Integrative Cardiovascular Control 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、充血性心力衰竭、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。虽然日常锻炼的益处众所周知，但在患有高血压的患者中，交感神经活动、动脉压和心率的异常大幅增加往往是对锻炼的反应，这排除了任何剧烈体力活动的建议，因为动脉压危险的升高增加了突发不良心血管事件的可能性，如心肌梗死和中风。高血压患者对运动的这些异常心血管反应的调节机制几乎是未知的。来自不同实验室的许多研究表明，激活活跃的骨骼肌中代谢敏感的传入神经(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、紧张性冠脉收缩和增加心肌收缩能力受损而导致的心功能受损，可能导致动态运动中骨骼肌血流量降低，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。虽然已知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，我们开发了一种强大的、高度创新的、技术复杂的意识犬模型，该模型使用最先进的仪器，允许连续逐拍监测各种血流动力学参数和多个心功能指数，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。我们现在已经将这个模型扩展到高血压的病理生理状态。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。该项目的重要性在于几乎完全缺乏关于高血压对运动对心血管反应的影响的信息，这些结果可能有助于高血压患者制定运动方案，并加深我们对高血压对心血管控制的最大挑战之一-全身剧烈动态运动-期间高血压对循环神经控制的影响的理解。公共卫生相关性：在美国，近三分之一的成年人患有高血压，被公认为是中风、充血性心力衰竭、动脉粥样硬化、肾脏疾病和充血性心力衰竭等一系列心血管疾病的主要风险因素。尽管众所周知，定期锻炼有许多有益的效果，但在患有公认的高血压的患者中，经常会发生因锻炼而导致的动脉压和心率异常大幅增加，这可能会排除任何剧烈体力活动的建议，因为动脉压的危险升高增加了发生突发不良心血管事件(如心肌梗死和中风)的可能性。高血压患者对运动的这些异常心血管反应的调节机制几乎是未知的。这一建议的重点是增加我们对感觉神经在高血压患者运动异常反应中的作用的理解，感觉神经对活动肌肉中代谢物浓度的变化做出反应，以及那些感觉到血压变化的感觉神经。

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, congestive heart failure, renal disease, and congestive heart failure. Although the beneficial effects of daily exercise are well known, in patients with established hypertension abnormally large increases in sympathetic nerve activity, arterial pressure and heart rate often occur in response to exercise which precludes advisement of any strenuous physical activity due to the dangerous elevations in arterial pressure 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 virtually unknown. Many studies from a variety of laboratories using a number of species, including humans, 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 dynamic exercise thereby causing excessive activation of the muscle metaboreflex. Furthermore, the mechanisms of the muscle metaboreflex are intimately dependent on the arterial baroreflex. Although, it is known 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 powerful and 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 wide variety of 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 now expanded this model to the patho- physiological state of hypertension. Our approach is to study the same animal before and after the induction of hypertension thereby each animal serves as its own control. The significance of the project is underscored by the near total lack of information on the effects of hypertension on cardiovascular responses to exercise and 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. PUBLIC HEALTH RELEVANCE: 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, congestive heart failure, atherosclerosis, renal disease, and congestive heart failure. Although regular exercise is well known to have a multitude of beneficial effects, in patients with well established hypertension abnormally large increases in arterial pressure and heart rate in response to exercise often occur which may preclude advisement of any strenuous physical activity due to the dangerous elevations in arterial pressure 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 virtually unknown. This proposal is focused on increasing our understanding of the role of sensory nerves that respond to changes in metabolite concentration in the active muscles and those that sense changes in blood pressure in mediating the abnormal responses to exercise in hypertension.