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: 10174722
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174722
• 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; 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; Output; Pain management; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Potassium Chloride; Public Health; Publishing; Rattus; Recommendation; Renin; Renin-Angiotensin System; Rest; Risk Factors; Running; Signal Transduction; Societies; Sodium; Sodium Chloride; Stress; Stroke; Subfornical Organ; Sympathetic Nervous System; Testing; Thinness; Time; Tubular formation; United States; Veterans; Work; absorption; acute stress; biological adaptation to stress; cardiovascular risk factor; dietary salt; disability; drinking water; exercise regimen; exercise training; fast food; functional plasticity; gamma-Aminobutyric Acid; hemodynamics; instrument; mortality; nervous system disorder; non-diabetic; novel; nutrition; nutritional guideline; obesity development; paraventricular nucleus; pressure; prevent; programs; response; restoration; salt intake; stressor; stroke risk; symporter; treatment guidelines

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.

在美国，高血压是一个主要的公共卫生问题，影响着大约7000万成年人。高达36%的 退伍军人患有高血压，高血压是发生中风和其他心血管疾病的主要危险因素。 血管疾病。营养不良是心脏病和中风的危险因素。年内果糖摄入量有所增加 普通人群和退伍军人中也是如此，高达25%的退伍军人摄入超过82克果糖 与1970年每人每天只有0.8克相比，增加了100倍。高果糖 摄入量超过了肝脏将果糖转化为葡萄糖的能力，因此果糖进入血液。 这通常是不会发生的。摄入果糖本身与高血压有多种联系。 机械装置。循环中的果糖(A)增加肠道对钠的吸收，降低肾脏钠。 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)可跨血脑屏障运输，是 在脑脊液中的浓度高达30倍，在那里它可以促进交感神经超负荷。电浆 容量扩张、血管紧张素II和交感神经过度活动可导致动脉增粗。 压力。喂食果糖的大鼠脑内AT1R表达上调。穹隆下器(SFO)，位于穹隆外 血脑屏障富含AT1R，投射到室旁核(PVN) 会影响同情的语气。果糖有可能通过影响交感反应而增强交感反应。 神经元性钠钾共转运体(NKCC1)或氯化钾共转运体(KCC2) 在PVN内，类似于果糖对肾脏转运体的作用。这些转运蛋白传递的功能 对GABA能神经元的可塑性和限制GABA对交感输出的抑制，进一步有助于 神经兴奋性。交感神经传入肾脏刺激肾素的分泌和随后的Ang II的产生， 导致了恶性循环。现有证据是间接的，长期和/或高度暴露于 而不能区分摄入果糖本身是否会导致高Ang II、交感兴奋和 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。在这项提议中，我们将检验这样一个假设，即高果糖摄入量与高钠相结合 氯化物饮食导致大鼠血压升高，这是由于肾素-血管紧张素系统的激活和 在代谢综合征发展之前增强的RSNA，可以通过定期锻炼来缓解。 将解决三个具体目标：(1)喂食果糖而不喂食葡萄糖的高盐饮食的大鼠将有 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 28天以及对急性应激的更大反应；(2)动脉压、心率和RSNA将 在高盐饮食的果糖喂养的大鼠中增强，而在相同氯化钠饮食的葡萄糖喂养的大鼠中不增加，这是因为 果糖诱导的PVN-GABA能调制交感神经输出的功能可塑性；以及(3)升高 高盐饮食果糖喂养大鼠的动脉压、PRA、Ang II和RSNA以及应激反应 由于GABA能的恢复，通过每日自愿车轮跑练习来减少BE 抑制交感神经输出。这些研究将为采取主动行动提供实质性证据。 营养建议和运动养生法，即使是在瘦的，非糖尿病的人来治疗，甚至 预防高血压及其后果。此外，新型氯离子挤出促进剂或阻断剂 增加GABA能抑制信号的氯离子进入正在被测试用于治疗疼痛和其他 神经系统疾病，也有可能利用中枢交感神经抑制的可塑性 减少中风和残疾风险的途径。运动对失控的患者来说风险太大 对于患有中风的残疾人来说，高血压或困难。模仿有益事物的能力 通过改变氯离子电位的运动效果将对我们的退伍军人有很大的临床好处。

项目成果

Bilateral renal cryodenervation decreases arterial pressure and improves insulin sensitivity in fructose-fed Sprague-Dawley rats.

双侧肾冷冻去神经术可降低果糖喂养的 Sprague-Dawley 大鼠的动脉压并提高胰岛素敏感性。

• DOI: 10.1152/ajpregu.00020.2018
• 发表时间: 2018
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Soncrant,Tyler;Komnenov,Dragana;Beierwaltes,WilliamH;Chen,Haiping;Wu,Min;Rossi,NoreenF
• 通讯作者: Rossi,NoreenF

Effects of voluntary exercise on blood pressure, angiotensin II, aldosterone, and renal function in two-kidney, one-clip hypertensive rats.

• DOI: 10.2147/ibpc.s147122
• 发表时间: 2017
• 期刊: Integrated blood pressure control
• 影响因子: 2.2
• 作者: Waldman BM;Augustyniak RA;Chen H;Rossi NF
• 通讯作者: Rossi NF

Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats.

• DOI: 10.1113/expphysiol.2009.051789
• 发表时间: 2010-08
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: Rossi NF;Maliszewska-Scislo M;Chen H;Black SM;Sharma S;Ravikov R;Augustyniak RA
• 通讯作者: Augustyniak RA

Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats.

中枢内皮素：对阿霉素心力衰竭大鼠加压素和动脉压力反射的影响。

• DOI: 10.1139/y08-027
• 发表时间: 2008
• 期刊: Canadian journal of physiology and pharmacology
• 影响因子: 2.1
• 作者: Rossi,NoreenF;Maliszewska-Scislo,Maria;Chen,Haiping
• 通讯作者: Chen,Haiping

Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats.

在两肾、一夹高血压大鼠中冷冻消融对剪断肾神经去神经的血流动力学和神经反应。

• DOI: 10.1152/ajpregu.00331.2015
• 发表时间: 2016
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Rossi,NoreenF;Pajewski,Russell;Chen,Haiping;Littrup,PeterJ;Maliszewska-Scislo,Maria
• 通讯作者: Maliszewska-Scislo,Maria