scholarly journals A comparative review on heart ion channels, action potentials and electrocardiogram in rodents and human: extrapolation of experimental insights to clinic

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Siyavash Joukar
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Heart Diseases ◽  
Cardiac Injury ◽  
Human Action ◽  
Basic Knowledge ◽  
Electrolyte Disturbances ◽  
Comparative Review ◽  
Experimental Findings

AbstractElectrocardiogram (ECG) is a non-invasive valuable diagnostic tool that is used in clinics for investigation and monitoring of heart electrical rhythm/conduction, ischemia/injury of heart, electrolyte disturbances and agents/drugs induced cardiac toxicity. Nowadays using animal models to study heart diseases such as electrical and mechanical disturbance is common. In addition, given to ethical consideration and availability, the use of small rodents has been a top priority for cardiovascular researchers. However, extrapolation of experimental findings from the lab to the clinic needs sufficient basic knowledge of similarities and differences between heart action potential and ECG of rodents and humans in normal and disease conditions. This review compares types of human action potentials, the dominant ion currents during action potential phases, alteration in ion channels activities in channelopathies-induced arrhythmias and the ECG appearance of mouse, rat, guinea pig, rabbit and human. Also, it briefly discusses the responsiveness and alterations in ECG following some interventions such as cardiac injury and arrhythmia induction. Overall, it provides a roadmap for researchers in selecting the best animal model/species whose studies results can be translated into clinical practice. In addition, this study will also be useful to biologists, physiologists, pharmacologists, veterinarians and physicians working in the fields of comparative physiology, pharmacology, toxicology and diseases.

scholarly journals Dendritic Voltage-Gated Ion Channels Regulate the Action Potential Firing Mode of Hippocampal CA1 Pyramidal Neurons

1999 ◽  
Vol 82 (4) ◽  
pp. 1895-1901 ◽  
Author(s):  
Jeffrey C. Magee ◽  
Michael Carruth
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Large Amplitude ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Burst Firing ◽  
Voltage Gated ◽  
Ca1 Pyramidal Neurons ◽  
Firing Mode ◽  
Voltage Gated Ion Channels

The role of dendritic voltage-gated ion channels in the generation of action potential bursting was investigated using whole cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons located in hippocampal slices of adult rats. Under control conditions somatic current injections evoked single action potentials that were associated with an afterhyperpolarization (AHP). After localized application of 4-aminopyridine (4-AP) to the distal apical dendritic arborization, the same current injections resulted in the generation of an afterdepolarization (ADP) and multiple action potentials. This burst firing was not observed after localized application of 4-AP to the soma/proximal dendrites. The dendritic 4-AP application allowed large-amplitude Na+-dependent action potentials, which were prolonged in duration, to backpropagate into the distal apical dendrites. No change in action potential backpropagation was seen with proximal 4-AP application. Both the ADP and action potential bursting could be inhibited by the bath application of nonspecific concentrations of divalent Ca2+ channel blockers (NiCl and CdCl). Ca2+ channel blockade also reduced the dendritic action potential duration without significantly affecting spike amplitude. Low concentrations of TTX (10–50 nM) also reduced the ability of the CA1 neurons to fire in the busting mode. This effect was found to be the result of an inhibition of backpropagating dendritic action potentials and could be overcome through the coordinated injection of transient, large-amplitude depolarizing current into the dendrite. Dendritic current injections were able to restore the burst firing mode (represented as a large ADP) even in the presence of high concentrations of TTX (300–500 μM). These data suggest the role of dendritic Na+ channels in bursting is to allow somatic/axonal action potentials to backpropagate into the dendrites where they then activate dendritic Ca2+ channels. Although it appears that most Ca2+ channel subtypes are important in burst generation, blockade of T- and R-type Ca2+ channels by NiCl (75 μM) inhibited action potential bursting to a greater extent than L-channel (10 μM nimodipine) or N-, P/Q-type (1 μM ω-conotoxin MVIIC) Ca2+ channel blockade. This suggest that the Ni-sensitive voltage-gated Ca2+ channels have the most important role in action potential burst generation. In summary, these data suggest that the activation of dendritic voltage-gated Ca2+ channels, by large-amplitude backpropagating spikes, provides a prolonged inward current that is capable of generating an ADP and burst of multiple action potentials in the soma of CA1 pyramidal neurons. Dendritic voltage-gated ion channels profoundly regulate the processing and storage of incoming information in CA1 pyramidal neurons by modulating the action potential firing mode from single spiking to burst firing.

