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This Article Full Text Full Text (PDF) All Versions of this Article: 582/2/695    most recent jphysiol.2007.134486v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lamberts, R. R. Articles by Stienen, G. J. M. Search for Related Content PubMed PubMed Citation Articles by Lamberts, R. R. Articles by Stienen, G. J. M. Related Collections Cardiovascular

¹ Department of Anaesthesiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center (VUMC) Amsterdam, The Netherlands
² Laboratory for Physiology, ICaR-VU, VUMC, Amsterdam, The Netherlands
³ University of Colorado, Health Sciences Center Department of Medicine Section of Cardiology, Denver, CO, USA
⁴ Center for Cardiovascular Research, Department of Physiology and Biophysics, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

The positive force–frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca²⁺ influx per unit of time. In failing hearts, a blunted, flat or negative force–frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca²⁺ sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca²⁺ ([Ca²⁺]_i), Ca²⁺ sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 ± 3.0 mN mm^–2) and a decrease in force in failing trabeculae (9.4 ± 3.2 mN mm^–2), whereas in both groups the amplitude of [Ca²⁺]_i transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca²⁺ sensitivity remained constant with frequency (pCa₅₀: 5.55 ± 0.02 and 5.58 ± 0.01, respectively, P > 0.05), whereas in cardiomyocytes from failing hearts Ca²⁺ sensitivity decreased with frequency (pCa₅₀: 5.62 ± 0.01 and 5.57 ± 0.01, respectively, P < 0.05). After incubation of the cardiomyocytes with protein kinase A (PKA) this frequency dependency of Ca²⁺ sensitivity was abolished. Troponin I (TnI) and myosin light chain 2 (MLC2) phosphorylation remained constant in control hearts but both increased with frequency in failing hearts. In conclusion, in heart failure frequency-dependent myofilament Ca²⁺ desensitization, through increased TnI phosphorylation, contributes to the negative force–frequency relation and is counteracted by a frequency-dependent MLC2 phosphorylation. We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force–frequency relation.

(Received 13 April 2007; accepted after revision 1 April 2007; first published online 3 May 2007)
Corresponding author R. R. Lamberts: Department of Anesthesiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center (VUMC), 1081 BT Amsterdam, The Netherlands. Email: r.lamberts{at}vumc.nl

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