scholarly journals Synergistic Inhibition of Delayed Rectifier K+ and Voltage-Gated Na+ Currents by Artemisinin in Pituitary Tumor (GH3) Cells

2017 ◽  
Vol 41 (5) ◽  
pp. 2053-2066 ◽  
Author(s):  
Edmund Cheung So ◽  
Sheng-Nan Wu ◽  
Ping-Ching Wu ◽  
Hui-Zhen  Chen ◽  
Chia-Jung Yang
Keyword(s):  
Pituitary Tumor ◽  
Ionic Currents ◽  
Neuroendocrine Cells ◽  
Endocrine Function ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Membrane Excitability ◽  
Inactivation Curve ◽  
Voltage Gated

Background: Artemisinin (ART) is an anti-malarial agent reported to influence endocrine function. Methods: Effects of ART on ionic currents and action potentials (APs) in pituitary tumor (GH3) cells were evaluated by patch clamp techniques. Results: ART inhibited the amplitude of delayed-rectifier K+ current (IK(DR)) in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on IK(DR) with an IC50 value of 11.2 µM and enhanced IK(DR) inactivation with a KD value of 14.7 µM. The steady-state inactivation curve of IK(DR) was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 µM) or iloprost (100 nM) did not alter the magnitude of ART-induced inhibition of IK(DR) in GH3 cells. ART also decreased the peak amplitude of voltage-gated Na+ current (INa) with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late INa, was effective at reversing ART-induced prolongation in inactivation time constant of INa. Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. Conclusion: Under ART exposure, the inhibitory actions on both IK(DR) and INa could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.

scholarly journals Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on α2-Adrenergic Receptors

2020 ◽  
Vol 21 (23) ◽  
pp. 9110
Author(s):  
Te-Ling Lu ◽  
Te-Jung Lu ◽  
Sheng-Nan Wu
Keyword(s):  
Adrenergic Receptors ◽  
Time Course ◽  
Ionic Currents ◽  
Inhibitory Effect ◽  
Firing Frequency ◽  
Neuroendocrine Cells ◽  
Gh3 Cells ◽  
Membrane Excitability ◽  
Cation Current

Dexmedetomidine (DEX), a highly selective agonist of α2-adrenergic receptors, has been tailored for sedation without risk of respiratory depression. Our hypothesis is that DEX produces any direct perturbations on ionic currents (e.g., hyperpolarization-activated cation current, Ih). In this study, addition of DEX to pituitary GH3 cells caused a time- and concentration-dependent reduction in the amplitude of Ih with an IC50 value of 1.21 μM and a KD value of 1.97 μM. A hyperpolarizing shift in the activation curve of Ih by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of Ih elicited by long-lasting triangular ramp pulse was also dose-dependently reduced during its presence. In continued presence of DEX (1 μM), further addition of OXAL (10 μM) or replacement with high K+ could reverse DEX-mediated inhibition of Ih, while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on Ih amplitude. The addition of 3 μM DEX mildly suppressed the amplitude of erg-mediated K+ current. Under current-clamp potential recordings, the exposure to DEX could diminish the firing frequency of spontaneous action potentials. In pheochromocytoma PC12 cells, DEX was effective at suppressing Ih together with a slowing in activation time course of the current. Taken together, findings from this study strongly suggest that during cell exposure to DEX used at clinically relevant concentrations, the DEX-mediated block of Ih appears to be direct and would particularly be one of the ionic mechanisms underlying reduced membrane excitability in the in vivo endocrine or neuroendocrine cells.

scholarly journals Effectiveness of Columbianadin, a Bioactive Coumarin Derivative, in Perturbing Transient and Persistent INa

2021 ◽  
Vol 22 (2) ◽  
pp. 621
Author(s):  
Wei-Ting Chang ◽  
Sheng-Nan Wu
Keyword(s):  
Time Course ◽  
Biological Activities ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Excitable Cells ◽  
Inactivation Curve ◽  
Voltage Gated ◽  
Atrial Cardiomyocytes ◽  
Subsequent Addition

