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 transmember potentials of the subepicardial ventricular cells that survive in the epicardial border zone of 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 use the technique of disaggregated single cells to separate these cells from the epicardial border zone of the infarcted myocardium. Then, by using a variety of electrophysiologic techniques we can determine the underlying basis for the electrical abnormalities. For this proposal, we have focused on clarifying the abnormalities of some of the ionic currents known to be integral to normal cell electrophysiology (iNa, iCaL, iCl(Ca), iK). In addition, upon recognition of the dysfunction of a normal ion channel in cells from the infarcted heart, we will proceed in defining the sensitivity of these altered ion channels to certain pharmacologic agents, e.g. Class I agents, adrenergic amines, Class III antiarrhythmic agents, etc. Finally, we will quantitate and compare resting Cai as well as amplitude of Cai transients in cells dispersed from the epicardial border zone with control cells. In particular, we will focus on rates of relaxation of Cai transients during pharmacologic interventions (e.g. beta adrenergic stimulation) and specific pacing protocols. For these experiments, we will also combine whole cell voltage clamp techniques with the measurement of Cai transients using fura-2 fluorescence microscopy. In this way we can test the hypothesis that alterations in normal cardiac function as well as ion channel function result from or result in measured changes in Cai.
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