CA2+-MEDIATED MECHANISMS OF ATRIAL PACEMAKER ACTIVITY

描述（根据申请人的描述改编）： 申请人要了解决定和 调节心房起搏器活动，特别是关于潜伏性心房起搏器活动， 起搏器及其对心房功能障碍的作用。潜伏心房 起搏器是位于右心室特定区域的特化细胞 窦房结区域外的心房。他们被认为参与了广泛的 各种房性心律失常，包括心动过缓-心动过速综合征、房性 心动过速、室上性心动过速和心房颤动。虽然， 主要临床意义，潜在的心房肌细胞机制， 起搏器的活动还不太清楚。初步结果， 申请人指出，潜在的心房起搏器活动由以下因素调节： 局部细胞内Ca 2+释放的爆发，即，Ca 2+火花，从 肌浆网（SR），特别是在舒张晚期 去极化舒张期心房肌SR Ca ~（2+）释放的机制 起搏细胞尚不清楚。全细胞（穿孔和破裂贴片） 细胞内Ca ~（2+）浓度（（Ca）i）的记录方法和测量 使用激光扫描共聚焦显微镜将用于确定 潜伏性心房和窦房结舒张期SR Ca ~（2+）释放的机制 从猫右心房分离起搏细胞。以下假设将 待测：1）电压依赖性激活T型钙电流（伊卡，T） 在舒张晚期斜率期间触发SR Ca 2+释放， 刺激内向Na/Ca交换电流，使膜脱钙， 乙酰胆碱和去甲肾上腺素均调节舒张期SR Ca ~（2+） 由伊卡，T触发释放，从而调节心房起搏器活动，3） 通过升高（Ca）i，强心苷和低细胞外（K）， 心房起搏器自律性的正常机制，从而引起心房 心律失常不依赖于SR的Ca 2+超载，4）低温 通过抑制舒张期SR Ca 2+释放抑制心房起搏活性 由伊卡、T触发，以及4）过渡性心房起搏细胞缺乏舒张功能 时间依赖性电流，因此主要取决于SR Ca 2+释放 由伊卡，T触发的起搏机制。预计该 从这些研究中获得的结果将提供基本的见解， 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.