Muscle Reflex Control of the Coronary Circulation

描述（由申请人提供）：主要研究者的长期目标是研究调节人体循环的机制。这个项目的具体目标是更好地了解运动过程中调节冠状动脉血流的机制。本建议的一个关键特征是我们将使用双工超声测量左冠状动脉前降支的冠状动脉血流量。本应用的具体目的是：我们将证明在握力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剂对握力的反应是否随着年龄和心力衰竭（HF）而增强。我们假设这将是事实，并且这种强化效应将是由于老年人和心衰患者肌肉机械反射的激活增强。然后我们将研究调节人类冠状动脉收缩反应的传出机制。我们假设收缩机制会被静脉注射1受体阻滞剂（酚妥拉明）阻断，在急性静脉注射2受体阻滞剂（普萘洛尔）和高氧（一种增加一氧化氮氧化猝灭的干预措施）存在时，收缩机制会被强化。在过去的5到6年里，我们一直在努力开发双相方法来检测肾脏血流速度。这导致了一系列的论文，这些论文定义了肌肉机械感受器在正常人、老年人和心衰患者肾脏产生交感神经收缩中的作用。最近，我们把注意力集中在有意识的人类冠状动脉血流的调节上。我们通过使用心内多普勒导线侵入性测量冠状动脉血流开始这项工作；然后，我们对接受手术治疗的冠状动脉疾病患者进行了左乳内动脉旁路移植术的血流速度测量。最近，我们收集了检测原生冠状动脉冠状动脉血流的试点数据。这种方法花了好几年的时间才发展起来。我们现在准备利用这种方法来解决控制正常志愿者、心衰患者和老年人左前降动脉血流的机制。了解运动过程中控制血液流动的机制是一个重要的研究领域，因为血液流向心脏是一个人进行日常生活活动能力的关键决定因素。更深入地了解神经系统调节冠状动脉循环的能力将使我们有机会开发新的方法来治疗冠状动脉调节受损的疾病，如心衰。公共卫生相关性：我们将在运动期间检查冠状动脉血流。了解运动过程中控制血流量的机制是一个重要的研究领域，因为流向心脏的血流量是一个人进行日常生活活动能力的重要决定因素。更深入地了解神经系统调节冠状动脉循环的能力将使我们有机会开发新的方法来治疗冠状动脉调节受损的疾病，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.