Original ArticleThe Cardioprotective Effect of Dexmedetomidine in Rats Is Dose-Dependent and Mediated by BKCa ChannelsBehmenburg, Friederike MD*; Pickert, Eileen*; Mathes, Alexander MD, DESA†; Heinen, André MD, PhD‡; Hollmann, Markus W. MD, PhD, DESA§; Huhn, Ragnar MD, PhD*; Berger, Marc M. MD, DESA¶,‖Author Information *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. Reprints: Ragnar Huhn, MD, PhD, Department of Anesthesiology, University Hospital Düsseldorf Moorenstr. 5, 40225 Düsseldorf, Germany (e-mail: [email protected]). Supported by institutional and departmental sources. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Journal of Cardiovascular Pharmacology: April 2017 - Volume 69 - Issue 4 - p 228-235 doi: 10.1097/FJC.0000000000000466 Buy SDC Metrics Abstract 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. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.