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

Research output: Contribution to journalArticle

  • Ewan D. Fowler
  • Mark J. Drinkhill
  • Ruth Norman
  • Eleftheria Pervolaraki
  • Rachel Stones
  • Emma Steer
  • David Benoist
  • Derek S. Steele
  • Sarah C. Calaghan
  • Ed White
Original languageEnglish
Pages (from-to)74-83
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume120
Early online date26 May 2018
DOIs
DateAccepted/In press - 22 May 2018
DateE-pub ahead of print - 26 May 2018
DatePublished (current) - 1 Jul 2018

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.

    Research areas

  • Beta-blocker, Ca handling, Cardiac myocyte, Monocrotaline, Pulmonary artery hypertension, Right heart failure

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0022282818301767 . Please refer to any applicable terms of use of the publisher.

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