scholarly journals Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue

2010 ◽  
Vol 299 (2) ◽  
pp. H454-H469 ◽  
Author(s):  
Vladimir E. Bondarenko ◽  
Randall L. Rasmusson
Keyword(s):  
Action Potentials ◽  
Cardiac Cells ◽  
Two Dimensional ◽  
Epicardial Cells ◽  
Irregular Structures ◽  
Ventricular Tissue ◽  
Intracellular Ca ◽  
Heterogeneous Tissue ◽  
Transmural Heterogeneity ◽  
Epicardial Myocytes

Mouse hearts have a diversity of action potentials (APs) generated by the cardiac myocytes from different regions. Recent evidence shows that cells from the epicardial and endocardial regions of the mouse ventricle have a diversity in Ca2+ handling properties as well as K+ current expression. To examine the mechanisms of AP generation, propagation, and stability in transmurally heterogeneous tissue, we developed a comprehensive model of the mouse cardiac cells from the epicardial and endocardial regions of the heart. Our computer model simulates the following differences between epicardial and endocardial myocytes: 1) AP duration is longer in endocardial and shorter in epicardial myocytes, 2) diastolic and systolic intracellular Ca2+ concentration and intracellular Ca2+ concentration transients are higher in paced endocardial and lower in epicardial myocytes, 3) Ca2+ release rate is about two times larger in endocardial than in epicardial myocytes, and 4) Na+/Ca2+ exchanger rate is greater in epicardial than in endocardial myocytes. Isolated epicardial cells showed a higher threshold for stability of AP generation but more complex patterns of AP duration at fast pacing rates. AP propagation velocities in the model of two-dimensional tissue are close to those measured experimentally. Simulations show that heterogeneity of repolarization and Ca2+ handling are sustained across the mouse ventricular wall. Stability analysis of AP propagation in the two-dimensional model showed the generation of Ca2+ alternans and more complex transmurally heterogeneous irregular structures of repolarization and intracellular Ca2+ transients at fast pacing rates.

MODELING EXCITATION AND PROPAGATION OF ACTION POTENTIALS ACROSS INHOMOGENEOUS VENTRICULAR TISSUE

2003 ◽  
Vol 13 (12) ◽  
pp. 3845-3863 ◽  
Author(s):  
Z. LI ◽  
A. V. HOLDEN ◽  
C. H. ORCHARD ◽  
H. ZHANG
Keyword(s):  
Action Potentials ◽  
Computational Models ◽  
Ionic Current ◽  
Cell Models ◽  
Intercellular Coupling ◽  
Ventricular Tissue ◽  
Current Densities ◽  
Myocardial Membrane ◽  
Transmural Heterogeneity ◽  
Kinetics Of

Heterogeneity in the electrical activity across the ventricular wall might result from transmural differences in myocardial membrane ionic current densities. Computational models of endo- and epi-cardial action potentials of guinea-pig myocytes were developed, assuming transmural differences in the ionic current densities and kinetics of i Kr and i Ks . The cell models were able to reproduce the characteristics of action potentials of endo and epi cells. One- and two-dimensional models of ventricular tissue were also developed to study the effects of transmural heterogeneity on the propagation of excitation waves across the ventricle wall. It was shown that intercellular coupling reduces the transmural heterogeneity across the ventricle wall.

Effect of Lamotrigine on the Ca2+-Sensing Cation Current in Cultured Hippocampal Neurons

2001 ◽  
Vol 86 (5) ◽  
pp. 2520-2526 ◽  
Author(s):  
Zhi-Gang Xiong ◽  
Xiang-Ping Chu ◽  
J. F. MacDonald
Keyword(s):  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Membrane Depolarization ◽  
Slow Inward Current ◽  
Calcium Sensing ◽  
Cation Current ◽  
Imaging Experiment ◽  
Intracellular Ca ◽  
Cultured Hippocampal Neurons

