Cellular mechanisms of delayed recovery of excitability in ventricular tissue

1991 ◽  
Vol 260 (1) ◽  
pp. H225-H233 ◽  
Author(s):  
R. W. Joyner ◽  
B. M. Ramza ◽  
T. Osaka ◽  
R. C. Tan
Keyword(s):  
Time Course ◽  
Cellular Mechanisms ◽  
Isolated Cells ◽  
Ventricular Cells ◽  
Ventricular Tissue ◽  
Cellular Excitability ◽  
Current Threshold ◽  
Delayed Recovery ◽  
K Concentration ◽  
Cellular Responsiveness

It is well established that ventricular tissue, under some conditions, exhibits the phenomenon of postrepolarization refractoriness (PRR) in which the tissue excitability is depressed after an action potential. We have done parallel experiments on rabbit papillary muscles and on isolated rabbit ventricular cells to explain the cellular basis of this phenomenon, using elevated extracellular K+ concentration ([K+]o) (8 mM) to depolarize the tissue and the isolated cells. For isolated cells, we could separately measure cellular excitability (the inverse of the cellular current threshold) and the cellular responsiveness (the ability of the cell to generate inward current after excitation has occurred). We present two hypotheses that could explain the magnitude and time course of tissue PRR in terms of either changes in cellular excitability or changes in cellular responsiveness. We show that, although small changes in cellular excitability do occur, the predominant cellular mechanism for tissue PRR is the time course of recovery of the cellular responsiveness.

Effects of tissue geometry on initiation of a cardiac action potential

1989 ◽  
Vol 256 (2) ◽  
pp. H391-H403 ◽  
Author(s):  
R. W. Joyner ◽  
B. M. Ramza ◽  
R. C. Tan ◽  
J. Matsuda ◽  
T. T. Do
Keyword(s):  
Action Potential ◽  
Numerical Solutions ◽  
Papillary Muscles ◽  
Electrical Load ◽  
Membrane Action ◽  
Isolated Cells ◽  
Inward Current ◽  
Cellular Excitability ◽  
Current Threshold ◽  
K Concentration

We used rabbit ventricular papillary muscles and isolated rabbit ventricular muscle cells to compare the effects of a decrease in cardiac excitability. For the papillary muscles, we defined tissue excitability as the inverse of the current required to initiate a propagated action potential from a local stimulus. For the isolated cells, we defined cellular excitability as the inverse of the current required to initiate a membrane action potential. For papillary muscles, lidocaine with elevated extracellular K+ concentration ([K+]o) decreased maximum rate of rise of membrane potential (Vmax), decreased conduction velocity, and strongly decreased tissue excitability. For the isolated cells, lidocaine with elevated [K+]o decreased Vmax but had little effect on cellular excitability. We interpret our results on the differences of effect on tissue excitability vs. cellular excitability as a consequence of the syncytial nature of the papillary muscle. The cell-to-cell electrical connections produce an electrical load on the locally stimulated region. This electrical load makes the tissue excitability dependent on the amount of inward current that the locally excited cells and the surrounding cells can generate. We simulated these phenomena with numerical solutions of action potential initiation in an isopotential cell compared with a two-dimensional disk of excitable tissue. The simulation results recreate the basic experimental observation that the sensitivity of the current threshold to agents that lower inward current is markedly larger for multidimensional current flow from a source compared with an isopotential system.

EFFECTS OF ACUTE GLOBAL ISCHEMIA ON RE-ENTRANT ARRHYTHMOGENESIS: A SIMULATION STUDY

2015 ◽  
Vol 23 (02) ◽  
pp. 213-230 ◽  
Author(s):  
WEIGANG LU ◽  
JIE LI ◽  
FEI YANG ◽  
CUNJIN LUO ◽  
KUANQUAN WANG ◽  
...  
Keyword(s):  
Global Ischemia ◽  
Therapeutic Interventions ◽  
Fiber Direction ◽  
Activation Patterns ◽  
Cardiac Electrical Activity ◽  
Ventricular Cells ◽  
Ventricular Tissue ◽  
Cellular Excitability ◽  
The Stability ◽  
Kinetics Of

