Ramp Pulse Research Articles

Field‐Free Memristive Spin–Orbit Torque Switching in A1 CoPt Single Layer for Image Edge Detection

AbstractWhile spin–orbit torque (SOT) devices are extensively investigated due to their potential for use in neural network computation, it remains challenging to explore the hardware for neural networks. In this paper, the field‐free memristive SOT switching of the CoPt single layer is used to propose a neuromorphic hardware circuit for detecting edges in images. Owing to its threefold symmetry of inversion, the polarity of SOT switching can be reversed by rotating the current by 60°. Moreover, the process of current‐induced SOT switching exhibits stable multi‐state magnetic switching behavior, and can be controllably tuned by using the pulse of the current. As the slope of the applied ramp pulse current increased, the wave of the anomalous Hall resistance changed from a curve with normally memristive property to trigonometric, and finally to cosine. The design of the hardware circuit for a single SOT device is subsequently formulated to detect the edges in images. The results of experiments verified the capability of this device to detect the edge lines in images with high accuracy, which confirms its potential for use in the hardware of neuromorphic computing platforms. The work here provides guidance for the application of SOT‐based devices to neuromorphic hardware.

A Virtual Inner Ear Model Selects Ramped Pulse Shapes for Vestibular Afferent Stimulation.

Bilateral vestibular deficiency (BVD) results in chronic dizziness, blurry vision when moving the head, and postural instability. Vestibular prostheses (VPs) show promise as a treatment, but the VP-restored vestibulo-ocular reflex (VOR) gain in human trials falls short of expectations. We hypothesize that the slope of the rising ramp in stimulation pulses plays an important role in the recruitment of vestibular afferent units. To test this hypothesis, we utilized customized programming to generate ramped pulses with different slopes, testing their efficacy in inducing electrically evoked compound action potentials (eCAPs) and current spread via bench tests and simulations in a virtual inner model created in this study. The results confirmed that the slope of the ramping pulses influenced the recruitment of vestibular afferent units. Subsequently, an optimized stimulation pulse train was identified using model simulations, exhibiting improved modulation of vestibular afferent activity. This optimized slope not only reduced the excitation spread within the semicircular canals (SCCs) but also expanded the neural dynamic range. While the model simulations exhibited promising results, in vitro and in vivo experiments are warranted to validate the findings of this study in future investigations.

Measurements of improved stability to achieve higher fuel compression in ICF

While nuclear fusion ignition has been achieved at the National Ignition Facility in inertial confinement fusion (ICF) experiments, obtaining higher gain and more efficient burn is still desired. In that regard, increasing the compression of the fuel is an important factor. In recent indirect-drive capsule implosions, the SQ-n campaign is testing the hypothesis that reducing the hydrodynamic growth of perturbations is key to achieving higher compression of high-density carbon based-ablators for ICF. SQ-n uses a design at lower adiabat with a ramped foot laser pulse shape to minimize early-time hydrodynamic instability growth, predicted to be reduced by a factor of 10, and an optimized ablator dopant distribution. Subsets of experiments were conducted within the SQ-n campaign to study the implosion symmetry, laser backscatter, stability, and compression. Only the latter two will be reviewed here. Shock timing experiments using the velocity interferometer system for any reflector diagnostic enabled the development of a gently accelerating shock velocity. The ice–ablator interface acceleration, important for managing the Richtmyer–Meshkov phase growth, was observed with refraction enhanced radiography and the ablation front growth was measured using radiography of pre-imposed modulations. Finally, layered tritium-hydrogen-deuterium (∼75% H, ∼25% T, ∼2–10% D) and deuterium–tritium implosions demonstrate that between 15% ± 3% and 30% ± 6% improved compression has been achieved.

Research on Hydrodynamic Characteristics of Electronic Paper Pixels Based on Electrowetting.

In this paper, we propose a driving waveform with a complex ramp pulse for an electrowetting display system. The relationship between the contact angle and viscosity of inks was calculated based on the fluid-motion characteristics of different viscosities. We obtained the suitable range of viscosity and voltage in the liquid-oil-solid three-phase contact display system. We carried out model simulation and driving waveform design. The result shows that the driving waveform improves the response speed and aperture ratio of electrowetting. The aperture ratio of electrowetting pixels is increased to 68.69%. This research is of great significance to optimizing the structure of fluid material and the design of driving waveforms in electrowetting displays.

