Stimulatory action of telmisartan, an antagonist of angiotensin II receptor, on voltage-gated Na ⁺ current: Experimental and theoretical studies

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.