Modulation of repolarization in rabbit Purkinje and ventricular myocytes coupled by a variable resistance

1999 ◽  
Vol 276 (2) ◽  
pp. H572-H581 ◽  
Author(s):  
Delilah J. Huelsing ◽  
Kenneth W. Spitzer ◽  
Jonathan M. Cordeiro ◽  
Andrew E. Pollard
Keyword(s):  
Action Potential ◽  
Computer Simulations ◽  
Calcium Current ◽  
Electronic Circuit ◽  
Ventricular Myocytes ◽  
Phase 1 ◽  
Inward Rectifier ◽  
The Difference ◽  
Coupling Current ◽  
Junctional Resistance

Purkinje-ventricular junctions (PVJs) have been implicated as potential sites of arrhythmogenesis, in part because of the dispersion of action potential duration (APD) between Purkinje (P) and ventricular (V) myocytes. To characterize electrotonic modulation of APD as a function of junctional resistance ( R j), we coupled single isolated rabbit P and V myocytes with an electronic circuit. In seven of eight PV myocyte pairs, both APDs shortened on coupling at R j = 50 MΩ. This was in contrast to modulation of APD in paired ventricular myocytes, which demonstrated APD shortening of the intrinsically longer action potential and APD prolongation of the intrinsically shorter action potential. Companion computer simulations, performed to suggest possible mechanisms for the paradoxical shortening of the V action potential in paired P and V myocytes, showed that the difference in intrinsic peak plateau potentials ( V pp) of the P and V myocytes determined whether the V action potential shortened or prolonged on coupling. This difference in V pp caused a large, repolarizing coupling current to flow to the V myocyte, contributing to early inactivation of the L-type calcium current and early activation of the inward rectifier current. These results suggest that intrinsic differences in phase 1 repolarization could yield differing patterns of APD shortening or prolongation in the network of subendocardial PVJs, leaving some PVJs vulnerable to conduction of premature stimuli while other PVJs remain refractory.

Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance

1998 ◽  
Vol 274 (4) ◽  
pp. H1163-H1173 ◽  
Author(s):  
Delilah J. Huelsing ◽  
Kenneth W. Spitzer ◽  
Jonathan M. Cordeiro ◽  
Andrew E. Pollard
Keyword(s):  
Electronic Circuit ◽  
Ventricular Myocytes ◽  
Phase 1 ◽  
Conduction Block ◽  
Outward Current ◽  
Transient Outward Current ◽  
Electrotonic Interactions ◽  
Unidirectional Block ◽  
The Mean ◽  
Junctional Resistance

Conduction at the Purkinje-ventricular junction (PVJ) demonstrates unidirectional block under both physiological and pathophysiological conditions. Although this block is typically attributed to multidimensional electrotonic interactions, we examined possible membrane-level contributions using single, isolated rabbit Purkinje (P) and ventricular (V) myocytes coupled by an electronic circuit. When we varied the junctional resistance ( R j) between paired V myocytes, conduction block occurred at lower R j values during conduction from the smaller to larger myocyte (115 ± 59 MΩ) than from the larger to smaller myocyte (201 ± 51 MΩ). In Purkinje-ventricular myocyte pairs, however, block occurred at lower R j values during P-to-V conduction (85 ± 39 MΩ) than during V-to-P conduction (912 ± 175 MΩ), although there was little difference in the mean cell size. Companion computer simulations, performed to examine how the early plateau currents affected conduction, showed that P-to-V block occurred at lower R j values when the transient outward current was increased or the calcium current was decreased in the model P cell. These results suggest that intrinsic differences in phase 1 repolarization can contribute to unidirectional block at the PVJ.

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.

