Fowler, ED, Drinkhill, MJ, Norman, R et al. (7 more authors) (2018) Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca²⁺ handling dysfunction in rats with pulmonary artery hypertension. Journal of Molecular and Cellular Cardiology, 120. pp. 74-83. ISSN 0022-2828
Abstract
Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the β₁–adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10 mg/kg/day metoprolol (MCT + BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23 days (MCT), to 31 days (MCT + BB). At 23 ± 1 days post-injection, MCT + BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCT + BB. Preserved t-tubule structure, more uniform evoked Ca²⁺ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca²⁺ overload was prevented in MCT + BB myocytes resulting in fewer spontaneous Ca²⁺ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by β₁–adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2018 The Authors. Published by Elsevier Ltd. Open Access funded by British Heart Foundation. Under a Creative Commons license; https://creativecommons.org/licenses/by/4.0/ |
Keywords: | Pulmonary artery hypertension; Right heart failure; Beta-blocker; Cardiac myocyte; Ca²⁺ handling; Monocrotaline |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/13/3/29924 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 May 2018 10:47 |
Last Modified: | 25 Jun 2023 21:21 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.yjmcc.2018.05.015 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131352 |