AUTONOMIC RECEPTOR FUNCTION IN LV HYPERTROPHY & FAILURE

左室肥厚中的自主受体功能

• 批准号: 3074168
• 负责人: Dorothy Eileen Vatner
• 金额: $ 6.68万
• 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 1992-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3074168
• 关键词: adenylate cyclase; autonomic nervous system; beta adrenergic receptor; biochemistry; cellular pathology; chemical structure; dogs; gel electrophoresis; guanosine diphosphate; heart failure; isoelectric point; muscarinic receptor; 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) decreases in muscarinic receptor density in left ventricular failure, 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 receptor and two dimensional electrophoresis to identify the molecular weight and isoelectric point of the beta-adrenergic receptor in the left 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 hypertension, 2) the progression of changes in high affinity beta-adrenergic and muscarinic agonist binding, muscarinic density and modulation of adenylate cyclase activity and function as left ventricular hypertrophy progresses from mild to severe left ventricular hypertrophy, 3) changes in 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 level, 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， 左心室衰竭，和4）减少毒蕈碱抑制 腺苷酸环化酶活性在左心室衰竭中的作用 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- β-肾上腺素能受体光亲和标记蛋白 和双向电泳来鉴定分子 β-肾上腺素能受体的重量和等电点 左室肥厚动物的左室 和失败，2）检查鸟嘌呤核苷酸调节蛋白 左心室肥大和衰竭的功能。 第二 此应用程序的目标是定义时间进程和通用性 的缺陷。 这将通过检查1）另一个 左心室肥大模型，即肾性高血压，2） 高亲和力β-肾上腺素能和 毒蕈碱激动剂结合，毒蕈碱密度和调节 腺苷酸环化酶活性和左心室功能 左心室肥厚从轻度发展到重度 肥大，3）肾上腺素能受体的变化，在正常，左 心室肥大和衰竭，4）α- 肾上腺素能受体 本申请的第三个目标是 确定心肌缺损的选择性， 使用纯化的肌膜制剂，最后研究 分离的肌细胞以去除大部分非肌细胞组织 在制备膜之前。 建议这些研究 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，即，左 心室肥大和心力衰竭。