Alcohol intoxication may induce arrhythmias, most frequently atrial fibrillation (AF). Increase of cardiac inward rectifier K+ currents, namely of voltage-gated current IK1 and acetylcholine-activated current IK(Ach), plays an important role in pathogenesis of AF. Data describing changes of these currents in presence of ethanol and its principle metabolite acetaldehyde are rare and, in case of IK1, even controversial. Our preliminary experiments have revealed a significant increase of IK1 under 0.92‰ ethanol in rat ventricular myocytes. We aim this project at a detail analysis of the effect of ethanol and acetaldehyde on IK1 and IK(Ach) by whole cell patch clamp technique in isolated rat/guinea pig cardiomyocytes and in human channels transiently expressed in Chinese Hamster Ovary cells. Using mathematical models of rat, guinea pig, and human cardiomyocytes, observed effects will be confronted with changes of action potential. Arrhythmogenic consequences on cellular level will be also assessed.

Konzumace alkoholu může vést ke vzniku arytmií, nejčastěji fibrilace síní (FS). Nárůst srdečních inward rectifier K+ proudů, zejména napětím řízeného proudu IK1 a acetylcholinem aktivovaného proudu IK(Ach), hraje významnou roli v patogenezi FS. Údaje o změnách těchto proudů v přítomnosti ethanolu a jeho metabolitu acetaldehydu jsou, bohužel, velmi omezené a v případě IK1 i kontroverzní. Naše nedávné pilotní pokusy odhalily signifikantní nárůst IK1 pod vlivem 0,92‰ ethanolu u komorových srdečních buněk potkana. Tento projekt jsme proto zaměřili na podrobnou analýzu vlivu ethanolu a acetaldehydu na IK1 a IK(Ach) metodou whole cell patch clamp u izolovaných srdečních buněk potkana/morčete a u lidských kanálů přechodně exprimovaných na buněčné linii z ovariálních buněk čínského křečka. Za pomoci matematických modelů srdečních buněk potkana, morčete a člověka budeme pozorované změny IK1 a IK(Ach) konfrontovat se změnami průběhu akčního napětí. Rovněž budou posouzeny arytmogenní důsledky na buněčné úrovni.

• MeSH
• acetaldehyd MeSH
• akční potenciály MeSH
• arytmogenní dysplazie pravé komory MeSH
• CHO buňky MeSH
• draslíkové kanály dovnitř usměrňující MeSH
• ethanol MeSH
• fibrilace síní MeSH
• kardiomyocyty MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• matematika MeSH
• metoda terčíkového zámku MeSH
• morčata MeSH
• pití alkoholu MeSH
• teoretické modely MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• morčata MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• kardiologie
• adiktologie
• fyziologie
• fyzika, biofyzika
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Alcohol consumption may result in electrocardiographic changes and arrhythmias, at least partly due to effects of ethanol on cardiac ionic currents. Contractility and intracellular Ca(2+) dynamics seem to be altered as well. In this study, we integrated the available (mostly animal) experimental data into previously published models of the rat and human ventricular myocytes to assess the share of ionic current components in ethanol-induced changes in AP configuration and cytosolic Ca(2+) transient in ventricular cardiomyocytes. The rat model reproduced well the experimentally observed changes in AP duration (APD) under ethanol (slight prolongation at 0.8 mM and shortening at ≥8 mM). These changes were almost exclusively caused by the ethanol-induced alterations of I K1. The cytosolic Ca(2+) transient decreased gradually with the increasing ethanol concentration as a result of the ethanol-induced inhibition of I Ca. In the human model, ethanol produced a dose-dependent APD lengthening, dominated by ethanol effect on I Kr, the key repolarising current in human ventricles. This effect might contribute to the clinically observed proarrhythmic effects of ethanol in predisposed individuals.

