EFFECT OF DRUGS ON DEVELOPMENT OF CARDIAC FAILURE

药物对心力衰竭发展的影响

• 批准号: 3335735
• 负责人: ARTHUR L BASSETT
• 金额: $ 17.73万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3335735
• 关键词: antiarrhythmic agent; arrhythmia; cardiotonic agents; cats; cellular pathology; congestive heart failure; electrophysiology; heart contraction; heart disorder chemotherapy; heart failure; heart pharmacology; hypertension; ionophores; myocardium; quinidine; radiotracer; sarcoplasmic reticulum; ventricular hypertrophy; verapamil

Ventricular hypertrophy due to chronic pressure overload is accompanied in experimental animals, by electrophysiolgic dysfunction, and is often associated clinically with progressive heart failure and/or sudden death due to arrhythmias. The basis for the progression form overload to electrical dysfunction and arrhythmias remains unclear. Our laboratory has been studying the relationships between experimental chronic pressure overload and electrophysiological dysfunction in hypertrophied ventricular tissue, including the mechanism of arrhythmias in normal and hypertrophied hearts. The results lead to the suggestion that endocardial cells on the ventricular free wall are the first cardiac cells to be affected by pressure overload, and that consequent chronic differences in regional electrophysiology of the left ventricle, especially action potential duration and refractoriness, underlie serious ischemia-induced electrophysiologic disturbances in the hypertrophied heart. Alteration of cellular K+ currents may be responsible for both action potential prolongation in chronic pressure overload and the enhanced arthythmogenicity during acute ischemia in the hypertrophied ventricle. To examine these hypotheses, three integrated specific aims and sets of experiments are outlined: 1. To characterize electrophysiologic properties of normal and hypertrophied subendocardial and subepicardial cells using preparations of isolated cells, and intact ventricles retaining important cellular architecture; 2. To compare the electrophysiologic responses of isolated and in situ normal and hypertrophied endo- and epicardial cells during acute ischemia; and 3. to determine the mechanisms underlying the changes in action potential duration of hypertrophied myocardium during ischemia and exposure to a prototype antiarrhythmic drug, quinidine. Methodology includes production of renovascular hypertension and conventional microelectrode technology; patch clamping of isolated hypertrophied myocytes is used to determine the role of unitary ATP-sensitive K+ channels in their ischemic response. The use of combined single cell and whole tissue approaches to study electrophysiologic changes will elicit information not obtainable by either technique alone. Collectively, the experiments will distinguish regional mechanisms of electrical dysfunction of the pressure overloaded-hypertrophied heart and provide a mechanistic basis for both understanding the apparent propensity of such hearts for enhanced arrhythmic activity and the pharmacologic management of ischemic arrhythmias.

慢性压力超负荷引起的心室肥大是 伴随着实验动物，通过电生理学 功能障碍，并且通常与临床上进行性 心力衰竭和/或由于心律失常而猝死。 基础 从超负荷发展到电功能障碍， 心律失常仍不清楚。 我们的实验室一直在研究 实验性慢性压力超负荷与 肥厚心室电生理功能障碍 组织，包括心律失常的机制在正常和 肥大的心脏 结果表明， 心室游离壁的内皮细胞是第一个 心脏细胞会受到压力超负荷的影响， 因此，慢性差异的区域电生理的 左心室，尤其是动作电位时程， 顽固性，是严重缺血诱导的基础 肥大心脏的电生理紊乱。 细胞K+电流的改变可能是导致这两种情况的原因 慢性压力超负荷的动作电位延长 急性缺血时增强的致关节炎性 心室肥大 为了验证这些假设，三 综合具体目标和成套实验概述如下：1. 为了表征正常和 肥大的心内膜下和心外膜下细胞， 制备分离的细胞，并保留完整的心室 重要的细胞结构; 2. 比较 电生理反应的孤立和原位正常和 急性缺血期间肥大的心内膜和心外膜细胞;和 3. 以确定行动变化背后的机制， 心肌缺血时肥厚心肌的潜在持续时间， 接触了抗抑郁药奎尼丁的原型 方法学包括产生肾血管性高血压， 传统微电极技术;膜片钳隔离 肥大的心肌细胞被用来确定单一的 ATP敏感性K+通道在缺血反应中的作用 使用 结合单细胞和全组织的方法来研究 电生理变化将引出无法获得的信息 通过单独的技术。 总的来说，这些实验将 区分脑电功能障碍的局部机制 压力超载-肥大心脏，并提供一个机制 这两种理解的基础明显倾向的心 用于增强药物活性和药理学管理 缺血性心律失常