© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes
aLaboratory for Physiology, Institute for Cardiovascular Research (ICaR-VU), Free University, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
bThorax Center, Erasmus University, Rotterdam, The Netherlands
cDepartment of Cardiac Surgery, National Heart and Lung Institute at the Imperial College School of Medicine, UK
* Corresponding author. Tel.: +31-20-444-8121; fax: +31-20-444-8255 j.van_der_velden.physiol{at}med.vu.nl
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 
pCa50=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 (pCa50=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.
KEYWORDS Heart failure; Contractile apparatus; Contractile function; Myocytes; Protein kinases; Protein phosphorylation
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