Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia

Zhen Tan; Zhichao Xiao; Jinhong Wei; Jingqun Zhang; Qiang Zhou; Chris D Smith; Alma Nani; Guogen Wu; Long-Sheng Song; Thomas G Back; Michael Fill; S R Wayne Chen

doi:10.1042/BCJ20160620

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Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia

Journal article

Peer reviewed

Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia

Zhen Tan, Zhichao Xiao, Jinhong Wei, Jingqun Zhang, Qiang Zhou, Chris D Smith, Alma Nani, Guogen Wu, Long-Sheng Song, Thomas G Back, …

Biochemical journal, Vol.473(22), pp.4159-4172

11/15/2016

DOI: 10.1042/BCJ20160620

PMCID: PMC9440763

PMID: 27623776

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https://www.ncbi.nlm.nih.gov/pmc/articles/9440763View

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Abstract

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 Ca waves during store Ca overload, also known as store overload-induced Ca 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 Ca 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 Ca 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 Ca -triggered arrhythmias.

Adrenergic beta-1 Receptor Agonists - pharmacology

Adrenergic beta-1 Receptor Agonists - therapeutic use

Adrenergic beta-Antagonists - pharmacology

Adrenergic beta-Antagonists - therapeutic use

Animals

Arrhythmias, Cardiac - drug therapy

Arrhythmias, Cardiac - metabolism

Calcium - metabolism

Carbazoles - pharmacology

Carbazoles - therapeutic use

Carvedilol

Electrocardiography

Heart - drug effects

Heart Rate - drug effects

HEK293 Cells

Humans

Lipid Bilayers

Mice

Mice, Mutant Strains

Nebivolol - pharmacology

Nebivolol - therapeutic use

Nitric Oxide Synthase - metabolism

Propanolamines - pharmacology

Propanolamines - therapeutic use

Ryanodine Receptor Calcium Release Channel

Tachycardia, Ventricular - drug therapy

Tachycardia, Ventricular - metabolism

Details

Title: Subtitle: Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia
Creators: Zhen Tan - Rush University Medical Center
Zhichao Xiao - Libin Cardiovascular Institute of Alberta
Jinhong Wei - Libin Cardiovascular Institute of Alberta
Jingqun Zhang - Rush University Medical Center
Qiang Zhou - Rush University Medical Center
Chris D Smith - University of Calgary
Alma Nani - Rush University Medical Center
Guogen Wu - Rush University Medical Center
Long-Sheng Song - University of Iowa
Thomas G Back - University of Calgary
Michael Fill - Rush University Medical Center
S R Wayne Chen - Rush University Medical Center
Resource Type: Journal article
Publication Details: Biochemical journal, Vol.473(22), pp.4159-4172
DOI: 10.1042/BCJ20160620
PMID: 27623776
PMCID: PMC9440763
NLM abbreviation: Biochem J
ISSN: 0264-6021
eISSN: 1470-8728
Language: English
Date published: 11/15/2016
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984293089402771

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