A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells

2004 ◽  
Vol 286 (5) ◽  
pp. H1757-H1766 ◽  
Author(s):  
Robert B. Clark ◽  
Matteo E. Mangoni ◽  
Andreas Lueger ◽  
Brigitte Couette ◽  
Joel Nargeot ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Adult Mouse ◽  
Sinoatrial Node ◽  
Physiological Role ◽  
Inward Rectification ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Class Iii ◽  
K Current

We have investigated the physiological role of the “rapidly activating” delayed rectifier K+ current ( IKr) in pacemaker activity in isolated sinoatrial node (SAN) myocytes and the expression of mouse ether-a-go-go (mERG) genes in the adult mouse SAN. In isolated, voltage-clamped SAN cells, outward currents evoked by depolarizing steps (greater than –40 mV) were strongly inhibited by the class III methanesulfonanilide compound E-4031 (1–2.5 μM), and the deactivation “tail” currents that occurred during repolarization to a membrane potential of –45 mV were completely blocked. E-4031-sensitive currents ( IKr) reached a maximum at a membrane potential of –10 mV and showed pronounced inward rectification at more-positive membrane potentials. Activation of IKr occurred at –40 to 0 mV, with half-activation at about –24 mV. The contribution of IKr to action potential repolarization and diastolic depolarization was estimated by determining the E-4031-sensitive current evoked during voltage clamp with a simulated mouse SAN action potential. IKr reached its peak value (∼0.6 pA/pF) near –25 mV, close to the midpoint of the repolarization phase of the simulated action potential, and deactivated almost completely during the diastolic interval. E-4031 (1 μM) slowed the spontaneous pacing rate of Langendorff-perfused, isolated adult mouse hearts by an average of 36.5% ( n = 5). Expression of mRNA corresponding to three isoforms coded by the mouse ERG1 gene (mERG1), mERG1a, mERG1a′, and mERG1b, was consistently found in the SAN. Our data provide the first detailed characterization of IKr in adult mouse SAN cells, demonstrate that this current plays an important role in pacemaker activity, and indicate that multiple isoforms of mERG1 can contribute to native SAN IKr.

Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity

1995 ◽  
Vol 269 (2) ◽  
pp. H453-H462 ◽  
Author(s):  
K. Ono ◽  
H. Ito
Keyword(s):  
Action Potential ◽  
Maximum Rate ◽  
Sinoatrial Node ◽  
Cell Voltage ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Amplitude Maximum ◽  
K Current ◽  
Sinoatrial Node Cells ◽  
Diastolic Potential

A rapidly activating component of delayed rectifier K+ current (IK,r) was dissected using a selective blocker, E-4031, during the action potential clamp (AP clamp) in rabbit sinoatrial node cells. Application of E-4031 induced a large compensation current, of which amplitude was similar to or larger than the net current during repolarization and was maximum (2.2 +/- 0.2 pA/pF) at -46.0 +/- 1.8 mV (n = 13). During the slow diastolic depolarization, the compensation current gradually decayed and then abruptly decreased at the peak of action potential. The time-dependent change of IK,r was calculated using a mathematical model, in which independent gates of activation and inactivation were assumed based on the whole cell voltage-clamp experiments. The reconstructed IK,r corresponded well with the E-4031-sensitive current measured by the AP clamp method. Partial block of IK,r by E-4031 in spontaneously beating cells decreased the action potential amplitude, maximum rate of rise, and maximum rate of repolarization and induced a positive shift of the maximum diastolic potential. Complete block of IK,r terminated the spontaneous action potential at -37.4 +/- 2.9 mV (n = 3). It is concluded that IK,r plays an essential role in determining the maximum diastolic potential and ensures the firing of the following action potential in sinoatrial node cells.

scholarly journals Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.

1990 ◽  
Vol 96 (1) ◽  
pp. 195-215 ◽  
Author(s):  
M C Sanguinetti ◽  
N K Jurkiewicz
Keyword(s):  
Antiarrhythmic Agent ◽  
Reversal Potential ◽  
Differential Sensitivity ◽  
Inward Rectification ◽  
Delayed Rectifier ◽  
Antiarrhythmic Agents ◽  
Class Iii ◽  
Activation Curve ◽  
Voltage Range ◽  
K Current

