Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Department of Cardiac Surgery, University of Halle, Halle, Germany.
Sci Rep. 2020 Mar 24;10(1):5358. doi: 10.1038/s41598-020-62156-y.
Heart transplantation remains the definitive therapy of end-stage heart failure. Ischemia-reperfusion injury occurring during transplantation is a primary determinant of long-term outcome of heart transplantation and primary graft insufficiency. Modification of the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate signaling pathway appears to be one of the most promising among the pharmacological interventional options. We aimed at characterizing the cardio-protective effects of the soluble guanylate cyclase stimulator riociguat in a rat model of heterotopic heart transplantation. Donor Lewis rats were treated orally with either riociguat or placebo for two days (n = 9) in each transplanted group and (n = 7) in donor groups. Following explantation, hearts were heterotopically transplanted. After one hour reperfusion, left ventricular pressure-volume relations and coronary blood flow were recorded. Molecular biological measurements and histological examination were also completed. Left ventricular contractility (systolic pressure: 117 ± 13 vs. 48 ± 5 mmHg, p < 0.001; dP/dt: 2963 ± 221 vs. 1653 ± 159 mmHg/s, p < 0.001), active relaxation (dP/dt: -2014 ± 305 vs. -1063 ± 177 mmHg/s, p = 0.02; all at 120 µl of left ventricular volume), and alteration of coronary blood flow standardized to heart weight (2.55 ± 0.32 vs. 1.67 ± 0.22 ml/min/g, p = 0.03) were markedly increased following preconditioning with riociguat. Myocardial apoptosis markers were also significantly reduced in the riociguat pretreated group as well as the antioxidant markers were elevated. Pharmacological preconditioning with riociguat decreases ischemia-reperfusion injury and improves donor organ function in our animal model of heart transplantation. Therefore, riociguat might be a potential cardioprotective agent.
心脏移植仍然是治疗终末期心力衰竭的确定性疗法。移植过程中发生的缺血再灌注损伤是心脏移植长期预后和原发性移植物功能不全的主要决定因素。一氧化氮/可溶性鸟苷酸环化酶/环鸟苷单磷酸信号通路的修饰似乎是最有前途的药物干预选择之一。我们旨在描述可溶性鸟苷酸环化酶刺激剂 riociguat 在大鼠异位心脏移植模型中的心脏保护作用。在每个移植组中，供体 Lewis 大鼠接受 riociguat 或安慰剂口服治疗两天（每组 9 只），在供体组中（n = 7）。在取出后，心脏被异位移植。再灌注 1 小时后，记录左心室压力-容积关系和冠状动脉血流。还完成了分子生物学测量和组织学检查。左心室收缩性（收缩压：117 ± 13 与 48 ± 5 毫米汞柱，p < 0.001；dP/dt：2963 ± 221 与 1653 ± 159 毫米汞柱/s，p < 0.001）、主动松弛（dP/dt：-2014 ± 305 与-1063 ± 177 毫米汞柱/s，p = 0.02；均在左心室容积 120 µl 时）和标准化为心脏重量的冠状动脉血流变化（2.55 ± 0.32 与 1.67 ± 0.22 ml/min/g，p = 0.03）在 riociguat 预处理后明显增加。riociguat 预处理组的心肌凋亡标志物也显著减少，抗氧化标志物升高。在我们的心脏移植动物模型中，riociguat 的药物预处理可减少缺血再灌注损伤并改善供体器官功能。因此，riociguat 可能是一种有潜力的心脏保护剂。
