Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine

Bébarová, Markéta; Matejovič, Peter; Pásek, Michal; Hořáková, Zuzana; Hošek, Jan; Šimurdová, Milena; Šimurda, Jiří

doi:10.1007/s00210-016-1265-z

Cited by 13 publications

(22 citation statements)

References 24 publications

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“…Ethanol reduces I Na , I Ca,L , I to , I Kur , and I Kr [8,11,12] and exhibits dual effects on I K1 and I K,ACh [9,10], with inhibition of these latter currents at low concentrations and augmentation at high concentrations. Moreover, ethanol also enhanced I NCX , sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) function and SR Ca 2+ leak, increasing proarrhythmic spontaneous Ca 2+ release events [13].…”

Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 99%

“…Bottom panels: peak currents of different ion channels relative to the baseline condition (not shown) with 0 mM ethanol. Experimental data are shown in white bars ([*] = [8], [#] = [9], [%] = [11], [^] = [12], [@] = [10], [&] = [13]), and simulated counterparts in blue bars. For I K1 and I K,ACh the relative change is shown for both the inward current (at −120 mV and − 110 mV) and the outward current at (−40 mV and − 50 mV) through these channels.…”

Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 99%

“…We assumed that the relative changes were similar across species. Furthermore, significant cell-to-cell variability in the acute effects of ethanol have been described [9,10] and may result in diverse effects at higher scales (Supplemental Fig. 14) [48].…”

Section: Study Limitationsmentioning

confidence: 99%

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Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Sutanto

Cluitmans

Dobrev

et al. 2020

Journal of Molecular and Cellular Cardiology

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Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca 2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular-and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced I Na , I Ca,L , I to , I Kr and I Kur , dual effects on I K1 and I K,ACh (inhibition at low and augmentation at high concentrations), and increased I NCX and SR Ca 2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

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Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 99%

Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 99%

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Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Sutanto

Cluitmans

Dobrev

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…In this study, we apply the conception of different channel populations to analyse the responses of acetylcholine-sensitive inward rectifying potassium current ( I KAch ) to ethanol [3] and nicotine [4]. These responses showed some similar features to those revealed previously in the ethanol- I K1 interactions [1–2], as mentioned above.…”

Section: Introductionmentioning

confidence: 87%

The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model

2019

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Recent experimental work has revealed unusual features of the effect of certain drugs on cardiac inwardly rectifying potassium currents, including the constitutively active and acetylcholine-induced components of acetylcholine-sensitive current (IKAch). These unusual features have included alternating susceptibility of the current components to activation and inhibition induced by ethanol or nicotine applied at various concentrations, and significant correlation between the drug effect and the current magnitude measured under drug-free conditions. To explain these complex drug effects, we have developed a new type of quantitative model to offer a possible interpretation of the effect of ethanol and nicotine on the IKAch channels. The model is based on a description of IKAch as a sum of particular currents related to the populations of channels formed by identical assemblies of different α-subunits. Assuming two different channel populations in agreement with the two reported functional IKAch-channels (GIRK1/4 and GIRK4), the model was able to simulate all the above-mentioned characteristic features of drug-channel interactions and also the dispersion of the current measured in different cells. The formulation of our model equations allows the model to be incorporated easily into the existing integrative models of electrical activity of cardiac cells involving quantitative description of IKAch. We suppose that the model could also help make sense of certain observations related to the channels that do not show inward rectification. This new ionic channel model, based on a concept we call population type, may allow for the interpretation of complex interactions of drugs with ionic channels of various types, which cannot be done using the ionic channel models available so far.

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“…Recordings were made following Bébarová et al [33]. Briefly, the whole cell patch-clamp technique in current clamp and voltage clamp modes was used (Axopatch 200B equipment, pCLAMP 9.2 software; Molecular Devices ).…”

Section: Methodsmentioning

confidence: 99%

The acceleration of cardiomyogenesis in embryonic stem cells in vitro by serum depletion does not increase the number of developed cardiomyocytes

Radaszkiewicz¹,

Sýkorová²,

Binó³

et al. 2017

PLoS ONE

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The differentiation of pluripotent embryonic stem (ES) cells into various lineages in vitro represents an important tool for studying the mechanisms underlying mammalian embryogenesis. It is a key technique in studies evaluating the molecular mechanisms of cardiomyogenesis and heart development and also in embryotoxicology. Herein, modest modifications of the basic protocol for ES cell differentiation into cardiomyocytes were evaluated in order to increase the yield and differentiation status of developed cardiomyocytes. Primarily, the data show that ES cell cultivation in the form of non-adherent embryoid bodies (EBs) for 5 days compared to 8 days significantly improved cardiomyogenic differentiation. This is illustrated by the appearance of beating foci in the adherent EBs layer at earlier phases of differentiation from day 10 up to day 16 and by the significantly higher expression of genes characteristic of cardiomyogenic differentiation (sarcomeric alpha actinin, myosin heavy chain alpha and beta, myosin light chain 2 and 7, and transcriptional factor Nkx2.5) in EBs cultivated under non-adherent conditions for 5 days. The ratio of cardiomyocytes per other cells was also potentiated in EBs cultivated in non-adherent conditions for only 5 days followed by cultivation in adherent serum-free culture conditions. Nevertheless, the alteration in the percentage of beating foci among these two tested cultivation conditions vanished at later phases and also did not affect the total number of cardiomyocytes determined as myosin heavy chain positive cells at the end of the differentiation process on day 20. Thus, although these modifications of the conditions of ES cells differentiation may intensify cardiomyocyte differentiation, the final count of cardiomyocytes might not change. Thus, serum depletion was identified as a key factor that intensified cardiomyogenesis. Further, the treatment of EBs with N-acetylcysteine, a reactive oxygen species scavenger, did not affect the observed increase in cardiomyogenesis under serum depleted conditions. Interestingly, a mild induction of the ventricular-like phenotype of cardiomyocytes was observed in 5-day-old EBs compared to 8-day-old EBs. Overall, these findings bring crucial information on the mechanisms of ES cells differentiation into cardiomyocytes and on the establishment of efficient protocols for the cardiomyogenic differentiation of ES cells. Further, the importance of determining the absolute number of formed cardiomyocyte-like cells per seeded pluripotent cells in contrast to the simple quantification of the ratios of cells is highlighted.

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Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine

Cited by 13 publications

References 24 publications

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model

The acceleration of cardiomyogenesis in embryonic stem cells in vitro by serum depletion does not increase the number of developed cardiomyocytes

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