Antihypertensive Effects of Tetanic Baraoreceptor Input Stimulation

描述（由申请人提供）：五千万美国人患有高血压，其中66%没有得到充分控制，至少10%有多重耐药。刺激血管中的压力传感器，即压力感受器，可降低血压（BP）；植入式电刺激器已被用于提供持续的压力感受器激活；尽管这些装置能有效降低基础血压，但由于持续刺激使内源性血压调节机制失效，使用这些装置的患者对直立和其他日常心血管挑战的反应受到损害。此外，持续刺激消耗大量能量，频繁更换电池是侵入性的，成本高昂。我们建议测试另一种策略：通过偶尔的、短暂的高频（强直性）刺激气压传入通路来长期增强内源性气压反射机制。主动脉降压神经（ADN）和颈动脉窦神经（CSN）是将压力感受器的血压信号传递到大脑的主要气压输入。在脑干，孤立束背内侧核（dmNTS）是ADN和CSN信号的第一个中继。最近，我们利用大鼠模型发现，短暂的强直刺激ADN，增加了dmNTS中随后ADN引起的反应的大小，持续10-15小时，这表明在ADN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在数小时内改善高血压。在这一提议中，我们将系统地研究单侧和双侧CSN破伤风对正常血压和肥胖引起的高血压狗的基础血压的影响。共13只（10只实验犬+ 3只对照犬）；每只狗将被植入双侧CSN电极。目标1包括3个阶段：基线期（7天）-破伤风期（7天）-康复期（7天）。对于实验犬，破伤风期包括每天一次破伤风。在Aim 2中，高脂肪饮食将在数周内诱发肥胖高血压；然后重复第一个目标。我们假设，对于实验犬，连续7天的破伤风应用将产生增加的血压降低；单侧破伤风的影响预计为双边的50-75%。在目标3中将使用信号处理算法来确定破伤风是否改变了气压反射的增益和/或阈值；这对于预测破伤风对血压稳定性的影响是重要的。临床意义：偶而短暂的破伤风刺激为控制高血压，尤其是耐多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，该方法产生的组织损伤较小；增强而不是削弱正常的时刻-时刻压力反射控制血压，更好地保持正常的直立和运动调节血压。所提出的方法自然使其成为一种极其紧凑、无电（无电池）、可植入的气压刺激器，我们的最终目标是开发这样一种设备。

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.