EARLY AFTER DEPOLARIZATIONS--MECHANISM/ROLE OF CALCIUM

这项研究申请提出了机制的研究， 早期后去极化（埃兹）。 埃兹被触发 在动作电位平台附近发生的去极化 电压。 它们被认为会导致某些心律失常 包括尖端扭转型室性心动过速 细胞机制 埃兹未知。 我们建立了一个利用Ca++电流诱导埃兹的模型 激动剂Bay k 8644。 在电压下获得的实验结果 钳位和非电压钳位浦肯野线与此模型 允许我们假设EAD诱导1需要： 1)动作电位平台的延长和平坦 在电压范围内，2）可以从 在“窗口”内失活和重新打开Ca++通道 它们的激活和失活关系的重叠。 这些发现为Ca 通道和“窗口”电流。 这种假设， 电流可以在复极化过程中被激活，构成了一个新的 致瘤机制 该机制应参与 正常的动作电位平台 我们建议继续 研究导致埃兹的细胞机制。 我们将 进一步研究Bay k 8644模型的EAD诱导，我们 将继续测试我们的假设对其他模型， 诱导埃兹。 关于基本机制的新信息 心律失常是可能的，这可能有临床影响， 好. 由于Ca++通道电流是诱导埃兹的核心， 这项研究申请还提出了详细的研究， 分离的浦肯野细胞中的电流。 初始全细胞电压 钳夹实验表明，L型和T型钙通道 电流存在并且可以被分离。 相比 心室细胞，两种类型的Ca++电流仍然很大，即使 在生理Ca. 关于这方面的信息很少。 调节T型电流。 电压和Ca ~（++）在 失活、活化和从失活中恢复将是 研究了 将研究稳态电流。 相互作用 将寻求T型电流和L型电流之间的关系。 相同小区中 在相似的实验条件下， 将研究T型和L型电流。 数据将 在信道模型中解释。 Ca通道的新信息 浦肯野细胞中的电流和促凋亡机制将是 得到了

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.