Antihypertensive Effects of Tetanic Baraoreceptor Input Stimulation

描述(申请人提供)：5000万美国人患有高血压，其中66%的人没有得到充分的控制，至少10%的人具有多药耐药性。刺激血管中的压力传感器，即压力感受器，可降低血压；植入式电刺激器已被用于提供持续的压力感受器激活；虽然这些设备有效地降低了基础血压，因为持续的刺激使血压调节的内生机制失效，但使用这些设备的患者，对立位和其他日常心血管挑战的反应迟缓。此外，持续刺激消耗大量能量，频繁更换电池是侵入性的，成本也很高。我们建议测试另一种策略：通过偶尔、短暂的高频(强直)刺激压力传入通路来长期增强内源性压力感受性反射机制。主动脉降压神经(ADN)和颈动脉窦神经(CSN)是从压力感受器向脑传递血压信号的主要压力传入神经。在脑干中，孤束背内侧核(DmNTS)是ADN和CSN信号的第一中继者。最近，我们在一个大鼠模型上发现，短暂的强直刺激ADN，在10-15小时内增加了dmNTS中随后的ADN诱发反应的大小，这表明在ADN被强烈激活后，压力感受性降压反应被增强；因此，突然的压力感受器神经刺激可能会在数小时内缓解高血压。在这项研究中，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诱导的高血压犬基础血压的影响。将使用13只狗(10只实验+3只对照)；每只狗都有双侧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，破伤风阶段包括每天一次破伤风。在目标2中，高脂饮食将在几周内诱发肥胖性高血压；然后重复目标1。我们假设，对于实验犬，每天连续7次应用破伤风将导致血压下降；单侧破伤风的影响预计为双侧的50%-75%。目标3将使用信号处理算法来确定压力反射的增益和/或阈值是否因破伤风而改变；这对于预测破伤风对血压稳定性的影响非常重要。临床意义：偶尔的短暂强直刺激为控制高血压，特别是耐多药类型的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更小；增强而不是减少了正常的压力感受性反射对血压的控制，并更好地保持了正常的立位和运动血压调节。建议的方法自然适合于一种非常紧凑、电被动(没有电池)、可植入的压力传入刺激器，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；拟议的实验调查了短暂的高频(强直)刺激颈动脉窦神经对正常血压和高血压狗的长期降压的影响。积极的结果可能为开发更有效的高血压疗法开辟全新的途径；并为许多患有抗药性高血压的患者提供有效的治疗。

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.