Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes

J. Van Der Velden, J. W. De Jong, V. J. Owen, P. B.J. Burton, G. J.M. Stienen

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Objective: We investigated whether the Frank-Starling mechanism is absent or preserved in end-stage failing human myocardium and if phosphorylation of contractile proteins modulates its magnitude through the sarcomere length-dependence of calcium sensitivity of isometric force development. Methods: The effect of phosphorylation of troponin I and C-protein by the catalytic subunit of protein kinase A (3 μg/ml; 40 min at 20°C) was studied in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at sarcomere lengths measured at rest of 1.8, 2.0 and 2.2 μm. Isometric force development was studied at various free-calcium concentrations before and after protein kinase A incubation at 15°C (pH 7.1). Results: Maximal isometric tension at 2.2 μm amounted to 39.6±10.4 and 33.7±3.5 kN/m2 in donor and end-stage failing cardiomyocytes, respectively. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean ΔpCa50=0.22). A reduction in sarcomere length from 2.2 to 1.8 μm caused reductions in maximum isometric force to 64% and 65% and in pCa50 by 0.10 and 0.08 pCa units in donor and failing cardiomyocytes, respectively. In donor tissue, the effect of protein kinase A treatment was rather small, while in end-stage failing myocardium it was much larger (ΔpCa50=0.24) irrespective of sarcomere length. Conclusions: The data obtained indicate that the Frank-Starling mechanism is preserved in end-stage failing myocardium and suggest that sarcomere length dependence of calcium sensitivity and the effects of phosphorylation of troponin I and C-protein are independent. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)487-495
Number of pages9
JournalCardiovascular research
Issue number3
Publication statusPublished - 1 Jun 2000


  • Contractile apparatus
  • Contractile function
  • Heart failure
  • Myocytes
  • Protein kinases
  • Protein phosphorylation

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