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

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.

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

Membranes ◽

10.3390/membranes11080636 ◽

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.

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High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BKCa-Channel Activity and Inhibits IK(M) or Ih

Biomolecules ◽

10.3390/biom10020188 ◽

2020 ◽

Vol 10 (2) ◽

pp. 188

Author(s):

Te-Ling Lu ◽

Zi-Han Gao ◽

Shih-Wei Li ◽

Sheng-Nan Wu

Keyword(s):

Ionic Currents ◽

Gh3 Cells ◽

Delayed Rectifier ◽

Bkca Channel ◽

Dependent Manner ◽

Channel Activity ◽

Bkca Channels ◽

Cationic Current ◽

K Current ◽

Change In Mean

GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca2+-activated K+ (BKCa) channels has been reported. In pituitary tumor (GH3) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an effective IC50 of 2.33 μM. GAL-021-mediated reduction of IK(Ca) was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BKCa channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BKCa channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BKCa channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K+ current with an effective IC50 of 3.75 μM; however, its presence did not alter the amplitude of erg-mediated K+ current, or mildly suppressed delayed-rectifier K+ current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing α-hSlo, the addition of GAL-021 was also able to suppress the BKCa-channel open probabilities, and GAL-021-mediated suppression of BKCa-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BKCa channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo.

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High Capability of Pentagalloylglucose (PGG) in Inhibiting Multiple Types of Membrane Ionic Currents

International Journal of Molecular Sciences ◽

10.3390/ijms21249369 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9369

Author(s):

Wei-Ting Chang ◽

Ping-Yen Liu ◽

Sheng-Nan Wu

Keyword(s):

Ionic Currents ◽

Gh3 Cells ◽

Delayed Rectifier ◽

Oxidative Property ◽

Ic50 Value ◽

Voltage Dependent ◽

Ramp Voltage ◽

Pentagalloyl Glucose ◽

K Current ◽

Membrane Ionic Currents

Pentagalloyglucose (PGG, penta-O-galloyl-β-d-glucose; 1,2,3,4,6-pentagalloyl glucose), a pentagallic acid ester of glucose, is recognized to possess anti-bacterial, anti-oxidative and anti-neoplastic activities. However, to what extent PGG or other polyphenolic compounds can perturb the magnitude and/or gating of different types of plasmalemmal ionic currents remains largely uncertain. In pituitary tumor (GH3) cells, we found out that PGG was effective at suppressing the density of delayed-rectifier K+ current (IK(DR)) concentration-dependently. The addition of PGG could suppress the density of proton-activated Cl− current (IPAC) observed in GH3 cells. The IC50 value required for the inhibitory action of PGG on IK(DR) or IPAC observed in GH3 cells was estimated to be 3.6 or 12.2 μM, respectively, while PGG (10 μM) mildly inhibited the density of the erg-mediated K+ current or voltage-gated Na+ current. The presence of neither chlorotoxin, hesperetin, kaempferol, morin nor iberiotoxin had any effects on IPAC density, whereas hydroxychloroquine or 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5yl)oxy] butanoic acid suppressed current density effectively. The application of PGG also led to a decrease in the area of voltage-dependent hysteresis of IPAC elicited by long-lasting isosceles-triangular ramp voltage command, suggesting that hysteretic strength was lessened in its presence. In human cardiac myocytes, the exposure to PGG also resulted in a reduction of ramp-induced IK(DR) density. Taken literally, PGG-perturbed adjustment of ionic currents could be direct and appears to be independent of its anti-oxidative property.

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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

International Journal of Molecular Sciences ◽

10.3390/ijms21072416 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2416 ◽

Cited By ~ 3

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.

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Characterization of Effectiveness in Concerted Ih Inhibition and IK(Ca) Stimulation by Pterostilbene (Trans-3,5-dimethoxy-4′-hydroxystilbene), a Stilbenoid

International Journal of Molecular Sciences ◽

10.3390/ijms21010357 ◽

2020 ◽

Vol 21 (1) ◽

pp. 357 ◽

Cited By ~ 2

Author(s):

Edmund Cheung So ◽

Zi-Han Gao ◽

Shun Yao Ko ◽

Sheng-Nan Wu

Keyword(s):

Single Channel ◽

Ionic Currents ◽

Gh3 Cells ◽

Dependent Manner ◽

Excitable Cells ◽

Bkca Channels ◽

Concentration Dependent Manner ◽

Cell Current ◽

K Current ◽

Neuroprotective Actions

Pterostilbene (PTER), a natural dimethylated analog of resveratrol, has been demonstrated to produce anti-neoplastic or neuroprotective actions. However, how and whether this compound can entail any perturbations on ionic currents in electrically excitable cells remains unknown. In whole-cell current recordings, addition of PTER decreased the amplitude of macroscopic Ih during long-lasting hyperpolarization in GH3 cells in a concentration-dependent manner, with an effective IC50 value of 0.84 μM. Its presence also shifted the activation curve of Ih along the voltage axis to a more hyperpolarized potential, by 11 mV. PTER at a concentration greater than 10 μM could also suppress l-type Ca2+ and transient outward K+ currents in GH3 cells. With the addition of PTER, IK(Ca) amplitude was increased, with an EC50 value of 2.23 μM. This increase in IK(Ca) amplitude was attenuated by further addition of verruculogen, but not by tolbutamide or TRAM-39. Neither atropine nor nicotine, in the continued presence of PTER, modified the PTER-stimulated IK(Ca). PTER (10 μM) slightly suppressed the amplitude of l-type Ca2+ current and transient outward K+ current. The presence of PTER (3 μM) was also effective at increasing the open-state probability of large-conductance Ca2+-activated K+ (BKCa) channels identified in hippocampal mHippoE-14 neurons; however, its inability to alter single-channel conductance was detected. Our study highlights evidence to show that PTER has the propensity to perturb ionic currents (e.g., Ih and IK(Ca)), thereby influencing the functional activities of neurons, and neuroendocrine or endocrine cells.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21020396 ◽

2020 ◽

Vol 21 (2) ◽

pp. 396 ◽

Cited By ~ 5

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.

