scholarly journals Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model

2011 ◽  
Vol 301 (4) ◽  
pp. H1615-H1624 ◽  
Author(s):  
Vladislav V. Nesterenko ◽  
Andrew C. Zygmunt ◽  
Sridharan Rajamani ◽  
Luiz Belardinelli ◽  
Charles Antzelevitch
Keyword(s):  
Action Potential ◽  
Voltage Dependence ◽  
Channel Gating ◽  
Inactivation Curve ◽  
Ventricular Cells ◽  
Kinetic Rate Constants ◽  
Steady State Inactivation ◽  
Order Of Magnitude ◽  
Action Potential Prolongation ◽  
Channel Kinetic

Block of Na+ channel conductance by ranolazine displays marked atrial selectivity that is an order of magnitude higher that of other class I antiarrhythmic drugs. Here, we present a Markovian model of the Na+ channel gating, which includes activation-inactivation coupling, aimed at elucidating the mechanisms underlying this potent atrial selectivity of ranolazine. The model incorporates experimentally observed differences between atrial and ventricular Na+ channel gating, including a more negative position of the steady-state inactivation curve in atrial versus ventricular cells. The model assumes that ranolazine requires a hydrophilic access pathway to the channel binding site, which is modulated by both activation and inactivation gates of the channel. Kinetic rate constants were obtained using guarded receptor analysis of the use-dependent block of the fast Na+ current ( INa). The model successfully reproduces all experimentally observed phenomena, including the shift of channel availability, the sensitivity of block to holding or diastolic potential, and the preferential block of slow versus fast INa. Using atrial and ventricular action potential-shaped voltage pulses, the model confirms significantly greater use-dependent block of peak INa in atrial versus ventricular cells. The model highlights the importance of action potential prolongation and of a steeper voltage dependence of the time constant of unbinding of ranolazine from the atrial Na+ channel in the development of use-dependent INa block. Our model predictions indicate that differences in channel gating properties as well as action potential morphology between atrial and ventricular cells contribute equally to the atrial selectivity of ranolazine. The model indicates that the steep voltage dependence of ranolazine interaction with the Na+ channel at negative potentials underlies the mechanism of the predominant block of INa in atrial cells by ranolazine.

Synaptic Current at the Rat Ganglionic Synapse and Its Interactions With the Neuronal Voltage-Dependent Currents

1998 ◽  
Vol 79 (2) ◽  
pp. 727-742 ◽  
Author(s):  
Oscar Sacchi ◽  
Maria Lisa Rossi ◽  
Rita Canella ◽  
Riccardo Fesce
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Time Constant ◽  
Voltage Dependence ◽  
Sympathetic Neurons ◽  
Excitatory Postsynaptic Potential ◽  
Synaptic Current ◽  
Inactivation Curve ◽  
Voltage Dependent ◽  
Steady State Inactivation

Sacchi, Oscar, Maria Lisa Rossi, Rita Canella, and Riccardo Fesce. Synaptic current at the rat ganglionic synapse and its interactions with the neuronal voltage-dependent currents. J. Neurophysiol. 79: 727–742, 1998. The membrane current activated by fast nicotinic excitation of intact and mature rat sympathetic neurons was studied at 37°C, by using the two-microelectrode voltage-clamp technique. The excitatory postsynaptic current (EPSC) was modeled as the difference between two exponentials. A fast time constant (τ2; mean value 0.57 ms), which proves to be virtually voltage-independent, governs the current rise phase and a longer time constant (τ1; range 5.2–6.8 ms in 2 mM Ca2+) describes the current decay and shows a small negative voltage dependence. A mean peak synaptic conductance of 0.58 μS per neuron is measured after activation of the whole presynaptic input in 5 mM Ca2+ external solution (0.40 μS in 2 mM Ca2+). The miniature EPSCs also rise and decay with exponential time constants very similar to those of the compound EPSC recorded at the same voltage. A mean peak conductance of 4.04 nS is estimated for the unitary event. Deconvolution procedures were employed to decompose evoked macrocurrents. It is shown that under appropriate conditions the duration of the driving function describing quantal secretion can be reduced to <1 ms. The shape of the EPSC is accurately mimicked by a complete mathematical model of the sympathetic neuron incorporating the kinetic properties of five different voltage-dependent current types, which were characterized in a previous work. We show that I A channels are opened by depolarizing voltage steps or by synaptic potentials in the subthreshold voltage range, provided that the starting holding voltage is sufficiently negative to remove I A steady-state inactivation (less than −50 mV) and the voltage trajectories are sufficiently large to enter the I A activation range (greater than −65 mV). Under current-clamp conditions, this gives rise to an additional fast component in the early phase of membrane repolarization—in response to voltage pulses—and to a consistent distortion of the excitatory postsynaptic potential (EPSP) time course around its peak—in response to the synaptic signal. When the stimulation initiates an action potential, I A is shown to significantly increase the synaptic threshold conductance (up to a factor of 2 when I A is fully deinactivated), compared with that required when I A is omitted. The voltage dependence of this effect is consistent with the I A steady-state inactivation curve. It is concluded that I A, in addition to speeding up the spike repolarization process, also shunts the excitatory drive and delays or prevents the firing of the neuron action potential.

