Human embryonic stem cell-derived cardiomyocytes: demonstration of a portion of cardiac cells with fairly mature electrical phenotype

2010 ◽  
Vol 235 (4) ◽  
pp. 522-530 ◽  
Author(s):  
Mari Pekkanen-Mattila ◽  
Hugh Chapman ◽  
Erja Kerkelä ◽  
Riitta Suuronen ◽  
Heli Skottman ◽  
...  
Keyword(s):  
Electrical Properties ◽  
Cell Model ◽  
Embryonic Stem ◽  
Cardiac Cells ◽  
Patch Clamp Technique ◽  
Drug Induced ◽  
Electrophysiological Properties ◽  
Promising Tool ◽  
Whole Cell Patch Clamp ◽  
Significant Difference

Cardiomyocytes (CMs) derived from human embryonic stem cells (hESC) provide a promising tool for the pharmaceutical industry. In this study the electrical properties and maturation of hESC-CM derived using two differentiation methods were compared and the suitability of hESC-CMs as a cell model for the assessment of drug-induced repolarization delay was evaluated. CMs were differentiated either in END-2 co-culture or by spontaneous differentiation. Action potentials (APs) were recorded from cells in spontaneously beating areas using the whole-cell patch-clamp technique. The hESC-CMs exhibited predominantly a ventricular-like phenotype with heterogeneous properties. Heterogeneity was indicative of the spectrum of hESC-CM maturation from embryonic-like with AP upstroke velocities <30 V/s and maximum diastolic potential (MDP) of close to −60 mV to more mature with values >150 V/s and −80 mV, respectively. The mean MDP was −70 mV and a significant difference was observed between the two differentiation methods (−66 versus −75 mV, P < 0.001). The age of the CMs did not correlate with phenotype maturation. The addition of the hERG blocker E-4031 and the sodium channel modulator veratridine significantly prolonged the AP duration. Furthermore, proarrhythmic indices were induced. In conclusion, the main observation was the heterogeneity in electrical properties of the hESC-CMs and this was observed with both differentiation methods. One-third of the hESC-CMs exhibited fairly mature electrophysiological properties, suggesting that mature CMs could be obtained from hESCs. However, improved differentiation methods are needed to produce homogeneous mature human CMs for pharmaceutical and toxicological applications.

scholarly journals Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iva Synková ◽  
Markéta Bébarová ◽  
Irena Andršová ◽  
Larisa Chmelikova ◽  
Olga Švecová ◽  
...  
Keyword(s):  
Calcium Current ◽  
Cell Model ◽  
Dominant Negative ◽  
Qtc Interval ◽  
Adrenergic Stimulation ◽  
Patch Clamp Technique ◽  
Long Qt ◽  
Channel Trafficking ◽  
Whole Cell Patch Clamp ◽  
Delayed Afterdepolarizations

AbstractThe variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

Channels involved in transient currents unmasked by removal of extracellular calcium in cardiac cells

2002 ◽  
Vol 282 (5) ◽  
pp. H1879-H1888 ◽  
Author(s):  
Regina Macianskiene ◽  
Francesco Moccia ◽  
Karin R. Sipido ◽  
Willem Flameng ◽  
Kanigula Mubagwa
Keyword(s):  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Monovalent Cation ◽  
Cardiac Cells ◽  
Time Dependent ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
High Concentrations ◽  
Low Sensitivity

In cardiac cells that lack macroscopic transient outward K+ currents ( I to), the removal of extracellular Ca2+ can unmask “ I to-like” currents. With the use of pig ventricular myocytes and the whole cell patch-clamp technique, we examined the possibility that cation efflux via L-type Ca2+channels underlies these currents. Removal of extracellular Ca2+ and extracellular Mg2+ induced time-independent currents at all potentials and time-dependent currents at potentials greater than −50 mV. Either K+ or Cs+ could carry the time-dependent currents, with reversal potential of +8 mV with internal K+ and +34 mV with Cs+. Activation and inactivation were voltage dependent [Boltzmann distributions with potential of half-maximal value ( V 1/2) = −24 mV and slope = −9 mV for activation; V 1/2 = −58 mV and slope = 13 mV for inactivation]. The time-dependent currents were resistant to 4-aminopyridine and to DIDS but blocked by nifedipine at high concentrations (IC50 = 2 μM) as well as by verapamil and diltiazem. They could be increased by BAY K-8644 or by isoproterenol. We conclude that the I to-like currents are due to monovalent cation flow through L-type Ca2+ channels, which in pig myocytes show low sensitivity to nifedipine.

