Targeted sympathetic ablation for treatment of hypertension

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。尽管可用的降压药物越来越多，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。现在有无可争辩的证据表明，交感神经系统活动（SNA）的增加是HT发病的主要原因。由于副作用较差，损害神经源性心血管调节的药物效用有限。是否有可能以更有区域选择性的方式（使用药物或其他方法）降低SNA，同时仍然降低血压？令人兴奋的是，最近在人类患者中对一种基于选择性肾去神经的新装置的长期降压反应表明答案是肯定的。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“新的靶向特异性”治疗方法。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，在DS大鼠中，通过腹腔神经节切除术（CGX）进行肾去神经支配（RDNX）和内脏去神经支配（CGX）都能引起AP的显著降低，其程度与人类在导管肾神经消融后所见的相似。特异性目的1将确定心血管对肾去神经支配（RDNX）的反应是否由于肾传出或传入神经元的消融。特异性目的2将定义介导RDNX和/或肾脱突急性和持续降压反应的心血管和交感机制。特异性目的3将定义通过CGX介导内脏交感神经切除术后急性和持续降压反应的心血管和交感神经机制。该项目的预期结果是详细了解靶向交感神经消融术用于治疗HT的机制。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，并有可能导致新的、耐受性良好的器官特异性交感神经阻断疗法来治疗HT和其他心血管疾病。

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.