scholarly journals Uncertainty quantification of fast sodium current steady-state inactivation for multi-scale models of cardiac electrophysiology

2015 ◽  
Vol 117 (1) ◽  
pp. 4-18 ◽  
Author(s):  
Pras Pathmanathan ◽  
Matthew S. Shotwell ◽  
David J. Gavaghan ◽  
Jonathan M. Cordeiro ◽  
Richard A. Gray
Keyword(s):  
Steady State ◽  
Uncertainty Quantification ◽  
Cardiac Electrophysiology ◽  
Sodium Current ◽  
Multi Scale ◽  
Scale Models ◽  
Steady State Inactivation ◽  
Fast Sodium Current

Nitrogen narcosis and pressure reversal of anesthetic effects in node of Ranvier

1984 ◽  
Vol 246 (1) ◽  
pp. C91-C95 ◽  
Author(s):  
J. J. Kendig
Keyword(s):  
Steady State ◽  
Sodium Current ◽  
Conduction Block ◽  
Volatile Anesthetic ◽  
Inert Gases ◽  
Helium Pressure ◽  
General Anesthetic ◽  
H Infinity ◽  
Anesthetic Agents ◽  
Steady State Inactivation

To compare sodium channel block by hyperbaric nitrogen with that induced by other anesthetics and to examine the basis for pressure antagonism to anesthetic condition block, voltage clamped nodes of Ranvier were exposed to nitrogen at pressures at 1-14 atm alone and in combination with helium to a total pressure of up to 100 atm. At 7 and 14 atm nitrogen, sodium currents were reversibly depressed without accompanying changes in the current-voltage relation. The curve relating steady-state inactivation (h infinity) to voltage was shifted in the hyperpolarizing direction, as is the case with other general anesthetic agents. The time constant of inactivation (tau h) was slightly decreased at depolarized potentials. The preceding companion paper demonstrated an opposite effect of hyperbaric helium on the properties of sodium inactivation. Addition of helium pressure in the presence of nitrogen at 14 atm did not increase peak sodium current with inactivation maximally removed, but it did shift the h infinity curve back toward control levels, thus increasing sodium current at points on the slope of the curve. It is proposed that these opposing shifts in steady-state inactivation levels are the basis for pressure antagonism to anesthetic conduction block. In the case of inert gases and volatile anesthetic agents, the antagonism may be direct but has not been shown to be so. In the case of the local anesthetic benzocaine, differences in the voltage dependence of anesthetic and pressure-induced changes in tau h indicate the antagonism is indirect.

Ionic currents in vertebrate myelinated nerve at hyperbaric pressure

1984 ◽  
Vol 246 (1) ◽  
pp. C84-C90 ◽  
Author(s):  
J. J. Kendig
Keyword(s):  
Steady State ◽  
Sodium Current ◽  
Ionic Currents ◽  
Base Line ◽  
Myelinated Nerve ◽  
Hyperbaric Pressure ◽  
Voltage Curve ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Steady State Inactivation

To establish a base line for a study of anesthetic-pressure antagonism in axons, voltage-clamped nodes of Ranvier from amphibian sciatic nerve were subjected to pressures of 1-100 atm. Over the time of compression, there was usually an irreversible decrease in peak inward sodium current, but there was no change in peak outward sodium current or in the current-voltage relationship. The steady-state inactivation-voltage curve was shifted 5-15 mV in the depolarizing direction at 70-100 atm. The rate of rise of the sodium current was slowed, as was the time constant of inactivation (tau h). Increase in tau h was markedly voltage dependent, suggesting a selective effect of pressure on beta h, the rate constant governing development of the inactive state. The rate of development of steady-state outward potassium current was also decreased, without significant change in maximum current. The effects of pressure are qualitatively similar to, but different in detail from, those reported in squid axon and different in some details from the effects of cooling in this preparation. None of the effects can presently be related to the high-pressure nervous syndrome.

scholarly journals Effects of Allicin on Late Sodium Current Caused by ΔKPQ-SCN5A Mutation in HEK293 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Yating Chen ◽  
Yun Huang ◽  
Jing Bai ◽  
Chuanbin Liu ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Steady State ◽  
Intermediate State ◽  
Sodium Current ◽  
New Drugs ◽  
Hek293 Cells ◽  
Late Sodium Current ◽  
Technology Application ◽  
Steady State Inactivation ◽  
Window Current ◽  
Scn5a Mutation

