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: 8440112
• 负责人: WANPEN VONGPATANASIN
• 金额: $ 55.1万
• 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/8440112
• 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（由申请人提供）：高血压患者在运动时血压升高明显，但其潜在机制尚不清楚。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，这是由中枢指令和薄纤维肌肉传入神经的激活引起的，从而反射性地增加交感神经流出和血压。传统上，肌肉传入神经被分为代谢受体和机械受体，前者仅在肌肉剧烈或缺血收缩时缓慢激活，后者对其感受野的轻微变形反应迅速。这些受体的激活引起的SNA和BP的增加，称为运动加压反射，通常通过激活动脉压力感受器来缓冲，动脉压力感受器被重置为在更高的血压范围内工作，但在相同的敏感性水平上。我们最近对自发性高血压大鼠（SHR）和原发性高血压患者的研究表明，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）和血压也会出现夸张的上升。此外，运动时交感神经反应潜伏期比正常情况短得多，增加肌肉SNA所需的运动强度阈值水平也比正常情况低得多，这暗示了机械感受器的作用。高血压过度活跃运动压反射（EPR）的机制尚不清楚，但越来越多的证据表明，醛固酮在高血压大鼠和人类静息中枢性交感神经流出中起着调节作用。此外，尽管循环中的醛固酮水平正常，但在SHRs和dahl盐敏感大鼠中，脑内局部醛固酮合成已被证明有助于交感神经激活和高血压。醛固酮是否导致运动时交感神经过度兴奋和血压升高尚不清楚。我们在高血压大鼠和血清醛固酮水平正常和升高的人类中进行的试验数据表明，醛固酮通过机械反射致敏作用在运动加压反射中起主要作用。因此，我们现在建议在高血压大鼠和原发性高血压以及肾上腺醛固酮过量（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转化研究，在运动期间使用多种干预措施直接激活肌肉机械感受器、代谢感受器或动脉压力感受器，并通过微电极记录SNA来测量反射反应。该提案的显著特点包括：(1)使用最先进的技术（微电极记录）