Studying the Thermoelastic Waves Induced by Pulsed Lasers Due to the Interaction between Electrons and Holes on Semiconductor Materials under the Hall Current Effect

In the present work, the interaction between electrons and holes in semiconductor materials is investigated. According to the excitation process, the optical-elastic-thermal-diffusion (OETD) process is considered when the medium is exposed to a strong magnetic field and laser pulses. Photo-elastic and photo-electronics deformations are taken into account when the Hall current impact appears due to the magnetic field pressure on the semiconductor medium. Due to the complexity of the model, the governing equations that describe the system in one dimension (1D) are studied. Mathematical transformations (Laplace transform) were used to simplify the equations to obtain the physical quantities under study which were affected by laser pulses. To obtain complete solutions, some conditions were obtained from the free surface as well as from a mechanical ramp type and pulse heat flux, and then numerical transformations were applied using the inverse Laplace transform. Under the influence of several variables in this question, the results were explained graphically for silicon (Si) material and the results were analyzed in terms of their physical significance.

What Is the Benefit of Ramped Pulse Shapes for Activating Auditory Cortex Neurons? An Electrophysiological Study in an Animal Model of Cochlear Implant.

In all commercial cochlear implant (CI) devices, the activation of auditory nerve fibers is performed with rectangular pulses that have two phases of opposite polarity. Recently, several papers proposed that ramped pulse shapes could be an alternative shape for efficiently activating auditory nerve fibers. Here, we investigate whether ramped pulse shapes can activate auditory cortex (ACx) neurons in a more efficient way than the classical rectangular pulses. Guinea pigs were implanted with CI devices and responses of ACx neurons were tested with rectangular pulses and with four ramped pulse shapes, with a first-phase being either cathodic or anodic. The thresholds, i.e., the charge level necessary for obtaining significant cortical responses, were almost systematically lower with ramped pulses than with rectangular pulses. The maximal firing rate (FR) elicited by the ramped pulses was higher than with rectangular pulses. As the maximal FR occurred with lower charge levels, the dynamic range (between threshold and the maximal FR) was not modified. These effects were obtained with cathodic and anodic ramped pulses. By reducing the charge levels required to activate ACx neurons, the ramped pulse shapes should reduce charge consumption and should contribute to more battery-efficient CI devices in the future.

Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents.

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels' activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.

Interaction of multiple shocks in planar targets with a ramp-pulse ablation

Interaction of multiple shocks plays a critical role in setting up an adiabatic compression of megabar pressure in nanosecond timescale in inertial confinement fusion. In this paper, we present observations of dynamic behavior and interaction of multiple shocks in polystyrene (CH) planar targets driven by a single-ramp pulse of 2.5 ns at the SG-II laser facility with a specially designed velocity interferometer system for any reflector (VISAR). A maximum pressure of 7.65 Mbar and a mass density of 3.46 g/cm3 are measured, respectively. Radiation-hydrodynamic simulations reveal the interaction process of the multiple shocks and are in good agreement with the measurements. A theoretical model is proposed to invert the space-time history of the shock generation with the VISAR data. Moreover, an optimized double-slope ramp pulse is proposed for further compression experiments. The improved multiple-shock coalescence is expected to effectively enhance both density and velocity for an initial compression of the CH target.

Effective Modulation by Lacosamide on Cumulative Inhibition of INa during High-Frequency Stimulation and Recovery of INa Block during Conditioning Pulse Train.

The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 μM found in GH3 cells and of 112 and 26 μM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ’s of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.

The Modulation of Ubiquinone, a Lipid Antioxidant, on Neuronal Voltage-Gated Sodium Current.

Ubiquinone, composed of a 1,4-benzoquinone and naturally produced in the body, actively participates in the mitochondrial redox reaction and functions as an endogenous lipid antioxidant, protecting against peroxidation in the pituitary-dependent hormonal system. However, the questions of if and how ubiquinone directly affects neuronal ionic currents remain largely unsettled. We investigated its effects on ionic currents in pituitary neurons (GH3 and MMQ cells) with the aid of patch-clamp technology. Ubiquinone decreased the peak amplitude of the voltage-gated Na+ current (INa) with a slowing of the inactivation rate. Neither menadione nor superoxide dismutase modified the ubiquinone-induced INa inhibition. In response to an isosceles-triangular ramp pulse, the persistent INa (INa(P)) at high- and low- threshold potentials occurred concurrently with a figure-eight hysteresis loop. With ubiquinone, the INa(P) increased with no change in the intersection voltage, and the magnitude of the voltage-dependent hysteresis of the current was enhanced. Ubiquinone was ineffective in modifying the gating of hyperpolarization-activated cation currents. In MMQ lactotrophs, ubiquinone effectively decreased the amplitude of the INa and the current inactivation rate. In sum, the effects of ubiquinone demonstrated herein occur upstream of its effects on mitochondrial redox processes, involved in its modulation of sodium channels and neuronal excitability.

