The determinants of antiarrhythmic drug action at the single channel and single cell levels are the focus of studies in Projects 2, 3, and 4 in this Program. However, some important drug actions cannot be fully understood at the single channel level. For example, impulse propagation in the ventricle is determined not only by Na+ channel availability, but also by the prominent anisotropic properties of the heart. Propagation following a cathodal stimulus does not occur from the physical cathode, but from a larger """"""""virtual cathode"""""""" which has a complex geometry determined by these anisotropic properties. Similarly, the ability to defibrillate the heart can be modulated by antiarrhythmic drugs although the mechanisms are poorly understood. Moreover, the electrical properties of the heart are also influenced by neurohormonal and loading conditions. This Project will test the hypothesis that drug actions in vivo are determined not only by ion channel block but also by the complex multidimensional properties of the cardiac syncytium. These studies will be conducted in isolated perfused hearts thereby eliminating important confounding variables such as autonomic tone or anesthesia. Arrays of closely-spaced electrodes specifically designed to study the direction-dependency of activation and propagation will be used to acquire biologic data which will also be incorporated into increasingly sophisticated computer models of cardiac electrical behavior. Resistivity and transmembrane potential will be measured in vivo using techniques being developed in Core C. The mechanisms underlying the virtual cathode and successful defibrillation, and the relationship between the two, will be probed by ion channel blockers and by interventions through to alter cell-cell coupling. The effects of altered loading on impulse initiation and propagation and of neurohormones on defibrillation will be assessed. The conditions under which drug treatment may produce unidirectional block based on cardiac anisotropy (and hence can result in reentrant arrhythmias) will be determined. This Project will therefore improve our understanding not only of the relationship between the in vitro and in vivo effects of antiarrhythmics, but also of drug actions in the whole heart which may be important for arrhythmia aggravation or suppression.
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