AimThe aim was to study the effect of Allitridum (Allicin) on the heterologous expression of the late sodium current on the ΔKPQ-SCN5A mutations in HEK293 cells, with a view to screening new drugs for the treatment of long QT syndrome type 3 (LQT3).Methods and ResultsThe ΔKPQ-SCN5A plasmid was transiently transferred into HEK293 cells by liposome technology and administered by extracellular perfusion, and the sodium current was recorded by whole-cell patch-clamp technology. Application of Allicin 30 μM reduced the late sodium current (INa,L) of the Nav1.5 channel current encoded by ΔKPQ-SCN5A from 1.92 ± 0.12 to 0.65 ± 0.03 pA/pF (P < 0.01, n = 15), which resulted in the decrease of INa,L/INa,P (from 0.94% ± 0.04% to 0.32% ± 0.02%). Furthermore, treatment with Allicin could move the steady-state inactivation of the channel to a more negative direction, resulting in an increase in channel inactivation at the same voltage, which reduced the increase in the window current and further increased the inactivation of the channel intermediate state. However, it had no effect on channel steady-state activation (SSA), inactivation mechanics, and recovery dynamics after inactivation. What’s more, the Nav1.5 channel protein levels of membrane in the ΔKPQ-SCN5A mutation were enhanced from 0.49% ± 0.04% to 0.76% ± 0.02% with the effect of 30 mM Allicin, close to 0.89% ± 0.02% of the WT.ConclusionAllicin reduced the late sodium current of ΔKPQ-SCN5A, whose mechanism may be related to the increase of channel steady-state inactivation (SSI) and intermediate-state inactivation (ISI) by the drug, thus reducing the window current.

scholarly journals Inactivation of the Sodium Current in Myxicola Giant Axons

1972 ◽  
Vol 59 (6) ◽  
pp. 659-675 ◽  
Author(s):  
L. Goldman ◽  
C. L. Schauf
Keyword(s):  
Steady State ◽  
Sodium Current ◽  
Voltage Characteristic ◽  
Current Voltage Characteristic ◽  
Inactivation Curve ◽  
Giant Axons ◽  
Sodium Conductance ◽  
Current Voltage ◽  
Steady State Inactivation ◽  
The Right

Experiments were conducted on Myxicola giant axons to determine if the sodium activation and inactivation processes are coupled or independent. The main experimental approach was to examine the effects of changing test pulses on steady-state inactivation curves. Arguments were presented to show that in the presence of a residual uncompensated series resistance the interpretation of the results depends critically on the manner of conducting the experiment. Analytical and numerical calculations were presented to show that as long as test pulses are confined to an approximately linear negative conductance region of the sodium current-voltage characteristic, unambiguous interpretations can be made. When examined in the manner of Hodgkin and Huxley, inactivation in Myxicola is quantitatively similar to that described by the h variable in squid axons. However, when test pulses were increased along the linear negative region of the sodium current-voltage characteristic, steady-state inactivation curves translate to the right along the voltage axis. The shift in the inactivation curve is a linear function of the ratio of the sodium, conductance of the test pulses, showing a 5.8 mv shift for a twofold increase in conductance. An independent line of evidence indicated that the early rate of development of inactivation is a function of the rise of the sodium conductance.

Effect of intracellular and extracellular acidosis on sodium current in ventricular myocytes

1995 ◽  
Vol 268 (4) ◽  
pp. H1749-H1756 ◽  
Author(s):  
C. L. Watson ◽  
M. R. Gold
Keyword(s):  
Steady State ◽  
Time Course ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Essential Element ◽  
Neonatal Rat ◽  
Cardiac Conduction ◽  
Inactivation Kinetics ◽  
Extracellular Acidosis ◽  
Steady State Inactivation

Conduction slowing is an essential element in the generation of ischemic ventricular arrhythmias and is determined in part by the inward Na+ current (INa). Because intracellular acidosis is an early consequence of ischemia, we hypothesized that lowering intracellular pH (pHi) would reduce or kinetically modulate INa and thus affect cardiac conduction. To test this hypothesis, the whole cell patch-clamp method was used to measure INa in neonatal rat ventricular myocytes exposed to varying extracellular pH (pHo 6.4–7.4), while perfusing the cells with acidic solutions (pHi 6.2–7.2). With simultaneous acidification of pHo and pHi there was a progressive increase in time to peak current, a 31% decrease in peak INa (298 +/- 18 to 206 +/- 16 pA/pF), and a complex slowing of inactivation kinetics. At the most extreme levels of acidification, there was a 5-mV hyperpolarizing shift in steady-state inactivation and a 6-mV depolarizing shift in activation. Independent changes of pHo and pHi indicate that the reduction of peak INa is a function of pHo. However, steady-state inactivation is modulated by pHi. The time course of activation and inactivation appears to depend on both pHo and pHi. We conclude that both intracellular and extracellular acidosis are significant but distinct modulators of INa amplitude and kinetics in cardiac myocytes.

