Exercise Training and Blood Pressure in Hypertension: Integrated Mechanisms

高血压是美国主要的公共卫生问题，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。果糖的摄入量增加了， 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 这通常不会发生。果糖的摄入本身就与高血压有关， 的机制。循环果糖（a）增强肠道对钠的吸收，降低肾钠 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（AT 1 R），和（c）可被转运穿过血脑屏障， 在脑脊髓液中浓度高达30倍，可导致交感神经麻痹。血浆 容量扩张与血管紧张素II和交感神经过度活动一起，然后可导致动脉血管紧张素II和交感神经过度活动增加。 压力在果糖喂养的大鼠中，脑AT 1 R上调。穹窿下器官（SFO）位于 血脑屏障具有良好的AT 1 R并投射到室旁核（PVN）， 影响交感神经张力果糖具有通过影响交感神经系统而增强交感神经反应的潜力。 神经元钠钾氯化物共转运蛋白（NKCC 1）或氯化钾共转运蛋白（KCC 2） 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性 可塑性的GABA能神经元和限制GABA抑制交感神经输出，进一步有助于 神经兴奋性对肾脏的交感神经输入刺激肾素分泌和随后的Ang II产生， 导致恶性循环。现有的证据是间接的，长期和/或高暴露于 果糖，不能区分果糖摄入本身是否导致高血管紧张素II，交感神经兴奋， 高血压或升高的血管紧张素II和交感神经兴奋是否是代谢的结果， 综合征在这个建议中，我们将测试的假设，高果糖摄入量结合高钠 大鼠的氯化物饮食由于激活了肾素-血管紧张素系统而导致血压升高， 在代谢综合征发展之前增强RSNA，可以通过定期运动减轻。 三个具体目标将被解决：（1）果糖喂养，但不是葡萄糖喂养，大鼠在高NaCl饮食将有 在7至10周内，基础动脉压、血浆肾素活性（PRA）、血管紧张素II（Ang II）水平和RSNA升高， 28天，以及更大的反应，急性应激;（2）动脉压，心率和RSNA将 在高NaCl饮食的果糖喂养大鼠中增强，但在相同NaCl饮食的葡萄糖喂养大鼠中没有增强， 果糖诱导的交感神经输出PVN-GABA能调节的功能可塑性;和（3）升高的 高盐饮食果糖喂养大鼠的动脉压、PRA、Ang II和RSNA以及应激反应将 由于GABA能的恢复，通过每日自愿车轮运行锻炼计划减少 交感神经输出的抑制。这些研究将提供实质性证据， 营养建议和运动方案，甚至在瘦，非糖尿病个体治疗， 预防高血压及其后果。此外，本发明还提供了新的氯化物挤出增强剂或阻断剂， 增加GABA能抑制信号传导的氯离子进入正在被测试作为疼痛和其他疾病的治疗。 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， 减少中风和残疾风险的途径。运动对于不受控制的患者来说太危险了。 高血压或患有中风的残疾人的困难。模仿有益的 通过改变氯化物的潜力，运动的效果将是我们的退伍军人的实质性临床效益。

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.