EARLY AFTER DEPOLARIZATIONS--MECHANISM/ROLE OF CALCIUM

这项研究申请提出了对以下机制的研究 早期后除极(EADS)是其基础。EAD被触发 发生在动作电位平台区附近的去极化 电压。它们被认为会导致某些心律失常。 包括“尖端扭力”。的细胞机制 EAD是未知的。 我们已经开发了一种利用钙电流诱发EADS的模型 激动者湾K 8644。在电压中获得的实验结果 带有该型号的夹持式和无电压夹持式浦肯野绞线 允许我们假设EAD归纳1需要： 1)动作电位平台延长和平坦化 在电压范围内，2)可以从以下位置恢复 “窗”内钙离子通道的失活和重新开放 它们的激活和失活关系的重叠。 这些发现为了解案例的角色提供了潜在的新见解 通道和“窗口”电流。这一假设，即向内 电流可以在复极过程中被激活，构成新的 心律失常的发生机制。这一机制应该参与 正常动作电位平台期。我们建议继续 研究导致EADS的细胞机制。我们会 进一步研究用于EAD诱导的Bay k 8644模型和我们 将继续用其他模型来检验我们的假设 诱发EADS。关于基本机制的新信息 心律失常很可能发生，这可能会对临床产生影响，因为 井。 因为钙离子通道电流是诱发EADS的中心， 本研究申请还提出了对案例的详细研究 孤立浦肯野细胞中的电流。初始全电池电压 钳制实验表明，L和T型钙通道 电流是存在的，并且可以分开。与之形成鲜明对比的是 心室细胞，两种类型的钙电流均保持较大 在生理性钙。关于这一点的信息很少 T型电流的调节。电压和Ca~(++)在细胞周期中的作用 停用、激活和从停用中恢复将是 学习。我们将研究稳态电流。互动 将在T型和L型洋流之间寻找。在同一个单元格中 在相似的实验条件下，代谢调节 对T型和L型电流的影响进行了研究。数据将是 在渠道模型中进行解释。关于钙通道的新信息 浦肯野细胞的电流和心律失常发生机制将是 获得。

This research application proposes studies of the mechanisms that underlie early afterdepolarizations (EADs). EADs are triggered depolarizations that occur near action potential plateau voltages. They are thought to cause certain cardiac arrhythmias including "torsades de pointes". The cellular mechanisms for EADs are unknown. We have developed a model to induce EADs using the Ca++ current agonist Bay k 8644. Experimental results obtained in voltage clamped and non-voltage clamped Purkinje strands with this model have permitted us to hypothesize that EAD induction 1 requires: 1) Lengthening and flattening of the action potential plateau within a voltage range where, 2) there can occur recovery from inactivation and reopening of Ca++ channels within the "window" of overlap of their activation and inactivation relationships. These findings provide potentially new insights into roles for Ca channels and "window" currents. This hypothesis, whereby inward current can be activated during repolarization, constitutes a new arrhythmogenic mechanism. This mechanism should participate in the normal action potential plateau. We propose to continue to study the cellular mechanisms that cause EADs. We will investigate further the Bay k 8644 model for EAD induction and we will continue to test our hypotheses against other models that induce EADs. New information about fundamental mechanisms for arrhytmogenesis is likely and this may have clinical impact as well. Because Ca++ channel current is central to the induction of EADs, this research application also proposes detailed studies of Ca currents in isolated Purkinje cells. Initial whole-cell voltage clamp experiments have shown that L- and T-type Ca channel current are present and can be separated. In contrast to ventricular cells, both types of Ca++ current remain large even at physiological Ca. Little information exists about the regulation of T-type current. The roles of voltage and Ca++ in inactivation, activation, and recovery from inactivation will be studied. Steady-state currents will be studied. Interactions between T- and L-type currents will be sought. In the same cell under similar experimental conditions, the metabolic regulation of T- and L-type currents will be investigated. Data will be interpreted in channel models. New information about Ca channel currents and arrhythmogenic mechanisms in Purkinje cells will be obtained.