scholarly journals Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes

2008 ◽  
Vol 295 (2) ◽  
pp. H851-H859 ◽  
Author(s):  
Y. G. Wang ◽  
A. V. Zima ◽  
X. Ji ◽  
R. Pabbidi ◽  
L. A. Blatter ◽  
...  
Keyword(s):  
Action Potential ◽  
Lipid Bilayers ◽  
Ventricular Myocytes ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Ginsenoside Re ◽  
Human Atrial Myocytes ◽  
Human Cardiomyocytes ◽  
Intracellular Ca ◽  
Action Potential Configuration

Ginseng botanicals are increasingly used as complementary or alternative medicines for a variety of cardiovascular diseases, yet little is known about their cellular actions in cardiac muscle. Electromechanical alternans (EMA) is a proarrhythmic cardiac abnormality that results from disturbances of intracellular Ca2+ homeostasis. This study sought to determine whether a purified ginsenoside extract of ginseng, Re, exerts effects to suppress EMA and to gain insight into its mechanism of action. Alternans was induced by electrically pacing cardiomyocytes at room temperature. Re (≥10 nM) reversibly suppressed EMA recorded from cat ventricular and atrial myocytes and Langendorff-perfused cat hearts. In cat ventricular myocytes, Re reversibly suppressed intracellular Ca2+ concentration ([Ca2+]i) transient alternans. Re exerted no significant effects on baseline action potential configuration or sarcolemmal L-type Ca2+ current ( ICa,L), Na+ current, or total K+ conductance. In human atrial myocytes, Re suppressed mechanical alternans and exerted no effect on ICa,L. In cat ventricular myocytes, Re increased [Ca2+]i transient amplitude and decreased sarcoplasmic reticulum (SR) Ca2+ content, resulting in an increase in fractional SR Ca2+ release. In SR microsomes isolated from cat ventricles, Re had no effect on SR Ca2+ uptake. Re increased the open probability of ryanodine receptors (RyRs), i.e., SR Ca2+-release channels, isolated from cat ventricles and incorporated into planar lipid bilayers. We concluded that ginsenoside Re suppresses EMA in cat atrial and ventricular myocytes, cat ventricular muscle, and human atrial myocytes. The effects of Re are not mediated via actions on sarcolemmal ion channels or action potential configuration. Re acts via a subcellular mechanism to enhance the opening of RyRs and thereby overcome the impaired SR Ca2+ release underlying EMA.

Rate-dependent changes in cell shortening, intracellular Ca(2+) levels and membrane potential in single, isolated rainbow trout (Oncorhynchus mykiss) ventricular myocytes

2000 ◽  
Vol 203 (3) ◽  
pp. 493-504 ◽  
Author(s):  
C.L. Harwood ◽  
F.C. Howarth ◽  
J.D. Altringham ◽  
E. White
Keyword(s):  
Membrane Potential ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Stimulation Frequency ◽  
Cell Shortening ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Rate Dependent ◽  
Intracellular Ca ◽  
Action Potential Configuration