scholarly journals Prediction of Liner Metal Temperature of an Aeroengine Combustor with Multi-Physics Scale-Resolving CFD

Entropy ◽  
2021 ◽  
Vol 23 (7) ◽  
pp. 901
Author(s):  
Davide Bertini ◽  
Lorenzo Mazzei ◽  
Antonio Andreini
Keyword(s):  
Heat Transfer ◽  
Steady State ◽  
Turbulence Models ◽  
Metal Temperature ◽  
Lean Burn ◽  
Turbulence Scale ◽  
Ansys Fluent ◽  
Multi Scale ◽  
Assessment Tests ◽  
Rans Turbulence Models

Computational Fluid Dynamics is a fundamental tool to simulate the flow field and the multi-physics nature of the phenomena involved in gas turbine combustors, supporting their design since the very preliminary phases. Standard steady state RANS turbulence models provide a reasonable prediction, despite some well-known limitations in reproducing the turbulent mixing in highly unsteady flows. Their affordable cost is ideal in the preliminary design steps, whereas, in the detailed phase of the design process, turbulence scale-resolving methods (such as LES or similar approaches) can be preferred to significantly improve the accuracy. Despite that, in dealing with multi-physics and multi-scale problems, as for Conjugate Heat Transfer (CHT) in presence of radiation, transient approaches are not always affordable and appropriate numerical treatments are necessary to properly account for the huge range of characteristics scales in space and time that occur when turbulence is resolved and heat conduction is simulated contextually. The present work describes an innovative methodology to perform CHT simulations accounting for multi-physics and multi-scale problems. Such methodology, named U-THERM3D, is applied for the metal temperature prediction of an annular aeroengine lean burn combustor. The theoretical formulations of the tool are described, together with its numerical implementation in the commercial CFD code ANSYS Fluent. The proposed approach is based on a time de-synchronization of the involved time dependent physics permitting to significantly speed up the calculation with respect to fully coupled strategy, preserving at the same time the effect of unsteady heat transfer on the final time averaged predicted metal temperature. The results of some preliminary assessment tests of its consistency and accuracy are reported before showing its exploitation on the real combustor. The results are compared against steady-state calculations and experimental data obtained by full annular tests at real scale conditions. The work confirms the importance of high-fidelity CFD approaches for the aerothermal prediction of liner metal temperature.

scholarly journals The Winter Habitat Selection of Red Deer (Cervus elaphus) Based on a Multi-Scale Model

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2454
Author(s):  
Yue Sun ◽  
Yanze Yu ◽  
Jinhao Guo ◽  
Minghai Zhang
Keyword(s):  
Habitat Selection ◽  
Environmental Factors ◽  
Cervus Elaphus ◽  
Red Deer ◽  
Scale Model ◽  
Winter Habitat ◽  
Multi Scale ◽  
Optimal Scale ◽  
Scale Models ◽  
Selection Of

Single-scale frameworks are often used to analyze the habitat selections of species. Research on habitat selection can be significantly improved using multi-scale models that enable greater in-depth analyses of the scale dependence between species and specific environmental factors. In this study, the winter habitat selection of red deer in the Gogostaihanwula Nature Reserve, Inner Mongolia, was studied using a multi-scale model. Each selected covariate was included in multi-scale models at their “characteristic scale”, and we used an all subsets approach and model selection framework to assess habitat selection. The results showed that: (1) Univariate logistic regression analysis showed that the response scale of red deer to environmental factors was different among different covariate. The optimal scale of the single covariate was 800–3200 m, slope (SLP), altitude (ELE), and ratio of deciduous broad-leaved forests were 800 m in large scale, except that the farmland ratio was 200 m in fine scale. The optimal scale of road density and grassland ratio is both 1600 m, and the optimal scale of net forest production capacity is 3200 m; (2) distance to forest edges, distance to cement roads, distance to villages, altitude, distance to all road, and slope of the region were the most important factors affecting winter habitat selection. The outcomes of this study indicate that future studies on the effectiveness of habitat selections will benefit from multi-scale models. In addition to increasing interpretive and predictive capabilities, multi-scale habitat selection models enhance our understanding of how species respond to their environments and contribute to the formulation of effective conservation and management strategies for ungulata.

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