Universität zu Köln

Stroethoff, Martin, Christoph, Iris, Behmenburg, Friederike, Raupach, Annika, Bunte, Sebastian, Senpolat, Semra, Heinen, Andre, Hollmann, Markus W., Mathes, Alexander and Huhn, Ragnar (2018). Melatonin Receptor Agonist Ramelteon Reduces Ischemia-Reperfusion Injury Through Activation of Mitochondrial Potassium Channels. J. Cardiovasc. Pharmacol., 72 (2). S. 106 - 112. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1533-4023

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Abstract

Activation of melatonin receptors induces cardioprotection. Mitochondrial potassium channels (mK(Ca) and mK(ATP)) are involved in the signaling cascade of preconditioning. The melatonin receptor agonist ramelteon is an approved oral medication for treatment of insomnia, but nothing is known about possible cardioprotective properties. We investigated whether (1) ramelteon induces cardioprotection mediated by the melatonin receptor; (2) this effect is concentration-dependent; and (3) mK(Ca) and/or mK(ATP )channels are critically involved in ramelteon-induced cardioprotection. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. Before, ischemic hearts were perfused with different concentrations of ramelteon (0.01-5 mu M) for determination of a concentration-effect curve. In subsequent experiments, the lowest protective concentration of ramelteon was administered together with paxilline (mK(Ca) channel inhibitor) and 5-hydroxydecanoate (mK(ATP) channel inhibitor). To determine whether the reduction of ischemia and reperfusion injury by ramelteon is mediated by melatonin receptor, we combined ramelteon with luzindole, a melatonin receptor antagonist. Infarct size was determined by triphenyltetrazolium chloride staining. In control animals, infarct size was 58% +/- 6%. Ramelteon in a concentration of 0.03 mu M reduced infarct size to 28% +/- 4% (P < 0.0001 vs. Con). A lower concentration of ramelteon did not initiate cardioprotection, and higher concentrations did not further decrease infarct size. Paxilline, 5-hydroxydecanoate, and luzindole completely blocked the ramelteon-induced cardioprotection. This study shows for the first time that (1) ramelteon induces cardioprotection through melatonin receptor; (2) the effect is not concentration-dependent; and (3) activation of mK(Ca) and mK(ATP) channels is involved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stroethoff, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Christoph, Iris UNSPECIFIED UNSPECIFIED UNSPECIFIED Behmenburg, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Raupach, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Bunte, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Senpolat, Semra UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinen, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Hollmann, Markus W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mathes, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Huhn, Ragnar UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-177628
DOI:	10.1097/FJC.0000000000000600
Journal or Publication Title:	J. Cardiovasc. Pharmacol.
Volume:	72
Number:	2
Page Range:	S. 106 - 112
Date:	2018
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1533-4023
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PERMEABILITY TRANSITION PORE; SENSITIVE K+ CHANNELS; ISCHEMIA/REPERFUSION INJURY; POSSIBLE MECHANISM; RAT-HEART; IN-VIVO; CARDIOPROTECTION; INHIBITION; MYOCARDIUM Multiple languages Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17762