ROLE OF ADENOSINE ON CARDIAC CONDUCTION AND ARRHYTHMIAS

我们已经证明，腺苷具有重要的电生理效应。 这可能会影响一些心脏疾病的发生和治疗 心律失常，尤指在缺氧或缺血时观察到的心律失常。这 这项提案代表了我们继续努力了解 腺苷的心脏效应及其作为心脏冲动调节剂的作用 产生和传导。本研究旨在：1) 具体解决负向动力效应的几个重要方面 腺苷的作用，2)定义腺苷如何以及在多大程度上作为一种 缺氧缺血时房室传导障碍的介体，3) 确定腺苷如何抑制已知干预措施的心脏活动 修饰细胞环磷酸腺苷(CAMP)和4)确定 腺苷开启触发了自律性。 我们的方法是多学科的(基础和临床研究)，我们将 使用多个水平的实验，即单个心肌细胞， 隔离的房室结准备，隔离的心脏，和人类。通过使用 我们将识别各种电生理和形态技术 AV节点中的不同区域和小区类型，并确定 腺苷作用的准确位置。孤立性细胞和小房室结 制备(1mm2)是建议的电压钳位和动态电压的理想选择 研究；这些研究将使离子电流的分析和精确 腺苷作用动力学的测定。CAMP的作用 在介导腺苷对触发的自律性和 对介导这一作用的腺苷受体的表征将 通过测量细胞cAMP和使用 药理探头。内源性腺苷在静脉曲张中的重要性 与缺氧和缺血相关的传导障碍将是 用腺苷作用的药理调节剂进行检查。在……里面 此外，还将测量组织和血浆中的腺苷水平。作为一名 动物实验的直接延伸，一系列临床研究 目的是确定：1)腺苷的电生理效应 人心肌，2)腺苷对心房和心室的作用 快速性心律失常；3)腺苷在缺血性室性心动过速中的可能作用 阻止。这种多学科、多层次的方法应该提供 腺苷心脏活动的综合图像以及 有助于更好地了解病因、诊断和 相关某些传导节律紊乱的可能治疗 伴有心肌缺氧和缺血。

We have shown that adenosine has important electrophysiological effects that may impact on the genesis and therapy of a number of cardiac arrhythmias, particularly those observed during hypoxia or ischemia. This proposal represents an expansion of our continued effort to understand the cardiac effects of adenosine and its role as modulator of cardiac impulse generation and conduction. The present study has been designed to: 1) address specifically several important facets of -the negative dromotropic effect of adenosine, 2) define how, and to what extent, adenosine acts as a mediator of AV conduction disturbances during hypoxia and ischemia, 3) determine how adenosine inhibits the cardiac actions of interventions known to modify cellular cyclic AMP (cAMP) and 4) determine the effects of adenosine on triggered automaticity. Our approach is multidisciplinary (basic and clinical studies) and we will use multiple levels of experimentation, i.e., single cardiac cells, isolated AV node preparations, isolated hearts, and humans. By use of various electrophysiological and morphological techniques we will identify the different regions and cell types in the AV node and determine the precise site of adenosine action. The isolated cells and the small AV node preparation (1 mm2) are ideal for the proposed voltage clamp and kinetic studies; these studies will permit analysis of ionic currents and precise determination of the kinetics of the action of adenosine. The role of cAMP in mediating the adenosine effect on triggered automaticity and characterization of the adenosine receptor that mediates this action will be determined by measurement of cellular cAMP and the use of pharmacological probes. The importance of endogenous adenosine in AV conduction disturbances associated with hypoxia and ischemia will be examined with pharmacological modulators of the action of adenosine. In addition, tissue and plasma levels of adenosine will be measured. As a direct extension of the animal experiments, a series of clinical studies aimed at determining: 1) the electrophysiological effects of adenosine in the human myocardium, 2) the effect of adenosine in atrial and ventricular tachyarrhythmias, and 3) the possible role of adenosine in ischemic AV block. This multidisciplinary and multi-level approach should provide an integrated picture of the cardiac actions of adenosine as well as contribute to a better understanding of the etiology, diagnosis, and possible treatment of certain conduction rhythm disturbances associated with myocardial hypoxia and ischemia.