Columbianadin (CBN) is a bioactive coumarin-type compound with various biological activities. However, the action of CBN on the ionic mechanism remains largely uncertain, albeit it was reported to inhibit voltage-gated Ca2+ current or to modulate TRP-channel activity. In this study, whole-cell patch-clamp current recordings were undertaken to explore the modifications of CBN or other related compounds on ionic currents in excitable cells (e.g., pituitary GH3 cells and HL-1 atrial cardiomyocytes). GH3-cell exposure to CBN differentially decreased peak or late component of voltage-gated Na+ current (INa) with effective IC50 of 14.7 or 2.8 µM, respectively. The inactivation time course of INa activated by short depolarization became fastened in the presence of CBN with estimated KD value of 3.15 µM. The peak INa diminished by 10 µM CBN was further suppressed by subsequent addition of either sesamin (10 µM), ranolazine (10 µM), or tetrodotoxin (1 µM), but it was reversed by 10 µM tefluthrin (Tef); however, further application of 10 µM nimodipine failed to alter CBN-mediated inhibition of INa. CBN (10 µM) shifted the midpoint of inactivation curve of INa to the leftward direction. The CBN-mediated inhibition of peak INa exhibited tonic and use-dependent characteristics. Using triangular ramp pulse, the hysteresis of persistent INa enhanced by Tef was noticed, and the behavior was attenuated by subsequent addition of CBN. The delayed-rectifier or erg-mediated K+ current was mildly inhibited by 10 µM CBN, while it also slightly inhibited the amplitude of hyperpolarization-activated cation current. In HL-1 atrial cardiomyocytes, CBN inhibited peak INa and raised the inactivation rate of the current; moreover, further application of 10 µM Tef attenuated CBN-mediated decrease in INa. Collectively, this study provides an important yet unidentified finding revealing that CBN modifies INa in electrically excitable cells.

scholarly journals Effectiveness in the Block by Honokiol, a Dimerized Allylphenol from Magnolia Officinalis, of Hyperpolarization-Activated Cation Current and Delayed-Rectifier K+ Current

2020 ◽  
Vol 21 (12) ◽  
pp. 4260
Author(s):  
Ming-Huan Chan ◽  
Hwei-Hsien Chen ◽  
Yi-Ching Lo ◽  
Sheng-Nan Wu
Keyword(s):  
Surface Membrane ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Voltage Dependent ◽  
K Current ◽  
Magnolia Officinalis

Background: Honokiol (HNK), a dimer of allylphenol obtained from the bark of Magnolia officinalis was demonstrated to exert an array of biological actions in different excitable cell types. However, whether or how this compound can lead to any perturbations on surface–membrane ionic currents remains largely unknown. Methods: We used the patch clamp method and found that addition of HNK effectively depressed the density of macroscopic hyperpolarization-activated cation currents (Ih) in pituitary GH3 cells in a concentration-, time- and voltage-dependent manner. By the use of a two-step voltage protocol, the presence of HNK (10 μM) shifted the steady-state activation curve of Ih density along the voltage axis to a more negative potential by approximately 11 mV, together with no noteworthy modification in the gating charge of the current. Results: The voltage-dependent hysteresis of Ih density elicited by long-lasting triangular ramp pulse was attenuated by the presence of HNK. The HNK addition also diminished the magnitude of deactivating Ih density elicited by ramp-up depolarization with varying durations. The effective half-maximal concentration (IC50) value needed to inhibit the density of Ih or delayed rectifier K+ current identified in GH3 cells was estimated to be 2.1 or 6.8 μM, respectively. In cell-attached current recordings, HNK decreased the frequency of spontaneous action currents. In Rolf B1.T olfactory sensory neurons, HNK was also observed to decrease Ih density in a concentration-dependent manner. Conclusions: The present study highlights the evidence revealing that HNK has the propensity to perturb these ionic currents and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is proposed to be a potential target for the in vivo actions of HNK and its structurally similar compounds.

scholarly journals Inhibitory Effectiveness of Gomisin A, a Dibenzocyclooctadiene Lignan Isolated from Schizandra chinensis, on the Amplitude and Gating of Voltage-Gated Na+ Current