Molecular Physiology of Cardiac Repolarization

2005 ◽  
Vol 85 (4) ◽  
pp. 1205-1253 ◽  
Author(s):  
Jeanne M. Nerbonne ◽  
Robert S. Kass
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Future Research ◽  
Cardiac Repolarization ◽  
Molecular Physiology ◽  
Cardiac Ion Channels ◽  
Α Subunits

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na+ and Ca2+) and outward (K+) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na+, Ca2+, and K+ channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na+, Ca2+, and K+ currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (α) and accessory (β, δ, and γ) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the α-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the α-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

scholarly journals Basis for the Induction of Tissue-Level Phase-2 Reentry as a Repolarization Disorder in the Brugada Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Alfonso Bueno-Orovio ◽  
Elizabeth M. Cherry ◽  
Steven J. Evans ◽  
Flavio H. Fenton
Keyword(s):  
Action Potential ◽  
Right Ventricular ◽  
Brugada Syndrome ◽  
Action Potentials ◽  
Human Action ◽  
Three Dimensions ◽  
Phase 2 ◽  
Three Dimensional Model ◽  
Right Ventricular Free Wall ◽  
The Right

Aims. Human action potentials in the Brugada syndrome have been characterized by delayed or even complete loss of dome formation, especially in the right ventricular epicardial layers. Such a repolarization pattern is believed to trigger phase-2 reentry (P2R); however, little is known about the conditions necessary for its initiation. This study aims to determine the specific mechanisms that facilitate P2R induction in Brugada-affected cardiac tissue in humans.Methods. Ionic models for Brugada syndrome in human epicardial cells were developed and used to study the induction of P2R in cables, sheets, and a three-dimensional model of the right ventricular free wall.Results. In one-dimensional cables, P2R can be induced by adjoining lost-dome and delayed-dome regions, as mediated by tissue excitability and transmembrane voltage profiles, and reduced coupling facilitates its induction. In two and three dimensions, sustained reentry can arise when three regions (delayed-dome, lost-dome, and normal epicardium) are present.Conclusions. Not only does P2R induction by Brugada syndrome require regions of action potential with delayed-dome and lost-dome, but in order to generate a sustained reentry from a triggered waveback multiple factors are necessary, including heterogeneity in action potential distribution, tissue coupling, direction of stimulation, the shape of the late plateau, the duration of lost-dome action potentials, and recovery of tissue excitability, which is predominantly modulated by tissue coupling.

Ion Channels, Membrane Ion Currents, and the Action Potential

The Neuron ◽  
2015 ◽  
pp. 103-126
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Plasma Membrane ◽  
Membrane Potential ◽  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Firing Pattern ◽  
Ion Currents ◽  
Detailed Understanding ◽  
Neuronal Plasma Membrane ◽  
Sodium And Potassium

The flow of ions down their electrochemical gradients, through populations of ion channels in the neuronal plasma membrane, gives rise to transmembrane ion currents. It is the sum of the various currents flowing at any point in time that determines the neuron’s membrane potential. Thus the normal firing pattern of a neuron, and its response to different kinds of stimulation, can be seen as a play of interactions among the currents flowing through the different kinds of ion channels in its membrane. The activities of the sodium and potassium channels responsible for axonal action potentials are themselves dependent on voltage. Voltage clamp studies, which allow the measurement of the current flowing through these channels at fixed voltage, have provided a detailed understanding of the sequence of changes in sodium and potassium channel activity that give rise to action potentials.

scholarly journals FIBRILASI ATRIAL DARI SUDUT PANDANG BIOFISIKA

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Indra N. S. Ruray ◽  
Vennetia R. Danes ◽  
Fransiska Lintong
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Heart Disease ◽  
Ion Channels ◽  
Myocardial Ischemia ◽  
Action Potential ◽  
Heart Diseases ◽  
Common Type ◽  
Ion Currents ◽  
Coronary Heart Diseases

Abstract: Atrial fibrillation (AF) is the most common type of arrhythmia found in daily practices. Moreover, AF is one of the risk factors of emboli stroke and myocardial ischemia in patients with coronary heart diseases. From the biophysics perspective, alterations in ion currents (especially K+) that play some important role in the occurence of action potential can lead to an arrhythmia state. Mutations of genes S140G and V141M that create slow activation of ion channels can participate in the occurence of AF. Keywords: atrial fibrillation, arrhythmia, biophysics, heart disease.     Abstrak: Fibrilasi atrial (FA) merupakan bentuk aritmia yang paling sering dijumpai dalam praktek sehari-hari. FA merupakan salah satu faktor risiko yang menyebabkan stroke emboli, dan dapat mencetuskan gejala iskemik pada kasus dengan dasar penyakit jantung koroner. Ditinjau dari sudut biofisika, gangguan terhadap arus ion (terutama ion K+) yang berperan penting dalam menimbulkan potensial aksi bagi jantung, dapat memicu terjadinya aritmia jantung. Mutasi gen S140G dan V141M yang menyebabkan pengaktifan lambat dari saluran ion turut berperan dalam terjadinya FA. Kata kunci: fibrilasi atrial, aritmia, biofisika,  penyakit jantung.

scholarly journals A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Celinda M. Kofron ◽  
Tae Yun Kim ◽  
Fabiola Munarin ◽  
Arvin H. Soepriatna ◽  
Rajeev J. Kant ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Action Potentials ◽  
Induced Pluripotent Stem Cell ◽  
Human Action ◽  
Environmental Toxicants ◽  
Pharmaceutical Drugs ◽  
Industrial Chemicals ◽  
Endocrine Disrupting Chemical

AbstractCardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.

