The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

描述（由申请人提供）：已知高血压患者在运动过程中血压（BP）会过度升高，但其潜在机制尚不清楚。通常，运动伴随着由中枢命令和激活细纤维肌肉传入引起的副交感神经活动减少和交感神经活动增加，其反射性地增加交感神经流出和BP。传统上，肌肉传入被分为代谢受体，其被缓慢地激活并且仅在剧烈或缺血性肌肉收缩期间，或机械受体，其对它们的感受野的甚至轻微的变形迅速响应。由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较高的BP范围但在相同的灵敏度水平下操作。我们最近在自发性高血压大鼠（SHR）和原发性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，肌肉收缩期间交感神经活动（SNA）和血压也会过度升高。此外，运动期间交感神经反应的潜伏期比正常情况短得多，并且增加肌肉SNA所需的运动强度的阈值水平比正常情况低得多，这涉及机械受体介导。高血压患者运动加压反射（EPR）过度活跃的机制尚不清楚，但越来越多的证据表明醛固酮在调节高血压大鼠和人类静息状态下的中枢交感神经流出中发挥作用。此外，脑中的局部醛固酮合成已被证明有助于SHR和达尔盐敏感大鼠中的交感神经激活和高血压，尽管醛固酮的循环水平正常。醛固酮是否有助于运动时过度的交感神经兴奋和血压升高仍不清楚。我们在高血压大鼠和血清醛固酮水平正常和升高的人中的初步数据表明，醛固酮通过机械反射敏化在运动升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患者和肾上腺过度生产醛固酮（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，并在运动和SNA微电极记录期间测量反射反应。这项建议的显著特点包括：（1）使用最先进的技术（微电极记录的 SNA）直接测试有意识的人的机制假设;（2）使用我们实验室开发的新范式评估机械反射，该范式引起SNA和BP的持续升高，而不是先前在人类中描述的其他方法;（3）使用补充方法评估醛固酮对高血压大鼠肌肉收缩期间循环神经控制的中枢与外周效应。

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.