Abstract
Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na + (Na V ) current (I Na ) accompanied by the increased time constant of I Na inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of I Na in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented to predict changes in membrane potentials (V) as a function of maximal Na + (GN a ), K + conductance (G K ), or both. As inactivation time course of I Na was increased, the bifurcation point of V versus G Na became lower, and the range between subcritical and supercritical values at the bifurcation of V versus G K correspondingly became larger. During a slowing in I Na inactivation, the critical boundary between G Na and G K was shifted towards the left. Simulation studies demonstrated that progressive slowing in the inactivation time course of I Na resulted in unanticipated increase of neuronal excitability by mimicking the effect of Tel in neuronal cells. Collectively, Tel can directly interact with the Na V channel to increase peak I Na as well as to slow I Na inactivation. It is thus highly likely that the effects of Tel or its structurally similar drugs could be another intriguing mechanism underlying their pharmacological actions in neurons or neuroendocrine cells occurring in vivo.
| Original language | English |
|---|---|
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Chinese Journal of Physiology |
| Volume | 61 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Physiology (medical)
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Stimulatory action of telmisartan, an antagonist of angiotensin II receptor, on voltage-gated Na + current : Experimental and theoretical studies. / Chang, Tzu Tung; Yang, Chia Jung; Lee, Yu Chi; Wu, Sheng-Nan.
In: Chinese Journal of Physiology, Vol. 61, No. 1, 01.01.2018, p. 1-13.Research output: Contribution to journal › Article
TY - JOUR
T1 - Stimulatory action of telmisartan, an antagonist of angiotensin II receptor, on voltage-gated Na + current
T2 - Experimental and theoretical studies
AU - Chang, Tzu Tung
AU - Yang, Chia Jung
AU - Lee, Yu Chi
AU - Wu, Sheng-Nan
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na + (Na V ) current (I Na ) accompanied by the increased time constant of I Na inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of I Na in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented to predict changes in membrane potentials (V) as a function of maximal Na + (GN a ), K + conductance (G K ), or both. As inactivation time course of I Na was increased, the bifurcation point of V versus G Na became lower, and the range between subcritical and supercritical values at the bifurcation of V versus G K correspondingly became larger. During a slowing in I Na inactivation, the critical boundary between G Na and G K was shifted towards the left. Simulation studies demonstrated that progressive slowing in the inactivation time course of I Na resulted in unanticipated increase of neuronal excitability by mimicking the effect of Tel in neuronal cells. Collectively, Tel can directly interact with the Na V channel to increase peak I Na as well as to slow I Na inactivation. It is thus highly likely that the effects of Tel or its structurally similar drugs could be another intriguing mechanism underlying their pharmacological actions in neurons or neuroendocrine cells occurring in vivo.
AB - Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na + (Na V ) current (I Na ) accompanied by the increased time constant of I Na inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of I Na in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented to predict changes in membrane potentials (V) as a function of maximal Na + (GN a ), K + conductance (G K ), or both. As inactivation time course of I Na was increased, the bifurcation point of V versus G Na became lower, and the range between subcritical and supercritical values at the bifurcation of V versus G K correspondingly became larger. During a slowing in I Na inactivation, the critical boundary between G Na and G K was shifted towards the left. Simulation studies demonstrated that progressive slowing in the inactivation time course of I Na resulted in unanticipated increase of neuronal excitability by mimicking the effect of Tel in neuronal cells. Collectively, Tel can directly interact with the Na V channel to increase peak I Na as well as to slow I Na inactivation. It is thus highly likely that the effects of Tel or its structurally similar drugs could be another intriguing mechanism underlying their pharmacological actions in neurons or neuroendocrine cells occurring in vivo.
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U2 - 10.4077/CJP.2018.BAG516
DO - 10.4077/CJP.2018.BAG516
M3 - Article
VL - 61
SP - 1
EP - 13
JO - Chinese Journal of Physiology
JF - Chinese Journal of Physiology
SN - 0304-4920
IS - 1
ER -