AUTONOMIC RECEPTOR FUNCTION IN LV HYPERTROPHY & FAILURE

左室肥厚中的自主受体功能

• 批准号: 3353036
• 负责人: Dorothy Eileen Vatner
• 金额: $ 7.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3353036
• 关键词: adenylate cyclase; autonomic nervous system; beta adrenergic receptor; cellular pathology; dogs; gel electrophoresis; guanosine diphosphate; heart failure; isoelectric point; muscarinic receptor; protein structure function; renal hypertension; sarcolemma; ventricular hypertrophy

The principal investigator and her colleagues have identified several alterations in beta-adrenergic and muscarinic receptor function and adenylate cyclase activity in left ventricular hypertrophy and failure. These include: 1) decreases in the beta- adrenergic receptor high affinity agonist binding sites in left ventricular failure, 2) decrease in muscarinic receptor density in left ventricular failures, 3) decreased adenylate cyclase activity in left ventricular failure, and 4) decreased muscarinic inhibition of adenylate cyclase activity in left ventricular failure. The first goal of this application is to delineate the biochemical mechanisms underlying these alterations. This will be accomplished by 1) identifying a potentially altered receptor- protein by photoaffinity labelling of the beta-adrenergic receoptor and two dimensional electrophoresis to identify the molecular weight and isoelectric point of the beta-adrenergic receoptor in theleft ventricular of animals with left ventricular hypertrophy and failure, 2) to examine guanine nucleotide regulatory protein function in left ventricular hypertrophy and failure. The second goal of this application is to define the time course and generality of the defects. This will be accomplished by examining 1) another model of left ventricular hypertrophy, i.e. renal hyeprtension, 2) the progression of changes in high affinity beta-adrenergic and muscarinic agonist binding, muscarinic density and modulation of adenylate cyclase activity and functions as left hypertrophy progresses from mild to severe left ventricular hypertrophy, 3) changes in beta2-adrenergic receptors in normal, left ventricular hypertrophy, and failure, 4) changes in alpha-adrenergic receptors. The third goal of the present application is to determine the selectivity of defects for cardiac muscle by using a purified sarcolemma preparation and finally the study of isolated myocytes to remove most of the non- myocyte tissue before preparing membranes. It is proposed that these studies will enhance our understanding at the cellular levle, of one of the most important problems in clinical cardiology, i.e., left ventricular hypertrophy and heart failure.

首席研究员和她的同事已经确认 β-肾上腺素能和毒蕈碱受体的几种改变 左室功能和腺苷酸环化酶活性 肥大和衰竭。 其中包括：（1）降低beta- 肾上腺素能受体高亲和力激动剂结合位点 心室衰竭，2）毒蕈碱受体密度降低， 左心室衰竭，3）腺苷酸环化酶活性降低 在左心室衰竭，和4）减少毒蕈碱抑制 腺苷酸环化酶活性的变化。 第一 本申请的目的是描绘生物化学 这些变化背后的机制。 这将是 通过1）鉴定潜在改变的受体来实现- 通过β-肾上腺素能的光亲和标记的蛋白质 受体和双向电泳，以确定 β-肾上腺素能受体的分子量和等电点 左心室肌受体 肥大和衰竭，2）检查鸟嘌呤核苷酸 调节蛋白在左心室肥厚中的作用， 失败 此应用程序的第二个目标是定义时间 缺陷的过程和一般性。 这将是完成 通过检查1）另一种左心室肥大模型， 即肾性高血压，2）高血压变化的进展 亲和力β-肾上腺素能和毒蕈碱激动剂结合， 毒蕈碱密度和腺苷酸环化酶活性的调节 随着左心室肥大从轻度发展到重度 左心室肥大，3）β 2-肾上腺素能 正常、左心室肥大和衰竭中的受体，4） α-肾上腺素能受体的变化。 第三个目标 本申请的目的是确定缺陷的选择性， 通过使用纯化的肌膜制剂制备心肌， 最后，研究分离的肌细胞，以去除大部分非- 在制备膜之前，先将肌细胞组织切片。 拟将 这些研究将增强我们在细胞水平上的理解， 临床心脏病学中最重要的问题之一，即， 左心室肥大和心力衰竭。