Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia.
β-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ∼30 commonly used β-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 β-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+waves during store Ca2+overload, also known as store overload-induced Ca2+release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other β-blockers that suppress SOICR. Here, we assessed the effect of other commonly used β-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+imaging. Of the 13 β-blockers tested, only nebivolol, a β-1-selective β-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-l-arginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-β-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias.
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Zhen
Z
Tan
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1.
Zhichao
Z
Xiao
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1.
Jinhong
J
Wei
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Jingqun
J
Zhang
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Qiang
Q
Zhou
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4.
Chris D
CD
Smith
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Alma
A
Nani
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Guogen
G
Wu
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, U.S.A.
Long-Sheng
LS
Song
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4.
Thomas G
TG
Back
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.
Michael
M
Fill
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, U.S.A.|The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1.
S R Wayne
SR
Chen
D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D000077261:Carvedilol; D004562:Electrocardiography; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008051:Lipid Bilayers; D051379:Mice; D008817:Mice, Mutant Strains; D000068577:Nebivolol / Q000494:pharmacology* / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D019837:Ryanodine Receptor Calcium Release Channel; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000378:metabolism; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
D058665:Adrenergic beta-1 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D008051:Lipid Bilayers; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000068577:Nebivolol; D000077261:Carvedilol; D019001:Nitric Oxide Synthase; D002118:Calcium
nebivolol; ryanodine receptor; sarcoplasmic reticulum; spontaneous calcium release; ventricular tachycardia; β-blockers