CA2+-MEDIATED MECHANISMS OF ATRIAL PACEMAKER ACTIVITY

描述(改编自申请者的描述)：长远目标 申请者要了解决定和 调节心房起搏器的活动，特别是对潜伏期的心房 起搏器及其对心房功能障碍的贡献。潜伏性心房 起搏器是位于右侧特定区域的特殊细胞 窦房结区域外的中庭。他们被认为参与了一项广泛的 各种房性心律失常，包括缓速综合征、房性心律失常 心动过速、室上性心动过速和房颤。虽然是 主要临床重要性，潜在心房的细胞机制 起搏器的活动还没有被很好地理解。委员会的初步结果 申请人表示，潜在的心房起搏器活动受以下因素调节 局部细胞内钙释放的爆发，即钙火花，从 肌浆网(SR)在舒张期晚期的特异性 去极化。心房舒张期肌浆网钙释放的调控机制 起搏细胞尚不清楚。全细胞(穿孔和破裂补片) 细胞内钙离子浓度((Ca)i)的记录方法和测量 将使用激光扫描共聚焦显微镜来确定 潜伏期心房和窦房结舒张期SR钙释放的机制 从猫右心房分离起搏细胞。以下假设将 被测：1)电压依赖性激活T型钙电流(ICa，T) 在舒张期晚期斜率触发肌浆网钙释放，进而 刺激内向钠/钙交换电流使膜去极化 阈值，2)乙酰胆碱和去甲肾上腺素对舒张期SR钙的调节 由ICA、T触发的释放，从而调节心房起搏器活动，3) 通过升高(Ca)i，心脏糖苷和低细胞外(K)增强这一作用 心房起搏器自律性的正常机制，从而诱发心房 不依赖肌浆网钙超载的心律失常，4)低温 通过抑制舒张期SR钙释放抑制心房起搏器活动 由ICA、T和4)移行心房起搏细胞缺乏舒张期 依赖于时间的电流，因此主要依赖于肌质网钙释放 由ICA，T触发的起搏器机制。预计将会有 从这些研究中获得的结果将提供对 控制正常和异常心房起搏器功能的细胞机制。

DESCRIPTION (adapted from the applicant's description): The long-range goal of the applicant is to understand the physiological mechanisms that determine and regulate atrial pacemaker activity, particularly with respect to latent atrial pacemakers and their contribution to atrial dysfunction. Latent atrial pacemakers are specialized cells localized in specific regions of the right atrium outside of the SA node region. They are thought to participate in a wide variety of atrial arrhythmias including brady-tachy syndrome, atrial tachycardia, supraventricular tachycardia and atrial fibrillation. Although of major clinical importance, the cellular mechanisms underlying latent atrial pacemaker activity are not well understood. Preliminary results by the applicant indicate that latent atrial pacemaker activity is regulated by bursting of local intracellular Ca2+ release, i.e., Ca2+ sparks, from the sarcoplasmic reticulum (SR) specifically during the late phase of diastolic depolarization. The mechanisms governing diastolic release of SR Ca2+ in atrial pacemaker cells is not clear. Whole-cell (perforated & ruptured patch) recording methods and measurements of intracellular Ca2+ concentration ((Ca)i) using laser scanning confocal microscopy will be used to determine the mechanism governing diastolic SR Ca2+ release in latent atrial and SA node pacemaker cells isolated from cat right atrium. The following hypotheses will be tested: 1) voltage-dependent activation of T-type Ca2+ current (ICa,T) during the late diastolic slope triggers SR Ca2+ release which in turn stimulates inward Na/Ca exchange current to depolarize the membrane to threshold, 2) both acetylcholine and norepinephrine regulate diastolic SR Ca2+ release triggered by ICa,T and thereby regulate atrial pacemaker activity, 3) by elevating (Ca)i, cardiac glycosides and low extracellular (K) enhance this normal mechanism of atrial pacemaker automaticity, and thereby elicit atrial dysrhythmias not dependent on Ca2+ overload of the SR, 4) low temperature inhibits atrial pacemaker activity by inhibiting diastolic SR Ca2+ release triggered by ICa,T, and 4) transitional atrial pacemaker cells lack diastolic time-dependent currents and therefore depend primarily on SR Ca2+ release triggered by ICa,T for their pacemaker mechanism. It is expected that the results gained from these studies will provide fundamental insight into the cellular mechanisms governing normal and abnormal atrial pacemaker function.