Kielstein Jan T, Donnerstag Frank, Gasper Sandra, Menne Jan, Kielstein Anousheh, Martens-Lobenhoffer Jens, Scalera Fortunato, Cooke John P, Fliser Danilo, Bode-Böger Stefanie M
Department of Nephrology, Medical School, Hannover, Germany.
Stroke. 2006 Aug;37(8):2024-9. doi: 10.1161/01.STR.0000231640.32543.11. Epub 2006 Jun 29.
Preclinical studies have revealed that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), increases vascular tone in cerebral blood vessels. Marked elevations of ADMA blood levels were found in patients with diseases characterized by decreased cerebral perfusion, such as ischemic stroke. Arterial stiffness is an independent predictor of stroke and other adverse cardiovascular events. The aim of this study was to investigate the influence of a systemic subpressor dose of ADMA on arterial stiffness and cerebral perfusion in humans.
Using a double-blind, vehicle-controlled study design, we allocated 20 healthy men in random order to infusion of either ADMA (0.10 mg ADMA/kg per min) or vehicle over a period of 40 minutes. Arterial stiffness was assessed noninvasively by pulse wave analysis. All volunteers underwent measurement of cerebral perfusion by dynamic contrast-enhanced perfusion magnetic resonance imaging of the brain.
Infusion of ADMA significantly decreased total cerebral perfusion by 15.1+/-4.5% (P=0.007), whereas blood flow in the vehicle group increased by 7.7+/-2.8% (P=0.02). ADMA also increased arterial stiffness as assessed by measurement of the augmentation index (-12.6+/-1.9 to -9.6+/-1.5, P=0.007).
Our results document for the first time that subpressor doses of ADMA increase vascular stiffness and decrease cerebral perfusion in healthy subjects. Thus, ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease.
临床前研究表明，内源性一氧化氮合酶抑制剂非对称二甲基精氨酸（ADMA）可增加脑血管的血管张力。在以脑灌注减少为特征的疾病患者中，如缺血性卒中患者，发现其血液中ADMA水平显著升高。动脉僵硬度是卒中及其他不良心血管事件的独立预测指标。本研究旨在探讨全身亚升压剂量的ADMA对人体动脉僵硬度和脑灌注的影响。
采用双盲、安慰剂对照研究设计，将20名健康男性随机分为两组，分别在40分钟内输注ADMA（0.10 mg ADMA/kg每分钟）或安慰剂。通过脉搏波分析无创评估动脉僵硬度。所有志愿者均接受脑部动态对比增强灌注磁共振成像测量脑灌注。
输注ADMA使总脑灌注显著降低15.1±4.5%（P = 0.007），而安慰剂组的血流量增加了7.7±2.8%（P = 0.02）。通过测量增强指数评估，ADMA还增加了动脉僵硬度（从-12.6±1.9变为-9.6±1.5，P = 0.007）。
我们的结果首次证明，亚升压剂量的ADMA可增加健康受试者的血管僵硬度并降低脑灌注。因此，ADMA是脑血管张力的重要内源性调节因子，可能参与脑血管疾病的发病机制。
