Cilostazol, an Inhibitor of Type 3 Phosphodiesterase, Stimulates Large-Conductance, Calcium-Activated Potassium Channels in Pituitary GH ₃ Cells and Pheochromocytoma PC12 Cells

The effects of cilostazol, a dual inhibitor of type 3 phosphodiesterase and adenosine uptake, on ion currents were investigated in pituitary GH ₃ cells and pheochromocytoma PC12 cells. In whole-cell configuration, cilostazol (10 μM) reversibly increased the amplitude of Ca ²⁺-activated K⁺ current [I_K(Ca)]-Cilostazol- induced increase in I_K(Ca) was suppressed by paxilline (1 μM) but not glibenclamide (10 μM), dequalinium dichloride (10 μM), or β-bungarotoxin (200 nM). Pretreatment of adenosine deaminase (1 U/ml) or α,β-methylene-ADP (100 μM) for 5 h did not alter the magnitude of cilostazol-stimulated I_K(Ca). Cilostazol (30 μM) slightly suppressed voltage-dependent L-type Ca²⁺ current. In inside-out configuration, bath application of cilostazol (10 μM) into intracellular surface caused no change in single-channel conductance; however, it did increase the activity of large-conductance Ca²⁺-activated K ⁺ (BK_ca) channels. Cilostazol enhanced the channel activity in a concentration-dependent manner with an EC₅₀ value of 3.5 μM. Cilostazol (10 μM) shifted the activation curve of BK _Ca channels to less positive membrane potentials. Changes in the kinetic behavior of BK_Ca channels caused by cilostazol were related to an increase in mean open time and a decrease in mean closed time. Under current-clamp configuration, cilostazol decreased the firing frequency of action potentials. In pheochromocytoma PC12 cells, cilostazol (10 μM) also increased I_K(Ca) channel activity. Cilostazol-mediated stimulation of I_K(Ca) appeared to be not linked to its inhibition of adenosine uptake or phosphodiesterase. The channel-stimulating properties of cilostazol may, at least in part, contribute to the underlying mechanisms by which it affects neuroendocrine function.