The overall long term objectives of the studies proposed in this application are to identify and to understand the ionic mechanisms that underlie the abnormalities in the transmembrane potentials of the subendocardial Purkinje cells that survive in the infarcted heart. It has been suggested that one or more of these electrophysiologic abnormalities may lead to the serious ventricular arrhythmias known to occur after infarction. Therefore, by more clearly defining and understanding the mechanisms for these electrophysiologic changes, we will provide information that may lead to the development of effective therapeutic interventions needed in this clinical setting. We will disaggregate single Purkinje cells from the subendocardium. Then, by using a variety of techniques we can determine the underlying basis for the electrical abnormalities. Transmembrane potential recordings and voltage clamp techniques will be used to identify whether there is a lesion in the availability of the Na+ current in the cells dispersed from the infarcted heart. Patch pipettes will be used to voltage clamp and identify whether there is a lesion in the Ca++ currents, inward rectifying, the delayed rectifier or the transient outward currents in these cells. In addition, in a series of microinjection of compounds that are known to alter action potential repolarization. In parallel, we will determine during voltage clamp protocols of the delayed rectifier and Ca++ currents, whether inclusion of these compounds restores the diseased depressed ionic current(s).
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