Mechanisms Mediating Enhanced Sympatho-Activation During Exercise in Hypertension

 描述（由申请人提供）：高血压影响美国近三分之一的成年人，并且被公认为是多种心血管疾病（如中风、肾脏疾病和充血性心力衰竭）的主要风险因素。当高血压患者进行剧烈运动时，交感神经活动可上升到危险的高水平，导致动脉压和心率明显过度增加，这增加了突发心血管不良事件（如心肌梗死和中风）的可能性。高血压患者运动引起的这些异常心血管反应的机制尚不清楚。许多研究表明，激活骨骼肌内的代谢敏感传入（称为肌肉代谢反射）可以引起交感神经活动的显著增加。由于后负荷升高、心脏肥大、紧张性冠状血管收缩和增加心室收缩力的能力受损而导致的高血压心脏功能受损可能导致运动期间骨骼肌血流量降低，从而导致肌肉代谢反射过度激活。此外，肌肉代谢反射的机制与动脉压力反射密切相关。虽然有证据表明高血压损害静息时的压力反射功能，但运动是否进一步改变高血压的压力反射功能尚不清楚。该建议的重点是确定肌肉代谢反射在介导动态运动改变心血管反应中的作用，以及动脉压力反射在介导这些反应中的参与。我们的实验室是唯一准备解决这个问题。在过去的二十年里，我们开发了一种高度创新和技术复杂的意识，使用“最先进的”仪器的长期仪器化的犬模型，其允许连续的对全身血流动力学参数和心室功能的多种指数进行搏动监测，以评估正常动物在静息和动态运动期间以及诱发疾病后心血管反射的强度和机制states.我们已经将该模型扩展到高血压的病理生理状态。我们提出了第一个纵向研究的影响，高血压的综合机制介导的神经控制的心血管功能在运动过程中。我们的方法是在诱导高血压之前和之后研究相同的动物，从而每只动物作为其自身的对照。这些结果可能有助于高血压患者运动方案的处方，以及增加我们对高血压对循环神经控制的影响的理解，这是对心血管控制的最大挑战之一-全身剧烈动态运动。

 DESCRIPTION (provided by applicant): Hypertension affects nearly 1 in 3 of all adults in the U.S. and is well recognized as a major risk factor for a broad range of cardiovascular diseases such as stroke, renal disease, and congestive heart failure. When hypertensive patients engage in strenuous exercise, sympathetic nerve activity can rise to dangerously high levels causing markedly exaggerated increases in arterial pressure and heart rate which increase the probability of sudden, adverse cardiovascular events such as myocardial infarction and stroke. The mechanisms mediating these abnormal cardiovascular responses to exercise in hypertension are unknown. Many studies have shown that activation of the metabolically sensitive afferents within the active skeletal muscle (termed the muscle metaboreflex) can elicit profound increases in sympathetic nerve activity. Impaired cardiac function in hypertension due to elevated afterload, cardiac hypertrophy, tonic coronary vasoconstriction and impaired ability to increase ventricular contractility may lead to lower skeletal muscle blood flow during exercise thereby causing excessive activation of the muscle metaboreflex. Furthermore, the mechanisms of the muscle metaboreflex are intimately dependent on the arterial baroreflex. Although, there is evidence that hypertension impairs baroreflex function at rest, whether exercise further alters baroreflex function in hypertension is unknown. This proposal is focused on determining the role of the muscle metaboreflex in mediating the altered cardiovascular response to dynamic exercise and the involvement of the arterial baroreflex in mediating these responses. Our laboratory is uniquely poised to address this issue. Over the last two decades we have developed a highly innovative and technically complex conscious, chronically instrumented canine model using "state of the art" instrumentation which permits the continuous beat-by-beat monitoring of systemic hemodynamic parameters and multiple indices of ventricular function in order to assess the strength and mechanisms of cardiovascular reflexes at rest and during dynamic exercise in normal animals and after induction of disease states. We have expanded this model to the patho-physiological state of hypertension. We propose the first longitudinal study of the effects of hypertension on integrative mechanisms mediating neural control of cardiovascular function during exercise. Our approach is to study the same animal before and after the induction of hypertension thereby each animal serves as its own control. These results may aid in the prescription of exercise regimes for hypertensive patients as well as increasing our understanding of the impact of hypertension on neural control of the circulation during one of the greatest challenges to cardiovascular control - whole body strenuous dynamic exercise.