scholarly journals Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species

2018 ◽  
Vol 11 (10) ◽  
Author(s):  
Meera Varshneya ◽  
Ryan A. Devenyi ◽  
Eric A. Sobie
Keyword(s):  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Multiple Species

Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization

2000 ◽  
Vol 278 (3) ◽  
pp. H806-H817 ◽  
Author(s):  
Gary A. Gintant
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Ventricular Repolarization ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Voltage Dependent

Although inactivation of the rapidly activating delayed rectifier current ( I Kr) limits outward current on depolarization, the role of I Kr (and recovery from inactivation) during repolarization is uncertain. To characterize I Krduring ventricular repolarization (and compare with the inward rectifier current, I K1), voltage-clamp waveforms simulating the action potential were applied to canine ventricular, atrial, and Purkinje myocytes. In ventricular myocytes, I Kr was minimal at plateau potentials but transiently increased during repolarizing ramps. The I Kr transient was unaffected by repolarization rate and maximal after 150-ms depolarizations (+25 mV). Action potential clamps revealed the I Kr transient terminating the plateau. Although peak I Kr transient density was relatively uniform among myocytes, potentials characterizing the peak transients were widely dispersed. In contrast, peak inward rectifier current ( I K1) density during repolarization was dispersed, whereas potentials characterizing I K1 defined a narrower (more negative) voltage range. In summary, rapidly activating I Kr provides a delayed voltage-dependent (and functionally time-independent) outward transient during ventricular repolarization, consistent with rapid recovery from inactivation. The heterogeneous voltage dependence of I Kr provides a novel means for modulating the contribution of this current during repolarization.

Temperature-dependent expression of sarcolemmal K+ currents in rainbow trout atrial and ventricular myocytes

2002 ◽  
Vol 282 (4) ◽  
pp. R1191-R1199 ◽  
Author(s):  
Matti Vornanen ◽  
Ari Ryökkynen ◽  
Antti Nurmi
Keyword(s):  
Rainbow Trout ◽  
Cardiac Myocytes ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Temperature Acclimation ◽  
Delayed Rectifier ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Delayed Rectifier Current ◽  
Ventricular Cells

Temperature has a strong influence on the excitability and the contractility of the ectothermic heart that can be alleviated in some species by temperature acclimation. The molecular mechanisms involved in the temperature-induced improvement of cardiac contractility and excitability are, however, still poorly known. The present study examines the role of sarcolemmal K+ currents from rainbow trout ( Oncorhynchus mykiss) cardiac myocytes after thermal acclimation. The two major K+ conductances of the rainbow trout cardiac myocytes were identified as the Ba2+-sensitive background inward rectifier current ( I K1) and the E-4031-sensitive delayed rectifier current ( I Kr). In atrial cells, the density of I K1 is very low and the density of I Kr is remarkably high. The opposite is true for ventricular cells. Acclimation to cold (4°C) modified the two K+ currents in opposite ways. Acclimation to cold increases the density of I Kr and depresses the density of I K1. These changes in repolarizing K+ currents alter the shape of the action potential, which is much shorter in cold-acclimated than warm-acclimated (17°C) trout. These results provide the first concrete evidence that K+channels of trout cardiac myocytes are adaptable units that provide means to regulate cardiac excitability and contractility as a function of temperature.

SUPPRESSION OF CELLULAR ALTERNANS IN GUINEA PIG VENTRICULAR MYOCYTES WITH LQT2: INSIGHTS FROM THE LUO–RUDY MODEL

2007 ◽  
Vol 17 (02) ◽  
pp. 381-425 ◽  
Author(s):  
VLADIMIR E. BONDARENKO ◽  
RANDALL L. RASMUSSON
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Chaotic Behavior ◽  
Heart Diseases ◽  
Pump Current ◽  
Delayed Rectifier ◽  
Drug Induced ◽  
Delayed Rectifier Current ◽  
Model Control ◽  
Pump Activity

