Exercise Training and Blood Pressure in Hypertension: Integrated Mechanisms

运动训练与高血压的血压：综合机制

• 批准号: 9315582
• 负责人: Noreen F Rossi
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315582
• 关键词: Acute; Address; Adult; Affect; Angiotensin II; Angiotensin Receptor; Angiotensins; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Blood Plasma Volume; Blood Pressure; Blood Vessels; Brain; Cardiovascular Diseases; Cerebrospinal Fluid; Chlorides; Chronic; Clinical; Consumption; Data; Development; Diabetes Mellitus; Diet; Disabled Persons; Energy Intake; Enhancers; Essential Hypertension; Event; Excretory function; Exercise; Exposure to; Failure; Fructose; Funding; General Population; Generations; Glucose; Goals; Guidelines; Heart Diseases; Heart Rate; Heart failure; Hormones; Hypertension; Hypothalamic structure; Impairment; Individual; Ingestion; Intake; Interruption; Kidney; Kidney Failure; Link; Liquid substance; Liver; Metabolic syndrome; Military Personnel; Nerve; Neurons; Nutritional; Obesity; Output; Pain management; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Potassium Chloride; Public Health; Publishing; Rattus; Recommendation; Renin; Renin-Angiotensin System; Rest; Risk; Risk Factors; Running; Signal Transduction; Societies; Sodium; Sodium Chloride; Stress; Stroke; Subfornical Organ; Sympathetic Nervous System; Testing; Thinness; Time; Training; Tubular formation; United States; Veterans; Work; absorption; acute stress; biological adaptation to stress; cardiovascular risk factor; dietary salt; disability; drinking water; exercise regimen; fast food; functional plasticity; gamma-Aminobutyric Acid; hemodynamics; instrument; mortality; nervous system disorder; non-diabetic; novel; nutrition; nutritional guideline; paraventricular nucleus; pressure; prevent; programs; response; restoration; salt intake; stressor; symporter

Hypertension is a major public health concern in the U.S. and affects ~70 million adults. Up to 36% of military Veterans have hypertension which is the primary risk-factor for development of stroke and other cardio- vascular diseases. Poor nutrition is a risk factor for heart disease and stroke. Fructose intake has increased in the general population and also in Veterans with up to 25% of Veterans consuming more than 82 g of fructose per person per day compared with only 0.8 g per person per day in 1970, a 100-fold increase. High fructose intake exceeds the ability of the liver to convert fructose to glucose, so that fructose enters the bloodstream which normally does not occur. Fructose ingestion in and of itself has been linked to hypertension by a variety of mechanisms. Circulating fructose (a) enhances sodium absorption by the gut and decreases renal sodium excretion, leading to plasma volume expansion, (b) activates the renin-angiotensin system and upregulates brain angiotensin (Ang II) receptors (AT1R), and (c) can be transported across the blood brain barrier and is concentrated up to 30-fold in cerebrospinal fluid where it can contribute to sympathetic overdrive. Plasma volume expansion together with Ang II and sympathetic over activity can then result in increased arterial pressure. Brain AT1R are upregulated in fructose-fed rats. The subfornical organ (SFO) which is outside the blood brain barrier is well endowed with AT1R and projects to the paraventricular nucleus (PVN) which influences sympathetic tone. Fructose has the potential to enhance sympathetic responses by influencing the neuronal sodium potassium chloride co-transporter (NKCC1) or the potassium chloride co-transporter (KCC2) within the PVN, similar to actions of fructose on renal transporters. These transporters impart functional plasticity to GABAergic neurons and limit GABA inhibition of sympathetic outputs, further contributing to neuroexcitability. Sympathetic input to the kidney stimulates renin secretion and subsequent Ang II generation, resulting in a vicious cycle. Existing evidence has been indirect with prolonged and/or high exposure to fructose and cannot distinguish whether fructose ingestion itself results in high Ang II, sympathoexcitation and hypertension or whether the elevated Ang II and sympathoexcitation are a consequence of the metabolic syndrome. In this proposal we will test the hypothesis that a high fructose intake combined with a high sodium chloride diet in rats results in elevated blood pressure due to activation of the renin-angiotensin system and enhanced RSNA prior to development of the metabolic syndrome that can be mitigated by regular exercise. Three specific aims will be addressed: (1) fructose-fed, but not glucose-fed, rats on a high NaCl diet will have higher basal arterial pressure, plasma renin activity (PRA), angiotensin II (Ang II) levels and RSNA within 7 to 28 days as well as greater responses to acute stress; (2) arterial pressure, heart rate and RSNA will be augmented in fructose-fed rats on high NaCl diet but not in glucose-fed rats on the same NaCl diet due to fructose-induced functional plasticity in PVN-GABAergic modulation of sympathetic outputs; and (3) elevated arterial pressure, PRA, Ang II and RSNA as well as stress responses in fructose-fed rats on high NaCl diet will be decreased by a program of daily voluntary wheel running exercise due to restoration of GABAergic inhibition of sympathetic output. These studies will provide substantive evidence for initiatives to address nutritional recommendations and exercise regimens even in lean, non-diabetic individuals to treat and even prevent hypertension and its consequences. In addition, novel chloride extrusion enhancers or blockers of chloride entry that increase GABAergic inhibition signaling are being tested as treatments for pain and other neurological diseases and may also have potential to exploit the plasticity of central sympathoinhibitory pathways to mitigate the risk of stroke and disability. Exercise be too risky for patients with uncontrolled hypertension or difficult for disabled individuals who have sustained a stroke. The ability to mimic the beneficial effects of exercise by modifying chloride potential will be of substantial clinical benefit to our Veterans.

