scholarly journals Mechanisms Underlying the Heart Pacemaker Activity as Revealed by the Voltage Clamp Experiment

1981 ◽  
Vol 21 (6) ◽  
pp. 302-310
Author(s):  
Akinori NOMA
Keyword(s):  
Voltage Clamp ◽  
Pacemaker Activity ◽  
Voltage Clamp Experiment

Cellular and subcellular mechanisms of cardiac pacemaker oscillations

1979 ◽  
Vol 81 (1) ◽  
pp. 205-215
Author(s):  
R. W. Tsien ◽  
R. S. Kass ◽  
R. Weingart
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Surface Membrane ◽  
Cardiac Pacemaker ◽  
Oscillatory Activity ◽  
Purkinje Fibre ◽  
Pacemaker Activity ◽  
Heart Cells ◽  
Control Loop ◽  
Internal Oscillation

Rhythmic oscillations in the membrane potential of heart cells are important in normal cardiac pacemaker activity as well as cardiac arrhythmias. Two fundamentally different mechanisms of oscillatory activity can be distinguished at the cellular and subcellular level. The first mechanism, referred to as a surface membrane oscillator, can be represented by a control loop in which membrane potential changes evoke delayed conductance changes and vice versa. Since the surface membrane potential is a key variable within the control loop, the oscillation can be interrupted at any time by holding the membrane potential constant with a voltage clamp. This mode of oscillation seems to describe spontaneous pacemaker activity in the primary cardiac pacemaker (sinoatrial node) as well as other regions (Purkinje fibre, atrial or ventricular muscle). In all tissues studied so far, the pacemaker depolarization is dominated by the slow shutting-off of an outward current, largely carried by potassium ions. The second mechanism can be called an internal oscillator since it depends upon a subcellular rhythm generator which is largely independent from the surface membrane. Under voltage clamp, the existence of the internal oscillation is revealed by the presence of oscillations in membrane conductance or contractile force which occur even though the membrane potential is held fixed. The two oscillatory mechanisms are not mutually exclusive; the subcellular mechanism can be preferentially enhanced in any given cardiac cell by conditions which elevate intracellular calcium. Such conditions include digitalis intoxication, high Cao, low Nao, low or high Ko, cooling, or rapid stimulation. Several lines of evidence suggest that the subcellular mechanism involves oscillatory variations in myoplasmic calcium, probably due to cycles of Ca uptake and release by the sarcoplasmic reticulum. The detailed nature of the Cai oscillator and its interaction with the surface membrane await further investigation.

scholarly journals Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments

2020 ◽  
Vol 378 (2173) ◽  
pp. 20190348 ◽  
Author(s):  
Chon Lok Lei ◽  
Michael Clerx ◽  
Dominic G. Whittaker ◽  
David J. Gavaghan ◽  
Teun P. de Boer ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Voltage Clamp ◽  
Ion Current ◽  
Model Parameters ◽  
Whole Cell Patch Clamp ◽  
Patch Clamp Experiment ◽  
Ion Channel Kinetics ◽  
Voltage Clamp Experiment ◽  
Model Variability ◽  
Cell Cell

Mathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific models to hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability by inspecting the resulting model parameters. However, the origin of the observed variability was not identified. Here, we study the source of variability by constructing a model that describes not just ion current dynamics, but the entire voltage-clamp experiment. The experimental artefact components of the model include: series resistance, membrane and pipette capacitance, voltage offsets, imperfect compensations made by the amplifier for these phenomena, and leak current. In this model, variability in the observations can be explained by either cell properties, measurement artefacts, or both. Remarkably, by assuming that variability arises exclusively from measurement artefacts, it is possible to explain a larger amount of the observed variability than when assuming cell-specific ion current kinetics. This assumption also leads to a smaller number of model parameters. This result suggests that most of the observed variability in patch-clamp data measured under the same conditions is caused by experimental artefacts, and hence can be compensated for in post-processing by using our model for the patch-clamp experiment. This study has implications for the question of the extent to which cell-cell variability in ion channel kinetics exists, and opens up routes for better correction of artefacts in patch-clamp data. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

scholarly journals Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments

2019 ◽  
Author(s):  
Chon Lok Lei ◽  
Michael Clerx ◽  
Dominic G. Whittaker ◽  
David J. Gavaghan ◽  
Teun P. de Boer ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Voltage Clamp ◽  
Ion Current ◽  
Model Parameters ◽  
Whole Cell Patch Clamp ◽  
Patch Clamp Experiment ◽  
Ion Channel Kinetics ◽  
Voltage Clamp Experiment ◽  
Model Variability ◽  
Cell Cell

AbstractMathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study we fitted cell-specific models to hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability by inspecting the resulting model parameters. However, the origin of the observed variability was not identified. Here we study the source of variability by constructing a model that describes not just ion current dynamics, but the entire voltage-clamp experiment. The experimental artefact components of the model include: series resistance, membrane and pipette capacitance, voltage offsets, imperfect compensations made by the amplifier for these phenomena, and leak current. In this model, variability in the observations can be explained by either cell properties, measurement artefacts, or both. Remarkably, by assuming that variability arises exclusively from measurement artefacts, it is possible to explain a larger amount of the observed variability than when assuming cell-specific ion current kinetics. This assumption also leads to a smaller number of model parameters. This result suggests that most of the observed variability in patch-clamp data measured under the same conditions is caused by experimental artefacts, and hence can be compensated for in post-processing by using our model for the patch-clamp experiment. This study has implications for the question of the extent to which cell-cell variability in ion channel kinetics exists, and opens up routes for better correction of artefacts in patch-clamp data.

