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 GH(3) and in neuroblastoma IMR-32 cells. In GH(3) cells, LY-171883 (1-300 muM) reversibly increased the amplitude of Ca2+-activated K+ current in a concentration-dependent manner with ail EC50 value of 15 muM. In excised indside-out patches recorded from CH3 cells, the application of LY-171883 into cytosolic face did not modify single channel conductance of large-conductance Ca2+-activated K+ (BKCa) channels; however, it did increase the channel activity. The LY-171883-stimulated activity of BKCa 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 muM) suppressed the activity of BKCa channels and MK-571 (30 muM) did not have any effect on it. Under the current-clamp condition, LY-171883 (30 muM) caused membrane hyperpolarization as well as decreased the firing rate of action potentials in GH(3) cells. In neuroblastoma IMR-32 cells, the application of LY-171883 (30 muM) also stimulated BKCa channel activity in a voltage-dependent manner. However, neither clofibrate (30 muM) nor leukotriene D-4 (10 muM) affected the channel activity in IMR-32 cells. Troglitazone (30 muM) decreased the channel activity, but ciglitazone (30 muM) enhanced it. This study clearly demonstrates that LY-171883 stimulates the activity of BKCa 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. (C) 2002 Wiley-Liss, Inc.