This proposal has a long-term objective of providing a better understanding of the mechanisms of cardiac arrhythmias, particularly in the setting of myocardial ischemia. It is clear that the generation and continuance of arrhythmic activity depends on a nonhomogeneous spatial distribution of cellular properties (e.g. excitability, refractoriness, automaticity) and also of intercellular coupling resistance and the geometrical arrangement of cells and cell bundles. Our experimental design incorporates Parallel studies on intact cardiac tissue (rabbit papillary muscles) and on isolated rabbit ventricular cells and cell pairs. We propose specific hypotheses for how the time-dependent changes in tissue excitability are produced at the cellular level by alterations in the ability of the individual cells to produce a net inward current. Our experimental design focuses on the cellular mechanisms of action of anti-arrhythmic drugs and the cellular mechanisms of postrepolarization refractoriness (a delay in the recovery of excitability after an action potential has completely repolarized). In addition to our experimental design for analysis of propagational phenomena at the cellular level, our experimental design also includes a synthesis of propagational phenomena by the study of a pair of isolated cells electrically coupled to each other by a variable resistance. It has become increasingly clear that the complex electrical phenomena of the heart cannot be explained by the application of concepts of continuous conduction as in nerve axons. The discontinuous conduction normally found in cardiac tissue and the effects of enhanced spatial discontinuities of membrane properties and cell-cell coupling produced by myocardial ischemia demand a new mechanistic framework for analyzing cardiac electrical phenomena. The accomplishment of our specific aims will significantly contribute to the understanding of these electrical phenomena.
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