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(Circulation Research. 1999;84:906-912.)
© 1999 American Heart Association, Inc.

Original Contribution

Calmodulin Kinase Inhibition Prevents Development of the Arrhythmogenic Transient Inward Current

Yuejin Wu, Dan M. Roden, Mark E. Anderson

From the Departments of Medicine (Y.W., D.M.R., M.E.A.) and Pharmacology (D.M.R., M.E.A.), Vanderbilt University, Nashville, Tenn.

Correspondence to Mark Anderson, Vanderbilt University Medical Center, 315 Medical Research Building II, Nashville, TN 37232-6300. E-mail mark.anderson{at}mcmail.vanderbilt.edu

Abstract—Although it is widely accepted that afterdepolarizations initiate arrhythmias when action potentials are prolonged, the underlying mechanisms are unclear. In this study, we tested the hypothesis that action potential prolongation would raise intracellular calcium and thereby activate the arrhythmogenic transient inward current (I_ti). Furthermore, given that I_ti can be activated by sarcoplasmic reticulum Ca²⁺ release, we tested the hypothesis that inhibition of calmodulin (CaM) kinase would prevent I_ti. Isolated rabbit ventricular myocytes were studied with whole-cell–mode voltage clamp. Stimulation with a prolonged action potential clamp, under near-physiological conditions, increased [Ca²⁺]_i. I_ti was reproducibly induced in 60 of 60 cells, but I_ti was not seen with the use of a shorter action potential waveform (n=12). I_ti was associated with a secondary elevation in [Ca²⁺]_i. When [Ca²⁺]_i buffering was enhanced by dialysis with BAPTA (20 mmol/L, n=9), no I_ti was present. The Na⁺/Ca²⁺ exchanger was likely responsible for I_ti, because I_ti was inhibited by the Na⁺/Ca²⁺ exchanger inhibitory peptide XIP (10 µmol/L, n=6), but not by an inactive scrambled peptide (10 µmol/L, n=5) or by the Cl^– current antagonist niflumic acid (10 to 40 µmol/L, n=9). Activator Ca²⁺ from the sarcoplasmic reticulum was essential for development of I_ti, because it was prevented by pretreatment with ryanodine (10 µmol/L, n=6) or thapsigargin (1 µmol/L, n=6). Two different CaM kinase inhibitory peptides (n=16) and a CaM inhibitory peptide (n=4) completely suppressed I_ti. These results are consistent with the hypothesis that CaM kinase plays a role in arrhythmias related to increased [Ca²⁺]_i.

Key Words: calmodulin kinase • sarcoplasmic reticulum • transient inward current • Ca²⁺-activated chloride current • Na⁺/Ca²⁺ exchanger

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