The importance of repolarization reserve in mammalian ventricle

2018 ◽  
Author(s):  
Attila András Kristóf
Keyword(s):  
Repolarization Reserve ◽  
Mammalian Ventricle

scholarly journals Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

2021 ◽  
Vol 14 (8) ◽  
pp. 748
Author(s):  
Péter P. Nánási ◽  
Balázs Horváth ◽  
Fábián Tar ◽  
János Almássy ◽  
Norbert Szentandrássy ◽  
...  
Keyword(s):  
Action Potential ◽  
Time Course ◽  
Laboratory Animals ◽  
Delayed Rectifier ◽  
Ion Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Repolarization Reserve ◽  
Electrophysiological Studies ◽  
K Current

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

scholarly journals The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

2021 ◽  
Author(s):  
Leila Topal ◽  
Muhammad Naveed ◽  
Péter Orvos ◽  
Bence Pászti ◽  
János Prorok ◽  
...  
Keyword(s):  
Side Effects ◽  
Action Potentials ◽  
Oral Intake ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiovascular Side Effects ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

scholarly journals Activation of ATP-sensitive K+ channels by cromakalim. Effects on cellular K+ loss and cardiac function in ischemic and reperfused mammalian ventricle.

1992 ◽  
Vol 71 (6) ◽  
pp. 1324-1333 ◽  
Author(s):  
N Venkatesh ◽  
J S Stuart ◽  
S T Lamp ◽  
L D Alexander ◽  
J N Weiss
Keyword(s):  
Cardiac Function ◽  
K Channels ◽  
Mammalian Ventricle

Interaction of different potassium channels in dog ventricular repolarization: Role of the repolarization reserve

2002 ◽  
Vol 34 (6) ◽  
pp. A10
Author(s):  
Péter Biliczki ◽  
László Virág ◽  
Norbert Iost ◽  
Julius Gy. Papp ◽  
András Varró
Keyword(s):  
Potassium Channels ◽  
Ventricular Repolarization ◽  
Repolarization Reserve

Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart

2009 ◽  
Vol 297 (3) ◽  
pp. H1048-H1057 ◽  
Author(s):  
Lin Wu ◽  
Sridharan Rajamani ◽  
Hong Li ◽  
Craig T. January ◽  
John C. Shryock ◽  
...  
Keyword(s):  
Torsade De Pointes ◽  
Polymorphic Ventricular Tachycardia ◽  
Isolated Hearts ◽  
T Wave ◽  
Dispersion Of Repolarization ◽  
Transmural Dispersion Of Repolarization ◽  
Repolarization Reserve ◽  
Monophasic Action Potentials ◽  
Transmural Dispersion

Reduction of repolarization reserve increases the risk of arrhythmia. We hypothesized that inhibition of K+ current ( IK) to decrease repolarization reserve would unmask the proarrhythmic role of endogenous, physiological late Na+ current (late INa). Monophasic action potentials (MAP) and 12-lead electrocardiogram were recorded from female rabbit isolated hearts. To block IK and reduce repolarization reserve, E-4031, 4-aminopyridine, and BaCl2 were used; to block endogenous late INa, tetrodotoxin (TTX) and ranolazine were used. E-4031 (1–60 nM) concentration-dependently prolonged MAP duration (MAPD90) and increased duration of the T wave from Tpeak to Tend (Tpeak-Tend), transmural dispersion of repolarization (TDR), and beat-to-beat variability (BVR) of MAPD90. E-4031 caused spontaneous and pause-triggered polymorphic ventricular tachycardia [ torsade de pointes (TdP)]. In the presence of 60 nM E-4031, TTX (0.6–3 μM) and ranolazine (5–10 μM) shortened MAPD90, decreased TDR, BVR, and Tpeak-Tend ( n = 9–20, P < 0.01), and abolished episodes of TdP. In hearts treated with BaCl2 or 4-aminopyridine plus E-4031, TTX (0.6–3 μM) shortened MAPD90 and decreased Tpeak-Tend. Ranolazine could not reverse the effect of E-4031 to inhibit human ether-a-go-go-related gene (HERG) K+ current; thus, the reversal by ranolazine of effects of E-4031 was likely due to inhibition of late INa and not to antagonism of the HERG-blocking action of E-4031. We conclude that endogenous, physiological late INa contributes to arrhythmogenesis in hearts with reduced repolarization reserve. Inhibition of this current partially reverses MAPD prolongation and abolishes arrhythmic activity caused by IK inhibitors.

