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; Graham, HK; Hall, MCS; Eisner, DA; Dibb, KM; Trafford, AW

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.

Citation

Briston, S., Caldwell, J., Horn, M., Clarke, J., Richards, M., Greensmith, D., …Trafford, A. (2011). Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure. Journal of Physiology, 589(Pt 6), 1367-82. https://doi.org/10.1113/jphysiol.2010.203984

• Journal Article Type: Article
• Publication Date: Mar 15, 2011
• Deposit Date: Feb 10, 2015
• Journal: The Journal of physiology
• Print ISSN: 0022-3751
• Electronic ISSN: 1469-7793
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 589
• Issue: Pt 6
• Pages: 1367-82
• DOI: https://doi.org/10.1113/jphysiol.2010.203984
• Publisher URL: http://dx.doi.org/10.1113/jphysiol.2010.203984
• Related Public URLs: http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1469-7793/
• Additional Information: Funders : The British Heart Foundation;European Union 6th Framework Programme specific targeted research project (‘Normacor’)