Aminophylline, a bronchodilator mainly used to treat severe asthma attacks, may induce arrhythmias. Unfortunately, the underlying mechanism is not well understood. We have recently described a significant, on average inhibitory effect of aminophylline on inward rectifier potassium current IK1, known to substantially contribute to arrhythmogenesis, in rat ventricular myocytes at room temperature. This study was aimed to examine whether a similar effect may be observed under clinically relevant conditions. Experiments were performed using the whole cell patch clamp technique at 37°C on enzymatically isolated healthy porcine and failing human ventricular myocytes. The effect of clinically relevant concentrations of aminophylline (10-100 μM) on IK1 did not significantly differ in healthy porcine and failing human ventricular myocytes. IK1 was reversibly inhibited by ∼20 and 30 % in the presence of 30 and 100 μM aminophylline, respectively, at -110 mV; an analogical effect was observed at -50 mV. To separate the impact of IK1 changes on AP configuration, potentially interfering ionic currents were blocked (L-type calcium and delayed rectifier potassium currents). A significant prolongation of AP duration was observed in the presence of 100 μM aminophylline in porcine cardiomyocytes which well agreed with the effect of a specific IK1 inhibitor Ba2+ (10 μM) and with the result of simulations using a porcine ventricular cell model. We conclude that the observed effect of aminophylline on healthy porcine and failing human IK1 might be involved in its proarrhythmic action. To fully understand the underlying mechanism, potential aminophylline impact on other ionic currents should be explored.

• MeSH
• akční potenciály účinky léků   MeSH
• aminofylin * farmakologie   MeSH
• draslíkové kanály dovnitř usměrňující * metabolismus   MeSH
• kardiomyocyty * účinky léků   metabolismus   MeSH
• lidé MeSH
• metoda terčíkového zámku MeSH
• prasata MeSH
• srdeční komory účinky léků   metabolismus   MeSH
• srdeční selhání metabolismus   farmakoterapie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

• MeSH
• biologický transport * fyziologie   MeSH
• buněčná membrána fyziologie   MeSH
• iontové kanály řízené ligandy fyziologie   MeSH
• lidé MeSH
• membránové transportní proteiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• buněčná membrána fyziologie   MeSH
• elektrofyziologie normy   MeSH
• kardiologie normy   MeSH
• kardiomyocyty fyziologie   MeSH
• lidé MeSH
• reprodukovatelnost výsledků MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• úvodní články MeSH
• úvodníky 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

Nicotine abuse is associated with variety of diseases including arrhythmias, most often atrial fibrillation (AF). Altered inward rectifier potassium currents including acetylcholine-sensitive current I K(Ach) are known to be related to AF pathogenesis. Since relevant data are missing, we aimed to investigate I K(Ach) changes at clinically relevant concentrations of nicotine. Experiments were performed by the whole cell patch clamp technique at 23 ± 1 °C on isolated rat atrial myocytes. Nicotine was applied at following concentrations: 4, 40 and 400 nM; ethanol at 20 mM (∼0.09%). Nicotine at 40 and 400 nM significantly activated constitutively active component of I K(Ach) with the maximum effect at 40 nM (an increase by ∼100%); similar effect was observed at -110 and -50 mV. Changes at 4 nM nicotine were negligible on average. Coapplication of 40 nM nicotine and 20 mM ethanol (which is also known to activate this current) did not show cumulative effect. In the case of acetylcholine-induced component of I K(Ach), a dual effect of nicotine and its correlation with the current magnitude in control were apparent: the current was increased by nicotine in the cells showing small current in control and vice versa. The effect of 40 and 400 nM nicotine on acetylcholine-induced component of I K(Ach) was significantly different at -110 and -50 mV. We conclude that nicotine at clinically relevant concentrations significantly increased constitutively active component of I K(Ach) and showed a dual effect on its acetylcholine-induced component, similarly as ethanol. Synchronous application of nicotine and ethanol did not cause additive effect.

• MeSH
• acetylcholin farmakologie   MeSH
• časové faktory MeSH
• dovnitř usměrňující draslíkové kanály spřažené s G proteiny agonisté   účinky léků   MeSH
• ethanol toxicita   MeSH
• hodnocení rizik MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• membránové potenciály MeSH
• nikotin toxicita   MeSH
• potkani Wistar MeSH
• srdeční arytmie chemicky indukované   metabolismus   MeSH
• srdeční síně účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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

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

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

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