NEURAL MECHANISMS OF LONG-TERM CARDIOVASCULAR CONTROL

描述（来自申请人摘要的逐字）：多种形式的高血压 增加饮食中的盐（盐依赖性高血压）， 机制不明。本建议的总体目标是 探讨盐依赖性心脏病的自主神经和血流动力学机制 高血压在初步实验中，申请人持续监测 平均动脉压（MAP）、心率（HR）和心输出量（CO） （SHAM）和窦弓去神经（SAD）大鼠消耗正常和高盐 节食。增加饮食中的盐两周后， 在SHAM大鼠中，总外周阻力（TPR）持续增加，但 高血压，因为HR和CO均降低。在SAD大鼠中， 观察到盐诱导的TPR增加，但CO和HR没有下降， 导致盐依赖性高血压。这些结果导致了以下结果 假设和具体目标。具体目标1中的实验将测试 增加膳食盐刺激神经肽Y释放假说 (NPY)交感神经血管神经元引起血管收缩， 正常血压大鼠。在方案1中，血流动力学（MAP、CO、HR和 TPR）和血浆NPY对高盐饮食的反应 用NPY Y1受体拮抗剂BIPP 3266长期治疗的患者将 测定了BIPP 3266对盐引起的血流动力学反应的影响将 也可在长期接受α和β-肾上腺素能受体药物治疗的大鼠中进行研究 拮抗剂，其已显示调节血管收缩活性， NPY。在方案2中，研究了去肾神经和去内脏神经对NPY的影响， 介导的肾脏和肠系膜血管扩张对增加的膳食盐的反应 将分别确定。在这些动物中，申请人将 使用RT-PCR检测血管Y1受体mRNA表达，并将这些相关性 血管对NPY的敏感性。《特定目标2》中的实验将 检验慢性盐引起的心输出量减少是 由心脏交感神经和迷走神经张力的压力反射控制介导。测试 这一假设心输出量、心率和动脉压 在完整和压力感受器去神经大鼠中每天24小时监测， 正常和高盐饮食。心率的功率谱分析将 预先进行评估增加的盐对心脏迷走神经的影响， 在整个实验过程中的交感神经活动。在这些老鼠中， 长期药理学阻断M2毒蕈碱受体和β 1 肾上腺素能受体分别对心脏迷走神经和交感神经紧张（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。申请人预测， 心脏的自主控制将导致盐依赖性高血压， 由于心脏收缩能力的降低， 输出.这些实验将提供重要的新信息的作用 自主神经系统在血流动力学的长期控制下 增加饮食盐的条件。

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.