Modification of multiple ion channel functions in vivo by pharmacological inhibition: observation by threshold tracking and modeling

Abstract

Maintenance of axonal excitability relies on complex balance by multiple ion currents, but its evaluation is limited by in vitro single channel neurophysiological study on overall behavior. We sought to evaluate behaviors of multiple ion currents by pharmacological blockade. The threshold tracking technique was used to measure multiple excitability indices on tail sensory nerve of normal male mice before and after administration of either BaCl₂ or ivabradine. Mathematical modeling was used to identify the interval changes of the channel parameters. After administration of BaCl₂ and ivabradine, the following changes were present: greater threshold changes of both depolarizing and hyperpolarizing threshold electrotonus by both; additionally, reduced S2 accommodation, reduced late subexcitability and increased superexcitability by BaCl₂, increased S3 accommodation by ivabradine. Mathematical modelling implied reduction of slow K⁺ conductance, along with reduction of H conductance (Ih) by BaCl₂; and reduction of Ih while augmentation of K⁺ conductances by ivabradine. Pharmacological blockade of a selective ion channel may be compensated by other ion channels. Unintended effects by ion channel modification could be caused by secondary current alteration by multiple ion channels. J. Med. Invest. 64: 30-38, February, 2017