Recovery Time Constant Research Articles

An unidentified yet notable modification on I Na and I K (DR) caused by ramelteon.

Despite advancement in anti-seizure medications, 30% of patients continue to experience recurrent seizures. Previous data indicated the antiepileptic properties of melatonin and its agonists in several animal models. However, the underlying mechanisms of melatonin and its agonists on cellular excitability remain poorly understood. In this study, we demonstrated the electrophysiological changes of two main kinds of ion channels that are responsible for hyperexcitability of neurons after introduction of melatonin agonists- ramelteon (RAM). In Neuro-2a cells, the amplitude of voltage-gated Na+ (I Na) and delayed-rectifier K+ currents (I K (DR)) could be suppressed under RAM. The IC50 values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na+ current (I Na (W)) elicited by short ascending ramp voltage, with unchanged the overall steady-state current-voltage relationship. The decaying time course of I Na during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked I Na fitted the recovery time course into two exponential processes and increased the fast and slow time constant of recovery the presence of RAM. In pituitary tumor (GH3) cells, I Na amplitude was also effectively suppressed by the RAM. In addition, GH3-cells exposure to RAM decreased the firing frequency of spontaneous action potentials observed under current-clamp conditions. As a result, the RAM-mediated effect on INa was closely associated with its ability to decrease spontaneous action potentials. Collectively, we found the direct attenuation of I Na and I K (DR) caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti-seizure activity.

Second-generation antipsychotic quetiapine blocks voltage-dependent potassium channels in coronary arterial smooth muscle cells.

Voltage-dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration-dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 μM. Although quetiapine (50 μM) did not alter the steady-state activation curve, it caused a negative shift in the steady-state inactivation curve. The application of 1 and 2Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)-dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration- and use (state)-dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels.

Novel elastomeric spiropyran-doped poly(dimethylsiloxane) optical waveguide for UV sensing

Novel poly(dimethylsiloxane) (PDMS) doped with two different spiropyran derivatives (SP) were investigated as potential candidates for the preparation of elastomeric waveguides with UV-dependent optical properties. First, free-standing films were prepared and evaluated with respect to their photochromic response to UV irradiation. Kinetics, reversibility as well as photofatigue and refractive index of the SP-doped PDMS samples were assessed. Second, SP-doped PDMS waveguides were fabricated and tested as UV sensors by monitoring changes in the transmitted optical power of a visible laser (633 nm). UV sensing was successfully demonstrated by doping PDMS using one spiropyran derivative whose propagation loss was measured as 1.04 dB/cm at 633 nm, and sensitivity estimated at 115% change in transmitted optical power per unit change in UV dose. The decay and recovery time constants were measured at 42 and 107 s, respectively, with an average UV saturation dose of 0.4 J/cm2. The prepared waveguides exhibited a reversible and consistent response even under bending. The sensor parameters can be tailored by varying the waveguide length up to 21 cm, and are affected by white light and temperatures up to 70 ℃. This work is relevant to elastomeric optics, smart optical materials, and polymer optical waveguide sensors.Graphical

The Novel Long QT Syndrome Type 2-associated F129I Mutation in the KCNH2 Gene Significantly Affects I Kr Through the hERG1 Homomeric and Heteromeric Potassium Channels

