Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current

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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).

Original languageEnglish (US)
Pages (from-to)906-912
Number of pages7
JournalCirculation research
Issue number8
StatePublished - Apr 30 1999
Externally publishedYes


  • Ca-activated chloride current
  • Calmodulin kinase
  • Na/Ca exchanger
  • Sarcoplasmic reticulum
  • Transient inward current

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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