Sudden cardiac death is mainly caused by arrhythmogenesis. For a functional abnormal heart, such as an ischemic heart, the probability of arrhythmia occurring is greatly increased. During myocardial ischemia, re-entry is prone to degenerate into ventricular fibrillation (VF). Therefore it has important meaning to investigate the intricate mechanisms underlying VF under an ischemic condition in order to better facilitate therapeutic interventions. In this paper, to analyze the functional influence of acute global ischemia on cardiac electrical activity and subsequently on re-entrant arrhythmogenesis, we take into account three main pathophysiological consequences of ischemia: hyperkalaemia, acidosis, and anoxia, and develop a 3D human ventricular ischemic model that combines a detailed biophysical description of the excitation kinetics of human ventricular cells with an integrated geometry of human ventricular tissue which incorporates fiber direction anisotropy and the stimulation activation sequence. The results show that under acute global ischemia, the tissue excitability and the slope of ventricular cellular action potential duration restitution (APDR) are greatly decreased. As a result, the complexity of VF activation patterns is reduced. For the three components of ischemia, hyperkalaemia is the dominant contributor to the stability of re-entry under acute global ischemia. Increasing [K+]o acts to prolong the cell refractory period, reduce the tissue excitability and slow the conduction velocity. Our results also show that VF can be eliminated by decreasing cellular excitability, primarily by elevating the concentration value of extracellular K+.

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.

In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.

1998 ◽  
Vol 9 (7) ◽  
pp. 1213-1224 ◽  
Author(s):  
M Abbate ◽  
C Zoja ◽  
D Corna ◽  
M Capitanio ◽  
T Bertani ◽  
...  
Keyword(s):  
Time Course ◽  
Early Stage ◽  
Protein Accumulation ◽  
Glomerular Injury ◽  
Cellular Mechanisms ◽  
Proinflammatory Response ◽  
Glomerular Permeability ◽  
Tubular Cells ◽  
Interstitial Inflammation ◽  
Tubulointerstitial Lesions

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.

Time course of postnatal changes in rat heart action potential and in transient outward current is different

1994 ◽  
Vol 267 (3) ◽  
pp. H1157-H1166 ◽  
Author(s):  
G. M. Wahler ◽  
S. J. Dollinger ◽  
J. M. Smith ◽  
K. L. Flemal
Keyword(s):  
Action Potential ◽  
Rat Heart ◽  
Action Potentials ◽  
Time Course ◽  
Outward Current ◽  
Transient Outward Current ◽  
Papillary Muscles ◽  
Isolated Cells ◽  
Time Courses ◽  
Action Potential Shortening

The rat ventricular action potential shortens after birth. The contribution of increases in the transient outward current (Ito) to postnatal action potential shortening was assessed by measuring Ito in isolated cells and by determining the effect of 2 mM 4-aminopyridine (4-AP) on the action potentials of papillary muscles. 4-AP had no effect on 1-day action potential duration at 25% repolarization (APD25), and 1-day cells had little Ito. In 8- to 10-day muscles, 4-AP caused a small, but significant, increase in APD25. Ito increased slightly between day 1 and days 8-10, but this increase was not significant. Most of the increase in Ito (79%) and in the response to 4-AP (64%) occurred between days 8-10 and adult; however, approximately 75% of the APD25 shortening took place by days 8-10. Thus, while Ito may contribute to repolarization in late neonatal and adult cells, the different time courses of action potential shortening and increases in Ito suggest that changes in Ito are unlikely to be responsible for most of the postnatal action potential shortening.

Apamin, a highly specific Ca2+ blocking agent in heart muscle

1985 ◽  
Vol 248 (6) ◽  
pp. H961-H965 ◽  
Author(s):  
G. Bkaily ◽  
N. Sperelakis ◽  
J. F. Renaud ◽  
M. D. Payet
Keyword(s):  
Heart Muscle ◽  
Blocking Agent ◽  
Tyrode Solution ◽  
Tetraethylammonium Chloride ◽  
Naturally Occurring ◽  
Ventricular Cells ◽  
Dose Dependent Fashion ◽  
K Concentration ◽  
Dose Dependent ◽  
Slow Action Potentials