Action potential conduction between guinea pig ventricular cells can be modulated by calcium current

1992 ◽  
Vol 263 (5) ◽  
pp. H1591-H1604 ◽  
Author(s):  
H. Sugiura ◽  
R. W. Joyner
Keyword(s):  
Action Potential ◽  
Calcium Current ◽  
Ionic Current ◽  
Cardiac Cells ◽  
Conduction Delay ◽  
Early Repolarization ◽  
Conduction Process ◽  
Ventricular Cells ◽  
Coupling Current ◽  
Frequency Of Stimulation

We used cell pairs electrically coupled with relatively high intercellular resistance to investigate the involvement of calcium current in the origin of the source current during the conduction process of the action potential (AP). Three interventions were used to reduce the calcium current: a specific calcium channel blocker [nifedipine (NIF)], premature stimulation, and increments in the frequency of stimulation of the cell. The ionic membrane current (Iion) after the peak of the AP of the stimulated cell was positive and small when the cell was uncoupled. However, when the stimulated cell was coupled to a cell model or to another cell, Iion during this period became negative and large to supply the coupling current. A rapid early repolarization of the AP occurred in the stimulated cell because of the removal of charge from the stimulated cell. NIF decreased the magnitude of the net negative Iion during this period and caused a more rapid early repolarization in the stimulated cell. NIF increased the delay between the activations of two coupled cells at a given coupling resistance (Rc) but decreased the longest delay that could be produced without conduction failure for a given cell pair. The highest Rc below which conduction of AP occurred was also decreased by NIF. Premature stimulation and an increase of the stimulation frequency also caused an increase in the extent of the early repolarization and increased the delay between two cell activations at a given Rc. Conduction block occurred with sufficient prematurity or at a sufficiently high frequency of stimulation even though activation of the stimulated cell occurred for each stimulus. The Iion that flows during the early plateau phase of the AP in the stimulated cell became negative and significantly large by coupling two cardiac cells together. This current flow is a major component needed to supply the coupling current through the intercellular resistance. The decrease of calcium current caused a decrease in the magnitude of this net inward ionic current, resulting in an increase of the rate of early repolarization and an increase in the conduction delay between two cells at a given Rc. These results suggest the involvement of calcium current in the conduction process when cells are coupled at relatively high Rc.

Ito1 dictates behavior of ICl(Ca) during early repolarization of canine ventricle

1997 ◽  
Vol 273 (3) ◽  
pp. H1096-H1106 ◽  
Author(s):  
A. C. Zygmunt ◽  
D. C. Robitelle ◽  
G. T. Eddlestone
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Time Course ◽  
Ventricular Myocytes ◽  
Phase 1 ◽  
Potassium Conductance ◽  
Outward Current ◽  
Direct Result ◽  
Disulfonic Acid ◽  
Early Repolarization

The contributions of the 4-aminopyridine (4-AP)-sensitive transient outward potassium conductance (Ito1) and the calcium-activated chloride conductance (ICl(Ca)] to cardiac action potentials were investigated in canine ventricular myocytes. Action potentials or currents were recorded at 37 degrees C using standard whole cell or amphotericin B perforated-patch-clamp techniques. Inhibition of Ito1 by 1 mM 4-AP prolonged phase 1 repolarization, elevated the action potential notch, and depressed the plateau. Action potential voltage clamp revealed that 4-AP blocked a rapidly decaying outward current during phase 1 without affecting plateau or diastolic currents. These results suggested that depression of the plateau was not a direct result of Ito1 inhibition but followed from delayed phase 1 repolarization. Calcium current (ICa) at the peak of the action potential dome was reduced 60 +/- 4% when the rate of phase 1 repolarization was reduced. ICl(Ca) measured by action potential clamp reversed over the course of the action potential. Chloride fluxes associated with outward and inward components of the 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid-sensitive current were +130 +/- 17 and -184 +/- 20 (pA.ms)/pF, respectively. The effects of selective inhibition of ICl(Ca) on the action potential were dependent on the rate of early repolarization and the prominence of the notch. Inhibition of ICl(Ca) elevated the plateau and slightly abbreviated action potential duration when the notch was prominent. When repolarization was prolonged and the notch was shallow, inhibition of ICl(Ca) elevated the notch and the plateau and abbreviated duration. We have shown that Ito1 and ICl(Ca) contribute to canine ventricular action potentials. The extent of overlap between Ito1 and ICl(Ca) during the action potential is largely determined by the amplitude of Ito1 and the depth of the notch. Regional differences in the density of Ito1, or interventions that moderate phase 1 repolarization by reducing this current, will have considerable effect on the time course of ICa and calcium-dependent conductances.

Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes

2004 ◽  
Vol 286 (6) ◽  
pp. H2342-H2351 ◽  
Author(s):  
Fei Hua ◽  
David C. Johns ◽  
Robert F. Gilmour
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Rate Dependent ◽  
Whole Cell Patch Clamp ◽  
The Difference ◽  
Viable Approach ◽  
Electrical Alternans

Suppression of electrical alternans may be antiarrhythmic. Our previous computer simulations have suggested that increasing the rapid component of the delayed rectifier K+ current ( IKr) suppresses alternans. To test this hypothesis, IKr in isolated canine ventricular myocytes was increased by infection with an adenovirus containing the gene for the pore-forming domain of IKr [human ether-a-go-go gene (HERG)]. With the use of the perforated or whole cell patch-clamp technique, action potentials recorded at different pacing cycle lengths (CLs) were applied to the myocytes as the command waveforms. HERG infection markedly increased peak IKr during the action potential (from 0.54 ± 0.03 pA/pF in control to 3.60 ± 0.81 pA/pF). Rate-dependent alterations of peak IKr were similar for freshly isolated myocytes and HERG-infected myocytes. In both cell types, IKr increased when CL decreased from 1,000 to 500 ms and then decreased progressively as CL decreased further. During alternans at CL = 170 ms, peak IKr was larger for the short than for the long action potential for both groups, but the difference in peak IKr was larger for HERG-infected myocytes. The voltage at which peak IKr occurred was significantly less negative in HERG-infected myocytes, in association with shifts of the steady-state voltage-dependent activation and inactivation curves to less negative potentials. Pacing at short CL induced stable alternans in freshly isolated myocytes and in cultured myocytes without HERG infection, but not in HERG-infected myocytes. These data support the idea that increasing IKr may be a viable approach to suppressing electrical alternans.

Changes in ionic currents and β-adrenergic receptor signaling in hypertrophied myocytes overexpressing Gαq

2000 ◽  
Vol 279 (1) ◽  
pp. H139-H148 ◽  
Author(s):  
Sayaka Mitarai ◽  
Thomas D. Reed ◽  
Atsuko Yatani
Keyword(s):  
Action Potential ◽  
Cardiac Hypertrophy ◽  
Adrenergic Receptor ◽  
Myocardial Function ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Left Ventricular ◽  
Inward Rectifier ◽  
Maximal Response ◽  
Maximal Increase

Transgenic overexpression of Gαq causes cardiac hypertrophy and depressed contractile responses to β-adrenergic receptor agonists. The electrophysiological basis of the altered myocardial function was examined in left ventricular myocytes isolated from transgenic (Gαq) mice. Action potential duration was significantly prolonged in Gαq compared with nontransgenic (NTG) myocytes. The densities of inward rectifier K+ currents, transient outward K+ currents ( I to), and Na+/Ca2+ exchange currents were reduced in Gαq myocytes. Consistent with functional measurements, Na+/Ca2+ exchanger gene expression was reduced in Gαq hearts. Kinetics or sensitivity of I to to 4-aminopyridine was unchanged, but 4-aminopyridine prolonged the action potential more in Gαq myocytes. Isoproterenol increased L-type Ca2+ currents ( I Ca) in both groups, with a similar EC50, but the maximal response in Gαq myocytes was ∼24% of that in NTG myocytes. In NTG myocytes, the maximal increase of I Ca with isoproterenol or forskolin was similar. In Gαq myocytes, forskolin was more effective and enhanced I Ca up to ∼55% of that in NTG myocytes. These results indicate that the changes in ionic currents and multiple defects in the β-adrenergic receptor/Ca2+ channel signaling pathway contribute to altered ventricular function in this model of cardiac hypertrophy.

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