scholarly journals Effect of acidosis on transient outward potassium current in isolated rat ventricular myocytes

2000 ◽  
Vol 278 (1) ◽  
pp. H50-H59 ◽  
Author(s):  
J. T. Hulme ◽  
C. H. Orchard
Keyword(s):  
Potassium Current ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Solution Ph ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Rat Ventricular Myocytes ◽  
Steady State Inactivation ◽  
Perforated Patch Clamp ◽  
Outward Potassium Current

The effect of acidosis on the transient outward K+ current ( Ito ) of rat ventricular myocytes has been investigated using the perforated patch-clamp technique. When the holding potential was −80 mV, depolarizing pulses to potentials positive to −20 mV activated Ito in subepicardial cells but activated little Ito in subendocardial cells. Exposure to an acid solution (pH 6.5) had no significant effect on Ito activated from this holding potential in either subepicardial or subendocardial cells. When the holding potential was −40 mV, acidosis significantly increased Ito at potentials positive to −20 mV in subepicardial cells but had little effect on Ito in subendocardial cells. The increase in Ito in subepicardial cells was inhibited by 10 mM 4-aminopyridine. In subepicardial cells, acidosis caused a +8.57-mV shift in the steady-state inactivation curve. It is concluded that in subepicardial rat ventricular myocytes acidosis increases the amplitude of Ito as a consequence of a depolarizing shift in the voltage dependence of inactivation.

scholarly journals Voltage-dependent inactivation of slow calcium channels in intact twitch muscle fibers of the frog.

1989 ◽  
Vol 94 (5) ◽  
pp. 937-951 ◽  
Author(s):  
G Cota ◽  
E Stefani
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Voltage Dependence ◽  
Muscle Fibers ◽  
Dependent Manner ◽  
Inactivation Curve ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Intact Muscle ◽  
Ca2 Channels

Inactivation of slow Ca2+ channels was studied in intact twitch skeletal muscle fibers of the frog by using the three-microelectrode voltage-clamp technique. Hypertonic sucrose solutions were used to abolish contraction. The rate constant of decay of the slow Ca2+ current (ICa) remained practically unchanged when the recording solution containing 10 mM Ca2+ was replaced by a Ca2+-buffered solution (126 mM Ca-maleate). The rate constant of decay of ICa monotonically increased with depolarization although the corresponding time integral of ICa followed a bell-shaped function. The replacement of Ca2+ by Ba2+ did not result in a slowing of the rate of decay of the inward current nor did it reduce the degree of steady-state inactivation. The voltage dependence of the steady-state inactivation curve was steeper in the presence of Ba2+. In two-pulse experiments with large conditioning depolarizations ICa inactivation remained unchanged although Ca2+ influx during the prepulse greatly decreased. Dantrolene (12 microM) increased mechanical threshold at all pulse durations tested, the effect being more prominent for short pulses. Dantrolene did not significantly modify ICa decay and the voltage dependence of inactivation. These results indicate that in intact muscle fibers Ca2+ channels inactivate in a voltage-dependent manner through a mechanism that does not require Ca2+ entry into the cell.

scholarly journals Extracellular proton depression of peak and late Na+ current in the canine left ventricle

