1 Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
2 The Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
J Cardiovasc Pharmacol Ther. 2019 Jan;24(1):78-89. doi: 10.1177/1074248418788301. Epub 2018 Jul 22.
Cardiac steroids (CSs), such as ouabain and digoxin, increase the force of contraction of heart muscle and are used for the treatment of congestive heart failure (CHF). However, their small therapeutic window limits their use. It is well established that Na, K-ATPase inhibition mediates CS-induced increase in heart contractility. Recently, the involvement of intracellular signal transduction was implicated in this effect. The aim of the present study was to test the hypothesis that combined treatment with ouabain and Akt inhibitor (MK-2206) augments ouabain-induced inotropy in mammalian models. We demonstrate that the combined treatment led to an ouabain-induced increase in contractility at concentrations at which ouabain alone was ineffective. This was shown in 3 experimental systems: neonatal primary rat cardiomyocytes, a Langendorff preparation, and an in vivo myocardial infarction induced by left anterior descending coronary artery (LAD) ligation. Furthermore, cell viability experiments revealed that this treatment protected primary cardiomyocytes from MK-2206 toxicity and in vivo reduced the size of scar tissue 10 days post-LAD ligation. We propose that Akt activity imposes a constant inhibitory force on muscle contraction, which is attenuated by low concentrations of MK-2206, resulting in potentiation of the ouabain effect. This demonstration of the increase in the CS effect advocates the development of the combined treatment in CHF.
强心甾体（CSs），如哇巴因和地高辛，可增强心肌收缩力，用于治疗充血性心力衰竭（CHF）。然而，其治疗窗口较小限制了其应用。Na + ，K + -ATP 酶抑制介导 CS 诱导的心肌收缩力增加已得到充分证实。最近，细胞内信号转导的参与被牵连在这种效应中。本研究的目的是检验以下假说，即哇巴因和 Akt 抑制剂（MK-2206）联合治疗可增强哺乳动物模型中哇巴因诱导的变力作用。我们证明，联合治疗导致哇巴因诱导的收缩力增加，而单独使用哇巴因则无效。这在 3 个实验系统中得到了证明：新生大鼠原代心肌细胞、Langendorff 制剂和通过左前降支冠状动脉（LAD）结扎诱导的体内心肌梗死。此外，细胞活力实验表明，这种治疗可保护原代心肌细胞免受 MK-2206 毒性的影响，并在体内结扎 LAD 后 10 天减少瘢痕组织的大小。我们提出 Akt 活性对肌肉收缩施加恒定的抑制力，而低浓度的 MK-2206 可减弱这种抑制力，从而增强哇巴因的作用。CS 作用增强的这种证明提倡在 CHF 中发展联合治疗。
