Behmenburg Friederike, Pickert Eileen, Mathes Alexander, Heinen André, Hollmann Markus W, Huhn Ragnar, Berger Marc M
*Department of Anesthesiology, University Hospital Düsseldorf, Düsseldorf, Germany; †Department of Anesthesiology, University Hospital Cologne, Cologne, Germany; ‡Institute of Cardiovascular Physiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; §Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; ¶Department of Anesthesiology, Perioperative and General Critical Care Medicine, Salzburg General Hospital, Paracelsus Medical University, Salzburg, Austria; and ‖Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany.
J Cardiovasc Pharmacol. 2017 Apr;69(4):228-235. doi: 10.1097/FJC.0000000000000466.
The alpha-2 receptor 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. 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. 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. In male rats, the Dex-induced protection against ischemia-reperfusion injury involves connexin-43 and activation of BKCa channels.
α2受体激动剂右美托咪定（Dex）可保护心脏免受缺血再灌注损伤。我们研究了Dex诱导急性心脏保护作用的信号级联反应，特别关注大电导钙敏感钾（BKCa）通道。大鼠用戊巴比妥麻醉。分离心脏，安装在Langendorff系统上，并用Krebs-Henseleit缓冲液灌注。心脏经历33分钟的缺血，随后是60分钟的再灌注。在缺血开始前，给予不同剂量（0.1 - 30 nM）的Dex以表征剂量效应关系。在另一组实验中，将Dex（3 nM）与BKCa通道抑制剂紫杉醇和连接蛋白43抑制剂肽Gap27一起给药。此外，还给予了BKCa通道开放剂NS1619。在对照动物中，梗死面积为49%±5%。3 - 30 nM的Dex将梗死面积减少至约22%，而较低剂量（0.1 - 1 nM）则将梗死面积减少至约38%。紫杉醇（1 μM）和GAP27（6 μM）阻断了Dex诱导的心脏保护作用。NS1619（10 μM）将梗死面积减少至与较高剂量Dex大致相同的程度。研究组之间的心脏功能参数和冠状动脉血流没有差异。在雄性大鼠中，Dex诱导的对缺血再灌注损伤的保护作用涉及连接蛋白43和BKCa通道的激活。
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