FEEDFORWARD CONTROL OF CORONARY BLOOD FLOW

冠状动脉血流的前馈控制

• 批准号: 6144001
• 负责人: ERIC O FEIGL
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6144001
• 关键词: baroreflex; beta adrenergic receptor; carotid sinus; coronary vasodilator; coronary vessels; dogs; exercise; heart conduction system; heart innervation; heart metabolism; hormone regulation /control mechanism; norepinephrine; oxygen consumption; tachycardia; vasodilation

DESCRIPTION: (Adapted from the Investigator's Abstract) This is an application that is intended to address the hypothesis that activation of sympathetic fibers to the heart as well as elevations in circulating catecholamine levels activate beta-receptors that simultaneously result in tachycardia, increases in myocardial contractility and beta-adrenergic vasodilation of the coronary circulation. The applicant postulates that beta-mediated coronary vasodilation is a form of feedforward or parallel control that helps to match coronary blood flow to myocardial metabolism preventing myocardial ischemia during physiological adjustments to flow that occur during adrenergic activation. The central focus of the application is that feedforward beta-dilation combines with the previously demonstrated feedback control mechanisms that, to a large extent, are sensitive to regional myocardial oxygen tension. Under normal circumstances, major increases in myocardial metabolism are secondary to adrenergic beta-receptor-mediated increases in the determinants of oxygen consumption. It is likely that beta-receptor-mediated coronary vasodilation is a significant part of the physiological response to sympathetic activation. The experiments propose to address three Specific Aims. The first will test the hypothesis that there is beta-receptor-mediated coronary vasodilation when oxygen consumption is augmented by epinephrine infusion and determine the dose-response relation for arterial epinephrine that causes coronary beta-vasodilation. These will extend the previous observations of the applicant during the intracoronary norepinephrine infusion. The second Specific Aim will be to test the hypothesis that beta-receptor-mediated coronary vasodilation is an important part of the carotid sinus baro reflex and determine what component of this vasodilation is related to circulating catecholamines released by the adrenal gland as opposed to direct activation of sympathetic nerves and the local release of norepinephrine. The third Specific Aim will be to test the hypothesis that beta-receptor-mediated coronary vasodilation is important in matching flow to myocardial metabolism during graded levels of exercise and define what fraction of this is due to circulating epinephrine as opposed to direct sympathetic activation. Abnormalities in myocardial blood flow in patients with coronary artery disease are a major health problem. The proposed research will investigate the basic physiological mechanisms that control coronary blood flow with beta-receptor-mediated feedforward control. Beta-receptor blocking agents are frequently used to treat patients with angina pectoris with the rationale that limiting adrenergically-mediated increases in heart rate and myocardial contractility restricts oxygen consumption so that the oxygen supply demand ratio will be in better balance. However, not all patients benefit from beta-receptor blockade and the proposed research may clarify this problem since beta-receptor-mediated coronary vasodilation may have a beneficial effect on the oxygen supply-demand ratio that will be prevented by beta-receptor blockade. Furthermore, characterizing the beta-receptor-mediated coronary vasodilation may be the first step to developing agents that selectively inhibit cardiac beta-receptor activation without blocking the vascular beta-receptor dilation.

描述：(改编自《调查者摘要》) 旨在解决以下假设的应用程序： 心脏的交感神经纤维和循环中的升高区 儿茶酚胺水平激活β受体，同时导致 心动过速，心肌收缩能力和β-肾上腺素能增加 冠状动脉循环的血管扩张。申请人假定 β-介导的冠状动脉扩张是前馈或平行的一种形式 有助于将冠脉血流量与心肌代谢相匹配的控制 在生理调节期间预防心肌缺血 发生在肾上腺素能激活期间。应用程序的中心关注点是 前馈的贝塔扩张与之前证明的 反馈控制机制，在很大程度上对 局部心肌氧分压。在正常情况下，少校 心肌代谢增加仅次于肾上腺素能 β受体介导的氧气消耗决定因素的增加。 β受体介导的冠状动脉血管扩张很可能是一种 交感神经激活的生理反应的重要部分。 这些实验提出了三个具体目标。第一个将测试 存在β受体介导的冠状动脉扩张的假说 当肾上腺素输注增加耗氧量时，测定 动脉肾上腺素致冠状动脉病变的剂量-反应关系 β-血管扩张。这些将扩展先前对 在冠脉内注射去甲肾上腺素的过程中申请。第二 具体目的将是检验β受体介导的假说 冠状动脉扩张是颈动脉窦压力反射的重要组成部分。 并确定这种血管扩张的哪种成分与循环有关 肾上腺释放的儿茶酚胺，而不是直接激活 交感神经和局部去甲肾上腺素的释放。第三 具体目的将是检验β受体介导的假说 冠状动脉扩张在使血流与心肌代谢相匹配方面很重要 在分级的锻炼水平期间，并定义这其中的一部分是由于 循环肾上腺素，而不是直接的交感神经激活。 冠状动脉病变患者的心肌血流量异常 疾病是一个主要的健康问题。拟议的研究将调查 血管紧张素转换酶控制冠脉血流的基本生理机制 β受体介导的前馈控制。β受体阻滞剂 常用于治疗心绞痛患者 限制肾上腺素介导的心率增加和 心肌的收缩能力限制了氧气的消耗，因此氧气 供需比将处于更好的平衡状态。然而，并不是所有的患者 从β受体阻断中受益，拟议中的研究可能会澄清 这个问题因为β受体介导的冠状动脉血管扩张可能有 对氧气供需比的有利影响将被阻止 通过β受体阻滞剂。此外，将其描述为 β受体介导的冠状动脉血管扩张可能是 开发选择性抑制心脏β受体激活的药物 而不会阻断血管的β-受体扩张。