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:
CreatorsEmailORCIDORCID Put Code
Raupach, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinle, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroethoff, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mathes, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinen, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollmann, Markus W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huhn, RagnarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bunte, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
PERMEABILITY TRANSITION PORE; REPERFUSION INJURY; HEART; ISCHEMIA; INHIBITION; ACTIVATION; CHANNELS; ROSMultiple languages
Medicine, General & InternalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15164

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