• MeSH
• akční potenciály účinky léků   MeSH
• biologické modely MeSH
• ethanol farmakologie   MeSH
• intracelulární prostor účinky léků   metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• počítačová simulace * MeSH
• sarkoplazmatické retikulum účinky léků   metabolismus   MeSH
• srdeční komory cytologie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.8-80 mM) on acetylcholine-sensitive inward rectifier potassium current I K(Ach). Experiments were performed by the whole-cell patch clamp technique at 23 ± 1 °C on isolated rat and guinea-pig atrial myocytes, and on expressed human Kir3.1/3.4 channels. Ethanol induced changes of I K(Ach) in the whole range of concentrations applied; the effect was not voltage dependent. The constitutively active component of I K(Ach) was significantly increased by ethanol with the maximum effect (an increase by ∼100 %) between 8 and 20 mM. The changes were comparable in rat and guinea-pig atrial myocytes and also in expressed human Kir3.1/3.4 channels (i.e., structural correlate of I K(Ach)). In the case of the acetylcholine-induced component of I K(Ach), a dual ethanol effect was apparent with a striking heterogeneity of changes in individual cells. The effect correlated with the current magnitude in control: the current was increased by eth-anol in the cells showing small current in control and vice versa. The average effect peaked at 20 mM ethanol (an increase of the current by ∼20 %). Observed changes of action potential duration agreed well with the voltage clamp data. Ethanol significantly affected both components of I K(Ach) even in concentrations corresponding to light alcohol consumption.

• MeSH
• acetylcholin farmakologie   MeSH
• akční potenciály MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• dovnitř usměrňující draslíkové kanály spřažené s G proteiny účinky léků   genetika   metabolismus   MeSH
• ethanol toxicita   MeSH
• hodnocení rizik MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• modely kardiovaskulární MeSH
• morčata MeSH
• počítačová simulace MeSH
• potkani Wistar MeSH
• srdeční arytmie chemicky indukované   metabolismus   patofyziologie   MeSH
• srdeční frekvence účinky léků   MeSH
• srdeční síně účinky léků   metabolismus   patofyziologie   MeSH
• transfekce MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Considering the effects of alcohol on cardiac electrical behavior as well as the important role of the inward rectifier potassium current I(K1) in arrhythmogenesis, this study was aimed at the effect of acetaldehyde, the primary metabolite of ethanol, on I(K1) in rat ventricular myocytes. Acetaldehyde induced a reversible inhibition of I(K1) with IC(50) = 53.7+/-7.7 microM at -110 mV; a significant inhibition was documented even at clinically-relevant concentrations (at 3 microM by 13.1+/-3.0 %). The inhibition was voltage-independent at physiological voltages above -90 mV. The I(K1) changes under acetaldehyde may contribute to alcohol-induced alterations of cardiac electrophysiology, especially in individuals with a genetic defect of aldehyde dehydrogenase where the acetaldehyde level may be elevated.

• MeSH
• acetaldehyd farmakologie   MeSH
• draslíkové kanály dovnitř usměrňující antagonisté a inhibitory   metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• metoda terčíkového zámku MeSH
• otrava alkoholem metabolismus   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In many addictive drugs including alcohol and nicotine, proarrhythmic effects were reported. This review provides an overview of the current knowledge in this field (with a focus on the inward rectifier potassium currents) to promote the lacking data and appeal for their completion, thus, to improve understanding of the proarrhythmic potential of addictive drugs. Copyright Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

• MeSH
• akční potenciály MeSH
• draslík * metabolismus   MeSH
• draslíkové kanály dovnitř usměrňující * metabolismus   účinky léků   MeSH
• ethanol * škodlivé účinky   MeSH
• kouření * škodlivé účinky   MeSH
• lidé MeSH
• nikotin * škodlivé účinky   MeSH
• nikotinoví agonisté * škodlivé účinky   MeSH
• pití alkoholu * škodlivé účinky   MeSH
• převodní systém srdeční * metabolismus   patofyziologie   účinky léků   MeSH
• rizikové faktory MeSH
• srdeční arytmie * chemicky indukované   metabolismus   patofyziologie   MeSH
• srdeční frekvence * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

Podkladem potenciálně arytmogenních změn elektrických vlastností srdeční tkáně vyvolaných konzumací alkoholu může být jak přímé působení etanolu a jeho metabolitů, acetaldehydu a acetátu, na srdeční iontové kanály a přenašeče, tak nepřímý vliv zprostředkovaný zejména uvolněnými katecholaminy, změnami pH či elektrolytovou nerovnováhou. Individuálně pak mohou přispívat abnormality ve funkci i struktuře srdeční tkáně. V důsledku neúplných informací a komplexnosti potenciálně spolupůsobících faktorů zůstává konkrétní arytmogenní mechaniz­mus nejasný. Tato práce podává ucelený přehled současných poznatků týkajících se arytmií pozorovaných v souvislosti s konzumací alkoholu a změn elektrických vlastností srdeční tkáně pod vlivem etanolu a jeho metabolitů. Krátce jsou diskutovány možné faktory přispívající ke vzniku arytmií souvisejících s konzumací alkoholu.