Objective: The long QT syndrome type 2 is caused by the loss-of-function mutations in the KCNH2 gene, which encodes hERG1, the voltage-gated potassium channel. The hERG1 channels conduct rapid delayed rectifier K+ currents (I Kr) in the human cardiac tissue. KCNH2 encodes 2 main isoforms—hERG1a and hERG1b, which assemble to form the homomeric or heteromeric hERG1 channels. However, the functional characteristics of the heteromeric hERG1 channels in long QT syndrome type 2 are not clear. In this study, a novel mutation in the N-terminus of hERG1a (F129I) was identified in a proband of long QT syndrome type 2. The purpose of this study was to identify the electrophysiological change of homomeric and heteromeric hERG1 channels with the F129I-hERG1a. Methods: Candidate genes were screened by direct sequencing. F129I-hERG1a was cloned in the pcDNA3.1 vector by site-directed mutagenesis. Then, the wild-type (WT) hERG1a and/or F129I-hERG1a were transiently expressed in the HEK293 cells with or without hERG1b co-expression. The expression levels of the transgenes, cellular distribution of hERG1a and hERG1b, and the electrophysiological features of the homomeric and the heteromeric hERG1 channels with the WT-hERG1a or F129I-hERG1a were analyzed using whole-cell patch-clamp electrophysiology, western blotting, and immunofluorescence techniques. Results: The proband was clinically diagnosed with long QT syndrome type 2 and carried a heterozygous mutation c.385T>A (F129I) in the KCNH2 gene. Electrophysiology study proved that the F129I substitution in hERG1a significantly decreased I Kr in both the homomeric and heteromeric hERG1channels by 86% and 70%, respectively (WT-hERG1a (54.88 ± 18.74) pA/pF vs. F129I-hERG1a (7.34 ± 1.90) pA/pF, P < 0.001; WT-hERG1a/hERG1b (89.92 ± 24.51) pA/pF vs. F129I-hERG1a/hERG1b (26.54 ± 9.83) pA/pF, P < 0.001). The voltage dependence of IKr activation (V½ and k) was not affected by the mutation in both the homomeric and heteromeric hERG1 channels. The peak current densities and the kinetic characteristics of IKr were comparable for both WT/F129I-hERG1a and WT-hERG1a. The channel inactivation and deactivation analysis showed that F129I substitution did not affect deactivation of the homomeric hERG1a channel, but significantly accelerated the deactivation and recovery from inactivation of the heteromeric hERG1a/hERG1b channel based on the time constants of fast and slow recovery from deactivation F129I-hERG1a/hERG1b vs. WT-hERG1a/hERG1b (P < 0.05). Western blotting and immunofluorescence labeling experiments showed that maturation and intracellular trafficking of the F129I-hERG1a protein was impaired and potentially increased the ratio of hERG1b to hERG1a in the F129I-hERG1a/hERG1b tetramer channel, thereby resulting in electrophysiological changes characteristic of the long QT syndrome type 2 pathology. Conclusions: I Kr was significantly reduced in the homomeric and heteromeric hERG1 channels with F129I-hERG1a. The F129I mutation significantly accelerated the deactivation and recovery from inactivation of the heteromeric F129I-hERG1a/hERG1b channel. F129I-hERG1a exhibited impaired maturation and intracellular trafficking, thereby potentially increasing the ratio of the hERG1b to hERG1a stoichiometry in the hERG1 tetrameric channel. These changes demonstrated the importance of the heteromeric hERG1 channel in long QT syndrome type 2 pathophysiology.

Inhibition of voltage-gated potassium channel by aripiprazole in rabbit coronary arterial smooth muscle cells

Aripiprazole, a third-generation antipsychotic, has been widely used to treat schizophrenia. In this study, we evaluated the effect of aripiprazole on voltage-gated potassium (Kv) channels in rabbit coronary arterial smooth muscle cells using the patch clamp technique. Aripiprazole reduced the Kv current in a concentration-dependent manner with a half-maximal inhibitory concentration of 0.89 ± 0.20 μM and a Hill coefficient of 1.30 ± 0.25. The inhibitory effect of aripiprazole on Kv channels was voltage-dependent, and an additional aripiprazole-induced decrease in the Kv current was observed in the voltage range of full channel activation. The decay rate of Kv channel inactivation was accelerated by aripiprazole. Aripiprazole shifted the steady-state activation curve to the right and the inactivation curve to the left. Application of a repetitive train of pulses (1 and 2 Hz) promoted inhibition of the Kv current by aripiprazole. Furthermore, the recovery time constant from inactivation increased in the presence of aripiprazole. Pretreatment of Kv1.5 subtype inhibitor reduced the inhibitory effect of aripiprazole. However, pretreatment with Kv 7 and Kv2.1 subtype inhibitors did not change the degree of aripiprazole-induced inhibition of the Kv current. We conclude that aripiprazole inhibits Kv channels in a concentration-, voltage-, time-, and use (state)-dependent manner by affecting the gating properties of the channels.