Low Ba-induced pacemaker current in well-polarized cat papillary muscle

1987 ◽  
Vol 252 (2) ◽  
pp. H258-H268 ◽  
Author(s):  
M. Delmar ◽  
J. Jalife
Keyword(s):  
Voltage Clamp ◽  
Papillary Muscle ◽  
Time Dependent ◽  
Resting Potential ◽  
Pacemaker Activity ◽  
Dependent Manner ◽  
Ventricular Muscle ◽  
Induced Current ◽  
Cat Papillary Muscle ◽  
Voltage Dependent

It has previously been reported that superfusion of normally quiescent mammalian ventricular muscle with low concentrations of Ba (less than 0.3 mM) can induce spontaneous activity with maximum diastolic potentials (MDP) that are similar to the normal resting potential (-80 mV or larger). The mechanism for this activity was studied in cat papillary muscle sucrose-gap preparations under current clamp and voltage-clamp conditions. Hyperpolarizing current pulses decreased or abolished the amplitude of the pacemaker potential in a voltage-dependent manner. When Ba concentration was increased to 2 mM the MDP depolarized by approximately 20 mV. Hyperpolarizing steps under these conditions abolished the diastolic depolarization, also in a voltage-dependent manner. Voltage clamping the preparation at the MDP during superfusion of 0.2 mM Ba revealed a time-dependent, inwardly directed current. Hyperpolarizing voltage-clamp steps from a holding potential of -50 mV showed that this current was maximal at approximately -70 mV and frequently reversed at membrane potentials of approximately -95 to -115 mV. The time course of this current was biexponential, and the time constant of the faster component decreased with larger hyperpolarization. When the same voltage-clamp protocol was repeated in the presence of 2 mM Ba, no time-dependent current change was detected. In four out of five experiments, Cs (2.5 mM) reduced (but never abolished) the amplitude of the low Ba-induced current. Our results do not support the hypothesis that a hyperpolarization-induced current (iF-like current) is responsible for the automaticity in well-polarized ventricular muscle at low Ba concentrations. Instead, our data suggest that this pacemaker activity is the result of a Ba-induced, time-dependent blockade of the inward rectifier potassium current (iK1).

Selected Contribution: Axial stretch increases spontaneous pacemaker activity in rabbit isolated sinoatrial node cells

2000 ◽  
Vol 89 (5) ◽  
pp. 2099-2104 ◽  
Author(s):  
Patricia J. Cooper ◽  
Ming Lei ◽  
Long-Xian Cheng ◽  
Peter Kohl
Keyword(s):  
Voltage Clamp ◽  
Sinoatrial Node ◽  
Reversal Potential ◽  
Pacemaker Activity ◽  
Chronotropic Response ◽  
Beating Rate ◽  
Sinoatrial Node Cells ◽  
Patch Configuration ◽  
Longitudinal Stretch ◽  
Reported Data

Isolated, spontaneously beating rabbit sinoatrial node cells were subjected to longitudinal stretch, using carbon fibers attached to both ends of the cell. Their electrical behavior was studied simultaneously in current-clamp or voltage-clamp mode using the perforated patch configuration. Moderate stretch (∼7%) caused an increase in spontaneous beating rate (by ∼5%) and a reduction in maximum diastolic and systolic potentials (by ∼2.5%), as seen in multicellular preparations. Mathematical modeling of the stretch intervention showed the experimental results to be compatible with stretch activation of cation nonselective ion channels, similar to those found in other cardiac cell populations. Voltage-clamp experiments validated the presence of a stretch-induced current component with a reversal potential near −11 mV. These data confirm, for the first time, that the positive chronotropic response of the heart to stretch is, at least in part, encoded on the level of individual sinoatrial node pacemaker cells; all reported data are in agreement with a major contribution of stretch-activated cation nonselective channels to this response.

scholarly journals Two Fast Transient Current Components during Voltage Clamp on Snail Neurons

1971 ◽  
Vol 58 (1) ◽  
pp. 36-53 ◽  
Author(s):  
Erwin Neher
Keyword(s):  
Voltage Clamp ◽  
Ganglion Cells ◽  
Helix Pomatia ◽  
Outward Current ◽  
Giant Cells ◽  
Resting Potential ◽  
Transient Outward Current ◽  
Pacemaker Activity ◽  
Inward Currents ◽  
Fast Transient

Voltage clamp currents from medium sized ganglion cells of Helix pomatia have a fast transient outward current component in addition to the usually observed inward and outward currents. This component is inactivated at normal resting potential. The current, which is carried by K+ ions, may surpass leakage currents by a factor of 100 after inactivation has been removed by hyperpolarizing conditioning pulses. Its kinetics are similar to those of the inward current, except that it has a longer time constant of inactivation. It has a threshold close to resting potential. This additional component is also present in giant cells, where however, it is less prominent. Pacemaker activity is controlled by this current. It was found that inward currents have a slow inactivating process in addition to a fast, Hodgkin-Huxley type inactivation. The time constants of the slow process are similar to those of slow outward current inactivation.

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