Background: For drug development, ion-channel modulating drugs are clinically promising. However, confirmation of an expected drug effect in human subjects may not be straightforward. Quantitative in vivo assessment system of ion channel functions is useful. Threshold tracking (QTRAC) has elucidated dysfunction of ion channels in various neurological diseases. Multiple ion channels regulate axonal excitability, such as slow K⁺ channels, persistent Na⁺ channels (INap), and HCN channels (Ih).

Objective: To assess the effects of slow K⁺ channel inhibition on other ion channels in vivo to maintain axonal excitability.

Methods: BaCl2 (20 mg/kg) was given i.p. to seven normal, 6-week-old, male mice. Sensory nerve action potential was recorded at the tail. Axonal excitability was recorded by threshold tracking (QtracW, Digitimer, UK) before and 30 min post-infusion. Mathematical modeling assessed the interval changes of the ion channel functions.

Results: After the injection, there were the following interval changes: (1) increased supernormality (P = 0.001) and decreased late subexcitability (P = 0.009) (recovery cycle), (2) increased threshold by long hyperpolarization (threshold electrotonus (P = 0.01)). Modeling showed the following interval changes: 55% decrease of INap, 82% decrease of nodal slow K⁺ current, 56% decrease of Ih.

Conclusions: (1) Inhibition of slow K⁺ current was counterbalanced by reduction of INap and Ih to tightly regulate axonal excitability. (2) In vivo axonal excitability testing can be a useful biomarker to monitor ion channel functions by ion channel modulating drugs.