人子宫肌细胞中β3-肾上腺素能受体与大电导钙激活钾通道的功能偶联
Functional coupling of beta3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes.
作者信息
Doheny Helen C, Lynch Caoimhe M, Smith Terry J, Morrison John J
机构信息
Department of Obstetrics and Gynecology, National University of Ireland Galway, Clinical Science Institute, University College Hospital Galway, Galway, Ireland.
出版信息
J Clin Endocrinol Metab. 2005 Oct;90(10):5786-96. doi: 10.1210/jc.2005-0574. Epub 2005 Jul 12.
CONTEXT
Beta3-adrenoreceptor modulation in human myometrium during pregnancy is linked functionally to myometrial inhibition. Maxi-K+ channels (BK(Ca)) play a significant role in modulating cell membrane potential and excitability.
OBJECTIVE
This study was designed to investigate the potential involvement of BK(Ca) channel function in the response of human myometrium to beta3-adrenoceptor activation.
DESIGN
Single and whole-cell electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of BRL37344, a specific beta3-adrenoreceptor agonist. The in vitro effects of BRL37344 on isolated myometrial contractions, in the presence and absence of the specific BK(Ca) channel blocker, iberiotoxin (IbTX), were investigated.
SETTING
The study was carried out at the Clinical Science Institute.
PATIENTS OR OTHER PARTICIPANTS
Myometrial biopsies were obtained at elective cesarean delivery.
INTERVENTION
No intervention was applied.
MAIN OUTCOME MEASURES
Open state probability of single channel recordings, whole cell currents, and myometrial contractile activity were measured.
RESULTS
Single-channel recordings identified the BK(Ca) channel as a target of BRL37344. BRL37344 significantly increased the open state probability of this channel in a concentration-dependent manner (control 0.031 +/- 0.004; 50 microM BRL37344 0.073 +/- 0.005 (P < 0.001); and 100 microM BRL37344 0.101 +/- 0.005 (P < 0.001). This effect was completely blocked after preincubation of the cells with 1 microM bupranolol, a nonspecific beta-adrenoreceptor blocker, or 100 nM SR59230a, a specific beta3-adrenoreceptor antagonist. In addition, BRL37344 increased whole-cell currents over a range of membrane potentials, and this effect was reversed by 100 nM IbTX. In vitro isometric tension studies demonstrated that BRL37344 exerted a significant concentration-dependent relaxant effect on human myometrial tissue (P < 0.05), and preincubation of these strips with IbTX attenuated this effect on both spontaneous and oxytocin-induced contractions (44.44 and 57.84% at 10(-5) M, respectively).
CONCLUSIONS
These findings outline that activation of the BK(Ca) channel may explain the potent uterorelaxant effect of beta3-adrenoreceptor agonists.
背景
孕期人子宫肌层中的β3 - 肾上腺素能受体调节在功能上与子宫肌层抑制相关。大电导钙激活钾通道（BK(Ca)）在调节细胞膜电位和兴奋性方面发挥重要作用。
目的
本研究旨在探讨BK(Ca)通道功能在人子宫肌层对β3 - 肾上腺素能受体激活反应中的潜在作用。
设计
在存在和不存在特异性β3 - 肾上腺素能受体激动剂BRL37344的情况下，对新鲜分离的肌细胞进行单通道和全细胞电生理BK(Ca)通道记录。研究了在存在和不存在特异性BK(Ca)通道阻滞剂iberiotoxin（IbTX）的情况下，BRL37344对离体子宫肌层收缩的体外作用。
地点
该研究在临床科学研究所进行。
患者或其他参与者
择期剖宫产时获取子宫肌层活检组织。
干预措施
未施加干预。
主要观察指标
测量单通道记录的开放概率、全细胞电流和子宫肌层收缩活性。
结果
单通道记录确定BK(Ca)通道是BRL37344的作用靶点。BRL37344以浓度依赖性方式显著增加该通道的开放概率（对照组0.031±0.004；50μM BRL37344 0.073±0.005（P<0.001）；100μM BRL37344 0.101±0.005（P<0.001））。在用1μM布普洛尔（一种非特异性β - 肾上腺素能受体阻滞剂）或100 nM SR59230a（一种特异性β3 - 肾上腺素能受体拮抗剂）对细胞进行预孵育后，该效应完全被阻断。此外，BRL37344在一系列膜电位范围内增加全细胞电流，并且该效应被100 nM IbTX逆转。体外等长张力研究表明，BRL37344对人子宫肌层组织具有显著的浓度依赖性舒张作用（P<0.05），并且用IbTX对这些肌条进行预孵育可减弱其对自发收缩和催产素诱导收缩的作用（在10(-5) M时分别为44.44%和57.84%）。
结论
这些发现表明BK(Ca)通道的激活可能解释了β3 - 肾上腺素能受体激动剂强大的子宫舒张作用。
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