The effects of cilostazol, a dual inhibitor of type 3 phosphodiesterase and adenosine uptake, on ion currents were investigated in pituitary GH₃ cells and pheochromocytoma PC12 cells. In whole-cell configuration, cilostazol (10 µM) reversibly increased the amplitude of Ca²⁺-activated K⁺ current (I_K(Ca)). Cilostazol-induced increase in I_K(Ca) was suppressed by paxilline (1 µM), but not by glibenclamide (10 µM), dequalinium dichloride (10 µM), or -bungarotoxin (200 nM). Pretreatment of adenosine deaminase (1 U/ml) or ,-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 BK_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.