Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure.
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 Ca(2+) 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 Ca(2+) release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca(2+) oscillations in human embryonic kidney (HEK) 293 cells, Ca(2+) 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 Ca(2+)- 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.
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Jingqun
J
Zhang
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Qiang
Q
Zhou
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada, T2N 1N4.
Chris D
CD
Smith
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Haiyan
H
Chen
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Zhen
Z
Tan
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, U.S.A.
Biyi
B
Chen
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Alma
A
Nani
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A.
Guogen
G
Wu
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, U.S.A.
Long-Sheng
LS
Song
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612 U.S.A. michael_fill@rush.edu tgback@ucalgary.ca swchen@ucalgary.ca.
Michael
M
Fill
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada, T2N 1N4 michael_fill@rush.edu tgback@ucalgary.ca swchen@ucalgary.ca.
Thomas G
TG
Back
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 michael_fill@rush.edu tgback@ucalgary.ca swchen@ucalgary.ca.
S R Wayne
SR
Chen
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D002227:Carbazoles; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000077261:Carvedilol; D002118:Calcium
Ca2+ waves; Ca2+-triggered arrhythmias; carvedilol enantiomers; ryanodine receptor; sarcoplasmic reticulum; β-blockers