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.

高血压是美国的一个主要公共卫生问题，影响约 7000 万成年人。高达 36% 退伍军人患有高血压，这是中风和其他心血管疾病发生的主要危险因素。 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 一般人群和退伍军人中，高达 25% 的退伍军人消耗超过 82 克果糖 与1970年每人每天仅0.8克相比，增加了100倍。高果糖 摄入量超过肝脏将果糖转化为葡萄糖的能力，从而果糖进入血液 这通常不会发生。果糖摄入本身与高血压有多种关系 的机制。循环果糖 (a) 增强肠道对钠的吸收并减少肾钠 排泄，导致血浆容量扩张，(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)，并且 (c) 可以跨血脑屏障转运，并且 在脑脊液中浓度高达 30 倍，可导致交感神经过度兴奋。等离子体 血容量扩张与 Ang II 和交感神经过度活动一起可导致动脉血流量增加 压力。果糖喂养的大鼠大脑 AT1R 表达上调。穹窿下器官 (SFO) 位于穹窿外部 血脑屏障富含 AT1R 并投射到室旁核 (PVN)， 影响交感神经的张力。果糖有可能通过影响交感神经来增强交感反应 神经元氯化钠钾协同转运蛋白 (NKCC1) 或氯化钾协同转运蛋白 (KCC2) 在 PVN 内，类似于果糖对肾转运蛋白的作用。这些转运蛋白赋予功能 GABA 能神经元的可塑性并限制 GABA 对交感神经输出的抑制，进一步促进 神经兴奋性。肾脏的交感神经输入刺激肾素分泌和随后的 Ang II 生成， 从而形成恶性循环。现有证据是间接的，与长期和/或高度暴露于 果糖，无法区分果糖摄入本身是否会导致高 Ang II、交感神经兴奋和 高血压或 Ang II 升高和交感神经兴奋是否是代谢的结果 综合症。在本提案中，我们将检验以下假设：高果糖摄入量与高钠摄入量相结合 大鼠的氯化物饮食会由于肾素-血管紧张素系统的激活而导致血压升高 在代谢综合征发生之前增强放射放射学检查（RSNA），而代谢综合征可以通过定期锻炼来缓解。 将解决三个具体目标：（1）果糖喂养，但不是葡萄糖喂养，高氯化钠饮食的老鼠会出现 基础动脉压、血浆肾素活性 (PRA)、血管紧张素 II (Ang II) 水平和 RSNA 水平在 7 至 28天以及对急性压力有更好的反应； (2) 动脉压、心率和RSNA 在高氯化钠饮食的果糖喂养的大鼠中增强，但在相同氯化钠饮食的葡萄糖喂养的大鼠中没有增强，因为 果糖诱导的 PVN-GABA 能调节交感神经输出的功能可塑性； (3) 升高 动脉压、PRA、Ang II 和 RSNA 以及高 NaCl 饮食的果糖喂养大鼠的应激反应 由于 GABA 能的恢复，可以通过每日自愿轮跑锻炼计划来减少 抑制交感神经输出。这些研究将为解决这些问题的举措提供实质性证据 营养建议和锻炼方案，即使是瘦身、非糖尿病患者也可以治疗，甚至 预防高血压及其后果。此外，新型氯化物挤出增强剂或阻滞剂 增加 GABA 抑制信号传导的氯化物进入正在测试作为疼痛和其他疾病的治疗方法 神经系统疾病，也可能有潜力利用中枢交感神经抑制的可塑性 降低中风和残疾风险的途径。运动对不受控制的患者来说风险太大 高血压或患有中风的残疾人士有困难。模仿有益事物的能力 通过改变氯化物潜力进行运动的效果将为我们的退伍军人带来巨大的临床益处。