Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?

Objective and methods: In this study, we investigated the effects of a PKA Stimulating cocktail on sodium currents from normal epicardial cells (NZs) and on those from cells dispersed from the epicardial zone of the 5-day infarcted canine heart (IZs). To do so, we used whole-cell voltage-clamp techniques. Results: During superfusion with the PKA activator cocktail, peak sodium current (I-Na) density significantly increased by 32 +/- 5.3% (NZs) and 17 +/- 5.4% (IZs). However, despite this increase, IZ peak I-Na still was not fully restored to NZ values. In both cell types, the density effect was accompanied by a shift in I/I-max curves, as well as a slowing in recovery from inactivation. Inactivation from a closed state was accelerated. Furthermore, in the presence of chloroquine, which is known to interrupt intracellular vesicular traffic, PKA activator effects to augment I-Na were only partially inhibited in NZs but abolished in IZs. To understand whether the phosphorylation status of basal Na+ channels in the two cell groups differed, the effects of okadaic acid and PP2A1 were studied. Results suggest that in IZs, Na+ channels in the basal state are already phosphorylated. Conclusions: PKA stimulation of I-Na of the remodeled IZ does augment current density possibly by augmenting the trafficking of channels to an active site on the membrane. However, the resulting I-Na while partially rescued, is not similar to the potentiated I-Na of NZs. Specific kinetic changes also occur with the PKA stimulation of IZs and results with okadaic acid and PP2A1 suggest that in their remodeled state, Na+ channels in IZs are already phosphorylated. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.