Effects of Ranolazine, a Novel Anti-anginal Drug, on Ion Currents and Membrane Potential in Pituitary Tumor GH₃ Cells and NG108-15 Neuronal Cells

Abstract

Ranolazine, a piperazine derivative, is currently approved for the treatment of chronic angina. However, its ionic mechanisms in other types of cells remain unclear, although it is thought to be a selective blocker of late Na⁺ current. This study was conducted to evaluate the possible effects of ranolazine on Na⁺ current (I_Na), L-type Ca²⁺ current (I_Ca,L), inwardly rectifying K⁺ current (I_K(IR)), delayed-rectifier K⁺ current (I_K(DR)), and Ca²⁺-activated K⁺ current (I_K(Ca)) in pituitary tumor (GH₃) cells. Ranolazine depressed the transient and late components of I_Na with different potencies. This drug exerted an inhibitory effect on I_K(IR) with an IC₅₀ value of 0.92 μM, while it slightly inhibited I_K(DR) and I_K(Ca). It shifted the steady-state activation curve of I_K(IR) to more positive potentials with no change in the gating charge of the channel. Ranolazine (30 μM) also reduced the activity of large-conductance Ca²⁺-activated K⁺ channels in HEK293T cells expressing α-hSlo. Under current-clamp conditions, low concentrations (e.g., 1 μM) of ranolazine increased the firing of action potentials, while at high concentrations (≥10 μM), it diminished the firing discharge. The exposure to ranolazine also suppressed I_Na and I_K(IR) effectively in NG108-15 neuronal cells. Our study provides evidence that ranolazine could block multiple ion currents such as I_Na and I_K(IR) and suggests that these actions may contribute to some of the functional activities of neurons and endocrine or neuroendocrine cells in vivo.