Frequency-dependent acceleration of relaxation in the heart depends on CamKII, but not phospholamban

Jaime DeSantiago, Lars S. Maier, Donald M Bers

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


Frequency-dependent acceleration of relaxation (FDAR) is an intrinsic physiological mechanism, which allows more rapid ventricular diastolic filling at higher heart rates. FDAR is also observed in isolated myocardial trabeculae and cardiac myocytes, but its mechanism is still poorly understood. We tested the hypothesis that FDAR results mainly from Ca/calmodulin-dependent protein kinase II (CaMKII) dependent stimulation of sarcoplasmic reticulum (SR) Ca transport, but does not require phospholamban. Experiments were performed at 23 or 35°C in isolated ventricular muscle and single myocytes from wild-type (WT) and phospholamban knockout (PLB-KO) mice and rat ventricular myocytes. Isometric twitch force of muscles and unloaded shortening and Ca transients in myocytes were measured ([Ca]o = 1 mM) in the absence and presence of CaMKII inhibitors (1 μM KN-93 or 20 μM autocamtide-2 related inhibitory peptide, AIP). Stimulation frequency was altered over a wide range (0.2-8 Hz) and post-rest vs steady state twitches were also compared. In both WT and PLB-KO mouse muscles FDAR of twitch force was prominent, but was largely suppressed by KN-93. FDAR of twitch contractions was associated with FDAR of Ca transients in PLB-KO myocytes, and both were inhibited by KN-93. Similarly, a different CaMKII inhibitor (AIP) inhibited FDAR of contraction and Ca transients in rat ventricular myocytes. We conclude that FDAR results mainly from CaMKII-dependent stimulation of SR Ca transport, but does not require phospholamban.

Original languageEnglish (US)
Pages (from-to)975-984
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Issue number8
StatePublished - Aug 1 2002
Externally publishedYes


  • CaMKII
  • Force-frequency relation
  • Phospholamban
  • Postrest-behavior
  • Relaxation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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