Antihypertensive Effects of Tetanic Baraoreceptor Input Stimulation

强直性压力感受器输入刺激的抗高血压作用

• 批准号: 8011973
• 负责人: SEAN D STOCKER
• 金额: $ 19.39万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-12 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011973
• 关键词: Address; Adverse drug effect; Affect; Algorithms; American; Antihypertensive Agents; Baroreflex; Bilateral; Blood Pressure; Blood Vessels; Brain; Brain Stem; Canis familiaris; Cardiovascular system; Clinical; Devices; Diet; Drug resistance; Electric Stimulation; Electrodes; Energy Supply; Exercise; Fatty acid glycerol esters; Frequencies; Goals; High Prevalence; Hour; Hypertension; Hypotension; Implant; Lateral; Long-Term Potentiation; Medial Dorsal Nucleus; Methods; Modeling; Multi-Drug Resistance; Multi-Institutional Clinical Trial; Nerve; Obesity; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pressoreceptors; Procedures; Protocols documentation; Publishing; Rattus; Recovery; Regimen; Regulation; Signal Transduction; System; Testing; Tetanus; Time; Tissues; base; blood pressure regulation; carotid sinus; clinically significant; computerized data processing; effective therapy; hypertension control; implantable device; neurophysiology; non-drug; normotensive; pressure; public health relevance; receptor; research study; response; sensor

DESCRIPTION (provided by applicant): Fifty (50) million Americans suffer from hypertension, of which 66% are not adequately controlled and at least 10% are multi-drug resistant. Stimulation of pressure sensors in blood vessels, the baroreceptors, decreases blood pressure (BP); implantable electrical stimulators have been used to provide continuous baroreceptor activation; although these devices effectively lower basal BP, because constant stimulation disables endogenous mechanisms of BP regulation, patients, using these devices, suffer compromised responses to orthostatic, and other daily cardiovascular challenges. Also, continuous stimulation consumes a large amount of energy, and frequent battery replacement is invasive and costly. We propose to test an alternative strategy: long-term potentiation of the endogenous baroreflex mechanisms by occasional, brief high frequency (tetanic) stimulation of the baroafferent pathway. The aortic depressor nerve (ADN) and carotid sinus nerve (CSN) are the major baroafferent inputs carrying BP signals from the baroreceptors to the brain. In the brainstem, the dorsal medial nucleus of the solitary tract (dmNTS) is the first relay of ADN and CSN signals. Recently, using a rat model, we showed that a brief burst of tetanic stimulation of the ADN, increased the size of subsequent ADN evoked responses in the dmNTS for 10-15 hours, which indicates that following a strong activation of the ADN, baroreflex depressor responses are enhanced; thus, a burst of baroreceptor nerve stimulation might ameliorate hypertension for many hours. In this proposal, we will systematically investigate the effects of uni- and bi-lateral CSN tetanus on basal BP in normotensive and obesity-induced hypertensive dogs. Thirteen (10 experimental + 3 control) dogs will be used; every dog will have bilateral CSN electrodes. Aim 1 consists of 3 phases: Baseline (7 days) -> Tetanus (7 days) -> Recovery (7 days). For the experimental dogs, the tetanus phase consists of one daily bout of tetanus. In Aim 2, obesity hypertension will be induced over several weeks by a high-fat diet; and then Aim 1 will be repeated. We hypothesize that, for the experimental dogs, the 7 successive daily tetanus applications will produce increasing BP reductions; the unilateral tetanus effects are expected to be 50-75% of the bilateral. Signal processing algorithms will be used in Aim 3 to determine whether the gain and/or threshold of the baroreflex are changed by the tetanus; this is important for anticipating the effects of tetanus on BP stability. Clinical Significance: Occasional brief tetanic stimulation offers a new and effective clinical method for controlling hypertension, especially multi-drug resistant forms. In contrast to continuous stimulation, the method proposed would produce less tissue damage; enhance, rather than diminish normal moment-to-moment baroreflex control of BP, and better preserve the normal orthostatic and exercise regulation of BP. The proposed method naturally lends itself to an extremely compact, electrically passive (no battery), implantable baroafferent stimulator, and our eventual goal is to develop such a device. PUBLIC HEALTH RELEVANCE: 50 million Americans suffer from high blood pressure; the proposed experiments investigate the effects of brief high frequency (tetanic) stimulation of the carotid sinus nerve on a long lasting blood pressure reduction in normotensive and hypertensive dogs. Positive results could open entirely new avenues for developing more efficient hypertension therapies; and provide an effective treatment for the many patients suffering from drug resistant hypertension.

描述（由申请人提供）：五千（50）万美国人患有高血压，其中66%未得到充分控制，至少10%具有多药耐药性。刺激血管中的压力传感器（压力感受器）降低血压（BP）;植入式电刺激器已用于提供连续的压力感受器激活;尽管这些装置有效地降低基础BP，但由于恒定刺激禁用BP调节的内源性机制，使用这些装置的患者遭受对直立和其他日常心血管挑战的受损反应。此外，连续刺激消耗大量能量，并且频繁更换电池是侵入性的且昂贵的。我们建议测试一种替代策略：内源性压力感受器反射机制的长时程增强，偶尔，短暂的高频率（强直）刺激的压力传入通路。 主动脉降压神经（ADN）和颈动脉窦神经（CSN）是将血压信号从压力感受器传递到大脑的主要压力传入神经。在脑干中，孤束背内侧核（dmNTS）是ADN和CSN信号的第一中继。最近，使用大鼠模型，我们表明，短暂的强直刺激ADN，增加了随后的ADN诱发反应的大小在dmNTS的10-15小时，这表明，ADN的强烈激活后，压力反射抑制反应增强;因此，压力感受器神经刺激的爆发可能会改善高血压许多小时。在这个建议中，我们将系统地研究单侧和双侧CSN破伤风对血压正常和肥胖引起的高血压犬基础血压的影响。将使用13只（10只实验组+3只对照组）犬;每只犬将具有双侧CSN电极。目标1包括3个阶段：基线（7天）->破伤风（7天）->恢复（7天）。对于实验犬，破伤风阶段包括每日一次破伤风。在目标2中，将通过高脂肪饮食在数周内诱导肥胖高血压;然后将重复目标1。我们假设，对于实验犬，连续7次每日破伤风应用将产生增加的BP降低;单侧破伤风效应预计为双侧的50-75%。目标3中将使用信号处理算法来确定压力反射的增益和/或阈值是否因强直而改变;这对于预测强直对BP稳定性的影响很重要。临床意义：偶尔短暂的强直刺激为控制高血压，特别是多药耐药型高血压提供了一种新的有效的临床方法。与连续刺激相比，所提出的方法将产生更少的组织损伤;增强而不是减少BP的正常时刻到时刻的压力反射控制，并且更好地保持BP的正常直立和运动调节。所提出的方法自然适合于一个非常紧凑，电被动（无电池），植入式压力传入刺激器，我们的最终目标是开发这样的设备。 公共卫生相关性：5000万美国人患有高血压;拟议的实验研究了短暂的高频（强直）刺激颈动脉窦神经对血压正常和高血压犬的长期血压降低的影响。积极的结果可以为开发更有效的高血压治疗开辟全新的途径;并为许多患有耐药性高血压的患者提供有效的治疗。