Calcium Dynamics and Compartmentalization in Leech Neurons

2005 ◽  
Vol 94 (6) ◽  
pp. 4430-4440 ◽  
Author(s):  
Sofija Andjelic ◽  
Vincent Torre
Keyword(s):  
Information Processing ◽  
Action Potential ◽  
Action Potentials ◽  
Time Course ◽  
Ccd Camera ◽  
Calcium Dynamics ◽  
Single Action ◽  
Single Action Potential ◽  
Calcium Indicator ◽  
Mechanosensory Neurons

Calcium dynamics in leech neurons were studied using a fast CCD camera. Fluorescence changes (Δ F/ F) of the membrane impermeable calcium indicator Oregon Green were measured. The dye was pressure injected into the soma of neurons under investigation. Δ F/ F caused by a single action potential (AP) in mechanosensory neurons had approximately the same amplitude and time course in the soma and in distal processes. By contrast, in other neurons such as the Anterior Pagoda neuron, the Annulus Erector motoneuron, the L motoneuron, and other motoneurons, APs evoked by passing depolarizing current in the soma produced much larger fluorescence changes in distal processes than in the soma. When APs were evoked by stimulating one distal axon through the root, Δ F/ F was large in all distal processes but very small in the soma. Our results show a clear compartmentalization of calcium dynamics in most leech neurons in which the soma does not give propagating action potentials. In such cells, the soma, while not excitable, can affect information processing by modulating the sites of origin and conduction of AP propagation in distal excitable processes.

scholarly journals Zinc Enhances the Inhibitory Effects of Strychnine-Sensitive Glycine Receptors in Mouse Hippocampal Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3666-3676 ◽  
Author(s):  
Hai Xia Zhang ◽  
Liu Lin Thio
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Hippocampal Slices ◽  
Glycine Receptors ◽  
Inhibitory Effects ◽  
Action Potential Firing ◽  
Embryonic Mouse ◽  
Potential Firing

Although extracellular Zn2+ is an endogenous biphasic modulator of strychnine-sensitive glycine receptors (GlyRs), the physiological significance of this modulation remains poorly understood. Zn2+ modulation of GlyR may be especially important in the hippocampus where presynaptic Zn2+ is abundant. Using cultured embryonic mouse hippocampal neurons, we examined whether 1 μM Zn2+, a potentiating concentration, enhances the inhibitory effects of GlyRs activated by sustained glycine applications. Sustained 20 μM glycine (EC25) applications alone did not decrease the number of action potentials evoked by depolarizing steps, but they did in 1 μM Zn2+. At least part of this effect resulted from Zn2+ enhancing the GlyR-induced decrease in input resistance. Sustained 20 μM glycine applications alone did not alter neuronal bursting, a form of hyperexcitability induced by omitting extracellular Mg2+. However, sustained 20 μM glycine applications depressed neuronal bursting in 1 μM Zn2+. Zn2+ did not enhance the inhibitory effects of sustained 60 μM glycine (EC70) applications in these paradigms. These results suggest that tonic GlyR activation could decrease neuronal excitability. To test this possibility, we examined the effect of the GlyR antagonist strychnine and the Zn2+ chelator tricine on action potential firing by CA1 pyramidal neurons in mouse hippocampal slices. Co-applying strychnine and tricine slightly but significantly increased the number of action potentials fired during a depolarizing current step and decreased the rheobase for action potential firing. Thus Zn2+ may modulate neuronal excitability normally and in pathological conditions such as seizures by potentiating GlyRs tonically activated by low agonist concentrations.

Outward current and repolarization in hypoxic rat myocardium

1983 ◽  
Vol 244 (3) ◽  
pp. H341-H350
Author(s):  
C. H. Conrad ◽  
R. G. Mark ◽  
O. H. Bing
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Outward Current ◽  
Iodoacetic Acid ◽  
Mechanical Activity ◽  
Potential Range ◽  
Papillary Muscles ◽  
Rat Myocardium ◽  
Cable Properties ◽  
Sucrose Gap

We studied the effects of brief periods (20-30 min) of hypoxia in the presence of 5 and 50 mM glucose and of glycolytic blockade (10(-4) M iodoacetic acid, IAA) on action potentials, membrane currents, and mechanical activity in rat ventricular papillary muscles using a single sucrose gap voltage-clamp technique. Steady-state outward current (iss) was determined at the end of a 500-ms clamp to the test potential following a 600-ms clamp to a holding potential of -50 mV. In the presence of 5 mM glucose, hypoxia resulted in a decrease in action potential duration (APD) and an increase in iss (on the order of 60% at 0 mV) over the potential range studied. The increase in iss did not appear to be due to an increase in leakage current or to a change in the cable properties of the preparation. Addition of 50 mM glucose prevented the change in both APD and iss with hypoxia. In addition, glycolytic blockade with IAA did not alter iss in the presence of oxygen. We conclude that an increase in iss appears to be a major factor in the abbreviation of rat ventricular action potential seen with hypoxia. Glycolysis appears to be a sufficient (with 50 mM glucose) but not necessary source of energy for the maintenance of normal iss.

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