Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure

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
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:	Publication
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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