Universität zu Köln

Stroethoff, Martin, Goetze, Lukas, Torregroza, Carolin, Bunte, Sebastian, Raupach, Annika, Heinen, Andre, Mathes, Alexander, Hollmann, Markus W. and Huhn, Ragnar ORCID: 0000-0002-3114-7190 (2020). The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species. Cardiovasc. Drugs Ther., 34 (3). S. 303 - 311. DORDRECHT: SPRINGER. ISSN 1573-7241

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Abstract

Purpose 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. Methods 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. Results 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. Conclusions 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stroethoff, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Goetze, Lukas UNSPECIFIED UNSPECIFIED UNSPECIFIED Torregroza, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bunte, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Raupach, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinen, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Mathes, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Hollmann, Markus W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Huhn, Ragnar UNSPECIFIED orcid.org/0000-0002-3114-7190 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-339960
DOI:	10.1007/s10557-020-06972-4
Journal or Publication Title:	Cardiovasc. Drugs Ther.
Volume:	34
Number:	3
Page Range:	S. 303 - 311
Date:	2020
Publisher:	SPRINGER
Place of Publication:	DORDRECHT
ISSN:	1573-7241
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY; CYCLOSPORINE; SEVOFLURANE; PATHWAY; INSULIN; HEART Multiple languages Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33996