种治疗策略，用于预防CKD中的冠状动脉功能障碍。
Cardiovascular events are accelerated in chronic kidney disease (CKD). Although deranged nitric oxide (NO) pathways and asymmetric dimethylarginine (ADMA) cause endothelial dysfunction, no direct evidence for coronary artery endothelial dysfunction in CKD has been documented. CKD was induced in male dogs by heminephrectomy (1/2Nx) or five-sixths nephrectomy (5/6Nx). After 4 wk, renal ablation reduced GFR (control 76 [54 to 85]; 1/2Nx 38 [29 to 47]; 5/6Nx 15 [12 to 46] ml/min) and elevated plasma ADMA (control 1.88 [1.68 to 2.54]; 1/2Nx 2.51 [2.11 to 3.55]; 5/6Nx 3.84 [2.16 to 3.95] micromol/L). Coronary circulatory responses to acetylcholine revealed marked increases in coronary blood flow in control group (83 +/- 17% increment) but blunted responses in 1/2Nx (34 +/- 8% increment) and 5/6Nx (20 +/- 4% increment). The acetylcholine-induced changes in epicardial arteriolar diameter, using needle-lens probe charge-coupled device videomicroscopy, showed similar results. The responsiveness to sodium nitroprusside did not differ among three groups. Plasma nitrite/nitrate levels decreased in 1/2Nx and 5/6Nx, and the mRNA expressions of dimethylarginine dimethylaminohydrolase-II (DDAH-II), ADMA-degrading enzyme, and endothelial NO synthase (eNOS) in coronary arteries were downregulated in 1/2Nx and 5/6Nx. Finally, 4-wk treatment with all-trans retinoic acid restored the impaired endothelium-dependent vasodilation and reversed the expression of eNOS but not DDAH-II. Coronary endothelial function is impaired in the early stage of CKD. The dysfunction is attributed to the downregulation of eNOS and/or DDAH-II in coronary arteries. Furthermore, the manipulation of NO pathways may constitute a therapeutic strategy for the prevention of coronary dysfunction in CKD.