Large conductance voltage‐ and Ca 2+ ‐activated K + channels mediate the 17β‐estradiol inhibitory effects on human urinary bladder smooth muscle cell excitability and contractility

Abstract

Estrogens are critical regulators of smooth muscle function, including urinary bladder smooth muscle (UBSM) contractility. However, the mechanism underlying estrogen's regulatory role in UBSM has not been fully elucidated. Here, we explored whether 17β-estradiol,a physiologically active estrogen, activates large conductance voltage- and Ca2+-activated K+ (BK) channels in human UBSM. We obtained UBSM samples from 18 patients to examine the physiological role of 17β-estradiol in regulating UBSM function. 17β-estradiol inhibited UBSM spontaneous phasic contractions in a concentration-dependent manner (100 nM-1 µM). These 17β-estradiol inhibitory effects were prevented in the presence of paxilline (1 µM), a selective inhibitor of BK channels. 17β-estradiol (100 nM) also inhibited nerved-evoked contractions of UBSM isolated strips. Perforated patch-clamp data showed that 17β-estradiol increased the depolarization-induced whole cell outward currents, effects that were blocked by paxilline (1 µM). 17β-estradiol (100 nM) also increased the frequency of the transient BK currents in human UBSM cells. 17β-estradiol (100 nM) increased the BK channel open probability in inside-out excised patches from UBSM cells, supporting the concept that 17β-estradiol activates BK channels directly. Our results suggest that 17β-estradiol has a direct stimulatory effect on BK channel activity, thus decreasing the human UBSM excitability and contractility. Supported by NIH R01DK04284 to G.V. Petkov & NIH F31DK104528 to A. Provence.