ION CHANNEL FUNCTION IN CELLS FROM INFARCTED HEARTS

本报告建议的研究的整体长远目标 应用的目的是识别和理解离子机制 潜在性的跨分子电位的异常 存活于心外膜边界的心外膜下心室细胞 梗塞心脏的区域。有人建议，一个或多个 这些电生理异常可能导致严重的 已知的室性心律失常发生在梗塞后。因此，通过 更清楚地定义和理解这些问题的机制 电生理变化，我们将提供可能导致 这需要有效的治疗干预措施的发展 临床环境。我们将使用分解单一的技术 将这些细胞从心外膜交界区分离出来。 心肌梗死。然后，通过使用各种电生理学 我们可以确定电学的潜在基础的技术 异常现象。对于这项建议，我们重点澄清了 一些已知的离子流的反常现象 正常细胞电生理学(INA、ICI、ICL(Ca)、IK)。此外, 在认识到细胞中正常离子通道的功能障碍后 梗塞的心脏，我们将继续定义这些的敏感性 某些药物的离子通道改变，例如I类 药物、肾上腺素能胺、三类抗心律失常药等。 最后，我们将量化和比较静息cai和振幅。 心外膜交界区弥散分布的细胞中的CaI瞬变 控制单元。我们将特别关注放松的速度。 药物干预期间的一过性脑梗塞(例如，β-肾上腺素能 刺激)和特定的起搏方案。对于这些实验，我们 还将结合全电池电压钳位技术与 用Fura-2荧光显微镜测量CaI瞬变。在……里面 这样我们就可以检验这样一种假设，即正常心脏的变化 功能以及离子通道功能导致或导致 可测量的变化在蔡氏。

The overall long term objectives of the studies proposed in this application are to identify and to understand the ionic mechanisms that underlie the abnormalities in the transmember potentials of the subepicardial ventricular cells that survive in the epicardial border zone of the infarcted heart. It has been suggested that one or more of these electrophysiologic abnormalities may lead to the serious ventricular arrhythmias known to occur after infarction. Therefore, by more clearly defining and understanding the mechanisms for these electrophysiologic changes, we will provide information that may lead to the development of effective therapeutic interventions needed in this clinical setting. We will use the technique of disaggregated single cells to separate these cells from the epicardial border zone of the infarcted myocardium. Then, by using a variety of electrophysiologic techniques we can determine the underlying basis for the electrical abnormalities. For this proposal, we have focused on clarifying the abnormalities of some of the ionic currents known to be integral to normal cell electrophysiology (iNa, iCaL, iCl(Ca), iK). In addition, upon recognition of the dysfunction of a normal ion channel in cells from the infarcted heart, we will proceed in defining the sensitivity of these altered ion channels to certain pharmacologic agents, e.g. Class I agents, adrenergic amines, Class III antiarrhythmic agents, etc. Finally, we will quantitate and compare resting Cai as well as amplitude of Cai transients in cells dispersed from the epicardial border zone with control cells. In particular, we will focus on rates of relaxation of Cai transients during pharmacologic interventions (e.g. beta adrenergic stimulation) and specific pacing protocols. For these experiments, we will also combine whole cell voltage clamp techniques with the measurement of Cai transients using fura-2 fluorescence microscopy. In this way we can test the hypothesis that alterations in normal cardiac function as well as ion channel function result from or result in measured changes in Cai.