Integrative Cardiovascular Control During Exercise in Hypertension

描述（由申请人提供）：高血压影响了美国近三分之一的成年人，并且被公认为是广泛的心血管疾病（如中风、充血性心力衰竭、肾脏疾病和充血性心力衰竭）的主要危险因素。虽然日常运动的有益作用是众所周知的，但在高血压患者中，交感神经活动、动脉压和心率的异常大幅度增加往往是运动的反应，这就排除了任何剧烈体育活动的建议，因为动脉压的危险升高会增加突发不良心血管事件（如心肌梗死和中风）的可能性。高血压患者运动时心血管异常反应的机制目前尚不清楚。许多实验室对包括人类在内的许多物种进行的研究表明，激活活跃骨骼肌内的代谢敏感传入神经（称为肌肉代谢反射）可以引起交感神经活动的深刻增加。高血压患者由于后负荷升高、心脏肥厚、强直性冠状血管收缩和增加心室收缩能力受损导致心功能受损，可能导致动态运动时骨骼肌血流量降低，从而引起肌肉代谢反射过度激活。此外，肌肉代谢反射的机制密切依赖于动脉压力反射。虽然已知高血压会损害静息时的血压反射功能，但运动是否会进一步改变高血压患者的血压反射功能尚不清楚。这一建议的重点是确定肌肉代谢反射在调节心血管对动态运动反应的改变中的作用，以及动脉压力反射在调节这些反应中的作用。我们的实验室在解决这个问题上有独特的优势。在过去的二十年里，我们开发了一种强大的、高度创新的、技术复杂的有意识的、长期仪器化的犬类模型，使用“最先进的”仪器，允许对各种血液动力学参数和心室功能的多个指标进行连续的每拍监测，以评估正常动物在静止和动态运动期间以及诱导疾病状态后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。我们的方法是在诱导高血压之前和之后研究同一只动物，因此每只动物都作为自己的对照。由于几乎完全缺乏关于高血压对心血管运动反应的影响的信息，因此强调了该项目的重要性，这些结果可能有助于为高血压患者制定运动方案，并增加我们对高血压在心血管控制的最大挑战之一-全身剧烈动态运动期间对循环神经控制的影响的理解。公共卫生相关性：高血压影响了美国近三分之一的成年人，并且被公认为广泛的心血管疾病（如中风、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）的主要危险因素。虽然我们都知道有规律的运动有许多有益的作用，但在高血压患者中，运动引起的动脉压和心率的异常升高往往会出现，这可能会使任何剧烈的体育活动都无法进行，因为动脉压的危险升高会增加突发不良心血管事件（如心肌梗死和中风）的可能性。高血压患者运动时心血管异常反应的机制目前尚不清楚。这一建议的重点是增加我们对活动肌肉中代谢物浓度变化的感觉神经和血压变化的感觉神经在介导高血压运动异常反应中的作用的理解。

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, 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.