The effects of increasing stimulation frequency (from 0.2 to 1.4 Hz) on the contractility, intracellular Ca(2+) concentration ([Ca(2+)](i)) and membrane potential of single ventricular myocytes isolated from the heart of rainbow trout (Oncorhynchus mykiss) were measured. Cell shortening, expressed as a percentage of resting cell length, was our index of contractility. The fluorescent Ca(2+) indicator Fura-2 was used to monitor changes in [Ca(2+)](i). Action potentials and L-type Ca(2+) currents (I(Ca)) were recorded using the whole-cell patch-clamp technique. Experiments were performed at 15 degrees C. Increasing the stimulation frequency caused a significant increase in diastolic [Ca(2+)](i) and a significant decrease in diastolic cell length and membrane potential. During systole, there was a significant fall in the amplitude of the [Ca(2+)](i) transient, cell shortening and action potential with a decrease in the duration of the action potential at both 20 % and 90 % repolarisation. Caffeine was used to assess the Ca(2+) content of the sarcoplasmic reticulum. We observed that sarcoplasmic reticulum Ca(2+) load was greater at 1.0 Hz than at 0.6 Hz, despite a smaller electrically evoked [Ca(2+)](i) transient. The amplitude of I(Ca) was found to decrease with increased stimulation frequency. At 0.6 Hz, electrically evoked [Ca(2+)](i) transients in the presence of 10 mmol l(−)(1) caffeine or 10 micromol l(−)(1) ryanodine and 2 micromol l(−)(1) thapsigargin were reduced by approximately 15 %. We have described the changes in contractility, [Ca(2+)](i) and action potential configuration in a fish cardiac muscle system. Under the conditions tested (0.6 Hz, 15 degrees C), we conclude that the sarcoplasmic reticulum contributes at least 15 % of the Ca(2+) associated with the [Ca(2+)](i) transient. The rate-dependent decrease in contraction amplitude appears to be associated with the fall in the amplitude of the [Ca(2+)](i) transient. This, in turn, may be influenced by changes in the action potential configuration via mechanisms such as altered Ca(2+) efflux and Ca(2+) influx. In support of our conclusions, we present evidence that there is a rate-dependent decrease in Ca(2+) influx via I(Ca) but that the Ca(2+) load of the sarcoplasmic reticulum is not reduced at increased contraction frequencies.

scholarly journals A compartmentalized mathematical model of mouse atrial myocytes

2020 ◽  
Vol 318 (3) ◽  
pp. H485-H507 ◽  
Author(s):  
Tesfaye Negash Asfaw ◽  
Leonid Tyan ◽  
Alexey V. Glukhov ◽  
Vladimir E. Bondarenko
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Right Atrial ◽  
Minor Effect ◽  
Atrial Myocytes ◽  
Adrenergic Signaling ◽  
Intracellular Ca ◽  
Ionic Mechanisms ◽  
Small Conductance

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and β-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to β-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis. NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the β-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.

Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes

2014 ◽  
Vol 306 (3) ◽  
pp. H455-H461 ◽  
Author(s):  
Antao Luo ◽  
Jihua Ma ◽  
Yejia Song ◽  
Chunping Qian ◽  
Ying Wu ◽  
...  
Keyword(s):  
Left Atrial ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Left Ventricular ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Late Sodium Current ◽  
Ventricular Cells ◽  
Open Time ◽  
Hill Slope

An increase of cardiac late sodium current ( INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na+) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P < 0.01) when elicited by step pulses from −120 to −20 mV at a rate of 0.2 Hz. Similar results were obtained using step pulses from −90 to −20 mV. Anemone toxin II (ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 ( n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 ( n = 12) in ventricular myocytes. Na+ channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

Modulation of membrane potential by an acetylcholine-activated potassium current in trout atrial myocytes

2007 ◽  
Vol 292 (1) ◽  
pp. R388-R395 ◽  
Author(s):  
Cristina E. Molina ◽  
Hans Gesser ◽  
Anna Llach ◽  
Lluis Tort ◽  
Leif Hove-Madsen
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Atrial Myocytes ◽  
Atrial Tissue ◽  
Isolated Cardiac Myocytes ◽  
Inwardly Rectifying

Application of the current-clamp technique in rainbow trout atrial myocytes has yielded resting membrane potentials that are incompatible with normal atrial function. To investigate this paradox, we recorded the whole membrane current ( Im) and compared membrane potentials recorded in isolated cardiac myocytes and multicellular preparations. Atrial tissue and ventricular myocytes had stable resting potentials of −87 ± 2 mV and −83.9 ± 0.4 mV, respectively. In contrast, 50 out of 59 atrial myocytes had unstable depolarized membrane potentials that were sensitive to the holding current. We hypothesized that this is at least partly due to a small slope conductance of Im around the resting membrane potential in atrial myocytes. In accordance with this hypothesis, the slope conductance of Im was about sevenfold smaller in atrial than in ventricular myocytes. Interestingly, ACh increased Im at −120 mV from 4.3 pA/pF to 27 pA/pF with an EC50 of 45 nM in atrial myocytes. Moreover, 3 nM ACh increased the slope conductance of Im fourfold, shifted its reversal potential from −78 ± 3 to −84 ± 3 mV, and stabilized the resting membrane potential at −92 ± 4 mV. ACh also shortened the action potential in both atrial myocytes and tissue, and this effect was antagonized by atropine. When applied alone, atropine prolonged the action potential in atrial tissue but had no effect on membrane potential, action potential, or Im in isolated atrial myocytes. This suggests that ACh-mediated activation of an inwardly rectifying K+ current can modulate the membrane potential in the trout atrial myocytes and stabilize the resting membrane potential.