Near-InfraRed Spectroscopy Provides a Reproducible Estimate of Muscle Aerobic Capacity, but Not Whole-Body Aerobic Power.

Near-infrared spectroscopy (NIRS) during repeated limb occlusions is a noninvasive tool for assessing muscle oxidative capacity. However, the method's reliability and validity remain under investigation. This study aimed to determine the reliability of the NIRS-derived mitochondrial power of the musculus vastus lateralis and its correlation with whole-body (cycling) aerobic power (V̇O2 peak). Eleven healthy active men (28 ± 10 y) twice (2 days apart) underwent repeated arterial occlusions to induce changes in muscle oxygen delivery after 15 s of electrical muscle stimulation. The muscle oxygen consumption (mV̇O2) recovery time and rate (k) constants were calculated from the NIRS O2Hb signal. We assessed the reliability (coefficient of variation and intraclass coefficient of correlation [ICC]) and equivalency (t-test) between visits. The results showed high reproducibility for the mV̇O2 recovery time constant (ICC = 0.859) and moderate reproducibility for the k value (ICC = 0.674), with no significant differences between visits (p > 0.05). NIRS-derived k did not correlate with the V̇O2 peak relative to body mass (r = 0.441, p = 0.17) or the absolute V̇O2 peak (r = 0.366, p = 0.26). In conclusion, NIRS provides a reproducible estimate of muscle mitochondrial power, which, however, was not correlated with whole-body aerobic capacity in the current study, suggesting that even if somewhat overlapping, not the same set of factors underpin these distinct indices of aerobic capacity at the different (peripheral and whole-body systemic) levels.

Confounding factors in peripheral thermal recovery time after active cooling

ObjectivesThe effectiveness of normal physiological thermoregulation complicates differentiation between pathologic changes in medical thermography associated with peripheral artery disease and a number of other clinical conditions. In this study we investigate a number of potential confounding factors to the thermal recovery rate after active limb cooling, with the main focus on age and sex. ApproachThe source data consists of 53 healthy individuals with no diagnosed cardiovascular disease or reported symptoms and with a mean age of 38.4 (± 12.1) years. The sample population was further divided into male (N = 14) and female groups (N = 39). The thermal recovery time was measured using two thermal cameras from both lower limbs on plantar and dorsal sides. The active cooling was achieved using moldable cold pads placed on the plantar and dorsal side of the lower limb. The recovery was measured until the temperature had reached a stable level. The recovery time was determined from an exponential fit to the measured data. ResultsThe correlation between the thermal recovery time constant and age varied from low to moderate linear correlation (0.31 ≤ ⍴ ≤ 70), depending on the inspected region of interest, with a higher statistically significant correlation in the medial regions. The contralateral limb temperature differences or the thermal time constants did not have statistically significant differences between the male and female sexes. Further, the secondary metrics such as participant's body mass, body-mass index, or systolic blood pressure had low or no correlation with the thermal recovery time in the study group. ConclusionThe thermal recovery time constant after active cooling appears as a relatively independent metric from the majority of the measured potential confounding factors. Age should be accounted for when performing thermal recovery measurements. However, dynamic thermal imaging and its methodologies require further research and exploration.

Contrast threshold recovery after bleaching during cone‐mediated mesopic adaptation: The effect of test conditions

