Li Yan, Bai Jin, Yang Yi-Hua, Hoshi Naoto, Chen Dong-Bao
Department of Obstetrics & Gynecology, University of California, Irvine, CA 92697, USA.
Department of Pharmacology, University of California, Irvine, CA 92697, USA.
Antioxidants (Basel). 2020 Nov 13;9(11):1127. doi: 10.3390/antiox9111127.
Opening of large conductance calcium-activated and voltage-dependent potassium (BK) 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 (HS) has been recently identified as a new UA vasodilator, yet the mechanism underlying HS-induced UA dilation is unknown. Here, we tested whether HS activated BK channels in human UA smooth muscle cells (hUASMC) to mediate UA relaxation. Multiple BK 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 BK blockers iberiotoxin (IBTX) or tetraethylammonium, showing specific BK activity in hUASMC. HS dose (NaHS, 1-1000 µM)-dependently potentiated BK currents and open probability. Co-incubation with a Ca 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 HS-potentiated BK currents and open probability. NaHS also dose-dependently relaxed phenylephrine pre-constricted freshly prepared human UA rings, which was inhibited by IBTX. Thus, HS stimulated human UA relaxation at least partially via activating SM BK channels independent of extracellular Ca.
大电导钙激活和电压依赖性钾（BK）通道的开放使平滑肌（SM）质膜超极化，从而引起血管舒张，这是介导妊娠子宫动脉（UA）舒张的关键机制。硫化氢（HS）最近被确定为一种新的UA血管舒张剂，但其诱导UA舒张的机制尚不清楚。在这里，我们测试了HS是否激活人UA平滑肌细胞（hUASMC）中的BK通道以介导UA舒张。在体外人UA和体外hUASMC中发现了多个BK亚基，并且高β1和γ1蛋白定位于人UA的SM细胞中。通过全细胞和单通道膜片钳记录的基线外向电流被特异性BK阻滞剂iberiotoxin（IBTX）或四乙铵显著抑制，表明hUASMC中存在特异性BK活性。HS剂量（NaHS，1 - 1000 μM）依赖性地增强BK电流和开放概率。与钙阻滞剂硝苯地平（5 μM）或螯合剂（乙二醇双（β-氨基乙醚）-N，N，N'，N'-四乙酸（EGTA），5 mM）共同孵育不会改变HS增强的BK电流和开放概率。NaHS还剂量依赖性地使去氧肾上腺素预收缩的新鲜制备的人UA环舒张，这被IBTX抑制。因此，HS至少部分地通过激活SM BK通道刺激人UA舒张，且不依赖于细胞外钙。
