CA2+-MEDIATED MECHANISMS OF ATRIAL PACEMAKER ACTIVITY

CA2 介导的心房起搏器活动机制

• 批准号: 6390554
• 负责人: STEPHEN Lloyd LIPSIUS
• 金额: $ 29.79万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390554
• 关键词: acetylcholine; calcium channel; calcium flux; cardiac glycosides; cats; cold temperature; heart electrical activity; heart pacemaker tissue; norepinephrine; potassium ion; sarcoplasmic reticulum; tissue /cell culture; voltage /patch clamp

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.

描述（改编自申请人的描述）：的长期目标