Aims/Purpose: To determine the optimal luminance conditions and the staircase procedures for evaluating the time course of macular contrast sensitivity recovery after photobleaching in order to decide the best protocol to assess cone‐mediated mesopic adaptation.Methods: The dynamics of contrast threshold (CT) recovery following photopigment bleach were measured psychophysically for five minutes in twenty‐four healthy adults (23.7 ± 3.7 years old). The stimuli used were sine‐wave gratings of low‐spatial frequency (1 cycle‐per‐degree). In each subject, six tests were performed, combining three luminance levels (0.1, 1.0, and 10 cd/m2) and two modified staircase procedures (3‐down/1‐up and 2‐down/1‐up) to estimate CTs. The test order was randomized, conducted in two visits, with a 15‐min washout period between tests. Outlier detection techniques were applied to verify the integrity of the sample. Non‐linear exponential‐based optimization was adopted to fit CT recovery functions to estimate the time constant (τ, seconds) of cone sensitivity recovery and the final CT (CTf, log units). Classical and heteroscedastic ANOVA analyses were performed to assess the effect of test conditions.Results: The 2‐down/1‐up staircase allowed for denser point sampling of CTs measurements than the 3‐down/1‐up. Under the lowest luminance test condition, the CT recovery was modelled by bumpier functions, for both staircases procedures, than the other luminance levels. Mean cone τ increased (21.7, 42.5, and 72.0 seconds (p < 0.001)) and CTf worsened (−1.99, −1.85, and − 1.47 log units (p < 0.001)) as luminance level decreased. The best fit (median R2 = 0.87) was achieved under 1 cd/m2 mesopic luminance conditions. There were no statistically significant differences in mean cone τ and CTf between the two staircases procedures.Conclusions: An intermediate mesopic light level and a 2‐down/1‐up staircase provided the best protocol for assessing cone‐mediated mesopic adaptation.

Development of a cone‐mediated dark adaptation test on a smartphone

Aims/Purpose: Dark adaptometry is considered a useful tool for investigating retinal neurodegenerative diseases. While it has been demonstrated that the loss of rod photoreceptors occurs before the loss of cones, foveal cones are also impacted during the initial stages of age‐related macular degeneration. Our aim was to develop a test to assess cone‐mediated dark adaptation (DA) based on the MOBILE‐DA smartphone app.Methods: The MOBILE‐DA smartphone app for testing rod‐mediated DA was modified to assess cone‐mediated DA. Using an Android smartphone, and a 3° diameter achromatic flashing stimulus centered on the fovea, the measurements were made using an adaptive staircase of 0.007 cd/m2 level up – 0.009 cd/m2 level down. In a dark room, the smartphone was placed 40 cm from the subject, and the luminance thresholds were measured monocularly for 5 min following almost complete photopigment bleaching using a long‐duration light exposure (60 seconds). Luminance Threshold (LT) recovery functions were fitted to an exponential decay model to determine the time constant (τ, seconds) of cone sensitivity recovery and final cone LT.Results: The cone‐mediated DA measured by the smartphone app resulted in τ of 91 ± 15 seconds; final cone LT of −2.29 ± 0.10 log cd/m2, and R2 of 0.96 ± 0.02. The time constant and final threshold values obtained through this app were comparable to those obtained through other established techniques.Conclusions: The smartphone app for evaluating cone‐mediated dark adaptation proved effective in tracking the rapid changes in luminance threshold that take place during this process. These findings suggest that the MOBILE‐DA app is well‐suited for measuring cone‐mediated dark adaptation.

Symmetrical recovery time course between impedance and intramyocardial temperature after bipolar radiofrequency ablation; Role of impedance monitoring to estimate temperature rise

IntroductionDuring radiofrequency (RF) ablation, impedance monitoring has been used to avoid steam-pop caused by excessive intramyocardial temperature (IMT) rise. However, it is uncertain why the impedance decline is related to steam-pop and whether the impedance decline is correlated to IMT. MethodsTwenty-one bipolar ablations (40 W, 30-g contact, 120 s) were attempted for seven perfused porcine myocardium. Immediately after ablation, a temperature electrode was inserted into the mid-myocardial portion, and the recovery process of impedance and its correlation to IMT were assessed. ResultsTransmural lesion was created in all 21 applications but steam-pop occurred in 5/21 applications with large impedance decline. In the 16 applications without steam-pop, impedance and IMT soon after ablation were 97.2 ± 4.0 Ω and 66.1 ± 4.8 °C, respectively. Reasonably high linear correlation was demonstrated between the maximum IMT after ablation and impedance differences before and after ablation. Recovery processes of the decreased impedance and the elevated IMT fit well to each equation of the single exponential decay function and showed symmetric shapes with no statistical difference of time constant (100.1 ± 34.5 s in impedance vs. 108.7 ± 27.3 s in IMT) and half-time of recovery (144.5 ± 49.8 s in impedance vs. 156.9 ± 39.4 s in IMT). Recovered impedance after ablation (104.8 ± 3.9 Ω) was 5.1 ± 2.0 Ω smaller than that before ablation (109.9 ± 2.7 Ω), suggesting several factors other than IMT rise participate in impedance decline in RF ablation. ConclusionsRecovery of impedance and IMT after ablation well correlated, which supports the usefulness of impedance monitoring for safe RF ablation.

