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

Journal of Clinical Medicine

Alexander Mathes¹  MarkusW. Hollmann²  Ragnar Huhn³  Julia Reinle³  Annika Raupach³  Martin Stroethoff³  Sebastian Bunte³  André Heinen⁴ 

[1] Department of Anesthesiology and Intensive Care Medicine, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany;Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands;Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany;Institute of Cardiovascular Physiology, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany;

关键词: milrinone;    preconditioning;    cardioprotection;    reperfusion injury;    mPTP;   

DOI  :  10.3390/jcm8040507

来源: DOAJ

【 摘 要 】

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 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 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 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 mBK_Ca-channels, release of ROS and mPTP inhibition.

【 授权许可】

Unknown