Sympathetic overactivity & hypertension in ERSD: A role for ADMA

交感神经过度活跃

• 批准号: 7176295
• 负责人: PAUL J FADEL
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176295
• 关键词: Arginine; Automobile Driving; Baroreflex; Blood Pressure; Brain Stem; Cardiovascular system; Chronic; Clinical Research; Cutaneous; Disease; Drug Delivery Systems; Elevation; End stage renal failure; Endothelium-Dependent Relaxing Factors; Excision; Heart Diseases; Hemodialysis; High Prevalence; Human; Hypertension; Infusion procedures; Kidney; Kidney Diseases; Laboratories; Measures; Mediating; Morbidity - disease rate; Muscle; N,N-dimethylarginine; Nerve; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Outcome; Patients; Plasma; Pressoreceptors; Production; Protein Isoforms; Regulation; Renal function; Research Personnel; Risk Factors; Role; Signal Transduction; Signaling Molecule; Skin; Staging; Stereoisomer; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Vasodilation; base; hypertensive heart disease; inhibitor/antagonist; insight; mortality; novel; programs; research study; response; restoration; restraint; therapeutic target

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.

描述（由申请人提供）：高血压存在于高达80%的终末期肾病（ESRD）患者中，并且是这些患者中心血管疾病发病率和死亡率过高的主要危险因素。ESRD的另一个危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，还可能加速独立于血压升高的心脏病的进展。因此，交感神经系统被认为是抑制ESRD患者高血压性心脏病进展的新药物靶点。为了制定有效的对策，重要的是识别驱动交感神经过度活动的信号。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外流强直抑制的关键信号分子。由于ADMA部分被肾脏清除，因此在ESRD患者中异常高水平的积累。因此，我们的中心假设是ADMA的积累是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ESRD患者的肌肉和皮肤SNA，以确定内源性NOS抑制剂ADMA增加所产生的NO缺乏是否是介导ESRD交感神经过度活跃和高血压的主要机制。具体来说，我们将确定通过输注l -精氨酸恢复NO的产生是否会降低SNA和BP。这些研究将提供关于人类中枢产生NO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途径是否构成ESRD患者交感神经过度活跃和高血压以及其他形式的血浆ADMA浓度升高的疾病的有效治疗靶点。尽管血浆ADMA升高已被证明是ESRD患者总死亡率和心血管结局的一个强有力且独立的预测因子，但ADMA全身性升高对心血管的影响尚不清楚。确定adma诱导的NOS抑制在增加交感神经流出中的作用，对于帮助降低ESRD患者极高的高血压患病率和心血管发病率具有重要的治疗意义。