scholarly journals Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

2019 ◽  
Vol 151 (2) ◽  
pp. 214-230 ◽  
Author(s):  
Kazuharu Furutani ◽  
Kunichika Tsumoto ◽  
I-Shan Chen ◽  
Kenichiro Handa ◽  
Yuko Yamakawa ◽  
...  
Keyword(s):  
Action Potential ◽  
Computational Models ◽  
Low Voltage ◽  
Herg Channel ◽  
Channel Blockers ◽  
Cardiac Safety ◽  
Early Afterdepolarizations ◽  
Repolarization Reserve ◽  
Action Potential Prolongation ◽  
Herg Channels

Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

scholarly journals Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias

2018 ◽  
Author(s):  
Kazuharu Furutani ◽  
Kunichika Tsumoto ◽  
I-Shan Chen ◽  
Kenichiro Handa ◽  
Yuko Yamakawa ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Arrhythmias ◽  
Action Potential Duration ◽  
Potassium Current ◽  
Low Voltage ◽  
Sodium Current ◽  
Ionic Current ◽  
Delayed Rectifier ◽  
Early Afterdepolarizations ◽  
Herg Channels

AbstractFatal cardiac arrhythmias are caused by some, but not all, drugs that inhibit the cardiac rapid delayed-rectifier current (IKr) by blocking hERG channels. Here, we propose a novel mechanism that could make certain hERG blockers less proarrhythmic. Several drugs that block hERG channels, yet have favorable cardiac safety profiles, also evoke another effect; they increase the current amplitude upon low-voltage depolarization (facilitation). Voltage-clamp recordings of hERG block and facilitation by nifekalant, a Class III antiarrhythmic agent, constrained a model of human cardiac IKr. In human ventricular action potential simulations, nifekalant showed its therapeutic ability to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evoked early afterdepolarizations, which cause lethal arrhythmias. Facilitation prevented early afterdepolarizations at the same degree of block by increasing IKr during repolarization phase of action potentials. Thus, facilitation is proposed to reduce the arrhythmogenic risk of hERG blockers.AbbreviationsAP: action potential; APD: action potential duration; APD90: action potential duration measured at 90% repolarization; EAD: early afterdepolarization; hERG: human ether-ago-go-related gene; ICaL: L-type Ca2+ channel current; Inet: net ionic current; IK1: inward-rectifier potassium current; IKr: rapid component of the delayed-rectifier potassium current; INa: sodium current; ORd: O’Hara-Rudy dynamic

Modulation of the effects of sotalol on Purkinje strand electromechanical characteristics

1989 ◽  
Vol 67 (11) ◽  
pp. 1463-1467 ◽  
Author(s):  
David A. Lathrop ◽  
András Varró
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Potassium Conductance ◽  
Channel Blockers ◽  
Early Afterdepolarizations ◽  
Force Development ◽  
Transmembrane Action Potential ◽  
Potassium Channel Activator ◽  
Cardiac Sodium Channels ◽  
Arrhythmogenic Effects

The modulation of the effects of sotalol (30 μM) by two sodium channel blockers, tetrodotoxin (0.07 μM) and lidocaine (50 μM), and by a potassium channel activator, nicorandil (30 μM), were examined. Sotalol alone greatly increased Purkinje fiber transmembrane action potential duration and, in some preparations, induced early afterdepolarizations. Concurrent with the changes in action potential duration, sotalol also increased isolated Purkinje strand developed force paced at slow rates (0.33 Hz). These sotalol-induced alterations of Purkinje strand electromechanical characteristics were similar to those produced by either veratrine (0.6 or 1.0 μg/mL) or by tetraethylammonium (10 mM). The effects of sotalol on action potential duration and force development were reversed by exposure to either tetrodotoxin or nicorandil. Lidocaine also reversed the effects of sotalol on action potential duration and developed force. The sotalol-induced increase in action potential duration and development of early afterdepolarizations may, therefore, be abated by combination with drugs that either block cardiac sodium channels or that increase membrane potassium conductance. Combination with such drugs may help prevent the adverse arrhythmogenic effects of sotalol.Key words: sotalol, lidocaine, action potential duration, nicorandil, force development, tetrodotoxin.

scholarly journals Developmental Changes in Action Potential Prolongation by K+-Channel Blockers in Chick Myocardium

2011 ◽  
Vol 115 (2) ◽  
pp. 235-238 ◽  
Author(s):  
Hideaki Nouchi ◽  
Naoaki Kiryu ◽  
Mikio Kimata ◽  
Yayoi Tsuneoka ◽  
Shogo Hamaguchi ◽  
...  
Keyword(s):  
Action Potential ◽  
Developmental Changes ◽  
K Channel ◽  
Channel Blockers ◽  
Action Potential Prolongation

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

2007 ◽  
Vol 292 (6) ◽  
pp. H3089-H3102 ◽  
Author(s):  
Ray B. Huffaker ◽  
James N. Weiss ◽  
Boris Kogan
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Genetic Diseases ◽  
Three Dimensional ◽  
New Wave ◽  
Early Afterdepolarizations ◽  
Heart Rates ◽  
Torsades Des Pointes ◽  
Repolarization Reserve ◽  
Inward Currents

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.

scholarly journals Determinants of early afterdepolarization properties in ventricular myocyte models

2018 ◽  
Author(s):  
Xiaodong Huang ◽  
Zhen Song ◽  
Zhilin Qu
Keyword(s):  
Action Potential ◽  
Mathematical Models ◽  
Cardiac Myocytes ◽  
Potential Model ◽  
Model Development ◽  
Computer Models ◽  
Homoclinic Bifurcation ◽  
Early Afterdepolarizations ◽  
Potential Models ◽  
Repolarization Reserve

AbstractEarly afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.Author summaryEarly afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of action potential in cardiac myocytes, arising from a dual Hopf-homoclinic bifurcation. The same bifurcations are also responsible for certain types of bursting behaviors in other cell types, such as beta cells and neuronal cells. EADs are known to play important role in the genesis of lethal arrhythmias and have been widely studied in both experiments and computer models. However, a detailed comparison between the properties of EADs observed in experiments and those from mathematical models have not been carried out. In this study, we performed theoretical analyses and computer simulations of different ventricular action potential models as well as different species to investigate the properties of EADs and compared these properties to those observed in experiments. While the EAD properties in the action potential models capture many of the EAD properties seen in experiments, the inter-EAD intervals in the computer models differ a lot from model to model, and some of them show very large discrepancy with those observed in experiments. This discrepancy needs to be addressed in future cardiac action potential model development.

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