Properties of human atrial ICa at physiological temperatures and relevance to action potential

1997 ◽  
Vol 272 (1) ◽  
pp. H227-H235 ◽  
Author(s):  
G. R. Li ◽  
S. Nattel
Keyword(s):  
Action Potential ◽  
Human Atrium ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Maximum Current Density ◽  
Rate Dependent ◽  
Atrial Cells ◽  
Maximum Current ◽  
Reduced Rate

There are no published characterizations of Ca2+ current (ICa) at physiological temperatures in human atrium. Depolarization of human atrial myocytes at 36 degrees C elicited ICa that peaked at +10 mV, with a mean maximum current density of 10.8 +/- 1.1 pA/pF and no evidence for T-type current. Overlap between activation and inactivation curves and incomplete inactivation during pulses comparable to normal action potential duration (APD) were compatible with the observed role of ICa in maintaining the plateau. ICa was frequency dependent between 0.1 and 2 Hz and ICa blockade with 0.2 mM Cd2+ reduced rate-dependent changes in APD: under control, APD at 90% repolarization was 230 +/- 15 ms at 0.1 Hz and 178 +/- 14 ms at 2 Hz (decrease of 52 +/- 5 ms); with Cd2+, values were 121 +/- 7 ms at 0.1 H2 and 115 +/- 6 ms at 2 Hz (decrease of 6 +/- 3 ms, P < 0.01) Isoproterenol (1 microM) increased ICa and prolonged APD from 138 +/- 13 to 199 +/- 15 ms (P < 0.01). These results indicate that, in human atrial cells at 36 degrees C, the properties of L-type ICa contribute importantly to the rate-dependent and autonomic control of APD.

P2869Role of PDE8 in cAMP dynamics in human atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
N Grammatika Pavlidou ◽  
S Pecha ◽  
H Reichenspurner ◽  
T Christ ◽  
V O Nikolaev ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ventricular Myocytes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Membrane Receptors ◽  
Intracellular Camp ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Intracellular Compartments ◽  
Camp Levels

Abstract Background Cardiac arrhythmias, such as atrial fibrillation (AF), are often related to remodeling of membrane receptors and alterations in cAMP-dependent regulation of Ca2+ handling mechanisms. For instance, decreased L-type calcium current (ICa,L) density but upregulated RyR2 are major hallmarks of AF. These inhomogeneous AF-associated changes of protein phosphorylation point to a local regulation of PKA activity within these intracellular compartments. Local cAMP compartmentation and the role of phosphodiesterase (PDEs) have ben extensively studied in ventricular myocytes from animals. However, only a few studies have evaluated the contribution of PDEs to the pathophysiology of AF and the reason for the persistent AF-associated hypophosphorylation of the L-type calcium channel (LTCC) is currently unknown. The aim of this study was to investigate whether a change in the expression level of PDE8 in human atrium may affects cAMP nearby LTCC promoting the reduction of the ICa,L observed in persistent AF. Methods Atrial myocytes were isolated from tissue of 47 patients in sinus rhythm (SR) and with AF. Cells were then transfect with an adenovirus (Epac1-camps or pm-Epac1-camps) in order to express the (cytosolic or membrane, respectively) FRET-based cAMP sensor and cultured during 48 hours. Föster-resonance energy transfer (FRET) was used to measure cAMP in 232 isolated human atrial myocytes. Ro-20-1724 (10 μM), Cilostamide (1 μM) and PF-04957325 (30 nM) and IBMX (100 μM) were used as PDE4, PDE3, PDE8 and non-selective phosphodiesterases (PDEs) inhibitor respectively. Results Effects of PDE4 and especially PDE3 inhibition on cytosolic [cAMP] are reduced in AF. Pharmacological PDE8 inhibition induces only a small increase in basal intracellular [cAMP] in AF but it showed a big synergic effect when PDE4 was inhibit at the same time. By contrast, PDE8 inhibition dramatically increased basal [cAMP] in the subsarcolemmal compartment in AF while PDE3 or PDE4 inhibition had a smaller effect that didn't change between SR and AF. Conclusions PDE8 controls basal cytosolic cAMP levels in human atrial myocytes from patients with persistent AF while PDE3 effects tends to be reduced in these patients. Furthermore, PDE8 is the main PDE in controlling cAMP levels at the membrane in persistent AF. Thus, our study may provide a clue for the reported reduction of the ICa,L in persistent AF.

