Hydrogen Sulfide Relaxes Human Uterine Artery via Activating Smooth Muscle BKCa Channels

Abstract

Opening of large conductance calcium-activated and voltage-dependent potassium (BKCa) channels hyperpolarizes plasma membranes of smooth muscle (SM) to cause vasodilation, underling a key mechanism for mediating uterine artery (UA) dilation in pregnancy. Hydrogen sulfide (H2S) has been recently identified as a new UA vasodilator, yet the mechanism underlying H2S-induced UA dilation is unknown. Here, we tested whether H2S activated BKCa channels in human UA smooth muscle cells (hUASMC) to mediate UA relaxation. Multiple BKCa subunits were found in human UA in vitro and hUASMC in vitro, and high β1 and γ1 proteins were localized in SM cells in human UA. Baseline outward currents, recorded by whole-cell and single-channel patch clamps, were significantly inhibited by specific BKCa blockers iberiotoxin (IBTX) or tetraethylammonium, showing specific BKCa activity in hUASMC. H2S dose (NaHS, 1–1000 µM)-dependently potentiated BKCa currents and open probability. Co-incubation with a Ca2+ blocker nifedipine (5 µM) or a chelator (ethylene glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM) did not alter H2S-potentiated BKCa currents and open probability. NaHS also dose-dependently relaxed phenylephrine pre-constricted freshly prepared human UA rings, which was inhibited by IBTX. Thus, H2S stimulated human UA relaxation at least partially via activating SM BKCa channels independent of extracellular Ca2+.

Targeting Mitochondrial Large-Conductance Calcium-Activated Potassium Channel by Hydrogen Sulfide via Heme-Binding Site

“…Published studies showed that ion channels undergo direct regulation by H 2 S. Differing effects of H 2 S were shown for BK Ca channels. H 2 S potentiated BK Ca currents in human uterine artery smooth muscle cells (Li et al, 2020). H 2 S also increased the activity of BK Ca channels in rat pituitary tumor cells, and this effect was linked to its action on sulfhydryl groups of the channel protein (Sitdikova et al, 2010).…”

“…Therefore, whether and how mitoBK Ca activity is modulated by H 2 S remains an intriguing issue. Previous research on the impact of H 2 S on the activity of BK Ca channels is ambiguous, thus showing either channel activation (Jackson-Weaver et al, 2013, Li et al, 2020 or inhibition (Fernandes et al, 2015, Li et al, 2010, Telezhkin et al, 2010. Therefore, further studies are needed in this field.…”

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

“…Correspondingly, stimulation of H 2 S production with PLP enzyme significantly elevates H 2 S levels and improves vascular relaxation together with oxidative and nitrosative statuses in adult rats [ 95 ]. Similarly, treatment with NaHS has also been shown to induce the relaxation of human uterine artery, partly by triggering the large conductance calcium-activated and voltage-dependent K + (BK) channels [ 96 ]. An isothiocyanate vasodilating compound, sulforaphane, has also been reported to induce its effect by activating K ATP and BK channels in a CBS/CSE/H 2 S-dependent manner [ 97 ].…”

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

“…The γ1 subunit also increases BK Ca channel activation and promotes vasodilation of uterine arteries. Notably, the BK Ca channel mediates uterine vasodilation induced by NO, H 2 S, calcitonin gene-related peptide and adrenomedullin [55,56,210,214,215]. However, the vasodilation of human placenta vessels induced by H 2 S is mediated by NO and ATP-sensitive K + (K ATP ) channels [133].…”