Briston, SJ, Caldwell, JL, Horn, MA, Clarke, JD, Richards, MA, Greensmith, DJ ORCID: https://orcid.org/0000-0002-6459-523X, Graham, HK, Hall, MCS, Eisner, DA, Dibb, KM and Trafford, AW
2011,
'Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure'
, The Journal of physiology, 589 (Pt 6)
, pp. 1367-82.
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Abstract
Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing the blunted β-adrenergic (β-AR) response in HF.We induced HF by tachypacing in sheep; intracellular Ca2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca2+ transient amplitude and peak L-type Ca2+ current (ICa-L) were reduced (to 70 ± 11% and 50 ± 3.7% of control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) Ca2+ content was unchanged. β-AR stimulation with isoprenaline (ISO) increased Ca2+ transient amplitude, ICa-L and SRCa2+ content in both cell types; however, the response of HF cells was markedly diminished (P <0.05).Western blotting revealed an increase in protein phosphatase levels (PP1, 158 ± 17% and PP2A, 188 ± 34% of control, P <0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 ± 10% and Thr17, 41 ± 15% of control, P <0.05). The β-AR receptor kinase GRK-2 was also increased in HF (173 ± 38% of control, P <0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca2+ transient, SR Ca2+ content and SR Ca2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to β-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca2+ content and therefore failure of the systolic Ca2+ transient to increase appropriately during β-AR stimulation.
Item Type: | Article |
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Themes: | Health and Wellbeing Subjects outside of the University Themes |
Schools: | Schools > School of Environment and Life Sciences > Biomedical Research Centre |
Journal or Publication Title: | The Journal of physiology |
Publisher: | Wiley |
Refereed: | Yes |
ISSN: | 1469-7793 |
Related URLs: | |
Funders: | The British Heart Foundation, European Union 6th Framework Programme specific targeted research project (‘Normacor’) |
Depositing User: | D Greensmith |
Date Deposited: | 10 Feb 2015 21:04 |
Last Modified: | 16 Feb 2022 16:06 |
URI: | https://usir.salford.ac.uk/id/eprint/33385 |
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