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line.

Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 μM, respectively. The overall current–voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)’s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 μM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one).

QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of KV7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K+ current (IK(M)), Ca2+-activated K+ current (IK(Ca)), large-conductance Ca2+-activated K+ (BKCa) channels, and erg-mediated K+ current (IK(erg)) identified from pituitary tumor (GH3) cells. Addition of QO-58 can increase the amplitude of IK(M) and IK(Ca) in a concentration-dependent fashion, with effective EC50 of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of IK(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (Vhys) of IK(M) evoked by upright triangular ramp pulse (Vramp) was enhanced by adding QO-58. The probabilities of M-type K+ (KM) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH3-cell exposure to QO-58 effectively increased the amplitude of IK(Ca) as well as enhanced the activity of BKCa channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BKCa-channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BKCa channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of IK(erg) amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or KCa1.1 channel. Overall, dual activation of IK(M) and IK(Ca) caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/KV7 selective.

Exploring implosion designs for increased compression on the National Ignition Facility using high density carbon ablators

It has long been recognized that high compression, and hence good confinement, is essential to achieving high yields in inertial confinement fusion implosions. In pursuit of multi-megajoule yields on the National Ignition Facility (NIF), a new campaign has begun aimed at testing the hypothesis that controlling hydrodynamic stability is key to achieving effective higher compression with the high density carbon ablators currently fielded on NIF. This campaign is built around a new implosion design, called SQ-n, that is derived from the uniquely stable Bigfoot design tested on NIF in 2016–2019. While very stable and with performance that was quite close to one-dimensional expectations, Bigfoot was a relatively high adiabat, and consequently lower compression design. The goal of SQ-n is then to evolve Bigfoot toward a higher compression design but without compromising its unique stability characteristics. Specifically, SQ-n adopts a ramped foot pulse shape to minimize early time Richtmyer–Meshkov instability growth and uses an ablator dopant distribution extending all of the way to the fuel–ablator interface that simulations suggest further reduces perturbation growth. This paper describes the design philosophy pursued with SQ-n, the results of instability modeling of the candidate design, and the experimental campaign planned to test these ideas in the near future.

The Evidence for Effective Inhibition of INa Produced by Mirogabalin ((1R,5S,6S)-6-(aminomethyl)-3-ethyl-bicyclo [3.2.0] hept-3-ene-6-acetic acid), a Known Blocker of CaV Channels.

Mirogabalin (MGB, Tarlige®), an inhibitor of the α2δ-1 subunit of voltage-gated Ca2+ (CaV) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH3) cells, we found that MGB was effective at suppressing the peak (transient, INa(T)) and sustained (late, INa(L)) components of the voltage-gated Na+ current (INa) in a concentration-dependent manner, with an effective IC50 of 19.5 and 7.3 μM, respectively, while the KD value calculated on the basis of minimum reaction scheme was 8.2 μM. The recovery of INa(T) inactivation slowed in the presence of MGB, although the overall current–voltage relation of INa(T) was unaltered; however, there was a leftward shift in the inactivation curve of the current. The magnitude of the window (INa(W)) or resurgent INa (INa(R)) evoked by the respective ascending or descending ramp pulse (Vramp) was reduced during cell exposure to MGB. MGB-induced attenuation in INa(W) or INa(R) was reversed by the further addition of tefluthrin, a pyrethroid insecticide known to stimulate INa. MGB also effectively lessened the strength of voltage-dependent hysteresis of persistent INa in response to the isosceles triangular Vramp. The cumulative inhibition of INa(T), evoked by pulse train stimulation, was enhanced in its presence. Taken together, in addition to the inhibition of CaV channels, the NaV channel attenuation produced by MGB might have an impact in its analgesic effects occurring in vivo.