Contribution of Na+/Ca2+ exchange to action potential of human atrial myocytes

1996 ◽  
Vol 271 (3) ◽  
pp. H1151-H1161 ◽  
Author(s):  
A. Benardeau ◽  
S. N. Hatem ◽  
C. Rucker-Martin ◽  
B. Le Grand ◽  
L. Mace ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Time Course ◽  
Significant Proportion ◽  
Type A ◽  
Plateau Phase ◽  
Type B ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Delayed Afterdepolarizations

The Ca2+ dye indo 1 was used to record internal Ca2+ (Cai) transients in order to investigate the role of the Na+/Ca2+ exchange current (INa/Ca) in whole cell patch-clamped human atrial myocytes After the activation of the L-type Ca2+ current by test pulses (20 ms) at +20 mV, a tail current (I(tail)) was activated at a holding potential of -80 mV with a density of -1.29 +/- 0.06 pA/pF. The time course of I(tail) followed that of Cai transients I(tail) was suppressed by dialyzing cells with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, applying 5 mM caffeine, or substituting external Na+ with Li+, indicating that this current was mainly generated by INa/Ca. Two types of action potential were recorded: type A, which is characterized by a narrow early plateau followed by a late low plateau phase, and type B, which is characterized by a small initial peak followed by a prolonged high plateau phase. Type B action potentials were found in larger cells than type A action potentials (membrane capacitance 81.8 +/- 4.5 and 122.4 +/- 7.0 pF in types A and B, respectively, P < 0.001). Substitution of external Na+ with Li+ shortened the late plateau of the type A action potential and the prolonged plateau of the type B action potential. Suppression of Cai transients by caffeine shortens the late part of both types of action potentials, whereas its lengthening effect on the initial phase of action potentials can result from several different mechanisms. The beat-to-beat dependent relationship between Cai transients and action potentials could be mediated by Ina/Ca- Delayed afterdepolarizations were present in a significant proportion of atrial myocytes in our experimental conditions. They were reversibly suppressed by Li+ substitution for Na+, suggesting that they are generated by INa/Ca. We conclude that INa/Ca plays a major role in the development of action potentials and delayed afterdepolarizations in isolated human atrial myocytes.

scholarly journals From ionic to cellular variability in human atrial myocytes: an integrative computational and experimental study

2018 ◽  
Vol 314 (5) ◽  
pp. H895-H916 ◽  
Author(s):  
Anna Muszkiewicz ◽  
Xing Liu ◽  
Alfonso Bueno-Orovio ◽  
Brodie A. J. Lawson ◽  
Kevin Burrage ◽  
...  
Keyword(s):  
Ion Channel ◽  
Phenotypic Variability ◽  
Right Atrial ◽  
Resting Potential ◽  
Generic Model ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Human Cardiomyocytes ◽  
Atrial Electrophysiology ◽  
The Impact

Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na+/Ca2+ exchanger is identified as a primary mechanism underlying diastolic Ca2+ fluctuations in human atrial myocytes.

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