The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

醛固酮对高血压运动加压反射的作用

• 批准号: 8606888
• 负责人: WANPEN VONGPATANASIN
• 金额: $ 54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606888
• 关键词: Adrenal Glands; Age; Aldosterone; Amlodipine; Antihypertensive Agents; Asses; Attenuated; Baroreflex; Blood Circulation; Blood Pressure; Brain; Buffers; Capsaicin; Cardiovascular system; Clinical; Congestive Heart Failure; Conscious; Dahl Hypertensive Rats; Data; Dose; Essential Hypertension; Ethnic Origin; Excision; Exercise; Functional disorder; Gender; Generations; Heart Rate; Human; Hyperaldosteronism; Hypertension; Inbred SHR Rats; Infusion procedures; Intervention; Kidney; Laboratories; Measures; Mechanoreceptors; Mediating; Mediation; Methods; Microelectrodes; Mineralocorticoid Receptor; Modeling; Muscle; Muscle Contraction; Muscle Fibers; Nerve; Neuraxis; Outcome; Pathogenesis; Patients; Peripheral; Pressoreceptors; Rattus; Receptor Activation; Reflex action; Rest; Role; Safety; Serum; Skin; Stimulus; Stretching; Sympathetic Nervous System; Techniques; Testing; Work; adenoma; arm; effective therapy; improved; indexing; neuroregulation; normotensive; public health relevance; receptive field; response; translational study; tumor

DESCRIPTION (provided by applicant): Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but the underlying mechanisms are poorly understood. Normally, exercise is accompanied by decreased parasympathetic activity and increased sympathetic activity caused by central command and activation of thin fiber muscle afferents that reflexively increase sympathetic outflow and BP. Traditionally, muscle afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of their receptive fields. The increase in SNA and BP caused by activation of these receptors, known as exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to operate at higher BP range but at the same level of sensitivity. Our recent work in spontaneously hypertensive rats (SHR) and patients with essential hypertension indicated an exaggerated rise in sympathetic nerve activity (SNA) and BP during muscle contraction even in the absence of congestive heart failure. Furthermore, the latency of the sympathetic response during exercise is much shorter than normal and the threshold level of exercise intensity required to increase muscle SNA is much lower than normal, implicating mechanoreceptor mediation. Mechanisms responsible for overactive exercise pressor reflex (EPR) in hypertension remain unknown but an increasing body of evidence suggested a role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and humans. Furthermore, local aldosterone synthesis in the brain has been shown to contribute to sympathetic activation and hypertension in the SHRs and Dahl-salt sensitive rats despite normal circulating levels of aldosterone. Whether aldosterone contributes to excessive sympathoexcitation and BP elevation during exercise remains unknown. Our pilot data in hypertensive rats and humans with normal and elevated serum aldosterone levels demonstrated a major role of aldosterone on exercise pressor reflex via mechanoreflex sensitization. Therefore, we now propose parallel translational studies in hypertensive rats and patients with primary hypertension and secondary form of hypertension caused by adrenal overproduction of aldosterone (primary aldosteronism), using multiple interventions to directly activate muscle mechanoreceptors, metaboreceptors, or arterial baroreceptors during exercise and microelectrode recordings of SNA to measure the reflex response. The distinctive features of this proposal include: (1) the use of state-of- the-art techniques (microelectrode recordings of SNA) to directly test mechanistic hypotheses in conscious humans; (2) assessment of mechanoreflex using a new paradigm which is developed in our laboratory which evokes sustained elevation in SNA and BP than other methods previously described in humans; and (3) the use of complimentary approach to asses central vs. peripheral effects of aldosterone on neural control of circulation during muscle contraction in the hypertensive rats.

描述(申请人提供)：众所周知，高血压患者在运动过程中表现出血压(BP)的夸大上升，但其潜在的机制尚不清楚。正常情况下，运动伴随着副交感神经活动的减少和交感神经活动的增加，这是由于中枢指令和激活细纤维肌肉传入反射性地增加交感神经流出和血压而引起的。传统上，肌肉传入被分为代谢性受体和机械感受器，前者仅在剧烈或缺血肌肉收缩时缓慢激活，后者对其感受场的轻微变形都能迅速做出反应。由激活这些受体引起的SNA和BP增加，称为运动加压反射，通常被激活的动脉压力感受器缓冲，这些感受器被重新设置为在更高的血压范围内工作，但在相同的敏感度水平上。我们最近在自发性高血压大鼠(SHR)和高血压患者中的研究表明，即使在没有充血性心力衰竭的情况下，肌肉收缩时交感神经活动(SNA)和血压也会过度升高。此外，运动中交感反应的潜伏期比正常短得多，增加肌肉SNA所需的运动强度阈值水平也比正常低得多，这意味着机械感受器的调节。高血压患者过度活跃的运动加压反射(EPR)的机制尚不清楚，但越来越多的证据表明，在高血压大鼠和人类中，醛固酮都在调节静息交感神经流出中发挥作用。此外，脑中局部的醛固酮合成已被证明有助于SHR和Dahl盐敏感大鼠的交感神经激活和高血压，尽管循环中的醛固酮水平正常。在运动过程中，醛固酮是否会引起交感神经过度兴奋和血压升高，目前尚不清楚。我们在血清醛固酮水平正常和升高的高血压大鼠和人类中的试验数据表明，醛固酮通过机械反射敏化在运动加压反射中发挥主要作用。因此，我们现在建议在高血压大鼠和由肾上腺醛固酮过度产生(原发性醛固酮增多症)引起的继发性高血压患者中进行平行翻译研究，使用多种干预措施在运动中直接激活肌肉机械受体、代谢物受体或动脉压力感受器，并记录SNA的微电极以测量反射反应。这一建议的显著特点包括：(1)使用最先进的技术(微电极记录 SNA)直接测试有意识的人类的机械学假说；(2)使用我们实验室开发的新范式来评估机械反射，该新范式比以前在人类中描述的其他方法更能引起SNA和BP的持续升高；以及(3)使用互补的方法来评估醛固酮对高血压大鼠肌肉收缩过程中循环的神经控制的中枢和外周影响。