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 这可能会影响许多心脏病的发生和治疗， 心律失常，特别是在缺氧或缺血期间观察到的心律失常。 这 这项建议代表着我们继续努力了解 腺苷的心脏效应及其作为心脏冲动调节剂的作用 生成和传导。 本研究旨在：1） 具体解决几个重要方面-负传导性 腺苷的影响，2）定义如何，以及在何种程度上，腺苷作为一个 缺氧和缺血期间AV传导障碍的介质，3） 确定腺苷如何抑制已知干预的心脏作用 修饰细胞环腺苷酸（cAMP）和4）确定的影响 腺苷对触发自律性的影响。 我们的方法是多学科的（基础和临床研究），我们将 使用多层次的实验，即，单个心脏细胞， 分离的AV结制备物、分离的心脏和人。 通过使用 各种电生理和形态学技术，我们将确定 房室结中的不同区域和细胞类型，并确定 腺苷作用的精确位点。 孤立的细胞和小房室结 制备（1平方毫米）是理想的建议电压钳和动力学 研究;这些研究将允许分析离子电流和精确的 腺苷作用动力学的测定。 cAMP的作用 在介导腺苷对触发自律性的作用中， 介导该作用的腺苷受体的表征将 通过测量细胞cAMP和使用 药理学探针 内源性腺苷在房室结中的重要性 与缺氧和缺血相关的传导障碍将是 用腺苷作用的药理学调节剂检查。 在 此外，将测量腺苷的组织和血浆水平。 作为 直接延伸的动物实验，一系列的临床研究 目的是确定：1）腺苷在脑内的电生理作用， 2）腺苷对心房和心室肌细胞的作用 快速性心律失常，3）腺苷在缺血性AV中的可能作用 块 这种多学科和多层次的办法应提供一个 腺苷的心脏作用的综合图片以及 有助于更好地了解病因，诊断， 某些传导节律紊乱的可能治疗 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.