An envelope of tails test was used to show that the delayed rectifier K+ current (IK) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM). The drug-sensitive current, "IKr" exhibits prominent rectification and activates very rapidly relative to the slowly activating drug-insensitive current, "IKs." IKs was characterized by a delayed onset of activation that occurs over a voltage range typical of the classically described cardiac IK. Fully activated IKs, measured as tail current after 7.5-s test pulses, was 11.4 times larger than the fully activated IKr. IKr was also blocked by d-sotalol (100 microM), a less potent benzenesulfonamide Class III antiarrhythmic agent. The activation curve of IKr had a steep slope (+7.5 mV) and a negative half-point (-21.5 mV) relative to the activation curve of IKs (slope = +12.7 mV, half-point = +15.7 mV). The reversal potential (Erev) of IKr (-93 mV) was similar to EK (-94 mV for [K+]o = 4 mM), whereas Erev of IKs was -77 mV. The time constants for activation and deactivation of IKr made up a bell-shaped function of membrane potential, peaking between -30 and -40 mV (170 ms). The slope conductance of the linear portion of the fully activated IKr-V relation was 22.5 S/F. Inward rectification of this relation occurred at potentials greater than -50 mV, resulting in a voltage-dependent decrease in peak IKr at test potentials greater than 0 mV. Peak IKr at 0 mV averaged 0.8 pA/pF (n = 21). Although the magnitude of IKr was small relative to fully activated IKs, the two currents were of similar magnitude when measured during a relatively short pulse protocol (225 ms) at membrane potentials (-20 to +20 mV) typical of the plateau phase of cardiac action potentials.

Delayed rectifier K+ current in rabbit atrial myocytes

1995 ◽  
Vol 269 (2) ◽  
pp. H524-H532 ◽  
Author(s):  
K. Muraki ◽  
Y. Imaizumi ◽  
M. Watanabe ◽  
Y. Habuchi ◽  
W. R. Giles
Keyword(s):  
Maximum Amplitude ◽  
Outward Current ◽  
Cell Voltage ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Delayed Rectifier ◽  
Wave Form ◽  
Class Iii ◽  
Atrial Myocytes ◽  
K Current

The role of delayed rectifier K+ current(s) (IK) in rabbit left atrium was examined by applying the whole cell voltage-clamp technique to isolated single myocytes. Right-triangular waveforms, which mimic the shape of atrial action potentials (APs), and selective blockers were used to compare the contribution of IK with other K+ currents to repolarization of the APs. IK measured at 34 degrees C in atrial myocytes was very small; the maximum peak amplitude of the tail current (IK,tail) at -40 mV was approximately 50 pA. The IK,tail was almost abolished in most cells (approximately 80%) by the application of 1 microM E-4031, a class III antiarrhythmic drug. The E-4031-sensitive current recorded with the triangular command wave-form showed strong inward rectification and had a maximum amplitude of approximately 30 pA at -40 mV. Total outward current elicited by triangular command pulses depended strongly on stimulation frequency. The main frequency-dependent component was a Ca(2+)-independent transient K+ current (I(t)). I(t) elicited by triangular pulses at 1 Hz was substantially reduced by 4-aminopyridine (4-AP) at potentials positive to 0 mV but was not changed significantly by 1 microM E-4031; 100 microM E-4031 reduced I(t) by approximately 30%. The shape of the APs which were recorded from a single rabbit atrial cell strongly depended on the pulse frequency. Application of 1 microM E-4031 increased action potential duration (APD) in > 50% of cells examined but had little effect on the resting membrane potential (RMP). Application of 0.1 mM BaCl2 also lengthened APD and reduced RMP by approximately 20 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4761
Author(s):  
Wei Hu ◽  
Robert B. Clark ◽  
Wayne R. Giles ◽  
Erwin Shibata ◽  
Henggui Zhang
Keyword(s):  
Adult Mouse ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Mouse Heart ◽  
Voltage Dependent ◽  
Electrophysiological Studies ◽  
Ionic Mechanisms ◽  
K Current ◽  
Significant Expression

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.

Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells

1991 ◽  
Vol 260 (2) ◽  
pp. H393-H399 ◽  
Author(s):  
M. C. Sanguinetti ◽  
N. K. Jurkiewicz
Keyword(s):  
Guinea Pig ◽  
Inward Rectification ◽  
Delayed Rectifier ◽  
Class Iii ◽  
Activation Curve ◽  
Atrial Cells ◽  
Ventricular Cells ◽  
Steady State Current ◽  
Slope Factor ◽  
K Current

The delayed rectifier outward K+ current (IK) was studied in isolated guinea pig atrial myocytes using the whole cell voltage-clamp technique. Similar to previous findings in ventricular cells, IK of atrial cells is the composite of two distinct components: IK,r, a rapidly activating current that exhibits strong inward rectification and IK,s, a slowly activating current with only modest rectification. IK,r was defined by its sensitivity to block by Co2+ and the class III antiarrhythmic agent, E-4031. IK,r underlies the prominent outward "hump" (between -30 and +40 mV) in the steady-state current-voltage relationship. Activation of IK,r was not dependent on transient changes in intracellular Ca2+ concentration. Block of Ca2+ current by nisoldipine or nitrendipine did not prevent activation of IK,r. Peak IK,r was not decreased in cells when intracellular Ca2+ was strongly buffered with 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. The activation curve for IK,r in atrial cells had a threshold of -40 mV, a half-point of -19 mV, and a slope factor of 5.2 mV. The activation curve for IK,s had a half-point of +24 mV and a slope factor of 15.7 mV. The peak tail currents of fully activated IK,s (21.1 pA/pF) and IK,r (2.53 pA/pF) are about two times that previously measured in guinea pig ventricular cells. This difference in current density may partly explain why action potentials of atrial cells are shorter than those of ventricular cells in guinea pig hearts.

