Exercise training and blood pressure in hypertension: integrated mechanisms

描述(由申请人提供)： 在美国，高血压是一个主要的公共卫生问题，大约有7000万成年人受到影响，其中包括退伍军人。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全国预防、检测、评估和治疗高血压联合委员会(JNC7)关于动脉压和血压140/90毫米汞柱的建议。虽然高血压是最常见的，但动脉粥样硬化性肾血管性高血压的患病率正在上升，在合并肾外动脉硬化和心力衰竭的高危患者中患病率高达50%。在接受心导管置入术的退伍军人中，28%的人发生肾动脉狭窄，而65岁以上的退伍军人发生肾动脉狭窄的风险是后者的3倍以上。支架成形术与非支架成形术在控制血管病变中的作用 动脉血压，减少心脏或肾脏事件，或减少发病率和死亡率仍然是未经证实和有争议的。外科干预和血管紧张素II的抑制具有很大的风险。因此，重要的是寻求替代或附加战略。定期锻炼是康复策略的支柱，也是心血管健康的关键。久坐的生活方式很普遍，许多退伍军人都遭受着限制动态运动的伤害或疾病：截肢、瘫痪、周围血管疾病、心肺疾病，甚至抑郁症。除了降低动脉压，有规律的动态运动还会减少交感神经流出，而交感神经流出会增加心血管风险。虽然这些机制已经在原发性高血压中得到了探索，但在肾血管疾病中却鲜有人关注。因此，我们将检验一种假设，即在肾血管性高血压模型中，两肾一夹(2K1C)大鼠，动态运动训练通过减少来自狭窄肾脏的传入神经输入，从而增强中枢氮能信号，减少调节远端肾小管钠重吸收的交感神经活动，从而降低全身血压。将致力于三个具体目标：(1)我们将评估运动训练是否会通过抑制来自夹肾的传入神经来降低2K-1C(或假夹闭)大鼠的动脉压和对侧RSNA；(2)我们将评估运动训练是否通过加强室旁核(其神经元投射到脑干心血管中心以及直接到达肾脏)对RSNA的影响；以及(3)我们将确定运动训练对肾素释放、血浆和肾组织Ang II以及通过远端氯化钠共转运体(NCC)和上皮钠通道(ENaC)排泄肾脏钠的影响。我们在长期使用仪器的清醒自由活动的大鼠身上进行血流动力学、肾神经记录和血浆血管紧张素II和醛固酮的测量，从而将麻醉的混杂影响降至最低。我们使用冷冻消融来自狭窄的肾脏的肾神经，而不是手术去神经。这种新的冷冻治疗将允许我们评估两件事：肾去神经治疗将是有效的概念证据，以及这种装置可能是一种 开发非侵入性方法在动脉粥样硬化性肾血管疾病患者中进行肾去神经治疗的可行原型。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。这项研究的结果将直接影响退伍军人的健康，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性肾动脉狭窄的肾去神经新冷冻技术的原理，并确定模拟运动对交感神经兴奋和肾脏钠重吸收的生理益处的疗法，这些退伍军人因肢体丧失、瘫痪或外周血管疾病而无法运动。

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.