Universität zu Köln

Raupach, Annika, Reinle, Julia, Stroethoff, Martin, Mathes, Alexander, Heinen, Andre, Hollmann, Markus W., Huhn, Ragnar and Bunte, Sebastian (2019). Milrinone-Induced Pharmacological Preconditioning in Cardioprotection: Hints for a Role of Mitochondrial Mechanisms. J. Clin. Med., 8 (4). BASEL: MDPI. ISSN 2077-0383

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Abstract

The activation of mitochondrial calcium-sensitive potassium (mBK(Ca)) channels is crucially involved in cardioprotection induced by preconditioning. For milrinone (Mil)-induced preconditioning, the involvement of mBK(Ca)-channels and further mitochondrial signaling is unknown. We hypothesize that (1) Mil-induced preconditioning is concentration-dependent and (2) that the activation of mBK(Ca)-channels, release of reactive oxygen species (ROS), and the mitochondrial permeability transition pore (mPTP) could be involved. Isolated hearts of male Wistar rats were perfused with Krebs-Henseleit buffer and underwent 33 min of ischemia followed by 60 min of reperfusion. For determination of a concentration-dependent effect of Mil, hearts were perfused with different concentrations of Mil (0.3-10 mu M) over 10 min before ischemia. In a second set of experiments, in addition to controls, hearts were pretreated with the lowest protective concentration of 1 mu M Mil either alone or combined with the mBK(Ca)-channel blocker paxilline (Pax + Mil), or paxilline alone (Pax). In additional groups, Mil was administered with and without the ROS scavenger N-2-mercaptopropionylglycine (MPG + Mil, MPG) or the mPTP inhibitor cyclosporine A (MPG + Mil + CsA, CsA + Mil), respectively. Infarct sizes were determined by triphenyltetrazolium chloride (TTC) staining. The lowest and most cardioprotective concentration was 1 mu M Mil (Mil 1: 32 +/- 6%; p < 0.05 vs. Con: 63 +/- 8% and Mil 0.3: 49 +/- 6%). Pax and MPG blocked the infarct size reduction of Mil (Pax + Mil: 53 +/- 6%, MPG + Mil: 59 +/- 7%; p < 0.05 vs. Mil: 34 +/- 6%) without having an effect on infarct size when administered alone (Pax: 53 +/- 7%, MPG: 58 +/- 5%; ns vs. Con). The combined administration of CsA completely restored the MPG-inhibited cardioprotection of Mil (MPG + Mil + CsA: 35 +/- 7%, p < 0.05 vs. MPG + Mil). Milrinone concentration-dependently induces preconditioning. Cardioprotection is mediated by the activation of mBK(Ca)-channels, release of ROS and mPTP inhibition.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Raupach, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinle, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroethoff, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Mathes, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinen, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Hollmann, Markus W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Huhn, Ragnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Bunte, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-151646
DOI:	10.3390/jcm8040507
Journal or Publication Title:	J. Clin. Med.
Volume:	8
Number:	4
Date:	2019
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2077-0383
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PERMEABILITY TRANSITION PORE; REPERFUSION INJURY; HEART; ISCHEMIA; INHIBITION; ACTIVATION; CHANNELS; ROS Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15164