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J. Clin. Med. 2019, 8(4), 507; https://doi.org/10.3390/jcm8040507

Milrinone-Induced Pharmacological Preconditioning in Cardioprotection: Hints for a Role of Mitochondrial Mechanisms

1
Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
2
Department of Anesthesiology and Intensive Care Medicine, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
3
Institute of Cardiovascular Physiology, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany
4
Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 27 February 2019 / Revised: 29 March 2019 / Accepted: 10 April 2019 / Published: 12 April 2019
(This article belongs to the Section Anesthesiology)
PDF [773 KB, uploaded 12 April 2019]

Abstract

The activation of mitochondrial calcium-sensitive potassium (mBKCa) channels is crucially involved in cardioprotection induced by preconditioning. For milrinone (Mil)-induced preconditioning, the involvement of mBKCa-channels and further mitochondrial signaling is unknown. We hypothesize that (1) Mil-induced preconditioning is concentration-dependent and (2) that the activation of mBKCa-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 µM) 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 µM Mil either alone or combined with the mBKCa-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 µM 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 mBKCa-channels, release of ROS and mPTP inhibition.
Keywords: milrinone; preconditioning; cardioprotection; reperfusion injury; mPTP milrinone; preconditioning; cardioprotection; reperfusion injury; mPTP
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Raupach, A.; Reinle, J.; Stroethoff, M.; Mathes, A.; Heinen, A.; Hollmann, M.W.; Huhn, R.; Bunte, S. Milrinone-Induced Pharmacological Preconditioning in Cardioprotection: Hints for a Role of Mitochondrial Mechanisms. J. Clin. Med. 2019, 8, 507.

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