Genetic and drug-induced abnormalities of cardiac repolarization have been linked to fatal arrhythmias. These arrhythmias result from a complex interaction of the remaining currents during excitation and repolarization. In this review, we examine recent advancement in investigations of genetic heart diseases and mechanisms of arrhythmia generation. We also present our simulation of repolarization during rapid pacing for different levels of block of the rapid delayed rectifier current, I Kr , and pharmacological interventions using the Luo–Rudy model. Control simulations showed the development of alternans at a basic cycle length (BCL) of 131 ms. Two levels of I Kr block were simulated corresponding to type 2 of familial long QT syndrome, LQT2. At 100% I Kr block, the threshold BCL for the appearance of alternans increased to 145 ms and for shorter cycle lengths showed increasingly complex patterns of periodic and chaotic behavior. We examined the potential of other currents to correct this complex behavior. Improvement of the threshold for bifurcation as a function of BCL was achieved by: (1) 100% block of a nonspecific Ca 2+-activated current; (2) 15% block of L-type Ca 2+ current; (3) 20% increase of Na +/ K + pump current; (4) 50% increase of SERCA2 pump activity. Conversely, increased L-type Ca 2+ current, decreased Na +/ K + pump current, or decreased SERCA2 pump activity increased the threshold BCL. Modification of several other currents had little effect. Alternans and chaotic activity develop at fast pacing rates in model guinea pig ventricular myocytes through a sequence of bifurcations. We elucidated mechanisms that modify the development of alternans which may provide novel targets for treatment of patients with LQT2.

Mechanism of enhancement of slow delayed rectifier current by extracellular sulfhydryl modification

1997 ◽  
Vol 273 (1) ◽  
pp. H208-H219 ◽  
Author(s):  
J. A. Yao ◽  
M. Jiang ◽  
G. N. Tseng
Keyword(s):  
Transmembrane Domain ◽  
Ventricular Myocytes ◽  
Current Model ◽  
The Other ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Sh Group ◽  
Intracellular Ca ◽  
Sulfhydryl Modification

To explore the role of sulfhydryl (SH) groups in the function of cardiac slow delayed rectifier channels, we tested the effects of extracellular thimerosal (TMS, a hydrophilic SH modifier) on slow delayed rectifier current (IKs) induced by human IsK (hIsK) in oocytes and on the native IKs in canine ventricular myocytes. TMS (25 or 50 microM) had similar effects on the two currents: current amplitude increased, and there was an acceleration of activation and a slowing of deactivation. These effects showed little or no reversal after washout of TMS. The effects did not depend on intracellular Ca release or protein kinase activities but could be suppressed by dithiothreitol pretreatment. According to the current model of transmembrane topology, there is no cystein in the extracellular domain of hIsK. A likely candidate for TMS modification is the SH group on another subunit in oocyte cell membrane that interacts with IsK to form a functional channel. To explore the domain of hIsK involved in the interaction, extracellular serines of hIsK were mutated to cysteines at three locations: S37C (close to the transmembrane domain), S4C (close to the NH2-terminus), and S28C (in between). S37C and S28C mutations did not affect channel properties or hIsK response to TMS. On the other hand, S4C mutation reduced current expression even when S4C cRNA was injected at a quantity 50-fold higher than that of the other three proteins. Importantly, the response to TMS was markedly reduced in S4C compared with the other three proteins. Therefore, the NH2-terminus of hIsK may be involved in hIsK interaction with the SH-bearing subunit, and this interaction modulates slow delayed rectifier channel function.

Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling

2000 ◽  
Vol 278 (3) ◽  
pp. H677-H687 ◽  
Author(s):  
Massimiliano Zaniboni ◽  
Andrew E. Pollard ◽  
Lin Yang ◽  
Kenneth W. Spitzer
Keyword(s):  
Ventricular Myocytes ◽  
Single Cells ◽  
Electrical Coupling ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Constant Rate ◽  
Electrotonic Interactions ◽  
Single Ventricular Myocytes ◽  
The Mean ◽  
Junctional Resistance

Single ventricular myocytes paced at a constant rate and held at a constant temperature exhibit beat-to-beat variations in action potential duration (APD). In this study we sought to quantify this variability, assess its mechanism, and determine its responsiveness to electrotonic interactions with another myocyte. Interbeat APD90 (90% repolarization) of single cells was normally distributed. We thus quantified APD90 variability as the coefficient of variability, CV = (SD/mean APD90) × 100. The mean ± SD of the CV in normal solution was 2.3 ± 0.9 (132 cells). Extracellular TTX (13 μM) and intracellular EGTA (14 mM) both significantly reduced the CV by 44 and 26%, respectively. When applied in combination the CV fell by 54%. In contrast, inhibition of the rapid delayed rectifier current with L-691,121 (100 nM) increased the CV by 300%. The CV was also significantly reduced by 35% when two normal myocytes were electrically connected with a junctional resistance ( R j) of 100 MΩ. Electrical coupling ( R j = 100 MΩ) of a normal myocyte to one producing early afterdepolarization (EAD) completely blocked EAD formation. These results indicate that beat-to-beat APD variability is likely mediated by stochastic behavior of ion channels and that electrotonic interactions act to limit temporal dispersion of refractoriness, a major contributor to arrhythmogenesis.

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