Kang E S, Tevlin M T, Wang Y B, Chiang T M, Cardenas R, Myers L K, Acchiardo S R
Department of Pediatrics, University of Tennessee, Memphis 38163, USA.
Am J Med Sci. 1999 Jan;317(1):9-21. doi: 10.1097/00000441-199901000-00003.
Hypotension during hemodialysis in end-stage renal disease (ESRD) not explained by excessive ultrafiltration has been linked to an apparent increase in the synthesis of nitric oxide (NO). The authors tested whether the induction of NO synthase (iNOS) by cytokines or differences in the concentrations of inhibitors of NOS or both could account for variability in the amount of NO synthesized during hemodialysis. Plasma levels of an inhibitor of NOS, asymmetric dimethylarginine (ADMA), L-arginine, the substrate for NOS, the end-products N02+N03, iNOS activity in circulating buffy coat cells, and their interdialytic changes were measured in 10 patients during three treatments. Predialysis (0') levels of ADMA were markedly elevated with a mean of 0.008+/-0.002 micromol/mL of deproteinized plasma, compared to controls where ADMA is present in trace amounts. ADMA levels from 30 minutes to the end of dialysis correlated directly with the drop in blood pressure (BP), with levels being much higher in patients with severe hypotension. Postdialysis ADMA levels correlated directly with the 0' systolic BP and the drop in BP at the next dialysis treatment. NOS activity was detected in two thirds of the predialysis buffy coat samples, and appeared to increase as dialysis progressed. 0' iNOS activity correlated inversely with the 0' BP, but activities did not differ based on percent drop in BP. iNOS activity in the 0' samples correlated inversely with the time since the last dialysis, reflecting the greater accumulation of dialyzable inhibitors of NOS as the interval is prolonged. The interdialytic change in iNOS activity correlated inversely with the drop in BP. The isoform detected immunochemically in the buffy coat samples had an Mr of 130 kDa and was reactive with antihuman iNOS. Thus, iNOS is already induced in the cells of the buffy coat in many intermittently hemodialyzed ESRD subjects, but its expression may be masked by inhibitors. After 60 minutes of dialysis (too brief a time for the de novo induction of iNOS,) the appearance of or increase in iNOS activity suggests that an inhibitor had been removed. Because ADMA levels are associated with higher predialysis systolic BPs that result in a greater severity of hypotension, reduction in ADMA concentrations would appear to play a major role in the resumption of NO synthesis by various isoforms.
终末期肾病（ESRD）患者血液透析期间出现的低血压，若不能用超滤过多来解释，则与一氧化氮（NO）合成明显增加有关。作者测试了细胞因子诱导一氧化氮合酶（iNOS），或一氧化氮合酶抑制剂浓度差异，或两者兼而有之，是否能解释血液透析期间NO合成量的变化。在10例患者的三次治疗过程中，测量了一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）、一氧化氮合酶底物L-精氨酸、终产物NO2+NO3的血浆水平、循环中血沉棕黄层细胞中的iNOS活性及其透析间期的变化。与ADMA含量微量的对照组相比，透析前（0'）ADMA水平显著升高，脱蛋白血浆中平均为0.008±0.002μmol/mL。从透析30分钟至结束，ADMA水平与血压（BP）下降直接相关，重度低血压患者的ADMA水平更高。透析后ADMA水平与0'收缩压及下次透析治疗时的血压下降直接相关。在三分之二的透析前血沉棕黄层样本中检测到了NOS活性，且随着透析进行似乎有所增加。0'时的iNOS活性与0'时的血压呈负相关，但基于血压下降百分比，活性并无差异。0'样本中的iNOS活性与上次透析后的时间呈负相关，反映出随着间隔时间延长，可透析的NOS抑制剂积累更多。iNOS活性的透析间期变化与血压下降呈负相关。在血沉棕黄层样本中通过免疫化学检测到的同工型分子量为130 kDa，与抗人iNOS反应。因此，在许多间歇性血液透析的ESRD患者中，血沉棕黄层细胞中已诱导出iNOS，但其表达可能被抑制剂掩盖。透析60分钟后（时间过短不足以从头诱导iNOS），iNOS活性的出现或增加表明一种抑制剂已被清除。由于ADMA水平与更高的透析前收缩压相关，而这会导致更严重的低血压，ADMA浓度降低似乎在各种同工型恢复NO合成中起主要作用。
