BKCa通道介导的右美托咪定剂量依赖性的大鼠心脏保护作用
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The Cardioprotective Effect of Dexmedetomidine in Rats Is Dose-Dependent and Mediated by BKCa Channels
背景与目的
α2受体激动剂右美托咪定(Dex)可保护心肌免受缺血-再灌注损伤。 我们研究了Dex诱导的急性心肌保护作用下的信号级联反应，并特别关注了大电导钙依赖钾离子（BKCa）通道。
方 法
戊巴比妥麻醉雄性大鼠后，分离心脏，安置在langendorff灌注系统上，并灌入krebs-henseleit缓冲液。心脏缺血33分钟，再灌注60分钟。在缺血开始之前，Dex以不同剂量（0.1-30nm）给药，用于描述药物的剂量-效应关系。另一组实验中，Dex（3nm）与BKCa通道抑制剂蕈青霉素和缝隙连接蛋白43抑制剂GAP27联合应用。另外，BKCa通道开放剂NS1619也应用其中。
结 果
在对照组中，梗死面积为49%±5%。Dex（3-30nm）可减少梗死面积至22%，而低剂量（0.1-1 nm）Dex减少梗死面积至38%。蕈青霉素(1μm)和gap 27(6μm)可阻断Dex诱导的心脏保护作用。NS 1619(10μm)可使梗死范围缩小至与较高剂量Dex相同的程度。各研究组心脏功能和冠状动脉血流参数没有差异。
结 论
在雄性大鼠中，Dex对缺血再灌注损伤的保护作用与连接蛋白-43和激活BKCa通道有关。
原始文献摘要
Behmenburg F, Pickert E, Mathes A,The Cardioprotective Effect of Dexmedetomidine in Rats Is Dose-Dependent and Mediated by BKCa Channels.J Cardiovasc Pharmacol. 2017 Apr;69(4):228-235.
BACKGROUND：The alpha-2 rec:eptor agonist Dexmedetomidine (Dex) protects the heart against ischemia-reperfusion injury. We investigated the signaling cascade underlying Dex-induced acute cardioprotection, with special emphasis on large-conductance Ca2+-sensitive potassium (BKCa) channels.
METHODS: Rats were anesthetized with pentobarbital. Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer. Hearts underwent 33 minutes of ischemia followed by 60 minutes of reperfusion. Before the beginning of ischemia, Dex was administered at different doses (0.1-30 nM) for characterization of a dose-effect relationship. In another set of experiments, Dex (3 nM) was administered together with the BKCa channel inhibitor paxilline and the connexin-43 inhibitor peptide Gap27. Also, the BKCa channel opener NS1619 was administered.
RESULTS: In control animals, infarct size was 49% ± 5%. Dex at 3-30 nM reduced infarct size to ∼22%, whereas lower (0.1-1 nM) doses reduced infarct size to ∼38%. Paxilline (1 μM) and GAP27 (6 μM) blocked the Dex-induced cardioprotection. NS1619 (10 μM) reduced infarct size to about the same magnitude as did the higher doses of Dex. Functional heart parameters and coronary flow were not different between the study groups.
CONCLUSIONS:In male rats, the Dex-induced protection against ischemia-reperfusion injury involves connexin-43 and activation of BKCa channels.
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