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Cilostazol, an Inhibitor of Type 3 Phosphodiesterase, Stimulates Large-Conductance, Calcium-Activated Potassium Channels in Pituitary GH₃ Cells and Pheochromocytoma PC12 Cells

Institute of Basic Medical Sciences (S.-N.W., M.-H.H.), National Cheng-Kung University Medical College, 701 Tainan, Taiwan; and Department of Surgery (S.-.I.L.), Kaohsiung Veterans General Hospital, 813 Kaohsiung City, Taiwan

Address all correspondence and requests for reprints to: Dr. Sheng-Nan Wu, Institute of Basic Medical Sciences, National Cheng-Kung University Medical College, No. 1, University Road, 701 Tainan, Taiwan. E-mail: snwu{at}mail.ncku.edu.tw.

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 glibenclamide (10 µM), dequalinium dichloride (10 µM), or ß-bungarotoxin (200 nM). Pretreatment of adenosine deaminase (1 U/ml) or ,ß-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.

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