Journal article
Non-beta-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure
The Biochemical journal, Vol.470(2), pp.233-242
09/01/2015
DOI: 10.1042/BJ20150548
PMCID: PMC4902270
PMID: 26348911
Abstract
Carvedilol is the current beta-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol's benefits are dose-limited, attributable to its potent beta-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of beta-blocking S-carvedilol and non-beta-blocking R-carvedilol. We recently reported that novel non-beta-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca2+ waves and stress-induced VT without causing bradycardia. Thus, the non-beta-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-beta-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.
Details
- Title: Subtitle
- Non-beta-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure
- Creators
- Jingqun Zhang - Rush University Medical CenterQiang Zhou - Rush University Medical CenterChris D. Smith - Univ Calgary, Dept Chem, Calgary, AB T2N 1N4, CanadaHaiyan Chen - Rush University Medical CenterZhen Tan - Rush University Medical CenterBiyi Chen - Roy J. and Lucille A. Carver College of MedicineAlma Nani - Rush University Medical CenterGuogen Wu - Rush University Medical CenterLong-Sheng Song - Roy J. and Lucille A. Carver College of MedicineMichael Fill - Rush University Medical CenterThomas G. Back - University of CalgaryS. R. Wayne Chen - Rush University Medical Center
- Resource Type
- Journal article
- Publication Details
- The Biochemical journal, Vol.470(2), pp.233-242
- DOI
- 10.1042/BJ20150548
- PMID
- 26348911
- PMCID
- PMC4902270
- NLM abbreviation
- Biochem J
- ISSN
- 0264-6021
- eISSN
- 1470-8728
- Publisher
- Portland Press Ltd
- Number of pages
- 10
- Grant note
- R01HL057832 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Canadian Institutes of Health Research the Heart and Stroke Foundation of Alberta R01GM111397 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01HL075210; R01HL057832; R01HL090905 / U.S. National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Heart and Stroke Foundation/Libin Cardiovascular Institute Professorship in Cardiovascular Research 201200822 / Alberta Innovates Canada Foundation for Innovation; CGIAR
- Language
- English
- Date published
- 09/01/2015
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293072502771
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