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.

Outward currents in normal and hypertrophied feline ventricular myocytes

1989 ◽  
Vol 256 (5) ◽  
pp. H1450-H1461 ◽  
Author(s):  
R. B. Kleiman ◽  
S. R. Houser
Keyword(s):  
Time Course ◽  
Ventricular Myocytes ◽  
Pressure Overload ◽  
Negative Slope ◽  
Inward Rectification ◽  
Delayed Rectifier ◽  
Outward Currents ◽  
K Current ◽  
Prolongation Of Action Potential ◽  
The Right

The properties of the inward rectifier K current (IK1) and the delayed rectifier K current (IK) were studied in single feline myocytes isolated from the right ventricle of normal cats and cats with experimentally induced right ventricular hypertrophy (RVH). IK1 demonstrated time-dependent decay during hyperpolarizations and showed inward rectification with a prominent negative-slope region between -30 and -10 mV. Both IK1 and IK was carried primarily by K ions. The activation of IK during depolarizations followed a monoexponential time course, whereas the deactivation of IK tail currents was either mono- or biexponential depending on the repolarization potential. IK showed marked rectification at positive potentials. A comparison of these currents in normal and hypertrophy myocytes revealed that in RVH the magnitude of IK1 is increased, whereas the magnitude of IK is decreased. IK showed steeper rectification, had slower activation, and had more rapid deactivation in RVH. These abnormalities of the IK may contribute to the prolongation of action potential duration, which characterizes pressure-overload cardiac hypertrophy.

scholarly journals Charybdotoxin selectively blocks small Ca-activated K channels in Aplysia neurons.

1987 ◽  
Vol 90 (1) ◽  
pp. 27-47 ◽  
Author(s):  
A Hermann ◽  
C Erxleben
Keyword(s):  
Single Channel ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Dependent Manner ◽  
Open Probability ◽  
Apparent Dissociation Constant ◽  
External Application ◽  
K Channels ◽  
Voltage Dependent ◽  
K Current

The action of charybdotoxin (ChTX), a peptide component isolated from the venom of the scorpion Leiurus quinquestriatus, was investigated on membrane currents of identified neurons from the marine mollusk, Aplysia californica. Macroscopic current recordings showed that the external application of ChTX blocks the Ca-activated K current in a dose- and voltage-dependent manner. The apparent dissociation constant is 30 nM at V = -30 mV and increases e-fold for a +50- to +70-mV change in membrane potential, which indicates that the toxin molecule is sensitive to approximately 35% of the transmembrane electric field. The toxin is bound to the receptor with a 1:1 stoichiometry and its effect is reversible after washout. The toxin also suppresses the membrane leakage conductance and a resting K conductance activated by internal Ca ions. The toxin has no significant effect on the inward Na or Ca currents, the transient K current, or the delayed rectifier K current. Records from Ca-activated K channels revealed a single channel conductance of 35 +/- 5 pS at V = 0 mV in asymmetrical K solution. The channel open probability increased with the internal Ca concentration and with membrane voltage. The K channels were blocked by submillimolar concentrations of tetraethylammonium ions and by nanomolar concentrations of ChTX, but were not blocked by 4-aminopyridine if applied externally on outside-out patches. From the effects of ChTX on K current and on bursting pacemaker activity, it is concluded that the termination of bursts is in part controlled by a Ca-activated K conductance.

scholarly journals Isoprenaline: A Potential Contributor in Sick Sinus Syndrome—Insights from a Mathematical Model of the Rabbit Sinoatrial Node

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang Li ◽  
Ji-qian Zhang ◽  
Jian-wei Shuai
Keyword(s):  
Action Potential ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Surrounding Tissue ◽  
Pacemaker Activity ◽  
Histological Structure ◽  
Cell Models ◽  
Peripheral Cell ◽  
Positive Effects ◽  
Rabbit Sinoatrial Node

The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca2+transient, andiNachanges induced by SCN5A gene mutations; the cell models were also incorporated into an intact SAN-atrium model of the rabbit heart that is based on both heterogeneities of the SAN electrophysiology and histological structure. Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase iniNaandiCa,Twhich were reduced by the mutation.

Sign in / Sign up

Export Citation Format

Share Document