2020 ◽  
Vol 21 (22) ◽  
pp. 8816
Author(s):  
Wei-Ting Chang ◽  
Sheng-Nan Wu
Keyword(s):  
Biological Activities ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Na Current ◽  
Inactivation Curve ◽  
Voltage Gated ◽  
Steady State Inactivation ◽  
Gomisin A ◽  
Ramp Voltage ◽  
Ionic Mechanisms

Gomisin A (Gom A), a lignan isolated from Schisandra chinensis, has been reported produce numerous biological activities. However, its action on the ionic mechanisms remains largely unanswered. The present experiments were undertaken to investigate the possible perturbations of Gom A or other related compounds on different types of membrane ionic currents in electrically excitable cells (i.e., pituitary GH3 and pancreatic INS-1 cells). The exposure to Gom A led to the differential inhibition of peak and end-pulse components of voltage-gated Na+ current (INa) in GH3 cells with effective IC50 of 6.2 and 0.73 μM, respectively. The steady-state inactivation curve of INa in the presence of Gom A was shifted towards a more hyperpolarized potential. However, neither changes in the overall current-voltage relationship nor those for the gating charge of the current were demonstrated. The application of neither morin (10 μM) nor hesperidin (10 μM) perturbed the strength of INa, while sesamine could suppress it. However, in the continued presence of Gom A, the addition of sesamine failed to suppress INa further. Gom A also effectively suppressed the strength of persistent INa activated by long ramp voltage command, and further application of tefluthrin effectively attenuated Gom A-mediated inhibition of the current. The presence of Gom A mildly inhibited erg-mediated K+ current, while a lack of change in the amplitude of hyperpolarization-activated cation current was observed in its presence. Under cell-attached current recordings, the exposure to Gom A resulted in the decreased firing of spontaneous action currents with a minimal change in AC amplitude. In pancreatic INS-1 cells, the presence of Gom A was also noticed to inhibit peak and end-pulse components of INa differentially with the IC50 of 5.9 and 0.84 μM, respectively. Taken together, the emerging results presented herein provide the evidence that Gom A can differentially inhibit peak and sustained INa in endocrine cells (e.g., GH3 and INS-1 cells).

scholarly journals Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

2020 ◽  
Vol 21 (21) ◽  
pp. 8078
Author(s):  
Pin-Yen Liu ◽  
Wei-Ting Chang ◽  
Sheng-Nan Wu
Keyword(s):  
Pituitary Tumor ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Ionic Currents ◽  
Transforming Growth Factor Β ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Cyclin Dependent Kinase ◽  
Cation Current ◽  
K Current

Ribociclib (RIB, LE011, Kisqali®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this study, the addition of RIB to pituitary tumor (GH3) cells decreased the peak amplitude of erg-mediated K+ current (IK(erg)), which was accompanied by a slowed deactivation rate of the current. The IC50 value for RIB-perturbed inhibition of deactivating IK(erg) in these cells was 2.7 μM. In continued presence of μM RIB, neither the subsequent addition of 17β-estradiol (30 μM), phorbol 12-myristate 13-acetate (10 μM), or transforming growth factor-β (1 μM) counteracted the inhibition of deactivating IK(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for IK(erg) elicitation by long-duration triangular ramp voltage commands. The presence of RIB differentially inhibited the peak or sustained component of delayed rectifier K+ current (IK(DR)) with an effective IC50 of 28.7 or 11.4 μM, respectively, while it concentration-dependently decreased the amplitude of M-type K+ current with IC50 of 13.3 μM. Upon 10-s long membrane depolarization, RIB elicited a decrease in the IK(DR) amplitude, which was concomitant with an accelerated inactivation time course. However, the inability of RIB (10 μM) to modify the magnitude of the hyperpolarization-activated cation current was disclosed. The mean current–voltage relationship of IK(erg) present in HL-1 atrial cardiomyocytes was inhibited in the presence of RIB (10 μM). Collectively, the hyperpolarization-activated cation current was observed. RIB-mediated perturbations in ionic currents presented herein are upstream of its suppressive action on cytosolic CDK-4/6 activities and partly participates in its modulatory effects on the functional activities of pituitary tumor cells (e.g., GH3 cells) or cardiac myocytes (e.g., HL-1 cells).

