title: The Cardioprotective Effect of Dexmedetomidine in Rats Is Dose-Dependent and Mediated by BKCa Channels.
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.
authors.affiliation: *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.
authors.forename: Friederike
authors.initials: F
authors.lastname: Behmenburg
authors.forename: Eileen
authors.initials: E
authors.lastname: Pickert
authors.forename: Alexander
authors.initials: A
authors.lastname: Mathes
authors.forename: André
authors.initials: A
authors.lastname: Heinen
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: Ragnar
authors.initials: R
authors.lastname: Huhn
authors.forename: Marc M
authors.initials: MM
authors.lastname: Berger
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020927:Dexmedetomidine / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D002316:Cardiotonic Agents; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D020927:Dexmedetomidine