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: 8278294
• 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/8278294
• 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; Life Style; 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 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; 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. PUBLIC HEALTH RELEVANCE: Narrative: Public Health Relevance Statement Hypertension is a major public health concern in the U.S. that affects ~70 million adults including an increasing number of Veterans. Physical inactivity has become a significant contributor to poor cardiovascular health and greater morbidity and mortality. Regular exercise improves blood pressure and decreases cardiovascular risk in essential hypertension. A type of hypertension due to build up of fatty plaques in the wall of the artery to the kidney, known as renovascular hypertension, is becoming more widespread. Individuals with this type of hypertension often have other medical problems that prevent them from engaging in meaningful exercise. Our proposal is designed to study the mechanisms whereby regular exercise alters the interactions between the brain and the kidneys in renovascular hypertension. By better understanding of these mechanisms we may be able to devise evidence based strategies for exercise rehabilitation programs for individuals who suffer from atherosclerotic renovascular and peripheral vascular disease and identify therapeutic targets for mimicking the benefits of exercise in individual who cannot engage in dynamic exercise, such as those who suffer from paralysis, amputation, heart failure and even depression.

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降低血压。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、可用于治疗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，以及确定模拟运动对因肢体丧失、瘫痪或周围血管疾病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。 公共卫生相关性： 叙述：公共卫生相关性声明 高血压是美国的一个主要公共卫生问题，影响着大约 7000 万成年人，其中包括越来越多的退伍军人。缺乏身体活动已成为心血管健康状况不佳以及发病率和死亡率增加的重要原因。定期运动可以改善血压并降低原发性高血压的心血管风险。由于肾动脉壁脂肪斑块堆积而导致的一种高血压（称为肾血管性高血压）正变得越来越普遍。患有这种类型高血压的人通常有其他健康问题，导致他们无法进行有意义的锻炼。我们的提案旨在研究定期运动改变肾血管性高血压中大脑和肾脏之间相互作用的机制。通过更好地了解这些机制，我们也许能够为患有动脉粥样硬化性肾血管和周围血管疾病的个体制定基于证据的运动康复计划策略，并确定治疗目标，以模仿无法进行动态运动的个体的运动益处，例如比如那些患有瘫痪、截肢、心力衰竭甚至抑郁症的人。