Enhanced activity of Ca²⁺-activated K⁺ channels by 1-[2-hydroxy-3-propyl-4-[(1H-tetrazol-5-yl) butoxyl]phenyl] ethanone (LY-171883) in neuroendocrine and neuroblastoma cell lines

The effects of LY-171883, an orally active leukotriene antagonist, on membrane currents were examined in pituitary GH₃ and in neuroblastoma IMR-32 cells. In GH₃ cells, LY-171883 (1-300 μM) reversibly increased the amplitude of Ca²⁺-activated K⁺ current in a concentration-dependent manner with an EC₅₀ value of 15 μM. In excised inside-out patches recorded from GH₃ cells, the application of LY-171883 into cytosolic face did not modify single channel conductance of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels; however, it did increase the channel activity. The LY-171883-stimulated activity of BK_Ca channels is dependent on membrane potential, and results mainly from an increase in mean open time and a decrease in mean closed time. However, REV-5901 (30 μM) suppressed the activity of BK_Ca channels and MK-571 (30 μM) did not have any effect on it. Under the current-clamp condition, LY-171883 (30 μM) caused membrane hyperpolarization as well as decreased the firing rate of action potentials in GH₃ cells. In neuroblastoma IMR-32 cells, the application of LY-171883 (30 μM) also stimulated BK_Ca channel activity in a voltage-dependent manner. However, neither clofibrate (30 μM) nor leukotriene D₄ (10 μM) affected the channel activity in IMR-32 cells. Troglitazone (30 μM) decreased the channel activity, but ciglitazone (30 μM) enhanced it. This study clearly demonstrates that LY-171883 stimulates the activity of BK_Ca channels in a manner unlikely to be linked to its blockade of leukotriene receptors or stimulation of peroxisome proliferator-activated receptors. The stimulatory effects on these channels may, at least in part, contribute to the underlying cellular mechanisms by which LY-171883 affects neuronal or neuroendocrine function.