Copyright © 2005, European Society of Cardiology
Ca2+-dependent reduction of IK1 in rat ventricular cells: A novel paradigm for arrhythmia in heart failure?
INSERM U-637, Physiopathologie Cardiovasculaire; Université Montpellier 1, CHU Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France
* Corresponding author. Tel.: +33 467 41 52 44; fax: +33 467 41 52 42. Email address: srichard{at}montp.inserm.fr
Objectives: We investigated the inward rectifier potassium current (IK1), which can be blocked by intracellular Ca2+, in heart failure (HF).
Methods: We used the whole-cell patch-clamp technique to record IK1 from single rat ventricular myocytes in voltage-clamp conditions. Fluorescence measurements of diastolic Ca2+ were performed with Indo-1 AM. HF was examined 8 weeks after myocardial infarction (coronary artery ligation).
Results: IK1 was reduced and diastolic Ca2+ was increased in HF cells. The reduction of IK1 was attenuated when EGTA was elevated from 0.5 to 10 mM in the patch pipette and prevented with high BAPTA (20 mM). Ryanodine (100 nM) and FK506 (10 µM), both of which promote spontaneous SR Ca2+ release from ryanodine receptor (RyR2) during diastole, reproduced the effect of HF on IK1 in normal cells but had no effect in HF cells. The effects of ryanodine and FK506 were not additive and were prevented by BAPTA. Rapamycin (10 µM), which removes FKBP binding proteins from RyR2 with no effect on calcineurin, mimicked the effect of FK506 on IK1. Cyclosporine A (10 µM), which inhibits calcineurin via cyclophilins, had no effect. In both HF cells and normal cells treated by FK506, the protein kinase C (PKC) inhibitor staurosporine totally restored the inward component of IK1, but only partially restored its outward component at potentials corresponding to the late repolarizing phase of the action potential (–80 to –40 mV).
Conclusions: IK1 is reduced by elevated diastolic Ca2+in HF, which involves in parallel PKC-dependent and PKC-independent mechanisms. This regulation provides a novel paradigm for Ca2+-dependent modulation of membrane potential in HF. Since enhanced RyR2-mediated Ca2+release also reduces IK1, this paradigm might be relevant for arrhythmias related to acquired or inherited RyR2 dysfunction.
KEYWORDS Arrhythmia (mechanisms); Calcium (cellular); Heart failure; K channels; SR (function)
Time for primary review 11 days
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