© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?
aDepartment of Pharmacology, Columbia University, New York, NY, United States
bCenter for Molecular Therapeutics, Columbia University, New York, NY, United States
* Corresponding author. Department of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th ST., New York, NY 10032, United States. Tel.: +1 212 305 7907; fax: +1 212 305 0529. Email address: pab4{at}columbia.edu
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 (INa) density significantly increased by 32±5.3% (NZs) and 17±5.4% (IZs). However, despite this increase, IZ peak INa still was not fully restored to NZ values. In both cell types, the density effect was accompanied by a shift in I/Imax 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 INa 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 INa 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 INa, while partially rescued, is not similar to the potentiated INa 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.
KEYWORDS Myocardial infarction; Ion channels; Remodeling; Arrhythmias
Time for primary review 25 days
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