Muscle Reflex Control of the Coronary Circulation

描述(由申请人提供)：首席研究人员的长期目标是检查调节人体循环的机制。该项目的具体目标是更好地了解运动过程中冠状动脉血流的调节机制。这项提议的一个关键特点是，我们将使用双功超声测量冠状动脉左前降支的血流量。这项应用的具体目的是：我们将证明在握手过程中发生冠状动脉收缩(即冠状动脉血管阻力的增加)。我们还将确定这种收缩的机制。我们假设收缩将发生在最大自愿收缩(MVC)的高百分比。我们假设，这种影响主要是由于肌肉机械反射的参与。我们还将确定冠状动脉血管收缩反应是否随着年龄和心力衰竭(HF)的增加而增强。我们假设情况会是这样，这种加重效应是由于老年人和心力衰竭患者肌肉机械反射的高度激活所致。然后，我们将研究调节人类冠状动脉收缩反应的传出机制。我们假设，静脉注射1-受体阻滞剂(酚妥拉明)，在急性静脉注射2-受体阻滞剂(心得安)和高氧(一种增加一氧化氮氧化猝灭的干预措施)存在的情况下，加强2-受体阻滞剂(心得安)的存在，将阻断收缩机制。在过去的5到6年中，我们一直致力于开发检测肾血流速度的双功方法。这导致了一系列论文的发表，这些论文定义了肌肉机械感受器在正常人、老年人和心力衰竭患者的肾脏交感收缩中的作用。最近，我们将注意力集中在清醒人类冠状动脉血流的调节上。我们首先使用心内多普勒线有创性地测量冠状动脉血流；然后我们进行研究，测量接受手术治疗的冠状动脉疾病患者左乳内动脉搭桥术中的血流速度。最近，我们收集了检测冠状动脉血流的先导性数据。这种方法花了几年时间才开发出来。我们现在准备利用这种方法来解决在正常志愿者、心力衰竭患者和老年人中控制左前降支血流的机制。了解运动中控制血流的机制是一个重要的研究领域，因为流向心脏的血液是一个人进行日常生活活动能力的关键决定因素。更多地了解神经系统调节冠脉循环的能力将使我们有机会开发新的方法来治疗冠脉调节受损的情况，如心衰。公共卫生相关性：我们将在运动过程中非侵入性地检测冠脉血流。了解运动中控制血流的机制是一个重要的研究领域，因为流向心脏的血液是一个人进行日常生活活动能力的重要决定因素。更多地了解神经系统调节冠脉循环的能力将使我们有机会开发新的方法来治疗冠脉调节受损的情况，如心衰。

DESCRIPTION (provided by applicant): The long-range goals of the principal investigator are to examine mechanisms that regulate the circulation in humans. The specific goals of this program are to better understand the mechanisms regulating coronary blood flow during exercise. A key feature of this proposal is that we will use duplex ultrasound to measure coronary blood flow in the left anterior descending coronary artery. The specific aims of this application are: We will demonstrate that coronary constriction (i.e. a rise in coronary vascular resistance) occurs during handgrip. We will also determine the mechanism for this constriction. We hypothesize that constriction will occur at high percentages of maximal voluntary contraction (MVC). We hypothesize that this effect will be due predominantly to engagement of the muscle mechanoreflex. We will also determine if coronary vasoconstrictor responses to handgrip are enhanced with aging and heart failure (HF). We hypothesize that this will be the case and that this accentuated effect will be due to heightened activation of muscle mechanoreflexes in the aged and HF. We will then examine the efferent mechanisms that regulate coronary constrictor responses in humans. We hypothesize that constrictor mechanisms will be blocked by the intravenous use of a 1-blocker (phentolamine), accentuated in the presence of acute intravenous 2-blocker (propranolol), and in the presence of hyperoxia (an intervention to increase the oxidative quenching of nitric oxide). Over the past 5 to 6 years we have worked hard to develop the duplex method to examine renal blood flow velocity. This has resulted in a series of papers that have defined the role of muscle mechanoreceptors in generating sympathetic constriction to the kidney in normal humans, the aged and in HF. Recently we have focused attention on the regulation of blood flow in coronary arteries of conscious humans. We began this effort by invasively measuring coronary blood flow using an intracardiac Doppler wire; we then performed studies measuring flow velocity in left internal mammary artery bypass grafts in subjects with surgically treated coronary artery disease. Most recently we have gathered pilot data examining coronary flow in native coronary arteries. This method has taken several years to develop. We are now poised to utilize this method to address the mechanisms that control blood flow to the left anterior descending artery in normal volunteers, in those with HF, and in the aged. Understanding the mechanisms that control blood flow during exercise is an important area of study as blood flow to the heart is a crucial determinant of a person's ability to perform the activities of daily living. Greater understanding of the nervous system's ability to regulate the coronary circulation will afford us the opportunity to develop novel ways of treating conditions where coronary regulation is impaired such as HF. PUBLIC HEALTH RELEVANCE: We will examine coronary blood flow non-invasively during exercise. Understanding the mechanisms that control blood flow during exercise is an important area of study as blood flow to the heart is an important determinant of a person's ability to perform the activities of daily living. Greater understanding of the nervous system's ability to regulate the coronary circulation will afford us the opportunity to develop novel ways of treating conditions where coronary regulation is impaired such as HF.