Exercise training and blood pressure in hypertension: integrated mechanisms

描述（由申请人提供）： 高血压是美国主要的公共卫生问题，约有7000万成年人受到影响，包括退伍军人。它是中风和心力衰竭的主要危险因素，也是肾衰竭的第二大常见原因。及时的诊断和有效的治疗是次优的，只有60%的退伍军人符合第七届国家高血压预防、检测、评估和治疗联合委员会（JNC 7）的建议，即动脉压<140/90 mmHg。虽然原发性高血压是最常见的，但动脉粥样硬化性肾血管性高血压的患病率正在上升，在并发肾外动脉粥样硬化和心力衰竭的高危患者中患病率高达50%。28%的接受心导管插入术的退伍军人发生肾动脉狭窄，65岁以上的患者发生肾动脉狭窄的风险大于3倍。血管成形术（带或不带支架）在控制 动脉压，减少心脏或肾脏事件，或降低发病率和死亡率仍然未经证实和有争议。手术干预和抑制血管紧张素II具有很大的风险。因此，重要的是寻求替代或替代战略。定期锻炼是康复策略的支柱，也是心血管健康的关键。久坐不动的生活方式很普遍，许多退伍军人患有限制动态运动的伤害或疾病：截肢，瘫痪，外周血管疾病，心肺功能障碍，甚至抑郁症。除了降低动脉压外，定期的动态运动还可以减少交感神经流出，这独立地导致更大的心血管风险。虽然这些机制已在原发性高血压中进行了探索，但在肾血管疾病中很少受到关注。因此，我们将测试的假设，在肾血管性高血压模型，两肾一夹（2K 1C）大鼠，动态运动训练降低全身血压，通过减少来自狭窄的肾脏传入神经输入，从而增强中枢硝酸能信号传导和减少肾交感神经活动，调节远端肾小管钠重吸收。本研究的目的有三：（1）评估运动训练是否会降低2K-1C患者的动脉压和对侧RSNA（或假夹）大鼠通过抑制来自夹闭肾脏的传入神经输入;（二）我们将评估运动训练是否通过增强室旁核内的一氧化氮能信号传导来影响RSNA，室旁核的神经元投射到脑干心血管中心，以及直接投射到脑干心血管中心。肾脏;（3）通过远端氯化钠协同转运体（NCC）和上皮钠通道（ENaC）研究运动训练对大鼠血浆和肾组织中肾素释放、血管紧张素Ⅱ（Ang Ⅱ）和肾钠排泄的影响。我们进行我们的血液动力学，肾神经记录和测量血浆血管紧张素II和醛固酮在慢性仪器，清醒，自由活动的大鼠，从而尽量减少麻醉的混杂影响。我们使用冷冻消融术从狭窄的肾脏中切除肾神经，而不是手术去神经。这种新的冷冻治疗将使我们能够评估两件事：肾脏去神经支配将是有效的概念证明，以及这种设备可能是一种 用于开发非侵入性方法的可行原型，以在患有动脉粥样硬化性肾血管疾病的个体中进行肾脏去神经支配。我们还将应用标准清除方法来评估尿钠排泄，以及分子方法来评估运动对NCC和ENaC的影响。这项研究将产生直接影响退伍军人健康的发现，并实现我们的长期目标，即提供基于证据的运动和康复计划，证明可用于动脉粥样硬化肾动脉狭窄的肾去神经新冷冻技术的原理，并确定模拟生理益处的治疗方法，对不能进行交感神经兴奋和肾钠重吸收的退伍军人进行运动，由于肢体缺失、瘫痪或周围血管疾病而导致的运动。

DESCRIPTION (provided by applicant): Hypertension is a major public health concern in the U.S. with ~70 million adults affected including Veterans. It is the primary risk-factor for development of stroke and heart failure and the second most common cause of kidney failure. Prompt diagnosis and effective treatment are suboptimal with only 60% of Veterans meeting the 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) recommendation of arterial pressure <140/90 mmHg. While essential hypertension is most common, the prevalence of atherosclerotic renovascular hypertension is rising with prevalence as high as 50% in high risk patients who have concurrent extrarenal atherosclerosis and heart failure. Renal artery stenosis occurred in 28% of Veterans undergoing cardiac catheterization with a greater than 3-fold risk in those over age 65. The benefits of angioplasty with or without stenting in controlling arterial pressure, decreasing cardiac or renal events, or reducing morbidity and mortality remain unproven and controversial. Surgical intervention and inhibition of angiotensin II carry substantial risk. Thus, it is important to seek alternative or adjunctive strategies. Regular exercise is a mainstay of rehabilitative strategies and is key to cardiovascular health. Sedentary lifestyle is widespread and many veterans suffer from injuries or diseases that limit dynamic exercise: amputation, paralysis, peripheral vascular disease, cardiopulmonary disorders, and even depression. In addition to decreasing arterial pressure, regular dynamic exercise decreases sympathetic outflow which independently contributes to greater cardiovascular risk. While these mechanisms have been explored in essential hypertension, they have received little attention in renovascular disease. Thus, we will test the hypothesis that in a model of renovascular hypertension, the two-kidney one-clip (2K1C) rat, dynamic exercise training decreases systemic blood pressure by decreasing afferent neural inputs from the stenosed kidney thereby enhancing central nitritergic signaling and decreasing renal sympathetic nerve activity that regulates distal tubular sodium reabsorption. Three Specific Aims will be addressed: (1) We will assess whether exercise training will decrease arterial pressure and contralateral RSNA in 2K-1C (or sham-clipped) rats via inhibition of afferent nerve inputs from the clipped kidney; (2) We will evaluate whether exercise training influences RSNA by enhancing nitritergic signaling within the paraventricular nucleus whose neurons project to brainstem cardiovascular centers as well as directly to the kidney; and (3) We will determine the effect of exercise trainin on renin release, plasma and renal tissue Ang II and renal sodium excretion via the distal sodium chloride co-transporter (NCC) and epithelial sodium channel (ENaC). We perform our hemodynamic, renal nerve recordings and measurements of plasma angiotensin II and aldosterone in chronically instrumented, conscious, freely moving rats, thereby minimizing the confounding affects of anesthesia. We use cryoablation of the renal nerve from the kidney with the stenosis rather than surgical denervation. This novel cryotreatment will permit us to evaluate two things: proof of concept that renal denervation will be effective and that this device may be a viable prototype for developing noninvasive methods to perform renal denervation in individuals with atherosclerotic renovascular disease. We also will apply standard clearance methodology to evaluate urinary sodium excretion as well as molecular approaches to evaluate the impact of exercise on NCC and ENaC. This research will result in findings that would directly impact the health of Veterans and achieve our long term goal of providing evidence based programs of exercise and rehabilitation, proof of principle for new cryotechniques for renal denervation that can be used in atherosclerotic renal artery stenosis, and identifying therapies that mimic the physiologic benefits exercise on sympathoexcitation and renal sodium reabsorption in Veterans who are unable to exercise due to loss of limbs, paralysis or peripheral vascular disease.