Targeted Sympathetic Ablation for Treatment of Hypertension

靶向交感神经消融治疗高血压

• 批准号: 9187039
• 负责人: John W Osborn
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187039
• 关键词: Ablation; Acute; Address; Adverse effects; Afferent Neurons; Animal Genetics; Animal Model; Antihypertensive Agents; Attention; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Catheters; Clinical; Consensus; Data; Deafferentation procedure; Denervation; Development; Devices; Drug resistance; Drug usage; Efferent Neurons; Epidemic; Excision; Ganglionectomy; Genetic Models; Goals; Human; Hypertension; Impairment; Kidney; Knowledge; Lead; Light; Mediating; Methods; Nerve; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Play; Rattus; Recovery; Regulation; Research; Role; Secondary to; Study models; Sympathectomy; Sympathetic Nerve Block; Sympathetic Nervous System; Sympatholytics; Testing; Therapeutic; Time; United States; Vascular resistance; Work; adverse outcome; base; blood pressure reduction; falls; hypertension treatment; minimally invasive; mortality; novel; novel therapeutics; pressure; public health relevance; response; salt sensitive; success; treatment response; vascular bed

DESCRIPTION (provided by applicant): High blood pressure (hypertension; HT) continues at epidemic levels in the United States. Despite the growing arsenal of antihypertensive drugs available, the fraction of patients responding adequately to traditional drug therapy remains unacceptably low. There is now indisputable evidence that increased sympathetic nervous system activity (SNA) is a major in the pathogenesis of HT. Drugs that globally impair neurogenic cardiovascular regulation have limited utility due to a poor side-effect profile. Is it possible to reduce SNA in a more regionally selective way (using drugs or other methods) and still lower blood pressure? The exciting recent demonstration in human patients of long-term antihypertensive responses to a novel device- based method of selective renal denervation suggests the answer is yes. The overall goal of this project is to advance our understanding of changes in regional specific SNA in experimental HT with the goal of developing "novel target specific" therapies. We will address these issues using a genetic model of salt-sensitive HT - the Dahl-S (DS) rat. Our preliminary data suggests that both renal denervation (RDNX) and splanchnic denervation, via celiac ganglionectomy (CGX), in DS rats cause dramatic reductions in AP of a magnitude similar to that seen in humans after catheter based renal nerve ablation. Specific Aim 1 will establish whether the cardiovascular responses to renal denervation (RDNX) are due to ablation of renal efferent or afferent neurons. Specific Aim 2 will define the cardiovascular and sympathetic mechanisms that mediate the acute and sustained antihypertensive responses to RDNX and/or renal deafferentation. Specific Aim 3 will define the cardiovascular and sympathetic mechanisms that mediate the acute and sustained antihypertensive responses to splanchnic sympathectomy via CGX. The expected outcome of the project is to generate a detailed understanding of the mechanisms whereby targeted sympathetic ablation can be used to treat HT. The expected impact is to focus new research attention on SNA and its effect on long-term cardiovascular regulation, and to potentially lead to novel, well-tolerated, organ-specific sympathetic blockade therapies to treat HT and other cardiovascular diseases.

描述（由申请人提供）：高血压（高血压; HT）在美国仍处于流行水平。尽管越来越多的抗高血压药物可用，患者的比例充分响应传统药物治疗仍然是不可接受的低。现在有无可争辩的证据表明，增加交感神经系统活动（SNA）是HT的发病机制的主要。全面损害神经源性心血管调节的药物由于不良副作用而效用有限。是否有可能以更具区域选择性的方式（使用药物或其他方法）降低SNA，同时降低血压？令人兴奋的是，最近在人类患者中证明了对一种新的基于器械的选择性肾脏去神经方法的长期降压反应，这表明答案是肯定的。该项目的总体目标是促进我们对实验性HT中区域特异性SNA变化的理解，以开发“新靶点特异性”疗法为目标。我们将使用盐敏感HT的遗传模型-Dahl-S（DS）大鼠来解决这些问题。我们的初步数据表明，肾去神经支配（RDNX）和内脏去神经支配，通过腹腔神经节切除术（CGX），在DS大鼠引起AP的幅度类似于在人类中所看到的基于导管的肾神经消融术后的显着减少。具体目标1将确定对肾去神经支配（RDNX）的心血管反应是否是由于肾传出或传入神经元的消融。具体目标2将定义介导对RDNX和/或肾传入阻滞的急性和持续抗高血压反应的心血管和交感神经机制。具体目标3将定义通过CGX介导内脏交感神经切除术的急性和持续抗高血压反应的心血管和交感神经机制。该项目的预期成果是产生一个详细的了解机制，从而有针对性的交感神经消融可用于治疗HT。预期的影响是将新的研究重点集中在SNA及其对长期心血管调节的影响上，并可能导致新的、耐受性良好的、器官特异性交感神经阻滞疗法来治疗HT和其他心血管疾病。