| Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure. | |
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MedLine Citation:
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PMID: 21242250 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarah J Briston; Jessica L Caldwell; Margaux A Horn; Jessica D Clarke; Mark A Richards; David J Greensmith; Helen K Graham; Mark C S Hall; David A Eisner; Katharine M Dibb; Andrew W Trafford |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2011-01-17 |
Journal Detail:
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Title: The Journal of physiology Volume: 589 ISSN: 1469-7793 ISO Abbreviation: J. Physiol. (Lond.) Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-04-13 Completed Date: 2012-03-06 Revised Date: 2012-09-18 |
Medline Journal Info:
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Nlm Unique ID: 0266262 Medline TA: J Physiol Country: England |
Other Details:
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Languages: eng Pagination: 1367-82 Citation Subset: IM |
Affiliation:
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Unit of Cardiac Physiology, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9NT, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Disease Models, Animal* Excitation Contraction Coupling / physiology* Female Heart Failure / etiology, physiopathology* Myocardial Contraction / physiology Receptors, Adrenergic, beta / physiology* Sheep Tachycardia, Ventricular / complications, physiopathology* |
| Grant Support | |
ID/Acronym/Agency:
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PG06/150//British Heart Foundation; PG07/099//British Heart Foundation; PG07/124//British Heart Foundation; PG09/062//British Heart Foundation |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Adrenergic, beta |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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