Novaković R, Radunović N, Marković-Lipkovski J, Ćirović S, Beleslin-Čokić B, Ilić B, Ivković B, Heinle H, Živanović V, Gojković-Bukarica L J
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
Institute of Gynecology and Obstetrics, Clinical Center of Serbia, 11000 Belgrade, Serbia.
Mol Hum Reprod. 2015 Jun;21(6):545-51. doi: 10.1093/molehr/gav011. Epub 2015 Mar 6.
The ideal agent for prevention and treatment of uterine abnormal contractility has not been found. The polyphenol resveratrol possesses a wide spectrum of pharmacologic properties, but its influence on the contractility of human myometrium is not defined. The present study evaluated the effect of resveratrol on the oxytocin-induced contractions of human term pregnant myometrium in vitro and the contribution of different K(+) channels to resveratrol action. Resveratrol induced a concentration-dependent relaxation of myometrium contractions (pD2 value and maximal responses were 4.52 and 82.25%, respectively). Glibenclamide, a selective blocker of ATP-sensitive (KATP), iberiotoxin, a selective blockers of big-calcium sensitive (BK(Ca)) and 4-aminopiridine, a non-selective blocker of voltage-sensitive (Kv) channels induced a significant shift to the right of the concentration-response curves of resveratrol. Inhibition achieved by 0.1 mM resveratrol was insensitive to all K(+) channel blockers. A K(+) channel opener, pinacidil, inhibited oxytocin-induced contractions of pregnant myometrium with comparable potency and efficacy to resveratrol (pD2 values and maximal relaxation were 4.52 and 83.67%, respectively). Based on K(+) channel opener/blocker affinities, it appears that the inhibitory response of resveratrol involves different myometrial K(+) channels. When applied in high concentrations, resveratrol has an additional K(+)-channel-independent mechanism(s) of action. Furthermore, immunohistochemistry staining and western blot analyses detected the presence and distribution of KATP, BK(Ca) and Kv channel proteins in pregnant myometrium.
尚未找到预防和治疗子宫异常收缩的理想药物。多酚白藜芦醇具有广泛的药理特性，但其对人子宫肌层收缩性的影响尚不明确。本研究评估了白藜芦醇对体外催产素诱导的足月妊娠人子宫肌层收缩的影响以及不同钾通道在白藜芦醇作用中的贡献。白藜芦醇诱导子宫肌层收缩呈浓度依赖性松弛（pD2值和最大反应分别为4.52和82.25%）。格列本脲（一种ATP敏感性钾通道（KATP）的选择性阻滞剂）、iberiotoxin（一种大钙敏感性钾通道（BK(Ca)）的选择性阻滞剂）和4-氨基吡啶（一种电压敏感性钾通道（Kv）的非选择性阻滞剂）使白藜芦醇的浓度-反应曲线显著右移。0.1 mM白藜芦醇所产生的抑制作用对所有钾通道阻滞剂均不敏感。一种钾通道开放剂吡那地尔抑制催产素诱导的妊娠子宫肌层收缩，其效力和效果与白藜芦醇相当（pD2值和最大松弛分别为4.52和83.67%）。根据钾通道开放剂/阻滞剂的亲和力，白藜芦醇的抑制反应似乎涉及不同的子宫肌层钾通道。高浓度应用时，白藜芦醇具有额外的非钾通道依赖性作用机制。此外，免疫组织化学染色和蛋白质印迹分析检测到妊娠子宫肌层中KATP、BK(Ca)和Kv通道蛋白的存在及分布。