The Effectiveness of Isoplumbagin and Plumbagin in Regulating Amplitude, Gating Kinetics, and Voltage-Dependent Hysteresis of erg-mediated K+ Currents.

Isoplumbagin (isoPLB, 5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone, has been observed to exercise anti-inflammatory, antimicrobial, and antineoplastic activities. Notably, whether and how isoPLB, plumbagin (PLB), or other related compounds impact transmembrane ionic currents is not entirely clear. In this study, during GH3-cell exposure to isoPLB, the peak and sustained components of an erg (ether-à-go-go related gene)-mediated K+ current (IK(erg)) evoked with long-lasting-step hyperpolarization were concentration-dependently decreased, with a concomitant increase in the decaying time constant of the deactivating current. The presence of isoPLB led to a differential reduction in the peak and sustained components of deactivating IK(erg) with effective IC50 values of 18.3 and 2.4 μM, respectively, while the KD value according to the minimum binding scheme was estimated to be 2.58 μM. Inhibition by isoPLB of IK(erg) was not reversed by diazoxide; however, further addition of isoPLB, during the continued exposure to 4,4′-dithiopyridine, did not suppress IK(erg) further. The recovery of IK(erg) by a two-step voltage pulse with a geometric progression was slowed in the presence of isoPLB, and the decaying rate of IK(erg) activated by the envelope-of-tail method was increased in its presence. The strength of the IK(erg) hysteresis in response to an inverted isosceles-triangular ramp pulse was diminished by adding isoPLB. A mild inhibition of the delayed-rectifier K+ current (IK(DR)) produced by the presence of isoPLB was seen in GH3 cells, while minimal changes in the magnitude of the voltage-gated Na+ current were demonstrated in its presence. Moreover, the IK(erg) identified in MA-10 Leydig tumor cells was blocked by adding isoPLB. Therefore, the effects of isoPLB or PLB on ionic currents (e.g., IK(erg) and IK(DR)) demonstrated herein would be upstream of our previously reported perturbations on mitochondrial morphogenesis or respiration. Taken together, the perturbations of ionic currents by isoPLB or PLB demonstrated herein are likely to contribute to the underlying mechanism through which they, or other structurally similar compounds, result in adjustments in the functional activities of different neoplastic cells (e.g., GH3 and MA-10 cells), presuming that similar in vivo observations occur.

Zingerone Modulates Neuronal Voltage-Gated Na+ and L-Type Ca2+ Currents.

Zingerone (ZO), a nontoxic methoxyphenol, has been demonstrated to exert various important biological effects. However, its action on varying types of ionic currents and how they concert in neuronal cells remain incompletely understood. With the aid of patch clamp technology, we investigated the effects of ZO on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from both pituitary tumor (GH3) cells and hippocampal (mHippoE-14) neurons. The exposure of the GH3 cells to ZO differentially diminished the peak and late components of the INa. Using a double ramp pulse, the amplitude of the INa(P) was measured, and the appearance of a hysteresis loop was observed. Moreover, ZO reversed the tefluthrin-mediated augmentation of the hysteretic strength of the INa(P) and led to a reduction in the ICa,L. As a double ramp pulse was applied, two types of voltage-dependent hysteresis loops were identified in the ICa,L, and the replacement with BaCl2-attenuated hysteresis of the ICa,L enhanced the ICa,L amplitude along with the current amplitude (i.e., the IBa). The hysteretic magnitude of the ICa,L activated by the double pulse was attenuated by ZO. The peak and late INa in the hippocampal mHippoE-14 neurons was also differentially inhibited by ZO. In addition to acting on the production of reactive oxygen species, ZO produced effects on multiple ionic currents demonstrated herein that, considered together, may significantly impact the functional activities of neuronal cells.

The Evidence for Sparsentan-Mediated Inhibition of INa and IK(erg): Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor.