scholarly journals Altered Spontaneous Glutamatergic and GABAergic Activity in the Peritumoral Cortex of Low-Grade Gliomas Presenting With History of Seizures

2021 ◽  
Vol 15 ◽  
Author(s):  
Soumil Dey ◽  
Ramesh Sharanappa Doddamani ◽  
Aparna Banerjee Dixit ◽  
Manjari Tripathi ◽  
Meher Chand Sharma ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Low Grade ◽  
Proliferating Cells ◽  
Patch Clamp Technique ◽  
Who Grade ◽  
Electrophysiological Properties ◽  
Whole Cell Patch Clamp ◽  
History Of ◽  
Gabaergic Activity

The peritumoral regions of WHO grade II gliomas, like astrocytoma and oligodendroglioma, have been reported to show epileptiform activities. An imbalance of glutamatergic and GABAergic mechanisms is primarily responsible for the generation of epileptiform activities. Here we have compared the electrophysiological properties of pyramidal neurons in intraoperative peritumoral specimens obtained from glioma patients with (GS) and without (GN) a history of seizures at presentation. Histology and immunohistochemistry were performed to assess the infiltration of proliferating cells at the peritumoral tissues. Whole-cell patch clamp technique was performed to measure the spontaneous glutamatergic and GABAergic activity onto pyramidal neurons in the peritumoral samples of GS (n = 11) and GN (n = 15) patients. The cytoarchitecture of the peritumoral tissues was devoid of Ki67 immuno-positive cells. We observed a higher frequency of spontaneous glutamatergic and GABAergic activities onto pyramidal neurons of the peritumoral samples of GS patients. Our findings suggest that, in spite of similar histopathological features, the pyramidal neurons in the peritumoral samples of GS and GN patients showed differences in spontaneous excitatory and inhibitory synaptic neurotransmission. An alteration in postsynaptic currents may contribute to the spontaneous epileptiform activity in GS patients.

A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels

2001 ◽  
Vol 85 (5) ◽  
pp. 2293-2297 ◽  
Author(s):  
Françoise Grolleau ◽  
Laurence Gamelin ◽  
Michèle Boisdron-Celle ◽  
Bruno Lapied ◽  
Marcel Pelhate ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Calcium Ions ◽  
Periplaneta Americana ◽  
Sodium Current ◽  
Current Amplitude ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Whole Cell Patch Clamp

Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40–500 μM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichloro-diaminocyclohexane platinum (dach-Cl2-platin) and oxalate. Oxalate (500 μM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl2-platin (500 μM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca2+ and Mg2+ is discussed.

Ionic currents in rat pulmonary and mesenteric arterial myocytes in primary culture and subculture

1993 ◽  
Vol 264 (2) ◽  
pp. L107-L115 ◽  
Author(s):  
X. J. Yuan ◽  
W. F. Goldman ◽  
M. L. Tod ◽  
L. J. Rubin ◽  
M. P. Blaustein
Keyword(s):  
Cultured Cells ◽  
Primary Cultures ◽  
Outward Current ◽  
Ionic Currents ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
Bath Solution ◽  
Transient Component ◽  
Whole Cell Patch Clamp ◽  
Three Components