高血压是美国的主要公共卫生问题，影响约7000万成年人。多达36％ 退伍军人患有高血压，这是中风和其他心脏发展的主要风险因素 血管疾病。营养不良是心脏病和中风的危险因素。果糖摄入量增加了 一般人口以及多达25％的退伍军人食用超过82克果糖的退伍军人 每天每天每天只有每天仅0.8克，1970年每天每天每天增加100倍。高果糖 摄入量超过肝脏将果糖转化为葡萄糖的能力，因此果糖进入血液 通常不会发生。果糖本身与多种多样的高血压有关 机制。循环果糖（a）通过肠道增强钠的吸收并减少肾脏钠 排泄，导致血浆体积膨胀，（b）激活肾素 - 血管紧张素系统并上调 脑血管紧张素（ANG II）受体（AT1R）和（c）可以在整个血脑屏障上运输，并且IS 在脑脊液中最多浓缩30倍，在那里它可以导致交感神经过度。等离子体 体积膨胀与ANG II和交感神经有关，可能会导致动脉增加 压力。大脑AT1R在果糖喂养的大鼠中被上调。在外面 血脑屏障已充分赋予AT1R，并投影到室室核（PVN），该核 影响同情的语气。果糖有可能通过影响 神经元钠氯化钠共转运蛋白（NKCC1）或氯化钾共转运蛋白（KCC2） 在PVN中，类似于果糖对肾运蛋白的作用。这些转运蛋白赋予功能 对GABA能神经元的可塑性并限制了GABA抑制交感神经输出，进一步有助于 神经兴奋性。对肾脏的同情输入刺激肾素分泌和随后的ANG II产生， 导致恶性循环。现有证据是间接的，延长和/或高度接触 果糖，无法区分果糖摄入本身是否会导致高ang II，交感神经和 高血压还是高架ANG II和交感神经兴奋是代谢的结果 综合征。在此提案中，我们将检验以下假设：高果糖摄入量与高钠结合 大鼠的氯化物饮食会导致由于肾素 - 血管紧张素系统的激活而导致血压升高 在发展代谢综合征之前，可以通过定期运动来减轻RSNA。 将解决三个具体目的：（1）果糖喂养但不含葡萄糖的饮食中的大鼠将具有高NaCl饮食的大鼠 较高的基础动脉压，血浆肾素活性（PRA），血管紧张素II（ANG II）水平和RSNA在7到7 28天以及对急性应力的反应更大； （2）动脉压，心率和RSNA将是 在高NaCl饮食中以果糖喂养的大鼠增强，而不是在同一NaCl饮食的葡萄糖喂养大鼠中增加 果糖诱导的交感输出PVN-GABA能调节中的功能可塑性； （3）高架 动脉压，PRA，ANG II和RSNA以及高NaCl饮食中果糖喂养大鼠的压力反应将 由于GABA能的恢复 抑制交感神经输出。这些研究将为倡议提供实质性证据 营养建议和运动方案，即使在精益的非糖尿病人中也可以治疗甚至 防止高血压及其后果。此外，新型的氯化物挤出增强剂或阻滞剂 增加GABA能抑制信号传导的氯化物进入正在测试作为疼痛和其他的治疗方法 神经系统疾病，也可能有可能利用中央抑制性的可塑性 减轻中风和残疾风险的途径。运动对于不受控制的患者来说太冒险了 对患有中风的残疾人的高血压或困难。模仿有益的能力 通过修改氯化潜力的锻炼的影响对我们的退伍军人具有很大的临床益处。