Abstract:
RATIONALE:Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of the combined actions of direct blockade of ryanodine receptors (RyR2) and Na(+) channel inhibition. However, there is presently no direct evidence to support the notion that flecainide blocks RyR2 Ca(2+) flux in the physiologically relevant (luminal-to-cytoplasmic) direction. The mechanism of flecainide action remains controversial. OBJECTIVE:To examine, in detail, the effect of flecainide on the human RyR2 channel and to establish whether the direct blockade of physiologically relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT. METHODS AND RESULTS:Using single-channel analysis, we show that, even at supraphysiological concentrations, flecainide did not inhibit the physiologically relevant, luminal-to-cytosolic flux of cations through the channel. Moreover, flecainide did not alter RyR2 channel gating and had negligible effect on the mechanisms responsible for the sarcoplasmic reticulum charge-compensating counter current. Using permeabilized cardiac myocytes to eliminate any contribution of plasmalemmal Na(+) channels to the observed actions of the drug at the cellular level, flecainide did not inhibit RyR2-dependent sarcoplasmic reticulum Ca(2+) release. CONCLUSIONS:The principal action of flecainide in CPVT is not via a direct interaction with RyR2. Our data support a model of flecainide action in which Na(+)-dependent modulation of intracellular Ca(2+) handling attenuates RyR2 dysfunction in CPVT.
journal_name
Circ Resjournal_title
Circulation researchauthors
Bannister ML,Thomas NL,Sikkel MB,Mukherjee S,Maxwell C,MacLeod KT,George CH,Williams AJdoi
10.1161/CIRCRESAHA.116.305347subject
Has Abstractpub_date
2015-04-10 00:00:00pages
1324-35issue
8eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.116.305347journal_volume
116pub_type
杂志文章abstract::We have investigated the requirement for c-myc downregulation in the growth arrest of vascular smooth muscle cells (VSMCs). Rat VSMCs were infected with a retrovirus vector directing constitutive expression of either the complete human c-Myc protein (VSM-myc cells) or the c-Myc deletion mutant D106-143, which is inact...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.3.525
更新日期:1994-03-01 00:00:00
abstract::One of the major manifestations of obesity is increased production of the adipocyte-derived 16-kDa peptide leptin, which is also elevated in heart disease, including congestive heart failure. However, whether leptin can directly alter the cardiac phenotype is not known. We therefore studied the effect of leptin as a p...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000089255.37804.72
更新日期:2003-08-22 00:00:00
abstract::We studied the mechanisms underlying the increase in automaticity induced by alpha 1-adrenergic stimulation of normal and "ischemic" canine Purkinje fibers. Fibers were superfused with a control Tyrode's solution, followed by an ischemic superfusate that included 10 mM KCl, 5 mM NaHCO3, Po2 of 10-25 mm Hg, and pH 6.7....
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.3.526
更新日期:1992-09-01 00:00:00
abstract::In this review current hypotheses for the regulation of filtration rate and the subsequent reabsorption of that filtrate by the proximal tubule are discussed. In the rat the filtration rate is highly plasma flow dependent because of the phenomenon of filtration equilibrium. On the other hand, in man and dog filtration...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.36.6.107
更新日期:1975-06-01 00:00:00
abstract:RATIONALE:Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. OBJECTIVE:We tested the hypothesis that removal of a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.305518
更新日期:2015-08-14 00:00:00
abstract:RATIONALE:Activin receptor-like kinase-1 (ALK1) is an endothelial transforming growth factor β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.112.275586
更新日期:2013-01-04 00:00:00
abstract:RATIONALE:The impact of severe cardiovascular disease and critical limb ischemia (CLI) on the bone marrow (BM) is largely unknown. OBJECTIVE:To investigate microvascular and neuropathic changes in BM of patients with CLI. METHODS AND RESULTS:BM biopsies were obtained from patients with CLI (n=33) included in the Reju...
