Evidence for direct stimulation by estrogen receptor agonists (diarylpropionitrile and propylpyrazole-triol) of the large-conductance Ca2+-activated K+ channel in human cardiac fibroblasts.

The agonists selective for estrogen receptor (ER)-α propylpyrazole-triol, PPT) and ER-β diarylpropionitrile, DPN) can bind to the ER-α and ER-β receptors which may be localized to the plasma membrane. It is unclear whether DPN or PPT influence ion channels linked to non-genomic mechanism. We tested the hypothesis that DPN or PPT directly stimulates the large-conductance Ca2+-activated K+ (BKCa) channels in human cardiac fibroblasts (HCFs). In whole-cell configuration, depolarizing pulses evoked K+ outward currents in an outward rectification in HCFs, the amplitude of which was increased by DPN or PPT. Applied to the intracellular surface of excised patches, PPT or DPN enhanced BKCa-channel activity with no change in single-channel conductance. DPN and PPT increased BKCa-channel activity with an EC50 value of 2.3 and 2.6 µM, respectively. The mean closed time of these channels measured during the exposure to DPN or PPT was reduced with no change in the gating charge of the channels. Intracellular Ca2+ was not altered in the presence of these two compounds. RT-PCR study also revealed that no change in the transcriptional level of the BKCa channel α-subunit was observed in treatment with DPN or PPT. Our data suggest that PPT- and DPN-mediated activation of BKCa channels reveal novel pharmacological properties attributable to the activity of these channels. [ABSTRACT FROM AUTHOR]