2011 ◽  
Vol 301 (3) ◽  
pp. H936-H944 ◽  
Author(s):  
Lisa Murphy ◽  
Danielle Renodin ◽  
Charles Antzelevitch ◽  
José M. Di Diego ◽  
Jonathan M. Cordeiro
Keyword(s):  
Action Potential ◽  
Cell Types ◽  
Left Ventricular ◽  
Extracellular Acidosis ◽  
Epicardial Cells ◽  
Ventricular Cells ◽  
Recovery From Inactivation ◽  
Ventricular Tissue ◽  
Steady State Inactivation ◽  
Acidic Conditions

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na+ current ( INa) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record INa. Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast INa showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast INa magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast INa was observed at pH 6.6. Acidosis did not affect steady-state inactivation of INa or recovery from inactivation. Analysis of late INa during a 500-ms pulse showed that the acidosis significantly reduced late INa at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late INa compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late INa when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late INa in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.

Differences in Na+ Conductance Density and Na+ Channel Functional Properties Between Dopamine and GABA Neurons of the Rat Substantia Nigra

2010 ◽  
Vol 103 (6) ◽  
pp. 3099-3114 ◽  
Author(s):  
Vincent Seutin ◽  
Dominique Engel
Keyword(s):  
Substantia Nigra ◽  
Functional Properties ◽  
Voltage Dependence ◽  
Na Channel ◽  
Inactivation Curve ◽  
Voltage Gated ◽  
Gaba Neurons ◽  
Steady State Inactivation ◽  
The Mean ◽  
Firing Properties

Dopamine (DA) neurons and GABA neurons of the substantia nigra (SN) promote distinct functions in the control of movement and have different firing properties and action potential (AP) waveforms. APs recorded from DA and GABA neurons differed in amplitude, maximal rate of rise, and duration. In addition, the threshold potential for APs was higher in DA neurons than in GABA neurons. The activation of voltage-gated Na+ channels accounts largely for these differences as the application of a low concentration of the voltage-gated Na+ channel blocker TTX had an effect on all of these parameters. We have examined functional properties of somatic Na+ channels in nucleated patches isolated from DA and GABA neurons. Peak amplitudes of macroscopic Na+ currents were smaller in DA neurons in comparison to those in GABA neurons. The mean peak Na+ conductance density was 24.5 pS μm−2 in DA neurons and almost twice as large, 41.6 pS μm−2, in GABA neurons. The voltage dependence of Na+ channel activation was not different between the two types of SN neurons. Na+ channels in DA and GABA neurons, however, differed in the voltage dependence of inactivation, the mean mid-point potential of steady-state inactivation curve being more positive in DA neurons than in GABA neurons. The results suggest that specific Na+ channel gating properties and Na+ conductance densities in the somatic membrane of SN neurons may have consequences on synaptic signal integration in the soma of both types of neurons and on somatodendritic release of dopamine by DA neurons.

scholarly journals Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block

2011 ◽  
Vol 301 (4) ◽  
pp. H1606-H1614 ◽  
Author(s):  
Andrew C. Zygmunt ◽  
Vladislav V. Nesterenko ◽  
Sridharan Rajamani ◽  
Dan Hu ◽  
Hector Barajas-Martinez ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Selective Inhibition ◽  
Resting Membrane Potential ◽  
Inactivation Curve ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Channel Current ◽  
Ventricular Cells ◽  
293 Cells ◽  
Steady State Inactivation

Atrial-selective inhibition of cardiac Na+ channel current ( INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study examined the basis for the atrial-selective actions of ranolazine. Whole cell INa was recorded at 15°C in canine atrial and ventricular myocytes and in human embryonic kidney (HEK)-293 cells expressing SCN5A. Tonic block was negligible at holding potentials from −140 to −100 mV, suggesting minimal drug interactions with the closed state. Trains of 40 pulses were elicited over a range of holding potentials to determine use-dependent block. Guarded receptor formalism was used to analyze the development of block during pulse trains. Use-dependent block by ranolazine increased at more depolarized holding potentials, consistent with an interaction of the drug with either preopen or inactivated states, but was unaffected by longer pulse durations between 5 and 200 ms, suggesting a weak interaction with the inactivated state. Block was significantly increased at shorter diastolic intervals between 20 and 200 ms. Responses in atrial and ventricular myocytes and in HEK-293 cells displayed a similar pattern. Ranolazine is an open state blocker that unbinds from closed Na+ channels unusually fast but is trapped in the inactivated state. Kinetic rates of ranolazine interactions with different states of atrial and ventricular Na+ channels were similar. Our data suggest that the atrial selectivity of ranolazine is due to a more negative steady-state inactivation curve, less negative resting membrane potential, and shorter diastolic intervals in atrial cells compared with ventricular cells at rapid rates.

