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: 8838219
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838219
• 关键词: Address; Adult; Affect; Age; Aldosterone; Amputation; Anesthesia procedures; Angioplasty; Angiotensin II; Arteries; Atherosclerosis; Attention; Blood; Blood Pressure; Brain; Brain Stem; Cardiac; Cardiac Catheterization Procedures; Cardiovascular system; Clip; Conscious; Contralateral; Cryosurgery; Denervation; Detection; Development; Devices; Diagnosis; Disease; Distal; Elderly; Epithelial; Equilibrium; Essential Hypertension; Evaluation; Event; Evidence based program; Excretory function; Exercise; Goals; Health; Heart; Heart failure; Hypertension; Individual; Injury; Joints; Kidney; Kidney Failure; Lead; Lesion; Limb structure; Measurement; Medical; Mental Depression; Methodology; Methods; Modeling; Molecular; Morbidity - disease rate; Nerve; Neurons; Operative Surgical Procedures; Output; Paralysed; Patients; Peripheral Vascular Diseases; Pharmaceutical Preparations; Physiological; Plasma; Prevalence; Prevention; Public Health; Pulmonary Heart Disease; Rattus; Recommendation; Regimen; Rehabilitation therapy; Renal Artery Stenosis; Renal Tissue; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Renovascular Hypertension; Research; Risk; Risk Factors; Running; Signal Transduction; Site; Sodium; Sodium Channel; Sodium Chloride; Stenosis; Stroke; Testing; Training; Tubular formation; United States Department of Veterans Affairs; Veterans; afferent nerve; blood pressure regulation; cardiovascular health; cardiovascular risk factor; design; effective therapy; epithelial Na+ channel; evidence base; hemodynamics; high risk; improved; instrument; kidney vascular structure; meetings; mortality; novel; novel strategies; paraventricular nucleus; pressure; prevent; programs; prototype; public health relevance; relating to nervous system; renal artery; sedentary lifestyle; symporter; therapeutic target; urinary

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.

描述（由申请人提供）： 高血压是美国的一个主要公共卫生问题，约 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发展的主要危险因素，也是肾衰竭的第二常见原因。及时诊断和有效治疗并不理想，只有 60% 的退伍军人符合第七届全国高血压预防、检测、评估和治疗联合委员会 (JNC7) 动脉压 <140/90 mmHg 的建议。虽然原发性高血压最常见，但动脉粥样硬化性肾血管性高血压的患病率正在上升，在同时患有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%。接受心导管插入术的退伍军人中有 28% 发生肾动脉狭窄，65 岁以上退伍军人的风险是其 3 倍以上。血管成形术（带或不带支架）在控制肾动脉狭窄方面的优势 动脉压、减少心脏或肾脏事件或降低发病率和死亡率尚未得到证实和争议。手术干预和抑制血管紧张素 II 具有很大的风险。因此，寻求替代或辅助策略非常重要。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，许多退伍军人遭受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。除了降低动脉压之外，定期的动态运动还可以减少交感神经的流出，从而独立地增加心血管风险。虽然这些机制已在原发性高血压中得到探索，但在肾血管疾病中却很少受到关注。因此，我们将检验这样的假设：在肾血管性高血压模型（两肾单夹（2K1C）大鼠）中，动态运动训练通过减少狭窄肾脏的传入神经输入来降低全身血压，从而增强中枢硝酸盐信号传导并减少调节远端肾小管钠重吸收的肾交感神经活动。将解决三个具体目标：（1）我们将评估运动训练是否会通过抑制来自剪断肾脏的传入神经输入来降低 2K-1C（或假剪断）大鼠的动脉压和对侧 RSNA； (2) 我们将评估运动训练是否通过增强室旁核内的硝酸信号传导来影响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肾脏； (3) 我们将通过远端氯化钠协同转运蛋白 (NCC) 和上皮钠通道 (ENaC) 确定运动训练对肾素释放、血浆和肾组织 Ang II 以及肾钠排泄的影响。我们对长期使用仪器、有意识、自由活动的大鼠进行血流动力学、肾神经记录和血浆血管紧张素 II 和醛固酮测量，从而最大限度地减少麻醉的混杂影响。我们采用冷冻消融术从狭窄的肾脏中切除肾神经，而不是手术去神经术。这种新颖的冷冻治疗将使我们能够评估两件事：概念证明肾去神经术将是有效的，并且该装置可能是一种 开发无创方法对患有动脉粥样硬化性肾血管疾病的个体进行肾去神经术的可行原型。我们还将应用标准清除方法来评估尿钠排泄，并应用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，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证明，并确定模拟运动对因运动丧失而无法运动的退伍军人的交感神经兴奋和肾钠重吸收的生理益处的疗法 四肢麻痹或周围血管疾病。