The electrophysiological properties of cultured single vascular smooth muscle (VSM) cells from rat pulmonary (PA) and mesenteric (MA) arteries were studied using the whole cell patch-clamp technique. Cells were studied at 3–7 days as primary cultures, or were replated after 10–20 days and subcultured for 2–5 days. In the standard physiological bath solution (containing 1.8 mM Ca2+), and with 125 mM K+ + 10 mM ethylene glycol-bis(beta-aminoethyl ether)- N,N,N',N'-tetraacetic acid (EGTA)-filled pipettes, both PA and MA primary cultured cells had high input resistances (mean = 2-3 G omega) and resting membrane potentials of about -40 mV. The cells were clamped at a holding potential of -70 mV. Depolarization to -20 mV or more evoked a transient inward current (Iin) that was eliminated in Ca(2+)-free bath solution; this indicates that Iin was carried by Ca2+. Iin was substantially smaller in subcultured cells from both PA and MA. Depolarization also activated three components of outward current (Iout) in primary cultured PA and MA cells: a rapidly inactivating transient component (Irt), a slowly inactivating transient component (Ist), and a steady-state (noninactivating) component (Iss). All three components of Iout were inhibited to varying degrees by 5 mM 4-aminopyridine and were eliminated by replacing intracellular K+ with Cs+, but were only minimally affected by removal of extracellular Ca2+. These results suggest that this Iout was carried by K+ and was voltage gated. Little external Ca(2+)-dependent Iout was observed under these conditions, but a substantial Ca(2+)-dependent component was seen when the EGTA concentration in the pipettes was reduced to 0.1 mM.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Serotonergic Modulation of Persistent Inward Currents in Serotonergic Neurons of Medulla in ePet-EYFP Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Yi Cheng ◽  
Nan Song ◽  
Renkai Ge ◽  
Yue Dai
Keyword(s):  
Morphological Data ◽  
Repetitive Firing ◽  
Patch Clamp Technique ◽  
Serotonergic Neurons ◽  
Persistent Inward Currents ◽  
Functional Roles ◽  
Whole Cell Patch Clamp ◽  
Significant Difference ◽  
Inward Currents ◽  
Serotonergic Modulation

Serotonergic (5-HT) neurons in the medulla play multiple functional roles associated with many symptoms and motor activities. The descending serotonergic pathway from medulla is essential for initiating locomotion. However, the ionic properties of 5-HT neurons in the medulla remain unclear. Using whole-cell patch-clamp technique, we studied the biophysical and modulatory properties of persistent inward currents (PICs) in 5-HT neurons of medulla in ePet-EYFP transgenic mice (P3–P6). PICs were recorded by a family of voltage bi-ramps (10-s duration, 40-mV peak step), and the ascending and descending PICs were mirrored to analyze the PIC hysteresis. PICs were found in 77% of 5-HT neurons (198/258) with no significant difference between parapyramidal region (n = 107) and midline raphe nuclei (MRN) (n = 91) in either PIC onset (−47.4 ± 10 mV and −48.7 ± 7 mV; P = 0.44) or PIC amplitude (226.9 ± 138 pA and 259.2 ± 141 pA; P = 0.29). Ninety-six percentage (191/198) of the 5-HT neurons displayed counterclockwise hysteresis and four percentage (7/198) exhibited the clockwise hysteresis. The composite PICs could be differentiated as calcium component (Ca_PIC) by bath application of nimodipine (25 μM), sodium component (Na_PIC) by tetrodotoxin (TTX, 2 μM), and TTX- and dihydropyridine-resistance component (TDR_PIC) by TTX and nimodipine. Ca_PIC, Na_PIC and TDR_PIC all contributed to upregulation of excitability of 5-HT neurons. 5-HT (15 μM) enhanced the PICs, including a 26% increase in amplitude of the compound currents of Ca_PIC and TDR_PIC (P &lt; 0.001, n = 9), 3.6 ± 5 mV hyperpolarization of Na_PIC and TDR_PIC onset (P &lt; 0.05, n = 12), 30% increase in amplitude of TDR_PIC (P &lt; 0.01), and 2.0 ± 3 mV hyperpolarization of TDR_PIC onset (P &lt; 0.05, n = 18). 5-HT also facilitated repetitive firing of 5-HT neurons through modulation of composite PIC, Na_PIC and TDR_PIC, and Ca_PIC and TDR_PIC, respectively. In particular, the high voltage-activated TDR_PIC facilitated the repetitive firing in higher membrane potential, and this facilitation could be amplified by 5-HT. Morphological data analysis indicated that the dendrites of 5-HT neurons possessed dense spherical varicosities intensively crossing 5-HT neurons in medulla. We characterized the PICs in 5-HT neurons and unveiled the mechanism underlying upregulation of excitability of 5-HT neurons through serotonergic modulation of PICs. This study provided insight into channel mechanisms responsible for the serotonergic modulation of serotonergic neurons in brainstem.