journal_title:Circulation research
pub_type: 临床试验,杂志文章
doi:10.1161/CIRCRESAHA.114.302791
更新日期:2014-01-17 00:00:00
abstract::The mechanisms underlying the blunted contractile response to beta-adrenergic receptor (beta-AR) stimulation in heart failure (HF) are incompletely understood, especially with regard to beta-AR subtype-specific regulation of L-type Ca2+ channels. We evaluated the impact of HF induced by pacing tachycardia on beta-AR r...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000181160.31851.05
更新日期:2005-09-16 00:00:00
abstract::Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.108.176826
更新日期:2008-11-21 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.75.5.844
更新日期:1994-11-01 00:00:00
abstract::Previous studies have postulated an important role for the inwardly rectifying potassium current (I(K1)) in controlling the dynamics of electrophysiological spiral waves responsible for ventricular tachycardia and fibrillation. In this study, we developed a novel tissue model of cultured neonatal rat ventricular myocy...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.178335
更新日期:2009-02-13 00:00:00
abstract::Choline acetyltransferase activity, which is rate limiting in acetylcholine biosynthesis, was measured in the four heart chambers of guinea pigs subjected to (1) sham surgery, (2) constriction of the ascending aorta, (3) constriction of the descending thoracic aorta, and (4) constriction of the pulmonary artery. After...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.36.4.547
更新日期:1975-04-01 00:00:00
abstract::Ablation of the enzyme phosphoinositide 3-kinase (PI3K)gamma (PI3Kgamma(-/-)) in mice increases cardiac contractility by elevating intracellular cAMP and enhancing sarcoplasmic reticulum Ca(2+) handling. Because cAMP is a critical determinant of heart rate, we investigated whether heart rate is altered in mice lacking...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.158428
更新日期:2007-12-07 00:00:00
abstract::Body surface electrocardiograms and electrograms recorded from the surfaces of the heart are the basis for diagnosis and treatment of cardiac electrophysiological disorders and arrhythmias. Given recent advances in understanding the molecular mechanisms of arrhythmia, it is important to relate these electrocardiograph...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000016960.61087.86
更新日期:2002-05-03 00:00:00
abstract::The major goal of this study was to determine the interactions of VLDL surface and core lipids with the artery wall. We first demonstrated in vitro that surface lipid in VLDL could be traced using the phospholipid-like fluorescent probe 1,1'-dioctadecyl-3,3, 3',3'-tetramethyl-indocarbocyanine (DiI). The core of VLDL p...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.7.768
更新日期:2000-04-14 00:00:00
abstract::The recent discovery of neutral active choline and ethanolamine glycerophospholipid specific phospholipase C in myocardium (Wolf RA, Gross RW. J Biol Chem 1985;260:7295) has demonstrated a novel catabolic pathway that potentially contributes to the accumulation of amphiphilic metabolites during myocardial ischemia. To...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.1.173
更新日期:1989-01-01 00:00:00
abstract::We administered ascitic fluid containing atrial natriuretic factor (ANF) monoclonal antibody to rats after 3 weeks of exposure to hypoxia while the rats were still hypoxic. In additional chronically hypoxic rats, we infused synthetic rat ANF. In conscious chronically instrumented rats, after a bolus dose of 5 microgra...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.1.184
更新日期:1992-01-01 00:00:00
abstract:RATIONALE:Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex proces...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.119.315804
更新日期:2020-02-28 00:00:00
abstract::Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by wh...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.4.493
更新日期:1997-10-01 00:00:00
abstract::Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 wee...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.78.2.262
更新日期:1996-02-01 00:00:00
abstract:RATIONALE:The mechanisms driving atherothrombotic risk in individuals with JAK2 V617F ( Jak2 VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. OBJECTIVE:The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.118.313283
更新日期:2018-11-09 00:00:00
abstract::Inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes of patients and experimental animals with congestive heart failure (CHF). Here we show that iNOS expression plays a role in pressure overload-induced myocardial chamber dilation and hypertrophy. In wild-type mice, chronic transverse aortic...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000264081.78659.45
更新日期:2007-04-13 00:00:00
abstract::Ventricular muscle fibers from dog hearts were superfused with K+-free, high Ca2+ solutions after exposure to a K+-free, Ca2+-free superfusate. Following a series of driven action potentials, oscillatory after potentials (OAPs) were elicited in all 40 preparations at a resting potential of greater than -60 mV. The OAP...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.48.4.510
更新日期:1981-04-01 00:00:00
abstract::We studied product inhibition of the actin-activated ATPase of myosin subfragment-1 (S-1) from the three types of muscle tissue: skeletal, cardiac, and smooth. Increasing levels of [MgADP] in the 0-1-mM range caused significant inhibition of the actin-activated MgATPase activity of cardiac and gizzard but not skeletal...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.5.1067
更新日期:1992-11-01 00:00:00
abstract::Morphometric data from stable (nonedematous) isolated dog lungs, perfused with nearly cell-free perfusates, were compared to similar stereological evaluations of isolated dog lungs after induction of severe acute hydrostatic edema. In the edematous lungs, capillary surface and volume densities were substantially incre...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.43.1.72
更新日期:1978-07-01 00:00:00
abstract::Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual's body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000014226.74709.90
更新日期:2002-04-05 00:00:00
abstract::First-generation, E1-deleted adenoviral vectors (E1-AV) can transduce the vascular endothelium with high efficiency, but their use is limited by the resulting acute endothelial injury and the long-term development of intimal hyperplasia. To reduce the impact of viral proteins on the gene-modified cells, a second-gener...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh0901.090926
更新日期:2001-05-11 00:00:00
abstract::We studied the influence of hypophysectomy on endothelial cell regrowth and intimal thickening following aortic endothelial removal. Modification of this influence by replacement doses of glucocorticoids, mineralocorticoids, thyroxin, and growth hormone also was investigated. Young adult male rats were used, and endot...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.48.6.907
更新日期:1981-06-01 00:00:00
abstract::The transverse tubular system (t-system) of cardiac muscle is a structure that allows rapid propagation of excitation into the cell interior. Using 2-photon molecular excitation microscopy and digital image-processing methods, we have obtained a comprehensive overview of the t-system of rat ventricular myocytes in liv...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.84.3.266
更新日期:1999-02-19 00:00:00
abstract:RATIONALE:Nuclear factor of activated T-cells (NFAT) is importantly implicated in pathological cardiac remodeling and vascular lesion formation. NFAT functionality is mainly regulated by calcineurin, a Ca(2+)-dependent multi-effector phosphatase. Calcineurin inhibitors such as cyclosporine A (CsA) were shown to be effe...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.240895
更新日期:2012-01-20 00:00:00