Aslam S, Santha T, Leone A, Wilcox C
Department of Internal Medicine, Division of Nephrology and Hypertension, Georgetown University Hospital, Washington, District of Columbia 20007, USA.
Kidney Int. 2006 Dec;70(12):2109-15. doi: 10.1038/sj.ki.5001983. Epub 2006 Oct 25.
Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) treatment have a markedly shortened life expectancy in large part owing to cardiovascular disease (CVD), not explained by established risk factors. We tested the hypothesis that therapy with valsartan, an angiotensin receptor blocker and amlodipine, an antioxidant calcium channel blocker will reduce oxidative stress and the plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. We confirmed that compared with age- and gender-matched healthy controls, ESRD patients have excessive oxidative stress and arginine methylation as indexed by elevated plasma levels of oxidation products of lipids (13-hydroxyoctadecadienoic acid (13-HODE)), thiols (oxidized:reduced glutathione, oxidized glutathione (GSSG):GSH), proteins, and nucleic acids, and the methylation products ADMA and symmetric dimethylarginine (SDMA). We undertook a double blind, crossover study of equi-antihypertensive treatment with amlodipine and valsartan for 6 weeks each to test our hypothesis. Both treatments significantly reduced GSSG:GSH, 8-hydroxy 2-deoxyguanosine, ADMA, and SDMA levels and amlodipine reduced 13-HODE. We conclude that hypertensive patients with ESRD receiving HD have evidence of extensive oxidation of lipids, thiols, proteins, and nucleic acids and methylation of arginine that could contribute to CVD. Many of these changes can be reduced by short-term treatment with amlodipine and valsartan.
接受血液透析（HD）治疗的终末期肾病（ESRD）患者预期寿命显著缩短，很大程度上是由于心血管疾病（CVD），而既定的风险因素无法解释这一现象。我们检验了以下假设：使用缬沙坦（一种血管紧张素受体阻滞剂）和氨氯地平（一种抗氧化钙通道阻滞剂）进行治疗，将降低氧化应激以及不对称二甲基精氨酸（ADMA，一种一氧化氮合酶的内源性抑制剂）的血浆水平。我们证实，与年龄和性别匹配的健康对照相比，ESRD患者存在过度的氧化应激和精氨酸甲基化，这可通过血浆中脂质氧化产物（13-羟基十八碳二烯酸（13-HODE））、硫醇（氧化型：还原型谷胱甘肽，氧化型谷胱甘肽（GSSG）：GSH）、蛋白质和核酸以及甲基化产物ADMA和对称二甲基精氨酸（SDMA）水平升高来体现。我们进行了一项双盲交叉研究，分别用氨氯地平和缬沙坦进行为期6周的等效抗高血压治疗，以检验我们的假设。两种治疗均显著降低了GSSG：GSH、8-羟基-2'-脱氧鸟苷、ADMA和SDMA水平，且氨氯地平降低了13-HODE水平。我们得出结论，接受HD治疗的ESRD高血压患者存在脂质、硫醇、蛋白质和核酸广泛氧化以及精氨酸甲基化的证据，这些可能导致CVD。通过氨氯地平和缬沙坦的短期治疗，其中许多变化可以得到缓解。