scholarly journals The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 453
Author(s):  
Susana M. Chuva de Sousa Lopes ◽  
Marta S. Alexdottir ◽  
Gudrun Valdimarsdottir
Keyword(s):  
Stem Cell ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Embryonic Stem ◽  
Model Systems ◽  
Special Focus ◽  
Placental Development

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

scholarly journals POS0291 THE IMPACT OF DRUG INDUCED AND OTHER RHEUMATIC MUSCULOSKELETAL DISORDERS (MD) ON THE QUALITY OF LIFE (QOL) OF CANCER PATIENTS RECEIVED ANTICANCER DRUG TREATMENT

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 371.1-371
Author(s):  
A. Koltakova ◽  
A. Lila ◽  
L. P. Ananyeva ◽  
A. Fedenko
Keyword(s):  
Drug Treatment ◽  
Cancer Patients ◽  
Anticancer Drug ◽  
Physical Functioning ◽  
Role Functioning ◽  
Drug Induced ◽  
Significant Difference ◽  
Eortc Qlq C30 ◽  
Eortc Qlq ◽  
The Impact

Background:Pts with cancer may have MD that can be caused by neoplastic/paraneoplastic disease, rheumatic diseases or be induced by anticancer drug treatment. There is no data about MD influence on the QoL of cancer patients. The EORTC QoL questionnaire (QLQ)-C30 is a valid questionnaire designed to assess different aspects (Global health (GH), Functional (FS) and symptoms (SS) scales) that define the QoL of cancer patients [1].Objectives:The objective of the study was to assess the impact of drug induced and other types of MD on the QoL of cancer patients that received anticancer drug treatment by using of EORTC QLQ-C30 v3.0.Methods:The sampling of 123 pts (M/F – 40/83; mean age 54.4±12.8) with breast (32,5%), gastrointestinal (17%), ovary (8%), lung (7%) and other cancer was observed by rheumatologist in the oncology outpatient clinic. All pts received anticancer drug treatment: chemotherapy (104 pts), target therapy (16 pts) checkpoint-inhibitors (14 pts), hormone therapy (13 pts) in different combinations. 102(82.9%) of 123pts had MD include arthritis (12 pts), synovitis (5 pts), arthralgia (66 pts), periarthritis (34 pts), osteodynia (13 pts). There were 58 pts (group 1; M/F – 14/44; mean age 52.5±12.2) with anticancer drug treatment induced MD and 44 pts (group 2; M/F – 16/27; mean age 57.6±13.5) with other type of MD include 26 pts with skeletal metastasis. The were 21 pts (group 3; M/F – 10/11; mean age 52.9±11.1) without MD. All pts fulfilled EORTC QLQ-C30 v3.0 (tab.1).Table 1.The median [Q1;Q3] of results of GH, SS and SS of EORTC QLQ-C30ScaleSubscaleGroup1Group2Group3GH58.3[50;58]58.3[41.7;83.3]50[50;66.7]FS*Physical functioning73.3[60;86.7]73.3[66.7;86.7]86.7[80;93]Role functioning66.7[66.7;100]83.3[50;100]100[83;100]Emotional functioning83.3[66.7;100]75[66.7;91.7]91.6[83.3;100]Social functioning83.3[66.7;100]83.3[50;100]100[83.3;100]SS*Pain33.3[0;50]16.7[0;33.3]0[0;16.7]*There are only the scores that had got a statistical difference between the groups.Kruskal-Wallis H and post-hoc (Dwass-Steel-Critchlow-Fligner (DSCF) pairwise comparisons) tests for data analysis were performed.Results:A Kruskal-Wallis H test has shown a statistically significant difference in physical (χ2(2)=7.54; p=0.023), role (χ2(2)=9.87; p=0.007), emotion (χ2(2)=7.69; p=0.021) functioning and pain (χ2(2)=8.44; p=0.015) scores between the different groups. A post-hoc test with DSCF pairwise comparisons of median has shown a statistically significant difference between 1 and 3 groups (W=3.904; p=0.016) for physical functioning, between 2 and 3 groups (W=3.35; p=0.004) for role functioning, between 2 and 3 groups (W=4.03; p=0.012) for emotional functioning, between 1 and 3 groups (W=-3.97; p=0.014) for pain scale.Conclusion:The study has shown that MD associated with anticancer drug treatment adversely affected the QoL of cancer patients received anticancer drug treatment by reducing a physical functioning and by increasing pain scores. Presence of other types of MD adversely affect the QoL by reducing emotional and role functioning.References:[1]Aaronson NK,et al.The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst.1993;85(5):365-376. doi:10.1093/jnci/85.5.365Disclosure of Interests:None declared

