Mechanisms of Exercise Pressor Reflex Overactivity in Hypertension

描述（由申请人提供）：在高血压患者中，运动可引起动脉血压、心率和血管阻力的过度增加。这些循环血流动力学的潜在危险升高增加了运动期间发生不良心脏事件或中风的风险。我们之前已经确定，运动加压反射（一种源自骨骼肌的循环反射）的过度活动对这些心血管反应的产生有重要作用。此外，我们实验室的证据表明，肌肉机械反射和代谢反射，运动压力反射的两个功能组成部分，都驱动了这种过度活动。然而，高血压运动加压反射功能障碍的机制尚不清楚。由运动压力反射激活产生的感觉信息在延髓的孤束核（NTS）内处理。髓质内接收和处理这些信息的神经元的活动可以通过内源性一氧化氮（NO）的产生来调节。一氧化氮合酶（NOS）介导一氧化氮的生成。同样，NTS内的NO活性可以通过活性氧（ROS）的产生而改变。因此，NOS表达/活性或ROS产生的改变都可能导致NTS内NO活性的变化。因此，NTS内的NO通路代表了疾病引起的运动压力反射功能改变的可行靶标。基于这些知识，我们假设高血压患者运动加压反射介导的心血管运动反应增强是由一氧化氮活性改变、一氧化氮表达和/或功能改变以及NTS内ROS生成的改变引起的。为了验证这些假设，我们将在正常和高血压大鼠中进行生理和神经生化研究，以解决以下具体目标：1)确定NTS中NO在高血压运动加压反射、机械反射和代谢反射过度活动的产生中的作用；2)确定NTS内NOS在高血压运动加压反射、机械反射和代谢反射过度活动产生中的作用；3)确定NTS内ROS在高血压运动加压反射、机械反射和代谢反射过度活动产生中的作用。

DESCRIPTION (provided by applicant): In hypertensive individuals, exercise elicits excessive increases in arterial blood pressure, heart rate and vascular resistance. These potentially dangerous elevations in circulatory hemodynamics increase the risk for adverse cardiac events or stroke during exercise. We have previously established that overactivity of the exercise pressor reflex, a circulatory reflex originating within skeletal muscle, contributes importantly to the generation of these heightened cardiovascular responses. Further, evidence from our laboratory suggests that both the muscle mechanoreflex and metaboreflex, the two functional components of the exercise pressor reflex, drive this overactivity. However, the mechanisms underlying exercise pressor reflex dysfunction in hypertension are not clear. Sensory information generated by activation of the exercise pressor reflex is processed within the nucleus tractus solitarius (NTS) of the medulla oblongata. The activity of neurons within the medulla that receive and process this information can be modulated by the endogenous production of nitric oxide (NO). NO production is mediated by nitric oxide synthase (NOS). Likewise, NO activity within the NTS can be modified by the generation of reactive oxygen species (ROS). Therefore, alterations in either NOS expression/activity or ROS production potentially contribute to changes in NO activity within the NTS. As such, the NO pathway within the NTS represents a viable target for disease induced alterations in exercise pressor reflex function. Based on this knowledge, we hypothesize that the enhanced cardiovascular response to exercise mediated by the exercise pressor reflex in hypertension is induced by alterations in NO activity, changes in NOS expression and/or function as well as alterations in the generation of ROS within the NTS. To test these hypotheses, we will perform physiologic and neuro-biochemical studies in normotensive and hypertensive rats to address the following specific aims: 1) determine the role of NO within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension; 2) determine the role of NOS within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension; and 3) determine the role of ROS within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension.