Early afterdepolarizations (EAD) caused by L-type Ca²⁺ current (I_Ca,L) are thought to initiate long Q-T arrhythmias, but the role of intracellular Ca²⁺ in these arrhythmias is controversial. Rabbit ventricular myocytes were stimulated with a prolonged EAD-containing action potential-clamp waveform to investigate the role of Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase) in I_Ca,L during repolarization. I_Ca,L was initially augmented, and augmentation was dependent on Ca²⁺ from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. I_Ca,L augmentation was also dependent on CaM kinase, because it was prevented by dialysis with the inhibitor peptide AC3-I and reconstituted by exogenous constitutively active CaM kinase when Ba²⁺ was substituted for bath Ca²⁺. Ultrastructural studies confirmed that endogenous CaM kinase, L-type Ca²⁺ channels, and ryanodine receptors colocalized near T tubules. EAD induction was significantly reduced in current-clamped cells dialyzed with AC3-I (4/15) compared with cells dialyzed with an inactive control peptide (11/15, P = 0.013). These findings support the hypothesis that EADs are facilitated by CaM kinase.

arrhythmia; calcium channels; action potential; long Q-T syndrome; sarcoplasmic reticulum

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