CELLULAR ELECTROPHYSIOLOGY OF REPOLARIZATION

细胞复极化电生理学

• 批准号: 6322738
• 负责人: KENNETH W SPITZER
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6322738
• 关键词: action potentials; calcium flux; calcium indicator; cardiac myocytes; cell cell interaction; dogs; fluorescent dye /probe; gap junctions; guinea pigs; heart electrical activity; hormone analog; ion transport; laboratory rabbit; membrane potentials; myocardial infarction; neuromuscular transmission; sarcoplasmic reticulum; sodium ion; thyroid hormones; voltage /patch clamp

The overall objective of this project is to obtain new insight concerning the cellular aspects of ventricular repolarization and their relationship to intracellular Ca2_ regulation and electronic interactions. Studies will be performed on left ventricular myocytes from both normal and disease hearts. Project 3 contains three subprojects. Subproject 3.1 focuses on repolarization abnormalities in myocytes surviving chronic myocardial infarction (post-MI myocytes). The experiments are designed to determine the ionic basis of post-MI-induced changes in repolarization and their reversal by the thyroid hormone analogue, DITPA. The central hypothesis is that repolarization abnormalities and their recovery are mediated by changes in I/Kp Ca2+ uptake by the sarcoplasmic reticulum (SR), I/Ca and I/NaCa. Voltage clamping and fluorescence measurements of intracellular Ca2+ (Ca/i) (confocal and conventional epifluorescence) will be used to test this hypothesis. Subject 3.2 focuses on the relationship between Ca+ influx and triggered Ca2+ release from SR. The central hypotheses is that conditions which promote Na+ entry, as occur in one inherited form of the long QT syndrome, will increase the gain of excitation-contradiction coupling and thus promote Cai-induced arrhythmias. Voltage clamp and fluorescence techniques will be used to test this hypothesis in myocytes exposed to anthopleurin-A which prolongs I/Na inactivation. Subproject 3.3 focuses on the relationship between intercellular communication and repolarization. The central hypothesis is that cell-cell electrical coupling during repolarization modulation action potential propagation and the formation of early after-depolarizations. This hypothesis will be tested with an electronic circuit which enables us to electrically connect physically separate myocytes with a variable resistance and thus simulate in vitro change in gap functional resistance.

该项目的总体目标是获得有关心室复极的细胞方面及其与细胞内 Ca2+ 调节和电子相互作用的关系的新见解。将对正常心脏和患病心脏的左心室肌细胞进行研究。项目3包含三个子项目。子项目 3.1 重点关注慢性心肌梗死后存活的肌细胞（MI 后肌细胞）的复极异常。这些实验旨在确定心肌梗死后诱导的复极变化的离子基础及其通过甲状腺激素类似物 DITPA 的逆转。核心假设是复极异常及其恢复是由肌浆网 (SR)、I/Ca 和 I/NaCa 摄取 I/Kp Ca2+ 的变化介导的。将使用电压钳和细胞内 Ca2+ (Ca/i) 的荧光测量（共焦和传统落射荧光）来检验这一假设。主题 3.2 重点关注 Ca+ 流入与 SR 触发的 Ca2+ 释放之间的关系。中心假设是，促进 Na+ 进入的条件（如长 QT 综合征的一种遗传形式）将增加兴奋-矛盾耦合的增益，从而促进 Cai 诱发的心律失常。电压钳和荧光技术将用于在暴露于 anthopleurin-A 的心肌细胞中测试这一假设，这会延长 I/Na 失活时间。子项目 3.3 重点研究细胞间通讯和复极化之间的关系。中心假设是复极调节动作电位传播期间细胞间的电耦合和早期后去极化的形成。这一假设将用电子电路进行测试，该电路使我们能够以可变电阻电连接物理上分离的肌细胞，从而模拟间隙功能电阻的体外变化。