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Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension

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Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension. / Fowler, Ewan D.; Drinkhill, Mark J.; Norman, Ruth; Pervolaraki, Eleftheria; Stones, Rachel; Steer, Emma; Benoist, David; Steele, Derek S.; Calaghan, Sarah C.; White, Ed.

In: Journal of Molecular and Cellular Cardiology, Vol. 120, 01.07.2018, p. 74-83.

Research output: Contribution to journalArticle

Harvard

Fowler, ED, Drinkhill, MJ, Norman, R, Pervolaraki, E, Stones, R, Steer, E, Benoist, D, Steele, DS, Calaghan, SC & White, E 2018, 'Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension', Journal of Molecular and Cellular Cardiology, vol. 120, pp. 74-83. https://doi.org/10.1016/j.yjmcc.2018.05.015

APA

Fowler, E. D., Drinkhill, M. J., Norman, R., Pervolaraki, E., Stones, R., Steer, E., ... White, E. (2018). Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension. Journal of Molecular and Cellular Cardiology, 120, 74-83. https://doi.org/10.1016/j.yjmcc.2018.05.015

Vancouver

Fowler ED, Drinkhill MJ, Norman R, Pervolaraki E, Stones R, Steer E et al. Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension. Journal of Molecular and Cellular Cardiology. 2018 Jul 1;120:74-83. https://doi.org/10.1016/j.yjmcc.2018.05.015

Author

Fowler, Ewan D. ; Drinkhill, Mark J. ; Norman, Ruth ; Pervolaraki, Eleftheria ; Stones, Rachel ; Steer, Emma ; Benoist, David ; Steele, Derek S. ; Calaghan, Sarah C. ; White, Ed. / Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension. In: Journal of Molecular and Cellular Cardiology. 2018 ; Vol. 120. pp. 74-83.

Bibtex

@article{48627d17c3f443808bbd0c3836169b0a,
title = "Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension",
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.",
keywords = "Beta-blocker, Ca handling, Cardiac myocyte, Monocrotaline, Pulmonary artery hypertension, Right heart failure",
author = "Fowler, {Ewan D.} and Drinkhill, {Mark J.} and Ruth Norman and Eleftheria Pervolaraki and Rachel Stones and Emma Steer and David Benoist and Steele, {Derek S.} and Calaghan, {Sarah C.} and Ed White",
year = "2018",
month = "7",
day = "1",
doi = "10.1016/j.yjmcc.2018.05.015",
language = "English",
volume = "120",
pages = "74--83",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Elsevier",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension

AU - Fowler, Ewan D.

AU - Drinkhill, Mark J.

AU - Norman, Ruth

AU - Pervolaraki, Eleftheria

AU - Stones, Rachel

AU - Steer, Emma

AU - Benoist, David

AU - Steele, Derek S.

AU - Calaghan, Sarah C.

AU - White, Ed

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - Beta-blocker

KW - Ca handling

KW - Cardiac myocyte

KW - Monocrotaline

KW - Pulmonary artery hypertension

KW - Right heart failure

UR - http://www.scopus.com/inward/record.url?scp=85047521112&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2018.05.015

DO - 10.1016/j.yjmcc.2018.05.015

M3 - Article

VL - 120

SP - 74

EP - 83

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -