Activation of voltage‐gated sodium current and inhibition of <i>erg</i>‐mediated potassium current caused by telmisartan, an antagonist of angiotensin II type‐1 receptor, in HL‐1 atrial cardiomyocytes

Chang, Wei Ting; Wu, Sheng‐Nan

doi:10.1111/1440-1681.12943

Cited by 19 publications

(26 citation statements)

References 52 publications

(139 reference statements)

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“…Furthermore, in the continued presence of SSM (3 µM), the subsequent addition of either tefluthrin (10 µM) or telmisartan (10 µM) was effective in reversing the SSM-induced inhibition of peak I Na . [20,[30][31][32][33]. As shown in Figure 2, SSM or SesA, at a concentration of 3 μM, produced inhibitory effects on the peak amplitude of INa.…”

Section: Comparison Between Effects Of Ssm Sesa Ssm Plus Tefluthrinmentioning

confidence: 78%

“…In another experiment, we tested the effects of SSM, sesamolin (SesA), SSM plus tefluthrin, and SSM plus telmisartan on the peak amplitude of I Na responding to rapid membrane depolarization to −10 mV from a holding potential of −80 mV. Tefluthrin, a type I pyrethroid insecticide, and telmisartan, a blocker of angiotensin II receptors, were previously demonstrated to activate I Na directly and effectively [ 20 , 30 , 31 , 32 , 33 ]. As shown in Figure 2 , SSM or SesA, at a concentration of 3 μM, produced inhibitory effects on the peak amplitude of I Na .…”

Section: Resultsmentioning

confidence: 99%

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Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

et al. 2020

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Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na+ currents (INa), erg-mediated K+ currents (IK(erg)), M-type K+ currents (IK(M)), delayed-rectifier K+ currents (IK(DR)) and hyperpolarization-activated cation currents (Ih) identified from pituitary tumor (GH3) cells. The exposure to SSM or SesA depressed the transient and late components of INa with different potencies. The IC50 value of SSM needed to lessen the peak or sustained INa was calculated to be 7.2 or 0.6 μM, while that of SesA was 9.8 or 2.5 μM, respectively. The dissociation constant of SSM-perturbed inhibition on INa, based on the first-order reaction scheme, was measured to be 0.93 μM, a value very similar to the IC50 for its depressant action on sustained INa. The addition of SSM was also effective at suppressing the amplitude of resurgent INa. The addition of SSM could concentration-dependently inhibit the IK(M) amplitude with an IC50 value of 4.8 μM. SSM at a concentration of 30 μM could suppress the amplitude of IK(erg), while at 10 μM, it mildly decreased the IK(DR) amplitude. However, the addition of neither SSM (10 μM) nor SesA (10 μM) altered the amplitude or kinetics of Ih in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for SCN8A-encoded (or NaV1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of NaV channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak INa, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of NaV channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as INa and IK(M), and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.

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Section: Comparison Between Effects Of Ssm Sesa Ssm Plus Tefluthrinmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

et al. 2020

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“…It has been shown that GL might prevent cardiac damage by decreasing the oxidative stress associated with myocardial injury [8]. We therefore also tested whether GTs exerts any effects on I h present in HL-1 heart cells [44,45]. These experiments were conducted in cells bathed in Ca 2+ -free Tyrode’s solution, and the downsloping ramp pulse from −52 to −162 mV with a duration of 1 sec was applied to evoke I h in these cells.…”

Section: Resultsmentioning

confidence: 99%

Evidence for Effective Inhibitory Actions on Hyperpolarization-Activated Cation Current Caused by Ganoderma Triterpenoids, the Main Active Constitutents of Ganoderma Spores