scholarly journals Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 636
Author(s):  
Hung-Tsung Hsiao ◽  
Guan-Ling Lu ◽  
Yen-Chin Liu ◽  
Sheng-Nan Wu
Keyword(s):  
Slow Component ◽  
Surface Membrane ◽  
Glioma Cells ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Inactivation Curve

PT-2385 is currently regarded as a potent and selective inhibitor of hypoxia-inducible factor-2α (HIF-2α), with potential antineoplastic activity. However, the membrane ion channels changed by this compound are obscure, although it is reasonable to assume that the compound might act on surface membrane before entering the cell´s interior. In this study, we intended to explore whether it and related compounds make any adjustments to the plasmalemmal ionic currents of pituitary tumor (GH3) cells and human 13-06-MG glioma cells. Cell exposure to PT-2385 suppressed the peak or late amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner, with IC50 values of 8.1 or 2.2 µM, respectively, while the KD value in PT-2385-induced shortening in the slow component of IK(DR) inactivation was estimated to be 2.9 µM. The PT-2385-mediated block of IK(DR) in GH3 cells was little-affected by the further application of diazoxide, cilostazol, or sorafenib. Increasing PT-2385 concentrations shifted the steady-state inactivation curve of IK(DR) towards a more hyperpolarized potential, with no change in the gating charge of the current, and also prolonged the time-dependent recovery of the IK(DR) block. The hysteretic strength of IK(DR) elicited by upright or inverted isosceles-triangular ramp voltage was decreased during exposure to PT-2385; meanwhile, the activation energy involved in the gating of IK(DR) elicitation was noticeably raised in its presence. Alternatively, the presence of PT-2385 in human 13-06-MG glioma cells effectively decreased the amplitude of IK(DR). Considering all of the experimental results together, the effects of PT-2385 on ionic currents demonstrated herein could be non-canonical and tend to be upstream of the inhibition of HIF-2α. This action therefore probably contributes to down-streaming mechanisms through the changes that it or other structurally resemblant compounds lead to in the perturbations of the functional activities of pituitary cells or neoplastic astrocytes, in the case that in vivo observations occur.

scholarly journals Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1146
Author(s):  
Tzu-Hsien Chuang ◽  
Hsin-Yen Cho ◽  
Sheng-Nan Wu
Keyword(s):  
Slow Component ◽  
Sodium Current ◽  
Ionic Currents ◽  
Ionic Channels ◽  
Oxidase Inhibitor ◽  
Gh3 Cells ◽  
High Threshold ◽  
Excitable Cells ◽  
Inactivation Curve ◽  
Voltage Gated

Apocynin (aPO, 4′-Hydroxy-3′-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH3 cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH3-cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (INa) with different potencies. The EC50 value of aPO required for its differential increase in peak or late INa in GH3 cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the KD value required for its retardation in the slow component of current inactivation was 3.4 μM. The current–voltage relation of INa was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak INa inactivation was increased in the presence of 10 μM aPO. In continued presence of aPO, further application of rufinamide or ranolazine attenuated aPO-stimulated INa. In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak INa remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent INa measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of INa as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO-accentuated INa. Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of INa in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function.

scholarly journals Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

2020 ◽  
Vol 21 (7) ◽  
pp. 2416 ◽  
Author(s):  
Te-Ling Lu ◽  
Te-Jung Lu ◽  
Sheng-Nan Wu
Keyword(s):  
Time Course ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Hcn Channels ◽  
Dependent Manner ◽  
H9c2 Cells ◽  
Excitable Cells ◽  
Concentration Dependent Manner ◽  
Inactivation Curve

Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (Ih), has been observed to possess pro-arrhythmic properties. Whether and how CIL is capable of perturbing different types of membrane ionic currents existing in electrically excitable cells, however, is incompletely understood. In this study, we intended to examine possible modifications by it or other structurally similar compounds of ionic currents in pituitary tumor (GH3) cells and in heart-derived H9c2 cells. The standard whole-cell voltage-clamp technique was performed to examine the effect of CIL on ionic currents. GH3-cell exposure to CIL suppressed the density of hyperpolarization-evoked Ih in a concentration-dependent manner with an effective IC50 of 3.38 μM. Apart from its increase in the activation time constant of Ih during long-lasting hyperpolarization, the presence of CIL (3 μM) distinctly shifted the steady-state activation curve of Ih triggered by a 2-s conditioning pulse to a hyperpolarizing direction by 10 mV. As the impedance-frequency relation of Ih was studied, its presence raised the impedance magnitude at the resonance frequency induced by chirp voltage. CIL also suppressed delayed-rectifier K+ current (IK(DR)) followed by the accelerated inactivation time course of this current, with effective IC50 (measured at late IK(DR)) or KD value of 3.54 or 3.77 μM, respectively. As the CIL concentration increased 1 to 3 μM, the inactivation curve of IK(DR) elicited by 1- or 10-s conditioning pulses was shifted to a hyperpolarizing potential by approximately 10 mV, and the recovery of IK(DR) inactivation during its presence was prolonged. The peak Na+ current (INa) during brief depolarization was resistant to being sensitive to the presence of CIL, yet to be either decreased by subsequent addition of A-803467 or enhanced by that of tefluthrin. In cardiac H9c2 cells, unlike the CIL effect, the addition of either ivabradine or zatebradine mildly led to a lowering in IK(DR) amplitude with no conceivable change in the inactivation time course of the current. Taken together, the compound like CIL, which was tailored to block hyperpolarization-activated cation (HCN) channels effectively, was also capable of altering the amplitude and gating of IK(DR), thereby influencing the functional activities of electrically excitable cells, such as GH3 cells.

scholarly journals Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents

2020 ◽  
Vol 21 (2) ◽  
pp. 396 ◽  
Author(s):  
Wei-Ting Chang ◽  
Zi-Han Gao ◽  
Shih-Wei Li ◽  
Ping-Yen Liu ◽  
Yi-Ching Lo ◽  
...  
Keyword(s):  
Ionic Currents ◽  
Gh3 Cells ◽  
Dependent Manner ◽  
Induced Current ◽  
Membrane Excitability ◽  
Concentration Dependent Manner ◽  
Term Administration ◽  
Inward Currents ◽  
Dual Activation

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 μM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in Ih activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of IMEP elicited by large hyperpolarization in GH3 cells with an EC50 value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.

scholarly journals Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 549
Author(s):  
Wei-Ting Chang ◽  
Sheng-Nan Wu
Keyword(s):  
Mineralocorticoid Receptor ◽  
Sodium Current ◽  
Ionic Currents ◽  
Antagonistic Effect ◽  
Gh3 Cells ◽  
Excitable Cells ◽  
Voltage Gated ◽  
Ic50 Value ◽  
Low Threshold

Esaxerenone (ESAX; CS-3150, Minnebro®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible perturbations of ESAX on the transient, late and persistent components of voltage-gated Na+ current (INa) identified from pituitary GH3 or MMQ cells. GH3-cell exposure to ESAX depressed the transient and late components of INa with varying potencies. The IC50 value of ESAX required for its differential reduction in peak or late INa in GH3 cells was estimated to be 13.2 or 3.2 μM, respectively. The steady-state activation curve of peak INa remained unchanged during exposure to ESAX; however, recovery of peak INa block was prolonged in the presence 3 μM ESAX. In continued presence of aldosterone (10 μM), further addition of 3 μM ESAX remained effective at inhibiting INa. ESAX (3 μM) potently reversed Tef-induced augmentation of INa. By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent INa measured at high or low threshold was enhanced by the presence of tefluthrin (Tef), in combination with the appearance of the figure-of-eight hysteretic loop; moreover, hysteretic strength of the current was attenuated by subsequent addition of ESAX. Likewise, in MMQ lactotrophs, the addition of ESAX also effectively decreased the peak amplitude of INa along with the increased current inactivation rate. Taken together, the present results provide a noticeable yet unidentified finding disclosing that, apart from its antagonistic effect on MR receptor, ESAX may directly and concertedly modify the amplitude, gating properties and hysteresis of INa in electrically excitable cells.

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