Abstract 930: Feedback Remodeling of Cardiac Potassium Channel Expression: A Novel Mechanism Controlling Repolarization Reserve?
It is well recognized that loss or inhibition of a K+-current causes functionally-based compensatory increases in other K+-currents that minimize changes in action potential (AP) duration (APD), a phenomenon know as repolarization reserve. However, there is no information available regarding the possibility that sustained APD changes caused by K+-channel inhibition may result in remodeling of K+-current expression. This study was designed to assess the possibility that sustained inhibition of one K+-current can lead to modified properties of other ion channels.
Methods: We studied adult canine left ventricular epicardial myocytes incubated in primary culture for 24 hrs in the presence (DOF) or absence (CTL) of the highly selective rapid delayed rectifier current (IKr) blocker dofetilide (5 nM). The myocytes were paced in culture at 1 Hz to produce physiological APs. After 24 hrs, cells were triply-washed to remove any residual dofetilide and submitted to whole-cell voltage-clamp under conditions designed to record the slow delayed rectifier IKs, IKr, transient outward current Ito, inward rectifier current IK1 and L-type Ca2+ current ICaL; or assessed with current clamp to record dofetilide-free APs.
Results: Cells chronically incubated in dofetilide had accelerated repolarization (eg APD90 at 0.1 Hz: 300±20 ms CTL vs 231±13 ms DOF, N=8, 9 cells respectively, P<0.05). IKs showed significant upregulation in DOF cells (Table⇓), with no changes in kinetics or voltage dependence. Other currents were unaltered. Preliminary data indicate no change in mRNA expression for KvLQT1, minK, ERG and MiRP1 (real time RT-PCR) and a non-significant ~17% increase in KvLQT1 protein but a 125% increase in minK protein expression (Western blot, normalized to GAPDH).
Conclusion: Chronic reduction in IKr may lead to compensatory upregulation of IKs, suggesting that repolarization reserve may be governed by feedback control of ion channel expression.