scholarly journals CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 1858
Author(s):  
Waheed Shabbir ◽  
Nermina Topcagic ◽  
Mohammed Aufy ◽  
Murat Oz
Keyword(s):  
A549 Cells ◽  
Na Channel ◽  
Na Current ◽  
Patch Clamp Technique ◽  
Whole Cell ◽  
Knock Down ◽  
Whole Cell Patch Clamp ◽  
Glycosylation Sites ◽  
Epithelial Na Channel

Tumor necrosis factor (TNF) is known to activate the epithelial Na+ channel (ENaC) in A549 cells. A549 cells are widely used model for ENaC research. The role of δ-ENaC subunit in TNF-induced activation has not been studied. In this study we hypothesized that δ-ENaC plays a major role in TNF-induced activation of ENaC channel in A549 cells which are widely used model for ENaC research. We used CRISPR/Cas 9 approach to knock down (KD) the δ-ENaC in A549 cells. Western blot and immunofluorescence assays were performed to analyze efficacy of δ-ENaC protein KD. Whole-cell patch clamp technique was used to analyze the TNF-induced activation of ENaC. Overexpression of wild type δ-ENaC in the δ-ENaC KD of A549 cells restored the TNF-induced activation of whole-cell Na+ current. Neither N-linked glycosylation sites nor carboxyl terminus domain of δ-ENaC was necessary for the TNF-induced activation of whole-cell Na+ current in δ-ENaC KD of A549 cells. Our data demonstrated that in A549 cells the δ-ENaC plays a major role in TNF-induced activation of ENaC.

Acute effects of repetitive depolarization on sodium current in chick myocytes

1991 ◽  
Vol 260 (6) ◽  
pp. H1810-H1818
Author(s):  
M. R. Gold ◽  
G. R. Strichartz
Keyword(s):  
Time Course ◽  
Sodium Current ◽  
Complete Recovery ◽  
Acute Effects ◽  
Na Current ◽  
Patch Clamp Technique ◽  
Membrane Hyperpolarization ◽  
Atrial Cells ◽  
Whole Cell Patch Clamp ◽  
Recovery From Inactivation

Acute effects of repetitive depolarization on the inward Na+ current (INa) of cultured embryonic chick atrial cells were studied using the whole cell patch-clamp technique. Stimulation rates of 1 Hz or greater produced a progressive decrement of peak INa. With depolarizations to 0 mV of 150-ms duration, applied at 2 Hz from a holding potential of -100 mV, the steady-state decrement was approximately 20%. The magnitude of this effect increased with stimulation frequency and with test potential depolarization and decreased with membrane hyperpolarization. Analysis of INa kinetics revealed that reactivation was sufficiently slow to preclude complete recovery from inactivation with interpulse intervals less than 1,000 ms. Moreover, reactivation accelerated markedly with membrane hyperpolarization, in parallel with the response to repetitive stimulation. The multiexponential time course of recovery of peak INa from repetitive depolarization was similar to that observed after single stimuli; however, there was a shift toward a greater proportion of current recovering with the slower of two time constants. It is concluded that incomplete recovery from inactivation is responsible for the decrement in INa observed with short interpulse intervals.

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