Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr, Duesseldorf, Germany.
Department of Anesthesiology, Amsterdam University Medical Centers (AUMC), Meiberdreef, Amsterdam, Netherlands; and.
J Cardiovasc Pharmacol. 2020 Dec;76(6):684-691. doi: 10.1097/FJC.0000000000000919.
Ischemic preconditioning and postconditioning are strong measures preserving the heart against ischemia-reperfusion injury in experimental setting but are too invasive and impractical for clinical routine. The cardioprotective effects of ischemic preconditioning and postconditioning can be imitated pharmacologically, for example, with the phosphodiesterase inhibitors sildenafil and milrinone. We hypothesize that sildenafil-induced preconditioning is concentration dependent and further that a combined treatment of "nonprotective" versus "protective" concentrations of sildenafil and milrinone leads to a significant infarct size reduction. Experiments were performed on isolated hearts of male Wistar rats, randomized into 12 groups, mounted onto a Langendorff system, and perfused with Krebs-Henseleit buffer. All hearts underwent 33 minutes ischemia and 60 minutes of reperfusion. For determination of a concentration-dependent effect of sildenafil, hearts were perfused with increasing concentrations of sildenafil (0.1-1 µM) over 10 minutes before ischemia. In a second series of experiments, hearts were treated with 0.3 µM sildenafil or 1 µM milrinone as the "protective" concentrations. A higher concentration of respective drugs did not further reduce infarct size. In addition, a combination of "protective" and "nonprotective" concentrations of sildenafil and milrinone was applied. Sildenafil and milrinone in lower concentrations led to significant infarct size reduction, whereas combining both substances in cardioprotective concentrations did not enhance this effect. Sildenafil in a concentration of 0.3 µM induces myocardial protection. Furthermore, treatment with sildenafil and milrinone in lower concentrations had an equally strong cardioprotective effect regarding infarct size reduction compared with the administration of "protective" concentrations.
缺血预处理和后处理是在实验环境中保护心脏免受缺血再灌注损伤的强有力措施，但对于临床常规来说过于侵入性和不切实际。缺血预处理和后处理的心脏保护作用可以通过药理学模拟，例如使用磷酸二酯酶抑制剂西地那非和米力农。我们假设西地那非诱导的预处理是浓度依赖性的，进一步假设“非保护”浓度与“保护”浓度的西地那非和米力农联合治疗会导致梗塞面积显著减少。实验在雄性 Wistar 大鼠的离体心脏上进行，随机分为 12 组，安装在 Langendorff 系统上，并灌注 Krebs-Henseleit 缓冲液。所有心脏都经历了 33 分钟的缺血和 60 分钟的再灌注。为了确定西地那非的浓度依赖性效应，在缺血前用递增浓度的西地那非（0.1-1 μM）灌注心脏 10 分钟。在第二个系列实验中，用 0.3 μM 西地那非或 1 μM 米力农作为“保护”浓度处理心脏。较高浓度的药物不会进一步减少梗塞面积。此外，还应用了“保护”和“非保护”浓度的西地那非和米力农的组合。西地那非和米力农的低浓度可显著减少梗塞面积，而将两种物质组合在保护浓度下不会增强这种作用。0.3 μM 的西地那非可诱导心肌保护。此外，与给予“保护”浓度相比，用较低浓度的西地那非和米力农治疗对梗塞面积减少具有同等强烈的心脏保护作用。