Apamin, a bee venom polypeptide, was recently reported to block specifically the Ca2+-dependent K+ channels that are not blocked by tetraethylammonium chloride in muscle cells. We report here that apamin blocked the naturally occurring slow action potentials (APs) in cultured cell reaggregates from chick hearts. The effects of apamin were not reversible on washout with Tyrode solution only (up to 24 h), but quinidine (10(-8) M) reversed the apamin blockade of the slow channels. Apamin also blocked the isoproterenol-induced slow APs in freshly isolated chick ventricular cells depolarized by 22 mM extracellular K+ concentration ([K+]o) in a dose-dependent fashion (10(-12) to 10(-10) M). Apamin at 5 X 10(-11) M blocked the isoproterenol-induced slow APs without affecting the membrane potential. Washout (with Tyrode solution containing 22 mM [K+]o and 10(-6) M isoproterenol) did not recover the slow APs. However, recovery of the slow APs was possible only when quinidine (10(-8) M) was added to the superfusion medium. The fast APs were rapidly restored by washout with Tyrode solution only. The present data show that apamin is a highly specific compound that tightly binds to the Ca2+ slow channels, thus blocking the slow APs in heart muscle. In addition, quinidine antagonizes the apamin binding on the slow APs.

Determinants of action potential initiation in isolated rabbit atrial and ventricular myocytes

1998 ◽  
Vol 274 (6) ◽  
pp. H1902-H1913 ◽  
Author(s):  
David A. Golod ◽  
Rajiv Kumar ◽  
Ronald W. Joyner
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Cell Types ◽  
Membrane Properties ◽  
Resting Membrane Potential ◽  
Isolated Cells ◽  
Atrial Cells ◽  
Ventricular Cells ◽  
Action Potential Initiation ◽  
Potential Initiation

Action potential conduction through the atrium and the ventricle of the heart depends on the membrane properties of the atrial and ventricular cells, particularly with respect to the determinants of the initiation of action potentials in each cell type. We have utilized both current- and voltage-clamp techniques on isolated cells to examine biophysical properties of the two cell types at physiological temperature. The resting membrane potential, action potential amplitude, current threshold, voltage threshold, and maximum rate of rise measured from atrial cells (−80 ± 1 mV, 109 ± 3 mV, 0.69 ± 0.05 nA, −59 ± 1 mV, and 206 ± 17 V/s, respectively; means ± SE) differed significantly ( P < 0.05) from those values measured from ventricular cells (−82.7 ± 0.4 mV, 127 ± 1 mV, 2.45 ± 0.13 nA, −46 ± 2 mV, and 395 ± 21 V/s, respectively). Input impedance, capacitance, time constant, and critical depolarization for activation also were significantly different between atrial (341 ± 41 MΩ, 70 ± 4 pF, 23.8 ± 2.3 ms, and 19 ± 1 mV, respectively) and ventricular (16.5 ± 5.4 MΩ, 99 ± 4.3 pF, 1.56 ± 0.32 ms, and 36 ± 1 mV, respectively) cells. The major mechanism of these differences is the much greater magnitude of the inward rectifying potassium current in ventricular cells compared with that in atrial cells, with an additional difference of an apparently lower availability of inward Na current in atrial cells. These differences in the two cell types may be important in allowing the atrial cells to be driven successfully by normal regions of automaticity (e.g., the sinoatrial node), whereas ventricular cells would suppress action potential initiation from a region of automaticity (e.g., an ectopic focus).

Tracer microinjection studies of renal tubular permeability

1965 ◽  
Vol 209 (1) ◽  
pp. 173-178 ◽  
Author(s):  
Carl W. Gottschalk ◽  
Francois Morel ◽  
Margaret Mylle
Keyword(s):  
Epithelial Cells ◽  
Time Course ◽  
Tritiated Water ◽  
Tubular Epithelial Cells ◽  
Osmotic Diuresis ◽  
Contralateral Kidney ◽  
Delayed Recovery ◽  
Renal Tubular ◽  
Convoluted Tubules ◽  
Tubular Permeability

Renal tubular permeability was studied in rats with a tracer microinjection technique in which radioactive inulin and another isotope were simultaneously microinjected into proximal or distal convoluted tubules during osmotic diuresis and their excretion by that kidney measured. Noninulin radioactivity excreted with a time course similar to that of inulin is termed direct recovery and that excreted more slowly, delayed recovery. The absence of inulin excretion by the contralateral kidney demonstrated that there was no transtubular efflux of this substance under these conditions. Inulin transit time averaged 0.84 min and 0.33 min following proximal and distal microinjection, respectively. Excreted sodium 22 molecules apparently followed closely the path of inulin molecules, since they appeared in the urine simultaneously. There was no delayed recovery of sodium 22. There was considerable direct and delayed recovery of urea-C14, indicating its diffusion into the tubular epithelial cells and subsequent return to the lumen. There was very little delayed and almost no direct recovery of tritiated water under these conditions in which physiologically maximally effective amounts of ADH were probably present. The injected quantity of isotope minus its direct recovery is believed to approximate its total tubular efflux.

