OR-1896 ((R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide) is the main active metabolite of levosimendan. However, nobody has reported a positive inotropic effect of OR-1896 in isolated human cardiac preparations. The mechanism of action of OR-1896 remains controversial. Hence, we wanted to know whether OR-1896 exerts a positive inotropic effect in humans and what might be the underlying mechanism. Therefore, we measured the contractile effects of OR-1896 (0.01–10 µM cumulatively applied) in isolated electrically stimulated (1 Hz) human right atrial preparations (HAP) obtained during cardiac surgery. OR-1896, given alone, exerted time- and concentration-dependent positive inotropic effects; 1-µM OR-1896 increased force by 72 ± 14.7% (p < 0.05, n = 6) and shortened the time of relaxation by 10.6 ± 3.6% (p < 0.05, n = 11) in HAP started at 0.1 µM, plateaued at 1-µM OR-1896, and was antagonized by 1-µM propranolol. The maximum positive inotropic effect of OR-1896 in human right atrial preparations was less than that of 10-µM isoprenaline. EMD 57033 (10 µM), a calcium sensitizer, enhanced the force of contraction further in the additional presence of 1-µM OR-1896 by 109 ± 19% (p < 0.05, n = 4). Cilostamide (10 µM), an inhibitor of phosphodiesterase III given before OR-1896 (1 µM), blocked the positive inotropic effect of OR-1896 in HAP. Our data suggest that OR-1896 is, indeed, a positive inotropic agent in the human heart. OR-1896 acts as a PDE III inhibitor. OR-1896 is unlikely to act as a calcium sensitizer in the human heart.

OR-1896 ((R)-N-(4-(4-甲基-6-氧代-1,4,5,6-四氢哒嗪-3-基)苯基)乙酰胺)是左西孟旦的主要活性代谢物。然而，没有人报道 OR-1896 在分离的人心脏制剂中具有正性肌力作用。 OR-1896 的作用机制仍存在争议。因此，我们想知道 OR-1896 是否对人类产生正性肌力作用以及潜在的机制是什么。因此，我们测量了 OR-1896（累积应用 0.01–10 µM）在心脏手术期间获得的隔离电刺激 (1 Hz) 人右心房制剂 (HAP) 中的收缩效应。 OR-1896单独给药，可发挥时间和浓度依赖性正性肌力作用； 1-μM OR-1896 使 HAP 的力增加 72 ± 14.7%（ p < 0.05， n = 6），并将松弛时间缩短 10.6 ± 3.6%（ p < 0.05， n = 11），HAP 从 0.1 µM 开始，达到稳定水平1-μM OR-1896，并被 1-μM 普萘洛尔拮抗。 OR-1896 在人右心房制剂中的最大正性肌力作用小于 10 µM 异丙肾上腺素。 EMD 57033 (10 µM) 是一种钙敏化剂，在额外添加 1 µM OR-1896 的情况下，收缩力进一步增强 109 ± 19%（ p < 0.05， n = 4）。西洛酰胺 (10 µM) 是一种磷酸二酯酶 III 抑制剂，先于 OR-1896 (1 µM) 给药，可阻断 OR-1896 在 HAP 中的正性肌力作用。我们的数据表明 OR-1896 确实是人类心脏中的正性肌力剂。 OR-1896 充当 PDE III 抑制剂。 OR-1896 不太可能在人类心脏中充当钙敏化剂。