Abstract:
:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin. We recently found that the drug flecainide inhibits RyR2 channels and prevents CPVT in mice and humans. Here we compared the effects of flecainide and tetracaine, a known RyR2 inhibitor ineffective in CPVT myocytes, on arrhythmogenic Ca(2+) waves and elementary sarcoplasmic reticulum (SR) Ca(2+) release events, Ca(2+) sparks. In ventricular myocytes isolated from a CPVT mouse model, flecainide significantly reduced spark amplitude and spark width, resulting in a 40% reduction in spark mass. Surprisingly, flecainide significantly increased spark frequency. As a result, flecainide had no significant effect on spark-mediated SR Ca(2+) leak or SR Ca(2+) content. In contrast, tetracaine decreased spark frequency and spark-mediated SR Ca(2+) leak, resulting in a significantly increased SR Ca(2+) content. Measurements in permeabilized rat ventricular myocytes confirmed the different effects of flecainide and tetracaine on spark frequency and Ca(2+) waves. In lipid bilayers, flecainide inhibited RyR2 channels by open state block, whereas tetracaine primarily prolonged RyR2 closed times. The differential effects of flecainide and tetracaine on sparks and RyR2 gating can explain why flecainide, unlike tetracaine, does not change the balance of SR Ca(2+) fluxes. We suggest that the smaller spark mass contributes to flecainide's antiarrhythmic action by reducing the probability of saltatory wave propagation between adjacent Ca(2+) release units. Our results indicate that inhibition of the RyR2 open state provides a new therapeutic strategy to prevent diastolic Ca(2+) waves resulting in triggered arrhythmias, such as CPVT.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Hilliard FA,Steele DS,Laver D,Yang Z,Le Marchand SJ,Chopra N,Piston DW,Huke S,Knollmann BCdoi
10.1016/j.yjmcc.2009.10.005subject
Has Abstractpub_date
2010-02-01 00:00:00pages
293-301issue
2eissn
0022-2828issn
1095-8584pii
S0022-2828(09)00428-3journal_volume
48pub_type
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journal_title:Journal of molecular and cellular cardiology
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更新日期:1995-09-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1016/s0022-2828(05)82390-9
更新日期:1995-06-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1999.0966
更新日期:1999-07-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1006/jmcc.1998.0782
更新日期:1998-11-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1016/j.yjmcc.2015.05.008
更新日期:2015-08-01 00:00:00
abstract::Peroxynitrite and hydroxyl radical are reactive oxidants produced during myocardial reperfusion injury. In various cell types, including macrophages and smooth muscle cells, peroxynitrite and hydrogen peroxide cause DNA single strand breakage, which triggers the activation of the nuclear enzyme poly (ADP-ribose) synth...
journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1006/jmcc.1996.0095
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1994.1084
更新日期:1994-06-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/0022-2828(92)93155-d
更新日期:1992-02-01 00:00:00
abstract::Syndecan-4 (synd4) is a heparan sulfate proteoglycan, involved in repair following tissue damage, through modulating neovascularization and inflammation. In acute myocardial infarction its myocardial expression is up-regulated in a time-dependent manner, and in synd4-deficient mice severe cardiac dysfunction and abnor...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2012.04.014
更新日期:2012-08-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1006/jmcc.1996.0160
更新日期:1996-08-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2009.05.007
更新日期:2009-10-01 00:00:00
abstract::The loss of cardiomyocytes by apoptosis and the subsequent replacement by fibrous connective tissues are important features of cardiac remodeling in adult heart disease. In children with CHD, however, the cellular and molecular mechanisms of heart failure have not yet been fully understood because of the anatomical an...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2007.05.011
更新日期:2007-09-01 00:00:00
abstract::Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2015.04.019
更新日期:2015-07-01 00:00:00
abstract::In cardiomyocytes, Ca(2+) plays a central role in governing both contraction and signaling events that regulate gene expression. Current evidence indicates that discrimination between these two critical functions is achieved by segregating Ca(2+) within subcellular microdomains: transcription is regulated by Ca(2+) re...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2014.06.015
更新日期:2014-10-01 00:00:00
abstract::The biochemical and physiological effects of GS alpha activation are well known; however, little is known about the anatomical localisation of GS alpha in the myocardium. Knowledge of the localisation might yield insights into G protein function in heart. The utility of immunocytochemistry using immunofluorescent meth...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1997.0400
更新日期:1997-06-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
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更新日期:2011-05-01 00:00:00
abstract::The possibility to induce pluripotency in somatic cells or, even further, to induce cell transdifferentiation through the forced expression of reprogramming factors has offered new, attractive options for cardiovascular regenerative medicine. In fact, recent discoveries have demonstrated that induced pluripotent stem ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
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更新日期:2013-09-01 00:00:00
abstract::The relationship between reperfusion-induced arrhythmias and the size of the occluded zone was examined. The isolated perfuse rat heart was used because its negligible collateral flow maximizes susceptibility to arrhythmias and reduces variability. Ischemia lasting 10 min was followed by 10 min of reperfusion. A const...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/0022-2828(89)90828-6
更新日期:1989-06-01 00:00:00