Potentially arrhythmogenic changes of the cardiac electrical properties induced by the alcohol consumption may be based both on the direct action of ethanol and its metabolites, acetaldehyde and acetate, on cardiac ionic channels and carriers, and on the indirect effect mediated namely by the released catecholamines, pH changes or electrolyte imbalance. Abnormalities in the cardiac function and structure may individually contribute as well. Owing to the deficient information and complexity of the concurrent factors, the concrete arrhythmogenic mechanism remains unclear. This review shows a comprehensive view on the current knowledge in the arrhythmias observed in relation to the alcohol consumption and in changes of electrical properties of the cardiac tissue under the effect of ethanol and its metabolites. Possible factors contributing to the genesis of arrhythmias related to the alcohol consumption are briefly discussed.

• Klíčová slova
• arytmogeneze, akční napětí,
• MeSH
• acetaldehyd MeSH
• draslíkové kanály fyziologie   účinky léků   MeSH
• elektrokardiografie MeSH
• ethanol metabolismus   škodlivé účinky   MeSH
• iontové kanály účinky léků   MeSH
• lidé MeSH
• pití alkoholu * patofyziologie   škodlivé účinky   MeSH
• převodní systém srdeční * účinky léků   MeSH
• sodíkové kanály fyziologie   účinky léků   MeSH
• srdeční arytmie * etiologie   patofyziologie   MeSH
• srdeční frekvence účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM). Depletion of Ca2+ and accumulation of K+ occurring in extracellular spaces slightly affected the transmembrane Ca2+ flux, but not the action potential duration (APD90). The [Ca2+]i-transient was reduced (by 2%-9%), depending on the stimulation frequency, the rate of ion exchange between t-tubules and clefts and fractions of ion-transfer proteins in the t-tubular membrane. Under non-steady state, the responses of the model to changes of stimulation frequency were analyzed. A sudden increase of frequency (1-2.5 Hz) caused a temporal decrease of [Ca2+] in both extracellular spaces, a reduction of [Ca2+]i-transient (by 15%) and APD90 (by 13 ms). The results reveal different effects of activity-related ion concentration changes in human cardiac t-tubules (steady-state effects) and intercellular clefts (transient effects) in the modulation of membrane ion transport and Ca2+ turnover.

• MeSH
• akční potenciály MeSH
• biologické modely * MeSH
• extracelulární prostor metabolismus   MeSH
• iontový transport MeSH
• ionty chemie   metabolismus   MeSH
• kardiomyocyty cytologie   metabolismus   MeSH
• lidé MeSH
• sarkolema metabolismus   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Atrial fibrillation is the most common arrhythmia at alcohol consumption. Its pathogenesis is complex, at least partly related to changes of cardiac inward rectifier potassium currents including IK1. Both ethanol and acetaldehyde have been demonstrated to considerably modify IK1 in rat ventricular myocytes. However, analogical data on the atrial IK1 are lacking. The present study aimed to analyse IK1 changes induced by ethanol and acetyldehyde in atrial myocytes. The experiments were performed by the whole cell patch-clamp technique at 23 ± 1°C on enzymatically isolated rat and guinea-pig atrial myocytes as well as on expressed human Kir2.3 channels. Ethanol (8 - 80 mM) caused a dual effect on the atrial IK1 showing the steady-state activation in some cells but inhibition in others in agreement with the ventricular data; on average, the activation was observed (at 20 mM by 4.3 and 4.5% in rat and guinea-pig atrial myocytes, respectively). The effect slightly increased with depolarization above -60 mV. In contrast, the current through human Kir2.3 channels (prevailing atrial IK1 subunit) was inhibited in all measured cells. Unlike ethanol, acetaldehyde (3 μM) markedly inhibited the rat atrial IK1 (by 15.1%) in a voltage-independent manner, comparably to the rat ventricular IK1. The concurrent application of ethanol (20 mM) and acetaldehyde (3 μM) resulted in the steady-state IK1 activation by 2.1% on average. We conclude that ethanol and even more acetaldehyde affected IK1 at clinically relevant concentrations if applied separately. Their combined effect did not significantly differ from the effect of ethanol alone.

