Sympathetic overactivity & hypertension in ERSD: A role for ADMA

描述（由申请方提供）：高达80%的终末期肾病（ESRD）患者存在高血压，是这些患者心血管发病率和死亡率过高的主要风险因素。ESRD中存在的另一个风险因素是交感神经系统的过度活跃，这不仅可能导致高血压，而且还可能加速心脏病的进展，而不依赖于血压（BP）的升高。因此，交感神经系统构成了一个推定的新药靶点，用于阻止ESRD中高血压性心脏病的进展。为了开发有效的对策，重要的是识别驱动交感神经过度活跃的信号。一个潜在的信号涉及内源性一氧化氮合酶（NOS）抑制剂不对称二甲基精氨酸（ADMA）的积累。越来越多的功能证据表明，一氧化氮（NO）不仅是一种内皮依赖性血管扩张剂，而且是参与中枢交感神经流出紧张性抑制的关键信号分子。由于ADMA部分由肾脏清除，因此在ESRD患者中蓄积异常高的水平。因此，我们的中心假设是ADMA的积累构成了ESRD患者交感神经过度活跃和高血压的主要机制。为了验证这一假设，我们将首先直接测量肾功能正常的健康受试者的肌肉和皮肤交感神经活动（SNA），以确定实验性NOS抑制是否会增加SNA。其次，我们将测量肌肉和皮肤SNA在ESRD患者，以确定是否NO缺乏所产生的内源性NOS抑制剂ADMA的增加是一个主要的机制介导的交感神经过度活跃和高血压的ESRD。具体来说，我们将确定是否恢复NO的生产与L-精氨酸的输注降低SNA和BP。这些研究将提供关于中枢产生的NO在人类中的交感神经抑制作用的新信息，并为临床研究提供概念框架，以确定NO通路是否构成ESRD患者以及血浆ADMA浓度升高的其他形式疾病的交感神经过度活跃和高血压的有效治疗靶点。尽管血浆ADMA升高已被证明是ESRD患者总体死亡率和心血管结局的一个强有力的独立预测因子，但ADMA全身性升高的心血管效应仍不清楚。确定ADMA诱导的NOS抑制在增加交感神经流出中的作用具有重要的治疗意义，有助于降低ESRD患者极高的高血压和心血管发病率。

DESCRIPTION (provided by applicant): Hypertension is present in up to 80% of patients with end stage renal disease (ESRD) and is a major risk factor for the excessive cardiovascular morbidity and mortality among these patients. An additional risk factor present in ESRD is overactivity of the sympathetic nervous system, which may not only contribute to the hypertension but could also accelerate the progression of heart disease independent of the rise in blood pressure (BP). Thus, the sympathetic nervous system constitutes a putative new drug target for arresting the progression,,of hypertensive heart disease in ESRD. To develop effective countermeasures, it is important to identify the signal driving the sympathetic overactivity. One potential signal involves the accumulation of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Increasing functional evidence indicates that nitric oxide (NO) is not only an endothelium-dependent vasodilator but also a key signaling molecule involved in the tonic restraint of central sympathetic outflow. Since ADMA is in part cleared by the kidney, abnormally high levels accumulate in patients with ESRD. Thus, our central hypothesis is that accumulation of ADMA constitutes a major mechanism for the sympathetic overactivity and hypertension in patients with ESRD. To test this hypothesis, we will first directly measure muscle and skin sympathetic nerve activity (SNA) in healthy subjects with normal renal function to determine if experimental NOS inhibition increases SNA. Second, we will measure muscle and skin SNA in ESRD patients to determine if NO deficiency produced by increases in the endogenous NOS inhibitor ADMA is a major mechanism mediating the sympathetic overactivity and hypertension in ESRD. Specifically, we will determine if restoration of NO production with the infusion of L-arginine reduces SNA and BP. These studies will provide novel information about the sympathoinhibitory role of centrally produced NO in humans and provide a conceptual framework for clinical research to determine if the NO pathway constitutes an effective therapeutic target for the sympathetic overactivity and hypertension in patients with ESRD as well as other forms of disease with elevated plasma ADMA concentrations. Although elevated plasma ADMA has been shown to be a strong and independent predictor of overall mortality and cardiovascular outcome in ESRD patients, the cardiovascular effects of this systemic increase in ADMA remain unclear. Identifying a role for ADMA-induced NOS inhibition in increasing sympathetic outflow has major therapeutic implications to help reduce the extremely high prevalence of hypertension and cardiovascular morbidity in patients with ESRD.