Concentrations of extracellular calcium ([Ca2+]e) in the CNS decrease substantially during seizure activity. We have demonstrated previously that decreases in [Ca2+]e activate a novel calcium-sensing nonselective cation (csNSC) channel in hippocampal neurons. Activation of csNSC channels is responsible for a sustained membrane depolarization and increased neuronal excitability. Our study has suggested that the csNSC channel is likely involved in generating and maintaining seizure activities. In the present study, the effects of anti-epileptic agent lamotrigine (LTG) on csNSC channels were studied in cultured mouse hippocampal neurons using patch-clamp techniques. At a holding potential of −60 mV, a slow inward current through csNSC channels was activated by a step reduction of [Ca2+]e from 1.5 to 0.2 mM. LTG decreased the amplitude of csNSC currents dose dependently with an IC50 of 171 ± 25.8 (SE) μM. The effect of LTG was independent of membrane potential. In the presence of 300 μM LTG, the amplitude of csNSC current was decreased by 31 ± 3% at −60 mV and 29 ± 2.9% at +40 mV ( P > 0.05). LTG depressed csNSC current without affecting the potency of Ca2+ block of the current (IC50 for Ca2+block of csNSC currents in the absence of LTG: 145 ± 18 μM; in the presence of 300 μM LTG: 136 ± 10 μM. n = 5, P > 0.05). In current-clamp recordings, activation of csNSC channel by reducing the [Ca2+]e caused a sustained membrane depolarization and an increase in the frequency of spontaneous firing of action potentials. LTG (300 μM) significantly inhibited csNSC channel-mediated membrane depolarization and the excitation of neurons. Fura-2 ratiometric Ca2+imaging experiment showed that LTG also inhibited the increase in intracellular Ca2+ concentration induced by csNSC channel activation. The effect of LTG on csNSC channels may partially contribute to its broad spectrum of anti-epileptic actions.

scholarly journals Cardiac Transmembrane Ion Channels and Action Potentials: Cellular Physiology and Arrhythmogenic Behavior

2020 ◽  
Author(s):  
András Varró ◽  
Jakub Tomek ◽  
Norbert Nagy ◽  
Laszlo Virag ◽  
Elisa Passini ◽  
...  
Keyword(s):  
Ion Channel ◽  
Action Potentials ◽  
Cardiac Electrophysiology ◽  
Current Knowledge ◽  
Animal Experiments ◽  
Cardiac Cells ◽  
Cellular Mechanisms ◽  
Electrophysiological Properties ◽  
Channel Expression ◽  
Ionic Mechanisms

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells, and their underlying ionic mechanisms. It is therefore critical to further unravel the patho-physiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodelling) are discussed. The focus is human relevant findings obtained with clinical, experimental and computational studies, given that interspecies differences make the extrapolation from animal experiments to the human clinical settings difficult. Deepening the understanding of the diverse patholophysiology of human cellular electrophysiology will help developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.

scholarly journals Mechanisms for Intracellular Calcium Regulation in Heart

1973 ◽  
Vol 62 (6) ◽  
pp. 756-772 ◽  
Author(s):  
Antonio Scarpa ◽  
Pierpaolo Graziotti
Keyword(s):  
Cardiac Cells ◽  
Heart Mitochondria ◽  
Frog Heart ◽  
Cardiac Mitochondria ◽  
Physiological Regulation ◽  
Ca Transport ◽  
Ca Uptake ◽  
Intracellular Ca

Initial velocities of energy-dependent Ca++ uptake were measured by stopped-flow and dual-wavelength techniques in mitochondria isolated from hearts of rats, guinea pigs, squirrels, pigeons, and frogs. The rate of Ca++ uptake by rat heart mitochondria was 0.05 nmol/mg/s at 5 µM Ca++ and increased sigmoidally to 8 nmol/mg/s at 200 µM Ca++. A Hill plot of the data yields a straight line with slope n of 2, indicating a cooperativity for Ca++ transport in cardiac mitochondria. Comparable rates of Ca++ uptake and sigmoidal plots were obtained with mitochondria from other mammalian hearts. On the other hand, the rates of Ca++ uptake by frog heart mitochondria were higher at any Ca++ concentrations. The half-maximal rate of Ca++ transport was observed at 30, 60, 72, 87, 92 µM Ca++ for cardiac mitochondria from frog, squirrel, pigeon, guinea pig, and rat, respectively. The sigmoidicity and the high apparent Km render mitochondrial Ca++ uptake slow below 10 µM. At these concentrations the rate of Ca++ uptake by cardiac mitochondria in vitro and the amount of mitochondria present in the heart are not consistent with the amount of Ca++ to be sequestered in vivo during heart relaxation. Therefore, it appears that, at least in mammalian hearts, the energy-linked transport of Ca++ by mitochondria is inadequate for regulating the beat-to-beat Ca++ cycle. The results obtained and the proposed cooperativity for mitochondrial Ca++ uptake are discussed in terms of physiological regulation of intracellular Ca++ homeostasis in cardiac cells.