Electrophysiologic Mechanism Underlying Action Potential Prolongation by Sevoflurane in Rat Ventricular Myocytes

2007 ◽  
Vol 107 (1) ◽  
pp. 67-74 ◽  
Author(s):  
Jee Eun Chae ◽  
Duck Sun Ahn ◽  
Myung Hee Kim ◽  
Carl Lynch ◽  
Wyun Kon Park
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Inward Rectifier ◽  
Rat Ventricular Myocytes ◽  
Steady State Inactivation ◽  
K Current ◽  
Action Potential Prolongation ◽  
Sustained Outward Current

Abstract Background: Despite prolongation of the QTc interval in humans during sevoflurane anesthesia, little is known about the mechanisms that underlie these actions. In rat ventricular myocytes, the effect of sevoflurane on action potential duration and underlying electrophysiologic mechanisms were investigated. Methods: The action potential was measured by using a current clamp technique. The transient outward K+ current was recorded during depolarizing steps from −80 mV, followed by brief depolarization to −40 mV and then depolarization up to +60 mV. The voltage dependence of steady state inactivation was determined by using a standard double-pulse protocol. The sustained outward current was obtained by addition of 5 mm 4-aminopyridine. The inward rectifier K+ current was recorded from a holding potential of −40 mV before their membrane potential was changed from −130 to 0 mV. Sevoflurane actions on L-type Ca2+ current were also obtained. Results: Sevoflurane prolonged action potential duration, whereas the amplitude and resting membrane potential remained unchanged. The peak transient outward K+ current at +60 mV was reduced by 18 ± 2% (P &lt; 0.05) and 24 ± 2% (P &lt; 0.05) by 0.35 and 0.7 mm sevoflurane, respectively. Sevoflurane had no effect on the sustained outward current. Whereas 0.7 mm sevoflurane did not shift the steady state inactivation curve, it accelerated the current inactivation (P &lt; 0.05). The inward rectifier K+ current at −130 mV was little altered by 0.7 mm sevoflurane. L-type Ca2+ current was reduced by 28 ± 3% (P &lt; 0.05) and 33 ± 1% (P &lt; 0.05) by 0.35 and 0.7 mm sevoflurane, respectively. Conclusions: Action potential prolongation by clinically relevant concentrations of sevoflurane is due to the suppression of transient outward K+ current in rat ventricular myocytes.

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.

Effects of estrogen on action potential and membrane currents in guinea pig ventricular myocytes

1999 ◽  
Vol 277 (2) ◽  
pp. H826-H833 ◽  
Author(s):  
Seiko Tanabe ◽  
Toshio Hata ◽  
Masayasu Hiraoka
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Action Potentials ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Membrane Currents ◽  
Patch Clamp Technique ◽  
17Β Estradiol ◽  
Electrophysiological Effects ◽  
Ionic Basis

To explore a possible ionic basis for the prolonged Q-T interval in women compared with that in men, we investigated the electrophysiological effects of estrogen in isolated guinea pig ventricular myocytes. Action potentials and membrane currents were recorded using the whole cell configuration of the patch-clamp technique. Application of 17β-estradiol (10–30 μM) significantly prolonged the action potential duration (APD) at 20% (APD20) and 90% repolarization (APD90) at stimulation rates of 0.1–2.0 Hz. In the presence of 30 μM 17β-estradiol, APD20 and APD90 at 0.1 Hz were prolonged by 46.2 ± 17.1 and 63.4 ± 11.7% of the control ( n = 5), respectively. In the presence of 30 μM 17β-estradiol the peak inward Ca2+ current ( I CaL) was decreased to 80.1 ± 2.5% of the control ( n = 4) without a shift in its voltage dependence. Application of 30 μM 17β-estradiol decreased the rapidly activating component of the delayed outward K+ current ( I Kr) to 63.4 ± 8% and the slowly activating component ( I Ks) to 65.8 ± 8.7% with respect to the control; the inward rectifier K+ current was barely affected. The results suggest that 17β-estradiol prolonged APD mainly by inhibiting the I Kcomponents I Krand I Ks.

Sign in / Sign up

Export Citation Format

Share Document