Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na^+ Current: Experimental and Theoretical Studies

Tzu-Tung Chang ； Chia-Jung Yang ； Yu-Chi Lee ； Sheng-Nan Wu

《The Chinese Journal of Physiology》 61卷1期 (2018/02) Pp. 1-13

https://doi.org/10.4077/CJP.2018.BAG516

摘要

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 I_(Na) 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^+ (G_(Na)), 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.

關鍵字

bifurcation analysis ； Hodgkin-Huxley kinetics ； potassium current ； sodium current ； Telmisartan

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