Chang

Gao

et al. 2019

Molecules

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The triterpenoid fraction of Ganoderma (Ganoderma triterpenoids, GTs) has been increasingly demonstrated to provide effective antioxidant, neuroprotective or cardioprotective activities. However, whether GTs is capable of perturbing the transmembrane ionic currents existing in electrically excitable cells is not thoroughly investigated. In this study, an attempt was made to study whether GTs could modify hyperpolarization-activated cation currents (Ih) in pituitary tumor (GH3) cells and in HL-1 atrial cardiomyocytes. In whole-cell current recordings, the addition of GTs produced a dose-dependent reduction in the amplitude of Ih in GH3 cells with an IC50 value of 11.7 µg/mL, in combination with a lengthening in activation time constant of the current. GTs (10 µg/mL) also caused a conceivable shift in the steady-state activation curve of Ih along the voltage axis to a more negative potential by approximately 11 mV. Subsequent addition of neither 8-cyclopentyl-1,3-dipropylxanthine nor 8-(p-sulfophenyl)theophylline, still in the presence of GTs, could attenuate GTs-mediated inhibition of Ih. In current-clamp voltage recordings, GTs diminished the firing frequency of spontaneous action potentials in GH3 cells, and it also decreased the amplitude of sag potential in response to hyperpolarizing current stimuli. In murine HL-1 cardiomyocytes, the GTs addition also suppressed the amplitude of Ih effectively. In DPCPX (1 µM)-treated HL-1 cells, the inhibitory effect of GTs on Ih remained efficacious. Collectively, the inhibition of Ih caused by GTs is independent of its possible binding to adenosine receptors and it might have profound influence in electrical behaviors of different types of electrically excitable cells (e.g., pituitary and heart cells) if similar in vitro or in vivo findings occur.

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“…The I K(erg) has been previously reported to be linked to the regulation of HIF (17). We next tested whether roxadustat can modify another type of K + current (i.e., I K(erg) ) which is inherently present in GH 3 cells [40,41,42]. These experiments were conducted in cells bathed in high-K + , Ca 2+ -free solution, and we filled the recording pipette with K + -containing solution.…”

Section: Resultsmentioning

confidence: 99%

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

Chang

Gao

et al. 2019

IJMS

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Roxadustat (FG-4592), an analog of 2-oxoglutarate, is an orally-administered, heterocyclic small molecule known to be an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. However, none of the studies have thus far thoroughly investigated its possible perturbations on membrane ion currents in endocrine or heart cells. In our studies, the whole-cell current recordings of the patch-clamp technique showed that the presence of roxadustat effectively and differentially suppressed the peak and late components of IK(DR) amplitude in response to membrane depolarization in pituitary tumor (GH3) cells with an IC50 value of 5.71 and 1.32 μM, respectively. The current inactivation of IK(DR) elicited by 10-sec membrane depolarization became raised in the presence of roxadustatt. When cells were exposed to either CoCl2 or deferoxamine (DFO), the IK(DR) elicited by membrane depolarization was not modified; however, nonactin, a K+-selective ionophore, in continued presence of roxadustat, attenuated roxadustat-mediated inhibition of the amplitude. The steady-state inactivation of IK(DR) could be constructed in the presence of roxadustat. Recovery of IK(DR) block by roxadustat (3 and 10 μM) could be fitted by a single exponential with 382 and 523 msec, respectively. The roxadustat addition slightly suppressed erg-mediated K+ or hyperpolarization-activated cation currents. This drug also decreased the peak amplitude of voltage-gated Na+ current with a slowing in inactivation rate of the current. Likewise, in H9c2 heart-derived cells, the addition of roxadustat suppressed IK(DR) amplitude in combination with the shortening in inactivation time course of the current. In high glucose-treated H9c2 cells, roxadustat-mediated inhibition of IK(DR) remained unchanged. Collectively, despite its suppression of HIF prolyl hydroxylase, inhibitory actions of roxadustat on different types of ionic currents possibly in a non-genomic fashion might provide another yet unidentified mechanism through which cellular functions are seriously perturbed, if similar findings occur in vivo.

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Activation of voltage‐gated sodium current and inhibition of erg‐mediated potassium current caused by telmisartan, an antagonist of angiotensin II type‐1 receptor, in HL‐1 atrial cardiomyocytes

Cited by 19 publications

References 52 publications

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

Evidence for Effective Inhibitory Actions on Hyperpolarization-Activated Cation Current Caused by Ganoderma Triterpenoids, the Main Active Constitutents of Ganoderma Spores

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

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