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Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

International Journal of Molecular Sciences ◽

10.3390/ijms21041268 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1268 ◽

Cited By ~ 3

Author(s):

Ping-Chung Kuo ◽

Yen-Chin Liu ◽

Yi-Ching Lo ◽

Sheng-Nan Wu

Keyword(s):

Ionic Currents ◽

Neuroendocrine Cells ◽

Flowering Plant ◽

Gh3 Cells ◽

Functional Activities ◽

Cation Current ◽

Voltage Dependent ◽

K Current ◽

The Common

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

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Direct block of cloned hKv1.5 channel by cytochalasins, actin-disrupting agents

AJP Cell Physiology ◽

10.1152/ajpcell.00450.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. C425-C436 ◽

Cited By ~ 5

Author(s):

Bok Hee Choi ◽

Jung-Ah Park ◽

Kyung-Ryoul Kim ◽

Ggot-Im Lee ◽

Yong-Tae Lee ◽

...

Keyword(s):

Actin Filament ◽

Cytochalasin B ◽

Delayed Rectifier ◽

Dependent Manner ◽

Patch Clamp Technique ◽

Independent Manner ◽

Concentration Dependent Manner ◽

Voltage Range ◽

Whole Cell Patch Clamp ◽

Voltage Dependent

The action of cytochalasins, actin-disrupting agents on human Kv1.5 channel (hKv1.5) stably expressed in Ltk− cells was investigated using the whole cell patch-clamp technique. Cytochalasin B inhibited hKv1.5 currents rapidly and reversibly at +60 mV in a concentration-dependent manner with an IC50 of 4.2 μM. Cytochalasin A, which has a structure very similar to cytochalasin B, inhibited hKv1.5 (IC50 of 1.4 μM at +60 mV). Pretreatment with other actin filament disruptors cytochalasin D and cytochalasin J, and an actin filament stabilizing agent phalloidin had no effect on the cytochalasin B-induced inhibition of hKv1.5 currents. Cytochalasin B accelerated the decay rate of inactivation for the hKv1.5 currents. Cytochalasin B-induced inhibition of the hKv1.5 channels was voltage dependent with a steep increase over the voltage range of the channel's opening. However, the inhibition exhibited voltage independence over the voltage range in which channels are fully activated. Cytochalasin B produced no significant effect on the steady-state activation or inactivation curves. The rate constants for association and dissociation of cytochalasin B were 3.7 μM/s and 7.5 s−1, respectively. Cytochalasin B produced a use-dependent inhibition of hKv1.5 current that was consistent with the slow recovery from inactivation in the presence of the drug. Cytochalasin B (10 μM) also inhibited an ultrarapid delayed rectifier K+ current ( IK,ur) in human atrial myocytes. These results indicate that cytochalasin B primarily blocks activated hKv1.5 channels and endogenous IK,ur in a cytoskeleton-independent manner as an open-channel blocker.

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Charybdotoxin selectively blocks small Ca-activated K channels in Aplysia neurons.

The Journal of General Physiology ◽

10.1085/jgp.90.1.27 ◽

1987 ◽

Vol 90 (1) ◽

pp. 27-47 ◽

Cited By ~ 85

Author(s):

A Hermann ◽

C Erxleben

Keyword(s):

Single Channel ◽

Delayed Rectifier ◽

Pacemaker Activity ◽

Dependent Manner ◽

Open Probability ◽

Apparent Dissociation Constant ◽

External Application ◽

K Channels ◽

Voltage Dependent ◽

K Current

The action of charybdotoxin (ChTX), a peptide component isolated from the venom of the scorpion Leiurus quinquestriatus, was investigated on membrane currents of identified neurons from the marine mollusk, Aplysia californica. Macroscopic current recordings showed that the external application of ChTX blocks the Ca-activated K current in a dose- and voltage-dependent manner. The apparent dissociation constant is 30 nM at V = -30 mV and increases e-fold for a +50- to +70-mV change in membrane potential, which indicates that the toxin molecule is sensitive to approximately 35% of the transmembrane electric field. The toxin is bound to the receptor with a 1:1 stoichiometry and its effect is reversible after washout. The toxin also suppresses the membrane leakage conductance and a resting K conductance activated by internal Ca ions. The toxin has no significant effect on the inward Na or Ca currents, the transient K current, or the delayed rectifier K current. Records from Ca-activated K channels revealed a single channel conductance of 35 +/- 5 pS at V = 0 mV in asymmetrical K solution. The channel open probability increased with the internal Ca concentration and with membrane voltage. The K channels were blocked by submillimolar concentrations of tetraethylammonium ions and by nanomolar concentrations of ChTX, but were not blocked by 4-aminopyridine if applied externally on outside-out patches. From the effects of ChTX on K current and on bursting pacemaker activity, it is concluded that the termination of bursts is in part controlled by a Ca-activated K conductance.

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

Cellular Physiology and Biochemistry ◽

10.1159/000475436 ◽

2017 ◽

Vol 41 (5) ◽

pp. 2053-2066 ◽

Cited By ~ 4

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.

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