Inhibition of voltage-dependent K+ currents of rabbit coronary arterial smooth muscle cells by the atypical antipsychotic paliperidone.

Paliperidone, an atypical antipsychotic, is widely used to treat schizophrenia. In this study, we explored whether paliperidone inhibited the voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells. Paliperidone reduced Kv channel activity in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 16.58 ± 3.03 μM and a Hill coefficient of 0.60 ±0.04. It did not significantly shift the steady-state activation or inactivation curves, suggesting that the drug did not affect the gating properties of Kv channels. In the presence of paliperidone, the application of 20 repetitive depolarizing pulses at 1 and 2Hz gradually increased the inhibition of the Kv current. Further, the recovery time constant after Kv channel inactivation was increased by paliperidone, indicating that it inhibited the Kv channel in a use (state)-dependent manner. Its inhibitory effects were reduced by pretreatment with a Kv1.5 subtype inhibitor. However, pretreatment with a Kv2.1 or Kv7 inhibitor did not reduce its inhibitory effect. We conclude that paliperidone inhibits Kv channels (mainly Kv1.5 subtype channels) in a concentration- and use (state)-dependent manner without changing channel gating.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator.

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

Seizure duration predicts postictal electroencephalographic recovery after electroconvulsive therapy-induced seizures

ObjectiveWe aim to provide a quantitative description of the relation between seizure duration and the postictal state using features extracted from the postictal electroencephalogram (EEG). MethodsThirty patients with major depressive disorder treated with electroconvulsive therapy (ECT) were studied with continuous EEG before, during, and after ECT-induced seizures. EEG recovery was quantified as the spectral difference between postictal and baseline EEG using the temporal brain symmetry index (BSI). The postictal temporal EEG evolution was modeled with a single exponential. The parameters of the model, including the time constant τ, describe the change and speed of postictal EEG recovery. The change from baseline EEG at t = 60 minutes post-seizure (ΔBSI) was calculated from the exponential fit. Postictal clinical reorientation time (ROT) was clinically established. A multivariate generalized multi-level Bayesian model was estimated with seizure duration and ROT as predictors of τ and ΔBSI. ResultsEEG features of 290 seizures and postictal states were used for analyses. The model faithfully described the dynamics of the postictal EEG in nearly all patients. Seizure duration was associated with the recovery time constant, τ, and ΔBSI. ROT was associated with τ, but not with ΔBSI. ConclusionsLonger seizures are associated with slower postictal EEG recovery and more enduring EEG changes compared to baseline. SignificanceQuantitative EEG allows objective assessment of the postictal state.

Assessment of chronic limb threatening ischemia using thermal imaging

ObjectivesCurrent chronic limb threatening ischemia (CLTI) diagnostics require expensive equipment, using ionizing radiation or contrast agents, or summative surrogate methods lacking in spatial information. Our aim is to develop and improve contactless, non-ionizing and cost-effective diagnostic methods for CLTI assessment with high spatial accuracy by utilizing dynamic thermal imaging and the angiosome concept. ApproachDynamic thermal imaging test protocol was suggested and implemented with a number of computational parameters. Pilot data was measured from 3 healthy young subjects, 4 peripheral artery disease (PAD) patients and 4 CLTI patients. The protocol consists of clinical reference measurements, including ankle- and toe-brachial indices (ABI, TBI), and a modified patient bed for hydrostatic and thermal modulation tests. The data was analyzed using bivariate correlation. ResultsThe thermal recovery time constant was on average higher for the PAD (88%) and CLTI (83%) groups with respect to the healthy young subjects. The contralateral symmetry was high for the healthy young group and low for the CLTI group. The recovery time constants showed high negative correlation to TBI (ρ = -0.73) and ABI (ρ = -0.60). The relation of these clinical parameters to the hydrostatic response and absolute temperatures (|ρ|<0.3) remained unclear. ConclusionThe lack of correlation for absolute temperatures or their contralateral differences with the clinical status, ABI and TBI disputes their use in CLTI diagnostics. Thermal modulation tests tend to augment the signs of thermoregulation deficiencies and accordingly high correlations were found with all reference metrics. The method is promising for establishing the connection between impaired perfusion and thermography. The hydrostatic modulation test requires more research with stricter test conditions.

