Inhibitory action of ICI-182,780, an estrogen receptor antagonist, on BKCa channel activity in cultured endothelial cells of human coronary artery

ICI-182,780 is known to be a selective inhibitor of the intracellular estrogen receptors. The effect of ICI-182,780 on ion currents was studied in cultured endothelial cells of human coronary artery. In whole-cell current recordings, ICI-182,780 reversibly decreased the amplitude of K+ outward currents. The decrease in outward current caused by ICI-182,780 could be counteracted by further application of magnolol or nordihydroguaiaretic acid, yet not by 17beta-estradiol. Under current-clamp condition, ICI-182,780 (3 muM) depolarized the membrane potentials of the cells, and magnolol (10 muM) or nordihydroguaiaretic acid (10 muM) reversed ICI-182,780-induced depolarization. In inside-out patches, ICI-182,780 added to the bath did not alter single-channel conductance of large-conductance Ca2+-activated K+ channels (BKCa channels), but decreased their open probability. ICT-182,780 reduced channel activity in a concentration-dependent manner with an IC50 value of 3 muM. After BKCa channel activity was suppressed by 2-methoxyestradiol (3 muM), subsequent application of ICT-182,780 (3 muM) did not further reduce the channel activity. The application of ICI-182,780 shifted the activation curve of BKCa channels to positive potentials. Its decrease in the open probability primarily involved a reduction in channel open duration. ICI-182,780 also suppressed the proliferation of these endothelial cells with an IC50 value of 2 muM. However, in coronary smooth muscle cells, a bell-shaped concentration-response curve for the ICI-182,780 effect on BKCa channel activity was observed. This study provides evidence that ICI-182,780 can inhibit BKCa channels in vascular endothelial cells in a mechanism unlikely to be linked to its anti-estrogen activity. The inhibitory effects on these channels may partly contribute to the underlying mechanisms by which ICI-182,780 affects endothelial function. (C) 2003 Elsevier Inc. All rights reserved.