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Role of Nitric Oxide–Producing and –Degrading Pathways in Coronary Endothelial Dysfunction in Chronic Kidney Disease

Satoru Tatematsu^*, Shu Wakino^*, Takeshi Kanda^*, Koichiro Homma^*, Kyoko Yoshioka^*, Kazuhiro Hasegawa^*, Naoki Sugano^*, Masumi Kimoto, Takao Saruta^* and Koichi Hayashi^*

^* Department of Internal Medicine, School of Medicine, Keio University, Tokyo; and Department of Nutritional Science, Okayama Prefectural University, Okayama, Japan

Address correspondence to: Dr. Koichi Hayashi, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Phone: +81-3-5363-3796; Fax: +81-3-3359-2745; E-mail: khayashi{at}sc.itc.keio.ac.jp

Received for publication April 19, 2006. Accepted for publication December 29, 2006.

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] µmol/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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673