Characterization in Potent Modulation on Voltage-Gated Na+ Current Exerted by Deltamethrin, a Pyrethroid Insecticide

Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na+ (NaV) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na+ current (INa) in pituitary tumor (GH3) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient, INa(T)) or sustained (late, INa(L)) INa; consequently, the EC50 value required for DLT-stimulated INa(T) or INa(L) was determined to be 11.2 or 2.5 μM, respectively. However, neither the fast nor slow component in the inactivation time constant of INa(T) activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate INa with a slowing in inactivation time course of the current. The INa(L) augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of INa(T) became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of INa(L) and tail INa (INa(Tail)) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys(V)) of persistent INa was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys(V) behavior of INa exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.

A theoretical model reveals specialized synaptic depressions and temporal frequency tuning in retinal parallel channels.

In the Outer Plexiform Layer of a retina, a cone pedicle provides synaptic inputs for multiple cone bipolar cell (CBC) subtypes so that each subtype formats a parallelized processing channel to filter visual features from the environment. Due to the diversity of short-term depressions among cone-CBC contacts, these channels have different temporal frequency tunings. Here, we propose a theoretical model based on the hierarchy Linear-Nonlinear-Synapse framework to link the synaptic depression and the neural activities of the cone-CBC circuit. The model successfully captures various frequency tunings of subtype-specialized channels and infers synaptic depression recovery time constants inside circuits. Furthermore, the model can predict frequency-tuning behaviors based on synaptic activities. With the prediction of region-specialized UV cone parallel channels, we suggest the acute zone in the zebrafish retina supports detecting light-off events at high temporal frequencies.

Sex-Related Differences in Oxygen Consumption Recovery After High-Intensity Rowing Exercise During Childhood and Adolescence.

To determine sex-related differences in oxygen consumption (V˙O2) recovery after high-intensity exercise during childhood and adolescence. Forty-two boys and 35 girls (10-17 y) performed a 60-second all-out test on a rowing ergometer. Postexercise V˙O2 recovery was analyzed from (1) the V˙O2 recovery time constant obtained from a biexponential model (τ1V˙O2) and (2) excess postexercise oxygen consumption calculated over a period of 8 minutes (EPOC8) and until τ1V˙O2 was reached (EPOCτ1). Multiplicative allometric modeling was used to assess the concurrent effects of body mass or lean body mass, and age on EPOC8 and EPOCτ1. EPOC8 increased significantly more in boys from the age of 14 years. However, the sex difference was no longer significant when EPOC8 was analyzed using an allometric model including body mass + age or lean body mass + age. In addition, despite a greater increase in EPOCτ1 in boys from the age of 14 years, τ1V˙O2 was not significantly different between sexes whatever age. While age and lean body mass accounted for the sex-related differences of EPOC during childhood and adolescence, no significant effect of age and sex was observed on the V˙O2 recovery time constant after high-intensity exercise.

Asenapine, an atypical antipsychotic, blocks voltage-gated potassium channels in rabbit coronary artery smooth muscle cells

We investigated the effect of asenapine, a commonly used atypical antipsychotic, on voltage-dependent K+ (Kv) channels in rabbit coronary artery smooth muscle cells. Asenapine inhibited the Kv current in a concentration-dependent manner, with an half-inhibitory concentration (IC50) value of 8.59 ± 2.25 μM and Hill coefficient of 0.64 ± 0.06. Although asenapine did not affect the steady-state activation curve of Kv channels, it shifted the voltage dependence of the steady-state inactivation curve toward a more negative potential. Asenapine increased the recovery time constant of channel inactivation and produced use (state)-dependent inhibition of Kv channels at a stimulation frequency of 1 or 2 Hz. Pretreatment with the Kv1.5 subtype inhibitor DPO-1 reduced the Kv current; however, additional application of asenapine did not further inhibit the Kv current. Pretreatment with the Kv2.1 subtype inhibitor guangxitoxin and Kv7 inhibitor linopirdine also reduced the Kv current. However, additional application of asenapine further reduced the Kv current, similar to the application of asenapine alone. Asenapine induced membrane depolarization and vasoconstriction. Based on these results, we conclude that asenapine inhibits the Kv current in concentration- and use (state)-dependent manners by shifting the inactivation curve. The major target of asenapine is the Kv1.5 subtype channel.