Sparsentan is viewed as a dual antagonist of endothelin type A (ETA) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis. The ionic mechanisms through which it interacts with the magnitude and/or gating kinetics of ionic currents in excitable cells were not thoroughly investigated. Herein, we aimed to examine the effects of varying sparsentan concentrations on ionic currents residing in pituitary GH3 somatolactotrophs. From whole-cell current recordings made in GH3 cells, sparsentan (0.3–100 μM) differentially inhibited the peak and late components of voltage-gated Na+ current (INa). The IC50 value of sparsentan required to exert a reduction in peak and late INa in GH3 cells was 15.04 and 1.21 μM, respectively; meanwhile, the KD value estimated from its shortening in the slow component of INa inactivation time constant was 2.09 μM. The sparsentan (10 μM) presence did not change the overall current–voltage relationship of INa; however, the steady-state inactivation curve of the current was shifted to more negative potential in its presence (10 μM), with no change in the gating charge of the curve. The window INa activated by a brief upsloping ramp was decreased during exposure to sparsentan (10 μM); moreover, recovery of peak INa became slowed in its presence. The Tefluthrin (Tef)-stimulated resurgent INa activated in response to abrupt depolarization followed by the descending ramp pulse was additionally attenuated by subsequent application of sparsentan. In continued presence of Tef (3 μM) or β-pompilidotoxin (3 μM), further application of sparsentan (3 μM) reversed their stimulation of INa. However, sparsentan-induced inhibition of INa failed to be overcome by subsequent application of either endothelin 1 (1 μM) or angiotensin II (1 μM); moreover, in continued presence of endothelin (1 μM) or angiotensin II (1 μM), further addition of sparsentan (3 μM) effectively decreased peak INa. Additionally, the application of sparsentan (3 μM) inhibited the peak and late components of erg-mediated K+ current in GH3 cells, although it mildly decreased the amplitude of delayed-rectifier K+ current. Altogether, this study provides a distinct yet unidentified finding that sparsentan may perturb the amplitude or gating of varying ionic currents in excitable cells.

The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action.

Solifenacin (Vesicare®, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH3 cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K+ current (IK(M)) with effective EC50 value of 0.34 μM. The activation time constant of IK(M) was concurrently shortened in the SOL presence, hence yielding the KD value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of IK(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of IK(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated IK(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in IK(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K+ (KM) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH3 cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the IK(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with KM channels and hence in stimulating IK(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH3 or mHippoE-14 cells.

The role of potassium in muscle membrane dysfunction in end-stage renal disease

ObjectiveUremic myopathy is a condition seen in end-stage renal disease (ESRD), characterized by muscle weakness and muscle fatigue, in which the pathophysiology is uncertain. The aim of this study was to assess the role of abnormal serum constituents in ESRD patients by relating them to the excitability properties of the tibialis anterior muscle, at rest and during electrically induced muscle activation, by recording muscle velocity recovery cycles (MVRC) and frequency ramp responses. MethodsEighteen ESRD patients undergoing hemodialysis were evaluated by blood sample, MVRC, and frequency ramp (before and near the end of dialysis treatment), quantitative electromyography, and nerve conduction studies. Patients were compared to 24 control subjects. ResultsIn patients, muscle relative refractory period, early supernormality, late supernormality after 5 conditioning stimuli, and latency of the last of 15 and 30 frequency ramp pulses were strongly associated with potassium levels (p < 0.01), showing depolarization before and normalization in the end of hemodialysis. ConclusionsIn ESRD patients, the muscle membrane is depolarized, mainly due to hyperkalemia. SignificanceSince normal muscle fatigue has been attributed to potassium-induced depolarization, it seems likely that this mechanism is also a major cause of the exaggerated muscle fatigue and weakness in ESRD patients.

Tidal pressure as a mechanism to explain the steep rise in ambient infrasound below 0.1 Hz at Eleuthera reported by Nichols in 1981

R. H. Nichols reported measurements of ambient ocean noise made off Eleuthera Island [J. Acoust. Soc. Am. 69, 974–981 (1981)]. Nichols was unable to identify a mechanism to explain the steep rise of 20 dB per octave from 0.02–0.1 Hz in spectrum levels obtained with hydrophones at depths of 300 and 1,200 m. Here we show that a tidal pressure signal modeled as a ramp pulse waveform through an octave bandpass filter results in spectrum levels increasing about 12 dB per octave with decreasing frequency below 0.1 Hz. If the infrasound noise levels continue to follow the 6 dB per octave increase with decreasing frequency down to 0.02 Hz as they do from 0.1–1Hz, the tidal pressure signal will dominate the infrasound. After a crossover point the infrasound noise signal becomes dominant with increasing frequency. This proposed tidal pressure mechanism could be tested by correlation of observed spectrum levels with the tides just as measurements of surface wind speeds have been shown to correlate with increased infrasound spectrum levels.