Ca(2+)-induced inhibition of 45Ca2+ influx and Ca2+ current in smooth muscle of the rat vas deferens

1996 ◽  
Vol 270 (5) ◽  
pp. C1468-C1477 ◽  
Author(s):  
M. A. Khoyi ◽  
T. Ishikawa ◽  
K. D. Keef ◽  
D. P. Westfall
Keyword(s):  
Vas Deferens ◽  
Rat Vas Deferens ◽  
Inhibitory Effects ◽  
Isolated Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Inward Currents ◽  
K Concentration ◽  
Ca2 Channels

The present study investigates how changes in intracellular Ca2+ concentration modulate the influx of 45Ca2+ in isolated rat vasa deferentia. Raising extracellular K+ concentration ([K+]0) to > or = 32 mM increased 45Ca2+ influx during the 1st min in solutions containing 0.03-1.5 mM extracellular Ca2+ concentration ([Ca2+]0). During the 6th min in [K+]0 > or = 50 mM, 45Ca2+ influx was less than during the 1st min. This decline in 45Ca2+ influx occurred for [Ca2+]0 > or = 0.4 mM. Procaine potentiated K(+)-stimulated 45Ca2+ influx in 1.5 mM [Ca2+]0 and eliminated the decline of 45Ca2+ influx in low [Ca2-]0. Ryanodine and norepinephrine reduced K(+)-stimulated 45Ca2+ influx. 45Ca2+ content changed with time in accordance with the changes observed in 45Ca2+ influx. In isolated cells, voltage-dependent inward currents inactivated more rapidly with 1.5 mM Ca2+ as the charge carrier than with 1.5 mM Ba2+, and the steady-state inactivation relationship was shifted in the hyperpolarizing direction. Inward current was reduced with either caffeine, ryanodine, or norepinephrine. The inhibitory effects of norepinephrine were abolished by depletion of intracellular Ca2+ stores. These results are compatible with the hypothesis that K(+)-stimulated 45Ca2+ influx declines with time due to Ca(2+)-induced inhibition of Ca2- channels. Ca(2+)- and inositol 1,4,5-trisphosphate-induced releases of Ca2+ from the sarcoplasmic reticulum appear to play an important role in this process.

A computationally efficient electrophysiological model of human ventricular cells

2002 ◽  
Vol 282 (6) ◽  
pp. H2296-H2308 ◽  
Author(s):  
O. Bernus ◽  
R. Wilders ◽  
C. W. Zemlin ◽  
H. Verschelde ◽  
A. V. Panfilov
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Spiral Wave ◽  
Ionic Currents ◽  
Average Frequency ◽  
Computationally Efficient ◽  
Variable Model ◽  
Potential Shape ◽  
Ventricular Cells ◽  
Ventricular Tissue

Recent experimental and theoretical results have stressed the importance of modeling studies of reentrant arrhythmias in cardiac tissue and at the whole heart level. We introduce a six-variable model obtained by a reformulation of the Priebe-Beuckelmann model of a single human ventricular cell. The reformulated model is 4.9 times faster for numerical computations and it is more stable than the original model. It retains the action potential shape at various frequencies, restitution of action potential duration, and restitution of conduction velocity. We were able to reproduce the main properties of epicardial, endocardial, and M cells by modifying selected ionic currents. We performed a simulation study of spiral wave behavior in a two-dimensional sheet of human ventricular tissue and showed that spiral waves have a frequency of 3.3 Hz and a linear core of ∼50-mm diameter that rotates with an average frequency of 0.62 rad/s. Simulation results agreed with experimental data. In conclusion, the proposed model is suitable for efficient and accurate studies of reentrant phenomena in human ventricular tissue.

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