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

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-CaL), inwardly rectifying K+ Current delayed-rectifier K+ current (I-K(DR)), and Ca2+-activated K Current (I-K(Ca)) in pituitary tumor (GH(3)) 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 ail IC50 value of 0.92 mu M, 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 mu M) also reduced the activity of large-conductance Ca2+-activated K+ channels in HEK293T cells expressing alpha-hSlo. Under current-clamp conditions, low concentrations (e.g., I IN) of ranolazine increased the firing of action potentials, while at high concentrations (>= 10 mu m), 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.