FEEDFORWARD CONTROL OF CORONARY BLOOD FLOW

冠状动脉血流的前馈控制

• 批准号: 2519346
• 负责人: ERIC O FEIGL
• 金额: $ 17.74万
• 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 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519346
• 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：（改编自研究者摘要）这是一个 该应用程序旨在解决以下假设： 交感神经纤维的心脏以及升高的循环 儿茶酚胺水平激活β受体，同时导致 心动过速，心肌收缩力和β-肾上腺素能增加 冠状循环的血管扩张。 申请人假定， β-介导的冠状血管舒张是一种前馈或平行的形式， 有助于使冠状动脉血流与心肌代谢相匹配的控制 在对血流进行生理调节期间防止心肌缺血， 发生在肾上腺素能激活期间。 该应用程序的中心焦点是 前馈β扩张结合了之前证明的 反馈控制机制，在很大程度上， 局部心肌氧分压 在正常情况下，少校 心肌代谢增加继发于肾上腺素能 β受体介导的氧消耗决定因素的增加。 β受体介导的冠状动脉血管舒张可能是一种 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受体介导的冠状血管舒张的假设 当通过肾上腺素输注增加耗氧量时， 动脉肾上腺素引起冠状动脉粥样硬化的剂量-反应关系 β-血管舒张。 这将扩展以前的观察， 申请人在冠状动脉内输注去甲肾上腺素期间。 第二 具体目的是检验β受体介导的 冠状血管舒张是颈动脉窦压力反射的重要组成部分 并确定这种血管舒张的哪些成分与循环有关， 肾上腺释放的儿茶酚胺，而不是直接激活 交感神经和去甲肾上腺素的局部释放。 第三 具体目的是检验β受体介导的 冠状动脉血管舒张在使血流与心肌代谢相匹配方面是重要的 在分级的运动水平，并确定这是由于什么分数， 循环肾上腺素而不是直接交感神经激活。 冠状动脉病变患者心肌血流异常 疾病是主要的健康问题。 拟议的研究将调查 控制冠状动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， 限制肾上腺素能介导的心率增加和 心肌收缩力限制氧气消耗，使氧气 供求比例将更好地平衡。 然而，并非所有患者 从β受体阻滞剂中受益，拟议的研究可能会澄清 由于β受体介导的冠状血管舒张可能具有 对氧气供需比的有益影响， 通过阻断β受体 此外，表征 β受体介导的冠状血管舒张可能是第一步， 开发选择性抑制心脏β-受体激活的药物 而不会阻碍血管β受体的扩张