The cardiac action potential is initiated and propagated because of nonlinear voltage and time dependent membrane conductances. However, the frequency of initiation and rate of propagation are strongly influenced by the complex structure of cardiac tissue. The structure is therefore an importance physiological parameter. The structure also has important experimental consequences, since conventional voltage clamp studies are difficult to interpret in the presence of structural complixities, hence we have a limited knowledge of the membrane conductances responsible for the action potential. We propose to study plateau and pacemaker conductances, and the relationships between the membrane conductances and tissue currents that determine frequency and propagation of action potentials. We plan to use a new technique, one which is relatively insensitive to the problems of voltage clamp studies, and one which directly measures interactions of membrane currents with geometry. We will perform small signal linear impedance studies on preparations under voltage clamp and following pharamacological interventions. We will complement these studies with conventional voltage clamp experiments and try to extract the most reliable information from each technique. We believe that by combining these techniques, we can better identify membrane related conductances; moreover, the total tissue current, which represents interactions of membrane conductance, capacitance and series resistance, is by definition the impedance of the preparation. Hence we believe the physiological significance of the structure of different regions of the heart can be illucidated by these techniques. One of the effects of structure is to cause accumulation/depletion of ions in small isolated compartments. We will study these effects, both theoretically and experimentally, and try to derive the effect of these phenomena on the frequency of action potentials, cell to cell coupling and propagation. All of these results will be integrated through computer simulations of the electrical behavior of heart muscle under voltage clamp conditions, during nonpropagated action potentials and during propagated action potentials.