• MeSH
• acetaldehyd farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• draslíkové kanály dovnitř usměrňující genetika   fyziologie   MeSH
• ethanol farmakologie   MeSH
• kardiomyocyty účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• morčata MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Alcohol consumption may result in electrocardiographic changes and arrhythmias. Important role of modifications of the inward rectifier potassium current I(K1) in arrhythmogenesis is well established. Considering lack of relevant data, we aimed at studying the effect of 0.2-200 mM ethanol on I(K1) in enzymatically isolated rat right ventricular myocytes using the whole cell patch-clamp technique at 23±1°C. Ethanol reversibly affected I(K1) in a dual way. At a very low concentration of 0.8 mM (≈~0.004%), ethanol significantly decreased IK1 by 6.9±2.7%. However, at concentrations of ethanol ≥20 mM (≈0.09%), I(K1) was conversely significantly increased (by 16.6±4.0% at 20 mM and 24.5±2.4% at 80 mM). The steady-state I(K1) increase was regularly preceded by its transient decrease at the beginning of ethanol application. Under 2 and 8 mM ethanol, I(K1) was decreased at the steady-state in some cells but increased in others. Both effects were voltage-independent. In agreement with the observed effects of ethanol on I(K1), a transient action potential (AP) prolongation followed by its final shortening were observed after the application of ethanol in a low concentration of 8 mM (≈0.04%). Under the effect of 0.8 mM ethanol, only AP prolongation was apparent which agreed well with the above described I(K1) decrease. Other AP characteristics remained unaltered in both concentrations. These observations corresponded with the results of mathematical simulations in a model of the rat ventricular myocyte. To summarize, changes of the cardiac I(K1) under ethanol at concentrations relevant to the current alcohol consumption were first demonstrated in ventricular myocytes in this study. The observed dual ethanol effect suggests at least two underlying mechanisms that remain to be clarified. The ethanol-induced I(K1) changes might contribute to the reported alterations of cardiac electrophysiology related to alcohol consumption.

• MeSH
• akční potenciály účinky léků   MeSH
• draslíkové kanály dovnitř usměrňující fyziologie   MeSH
• ethanol farmakologie   MeSH
• kardiomyocyty účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• srdeční komory cytologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca(2+) efflux pathways (SERCA, Na(+)/Ca(2+) exchange, and sarcolemmal Ca(2+) ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca(2+) buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca(2+) in the dyad and bulk cytoplasm, on cellular Ca(2+) cycling. Increasing the dyadic fraction of a particular Ca(2+) efflux pathway increases the amount of Ca(2+) removed by that pathway, with corresponding changes in Ca(2+) efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca(2+) removed from the cytoplasm by that pathway. Differences in the response to EGTA and BAPTA, including changes in Ca(2+)-dependent inactivation of the L-type Ca(2+) current, resulted from the buffers acting as slow and fast "shuttles," respectively, removing Ca(2+) from the dyadic space. The data suggest that complex changes in dyadic Ca(2+) and cellular Ca(2+) cycling occur as a result of changes in the location of Ca(2+) removal pathways or the presence of exogenous Ca(2+) buffers, although changing the distribution of Ca(2+) efflux pathways has relatively small effects on the systolic Ca(2+) transient.

• MeSH
• biologické modely MeSH
• časové faktory MeSH
• EGTA analogy a deriváty   farmakologie   MeSH
• gating iontového kanálu účinky léků   MeSH
• intracelulární prostor účinky léků   metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kompartmentace buňky MeSH
• krysa rodu rattus MeSH
• počítačová simulace MeSH
• pufry MeSH
• pumpa pro výměnu sodíku a vápníku metabolismus   MeSH
• sarkolema účinky léků   metabolismus   MeSH
• srdeční komory cytologie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH