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The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species.

Authors
  • Stroethoff, Martin1
  • Goetze, Lukas1
  • Torregroza, Carolin2
  • Bunte, Sebastian1
  • Raupach, Annika1
  • Heinen, André3
  • Mathes, Alexander4
  • Hollmann, Markus W5
  • Huhn, Ragnar1
  • 1 Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. , (Germany)
  • 2 Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. [email protected] , (Germany)
  • 3 Institute of Cardiovascular Physiology, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225, Duesseldorf, Germany. , (Germany)
  • 4 Department of Anesthesiology and Intensive Care Medicine, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. , (Germany)
  • 5 Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1100 DD, Amsterdam, Netherlands. , (Netherlands)
Type
Published Article
Journal
Cardiovascular drugs and therapy
Publication Date
Jun 01, 2020
Volume
34
Issue
3
Pages
303–310
Identifiers
DOI: 10.1007/s10557-020-06972-4
PMID: 32236860
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection. Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. Ramelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction. This study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.

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