Targeted sympathetic ablation for treatment of hypertension

靶向交感神经消融治疗高血压

• 批准号: 8786097
• 负责人: John W Osborn
• 金额: $ 46.26万
• 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 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786097
• 关键词: Ablation; Acute; Address; Adverse effects; Afferent Neurons; 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; Figs - dietary; Ganglionectomy; Genetic; Genetic Models; Goals; Health; Human; Hypertension; Hypotension; 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; kidney vascular structure; minimally invasive; mortality; novel; pressure; response; salt sensitive; success; 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）在美国持续处于流行水平。尽管可用的抗高血压药物不断增加，但对传统药物治疗有充分反应的患者比例仍然低得令人无法接受。现在有无可争议的证据表明，交感神经系统活动（SNA）增加是 HT 发病机制的一个主要因素。由于副作用较差，全面损害神经源性心血管调节的药物的效用有限。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）减少国民账户体系（SNA）并仍然降低血压？最近令人兴奋的人类患者对基于新型装置的选择性肾去神经术方法的长期抗高血压反应的证明表明答案是肯定的。该项目的总体目标是增进我们对实验性 HT 中区域特异性 SNA 变化的理解，以开发“新的靶标特异性”疗法。我们将使用盐敏感 HT 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，DS 大鼠中的去肾神经 (RDNX) 和通过腹腔神经节切除术 (CGX) 进行的内脏去神经可导致 AP 显着降低，其幅度与人类导管肾神经消融后观察到的相似。具体目标 1 将确定心血管对肾去神经支配 (RDNX) 的反应是否是由于肾传出或传入神经元的消融所致。具体目标 2 将定义介导对 RDNX 和/或肾传入神经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 将定义心血管和交感神经机制，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。该项目的预期成果是详细了解靶向交感神经消融治疗 HT 的机制。预期的影响是将新的研究注意力集中在 SNA 及其对长期心血管调节的影响上，并有可能导致新型、耐受性良好、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。