Mechanisms Mediating Enhanced Sympatho-Activation During Exercise in Hypertension

 描述(申请人提供)：高血压影响着美国近三分之一的成年人，被公认为是中风、肾脏疾病和充血性心力衰竭等一系列心血管疾病的主要危险因素。当高血压患者进行剧烈运动时，交感神经活动可能会上升到危险的高水平，导致动脉压和心率明显夸大，从而增加发生心肌梗死和中风等突发不良心血管事件的可能性。高血压患者运动后心血管异常反应的调节机制尚不清楚。许多研究表明，激活活跃的骨骼肌中对代谢敏感的传入(称为肌肉代谢反射)可以引起交感神经活动的显著增加。高血压患者由于后负荷增加、心肌肥厚、紧张性冠状动脉血管收缩和增加心肌收缩能力受损而导致的心功能受损，可能导致运动时骨骼肌血流量降低，从而导致肌肉代谢反射过度激活。此外，肌肉代谢性反射的机制与动脉压力反射密切相关。尽管有证据表明高血压会损害静息状态下的压力感受器反射功能，但运动是否会进一步改变高血压患者的压力感受器反射功能尚不清楚。本研究的重点是确定肌肉代谢性反射在动态运动引起的心血管反应改变中的作用，以及动脉压力感受性反射参与调节这些反应。我们的实验室正独一无二地准备解决这个问题。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犬模型，该模型使用最先进的仪器，允许连续逐跳监测全身血流动力学参数和多个心脏功能指数，以评估正常动物在休息、动态运动期间和疾病状态诱导后的心血管反射的强度和机制。我们已经将这个模型扩展到高血压的病理生理状态。我们提出了第一个关于高血压对运动中神经控制心血管功能综合机制的影响的纵向研究。我们的方法是研究同一动物在高血压诱导之前和之后，因此每个动物都作为自己的对照。这些结果可能有助于高血压患者的运动方案的处方，以及在心血管控制的最大挑战之一-全身剧烈动态运动中，提高我们对高血压对循环神经控制的影响的理解。

 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.