CONTROL OF METABOLISM BY NO IN THE FAILING HEART

在衰竭心脏中通过“NO”控制新陈代谢

• 批准号: 6351566
• 负责人: FABIO A RECCHIA
• 金额: $ 31.42万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-04 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351566
• 关键词: aerobiosis; carbohydrate metabolism; cardiovascular agents; dogs; enzyme inhibitors; fatty acid metabolism; free fatty acids; heart failure; heart metabolism; nitric oxide; nitric oxide synthase; oxygen consumption; paracrine; radiotracer; vascular endothelium

A role for NO in the control of cardiac metabolism is receiving support from an increasing number of studies. We recently found that the acute blockade of NO synthase (NOS) in normal dogs and the fall in NO production during pacing induced heart failure are both associated with a switch from free fatty acids (FFA) to carbohydrate utilization by the heart. The mechanisms underlying these phenomena are unknown. This research proposal will determine the role of NO in the control of cardiac substrate utilization and whether this role is lost during heart failure. The first specific aim is to determine whether NO controls cardiac FFA and carbohydrate metabolism. The rate of FFA and carbohydrate oxidation in the heart, before and after NOS blockade, will be measured in conscious dogs by infusing isotope-labeled FFA, glucose and lactate. Labeled substrate accumulation and the activity of key enzymes for carbohydrate and FFA oxidation will be measured in cardiac biopsies freeze-clamped at the end of the in vivo experiment. The rapid freezing of the tissue will preserve the activation state of enzymes from in vivo to in vitro. The second specific aim is to determine whether the myocardial metabolic and biochemical alterations occurring during heart failure are similar to those found after NOS blockade in normal hearts and if they can be reversed by a NO-releasing agent. The same methods in vivo and in vitro will be employed. Heart failure will be induced in dogs by chronic pacing. The third specific aim is to determine whether acute alterations of arterial substrate concentration can affect cardiac oxygen consumption during heart failure and if this effect can be reversed by NO-releasing agents. Our preliminary data indicate that FFA consumption can cause increased in cardiac O2 consumption unrelated to hemodynamic changes, but only when NO is absent. These studies will elucidate the role of NO in the pathophysiology of heart failure. This will also provide a new pharmacological mechanism of NO-donors in the treatment of heart failure. based on direct control by these agents on cardiac metabolism.

NO 在控制心脏代谢中的作用正在得到越来越多研究的支持。我们最近发现，正常狗中一氧化氮合酶（NOS）的急性阻断以及起搏引起的心力衰竭期间一氧化氮生成的下降都与心脏从游离脂肪酸（FFA）利用碳水化合物的转变有关。这些现象背后的机制尚不清楚。这项研究计划将确定一氧化氮在控制心脏底物利用中的作用以及这种作用是否在心力衰竭期间丧失。第一个具体目标是确定 NO 是否控制心脏 FFA 和碳水化合物代谢。通过向清醒的狗输注同位素标记的 FFA、葡萄糖和乳酸，测量 NOS 阻断前后心脏中 FFA 和碳水化合物氧化的速率。标记的底物积累以及碳水化合物和 FFA 氧化的关键酶的活性将在体内实验结束时通过冷冻钳制的心脏活检进行测量。组织的快速冷冻将保留酶从体内到体外的激活状态。第二个具体目标是确定心力衰竭期间发生的心肌代谢和生化改变是否与正常心脏中 NOS 阻断后发现的相似，以及是否可以通过 NO 释放剂逆转。将采用相同的体内和体外方法。慢性起搏会引起狗的心力衰竭。第三个具体目标是确定动脉底物浓度的急性变化是否会影响心力衰竭期间的心脏耗氧量，以及这种影响是否可以通过NO释放剂逆转。我们的初步数据表明，FFA 消耗可导致心脏 O2 消耗增加，与血流动力学变化无关，但仅限于 NO 不存在时。这些研究将阐明 NO 在心力衰竭病理生理学中的作用。这也将为NO供体治疗心力衰竭提供新的药理机制。基于这些药物对心脏代谢的直接控制。