NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL

描述(摘自申请者摘要)：多种形式的高血压 会因食盐增加(盐依赖型高血压)而加剧，但 机制尚不清楚。这项提议的总体目标是 探讨盐依赖的自主神经和血流动力学机制 高血压。在初步实验中，申请者持续监测 正常成人的平均动脉压(MAP)、心率(HR)和心输出量(CO) (Sham)和去窦弓神经(SAD)大鼠摄入正常和高盐 节食。连续两周增加食盐会导致立即和 假手术大鼠总外周阻力(TPR)持续增加 高血压，因为HR和CO都降低了。在SAD大鼠中，相当于 盐诱导的TPR升高，但CO和HR未见下降。 出现盐依赖型高血压。这些结果导致了以下结果 假设和具体目标。在特定目标1中的实验将测试 食盐增加刺激神经肽-Y释放的假说 交感血管运动神经元(NPY)引起的血管收缩 血压正常的大鼠。在方案1中，血流动力学(MAP、CO、HR和 TPR)和血浆NPY对正常大鼠和大鼠膳食盐分增加的影响 长期使用NPY Yl受体拮抗剂BIPP 3266治疗将是 量过了。BIPP 3266对盐诱导血流动力学反应的影响 在长期使用α和β-肾上腺素能治疗的大鼠中也进行了研究 拮抗剂，已被证明调节血管收缩活性 NPY。在方案2中，肾和内脏去神经对神经肽Y的影响 介导的肾脏和肠系膜血管舒缩反应对高盐饮食的影响 将分别确定。在这些动物中，申请者将 逆转录-聚合酶链式反应检测血管Yl受体基因表达及其相关性 血管对神经肽Y敏感的发现。在特定目标2中的实验将 检验慢性盐导致心输出量减少的假设 由压力感受性反射控制心脏交感神经和迷走神经张力。为了测试 这个假说是心输出量、心率和动脉压 24小时全天监测正常和压力感受器失神经的大鼠 正常和高盐饮食。心率的功率谱分析将是 预先评估增加的盐对心脏迷走神经和心脏的影响 整个实验过程中的交感神经活动。在这些大鼠身上，这种影响 长期药理阻断M2受体和β-L 心脏迷走神经和交感神经张力上的肾上腺素能受体(心脏 心率功率谱)、心输出量和动脉压 在饮食盐负荷之前和期间。申请者预测，受损者 心脏的自主控制会导致盐依赖型高血压 未能通过心脏收缩来缓冲盐诱导的血管收缩 输出。这些实验将提供有关这一角色的重要新信息 自主神经系统在血液动力学长期控制中的作用 食盐增加的条件。

DESCRIPTION (Verbatim from Applicant's Abstract): Many forms of hypertension are exacerbated by increased dietary salt (salt-dependent hypertension) but the mechanisms are unknown. The overall objective of this proposal is to investigate the autonomic and hemodynamic mechanisms of salt-dependent hypertension. In preliminary experiments the applicants continuously monitored mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO) in intact (SHAM) and sinoaortic denervated (SAD) rats consuming normal and high salt diets. Increasing dietary salt for two weeks resulted in an immediate and sustained increase in total peripheral resistance (TPR) in SHAM rats, but not hypertension since both HR and CO were decreased. In SAD rats, an equivalent salt-induced increase in TPR was observed, but CO and HR did not fall and salt-dependent hypertension resulted. These results led to the following hypotheses and specific aims. Experiments in Specific Aim 1 will test the hypothesis that increased dietary salt stimulates release of neuropeptide-Y (NPY) from sympathetic vasomotor neurons to cause vasoconstriction in normotensive rats. In protocol 1, the response of hemodynamics (MAP, CO, HR and TPR) and plasma NPY to increased dietary salt in normal rats and rats chronically treated with the NPY Yl receptor antagonist BIPP 3266 will be measured. The effect of BIPP 3266 on the hemodynamic responses to salt will also be studied in rats chronically treated with alpha and beta-adrenergic antagonists, which have been shown to modulate the vasoconstrictor activity of NPY. In protocol 2, the effect of renal and splanchnic denervation on NPY mediated renal and mesenteric vasomotor responses to increased dietary salt respectively will be determined. In these same animals, the applicants will examine vascular Yl receptor MRNA expression using RT-PCR and correlate these findings with vascular sensitivity to NPY. Experiments in Specific Aim 2 will test the hypothesis that chronic salt induced decreases in cardiac output are mediated by baroreflex control of cardiac sympathetic and vagal tone. To test this hypothesis cardiac output, heart rate and arterial pressure will be monitored 24 hours/day in intact and baroreceptor denervated rats consuming normal and high salt diets. Power spectral analysis of heart rate will be preformed to assess the effect of increased salt on cardiac vagal and sympathetic activity throughout the experiment. In these same rats, the effect of long-term pharmacological blockade of M2 muscarinic receptors and beta l adrenergic receptors on cardiac vagal and sympathetic tone respectively (heart rate power spectra), cardiac output and arterial pressure will be examined before and during dietary salt loading. The applicants predict that impaired autonomic control of the heart will result in salt-dependent hypertension due to failure to buffer salt-induced vasoconstriction by a decrease in cardiac output. These experiments will provide important novel information on the role of the autonomic nervous system in the long-term control of hemodynamics under conditions of increased dietary salt.