Inhibition of voltage-dependent K+ channels by antimuscarinic drug fesoterodine in coronary arterial smooth muscle cells

Fesoterodine, an antimuscarinic drug, is widely used to treat overactive bladder syndrome. However, there is little information about its effects on vascular K+ channels. In this study, voltage-dependent K+ (Kv) channel inhibition by fesoterodine was investigated using the patch-clamp technique in rabbit coronary artery. In whole-cell patches, the addition of fesoterodine to the bath inhibited the Kv currents in a concentration-dependent manner, with an IC50 value of 3.19 ± 0.91 μM and a Hill coefficient of 0.56 ± 0.03. Although the drug did not alter the voltage-dependence of steady-state activation, it shifted the steady-state inactivation curve to a more negative potential, suggesting that fesoterodine affects the voltage-sensor of the Kv channel. Inhibition by fesoterodine was significantly enhanced by repetitive train pulses (1 or 2 Hz). Furthermore, it significantly increased the recovery time constant from inactivation, suggesting that the Kv channel inhibition by fesoterodine is use (state)-dependent. Its inhibitory effect disappeared by pretreatment with a Kv 1.5 inhibitor. However, pretreatment with Kv2.1 or Kv7 inhibitors did not affect the inhibitory effects on Kv channels. Based on these results, we conclude that fesoterodine inhibits vascular Kv channels (mainly the Kv1.5 subtype) in a concentration- and use (state)-dependent manner, independent of muscarinic receptor antagonism.

Characterization in Effective Stimulation on the Magnitude, Gating, Frequency Dependence, and Hysteresis of INa Exerted by Picaridin (or Icaridin), a Known Insect Repellent.

Picaridin (icaridin), a member of the piperidine chemical family, is a broad-spectrum arthropod repellent. Its actions have been largely thought to be due to its interaction with odorant receptor proteins. However, to our knowledge, to what extent the presence of picaridin can modify the magnitude, gating, and/or the strength of voltage-dependent hysteresis (Hys(V)) of plasmalemmal ionic currents, such as, voltage-gated Na+ current [INa], has not been entirely explored. In GH3 pituitary tumor cells, we demonstrated that with exposure to picaridin the transient (INa(T)) and late (INa(L)) components of voltage-gated Na+ current (INa) were differentially stimulated with effective EC50’s of 32.7 and 2.8 μM, respectively. Upon cell exposure to it, the steady-state current versus voltage relationship INa(T) was shifted to more hyperpolarized potentials. Moreover, its presence caused a rightward shift in the midpoint for the steady-state inactivate curve of the current. The cumulative inhibition of INa(T) induced during repetitive stimuli became retarded during its exposure. The recovery time course from the INa block elicited, following the conditioning pulse stimulation, was satisfactorily fitted by two exponential processes. Moreover, the fast and slow time constants of recovery from the INa block by the same conditioning protocol were noticeably increased in the presence of picaridin. However, the fraction in fast or slow component of recovery time course was, respectively, increased or decreased with an increase in picaridin concentrations. The Hys(V)’s strength of persistent INa (INa(P)), responding to triangular ramp voltage, was also enhanced during cell exposure to picaridin. The magnitude of resurgent INa (INa(R)) was raised in its presence. Picaritin-induced increases of INa(P) or INa(R) intrinsically in GH3 cells could be attenuated by further addition of ranolazine. The predictions of molecular docking also disclosed that there are possible interactions of the picaridin molecule with the hNaV1.7 channel. Taken literally, the stimulation of INa exerted by the exposure to picaridin is expected to exert impacts on the functional activities residing in electrically excitable cells.