The long term objective 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 and subepicardial cells that survive in the infarcted heart. It has been suggested that one or more these electrophysiologic abnormalities may lead to or at least contribute to the serious ventricular arrhythmias known to occur after myocardial infarction. Therefore by more closely defining and understanding the mechanisms for these electrophysiologic changes we will provide new 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 and ventricular cells from the epicardial border zone of the infarcted heart at precise times after the coronary artery occlusion (at 24 hours, at 48 hours and at 5 days). We will compare our results using these myocytes with appropriate controls from subendocardium and subepicardium of noninfarcted hearts. We will focus on identifying, characterizing and quantifying the function (or dysfunction) of several K currents (i-K1,i-K, and i-to1), Ca-i dependent outward currents as well as the L type Ca++ currents in the different cell types from the different cell groups. Standard whole cell patch clamp, nystatin-patch and microelectrode techniques will be used to study the chronic changes in macroscopic currents and transmembrane potentials. Additional studies are proposed that will determine and compare the response of specific ionic currents of the cells from the infarcted heart to certain pharmacologic agents. Results from these studies will provide important new information and understanding of the pathelectrophysiology of cells that survive in the infarcted heart as well as provide an important substrate in the infarcted heart where serious ventricular arrhythmias occur. At completion, we will have defined chronic changes that have occurred in ion channel function in cells that survive in the infarcted heart.
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