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

2003 ◽  
Vol 83 (1) ◽  
pp. 117-161 ◽  
Author(s):  
Edward Perez-Reyes
Keyword(s):  
Plasma Membrane ◽  
Action Potentials ◽  
Low Voltage ◽  
Absence Epilepsy ◽  
Molecular Physiology ◽  
Comprehensive Description ◽  
Cellular Processes ◽  
Repeat Structure ◽  
Intracellular Ca ◽  
Low Threshold

T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

scholarly journals Synchronized Ca2+ signaling by intercellular propagation of Ca2+ action potentials in NRK fibroblasts

1997 ◽  
Vol 273 (6) ◽  
pp. C1900-C1907 ◽  
Author(s):  
Albert D. G. De Roos ◽  
Peter H. G. M. Willems ◽  
Everardus J. J. Van Zoelen ◽  
Alexander P. R. Theuvenet
Keyword(s):  
Action Potentials ◽  
Rat Kidney ◽  
Inositol Trisphosphate ◽  
Threshold Value ◽  
General Mechanism ◽  
Channel Blockers ◽  
Excitable Tissue ◽  
Large Numbers ◽  
Intracellular Ca ◽  
Normal Rat

The intercellular propagation of Ca2+waves by diffusion of inositol trisphosphate has been shown to be a general mechanism by which nonexcitable cells communicate. Here, we show that monolayers of normal rat kidney (NRK) fibroblasts behave like a typical excitable tissue. In confluent monolayers of these cells, Ca2+ action potentials can be generated by local depolarization of the monolayer on treatment with either bradykinin or an elevation of the extracellular K+ concentration. These electrotonically propagating action potentials travel intercellularly over long distances in an all-or-none fashion at a speed of ∼6.1 mm/s and can be blocked by L-type Ca2+ channel blockers. The action potentials are generated by depolarizations beyond the threshold value for L-type Ca2+ channels of about −15 mV. The result of these locally induced, propagating Ca2+ action potentials is an almost synchronous, transient increase in the intracellular Ca2+ concentration in large numbers of cells. These data show that electrically coupled fibroblasts can form an excitable syncytium, and they elucidate a novel mechanism of intercellular Ca2+ signaling in these cells that may coordinate synchronized multicellular responses to local stimuli.

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.

Action potential morphology heterogeneity in the atrium and its effect on atrial reentry: a two-dimensional and quasi-three-dimensional study

2006 ◽  
Vol 364 (1843) ◽  
pp. 1349-1366 ◽  
Author(s):  
Samuel R Kuo ◽  
Natalia A Trayanova
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Three Dimensional ◽  
Spiral Wave ◽  
Spiral Waves ◽  
Two Dimensional ◽  
Crista Terminalis ◽  
Wave Dynamics ◽  
Continuous Surface ◽  
The Right

Atrial fibrillation (AF) is believed to be perpetuated by recirculating spiral waves. Atrial structures are often characterized with action potentials of varying morphologies; however, the role of the structure-dependent atrial electrophysiological heterogeneity in spiral wave behaviour is not well understood. The purpose of this study is to determine the effect of action potential morphology heterogeneity associated with the major atrial structures in spiral wave maintenance. The present study also focuses on how this effect is further modulated by the presence of the inherent periodicity in atrial structure. The goals of the study are achieved through the simulation of electrical behaviour in a two-dimensional atrial tissue model that incorporates the representation of action potentials in various structurally distinct regions in the right atrium. Periodic boundary conditions are then imposed to form a cylinder (quasi three-dimensional), thus allowing exploration of the additional effect of structure periodicity on spiral wave behaviour. Transmembrane potential maps and phase singularity traces are analysed to determine effects on spiral wave behaviour. Results demonstrate that the prolonged refractoriness of the crista terminalis (CT) affects the pattern of spiral wave reentry, while the variation in action potential morphology of the other structures does not. The CT anchors the spiral waves, preventing them from drifting away. Spiral wave dynamics is altered when the ends of the sheet are spliced together to form a cylinder. The main effect of the continuous surface is the generation of secondary spiral waves which influences the primary rotors. The interaction of the primary and secondary spiral waves decreased as cylinder diameter increased.

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