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）：五十（50）百万美国人患有高血压，其中66％没有得到充分控制，至少10％具有多药耐药性。刺激血管中压力传感器，压力感受器会降低血压（BP）；可植入的电刺激剂已用于提供连续的压力感受器激活。尽管这些设备有效地降低了基础BP，但由于恒定的刺激会禁用BP调节的内源性机制，但使用这些设备，对原位抑制和其他每日心血管挑战的反应受到损害。同样，连续刺激会消耗大量能量，频繁更换电池是侵入性和昂贵的。我们建议测试一种替代策略：通过偶尔的短频率（Tetanic）刺激缓冲途径的内源性压力反射机制的长期增强。 主动脉抑制神经（ADN）和颈动脉窦神经（CSN）是从压力感受器到大脑的BP信号的主要负压输入。在脑干中，孤立道（DMNT）的背侧核是ADN和CSN信号的第一个继电器。最近，使用大鼠模型，我们显示了对ADN的短暂刺激，随后的ADN诱发反应增加了10-15小时，这表明在ADN强烈激活后，BaroreFlex dowmessor响应得到了增强；因此，一连串的压力受体神经刺激可能会使高血压缓解多个小时。在此提案中，我们将系统地研究单层和双边CSN破伤风对基础BP的影响在正常和肥胖引起的高血压狗中。将使用13只狗（10个实验 + 3个对照）狗；每只狗都有双侧CSN电极。 AIM 1由3个阶段组成：基线（7天） - >破伤风（7天） - >恢复（7天）。对于实验犬，破伤风阶段由每日破伤风组成。在AIM 2中，高脂饮食将在数周内诱导肥胖高血压。然后将重复AIM 1。我们假设，对于实验犬来说，连续的7种破伤风应用将导致BP减少的增加。单侧破伤风效应预计为双侧的50-75％。信号处理算法将在AIM 3中使用，以确定破伤风的增益和/或阈值是否改变了。这对于预测破伤风对BP稳定性的影响很重要。临床意义：偶尔的短暂tetanic刺激为控制高血压，尤其是多药耐药形式提供了一种新的有效的临床方法。与连续刺激相反，提出的方法会产生较小的组织损伤。增强BP的正常矩对矩刺激的影响，而不是减少正常的压力反射控制，并更好地保留BP的正常体位和运动调节。所提出的方法自然可以使自己具有极度紧凑，被动的（无电池），可植入的缓冲刺激器，我们最终的目标是开发这种设备。 公共卫生相关性：5000万美国人患有高血压；提出的实验研究了颈动脉窦神经对短频率（四频）刺激对正常和高血压狗的持久血压降低的影响。积极的结果可能会为开发更有效的高血压疗法开放全新的途径。并为许多患有耐药性高血压的患者提供有效的治疗方法。