Integrative Cardiovascular Control 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、充血性心力衰竭、肾脏疾病和充血性心力衰竭）的主要风险因素。尽管日常锻炼的有益效果是众所周知的，但在患有已确立的高血压的患者中，交感神经活动、动脉压和心率的异常大的增加通常是响应于锻炼而发生的，这由于动脉压的危险升高而排除了任何剧烈的身体活动，动脉压的危险升高增加了突发的、不利的心血管事件（例如心肌梗塞和中风）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。许多实验室使用包括人类在内的许多物种进行的许多研究表明，激活活动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动态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，它是已知的，高血压损害压力反射功能在休息，是否运动进一步改变压力反射功能的高血压是未知的。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，我们开发了一种强大的、高度创新的、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，其允许连续的对各种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在运动后心血管反射的强度和机制。疾病状态的诱导。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相同的动物，从而每只动物作为其自身的对照。该项目的重要性是强调了几乎完全缺乏高血压对心血管运动反应的影响的信息，这些结果可能有助于高血压患者的运动方案的处方，以及增加我们对高血压对神经控制的影响的理解在心血管控制的最大挑战之一-全身剧烈动态运动。公共卫生相关性：高血压影响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、动脉粥样硬化、肾脏疾病和充血性心力衰竭的主要风险因素。尽管众所周知有规律的运动具有多种有益效果，但在患有明确的高血压的患者中，经常发生响应于运动的动脉压和心率的异常大的增加，这可能由于动脉压的危险升高而妨碍任何剧烈的体力活动，这增加了突发的、不利的心血管事件（例如心肌梗塞和中风）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。该提案的重点是增加我们对感觉神经的作用的理解，这些感觉神经对活动肌肉中代谢物浓度的变化做出反应，以及那些感觉血压变化的神经在介导高血压运动异常反应中的作用。

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.