scholarly journals Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

2020 ◽  
Author(s):  
Richard S Varga ◽  
Tibor Hornyik ◽  
Zoltán Husti ◽  
Zsófia Kohajda ◽  
Gábor Krajsovszky ◽  
...  
Keyword(s):  
Torsades De Pointes ◽  
Coronary Artery Occlusion ◽  
Canine Model ◽  
Artery Occlusion ◽  
Class I ◽  
Class Iii ◽  
Drug Induced ◽  
Pharmacological Management ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion, reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged frequency corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations and blocked IKr in isolated cardiomyocytes (Class III effects), reduced maximum rate of depolarization (Vmax) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent re-entry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

scholarly journals Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs

2013 ◽  
Vol 591 (17) ◽  
pp. 4189-4206 ◽  
Author(s):  
Norbert Jost ◽  
László Virág ◽  
Philippe Comtois ◽  
Balázs Ördög ◽  
Viktória Szuts ◽  
...  
Keyword(s):  
Cardiac Repolarization ◽  
Repolarization Reserve ◽  
Ionic Mechanisms

Abstract 3503: Hydrogen Peroxide-Induced Afterdepolarizations are Dependent on Calmodulin Kinase II Signaling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Lai-Hua Xie ◽  
Fuhua Chen ◽  
James N Weiss
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Ventricular Myocytes ◽  
Heart Association ◽  
Early Afterdepolarizations ◽  
Calmodulin Kinase ◽  
Repolarization Reserve ◽  
Delayed Afterdepolarizations ◽  
Rabbit Ventricular Myocytes ◽  
Camkii Activation

Background: In the heart, hydrogen peroxide (H 2 O 2 ) has been shown to cause early afterdepolarizations (EADs) and triggered activity by impairing Na current (I Na ) inactivation. Since H 2 O 2 has been recently shown to activate Ca 2+ /calmodulin kinase II (CaMKII), and since CaMKII activation has also been reported to impair I Na inactivation and predispose to EADs, we hypothesized that CaMKII activation by H 2 O 2 may be an important factor in the genesis of EADs induced by oxidative stress. Methods and Results: Patch-clamped Fluo-4 AM-loaded rabbit ventricular myocytes were exposed to H 2 O 2 (0.1–1mM), which induced spontaneous EADs after 5–15 min. Both the I Na blocker tetrodoxtin (TTX, 10 μM) and the I Ca,L blocker nifedipine shortened AP duration (APD) and suppressed EADs. H 2 O 2 increased both peak and steady-state I Ca,L under square-pulse voltage clamp, and enhanced I Ca,L to a greater extent during the AP plateau than during the AP upstroke under AP clamp conditions. In addition, by prolonging the AP plateau and increasing Ca influx via maintained I Ca,L , H 2 O 2 -induced EADs frequently caused DADs delayed afterdepolarizations (DADs) due to spontaneous SR Ca release waves after repolarization. KN-93(1 μM), a CaMKII inhibitor, prevented H 2 O 2 -induced EADs (n=4), whereas the inactive analogue KN-92 did not (n=5). Conclusion: These findings indicate that H 2 O 2 -induced EADs depend on both impaired I Na inactivation to reduce repolarization reserve and enhanced I Ca,L to reverse repolarization. Intact CaMKII signaling is necessary for EAD generation in this setting, presumably via its actions on I Na and I Ca,L , although direct redox effects on other ion channels/transporters may also be important. Our observations support a link between increased oxidative stress, CaMKII activation and afterdepolarizations as triggers of lethal ventricular arrhythmias in diseased heart. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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