The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species
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| Název: | The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species |
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| Autoři: | Stroethoff, Martin, Goetze, Lukas, Torregroza, Carolin, Bunte, Sebastian, Raupach, Annika, Heinen, André, Mathes, Alexander, Hollmann, Markus W., Huhn, Ragnar |
| Zdroj: | Cardiovasc Drugs Ther |
| Informace o vydavateli: | Springer Science and Business Media LLC, 2020. |
| Rok vydání: | 2020 |
| Témata: | Male, 0301 basic medicine, Myocardial Infarction, Myocardial Reperfusion Injury, Cardioprotection, Mitochondrial Membrane Transport Proteins, Mitochondria, Heart, Ventricular Function, Left, 03 medical and health sciences, Myocardial Reperfusion Injury/physiopathology [MeSH], Pharmacology, Myocardial Infarction/pathology [MeSH], Indenes/pharmacology [MeSH], Myocardial Infarction/metabolism [MeSH], Original Article, Mitochondria, Heart/metabolism [MeSH], Male [MeSH], Myocardial Infarction/physiopathology [MeSH], Receptor, Melatonin, MT2/metabolism [MeSH], Myocytes, Cardiac/metabolism [MeSH], Myocytes, Cardiac/drug effects [MeSH], Disease Models, Animal [MeSH], Receptor, Melatonin, MT2/agonists [MeSH], Mitochondrial Membrane Transport Proteins/metabolism [MeSH], Myocardial Reperfusion Injury/pathology [MeSH], Mitochondria, Heart/pathology [MeSH], Myocardial Infarction/prevention, Myocardial Reperfusion Injury/metabolism [MeSH], Reactive Oxygen Species/metabolism [MeSH], Mitochondria, Heart/drug effects [MeSH], Animals [MeSH], Myocytes, Cardiac/pathology [MeSH], Rats, Wistar [MeSH], Myocardial Reperfusion Injury/prevention, Mitochondrial Permeability Transition Pore [MeSH], Ventricular Function, Left/drug effects [MeSH], Signal Transduction [MeSH], Melatonin receptor agonist, Cardiovascular Agents/pharmacology [MeSH], Isolated Heart Preparation [MeSH], Animals, Myocytes, Cardiac, Rats, Wistar, 0303 health sciences, Mitochondrial Permeability Transition Pore, Receptor, Melatonin, MT2, Cardiovascular Agents, Isolated Heart Preparation, 3. Good health, Disease Models, Animal, Indenes, Reactive Oxygen Species, Signal Transduction |
| Popis: | PurposeThe 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.MethodsHearts 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.ResultsRamelteon-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.ConclusionsThis 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. |
| Druh dokumentu: | Article Other literature type |
| Jazyk: | English |
| ISSN: | 1573-7241 0920-3206 |
| DOI: | 10.1007/s10557-020-06972-4 |
| Přístupová URL adresa: | https://link.springer.com/content/pdf/10.1007/s10557-020-06972-4.pdf https://pubmed.ncbi.nlm.nih.gov/32236860 https://www.scilit.net/article/5cf36ecad0de0bd79b64eab2d29c7fd2 https://www.narcis.nl/publication/RecordID/oai%3Apure.amc.nl%3Apublications%2Fb5eab9c6-3977-45a1-b100-bfb45916dddb https://link.springer.com/content/pdf/10.1007/s10557-020-06972-4.pdf https://link.springer.com/article/10.1007/s10557-020-06972-4 https://pubmed.ncbi.nlm.nih.gov/32236860/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242242 https://repository.publisso.de/resource/frl:6470798 |
| Rights: | CC BY |
| Přístupové číslo: | edsair.doi.dedup.....ab3ce30fe5c1f96393d89a143e955719 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | PurposeThe 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.MethodsHearts 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.ResultsRamelteon-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.ConclusionsThis 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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| ISSN: | 15737241 09203206 |
| DOI: | 10.1007/s10557-020-06972-4 |