Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil
Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil
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DOI：
10.1016/s0002-9378(98)70543-5
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发表时间：
1998-05-01
影响因子：
9.8
通讯作者：
Ashford, MLJ
中科院分区：
文献类型：
--
作者：
Khan, RN;Morrison, JJ;Ashford, MLJ
目的：探讨钾通道开放剂匹那地尔对单条子宫钾通道的作用及其在匹那地尔引起的子宫肌层松弛中的作用。研究设计：从足月择期非临产剖宫产患者的子宫肌层活检标本中制备肌条和新鲜分散的子宫肌细胞。结果：在等长张力实验中，匹那地尔能有效地松弛非妊娠分娩的人子宫肌条，激动剂浓度可产生0.4+/-0.1mU·mol/L的半数最大反应，这种作用可被500nmol/L的查氏毒素拮抗。应用10MU/L格列本脲也可抑制吡那地尔的松弛作用。查氏毒素(500nmoL/L)和格列本脲(10mMol/L)共同作用产生一条双相曲线，该曲线符合双部位模型，其激动剂浓度的一半最大反应分别为0.6+/-0.2mU/L和189.7+/-0.8mU/L。在内向外和外向膜上应用吡那地尔(10~100mU/L)后，大电导钙依赖性钾通道的活动均显著增强。这种激活需要在细胞膜的细胞内存在钙离子。结论：吡那地尔对人妊娠子宫肌条的松弛作用可能与子宫大电导钙依赖性钾通道的开放和三磷酸腺苷钾通道的激活有关。具有特殊钾通道激活特性的药物作为治疗早产的新型药物可能具有重要的临床应用价值。
OBJECTIVE: The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation.STUDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation.RESULTS: In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 mu mol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 mu mol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 mu mol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 mu mol/L and 189.7 +/- 0.8 mu mol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 mu mol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but rot glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity.CONCLUSION: Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.