Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions

Wei, Xiao‐Hong; Yu, Shandong; Ren, Lu; Huang, Shiyuan; Yang, Qing; Wang, Ping; Chu, Yanpeng; Yang, Wei; Ding, Ye; Huo, Yong; Wu, Lin

doi:10.1038/s41598-017-01056-0

Cited by 19 publications

(15 citation statements)

References 37 publications

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“…While discussing CaMKII, it is also important to discuss the late Na + current. Recent work has shown that inhibition of this current is able to suppress Ca 2+ related arrhythmias by reducing CaMKII phosphorylation ( Wei et al, 2017 ). Furthermore, ranolazine, an agent that inhibits both late Na + and K + channels has been shown to have antiarrhythmic effects in the intact heart in CHF and, interestingly, was not associated with drug-induced proarrhythmia ( Frommeyer et al, 2012 ).…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Johnson

Antoons

2018

Front. Physiol.

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Heart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca2+ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca2+ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca2+ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF.

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Section: Therapeutic Interventionsmentioning

confidence: 99%

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Johnson

Antoons

2018

Front. Physiol.

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“…Though less common, some drugs prolong the QT C interval by increasing I NaL [7,8]. Basic science studies also show that delayed repolarization and ventricular arrhythmias can occur by pharmacologically enhancing I CaL [9]. Knowledge of drug effects on inward and outward ventricular ionic currents is thus important for proarrhythmia risk assessment.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

et al. 2020

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Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QTC prolongation and TdP are most commonly caused by acute inhibition of hERG current (IhERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (INaL) and/or L-type Ca2+ (ICaL) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca2+, and Na+ ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QTC prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, CaV1.2, and NaV1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on IhERG, ICaL, INaL, and peak Na+ current (INaP) at clinically relevant concentrations. In contrast, methadone inhibited IhERG, ICaL, and INaL. Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QTC prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QTC prolongation not mediated by acute hERG channel block warrants further study.

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“…found that PLC activity can increase Ca 2+ , thereby activating the apoptotic signal pathway 20 . Furthermore, severe increases in cytosolic Ca 2+ concentration could stimulate Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) 21 . CaMKII, an important member of the calcium/calmodulin-activated protein kinase family, plays a vital role in the regulation of both neuronal death and neuronal survival 22 .…”

Section: Introductionmentioning

confidence: 99%

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

Wang

et al. 2017

Sci Rep

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As documented in our previous study, notoginsenoside R1 (NGR1) can inhibit neuron apoptosis and the expression of endoplasmic reticulum (ER) stress-associated pro-apoptotic proteins in hypoxic–ischemic encephalopathy. Recent evidence indicates that the Phospholipase C (PLC)/inositol 1,4,5-trisphosphate receptor (IP3R) is important for the regulation of Ca2+ release in the ER. Ca2+ imbalance can stimulate ER stress, CAMKII, and cell apoptosis. The purpose of this study was to further investigate the neuroprotective effect of NGR1 and elucidate how NGR1 regulates ER stress and cell apoptosis in the oxygen–glucose deprivation/reoxygenation (OGD/R) model. Cells were exposed to NGR1 or the PLC activator m-3M3FBS. Then, IP3R- and IP3-induced Ca2+ release (IICR) and activation of the ER stress and CaMKII signal pathway were measured. The results showed that NGR1 inhibited IICR and strengthened the binding of GRP78 with PERK and IRE1. NGR1 also alleviated the activation of the CaMKII pathway. Pretreatment with m-3M3FBS attenuated the neuroprotective effect of NGR1; IICR was activated, activation of the ER stress and CaMKII pathway was increased, and more cells were injured. These results indicate that NGR1 may suppress activation of the PLC/IP3R pathway, subsequently inhibiting ER Ca2+ release, ER stress, and CaMKII and resulting in suppressed cell apoptosis.

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Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions

Cited by 19 publications

References 37 publications

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

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