Carvedilol is the current β-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol's benefits are dose-limited, attributable to its potent β-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of β-blocking S-carvedilol and non-β-blocking R-carvedilol. We recently reported that novel non-β-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca2+ waves and stress-induced VT without causing bradycardia. Thus, the non-β-blocking R-carvedilol enantiomer may also possess this favourable anti-arrhythmic property. To test this possibility, we synthesized R-carvedilol and assessed its effect on Ca2+ release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca2+ oscillations in human embryonic kidney (HEK) 293 cells, Ca2+ waves in cardiomyocytes in intact hearts and stress-induced VT in mice harbouring a catecholaminergic polymorphic ventricular tachycardia (CPVT)-causing RyR2 mutation. Importantly, R-carvedilol did not significantly alter heart rate or blood pressure. Therefore, the non-β-blocking R-carvedilol enantiomer represents a very promising prophylactic treatment for Ca2+- triggered arrhythmia without the bradycardia and hypotension often associated with racemic carvedilol. Systematic clinical assessments of R-carvedilol as a new anti-arrhythmic agent may be warranted.
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September 2015
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Research Article|
August 20 2015
Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure
Jingqun Zhang;
Jingqun Zhang
1
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Qiang Zhou;
Qiang Zhou
1
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Chris D. Smith;
Chris D. Smith
†Department of Chemistry, University of Calgary, Calgary, Alberta, Canada, T2N 1N4
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Haiyan Chen;
Haiyan Chen
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Zhen Tan;
Zhen Tan
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Biyi Chen;
Biyi Chen
‡Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, U.S.A.
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Alma Nani;
Alma Nani
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Guogen Wu;
Guogen Wu
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
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Long-Sheng Song;
Long-Sheng Song
‡Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, U.S.A.
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Michael Fill;
Michael Fill
2
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
2Correspondence may be addressed to any of these authors (email michael_fill@rush.edu, tgback@ucalgary.ca or swchen@ucalgary.ca).
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Thomas G. Back;
Thomas G. Back
2
†Department of Chemistry, University of Calgary, Calgary, Alberta, Canada, T2N 1N4
2Correspondence may be addressed to any of these authors (email michael_fill@rush.edu, tgback@ucalgary.ca or swchen@ucalgary.ca).
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S.R. Wayne Chen
*Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
§The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1
2Correspondence may be addressed to any of these authors (email michael_fill@rush.edu, tgback@ucalgary.ca or swchen@ucalgary.ca).
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Publisher: Portland Press Ltd
Received:
May 13 2015
Revision Received:
July 01 2015
Accepted:
July 08 2015
Accepted Manuscript online:
July 08 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2015 Authors; published by Portland Press Limited
2015
Biochem J (2015) 470 (2): 233–242.
Article history
Received:
May 13 2015
Revision Received:
July 01 2015
Accepted:
July 08 2015
Accepted Manuscript online:
July 08 2015
Citation
Jingqun Zhang, Qiang Zhou, Chris D. Smith, Haiyan Chen, Zhen Tan, Biyi Chen, Alma Nani, Guogen Wu, Long-Sheng Song, Michael Fill, Thomas G. Back, S.R. Wayne Chen; Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure. Biochem J 1 September 2015; 470 (2): 233–242. doi: https://doi.org/10.1042/BJ20150548
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